Pyridone derivatives, method of their production and application

(72) Robert David Anthony, Macclesfield, GB Ral.cli.ffe Arnold Harry, Macclesfield, E'R Bradbury Robert Hugh, Macclesfield, GB (54) Pyridine derivatives, process for their manufacture and use (57) Pharmaceutically usable new the compound of Formula 1 wherein IC, R 1², R^and, R *, R^withR, R⁷X and Z have the meanings defined in the claims and their non-toxic salts and pharmaceutical compositions containing them. The novel compounds are valuable in the treatment of conditions such as hypertension and heart attack. The invention further relates to a process for the preparation of these novel compounds and their use in the broom.

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The present invention relates to novel pyridine derivatives, in particular to novel pyridine derivatives having pharmacological properties which make it possible to at least partially antagonize one or more actions of substances known as anglotensins, in particular substances known as angiotensin II (hereinafter referred to as AII). containing said novel compounds useful in the treatment of diseases or conditions such as hypertension, heart attack and / or hyperaldosteronism, in warm-blooded animals (including humans), as well as other diseases or conditions in which the renin-angiotensin-aldosterone system plays an important causal role. The invention also encompasses processes for the manufacture of these novel compounds and their use in the treatment of any of the above-mentioned diseases or conditions, and the production of novel pharmaceuticals for use in such treatment.

BACKGROUND OF THE INVENTION

Anglotensins have a key mediating role in the renin-angiotensin-aldosterone system, which regulates homeostasis and liquid / electrolyte balance in many warm-blooded animals, including humans. Angiotensin, known as AII, is produced by the action of angiotensin converting enzyme (ACE) from angiotensin I, which is produced by the action of the renin enzyme from the angiotensinogen plasma protein. AII is an effective spmogen, particularly in the vascular system, and is known to increase vascular resistance and blood pressure. In addition, angiotensins are known to stimulate the release of aldosterone, leading to vascular congestion and hypertension through sodium and fluid retention mechanisms. So far, there are numerous different approaches to pharmacology

-!

C.

intervention in the renin-anglotensin-aldosterone system for the therapeutic regulation of blood pressure and / or fluid / electrolyte balance, including, for example, inhibiting the action of renin or ACE. However, due to the side effects and / or idiosyncratic reactions associated with each particular therapeutic approach, there is still a need for an alternative approach.

Our published European patent application No. 412843 discloses certain quinolone derivatives having AII antagonistic activity.

We have now found that the compounds of the invention surprisingly antagonize one or more actions, known as angiotensins (and in particular AII), thus minimizing the physiological effects associated with their presence in warm-blooded animals (including humans), and this is the basis invention.

SUMMARY OF THE INVENTION

The present invention provides a pyridine derivative of the Formula I wherein p 1 'is hydrogen, (C 1 -C 8) alkyl, (C 3 -C 8) cycloalkyl, phenyl or (C 1 -C 4) alkyl substituted by one or more. fluorine atoms or C 3 -C 8 cycloalkyl, C 1 -C 4 alkoxy or phenyl, -2 = .................. ............

R is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkyl of 1 to 4 carbon atoms, substituted cycloalkyl of 3 to 8 carbon atoms, carboxy, alkoxycarbonyl of 1 to 4 o

carbon atoms, C3 -C4 alkenyloxycarbonyl, cyano, nitro, phenyl or phenylalkyl having 1 to 4 carbon atoms in the alkyl moiety,

R is a substituent selected from the group consisting of halogen, C1-C4alkoxy, amino, alkylamino and dialkylamino of up to 6 carbon atoms and all the meanings of R,

R is a substituent selected from the group consisting of hydrogen, (C 1 -C 4) alkyl, optionally substituted amino, (C 1 -C 4) alkanoylamino, phenylcarbonylamino, hydroxy or (C 1 -C 4) alkoxy, carboxy, (C 1 -C 4) alkoxycarbonyl (4) carbon atoms, (C 3 -C 5) alkenyloxycarbonyl, cyano, nitro, carbamoyl, (C 1 -C 4) alkanoyl, N-alkylcarbamoyl and dl- (N-alkyl) carbamoyl of up to 7 carbon atoms, halogen, amino, alkylamino and dialkylamino of up to 6 carbon atoms, 3-alkylureido of 1 to 4 carbon atoms in the alkyl moiety and alkanoylamino of 1 to 4 carbon atoms Or R 4 represents a group of formula

1 A is a carbonyloxy group, A is a C1-6 alkylene group and 3 is a substituent selected from the group consisting of hydroxy, C1-4 alkoxy, phenyloxy, phenylalkoxy of 1 to 4 carbon atoms; carbon atoms in the alkoxy radical, pyridylalkoxy having 1 to 4 carbon atoms in the alkoxy radical, 4-morpholinoalkoxy having 1 to 4 carbon atoms in the alkoxy radical, phenylamino, amino, alkylamino and dialkylamino of up to 6 carbon atoms, alkanoylamino of 1 to 4 carbon atoms, alkylsulfonylamino of 1 to 4 carbon atoms, phenyl4 sulfonylamino, sulfamoylamino / -NH, 50₂, NH₂(, carboxamldomethylaminobutyl) - (NH.CH.sub.2 CO.sub.2), alkanoyloxy of 1 to 4 carbon atoms, phenylcarbonyloxy, aminocarbonyloxy (- O.CO.NH)₂(C1-C4) alkylaminocarbonyloxy, carboxy, (C1-C4) alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl (3) di- (N-alkyl) carbamoyl (C1-C4), alkanoyl (1-4) carbon atoms, 4-morpholino, 1-imidazolyl and succinimido, or B is -A. B, wherein A is oxy, oxycarbonyl or imino and B represents a 5- or 6-membered saturated or unsaturated heterocycle containing 1 or 2 nitrogen atoms and linked to the remainder A by a ring carbon atom, or A represents an oxycarbonyl group and 3¹ is 4-morpholino or a 5 or 6-membered saturated heterocycle having 1 or 2 nitrogen atoms, optionally substituted with 1 to 4 carbon atoms and bonded to radical A with a ring nitrogen atom, the radical of the ring atoms B being carbon atoms,

4 or R and R together form an alkylene group having 3 to 6 carbon atoms, where optionally one of the methylene groups may be replaced by a carbonyl group, or an alkenylene group having 3 to 6 carbon atoms,

R is hydrogen, rS is hydrogen or (C1-C4) -alkyl,

R? is a substituent selected from the group consisting of hydrogen, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, halogen, trifluoromethyl, cyano and nitro;

X is a phenylene group optionally bearing a substituent selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, C 1 -C 4 alkanoyl, trifluoromethyl, cyano and nitro; or X represents a direct bond between an adjacent phenyl group and a carbon atom bearing R⁵ and R⁶, and

Z is 1H-tetrazol-5-yl, -CO.NH./1H- tetrazol-5-yl, or -CO.OR or

Wherein R. is hydrogen or a nontoxic biodegradable moiety of a physiologically acceptable alcohol or phenol and R is an alkyl group of 1 to 6 carbon atoms, a cycloalkyl group of 3 to 8 carbon atoms or a phenyl group, all of which is said phenyl groups may be unsubstituted or carry one or two substituents independently selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, cyano and trifluoromethyl, or its N-oxide or non-toxic salt thereof.

Depending on the nature of the substituents, certain compounds of formula I may have one or more chiral centers and may be isolated in one or more racemic or optically active forms. In this connection, the invention relates to any of these forms of a compound of formula I having the aforementioned useful pharmacological properties, wherein both a method for producing optically active forms, e.g. by synthesis from suitable chiral intermediates, and a method for determining their pharmacological properties, e.g. of the standard tests described.

General terms, such as alkyl, include, as far as the number of carbon atoms permits, both straight and branched variants. However, when a particular residue is mentioned, for example propyl, it refers to a straight chain variant; when branched chain is meant, it is mentioned explicitly, for example isopropyl. The same convention applies to other residues.

. 12 3

Particular values ​​for R, R or R when they represent an alkyl group are, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl or hexyl, and when they represent cycloalkyl, for example cyclopropyl, cyclopentyl or cyclohexyl.

3

Particular significance for R or R when they represent an alkyl group with one or more fluorine substituents,

It is, for example, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or pentafluoroethyl, and when they represent an alkyl group substituted by cycloalkyl, alkoxy of 1 to 1 carbon atoms or a phenyl group, for example cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-methoxyethyl, 2 -ethoxyethyl, benzyl, 1-phenylethyl or 2-phenylethyl.

A particular value for R when it represents a cycloalkylalkyl group is, for example, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl or 2-cyclopentyl-ethyl, and when it represents a phenylalkyl group it is, for example, benzyl, 1-phenylethyl or 2-phenylethyl.

4

A particular value for R or R when it represents an alkoxycarbonyl group is, for example, methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl, and if it represents an alkenyloxycarbonyl group, for example it is allyloxycarbonyl,

2-methyl-2-propenyloxycarbonyl or 3-methyl-3-butenyloxycarbonyl.

A particular value for R *, R °, or R or an optional substituent that may be present is when X is phenyl when it is an alkyl group, for example methyl or ethyl.

A particular meaning for R, R, R or for any optional substituent that may be present when X is phenylene when it is halogen is, for example, fluorine, chlorine, bromine or iodine.

7

A particular value for R, R or an optional substituent that may be present when X is phenylene when it is an alkoxy group is, for example, methoxy or ethoxy.

4

A particular value for R or R when it is an alkylamino group is, for example, methylamino, ethylamino or butylamino, and when it is a dialkylamino group it is, for example, dimethylamino, diethylamino or dipropylamino.

Examples of the specific meanings of R are, in the case of alkanoylamino: formamdo, acetamido or propanamido, for alkanoyl: formyl, acetyl or butyryl, for N-alkylcarbamoyl: N-methyl or N-ethylcarbamoyl, for di- (N-alkyl) carbamoyl: N, Ν-dimethylcarbamoyl or N, N-diethylcarbamoyl, for 3-alkylureido: 3-methylureido, 3-ethylureido or 3-propylureido, and for alkyl substituted with amino, alkanoylamino, phenylcarbonylamino, hydroxy or alkoxy: aminomethyl, 2-aminoethyl, acetylaminomethyl, acetylaminoethyl, propionylaminomethyl, propionylamino-ethyl, phenylcarbonylaminoethyl, phenylcarbonylamino-ethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxymethyl, 2-methoxyethyl or 2-ethoxyethyl.

4

Particular values ​​for R and R when taken together to form an alkylene group having 3 to 6 carbon atoms are, for example, trimethylene, tetramethylene or pentamethylene, when together they form an alkenylene group having 3 to 6 carbon atoms, for example 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene or 3-butenylene, and when taken together to form alkylene of 3 to 6 carbon atoms wherein one of the methylene groups is replaced by a carbonyl group, for example, is 1-oxopropylidene, 3-oxopropylidene, 1-oxobutylidene or 4-oxobutylidene.

A particular meaning for an optional substituent on X when it is phenylene when it is alkanoyl is, for example, form I, acetyl or propionyl.

A particular value for A is, for example, methylene, ethylene, trimethylene or tetramethylene, wherein methylene may carry 1 or 2 methyl substituents.

Particular values ​​for B include, for example, for alkoxy: methoxy, ethoxy or isopropoxy, for phenylalkoxy: benzyloxy and phenethyloxy, for pyridylalkoxy: 2-pyridylmethoxy, 3-pyrldylmethoxy, 4-pyridylmethoxy and 3-pyridylethoxy, for 4-morpholinoalkoxy: 4-morpholinomethoxy and 4-morpholinoethoxy, for alkyl amino: methylamino, ethylamino and butylamino, for dialkylamino: dlmethylamino, dlethylamino and dipropylamino, for alkanoylamino: formamido, acetamldo and propanamido, for alkylsulfonylamino: methylsulfonylamino and ethylsulfonylamino, for alkanoyloxy: acetyloxy and propionyloxy, for alkylaminocarbonyloxy: methylaminocarbonyloxy and ethylaminocarbonyloxy, for alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl, for N-alkylcarbamoyl: N-methyl and N-ethylcarbamoyl: N-methyl and N-ethyl and N-ethyl Ν, Ν-dimethylcarbamoyl and N, N-diethylcarbamoyl, for alkanoyl: formyl, acetyl and propionyl.

Particular values ​​for B when it is a 5 or 6 membered unsaturated heterocycle with 1 or 2 nitrogen atoms are, for example, pyrrolyl, imidazolyl, pyrazolyl, -pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, and when it is a 5 or 6 membered saturated heterocycle with 1 or 2 nitrogen atoms is, for example, pyrrolinyl, imldazolidinyl, pyrazolinyl, piperidinyl or piperazinyl.

A particular value for an alkyl group that may be present on B * 'when it represents a 5 or a membered saturated heterocycle is, for example, methyl or ethyl.

and

Particular value for R when it represents a non-toxic biodegradable moiety of a physiologically acceptable alcohol or phenol is, for example, a moiety derived from an alkanol of 1 to 6 carbon atoms, such as methanol or ethanol, or a phenol, glycerol and the like.

A particular value for R when it represents an alkyl group is, for example, methyl, ethyl, propyl, isopropyl, butyl or pentyl, and if it represents a cycloalkyl group, it is, for example, cyclobutyl, cyclooentyl or cyclohexyl.

Particular values ​​for or substituents that may be present on the phenyl group include, for example, for halogen: fluorine, chlorine and bromine, for alkyl: methyl and ethyl, and for alkoxy: methoxy and ethoxy.

A particular value of p.ro X which is of particular interest is, for example, p-phenylene.

3

A preferred meaning of R or R is, for example, methyl or ethyl

A preferred value for R is, for example, hydrogen, unsubstituted phenyl or phenyl bearing one or two substituents independently selected from methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, iodo, cyano and trifluoromethyl.

A preferred value for R is, for example, hydrogen, alkoxycarbonyl (especially methoxycarbonyl or ethoxycarbonyl) or alkenyloxycarbonyl (especially allyloxycarbonyl).

4

Preferred meanings of R and R when taken together are alkylene,

For example, trimethylene or tetramethylene is particularly preferred.

7 (B)

A preferred value for R, R or R is, for example, hydrogen.

A preferred meaning of Z is, for example, 1H-tetrazol-5-yl, especially -------------- when attached to the X group in the ortho position. ........

A particularly preferred combination of meanings is,

When R 11 is alkyl / e.g. R 6 is methyl or ethyl and R 6 is methyl

It is methyl or ethyl (or when R is alkyl (for example methyl 34 or ethyl) and R together with R forms alkylene (for example tri1D methylene, tetramethylene or pentamethylene)).

Another particularly preferred combination of meanings occurs when, for example, R is⁴ hydrogen and R 'is unsubstituted phenyl or phenyl bearing one or two substituents independently selected from the group consisting of alkyl of 1 to 4 carbon atoms (such as methyl, ethyl or propyl), alkoxy of 1 to 4 carbon atoms (such as methoxy or ethoxy), halogen (such as fluorine, chlorine, bromine or iodine), cyano and trifluoromethyl.

Another particularly preferred combination of meanings is, for example, when R is²_{VO (}j £ k _and alkoxycarbonyl (such as methoxycarbonyl or ethoxycarbonyl) or alkenyloxycarbonyl (such as allyloxycarbonyl).

Of particular interest is the group of compounds of formula I according to the invention, wherein R 1¹ , R², R³, R⁵, R^WITH, R⁷, X and Z have any of the above meanings and R is a group of formula Α^Ί.Α .B, where 12

A, A and B have any of the above meanings, and non-toxic salts thereof.

A preferred group of compounds of formula I comprises compounds of formula I wherein X is p-phenylene and Z is 1H-tetrazol-5-yl and wherein R 1 is R 1 -R 2², R³, R⁴ , R³, _G and any non-toxic salts thereof. Particularly preferred in this group are those compounds wherein Z is to X in the ortho position.

in

A particularly preferred group of compounds of formula (I) for 40 ° C comprises compounds of formula (I) wherein R, R, R, R³ and R 'have any of the meanings given above, R⁴ It is an alkoxycarbonyl group having 1 to 4 carbon atoms or an alkenyloxycarbonyl group having 3 to 5 carbon atoms, R³ It is hydrogen and Z is a carboxy group, or -B = tetrezol-5'-y1, -a-4e, but not toxic -so. particularly preferred compounds wherein Z is ortho to X, and particularly those wherein Z is 1H-tetrazol-5-yl.

Another particularly preferred group of compounds of the invention includes compounds of formula Ia wherein n is an integer of 1, 2 or

3, R 2 is hydrogen or a substituent selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, C 1 -C 4 alkanoyl, trifluoromethyl, cyano and nitro, Za is 1H -tetrazol-5-yl or 12,7 carboxy and R, R and R have any of the above meanings, and non-toxic salts thereof. Particularly preferred in this group are those compounds wherein Za is 1H-tetrazol-5-yl.

Another particularly preferred group of compounds of the present invention includes compounds of formula Ib, wherein R, R, R, and R have any of the above meanings, R 2 is hydrogen or a substituent selected from the group consisting of C 1 -C 4 alkyl, alkoxy C 1-4 alkyl, halogen, C 1-4 alkanoyl, cyano and nitro, R x and R y are independently selected from hydrogen, C 1-4 alkyl, C 1 -C 4 alkoxy, halogen, cyano and trifluoromethyl, and Z b is 1H-tetrazol-5-yl or carboxy, and non-toxic salts thereof.

Particularly preferred in this group are those compounds wherein Z is 1H-tetrazol-5-yl.

Of particular interest are, for example, those compounds of the invention which are specifically disclosed in the Examples. Particularly preferred are the compounds of formula I described in Examples 2, 5, 6, 9, 10, 11, 12, 13, 14 and 41, and non-toxic salts thereof.

Although all compounds of formula I may form salts with suitable acids, compounds of formula I wherein Z is other than an ester group or in which R or R carries a carboxy group may form salts with bases as well as acids. Particularly suitable non-toxic salts of these compounds thus also include, for example, salts with bases providing physiologically acceptable cations, for example alkali metal salts (such as sodium and potassium), alkaline earth metals (such as magnesium and calcium), aluminum and ammonium salts; salts with suitable organic bases, such as ethanolamine, methylamine, diethylamine or trlethylamine, as well as salts with acids forming physiologically acceptable anons, such as salts with mineral acids, for example, hydrogen halides (such as hydrogen chloride and hydrogen bromide), sulfuric and phosphoric acids, and strong organic acids such as p-toluenesulfonic and methanesulfonic acids.

Compounds of formula I may be obtained by standard organic chemistry known for the preparation of structurally analogous compounds. These processes are also within the scope of the invention and include, for example, the following processes in which, unless otherwise indicated, the general radicals have the meanings given above:

and / In the case of compounds wherein Z is a carboxy group / i.

pp wherein Z is a group of the formula -C0R, where R 0 is hydrogen /, a carboxylic acid derivative of formula II wherein Q is a protected carboxy group selected from the group consisting of C 1 -C 6 alkoxycarbonyl (especially methoxy-, ethoxy-), propoxy- or tert. butoxycarbonyl, phenoxycarbonyl, benzylaxycarbonyl and carbamoyl are converted to carboxy derivatives.

This conversion can be carried out, for example, by hydrolysis, preferably in the presence of a suitable base, such as an alkali metal hydroxide, for example lithium, sodium or potassium hydroxide. The hydrolysis is usually carried out in the presence of a suitable aqueous solvent or diluent, for example in an aqueous C 1 -C 4 alkanol, such as aqueous methanol or ethanol.

However, it can also be carried out in a mixture of aqueous and non-aqueous solvents, for example water and toluene, using a conventional quaternary ammonium phase transfer catalyst. The hydrolysis is generally carried out at a temperature in the range, for example, 0 to 120 ° C, depending on the reactivity of the Q group. In general, when Q is carbamoyl, a temperature in the range, for example, 40 to 120 ° C is required.

If 11 is benzyloxycarbonyl, the conversion may also be carried out by hydrogenolysis, for example using hydrogen at a pressure of 0.1 to 0.3 ITPa in the presence of a suitable catalyst such as palladium on activated carbon or calcium sulfate, in a suitable solvent or diluent. Such as an alkanol having 1 to 4 carbon atoms (most commonly ethanol or 2-propanol) and at a temperature in the range, for example, 0 to 40 ° C.

When Q is tert-butoxycarbonyl, the conversion can also be carried out by hydrolysis at a temperature in the range, for example, 0 to 100 ° C in the presence of a strong acid catalyst such as trifluoroacetic acid. The hydrolysis may be carried out either in excess of acid or in the presence of a suitable diluent such as tetrahydrofuran, tert-butyl methyl ether or 1,2-dimethoxyethane.

b) For compounds of formula I wherein Z is tetrazolyl, a compound of formula III wherein L is a suitable protecting group, such as trityl, benzhydryl, triakyltin (e.g. trimethyltin or tributyltin) or triphenyltin, attached to the nitrogen of the tetrazolyl group, is protecting group splits.

The reaction conditions used to remove the protecting group necessarily depend on the nature of the protecting group L. For example, when trityl, benzhydryl, triakyltin or triphenyltin is present, the decomposition conditions include acid catalyzed hydrolysis in a mineral acid (such as aqueous hydrochloric acid), preferably in an aqueous solvent. Such as aqueous dioxane or 2-propardine. The trtyl or benzhydryl group can also be cleaved by hydrogenolysis, for example as described under a) to convert the benzyloxycarbonyl group to the carboxy group.

Compounds of formula III wherein L is triakyltin or triphenyltin can be obtained, for example, by reacting a nitrile of formula IX with a trialkyltin azide, such as tributyltin azide, respectively. triphenyltin-azld. The reaction is preferably carried out in a suitable solvent or diluent, such as toluene or xylene, and at a temperature in the range, for example, 50 to 150 ° C. By a modified process, a compound of formula I wherein Z is tetrazolyl can be obtained directly by removing the trialkyltin or triphenyltin tin group in situ without first isolating the compound of formula III, for example by adding an aqueous mineral acid or hydrogen chloride gas to the reaction mixture. The nitriles of formula IX can be obtained, for example, by alkylation of pyridone of formula IV wherein R and R are other than hydrogen with nitrile of formula X wherein Hal represents a suitable readily cleavable group such as chlorine, bromine, iodine, methanesulfonyloxy or p-toluenesulfonyloxy under similar conditions As in paragraph c /. The required compounds of formula X may be prepared by standard procedures, for example, illustrated in Scheme 1 for compounds wherein X is phenylene, or from a compound of formula XI by known organic chemistry techniques. Nitriles of Formula IX can also be obtained by sequentially converting a compound of Formula I wherein Z is a group of formula -CO.OR, under standard conditions. The nitriles of formula IX can further be obtained, for example, by reacting pyridine of formula VII, wherein Y is a suitable readily removable group (such as chlorine, bromine, iodine, methanesulfonyl, methanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy) with an alcohol of formula XI under similar conditions. in paragraph d /. The alcohol of formula XI can be obtained, for example, by a standard procedure, for example as in Scheme 1 for compounds wherein X is phenylene, or analogously to Scheme 2. The nitriles of formula IX can also be obtained as shown in scheme 4 for compounds wherein X is phenylene . Trialkyltin azides and triphenyltin azides are either commercially available or can be prepared by known standard procedures,

Such as the reaction of a trialkyltin halide with an alkali metal azide

Compounds of formula III may also be obtained, for example, by reacting pyridine of formula VII, wherein Y VII is as defined above, with an alcohol of formula XII under similar conditions as in section d) below. Alcohols of formula XII can be obtained, for example, from the corresponding bromomethyl compound by standard procedures, for example, as in Scheme 2.

The compound of formula III can also be obtained from another preformed compound of formula III using standard functional group transformations or groups already present in the compound. Such transformations are known. For example, a compound of formula III wherein R 1 is an alkoxycarbonyl group can be converted to a compound of formula III wherein R 1 is a carboxyl group by alkaline hydrolysis, or to a compound of formula III wherein R 1 is a hydroxymethyl group by reduction with, for example, alkali metal cyanoborohydride. The hydroxymethyl group can then be converted, for example, into the sodium salt of an alkali metal hydride and alkylated with, for example, an alkyl halide (such as iodomethane) to form an alkoxymethyl group. The hydroxymethyl group can also be converted, for example, to a halomethyl group (e.g., a chloromethyl group, with methanesulfonyl chloride and triethylamine), which can then be converted to an aminomethyl group by treatment with ammonia in an autoclave at high temperature. If a compound of formula (III) wherein R is an alkanoylamino, phenylcarbonylamino or 3-alkylureido group is desired, then, for example, the aminomethyl group can be acylated under standard conditions with the appropriate acylating or benzoylating reagent or reacted with an alkylisocyanate.

3 c) Pyridone of formula IV wherein R and R are other than hydrogen is alkylated with a compound of formula V wherein Hal represents a suitable readily cleavable group such as chlorine, bromine, iodine, methanesulfonyloxy or p-toluenesulfonyloxy. The reaction is usually carried out in the presence a suitable base, for example an alkali metal alkoxide, such as sodium methoxide or sodium ethoxide, or an alkali metal hydride, such as sodium hydride, or an alkali metal carbonate, such as sodium or potassium carbonate, or an organic base, such as dlisopropylethylamine, and in a suitable solvent or diluent, for example in a C 1 -C 4 alkanol, such as methanol or ethanol, when an alkali metal alkoxide is used, or in a polar solvent such as N, N-dimethylformamide or N-methylpyrrolidone, and at a temperature in the range, for example, 10 to 100 ° C. Quaternary ammonium hydroxide can also be used in a mixture of aqueous and non-aqueous solvents such as water and dichloromethane. In carrying out process (c), if there is an acidic moiety in the starting material, two molar equivalents of a suitable base is usually required, whereas when Z is a non-acidic moiety, the presence of one molar equivalent of a suitable base is usually sufficient.

Process c) It is particularly suitable to prepare those compounds of formula I wherein Z is a group of the formula -CO.DR wherein R is other than hydrogen, for example, when R is an alkyl group of 1 to 5 carbon atoms, benzyl or phenyl which compounds are also starting materials of the formula II for the reaction described in a) above. In an analogous manner using the corresponding starting halomethyltetrazolyl derivative of formula VI, starting materials of formula III for process b) can be obtained.

Many of the pyridones of formula IV are known and the rest can be prepared analogously using standard organic chemistry procedures known in the art and described, for example, in standard heterocyclic chemistry, e.g., edited by Elderfleld, or using the procedures described in Monatshefte filr Chemie, 1969 , 1 DD, 132, J. Chem. Soc. / Β / 196B, 366, Liebigs Ann. Chem., 1982, 1656 or 1979, 371,

Heterocycle s, ... 1932, 13, 239, or European Patent Application Publication No. 177965, or a method analogous thereto. Pyridones of formula IV wherein R is substituted or unsubstituted phenyl or phenylalkyl may be obtained as shown in Scheme 3 (or a method analogous thereto) in the case of compounds wherein R @ 1 is methyl or ethyl and R @ 1 is hydrogen. Necessary compounds of formula V (as well as formula VI) can be prepared by standard procedures, for example as shown in Scheme 1 for compounds wherein X is phenylene. A compound of formula V or VI may also be obtained from a compound of formula VIII (wherein Z is COOROR), respectively. of formula XII using known organic chemistry techniques.

WITH

Compounds of formula VI wherein X is phenylene and R1 and R2 are hydrogen may also be conveniently obtained by reacting a Grignard reagent formed from an appropriately substituted 4-bromotoluene with a trialkyltin halide such as tributyltin chloride and then reacting the (substituted) phenyltrialkyltin tin compound with bromobenzonitrile in the presence of a zero-valent palladium catalyst such as tetrakis (triphenylphosphine) palladium, and azo (bisisobutyronitrile). The substituted 4'-methyl-biphenylcarbonitrile obtained can then be converted to the compound of formula VI by carrying out steps b), c) and d) in a similar manner to Scheme 1. Appropriate substituted 4'-methylbiphenylcarbonitriles can also be obtained by reacting 4-methylphenylboronic acid with substituted bromobenzonitrile in the presence of a suitable palladium catalyst, such as palladium chloride or tetrakis (triphenylphosphine) palladium, and azo (bisisobutyronitrile).

d) A pyridine derivative of formula VII wherein an easily cleavable group (such as chlorine, bromine, iodine, methanesulfonyl, methanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethylphenylphonyloxy) is suitable is reacted with an alcohol of formula VIII.

The reaction is usually carried out in the presence of a suitable base, for example an alkali metal alkoxide, such as a methoxide or an alkoxide

Sodium ethoxide, or an alkali metal hydride, such as sodium hybrid, and in a suitable solvent or diluent, for example a C 1 -C 4 alkanol, such as methanol or ethanol, when an alkali alkoxide is used metal, or in a polar solvent, such as N, N-dimethylformamide. Alcohol formulas

VIII may also be used in the form of a pre-formed alkali metal salt (when Z is a non-acidic group) or a salt with two alkali metal atoms in the molecule (if Z is an acidic group). The reaction is usually carried out at a temperature in the range of 40 to 120 ° C. Preferably, the reaction may be carried out with a compound of formula VIII in the presence of an acid catalyst, such as p-toluenesulfonic acid, instead of basic conditions, and in the presence of an inert solvent or diluent, such as toluene. Another alternative consists in heating the compound of formula VII with the compound of formula VIII to an elevated temperature, for example in the range of 120 to 180 ° C, in the absence of a solvent or in the presence of a high boiling solvent or diluent such as diphenyl ether.

Pyridine derivatives of formula VII wherein Y is halogen may be obtained, for example, by halogenation of the corresponding pyrdones of formula IV, for example by reaction with phosphorus oxychloride in the absence of a solvent or in the presence of an inert solvent or diluent such as toluene or dioxane. to 110 ° C. Compounds of formula VII wherein Y is methanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy and R and R are other than hydrogen may be obtained, for example, by acylating the corresponding pyridones of formula IV with the corresponding sulfonyl chloride under standard conditions. Compounds of formula VII wherein Y 4 is methanesulfonyl can be obtained from the alkylation of the corresponding mercaptopyridines, followed by. oxidation under standard conditions. Alcohols of formula VIII are known or can be prepared by known standard procedures, for example analogously to Scheme 2 or by deprotection of the compound thus obtained.

Compounds of formula I wherein Z is 1H-tetrazol-5-yl can be obtained by sequentially converting a compound of formula I wherein Z is a group -CO.OR, to the corresponding nitrile under standard conditions, and then reacting the nitrile with an azide, such as It is an alkali metal azide, preferably in the presence of ammonium halide and preferably in the presence of a suitable polar solvent, such as N, N-dimethylformamide, and at a temperature in the range, for example, 50 to 160 ° C.

Compounds of Formula I wherein Z is -CO.NH./1H- tetrazol-5-yl/, Q □ ^J * a group of formula -C0.NH.S0₂R or a group of formula -CO.OR, where R is other than hydrogen, can be obtained, for example, by reacting a carboxylic acid of formula I, wherein Z is a carboxy group (or a reactive derivative thereof) with 5-aminotetrazole, a sulfonamide of formula R or a salt thereof (e.g. an alkali metal salt) or a hydroxy compound of the formula HO.R® or a salt thereof (e.g. an alkali metal salt). Suitable reactive derivatives include, for example, the chloride, bromide, azide, anhydride and mixed anhydride of the aforementioned carboxylic acid of Formula I with formic or acetic acid. When the acid is used in the free form, the reaction is usually carried out in the presence of a suitable dehydrating agent, such as dicyclohexylcarbodiimide or 3- (3-dimethylaminopropyl) -1-ethylcarbodiimide, in the presence of a base such as triethylamine, pyridine or 4-dimethylaminopyridine. When a reactive derivative is used, the reaction is carried out either in the presence of a base, for example the same as above, or for the preparation of a compound of formula I, wherein Z is a group of formula -CO.NH.SC2R or a group of formula -CO.OR , a sulphonamide or a hydroxy compound in salt form is used,

Such as the alkali metal salt (especially its lithium, sodium or potassium salt). The reaction is conveniently carried out in the presence of a suitable solvent or diluent, such as dioxane, tert-butyl methyl ether or tetrahydrofuran, and at a temperature in the range, for example, 0 to 60 ° C.

If the N-oxo compound of formula I is desired, then the compound of formula I is oxidized. Suitable oxidizing agents include those known for the conversion of nitrogen heterocycles to the corresponding N-oxides, for example hydrogen peroxide or organic peroxyacids, such as m-chloroperoxybenzoic acid or peracetic acid. The oxidation is preferably carried out in a suitable solvent or diluent customary for such oxidations, for example dichloromethane, chloroform or acetic acid, at a temperature in the usual range, for example 0 to 30 ° C.

If a non-toxic salt of the compound of formula (I) is desired, it may be obtained, for example, by reaction with an appropriate base providing a physiologically acceptable catlon, or with an appropriate acid providing a physiologically acceptable anlon, or other conventional salt formation process.

If an optically active form of a compound of formula (I) is desired, one of the above procedures may be used starting from the optically active agent. Another possibility is to resolve the racemic form of a compound of formula I wherein Z is an acidic group, for example by reaction with an optically active form of a suitable organic base such as ephedrine, N, N, N-trimethyl / 1-phenylethyl / ammonium hydroxide or 1-phenylethylamine and then conventional. by separating the dlastereolsomeric mixture of the salts obtained, for example by fractional crystallization from a suitable solvent, for example an alkanol having 1 to 4 carbon atoms, whereupon the optically active form of the compound of formula I can be liberated by treatment with an acid by a conventional method, for example using an aqueous mineral acid such as dilute hydrochloric acid.

Some of said intermediates are novel, for example compounds of formulas II, III, IV and IX, and are also subject of the invention.

As noted above, the compounds of Formula I have beneficial pharmacological effects on warm-blooded animals (including human and / or diseases and / or diseases where it is desirable) to improve vasoconstrictor properties and fluid retention in renin-anglotensin. aldosterone system, at least in part due to antagonism of one or more of the physiological effects of AII. The compounds of the invention are therefore suitable₀

For the treatment of diseases or conditions, such as hypertension, heart attack and / or hyperaldosteronism, in warm-blooded animals (including humans), as well as other diseases or conditions in which the renin-anglotensin-aldosterone system plays an important causal role.

Antagonism One or more of the physiological functions of AII, and in particular antagonism of the interaction of AII with receptors that mediate its effect on the target tissue, can be evaluated by one or more of the following routine laboratory procedures:

Test A: This in vitro procedure consists in incubating the test compound first at a concentration of 100 mmol (1) or lower) in a buffered mixture containing a fixed concentration of radiolabeled AII and a cell surface membrane fraction prepared from an appropriate target anglotensin tissue. In this assay, the source of cell surface membranes is a guinea pig adrenal gland, which is known to respond to AII. The interaction of radiolabeled AII with its receptors (determined as radioactivity bound to a particular membrane fraction after removal of unbound radioactivity by rapid filtration, standardly used in relevant studies) is antagonized by compounds that also bind to receptor sites of the membranes, and the degree of antagonism (observed in the assay) As a membrane-bound radioactivity shift, it is readily determined by comparing the receptor-bound radioactivity in the presence of the test compound at a certain concentration to a control value determined in the absence of the test compound. Compounds which exhibit at least a 50% shift in the binding of radioactive ATT at the concentration of the TG concentration in this procedure. To determine the IC 50 (concentration at which a 50% shift in bound radioactive AII occurs), the concentration of the test compound is typically chosen, allowing the assay to be at least four orders of magnitude centered around the estimated approximate IC 50 value. dependence of percent shift on test compound concentration.

In Test A, generally the acidic compounds of formula I as defined above exhibit a significant inclusion at a concentration of 50 mmol / l or much lower.

Test 3: This in vitro assay consists of measuring the antagonist effects of the test compound against isolated rabbit aorta contractions stored in physiological saline at 37 ° C induced by AII. To confirm that the effect of the compound is specific for AII antagonism, the effect of the test compound on noradrenaline-induced contractions can be simultaneously determined on the same preparation.

In general, the above acidic compounds of formula I exhibit significant inclusions at a final concentration of 50 mmol / l or much lower in Test 3. / Pozn .; Compounds of formula I wherein Z is a group of formula -CO.OR®, where Ρθ is other than hydrogen, generally exhibit only weak activity in tests A and 3./

Test C: This in vivo test is used to measure blood pressure changes in terminally anesthetized or conscious rats that have been implanted with an arterial catheter in anesthesia. · The effect of the test compound, AII antagonist, after oral or parenteral administration is determined against the pressor response induced anglotensin II. To confirm that the effect of the test compound is specific, the effect of the test compound on vasorpresin-induced pressor responses can be simultaneously determined on the same preparation.

---------------------- pfi — t_BSIn general, compounds of the formula having specific AII-antagonistic properties at a dose of 50 mg / kg body weight or much lower without apparent toxicological or other inappropriate pharmacological effects.

Test D: This in vivo test consists in stimulating endogenous AII biosynthesis in a variety of animal species including rat, marmoset and dog by introducing a low sodium diet and administering appropriate daily doses of a saluretic known as frusemlde. Then, orally or parenterally, the test compound is administered to an animal having an anesthesia implanted arterial catheter to measure changes in blood pressure.

In Test D, the compounds of Formula I generally exhibit All-antagonistic properties, demonstrated by a significant reduction in blood pressure at a dose of 50 mg / kg body weight or much lower, with no apparent toxicological or other inappropriate pharmacological effects.

To illustrate angiotensin II inhibitory properties, Test Results A and C for the compound of Formula I of Example 2 may be given:

Test A: IC 50 g..W^-^ mol / L

Test C: 0.1 mg / kg (administered iv)

For therapeutic or prophylactic purposes, the compounds of formula I are usually administered to warm-blooded animals (including humans) in need of such treatment in the form of pharmaceutical compositions of known composition. The present invention also provides a pharmaceutical composition comprising a compound of Formula I, or a salt or N-oxide thereof, as hereinbefore defined, together with a pharmaceutically acceptable diluent or carrier. These compositions are preferably in a form suitable for oral administration (e.g. tablets, capsules, solutions, suspensions or emulsions) or parenteral administration (e.g. injectable aqueous or oily solutions or injection emulsions).

For therapeutic or prophylactic purposes, the compounds of formula (I) may also be advantageously administered together with another generally known agent capable of treating one or more of the diseases or conditions mentioned above.

The compound of formula I (or optionally a pharmaceutically acceptable salt thereof) may generally be administered to a human such that it receives, for example, a daily oral dose of up to 50 mg / kg body weight (preferably up to 10 mg / kg) or daily parenteral dose of up to 5 mg / kg body weight. (preferably up to 1 mg / kg), optionally subdivided, wherein the exact amount of compound (or salt) administered and the route and form of administration depend on the size, age and sex of the subject being treated and the particular disease or condition, treated according to known medical principles.

In addition to the aforementioned use in human therapy, the compounds of formula I are also suitable for the veterinary treatment of similar conditions occurring in commercially valuable warm-blooded animals such as dogs, cats, horses and cattle.

In this treatment, the compounds of formula I are generally administered in an analogous amount and in an analogous manner to that in human medicine. The compounds of formula I are also valuable as pharmacological agents in the development and standardization of test systems for evaluating the effects of AII in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice as part of ongoing research into new and improved therapeutic agents.

Examples of the invention

The invention is illustrated by the following non-limiting examples wherein, unless otherwise stated, a) the concentration and evaporation are carried out under vacuum in a rotary evaporator, b / operations are carried out at room temperature, i.e. in the range 10 to 26 ° C, c / flash column chromatography is performed on ITerck Kleselgel 60 / Nr. No. 9335 / supplied by fou

E. ITlerck, Darmstadt, Germany, d / yields, if given, They are informative only and do not necessarily represent the maximum achievable with careful execution of the procedure,

- | The e / H NYR spectra are usually determined at 200 ΠΉζ in deuterochloroform (CDClg) using tetramethylsilane (TITo) as internal standard and expressed as chemical shifts (delta values) in parts per million (ppm) relative to TYS using standard abbreviations for labeling main peaks: s - singlet, m - multlplet, t - triplet, br - wide, d - doublet f /¹³The C NITR spectra are typically determined at 100 µHz in CDCl 3₃ or dg-dimethylsulphoxide (dg-DITO) using a solvent signal As an internal standard and expressed as chemical shifts (delta values) in ppm relative to Tfis, g (all end products had satisfactory microanalysis and h) 1H-tetrazol-5-yl means 1 H -1,2,3,4-tetrazol-5-yl.

Example 1 ml of 6 mol / l hydrochloric acid is added to a solution of 600 mg of ethyl 2,6-dimethyl-4 - [(2)]^yN - (2-triphenylmethyl-2H-tetrazol-5-yl) -phenyl-4-yl) methoxy-7-pyridine-3-carboxylate (A) in 15 mL of dioxane and stirred for 3 h. The volatiles were evaporated and the residue stirred in 20 ml of a mixture of 1 volume of ethanol and 3 volumes of ether for 30 min. The insoluble solid was filtered off and recrystallized from a mixture of 1 volume of ethanol and 1 volume of methanol to give ---- 270 mg of ethyl 2: 6,6-methyl-4 - [(2 ') - 1 H] -1H. tetrazol-5-yl (biphenyl-4-yl) methoxy-7-pyridine-3-carboxylate hydrochloride as a white powder, m.p. 205 ° C.

NfrR (dg-DfiSO, d6-acetic acid): 1,2 (t, 3H), 2,6 (s, 3H), 2,7 (s, 3H), 4,4 (q, 2H), 5 1.5 (s, 2H), 7.2 (d, 2H), 7.4 (d, 1H), 7.5526

-7.55 (m, 3H), 7.67-7.75 (m, 2H).

Mass spectrum (Negative fast atom bombardment) -in FA 9), DIYSO (glycerol) GLY (J): 423 (MH +), 234, 194.

fflrocanalysis: calculated for C23H24N5O3.HCl: 61.9% C,

H, 5.2; N, 15.0. Found: C, 61.7; H, 5.0; N, 14.9.

The starting material (A) is obtained as follows:

206 mg of sodium hydride in a 50% dispersion in mineral oil is added to a stirred solution of 1.0 g of 1,4-dihydro-2,5-dimethyl-4-oxopyridine-3-carboxylate (obtained as described in (Tonatshefte fíir Chemie, 1969) 100 (132) in 25 ml of N, N-dimethylformamide (DIYF), and the mixture is stirred at 50 ° C until hydrogen evolution ceases, and then 2.36 g of 5- (2- (4'-bromomethylbiphenylyl) -7-2) are added. -triphenylmethyl-2H-tetrazole (prepared according to European patent 0291959) and stirred for 30 min at 50 ° C. ⁰C and then 72 h at room temperature. The solvent was evaporated and the residue was partitioned between 30 mL of ethyl acetate and 30 mL of water. The organic layer was separated, washed with 30 mL of saturated sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by flash chromatography. eluting with a mixture of ethyl acetate and hexane (1: 1 by volume, gradually changing to 9: 1) to give 2.38 g of ethyl 2,6-dimethyl-4 - [(2 ') - (2-triphenylmethyl) -2H- tetrazol-5-yl (biphenyl-4-yl) methoxy-7-pyridine-3-carboxylate (A) in the form of a foam.

NIYiR (dg-DfY1SO, d6-acetic acid): 1.2 (t, 3H), 2.4 (s), 3H), 2.45 (s, 3H), 4.3 (q, 2H), 5 2 (s, 2H), 6.35-5.95 (m, 5H), 7.0 (s, 1H), 7.15 (d, 2H), 7.25-7.4 (comp. M, 11H], 7.45-7.75 (complex m, 3H), 7.85 (dd, 1H).

- (-) - (Cg-DiSOSO): 69.0 (benzylic CH 2). ..... ~

Examples 2 to 6

Analogous to the procedure of Example I, using the appropriate starting compounds of the formula III, where L is triphenylmethyl, the following compounds are obtained in a yield of 50 to 80%:

Example 2

Methyl-2,5-dimethyl-4- [2 '- (1 H -tetrazol-5-yl) -phenyl-4-yl] -methoxy-yoyl-dine-3-carboxylate hydrochloride, m.p. 137-140 ° C.

NMR (d 6 -DMSO, d 6 -acetic acid): 2.6 (s, 3H), 2.7 (s, 3H), 3.9 (s, 3H), 5.4 (s, 2H), 7 2 (d, 2H), 7.4 (d, 2H), 7.45-7, 75 (complex m, 5H).

Mass spectrum (in FA3, DMSO / GLY): 414 (MH) &amp; lt; + &amp; gt ;, 234.

Microanalysis:

for? 23? 21? 5? 3'HCl.H_?H, 5.1; N, 14.9. Found: C, 58.9; H, 4.8; N, 14.8.

Example 3

2,6-Dimethyl-4- [2 '- (1H-tetrazol-5-yl) -phenyl-4-yl] methoxy-7-pyridine hydrochloride, m.p. 225 ° C.

NMR (d 6 -DMSO, d 6 -acetic acid): 2.5 (S, 6H), 5.4 (s, 2H), 7.2 (d, 2H), 7.3 (s, 2H), 7 , 45 (d, 2H), 7.55-7.8 (complex m, 4H),

Mass spectrum (-in FA3, DMSO (GLY): 355 (MH)).

234, 122.

Microanalysis:

H, 4.8%; N, 17.8% calculated: C, 64.2;_Ř Found: C, 63.7; H, 5.2; N, 18.0.

Example 4

2-methyl-5,5,7,3-tetrahydro-4 - [(2 ') - (1 H -tetrazol-5-yl) biphenyl-4-yl] methoxyquinoline hydrochloride, m.p. 222-223 ° C.

NMR (d 6 -DMSO): 1.7-1.9 (m, 4H), 2.55-2.7 (m, 2H), 2.7 (s, 3H),

28 2.95-3.05 (m, 2Η), 5.4 (s, 2H), 7.2 (d, 2H), 7.4 (d, 2H), 7.45 (s, 1H)

7.5-7.8 (complex m, 4H), 12.9 (br, 1H).

Mass spectrum (in FAB, DMSO-d6): 396 (M-H), 234.162.

fYlkroanalysis:

for C 24 H 23 N 5 O.HCl.0.13Η₂0 calculated: 66.0% C, 5.6% H, 16.1% N, 0.5% H₂Found: 65.9% C, 5.7% H, 16.0% N, 0.3% h₂° Example 5

2-ethyl-5,5,7,5-tetrahydro-4 - [(2 ') - (1H-tetradol-5-yl) biphenyl-4-yl] methoxyquinoline hydrochloride, m.p. 232-233 ° C.

NiYR (dg-DiYlSO): 1.3 (t, 3H), 1.7-1.9 (m, 4H), 2.6-2.7 (m, 2H),

2.9-3.0 (m, 4H), 5.5 (s, 2H), 7.2 (d, 2H), 7.4 (s, 1H), 7.45 (d, 2H),

7.55-7.8 (complex m, 4H).

Mass spectrum (-in FAB, DfYSO (GLY): 410 (M-H) -, 234; 176.

Ik Microanalysis: calculated for C,0 02 25 25 ^ ^ 0 ^ ^ 01 01: C, 67.0%; H, 5.9%; N, 15.6%; N, 8.2% Cl.

Example 6

6,7-dihydro-2-methyl-4- [2 '- (1H-tetrazol-5-yl) -phenyl-4-yl] methoxy-7H-cyclopenta] -pyridine hydrochloride, m.p. 210-212 ° C. ....... “.....

NiYR (dg-DHlSO): 2.1-2.3 (m, 2H), 2.65 (s, 3H), 2.9 (t, 2H), 3.2 (m, 2H), 5.4 (s, 2H), 7.2 (d, 2H), 7.4 (d, 2H), 7.45 (s, 1H), 7.55-7.75 (complex m, 4H).

FAB, DIYSO (GLY): 382 (IY-H),

234, 148.

ÍTíikroanalýza:

why₂₃H2₁H, 5.3; N, 16.3. Found: C, 65.7; H, 5.4; N, 16.8.

The necessary starting materials of formula III used in Examples 2 to 6, corresponding to the starting material A in Example 1, were prepared in the yields of 50 to 70% analogously to Example 1 as follows:

Example 2A (Tethyl-2,6-dimethyl-4- [2] ^of- (2-Triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-yl) methoxy-7-pyridine-3-carboxylate, isolated as a foam.

NIR (d 6 -DISO, d 6 -acetic acid): 2.4 (s, 3H), 2.45 (s), 3H (3.7), 3H), 5.1 (s, 2H), 9 (dd, 5H), 7.0 (s, 1H), 7, G5 (d, 2H),

7.15-7.3 (complex m, 11H), 7.5-7.8 (complex m, 3H), 7.8 (dd, 1H).

Starting material methyl 1,4-dihydro-2,5-dimethyl-4-oxopyridine-3-carboxylate, obtained as a solid, m.p. 218-219 ° C from methyl 3-aminocrotonate and diketene by a procedure analogous to that described in Ionatshefte filar Chemie, 1969 100, 132 for the preparation of ethyl 1,4-dihydro-2,6-dimethyl-4-oxopyridine-3-carboxylate.

Example 3A

2,6-Dimethyl-4 - [(2 ') - (2-trifluoromethyl-2H-tetrazol-5-yl) biphenyl-4-yl] methoxy] pyridine, isolated in the form of a foam.

IR (dg-D 2 SO 5, d 6 -acetic acid): 2.5 (s, 5H), 5.2 (s, 2H), 6.85-6.95 (m, 6H), 7.0 (s), 2H (7.15 (d, 2H), 7.25-7.4 (complex m, 11H), 7.45-7.7 (complex m, 3H), 7.85 (dd, 1H)).

3C

Starting material 2,5-dimethyl-4 (1H) -pyridone, obtained according to J. Chem. Soc. (B), 1968, 856.

Example 4A

2-methyl-5,5,7,8-tetrahydro-4 - [(2)]^of(2-Triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-yl) methoxyquinoline, m.p. 156-155.5 ° C.

NfYR (dg-DIHSO): 1, 6-1, 85 (complex m, 4H), 2.4 (s, 3H),

2.55-2.65 (m, 2H), 2.55-2, 75 (m, 3H), 5.1 (s), 3H (s), 5.7 (s), W, 6.9 (dd, 6H) (7.1 / d, 2H), 7.2-7.4 (complex m, 11H), 7.4-7.65 (complex m, 3H), 7.8 (dd, 1H),

Starting material 2-methyl-5,6,7, 5-tetrahydro-4 (1H) -quinolone, obtained according to Liebigs Ann. Chem., 1982, 1656.

Example 5A

2-ethyl-5,6,7,7,8-tetrahydro-4 - [(2 ') - (2-triphenylmethyl- [-2H-tetrazol-5-yl] phenyl-4-yl) methoxy] quinol), m.p. Mp 111-115 ° C.

NTTCR (dg-D 6 SO 2): 1.2 (t, 3H), 1.6-1.8 (m, 4H), 2.5-2.8 (complex m, 6H), 5.1 / s, 2H (6.75 (s, 1H), 5.3-5.9 (m, 6H), 7.1 (d, 2H)),

7.25-7.4 (complex m, 11H), 7.45-7.7 (complex m, 3H), 7.8 / dd,

1H /,

Starting material - a mixture of 9 parts by weight of 2-ethyl-5,5,7,8-tetrahydro-4 (1H) -quinolone and 1 part by weight of 2-ethyl-4 (1H) -quinolone obtained as 2-ethyl-4) 1H-quinolone similarly,

As in the preparation of 2-methyl-5, 5, 7, 5-tetrahydro-4 (1H) -quinolorin in Liebigs Ann. Chem., 1982, 1656; Purification by flash chromatography eluting with a mixture of 1 volume ethyl acetate and 1 volume hexane.

Example 6A, 7-dlhydro-2-methyl-4 - [[2- (2-triphenylmethyl) -2H-tetraazol-5-yl] biphenyl-4-yl] methoxy] -5H-cyclopenta [b] pyridine, isolated in the form of oenya.

Rf (dg-DmSO): 1.9-2.1 (m, 2H), 2.4 (s, 3H), 2.7 (t, 2H), 2.3 (t, 2H), 5.1 (s, 2H), 5.75 (s, 1H), 6.3-6.3 (m, 6H), 7.1 (d, 2H),

7.25-7.4 (complex m, 11H), 7.45-7.7 (complex m, 3H), 7.3 (dd, 1H).

Starting material - a mixture of 35 parts by weight of 2-methyl-1,5,5,7-tetrahydro-4 (1H) -cyclopenta] -7-pyridone and 15 parts by weight of 3-methoxycarbonyl-2-methyl-1,5,6,7-tetrahydro 4/1 H -cyclopenta / b -pyridone, obtained according to Heterocycles, 1982, 13, 239, purified by flash chromatography with ethyl acetate as eluent.

Example 7

A solution of 240 mg of ethyl 2,5-dimethyl-4- [**] 2^of- (1H-Tetrazol-5-yl) biphenyl-4-yl) methoxy-7-pyridine-3-carboxylate hydrochloride in 5 moles of 2 mol / L aqueous sodium hydroxide solution was heated under reflux for 2 h. The solution was cooled and acidified to pH 3 with 6 mol / L hydrochloric acid. The precipitated solid was filtered off and triturated with hot methanol to give 67 mg of 2,5-dimethyl-4- [2 '- [1H-tetrazol-5-yl] biphenyl-4-yl] methoxy] pyridine-3-carboxylic acid in 237 ° C.

NiR (dg-DfrSO, d 6 -acetic acid): 2.45 (s, 3H), 2.55 (s, 3H), 5.3 (s, 2H), 7.1 (s, 1H), 7 2 (d, 2H), 7.4 (d, 2H), 7.4-7.75 (complex m, 4H).

Mass spectrum (DfTSO / OLY): 400 (MH +), 166.

(Ticroanalysis:

why₂₂H_igN₅L)₃.D, 5 H₂0 calculated: 64.5% C, 4.9% H, 17.1% N, found 64.5% C, 4.5% H, 17.0% N.

Example 8

Analogous to Example 1, 2,6-dimethyl-3-hydroxymethyl-4- [2 '- (2-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-yl] methoxy-7-pyridine (A) yielded 2 6-dimethyl-3-hydroxymethyl-4- (2 '- (1 H -tetrazol-5-yl) biphenyl-4-yl) methoxy] pyridine hydrochloride as a solid, m.p. 224 ° C.

N-Y-R (dg-DffSO, d 6 -acetic acid), 2.55 (s, 3H), 2.6 (s, 3H), 4.6 (s, 2H), 5.4 (s, 2H) 7.2 (d, 2H), 7.45 (s + d, 3H), 7.55-7.65 (m, 2H), 7.6-7, 65 (m, 2H).

Mass spectrum (DMSO / GLY): 385 (phyl-H).

(Ticroanalysis:

for Ν ^ 0₂· HCl.0.5H₂H, 5.3; N, 16.0. Found: C, 60.9; H, 4.9; N, 15.8.

The starting material (A) is prepared as follows:

mg of lithium borohydride is added to a solution of 800 mg of ethyl-2,6-dimethyl-4 - (*) 2 over 10 min.^,- (2-Trenylphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-yl) methoxy-7-pyridine-3-carboxylate in 25 mL of tetrahydrofuran (THF), stirred at 0 ° C under argon. The solution was stirred at room temperature for 15 h, cooled to 0 ° C and 100 mL of water was added. The mixture is extracted twice with 50 ml of dichloromethane and the extracts are washed with 50 ml of saturated sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by flash chromatography with a mixture of 1 volume of methanol and 19 volumes of dichloromethane as the eluent to give 246 mg of 2,6-dimethyl-3-hydroxymethyl-4 - [(2 ') -] 2- triphenylmethyl-2H-tetrazol-5-yl (biphenyl-4-yl) methoxy-7-pyridine (A) in the form of a foam.

N 1 R 1 (d 6 -D 15 F, d 6 -acetic acid): 2.55 (s, 3H), 2.55 (s, 3H), 4.7 (s, 2H), 5.4 (s, 2H), 6.9-7.0 (m, 5H), 7.2 (d, 2H), 7.25-7.45 (complex m, 12H), 7.45-7.3 (complex m, 3H), 7.9 (dd, 1H).

Examples 9 to 14

In analogy to Example 1, the following compounds of formula I are obtained in the yield of 76 to 91% from the corresponding compound of formula III, where L is 3-enylmethyl:

EXAMPLE 9 (2-Ethyl-5-methyl-4 - [(2 ') - (1H-tetrazol-5-yl) biphenyl-4-yl) methoxy] pyridine-3-carboxylate hydrochloride, m.p. 109-190 ° C.

NIIR (d 6 -Di 2 SO 2) d -acetic acid: 1.3 (t, 3H), 2.7 (s, 3H), 2.9 (q, 2H), 3.9 (s, 3H), 5 5 (s, 2H), 7.2 (d, 2H), 7.4 (d, 2H), 7.557.0 (complex m, 5H).

Mass Spectrum (Positive Fast Atom Bombardment / + in FAB), DffSO (nitrobenzyl alcohol): 859 (2Ιϊΐ + Η)⁺, 430 / (Y) + H /⁺.

fficroanalysis:

for ^ 24 ^ 23 ^ 5 ^ 3 * ^^^ ⁱⁿC, 61.9; H, 5.2; N, 15.0. Found: C, 61.0; H, 4.9; N, 14.9.

Example 10 [r_E4-Methyl-5-ethyl-2-methyl-4- [* (2 *) - (1H-tetrazol-5-yl) biphenyl-4-yl] methoxy] pyridine-3-carboxylate hydrochloride, m.p. 152-154 ° C .

NfYiR (dg-DTSO) d -acetic acid: 1.35 (t, 3H), 2.6 (s), 3H), 3.0 (q, 2H), 3.9 (s, 3H), 5 1.5 (s, 2H), 7.2 (d, 2H), 7.4 (d, 2H), 7.534

-7% (complete m, 5H).

Mass Spectrum (+ ve FAB, DMSO) (m-nitrobenzyl alcohol): 430 (ΓΓ + Η / +).

fficroanalysis:

for ^ 24 ^ 23 ^ 5 ^ 3 ^^¹ calculated: C 61.9%, H 5.2%, N 15.0%, found C 61.6%, H 5.4%, 14.5 N.

EXAMPLE 11 Ethyl 2,5-diethyl-4 - [(2 ') - [1 H -tetrazol-5-yl] biphenyl-4-yl] methoxy] yridine-3-carboxylate hydrochloride, m.p. 174-175 ° C.

ΝΠΓ.Ρ (dg-DfYSG / d 6 -acetic acid): 1.2-1.4 (m, 6H), 2.85-3.1 (m, 4H), 3.9 (s, 3H), 5.5 (s, 2H), 7.2 (d, 2H), 7.4 (d, 2H), 7.55-7.8 (complex m, 5H).

Mass Spectrum / + ve FAB, DlfSO (m-nitrobenzyl alcohol): 444 / (ϊ + Η)⁺.

fficroanalysis:

why₂₅H₂₅N₅O₃H, 5.4; N, 14.5. Found: C, 62.0; H, 5.4; N, 14.4.

Example 12

6,7-dihydro-2-ethyl-4- [2- (1H-tetrazol-5-yl) biphenyl-4-yl] methoxy-7H-cyclopenta [b] pyridine hydrochloride, m.p. 212 DEG-214 DEG C. (dec.) .

NMR (d 6 -DITSO): 1.3 (t, 3H), 2.1-2.3 (m, 2H), 2.8-3.0 (m, 4H), 3.2 (t, 2H) 5.45 (s, 2H), 7.2 (d, 2H), 7.4-7.5 (m, 3H), 7.5-7.75 (m, 4H).

Mass Spectrum / + ve FAB, DfYiSO (m-nitrobenzyl alcohol): 398 (ff + H)⁺.

fficroanalysis:

for -24^H23^N5^{Q, HCl v}yP^očteno Found: C, 65.0; H, 5.9; N, 16.0.

Example 13

2,5-dimethyl-3-phenyl-4- [2- (1H-tetrazol-5-yl) -phenyl-4-yl] methoxy] -pyridine hydrochloride, m.p. 144 DEG C. (decomposition).

NfY1R (dg-DPUSO) d-acetic acid: 2.4 (s, 3H), 2.7 (s, 3H), 5.4 (s, 2H), 7.1 (d, 2H), 7 2 (d, 2H), 7.3-7.4 (m, 2H), 7.4-7.8 (complex m, 8H).

Mass Spectrum (+ ve FAB, Df /SO) (m-nitrobenzyl alcohol): 868 (2ΙΥΪ + Η / +, 434 (m + H))⁺.

fifiicroanalysis:

for 02γΗ22Ν ^ 0.ΗΟ1.0,5Εί20 · 0.53Η2θ calculated 67.3% C, 5.8%

H, 13.5; N, 1.9%. Found: C, 66.9; H, 6.0; N, 13.3.₂0.

Example 14

Allyl-2,6-dimethyl-4 - [(2H) - (1H-tetrazol-5-yl) biphenyl-4-yl] methoxy] pyridine-3-carboxylate hydrochloride, m.p. 177-179 ° C.

Ni (CDCl 3): 2.6 (s, 3H), 2.7 (s, 3H), 4.3-4.85 (d, 2H),

5.2-5.4 (m, 2H), 5.45 (s, 2H), 5.8-6.0 (m, 1H), 7.1-7.2 (d, 2H), 7, 3-7.9 (d, 2H), 7.5-7.8 (complex m, 5H).

H_msweep spectrum (+ ve FAB, DfYlSO) / ntrobenzyl alcohol /: 442 (fifi + H)⁺.------------------------------------------------- -------------------------------------------------- Necessary starting materials of the formula III used in Examples 9 to 11 14, corresponding to the starting material A in Example 1, were obtained in a manner analogous to Example 1 in a yield of 63 to 81% as follows:

Example 9A

Ethyl 2-ethyl-6-methyl-4- (2 '- (2-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-yl) methoxy] pyridine-3-carboxylate, m.p. 157-153 ° C) decomposition/.

NiYiR / CDCl3₃[Α]: 1.3 (t, 3H), 2.5 (s), 3H (2.8), q (2H), 3.85 (s), 3H (5.0), 2H (6.5) (s, 1H), 5.85-7, Q (complex m, 6H), 7.15 (s, 4H), 7.2-7.5 (complex m, 12H), 7.9-8.0 (m, 1H).

Mass Spectrum (+ ve FA8, DMSO / m-nitrobenzyl alcohol): 672 (ΡΠ + Η / +).

Starting material methyl 1,4-dihydro-2-ethyl-5-methyl-4-oxopyridine-3-carboxylate, obtained from methyl 3-amino-2-oentenoate and dlketene in analogy to the procedure of Example 2A. mp 148-150 ° C.

NITR / CDC1₃(1.25 (t, 3H), 2.3 (s), 3H), 2.7 (q, 2H), 3e (s, 3H), 6.7 (s, 1H).

Mass Spectrum (Chemical Ionization, Ammonia): 195 (IY] + H)⁺.

Example 10A (T.ethyl-6-ethyl-2-methyl-4 - [(2 ') - [2-triphenylmethyl-2H-tetrazol-5-yl] biphenyl-4-yl) methoxy] pyridine-3-carboxylate, temperature mp 57-70 ° C.

WR / CDC1₃(1.25 (t, 3H), 2.5 (s), 3H), 2.75 (q, 2H), 3.85 (s, 3H), 5.05 (s, 2H), 5.1 (s, 1H), 5.9-7.0 (complex m, 5H), 7.1-7.5 (complex m, 22H), 7.9-3.0 (m, 1H) ._____________________________________________________________________________

Mass spectrum (+ ve FA9, DIDSO (m-nitrobenzyl alcohol)): 672 (Π. + + / +).

Starting material methyl 1,4-dlhydro-6-ethyl-2-methyl-4-oxopyridine-3-carboxylate, obtained by the following procedure:

A mixture of 5 g of methyl 3-aminocrotanate and 10 g of 5- (1-hydroxy-37-propylldene) -2,2-dimethyl-1,3-dioxane-4,5-dione obtained according to J. Org. Chem., 1973, 43, 2037] was heated at 120 ° C for 1 h. The residue was cooled to room temperature, treated with 35 ml of a mixture of 1 part of ether and 6 parts of hexane and allowed to stand for 18 hours. The solvent was then removed by decantation and the insoluble residue was purified by flash chromatography with a mixture of 1 volume of methanol and 9 volumes of dichloromethane as eluent to give 1 g of methyl 1,4-dihydro-5-ethyl-2-methyl-4- 176 DEG-130 DEG C. oxopyridine-3-carboxylate as a yellow solid.

f &lt;9 (CDCl 3): 1.2 (t, 3H), 2.45 (s, 3H), 2.65 (q, 2H), 3.8 (s, 3H), 6.3 (s), 1H /.

Mass Spectrum (Chemical Ionization, Ammonia): 196 (IHH-H)⁺.

Example 11A Ethyl-2,6-diethyl-4- [5]^of(2-Triphenylmethyl-2H-tetrazol-5-yl) -phenyl-4-yl) methoxy-7-pyridine-3-carboxylate, m.p. 59-54 ° C.

NIY! P / CDC1₃(1: 2-1, 4 (m, 6H), 2.5-2.9 (m, 4H), 3.85 (s), 3H), 5.05 (s, 2H), 5.5] s, 1H), 6.9-7.0 (complex m, 6H), 7.1-7.55 (complex m, 16H), 7.9-3.0 (m, 1H).

Mass Spectrum / + ve FAB, Dff.SO/m- nitrobenzyl alcohol/: 5-6 (ΓΓί + Η)⁺.

Starting material methyl 2,6-diethyl-1,4-dihydro-4-oxopyridine-3-carboxylate, obtained from methyl 3-amino-2-pentenoate and 5 ---------- / 1- hydroxypropylidine / -2,2-dimethyl-1,3-dioxane-4,5-dione in analogy to Example 10A as a solid, m.p. 127-130 ° C.

NMR / CDCl3₃(1.2-1.35 (m, 6H), 2.4-2.9 (m, 4H), 3.8 (s, 3H), 6.3 (s, 1H)).

Mass Spectrum (Chemical Ionization, Ammonia); 210 (MH + H).

EXAMPLE 12A 7,7-Dihydro-2-ethyl-4- [2 '- (2-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-yl] methoxy-5H-cyclopenta] -7-pyrrolidine as an amorphous solid substances.

NIYr (d 6 -DiO 2): 1.19 (t, 3H), 1.92-2.08 (m, 2H), 2.57-2.77 (m, 4H), 2.84 (t, 2H) 5.13 (s, 2H), 6.77 (s, 1H), 6.83-6.92 (complex m, 6H), 7.11 (d, 2H), 7.25-7.40) complex m, 11H (7.43-7.58 (m, 3H), 7.82 (dd, 1H)).

ÍTicroanalysis:

H, 5.9; N, 11.3. Found: C, 79.7; H, 5.6; N, 10.8.

Starting material 2-ethyl-1,5,6,7-tetrahydro-4- (1H) -cyclopenta / b7pyridone, obtained as follows:

A mixture of 7.7 g of 4- (1-cyclopenten-1-yl) morpholine and 20 g of 5- (1-hydroxypropylidin-2,2-dimethyl-1,3-dioxane-4,6-dione) obtained according to J. Org . Chem., 1978, 43, 2087] was heated at 120 ° C for 1 h. The residue was then cooled to room temperature and purified by flash chromatography with a mixture of 1 volume of methanol and 19 volumes of dichloromethane as eluent to give a mixture of 6,7-dihydro-2-ethylcyclopenta [b] pyran-4 (5H) -one and 4- (1,3-dioxobutyl) morpholine. The mixture was treated with 150 ml of concentrated ammonia solution at 120 ° C for 15 h and then cooled to room temperature. The volatiles were evaporated and the residue was partitioned between 300 ml of a mixture of 1 volume of ether and 1 volume of ethyl acetate and 200 ml of 2M sodium hydroxide solution. The aqueous layer was separated, acidified to pH 6 with concentrated hydrochloric acid, and extracted with ethyl acetate (3 x 100 mL) and chloroform (3 x 100 mL). The organic extracts were washed once with saturated sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated and the combined residues were purified by flash chromatography with a mixture of 1 volume of ethyl acetate and 9 volumes of methanol as eluent to give 2.2 g of 2-ethyl-1,5,5,7-tetahydro-4 / 1H (cyclopenta) -7-pyridone as a light yellow solid, m.p. 212 DEG-214 DEG C. (decomposition).

NMR (d 6 -DMSO): 1.5 (t, 3H), 1.96-2.04 (m, 2H), 2.35-2.6D (m, 4H), 2.78 (t, 2H) 11.33 (bs, 1H).

Mass Spectrum (Chemical Ionization, Ammonia): 164 (M + H)⁺.

Example 13A

2,6-dimethyl-3-phenyl-4- [t] 2^,2-Triphenylmethyl-2H-tetrazol-5-yl / biphenyl-4-yl / methoxy-7-pyridine, m.p.

NMR / CDCl3₃(2.3, s, 3H), 2.5 (s), 3H, 4.95 (s, 2H), 5.6 (s, 1H), 5.9 (m complex, 8H), 7, Δ (d, 2H), 7.1-7.5 (complex m, 17H), 7.9 (m, 1H).

Mass Spectrum (+ vs FA3, DMSO / m-nitrobenzyl alcohol): 676 (M + H)⁺.

Starting material 2,5-dimethyl-3-phenyl-4 (1H) -pyridone, obtained from 2,6-dimethyl-3-phenyl-4H-pyran-4-one and ammonia in an analogous manner to that described in J. Am. Chem. Soc., 1974, 96 (4) (1152) as a solid, m.p. 231 DEG-235 DEG C. (decomposition).

NMR / CDCl3₃(dg-DMSO): 2.1 (s, 3H), 2.3 (s, 3H), 6.2 (s, 1H),

7.1-7.5 (complex m, 5H).

Mass Spectrum (Electron Impact Ionization): 199 (M)⁺, 170, 128, 115.

- 40 Example 14A

Allyl-2, S-dimethyl-4- (2 '- (2-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-yl) methoxy7oyrldine-3-carboxylate, m.p. 55-70 ° C (dec.) .

NfR (dg-DfISO): 2.3-2.4 (2) _{x S}, 5H /, 4.7-4.8 (m, 2H), 5.1-5.4 (m, 4H), 5.3-5.0 / m, 1 1 /, 5.3-7, 35 (complex m, 24H).

Mass spectrum (+ ve PAR, D 30) (m-nitrobenzyl alcohol): 634 (t + H)⁺.

Starting material allyl-1,4-dihydro-2,5-dimethyl-4-oxopyridine-3-carboxylate, obtained from allyl-3-amlnocrotonate and dlketene analogously to Example 2A as a solid, m.p. 139-141 °. C.

Nfr (dg-DETO): 2.1-2.25 (s, 5H), 4.55-4.75 (s, 2H), 5.2-5.5 (m, 2H), 5.3- 5.1 (m, 2H), 11.2-11.4 (br s, 1H).

Example 15

Analogous to Example 1, methyl 2-chloro-5-methyl-4- [2 '- (2-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-yl] methox-7-pyridine-3-carboxylate (A) yields methyl 2-chloro-6-methyl-4 - [(2 ') - (1H-tetrazol-5-yl) biphenyl-4-yl] methoxy] pyridine-3-carboxylate as a white powder in 50% yield mp 204-207 ° C.

NfR (dg-DfiSO, d6-acetic acid): 2.45 (s, 3H), 3.35 (s),

3H), 5.3 (s, 2H), 7.1-7.3 (complex m, 3H).

Mass Spectrum (+ ve FA 3, D 6 SO 2 / m-nitrobenzyl alcohol): 435 (MH +)⁺.------------------------------------------------- ----------- The starting material (A) is obtained as follows:

a) 17.5 g of peanut potassium acetate are added to a solution of 50 g of 5- (2- (4'-bromomethyl-biphenylyl) -7-2-triphenyl-ethyl) -41

-2H-tetrazole (obtained according to published European Patent Application No. 0291959) and 100 mg of 1,4,7,10,13,16-hexaoxacyclooctadecane in 500 ml of 1,2-dimethoxyethane (DfT.F) and the mixture was stirred for 20 h Heat to reflux. The insoluble material is filtered off and the residue is triturated with a mixture of 1 volume of ethyl acetate and 4 volumes of hexane to give 41.3 g of 5- (2- (4'-acetoxymethylbiphenylyl) 7-2-triphenylmethyl-2H-tetrazole) as a cream. m.p. 119-121 ° C.

NfYiR / CDCl3₃(2.1 / s, 3H), 5.0 (s, 2H), 6.8-6.95 (complex m, 8H), 7.2-7.55 (complex m, 14H), 7, 9-8.0 (m, 1H).

b) A solution of 41.3 g of (B) in 200 ml of THF was added over a period of 40 min to a suspension of 4.1 g of lithium borohydride in 400 ml of THF, stirred under argon at 0 ° C. The mixture was stirred at room temperature for 20 h and then cooled to 0 ° C. 40 ml of 20% aqueous citric acid solution are added and the mixture is diluted with 600 ml of saturated sodium chloride solution. The mixture is extracted twice with 500 ml of ethyl acetate and the extracts are washed with 500 ml of water and 500 ml of saturated sodium chloride solution. The combined extracts were dried over magnesium sulphate and the volatiles were evaporated. The residue was purified by flash chromatography using a mixture of 2 volumes of ethyl acetate and 3 volumes of hexane as eluent to give 17.4 g of 5- / 2- / 4.^?Hydroxymethylbiphenylyl (7,7-2-triphenylmethyl-2H-tetrazole) (0) as a white solid, m.p. 168-169 ° C (after recrystallization from a mixture of 1 volume of ethyl acetate and 9 volumes of hexane).

NFR / CDC1₃/: 4,6/_with2H, 6.85-7.0 (m, 5H), 7.2-7.5 (multiplex, 16H), 7.9-8.0 (m, 1H).

c) A mixture of 1.53 g of compound (0), 700 mg of methyl 2,4-dichloro-6-methylpyridine-3-carboxylate (obtained according to Synthesis, 1988, 479), 400 mg of potassium t-butoxide, 10 mg of potassium fluoride and 10 mg of 1,4,7,10,13,16-hexaoxacycloocta42 decane in 5 ml of acetonitrile was heated at 50 ° C for 24 h. The volatiles were evaporated and the residue was partitioned between 20 ml of water and 20 ml of dichloromethane. The organic phase is separated, washed with 20 ml of saturated sodium chloride solution and dried over magnesium sulfate. The volatiles were evaporated and the residue was purified by flash chromatography with ethyl acetate as eluent to give 1.25 g of methyl 2-chloro-5-methyl-4 - [(2 '-) - 2-triphenylmethyl-2H-tetrazole-5]. 1-yl (biphenyl-4-yl) methoxy-7-pyridine-3-carboxylate (A) in the form of a foam.

NIT.R / CDC1₃(2.45 (s, 3H), 3.9 (s, 3H), 5.05 s, 2H), 5.5-7.95 (complex m, 24H).

Examples 15 to 32

In analogy to Example 1, the following compounds of formula I are obtained from the corresponding compound of formula III, wherein L is triphenylmethyl, in a yield of 75-91%:

Example 15 (Ylethyl-2-methoxymethyl-5-methyl-4- [2 '- (1H) -tetrazol-5-yl) -phenyl-4-yl] -methoxy] -pyridine-3-carboxylate dihydrochloride, m.p. 15Θ-159 ° C.

NIT.R (dg-DIT.SD) dd / acetic acid /: 2.7 / s, 3H / 3.4 / s, 3H / 3.85 / s, 3H / 4.7 / s, 2H (5.5), 2H (7.2), d (2H), 7.4 (d, 2H), 7.5-7.8 (complex m, 5H).

Mass Spectrum (+ ve FA3, DOTSO (m-nitrobenzyl alcohol)): 446 (ΓΤ + Η / +).

fTlkroanalysis:

for C24^H23^N5^G4 * ⁱⁿyP ° ^^terto N, 14.5. Found: C, 50.0; H, 4.9; N, 14.5.

Example 17 * u.

1.1. (C-Id ethoxyethyl) -o-methyl-4- [2 '- (1 H -tetrol-5-yl) -phenyl-4-yl] -methoxy] -pyridine-3-carboxylate hydrochloride, m.p. 134 a? 135 ° C.

Δ (CDCl 3): 2.7 (s, 3H), 3.1-3.25 (m, 5H), 3.55 (t, 2H), 3.9 (s, 3H), 5 45 (s, 2H), 7.15 (d, 2H), 7.35 (d, 2H), 7.5-7.7 (m, 5H).

Mass Spectrum (+ ve FA3, DIlSO) (m-nitrobenzyl alcohol): 460 (Et + H)⁺.

ÍTicroanalysis:

H, 5.2; N, 14.1. Found: C, 50.6; H, 5.5; N, 14.1.

Example 18

Ethyl 5-methyl-2-phenyl-4- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methoxy] pyridine-3-carboxylate dihydrochloride, m.p. 143-151 °.

Δ (dg-DIYiSO): 1.0 (t, 3H), 2.7 (s, 3H), 4.1 (q, 2H), 5.5 (s, 2H), 7.2 (d, 2H) (7.4) (d, 2H), 7.5-7.8 (complex m, 10H).

Mass spectrum (+ in FA3, DITSD / GLY): 492 (Π1 + Η)⁺. ÍTicroanalysis:

for C2gH25N5Og.HCl.H2O N, 3.3%₂0, found h₂O.

calculated 63.5% C,

63.7% C, 5.1% H, 12.8% H 5.0%, N 12.4%, 3.9%

Example 19

Ethyl-2-iso-propyl-6-methyl-4- [2 '- (1H-tetrazol-5-yl) -phenyl-4-yl] -methoxy-7-pyridine-3-carboxylate dihydrochloride, m.p. 153-160 ° C.

NIYR (d 6 -DETO): 1.2 (t, 3H), 1.4 (d, 6H), 2.3 (s, 3H), 3.1-3.3 (m, 1H), 4, 3 (q, HH), 5.4 /_with2H, 7.2 (d, 2H), 7.4 (d, 2H), 7.5-7.9 (complex m, 5H).

mass spectrum / + in FAS, CHILDREN / m-nitrobenzyl alcohol /: 4 58 / ΠΓ + Η /⁺.

ííroroanalýza:

H, 5.9%; N, 13.7%.

3.5% H₂Found: C, 81.1; H, 6.2; N, 13.3; H, 3.7₂D.

EXAMPLE 20 Ethyl 6-methyl-2- (2-phenylethyl) -4- [2 '- (1') - (1H-tetrazol-5-yl) biphenyl-4-yl) methoxy] pyridine-3-carboxylatehyldryl chloride, m.p. Mp 130-181 ° C.

NIYiF? [α] D-D 6 SO 2 (d 6 -acetic acid): 2.7 (s, 3H), 3.0 (dd, 2H), 3.2 (dd, 2H), 3.9 (s, 3H), 5 (s, 2H), 5.9-7.4 (complex m, 9H),

7.5-7.75 (complex m, 5H).

Mass Spectrum (+ ve FAS, DIYoO / m-nitrobenzyl alcohol): 506 (PT + H)⁺.

(hicroanalysis:

why₂QH₂^ NgO₂H, C, 66.5; H, 5.0; N, 12.9. Found: C, 55.5; H, 5.3;

Example 21

Ethyl 5-methyl-2-propyl-4 - [(2 ') - (1 H -tetrazol-5-yl) biphenyl-4-yl] methoxy] pyridine-3-carboxylate hydrochloride, m.p. 137-139 ° C.

“- / dg -ΌΓΓ507: 0.9 / 1.3Η /, 1.2 / 1.3Η /, 1.5-1.3 / m, 2H /,

2.7 (s, 3H), 2.8-2.95 (m, 2H), 4.3 (q, 2H), 5.4 (s, 2H), 7.15 (d, 2H), 7 (s) 4 (d, 2H), 7.5-7.8 (complex m, 5H).

Mass Spectrum (+ in FA3, DMSO) (m-nitrobenzylalkahal): 453 (M + H)⁺.

fYircoanalysis:

H, 5.7; H, 14.0; N, 1.2% H2O. Found: C, 52.2%; H, 5.0%; 13.3%. n, 1.2% h₂O.

Example 22

Ethyl 5-methyl-2-propyl-4- [72 '- (1 H -tetrazol-5-yl) biphenyl-4-yl) methoxy] pyridine-3-carboxylateydrocyclohexyl, mp 152-153 ° C.

NIYiR (dg-DIYiSO, d6-acetic acid): 0.95 (t, 3H), 1.5-1.8 (m, 2H), 2.7 (s, 3H), 2.35 (t), 2H (3.7 / s, 3H), 5.5 (s), 2H), 7.2 (d, 2H), 7.4 (d, 2H), 7.5-7.8 (m, 5H) /.

Mass Spectrum (+ ve FA 3, D 33-33 (m-nitrobanyl alcohol)): 444 (Y + + H)⁺► mcroanalysis:

N, 14.5; N, 14.5. Found: C, 52.5; H, 5.5; N.

The required starting compounds of formula III used in Examples 15 to 22, corresponding to the starting material A in Example 1, were prepared in a similar manner to Example 1 in a yield of 57-37% as follows:

Example 1SA

IT; ethyl 2-methoxymethy 1-5-methyl 1-4 - [2 '- (2-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-yl] methoxy] pyridine-3-carboxylate, m.p. 59 to 70

NIYiR / CDC1₃(2.5: s, 3H), 3.4 (s), 3H), 3.35 (s), 3H (4.6), 2H), 5.05 (s, 2H), 5.55) s, 1H), 5.85-7.0 (m, 5H), 7.15 (s, 4H), 7.2-7.5 (complex m, 12H), 7.9-3.0 (m) , 1H).

The starting material methyl 1,4-dihydro-2-methoxymethyl-5-methyl-4-oxooyridine-3-carboxylate, obtained from methyl 3-amino-4-methoxy-2-butenoate / obtained according to European patent application no. 177955) and a diketene analogous to Example 2A in 25% yield as a resin.

NffR / CDC1₃(2.4 / s, 3H), 3.5 (s), 3H / 3.9 (m, 3H), 4.5 (s, 2H),

Example 17A

HCethyl 1- [2- (2-ethoxyethyl) -5-methyl-4 - [(2H) -triphenylmethyl-2H-tetrazol-5-yl] biphenyl-4-yl] methoxy] pyridine-3-carboxylate, m.p. to 57 ° C.

NffR / CDC1₃(2.5: s, 3H), 3.1 (t, 2H), 3.5 (s, 3H), 3.75 (t, 2H), 3.35 (s, 3H), 5, C (s, 2H7, S, 6 (s), 1H), 5.85-7.0 (m, 5H), 7.1-7.5 (complex m, 15H), 7.9-3.0 (m) , 1H).

Starting material methyl 1,4-dihydro-2- (2-methoxyethyl) -5-methyl-4-oxopyridine-3-carboxylate, obtained from methyl 3-amino-4- (2-methoxyethyl) -2-butenoate and of diketene in analogy to Example 2A in 17% yield as a solid, m.p. 158-151 ° C.

NffR / CDC1₃(2.3 '/ s, 3H), 3.1 (t, 2H), 3.4 (s, 3H), 3.7 (t, 2H), 3.9 (s, 3H), 4 (s, 1H).

Example 1SA

Ethyl 5-methyl-2-phenyl-4- [(2'-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-yl] methoxy] pyridine-3-carboxylate, m.p. 105 ° 0.

~ ~ ....... 'NffR / CDC1₃(1: C (t, 3H), 2.55 (s), 3H), 4.1 (o, 2H), 5.1 (s),

2H), 5.7 (s, 1H), 5.9-7.0 (m, 5H), 7.15-7.5 (complete m, 20H),

7.5-7.7 (m, 1 H), 7.9-3.0 (m, 1H).

Starting material ethyl 1, 4-dihydro-5-methyl-4-oxo-2-phenyloyridine-3-carboxylate, obtained from ethyl 3-amino-3-phenylpropenoate and diketene in analogy to Example 2A in 52¾ yield in -form^with m.p. 192-195 ° C.

IR (CDCl3) d -acetic acid: 0.9 (t, 3H), 2.4 (s), 3H (4.0) q, 2H (5.45) s, 1H), 7.4 (s, 5H).

Example 19A

Ethyl-2-isopropyl-5-methyl-4 - [[2- (2-trifluoromethyl-2H-tetrazol-5-yl) biphenyl-4-yl] methoxy] pyridine-3-carboxylate, m.p. 71-72 ° C.

R / CDC1₃Δ: 1.2-1.35 (m, 9H), 2.5 (s), 3H /, 2.9-3.1 (m), 1Η /, 4.35 (q, 2H), 5.0 (s, 2H), 5.5 (s, 1H), 6.85-7.0 (m, 6H), 7.1-7.5 (complex m, 15H), 7.9-3, D) m, 1H].

Starting material ethyl 1,4-dihydro-2-isopropyl-5-methyl-4-oxopyridine-3-carboxylate, obtained from ethyl-3-am, ino-4-methyl 1-2-pentenoate and diketene in an analogous manner to in the example

2A in 40% yield as a solid with a melting point of 153 to 150 ° C.

NffR / CDC1₃Δ: 1.2-1.4 (m, 9H), 2.3 (s, 3H), 2.9-3.1 (m), 1Η /, 4.3 (q, 2H), 5.2 (br s, 1H), 11.8 (s, 1H).

EXAMPLE 20A Ethyl 1-5-methyl-2- (2-phenylethyl) -4 - [(2 ') - (2-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-yl] methoxy] pyridin-3- mp 59-72 ° C.

R / CDC1₃(2.5: s, 3H), 3.0 (s), 4H (3.3), 3H (5.1), 2H)

5.6 / s, 1 Η /, 6.9-7, D / m, 5H /, ...... 7.1-7.5 / complex ..... m, 21H. /, 7 9-3.0 (m, 1H).

Starting material methyl-1,4-dihydro-5-methyl-4-oxo-2- / 2-^pEthylethyl / pyridine-3-carboxylate, obtained from methyl 3-amino-5-phenyl-2-oentenoate and diketene in analogy to Example 2A in 3% yield as a solid, m.p. 201-210 ° C. .

Ni (CDCl 3): 2.35 (s, 3H), 3.0 (s), 4H (3.9), 3H (6.5), 1H (7.15-7.4) 7.5 (s, 1H).

Example 21A

Ethyl S-methyl-2-propyl-4- [2 '- (2-trifluoromethyl-2H-tetrazol-5-yl) biphenyl-4-yl] methoxy] pyridine-3-carboxylate, m.p. 135-133 ° C.

NITR / CDC1₃(1.0) (t, 3H), 1.3 (t, 3H), 1.5-1.3 (m, 2H), 2.5 (s), 3H (2.7-2, B) m, 2H), 4.3 (q, 2H), 5.0 (s, 2H), 5.55 (s, 1H),

6.9-7.0 (m, 5H), 7.1-7.5 (complex m, 1H), 7.9-3.0 (m, 1H).

The starting material ethyl 1,4-dihydro-5-methyl-4-oxo-2-propylpyridine-3-carboxylate, obtained from ethyl 3-amino-2-hexenoate and diketene, by analogy to Example 2A, in 23% yield 103 DEG-112 DEG.

NfR / CDCl3₃(C, 9 (t, 3H), 1.3 (t, 3H), 1.6-1.3 (m, 2H), 2.5 (s), 3H), 2.5-2.7) m, 2H), 4.3 (q, 2H), 5.2 (s, 1H).

Example 22A

Ethyl 1-5-methyl-2-propyl-1-4- [N '- (2') - (2-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-yl] methoxy-7-anoyl-3-carboxylate, m.p. 65 to 71 ° C.

NITR / CDC1₃1.0 (t, 3H), 1.7-1.9 (m, 2H), 2.5 (s), 3H), 2.55-2.3 (m, 2H), 3.9) s, 3H), 5.2 (s, 2H), 5.5 (s, 1H), 5.3-5.95 (m, SH),

7.1-7.6 (complex m, 15H), 7.9-3.0 (m, 1H).

Starting material methyl 1,4-dihydro-5-methyl-4-oxo-2-propyl pyridine-3-carboxylate, obtained from methyl 3-amino-2-hexsnoate and diketene in analogy to Example 2A in 46% yield. as a solid, m.p. 142-144 ° C.

NITR / CDC1₃(0.9) (t, 3H), 1.5-1.3 (m, 2H), 2.3 (s, 3H), 2.65 (t, 2H), 3.8 (s, 3H) 5.2 (s, 1H), 12, C / br, W.

Example 23

By analogy to Example 1, from 2,8-dimethyl-3-methoxymethyl-4 - [(2)] ^?R-triphenylmethyl-2H-tetrazol-5-yl (biphenyl-4-yl) methoxy (pyridine) A in 31% yield

2,6-Dimethyl-3-methoxymethyl-4- [(2H) - (1H-tetrazol-5-yl) -phenyl-4-yl] -methoxy] -pyridine hydrochloride as a white powder, m.p. 193 ^DC.

NIYIR / d_with-DIY50 / d₄- acetic acid (2.7 / s, 5H), 3.3 (s, 3H), 4.5 (s, 2H), 5.45 (s, 2H), 7 (2-7.3) complex m, 9H].

Mass Spectrum (+ ve FA3, DIYISO / m-nitrobenzyl alcohol): 402 (IY) + H /⁺.

The starting material (A) is prepared as follows:

115 mg of sodium hydride is added to a solution of 1.0 g of 2,5-dimethyl-3-hydroxymethyl-4- [2 '- (2-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-yl] methoxy] pyridine in 30 ml DIYF and stirred for 10 min. 0.3 ml of iodomethane is then added and the mixture is stirred for 18 h. 100 ml of water are added and the mixture is extracted twice with 50 ml of ethyl acetate. The combined extracts are washed with 50 ml of saturated sodium chloride solution and then dried over magnesium sulfate. The solvent was evaporated and the residue was purified by flash chromatography using a mixture of methanol and dichloromethane with a gradient of from 1:50 to 1:20 as eluent to give 0.74 g of 2, dl-dimethyl-3-methoxymethyl-4- (2 '- (2-Triphenylmethyl-2H-tetrazol-5-yl) -phenyl-4-yl) methoxy] pyridine (A), m.p. 132-135 ° C.

NIYIR (dg-DIYSO) (d-acetic acid): 2.55 (s, SH), 3.2 (s, 3H), 4.45 (s, 2H), 6.8-7.9 (complex m) , 24H /.

Example 24

Analogous to Example 1, from 2,3,5-tri50 methyl-4- [2 '- (2-triphenylmethyl-2H-tetrazol-5-yl) -phenyl-4-yl] methoxy-7-yridine (A) at 50% yield of 2,3,6-trimethyl-4- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methoxy] pyridine hydrochloride as a white powder, m.p. 212 ° C.

NYY.R / d₆- Hole.50 / d₄-acetic acid (2.2: s, 3H), 2.5 (s), 3H (2.7), 3H (5.45), 2H), 7.2-7.3 (complex) m, 9H].

Mass Spectrum (+ ve FAB, DIYSO (m-nitrobenzyl alcohol)): 372 (1Y + H)⁺.

ÍYicroanalysis:

why₂₂H₂₁N₅H, 5.4; N, 17.2; Cl, ​​8.7%. found: 54.2% C, 6.1% H, 17.0% N, 3.4% Cl.

The starting material (A) is prepared as follows:

a) 2.2 ml of triethylamine and 1.24 ml of methanesulfonyl chloride were added to a solution of 10.0 g of 2,5-dimethyl-3-hydroxymethyl-4- [2 '- (2-triphenylmethyl-2H-tetrazol-5-yl)]. (biphenyl-4-yl) methoxy] pyridine in 150 mL of dichloromethane. The solution is allowed to stand for 20 h and then diluted with 150 ml of water. The organic phase is separated, washed with 150 ml of saturated sodium chloride solution and dried over magnesium sulfate. The volatiles were evaporated and the residue was purified by flash chromatography with a mixture of 1 volume of methanol and 19 volumes of dichloromethane as eluent to give 3.5 g of 3-chloromethyl-2,6-dimethyl-4 - [(2 ') -] 2-triphenylmethyl-2H-tetrazol-5-yl (biphenyl-4-yl) methoxy-7-pyridine (3) as a white solid, m.p. 110-112 ° C.

NYY.R / d₆-DIYSO / d₄- acetic acid (2.5: s, 3H), 2.65 (s, 3H), 4.75 (s, 2H), 5.45 (s, 2H), 6.9-7.9] complex m, 24H /.

(b) A solution of 1.0 g of compound B and 232 mg of sodium iodide in 20 ml of acetone 5 is heated to reflux. The volatiles were evaporated and the residue was partitioned between 20 mL of dichloromethane and 20 mL of water. The organic phase is separated, washed with 20 ml of saturated sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated and the residue was dissolved in 25 ml

DÍTF. 221 mg of sodium cyanotetraborltene are added and the mixture is stirred for 3 h. The volatiles were evaporated and the residue was partitioned between 20 ml of dichloromethane and 20 ml of water. The organic phase was separated, washed with 20 ml of saturated sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by flash chromatography using a mixture of 1 volume of methanol and 19 volumes of dichloromethane as eluent and yielding 0.65 g of 2,3,6-trimethyl-4 - [(2 * -) - 2]. triphenylmethyl-2H-tetrazol-5-yl (biphenyl-4-yl) methoxy-7-pyridine (A), m.p. 136-138 ° C.

NMR (d 6 -DMSO) d 6 -acetic acid: 2.1 (s, 3H), 2.5 (s), 3H), 2.6 (s, 3H), 5.3 (s, 2H), 6 , 8-7.0 (m, 5H), 7.2-7.35 (complex m, 13H).

Example 25

In analogy to Example 1, from 3-aminomethyl-2,0-dlmethyl-4- (2 '- (2-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-yl) methoxy] pyridine (A) was 50% yield

3-Aminomethyl-2,5-dimethyl-4- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methoxy] pyridine hydrochloride, m.p. 147-150 ° C

NMR (d 6 -DMSO) d₄acetic acid (2.7), 3H (2.85), 3H (4.15), 2H (5.5), 2H), 7.2-7.8 (complex m, 9H).

Mass Spectrum (+ ve FAB, DMSO / m-nitrobenzyl alcohol): 387 (M + H)⁺.

The starting material (A) is obtained as follows:

A solution of 1.0 g of 3-chloromethyl-2,6-dimethyl-4 - [(2 ') - (2'-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-ylmethoxy] pyrimidine ------ The reaction mixture was saturated with ammonia gas in 10 ml of dioxane and then kept in an autoclave at 85 ° C for 3 hours. The volatiles were evaporated and the residue was purified by flash chromatography with a mixture of 1 volume of methanol and 9 volumes of dichloromethane as eluent to give 320 mg of 3-aminomethyl-2,5-dimethy1-452.

- [2- (2-Triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-yl] methoxy pyridine as a foam.

NfTR (d 6 -DETO) d 6 -acetic acid: 2.4 (s, 5H), 4.05 (s, 2H), 5.2 (s, 2H), 5.9-7.8 (complex) m, 24H].

Example 25

In analogy to Example 1, from 2,5-dimethyl-3-formyl-4- (2 '-) - 2-tri'^Fenylmethyl-2H-tetrazol-5-yl (biphenyl-4-yl) methoxy-7-pyridine (A) in 95% yield gives 2,5-dimethyl-3-formyl-4- [2 '- (1 H) -tetrazole- 124 DEG-130 DEG C. 5-yl (biphenyl-4-yl) methoxy] pyridine hydrochloride.

NfTR (DMSO-D 6): 2.7 / s, 3H / 2.9 / s, 3H / 5.5 / s 2H / 7.2 / d 2H / 7.5-7 3 (complex m, 7H), 1D, 4 (s, 1H).

Mass spectrum (-ve -A 3, D 10 -SO 2 / GLY): 334 (IT, -H) -.

(Ticroanalysis:

for C29H18NgO2HCl.0.75H2O calculated C 50.7%, H 4.9%,

N, 15.0. Found: C, 50.8; H, 5.1; N, 15.9.

The starting material is added as follows:

a) 12 ml of chloroform are added in 1 ml aliquots to a solution of 5.2 g of 2,5-dimethyl-4- (1H) -pyrrolidine in 112 ml of 4 mol / l aqueous sodium hydroxide solution maintained at reflux temperature. The solution was heated to reflux for 5 h, cooled and acidified to pH 6 with acetic acid. The volatiles were evaporated and the residue was extracted three times with 100 ml of methanol. The extracts were concentrated and the residue was purified by flash chromatography with a mixture of 1 volume of methanol and 9 volumes of dichloromethane as eluent to give 2.1 g of 2,5-dlmethyl 3-formyl-4 (1H) -pyridone (B) as a solid, m.p. &amp; gt; 100 DEG C. (decomposition).

NITR (dg-DfTSO): 2.2 (s, 3H), 2.5 (s), 3H), 6.1 (s, 1H), 10.25 (s, 1H).

b) In analogy to Example 1, 2,5-dimethyl-3-formyl-4 - [(2 '- (2-triphenylmethyl-2H-tetrazol-5-yl)] is obtained in 57% yield from compound (3). biphenyl-4-yl (methoxy) pyridine (A), m.p. 160-152 ° C.

NXR / OOC1₃(2.5 / s, 3H), 2.3 (s, 3H), 5.1 (s, 2H), 5.7 (s, 1H), 5.35-5.95 (m, 5H) 7.1-7.5 (complex m, 15H), 7.95-3.0 (m, 1 1), 10.5 (s, 1H).

Examples 27 to 23

In analogy to Example 1, the following compounds were prepared from the corresponding compound of formula III, where L is triphenylmethyl, in a yield of 53-93%:

Example 27

3-Acetyl-2,6-dimethyl-4- [2 '- (1 H -tetolol-5-yl) biphenyl-4-yl] methoxy] yridine hydrochloride, m.p. 133-141

Q f- »

L. ·

IR (dg-DirSO): 2.4-2.6 (m, 6H), 2.7 (s, 3H), 5.4 (s, 2H), 7.2 (d, 2H), 7.4 (d, 2H), 7.5-7.8 (m, 5H).

Mass spectrum (in FAB, DMSO-d6): 393 (f-H).

ITicroanalysis:

calcd for C 23 H 21 N 5 O 4 S 2 H, C, 62.9; H, 5.1; N, 15.9.₂Found: C, 62.5; H, 5.0; N, 15.6;₂O.

Example 23

6-ethyl-2-methyl-3-prooanoyl-4- [7/2 * - (1H-tetrazol-5-yl)] -^Cenyl-4-yl / methaxypyridine hydrochloride, m.p. 160-152 ° C.

NIRR / d_with-Dn'.S0 / d₄-acetic acid: 1.0 (t, 3H), 1.25 (t, 3H),

2.7 (m, 4H), m, 5H].

5.4 (s, 2H), 7.2 (d, 2H), 7.4 (d, 2H),

7.5-7.3 / comolex

Mass Spectrum (-in FA3, DIY.SC/m-nitrobenzyl alcohol): 428 (MH + H)⁺.

fílkroanalýza:

oro. H, 5.5; N, 15.1. Found: C, 64.4; H, 5.7; N, 15.0.

The necessary starting materials of formula III used in Examples 27 and 28, corresponding to starting material A in Example 1, are obtained in a yield of 33 to 77% analogous to the procedure described in Example 1 as follows:

Example 27A

3-acetyl-2,6-dimethyl-4- [1/2] ^of(2-Triphenylmethyl-2H-tetrazol-5-yl) -phenyl-4-yl] methoxy / pyridine, m.p. 79-82 ° C.

NfTP / CDCl1₃(2.4-2.5 (m, 9H), 5.0 (s, 2H), 5.6 (s, 1H), 6.9-7.0 (m, 6H), 7.1-) 7.55 (complex m, 16H), 7.9-8.0 (m, 1H).

Starting material 3-acetyl-2,6-dimethyl-4- (14) oyridone, obtained according to Lieblgs Ann. Chem., 1979, 371.

Example 28A

6-ethyl-2-methyl-3-propanoyl-4- [2 '- (2-triphenylmethyl-2H-tetrazol-5-yl) biphenyl] methoxy] pyridine, m.p. 123-124 ° C.

-------------------- NIT.P / COC1₃/:.....1, 1 / t, 3H /, ...... 1.3 / t, 3H /, ..... 2.5 / s, 3H /, ..... 2.55 (o, 2H)

2.8 (q, 2H), 5.0 (s, 2H), 5.5 (s, 1H), 5.9-7.0 (m, 6H), 7.05-7.5 (complex m) 16H (7.9-3.0 (m, 1H)).

Starting material 5-ethyl-2-methyl-3-propanoyl-4- (1H) -pyridone, obtained according to Liebigs Ann. Chem., 1979, 371.

Example 29

In analogy to Example 1, from 3-cyano-2,5-dimethyl-4- [2 '- (2-triphenylmethyl) -2H-tetrazol-5-yl] biphenyl-4-yl] methoxy-7-pyridine (A) v The yield was 3-cyano-2,6-dimethyl-4- (2)⁷147-149 ° C (1H-1strazol-5-yl) biphenyl-4-yl) methoxy-7-pyridine hydrochloride as a white solid.

NITR (dg-DIT-SO) d -acetic acid: 2.7 (s, 3H), 2.3 (s, 3H), 5.5 (s, 2H), 7.2-7.7) complex m, 9H /.

Mass Spectrum (+ ve FA3, DUSQ / m-nitrobenzyl alcohol): 383 (MH + H)⁺.

ÍTlkroanalýza:

for ^ 2ρΗ ^ gNgO.HCl.0.5H₂0 calculated: 61.3% C, 4.7% H, 19.6% N, found 61.7% C, 4.6% H, 18.9% N.

The starting material (A) is obtained as follows:

By analogous procedure to Example 15, part c), starting from 4-chloro-3-cyano-2,6-dimethylpyridine (obtained according to ev.