GB2284419A - Pyrimidine derivative and pharmaceutical composition - Google Patents

Pyrimidine derivative and pharmaceutical composition Download PDF

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GB2284419A
GB2284419A GB9500538A GB9500538A GB2284419A GB 2284419 A GB2284419 A GB 2284419A GB 9500538 A GB9500538 A GB 9500538A GB 9500538 A GB9500538 A GB 9500538A GB 2284419 A GB2284419 A GB 2284419A
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group
carbon atoms
tetrazolyl
general formula
carboxyl
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GB9500538D0 (en
Inventor
Torataro Minegishi
Akihiro Ohkubo
Izumi Shimoyama
Hideki Nagano
Shigeo Iida
Hiroaki Sato
Yoshiko Kawada
Tadashi Mizuta
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JFE Engineering Corp
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NKK Corp
Nippon Kokan Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

A pyrimidine derivative having an angiotensin (II) antagonism and represented by general formula (I), wherein A represents (I-1) or (I-2), R<1> and R<2> represent each hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen or optionally substituted phenyl; R<3> and R<4> represent each hydrogen, alkyl, alkoxy, halogen, nitro, sulfone, carboxy, alkoxycarbonyl cycloalkoxycarbonyloxyalkoxycarbonyl alkanoyloxy alkoxycabonyl or optionally protected tetrazolyl, or R<3> and R<4> may be combined together to form a fused 5- or 6-membered ring which may be substituted; X represents O, NH or S(O)p; p represents an integer of 0 to 2; m represents 1 or 2; B represents carboxy, alkoxycarbonyl or optionally protected tetrazolyl; and n represents 1 or 2. <IMAGE>

Description

DESCRIPTION PYRIMIDINE DERIVATIVE AND PHARMACEUTICAL COMPOSITION TECHNICAL FIELD The present invention relates to a novel pyrimidine derivative and a pharmaceutical composition containing the pyrimidine derivative as an effective ingredient, more particularly to an angiotensin II antagonist. The abovementioned novel pyrimidine derivative according to the present invention exhibits an angiotensin II antagonism, and so is useful for various cardiovascular system diseases, for example, hypertension, cordiac disease, cerebral apoplexy, and arteriosclerosis.
BACKGROUND ART Renin-angiotensin system is known as a major factor to raise blood pressure. It is believed that the active renin (i.e., proteinase) secreted from the kidneys acts specifically on the renin substrate (angiotensinogen) produced in the liver to produce angiotensin I (AI), then, the resulting AI is converted to angiotensin II (AII) by the angiotensin converting enzyme (ACE) produced in the lungs, and the resulting AII exhibits a strong activity to raise blood pressure. Therefore, an AII antagonist may be used for the treatment of cardiovascular system diseases, such as hypertension.
Hitherto, many angiotensin II analogues, such as [Sarl, Ala8] AII (saralasin), was reported to exhibit an angiotensin II antagonism. However, these AII antagonists had disadvantages in that the duration to exhibit efficacy is short and no effect is exhibited in oral administration.
Further, imidazole derivatives as non-peptide type AII antagonists were disclosed in many patent publications; for example, Japanese Unexamined Patent Publications (Kokai) No. 56-71074, No. 57-98270, No. 58-157768, No. 63-23868, and No. 1-287071. Further, pyrimidine derivatives have been disclosed in EP-0407342, Japanese Unexamined Patent Publications (Kokai) No. 3-133964, No. 3-197466, No. 4 120072, No. 4-230370, No. 4-261156, and No. 4-330073, and EP-0445811.
DISCLOSURE OF INVENTION The inventors of the present invention engaged in intensive research to obtain a non-peptide AII antagonist which exhibits a superior AII antagonism, can be administered orally, and is highly safe, and as a result, found that a group of pyrimidine derivatives having a chemical structure different from that of the conventional pyrimidine derivatives and carrying a substituted phenylalkyl group at 5-position of the pyrimidine ring exhibit a strong antagonism. The present invention is based on this finding.
Accordingly, the present invention relates to a pyrimidine derivative of the general formula (I):
wherein A is a group of the general formula (I-l):
wherein R1 and R2, which may be same or different, are a hydrogen or hologen atom, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkylthio, phenyl or substituted phenyl group, R3 and R4, which may be same or different, are a hydrogen or halogen atom, lower alkyl, lower alkoxy, nitro, sulfone, carboxyl, lower alkoxycarbonyl, cycloalkoxycarbonyloxyalkoxycarbonyl, lower alkanoyloxyalkoxycarbonyl, tetrazolyl or protected tetrazolyl group, or R3 and R4 may be combined together with the ring carbon atoms to which they are bonded to form a condensed 5- or 6-membered ring which may be substituted, X is O, NH or S(O)p, p is an integer of 0 to 2, and m is an integer of 1 to 2, or a group of the general formula (I-2):
wherein R1, R2, R3, R4, X and m have the same meanings as above, B is a carboxyl, lower alkoxycarbonyl, tetrazolyl, or protected tetrazolyl group, and n is an integer of 1 to 2 [hereinafter, sometimes referred to as the compound (I) of the present invention], or a salt thereof.
Further, the present invention relates to a pharmaceutical composition, in particular an angiotensin II antagonist, characterized by containing the pyrimidine derivative of the above-mentioned general formula (I) or pharmaceutically acceptable salt thereof as an effective ingredient.
BEST MODE FOR CARRYING OUT THE INVENTION The term "lower alkyl group" used herein means, for example, a straight or branched alkyl group with 1 to 6 carbon atoms, such as, methyl, ethyl, propyl, isopropyl, nbutyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, t-pentyl, l-methylbutyl, 2-methylbutyl, 1,2dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 1,2dimethylbutyl, 1,3-dimethylbutyl, 2,2 -dimethylbutyl, 2,3dimethylbutyl, 3, 3-dimethylbutyl, l-ethylbutyl, 2ethylbutyl, 1,1, 2-trimethylpropyl, 1,2, 2-trimethylpropyl or l-ethyl-2-methylpropyl group, or the like.
The term "lower alkenyl group" means, for example, a straight or branched alkenyl group with 2 to 6 (in particular 2 to 4) carbon atoms, such as, vinyl, allyl, 1propenyl, isopropenyl, l-butenyl, 2-butenyl, 3-butenyl, 1methyl-l-propenyl, 2-methyl-l-propenyl, 1-methylallyl, 2methylallyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4 pentenyl, l-methyl-l-butenyl, l-methyl-2-butenyl, 1-methyl3-butenyl, 2-methyl-l-butenyl, 2-methyl-2-butenyl, 2methyl-3-butenyl, 3-methyl-l-butenyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1,1-dimethylallyl 1,2-dimethyl-lpropenyl, 1,2-dimethyl-2-propenyl, l-ethyl-l-propenyl, 1ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4hexenyl or 5-hexenyl group, or the like.
The lower alkynyl group is, for example, a straight or branched alkynyl group with 2 to 6 (in particular 2 to 4) carbon atoms, such as, ethynyl, 1-propynyl, 2-propynyl, 1butynyl, 2-butynyl, 3-butynyl, l-methyl-2-propynyl, 1pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2butynyl, l-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl1-butynyl, 1, l-dimethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl or 5-hexynyl group, or the like.
The lower alkoxy group is, for example, a straight or branched alkoxy group with 1 to 6 (in particular 1 to 4) carbon atoms, such as, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentyloxy or n-hexanoxy group, or the like.
The lower alkylthio group is, for example, a straight or branched alkylthio group with 1 to 6 (in particular 1 to 4) carbon atoms, such as, methylthio, ethylthio, npropylthio, isopropylthio, n-butylthio, isobutylthio, secbutylthio, t-butylthio, n-pentylthio or n-hexylthio group, or the like. The halogen atom is, for example, fluorine, chlorine, bromine or iodine atom.
Examples of the substituent of the substituted phenyl group are a lower alkyl group with 1 to 6 (in particular 1 to 4) carbon atoms, a lower alkoxy group with 1 to 6 (in particular 1 to 4) carbon atoms, a halogen atom, nitro, trifluoromethyl or carboxyl group or a lower alkoxycarbonyl group, or the like. The lower alkoxycarbonyl group, for example, an alkoxycarbonyl group with 2 to 6 (in particular, 2 to 4) carbon atoms, such as, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, nbutoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, butoxycarbonyl or n-pentyloxycarbonyl group, or the like.
The cycloalkoxycarbonyloxyalkoxycarbonyl group is, for example, a cycloalkoxycarbonyloxyalkoxycarbonyl group wherein a cycloalkoxy moiety has 5 to 7 carbon atoms and an alkoxy moiety has 1 to 2 carbon atoms, for example, 1 (cyclohexyloxycarbonyloxy) ethoxycarbonyl group or the like. The lower alkanoyloxyalkoxycarbonyl group is, for example, a lower alkanoyloxyalkoxycarbonyl group wherein a lower alkanoyl moiety has 2 to 6 carbon atoms, for example, pivaloyloxymethoxycarbonyl group or the like. The protecting group for the tetrazolyl group is, for example, trityl, p-nitrobenzyl, 1-ethoxyethyl or t-butoxycarbonyl group, or the like. The condensed 5- or 6-membered ring formed from R3 and R4 together with the ring carbon atoms to which they are bonded are, for example, a nitrogencontaining heterocyclic ring, for example, triazole, imidazole, pyrrole, pyridine, pyrimidine or, pyradine ring, or the like. The condensed rings may be substituted by a protecting group, such as, trityl, p-nitrobenzyl, 1ethoxyethyl or t-butoxycarbonyl group, or the like.
As the preferred compound of the general formula (I), there may be mentioned the compound in which R1 is a hydrogen atom, a lower alkyl group of 1 to 6 carbon atoms, or a phenyl group, R2 is a lower alkyl group of 1 to 4 carbon atoms, R3 is a hydrogen atom, R4 is a lower alkyl group of 1 to 2 carbon atoms, a lower alkoxy group of 1 to 2 carbon atoms, a halogen atom, nitro or carboxyl group, a lower alkoxycarbonyl group wherein the lower alkoxy moiety has 1 to 2 carbon atoms, a cycloalkoxycarbonyloxyalkoxycarbonyl group wherein the cycloalkoxy moiety has 5 to 7 carbon atoms and the alkoxy moiety has 1 to 2 carbon atoms, a lower alkanoyloxyalkoxycarbonyl group wherein the lower alkanoyl moiety has 2 to 6 carbon atoms and the alkoxy moiety has 1 to 2 carbon atoms, or a tetrazolyl group, or R3 and R4 may be combined together with the ring carbon atoms with which they are bonded to form a condensed 5membered nitrogen-containing ring which may be substituted, X is o, m is 1, B is a carboxyl group, a lower alkoxycarbonyl group wherein the lower alkoxy moiety has 1 to 2 carbon atoms, a tetrazolyl group, or a protected tetrazolyl group, and n is 1.
Further, as a more preferred compound of the general formula (I), there may be mentioned the compound wherein R1 is a hydrogen atom, methyl, ethyl, n-propyl, n-butyl, npentyl or phenyl group, R2 is a methyl, ethyl, n-propyl or n-butyl group, R3 is a hydrogen atom, and R4 is a chlorine atom, methyl, methoxy, nitro, carboxyl, methoxycarbonyl, cyclohexyloxycarbonyloxyethoxycarbonyl, pivaloyloxymethoxycarbonyl or tetrazolyl group, or R3 and R4 may be combined together with the ring carbon atoms to which they are bonded to form a condensed 1,2,3-triazole ring or a condensed 1,2,3-triazole ring substituted by a trityl group, X is O, m is 1, B is a carboxyl, methoxycarbonyl tetrazolyl, or trityl tetrazolyl group and n is 1.
As the salt of the compound (I) of the present invention, there may be mentioned, alkali metal salts, such as sodium or potassium salts, alkali earth metal salts, such as magnesium or calcium salts, organic amine salts, such as methylamine, ethylamine, triethylamine or pyridine salts, or basic amino acid salts, such as lysine or arginine, or ammonium salts, or the like.
The compound (I) of the present invention may be one of geometrical isomers, optical isomers, or tautomers. One of the above isomers or the mixtures thereof is involved in the scope of the present invention.
The compound (I) of the present invention may be prepared, for example, by the following method. That is, the compound (I) of the present invention may be prepared by reacting, in the presence of a base, a compound of the general formula (II):
wherein R1, R2, R3, R4, X, and m have the same meanings as the above, and a compound of the general formula (III):
wherein B and n have the same meanings as the above, Y is a halogen atom, alkylsulfonyloxy, or arylsulfonyloxy group.
As examples of the base which can be used in the above reaction, there may be mentioned alkali metal compounds, such as sodium hydroxide, potassium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide or potassium tbutoxide; alkali metal carbonates, such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate; organic gamines, such as triethylamine, diisopropylethylamine, pyridine or N, Ndimethylaminopyridine. Solvents which do not take part in the reaction may be used. Examples of the solvent are an organic solvent, such as N, N-dimethylformmide, dirnethylsulfoxide, N-methylpyrrolidone, dioxane, tetrahydrofuran, acetone or alcohol, or a mixtures of one or more of the above solvents with water. The reaction temperature is in the range of -20 to 2000C, preferably 0 to 1000C and the reaction is generally completed in 1 to 48 hours.
Further, the compound (I) of the present invention may be prepared by reacting, in a similar manner as above, a compound of the general formula (IV):
wherein R1, R2, R3, R4, and m have the same meanings as the above, and Z is a halogen atom, and a compound of the general formula (V):
wherein B and n have the same meanings as above, v is a hydroxy, amino or mercapto group.
The compound (I) of the present invention having as the substituent a carboxyl group may be prepared by hydrolysis of a corresponding compound (I) of the present invention having a lower alkoxycarbonyl group in the presence of an acid or a base. The acid which may be used in the reaction is, for example, hydrochloric or sulfuric acid or the like, and the base which may be used is, for example, sodium hydroxide, potassium hydroxide, or the like. The solvent is preferably a mixture of water and an alcohol, such as methanol, ethanol, or the like. In general, the reaction is completed in the temperature range of ordinary temperature to reflux in 10 minutes to 10 hours.
The compound (I) of the present invention having as a substituent a lower alkoxycarbonyl group may be prepared by esterification of a corresponding compound (I) of the present invention having a carboxyl group in the presence of an acid. The acid which may be used in the reaction is, for example, hydrochloric, sulfuric or aryl sulfonic acid, or the like. The reaction is carried out in an alcohol solvent which is also a reactant, for example, methanol, ethanol, propanol, butanol, in the temperature range of ordinary temperature to reflux, and completed in 1 to 24 hours.
The compound (I) of the present invention having as a substituent a tetrazolyl group may also be prepared by removing the protecting group from the corresponding compound (I) of the present invention having a protecting tetrazolyl group, or by reacting a corresponding cyano compound with various azides.
The compound (I) of the present invention having as a substituent a sulfoxide or sulfone group may be prepared by oxidizing the corresponding compound (I) of the present invention having the sulfide group. As the oxidizing agent used in the reaction, there may be mentioned hydrogen peroxide, peracetic acid, trifluoro peracetic acid, metachloroperbenzoic acid, manganese dioxide, and the like.
The solvent, is for example methylene chloride, chloroform, benzene, methanol, ethanol, formic acid, acetic acid, water or a mixture thereof. The reaction is completed in the range of -40 to 600C in 5 minutes to 6 hours.
The starting compounds, that is, the compounds of the general formulae (II), (III), (IV) and (V), are known per se or may be prepared by known methods.
The compound (I) of the present invention has an angiotensin II antagonism and is highly safe, and thus may be used as a pharmaceutical composition, particularly, an angiotensin II antagonist, for the treatment of various cardiovascular system diseases. Example of such cardiovascular system diseases are hypertension, cordiac disease, cerebral apoplexy, arteriosclerosis, or the like.
Further, the compound (I) of the present invention is effective as agent for the treatment of high intraocular pressure.
A pharmaceutical composition, in particular, an angiotensin II antagonist, containing the compound (I) of the present invention or a pharmaceutically acceptable salt thereof as an effective ingredient may be administered orally or parenterally, for example, intramuscularly, intravenously, subcutaneously, percutaneously, or per rectum, or the like. The composition may be reformulated with one or more pharmaceutically acceptable auxiliaries to form tablets, capsules, granules, dispersions, pills, fine granules, injections, rectal agents, suppositories, or the like. As the pharmaceutically acceptable auxiliaries, there may be mentioned excipients, binding agents, disintegrating agents, lubricants, buffers, preservatives, solubilizing auxiliaries, antiseptics, agents for adjusting taste and/or smell, analgesics, stabilizers, coloring agents, or the like. The auxiliaries as above may be appropriately combined by ordinary methods.
As the excipients, lactose, sucrose, glucose, sorbitol, corn starch, crystalline cellulose, or the like may be used. As the binding agent, a cellulose derivative, gum arabic, gelatine, polyvinyl alcohol, polyvinyl ether, or the like may be used. The disintegrating agent is, for example, calcium carboxylmethylcellulose or the like. The lubricant is, for example, talc, magnesium stearate, polyethyleneglycol or the like. The preservative is, for example, methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, chlorocresol or the like. The solubilizing auxiliary is, for example, polyoxyethylene hardened castor oil, polysorbate 80, nicotinic acid amide, polyoxyethylene sorbitan monolaurate, macrogol, or the like. The agent for adjusting taste and/or smell is, for example, cocoa powder, peppermint oil, cinnamin powder, or the like. The stabilizer is, for example, sodium sulfite, sodium metasulfite, ether, or the like.
The dose effective for the angiotensin II antagonism varies with the age, body weight, sex, symptoms, method of administration, period of administration, desired therapeutic effect, or the like, but in the case of oral administration, the dose is normally 1 to 1000 mg, preferably 5 to 200 mg, per day for an adult, usually divided into one to three dosages.
Examples The present invention now will be further illustrated by, but is by no means limited to, the following Examples.
Reference Example 1: PreDaration of 5-(4 methOxvCarbonylbenzyl)-2.6-dimethvlpyrlmldln-4(3H)-one Sodium methoxide (1.64 g) was dissolved in 40 ml of absolute methanol. To the solution, 2.87 g of acetamidine hydrochoride was added. The whole was stirred at room temperature for 10 minutes. Then, 4.22 g of ethyl 2-(4methoxycarbonylbenzyl)-3-oxobutanate and 40 ml of absolute methanol were added and the mixture was stirred at 500C overnight. After the solvent was evaporated under reduced pressure, water was added. The mixture was adjusted to weak acidic with 1N hydrochloric acid, extracted with ethyl acetate, washed with water and saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the resulting crystal was washed with n-hexane to obtain 2.70 g of the abovetitled compound.
Yield: 65%, Melting point: 224 - 2250C, 1H-NMR (CDCl3)#: 2.30 (3H, s), 2.39 (3H, s), 3.89 (3H, s).
3.94 (2H, s), 7.30 (2H d, J=8.1Hz), 7.93 (2H, d, J=8.lHz) IR (KBr) cm-1: 1725, 1660, 1610, 1280, MS (FAB) m/z: 273 (M+1) Reference Examples 2 to 42 The compounds of the following Reference Examples 2 to 42 were prepared in accordance with the method described in Reference Example 1.
Reference Example 2. 2-ethyl-5- (4-methoxycarbonylbenzvly)-6- methylpyrimidin-4 (3H) -one [Yield: 56%, Melting point: 205 - 207 C) Reference Example 3: 5- (4-methoxycarbonylbenzyl) -6-methyl2-propylpyrimidin-4 (3H) -one [Yield: 40%, Melting point: 2100C (decomposition)j Reference Example 4: 2-butyl-5-(4-methoxycarbonylbenzyl)-6- methvltvrimidin-4 (3H) -one [Yield: 60%, Melting point: 195 - 1970C] Reference Example 5 5-(4-methoxycarbonylbenzyl)-6-methyl- 2-pentylpyrimidin-4 (3H) -one [Yield: 85%, Melting point: 178 - 1790C] Reference Example 6. 5-(4-methoxvcarbonvlbenzvl)-6methylpyrimidine-4 (3H) -one [Yield: 52%, Melting point: oil] Reference Example 7: 5- (4-methoxycarbonylbenzyl) -6-methyl- 2-phenyl pvrlmicin-4(3H)-one [Yield: 40%, Melting point: 280 - 282 C] Reference Example 8: 6-ethyl-5-(4-methoxycarbonylbenzyl)-2 methvltvrimidin-4 (3H) -one [Yield: 61%, Melting point: 186 - 187 C] Reference Example 9. 6-butyl-5-(4-methoxycarbonylbenzyl)-2- methvlcvrimidin-4(3H)-one [Yield: 65%, Melting point: 143 - 1450C] Reference Example 10. 6-butyl-5-(4-methoxycarbonylbenzyl '2-propylpyrlmidin-4 (3H) -one [Yield: 40%, Melting point: 173 - 174 C] Reference Example 11. 2-butyl-5-(4-methoxycarbonylbenzyl] - 6-DroDvlovrlmlain-4(3H)-one [Yield: 51%, Melting point: 125 - 127 C] Reference Example 12: 2,6-dibutyl-5- (4- methoxycarbonylbenzyl)pyrlmidn-4 (3H) -one [Yield: 66 %, Melting point: 126 - 1280C] Reference Example 13: 2,6-diethyl-5-(4methoxycarbonylbenzyl)pyrimidin-4 (3H) -one [Yield: 78%, Melting point: 177 - 1790C] Reference Example 14. 6-ethyl-5- (4-methoxycarbonylbenzyl) 2-DroDvlDvrimldin-4(3H)-one [Yield: 72%, Melting point: 151 - 1520C] Reference Example 15: 2-butyl-6-ethyl-5- (4-methoxycarbonyl benzyl) pyrimidin-4 (3H) -one [Yield: 76 %, Melting point: 140 - 1410C] Reference Example 16. 5-(3-methoxvcarbonvlbenzvl)-2,6- dimethvlDvrimldin-4(3H)-one [Yield: 42%, Melting point: 173 - 175 C] Reference Example 17: 2-ethvl-5- (3-methoxvcarbonvlbenzvl )- 6-methvltvrimidin-4 (3H) -one [Yield: 50%, Melting point: 180 - 1810C] Reference Example 18: 5- (3-methoxycarbonylbenzyl) -6-methyl- 2-propylpyrimidin-4-(3H) -one [Yield: 65%, Melting point: 161 - 16 20C] Reference Examole 19: 5-(3-methyloxycarbonylbenzyl) -6-methyl- 2-pentylpyrlmidin-4 (3H) -one [Yield: 65%, Melting point: 155 - 156 OC] Reference Example 20. 6-ethyl-5- (3-methoxycarbonylbenzy) - 2-methvlDvrlmidin-4(3H)-one [Yield: 77%, Melting point: 138 - 1400C] Reference Examole 21. 2,6-diethyl-5-(3- methoxycarbonylbenzyl) pyrlmidin-4 (3H) -one [Yield: 70%, Melting point: 133 - 1350C] Reference Examole 22. 6-ethyl-5-(3-methoxycarbonylbenzyl)- 2-propylpyrimidin-4 (3H) -one [Yield: 71%, Melting point: 111 - 1130C] Reference Example 23. 2-butyl-6-ethyl-5-(3-methoxycarbonyl benzyl) pyrimidin-4 (3H) -one [Yield: 50%, Melting point: 93 - 950C] Reference Examole 24: 5-(3-methoxycarbonylbenzyl) -2-methyl- 6-propylpyrimidin-4 (3H) -one [Yield: 62%, Melting point: 131 - 1330C] Reference Example 25: 2-ethvl-5-(3-methoxvcarbonvlbenzvl)6-propylpyrimidin-4 (3H) -one [Yield: 56 %, Melting point: 122 - 1240C] Reference Example 26: 5- (3-methoxycarbonylbenzyl) -2.6- dipropylpyrimidin-4 (3H) -one [Yield: 53%, Melting point: 109 - 1100C] Reference Example 27: 2-butyl-5- (3-methoxycarbonylbenzyl) 6-DrorvlDvrimidln-4(3H)-one [Yield: 61%, Melting point: 115 - 1170C] Reference Example 28: 2-butyl-5- (3-methoxycarbonylbenzyl)6-methylpyrimidin-4 (3H) -one [Yield: 80%, Melting point: 171 - 173CCj Reference Example 29: 6-butyl-5- (3-methoxycarbonylbenzyl) 2-methvlDvrimldln-4(3H)-one [Yield: 55%, Melting point: 157 - 1590C] Reference Example 30: 2.6-dibutyl-5-(3- methoxycarbonylbenzyl) pyrimidin-4 (3H) -one [Yield: 59%, Melting point: 114 - 1150C] Reference Example 31. 2-butyl-5-(4-chlorobenzyl)-6- methylpvrimidin-4(3H)-one [Yield: 78%, Melting point: 172 - 1740C] Reference Example 32. 2-butyl-6-methyl-5-(4-methylbenzyl) pyrimidin-4 (3H) -one [Yield: 81t, Melting point: 194 - 196 C] Reference Example 33. 2-butvl-5-(4-methoxvbenzvl)-6- methylpyrimidin-4 (3H) -one [Yield: 40%, Melting point: 173 - 174"C] Reference Example 34. 2-butvl-6-methvl-5-(4-nltrobenzvl) pyrimidin-4(3H)-one [Yield: 38%, Melting point: 192 - 1940C] Reference Example 35: 5-(3-chlorobenzyl) -6-methyl-2- DroDvlDvrlmldln-4(3H)-one [Yield: 56 %, Melting point: 176 - 1780C] Reference Example 36 6-methvl-5-(3-methvlbenzvl)-2propylpyrimidin-4 (3H) -one [Yield: 73%, Melting point: 166 - 1670C] Reference Examole 37: 5- (3-methoxybenzyl) -6-methyl-2- propylpyrimidin-4 (3H) -one [Yield: 25%, Melting point: 134 - 136 OC] Reference Example 38: 6-methyl-5- (3-nitrobenzyl) -2propylpyrimidin-4 (3H -one [Yield: 66 %, Melting point: 1780C (decomposition) Reference Example 39 5-(4-cwanobenzvl)-6-methvl-2- propylpyrimidin-4 (3H) -one [Yield: 80%, Melting point: 223 - 2250C] Reference Examole 40: 5-(3-cvanobenzvl)-6-methvl-2 DroDvlDvrlmldln-4(3H)-one [Yield: 72%, Melting point: 194 - 196 C] Reference Example 41: 2-butyl-6-methyl-5-(1-triphenyl- methylbenzotrlazol-5-yl)methylpyrimidin-4 (3H) -one [Yield: 74%] Reference Example 42. 6-butyl-2-methyl-5-(1-trlphenyl- methylbenzotriazol-5-yl)methylpyrimidin-4 (3H) -one [Yield: 36 81 Example 1: Preraratlon of 5-(4-methoxvcarbonvlbenzvl)-4 (2' -methoxycarbonylbiphenyl-4-yl)metoxy-2,6 dimethyltyrimidine Sodium methoxide (81 mg) was suspended in 6 ml of dry DMF (N,N-dimethylformamide). The suspension was stirred at room temperature for 20 minutes. Then, 408 mg of 5-(4 methOxyCarbonylbenzyl)-2,6-dimethylpyrimidin-4(3H)-one and 6 ml of dry DMF were added and the mixture was stirred further for 1 hour. Then, 458 mg of methyl 4'-bromomethyl- biphenyl-2-carbonate was dissolved in 6 ml of dry DMF and the resulting solution was added dropwise to the reaction mixture. The whole was stirred at room temperature for 24 hours. After the reaction was completed, the reaction mixture was evaporated under reduced pressure and 10 ml of water was added. Then, extraction was performed twice with 80 ml of ethyl acetate. The ethyl acetate extract layer was washed with water and saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography by eluting with n-hexane/ethyl acetate (2:1) to obtain 127 mg of the above-titled compound as a colorless transparent syrup.
Yield: 17%, 1H-NMR (CDCl3)8: 2.37 (3H, s), 2.53 (3H, s), 3.62 (3H, s), 3.85 (3H, s), 4.03 (2H, s), 5.43 (2H, s), 7.16 (2H, d, J=8.3Hz), 7.21-7.46 (6H, m), 7.52 (1H, dt, J=1.5, 7.6Hz), 7.83 (1H, dd, J=1.5, 7.6Hz), 7.91 (2H, d, J=8.3Hz), MS (FAB) m/z: 497 (M+1) Example 2: PreDaration of 5-(4-methoxvcarbonvlbenzvl)-3- (2'-methoxycarbonylbinphenyl-4-yl)methyl-2,6 dlmethvlDvrlmldln-4-one The above-titled compound (425 mg) was obtained from the n-hexane/ethyl acetate (1:1) eluate of the reaction product of Example 1 in the purification step by silica gel column chromatography.
Yield: 57%, Melting point: oil, 1H-NMR (CDCl3)8: 2.24 (3H, s), 2.43 (3H, s), 3.59 (3H, s), 3.84 (3H, s), 3.97 (2H, s), 5.30 (2H, s), 7.16 (2H, d, J=8.1Hz), 7.24-7.43 (6H, m), 7.51 (lH, dt, J=1.5, 7.6Hz), 7.82 (1H, dd, J=1.5, 7.6Hz), 7.93 (2H, d, J=8.1Hz), MS (FAB) m/z: 497 (M+1) Examples 3 to 6 The compounds of the following Examples 3 to 6 were prepared in accordance with the methods described in Examples 1 and 2.
Example 3: 6-butyl-5-(4-methoxycarbonylbenzyl)-4-(2' methOxvCarbonvlblchenv1-4-vl)methoxv-2-methvlOvrlm1dlne Yield: 17%, Melting point: oil, 1H-NMR (CDCl3) # : 0.84 (3H, t, J=7.3Hz), 1.23-1.36 (2H, m), 1.46-1.58 (2H, m), 2.55 (3H, s), 2.65 (2H, t, J=7.6Hz), 3.62 (3H, s), 3.87 (3H, s), 4.04 (2H, s), 5.45 (2H, s) 7.18 (2H, d, J=8.3Hz), 7.24-7.72 (8H, m), 7.89 (2H, d, J=8.3Hz), MS (FAB) m/z: 539 (M+1) Example 4; 6-butyl-5-(4-methoxycarbonylbenzyl) -3- (2'methoxycarbonylbiphenyl-4-yl)methyl-2-methylpyrimidin-4-one Yield: 58%, Melting point: oil, 1H-NMR (CDC13)d: 0.86 (3H, t, J=7.3Hz), 1.22-1.35 (2H, m), 1.43-1.55 (2H, m), 2.45 (3H, s), 2.53 (2H, t, J=7.6Hz), 3.63 (3H, s), 3.88 (3H, s), 4.02 (2H, s), 5.33 (2H, s), 7.18 (2H, d, J=8.1Hz), 7.2 Yield: 44%, Melting point: oil, 1H-NMR (CDC13)d: 0.89 (3H, t, J=7.2Hz), 0.90 (3H, t, J=7.2Hz), 1.26-1.43 (4H, m), 1.51-1.74 (4H, m), 2.56 (2H, t, J=7.8Hz), 2.68 (2H, t, J=7.7Hz), '.62 (3H, s) 3.88 (3H, s), 4.00 (2H, s), 5.34 (2H, s). 7.17 (2, d, J=8.1Hz), 7.26-7.34 (5H, m), 7.40 (1H, dt, J=1.0, 7.6Hz), 7.52 (1H, dt, J=1.5, 7.6Hz), 7.82 (1H, dd, J=1.5, 7.6Hz), 7.93 (2H, d, J=8.1Hz), MS (FAB) m/z: 581 (M+1) Example 7 PreDaration of 5-(4-carboxvbenzvl) -4-(2'- carboxybiphenyl-4-yl)methoxy-2,6-dimethylpyrimidine The compound (127 mg) of Example 1 was dissolved in 10 ml of ethanol. To the solution, 1.5 ml of 1N NaOH was added. The mixture was heated under reflux for 8 hours.
After the reaction was completed, the reaction liquid was concentrated to a solid under reduced pressure, and 10 ml of water was added to dissolve the resulting residue. The pH of the resulting aqueous solution was adjusted to 4 with 1N hydrochloric acid. The precipitated crystals were obtained by filtration, and thereby 117 mg of a white powder of the above-titled compound was obtained.
Yield: 98%, Melting point: 144 - 146 C, 1H-NMR (DMSO-d6)5: 2.35 (3H, s), 2.49 (3H, s), 4.03 (2H, s), 5.46 (2H, s), 7.22 (2H, d, J=8.3Hz), 7.31 (2H, d, J=8.5Hz), 7.33-7.55 (4H, m), 7.70-7.84 (4H, m), IR (KBr)cm~l: 1710, 1575, 1425, 1340, MS (FAB) m/z: 469 (M+1) Examples 8 to 12 The compounds described in the following Examples 8 to 12 were prepared in accordance with the method of Example 7. example 8: 5- (4-carboxyenzyl) -4-(2'-carboxybiphenyl-4yl)methyl-2,6-dimethylpyrimidin-4-one Yield: 98%, Melting point: 170 - 1720C, 1H-NMR (DMSO-d6)5: 2.21 (3H, s), 2.41 (3H, s), 3.93 (2H, s), 5.33 (2H, s), 7.19 (2H, d, J=8.1Hz), 7.29-7.73 (8H, m), 7.84 (2H, d, J=8.1Hz), IR (KBr) cm-1: 1705, 1660, 1610, 1545, MS (FAB) m/z: 469 (M+1) Example 9; 6-butyl-5-(4-carboxybenzyl)-4-(2'carboxybiphenyl-4-yl)methoxy-2-methylpyrimidine Yield: 98%, Melting point: 167.5 - 1680C, 1H-NMR (DMSO-d6)5: 0.82 (3H, t, J=7.2Hz), 1.22-1.35 (2H, m), 1.47-1.58 (2H, m), 2.49 (3H, s), 2.64 (2H, t, J=7.6Hz), 4.05 (2H, s), 5.45 (2H, s), 7.21 (2H, d, J=8.3Hz), 7.25-7.73 (8H, m), 7.82 (2H, d, J=8.1Hz) IR (KBr) cm-1: 1710, 1695, 1570, 1415, MS (FAB) m/z: 511 (M+1) Example 10; 6-butyl-5-(4-carboxybenzyl)-3-(2'carboxybiphenyl-4-yl)methyl-2-methylpyrimidin-4-one Yield: 96%, Melting point: 136 - 1370C, 1H-NMR (DMSO-d6)8: 0.83 (3H, t, J=7.3Hz), 1.22-1.35 (2H, m), 1.43-1.54 (2H, m), 2.42 (3H, s), 2.51 (2H, t, J=7.6Hz), 3.95 (2H, s), 5.33 (2H, s), 7.19 (2H, d, J=8.lHz), 7.27-7.73 (8H, m), 7.84 (2H, d, J=8.lHz), IR (KBr) cm-1: 1695, 1655, 1610, 1540, MS (FAB) m/z: 511 (M+1) Example 11: 2,6-dibutyl-5-(4-carboxyenzyl)-4-(2'carboxybiphenyl-4-yl)methoxypyrimindine Yield: 97%, Melting point: 87 - 890C, 1H-NMR (DMSO-d6)6: 0.82 (3H, t, J=7.3Hz), 0.91 (3H, t, J=7.3Hz), 1.21-1.43 (4H, m), 1.47-1.59 (2H, m), 1.70 1.81 (2H, m), 2.65 (2H, t, J=7.7Hz), 2.77 (2H, t, J=7.4Hz), 4.05 (2H, s), 5.46 (2H, s), 7.20 (2H, d, J=8.3Hz), 7.24-7.73 (8H, m), 7.82 (2H, d, J=8.1Hz), MS (FAB) m/z: 554 (M+2) Example 12, 2,6-dibutyl-5-(4-carboxybenzyl)-3- (2'carboxybiphenyl-4-yl)methylpyrimidin-4-one Yield: 92%, Melting point: 96 - 980C, 1H-NMR (DMSO-d6)d: 0.82 (3H, t, J=7.3Hz), 0.83 (3H, J=7.2Hz), 1.22-1.37 (4H, m), 1.47-1.67 (4H, m), 2.52 (2H, t, s=7.0Hz), 2.68 (2H, t, J=7.3Hz), 3.95 (2H, s), 5.35 (2H, s), 7.16 (2H, d, J=8.3Hz), 7.29-7.72 (8H, m), 7.84 (2H, d, J=8.3Hz), MS (FAB) m/z: 554 (M+2) Example 13: PreDaration of 5-(4-methoxvcarbonvlbenzvl)-2.6- dimethyl-4-[2'-(triphenylmethyltetrazol-5-yl)blphenyl-4 vl rnethoxvoyrimidine Sodium methoxide (162 mg) was suspended in 10 ml of dry DMF. The suspension was stirred at room temperature for 20 minutes. Then, 816 mg of 5-(4-methoxycarbobenzyl)2,6-dimethylpyrimidin-4(3H)-one and 10 ml of dry DMF were added. The mixture was further stirred for 1 hour. Then, 1.838 g of 4' -bromomethyl-2-(triphenylmethyltetrazol-5- yl)biphenyl was dissolved in 10 ml of dry DMF and the resulting solution was added dropwise to the reaction mixture. The mixture was stirred at room temperature for 60 hours. After the reaction was completed, the reaction mixture was evaporated and 20 ml of water was added. Then, the mixture was extracted twice with 150 ml of ethyl acetate. The ethyl acetate extract layer was washed with water and saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography with n-hexane/ethyl acetate (2:1) to obtain 474 mg of the above-titled compound as amorphous.
Yield: 21%, Melting point: 79 - 80 C, H-NMR (CDCl3) #: 2.39 (3H, s), 2.59 (3H, s), 3.87 (3H, s), 3.97 (2H, s), 5.32 (2H, s), 6.87-6.92 (6H, m), 7.03 7.51 (18H, m) , 7.87-7.95 (3H, m), MS (FAB) m/z: 749 (M+1) Example 14. Preparation of 5- (4-methoxycarbonylbenzyl)-2,6dimehyl-3-[2'-(triphenylmethyltetrazol-5-yl)biphenyl-4yllmethylpyrimidin-4-one The above-titled compound (1.26 g) was obtained from the n-hexane/ethyl acetate (1:1) eluate of the reaction product of Example 13 in the purification step by silica gel column chromatography.
Yield: 56%, Melting point: 104 - 1060C, 1H-NMR (CDC13)6: 2.28 (3H, s), 2.29 (3H, s), 3.88 (3H, s) 4.01 (2H, s), 5.17 (2H, s) 6.88-6.96 (8H, m), 7.11 (2H, d, J=8.3Hz), 7.20-7.35 (12H, m), 7.43-7.52 (2H, m), 7.93-7.96 (3H, m), MS (FAB) m/z: 749 (M+1) Examples 15 to 50 The compounds described in the following Examples 15 to 50 were prepared in accordance with the methods of Examples 13 and 14.
Example 15: 2-ethyl-5-(4-methoxycarbonylbenzyl) -6-methyl-4 [2'-(triphenylmethyltetrazol-5-yl)bihenyl-4yllmethoxypyrimidine Yield: 31%, Melting point: 142 - 1440C, 1H-NMR (CDC13): 1.36 (3H, t, J=7.6Hz), 2.40 (3H, s) 2.85 (2H, q, J=7.6Hz), 3.87 (3H, s) 3.97 (2H, s) 5.35 (2H, s), 6.84-7.96 (27H, m), IR (KBr) cm-1: 1720, 1570, 1415, 1340, 1280, MS (FAB) m/z: 763 (M+1) Example 16: 2-ethyl-5-(4-methoxycarbonylbenzyl) -6-methyl-3 [2'- (triphenylmethyltertrazol-5-yl)biphenyl-4yllmethylpyrimidin-4-one Yield: 36%, Melting point: 104 - 1060C, 1H-NMR (CDCl3) #: 1.13 (3H, t, J=7.3Hz), 2.32 (3H, s), 2.52 (2H, q, J=7.3Hz), 3.87 (3H, s), 4.00 (2H, s), 5.20 (2H, s), 6.86-7.96 (27H, m), IR (KBr) cm-1: 1720, 1655, 1540, 1435, 1280, MS (FAB) m/z: 763 (M+1) Example 17; 5-(4-methoxycarbonylbenzyl)-6-methyl-2-propyl4-[2'-(triphenylmethyltetrazol-5-yl)biphenyl-4yllmethoxypyrimidine Yield: 33%, 1H-NMR (CDCl3) #: 0.90 (3H, t, J=7.2Hz), 1.73-1.85 (2H, m), 2.38 (3H, s), 2.80 (2H, t, J=7.8Hz), 3.86 (3H, s), 3.98 (2H, s), 5.34 (2H, s), 6.88-6.96 (8H, m), 7.12 (2H, d, J=8.3Hz), 7.21-7.36 (12H, m), 7.43-7.51 (2H, m), 7.92 7.97 (3H, m), MS (FAB) m/z: 777 (M+1) Example 18; 5-(4-methoxycarbonylbenzyl)-6-methyl-2-propyl3-[2'-(triphenylmethyltetrazol-5-yl)biphenyl-4yllmethoxypyrimidin-4-one Yield: 31%, 1H-NMR (CDCl3) #: 0.87 (3H, t, J=7.2Hz), 1.58-1.66 (2H, m), 2.29 (3H, s), 2.53 (2H, t, J=7.8Hz), 3.89 (3H, s), 3.99 (2H, s), 5.22 (2H, s), 6.87-6.90 (6H, m), 7.01-7.30 (15H, m), 7.35-7.54 (3H, m), 7.86-7.96 (3H, m), MS (FAB) m/z: 777 (M+1) Example 19: 2-ethyl-5-(4-methoxycarbonylbenzyl) -6-methyl-4 [2'- (triphenylmethyltertrazol-5-yl)biphenyl-4yllmethylpyrimidine Yield: 35%, Melting point: 118 - 120 C, 1H-NMR (CDCl3) #: 0.96 (3H, t, J=7.2Hz), 1.34-1.50 (2H, m), 1.74-1.88 (2H, m), 2.39 (3H s), 2.82 (2H, t, J=7.7Hz) 3.87 (3H, s), 3.97 (2H, s), 5.33 (2H, s), 6.84-7.96 (27H, m), IR (KBr) cm-1: 1720, 1570, 1415, 1340, 1280, MS (FAB) m/z: 791 (M+1) Example 20: 2-ethyl-5- (4-methoxycarbonylbenzyl) -6-methyl-3 [2'- (triphenylmethyltertrazol-5-yl)biphenyl-4yllmethylpyrimidin-4-one Yield: 33%, Melting point: 90 - 920C, 1H-NMR (CDCl3) #: 0.86 (3H, t, J=7.3Hz), 1.22-1.38 (2H, m), 1.54-1.68 (2H, m), 2.33 (3H, s), 2.52-2.64 (2H, m), 3.88 (3H, s), 3.99 (2H, s), 5.21 (2H, s), 6.86-7.96 (27H, m), IR (KBr) cm-1: 1720, 1655, 1540, 1445, 1280, MS (FAB) m/z: 791 (M+1) Example 21; 5-(4-methoxycarbonylbenzyl)-6-methyl-2-penpyl4-[2'-(triphenylmethyltetrazol-5-yl)biphenyl-4yllmethoxypyrimidine Yield: 36%, Melting point: 61 - 630C, 1H-NMR (CDC13)3: 0.91 (3H, t, J=7.1Hz), 1.36-1.43 (4H, m), 1.77-1.85 (2H, m), 2.39 (3H, s), 2.81 (2H, t, J=7.8Hz), 3.87 (3H, s), 3.97 (2H, s), 5.33 (2H, s), 6.87-6.91 (6H, m), 7.07 (4H, s), 7.11-7.30 (11H, m), 7.36-7.53 (3H, m), 7.87-7.95 (3H, m), IR (KBr) cm-1: 1725, 1575, 1340, 1280, MS (FAB) m/z: 805 (M+1) Example 22; 5-(4-methoxycarbonylbenzyl)-6-methyl-2-penpyl3-[2'-(triphenylmethyltetrazol-5-yl)biphenyl-4yllmethoxypyrimidin-4-one Yield: 38%, Melting point: 93 - 95 C, 1H-NMR (CDC13)6: 0.84 (3H t, J=7.2Hz), 1.24-1.42 (4H, m), 1.59-1.64 (2H, m), 2.31 (3H, s), 2.53 (2H, t, J=7.6Hz), 3.88 (3H, s), 3.99 (2H, s), 5.20 (2H, s), 6.90-6.93 (6H, m), 7.09 (2H, d, J=8.1Hz), 7.21-7.35 (14H, m), 7.41-7.51 (2H, m), 7.90-7.95 (3H, m), IR (KBr) cm-1: 1720, 1655, 1540, 1280, MS (FAB) m/z: 805 (M+1) Exampl 23: 5-(4-methoxycarbonylbenzyl)-6-methyl-4-[2' (triphenylmethyltetrazol-5-yl)biphenyl-4 vl 1 mehoxvtvrimidine Yield: 7%, Melting point: 82 - 840C, 1H-NMR (CDCl3) #: 2.44 (3H, s), 3.87 (3H, s), 4.01 (2H, s), 5.32 (2H, s), 6.86-6.90 (6H, m), 7.03-7.30 (15H, m), 7.36-7.51 (3H, m), 7.89-7.96 (3H, m), 8.61 (1H, s), MS (FAB) m/z: 735 (M+1) Exampl 24: 5-(4-methoxycarbonylbenzyl)-6-methyl-3-[2' (triphenylmethyltetrazol-5-yl)biphenyl-4 vl 1 methvlDvrlmldln-4-one Yield: 70%, Melting point: 83 - 85 C), 1H-NMR (CDCl3) #: 2.29 (3H, s), 3.88 (3H, s), 3.97 (2H, s), 4.96 (2H, s), 6.86-6.90 (6H, m), 7.05 (2H, d, J=8. 1Hz), 7.12 (2H, d, J=8.3Hz), 7.20-7.36 (13H, m), 7.46-7.50 (2H, m), 7.87 (1H, s), 7.92-7.99 (2H, m), IR (KBr) cm-1: 1720, 1655, 1605, 1280, MS (FAB) m/z: 735 (M+1) Example 17; 5-(4-methoxycarbonylbenzyl)-6-methyl-2-phenyl4-[2'-(triphenylmethyltetrazol-5-yl)biphenyl-4yllmethoxypyrimidine Yield: 47%, Melting point: 93 - 950C, 1H-NMR (CDC13)6: 2.50 (3H, s), 3.87 (3H, s), 4.04 (2H, s), 5.47 (2H, s), 6.88-6.91 (6H, m), 7.10 (4H, s), 7.16 7.29 (6H, m), 7.37-7.50 (6H, m), 7.88-7.95 (3H, m), 8.44-8.47 (2H, m), MS (FAB) m/z: 811 (M+1) Example 17; 5-(4-methoxycarbonylbenzyl)-2-methyl-4 [2'-(triphenylmethyltetrazol-5-yl)biphenyl-4yllmethoxypyrimidine Yield: 17%, Melting point: 76 - 780C, 1H-NMR (CDC13)6: 1.16 (3H, t, J=7.6Hz), 2.61 (3H, s), 2.69 (2H, q J=7.6Hz), 3.87 (3H, s), 3.99 (2H, s), 5.31 (2H, s), 6.87-6.91 (6H, m), 7.00-7.30 (15H, m), 7.36-7.50 (3H, m), 7.87-7.95 (3H, m), MS (FAB) m/z: 763 (M+1) Example 27; 6-ethyl-5-(4-methoxycarbonylbenzyl)-2-methyl-3 [2'-(triphenylmethyltetrazol-5-yl)biphenyl-4 yl 1 methvlDyrlmldn -4-one Yield: 57%, Melting point: 95 - 970C, 1H-NMR (CDC13)8: 1.13 (3H, t, J=7.6Hz), 2.29 (3H, s), 2.57 (2H, q, J=7.6Hz), 3.88 (3H, s), 4.02 (2H, s), 5.17 (2H, s), 6.88-6.99 (8H, m), 7.11 (2H, d, J=8.1Hz), 7.17-7.37 (12H, m), 7.42-7.52 (2H, m), 7.90-7.96 (3H, m), MS (FAB) m/z: 763 (M+1) Example 28; 6-butyl-5-(4-methoxycarbonylbenzyl)-2-methyl-4 [2'-(triphenylmethyltetrazol-5-yl)biphenyl-4yllmethoxypyrimidine Yield: 19%, Melting point: 81 - 830C, 1H-NMR (CDC13)8: 0.87 (3H, t, J=7.2Hz), 1.27-1.40 (2H, m), 1.50-1.60 (2H, m), 2.60 (3H, s), 2.65 (2H, t, J=7.8Hz), 3.87 (3H, s), 3.98 (2H, s), 5.30 (2H, s), 6.87-6.91 (6H, m), 7.00-7.30 (15H, m), 7.36-7.50 (3H, m), 7.87 7.95 (3H, m), MS (FAB) m/z: 791 (M+1) Example 29: 6-butvl-5- (4 -methoxvcarbonvlbenzvl ) -2-methvl-3 - [2'-(triphenylmethyltetrazol-5-yl)biphenyl-4vllmethvlDvrimldln-4-one Yield: 56%, Melting point: 85 - 87 C, 1H-NMR (CDC13)8: 0.89 (3H, t, J=7.2Hz), 1.29-1.41 (2H, m), 1.47-1.57 (2H, m), 2.28 (3H, s), 2.53 (2H, t, J=7.8Hz), 3.88 (3H, s), 4.02 (2H, s), 5.17 (2H, s), 6.88-6.97 (8H, m), 7.11 (2H, d, J=8.3Hz), 7.20-7.36 (12H, m), 7.42-7.52 (2H, m), 7.93-7.96 (3H, m), MS (FAB) m/z: 791 (M+1) Example 30; 6-butyl-5-(4-methoxycarbonylbenzyl)-2-propyl-4 [2'-(triphenylmethyltetrazol-5-yl)biphenyl-4yllmethoxypyrimidine Yield: 26%, Melting point: 56 - 580C, 1H-NMR (CDCl3)8: 0.88 (3H, t, J=7.3Hz), 0.89 (3H, t, J=7.3Hz), 1.23-1.43 (2H, m), 1.50-1.73 (4H, m), 2.52 (2H, t, J=7.8Hz), 2.55 (2H, t, J=7.8Hz), 3.88 (3H, s), 4.00 (2H, s), 5.19 (2H, s), 6.90-6.95 (8H, m), 7.10 (2H, d, J=8.3Hz), 7.21-7.36 (12H, m), 7.44-7.50 (2H, m), 7.90-7.95 (3H, m), MS (FAB) m/z: 819 (M+1) Example 31; 6-butyl-5-(4-methoxycarbonylbenzyl)-2propyl-3 [2'-(triphenylmethyltetrazol-5-yl)biphenyl-4 vl 1 methvlnvrlmldln-4-one Yield: 34%, Melting point: 75 - 770C, 1H-NMR (CDCl3) #: 0.86 (3H, t, J=7.2Hz), 1.00 (3H, t, J=7.4Hz), 1.26-1.40 (2H, m), 1.49-1.60 (2H, m), 1.78 1.92 (2H, m), 2.65 (2H, t, J=7.8Hz), 2.80 (2H, t, J=7.7Hz), 3.87 (3H, s), 3.98 (2H, s), 5.31 (2H, s), 6.87-6.91 (6H, m), 7.01-7.30 (15H, m), 7.36-7.53 (3H, m), 7.87-7.95 (3H, m), MS (FAB) m/z: 819 (M+1) Example 32; 2-butyl-5-(4-methoxycarbonylbenzyl)-6-propyl-4 [2'-(triphenylmethyltetrazol-5-yl)biphenyl-4yllmethoxypyrimidine Yield: 28%, Melting point: oil, 1H-NMR (CDCl3) #: 0.91 (3H, t, J=7.3Hz), 0.96 (3H, t, J=7.3Hz), 1.38-1.46 (2H, m), 1.54-1.68 (2H, m), 1.75 1.86 (2H, m), 2.61-2.67 (2H, m), 2.83 (2H, t J=7.7Hz), 3.87 (3H, s), 3.98 (2H, s), 5.31 (2H, s), 6.87-6.91 (6H, m), 7.00-7.32 (16H, m), 7.36-7.52 (3H, m), 7.87 7.95 (2H, m), IR (KBr) cm-1: 2960, 1720, 1560, 1440, MS (FAB) m/z: 819 (M+1) Example 33; 2-butyl-5-(4-methoxycarbonylbenzyl)-6-propyl-3 [2'-(triphenylmethyltetrazol-5-yl)biphenyl-4 vllmethvlDvrlmldln-4-one Yield: 33%, Melting point: oil, 1H-NMR (CDCl3)8: 0.85 (3H, t, J=7.2Hz), 0.92 (3H, t, J=7.3Hz), 1.21-1.34 (2H, m), 1.56-1.68 (4H, m), 2.51 2.57 (4H, m), 3.88 (3H, s), 4.00 (2H, s), 5.20 (2H, s), 6.90-6.95 (8H, m), 7.09 (2H, d, J=7.8Hz), 7.20-7.37 (15H, m), 7.41-7.52 (2H, m), 7.93 (2H, d, J=8.0Hz), IR (KBr) cm-1: 3470, 2960, 1720, 1650, MS (FAB) m/z: 819 (M+1) Example 34; 2-butyl-5-(3-methoxycarbonylbenzyl)-6-methyl-4 [2'-(triphenylmethyltetrazol-5-yl)biphenyl-4yllmethoxypyrimidine Yield: 33%, Melting point: 59 - 610C, 1H-NMR (CDCl3) #: 0.96 (3H, t, J=7.3Hz), 1.38-1.46 (2H, m), 1.74-1.83 (2H, m), 2.41 (3H, s), 2.81 (2H, t, J=7.7Hz), 3.85 (3H, s), 3.96 (2H, s), 5.33 (2H, s), 6.87-6.92 (6H, m), 7.08 (4H, s), 7.17-7.30 (11H, m), 7.36-7.39 (1H, m), 7.43-7.50 (2H, m), 7.83-7.86 (2H, m), 7.91 7.95 (1H, m), MS (FAB) m/z: 791 (M+1) Example 35; 2-butyl-5-(3-methoxycarbonylbenzyl)-6-methyl-3 [2'-(triphenylmethyltetrazol-5-yl)biphenyl-4 vl l methylovrlmldLn-4-one Yield: 35%, Melting point: 73 - 750C, H-NMR (CDCl3) #: 0.85 (3H, t, J=7.3Hz), 1.23-1.33 (2H, m), 1.53-1.63 (2H, m), 2.31 (3H, s), 2.53 (2H, t, J=7.9Hz), 3.86 (3H, s), 3.99 (2H, s), 5.21 (2H, s), 6.90-6.95 (8H, m), 7.10 (2H, d, J=8.1Hz), 7.21-7.36 (11H, m), 7.42-7.51 (3H, m), 7.85-7.94 (3H, m), MS (FAB) m/z: 791 (M+1) Example 36; 6-butyl-5-(3-methoxycarbonylbenzyl)-2-methyl-4 [2'-(triphenylmethyltetrazol-5-yl)biphenyl-4yllmethoxypyrimidine Yield: 17%, Melting point: 68 - 700C, 1H-NMR (CDCl3)6: 0.87 (3H, t, J=7.2Hz), 1.29-1.41 (2H, m), 1.49-1.60 (2H, m), 2.61 (3H, s), 2.69 (2H, t, J=7.9Hz), 3.85 (3H, s), 3.98 (2H, s), 5.31 (2H, s), 6.87-6.90 (6H, m), 7.01-7.08 (4H, m), 7.17-7.29 (llH, m), 7.36 7.50 (3H, m), 7.81-7.94 (3H, m), MS (FAB) m/z: 791 (M+1) Example 37: 6-butvl-5-(3-methoxvcarbonvlbenzvl)-2-methvl-3 [2'-(triphenylmethyltetrazol-5-yl)biphenyl-4 vl 1 methvlDvrlmldln-4-one Yield: 51%, Melting point: 83 - 85 C, 1H-NMR (CDCl3)5: 0.88 (3K t, J=7.2Hz), 1.28-1.39 (2H, m), 1.48-1.56 (2H, m), 2.27 (3H, s), 2.56 (2H, t, J=7.8Hz), 3.86 (3H, s), 4.01 (2H, s), 5.17 (2H, s), 6.88-6.98 (8H, m), 7.10 (2H, d, J=8.1Hz), 7.20-7.36 (11H, m).
7.45-7.51 (3H, m), 7.85-7.96 (3H, m), MS (FAB) m/z: 791 (M+1) Example 38; 2,6-dibutyl-5-(3-methoxycarbonylbenzyl)-4-[2' (triphenylmethyltetrazol-5-yl)biphenyl-4yllmethoxypyrimidine Yield: 31%, Melting point: oil, 1K-NMR (CDCl3) #: 0.87 (3H, t, J=7.2Hz), 0.95 (3H, t, J=7.3Hz), 1.28-1.58 (6H, m), 1.74-1.83 (2H, m), 2.68 (2H, t, J=7.9Hz), 2.82 (2H, t, J=7.8Hz), 3.85 (3H, s), 3.97 (2H, s), 5.31 (2H, s), 6.87-6.90 (6H, m), 7.05 (4H, s), 7.17-7.30 (11H, m), 7.38 (1H, dd, J=2.0, 7.1Hz), 7.42-7.50 (2H, m), 7.83-7.85 (2H, m), 7.92 (1H, dd, J=2.0, 7.1Hz), MS (FAB) m/z: 833 (M+1) Example 39; 2,6-dibutyl-5-(3-methoxycarbonylbenzyl)-3-[2' (triphenylmethyltetrazol-5-yl)biphenyl-4 vllmethvlDvrlmldln-4-one Yield: 28%, Melting point: 65 - 670C, 1H-NMR (CDC13)6: 0.85 (3H, t, J=7.3Hz), 0.89 (3H, t, J=7.3Hz), 1.23-1.39 (4H, m), 1.50-1.67 (4H, m), 2.50 2.60 (4H, m), 3.86 (3H, s), 4.00 (2H, s), 5.20 (2H, s).
6.90-6.96 (8H, m), 7.09 (2H, d, J=8.1Hz), 7.21-7.35 (11H, m), 7.42-7.49 (3H, m), 7.84-7.94 (3H, m), MS (FAB) m/z: 833 (M+1) Example 40; 2-butyl-5-(4-chlorobenzyl)-6-methyl-4-[2' (triphenylmethyltetrazol-5-yl)biphenyl-4yllmethoxypyrimidine Yield: 35%, Melting point: 60 - 620C, 1K-NMR (CDCl3) #: 0.95 (3H, t, J=7.3Hz), 1.38-1.46 (2H, m), 1.74-1.85 (2H, m), 2.40 (3H, s), 2.81 (2H, t, J=7.8Hz), 3.88 (2H, s), 5.33 (2H, s), 6.88-6.90 (6H, m), 6.91 6.99 (2H, m), 7.02-7.11 (4H, m), 7.15-7.30 (11H, m), 7.37-7.51 (3H, m), 7.92-7.95 (1H, m), MS (FAB) m/z: 767 (M+1) Example 41; 2-butyl-5-(4-chlorobenzyl)-6-methyl-3-[2' (triphenylmethyltetrazol-5-yl)biphenyl-4vll methvlvrimidin-4-one Yield: 35%, Melting point: 83 - 85 C, 1H-NMR (CDCl3) #: 0.85 (3H, t, J=7.3Hz), 1.24-1.33 (2H, m), 1.43-1.62 (2H, m), 2.32 (3H, s), 2.53 (2H, t, J=7.9Hz), 3.90 (2H, s), 5.20 (2H, s), 6.90-6.94 (8H, m), 7.10 (2H, d, J=8.lHz), 7.22-7.35 (14H, m), 7.44-7.49 (2H, m), 7.90-7.93 (1H, m), MS (FAB) m/z: 767 (M+1) Example 42; 2-butyl-6-methyl-5-(4-methylbenzyl)-4-[2' (triphenylmethyltetrazol-5-yl)biphenyl-4yllmethoxypyrimidine Yield: 31%, Melting point: 64 - 66 C, H-NMR (CDCl3) #: 0.95 (3H, t, J=7.3Hz), 1.35-1.48 (2H, m), 1.37-1.85 (2H, m), 2.28 (3H, s), 2.43 (3H, s), 2.82 (2H, t, J=7.6Hz), 3.89 (2K, s), 5.34 (2H, s), 6.87-6.1 (6H, m), 6.92-7.08 (8H, m), 7.17-7.30 (9H, m), 7.36 7.52 (3H, m), 7.93 (1H, dd, J=2.0, 7.3Hz), MS (FAB) m/z: 747 (M+1) Example 43; 2-butyl-6-methyl-5-(4-methylbenzyl)-3-[2' (triphenylmethyltetrazol-5-yl)biphenyl-4 vl 1 methvlDvrlmldln-4-one Yield: 32%, Melting point: 82 - 840C, H-NMR (CDCl3) #: 0.86 (3H, t, J=7.3Hz), 1.21-1.35 (2H, m), 1.52-1.64 (2H, m), 2.29 (3H, s), 2.33 (3H, s), 2.51 (2H, t, J=7.8Hz), 3.90 (2H, s), 5.20 (2H, s), 6.90-6.94 (8H, m), 7.05-7.10 (4H, m), 7.17-7.35 (12H, m), 7.44 7.49 (2H, m), 7.92 (1H, dd, J=2.0, J=7.1Hz), MS (FAB) m/z: 747 (M+1) Example 44; 2-butyl-5-(4-methoxybenzyl)-6-methyl-4-[2' (triphenylmethyltetrazol-5-yl)biphenyl-4yllmethoxypyrimidine Yield: 36%, Melting point: 56 - 580C, 1H-NMR (CDCl3)8: 0.95 (3H, t, J=7.3Hz), 1.35-1.48 (2H, m), 1.73-1.85 (2H, m), 2.41 (3H, s), 2.80 (2H, t, J=7.7Hz), 3.73 (3H, s), 3.87 (2H, s), 5.34 (2H, s), 6.75 (2H, d, J=8.8Hz), 6.78-6.92 (6H, m), 7.01 (2H, d, J=8.3Hz), 7.09 (4H, s), 7.12-7.31 (9H, m), 7.36-7.52 (3H, m), 7.93 (1H, dd, J=2.0, 7.1Hz), IR (KBr) cm-1: 1575, 1510, 1445, 1430, MS (FAB) m/z: 763 (M+1) Example 45; 2-dibutyl-5-(4-methoxybenzyl)-6-methyl-3-[2' (trlDhenvlmethvltetrazol-5-vl)blDhenvl-4 yllmethoxypyrimidin-4-one Yield: 34%, Melting point: 48 - 500C, 1H-NMR (CDCl3) #: 0.85 (3H, t, J=7.3Hz), 1.23-1.35 (2H, m), 1.53-1.64 (2H, m), 2.33 (3H, s), 2.51 (2H, t, J=7.8Hz), 3.76 (3H, s), 3.88 (2H, s), 5.20 (2H, s), 6.80 (2H, d, J=8.6Hz), 6.90-6.94 (8H, m), 7.09 (2H, d, J=8.3Hz), 7.20-7.35 (11H, m), 7.41-7.52 (2H, m), 7.80-793 (1H, m), IR (KBr) cm-1: 3060, 3030, 2960, 2930, 1605, 1595, 1345, MS (FAB) m/z: 763 (M+1) Example 46; 2-butyl-6-methyl-5-(3-nitrobenzyl)-4-[2' (triphenylmethyltetrazol-5-yl)biphenyl-4yllmethoxypyrimidine Yield: 36%, Melting point: 136 - 1380C, 1H-NMR (CDCl)8: 0.96 (3H, t, J=7.3Hz), 1.36-1.50 (2H, m), 1.75-1.87 (2H, m), 2.40 (3H, s), 2.83 (2H, t, J=7.8Hz), 4.00 (2H, s), 5.34 (2H, s), 6.91 (6H, d, J=6.4Hz), 7.10 (4H, s), 7.19-7.31 (12H, m), 7.38 (1H, dd, J=1.6, 6.4Hz), 7.42-7.53 (1H, m), 7.91-7.94 (1H, m), 8.05 (2H, d, J=8.3Hz), IR (KBr) cm-1: 3060, 3030, 2950, 2930, 1605, 1595, 1345, MS (FAB) m/z: 778 (M+1) Example 47; 2-butyl-6-methyl-5-(4-nitrobenzyl)-3-[2' (triphenylmethyltetrazol-5-yl)biphenyl-4 vii methvltvrimidin-4-one Yield: 27%, Melting point: 83 - 850C, 1H-NMR (CDCl3) #: 0.86 (3H, t, J=7. 32Hz), 1.23-1.33 (2H, m), 1.43-1.67 (2H, m), 2.32 (3H, s), 2.55 (2H, t, J=7.8Hz), 4.02 (2H, s), 5.20 (2H, s), 6.91-6.95 (6H, m), 7.09-7.12 (2H, m), 7.22-7.37 (12H, m), 7.42-7.52 (4H, m), IR (KBr) cm-1: 1650, 1540, 1515, 1345, MS (FAB) m/z: 778 (M+1) Example 48: 2-butyl-6-methyl-5-(1-triphenylmethyl benzotriazol-5-yl)methyl-4-[2'-(triphenylmethyltetrazol-5yl)biphenyl-4-ylmethoxypyrimindine Yield: 19%, H-NMR (CDCl3) #: 0.90 (3H, t, J=7.3Hz), 1.26-1.82 (4H, m), 2.41 (3H, s), 2.79 (2H, t, J=7.6Hz) , 3.99 (2H, s), 5.36 (2H, s), 6.80-7.99 (41H, m), MS (FAB) m/z: 1016 (M+1) Example 49; 2-butyl-6-methyl-5-(1-triphenylmethyl benzOtrlazol-5-vl)methvl-3-r2'-(tri;henvlmethyltetrazol-5- yl)biphenyl-4-yllmethylpyrimidine-4-one Yield: 32%, 1H-NMR (CDC13)8: 0.82 (3H, t, J=7.3Hz), 1.22-1.70 (4H, m), 2.29 (3H, s), 2.60 (2H, t, J=7.6Hz), 3.83 (2H, s), 5.97 (2H, s), 6.80-8.02 (41H, m), MS (FAB) m/z: 1016 (M+1) Example 50; 6-butyl-2-methyl-5-(1-triphenylmethyl benzotriazol-5-v1)methyl-3-F2'-(trithenvlmethyltetrazol-5- yl)biphenyl-4-yllmethylpyrimidin-4-one Yield: 52%, Melting point: 1300C, H-NMR (CDCl3) #: 0.74 (3H, t, J=7.2Hz), 1.12-1.53 (4H, m), 2.25 and 2.61 (total 2H, each t, J=7.8Hz), 2.52 and 2.56 (total 3H, each s), 3.74 and 3.92 (total 2H, each s), 5.08 and 5.22 (total 2H, each s), 5.75 (0.5H, s), 6.18 (0.5H, d, J=8.6Hz), 6.77-7.41 (38H, m), 7.63 (0.5H, s), 7.83-7.90 (1.5H, m), MS (FAB) m/z: 1016 (M+1) Example 51: Preparation of 5- (4-methoxycarbonylbenzyl)-2,6dimethyl-4-[2'- (1H-tetrazol-5-yl)biphenyl-4yllmethoxypyrimdine The compound (447 mg) of Example 13 was dissolved in 30 ml of methanol, and several drops of concentrated hydrochloric acid were added. The mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was evaporated and the residue was recrystallized from methanol/diisopropylether to obtain 288 mg of the above-titled compound as white powder.
Yield: 95%, Melting point: 120 - 1220C, 1H-NMR (DMSO-d6)6: 2.28 (3H, s), 2.50 (3H, s), 3.83 (3H, s), 4.05 (2H, s), 5.48 (2H, s), 7.05-7.37 (4H, m), 7.12 (2H, d, J=8.1Hz), 7.49-7.80 (4H, m), 7.85 (2H, d, J=8.1Hz), IR (KBr) cm-1: 1720, 1610, 1345, 1285, MS (FAB) m/z: 507 (M+1) Examples 52 to 99 The compounds described in the following Examples 52 to 99 were prepared in accordance with the method of Example 51.
Example 52; 5- (4-methoxycarbonylbenzyl)-2,6-dimethyl-3-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Yield: 98%, Melting point: 148 - 1500C, H-NMR (DMSO-d6)8: 2.27 (3H, s), 2.48 (3H, s), 3.83 (3H, s), 3.93 (2H, s), 5.29 (2H, s), 7.07-7.27 (4H, m), 7.34 (2H, d, J=8.1Hz), 7.49-7.66 (4H, m), 7.85 (2H, d, J=8.1Hz), IR (KBr) cm-1 : 1700, 1665, 1595, 1285, MS (FAB) m/z: 507 (M+1) Example 53: 2-ethvl-5-(4-methoxvcarbonvlbenzvl)-6-methvl-4 [2'- (1H-tetrazol-5-yl)blphenyl-4-yllmethoxypyrimidine Yield: 86%, Melting point: 202 - 2040C, H-NMR (DMSO-d6)8: 1.25 (3H, t, J=7.6Hz), 2.36 (3H, s), 2.74 (2H, q, J=7.6Hz), 3.82 (3H, s), 4.01 (2H, s), 5.42 (2H, s), 7.06 (2H, d, J=8.4Hz), 7.2-7.3 (2H, m), 7.4 7.7 (4H, m), 7.82 (2H, d, J=8.4Hz), IR (KBr) cm-1: 1715, 1570, 1350, 1280, MS (FAB) m/z: 521 (M+1) Example 54: 2-thvl-5-(4-methoxvcarbonvlbenzvl)-6-metnvl-3 [2'- (1H-tetrazol-5-yl)biphenyl-4-yllmethypyrimidin-4-one Melting point: 2150C (decomposition), 1H-NMR (DMSO-d6)8: 1.14 (3H, t, J=7.3Hz), 2.32 (3H, s), 2.81 (2H, q, J=7.3Hz), 3.83 (3H, s), 3.94 (2H, s), 5.32 (2H, s), 7.10 (4H, s), 7.35 (2H, d, J=8.1Hz), 7.4-7.7 (4H, m), 7.86 (2H, d, J=8.1Hz), IR (KBr) cm-1: 1695, 1665, 1545, 1285, MS (FAB) m/z: 521 (M+1) Example 55: 5-(4-methoxycarbonylbenzyl)-6-methyl-2-propyl4-[2'- (1H-tetrazol-5-yl)blphenyl-4-yllmethoxypyrimidine Yield: 99%, Melting point: 219 - 2210C, 1K-NMR (DMSO-d6)8: 0.94 (3H, t, J=7.3Hz), 1.75-1.83 (2H, m), 2.49 (3H, s), 2.84 (2H, t, J=7.4Hz), 3.82 (3H, s), 4.05 (2H, s), 5.49 (2H, s), 7.06 (2H, d, J=8.3Hz), 7.21 (2H, d, J=8.1Hz), 7.25 (2H, d, J=8.3Hz), 7.32-7.69 (4H, m), 7.82 (2H, d, J=8.1Hz), IR (KBr) cm-1: 1710, 161 H-NMR (CDCl3) #: 0.91 (3H, t, J=7.3Hz), 1.3-1.5 (2H, m), 1.6-1.8 (2H, m), 2.84 (3H, s), 3.16 (2H, t, J=7.6Hz), 3.88 (3H, s), 3.97 (2H, s), 5.45 (2H, s), 6.77 (2H, d, J=7.9Hz), 7.09 (2H, d, J=7.9Hz), 7.15 (2H, d, J=8.2Hz), 7.2-7.4 (1H, m), 7.4-7.7 (2H, m), 7.92 (2H, d, J=8.2Hz), 7.8-8.0 (1H, m), IR (KBr) cm-1: 1715, 1610, 1345, 1290, MS (FAB) m/z: 549 (M+1) Example 58; 2-butyl-5-(4-methoxycarbonylbenzyl)-6-methyl-3 [2'- (1H-tetrazol-5-yl)biphenyl-4-yllmethoxypyrimidin-4-one Yield: 73%, Melting point: 231 C (decomposition), 1H-NMR (DMSO-d6)d: 0.82 (3H, t, J=7.3Hz), 1.2-1.4 (2H, m), 1.5-1.7 (2H, m), 2.31 (3H, s), 2.78 (2H, t, J=7.6Hz), 3.83 (3H, s), 3.94 (2H, s), 5.33 (2H, s), 7.11(4H, s), 7.35 (2H, d, J=8.1Hz), 7.4-7.6 (2H, m), 7.6-7.7 (2H, m), 7.86 (2H, d, J=8.1Hz), IR (KBr) cm-1: 1720, 1695, 1665, 1280, MS (FAB) m/z: 549 (M+1) Example 59; 5-(4-methoxycarbonylbenzyl)-6-methyl-2-pentyl4-[2'- (1H-tetrazol-5-yl)biphenyl-4-yllmethoxypyrimidine Yield: 68%, Melting point: 158 - 1600C, 1H-NMR (DMSO-d6) #: 0.87 (3H, t, J=7.1Hz), 1.31-1.37 (4H, m), 1.73-1.81 (2H, m) , 2.58 (3H, s), 2.94 (2H, t, J=7.6Hz), 3.82 (3H, s), 4.07 (2H, s), 5.53 (2H, s), 7.06 (2H, d, J=8.1Hz), 7.21 (2H, d, J=8.3Hz), 7.27 (2H, d, J=8.1Hz), 7.48-7.60 (2H, m), 7.65-7.70 (2H, m), 7.83 (2H, d, J=8.3Hz), IR (KBr) cm-1: 1715, 1610, 1350, 1285, MS (FAB) m/z: 563 (M+1) Example 60; 5-(4-methoxycarbonylbenzyl)-6-methyl-2-pentyl3-[2'- (1H-tetrazol-5-yl)biphenyl-4-yllmethoxypyrimidin-4-one Yield: 76%, Melting point: 202 - 2040C, 1K-NMR (DMSO-d6)5: 0.81 (3H1, t, J=7.0Hz), 1.18-1.28 (4H, m), 1.51-1.59 (2H, m), 2.30 (3H, s), 2.75 (2H, t, J=7.7Hz), 3.83 (3H, s), 3.94 (2H, s), 5.32 (2H, s) 7.04-7.13 (4H, m), 7.35 (2H, d, J=8.1Hz), 7.49 (1H, d, J=6.8Hz), 7.55 (1H, t, J=6.8Hz), 7.63-7.68 (2H, m), 7.86 (2H, d, J=8.1Hz), IR (KBr) cm-1: 1720, 1595, 1435, 1290, MS (FAB) m/z: 563 (M+1) Example 61; 5-(4-methoxycarbonylbenzyl)-6-methyl-3-[2'-(1Htetrazol-5-yl)biphenyl-4-yllmethoxypyrimidin-4-one Yield: 98%, Melting point: 188 - 1900C, 1K-NMR (CDC13+DMSO-d6)8: 2.34 (3H, s), 3.84 (3H, s), 3.93 (2H, s), 5.20 (2H, s), 7.11 (2H, d, J=8.3Hz), 7.29-7.67 (8H, m), 7.87 (2H, d, J=8.1Hz), 9.09 (1H, s), IR (KBr) cm-1: 1695, 1560, 1285, 760, MS (FAB) m/z: 493 (M+1) Example 62; 5-(4-methoxycarbonylbenzyl)-6-methyl-2-pentyl4-[2'- (1H-tetrazol-5-yl)biphenyl-4-yllmethoxypyrimidine Yield: 95%, Melting point: 119 - 121 C, 1K-NMR (DMSO-d5)6: 2.50 (3H, s), 3.82 (3H, s), 4.11 (2H, s), 5.59 (2H, s), 7.07 (2H, d, J=8.1Hz), 7.27-7.31 (4H, m), 7.52-7.59 (5H, m), 7.65-7.70 (2H, m), 7.85 (2H, d, J=7.8Hz), 8.38-8.41 (2H, m), IR (KBr) cm-1: 1720, 1625, 1350, 1280, MS (FAB) m/z: 569 (M+1) Example 63; 6-ethyl-5-(4-methoxycarbonylbenzyl)-2-methyl-4 [2'- (1H-tetrazol-5-yl)biphenyl-4-yllmethoxypyrimidine Yield: 99%, Melting point: 113 - 1150C, 1K-NMR (DMSO-d6)6: 1.06 (3H, t, J=8.2Hz), 2.49 (3H, s), 2.80 (2H, q, J=7. 4Hz), 3.82 (3H, s), 4.06 (2H, s), 5.47 (2H, s), 7.03-7.13 (2H, m), 7.19 (2H, d, J=8.3Hz), 7.21-7.35 (2H, m), 7.48-7.78 (4H, m), 7.82 (2H, d, J=8.3Hz), IR (KBr) cm-1: 1720, 1610, 1435, 1280, MS (FAB) m/z: 521 (M+1) Example 64; 6-ethyl-5-(4-methoxycarbonylbenzyl)-2-methyl-3 [2'- (1H-tetrazol-5-yl)biphenyl-4-yllmethoxypyrimidin-4-one Yield: 99%, Melting point: 176 - 1770C, H-NMR (DMSO-d6)5: 1.07 (3H, t, J=7.4Hz), 2.49 (3H, s), 2.55 (2H, q, J=7.6Hz), 3.83 (3H, s), 3.95 (2H, s), 5.29 (2H, s), 7.04-7.28 (4H, m), 7.33 (2H, d, J=8.3Hz), 7.42-7.68 (4H, m), 7.85 (2H, d, J=8.3Hz), IR (KBr) cm-1: 1700, 1660, 1595, 1280, MS (FAB) m/z: 521 (M+1) Example 65; 6-butyl-5-(4-methoxycarbonylbenzyl)-2-methyl-4 [2'- (1H-tetrazol-5-yl)biphenyl-4-yllmethoxypyrimidine Yield: 95%, Melting point: 108 - 110 c, 1H-NMR (DMSO-d6)8: 0.83 (3H, t, J=7.2Hz), 1.24-1.35 (2H, m), 1.50-1.56 (2H, m), 2.49 (3H, s), 2.76 (2H, t, J=7.7Hz), 3.82 (3H, s), 4.06 (2H, s), 5.46 (2H, s), 7.04 (2H, d, J=8.1Hz), 7.10-7.37 (2H, m), 7.22 (2H, d, J=8.3Hz), 7.49-7.86 (6H, m), IR (KBr) cm-1: 1720, 1610, 1345, 1285, MS (FAB) m/z: 549 (M+1) Example 66: 6-butvl-5- (4-methoxvcarbonvlbenzvl) -2-methvl-3- [2'- (1H-tetrazol-5-yl)biphenyl-4-yllmethoxypyrimidin-4-one Yield: 99%, Melting point: 135 - 137 C, H-NMR (DMSO-d6)3: 0.82 (3H, t, J=7.2Hz), 1.24-1.32 (2H, m), 1.43-1.51 (2H, m), 2.49 (3H, s), 2.52 (2H, t, J=7.5Hz), 3.83 (3H, s), 3.95 (2H, s), 5.28 (2H, s), 7.07-7.27 (4H, m), 7.32 (2H, d, J=8.1Hz), 7.50-7.66 (4H, m), 7.85 (2H, d, J=8.1Hz) IR (KBr) cm-1: 1700, 1660, 1590, 1285, MS (FAB) m/z: 549 (M+1) Example 67; 6-butyl-5-(4-methoxycarbonylbenzyl)-2-propyl-4 [2'- (1H-tetrazol-5-yl)biphenyl-4-yllmethoxypyrimidine Yield: 81%, Melting point: 113 - 115 C, 1K-NMR (DMSO-d6) #: 0.83 (3H, t, J=7.3Hz), 0.94 (3H, t, J=7.3Hz), 1.24-1.37 (2H, m), 1.48-1.56 (2H, m), 1.76 1.84 (2H, m), 2.78 (2H, t, J=7.7Hz), 2.85 (2H, t, J=7.3Hz), 3.82 (3H, s), 4.06 (2H, s), 5.47 (2H, s), 7.04 (2H, d, J=8.3Hz), 7.19 (2H, d, J=8.3Hz), 7.23 (2H, d, J=8.3Hz), 7.31-7.69 (4H, m), 7.82 (2H, d, J=8.3Hz), IR (KBr) cm-1: 1720, 1600, 1345, 1285, MS (FAB) m/z: 577 (M+1) Example 68; 6-butyl-5-(4-methoxycarbonylbenzyl)-2-propyl-3 [2'- (1H-tetrazol-5-yl)biphenyl-4-yllmethoxypyrimidin-4-one Yield: 95%, Melting point: 140 - 142 C, 1H-NMR DMSO-d6) #: 0.82 (3H, t, J=7.2Hz), 0.86 (3H, t, J=7.3Kz), 1.24-1.32 (2H, m), 1.45-1.54 (2H, m), 1.58 1.66 (2H, m), 2.53 (2H, t, J=7.3Hz), 2.65 (2H, t, J=7.2Hz), 3.82 (3H, s), 3.95 (2H, s), 5.30 (2H, s), 7.09 (4H, s), 7.32 (2H, d, J=8.1Hz), 7.49-7.68 (4H, m), 7.85 (2H, d, J=8.3Hz), IR (KBr) cm-1: 1700, 1660, 1540, 1285, MS (FAB) m/z: 577 (M+1) Example 69; 2-butyl-5-(4-methoxycarbonylbenzyl)-6-propyl-4 [2'- (1H-tetrazol-5-yl)biphenyl-4-yllmethoxypyrimidine Yield: 84%, Melting point: 110 - 1120C, H-NMR (DMSO-d6) #: 0.89 (3H, t, J=7.3Hz), 0.91 (3H, t, J=7.3Hz), 1.33-1.42 (2H, m), 1.53-1.65 (2H, m), 1.72 1.81 (2K, m), 2.78-2.90 (2H, m), 2.91-2.98 (2H, m), 3.82 (3H, s), 4.08 (2H, s), 5.50 (2H, s), 7.06-7.84 (12H, m), IR (KBr) cm-1: 2960, 1720, 1610, 1350, MS (FAB) m/z: 577 (M+1) Example 70; 2-butyl-5-(4-methoxycarbonylbenzyl)-6-propyl-3 [2'- (1H-tetrazol-5-yl)biphenyl-4-yllmethoxypyrimidin-4-one Yield: 90%, Melting point: 108 - 11 C, H-NMR (DMSO-d6)8: 0.81 (3H, t, J=7.2Hz), 0.86 (3H, t, J=7.3Hz), 1.25-1.33 (2H, m), 1.53-1.63 (4H, m), 2.55 (2H, t, J=7.3Hz), 2.73 (2H, t, J=7.3Hz), 3.83 (3H, s), 3.95 (2H, s), 5.31 (2H, s), 7.10-7.87 (12H, m), IR (KBr) cm-1: 1700, 1660, 1540, 1280, MS (FAB) m/z: 577 (M+1) Example 71; 2-butyl-5-(3-methoxycarbonylbenzyl)-6-methyl-4 [2'- (1H-tetrazol-5-yl)biphenyl-4-yllmethoxypyrimidine Yield: 87%, Melting point: 128 - 1300C, 1H-NMR (DMSO-d6)8: 0.90 (3H, t, J=7.3Hz), 1.30-1.40 (2H, m), 1.66-1.82 (2H, m), 2.32 (3H, s), 2.73 (2H, t, J=7.7Hz), 3.81 (3H, s), 4.06 (2H, s), 5.53 (2H, s), 7.06 (2H, d, J=8.1Hz), 7.23 (2H, d, J=8.1Hz), 7.34-7.82 (8H, m), IR (KBr) cm-1: 1720, 1695, 1605, 1285, MS (FAB) m/z: 549 (M+1) Example 72; 2-butyl-5-(3-methoxycarbonylbenzyl)-6-methyl-3 [2'- (1H-tetrazol-5-yl)biphenyl-4-yllmethoxypyrimidin-4-one Yield: 99%, Melting point: 205 - 2070C, 1H-NMR (DMSO-d6)3: 0.84 (3H, t, J=7.3Hz), 1.26-1.34 (2H, m), 1.50-1.61 (2H, m), 2.30 (3H, s), 2.74 (2H, t, J=7.7Hz), 3.83 (3H, s), 3.93 (2H, s), 5.33 (2H, s), 7.10 (4H, s), 7.4-7.9 (8H, m), IR (KBr) cm-1: 1700, 1660, 1590, 1285, MS (FAB) m/z: 549 (M+1) Example 73; 6-butyl-5-(3-methoxycarbonylbenzyl)-2-methyl-4 [2'- (1H-tetrazol-5-yl)biphenyl-4-yllmethoxypyrimidine Yield: 95%, Melting point: 94 - 960C, 1K-NMR (DMSO-d6)8: 0.83 (3H, t, J=7.3Hz), 1.28-1.36 (2H, m), 1.45-1.56 (2H, m), 2.49 (3H, s), 2.78 (2H, t, J=3. 8Hz), 3.80 (3H, s), 4.06 (2H, s), 5.47 (2H, s), 7.05 (2H, d, J=8.3Hz), 7.21 (2H, d, J=8.1Hz), 7.23-7.81 (8H, m), IR (KBr) cm-1: 1720, 1600, 1345, 1285, MS (FAB) m/z: 549 (M+1) Example 74; 2-butyl-5-(3-methoxycarbonylbenzyl)-2-methyl-3 [2-(lH-tetrazol-5-vl)blohenvl-4-yllmethvlDvrlmldln-4-one Yield: 98%, Melting point: 147 - 1490C, 1K-NMR (DMSO-d6)5: 0.82 (3H, t, J=7.2Hz), 1.26-1.34 (2H, m), 1.43-1.51 (2H, m), 2.49 (3H, s), 2.56 (2H, t, J=7.7Hz), 3.83 (3H, s), 3.95 (2H, s), 5.29 (2H, s), 7.07-7.16 (4H, m), 7.23-7.81 (8H, m), IR (KBr) cm-1 : 1700, 1590, 1445, 1285, MS (FAB) m/z: 549 (M+1) Example 75; 2,6-dibutyl-5-(3-methoxycarbonylbenzyl)-4-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethoxypyrimidine Yield: 92%, Melting point: 119 - 1210C, 1H-NMR (DMSO-d6) #: 0.83 (3H, t, J=7.3Hz), 0.90 (3H, t, J=7.3Hz), 1.25-1.40 (4H, m), 1.43-1.59 (2H, m), 1.68 1.82 (2H, m), 2.84 (2H, t, J=7.8Hz), 2.91 (2H, t J=7.4Hz), 3.80 (3H, s), 4.07 (2H, s), 5.50 (2H, s), 7.05 (2H, d, J=8. 1Hz), 7.21 (2H, d, J=7. 8Hz), 7.34-7.42 (2H, m), 7.46-7.81 (6H, m), IR (KBr) cm-1: 1605, 1465, 1430, 1345, MS (FAB) m/z: 591 (M+1) Example 76; 2,6-dibutyl-5-(3-methoxycarbonylbenzyl)-3-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethoxypyrimidin-4-one Yield: 99%, Melting point: 113 - 1150C, 1H-NMR (DMSO-d6) #: 0.81 (3H, t, J=7.3Hz), 0.82 (3H, t, J=7.3Hz), 1.22-1.36 (4H, m), 1.46-1.63 (4H, m), 2.57 (2H, t, J=7.6Hz), 2.71 (2H, t, J=7.4Hz), 3.82 (3H, s), 3.95 (2H, s), 5.31 (2H, s), 7.09 (4H, s), 7.37-7.81 (8H, m), IR (KBr) cm-1: 2960, 1700, 1590, 1285, MS (FAB) m/z: 591 (M+1) Example 77; 2-butyl-5-(3-chlorobenzyl)-6-methyl-4-[2'-(1Htetrazol-5-yl)biphenyl-4-yllmethoxypyrimidine Yield: 89%, Melting point: 158 - 1600C, 1H-NMR (DMSO-d6)6: 0.89 (3H, t, J=7.3Hz), 1.26-1.39 (2H, m), 1.65-1.76 (2H, m), 2.37 (3H, s), 2.72 (2H, t, J=7.6Hz), 3.92 (2H, s), 5.41 (2H, s), 7.07 (2H, d, J=8.1Hz), 7.12 (2H, d, J=8.6Hz), 7.20-7.36 (4H, m), 7.52-7.71 (4H, m), IR (KBr) cm-1: 1575, 1490, 1425, 1345, MS (FAB) m/z: 525 (M+1) Example 78; 2-butyl-5-(4-chlorobenzyl)-6-methyl-3-[2'- (1Htetrazol-5-yl)biphenyl-4-yllmethoxypyrimindin-4-one Yield: 81%, Melting point: 111 - 113 C, 1H-NMR (DMSO-d6)6: 0.81 (3H, t, J=7.3Hz), 1.22-1.33 (2H, m), 1.49-1.60 (2H, m), 2.22 (3H, s), 2.60 (2H, t, J=7.7Hz), 3.83 (2H, s), 5.29 (2H, s), 7.08 (4H, s), 7.23 (2H, d, J=8.5Hz), 7.31 (2H, d, J=8.3Hz), 7.51-7.70 (4H, m), IR (KBr) cm-1: 3440, 1650, 1540, 1490, MS (FAB) m/z: 525 (M+1) Example 79; 2-butyl-6-methyl-5-(4-methylbenzyl)-4-[2'- (1Htetrazol-5-yl)biphenyl-4-yllmethoxypyrimidine Yield: 83%, Melting point: 165 - 165.50C, 1H-NMR (DMSO-d6) #: 0.89 (3H, t, J=7.3Hz), 1.25-1.40 (2H, m), 1.65-1.76 (2H, m), 2.23 (3H, s), 2.34 (3H, s), 2.71 (2H, t, J=7.5Hz), 3.88 (2H, s), 5.42 (2H, s), 6.95-7.04 (4H, m), 7.06 (2H, d, J=8.1Hz), 7.25 (2H, d, J=8.1Hz), 7.49-7.68 (4H, m), IR (KBr) cm-1: 2960, 1575, 1425, 1350, MS (FAB) m/z: 505 (M+1) Example 80; 2-butyl-6-methyl-5-(4-methylbenzyl)-3-[2'- (1Htetrazol-5-yl)biphenyl-4-yllmethoxypyrimidin-4-one Yield: 86%, Melting point: 171 - 1730C, 1H-NMR (DMSO-d6) #: 0.81 (3H, t, J=7.3Hz), 1.21-1.34 (2H, m), 1.50-1.61 (2H, m), 2.21 (3H, s), 2.24 (3H, s), 2.61 (2H, t, J=7.6Hz), 3.79 (2H, s), 5.29 (2H, s), 7.02-7.39 (8H, m), 7.48-7.68 (4H, m), IR (KBr) cm-1: 2960, 1665, 1600, 1540, MS (FAB) m/z: 505 (M+1) Example 81; 2-butyl-5-(4-methylbenzyl)-6-methyl-4-[2'- (1Htetrazol-5-yl)biphenyl-4-yllmethoxypyrimidine Yield: 98%, Melting point: 1350C (decomposition), 1H-NMR (DMSO-d6)8: 0.81 (3H, t, J=7.3Hz), 2.33 (3H, s), 2.81 (2H, t, J=7.7Hz), 3.72 (3H, s), 3.78 (2H, s), 5.33 (2H, s), 6.82 (2H, d, J=8.5Hz), 6.85-7.15 (2H, m), 7.63-7.69 (2H, m), IR (KBr) cm-1: 1645, 1540, 1510, 1245, MS (FAB) m/z: 521 (M+1) Example 82; 2-butyl-5-(4-methylbenzyl)-6-methyl-3-[2'- (1Htetrazol-5-yl)biphenyl-4-yllmethoxypyrimidin-one Yield: 99%, Melting point: 1800C (decomposition), 1H-NMR (DMSO-d6)8: 1.05 (3H, t, J=7.3Hz), 1.43-1.57 (2H, m), 2.74 (3H, s), 3.11 (2H, t, J=7.4Hz), 3.85 (3H, s), 4.06 (2H, s), 5.71 (2H, s), 6.92-6.98 (2H, m), 7.19 7.29 (4H, m), 7.41 (2H, d, J=8.1Hz), 7.64-7.74 (2H, m), 7.79-7.85 (2H, m), IR (KBr) cm-1: 1625, 1605, 1515, 1350, MS (FAB) m/z: 521 (M+1) Example 83; 2-butyl-6-methyl-5-(4-nitrobenzyl)-4-[2'-(1Htetrazol-5-yl)biphenyl-4-yllmethoxypyrimidine Yield: 90%, Melting point: 158 - 1600C, H-NMR (DMSO-d6)5: 0.91 (3H, t, J=7.3Hz), 1.30-1.44 (2H, m), 1.72-1.83 (2H, m), 2.58 (3H, s), 2.94 (2H, t, J=7.6Hz), 4.13 (2H, s), 5.52 (2H, s), 7.07 (2H, d, J=8.3Hz), 7.23 (2H, d, J=8.1Hz), 7.41 (2H, d, J=8.8Hz), 7.48-7.60 (2H, m), 7.64-7.70 (2H, m), 8.09 (2H, d, J=8.5Hz), IR (KBr) cm-1: 1610, 1520, 1435, 1345, MS (FAB) m/z: 536 (M+1) Example 84; 2-butyl-6-methyl-5-(4-nitrobenzyl)-3-[2'-(1Htetrazol-5-yl)biphenyl-4-yllmethoxypyrimidin-4-one Yield: 68%, Melting point: 200 - 2020C, 1K-NMR (DMSO-d6)8: 0.81 (3K, t, J=7.3Hz), 1.21-1.35 (2H, m), 1.51-1.62 (2H, m), 2.24 (3H, s), 2.61 (2H, t, J=7. 6Hz), 3.98 (2H, s), 5.29 (2H, s), 7.08 (4H, s), 7.46-7.58 (4H, m), 7.63-7.69 (2H, m), 8.12 (2H, d, J=8.6Hz), IR (KBr) cm-1: 1660, 1605, 1530, 1345, MS (FAB) m/z: 536 (M+1) Example 85; 5-(3-chlorobenzyl)-6-methyl-2-propy-4-[2'- (1Htetrazol-5-yl)biphenyl-4-yllmethoxypyrimidine Melting point: 161 - 1630C, 1H-NMR (DMSO-d6)8: 0.91 (3H, t, J=7.4Hz), 1.70-1.79 (2H, m), 2.36 (3H, s), 2.69 (2H, t, J=7.5Hz), 3.95 (2H, s), 5.42 (2H, s), 7.03-7.08 (2H, m), 7.15-7.28 (6H, m), 7.50-7.69 (4H, m), IR (KEr) cm-1: 1575, 1420, 1345, 1080, MS (FAB) m/z: 511 (M) Example 86; 5- (3-chlorophenzyl)-6-methyl-2-propyl-3-[2'- (1Htetrazol-5-yl)biphenyl-4-yllmethoxypyrimidin-4-one Melting point: 91 - 930C, 1H-NMR (DMSO-d6)3: 0.86 (3K, t, J=7.3Hz), 1.56-1.64 (2H, m), 2.24 (3H, s), 2.59 (2H, t, J=7.5Hz), 3.86 (2H, s), 5.30 (2H, s), 7.08 (4H, s), 7.16-7.36 (4H, m), 7.50 7.68 (4H, m), IR (KBr) cm-1: 1650, 1595, 1540, 1430, MS (FAB) m/z: 511 (M) Example 87 ; 6-methyl-5-(3-methylbenzyl-2-propyl-4-[2'-(1Htetrazol-5-yl)blphenyl-4-yllmethoxypyrimidine Melting point: 1540C (decomposition), 1K-NMR (DMSO-d6)8: 0.91 (3H, t, J=7.3Hz), 1.71-1.79 (2H, m), 2.20 (3H, s), 2.37 (3H, s), 2.70 (2H, t, J=7.4Hz), 3.90 (2H, s), 5.43 (2H, s), 6.86-6.98 (3H, m), 7.05 7.13 (3H, m), 7.26 (2H, d, J=8.3Hz), 7.49-7.58 (2H, m), 7.65 (2H, d, J=8.6Hz), IR (KBr) cm-1. 1605, 1570, 1420, 1345, MS (FAB) m/z: 491 (M+1) Example 88; 6-methyl-5-(3-methylbenzyl)-2-propyl-3-[2'-(1Htetrazol-5-yl)biphenyl-4-yllmethoxypyrimidin-4-one Melting point: 1620C (decomposition), H-NMR (DMSO-d6)8: 0.87 (3H, t, J=7.3Hz), 1.56-1.64 (2H, m), 2.24 (6H, s), 2.63 (2H, t, J=7.5Hz), 3.81 (2H, s), 5.31 (2H, s), 6.98-7.01 (3H, m), 7.08-7.16 15H, m), 7.50-7.57 (2H, m), 7.63-7.68 (2H, m), IR (KBr) cm-1: 2970, 1650, 1605, 1540, MS (FAB) m/z: 491 (M+1) Example 89; 5-(3-methoxybenzyl)-6-methyl-2-propyl-4-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethoxypyrimidine Melting point: 103 - 105 C, 1H-NMR (DMSO-d6)6: 0.90 (3H, t, J=7.3Hz), 1.69-1.76 (2H, m), 2.25 (3H, s), 2.58 (2H, t, J=7.6Hz), 3.69 (3H, s), 3.76 (2H, s), 5.42 (2H, s), 6.41-6.90 (1H, m), 7.08 7.62 (10H, m), 8.00-8.05 (1H, m), IR (KBr) cm-1: 3440, 2960, 1650, 1600, MS (FAB) m/z: 507 (M+1) Example 90; 5-(3-methoxybenzyl)-6-methyl-2-propyl-3-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Melting point: 98 - 1000C, 1H-NMR (DMSO-d6)6: 0.94 (3H, t, J=7.3Hz), 1.62-1.76 (2H, m), 2.27 (3H, s), 2.60 (2H, t, J=7.6Hz), 3.72 (3H, s), 3.80 (2H, s), 5.20 (2H, s), 6.68-6.73 (3H, m), 6.93 7.58 (8H, m), 7.86-7.90 (1H, m), IR (KBr) cm-1: 3420, 2960, 1600, 1345, MS (FAB) m/z: 507 (M+1) Example 91, 6-methyl-5-(3-nitrobenzyl)-2-propyl-4-[2'- (1Htetrazol-5-yl)biphenyl-4-yllmethoxypyrimidinone Melting point: 92 - 940C, 1H-NMR (DMSO-d6)8: 0.91 (3H, t, J=7.3Hz), 1.70-1.98 (2H, m), 2.39 (3H, s), 2.70 (2H, t, J=7.5Hz), 4.08 (2H, s), 5.41 (2H, s), 7.03-7.07 (2H, m), 7.22-7.25 (2H, m), 7.50-7.69 (6H, m), 7.95-8.04 (2H, m), IR (KBr) cm-1: 3420, 1575, 1530, 1350, MS (FAB) m/z: 522 (M+1) Example 92: 6-methyl-5-(3-nitrobenzyl)-2-propyl-3-(2'-(1Htetrazol-5-yl)biphenyl-4-yllmethylpyrimdin-4-one Melting point: 110 - 1120C, 1H-NMR (DMSO-d6)8: 0.86 (3H, t, J=7.3Hz), 1.57-1.65 (2H, m), 2.27 (3H, s), 2.60 (2H, t, J=7.4Hz), 4.00 (2H, s), 5.31 (2H, s), 7.08 (4H, s), 7.53-7.70 (6H, m), 8.02 8.05 (2H, m), IR (KBr) cm-1: 3450, 1650, 1530, 1350, MS (FAB) m/z: 522 (M+1) Example 93: 6-methyl-2-propyl-5-[4-(1H-tetrazol-5yl)benzyl]-4-[2'-(1H-tetrazol5-yl)biphenyl-4yl]methoxypyrimidine Melting point: 201 - 2030C, H-NMR (DMSO-d6)6: 0.89-0.94 (3H, m), 1.71-1.79 (2H, m), 2.38 (3H, s), 2.66-2.72 (2H, m), 4.03 (2H, s), 5.43 (2H, s), 7.04-7.06 (2H, m), 7.25-7.34 (4H, m), 7.47 7.64 (4H, m), 7.90-7.92 (2H, m), IR (KBr) cm-1: 1615, 1570, 1425, 1345, MS (FAB) m/z: 545 (M+1) Example 94: 6-mthvl-2-DroDvl-5-14-(1H-tetrazol-5- yl)benzyl]-3-[2'-(1H-tetrazol]-5-yl)biphenyl-4yl]methylpyrimidin-4-one Melting point: 154 - 1560C, H-NMR (DMSO-d6)#: 0.83-0.91 (3H, m), 1.57-1.65 (2H, m), 2.26 (3H, s), 2.57-2.64 (2H, m), 3.94 (2H, s), 5.31 (2H, s), 7.08 (4H, s), 7.41-7.50 (2H, m), 7.50-7.61 (3H, m), 7.63-7.69 (2H, m), 7.92-7.95 (3H, m), IR (KBr) cm-1: 3440, 2960, 1645, 1540, MS (FAB) m/z: 545 (M+1) Example 95, 6-methyl-2-propyl-5-[3-(1H-tetrazol-5yl)benzyl1-4-[2'- (1H-tetrazol-5-yl)biphenyl-4 vii methoxvovrimidine Melting point: 206 - 208 C, 1H-NMR (DMSO-d6)5: 0.92 (3H, t, J=7.3Hz), 1.71-1.80 (2H, m), 2.41 (3H, s), 2.71 (2H, t, J=7.6Hz), 4.05 (2H, s), 5.43 (2H, s), 7.00-7.03 (2H, m), 7.23-7.33 (3H, m), 7.43-7.69 (5H, m), 7.84-7.87 (2H, m), IR (KBr) cm-1: 3400, 1610, 1460, 1345, MS (FAB) m/z: 545 (M+1) Example 96; 6-methyl-2-propyl-5-[3-(1H-tetrazol-5yl)benzyll-3-[2'- (1H-tetrazol-5-yl)biphenyl-4yllmethylpyrimidin-4-one Melting point: 217 - 2190C, H-NMR (DMSO-d6)6: 0.84-0.91 (3H, m), 1.57-1.65 (2H, m), 2.28 (3H, s), 2.57-2.67 (2H, m), 3.96 (2H, s), 5.31 (2H, s), 7.05-7.12 (4H, m), 7.41-7.69 (6H, m), 7.82 7.90 (2H, m), IR (KBr) cm-1: 2960, 2930, 1650, 1540, MS (FAB) m/z: 545 (M+1) Example 97 ; 5- (benzotriazol-5-yl)methyl-2-butyl-6-methyl-4 12'-(1H-tetrazol-5-yl)biphenyl-4-yl)methoxypyrlmidine Yield: 86%, Melting point: 74 - 760C, 1H-NMR (DMSO-d6)8: 0.90 (3H, t, J=7.3Hz), 1.28-1.42 (2H, m), 1.67-1.78 (2H, m), 2.40 (3H, s), 2.74 (2H, t, J=7.5Hz), 4.12 (2H, s), 5.44 (2H, s), 7.02 (2H, d, J=8.1Hz), 7.20-7.24 (3H, m), 7.47-7.78 (7H, m), IR (KBr) cm-1: 2960, 2930, 1570, 1420, MS (FAB) m/z: 532 (M+1) Example 98. 5-(benzotrlazol-5-yl)methyl-2-butyl-6-methyl-3 [2'- (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Yield: 85%, Melting point: 121 - 1230C, H-NMR (DMSO-d6)8: 0.81 (3H, t, J=7.3Hz), 1.23-1.34 (2H, m), 1.54-1.62 (2H, m), 2.26 (3H, s), 2.61 (2H, t, J=7.6Hz), 4.02 (2H, s), 5.31 (2H, s), 7.09 (4H, s), 7.30-7.80 (7H, m), IR (KBr) cm~1: 2960, 2925, 2870, 1640, MS (FAB) m/z: 532 (M+1) Example 99: 5-(benzotriazol-5-vl)methvl-6-butvl-2-methvl-3- [2'-(lH-tetrazol-5-vl)blDhenvl-4-vllmethvlDvrlmldln-4-one Yield: 86%, Melting point: 139 - 1410C, H-NMR (DMSO-d6)8: 0.79 (3H, t, J=7.3Hz), 1.23-1.34 (2H, m), 1.42-1.50 (2H, m), 2.38 (3H, s), 2.47-2.55 (2H, m), 4.04 (2H, s), 5.29 (2H, s), 7.11 (4H, s), 7.14-7.8 (7H, m), IR (KRb) cm-1: 2960, 2925, 2870, 1650, MS (FAB) m/z: 532 (M+1) Example 100: PreDaratlon of 5-(4-carboxvbenzvl)-2.6- dimethyl-4-[2'- (1H-tetrazol-5-yl)biphenyl-4yllmethoxypyrimidine The compound (155 mg) of Example 51 was dissolved in 10 ml of ethanol. To the solution, 0.9 ml of 1N NaOH was added. The mixture was heated under reflux for 4 hours.
After the reaction was completed, the reaction mixture was evaporated under reduced pressure, and 10 ml of water was added to dissolve the resulting residue. The pH of the aqueous solution was adjusted to 4 with 1N hydrochloric acid. The precipitated crystals were collected by filtration to obtain 103 mg of the above-titled compound as white powder.
Yield: 68%, Melting point: 143 - 1450C, H-NMR (DMSO-d6)5: 2.34 (3H, s), 2.47 (3H, s), 4.00 (2H, s), 5.40 (2H, s), 7.06 (2H, d, J=B.lHz), 7.19 (2H, d, J=8.3Hz), 7.23 (2H, d, J=8.1Hz), 7.49-7.68 (4H, m), 7.81 (2K, d, J=8.1Hz), IR (KBr) cm-1: 1610, 1575, 1420, 1340, MS (FAB) m/z: 493 (M+1) Examples 101 to 132 The compounds described in the following Examples 101 to 132 were prepared in accordance with the method of Example 100.
Example 101; 5- (4-carboxybenzyl)-2,6-dimethyl-3-[2'-(1Htetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Yield: 88%, Melting point: 203 - 2050C, 1H-NMR (DMSO-d6) #: 2.20 (3H, s), 2.36 (3H, s), 3.91 (2H, s), 5.27 (2H, s), 7.09 (4H, s), 7.31 (2H, d, J=8.3Hz), 7.50-7.58 (2H, m), 7.62-7.68 (2H, m), 7.84 (2H, d, J=8.1Hz), IR (KBr) cm-1 : 1655, 1540, 1180, 760, MS (FAB) m/z: 493 (M+1) Example 102; 5- (4-carboxybenzyl)-2-ethyl-6-methyl-4-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Yield: 74%, Melting point: 212 - 2140C, H-NMR (DMSO-d6) #: 1.25 (3H, t, J=7.6Hz), 2.36 (3H, s), 2.74 (2H, q, J=7.6Hz), 4.01 (2H, s), 5.43 (2H, s), 7.07 (2H, d, J=8.3Hz), 7.20 (2H, d, J=8.3Hz), 7.25 (2H, d, J=8.3Hz), 7.4-7.6 (2H, m), 7.6-7.7 (2H, m), 7.82 (2H, d, J=8.3Hz), IR (KBr) cm-1: 1710, 1610, 1570, 1350, MS (FAB) m/z: 507 (M+1) Example 103; 5- (4-carboxybenzyl)-2-ethyl-6-methyl-3-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Melting point: 183 - 1850C, H-NMR (DMSO-d6) #: 1.12 (3H, t, J=7.3Hz), 2.25 (3H, s), 2.67 (2H, q, J=7.3Hz), 3.93 (2H, s), 5.31 (2H, s), 7.09 (4H, s), 7.31 (2H, d, J=8.2Hz), 7.5-7.7 (4H, m), 7.85 (2H, d, J=8.2Hz), IR (KBr) cm-1: 1710, 1655, 1610, 1540, MS (FAB) m/z: 507 (M+1) Example 104; 5- (4-carboxybenzyl)-6-methyl-2-propyl-4-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Yield: 82%, Melting point: 167 - 1690C, 1H-NMR (DMSO-d6)8: 0.92 (3H, t, J=7.5Hz), 1.69-1.82 (2H, m), 2.36 (3H, s), 2.70 (2H, t, J=7.4Hz), 4.01 (2H, s), 5.42 (2K, s), 7.06 (2H, d, J=8.3Hz), 7.21 (2H, d, J=8.1Hz), 7.24 (2H, d, J=8.3Hz), 7.49-7.68 (4H, m), 7.82 (2H, d, J=8.3Hz), IR (KBr) cm-1: 1610, 1570, 1425, 1345, MS (FAB) m/z: 521 (M+1) Example 105; 5- (4-carboxybenzyl)-6-methyl-2-propyl-3-[2' (lH-tetrazol-S-vl)blchenvl-4-vllmethvlDvrlmldln-4-one Yield: 94%, Melting point: 145 - 1460C, 1H-NMR (DMSO-d6)6: 0.86 (3H, t, J=7.3Hz), 1.54-1.68 (2H, m), 2.23 (3H, s), 2.60 (2H, t, J=7.4Hz), 3.92 (2H, s), 5.30 (2H, s), 7.08 (4H, s), 7.31 (2H, d, J=8.1Hz), 7.49-7.57 (2H, m), 7.62-7.68 (2H, m), 7.84 (2H, d, J=8.3Hz), IR (KBr) cm-1: 1705, 1650, 1610, 1540, MS (FAB) m/z: 521 (M+1) Example 106; 1-butyl-5- (4-carboxybenzyl)-6-methyl-4-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Yield: 56%, Melting point: 143 - 1450C H-NMR (DMSO-d6)8: 0.90 (3H, t, J=7.3Hz), 1.2-1.5 (2H, m), 1.6-1.8 (2H, m), 2.35 (3H, s), 2.72 (2H, t, J=7.6Hz), 4.01 (2H, s), 5.42 (2H, s), 7.0-7.3 (6H, m), 7.4-7.7 (4H, m), 7.82 (2H, d, J=8.3Hz), IR (KBr) cm-1: 2960, 1685, 1570, 1345, MS (FAB) m/z: 535 (M+1) Example 107; 2-butyl-5- (4-carboxybenzyl)-6-methyl-3-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Yield: 88%, Melting point: 241 - 2430C, H-NMR (DMSO-d6) #: 0.81 (3K, t, J=7.3Hz), 1.2-1.4 (2H, m), 1.5-1.7 (2H, m), 2.23 (3H, s), 2.63 (2H, t, J=7.6Hz), 3.92 (2H, s), 5.30 (2H, s), 7.09 (4H, s), 7.31 (2H, d, J=8.1Hz), 7.4-7.6 (2H, m), 7.6-7.7 (2H, m), 7.84 (2H, d, J=8.lKz), IR (KBr) cm-1: 1715, 1680, 1665, 1660, MS (FAB) m/z: 535 (M+1) Example 108; 5- (4-carboxybenzyl)-6-methyl-2-pentyl-4-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Yield: 52%, Melting point: 166 - 1680C, 1K-NMR (DMSO-d6) # : 0.86 (3H, t, J=7.0Hz), 1.28-1.33 (4H, m), 1.68-1.78 (2H, m), 2.35 (3H, s), 2.71 (2H, t, J=7.6Hz), 4.01 (2H, s), 5.41 (2H, s), 7.05 (2H, d, J=8.1Hz), 7.19-7.26 (4H, m), 7.50-7.59 (2H, m), 7.63 7.69 (2H, m), 7.82 (2H, d, J=8.1Hz), IR (KBr) cm-1: 1705, 1610, 1580, 1345, MS (FAB) m/z: 549 (M+1) Example 109; 5- (4-carboxybenzyl)-6-methyl-2-pentyl-3-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Yi 1K-NMR (DMSO-d6)8: 2.41 (3H, s), 4.06 (2H, s), 5.43 (2H, s), 7.06 (2H, d, J=8.1Hz), 7.21-7.26 (4H, m), 7.51-7.70 (4H, m), 7.84 (2H, d, J=8.1Hz), 8.57 (1H, s), IR (KBr) cm-1 : 1715, 1580, 1350, 1280, MS (FAB) m/z: 479 (M+1) ExamDle 111: 5-(4-carboxvbenzvl)-6-methvl-3-r2"-(1H- tetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Yield: 78%, Melting point: 155 - 157 C, 1K-NMR (DMSO-d6)8: 2.23 (3H, s), 3.90 (2H, s), 5.10 (2H, s), 7.09 (2H, d, J=8.3Hz), 7.23-7.30 (4H, m), 7.50-7.59 (2H, m), 7.64-7.69 (2H, m), 7.84 (2H, d, J=8.3Hz), 8.44 (1H, s), IR (KBr) cm-1: 1660, 1605, 1175, 755, MS (FAB) m/z: 479 (M+1) Example 112; 5- (4-carboxybenzyl)-6-methyl-2-phenyl-4-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Yield: 87%, Melting point: 146 - 1480C, H-NMR (DMSO-d6)8: 2.49 (3H, s), 4.10 (2H, s), 5.58 (2H, s), 7.07 (2H, d, J=8.1Hz), 7.26-7.32 (4H, m), 7.50-7.59 (5H, m), 7.64-7.70 (2H, m), 7.85 (2H, d, J=8.1Hz), 8.37-8.40 (2H, m), IR (KBr) cm-1 : 1610, 1560, 1400, 1345, MS (FAB) m/z: 555 (M+1) Example 113; 5- (4-carboxybenzyl)-6-methyl-2-methyl-4-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Yield: 61%, Melting point: 122 - 123 C, 1K-NMR (DMSO-d6)5: 1.10 (3H, t, J=7.4Hz), 2.49 (3H, s), 2.66 (2H, q, J=7.5Hz), 4.02 (2H, s), 5.40 (2H, s), 7.04-7.17 (2H, m), 7.22 (2H, d, J=8.1Hz), 7.25-7.36 (2H, m), 7.50-7.68 (4H, m), 7.81 (2H, d, J=8.lKz), IR (KBr) cm-1 : 1610, 1575, 1420, 1345, MS (FAB) m/z: 507 (M+1) Example 114; 5- (4-carboxybenzyl)-6-ethyl-2-methyl-3-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Yield: 85%, Melting point: 175 - 1760C, 1H-NMR (DMSO-d6)8: 1.05 (3H, t, J=7. 4Hz), 2.39 (3H, s), 2.50 (2H, q, J=7.4Hz), 3.94 (2H, s), 5.28 (2H, s), 7.10 (4H, s), 7.29 (2H, d, J=8.3Hz), 7.49-7.57 (2K, m), 7.62-7.67 (2H, m) , 7.83 (2H, d, J=8.3Hz), IR (KBr) cm-1: 1705, 1650, 1610, 1540, MS (FAB) m/z: 507 (M+1) Example 115; 6-butyl-5- (4-carboxybenzyl)-2-methyl-4-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Yield: 72%, Melting point: 127 - 1280C, 1H-NMR (DMSO-d6)8: 0.82 (3H, t, J=7.3Hz), 1.24-1.32 (2H, m), 1.49-1.54 (2H, m), 2.49 (3H, s), 2.63 (2H, t, J=7.7Hz), 4.02 (2H, s), 5.39 (2H, s), 7.05 (2H, d, J=8.3Hz), 7.18 (2H, d, J=8.3Hz), 7.21 (2H, d, J=8.3Hz), 7.49-7.68 (4H, m), 7.80 (2H, d, J=8.3Hz), IR (KBr) cm-1: 1610, 1570, 1420, 1345, MS (FAB) m/z: 535 (M+1) Example 116; 6-butyl-5- (4-carboxybenzyl)-2-methyl-3-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Yield: 85%, Melting point: 144 - 1460C, 1H-NMR (DMSO-d6)6: 0.82 (3H, t, J=7.3Hz), 1.23-1.31 (2H, m), 1.42-1.50 (2H, m), 2.38 (3H, s), 2.47 (2H, t, J=7.6Hz), 3.93 (2H, s), 5.28 (2H, s), 7.10 (4H, s), 7.29 (2H, d, J=8.1Hz), 7.50-7.58 (2H, m), 7.63-7.68 (2H, m), 7.83 (2H, d, J=8.1Hz), IR (KBr) cm-1 : 1705, 1655, 1610, 1540, MS (FAB) m/z: 535 (M+1) Example 117; 6-butyl-5- (4-carboxybenzyl)-2-propyl-4-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Yield: 90%, Melting point: 158 - 1600C, 1H-NMR (DSO-d6) # : 0.82 (3H, t, J=7.2Hz), 0.92 (3H, t, J=7.3Hz), 1.21-1.34 (2H, m), 1.47-1.59 (2H, m), 1.69 1.83 (2H, m), 2.64 (2H, t, J=7.6Hz), 2.71 (2H, t, J=7.3Hz), 4.02 (2H, s), 5.41 (2H, s), 7.05 (2H, d, J=8.1Hz), 7.18 (2H, d, J=8.3Hz), 7.22 (2H, d, J=8.3Hz), 7.49-7.68 (4H, m), 7.81 (2H, d, J=8.3Hz), IR (KBr) cm-1 : 1610, 1570, 1420, 1345, MS (FAB) m/z: 563 (M+1) Example 118; 6-butyl-5- (4-carboxybenzyl)-2-propyl-3-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Yield: 82%, Melting point: 127 - 1290C, 1H-NMR (DMSO-d6)5: 0.82 (3H, t, J=7.3Hz), 0.86 (3H, t, J=7.3Hz), 1.21-1.34 (2H, m), 1.46-1.57 (2H, m), 1.59 1.70 (2H, m), 2.50 (2H, t, J=8.1Hz), 2.61 (2H, t, J=7.2Hz), 3.94 (2H, s), 5.29 (2H, s), 7.08 (4H, s), 7.29 (2H, d, J=8.3Hz), 7.49-7.58 (2H, m), 7.62-7.68 (2K, m), 7.83 (2H, d, J=8.3Hz), IR (KBr) cm-1 : 1700, 1650, 1540, 1415, MS (FAB) m/z: 563 (M+1) Example 119; 2-butyl-5- (4-carboxybenzyl)-6-propyl-4-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Yield: 64%, Melting point: 1050C (decomposition), 1H-NMR (DMSO-d6)5: 0.80-0.94 (6H, m), 1.29-1.43 (2H, m), 1.53-1.64 (2H, m), 1.66-1.81 (2H, m), 2.74 (2H, t, J=7.5Hz), 2.85 (2H, t, J=7. 4Hz), 4.05 (2H, s), 5.46 (2H, s), 7.04-7.83 (12H, m), IR (KBr) cm-1 : 3435, 2960, 1610, 1345, MS (FAB) m/z: 563 (M+1) Example 120; 2-butyl-5- (4-carboxybenzyl)-6-propyl-3-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Yield: 58%, Melting point: 103 - 150 C, H-NMR (DMSO-d6)5: 0.81 (3H, t, J=7.3Hz), 0.85 (3H, t, J=7.3Hz), 1.21-1.35 (2H, m), 1.50-1.64 (4H, m), 2.50 (2H, t, J=7.1Hz), 3.94 (2H, s), 5.30 (2H, s), 7.05-7.85 (12H, m), IR (KBr) cm-1 : 3440, 2960, 1650, 1540, MS (FAB) m/z: 563 (M+1) Example 121; 5- (4-carboxybenzyl)-2,6-diethyl-4-[2'-(1Htetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Melting point: 154 - 1560C, H-NMR (DMSO-d6)5: 1.10 (3H, t, J=7.6Hz), 1.26 (3H, t, J=7.6Hz), 2.68 (2H, q, J=7.5Hz), 2.77 (2H, q, J=7.6Hz), 4.03 (2H, s), 5.42 (2H, s), 7.05 (2H, d, J=8.1Hz), 7.19-7.25 (4H, m), 7.50-7.69 (4H, m), 7.82 (2H, d, J=8.3Hz), IR (RBr) cm-1: 1610, 1570, 1420, 1345, MS (FAB) m/z: 521 (M+1) Example 122; 5- (4-carboxybenzyl)-2,6-diethyl-3-[2'-(1Htetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-one Melting point: 139 - 1410C, H-NMR (DMSO-d6) # : 1.08 (3H, t, J=7.4Hz), 1.13 (3H, t, J=7.2Hz), 2.54 (2H, q, J=7.4Hz), 2.66 (2H, q J=7.3Hz), 3.95 (2H, s), 5.30 (2H, s), 7.09 (4H, s), 7.31 (2H, d, J=8.3Hz), 7.50-7.68 (4H, m), 7.85 (2H, d, J=8.3Hz), IR (KBr) cm-1 : 1710, 1645, 1610, 1540, MS (FAB) m/z: 521 (M+1) Example 123; 5- (4-carboxybenzyl)-6-ethyl-2-propyl-4-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Melting point: 1950C (decomposition), H-NMR (DMSO-d6)5: 0.93 (3H, t, J=7.3Hz), 1.11 (3H, t, J=7.4Hz), 1.73-1.81 (2H, m), 2.69 (2H, q, J=7.4Hz), 2.75 (2H, t, J=7.4Hz), 4.04 (2H, s), 5.43 (2H, s), 7.05 (2H, d, J=8.3Hz), 7.19-7.24 (4H, m), 7.50-7.70 (4H, m), 7.82 (2H, d, J=8.3Hz), IR (KBr) cm-1: 1610, 1570, 1420, 1345, MS (FAB) m/z: 535 (M+l) Example 1247; 5- (4-carboxybenzyl)-6-ethyl-2-propyl-3-[2' (lH-tetrazol-5-vl)bishenvl-4-vllmethvlDvrimidin-4-one Melting point: 136 - 1380C, H-NMR (DMSO-d6)3: 0.87 (3H, t, J=7.3Hz), 1.07 (3H, t, J=7.4Hz), 1.59-1.68 (2H, m), 2.54 (2H, q, J=7.4Hz), 2.62 (2H, t, J=7.3Hz), 3.94 (2H, s), 5.30 (2H, s), 7.09 (4H, s), 7.30 (2H, d, J=8.3Hz), 7.50-7.69 (4H, m), 7.84 (2H, d, J=8.3Hz), IR (KBr) cm-1 : 3450, 2970, 1645, 1540, MS (FAB) m/z: 535 (M+1) Example 125; 2-butyl-5- (4-carboxybenzyl)-6-ethyl-4-[2'-(1Htetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Melting point: 106 - 1080C, H-NMR (DMSO-d6) # : 0.90 (3H, t, J=7.3Hz), 1.09 (3H, t, J=7.4Hz), 1.28-1.41 (2H, m), 1.67-1.78 (2H, m), 2.66 (2H, q, J=7.6Hz), 2.74 (2H, t, J=7.6Hz), 4.02 (2H, s), 5.41 (2H, s), 7.05 (2H, d, J=8.3Hz), 7.18-7.24 (4H, m), 7.50-7.69 (4H, m), 7.82 (2H, d, J=8.3Hz), IR (KBr) cm-1 : 1610, 1570, 1415, 1345, MS (FAB) m/z: 549 (M+1) Example 1267; 2-butyl-5- (4-carboxybenzyl)-6-ethyl-3-[2'-(1Htetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Melting point: 125 - 1270C, 1K-NMR (DMSO-d6) #: 0.81 (3H, t, J=7.3Hz), 1.07 (3H, t, J=7.5Hz), 1.24-1.32 (2H, m), 1.57-1.62 (2H, m), 2.48 2.66 (4H, m), 3.94 (2H, s), 5.30 (2H, s), 7.09 (4H, s), 7.31 (2H, d, J=8.5Hz), 7.49-7.89 (7H, m), IR (KBr) cm-1 : 2960, 1705, 1655, 1545, MS (FAB) m/z: 549 (M+1) Example 127; 2-butyl-5- (3-carboxybenzyl)-6-methyl-4-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Yield: 79%, Melting point: 115 - 1170C, H-NMR (DMSO-d6) #: 0.89 (3H, t, J=7.3Hz), 1.26-1.40 (2H, m), 1.58-1.77 (2H, m), 2.36 (3H, s), 2.72 (2H, t, J=7.6Hz), 4.01 (2H, s), 5.42 (2H, s), 7.06 (2H, d, J=8.1Hz), 7.24 (2H, d, J=8.1Hz), 7.33-7.44 (2H, m), 7.48-7.77 (6H, m), IR (KBr) cm-1 : 1690, 1605, 1575, 1345, MS (FAB) m/z: 535 (M+1) Example 128; 2-butyl-5- (3-carboxybenzyl)-6-methyl-3-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Yield: 93%, Melting point: 128 - 1300C, H-NMR (DMSO-d6)8: 0.81 (3H, t, J=7.2Hz), 1.21-1.35 (2H, m), 1.51-1.62 (2H, m), 2.22 (3H, s), 2.61 (2H, t, J=7.6Hz), 3.92 (2H, s), 5.31 (2H, s), 7.09 (4H, s), 7.34-7.80 (8H, m), IR (KBr) cm-1 : 2960, 1705, 1650, 1535, MS (FAB) m/z: 534 (M+1) Example 129; 6-butyl-5- (3-carboxybenzyl)-2-methyl-4-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Yield: 64%, Melting point: 116 - 1180C, H-NMR (DMSO-d6) # : 0.82 (3H, t, J=7.3Hz), 1.26-1.37 (2H, m), 1.46-1.57 (2H, m), 2.49 (3H, s), 2.73 (2H, t, J=7.7Hz), 4.04 (2H, s), 5.45 (2H, s), 7.05 (2H, d, J=8.3Hz), 7.22 (2H, d, J=8.3Hz), 7.25-7.37 (2H, m), 7.49-7.77 (6H, m), IR (KBr) cm-1 : 2960, 2930, 1605, 1345, MS (FAB) m/z: 535 (M+1) Example 130; 6-butyl-5- (3-carboxybenzyl)-2-methyl-3-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Yield: 85%, Melting point: 132 - 1340C, 1H-NMR (DMSO-d6)5: 0.81 (3H, t, J=7.2Hz), 1.23-1.31 (2H, m), 1.41-1.49 (2H, m), 2.38 (3H, s), 2.49 (2H, t, J=7.7Hz), 3.93 (2H, s), 5.28 (2H, s), 7.10 (4H, s), 7.34-7.77 (8H, m), IR (KBr) cm-1 : 2960, 1705, 1655, 1545, MS (FAB) m/z: 535 (M+1) Example 131; 2,6-dibutyl-5- (3-carboxybenzyl)-4-[2'-(1Htetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Yield: 88%, Melting point: 93 - 950C, H-NMR (DMSO-d6) # : 0.82 (3H, t, J=7.3Hz), 0.89 (3H, t, J=7.3Hz), 1.21-1.41 (4H, m), 1.47-1.58 (2H, m), 1.65 1.78 (2H, m), 2.66 (2H, t, J=7.6Hz), 2.74 (2H, t, J=7.4Hz), 4.02 (2H, s), 5.42 (2H, s), 7.05 (2H, d, J=8.6Hz), 7.23 (2H, d, J=8.3Hz), 7.30-7.37 (2H, m), 7.49-7.77 (6H, m), IR (KBr) cm-1 : 2960, 1570, 1420, 1345, MS (FAB) m/z: 577 (M+1) Example 132; 2,6-dibutyl-5- (3-carboxybenzyl)-3-[2'-(1Htetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Yield: 83%, Melting point: 105 - 1070C, 1H-NMR (DMSO-d6)8: 0.81 (3H, t, J=7.3Hz), 0.82 (3H, t, J=7.2Hz), 1.20-1.35 (4H, m), 1.45-1.64 (4H, m), 2.51 (2H, t, J=7.4Hz), 2.62 (2H, t, J=7.3Hz), 3.94 (2H, s), 5.31 (2H, s), 7.09 (4H, s), 7.34-7.79 (8H, m), IR (KBr) cm-1 : 2960, 1650, 1630, 1540, MS (FAB) m/z: 577 (M+1) Example 133; 5- (3-carboxybenzyl)-2,6-dimethyl-4-[2'-(1Htetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Melting point: 1510C (decomposition), 1K-NMR (DMSO-d6)6: 2.37 (3H, s), 2.48 (3H, s), 4.01 (2H, s), 5.41 (2H, s), 7.05 (2H, d, J=8.1Hz), 7.24 (2H, d, J=8.3Hz), 7.34-7.39 (2H, m), 7.50-7.78 (6H, m), IR (KBr) cm-1 : 3440, 1575, 1425, 1345, MS (FAB) m/z: 493 (M+1) Example 134; 5- (3-carboxybenzyl)-2,6-dimethyl-3-[2'-(1Htetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Melting point: 1410C (decomposition), H-NMR (DMSO-d6)8: 2.21 (3H, s), 2.36 (3H, s), 3.91 (2H, s), 5.29 (2H, s), 7.10 (4H, s), 7.35-7.79 (8H, m), IR (KBr) cm-1 : 3450, 1705, 1650, 1540, MS (FAB) m/z: 493 (M+1) Example 135; 5- (3-carboxybenzyl)-2-ethyl-6-methyl-4-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Melting point: 840C (decomposition), 1H-NMR (DMSO-d6)6: 1.25 (3H, t, J=7.6Hz), 2.40 (3H, s), 2.76 (2H, q, J=7.6Hz), 4.02 (2H, s), 5.44 (2H, s), 7.06 (2H, d, J=8.3Hz), 7.26 (2H, d, J=8.3Hz), 7.34-7.36 (4H, m), 7.50-7.78 (4H, m), IR (KBr) cm-1 : 1605, 1575, 1420, 1345, MS (FAB) m/z: 507 (M+1) Example 136; 5- (3-carboxybenzyl)-2-ethyl-6-methyl-3-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-one Melting point: 930C (decomposition), 1H-NMR (DMSO-d6) #: 1.10 (3H, t, J=7.3Hz), 2.24 (3H, s), 2.64 (2H, q, J=7.2Hz), 3.92 (2H, s), 5.31 (2H, s), 7.08 (4H, s), 7.35-7.79 (8H, m), IR (KBr) cm-1 : 3430, 1710, 1650, 1540 MS (FAB) m/z: 507 (M+1) Example 137; 5- (3-carboxybenzyl)-6-methyl-2-propyl-4-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Melting point: 119 - 1210C, H-NMR (DMSO-d6) # : 0.91 (3H, t, J=7.3Hz), 1.68-1.79 (2H, m), 2.39 (3H, s), 2.71 (2H, t, J=7.4Hz), 4.02 (2H, s), 5.44 (2H, s), 7.06 (2H, d, J=8.3Hz), 7.25 (2H, d, J=8.3Hz), 7.34-7.37 (2H, m), 7.50-7.78 (6H, m), IR (KBr) cm-1 : 1605, 1575, 1425, 1345, MS (FAB) m/z: 521 (M+1) Example 138; 5- (3-carboxybenzyl)-6-methyl-2-propyl-3-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-one Melting point: 128 - 1300C, 1K-NMR (DMSO-d6)8: 0.86 (3H, t, J=7. 3Hz), 1.56-1.64 (2H, m), 2.23 (3H, s), 2.59 (2H, t, J=7.4Hz), 3.92 (2H, s), 5.31 (2H, s), 7.09 (4H, s), 7.35-7.80 (8H, m), IR (KBr) cm-1 : 2970, 1705, 1650, 1535, MS (FAB) m/z: 521 (M+1) Example 139; 5- (3-carboxybenzyl)-6-methyl-2-pentyl-4-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Melting point: 1610C (decomposition), H-NMR (DMSO-d6)8: 0.86 (3H, t, J=7.0Hz), 1.27-1.32 (4H, m), 1.70-1.75 (2H, m), 2.37 (3H, s), 2.71 (2H, t, J=7.6Hz), 4.01 (2H, s), 5.42 (2H, s), 7.04-7.07 (2H, m), 7.23-7.26 (2H, m), 7.34-7.36 (2H, m), 7.50-7.77 (6H, m), IR (KBr) cm-1 : 3600-3300, 2950, 1710, 1575, 1345, MS (FAB) m/z: 549 (M+1) Example 140; 5- (3-carboxybenzyl)-6-methyl-2-pentyl-3-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Melting point: 1360C (decomposition), 1H-NMR (DMSO-d6)5: 0.82 (3H, t, J=7.0Hz), 1.21-1.26 (4H, m), 1.55-1.61 (2H, m), 2.23 (3H, s), 2.60 (2H, t, J=7.7Hz), 3.92 (2H, s), 5.31 (2H, s), 7.09 (4H, s), 7.35-7.58 (4H, m), 7.64-7.69 (2H, m), 7.74-7.80 (2H, m), IR (KBr) cm-1 : 3600-3300, 2960, 1715, 1655, 1445, MS (FAB) m/z: 549 (M+1) Example 141; 5- (3-carboxybenzyl)-6-ethyl-2-methyl-4-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Melting point: 126 - 1280C, H-NMR (DMSO-d6)5: 1.05 (3H, t, J=7.6Hz), 2.48 (3H, s), 2.68 (2H, q, J=7.5Hz), 4.02 (2H, s), 5.40 (2H, s), 7.04 (2H, d, J=8.3Hz), 7.22 (2H, d, J=8.3Hz), 7.33-7.38 (2H, m), 7.51-7.76 (6H, m), IR (KBr) cm-1 : 1605, 1570, 1425, 1345, MS (FAB) m/z: 507 (M+1) Example 142; 5- (3-carboxybenzyl)-6-ethyl-2-methyl-3-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Melting point: 143 - 1450C, 1K-NMR (DMSO-d6)5: 1.05 (3H, t, J=7.4Hz), 2.38 (3H, s), 2.52-2.55 (2H, m), 3.93 (2H, s), 5.29 (2H, s), 7.06 7.14 (4H, m), 7.35-7.77 (8H, m), IR (KBr) cm-1 : 3440, 1705, 1655, 1540, MS (FAB) m/z: 507 (M+1) Example 143; 5- (3-carboxybenzyl)-2,6-diethyl-4-[2'-(1Htetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Melting point: 116 - 118 C, H-NMR (DMSO-d6)5: 1.11 (3H, t, J=7.6Hz), 1.26 (3H, t, J=7.6Hz), 2.70 (2H, q, J=7.5Hz), 2.76 (2H, q, J=7.6Hz), 4.03 (2H, s), 5.43 (2H, s), 7.05 (2H, d, J=8.3Hz), 7.24 (2H, d, J=8.6Hz), 7.34-7.39 (2H, m), 7.50-7.78 (6H, m), IR (KBr) cm-1 : 1605, 1570, 1420, 1345, MS (FAB) m/z: 521 (M+1) Example 144; 5- (3-carboxybenzyl)-2,6-diethyl-3-[2'-(1Htetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Melting point: 125 - 1270C, 1H-NMR (DMSO-d6)6: 1.08 (3H, t, J=7.6Hz), 1.12 (3H, t, J=7.3Hz), 2.54 (2H, q, J=7. 4Hz), 2.66 (2H, q, J=7.2Hz), 3.94 (2H, s), 5.31 (2H, s), 7.09 (4H, s), 7.35-7.78 (8H, m), IR (KBr) cm-1 : 2980, 1700, 1645, 1540, MS (FAB) m/z: 521 (M+1) Example 145; 5- (3-carboxybenzyl)-6-ethyl-2-propyl-4-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Melting point: 112 - 1140C, H-NMR (DMSO-d6)6: 0.92 (3H, t, J=7.4Hz), 1.11 (3H, t, J=7.4Hz), 1.69-1.83 (2H, m), 2.69 (2H, q, J=7.5Hz), 2.72 (2H, t, J=7.4Hz), 4.03 (2H, s), 5.42 (2H, s), 7.05 (2H, d, J=7.8Hz), 7.23 (2H, d, J=8.1Hz), 7.34-7.41 (2H, m), 7.50-7.79 (6H, m), IR (KBr) cm-1 : 3440, 1570, 1420, 1345, MS (FAB) m/z: 535 (M+1) Example 146; 5- (3-carboxybenzyl)-6-ethyl-2-propyl-4-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Melting point: 123 - 1250C, H-NMR (DMSO-d6) # : 0.87 (3H, t, J=7.3Hz), 1.08 (3H, t, J=7.6Hz), 1.59-1.68 (2H, m), 2.51-2.55 (2H, m), 2.61 (2H, t, J=7.4Hz), 3.94 (2H, s), 5.31 (2H, s), 7.09 (4H, s), 7.38-7.79 (8H, m), IR (KBr) cm-1 : 3440, 2970, 1650, 1540, MS (FAB) m/z: 535 (M+1) Example 135; 2-butyl-5- (3-carboxybenzyl)-2-ethyl-4-[2'-(1Htetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Melting point: 99 - 1000C, H-NMR (DMSO-d6)8: 0.89 (3H, t, J=7.3Hz), 1.11 (3H, t, J=7.4Hz), 1.27-1.41 (2H, m), 1.67-1.78 (2H, m), 2.68 (2H, q, J=7.6Hz), 2.74 (2H, t, J=7.5Hz), 4.02 (1H, s), 5.41 (2H, s), 7.04 (2H, d, J=8.3Hz), 7.23 (2H, d, J=8.1Hz), 7.33-7.39 (2H, m), 7.49-7.77 (6H, m), IR (KBr) cm-1: 2960, 1570, 1420, 1345, MS (FAB) m/z: 549 (M+1) Example 148; 2-butyl-5- (3-carboxybenzyl)-6-ethyl-3-[2'-(1Htetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Melting point: 108 to 1100C, H-NMR (DMSO-d6)3: 0.82 (3H, t, J=7.3Hz), 1.07 (3H, t, J=7.6Hz), 1.24-1.33 (2H, m), 1.57-1.62 (2H, m), 2.52 (2H, q, J=7.3Hz), 2.61 (2H, t, J=7.4Hz), 3.94 (2H, s), 5.31 (2H, s), 7.09 (4H, s), 7.35-7.78 (8H, m), IR (KBr) cm-1 : 2960, 1700, 1650, 1540, MS (FAB) m/z: 549 (M+1) Example 149; 5- (3-carboxybenzyl)-2-methyl-6-propyl-3-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Melting point: 144 - 1460C, 1K-NMR (DMSO-d6) #: 0.89 (3H, t, J=7.3Hz), 1.54-1.63 (2H, m), 2.48 (3H, s), 2.81 (2H, t, J=7.3Hz), 4.07 (2H, s), 5.48 (2H, s), 7.03-7.22 (4H, m), 7.34-7.78 (8H, m), IR (KBr) cm-1 : 2960, 1605, 1440, 1345, MS (FAB) m/z: 521 (M+1) Example 150; 5- (3-carboxybenzyl)-2-ethyl-6-propyl-4-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Melting point: 130 - 1320C, 1K-NMR (DMSO-d6)8: 0.85 (3H, t, J=7.4Hz), 1.25 (3H, t, J=7.5Hz), 1.55-1.62 (2H, m), 2.63-2.80 (4H, m), 4.03 (2H, s), 5.42 (2H, s), 7.05 (2H, d, J=7.8Hz), 7.24 (2H, d, J=8.0Hz), 7.34-7.39 (2H, m), 7.50-7.77 (6H, m), IR (KBr) cm-1 : 2960, 1710, 1570, 1345, MS (FAB) m/z: 535 (M+1) Example 151; 5- (3-carboxybenzyl)-2-ethyl-6-propyl-3-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Melting point: 140 - 1420C, 1H-NMR (DMSO-d6) # : 0.85 (3H, t, J=7.3Hz), 1.11 (3H, t, J=7.3Hz), 1.52-1.60 (2H, m), 2.48-2.53 (2H, m), 2.61 2.69 (2H, m), 3.94 (2H, s), 5.31 (2H, s), 7.09 (4H, s), 7.35-7.78 (8H, m), IR (KBr) cm-1 : 3440, 2960, 1650, 1540, MS (FAB) m/z: 535 (M+1) Example 152; 5- (3-carboxybenzyl)-2,6-dipropyl-4-[2'-(1H tetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Melting point: 133 - 1350C, 1H-NMR (DMSO-d6)3: 0.86 (3H, t, J=7.3Hz), 0.92 (3H, t, J=7.4Hz), 1.51-1.65 (2H, m), 1.69-1.83 (2H, m), 2.51 2.78 (4H, m), 4.03 (2H, s), 5.42 (2H, s), 7.05 (2H, d, J=7.6 Hz), 7.22 (2H, d, J=8.2Hz), 7.33-7.36 (2H, m), 7.50-7.78 (6H, m), IR (KBr) cm-1 : 2960, 1710, 1570, 1420, MS (FAB) m/z: 549 (M+1) Example 1453; 5- (3-carboxybenzyl)-2,6-dipropyl-3-[2'-(1H tetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Melting point: 128 - 1300C, H-NMR (DMSO-d6)8: 0.83 (3H, t, J=7.3Hz), 0.86 (3H, t, J=7.3Hz), 1.51-1.66 (4H, m), 2.51 (2H, t, J=7.3Hz), 2.61 (2H, t, J=7.2Hz), 3.94 (2H, s), 5.31 (2H, s), 7.09 (4H, s), 7.35-7.58 (4H, m), 7.63-7.68 (2H, m), 7.73 7.78 (2H, m), IR (KBr) cm-1 : 2960, 2930,1655, 1540, MS (FAB) m/z: 549 (M+1) Example 154; 2-butyl-5- (3-carboxybenzyl)-6-propyl-4-[2' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidine Melting point: 90 - 920C, 1K-NMR (DMSO-d6) # : 0.86 (3H, t, J=7.6Hz), 0.89 (3H, t, J=7.3Hz), 1.30-1.38 (2H, m), 1.54-1.62 (2H, m), 1.70 1.76 (2H, m), 2.71 (2H, t, J=7.6Hz), 2.79 (2H, t, J=7.6Hz), 4.04 (2H, s), 5.44 (2H, s), 7.03-7.07 (2H, m), 7.20-7.26 (2H, m), 7.34-7.36 (2H, m), 7.49-7.77 (6H, m), IR (KBr) cm-1 : 3440, 2960, 1570, 1345, MS (FAB) m/z: 563 (M+1) Example 155; 2-butyl-5- (3-carboxybenzyl)-6-propyl-3-[2-' (1H-tetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Melting point: 103 - 1050C, 1K-NMR (DMSO-d6)8: 0.81 (3H, t, J=7.3Hz), 0.84 (3H, t, J=7.3Hz), 1.23-1.31 (2H, m), 1.51-1.61 (4H, m), 2.50 (2H, t, J=7.4Hz), 2.62 (2H, t, J=7.4Hz), 3.94 (2H, s), 5.31 (2H, s), 7.09 (4H, s), 7.35-7.78 (8H, m), IR (KBr) cm-1: 2960, 1705, 1650, 1540, MS (FAB) m/z: 563 (M+1) Example 156; 6-methyl-5- (4-plavlovloxymethoxycarboxylbenzyl)-2-propyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4yllmethylpyrimidin-4-one Melting point: 1050C (decomposition), H-NMR (DMSO-d6) # : 0.88 (3H, t, J=7.3Hz), 1.15 (9H, s), 1.54-1.63 (2H, m), 2.31 (3K, s), 2.74 (2H, t, J=7.6Hz), 3.95 (2H, 2), 5.32 (2H, s), 5.93 (2H, s), 7.10 (4H, s), 7.39 (2H, d, J=8.5Hz), 7.49-7.68 (4H, m), 7.88 (2H, d, J=8.5Hz), IR (KBr) cm-1: 3420, 1740, 1705, 1085, MS (FAB) m/z: 635 (M+1) Example 157; 6-methyl-5- (3-plavlovloxymethoxycarbonybenzyl)-2-propyl-3-[2'- (1H-tetrazol-5-yl)biphenyl4-yllmethylpyrimidin-4-one Melting point: 90 - 920C, H-NMR (DMSO-d6)6: 0.86 (3H, t, J=7.3Hz), 1.14 (9H, s), 1.56-1.65 (2H, m), 2.24 (3H, s), 2.59 (2H, t, J=7.4Hz), 3.93 (2H, s), 5.30 (2H, s), 5.94 (2H, s), 7.07 (4H, s), 7.44-7.82 (12H, m), IR (KBr) cm-1 : 1650, 1540, 1445, 1100, MS (FAB) m/z: 635 (M+1) Example 156; 2-butyl-6-methyl-5- (3-plavlovloxymethoxycarbonylbenzyl)-3-[2'-(1H-tetrazol-5-yl)biphenyl-4 v1 1 methvlovrimidin-4-one Melting point: 91 - 930C, H-NMR (DMSO-d6)8: 0.81 (3H, t, J=7.3Hz), 1.14 (9H, s), 1.23-1.31 (2H, m), 1.52-1.59 (2H, m), 2.24 (3H, s), 2.61 (2H, t, J=7.6Hz), 3.93 (2H, s), 5.30 (2H, s), 5.93 (2H, s), 7.08 (4H, s), 7.44-7.57 (4H, m), 7.63-7.66 (2H, m), 7.76-7.82 (2H, m), IR (KBr) cm-1 : 1750, 1650, 1540, 1085, MS (FAB) m/z: 650 (M+1) Example 159: 5-14-(l-(cvclohexvloxvcarbonvloxv) ethoxycarbonyl)benzyll-6-methyl-2-propyl-3- [2'[-1Htetrazol-5-yl)biphenyl-4-yllmethylpyrimidin-4-one Melting point: 1150C (decomposition), H-NMR (DMSO-d6) # : 0.87 (3H, t, J=7.3Hz), 1.03-1.05 (14H, m), 1.56-1.61 (2H, m), 2.28 (3H, s), 2.64-2.76 (2H, m), 3.94 (2H, s), 5.31 (2H, s), 7.09 (4H, s), 7.24 (2H, d, J=8.6Hz), 7.31-7.66 (4H, m), 7.87 (2H, d, J=8.1Hz), IR (KBr) cm-1 : 2940, 1755, 1700, 1250, MS (FAB) m/z: 691 (M+1) Pharmacoloaical Example 1. Angiotension II receDtor binding assav The affinity of the compound of the present invention to an angiotensin II receptor was evaluated by substitution of radioactive ligands specifically bound to an angiotensin II receptor sample prepared from rat livers.
(1) Preparation of angiotensin II receptor sample The livers were extracted from 5-week-old Wistar male rats (Japan Charles River Inc.) and homogenized in a homogenizer buffer (see Table 1) to prepare 10% homogenate.
The homogenate was centrifuged at 3000 x g for 15 minutes and the supernatant was collected. The collected supernatant was centrifuged at 50000 x g for 30 minutes to obtain pellets. The homogenizer buffer was added to resuspend the resulting pellets and prepare the angiotensin II receptor sample. The product was frozen at -800C for storage.
Table 1: Homoaenizer Buffer 10 mM HEPES (pH 7.4) (*) 0.28 bovine serum albumin 10 m pepstatin A 10 m bestatin 10 Rm leupeptin 10 pxn captopryl 100 gm phenylmethanesulfonyl fluoride (*) HEPES = N-(2-hydroxyethyl)piperadine-N'-2- ethansulfonate (2) Receptor binding test The above receptor sample was thawed, and diluted with an assay buffer (see Table 2) so that the content of the total proteins is 250 g/ml. Then, 0.5nM [3H]-angiotensin II and the compound to be tested in various concentrations were added. The whole was incubated at 250C for 1 hour.
The reaction mixture was filtered under suction through a glass fiber filter (Whatman GF/B filter) to commence the reaction and at the same time separate the [3H]-angiotensin II bound to the receptor and the free [3H]-angiotensin II.
After the filter was rinsed with a washing buffer (10 mM HEPES, pH 7.4), the radioactivity absorbed to the filter was measured by a liquid scintillation counter (Beckman).
The non-specific bindings were measured after adding 105M non-labeled angiotensin II to cause a reaction.
Table 2. Assay Buffer 10 mM HEPES (pH 7.4) 0.2% bovine serum albumin 10 mM MgCl2 (3) Calculation of IC50 value The IC50 value was calculated by the formula: Y = T - SxD/(D+K) (R.F. Bruns, et. al., Molecular Pharmacology, 29: 331-346, 1986). In the formula, Y is the bound radioactivity in the presence of the compound to be tested, T is the bound radioactivity in the absence of the compound to be tested, S is the specifically bound radioactivity in the absence of the compound to be tested, D is the concentration of the compound to be tested, and K is the IC50 value of the compound to be tested. The test results are shown in Table 3.
Table 3 Compound to be tested IC50 (M) Compound of Example 53 1.9 x 10-8 Compound of Example 56 2.6 x 10-8 Compound of Example 58 2.7 x 10-8 Compound of Example 78 2.6 x 10-8 Compound of Example 80 3.2 x 10-8 Compound of Example 82 1.6 x 10-8 Compound of Example 84 2.4 x 10-8 Compound of Example 88 3.6 x 10-8 Compound of Example 90 3.0 x 10-8 Compound of Example 92 1.7 x 10-8 Compound of Example 94 1.7 x 10-8 Compound of Example 98 1.2 x 10-8 Compound of Example 102 2.3 x 10-8 Compound of Example 103 2.2 x 10-8 Compound of Example 105 1.9 x 10-8 Compound of Example 107 2.8 x 10-8 Compound of Example 122 3.2 x 10-8 Compound of Example 124 3.6 x 10-8 Compound of Example 126 3.2 x 10-8 Compound of Example 133 3.1 x 10-8 Compound of Example 141 3.9 x 10-8 Compound of Example 157 3.2 x 10-8 Pharmacoloaical Example 2. Inhibitory Activity of Vasoconstriction The applicability of the compound of the present invention was confirmed by the function to inhibit constriction of rat arteries induced by angiotensin II.
(1) Measurement of vasoconstriction using Magnus apparatus Wistar male rats having body weights of 150 to 250 g (Japan Charles River Inc.) were beaten and allowed to bleed and death. Then, their stetharteries were excised. After the attached connective tissue was removed, the cavities of the veins were rubbed by yarn to remove the endothelial cells and prepare ring samples. The samples were suspended in a 5ml organ bath which was filled with Krebs-Kenseleit solution (unit mM; NaCl = 118, KCl = 4.7, CaCl2 = 2.55, MgSO4 = 1.18, KH2P04 = 1.18, NaHC03 = 24.88, glucose 11.1) and held at 370C under a stream of 95% 02-5% C02. After an initial tension of 1.5 g was applied and preincubation was carried out for 60 minutes, measurement was started. The compounds to be tested were added in various concentrations. After 15 minutes, angiotensin II was accumulatively added. The function to inhibit constriction induced by the angiotensin II was evaluated by preparing a Schildplot to determine the pA2. The constriction of the samples was ionotropicaly measured using an isometric transducer (UL-1OGR: Minebea) and amplifier (6M92: NEC Mie) and recorded by a recticorder (RECTI-HORIZ-8K: NEC Mie).
The test results are shown in Table 4.
Table 4 Compound to be tested PA2 Compound of Example 80 8.37 Compound of Example 84 8.50 Compound of Example 102 8.08 Compound of Example 105 9.43 Compound of Example 107 8.81 Compound of Example 121 8.96 Compound of Example 137 9.17 Compound of Example 143 8.40 Control compound A a) 8.01 Control compound B b) 7.91 a) 2-butyl-6-methyl-3-[2'-(lK-etrazol-5- yl)biphenyl-4-yl]methylpyrimidin-4-one: compound described in EP-0407342 b) 5-benzyl-2-butyl-6-methyl-3- [2 - (1K-tetrazol-5- yl)biphenyl-4-yl]methylpyrimidin-4-one As clear from Table 4, the compound (I) of the present invention is superior in activity of inhibiting vasoconstriction, in comparison with the compound described in EP-0407342 and the pyrimidine derivative having a benzyl group at 5-position used as the control compounds.
Toxicitv Example The compounds of Examples 98, 102, 103, 105 and 107 were intraperitoneally administered to 4- to 5-week-old ICR male mice in an amount of 200 mg/kg. No deaths were observed in any of the groups.
Formulation ExamDle 1 Compound of Example 102 20 g Lactose 100 g Corn starch 36 g Microcrystalline cellulose 30 g Calcium carboxylmethylcellulose 10 g Magnesium stearate 4g The components of the above composition were homogeneously mixed to prepare tablets of 200 mg per tablet.
Formulation ExamDle 2 Compound of Example 105 20 g Lactose 315 g Corn starch 125 g Microcrystalline cellulose 25 g The components of the above composition were homogeneously mixed, and then granulated to prepare granules.
Formulation example 3 Compound of Example 107 20 g Lactose 100 g Microcrystalline cellulose 70 g Magnesium stearate 10 g The components of the above composition were homogeneously mixed, then granulated and encapsulated into gelatine capsules to prepare capsules of 200 mg content per capsule.
Formulation Examole 4 Sodium salt of compound of Example 98 5 g Glucose 50 g Benzyl alcohol 10 g The components of the above composition were dissolved in distilled water for injections so that a total volume became 1000 ml. The solution was poured into ampules to prepare an injection of 1 ml per ampule.
INDUSTRIAL APPLICABILITY As explained above, the compound (I) of the present invention exhibits a superior angiotensin II antagonism and is very safe, and thus is useful as a superior agent for the cardiovascular system. Accordingly, the compound of the present invention is useful as an agent for the treatment of various cardiovascular system diseases, for example, hypertension, cordiac disease, cerebral apoplexy, and arteriosclerosis.
The structural formulas of the compounds described in Example 1 to Example 159 are shown hereinafter. In the following structural formulas, Me is a methyl group, Et is an ethyl group, n-Pr is an n-propyl group, n-Bu is an nbutyl group, n-Pen is an n-pentyl group, and Ph is a phenyl group.
Example 1 Example 2
Example 3 Example 4
Example 5 Example 6
Example 7 example 8
Example 9 Example 10
Example 11 Example 12
Example 13 Example 14
Example 15 Example 16
Example 17 Example 18
Example 19 Example 20
Example 21 Example 22
Example 23 Example 24
Example 25 Example 26
Example 27 Example 28
Example 29 Example 30
Example 31 Example 32
Example 33 Example 34
Example 35 Example 36
Example 37 Example 38
Example 39 Example 40
Example 41 Example 42
Example 43 Example 44
Example 45 Example 46
Example 47 Example 46
Example 49 Example 50
Example 51 Example 52
Example 53 Example 54
Example 55 Example 56
Example 57 Example 58
Example 59 Example 60
Example 61 Example 62
Example 63 Example 64
Example 65 Example 66
Example 67 Example 68
Example 69 Example 70
Example 71 Example 72
Example 73 Example 74
Example 75 Example 76
Example 77 Example 78
Example 79 Example 80
Example 81 Example 82
Example 83 Example 89
Example 85 Example 86
Example 87 Example 88
Example 89 Example 90
Example 91 Example 92
Example 93 Example 94
Example 95 Example 96
Example 97 Example 98
Example 99 Example 100
Example 101 Example 102
Example 103 Example 104
Example 105 Example 106
Example 107 Example 108
Example 109 Example 110
Example 111 Example 112
Example 113 Example 114
Example 115 Example 116
Example 117 Example 118
Example 119 Example 120
Example 121 Example 122
Example 123 Example 124
Example 125 Example 126
Example 127 Example 128
Example 129 Example 130
Example 131 Example 132
Example 133 Example 134
Example 135 Example 136
Example 137 Example 138
Example 139 Example 140
Example 141 Example 142
Example 143 Example 144
Example 145 Example 146
Example 147 Example 148
Example 149 Example 150
Example 151 Example 152
Example 153 Example 154
Example 155 Example 156
Example 157
Example 158
Example 159

Claims (13)

  1. CLAIMS 1. A pyrimidine derivative of the general formula (I):
    wherein A is a group of the general formula (1-1):
    wherein R1 and R2, which may be same or different, are a hydrogen or hologen atom, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkylthio, phenyl or substituted phenyl group, R3 and R4, which may be same or different, are a hydrogen or halogen atom, lower alkyl, lower alkoxy, nitro, sulfone, carboxyl, lower alkoxycarbonyl, cycloalkoxycarbonyloxyalkoxycarbonyl, lower alkanoyloxyalkoxycarbonyl, tetrazolyl or protected tetrazolyl group, or R3 and R4 may be combined together with the ring carbon atoms to which they are bonded to form a condensed 5- or 6-membered ring which may be substituted, X is 0, NH or S(O)p, p is an integer of O to 2, and m is an integer of 1 to 2, or a group of the general formula (I-2):
    wherein R1, R2, R3, R4, X and m have the same meanings as above, B is a carboxyl, lower alkoxycarbonyl, tetrazolyl, or protected tetrazolyl group, and n is an integer of 1 to 2, or a salt thereof.
  2. 2. A pyrimidine derivative according to claim 1, wherein R1 is a hydrogen atom, a lower alkyl group of 1 to 6 carbon atoms, or a phenyl group, R2 is a lower alkyl group of 1 to 4 carbon atomS, R3 is a hydrogen atom, R4 is a lower alkyl group of 1 to 2 carbon atoms, a lower alkoxy group of 1 to 2 carbon atoms, a halogen atom, nitro or carboxyl group, a lower alkoxycarbonyl group wherein the lower alkoxy moiety has 1 to 2 carbon atoms, a cycloalkoxycarbonyloxyalkoxycarbonyl group wherein the cycloalkoxy moiety has 5 to 7 carbon atoms and the alkoxy moiety has 1 to 2 carbon atoms, a lower alkanoyloxyalkoxycarbonyl group wherein the lower alkanoyl moiety has 2 to 6 carbon atoms and the alkoxy moiety has 1 to 2 carbon atoms, or a tetrazolyl group, or R3 and R4 may be combined together with the ring carbon atoms with which they are bonded to form a condensed 5membered nitrogen-containing ring which may be substituted, X is 0, m is 1, B is a carboxyl group, a lower alkoxycarbonyl group wherein the lower alkoxy moiety has 1 to 2 carbon atoms, a tetrazolyl group, or a protected tetrazolyl group, and n is 1, or a salt thereof.
    3. A pyrimidine derivative according to claim 1, wherein R1 is a hydrogen atom, methyl, ethyl, n-propyl, n-butyl, npentyl or phenyl group, R2 is a methyl, ethyl, n-propyl or n-butyl group, R3 is a hydrogen atom, and R4 is a chlorine atom, methyl, methoxy, nitro, carboxyl, methoxycarbonyl, cyclohexyloxycarbonyloxyethoxycarbonyl, pivaloyloxymethoxycarbonyl or tetrazolyl group, or R3 and R4 may be combined together with the ring carbon atoms to which they are bonded to form a condensed 1,2,3-triazole ring or a condensed 1,2,3-triazole ring substituted by a trityl group, X is 0, m is 1, B is a carboxyl, methoxycarbonyl tetrazolyl, or trityl tetrazolyl group and n is 1, or a salt thereof.
    4. A process for manufacturing a pyrimidine derivative of the general formula (I):
    wherein A is a group of the general formula (1-1):
    wherein R1 and R2, which may be same or different, are a hydrogen or hologen atom, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkylthio, phenyl or substituted phenyl group, R3 and R4, which may be same or different, are a hydrogen or halogen atom, lower alkyl, lower alkoxy, nitro, sulfone, carboxyl, lower alkoxycarbonyl, cycloalkoxycarbonyloxyalkoxycarbonyl, lower alkanoyloxyalkoxycarbonyl, tetrazolyl or protected tetrazolyl group, or R3 and R4 may be combined together with the ring carbon atoms to which they are bonded to form a condensed 5- or 6-membered ring which may be substituted, Xis O, NH or S(O)p, p is an integer of O to 2, and mis an integer of 1 to 2, or a group of the general formula (I-2):
    wherein R1, R2, R3, R4, X and m have the same meanings as above, B is a carboxyl, lower alkoxycarbonyl, tetrazolyl, or protected tetrazolyl group, and n is an integer of 1 to 2, or a salt thereof, characterized by reacting, in the presence of a base, a compound of the general formula (If):
    wherein R1, R2, R3, R4, X, and m have the same meanings as the above, and a compound of the general formula (III):
    wherein B and n have the same meanings as the above, Y is a halogen atom, alkylsulfonyloxy, or arylsulfonyloxy group.
    5. A process for manufacturing a pyrimidine derivative of the general formula (I):
    wherein A is a group of the general formula (I-l):
    wherein R1 and R2, which may be same or different, are a hydrogen or hologen atom, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkylthio, phenyl or substituted phenyl group, R3 and R4, which may be same or different, are a hydrogen or halogen atom, lower alkyl, lower alkoxy, nitro, sulfone, carboxyl, lower alkoxycarbonyl, cycloalkoxycarbonyloxyalkoxycarbonyl, lower alkanoyloxyalkoxycarbonyl, tetrazolyl or protected tetrazolyl group, or R3 and R4 may be combined together with the ring carbon atoms to which they are bonded to form a condensed 5- or 6-membered ring which may be substituted, X is O, NH or S(O)p, p is an integer of O to 2, and m is an integer of 1 to 2, or a group of the general formula (I-2):
    wherein R1, R2, R3, R4, X and m have the same meanings as above, B is a carboxyl, lower alkoxycarbonyl, tetrazolyl, or protected tetrazolyl group, and n is an integer of 1 to 2, or a salt thereof, characterized by reacting, in the presence of a base, a compound of the general formula (IV):
    wherein R1, R2, R3, R4, and m have the same meanings as the above, and Z is a halogen atom, and a compound of the general formula (V):
    wherein B and n have the same meanings as above, V is a hydroxy, amino or mercapto group.
    6. A pharmaceutical composition characterized by containing a pyrimidine derivative of the general formula (I):
    wherein A is a group of the general formula (1-1):
    wherein R1 and R2, which may be same or different, are a hydrogen or hologen atom, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkylthio, phenyl or substituted phenyl group, R3 and R4, which may be same or different, are a hydrogen or halogen atom, lower alkyl, lower alkoxy, nitro, sulfone, carboxyl, lower alkoxycarbonyl, cycloalkoxycarbonyloxyalkoxycarbonyl, lower alkanoyloxyalkoxycarbonyl, tetrazolyl or protected tetrazolyl group, or R3 and R4 may be combined together with the ring carbon atoms to which they are bonded to form a condensed 5- or 6-membered ring which may be substituted, X is 0, NH or S(O)p, p is an integer of O to 2 and m is an integer of 1 to 2, or a group of the general formula (I-2):
    wherein R1, R2, R3, R4, X and m have the same meanings as above, B is a carboxyl, lower alkoxycarbonyl, tetrazolyl, or protected tetrazolyl group, and n is an integer of 1 to 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
    7. A pharmaceutical composition according to claim 6, which is an angiotensin II antagonist.
    8. A pharmaceutical composition according to claim 6, which is an agent for treating cardiovascular system diseases.
    9. Use of the compound according to claim 1 for preparing a pharmaceutical composition.
    10. A method for treatment of angiotensin II inhibition comprising administering to a mammal in need thereof the compound according to claim 1 in an amount effective for angiotensin II inhibition.
    Amendments to the claims have been filed as follows CLAIMS 1. A pyritnidine derivative of the general formula (I)
    wherein A is a group of the general formula (1-1):
    wherein R1 and R2, which may be same or different, are a hydrogen or hologen atom, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkylthio, phenyl or substituted phenyl group, R3 and R4, which may be same or different, are a hydrogen or halogen atom, lower alkyl, lower alkoxy, nitro, sulfone, carboxyl, lower alkoxycarbonyl, cycloalkoxycarbonyloxyalkoxycarbonyl, lower alkanoyloxyalkoxycarbonyl, tetrazoly or protected tetrazolyl group, or R3 and R4 may be combined together with the ring carbon atoms to which they are bonded to form a condensed 5- or 6-membered ring which may be substituted, X is O, NH or S(O)p, p is an integer of O to 2, and m is an integer of 1 to 2, or a group of the general formula (I-2) :
    n R1, R2, R3, R4, X and run have the same meanings as @ is a carboxyl, lower alkoxycarbonyl, tetrazolyl, ted tetrazolyl group, and n is an integer of 1 to it thereof. dine derivative according to claim 1, wherein R1 2 atom, a lower alkyl group of 1 to 6 carbon atoms, or a phenyl group, R2 is a lower alkyl group of 1 to 4 carbon atoms, R3 is a hydrogen atom, R4 is a lower alkyl group of 1 to 2 carbon atoms, a lower alkoxy group of 1 to 2 carbon atoms, a halogen atom, nitro or carboxyl group, a lower alkoxycarbonyl group wherein the lower alkoxy moiety has 1 to 2 carbon atoms, a cycloalkoxycarbonyloxyalkoxycarbonyl group wherein the cycloalkoxy moiety has 5 to 7 carbon atoms and the alkoxy moiety has 1 to 2 carbon atoms, a lower alkanoyloxyalkoxycarbonyl group wherein the lower alkanoyl moiety has 2 to 6 carbon atoms and the alkoxy moiety has 1 to 2 carbon atoms, or a tetrazolyl group, or R3 and R4 may be combined together with the ring carbon atoms with which they are bonded to form a condensed 5membered nitrogen-containing ring which may be substituted, X is 0, m is 1, B is a carboxyl group, a lower alkoxycarbonyl group wherein the lower alkoxy moiety has 1 to 2 carbon atoms, a tetrazolyl group, or a protected tetrazolyl group, and n is 1, or a salt thereof.
  3. 3. A pyrimidine derivative according to claim 1, wherein R1 is a hydrogen atom, methyl, ethyl, n-propyl, n-butyl, npentyl or phenyl group, R2 is a methyl, ethyl, n-propyl or n-butyl group, R3 is a hydrogen atom, and R4 is a chlorine atom, methyl, methoxy, nitro, carboxyl, methoxycarbonyl, cyclohexyloxycarbonyloxyethoxycarbonyl, pivaloyloxymethoxycarbonyl or tetrazolyl group, or R3 and R4 may be combined together with the ring carbon atoms to which they are bonded to form a condensed 1,2,3-triazole ring or a condensed 1,2,3-triazole ring substituted by a trityl group, X is o, m is 1, B is a carboxyl, methoxycarbonyl, tetrazolyl, or trityl tetrazolyl group and n is 1, or a salt thereof.
  4. 4. A process for manufacturing a pyrimidine derivative of the general formula (I):
    wherein A is a group of the general formula (I-1):
    wherein R1 and R2, which may be same or different, are a hydrogen or hologen atom, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkylthio, phenyl or substituted phenyl group, R3 and R4, which may be same or different, are a hydrogen or halogen atom, lower alkyl, lower alkoxy, nitro, sulfone, carboxyl, lower alkoxycarbonyl, cycloalkoxycarbonyloxyalkoxycarbonyl, lower alkanoyloxyalkoxycarbonyl, tetrazolyl or protected tetrazolyl group, or R3 and R4 may be combined together with the ring carbon atoms to which they are bonded to form a condensed 5- or 6-membered ring which may be substituted, X is 0, NH or S(O)p, p is an integer of O to 2, and m is an integer of 1 to 2, or a group of the general formula (I-2):
    wherein R1, R2, R3, R4, X and m have the same meanings as above, B is a carboxyl, lower alkoxycarbonyl, tetrazolyl, or protected tetrazolyl group, and n is an integer of 1 to 2, or a salt thereof, characterized by reacting, in the presence of a base, a compound of the general formula (II):
    wherein R1, R2, R3, R4, X, and m have the same meanings as the above, and a compound of the general formula (III):
    wherein B and n have the same meanings as the above, Y is a halogen atom, alkylsulfonyloxy, or arylsulfonyloxy group.
  5. 5. A process for manufacturing a pyrimidine derivative of the general formula (I):
    wherein A is a group of the general formula (1-1):
    wherein R1 and R2, which may be same or different, are a hydrogen or hologen atom, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkylthio, phenyl or substituted phenyl group, R3 and R4, which may be same or different, are a hydrogen or halogen atom, lower alkyl, lower alkoxy, nitro, sulfone, carboxyl, lower alkoxycarbonyl, cycloalkoxycarbonyloxyalkoxycarbonyl, lower alkanoyloxyalkoxycarbonyl, tetrazolyl or protected tetrazolyl group, or R3 and R4 may be combined together with the ring carbon atoms to which they are bonded to form a condensed 5- or 6-membered ring which may be substituted, X is 0, NH or S(O)p, p is an integer of O to 2, and m is an integer of 1 to 2, or a group of the general formula (I-2):
    wherein R1, R2, R3, R4, X and m have the same meanings as above, B is a carboxyl, lower alkoxycarbonyl, tetrazolyl, or protected tetrazolyl group, and n is an integer of 1 to 2, or a salt thereof, characterized by reacting, in the presence of a base, a compound of the general formula (IV):
    wherein R1, R2, R3, R4, and m have the same meanings as the above, and Z is a halogen atom, and a compound of the general formula (V):
    wherein B and n have the same meanings as above, V is a hydroxy, amino or mercapto group.
  6. 6. A pharmaceutical composition characterized by containing a pyrimidine derivative of the general formula (I):
    wherein A is a group of the general formula (1-1):
    wherein R1 and R2, which may be same or different, are a hydrogen or hologen atom, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkylthio, phenyl or substituted phenyl group, R3 and R4, which may be same or different, are a hydrogen or halogen atom, lower alkyl, lower alkoxy, nitro, sulfone, carboxyl, lower alkoxycarbonyl, cycloalkoxycarbonyloxyalkoxycarbonyl, lower alkanoyloxyalkoxycarbonyl, tetrazolyl or protected tetrazolyl group, or R3 and R4 may be combined together with the ring carbon atoms to which they are bonded to form a condensed 5- or 6-membered ring which may be substitu=ed, X is O, NH or S(O)p, p is an integer of O to 2, and m is an integer of 1 to 2, or a group of the general formula (1-2):
    wherein R1, R2, R3, R4, X and m have the same meanings as above, B is a carboxyl, lower alkoxycarbonyl, tetrazolyl, or protected tetrazolyl group, and n is an integer of 1 to 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  7. 7. A pharmaceutical composition according to claim 6, which is an angiotensin II antagonist.
  8. 8. A pharmaceutical composition according to claim 6, which is an agent for treating cardiovascular system diseases.
  9. 9. Use of the compound according to claim 1 for preparing a pharmaceutical composition.
  10. 10. A method for treatment of angiotensin II inhibition comprising administering to a mammal in need thereof the compound according to claim 1 in an amount effective for angiotensin II inhibition.
  11. 11. A pyrimidine derivative substantially as herein described.
  12. 12. A process for manufacturing a pyrimidine derivative, the process being substantially as herein described.
  13. 13. A pharmaceutical composition substantially as herein described.
GB9500538A 1993-05-13 1995-01-11 Pyrimidine derivative and pharmaceutical composition Withdrawn GB2284419A (en)

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EP0685467A4 (en) * 1993-12-16 1996-04-17 Nippon Kokan Kk Novel pyrimidine derivative and medicinal composition.
CA2479036A1 (en) 2002-03-13 2003-09-18 Euro-Celtique S.A. Aryl substituted pyrimidines and the use thereof
EP3046912A1 (en) 2013-09-16 2016-07-27 Bayer Pharma Aktiengesellschaft Disubstituted trifluormethyl pyrimidinones and use thereof as ccr2 antagonists

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
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J. Med. Chem., 1992, Vol. 35, No 20, pages 3714-3717 *
J. Med. Chem., 1992, Vol. 35, No 25, pages 4751-4763 *

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