BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to novel substituted imidazoles, and processes for their preparation. The invention also relates to pharmaceutical compositions containing the novel imidazoles and pharmaceutical methods using them, alone and in conjunction with other drugs, especially diuretics and non-steroidal anti- inflammatory drugs (NSAID's). The compounds of this invention inhibit the action of the hormone angiotensin II (All) and are useful therefore in alleviating angiotensin induced hypertension. The enzyme renin acts on a blood plasma A2-globulin, angiotensinogen, to produce angiotensin I, which is then converted by angiotensin converting- enzyme to All. The latter substance is a powerful vasopressor agent which has been implicated as a causitive agent for producing high blood pressure in various mammalian species, such as the rat, dog, and man. The compounds of this invention inhibit the action of All at its receptors on target cells and thus prevent the increase in blood pressure produced by this hormone-receptor interaction. By administering a compound of this invention to a species of mammal with hypertension due to All, the blood pressure is reduced.

The compounds of this invention are also useful for the treatment of congestive heart failure. Administration of a compound of this invention with a diuretic such as furosemlde or hydrochlorothlazlde, either as a stepwise combined therapy (diuretic first) or as a physical mixture, enhances the antihypertensive effect of the compound. Administration of a compound of this Invention with a non-stero1dal anti-Inflammatory drug (NSAID) can prevent renal failure which sometimes results from administration of a NSAID.

European Published Application 0253310, published January 20, 1988, discloses that certain substituted Imidazoles block the All receptor and are useful therefore 1n alleviating angiotensin Induced hypertension as well as in treating congestive heart failure. The imidazoles disclosed have the formula:

The imidazoles of the present Invention differ from those of EPA 0253310 In the substituents R ⁷ and R ⁸ at positions 4 and 5 of the Imidazole ring. In EPA

0253 310, R ⁷ and R ⁸ are defined as follows:

R ⁷ is H, F, Cl, Br, I, N0 ₂ , CF3 or CN;

R ⁸ Is H, CN, alkyl of 1 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, or the same groups substituted

SUBSTITUTE SHEET,

with F; phenylalkenyl wherein the aliphatic portion 1s 2 to 6 carbon atoms; -(CHgJm-lmldazol-l-yl; -(CH2) _m -l,2,3-tr1azolyl optionally substituted with one or two groups selected from CO2CH3 or alkyl of 1 to 4 carbon atoms; -(CH2) -tetrazolyl;

0 -(CH ₂ )nOR ⁿ ; -(CH ₂ ) _n 0CR ¹⁴ ; -(CH ₂ ) _n SR ¹⁵ ;

R ¹⁴ 0 0

-CH=CH(CH ₂ ) _s CHOR ¹⁵ ; -CH=CH(CH ₂ ) _S CR ¹⁶ ; -CR ¹⁶ ;

-CH=CH(CH2) _s 0CR ^π ;

Y

•(CH ₂ )s-CH-C0R ¹⁶ ; -(CH ₂ )r|CR ¹⁶ ; -(CH ₂ ) _n 0CNHR ¹⁰ ;

CH ₃

Y 0

-(CH2) _n NR ¹¹ C0R ¹⁰ ; -(CH2) _n NR ^π CNHR ¹⁰ ; -(CH ₂ )n R ⁿ S02 ¹⁰

Y -(CH2) _n NR ¹¹ CR ¹⁰ , etc., where R ¹⁰ , R ^π , R ¹⁴ , R ¹⁵ , R ¹⁶ , and

Y are as defined below for the present invention.

Pals et al., Circulation Research. 2jJ, 673

(1971) describe the introduction of a sarcosine residue in position 1 and alanine in position 8 of the endogenous vasoconstrictor hormone All to yield an (octa)peptlde that blocks the effects of All on the blood pressure of pithed rats. This analog, [Sar*. Ala ⁸ ] All, Initially called "P-113" and subsequently "Saralasin", was found to be one of the most potent competitive antagonists of the actions of All, although, like most of the so-called pept1de-AII-

antagonists, 1t also possesses agonistic actions of Its own. Saralasln has been demonstrated to lower arterial pressure 1n mammals and man when the (elevated) pressure 1s dependent on circulating All (Pals et al.,' Circulation Research. 29, 673 (1971); Streeten and Anderson, Handbook of Hypertension, Vol. 5, Clinical Pharmacology of Antihypertensive Drugs, A. E. Doyle (Editor), Elsevier Science Publishers B.V., p. 246 (1984)). However, due to Its agonistic character, saralasin generally elicits pressor effects when the pressure is not sustained by All. Being a peptlde, the pharmacological effects to saralasln are relatively short-lasting and are only manifest after parenteral administration, oral doses being Ineffective. Although the therapeutic uses of peptlde AU-blockers, like saralasln, are severely limited due to their oral ineffectiveness and short duration of action, their major utility 1s as a pharmaceutical standard.

Some known non-pept1de antihypertensive agents act by Inhibiting an enzyme, called angiotensin converting enzyme (ACE), which 1s responsible for conversion of angiotensin I to All. Such agents are thus referred to as ACE Inhibitors, or converting enzyme Inhibitors (CEI's). Captopril and enalaprll are commercially available CEI's. Based on experimental and clinical evidence, about 40% of hypertensive patients are non-responsive to treatment with CEI's. But when a diuretic such as furose lde or hydrochlorothiazlde 1s given together with a CEI, the blood pressure of the majority of hypertensive patients is effectively normalized. Diuretic treatment converts the non-renin dependent state in regulating blood pressure to a renln-dependent state. Although the Imidazoles of this Invention act by a different mechanism, I.e., by blocking the All receptor rather

than by Inhibiting the angiotensin converting enzyme, both mechanisms involve interference with the renin- angiotensin cascade. A combination of the CEI enalaprll maleate and the diuretic hydrochlorothiazide is commercially available under the trademark

Vaseretic® from Merck & Co. Publications which relate to the use of diuretics with CEI's to treat hypertension, in either a diuretic-first, stepwise approach or in physical combination, include Keeton, T. K. and Campbell, W. B., Pharmacol. Rev., 31:81 (1981) and Weinberger, M. H., Medical Clinics N. America, 71:979 (1987). Diuretics have also been administered in combination with saralasln to enhance the antihypertensive effect. Non-steroidal anti-inflammatory drugs

(NSAID's) have been reported to Induce renal failure in patients with renal underperfuslon and high plasma level of All. (Dunn, M.J., Hospital Practice, 19:99, 1984). Administration of an All blocking compound of this invention in combination with an NSAID (either stepwise 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):I-89, 1975; Blasingha et al., Am. J.

Phvsiol. 239:F360, 1980). The CEI captopril has been demonstrated to reverse the renal vasoconstrictor effect of Indomethacin 1n dogs with non-hypotens1ve hemorrhage. (Wong et al., J. Pharmacol. Exp. Ther. 219:104, 1980).

Summary Of The Invention According to the present invention there are provided novel compounds of formula (I) which have angiotensin Il-antagonizing properties and are useful as antihypertensives.

SUBSTITUTE SHEET

^• wherein

R ^' is 4-CO2H; 4-C02R ^9: -O-S-OH; -SO3H;

0 O O a ■

-C(CF3) ₂ OH; -O-P-OH; - O3H2; -NH-P-OH; OH OH

4 - NHSO2CH3 ; 4~ NHS0 ₂ CF ₃ ; - CONHOR ^{1 :}

OH O N-N

-SO2NH2; -c ¹ — ^■ p-OH ; 3^ J ** \_ R ²⁷ OH H

-

2C6H5 ;

H (fc-isomer)

R ² is H; Cl; Br; I; F; O2; CN; alkyl of 1 to 4 carbon atoms; acyloxy of 1 to 4 carbon atoms; alkoxy of 1 to 4 carbon atoms; C0 ₂ H; C0 ₂ R ⁹ ; NHS0 ₂ CH ₃ ; NHS0 ₂ CF ₃ ;

N-N

C0NH0R ¹² ; S0 ₂ NH ₂ ; l M ; aryl; or furyl;

^ H

R ³ 1s H; Cl, Br, I or F; alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms;

R ⁴ is CN, N0 ₂ or C0 ₂ R ^U ;

R^ is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms alkenyl or alkynyl of 2 to 4 carbon atoms;

R> is alkyl of 2 to 10 carbon atoms, alkenyl or alkynyl of 3 to 10 carbon atoms or the same groups substituted with F or CO2R ¹⁴ ; cycloalkyl of 3 to 8 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms; cycloalkylalkenyl or cycloalkylalkynyl

of 5 to 10 carbon atoms; (CH ₂ ) _s Z(CH ₂ ) _m R ⁵ optionally substituted with F or C0 ₂ R ¹⁴ ; benzyl or benzyl substituted on the phenyl ring with 1 or 2 halogens, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or nitro; is vinyl; cycloalkyϋdenyl; alkynyl of 2-10 carbon atoms; phenylal ynyl where the alkynyl portion is 2-6 carbon atoms; heteroaryl selected from 2- and 3-th1enyl, 2- and 3-furyl, 2-, 3-, and 4-pyr1dyl, 2-pyraz1nyl, 2-, 4-, and 5-pyr1m1dinyl, 3- and 4-pyridazinyl, 2-, 4- and 5-th1azolyl, 2-, 4-, and 5-selenazolyl, and 2-, 4-, and 5-oxazolyl, 2- or 3-pyrrolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-im1dazolyl; 0-, m- or p- biphenylyl; o-, m- or p-phenoxyphenyl ; 2-oxazolinyl; 2-thiazolinyl; substituted phenylalkynyl, heteroaryl, biphenylyl or phenoxyphenyl as defined above substituted with 1 or 2 substituents selected from halogen, hydroxy, mercapto, alkoxy of 1-5 carbon atoms, alkyl of 1-5 carbon atoms, -N0 ₂ , -CN, -CF ₃ , -COR ¹⁶ , -CH ₂ 0R ¹⁷ , -NHC0R ¹⁷ , -C0NR ¹⁸ R ¹⁹ , S(0) _r R ¹⁷ , and S0 ₂ NR ¹⁸ R ¹⁹ ; pyrrolyl , pyrazolyl or iπridazolyl as defined above substituted on ring nitrogen with alkyl of 1-5 carbon atoms, phenyl or benzyl; or substituted alkyl, alkenyl, or alkynyl of 1 to 10 carbon atoms substituted with a substituted or unsubstituted heteroaryl, biphenylyl or phenoxyphenyl group as defined above; -S(0) _r -heteroaryl, -S-(0) _r -biphenylyl, -S(0) _r -phenoxyphenyl, -S-tetrazole, -S(0) _r R ¹⁷ , -NR ¹⁸ R ¹⁹ , -NR ¹⁸ -heteroaryl , -NR ¹⁸ -phenyl , -NR ^l8 -b1phenylyl ,

-NR ¹⁸ -phenoxyphenyl , -N-phthalimido, -NH-S0 ₂ -phenoxyphenyl, -NH-S0 ₂ -heteroaryl , -NH-S0 ₂ -biphenylyl , -NH-S0 -R ¹⁷ , and -S- (C=0)-R ¹⁷ , N-imidazolyl, N-l,2,3-triazolyl, N-l,2,4-triazolyl, where heteroaryl 1s a heterocycle defined 1n the scope of R ⁷ and where the phenyl group 1n R ¹⁷ of -S-(0) _r R ¹⁷ , the N- i idazolyl, N-l,2,3-tr1azolyl, and N-l,2,4-tr1azolyls may be substituted with one or two substituents as described above for heteroaryl ;

0 R ⁸ is -(CH ₂ ) _n 0CR ¹⁴ ; -(CH ₂ ) _n SR ¹⁵ ;

R ¹⁴ 0 0

I -CH=CH(CH ₂ ) _s CH0R ¹⁵ ; -CH=CH(CH ₂ ) _S CR ¹⁶ ; -CR ¹⁶ ;

0

-CH=CH(CH ) _s 0CR ^π ; -(CH ₂ ) _m -tetrazolyl;

0 Y

(CH ₂ ) _s -CH-C0R ¹⁶ ; -(CH ₂ ) _n CR ¹⁶ ; -(CH ) _n 0CNHR ¹⁰ ;

CH ₃

Y 0 -(CH ₂ ) _n NR ⁿ C0R ¹⁰ ; -(CH ₂ ) _n NR ⁿ CNHR ¹⁰ ; -(CH ₂ ) _n NR ⁿ Sθ2R ¹⁰ ;

Y -(CH ₂ ) _n NR ^π CR ¹⁰ ;

R ¹⁰ is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6 carbon atoms, 1-adamantyl, 1-naphthyl, 1-(1-naphthyl)ethyl, or (CH ₂ ) _p C ₆ H ₅ ;

R ¹¹ is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;

R* ² is H, methyl or benzyl;

R ¹³ is -C0 ₂ H; -C0 R ⁹ ; -CH ₂ C0 ₂ H, -CH ₂ C0 ₂ R ⁹ ; 0 0 0

-0- -OH; -O- OH; -S0 H; -NH H

-P0 H2; -C(CF ₃ ) ₂ 0H; -NHS0 ₂ CH ₃ ; -NHS0 ₂ CF ₃ ; -NHCOCF3;

■C0NH0R ¹² ; -S0 ₂ NH ₂ ; -

SUBSTITUTE SHEE

^' ITδΪE * ϋirø(i_.t_,Ti

"• -CONHNHS0 ₂ CF ₃ ;

^R2 °

R ¹⁴ is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R ¹⁵ is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenacyl;

R ¹⁶ 1s H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH ) _p C6H5, OR ¹⁷ , or NR ¹⁸ R ¹⁹ ; R ¹⁷ is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R ¹⁸ and R ¹⁹ independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, β-methylbenzyl , or taken together with the nitrogen form a ring of the formula

Q is NR ²⁰ , 0 or CH ₂ ;

R ²⁰ 1s H, alkyl of 1-4 carbon atoms, or phenyl; R ²¹ is alkyl of 1 to 6 carbon atoms, -NR ²² R ²³ ,

R ²² and R ²³ Independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together as (CH ₂ ) _U where u is 3-6;

R ²⁴ 1s H, CH ₃ or -C ₆ H ₅ ;

SUBSTITUTE SHEET

R ²⁵ is NR ²⁷ R ²⁸ , OR ²⁸ , NHC0NH ₂ , NHCSNH ₂ ,

-NHS0 ₂ —ζ V-CH ₃ ,or -NHS0 ₂ - J ;

R ²⁶ Is hydrogen, alkyl with from 1 to 6 carbon atoms, benzyl, or allyl; R ²⁷ and R ²⁸ are independently hydrogen, alkyl with from

1 to 5 carbon atoms, or phenyl; R ²⁹ and R ³⁰ are Independently alkyl of 1-4 carbon atoms or taken together are -(CH ₂ )q-;

R ³¹ is H, alkyl of 1 to 4 carbon atoms, -CH ₂ CH=CH ₂ or

-CH ₂ C ₆ H ₄ R ³² ; R ³² 1s H, N0 _2f NH ₂ , OH or OCH3; X 1s a carbon-carbon single bond, -CO-, -CH ₂ -, -0-, -S-,

-NH- -N- -CON- -NC0-, -0CH ₂ -, -CH ₂ 0-

R ²⁶ R ²³ R ²³

-SCH ₂ -, - -CCHH ₂₂ SS--,, --NNHHCC((RR ^Σ27 )(R ²⁸ ), -NR ²³ S0 ₂ ",

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

R ³⁰ Y is 0 or S; Z 1s 0, NR ¹¹ , or S; m is 1 to 5; n 1s 1 to 10; p Is 0 to 3; q is 2 to 3; r Is 0 to 2; s is 0 to 5; t is 0 or 1;

and pharmaceutically acceptable salts of these compounds; provided that:

(1) the R ¹ group is not 1n the ortho position;

and R ¹³ 1s C0 H, or then R 13 must be 1n the ortho or meta position; or when R- and X are as above and R ¹³ is NHS0 ₂ CF ₃ or NHS0 ₂ CH ₃ , R ¹³ must be ortho;

(3) when R ¹ 1s and X 1s other than

a single bond, then R ¹³ must be ortho except when X = NR ²³ C0 and R ¹³ 1s NHS0 ₂ CF ₃ or NHS0 CH ₃ , then R ¹³ must be ortho or meta;

(4) when R ¹ 1s 4-C0 ₂ H or a salt thereof, R ⁶ cannot be S-alkyl;

(5) when R ¹ is 4-C0 ₂ H or a salt thereof, the substituent on the 4-pos1tion of the Imidazole cannot be CH ₂ 0H, CH ₂ 0C0CH ₃ , or CH ₂ C0 H;

CFaSOaHN

(6) when R ¹ Is -NHCO- \ _{t R} 6 _{1S not met} hoxy-

benzyl;

SUBSTITUTE SHEET

(7) the R ⁶ group is not -CHCH ₂ CH ₂ CH ₃ or CH ₂ 0H;

F

Preferred for their antihypertensive activity are novel compounds having the formula:

wherein

_R t3

N-N \ .

R ^! is -C0 ₂ H; -NHSO ₂ CF ₃ ; ff / ^S= ^' ^R

^ N H ^■■ ' - ^X Λ

R ⁶ 1s alkyl 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 on the phenyl ring with up to two groups selected from alkoxy of 1 to 4 carbon atoms, halogen, alkyl of 1 to 4 carbon atoms, and nltro;

0 R ⁸ is -(CH ₂ ) _m -tetrazolyl, -(CH ₂ ) _n 0R ^π ; -(CH ₂ ) _n 0CR ¹⁴ ;

SUBSTITUTE SliEEi

R ¹⁴

-CH=CH(CH ₂ ) _S CR ¹⁶ , -CH=CH(CH ₂ ) _s CH0R ¹⁵ ;

0 0

- (CH ₂ ) _n CR ¹⁶ ; - (CH ₂ ) _n NH-C0R ¹⁰ ; -(CH ₂ ) _n NHS0 ₂ R ¹⁰ ; ?

R ¹³ i s -C0 ₂ H, -C0 ₂ R ⁹ , NHS0 ₂ CF ₃ ; S0 ₃ H; or ^N I

"N H

R ¹⁶ is H, alkyl of 1 to 5 carbon atoms, OR ¹⁷ , or NR ¹⁸ R ¹⁹

X is carbon-carbon single bond, -CO-, -CON- , -CH ₂ CH ₂ -, -NC0-, -0CH ₂ -, -CH 0-, -SCH ₂ -,

_R 23 -CH ₂ S-, -NHCH ₂ -, -CH ₂ NH- or -CH=CH-; and

pharmaceutically acceptable salts of these compounds.

More preferred are compounds of the preferred scope where: R ² 1s H, alkyl of 1 to 4 carbon atoms, halogen, or alkoxy of 1 to 4 carbon atoms; R ⁶ 1s alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms; R ⁷ 1s heteroaryl selected from 2- and 3-thienyl, 2- and

3-furyl, 2-, 3-, and 4-pyridyl, or p-b1phenylyl,

SilBSilTb -ϋ ύπt i

R ¹⁴ 0

R ⁸ is -(CH ₂ ) OR ¹¹ ; -(CH^OCR ¹⁴ ; -CH=CH-CH0R ¹⁵ ; 0 0

-(CH ₂ ) _m CR ¹⁶ ; -CH ₂ NHC0R ¹⁰ ; -(CH2) _m NHS0 ₂ R ¹⁰ ; or -COR ¹⁶ ;

R ¹⁰ 1s CF ₃ , alkyl of 1 to 6 carbon atoms or phenyl; R ¹¹ 1s H, or alkyl of 1 to 4 carbon atoms; R ¹³ is C0 ₂ H; C0 CH ₂ 0C0C(CH ₃ )3; NHS0 ₂ CF ₃

N-N or 1

N H

R ¹⁴ is H, or alkyl of 1 to 4 carbon atoms;

R ¹⁵ is H, alkyl of 1 to 4 carbon atoms, or acyl of 1 to

4 carbon atoms;

R ¹⁶ 1s H, alkyl of 1 to 5 carbon atoms; OR ¹⁷ ; or

m Is 1 to 5;

X = single bond, -0-; -C0-; -NHC0-; or -0CH ₂ -; and pharmaceutically acceptable salts.

Note that throughout the text when an alkyl substituent 1s mentioned, the normal alkyl structure is meant (i.e., butyl is n-butyl) unless otherwise specified.

Pharmaceutically suitable salts include both the metallic (inorganic) salts and organic salts; a 11st of which 1s given 1n Remington's Pharmaceutical Sciences. 17th Edition, pg. 1418 (1985). It Is well known to one skilled in the art that an appropriate salt form 1s chosen based on physical and chemical stability,

SUBSTITUTE SHEE

flowability, hydroscopicity and solubility. Preferred salts of this invention for the reasons cited above Include potassium, sodium, calcium and ammonium salts. Also within the scope of this invention are 5 pharmaceutical compositions comprising a suitable pharmaceutical carrier and a compound of Formula (I), and methods of using the compounds of Formula (I) to treat hypertension and congestive heart failure. The pharmaceutical compositions can optionally contain one

10 or more other therapeutic agents, such as a diuretic or a non-steroidal antiinflammatory drug. Also within the scope of this Invention is a method of preventing renal failure resulting from administration of a non- steroidal antiinflammatory drug (NSAID) which comprises

15 administering a compound of Formula (I) 1n stepwise or physical combination with the NSAID. The compounds of this Invention can also be used as diagnostic agents to * ^~ ψ- ι test the renln angiotensin system.

It should be noted in the foregoing structural

20 formula, when a radical can be a substituent in more than one previously defined radical, that first radical can be selected independently 1n each previously defined radical. For example, R-, R ² and R ³ can each be CONHOR ¹² . R ¹² need not be the same substituent in

25 each of R ¹ , R ² and R ³ but can be selected independently for each of them.

Detailed Description Synthesis

30 The novel compounds of Formula (I) may be prepared using the reactions and techniques described in this section. The reactions are performed 1n a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. It is

35 understood by those skilled 1n the art of organic

SUBSTITUTE SHEET

1 * ' J-ϊ rt ^•*• " ^■• f *-'. » ^■ — r" r." 'i ^m ~"f a ^* u&>Hi i f £ V *~f i

synthesis that the functionality present on the imidazole and other portions of the molecule must be consistent with the chemical transformations proposed. This will frequently necessitate judgment as to the order of synthetic steps, protecting groups required, deprotection conditions, and activation of a benzyl1c position to enable attachment to nitrogen on the imidazole nucleus. Throughout the following section, not all compounds of Formula (I) falling Into a given class may necessarily be prepared by all methods described for that class. Substituents on the starting materials may be Incompatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled 1n the art and alternative methods described must then be used.

^SUBST ITUTESHEET

Scheββ 1

SUBSTITUTE SHEET

Generally, compounds of Formula (3_) can be prepared by direct alkylation onto Imidazole (J_) , with an appropriately protected benzyl halide, tosylate or mesylate (2) in the presence of base, as shown in path a). Preferably, the metallic imidazolide salt 1s prepared by reacting imidazole (I) with a proton acceptor such as MH where M Is lithium, sodium or potassium in a solvent such as dimethylformamide (DMF) or by reacting it with a metal alkoxlde of formula MOR where R is methyl, ethyl, t-butyl or the like 1n an alcohol solvent such as ethanol or t-butanol, or a dipolar aprotic solvent such as dimethylformamide. The imidazole salt is dissolved 1n an inert aprotic solvent such as DMF, and treated with an appropriate alkylatlng agent (2). Alternatively, imidazole (I) can be alkylated with a benzyl halide (2, where X=Br, Cl) in the presence of a base such as sodium carbonate, potassium carbonate, triethylamlne or pyridine. The reaction 1s run in an inert solvent such as DMF or DMSO at 20°C to the reflux temperature of the solvent for 1-10 hours.

For example, the 4-nitrobenzyl Intermediate (3a, wherein R ¹ = 4-N0 ₂ , R ² = R ³ = H) may be obtained by direct alkylation onto imidazole (I) with a 4-nitrobenzyl halide, tosylate or mesylate in the presence of base.

As R ⁷ and R ⁸ are different, mixtures of two regioisomer alkylation products (3b, and 3c) are obtained 1n which R ⁷ and R ⁸ are Interchanged. When R ⁸ is CH0 the alkylation is such that the benzyl group becomes attached to the adjacent nitrogen preferentially. These isomers possess distinct physical and biological properties and can usually be separated and isolated by conventional separation techniques such as chro atography and/or crystallization.

SUBSTITUTE SiϊEhi

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

Alternatively, any properly functional1zed benzylamine derivative (4) may be converted to 1m1ne (6) by treatment with an acylamlno ketone (5) in the presence of an Inert solvent such as benzene, toluene, or the like, and a catalytic amount of p-toluene- sulfonic acid or molecular sieves, N. Engel, and W. StegHch, Liebiαs Ann. Che .. 1916, (1978), or In the presence of alumina, F. Texler-Boulet, Synthesis. 679 (1985). The resulting imine (6) can be cyclized to the N-benzyl imidazole (3) with phosphorus penta- chloride (PCI5), phosphorus oxychlorlde (P0C1 ) or triphenylphosphine (PPh ₃ ) 1n dichloroethane 1n the presence of a base such as triethylamine, N. Engel and W. Stegllch, Liebiαs Ann. Chem.. 1916, (1978).

Acylamlno ketone (5) 1s readily obtainable from amino acids via the Dakin-West reaction, H.D. Dakin, R. West, J. B1o1. Chem.. 78, 95 and 745 (1928), and various modifications thereof, W. Stegllch, G. ' Hofle, Anqew. Chem. Int. Ed. Enαl.. 8, 981 (1969); G. Hofle, W. Stegllch, H. Vorbruggen, Anoew. Chem. Int. Ed. Enαl.. J7, 569 (1978); W. Stegllch, G. Hofle, Ber.. 102. 883 (1969), or by selective reduction of acyl cyanides, A. Pfaltz, S. Anwar, Tet. Lett. 2977 (1984), or from a-halo, Λ-tosyl or a-mesyl ketones via the appropriate substitution reactions that one skilled 1n the art will readily recognize. The functional1zed benzylamlnes (4) may be made from the corresponding benzyl halide, tosylate or mesylate (2) via displacement with a nitrogen nucleophile, a procedure familiar to one skilled 1n the art. This displacement may be achieved using azlde ion, ammonia, or phthalimlde anion, etc., 1n a neutral

STITUTE SHEET

solvent such as dimethylformamide, dimethylsulfoxide etc., or under phase transfer conditions. The benzyl halide (2) may be made by a variety of benzyl1c halo¬ genation methods familiar to one skilled in the art, for example benzyl1c bromination of toluene derivatives with N-bromosucc1nim1de 1n an inert solvent such as carbon tetrachlorlde 1n the presence of a radical Initiator such as benzoyl peroxide at temperatures up to reflux conditions. A wide variety of toluene derivatives may be made from simple electrophlHc substitution reactions on an aromatic ring. This Includes nitration, sulfonation, phosphorylatlon, Friedel-Crafts alkylation, Friedel-Crafts acylation, halogenation, and other similar reactions known to one skilled 1n the art, G. A. Olah, "Friedel-Crafts and Related Reactions," Vol. 2^5, Intersdence, New York, (1965).

Another way to synthesize functional!zed benzyl halldes is via chloromethylatlon of the corresponding aromatic precursor. Thus, the appropriately substituted benzene ring may be chloromethylated with formaldehyde and hydrochloric acid (HCl) for example with or without an inert solvent such as chloroform, carbon tetrachlorlde, light petroleum ether or acetic add. A Lewis acid such as zinc chloride (ZnCl ₂ ) or a mineral acid such as phosphoric acid may also be added as a catalyst or condensing agent, R. C. Fuson, C. H. McKeever, Orα. Reactions. I, 63 (1942). Alternatively, N-benzylImidazoles (3) can also be prepared as shown 1n path b) by forming an R ⁶ sub¬ stituted a idine (2) from an appropriately substituted benzylamine (4) which 1s 1n turn reacted with an β-haloketone, α-hydroxyketone (8), β-haloaldehyde, or

SUBSTITUTE SHEEI

α-hydroxyaldehyde, F. Kunckell, Ber.. 34, 637 (1901).

As shown 1n path a), imidazole (I) may be alkylated by a variety of benzyl derivatives. These include compounds with latent acid functionalities such as o, , and p-cyanobenzylhalides, mesylates or tosylates as shown in path c). Nitriles of formula (9) may be hydrolyzed to carboxylic adds of formula (10) by treatment with strong add or alkali. Preferably, treatment with a 1:1 (v/v) mixture of concentrated aqueous hydrochloric add/glacial acetic add at reflux temperatures for 2-96 hours or by treatment with IN sodium hydroxide in an alcohol solvent such as ethanol or ethylene glycol for 2-96 hours at temperatures from 20°C to reflux can be used. If another nitrile group 1s present 1t will also be hydrolyzed. The nitrile functionality can also be hydrolyzed in two steps by first stirring in sulfuric add to form the amide followed by hydrolysis with sodium hydroxide or a mineral add to give the carboxylic acid Qθ).

The nitriles (9) can be converted Into the corresponding tetrazole derivative (il) by a variety of methods using hydrazoic acid. For example, the nitrile can be heated with sodium azide and ammonium chloride 1n DMF at temperatures between 30 ^β C and reflux for 1-10 days, J. P. Hurwitz and A. J. Tomson, J. Orα. Chem.. 26, 3392 (1961). Preferably, the tetrazole is prepared by the 1,3-dipolar cycloaddltion of trialkyltin or trlaryltln azldes to the appropriately substituted nitrile as described in detail by Scheme 15.

The starting Imidazole compounds (1) are readily available by any of a number of standard methods. For example, acylamlnoketone (5) can be cyclized with ammonia or equivalents thereof, D. Davidson, et al., J. Orq. Chem.. 2, 319 (1937) to the

SUBSTITUTE SHEET

corresponding imidazole as shown in Scheme 1. The corresponding oxazole can also be converted to imidazole (1) by action of ammonia or amines in general, H. Bredereck, et al., Ber.. 88, 1351 (1955); J. W. Cornforth and R. H. Cornforth, J. Chem Soc. 96, (1947).

Several alternative routes to Imidazoles (1) are illustrated in Scheme 2. As shown 1n Scheme 2 equation a), reaction of the appropriate R ⁶ substituted Imidate esters (12 with an appropriately substituted α-hydroxy- or α-haloketone or aldehyde (8) 1n ammonia leads to Imidazoles of formula (1), P. Dziuron, and W. Schunack, Archiv. Pharmaz.. 307 and 470 (1974).

The starting Imidazole compounds (1) wherein R ⁷ and R ⁸ are both hydrogen can be prepared as shown in equation b) by reaction of the appropriate R ⁶ -substituted imidate ester Q2) with α- aminoacetaldehyde dimethyl acetal (13), M. R. Grimmett, Adv. HeterocvcHc Chem.. 12, 103 (1970). As shown in equation c), imidazole (15; wherein R ⁷ = hydrogen and R ⁸ = CH ₂ 0H) can be prepared by treatment of the imidate ester (12) with 1,3-dihydroxyacetone (14.) in ammonia by the procedure described 1n Archive der Pharmazie. 307, 470 (1974). Halogenation of imidazole (.15) or any Imidazole wherein R ⁷ or R ⁸ 1s hydrogen is preferably accomplished by reaction with one to two equivalents of N- halosuccin1m1de 1n a polar solvent such as dioxane or 2-methoxyethanol at a temperature of 40-100°C for 1-10 hours. Reaction of the halogenated imidazole (16) with a benzylhallde (2) in the manner described in Scheme 1 affords the corresponding N-benzylimidazole (17); wherein R ⁷ 1s halogen and R ⁸ is CH ₂ 0H). This procedure 1s described in U.S. Patent 4,355,040. Alternatively,

SUBSTITUTE SHEET

imidazole (12) can be prepared by the procedure described 1n U.S. Patent 4,207,324.

Compounds of formula (17) can also be prepared by treatment of the starting imidazole compound (1) wherein R ⁷ and R ⁸ are both hydrogen, with the appropriate benzyl halide followed by functionalization of R ⁷ and R ⁸ by treatment with formaldehyde as described in E. F. Godefrol, et al., Recueil. 91, 1383 (1972) followed by halogenation as was described above. As shown in equation d) the Imidazoles (1) can also be prepared by reaction of R ⁶ substituted amidlnes (18) with an β-hydroxy- or a-haloketone or aldehyde (8) as described by F. Kunckel, Ber.. 34, 637, (1901).

Compounds of Formula (1) wherein R ⁸ = CH ₂ 0H can be prepared as shown in equation e). The Imidazoles

(1) were prepared as described In L. A. Reiter, J. Orq. Chem.. 52, 2714 (1987). Hydroxymethylatlon of (1) as described by U. Kempe, et al. in U.S. Patent 4,278,801 provides the hydroxymethylimidazoles (la).

SUBSTITUTE SHEET

Scheme 2

12

13

1 ⁽ wherein R ⁷ .R8«H)

c) 12 ⁿ - e ^~ o ,«A »

Q^CH

11 •

STO SE

Scheme 2 (continued)

RCOCH2θH+R ⁶ CHO ² - ^H

F pyridyl, p-biphenyiyl, etc.

la

SUBSTITUTE SHEET

27 Scheme 3

2?

28

Siffisiϊπ/T- ?* ^< EEΓ

As shown in Scheme 3. path a) for benzylimidazoles (12) where R ⁸ = CH 0H, the hydroxymethyl groups may be easily converted to the corresponding halide, mesylate or tosylate by a variety of methods familiar to one skilled in the art. Preferably, the alcohol (12) is converted to the chloride (25) with thionyl chloride 1n an inert solvent at temperatures of 20°C to the reflux temperature of the solvent. Chloride (25) may be displaced by a variety of nucleophlles by nucleophlHc displacement reaction procedures familiar to one skilled 1n the art. For example, excess sodium cyanide in DMSO may be used to form cyanomethyl derivatives (26) at temperatures of 20°C to 100°C.

Nitrile (26) may be hydrolyzed to an acetic acid derivative (22), by a variety of methods. These methods include methods described previously for the hydrolysis of nitriles of formula (9). Examples of desired adds and bases for this hydrolysis include mineral adds such as sulfurlc add, hydrochloric add, and mixtures of either of the above with 30-50% acetic add (when solubility 1s a problem), and alkali metal hydroxides such as sodium hydroxide or potassium hydroxide. The hydrolysis reaction proceeds under heating at temperatures ranging from 50-160°C for 2-48 hours. Carboxylic acid (27) may be esterified by a variety of methods without affecting other parts of the molecule. Preferably, (£2) is refluxed In a hydrochloric add/methanol solution for 2-48 hours to give ester (28).

Ester (28) may be hydrolyzed to carboxylic add (22), for Instance, after R ¹ , R ² and R- have been elaborated. Various methods, addle or basic, may be used. For example, compound (28) is stirred with 0.5N

ml

potassium hydroxide in methanol, or if base soluble, it is stirred in 1.0N sodium hydroxide for 1-48 h at 20°C to reflux temperatures.

Hydroxymethyl derivative (J7) may be acylated to give (29) by a variety of procedures. As shown in path b) acylation can be achieved with 1-3 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 (12) may be acylated by reaction with a carboxylic acid and dicyclohexylcarbo- diimide (DCC) in the presence of a catalytic amount of 4-(N,N-dimethylam1no)pyr1dine (DMAP) via the procedure described by A. Hassner, Tet. Lett.. 46, 4475 (1978). Treatment of (12) with a solution of carboxylic acid anhydride in pyridine optionally with a catalytic amount of DMAP at temperatures of 20-100°C for 2-48 hours is the preferred method.

The ether (30) can be prepared from the alcohol (12) as shown in path c) by methods such as treatment of (12) in a solvent such as dimethylformamide or dimethylsulfoxide with potassium t-butoxide, sodium hydride, or the like followed by treatment with R ^π L at 25°C for 1-20 hours, where L is a halogen, tosylate or mesylate.

Alternatively, treatment of (12) with 1-5 equivalents of thionyl chloride in chloroform for 2-6 hours at 25°C followed by treatment of the intermediate (25) with 1-3 equivalents of MOR ¹¹ , where M 1s sodium or potassium, for 2-10 hours at 25°C either in R^OH as solvent or in a polar solvent such as dimethylform¬ amide or the like will also yield ether (30).

The ether (30) can also be prepared for example by heating (12) for 3-15 hours at 60-160°C in

-ϋBsmm m

R ^J1 0H containing an inorganic acid such as a hydrochloric acid or sulfuric add.

N-arylimidazoles of formula I (compounds wherein r=o) can be prepared by the following methods, it being understood by one skilled 1n the art that certain manipulations, protecting and deprotecting steps, and other synthetic procedures disclosed above may be necessary to produce compounds with the desired combinations of R ⁶ , R ⁷ , R ⁸ and R ¹³ - As shown in Scheme 4. equation a) the reaction of aniline derivative (34) with Imidate ester (12) to form the substituted amidlne (35) provides material which can be cyclized with dlhydroxyacetone to form structure (36). Subsequent elaboration Into (I) provides the N-arylimidazole compounds of the invention.

Alternatively as shown by equation b) the Marckwald procedure, described by Marckwald et al., Ber.. 22, 568, 1353 (1889); 25, 2354 (1892) can form a 2-mercapto1m1dazole (38) from aniline derivative (34) via isothlocyanate (32). Desulfurlzation of (38) with dilute nitric add followed by anion formation at the 2-position of the imidazole (39) and reaction with R ⁶ X where X 1s Cl, Br, I, allows the formation of (40) which can be subsequently elaborated to I.

A variation of Marckwald*s process as shown in equation c) using an β-am1noketone (41) and isothlocyanate (32) can also be employed, see Norrls and McKee, J. A er. Chem. Soc. 77, 1056 (1955) can also be employed. Intermediate (4 ) can be converted to (I) by known sequences. The general procedure of Carbonl et al., J. Amer. Chem. Soc. 89, 2626 (1967) (Illustrated by equation d)) can also be used to prepare N-aryl substituted imidazoles from appropriate haloaromatic compounds (4_3; X=F, Cl , Br) and imidazoles (1):

mi HEET

31 Scheme 4

30

35

SUBSTITUTE SHEET

42

'""^ ^'

In various synthetic routes R ¹ , R ² and R ³ do not necessarily remain the same from the starting compound to the final products, but are often manipulated through known reactions 1n the intermediate steps as shown in Schemes 5-22. All of the transformations shown in Schemes 5-10 and 12 can also be carried out on the terminal aromatic ring (i.e., b1phenyl ring).

Scheme 5

As shown in Scheme 5, compounds where R ¹ is a sulfonic acid group may be prepared by oxidation of the corresponding thiol (45). Thus, an N-benzylimidazole derivative bearing a thiol group may be converted into a sulfonic acid (46) by the action of hydrogen peroxide, peroxyadds such as metachloroperoxybenzoic add, potassium permanganate or by a variety, of other oxidizing agents, E. E. Reid, Organic Chemistry of

Bivalent Sulfur. 1, Chemical Publishing Co., New York, 120-121 (1958).

Aromatic hydroxy or thiol groups are obtained from deprotectlon of the corresponding alkyl ether or thloethers. Thus, for example, a methyl ether or a

SUBSTITUTE SHEET

methyl thioether derivative (44) of an N-benzylimid¬ azole containing one or more aromatic rings may be converted into the free phenol or thiophenol (45) by the action of boron tribromide methyl sulfide, P. 6. Willard and C. F. Fryhle, Tet. Lett.. 21, 3731 (1980); trimethylsilyl iodide, M. E. Jung and M. A. Lyster, J. Orα. Chem.. 42, 3761 (1977); KSEt and derivatives thereof, 6. I. Feutrlll, R. N. Mirrington, Tet. Lett.. 1327, (1970), and a variety of other reagents. Alternatively, N-benzylimidazoles may be sulfonated by stirring with H2SO4 at a variety of different concentrations or with other sulfonatlng agents such as chlorosulfonic acid or sulfur trioxide with or without complexlng 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. Ill part 2, 6. A. Olah, ed., Interscience Publ., 1355 (1964).

The synthesis of compounds where R* 1s a sulfate, phosphate or phosphonic add are depicted in Scheme 6;

msm $

35 Scheme 6

m $m

Scheme 6 (continued)

ICl,_Cuiϊl

53 j 5>4« X • __T .9iT _t . ZΛl _j

NX, (X-h-tlsgm)

SUBSTITOTE SHEET

N-Benzylimidazoles containing a phenolic hydroxyl group (42) may be readily converted into the corresponding sulfate (48) or phosphate (49). As shown in equation a), reaction of the phenol with a sulfur t ioxide-amine complex will give the corresponding sulfate (48). E. E- Gilbert, Sulfonation and Related Reactions. Interscience, New York, chapter 6 (1965). Reaction of the phenol (47) with phosphorus pentachloride followed by hydrolysis will give the corresponding phosphate (49), G. M. osolapoff, Orqanophosphorus Compounds. John Wiley, New York, 235 (1950).

As shown in equation b) N-benzylimidazoles may be converted into the corresponding phosphonic adds by reaction with phosphorus trichloride (PCI3) and aluminum chloride (AICI3) in an inert solvent for 0.5-96 hours from temperatures of 25°C to the reflux temperatures of the solvent. Appropriate workup followed by reaction with chlorine (CI2) and subsequent hydrolysis of the tetrachloride (51) gives the phosphonic acid derivative (52), G. M. Kosolapoff 1n Orα. Reactions. 6, R. Adams, editor, John Wiley and Sons, New York, 297 (1951). Another more direct route involves reaction of the N-benzylimidazole with PSCI3 and A I3 followed by hydrolysis, R. S. Edmunson in

Comprehensive Organic Chemistry. Vol. 2, D. Barton and W. D. 011is editors, Pergamon Press, New York, 1285 (1979).

Alternatively, equation c) Illustrates that aryl phosphonic acids (52) may be formed from reaction of the corresponding dlazonium salt (53) with PCI3 1n the presence of Cu(I) followed by hydrolysis with water (ibid, p. 1286).

As shown in equation d), the aryl halides (55) may be photolyzed in the presence of phosphite esters

t onEtl

to give phosphonate esters (56), R. Kluger, J. 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 give phosphonate esters, P. Tavs, Chem. Ber.. 103. 2428 (1970), which can be subsequently converted to phosphonic acids (52) by procedures known to one skilled in the art.

N-Benzylimidazoles containing an aldehyde or ketone (57) may be reacted with a phosphorus trihalide followed by water hydrolysis to give α-hydroxyphos- phonic acid derivatives, G.M. Kosolapoff, op. dt.. 304, as shown in Scheme 7.

Scheme 7

57 IX - I, er al*yl| _5B

SUBSTITUTE SHEET

Compounds where R ¹ is -C0NH0R ¹² may be prepared as shown 1n Scheme 8. by the treatment of a carboxylic acid (10) with 1-4 equivalents of thionyl chloride for 1-10 hours. This reaction can be run without solvent or in a nonreactive solvent such as benzene or chloroform at temperatures of 25-65°C. The intermediate acid chloride is then treated with 2-10 equivalents of the appropriate amine derivative, H2 - OR ¹² , for 2-18 hours at temperatures of 25-80°C in a polar aprotic solvent such as tetrahydrofuran or di ethylsulfoxide to give the hydroxamic add (59).

Scheme 8

Ilia 52a

Alternatively, the carboxylic add Q0) can be converted to the hydroxamic acid (59) according to the procedure 1n J. Med. Chem.. 28, 1158 (1985) by employing dicyclohexylcarbodiimide, 1-hydroxybenzo-

SUBSTITUTE SHEET

triazole, and H2NOR ¹² or according to the procedure described 1n Synthesis. 929 (1985) employing the Vilsmeier reagent and H2NOR ¹² .

Compounds where R ¹ is -CONHSθ2Ar (59a. Ar=phenyl, o-tolyl, etc.) may be produced by treatment of the intermediate acid chlorides from the preparation of the hydroxamic adds (59), with ArS02 HNa. Alternatively, these acylsulfonamldes (59a) can be prepared from the carboxylic acids QO) through the corresponding N,N-diphenylcarbamoyl anhydrides (10a) as described by F. J. Brown, et al. in Eur. Pat. Appl . P 9943 (see Scheme 8).

SUBSTITUTE SiiEϊ

Aniline intermediates (63) are disclosed in U.S. Patent No. 4,355,040 and may be obtained from the corresponding nitro compound precursor by reduction. A variety of reduction procedures may be used such as iron/acetic acid, D. C. Owsley, J. J. Bloomfield, Synthesis. 118, (1977), stannous chloride, F. D. Bellamy, Tet. Lett.. 839, (1984) or careful hydro- genation over a metal catalyst such as palladium.

As shown in Scheme 9. aniline intermediates of N-benzylimidazoles may also be prepared from the corre¬ sponding carboxylic acid (10) or add chloride via a Curtius rearrangement of an intermediate acyl azide (60). More modern methods include using dlphenyl- phosphoryl azide as a source of azide, T. Shioiri, K. Ninomiya, S. Yamada, J. Am. Chem. Soc. 94, 6203 (1972), and trapping the intermediate isocyanate (61) produced by the Curtius rearrangement with 2-trimethyl- silylethanol and cleaving the resultant carbamate (62) with fluoride to liberate the amine (63), T. L. Capson and C. D. Poulter, Tet. Lett.. 25, 3515 (1984).

Classical procedures familiar to one skilled in the art may also be employed.

Compounds where R* is -SO2NH2 may be made as shown in Scheme 10;

SUBSTITUTE SHEET

Sulfonamlde compounds (65) may be made by reacting an arylsulfonyl chloride (64) with ammonia, or Its equivalent. Unsubstituted arylsulfonamides are made 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 dry powdered ammonium carbonate, E. H. Huntress and J. S. Autenrieth, J. Am. Chem. Soc. 63, 3446 (1941); E. H. Huntress and F. H. Carten, J. Am. Chem. Soc. 62, 511 (1940).

The sulfonyl chloride precursor may be prepared by chlorosulfonation with chlorosulfonic acid on the aromatic ring directly, E. H. Huntress and F. H. Carten, ibid.: E. E. Gilbert, op. cit.. 84, or by reacting the corresponding aromatic diazonlum chloride salt (53) with sulfur dioxide 1n the presence of a copper catalyst, H. Meerweln, et al., J. Prakt. Chem.. [11], 152, 251 (1939), or by reacting the aromatic sulfonic acid (46) with PCI5 or POCI3, C. M. Suter, The Organic Chemistry of Sulfur. John Wiley, 459 (1948).

SBBSHTBΪl SHEET

Linked ester compounds of formula (I) where R- 0 is -C02CH(R ² )0CR ²¹ can be made by procedures well known in penicillin and cephalosporin chemistry. The purpose is to provide materials which are more

1ipophilie and which will be useful orally by rapid transit from the gut into the bloodstream, and which will then cleave at a sufficiently rapid rate to provide therapeutically useful concentrations of the active carboxylic acid form. The following review articles and references cited therein discuss this concept and the chemistry involved in preparing such compounds V. J. Stella, et al., Drugs. 29, 455-473 (1985); H. Ferres, Drugs of Today.19 (9), 499-538 (1983); A. A. Sirkula, Ann. Repts. Med. Chem.. H), 306-315 (1975).

Experimental procedures which are applicable to the preparation of chemically stable linked esters are Illustrated by equations a-e of Scheme 11.

Scheme 11

(a) RC0 ₂ Na ♦ (CH3) ₃ CC0 ₂ CH ₂ Br — > C0 ₂ CH ₂ OCOC(CH3 3

10 Α G. Francheεchi et al., J. Antibiotics. 6., (7),

918-941 (1983).

(b) RC0 © ₂ «• (CH ₃ )2NCONCCH3) ₂ ♦

RC0 ₂ fCHOCO IC(CH ₃ )3 £7 J. Budavin. U.S. Patent 4.440.942

68

B. Daehne et al., G.B. Patent 1.290,787

€9 Ferreε. Chem. Ind.. 435-440 (1980)

70

SUBSTITUTE SHEET

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

In equations a-e:

Compounds of Formula I where R ¹ 1s -C(CF3)2θH may be prepared as shown n Scheme 12.

w*rf - * .*- ^Λ

SOBSΪiϊϋϊ^ Sri

Scheme 12

Jϊ, 72

Hexafluorolsopropanol compounds (72) may be prepared by treatment of arylsllane (71) with 1-5 equivalents of hexafluoroacetone 1n a solvent such as methylene chloride at temperatures ranging from about -50° to 25°C for a period of 2-10 hours. The requisite arylsllane (7_I) can be prepared using methods known to one skilled 1n the art such as the procedures described 1n Chapter 10 of Butterwort 's "Silicon 1n Organic Chemistry".

SUBSTITUTE SHEET

47 Scheme 13

47

SUBSTITUTE SHEET

As shown 1n Scheme 13. compound (73) in which X= -NHCO and R ¹³ = -C00H may be easily prepared, for example, by reacting aniline precursor (63) with a phthalic anhydride derivative in an appropriate solvent such as benzene, chloroform, ethyl acetate, etc. Often the carboxylic add product will precipitate from solution with the reactants remaining behind, M.L. Sherrill, F.L. Schaeffer, E.P. Shoyer, J. Am. Chem. Soc. 50, 474 (1928). When R ¹³ =NHS0 ₂ CH3, NHS0 ₂ CF ₃ or tetrazolyl (or a variety of.other carboxylic acid equivalents), compound (73) may be obtained by reacting aniline (61) with the requisite acid chloride by either a Schotten-Baumann procedure, or simply stirring in a solvent such as methylene chloride in the presence of a base such as sodium bicarbonate, pyridine, or triethylamine.

Likewise, aniline (63) may be coupled with an appropriate carboxylic acid via a variety of amide or peptlde bond forming reactions such as DCC coupling, azide coupling, mixed anhydride synthesis, or any other coupling procedure familiar to one skilled in the art. Aniline derivatives Q53) will undergo reductive amination with aldehydes and ketones to form secondary amines (74). Thus the aniline is first stirred with the carbonyl compound 1n the presence of a dehydration catalyst such as molecular sieves or p-toluenesulfon1c acid. Afterwards the resultant Imine is reduced to the amine with a borohydrlde reducing agent such as sodium cyanσborohydride or sodium borohydrlde. Standard catalytic hydrogenation reagents such as hydrogen and palladium/carbon can also be employed.

Alternatively, aniline (63) may be monoalkylated by reaction with ethyl formate followed by reduction with, for example, lithium aluminum hydride to produce the N-methyl derivative (74). Anilines (74) may in turn

50 Scheme 14

79

49 be reacted with carboxylic add anhydrides and add chlorides or carboxylic acids by any of the coupling procedures described previously to yield (.73) where X= -N(CH3)C0-. Aniline (63) or (74) or other Intermediate anilines where the amino group may be located on another aromatic ring for example, also react with other anhydrides to make amide-carboxyllc acid derivatives of formula (7_5) . Thus, for example, maleic anhydride, 2,3-naphthalenedicarboxylic add anhydride, and diphenic anhydride are reacted in a similar fashion to phthalic anhydride with aniline (63) or (74) to yield carboxylic acids (76), (77), and (78), respectively.

Phthalimide derivatives of aniline (62) may be made by a variety of methods, preferably by stirring aniline (63) with phthalic anhydride ,1n acetic acid at a temperature between 20°C and reflux, G. Wanag, A. Veinbergs, Ber., 75, 1558 (1942), or by stirring (63) with phthaloyl chloride, a base such as triethylamine, and an inert solvent.

Aniline (63) may be converted into its tr1- fluoromethanesulfonamlde derivative or its trlfluoroacetamldo derivative preferably by reacting 1t with triflic anhydride or trlfluoroacetic anhydride and a base such as triethylamine in an Inert solvent such as methylene chloride at -78°C followed by warming to room temperature.

Compounds of structure (I) where X is a carbon- carbon linkage which are depicted as (80) can be made as shown in Scheme 14.

49

Scheme 14 (continued) e)

Equation a) illustrates that the b1phenyl com- pounds (80) can be prepared by alkylation of imidazole (I) with the appropriate halomethylbiphenyl compound (.79) by the general procedure described in Scheme 1. The requisite halomethylbiphenyl intermediates (79) are prepared by Ullman Coupling of (81) and (82) as described in "Organic Reactions", 2, 6 (1944) to provide intermediates (83), which are in turn halogenated. Halogenation can be accomplished by refluxing (83) 1n an Inert solvent such as carbon tetrachloride for 1-6 hours 1n the presence of a N-halosucdnim1de and an initiator such as azob1s1sobutyron1trile (equation b).

As shown in equation c), derivatives of Inter¬ mediate (83) 1n which R ¹³ 1s at the 2' position (83a) can also be prepared by the method described in Orα. Chem.. 41, 1320 (1976), that 1s D1els-Alder addition of a l,3-butad1ene to a styrene (84) followed by aromatizatlon of Intermediate (85).

Alternatively, the substituted blphenyl precursors (83; where R ¹³ = C00H) and their esters (89) can be prepared as illustrated 1n equation d), which involves oxazoline compounds as key Intermediates, A. I. Meyers and E. D. Mlhellch, J. Am. Chem. Soc. 97, 7383 (1975).

SOOSTiTiJTE SHEET

Further, as shown 1n Equation e), nickel- catalyzed cross-coupling of an arylzlnc halide with a halobenzonltrlle yields a b1phenylnitrile which can In turn be hydrolyzed by standard methods to afford add 88-

The substituted blphenyl tetrazoles (83; where

R 13s can be prepared from the nitrile precursors (R ¹³ *CN) by the methods described 1n Scheme 1. equation c) and Scheme 15. equation c).

However, a preferred method for preparing tetrazoles is described 1n Scheme 15. equations a) and b). Compounds (90) may be prepared by the l,3-d1polar cycloaddltlon of trlalkyltin or trlphenyltln azldes to the appropriately substituted nitrile (£1) as 1n equation a). Alkyl 1s defined as normal alkyl of 1-6 carbon atoms and cyclohexyl. An example of this technique 1s described by S. ozima, et al., ι _ OrαanometalUc Chemistry. 337 (1971). The required tri lkyl or tr1 ryltin azldes are made from the requisite commercial trlalkyl or trlaryl tin chloride and sodium azide. The trlalkyl or trlaryltln group Is removed via addle or basic hydrolysis and the tetrazole can be protected with the trltyl group by reaction with trltyl chloride and trlethylamlne to give (ϋ). Brominatlon as previously described herein with N-bromosucclnlmlde and dlbenzoylperoxide affords compound (92J. Alkylation of (1) with the appropriately substituted benzyl halide using conditions previously described followed by deprotectlon of the trltyl group via hydrolysis affords (80; R ¹³ = tetrazole). Other protecting groups such as p-nitrobenzyl and 1-ethoxyethyl can be used Instead of the trltyl group to protect the tetrazole moiety.

These groups as .11 as the trltyl group can be Introduced and removed by procedures described In Greene, Protective Groups 1n Organic Synthesis. Wiley- Intersdence, (1980) .

Scheme 15

83 (R ¹³ -CN) 90 F ■ alkyl of 1 to 6 carbon **"' atoms , phenyl

91 §2

C

63 _8 a

SUBSTITUTE SHEET

Compounds of structure 93-95 where X is an -0-, -S-, or - linkage can be prepared as shown

1n Scheme 16 by alkylation of Imidazole (I) with the appropriate benzyl halide (96).

Scheme 16

^3; -0

94; X-S

"9s; X-BE ²⁶

The halomethyldiphenyl ether (109) employed as an alkylating agent in the present invention is prepared as shown in equation b) . An Ullman ether condensation of the phenol (97) and a halobenzoic acid as described 1n Russian Chemical Reviews. 43, 679 (1974) provides the Intermediate acid (101). The conversion of (101) Into (109) 1s accomplished by esterification with diazomethane to afford (105) followed by halogenation employing the procedure used 1n the preparation of (79). The diphenylsulfide (110) and the dlphenylamine (111) can be prepared from the appropriate thiophenol (98) or aniline (99) by this procedure.

The tertiary dlphenylamine (112) can be prepared from the secondary aniline (100) by the above procedure. Alternatively (107) can be alkylated by one of the following procedures: 1) direct alkylation of (107) with R ²⁶ L where L is a leaving group such as a halogen or tosylate employing phase-transfer conditions and ultrasound as described in Tetrahedron Letters. 24, 5907 (1983), 2) treatment of (107) with 1-1.5 equivalents of an appropriate aldehyde and 0.5-5.0 equivalents of sodium cyanoborohydrlde in a solvent such as methanol at 25°C at a pH of 3-6 for 1-24 hours, or 3) reductive amination of (107) employing an appropriate carboxylic acid and sodium borohydrlde as described In jh Am. Chem. Soc. 96, 7812 (1974). The tertiary amine (108) is then halogenated by the procedure previously described to give (112).

Scheme 17

1 _. 4; x" - J- D^, X - h-Otfl ^β ^115, j» _m a-CD _j CB _j . X • ■ 73a

113 I X .1*3* - a-CD _j CH _j

116

SUBSTITUTE SHEET

Compounds of structure (73) where X is -CO- are prepared as shown in Scheme 17 by alkylation of imidazole (i) with the requisite benzoylbenzyl halides. For example, esters (113) where R ¹³ is 2-CO2CH3 are prepared by alkylation of imidazole (1) with carbomethoxybenzoyl benzyl halide (114). Ester (113) may be hydrolyzed to the corresponding carboxylic add (116) by a variety of methods including hydrolysis with a base such as sodium hydroxide or potassium hydroxide in an alcoholic aqueous solvent such as methanol/H2O at a temperature from 20°C to the reflux temperature of the solvent.

Carboalkoxybenzoylbenzyl halides (114) are prepared by benzyl1c halogenation of the corresponding to!uoylbenzene precursor by a variety of methods previously described herein. For example, methyl 2-(4-methylbenzoyl)benzoate (115) can be refluxed for 2-48 hours with N-bromosucc1n1m1de, benzoyl peroxide and carbon tetrachlorlde to effect benzyl1c bromlnation.

58

SUBSTITUTE SHEET

Scheme 18

As shown 1n Scheme IB the toluoyl ketones (73; where X=C0) may be further transformed Into a variety of ketone derivatives Including compounds where X Is

NR ²⁵ R ²⁹ 0 OR ³⁰ OCOR ¹⁷ OR ¹⁴

W I I -C- , -C- , -CH , and -C- .

Reaction of ketone (73a) with a hydroxyl mine or an appropriately substituted hydrazlne will give the requisite oxlmes (117) and hydrazones (118). Reaction with alcohols 1n the presence of an a dle catalyst with removal of water will give ketals (119). Reduction, with lithium aluminum hydride, a metal borohydrlde, zinc/acetic add or catalytic hydrogenatlon will give the corresponding alcohol (120) or fully reduced methylene compound (121). These alcohols may be acylated by a variety of anhydrides or add halides In the presence of a base with or without solvent to give the corresponding esters (122). The alcohols (120) may be converted Into their corresponding ethers (123) by reaction of the metal alkoxlde with an alkyl halide, mesylate or tosylate In the appropriate solvent or by treatment with a mineral add 1n an alcoholic solvent, or by reaction of the alcohol with dlazomethane as described in G. Hllgetag and A. Martini, "Preparative Organic Chemistry", John Wiley, New York, 355-368 (1972).

Compounds of formula (I) where X is -OCH2-, -SCH2-, and -NHCH2- are prepared as shown 1n Scheme 19.

Scheme 19

63 130

As Illustrated 1n Scheme 19. equation a., hydrolysis of benzyl ether (124) or methyl ether (125) affords hydroxy compound Q26) which can be alkylated with the appropriate benzyl halide to give (127). In 5 the case of the methyl ethers (125). the hydrolysis step can be effected by heating the ether at temperatures of 50 ^β -150 ^β C for 1-10 hours In 20-60% hydrobromic acid, or heating at 50 ^β -90°C 1n acetonltrlle with 1-5 equivalents of trimethylsllyl Iodide for 10-50 hours followed by

10 treatment with water. Hydrolysis can also be carried out by treatment with 1-2 equivalents of boron trlbro ide in methylene chloride at 10*-30 ^β C for 1-10 hours followed by treatment with water, or by treatment with an acid such as aluminum chloride and 3-30

15 equivalents of a sulfur-containing compound such as thiophenol, ethanedlthiol, or dimethyl dlsulflde In methylene chloride at 0-30*C for 1-20 hours followed by treatment with water. For compound (124) _f hydrolysis can be accomplished by refluxing in trlfluoroacetlc acid

20 for 0.2-1 hours or by catalytic hydrogenolysls In the

-v. presence of a suitable catalyst such as 10% palladium on carbon. Deprotonatlon of (126) with a base, such as sodium methoxlde, sodium hydride or the like In a solvent such' as dimethylformamide or dimethylsulfoxide

25 at room temperature followed by alkylation with an appropriate benzyl halide at 25*C for 2-20 hours affords ethers of formula (127). as shown 1n equation a.. The sulflde (129) can be prepared from the thiophenol (45) by the procedure described above to

30 prepare the ether (127) from the phenol (126). The thiophenol (J5) can be prepared for example by treatment of the benzylsulflde (128) with sodium 1n liquid ammonia.

The amine (130) can be prepared as shown In

35 equation c, from the aniline (63), Itself available from

which has previously been described. The reductive aminatlon can be carried out by the same procedure as described 1n Scheme J_3 for the preparation of compound (74).

Compounds of Formula (I) where the X linkage Is -CH=CH-, -CH2CH2-, and \ are prepared as shown In Scheme 20. / \

Scheme 20

133

134

The cis or trans stilbene (132) can be obtained by employing a Wittlg reaction between the aldehyde (5_7) and the phosphorane (131).

The stilbene (132) can readily be converted to the saturated derivative (133) for example by catalytic hydrogenation employing a heterogeneous catalyst such as palladium/carbon or platinum/carbon or alternatively with a homogeneous catalyst such as trlstriphenylphos- phine rhodium chloride. The reduction is performed in a solvent such as benzene, tetrahydrofuran or ethanol at 25°C under 1-3 atmospheres of hydrogen for 1-24 hours.

The cyclopropane (134) can be prepared by treating the stilbene (132) with the Simmons-Smith reagent as described in J. Am. Chem. Soc. 81, 4256 (1959), or by treating (132) with methylene diiodide and copper powder as described in J. Am. Chem. Soc. 101. 2139 (1979), or by treatment with the iron-containing methylene- transfer reagent described in J. Am. Chem. Soc. 101, 6473 (1979). The preparation of compounds of formula (I) where X is -CF ₂ CH2~, -CF=CH-, -CH=CF-, -CF=CF- and -CF ₂ CF - are depicted in Scheme 21.

64

'

Scheme 21

•) AxccB _j Xr* ♦ tt ₂ usr _i — -— ^■ * ^■ Arcf _a cι ₂ xr ^l

137

? . CH.Ci. . b) λrCH^CAr* ♦ rt ₂ NS_F ₃ — * ArCH _j CT _j Ar*

140

■?* ι CH,C1, e) ΛrCCHAx ^{1 •} ♦ tt ₂ KSr ₃ - *- * > Λx T ₂ tTΛz ^l

143

00 ) λrCCλr ¹ ♦ r ₂ Mf ₃ ^ ArCf _a Cr ₂ Xr ^,

144 145

SUBSΪIΪΪIϊc SHE

Vinylene fluorides (137) and (140) can be prepared by reaction of SF4 or Et2NSF3 (DAST) with the appropriate ketone (135) or (138) in which Ar bears a methyl group convertible to a benzyHc halide suitable for attachment to an imidazole nitrogen, and Ar' bears a cyano, nitro, ester, or other suitable group which can be subsequently converted to CO H, NHSO2CF3, etc. The initially formed difluoroethylene (136) and (139) can be formed in a non-polar solvent such as methylene chloride and subsequently converted to the vinylene fluoride by means of alumina, or converted directly into the unsaturated fluoride by running the reaction in a polar solvent such as tetrahydrofuran, diglyme or N- ethylpyrήolidone in the presence of mineral acid. [Equations a and bj. Experimental details of such procedures are found 1n D.R. Strobach and 6.A. Boswell, J. Orα. Chem.. 36, 818 (1971); G.A. Boswell, U.S. Patents 3,413,321 (1968) and 4,212,515 (1980).

As shown 1n equation c) an appropriate benzoin (141) may be similarly converted to the corresponding 1,2-difluorostilbene (143). Likewise as shown in equation d) an appropriate benzil (144) can be converted to a tetrafluorodiarylethylene (145) using DAST or SF4. Experimental details are described in M.E. Christy, et al., J. Med. Chem.. 20, (3), 421-430, (1977).

R ²³

Compounds of formula 1 where X ~ -CON-, -CH ₂ 0-, -CH2S-, -CH2NH-, can be made as shown in Scheme 22.

67 Scheme 22

SUBSTITUTE SHEET

As previously described, acid Qo) can be made 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. Compound (10) can be converted to

(148) by reaction with the requisite amine (146) (R ¹³ may need to be protected and subsequently deprotected) and dicyclohexyl carbodϋmide (DCC) 1n methylene chloride [J. R. Beek, et al., J. Am. Chem. Soc. 90, 4706 (1968)] or by reaction with tosyl chloride in pyridine [J. H. Brewster and C. J. Ciotti, Jr., J___ Am. Chem. Soc. 77, 6214 (1955)]. Yet another process involves conversion of carboxylic acid (10) to its acid chloride with, for example, thionyl chloride followed by reaction with the amine in aqueous base (Schotten-Baumann conditions) or in an organic solvent in the presence of an acid scavenger such as NaHC03, pyridine or triethylamine, or by other procedures known to form an amide bond between an aromatic acid and an amine. The compounds where X= -CH2O-, -CH2S-, and -CH2 H2- can be made as shown in pathway b. The ester

(149) is reduced with a reducing agent such as lithium aluminum hydride in an inert solvent to form the alcohol (150) which, can then be reacted with tosyl chloride in pyridine to form tosylate (151) . which is in turn reacted 1n the presence of base with a corresponding phenol (152) thiophenol (153). or aniline (146: where R ²³ =H) to form compounds (154). (155) or (156). Again this may require that R ¹³ be protected with a suitable protecting group, however modifications necessary because of specific functional groups are understood to be incorporated by one skilled in the art of organic synthesis.

SUBSTITUTE SHEET.

Alternatively, the alcohol (150) can be converted to the corresponding halide with SOCI2, (C0C1)2, etc, and the resulting halide can then be reacted with a phenol, thiophenol or aniline 1n the presence of base to form the desired compound, where X is -CH2O-, -CH2S-, -CH2NH- respectively.

Scheme 23

SUBSTITUTESHEET

Compounds of Formula (I) where X= -SO2NR ²³ - and -NR ²³ Sθ2- may be prepared as shown in Scheme 23. As shown in equation a, sulfonylchloride derivative (157) can be reacted with aniline derivative (158) in a solvent in the presence of an acid scavenger such as sodium bicarbonate, triethylamine or pyridine or under Schotten-Bau ann like conditions to give (159). Sulfonylchloride derivative (157) can be obtained by sulfonation of the corresponding benzyl derivative as described earlier, followed by reaction with PCI5 or POCI3. Likewise, aniline (74) may be reacted in the same manner as described above with sulfonylchloride derivative (160) to give (161).

Scheme 24 shows the preparation of furan analogs of the biphenyl compounds (80). Thus, o-ketoester (162). W. Wierenga and H. I. Skulnick, J. Orα. Chem.. 44, 310 (1979), or the corresponding nitrile (E=CN) can be easily alkylated via standard procedures already mentioned by an alkyl bromide derivative to give (163). The alkene moiety of (163) can be subsequently cleaved by oxidation, for example, with osmium tetroxide, Fieser and Fieser, V.l, p. 812 (Lemieux-Johnson oxidation) to yield dicarbonyl-containing compound (164). Cyclization in mineral acids, acidic ion-exchange resin, P0Cl3/pyridine, ^" or trifluoroacetic anhydride with a catalytic amount of trifluoroacetic acid yields furan (165; Z=0). Reaction of (164) with P4S10, for example, will yield the corresponding thiophene (165; Z=S). Reaction of (164) with an amine In refluxing benzene, with azeotropic removal of water or by using molecular sieves to absorb the water will yield the corresponding pyrrole (165; Z=NR ¹¹ ). Compounds (166) may be prepared from (165) by standard procedures already described.

Sffisππiic SHE

71

163

166 11

2-0. S. MB

Compounds wherein a methylene group is inserted between the terminal aromatic ring and the acidic functionality may be prepared as shown in Scheme 25. equation a). Thus reduction of ester (167) with, for example, lithium aluminum hydride, gives alcohol (168). Conversion of (168) to the chloride (169) via thionyl chloride followed by reaction with cyanide anion as previously described yields nitrile (170). Compound (170) may be hydrolyzed to carboxylic acid (171) by methods already described or reacted with a hydrazoic add equivalent to produce tetrazole (172).

Compounds wherein R ¹³ is a trlfluoro ethylsul- fonyl hydrazide acidic functional group were prepared by the procedure described in equation b) . That is, conversion of ester (167) to the hydrazide (173) by standard hydrazinolysis followed by reaction with triflic anhydride affords hydrazides (174).

.Tf-

ΛiKiff u *-

swise SHEET

The syntneses of compounds wherein R ¹ ^ Is substituted and unsubstituted 1,2,3-trlazoles are described 1n Scheme 2_i- Thus reduction of ester (175) with a reducing agent such as lithium aluminum hydride or dilsobutylaluminum hydride gives alcohol (176).

Oxidation with Mnθ2 or pyr1d1n1um chlorochromate converts (176) Into aldehyde (177). Nltroethylene derivative (178) Is prepared by condensation of aldehyde

(177) with nltromethane 1n the presence of a catalyst, R. . Letcher and M. P. Sammes, _J . Chem. Ed.. 62, 262

(1985). Reaction of (178) with sodium azide produces the 1,2,3-trlazole (179). (N. S. Zeflrov, et al.. jL Chem. Soc. Chem. Comm.. 1001 (1971)) which may be transformed via procedures already described Into product (180).

Aldehyde (177) can also be converted Into substituted 1,2,3-trlazoles (183) via the sulfone (181).

G. Beck, D. Gunther Chem. Ber. . 106. 2758 (1973), followed by reaction with sodium azide to give the 1.2.3-triazo e (182). Subsequent standard manipulations lead to 1,2,3-trlazoles (183) where E=CN and C0 ₂ R ⁿ .

The nltrotrlazole (183: E*N02) may be synthesized from the unprotected triazole (122; P*H) via nitration,

R. Huttel, et al., Chem. Ber. . 88, 1586 (1955), C. L. Habraken and P. Cohen-Fernandes J. Chem. Soc. 37

(1972), or from bromonltroethylene derivative (184). G.

Kh. hisamutdlnov, et al., Zh. Orα. Kh1m.. Hi 2445

(1975), by reaction with sodium azide.

A variety of protecting groups may be used 1n the manipulation of the above trlazoles, amongst which 1s the trltyl group. This group may be easily attached by reaction of the triazole with tri henyl ethyl bromide or chloride 1n an Inert solvent such as methylene chloride

In the presence of an add scavenger such as triethyl amine. The trltyl group may be later removed by

stirring or refluxing 1n an acidic medium such as tri fluoroacetic acid/water, HCl In methylene chloride, or acetic add/water. The trltyl group may also be hydrogenolyzed using a noble metal catalyst such as pal ladium and hydrogen.

P = protecting group

183

76

WΛSΠΠJIE SHEE

The synw..<s1s of tr1fluoromethyl-l,2,4-tr1azc ,s

(190) Is depicted 1n Scheme 21- Add chloride (186) Is converted to amide (187) using standard procedures familiar to one skilled In the art. A preferred protecting group 1s the 2-prop1on1tr1le group

(P=CH2CH ₂ CN). Thus (182; P=CH ₂ CH ₂ CN) can be synthesized from (186) and /7-am1noprop1on1tr1le under Schotten-

Baumann like conditions, using aqueous base in an organic solvent to help solublltze (186) and (187). Amide (187) 1s converted to amldrazone (188) by reaction with PCI5 or phosgene to make an Iminoyl chloride which then 1n turn 1s reacted with excess hydrazlne.

Amidrazone (188) . s cycl1zed to the trlfluoromethyl-

1,2,4-triazole (189) with trifluoroacetic anhydride and then converted to 190 via bromlnatlon, alkylation and deprotection as previously described.

c eme

V « pro

Pertinent R ⁶ groups may be variously Introduced by many procedures Including those described 1n Scheme 28 which describes Imidazole construction.

The R ⁶ groups so Introduced may stand unchanged or may be further elaborated If appropriately functional1zed, according to methods familiar to those skilled 1n the art such as are illustrated In Scheme 28.

in o © tn tn

The 2-alkenylImidazoles (201) can be prepared by brominatlon of the 2-alkylImidazoles (]_99) followed by elimination of hydrogen bromide. The brominatlon Is preferably accomplished by UV-Irradiation for 1-4 hours of Imidazole (199) and N-bromosucc1n1m1de, n an Inert solvent, such as carbon tetrachlorlde at 25*C. Treatment of the Intermediate bromide (200) with a base, such as DBU, tr1ethylam1ne, or potassium t-butox1de, affords the trans 2-alkenylImidazoles (201). Cls al enyl derivatives (203) are prepared from the trans alkenyl compounds by treatment with osmium tetroxide and sodium periodate to afford aldehydes (202) followed by Wittig reaction.

5

5

0

5

bromination

* - alkyl. cycloalkyl

2-methyl1m1dazole followed by addition of an appropriate electrophlle as Illustrated In Scheme 30. equations a.) and b). The products (alcohols, esters, halides, aldehydes, alkyls) are suitable for further elaboration by methods familiar to those skilled In the art. Metallation of Imidazoles 1s described 1n K.L. Kirk, ^ Orα. Chem.. 43, 4381 (1978); R.J. Sundberg, J. Het. Chem.. 14, 517 (1977); J.V. Hay et al., J. Orα. Chem.. 38, 4379 (1973); B. Iddon, Heterocv les. £3, 417 (1985). Condensation of 2- ethylImidazole and appropriate electrophlles (equation b) with catalytic add or base as described In A.R. Katrltzky (Ed.), "Comprehensive Heterocycllc Chemistry", Vol. 5. p. 431, Peroamon Press. N.Y., 1984 affords products wherein R(_ 1s alkenyl which are suitable for further elaboration.

₂₀ J£| 1 (where R ⁷ -R ^β .H>

209

Various 2-substltuted Imidazoles can be prepaid by reaction of a protected 2-tr1methylsilylImidazole with a suitable electrophlie by the method described by F.H. Pinkerton and S.F. Thames, J. Het. Chem.. £, 67 (1972), which can be further elaborated as desired. Alternatively, R ⁶ may also be Introduced by nickel catalyzed cross-coupling of Grlgnard reagents with 2-(methyltbio)imidazoles (Scheme 31) as described by E. Wenkert and T.W. Ferrelra, J. Chem. Soc. Chem. Commun.. 840, (1982); E. Wenkert et a , J. Chem. Soc. Chem. Commun.. 637, (1979); and H. Suglmura and H. Takel, Bull. Chem. Soc. Japan. 58, 664 (1985). The 2-(methylthio)imidazoles can be produced by the procedure described 1n German Patent No. 2,618,370 and the references dted therein.

Scheme 31

• KmNarCSc _ ^• +_.

210 R

211

^R IϊiCl ₂ (cTppp)

212 213

As shown In Schemes 32-36. elaboration of R ⁸ can be accomplished by some of the procedures described in Schemes 3 and 2JJ, by chain extension reactions familiar to those skilled In the art, or by degradation reactions such as conversion of an ester to an add or an alkene to an aldehyde.

Specifically, the hydroxymethyl group can be activated for the displacement reaction by reacting with thionyl chloride, PCI5 or with carbon tetra- chloride/trlphenylphosphlne to form a corresponding chloro derivative. By a similar reaction bromo and 1odo derivatives can be obtained. The hydroxymethyl group can also be activated by forming the corresponding p- toluenesulfonate, methanesulfonate and trlfluoromethane sulfonate derivatives.

As shown 1n Scheme 32. the hydroxyl group cai. e converted to thlolacetlc add derivative (215). J. Y. Gauthier, Tet. Lett.. 15 (1986), and to thiol derivative (216) by subsequent hydrolysis. The hydroxymethyl group on compound (17) can be readily oxidized to an aldehyde group by means of manganese dioxide or eerie ammonium nitrate. The aldehyde group will undergo chain extension reactions such as the WUt g and Wittlg-Horner reactions and enter Into typical carbon-carbon bond forming reactions w th Grlgnard and lithium reagents as well as with compounds bearing activated βethylene groups. Alternatively, the hydroxymethyl group can be oxldl∑ed directly to an add functionality which can 1n turn be converted to ester and amide derivatives. The esters and amides can be prepared directly from the aldehydes by manganese dioxide oxidation 1n the presence of sodium cyanide and an alcohol or amine, J. Am. Chem. Sec. 90, 5616 (1968) and J. Chem. Soc (C), 2355 (1971). As shown 1n Scheme 33. the chlorine on compound (j>) can be displaced by the anion of dialkyl malonate to give the corresponding malonate derivative (217). The saponlfication of (217) with NaOH (or KOH) gives the corresponding diadd which can be decarboxyiated to give the corresponding proplonic add derivative (218) by heating to 120 ^β C. Alternatively, (218) can be directly obtained by refluxing (217^ with a mineral add such as HCl or sulfurlc add. The free add (218) can be esterified by heating 1n a medium of the various alcohols and a catalytic amount of mineral adds such as HCl or sulfurlc add to give the corresponding esters (219). Alternatively the esters can be obtained by reacting the free acid (218) and the corresponding alcohols 1n the presence of coupling reagents such as DDQ or EEDQ. A similar reaction with various mono-

substituted and disubstituted amines produces the corresponding amides (220). A similar reaction with various mercaptans produces the corresponding thloesters.

Scheme 33

As shown in Scheme 34., the chloro group on (2»j can be displaced by the sodium salt or potassium salt of the alkyl, aryl or arylalkyl mercaptans to give the corresponding sulflde derivatives (221). The amine derivative (222) can be obtained by treating (2j>) with ammonia or with the corresponding mono-substituted amines. Alternatively, the chloro group may be dis¬ placed ^' by sodium azide to give an azide Intermediate which upon reduction with H£ over a noble metal catalyst or with a reducing agent such as chromous chloride (W. K. Warburton, J. Chem. Soc. 2651 (1961)) yields (222) where R-° and R ¹¹ are hydrogen. This amine can be subsequently alkylated with alkyl halides, or reductively alkylated with aldehydes and ketones to give alkyl derivatives of (222). The amines (222) are converted to the corresponding carbamates (224). sulfonamides (2251. amides (226) or ureas (227) by standard procedures illustrated 1n Scheme 34. and familiar to one skilled 1n the art.

224 725 226

Scheme 34 (Cont'd)

227

The reaction between the thlopyrldyl ester (229) and a suitable Grignard reagent produces the ketones (230).

Scheme 35

alkyl.

229 (R = pyridyl) /

As shown 1n Scheme 36 when the Imidazole 4- and/or 5-position contains an aldehyde (231) then reaction with organometallic reagents such as Grignard or alkyl /aryl lithium reagents will yield alcohols (232) which 1n turn may be transformed Into a variety of other functionality familiar to one skilled in the art.

232

As shown 1n Scheme 37. ester £34 may be obtained by direct oxidation of aldehyde 233 with NaCN, Mn0 In methanol (Corey, E. J., et al. J. Am. Chem. Soc. (1968) £0, 5616). Oxidation of 2J3 with NaCN, Mnθ2, and an amine 1n 2-propanol leads to the corresponding amide 22£ (Gllman, N. W. Chem. Comm. (1971) 733).

U 90/03683 Scheme 37

234

233

•Λ R *= alkyl

235 R' or R" = H or alkyl 236

ΛΛ «Λ

Saponlfication of ester £34 win leaα to carboxylic add 236.

Aldehyde £33, 1n turn, may be made from the corresponding alcohol J7 by a variety of methods familiar to one skilled 1n the art, Including pyrldiu chlorochromate (PCC), Swern and eerie ammonium nitrate (CAN) oxidations.

Likewise, the unalkylated hydroxymethylImidazole derivative 1(R ⁸ =CH20H) may undergo the transformations to the aldehyde, ester, carboxylic acid and carboxamlde by the reactions mentioned above for the alkylated case.

phenoxyphenyl, or a heteroaryl group as described In the scope under the definition of R ⁷ ) can be prepared by the coupling of an arylmetal derivative (ArM, where M=ZnBr, Me3Sn, B(0H)2, etc.) with a halolmldazole £37 1n the presence of a transition metal catalyst such as palladium, nickel, platinum, zirconium, etc (Scheme

38a). Alternatively an Imidazole metal derivative £39 can be coupled to an arylhalide to prepare £38 (Scheme 38b).

The arylmet yl derivatives 240 can be prepared employing the transition metal catalysed coupling of £32 and an arylmethylrøetal (ArCH2M' , where M'=ZnBr, etc.), as shown 1n Scheme 38c Compounds 241 may be prepared, as described In Scheme 38d, by the coupling of an alkenyl- or alkylnylmetal derivative (AM) or the corresponding alkene or al yne (AH) with 237.

Likewise, the unalkylated Imidazoles (1, where R ^7s Br or I) may undergo the coupling reactions described 1n Scheme 38a-d [For references to transition metal catalysed coupling reactions, see: Richard C. Heck, Palladium Reagents 1n Organic Synthesis, Academic Press, New York, Chapters 6, 7, and 8; and references cited therein.]

The compounds of formula I where R ⁷ Is an alkynyl group, a substituted alkynyl group, or a substituted alkenyl group and the carbon-carbon double or triple bond 1s not adjacent to the Imidazole ring (e.g., R ⁷ =(CH2) CH=CH(CH2) »\ *tere v≠O) can be prepared by a variety of chain elongation methods and chain coupling reactions known to one skilled 1n the art including those described 1n Schemes 3, 28, 29, 33, 35, 36, and 38.

substituted alkyl group (R ⁷ =(CH2) _w Ar, where w=2-10) can be prepared by reduction of the corresponding alkenes

(241) by catalytic hydrogenation.

96

239

240

^■ »» ^■ " fϊj

^■ >' ^. "«* S//££r

c eme .

CsC(CH ₂ ) _y CH _{3 15} CsC(CH2) _x Ph ^*

C-«C(CHώcAr

Ph '-phenyl or substituted phenyl

20 x * 0-8 y = 0-7 z * 0-4

25

30

35

arylalkenyl and R ^{8 ■} CH2OH, aldehyde, or C00H can be prepared as shown 1n Scheme 39.

2-Alkyl1m1dazole-4,5-d1carboxyl1c acids (242). prepared by the method of R.G. Fargher and F.L. Pyman ^'

(J. Chem. Soc. (1919) 115, 217), can be converted Into their corresponding diesters (243) by simply refluxing

1n an alcohol solvent In the presence of an acid such as

HCl, or by many other methods familiar to one skilled 1n the art.

Diester (243) can then be converted Into Its metallic salt by reaction with sodium ethoxlde, sodium ethoxide, sodium hydride, potassium hydride or any other base in an appropriate solvent such as DMF. The resultant salt 1s then alkylated with the appropriately substituted benzyl derivative ( ) to yield benzylimidazole (244). The above alkylation sequence may be also performed by heating or refluxing the benzyl halide (tosylate or mesylate) (£) with Imidazole (243) in a solvent such as DMF In the presence of an acid scavenger such as potassium or sodium carbonate.

Diester (244) can be reduced with lithium aluminum hydride in an inert solvent such as THF to the corresponding dlalcohol (245). Selective oxidation of dialcohol (245) with manganese dioxide in an Inert solvent such as THF yields primarily aldehyde (247) with a minor product dialdehyde (246). Separation of (247) from (246) either by crystallization or chromatographlcally, followed by Wlttlg reaction of (247) with methylenetrlphenylphosphorane or the appropriately substituted arylalkylldenetrlphenyl- phosphorane 1n an Inert solvent such as THF yields the 4-alkenyl-5-hydroxymethyl1m1dazole (248). Further oxidation of (248) with the Dess-Mart1n perlodlnane G . Orα. Chem.. (1983) 48, 4155), with manganese dioxide, ^'

with pyridinium c oroc romate, with barium manganate or with other oxidants familiar to one skilled in the art,

1n an Inert solvent such as THF or methylene chloride followed by deprotectlon of either R-, R ² , or R ³ If necessary yields the 4-alkenyl1midazole-5-carboxaldehyde

(249).

Oxidation of (249) with, for example, manganese dioxide/cyanide ion (Corey, E.J., et al. J. Am. Chem,

Soc. (1968) 90, 5616) or with potassium permanganate (Sam, D.J. et al. J. Am. Chem. Soc. (1972) 94, 4024) yields 4-alkenyliroida2ole-5-carboxyl1c add (250).

Scheme 39

248 249 250

where T=H, y=H, (CH2) -Aryl or T and y taken together form a cyclic ring of 3-8 carbons and the regiochemistry about the double bond in 248, 249 and 250 can be Z or E.

Imidazoles represented by structure (251) where X

1s Cl, Br, or I and E Is an electron withdrawing group such as an ester, ketone, nitro, alkylsulfonyl, arylsulfonyl, etc., can undergo the nucleophlllc aromatic substitution reaction (H. Schubert, H. Slmoni

A. Jumar, _r Chem. (1968) 62-63) where the leaving group

X 1s substituted by a nucleophile such as sulfur, carbon,- or nitrogen to yield adducts (252) (Scheme 40).

The reaction can be done 1n hydroxyllc solvent such as methanol or non-hydroxylic solvent such as DMSO at room temperature to the reflux temperature of the solvent. The nucleophile sometimes must be converted into its anlon to make 1t more nucleophlllc. For example, thiophenol can be refluxed 1n methanol In the presence of sodium methoxlde and the haloi ldazole (251). Other nucleophiles include other alkyl and arylthlols, heteroarylthiols, thlolacetlc acid, alkyl and arylsulfonamides, heteroarylsulfυnamldes, diacylamlnes, alkyl and arylamines, heteroarylamines, etc., familiar to one skilled 1n the art.

If a sulfur nucleophile Is used, the resultant sulfides can be oxidized to the corresponding sulfoxides and sulfones by methods familiar to one skilled in the art.

251

252

The compounds of this invention and their preparation can be understood further by the following examples, which do not constitute a limitation of the Invention. In these examples, unless otherwise indicated, all temperatures are In degrees centigrade and parts and percentages are by weight.

PART A: Preparation of 2-n-Propyl-4,5- dicarbomethoxyimldazole.

2-n-Propyl1m1dazole-4,5-d1carboxyl1c add [prepared by the method of R.6. Fargher and F.L. Pyman (J. Chem. Soc, (1919) 115, 217), p 257 (dec.) ^# C] (17.14 g, 86.6 mmol, 1 eq), methanol (400 mi.) and acetyl chloride (38.1 mL, 534 mmol, 6 eq) were cautiously mixed (acetyl chloride addition to methanol is very exothermic) and refluxed overnight. The solvent was removed 1n vacuo and water (100 mL) and 10 N NaOH were added until pH=7. The aqueous mixture was extracted with ethyl acetate (3X), the organic layers combined, dried (MgS04) and the solvent removed In vacuo to yield 12.00 g of a white solid.

Recrystallization from hexane/ethyl acetate yielded 11.41 g of a white solid (58%); mp: 162.0-164.5 ^β C. NMR (CDC1 ₃ ) 63.95 (s,6H); 2.78 (t,2H); 1.83 (t of t, 2H,* 7,7Hz); 0.97 (t,3H,* 7Hz); IR (neat) 1735 cm- ¹ . Anal, calcd. for C]nHi4N2θ - ^» (H2θ)o.25 ^: C, 52.06; H, 6.28; N, 12.14. Found: C, 52.06; H, 6.17; N, 12.49.

Part B: Preparation of 4-Methyl-2'-(N-tr1phenylmethyl* (lH-tetrazol-5-yl))biphenyl

4'-Methylbiphenyl-2-n1tr1le (preparation described 1n European patent application 0253310, published on 20.01.88) (10.00 g, 51.7 mmol, 1 eq), trl- n-butyltin chloride (14.0 mL, 51.7 mmol, 1 eq), sodium azide (3.4 g, 51.7 mmol, 1 eq), and xylene (50 mL) were mixed and refluxed for 64 h after which the reaction mixture was cooled to room temperature. 10.0 N NaOH (6.10 mL, .061 mmol, 1.2 eq) and trltyl chloride (14.99 g, 53.8 mmol, 1.04 eq) were then added and the mixture stirred for 24 h after which water (39 L) and heptane (100 L) were added. The resultant slurry was stirred at 0 ^β C for 1.5 h. The resultant solids thus obtained were filtered, washed with water (2X 55 mL) washed once with 3:2 heptane/toluene (55 mL) and dried overnight under high vacuum to yield 19.97g of a light yellow powder: mp 148.0-155.0°C (dec). These solids were slurried in ethyl acetate (75 L) and filtered to yield 15.Og of a light yellow powder: mp 164.0-165.5 ^β C

(dec) . NMR (CDCI3) δ 7.91 (d, lH,J=9Hz) ; 7.53-7.18 (m, 13H) 7.02-6.84 (m,9H) ; 2.25 (s ,3H) .

PART C : Preparation of 4-Bromomethyl-2'-(N- tr1ρhenylmethyl -(lH-tetrazol -5-yl ))b1phenyl , a representative procedure.

4-Methyl-2'-(N-tr1phenylmethyl-(lH-tetrazol- 5-yl))biphenyl (52.07 g, 109 mmol, 1 eq), N- bromosuccinimide (19.4 g, 109 mmol, 1 eq), benzoyl peroxide (1.0 g) and carbon tetrachlorlde (300 mL) were mixed and refluxed for 2.5 h. The reaction was cooled to room temperature and the sucdnimlde filtered. The filtrate was concentrated and the residue triturated with ether to yield a first crop of 36.0 g: mp 129.5- 133.0°C (dec). NMR (CDCI3) δ 4.37 (O^Br). This material was suitable for further transformation.

PART D: Preparation of 4,5-dicarbomethoxy-2-n-propyl- l-[(2'-(N-tr1phenylmethyl-(lH-tetrazol-5- yl))b1phenyl-4-yl)ιnethyl]imidazole.

Sodium hydride (1.06 g, 44.2 mmol, 1 eq) was added to a solution of 4,5-d1carbomethoxy-2-n- propyl imidazole (10.00 g, 44.2 mmol, 1 eq) In DMF at room temperature. Foaming and gas evolution occurred. The temperature was Increased to 60 ^β C for 15 minutes to dissolve all of the sodium hydride. Gas evolution ceased and the mixture was cooled to room temperature. To this mixture was added a DMF solution of 4- bromomethy1-2'-(N-tr1phenyimethy1-(lH-tetrazol-5- yl))biphenyl (24.64 g, 44.2 mmol, 1 eq). After 24 h, the solvent was removed In vacuo, and the residue was flash chromatographed 1n 75:25 hexane/ethyl acetate to 100% ethyl acetate over silica gel to yield 15.78 g (51%) of a white glass which was suitable for further transformation. RecrystallIzation from ethanol yielded

an analytical sample (white crystals) ; mp: 124.0- 125.5 ^β C. NMR (CDCI3) δ 7.91 (d of d, lH,J=3,9 Hz) ; 7.59-7.20 (m, 12H) ; 7.09 (d,2H,J=9Hz) ; 6.94 (m, 6H) ; 6.76 (d,2H,J=9Hz) ; 5.30 (s,2H) ; 3.89 (s,3H) ; 2.50 (t, 2H,J=7Hz) ; 1.67 (t of t, 2H,J=7, 7Hz) ; 0.85

(t, 3H,J=7Hz) . IR (neat) 1718 cm ^"1 . Anal , calcd. for C ₄ 3H ₃₈ N ₆ 04 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-dlhydroxymethyl-2-n- propyl-l-[(2'-(N-tr1phenylmethyl-(lH- tetrazol-5-yl))biphenyl-4-yl)methyl]Imidazole,

4,5-Dicarbomethoxy-2-n-propyl-l-[(2'-(N- triphenylmethyl-(lH-tetrazol-5-yl))b1phenyl-4- yl)i))ethy1]Imidazole (9.88 g, 14.1 mmol, 1 eq) was dissolved 1n a minimum of THF and to this solution, lithium aluminum hydride (1.0 M In THF) (15.48 mL, 15.48 mmol, 1.1 eq) was slowly added dropwlse. The mixture was allowed to stir at room temperature overnight after which It was quenched by the Steinhardt procedure (Fieser & Fieser V.l, p.584) as follows: to the reaction mixture water (0.66 mL) was first carefully added followed by 15% NaOH (0.66 mL) followed by water (1.97 mL). After stirring for 72 h, a very

fine suspension of particulate had formed which was slowly filtered through Cellte™. The filtrate was dried ( S04) and the solvent removed j_n vacuo to yield 8.83 g of a yellow glass which could not be recrystallIzed. This Intermediate was suitable for further transformation. NMR (DMSO-de) δ 7.82 (d,lH,J=9Hz); 7.68-7.28 (m,12H); 7.05 (d,2H,J=9Hz); 6.87 (d,6H,J=9Hz); 5.16 (s,2H); 4.94 (t,lH,J=7Hz); 4.66 (t,lH,J=7Hz); 4.37 (d,2H,J=7Hz); 4.32 (d,2H,J=7Hz); 2.34 (t,2H,J=7Hz); 1.52 (t of q,2H,J=7,7Hz); 0.77 (t,3H,J=7Hz). IR (neat) 3300 br; 3061; 1027; 1006; 909; 732; 699 cm ^"1 . Anal, calcd. for C jH38N6θ2»H2θ: C, 74.07; H, 6.06; N, 12.64. Found: C, 74.06; H, 5.95; N, 11.86.

PART F: Preparation of 5-hydroxymethyl-2-π-propyl-l- [(2'-(N-triphenylmethyl-(lH-tetrazol-5- 1))biphen l-4-yl)methy1]1midazole- 4-carboxaldehyde and 2-n-propyl-l-[(2'-(N- tr1phenylmethyl-(lH-tetrazol-5-yl))biphenyl-4- y1)methyl]1midazole-4,5-dicarboxaldehyde.

4,5-Dihydroxymethyl-2-n-propyl-1-[(2'-(N- triphenylmethyl (lH-tetrazol-5-yl))b1phenyl-4- yl)methyl]imidazole (8.56 g, 13.2 mmol, 1 eq) was dissolved in a minimum of THF and added to a slurry of manganese dioxide (11.14 g, 128.1 mmol, 9.7 eq) in THF (100 mL) at room temperature. After 24 h, the contents were filtered through Celite™, the cake washed with THF, and the solvent of the filtrate removed i_n vacuo. The residue was flash chromatographed in 1:1 hexane/ethyl acetate to 100% ethyl acetate over silica gel to yield the dialdehyde which eluted first; 1.25 g (15%) of a tan glass. NMR (DMS0-d ₆ ) δ 10.27 (s.lH);

10.17 (s.lH); 7.81 (d,lH,J=7Hz); 7.68 (m,2H); 7.50-7.23 (m.lOH); 7.09 (d,2H,J=9Hz); 6.96 (d,2H,J=9Hz); 6.86 (m,6H); 5.59 (s,2H); 2.52 (t,2H,J=7Hz); 1.58 (t of q, 2H,J=7,7Hz); 0.77 (t,3H,J=7Hz) . IR (neat) 1697; 1672 cm ^*1 . Anal, calcd. for C41H34N6O2: C, 76.62; H, 5.33; N, 13.07. Found: C, 76.46; H, 5.54; N, 12.94.

Continued elutlon yielded the 4- hydroxymethylimidazole-5-carboxaldehyde product as a light yellow solid: mp 164.5-166.0°C. NMR (DMSO-dβ) δ 9.86 (s.lH); 7.80 (d,lH,J=9Hz); 7.63 (t,lH,J=9Hz); 7.53 (t,lH,J=7Hz); 7.50-7.25 (m.lOH); 7.07 (d,2H,J=9Hz); 6.97-6.80 (m,8H); 5.47 (t,lH,J=7Hz); 5.29 (s,2H); 4.63 (d,2H,J=7Hz); 2.37 (t,2H,J=7Hz); 1.49 (t of q,2H,J=7,7Hz); 0.73 (t,3H,J=7Hz) . IR (Nujol) 1688 cm- ¹ . Anal , cal cd. for C4iH36 6θ2 ^» (H2θ)n. ι ^: C, 76.16;

SUBSTITUTE SHEET

ill

H, 5.64; N, 12.84. Found: C, 76.02; H, 5.36; N, 12.84.

PART G: Preparation of 5-hydroxymethyl-2-n-propyl-l- [(2'-(N-triphenylmethyl-(lH-tetrazol-5- yl))biphenyl-4-yl)methyl]-4-vinyl-imidazole.

n-BuL1 (2.5 M in THF) (1.70 mL, 4.3 mmol, 2.1 eq) was added dropwise to a suspension of methyltri- phenylphosphoniurn bromide (1.53 g, 4.3 mmol, 2.1 eq) in THF (50mL) at 0°C under N2.

The suspension became a dark yellow solution. Afterwards, a solution of 5-hydroxymethyl-2-n-propyl-l- [(2'-(N-triρhenylmethyl-(lH-tetrazol-5-yl))biphenyl-4- yl)methyl]1midazole-4-carboxaldehyde (1.31 g, 2.0 mmol, 1.0 eq) in THF (minimum to dissolve) was added thereto and the resultant light milky yellow solution was stirred overnight at room temperature. The solution was diluted with ethyl acetate and washed with water (3X). The organic layer was dried (MgS04), the solvent removed 1n vacuo, and the residue flash chromatographed over silica gel in 1:1 hexane/ethyl acetate to yield 620 mg (48%) of a white glass: NMR (DMS0-d ₆ ) 57.79 (d,lH,J=7Hz); 7.62 (t,lH,J=7Hz); 7.55 (t,lH,J=7Hz); 7.45 (d,lH,J=7Hz); 7.41-7.18 (m,9H); 7.06 (d,2H,J=9Hz); 6.95-6.80 (m,8H); 6.80-6.55 ( .lH); 5.73 (d of

m i HEET

d,lH,J*-17,3 Hz); 5.17 (s,2H); 5.10 (t,lH,J=7Hz); 5.05 (d of d.lH.J-^.SHz); 4.28 (d,2H,J=7Hz); 2.37 (t,2H,J=7Hz); 1.50 (t of q,2H,J=7,7Hz); 0.78 (t,3H,J=7Hz). IR (neat) 1029; 1006; 909; 733; 698 cm- ¹ . Anal, calcd. for C^h^βNόO^O: C, 76.34; H, 6.10; N, 12.72. Found: C, 76.49; H, 5.88; N, 12.52.

PART H: Preparation of 2-n-propyl-l-[(2'-(N- triphenylmeth l-(lH-tetrazol-5- y1))biphen 1-4- 1)methy1]-4-v1ny1-1midazole- 5-carboxaldehyde.

5-hydroxymethyl-2-n-propyl-1-[(2'-(N- triphenylmethyl-(lH-tetrazol-5-yl))biphenyl-4- yl)methyl]-4-vinylimidazole (470 g, 0.73 mmol, 1 eq), Dess-Martin periodinane (J. Pro. Chem. (1983) 48, 4155) (341 mg, 0.80 mmol, 1.1 eq) and methylene chloride (lOmL) were mixed and stirred under nitrogen overnight. The solvent was removed in vacuo and the residue flash chromatographed In 3:2 hexane ethyl acetate over silica gel to yield 310 mg (66%) of a white glass. NMR (DMSO- d ₆ ) -59.91 (s,lH); 7.80 (d,lH,J=7Hz); 7.61 (t,lH, J=7Hz); 7.54 (t.lH,J=7Hz); 7.48-7.22(m,10H); 7.20 (d,lH,J=9Hz); 7.06 (d,2H,J=9Hz); 7.00-6.75 (m,8H); 6.15 (d of d,lH,J=17,3 Hz); 5.52 (s,2H); 5.47 (d of

SUBSTITUTE SHEET

d,lH,J*12,3 Hz); 2.49 (t,2H,J=7Hz); 1.57 (t of q,2H,J=7,7Hz); 0.79 (t,3H,J=7Hz) . IR (neat) 1658 cm' ¹ . Anal, calcd. for C42H36N6θ- ^» (H2θ)o.s: C, 77.63? H, 5.74; N, 12.93. Found: C, 77.53; H, 5.73; N, 12.64.

PART I: Preparation of 2-n-propyl-l-[(2'-(lH-tetrazol- 5- 1)biphenyl-4-y1)meth 1]-4-vin 1-imidazole- 5-carboxaldehyde.

2-n-propyl-l-[(2'-(N-triphenylmethyl-(lH- tetrazol-5-yl))biphenyl-4-yl)methyl]-4-v1nyl-imidazole- 5-carboxaldehyde (330 mg), trifluoroacetic add (1.65 mL), water (1.65 mL) , and THF (1.65 mL) were mixed and stirred at room temperature. After 8 h, the mixture was neutralized to pH=7 with ION NaOH and the solvents removed j_n vacuo. The residue was flash chromatographed in 1:1 hexane/ethyl acetate to 100% ethanol to yield 270 mg of a white glass. NMR (DMSO- d ₆ ) δ 9.92 (s.lH); 7.65-7.50 (m.lH); 7.50-7.12 (m,3H); 7.09 (d,2H,J=9Hz); 6.89 (d,2H,J=9Hz); 6.11 (d of d,lH,J=17,3Hz); 5.55 (s,2H); 5.45 (d of d, 1H.J-12.3

Hz); 2.63 (t,2H,J=7Hz); 1.64 (t of q,2H,J=7,7Hz); 0.90 (t,3H,J=7Hz). IR (Nujol) 1680 cm" ¹ .

SUBSTITUTE SHEET

Example 2

PART A: Preparation of 5-hydroxymethyl-4-1odo-2-n- propylimidazole.

A solution of 31.5 g of 4(5)-hydroxymethyl-2- n-propylimidazole and 50.6 g of N-iodosuccinimide in 560 mL of 1,4-dioxane and 480 mL of 2-methoxyethanol was stirred at 45°C for 2 h. The solvents then were removed under vacuum. The resulting solIds were washed with distilled water and then were dried to afford 54.6 g of the product as a yellow solid; mp 169-170°C. NMR (DMS0-d ₆ ) 512.06 (br s.lH); 5.08 (t.lH); 4.27 (d,2H); 2.50; (t,2H); 1.59 (sext.,2H); 0.84 (t,3H).

PART B: Preparation of 4-1 odo-2-n-propyl imi dazol e-5 carboxaldehyde

To a solution of 35.8 g of 5-hydroxymethyl-4- 1odo-2-n-propyl imidazole i n 325 mL of glacial acetic

SUBSTITUTE SHEET

acid at 20°C was added dropwise over 1 h 290 mL of 1.0 N aqueous eerie ammonium nitrate solution. The resulting mixture was stirred at 20°C for 1 h. The reaction mixture then was diluted with water, adjusted to pH 5-6 employing aqueous sodium hydroxide solution, and extracted with chloroform. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude solid was recrystallized from 1- chlorobutane to furnish 29.9 g of product as a light yellow solid; mp 141-142°C. NMR (CDC1 ₃ ) δ 11.51 (br s.lH); 9.43 (s.lH); 2.81 (t,2H); 1.81 (sext., 2H); 0.97 (t,3H).

PART C: Preparation of 3-n-propyl-4-

(pheny1ethyny1)1m1dazole-5-carboxaldehyde.

A solution of 2.64 g (0.01 mol) of 4-1odo-2-n- propylimidazole-5-carboxaldehyde, 25 L of dry DMF, 2.5 mL of tr1ethylamine, 1.00 g (0.001426 mol) of bis(tr1phenylphosph1ne)pallad1um chloride and 5.00 g

(0.017 mol) of (phenylethynyl)trlbutyltln was heated to 70°C under nitrogen. The reaction was stirred for 120 hours, then cooled. The precipitate was filtered and washed with methylene chloride, and the resulting ' filtrate was evaporated under reduced pressure. The

Sli iW SHEET

residue was dissolved in 200 L of methylene chloride and extracted three times with 100 mL of 10% HCl. The aqueous layer pH was adjusted to 10 with 50% sodium hydroxide and extracted three times with 100 mL of methylene chloride. The organic phase was dried over sodium sulfate and evaporated under reduced pressure. Yield 0.56 g (0.0023 mol, 23%) of 3-n-propyl- 4-(phen lethyn 1)imidazole-5-carboxaldehyde. NMR (CDC13) δ 9.89 (s,lH); 8.22 (s.lH); 7.93 (m,3H); 7.53 (m,2H); 2.87 (t,2H); 1.87 (m,2H); 1.03 (t,3H).

SUBSTITUTE SHEE

The following intermediates could be prepared by the procedure described in example 2, part C:

SUBSTITUTE SHEET

PART D. Preparation of 4-phenylethynyl-3-n-propyl-l- [(2'-(lH-tetrazol-5-y1)biphenyl-4-y1) methyl]imidazole-5-carboxaldehyde.

3-n-Propy1-4-(phenylethyny1)Imidazole-5- carboxaldehyde was alkylated with 4-bromomethyl-2'-(N- triphenylmethyl-(lH-tetrazol-5-yl))b1phenyl by the procedure described 1n example 1, parts D and I, to yield the entitled product. NMR (CDCI3) δ 9.88 (s.lH); 8.03 (m,lH); 7.57-7.27 (m,8H); 7.17 (m,2H); 7.01 (m,2H); 5.55 (s,2H); 2.61 (t,2H); 1.75 (m,2H); 0.99 (t,3H).

Examples 3-26 (Table 1) could be made by the procedures described in Example 2.

MSWύT

Table 1

Example No. R6 mp (OC)

SUBSTITUTE SHEET

Exampl e 27

PART A: Preparation of 4-(furan-2-yl)-2-n- propylimidazole-5-carboxaldehyde.

A solution of 2.64 g (0.01 mol) of 4-1odo-3-n- propylimidazole-5-carboxaldehyde, 60 mL of toluene, and 0.33 g (0.00029 mol) of tetrakistriphenylphosphine palladium (0) was stirred at room temperature under nitrogen, while a solution of 2.34 g (0.0174 mol) of furan-2-ylboron1c acid in 50 mL of ethanol was slowly added. The reaction was stirred for 5 minutes, after which 12 mL of 2M sodium carbonate was slowly added. After the addition was completed, the reaction was refluxed for 8 h and cooled. The reaction 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% HCl. The HCl layer was made basic 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: 0.34 g (0. 00156 mol,

SUBSTITUTE SHEET

5-carboxaldehyde. NMR (CDCI3) δ 10.14 (s.lH); 7.54 (s,lH); 7.00 (d,lH); 6.55 (m.lH); 2.79 (t,2H); 1.80 (m,2H); 1.02 (t,3H).

The following intermediates (Table 2) were or could be prepared by the procedure described in Example 27, part A:

SUBSTITUTE SHEET

π-propyl glassa

n-propyl wax

n-propyl

n-propyl

n-propy)

n-propyl

n-propyl

122

Table 2, continued.

R6 R7 mp (OC)

n-propyl

n-propyl

n-propyl

n-propyl

n-propyl

n-propyl

Table 2, continued.

R6 R7 mp ( ^O C)

n-propyl | ^X

n-propyl

n-propyl *

n-propyl

n-propyl

, .

R6 R7 mp (OC)

n-propyl

n-propyl wax

n-propyl

Table 2, continued.

R6 R7 mp (OC)

n-butyl ^> 0

n-butyl

n-butyl

n-butyl

n-butyl

n-butyl

n-butyl o

n-butyl O

n-butyl τ ^y

Table 2, contnue .

R6 R7 mp PC)

n-butyl ^X)

n-butyl

n-butyl _lr K_m»

n-butyl

n-butyl

n-butyl

n-butyl

aNMR (CDCI3) 3 10.25 (s,1 H); 9.85 (s, 1 H); 7.85 (m, 2H); 7.65 (m, 3

7.25 (m, 4H); 2.83 (t, 2H); 1.85 (m, 2H); 1.05 (t, 3H). bNMR (CDCI3) 3 11.45 (bs,1H); 9.88 (s, 1 H); 7.55 (m, 1H); 7.37 (m,

1 H); 7.13 (m, 1 H); 2.73 (t, 2H); 1.80 (m, 2H); 0.91 (t, 3H).

^C NMR (DMSO-D6) 39.66 (s, 1 H), 7.70 (m, 1 H), 7.38 ( , 2H), 7.11 2H), 7.04 (m, 4H), 2.70 )t, 2H), 1.80 (m, 2H), 0.97 (t, 3H).

SUBSTITUTE SKEET

PART B: Preparation of 4-(furan-2-yl)-2-n-propyl-l- [(2'-(lH-tetrazol-5-yl)b1phenyl-4- y1)methyl]1mldazole-5-carboxaldehyde.

4-(furan-2-y1)-2-n-propyl1midazole-5- carboxaldehyde was transformed Into the entitled product by the procedures described 1n Example 1, parts

D and I: mp 129 (dec). NMR (CDC1 ₃ ) δ 10.15 (s.lH);

7.95 (d.lH); 7.55 (m,2H); 7.38 (m,2H); 7.10 (d,2H);

6.98 (d,2H); 6.85 (d. H); 6.45 (m.lH); 5.55 (s,2H); 2.55 (t,2H); 1.70 (m,2H); 0.91 (t,3H).

The examples 1n Table 3 could be prepared by the procedures described 1n example 27 using the appropriate starting materials:

Example No. mp (OC)

28 n-propyl

29 n-propyl

30 n-propyl

31 n-propyl ^O

32 n-propyl J ^O

33 n-propyl ^[ τ>

34 n-propyl o

Table 3, continued.

Example No. mp (OC)

35 n-propyl O

36 n-propyl ^l τ ^y

37 π-propyl

38 n-propyl

39 n-propyl JO

40 n-propyl

Table 3, continued.

Example No. mp (OC)

41 n-propyl

42 n-propyl

43 π-propyl

44 n-propyl

45 n-propyl

Table 3, continued.

Example No. mp (OC)

46 n-propyl

lass'

47 n-propyl x ^X) g

48 n-propyl , ^θ

Table 3, continued.

Example No. mp (OC)

49 n-butyl -0

50 n-butyl v~ ^Q

51 n-butyl

52 n-butyl

53 n-butyl

54 n-butyl

55 n-butyl

56 n-butyl

57 n-butyl

58 n-butyl

59 n-butyl

60 n-butyl

61 n-butyl

Example No. mp (OC)

62 n-butyl

63 n-butyl

64 n-butyl

65 n-butyl

66 n-butyl ~

Table 3, continued.

Example No. mp (OC)

67 n-butyl

68 n-butyl

69 n-butyl

aNMR (CDCI3) 39.81 (s, 1H), 7.92 (d, 2H), 7.53 (m, 9H), 7.27 (m, 4H),

7.11 (d, 2H), 6.98 (d, 2H), 5.60 (s, 2H), 2.51 (t, 2H), 1.73 (m, 2H),

0.99(t, 3H). bN R (CDCI3) 39.69 (s, 1 H), 8.10 (m, 1 H), 7.58 (m, 4H), 7.48 (m,

3H), 7.18 (d, 2H), 7.00 (m, 7H), 5.62 (s, 2H), 2.61 (t, 2H), 1.79 (m, 2H), 1.02 (t, 3H).

The examples In Tables 4 and 5 can be made by procedures described 1n examples 1, 2, or 27 using the biphenyl starting materials disclosed in this patent or by other methods familiar to one skilled 1n the art.

Table 4

Ex. No. Rδ R8 mp (OC)

0 n-propyl 4-CF3 CHO single bond COOH 1 n-propyl 4-OMe CHO single bond COOH 2 π-propyl 4-COOH CHO single bond COOH 3 n-propyl 4-CON(Me)2 CHO single bond COOH 4 n-propyl 4-SO2CH3 CHO single bond COOH 5 n-propyl 4-Sθ2NMe2 CHO single bond COOH 6 n-propyl 3-CF3 CHO single bond COOH 7 n-propyl 3-OMe CHO single bond COOH 8 n-propyl 3-COOH CHO single bond COOH 9 n-propyl 3-CON(Me)2 CHO single bond COOH 0 n-propyl 3-SO2CH3 CHO single bond COOH 1 n-propyl 3-Sθ2NMe2 CHO single bond COOH 2 n-butyl 4-CF3 CHO single bond COOH 3 n-butyl 4-OMe CHO single bond COOH 4 n-butyl 4-COOH CHO single bond COOH 5 n-butyl 4-CON(Me)2 CHO single bond COOH 6 n-butyl 4-SO2CH3 CHO single bond COOH 7 n-butyl 4-Sθ2NMe2 CHO single bond COOH 8 n-butyl 3-CF3 CHO single bond COOH 9 n-butyl 3-OMe CHO single bond COOH 0 n-butyl 3-COOH CHO single bond COOH 1 n-butyl 3-SO2CH3 CHO single bond COOH 2 n-butyl 3-S02NMe2 CHO single bond COOH

Table 4 (continued)

Table 4 (continued)

Ex. No. R6 R8 mp(oc)

127 n-butyl 4-CF3 CHO single bond

128 n-butyl 4-OMe CHO NHSO2CF3 single bond

129 n-butyl 4-COOH CHO NHSO2CF3 single bond 30 NHSO2CF3 n-butyl 4-CON(Me)2 CHO single bond 31 n-butyl 4-SO2CH3 CHO NHSO2CF3 single bond 32 NHSO2CF3 n-buty! 4-Sθ2NMe2 CHO single bond 33 NHSO2CF3 n-butyl 3-CF3 CHO single bond 34 n-butyl ,3-OMe CHO NHSO2CF3 single bond 35 NHSO2CF3 n-butyl 3-COOH CHO single bond 36 NHSO2CF3 n-butyl 3-Sθ2NMe2 CHO single bond NHSO2CF3

a e con nue

158 n-propyϊ < I/MO COOH single bond CN4H

159 n-propyl COOH single bond CN4H

160 n-propyl COOH single bond CN4H

161 n-propyl COOH single bond CN4H

162 n-propyl COOH single bond CN4H

163 n-propyl ^{C00H sin} 9 ^{,e bond CN} 4 ^H

164 n-propyl COOH single bond CN4H

165 n-propyl CHO single bond COOH

66 n-propyl CHO single bond COOH

167 n-propyl JP ^CH0 single bond COOH

^* Se

168 n-propyl CHO single bond COOH

169 n-propyl ± JΛ ^O CHO single bond COOH

170 n-propyl CHO single bond COOH

^{CH0 sin} 9 ^lebond ∞****

172 n-propyl ^{CH0 sln} 9 ^,ebond ∞® ⁰ ***

.N,

173 n-propyl _! >A _/ * _^ ^{NN CH0 sin} 9 ^{lebond NHS} ° ^2CT3

174 n-propyl ^CH0 s*ng ^{|e bond} ∞∞>-~*-

175 n-propyl °HO single bond HSQICF,

177 n-propyl jQf CHO -O- CN4H

178 n-propyl ^CH0 " ^S" CN4H

179 n-propyl | ^{CH0 "C0"} CN4H

180 CHO -OCH2- CN4H

181 n-propyl CHO -CH-CH- CN4H

182 n-propyl CHO single bond CN4H

183 n-propyl N CHO single bond CN4H

I CH ₃

184 n-propyl CHO single bond CN4H

185 n-propyl CHO single bond CN4H

186 n-propyl CHO single bond CN4H

187 n-propyl CHO single bond CN4H

188 n-propyl CHO single bond CN4H

189 n-propyl ι' ^N CHO single bond CN4H

I CH ₃

Ta le 5 continued

190 n-propyl ~r- CHO single bond CN4H

I H

191 n-propyl CHO single bond CN4H

192 n-propyl CHO single bond CN4H

193 n-propyl CHO single bond CN4H

194 n-propyl V r- ^Q CHO single bond CN4H

I H

195 n-propyl > >

N CHO single bond CN4H

I H

196 n-propyl COOH single bond CN4H

197 n-propyl COOH single bond CN4H

198 n-propyl J CH2OH single bond CN4H

Ar °

99 n-propyl ) CH2OH single bond CN4H

AT

200 n-propyl CH2OH single bond CN4H

CH2OH single bond CN4H

202 n-propyl _$ /S ^O _» / CH2OH single bond CN4H

203 n-propyl CH2OH single bond CN4H

204 n-propyl CH2OH single bond CN4H

206 n-propyl CHO single bond CN4H

207 n-propyl -CsC-CH ₂ -CH ₃ CHO single bond CN4H

208 n-propyl - -c=c— CH ₂ -Ph CHO single bond CN4H

209 n-propyl CHO single bond CN4H

210 n-propyl CHO single bond CN4H

211 n-propyl single bond CN4H

212 n-propyl CHO single bond CN4H

215 n-propyl CHO single bond CN4H

216 n-propyl CHO single bond CN4H

217 n-propyl CHO single bond CN4H

218 n-propyl CHO single bond CN4H

219 n-propyl CHO single bond CN4H

220 n-propyl CHO single bond CN4H

The following compounds in Table 6 were prepared or could be prepared by the procedure in example 1 :

Table 6

221 n-butyl CN ₄ H

222 n-butyl CHO CN ₄ H

223 n-butyl CHO CN ₄ H

224 n-butyl CHO CN ₄ H

225 n-butyl CHO CN ₄ H

Example 242

Preparation of 2-n-Butyl-4-phenylth1o-l-[(2'-(lH- tetrazol-5-yl)biphenyl-4-yl)methyl]1m1dazole- 5-carboxyaldehyde

2-n-Butyl-4-chloro-l-[(2'-N-tr1phenyl- methyl(lH-tetrazol-5-yl)b1phenyl-4-yl)methylJ-

1midazole-5-carboxyaldehyde (synthesized as described in European Patent Application Number 89100144.8, published 7.19.89) (590 mg, 0.89 mmol, 1 eq), and thiophenol (0.91 mL, 8.9 mmol, 10 eq) were added to a freshly prepared solution of sodium ethoxlde 1n methanol (sodium: 205 mg,8.9 mmol, 10 eq; methanol, 40 mL) and the mixture refluxed overnight under N . The solvent was removed in vacuo and the residue dissolved in water (50 mL). The pH was adjusted to 10-12 with 10 N NaOH. Gummy solIds (trltyl group-containing compound) formed which were dissolved by the addition of ethyl ether (50 L). The layers were separated and the aqueous layer extracted with ethyl ether (2 x 50

mL). The aqueous layer was then extracted with ethyl acetate (6 x 50 mL) . The ethyl acetate layers were collected, dried (MgSO^, and the solvent removed in vacuo to yield a residue which was redissolved 1n water (50 L) . The pH was adjusted to 1 with cone. HCl. A gummy precipitate containing product formed which was dissolved in ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The ethyl acetate layers were collected, dried (MgSO^, and the solvent removed in vacuo to yield a white glass (200 mg) . Crystallization from hot n-butylchlorlde yielded a white solid (142 mg) : mp 1435-145.5°C. NMR (DMSO-de) δ 9.82 (s, 1H); 7.80-761 ( , 2H); 7.58 (d, 1H, J=8Hz); 7.52 (d, 1H, J=8Hz); 7.45-7.20 (m, 5H); 7.09 (d, 1H,

J=8Hz); 7.03 (d, 2H, J=8Hz); 5.62 (s, 2H); 2.64 (t, 2H, J=7Hz); 1.50 (t of t, 1H, J=7,7Hz); 1.25 (t of q, 2H, J=7,7Hz); 0.80( t, 3H, J=7Hz). Anal, calcd. for CC ₂ 8H26N60S-(H ₂ 0)o.4: C, 67.02; H, 5.38; N, 16.75; S, 6.39. Found: C, 66.90; H, 5.20; N, 16.75; S, 6.00. Examples 243-253 in Table 7 can be made by procedures described in example 242 and other examples in this patent application and In EP 89100144.8 (published 7.19.89) or by other methods familiar to one skilled in the art.

Table 7 (continued)

CHO COOH

CHO CN4H

CHO CN4H

CHO CN4H

263 n-butyl — N .N CHO CN4H

264 n-propyl CHO CN4H

Table 7 (continued)

265 n-propyl CH20H COOH

266 n-butyl ^X > CHO COOH

CNMR (DMSO-d6) d 9.83 (s, 1H); 7.72 (d, 1H, J=8Hz); 7.65-7.15 (m, 9H); 7.10(d,2H,J=8Hz); 5.64 (s,2H); 2.64 (t, 2H, J=7Hz); 1.50 (toft, 2H,J«7,7Hz); 1.23{tof q, 2H, J=7,7Hz); 0.78 (t, 3H, J=7Hz).

Example 268

PART A: Preparation of 2-n-propyl-4-cyclobutyl1denyl-

5-hydroxymethyl-l-[(2'-(N-triphenylmethyl-(lH- tetrazol-5-yl))biphenyl-4-yl)methyl]imidazole.

(δ-Bro o-n-butyl)trlphenylphosphonium bromide (7.42 g, 0.0155 mmol, 2 eq) was suspended 1n THF (125 L) and 0.75 M potassium hexamethyldisilazane (41.4 mL, 0.031 mmol, 4 eq) was added at room temperature. The mixture turned blood red. After 0.5 h, 2-n-propyl-5- hydroxymet 1-1-[(2'-(N-tr1phenylmethyl-(lH-tetrazol-5- yl))biphenyl-4-yl-methyl]imidazole-4-carboxaldehyde (5.00 g, 7.75 mmol, 1 eq) as a slurry in THF was added. The mixture eventually turned Into a yellow-orange suspension. After 24 h, the reaction was worked up by adding a little methanol to quench, followed by ethyl acetate and water. The layers were seperated and the organic layer was washed with water (2X) and brine (IX). The organic layer was dried (MgS04) , and solvent removed in vacuo. and the residue flash chromatographed in 60:40 pentane/ethyl acetate to 100% ethyl acetate to yield 4.12 g (78%) of a white solid: mp 181.5- 182.5°C. NMR (DMS0-d ₆ ) δ 7.78 (m,lH); 7.61 (t,lH, J=7Hz); 7.54 (t,1H,J=7Hz) ; 7.48-7.20 (m.lOH); 7.03

(d,2H,J=8Hz); 6.96-6.70 ( ,8H); 5.99 (s.lH); 5.13 (s,2H); 4.97 (t,lH,J=7Hz); 4.21 (d,2H,J=7Hz); 3.05 (m,2H); 2.79 (m,2H); 2.31 (t,2H,J=7Hz); 1.98 (m,2H); 1.48 (t of q, 2H,J=7,7Hz); 0.77 (t,3H,J*=7Hz). Anal. ((C ₄ 5H42 ₆ 0.(H ₂ 0)o.75) C, H, N.

PART B: Preparation of 2-n-propyl-4-cyclobutylidenyl 5-hydroxymethyl-1-[(2'-(lH-tetrazol-5- yl)biphenyl-4-yl)methyl]Imidazole.

2-n-Propy1-4-cyclobutylideny1-5-hydroxymethyl- l-[(2'-(N-triphenylmethyl-(lH-tetrazol-5-yl))biphenyl- 4-yl)methyl]im1dazole (1.00 g), methanol (25 L) and THF (15 L) were mixed and refluxed for 24 h. The solvents we _^ re removed in vacuo and the residue immediately flash chromatographed quickly In 1:1 pentane/ethyl acetate to 100% Isopropanol and eventually to 100% ethanol to yield 320 mg of a light yellow glass: NMR (DMS0-d ₆ ) 5- 7.59 (d,lH,J=7Hz); 7.54 (t,lH,J=7Hz); 7.46 (t,lH,J=7Hz); 7.42 (d,lH,J=7Hz); 7.06 (d,2H,J=7Hz); 6.90 (d,2H,J=7Hz); 5.97 (s.lH); 5.17 (s,2H); 4.31 (s,2H); 3.04 (m,2H); 2.77 (m,2H); 2.42 (t,2H,J=7Hz); 1.97 (m,2H); 1.53 (t of q,2H,J=7,7Hz); 0.86 (t 3H,J=7Hz). Anal. (C ₂ 6H28 ^N 6°) ~ _* «. N.

Uti l ity

The hormone angiotensin II (All) produces numerous biological responses (e.g. vasoconstrlctlon) through stimulation of its receptors on cell membranes. For the purpose of Identifying compounds such as All antagonists which are capable of Interacting with the All receptor, a ligand-receptor binding assay was utilized for the initial screen. The assay was carried out according to the method described by [Glossmann et al., J. Biol. Chem.. 249. 825 (1974)], but with some modifications. The reaction mixture contained rat adrenal cortical microsomes (source of All receptor) In Tr1s buffer and 2 nM of ³ H-AII with or without potential All antagonist. This mixture was Incubated for 1 hour at room temperature and the reaction was subsequently terminated by rapid filtration and rinsing through glass micro-fibre filter. Receptor-bound ^H- AII trapped in filter was quantltated by scintillation counting. The Inhibitory concentration (IC50) of potential All antagonist which gives 50% displacement of the total specifically bound ³ H-AII is a measure of the affinity of such compound for the All receptor. Compounds of this invention which were tested in this binding assay exhibited IC50 of 10 ^" ^M or less (Table 8).

Table 8

Angiotensin II Antihypertensive

Receptor Effects In renal

Binding Hypertensive Rats IC50 Intravenous Oral

Ex. No. (//molar) Activity ¹ Activity ²

T ^~ OTθT3 2 0.021

ϊ Significant decrease 1n blood pressure at 3.0 mg/kg or less 2 Significant decrease In blood pressure at 30 mg/kg or less NA - Not active at 3 mg/kg or 30 mg/kg dosage tested. Although some of the compounds tested were not active orally, they were active Intravenously.

NT Not tested.

NT ³ Not tested at 30 mg/kg p.o.

The potential antlhypertenslve effects of the compounds of this invention may be demonstrated by administering the compounds to awake rats made hypertensive by ligation of the left renal artery [Cangiano et al., J. Pharmacol. Exp. Ther.. 208. 310 (1979)]. This procedure Increases blood pressure by increasing renin production with consequent elevation of All levels. Compounds are administered orally at 30 mg/kg and/or intravenously via a cannula 1n the jugular vein at 3 mg/kg. Arterial blood pressure is continuously measured directly through a carotid artery cannula and recorded using a pressure transducer and a polygraph. Blood pressure levels after treatment are compared to pretreat ent levels to determine the antlhypertenslve effects of the compounds which were tested. Some compounds of this invention exhibited intravenous activity at 3 mg/kg and some exhibited oral activity at 30 mg/kg (Table 8). Dosage Forms The compounds of this Invention can be administered for the treatment of hypertension according to the invention by any means that effects contact of the active ingredient compound with the site of action in the body of a warm-blooded animal. For example, administration can be parenteral, i.e., subcutaneous, Intravenous, Intramuscular, or Intra peritoneal. Alternatively, or concurrently, In some cases administration can be by the oral route. The compounds can be administered by any conventional means available for use In conjunction with pharmaceuticals, either as Individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on

the basis of the chosen route of administration and standard pharmaceutical practice.

For the purpose of this disclosure, a warm¬ blooded animal 1s a member of the animal kingdom possessed of a homeostatic mechanism and Includes mammals and birds.

The dosage administered will be dependent on the age, health and weight of the recipient, the extent of disease, kind of concurrent treatment, 1f any, frequency of treatment and the nature of the effect desired. Usually, a dally dosage of active Ingredient compound will be from about 1-500 milligrams per day. Ordinarily, from 10 to 100 milligrams per day in one or more applications is effective to obtain desired results. These dosages are the effective amounts both for treatment of hypertension and for treatment of congestive heart failure, I.e., for lowering blood pressure and for correcting the hemodynamlc burden on the heart to relieve the congestion. The 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 carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearlc acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric

coated for selective disintegration 1n the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to Increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active Ingredient, suitable stabilizing agents, and 1f necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulflte, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric add and Its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propylparaben, and chlorobutanol. Suitable pharmaceutical carriers are described 1n Remington's Pharmaceutical Sciences. A. Osol, a standard reference text 1n this field.

Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be Illustrated as follows:

Capsules A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules A mixture of active Ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil Is prepared and injected by means of a positive

displacement pump Into gelatin to form soft gelatin capsules containing 100 milligrams of the active Ingredient. The capsules are washed and dried.

Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit 1s 100 milligrams of active Ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalllne cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to Increase palatability or delay absorption.

In.lectable A parenteral composition suitable for administration by injection 1s prepared by stirring 1.5% by weight of active Ingredient 1n 10% by volume propylene glycol. The solution 1s made to volume with water for injection and sterilized.

Suspension An aqueous suspension 1s prepared for oral administration so that each 5 mill11Iters contain 100 milligrams of finely divided active ingredient, 100 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 of vanillin.

The same dosage forms can generally be used when the compounds of this invention are administered stepwise in conjunction with another therapeutic agent. When the drugs are administered 1n physical combination, the dosage form and administration route should be selected for compatibility with both drugs. Suitable dosages, dosage forms and administration routes are illustrated in the following tables.

Examples of NSAID's that can be combined with All blockers of this Invention:

Dose Drug (mg) Formulation Route

Indomethacin 25 Tablet Oral

(2/3 times dally)

Meclofenamate 50-100 Tablet Oral

(2/3 times dally)

Ibuprofen 300-400 Tablet Oral

(3/4 times dally)

Plroxica 10-20 Tablet Oral

(1/2 times dally)

SuHndac 150-200 Tablet Oral (2 times dally)

Azapropazone 200-500 Tablet Oral

(3/4 times dally)

Examples of diuretics that can be combined with All blockers of this Invention:

Dose Drug (mg) Formulation Route

Benzoth1adiz1des 25-100 (dally) Tablet Oral (e.g. hydrochlorothiazide)

Loop diuretics 50-80 (dally) Tablet Oral

(e.g. furose ide)

When used with an NSAID, the dosage of All blockers will generally be the same as when the All blocker 1s used alone, i.e., 1-500 milligrams per day, ordinarily from 10 to 100 milligrams per day In one or more applications. When used with diuretics, the initial dose of All blocker can be less, e.g., 1-100 milligrams per day and for the more active compounds 1-10 milligrams per day.

It 1s expected that the compounds of this invention will also be useful 1n the treatment of chronic renal failure.