BE1005473A3 - Heterocyclic derivatives. - Google Patents

Abstract

The invention relates to pharmaceutically useful compounds of formula I where R1, R2, R3, R4 and A1 have the different meanings specified, as well as their non-toxic salts, and the pharmaceutical compositions containing them. The new compounds are valuable for the treatment of conditions such as hypertension and congestive heart failure. The invention also relates to the methods for preparing the new compounds and to the use thereof in medical treatments.

Description

       

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  Heterocyclic derivatives.



   The present invention relates to new heterocyclic derivatives, more particularly new pyrimidine derivatives which have useful pharmacological properties by at least partially antagonizing one or more of the actions of the substances known as angiotensins, in particular that known under the name of angiotensin II (hereinafter called garlic). The invention also relates to the pharmaceutical compositions of the new compounds for use in the treatment of diseases or medical conditions such as hypertension, congestive heart failure and / or hyperaldosteronism in warm-blooded animals (including the human), as in other diseases or medical conditions where the renin-angiotensin-aldosterone system has a significant causal role.

   The subject of the invention is also methods for the preparation of the new compounds, as well as their use in the treatment of one of the abovementioned medical diseases or conditions, as well as for the production of new pharmaceutical agents for use in these medical treatments .



   Angiotensins are the key mediators of the renin-angiotensin-aldosterone system which is involved in the maintenance of homeostasis and fluid-electrolyte balance in many warm-blooded animals, including humans. Angiotensin known as AII is produced by the action of the angiotensin converting enzyme (ACE) on angiotensin I, itself produced by the action of the enzyme renin on angiotensinogen, which is a protein from the blood plasma.



  IIA is a potent spasmogen specially for the vascular system and is known to increase vascular resistance and blood pressure. In addition, angiotensins are known to stimulate the release of aldosterone and thus lead to vascular congestion and hypertension by sodium and fluid retention mechanisms. So far, from

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 vascular and hypertension by sodium and fluid retention mechanisms.

   Up to now, many different approaches have been considered for a pharmacological intervention in the reningiotensin-aldosterone system with a view to therapeutic control of blood pressure and / or of the liquid-electrolyte balance, in particular by inhibiting the actions renin or ACE. However, there is a persistent need for a different approach due to the side effects and / or idiosyncratic reactions associated with any particular therapeutic approach.



   Certain pyrimidines having an IIA antagonist activity are described in the published European patent applications EPA 424 317 and EPA 465 323 and in the published international patent application WO 91/15209.



  EPA 475,206 and U.S. Patent 5,149,699 (both issued after the priority date of the present invention) respectively describe certain pyrimidines and
 EMI2.1
 pyridopyrimidines with IIA antagonist activity. EPA document 475 206 describes 4- [N-butyl-N- (2'- (1Htetrazol-5-yl) biphenyl-4-ylmethyl) amino] -2, 6-dimethylpyrimidine.



   The Applicant has now surprisingly discovered that the compounds of the invention (see below) antagonize one or more of the actions of the substances called angiotensins (and in particular of IIA) and therefore minimize the physiological effects associated with their presence in warm-blooded animals (including humans) and this constitutes the basis of the invention.



   The subject of the invention is a pyrimidine derivative of formula I (see below, together with the other chemical formulas identified by Roman numerals) where R is hydrogen, (1-8C) alkyl, (3-8C) cycloalkyl ), phenyl or substituted (1-4C) alkyl, the latter containing one or more fluoro substituents or carrying a substituent

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 (3-8C) cycloalkyl, (1-4C) alkoxy or phenyl;

   R2 is chosen from (1-8C) alkyl, (3-8C) cycloalkyl, phenyl or (1-4C) substituted alkyl, the latter containing one or more fluoro substituents or carrying a (3-8C) cycloalkyl substituent, (1- 4C) alkoxy or phenyl, halo, (1-4C) alkoxy, amino and alkylamino and dialkoylamino of up to 6 carbon atoms;

     R3 is chosen from hydrogen, (1-8C) alkyl, (3-8C) cycloalkyl, (1-4C) substituted alkyl carrying a substituent
 EMI3.1
 (3-8C) cycloalkyl, amino, hydroxy, (1-4C) alkoxy, carboxy or (1-4C) alkoxycarbonyl or containing one or more substituents fluoro, hydroxy (1-4C) alkoxy, carboxy, (1-4C) alkoxycarbonyl , (3-6C) alkenyloxycarbonyl, cyano, nitro, carbamoyl, (1-4C) alkanoyl, N-alkylcarbamoyl and di- (N-alkyl) carbamoyl of up to 7 carbon atoms, halogeno, amino, alkylamino and dialkoylamino de up to 6 carbon atoms, (1-4C) alkylamino, phenyl, phenyl- (1-4C) alkyl and benzoyl,

   the benzene ring of the last three radicals optionally carrying one or two substituents chosen from (1-4C) alkyl, (1-4C) alkoxy, halo, cyano, trifluoromethyl, nitro, hydroxy, carboxy, (1-4C) alkanoylamino, (1 -4C) alkanoyl, fluoro (1-4C) alkoxy, hydroxy (1-4C) alkyl, (1-4C) alkoxy (1-4C) alkyl, carbamoyl, alkyl- or dialkoylcarbamoyl of up to 7 carbon atoms, sulfamoyl , N-alkyl-or di- (N-alkyl) sulfamoyl of up to 6 carbon atoms, (1-4C) alkoxycarbonyl, (1-4C) alkanesulfonamido, (1-4C) alkyl.

   S (0) n- [where n is zero, 1 or 2], 1H-tetrazol-5-yl, phenyl, phenoxy, benzyloxy, benzyloxycarbonyl, benzamido and benzenesulfonamido, the benzene part of the last six radicals optionally carrying a halogen substituent, (1-4C) alkyl or (1-4C) alkoxy; R4 is hydrogen or (1-4C) alkyl; or R2 and R3 together complete a benzene ring, this benzene ring optionally carrying one or two substituents chosen independently from any meanings

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 previously defined for R3; or R2 and R3 together form a (3-6C) alkenylene radical, a (3-6C) alkylene radical or a (3-6C) alkylene radical in which a methylene is replaced by carbonyl;

   
 EMI4.1
 or R3 and R4 together form a bonding radical A which is chosen from-CH-CH -, - CH-CH-CH -, - CO-CH -, - CH-CO-, - CO-CH-CH -, - CH-CH-CO -, - CO-CH = CH-and-CH-CH-CO-, and in which this linking radical optionally carries one or two substituents chosen independently from (1-4C) alkyl, (1-4C ) substituted alkyl containing one or more fluoro substituents or carrying a (3-8C) cycloalkyl, (1-4C) alkoxy or phenyl, (3-8C) cycloalkyl, (1-4C) alkoxy, halo, carboxy, (1- 4C) alkoxycarbonyl, (3-6C) alkenyloxycarbonyl, cyano, nitro, (1-4C) alkanoyl, (1-4C) alkyl.

   S (0) m- [where m is zero, 1 or 2] and phenylsulfonyl; A1 is a radical of the partial formula IIa, IIb or IIc where (1) in the partial formula IIa, B1 is a direct bond or is phenylene optionally carrying a substituent chosen from (1-4C) alkyl, (1-4C) alkoxy , halo, (1-4C) alkanoyl, trifluoromethyl, cyano and nitro; Ra is hydrogen, (1-4C) alkyl, (1-4C) alkoxy, halo, cyano, trifluoromethyl or nitro; and Za is 1H-tetrazol-5-yl, a carboxy radical or an ester thereof hydrolyzable in vivo, -CO. NH. (1H-tetrazol-5-yl), or a radical of formula -CO. NH.

   CO2R8 where R8 is (1-6C) alkyl, (3-8C) cycloalkyl, trifluoromethyl or phenyl; (2) in the partial formula IIb, B2 is oxygen, sulfur or
 EMI4.2
 a radical of formula-NR-where R is hydrogen or (1-4C) alkyl; Zb has any of the meanings defined above for Za; B3 is phenyl optionally carrying one or two substituents independently selected from (1-4C) alkyl, (1-4C) alkoxy and halo; and Rb and Rc are independently selected from hydrogen, (1-4C) alkyl, (1-4C) alkoxy and halo; and (3) in the partial formula IIc, Zc- is 1H-tetrazol-5-yl,

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 carboxy or an ester thereof hydrolyzable in vivo or a radical of formula CFSONH-;

   Rdis selected from hydrogen, (1-4C) alkyl, (1-4C) alkoxy, halo, trifluoromethyl, cyano and nitro; Xi is oxygen, sulfur or a radical of formula-NR-whereR is hydrogen or (1-4C) alkyl; and X2 is nitrogen or a radical of formula-C (R /) = where R7 is hydrogen, (1-4C) alkyl optionally containing one or more substituents fluoro, carbamoyl or N-alkyl-or di- (N-alkyl) carbamoyl of up to 7 carbon atoms, halo, cyano, (1-4C) alkoxycarbonyl or (1-4C) alkanoyl;

   and in which any of the phenyl parts of R1, R2 or R8 or of an optional substituent of the linking radical A can be unsubstituted or carries one or two substituents chosen independently from (1-4C) alkyl, (1- 4C) alkoxy, halogeno, cyano and trifluoromethyl; or a non-toxic salt thereof; but excluding 4- [N-butyl-N- (2'- (1H-tetrazol-5yl) biphenyl-4-ylmethyl) amino-2,6-dimethylpyrimidine.



   It should be noted that, depending on the nature of the substituents, some of the compounds of formula I can comprise one or more chiral centers and can be isolated in one or more racemic or optically active forms. It should be understood that the present invention relates to any form of such a compound of formula I which has the above-mentioned useful pharmacological properties, since it is well known to prepare the optically active forms, for example by synthesis from 'appropriate chiral intermediates, and to determine their pharmacological properties, for example using the standard tests described below.



   It should be understood that generic terms such as "alkyl" refer to both straight and branched chain variants when the number of carbon atoms allows. However, when a particular radical, such as "propyl", is indicated, it is specific for the straight chain variant, the branched chain variants, such as

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   "isopropyl" being specifically named where appropriate.



  The same convention applies to other radicals.



   Of particular significance for R 'or R2 when it is alkyl is, for example, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl or hexyl; when cycloalkyl is, for example, cyclopropyl, cyclopentyl or cyclohexyl; when it is alkyl containing one or more fluoro substituents is, for example, fluoromethyl, trifluoromethyl, 2,2, 2-trifluoroethyl or pentafluoroethyl; and when it is alkyl carrying a cycloalkyl substituent, (1-4C) alkoxy or phenyl is, for example, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopentylethyl, 2-methoxyethyl, 2-ethoxyethyl, benzyl, 1-phenylethyl or 2-phenylethyl.



   A particular meaning for R2 when it is halo is, for example, fluoro, chloro, bromo or iodo; when alkoxy is, for example, methoxy, ethoxy; when it is alkylamino or dialkoylamino of up to 6 carbon atoms is, for example, methylamino, ethylamino, butylamino, dimethylamino, diethylamino or dipropylamino.



   Particular meanings for R3 are, for example, for alkyl: methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl or hexyl; for cycloalkyl: cyclopropyl, cyclopentyl or cyclohexyl; for alkyl bearing a cycloalkyl, amino, hydroxy, alkoxy, carboxy or alkoxycarbonyl substituent: cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopentylethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 2-aminoethyl, methyl-2-aminoethyl -ethoxyetyl, carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, 2-methoxycarbonylethyl or 2-ethoxycarbonylethyl;

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 for alkyl containing one or more fluoro substituents:

   fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or pentafluoroethyl;
 EMI7.1
 for hydroxyalkoxy: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl or 3-hydroxypropyl; for alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl; for alkenyloxycarbonyl: allyloxycarbonyl; 2-methyl-2-
 EMI7.2
 propenyloxycarbonyl or 3-methyl-3-butenyloxycarbonyl; for alkanoyl: formyl, acetyl or butyryl; for N-alkylcarbamoyl: N-methyl- or N-ethylcarbamoyl; for di (N-alkyl) carbamoyl:

   N, N-dimethylcarbamoyl orN, Ndiethylcarbamoyl; for halo: fluoro, chloro, bromo or iodo; for alkylamino: methylamino, ethylamino or butylamino; for dialkoylamino: dimethylamino, diethylamino or dipropylamino; for alkanoylamino: formamido, acetamido or propanamido; and for phenylalkyl: benzyl, 1-phenylethyl or 2-phenylethyl.



   Of particular significance for R4, R '' or R when it is alkyl is, for example, methyl, ethyl or propyl.



   Special meanings for. an optional substituent on R3 when it is phenyl, phenyl (1-4C) alkyl or benzoyl, or for optional substituents on R2 and R3 when they complete a benzene ring are in particular, for example, for alkyl: methyl and ethyl ; for alkoxy: methoxy and ethoxy; for halo: chloro, bromo and iodo; for alkanoylamino: formamido, acetamido and propanamido; for alkanoyl: formyl, acetyl and butyryl; for fluoroalkoxy: trifluoromethoxy, 2-fluoroethoxy, 2, 2, 2-trifluoroethoxy and 3, 3, 3-trifluoropropoxy;

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 for hydroxyalkyl: hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl; for alkoxyalkyl: 2-methoxyethyl and 2-ethoxyethyl;
 EMI8.1
 for N-alcoylecarbamoyle:

   N-methyl- and N-ethylcarmaboylej pourdi (N-alkyl) carbamoyl: N, N-dimethylcarbamoyl and N, N-diethylcarbamoyl; for N-alkylsulfamoyl: N-methyl- and N-ethylsulfamoyl; pourdi (N-alcoyl) sulfamoyl:

   N, N-dimethylsulfamoyl and N, N-diethylsulfamoyl; for alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; for alkanesulfonamido: methanesulfonamido and ethanesulfonamido;
 EMI8.2
 for alkylthio: methylthio and ethylthio; for alkylsulfinyl: methylsulfinyl and ethylsulfinyl; for alkylsulphonyl: methylsulphonyl and ethylsulphonyl; and for phenyl, phenoxy, benzyloxy, benzyloxycarbonyl, benzamido and benzenesulfonamido optionally carrying a substituent: phenyl, phenoxy, benzyloxy, benzyloxycarbonyl, benzamido and benzenesulfonamido optionally bearing a substituent fluoro, chloro, bromo, methyl, ethyl, methoxy or ethoxy.



   Of particular significance for R2 and R3 when they together form (3-6C) alkylene is, for example, trimethylene, tetramethylene or pentamethylene; when they form together (3-6C) alkenylene is, for example, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene or 3-butenylene; and when they form together (3-6C) alkylene in which one of the methylene radicals is replaced by a carbonyl radical is, for example, 1-oxopropylidene, 3-oxopropylidene, 1-oxobutylidene or 4-oxobutylidene.



   Particular meanings for optional substituents on R3 and R4 when they together form a linking radical A are in particular, for example, for alkyl: methyl and ethyl;

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 for alkyl containing one or more fluoro substituents: fluoromethyl, trifluoromethyl, 2,2, 2-trifluoroethyl and pentafluoroethyl; for alkyl carrying a cycloalkyl substituent, (1-4C) alkoxy or phenyl; cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopentylethyl, 2-methoxyethyl, 2-ethoxyethyl, benzyl, 1-phenylethyl and 2-phenylethyl; for cycloalkyl: cyclopropyl, cyclopentyl and cyclohexyl; for alkoxy: methoxy, ethoxy and propoxy; for halo: fluoro, chloro, bromo and iodo;
 EMI9.1
 for alkoxycarbonyl:

   methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; for alkenyloxycarbonyl: allyloxycarbonyl, 2-methyl-2propenyloxycarbonyl and 3-methyl-3-butenyloxycarbonyl; for alkanoyl formyl, acetyl and butyryl; for alkylthio: methylthio and ethylthio; for alkylsulfinyl: methylsulfinyl and ethylsulfinyl; and for alkylsulfonyl: methylsulfonyl and ethylsulfonyl.



   Of particular significance for Ra, Rb, Rc, Rd or an optional substituent on B when it is phenylene, or one or more optional substituents on B3 when it is alkyl is, for example, methyl or ethyl; when it is alkoxy is, for example, methoxy or ethoxy; and when halo is, for example, fluoro, chloro or bromo.



   Of particular significance for an alkanoyl substituent on B when it is phenylene is, for example, formyl, acetyl or propionyl.



   A particular meaning for Za, Zb or Zc when it is an ester hydrolyzable in vivo is, for example, an ester derived from a (1-6C) alkanol such as methanol or ethanol, phenol, glycerol or similar.



   Special significance for R8 when

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 is alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl or pentyl; and when it is cycloalkyl is, for example, cyclobutyl, cyclopentyl or cyclohexyl.



   Of particular significance for R7 is, for example, for alkyl: methyl and ethyl; for alkyl containing one or more fluoro substituents: fluoromethyl, trifluoromethyl, 2,2, 2-trifluoroethyl and pentafluoroethyl; for N-alkylcarbamoyl: N-methyl- and N-ethylcarbamoyl; for di (N-alkyl) carbamoyl: N, N-dimethylcarbamoyl and N, N-diethylcarbamoyl; for halo: fluoro, chloro, bromo or iodo; for alkoxycarbonyl: methoxycarbonyl or ethoxycarbonyl; and for alkanoyl: formyl, acetyl or propionyl.



   Particular meanings for optional substituents which may be present on phenyl parts of R1, R2 or R8 or on the linking radical A are in particular, for example, for halo: fluoro, chloro and bromo; for alkyl: methyl and ethyl; and for alkoxy: methoxy and ethoxy.



   A preferred meaning for R1 or R2 is, for example, methyl, ethyl or propyl.



   A preferred meaning for R3 is, for example, hydrogen, halo (especially iodo) or phenyl (1-4C) alkyl.



   Meaning for R4 is, for example, hydrogen or methyl.



   A preferred meaning for R2 or R3 when they together form alkylene is, for example, trimethylene or tetramethylene.



   A preferred meaning for R3 and R4
 EMI10.1
 when they form together a bonding radical A is, for example-CH = CH-CO -, - CH-CH-CH-or-CH-CH-CO-.



  A preferred meaning for A1 is, for

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 EMI11.1
 example, a radical of partial formula IIa.



  A preferred meaning for B is, for example, a p-phenylene radical.



   A preferred meaning for Za, Zb or Zc is, for example, carboxy or 1H-tetrazol-S-yl.



   Especially preferred meaning for Za is when attached to the ortho position with respect to B. Za representing 1H-tetrazol-5-yl is particularly preferred.



   A preferred meaning for B2 is, for example, oxygen.



   A particularly preferred combination of meanings is, for example, R and R which are both alkyl.



   A preferred group of compounds of formula I includes the compounds of formula I where Al is a radical of partial formula IIa where Za is 1H-tetrazol-5-yl or carboxy
 EMI11.2
 2 and R \ R2, R3, R4, Ra and Bu have any of the meanings defined above, in addition to their non-toxic salts. Particular preference in this group goes to compounds in which Za is a 1H-tetrazol-5-yl radical, especially when it is attached to the position ortho with respect to B '.



   Particular groups of new compounds of the invention include, for example, the compounds of formula I where:
 EMI11.3
 (1) R3 is halo and RI, R2, R4 and A1 have any of the meanings defined above; (2) R3 is (1-4 C) alkoxycarbonyl and R ', R2, R4 and A 1 have any of the meanings defined above;

   (3) R3 is benzoyl optionally carrying one or two substituents chosen independently from (1-4C) alkyl, (1-4C) alkoxy, halo, cyano, trifluoromethyl ,. nitro, hydroxy, carboxy, (1-4C) alkanoylamino, (1-4C) alkanoyl, fluoro (1-4C) alkoxy, hydroxy (1-4C) alkyl, (1-4C) alkoxy- (1-4C) alkyl, carbamoyl, alkyl-or dialcoylcarbamoyl from

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 up to 7 carbon atoms, sulfamoyl, alkyl- or dialkoylsulfamoyl of up to 6 carbon atoms, (1-4C) alkoxycarbonyl, (1-4C) alkanesulfonamido, (1-4C) alkyl.

   S (0) n - [where n is zero, 1 or 2], IH-tetrazol-5-yl, phenyl, phenoxy, benzyloxy, benzyloxycarbonyl, benzamido and benzenesulfonamido, the benzene part of the last six radicals optionally carrying a substituent
 EMI12.1
 2 halo, (1-4C) alkyl or (1-4C) alkoxy; and R1, R2, R4 and A1 have any of the meanings defined above;

   (4) R3 is phenyl optionally carrying one or two substituents independently chosen from (1-4C) alkyl, (1-4C) alkoxy, halo, cyano, trifluoromethyl, nitro,
 EMI12.2
 hydroxy, carboxy, (1-4C) alkanoylamino, (1-4C) alkanoyl, fluoro (1-4C) alkoxy, hydroxy (1-4C) alkyl, (1-4C) alkoxy- (1-4C) alkyl, carbamoyl, alkyl- or dialkoylcarbamoyl of up to 7 carbon atoms, sulfamoyl, alkyl- or dialkoylsulfamoyl of up to 6 carbon atoms, (1-4C) alkoxycarbonyl, (1-4C) alkanesulfonamido, (1-4C) alkyl.

   S (0) n - [where n is zero, 1 or 2), 1H-tetrazol-5-yl, phenyl, phenoxy, benzyloxy, benzyloxycarbonyl, benzamido and benzenesulfonamido, the benzene part of the last six radicals optionally carrying a halogen substituent, (1-4C) alkyl or (1-4C) alkoxy; and R \ R2, R4 and A1 have any of the meanings defined above; (5) R2 and R3 together form a (3-6C) alkylene radical; and R1, R4 and A1 have any of the meanings defined above; or (6) R3 and R4 together form a bonding radical A as defined above;

   and Ri, R and A1 have any of the meanings defined above.



   Other particular groups of new compounds of the invention include, for example, the compounds of formula I in which: (7) R3 is phenyl (1-4C) alkyl optionally carrying one or two substituents chosen independently from (1-4C) alkyl, (1-4C) alkoxy, halo, cyano, trifluoro-

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 methyl, nitro, hydroxy, carboxy, (1-4C) alkanoylamino, (1-4C) alkanoyl, fluoro (1-4C) alkoxy, hydroxy (1-4C) alkyl, (1-4C) alkoxy (1-4C) alkyl , carbamoyl, alkyl- or dialkoylcarbamoyl of up to 7 carbon atoms,
 EMI13.1
 sulfamoyl, alkyl- or dialkoylsulfamoyl of up to 6 carbon atoms, (1-4C) alkoxycarbonyl, (1-4C) alkane-sulfonamido, (1-4C) alkyl.

   S (0) n [where n is zero, 1 or 2), 1H-tetrazol-5-yl, phenyl, phenoxy, benzyloxy, benzyloxycarbonyl, benzamido and benzenesulfonamido, the benzene part of the last six radicals optionally carrying a halogen substituent, ( 1-4C) alkyl or (1-4C) alkoxy; and R \ R2, R4 and A ′ have any one of the meanings defined above; or (8) R3 and R4 together form a bonding radical -CH-CH- or -CH2-CH2-CH2- (the latter of which is of particular interest); and R ', R2 and A have any of the meanings defined above.



   Compounds of the invention which are of particular interest are in particular, for example, the specific compounds indicated below in the examples, in particular the compounds of Examples 1,3, 4,6, 7, 8, 9 and 10. These compounds and their non-toxic salts constitute another object of the invention.



   Although all the compounds of formula I can form salts with suitable acids, it should be observed that the compounds of formula l or Za, Zb or Zc is other than an ester radical or else where R3 or the linking radical A carries a carboxy radical can form salts with bases and also with acids.

   Particularly suitable non-toxic salts of these compounds are therefore in particular, for example, the salts formed with bases providing physiologically acceptable cations, for example the alkali metal (for example sodium and potassium), alkali metal salts earthy (e.g. magnesium and calcium), aluminum and ammonium, as well as organic base salts

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 suitable, for example ethanolamine, methylamine, diethylamine or triethylamine, in addition to the acid salts providing physiologically acceptable anions, for example the salts of mineral acids such as the salts of hydrogen halides (such as chloride d 'hydrogen and hydrogen bromide), sulfuric or phosphoric acid and strong organic acids,

   such as p-toluenesulfonic acid and methanesulfonic acid.



   The compounds of formula I can be obtained according to the common methods of organic chemistry well known in the art for the preparation of compounds of an analogous structure. These methods constitute another object of the present invention and are in particular, for example, the following methods in which the generic radicals have any of the meanings assigned above, unless otherwise indicated.

   a) For the compounds in which A is a radical of the partial formula IIa, IIb or IIc where Za, Zb and Zc respectively are carboxy, a carboxylic acid derivative of formula IIIa, IIIb or IIIc, where Qa, Qb and Qc respectively are protected carboxy radicals chosen from (1-6C) alkoxycarbonyl (especially methoxy-, ethoxy-, propoxy- or t-butoxy-carbonyl), phenoxycarbonyl, benzyloxycarbonyl and carbamoyl, is converted to carboxy.



   The conversion can be carried out, for example by hydrolysis, advantageously in the presence of an appropriate base, such as an alkali metal hydroxide, for example lithium, sodium or potassium hydroxide. The hydrolysis is generally carried out in the presence of an appropriate aqueous solvent or diluent, for example in an (1-4C) aqueous alkanol, such as methanol or aqueous ethanol. However, it can also be carried out in a mixture of an aqueous solvent and a non-aqueous solvent, such as water and toluene in the presence of a conventional quaternary ammonium derivative which is a phase transfer catalyst. Hydrolysis is generally carried out at an interval temperature, for

  <Desc / Clms Page number 15>

 example, from 0 to 120 C, depending on the reactivity of the radical Qa, Qb or Qc.

   In general, when Qa, Qb or Qc is carbamoyl, temperatures in the range, for example, from 40 to 1200C are necessary to operate the hydrolysis.



   Alternatively, when Qa, Qb or Qc is benzyloxycarbonyl, the conversion can also be carried out by hydrogenolysis, for example by means of hydrogen at 1 to 3 bars in the presence of a suitable catalyst, such as palladium on carbon or on sulphate of calcium, in a suitable solvent or diluent, such as a (1-4C) alkanol (typically ethanol or 2-propanol) and at a temperature in the range, for example, 0 to 40 C.



   Furthermore, when Qa, Qb or Qc is t-butoxycarbonyl, the conversion can also be carried out by hydrolysis at an interval temperature, for example, from 0 to 100 C, in the presence of a strong catalytic acid, such as l trifluoroacetic acid. The hydrolysis can be carried out in an excess of the acid or in the presence of an appropriate diluent such as tetrahydrofuran, t-butyl methyl ether or 1,2-dimethoxyethane.

   b) For the compounds of formula l where A1 is a radical of partial formula lia, IIb or IIc where Za, Zb and Zc are respectively tetrazolyl, a compound of formula IVa, IVb or IVc, where La, Lb and Lc are respectively suitable protective radicals, such as trityl, benzhydryl, trialkyltin (for example trimethyltin or tributyltin) or triphenyltin attached to a nitrogen atom of the tetrazolyl part, is deprotected.



   The reaction conditions for carrying out the deprotection necessarily depend on the nature of the radical La, Lb or Le. For example, when it is trityl, benzhydryl, trialcoylétain or triphenylétain, the deprotection conditions include, for example, acid catalyzed hydrolysis in a mineral acid (such as aqueous hydrochloric acid) with advantage in an aqueous solvent ( such as dioxane or aqueous 2-propanol).

  <Desc / Clms Page number 16>

 Alternatively, a trityl or benzhydryl radical can be removed by hydrogenolysis, for example as described in (a) above with regard to the conversion of benzyloxycarbonyl to carboxy.



   The compounds of formula IVa, IVb or IVc where La, Lb and Lc respectively are trialkyltin or triphenyltin can be obtained, for example, by reaction of a nitrile of formula IXa, IXb or IXc respectively with a trialkyltin azide, such as tributyltin azide, or triphenyltin azide respectively.

   The reaction is advantageously carried out in a suitable solvent or diluent, such as toluene or xylene, and at a temperature in the range, for example, from 50 to 1500C. The nitriles of formula IXa, IXb or IXc can be obtained, for example, by alkylation of a 4-aminopyrimidine of formula V where R 'and R2 are other than hydrogen with a nitrile of formula Xa, Xb or Xc respectively where Hal . represents a suitable leaving radical, such as chloro, bromo, iodo, methanesulfonyloxy or p-toluenesulfonyloxy, under conditions similar to those applied in process (c) described below.

   The necessary compounds of formula Xa, Xb or Xc, as well as those of formula VIIa, VIIb, VIIc, Villa, VIIIb or Ville described here can be obtained, for example, as described in the published European patent applications No. 253 310, 291,969,453 210,434 249,430 709,429,257 and international patent application no WO 91/11999.



   The nitriles of formula IXa, IXb or IXc can also be obtained, for example, by reaction of a pyrimidine of formula VI where y is an appropriate leaving radical (for example chloro, bromo, iodo, methanesulfonyl, methanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy) with an amine of formula XIa, XIb or XIc respectively under conditions similar to those applied for process (d) described below.



   The amines of formula XIa, XIb or XIc can be obtained, for example, according to standard methods,

  <Desc / Clms Page number 17>

 for example from the corresponding compounds of formula Xa, Xb or Xc by reaction with the appropriate amine of formula R4NH2 under conventional conditions.



   Alternatively, the compounds of formula IVa, IVb or IVc can be obtained, for example, by reacting a pyrimidine of formula VI where y1 is as defined above with an amine of formula XIIa, XIIb or XIIc respectively in conditions similar to those described in connection with process (d) below.

   The amines of formula XIIa, XIIb or XIIc can be obtained, for example, from the corresponding compound of formula Villa, VIIIb or Ville respectively by reaction with the appropriate amine of formula R4NH2 under conventional conditions. c) For the compounds of formula I, an aminopyrimidine of formula V is alkylated with a compound of formula VIIa, VIIb or VIIc where Hal. represents a suitable leaving radical, such as chloro, bromo, iodo, methanesulfonyloxy or 2-toluenesulfonyloxy.



   The reaction is preferably carried out in the presence of a suitable non-nucleophilic base, for example an alkali metal t-butoxide such as sodium or potassium t-butoxide, an alkali metal hydride such as sodium hydride, or an alkali metal carbonate such as sodium or potassium carbonate, or an organic base such as diisopropylethylamine or 4-dimethylaminopyridine. The reaction is advantageously carried out in a suitable solvent or diluent, for example a (1-4C) alkanol such as methanol or ethanol, or in a polar solvent such as N, N-dimethylformamide or
 EMI17.1
 N-methylpyrrolidone and at a temperature in the range, for example, from 10 to 1000C.

   When carrying out process (c), when in the starting compound Za, Zb or Zc is an acid radical, in general about two molecular equivalents of an appropriate base are required, whereas when Za, Zb or Zc does not does not have an acid radical, the presence of a molecular equivalent of an appropriate base is sufficient

  <Desc / Clms Page number 18>

 usually.



   Process (c) is particularly suitable for the production of compounds of formula I where Za, Zb or Zc is an ester radical, for example where Za, Zb or Zc is an (1-6C) alkyl, benzyl or phenyl ester, which compounds are also starting compounds of formula IIIa, IIIb and IIIc respectively for the reactions described in (a) above. Likewise, according to an analogous process, but starting from the appropriate compound of formula Villa, VIIIb or Ville, the starting compounds of formula IVa, IVb or IVc respectively can be obtained with a view to process (b).



   Many of the aminopyrimidines of formula V are already known and the others can be obtained by analogy with these following conventional methods of organic chemistry well known in the art, for example as described in the reference works on heterocyclic chemistry, for example "Chemistry of Heterocyclic Compounds" edited by Weissberger, or as illustrated in diagram 1.



  (d) For the compounds of formula I, a heterocyclic derivative of formula VI where y1 is an appropriate leaving radical (such as chloro, bromo, iodo, methanesulfonyl, methanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy) is reacted with an amine of formula XIIIa, XIIIb or XIIIc.



   The reaction is optionally carried out in the presence of a suitable base, for example an alkali metal carbonate or bicarbonate such as sodium carbonate or bicarbonate, or an organic base, for example a tertiary amine such as triethylamine. The reaction is advantageously carried out in a suitable solvent or diluent, for example a (1-4C) alkanol such as methanol, ethanol or butanol, a non-polar solvent such as
 EMI18.1
 dioxane or diphenyl ether, or a polar solvent such as N, N-dimethylformamide or N-methylpyrrolidone, and usually at a temperature in the range of 40 to 1800C.

  <Desc / Clms Page number 19>

 



   The heterocyclic derivatives of formula VI where Y is halogeno can be obtained, for example, by halogenation of the corresponding 4-pyrimidones, which are themselves already known or which can be obtained by analogy with them according to methods known in the art and described in reference works in organic chemistry, such as "Chemistry of Heterocyclic Compounds" edited by Weissberger.

   For example, the compounds of formula VI can be obtained by reaction of the corresponding 4-pyrimidone with phosphorus oxychloride in the absence of solvent, or in the presence of an inert solvent or diluent such as toluene or dioxane, at a temperature in the range of 60 to 100 C. The compounds of formula VII where y1 is methanesulfonyloxy, R-toluenesulfonyloxy or trifluoromethanesulfonyloxy and R and R are other than hydrogen can be obtained, for example, by acylation of 4- corresponding pyrimidone by the corresponding sulfonyl chloride under standard conditions.

   The compounds of formula VI where y1 is methanesulfonyl can be obtained by alkylation of the corresponding mercaptopyrimidine, which is itself known or can be obtained by analogy, then by oxidation under standard conditions. The amines of formula XIIIa, XIIIb and XIIIc can be obtained, for example, from the corresponding compound of formula VIIa, VIIb and VIIc respectively by reaction with the appropriate amine of formula R4NH2 under standard conditions.



  (e) For the compounds of formula l where A1 is a
 EMI19.1
 radical of partial formula IIc where Zc is a radical of formula CF, SOyNH-, a compound of formula XIV is reacted with the anhydride of trifluoromethanesulfonic acid.



   The reaction is preferably carried out in the presence of a base, such as triethylamine, and advantageously in a suitable solvent or diluent, for example dichloromethane, at a temperature in the range of

  <Desc / Clms Page number 20>

   - 78 C at room temperature. The compounds of formula XIV can be obtained by alkylating a compound of formula V with a compound of formula X7 (itself obtained according to methods analogous to those described in documents EPA 429 257 and 430 709) under conditions similar to those of process (c) above, then by reduction of the nitro radical of the intermediate compound obtained, for example by conventional catalytic hydrogenation.



   Then, the compounds of formula I where Za, Zb or Zc is 1H-tetrazol-5-yl can be obtained by step-by-step conversion of a compound of formula I where Za, Zb or Zc is a carboxylic acid or carboxylic ester radical respectively into the corresponding nitrile under standard conditions, then by reaction of the nitrile with an azide such as an alkali metal azide, preferably in the presence of an ammonium halide, and preferably in the presence of a suitable polar solvent such as N, N-dimethylformamide, at a temperature in the range, for example, from 50 to 1600C.



   Next, the compounds of formula I where Za, Zb or Zc is -CO. NH. (1H-tetrazol-5-yl), a radical of formula -CO. NH. So or an ester radical, can be obtained, for example, by reaction of a carboxylic acid of formula I where Za, Zb and Zc is carboxyl (or a reactive derivative of this acid) with c-aminotetrazole, a sulfonamide of formula NH. SO cu a salt thereof (eg an alkali metal salt) or a suitable alcohol or with a salt thereof (eg an alkali metal salt). Suitable reactive derivatives include, for example, chloride, bromide, azide, anhydride or anhydride mixed with formic or acetic acid of the carboxylic acid of formula I as defined above.

   When the free acid form is used, the reaction is generally carried out in the presence of an appropriate dehydrating agent such as
 EMI20.1
 dicyclohe:: ylcarhcdiimi e or 1 3-3 (diméhylaminoprcpyl) -l- ethylcarbcdiimide in the presence of a base such as

  <Desc / Clms Page number 21>

 triethylamine or pyridine. When a reactive derivative is used, the reaction is carried out in the presence of a base as mentioned above, or else, for the preparation of a compound of formula I where Za, Zb or Zc is a radical of formula- CO. NH. SO2R8 or an ester radical, the sulfonamido- or hydroxy-compound is used in the form of a salt, such as its alkali metal salt (in particular its lithium, sodium or potassium salt).

   The reaction is generally carried out in the presence of a suitable solvent or diluent such as dioxane, t-butyl methyl ether or tetrahydrofuran, at a temperature in the range, for example, from 0 to 600C.



   Then, when a non-toxic salt or a compound of formula I is required, it can be obtained, for example, by reaction with the appropriate base providing the physiologically acceptable cation or with the appropriate acid providing the physiologically acceptable anion , or according to any other conventional salt formation process.



   Furthermore, when an optically active form of a compound of formula I is required, one of the above methods can be carried out with an optically active starting compound. Alternatively, the racemic form of a compound of formula I where Za, Zb or Zc is an acid radical can be split, for example by reaction with an optically active form of an appropriate organic base, for example ephedrine, hydroxide of N, N, N-trimethyl- (1-phenylethyl) ammonium or 1-phenylethylamine, then by conventional separation of the diastereoisomeric mixture of the salts thus obtained, for example by fractional crystallization in a suitable solvent, for example a (1 -4C) alkanol,

   after which the optically active form of the compound of formula I can be released by reaction with an acid according to a conventional technique, for example with an aqueous mineral acid such as dilute hydrochloric acid.



   In another aspect, the present invention has

  <Desc / Clms Page number 22>

 relates to a process for the preparation of a compound of formula I where Al is a radical of partial formula IIa where Za is tetrazolyl, B is R-phenylene optionally carrying a substituent chosen from (1-4C) alkyl, (1-4C) alkoxy, halo, (1-4C) alkanoyl, trifluoromethyl, cyano and nitro and R1, R2, R3, R4 and Ra have any of the meanings defined above, which includes reacting a compound of formula XVI where pu is an electron deficient phenyl radical or a pyrimidyl or pyridyl radical;

   Re is hydrogen, (1-4C) alkyl, (1-4C) alkoxy, halo, (1-4C) alkanoyl, trifluoromethyl, cyano or nitro; and R \ R2, R3, R4 and Ra have any of the meanings defined above, with a base chosen from a hydroxide, (1-12C) alkanolate, (1-12C) alkanethiolate, phenolate, thiophenolate or diphenylphosphide of alkali metal, where any phenyl ring of the last three radicals can optionally carry an (1-4C) alkyl, (1-4C) alkoxy or halogen radical.



   A particular meaning for P is, for example, a phenyl radical bearing 1, 2 or 3 radicals attracting the electrons chosen independently from nitro, cyano and trifluoromethyl.



   Of particular significance for Re when it is alkyl is, for example, methyl or ethyl; when it is alkoxy is, for example, methoxy or ethoxy; and when it is halo is, for example, fluoro, chloro, bromo or iodo.



   Particular significance for a base includes one of the following by way of example: for an alkali metal hydroxide: sodium or potassium hydroxide; for an alkali metal alkanolate: an (1-8C) alkali metal alkanolate, for example an (1-4C) alkali metal alcoholate such as sodium or potassium methylate, ethylate, propylate or butylate; for an alkali metal alkanethiolate: a (1-8C) alkane-

  <Desc / Clms Page number 23>

 alkali metal thiolate, for example an alkali metal (1-4C) alkanethiolate such as methanethiolate, ethanethiolate, propanethiolate or sodium or potassium butanethiolate.



   Of particular significance for an optional substituent on a phenyl radical of an alkali metal phenolate, thiophenolate or diphenylphosphide, when it is alkyl and, for example, methyl or ethyl; when it is alkoxy is, for example, methoxy or ethoxy; and when halo is, for example, fluoro, chloro or bromo.



   A preferred meaning for p1 is, for example, a nitrophenyl radical, especially 4-nitrophenyl.



   A preferred meaning for X is, for example, when it is unsubstituted 2-phenylene.



   A particularly preferred base is an alkali metal alkanethiolate such as sodium or potassium propanethiolate, an alkali metal alkanolate such as sodium or potassium ethylate, or an alkali metal thiophenolate such as sodium 4-fluorothiophenolate or potassium.



   It should be observed that when the base is an alkanolate, alkanethiolate, phenolate, thiophenolate or alkali metal diphenylphosphide, it can be formed in situ from the corresponding alkanol, alkanethiol, phenol, thiophenol or diphenylphosphine with a metal base suitable alkali, such as an alkali metal hydride, for example lithium, potassium or sodium hydride.



   The process of the invention is particularly useful for the preparation of compounds of formula I in which the tetrazolyl radical occupies the position ortho with respect to the adjacent phenyl radical.



   The reaction is advantageously carried out in a suitable inert organic solvent or diluent, for example

  <Desc / Clms Page number 24>

 a polar solvent such as N, N-dimethylformamide or N-methylpyrrolidone. Alternatively, an alkanol such as methanol or ethanol can be used, for example, when an alkali metal hydroxide or alkolate such as sodium or potassium hydroxide, methylate or ethylate is used. The reaction is generally carried out at a temperature in the range, for example, from -30 to 50 C. It should be noted that the choice of temperature depends on the nature of the base used.

   For example, when an alkanethiolate or alkali metal alkanolate is used, a temperature in the range of 00 C to room temperature is preferred.



   The compounds of formula XVI can be obtained by reaction of a boronic acid of formula XVII with a compound of formula XVIII where p1 is a phenyl radical deficient in electrons or a pyrimidyl or pyridyl radical having any of the meanings defined above and West a bromo, iodo or trifluoromethanesulfonylcxy radical, in the presence of a palladium (0) or palladium (II) catalyst, such as tetrakis (triphenylphosphine) palladium (0) or palladium (II) chloride.

   The reaction is preferably carried out in the presence of a base, such as sodium or potassium carbonate, in an inert solvent or diluent, for example a hydrocarbon such as tcluene or xylene, an ether such as dioxane or tetrahydrofuran , a (1- 4C) alkanol such as methanol or ethanol, water, or a mixture thereof, for example a mixture of water, methanol and toluene, and at a temperature of range, for example, 50 to 150 C, and advantageously at or about the reflux temperature of the solvent or mixture of solvents.



   The compounds of formula XVII can be
 EMI24.1
 obtained, for example, by heating to reflux of a 4-methylphenylboroniqua acid in a solvan. t l qe methylchloroform with azeotropic elimination of water, followed

  <Desc / Clms Page number 25>

 radical bromination of the product, which can be carried out in situ, for example with bromine or Nbromosuccinimide in the presence of azo (bisisobutyronitrile). The resulting 4-bromomethylphenylboronic acid anhydride can then be used to alkylate a product of formula V (under alkylation conditions similar to those applied in process (c) described above), operation which is followed by hydrolysis acid giving a compound of formula XVII.

   Alternatively, the product from the alkylation stage preceding the hydrolysis can be isolated and reacted directly with a compound of formula XVIII under conditions similar to those described above to directly obtain a compound of formula XVI. According to another operating variant, a 4-methylphenylboronic acid and an appropriate alkanediol, for example 2,2-dimethylpropane-1,3-diol, can be heated to reflux in a solvent (such as cyclohexane) with azeotropic elimination of the water before free radical bromination of the product, which can be carried out in situ.

   The resulting bromomethylated compound can then be reacted according to techniques analogous to those described above with respect to 4-bromomethylphenylboronic acid anhydride to give a compound of formula XVII or a compound of formula XVI directly. The compounds of formula XVIII can be obtained, for example, by reaction of a suitably substituted benzoyl chloride with an amine of formula PI. NHz under standard conditions.

   The resulting amide is then, for example, reacted with thionyl chloride in the presence of triethylamine and N, N-dimethylformamide in acetonitrile at room temperature to give the corresponding imidoyl chloride, which is then put reacting in situ with triethylamine, sodium azide and tetrabutylammonium bromide at 10-30 C to give the compound of formula XVIII.



   Then, the possible later stages of formation of a non-toxic salt and / or of formation of a

  <Desc / Clms Page number 26>

 optically active form of a compound of formula I can be performed as described above in connection with methods (a) to (e).



   Some of the intermediaries defined here are new, for example the compounds of formula IIIa, IIIb, IIIc, IVa, IVb, IVc, IXa, IXb and IXc and constitute another subject of the invention.



   As indicated above, the compounds of formula I have favorable pharmacological effects in warm-blooded animals (including humans) in diseases and medical conditions where an improvement in the properties of vasoconstriction and retention of system fluids renin-angiotensin-aldosterone is desirable, at least in part by antagonism of one or more of the physiological actions of the IIA. The compounds of the invention are therefore useful for the treatment of diseases or medical conditions such as hypertension, congestive heart failure and / or hyperaldosterol in warm-blooded animals (including humans) ), as in other diseases or medical conditions where the renin-angiotensin-aldosterone system plays a significant causal role.

   The compounds of the invention may also be useful for the treatment of ocular hypertension, glaucoma, cognitive disorders (such as Alzheimer's disease, amnesia, senile dementia and learning outcomes), same as in other diseases such as renal failure, heart failure, post-myocardial infarction, cerebrovascular disorders, anxiety, depression and certain mental alterations such as schizophrenia.



   The antagonism of one or more of the actions
 EMI26.1
 Physiological IIA and, in particular, the antagonism of the interaction of IIA with the receptors that transmit these effects to target tissue, can be assessed by following several of the following routine laboratory techniques.

  <Desc / Clms Page number 27>

 Test A: This in vitro technique involves the incubation of the compound to be tested initially at a concentration of 100 micromolar (if not less) in a buffered mixture containing fixed concentrations of radiolabelled IIA and a fraction of cell surface membrane prepared from a target tissue of angiotensin. For this test, the source of cell surface membranes is the guinea pig adrenal gland, which is known to respond to AII.

   The interaction of radiolabelled IIA with its receptors (evaluated in the form of the radiolabelled species linked to the particulate membrane fraction after elimination of the non-fixed radiolabelled species by a rapid filtration technique which is common for such studies) is antagonized by compounds which also bind to membrane receptor sites and the degree of antagonism (observed during the test in the form of the displacement of radioactivity bound to the membrane) is easily determined by comparison of the radioactivity bound to the receptors in the presence of the test compound at the specified test concentration with a reference value determined in the absence of the test compound.

   According to this procedure, the compounds showing a displacement of at least 50% of the
 EMI27.1
 fixation of radiolabelled IIA at a concentration 10-4 M archived at a conc m are tested again at lower concentrations to determine their potency. For the
 EMI27.2
 determination of the IC 50 (concentration for the displacement of 50% of the fixation of the radiolabelled IIA), concentrations of the test compound are usually chosen to allow the test on at least four orders of magnitude centered around the approximate IC 50 expected, which is then determined from a diagram of the percentage of displacement as a function of the concentration of the test compound.



   In general, the acidic compounds of formula I above show significant inhibition in Test A at a concentration of 50 micromoles per liter or much

  <Desc / Clms Page number 28>

 weaker.



  Test B: This in vitro test includes the measurement of the antagonistic effects of the compound to be tested against the contractions induced by the IIA in the isolated rabbit aorta, maintained in physiological saline solution at 37 C. To ensure that the effect of the compound is specific for IIA antagonism, the effect of the compound to be tested on norepinephrine-induced contractions can also be determined on the same preparation.



   In general, the acidic compounds of formula I above show appreciable inhibition in Test B at a final concentration of 50 micromoles per liter or much lower. [Note: the compounds of formula I where Za, Zb or Zc is an ester radical generally have only a weak activity in vitro in Tests A and B].



  Test C: This in vivo test involves using conscious rats or in terminal anesthesia in which an arterial catheter has been implanted under anesthesia in order to measure changes in blood pressure. The antagonistic effects of AII exerted by the test compound, after oral or parenteral administration, are evaluated against the pressure increase responses induced by angiotensin II. To ensure that the effect is specific, the effect of the compound to be tested on the pressure increase responses induced by vasopressin can also be determined on the same preparation.



   The compounds of formula I generally show specific IIA antagonistic properties in Test C at a dose of 50 mg / kg body weight or much lower without any other obvious toxic or pharmacological effect.



  Test D: This in vivo test involves the stimulation of the biosynthesis of endogenous AI in various species, notably the rat, the marmoset and the dog. i, by administration of a low sodium diet and appropriate daily doses of a known saluretic

  <Desc / Clms Page number 29>

 under the name of frusemide. The test compound is then administered orally or parenterally to the animal in which an arterial catheter has been implanted under anesthesia to measure changes in blood pressure.



   In general, the compounds of formula I show IIA antagonistic properties in Test D as proven by a significant reduction in blood pressure at a dose of 50 mg / kg of body weight or much lower without any toxic effect or other obvious annoying pharmacological.



   The compounds of formula I will generally be administered for therapeutic or prophylactic purposes to warm-blooded animals (including humans) requiring such treatment in the form of a pharmaceutical composition, as is well known in the art. pharmaceutical field. according to another embodiment, the invention relates to a pharmaceutical composition comprising a compound of formula I, or a salt as defined above, together with a pharmaceutically acceptable diluent or excipient. These compositions are advantageously presented in a form suitable for oral administration (for example in the form of a tablet, capsule, solution, suspension or emulsion) or for parenteral administration (for example injectable aqueous or oily solution or injectable emulsion).



   The compound of formula I or a non-toxic salt thereof can also be advantageously administered for therapeutic or prophylactic purposes in conjunction with another pharmacological agent known in the art as useful for the treatment of one or more of the diseases or conditions above, for example a beta-blocker (such as atenolol), a calcium channel blocker (such as nifedipine), an angiotensin converting enzyme (ACE) inhibitor (such as lisinopril) or a diuretic (such as furosemide or hydrochlorothiazide). It suits

  <Desc / Clms Page number 30>

 to observe that such a therapeutic combination constitutes another object of the present invention.



   In general, a compound of formula I (or a pharmaceutically acceptable salt thereof, where appropriate) is administered to humans, for example, in a daily oral dose of up to 50 mg / kg bodyweight (preferably up to 10 mg / kg) or in a daily parenteral dose up to 5 mg / kg bodyweight (and preferably up to 1 mg / kg), to be given in divided doses if necessary, the precise quantity of the compound (or salt) which is administered, as well as the route and the form of administration depending on the size, age and sex of the patient, as well as the particular disease or medical condition treated in accordance with principles well known in the medical art.



   In addition to their aforementioned application, in medical therapy in humans, the compounds of formula I are also useful in veterinary medicine for the treatment of similar diseases affecting warm-blooded animals of economic importance, such as dogs, cats. , horse and cattle. In general, for such treatment, the compounds of formula I are administered in an amount and in a manner similar to those described in connection with administration to humans.

   The compounds of formula 1 are also valuable as pharmacological tools in the development and standardization of test systems for the evaluation of the effects of IIA in laboratory animals, such as cats, dogs, rabbits, monkeys , the rat and the mouse, in the pursuit of research into new and improved therapeutic agents.



   The invention is illustrated by the following nonlimiting examples, in which, unless otherwise indicated: (i) the concentrations and evaporations are carried out under vacuum in a rotary evaporator; (ii) operations are carried out at temperature

  <Desc / Clms Page number 31>

 ambient, i.e. in the range 18 to 26OC; (iii) flash column chromatography is carried out on Kieselgel Merck 60 (Art. No. 9385) purchased from E Merck, Darmstadt, Germany; (iv) the yields, when indicated, are specified for the convenience of the reader only and are not necessarily the maximum achievable by process development;

   (v) H NMR spectra are normally determined at 200 MHz in CDCl3 in the presence of tetramethylsilane (TMS) as internal standard and are expressed in the form of chemical shifts (delta) in parts per million compared to TMS, at using traditional abbreviations for the designation of the main peaks: s = singlet; m = multiplet; t = triplet; l = wide; d = doublet; (vi) the 13C NMR spectra are normally determined at 100 MHz in CDCl3 or cL-dimethylsulfoxide (cL-DMSO) using the solvent signal as an internal standard and are expressed in chemical shifts (delta) in parts per million per million report to TMS; and (vii) all the end products give satisfactory microanalysis.



  EXAMPLE 1
Concentrated hydrochloric acid (0.5
 EMI31.1
 ml) to a solution of 2,6-dimethyl-4- [N- (2'- (2-triphenylmethyl-2tl-tetrazol-S-yl) biphenyl-4-ylmethyl) amino] pyrimidine (A) (0, 5 g) in methanol and the mixture is stirred for 10 minutes. The volatile constituents are removed by evaporation and the residue is purified by crystallization from
 EMI31.2
 isopropanol-ethanol to obtain 2,6-dimethyl-4- [N- (2'- (1H-tetrazol-5-yl) -biphenyl-4-ylmethyl) amino] pyrimidine hydrochloride, in the form off-white solid, P.

   F. 248 at 2520C (decomposition); NMR (d6-DMSO): 2.37 (s, 3H), 2.52 (s, 3H), 4.63 (d, 2H), 6.54 (s, 1H), 7.11 (d, 2H ), 7, 25 (d, 2H), 7, 43-7, 66 (m, 4H),

  <Desc / Clms Page number 32>

 9.29 (br s, 1H); mass spectrum (bombardment by positive rapid atoms (+ ve FAB), DMSO-methanol-nitrobenzyl alcohol): 358 (M + H) ";
 EMI32.1
 microanalysis for: CHN. HCl. 0.25CHgOH. O, 25HO:
Calculated: C, 60, 0; H, 5.4; N, 23.2%.



   Found: C, 60, 1; H, 5, 3; N, 23.4%.



   The starting compound A is prepared in the following manner: (i) 4-amino-2,6-dimethylpyrimidine (B) (2.5 g) is added to a suspension of sodium hydride (60% dispersion in mineral oil; 1.11 g) in N, N-dimethylformamide (DMF) (180 ml) and the mixture is stirred for 6 hours. 5- [2- (41-bromomethYl-biphenyl)] -2-triphenylmethyl-2H-tetrazole (14.8 g) (obtained as described in published European patent application no. 291,969) is added and the mixture is stirred for 16 hours. The solvent is removed by evaporation and the residue is partitioned between ethyl acetate and water. The organic layer is separated, washed with saturated sodium chloride solution and dried.

   The solvent is removed by evaporation and the residue is purified by flash chromatography with elution with ethyl acetate-methanol (49: 1 v / v). The fractions containing the desired compound are combined and the solvent is removed by evaporation. The residue is further purified by flash chromatography with elution with dichloromethane-methanol (19: 1 v / v) to obtain the 2,6-
 EMI32.2
 dimethyl-4- [N- (2'- (1H-triphenylmethyl-2H-tetrazol-5yl) biphenyl-4-ylmethyl) amino] pyrimidine (A) (1.52 g) in the form of a white foam;

   R'lli (CDC13): 2, 26 (s, 3H), 2, 50 (s, 3H), 4, 41 (d, 2H), 4, 88 (s R "- (CDC13) 1 large, 1H) , 5, 90 (s, 1R) / 6, 86-6, 97 (m, 6H), 7, 02-7, 17 (m, 4H), 7.19-7, 55 (complex m, 12H), 7.96 (m, 13);
 EMI32.3
 mass spectrum (+ ve? AB, methanol-nitrobenzyl alcohol): 600 (M + H) +.



  EXAMPLES 2 TO 7

  <Desc / Clms Page number 33>

 
According to a technique analogous to that described in Example 1, but starting from the appropriate compound of formula IVa where La is triphenylmethyl, the following compounds of formula I (where A 1 is a radical of partial formula IIa) are prepared with yields from 52 to 92%.



  (Example 2): 2,6-dimethyl-4- [N-methyl-N- hydrochloride
 EMI33.1
 (2'- (1H) tetrazol-5-yl) -biphenyl-4-ylmethyl) amino] pyrimidine, in the form of a solid, P. F. 222 at 226 C; NMR (d6-DMSO / d4-acetic acid): 2.41, 2.46 (d of s, 3H), 2.56, 2.58 (d of s, 3H), 3.17, 3.32 ( d of s, 3H), 4.85, 5.05 (d of s, 2H), 6.75, 6.9 (d of s, 1H), 7.05-7.4 (complex m, 4H) , 7.45-7.8 (complex m, 4H); mass spectrum (+ ve FAB, glycerol-methanol): 375 (M + H) +; microanalysis for C21H21N7. HCl:
Calculated: C, 61.8; H, 5.44; N, 24.0%.



   Found: C, 61.3; H, 5.2; N, 26.6%.



  (Example 3): 2-ethyl-4- hydrochloride [(2'- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl) amino] -5, 6,7, 8-tetrahydroquinazoline, in the form of a solid, PF 277 at 2780C NMR (d6-DMSO): 1.19 (t, 3H), 1.78 (m, 4H), 2.38 (m, 2H), 2.67 (m, 2H), 2.74 (q, 2H), 4.70 (d, 2H), 7.06 (d, 2H), 7.27 (d, 2H), 7.56 (m, 4H), 9.05 (t , 1H); mass spectrum (+ ve FAB methanol-nitrobenzyl alcohol): 412 (M + H) +; microanalysis for C24H25N7.HCl:
Calculated: C, 64.3; H, 5.8; N, 21.9%.



   Found: C, 64.1; H, 5.9; N, 21.8%.



  (Example 4): 2,6-dimethyl-5-iodo-4- hydrochloride [(2'- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl) amino] pyrimidines in the form of a solid PF 221 to 223 C; NMR (d6-DMSO): 2.40 (s, 3H), 2.50 (s, 3H), 4.72 (d, 2H), 7.06 (d, 2H), 7.25 (d, 2H ), 7.64 (m, 4H), 8.92 (wide t, 1H); mass spectrum (+ ve FAB, DMSO-glycerol): 484 (M + H) +; microanalysis for CHgIN. HCl:
Calculated: C, 46.2; H, 3.7; N, 18.9%.



   Found: C, 45.8; H, 3.7; N, 18.6%.

  <Desc / Clms Page number 34>

 



  (Example 5): 2-ethyl-4 - [(2 '- (1H-tetrazol-5yl) biphenyl-4-ylmethyl) -amino] quinazoline hydrochloride in the form of a solid P. F. 256 at 257 C; NMR (d6-DMSO): 1.31 (t, 3H), 2.93 (q, 2H), 4.95 (d, 2H), 7.07 (d, 2H), 7.37 (d, 2H ), 7.60 (m, 5H), 7.88 (d, 1H), 8.00 (m, 1H), 8.59 (d, 1H), 10.83 (t, 1H); mass spectrum (+ ve FAB, DMSO-methanol-nitrobenzyl alcohol): 408 (M + H) T; microanalysis for C24H21N7.HCl. 0, 2 5CH30H:
Calculated: C, 64, 4; H, 5, 1; N, 21.7%.



   Found: C, 64.3; H, 5.0; N, 21.6%.



  (Example 6): 2,6-diethyl-5-ido-4 hydrochloride - [(2 '- (1H-
 EMI34.1
 tetrazol-5-yl) biphenyl-4-ylmethyl) amino] pyrimidine in the form of a solid, P. F. 226 to 229OC; NMR (d6-DMSO): 1.18 (d of t, 6H), 2.80 (d of q, 4H), 4, 7 (d, 2H), 7.05 (d, 2H), 7.27 (d, 2H), 7.85 (m, 4H), 8.9 (br s, 1H); mass spectrum (+ ve FAB, DMSO-nitrobenzyl alcohol): 512 (M + H) -1-;
 EMI34.2
 H IN ,. HCl microanalysis for CHINy .. HCl:
Calculated: C, 48, 2; H, 4.2; N, 17.9%.



   Found: C, 48, 6; H, 4.2; N, 17.8%.



  (Example 7): 2,4-diethyl-8 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl) pyrido [2,3-d] pyrimidine-7 (8H) -one under formed of a solid, PF 214 to 215OC; NMR (d6-DMSO): 1.26 (d of t, 6H), 2.89 (q, 2H), 3.05 (q, 2H), 5.53 (s, 2H), 6.72 (d , 1H), 7.01 (d, 2H), 7.26 (d, 2H), 7.56 (m, 4H), 8.21 (d, 1H); mass spectrum (+ ve FAB; methanol-nitrobenzyl alcohol): 438 (M + H) +; microanalysis for C25H23N7O.0,5H2O:
Calculated: C, 67.2; H, 5, 4; N, 21.9%.



   Found: C, 67.1; H, 5, 4; N, 25.1%.



   The necessary starting compounds of formula IV used in Examples 2 to 7 corresponding to the starting compound A of Example 1 are obtained with yields

  <Desc / Clms Page number 35>

 from 30 to 75% according to a procedure similar to that described in Example 1, part (i), as follows: Example 2A): 2,6-dimethyl-4- [N-methyl-N- (2 '- (2-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-ylmethyl) amino] pyrimidine in the form of a solid, P.

   F. 1550C (decomposition); NMR (CDCI 3): 2.31 (s, 3H), 2.51 (s, 3H), 2.65 (s, 3H), 4.72 (s, 2H), 6.07 (s, 1H), 6.6-6.92 (m, 6H), 6.93 (d, 2H), 7.09 (d, 2H), 7.15-7.4 (complex m, 10H), 7.45 (m , 2H), 7.95 (m, 1H); mass spectrum (+ ve FAB, DMSO-methanol-nitrobenzyl alcohol): 614 (M + H) +.



  (Example 3A): 2-ethyl-4 [(2'-triphenylmethyl-2H-tetrazol-5yl) biphenyl-4-ylmethyl) amino] -5, 6,7, 8-tetrahydroquinazoline as a solid, PF 190 at 192 C; NMR (CDClg): 1.32 (t, 3H), 1.75 (m, 4H), 2.08 (m, 2H), 2.69 (m, 2H), 2.74 (q, 2H), 4.5 (wide t, 1H), 4.64 (d, 2H), 6.91 (m, 6H), 7.10 (s, 4H), 7.25 (complex m, 10H), 7.48 (m, 2H), 7.95 (m, 1H).



  (Example 4A): 2,6-dimethyl-5-iodo-4 [(2'-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-ylmethyl) amino] pyrimidine in the form of a solid; NMR (CDClg): 2.48 (s, 3H), 2.57 (s, 3H), 4.62 (d, 2H), 5.55 (broad t, 1H), 6.92 (m, 6H) , 7.10 (m, 4H), 7.26 (complex m, 10H), 7.48 (m, 2H), 7.95 (m, 1H).



  (Example 5A): 2-ethyl-4- [(2'- (2-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-ylmethyl) amino] quinazoline in the form of a foam; NMR (CDC13): 1.39 (t, 3H), 2.92 (q, 2H), 4.79 (d, 2H), 5.55 (wide t, 1H), 6.90 (m, 6H) , 7.26 (m complex, 15H), 7.41 (m, 1H), 7.48 (m, 2H), 7.67 (m, 1H), 7.80 (d, 1H), 7.98 (m, 1H).



  (Example 6A): 4-amino-2,6-diethyl-5iodopyrimidine (320 mg) is added to a mixture of potassium t-butoxide (130 mg) and 1,4, 7,10, 13,16hexaoxacyclooctadecane (20 mg) in THF (25 ml) and the mixture is stirred for 5 minutes. Add a solution of 5- [2- (4'-bromomethylbiphenyl)] -2-triphenylmethyl-2H-tetrazole (111 mg) in tetrahydrofuran (THF) (2 ml)

  <Desc / Clms Page number 36>

 and the mixture is stirred for 4 hours. The solvent is removed by evaporation and the residue is partitioned between ethyl acetate and a saturated solution of sodium chloride. The aqueous layer is separated, extracted with ethyl acetate and the combined organic extracts are dried.

   The solvent is removed by evaporation and the residue is purified by flash chromatography with elution with diethyl ether-hexane (2: 3 v / v) to obtain la2, 6-diethyl-5-iodo-4- [2 '- ( 2-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-ylmethyl) -amino] pyrimidine in the form of a foam; NMR (CDClg): 1.25 (double t, 6H), 2.82 (d of q, 4H), 4.36 (d, 2H), 5.68 (broad s, 1H), 6.92 (m , 6H), 7.09 (s, 4H), 7.26 (m complex, 8H), 7.38 (m, 2H), 7.47 (m, ZH), 7.95 (m, lE).



  (Example 7A): 2,4-diethyl-8- [(2'- (2-triphenylmethyl) -2H-tetrazol-5-yl) biphenyl-4-ylmethyl)] - pyrido [2, 3-d is obtained ] pyrimidine-7 (8H) -one according to a process analogous to that described in Example 6A, in the form of a solid; NMR (CDCI 3): 1.35 (t, 6H), 3.0 (d of q, 4H), 5.60 (s, 2H),
 EMI36.1
 6, 69 (d, 1H), 6, 93 (m, 6H), 7.04 (d, 2H), 7.35 (complex m, 14H), 7.33 (d, 1H), 7.89 ( m, 1H).



   The necessary starting compounds of formula V used in Examples 2 to 4 corresponding to compound B in Example 1 are obtained in the following manner: (Example 2B): An 8M solution of methylamine in ethanol is added (6, 2 ml) to a solution of 6-chloro-2,4-dimethyl-pyrimidine (1, 42 g) (obtained as described in Chem. Ber., 1902.35, 1576) in ethanol (5 ml) and stirred mixing for 16 hours. The solvent is removed by evaporation and the residue is partitioned between a 0.25M solution of sodium carbonate (50 ml) and ethyl acetate (25 ml). The aqueous phase is separated and extracted with ethyl acetate (2 x 25 ml.

   The combined organic extracts are washed with saturated sodium chloride solution and dried. We remove the solvent

  <Desc / Clms Page number 37>

 by evaporation and the residue is triturated in ethyl acetate to obtain 2, 6-dimethyl-4- (N-methylamino) - pyrimidine (1.07 g), in the form of a pale yellow solid; NMR (CDCl3): 2.33 (s, 3H), 2.47 (s, 3H), 2.09 and 2.92 (two s, 3H), 5.2 (broad s, 1H), 6.00 (s, 1H); mass spectrum (CI, ammonia): 138 (M + H) +.



  (Example 3B): (i) A solution of propionamidine hydrochloride (2.7 g) in ethanol (25 ml) is added to a solution of sodium (600 mg) in ethanol (25 ml) and the mixture is stirred for 10 minutes. Ethyl cyclohexanone-2-carboxylate (4.25 g) is added and the mixture is stirred for two days, then heated to reflux for 1 hour. The solvent is removed by evaporation and ice is added to the residue. The mixture is then extracted with ethyl acetate (2 x 50 ml). The combined extracts are subjected to washing with water and saturated sodium chloride solution, then dried (MgSO).



  The solvent is removed by evaporation and the residue is triturated in hexane. The resulting solid is collected by filtration to obtain 4-hydroxy-2-ethyl-5, 6, 7, 8tetrahydroquinazoline (C) (1.1 g), in the form of a solid, m.p. 199 at 200 C; NMR (CDC13): 1.33 (t, 3H), 1.77 (m, 4H), 2.5 (m, 2H), 2.66 (m, 4H), 12.5 (broad s, 1H) ; mass spectrum (CI, ammonia): 179 (M + H) +.



  (ii) A solution of compound C (100 mg) in phosphorus oxychloride (2 ml) is heated under reflux for 45 minutes. The mixture is cooled to room temperature and the volatile constituents are removed by evaporation. Ice is added to the residue and the mixture is made alkaline with sodium bicarbonate. The mixture is extracted with ethyl acetate and the extract is dried (MgSO). The solvent is removed by evaporation to obtain 4-chloro-2-ethyl-5, 6,7, 8-tetrahydroquinazoline (D) (92 mg) in the form of a solid with low melting point;

  <Desc / Clms Page number 38>

 
 EMI38.1
 NMR (CDCl): 1.33 (t, 3H), 1.66 (m, 4H), 2.69 (m, 2H), 2.85 (m, 4H); mass spectrum (CI, ammonia): 196, 198 (M + H) +.

   (iii) Compound D (4.7 g) is added to a saturated solution of ammonia in ethanol (50 ml) and the mixture is heated at 135 C for 12 hours in a sealed tube. The volatile constituents are removed by evaporation and the residue is partitioned between ethyl acetate and water. The organic layer is separated and the solvent is removed by evaporation. The residue is purified by flash chromatography with elution with ethyl methanol acetate (9: 1 v / v) to obtain 4-amino-2-ethyl-5, 6, 7, 8tetrahydroquinazoline (2.1 g), under form of a solid, PF



    1840C; NMR (d6-DMSO): 1.15 (t, 3H), 1.7 (m, 4H), 2.25 (wide, 2H), 2.5 (m, 4H), 6.25 (wide , 2H); mass spectrum (CI, ammonia): 178 (M + H) +.



  (Example 4B): Bis (trifluoroacetoxy) iodobenzene (4.3 g) and iodine (1.27 g) are added to a solution of 4-amino-2,6-dimethylpyrimidine (1.23 g) in dichloromethane. (30 ml) and methanol (70 ml) and the mixture is stirred for 16 hours. The solvent is removed by evaporation and a 5% solution of sodium metabisulfite (50 ml) is added to the residue. The mixture was basified with sodium bicarbonate and the resulting solid was collected by filtration to obtain 6-iodo-2,4-dimethylpyrimidine (1.5 g), in the form of a yellow solid, P. F. 133-134OC; NMR (d6-DMSO): 2.26 (s, 3H), 2.40 (s, 3H), 6.73 (broad s, 2H); mass spectrum (CI, ammonia): 250 (M-fH) *.



  (Example 5B): (i) A mixture of 2-aminobenzamide (13.6 g), methyl propionylacetate (26.6 ml) and p-toluenesulfonic acid (150 mg) in benzene (200 ml) is heated ) at reflux for 6 hours, removing the water by azeotropy. The mixture is cooled to room temperature and the solvent is removed by evaporation. We

  <Desc / Clms Page number 39>

 dissolve the residue in a diphenyl-diphenyl ether mixture (1: 2.77 v / v) (10 ml) and the solution is added to a diphenyl-diphenyl ether reflux eutectic mixture (1: 2.77 v / v) (40 ml). The mixture is heated at reflux for 20 minutes, then cooled to room temperature. Hexane (200 ml) is added, then the mixture is decanted to leave a solid residue.

   The residue is washed with hexane (2 x 200 ml) and collected by filtration to obtain 2-ethyl-4hydroxyquinazoline (C) (16.9 g), in the form of a brown solid, PF 199 to 201 VS ; NMR (d6-DMSO): 1.25 (t, 3H), 2.64 (q, 2H), 7.4 (m, 1H), 7.6 (d, 1H), 7.78 (m, 1H ), 8.06 (dd, 1H), 12.12 (broad s, 1H).



  (ii) A solution of compound C (1 g) in phosphorus oxychloride (12 ml) is heated at reflux for 1 hour. The mixture is cooled to room temperature and the volatile constituents are removed by evaporation.



  Ice is added to the residue and the mixture is made alkaline with potassium carbonate. The mixture is extracted with ether (2 x 10 ml) and the combined extracts are dried (MgSO). Bleaching active charcoal is added to the ethereal solution, then the charcoal is separated by filtration.



  The solvent is removed by evaporation to obtain 4-chloro-2-ethylquinazoline (D) (500 mg), in the form of a yellow solid; NMR (CDCl): 1.4 (t, 3H), 3.10 (q, 2H), 7.64 (m, 1H), 7.98 (m, 2H), 8.23 (dd, 1R); mass spectrum (CI, ammonia): 192.194 (M + H) +.



  (iii) Compound D (600 mg) is added to a saturated solution of ammonia in ethanol (25 ml) and the mixture is heated at 1800C for 18 hours. The volatile constituents are removed by evaporation and a saturated sodium bicarbonate solution (25 ml) is added to the residue.



  The resulting solid is collected by filtration to obtain 4-amino-2-ethyl-quinazoline (B) (250 mg), in the form of an off-white solid, M.P. 214 to 216 C (decomposition);

  <Desc / Clms Page number 40>

 NMR (CDCl3): 1.39 (t, 3H), 2.87 (q, 2H), 5.53 (broad s, 2H), 7.44 (m, 1H), 7.75 (m, 3H) ; mass spectrum (CI, ammonia): 174 (M + H) +.



  (Example 6B): (i) 4-chloro-2,6-diethylpyrimidine (0.86 g) is added (obtained as described in J. Chem.



  Soc., 1963,5642) to a saturated solution of ammonia in ethanol (50 ml) and the mixture is heated at 1350C for 16 hours in a sealed tube. The mixture is cooled to room temperature and the solvent is removed by evaporation. The residue is triturated in diethyl ether (3 x 2.5 ml) to obtain 4-amino-2, 6-diethylpyrimidine hydrochloride (C) (0.57 g), in the form of an off-white solid ;
 EMI40.1
 NMR (d6-DMSO): 1.18 (d from t, 6H), 2.55 (q, 2H), 2.66 (q, 2H), 7.6 (br s, 1H); mass spectrum (CI, ammonia): 152 (M + H) +.



  (ii) According to a procedure analogous to that described in Example 43, but starting from compound C, 4-amino-2,6-diethyl-5-iodopyrimidine is obtained in a yield of 38%. a solid ; NMR (CDCl): 1.28 (d of t, 6H), 2.71 (q, 2H), 2.85 (q, 2H), 5.42 (broad s, 2H); mass spectrum (CI, ammonia): 273 (X + H) +.



  (Example 7B): (i) Iodine (20.3 g) is added to a solution of 2,6-diethyl-4-hydroxypyrimidine (15.2 g) (obtained as described in J. Chem. Soc. , 1963, 5642) in a 1M sodium hydroxide solution (105 ml) and the mixture is stirred for 2 hours. The product is collected by filtration, washed with water and dried to obtain 2, 6-diethyl-4-hydroxy-5-iodopyimidine (C) (14.6 g) as a white solid broken, PF 166 to 168OC; NMR (d6-DMSO): 1.13 (d of t, EH), 2.51 (q, 2H), 2.70 (q, 2H), 12.53 (broad s, 1H); mass spectrum (CI, ammonia): 279 (M + H +.



  (ii) A mixture of compound C (555 mg), ethyl acrylate (0.33 ml), palladium (II) acetate is heated

  <Desc / Clms Page number 41>

 (50 mg) and triethylamine (1 ml) in DMF (3 ml) at 1200C for 6 hours. The mixture is cooled to room temperature and triturated in a saturated sodium carbonate solution. The product is collected by filtration and recrystallized from ethyl acetate to obtain ethyl 3- [(2,6-diethyl-4-hydroxy) pyrimidin-5-yl] acrylate (D) (200 mg ) in the form of an off-white solid, PF 171 to 174 C; NMR (CDCl): 1.33 (t of t, 9H), 2.80 (d of q, 4H), 4.26 (q, 2H), 7.30 (d, 1H), 7.70 (d , 1H); mass spectrum (CI, ammonia): 268 (M + NH4) +, 251 (M + H) +.



  (iii) A solution of compound D (1 g) in phosphorus oxychloride (10 ml) is heated at reflux for 1 hour. The mixture is cooled to room temperature and the volatile constituents are removed by evaporation. Ice is added to the residue and the mixture is basified with potassium carbonate. The mixture is extracted with ether (3 x 50 ml) and the combined extracts are dried (MgSO4).

   The solvent is removed by evaporation and the residue is purified by flash chromatography eluting with 11 ethyl acetate-hexane (1: 9 v / v) to obtain 3- [(4-chloro-2,6-diethyl) pyrimidin -3-yl] ethyl acrylate (E) (720 mg) in the form of an oil; NMR (CDClg): 1.32 (t of t, 9H), 2.89 (d of q, 4H), 4.30 (q, 2H), 6.35 (d, 1H), 7.71 (d , 1H); mass spectrum (CI, ammonia): 268.270 (M + H).



  (iv) Compound E (700 mg) is added to a saturated solution of ammonia in ethanol (50 ml) and the mixture is heated at 1200C for 12 hours in a sealed tube.



  The mixture is cooled to room temperature and the solvent is removed by evaporation. The residue is triturated with acetone and the solid is filtered off, then discarded. The filtrate is concentrated by evaporation and the residue is purified by flash chromatography to obtain ethyl 3- [(4-amino-2, 6-diethyl) pyrimidin-5-yl] acrylate (F) (220 mg) an oil;

  <Desc / Clms Page number 42>

 NMR (CDCl3): 1.30 (t of t, 9H), 2.73 (d of q, 4H), 4.28 (q, 2H), 5.07 (broad s, 2H); 6.29 (d, 1H), 7.73 (d, 1H); mass spectrum (CI, ammonia): 250 (M + H) +.



  (v) Compound F (50 mg) is added to a solution of sodium (18 mg) in ethanol (10 ml) and the mixture is heated at reflux for 2 hours. The mixture is cooled to room temperature and the solvent is removed by evaporation. A saturated solution of sodium chloride (10 ml) is added to the residue and the mixture is acidified to pH 4 with a solution of im citric acid. The mixture is then extracted with dichlcromethane (2 x 10 ml) and the combined extracts are dried (MgSO4).

   The solvent is removed by evaporation to obtain 2,4-diethylpyrido [2, 3-d] pyrimidin-7 (8H) -one (B) (22 mg), in the form of a foam; NMR (CDC13): 1.37 (t, 6H), 3.01 (d of q, 4H), 6.66 (d, 1H), 7.89 (d, 1H), 9.57 (s wide, 1H); mass spectrum (CI, ammonia): 204 (M-H) ".



  EXAMPLES 8 TO 11
According to a procedure analogous to that described in Example 1, but starting from the appropriate compound corresponding to the starting compound A of Example 1, the following compounds are obtained with yields of 53 to 85%.
 EMI42.1
 



  (Example 8): 2,4-diethyl-8- [(2'- (1Htetrazol-5-yl) biphenyl-4-yl) -methyl] hydrochloride -5, 6, 7, 8-tetrahydro-pyrido [2 , 3-d] pyrimidin-7-one as a solid, PF



  240 to 241OC; NMR (d-DMSO): 1.2 (dt, 6H), 2.85 (m, 6H), 2.99 (q, 2H), 5.22 (s, 2H), 7.01 (d, 2H ), 7.24 (d, 2H), 7.60 (m, 4H);
 EMI42.2
 mass spectrum (+ ve FA3, methanol-nitrobenzyl alcohol): 462 (M + Na) ", 440 (M-rH)"; microanalysis for C2HHN. 0.1, OHC1. 0, 1 (CH,;) 0: 25 27 7 51 2 Calculated: C, 62, 1; H, 5.5; N, 19.9%.



  Found: C, 62, 4; H, 5.5; N, 19.7%.

  <Desc / Clms Page number 43>

 
 EMI43.1
 (Example 9): 2/6-diethyl-5- (4-methylphenyl) -4- [(2'- (ltl-tetrazol-5-yl) methylamino] pyrimidine hydrochloride in the form of a solid, PF 246 C ; NMR (d6-DMSO): 1.05 (t, 3H), 1.24 (t, 3H), 2.39 (q, 2H), 2.40 (s, 3H), 2.86 (q, 2H), 4.60 (d, 2H), 7.03 (d, 2H), 7.20 (d, 4H), 7.39 (d, 2H), 7.48 (m, 4H), 8, 30 (t, 1H); mass spectrum (+ ve FAB, methanol-nitrobenzyl alcohol): 476 (M + H) +; microanalysis for CHN. 1.0HCl:
Calculated: C, 68, 0; H, 5.9; N, 19.1%.



   Found: C, 67.9; H, 6.0; N, 19.3%.



  (Example 10): 2,6-diethyl-5- (phenylmethyl) - 4 - [(2 '- (1H-tetrazol-5-yl) methylamino] pyrimidine hydrochloride in the form of a solid, PF 202 to 203OC; NMR (d6-DMSO): 1.02 (t, 3H), 1.15 (t, 3H), 2.5 (q, 2H), 2.55 (q, 2H), 3.93 (s, 2H ), 4.58 (d, 2H), 6.95 (d, 2H), 7.07 (d, 4H), 7.2 (m, 3H), 7.55 (m, 5H); mass spectrum (+ ve FAB, methanol-nitrobenzyl alcohol: 476 (M + H) "; microanalysis for C29H29N7.1,0HCl.1,0H2O:
Calculated: C, 70, 5; H, 6.3; N, 19.8%.



   Found: C, 70.4; H, 6.4; N, 19.6%.



  (Example 11): 2,4-diethyl-8- [(21- (1H-tetrazol-5-yl) biphenyl-4-yl) -methyl] hydrochloride-5, 6,7, 8-tetrahydropyrido [2, 3-d] pyrimidine in the form of a solid, PF 255 to 256OC; NMR (d6-DMSO): 1.20 (dt, 6H), 1.88 (m, 2H), 2.70 (m, 6H), 3.55 (m, 2H), 4.98 (s, 2H ), 7.08 (d, 2H), 7.27 (d, 2H), 7.60 (m, 4H); mass spectrum (+ ve FAB, methanol-nitrobenzyl alcohol): 426 (M + H) +; microanalysis for C25N27N5.1,0.HCl. 0.15 (C2H5) 20:
Calculated: C, 64.3; H, 6.0; N, 20.5%.



   Found: C, 64.1; H, 5, 9; N, 20.1%.



   The necessary starting compounds of formula IVa used in Examples 8 to 11 corresponding to the compound

  <Desc / Clms Page number 44>

 starting A of Example 1 are obtained with yields of 28 to 75% in the following manner: (Example 8A): According to a procedure analogous to that described in Example 6A, 2,4-diethyl is obtained -8- [(2'- (2-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-yl) methyl] - 5,6, 7, 8-tetrahydropyrido [2, 3-d] pyrimidin-7- one in the form of a foam; NMR (CDClg): 1.24 (t, 3H), 1.32 (t, 3H), 2.8 (m, 8H), 5.26 (s, 2H), 6.9 (m, 6H), 7.03 (d, 2H), 7.28 (complex m, 12H), 7.45 (m, 2H), 7.89 (m, 1H).



  (Example 9A): According to a procedure analogous to that described in Example 6A, 2, 6-diethyl-5- (4-methylphenyl) -4 - [(2'-2-triphenylmethyl-2H-tetrazol) is obtained. -5- yl) 4-biphenyl-yl) methylamino] -pyrimidine in the form of a foam;
 EMI44.1
 NMR (CDCl3): 1.10 (t, 3H), 1.35 (t, 3H), 2.36 (s, 3H), 2.40 (q, 2H), 2.83 (q, 2H), 4.95 (d, 2H), 4.6 (broad s, H), 6.90 (complex m, 8H), 7.05 (complex m, 7H), 7.25 (complex m, 9H), 7 , 45 (m, 2H), 7.90 (m, 1H).



  (Example 10A): According to a procedure similar to that
 EMI44.2
 described in Example 6A, 2, 6-die-thyl-5- (phánylmethyl) -4- [2- (2-riphenylmethyl-2H-tetrazcl-5-yl) biphenyl-4-yl) methylamino] is obtained -pyrimidine in the form of a foam; NMR (CDCl3): 1.31 (dt, 6H), 3.0 (broad s, 4H), 3.81 (s, 1H), 4.57 (d, 2H), 6.73 (d, 2H) , 6.90 (complex m, 6H), 7.00 (complex m, 4H), 7.10 (s, 1R), 7.26 (complex m, 11H), 7.50 (m, 3H), 7 , 91 (m, 1H); mass spectrum (-t-ve FAB, DMSO-alcoo2. nitrobenzyl: 718 (M + H) '.



  (Example 11A): According to a procedure analogous to that described in Example 1, part (i), the 2,4-
 EMI44.3
 dietyl-8- [21- (2-triphenylmethyl-2H-tetrazol-5-yl) biphenylL 4-yl) methyl] -5, 6, 7, 8-tetrahydropyrido [2, 3-d] -pyrimidine in the form of a foam; NMR (CDCl3): 1.25 (dt, 6R), 1.8 (m, 2H), 2.59 (m, 4H), 2.72 (q,

  <Desc / Clms Page number 45>

 2H), 3.13 (m, 2H), 4.82 (s, 2H), 6.9 (m, 6H), 7.07 (s, 3H), 7.15-7.5 (complex m, 14H), 7.92 (m, 1H); mass spectrum (+ ve FAB, methanol-nitrobenzyl alcohol): 668 (M + H) +.



   The necessary starting compounds of formula V used in Examples 8 to 11 corresponding to compound B of Example 1 are prepared in the following manner: (Example 8B): (i) A solution of 3- [4-amino -2, 6-diethyl) -pyrimidin-5-yl] ethyl acrylate (100 mg) in ethanol (6 ml) with catalytic hydrogenation on 30% palladium on charcoal. When the absorption of hydrogen ceases, the catalyst is separated by filtration on diatomaceous earth.

   The solvent is removed from the filtrate by evaporation to obtain ethyl 3- [(4-amino-2, 6diethyl) pyrimidin-5-yl] propionate (B) (88 mg) in the form of an oil; NMR (CDCl3): 1.18 (m, 9H), 2.6 (m, 8H), 4.09 (q, 2H), 5.09 (broad s, 2H); mass spectrum: (chemical ionization, ammonia): 252 (M + H) +.



  (ii) Metallic sodium (27 mg) is added to a solution of compound B (290 mg) in ethanol (15 ml) and the mixture is stirred at room temperature for 2 hours. The solvent is removed by evaporation and the residue is partitioned between water (5 ml) and ethyl acetate (20 ml). The aqueous layer is separated and extracted with ethyl acetate (20 ml). The combined organic solutions are dried (MgSO4) and the solvent is removed by evaporation to obtain 2, 4-diethyl-5, 6,7, 8tetrahydropyrido [2, 3-d] pyrimidin-7-one (C) (205 mg) in the form of a pale pink solid, PF 93 at 96 C; NMR (CDCl): 1.30 (dt, 6H), 2.86 (m, 8H), 8.02 (broad s, 2H); mass spectrum (chemical ionization, ammonia): 206 (M + H) +.



  (Example 9B): (i) A solution of 2,6-diethyl-4hydroxy-5-iodopyrimidine (1.0 g) in oxychloride is heated.

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 phosphorus (10 ml) at reflux for 2 hours. The solution is cooled to room temperature and the volatile constituents are removed by evaporation. Water (1CO ml) is added to the residue and the mixture is basified with solid potassium carbonate. The mixture is extracted with ether (2 x 50 ml) and the combined organic extracts are dried (MgSO4). The solvent is removed by evaporation to obtain 4-chloro-2,6-diethyl-5-iodopyrimidine (C) (1.01 g); NMR (CDClg): 1.31 (dt, 6H), 2.94 (dq, 4H); mass spectrum (chemical ionization, ammonia): 296.298 (M + H) +.



  (ii) A mixture of compound C (0.72 g), 4-methylphenylboronic acid (0.35 g), tetrakis- (triphenylphosphine) palladium (86 mg), saturated bicarbonate solution is heated. sodium (12 ml) and toluene (40 ml) at reflux for 6 hours. The mixture is cooled to room temperature and the organic phase is separated. The aqueous layer is extracted with ethyl acetate and the combined organic phases are dried (MgSO 4), then the solvent is removed by evaporation.

   The residue is purified by flash chromatography with elution with ethyl acetate hexane (1: 9 v / v) to obtain 4-chloro-2,6-diethyl-5- (4-methylphenyl) pyrimidine (D) (0 , 42 mg) as a solid;
 EMI46.1
 NMR (CDC13): 1.13 (t, 3H), 1.39 (t, 3H), 2.56 (q, 2H), 2.97 (q, 2H), 7.10 (d, 2H), 7.27 (d, 2H); mass spectrum (chemical ionization, ammonia): 261 (M "-H) +.



  (iii) Compound D (0.40 g) is added to a saturated solution of ammonia in ethanol (10 ml) and the mixture is heated at 1500C for 12 hours. The volatile constituents are removed by evaporation and the residue is subjected to partition between a saturated sodium bicarbonate solution (5 ml) and acetate. ethyl (2 ml). : n separates the aqueous layer, cn the extract with ethyl acetate (20 ml)

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 and the combined organic extracts are dried (MgSO 4). The solvent is removed by evaporation and the residue is purified by flash chromatography with elution with ethyl acetate to obtain 4-amino-2,6-diethyl-5- (4-methylphenyl) - pyrimidine (E) (0 , 2 g) in the form of a solid, P.

   F. 110-114 C; NMR (CDCI 3): 1.10 (t, 3H), 1.35 (t, 3H), 2.41 (s, 3H), 2.42 (q, 2H), 2.78 (q, 2H), 4.62 (br s, 2H), 7.12 (d, 2H), 7.27 (d, 2H); mass spectrum (chemical ionization, ammonia): 242 (M + H) - \ (Example 10B): (i) Benzyl bromide (1.18 ml) is added to a suspension of zinc powder (1.0 g in THF (25 ml) containing dibromoethane (20 mg) and the mixture is stirred at room temperature for 1 hour. 4-Chloro-2,6-diethyl-5-iodopyrimidine (0.9 g) is added and tetrakis (triphenylphosphine) palladium (0.1 g), then the mixture is heated at reflux for 4 hours under an argon atmosphere, the mixture is cooled to room temperature and the insoluble substances are filtered off.

   The filtrate is extracted with a saturated solution of ethylenediaminetetraacetic acid, the organic phase is separated and dried (MgSO). The volatile constituents are removed by evaporation and the residue is purified by flash chromatography with elution with ethyl acetate-hexane (1: 9 v / v) to obtain 4-chloro-2,6-diethyl-5- ( phenylmethyl) pyrimidine (C) (0.5 g) as an oil; NMR (CDCl): 1.19 (t, 3H), 1.38 (t, 3H), 2.74 (q, 2H), 2.93 (q, 2H), 4.18 (s, 2H), 7.08 (d, 2H), 7.27 (m, 3H).



  (ii) Compound C (0.5 g) is added to a saturated solution of ammonia in ethanol (15 ml) and the mixture is heated at 1500C for 18 hours. The volatile constituents are removed by evaporation and the residue is purified by flash chromatography with elution with ethyl acetate to obtain 4-amino-2, 6-diethyl-5-

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 (phenylmethyl) pyrimidine (0.15 g) as an oil; NMR (CDCl3): 1.28 (dt, 6H), 2.77 (dq, 4H), 3.91 (s, 2H), 4.67 (broad s, 2H), 7.13 (m, 2H) , 7.28 (m, 3H); mass spectrum (chemical ionization, ammonia): 242 (M + H) +.



  (Example 11B): A solution of 2,4-diethyl-5,6, 7, 8-tetrahydro-pyrido [2,3-d] pyrimidin-7-one (205 mg) in THF (5 ml) is added. dropwise to a suspension of lithium aluminum hydride (40 mg) in THF (10 ml).



  The mixture is heated at reflux for 1 hour under an argon atmosphere. The mixture is cooled to room temperature and a 1M solution of sodium hydroxide (1 ml) is added thereto. The volatile constituents are removed by evaporation and the residue is partitioned between ethyl acetate (20 ml) and water (5 ml). The organic layer is separated and dried (MgSO.). The solvent is removed by evaporation to obtain 2,4diethyl-5, 6,7, 8-tetrahydropyrido [2,3-d] pyrimidine in the form of a solid; NMR (CDCl): 1.23 (dt, 6H), 1.94 (m, 2H), 2.62 (m, 6H), 3.40 (m, 2H), 5.22 (broad s, 1H) ; mass spectrum (chemical ionization, ammonia): 192 (M + H).



  EXAMPLE 12 (Note: all parts are by weight)
The compounds of the invention can be administered for therapeutic or prophylactic purposes to warm-blooded animals, for example human beings, in the form of conventional pharmaceutical compositions, of which typical examples are the following:

   a) Capsule (for oral administration) Active constituent 20 Lactose in powder 578, 5 Magnesium stearate 1.5 b) Tablet (for oral administration) Constituent ac-c. if * 50

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 Microcrystalline cellulose 400 Starch (pregelatinized) 47.5 Magnesium stearate 2.5 c) Solution for injection (for intravenous administration) Active ingredient * 0.05-1.0 Propylene glycol 5.0 Polyethylene glycol (300) 3.0-5 , 0 Purified water to make 100% d) Suspension iniectable (for intramuscular administration) Active constituent * -0, 05-1, 0 Methylcellulose 0.5 Tween 80 0.05 Benzyl alcohol 0, 9 Benzalkonium chloride 0.1 Purified water to make 100% Note:

   The active ingredient * can typically be an example described above and is advantageously presented in the form of a pharmaceutically acceptable acid addition salt, such as the hydrochloride. The tablet and capsule compositions can be coated in a conventional manner to modify or slow down the dissolution of the active ingredient. For example, they can be provided with a conventional coating suitable for intestinal digestion.

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 EMI50.1
 

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 EMI51.1
 

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 EMI52.1
 

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 EMI53.1
 

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 EMI54.1
 

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  Diagram 1
 EMI55.1
 

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 Note: R '= lower alkyl; Rx and Ry are optional active substituents: a) sodium ethylate, ethanol, room temperature
 EMI56.1
 b) 2-toluenesulfonic acid, benzene, reflux with azeotropic elimination of water; heating c) POClg, reflux d) RNH., ethanol, room temperature up to 1800C e) bis (trifluoroacetoxy) iodobenzene, 12'CH2C12 / MeOH f) tetrakis (triphenylphosphine) palladium, triethylamine, dimethoxyethane g) ethyl acrylate, Pd (II) acetate, Et3N, 120 C, DMF h) sodium ethylate, ethanol, reflux i) hydrogenation, palladium on carbon.


    

Claims (12)

 EMI57.1   R E V E N D I C A T I O N S CLAIMS 1. - Pyrimidine derivative of formula I  EMI57.2    EMI57.3  where R′ is hydrogen, (1-8C) alkyl, (3-8C) cycloalkyl), phenyl or (1-4C) substituted alkyl, the latter containing one or more fluoro substituents or carrying a (3-SC) cycloalkyl substituent, (1-4C) alkoxy or phenyl; R2 is chosen from (1-8C) alkyl, (3-8C) cycloalkyl, phenyl or (1-4C) substituted alkyl, the latter containing one or more fluoro substituents or carrying a substituent (3-8C) cycloalkyl, (1- 4C) alkoxy or phenyl, halo, (1-4C) alkoxy, amino and alkylamino and dialkoylamino of up to 6 carbon atoms;    R3 is chosen from hydrogen, (1-8C) alkyl, (3-8C) cycloalkyl, (1-4C) substituted alkyl carrying a substituent (3-8C) cycloalkyl, amino, hydroxy, (1-4C) alkoxy, carboxy or (1-4C) alkoxycarbonyl or containing one or more fluoro, hydroxy (1-4C) alkoxy, carboxy, (1-4C) alkoxycarbonyl, (3-6C) alkenyloxycarbonyl, cyano, nitro, carbamoyl, (1-4C) alkanoyl substituents , N-alkyl carbamoyl and di- (N-alkyl) carbamoyl of up to 7 carbon atoms, halo, amino, alkyllamino and dialkoylamino of up to 6 carbon atoms, (1-4C) alkylamino, phenyl, phenyl - (1-4C) alkyl and benzoyl,  the benzene ring of the last three radicals optionally carrying one or two substituents chosen from (1-4C) alkyl, (1-4C) alkoxy,  <Desc / Clms Page number 58>  halo, cyano, trifluoromethyl, nitro, hydroxy, carboxy, (1-4C) alkanoylamino, (1-4C) alkanoyl, fluoro (1-4C) alkoxy, hydroxy (1-4C) alkyl, (1-4C) alkoxy (1 -4C) alkyl, carbamoyl,  EMI58.1  alkyl- or dialkoylcarbamoyl of up to 7 carbon atoms, sulfamoyie, N-alkyl or di- (N-alkyl) sulfamoyl of up to 6 carbon atoms, (1-4C) alkoxycarbonyl, (1-4C) alkanesulfonamido, (1-4C) alkyl.  S (0) n- [where n is zero, 1 or 2], 1H-tetrazol-5-yl, phenyl, phenoxy, benzyloxy, benzyloxycarbonyl, benzamido and benzenesulfonamido, the benzene part of the last six radicals optionally carrying a halogen substituent, (1-4C) alkyl or (1-4C) alkoxy; R4 is hydrogen or (1-4C) alkyl; or R2 and R3 together complete a benzene ring, this benzene ring optionally carrying one or two substituents chosen independently from any of the meanings previously defined for R; or R2 and R3 together form a (3-6C) alkenylene radical, a (3-6C) alkylene radical or a (3-6C) alkylene radical in which a methylene is replaced by carbonyl;    EMI58.2  or R3 and R4 together form a bonding radical A which is chosen from-CH-CH -, - CH-CH-CH -, - CO-CH -, - CH-CO-, - CO-CH-CH -, - CH-CH-CO -, - CO-CH = CH-and-CH == CH-CO-, and in which this linking radical optionally carries one or two substituents independently chosen from (1-4C) alkyl, (1- 4C) substituted alkyl containing one or more fluoro substituents or carrying a (3-8C) cycloalkyl, (1-4C) alkoxy or phenyl, (3-8C) cycloalkyl, (1-4C) alkoxy, halogen, carboxy, (1 -4C) 4-alkoxycarbonyl, (3-6C) alkenyloxycarbonyl, cyano, nitro, (1-4C) alkanoyl, (1-4C) alkyl.  S (0) m- [where m is zero, 1 or 2] and phenylsulfonyl; A is a radical of the partial formula IIa, IIb or IIc  <Desc / Clms Page number 59>    EMI59.1  where (1) in partial formula IIa, B is a direct bond or is phenylene optionally carrying a substituent chosen from (1-4C) alkyl, (1-4C) alkoxy, halo, (1-4C) alkanoyl, trifluoromethyl, cyano and nitro; Ra is hydrogen, (1-4C) alkyl, (1-4C) alkoxy, halo, cyano, trifluoromethyl or nitro; and Za is 1H-tetrazol-5yl, a carboxy radical or an ester thereof hydrolyzable in vivo, -CO. NH. (1H-tetrazol-5-yl), or a radical of formula-CO. NH.  COQ where R8 is (1-6C) alkyl, (3-8C) cycloalkyl, trifluoromethyl or phenyl; (2) in partial formula IIb, B2 is oxygen, sulfur or a radical of formula -NR5- where R5 is hydrogen or (1-4C) alkyl; Zb has any of the meanings defined above for Za; B3 is phenyl optionally carrying one or two substituents independently selected from (1-4C) alkyl, (1-4C) alkoxy and halo; and Rb and Rc are independently selected from  EMI59.2  hydrogen, (1-4C) alkyl, (1-4C) alkoxy and halo; and (3) in partial formula IIc, Zc is 1H-tetrazol-5-yl, carboxy or an ester thereof hydrolyzable in vivo or a radical of formula CF3SO2NH-;  Rd is selected from hydrogen, (1-4C) alkyl, (1-4C) alkoxy, halo, trifluoromethyl, cyano and nitro; Xr is oxygen, sulfur or a radical of  <Desc / Clms Page number 60>    formula-NR-whereRest hydrogen or (1-4C) alkyl; and X2 is nitrogen or a radical of formula -C (R7) = where R7 is hydrogen, (1-4C) alkyl optionally containing one or more substituents fluoro, carbamoyl or N-alkyl- or di- (Nalkyl) carbamoyl up to with 7 carbon atoms, halo, cyano, (1-4C) alkoxycarbonyl or (1-4C) alkanoyl;  and in which any of the phenyl parts of R ', R2 or R8 or of an optional substituent of the linking radical A can be unsubstituted or carries one or two substituents chosen independently from (1-4C) alkyl, (l -4C) alkoxy, halo, cyano and trifluoromethyl; or a non-toxic salt thereof; but excluding 4- [N-butyl-N- (2 '- (1H-tetrazol-5yl) biphenyl-4-ylmethyl) amino] -2,6-dimethylpyrimidine.  (2) in the partial formula IIb, B2 is oxygen, sulfur or  <Desc / Clms Page number 63>  a radical of formula-NR-where R is hydrogen, methyl, ethyl or propyl; B3 is phenyl optionally carrying one or two substituents independently chosen from methyl, ethyl, methoxy, ethoxy, fluoro, chloro or bromo; and Rb and Rc are independently selected from hydrogen, methyl, ethyl, methoxy, ethoxy, fluoro, chloro and bromo; and (3) in the partial formula IIc, Rd is chosen from hydrogen, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl, cyano and nitro;  X1 is oxygen, sulfur or a radical of formula-NR-where R is hydrogen, methyl, ethyl or propyl; and X2 is nitrogen or a radical of formula -C (R7) = where R7 is hydrogen, methyl, ethyl, fluoromethyl, trifluoromethyl, 2,2, 2-trifluoroethyl, pentafluoroethyl, carbamoyl, N-methylcarbamoyl,  EMI63.1  N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, fluoro, chloro, bromo, iodo, cyano, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl or propionyl;  and where any one of the phenyl parts of R1, R2 or rua or of an optional substituent on the linking radical A can be unsubstituted or carry one or two substituents chosen independently from methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, cyano and trifluoromethyl; or a non-toxic salt thereof.    2-methyl-2-propenyloxy-  EMI61.1  carbonyl, 3-methyl-3-butenyloxycarbonyl, cyano, nitro, carbamoyl, formyl, acetyl, butyryl, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, H, N, -diethyl- carbamoyl, fluoro, chloro, bromo , iodo, amino, methylamino, ethylamino, butylamino, dimethylamino, diethylamino, dipropylamino, formamido, acetamido, propanamido, phenyl, benzyl, 1-phenylethyl, 2-phenylethyl or benzoyl, the benzene ring of the last five radicals optionally bearing one or two substituents chosen from methyl, ethyl, methoxy, ethoxy, chloro, bromo, iodo, cyano, trifluoromethyl, nitro, hydroxy, carboxy, formamido, acetamido, propamido, formyl, acetyl, butyryl, trifluoromethoxy, 2-fluoroethoxy, 2,2, 2- trifluoroethoxy, 3,3, 3-trifluoropropoxy,  hydroxymethyl, 1-hydroxyethyl,  EMI61.2  2-hydroxyethyl, 2-methoxyethyl, 2-ethoxyethyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, sulfamoyl, N-methylsulfamoyl, N-ethylsulfamoyl, N-ethylsulfamoyl N, N-diethylsulfamoyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, methanesulfonamido, ethanesulfonamido, methylthio, ethylthio, methylsulfinyl,  EMI61.3  ethylsulfinyl, methylsulfonyl, ethylsulfonyl, 1H-tetrazol-5-yl, phenyl, phenoxy, benzyloxy, benzyloxycarbonyl, benzamido and benzenesulfonamido, the benzene part of the last six radicals optionally bearing a substituent fluoro, chloro, bromo, methyl, ethyl, methoxy or ; R4 is hydrogen, methyl, ethyl or propyl;    <Desc / Clms Page number 62>  or R2 and R3 together complete a benzene ring, this benzene ring optionally carrying one or two substituents chosen independently from any of the preceding meanings defined for R3; or R2 and R3 together form a radical 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, trimethylene, tetramethylene, pentamethylene, 1-oxopropylidene, 3-oxopropylidene, 1-oxobutylidene or 4- oxobutylidene;    EMI62.1  or R3 and R4 together form a bonding radical A which is chosen from-CH-CH -, - CH-CH-CH -, - CO-CH -, - CH-CO-, - CO-CH-CH, -CH -CH-CO -, - CO-CH = CH-and-CH = CH-CO-, and where the linking radical A optionally carries one or two substituents chosen from methyl, ethyl, fluoromethyl, trifluoromethyl, 2,2,2 -trifluoroethyl, pentafluoroethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylethyl, cyclopentylethyl, 2-methoxyethyl, 2-ethoxyethyl, benzyl, 1-phenylethyl, 2-phenylethyl, cyclopropyl, cyclopentyl, cyclopentyl, cycloheoxyethyl, cycloheoxyoxy , carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, allyloxycarbonyl, 2-methyl-2-propenyloxycarbonyl, 3-methyl-3-butenyloxycarbonyl, cyano, nitro, formyl, acetyl,  butyryl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl and phenylsulfonyl; Al is a radical of partial formula IIa, IIb or IIc where (1) in partial formula IIa, Bu is a direct bond or is phenylene optionally carrying a substituent chosen from methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, formyl, acetyl, propionyl, trifluoromethyl, cyano and nitro; Ra is hydrogen, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl, cyano or nitro; R8 is methyl, ethyl, propyl, isopropyl, butyl, pentyl, cyclcbutyl, cyclopentyl, cyclchexyl, trifluoromethyl or phenyl; 2. A compound according to claim 1, wherein Ru is hydrogen, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, fluoromethyl, trifluoromethyl, 2.2, 2- trifluoroethyl, pentafluoroethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexymethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopentylethyl, 2-methoxyethyl, 2-ethoxyethyl, benzyl, 1-phenylethyl or 2-phenylethyl;  R2 is methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, fluoromethyl, trifluoromethyl, 2,2, 2-trifluoroethyl, pentafluoroethyl, cycloprcpylmethyl, cyclopentylmethyl, cyclohexyl, cyclohexyl cyclohexylmethyl, cyclopentylethyl, 2-methoxyethyl, 2-ethoxyethyl, benzyl, 1-phenylethyl or 2-phenylethyl;    R3 is hydrogen, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cycicpentylmethyl, cyclohexylmethyl, cyclopentylethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxyethyl 2-  <Desc / Clms Page number 61>  aminoethyl, methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonytlethyl, fluoromethyl, trifluorethyl, fluoromethyl, trifluoroethyl hydroxymethyloxy, 1-hydroxyethyloxy, 2-hydroxyethyloxy, 3-carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, allyloxycarbonyl, 3. The compound according to claim 1, wherein R1 and R2 are both (1-8c) alkyl. 4. The compound of claim 1 or 3, wherein R1 is (1-8C) alkyl; R2 is (1-8C) alkyl; R3 is halo; R4 is hydrogen or (1-4C) alkyl;  EMI63.2  or R2 and R3 together form a (3-6C) alkylene radical;  or R3 and R4 together form a bonding radical A which is chosen from-CH-CH -, - CH-CH-CtL -, - CO-CH -, - CH-CO-, - CO-CH-CH -, - CH-CH-CO -, - CO-CH = CH-and-CH = CH-CO-, and where  <Desc / Clms Page number 64>  the linking radical A optionally carries one or two substituents independently selected by (1-4C) alkyl, (1-4C) substituted alkyl containing one or more fluoro substituents or carrying a substituent (3-8C) cycloalkyl, (1-4C) alkoxy or phenyl, (3-8C) cycloalkyl, (1-4C) alkoxy, halo, carboxy, (1-4C) alkoxycarbonyl, (3-6C) alkenyloxycarbonyl, cyano, nitro, (1-4C) alkanoyl, (1-4C) 4C) alkyl.  S (0) m- [where m is zero, 1 or 2] and phenylsulfonyl; A1 is a radical of partial formula IIa, IIb or IIc where (1) in the partial formula III, Bu is a direct bond or is phenylene optionally carrying a substituent chosen from (1-4C) alkyl, (1-4C) alkoxy, halo, (1-4C) alkanoyl, trifluoromethyl, cyano and nitrc; Ra is hydrogen, (1-4C) alkyl, (1-4C) alkoxy, halo, cyano, trifluoromethyl or nitro; and Za is 1H-tetrazol-5-yl, a carboxy radical or an ester thereof hydrolyzable in vivo, -CO. NH. (1H-tetrazol-5-yl), or a radical of formula -CO. NH.  CO where R8 is (1-6C) alkyl, (3-8C) cycloalkyl, trifluoromethyl or phenyl; (2) in partial formula IIb, B2 is oxygen, sulfur or a radical of formula-NR-where R is hydrogen or (1-4C) alkyl; Zb has any of the meanings defined above for Za; B3 is phenyl optionally carrying one or two substituents independently selected from (1-4C) alkyl, (1-4C) alkoxy and halo; and Rb and Rc are independently selected from hydrogen, (1-4C) alkyl, (1-4C) alkoxy and halo; and (3) in partial formula IIc, Zc is 1H-tetrazol-5-yl, carboxy or an ester thereof hydrolyzable in vivo or a radical of formula CF3SO2NH-;  Rd is selected from hydrogen, (1-4C) alkyl, (1-4C) alkoxy, halo, trifluoromethyl, cyano and nitro; X is oxygen, sulfur or a radical of formula -NR6- where R6 is hydrogen or (1-4C) alkyl; and Xes nitrogen or is a radical of formula -C (R7) = where R7 is-: hydrogen, (1-4C) alkyl optionally containing one or  <Desc / Clms Page number 65>    EMI65.1  several fluoro, carbamoyl or N-alkyl-or di- (N-alkyl) carbamoyl substituents of up to 7 carbon atoms, halogeno, cyano, (1-4C) alkoxycarbonyl or (1-4C) alkanoyl;  and wherein any of the phenyl parts of R1, R2 or R8 or of an optional substituent on the linking radical A can be unsubstituted or carry one or two substituents independently chosen from (1-4C) alkyl, (1- 4C) alkoxy, halogeno, cyano and trifluoromethyl; or a non-toxic salt thereof. 5. A compound according to claim 3 or 4, wherein R3 is halo. 6. A compound according to claim 1,3 or 4, wherein R2 and R3 together form an alkylene radical (3-6C). 7. A compound according to claim 1 or 3, in which R3 is phenyl or benzoyl, one or the other optionally carrying one or two substituents chosen independently from (1-4C) alkyl, (1-4C) alkoxy, halo, cyano, trifluoromethyl, nitro, hydroxy, carboxy, (1-4C) alkanoylamino, (1-4C) alkanoyl, fluoro (1-4C) alkoxy, hydroxy (1-4C) alkyl, (1-4C) alkoxy (1-4C ) alkyl, carbamoyl,  EMI65.2  alkyl- or dialkoylcarbamoyl of up to 7 carbon atoms, sulfamoyl, alkyl- or dialkoylsulfamoyl of up to 6 carbon atoms, (1-4C) alkoxycarbonyl, (1-4C) alkanesulfonamido, (1-4C) alkyl.  S (0) n- [where n is zero, 1 or 2], 1H-tetrazol-5-yl, phenyl, phenoxy, benzyloxy, benzyloxycarbonyl, benzamido or benzenesulfonamido, the benzene part of the last six radicals optionally carrying a halogen substituent, (1-4C) alkyl or (1-4C) alkoxy; or a non-toxic salt thereof. 8. A compound according to claim 1 or 3, in which R3 is phenyl (1-4C) alkyl optionally carrying one or two substituents chosen independently from (1-4C) alkyl, (1-4C) alkoxy, halogeno, cyano, trifluoromethyl, nitro, hydroxy, carboxy, (1-4C) alkanoylamino, (1-4C) alkanoyl, fluoro (1-4C) alkoxy, hydroxy (1-4C) alkyl,  <Desc / Clms Page number 66>    (1-4C) alkoxy (1-4C) alkyl, carbamoyl, alkyl- or dialkoylcarbamoyl of up to 7 carbon atoms,  EMI66.1  sulfamoyie, alkyl- or dialkoylsulfamoyl of up to 6 carbon atoms, (1-4C) alkoxycarbonyl, (1-4C) alkanesulfonamido, (1-4C) alkyl.  SC) n- [where n is zero, 1 or 2], 1H-tetrazol-5-yl, phenyl, phenoxy, benzyloxy, benzyloxycarbonyl, benzamido and benzenesulfonamido, the benzene part of the last six radicals optionally carrying a halogen substituent, (1 -4C) alkyl or (1-4C) alkoxy; or a non-toxic salt thereof. 9. Compound of formula I chosen from: 2,6-dimethyl-4 [N- (2'- (1H-tetrazol-5-yl) biphenyl-4ylmethyl) amino] -pyrimidine; 2-ethyl-4- [(2'- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl) -  EMI66.2  amino] -5,6,7,8-tetrahydroquinazoline; la2, 6-dimethyl-5-iodo-4- [(2'- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl) amino] pyrimidine; 2,6-diethyl-5-iodo-4 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4ylmethyl) amino] pyrimidine;  EMI66.3  2,4-diethyl-S- [(2'- (1H-tetrazol-5-yl) biphenyl-4ylmethyl) pyrido [2,3-d] pyrimidin-7 (8H) -one; 2,4-diethyl-S- [(2'- (1H-tetrazol-S-yl) biphenyl-4yl) methyl] -5, 6, 7, 8-tetrahydropyrido [2, 3-d] pyrimidin-7- one;  2,6-diethyl-5- (4-methylphenyl) -4- [(2'- (1H-tetrazol-5- yl) methylamino] pyrimidine; and 2,6-diethyl-5- (phenylmethyl) -4 - [(2 [- (1H-tetrazol-5yl) methylamino] pyrimidine; and their non-toxic salts. 10. Salt according to any one of the preceding claims, which is chosen from the salts with acids forming physiologically acceptable anions and, for the compounds of formula I which are acid, the salts of alkali metals, of alkaline earth metals, aluminum and ammonium, and salts with organic bases providing physiologically acceptable cations.  <Desc / Clms Page number 67>   11. Process for the preparation of a compound of formula I or of a non-toxic salt thereof, according to any one of the preceding claims, which is characterized in that: (a) for the compounds of formula I where A1 is a radical of partial formula IIa, IIb or IIc where Za, Zb and Zc are respectively carboxylated, a carboxylic acid derivative of formula IIIa, IIIb or IIIc  EMI67.1  where Qa, Qb and Qc are respectively protected carboxy radicals chosen from (1-6C) alkoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl and carbamoyl, is converted to carboxy;  (b) for the compounds of formula l where A is a radical of partial formula IIa, IIb or IIc where Za, Zb and Zc are respectively tetrazolyl, a compound of formula IVa, IVb or IVc  <Desc / Clms Page number 68>    EMI68.1  where La, Lb and Lc are respectively protective radicals attached to a nitrogen atom of the tetrazolyl part, is deprotected; (c) an aminopyrimidine of formula V  EMI68.2    EMI68.3  is alkylated using a compound of formula VIIa, VIII or Vile  <Desc / Clms Page number 69>    EMI69.1  where Hal. represents an appropriate leaving radical;  (d) a heterocyclic derivative of formula VI  EMI69.2  where y1 represents an appropriate leaving radical, is reacted with an amine of formula XIIIa, XIIIb or XIIIc  EMI69.3    <Desc / Clms Page number 70>    EMI70.1  (e) for the compounds of formula l where A1 is a radical of partial formula IIc where Zc is a radical of formula CF3SO2NH-, a compound of formula XIV  EMI70.2  is reacted with triflucromethanesulfonic acid anhydride;  or (f) for the compounds of formula l where A is a radical of partial formula IIa where Za is tetrazolyl, B1 is R-phenylene optionally carrying a substituent chosen from (1-4C) alkyl, (1-4C) alkoxy, halo, (1-4C) alkanoyl, trifluoromethyl, cyano and nitro, a  <Desc / Clms Page number 71>  compound of formula XVI  EMI71.1  where p1 is an electron deficient phenyl radical or a pyrimidyl or pyridyl radical;  Re is hydrogen, (1-4C) alkyl, (1-4C) alkoxy, halo, (1-4C) alkanoyl, trifluoromethyl, cyano or nitro, is reacted with a base chosen from a hydroxide, (1-12C) alkanolate, (1-12C) alkanethiolate, phenolate, thiophenolate or diphenylphosphide of alkali metal, where any phenyl ring of the last three radicals can optionally carry a (1-4C) alkyl radical, (1-4C) alkoxy or halo; after which: when a compound of formula I is required where Za, Zb or Zc is CO. NH. (1H-tetrazol-5-yl), a radical of formula - CO.  NH. SO2R8 or an ester radical, a carboxylic acid of formula I where Za, Zb and Zc is carboxy (or a reactive derivative of this acid) is reacted with 5-aminotetrazole, a sulfonamide of formula NH2. SO2R8 or a salt thereof or a suitable alcohol or with a salt thereof; when a non-toxic salt of a compound of formula I is required, it is obtained by reaction with the appropriate base providing a physiologically acceptable cation, or with the appropriate acid providing a physiologically acceptable anion or by any other conventional method of formation a salt;  and when an optically active form of a compound of  <Desc / Clms Page number 72>  formula I is required, one of the methods (a) to (e) above is carried out on an optically active starting compound, or the racemic form of a compound of formula I where Za, Zb or Zc is a radical acid is split by reaction with an optically active form of an appropriate organic base, followed by the conventional separation of the diastereoisomeric mixture of the salts thus obtained and the release of the required optically active form of the compound of formula I by conventional treatment with an acid ; and where the radical Pm is a radical of partial formula  EMI72.1  and wherein the generic radicals have any of the meanings defined in any of claims 1 to 8 unless otherwise indicated. 12. pharmaceutical composition which comprises a  EMI72.2  compound of formula I or a non-toxic salt thereof, according to any one of claims 1 to 10, together with a pharmaceutically acceptable diluent or excipient.