KR940006532B1 - Substituted pyrrole angiotensin ñœ antagonists - Google Patents

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Description

Substituted Pyrrole Angiotensin II Antagonists

The present invention relates to novel, substituted pyrrole compounds, methods for their preparation, pharmaceutical compositions containing the same, agents for treating hypertension and their use as agents for treating congestive heart failure in mammals.

The compounds of the present invention are useful for inhibiting the action of the hormone angiotensin II (AII) and thus alleviating angiotensin induced hypertension. The enzyme renin acts on the plasma α -globulin, angiotensinogen, producing angiotensin I, which is converted to AII by the angiotensin converting enzyme. The latter substance is a potent vasoconstrictor that has been associated as a causative agent for causing hypertension in several mammalian species such as rats, dogs, and humans. The compounds of the present invention inhibit the action of AII at their receptors on target cells, thus preventing the increase in blood pressure produced by this hormone-receptor interaction. The blood pressure is reduced by administering a compound of the invention to a mammalian species that is hypertensive due to AII. The compounds of the present invention are also useful for treating congestive heart failure.

U.S. Patent No. 4,577,020 to M. Gall, issued March 18, 1986, discloses a psychotropic triazole of the general formula or an enantiomer or stereoisomer thereof, or a pharmacologically acceptable acid addition salt. , Or solvates or hydrates thereof are described:

Wherein R ₄ is (a) hydrogen, (b) C ₁ -C ₃ ) alkyl, (c) -CH ₂ OH, (d) -CH ₂ OCOCH ₃ , (e) -S (O) qCH ₃ , (f) -SCH ₂ CH ₃ , or (g) -R ₁₅ ; R ₅ , R ₁₅ and R ₂₅ are the same or different and (a) 0 to 2 chloro, fluoro, bromo, phenyl substituted by alkoxy having 1 to 3 carbon atoms, or (b) one trifluor Phenyl substituted with 0 to 1 of methyl and phenyl substituents above; W ₁ is (a) cis-C (R ₃ ) = CH-CH ₂ NR ₁ R ₂ , (b) trans-C (R ₃ ) = CH-CH ₂ NR ₁ R ₂ , (c) -C (CH ₃ ) (OR ₁₄ ) -CH ₂ -CH ₂ NR ₁ R ₂ , (d) substituents of general formula (III)

(Ⅲ) 또는

(III) or

(e) Substituents of Formula (IV)

(Ⅳ)

(Ⅳ)

[Wherein, -NR ₁ R ₂ is (a) -N (CH ₃ ) -CH ₂ (CH ₂ ) mR ₂₅ , (b) -NH-CH ₂ (CH ₂ ) mR ₂₅ , (c) general formula ( Substituent of V)

(Ⅴ)

(Ⅴ)

(d) substituents of general formula (VI)

(Ⅵ)

(Ⅵ)

(e) substituents of general formula

(Ⅶ)

(Ⅶ)

Or (f) -N (CH ₃ )-(CH ₂ ) ₃ -CH (R ₅₁ ) ₂ ; R ₁₄ is (a) hydrogen, (b) -COCH ₃ , or (c) -COCH ₂ CH ₃ ; R ₅₁ is (a) phenyl, (b) p-fluorophenyl, or (c) p-chlorophenyl; R ₃ is (a) hydrogen or (b) methyl; The dotted line represents a single or double bond; m is an integer of 1 to 2; n is an integer of 0 to 3; q is an integer of 0 to 2].

In European Patent Application No. 165,777, filed June 14, 1985, Hirsh et al., N-substituted imidazoles in the manufacture of a medicament for inhibiting aromatase or preventing or treating estrogen related diseases and Triazole compounds have been described. This compound is illustrated by the following general formula:

, 수소, C₃-C₈사이클로알킬, C₁-C₄알킬 또는 아세테닐이고 ; X는

, 수소, 피리딜, 또는 5-피리미딜이고, 또는 R 및 X는 함께인 경우 =CH₂이거나, 이에 결합되어 있는 탄소 원자와 함께 탄소원자수 5 내지 8의 사이클로알킬 환을 형성하고 ; Q는 수소 또는 메틸이며 ; R₁은 수소, 플루오로, 클로로, 브로모, 메톡시, 에톡시, 페닐, 메틸티오, 메틸, 에틸, 니트로, 트리플루오로메틸, 또는

이고 ; R₂, R₄, R₅, R₆, R₇및 R₈은 독립적으로 수소, 클로로 또는 플루오로이고 ; 또는 R₁및 R₂가 이에 결합되어 있는 벤젠 환과 함께 나프탈렌 환을 형성하며 ; R₃는 수소, 플루오로, 클로로, 트리플루오로에틸, 메톡시 또는 니트로이고 ; n은 1또는 2이고 ; E 및 G는 독립적으로 N 또는 CH이나, 단 E 및 G는 동시에 N 일 수 없다.Wherein R is

, Hydrogen, C ₃ -C ₈ cycloalkyl, C ₁ -C ₄ alkyl or acetenyl; X is

, Hydrogen, pyridyl, or 5-pyrimidyl, or when R and X together are = CH _2, or together with a carbon atom bonded thereto form a cycloalkyl ring of 5 to 8 carbon atoms; Q is hydrogen or methyl; R ₁ is hydrogen, fluoro, chloro, bromo, methoxy, ethoxy, phenyl, methylthio, methyl, ethyl, nitro, trifluoromethyl, or

ego ; R ₂ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are independently hydrogen, chloro or fluoro; Or R ₁ and R ₂ together with the benzene ring bonded thereto form a naphthalene ring; R ₃ is hydrogen, fluoro, chloro, trifluoroethyl, methoxy or nitro; n is 1 or 2; E and G are independently N or CH, provided that E and G cannot be N at the same time.

Japanese Patent Application No. J4 9101-372 describes an anti-inflammatory pyrazole of the following general formula.

Wherein R is tolyl, p-nitrophenyl, benzyl and phenethyl.

Japanese Patent Application J4 9042-668 describes the preparation of 1-P-chlorobenzyl-3-methyl-2-pyrazolin-5-one.

Pals et al., See; Circulation Research, 29 , 673 (1971), which introduced a sacosin residue at position 1 and alanine at position 8 of endogenous vasoconstrictor hormone AII to block the effect of AII on blood pressure in rats that had killed the spinal cord ( It is described to obtain an octa) peptide. This homologue, initially called “p-113” and later called “Saralasin” [Sar ', Ala ⁸ ] AII, has its own potent action like most so-called peptide-AII-antagonists. However, it has been found to be one of the strongest competitive antagonists for the action of AII. Saralacin has been shown to lower arterial pressure in humans and mammals when blood pressure (elevated) depends on circulating AII [see; Pals et al., Circulation Research, 29 , 673 (1971); Streeten and Anderson, Handbook of Hypertension, Vol, 5, clinical Phannacology of Antihypertensive Drugs, AEDoyle (Editor), Elsevier Science Publishers BV, p.246, (1984)]. However, salaline is its efficacious nature and generally induces a blood pressure enhancing effect when blood pressure is not maintained by AII. As a peptide, the pharmacological effect on salaline is relatively short in duration and becomes apparent only after parenteral administration (oral administration is ineffective). Therapeutic use of peptide AII-blockers, such as salaline, is very limited by the oral ineffectiveness and short duration of action, but its main utility is as a pharmaceutical standard.

Non-peptide antagonists of AII that are orally useful or that bind in vitro in the IC range we observe are not known other than those described in pending US patent applications.

The present invention is a novel substituted pyrrole, a method for preparing the same. Pharmaceutical compositions containing them, and their use as therapeutic agents for hypertension, as well as their use for the treatment of congestive heart failure in animals. The heterocyclic compound of the present invention is the following general formula (I) or a pharmaceutically suitable salt thereof.

Wherein X, Y and Z are independently N or CH ² , provided that 1) when R ² is not H, only one of X, Y or Z may be CR ² ; 2) when Z is N, Y and X are not CR ² ; Or 3) when Y is N, Z and X are not CR ² ; 4) when X and Y are N, Z is not N; 5) when X is N, Y and Z is CR ^2, R ² with respect to Y is not alkenyl are C _3-4 alkyl or C ₄ alkenyl, Z with respect to R ² is not H or CI, R ¹ is (CH ₂ ) nOR ⁴ where n is 1 and R ⁴ is C ₁ alkyl; A is not an inter-carbon single bond, R ³ is not CO ₂ H and R ⁵ is not H; A is a single carbon to carbon bond, CO, O, NHCO or OCH ₂ ; R ¹ is alkyl having 2 to 6 carbon atoms, alkenyl or alkynyl having 3 to 6 carbon atoms, or (CH ₂ ) nOR ⁴ provided that when R ¹ is (CH ₂ ) nOR ⁴ , R ² is H and 2 to C 2; Alkyl of 6, alkenyl or alkynyl of 3 to 6 carbon atoms; R ² is H, alkyl having 2 to 6 carbon atoms, alkenyl or alkynyl having 3 to 6 carbon atoms; -(CH ₂ ) nOR ⁴ ;

이며 ; R³은 -CO₂H,-NHSO₂CF₃;

또는 (CH₂)nSH이고 ; R⁴는 H 또는 탄소수 1 내지 4의 알킬이며 ; R⁵는 H, 할로겐, NO₂, 메톡시 또는 탄소수 1 내지 4의 알킬이고 ; R⁶은 H, 탄소수 1 내지 6의 알킬 ; 탄소수 3 내지 6의 사이클로알킬, (CH₂)mC₆H₅, OR⁷또는 NR⁸R⁹이며 ; R⁷은 H, 탄소수 1 내지 5의 알킬, 탄소수 3 내지 6의 사이클로알킬, 페닐 또는 벤질이고 ; R⁸및 R⁹는 독립적으로 H, 탄소수 1 내지 4의 알킬, 페닐 또는 벤질이거나 NR⁸R⁹는 함께 결합되어 일반식

의 환을 형성하며 ; Q는 NR¹⁰, O 또는 CH₂이고 ; R¹⁰은 H, 탄소수 1 내지 4의 알킬 또는 페닐이고 ; R¹¹은 탄소수 1 내지 6의 알킬, 탄소수 1 내지 6의 퍼플루오로알킬 또는 (CH₂)pC₆H₅이고 ; R¹²는 H, 탄소수 1 내지 4의 알킬 또는탄소수 1 내지 4의 아실이며 ; m은 0 내지 6이고 ; n은 1 내지 6이며 ; p는 0 내지 3이고 ; r은 0 내지 1이며 ; t는 0 내지 2이다.or

And; R ³ is —CO ₂ H, —NHSO ₂ CF ₃ ;

Or (CH ₂ ) nSH; R ⁴ is H or alkyl having 1 to 4 carbon atoms; R ⁵ is H, halogen, NO ₂ , methoxy or alkyl of 1 to 4 carbon atoms; R ⁶ is H, alkyl having 1 to 6 carbon atoms; Cycloalkyl having 3 to 6 carbon atoms, (CH ₂ ) mC ₆ H ₅ , OR ⁷ or NR ⁸ R ⁹ ; R ⁷ is H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R ⁸ and R ⁹ are independently H, alkyl having 1 to 4 carbon atoms, phenyl or benzyl or NR ⁸ R ⁹ are bonded together to form a general formula

Forms a ring of; Q is NR ¹⁰ , O or CH ₂ ; R ¹⁰ is H, alkyl or phenyl having 1 to 4 carbon atoms; R ¹¹ is alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, or (CH ₂ ) pC ₆ H ₅ ; R ¹² is H, alkyl of 1 to 4 carbon atoms or acyl of 1 to 4 carbon atoms; m is 0-6; n is 1 to 6; p is 0 to 3; r is 0 to 1; t is 0-2.

In particular, this invention relates to the pyrrole compound of the following general formula (I).

Wherein X, Y and Z are independently CR ² ; A is a single carbon to carbon bond, CO, O, NHCO or OCH ₂ ; R ¹ is alkyl having 2 to 6 carbon atoms, alkenyl or alkynyl having 3 to 6 carbon atoms, or (CH ₂ ) nOR ⁴ , provided that when R ¹ is (CH ₂ ) nOR ⁴ , R ² is H and 2 to C 2; Alkyl of 6, alkenyl or alkynyl of 3 to 6 carbon atoms; R ² is H, alkyl having 2 to 6 carbon atoms, alkenyl or alkynyl having 3 to 6 carbon atoms; -(CH ₂ ) nOR ⁴ ;

이며 ;

; 또는 (CH₂)nSH고 ; R⁴는 H 또는 탄소수 1 내지 4의 알킬이며 ; R⁴는 H, 할로겐, NO₂, 메톡시 또는 탄소수 1 내지 4의 알킬이 ; R⁶은 H, 탄소수 1 내지 6의 알킬 ; 탄소수 3 내지 6의 사이클로알킬, (CH₂)mC₆H₅, OR⁷또는NR⁸R⁹이며 ; R⁷은 H, 탄소수 1 내지 5의 알킬, 탄소수 3 내지 6의 사이클로알킬, 페닐 또는 벤질이고 ; R⁸및 R⁹는 독립적으로 H, 탄소수 1 내지 4의 알킬, 페닐 또는 벤질이거나 NR⁸R⁹는 함께 결합 되어 일반식

의 환을 형성하며 ; Q는 NR¹⁰, O 또는 CH₂이고 ; R¹⁰은 H, 탄소수 1 내지 4의 알킬 또는 페닐이고 ; R¹¹은 탄소수 1 내지 6의 알킬, 탄소수 1 내지 6의 퍼플루오로알킬 또는 (CH₂)pC₆H₅이고 ; R¹²는 H, 탄소수 1 내지 4의 알킬 또는 탄소수 1 내지 4의 아실이며 ; m은 0 내지 6이고 ; n은 1 내지 6이며 ; p는 0 내지 3이고 ; r은 0 내지 1이며 ; t는 0 내지 2이다.or

And;

; Or (CH ₂ ) n SH; R ⁴ is H or alkyl having 1 to 4 carbon atoms; R ⁴ is H, halogen, NO ₂ , methoxy or alkyl having 1 to 4 carbon atoms; R ⁶ is H, alkyl having 1 to 6 carbon atoms; Cycloalkyl having 3 to 6 carbon atoms, (CH ₂ ) mC ₆ H ₅ , OR ⁷ or NR ⁸ R ⁹ ; R ⁷ is H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R ⁸ and R ⁹ are independently H, alkyl having 1 to 4 carbon atoms, phenyl or benzyl or NR ⁸ R ⁹ are bonded together to

Forms a ring of; Q is NR ¹⁰ , O or CH ₂ ; R ¹⁰ is H, alkyl or phenyl having 1 to 4 carbon atoms; R ¹¹ is alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, or (CH ₂ ) pC ₆ H ₅ ; R ¹² is H, alkyl of 1 to 4 carbon atoms or acyl of 1 to 4 carbon atoms; m is 0-6; n is 1 to 6; p is 0 to 3; r is 0 to 1; t is 0-2.

Preferred compounds of formula (I) are those wherein A is an inter-carbon single bond or NHCO; R ¹ is alkyl, alkenyl or alkynyl having 3 to 5 carbon atoms; R ² is H, alkyl; Alkenyl having 3 to 5 carbon atoms or

또는 (CH₂)nF이고; R³이 -CO₂H,-NHSO₂CF 및

Or (CH ₂ ) nF; R ³ is -CO ₂ H, -NHSO ₂ CF and

환을형성하여, R¹¹이 CF₃, 탄소수1 내지 4의 알킬 또는 페닐이며 ; m이 0 내지 3이고 n이 1 내지 3인 화합물 또는 이의 약제학적으로 적합한 염이다.And; R ⁴ is H or CH ₃ ; R ⁵ is H; R ⁶ is H, alkyl of 1 to 6 carbon atoms, OR ⁷ or NR ⁸ R ⁹ ; R ⁷ is alkyl having 1 to 6 carbon atoms; R ⁸ and R ⁹ are independently H, alkyl of 1 to 4 carbon atoms or combine with nitrogen

Forming a ring, R ¹¹ is CF ₃ , alkyl or phenyl having 1 to 4 carbon atoms; m is 0-3 and n is 1-3 or a pharmaceutically suitable salt thereof.

,

또는

이고 ; R⁶이 H, OH 또는 탄소수 1 내지 4의 알킬이며 ; R⁷이 탄소수 1 내지 4의 알킬인 화합물 또는 이의 약제학적으로 적합한 염이다.More preferred compounds of formula (I) wherein A is a single bond between carbon atoms, and R ¹ or alkenyl alkyl or alkenyl of 3 to 5 carbon atoms or CH ₂ OR ^4, only R When ¹ is a CH ₂ OR ⁴ R ² Is alkyl or alkenyl having 3 to 5 carbon atoms; R ² is alkyl or alkenyl having 3 to 5 carbon atoms, CH ₂ OR ⁴ , COR ⁶ ,

,

or

ego ; R ⁶ is H, OH or alkyl having 1 to 4 carbon atoms; R ⁷ is alkyl having 1 to 4 carbon atoms or a pharmaceutically suitable salt thereof.

Particularly preferred compounds because of their high blood pressure activity are:

3-methoxymethyl-5-n-propyl-4-[(2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -1,2,4-triazole; 3-methoxymethyl-5-n-butyl-1-[(2'-carboxybiphenyl-4-yl) methyl] pyrazole; 5-n-butyl-1-[(2'-carboxybiphenyl-4-yl) methyl] -1,2,4-triazole; 5-methoxymethyl-3-n-propyl-1-[(2'-carboxybiphenyl-4-yl) methyl] pyrazole; 3-carboxy-5- n -propyl-1-[(2 '-(carboxybiphenyl-4-yl) methyl] pyrazole; 5- n -propyl-1-[(2'-(carboxybiphenyl-4 -Yl) methyl] pyrrole-2-carboxylic acid and pharmaceutically suitable salts thereof.

Pharmaceutically suitable salts include metallic (inorganic) salts and organic salts (see Remingto's Phanhaceu-tical Sciences, 17th Edition, page 1418 (1985)). It is well known to those skilled in the art to select the appropriate salt form based on physical and chemical stability, runoff, wetness and solubility. For the reasons cited above, preferred salts of the present invention include potassium, sodium, Kalsch and ammonium salts.

The novel compounds of general formula (I) can be prepared using the reactions and techniques described in this section. The reaction is carried out in a solvent suitable for the reagents and materials used and suitable for carrying out the modifications. Functionality appears on heterocycles and it is understood by those skilled in organic synthesis that other parts of the molecule must be consistent with the proposed chemical modifications. This often requires judgment of the order of the synthetic steps, the necessary groups to protect, deprotection conditions, and activation of the benzyl position to allow attachment to nitrogen on the heterocyclic nucleus. Through the following sections, not all compounds of formula (I) belonging to a given group can necessarily be prepared by all the methods described for that group. Substituents for the starting material may be inadequate for some of the reaction conditions required in some of the described methods. Such limitations on the substituents suitable for the reaction conditions will be readily apparent to those skilled in the art and therefore the alternative methods described should be carried out.

Attempts described for each group of heterocycles generally encompass two main strategies. The first involves N-alkylating preformed mono- or disubstituted heterocycles with suitably functionalized benzyl halides. The second is a ring addition or ring condensation reaction of two or three strategically prepared components to produce heterocycles with the functionality required for the preparation of the final product directly, with very few variants (eg amide or ether linkages). Formation, deprotection reaction). The attempts used for a given example depend on the availability of starting materials and the suitability of the accessory functionality for the desired reaction conditions.

If one or more regioisomers are produced during synthesis (eg, 1, 2, 3-triazole, pyrazole), the apparent identification of each regioisomer is via the Nucleus Overhauser Effect (NOE) NMR spectrum.

Most of the major reaction pathways leading to 1,2,3-triazole are related to azide and several reviews have been published in this field. G. L'abbe ', Chem. Rev. 69 , 345 (1969); T. Srodsky, in " The chemiatry of the Azido Group ", Wiley, New York (1971), p. 331]. The most common and flexible approach is the thermal reaction of azide to alkyne [see; H. Wamhoff in " Comprehensive Heterocyclic Chemistry ", SR Katritzky (Ed.), Pergamon Press, New York (1984), Vol. 5, p . 705; KT Finley, Chem. Heterocycl. Compd. 39 , 1 (1980)]. The broad functionality of the alkyne and azide components is tolerated by heat-affected functionality, and attempts on specific targets are generally determined by the availability of the necessary precursors. Thus, disubstituted 1,2,3-triazoles such as 4 in Scheme 1 can be prepared by heating terminal alkyl 1 with an azide such as 3. Although 1,4-isomers are often produced regiospecific, the result can be a mixture of 1,4- and 1,5-regioisomers. Alternatively, 4 (5) -substituted-1,2,3-triazole can be N-alkylated with a suitable functionalized benzyl halide such as 5. Some or all of the three ring nitrogens in this trial are competitive in alkylation depending on the nature of the substituents on the components and the specific reaction conditions [cf. H. Gold, Liebigs Ann. Chem .. 688 , 205 (1965); TL Gilchrist, et al., J. Chem, Soc., Perkin Trans. 1 , 1 (1975). Thus, compound 6 may also be produced.

As shown in Scheme 2, a compound of Formula 15 wherein A = NHCO can be prepared from the aniline precursor 11 available by reduction of the corresponding nitrobenzyl derivative 9 . This important intermediate 9 can be prepared by ring addition or alkylation chemistry, as already described for Scheme 1. Compounds of formula 15 wherein R ³ = CO ₂ H can be prepared by reacting aniline 11 with a phthalic anhydride derivative in a suitable solvent such as benzene, chloroform, methyl acetate and the like. Often phthalamic acid 14 is described in literature; MLSherril 1, et al., J. Amer. Chem. Soc ., 50 , 474 (1928)], followed by precipitation from solution with the remaining reactants. The compound of formula (15), wherein R ³ = NHSO ₂ CF ₃ or tetrazoyl, is reacted in a solvent such as methylene chloride in the presence of a Schott-Baumann method or a base such as sodium bicarbonate, pyridine or trimethylamine. Can be prepared by simply stirring and reacting the required acid chloride 13 with aniline 11 . Otherwise, aniline 11 is coupled to the appropriate carboxylic acid through many amide bond-forming reactions such as dicyclohexyl carbodiimide coupling, azide coupling, mixed anhydride synthesis, or other coupling methods familiar to those skilled in the art. You can ring.

Scheme 3 illustrates the attempt when A = OCH ₂ in the compound of Formula 22 . Hydrolysis of methyl ether ( 18 ) or benzyl ether ( 19 ) gives hydroxy compound ( 20 ) which can be alkylated with a suitable benzyl halide ( 21 ) to afford compound ( 22 ). In the case of methyl ether ( 18 ), hydrolysis is carried out by heating the ether in 20 to 60% hydrobromic acid for 50 to 150 ° C. for 1 to 10 hours or with acetonitrile with 1 to 5 equivalents of trimethylsilyl iodide In 50 to 90 ° C. for 10 to 50 hours and treated with water. Hydrolysis can also be performed with 1 to 2 equivalents of boron tribromide in methylene chloride for 1 to 10 hours at 10 ° to 30 ° C. followed by water or Lewis acids such as aluminum chloride in methylene chloride and 3 to 10 equivalents of thio Treatment with phenol, ethanedithiol or dimethyl disulfide at 0 ° to 30 ° C. for 1-20 hours followed by water or with aluminum chloride in methylene chloride and 3-10 equivalents of thiophenyl, ethanedithiol or dimethyl disulfide After treatment for 1 to 20 hours at to 30 ℃ may be carried out by treatment with water. Hydrolysis of benzyl ether ( 19 ) can be carried out by refluxing in trifluoroacetic acid for 0.2 to 1 hour or by catalytic hydrogenolysis in the presence of a suitable catalyst such as 10% palladium on carbon and 1 atm of hydrogen. Alkylation of compound (20) with a suitable base such as sodium methoxide or sodium hydrogen in a solvent such as dimethylformamide (DMF) or dimethylsulfoxide (DMSO) at 25 ° C. for 2-20 hours at a suitable benzyl halide To provide a compound of formula (22).

As in Scheme 4 , functionalized benzyl azide ( 25 ) is replaced by the corresponding benzyl halide ( 24 ) with an azide salt such as sodium azide in a polar solvent such as dimethylformamide, dimethyl sulfoxide or It can be prepared under phase change conditions at room temperature for 18 to 48 hours. Benzyl bromide 24 may be prepared by many benzyl acid halogenation methods that are familiar to those skilled in the art. For example, benzyl bromide of the toluene derivative ( 23 ) takes place in an inert solvent such as carbon tetrachloride from room temperature to reflux in the presence of a radical initiator such as benzoyl peroxide.

Scheme 5 illustrates a preferred attempt to incorporate A as a single bond ( 31 ), ether ( 34 ) and carbonyl ( 37 ) linker. Biphenyl ( 31 ) is described in the literature; Compounds ( 29 ) and ( 30 ) are prepared by Ullman coupling as described in "Organic Reactions", 2 , 6 (1944). Ether 34 can likewise be prepared by the Ullman ether condensation reaction between phenol 32 and halide 33 . Russian Chemical Reviews , 43 , 679 (1974). Benzophenone intermediates ( 37 ) are generally obtainable by classical Friedel-Crafts acylation between toluene ( 35 ) and suitable benzoyl halides ( 36 ) [see; G.Olah, "Friedel-Crafts and Related Reactions", Interscience, New York 1963-1964).

Alternatively, substituted biphenyl precursors 40 and corresponding esters 41 may be prepared by reacting methoxy oxazoline 39 with tolyl Grignard reagent [see; SIMeyers and EDMikelich, J. Am . Chem . Soc ., 97, 7383 (1975); Scheme 6 ]

Substituted biphenyl tetrazole ( 31 ; R ³ = CN ₄ H) can be prepared by a variety of methods using hydrazonic acid (Scheme 7 , Scheme b ) from a nitrile precursor (R ³ = CN). For example, nitrile ( 31 ) may be heated with sodium azide and ammonium chloride in dimethyl formamide for 30 days at room temperature to reflux temperature for 1 to 10 days. JPHurwitz and AJ Thomson, J. Org. Chem ., 26 , 3392 (l961)]. Preferably, tetrazole is prepared by reacting trialkyltin or triaryltin azide with a 1,3-bipolar ring addition salt to a suitably substituted nitrile ( 31 ) as shown in Scheme 7 , Scheme a). S. Kozuma, et al., J. Organicmetllic chem ., 337 (1971). The required trialkyl or triaryltin azide is prepared from the corresponding trialkyl or triaryltin chlorides and sodium azide. The accessory tin group of compound 42 is removed by acidic or basic hydrolysis and the resulting free detrazole is protected with trityl group by reaction with trityl chloride and trimethylamine to give compound 43. Bromination provides compound 24 as described above. Other protecting groups such as P-nitrobenzyl and 1-ethoxyethyl can be used in place of the trityl group to protect the tetrazole moiety. Among other groups, such protection groups can be introduced and described in the literature; TW Greene, Protctive Groups in Organic Chemistgy , Wi1ey -Interscience (1980)].

(A = single bond O.CO)

Reaction Scheme 2

Scheme 3

Reaction Scheme 4

Scheme 5

Scheme 6

Scheme 7

The more common and clear synthesis of l, 2,4-triazoles from bicyclic precursors is generally related to hydrazine derivatives, since the formation of CN and C = N bonds is easy compared to the relative difficulty of NN bond formation [ Reference ; JBPalya in Comprehensive Heterocyclic Chemistry , ARKatritzky (Ed.), Pergamon Press, New York (1984), Vol . 5 , p.762]. Synthesis of compounds with substituents on N-4 can be attempted by the method described in Scheme 8. An essential mixture of orthoesters ( 45 ), acylhydrazines ( 46 ), and amines ( 47 ) in a suitable solvent such as either xylene or lower alcohol is reacted for 1 to 24 hours at or near reflux temperature, 1,2 , 4-triazole ( 48 ) is obtained. PJ Nelson and KTPotts, J. Org. Chem. 27, 3243 (1962); Y. Kurasawa et al., J. Heterocyclic Chem ., 23 , 633 (1986)]. An alternative approach to this structure also condenses N, N'-diacylhydrazine ( 49 ) with amine ( 47 ) ( It may also be carried out by ring condensation of a suitable substituted amidrazone such as 50 ). Comp . Het . Chem . Vol. 5, p 763].

The flexibility of this approach is developed in Scheme 9 . Groups R ¹ and R ² may be accompanied by orthoester ( 45 , 52 ) or acylhydrazine ( 46 , 51 ) moieties that depend on their availability. Experimentally, orthoesters and acylhydrazines are first reacted to produce amido, 1,2,4-oxadiazoles (53), which can be separated (if stable) but are usually amine ( 47) in situ. ) (Or 58 or 64 ; Schemes 10 and 11 ) may ultimately yield compound ( 48 ). Alternatively, oxadiazole 53 can be transformed into simpler triazole 54 by treatment with ammonia. This kind of alkylation gives a mixture of N-1 and N-2 substituted products 55 [see; KT Potts, Chem. Rev. , 61 , 87 (1961); K. Schofield, MRGrimmett and BRT Keene; Heteroaromatic Nitrogen Compounds: The Azoles , Cambridge University Press, Cambridge, (1976), p. 81]. N-4 alkylation of simple 1,2,4-triazoles is only rarely found in literature; MRAtkinson and JBPalya, J. Chem . Soc., 141 (1954). Such other attempts with N-1 and N-2 substituted triazoles can be explained by the reaction of compound ( 56 ) and benzylhydrazine ( 57 ). In compound ( 56 ), the dashed lines indicate the presence or absence of a bond, so that possible reactants are (R ¹ COX, R ² COX and NH ₃ ) or (R ¹ CONH ₂ and R ² COX) or (R ¹ COX and R ² CONH ₂ ) or (R ¹ CONHCOR ² ); X represents a suitable leaving group such as C1, OH or H ₂ O.

An approach for compounds with A = NHCO is to use commercial 4-nitrobenzylamine ( 58 ) instead of very high functionalized benzylamine ( 47 ). In this way an N-4-substituted nitrobenzyltriazole ( 59 ) is obtained, which can also be prepared in amide-bonded systems ( 62 ) and ( 63 ) in a manner similar to that described above (Scheme 2). . An alternative approach to compound ( 59 ) may be through N, N'-diacylhydrazine ( 49 ) or amidrazone ( 60 ) as described earlier in Scheme 8. Related N-1 (2) substituted systems can be prepared by alkylating ( 54 ) with 4-nitrobenzyl bromide, as generalized in Scheme 9 .

Otherwise, for compounds where A = OCH, Scheme 11 can be deprotected with the use of commercial 4-methoxy- or 4-benzyloxybenzylamine ( 64 ) and further as described above (Scheme 3). It is shown that compounds 65 which can be functionalized can be prepared.

compound(45) And (52Orthoesters, such as Scheme 12, are most commonly used as imidate ester hydrochlorides (70Obtainable through alcohol decomposition of70) Is generally the equivalent nitrile (69Is prepared by the addition of an alcohol (generally methanol or ethanol) in the presence of anhydrous hydrogen chloride. R.H.De Wolfe,Carboxylic Ortho Acid Derivatives: Preparation and Synthetic Applications,Academic Press, New York, pp. 1-54]. Synthesis is usually carried out in a two step process, the first step being imide ester hydrochloride (70) Production and separation. Lower aliphatic members of this group are often prepared by adding anhydrous hydrogen chloride excess to a nitrile cold solution in a rather excess alcohol. After addition of a suitably inert solvent such as ether, benzene, chloroform, nitrobenzene or 1,4-dioxane, the resulting mixture is left to cool (60 ° C.) for several hours to one week and the product is aspirated. Collect by filtration and wash without residue solution and hydrogen chloride. S.M.McElvain and J.W.Nelson,J.Amer.Chem.Soc.,64, 1825 (1942); S.W.McElvain and J.P.Schroeder,J.Amer.Chem.Soc.,71, 40 (1949). This imidate ester hydrochloride is stirred with excess alcohol (usually the same as used above) for up to 6 weeks, or more preferably, the imidate ester hydrochloride with 5-10 times excess alcohol in ether. Convert to orthoester by refluxing up to 2 days. Higher yields can be obtained by stirring the imidate ester at room temperature in a mixture of alcohol and petroleum ether [see; S.M.McElvain and C.L> Aldridge, J. Am. Chem. Soc.,75, 3987 (1953);Ibid, 80, 3915 (1958). The orthoesters prepared by the process described above are a fairly large series of groups, including aliphatic, alkenyl, alkynyl, aromatic, halogen, ether, ester, amino, nitro, thio (in various oxidation states), amide or urethane groups. Functionality can be incorporated. Another rarely used approach is a trihalomethyl compound (71) orαThere is electrolysis of halo ethers but this attemptαIt is limited to hydrogen-free halides and is generally applied to the synthesis of trialkyl orthobenzoates. See H. Kevart and M. B. Price,J.Amer.Chem.Soc.,82, 5123 (1960); R.A. McDonald and R. S. Krueger,J.Org.Chem, 488 (1966)].

Acyl hydrazine ( 46 , 51 ) is used to prepare the corresponding ester ( 72 ; X = OR) with hydrazine (or hydrazine monohydrate) in a suitable solvent such as alcohol, acetonitrile, DMF or pyrroline at 0 ° C. to reflux temperature. It can be prepared by a simple method of reacting for 18 hours (Scheme 13). Relevant acids (X = OH), anhydrides (X = OCOR), amides (X = NH ₂ ) or acid halides (X = CI, Br) can also be used, but more reactive acid derivatives (e.g., acid halides) Is generally used for the preparation of N, N'- diacylhydrazines ( 49 ), except when larger size R ¹ (2) groups lead to significantly less reactive species.

Symmetric N, N'- diacylhydrazines ( 49 ) are best prepared by reacting two equivalents of acyl halides 72 (X = C1, Br) with hydrazine or otherwise oxidizing the corresponding monoacylhydrazines. . A "mixed" N, N "-diacylhydrazine ( 49 ) is a two-step method of first preparing a monoacylhydrazine ( 46 , 51 ) and then reacting with a suitable acyl halide ( 72 ; X-C1, Br). Obtained through.

Benzylhydrazine ( 57 ; 77 ) can be prepared by modifying the Raschig method for hydrazine by replacing ammonia with benzyl amine ( 76 ) and aminating it with chloramine or hydroxyl amine-o-sulfonic acid. [See; WWSchien1, Aldrichimica Acta, 13, is described in 33 (1980), Scheme b of the reaction scheme 14). Alkylhydrazines have also been prepared from alkyl halides or sulfates. This tendency is for polyalkylation, but monoalkylation is facilitated by the use of bulk groups (ie benzyl, 24 ) or very large hydrazines [see; SNKast, et al, Zh . Obshch, Khim , 33 , 867 (1963); CA. , 59 , 8724e (1963).

Benzylamine 76 can be prepared in a number of ways. The most common of these is described in Scheme a) in Scheme 14 . Aminolysis of halides, the most direct attempt, is often accompanied by the formation of secondary, tertiary and quaternary amines [see; J. Amer. Chem. Soc., 54, 1499, 3441 (1932)].

More efficient attempts have been made to reduce the corresponding benzyl azide by catalytic reduction, hydride reagents, triphenylphosphine or tin chloride, among others. SNMaiti, et al., Tetrahedron Letters , l423 (1986)]. Hydrolysis or hydrazine degradation of intermediate N-benzyl phthalimide ( 73 ) after the reaction of benzyl halide ( 24 ) with potassium (or sodium) phthalimide is carried out by Gabriel synthesis of primary amines. It is of great interest in terms of a broad range of resistance groups for resistance and mildness of antagonism . MSGibson and RW Bradshaw, Angew. Chem. Int.Ed.Engl . 7 , 919 (1968). Benzaldehyde (75) a The Oh enemy reduction with ammonia and hydrogen using a nickel catalyst folk is another conventional attempt [see: Organic Reactions, 4, 174 ( 1948)]. Reduction or catalytic hydrogenation of benzonitriles with metal hydrides is also commonly used. See J. Chem . Soc . 426 (1942); J. Amer . Che . Soc ., 82, 681, 2386 (1960); Organic Reactions , 6 , 469 (1951)]. Other reagents have been used for the conversion of intermediate 24, 74 and 75 to 76. [Reference; JT Harrison and S. Harrison, Compendium of Organic Synthetic Methods , John Wiley and Sons, New York Vol. 1-5 (1971-1984)].

Scheme 8

Scheme 9

Scheme 10

Scheme 11

Scheme 12

Scheme 13

Scheme 14

A common and flexible approach to pyrazole is the general formula (0Scheme of Pyrazole of15As in, related to the condensation of 1,3-difunctional compounds with (generally dicarbonyl) hydrazines or derivatives thereof, see literature; G. Corspeau and J. Elguerv.Bull.Soc.Chim. Fr. 2717 (1970). Rarely, pyrazoles are prepared at the last stage at which N-N bonds are closed. J. Elguerw inComprehensive Heterocyclic Chemistry, S. R. Katritzky (Ed.) Pergamon Press, New York, Vol.5(1984), p. 274; J. Barluenga,J.Chem.Soc.,Perkin trans. 1, 2275 (1983).

For example, compounds of formulas 84 and 87 , wherein A = NHCO or OCH ₂ , can be prepared by nitrobenzyl ( 81 ) and as described in respective schemes 16 and 17 described for the triazole series (Scheme 2 and 3 ). It may be prepared via the alkoxybenzyl ( 85 ) intermediate.

Condensation of 1,3-dicarbonyl compounds with hydrazine hydrates or benzyl hydrazine derivatives is generally carried out by mixing the two components in a suitable solvent such as lower alcohol, ether, or THF for 1 to 18 hours at 0 ° C. to reflux temperature. do.

Alkylation of pyrazole ( 79 ) is carried out by reacting the preformed sodium (or potassium) pyrazole salt with the appropriately substituted benzyl halide (5) in a polar solvent such as DMF or DMSO at 0 ° C. to room temperature, or for the triazole series As described, it can be carried out by reaction of the free pyrazoles 79 and 5 in a pseudosolvent and an acid trapping agent such as sodium bicarbonate or potassium carbonate.

In either trial, mixtures of various ratios of N-1 and N-2 substituted pyrazoles ( 80 , 81 or 85 ) are generally obtained and can be separated by conventional chromatographic methods.

The synthesis of 1,3-dicarbonyl compounds has attracted considerable interest in the literature and an important approach to 1,3-diketone ( 78 ), which is of interest to the present invention, is described in Scheme 18 .

Esters 72 (X = OR) are 30 to 70 for 4 to 18 hours at 0 ° C. to reflux using a base such as sodium ethoxide, sodium hydrate or sodium amide in a suitable solvent such as alcohol, DMF, DMSO or benzene. Can be reacted with methyl ketone 88 at% efficiency [see; JM Spragtie, LJ Bechnam and H. Adkins, J. Amer , Chem . Soc ., 56 , 2665 (1934). Following metallization of hydrazine ( 89 ) with n-BuLi, it is then reacted with carboxylic acid chloride (72; X = CI) and subsequently hydrolyzed to give compound ( 78 ). D, Enders AND P. Wenster, Tetrahedron Lett . 2853 (1978). Metallization of compound ( 88 ) with non-nucleophilic mesityllithium followed by acylation also affords compound ( 78 ). AK Beck. M S. Hoelstein and D. Seebach, Tetrahedron Lett ., 1187 (1977); D. Seebach, Tetrahedron Lett . 4893 (1976).

As in Scheme b) of Scheme 18 , the addition of Grignard reagent to β -keto carboxylic acid chloride can be limited to a single addition reaction at low temperature to yield compound ( 78 ). CD Hurd and GD Kelso, J. Amer . Chem . Soc . 62 , 1548 (1940); F. Sato, M. Trone, K. Oyuro, and M. Sato, Tetrahedron Lett ., 4303 (1979). Lithium dialkyl copper (R ₂ CuLi) reagents have also been used. Luong-Thiand Riviero, J. Organomet. Chem. 77 , C52 (1974). Similarly, alkyllithium reagent (R ² Li) is added to a single anion of β -keto ester 91 to obtain 1,3-diketone [see; SN Huckin and L. Weiler, Can . J. Chem . 52 , 1379 (1974).

Eschenmoser has demonstrated the synthesis of β -diketones through the sulfur extrusion reaction of tributylphosphine, trimethylamine and lithium perchlorate with keto thioester ( 92 ) [see; S. Eshenmoser, Helv . Chim . Acta ., 54 , 710 (1971).

Inversion reactions of α , β -epoxy ketones ( 93 ) have been reported for β -diketones ( 78 ) catalyzed by Pd ° [cf. R. Noyori, J. Amer . Chem . Soc. 102, 2095 (1980)].

Mixed anhydrides, such as compound ( 95 ), are obtainable from carboxylic acid ( 94 ) and trifluoroacetic anhydride and appear as acylate alkyl (1) to prepare enol trifluoroacetate of β -diketone ( 97 ). . Transesterification by reflux with methanol liberates β -diketone ( 78 ) [see; AL Hame and JM Tedder, J. Chem . Soc ., 3628 (1953).

Scheme 15

Scheme 16

Scheme 17

Scheme 18

Approaches to pyrrole synthesis have attracted wider attention in the literature than most other heterocycles, and many of their preparations have been published. See RJ Sundberg in "Comprehensive Heterocyclic Chemistry", AR Katritzky (Ed.), Pergamon Press. , New York (1984), Vol . 4 , p. 705; Synthesis , 1946 , 281]. The following discussion is limited to the most common and stable methods for pyrrole synthesis belonging to the general scope of the present invention.

The PAa1-Knorr reaction, a ring condensation reaction of a 1,4-dicarbonyl compound with an ammonia primary amine or related compounds, is one of the most common and widely used pyrrole synthesis methods. See RA Jones and GP. Bean, "The Chemistry of Pyrroles", Academic Press. London, 1977; p. 77-81]. The universality of this approach is largely determined by the utility of the dicarbonyl precursor 98 , as shown in Scheme (19). The diketones are heated with ammonia or amine using a catalyst (e.g. sulfuric acid, acetic acid, P-toluenesulfonic acid, alumina or even titanium tetrachloride) in a solvent (e.g. benzene, toluene or methylene chloride) Can produce pyrrole such as ( 99 ). By selecting the appropriate arylmethylamine ( 76 , Scheme 14 ) it is possible to ultimately insert various A-binders into the fully prepared pyrrole 100 using the methods described above (Scheme 1 to 3). Alternatively, the disubstituted pyrrole ( 99a ) can be alkylated with benzyl halide ( 24 ) under the conditions described above ( Scheme 1, 9 or 15 ) to afford the same compound ( 100 ).

Although reactions involving the closure of dynes ( 101 ) with amines in the presence of cuprous chloride have been reported ( Scheme 20 , Scheme a), this approach is generally symmetric, since diynes are usually produced by oxidative coupling of alkyne. It is limited to the process for preparing pyrrole substituted with KE Schulte, J. Reish, and H. Walker, Chem . Ber . 98 (1965); AJ Chalk, Tetrahedron Lett . 3487 (1972).

Furan 103 is converted directly to pyrrole by treatment with amines, but the demanding conditions (400 ° C./Al ₂ O ₃ ) interfere with their universality. 2,5-dialkoxytetrahydrofuran ( 105 ) has been used more frequently than furan (or 1,4-dicarbonyl) equivalents and readily reacts with aliphatic or aromatic amines (and even weak nucleophilic sulfonamides). To obtain the pyrrole as shown in Scheme (b ) of Scheme (20) . JWF Wasley and K. Char, Synth . Commun . 3 , 303 (1973). Although commercially available 2,5-dialkoxytetrahydrofuran ( 105 ) (R ^l = R ² = H) is generally limited to compounds for preparing 1-substituted pyrrole, more substituted systems are suitable furan ( 103 ) can be obtained by three-step alcohol hydrolysis of the more substituted 2,5-dialkoxytetrahydrofuran ( 105 ) shown in Scheme (b ) of Scheme (20) (see NL Weinberg and HR Weinberg). , Chem . Rev. , 68 , 449 (1968); N. Elming, Adv . Org . Chem . 2, 67 (1960).

The Hantzsch synthesis method involves the condensation of α -haloketone ( 106 ) with β -ketoester in the presence of ammonia or primary amine (21) , compound ( 108 ) as shown in scheme (a). (See A. Hantzsch. Chem . Ber ., 23 , 1474 (1890); DC Von Beelen, J. Walters, and S. von der Gen, Rec . Trav . Chim . 98 , 43 1979). Of the numerous modifications reported over the years, the substitution of Compound ( 106 ) with readily available α -hydroxyaldehydes or nitroalkenes has extended the flexibility and universality of this important method (see DM Mckinnon, Can . J.) . .. Chem 43, 2628 (1965 ); H. George and HJ Roth, Arch Phann 307, 699 (1974);..... CA Grok and K. Camenisch, Helv Chem Acta 36, 49 (1953)].

Closely related knor condensation involves the reaction of amino carbonyl compounds (or their precursors) with carbonyl (or dicarbonyl) compounds. J. M. Patterson Synthesis, 282 (1976). 2,3- or 2,5-disubstituted pyrrole (111And114Representative manufacturing methodScheme 21)In Schemes (b) and (c). S. Umio et al., Jap. Pat. 7018653, Ffujisawa Pharmacenticals Co., Ltd., 1970C.A.73, 77039, 1970); K.Tanaka, K. Kariyone, S. Umio,Chem.Pham,Bull. (Tokyo),17, 611 (1969)].

Preparation of suitably functionalized pyrrole is another process for preparing pyrrole of formula (I). Methyl (or methyl) 5-formyl-1H-pyrrole-2-carboxylate ( 119 ) is a particularly useful intermediate for the pyrrole claimed in the present invention, and by the numerous methods set forth in scheme (a) of scheme 22 Manufactured by WA Davies, AR Pinder and IG Morris, Tetrashedron 18 , 405 (1962); Org . Syn . Vol . 36 , p. 74; Org , Syn , Vol . 51 ].

More recently, Ulrich has used 3- (N, N-dimethylamino) acrolein 121 as the N, N-dimethylformamide derivative at the vinyl position shown in Scheme (b ) of Scheme (22) . Bilsmeyer-Haack formylation of pyrrole comprising a vinyllocation system such as Compound ( 122 ) has been extended (FW Ullrich and E. Breitmaier, Synthesis , 641 (1983); W. Heinz, et al., Tetrahedron , 42 , 3753 (1986)].

Attempts of particular interest for the pyrrole claimed in the present invention have recently been reported, whereby lithiation of 6-dimethylamino-1-azafulbene dimer ( 125 ) is followed by treatment with a suitable electrophile followed by hydrolysis. Induces the 5-substituted pyrrole- _2- carboxyaldehyde (99a; R ₂ = CHO) shown in Scheme (23) . JM Muchowski and P. Hess, Tetrahedron Lett., 29 , 777 (1988). ].

Scheme (23a) generally uses N-alkylation of compound (99a) with appropriate benzyl halides ( scheme 1,9 or 15 , as already mentioned), followed by similar methods known to those skilled in the art. To describe the preparation of pyrrole 100 of formula (I) by standard adjustment of an incomplete group.

Scheme 19

Scheme 20

Scheme 21

Scheme 22

Scheme 23

Scheme 23a

Described herein is a general method of making specific functional groups for R ¹ and R ² claimed in the present invention. As before, experts in the field of organic synthesis should understand that all functional groups present must be consistent with the proposed chemical modification.

As shown in Scheme (a ) of Scheme (24) , benzylic heterocycles ( 125 ) wherein R ¹ or R ² is CH ₂ OH can be prepared using the corresponding halides, It can be converted to mesylate or tosylate. Preferably, alcohol 125 is converted to chloride 126 using thionylchloride in an inert solvent at 20 ° C. to reflux temperature of the solvent.

Chloride 126 may be substituted with various nucleophiles. For example, excess sodium cyanide in DMSO at 20 ° to 100 ° C. can be used to form cyanomethyl derivative ( 127 ). These nitriles 127 can be hydrolyzed to carboxylic acids 128 by treatment with strong acids or bases. Preferably, the mixture is treated with a 1: 1 (V / V /) mixture of aqueous concentrated hydrochloric acid / glacial acetic acid at reflux for 2 to 96 hours or from 2 ° C. to a solvent of alcohol at 20 ° C. to reflux for 96 hours (eg, Ethanol or methylene glycol) may be used to treat with 1N sodium hydroxide. Alternatively, the nitrile group can be first stirred in sulfuric acid to form an amide, and then hydrolyzed in two steps, feeding acid carboxylic acid 128 by acidic or basic hydrolysis.

These carboxylic acids 128 are standard methods, for example, the carboxylic acid 128 is stirred with alcohol in a suitable inert solvent containing hydrogen chloride or similar catalyst, or the carboxylic acid 128 is first thionyl chloride or oxalyl chloride. Can be converted to the corresponding acid chloride and then esterified to ester 129 by treatment with a suitable alcohol. The carboxylic acid 128 may also be reduced to the corresponding hydroxymethyl compound 130 by carrying out the overall homologation of methods 125 to 130 by using a reducing agent such as LiAlH ₄ or B ₂ H _6. Can be.

Alcohol derivatives ( 125 or 130 ) are acylated to give esters ( 131 ) in various ways. As shown in Scheme (b ) of Scheme (24) , acylation is carried out in the presence of a base (e.g. pyridine or triethylamine) in an appropriate solvent (e.g. diethylether or tetrahydrofuran) It can be taken using a halide or anhydride. Alternatively, the alcohols ( 125 , 130 ) may be prepared in the presence of a catalytic amount of 4- (N, N-dimethylamino) pyridine (DMAP), see A. Hasmer, Tetrahedron Lett . 46 , 4475 (1978)] can be acylated by reaction with carboxylic acid and dicyclohexyl carbodiimide (DCC). Preferred is a method of treating compound ( 125 ) or ( 130 ) with a solution of carboxylic anhydride in pyridine at 20 ° C. to 100 ° C. for 2 to 48 hours, optionally using a catalytic amount of DMAP.

Ether 132 as shown in the reaction scheme (c) of reaction scheme 24, the solvent from the alcohol (for example: DMF or DMSO) in the compound 125. 1 a at 25 ℃ followed by potassium tert-butoxide or sodium hydride It can be prepared by treatment with R ⁴ L, wherein L is a halogen, mesylate or tosylate group for from 20 hours. Alternatively, chloride ( 126 ) is used as a solvent in R ⁴ OH or in a polar solvent such as DMF in an amount of 1 to 3 equivalents of R ⁴ OM, wherein M is sodium or potassium, from 2 to 25 ° C. The ether 132 will also be obtained by treatment for 10 hours. The ether 132 can also be prepared, for example, by heating compound 125 for 3-15 hours in R ⁴ OH containing an inorganic acid such as hydrochloric acid or sulfuric acid at 60 ° C. to 160 ° C. .

As shown in Scheme (d ) of Scheme 24 , the amide 133 can be prepared from carboxylic acid 128 as described above ( Scheme 2 ) and by methods similar to those known to those skilled in the art. have.

Scheme (a) in Scheme (25) can be substituted by ammonia, or by the galbriel synthesis method, or by sodium azide and then reduced as described above ( Scheme 14 ). A method for obtaining the amine ( 134 ) from is provided. Access to the homologue amine 134 can be obtained by reducing the nitrile 127 to, for example, a metal hydride formulation (eg L LiA1H ₄ ) or through catalytic hydrogenation. The amine 134 can be converted to sulfonamide ( 135 ) and carbamate ( 136 ) using standard methods similar to those known to those skilled in the art.

Scheme (b ) of Scheme 25 describes a method for preparing thioether 137 by replacing chloride ( 126 ) with sodium or potassium salts of butane alkyl mercaptan. The sulfide 137 can be oxidized to the corresponding sulfoxide and sulfone derivatives 138 using various oxidizing agents, for example hydrogen peroxide, sodium peroxide, tertiary butyl hypochlorite, sodium perbromide or carboxylic acid. S. Palai, The Chemistry of Funtional Groups, Supple Inent E , PT.1, pp. 539-608, Wiley, NeW York (1980).

Another introduction of sulfur converts the hydroxyl group of compound ( 139 ) to thiolacetic acid derivative ( 141 ) [JY Gauthier, Tetrahedron Lett. 15 (1986)], and then in Scheme (c) of Scheme ( 25 ). It can be achieved by converting to mercaptan 142 by hydrolysis as described.

As also shown in Scheme (c ) of Scheme 25, the hydroxyl group can be converted to its corresponding fluoro compound 140 by various fluorinating agents (eg DAST).

Nitrile 127 can be converted to the corresponding detrazole derivative 143 by various methods using hydrazonic acid, as shown in Scheme (d ) of Scheme 25 . For example, nitrile can be heated with sodium azide and ammonium chloride in DMF at 30 ° C. to reflux for 1 to 10 days. JP Hurwitz and AJ Tomson, J. Org . Chem ., 26 , 3392 (1961). Preferably, the tetrazole is prepared by 2,3-dipolar ring addition of trialkyltin or triaryltin azide to suitably substituted nitriles, as described above in Scheme (7) .

As shown in Scheme (a ) of Scheme 26, the hydroxymethyl group of Compound 125 may be oxidized to the corresponding aldehyde 144 using a mild oxidizing agent such as manganese dioxide or ceric ammonium nitrate. have. The aldehydes can be directly obtained alkenyl compounds, such as compound (146), by a typical chain-extension reaction through the Wittig and Wittig-Horner-Emmons reaction, or the Grigg The alcohol 145 can be obtained by reacting with Grignard and a lithium reagent. These alcohols are standard methods, for example, first converting the alcohol 145 above into the corresponding mesylate, tosylate or halide derivatives, and then the appropriate base (e.g. DBU, triethylamine or potassium tert-butoxide). Side) to dehydrate with the corresponding alkenyl compound ( 146 ).

Another approach to the alkenyl-substituted heterocycle can be obtained via the corresponding alkyl heterocycle 147 , as shown in Scheme (b) of Scheme 26 . Compound ( 147 ) is free-radical brominated by UV-irradiation for 1 to 4 hours in the presence of N-bromosuccinimide in an inert solvent (eg carbon tetrachloride) at 25 ° C. to give bromide ( 148 ). These intermediates 148 are treated with an appropriate base (e.g., DBU, triethylamine, or potassium tert-butoxide) (overwhelmingly or solely) to give the trans-alkenylheterocycle ( 149 ). The corresponding cis-alkenyl derivatives 151 are prepared as described above (for compound 146) or by oxidative degradation from trans-alkenyl compounds 149 using osmium teroxide and sodium iodide. It is possible to obtain aldehydes 150 which follow chemistry.

Scheme 24

Scheme 25

Scheme 26

Described herein is a general method for preparing specific functional groups for R ¹ and R ² claimed in the present invention. As noted above, it should be understood by those skilled in the art of organic synthesis that all functional groups present must be consistent with the proposed chemical modification.

The compounds of the present invention and their preparation methods can also be understood by the following examples, but are not intended to be limiting.

Example 1

Part A: Methyl 4'-azidomethylbiphenyl-2-carboxylate

To a solution of methyl 4'-bromomethylbiphenyl-2-carboxylate (5.0 g, 16.4 mmol) in DMF (40 ml) is added sodium azide (2.7 g, 41 mmol). The mixture is stirred at rt overnight, filtered and the filtrate is partitioned between water and ethyl acetate (100 ml). The aqueous phase was extracted one or more times with ethyl acetate (100 ml), the combined organic phases were washed with water (3 × 100 ml) and saturated aqueous sodium chloride (100 ml), then dried (MgSO ₄ ), filtered and concentrated to give an oily residue (3.9). g) is obtained, which is used in the subsequent process without purification again:

NMR (200 MHz; CDCl ₃ , TMS) δ: 7.9-7.2 (m, 8H), 4.37 (s, 2H), and 3,60 (s, 3H).

Part B: 4- and 5-butyl-1-[(2'-carbo-methoxybiphenyl-4-yl) methyl] -1,2,3-triazole

A solution of methyl 4'-azidomethylbiphenyl-2-carboxylate (2.0 g, 9.7 mmol) and 1-hexine (10 ml) was refluxed (70-71 [deg.] C.) for 2 days. Concentration in vacuo afforded 3.2 g of a yellow oily residue from which two isomers can be separated via flash chromatography with neutral alumina (150 g, active I; 20% EtOAc / hexanes).

0.58 g of 4-isomer (high Rf value) and 0.47 g of 5-isomer (low Rf value) are separated:

NMR (4-isomer; 200 MHz; CDCl ₃ , TMS) δ: 7.86-7.20 (m, 9H), 5.55 (s, 2H), 3,63 (s, 3H), 2.72 (t, J = 7 Hz, 2H) 1.69-1.61 (m, 2H), 1.43-1.25 (m, 2H), 0.92 (t, J = 7.5 Hz, 3H).

NMR (5-isomer; 200MHz; CDCl ₃ , TMS) is identical to 4-isomer except that the triplet at 2.72ppm is shifted to 2.54ppm.

Part C: 4-Butyl-1-[(2'-carboxybiphenyl-4-yl) methyl] -1,2,3-triazole

To 480 mg (1.37 mmol) of 4-butyl-1-[(2'-carbomethoxybiphenyl-4-yl) methyl] -1,2,3-triazole in methanol (20 ml) is added 4N NaOH (20 ml). . The resulting slurry is stirred under reflux for 2-6 hours (or until a homogeneous solution is produced). Methanol is removed by rotary evaporation and the residue is diluted to 35 ml volume with water. Sticking to pH 4 with dilute HCl gives a sticky precipitate which is extracted with ethyl acetate; The organic layer was dried over MgSO 4, filtered and concentrated to give 438 mg of a white solid;

Melting point 90-95 ° C.

NMR (200 MHz; CDCl ₃ , CD ₃ OD, TMS) δ: 7.93-7.24 (m, 9H), 5.52 (s, 2H), 2.69 (t, J = 7.5 Hz, 2H), 1.67-1.59 (m, 2H ), 1.42-1.37 (m, 2H), 0.92 (t, J = 7 Hz, 3H).

Example 2

5-butyl-1 [(2'-carboxybiphenyl-4-yl) -methyl] -1,2,3-triazole

Example 1, Part C from 5-butyl-1-[(2'-carboxymethylbiphenyl-4-yl) -methyl] -1,2,3-triazole (458 mg, 1.3 mmol) 363 mg of the title compound are obtained;

Melting point 50 to 56 ° C.

NMR (200 MHz; CDCl ₃ , TMS) δ: 7.96-7.13 (m, 9H), 5.53 (s, 2H), 2.52 (t, J = 7 Hz, 2H) 1.60-1.45 (m, 2H), 1.40-1.25 ( m, 2H), 0.85 (t, J = 7 Hz, 3H).

Example 3

Part A: 4'-azidomethyl-2- (1-triphenylmethyltetrazol-5-yl) biphenyl

This compound is prepared according to the method of Example 1, part A. 4.5 g of the title compound as a white solid is obtained from 4'-broomethyl-2- (1-triphenylmethyl-2-tetrazol-5-yl) biphenyl (5.0 g, 9 mmol).

NMR (200 MHz; CDCl ₃ , TMS) δ: 7.93-6.88 (m, 23H), 4.24 (s, 2H).

Part B: 4- and 5-butyl-1- [2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl-4-yl-methyl] -1,2,3-triazole

These compounds are prepared according to the method of Example 1, part B. 5.4 g of the crude isomer is obtained from 4'-azidomethyl-2- (1-triphenylmethyltetrazol-5-yl) biphenyl (4.5 g, 8.7 mmol), which is on silica gel (300 g, 50% Et _2). O / hexane). 1.81 g of 4-butyl isomer are obtained:

NMR (200 MHz; CDCl ₃ , TMS) δ: 8.0-6.87 (m, 24H), 5.35 (s, 2H), 2.60 (t, J = 7.5 Hz, 2H), 1.59-1.51 (m, 2H), 1.38- 1.27 (m, 2 H), 0.89 (t, J = 7 Hz, 3 H).

1.49 g of 5-butyl isomers are also obtained which exhibit almost the same NMR except that small changes in the form of dispersion in the aromatic region and triplets at 2.60 ppm are shifted to 2.40 ppm.

Part C: 4-Butyl-1-[(2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl) methyl] -1,2,3-triazole

Trifluoroacetic acid solution (1 / 1,30 ml) in water is added dropwise to the slurry in water (15 ml) over several minutes. The slurry is stirred for another 30 minutes and then made basic with 4N NaOH (50 ml). The mixture was extracted twice with ether (100 ml) and the aqueous phase was acidified to pH 4 with 4N HC1 to give a white solid which was filtered off with suction, washed with water and hexane and dried under vacuum to give 754 mg of white solid. (87%) is obtained:

NMR (200 MHz; CDCl ₃ , TMS) δ: 7.91-7.00 (m, 9H), 5.40 (s, 2H), 2.53 (t, J = 7 Hz, 2H) 1.56-1.48 (m, 2H), 1.33-1.22 ( m, 2H), 0.86 (t, J = 7 Hz, 3H).

Example 4

5-butyl-1- [2 '-(1H-detrazol-5-yl) biphenyl-4-yl) methyl] -1,2,3-triazole

This compound is obtained using the same method as in Example 3, Part C.

In this case, the aqueous phase is acidified to produce a rubbery precipitate which can be extracted with ethyl acetate. The organic layer was dried (MgSO ₄ ), filtered and concentrated to yield 600 mg (71%) of the title compound as a white solid.

NMR (200 MHz; CDCl ₃ , CD ₃ OD, TMS) δ: 7.78-7.06 (m, 9H), 5.47 (s, 2H), 2.60-2.52 (t, J = 8 Hz, 2H) 1.65-1.50 (m, 2H ), 1.41-1.30 (m, 2H), 0.91 (t, J = 7 Hz, 3H).

The 1,2,3-triazoles shown in Table I are examples of compounds of the invention which can be prepared or prepared by the process of Examples 1-4 or by the above-described methods.

Table 1 1,2,3-triazole

Example 67

Part A: Methyl 4'-aminomethylbiphenyl-2-carboxylate hydrochloride

A mixture of methyl 4'-azidomethylbiphenyl-2-carboxylate (111 g, 0.42 mol; part A, see Example 1) and 5% Pd on 5% carbon in methanol (1 L) at room temperature overnight under 50 psi H ₂ atmosphere Applied to the parr device. The mixture is filtered through celite and the filtrate is concentrated to a yellow viscous residue (88 g). The crude amine is dissolved in ethyl acetate (500 ml), cooled to 0 ° C., titrated with a 0 ° C. solution of ethyl acetate saturated with hydrogen chloride to form a precipitate (110 ml).

The precipitate was collected by vacuum filtration, washed with ethyl acetate, hexane and dried in vacuo to give 48.5 g (42%);

Melting point 200 to 203 캜.

NMR (200 MHz; CDCl ₃ , CD ₃ OD, TMS) δ: 7.90-7.25 (m, 8H), 4.15 (s, 2H), 4.10-3.80 (br, 3H; exchange D ₂ O), 3.55 (s, 3H ).

Corresponding nitriles are prepared analogously. The corresponding amine hydrochloride (15.4 g; 68%) is obtained from 4'-azidomethylbiphenyl-2-nitrile (22.8 g, 97.3 mmol) (see Example 1, Part A);

Melting point 230 ° C. (decomposition).

NMR (200 MHz; CDCl ₃ , CD ₃ OD, TMS) δ: 7.81-7.47 (m, 8H), 4.19 (s, 2H), 4.0 (br, 3H; exchange D ₂ O).

Part B: 3-Butyl-5-methoxymethyl-4-[(2'-carbomethoxybiphenel-4-yl) methyl] -1,2,4-triazole

A solution of triethyl orthovalerate (3.3 g, 16.2 mmol), methoxyacetyl hydrazide (1.7 g, 16.2 mmol) and DBU (1.8 g, 11.9 mmol) in xylene (50 ml) was refluxed for 2 hours and allowed to stand at room temperature. After cooling, methyl 4'-aminomethylbiphenyl-2-carboxylate hydrochloride (3.0 g, 10.0 mmol) is added. The reaction is again refluxed for 24 hours. After cooling to room temperature, the mixture is diluted with ethyl acetate (150 ml), washed with water (100 ml), saturated aqueous sodium chloride and dried (MgSO). Filtration and evaporation of the solvent gave 4.8 g of a yellow oil which was purified by flash chromatography in silica gel (150 g, 5-10% EtOAc / hexanes) to afford 3.4 g (78%) of the title compound on a yellow viscous oil. .

NMR (200 MHz; CDCl ₃ , TMS) δ: 7.87-7.05 (m, 8H), 5.25 (s, 2H), 4.56 (s, 2H), 3.67 (s, 3H), 3.37 (s, 3H), 2.68 ( t, J = 8 Hz, 2H), 1.73 (m, 2H), 1.38 (m, 2H), 0.90 (t, J = 9 Hz, 3H).

Part C: 3-Butyl-5-methoxymethyl-4-[(2'-carboxybiphenyl-4-yl) methyl] -1,2,4-triazole

Hydrolysis of the 1,2,4-triazole esters is carried out in the same manner for 1,2,3-triazoles, as described in Example 1, Part C.

218 mg of the title compound as a white solid from 3-butyl-5-methoxymethyl-4-[(2'-carbomethoxybiphenyl-4-yl) methyl] -1,2,4-triazole (273 mg, 0.69 mmol) Obtained in (83%);

Melting point 229-232 DEG C (decomposition).

NMR (200 MHz; CDCl ₃ , CD ₃ OD, TMS) δ: 7.90-7.04 (m, 8H), 5.24 (s, 2H), 4.50 (s, 2H), 3.34 (s, 3H), 2.69 (t, J = 8 Hz, 2H), 1.67 (m, 2H), 1.37 (m, 2H), 0.90 (t, J = 7 Hz, 3H).

Example 68

Part A: 3-Butyl-4-[(2'-carbomethoxybiphenyl-4-yl) methyl] -1,2,4-triazole

This compound is prepared according to the method of Example 67, part B.

Triethyl orthoformate (2.7 ml, 16.2 mmol), valeryl hydrazide (1.9 g, 16.2 mmol), DBU (1.8 ml, 11.9 mmol) and methyl 4′-aminomethylbiphenyl in refluxing xylene (50 ml) 2.14 g (56%) of the title compound as a pale yellow oil was obtained from 2-carboxylate hydrochloride (3.0 g, 10.8 mmol), followed by flash chromatography.

NMR (200 MHz; CDCl ₃ , TMS) δ: 8.10 (s, 1H), 7.89-7.11 (m, 8H), 5.14 (s, 2H), 3.66 (s, 3H), 2.71 (t, J = 7 Hz, 2H ), 1.78-1.66 (m, 2H), 1.46-1.34 (m, 2H), 0.92 (t, J = 7 Hz, 3H).

Part B: 3-Butyl-4-[(2'-carboxybiphenyl-4-yl) methyl] -1,2,4-triazole

This compound is prepared according to the method of Example 1, part C.

219 mg (74%) of the title compound as a white solid were obtained from 3-butyl-4-[(2'-carbomethoxybiphenyl-4-yl) -methyl] -1,2,4-triazole (308 mg, 0.88 mmol). To obtain;

Melting point 179 to 201 ° C. (decomposition).

NMR (200 MHz; CDCl ₃ , CD ₃ OD, TMS) δ: 8.10 (s, 1H), 7.95-7.12 (m, 8H), 5.11 (s, 2H), 2.72 (t, J = 8 Hz, 2H), 1.72 -1.68 (m, 2H), 0.92 (t, J = 7 Hz, 3H).

Example 69

Part A: 3-methoxymethyl-5-propyl-4-[(2'-carbomethoxybiphenyl-4-yl) methyl] -1,2,4-triazole

This compound is prepared according to the method of Example 67, part B.

Triethyl orthobutyrate (3.lg, 16.2 mmol), methoxyacetyl hydrazide (1.7 g, 16.2 mmol), DBU (1.8 ml, 11.9 mmol) and methyl 4′-aminomethyl ratio in refluxed xylene (50 ml) 2.3 g (56%) of the title compound as a colorless oil are obtained from phenyl-2-carboxylate hydrochloride (3.0 g, 10.8 mmol), which is flash chromatographed.

NMR (200 MHz; CDCl ₃ , TMS) δ: 7.88-7.04 (m, 8H), 5.25 (s, 2H), 4.56 (s, 2H), 3.65 (s, 3H), 3.34 (s, 3H), 2.66 ( t, J = 7 Hz, 2H), 1.78 (m, 2H), 0.98 (t, J = 7 Hz, 3H).

Part B: 3-methoxymethyl-5-propyl-4-[(2'-carboxybiphenyl-4-yl) methyl] -1,2,4-triazole

This compound is prepared according to the method of Example 1, part C.

Title of white solid from 3-methoxymethyl-5-propyl-4- [(2'-carbomethoxybiphenyl-4-yl) methyl] -1,2,4-triazole (2.lg, 5.5 mmol) 1.84 g (91%) of a compound are obtained;

Melting point 225 to 227.5 ° C. (decomposition).

NMR (200 MHz; CDCl ₃ , CD ₃ OD, TMS) δ: 7.93-7.03 (m, 8H), 5.24 (s, 2H), 4.51 (s, 2H), 3.33 (s, 3H), 2.65 (t, J = 7 Hz, 2H), l.73 (m, 2H), 0.96 (t, J = 7 Hz, 3H).

Example 70

Part A: 3-ethyl-5-methoxymethyl-4-[(2'-carbomethoxybiphenyl-4-yl) methyl] -1,2,4-triazole

This compound is prepared according to the method of Example 67, part B.

Triethylortho propionate (2.86 g, 16.2 mmol), methoxyacetyl hydrazide (1.7 g, 16.2 mmol), DBU (1.8 ml, 11.9 mmol) and ethyl 4'-aminomethyl in refluxed xylene (50 ml) 2.4 g (60%) of the title compound as a pale yellow oil is obtained from biphenyl-2-carbosylate hydrochloride (3.0 g, 10.8 mmol), which is subjected to flash chromatography.

NMR (200 MHz; CDCl ₃ , TMS) δ: 7.88-7.05 (m, 8H), 5.24 (s, 2H), 4.58 (s, 2H), 3.65 (s, 3H), 3.35 (s, 3H), 2.67 ( q, J = 7 Hz, 2H), 1.32 (t, J = 7 Hz, 3H).

Part B: 3-ethyl-5-methoxymethyl-4-[(2'-carboxybiphenyl-4-yl) methyl] -1,2,4-triazole

Title compound of the white solid, from 3-ethyl-5-methoxymethyl-4-[(2'-carbomethoxybiphenyl-4-yl) methyl] -1,2,4-triazole (2.2 g, 6.0 mmol) 1.81 g (86%) are obtained;

Melting point 234-235.5 ° C. (decomposition).

NMR (200 MHz; CDCl ₃ , CD ₃ OD, TMS) δ: 7.93-7.04 (m, 8H), 5.24 (s, 2H), 4.53 (s, 2H), 3.34 (s, 3H), 2.69 (q, J = 7 Hz, 2H), 1.29 (t, J = 7 Hz, 3H).

Example 71

Part A: 3,5-dibutyl-4-[(2'-carbomethoxybiphenyl-4-yl) methyl-1,2,4-triazole

This compound is manufactured according to the method of Example 67, Part B.

Triethyl orthovalerate (3.3 g, 16.2 mmol), valeryl hydrazide (1.9 g, 16.2 mmol), DBU (1.8 ml, 11.9 mmol) methyl 4'-aminomethylbiphenyl- in refluxed xylene (50 ml) 2.5 g, (57%) of the title compound as a pale yellow oil are obtained from 2-carboxylate (3.0 g, 10.8 mmol).

NMR (200 MHz; CDCl ₃ , TMS) δ: 7.88-6.98 (m, 8H), 5.11 (s, 2H), 3.65 (s, 3H), 2.66 (t, J = 7 Hz, 4H), 1.79-1.63 (m , 4H), 1.48-1.33 (m, 4H), 0.89 (t, J = 7 Hz, 6H).

Part B: 3,5-Dibutyl-4-[(2'-carboxybiphenyl-4-yl) methyl] -1,2,4-triazole

This compound is prepared according to the method of Example 1, part C.

From 3,5-dibutyl-4-[(2'-carbomethoxy biphenyl-4-yl) methyl] -1,2,4-triazole (2.4 g, 5.92 mmol)

1.88 g (8%) of the title compound as a white solid is obtained;

Melting point 207-209 캜.

NMR (200 MHz; CDCl ₃ , CD ₃ OD, TMS) δ: 7.93-6.96 (m, 8H), 5.12 (s, 2H), 4.06 (s, 2H), 2.66 (t, J = 7 Hz, 4H), 1.74 -1.59 (m, 4H), 1.45-1.27 (m, 4H), 0.89 (t, J = 7 Hz, 6H).

Example 72

Part A: 3-methoxymethyl-5-propyl-4-[(2'-cyanobiphenyl-4-yl) methyl] -1,2,4-triazole

This compound is prepared according to the method of Example 67, part B.

Triethyl orthobutyrate (2.3 g, 12.3 mmol), methoxyacetylhydrazide (1.4 g, 12.3 mmol), DBU (1.4 ml, 8.9 mmol) and 4'-aminomethylbiphenyl- in refluxed xylene (50 ml) 1.6 g (57%) of the title compound on viscous oil are obtained from 2-nitrile (2.0 g, 8.2 mmol) which slowly crystallizes on standing at room temperature.

NMR (200 MHz; CDCl ₃ , TMS) δ: 7.80-7.12 (m, 8H), 5.28 (s, 2H), 4.56 (s, 2H), 3.34 (s, 2H), 2.65 (t, J = 7 Hz, 2H ), 1.78 (m, 4H), 0.99 (t, J = 7 Hz, 3H).

Part B: 3-methoxymethyl-5-propyl-4-[(2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) -methyl] -1,2,4-triazole

To a solution of 3-methoxymethyl-5-propyl-4-[(2'-cyanobiphenyl-4-yl) methyl] -1,2,4-triazole (1.5 g, 4.33 mmol) in DMF (35 mM) Sodium azide (NaN ₃ , 0.84 g, 13 mmol) and ammonium chloride (NH ₄ Cl, 0.69 g, 13 mmol) are added. The mixture is stirred at 100 ° C. for 4 days and additionally 0.3 g NaN ₃ and 0.23 g NH ₄ Cl are added. Stirring was continued for 2 days at 100 ° C. The solvent is removed (rotary evaporation) and the residue is partitioned between ethyl acetate and water (100 ml). The organic phase is dried (MgSO ₄ ), filtered and viscous light brown oil (1.5 g), which is purified by flash chromatography on silica gel to give 350nlg (21%) of a grayish or white solid;

Melting point 201-205 캜 (decomposition).

NMR (200 MHz; CDCl ₃ , CD ₃ OD, TMS) δ: 7.75-6.93 (m, 8H), 5.19 (s, 2H), 4.47 (s, 2H), 3.31 (s, 3H), 2.62 (t, J = 7 Hz, 2H), 1.78-1.66 (m, 2H), 0.96 (t, J = 7 Hz, 3H).

Table 2 shows examples of the 1,2,4-triazoles of the present invention which may be prepared or prepared by the methods of Examples 67-72 or by the methods described above.

Table 2 1, 2, 4-triazole

Example 170

Part A: 1-methoxy-2,4-octadiun

To a solution of methyl methoxyacetate (20.8 g, 200 mmol) in toluene (250 ml) is added sodium ethoxide (7.5 g, 110 mmol) followed by 2-hexanone (10 g, 100 mmol). The mixture is stirred overnight at room temperature, quenched with water (˜100 ml) and acidified to about pH 5 with glacial acetic acid. The aqueous phase is extracted with ethyl acetate (100 ml) and the combined organic phases are washed with saturated brine, dried (MgSO ₄ ), filtered and concentrated under moderate vacuum (20 mmHg, rotary evaporator) to give 15.8 g of a brown liquid. Fractional distillation at 4 mmHg affords the purified product.

Melting point 111-116 ° C.

The yield is 7.2 g (42%) of clear liquid.

NMR (200 MHz; CDCl ₃ , TMS) δ: 5.79 (s, 1H), 3.99 (s, 2H), 3.43 (s, 3H), 2.33 (t, J = 7 Hz, 2H), 1.65-1.54 (m, 2H ), 1.42-1.27 (m, 2H), 0.93 (t, J = 7 Hz, 3H).

Part B: 3 (5) -Butyl-5 (3) -methoxymethylpyrazole

To a 1-methoxy-2,4-octadione (l.9 g, 11.0 mmol) solution in ethanol (20 ml) is added dropwise a solution of hydrazine hydrate (0.8 g, 16.5 mmol) in ethanol (10 ml) under stirring. After 1 hour at room temperature, the mixture is refluxed for 1 hour and concentrated to an oily residue. The crude product is dissolved in CH ₂ Cl ₂ , dried over MgSO ₄ , filtered and concentrated to yield 1.69 g (91%) of the title compound as a sulfur-orange oil, which is used for subsequent modification without purification again.

NMR (200 MHz; CDCl ₃ , TMS) δ: 6.07 (s, 1H), 4.47 (s, 2H), 3.39 (s, 3H), 2.64 (t, J = 7 Hz, 2H), 1.63 (m, 2H), 1.39 (m, 2H), 0.92 (t, J = 7 Hz, 3H).

Part C: 3-methoxymethyl-5-butyl- and 5-methoxymethyl-3-1-[(2'-carbomethoxybiphenyl-4-yl) methyl] pizol

To a solution of 3 (5) -butyl-5 (3) -methoxymethyl pyrazole (0.86 g, 5.lmmol) in DMF (30 ml) was added NaH (141 mg, 6.2 mmol). The mixture is stirred for 15 minutes and methyl 4'-bromomethylbiphenyl-2-carboxylate (1.87 g, 6.1 mmol) is added as a solution in DMF (5 ml). The mixture is stirred overnight at room temperature and then poured into a separatory funnel containing ethyl acetate (100 ml) and water (100 ml). The aqueous phase is extracted once with ethyl acetate and the combined organic phases are washed twice with water (100 ml), dried (MgSO ₄ ), filtered and concentrated to give 1.6 g of crude product as a brown oil. Isomers are separated by flash chromatography on silica gel (65 g, 20% EtOAc / hexanes).

0.6 g of 5-methoxymethyl-3-butyl isomer (high Rf value) and 0.8 g of 3-methoxymethyl-5-butyl isomer (low Rf value) are separated.

NMR (high Rf isomer; 200 MHz; CDCl ₃ , TMS) δ: 7.82-7.12 (m, 8H), 6.08 (s, 1H), 5.37 (s, 2H), 4.33 (s, 2H), 3.62 (s, 3H), 3.29 (s, 3H), 2.63 (t, J = 7 Hz, 2H), 1.62 (m, 2H), 1.39 (m, 2H), 0.93 (t, J = 7 Hz, 3H).

NMR (low Rf isomer; 200 MHz; CDCl ₃ , TMS) δ: 7.82-7.06 (m, 8H), 6.13 (s, 1H), 5.32 (s, 2H), 4.46 (s, 2H), 3.61 (s, 3H), 3.41 (s, 3H), 2.51 (t, J = 7 Hz, 2H), 1.56 (m, 2H), 1.33 (m, 2H), 0.88 (t, J = 7 Hz, 3H).

Part D: 5-methoxymethyl-3-butyl-1-[(2'-carboxybiphenyl-4-yl) methyl] pyrazole

Hydrolysis of the esters is carried out according to the method of Example 1, part C.

390 mg (80%) of the title compound of light yellow powder were obtained from 5-methoxymethyl-3-butyl-1-[(2'-carboxybiphenyl-4-yl) methyl] pyrazole (500 mg, 1.25 mmol). To obtain;

Melting Point 129-134 ℃

NMR (200 MHz; CDCl ₃ , TMS) δ: 7.93-7.10 (m, 8H), 6.04 (s, 1H), 5.15 (s, 2H), 4.31 (s, 2H), 3.28 (s, 3H), 2.66 (t, J = 7 Hz, 2H), 1.65-1.53 (m, 2H), 1.42-1.32 (m, 2H), 0.92 (t, J = 7 Hz, 3H).

Example 171

3-methoxymethoxy-5-butyl-1-[(2'-carboxybiphenyl-4-yl) methyl] pyrazole

Hydrolysis is performed according to the method of Example 1, part C.

540 mg (81%) of the title compound as a light yellow powder are obtained from 3-methoxymethyl-5-butyl-1-[(2'-carboxybiphenyl-4-yl) methyl] pyrazole (690 mg, 1.76 mmol). ;

Melting point 112-119 ° C

NMR (200 MHz; CDCl ₃ , TMS) δ: 7.94-7.04 (m, 8H), 6.10 (s, 1H), 5.14 (s, 2H), 4.48 (s, 2H), 3.38 (s, 3H), 2.51 (t, J = 7 Hz, 2H), 1.57-1.46 (m, 2H), 1.38-1.27 (m, 2H), 0.87 (t, J = 7 Hz, 3H).

Example 172

Part A: 1-methoxy-7-octene-2,4-dione

Said diketone is manufactured according to the method of Example 170, Part A.

By fractionation at 4 mmHg from 5-hexen-2-one (19.6 g, 0.2 mol), methylmethoxyacetate (42 g, 0.4 mol) and sodium methoxide (15.1 g, 0.22 mol) in toluene (500 ml) 11.3 g (33%) of a compound is obtained;

Melting Point 111-122 ° C

NMR (200 MHz; CDCl ₃ , TMS) δ: 5.79 (m, 2H), 5.10-4.99 (m, 2H), 3.99 (s, 2H), 3.43 (s, 3H), 2.43-2.33 (m, 4H) .

Part B: 3 (5) -but-3-enyl-5 (3) -methoxymethylpyrazole

This compound is prepared in the same manner as in Example 170, Part B.

5.0 g (29.4 mmol) of 1-methoxy-7-octene-2,4-dione and 2.2 g (44.1 mmol) of hydrazine hydrate yield 3.4 g (69%) of the title compound as a yellow oil.

NMR (200 MHz; CDCl ₃ , TMS) ∂: 12-11 (br, 1H), 6.08 (s, 1H), 5.91-5.77 (m, 1H), 5.09-4.97 (m, 2H), 4.48 (s, 2H), 3.37 (s, 3H), 2.77-2.70 (t, J = 7 Hz, 2H), 2.43-2.33 (m, 2H).

Part C: 3-methoxymethyl-5-but-3-enyl and 5-methoxy-methyl-3-but-3-enyl-1-[(2'-carbomethoxyphenyl-4-yl) methyl] Pyrazole

This compound can be prepared using the method described in Example 170, Part C. Alternative methods may also replace NaH with an equivalent amount of K ₂ CO ₃ and heat the mixture at 65 ° C. for 18-24 hours to obtain significant results.

2.0 g (12.0 mmol) of 3 (5) -but-3-enyl-5 (3-)-methoxymethylpyrazole in 75 ml of DMF, 4.8 g of methyl 4′-bromo-methylbiphenyl-2-carboxylate ( 15.6 mmol), 0.33 g (14.3 mmol) sodium hydride or 2.0 g (14.3 mmol) potassium carbonate were obtained and then separated by flash chromatography on silica gel (400 g, 10-20% EtOAc / hexanes). .

1.22 g of 5-methoxymethyl-3-but-3-enyl isomer (high Rf) are isolated;

NMR (200 MHz; CDCl ₃ , TMS) δ: 7.83-7.12 (m, 8H), 6.10 (s, 1H), 5.96-5.83 (m, 1H), 5.38 (s, 2H), 5.11-4.96 (m, 2H), 4.34 (s, 2H), 3.63 (s, 3H), 3.29 (s, 3H), 2.74 (t, J = 8 Hz, 2H), 2.47-2.40 (m, 2H).

2.19 g of 3-methoxymethyl-5-but-3-enyl isomers (low Rf) are also isolated;

NMR (200 MHz; CDCl ₃ , TMS) δ: 7.83-7.07 (m, 8H), 6.15 (s, 1H), 5.81-5.72 (m, 1H), 5.33 (s, 2H), 5.06-4.97 (m, 2H), 4.46 (s, 2H), 3.60 (s, 3H), 3.42 (s, 3H), 2.62 (t, J = 7 Hz, 2H), 2.38-2.04 (m, 2H).

Part D: 3-methoxymethyl-5-but-3-enyl-1-[(2'-carboxybiphenyl-4-yl) methyl] -pyrazole

Ester hydrolysis is performed as in Example 1, Part C.

640 mg (81%) of the title compound having a melting point of 100 to l06 ° C. from 815 mg (2.09 mmol) of 3-methoxymethyl-5-but-3-enyl-1- [2′-carbomethoxyphenyl-yl) methyl] pyrazole Is obtained as a pale yellow solid;

NMR (200 MHz; CDCl ₃ , TMS) δ: 7.94-7.05 (m, 8H), 6.13 (s, 1H), 5.80-5.60 (m, 1H), 5.17 (s, 2H), 5.05-4.96 (m, 2H), 4.48 (s, 2H), 3.38 (s, 3H), 2.61 (t, J = 8 Hz, 2H), 2.31 (m, 2H).

Example 173

Part A: 1-methoxy-2,4-heptadione

This diketone is prepared using the same method as in Example 170, Part A.

6.3 g (40%) of the title compound having a boiling point of 98 to 108 ° C. was obtained from 8.6 g (100 mmol) of 2-pentanone, 200 mmol of methylmethoxyacetate and 7.5 g (110 mmol) of sodium ethoxide in 250 ml of toluene. And distilled at 4 mmHg;

NMR (200 MHz; CDC1 ₃ , TMS) δ: 5.79 (s, 1H), 3.99 (s, 2H), 3.43 (s, 3H), 2.30 (t, J = 7 Hz, 2H), 1.71-1.60 (m, 2H ), 0.96 (t, J = 7 Hz, 3H).

Part B: 3 (5) -methoxymethyl-5 (3) -propylpyrazole

This compound is prepared using the same method as in Example 170, Part B.

5.7 g (84%) of the title compound are obtained as a red solid from 7.0 g (44.2 mmol) of 1-methoxy-2,4-heptadione and 3.3 g (66.4 mmol) of hydrazine monohydrate;

NMR (200 MHz; CDC1 ₃ , TMS) δ: 10.5-9.5 (br, 1H), 6.06 (s, 1H), 4.48 (s, 2H), 3.37 (s, 3H), 2.60 (t, J = 7.5Ha , 2H), 1.70-1.59 (m, 2H), 0.94 (t, j = 7.5 Hz, 3H).

Part C: 3-methoxymethyl-5-propyl- and 5-methoxymethyl-3-propyl-1-[(2'-carbomethoxybiphenyl-4-yl) methyl] pyrazole

This compound is prepared using the method in Example 170, Part C.

3.4 g (22 mmol) of 3 (5) -methoxymethyl-5 (3) -propylpyrazole in 100 ml of DMF, 8.7 g (28.5 mmol) of methyl 4′-bromomethylbiphenyl-2-carboxylate and sodium hydride The material obtained from 0.6 g (26.4 mmol) was finished and flash chromatographed to give 1.23 g (15%) of 5-methoxymethyl (high Rf) isomer and 3.80 g (46%) of 3-methoxymethyl (low Rf) isomer. ) Is obtained;

NMR (high Rf; 200 MHz; CDC1 ₃ , TMS) δ: 7.82-7.06 (m, 8H), 6.14 (s, 1H), 5.32 (s, 2H), 4.46 (s, 2H), 3.61 (s, 3H) , 3.41 (s, 3H), 2.50 (t, J = 7 Hz, 2H), 1.67-1.56 (m, 2H), 0.94 (t, J = 7 Hz, 3H).

NMR (low Rf; 200 MHz; CDC1 ₃ , TMS) δ: 7.82-7.12 (m, 8 H), 6.08 (s, 1 H), 5.37 (s, 2H), 4.33 (s, 2H), 3.61 (s, 3H) , 3.29 (s, 3H), 2.51 (t, J = 7 Hz, 2H), 1.73-1.66 (m, 2H), 0.97 (t, J = 7 Hz, 3H).

Part D: 3-methoxymethyl-5-propyl-1-[(2'-carboxybiphenyl-4-yl) methyl] pyrazole

Hydrolysis of this pyrazole ester is carried out in the same manner as in Example 1, Part C.

546 mg (70%) of the title compound having a melting point of 48 to 53 ° C. from 807 mg (2.13 mmol) of 3-methoxyethyl-5-propyl-1-[(2'-carbomethoxybiphenyl-4yl) methyl] pyrazole Obtained as a solid.

NMR (200 MHz; CDC1 ₃ , TMS) δ: 7.94-7.05 (m, 8H), 6.11 (s, 1H), 5.16 (s, 2H), 4.48 (s, 2H), 3.38 (s, 3H), 2.49 ( t, J = 7.5 Hz, 2H), 1.64-1.53 (m, 2H), 0.93 (t, J = 5 Hz, 3H).

Example 174

5-Methoxymethyl-3-propyl-1-[(2'-carboxybiphenyl-4-yl) methyl] pyrazole

Hydrolysis is carried out in the same manner as in Example 1, Part C.

Melting point from 701 mg (1.85 mmol) of 5-methoxymethyl-3-propyl-1-[(2'-chibomethoxyphenyl-4-yl) methyl] pyrazole

432 mg (64%) of the title compound at 100-104 ° C. are obtained as a white solid.

NMR (200 MHz; CDC1 ₃ , TMS) ∂; 7.93-7.10 (m, 8H), 6.03 (s, 1H), 5.14 (s, 2H), 4.31 (s, 2H), 3.29 (s, 3H), 2.63 (t, J- = 7.5 Hz, 2H), 1.66-1.59 (m, 2H), 0.94 (t, J = 7 Hz, 3H).

Example 175

Part A: Ethyl 2,4-dioxoheptanoate

To a reflux solution of 51.2 g (0.75 mmol) of sodium ethoxide in 170 ml of ethanol was added dropwise over 30 minutes 59 g (0.68 mmol) of a solution of 99 g (0.68 mmol) of diethyl oxalate. The resulting cloudy yellow mixture is refluxed for a further 2 hours, cooled to room temperature, poured into 500 g of ice with stirring and adjusted to PH 1-2 with up to 40 ml of concentrated sulfuric acid. The organic phase was extracted three times with 300 ml each of benzene, washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated, fractional distillation at 0.1 mmHg to give a boiling point of 48.2 g 38% of the title compound. ) Is obtained as a yellow liquid.

NMR (200 MHz; CDC1 ₃ , TMS) δ: 14.6-14.3 (br, 1H; -OH enol), 6.37 (s, 1H; vinyl-H enol), 4.35 (q, j = 7 Hz, 2H), 2.48 (t , J = 7 Hz, 2H), 1.75 -1.64 (m, 2H), 1.38 (t, J = 7 Hz, 3H)), 0.98 (t, J = 7 Hz, 3H).

Part B: Ethyl 3 (5) -propylpyrazole-5- (3) -carboxylate

This compound is prepared in a similar manner to Example 170, Part B. In this case, however, equimolar amounts of diketone and hydrazine hydrate are used and the reaction mixture is stirred for several hours at room temperature (instead of reflux, in order to prevent the reaction of ester functional groups and hydrazine).

From 19.5 g (0.11 mmol) of methyl 2,4-dioxoheptanoate and 5.2 g (0.11 mmol) of hydrazine hydrate in 450 ml of ethanol, 20 g (100%) of the title compound used in the subsequent reaction without further purification were yellow oil. Obtained as

NMR (200 MHz; CDC1 ₃ , TMS) δ: 14.5-14.0 (br, 1H), 6.37 (s, 1H), 4.35 (q, J = 7 Hz, 2H), 2.48 (t, J = 7 Hz, 2H), 1.64 (m, 2H), 1.38 (t, J = 7 Hz, 3H), 0.97 (t, J = 7 Hz, 3H).

Part C: 3-Carboethoxy-5-propyl- and 5-carboethoxy-3-propyl-1-[(2'-carbomethoxybiphenyl-4yl) methyl] pyrazole

This compound is prepared using the method in Example 172, part C.

3.0 g (16.5 mmol) of 3 (5) -methoxymethyl-5 (3) -propylpyrazole-5 (3) -carboxylate in 100 ml of DMF, methyl 4′-bromomethylbiphenyl-2-carboxylate 5.5 The compound obtained from g (18.1 mmol) and 2.5 g (18.1 mmol) of potassium carbonate was finished and flash chromatographed to give 2.lg (31%) of 5-carboethoxy (high Rf) isomer and 3-carboethoxy ( Low Rf) 2.7 g (40%) of isomers are obtained.

NMR (low Rf; 200 MHz; CDCI ₃ , TMS) δ: 7.84-7.09 (m, 8H), 6.67 (s, 1H), 5.44 (s, 2H), 4.42 (q, J = 7 Hz, 2H), 3.62 ( s, 3H), 2.50 (t, J = 7 Hz, 2H), 1.68-1.56 (m, 2H), 1.41 (t, J = 7 Hz, 3H), 1.97 (t, J = 7 Hz, 3H).

NMR (high Rf; 200 MHz; CDCl ₃ , TMS) δ: 7.82-7.23 (m, 8H), 6.70 (s, 1H), 5.76 (s, 2H), 4.29 (q, J = 7 Hz, 2H), 3.60 ( s, 3H), 2.64 (t, J = 7 Hz, 2H), 1.75-1.64 (m, 2H), 1.33 (t, J = 7 Hz, 3H), 0.97 (t, J = 7 Hz, 3H).

Part D: 3-carboxy-5-propyl-1-[(25 ° carboxybiphenyl-4-yl) methyl] pyrazole

Hydrolysis of this pyrazole diester is carried out in the same manner as in Example 1, Part C.

0.92 g (73) of the corresponding title compound at a melting point of 218-222 ° C. from 1.4 g (3.4 mmol) of 3-carboethoxy-5-propyl-1-[(2'-carbomethoxybiphenyl-4yl) methyl] pyrazole %) Is obtained as a pale yellow solid.

NMR (200 MHz; CDC1 ₃ , TMS) δ: 7.90-7.08 (m, 8H), 6.66 (s, 1H), 5.39 (s, 2H), 3.67 (br, 4H; CO ₂ H + H ₂ O), 2.54 (t, J = 7.5 Hz, 2H), 1.69-1.58 (m, 2H), 0.935 (t, J = 7 Hz, 3H).

Example 176

Part A: 3 (5) -hydroxymethyl-5 (3) -propylpyrazole

To a slurry of 5.0 g (132 mmol) of lithium aluminum hydride in 250 ml of dry Ethlet is added dropwise 12.0 g (65.8 mmol) of ethyl 3 (5) -propylpyrazole-5 (3) -carboxylate in 250 ml of ether. The resulting mixture was refluxed for 2 hours and the excess reducing material was cooled by careful dropwise addition of ethyl acetate, then the organic phase was washed with water, dried over MgSO ₄ , filtered and concentrated to give 8.7 g (95) of the title compound. %) Is obtained as a pale yellow waxy solid.

NMR (200 MHz; CDCl ₃ , TMS) δ: 5.99 (s, 1H), 4.64 (s, 2H), 2.56 (t, J = 7.5 Hz, 2H), 1.68-1.57 (m, 2H), 0.93 (t, J = 7 Hz, 3H).

Part B: 3-hydroxymethyl-5-propyl- and 5-hydroxymethyl-3-propyl-1-[(2'-carbomethoxybiphenyl-4-yl) methyl) pyrazole

This isomer is prepared using the method of Example 172, part C.

Crude title isolated from 4.0 g (28.5 mmol) of 3 (5) -hydroxymethyl-5- (3) -propylpyrazole by flash chromatography on silica gel (50% EtOAc / hexanes then EtoAc). 10.6 g of compound is obtained.

5-hydroxymethyl-3-propyl isomer (high Rf) 3.79 (38%) was isolated;

NMR (200 MHz; CDC1 ₃ , TMS) δ: 7.83-7.12 (m, 8H), 6.06 (s, 1H), 5.38 (s, 2H), 4.54 (s, 2H), 3.61 (s, 3H), 2.59 (t, J = 8 Hz, 3H), 1.72-1.61 (m, 2H), 0,97 (t, J = 7 Hz, 3H).

Also, 1.70 g (17%) of 3-hydroxymethyl-5-propyl isomer (low Rf) are separated;

NMR (200 MHz; CDC1 ₃ , TMS) δ: 7.84-7.07 (m, 8H), 6.11 (s, 1H), 5.31 (s, 2H), 4.68 (s, 2H), 3.63 (s, 3H), 2.51 (t, J = 7.5 Hz, 2H), 1.68-1.57 (m, 2H), 0.96 (t, J = 7 Hz, 3H).

Part C: 3-hydroxymethyl-5-propyl-1-[(2'-carboxybiphenyl-4-yl) methyl] pyrazole

This compound is prepared according to Example 1, Part C.

1.4 g (99%) of the title compound having a melting point of 119 to 125 ° C. from 1.5 g (4.1 mmol) of 3-hydroxymethyl-5-propyl-1-[(2'-carbomethoxybiphenyl-4-yl) methyl pyrazole Is obtained as off-white solid.

NMR (200 MHz; CDC1 ₃ , TMS) δ: 7.48-7.00 (m, 8H), 6.03 (s, 1H), 4.85 (s, 2H), 4.62 (s, 2H), 2.47 (t, J = 8 Hz, 2H), 1.59 -1.49 (m, 2H), 0.93 (t, J = 7 Hz, 3H).

Example 177

5-hydroxymethyl-3-propyl-1-[(2'-carboxybifetyl-4-yl) methyl] pyrazole

This compound is prepared according to the method of Example 1, Part C.

2.0 g of 5-hydroxymethyl-3-propyl-1-[(2'-carbomethoxybiphenyl-4-yl) methyl] pyrazole (1.7 g (89%) of the title compound at a melting point of 51 to 58 ° C. from 5.5 mmol) Is obtained as off-white solid.

NMR (200 MHz; CDC1 ₃ , TMS) δ: 7.91-7.04 (m, 8H), 5.99 (s, 1H), 4.43 (s, 2H), 2.55 (t, J = 7.5 Hz, 2H), 1.66 -1.55 (m, 2H), 0.92 (t, J = 7 Hz, 3H).

Example 178

Part A: 3 (5) -Promil-5 (3) -propylpyrazole

To a solution of 6.6 g (47.1 mmol) of 3 (5) -hydroxymethyl-5 (3) -propylpyrazole in 250 ml of methylene chloride is added 41 g (471 mmol) of active magnesium dioxide. The mixture is stirred overnight at room temperature, filtered and concentrated to yield 5.8 g (89%) of the title compound as a pale yellow solid.

NMR (200 MHz; DMSO-d ₆ , TMS) δ: 9.84 (s, 1 H), 6.53 (2 s, 1 H), 2.61 (t, J = 7.5 Hz, 2H), 1.68 -1.53 (m, 2H), 0.89 (t, J = 8 Hz, 3H).

Part B: 3-formyl-5-propyl- and 5-formyl-3-propyl-1-[(2'-carbomethoxybiphenyl-4-yl) methyl] pyrazole

This isomer is prepared using the method of Example 172, part C.

The material obtained from 2.5 g (18.1 mmol) of 3 (5) -formyl-5 (3) -propylpyrazole was flash chromatographed on silica gel (15% EtOAc / hexanes) to yield 7.3 g of the crude title compound isolated. .

1.31 g (20%) of 5-formyl-3-propyl isomer (high temperature Rf) are separated:

NMR (200 MHz; CDC1 ₃ , TMS) δ: 9.79 (s, 1H), 7.82-7.20 (m, 8H), 6.73 (s, 1H), 5.71 (s, 2H), 3.59 (s, 3H), 2.55 (t, J = 7.5 Hz, 2H), 1.75-1.65 (m, 2H), 0.98 (t, J = 7 Hz, 3H).

Also, 2.94 g (45%) of 3-formyl-5-propyl isomer (low Rf) were separated;

NMR (200 MHz; CDC1 ₃ , TMS) δ: 9.97 (s, 1H), 7.86-7.12 (m, 8H), 6.65 (s, 1H), 5.43 (s, 2H), 3.64 (s, 3H), 2.55 (t, J = 7.5 Hz, 2H), 1.70-1.59 (m, 2H), 0.96 (t, J = 7 Hz, 3H).

Part C: 3-formyl-5-propyl-1-[(2'-carboxybiphenyl-4-yl) methyl] pyrazole

This compound is prepared according to the method described in Example 1, Part C.

1.5 g (4.1 mmol) of 3-formyl-5-propyl-1-[(2'-carbomethoxybiphenyl-4-yl) methyl] pyrazole afforded 420 mg (29%) of the title compound as an amorphous solid, Flash chromatography on silica gel (EtOAc).

NMR (200 MHz; CDC1 ₃ , TMS) δ: 9.94 (s, 1 H), 7.96-7.10 (m, 8 H), 6.64 (s, 1 H), 5.41 (s, 2H), 2.53 (t, J = 7.5 Hz , 2H), 1.67-1.56 (m, 2H), 0.93 (t, J = 7 Hz, 3H).

Example 179

Part A: 5-formyl-3-propyl-1-[(2'-carboxybiphenyl-4-yl) methyl] pyrazole

This compound is prepared according to the method of Example 1, Part C. From 0.94 g (2.6 mmol) of 5-formyl-3-propyl-1-[(2'-carbomethoxybiphenyl-4-yl) methyl] pyrazole 600 mg 966% of the title compound were obtained as a yellow solid, Flash chromatography on silica gel (EtOAc) (melting point: 149-153 ° C.).

NMR (200 MHz; CDC1 ₃ , CD ₃ OD, TMS) δ: 9.80 (m, 1H), 7.89-7.13 (m, 8H), 6.77 (s, 1H), 5.69 (s, 2H), 2.66 (t, J = 7.5 Hz, 2H), 1.76-1.61 (m, 2H), 0.98 (t, J = 7 Hz, 3H).

Table 3 below describes examples of the pyrazoles of the process of Examples 170-179 or of the invention which may be prepared or prepared by the process.

[Table 3] Pyrazole

Example 277

Part A: Ethyl-5-formyl-1 [(2'-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl-methyl] pyrrole-2-carboxylate

This compound is prepared according to the method of Example 172, part C.

10.0 g (57.8 mmol) ethyl-5-formylpyrrole-2-carboxylate and 37.0 g (65.8 mmol) biphenyl 4'-bromomethyl-2- (1-triphenylmethyl-tetrazol-5-yl) biphenyl 18.4 g (48%) of the title compound having a melting point of 64 to 72 DEG C.

NMR (20 MHz; CDC1 ₃ , TMS) δ: 9.6 (s, 1H), 7.9-6.8 (m, 25H), 6.05 (s, 2H), 4.2 (q, J = 7 Hz, 2H), 1.25 (t, J = 7 Hz, 3H).

Part B: Epi 5- (1-hydroxypropyl) -1-[(2 '-(1-triphenyl-methyltetrazol-5-yl) biphenyl-4-yl methyl] pyrrole-2-carboxylate

2.0 g of 5-formyl-1-[(2'-triphenyl-methyltetrazol-5-yl) biphenyl-4-yl-methyl] pyrrole-2-carboxylate in 100 ml of anhydrous ether cooled to −78 ° C. (3.1 mmol) 4.0 mmol of ethyl magnesium bromide solution (1.3 ml of 3.0 M solution in ether) is added dropwise over 10 minutes. The mixture is allowed to warm to room temperature with stirring for 2 hours. The mixture can be cooled with 20 ml of aqueous ammonium chloride solution, and the organic phase can be washed with 50 ml of saturated aqueous sodium bicarbonate solution and 50 ml of saturated sodium chloride solution, dried (MgSO ₄ ), filtered and concentrated and chromatographed on silica gel, but is generally no longer purified. 2.0 g (95%) of a white solid, which is used without, and has one spot present by thin layer chromatography.

NMR (200 MHz; CDCl ₃ , TMS) δ: 7.87-6.72 (m, 24H), 6.22 (d, J = 4 Hz, 1H), 5.72 (ABq, J = 12 Hz, J = 16 Hz, 2H), 4.42 -4.28 ( m, 1H), 4.16 (q, J = 7 Hz, 2H), 1.81-1.73 (m, 2H), 1.26 (t, J = 7 Hz, 3H), 0.82 (t, J = 7 Hz, 3H).

Part C: (cis- and trans-) ethyl 5- (1-propenyl) -1- [2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl-4-yl-methyl] pyrrole- 2-carboxylate

Ethyl 5- (1-hydroxypropyl) -1- (2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl-4-yl-methyl] pyrrole-2-carboxylate 2.0 in 100 ml of methylene chloride 2.0 ml (12.0 mmol) of DBU of g (3.0 mmol) is added followed by 0.7 ml (9.0 mmol) of methanesulfonyl chloride The mixture is stirred overnight at room temperature followed by 2.0 ml of DBU and methanesulfonyl chloride 0.7 ml of additional aliquot is added and the mixture is stirred for an additional 24 hours The mixture is poured into a separating funnel, washed three times with 50 ml of water, then with 50 ml of saturated sodium bicarbonate demand, filtered with dry (MgSO ₄ ) and Concentrate the crude residue by flash chromatography on silica gel (150 g, 10-30% EtOAc / hexanes) to afford the title compound as a mixture of cis / trans isomers (about 1/4).

NMR (200 MHz; CDCl ₃ , TMS; trans-isomer) δ: 7.88-6.75 (m, 24H), 6.33 (d, J = 4 Hz, 1H), 6.19-6.13 (m, 2H), 5.56 (s, 2H ), 4.14 (q, J = 7 Hz, 2H), 1.68 (d, J = 5 Hz, 3H), 1.24 (t, J = 7 Hz, 3H).

The cis-isomer is evident by weak allyl methyl (double, J = 5 Hz) at 1.85δ as well as weak benzyl methylene (single) at 5.66δ.

This cis-trans mixture can be carried out in the next step or can be subsequently transformed into propenyl homologs after separation.

Part D: Ethyl-5-n-propyl-1- [2 '-(1-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl-methyl] pyrrole-2-carboxylate

(Cis-mill trans-)-ethyl 5- (1-propenyl) -1- [2 '-(1-triphenylmethyl) in 35 ml of benzene containing 5% Pd / C (35 mg) in a Parar bottle A solution of 350 mg (0.53 mmol) of tetrazol-5-yl) biphenyl-4-yl-methyl] pyrrole-2-carboxylate is placed in a Parr apparatus under 40 psi H ₂ and stirred at room temperature for 4 hours. The mixture was suction filtered through Celite and concentrated to afford 350 mg of a white solid.

NMR (200 MHz; CDCl ₃ , TMS) δ: 7.88-6.68 (m, 24H), 6.01 (d, J = 4 Hz, 1H), 5.53 (s, 2H), 4.14 (q, J = 7 Hz, 2H), 2.33 (t, J = 7.5 Hz, 2H), 1.57-1.50 (m, 2H), 1.25 (t, J = 7 Hz, 3H), 0.83 (t, J = 7.5 Hz, 3H).

Part E: Ethyl 5-n-propyl-1- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl-methyl] pyrrole-2-carboxylate

This compound is prepared according to the method of Example 3, part C.

From 400 mg (0.6 mmol) of ethyl 5- n -propyl-1- [2 '-(1-triphenyl-1-methyltetrazol-5-yl) biphenyl-4-yl-methyl] pyrrole-2-carboxylate 126 mg (50%) of the title compound are obtained as an amorphous white solid.

NMR (200 MHz; CDCl ₃ , TMS) δ: 7.87-6.83 (m, 9H), 6.05 (d, J = 4 Hz, 1H), 5.56 (s, 2H), 4.20 (q, J = 7 Hz, 2H), 2.48 (t, J = 7.5 Hz, 2H), 1.68-1.57 (m, 2H), 1.31 (t, J = 7 Hz, 3H), 0.95 (t, J = 7 Hz, 3H).

Example 278

Part A: Ethyl 5-propyl-1-[(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] pyrrole-2-carboxylate

This compound is prepared according to the method of Example 172, part C.

8.2 g (71%) of the title compound from 4.0 g (23.9 mmol) of ethyl 5-formylpyrrole-2-carboxylate and 10.0 g (28.7 mmol) of tert -butyl 4'-bromomethylbiphenyl-2-carboxylate Was obtained as a pale yellow oil and then flash chromatographed on silica gel (10% EtOAc / hexanes).

NMR (200 MHz; CDC1 ₃ , TMS) δ: 9.75 (s, 1 H), 7.78-6.96 (m, 10 H), 6.19 (s, 2 H), 4.30 (q = J = d 7.5 Hz, 2H), 1.35 (t , J = 7.5 Hz, 3H), 1.15 (s, 9H).

Part B: ethyl 5- (1-hydroxypropyl) -1- [2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] pyrrole-2-carboxylate

This compound is prepared according to the method of Example 277, part B.

6.4 g (83%) of the title compound was obtained from 7.2 g (16.6 mmol) of ethyl 5-formyl-1-[(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] pyrrole-2-carboxylate. After obtained, flash chromatography on silica gel (10% EtOAc / hexanes).

NMR (200 MHz; CDCl ₃ , TMS) δ: 7.77-6.90 (m, 9H), 6.24 (d, J = 4 Hz, 1H), 5.85 (ABq, J = 17 Hz, J = 23 Hz, 2H), 4.51 (m, 1H), 4.20 (q, J = 7.5 Hz, 2H), 1.89 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H), 1.21 (s, 9H), 0.95 (t, J = 7.5 Hz, 3H).

Part C: (cis- and trans-) ethyl 5- (1-propenyl) -1- [2'-tert-butoxycarbonylbiphenyl-4-yl-methyl] pyrrole-2-carboxylate

This cis / trans mixture (in this case the cis-isomer is observed to be only about 10%) is prepared according to the method of Example 277, Part C.

The title compound was yellow viscous from 5.7 g (12.3 mmol) of ethyl 5- (1-hydroxypropyl) -1- [2'- tert -butoxycarbonylbiphenyl-4-yl-methyl] pyrrole-2-carboxylate Obtained as an oil, followed by flash chromatography on silica gel.

NMR (200 MHz; CDCl ₃ , TMS, trans-isomer) δ: 7.77-6.99 (m, 10H), 6.35-6.25 (m, 2H), 5.72 (s, 2H), 4.22 (q, J = 7 Hz, 2H ), 1.83 (d, J = 5 Hz, 3H), 1.26 (t, J = 7 Hz, 3H), 1.18 (s, 9H).

Part D; Ethyl 5-n-propyl-1-[(2'- tert -butoxycarbonylbiphenyl-4-yl) -methyl] pyrrole-2-carboxylate

This compound is prepared according to the method of Example 277, part D.

1.2 g (2.7 mmol) (cis- and trans-) ethyl 5- (1-propenyl) -1-[(2'- tert -butoxycarbonylbiphenyl-4-yl) methyl] pyrrole-2-carboxylate 0.9 g (75%) of the title compound as a viscous oil, followed by flash chromatography on silica gel (EtOAc / hexanes).

NMR (200 MHz; CDCl ₃ , TMS) δ: 7.78-6.90 (m, 9H), 6.05 (d, J = 4 Hz, 1H), 5.68 (s, 2H), 4.20 (q, J = 7 Hz, 2H), 2.51 (t, J = 7.5 Hz, 2H), 1.72-1.57 (m, 2H), 1.29 (t, J = 7 Hz, 3H), l.20 (s, 9H), 0.98 (t, J = 7 Hz, 3H) .

Part E: ethyl 5- n -propyl-1-[(2'-carboxybiphenyl-4-yl) -methyl] pyrrole-2-carboxylate

800 mg (1.34 mmol) of ethyl 5- n -propyl-1- [2'- tert -butoxycarbonylbiphenyl-4-yl-methyl] pyrrole-2-carboxylate were stirred with 6 ml of formic acid at room temperature for 4 hours. (Dissolve slowly into a homogeneous yellow solution). The mixture was diluted with water to about 50 ml to afford a white precipitate, which was then filtered and subsequently purified by flash chromatography on silica gel (10% EtOAc / hexanes) to give 419 mg (80%) of the compound at a melting point of 111 to 115 ° C. To obtain.

NMR (200 MHz; CDCl ₃ , TMS) δ: 7.92-6.91 (m, 9H), 6.02 (d, J = 4 Hz, 1H), 5.65 (s, 2H), 4.19 (q, J = 7 Hz, 2H), 2.49 (t, J = 7.5 Hz, 2H), 1.67-1.55 (m, 2H), 2.26 (t, J = 7 Hz, 3H), 0.92 (t, J = 7 Hz, 3H).

Example 279

Part A: 5-n-propyl-l-[(2'-carboxybiphenyl-4-yl) -methyl] -pyrrole-2-carboxylic acid

This compound is prepared using the method of Example 1, Part C.

188 mg of the title compound having a melting point of 135 to 137 ° C. (decomposition) from 235 mg (0.6 mmol) of ethyl 5-n-propyl-l-[(2'-carboxybiphenyl-4-yl) -methyl] -pyrrole-2-carboxylate (86%) is obtained as a white solid.

NMR (200 MHz; CDCl ₃ , CD ₃ OD, TMS) δ: 7.86-6.88 (m, 9H), 6.05 (d, J = 4 Hz, 1H), 5.62 (s, 2H), 2.50 (t, J = 7 Hz, 2H), 1.70-1.58 (m, 2H), 0.95 (t, J = 7 Hz, 3H).

Example 280

Part A: 5-n-propylpyrrole-2-carboxaldehyde

87 ml (147 mmol) of 5-butyllithium solution (l.5M) in pentane was added to 12.0 g (49.1 mmol) of anhydrous solution of 6-dimethylamino-1-azafulbene dimer (125) in 500 ml of THF at -15 ° C. Add dropwise over minutes. The yellow cloudy solution is slowly warmed to 0 ° C. over 10 minutes and stirred at this temperature for an additional 20 minutes. The resulting dark purple solution is treated with 19.2 ml (196 mmol) of 1-iodopropane and allowed to warm to room temperature over 2 hours. The mixture is treated with 20 ml of water and 20 ml of saturated aqueous sodium bicarbonate solution and refluxed for 15 hours. The mixture is extracted with methylene chloride and the organic phase is washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and rotary evaporated to concentrated to 15.2 g of a thick liquid residue. Flash chromatography (silica gel, 500 g; EtOAc / hexanes, 5/95) yields 7.85 g (60%) of the title compound as a light brown liquid.

NMR (200 MHz; CDCl ₃ , TMS) δ: 10.6-10.4 (br, 1H), 9.35 (s, 1H), 6.90 (t, J = 1-2 Hz, 1H), 6.05 (t, J = 1-2 Hz, 1H), 2.6 (t, J = 7 Hz, 2HO, 1.75-1.55 (m, 2H), 1.0-0.8 (t, J = 7 Hz, 3H).

Part B: 5-n-propyl-1-[(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] pyrrole-2-carboxaldehyde

2.5 g (18.9 mmol) of 5-n-propylpyrrole-2-carboxaldehyde and 7.2 g (20.7 mmol) of tert-butyl 4′-bromomethylbiphenyl-2-carboxylate in 75 ml of methylene chloride 15 ml of N NaOh and 1.5 g (3.7 mmol) are added. The mixture is stirred vigorously at room temperature overnight (up to 18 hours). The organic phase is washed with 50 ml of water and 50 ml of saturated aqueous sodium chloride solution, dried (MgSO ₄ ), filtered and concentrated to give 10.1 g of a thick oily residue. Flash chromatography (silica gel, 300 g; EtOAc / hexanes, 1/9) yields 5.85% (79%) of a pale yellow viscous oil.

NMR (200 MHz; CDCl ₃ , TMS) δ: 9.46 (s, 1 H), 7.78-6.96 (m, 9 H), 6.15 (d, J = 3 Hz, 1 H), 5.69 (s, 2H), (t, J = 7.5 Hz, 2H), 1.72-1.61 (m, 2H), 1.20 (s, 9H), 0.97 (6, J = 7 Hz, 3H).

Part C: 5-n-propyl-1-[(2'-carboxybiphenyl-4-yl) -methyl] pyrrole-2-carboxaldehyde

This compound is prepared according to the method of Example 278, part E. In this case, the reaction mixture is diluted with water to give an oily precipitate; Thus, extracted with EtOAc, the organic phase is dried (MgSO ₄ ), filtered and concentrated, and purified by flash chromatography.

1.0 g (0.55 mmol) of 5-n-propyl-1-[(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] pyrrole-2-carboxaldehyde and 10 ml of formic acid have a melting point of 117 to 120 ° C. 0.64 g (72%) of the title compound as an off-white solid are obtained.

NMR (200 MHz; CDCl ₃ , TMS) δ: 9.44 (s, 1 H), 7.93-6.95 (m, 9 H), 6.13 (d, J = 4 Hz, 1 H), 5.68 (s, 2H), 5.3-5.0 (br) , 1H, washes out in D20), 2.51 (t, J = 7.5 Hz, 2H), 1.67-1.55 (m, 2H), 0.92 (t, J = 7 Hz, 3H).

Table 4 below describes examples of the methods of Examples 277-280 or of the pyrrole of the present invention which may be prepared or prepared by the method.

[Table 4] Pyrrole

The compounds of Examples 370 to 372 are prepared as follows;

Example 370

Part A: Ethyl 5- (1-hydroxybutyl) -1- [2 '-(1-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl-methyl] pyrrole-2-carboxylate

This compound is prepared according to the method of Example 277, part B.

5.5 g (7.77 mmol) of ethyl 5-formyl-1- [2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl-4-yl-methyl] pyrrole-2-carboxylate and n-propyl From 5.8 ml (11.6 mmol) magnesium chloride (2.0 M solution in ether) 5.5 g of the title compound is obtained as a yellow viscous oil which is finished and used in the next step without further purification.

NMR (200 MHz; CDCl ₃ , TMS) δ: 7.77-6.90 (m, 9H), 6.24 (d, J = 4 Hz, 1H), 5.85 (q, J = 17 Hz and 23 Hz, 2H), 4.51 (m, 1H) , 4.20 (q, J = 7.5 Hz, 2H), 1.85 (m, 4H), 1.27 (t, J = 7.5 Hz, 3H), 1.21 (s, 9H), 0.95 (t, J = 7.5 Hz, 3H) .

Part B: (cis- and trans-) ethyl 5- (1-butenyl) -1- [2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl-4-yl-methyl] pyrrole- 2-carboxylate

This compound is prepared according to the method of Example 277, part C.

8.9 g of 5- (1-hydroxybutyl) -1- [2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl-4-yl-methyl] pyrrole-2-carboxylate in 150 ml of THF ( 12.9 mmol), 5.9 ml (77.6 mmol) of methanesulfonylcoolide and 11.8 ml (77.6 mmol) of DBU were obtained 4.3 g (49%) of the title compound as a white solid, followed by silica gel (400 g; EtOAc / hexane, 1 /). Flash chromatography on 4) (melting point; 119-121 ° C.).

NMR (200 MHz; CDCl ₃ , TMS) δ: 7.88-6.77 (m, 24H), 6.36-6.06 (m, 3H; 2H vinyl + 2H (pyrrole), 5.57 (s, 2H), 4.14 (q, J = 7 Hz , 2H), 2.10-1.97 (m, 2H), 1.25 (t, J = 7 Hz, 3H), 0.94 (t, J = 7 Hz, 3H).

Part C: Ethyl-5-n-butyl-1- [2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl-4-yl-methyl] pyrrole-2-carboxylate

This compound is prepared according to the method of Example 277, part D.

(Cis- and trans-) methyl 5- (1-butenyl) -1- [2 '-(1-triphenylmethyltechrazol-5-yl) biphenyl-4- in 200 ml of benzene under H ₂ (40 psi) 4.0 g (5.97 mmol) of 1 -methyl] pyrrole-2-carboxylate and 3.66 g (91%) of the title compound were obtained as a white solid from 5% PD / C 0.60, which were then filtered and concentrated without further purification. Continue to use it.

NMR (200 MHz; CDCI ₃ , TMS) δ: 7.88-6.68 (m, 24H), 6.01 (d, J = 4 Hz, 1H), 5.53 (s, 2H), 4.15 (q, J = 7 Hz, 2H), 2.36 (t, J = 7 Hz, 2H), 1.55-1.47 (m, 2H), 1.32-1,18 (m and t, J = 7 Hz, 5H), 0.83 (t, J = 7 Hz, 3H).

Part D: Ethyl-5-n-butyl-1- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl-methyl] pyrrole-2-carboxylate

This compound is prepared according to the method of Example 3, Part C.

In this case, the starting material is not easily slurried in water due to its waxy property, so it is first dissolved in EtOAc. Ethyl 5-n-butyl-1- [2'-1-triphenylmethyltetrazol-5-yl) biphenyl-4-yl-methyl] pyrrole in EtOAc / TFA / H ₂ O (20 ml / 10 ml / 10 ml) 1.23 g (64%) of the title compound was obtained as a white solid from 3.0 g (4.45 mmol) of 2-carboxylate, followed by silica gel (30 g; flash chromatography on EtOAc (reflux) and recrystallization from EtOAc / hexane (melting point; 157). To 158 ° C).

NMR (200 Hz; CDC1 ₃ , TMS) δ: 8.14-6.89 (m, 9H), 6.05 (d, J = 4 Hz, 1H), 5.59 (s, 2H), 4.15 (q, J = 7 Hz, 2H), 2.53 (t, J = 7 Hz, 2H), 1.64-1.53 (m, 2H), 1.42-1,22 (m and t, J = 7 Hz, 5H), 0.90 (t, J = 7 Hz, 3H).

Example 371

Part A: 5-n-butyl-1- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl-methyl] pyrrole-2-carboxylic acid

This compound is prepared according to the method of Example 1, Part C.

0.68 g (75) of the title compound from 0.97 g (2.26 mmol) of ethyl 5-n-butyl-1- [2'-1H-tetrazol-5-yl) biphenyl-4-yl-methyl] pyrrole-2-carboxylate %) Is obtained as off-white solid, which is then recrystallized from EtOAc / EtOH / hexane (melting point 190 to 191 ° C. (decomposition)).

NMR (200 Hz; CDC1 ₃ , TMS) δ: 7.86-6.82 (m, 9H), 6.05 (d, J = 4 Hz, 1H), 5.58 (s, 2H), 2.51 (t, J = 7 Hz, 2H), 1.62 -1.54 (m, 2H), 1.41-1, 26 (m, 2H), 0.89 (t, J = 7 Hz, 3H).

Example 372

Part A: 5-n-propyl-1- [2 '-(1-triphenyltetrazol-5-yl) biphenyl-4-yl-methyl] pyrrole-2-carboxaldehyde

This compound is prepared according to the method of Example 280, part B.

From 2.0 g (15.1 mmol) of 5-n-propylpyrrole-2-carboxaldehyde and 10.9 g (19.7 mmol) of 4'-bromomethyl-2- (1-triphenylmethyltetrazol-5-yl) biphenyl 5.2 g (75%) of the title compound are obtained as a yellow solid, followed by flash chromatography (silica gel, 550 g; EtOAc / hexanes, 1/9).

NMR (200 Hz; CDC1 ₃ , TMS) δ: 9.45 (m, 1H), 7.9-6.7 (m, 24H), 6.10 (d, J = 2 Hz, 1H), 5.50 (s, 2H), 2.35 (t, J = 7 Hz, 2H), 1.7-1.5 (m, 2H), 0.8 (t, J = 7 Hz, 3H).

Part B: 5-n-propyl-1- [2 '-(1H-detrazol-5-yl) biphenyl-4-yl-methyl] pyrrole-2-carboxaldehyde

4.05 g (6.6 mmol) of 5-n-propyl-1- [2 '-(1-triphenyldetrazol-5-yl) biphenyl-4-yl-methyl] pyrrole-2-carboxaldehyde in 25 ml of THF To the solution was added 11 ml of 4N HCl with stirring. The mixture is stirred at room temperature for 5 hours. THF is removed by rotary evaporation and the pH of the residue is adjusted to 5-6 with less than 10 ml of 4N NaOH. The product is extracted twice with 50 ml of EtOAc and the organic layer is dried (MgSO ₄ ), filtered and concentrated. Flash chromatography of 1.97 g of a red solid residue on silica gel (30 g; EtOAc / hexane, 1/1) afforded 1.4 g of the title compound as a light red solid at melting point 68-71 ° C.

NMR (200 Hz; CDC1 ₃ , TMS) δ: 9.34 (s, 1H), 7.87-6.86 (m, 9H), 6.19 (d, J = 4 Hz, 1H), 5.57 (s, 2H), 2.53 (t, J = 7 Hz, 2H), 1.70-1.59 (m, 2H), 0.93 (t, J = 7 Hz, 3H).

[Usage]

Hormone vasodilator II (AII) causes many biological responses (eg vasoconstriction) through stimulation of its receptors on cell membranes. To identify compounds such as AII antagonists that can interact with AII receptors, ligand-receptor binding assays are used as initial screens. Analyzes are described in Glossmann emd, J. Biol . Chem ., 249 , 825 (1974), but may be slightly modified. The reaction mixture contains "Tris buffer and rat adrenal cortical granules (AII receptor source) in 2 nm ³ H-AII with or without latent AII antagonist. The mixture is incubated for 1 hour at room temperature and subsequently freed. Filter rapidly through a micro-fiber filter, rinse to terminate the reaction Quantify receptor-bound ³ H-AII in the filter by scintillation counting Totally bound ³ H-AII The inhibitory concentration (IC ₅₀ ) of the 50% substitution potential AII antagonist of is expressed as a measure of the substitution of this compound for the AII receptor (Table 5).

The therapeutic effect of latent hypertension of a compound of the present invention can be found by administering this compound to rats with hypertension by ligation of the left renal vein. Cagniano et al., J. Phamacol Exp. Ther ., 208 , 310 (1979). This method results in increased blood pressure by increasing renin production while raising AII levels. The compound is administered orally and / or intravenously via cannula in the jugular vein. Arterial blood pressure is subsequently measured directly via the carotid cannula and recorded using a transformer and plural recording method. Post-treatment blood pressure levels are compared with pre-treatment levels to determine the effect of the compound's hypertension on treatment [Table 5].

[Capacity form]

The compounds of the present invention can be administered for the treatment of hypertension according to the present invention by a method of effecting contact between the active ingredient compound and the site of action of the warm-blooded animal. Parenteral administration can be, for example, subcutaneously, intravenously, intramuscularly or intraperitoneally. Or at the same time, in some cases, oral administration.

The compounds may be administered by conventional methods effective for use as a separate therapeutic agent or in combination with a pharmaceutical substance which is a mixture of therapeutic agents. They may be administered alone, but are generally administered with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice. When diuretics such as furosemide and hydroclothiazide are administered before the compound of the present invention, the therapeutic effect of the hypertension of the compound of the present invention can be enhanced.

The compounds of the present invention are sometimes used to prevent renal insufficiency caused by administration of NSAIDs such as ibuprofen, indometacin, pyroxicam, naproxen, and keto-phene. It can be used in combination with non-steroidal anti-inflammatory drugs (NSAID'S) such as profen, tolmetin, meclofenamate, sulindac and aza-propazone.

For the purposes of the present technology, warm-blooded animals are a member of the animal kingdom with equilibrium mechanisms, including mammals and birds.

Dosages will vary depending on the age, health and weight of the receptor, the severity of the disease, the type of concurrent treatment, and if desired the frequency of the desired treatment and the nature of the effect. Generally, the daily dose of the active ingredient compound will range from about 0.5 to 500 mg per kg of body weight. Generally, from 1 to 100 mg, and preferably from 2 to 80 mg, per kg of body weight per day is effective in one or more applications to achieve the desired results.

The active ingredient may be administered orally in solid dosage form (eg, capsules, tablets, powders) or in liquid dosage form (eg, elixir syrups, suspensions). Parenteral administration can also be in the form of sterile liquid doses.

Gelatin capsules contain the active ingredient and powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be made into sustained release products that provide continuous release of the drug over several hours. Compressed tablets can be sugar-derived or film-derived to remove unpleasant taste and protect the tablet from the atmosphere, or enteric-derived for selected disintegration within.

Liquid dosage forms for oral administration may contain coloring and flavoring agents to increase patient tolerance.

In general, water, suitable oils, salts, aqueous textrose, related sugar solutions and glycols such as propylene glycol or polymethylene glycol are suitable carriers for parenteral solutions. Solutions for parenteral administration are preferably water-soluble salts of the active ingredient, suitable stabilizers, and, if necessary, buffers. Antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid are suitable stabilizers used alone or in combination. It is also used as citric acid and its salts, and sodium EDTA. Parenteral solutions may also contain preservatives such as benzalkonium chloride, methyl- or propylparaben and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences , A. Osol.

Pharmaceutical dosage forms useful for administering a compound of the invention can be illustrated as follows:

[capsule]

Many unit capsules are prepared by filling standard 2-Piece hard gelatin capsules with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate, respectively.

[Soft Gelatin Capsule]

Mixtures of the active ingredients in digestible oils such as soybean oil, cottonseed oil or olive oil are prepared and infused with gelatin using a positive displacement pump to produce soft gelatin capsules containing 100 mg of the active ingredient. This capsule is washed and dried.

[refine]

Many tablets are prepared by conventional methods such that the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Appropriate coatings can be applied to improve taste and retard absorption.

[Injection amount]

Parenteral compositions suitable for injection administration are prepared by stirring 1.5% by weight of active ingredient in 10% by volume of propylene glycol. This solution is prepared in volume using distilled water for injection and sterilized.

[Suspension]

Aqueous suspensions are prepared for oral administration so that 5 ml each contains 100 mg of finely divided active ingredient, 100 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 mg of sorbitol solution U. S. P. and 0.025 ml of vanillin.

Table 5 Angiotensin II

Significant decrease in blood pressure below 1-10 mg / kg

Significant decrease in blood pressure below 2-100 mg / kg

NA ³ -no activity at 30 mg / kg intravenously or at oral 30 mg / kg

No activity at NA-100mg / kg dose

NT-Not tested.

Claims (27)

A hypertension therapeutic compound of formula (1) or a pharmaceutically suitable salt thereof.

(Ⅰ) Wherein X, Y and Z are independently CR²ego ; A is a carbon-to-carbon single bond, CO, O, NHCO or OCH₂And; R^OneSilver alkyl of 2 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms, or (CH₂) nOR⁴And R is^OneThis (CH₂) nOR⁴If R²Is H, alkyl of 2 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms; R²Is = H, alkyl having 2 to 6 carbon atoms, alkenyl or alkynyl having 3 to 6 carbon atoms; -(CH₂) nOR⁴;

-

; -(CH₂)_nS (O) tR⁴;

;

;

; -(CH₂)_nNHSO₂R¹¹; -(CH₂)_nF; or

And; R³Is -CO₂H, -NHSO₂CF₃;

Or (CH₂)_nSH and: R⁴Or H, alkyl of 1 to 4 carbon atoms and R⁵H halogen, NO₂Is methoxy or alkyl of 1 to 4 carbons: R⁶Is H, alkyl of 1 to 6 carbon atoms; Cycloalkyl having 3 to 6 carbon atoms, (CH₂)_mC₆H₅OR⁷Or NR⁸R⁹Is; R⁷Is H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R⁸And R⁹Is independently H, alkyl of 1 to 4 carbon atoms, phenyl or benzyl or NR⁸R⁹Are formulated together

Forms a ring of; Q is NR¹⁰, O or CH₂ego ; R¹⁰Is H, alkyl or phenyl having 1 to 4 carbon atoms; R¹¹Silver alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, or (CH₂)_pC₆H₅ego ; R¹²Is H, alkyl of 1 to 4 carbon atoms or acyl of 1 to 4 carbon atoms; m is 0-6; n is 1 to 6; p is 0 to 3; r is 0 to 1; t is 0-2. The compound of claim 1, wherein A is an intercarbon single bond or NHCO; Each R ¹ is alkyl, alkenyl or alkynyl having 3 to 5 carbon atoms; R ² is H, alkyl, alkenyl or alkynyl having 3 to 5 carbon atoms, respectively; -(CH ₂ ) _n OR;

;

;

;

; -(CH ₂ ) NHSO ₂ R ¹¹ ;

Or (CH ₂ ) _n F; R ³ is -CO ₂ H, -NHSO ₂ CF ₃ and

And; R ⁴ is H or CH ₃ ; R ⁵ is H; R ⁶ is H, alkyl of 1 to 6 carbon atoms, OR ⁷ or NR ⁸ R ⁹ ; R ⁷ is alkyl having 1 to 5 carbon atoms; R ⁸ and R ⁹ are independently H, alkyl of 1 to 4 carbon atoms or combine with nitrogen

Forming a ring; R ¹¹ is CF ₃ , alkyl or phenyl having 1 to 4 carbon atoms; m is 0-3 and n is 1-3 or a pharmaceutically suitable salt thereof. The method of claim 1 wherein, A is a single bond between carbon, R ¹ or alkenyl alkyl or alkenyl of 3 to 5 carbon atoms or CH ₂ OR ^4, and the proviso that when R ¹ is CH ₂ OR ⁴ R ² is C 3 -C 5 is alkyl or alkenyl; R ² is alkyl or alkenyl having 3 to 5 carbon atoms, CH ₂ OR ⁴ ,

,

, or

ego ; R ⁶ is H, OH or alkyl having 1 to 4 carbon atoms; R ⁷ is alkyl having 1 to 4 carbon atoms or a pharmaceutically suitable salt thereof. The compound of claim 1, which is 5- n -propyl-1-[(2'-carboxybiphenyl-4-yl) methyl] pyrrole-2-carboxylic acid. A pharmaceutical composition comprising a pharmaceutically suitable carrier and the compound of any one of claims 1-4. A process for preparing the compound of claim 1, wherein the compound of formula (99a) is reacted with a compound of formula (5), wherein the heterocyclic ring is pyrrole and A is a single bond, O or CO.

Wherein X is halogen. A process for preparing the compound of claim 1, wherein the compound of formula (98) is reacted with a compound of formula (47), wherein the heterocyclic ring is pyrrole and A is a single bond, O or CO.

A process for preparing the compound of claim 1, wherein the compound of formula (101) is reacted with a compound of formula (47), wherein the heterocyclic ring is pyrrole and A is a single bond, O or CO.

A process for preparing the compound of claim 1, wherein the compound of formula (105) is reacted with a compound of formula (47), wherein the heterocyclic ring is pyrrole and A is a single bond, O or CO.

After reacting a compound of the general formula (119) with a compound of the general formula (5), the heterocyclic ring is characterized by converting a pyrrole cyclic carbonyl group to a carbonyl group with R ¹ and R ² precisely. A process for preparing the compound of claim 1, wherein pyrrole and A is a single bond, O or CO.

R ² is CH ₂ CN to the corresponding compound of (formula 127) characterized by Sikkim hydrolysis, a method of preparing a R ² is CH ₂ CO ₂ H the compound of claim 1 (Compound 128). R ² is and wherein the Sikkim reduction of the compound (Compound 128) corresponding CH ₂ CO ₇ H of of paragraph 1, R ² is (CH _{2) 2} OH is for preparing a compound of claim 1 (Compound 130) Way. The compound of claim 1 wherein R ² is CH ₂ CO ₂ R ⁷ , characterized by reacting the corresponding compound of claim 1 wherein R ² is CH ₂ CO ₇ H (formula 128) with alcohol R ⁷ OH. 129). Reacting the corresponding compound of claim 1 wherein R ² is CH ₂ OH or (CH ₂ ) ₂ OH (Formula 125, Formula 130) with acid anhydride (R ⁴ CO) ₂ O or acid chloride R ⁴ COC ₁ A process for preparing the compound of formula 1 (General Formula 131) wherein R ² is (CH ₂ ) OCOR ⁴ or (CH ₂ ) ₂ OCOR ⁴ . Reacting the corresponding compound of claim 1 wherein R ² is CH ₂ OH (formula 125) with compound R ⁴ L, wherein L is halogen, mesylate or tosylate, wherein R ² is CH ₂ OR ⁴ Process for preparing the anti-compound (Formula 132). The compound of claim ¹ , wherein R ² is CH ₂ OR ⁴ , characterized by reacting the corresponding compound of formula ² with CH ₂ Cl (formula 126) with compound R ⁴ OM, wherein M is sodium or potassium (Formula 132) How to prepare. Reacting the corresponding compound of claim 1 wherein R ² is (CH ₂ ) _m CO ₂ H (formula 128) with a compound of formula R ⁸ R ⁹ NH, wherein R ² is — (CH ₂ ) _m A process for preparing the compound of Formula 1 (General Formula 133) which is CONR ⁸ R ⁹ . R ² is - (CH _{2) n} NH ₂ the corresponding compound (Compound 134) was characterized by a compound R ¹¹ SO ₂ Sikkim CI reaction with, R ² is a - a _{(CH 2) n NHSO 2 R} 11 claim Process for preparing the compound of Formula 1 (General Formula l35). A corresponding compound _wherein R ² is — (CH ₂ ) _n NH ₂ is reacted with a compound of the general formula R ¹¹ OCOC1 or R ¹¹ OCO ₂ R ¹¹ , whereby R ² is — (CH ₂ ) _n NHCO ₂ R ¹¹ A process for the preparation of the compound of claim 1 (formula 136). The corresponding compound of Formula ^{2 wherein} R ² is CH ² CI (formula 126) is reacted with compound R ⁴ SM, in which M is sodium or potassium, to give sulfide (Formula 137) and then optionally oxidized to sulfoxide or sulfone 138), wherein R ² is-(CH ₂ ) _n S (O) tR ⁴ , wherein the compounds of formula 1 (General Formulas 137, 138) are prepared. Reacting the corresponding compound of claim 1 _wherein R ² is-(CH ₂ ) _n OH (formula 139) with a fluorinating agent so that the compound of claim 1 _wherein R ₂ is-(CH ₂ ) _n F Formula 140). R ² is - (CH _{2) n} SCOCH ₃ of the corresponding compound (Compound 141) was characterized by Sikkim hydrolysis R ² is a - a (CH _{2) n} SH the compound of claim 1 (Compound 140) Preparation How to. R ² is characterized by reacting the corresponding compound of formula cyanomethyl (formula 127) with sodium azide and ammonium chloride or by addition reaction in a 2,3-bipolar cycle with trialkyltin or triaryltin azide A method for producing the compound of formula 1 (General Formula 143), which is ^divalent tetrazolylmethyl. A process for preparing the compound of formula 1 (formula 144) wherein R ² is -CHO, characterized by oxidizing the corresponding compound of formula 1 wherein R ² is -CH ₂ OH. R ² is -CHO the corresponding compound (Compound 144) a reacting alkenyl chain (chain), or R ² is extended by featuring Sikkim dehydration of the corresponding compound (Compound 145) to the CHOHCHRR 'are R ² Al to A process for preparing the compound of claim 1 (formula 146). A process for preparing the compound of formula 1 (formula 149) wherein R ¹ is alkenyl, characterized by contacting a corresponding compound (Formula 148) wherein R ¹ is bromoalkyl. R ¹ is a compound which corresponds to the -CHO (formula 150), the chain (chain) extending to the reaction or the general formula RCH = PPh ₃ compound and reacting the compound of claim 1 characterized by the alkenyl R ¹ is seen in ( Formula (151) is prepared.