PT95127B - PROCESS FOR THE PREPARATION OF IMIDAZOLIC COMPOUNDS BEHAVIORING AS SUBSTITUENTS ARILIC NUCLEOS CONDENSED WITH BLOCKING ACTION OF ANGIOTENSIN II AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM - Google Patents

Abstract

A description is given of a process for the preparation of compounds of the general formula <IMAGE> or of the salts thereof that are acceptable from the pharmaceutical point of view, which consists in binding, in appropriate solvents, the nitrogen atom of the imidazole group of an initial compound of the general formula <IMAGE> to a benzyl compound of the general formula <IMAGE> in order to obtain a compound of the general formula <IMAGE> and subjecting this compound, which in addition to the imidazole function includes other moieties of the molecule that are consistent with the necessary chemical transformations, to reactions which differ with regard to the order of the synthesis phases, the protecting groups needed, the conditions of exposure and the activation of the benzyl position. These compounds, which are angiotensin II blockers, are used in the treatment of hypertension or of heart failure, or in the prevention of renal insufficiency.

Description

PROCESS FOR THE PREPARATION OF IMIDAZOLIC COMPOUNDS

BEHAVING AS SUBSTITUTE ARYLIC NUCLEUS

CONDENSED WITH ANGIOTENSIN II BLOCKING ACTION AND PHARMACEUTICAL COMPOSITIONS THAT

CONTAIN THEM

J

Relative Study

This study is a partial continuation of USSN patent 07 / 375,069 filed on June 30, 1989. Also Carini, Duncia and Wong in US Patent Application No. 07 / 279,194, filed on December 6, 1988, reveal and claim substituted imidazoles that are angiotensin II (AII) blockers and their use, alone or in combination with other drugs, in the treatment of hypertension and congestive heart failure.

BACKGROUND OF THE INVENTION

Scope of the Invention

The present invention concerns new substituted imidazoles and processes for their preparation. The present invention also concerns pharmaceutical compositions containing the new imidazoles and pharmaceutical methods for their use, alone and in combination with other drugs, especially

diuretics and non-steroidal anti-inflammatory drugs.

des (NSAID's).

The compounds of the present invention inhibit the action of the hormone angiotensin II (AII) and, therefore, are useful in relieving angiotensin-induced hypertension. The renin enzyme acts on a globulin ₂ of the blood cell, the angiotensinogen, to produce angio tensin I which is then converted, via the angiotensin converting enzyme, to AII. The latter substance is a powerful vasopressor agent that has been considered as an agent that causes the production of high blood pressure in several species of mammals, such as rats, dogs and men. The compounds of the present invention inhibit the action of AII at its receptors on targeted cells and thus prevent the increase in blood pressure produced through this hormone-receptor interaction. By administering a compound of the present invention to a mammal species with hypertension due to IIA, it reduces blood pressure. The compounds of the present invention are also useful in the treatment of congestive heart failure. Administration of a compound of the present invention with a diuretic, such as furosemide or hydrochlorothiazide, either as a combination therapy, in stages (first, the diuretic}, or as a physical mixture, increases the antihypertensive effect of the compound Administration of a compound of the present invention with a non-steroidal anti-inflammatory drug (NSAID) can prevent renal failure, which sometimes results from administration

traction of an NSAID.

European patent application 0 253 310, published on January 20, 1988, states that certain substituted imidazois block the AII receptor and, therefore, are useful in the relief of angiotensin-induced hypertension, as well as in the treatment of heart failure congestive. The imidazois described have the general formula:

The imidazois of the present invention differ from those of European patent application 0 253 310 in the substituents and R _g in positions 4 and 5 of the imidazolic nucleus. In EPA 0 253 310, the symbols Rj and Rg have the following definitions:

R ₇ represents a hydrogen, fluorine, chlorine, bromine and iodine atom or a NO ₂ , CF 4 or CN group; Rg represents a hydrogen atom or a CN group, alkyl of 1 to 10 carbon atoms, alkenyl c

J from 3 to 10 carbon atoms, or the same groups substituted by F; phenylalkenyl, wherein the aliphatic moiety represents 2 to 6 carbon atoms; - (CH,) -imidazol-1-yl; - (CH,) -1,2,3-triazolyl optionally substituted m by one or two groups chosen from CO ₂ CH ₃ or alkyl of 1 to 4 carbon atoms; - (CH,) -tetrazolyl;

zu ΙΪΙ

- ^(CH 2'n ^0R ll ^! - ^(CH 2 ⁵ n ° ^CR 14 '· - - ^(CH 2> „ ^SE 15' ^R 14

-CH = CH (CH,) CHOR.,;

s lo

-CH = CH (CH _{2) s} COR _16;

O

II

-CR

16 '

-CH = CH (CH ₂ ) _s OCR ₁₁ ;

(CH,) _s -CH-COR ₁₆ ; - ( ^CH 2> n ^CR 16 ^; n ° ^C NH ^R 10;

CH ₃

T 0 “Wn ^NR ll ^COR lO '- < ^CH 2 ⁵ n ^NR ll ^CNHR l _O ; - (CH,) ^ SO ^; T

II

- (CH,) _n ^N RqqCR ^ Q; etc., wherein the symbols R- ^ θ, R. ^, ^R 14 ^{# R} 15 ' ^R 16 ^{and the} hoists defined below in the present invention.

Pais et al., In Circulation Research, 29, 673 (1971) describe the introduction of a sarcosine residue in position 1 and alanine in position 8 of the endogenous, vasoconstrictor hormone, AII to obtain a (octa) peptide that blocks the effects of AII on pressure

Blood from rats, without the spinal cord. This analogue, '1 Q

Sar, Ala / AII, initially called P-113 and, subsequently, Saralasina, was considered one of the most potent antagonist competitors of AII actions, although, like most of the so-called peptide AII antagonists, it also has agonist actions of itself. Saralasin has shown its action at lower blood pressures in mammals and humans when (high) pressure is dependent on circulating AII (Pais et al., Circulation Research, 29, 673 (1971); Streeten and Anderson, Handbook of Hypertension, Vol. 5, Clinical Pharmacology of Antihypertensive Drugs, AE Doyle (Editor), Elsevier Science Publishers BV, p. 246 (1984)). However, due to its agonist character, saralasin gradually and without violence usually presents pressure effects when the pressure is not maintained by the IIA. As a peptide, the pharmacological effects of saralasin are relatively short-lived and manifest only after parenteral administration, with oral doses being ineffective. Although the therapeutic use of AII peptide blockers, such as saralasin, is strictly limited due to its oral ineffectiveness and short duration of action, its greatest utility is as a standard pharmaceutical compound. Some known non-peptide antihypertensive agents act by inhibiting an enzyme, called an enzyme (ACE), which converts angiotensin, which is responsible for converting angiotensin I to AII. Such agents are thus referred to as ACE inhibitors or converting enzyme inhibitors (CEI's). Captppril and enalapril are commercially available CEIs. Based on clinical and experimental evidence # about 4% of hypertensive patients do not respond to treatment with CIS 's. But when a diuretic - such as furosemide or hydrochlorothiazide - is administered together with a CIS - the blood pressure of most hypertensive patients normalizes effectively. The diuretic treatment converts the non-renin-dependent state into a renin-dependent state # in the regulation of blood pressure. Although the imidazoles of the present invention act by a different mechanism - i.e., by blocking the AII receptor instead of inhibiting the enzyme that converts angiotensin - both mechanisms involve interference with the renin-angiotensin relationship. A combination of the CEI enalapril maleate and the diuretic hydrochlorothiazide is commercially available under the name Comer (r) ciai: Vaseretic ^ from Merck & Co. Publications that refer to the use of diuretics with CEI's for the treatment of hypertension, either with initial application of the diuretic # or in physical combination are disclosed by Keeton # TK and Campbell # W.B. # Parmacol Rev., 31:81 (1981) and Weinberger # M.K. # Medical Clinics N. America # 71: 979 (1987). Diuretics have also been administered - also - in combination with saralasin to increase the antihypertensive effect.

Non-steroidal anti-inflammatory drugs (NSAID ¹ s) have been reported to cause renal failure in patients with low renal perfusion and high

Plasma level AII (Dunn, M.J., Hospital Practice, 19:99, 1984). The administration of an AII blocking compound of the present invention in combination with an NSAID (either in stages or in physical combination) can prevent such renal failure. Saralasin has been shown to inhibit the renal vasoconstrictor effect of indomethacin and meclofenamate in dogs (Satoh et al., Circ. Res. 36/37 (Suppl. I): 1-89, 1975; Blasingham et al., Am, J> Physiol. 239:; F36O, 1980). The CEI captopril has been shown to nullify the renal vaso-constrictor effect of indomethacin in dogs with non-bipotensive hemorrhage (Wong et al., J. Pharmacol. Exp, Pher. 219: 104, 1980).

Summary of the Invention

In accordance with the present invention, new compounds of general formula (I) are prepared which have angiotensin II antagonist properties and are useful as antihypertensives.

(I) ζ

XÓ in which ο symbol represents 0

4-CO ₂ H; 4-CO ₂ R ₉ ; -OS-OH;

-SOgH;

-C (CF ₃ ) ₂ OH; -OP-OH; -POgH ^ -NH-P-OH;

OH

OH

4-NHSO ₂ CH ₃ ; 4-NHSO ₂ CF ₃ ; -CONNOR. ^;

SO ₂ NH ₂ ;

OH 0

I II

-C — P- OH

OH / n

CO ₂ H

-CONHNHSO ₂ ^CF 3? ⁴ -COHN-CHCH3 Hg;

(£ - isomer)

II

OR —C-NHS0 _o - (CHj zzs

R ₂ represents a hydrogen, chlorine, bromine, iodine or fluorine atom or a NO ₂ group; CN; alkyl with 1 to 4 carbon atoms; alkoxy with 1 to 4 carbon atoms; CO ₂ K; NHSO ₂ CH ₃ ; NHSO ₂ CF _g ; or a group of general formula CO ₂ Rg or CONHOR ^ ₂ ^{or a} 9 ^ru “po SO ₂ NH ₂ ;

H aryl or furyl;

R _g represents a hydrogen, chlorine, bromine, iodine or fluorine atom or an alkyl group of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms;

the symbol represents a CN or N0 ₂ group or a group of the general formula COgR · ^;

R4 represents a hydrogen atom or an alkyl group with 1 to 6 carbon atoms, cycloalkyl with 3 to 6 carbon atoms or alkenyl or alkynyl with 2 to 4 carbon atoms;

Rg represents an alkyl group with 2 to 10 carbon atoms, alkenyl or alkynyl with 3 to 10 carbon atoms or the same groups substituted by a fluorine atom or a group of the general formula ^CO 2 ^R 14 * cycloalkyl with 3 to 8 carbon atoms, cycloalkylalkyl with 4 to 10 carbon atoms; cycloalkylalkenyl or cycloalkylalkynyl with 5 to 10 carbon atoms; a group of general formula (CH / ^ ZÍCH / ^ Rg optionally substituted by a fluorine atom or by a group of general formula ^C0 2 ^R i4 'benzyl or benzyl substituted in the phenyl nucleus by 1 or 2 halogen atoms, alkoxy with 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or nitro;

R4 represents a 1- or 2-naphthyl group; 5- or

6-naphthoquinonyl; 3-, 4- or 5-acenaftyl; 3-, 4or 5-acenaphenyl; 1-, 2- or 9-anthracenyl; 1- or 2-anthraquinonyl; 1-, 2-, 3-, 4-, or 9-phenanthrenyl; 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl; 1-, 3-,

4-, 5-, 6-, 7- or 8-isoquinolinyl; 2-, 3-, 4-,

5-, 6- or 7 ~ indolyl which can be substituted in

lower alkyl nitrogen nucleus with 1 to 5 carbon atoms or benzyl; 4-, 5-, 6- or 7-indenyl?

2-, 3-, 4-, 5-, 6- or 7-benzofuryl; 2-, 3-, 4-,

5-, 6- or 7-benzothienyl; 1-, 2-, 3-, or 4-dibenzofuryl; 1-, 2-, 3- or 4-dibenzothienyl; 1-, 2-,

3- or 4-fluorenyl; any of the preceding polycyclic aryl groups substituted by 1 or 2 substituents chosen from halogen atoms or alkoxy groups having 1 to 5 carbon atoms, alkyl having 1 to 5 carbon atoms, -N0 ₂ , -CN, -CF ^ or groups of general formula: -COR ₁₆ , -CH ₂ OR ₁₇ , NHC0R ₁₇ ,

-CONR ^ gR ^ g, S (O) pR ₁₇ and SO ₂ NR ^ gR ^ g; 4,5-dicarboxyl-1- or 2-naphthyl anhydride; or alkyl substituted with 1 to 10 carbon atoms, alkenyl or alkynyl with 2 to 10 carbon atoms replaced by a polycyclic aryl group, optionally substituted, as defined above; -S (o) -heteroaryl;

P

-NR ^ g-heteroaryl and -NH-SO ₂ -heteroaryl; the symbol Rg represents the groups:

- (CH

OR

I ¹⁴

-CH = CH (CH_) CHOR.

S lo

II

-CH = CH (CH _{2) s} COR _i6;

II

-CR

II

-CH = CH (CH) OCR. _η ;

s 11 '

- (CH ₂ ) _m -tetrazolyl;

II

- ^(CH 2 ' _n ^CR 16

Y íl

- ⁽ CK ₂ ) _n OCNHR _lo

- 12 - / < ^CH 2'n ^NR ll ^C0R 10 ^! <= κρ _Λι 0Μ »ι ₀ ; - (CH ₂ ! _N NR _u so ₂ R _lo ;

- (C ^H 2> nNRii ^c R _{10 i the} symbol R _n represents the group of general formula; y ^r oa ⁰

I ²⁴ II

-CH-OCR ₂₁ ;

R- ^ θ represents an alkyl group with 1 to 6 carbon atoms or perfluoroalkyl with 1 to 6 carbon atoms, 1-adamantyl, 1-naphthyl, 1- (1-naphthyl) ethyl or (CH ,,) C, H _c ;

the symbol represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, phenyl or benzyl;

R ₁₂ represents a hydrogen atom or a methyl or benzyl group;

the symbol R ^ ₃ represents the groups: -C0 _o H; -C0 _or R _Q ;

9 '

-CH ₂ CO ₂ H; -CH ₂ CO ₂ R ₉ ;

-O-S-OH; -O-P-OH; -SOgH; -NHP-OH

OH

OH

-PO ₃ H ₂ ; -C (CP ₃ ) ₂ OH; -NHSO ₂ CH ₃ ; -NHSO ₂ CF ₃ ; -NHCOCF ^ ·

R ^ ₄ represents a hydrogen atom or an alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, phenyl or benzyl;

the symbol represents a hydrogen atom or an alkyl group with 1 to 6 carbon atoms, cycloalkyl with 3 to 6 carbon atoms, phenyl, benzyl, acyl with 1 to 4 carbon atoms or phenacyl;

the symbol represents a hydrogen atom or an alkyl group with 1 to 6 carbon atoms, cycloalkyl with 3 to 6 carbon atoms or (CFL ·) C, H _and pob or a group of the general formula QR4,? or ^NR i8 ^R 19 * the symbol R ^ ₇ represents a hydrogen atom or an alkyl group with 1 to 6 carbon atoms, cycloJ

alkyl having 3 to 6 carbon atoms, phenyl or benzyl;

the symbols R ^ g and R ^ each independently represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, phenyl, benzyl or ^ -methylbenzyl, or considered together with a nitrogen atom form a nucleus of formula;

wherein Q represents a group of the general formula NR ₂₀ , an oxygen atom or a CK ₂ group;

R ₂ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms or phenyl;

the symbol R ₂₁ represents an alkyl group with 1 to δ carbon atoms, a group of general formula:

-NR ₂₂ R ₂ 3 or the -CHCH ₂ CO ₂ CH _{3 group} ;

NH, the symbols R ₂₂ and R ₂₃ each independently represent a hydrogen atom or an alkyl group with 1 to 6 carbon or benzyl atoms or taken together, represent the group (CH „),

XI where the symbol u represents an integer from 3 to δ;

the symbol R ₂₄ represents a hydrogen atom or a

/

CHg or -C _g Hç- group;

the symbol R ₂ 5 represents an NHCONH ₂ group, nhcsnh ₂ ,

group of general formula NR ₂₇ R _2g or 0R _2g ;

R ₂ g represents a hydrogen atom or an alkyl group having 1 to 6 carbon, benzyl or allyl atoms;

the symbols R ₂₇ and R ₂ q each independently represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms or phenyl;

the symbols R ₂ ^ and each independently represent an alkyl group with 1 to 4 carbon atoms or, taken together, represent a group - (CH ₂ ) _q -, the symbol Rg ^ represents a hydrogen atom or a group alkyl with 1 to 4 carbon atoms,

-CH ₂ CH = CK ₂ or -CH ₂ C ₆ H ₄ Rg ₂ ;

Rg ₂ represents a hydrogen atom or an NO ₂ , NH _{2 #} OH or OCH _{3 group} ;

X represents a single carbon-carbon bond, or a group -CO-, -CH ₂ -, -0-, -S-, -NH-,

-N-, -CON-, -NCO-, -OCH ₂ -, -CH ₂ O-, ^R 26 ^R 23 ^R 23

-!

-SCH -, -CH ₂ S-, -NHC (R ₂₇ ) (R ₂₈ ), -NR ₂₃ SO ₂ -, -SO ₂ NR ₂₃ -, -C (R ₂₇ ) (R ₂₈ ) NH-, -CEí = CH—, -CF = CF-,

-CH = CF-, -CF = CH-, -CH ₂ CH ₂ -, -CF ₂ CF ₂ -,

p.4

-CHOCOR

-CH17

NR

-C- or ^R 29 ° / ^0R

-c30 symbol 1 represents an oxygen or sulfur atom;

Z represents an oxygen or sulfur atom or a group of the general formula NR NR ^;

m represents an integer from 1 to 5;

n represents an integer from 1 to 10;

the symbol p represents zero or an integer from 1 to

3;

q represents an integer 2 or 3; the symbol p represents zero or an integer 1 or 2; the symbol s represents zero or an integer from 1 to

5;

the symbol t represents zero or the integer 1; and the pharmaceutically acceptable salts of these compounds; with the proviso that:

(1) the group R ^ does not occupy the ortho position;

(2) when the R ^ symbol represents the formula group

-X, the symbol X represents a single bond and the symbol R ₁₃ represents the group CO ₂ H or, then the symbol R ^ ₃ must be in N the group

N '

goal or ortho position? or when the symbols and X have the meanings defined before, and the symbol

R ^ ₃ represents the groups NHSO ₂ CF ₃ or NHSOgCHg, the ^R i 3 symbol R ^ ₃ must occupy the ortho position; / (3) when the symbol represents the group -X and the symbol X does not represent a single bond, then the symbol R ^ ₃ must occupy the ortho position except when the symbol X = NR ₂₃ CO and the symbol R ^ ₃ represents the NHSO ₂ CF ₃ or NHSO ₂ CH _{3 groups} , and then the symbol R ₁₃ must occupy the ortho or meta positions;

(4) when the R4 symbol represents a 4-CO ₂ H group or a salt thereof / the R _g symbol cannot represent an S-alkyl group;

(5) when R ^ represents a 4-CO ₂ H group or a salt thereof, the substituent at position 4 of the imidazole cannot be CH ₂ OH, CH ₂ OCOCH ₃ or CH ₂ CO ₂ H;

(6) when the R ^ symbol represents a group -

methoxybenzyl powder;

the symbol Rg does not represent a group 18 Ζ, (7) the group R ^ does not represent -CHCH ^ CH ^ CHg or CH ^ OH, F

The substituents of R ^ mentioned above can be represented by the following formulas:

J

1- or 2-naphthyl

5- or 6-naphthoquinonyl

4,5-dicarboxyl anhydride

4,5-disubstituted

-1- or 2-naphthyl

1- or 2-naphthyl

J

1- or 2-anthraquinonil

1-, 2- or 9-anthracenyl

or 8-quinolinyl

1-, 3-, 4-, 5-, 6-, 7or 8-isoquinolinyl

indenil

2-, 3-, 4-, 5-, 6- or

2-, 3—, 4-, 5—, 6— or 7-benzothienyl

1-, 2-, 3- or 4-fluorenyl

1-, 2-, 3-, or 4-dibenzofuryl

1-, 2-, 3- or 4-

2—, 3—, 4 - _t 5—, 6— or 7-indolyl

1-, 2-, 3-, 4- or

9-phenanthrenyl in which symbol A represents a single carbon-carbon bond or a bivalent alkyl radical of 1 to 10 carbon atoms or a bivalent alkenyl or alkynyl radical of 2 to 10 carbon atoms and the symbol R represents a hydrogen atom , a lower alkyl group of 1 to 5 carbon atoms or a benzyl group.

For their antihypertensive activity, new compounds that have the following general formula are preferred:

in which R ₁ represents a -CO ₂ H group; -NHSO ₂ CF ₃ ;

Rg represents an alkyl group of 3 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, benzyl substituted in the phenyl nucleus with more than two chosen groups /

between halogen atoms, or alkoxy groups of 1 to 4 carbon atoms, alkyl of 1 to carbon atoms and nitro;

Rg represents the groups (CH ₂ > _m -tetrazolyl,

- ^(CH 2 ^! N ^0R ll ^! - ^(CH 2 ^! N ° ^R 14 ^; the symbol

-CH = CH (CH „) CE,., -CH = CH (CH) CHOR,.;

2s ± o> · «Lív

15 '

II

- ^(CH 2 ⁾ n ^CR ls' - ^(CH 2V ^HC0R 10 <CH ₂ > _n «HSO ₂ R _lo ; -CR _lg ;

the symbol represents a COgH group; -CO ₂ R _g ;

NHS0 ₀ CPo? SO.H; or - / \\ '

N H the symbol

J represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms, or a group of the general formula 0R ₁₇ or ^NR 18 ^R 19 ^; the symbol

X represents a single carbon-carbon bond or a -CO-, -CON-, ι zz ^R 23 group

-NCO-, -OCHg-, -CHgO-, -SCH -CHgS-, ^R 23

-NHCH -CHgNH- or -CH = CH-; and /

the pharmaceutically acceptable salts of these compounds.

The most preferred compounds are those in the group where:

R ₂ represents a hydrogen or halogen atom or an alkyl group of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms;

Rg represents an alkyl, alkenyl or alkynyl group of 3 to 7 carbon atoms;

R4 represents a 1- or 2-naphthyl group; 2-,

3- or 4-quinolinyl; 1-, 3- or 4-isoquinolinyl, 1-, 2- or 3-indolyl;

the Rg symbol represents a group of general formula:

O

II (CH ₂ ) _m OR ₁₁ ; - (CH ₂ ) _m OCR ₁₄ ; -CH = CH-CHOR ₁₅ ;

II

II

- ^tCH 2> m ^CR 16 '· -CH ₂ NHCOR _1o ;

OR -COR. } ^ _r symbol R represents _the group CF ^, alkyl of 1 to 6 carbon atoms or phenyl;

R ^^ representa represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms;

R ₁₃ represents a group C0 _or H; C0 _o CH _o 0C0C (CH _q ) _q ;

3 '

3

the symbol represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms;

the symbol represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms or acyl of 1 to 4 carbon atoms;

R ^ g represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms or a group of general formula 0R ^ ₇ or a group: y / \

-N Q;

the symbol m the symbol X represents an integer from 1 to 5; represents a single bond, an oxygen atom or a -CO- · group; -NHCO- or OCHg? and their pharmaceutically acceptable salts.

Note that during the text, when an alkyl substituent is mentioned, the normal alkyl structure (i.e., butyl is n-butyl) is mentioned, unless otherwise specified.

Pharmaceutically suitable salts include both metallic (inorganic) salts and organic salts, a list of which is given in Reminqton ¹ s Pharmaceutical Sciences, 17® Edition, pg. 1418 (1985). It is well known to those skilled in the art that an appropriate salt form is chosen based on its chemical and physical stability, abundance, hydroscopy and solubility. The preferred salts of the present invention, for the reasons mentioned above, are potassium salts

Sodium, calcium, calcium and ammonium.

Also within the scope of the present invention are pharmaceutical compositions comprising an appropriate pharmaceutical carrier and a compound of general formula (I) and methods of using compounds of general formula (I) in the treatment of hypertension and congestive heart failure. The pharmaceutical compositions may optionally contain one or more other therapeutic agents, such as a diuretic or a non-steroidal anti-inflammatory drug. Also within the scope of the present invention is a method of preventing renal failure resulting from the administration of a non-steroidal anti-inflammatory drug (NSAID) consisting of the administration of a compound of the general formula (I), in stages or in combination physical with the NSAID. The compounds of the present invention can also be used as diagnostic agents to test the renin-angiotensin system.

It will be noted that in the previous structural formula, when a radical can be a substituent in more than one previously defined radical, that first radical can be chosen, independently, from each previously defined radical. For example, the radicals R ^, R ₂ and Rg can each represent the group of general formula CQNHQR. ^. The radical R ₁₂ does not need to represent the same substituent in each of the radicals ^R 1 # ^R 2 ' ^{and R} 3' ^but P ° ^{must be} free, independently, for each of them.

J; z

Detailed Description

Synthesis

The new compounds of general formula (I) can be prepared using the reactions and techniques described in this section. Reactions are carried out in a solvent suitable for the reagents and materials used and suitable for carrying out the transformations. It is known by those skilled in the matter of organic synthesis that the present functioning of imidazois and other parts of the molecule must comply with the proposed chemical transformations. This will often be necessary to assess the synthetic phases, necessary protecting groups, deprotection conditions and activation of a benzyl position to facilitate the nitrogen bond in the imidazolic nucleus. Throughout the next section, not all compounds of general formula (I) that fit within a given group, can necessarily be prepared using all the methods described for that group. Substituents in the starting materials may be incompatible with some of the reaction conditions required in some of the described methods. Such restrictions for substituents that are compatible with the reaction conditions will become readily apparent to those skilled in the art and, therefore, alternative methods described should be used.

J

Layout 1

The)

Ν = Ν

Λ

Generally, compounds of the general formula (.3) can be prepared by means of direct alkylation on imidazois (JL), with a halide, tosylate or mesylate (_25, appropriately protected benzyl, in the presence of a base, as shown in phase a). Preferably, the metal imidazole salts are prepared by reacting the imidazole (JL) with a proton receptor, such as MH, in which the symbol M represents lithium, sodium or potassium, in a solvent such as dimethylformamide (DMF ) or by reacting it with a metal alkoxide of the general formula MOR, in which R represents a methyl, ethyl, t-butyl or similar group, in an alcoholic solvent such as ethanol or t-butanol, or in of a dipolar aprotic solvent, such as dimethylformamide. The imidazolic salt is dissolved in an inert aprotic solvent, such as DMF, and treated with an appropriate alkylating agent (.2). Alternatively, the ima. dazol (1) can be alkylated with a benzyl halide (2, where X = Br, Cl) in the presence of a base, such as sodium carbonate, potassium carbonate, triethylamine or pyridine. The reaction is carried out in an inert solvent, such as DMF or DMSO, at a temperature between 20 ° C and the reflux temperature of the solvent, for 1 to 10 hours.

For example, the intermediate compound 4-nitro benzyl (.3a, where R ^ = 4-NO2? ° ^R 2 ^{= R} 3 ⁼ = H) can be obtained by means of direct alkylation in imidazole (1) with a halide, tosylate or mesylate of

4-nitrobenzyl, in the presence of a base.

J

As the symbols R ^ and Rg are different, mixtures of two regioisomeric compounds are obtained by alkylation (3b and 3c), in which the symbols R ₇ and Rg are exchanged. When the R _g symbol represents the CHO group, the alkylation is such that the benzyl group appears to be well attached to the adjacent nitrogen, preferably. These isomers have distinct biological and physical properties, and can be commonly separated and isolated using conventional separation techniques, such as chromatography and / or crystallization.

In all the series examined, the most rapidly eluted isomer of a given pair has greater biological potency than the less rapidly eluted isomer.

Alternatively, any benzylamine derivative (£), conveniently functional, can be converted to imine (6) by treatment with an acyl minoketone (jõ) in the presence of an inert solvent, such as benzene, toluene or the like, and a catalytic amount of p-toluenesulfonic acid or molecular chips, N. Engel and W. Steglich, Liebiqs Ann. Chem., 1916, (1978), or in the presence of alumina, P. Texier-Boulet, Synthesis, 679, (1985). The resulting imine (6) can be cyclized to imidazole (3.) N-benzyl with phosphorus pentachloride (PCip, phosphorus oxychloride (POClg) or triphenylphosphine (PPhg) in dichloroethane in the presence of a base, such as triethylamine, N. Engel and W. Steglich, Liebigs Ann. Chem1916, (1978).

Acylaminoketone is easily obtained

J (j>) from amino acids, via Dakin-West reaction, H.D. Dakin, R. West, J, Biol. Chem., 78, 95 and 745 (1928), and their various modifications, W. Steglich, G, Hofle, Angew. Chem, Int. Ed, Engl., Q, 981 (1969); G. Hofle, W. Steglich, H. Vorbruggen, Angew. Chem. Int, Ed, Engl., 17, 569 (1978); W. Steglich, G. Hofle, Ber. 102, 883 (1969), or through selective reduction of acyl cyanides,

A. Pfaltz, S. Anwar, Tet. Lett. 2977 (1984), or from ct-halogen, d.-tosyl or o-mesyl ketones, via appropriate substitution reactions, which I understood, in the art readily recognize.

The functionalized benzylamines (4} can be prepared from the corresponding benzyl halides, tosylates or mesylates (2), via displacement, with a nitrogenous nucleophile, a process familiar to those skilled in the art. This displacement can be obtained using an azide ion, ammonia or a phthalimide anion, etc., in a neutral solvent, such as dimethylformamide, dimethylsulfoxide, etc. or under phase transfer conditions .. The benzyl halide (2) can be prepared by means of a variety of halo benzylation methods, familiar to those skilled in the art, for example, benzyl bromination of toluene derivatives with N-bromosuccinimide in an inert solvent, such as carbon tetrachloride, in the presence of a radical initiator, such as benzoyl peroxide, at temperatures above reflux temperatures.

A wide variety of toluene derivatives can be prepared from simple electrophilic reactions to substitution in an aromatic nucleus. This includes nitration, sulfonation, phosphorylation, Friedel-Crafts alkylation, Friedel-Crafts acylation, halogenation, and other similar reactions known to those skilled in the art, G.A. Olah, Friedel-Crafts and Related Reactions ”, Vol. 1-5, Interscience, New York, (1965).

Another process for synthesizing functional benzyl halides is the chloromethylation pathway of the corresponding aromatic precursor. Thus, the appropriately substituted benzene core can be chloromethylated with formaldehyde and hydrochloric acid (HCl), for example, with or without an inert solvent, such as chloroform. carbon tetrachloride, shiny petroleum ether or acetic acid. Lewis acid, such as zinc chloride (ZnCl ₂ ) or mineral acid, such as phosphoric acid, as a catalyst or condensing agent, RC Fuson, CH McKeever, Org. Reactions, 63 (194 2) .

Alternatively, the N-benzylimidazois (3.) / can also be prepared as shown in step b), by forming a substituted amidine (T), R &, from a benzylamine (4). appropriately substituted which, in turn, reacts with a haloketone or cC-hydroxyketetoa (8), or with a Î ± -halogenoaldehyde or an (O-hydroxyaldehyde, F. Kunckell, Ber., 34, 637 (1901).

As shown in step a), imidazole (JL) can be alkylated using a variety of benzyl derivatives. These include compounds with latent acid functions, such as, m and p-cyanobenzyl halides,

mesylates or tosylates as shown in step c). The nitriles of general formula (9) can be hydrolyzed to obtain carboxylic acids of general formula (10) by treatment with an acid or a strong base. Preferably # treatment with a mixture (1: 1) (v / v) of concentrated aqueous hydrochloric acid / glacial acetic acid # at reflux temperatures for 2 to 96 hours or a treatment with sodium hydroxide IN in an alcoholic solvent # such as ethanol or ethylene glycol # for 2 to 96 hours and at temperatures between 20 ° C and reflux temperature. If another nitrile group # is present, it can be hydrolyzed, too. Can the nitrile function # also be hydrolyzed in two phases? by stirring in sulfuric acid to form the amide # first # and then by hydrolysis with sodium hydroxide or a mineral acid to obtain the carboxylic acid (10).

Nitriles (9) can be converted to the corresponding tetrazolic derivative (11) by a variety of methods using hydrazoic acid. For example # nitrile can be heated with sodium azide and ammonium chloride in DMF at temperatures between 30 ° C and the reflux temperature for 1 to 10 days # J.P. Hurwitz and A. J. Tomson, J. 0rg. Chem, 26, 3392 (1961). Preferably, tetrazole is prepared by cycloaddition 1 # 3-dipolar trialquitine or triarylthino azides to the appropriately substituted nitrile # as described in detail in Scheme 15.

The initial imidazole compounds (1)

they are virtually available through any number of standard methods. For example, acylaminoketone (5) can be cyclized with ammonia or its equivalents, D. Davidson et al., J. Org, Chem., 2, 319 (1937) in the corresponding imidazole, as shown in Scheme 1.

the corresponding oxazole can also be converted to imidazole (1) through the action of ammonia or amines in general, R. Bredereck et al., Ber., 88, 1351 (1955); J.W. Cornforth and R.H. Cornforth, J. Chem. Soc., 96, (1947), Some alternative pathways for imidazois (1) are illustrated in Scheme 2. As shown in Scheme 2, equation a), the reaction of the imidate esters (12) replaced by the appropriate Rg, with a Î ± -hydroxy or Î ± -halogen ketone or an aldehyde (8), appropriately substituted in ammonia, leads to imidazois of general formula (1),

P. Dziuron and W. Schumack, Archiv. Pharmaz., 307 and 470 (1974).

The initial imidazole compounds (1), in which the symbols and Rg each represent a hydrogen atom, can be prepared as shown in equation b), by means of the ester reaction (12); of the appropriate R _g -substituted imidate with ¢ α-aminoacetaldehyde dimethyl acetal (13), MR Grimmett, Adv. Heterocyclic Chem., 12, 103 (1970).

As shown in equation c), imidazole (15; where the symbol R ^ = a hydrogen atom and the symbol Rg represents a CH ^ OH group) can be prepared by treating the imidate ester (12) with 1,3-dihydroxyacetone in ammonia through the process

described in Archive der Pharmazie, 307, 470 (1974). The halogenation of imidazole (15) or any imidazole in which the symbols R ₇ or R _g represent hydrogen atoms, is preferably carried out by reaction with one to two equivalents of N-halosuccinimide in a solvent polar, such as dioxane or 2-methoxyetole at a temperature of 40 ° to 100 ° C for 1 to 10 hours. The reaction of the halogenated imidazole (16) with a benzyl halide (2), as described in Scheme 1, gives rise to the corresponding N-benzylimidazole (17), in which the symbol represents a halogen atom and the symbol R _g represents the CH ₂ 0H group. This process is described in U.S. Patent No. 4,355,040. Alternatively, q imidazole (17) can be prepared using the process described in U.S. Patent No. 4,207,324.

The compounds of general formula (17) can also be prepared by treating the initial imidazolic compound (1), in which the symbols R ₇ and R _g each represent hydrogen atoms with the benzyl halide appropriate, following the Cold War functionalization R_ and R ₇ by treatment with formaldehyde as described in EE Godefroi et al., Recueil, 91, 1383 (1972) followed by halogenation as described above.

As shown in equation d), imidazois (1_) can also be prepared by reacting amidines (18) substituted in R ^, with an rf-hydroxy- or - o <? -Halogen ketone or a aldehyde (8), as described by F. Kunckel, Ber., 34, 637, (1901).

The compounds of the general formula (j.), In which the Rg symbol represents the CH ₂ GH group, can be prepared as shown in equation e). Imidazois (1) were prepared as described by LA Reiter, J. Org. Chem. 52, 2714 (1987). Hydroxymethylation of (1), as described by U. Kempe et al., In U.S. Patent No. 4,278,801, yields hydroxymethylimidazois (la).

J

The)

NH »HC1

R.

OCH ₂ CH ₃

B)

Scheme 2 + (Cl) HO

NH, + K ₂ NCH CH (OMe) ₂ 13.

c) + CH _n OH

nh ₃

->

balogenation (2)

-Br, I

j »

and)

1) NH ₃ , Cu ⁺²

As shown in Scheme 3, phase a), for benzylimidazois (17) in which the Rg symbol represents the CH OH group, hydroxymethyl groups can z

easily convert into the corresponding halides, mesylates or tosylates using a variety of methods familiar to those skilled in the art. Preferably, the alcohol (17) is converted to the chloride (25) with thionyl chloride in an inert solvent, at temperatures of 20 ° C to the reflux temperature of the solvent.

chloride (25) can be displaced through a variety of nucleophiles by means of nucleophilic displacement reaction processes, familiar to those skilled in the art. For example, excess sodium cyanide in DMSO can be used to form cyanomethyl derivatives (26) at temperatures of 20 ° C to 100 ° C.

nitrile (26) can be hydrolyzed to obtain a derivative (27) of acetic acid, by a variety of methods. These methods include previously described methods for the hydrolysis of nitriles of general formula (2). · Examples of desired acids and bases for this hydrolysis include mineral acids, such as sulfuric acid, hydrochloric acid and mixtures of both with 30% acetic acid. % -5G% (when solubility is a problem), and alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide. The hydrolysis reaction is carried out under heating at temperatures ranging from 50 ° _to 160 ° C for 2 to 48 hours

hours. The carboxylic acid (27) can be esterified by a variety of methods without affecting other parts of the molecule. Preferably, the carboxylic acid (27) is heated at reflux temperature in a hydrochloric acid / methanol solution for 2 to 48 hours to obtain the ester (28).

ester (28) can be hydrolyzed to give the carboxylic acid (27), for instance, after R ^, _R2 and R have been developed. Various methods, acidic or basic, can be used. For example, compound (28) is stirred with 0.5N potassium hydroxide in methanol, or if the base is soluble, it is stirred in 1.0N sodium hydroxide for 1 to 48 hours at 20 ° C to room temperature reflux.

hydroxymethyl derivative (17) can be acylated to obtain compound (29) by a variety of processes. As shown in step b), acylation can be achieved with 1 to 3 equivalents of an acyl halide or an anhydride in a solvent, such as diethyl ether, tetrahydrofuran, methylene chloride or the like in the presence of a base, such as pyridine or triethylamine. Alternatively, compound (17) can be acylated by reaction with a carboxylic acid and dicyclohexylcarbodiimide (DCC) in the presence of a catalytic amount of 4- (N, N-dimethylamino) pyridine (DMAP), via the process described by A. Eíassner, Tet. Lett, 46, 4475 (1978). Treatment of compound (17) with a solution of the carboxylic acid anhydride in pyridine, optionally with a catalytic amount of DMAP, at temperatures of 20 ° to 100 ° C for 2 to 48 hours, is the preferred method.

í

The ether (30) can be prepared from the alcohol (17) as shown in step c) by methods, such as treating the compound (17) in a solvent, such as dimethylformamide or dimethylsulfoxide with t- potassium butoxide, sodium hydride or the like, followed by treatment with R1 L at a temperature of 25 ° C for 1 to 20 hours, where L is a halogen atom or a tosylate or mesylate group.

Alternatively, treatment of compound (17) with 1 to 5 equivalents of thionyl chloride in chloroform for 2 to 6 hours, at a temperature of 25 ° C, followed by treatment of the intermediate compound (25) with 1 to 3 equivalents of MOR ^, where the symbol M represents a sodium or potassium atom, for 2 to 10 hours at a temperature of 25 ° C, both in R ^ OH as a solvent or in a polar solvent, such as dimethylformamide or similar, also give rise to ether (30).

The ether (30) can also be prepared, for example, by heating the compound (17) for 3 to 15 hours, at a temperature of 60 ° to 160 ° C, in Rjj ^OH containing an inorganic acid, such as hydrochloric acid or sulfuric acid.

The N-arylimidazois of general formula (I) (compounds in which the symbol ρ = O) can be prepared using the following methods, being understood by those skilled in the art that certain manipulations, protection and deprotection phases and other synthetic processes described above may be necessary to

- 43 /

prepare compounds with the desired combinations of R ,, R ₇ , R _g and R ₁₃ .

As shown in Scheme 4, equation a), the reaction of the aniline derivative (34) with the imidate ester (12) to form the substituted amidine (35) gives rise to material that can be cyclized with dihydroxyacetone to form the structure (36).

The subsequent elaboration in (I) gives rise to the N-arylimidazole compounds of the present invention.

Alternatively, as shown by equation b), the Marckwald process described by Marckwald et al., Ber., 22, 568, 1353 (1889); Ber., 25, 2354 (1892), can form a 2-mercaptoimidazole (38) from the aniline derivative (34), via isothiocyanate (37). Desulphurization of the compound (38) with dilute nitrogen acid followed by anionic formation in position 2 of the imidazole (39) and reaction with R ^ X, where the symbol X represents a chlorine, bromine or iodine atom, leads to the formation of the compound (4Q) which can subsequently be elaborated for (I).

A variation of the Marckwald process can also be used, as shown in equation c), using an Î ± -aminoacetone (41) and isothiocyanate (37); see Norris and Mckee, J, Amer. Chem. Soc., 77, 1056 (1955). the intermediate compound (42) can be converted to (I) by means of known sequences. The general process of Carboni et al., J. Amer. Chem. Soc., 89, 2626 (1967) (illustrated by equation d)) can also be used to prepare substituted N-arylimidazoles from appropriate balogenoaromatic compounds / (43; X = F, Cl, Br) and imidazois (3.);

Figure 4

NH

J

Scheme 4 (continued)

B)

NH- X x T + csci ₂ γΊ p ' ^R 13 x 34 37

1) H NCH ₂ CH (OEt) _{2 H}

2) HCl, Δ

R

N 38

7 ^ ^v 13

HNOg, Z \

J

Scheme 4 (continued)

ç)

I

- 47 _ / χ ¹

In several synthetic ways, the symbols

R., R_ and R _o do not necessarily remain constant ± from the starting compound to the final compounds, as they are manipulated, often, through known reactions, in the intermediate phases, as shown in Schemes 5-22. All transformations shown in Schemes 5-lo and 12 can also be carried out on the aromatic terminal nucleus (ie, biphenyl nucleus).

Layout 5

XX ^R 3

As shown in Scheme 5, compounds in which R4 represents a sulfonic acid group, can be prepared by oxidation of the corresponding thiol (45). Thus, an N-benzylimidazole derivative bearing a thiol group can be converted to a sulfonic acid (46.) by means of the action of hydrogen peroxide, peroxyacids such as methanlorloroperoxybenzoic acid, potassium permanganate or through a variety of others oxidizing agents, Ε. E. Reid, Organic Chemistry of Bivalent Sulfur, 1, Chemical Publishing Co., New York, 120-121 (1958).

Aromatic hydroxy groups or thiools are obtained from the deprotection of the corresponding alkyl ether or corresponding thioethers. Thus, for example, a methyl ether or a thioether methyl derivative. co (44) of an N-benzylimidazole, containing one or more aromatic nuclei, can be converted to free phenol or thiophenol (45) through the action of methyl sulfite and boron tribromide, P. G. Willard and C. F. Fryhle, Tet. Lett., 21, 3731 (1980)? trimethylsilyl iodide, Μ, E. Jung and M.A. Lyster, J. 0rg, Chem., 42, 3761 (1977);

KSet and its derivatives, G. I. Feutrill, R. N. Mirrington, Tet, Lett., 1327 (1970), and a variety of other reagents.

Alternatively, N-benzylimidazois can be sulfonated by stirring with H HSO SO in a variety of different concentrations or with other sulfonating agents, such as chlorosulfonic acid or sulfur trioxide with or without complexing agents, such as dioxane or pyridine , at temperatures from 0 ° to 200 ° C, with or without solvent, K. LeRoi Nelson in Friedel-Crafts and Related Reactions, III part 2,

G. A. Olah, ed., Interscience Publ., 1355 (1964)

- ⁴⁹ - / '

The synthesis of the compounds, in which the symbol represents a sulfate, phosphate or phosphonic acid, is shown in Scheme 6;

Scheme β a)

o [f

OP-OH ι

OH

- 50 - /

B)

Diagram 6 (continued)

2; where R ^ = H

Scheme 6 (continued?

ç)

Cu (l), (CH ₂ ) _r

R.

Ji ₂ ⁺ x '

R,

. /

Diagram 6 (continued)

d)

Br (Cl) + (EtO) gP

genus (EtO) ₃ P nx ₂ (X = halogen)

N-benzylimidazois containing a phenolic hydroxyl group (47) can be converted immediately to the corresponding sulfate (48) or phosphate (49). As shown in equation a), the reaction of the phenol with an amine complex of sulfur trioxide will give the corresponding sulfate (48), Ε. E. Gilbert, Sulfonation and Related Reactions, Interscience, New York, chapter 6 (1965).

The reaction of phenol (47) with phosphorus pentachloride followed by hydrolysis will give rise to the corresponding phosphate (49), G, M, Kosolapoff, Organophosphorus Compounds, John Wiley, New York, 235 (1950).

ç

As shown in equation b), H-benzylimidazois can be converted into the corresponding phosphonic acids by reacting with phosphorus trichloride (PClg) and aluminum chloride (AlClg) in an inert solvent for 0.5 at 96 hours, at temperatures between 25 ° C and the reflux temperature of the solvent. This phase, followed by the reaction with chlorine (Cl ₂ ) and subsequent hydrolysis of tetrachloride (51) gives rise to the phosphonic acid derivative (52), GM Kosolapoff in Org. Reactions, R. Adams, editor, John Wiley and Sons, New York, 297 (1951). Another more direct route involves the reaction of N-benzylimidazole with PSCl2 and AlCl2, followed by hydrolysis, RS Edmunson in Comprehensiv and Organic Chemistry, vol. 2, D. Barton and WD Ollis editors, Pergamon Press, New York, 1285 (1979).

Alternatively, equation c) illustrates that arylphosphonic acids (52) can be formed by reacting the corresponding diazonium salt (53) with PC1 ₃ in the presence of Cu (l) followed by hydrolysis with water (ibid, p. 1286),

As shown in equation d), aryl halides (55) can be photolyzed in the presence of phosphite esters to obtain phosphonate esters (56), R. Kluger, <T. L. W. Chan, J. Am, Chem, Soc.,

95, 2362 (1973). These same aryl halides also react with phosphite esters in the presence of nickel or palladium salts to obtain the phosphonate esters, P. Tavs, Chem. Ber., 103, 2428 (1970), which can subsequently be converted to phosphoric acids (52) 54 /

by means of processes known to those skilled in the art.

N-benzylimidazois containing an aldehyde or a ketone (57) can be reacted with a phosphorus trihalide, followed by hydrolysis by water, to obtain derivatives of <C-hydroxyphosphonic acid, G. M. Kosolapoff, op. cit., 304, as shown in Scheme 7.

Layout 7

- P - OH

The compounds in which the symbol represents the group of general formula: - C0NH0R ^ ₂ can be prepared as shown in Scheme 8, by treating a carboxylic acid (lo) with 1 to 4 equivalents of thionyl chloride for 1 to 10 hours. This reaction can be carried out without solvent or in non-reactive solvent, such as benzene or chloroform, at temperatures of 25 ° C to 65 ° C. Then, the intermediate compound, acid chloride, is treated with 2 to 10 equivalents of

- / appropriate amino derivative, E ^ N-OR. ^, for 2 to 18 hours, at temperatures between 25 ° and 80 ° C, in a polar aprotic solvent, such as tetrahydrofuran or dimethylsulfoxide, to obtain the hydroxamic acid (59).

Layout 8

Alternatively, the carboxylic acid (10 'can be converted to hydroxamic acid (59), according to the process in' J. Med. Chem., 28, 1158 (1985), using dicyclohexylcarbodiimide,

J

1-hydroxybenzo-triazole and E ^ NOR. ^ ^Or according to the procedure described in Synthesis, 929 (1985), using the Vilsmeier reagent and H ^ NOR. ^.

The compounds, in which the symbol R ^ represents the group: -KNOWLEDGE ₂ Ar (59a, Ar = phenyl, o-totyl, etc.), can be produced by treating the intermediate acid chlorides from the preparation of the acids hydroxamic (59) with ArSO ₂ NHNa. Alternatively, these acylsulfonamides (59a) can be prepared from carboxylic acids (10) using the corresponding Ν, Ν-diphenylcarbamoyl anhydrides (10a), as described

F. J. Brown et al. in the European invention patent application ΞΡ 199543 (see Scheme 8).

Layout 9

>

Diagram 9 (continued)

63

Intermediate anilines (.63) are described in U.S. Patent No. 24,355,040 and can be obtained from the corresponding nitrogenous compound precursor by means of reduction. A variety of reduction processes can be used, such as iron / acetic acid, D.C. Owsley, J.J. Bloomfield, Synthesis, 118 (1977), tin chloride, F.D. Bellamy, Tet, Lett., 839 (1984) or careful hydrogenation over a metallic catalyst, such as palladium.

As shown in Scheme 9, the aniline intermediate compounds of the N-benzylimidazois can also be prepared from the corresponding carboxylic acid (10) or an acid chloride, via Curtius rearrangement of an azide (6o) intermediate acyl. More modern methods include the use of diphenyl azide 58 /

phosphorium as the source of azido, T. Shioiri, K. Ninomiya,

S. Yamada, M. Am. Chem. Soc., 94, 6203 (1972), and the capture of the intermediate isocyanate (61) produced by the Curtius rearrangement with 2-trimethylsilyl ethanol and the cleavage

gem of carbamate (62) resulting with fluoride tar the amine (63), T.L. Capson and C. D. Poulter 25, 3515 (1984).

Classic processes, familiar to those skilled in the art, can also be used.

The compounds in which R4 represents the group: -SO ₂ NH ₂ can be prepared as shown in Scheme 10:

Layout 10

Ν '

N

NH.

SO ₂ C1

so ₂ nh ₂

The sulfonamide compounds (65) can be prepared by reacting an arylsulfonyl chloride

co (64) with ammonia or an equivalent. Unsubstituted arylsulfo- / \ namides are prepared by reaction with ammonia in aqueous solution or in an inert organic solvent # F. H. Bergheim and W. Braker, J. Am »

Chem. Soc., 66, 1459 (1944), or with powdered, anhydrous ammonium carbonate, Ε. H. Huntress and J. S. Autenrieth, J, Am.,

Chem, Soc., 63, 3446 (1941); Ε. H. Huntress and F. H. Carten, J. Am. Chem. Soc., 62, 511 (1940).

The precursor sulfonyl chloride can be prepared by means of chlorosulfonation with chlorosulfonic acid on the aromatic nucleus, directly, Ε. H. Huntress, and F. K. Carten, ibid .; Ε. E. Gilbert, op. cit,

84, or by reacting the corresponding aromatic diazonium chloride salt (53) with sulfur dioxide in the presence of a copper catalyst, H. Meerwein et al.,

J. Prakt. Chem., / Ii /, 152, 251 (1939), or by reacting aromatic sulfonic acid (46) with PCl4 or POClg, C.M. Suter, The Organic Chemistry of 5ulfur, John Wiley, 459 (1948).

Sterile, chain-linked compounds of general formula (I), where the symbol represents 0

II group of general formula: -CO ₂ CH (R ₂₄ ) OCR ₂₁ , can be prepared by means of processes well known in the chemistry of penicillin and cephalosporins. The purpose is to prepare materials that are more lipophilic and that should be used, orally, with rapid transit from the digestive tract to the bloodstream, which will then be fragmented at a speed sufficiently fast to provide effective concentrations, under the pon therapeutic view, of the active form of carboxylic acid, The following revised articles and cited references, here, deal with this concept and the chemistry involved in the preparation of such compounds, V. J, Stella et al., Drugs, 29, 455- 473 (1985); H. Ferres, Drugs of Today, 19 (9), 499-538 (1983); AA Sirkula, Ann. Repts. Med, Chem. 10, 306-315 (1975).

Experimental processes that are applicable a. preparation of chain-linked esters, chemically stable, are illustrated by means of equations a-e in Scheme 11.

Scheme 11 (a)

G. Francheschi et al., <1. Antibiotics, 36, (7), 938-941 (1983).

(B)

CH

R.C0 + (CK_) _n NCON (CH_) _ + C1CH0C0C (CHj _o Z □ Z □ Z oo

RCO ₂ CHOCOC (CH ₃ )

J · Budavin, US Patent No. 4,440,942

(Ο (d) ^RC0 2 ^H

RCO ₂ CH-OCOCHCH ₂ CO

NH,

B, Daehne et al., British patent number 1,290,787

RCO ₂ H ^R 24 rco ₂ chconr ₂₂ r ₂₃

Ferres, Chem. Ind., 435-440 (1980)

Clayton et al., Antimicrob. Agents Chemotherapy, 5, (6), 670-671 (1974)

In equations a-e: R =

The compounds of general formula (I), in which R R represents the group: -C (CF ₃ > ₂ OH, can be prepared as shown in Scheme 12.

Layout 12

72

Hexafluoroisopropanolic compounds (72) can be prepared by treating arylsilane (71) with 1 to 5 equivalents of hexafluoroacetone in a solvent, such as methylene chloride, at temperatures in the range of about -50 ° C at 25 ° C, for a period of 2 to 10 hours. The required arylsilane (71) can be prepared, using methods known to those skilled in the art, such as the processes described in chapter 10 of Butterwarth’s Silicon in Organic Chemistry.

Layout 13

N ~ Z \ a® ₂₃ (r ₂₃

HO (X

II

O

As shown in Scheme 13, the compound (73) in which the X symbol represents the -NHCO- group and the symbol represents the -COOH group, can be easily prepared, for example, by reacting the aniline precursor (63 ) with a phthalic anhydride derivative in an appropriate solvent, such as benzene, chloroform, ethyl acetate, etc. Often, the carboxylic acid compound may precipitate from a solution with the previous remaining reagents, M. L. Sherrill,

P. II. Schaeffer, Ε. P. Sfooyer, J. Am. Chem. Soc., 50,

474 (1928).

When the symbol represents a group

NHSO ₂ CH _{3 #} NHSO ₂ CF ₃ or tetrazolyl (or a variety of other equivalent carboxylic acids), compound (73) can be obtained by reacting aniline (63) with the required acid chloride, either by a process

Schotten-Baumann, either by simple stirring in a solvent, such as methylene chloride in the presence of a base, such as sodium bicarbonate, pyridine or triethylamine.

Likewise, aniline (63) can be linked to an appropriate carboxylic acid, via a variety of starch or peptide binding forming reactions such as DCC bonding, azide bonding, mixed anhydride synthesis, or any other bonding process familiar with actions in the field.

Aniline derivatives (63) may undergo reducing amination with aldehydes and ketones to form secondary amines (74). Thus, aniline is first stirred with the carbonyl compound in the presence of a dehydration catalyst, such as molecular shavings or p-toluenesulfonic acid. Then, the resulting imine is reduced to amine with a boron hydride reducing agent, such as sodium cyanoborohydride or sodium borohydride. Standard catalytic hydrogenation reagents, such as hydrogen and palladium on carbon, can also be used.

Alternatively, aniline (63) can be monoalkylated by reaction with ethyl formate. followed by reduction with, for example, aluminum hydride and lithium to prepare the (74) N-methyl derivative. The anilines (74) can in turn react with anhydrides of carboxylic acid and with acid chlorides or carboxylic acids by means of any of the bonding processes / \ described previously, to obtain the compound (73) in which the symbol X represents the group -N (CHg) CO-,

Anilines (63) or (74) or other intermediate anilines in which the amino group can be located on another aromatic nucleus, for example, also react with other anhydrides to prepare carboxylic acid-amide derivatives of the general formula (75). Thus, for example, maleic anhydride, 2,3-naphthalene-dicarboxylic acid anhydride and diphenic anhydride react similarly to phthalic anhydride with aniline (63) or (74) to obtain carboxylic acids (76), (77) and (78), respectively.

Phthalimide derivatives of aniline (63) can be prepared by a variety of methods, preferably by stirring aniline (63) with phthalic anhydride in acetic acid at a temperature between 20 ° C and the reflux temperature , G. Wanag, A. Veinbergs, Ber., 75, 1558 (1942), or by stirring aniline (63) with phthaloyl chloride, a base such as triethylamine and an inert solvent.

Aniline (63) can be converted to its trifluoromethanesulfonamide derivative or its trifluoroacetamide derivative, preferably by means of its reaction with triflic anhydride or trifluoroacetic anhydride and a base such as triethylamine in an inert solvent, such as chloride methylene at a temperature of -78 ° G, followed by heating to room temperature.

The compounds of structure (I) in which the

- 67 symbol X represents a carbon-carbon bond, which are represented as compounds (80), can be prepared as shown in Scheme 14.

Layout 14

Y = Cl, Br, OTs, OMs

>

Scheme 14 (continued)

c) ⁺ % L.

Scheme 14 (continued)

Equation a) illustrates that the biphenyl compounds (80) can be prepared by alkylating the imidazole (1) with the appropriate halogenomethylbiphenyl compound (79) using the general process described in Scheme 1.

The required intermediate compounds (79) halogenomethylbiphenyls are prepared by means of the Ullman bond of compounds (81) and (82), as described in “Organic Reactions, 2., 6 (1944), to prepare the intermediate compounds (83 ), which in turn are halogenated.

Halogenation can be carried out by heating the reflux temperature of the compounds (83) in an inert solvent, such as straight carbon tetracycline, for 1 to 6 hours in the presence of an N-halosuccinimide and an initiator, such as sisobutyronitrile azobi (equation b).

As shown in equation c), the derivatives of the intermediate compound (83), in which the R 2 g is in the 2 'position (83a), can also be prepared by the method described in J. Org. Chem. , 41, 1320 (1976), which represents the addition of Diels-Alder, from a 1,3-butadiene to a styrene (84), followed by the aromatization of the intermediate compound (85).

Alternatively, the substituted biphenyl precursors (83; where the symbol R ^ g = COOH) and their esters (89) can be prepared as shown in equation d) involving oxazoline compounds as key intermediate compounds, AI Meyers and ED Michelich J. Am. Chem, Soc., 97, 7383 (1975).

In addition, as shown in equation e), the nickel-catalyzed cross-linking of an arylzinced halide with a halogenobenzonitrile gives rise to a biphenylnitrile which in turn can be hydrolyzed using standard methods to give the acid (88).

The substituted biphenyl tetrazois (83; where the symbol R._ N— N - 13 = ι y j can prepareNH

from the nitrile precursors (R. _o = CN) using the methods described in Scheme 1, equation c) and Scheme 15, equation c).

However, a preferred method for preventing

comparison of tetrazoles is described in Scheme 15 # equations a) and b). Compounds (, 90 ¹ ) can be prepared by cycloaddition 1 # 3-dipolar of trialkylthine or triphenyltine azides to obtain nitrile (83) replaced # appropriately # as in equation a). The alkyl group is defined as a normal alkyl group of 1 to 6 carbon atoms and cyclohexyl. An example of this technique is described by S. Kozima et al. # J. Organometallic Chemistry # 337 (1971). The required trialkyl or triarylthino azides are prepared from the indispensable commercial commercial triaryl or trialkyl tin chloride and sodium azide. The trialkyl or triarylthino group is removed - via acidic or basic hydrolysis - and the tetrazole can be protected with the trityl group by reaction with the trityl chloride and triethylamine to obtain the compound (91). Bromination # as previously described here # with N-bromosuccinimide and dibenzoyl peroxide gives the compound (92). Alkylation of the compound (1) with the appropriately substituted benzyl halide, using previously described conditions - followed by deprotection of the trityl group - via hydrolysis gives the compound (80; R ^ g = tetrazole). Other protecting groups # such as p-nitrobenzyl and 1-ethoxyethyl can be used instead of the trityl group to protect the tetrazolic nucleus. These groups # as well as the trityl group can be introduced and eliminated by means of processes described by Greene # Protective Groups in Qrganic Synthesis # Wiley-InterScience # (1980).

- /

Layout 15

The)

CH.

SnRgNg

CN

SnR, (R _1O = CN) ““ ¹³ 1. H ⁺

2, Ph,

CC1, TEA, (R = alkyl 1 to 6 carbon atoms, phenyl)

CH.

NBS, DBO

-N

GJ>

'K XPh.

CH „Br

B)

H

D 92 / NaOEt 2) Deprotection

(R

13 = tetrazole)

Scheme 15 (continued)

ç)

T rf

NaNg

NH ₄ C1

CN

DMF

N - N // \\ 7 T v

83a

Compounds of structure 93-95, wherein X represents an oxygen or sulfur atom or a linking group of the general formula -N-,

I ^R 26 can be prepared as shown in Scheme 16 by alkylating the imidazole (1) with the appropriate benzyl halide (96).

J

Layout 16

The)

R

X, a

93? X = 0 94? X = S 95? X = NR

R

B)

CH.

Halogen

Ass

CH,

97-100

CO ₂ H

CH

-C0 ₂ H

101-104

97; X = 0

98? X = S

99? X = NH

100? X = NR ₂₆ ÇR ₂₆ ^ 4 H)

109? X = 0

110? X = S

111? X = NH

112? x = nr ₂₆ (r ₂₆ ^ h);

CFL ·

M;

-C0 „CH 2 3

105-108

CH ₂ Halogen

° 2 ^CH 3

109-112>

/ halogenomethyldiphenyl ether (109) (used as an alkylating agent in the present invention is prepared as shown in equation b), a Ullman etheric condensation of phenol (97) and a halobenzoic acid, as described in Russian Chemical Reviews, 43, 679 (1974) give the intermediate acid (101). Conversion of the compound (101) · into the compound (109) by means of esterification with diazomethane to obtain the compound (105), followed by halogenation, using the process used in the preparation of the compound (79). Diphenyl sulfite (110) and diphenylamine (111) can be prepared from thiophenol (98) or aniline (99) by this process.

Tertiary diphenylamine (112) can be prepared from secondary aniline (100) using the above process. Alternatively, compound (107) can be alkylated using one of the following processes:

1) direct alkylation of compound (107) with R ^ L, where L represents an leaving group, such as a halogen atom or a tosylate group, using phase transfer conditions and ultrasound, as if describes in Tetrahedron Letters, 24, 5907 (1983); 2) treatment of compound (107) with 1 to 1.5 equivalents of an appropriate aldehyde and 0.5 to 5.0 equivalents of sodium cyanoborohydride in a solvent, such as methanol, at a temperature of 25 ° C and at a pH of 3 to 6, for 1 to 24 hours or 3) reducing amination of the compound (10) using an appropriate carboxylic acid and sodium borohydride, as described in J. Am. Chem. Soc., 95, 7812

-,., - χ »*** '(1974). Then, the tertiary amine (108) is halogenated by means of the process previously described to obtain the compound (112).

Layout 17

116

ΊΊ

The compounds in structure (73), where X represents the -CO- group, are prepared as shown in Scheme 17 by means of alkylation of imidazole (1.) with the necessary benzoyl benzyl halides. For example, the esters (113), where the symbol R ^ ₃ represents the group: 2-00 ^ 011 ^, are prepared by alkylating the imidazole (3.) with the carbomethoxybenzoyl benzyl halide (114). The ester (113) can be hydrolyzed to obtain the corresponding carboxylic acid (116) by a variety of methods including hydrolysis with a base, such as sodium hydroxide or potassium hydroxide in such an aqueous alcoholic solvent. such as methanol / H2 O, at a temperature between 20 ° C and the reflux temperature of the solvent.

Carboalkoxybenzoyl benzyl halides are prepared by means of benzyl halogenation of the corresponding toluoylbenzene precursor using a variety of methods previously described here. For example, methyl 2- (4-methylbenzoyl) benzoate (115) can be heated at reflux temperature for 2 to 48 hours with N-bromosuccinimide, benzoyl peroxide and carbon tetrachloride to make benzyl bromination.

119

As shown in Scheme 18, toluoyl ketones (73; where θ symbol X = CO) can subsequently be transformed into a variety of ketone derivatives that include compounds where symbol X

The reaction of the ketone (73a) with a hydroxy represents a group

THE COLOR

OR

- C & xylamine or an appropriately substituted hydrazine will give the necessary oximes (117) and hydrazones (118). The reaction with alcohols in the presence of an acidic catalyst with water elimination will give rise to ketals (119). The reduction with aluminum and lithium hydride, a metallic borohydride, zinc / acetic acid or a catalytic hydrogenation should result in the corresponding alcohol (120) or methylene compound (121) completely reduced. These alcohols can be acylated using a variety of acid anhydrides or halides in the presence of a base with or without a solvent to obtain the corresponding esters (122). The alcohols (120) can be converted into their ethers (123 ) corresponding by reacting the metal alkoxide with an alkyl halide, mesylate or tosylate in the appropriate solvent or by treating with an inorganic acid in an alcoholic solvent, or by reacting the alcohol with diazomethane, as described by G. Hilgetag and A. Martin! in Preparative Organic Chemistry, John Wiley, New York, 355-368 (1972).

The compounds of general formula (I), where X represents a group -QCP ^ -, -SCH ^ - or -NHCH ^ -, are prepared as shown in Scheme 19.

As shown in Scheme 19, equation a), the hydrolysis of the benzyl ether (124) or the methyl ether (125) gives the hydroxy compound (126) which can / can be alkylated with the appropriate benzyl halide to obtain the compound (127 ), In the case of methyl ethers (125), the hydrolytic phase can be carried out by heating the ether at temperatures of 50 ° C to 150 ° C for 1 to 10 hours in 20% - 60% hydrobromic acid, or by heating in acetonitrile, at a temperature of 50 ° C to 90 ° C, with 1 to 5 equivalents of trimethylsilyl iodide for 10 to 5 hours, followed by treatment with water. Hydrolysis is also carried out by treatment with 1 to 2 equivalents of boron tribromide in methylene chloride, at a temperature of 10 ° C to 30 ° C for 1 to 10 hours, followed by treatment with water, or by treatment medium with an acid, such as aluminum chloride and 3 to 30 equivalents of a sulfur-containing compound, such as thiophenol, ethanedithiol or dimethyl disulfite in methylene chloride, at a temperature of 0 ° C to 3 ° C for 1 to 20 hours, followed by water treatment. For compound (124), hydrolysis can be carried out by heating at reflux temperature in trifluoroacetic acid for 0.2 to 1 hour «or by means of catalytic hydrogenolysis in the presence of an appropriate catalyst, such as 10% palladium about coal. Deprotonation of compound (126) with a base, such as sodium methoxide, sodium hydride or the like, in a solvent, such as dimethylformamide or dimethyl sulfoxide, at room temperature, followed by alkylation with a

appropriate benzyl halide at 25 ° C for 2 to 20 hours gives ethers of general formula (127), as shown in equation a.

sulfite (129) can be prepared from thiophenol (45) using the process described above for the preparation of ether (127) from phenol (126). Thiophenol (45) can be prepared, for example, by treating benzylsulfite (128) with sodium in liquid ammonia.

The amine (13o) can be prepared as shown in equation £, from aniline (63), itself available from the reduction of the corresponding p-nitro compound (3a) that has been previously described. The reducing amination can be carried out by the same process described in Scheme 13 for the preparation of the compound (74).

Cs compounds of the general formula (I), where the bond X represents a -CH = CH- group, or

, prepare as shown in Scheme 20,

133 134

J

Stybene ¢ 132) cis or trans can be obtained by using a Wittig reaction between aldehyde (57) and phosphoran ¢ 131).

Stybene (132) can be immediately converted to the saturated derivative (133), for example, by means of catalytic hydrogenation using a heterogeneous catalyst, such as palladium / coal or platinum / / coal or, alternatively, with a homogeneous catalyst

- /

neo, such as tristriphenylphosphine and rhodium chloride.

The reduction is carried out in a solvent, such as benzene, tetrahydrofuran or ethanol at a temperature of 25 ° C, under 1 to 3 atmospheres of hydrogen for 1 to 24 hours.

Cyclopropane (134) can be prepared by treating stylbene (132) with the Simmons-Smith reagent, as described in J. Am. Chem. Soc., 61, 4256 (1959), or by treating compound (132) with methylene diiodide and powdered copper, as described in J. Am, Chem. Soc., 101, 2139 (1979), or by treatment with the iron-containing methylene transfer reagent, as described in J. Am. Chem. Soc., 101, 6473 (1979).

The preparation of the compounds of general formula (I), in which X represents a group: -CE ^ CH ^ -, -CF = CH-, -CF = CF- or CF ₂ CF ₂ # © is represented in Scheme 21 .

Esouema 21

137

b) Ο

140

ArCF = GFAr ¹

143

d) 00.

IIII

ArCCAr '+ Et ₂ NSF ₃ _ArCF ₂ CF Ar'

144 145

Vinylene fluorides (137) and (140) can be prepared by reacting SF2 or Et ₂ NSF ₃ (DAST) with the appropriate ketone (135) or (138) in which Ar supports a methyl group convertible to a appropriate benzyl halide upon attachment to an imidazolic nitrogen and Ar 'supports a cyano, nitro, ester or other suitable group which can subsequently be converted to the C0 ₂ H, NHSO ₂ CF _{3 group} , etc. The difluoroethylene (136) and (139) formed initially, can be prepared in a non-polar solvent, such as methylene chloride and, subsequently, convert to the vinylene fluoride by means of alumina, or convert directly in the unsaturated fluoride by means of reaction in a polar solvent, such as tetrahydrofuran, diglyme or N-methylpyrrolidone, in the presence of an inorganic acid (equations a and b). Experimental details of such processes are described by DR Strobach and GA Boswell, in CT. Qrg, Chem., 36, 818 (1971); GA Boswell, U.S. Patent Nos. 3,413,321 (1968) and 4,212,515 (1980).

As shown in equation c), an appropriate benzoin (141) can similarly be converted to the corresponding 1,2-difluoro-stilbene (143). Likewise, as shown in equation d), an appropriate benzyl (144) can be converted to a tetrafluorodiarytylene (145) using DAST or SF SF. Experimental details are described by Μ. E. Christy et al., In J. Med. Chem., 20, (3), 421-430 (1977).

Compounds of general formula (1), in which the symbol X represents a group; -Cí ^ O-, -CHgS- or

-CH ^ NH- or a group of general formula: -CON-, can be prepared as shown in Scheme 22.

The)

R,

R

R,

Scheme 22.

^R 23

KN-ArR ₁₃ -F (146)>

dcc _z ch ₉ ci ₉ ou

N

R.

HN-ArR,., TsC1, PYr I 13

CON-ArR ₁₃ -P

N_, ^R 8

THE

147 and then deprotection

P = protective group (if applicable)

148 'CONArR \ L3

ArR ₁₃ «

ArR

ArR, =

- /

Scheme 22 (continued)

B)

N //

The ₂ Me

149

h ₂ ots

K CO-, DMF

- £ -í ->

152; HO-Ar-R ₁₃ -P 153; HS-Ar-R ₁₃ -P 146; H ₂ N-Ar-R ₁₃ -P deprotection

154;

155;

156;

X = -CH SX = -CH NHAs previously described, acid (10) can be prepared by alkylating the appropriate imidazole with methyl 4-chloromethylbenzoate in the presence of a base, such as potassium carbonate, in a polar solvent, such as dimethylformamide, followed by hydrolysis of the resulting ester. 0 compound (lo) can be converted to compound (148) by reaction with amine (146) required (R ^ ₃ may need to be gido protein and subsequently deprotected) and dicyclohexyl-90 - / carbodiimide (DCC) in methylene chloride / JR Beek et al., J. Am. Chem. Soc., 90, 4706 (1968} _ / or by reaction with tosyl chloride in pyridine JH Brewster and CJ Giotti, Jr., J. Am. Chem, Soc., 77, 6214 (1955) _7 «Yet another The process involves converting the carboxylic acid (10) into its acid chloride with, for example, thionyl chloride, followed by reaction with the aqueous amine (Schotten-Baumann conditions) or in an organic solvent in the presence of a acidic washing product, such as NaHCO4, pyridine or triethylamine, or by other known processes to form an amidic bond between an aromatic acid and an amine.

The compounds, where X represents a -CH, © -, -CH, S- or -CH, NH, - group, can be prepared as shown in step b. The ester (149) is reduced with a reducing agent, such as lithium aluminum hydride, in an inert solvent to form the alcohol (15o) which can then be reacted with tosyl chloride in pyridine to form the tosylate (151) which, in turn, reacts in the presence of a base, with a phenol (152), a thiophenol (153) or an aniline (146) (where R, ₃ = * corresponding, to form the compounds (154) , (155) or (156) · Again, this route requires that it be protected with an appropriate protective group, even though necessary modifications due to specific functional groups are to be admitted to be incorporated by any expert in the matter of organic synthesis.

Alternatively, the alcohol (15o) can be converted into the corresponding halide with SOC ^, (COC1) ₂ , etc. and the resulting halide can then be reacted with a phenol, thiophenol or aniline in the presence of a base to form the desired compound, where X is -CH ₂ O-, -CH ^ S- and -CHgNH- , respectively.

The)

Layout 23

HN

R

158

157

B)

Solvent base

ciso, ^R 13

160

Solvent base

161

The compounds of the general formula (I), wherein X represents the groups of the general formula; -SO ₂ NR ₂ g- ^and ' ^R 23 ^SO 2 ~' can be prepared as shown in Scheme 23. As shown in equation a), the sulfonyl chloride derivative (157) can react with the aniline derivative (158) in a solvent, in the presence of an acidic washing product, such as sodium bicarbonate, triethylamine or pyridine or under Schotten-Baumann-like conditions to obtain compound (159).

The sulfonyl chloride derivative (157) can be obtained by sulfonating the corresponding benzyl derivative, as described above, followed by the reaction with PCl _g or POClg. Likewise, aniline (74) can react in a similar manner as described above with the sulfonyl chloride derivative (160) to obtain compound (161).

Scheme 24 shows the preparation of furan analogs of the biphenyl compounds (80). Thus, a ketoester a (162), W. Wierenga and Η. I. Skulnick,

J, Qrg, Chem., 44, 310 (1979), or the corresponding nitrile (E = CN) can be easily alkylated via the standard processes already mentioned, by means of an alkyl bromide derivative to obtain the compound (163). The alkene group of compound (163) can subsequently be cleaved by means of oxidation, for example, with osmium tetroxide, Fieser and Fieser, V. 1, p. 812 (Eemieux-Johnson oxidation) to obtain the compound (164) containing dicarbonyl. Cycling in inorganic acids, resin by exchange with acid ion, POClg / pyridine or trifluorohydride

/ roacetic with a catalytic amount of roacetic trifluoro acid gives furan (165; 2 = 0). The reaction of compound (164) with P4S1Q, for example, should give rise to the corresponding thiophene (165; z = S). The reaction of compound (164) with an amine in benzene, a. reflux temperature with azeotropic elimination of water or through the use of molecular shavings to absorb water, may give rise to the corresponding pyrrole (165; Z = NR ^^). The compounds (166) can be prepared from the compound (165) using standard processes already described.

Br (Cl, I, OTs, OMs, etc.)

E =

Z =

0, S, NR _X1

164>

i

The compounds in which a methylene group is inserted between the terminal aromatic nucleus and the acidic nucleus, from the functional point of view, can be prepared as shown in Scheme 25, equation a). Thus, the reduction of the ester (167) with, for example, aluminum hydride and lithium gives rise to alcohol (168). The conversion of alcohol (168) to chloride (169), via thionyl chloride, followed by the reaction with the cyanide anion, as previously described, gives nitrile (170). The compound (170) can be hydrolyzed to obtain the carboxylic acid (171) using methods already described or reacted with an equivalent hydrazoic acid to obtain the tetrazole (172).

The compounds wherein R ^ ^{_3-R e} presenta trifluorometilsulfonilhidrazida acid functional group were prepared by the procedure • - ⁹⁵ described in equation b). That is, conversion of the ester (167) to the hydrazide (173) by means of standard hydrazinolysis followed by reaction with triflic anhydride gives rise to the bidrazides (174).

Layout 25

170

169

The syntheses of compounds in which the symbol R ₁₃ represents 1,2,3-triazoles, possibly substituted, are described in Scheme 26. Thus, the reduction of the ester (175) with a reducing agent, such as lithium aluminum hydride or diisobutylaluminum hydride, gives rise to alcohol (176). oxidation with MnO ₂ or pyridine chlorochromate converts the alcohol (176) to the aldehyde (177).

£ - 97 - / nitroethylene derivative (178) is prepared by condensing aldehyde (177) with nitromethane in the presence of a catalyst, R. M. Letcher and Μ. P. Sammes, J, Chem. Ed., 62, 262 (1985). Reaction of compound (178) with sodium azide gives 1,2,3-triazole (179), (N. S.

Zefirov et al., J, Chem. Soc. Chem, Comm., 1001 (1971)) which can be transformed, via previously described processes, into the compound (180).

aldehyde (177) can also be converted to the substituted 1,2,3-triazoles (183) via sulfone (181), G. Beck, D. Gunther Chem. Ber., 106, 2758 (1973), and then react with sodium azide to obtain 1,2,

3-triazole (182). Subsequent standard manipulations lead to 1,2,3-triazoles (183) where E = CN and ^CO 2 ^R 11 * nitrotriazole (183) (E - N0 ₂ ) can be synthesized from unprotected triazole (179 ? P = Η), via nitration,

R. Huttel et al., Chem. Ber .. 88, 1586 (1955), C. L. Habraken and P. Cohen-Eernandes J. Chem. Soc., 37, (1972), or from the bromonitroethylene derivative (184), G.

Kh. Khisamutdinov et al., Zh. Org. Khim., 11, 2445 (1975), by reaction with sodium azide.

A variety of protecting groups can be used in the manipulation of the previous triazoles, among which is the trityl group. This group can be easily linked by reacting the triazole with triphenylmethyl bromide or chloride in an inert solvent, such as methylene chloride, in the presence of an acidic washing product, such as triethylamine. The trityl group can then be eliminated by

stirring or heating at reflux temperature in an acidic medium, such as trifluoroacetic acid / water,

HCl in methylene chloride, or acetic acid / water. The trityl group can also be hydrogenated using a noble metal catalyst, such as palladium and hydrogen.

Layout 26

177iR = CHO

1) NaNg

2) protection

\

183

Ξ = ^C0 2 ^R U ' ^CN * ^N0 2 P = protecting group

The synthesis of trifluoromethyl-1,2,4-triazoles (190) is described in Scheme 27. The hydrochloric acid (186) is converted to the amide (187) using Standard 'processes, familiar to those skilled in the art. A preferred protecting group is the 2-propionitrile group (P = CH2 C3 CN). Thus, the compound (187; P = = CH ^ CHgCN) can be synthesized from compound (186) and J3-aminopropionitrile, under conditions similar to those of Schotten-Baumann, using an aqueous base in an organic solvent to help solubilize compounds (186) and (187). Starch (187) is converted to amidrazone (188) by reaction with PCl4 or phosgene to obtain an iminoyl chloride which then reacts with excess hydrazine. The amidrazone (188) is cyclized to obtain trifluoromethyl-1,2,4-triazole (189) with trifluoroacetic anhydride and then converted to compound (190) via bromination, alkylation

100 and deprotection, as previously described.

Layout 27

190

- 101

The relative Rg groups can be introduced # differently # through many processes including those described in Scheme 28 which describes the imidazole construction.

The Rg groups thus introduced may remain unchanged or can be worked on # later if they become functional # appropriately # according to methods familiar to those skilled in the art # as shown in Scheme 28.

Layout 28 j R ₂ (ch

194 R ₅ ( _C H ₂ ) _ffl Br

R = CPhg # SO ₂ Ph # CH ₃ CHOC ₂ H ₅ 192íR '= H 193: R' = Ts

PDC

PhgPCHR '

195

198

The 2-alkenylimidazois (201) can be prepared by bromination of the 2-alkylimidazois (199), followed by the elimination of hydrogen bromide. The bromination is preferably carried out by means of ultraviolet irradiation, for 1 to 4 hours, of imidazole (199) and N-bromosuccinimide, in an inert solvent, such as carbon tetrachloride, at a temperature of 25 ° C.

treatment of the intermediate bromide (200) with a base, such as DBU, triethylamine or potassium t-butoxide, gives rise to trans 2-alkenylimidazois (201). Cis alkenyl derivatives (203) are prepared from trans alkenyl compounds by treatment with osmium tetroxide and sodium periodate to obtain the aldehydes (202), followed by the Wittig reaction.

3

Layout 29

203

R = alkyl, cycloalkyl

104

Alternatively, the Rg groups can be introduced by metallising a protected imidazole or a protected 2-methylimidazole, followed by the addition of an appropriate electrophile, as shown in Scheme 30, equations a) and b). The compounds (alcohols, esters, halides, aldehydes and alkalis) are suitable for further work using methods familiar to those skilled in the art.

Metallization of imidazoles is described by K. L. Kirk in J. Org. Chem., 43, 4381 (1978)? R.

J. Sundberg, J. Het. Chem., 14, 517 (1977)? J. V. Hay et al., J. Org, Chem., 38, 4379 (1973); B. Iddon, Heterocycles, 23, 417 (1985).

The condensation of the ômethylimidazole and appropriate electrophilic des (equation b) with an acid or a base, catalysts, as described in A. R. Katritzky (Ed), Comprehensive Heterocyclic Chemistry, Vol.5, p. 431, Pergamon Press, N.T., 1984, gives rise to compounds in which the symbol Rg represents an alkenyl group, which are suitable for further elaboration.

J

105 - <

The)

Layout 30

B)

206

Various substituted 2-imidazois can be prepared by reacting a protected 2-trimethylsilylimidazole with an appropriate electrophile using the method described by F. H. Pinkerton and S. F. Thames in J. Het. Chem., 2 * 67 (1972), which can be further elaborated as desired.

Alternatively, R _& R can also be introduced using Grignard binding reagents

- 106 cross-linked, nickel catalyzed, oom 2- (methylthio) imidazois (Scheme 31) as described by E. Wenkert and T. W. Ferreira in J, Chem, Soc. Chem, Commun., 840 (1982); AND.

Wenkert et al., J. Chem._Soc.Chem. Commun., 637 (1979);

and H. Sugimura and H. Takei, Bull. Chem. Soc. Japan, 58, 664 (1985). Cs 2- (methylthio) imidazois can be prepared using the process described in German Patent No. 2,618,370 and in the references cited here.

Layout 31 ^R 8

210

KNCS + RN-CHCH (OCH ~) _A I O Z

RgMgCl (Ph ₃ P) ₂ NiCl ₂ or

NiCl ₂ (dppp)

R

213

As shown in Schemes 32-36, the preparation of Rg can be carried out by means of some of the processes described in Schemes 3 and 28, by means of extended chain reactions, familiar to those skilled in the art, or by means of reactions of degradation, such as the conversion of an ester to an acid or that of an alkene to an aldehyde.

107

Specifically, the hydroxymethyl group can be activated by the displacement reaction, via the reaction with thionyl chloride, PCl _g or with carbon tetrachloride / triphenylphosphine to form a corresponding chlorine derivative. By means of a similar reaction, bromine and iodine derivatives can be obtained. The hydroxymethyl group, too, can be activated by forming the corresponding p-toluenesulfonate, methanesulfonate and trifluoromethanesulfonate derivatives.

Scripture 32

CH ₃ CSH

Znl

215

216

108

As shown in Scheme 32, the hydroxyl group can be converted into the thiolacetic acid derivative (215), J. Y. Gauthier, Tet. Lett., 15 (1986), and in the thiol derivative (216) by means of subsequent hydrolysis, the hydroxymethyl group of compound (17) can be immediately oxidized to form an aldehyde group, by means of manganese dioxide or cyclic ammonium nitrate . The aldehyde group may undergo prolonged chain reactions, such as the Wittig and Wittig-Horner reactions and enter the typical carbon-carbon bond forming reactions with the Grignard and lithium reagents, as well as with compounds that support active methylene groups. As an alternative, the hydroxymethyl group can be directly oxidized to a functional acid, which in turn can be converted into ester and starch derivatives. Esters and starches can be prepared directly from aldehydes through oxidation by manganese dioxide in the presence of sodium cyanide and an alcohol or an amine, J. Am. Chem, Soc.,

90, 5616 (1968) .6 J. Chem. Soc. (C), 2355 (1971).

As shown in Scheme 33, the chlorine in compound (25) can be displaced by means of the dialkyl malonate anion to obtain the corresponding major derivative (217). Saponification of the compound (217) with NaOH (or KOH) gives the corresponding diacid which can be decarboxylated to obtain the corresponding propionic acid derivative (218) by heating at 120 ° C. Alternatively, compound (218) can be obtained directly by heating

- 109 - / at the reflux temperature of the compound (217) with an inorganic acid, such as HCl or sulfuric acid. The free acid (218) can be esterified by heating in a medium of various alcohols and a catalytic amount of inorganic acids, such as HCl or sulfuric acid to obtain the corresponding esters (219). Alternatively, esters can be obtained by reacting free acid (218) and corresponding alcohols in the presence of binding reagents, such as DDQ

J or EEDQ. A similar reaction with several mono- and di-substituted amines produces the corresponding amides (220). A similar reaction with several mercaptans produces the corresponding thioesters.

Layout 33

217

110

Scheme 33 (continued)

As shown in Scheme 34, the chlorine group in the compound (25) can be displaced by means of the sodium salt or the potassium salt of the alkyl, aryl or arylalkyl mercaptans to obtain the corresponding sulfite derivatives (221). The amine derivative (222) can be obtained by treating the compound (£ 5) with ammonia or the corresponding mono-substituted amines. Alternatively, the chlorine group can be displaced by means of sodium azide to obtain an intermediate azide which by reduction with H2, on a catalyst.

«B noble metallic lyser or with a reducing agent, such as chromium chloride (W, K. Warburton, J. Chem, Soc., 2651 (1961)) gives the compound (222), in which the symbols R _lo and Rj -i represent hydrogen atoms. This amine can subsequently be alkylated with alkyl halides or be alkylated, by reduction, with aldehydes and ketones to obtain the alkyl derivatives of the compound (222). The amines (222) are converted into the corresponding carbamates (224), sulfonamides (225), amides (226) or ureas (227) by means of the Standard processes illustrated in Scheme 34 and familiar to those skilled in the art.

Layout 34

112

Scheme 34 (continued)

R,

r ₂

^CH 2 ^} r

224

R,

M

R <'R-

R.

225

R,

226 /

113

Scheme 34 (continued)

222 R -N = C = 0

The reaction between the thiopyridyl ester (229) and an appropriate Grignard reagent gives rise to the ketones (23 °).

Layout 35

229 (R = pyridyl)

230

114

As shown in Scheme 36, when the imidazole at positions 4 and / or 5 contains an aldehyde (231), then the reaction with organometallic reagents, such as Grignard reagent or alkyl / arylithium reagent, will give rise to alcohols (232) which, in turn, they will become a variety of other functions familiar to those skilled in the art.

231 (X = halogen)

232

115

- 115

As shown in Scheme 37, the ester (234) can be obtained by directly oxidizing the aldehyde (233) with NaCN or MnO, in methanol (Corey, EJ et al., J. Am. Chem., Soc. (1968), 90, 5616). The oxidation of the compound (233) with NaCN, MnO, and an amine in 2-propanol leads to. corresponding amide (235) (Gilman, N.W. Chem. Comm. (1971) 733).

Layout 37

COLOR

NaCN

MnO,

ROH

234

NaCN

MnO,

NH, or R'RNH

ÍPrOH

R = alkyl

OH

116

- 116

Saponification of the ester (234) will lead to carboxylic acid (236).

aldehyde (233), in turn, can be prepared from the corresponding alcohol (1) 7) using a variety of methods familiar to those skilled in the art, including oxidations with pyridium chlorochromate (PCC), Swern and ammonium nitrate (CAN).

Likewise, the non-alkylated hydroxymethylimidazole derivative 1 (R _o = CH_OH) can undergo transe Z formations to give the aldehyde, ester, carboxylic acid and carboxamide through reactions mentioned above for the case of alkylation.

Compounds (238) (where Ar = aryl or heteroaryl as described within the scope of the invention, under the definition of R R) can be prepared by linking an aryl metal derivative (ArM, where M = ZnBr,

Me ₃ Sn, B (OH) ₂ , etc.) to a halogenoimidazole (237) in the presence of a transition metal catalyst, such as palladium, nickel, platinum, zirconium, etc. (Scheme 38a). Alternatively, an imidazolic metal derivative (239) can be attached to an arylbalide to prepare compound (238) (Scheme 38b).

Arylmethyl derivatives (24p) can be prepared using the transition metal catalyzed bond of compound (237) to an arylmethyl metal (ArCHgM ¹ , where M '= ZnBr, etc.), as shown in Scheme 38c .

Compounds (241) can be prepared, as described in Scheme 38d, by

117 is an alkenyl or alkynylmetallic derivative (AM) or the corresponding alkene or alkaline (AH) to the compound (237).

Likewise, non-alkylated imidazois (1, where R? = Br or I) may undergo binding reactions described in Scheme 38a-d / For references to transition metal catalyzed binding reactions, see Richard C. Heck , Palladium Reagents in Organic Synthesis, Academic Press, New York, Chapters 6,7 and 8; and references cited there; /.

Compounds of general formula (I), wherein R _? represents an arylalkenyl group or an arylalkynyl group and the carbon-carbon double or triple bond is not adjacent to the imidazolic nucleus (for example, FÍ ₇ = (CH ₂ ) _U CH = CH (CH> _v Ar, where u? is = o), can be prepared by a variety of extended chain and chain reaction methods known to those skilled in the art including those described in Schemes 3, 28, 29, 33, 35, 36 and 38.

The compounds of the general formula (I), where R_ represents an arylalkyl group (r ₇ = (CH_) Ar, flzw where w = 2-10), can be prepared by reducing alkenes (241) corresponding by means of catalytic hydrogenation.

- 118

Layout 38

The)

ArM

Pd °

237 (X = Br or I)

Air

RR.

Ar = aryl or heteroaryl

238

240

119

Scheme 38 (continued)

237

d)

AM OR AH Pd °

,)

A = C = 0 (0 ^ 5 ^ or

CH = CH (CH ₂ ) _x Ar

X = 0-8

The compounds of general formula (I), where R ₇ = arylalkenyl and R _g = CH ₂ OH, aldehyde or COOH, can be prepared as shown in Scheme 39.

(242) 2 — Alkylimidazole-4,5-dicarboxyl acids prepared by the R.G. Fargher and EL Pyman (J, Chem, Soc., 1919, 115, 217), can be converted into their corresponding diesters (243) by simply heating at reflux temperature in an alcoholic solvent and in the presence of a acid, such as HCl, or by many other methods familiar to those skilled in the art.

diester (243) can then be converted to its metal salt by reaction with sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride or any other base in an appropriate solvent, such as DMF. The resulting salt is alkylated

- 120

Then, with the benzyl derivative (_2) appropriately substituted, to obtain benzylimidazole (244).

The previous alkylation sequence can also be carried out by heating or by heating to the reflux temperature of the benzyl halide (tosylate or rnesylate) (2) with imidazole (243) in a solvent such as DMF and in presence of an acidic washing product, such as sodium or potassium carbonate.

diester (244) can be reduced with aluminum and lithium hydride in an inert solvent, such as THF, to obtain the corresponding color alcohol (245). The selective oxidation of the alcohol (245) with manganese dioxide in an inert solvent, such as THF, mainly predominates the aldehyde (247) with a smaller compound, the dialdehyde (246).

The separation of the compound (247) from the compound (246), by means of crystallization or chromatography, followed by Wittig's reaction of the compound (247) with the appropriately substituted arylalkylidenotriphenylphosphorane, in an inert solvent, such as THF, originates 4-arylalkenyl-5-hydroxymethylimidazole (248). The subsequent oxidation of the compound (248) with Dess-Martin periodinane (J. Org. Chem., 1983, 48, 4155), with manganese dioxide, with pyridinium chlorochromate, with barium manganate or with other oxidants familiar to the enten in the material, in an inert solvent such as THF or methylene chloride, followed by the deprotection of either R,, & ₂ or R ₃ , eventually gives rise to 4-aryl121 alkenylimidazole- ·· 5-carboxaldehyde (249).

The oxidation of the compound (249) with, for example, manganese dioxide / cyanide ion (Corey, EJ et al., J. Am. Chem. Soc., 1968, 90, 5615) or with potassium permanganate (Sam, DJ et al., J. Am, Chem, Soc., 1972, 94, 4024) gives (250) 4-arylalkenylimidazole-5-carboxylic acid.

Figure 39

246 245

Ph ₃ P = CH- / (CH ₂ ) _x -Aryl Wittig reaction

- 122

Scheme 39 (continued)

248

1, oxidizes

2, unprotect

The imidazois represented by structure (251), where the symbol X represents a chlorine, bromine or iodine atom and the symbol E represents a removable electronic group, such as an ester, ketone, nitro, alkylsulfonyl, arylsulfonyl, etc., may undergo the aromatic nucleophilic substitution reaction (H. Scbubert,

H. Simon, A. Jumar Z, Chem. (1968) 62-63) in which the leaving group X is replaced by a nucleophile, such as

- 123

as sulfur, carbon or nitrogen, to give adducts (252) (Scheme 4). The reaction can be carried out in a hydroxyl solvent, such as methanol or in a non-hydroxyl solvent, such as DMSO from room temperature to the reflux temperature of the solvent. Sometimes, the nucleophile can become its anion to make it more nucleophilic. For example, thionaftol can be heated to reflux temperature in methanol in the presence of sodium methoxide and halogenoimidazole (251). Other nucleophiles include other arylthiools, heteroarylthiois, arylsulfonamides, heteroarylsulfonamides, arylamines, beteroarylamines, etc., familiar to those skilled in the art.

If a sulfuric nucleophile is used, the resulting sulfites can be oxidized to obtain the corresponding sulfoxides and sulfones by methods familiar to those skilled in the art.

251

252

124

The compounds of the present invention and their preparation can be better understood by means of the following examples which are not a limitation of the present invention.

In these examples, unless otherwise indicated, all temperatures are in degrees centigrade and portions and percentages are by weight.

Example 1

PART A:

Preparation of 5-hydroxymethyl-4-iodo-2-n-propyl imidazole

A solution of 31.5 g of 4 (5) -hydroxymethyl-2-η-propylimidazole and 50.6 g of N-iodosuccinimide in 560 ml of 1,4- dioxane and 480 ml of 2-methoxyethanol. Then, the solvents were removed under vacuum. The resulting solids were washed with distilled water and then dried

to obtain 54.6 g of the compound, in the form of a yellow solid: yellow solid m.p .: 169 ° at 170 ° C. NMR (DMSO-d ^) O s 12.06 (br s, 1H); 5.08 (t, 1H); 4.27 (d, 2h); 2.50 (t, 2H);

1.59 (sext., 2H); 0.84 (t, 3H).

125

PART B: Preparation of 4-iodo-2 — n-propylimidazole-5-carboxaldehyde

To a solution of 35.8 g of 5-hydroxymethyl-4-iodo-2-n-propylimidazole in 325 ml of glacial acetic acid and at a temperature of 20 ° C, 290 ml of a solution of aqueous, ammonium nitrate, 1, ON. The resulting mixture was stirred at 20 ° C for 1 hour. Then, the reaction mixture was diluted with water and the pH was adjusted to

5-utilizando using an aqueous sodium hydroxide solution and extracted with chloroform. The combined organic phases were washed with water and a concentrated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude solid was recrystallized from 1-chlorobutane to obtain 29.9 g of the compound as a slightly yellow solid; mp 141 ° - 142 ° C. NMR (CDClg) / 11.51 (br s, 1H); 9.43 (s, 1H>; 2.81 (t, 2H); 1.81 (sext., 2H);

0.97 (t, 3H).

- 126

Ν á

PART C: Preparation of 4- (naphth-l-yl) -2-n-propylimide · zol-5-carboxaldehyde

A solution of 2.64 g (0.01 moles) of sodium chloride was stirred at room temperature under a nitrogen atmosphere.

4-iodo-2-n-propylimidazole-5-carboxaldehyde, 40 ml of toluene and 0.33 g (0.00029 moles) of tetraquistriphenylphosphine palladium (0), while slowly adding a solution of 3.44 g (0.022 moles) of 1-naphthylboronic acid in 5 ml of ethanol. The reaction was stirred for 5 minutes, after which 12 ml of 2M sodium carbonate was added slowly. After the addition was complete, the reaction was heated to reflux for 48 hours and cooled. The reaction mixture was filtered, the filtrate was evaporated under reduced pressure and the resulting residue was dissolved in 300 ml of methylene chloride, washed twice with 100 ml of saturated sodium chloride solution, washed twice with 100 ml of distilled water and washed twice with 300 ml of 10% HG1. The HCl layer was basified with 50% sodium hydroxide until the pH = 10. At this point, the basic water layer was extracted three times with 300 ml of methylene chloride;

the methylene chloride layer was dried over sodium sulfate and evaporated under reduced pressure. Yield: 0.90 g (0.0034 moles, 34%) of the compound. NMR (CDCl ₃ ) <f 11.45 (m, 1H); 9.42 (s, 1H); 7.28 (m, 7H); 2.82 (t, 2H); 1.85 (m, 2H); 1.01 (t, 3H).

SOURCE D: Preparation of 4-methyl-2 '- (N-triphenylmethyl- (1H-tetrazol-5-yl)) biphenyl

10.00 g (51.7 mmoles; 1 eq) of 4 * -methylbiphenyl-2-nitrile were mixed (preparation described in European Patent Application No. 0253310, published 20-01-88), 14, 0 ml (51.7 mmoles; 1 eq.) Of tri-n-butyltino chloride, 3.4 (51.7 mmoles; 1 eq.) Sodium azide and 50 ml of xylene and the mixture was heated to reflux temperature for 64 hours, after which it was cooled to room temperature. Then, 6.10 ml (0.061 mmoles; 1.2 eq.) Of 10.0 N NaOH and 14.99 g (53.8 mmoles; 1.04 eq.) Of trityl chloride were added and stirred. the mixture was run for 24 hours after which 39 ml of water and 100 ml of heptane were added. The resulting slurry was stirred at 0 ° C for 1.5 hours.

- 128

128

- /

The resulting solids thus obtained were filtered, washed with water (2 x 55 ml), washed once with 55 ml of heptane / toluene (3: 2) and dried overnight, under high vacuum, to obtain 19, 97 g of a slightly yellow powder; mp: 148 ° -155 °, OC (dec.). These solids formed a paste with 75 ml of ethyl acetate which was filtered to obtain 15.0 g of a slightly yellow powder: mp: 164 °, 0-165 ^M , 5C (dec.). NMR (CDCl3) S 7.91 (d, 1H, J = 9 Hz); 7.53 - 7.18 (m, 13H); 7.02 - 6.84

CPh.

PART E: Preparation of 4-bromomethyl-2 '- (N-triphenylmethyl- (1H-tetrazoI-5-yl)) foiphenyl, a representative process.

52.07 g (109 mmol; 1 eq. For preparation, see Example 95, Part B) of 4-methyl-2 '- (N-triphenylmethyl- (1H-tetrazol-5-yl)) biphenyl, 19 , 4 g (109 mmoles; 1 eq.) Of N-bromosuccinimide, 1.0 g of benzoyl peroxide and 300 ml of carbon tetrachloride and the mixture was heated to reflux for

129

2.5 hours. The reaction mixture was cooled to room temperature and the succinimide was filtered. The filtrate was concentrated and the residue was triturated with ether to obtain a first crop of 36.0 g; m.p .: 129 °, 5 - 133 °, OC (dec.). NMR (CDClg) ξ 4.37 (CH ^ Br). This material proved to be suitable for further processing.

PART F: Preparation of 4- (naphth-l-yl) -2-n-propyl-1- / (2 * - (N-triphenylmethyl- (1H-tetrazol-5-yl)) biphenyl-4-yl) - methyl7imidazole-5-carboxaldehyde

A suspension of 0.90 g (39.7 mmoles; 1 eq.) Of 4- (naphth-1-yl) -2-n-propylimidasol-5-carboxaldehyde was stirred at room temperature for 18 hours. ,

2.03 g (43.7 mmoles; 1.1 eq.) Of 4-bromomethyl-2 '- (N-triphenylmethyl- / 1H-tetrazol-5-yl) biphenyl, 20 ml of animal DMF

130 - ύ>

dra and 3.0 g of potassium carbonate. The reaction mixture was filtered, the precipitate was washed with methylene chloride and evaporated under reduced pressure. The residue was chromatographed with methylene chloride / ethyl acetate (98: 2) over silica gel to obtain a yellow foam. Yield: 1.50 g. NMR (CDCl ₃ ) 5 9.45 (s, 1H); 7.85 (m, 1H); 6.86 - 7.45 (m, 29H); 5.55 (s, 2H), 2.60 (t, 2H); 1.80 (m, 2H); 0.95 (t, 3H).

SOURCE G: Preparation of 4- (naphth-1-yl) -2-n-propyl-1- / ^- (2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl / imidazole-5- carboxaldehyde

Stirred at room temperature, 1.50 g of 4- (naphth-1-yl) -2-n-propyl-1- / (2 '- (N-triphenylmethyl- (1H— -tetrazol-5-yl)) biphenyl-4-yl) methyl7imidazole-5-carboxaldehyde, 80 ml of THF and 10% HCl. After 8 hours, the

131 mixture on ice / 5% NaOH and the pH = 10 was adjusted. The resulting solids were filtered and the pH of the filtrate was adjusted to 4-5 with 10% HCl. The cloudy solution was extracted with (80/20) methylene chloride / i-propanol (3x100ml), the organic phase was dried over sodium sulfate and evaporated under reduced pressure to obtain 0.51 g of a white glass. NMR (CDClg) <$ 9/35 (s, 1H); 7.78 (m, 1H);

7.60 - 7.38 (m, 2H); 7.35 - 6.96 (m, 12H); 5.62 (s, 1H);

2.60 (m, 2H); 1.85 (m, 2H); 0.90 (t, 3H).

J The following intermediate compounds can be prepared using the method described in Example 1,

Part C.

H

\ Z \ Z \ Z Q n-propyl

132

Table 1 (continued)

Ν · - ^ ^R 7 ^R õ ^ N- ^ XCHO

R „

H

R,

mp (° C)

n-propyl

n-propyl

n-propyl

wax

133

Table 1 (continued)

n-propyl

wax

n-propyl

134

Table 1 (continued)

mp (° C)

n-propyl

n-propyl

135

Table 1 (continued)

Hey

NMR The (DMSO-Dg) è 10 -7.99 (m, 4H), , 04 (s, 1H), 8.135 2.65 (t, 2H), 1.71 (s, 1H), 7.20 (m, 2H), 0.94 (t, 3H). NMR _b (CDC1 ₃ ) ò 9.44 (s, 1H), 8.55 (m, 2H), 8.15 (ra, 2H) 7.20 (m, 2H), 2.85 (t, 2H), 1.73 (m, 2H), 1.03 (t, 3K). NMR ç (CDClg) 9.53 (s, 1H), 7.74 (m, 1H), 7.64 (m, 1H) 7.28 (ra, 2H), 3.73 (q, 2H), 3.40 (s, 4H), 1.87 (m. 2H), 1.24 (t, 3H). NMR ^ (CDC1 ₃ ) 9.88 (s, 1H), 8.22 (s, 1H), 7.88 (m, 4H) 7.53 (m, 2H), 2.87 (t, 2H), 1.87 (m, 2H), 1.03 (t, 3H). NMR and (DMSO-Dg)>) 9, 85 (s, 1H), 8.30 (s i, 1H), 8.14 (s ! /

1H), 7.60-7.90 (m, 2H>, 7.01-7.21 (m, 2H), 3.93 (s, 3H), 2.78 (t, 2H), 1.85 (ra, 2H), 1.01 (t, 3H).

136

The compounds in Table 2 can be prepared by the process described in Example 1 or by the methods described in European patent application 0253310 (publication date: January 20, 1988).

^R 6

R

mp (° C) n-propyl

- 137

Table 2 (continued)

n-propyl

the wax

NMR (CDC1-) at 3

7.85 (s, 1.92 (m,

9.54 (s, 1H), 8.74 (m, 2H), 8.20 (b, 1H), 1H), 7.60-7.74 (m, 4H), 2.90 (t, 2H), 2H), 1.08 (t, 3H).

138

Table 2 (continued)

-R

RÇ ^x „ _T ·: hq ^R s

139

Table 2 (continued)

CHO

n-propyl

n-propyl

J

Table 2 (continued)

140 ^R 6

Ν

CHO

n-propyl

141

Table 2 (continued)

N- < ^R 7

Jt /

R '\ (3H0 ^ 6 N

H

n-propyl

n-propyl

n-propyl

wax

J

142

NMR (CDC1J S 10.13 (s, 1H), 7.66 (m, 2H), 7.43 (s, 1H), a j

7.29 (m, 2K), 2.65 (t, 2H), 1.74 (m, 2H), 0.92 (t, 3H).

Examples 2-94 in Tables 3 and 4 can be prepared using methods described in European Patent Application No. 0253310 (publication date: January 20, 1988).

J

J /

143

Table 3

n-propyl

n-propyl

144 /

n-propyl

³ n-propyl glass

glass \ / W n-propyl

II

130 dec

145

n-propyl n-propyl

- 146

Table 3 (continued)

J n-propyl

n-propyl

n-propyl

J

n-propyl

n-propyl

147

Table 3 (continued) n-propyl n-propyl n-propyl n-propyl

mp (° C)

\ ΑΛ /

148

Table 3 (continued)

mp (° C) glass ^and

149

J n-propyl n-propyl

n-propyl

J

x / W n-propyl

150

z ^v

\ / W

s

151 /

Table 3 (continued)

Ex. N-n-propyl

n-propyl

mp (° C)

152

P.KK (CDClo) 10.03 (s, 1H), 7.94 (m, 1H), 7.84 (m, 1H), at 2

7.77 (s, 1H), 7.54 (m, 1H), 7.38 (m, 4H), 7.24 (m,

1H), 7.18 (d, 2H), 7.05 (d, 2H), 5.58 (d, 2H),

2.61 Ct, 2H), 1.78 (m, 2H), 0.95 (t, 3H).

NMR _b (CDCl ₃ ) 9.37 (s, 1H), 8.10 Cm, 1H), 7.92 (m, 1H), 6.92-7.62 (m, 10H), 5.66 (s , 2H), 2.65 (t, 2H), 1.80 (m, 2H), 1.04 (t, 3H>.

NMR _c (CDCl ₃ ) 9.77 (s, 1H), 8.05 Cm, 1H), 7.85 (m, 2H), 7.00-7.83 (m, 10Η), 6.95 (m , 1H), 5.61 (s,

2.59 (t, 2H), 1.81 (m, 2H), 1.01 (t, 3H).

r <I4N _d (CDCl ₃ ) 9.76 (s, 1H), 8.14 (m, 1H), 7.92 (m, 2H), 7.73 (m, 2H), 7.55 (m, 3H), 7.28 (m, 4H), 7.11 (m, 2H), 5.64 (s, 2H), 3.96 (s, 3H), 2.53 (t, 2H), 1, 76 (m, 2H), 1.01 (t, 3H).

NMR _and (CDCl ₃ ) 9.46 (s, 1H), 8.67 (m, 1H), 7.88 (m, 1H),

7.41-7.65 (m, 6H), 6.90-7.34 (m, 10Η), 5.30 (s, 2H),

2.62 (t, 2H), 1.78 (m, 2H), 1.06 (t, 3H).

NMR _f (CDCl ₃ ) 10.45 (s, 1H), 8.00 (m, 1K), 7.46-7.62 (m,

4H), 7.23—7.40 (m, 5H), 7.23 (d, 2K), 7.02 (d, 2H),

5.56 (s, 2H), 2.58 (t, 2H), 1.74 (m, 2H), 0.94 (t,

153

Ex on

R.

COOH bond CN ^ H simple

COOH connection CN ₄ H simple

n-propyl

COOH bond CN ^ H simple

154

Table 4 (continued)

Λ »

Ex ns

mp (° C)

COOH connection CN ₄ H simple

n-propyl COOH simple CN ^ H bond

n-propyl

CHO single COOH bond

155

simple CCOH bond simple COOH bond simple COOH bond simple COOH bond

n-propyl CHO simple COOH bond NHSO ₂ CF simple n-propyl CHO bond

simple NHSO ₂ CF ₃ connection

157

Ex ns ^R 6

n-propyl CHO single NHSOgCF bond single HHSO ₂ CF ₃ bond

CHO connection NHSO ₂ CF ₃ simple

simple NHSO ₂ CF ₃ connection

158 /

Table 4 (continued)

mp (° C)

Ex. R _ó n °

159

-OCH ₂ - CN ₄ H

16th and ✓

z

Table 4 (continued)

Ex.

ns

R,

Re

Re

mp (° C)

ch ₃

CH3 n-propyl CHgOH

simple CN ₄ H connection simple CN ^ H connection simple CN ^ H connection

simple CN ^ H connection

CH OH connection GN ^ H simple

n-propyl ch ₂ oh bond CN ^ H simple bond CN ^ H simple bond CN ^ H simple

162 j ⁵

Ex.

n2

R.

t »

Table 4 (continued)

mp (° C)

simple CN ^ H connection

simple CN ^ H bond simple CN ^ H bond n-propyl CH ₂ QH simple CN ^ H bond

- 163 /

Table 4 (continued) / ..

Ex. R

R _r ní

R,

M.p. (° C)

n-propyl CH ₂ OH

simple CN ₄ H connection simple CN ^ H connection simple CN ^ H connection

CHO single CN / I connection

Table 4 (continued)

simple CN ^ H connection

-NH-CO- CN ₄ H

-CH -CH = CH n-propyl

-0- COOH

- 165 /

n-propyl COOH

-co- -nhso ₂ cf ₃

-G- NHSO ₂ CF ₃

166

Table 4 (continued)

Ex, ns ^R 6

mp (° C)

CH OH

-S- CN H n-propyl

-ch ₂ ch ₂ 92 1 Ί n-butyl CHO -CH = CH- COOH

z

- 167

Table 4 (continued)

N — r — R _?

R.

N.

\B

Ex ₍ ns

R, o

Rr

R,

mp (° C) n-butyl

COOH -CC- COOH

n-butyl

COOH

-NHCO- COOH

168 ./

Example 95

PART a: preparation of 2-n-propyl-4,5-dicarbomethoxyimi · dazole

They were mixed cautiously (the addition of acetyl chloride to methanol is very exothermic) and heated to reflux overnight,

17.14 g (86.6 mmoles; 1 eq.) Of 2-n-propyl imidazole acid.

-4,5-dicarboxylic / prepared by the method of RG Fargher and FL Pyman (ff. Chem. Soc., 1919, 115, 217); mp 257 ° C (dec.) _, 400 ml of methanol and 38.1 ml (534 mmoles; 6 eql of acetyl chloride. The solvent was removed in vacuo and 100 ml of water and 1N NaOH were added until pH = 7, The aqueous mixture was extracted with ethyl acetate (3x), the organic layers were combined, dried (MgS0 ₄ ) and the solvent was removed in vacuo to obtain 12.00 g of a solid recrystallization from hexane / ethyl acetate gave 11.41 g of a white solid (58%);

mp .: 162 ° - 164 °, 5 ° C. NMR (CDCIJ? 5 3.95 (s, 6H);

O

2.78 (t, 2K); 1.83 (t of t, 2H, J = 7.7 Hz); 0.97 (t, 3H,

J = 7 Hz); IV (pure) 1735 cm. Anal, calcd. for ^C 1O ^H 14 ^N 2 ° 4 · Í ^H 2 ^{O5o '25! C} '52.06; H, 6.28; N, 12.14. Found: C, 52.06; H, 6.17; N, 12.49.

169

PART Bj Preparation of 4-methyl-2 * - (N-triphenylmethyl- (1H-tetrazol-5-yl)) biphenyl

10.00 g (51.7 mmoles; 1 eq) of 4 ¹ -methylbiphenyl-2-nitrile (preparation described in European Patent Application No. 0253310, published on January 20, 1988), 14, 0 ml (51.7 mmoles; 1 eq) of tri-n-butyltino chloride, 3.4 g (51.7 mmoles; 1 eq.) Of sodium azide and 50 ml of xylene and the mixture was heated at reflux temperature for 64 hours, after which the reaction mixture was cooled to room temperature. Then, 6.10 ml (.061 mmoles; 1.2 eq.) Of NaOH 10, ON and 14.99 g (53.8 mmoles; 1.04 eq.) Of trityl chloride were added and stirred. the mixture for 24 hours, after which 30 ml of water and 100 ml of heptane were added. The resulting slurry was stirred at 0 ° C for 1.5 hours. Thus, the resulting solids were filtered, washed with water (2x55 ml), washed once with 55 ml heptane / toluene (3: 2) and dried overnight, under high vacuum, to obtain 19.97 g of a slightly yellow powder: mp: 148 °, O - 155.0 ° C (dec). These solids formed a paste with

170 /

ml of ethyl acetate which was filtered to obtain 15.0 g of a slightly yellow powder: m.p .: 164 °, o-165 °, 5 ° C (dec.). NMR (CDClg) <f 7.91 (d, 1H, J = 9 Hz);

7.53-7.18 (m, 13H); 7.02-6.84 (m, 9H); 2.25 (s, 3H).

CPh,

PART C: Preparation of 4-bromomethyl-2 * - (N-triphenylmethyl- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl bromide, a representative process.

They were mixed and heated at reflux for 2.5 hours, 52.07 g (109 mmoles;

eq.) of 4-methyl-2 '- (N-triphenylmethyl- (1H-tetrazol-5-yl)) biphenyl, 19.4 g (109 mmoles; 1 eq.) of N-bromosuccinimide, 1.0 g of benzoyl peroxide and 300 ml of carbon tetrachloride. The reaction mixture was cooled to room temperature and the succinimide was filtered. The filtrate was concentrated and the residue was triturated with ether to obtain a first crop of 36.0 g; m.p .: 129 °, 5-133 °, OC (dec.). NMR (CDClg) 4.37 (CHgBr). This material was used for further processing.

171

PART Ds Preparation of 4,5-dicarbomethoxy-2-n-propyl-1- / (2 '- (N-triphenylmethyl - (. 1H-tetrazol-5-yl)) biphenyl-4-yl) methyl / imidazole.

1.06 g (44.2 mmoles; 1 eq.) Of sodium hydride were added to a solution of 10.00 g (44.2 mmoles; 1 eq.) Of 4,5-dicarbomethoxy-2-n- propylimidazole in DMF at room temperature. Foaming and gas evolution occurred. The temperature was increased to 60 ° C for 15 minutes to dissolve all the sodium hydride. The gas evolution stopped and the mixture was cooled to room temperature. To this mixture was added a solution of 24.64-g (44.2 mmoles; 1 eq.) Of 2 '- (N-triphenylmethyl- (1H-tetrazol-5-yl)) biphenyl-4-yl ) methyl in DMF. After 24 hours, the solvent was removed in vacuo and the residue was quickly chromatographed in hexane / ethyl acetate (75:25) to 100% ethyl acetate on silica gel to obtain 25.78 g (51% ) of white glass that was used for further processing.

172

Recrystallization from ethanol gave an analytical sample (white crystals); m.p .: 124 °, 0-125 °, 5 ° C. NMR (CDClg) 7.91 (d d, 1H, J = 3.9 Hz); 7.59-7.20 (m, 12H); 7.09 (d, 2H, J = 9 Hz); 6.94 (m, 6H); 6.76 (d, 2H, J = 9 Hz); 5.3 (s, 2H); 3.89 (s, 3H); 2.50 (t, 2H, J = 7 Hz); 1.67 (t of t, 2H, J = 7.7 Hz); 0.85 (t,

3H, J = 8 Hz).

IV (pure) 1718 cm \ Anal, calcd. for C ^ HggNgO ^:

C, 73.49; H, 5.45; N, 11.96. Found: C, 73.23;

H, 5.48; N, 12.22.

PART E: Preparation of 4,5-dihydroxymethyl-2-n-propyl-1 (2 * - (N-triphenylmethyl- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] ./imidazole

9.88 g (14.1 mmoles; 1 eq.) Of 4,5-dicarbomethoxy-2-n-propyl-1- / ~ (2 '- (N-triphenylmethyl- (1H-tetrazole-5- il) biphenyl-4-yl) methyl / imidazole in a minimum of THE and to this solution slowly 15.48 ml (15.48 mmoles; 1.1 eq.) of lithium aluminum hydride were added dropwise (1.0 M in THF). The mixture was stirred

- 173 at room temperature, overnight, after which it was cooled by means of the Steinhardt process (Fieser & Fieser Vl, p. 584), which was desired next: to the reaction mixture, 0 , 66 ml of water, then 0.66 ml of 15% NaOH and, finally, 1.97 ml of water. After stirring for 72 hours, a very fine suspension of particles was formed which was slowly filtered through Celite. The filtrate was dried (PlgSO4) and the solvent was removed in vacuo to obtain 8.83 g of yellow glass that cannot be recrystallized. This intermediate compound was used for further processing. NMR (DMSO-dg)

à 7.82 (d, 1H, J = 9 Hz); 7.68-7.28 (m, 12H); 7.05 (d, 2H,

J = 9 Hz); 6.87 (d, 6H, J = 9 Hz); 5.16 (s, 2H); 4.94 (t, J = 7 Hz); 4.66 (t, 1H, J = 7 Hz); 4.37 (d, 2H, J = 7 Hz); 4.32 (d, 2H, J = 7 Hz); 2.34 (t, 2H, J = 7 Hz); 1.52 (t of q, 2H, J = Ί, 7 Hz); 0.77 (t. 3H, J = 7 Hz). IV. (pure) 3300 br; 3061; 1027; 1006; 909; 732; 699 cm ” ¹ .

Anal, calcd. for C ₄₁ H _3g NgO ₂ «H ₂ O: G, 74.07; K, 6.06; N, 12.64. Found C, 74.06; H, 5.95; N, 11.86.

174

)

PART F: Preparation of 5-hydroxymethyl-2-n-propyl-1- / (2 * - (N-triphenylmethyl- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl / imidazol-4-carboxaldehyde and 2-n-propyl-1- / (2 * - (N-triphenylmethyl- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl / imidazcl-4,5-dicarboxal deoxy.

8.56 g (13.2mmoles; X eq.) Of 4,5-dihydroxymethyl-2-n-propyl-1-- ~ (2 '- (N-triphenylmethyl- (1H-tetrazole-5 -yl) biphenyl-4-yl) methyl // imidazole in a minimum of THF and added to a paste of 11.14 g (128.1 mmoles; 9.7 eq.) of manganese dioxide in 100 ml of THF After 24 hours, the contents were filtered through Celite, the cake was washed with THF and the filtrate solvent was removed in vacuo. The residue was quickly chromatographed with hexane / ethyl acetate (1 : 1) to 100% ethyl acetate on silica gel to obtain the dialdehyde which was first eluted: 1.25 g (15%) of a cinnamon-colored glass.

175

NMR (DMSC-dJ Γ 10.27 (s, 1H); 10.17 (s, 1H); 7.81 (d,

The v

1H, J = 7 Hz); 7.68 µm, 2H); 7.50-7.23 (m, 10H); 7.09 (d, 2H, J = 9 Hz); 6.96 (d, 2H, J = 9 Hz); 6.86 (m, 6H)? 5.59 (s, 2H); 2.52 (t, 2H, J = 7 Hz); 1.58 (t of q, 2H, J = 7.7 Hz); 0.77 (t, 3H, J = 7 Hz). IV (pure) 1697; 1672cm ^-1 . Anal, calcd. for (--44 ^ 34 ^^ 2 * ^{G /} 76.62; H, 5.33;

N, 13.07.

Found: C, 76.46; H, 5.54; N, 12.94.

Continuing elution, the compound 4-hydroxymethyl-imidazole-5-carboxaldehyde gave rise to a slightly yellow solid: m.p .: 164 °, 5-166 °, OC. NMR (DMSO-dg) £ 9.86 (s, 1H); 7.80 (d, 1H,

J = 9 Hz); 7.63 (t, 1H, J = 9 Hz); 7.53 (t, 1H, J = 7 Hz);

7.50-7.25 (m, 10H); 7.07 (d, 2H, J = 9 Hz); 6.97-6.80 (m, 8H); 5.47 (t, 1H, J = 7 Hz); 5.29 (s, 2H); 4.63 (d, 2K,

J = 7 Hz); 2.37 (t, 2H, J = 7 Hz); 1.49 (t of q, 2H, J = 7.7

Hz); 0.73 (t, 3H, J = 7 Hz). IV. (Nujol) lcmS ^-1 .

Anal, calcd. for ^σ 44 ^Η 36 ^Ν 6 ^Ο 2 · ^ ^Η 2 ^σ ) 0 1 * ^{C # 76} ' ^1δ '

H, 5.64; N, 12.84.

Found: C, 76.02; H, 5.36; N, 12.84.

176

Ζ

SOURCE G: Preparation of 5-hydroxymethyl-4- / cis- (naphth-l-yl) ethenyl / -2-n-propyl-l- / (2 * - (N-triphenylmethyl- (1H-tetrazol-5-yl ) bi-enyl-4-yl) methyl / imidazole.

6.82 g (0.0155 moles; 2 eq.) Of 1-naphthylmethyltriphenylphosphonium chloride were suspended in 50 ml of TIIF and 20.68 ml (0.0155 moles; 2 eq) were added dropwise. .) of potassium bis (trimethylsilyl) amide (0.75 M in toluene) at room temperature. The resulting red solution was heated at 45 ° C for 0.5 hours. Then 5.00 g (7.75 mmol; 1 eq.) Of 5-hydroxymethyl-2-n-propyl-1- / £ (2 '- (N-triphenylmethyl- (1H-tetrazol-5-yl) toifenyl -4-yl) methyl / imidazole-4-carboxaldehyde dissolved in a minimum of THF, were added177 /

/ ί

at room temperature and stirred overnight. The reaction continued with the addition of 300 ml of ethyl acetate and 200 ml of water. The layers were separated and the organic layer was washed with water (2x200 ml). The organic layer was dried (MgSO4) and the solvent was removed in vacuo to obtain 9.29 g of a yellow glass. Flash chromatography with pentane / ethyl acetate (11) to 100% ethyl acetate on silica gel gave 7.95 g of a slightly yellow glass. NMR (DMSO-dg) £ 8.20-7.20 (m, 20H); 7.10-6.60 (m, 12H); 5.10 (s, 2H); 4.97 (t, 1H, J = 7 Hz); 4.00 (m, 2H); 2.20 (t, 2H, J = 7 Hz); 0.62 (t, 3H, J = 7 Hz). Anal, calcd. for C ₅₂ H ₄₄ NgO »(triphenylphosphinoxide) 1,6 · (Η ₂ 0); C, 78.76;

II, 5.73; N, 6.82. Found: G, 78.69; H, 5.67; N,

6.90.

: ·

178

PART Η: Preparation of 4- / cis- (naphth-l-yl) ethenyl7-2-n-propyl-1- / ~ (2 '- (N-triphenylmethyl- (1H-tetrazol-5-yl)) biphenyl- 4-yl) methyl / inazole-S-carboxaldehyde.

7.86 g (10.2 mmoles; 1 eq.) Of 5-hydroxymethyl-4- / cis- (naphth-l-) were mixed and heated at reflux under nitrogen atmosphere overnight il) ethenyl / -2-n-propyl-1- / (2 * - (N-triphenylmethyl-ClH-tetrazol-5-yl)) biphenyl-4-yl) methyl / imidazole, 4.44 g (51.1 mmoles; 5 eq.) of manganese dioxide and 25 ml of methylene chloride. The manganese dioxide was filtered through Celite and the cake was washed with methylene chloride. The filtrate was evaporated and the residue was rapidly chromatographed with pentane / ethyl acetate (75; 25)

179 to pentane / ethyl acetate (lsl) to obtain 3.78 g of orange glass. NMR (CDClg) δ 9.37 (s, 1H); 8.04 (m, 1H); 7.92 (d, 1H, J = 8 Hz); 7.80 (m, 1H); 7.72 (m, 1H); 7.60-7.10 (m, 16 H); 7.10-6.70 (m, 10H); 6.53 (d, 2H, J = 8 Hz); 5.30 (s, 2H); 2.38 (t, 2H, J = 7 Hz);

1.56 (t of q, 2H, J = 7.7 Hz); 0.77 (t, 3H, J = 7 Hz).

Anal, calcd. for C ₅₂ H ₄₂ NgO «(H ₂ O) θ yt C, 80.12;

H, 5.61; N, 10.78. Found C, 80.24; H, 5.91;

N, 10.46.

PART I; Preparation of 4 - / “cis- (naphth-l-yl) ethenyl7-2-n-propyl-1- / (2 * - (1H-tetrazol-5-yl)) biphenyl-4-yl) methylimidazole-5 -carbox aldehyde.

3.50 g of 4- / cis- (naphth-1-yl) ethenyl / -2-n-proPÍ1 “1“ Z “2 '- (N-triphenylmethyl- ( 1H-tetrazol-5-yl)) biphenyl-4-yl) methyl / imidazol-5-carboxaldehyde, 12 ml acid

180 trifluoroacetic, 12 ml of water and 4 ml of THF. After 2 hours, the mixture was basified with 10N NaOH at pH = 12 and the organic solvent was evaporated. Then, 100 ml of water was added and a gummy solid precipitate formed. 50 ml of ethyl ether was added and the solids were dissolved. The layers were separated and the aqueous layer was extracted with ethyl ether (2 x 50 ml). The aqueous layer was acidified with concentrated HCl at pH = 2. Again, a precipitate of gummy solids formed. 100 ml of ethyl acetate was added to dissolve these solids and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 100 ml) and the ethyl acetate layers were collected, dried (MgSO4) and the solvent was removed in vacuo and the residue was dissolved in methanol . Water was added and the pH = 2 was adjusted with concentrated HCl. The solvent was removed in vacuo and the residue was partitioned between 100 ml of ethyl acetate and 100 ml of water. The layers were separated and the aqueous layers were extracted with ethyl acetate (2 x 100 ml). The ethyl acetate layers were collected, dried (MgSO4) and the solvent was removed in vacuo and the residue was crystallized with ethyl acetate to obtain 1.48 g of a white solid: mp: 192 °, 5-193 °, 5C.

NMR (DMSO-dg) £ 9.53 (s, 1H); 8.10-7.30 (m, 1H); 7.83 (d, 1H, J = 7 III); 7.10 (d, 1H, J = 11 Hz); 7.01 (d, 2K,

J = 8 Hz); 6.76 (d, 1H, J = 8 Hz); 5.46 (s, 2Hj; 2.42 (t,

2H, J ~ 7 Hz); 1.34 (q t, 2H, J = 7.7 Hz); 0.67 (t, 3H,

J = 7 Hz). Anal, calcd. for Ο ^ Η ^ ΚθΟβ ^ Οΐθ ₄ : C, 74.53; H, 5.46; N, 15.80. Found: C, 74.48; H, 5.35; N,

15.65.

181

The following compounds in Table 5 can be prepared using the process of Example 95j

182

CHO CN ₄ H b

CHO CN ₄ H w /

Table 5 (continued)

Ex η5 ^R 6

/ v \

184

Table 5 (continued)

105 n-propyl

ΛΛ / V

CH OH COOH

185 - /

186

^To NMR (DMSO-d₆) ô 10.14 (s, 1H); 8.39 (d, 1H, J = 15 Hz);

8.27 (d, 1H, J = 8 Hz); 8.10-6.90 (m, 13H)? 7.80 (d, 1H, J = 15 Hz); 6.87 (d, 1H, J = 8 Hz); 5.67 (s, 2H); 2.77 (t,

2H, J = 7 Hz); 1.65 (t of q, 2H, J = 7.7 Hz); 0.93 (t, 3H,

J = 7 Hz).

^B NMR (DMSO-dg) d 10.15 (s, 1H); 8.13 (s, 1H); 8.08-7.40 (m, 12H); 7.20-6.90 (m, 2H); 5.63 (s, 2H); 2.66 (t, 2H,

J? Hz); 1.64 (t of q, 2H, J = 7.7 Hz); 0.90 (t, 3H, J = 7Hz). NMR (DMSO-dg) (main isomer only) 9.73 (s,

1H); 8.22 (s, 1H); 8.05-7.40 (m, 10H); 7.20-6.80 (m,

ÕH); 5.60 (s, 2H); 2.63 (t, 2H, J = 7 Hz); 1.60 (t of q,

2H, J = 7.7 Hz); 0.85 (t, 3H, J = 7 Hz).

Examples 111-123 of Table 6 can be prepared by nucleophilic aromatic substitution of a sulfur or nitrogen nucleophile instead of Cl,

Br or I in position 4 or 5 of the imidazole when a removable electronic group is also present in the imidazole nucleus. For example, a sulfur nucleophile can displace the 4-chloro group in 2-n-butyl-4-chloro-1- / (2 * - (N-triphenylmethyl- (1H-tetrazol-5-yl) bipheni1-4- il) methyl / imidazole-5-carboxaldehyde (synthesized as described in European patent application 89100144.8, published on July 19, 1989), followed by appropriate deprotection or elaboration, familiar to those skilled in the art, to obtain Examples 113, 115, 116, 117 and 122. Other examples are prepared from appropriate starting material The nucleophilic displacement reaction can be carried out in an alcoholic solvent, such as methanol or a solvent non-hydroxyl, such as DMSO or DMF with or without a base, such as sodium methoxide, depending on the nucleophile of the nucleophile

188

189

Ex. RO

R _r

Rg A m.p. (° C)

cn ₄ h

118

nhso ₂ ce ₃ cn ₄ h

COOH

190

Ex. R „o

120

R,

R _o A mp (° C)

O

COOH

COOH

COOH

ch ₂ oh

CN ₄ H

CHO

COOH

123 /

- 191 - / k

Use

The hormone angiotensin II (AII) produces numerous biological responses (for example, vasoconstriction) by stimulating its receptors on cell membranes. In order to identify compounds, such as AII antagonists that are capable of acting in conjunction with the AII receptor, a ligand-receptor binding assay was used for initial protection. The test was carried out according to the method described by / Glossmann et al., J. Biol. Chem., 249, 825 (19742./, but with some modifications. The reaction mixture contained microsomes of the rat adrenal cortex (origin of the AII receptor) in a Tris buffer and 2nM of 3 3 25

H -Air or 0.05 nt-1 of I -AII with or without potential AII antagonist. This mixture was incubated for 1 hour at room temperature, and the reaction was subsequently terminated by means of rapid filtration and washing through a micro-glass fiber filter. Receiver connected to 3 125

-H -AII or I -AII, caught in the filter, were quantified by scintillation counting. The inhibitory concentration (CI ^) of the potential AII antagonist that gives 50% displacement of the specifically total H -AH or I -AII binding represents a measure of the affinity of such a compound for the AII receptor. The compounds of the present invention that were tested in this Li-5 assay showed CI _5q of 10 M or less (Table 7).

The potential antihypertensive effects of the compounds of the present invention can be demonstrated by administering the compounds to awaken

rats made hypertensive by ligating the left renal artery / Cangiano et al., J. Pharmacol. Exp. Ther, 208, 310 (1979). This process increases blood pressure by increasing the production of renin with the consequent increase in AIX levels.

The compounds are administered orally at a dose of 30 mg / kg and / or intravenously, via a cannula in the jugular vein, at a dose of 3 mg / kg. Arterial blood pressure is measured continuously directly through a cannula in the carotid artery and recorded using a pressure translator and a polygraph. Blood pressure levels after treatment are compared with pretreatment levels to determine the antihypertensive effects of the compounds that were tested. Some compounds of the present invention showed intravenous activity at a dose of 3 mg / kg and others showed oral activity at a dose of 30 mg / kg (Table 7).

193

Painting 7 Angiotensin II Effects antihypertensive Receptor Hyperactive Rats Link tense Kidneys ^CI 50 Activity ¹ 2 Activity Ex . ns (μ molar) intravenous oral 1 Q, O21 + + 7 0.029 AT NT 8 0.17 AT NT 9 0.49 at NT 10 0.099 AT at 11 0.16 AT NT 24 0.17 + AT 41 0.11 + t 95 0.013 + + 96 0.55 + NT 97 0.54 + NT 98 0.12 + NT 1 Significant decrease blood pressure with 3, Omg / kg or less. 2 Significant decrease blood pressure with 30 mg / kg or less. Na None activity with 3 ί mg / kg or with 30 mg / kg, dosage

tested gem.

Although some of the tested compounds are not orally active, they have been shown to be active intravenously.

NT Not tested.

"-5

- 194

Dosage forms

The compounds of the present invention can be administered in the treatment of hypertension, according to the present invention, through some effects of contact of the active ingredient of the compound with the site of action in the body of a warm-blooded animal. For example, administration can be parenterally, that is, subcutaneously, intravenously, intramuscularly or intraperitoneally. Alternatively, or concurrently, in some cases, administration may be by mouth.

The compounds can be administered by any conventional means suitable for use in conjunction with pharmaceutical products, either as individual therapeutic agents or as a combination of therapeutic agents. They can be administered in isolation, but they are usually administered with a pharmaceutical carrier chosen on the basis of the route of administration used and in 'Standard' pharmaceutical practice.

For the purpose of this discovery, a warm-blooded animal is a member of the animal kingdom with a homeostatic mechanism and that kingdom includes mammals and birds.

The dosage administered will depend on the age, health status and weight of the patient, the extent of the disease, the type of concurrent treatment, if any, the frequency of treatment and the nature of the desired effect. Usually, a daily dosage of the compound's active ingredient should be about 1 to 500 milligrams per day. Usually, it is 100 milligrams per day, in one or

195 ΐ

more applications are sufficient to obtain the desired results. These dosages represent the effective amounts, both for the treatment of hypertension and for the treatment of congestive heart failure, that is, to lower blood pressure and to correct the hemodynamic load of the heart to relieve congestion.

active ingredient can be administered orally in solid dosage forms, such as capsules, tablets and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. It can also be administered parenterally, in sterile liquid dosage forms,

Gelatin capsules contain the active ingredient and powdered vehicles, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to prepare tablets. Both tablets and capsules can be prepared as delayed release products to deliver the drug in continuous release over a period of hours.

The tablets may be coated with sugar or film to mask any unpleasant taste and protect the tablet from the atmosphere, or they may have an enteric coating for selective disintegration in the gastro-intestinal tract.

The liquid dosage forms for oral administration may contain coloring agents and flavor correctors to increase patient acceptance.

/

- 196 ί

χ.

π ***

In general, water, an appropriate oil, a salt concentration, aqueous dextrose (glucose), sugary solutions and glycols, such as propylene glycol or polyethylene glycols, are suitable vehicles for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, appropriate stabilizing agents and, where appropriate, buffering substances. Antioxidant agents, such as sodium bisulfite, sodium sulfite or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Also, citric acid and its salts and sodium EDTA are used. In addition, parenteral solutions may contain preservatives, such as benzalkonium chloride, methyl- or propylparaben and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington * s Pharmaceutical Sciences, A. Osol, a text “Standard of reference in this field.

The pharmaceutical dosage forms used for the administration of the compounds of the present invention can be illustrated as follows:

Capsules

A large number of unit capsules are prepared by filling hardened gelatin capsules, two-piece, “Standard” type, each containing 100 milligrams of powdered active ingredient, 15 milligrams of lactose, 50 milligrams of cellulose and 6 milligrams but of magnesium stearate.

197

Soft gelatin capsules

A mixture of the active ingredient is prepared in a digestible oil, such as soybean oil, cottonseed oil or olive oil and injected, using a positive displacement pump, into gelatin to form soft gelatin capsules, each containing one, 100 milligrams of the active ingredient. The capsules are washed and dried.

A large number of tablets are prepared by conventional procedures, so that the unit dose is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silica dioxide, milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Coatings can be applied to increase palatability or delay absorption.

Injections

A parenteral composition suitable for administration is prepared by injection by stirring 1.5% of the active ingredient, by weight, in 10% of the volume of propylene glycol. The solution is swollen with water for injections and sterilized.

SuspensSes

An aqueous suspension is prepared for oral administration, so that each 5 milliliters contains 100 milligrams of finely divided active ingredient,

198

100 milligrams of cellulosic sodium carboxymethyl, 5 milligrams of sodium benzoate, 1.0 grams of a sorbitol solution, U.S.P. and 0.025 milliliters of vanillin.

Generally, the same dosage forms can be used when administering the compounds of the present invention, step by step in conjunction with another therapeutic agent. When drugs are administered in physical combination, the dosage form and route of administration should be chosen with compatibility for both drugs. Appropriate doses, dosage forms and routes of administration are illustrated in the following tables.

199

Examples of NSAID’s that can be combined with

AII of the present invention: Via Medication Dose (mg) Formulation Indomethacin 25 Tablet Oral (2/3 times per day) Meclofenamate 50-10C Tablet Oral (2/3 times per day) Ibuprofen 300-400 Tablet Oral (3/4 times per day) Piroxicam 10-20 Tablet Oral (1/2 times per day) Sulindac 150-200 Tablet Oral (2 times per day) Azapropazone 200-500 Tablet Oral

(3/4 times a day)

200

Examples of diuretics that can be combined with the AII blockers of the present invention:

Medication

Benzothiadizides (e.g. hydrochlorothiazide)

Diuretics

Dose (mg) Formulation Via

25-100 (per day) Oral tablet

50-80 (per day) Oral tablet (e.g. furosemide)

When used with an NSAID, the dosage of the AII blockers should generally be the same as the OU when the AII blocker is used alone, that is, 1 to 500 milligrams per day, usually 10 to 100 milligrams per day, in a or more applications. When used with diuretics, the initial dose of the AII blocker may be less, for example, 1 to 100 milligrams per day and, for the most active compounds, adose may be 1 to 10 milligrams per day.

The compounds of the present invention are expected to be useful, too, in the treatment of chronic renal failure.

Claims (51)

1.- Process for the preparation of compounds of the general formula r-202 / in which R4 represents a group-4-CO ₉ H; -OS-OH; -SO, H? -C (CF,) - OH; -OP-OH; -P0 _? H ₉ ; 2 3 2 j 3 2 0 OH (J -NH-P-OH; -4-NHSO ₂ CH ₃ ; 4-NHSO ₂ CF ₃ ; -SOjNH ^ - ^N; OH N - N // * II ÍNC N — N íí * ‘N H HCC « O: nk'X., X ⁿ ; 4-conhnhso ₂ cf ₃ ; CO ₂ H 4-COHN-CHCH „C, H _c ; ± 2 O □ (isomer) / *** _ X I PS NN or a group of general formula -4-CO ₂ Rg, · -CONNOR- ^; OH — 0 l I! -C-P-OH; and P. OH 2 ^v - ⁷ '\ ^Λ vy ^ς (// / Τ' ₌ -203Aww * ^ ** /. wherein R ₂ represents a hydrogen, chlorine, bromine, iodine or fluorine atom; a NO ₂ , CN group, C ^ _ ₄ alkyl, acoxy ο _Σ _ ₄ , c _x _ ₄ alkoxy, co ₂ h, nhso ₂ ch ₃ , nhso ₂ cf ₃ , so ₂ nh ₂ aryl, furyl or, N - N; or a group of formula ge ^ N H ral CO ₂ Rg or CONHOR ^ _n where R ^ represents a group of '24 II general formula -CH-OCR ^ in which R ₂ ^ represents a C 4 _g alkyl group or -CHC 6 ₂ CO ₂ CH ₃ or a group of the genh ₂ ral formula, -NR ₂₂ R ₂₃ in which R ₂₂ and R ₂₃ represent , each, independently, a hydrogen atom or an alkyl or benzyl group or R ₂₂ and R ₂₃ represent, taken together, a group of general formula (CH ₂ ) _u in which u represents an integer from 3 to 6 and R ₂₄ represents a hydrogen atom or a CH ₃ or "C ₅ H _{5 group} and R _{2 2} represents a hydrogen atom or a me-204tyl or benzyl group; _Rg is hydrogen, chlorine, bromine, iodine or fluorine or an alkyl group C ^ _ ₄ or alkoxy '> is CN or NO ₂ or a group of formula ^CO 2 ^R 11 ⁱⁿ C ¹¹³ · ^{4 R} ] _] _ represents a hydrogen atom or a ^C 1-4 alkyl, C ₃ -g cycloalkyl, phenyl or benzyl group; R ^ ₃ represents a PO group -CO ₂ H; -CH ₂ CO ₂ H; 0 0 0 II '1' II -O-S-OH; -O-P-OH; -SO-H; -NHP-OH; '11 ³ | 0 OH OH PO ₃ H ₂ ; -C (CF ₃ ) ₂ OH; -NHSO ₂ CH ₃ ; -NKSO ₂ CF ₃ ; -NHCOCF ₃ ; 2 2 ' N — N N — N -Α.Χ -comh / \ ^N. NH CONHNHSO ₂ CF ₃ ; N — N /> / CF N H 3; or .a formula group to generate -CO ₂ R ₉ ; -CH ₂ CO ₂ R ₉ ; OR <-ΝΗ50 ₂ - (0Η ₂ ) _3Λ , .R _2: OH CONHOR. ₉ ; -C ^X i R II P-OH; ÍH // N — N .N; CU, N — N R. -205- wherein represents a hydrogen atom or a C₁-th GRU _ ₄ or phenyl, R ₂₇ represents a hydrogen atom or an alkyl or phenyl group, represents a hydrogen atom, an alkyl group or C ^ _ ₄ -CH ₂ CH = CH ₂ or a group of the general formula -CH ^ gH ^ R ^ in which R ₃₂ represents a hydrogen atom or a N0 ₂ , NH ₂ , OH or OCHg group and represents zero or an integer of 1 to 5; X represents a single carbon-carbon bond, an oxygen or sulfur atom, a -CO- group; -CH ₂ -; -NH-; -OCH ₂ -; -CHgO-; -SCHg-; -CHgS-, -CH = CH-; -CF = CF-; -CH = CF-; -CF = CH-; -CHgCHg-; -CF ₂ CF ₂ ~ r \ or a group of general formula -N-; -CON-; r ₂₆ r ₂₃ -NCO-; -NHC (R ₂₇ ) (R ₂₈ ); -NR ^ SC ^ -; -SC ^ NR ^ -; -C (R2-y) ^z 'OCOR ^ 2 * ** ^^ 25 *, - ₁₄ - —17' -CH- -CH-C ^ 9 ° \ Z ^OR 30 -Ç- ; wherein R ₄ represents a hydrogen atom or a C 4 g alkyl or perfluoroalkyl group, C 6 g cycloalkyl, phenyl or benzyl; ^ R ₇ represents a hydrogen atom or a C ^ _g alkyl, cycloalkyl. lo Cg, g, phenyl or benzyl; R ₂ _ represents a group -NHCONH ₂ , nhcsnh ₂ .206-NHSG ₂ - \ -CH3 or -NKSG2 or a group of general formula NR ^ R ^ ^{or OR} 28 ⁱⁿ ^ ^{u and} ^ 28 ^ ⁱⁿ ° ^s i9 ⁿ ifi ^ca â · ⁰ defined before for R ₂ 7 'Rgg represents a hydrogen atom or a benzyl or allyl alkyl group, and R ₂ g and each independently represent a C ₄ _ ₄ alkyl group or R ₂ g and Rgg represent, taken together, a group of general formula (CH / g- in which q represents the integer 2 or 3; and Z represents an oxygen or sulfur atom or a group of general formula NRjjy Rg represents an alkyl group Ç.2-IQ ' ^at d ^cen id ° ^or alkynyl ^C 3_j_q having these groups, optionally, as a substituent, a fluorine atom or a group of general formula ^CO 2 ^R 14' cycloalkyl ^ ₃ _θ, cycloalkyl -C _d _ ^ g, ^ 5-10 cycloalkylalkenyl or cycloalkylalkynyl 'benzyl optionally bearing 1 or 2 substituents selected from halogen atoms; alkoxyC ^ _ ₄ alkyl 6 / -4 ^or uitro or a group of formula (CH _{2) s} Z (CH _{2) m} Rg having optionally substituted by a fluorine atom or a group of formula Nile alkynyl or C general CC ^ R. ^ ⁱⁿ which R ^ represents a hydrogen atom or a alkyl group C. _r , cycloalkyl C _or , moose 1-0 “J — o - ₂ _ ₄ in represents an integer 207 of 1 to 5; R ₇ represents a 1- or 2-naphthyl, 5- or 6-naphthoquinonyl group; 3-, 4- or 5-acenaftyl; 3-, 4- or 5-acenaftenyl; 1-, 2- or 9-anthracenyl; 1- or 2-anthraquinonyl; 1-, 2-, 3-, 4- or 9-phenan.trenyl; 2-, 3-, 4-, 5-, 6-, 7or 8-quinolinyl; 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl; 2-, 3-, 4-, 5-, 6- or 7-indolyl which may optionally contain, in the nucleus nitrogen atom, a substituent chosen from lower alkyl or benzyl groups; 4-, 5-, 6- or 7-indenyl; 2-, 3-, 4-, 5-, 6- or 7-benzofuryl; 2-, 3-, 4-, 5-, 6- or 7-benzothienyl; 1-, 2-, 3- or 4-dibenzofuryl; 1-, 2-, 3- or 4-dibenzothienyl; 1-, 2-, 3- or 4-fluorenyl; comprising any of the foregoing polycyclic aryl groups , 1 or 2 substituents selected from halogen atoms, alkoxy groups ^ _ _g alkyl, C ^ _ _g, -NO _2; CN or -CFg, or groups of general formula -COR ^ _g , -O ^ OR ^, -NHCOR ^, -CONR ^ gR ^ g, S (O) _r R ^ ₇ and S0 ₂ NR ^ gR ^ _g where R ^ g represents a hydrogen atom, a C ^ _g alkyl group or a Cg_g cycloalkyl group or a group of general formula ( CH ₂ ) CgHg, OR ₁₇ or NR _lg R _ig where R ^ g and R ^ ₉ each independently represent a hydrogen atom, a C1-4 alkyl group, phenyl, benzyl or V-methylbenzyl or R ^ _g and R ^ ₉ form , considered together with the nitrogen atom, a nucleus of general formula, - (CH.) in which Q represents an oxygen atom / \ _Znium, a CH ^ group or a group of general formula NR _2Q θ t represents zero or the integer 1, ep represents zero or an integer from 1 to 3; anhydride of a 4,5-dicarboxyl-1- or 2-naphthyl group; substituted alkyl, alkenyl or alkynyl having a polycyclic aryl group optionally substituted with the meaning defined above as a substituent; -NH-SC> ₂ heteroaryl or a group of general formula -S (0) _r ~ heteroaryl or -ΝΗ- ^ θ-heteroaryl where r represents zero or the integer 1 or 2 Rg represents a group of general formula ^0R ! 7? 14 O - (ÇF ^ iCH-R-li; -CH ^ OCR ^; - (CH,) ^; 0 0 ll -CH = CH _{(CH2) s} CHOR _15; -CH = CH (CH ₂ ) _g CR ₁₆ ; -CR _lg ; 0 -CE = CH (CH.) OCR. _η ; - (. CH.) -Tetrazolyl; 2 S 11 2 m ' II Y (CH ₂ ) _s -CH-COR ₁₆ ; - (CH ₂ ) _n CR ₁₆ ; - (C ^) ^ CNHR ^; ^CH 3 Y 0 H il - (CH ₂ ) _n NR ₁₁ COR ₁ _; - (CH ₂ ) _n NR ₁₃ _CNHR ₁₀ ; - (CH ₂ ) _n ^NR ] _] _ ^s ®2 ^R 10 ^; - ^IIC ^ 2 ^ n ^ ^NR ll ^R 10 ^{'in R} ^ ^{u re} 10 h at rt P ^rese Cj_ alkyl-6' p and ^r ^ l ^uoroa i9 ^u ^ 0 ° _θ yl, l ^-a úamantilo, 1-naphthyl or 1- (1-naphthyl) -ethyl or a group of the general formula (CH ₂ ) CgHg? ^ R g represents a hydrogen atom drogénio hi a C ^ _g alkyl, C ₃ _g cycloalkyl, phenyl, benzyl, C ^ _ ₄ acyl or phenacyl; Y represents an oxygen or sulfur atom and n represents an integer from 1 to 10, or its pharmaceutically acceptable salts, with the proviso that (!) The group represented by the symbol does not occupy the ortho position; (2) R ^ ₃ occupies the ortho or goal position when R ^ represents a group of general formula fi fi ₂ X represents a single bond and R represents a group CO ₂ H or nn Λ> N H or R ₁₃ occupy the ortho position when R ₁ and X have the meanings defined above and R ₁₃ represents an NHSO ₂ CF ₃ or 'Al'group; · NKSO ₂ CH ₃ ; (3) R ₁₃ occupies the ortho position when it represents a group of general formula and X does not represent a single bond, except when X represents a group of general formula NR ₂₃ CO and R ₁₃ represents an NHSO ₂ CF ₃ or NHSC> _{2 group} CH ₃ , situation in which R ^ ₃ must occupy the ortho or goal position; (4) Rg does not represent an S-alkyl group when R4 represents a 4-CO ₂ H group or a salt thereof; (5) the 4-position substitutent of the imidazole group is not a CH ₂ OK, CH ₂ OCOCH ₃ or CH ₂ CO ₂ H group when R 4 represents a 4-CO ₂ H group or a salt thereof; (6) R _g does not represent a methoxybenzyl group when R ^ represents a group - NHCO and (7) Rg does not represent a -CHCH ₂ CR ₂ CH ₃ or CH ₂ OH group, F characterized by the fact that, in appropriate solvents, the nitrogen atom of the imidazolic group of an initial compound of the general formula in which Rg, R ₇ and Rg have the meanings defined above, to a benzyl compound of general formula * 3 in which R ^, ^{and R} 3 have ^the meanings defined above, and X ^ represents a halogen atom or a p-toluene-sulfonyloxy or methyl-sulfonyloxy group, and to subject the resulting compound, which comprises other portions in addition to the imidazole function. of the molecule consistent with the necessary chemical transformations, reactions that differ in the order of the stages of synthesis, the necessary protecting groups, the deprotection conditions and the activation of the benzyl position. 2. A process according to claim 1 for the preparation of compounds of the general formula in which it represents a -COgH group; -NHSO ₂ CF ₃ ; N-N [Γ * V H or a group of general formula, 13 or where R ₁₃ represents a -CO ₂ H group; NHSOgCFg; SOgH, // - \ Ν 'or a group of the general formula -COgRg and X represents a single carbon-carbon bond, an oxygen atom, a -CO-, -CHgCHg-, -OCHg-, -CHgO-SCHg-, -CKgS-213- group NHCH ₂ ", or -CH = CH- or a group of general formula -CON- OR -NCO-; II ^ 23 ^R 23 Κθ represents an alkyl alkenyl group 0 ₃ _ ^ θ, alkynyl Cg _- ^ Q, cycloalkyl-Cg_g, benzyl possibly containing up to 2 substituents in the phenyl nucleus and collected between halogen atoms or alkoxy groups C- _{L- 4} , C- ₄ -alkyl or nitro; and Rg represents a group of general formula II - (CH.) -Tetrazolyl © ϊ - (CH,) OR ..; - (CH,) OCR ..; zm ζ η ii zn 14? ? 14 ⁰ II | -CH = CH (CH _O ) CR. ,; -CH = CH (CH _O ) CHOR, _q ; - (CH „) CR, _c ; Z S lo Z S! □ z n ± O o 0 II II - (CH ₂ ) _n NHCORi ₀ ^; - (CH2) nNHSO2R10; or -C lgΓ wherein ^R Rj_g represents a hydrogen atom, an alkyl group is ^C l-5 ^a 9 - ^ru ° ^U ° P ^AE formula 0R ^ ₇ ^ or NR g R _g, or their salts acceptable from the point of pharmaceutical view, characterized by the fact that correspondingly substituted starting compounds are used. 3. A process according to claim 2 for the preparation of compounds of formula II in which R ₂ represents a hydrogen or halogen atom or an alkyl group C ^ 2_ _{4 4} ^'R g is alkyl, alkenyl or winged C alkoxy 214cinilo C ₃ _ _7; R ₇ represents a 1- or 2-naphthyl group; 2-, 3- or 4-quinolinyl; 1-, 3- or 4-isoquinolinyl; or 1-, 2- or 3-indolyl; Rg represents a group of general formula - (CH) _m ^GR ii ' II 1 ^CH 2 µm ^OC ^ 14 '-CH = CH-CHOR ₁₅ ; - (CH ₂ ) _m CR ₁₆ ; -CH ₂ NHCOR ₁₀ ; ^(CH 2) m ^NHSO 2 ^R 10 '° ^{U "COLOR]} _5' ⁱⁿ * 3 ^{u R]} _Q represents a CFG group, C₁-_ _g or phenyl, represents a hydrogen atom or an alkyl group C ^ _ ₄ z R ^ ₄ represents a hydrogen atom or an alkyl group C ^ _ _4, R _LG represents a hydrogen atom or an alkyl group C ^ _ ₄ or acyl C ^ _ _4, R ^ , _g represents a hydrogen atom, alkyl group or C ₃ _ ^ N \) or a group of formula ₇ in 0R ^ is an integer from 1 to 5; R ^ ₃ represents a CO ₂ H group, CO ₂ CH ₂ OCOC (CHg) ₃ , NHSO ₂ CF ₃ or / 2J-N; and X represents N a single bond, an oxygen atom or a -CO-, -NHCO- or -OCH ₂ ~ group, or their pharmaceutically acceptable salts, characterized in that correspondingly substituted starting compounds are used. 4. A process according to claim 3 for the preparation of compounds of general formula II in which R ₁ represents a group of general formula and X represents a single bond, or one of its pharmaceutically acceptable salts, characterized because correspondingly substituted starting compounds are used. 5. A process according to claim 1 for the preparation of compounds of general formula I in which r represents the integer 1, characterized in that an imidazole derivative of general formula is reacted. K in which Rg, R ?, Rg have the meanings defined above, with a benzyl derivative of the general formula in which ^R l ' ^R 2 ^{and R} 3 mean ^the meanings defined above, and represent a halogen atom or a * 3 / Í16-p- toluene-sulfonyloxy or methylsulfonyloxy, in a solvent, in the presence of a base, for about 1 to approximately 10 hours, at a temperature between about 20 ° C and the reflux temperature of the solvent to obtain a compound of general formula 1 “Λ in which each of the symbols R ^, R ₂ , ^R 3 ' ^R g' ^R 7 ^{and R} g represents a group which is stable under the reaction conditions and was defined in claim 1, or an intermediate or protected form thereof, and, eventually, transforming the intermediate or protected forms of the groups represented by the symbols R into groups represented by the same symbols in claim 1. 6. A process according to claim 5, characterized in that the compounds of general formulas 1 and 2 are contacted in the presence of a base chosen from a group consisting of a metal hydride (MH), an alkoxide of a metal (MO?;, sodium carbonate, potassium carbonate, triethylamine and pyridine, in a dipolar aprotic solvent, or when the base is a metal alkoxide (MOR), for example, lithium , sodium or potassium, in an alcohol (ROH) such as, for example, methyl alcohol, ethyl alcohol or t-butyl alcohol. 7. A process according to claim 5, characterized in that, in the presence of a phase transfer catalyst such as, for example, tricapril methylammonium chloride, a two-phase solvent system, one of which is an organic phase such as methylene chloride and the other an aqueous phase. 8. A process according to claim 6, characterized in that a compound of general formula 3 is prepared in which R 2 represents a group of general formula in which R ₂ and R g each independently represent a hydrogen atom. chlorine, bromine, iodine or fluorine, a nog alkyl group C ^ _ ^ alkoxy-C ^ _ _4, aryl , or furyl group or a group of general formu la COGr ^ wherein R ^ ₄ is as defined above; R ₁₃ represents a CM, NO _{2 group} , trialkyl-tin-tetrazole or tritiltetrazole or a group of the general formula CO ₂ ^R 14 * ^ex "presents a single carbon-carbon bond, an oxygen or sulfur atom or a group - CO- or -NH-; Rg represents a group of general formula “( ^Cíi 2) n ^0R ll '“ ^ ^CH 2 ^ n ^SR 15 ^or ~ ^ ^CH 2X ^CN where R ^^ and R ^^ have the meanings defined above; and Rg and R4 have the meanings defined above, characterized in that correspondingly substituted starting compounds are used. 9. Process according to Claim 8, characterized in that a compound of general formula 3 is prepared in which R ^ g represents a group of general formula “ ^CO 2 ^R 14 ^and that compound of general formula 3 ^is reacted, with an alkali in an alcoholic solvent in aqueous solution or with trifluoroacetic acid at a temperature between about 20 ° C and the reflux temperature of the solvent for about 1 to 24 hours, and then the pH of the mixture is adjusted to a value between 3 and 7, to convert the resulting product into the desired product. 10. Process according to Claim 9, characterized in that in general formula 3 at least one of the symbols R ₂ , Rg or R ₁₃ represents a group of general formula -CO ₂ R ₁₄ and that this group is converted into another with the formula -COgH. 2. A process according to claim 9, characterized in that a compound of formula 3 is prepared in which it represents a t-butyl group and the reaction is carried out in trifluoroacetic acid. 12. - Method according to claim 8, characterized in that a compound of formula 3 wherein R ^ ₃ is -CN and this is contacting compound of formula 3 with (i) an acid strong at the reflux temperature of the solvent for about 2 to 96 hours or (ii) a strong base in an alcoholic solvent at a temperature between about 20 ° C and the reflux temperature of the solvent for about 2 to 96 hours and then the pH is adjusted to values between about 3 and 7, or (iii) sulfuric acid and then with an acid or a base, to convert the resulting compound into the corresponding compound in which R ^ ₃ represents a group -CC ^ E. 13. A process according to claim 12, characterized in that a compound of general formula 3 is prepared in which at least one of the symbols R ₂ , R 4 or R ₃ represents a group of the general formula -CO _2. R ^^ and to convert this group into another of the formula -CO ₂ H. 14. Process according to claim 12, characterized -220> used by the preparation of a compound of general formula 3 in which R _g represents a group of general formula - (CE ₂ ) _n CN and of converting this group into another group of general formula - (CH ₂ ) _n CO ₂ H or to prepare a compound of general formula 3 in which R _g represents a group of general formula ”( ^CH 2 ^ n ^0R ll ^and to convert this group into another group of general formula ( CH _n ) OH when R 2 n represents a -CO ₂ K group. 15. A process according to claim 8, characterized in that a compound of general formula 3 is prepared in which R ₃ represents a -CN group and that compound of general formula 3 is contacted with a mixture of equimolar amounts. of sodium azide and ammonium chloride in a polar aprotic solvent at a temperature between about 30 ° C and the reflux temperature of the solvent for approximately 1 hour to 10 days to convert that compound of formula 3 into the corresponding compound where ^R 13 ^re P ^resides a 5-tetrazolyl group. 16. Process according to Claim 15, characterized in that a compound of general formula 3 is prepared in which R _g represents a group of general formula - (CH ₂ ) CN and of converting this group into another group of general formula - (CH ₂ ) ^ - tetrazolyl when the group represented by the symbol R ₁₃ becomes the 5-tetrazolyl group. 17. A process according to claim 8, characterized in that a compound of formula 3 is prepared in which R3 g represents a -CN group, and that compound is reacted with trialkyl-tin-azide or triaryl-tin. acid and then an acidic or alkaline hydrolysis is carried out to convert that compound of formula 3 into the corresponding product in which R3g represents a 5-tetrazolyl group. 18. A process according to claim 8, characterized in that a compound · of formula 3 is prepared in which RCg represents a -CN group, that compound is reacted with trialkyl-tin-azide or triaryl- tin-azide to obtain another compound of the general formula 3 in which R ^g represents a trialkyl- or triaryl-stannyl-tetrazol-5-yl group, of reacting this last compound with triphenylmethyl chloride to obtain a compound of general formula 3 in which R ₁₃ represents a triphenylmethyl-tetrazol-5-yl group and then to hydrolyze this compound to obtain another tazibem compound of general formula 3 in which R3g represents a 5-tetrazolyl group. 19. Process according to Claim 17, characterized in that a compound of general formula 3 is prepared in which Rg represents a group of general formula - (CHg) CN and of converting this group into another group of general formula -222- -tetrazolyl when R ^ ₃ becomes the 5-tetrazolyl group. 20. A process according to claim 8, characterized in that a compound of general formula 3 is prepared in which R ₃ represents a -NC group, and that compound of general formula 3 is contacted with a reducing agent for obtaining another intermediate compound of general formula 3 in which R ^ ₃ represents an NH ₂ group and contacting the latter with an anhydride of formula (CH ^ SC ^) ₂ ° ^or (CF ₃ SO ₂ ) 2 ° ^{or a C-} L ° ^- rectum of the formula CH ^ SC ^ Cl or CF ^ SC ^ Cl of sulfonic acid in a solvent to obtain a compound in which R ₁₃ represents a group -NHSC ^ CH ^ or -NHSO ₂ CF ₃ . 21. The method of claim 20 wherein a compound of formula 3 is prepared in which at least one of the symbols R ₂ , R ₃ or R ₃ represents a group -N _{2 2} and convert this group into another formula -nhso ₂ ch ₃ or -nhso ₂ cf ₃ . 22. The process of claim 9 or 12, wherein a compound of formula 3 is prepared in which? ₁₃ represents a CC group> ₂ H and (a) contacting that compound with approximately 1 to 4 equivalents of thionyl chloride, in excess, or in another solvent at a temperature between about 20 ° C e -223- ·?) At the reflux temperature of the solvent for about 5 minutes to approximately 2 hours to obtain an intermediate compound of general formula 3 in which R ₁₃ represents a COC1 group and the latter to be contacted with approximately 2 to 10 equivalents of a derivative, in excess, of hydroxylamine of the general formula E ^ NOR ^ or in another solvent, at a temperature between approximately 25 ° and 80 ° C for about 2 to 18 hours, or (b) contacting the same compound with a hydroxylamine derivative of the general formula E4 NOR4, to dicyclohexylcarbodiimide or 1-hydroxybenzotriazole in a solvent at a temperature between approximately 0 ° and 30 ° for about 1 to 24 hours to obtain a compound in which R ₁₃ represents a group of the general formula COOH ₁₂ . 23. A process according to claim 5, characterized in that a compound of general formula 3 is prepared in which R de represents a group of general formula in which R ₂ and R ₃ have the meanings defined above and X represents a bond simple carbon-carbon, an oxygen or sulfur atom or a -CC- or -1ΊΗ- group; ? _ç and R? have the meanings defined in claim 1 and R _g represents a CHO group or a group of general formula ( ^CH 2 ^ n ^0R ll ⁷ ^ ^CIi 2 ^ n ^0C0R 14 '(CH ₂ ) _n CH (OH) R _lg , (CH ₂ ) _n COR ₁₆ , (CH ^ Cl or (CH ^ CN. 24. A process according to claim 23, characterized in that a compound of general formula 3 is prepared in which R _g represents a group of general formula (CH ₂ ) _n OH, and that compound is contacted with an anhydrous alcohol. of general formula R-qOH in the presence of a strong acid or Lewis acid and then saponify any group of general formula CO ₂ R ₁₄ formed concomitantly or present in the intermediate compound resulting from general formula 3, to obtain the compound corresponding: 3 of the formula wherein R _g represents a group of formula ^E ^ n ^ 2 ^0R 9 II ^{in water} - * - not ^re-presenta hydrogen. J 25. A process according to claim 23, characterized in that a compound of general formula 3 is prepared in which R _o represents a group of general formula (CH _n ) OR .. in ozn xx in which R ^^ does not represent a hydrogen atom and contacting that product with an aqueous acid medium at a temperature between about 25 ° C and the reflux temperature of the solvent for approximately 30 minutes to 24 hours to obtain the corresponding compound of formula 3 in in which R _g represents a group of general formula (CH ₂ ) OH. Β -225 / 26. A process according to claim 23, characterized in that a compound of general formula 3 is prepared in which R _g represents a group of general formula (CHg ^ OH and that compound is contacted with (a) an anhydride of carboxylic acid of general formula (R ^ CO) ₂₀ or a chloride of general formula R ^ COCl in a solvent in the presence of a base at a temperature between about 0 ° C and the reflux temperature of the solvent for approximately 30 minutes to 24 hours or (b) a carboxylic acid of the general formula R ₁₄ CO ₂ H under anhydrous conditions in the presence of a strong acid or Lewis acid at a temperature between approximately 0 ° and 100 ° C for approximately from 30 minutes to 24 hours, to obtain the corresponding compound in which R _g represents a group of general form (CH-) OCOR ... z n ± 4 27. A process according to claim 23, characterized in that a compound of formula 3 is prepared in which R _g represents a group of formula (CH ₂ ) _n OCOR ^ ₄ and that the compound is contacted with a acid or an alkali in aqueous solution to obtain the corresponding compound in which R _g represents a group of general formula (CH ₂ ) _n OH. 28. A process according to claim 23, characterized in that a compound of general formula 3 is prepared in which R _o represents a group of general formula (CH-) OH and ozn. -226- contacting that compound with an oxidizing agent at a temperature between approximately 25 ° and 45 ° C for about 1 to 200 hours to obtain the corresponding compound of general formula 3 in which Ηθ represents a group of general formula (CH ₂ ) _n _i ^c ^ ig na Φ ¹³ ·! ^R ] _g represents a hydrogen atom. 29. The method of claim 23, wherein a compound of general formula 3 is prepared in which Κθ represents a group of general formula (CH ₂ ) _n ^C0R ig in which it represents a hydrogen atom and being contacted that compound with another organometallic compound of the general formula R ^ gP in which P represents magnesium or lithium bromide in a solvent at a temperature between approximately -78 ° C and 100 ° C for about 30 minutes to 24 hours to obtaining a compound of general formula 3 in which Rg represents a group of general formula (CH ₂ ) _n CH (OH) R 4 in which R _1g does not represent a hydrogen atom. 30. A process according to claim 23, characterized in that a compound of general formula 3 is prepared in which R _g represents a group of general formula (CH ₂ ) _n CH (OH) Rig in which R ^ g does not represent a hydrogen atom and contacting that product with an oxidizing agent in a solvent to obtain the corresponding compound -227- te Formula 3 in which Rg represents a group of formula (CH _{2) n} COR wherein R _{4g g} ^ is not hydrogen. 31. A process according to claim 23, characterized in that a compound of general formula 3 is prepared in which Rg represents a group of general formula (CH ₂ ) _n COR ^ g in which R ^ _g represents a hydrogen atom. and contacting that compound with an oxidizing agent in a solvent to obtain the corresponding compound of general formula 3 in which Ηθ represents a group of general formula (CH ₂ ) _n COR ^ _g in which R ^ _g represents a hydroxy group. 32. The method of claim 23, wherein a compound of formula 3 is prepared in which Rg represents a group of formula (CH ₂ ) _n COR _1g in which Rg _g represents a hydroxy group. contacting that compound with excess thionyl chloride or in another solvent at a temperature between approximately 0 ° C and the reflux temperature of the solvent for about 5 minutes to approximately 24 hours to obtain the corresponding compound of general formula 3 in which R _g represents a group of general formula (CH-) COC1 and the latter compound is contacted with an excess amine of general formula NE? ^ gRjj.9 ^{or if not a} solvent at a temperature including -ííif *> between about 0 ° C and the reflux temperature of the solvent for 5 minutes to approximately 24 hours to obtain the corresponding compound of general formula 3 in which Rg represents a group of general formula (CH ₂ ) _n C ° ^NR 18 ^R 19 ' 33. The process of claim 23, wherein a compound of general formula 3 is prepared in which Rg represents a group of general formula (CI ^^ OR-q in which R ^^ represents a hydrogen atom and contacting that compound with excess thionyl chloride or in a solvent at a temperature between approximately 20 ° C and the reflux temperature of the solvent for about 30 minutes to 24 hours to obtain an intermediate compound of general formula 3 in which Rg 'represents a group of general formula (CH _n ) Cl. ζ n J 34. The method of claim 33 wherein a compound of general formula 3 is contacted in which R _Q represents a grease of general formula (CH-) Cl with a sodium or potassium salt of a mercaptan of formula general R ^ gSH in a solvent at a temperature between approximately 25 ° and 100 ° C for about 1 to 24 hours to obtain a compound of general formula 3 in which Rg represents a group of general formula (CHg ^ SR ^ g. -229- 35. A process according to claim 23, characterized in that a compound of general formula 3 is contacted in which Rg represents a group of general formula (CH ₂ ) _n Cl with an alkali metal cyanide within a solvent at a temperature between approximately 20 ° and 100 ° C for about 1 to 24 hours to obtain a compound of general formula 3 in which R _g represents a group of general formula (CH ₂ ) _n CN and to hydrolyze this latter compound to obtain another one of general formula 3 in which Rg represents a group of general formula (CH ₂ ) _n COR ^ ₆ in which R ^ g represents a hydroxy group. 36. The method of claim 23, wherein a compound of general formula 3 is contacted in which R _g represents a group of general formula ( ^CH 2 ^ nl ^C ^ with a sodium or potassium salt of a malonate dialkyl in a solvent at a temperature between approximately 20 ° and 100 ° C for about 30 minutes to 24 hours to obtain a compound of general formula 3 in which Rg represents a group of general formula (CH ₂ ) _n (C0 ₂ alkyl) ₂ , saponify this last compound with a base in an aqueous solution at a temperature between approximately 25 ° C and the reflux temperature of the solvent, and then acidify it with a mineral acid to obtain a compound of general formula 3 in which Rg represents a group of general formula (C ^ nl ^CH ( ^CO 2 ^H ^ 2 ^{and if <} 3 finally the latter ^{compound is heated} to a temperature close to 120 ° C or in an acid mineral diluted to ref temperature luxury to obtain a compos. of general formula 3 in which Rg represents a group of general formula (d ^^ COR · ^ in which R ^ g represents a hydroxy group. J 37. The process of claim 23, wherein a compound of general formula 3 is prepared in which Rg represents a -CHO group, and that compound is contacted with a methylene phosphoran of general formula (C ₆ H ₅ ) ₃ P = CH (CH ₂ ) _s CHR ₁₄ OR ₁₅ or (C _g H ₅ ) ₃ P = CH (CH ₂ ) _s COR _lg in a solvent at a temperature between approximately 25 ° C and reflux temperature of the solvent for about 1 to 24 hours to obtain a compound of general formula 3 in which Rg represents a group of general formula J -CH = CH (CH ₂ ) _s CHR ₁₄ OR ₁₅ or -CH = CH (C ^) _s COR _lg , except when R ^ g represents a hydrogen atom and R ^ g represents a hydroxy group, and the compound may be contacted afterwards, if necessary. The resultant of general formula 3 in Rg represents a group of general formula -CH = CH (CH ₂ ) _g COR ^ g with a reducing agent in a solvent at a temperature between approximately 0 ° and 25 ° C for approximately from 30 minutes to 24 hours to obtain a compound of formula 3 in which Rg represents a group of formula -CH = CH (CH ₂ ) _s CHR ^ ₄ OH. 3138. A process according to claim 23, characterized in that a compound of general formula 3 is prepared in which Rg represents a group of general formula (CH ₂ ) _n OH and that the compound is contacted with an isocyanide of formula general R _1Q NCO in a solvent at a temperature between approximately 25 ° C and the reflux temperature of the solvent for about 5 minutes to approximately 24 hours to obtain a compound of formula 3 in which Rg represents a group of general formula (CH ₂ ) _n OCONHR _1Q . 39. The method of claim 23, wherein a compound of general formula 3 is contacted in which Rg represents a group of general formula (CH ₂ ) _n Cl with an amine, in excess, of the general formula. NH ₂ or in another solvent for about 1 to 24 hours at a temperature between approximately 0 ° C and the reflux temperature of the solvent to obtain an intermediate compound of general formula 3 in which Εθ represents a group of general formula (CH ₂ ) NHR ^. 40. The process of claim 23, wherein a compound of general formula 3 is prepared in which Rg represents a group of general formula (CH ₂ ) Cl, that compound is contacted with an azide of one alkali metal in an aprotic solvent at a temperature comprised between approximately 25 ° and 80 ° C for about 1 to 24 hours to obtain a compound of general formula 3 in which Rg represents a group of general formula (CH ₂ ) Ng and contacting the latter compound with a reducing agent to obtain an intermediate compound of general formula 3 in which Rg represents a group of general formula (CH ₂ ) NH ₂ · 41. The process of claim 39 or 40, wherein a compound of the general formula is prepared. 3 in which R _g represents a group of the general formula (CH ₂ ) _n NHR ₁₁ or (CH-) NH- and that contact is made with a chlorine 2 n 2 format of the general formula R ^ _Q OCOC1 or a sulfonyl derivative of general formula R _1Q SO ₂ C1 or (R _1Q SO ₂ ) ₂ O in a solvent in the presence of a base at a temperature between about 0 ° C and the reflux temperature of the solvent for approximately 5 minutes at about 24 hours to obtain a compound of general formula 3 in which Rg represents a group of general formula - (CH-) NR..CO „R _in or - (CH _n ) NR,, SO-R.-. 2 n 11 2 10 2 n ii 2 10 42. The method of claim 39 or 40, wherein a compound of general formula 3 is contacted in which Rg represents a group of general formula. - (CH-) NHR ,. or (CH-) NH- with an isocyanate or isothiocyanate of 2 n lx 2 n 2 general formula r ^ qNÇY in a solvent at a temperature between approximately 25 ° C and the reflux temperature of the solvent for about 5 minutes to approximately 24 hours to obtain a compound of general formula 3 in which Rg represents a group of general formula - (CH ^) _n NR ₁₁ CYNHR _1Q . 43 - Process according to claim 5, characterized in that a compound of formula 3 wherein R ^ is a group N0 ₂ and R ₂ ^'R 3' ^R 6 ^'R 7 ^{and R} 8 ^ ¹¹¹ meanings defined in claim 28, of reducing that compound, using iron and acetic acid, stannous chloride or hydrogen and palladium, until obtaining a compound of general formula 3 in which R R represents an NH ₂ group and reacting this last compound with an appropriate acid anhydride such as phthalic anhydride optionally substituted in a solvent or with an appropriate acid chloride such as anthranilic acid chloride substituted in the presence of an aqueous solution of an alkali or an base or with anthranilic or phthalic acid suitably substituted in the presence of dicyclohexylcarbodiimide in a solvent to obtain a compound of general formula 3 in which R R represents a group of general formula where X represents an NHCO group. -234 44. The process according to claim 5, characterized in that a compound of formula 3 is prepared in which R 4 represents an OCI 4 group, R ₂ and R g each represent a hydrogen atom and R g. , R4 and Rg have the meanings defined in claim 5, of contacting that compound with trifluoroacetic acid at reflux temperature for approximately 12 minutes to 1 hour or with hydrogen and palladium to obtain the corresponding compound of formula 3 in which R represents a hydroxy group and to contact this last compound with a base at a temperature close to 25 ° C and an appropriate benzyl halide of general formula to obtain the corresponding compound of general formula 3 in which X represents a -OCH ₂ ~ group. 45. A process according to claim 5, characterized in that a compound of formula 3 is prepared in the -235- which Κθ represents a -CHO group linking the benzyl derivative of general formula 2 to the imidazolic derivative of general formula 1, preferably through the nitrogen atom adjacent to the carbon atom of the imidazolic nucleus comprising the group represented by symbol R _g . J 46. The process of claim 1 for the preparation of compounds of general formula I in which r represents zero, characterized in that an imidazolic derivative of general formula 1 or a metal salt with 4-fluoro is contacted. -l-nitrobenzene in a solvent, in the presence of a base when free imidazole is used, for 1 to 10 days at a temperature between 25 ° and 150 ° C to obtain an N-phenylimidazole and to prepare compounds wherein X represents an NHCO group using the process described in claim 43. Λ 47. A process according to claim 23, characterized in that a compound of formula 3 is prepared in which R _g represents a CHO group and X represents a single carbon-carbon bond, that product is contacted with a reagent. organometallic such as a compound of the general formula R ^ MgBr or R ^ Li in the presence of an anhydrous non-hydroxy solvent such as ether, tetrahydrofuran or dimethoxyethane at a temperature between -78 ° and 25 ° C , then treating with water and subjecting to acid hydrolysis any group of general formula CO ₂ R ₁₄ in which R ₄ represents a t-butyl group or to hydrolysis any protected tetrazol-trityl group to obtain the compound corresponding to general formula 3 in which R _g represents a group of general formula ( ^CH 2 ^ nl ” ^CIÍ_R ll ^{na c} 2 ^ua · '- ^R n ^na0 represents an atom of QRl? hydrogen. 48. A process according to claim 1 for the preparation of compounds of the general formula, optionally substituted aryl group, characterized by I in which R? represents a heteroaryl or eventual fact of coupling a halogenoimidazole compound of general formula in which R ^, R ₂ , R _g , Rg, R _g er have the meanings defined before, and X represents a bromine or iodine atom, with an arylmetallic derivative of the general formula / -237 / * .¾ ArM in which M represents zinc bromide, trimethyl tin or boron hydroxide, for example, and Ar represents an optionally substituted aryl or optionally substituted heteroaryl group, in the presence of a transition metal as a catalyst, for example palladium, platinum, nickel or zirconium, to obtain an arylimidazolic compound of the general formula R (238) in which ^R -l- ' ^R 2' ^R 3- ' ^R 6' ^R 8 ' ^{re Ar} the meanings defined above. 49. The method of claim 1 for preparing compounds of formula I in which R? represents an optionally substituted arylmethyl or optionally substituted heteroarylmethyl group, characterized by the fact that a halogenoimidazolic compound of the general formula is coupled, -238 in which ^R l · ' ^R 2-' ^R 3 ' ^R 6' ^R 8- ^er t® ^{111 os s} ig ^{ni ica s as} defined above, and X represents a bromine or iodine atom, with an arylmethylmethyl derivative of the general formula ArCH ₂ M 'in which M 'represents zinc bromide, for example, and Ar represents an optionally substituted arylmethyl or optionally substituted heteroarylmethyl group, in the presence of a transition metal as a catalyst to obtain an arylmethylimidazole compound of the general formula (240) in which Rj_ ' ^R -2' ^R -3 '^ -6 before. Rg_, r and Ar have the meanings defined 50. The process of claim 1 for preparing compounds of formula I in which R? represents a substituted alkynyl or substituted alkenyl group, characterized by the fact that a halogenoimidazole compound of the general formula is coupled to which R ^ _, R ₂ , Rj, Rg, R _g er have the meanings defined before, and X represents a bromine or iodine atom, with a 1-alkenylmethyl or 1-alkynylmethyl derivative of formula— general formula AM in which A represents a group of the general formula CH = CH (CH-) Ar or 3 x CH = CH (CH ₂ ) _x Ar where Ar represents an evenly substituted aryl group or optionally substituted heteroaryl and x represents zero or an integer from 1 to 8, and M represents a metal, or a lcene or 1-alkali of general formula AH in which A has the meanings defined above, in the presence of a transition metal as a catalyst, to obtain a (1-alkenyl) - or (1-alkynyl) -imidazole compound of the general formula in which R ^, R ₂ , Rg, Rg, Ηθ, r A have the meanings defined before. 51. The process of claim 1 for preparing compounds of formula I in which Ry represents a substituted alkenyl group, characterized in that -241 reacting an imidazole aldehyde of general formula _n _ ^ (CH ₂ ) _u CHO Λ N (CH ₂ ) _r ^R 3 ^ \ (251) na gual Rg_, Rg. and r have defined meanings. rather, I represents zero or an integer that added to the number represented by the symbol v does not exceed 8, with a methylenetriphenylphosphorium. s_ubs_tituí.dc to obtain an alkenylimidazole of the general formula _N - ^ (CH ₂ ) _u CH = CH {CKJ _¥ Ar The ^R 3 N (CK ₂ ) _f β (252) in which R_-j_, R ₃ z Rgz Rg.z Rg er have the meanings defined before, Ar represents an optionally substituted aryl or optionally substituted heteroaryl group and, -242- u + v represents zero or an integer from 1 to 8. 52. The process of claim 1 for the preparation of compounds of general formula I in which Ry represents an -NH-SO ₂ -heteroaryl group or a group of general formula -S (0) -heteroaryl or -NR. _o- heteroaryl, characterized by the fact that it undergoes an imidazolic compound, with a group E capable of losing an electron as a substitute, of a general formula in which R ^, R ₂ , and Rg have the meanings defined above, X represents a leaving group, and E represents a group capable of losing an electron. to an aromatic substitution reaction, by treatment with nucleophilic reagents, in an appropriate solvent, at a temperature between room temperature and the reflux temperature of the solvent, to replace the leaving group represented by the symbol X with a nucleophile represented by the Nu symbol like, for example, an atom of -243 / sulfur or nitrogen to obtain a compound of the general formula. (256) in which R ^, R ₂ , Rj _Z Rg_, E and Nu have the meanings defined before. 53.- Process for the preparation of pharmaceutical compositions used in the treatment of hypertension or congestive heart failure or in the prevention of renal failure caused by the administration of a non-steroidal anti-inflammatory, characterized by the fact that an effective amount of a compound is mixed of general formula I, prepared by the process according to claim 1, as an active ingredient, with a pharmaceutically acceptable carrier and, optionally, with a diuretic or a non-steroidal anti-inflammatory. Lisbon, August 28, 1990