NZ238785A

NZ238785A - 5-benzyl pyrimidine derivatives and medicaments

Info

Publication number: NZ238785A
Application number: NZ238785A
Authority: NZ
Inventors: Nicole Bru-Magniez; Jean-Marie Teulon; Eric Nicolai
Original assignee: Union Pharma Scient Appl
Priority date: 1990-07-02
Filing date: 1991-06-28
Publication date: 1993-10-26
Also published as: JPH04230370A; AU7949191A; CA2045327A1; IE912114A1; PT98171A; KR920002555A; EP0465323A1; IL98674A0

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £38785 2387 Pr.or.v i 'i- .V.'tfv, >l» u **!*- : 7-t. ^ n.-.-c; i-^p; xs- tOmcsIcw, 10, V^.iw,. C,Q"1,OM^=S\>?3 IW; CVWhO'/IIG^L, t; IVb&hu.Qfc,<W:/ (v.IPM71^,.l^, .. .. Pub-:/ J8 OCT 1993 , ; P.O. J:: "V. , • ■: • . 15>"W - ... ..... j Class Con;: fhy^\\$V£)5?£y.'?.Lt [>:V 3 a' . fc \i v^ V Patents Form No. 5 :'?s i1^". NEW ZEALAND C E f'! " PATENTS ACT 1953 COMPLETE SPECIFICATION NOVEL PYRIMIDINE DERIVATIVES WHICH ARE ANGIOTENSIN II RECEPTOR ANTAGONISTS, THEIR METHODS OF PREPARATION AND PHARMACEUTICAL COMPOSITIONS IN WHICH THEY ARE PRESENT WE, LABORATOIRES UPSA, a French company of 1 bis, AlOOO rue Docteur Camille Bru, 57000 Agen, FRANCE hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: - 1 - (followed by page la) 2 3 8 7 8 5. - if\— Novel pyrimidine derivatives which are angiotensin II receptor antagonists, their methods of preparation and pharmaceutical compositions in which they are present 05 The present invention relates, by way of novel products, to the pyrimidine derivatives of general formulae (I) and (I') below and, if appropriate, their addition salts, in particular the pharmaceutically acceptable addition salts. 10 The compounds in question have a very valuable pharmacological profile insofar as they possess antagonistic properties towards angiotensin II receptors. They are therefore especially indicated for the treatment of cardiovascular diseases and in particular for 15 the treatment of hypertension and the treatment of cardiac insufficiency. The present invention further relates to the method of preparing said products and to their applications in therapeutics. 20 These pyrimidine derivatives have general formulae (I) and (I'): 25 30 I2 N^N-R 3 Formula (I) Formula (I') In formula (I), 35 Rx is a lower alkyl radical having 1 to 6 (followed by page 2) / J f' carbon atoms or a lower alkenyl radical having 2 to 6 carbon atoms; R2 is the hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a lower 05 halogenoalkyl radical having 1 to 6 carbon atoms, a C3-C7 cycloalkyl radical, a group OH, SH or NH2/ a group 0R5, SR5 or NHRj., R5 being a lower alkyl radical having 1 to 6 carbon atoms, a lower halogenoalkyl radical having 1 to 6 carbon atoms or a C3-C7 cycloalkyl 10 radical, or a group NHCOR6, R6 being defined in the same way as R5 except that it can also be an aromatic ring, a substituted or unsubstituted methanebiphenyl or a heterocycle; R2 can also be an aromatic ring or a heterocycle; 15 X can be a bond, an oxygen or sulfur atom, a radical NH or a halogen; R3 will be absent when X is a halogen, or can be a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a C3-C7 cycloalkyl radical or else a 20 group - (CH2) „-CN, a group -(CH2)n-COOR7, a group -(CH2)s~ OR,, a group -(CH2)n-CH-CH2 Y a group - (CH2) c-0-C0R7, a group or a group -(CH2) -SR7, n being an integer from 0 to 5, s being an integer from 1 to 5 when X is other than a bond, or from 0 to 5 when X represents a bond, and being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms; R^ can also be a group - (CH2) p-CONRgRg or -(CH2)t-NRgRg, p being an integer from 0 to 5, t being an integer from 1 to 5 where X is other than a bond, or from 0 to 5 where X represents a bond and Rg and Rg independently being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, or it being possible for Rg and R^ to form, together with the nitrogen atom to which they are attached, a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine, a phthalimide or a piperazine which can be substituted by a lower alkyl, an aromatic ring or a heterocycle; R^ can also be a group -(CH2)q-NH-(CH2)r-COOR10, - (CH2 ) g-NH-CO-NHRi;L or -(CH2)g-NH-CS-NH-R^, q being an integer from 1 to 5, where X is other than a bond, or from 0 to 5 where X represents a bond, r being an integer from 0 to 5 and R10 and independently being a lower alkyl radical having 1 to 6 carbon atoms, it also being possible for R^ to be an aromatic ring, a heterocycle or else a group -(CH2)n-COOR7, n and R^ being as defined above; R^ can also be the group SO^H, one of its esters or one of its amides; R^ can also be an amino acid group /NH2 "(CH2)n- CH^ COOR7 25 or one of its amides .'i **" V '■'It NH-CORs fa" .(CH2)„-CH t COOR? ■ ' " *%. 30 ' V *c 0^ n, R6 and R, being as defined above; finally, R3 can be a radical -(CH2)n-aromatic ring or -(CH2)n-heterocycle, n being as defined above; and R4 can be a nitro or amino group or a group 35 -COOR12, R12 being a hydrogen atom, a lower alkyl J - 4 - radical having l to 6 carbon atoms or a benzyl; R4 can also be the following radicals: 05 10 15 r12ooc h03s' -nh-co h03s ' n3 cf3so2nh -nh-co • cf3s02nh 20 r12ooc N3 25 in which R12 is as defined above and Y and Z can independently be a hydrogen atom, a lower alkyl radical, a halogen atom, a lower alkoxy radical or a trifluoro-methyl radical. In formula (I'), Rx, R2 and R4 are as defined in formula 30 (I), R'j is defined in the same way as R3 except that, unlike the latter, it may not be a group S03H, one of its esters or one of its amides and that also, in the case of R'3, the number q may not be less than 2, the numbers p and t may not be equal to 0 and the numbers' 35 - , n and s may not be equal to 0, except in the,case . of R' representing a group ~(CH0) - ~> 2 n • -,-s_ ' I - 5 - COOR7, -(CH2)n~aromatic ring or -(CH2)n~heterocycle where n may be equal to 0. The afore-mentioned derivatives can take the form of addition salts, in particular pharmaceutical^ acceptable addition salts. 0 5 In the description and the claims, lower alkyl is understood as meaning a linear or branched hydrocarbon chain having from 1 to 6 carbon atoms. A lower alkyl radical is, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, iso-10 pentyl, hexyl or isohexyl radical. Lower alkenyl is understood as meaning a linear or branched hydrocarbon chain having from 2 to 6 carbon atoms and one unit of unsaturation. A lower alkenyl radical is, for example, an ethene, propene, iso-15 propene, butene, isobutene, pentene, isopentene, hexene or isohexene radical. Lower halogenoalkyl radical is understood as meaning an alkyl radical having 1 to 6 carbon atoms in which l to 7 hydrogen atoms have been substituted by 1 20 to 7 halogen atoms. A lower halogenoalkyl radical is, for example, a trifluoromethyl radical, a 2,2,2-tri-fluoroethyl radical, a pentafluoroethyl radical, a 2,2-difluoro-3,3,3-trifluoropropyl radical or a hepta-fluoropropyl radical. 2 5 C3~C7 cycloalkyl radical is understood as meaning a saturated cyclic hydrocarbon radical, preferably a cyclopropane, cyclobutane, cyclohexane or cycloheptane radical. Lower alkoxy is understood as meaning an 0- 3 0 lower alkyl group, lower alkyl being as defined above. Lower thioalkyl is understood as meaning an S-lower alkyl group, lower alkyl being as defined above. Halogen is understood as meaning a chlorine, bromine, iodine or fluorine atom. 3 5 Aromatic ring is understood as meaning a.phenyl ,.'v" ' < / r. ~".|l s *S*0> A. ■£ ' , Vv:o/' 05 *3 8 7 85 - 6 - or naphthyl ring, it being possible for the phenyl or naphthyl to be unsubstituted or substituted by a lower alkyl group, a halogen, a lower halogenoalkyl group, a lower alkoxy, a lower thioalkyl or a nitro. Heterocycle is understood as meaning an aromatic ring having 5 to 7 atoms and containing at least one heteroatom such as nitrogen, oxygen or sulfur, it being possible for the heterocycle to be unsubstituted or substituted by a lower alkyl radical, a halogen, a 10 lower halogenoalkyl group, a lower alkoxy, a lower thioalkyl, a nitro or an aromatic ring. A heterocycle is, for example, pyridine, thio-phene, furan, pyrimidine, piperazine, pyridazine, a diazepine, a thiazole, an imidazole, an oxazole, a 15 thiazepine, an oxazepine, a triazole or a tetrazole. According to one embodiment, R1 is an n-propyl group. According to another embodiment, R2 is an n-butyl group. 20 According to one embodiment, R2 is a methyl group. According to another embodiment, R2 is the hydrogen atom. According to another embodiment, R2 is a 25 methylthio group. According to one embodiment, X is the oxygen atom. According to another embodiment, X is the sulfur atom. 30 According to one embodiment, R3 is an ethoxy- carbonylmethyl group. According to another embodiment, R'3 is an ethoxycarbonylmethyl group. According to another embodiment, R3 is a 2-3 5 hydroxyethyl group. 23 87 8 5 7 According to another embodiment, R'3 is a 2-hydroxyethyl group. According to another embodiment, R3 is a methyl radical. the hydrogen atom. According to one embodiment, R4 is a 2-sulfoxy-benzoylamino group. According to another embodiment, R, is a 2-io carboxyphenyl group. According to another embodiment, R< is a 2-(tetrazol-5-yl)phenyl group. The particularly preferred compounds of the invention are those selected from the products of the 15 formulae According to another embodiment, R3 or R'3 is 25 20 hn-n" 5 30 35 05 10 s XOOC2H5 HN-N" 15 20 OCH, 25 30 35 ^^^so3H - 9 - 05 10 CH, 1 • n^N 0^sCOOC2H5 hn-n" 15 20 25 30 35 CH, N N N N HN-N* .OH HN^ ge og sz oz 9X ox so - 11 - 23 87 8 5 05 10 SCH, S03H 15 20 25 30 35 N^N OCH, N .N HN-N" OCH, " '' '1 5 - 12 - 05 10 hn-n* According to the invention, the compounds of formula (I) or (I') may be synthesized by the following 15 reaction sequence: Methods known per se, such as, for example, the Claisen reaction or the method using Meldrum's acid, some of which can be found in the following literature references: 20 - OIKAWA Y.; SUGANO K. ; YONEMITSU O. ; J. Org. Chem. , 1978, 43(10), 2087-88, - WIERENGA w.; SKULNICK H.I.; J. Org. Chem., 1979, 44/ 310, - HOUGHTON R.; LAPHAM D.; SYNTHESIS, 1982, 6, 451-2, 25 - BRAM G.; VILKAS M.; Bull. Soc. Chim. France, 1964(5), 945-51, - BALYAKINA M.V.? ZHDANOVICH E.S.; PREOBRAZHENSKII N.A.; Tr. Vses. Nauchn. Issled. Vitam in. Inst., 1961, 7, 8-16, 30 - RENARD M.; MAQUINAY A.; Bull. Soc. Chim. Belg., 1946, 55, 98-105, - BRUCE F.W.; COOVER H.W.; J. Am. Chem. SOC., 1944, 66, 2092-94, and - EBY C.J. and HAUSER C.R.; J. Am. Chem. Soc., 1957, 35 79, 723-5, 23 8 7 - 13 - will be used to prepare - the alkyl 3-oxoalkanoates of formula (II): r, -c -ch2 -coor13 05 || o Formula (II) 10 in which Rx is as defined above and R13 is a lower alkyl radical, preferably methyl or ethyl, - the 3-oxonitriles of formula (III): R1 -C -CH2- CN 15 II o Formula (III) 20 in which Rx is as defined above, and - the 1,3-diketones of formula (IV): R-C-CH-C- (CH,) -U-R14 1 \\ II 28 o o 25 Formula (IV) in which Rt is as defined above, s is an integer from 1 to 5, U can be an oxygen or sulfur atom or a methylene 30 and R14 is a hydrogen atom or a lower alkyl, preferably methyl or ethyl. The compounds of the formulae 35 - 14 - 238 7 05 o R COOR 13 V 10 Formula (VI) 15 20 Formula (VII) 25 O 0 (CH2)—U-R 14 30 Formula (VIII) will be obtained by benzylating the compounds of formulae (II), (III) and (IV) with compounds of formula (V): 35 23 8 7 - 15 - w Formula (V) in the presence of a base such as sodium or potassium 10 carbonate in acetone, a sodium or potassium alcoholate in an alcohol, or sodium or lithium hydride in solvents such as tetrahydrofuran, dioxane or dimethylformamide, for example, at a temperature of between 50 and 100°C, or else in the presence of one equivalent of lithium 15 chloride or bromide and two equivalents of diisopropyl-ethylamine in tetrahydrofuran under reflux, according to the following reference: - SUNG-EUN YOO; KYU YANG YI; Bull. Korean Chem. Soc., 1989, 10(1), 112. 20 These compounds of formulae (VI), (VII) and (VIII) can also be obtained by condensation of an aldehyde of formula (IX): cho 30 Formula (IX) with the compounds of formulae (II), (III) and (IV), followed by hydrogenation in the presence of a catalyst such as Raney nickel, palladium-on-charcoal or platinum 35 oxide, in a solvent such as an alcohol or tetrahydro- 2 3 8 7 8 5 - 16 - furan, under pressure or at ordinary pressure if the substituents present allow it. In more general terms, methods of preparing the compounds of formulae (VI), (VII) and (VIII) will be 05 found in the following references: - DURGESHWARI P.; CHAUDHURY N.D.; J. Ind. Chem. SOC., 1962, 39/ 735-6, - HEINZ P.; KREGLEWSKI A.; J. Prakt. Chem., 1963, 21(3-4), 186-197, 10 - ZAUGG H.E.; DUNNIGAN D.A.; MICHAELS R.J.; SWETT L.R.; J. Org. Chem., 1961, 26, 644-51, - KAGAN H.B.; HENG SUEN Y.; Bull. Soc. Chim. France, 1966(6), 1819-22, - RATHKE M.W.; DEITCH J.; Tetrahedron Lett., 1971(31), 15 2953-6, - BORRIES KUBEL; Liebigs Ann. Chem., 1980, 1392-1401, - MARQUET J.; MORENO-MANAS M. ; Chem. Lett., 1981, 2, 173-6, - IOFFE T.; POPOV E.M.; VATSURO K.V.; TULIKOVA E.K.; 20 KABACHNIK M.I.; Tetrahedron, 1962, 18, 923-940, and - SHEPHERD T.M.; Chem. Ind. (London), 1970, 17, 567. In formula (V), W is a halogen atom, preferably chlorine or bromine. In the same formula: 25 V can be a nitro group, in which case the derivative of formula (V) is commercially available. V can be a group COORls, R16 being a lower alkyl or benzyl radical, in which case the derivative of formula (V) will be prepared by chlorinating or bromi-30 nating a commercially available p-methylbenzoic acid ester with N-chlorosuccinimide or N-bromosuccinimide, in a solvent such as carbon tetrachloride or dibromo-ethane, according to the following reference: - JULIA M. ; CHASTRETTE F.; Bull. Soc. Chim. France, 35 1962(2), 2247. 238 7 - 17 - V can be a group 05 r16ooc 10 R16 being a lower alkyl or benzyl radical, in which case the compounds of formula (V) are prepared by reacting a magnesium compound of p-bromotoluene with a compound of the formula 15 CH3O, \A to give a compound of the formula 20 25 30 35 which is then hydrolyzed to give the compound of the formula ch hooc 9 238785 - 18 - Procedures for the three steps described above will be found in the following reference: - MEYERS A.I.; MIHELICH E.D.; J. Am. Chem. Soc., 1975, 97, 7383. 05 The acid is then esterified with an alcohol of the formula R160H, R16 being as defined above. These derivatives are then brominated or chlorinated, for example with N-bromosuccinimide, N-chlorosuccinimide or bromine, in a solvent such as carbon tetrachloride, 10 dibromoethane or dichloroethane, to give the compounds of formula (V) in which V is the group 15 r16ooc V can be the group 20 in which case the compound 25 30 HCOC prepared above will be converted to the primary amide by reacting the acid chloride, obtained with thionyl chloride or phosphorus oxychloride, with aqueous 35 ammonia and this amide will be converted to the nitrile 05 10 - 19 - by reaction with phosphorus oxychloride in dimethyl-formamide or with thionyl chloride. The nitrile obtained: will then be brominated or chlorinated under the same conditions as the above ester to give the compounds of formula (V) in which V is the group 15 no A/ 20 V can be the group 25 in which case the compound 30 ci ch 35 will be prepared by chloromethylating commercially 23 8 7 8 5 - 20 - 05 available 2-nitrobiphenyl according to the following references: - CA : 70(25) : 114837 d, and - CA : 69(2) : 3704. V can be a group 10 15 Has in which case the compounds of formula (V) are prepared in the following manner: A Wurtz reaction between para-iodotoluene and orthonitroiodobenzene in the presence of copper, with heating at between 180 and 210°C/ will give 20 Hydrogenation of the nitro group to the amine and 25 diazotization with NaN02 in concentrated hydrochloric acid, followed by treatment with S02 in the presence of CuCl2 in acetic acid, will give the compound 30 ci02s 35 which will be treated with methanol in the presence of 2 ■? 0 r, <- o u J Q - 21 - pyridine to give the ester 05 ch3 o3 s This derivative is then brominated or chlori-10 nated, for example with N-bromosuccinimide or N-chloro-succinimide, in a solvent such as carbon tetrachloride or dibromoethane, to lead to the compounds of formula (V) in which V is the group 15 o3 s 20 25 and, by hydrolysis, to the compounds of formula (V) in which V is the group X) h03s' The bromination or chlorination may also be carried out on the compound 30 ci 02s' 35 conversion to the sulfonic acid then being effected by 23 8 7 - 22 - hydrolysis of the sulfonyl chloride group. V can be a group 05 r16 o o c 10 R16 being a lower alkyl or benzyl radical, in which case the corresponding compounds of formula (IV) are obtained in the following manner: The compounds of the formula 15 r16ooc will be obtained from the compound 20 25 kdoc whose preparation can be found in the following reference: - FISSELMANN H. ; HABITCH H. ; Ger. Offen.: 1,092,929 30 (I960); CA : J>7 : 5894 g, by esterif ication with an alcohol of the formula R16OH, R16 being as defined above, using classical methods known to those skilled in the art. These compounds are then treated with N-chloro-35 succinimide or N-bromosuccinimide, in a solvent such as 238785 - 23 - carbon tetrachloride or dibromoethane, for example, to give the compounds of formula (IV) in which V is the group 05 ^3 r16ooc -s R16 being as defined above. 10 V can be the group 15 30 nc >3 in which case the corresponding compounds of formula (IV) will be prepared in the following manner: Treatment of the compound 3-(p-methylphenyl)-thiophene-2-carboxylic acid, whose preparation is given 20 above, with thionyl chloride and then ammonia gives the amide compound, which is then dehydrated with thionyl chloride or phosphorus oxychloride, without a solvent or in dimethylformamide, to give the nitrile compound 25 s N3 This nitrile compound is then halogenated with N-chlorosuccinimide or N-bromosuccinimide, in a solvent such as carbon tetrachloride or dibromoethane, to give the compounds of formula (IV) in which V is the group 35 05 30 238785 - 24 - n V 10 in which case the corresponding compounds of formula (IV) are synthesized in the following manner: Treatment of 4-chloro-4'-methylbutyrophenone of the formula 15 / \ ch3—\ V-cd-ch2-ch2-ch2-ci whose preparation can be found in Belgian patent 20 577,977 of 15 May 1959, CA : 54/ 4629 c, with phosphorus oxychloride and dimethylformamide, under the conditions described in the following reference: - VOLODINA M.A.; TENENT'EV A.P.; KUDRYASHOVA V.A.; KABOSHINA L.N.; Khim. Geterosikl. Soedim, 1967, 5-8, 25 will give the compound of the formula ch3—\ /—c=c-ch2-ch2-ci I CI if-o This compound is then treated with sodium sulfide, under reflux in a solvent such as tetrahydrofuran, to give the derivative 35 c~ - 25 - which is then converted in two steps to the nitrile derivative by dehydration of the oxime formed from the aldehyde and hydroxylamine. This dehydration may be 10 effected, for example, with acetic anhydride to give the nitrile compound which may then be aromatized by treatment with bromine 20 in carbon tetrachloride and then with potassium tert-butylate in tetrahydrofuran to give the compound This compound can then be chlorinated or bromi-30 nated with halogenating agents such as N-chlorosuccini-mide or N-bromosuccinimide, in a solvent such as carbon tetrachloride or dibromoethane, to give the compounds of formula (IV) in which V is the group 35 10 15 238 7 N3 0 5 V can be the group - 26 - jo r16ooc R16 being as defined above, in which case the corresponding compounds of formula (IV) may be prepared from the compound of the formula 20 by classical hydrolysis of the nitrile group followed by esterif ication of the acid obtained, or by direct conversion of the nitrile group to the ester group by the methods known to those skilled in the art, followed 25 by chlorination or bromination of the ester with N-chlorosuccinimide or N-bromosuccinimide, in carbon tetrachloride or dibromoethane, for example. In the formulae (VI), (VII) and (VIII), Rx, R13, s, U and R14 are as defined above and V is as defined 30 in formula (V). In formula (IX), V is as defined in formula (V), but this condensation method will only be used in cases where V contains a functional group which is unaffected by hydrogenation. Otherwise, these benzyli-35 dene compounds, obtained by condensation of the aide- 8 5 238785 - 27 - hydes, may be converted to the pyrimidine of formula (XI), without hydrogenation, by condensation with an aldehyde of the formula R2-CHO in the case where R2 is a lower alkyl having 1 to 6 carbon atoms or an aromatic 05 ring, in the presence of aqueous ammonia, according to the method described in the following literature reference: - KROHNKE, SCHMIDT and ZECHER, Chem. Ber., 1964, 97, 1163. 10 Reaction of a urea, a thiourea, an amidine or a guanidine, i.e. reaction of a compound of formula (X): 15 ish r2-cn NH, Formula (X) in which R2 is as defined above, with the compounds of 20 formula (VI), (VII) or (VIII) will give the compounds of formula (XI): 25 30 Formula (XI) 35 by condensation in an alcohol, in the presence of a sodium or potassium alcoholate, at a temperature which I 28 can range from room temperature to the boiling point of the solvent, in which formula R,, R2 and V are as defined above and it being possible for T to be OH when the condensation reaction is carried 05 out with the compounds of formula (VI), NH2 when starting from the compounds of formula (VII), or (CH2)s-U-R14 when starting from the compunds of formula (VIII), s, U and R14 being as defined above. 10 This condensation reaction may be found in the following literature references: -AROYAN A.A.; KRAMER M.S.; Arm. Khim. Zk. , 1969, 22(9), 835-41, and - KRAMER M.S.; AROYAN A.A.; Arm. Khim. Zk., 1970, 15 23(1), 69-73. hydrogen atom, a lower alkyl radical or a substituted or unsubstituted phenyl and T is (CH2)8UR14, in which s, U and R14 are as defined above, can also be prepared in 20 the following manner: derivative of formula (IV) gives the following deri vatives of formula (IV'): The compounds of formula (XI) in which R2 is a Reaction of an aldehyde of formula (IX) with a 25 O O 30 R (CH2)S U R 14 Formula (IV') in which Rlf s, U, R14 and V are as defined above. 35 Reaction of these compounds of formula (IV') 238785 - 29 - 05 10 15 20 25 30 with aldehydes of the formula R2CHO, R2 being as defined above, in the presence of ammonium acetate and acetic acid, according to the following reference: - KROHNKE F.; SCHMIDT E.; ZECHER W.; Chem. Ber., 1964, 97, 1163-1178, makes it possible to obtain the derivatives of formula (XI) in which T is -(CH2)„-U-R14, in which s, U and R14 are as defined above. The compounds of formulae (XII) and (XII'): Formula (XII) Formula (XII') 35 in which Rx, R2, R3, X and V for formula (XII) and Rx, R2, R'3 and V for formula (XII') are as defined above, may be obtained from the compounds of formula (XI) in the following manner: The derivative of formula (XI) in which T is a group OH may be metalated. According to the metalation conditions, substitution will be directed towards the oxygen atom to give the compounds of formula (XII) or towards the nitrogen atom to give the compounds of formula (XII'). In particular, the use of sodium or potassium carbonate or of a base such as sodium or potassium hydroxide in an aqueous, alcoholic, aceto-nitrile or toluene medium, or in a ketone such as acetone or methyl ethyl ketone, in the presence or absence of a quaternary ammonium salt, will favor 0- 2" 3 8 7 8 5 - 30 - substitution to give the compounds of formula (XII) preferentially, whereas the use of a metalating agent such as sodium or lithium hydride in dimethylformamide or tetrahydrofuran, for example, will favor the formation of the N-substituted derivatives of formula (XII'). formula Reaction with halogenated derivatives of the 10 a-(ch2)n-ch3 A- (CH2) n-aromatic A-(CH2) n-heterocycle A- ( CHj) n-CN A-(CH2)n-COOR7 15 A-(CH2)n-0-R7 A-(CH2)n-SR7 A-(CHjp-C0NRaR, A-(CH2)p-NR8R9 20 in which A is a halogen atom, more particularly chlorine or bromine, and n, p, R,, Re and R9 are as defined above, will give the derivatives of formula (XII) in which XR3 is 25 -0-(CH2)n-CH3 -0- (CH2) n-aromatic -0- (CH2) n-heterocycle -0-(CH2) n-CN -0-(CH2)n-COOR7 30 -0-(CH2)n-0R7 -0-(CH2) n-SR7 -0- ( CH2) p-C0NR8R9 -0-(CH2)p-NRaR9 35 or the compounds of formula (XII') in which R'3 is 23 - 31 - ~(CH2)n-CH3 - (CH2) n-aromatic - (CH2) n-heter ocycle ~ (CH2) n-CN 05 - (CH2)n-COOR7 -(CH2)n-0R7 -(CH2)n-SR7 -(CH2)p-C0NR8R, - (CH2) p-NRaR9 10 Heating of the derivatives of formula (XI) in which T is OH, in P0C13, will give the derivatives of formula (XII) in which XR3 is chlorine. Reaction of compounds of the formulae 15 HBR7 HB-(CH2)n-CN HB-(CH2)n-C00R7 HB- (CH2) „-0R, 20 HB-(CH2)n-0C0R7 HB- (CH2) „-0 25 HB-(CH2)n-SR7 HB-(CH2)p-C0NR8R, HB- (CH2) p-NR8R9 HB- (CH2) q-NH- (CH2) r-C00Rlo HB- (CH2 ) ,,-NH-CO-NHR^ 30 NH2-NH-C00R7 NH2-NR8R, NH-R8R9 35 hb-ch 238785 32 which have been metalated beforehand if necessary and in which n, p, q, r, R7, Rs, R,, RJO and RX1 are as defined above and B is an oxygen or sulfur atom or a group NH, with said chlorinated derivative, according 05 to methods known per se, which can be found in the following references: -KRAMER M.S.; AROYAN A.A.; Arm. Khim. Zk., 1970, 23(1), 69-73, -AROYAN A.A.; KRAMER M.S.; GARIBDZHANYAN B.T.; Arm. 10 Khim. Zk., 1969, 22(7), 617-22, and - SUNLEY R.L.; SNOWLING G.D.; Ger. Offen. 2,533,710, will give the compounds of formula (XII) in which XR3 is 15 -BR7 -b-(ch2)n-cn -b- ( ch2) n-c00r7 -b-(ch2)n-0r7 O 20 30 25 -b-(ch2)n-sr7 -b-(ch2)p-conr8r9 -b-(ch2)p-nr8r, -b- ( chj) q-nh- (ch2) r-coor10 -b- (ch2) q-nh-c0-nhr11 -nh-nh-c00r7 -nh-nrsr, -n-r8r9 35 238785 - 33 - On treatment of the compounds of formula (XII) in which XR3 is chlorine with thiourea, followed by basic hydrolysis of the intermediate obtained, the compounds of formula (XII) in which XR3 is a group SH will 05 be synthesized. Alkylation of these mercapto compounds with alkyl halides of the formula Y'r7, in which Y' is a halogen, preferably bromine or iodine, and R7 is as defined above, will give derivatives of formula (XII) in which XR3 is a group SR7. 10 This reaction sequence is described in the fol lowing publication: - AROYAN, A.A.; KRAMER, M.S.; Arm. Khim. Zk. , 1973, 26(5), 402-405. If the derivatives of formula (XI) in which T 15 is NH2 are subjected to a Sandmeyer reaction, i.e. diazotization with NaN02 and then treatment with the appropriate copper salt, according to the following references: - H.H. HODGSON, Chem. Revs., 1947, 40, 251, and 20 - W.A. COWDREY and D.S. DAVIES, Quart. Revs. (London), 1952, 6, 358, it will be possible to obtain the derivatives of formula (XII) in which XR3 is the iodine, bromine, chlorine or fluorine atom or else the group CN, which 25 may be hydrolyzed to give a group COOH, which in turn may be esterified to COOR,, in which R, is as defined above, or converted via the acid chloride to the amide C0NR8R9, in which R8 and R, are as defined above. Hydrogenation of the CN group may give the derivatives 30 in which XR3 is CH2NH2, which, when treated with an iso-cyanate or an isothiocyanate, would make it possible to obtain the compounds in which XR3 is -CHj-NH-CONHR^ or -CH2-NH-CS-NHR11, where R1X is as defined above. The derivatives of formula (XI) in which T is 35 - (CH2 )s—0-CH3 or - (CH2 )s-0C2Hs may be converted to the 20 25 23 8 7 8 5 - 34 - — (CH2 )s—Br derivative by heating in hydrobromic acid. These brominated compounds may be converted by reaction with sodium or potassium cyanide, in a solvent such as an alcohol or dimethyl sulfoxide, at a temperature of 05 20 to 100°C, to derivatives of formula (XII) in which XR3 is -(CH2)8-CN; as previously, these compounds may be converted by hydrolysis and then by esterification to compounds of formula (XII) in which XR3 is -(CH2)S-COOR,. Catalytic hydrogenation of these nitriles may 10 also give the compounds in which XR3 is -(CH2)n-CH2-NH2, which, by reaction with isocyanate or isothiocyanate, will give the compounds in which XR3 is the group - (CH2)s—CH2-NH-C°-NH-Ri1 or the group -(CH2)s-CH2-NH-CS-NH-Rlt. 15 Likewise, condensation of the brominated deri vatives with ethyl acetamidomalonate, metalated beforehand with a sodium or potassium alcoholate in an alcohol under reflux, will give the compounds of formula (XII) in which XR3 will be /NH-C0CH3 -(CH2)s C | COOEt COOEt Hydrolysis and then decarboxylation of these compounds will make it possible to obtain the amino acids of formula (XII) in which XR3 is 30 /NH2 -(CH2)s-CH ncooh which may be esterified and/or converted to the amide 35 according to methods known to those skilled in the art, 238785 - 35 - 05 for example by heating in an alcohol in the presence of thionyl chloride, or by reaction with an acid chloride, to give the derivatives of formula (XII) in which XR3 is / NH2 .NH-CORe -(CH2)s-CH -(CH2)S-CH c00r7 n coor7 10 The same reaction sequences may be applied to the derivatives of formula (XII') in which R'3 is a group -(CH.,)n-0H, n being as defined above but other than zero, to give the derivatives in which R'3 is the same amino acid, amino ester or amido acid groups, it 15 being possible here for the treatment of the alcohol to be carried out with thionyl chloride, leading to the chlorinated derivative, which will react like the above brominated derivatives with metalated ethyl acetamido-malonate. 20 In certain cases, the amine or acid groups may be protected by benzyloxycarbonyl groups for the amines or tert-butoxy groups for the acids, and then freed, if necessary, by hydrogenolysis or by treatment with tri-fluoroacetic acid according to the classical methods 25 known to those skilled in the art. The compounds of formulae (XII) and (XII') in which V is a nitro group may be subjected to catalytic hydrogenation, for example in the presence of Raney nickel, in an alcohol, at atmospheric pressure or under 30 pressure, to give the compounds of formulae (XII) and (XII') in which V is an amino group. Reaction of an appropriately substituted phthalic anhydride with this amine derivative will give the compounds of general formulae (I) and (I') in which 35 R4 is the group 23 3 7 36 - 05 o y hn'c. H30C 10 15 Y and Z being as defined above, it then being possible for the acid obtained to be esterified to give the group r12ooc Likewise, reaction of a benzosulfonic anhydride with these amine compounds will give the compounds of 20 general formulae (I) and (I7) in which R4 is the group Likewise, reaction of N-(trifluoromethylsul-30 fonyl)anthranilic acid chloride, whose preparation can be found in the following references: - CA 96.(13) : 103651Z, and - CA 97(7) : 55500W, with these amine compounds will give the compounds of 35 general formulae (I) and (I7) in which R4 is the group 2387 - 37 - 0 The compounds of formulae (XII) and (XII') in which V is a group -COOR11 may be hydrolyzed in an acid or basic medium, or hydrogenated in the case where RX1 10 is a benzyl so as not to affect the other ester groups present, to give the compounds of formulae (I) and (I') in which R4 is a group -COOH. After these acid derivatives have been converted to the acid chloride with thionyl chloride or to a 15 mixed anhydride with ethyl chlorofornate, reaction with anthranilic acid derivatives of the formula y in which Y, Z and R12 are as defined above, will give 25 the compounds of general formulae (I) and (I') in which R4 is the group 30 r12ooc The compounds of formulae (XII) and (XII') in 35 which V is the group - 38 - 238785 r16ooc 05 will likewise be hydrolyzed, or hydrogenated in the presence of a catalyst, such as palladium, in the case where R12 is a benzyl, to give the compounds of formulae (I) and (I7) in which R„ is a group 10 hxc .X) 15 The compounds of formulae (XII) and (XII7) in which V is a group 20 no X) may react with one equivalent of sodium nitride in a solvent such as dimethylformamide, in the presence of an ammonium salt such as ammonium chloride, or by heating in toluene with trimethyltin nitride followed 25 by treatment with gaseous hydrogen chloride in tetrahydrofuran, to give the compounds of general formula (I) or (I7) in which R4 is a group 35 To carry out this reaction in the case where R3 or R73 *3 87 8 5 10 - 39 - contains an aliphatic alcohol group, it can be desirable to protect said group, according to the methods known to those skilled in the art, with an acetate or a tetrahydropyran and then to free it, if necessary, after formation of the tetrazole. The compounds of formulae (XII) and (XII') in which V is a group 02N .X) may undergo catalytic hydrogenation, for example in the presence of Raney nickel, in an alcohol, at atmospheric 15 pressure or under pressure, to give compounds of general formula (I) or (I') in which R4 is a group 20 Reaction of trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride with the latter compounds in a solvent such as chloroform or in an 25 aromatic solvent such as toluene, in the presence of a base such as triethylamine or pyridine, or in pyridine, will give the compounds of general formula (I) or (I') in which R4 is a group 30 CF,S0,HN'^-^ 35 The compounds of formulae (XII) and (XII') in which V is the group *3 8 7 8 5 40 NO S may be treated with a trialkyltin nitride under reflux 0 6 in toluene, and then with gaseous hydrogen chloride in tetrahydrofuran, to give the derivatives of formula (I) or (I') in which R4 is the group To carry out this reaction in the case where R3 or R'3 contains an aliphatic alcohol group, it can be desi-15 rable to protect said group, according to the methods known to those skilled in the art, with an acetate or a tetrahydropyran and then to free it, if necessary, after formation of the tetrazole. 25 may be hydrolyzed, or hydrogenated in the presence of a catalyst, such as palladium-on-charcoal, in the case where R16 is a benzyl, to give the compounds of formula (I) in which R4 is the group i o H The compounds of formulae (XII) and (XII') in 20 which V is the group 30 35 It is possible to obtain addition salts of some of the compounds of formulae (I) and (I'), especially pharmaceutically acceptable addition salts. In parti- 2 3 8 7 8 5 - 41 - cular, when R-,, R3, R'3 or R4 contains an acid group, uhcre may be mentioned the salts of sodium, potassium, calcium, an amine such as dicyclohexylamine or an amino acid such as lysine. When R2, R3, R'3 or R4 contains an amine group, there may be mentioned the salts of a mineral or organic acid, such as the hydrochloride, methanesulfonate, acetate, maleate, succinate, fuma-rate, sulfate, lactate or citrate. The novel compounds according to the invention 10 possess remarkable pharmacological properties as angiotensin II receptor antagonists and can be used in ther.-pentics for the treatment of cardiovascular diseases and in particular for the treatment of hypertension and cardiac insufficiency. 15 Thus the invention covers the pharmaceutical compositions which contain, as the active principle, the drugs consisting of a pharmaceutically effective amount of at least one compound of formula (I) or (I7) as defined above, as well as its pharmaceutically 20 acceptable addition salts if appropriate. These compositions can be administered by the buccal, rectal, parenteral, percutaneous or ocular route. These compositions can be solid or liquid and 25 can take the pharmaceutical forms commonly used in human medicine, such as, for example, simple or coated tablets, gelatin capsules, granules, suppositories, injectable preparations, percutaneous systems and eye lotions. They are prepared by the customary methods. 30 In said compositions, the active principle, consisting of a pharmaceutically effective amount of at least one compound of formula (I) or (I') as defined above, or one of its pharmaceutically acceptable addition salts, can be incorporated with excipients normally employed 35 in these pharmaceutical compositions, such as talc, gum 238785 - 42 - arabic, lactose, starch, magnesium stearate, polyvi-done, cellulose derivatives, cocoa butter, semisynthetic glycerides, aqueous or non-aqueous vehicles, fats of animal or vegetable origin, glycols, various 05 wetting agents, dispersants or emulsifiers, silicone gels, certain polymers or copolymers, preservatives, flavorings and colors. The invention also covers a pharmaceutical composition with antagonistic activity towards angiotensin 10 II receptors, which makes it possible especially to favorably treat cardiovascular diseases, in particular hypertension and cardiac insufficiency, said composition comprising a pharmaceutically effective amount of at least one compound of formula (I) or (I') mentioned 15 above, or one of its pharmaceutically acceptable addition salts, which may be incorporated in a pharmaceutically acceptable excipient, vehicle or carrier. The dosage varies especially according to the route of administration, the complaint treated and the 20 subject in question. For example, for an adult with an average weight of 60 to 70 kg, it can vary between 1 and 400 mg of active principle, administered orally in one or more daily doses, or from 0.01 to 50 mg, administered paren-25 terally in one or more daily doses. The invention also covers a method of preparing a pharmaceutical composition, which comprises incorporating a pharmaceutically effective amount of at least one compound of formula (I) or (I7) as defined 30 above, or one of its pharmaceutically acceptable addition salts, into a pharmaceutically acceptable excipient, vehicle or carrier, this pharmaceutical composition being formulated for example as gelatin capsules or tablets containing from 1 to 400 mg of 35 active ingredient, or as injectable preparations 23 8 7 - 43 - containing from 0.01 to 50 mg of active ingredient. The invention also covers a method of therapeutic treatment for mammals, which comprises administering to this mammal a therapeutically effective 05 amount of at least one compound of formula (I) or (I') as defined above, or one of its pharmaceutically acceptable addition salts. In animal therapeutics, the daily dose which can be used should normally be between 1 and 100 rag per 10 kg. Further characteristics and advantages of the invention will be understood more clearly from the following description of some Preparatory Examples, which in no way imply a limitation but are given by way 15 of illustration. 20 25 30 35 - 44 - Example 1: Ethyl 3-oxohexanoate Formula (II): Rx = n-propyl, R13 = ethyl 05 176 g of 2,2-dimethyl-4,6-dioxo-l,3-dioxane (Meldrum's acid) are dissolved in 550 ml of methylene chloride and 188 ml of pyridine. The mixture is cooled to 0°C with a bath of water and ice and 133 ml of butyryl chloride are added dropwise. When the addition 10 is complete, the mixture is stirred for three hours at room temperature. The solution is washed with a dilute solution of hydrochloric acid, dried over magnesium sulfate and evaporated under vacuum to give an oil. This oil is dissolved in 700 ml of ethanol and the 15 mixture is refluxed for six hours. The ethanol is evaporated off under vacuum and the residue obtained is distilled to give 145.4 g of ethyl 3-oxohexanoate in the form of a liquid of b.p.2G = 98-100°C. 20 Example 2: Ethyl 3-oxoheptanoate Formula (II): Rx = n-butyl, R13 = ethyl Prepared by the procedure of Example 1. 25 Liquid of b.p.2Q = 115-120°C. Example 3: Ethyl 2-(4-nitrobenzyl)-3-oxohexanoate Formula (VI): R1 = n-propyl, V = N02, R13 = 30 ethyl 127.7 g of ethyl 3-oxohexanoate are dissolved in 700 ml of tetrahydrofuran. 174.5 g of 4-nitrobenzyl bromide and 35 g of lithium chloride are added and the 35 mixture is stirred at room temperature. 286 ml of 23 8 7 - 45 - diisopropylethylamine are then added dropwise, causing a slight exothermic effect. The mixture is subsequently stirred for three hours at room temperature and then for ten hours under reflux. The solvents are 05 evaporated off under vacuum and the residue is taken up with water and then extracted with chloroform. The organic phase is decanted and then washed with a dilute solution of hydrochloric acid, dried over magnesium sulfate and evaporated under vacuum. The oily residue 10 obtained is taken up with isopropyl ether and the crystals formed are filtered off. The mother liquors are concentrated under vacuum and the residue is heated under 20 mm of mercury at 130°C in order to eliminate the residual starting materials. This gives 174 g of 15 ethyl 2-(4-nitrobenzyl)-3-oxohexanoate in the form of an oil, which is used as such for the next step. Example 4: Ethyl 2-(4-nitrobenzyl)-3-oxoheptanoate 20 Formula (VI): Rx = n-butyl, V = N02, R13 = ethyl Prepared by the procedure of Example 3. Oil used as such for the next step. 25 Example 5: Ethyl 2-(2'-methoxycarbonylbiphenyl-4-yl) methyl-3-oxohexanoate 30 Formula (VI): Rx = n-propyl, V = R13 = ethyl Me02C 35 Prepared by the procedure of Example 3 from ethyl 3-oxohexanoate, prepared in Example 1, and methyl 23 87 8 5 - 46 - (4'-bromomethylbiphenyl—2-yl)carboxylate. Oil used as such for the next step. Preparation of methyl (4'-bromomethylbiphenyl-2-yl)car-05 boxylate A) Methyl (4'-methylbiphenyl-2-yl)carboxylate 15 ml of acetyl chloride are added to 300 ml of methanol cooled to 0°C. The mixture is stirred for 10 10 minutes at this temperature and 15 g of (4 '-methylbi-phenyl-2-yl)carboxylic acid, prepared according to MEYERS A.I.; MIHELICH E.D., J. Am. Chem. Soc., 1975, 97(25), 7383, by reacting (4-methylphenyl)magnesium bromide with 2-(2-methoxyphenyl)-4,4-dimethyloxazo-15 lidine, are then added. The mixture is subsequently refluxed for 4 hours and the solvents are evaporated off under vacuum to give 16 g of methyl (4'-methylbi-phenyl-2-yl)carboxylate in the form of an oil, which is used as such for the next step. 20 B) Methyl (4/-bromomethylbiphenyl-2-yl)carboxylate 16 g of methyl (4'-methylbiphenyl-2-yl)car-boxylate, prepared in A), are dissolved in 120 ml of carbon tetrachloride in the presence of 12.6 g of N- 25 bromosuccinimide and 0.5 g of benzoyl peroxide. The mixture is refluxed for 6 hours, the crystals are filtered off and the remaining solution is washed with a solution of sodium bicarbonate and then evaporated under vacuum. The residue is taken up with ether and 30 the solution is then filtered on charcoal and evaporated under vacuum to give 14.5 g of methyl (4'-bromo-methylbiphenyl-2-yl)carboxylate in the form of an oil, which is used as such for the next step. 35 05 15 238785 - 47 - Example 6; Ethyl 2-(2/-cyanobiphenyl-4-yl)methyl-3-oxohexanoate Formula (VI): Rx = n-propyl, R13 = ethyl, 10 Prepared by the procedure of Example 3 from 4'- bromomethyl-2-cyanobiphenyl. Oil used as such for the next step. Preparation of 4'-bromomethyl-2-cyanobiphenyl A) 4/-Methyl-2-cyanobiphenyl 18.5 g of (4'-methylbiphenyl-2-yl)carboxylic acid, prepared as in Example 5A), are refluxed in 60 ml of thionyl chloride for two hours. The thionyl chlo-20 ride is concentrated under vacuum, the residue is poured into a 28% solution of ammonium hydroxide, the mixture is stirred for 30 minutes and the crystals obtained are filtered off, washed with ether and then dried to give 14.5 g of (4'-methylbiphenyl-2-yl)car-25 boxamide in the form of crystals melting at 128°C. These crystals are taken up in 50 ml of thionyl chloride and the mixture is refluxed for 3 hours and then concentrated under vacuum to give 9 g of 4'-methyl-2-cyanobiphenyl in the form of crystals melting at 45-30 46 ° C. B) 4'-Bromomethyl-2-cyanobiphenyl 7.9 g of 4'-methyl-2-cyanobiphenyl, prepared in A), are dissolved in 100 ml of carbon tetrachloride in 35 the presence of 7.3 g of N-bromosuccinimide and 0.3 g 23 3 7 - 48 - of benzoyl peroxide. The mixture is refluxed for 6 hours, the crystals are filtered off, the remaining solution is concentrated under vacuum and the residue is crystallized from ether to give 6.6 g of 4'-bromo-05 methyl-2-cyanobiphenyl in the form of crystals melting at 115-118*C. Example 7: 6-n-Propyl-2-methyl-4-hydroxy-5-(4-nitrobenzyl )pyrimidine 10 Formula (XI): R1 = n-propyl, R., = methyl, T = OH, V = N02 3.5 g of sodium are dissolved in 175 ml of 15 ethanol. 9.5 g of acetamidine hydrochloride are added to this solution and the mixture is stirred for five minutes at room temperature. 20 g of ethyl 2-(4-nitrobenzyl) -3-oxohexanoate, prepared in Example 3, are then added and the mixture is stirred for four days at room 20 temperature. The solvents are then evaporated off under vacuum and the residue is taken up with a solution of hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and then evaporated under vacuum to give an 25 oily residue, which crystallizes from an acetone/ether mixture. The crystals are filtered off and dried to give 10.9 g of 6-n-propyl-2-methyl-4-hydroxy-5-(4-nitrobenzyl)pyrimidine in the form of crystals melting at 200°C. 30 Example 8: 6-n-Butyl-2~methyl-4-hydroxy-5-(4-nitro-benzyl)pyrimidine 35 Formula (XI): Rx = n-butyl, R2 = methyl, T = OH, V = N02 '£ * h 7 g rj - 49 - 10 15 20 Prepared by the procedure of Example 7. Crystals melting at 205°C. Example 9: 6-n-Propyl-2-methyl-4-hydroxy-5-(2'-methoxy-0 5 carbonylbiphenyl-4-yl)methylpyrimidine Formula (XI): = n-propyl, V = |J , R2 = methyl, T = OH Prepared by the procedure of Example 7. Crystals melting at 206°C. Example 10: 6-n-Propyl-2-methyl-4-hydroxy-5-(2'-cyano-biphenyl-4-yl)methylpyrimidine Formula (XI): R1 = n-propyl, R2 = methyl, Prepared by the procedure of Example 7. 25 Crystals melting at 206°C. Example 11: Ethyl [4-n-propyl-2-methyl-5-(4-nitrobenzyl )-6-oxopyrimidin-l(6h)-yl]acetate 30 Formula (XII'): Rx = n-propyl, R2 = methyl, R'3 = CH2C02Et, V = N02 4 g of 6-n-propyl-2-methyl-4-hydroxy-5-(4-nitrobenzyl)pyrimidine, prepared in Example 7, are dis-35 solved in 30 ml of anhydrous N,N-dimethylformamide. 23 8 7 8 5 - 50 - 0.6 g of 60% sodium hydride is added and the mixture is stirred for thirty minutes at room temperature. 2 ml of ethyl bromoacetate are then added and the mixture is subsequently heated at 60°C for one hour. After cool-05 ing, 200 ml of water are added, the solution is extracted with ether and the organic phase is dried over magnesium sulfate and evaporated under vacuum to give a residue, which crystallizes from an ether/pentane mixture to give 2 g of ethyl [4-n-propyl-2-methyl-5-(4-10 nitrobenzyl)-6-oxopyrimidin-l(6H)-yl]acetate in the form of crystals melting at 120°c. Example 12: Ethyl [4-n-propyl-2-methyl-5-(4-amino-benzyl)-6-oxopyrimidin-l(6H)-yl]acetate 15 Formula (XII'): Rx = n-propyl, R2 = methyl, R'3 = CH2C02Et, V = NH2 2 g of ethyl [4-n-propyl-2-methyl-5-(4-nitro-20 benzyl)-6-oxopyrimidin-l(6H)-yl]acetate, prepared in Example 11, are dissolved in 25 ml of ethanol in the presence of 0.5 g of Raney nickel and hydrogenated under atmospheric pressure and at room temperature. When the uptake of hydrogen has ceased, the catalyst is 2 5 filtered off and the ethanol is evaporated off under vacuum to give 1.8 g of ethyl [4-n-propyl-2-methyl-5-(4-aminobenzyl)-6-oxopyrimidin-l(6H)-yl]acetate in the form of an oil, which is used as such for the next step. 30 Example 13: Ethyl [4-n-propyl-2-methyl-6-oxo-5-[4-(2-sulfoxyphenyl)carbonylaminophenylmethyl]-pyrimidin-1(6H)-yl]acetate 35 Formula (I'): Rx = n-propyl, R2 = methyl, 23 87 8 5 51 R' 3 = CH2C02Et, o R '4 NH H03o 1 g of ethyl [4-n-propyl-2-methyl-5-(4-amino- benzyl)-6-oxopyrimidin-l(6H)-yl]acetate, prepared in 10 Example 12, is dissolved in 10 ml of acetonitrile. A solution of 0.6 g of sulfobenzoic anhydride in 5 ml of acetonitrile is added and the mixture is left to stand for one day at room temperature. The crystals formed are filtered off, washed with acetonitrile and then 15 with ether and dried to give 0.9 g of ethyl [4-n-propyl-2-methyl-6-oxo-5-[4-(2-sulfoxyphenyl)carbonylaminophenylmethyl ]pyrimidin-1(6H)-ylJ acetate in the form of crystals melting at 268-269°C. 20 Example 14: [4-n-Propyl-2-methyl-6-oxo-5-[4-(2-carboxy- 3,6-dichlorophenyl)carbonylaminophenylmethyl ]pyrimidin-1(6H)-y1]acetic acid 25 Formula (I'): Rx = n-propyl, R2 = methyl R'3 = CH2C02H, O CI 30 CI 35 1.1 g of ethyl [4-n-propyl-2-methyl-5-(4-amino-benzyl)-6-oxopyrimidin-1(6H)-yl]acetate, prepared in Example 12, are dissolved in 10 ml of acetonitrile in c A 52 the presence of 0.7 g of 3,6-dichlorophthalic anhydride. The mixture is left to stand at room temperature overnight and the acetonitrile is evaporated off under vacuum without excessive heating. The residue 05 obtained is taken up in water in the presence of 0.6 g of sodium hydroxide pellets and stirred for 30 minutes at 45°C. The solution is then neutralized with concentrated hydrochloric acid and the crystals obtained are filtered off, washed with water and then dried to give 10 0.6 g of [4-n-propyl-2-methyl-6-oxo-5-[4-(2-carboxy-3,6-dichlorophenyl)carbonylaminophenylmethyl]pyrimidin-1(6H)-yljacetic acid in the form of crystals melting at 167-168 ° C. 15 Example 15: 6-n-Propyl-2-methyl-4-hydroxyethoxy-5-(2'- methoxycarbonylbiphenyl-4-yl)methylpyri-midine methoxycarbonylbiphenyl-4-y1)methylpyrimidine, prepared in Example 9, are dissolved in 50 ml of acetonitrile in the presence of 3 g of potassium carbonate and 0.3 g of 30 triethylbenzylamine hydrochloride. 2 ml of 2-bromo-ethanol are added and the mixture is refluxed for ten hours. The solvent is evaporated off to dryness and the residue is taken up with water and then extracted with ether. The organic phase is dried and then eva-35 porated to dryness and the oily residue obtained is 20 Formula (I): Rx = n-propyl, R2 = methyl, R3 = CH2CH20H, X = 0, 25 5.5 g of 6-n-propyl-2-methyl-4-hydroxy-5-(2'- 05 238785 - 53 - chromatographed on silica in ether to give 3 g of 6-n-propyl-2-methyl-4-hydroxyethoxy-5-( 2' -methoxycarbo-nylbiphenyl-4-yl)raethylpyrimidine in the form of a colorless oil, which is used as such for the next step. Example 16: 4'-[ 6-n-Propyl-2-methyl-4-hydroxyethoxy- pyrimidin-5-yl]methylbiphenyl-2-carboxylic acid 10 Formula (I): Rx = n-propyl, R2 = methyl, R3 = CH2CH2OH, X = 0, R- = 15 1.8 g of 6-n-propyl-2-methyl-4-hydroxyethoxy-5-(2/-methoxycarbonylbiphenyl-4-yl)methylpyrimidine, prepared in Example 15, are dissolved in 20 ml of ethanol. 20 A solution of 1 g of sodium hydroxide in 10 ml of distilled water is added and the mixture is heated at 50°C for two hours. The solvents are evaporated off to dryness and the residue is taken up with water and washed with ethyl acetate. The aqueous phase is acidified 25 by having sulfur dioxide bubbled through it, and is extracted with chloroform. The organic phase is dried over magnesium sulfate and evaporated to dryness under vacuum. The residue obtained crystallizes from iso-propyl ether to give 1.2 g of 4'-[6-n-propyl-2-methyl-30 4-hydroxyethoxypyrimidin-5-yl ]methylbiphenyl-2-carboxy-lic acid in the form of crystals melting at 143-144°C. 35 2 3 8 7 8 5 - 54 - Example 17; [4-n-Propyl-2-methyl-6-oxo-5-( 4-nitrobenzyl )pyrimidin-l(6H)-yl]acetylmorpholine Formula (XII'): Rx = n-propyl, R2 = methyl, 0 5 / \ r' = chpcon o , 2 \ / 10 V = NO2 Prepared by the procedure of Example 11 from N-(chloroacetyl)morpholine and 6-n-propyl-2-methyl-4-hydroxy-5-(4-nitrobenzyl)pyrimidine, prepared in 15 Example 7. Crystals melting at 174°C. Example 18: [4-n-Propyl-2-methyl-6-oxo-5-(4-amino- benzyl) pyrimidin-l ( 6H)-yl ]acetylmorpholine Formula (XII'): Rx = n-propyl, R2 = methyl, / V R's = CH2C0N C 25 ^^ V = NH2 Prepared by the procedure of Example 12. 30 Crystals melting at 160°C. Example 19: 6-n-Propyl-2-methyl-5-( 4-nitrobenzyl)-4-chloropyrimidine 35 Formula (XII): Rx = n-propyl, Rz = methyl, 23 8 7 - 55 - XR3 = CI, V = NO2 32 g of 6-n-propyl-2-methyl-5-(4-nitrobenzyl)-4-hydroxypyrimidine, prepared in Example 7, are suspen-05 ded in 45 ml of phosphorus oxychloride. The mixture is refluxed for 6 hours and then concentrated under vacuum. The residue is taken up with water and extracted with methylene chloride. The organic phase is washed with a solution of potassium carbonate and then 10 dried over magnesium sulfate and evaporated to dryness to give 24 g of 6-n-propyl-2-methyl-5-(4-nitrobenzyl)-4-chloropyrimidine in the form of crystals melting at 65 ° C. 15 Example 20: 6-n-Butyl-2-methyl-5-(4-nitrobenzyl)-4- chloropyrimidine Formula (XII): Rx = n-butyl, R2 = methyl, XR3 = CI, V = N02 20 Prepared by the procedure of Example 19. Crystals melting at 45°C. Example 21: 6-n-Propyl-2-methyl-5-(2 '-cyanobiphenyl-4-25 yl)methyl-4-chloropyrimidine Formula (XII): Rx = n-propyl, R2 = methyl, 35 Prepared by the procedure of Example 19. Crystals melting at 95°C. / 3 5 - 56 - Example 22: Ethyl [6-n-propyl-2-methyl-5-(4-nitro-benzyl)pyrimidin-4-yl]mercaptoacetate Formula (XII): R1 = n-propyl, R2 = methyl, 05 X = S, R3 = CH2C02Et, V = N02 4 g of 6-n-propyl-2-methyl-5-(4-nitrobenzyl)-4-chloropyrimidine and 1.9 g of ethyl mercaptoacetate are 10 dissolved in 50 ml of ethanol. 1.2 g of anhydrous sodium acetate are added and the mixture is stirred for 6 hours at room temperature and then for 6 hours under reflux. The ethanol is evaporated off under vacuum and the residue is taken up with water and then extracted 15 with methylene chloride. The organic phase is dried over magnesium sulfate and evaporated to dryness under vacuum to give an oil, which crystallizes from a pen-tane/isopropyl ether mixture to give 2.9 g of ethyl [6-n-propyl-2-methyl-5-(4-nitrobenzyl)pyrimidin-4-yl]-20 mercaptoacetate in the form of crystals melting at 66-67 ° C. Example 23: Ethyl [6-n-propyl-2-methyl-5-(4-amino-benzyl)pyrimidin-4-yl]mercaptoacetate 25 Formula (XII): Rx = n-propyl, R2 = methyl, X = S, R3 = CH2C02Et, V = NH2 30 Prepared by the procedure of Example 12. Oil used as such for the next step. 35 238785 - 57 - Example 24: 2-[[6-n-Propyl-2-methyl-4-(ethoxycarbonyl-methylmercapto)pyrimidin-5-yl]methylphenyl-4-yl]aminocarbonylbenzenesulfonic acid 05 Formula (I): Rx = n-propyl, R2 = methyl, R3 = CH2C02Et, X = S, 10 15 20 25 R, = NH' Vl hoas^^ Prepared by the procedure of Example 13. Crystals melting at 252-253°C. Example 25: 6-n-Propy1-2-methy1-4-(N,N-dimethylamino-carbonyloxy) -5- (4-nitrobenzyl) pyrimidine Formula (XII): Rx = n-propyl, R2 = methyl, ~ /ch3 X = o, R3 = C—N. ft xh. '3 V = N02 5 g of 6-n-propyl-2-methyl-4-hydroxy-5-(4-nitrobenzyl)pyrimidine, prepared in Example 7, are dissolved in 100 ml of methylene chloride in the presence of 2.6 ml of triethylamine. 1.7 ml of N,N-30 dimethylcarbamoyl chloride are added and the mixture is refluxed for 12 hours. After cooling, the solution is washed with a dilute solution of hydrochloric acid, dried over magnesium sulfate and evaporated to dryness. The residue is chromatographed on silica gel, in the 35 eluent methylene chloride 9/acetone 1, to give 3.1 g of 23 8 7 8 58 6-n-propyl-2-methyl-4-(N,N-dimethylaminocarbonyloxy)-5-(4-nitrobenzyl)pyrimidine in the form of crystals melt'ig at 110°C. Example 26: 6-n-Propyl-2-methyl-4-(N,N-dimethylamino-carbonyloxy)-5-(4-aminobenzyl)pyrimidine Example 27: 2-[[6-n-Propyl-2-methyl-4-(N,N-dimethyl- Formula (XII): Rx = n-propyl, R2 = methyl, V = NH 2 Prepared by the procedure of Example 12. Oil used as such for the next step. aminocarbonyloxy)pyrimidin-5-yl]methyl-phenyl-4-yl]aminocarbonylbenzenesulfonic acid Formula (I): Rx = n-propyl, R2 = methyl o Prepared by the procedure of Example 13. Crystals melting at 215-218°c. 23 8 7 8 5 - 59 - Example 28: Ethyl [4-n-propyl-2-methyl-6-oxo-5-(2'- cyanobiphenyl-4-yl)methylpyrimidin-l(6H)-yl]acetate 05 Formula (XII'): = n-propyl, R2 = methyl, R' 3 = CH2C02Et, 10 V = Prepared by the procedure of Example 11. Crystals melting at 98°C. 15 Example 29: Ethyl [6-n-propyl-2-methyl-5-(2'-cyanobi- phenyl-4-yl)methylpyrimidin-4-yl]mercapto-acetate 20 Formula (XII): Rx = n-propyl, R2 = methyl, R3 = CH2C02Et, X = S, 25 V = Prepared by the procedure of Example 22. Oil used as such for the next step. 30 Example 30: 6-n-Propyl-2-methyl-4-methoxy-5-(2'-cyano- biphenyl-4-yl)methylpyrimidine 35 Formula (XII): Rx = n-propyl, R2 = methyl, R3 = methyl, X = O, 2 7 " ~r 60 V !\l 05 12 g of 6-n-propyl-2-methyl-4-chloro-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine, prepared in Example 21, are dissolved in 100 ml of methanol. 1.2 g of sodium dissolved in 20 ml of methanol are added and the mixture is stirred for 3 hours at room temperature, 10 then for one hour at 40 °C and finally for one hour under reflux. The reaction mixture is concentrated, water is then added and the resulting mixture is extracted with isopropyl ether. The organic phase is dried and then evaporated under vacuum and the residue 15 obtained crystallizes from an isopropyl ether/pentane mixture to give 8.9 g of 6-n-propyl-2-methyl-4-methoxy-5-(2/-cyanobiphenyl-4-yl)methylpyrimidine in the form of crystals melting at 108°C. 20 Example 31: 6-n-Propyl-2-methyl-4-methoxy-5-[2/- (tetrazol-5-yl)biphenyl-4-yl]methylpyrimi-dine 25 Formula (I): Rx = n-propyl, R2 = methyl, R3 = methyl, X = 0, 30 35 8.9 g of 6-n-propyl-2-methyl-4-methoxy-5-(2 cyanobiphenyl-4-yl)methylpyrimidine, prepared in Example 30, and 6.3 g of trimethyltin nitride are 23 8 7 - 61 - refluxed for 12 hours in 100 ml of toluene. The crystals obtained are filtered off hot to give 6.6 g of 6-n-propyl-2-methyl-4-methoxy-5-[2'-(1-trimethylstannyl-tetrazol-5-yl)biphenyl-4-ylJmethylpyrimidine in the 05 form of crystals melting at 235°C. These crystals are dissolved in a toluene/THF mixture (60 ml/10 ml) and treated with gaseous hydrogen chloride for one hour at room temperature. The mixture is concentrated, taken up with chloroform and then washed with water. The 10 organic phase is dried over magnesium sulfate and evaporated under vacuum to give an oil, which crystallizes from an ether/acet ■ -ne mixture to give 4.2 g of 6-n-propy1-2-methyl-4-methoxy-5-[2'-(tetrazol-5-yl)-biphenyl-4-yljmethylpyrimidine melting at 132-4°C. 15 Example 32: Ethyl [4-n-propyl-2-methyl-6-oxo-5-[2'-(tetrazol-5-yl )biphenyl-4-yl Jmethylpyri-midin-1(6H)-yl]acetate 20 Formula (I'): Rx = n-propyl, R2 = methyl, R'3 = CH2C02Et, Prepared by the procedure of Example 31. Crystals melting at 164-5°C. 30 Example 33: Ethyl [6-n-propy1-2-methy1-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidin-4-yl]-mercaptoacetate 35 Formula (I): Rx = n-propyl, R2 = methyl, - 62 - Prepared by the procedure of Example 31. Crystals melting at 137-8°C. 10 Example 34: 2-[6-n-Butyl-2-methyl-5-(4-nitrobenzyl)-pyrimidin-4-yl]mercaptoethanol Formula (xii): Rr = n-butyl, R2 = methyl, 15 X = S, R3 = CH2CH20H, V = NO, 10 g of 6-n-butyl-2-methyl-5-(4-nitrobenzyl)-4-chloropyrimidine, prepared in Example 20, are dissolved 20 in 150 ml of butan-2-one. 7 g of potassium carbonate and 3.7 g of 2-mercaptoethanol are added and the mixture is refluxed for 6 hours. After concentration of the solvent under vacuum, the residue is taken up with water and then extracted with ether and the 25 organic phase is washed with water and then dried over magnesium sulfate and evaporated to dryness to give a residue, which crystallizes from isopropyl ether to give 5.5 g of 2-[6-n-butyl-2-methyl-5-(4-nitrobenzyl)-pyrimidin-4-yl]mercaptoethanol melting at 65°C. 30 Example 35: 2-[6-n-Propyl-2-methyl-5-(4-nitrobenzyl)-pyrimidin-4-yl]mercaptoethanol 35 Formula (xii): R1 = n-propyl, R2 = methyl, X = S, R3 = CH2CH20H, 2387 35 - 63 - V = N02 Prepared by the procedure of Example 34. Crystals melting at 110°C. 05 Example 36: Ethyl [6-n-butyl-2-methyl-5-(4-nitrobenzyl )pyrimidin-4-yl]mercaptoacetate Formula (xii): Rx = n-butyl, R2 = methyl, 10 X = S, R3 = CH2C02Et, V = N02 Prepared by the procedure of Example 22. Oil used as such for the next step. 15 Example 37: 6-n-Butyl-2-methyl-4-amino-5-(4-nitrobenzyl )pyrimidine Formula (xii): Rx = n-butyl, R2 = methyl, 20 XR3 = NH2, V = N02 25.4 g of 6-n-butyl-2-methyl-4-chloro-5-(4-nitrobenzyl)pyrimidine, prepared in Example 20, are heated in 400 ml of ammoniacal methanol at 170"c for 12 25 hours in an autoclave. After cooling, the solution is evaporated under vacuum and the residue obtained is taken up with water and then extracted with methylene chloride. The organic phase is dried over magnesium sulfate and evaporated under vacuum. The residue 30 obtained crystallizes from ether to give 15.4 g of 6-n-butyl-2-methyl-4-amino-5-(4-nitrobenzyl)pyrimidine in the form of crystals melting at 135°C. 35 ■7nj -v ; / 4 ^ ' ; j - 64 - Example 38: 6-n-Propyl-2-methyl-4-amino-5-(4-nitro-benzyl)pyrimidine Formula (XII): R1 = n-propyl, R2 = methyl, 05 XR3 = NH2, V = N02 Prepared by the procedure of Example 37. Crystals melting at 152°C. 10 Example 39: N-[6-n-Butyl-2-methyl-5-(4-nitrobenzyl)- pyrimidin-4-yljmorpholine Formula (XII): Rx = n-butyl, R2 = methyl, /""~v 15 V = NO2, XR3 = n o 8 g of 6-n-butyl~2-methyl-4-chloro-5-(4-nitrobenzyl) pyrimidine, prepared in Example 20, are dis-20 solved in 100 ml of xylene. 10 ml of morpholine are added and the mixture is refluxed for 16 hours. After cooling, the xylene is evaporated off under vacuum and the residue is taken up with ether and washed with a dilute solution of sodium hydroxide and then with 25 water. The ether phase is dried over magnesium sulfate and evaporated under vacuum to give a residue, which crystallizes from isopropyl ether to give 5 g of N-[6-n-butyl-2-methyl-5-(4-nitrobenzyl)pyrimidin-4-yl]-morpholine in the form of crystals melting at 124°C. 30 Example 40: N-[6-n-Propyl-?-methyl-5-(4-nitrobenzyl)— pyrimidin-4-yl]morpholine 35 Formula (XII): Rx = n-propyl, R2 = methyl, V = N02, 238785 - 65 - xr3 = n 0 05 Prepared by the procedure of Example 39. Crystals melting at 125°C. Example 41: N-[6-n-Propyl-2-methyl-5-(4-nitrobenzyl)-pyrimidin-4-yljthiomorpholine 10 15 25 Formula (XII): Rx = n-propyl, R2 = methyl / \ v = n02, xr3 = n s Prepared by the procedure of Example 39. Crystals melting at 133°C. Example 42: 4-[6-n-Propyl-2-methyl-5-(4-nitrobenzyl)-20 pyrimidin-4-yl]-1-(2-methoxyphenyl)pipera zine Formula (XII): R1 = n-propyl, R2 = methyl, = n// ^N—i \ v = no2, xr3 ^^ ck,0 30 Prepared by the procedure of Example 39. Crystals melting at 110°C. 35 23 3 7 - 66 - Example 43: 6-n-Propyl-2-methyl-5-(4-nitrobenzyl)-4-mercaptopyrimidine Formula (XII): = n-propyl, R2 = methyl, 05 XR3 = SH, V = N02 24 g of 6-n-propyl-2-methyl-5-(4-nitrobenzyl)-4-chloropyrimidine, prepared in Example 19, and 5.5 g of thiourea are refluxed for 6 hours in 75 ml of ace-10 tone in the presence of 0.05 ml of concentrated hydrochloric acid. The crystals obtained are filtered off, washed with acetone and then taken up in a mixture composed of 150 ml of ethanol, 150 ml of water and 25 g of sodium hydroxide pellets. The mixture is refluxed for 15 5 hours, the solvents are then evaporated off under vacuum, the residue is taken up with water and then acidified with concentrated hydrochloric acid and the crystals obtained are filtered off and washed with water to give 12 g of 6-n-propyl-2-methyl-5-(4-nitro-20 benzyl)-4-mercaptopyrimidine melting at 212°C. Example 44: 6-n-Propyl-2-methyl-4-methylthio-5-(4-nitrobenzyl)pyrimidine 25 Formula (XII): R^^ = n-propyl, R2 = methyl, XR3 = SCH1, V = N02 4 g of 6-n-propyl-2-methyl-4-mercapto-5-(4-nitrobenzyl)pyrimidine, prepared in Example 43, are 30 dissolved in 75 ml of ethanol. 0.6 g of sodium hydroxide dissolved in 10 ml of water is added and the mixture is stirred at room temperature for a few minutes. 1.5 ml of methyl iodide are then added to the reaction medium and the solution is stirred for 2 hours 35 at room temperature and then for 2 hours under reflux. 238 - 67 - After evaporation of the solvents under vacuum, the residue is taken up with water and then extracted with ether; the ether phase is dried over magnesium sulfate and then evaporated to dryness to give 3.7 g of 6-05 n-propyl-2-methyl-4-methylthio-5-(4-nitrobenzyl)pyrimidine in the form of an oil, which is used as such for the next step. Example 45: 2- [6-n-Propyl-2-methyl-5-(4-aminobenzyl)-10 pyrimidin-4-yl]mercaptoethanol Formula (XII): Rx = n-propyl, R2 = methyl, R3 = CH2CH20H, X = S, V = NH2 15 Prepared by the procedure of Example 12. Oil used as such for the next step. Example 46: N-[6-n-Propyl-2-methyl-5-(4-aminobenzyl)-20 pyrimidin-4-yl]morpholine Formula (XII): Rx = n-propyl, R2 = methyl, 25 Prepared by the procedure of Example 12. Oil used as such for the next step. 30 Example 47: N-[6-n-Propy1-2-methy1-5-(4-aminobenzyl)- pyrimidin-4-yljthiomorpholine Formula (XII): Rx = n-propyl, R2 = methyl, 35 23 - 68 - / \ v = nh2, xr3 = N S 05 Prepared by the procedure of Example 12. Oil used as such for the next step. Example 48: 4-[6-n-Propyl-2-methyl-5-(4-aminobenzyl)-pyrimidin-4-yl]-l-(2-methoxyphenyl)pipera-10 zine Formula (XII): Rx = n-propyl, R2 = methyl, OCHj. 15 V - NH,, XR, = N' \_y/ Prepared by the procedure of Example 12. 20 Oil used as such for the next step. Example 49: Ethyl [6-n-butyl-2-methyl-5-(4-aminobenzyl )pyrimidin-4-yl ]mercaptoacetate 25 Formula (XII): Rx = n-butyl, R2 = methyl, V = NH2, R3 = CH2C02Et, X = S Prepared by the procedure of Example 12. 30 Oil used as such for the next step. Example 50: 2-[6-n-Butyl-2-methyl-5~(4-aminobenzyl)-pyrimidin-4-yl]mercaptoethanol 35 Formula (XII): Rx = n-butyl, R2 = methyl, 2^ 30 - 69 - v = nh2, r3 = ch2ch20h, X = s Prepared by the procedure of Example 12. 05 Oil used as such for the next step. Example 51: 6-n-Propyl-2-methyl-4-thiomethyl-5-(4-aminobenzyl)pyrimidine 10 Formula (XII): rx = n-propyl, r2 = methyl, v = nh2, xr3 = sch3 Prepared by the procedure of Example 12. Oil used as such for the next step. 15 Example 52: 6-n-Butyl-2-methyl-4-amino-5-(4-aminobenzyl )pyrimidine Formula (XII): r1 = n-butyl, r2 = methyl, 20 v = nh2, xr3 = nh2 Prepared by the procedure of Example 12. Oil used as such for the next step. 25 Example 53: 6-n-Propyl-2-methyl-4-amino-5-(4-amino- benzyl)pyrimidine Formula (XII): rx = n-propyl, r2 = methyl, v = nh2, xr3 = nh2 Prepared by the procedure of Example 12. Oil used as such for the next step. 35 238785 - 70 - Example 54: 2-[(6-n-Propyl-2-methyl-4-hydroxyethyl- mercaptopyrimidin-5-yl)methylphenyl-4-yl]• aminocarbonylbenzenesulfonic acid 05 Formula (I): = n-propyl, R2 = methyl, R3 = CH2CH20H, X = S, 10 r, = Prepared by the procedure of Example 13 Crystals melting at 226-8°C. 25 15 Example 55: 2-[(6-n-Butyl-2-methyl-4-hydroxyethylmer- captopyrimidin-5-yl)methylphenyl-4-yl]-aminocarbonylbenzenesulfonic acid Formula (I): R2 = n-butyl, R2 = methyl, 20 R3 = CH^CH^OH, X = S, X) R, = H03S' Prepared by the procedure of Example 13. Crystals melting at 198-9°C. Example 56: 2-[[6-n-Propyl-2-methyl-4-(morpholin-l-yl)-30 pyrimidin-5-yl]mcthylphenyl-4-yl]amino- carbonylbenzenesulfonic acid Formula (I): Rx = n-propyl, R2 = methyl, 35 ? - 71 - XR, = N p/ r4 = NHCO- H03S Prepared by the procedure of Example 13. Crystals melting at 213-6°C. Example 57: 2-[(6-n-Butyl-2-methyl-4-aminopyrimidin-5 yl)methylphenyl-4-yl]aminocarbonylbenzene sulfonic acid Formula (I): Rx = n-butyl, R2 = methyl, XR3 = NH2, R4 = I | H03S^^ Prepared by the procedure of Example 13. Crystals melting at 239-240°C. Example 58: 2-[[6-n-Propyl-2-methyl-4-((2-methoxy-phenyl)piperazin-4-yl)pyrimidin-5-yl]-methylphenyl-4-yl]aminocarbonylbenzenesul fonic acid Formula (I): Rx = n-propyl, R2 = methyl, 233785 - 72 - Prepared by the procedure of Example 13. Crystals melting at 215-7°C. Example 59: 2-[[6-n-Propyl-2-methyl-4-methylthiopyrimi-05 din-5-yl]methylphenyl-4-yl]aminocarbonyl benzenesulfonic acid Formula (I): Rx = n-propyl, R, = methyl, 10 xr3 = sch3, r4 = H03S^^ Prepared by the procedure of Example 13. 15 Crystals melting at 254-7°C. Example 60: 2-[[6-n-Propyl-2-methyl-4-(thiomorpholin-4-yl)pyrimidin-5-yl ]methylphenyl-4-yl ]aiaino-carbonylbenzenesulfonic acid Formula (I): ra = n-propyl, R2 = methyl, m-co xr, = n R, = 25 \ / ho3s Prepared by the procedure of Example 13. Crystals melting at 207-210°C. 30 Example 61: 2-[[6-n-Butyl-2-methyl-4-(ethoxycarbonyl-methy1thi o)pyrimidin-5-y1]methylpheny1-4-yl]aminocarbonylbenzenesulfonic acid 35 Formula (I): R1 = n-butyl, R2 = methyl, ? t r* * 5 - 73 - X = S, R3 = CH2C02Et, r. = 05 nhca h03s' 10 15 20 Prepared by the procedure of Example 13. Crystals melting at 262-3°C. Example 62: 2-[[6-n-Propyl-2-methyl-4-(ethoxycarbonyl-methylthio)pyrimidin-5-y1]methylphenyl-4-yl]aminocarbonyl-3-methylbenzenesulfonic acid Formula (I): Rx X n-propyl, R2 = methyl, S, R3 = CH2C02Et, r. = NHCO h03s Prepared by the procedure of Example 13 from 3-25 methylsulfobenzoic anhydride. Crystals melting at 224-227°C. Preparation of 3-methylsulfobenzoic anhydride 30 A) Ethyl 6-methvlanthranilate 16.2 g of 6-methylanthranilic acid are dissolved in 150 ml of tetrahydrofuran. 17.5 g of N,N-carbonyldiimidazole are added and the mixture is stirred for one hour at room temperature and then for 6 35 hours under reflux. The mixture is concentrated under 23 8 7 - 74 - vacuum, 200 ml of ethanol are added and the mixture is refluxed for 6 hours. After evaporation of the solvent under vacuum, the residue is taken up with isopropyl ether, the crystals are filtered off and the filtrate 05 is treated with charcoal and then evaporated to give 9.5 g of ethyl 6-methylanthranilate in the form of an oil, which is used as such for the next step. B) 3-Methvl-2-ethoxYcarbonylben2enesulfonyl chloride 10 10.4 g of ethyl 6-methylanthranilate are added at -5°c to 40 ml of concentrated hydrochloric acid. A solution of 4.4 g of sodium nitrite in 10 ml of water is added dropwise at -5°C and the mixture is stirred for 30 minutes at this temperature. 15 In a separate procedure, 8 g of sulfur dioxide are dissolved in 50 ml of acetic acid, and 1.9 g of copper(II) chloride are added. The solution obtained is added dropwise to the reaction mixture, still at -5°C. After having been stirred for one hour at 20°C 20 and then for one hour at 40°c, the mixture is poured on to ice and extracted with ether. The organic phase is dried over magnesium sulfate to give 6.7 g of 3-methyl-2-ethoxycarbonylbenzenesulfonyl chloride in the form of an oil, which is used as such for the next step. 25 C) 3-Methvlsulfobenzoic anhydride 6.7 g of 3-methyl-2-ethoxycarbonylbenzene-sulfonyl chloride are refluxed for 3 hours in 60 ml of distilled water and 5 ml of concentrated hydrochloric 30 acid. The solution obtained is filtered on active charcoal and then evaporated to dryness. The residue obtained is refluxed for 3 hours in 50 ml of acetic anhydride. The solution is evaporated to dryness under vacuum and the residue obtained crystallizes from an 3 5 ether/pentane mixture. The crystals obtained are *0 8 - 75 - filtered off and dried to give 3.2 g of 3-methyl-sulfobenzoic anhydride in the form of crystals melting at 130 ° C. 05 Example 63: 6-n-Butyl-2-isopropyl-4-hydroxy-5-(4- nitrobenzyl)pyrimidine Formula (XI): Rx = n-butyl, R2 = isopropyl, T = OH, V = N02 10 2.8 g of sodium are dissolved in 150 ml of ethanol and the solution is cooled to 5°C. 15.1 g of isobutyramidine hydrochloride are added and the mixture is stirred for fifteen minutes. 25 g of ethyl 2-(4- 15 nitrobenzyl)-3-oxoheptanoate, prepared in Example 4, are added and the mixture is stirred for 3 hours at room temperature and then poured into water and acidified with concentrated hydrochloric acid. The crystals obtained are filtered off and washed with water and 20 then with isopropyl ether and acetone to give 16.1 g of 6-n-butyl-2-isopropyl-4-hydroxy-5-(4-nitrobenzyl)pyri-midine in the form of crystals melting at 143°C. Example 64: 6-n-Butyl-2-phenyl-4-hydroxy-5-(4-nitro- 25 benzyl)pyrimidine Formula (XI): Rx = n-butyl, R2 = phenyl, T = OH, V = N02 30 Prepared by the procedure of Example 63 from benzamidine hydrochloride. Crystals melting at 270°C. 35 238785 - 76 - Example 65: 6-n-Butyl-2-isopropyl-4-chloro-5-(4-nitroberizy 1) pyrimidine Formula (XII): Rx = n-butyl, R2 = iso-05 propyl, XR3 = CI, V = NOa Prepared by the procedure of Example 19. Oil used as such for the next step. 10 Example 66: 6-n-Butyl-2-phenyl-4-chloro-5-(4-nitrobenzyl )pyrimidine Formula (XII): Rx = n-butyl, R2 = phenyl, XR3 = CI, V = NO2 15 Prepared by the procedure of Example 19. Crystals melting at 85°C. Example 67: Ethyl [6-n-butyl-2-phenyl-5-(4-nitro- 2 0 benzyl)pyrimidin-4-yl]mercaptoacetate Formula (XII): Rj = n-butyl, R2 = phenyl, X = S, R3 = CH2C02Et, V = N02 25 Prepared by the procedure of Example 22. Crystals melting at 102°C. Example 68: Ethyl [6-n-butyl-2-isopropyl-5-(4-nitro- 3 0 benzyl)pyrimidin-4-y1]mercaptoacetate Formula (XII): Rx = n-butyl, R2 = isopropyl, X = S, R3 = CH2C02Et, V = N02 35 2387 8 - 77 - Prepared by the procedure of Example 22. Oil used as such for the next step. Example 69: 2-[6-n-Butyl-2-phenyl-5-(4-nitrobenzyl)-05 pyrimidin-4-yl]mercaptoethanol Formula (XII): R1 = n-butyl, R2 = phenyl, X = S, R3 = CH2CH20H, V = N02 10 Prepared by the procedure of Example 34. Crystals melting at 98°C. Example 70: 2-[6-n-Butyl-2-isopropyl-5-(4-nitrobenzyl)■ 15 pyrimidin-4-yl]mercaptoethanol Formula (XII): RA = n-butyl, R2 = isopropyl, X = S, R3 = CH2CH20H, V = NO2 20 Prepared by the procedure of Example 34. Oil used as such for the next step. The following were prepared by the procedure of Example 25 12: Example 71: Ethyl [6-n-butyl-2-phenyl-5-(4-aminobenzyl )pyrimidin-4-yl]mercaptoacetate 30 Formula (XII): Rx = n-butyl, R2 = phenyl, X = S, R3 = CH2C02Et, V = NH, 35 Oil used as such for the next step. 238785 - 78 - Example 72: Ethyl [6-n-butyl-2-isopropyl-5-(4-aminobenzyl )pyrimidin-4-yl]mercaptoacetate Formula (XII): Rx = n-butyl, R2 = iso-05 propyl, X = S, Ra = CH2C02Et, V = NH2 Oil used as such for the next step. 10 Example 73: 2-[6-n-Butyl-2-phenyl-5-(4-aminobenzyl)- pyrimidin-4-yl]mercaptoethanol Formula (XII): Rx = n-butyl, Ra = phenyl, X = S, R3 = CH2CH2OH, V = 15 NH, Crystals melting at 103°c. Example 74: 2-[6-n-Butyl-2-isopropyl-5-(4-aminobenzyl)■ 20 pyrimidin-4-yl]mercaptoethanol Formula (XII): Rx = n-butyl, R2 = isopropyl, X = S, R3 = CH2CH2OH, V = NH2 25 Oil used as such for the next step. The following compounds were prepared by the procedure of Example 13: 30 Example 75: 2-[[6-n-Butyl~2-phenyl-4-(ethoxycarbonyl-methylthio)pyrimidin-5-yl]methylphenyl-4-yl]aminocarbonylbenzenesulfonic acid 35 Formula (I): Rx = n-butyl, R2 = phenyl, 238785 - 79 - X = S, R3 = CH2C02Et, R< = 7 H h03s""^/ Crystals melting at 241-242°C. 10 Example 76: 2-[[6-n-Butyl-2-isopropyl-4-(ethoxycarbo- nylmethylthio)pyrimidin-5-yl]methylphenyl-4-yl]aminocarbonylbenzenesulfonic acid 15 Formula (I): Rx = n-butyl, R2 = isopropyl, X = S, R3 = CH2C02Et, 20 R. = NHCO- h03s^^ Crystals melting at 227-229°C. Example 77: 2-[[6-n-Butyl-2-phenyl-4-(hydroxyethyl-2 5 thio)pyrimidin-5-yl]methylphenyl-4-y1] • aminocarbonylbenzenesulfonic acid 30 Formula (I): Rx = n-butyl, R2 = phenyl, X = S, R3 = CH2CH20H, r* = NHCO h03s 35 Crystals melting at 220-221°C. 23 8 7 - 80 - Example 78: 2-[[6-n-Butyl-2-isopropyl-4-(hydroxy- ethylthio)pyrimidin-5-yl]methylphenyl-4-yl]aminocarbonylbenzenesulfonic acid 05 Formula (I): Rx = n-butyl, R2 = isopropyl, X = S, R3 = CH2CH20H, 10 NHCO r, = Crystals melting at 240-241'c Example 79: l-Methoxy-4-oxoheptan-2-one 15 Formula (IV): Rx = n-propyl, s = 1, U = 0, = ch3 A solution of 127.5 ml of methyl methoxyacetate 20 and 214.5 ml of pentan-2-one in 100 ml of toluene is added dropwise to 33.5 g of finely divided sodium in 600 ml of hot toluene, the temperature being kept at between 60°C and 70°C. When the addition is complete, the mixture is heated for 2 hours at 55-60°C, 30 ml of 25 methanol are then added dropwise, the mixture obtained is taken up with water and washed with ether and the aqueous phase is acidified with concentrated hydrochloric acid and then extracted with ether. The organic phase is dried over magnesium sulfate and evapora-30 ted under vacuum. The oily residue is distilled under reduced pressure to give 103.8 g of l-methoxy-4-oxo-heptan-2-one boiling at 100-110°C. 35 238785 - 81 - Example 80: 3-(4-Acetamidobenzylidene)-l-methoxy-4-oxoheptan-2-one Formula (iv#): = n-propyl, s = 1, U = 05 0, R14 = methyl, V = NHC0CH3 63.2 g of l-methoxy-4-oxoheptan-2-one and 65.2 g of 4-acetamidobenzaldehyde are dissolved in 480 ml of toluene in the presence of 20 ml of acetic acid 10 and 4 ml of piperidine. The mixture is refluxed for 5 hours and 10.5 ml of water are removed via a Dean-Stark apparatus. The crystals obtained after cooling are filtered off and washed with water, methylene chloride and isopropanol and then recrystallized from 200 ml of 15 methanol to give 43 g of 3-(4-acetamidobenzylidene)-l-methoxy-4-oxoheptan-2-one in the form of crystals melting at 160°C. Example 81: 6-n-Propyl-2-phenyl-4-methoxymethyl-5-(4-2 0 acetamidobenzyl)pyrimidine Formula (xii): = n-propyl, r2 = phenyl, xr3 = ch2och3, v = nhcoch3 25 42 g of 3-(4-acetamidobenzylidene)-l-methoxy-4- oxoheptan-2-one, prepared in Example 80, are dissolved in 1250 ml of acetic acid. 128.7 g of dry ammonium acetate are added and the mixture is heated at 60-70°C for 10 minutes. 30 ml of benzaldehyde are added at 30 60°C and the mixture is stirred for 2 hours at this temperature. 500 ml of benzene are added and the mixture is then refluxed, 9.5 ml of water being removed via a Dean-Stark apparatus. The solvents are concentrated under vacuum and the residue is taken up with 35 water and extracted with ethyl acetate. The organic 2 3 3 7 82 phase is washed with water, dried over magnesium sulfate and evaporated under vacuum. The residue obtained is chromatographed on silica gel in the eluent chloroform 95/acetone 5 to give 3.5 g of 6-n-propyl-4-meth-05 oxymethyl-2-phenyl-5-(4-acetamidobenzyl)pyrimidine in the form of crystals melting at 135°C. Example 82: 6-n-Propyl-2-phenyl-4-methoxymethyl-5-(4- 15 (4-acetamidobenzyl)pyrimidine, prepared in Example 81, are dissolved in a mixture composed of 25 ml of ethanol and 25 ml of water. 2 g of sodium hydroxide pellets are added and the mixture is refluxed for 15 hours and then taken up with water and extracted with ether. The 20 organic phase is dried and then evaporated under vacuum. The residue obtained is chromatographed on silica gel with ether as the eluent to give 1.2 g of 6-n-propyl-2-phenyl-4-methoxymethyl-5-(4-aminobenzyl)-pyrimidine in the form of crystals melting at 115°C. aminobenzyl)pyrimidine 10 Formula (XII): Rj = n-propyl, R2 = phenyl, XR3 = CH20CH3, V = NH2 1.8 g of 6-n-propyl-2-phenyl-4-methoxymethyl-5- 25 Example 83: 2-[[6-n-Propyl-4-methoxymethyl-2-phenyl-pyrimidin-5-yl]methylphenyl-4-yl]aminocarbonylbenzenesulfonic acid 30 Formula (I): Rx = n-propyl, R2 = phenyl, XR3 = CH20CH3, 35 R '4 238785 - 83 - Prepared by the procedure of Example 13. Crystals melting at 186-187°C. Example 84: 2-[(6-n-Propyl-2-methyl-2-aminopyrimidin-05 5-yl)methylphenyl-4-yl]aminocarbonyl benzenesulfonic acid Formula (I): RA = n-propyl, R2 = methyl, nhco- 10 xr3 = nh2, r4 = h03s^^ Prepared by the procedure of Example 13. 15 Crystals melting at 310-312°C. Example 85: N-[6-n-Butyl-2-methyl-5-(4-aminobenzyl)-pyrimidin-4-yl"! morpholine 20 Formula (XII): r1 = n-butyl, r2 = methyl, v = nh2, xr3 = r/ 25 Prepared by the procedure of Example 12. Oil used as such for the next step. Example 86: 2-[(6-n-Butyl-2-methyl-4-(morpholin-l-yl)■ pyrimidin-5-yl)methylphenyl-4-yl]amino-30 carbonylbenzenesulfonic acid Formula (I): Rx = n-butyl, R2 = methyl, / \ XR3 = n o , 35 23 0 7 - 84 - nhccx K = h03s' 05 Prepared by the procedure of Example 13. Crystals melting at 213-6°C. Example 87: 6-n-Propyl-2-methyl-4-hydroxy-5-[2'-(tetra-10 zol-5-yl)biphenyl-4-yl]methylpyrimidine Formula (I): Rx = n-propyl, R2 = methyl, 15 XR3 = OH, R4 20 Prepared by the procedure of Example 31 from 6- n-propyl-2-methyl-4-hydroxy-5-(2'-cyanobiphenyl-4-yl)-methylpyrimidine, prepared in Example 10. Crystals melting at 204-6°C. 25 Example 88: 6-n-Propyl-2-methyl-4-(2-hydroxyethyl)oxy- 5-(2'-cyanobiphenyl-4-yl)methylpyrimidine 30 Formula (XII): Rx = n-propyl, R2 = methyl, X = 0, R3 = CH2CH20H, V = 35 8 g of 6-n-propyl-2-methyl-4-hydroxy-5-(2'- 23 8 7 85 cyanobiphenyl-4-yl)methylpyrimidine, prepared in Example 10, are dissolved in 80 ml of acetonitrile in the presence of 4 g of potassium carbonate, and 3 ml of 2-bromoethanol are added. The mixture is brought to the 05 reflux temperature and heaved for 8 hours; the solvents are concentrated under vacuum and the residue is taken up with water and then extracted with methylene chloride. The organic phase is dried over magnesium sulfate and evaporated under vacuum to give an oily 10 residue, which is chromatographed on silica gel. Elution with an 80/20 methylene chloride/acetone mixture gives 2.1 g of pure 6-n-propyl-2-methyl-4-(2-hydroxyethyl)oxy-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine in the form of crystals melting at 103°C. 15 If elution is continued with a 60/40 methylene chloride/acetone mixture, 2.8 g of 6-n-propyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methyl-3-(2-hydroxyethyl)-3,4-dihydro-4-oxopyrimidine are recovered in the form of an oil, which is used as such for the next step. 20 Example 89: 6-n-Propyl-2-methyl-4-(2-hydroxyethyl)oxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yljmethylpyrimidine 25 Formula (I): Ri = n-propyl, R., = methyl, 3.8 g of 6-n-propyl-2-methyl-4-(2-hydroxyethyl )oxy-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine, prepared in Example 88, are dissolved in 80 ml of 3 5 toluene. 2.7 g of trimethyltin nitride are added and X = 0, R3 = CH2CH20H 30 2 3 8 7 - 86 - the mixture is refluxed for 35 hours, cooled and extracted with a dilute solution of potassium hydroxide, which is washed with ethyl acetate. The aqueous phase is then acidified by having sulfur dioxide 05 bubbled through it, and is extracted with chloroform. After drying and evaporation of the solvent, the residue obtained is chromatographed on silica gel in an 85/15 chloroform/ethanol eluent to give 2 g of 6-n-propyl-2-methyl-4-(2-hydroxyethyl)oxy-5-[2'-(tetrazol-10 5-yl )biphenyl-4-yl Jmethylpyrimidine in the form of crystals melting at 154-155°C. Example 90: 6-n-Propyl-2-methyl-3-(2-hydroxyethyl)-5-12'-(tetrazol-5-yl)biphenyl-4-yl]methyl-15 3,4—dihydro-4—oxopyrimidine hydrochloride Formula (I'): Rx = n-propyl, R2 = methyl, R'3 = CH2CH2OH, 20 25 Prepared by the procedure of Example 89 from 6-n-propyl-2-methyl-3-(2-hydroxyethyl)-5-(2'-cyanobi-phenyl-4-yl)methyl-3,4-dihydro-4-oxopyrimidine, prepared in Example 88. The hydrochloride is obtained by 30 bubbling hydrochloric acid into a tetrahydrofuran solution of the compound in the form of the base. Crystals melting at 240-1°C. 35 238785 05 - 87 - Example 91: 6-n-Propyl-2-methyl-4-(prop-2-yl)oxy-5-(2' ■ cyanobiphenyl-4-ylJmethylpyrimidine Formula (XII): Rx = n-propyl, R2 = methyl, xr3 = 0 ( , v = 10 Prepared by the procedure of Example 30. Oil used as such for the next step. Example 92: 6-n-Propyl-2-methyl-4-(prop-2-yl)oxy-5-[2'■ (tetrazol-5-yl)biphenyl-4-yl ]methylpyri-15 midine Formula (I): Rx = n-propyl, R2 = methyl, 25 Prepared by the procedure of Example 89. Crystals melting at 190-1°C. Example 93: N-[6-n-Propy1-2-methy1-5-(2 '-cyanobiphenyl-4-yl )methylpyrimidin-4-yl ]thiomorpholine 30 Formula (XII): Rx = n-propyl, R2 = methyl, xr3 = t/ ^s , v = N3 35 - 88 - Prepared by the procedure of Example 39. Crystals melting at 153-4°C. Example 94: N-[6-n-Propyl-2-methyl-5-[2'-(tetrazol-5-05 yl)biphenyl-4-yl]methylpyrimidin-4-yl]- thiomorpholine hydrochloride Formula (I): = n-propyl, R2 = methyl, 10 xr3 = u , r4 = 20 25 15 Prepared by the procedure of Example 89. The hydrochloride is obtained by dissolving the compound in the form of the base in an acetone/ether mixture and bubbling hydrochloric acid. Crystals melting at 240-241°C. Example 95: 6-n-Propyl-2-methyl-4-mercapto-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine Formula (XII): Rx = n-propyl, R2 = methyl, 30 Prepared by the procedure of Example 43, Crystals melting at 202-3°C. 35 238785 - 89 - Example 96: 6-n-Propyl-2-methyl-4-mercapto-5-[2 (tetrazol-5-yl)biphenyl-4-yl]methylpyri-midine 05 Formula (I): = n-propyl, R2 = methyl, XR3 = SH, Rt = n 10 Prepared by the procedure of Example 89. Crystals melting at 247-248°C. 15 Example 97: 6-n-Propyl-2-methyl-4-methylthio-5-(2'- cyanobiphenyl-4-ylJmethylpyrimidine 30 Formula (XII): Rx = n-propyl, R2 = methyl, X) 20 XR3 = SCH3, V = n3 Prepared by the procedure of Example 44. 25 Crystals melting at 134°C. Example 98: 6-n-Propyl-2-methyl-4-methylthio-5-[2'-(tetrazol-5-yl)biphenyl-4-yljmethylpyrimidine Formula (I): Rt = n-propyl, R2 = methyl, 35 23 8 7 8 - 90 - XR3 = SCH3, R4 = 05 Prepared by the procedure of Example 89. Crystals melting at 173-174°C. Example 99: 6-n-Propyl-2-methyl-4-(2-hydroxyethyl)-10 mercapto-5-(2'-cyanobiphenyl-4-ylJmethyl pyrimidine 15 Formula (XII): Rx = n-propyl, R2 = methyl, X = S, R3 = CH2CH20H, v= 20 Prepared by the procedure of Example 34, Crystals melting at 97°C. 25 Example 100: 6-n-Propyl-2-methyl-4-(2-acetoxyethyl)- mercapto-5-(2'-cyanobiphenyl-4-ylJmethylpyrimidine Formula (XII): Rx = n-propyl, R2 = methyl, X = S, R3 = CH2CH20C0CH3, 30 V = 35 6.7 g of 6-n-propyl-2-methyl-4-(2-hydroxy- 23 8 7 8 - 91 - ethyl)mercapto-5-(2'-cyanobiphenyl-4-ylJmethylpyrimidine, prepared in Example 99, are refluxed in 35 ml of acetic anhydride for 3 hours. The acetic anhydride is evaporated off under vacuum, the residue is taken up 05 with ether and the ether solution is filtered on animal charcoal and then evaporated under vacuum to give 5.9 g of 6-n-propyl-2-methyl-4-(2-acetoxyethyl)mercapto-5-(2'-cyanobiphenyl-4-ylJmethylpyrimidine in the form of an oil, which is used as such for the next step. 10 Example 101: 6-n-Propyl-2-methyl-4-(2-hydroxyethyl)- mercapto-5-[2'-(tetrazol-5-ylJ biphenyl-4-yljmethylpyrimidine 15 Formula (I): Rx = n-propyl, R2 = methyl, X = S, R3 = CH2CH20H, 5.9 g of 6-n-propyl-2-methyl-4-(2-acetoxy-25 ethyl)mercapto-5-(2'-cyanobiphenyl-4-ylJmethylpyrimidine, prepared in Example 100, are dissolved in 100 ml of toluene, and 3.7 g of trimethyltin nitride are added. The mixture is refluxed for 12 hours, cooled, taken up with ether and extracted with a dilute solu-30 tion of potassium hydroxide. The aqueous phase is acidified by having sulfur dioxide bubbled through it, and is then extracted with chloroform. The chloroform phase is dried over magnesium sulfate and evaporated under vacuum; the residue obtained is chromatographed 35 on silica gel with an 85/15 chloroform/methanol eluent 238785 92 to give 2.5 g of a residue composed of a mixture of the expected alcohol and the acetylated derivative. This mixture is taken up in a dilute solution of potassium hydroxide and left to stand overnight at room tempera-05 ture. The aqueous solution is washed with ether and then acidified by having sulfur dioxide bubbled through it, and the crystals obtained are filtered off and washed with ether to give 2.3 g of 6-n-propyl-2-methyl-4-(2-hydroxyethyl)mercapto-5-[2'-(tetrazol-5-yl)bi-10 phenyl-4-yljmethylpyrimidine in the form of crystals melting at 186-189°C. Example 102; Ethyl 2-(2'-cyanobiphenyl-4-yl)methyl-3- 25 Example 103: 6-n-Butyl-2-xnethyl-4-hydroxy-5-(2'-cyano- oxoheptanoate 15 Formula (VI): Rx = n-butyl, R3 = ethyl, 20 Prepared by the procedure of Example 6. Oil used as such for the next step. biphenyl-4-ylJmethylpyrimidine Formula (XI): Rx = n-butyl, R2 = methyl, 30 35 Prepared by the procedure of Example 7. Crystals melting at 173°C. 2387 - 93 - Example 104: 6-n-Butyl-2-methyl-4-chloro-5-(2'-cyano-biphenyl-4-ylJmethylpyrimidine Formula (XII): Rx = n-butyl, R2 = methyl, XR, = CI *3 Prepared by the procedure of Example 19. Crystals melting at 75°C. Example 105: 6-n-Butyl-2-methyl-4-methoxy-5-(2'-cyano-biphenyl-4-y1)methylpyrimidine Formula (XII): RA = n-butyl, R2 = methyl, XR3 = OCH3, V = |1 Prepared by the procedure of Example 30. Oil used as such for the next step. Example 106: 6-n-Butyl-2-methyl-4-methoxy-5-[2'-(tetra-zol-5-yl)biphenyl-4-yljmethylpyrimidine Formula (I): Rx = n-butyl, R2 = methyl, XR3 = 0CH3, R4 = N n' VN R H 10 2 3 8 7ft - 94 - Prepared by the procedure of Example 89. Crystals melting at 148-149°C. Example 107: 6-n-Butyl-2-methyl-4-hydroxy-5-[2'-(tetra-05 zol-5-yl)biphenyl-4-yljmethylpyrimidine Formula (I): Rt = n-butyl, R2 = methyl, XR3 = OH, R4 = N 15 Prepared by the procedure of Example 31. Crystals melting at 248-249°C. Example 108: 6-n-Propyl-2-methyl-4-(2-methoxyethyl)-oxy-5- (2 ' -cyanobiphenyl-4-yl) methylpyri-20 midine Formula (XII): R± = n-propyl, R2 = methyl, X = 0, R3 = CHaCH20CH3, 25 Prepared by the procedure of Example 30 from 2-30 methoxyethanol. Oil used as such for the next step. 35 - 95 - 238 7 8 5 Example 109: 6-n-Propyl-2-methyl-4-(2-methoxyethyl)oxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yljmethylpyrimidine 05 Formula (I): Rx = n-propyl, R2 = methyl, X = 0, R3 = CH2CH20CH3, 10 15 Prepared by the procedure of Example 89. Crystals melting at 169-170°C. 20 Example 110: 6-n-Propyl-2-methyl-4-(2-dimethylamino- ethyl)oxy-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine Formula (XII): R1 = n-propyl, R2 = methyl, 25 ch3 = o, R3 = ch?ch2 , CH, 30 V = 35 6 g of 6-n-propyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methyl-4-chloropyrimidine, prepared in Example 21, are added to a solution obtained by adding 1 g of 60% sodium hydride to 75 ml of THF containing 2.7 g of 2- 23 8 7 8 5 - 96 05 10 dimethylaminoethanol. The mixture is stirred for 4 hours under reflux, the solvent is then concentrated under vacuum and the residue is taken up with water and extracted with ether. The organic phase is washed with water and then dried over magnesium sulfate to give 5.1 g of 6-n-propyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methyl-4-(2-dimethylaminoethyl)oxypyrimidine in the form of an oil, which is used as such for the next step. Example 111: 6-n-Propyl-2-methyl-4-(2-dimethylamino- ethyl) oxy-5- [ 2' - (tetrazol-5-yl) biphenyl-4-yljmethylpyrimidine 15 Formula (I): Rx = n-propyl, R2 = methyl, X = o, R3 = ch2ch2 l/ ch, *ch, 20 25 R, = Prepared by the procedure of Example 89 Crystals melting at 175-176°C. 30 Example 112: 6-n-Propyl-2-methyl-4-(2-morpholinoethyl)- amino-5- ( 2' -cyanobiphenyl-4-yl) methylpyrimidine 35 Formula (XII): Rx = n-propyl, R2 = methyl, 23 87 8 5 - 97 - r~\ x = NH, R3 = CH2CH2N O , 05 v - Prepared by the procedure of Example 39 from N-(2-aminoethyl)morpholine. 10 Oil used as such for the next step. Example 113: 6-n-Propyl-2-methyl-4-(2-morpholinoethyl)-amino-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]-methylpyrimidine 15 20 25 Formula (I): Rx = n-propyl, R2 = methyl, X = NH, R3 = CH2CH2 N O , R. = n-h Prepared by the procedure of Example 89. Crystals melting at 270-2°C. Example 114: 6-n-Propyl-2-methyl-5-(2'-cyanobiphenyl-3 0 4-yl) methyl-4- ( 2-hydroxyethyl) aminopyri- midine 35 Formula (XII): R1 = n-propyl, R2 = methyl, X = NH, R3 = CH2CH20H, 2387 8 5 - 98 - v = 05 Prepared by the procedure of Example 39 from ethanolamine. Crystals melting at 135°C. 10 Example 115: 6-n-Propyl-2-methyl-5-[2'-(tetrazol-5-yl)- biphenyl-4-yl]methyl-4-(2-hydroxyethyl)-aminopyrimidine Formula (I): R2 = n-propyl, R2 = methyl, 15 X = NH, R3 = CH2CH20H, 20 Prepared by the procedure of Example 89. Crystals melting at 149-150°C. 25 Example 116: 6-n-Propy 1-2-methy 1-4- (2-methylthioethyl) -oxy-5-(2'-cyanobiphenyl-4-ylJmethylpyrimidine 30 Formula (XII): rx = n-propyl, r2 = methyl, X = 0, r3 = ch2ch2sch3, 35 co 8 99 Prepared by the procedure of Example 110 from 2-methylthioethanol. Oil used as such for the next step. Example 117: 6-n-Propyl-2-methyl-4-(2-methylthioethyl)-oxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]-methylpyrimidine Example 118: 6-n-Butyl-2-methyl-4-(2-methoxyethyl)- oxy-5-(2'-cyanobipheny1-4-y1)methylpyrimidine Formula (I): Rx = n-propyl, R2 = methyl, x = o, r3 = ch2ch2sch3, nt Prepared by the procedure of Example 89. Crystals melting at 121-122°C. Formula (XII): Rx = n-butyl, R2 = methyl X = O, R3 = CH2CH20CH3, v NO Prepared by the procedure of Example 30. Oil used as such for the next step. 23 8 7 - .100 - Example 119: 6-n-Butyl-2-methyl-4-(2-methoxyethyl)oxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yljmethylpyrimidine 05 10 Formula (I): rx = n-butyl, r-, = methyl, x = 0, r3 = ch2ch2och3, 15 Prepared by the procedure of Example 89, Crystals melting at 128-129°C. 20 Example 120: 6-n-Butyl-2-methyl-4-(2-dimethylamino- ethyl)oxy-5-(2'-cyanobiphenyl-4-ylJmethylpyrimidine Formula (XII): rx = n-butyl, r2 = methyl, 25 = o, r3 = ch2ch2 t/ ch, chg 30 v = nc' Prepared by the procedure of Example 110, Oil used as such for the next step. 35 238785 - 101 - Example 121: 6-n-Butyl-2-methy1-4-(2-dimethylamino- ethyl)oxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yljmethylpyrimidine Formula (I): R1 = n-butyl, R2 = methyl, 10 15 x = o, r3 = CH2CH2 n( CH, CH, r- = Prepared by the procedure of Example 89. Crystals melting at 166-167"c. 20 Example 122: Ethyl 3-oxooctanoate Formula (II): Rx = n-pentyl, R13 = ethyl 25 Prepared by the procedure of Example 1 Oil of b.p.15 = 110-115°C. Example 123: Ethyl 2—(2'-cyanobiphenyl-4-yl)methyl-3-oxooctanoate 30 Formula (VI): R1 = n-pentyl, V = CN R13 = ethyl 35 Prepared by the procedure of Example 3. 23 8 7 - 102 - Oil used as such for the next step. Example 124: 6-n-Pentyl-2-methyl-4-hydroxy-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine Formula (XI): Rx = n-pentyl, R2 = methyl, Prepared by the procedure of Example 7. Crystals melting at 162°C. Example 125: 6-n-Penty1-2-methyl-4-hydroxy-5-[ 2' - (tet-razol-5-yl)biphenyl-4-yljmethylpyrimidine Formula (I): Rx = n-pentyl, R2 = methyl, Prepared by the procedure of Example 31. Crystals melting at 195-196°C. Example 126: 6-n-Pentyl-2,3-dimethyl-5-(2'-cyanobi- phenyl-4-yl)methyl-3,4-dihydro-4-oxopyri-midine Formula (XII'): Rx = n-pentyl, R2 = methyl, R'3 = methyl, 23 8 7 8 5 - 103 - 0 5 7 g of 6-n-pentyl-2-methyl-5-(2'-cyanobiphenyl- 4-yl)methyl-4-hydroxypyrimidine, prepared in Example 124, are dissolved in 70 ml of dimethylformaraide. After the addition of 0.8 g of 60% sodium hydride, the mixture is stirred for 30 minutes at room temperature. 10 2 ml of methyl iodide are added and the solution is heated for 2 hours at 80°C. The solvent is evaporated off under vacuum and the residue is taken up with water and extracted with ether. The ether phase is dried over magnesium sulfate and evaporated under vacuum and 15 the residue is chromatographed on silica gel in a 90/10 chloroform/acetone eluent to give 5.8 g of 6-n-pentyl-2,3-dimethyl-5-(2'-cyanobiphenyl-4-yl)methyl-3,4-di-hydro-4-oxopyrimidine in the form of an oil, which is used as such for the next step. 20 Example 127: 6-n-Pentyl-2,3-dimethyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-3,4-dihydro-4-oxo-pyrimidine hydrochloride 25 Formula (I'): Rx = n-pentyl, R2 = methyl, R'3 = methyl, R4 = 30 n v* n h 35 Prepared by the procedure of Example 90. Crystals melting at 215-217°C. 25 8/ 8 0 - 104 - Example 128: 6-n-Pentyl-2-methyl-4-chloro-5-(2'-cyano-biphenyl-4-ylJmethylpyrimidine Formula (XII): Rx = n-pentyl, R2 = methyl, 05 XR3 = CI, V = 10 Prepared by the procedure of Example 19. Oil used as such for the next step. Example 129: Ethyl 2-[6-n-pentyl-2-methyl-5-(2'-cyano-biphenyl-4-yl)methylpyrimidin-4-yl]oxy-15 acetate Formula (XII): Ri = n-pentyl, R2 = methyl, X = O, R3 = CH2C02Et, 20 V = N3 X) 3 g of ethyl 2-hydroxyacetate are dissolved in 25 50 ml of anhydrous tetrahydrofuran. 1.1 g of 60% sodium hydride are added and the mixture is stirred for 30 minutes at 50-60°C. 5.4 g of 6-n-pentyl-2-methyl-4-chloro-5-(2'-cyanobiphenyl-4-y1)methylpyrimidine, prepared in Example 128, are added and the mixture is 30 refluxed for 8 hours. The solvent is evaporated off under vacuum and the residue is taken up with water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated under vacuum to give an oil, which crystallizes from iso-35 propyl ether to give 3.4 g of ethyl 2-[6-n-pentyl-2- 2387 - 105 - methyl-5-(2'-cyanobiphenyl-4-yl)methylpyrimidin-4-yl] ■ oxyacetate in the form of crystals melting at 68°C. Example 130: Ethyl 2-[6-n-pentyl-2-methyl-5-[2'-05 (tetrazol-5-yl)biphenyl-4-yl]methylpyri- midin-4-yljoxyacetate Formula (I): = n-pentyl, R2 = methyl, X = O, R3 = CH2C02Et, 10 15 20 Prepared by the procedure of Example 89. Crystals melting at 146-148°C. Example 131: Ethyl 2-[6-n-propyl-2-methyl-5-(2/-cyano-biphenyl-4-yl)methylpyrimidin-4-yl]oxyacetate 25 Formula (XII): R1 = n-propyl, R2 = methyl, X = O, R3 = CH2C02Et, v = 30 Prepared by the procedure of Example 129. Oil used as such for the next step. 35 23 37 8 5 - 106 - Example 132: Ethyl 2-[6-n-propyl-2-methyl-5-[2'- (tetrazol-5-yl)biphenyl-4-yl]methylpyri-midin-4-yl]oxyacetate 05 Formula (I): Rx = n-propyl, R2 = methyl, X = O, R3 = CH2C02Et, R. = 10 Prepared by the procedure of Example 89. 15 Crystals melting at 149-150°C. Example 133: 6-n-Propyl-2-mercapto-4-hydroxy-5-(4-nitrobenzyl)pyrimidine 20 Formula (XI): Rx = n-propyl, R2 = SH, T = OH, V = N02 5.7 g of sodium are dissolved in 150 ml of methanol, and 19 g of thiourea are added. The mixture 25 is stirred for 5 minutes at room temperature and 55 g of ethyl 3-oxohexanoate, prepared in Example 1, are added. After refluxing for 8 hours, the solvent is concentrated to half its volume under vacuum and the residue is taken up with water and neutralized by the 30 addition of dilute hydrochloric acid. The mixture is left to stand overnight at room temperature and the crystals formed are filtered off, washed with ether and ethanol and dried to give 29 g of 6-n-propyl-2-mer-capto-4-hydroxy-5-(4-nitrobenzyl)pyrimidine in the form 35 of crystals melting at 240°C. 23 87 8 5 - 107 - Example 134: 6-n-Propyl-2-methylthio-4-hydroxy-5-(4-nitrobenzyl)pyrimidine Formula (XI): R1 = n-propyl, R2 = SCH3, 05 T = OH, V = N02 26 g of 6-n-propyl-2-mercapto-4-hydroxy-5-(4-nitrobenzyl)pyrimidine, prepared in Example 133, and 8.3 g of potassium hydroxide are dissolved in 200 ml of 10 methanol. The mixture is stirred for 10 minutes at room temperature and 5.3 ml of methyl iodide are added. The mixture is then refluxed for 2 hours. The solvent is evaporated off under vacuum and the residue is taken up with water. After acidification with a dilute solu-15 tion of hydrochloric acid, the aqueous phase is extracted with chloroform. The organic phase is dried over magnesium sulfate and then evaporated under vacuum and the residue crystallizes from a chloroform/methanol mixture to give 13.4 g of 6-n-propyl-2-methylthio-4-20 hydroxy-5-(4-nitrobenzyl)pyrimidine in the form of crystals melting at 223°C. Example 135: 6-n-Propyl-2-methylthio-4-chloro-5-(4-nitrobenzyl)pyrimidine 25 Formula (XII): Rx = n-propyl, R2 = SCH3, XR3 = CI, V = NO2 Prepared by the procedure of Example 19. 30 Crystals melting at 108°C. Example 136: 2-[6-n-Propyl-2-methylthio-5-(4-nitro-benzyl)pyrimidin-4-yl ] mercaptoethanol 35 Formula (XII): R^^ = n-propyl, R2 = SCH3, 238785 - 108 - X = S, R3 = CH2CH20H, V = no2 Prepared by the procedure of Example 34. 05 Crystals melting at 97°C. Example 137: 2- [6-n-Propyl-2-methylthio-5-(4-aminobenzyl )pyrimidin-4-yl]mercaptoethanol 10 Formula (XII): Rx = n-propyl, R2 = SCH3, X = S, R3 = CH,CH20H, V = nh2 Prepared by the procedure of Example 12. 15 Oil used as such for the next step. Example 138: 2-[[6-n-Propyl-2-methylthio-4-(2-hydroxyethyl )mercaptopyrimidin-5-yl ]methylphenyl -4-yl]aminocarbonylbenzenesulfonic acid 20 Formula (I): Rx = n-propyl, R2 = SCH3, X = S, R3 = CH2CH20H, 25 Prepared by the procedure of Example 13. 30 Crystals melting at 198-201°C. 35 23 8 7 109 Example 139: 3-[6-n-Propyl-2-methyl-5-(2'-cyanobi- phenyl-4-yl)methylpyrimidin-4-yl]mercapto-propanol cyanobiphenyl-4-ylJmethylpyrimidine, prepared in Example 95, are dissolved in 50 ml of ethanol. 0.4 g of 15 sodium dissolved in 10 ml of ethanol is added and the mixture is stirred for 10 minutes at room temperature. 2.5 g of 3-bromopropanol are added and the reaction mixture is refluxed for 6 hours. The solvent is then evaporated off under vacuum and the residue is taken up 20 with water and extracted with ether. The ether phase is dried over magnesium sulfate and evaporated under vacuum to give 5 g of 3-[6-n-propyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methylpyrimidin-4-yl]mercaptopropa-nol in the form of an oil, which is used as such for 25 the next step. Example 140: 6-n-Propyl-2-methyl-4-(3-acetoxypropyl)- 05 Formula (XII): rx = n-propyl, r2 = methyl, X = s, r3 = ch2ch2ch20h, 10 5 g of 6-n-propyl-2-methyl-4-mercapto-5-(2 mercapto-5-(2'-cyanobipheny1-4-y1Methylpyrimidine 30 Formula (XII): rx = n-propyl, r2 = methyl, x = s, r3 = ch2ch2ch20c0ch3, 35 233785 - no - Prepared by the procedure of Example 100. Oil used as such for the next step. Example 141; 6-n-Propyl-2-methyl-4-(3-acetoxypropyl)-0 5 mercapto-5-[2'-(tetrazol-5-yl)biphenyl-4- yljmethylpyrimidine Formula (I): Rx = n-propyl, R2 = methyl, X = S, R3 = CH2CH2CH20C0CH3, 10 r. = 15 Prepared by the procedure of Example 89. Oil used as such for the next step. Example 142: 3-[6-n-Propyl-2-methyl-5-[2'-(tetrazol-5-20 yl)biphenyl-4-yl]methylpyrimidin-4-ylj- mercaptopropanol 25 30 Formula (I): Rx = n-propyl, R2 = methyl, x = s, R3 = ch2ch2ch2oh, 35 3 g of 6-n-propyl-2-methyl-4-(3-acetoxypropyl)-mercapto-5-[2'-(tetrazol-5-yl)biphenyl-4-yljmethylpyrimidine, prepared in Example 141, are dissolved in 30 ml of ethanol in the presence of 1 g of sodium hydroxide pellets. The mixture is heated for one hour at 50°C. 10 15 20 25 30 238785 - Ill " The alcohol is evaporated off under vacuum, the residue is taken up with warm water, the solution is acidified by having sulfur dioxide bubbled through it, and is extracted with chloroform, the organic phase is concentrated under vacuum and the residue obtained crystallizes from acetone to give 2.2 g of 3-[ 6-n-propyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimi-din-4-yl]mercaptopropanol in the form of crystals melting at 157-158°C. Example 143: 6-n-Propyl-4-hydroxy-5-(2'-cyanobiphenyl-4—ylJmethylpyrimidine Formula (XI): Rx = n-propyl, R2 = H, 13 g of ethyl 2-(2'-cyanobiphenyl-4-yl)methyl-3-oxohexanoate, prepared in Example 6, are dissolved in 100 ml of diglyme. 8 g of formamidine acetate are added and the mixture is heated for 8 hours at 200 °C and then taken up with water and extracted with ethyl acetate. The organic phase is washed several times with a dilute solution of sodium hydroxide and the aqueous extracts are neutralized with hydrochloric acid to give 2.6 g of 6-n-propyl-4-hydroxy-5-(2'-cyanobi-phenyl-4-ylJmethylpyrimidine in the form of crystals melting at 152°c. Example 144: 6-n-Propyl-4-chloro-5-(2'-cyanobiphenyl-4-ylJmethylpyrimidine Formula (XIIJ: Rx = n-propyl, R2 = H, 2 3 3 7 8 5 - 112 - XR3 = CI, V = NO' 05 Prepared by the procedure of Example 19. Crystals melting at 58"c. 10 Example 145: 6-n-Propyl-4-methoxy-5-(2'-cyanobiphenyl-4-y1)methylpyrimi dine Formula (XII): Rx = n-propyl, R2 = H, 15 XR3 = 0CH3, V = Prepared by the procedure of Example 30. Crystals melting at 110°c. 20 Example 146: 6-n-Propyl-4-methoxy-5-[ 2 ' - (tetrazol-5- yl )biphenyl-4-yl Jmethylpyrimidine 25 Formula (I): Ra = n-propyl, R2 = H, X = O, R3 = CH3/ r, = 30 Prepared by the procedure of Example 89, Crystals melting at 148-149°C. 35 238785 - 113 - Example 147: 6-n-Propyl-2-amino-4-hydroxy-5-(4-nitro-benzyl)pyrimidine Formula (XI): Rx = n-propyl, R2 = NH2, T = 05 OH, V = N02 18.8 g of guanidine hydrochloride are added to a solution of sodium ethylate obtained by adding 4.5 g of sodium to 150 ml of ethanol. The mixture is stirred 10 for 5 minutes and 50 g of ethyl 3-oxo-2-( 4-nitrobenzyl )hexanoate, prepared in Example 3, are added. After 4 hours at room temperature and 4 hours under reflux, the mixture is taken up with water and the crystals are filtered off and washed with ether and 15 acetone to give 22.1 g of 6-n-propyl-2-amino-4-hydroxy-5-(4-nitrobenzyl)pyrimidine in the form of crystals melting at 245-8°c. Example 148: 6-n-Propyl-2-amino-4-chloro-5-(4-nitro-20 benzyl)pyrimidine Formula (XII): rx = n-propyl, r2 = nh2, xr3 = ci, v = no2 25 Prepared by the procedure of Example 19. Crystals melting at 140°C. Example 149: 2-[6-n-Propyl-2-amino-5-(4-nitrobenzyl)-pyrimidin-4-yl]mercaptoethanol 30 Formula (XII): R1 = n-propyl, R2 = NH2, X = S, R3 = CH2CH20H, V = no2 35 Prepared by the procedure of Example 34. 238785 05 - 114 - Crystals melting at 110°C. Example 150: 2-[6-n-Propyl-2-amino-5-(4-aminobenzyl)■ pyrimidin-4-yl]mercaptoethanol Formula (XII): Rx = n-propyl, R2 = NH2, X = S, R3 = CH2CH20H, V = NH, 10 Prepared by the procedure of Example 12. Crystals melting at 138°C. Example 151: 2-[[6-n-Propyl-2-amino-4-(2-hydroxyethyl) ■ mercaptopyrimidin-5-yl]methylphenyl-4-yl]-15 aminocarbonylbenzenesulfonic acid Formula (I): Rx = n-propyl, R2 = NH2, X = S, R3 = CH2CH20H, 20 R„ = 30 h03s' Prepared by the procedure of Example 13. 25 Crystals melting at 228-230°C. Example 152: N-2-[6-n-Buty1-2-methy1-5-(2'-cyanobi- phenyl^-yl )methylpyrimidin-4-yl ]oxyethyl-phthalimide Formula (XII): R1 = n-butyl, R2 = methyl, o x = o, R3 = ch2ch2 n 35 238785 115 V no Prepared by the procedure of Example 110 from 2-phthalimidoethanol. Crystals melting at 110°C. Example 153: N-2-[6-n-Butyl-2-methyl-5-[ 2 ' - (tetrazol-5-yl)biphenyl-4-yl]methylpyrimidin-4-yl]oxy-ethylphthalimi.de Example 154: 6-n-Butyl-2-methyl-4-(2-dimethylamino- ethyl)mercapto-5-(2 '-cyanobiphenyl-4-yl)-methylpyrimidine Formula (I): RA = n-butyl, R2 = methyl, o o Prepared by the procedure of Example 89. Crystals melting at 200-201"c. Formula (XII): Rx = n-butyl, R2 = methyl chg X = s, R3 = ch2ch2 nch3 238785 - 116 - V = 05 Prepared by the procedure of Example 22 from N- 2-mercaptoethyl-N,N-dimethylamine. Oil used as such for the next step. Example 155: 6-n-Butyl-2-methyl-4-(2-dimethylamino-10 ethyl)mercapto-5-[2'-(tetrazol-5-y1)bi- phenyl-4-yljmethylpyrimidine Formula (I): Rx = n-butyl, R2 = methyl, 15 x = s, r3 = ch2ch2 r/ cho 20 r. = 25 Prepared by the procedure of Example 89 Crystals melting at 187-188°C. 30 Example 156: 6-n-Butyl-2-methyl-4-(2-methylthioethyl)-oxy-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine Formula (XII): Rx = n-butyl, R2 = methyl, X = 0, R3 = CH2CH2SCH3, 35 V = 23 3 7 8 5 - 117 - Prepared by the procedure of Example 110 from 2-methylthioethanol. Oil used as such for the next step. 0 5 Example 157 : 6-n-Butyl-2-methyl-4- (2-methylthioethyl) - oxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]-methylpyrimidine Formula (I): Rx = n-butyl, R2 = methyl, 10 x = o, rj = ch2ch2sch3, 15 m-N N H Nv J. Prepared by the procedure of Example 89. Crystals melting at 121-122°C. 20 Example 158: 2-[ 6-n-Butyl-2-methyl-5-(2'-cyanobiphenyl-4-yl )methylpyrimidin-4-yl ]mercaptoethanol Formula (XII): Rx = n-butyl, R2 = methyl, 25 X = S, R3 = CH2CH20H, v = 30 AJ N3 Prepared by the procedure of Example 22, Oil used as such for the next step. 35 2387 85 - 118 - Example 159: 2-[6-n-Butyl-2-methyl-5-(2'-cyanobipheny1-4-yl)nethylpyrimidin-4-yl]mercaptoethyl acetate 05 Formula (XII): Rx = n-butyl, R2 = methyl, X = S, R3 = CH2CH20C0CH3, 10 Prepared by the procedure of Example 100. Oil used as such for the next step. 15 Example 160: 2-[6-n-Butyl-2-methyl-5-[2'-(tetrazol-5- yl)biphenyl-4-yl]methylpyrimidin-4-yl]-mercaptoethyl acetate Formula (I): Rx = n-butyl, R2 = methyl, 20 X = S, R3 = CH2CH20C0CH3, 25 Prepared by the procedure of Example 89. Crystals melting at 112-114°C. 30 Example 161: 2-[6-n-Butyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidin-4-yl]-mercaptoethanol 35 Formula (I): Rx = n-butyl, R2 = methyl, 2387 85 - 119 - x = s, r3 = ch2ch20h, 3.7 g of 2-[6-n-buty1-2-methy1-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]raethylpyrimidin-4-yl]mercaptoethyl 10 acetate, prepared in Example 160, are dissolved in 300 ml of ethanol and 100 ml of water in the presence of 1 g of sodium hydroxide pellets. The mixture is stirred for 48 hours at room temperature, the solvents are concentrated, 200 ml of water are added, the 15 aqueous phase is washed with ethyl acetate and then with ether and acidified by having sulfur dioxide bubbled through it, and the crystals obtained are filtered off, washed with water and ether and chromatographed on silica gel with a 9/1 methylene chloride/ 20 methanol eluent to give 1.7 g of 2-[6-n-butyl-2-methyl-5~[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidin-4-yljmercaptoethsnol in the form of crystals melting at 161-162 ° C. 25 Example 162; Ethyl 2-[6-n-butyl-2-methyl-5-(2'-cyanobipheny 1-4-yl )methylpyrimidin-4-yl ] oxyacetate Formula (XII): RA = n-butyl, R2 = methyl, 30 X = 0, R3 = CH2C02Et, 10 15 25 30 238785 - 120 - Prepared by the procedure of Example 129. Oil used as such for the next step. Example 163: Ethyl 2-[6-n-butyl-2-methyl-5-[2'-(tetra-05 zol-5-yl)biphenyl-4-yl]methylpyrimidin-4- yl]oxyacetate Formula (I): Rx = n-butyl, R2 = methyl, X = 0, R3 = CH2C02Et, OO vi Prepared by the procedure of Example 89. Crystals melting at 133-135°C. 20 Example 164: 4-[6-n-Propyl-2-methyl-5-(2'-cyanobi- phenyl-4-yl)methylpyrimidin-4-yl]oxy-methyl-2,2-dimethyl-l,3-dioxolane Formula (XII): R± = n-propyl, R2 = methyl, ^^2 7 \ X - °, R3 - Q^° 35 Prepared by the procedure of Example 110. Oil used as such for the next step. 05 10 15 25 23 8; - 121 - Example 165: Sodium salt of 4-[6-n-propyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-pyrimidin-4-yl]oxymethyl-2,2-dimethyl-l,3-dioxolane Formula (I): Rx = n-propyl, R2 = methyl, CH, X = O, R3 = '2 7 \ o R-= iOO Nnvn^N . Na Prepared by the procedure of Example 89, the sodium salt being obtained by treatment of the tetra-zole derivative with 0.9 equivalent of sodium hydroxide 20 in alcoholic solution. Crystals melting at 224-225°C. Example 166: Ethyl 2-[4-(3-cyanothien-2-yl)benzyl]-3-oxohexanoate Formula (VI): Rx = n-propyl, R13 = ethyl, v= y> :a/ nc 30 35 Prepared by the procedure of Example 3 from 4-(3-cyanothien-2-yl)benzyl bromide. Oil used as such for the next step. 2387 85 - 122 - Preparation of 4-(3-cyanothien-2-yl)benzyl bromide A) 4'-Methyl-4-chlorobutyrophenone 53 ml of toluene and 70.5 g of 4-chlorobutyroyl 05 chloride are dissolved in 100 ml of methylene chloride and the solution is added at 10°C to a suspension of 74 g of aluminum chloride in 200 ml of methylene chloride. The temperature is then allowed to rise for a quarter of an hour and the mixture is treated with 10 iced water. The organic phase is dried over magnesium sulfate and evaporated under vacuum to give 96.9 g of 4'-methyl-4-chlorobutyrophenone in the form of an oil, which is used as such for the next step. 15 B) a-Chloro-/3-(2-chloroethyl)-4'-methylcinnamaldehyde 130 ml of phosphorus oxychloride are added slowly, at 0 ° C, to 130 ml of dimethyl formamide, and 117.5 g of 4'-methyl-4-chlorobutyrophenone, prepared in A), dissolved in 50 ml of dimethylformamide are then 20 added dropwise. The mixture is subsequently stirred at room temperature for one hour and then at 50 °C for 2 hours and at 70°C for l hour. The mixture is then poured on to ice and taken up with ether and the ether phase is washed with a saturated solution of sodium 25 bicarbonate, dried over sodium sulfate and evaporated under vacuum to give 133.8 g of a-chloro-£-(2-chloro-ethyl)-4'-methylcinnamaldehyde in the form of an oil, which is used as such for the next step. 30 C) 2-(4-Methylphenyl)-4,5-dihydrothiophene-3-carboxal-dehyde 15.9 g of a-chloro-£-(2-chloroethyl)-4'-methylcinnamaldehyde, prepared in B), and 22 g of sodium sulfide (9H20) are added to 200 ml of THF. Water is 35 added in a sufficient amount for the sodium sulfide to 2387 85 - 123 - pass completely into solution, after which the mixture is refluxed for 3 hours, cooled and then taken up with ether. The organic phase is decanted, washed with water and then dried over magnesium sulfate and evapo-05 rated under vacuum to give 13.5 g of 2-(4-methyl-phenyl)-4,5-dihydrothiophene-3-carboxaldehyde in the form of an oil, which is used as such for the next step. 10 D) 2-(4-Methylphenyl)-3-cyano-4,5-dihydrothiophene 15 g of 2-(4-methylphenyl)-4,5-dihydrothio-phene-3-carboxaldehyde, prepared in C) , and 6.5 g of hydroxylamine hydrochloride are mixed in 40 ml of ethanol and 10 ml of water. A solution of 4.7 g of 15 sodium carbonate in 10 ml of water is added. The mixture is stirred at room temperature for half an hour and then extracted with ether. The ether phase is washed with water and then dried over sodium sulfate and evaporated under vacuum to give 15.2 g of a gummy 20 yellow residue. This residue is added to 13 ml of acetic anhydride and the mixture warms up slightly, turns brown and becomes liquid. The mixture is subsequently refluxed for 1 hour and then poured on to ice, extracted with methylene chloride and washed with 25 a saturated solution of sodium bicarbonate, the organic phase is then dried over magnesium sulfate and evaporated under vacuum and the residue obtained is chromatographed on silica gel in methylene chloride to give 10 g of 2-(4-methylphenyl)-3-cyano-4,5-dihydrothiophene 30 in the form of an oil, which is used as such for the next step. E) 2-(4-Methylphenyl)-3-cyanothiophene 49.9 g of 2-(4-methylphenyl)-3-cyano-4,5-35 dihydrothiophene, prepared in D), are dissolved in 200 - 124 - ml of carbon tetrachloride, the mixture is heated to the reflux temperature and, after two hours, 11 g of bromine dissolved in 200 ml of carbon tetrachloride are added dropwise. Reflux is continued until the evolution of hydrogen bromide has ceased, and the solvent is then evaporated off under vacuum. The residue is taken up in 200 ml of anhydrous tetrahydrofuran, and 28 g of potassium tert-butylate are added. The mixture is refluxed for one hour and then cooled, water and sodium chloride are added and the resulting mixture is extracted with ether. The organic phase is evaporated under vacuum to give 31.8 g of 2-(4-methylphenyl )-3-cyano-thiophene in the form of an oil, which is used as such for the next step. F) 4-(3-Cyanothien-2-yl)benzyl bromide 24.5 g of 2-(4-methylphenyl)-3-cyanothiophene, prepared in E), are dissolved in 200 ml of carbon tetrachloride. 21.9 g of N-bromosuccinimide and 0.1 g of benzoyl peroxide are added. The mixture is refluxed for 24 hours. The crystals of succinimide are filtered off and the solvent is evaporated off under vacuum. The residue is taken up in a mixture of hexane and ethyl acetate and the solution is kept for 24 hours in a refrigerator. The crystals formed are filtered off to give 14 g of 4-(3-cyanothien-2-yl)benzyl bromide in the form of crystals melting at 80°C. Example 167: 6-n-Propyl-2-methyl-4-hydroxy-5-[4-(3-cyanothien-2-yl)benzyl]pyrimidine Formula (XI): Rr = n-propyl, R2 = methyl T = OH, V # 2387 85 - 125 - Prepared by the procedure of Example 7. Crystals melting at 180°C. Example 168: 6-n-Propyl-2-methyl-4-chloro-5-[4-(3-0 5 cyanothien-2-y1)benzyl]pyrimidine Formula (XII): = n-propyl, R2 = methyl, 'X> xr3 = ci, v = 10 NC Prepared by the procedure of Example 19. Oil used as such for the next step. 15 Example 169: 6-n-Propyl-2-methyl-4-methoxy-5-[4-(3-cyanothien-2-yl)benzyl]pyrimidine Formula (XII): R, = n-propyl, R2 = methyl, S 20 v \—q xr3 = och3, v NC JQ 25 Prepared by the procedure of Example 30. Oil used as such for the next step. Example 170: 6-n-Propyl-2-methyl-4-methoxy-5-[4-[3-(tetrazol-5-yl)thien-2-yl]benzyl]pyrimi-30 dine Formula (I): Rx = n-propyl, R2 = methyl, 35 $ 2387 8 5 - 126 - XR3 = OCH^,, R4 = 05 Prepared by the procedure of Example 89. Crystals melting at 155°C. 10 Example 171: Ethyl 2-(2'-methoxycarbonylbiphenyl-4-yl) ■ methyl-3-oxoheptanoate Formula (VI): Rx = n-butyl; R13 = ethyl, 15 V = m602c Prepared by the procedure of Example 5. 20 Oil used as such for the next step. Example 172: 6-n-Butyl-2-methyl-4-hydroxy-5-(2*- methoxycarbonylbipheny1-4-y1)methylpyrimi -dine 25 30 Formula (XI): Rx = n-butyl, R2 = methyl, T = OH, V = Me02C Prepared by the procedure of Example 7. Crystals melting at 209-210°C. 35 # - 127 - 238785 Example 173: 6-n-Butyl-2-methyl-4-chloro-5-(2'-methoxy-carbonylbiphenyl-4-ylJmethylpyrimidine Formula (XII): = n-butyl, R2 = methyl, 05 xr = ci, v = m6o2c 10 Prepared by the procedure of Example 19. Oil used as such for the next step. Example 174: 6-n-Butyl-2-methyl-4-methoxy~5-(2'- methoxycarbonylbiphenyl-4-yl)methylpyrimi 15 dine Formula (XII): Ri = n-butyl, R2 = methyl, xr3 = och3, v = 20 MeQ2C Prepared by the procedure of Example 30. Oil used as such for the next step. 25 Example 175: 4'-[6-n-Butyl-2-methyl-4-methoxypyrimidin-5-yl]methylbiphenyl-2-carboxylic acid Formula (I): R± = n-butyl, R2 = methyl, 30 XR3 = 0CH3, V = H02C' 35 2.1 g of 6-n-butyl-2-methyl-4-methoxy-5-(2/- 21*7?? - 128 - methoxycarbonylbiphenyl-4-ylJmethylpyrimidine, prepared in Example 174, and 0.35 g of sodium hydroxide pellets are dissolved in 15 ml of methanol and 10 ml of water. The solution is heated at 60°C for 10 hours, the sol-05 vents are evaporated off under vacuum, the residue is taken up with water and the aqueous phase is acidified with dilute hydrochloric acid. The crystals are filtered off, washed several times with water and dried to give 1.8 g of 4'-[6-n-butyl-2-methyl-4-methoxypyri-10 midin-5-yl]methylbiphenyl-2-carboxylic acid in the form of crystals melting at 168°C. Example 176: 6-n-Propyl-2-methyl-4-methoxy-5-(4-nitrobenzyl )pyrimidine 15 Formula (XII): Rx = n-propyl, R2 = methyl, XR3 = 0CH3, V = NO2 Prepared by the procedure of Example 30. 20 Oil used as such for the next step. Example 177: 6-n-Propyl-2-methyl-4-methoxy-5-(4-aminobenzyl )pyrimidine 25 Formula (XII): Rx = n-propyl, R2 = methyl, XR3 = OMe, V = NH2 5.3 g of 6-n-propyl-2-methyl-4-methoxy-5-(4-nitrobenzyl)pyrimidine, prepared in Example 176, are 30 dissolved in 70 ml of diglyme. 1.15 g of lithium boro-hydride are added and the mixture is heated to the reflux temperature. 8 ml of methanol are added drop-wise over two hours and the mixture is subsequently refluxed for a further 2 hours and then taken up with 35 water. The crystals are filtered off and dissolved in « 23 8 7 8 J - 129 - isopropyl ether. The ether solution is dried over magnesium sulfate and evaporated under vacuum to give 3.8 g of 6-n-propyl-2-methyl-4-methoxy-5-(4-aminobenzyl ) pyrimidine in the form of crystals melting at 05 179-181° C. Example 178: 2-[(6-n-Propy1-2-methyl-4-methoxypyrimi-din-5-yl)methylpheny1-4-yl]aminocarbonyl-benzenesulfonic acid 10 Formula (I): Rj = n-propyl, R2 = methyl, NHCCX XR3 = OMe, R4 = > 15 h°3s Prepared by the procedure of Example 13. Crystals melting at 200-204°C. 20 Example 179: 6-n-Butyl-2-methyl-5-(4-nitrobenzyl)-4- (2-propionyloxyethyl) oxypyrimidine Formula (xii): Rx = n-butyl, R2 = methyl, X = O, R3 = CH2CH20C0CH2CH3, 25 V = N02 Prepared by the procedure of Example 100 from 2-hydroxyethyl propionate, obtained by the catalytic hydrogenation of commercial 2-hydroxyethyl acrylate in 30 the presence of Raney nickel. Oil used as such for the next step. 35 23 87 8 5 - 130 - Example 180: 2-[6-n-Butyl-2-methyl-5-(4-nitrobenzyl)-pyrimidin-4-ylJoxyethanol Formula (XII): Rx = n-butyl, R2 = methyl, 05 X = O, R3 = CH2CH20H, v = no2 Prepared by the procedure of Example 142. Oil used as such for the next step. 10 Example 181: 2-[6-n-Butyl-2-methyl-5-(4-aminobenzyl)-pyrimidin-4-yl]oxyethanol Formula (XII): R1 = n-butyl, R2 = methyl, 15 X = O, R3 = CH2CH20H, v = nh2 Prepared by the procedure of Example 12. Oil used as such for the next step. 20 Example 182: 2-[[6-n-Butyl-2-methyl-4-(2-hydroxyethyl)-oxypyrimidin-5-yl ]methylphenyl-4-yl ] aminocarbonylbenzenesulfonic acid 25 Formula (I): Rx = n-butyl, R2 = methyl, X = 0, R3 = CH2CH20H, nhca 30 R„ = ho3s"^^ Prepared by the procedure of Example 13. Crystals melting at 238-9°C. 35 23 8 7 # - 131 - Example 183: Ethyl [6-n-butyl-2-methyl-5-(2'-cyanobi-phenyl-4-y1)methyl-3,4-dihydro-4-oxo-pyrimidin-3-yl]acetate 05 Formula (XII'): Rx = n-butyl, R2 = methyl, JO 20 25 R'3 = CH2C02Et, V = 10 Prepared by the procedure of Example 88. Oil used as such for the next step. Example 184: Ethyl [6-n-butyl-2-methyl-5-[2'-(tetrazol-15 5-yl)biphenyl-4-yl]methyl-3,4-dihydro-4- oxopyrimidin-3-yl]acetate Formula (I'): Rx = n-butyl, R2 = methyl, R'3 = CH2C02Et, R4 = n n, n n h Prepared by the procedure of Example 89. Crystals melting at 170-1°C. Example 185: 6-n-Butyl-2,3-dimethyl-5-(2'-cyanobi-30 phenyl-4-y1)methyl-3,4-dihydro-4-oxopyri- midine Formula (XII'): R^ = n-butyl, R2 = methyl, 35 # 23 - 132 - R'3 = methyl, V = jo 05 Prepared by the procedure of Example 126 Oil used as such for the next step. 10 Example 186: 6-n-Butyl-2,3-dimethyl-5-[ 2' - (tetrazol-5-yl)biphenyl-4-yl]methyl-3,4-dihydro-4-oxo-pyrimidine Formula (I' ): Rx = n-butyl, R2 = methyl, 15 R'3 = methyl, R4 = n n H 20 Prepared by the procedure of Example 127. 25 30 Example 187: 6-n-Butyl-2-methy1-3-(2-chlorobenzy1)-5-(2' -cyanobiphenyl-4-yl )methyl-3,4-dihydro 4-oxopyrimidine Formula (XII'): R1 = n-butyl, Ra = methyl, r'a V = 35 23 8 7 9 - 133 - Prepared by the procedure of Example 88. Oil used as such for the next step. Example 188: 6-n-Butyl-2-methy1-3-(2-chlorobenzyl)-5-05 [2'-(tetrazol-5-yl)biphenyl-4-yl]methyl- 3,4-dihydro-4-oxopyrimidine Formula (I'): R1 = n-butyl, R2 = methyl, 10 cl v R'3 = ch rO"'" 15 Prepared by the procedure of Example 89, Example 189: 6-n-Butyl-2-methyl-5-(2'-cyanobiphenyl-4-yl )methyl-4-oxo-3,4-dihydro-3- (2-acetoxy-20 ethyl)pyrimidine Formula (XII'): Rx = n-butyl, R2 = methyl, R'3 = CH2CH20C0CH3, 25 V = 30 Prepared by the procedure of Example 88. Crystals melting at 107°C. 35 # 23 8 7 8 - 134 - Example 190: 6-n-Butyl-2-methyl-5-[ 2' - (tetrazol-5-yl) ■ biphenyl-4-yl]methyl-3,4-dihydro-4-oxo-3-(2-acetoxyethyl)pyrimidine 05 Formula (I'): Rx = n-butyl, R^, = methyl, R' 3 = CH2CH20C0CH3, 10 15 20 Prepared by the procedure of Example 89. Example 191: 3-[6-n-Butyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methylpyrimidin-4-yl]oxypropyl acetate Formula (XII): Rx = n-butyl, R2 = methyl, X = 0, R3 = CH2CH2CH20C0CH3, V = 25 30 Prepared by the procedure of Example 88 (eluent: 5/5 ethyl acetate/cyclohexane). Oil used as such for the next step. 35 2387 85 135 Example 192: 6-n-Butyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methyl-3,4-dihydro-4-oxo-3-(3-acetoxypropyl )pyrimidine Prepared by the procedure of Example 88 (eluent: 7/3 ethyl acetate/cyclohexane). Crystals melting at 108°C. Example 193: 6-n-Butyl-2-methyl-5-[ 2' - (tetrazol-5-yl)-biphenyl-4-yl]methyl-3,4-dihydro-4-oxo-3-(3-acetoxypropyl)pyrimidine Formula (XII'): RA = n-butyl, R2 = methyl, R'3 = CH2CH2CH20C0CH3, Formula (I'): Rj^ = n-butyl, R2 = methyl R'3 = CH2CH2CH2OCOCH3, Prepared by the procedure of Example 89. I 238785 - 136 - Example 194: 3-[6-n-Butyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidin-4-yl]-oxypropyl acetate 05 Formula (I): Rx = n-butyl, R2 = methyl, x = o, r3 = ch2ch2ch2ococh3 , 10 Prepared by the procedure of Example 89. 15 Example 195: 3-[6-n-Butyl-2-methyl-5-[2/-(tetrazol-5- yl )biphenyl-4-yl ]methyl-3,4-dihydro~4-oxo-pyrimidin-3-yl]propanol Formula (I' ): rx = n-butyl, r2 = methyl, 20 r'3 = ch2ch2ch20h, 25 R. = Prepared by the procedure of Example 142, Crystals melting at 181-2°C. 30 Example 196: 2-[6-n-Butyl-2-methyl-5-[2'-(tetrazol-5- yl)biphenyl-4-yl]methylpyrimidin-4-yl]-oxyethanol 35 Formula (I): rx = n-butyl, r2 = methyl, x = o, r3 = ch2ch2oh, * 23 87 8 5 - 137 - 05 Prepared by the procedure of Example 142. Crystals melting at 173-4°C. 10 Example 197: 2-[6-n-Butyl-2-methyl-5—[2'-(tetrazol-5- yl)biphenyl-4-yl]methyl-3,4-dihydro-4-oxo-pyrimidin-3-yl]ethanol 15 20 Formula (I'): Rx = n-butyl, R2 - methyl, R'3 = CH2CH20H, Prepared by the procedure of Example 142. Crystals melting at 195-6°C. 25 Example 198: 6-n-Propyl-2-mercapto-4-hydroxy-5-(2'- cyanobiphenyl-4-yl Jmethylpyrimidine 30 Formula (XI): Rx = n-propyl, R2 = SH, T = OH, V = 35 Prepared by the procedure of Example 133 Crystals melting at 191°C. 2387 - 138 - The following products may be prepared by the procedures described above: - 6-n-Propy1-2,4-dihydroxy-5-[2'-(tetrazol-5-yl)bi-phenyl-4-yljmethylpyrimidine - 6-n-Butyl-2,4-dihydroxy-5-[ 2' - (tetrazol-5-ylJbi-phenyl-4-yljmethylpyrimidine - 6-n-Propyl-2,4-dichloro-5-(2'-carboxybiphenyl-4-yl)-methylpyrimidine - 6-n-Butyl-2,4-dichloro-5-(2'-carboxybiphenyl-4-yl)-methylpyrimidine - 6-n-Propyl-2-chloro-4-methoxy-5-(2'-carboxybiphenyl-4-ylJmethylpyrimidine - 6-n-Butyl-2-chloro-4-methoxy-5-(2'-carboxybiphenyl-4-y1)methylpyrimidine - 6-n-Propyl-2-chloro-4-hydroxy-5-(2'-carboxybipheny1-4-ylJmethylpyrimidine - 6-n-Butyl-2-chloro-4-hydroxy-5-(2'-carboxybiphenyl-4-ylJmethylpyrimidine - 6-n-Propyl-2,4-dimethoxy-5-(2'-carboxybiphenyl-4-yl)-methylpyrimidine - 6-n-Butyl-2,4-dimethoxy-5-(2'-carboxybiphenyl-4-yl)-methylpyrimidine - 6-n-Propyl-2,4-dihydroxy-5-(2'-carboxybiphenyl-4-yl)-methylpyrimidine - 6-n-Butyl-2,4-dihydroxy-5-(2'-carboxybiphenyl-4-yl)-methylpyrimidine - 6-n-Propyl-2,4-dimethoxy-5-[2'-(tetrazol-5-yl)bi-phenyl-4-yljmethylpyrimidine - 6-n-Butyl-2,4-dimethoxy-5-[2'-(tetrazol-5-yl)bi-phenyl-4-yljmethylpyrimidine - 6-n-Propyl-2-mercapto-4-hydroxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yljmethylpyrimidine - 6-n-Butyl-2-mercapto-4-hydroxy-5-[2/-(tetrazol-5~ yl)biphenyl-4-yljmethylpyrimidine 2387 85 - 139 - - 6-n-Propy1-2-methylthio-4-hydroxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yl Jmethylpyrimidine - 6-n-Butyl-2-methylthio-4-hydroxy-5-[2'-(tetrazol-S-yl )bipheny1-4-y1]methylpyrimidine - 6-n-Propy1-2-methylthio-4-methoxy-5-[2'-(tetrazol-5-yl)biphenyl-4-ylJmethylpyrimidine - 6-n-Butyl-2-methylthio-4-methoxy-5-[2'-(tetrazol-S-yl )bipheny1-4-yl]methylpyrimidine - 6-n-Propyl-2-methyl-3-phenyl-3,4-dihydro-4-oxo-5-[2 (tetrazol-5-yl)biphenyl-4-ylJmethylpyrimidine - 6-n-Butyl-2-methyl-3-phenyl-3,4-dihydro-4-oxo-5-[2'-(tetrazol-5-yl)biphenyl-4-ylJmethylpyrimidine - 6-n-Propyl-2-methyl-3-(2-chlorophenyl)-3,4-dihydro-4-oxo-5-[2'-(tetrazol-5-yl)biphenyl-4-ylJmethylpyrimidine - 6-n-Butyl-2-methyl-3-(2-chlorophenyl)-3,4-dihydro-4-oxo-5-[2'-(tetrazol-5-yl)biphenyl-4-ylJmethylpyrimidine - 6-n-Propyl-2-methyl-4-methoxymethyl-5-[2'-(tetrazol-S-yl )biphenyl-4-y1J methylpyrimidine - 6-n-Butyl-2-methyl-4-methoxymethyl-5-[2'-(tetrazol-S-yl )biphenyl-4-ylJ methylpyrimidine - 6-n-Propyl-2-methyl-4-hydroxymethyl-5-[2'-(tetrazol-S-yl )biphenyl-4-ylJ methylpyrimidine - 6-n-Butyl-2-methyl-4-hydroxymethyl-5-[2'-(tetrazol-S-yl )biphenyl-4-yl Jmethylpyrimidine - 6-n-Propyl-4-hydroxymethy1-5-[2'-(tetrazol-5-yl)bi-phenyl-4-ylJmethylpyrimidine - 6-n-Butyl-4-hydroxymethyl-5-[2'-(tetrazol-5-yl bipheny 1-4-y 1 Jmethylpyrimidine - 6-n-Propyl-4-methoxymethyl-5-[2'-(tetrazol-5-yl)bi-phenyl-4-ylJmethylpyrimidine - 6-n-Butyl-4-methoxymethyl-5-[2'-(tetrazol-5-yl)bi-phenyl-4-ylJmethylpyrimidine - 6-n-Propyl-2-methyl-4-carboxy-5-[2'-(tetrazol-5-yl)-biphenyl-4-ylJmethylpyrimidine - 6-n-Butyl-2-methyl-4-carboxy-5-[2'-(tetrazol-5-yl)- $ 238785 - 140 - biphenyl-4-yljmethylpyrimidine - 6-n-Propyl-4-carboxy-5-[ 2' - (tetrazol-5-yl)bipheny1-4-yljmethylpyrimidine - 6-n-Butyl-4-carboxy-5-[2 '-(tetrazol-5-yl)biphenyl-4-05 yljmethylpyrimidine - 6-n-Propyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine-4-carbaldehyde - 6-n-Butyl-2-methyl-5-[2'-(tetrazol-5-yl)bipheny1-4-yl]methylpyrimidine-4-carbaldehyde 10 - 6-n-Propyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-pyrimidine-4-carbaldehyde - 6-n-Butyl-5-[ 2' - (tetrazol-5-y1)biphenyl-4-yl]methyl-pyrimidine-4-carbaldehyde 15 30 35 # 23 8 7 8 5 - 141 -PHARMACOLOGY I. Principle 05 The affinity of the products of the Examples for angiotensin II receptors is evaluated by the technique of displacing a radioligand specifically bound to rat adrenal angiotensin II receptors. 10 II. Procedure An aliquot of a rat adrenal gland honogenate incubates in the presence of a single concentration of [125I]-SIAII (Sar1/Tyr4/Ile8-angiotensin II), which is an 15 angiotensin II receptor antagonist, and two concentrations of competing agents (10"s M, 10-7 M) for 60 min at 25 °C. The reaction is completed by the addition of a buffer, followed by rapid filtration through glasspaper 20 filters. The non-specific binding is determined in the presence of angiotensin II. Ill. Expression of the results 25 The results are expressed, for the concentra tions tested, as the percentage displacement of the radioligand specifically bound to the adrenal angiotensin II receptors. 30 35 # 23 87 8 5 - 142 ~ IV. Results 05 15 20 25 30 Product of % displacement of the labeled ligand 1E-7M 1E-5M Example 13 64 96 Example 14 38 81 Example 16 31 65 Example 24 62 93 Example 27 20 76 Example 31 51 71 Example 32 67 94 Example 33 62 69 Example 54 65 84 Example 55 60 86 Example 56 59 86 Example 57 69 80 Example 58 53 78 Example 59 57 89 Example 61 63 96 Example 75 0 72 Example 76 37 93 Example 77 4 63 Example 78 41 74 35 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 238 7 - 143 -TOXICOLOGY The products of the Examples described have an excellent tolerance after oral administration. 05 Their 50% lethal dose in rats was found to be greater than 300 mg/kg. CONCLUSION 10 The products of the Examples described have a good affinity for angiotensin II receptors. In this respect, they may be used beneficially for the various pathological conditions in which angiotensin II is involved, in particular for the treatment of arterial 15 hypertension and cardiac insufficiency, in dosages of 1 to 400 mg by oral administration and 0.01 to 50 mg by intravenous administration, in one or more dosage units per day. 20 25 30 35 # 23 8 7 8 5 - 144 - gwer js jg: WHAT VWE CLAIM IS

1. Pyrimidine derivatives of general formula (I) or (I'): I2 . n^N'r 3 XT r4 Formula (I) Formula (I') in which, in formula (I), Rx is a lower alkyl radical having 1 to 6 carbon atoms or a lower alkenyl radical having 2 to 6 carbon atoms; R2 is the hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a lower halogenoalkyl radical having 1 to 6 carbon atoms, a C3-C7 cycloalkyl radical, a group OH, SH or NH2, a group OR5, SRs or NHRS, Rs being a lower alkyl radical having 1 to 6 carbon atoms, a lower halogenoalkyl radical having 1 to 6 carbon atoms or a C3-C7 cycloalkyl radical, or a group NHC0R6, R6 being defined in the same way as Rs except that it can also be an aromatic ring, a substituted or unsubstituted methanebiphenyl or a heterocycle; R2 can also be an aromatic ring or a heterocycle; X can be a bond, an oxygen or sulfur atom, a radical NH or a halogen; R3 will be absent when X is a halogen, or can 145 be a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a C3-C_ cycloalkyl radical or else a group -(CH2)n-CN, a group -(CH2)n-COOR?, a group or a group -(CH2)s-SR7, n being an integer from 0 to 5/ s being an integer from 1 to 5 when X is other than a bond, or from 0 to 5 where X represents a bond, and R_, being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms; R^ can also be a group -(CH2)p-CONRgRg or -(CH2)t~NRgRg, p being an integer from 0 to 5, t being an integer from 1 to 5 where X is other than a bond, or from 0 to 5 where X represents a bond and Rg ana Rg independently being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, or it being possible for Rs and R9 to form, together with the nitrogen atom to which they are attached, a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine, a phthalimide or a piperazine which can be substituted by a lower alkyl, an aromatic ring or a heterocycle; R3 can also be a group -(CH2)q-NH-(CH2)r-COOR10, -(CHa )q-NH-CO-NHR11 or ~^CH2) -NH-CS-NH-R,,, q being an integer from 1 to 5, where X is other than a bond, or from 0 to 5 where X represents a bond, r being an integer from 0 to 5 and D 10 and R^^ independently being a lower alkyl radical having 1 to 6 carbon atoms, it also being possible for RX1 to be an aromatic ring, a heterocycle or else a group -(CH2)n-COOR7, n and R7 being as defined above; R3 can also be the group S03H, one of its esters "(0^2) - OR-,, a group d -(ch 1 -ph-ch a group -(CH2)g-0-C0R7 , a group 2387 85 - 146 - or one of its amides; R3 can also be an amino acid group NH2 "(CH2)rf Ch " COOR7 or one of its amides NH-CORe -(CH2)n-CH COOR7 n, R6 and R7 being as defined above; finally, R3 can be a radical -(CH2)n-aromatic ring or -(CH2)n-heterocycle, n being as defined above; and R4 can be a nitro or amino group or a group -C00R12, R12 being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms or a benzyl; R4 can also be the following radicals: - 147 - 23 8 7 \ V\ s s s a i-r N3 N N in which R12 is as defined above and Y and Z can independently be a hydrogen atom, a lower alkyl radical, a halogen atom, a lower alkoxy radical or a trifluoro-methyl radical; and in formula (I'), Rlf R2 and R4 are as defined in formula (I), R'3 is defined in the same way as R3 except that, unlike the latter, it may not be a group S03H, one of its esters or one of its amides and that also, in the case of R'3, the number q may not be less than 2, the numbers p and t may not be equal to 0 and the numbers n and s may not be equal to 0, except in the case of R1^ representing a group - (CF^ ) ^COOR^ , -(CH_) -aromatic ring or -(CH, ) -heterocycle where n 2 n ^ n may be equal to 0, — — it being possible for the afore-mentio'ned derivatives to take the form of addition salts, in particular pharmaceutically acceptable addition salts.

2. Derivatives according to claim 1 wherein, in general formulae (I) and (I'): Rx is a lower alkyl radical having l to 6 carbon atoms, preferably n-propyl or n-butyl; R2 is the hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, preferably methyl or isopropyl, a group OH, SH or NH2, a group 0R5 or SRs, Rs being a lower alkyl radical having 1 to 6 carbon atoms, preferably methyl, or an aromatic ring; X is a bond, an oxygen atom, a sulfur atom, a radical NH or a halogen; R3 will be absent when X is a halogen, or can be a hydrogen atom, a lower alkyl radical having 1 to 6 238*785 - 148 - carbon atoms, preferably methyl or isopropyl, a group -(CH2)n-C00R7, a group -(CH2) -0R7/ a group -(CHJ O-COR,, s a group -(CH2) -SR7, a group s -(CH,) -CH-CH v 2' n J I 2 n being an integer from 0 to 5, preferably from 0 to 3, s being an integer from 1 to 5/ preferably 1 to 3, where X is other than a bond, or from 0 to 5, preferably 0 to 3, where X represents a bond, and being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, preferably methyl or ethyl; R^ can also be a group -(CH2)^-CONRgRg or - (CH2)t~NR8R9' p being an integer from 0 to 5, preferably from 0 to 2, t being an integer from 1 to 5, preferably 1 or 2, where X is other than a bond, or from 0 to 5, preferably 0 to 2, where X represents a bond, and Rg and R0, which are identical or different, being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, preferably methyl, or it being possible for R0 and R9 to form, together with the nitrogen atom to which they are attached, a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine, a phthalimide or a piperazine which can be substituted by an aromatic ring, or a radical -(CH2)n-aromatic ring, n being as defined above; and R4 is a group selected from the following radicals : 2387 85 149 s R12 being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms and Y and Z independently being a hydrogen atom, a lower alkyl radical or a halogen atom.

3. Pyrimidine derivatives of general formula (I7): in which: Rx is a lower alkyl radical having 1 to 6 carbon atoms or a lower alkenyl radical having 2 to 6 carbon atoms; lower alkyl radical having 1 to 6 carbon atoms, a lower halogenoalkyl radical having 1 to 6 carbon atoms, a group 0RS, SRs or NHRS, Rs being a lower alkyl radical having 1 to 6 carbon atoms or a C3-C7 cycloalkyl radical, or a group NHC0R6, R6 being defined in the same way as Rs except that it can also be an aromatic ring, a substituted or unsubstituted methanebiphenyl or R 4 Formula (I') R2 is the hydrogen atom, a halogen atom, a - 150 - t c r-»n also be an aromatic ring or a a heterocycle; R2 can aiso oe heterocycle; , R< can be a lower alkyl radical havmg 1 to 6 .3 r -r cvcloalkyl radical, a group carbon atoms, a C3-C7 cycioax^y -(CH,)„-CN, a group -CCH,)„-COOR„ a group -<CH,)s-0K,, group ~ (ch2) n-ch-^h2 X a group -(cha)s-o-COR„, a group or a group -(Cf^) -SR^, it being possible for n to be an integer from 0 to 5, s being an integer from 1 to 5/ where X is other than a bond, or from 0 to 5 where X represents a bone1, and being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms; R'3 can also be a group -(CH2)p-C0NR8R9 or - (CH2) p-NReR9, p being an integer from 1 to 5 and R8 and R9 independently being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, or it being possible for Ra and R9 to form, with the nitrogen atom to which they are attached, a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine, a phthalimide or a piperazine which can be substituted by a lower alkyl, an aromatic ring or a heterocycle; R'a can also be a group - (CH2 )q-NH-(CH2 )r-COOR10, -(CH2)tJ-NHC0NHR11 or -(CH2)q-NH-CSNHRi:i, q being an integer from 2 to 5, r being an integer from 0 to 5 and R10 and Rlx independently being a lower alkyl radical having 1 to 6 carbon atoms, it also being possible for R,, to be an aromatic * • ' Ji it ■[ 238785 - 151 - ring, a heterocycle or else a group -(CH2)n-COOR7, n and R, being as defined above; R'3 can also be an amino acid NH2 i -(CH2)n - CH \ COOR7 or one of its amides NH-CORe ■(CH2)n - CH x COORy n, R6 and R7 being as defined above; finally, R'3 can be a radical -(CH2)n-aromatic ring or -(CH2)n-heterocycle, n being as defined above; and R4 can be a nitro or amino group or a group -C00R12, R12 being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms or a benzyl; R4 can also be the following radicals: » - 152 - 23 87 8 5 -NH-CO h03s r12ooc -nh-co. ' cf3so2nh- nc o i ■i1 -nh r1200c V\ J* n' in which R12 is as defined above and Y and Z can independently be a hydrogen atom, a lower alkyl radical, a halogen atom, a lower alkoxy radical or a trifluoro-methyl radical, as well as their addition salts, in particular the pharmaceutically acceptable addition salts.

4. Pyrimidine derivatives according to claim 1 or 2 of general formula (I"): in which RA, R2, X and R3 are as defined above, as well as their addition salts, in particular the pharmaceutically acceptable addition salts. 23 8 7 8 153

5. Pyrimidine derivatives according to claim 1 or 2, of general formula (I'"): in which Rx, R2 and R4 are as defined above, as well as their addition salts, in particular the pharmaceutically acceptable addition salts.

6. Derivatives according to claims 1 to 5 wherein Rj is a group selected from n-propyl and n-butyl.

7. Derivatives according to claims 1 to 6 wherein R2 is selected from a methyl group or the hydrogen atom.

8. Derivatives according to claims 1 to 6 wherein R2 is a methylthio group.

9. Derivatives according to claims 1, 2, 3 or 6 to 8 wherein R^ is selected from an ethoxycarbonylmethyl group, a 2-hydroxyethyl group, a methyl group and the hydrogen atom.

10. Derivatives according to claims 1, 2, 3 and 6 to 8 wherein R'3 is selected from an ethoxycarbonylmethyl group, a 2-hydroxyethyl group and a methyl group.

11. Derivatives according to any one of claims 1, 2, 3 or 5 to 10 wherein R4 is selected from a 2-sulfoxy-benzoylamino group, a 2-carboxyphenyl group and a 2-(tetrazol-5-yl)phenyl group.

12. Derivatives according to any one of claims 1 or 5 to 9 or 11 which are selected from the derivatives of the formulae 23 8 7 8 5 - 154 - xooc2h5 HN^ oh 2 3 8 7 8 5 - 155 - o cooc2h5 hn-n* ch, I- n'^n ,0h CH,, X n^n 238785 - 156 - HrSf SCH, S03H 2337 85 - 157 - n^n OCH, HN-N" CH, N^N 23 8 7 - 158 -

13. Derivatives according to any one of claims 1, 2, 3 or 6 to 8 or 10 and 11 which are selected from the derivatives having the following structures: CH, N ^ N COOC2H5 HN-N" HN-N* hn-rf 2387 - 159 -

14. Methods of preparing the compounds of formulae (I) and (I7) according to any one of claims 1 to 13, wherein the pyrimidine ring is prepared by reacting a urea, a thiourea, an amidine or a guanidine with 1,3-keto-esters, 1,3-ketonitriles or 1,3-diketones of the formulae COOR 13 CN Formula (VI) o fV 1 I Formula (VII) o o (CH2)— U-Ru Formula (VIII) - 160 - Rt being as defined above, R13 being a lower alkyl radical, preferably methyl or ethyl, s being an integer from 1 to 5, it being possible for U to be an oxygen or sulfur atom or a methylene, R14 being a hydrogen atom or a lower alkyl, preferably methyl or ethyl, and V being a functional group making it possible, in the manner described, to obtain the groups R4 as defined above, in an alcohol, in the presence of a sodium or potassium alcoholate or of a base such as sodium hydroxide or potassium hydroxide, at a temperature which can range from room temperature to the reflux temperature of the solvent.

15. Methods of preparing the compounds of formula (I) or (I')/ as defined in claim 1, in which R4 is a group Z which comprise reacting an anhydride of the formula o y , ii HN-C or hooc z 15FEB1993 \ - 161 - or of the formula with an amine derivative of the formula or in which Rx, R2, R3 or R'a and X are as defined above and Y and Z are a hydrogen atom, a lower alkyl radical, a halogen atom or an alkoxy radical.

16. Methods of preparing the compounds of formula (I) or (I'), as defined in claim 1, in which is a group Xl H 7* ^5% which comprise reacting a compound of the formula " A- y\ ' ' J"'i ■} 15FEB1993 * 23 8 7 - 162 - r1 R, N N '*3 or in which R,, R2, X and R3 or R'3 are as defined above, with sodium nitride in dimethylformamide, in the presence of an ammonium salt such as ammonium chloride, at a temperature of between 100 and 150°C, or by heating in toluene with trimethyltin nitride, followed by treatment with gaseous hydrogen chloride.

17. A pharmaceutical composition which comprises a pharmaceutically effective amount of at least one compound of formula (I) or (I') as defined in any one of claims 1 to 13, or one of its pharmaceutically acceptable addition salts, which may or may not be incorporated in a pharmaceutically acceptable excipient, vehicle or carrier.

18. A pharmaceutical composition with antagonistic activity towards angiotensin II receptors, which makes it possible to favorably treat cardiovascular diseases, in particular hypertension and cardiac insufficiency, said composition containing a pharmaceutically effective amount of at least one compound of formula (I) or (I') as defined in any one of claims 1 to 13, or one of its pharmaceutically acceptable addition salts, which may or may not be incorporated in a pharmaceutically acceptable excipient, vehicle or carrier.

19. A method of preparing a pharmaceutical composition, 23 8 7 163 which comprises incorporating a pharmaceutically effective amount of at least one compound of formula (I) or (I') as defined in any one of claims 1 to 13, or one of its pharmaceutically acceptable addition salts, into a pharmaceutically acceptable excipient, vehicle or carrier.

20. A method according to claim 19 wherein the pharmaceutical composition is formulated as gelatin capsules or tablets containing from 1 to 400 mg of active ingredient, or as injectable preparations containing from 0.01 to 50 mg of active ingredient.

21. A compound as claimed in claim 1 specifically set forth herein.

22. A process for producing a compound as claimed in claim 1 substantially as herein described with reference to any one of the Examples. laboratoires upsa j-i A'wlhuoi Pj By Their Attorneys iJ BALDWIN SON & CAREY </div>