IL95258A - Substituted imidazoles, their preparation and pharmaceutical compositions containing them - Google Patents
Substituted imidazoles, their preparation and pharmaceutical compositions containing themInfo
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- IL95258A IL95258A IL9525890A IL9525890A IL95258A IL 95258 A IL95258 A IL 95258A IL 9525890 A IL9525890 A IL 9525890A IL 9525890 A IL9525890 A IL 9525890A IL 95258 A IL95258 A IL 95258A
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ninpn >i>voni οη,οη ,ο>-ιοηιο α^ηχτδ'κ Substituted imidazoles, their preparation and pharmaceutical compositions containing them E. I. DU PONT DE NEMOURS AND COMPANY C:- 81254 BACKGROUND OF THE INVENTION Field of the Invention This Invention relates to 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 1n conjunction with other drugs, especially diuretics and non-steroidal antiinflammatory 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 2-globulin, anglotenslnogen, to produce angiotensin I, which is then converted by angiotensin converting-enzyme to All. The latter substance 1s 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 1s 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 hydrochlorothiazide, 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-steroidal antl -Inflammatory drug (NSAID) can prevent renal failure which sometimes results from administration of a NSAID.
European Published Application 0 253 310, published January 20, 1988 (corresponding to Israel Patent 83153) discloses that certain substituted Imidazoles block the All receptor and are useful therefore 1n alleviating angiotensin Induced hypertension as well as 1n treating congestive heart failure. The imidazoles disclosed have the formula: The Imidazoles of the present invention differ from those of EPA 0253 310 1n the substltuents R7 and R8 at positions 4 and 5 of the Imidazole ring. In EPA 0 253 310, R7 and R8 are defined as follows: R7 1s H, F, CI, Br, I, N02, CF3 or CN; R8 1s H, CN, alkyl of 1 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, or the same groups substituted with F; phenylalkenyl wherein the aliphatic portion Is 2 to 6 carbon atoms; - (CH2)m-1m1dazol -1-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)m-tetrazolyl ; 0 -(CH2)nORn ; -(CH2)n0CR14; -(CH2)nSR15; R14 0 0 -CH=CH(CH2)s H0R15; -CH=CH(CH2) SCR16," -CR16; 0 -CH=CH(CH2)sOCRn; 0 Y (CH2)s-CH-C0R16; -(CH2)nCR16; -(CH2)n0CNHR10; CH3 Y 0 -(CH2)nNRuC0R10; -(CH2)nNRnCNHR10; -(CH2)nNR11S02R10; Y -(CH2)nNR11CR10, etc., where R10, R11, R14, R15, R16, and Y are as defined below for the present Invention.
Pals et al., Circulation Research. £9, 673 (1971) describe the introduction of a sarcoslne residue in position 1 and alanine 1n 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*, Ala8] 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 peptlde-AII- antagonists, it also possesses agonistic actions of Its own. Saralasin has been demonstrated to lower arterial pressure 1n m.unmals and man when the (elevated) pressure 1s dependent on circulating All (Pals et al., Circulation Research. 2j>, 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 (1964)). However, due to Its agonistic character, saralasin generally elicits pressor effects when the pressure Is not sustained by All. Being a peptide, the pharmacological effects to saralasin are relatively short-lasting and are only manifest after parenteral administration, oral doses being Ineffective. Although the therapeutic uses of peptide AII-blockers, like saralasin, are severely limited due to their oral ineffectlveness and short duration of action, their major utility 1s as a pharmaceutical standard.
Some known non-pept1de antihypertensi e 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). Captoprll 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 furosemlde or hydrochlorothiazide 1s given together with a CEI, the blood pressure of the majority of hypertensive patients 1s effectively normalized. Diuretic treatment converts the non-renln dependent state In regulating blood pressure to a ren1n-dependerit state. Although the Imidazoles of this Invention act by a different mechanism, I.e., by blocking the AI I receptor rather 4 than by Inhibiting the angiotensin converting enzyme, both mechanisms involve Interference with the renin-angiotensin cascade. A combination of the CEI enalapril maleate and the diuretic hydrochlorothiazide is commercially available under the trademark Vaseretlc® from Merck & Co. Publications which relate to the use of diuretics with CEI's to treat hypertension, 1n 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 1n combination with saralasin to enhance the antihypertensive effect.
Non-steroidal antl -inflammatory drugs (NSAID's) have been reported to Induce renal failure 1n 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 1n combination with an NSAID (either stepwise or 1n physical combination) can prevent such renal failure. Saralasin has been shown to Inhibit the renal vasoconstrictor effect of indomethacln and eclofenamate 1n dogs (Satoh et al . , Circ. Res. 36/37 (Suppl. I) : 1-89, 1975; Blaslngham et al . , Am. J.
Phvsiol . 239:F360, 1980). The CEI captoprll has been demonstrated to reverse the renal vasoconstrictor effect of Indomethacln 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 . ! compounds of formula (I) which have angiotensin II-antagon1z1ng properties and are useful as antihypertensives.
Trhare BiIS R2 Is H; CI; Br; I; F; N02; CN; alkyl of 1 to 4 carbon atoms; acyloxy of 1 to 4 carbon atoms; alkoxy of 1 to 4 carbon atoms; C02H; C02R9; NHS02CH3; NHS02CF3; CONHOR12; SO^ ; J*N . aryl ; or furyl ; N H R4 is CN, N02 or CO2 11; R5 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; R6 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 CO2 1 ; cycloalkyl of 3 to 8 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms; cycloalkylalkenyl or cycloal kyl al kynyl of 5 to 10 carbon atoms; (CH2) sz (CH2)mR5 optionally substituted with F or CO2 14; benzyl or benzyl substituted on the plienyl ring with 1 or 2 halogens, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or nitro; R7 is vinyl; cycloal kyl idenyl ; alkynyl of 2-10 carbon atoms; phenylalkynyl where the alkynyl portion 1s 2- 6 carbon atoms; heteroaryl selected from 2- and 3- thienyl, 2- and 3-furyl, 2-, 3-, and 4-pyridyl, 2- pyrazinyl, 2-, 4-, and 5-pyrimid1nyl , 3- and 4- pyridazinyl, 2-, 4- and 5-thi azolyl ,.2-, 4-, and 5- selenazolyl, and 2-, 4-, and 5-oxazolyl, 2- or 3- pyrrolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5- imidazolyl; 0-, m- or p-biphenylyl ; 0-, m- or p- phenoxyphenyl ; 2-oxazol 1 nyl ; 2-thlazol 1nyl ; said . · . phenylalkynyl, heteroaryl, blphenylyl or phenoxyphenyl b'e'ing optionally substituted with 1 or 2 substituents selected from halogen, hydroxy, mercapto, alkoxy of 1-5 carbon atoms, alkyl of 1-5 carbon atoms, -N02, -CN, -CF3, -COR16, -CH2OR17, -NHCOR17, -C0NR18R19, S(0) RR17, and S02 R18 19. pyrrolyl, pyrazolyl or 1mi dazolyl as defined above substituted on ring nitrogen with alkyl of 1-5 carbon atoms, phenyl or benzyl; or alkyl, alkenyl, or aikynyl of 1 to 10 carbon atoms optionally substituted with a . _ -■..· · ' ■ heteroaryl, blphenylyl or phenoxyphenyl group as defined above; -S (0) r-heteroaryl , -S-(0)r-blphenylyl, -S (0) r-phenoxyphenyl , -S-tetrazole, -S(0) RR17, -NR18R19, -NRia-heteroary], -NR18-phenyl , -NR18-b1phenylyl , -NR18-plienoxyphenyl , -N-phthallmldo, -NH-S02-phenoxyphenyl , -NH-SO2-heteroaryl, -NH-S02-b1phenylyl , -NH-S02-R17, . ·_· -S-(C=0)-R17, N-1m1dazolyl , N-l , 2 , 3-tr1 azoly 1 N- 1 , 2 , 4-tri azolyl , where heteroaryl 1s a heterocycle defined 1n the scope of R7 and where the phenyl group 1n R17 of -S-(0) RR17 , the N-1m1dazo1yl , N- 1,2,3-triazolyl . and N-l,2,4-tr1azolyls may be substituted with one or two substUuents as described above for heteroaryl; R8 Is -(CH2) 1; - (CH2)nOCR14; -(CH2)nSR15; R14 0 0 -CH=CH(CH2)sCHOR15; -CH=CH(CH2) SCR16; -CR16; 0 -CH=CH(CH2)s0CRn; -(CH2)m-tetrazolyl ; (CH2)s-CH-C0R16; -(CH2)nCR16; - (CH2)n0CNHR10; CH3 Y 0 -(CH2)nNRnC0R10; -(CH2)nNRnCNHR10; -(CH2)nNRnS02R10; Υ· -(CH2)nNRnCR10; R10 1s alkyl of 1 to 6 carbon atoms or perf luoroalkyl of 1 to 6 carbon atoms, 1-adamantyl, 1-naphthyl, l-(l-naphthyl)ethyl , or (CH2)pC6H5; R11 Is H, alkyl of 1 to 6 carbon atoms, cycloalkyi of 3 to 6 carbon atoms, phenyl or benzyl; R12 1s H, methyl or benzyl; R13 1s -C02H; -C02R9; -CH2C02H, -CH2C02R9; 0 0 0 R14 1s H, alkyl or perf luoroalkyl of 1 to 8 carbon atoms, cydoalkyl of 3 to 6 carbon atoms, phenyl or benzyl ; R15 Is H, alkyl of 1 to 6 carbon atoms, cydoalkyl of 3 to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenacyl; R16 Is H, alkyl of 1 to 6 carbon atoms, cydoalkyl of 3 to 6 carbon atoms, (Ο^ρΟβΗδ, OR17, or NR18R19; R17 Is H, alkyl of 1 to 6 carbon atoms, cydoalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R18 and R19 I dependently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, a-methyl benzyl , or taken together with the nitrogen form a ring of the fornuil a 0 is NR20, 0 or CH2; R20 1s H, alkyl of 1-4 carbon atoms, or phenyl; R21 1s alkyl of 1 to 6 carbon atoms, -NR22R23, R22 and R23 Independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together as (CH2)U where 11 Is 3-6; R24 Is H, CH3 or -C6H5; 10 R25 1s NR27R28, OR28, NHCONH2, NHCSNH2, R26 Is hydrogen, alkyl with from 1 to 6 carbon atoms, beii2y l , or al lyl ; R^' and R28 are Independently hydrogen, alkyl with from 1 to 5 carbon atoms, or phenyl; R29 and R30 are Independently alkyl of 1-4 carbon atoms or taken together are -(CH2)q-; R31 1s H. alkyl of 1 to 4 carbon atoms, -CH2CH=CH2 or -CH2C6H4R32; R32 1s H, N02, NH2, OH or OCH3; X Is a carbon-carbon single bond, -CO-, -CH2-, -0-, -S- -NH-, -N- , -CON- , -NC0-, -OCH2-, -CH2O-, R26 R23 R23 -SCH2-, -CH2S-, -NHC(R27)(R28), -NR23S02-, -S02NR23-, -C(R27)(R 8)NH-, -CH=CH-, -CF=CF-, y is 0 or S; Z Is 0, NR11, or m Is 1 to 5; n Is 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 11 a pharmaceutically acceptable salt thereof; provided that: when X Is a single bond, N — N 13 and R13 1s CO^, or *N , then R must be In the ortho or meta position? or when and X are as above and R^3 Is NHSO2CF3 or NHS02CH3( R13 must be ortho; when R1 Is . X Is a single bond, a single bond, then R* must be ortho except when X = NR23C0 and R13 1s NHS02CF3 or NHS02CH3, then R13 must be ortho or meta; (3) when R1 Is -CO2H or a salt thereof, R6 cannot be S-alkyl ; (4) when R1 1s -CO2H or a salt thereof, the substltiient on the 4-pos1t1on of the Imidazole cannot be CH20H, CH2OCOCH3, or CH2C02H; (5) when R1 1s , R6 1s not methoxy- benzyl ; (.6) the R° group 1s not -CHCH2CH2CH3 or CH20H; F Preferred for their antihypertensi e activity are novel compounds having the formula: 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 1s -(CH2)m-tetrazo1yl, -(CH2)n0Rn; -(CH2)n0CR14; ol4 -CH=CH(CH2)SCR16, -CH=CH(CH2)sCH0R15; 0 0 -(CH2)nCR16; -(CH2)nNH-C0R10 ; -(CH2)nNHS02R10; 0 R13 Is -C02H, -C02R9, | R16 Is H, alkyl of 1 NR18R19; X 1s carbon-carbon single bond, -CO-, -CO , -CH2CH2-, - -, -0CH2-, -CH20-, -SCH2-, -CH2S-( -NHCH - , -CH2NH- or -CH=CH-j and pharmaceutically acceptable salts of these compounds.
More preferred are compounds of the preferred scope where: R2 Is H, alkyl of 1 to 4 carbon atoms, halogen, or alkoxy of 1 to 4 carbon atoms; R6 1s alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms; R7 1s heteroaryl selected from 2- and 3-thlenyl, 2- and 3-furyl, 2-, 3-, and 4-pyrldyl, or p-blphenylyl , 4 -(CH2) CR16; -CH^NHCOR10; -(CH2)mNHS02R10; or -COR16; R10 is CF3, alkyl of 1 to 6 carbon atoms or phenyl; R11 1s H, or alkyl of 1 to 4 carbon atoms; R13 is C02H; C02CH2OCOC(CH3)3; NHS02CF3 R14 1s H, or alkyl of 1 to 4 carbon atoms; R151s H, alkyl of 1 to 4 carbon atoms, or acyl of 4 carbon atoms; R16 Is H, alkyl of 1 to 5 carbon atoms; OR17; or m Is 1 to 5; X = single bond, -0-; -CO-; -NHC0-; or -0CH2-; and pharmaceutically acceptable salts.
Note that throughout the text when an alkyl substltuent Is mentioned, the normal alkyl structure 1s meant (i.e., butyl 1s n-butyl) unless otherwise sped fled.
Pharmaceutically suitable salts Include both the metallic (Inorganic) salts and organic salts; a 11st of which Is given In Remlnnton's Pharmaceutical Sciences. 17th Edition, pg. 1418 (1985). It 1s well known to one skilled 1n the art that an appropriate salt form Is chosen based on physical and chemical stability, 15 16 95258/2 flowabiHty, hydroscopld ty and solubility. Preferred salts of this Invention for the reasons dted above Include potassium, sodium, calcium and ammonium salts. ~ - Also within the scope of this invention are 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 or more other therapeutic agents, such as a diuretic or a non-steroidal antiinflammatory drug. Also within the scope of this Invention 1s a method of preventing renal failure resulting from administration of a non-steroidal antiinflammatory drug (NSAID) in a non-human warmblooded animal, which comprises administering a compound of Formula (I) in stepwise or physical combination with the NSAID. The compounds of this invention can also be used as diagnostic agents to test the renin angiotensin system.
It should be noted in the foregoing structural formula, when a radical can be a substituent in more than one previously defined radical, that first radical can be selected independently in each previously defined radical. For example, R1 and R2 can each be CONHOR12.
R need not be the same substituent in each of R and R but can be selected independently for each of them.
Detailed Description Synthesis The ■-•• .v. compounds of Formula (I) may be prepared using the reactions and techniques described in this section. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. It 1s understood by those skilled in the art of organic 95258/2 17 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 benzyllc 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 1n 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.
The following description may include matter which exceeds the scope of the claims but is retained herein for the sake of clarity.
Scheme 1 Generally, compounds of Formula (3) can be prepared by direct alkylatlon onto midazole (i), with an appropriately protected benzyl hallde, tosylate or mesylate (2) 1n the presence of base, as shown In path a). Preferab]y, the metallic 1m1dazo11de salt 1s prepared by reacting Imidazole (1) with a proton acceptor such as MH where M 1s lithium, sodium or potassium In a solvent such as dimethyl formamlde (DMF) or by reacting It with a metal alkoxtde of formula MOR where R Is methyl, ethyl, t-butyl or the like 1n an alcohol solvent such as ethanol or t-btitanol, or a dipolar aprotic solvent such as dimethyl formamlde. The Imidazole salt 1s dissolved 1n an Inert aprotic solvent such as DMF, and treated with an appropriate alkylating agent (2). Alternatively, Imidazole (1) can be alkylated with a benzyl hallde (g, where XeBr, CI) In the presence of a base such as sodium carbonate, potassium carbonate, trlethylamlne or pyridine. The reaction 1s run 1n 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-n1trobenzyl Intermediate (3a, wherein R1 * 4-N02, R2 «= R3 = H) may be obtained by direct alkylatlon onto Imidazole (1) with a 4-n1trobenzyl hallde, tosylate or mesylate 1n the presence of base.
As R7 and R8 are different, mixtures of two reglolsomer alkylatlon products (3b, and 3_c) are obtained In ^hi h R7 and R8 are Interchanged. When R8 1s CHO the alkylatlon 1s 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 chromatography and/or crystal 1 izatlon.
In all series examined, the more rapidly el ted Isomer of a given pair has greater biological potency than the less rapidly eluted isomer.
Alternatively, any properly functional 1zed benzylamlne derivative (J 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-sulfonlc add or molecular sieves, N. Engel, and W. Stegllch, L1eb1os Ann. Chea.. 1916, (1978), or In the presence of a imlna, F. Texler-Boulet, Synthesis. 679 (1985). The resulting Imine (6) can be cycllzed to the N-benzyl midazole (3) with phosphorus penta-chlorlde (PC 5) , phosphorus oxychlorlde (POCI3) or tr1phenylphosph1ne (PPh ) 1n dlchloroethane 1n the presence of a base such as trlethylamlne, N. Engel and W. Stegllch, Lleblas Ann. Chem.. 1916, (1978).
Acylamlno ketone (5) Is readily obtainable from amino adds via the 0ak1n-West reaction, H.D.
Oakln, R. West, J. B1ol. Chem.. 78, 95 and 745 (1928), and various modifications thereof, W. Stegllch, 6.
Hofle, Annew. Chem. Int. Ed. Encil .. 8, 981 (1969); G. Hofle, W. Stegllch, H. vorbruggen, Annew. Chem. Int. Ed. Engl.. 17, 569 (1978); W. Stegllch, 6. Hofle, Ber.. 102. 883 (1969), or by selective reduction of acyl cyanides, A. Pfaltz, S. Anwar, Tet. Lett. 2977 (1984), or from a-halo, e-tosyl or a-mesyl ketones via the appropriate substitution reactions that one skilled 1n the art will readily recognize.
The functional Ized benzylamlnes (4) may be made from the corresponding benzyl hallde, tosylate or mesylate (2) via displacement with a nitrogen nucleophlle, a procedure familiar to one skilled In the art. This displacement may be achieved using azlde Ion, ammonia, or phthal1m1de anion, etc., 1n a neutral solvent such as dimethyl formamlde, dlmethylsulfoxide etc., or under phase transfer conditions. The benzyl hallde (Z) may be made by a variety of benzyllc halo-genatlon methods familiar to one skilled In the art, for example benzyllc bromlnatlon of toluene derivatives with N-bromosucc1n1m1de 1n an Inert solvent such as carbon tetrachloride In 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 electrophlllc substitution reactions on an aromatic ring. This Includes nitration, sulfonatton, phosphorylation, Frledel-Crafts alkylatlon, Frledel-Crafts acylatlon, halogenatlon, and other similar reactions known to one skilled In the art, 6. A. 01 ah, "Frledel-Crafts and Related Reactions," Vol. 1^5, Intersdence, New York, (1965).
Another way to synthesize functlonallzed benzyl halldes 1s via chloromethylatlon of the corresponding aromatic precursor. Thus, the appropriately substituted benzene ring may be chloromethylated with formaldehyde and hydrochloric add (HCl) for example with or without an inert solvent such as chloroform, carbon tetrachloride, light petroleum ether or acetic add. A Lewis acid such as zinc chloride (ZnCl 2) or a mineral add such as phosphoric add may also be added as a catalyst or condensing agent, R. C. Fuson, C. H. Mc eever, Org. Reactions, 1, 63 (1942).
Alternatively, N-benzyl Imidazoles (3) can also be prepared as shown 1n path b) by forming an R6 substituted amidlne (7) from an appropriately substituted benzylamlne (4) which Is 1n turn reacted with an a-haloketone, a-hydroxyketone (8), e-haloaldehyde, or o-liydroxyaldehyde, F. Kunckell, Ber, . 34, 637 (1901).
As shown 1n path a), Imidazole Q.) may be alkylated by a variety of benzyl derivatives. These Include compounds with latent add functionalities such as o, m, and p-cyanobenzylhal 1des, mesylates or tosylates as shown 1n path c). Nltrlles of formula (£) may be hydrolyzed to carboxyllc acids of formula (10) by treatment with strong add or alkali. Preferably, treatment with a 1:1 (v/v) mixture of concentrated aqueous hydrochloric add/gladal acetic acid at reflux temperatures for 2-96 hours or by treatment with \i sodium hydroxide 1n 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 nltrlle group 1s present It will also be hydrolyzed. The nltrlle functionality can also be hydrolyzed In two steps by first stirring 1n sulfuric add to form the amide followed by hydrolysis with sodium hydroxide or a mineral add to give the carboxyllc add QO).
The nltrlles (9) can be converted Into the corresponding tetrazole derivative (H) by * variety of methods using hydrazolc add. For example, the nltrlle can be heated with sodium azlde and ammonium chloride 1n DMF at temperatures between 30°C and reflux for 1-10 days, J. P. HurwUz and A. J. Tomson, J. Org. Chem.. 6, 3392 (1961). Preferably, the tetrazole 1s prepared by the ,3-dlpolar cycloadditlon of trial kyl tin or triaryltln azldes to the appropriately substituted nltrlle as described 1n detail by Scheme 15.
The starting Imidazole compounds (1) are readily available by any of a number of standard methods. For example, acylaminoketone (5) can be cyclized with ammonia or equivalents thereof, D.
Davidson, et al . , J. Org. Chem.. I, 319 (1937) to the corresponding Imidazole as shown in Scheme 1. The corresponding oxazole can also be converted to Imidazole (1) by action of ammonia or amines 1n 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 1n Scheme 2. As shown 1n Scheme 2 equation a), reaction of the appropriate R^ substituted 1m1date esters (12) with an appropriately substituted o-hydroxy- or a-haloketone or aldehyde (8) 1n ammonia leads to Imidazoles of formula (1), P. Dzluron, and W. Sch nack, Archl . Pharmaz.. 307 and 470 (1974).
The starting Imidazole compounds (1) wherein R7 and R8 are bot hydrogen can be prepared as shown in equation b) by reaction of the appropriate R6-subst1tuted 1m1date ester (12) with o-amlnoacetaldehyde dimethyl acetal (13), M. R. Grlmmett, Adv. Heterocyclic Chem.. 12, 103 (1970).
As shown 1n equation c), Imidazole (15; wherein R7 = hydrogen and R8 = CH2OH) can be prepared by treatment of the 1m1 date ester (12) with 1 , 3-d1hydroxyacetone (14) 1n ammonia by the procedure described in Archive der Pharmazle. 307, 470 (1974). Halogenatlon of Imidazole (15) or any Imidazole wherein R7 or R8 1s hydrogen 1s preferably accomplished by reaction with one to two equivalents of N-halosucdnlmlde 1n a polar solvent such as dloxane or 2-methoxyethanol at a temperature of 40-100°C for 1-10 hours. Reaction of the halogenated Imidazole (16) with a benzylhallde (£) In the manner described in Scheme 1 affords the corresponding N-nenzyl Imidazole (12); wherein R7 Is halogen and R8 1s CH2OH). This procedure 1s described In U.S. Patent 4,355,040. Alternatively, 23 Imidazole (J_7) can be prepared by the procedure described In U.S. Patent 4,207,324.
Compounds of formula (17) can also be prepared by treatment of the starting imidazole compound (1) wherein R7 and R8 are both hydrogen, with the appropriate benzyl hallde followed by functional 1zat1on of R7 and R8 by treatment with formaldehyde as described In E. F. Godefrol, et al., Recuell. 91, 1383 (1972) followed by halogenatlon as was described above.
As shown In equation d) the imidazoles (I) can also be prepared by reaction of R^ substituted amldlnes Q8) with an a-hydroxy- or o-haloketone or aldehyde (8) as described by F. Kunckel, Ber.. 34. 637, (1901).
Compounds of Formula (1) wherein R8= CH2OH can be prepared as shown 1n equation e). The Imidazoles (i) were prepared as described In L. A. Relter, J. Org. Chem.. 52, 2714 (1987). Hydroxymethylatlon of (I) as described by U. Kempe, et al . 1n U.S. Patent 4,278,801 provides the hydroxymethyl Imidazoles (li) . 24 12 i (wherein R7=R8=H) Scheme 2 (continued) 1) H3, Cu+2 RCOCH20H+R6CHO 2) H^ R R == ovyririddvyil, D p--bbiipphheennyyllyyLl, etc. R la As shown In Scheme 3. path a) for benzyl Imidazoles (H.) where 8 « CH20H, the hydroxymethyl groups may be easily converted to the corresponding halide, mesylate or tosylate by a variety of methods iamil r to one skilled In the art.
Preferably, the alcohol (17) Is converted to the chloride (£5) with thionyl chloride 1n an Inert solvent at temperatures of 20eC to the reflux temperature of the solvent.
Chloride (£5) may be displaced by a variety of nucleophiles by nucleophlllc displacement reaction procedures familiar to one skilled 1n the art. For example, excess sodium cyanide 1n DMSO may be used to form cyanomethyl derivatives (£6) at temperatures of 20eC to 100°C.
Nltrlle (26) may be hydrolyzed to an acetic acid derivative (£7), by a variety of methods. These methods Include methods described previously for the hydro)ysis of nltrlles of formula (j)). Examples of desired adds and bases for this hydrolysis Include mineral adds such as sulfuric add, hydrochloric add, and mixtures of either of the above with 30-50* acetic add (when solubility 1s a problem), and alkali metal \y(irox\des such as sodium hydroxide or potassium hydroxide. The hydrolysis reaction proceeds under heating at temperatures ranging from 50-160eC for 2-48 hours. Carboxyllc add (22) may be esterlfled by a variety of methods without affecting other parts of the molecule. Preferably, (£7) 1s refluxed 1n a hydrochloric add/methanol solution for 2-48 hours to give ester (£8).
Ester (£8) may be hydrolyzed to carboxyllc add (£7), for Instance, after R1, R2 and R3 have been elaborated. Various methods, addle or basic, may be used. For example, compound (£8) 1s stirred with 0.5M potassium hydroxide In methanol, or If base soluble, It Is stirred 1n l.Ofl sodium hydroxide for 1-48 h at 20°C to reflux temperatures.
Hydroxymethyl derivative (17) may be acylated to give (29) by a variety of procedures. As shown In path b) acylatlon can be achieved with 1-3 equivalents of an acyl hallde or an anhydride 1n a solvent such as diethyl ether, tetrahydrofuran, methylene chloride or the like 1n the presence of a base such as pyridine or trlethylaiulne. Alternati ely (12) ">a be acylated by reaction with a carboxyHc acid and dlcyclohexylcarbo-dllmide (DCC) in the presence of a catalytic amount of 4-(N,N-d1methylam1no)pyr1d1ne (DMAP) via the procedure described by A. Hassner, Tet. Lett.. 46, 4475 (1978). Treatment of (17) with a solution of carboxyllc acid anhydride In pyridine optionally with a catalytic amount of DMAP at temperatures of 20-100eC for 2-48 hours 1s the preferred method.
The ether (10) can be prepared from the alcohol (12) as shown 1n path c) by methods such as treatment of (12) 1n a solvent such as dimethyl foriiiamlde or dimethyl sul foxlde with potassium t-butox1de, sodium hydride, or the Hke followed by treatment with R L at 25°C for 1-20 hours, where L 1s a halogen, tosylate or mesylate.
Alternatively, treatment of (12) with 1-5 equivalents of thlonyl chloride 1n chloroform for 2-6 hours at 25°C followed by treatment of the Intermediate (2J>) with 1-3 equivalents of MOR11, where M 1s sodium or potassium, for 2-10 hours at 25eC either 1n Rn0H as solvent or In a polar solvent such as dimethyl form-amide or the like will also yield ether (3J)).
The ether (30) can also be prepared for example by heating (12) for 3-15 hours at 60-160eC In Rl10H containing an Inorganic add such as a hydrochloric add or sulfuric acid.
N-aryl Imidazoles of formula I (compounds wherein r=o) can be prepared by the following methods, 1t being understood by one skilled In the art that certain manipulations, protecting and deprotectlng steps, and other synthetic procedures disclosed above may be necessary to produce compounds with the desired combinations of R6, R7, R8 and R13« As shown 1n Scheme 4. equation a) the reaction of aniline derivative (34) with Imldate ester (12) to form the substituted amldlne (35) provides material which can be cyclfzed with dlhydroxyacetone to form structure (16). Subsequent elaboration Into (I) provides the N-aryl Imidazole compounds of the Invention.
Alternati ely as shown by equation b) the Marckwald procedure, described by Marckwald et al., Ber.. 22, 568, 1353 (1889); ger^, 25, 2354 (1892) can form a 2-niercapto1m1dazole (38) from aniline derivative (34) via Isothlocyanate (37). Desulfurlzatlon of (38) with dilute nitric add followed by anion formation at the 2-posltlon of the Imidazole (3J) and reaction with R6X where X 1s CI, Br, I, allows the formation of (4J)) which can be subsequently elaborated to I.
A variation of Marckwald's process as shown In equation c) using an o-ai 1noketone (4J.) and Isothlocyanate (37) can also be employed, see Norrls and McKee, J. Amer. Chem. Soc. 77, 1056 (1955) can also be employed. Intermediate (42J 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 haloaromatlc compounds (43; X=F, CI, Br) and Imidazoles (1): Scheme 4 35 In various synthetic routes R1, R2 and R3 do not necessarily remain the same from the starting compound to the final products, but are often manipulated through known reactions in 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., biphenyl ring) .
Scheme 5 As shown in Scheme 5, compounds where R1 is a sulfonic acid group may be prepared by oxidation of the corresponding thiol (4_5_) . Thus, an N-benzylimidazole derivative bearing a thiol group may be converted into a sulfonic acid (If.) by the action of hydrogen peroxide, peroxyacids such as metachloroperoxybenzoic acid, 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 deprotection of the corresponding alkyl ether or thioethers. Thus, for example, a methyl ether or a methyl thioether derivative (M) of an N-benzyl1m1d-azole containing one or more aromatic rings may be converted Into the free phenol or thiophenol (45) by the action of boron tr1brom1de methyl sulfide, P. 6. Wlllard and C. F. Fryhle, Tet. Lett.. 2J, 3731 (1980),· trlmethylsllyl Iodide, M. E. Jung and M. A. Lyster, sL Pro. Chem.. 42, 3761 (1977); KSEt and derivatives thereof, G. I. Feutrlll, R. N. M1rr1ngton, Tet. Lett.. 1327, (1970), and a variety of other reagents.
Alternatively, N-benzyl Imidazoles may be sulfonated by stirring with H2SO at a variety of different concentrations or with other sulfonating agents such as chlorosiilfonic add or sulfur trioxide with or without complex ng agents such as dloxane or pyridine at temperatures from 0 to 200'C with or without solvent, K. LeRol Nelson 1n Frledel-Crafts and Related Reactions. Ill part 2, 6. A. Olah, ed., Intersclence Publ., 1355 (1964).
The synthesis of compounds where R* Is a sulfate, phosphate or phosphonlc add are depicted in Scheme 6; Scheme 6 42 52 Scheme 6 (continued) 52 (EtO)^P J N1X2 (X = halogen) Δ N-Benzyl Imidazoles containing a phenolic hydroxyl group (47) may be readily converted Into the corresponding sulfate (48) or phosphate (42). As shown In equation a), reaction of the phenol with a sulfur tr1ox1de-am1ne complex will give the corresponding sulfate (4§), E. E. Gilbert, Sulfonatlon and Related Reactions. Intersdence, New York, chapter 6 (1965). Reaction of the phenol (£7) with phosphorus pentachlorlde followed by hydrolysis will give the corresponding phosphate (49), G. M. Kosolapoff, Orqanophosphorus Compounds. John Wiley, New York, 235 (1950).
As shown In equation b) N-benzyl Imidazoles may be converted into the corresponding phosphonic acids by reaction with phosphorus trichloride (PCI3) and aluminum chloride (AICI3) In an Inert solvent for 0.5-96 hours from temperatures of 25eC to the reflux temperatures of the solvent. Appropriate workup followed by reaction with chlorine (CI 2) and subsequent hydrolysis of the tetrachloride (51) gives the phosphonic add derivative ($Z) , G. M. Kosolapoff in Org. Reactions. 6, R. Adams, editor, John Wiley and Sons, New York, 297 (1951). Another more direct route Involves reaction of the N-benzyl Imidazole with PSCI3 and AICI3 followed by hydrolysis, R. S. Edmunson 1n Comprehensi e Organic Chemistry. Vol. 2, D. Barton and W. D. 0111s editors, Pergamon Press, New York, 1285 (1979).
Alternatively, equation c) Illustrates that aryl phosphonic adds (52) may be formed from reaction of the corresponding d1azon1um salt (53) with PCI3 in the presence of Cu(I) followed by hydrolysis with water (Ibid, p. 1286).
As shown 1n equation d), the aryl halldes (5Ji) may be p otolyzed In the presence of phosphite esters to give phosphonate esters (5_6J , 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 . f 103, 2428 (1970) , which can be subsequently converted to phosphonic acids (5_2J by procedures known to one skilled in the art.
N-Benzylimidazoles containing an aldehyde or ketone (5_7_) may be reacted with a phosphorus trihalide followed by water hydrolysis to give a-hydroxyphos-phonic acid derivatives, G.M. Kosolapoff, op. cit.f 304, as shown in Scheme 7.
Scheme 7 52 (R=¾oraIkyl) & Compounds where R1 1s -C0NH0R12 may be prepared as shown 1n Scheme 8. by the treatment of a carboxyl c add (10) with 1-4 equivalents of thlonyl chloride for 1-10 hours. This reaction can be run without solvent or 1n a nonreactlve solvent such as benzene or chloroform at temperatures of 25-65eC. The Intermediate add chloride 1s then treated with 2-10 equivalents of the appropriate amine derivative, H2N- OR12, for 2-18 hours at temperatures of 25-80*C In a polar aprotic solvent such as tetrahydrofuran or d1methylsulfo*1de to give the hydroxamic add (5JJ).
Scheme 8 Alternatively, the carboxyllc add Q0) can be converted to the hydroxamic add (59) according to the procedure 1n J. Wed. Chem.. 28, 1158 (1985) by employing d1cyclohexylcarbod11m1de, l-hydroxybenzo- triazole, and H2NOR12 or according to the procedure described in Synthesis , 929 (1985) employing the Vilsmeier reagent and H2N0R12.
Compounds where R1 is -CONHS02Ar (59a, Ar=phenyl, o-tolyl, etc.) may be produced by treatment of the intermediate acid chlorides from the preparation of the hydroxamic acids (5_9_) , with ArS02NHNa.
Alternatively, these acylsulfonamides (59a) can be prepared from the carboxylic acids (U2) through the corresponding N, -diphenylcarbamoyl anhydrides (10a) as described by F . J. Brown, et al . in Eur. Pat. Appl . EP 199543 (corresponding to Israel Patents 78569 and 80335) (see Scheme 8) Scheme 9 Aniline intermediates (63) are disclosed 1n U.S. Patent No. 4,355,040 and may be obtained from the corresponding nltro compound precursor by reduction. A variety of reduction procedures may be used such as iron/acetic add, D. C. Owsley, J. J. Bloomfleld, Synthesl s . 118, (1977), stannous chloride, F. D.
Bellamy, Tet. Lett.. 839, (1984) or careful hydro-genatlon over a metal catalyst such as palladium.
As shown 1n Scheme 9. aniline Intermediates of N-benzyl Imidazoles may also be prepared from the corresponding carboxyllc add (10) or add chloride via a Curtius rearrangement of an Intermediate acyl azlde (60). More modern methods Include using dlphenyl-phosphoryl azlde as a source of azlde, T. Sh1o1r1, K. Ninomlya, S. Yamada, J. Am. Chem. Soc. 94, 6203 (1972), and trapping the Intermediate Isocyanate (61) produced by the Curtius rearrangement with 2-tr1methyl-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 1n the art may also be employed.
Compounds where 1s -SO2NH2 may be made as shown in Scheme 10: 41 rJ Sulfonamide compounds (6J5) may be made by reacting an arylsulfonyl chloride (64) with ammonia, or its equivalent. Unsubstltuted aryl sulfonamides are made by reaction with ammonia 1n aqueous solution or In an Inert organic solvent, F. H. Berghel and W. Braker, J. Am. Chem. Soc. 66, 1459 (1944), or with dry powdered ammonium carbonate, E. H. Huntress and J. S. Autenrleth, J. Am. Chem. Soc. 63, 3446 (1941); E. H. Huntress and F. H. Carten, J. Am. Chem. Soc g, 511 (1940).
The sulfonyl chloride precursor may be prepared by chlorosulfonatlon with chlorosulfonic add on the aromatic ring directly, E. H. Huntress and F. H. Carten, 1 1 d . : E. E. Gilbert, OP. c1t.. 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 add (46) with PCI 5 or POCI3, C. M. Suter, The Organic Chemistry of Sulfur. John Wiley,. 59 (1948).
Linked ester compounds of formula (I) where R* 0 1s -C02CH(R24)0C 21 can be made by procedures well known In penicillin and cephalosporin chemistry. The purpose 1s to provide materials which are more lipophilic 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 carboxyllc add 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. 2J, 455-473 (1985); M. Ferres, Drugs of Today.19 (9), 499-538 (1983); A. A. Slrkula, Ann. Repts. Med. Chem..10, 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 1¾ Ca) PC02Na ♦ (CH3)jCC02CH2Br —> FC02CH2OCOC(CH3>j JO «6 C. Francheschi et al.. J. antibiotics. H, 17). 938-941 (1983). (b) PC 67 J. Budavin. U.S. Patect 4.440.942 R2« PC02H > FC02CH-OCOHCH2CO2CHj KH2 68 V B. Daehne et al.. C.B. Patent 1.290,767 RC02H > RC02CHCONR22R25 €9 Pexres. Chew. Infl.. 435-440 (I960) 70 44 Clayton et a ., Antlmlcrob. Agents Chemot erapy. £, (6), 670-671 (1974) In equations a-e: Rs Compounds of Formula 1 where R1 Is -C(CF3)20H prepared as shown 1n Scheme 12.
Scheme 12 Hexafluoroisopropanol compounds (12.) may be prepared by treatment of arylsilane {IX) with 1-5 equivalents of hexafluoroacetone in a solvent such as methylene chloride at temperatures ranging from about -50°C to 25°C for a period of 2-10 hours. The requisite arylsilane (71.) can be prepared using methods known to one skilled in the art such as the procedures described in Chapter 10 of Butterworth ' s "Silicon in Organic Chemistry". 95258/2 As shown In Scheme 13. compound (73) In which X» -NHCO and R13= -C00H may be easily prepared, for example, by reacting aniline precursor (63.) with a phthallc anhydride derivative 1n an appropriate solvent such as benzene, chloroform, ethyl acetate, etc. Often the carboxyllc acid product will precipitate from solution with the reactants remaining behind, M.L. Sherrlll, F.L. Schaeffer, E.P. Shoyer, J. Am. Chem. Soc. 50, 474 (1928).
When R13*NHS02CK3, NHSO2CF3 or tetrazolyl (or a variety of other carboxyllc add equivalents), compound (73) may be obtained by reacting aniline (63) with the requisite add chloride by either a Schotten-Baumann procedure, or simply stirring 1n a solvent such as methylene chloride 1n the presence of a base such as sodium bicarbonate, pyridine, or trlethylamlne.
Likewise, an line (63) may be coupled with an appropriate carboxyllc add via a variety of amide or peptide bond forming reactions such as DCC coupling, azlde coupling, mixed anhydride synthesis, or any other coupling procedure familiar to one skilled In the art.
Aniline derivatives (§3) will undergo reductive am1nat1on with aldehydes and ketones to form secondary amines (74)· Thus the aniline 1s first stirred with the carbonyl compound 1n the presence of a dehydration catalyst such as molecular sieves or p-toluenesulfon1c add. Afterwards the resultant Imlne Is reduced to the amine with a borohydrlde reducing agent such as sodium cyanoborohydHde or sodium borohydrlde. Standard catalytic liydrogena lon reagents such as hydrogen and palladium/carbon can also be employed.
Alternatively, aniline (63) may be mono lkylated by reaction with ethyl formate followed by reduction with, for example, lithium aluminum hydride to produce the N-methyl derivative (74). Anilines (74) may 1n turn be reacted with carboxyllc add anhydrides and acid chlorides or carboxyllc adds by any of the coupling procedures described previously to yield (22) where X» -N(CH3)C0-.
Aniline (63) or (7,) or other Intermediate anilines where the amino group may be located on another aromatic ring for example, also react with other anhydrides to make am1de-carboxyl1c add derivatives of formula (75). Thus, for example, malelc anhydride, 2,3-naphthalened1carboxyl1c add anhydride, and diphenic anhydride are reacted 1n a similar fashion to phthallc anhydride with aniline (63) or (74) to yield carboxyllc adds (76), (77), and (78), respectively.
Phthallmlde derivatives of aniline (£3) way be made by a variety of methods, preferably by stirring aniline (63) with phthallc anhydride ,1n acetic add at a temperature between 20eC and reflux, 6. Wanag, A. Velnbergs, fier., 75, 1558 (1942), or by stirring (63) with phthaloyl chloride, a base such as trlethylamlne, and an Inert solvent.
Aniline (63) may be converted Into Its tr1-f Uioromethanesulfonamlde derivative or Us t r1 f luoroacetamldo derivative preferably by reacting It with trlfHc anhydride or trlf luoroacetlc anhydride and a base such as trlethylamlne 1n an Inert solvent such as methylene chloride at -78eC followed by warming to room temperature.
Compounds of structure (I) where X Is a carbon-carbon linkage which are depicted as (fjO) can be made as shown 1n Scheme 14.
Scheme 14 Y=QBr,OTs,OMs Equation a) Illustrates that the b1 phenyl com-pounds (80) can be prepared by alkylatlon of Imidazole (i) with the appropriate halomethylblphenyl compound (7£) by the general procedure described 1n Scheme 1.
The requisite halomethylblphenyl Intermediates (79) are prepared by Ullman Coupling of (8J.) and (82J as described 1n "Organic Reactions", g, 6 (1944) to provide Intermediates (83)', which are 1n turn halogenated.
Halogenatlon can be accomplished by refluxlng (S ) In an nert solvent such as carbon tetrachloride for 1-6 hours 1n the presence of a N-halosucc1n1m1de and an initiator such as azob1s1sobutyron1tr1le (equation b).
As 1n equation c), derivatives of Intermediate (83) 1n which R13 1s at the 2' position (8Ji) can also be prepared by the method described In it Org. Chem.. ϋ, 1320 (1976), that Is D1els-Alder addition of a l,3-butad1ene to a styrene (84) followed by aromat1zat1on of Intermediate (85).
Alternatively, the substituted blphenyl precursors (§3; where R13 * C00H) and their esters (£9) can be prepared as Illustrated 1n equation d), which Involves oxazollne compounds as key Intermediates, A. I. Meyers and E. D. Mlhellch, JL Am. Chem. Soc. 9_Z, 7383 (1975).
Further, as shown In Equation e), nickel- catalyzed cross-coupling of an arylzlnc hallde with a halobenzonltrlle yields a blphenylnltrlle which can In turn be hydrolyzed by standard methods to afford ac d 8J.
Scheme 1. equation c) and Scheme 15. equation c).
However, a preferred method for preparing tetrazoles 1s described In Scheme 1$. equations a) and b). Compounds (go) may be prepared by the l,3-d1polar cycloaddltlon of trlalkylt n or trlphenyltln azldes to the appropriately substituted nltrlle (£2) as In equation a). Alkyl 1s defined as normal alkyl of 1-6 carbon atoms and cyclohexyl. An example of this technique 1s described by S. Kozlma, et al., Oraanometalllc Chemistry. 337 (1971). The required trlalkyl or trlaryltln azldes are made from the requisite commercial trlalkyl or trlaryl tin chloride and sodium azlde. The trlalkyl or trlaryltln group Is removed via addle or basic hydrolysis and the tetrazole can be protected with the trityl group by reaction with trityl chloride and tr1ethylam1ne to give (£i). Brom1nat1on as previously described herein with N-bromosucc1n1m1de and dlbenzoylperoxlde affords compound (92J. Alkylatlon of (1) with the appropriately substituted benzyl hallde using conditions previously described followed by deprotectlon of the trityl group via hydrolysis affords (80; R13 * tetrazole). Other protecting groups such as p-n1trobenzyl and 1-ethoxyethyl can be used instead of the trityl group to protect the tetrazole moiety.
Introduced and removed by procedures described 1n Greene, Protective Groups 1n Organic Synthesis. W1 Intersdence, (1980).
Scheme 15 Compounds of structure 93-95 where X is an -0-, -S-, or -N- linkage can be prepared as shown in Scheme 16 by alkylation of imidazole (1) with the appropriate benzyl halide (9_6J . £1; x = S 2ϋ; X = NR26 e a ome y p eny e er _ emp oye as an alkylating agent 1n the present invention 1s prepared as shown 1n equation b). An Ullman ether condensation of the phenol (97) and a halobenzolc acid as described In Russian Chemical Reviews. 43, 679 (1974) provides the Intermediate add (10].).· The conversion of (101) Into (109) 1s accomplished by ester1f1cat1on with dlazomethane to afford (105) followed by halogenatlon employing the procedure used 1n the preparation of (21)* The dlphenylsulfide (110) and the dl phenyl amine (111) can be prepared from the appropriate thlophenol (98) or aniline (99) by this procedure.
The tertiary dlphenylam ne (11?) 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 R26L where L 1s a leaving group such as a halogen or tosylate employing phase-transfer conditions and ultrasound as described In Tetrahedron Letters. 21, 5907 (1983), 2) treatment of (107) with 1-1.5 equivalents of an appropriate aldehyde and 0.5-5.0 equivalents of sodium cyanoborohydrlde 1n a solvent such as methanol at 25°C at a pH of 3-6 for 1-24 hours, or 3) reductive am1nat1on of (107) employing an appropriate carboxyllc add and sodium borohydrlde as described In JL. Am. Chem. Soc.. 96, 7812 (1974). The tertiary amine (108) 1s then halogenated by the procedure previously described to give (112).
US.
Compounds of structure (21) where X 1s -CO- are prepared as shown 1n Scheme 17 by alkylatlon of Imidazole (1) with the requisite benzoylbenzyl halldes. For example, esters (HI) where R13 Is 2-CO2CH3 are prepared by alkylatlon of Imidazole Q.) with carbomethoxybenzoyl benzyl hallde (114). Ester (113) may be hydrolyzed to the corresponding carboxyllc acid (116) by a variety of methods Including hydrolysis with a base such as sodium hydroxide or potassium hydroxide 1n an alcoholic aqueous solvent such as methanol /H2O at a temperature from 20eC to the reflux temperature of the sol ent.
Carboalkoxybenzoylbenzyl halldes (114) are prepared by benzyl 1c halogenatlon of the corresponding toltioylbenzene 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 tetrachloride to effect benzyl 1c bromlnatlon. 58 Scheme 18 As shown In Scheme IB the toluoyl ketones (73; where X=CO) may be further transformed Into a variety of ketone derivatives ncluding compounds where X Is NR25 R290 OR30 0C0R17 OR14 \ / I I -C- , -C- , -CH , and -C- .
Reaction of ketone (73ft) with a hydroxyl amine or an appropriately substituted hydrazine will give the requisite oxlmes (117) and hydrazones (118) . Reaction with alcohols In the presence of an addle catalyst with removal of water will give ketals (119) . Reduction, with lithium aluminum hydride, a metal borohydrlde, zinc/acetic acid or catalytic hydrogenatlon will give the corresponding alcohol (120) or fully reduced methylene compound (121). These alcohols may be acyl ted by a variety of anhydrides or add halldes 1n the presence of a base with or without solvent to give the corresponding esters (122). The alcohols (120) mav be converted Into their corresponding ethers (123) by reaction of the metal alkoxlde with an alkyl hallde, mesylate or tosylate 1n 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 1s -OCH2-, -SCH2-, and - HCH2- are prepared as shown 1n Scheme 19. 95258/2 61 Scheme 19 As Illustrated In Scheme 19, equation fi, hydrolysis of benzyl ether (124) or methyl ether (12J5) affords hydroxy compound (]£6) which can be alkylated with the appropriate benzyl hallde to give (\2J). In the case of the methyl ethers (125) . the hydrolysis step can be effected by heating the ether at temperatures of 50°-150eC for 1-10 hours In 20-60% hydrobromlc acid, or heating at 50e-90eC 1n acetonltrlle with 1-5 equivalents of trlmethylsllyl Iodide for 10-50 hours followed by treatment with water. Hydrolysis can also be carried out by treatment with 1-2 equivalents of boron tr1brom1de in methylene chloride at 10°-30eC for 1-10 hours followed by treatment with water, or by treatment with an add such as aluminum chloride and 3-30 equivalents of a sulfur-containing compound such as thiophenol, ethanedl thiol , or dimethyl disulfide in methylene chloride at 0-30°C for 1-20 hours followed by treatment with water. For compound (124). hydrolysis can be accomplished by refluxlng 1n trlfluoroacetlc acid for 0.2-1 hours or by catalytic hydrogenolysls 1n the 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 1n a solvent such as dimethyl formamlde or dlmethylsulfoxlde at room temperature followed by alkylatlon with an appropriate benzyl hallde at 25eC for 2-20 hours affords ethers of formula ( 127 ) , as shown 1n equation a..
The sulfide (J_29) can be prepared from the thiophenol (45) by the procedure described above to prepare the ether (127) from the phenol (1£6). The thiophenol (45) can be prepared for example by treatment of the benzyl sul ide (J 8) with sodium 1n liquid ammonia.
The amine (JJO) can be prepared as shown In equation c, from the aniline (63), Itself available from 62 reduction of the corresponding p-nitro compound (3a) which has previously been described. The -reductive amination can be carried out by the same procedure as described in Scheme 13 for the preparation of compound OA) .
Compounds of Formula (I) where the X linkage is -CH=CH-, - are prepared as shown in Scheme 20.
The cls or trans stllbene (112) can be obtained by employing a W1tt1g reaction between the aldehyde (57) and the phosphorane (131).
The stllbene (132) can readily be converted to the saturated derivative (123) for example by catalytic hydrogenatlon employing a heterogeneous catalyst such as palladium/carbon or platinum/carbon or alternatively with a homogeneous catalyst such as trlstrlphenylphos-phlne rhodium chloride. The reduction Is performed In a solvent such as benzene, tetrahydrofuran or ethanol at 25eC under 1-3 atmospheres of hydrogen for 1-24 hours.
The cyclopropane (134) can be prepared by treating the stllbene (232) with the S1mmons-Sm1th reagent as described 1n J. Am. Chem. Soc. 81, 4256 (1959), or by treating (132) methylene d1 Iodide and copper powder as described In J. Am. Chem. Soc. 101. 2139 (1979), or by treatment with the 1ron-conta1n1ng methylene-transfer reagent described 1n J. Am. Chem. Soc. 101, 6473 (1979).
The preparation of compounds of formula (I) where X 1s -CF2CH2-, -CF*CH-, -CH=CF-, -CF*CF- and -CF2CF2-are depicted In Scheme 21.
Scheme 21 a) AiCCH2Ar1 + Et2NSF3 ^2^2» AiCF2CH2Ar1 AiCF = CHAr1 132 0 b) A H2CAT1 + B2NSF3 ^2*^2*· Α Η^Ο^ΑΓ1 M AiCH = CFAr1 m OOH c) AiCCHAr1 + Et2NSF3 ^0 2*- AiCF2CHFAr1 oo d) AiCCAr1 + Et2NSF3 AiCF2CF2Ar1 144 145 Vlnylene fluorides (137) and (140) can be prepared by reaction of SF4 or Et2NSF3 (DAST) with the appropriate ketone (135J or (138) 1n which Ar bears a methyl group convertible to a benzyllc hallde suitable for attachment to an imidazole nitrogen, and Ar' bears a cyano, nltro, ester, or other suitable group which can be subsequently converted to CO2H, NHS02CF3, etc. The Initially formed difluoroethylene (136) and (139) can be formed 1n a non-polar solvent such as methylene chloride and subsequently converted to the vlnylene fluoride by means of alumina, or converted directly Into the unsaturated fluoride by running the reaction 1n a polar solvent such as tetrahydrofuran, dlglyme or N-methylpyrrol 1done 1n the presence of mineral add.
[Equations a and b]. Experimental details of such procedures are found In D.R. Strobach and 6.A. Boswell, J. Org. 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 (JJJ.) may De similarly converted to the corresponding 1,2-dl luorostllbene (143) . Likewise as shown 1n equation d) an appropriate benzll (IM) can be converted to a tetrafluorodlarylethylene (145) using DAST or SF4. Experimental details are described 1n M.E. Christy, et al., J. Med. Chem.. 2j0, (3), 421-430, (1977).
R23 Compounds of formula 1 where X ■ -CONI-, -C^O-, -CH2S-, -CH2NH-, can be made as shown In Scheme 22.
Scheme 22 P protecting group (if necessary) 154:X°-CH20- 155:X=-CH2S- 156:Χ°-α¾ΝΗ- As previously described, acid (10) can be made by alkylating the appropriate imidazole with methyl 4-cltloromethylbenzoate 1n the presence of a base such as potassium carbonate In a polar solvent such as dimethyl formamlde followed by hydrolysis of the resulting ester. Compound (10) can be converted to (148) by reaction with the requisite amine (146) ( ) may need to be protected and subsequently deprotected) and dlcyclohexyl carbodl Imtde (DCC) 1n methylene chloride [J. R. Beek, et al., J. Am. Chem. Soc. fiO, 4706 (1968)] or by reaction with tosyl chloride 1n pyridine [J. H. Brewster and C. J. C1ott1, Jr., Am. Chem.
Soc 77. 6214 (1955)]. Yet another process Involves conversion of carboxyllc add (10) to Its acid chloride with, for example, thlonyl chloride followed by reaction with the amine In aqueous base (Schotten-Baumann conditions) or 1n an organic solvent In the presence of an add scavenger such as aHC03, pyridine or trl ethyl amine, or by other procedures known to form an amide bond between an aromatic add and an amine.
The compounds where K= -CH2O-, -CH2S-, and -CH2NH2- can be made as shown 1n pathway |>. The ester (149) 1s reduced with a reducing agent such as lithium aluminum hydride 1n an Inert solvent to form the alcohol (150) which can then be reacted with tosyl chloride In pyridine to form tosylate (Hi), which Is In turn reacted 1n the presence of base with a corresponding phenol (15 ) thlophenol (153), or aniline (H6; where R23*H) to form compounds (154), (155) or (15$). Again this may require that R13 be protected with a suitable protecting group, however modifications necessary because of specific functional groups are understood to be incorporated by one skilled 1n the art of organic synthesis.
Alternatively, the alcohol (150) can be converted to the corresponding halide with S0C12, (C0C1)2, etc, and the resulting halide can then be reacted with a phenol, thiophenol or aniline in the presence of base to form the desired compound, where X is -CH20-, -CH2S-, -CH2NH- respectively.
Scheme 23 Compounds of Formula (I) where X* -S02 R2^- and - R23S02- may be prepared as shown In Scheme £3. As shown In equation g, sul fonylchlorlde derivative (157) can be reacted with aniline derivative (158) 1n a solvent In the presence of an acid scavenger such as sodium bicarbonate, trlethylamlne or pyridine or under Schotten-Baumann like conditions to give (159) .
Sul fonylchlorlde derivative (157) can be obtained by sulfonatlon of the corresponding benzyl derivative as described earlier, followed by reaction with PCI 5 or POCI3. Likewise, aniline (74J may be reacted in the same manner as described above with sulfonylchlorlde derivative (160) to give (161).
Scheme 21 shows the preparation of furan analogs of the blphenyl compounds (80). Thus, o-ketoester (162), W. Wterenga and H. I. Skuln ck, J. Org. Chem.. 44, 310 (1979), or the corresponding nitrlle (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 tetroxlde, Fleser and Fleser, V.l, p. 812 (Lemleux-Johnson oxidation) to yield dlcarbonyl-contalnlng compound (164) . CycHzatlon 1n mineral acids, addle 1on-exchange resin, P0Cl3/pyr1d1ne, or trl f luoroacetlc anhydride with a catalytic amount of trl f luoroacetlc add yields furan (165: Z=0). Reaction of (164) with P4S10. for example, will yield the corresponding thlophene (165; Z=S).
Reaction of (]64) with an amine 1n refluxlng benzene, with azeotroplc removal of water or by using molecular sieves to absorb the water will yield the corresponding pyrrole (165; Z=NRJ1). Compounds (166) may be prepared from (165) by standard procedures already described. between the terminal aromatic ring and the addle functionality may be prepared as shown 1n 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 thlonyi chloride followed by reaction with cyanide anion as previously described yields nltrlle (170). Compound (170) may be hydrolyzed to carboxyllc acid (121) by methods already described or reacted with a hydrazo c add equivalent to produce tetrazole (122).
Compounds wherein 15 Is a trlfluoro ethylsul-fonyl hydrazlde addle functional group were prepared by the procedure described 1n equation b). That 1s, conversion of ester (]67) to the hydrazlde (121) by standard hydraz1nolys1s followed by reaction with trlfllc anhydride affords hydrazldes (124). 95258/2 e syn eses o compoun s w ere n s substituted and unsubstltuted 1 ,2,3-trlazoles are described 1n Scheme 26. Thus reduction of ester (175) with a reducing agent such as lithium aluminum hydride or dl 1sobutylalum1num hydride gives alcohol (176) .
Oxidation with Mn0 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. M. Letcher and M. P, Sammes, Jj. Chem. Ed.. 6^, 262 (1985). Reaction of (178) with sodium az de produces the 1,2,3-trlazole (122), (N. S. 2ef1rov, et al., jL Chem. Soc. Chem. Comm.. 1001 (1971)) which may be transformed via procedures already described Into product (180).
Aldehyde (122) 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 azlde to give the 1,2,3-trlazole (182) . Subsequent standard manipulations lead to 1,2,3-trlazoles (183) where E*CN and CO2R11. The n1trotr1azole (183; E«NC>2) 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. h. hlsamutdlnov, et al., Zh. Org. Khlm.. U, 2445 (1975), by reaction with sodium azlde.
A variety of protecting groups may be used 1n the manipulation of the above trlazoles, amongst which Is the trltyl group. This group may be easily attached by reaction of the triazole with triphenylmethyi bromide or chloride 1n an Inert solvent such as methylene chloride In the presence of an add scavenger such as trlethyl amine. The trltyl group may be later removed by stirring or refiuxing 1n an acidic medium such as trif luoroacetlc acid/water, HC1 in methylene chloride, or acetic add/water. The trltyl group may also be hydrogenolyzed using a noble metal catalyst such as palladium and hydrogen. 76 , , (190) 1s depicted In Scheme 2Z. Acid chloride (186) Is converted to amide (187) using standard procedures familiar to one skilled In the art. A preferred protecting group Is the 2-prop1on1tr1 le group (P=CH2CH2CN). Thus (187; P=CH2CH2CN) can be synthesized from (186) and /7-am1noprop1on1 tr1 le under Schotten-Baumann like conditions, sing aqueous base In an organic solvent to help solubtltze (186) and (187).
Amide (187) Is converted to amldrazone (188) by reaction with PCI5 or phosgene to make an Imlnoyl chloride which then 1n turn 1s reacted with excess hydrazine.
Amldrazone (188) Is cycllzed to the trlfluoromethyl-1,2,4-trlazo e (189) with trlfluoroacetlc anhydride and then converted to 190 via brom1nat1on, alkylatlon and deprotectlon as previously described.
Scheme 27 Pertinent 6 groups may be variously Introduced by many procedures Including those described In Scheme 28 which describes imidazole construction.
The groups so Introduced may stand unchanged or may be further elaborated If appropriately functional 1zed, according to methods familiar to those skilled In the art such as are illustrated 1n Scheme 28.
Scheme 28 R = CPh3, S02Ph, CH3CHOC2H3 192:R'=H 193:R' = Ts JL2≥ 128 The 2-alkenyl Imidazoles (201) can be prepared by broin1nat1on of the 2-alkyl Imidazoles (199) followed by elimination of hydrogen bromide. The bromlnatlon 1$ preferably accomplished by UV- rradlatlon for 1-4 hours of Imidazole (199) and N-bromosucc1n1m1de, in an Inert solvent, such as carbon tetrachloride at 25*C.
Treatment of the intermediate bromide (200) with a base, such as DBU, tr1 ethyl amine, or potassium t-butox1de, affords the trans 2-alkenvl Imidazoles (201). Cls alkenyl derivatives (203) are prepared from the trans alkenyl compounds by treatment with osmium tetroxide and sodium perlodate to afford aldehydes (2J)2 followed by Wlttlg reaction.
Scheme 29 Alternatively, R6 groups may be Introduced by metallatlon of a protected imidazole or protected 2-methyl Imidazole followed by addition of an appropriate electrophlle as Illustrated in Scheme 30. equations 4) and b). The products (alcohols, esters, halldes, aldehydes, alkyls) are suitable for further elaboration by methods familiar to those skilled In the art.
Metallatlon of Imidazoles Is described In K.L. K1rk, ^ Pro. Chem.. 43, 4381 (1978); R.J. Sundberg, J. Het.
Chein.. 14. 517 (1977); J.V. Hay et al., J. Pro. Chem.. 38, 4379 (1973); B. Iddon, Heterocvcles. 23, 417 (1985).
Condensation of 2-methyl Imidazole and appropriate electrophlles (equation b) with catalytic add or base as described 1n A.R. Katrltzky (Ed.), "Comprehensi e Heterocyclic Chemistry", Vol. 5. p. 431, Pergamon Press. N.Y., 1984 affords products wherein R is alkenyl which are suitable for further elaboration.
Scheme 30 ¾ = CPh3, SC>2Ph Various 2-substltuted imidazoles can be prepared by reaction of a protected 2-tr1methyls1lyl Imidazole with a suitable electrophlle by the method described by F.H. Plnkerton and S.F. Thames, J. Het. Chem.. fi, 67 (1972), which can be further elaborated as desired. · Alternatively, R6 may also be introduced by nickel catalyzed cross-coupling of Grlgnard reagents with 2-(methyUh1o)1m1dazoles (Scheme 31) as described by E. Wenkert and T.V. Ferrelra, J. Chem. Soc. Chem.
Commun.. 840, (1982); E. Wenkert et al., J. Chem. Soc.
Chem. Commun.. 637, (1979); and H. Suglmura and H. Takel, Bull. Chem. Soc. Japan. 58, 664 (1985).
The 2-(methylth1o)1m1dazoles can be produced by the procedure described 1n German Patent No. 2,618,370 and the references cited therein.
Scheme 31 As shown 1n Schemes 32-36. elaboration of R8 can be accomplished by some of the procedures described In Schemes 3 and 2J, by chain extension reactions familiar to those skilled In the art, or by degradation reactions such as conversion of an ester to an a id or an alkene to an aldehyde.
Specifically, the hydroxymethyl group can be activated for the displacement reaction by reacting with thlonyl chloride, PCI5 or with carbon tetra-chlorlde/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 trlf luoromethane sulfonate derivatives. 66 87 As shown In Scheme 32. the hydroxy 1 group can be converted to thlolacetlc add derivative (215) . J. Y. Gauthler, Tet. Lett.. 15 (1986), and to thiol derivative (216) by subsequent hydrolysis.
The hydroxymethyl group on compound (12) can be readily oxidized to an aldehyde group by means of manganese dioxide or cerlc ammonium nitrate. The aldehyde group will undergo chain extension reactions such as the Wlttlg and W1tt1g-Morner reactions and enter Into typical carbon-carbon bond forming reactions with Grlgnard and lithium reagents as well as with compounds bearing activated methylene groups. Alternatively, the hydroxymethyl group can be oxld ed directly to an add functionality which can In 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 (25) can be displaced by the anion of dlalkyl malonate to give the corresponding malonate derivative (2)7) . The saponification of (117) with NaOH (or OH) gives the corresponding diacid which can be decarboxylated to give the corresponding propionic add derivative (2)8) by heating to 120eC. Alternati ely, (£J8) can be directly obtained by refhixlng (217) with a mineral add such as HC1 or sulfuric add. The free add (2J8) can be esterifled by heating 1n a medium of the various alcohols and a catalytic amount of mineral adds such as HC1 or sulfuric add to give the corresponding esters (219) . Alternatively the esters can be obtained by reacting the free add (218) and the corresponding alcohols In 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 thioesters .
Scheme 33 22Q As shown 1n Scheme 34, the chloro group on (£5) can be displaced by the sodium salt or potassium salt of the alkyl, aryl or arylalkyl mercaptans to give the corresponding sulfide derivatives (£21). The amine derivative (222) can be obtained by treating (25) with ammonia or with the corresponding mono-substituted amines. Alternatively, the chloro group may be displaced by sodium azlde to g ve an azlde intermediate which upon reduction with H? over a noble metal catalyst or wUh a reducing agent such as chromous chloride (W. . Warburton, J. Chem. Soc 2651 (1961)) yields (222) where fi10 and R11 are hydrogen. This amine can be subsequently alkylated with alkyl halldes, or reductlvely alkylated with aldehydes and ketones to give alkyl derivatives of {221)· The amines (122) *re converted to the corresponding carbamates (224). sulfonamides (225), amides (226) or ureas (221) by standard procedures Illustrated 1n Scheme 3J. and familiar to one skilled 1n the art.
Scheme 34 The reaction between the thlopyrldyl ester (229) and a suitable Grignard reagent produces the ketones (230).
Scheme 35 229 (R = pyridyl) As shown In Scheme 36 when the Imidazole 4- and/or 5-pos1t1on contains an aldehyde (231) then reaction with organometal 11c reagents such as Grignard or alkyl/aryl lithium reagents will yield alcohols (232J which In turn may be transformed Into a variety of other functionality familiar to one skilled 1n the art.
As shown 1n Scheme 37. ester 2JA may be obtained by direct oxidation of aldehyde £33 with NaCN, Μηθ21n methanol (Corey, E. J., et al. J. Am. Chem. Soc. (1968) 20, 5616). Oxidation of 213 with NaCN, Mn02, and an amine 1n 2-propanol leads to the corresponding amide £3J> (Gllman, N. W. Chem. Comm. (1971) 733). 234 233 R <= alkyl 235 R" or R" = H or a!kyl 236 Saponification of ester 3£ wi ι ι leaa xo carboxyllc add 236.
Aldehyde 212, 1n turn, may be made from the corresponding alcohol 12 by a variety of methods familiar to one skilled 1n the art, including pyr1d1um chlorochromate (PCC), Swern and cerlc ammonium nitrate (CAN) oxidations.
Likewise, the unalkylated hydroxymethyl Imidazole derivative l(R8eCH20H) may undergo the transformations to the aldehyde, ester, carboxyllc add and carboxamlde by the reactions mentioned above for the alkylated case.
Compounds 2_3J (where Ar « p-blphenylyl , p-phenoxyphenyl , or a heteroaryl group as described 1n the scope under the definition of R7) can be prepared by the coupling of an arylmetal derivative (ArM, where MsZnBr, Me3Sn, B(0H)2, etc.) with a halolmldazole 221 In the presence of a transition metal catalyst such as palladium, nickel, platinum, zirconium, etc. (Scheme 38a). Alternatively an Imidazole metal derivative 222 can be coupled to an arylhallde to prepare £38 (Scheme 38b).
The arylmethyl derivatives 24Q can be prepared employing the transition metal catalysed coupling of 221 and an arylmethylmetal (ArCf^M* , where M'eZnBr, etc.), as shown 1n Scheme 38c.
Compounds JLL may be prepared, as described 1n Scheme 38d, by the coupling of an alkenyl- or alkylnylmetal derivative (AM) or the corresponding alkene or alkyne (AH) with 237.
Likewise, the unalkylated Imidazoles (1, where R7eBr 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 R7 1s an alkynyl group, a substituted alkynyl group, or a substituted alkenyl group and the carbon-carbon double or triple bond is not adjacent to the Imidazole ring (e.g., where v 0) 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.
The compounds of formula I where R^ Is a substituted alkyl group (R^=(CH2)wAr, where w=2-10) can be prepared by reduction of the corresponding aikenes (241) by catalytic hydrogenatlon. 97 Scheme 38 (cont.) C£C(CH2)yCH3 CsCtCHj^P ' CEC(CH2),,Ar P ' « phenyl or substituted phenyl 20 x «= 0-8 y = 0-7 z = 0-4 25 30 35 Compounds of formula I where R^ « vinyl or arylalkenyl and R8 - CH2OH, aldehyde, or COOH can be prepared as shown n 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) H5, 217), can be converted Into their corresponding dlesters (2J3) by simply refluxlng 1n an alcohol solvent In the presence of an add such as HCl, or by many other methods familiar to one skilled In the art.
Dlester (£43) can then be converted Into Its metallic salt by reaction with sodium methoxlde, sodium ethoxlde, 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 (g) to yield benzyl Imidazole (244). The above alkylatlon sequence may be also performed by heating or refluxlng the benzyl hallde (tosylate or mesylate) (2) with Imidazole (243) 1n a solvent such as DMF In the presence of an acid scavenger such as potassium or sodium carbonate.
Dlester (2J4) can be reduced with lithium aluminum hydride 1n an Inert solvent such as THF to the corresponding dlalcohol (215). Selective oxidation of dlalcohol (245) with manganese dioxide in an inert solvent such as THF yields primarily aldehyde (2iZ) with a minor product dlaldehyde (£46). Separation of (2£7) from (246) either by crystallization or chromatocjraphlcally, followed by Wlttlg reaction of (£4 ) with methylenetrlphenylphosphorane or the appropriately substituted arylalkylldenetrlphenyl-phosphorane In an Inert solvent such as THF yields the 4-alkenyl-5-hydroxymethyl Imidazole (248). Further oxidation of (£48) with the Dess-Martln perlodlnane [J^ Org. Chem,. (1983) 48, 4155), with manganese dioxide," with pyrldlnlum chlorochromate, 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*, or R3 If „ necessary yields the 4-alkenyl 1m1dazole-5-carboxaldehyde (249).
Oxidation of (249) with, for example, manganese dioxide/cyanide 1on (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-aUenylimtdazole-5-carboxyl1c acid (250).
Scheme 39 where T=H, y=H, (CH2)X-Aryl or T and y taken together form a cyclic ring of 3-8 carbons and the reglochemlstry about the double bond In 248, 249 and 250 can be Z or E. 101 Imidazoles represented by structure (251) where X 1s CI, Br, or I and E is an electron withdrawing group such as an ester, ketone, nltro, alkylsulfonyl , arylsulfonyl, etc., can undergo the nudeophlllc aromatic substitution reaction (H. Schubert, H. Simon* A. J mar, Z. Chem. (1968) 62-63) where the leaving group X 1s substituted by a nucleophlle such as sulfur, carbon, or nitrogen to yield adducts (£52J (Scheme 40). The reaction can be done 1n hydroxyllc solvent such as methanol or non-hydroxyl 1c solvent such as DMSO at room temperature to the reflux temperature of the solvent. The nucleophlle sometimes must be converted Into Its anion to make 1t more nucleophlUc. For example, thlophenol can be refluxed 1n methanol 1n the presence of sodium etlioxlde and the halolmUazole (251). Other nucleophlles Include other alkyl and arylthlols, heteroarylthlols, thlolacetlc acid, alkyl and aryl sul onamldes, heleroarylsulfonainldes, dlacylamlnes, alkyl and arylamlnes, heteroarylamlnes, etc., familiar to one skilled 1n the art.
If a sulfur nucleophlle Is used, the resultant sulfides can be oxidized to the corresponding sulfoxides and stilfones by methods familiar to one skilled 1n the art. 102 j Scheme 40 251 252 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 1n degrees centigrade and parts and percentages are by weight.
Example 1 PART A: Preparation of 2-n-Propyl-4,5- d1carbomethoxy1m1dazole. 2-n-Propyl 1m1dazole-4,5-d1carboxy11c add [prepared by the method of R.G. Fargher and F.L. Pyman (J. Chem. Soc, (1919) 1J5, 217), mp 257 (dec.) »C] (17.14 g, 86.6 mmol, 1 eq), methanol (400 mL) and acetyl chloride (38.1 mL, 534 mmol, 6 eq) were cautiously mixed (acetyl chloride addition to methanol 1s 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.
Recrystall 1zat1on from hexane/ethyl acetate yielded 11.41 g of a white solid (58%); mp: 162.0-164.5eC. NMR (CDC13) 6 3.95 (s,6H); 2.78 (t,2H); 1.83 (t of t, 2H,J=7,7Hz); 0.97 (t , 3H, J=7Hz) ; IR (neat) 1735 cm-1. Anal, calcd. for (H20)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-tr1pheny1methyl- (lH-tetrazol-5-yl))b1phenyl 4 '-Methylbl henyl -2-n1tr11e (preparation described In European patent application 0253310, published on 20.01.88) (10.00 g, 51.7 mmol , 1 eq), trl-n-butylt1n 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 tr1tyl chloride (14.99 g, 53.8 mmol, 1.04 eq) were then added and the mixture stirred for 24 h after which water (39 mL) and heptane (100 mL) were added. The resultant slurry was stirred at 0eC 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 148.0-155.0eC (dec). These solids were slurried In ethyl acetate (75 mL) and filtered to yield 15.Og of a light yellow powder: mp 164.0-165.5°C (dec). NM (CDCI3) 6 7.91 (d, 1H, J*9Hz) ; 7.53-7. IB (m,13H); 7.02-6.84 (m,9H); 2.25 (s,3H).
Preparation of 4-Bromomethyl-2,-(N- tr1 henylmethyl-(lH-tetrazol-5-yl))b1 phenyl , a representative procedure. 4-Methyl-2'-(N-tr1phenylmethyl-(lH-tetrazol- 5-yl))b1phenyl (52.07 g, 109 mmol , 1 eq), N- bromosucc1n1m1de (19.4 g, 109 mmol, 1 eq) , benzoyl peroxide (1.0 g) and carbon tetrachloride (300 mL) were mixed and refluxed for 2.5 h. The reaction was cooled to room temperature and the succ1n1m1de 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) 6 4.37 (CH2Br). This material was suitable for further transformation. 106 Preparation of 4,5-d1carbomethoxy-2-n-propyl l-[(2'-(N-tr1phenylmethyl-(lH-tetrazol-5- yl ) )b1 phenyl -4-yl ) methyl] 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) 1n DMF at room temperature. Foaming and gas evolution occurred. The temperature was Increased to 60eC 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-tr1pheny1methyl-(lH-tetrazol-5-yl))b1phenyl (24.64 g, 44.2 mmol, 1 eq). After 24 h, the solvent was removed In vacuo, and the residue was flash chromatographed In 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. Recrystal 1 izatlon from ethanol yielded 107 an analytical sample (white crystals); mp: 124.0-125.5°C. N R (CDC13) 6 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 C43H38 4: C, 73.49; H, 5.45; N, 11.96. Found: C, 73.23; H, 5.48; N, 12.22.
PART F. : Preparation of 4,5-d1hydroxymethyl-2-n- propyl-l-[(2'-(N-tr1pheny1methyl-(lH- tetrazol-5-yl ) )b1 phenyl -4-yl )methyl] Imidazole. 4, 5-D1c rbontethoxy-2-n-prop l-l-[(2'-(N-tr1pheny1methyl-(lH-tetrazol-5-yl))b1phen l-4-yl )nietliyl] Imidazole (9.88 g, 14.1 mmol , 1 eq) was dissolved In a mlnlnuim of THF and to this solution, lithium aluminum hydride (1.0 M 1n 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 Stelnhardt procedure (Fleser & Fleser 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 CelUe™. The filtrate was dried (MgS0.j) and the solvent removed In vacuo to yield 8.83 g of a yellow glass which could not be recrystal 1 ized. This Intermediate was suitable for further transformation. N R (DMSO-de) 67.82 (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, 1H,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). I (neat) 3300 br; 3061; 1027; 1006; 909; 732; 699 cm"1. Anal, calcd. for C4 ιΗ3β 6θ2·Η2θ: C, 74.07; H, 6.06; N, 12.64. Found: C, 74.06; H, 5.95; N, 11.86. 109 PART F: Preparation of 5-hydroxymethy1-2-n-propy1-l- [(2'-(N-tr1phenylmethyl-(lH-tetrazol-5- yl))b1 phenyl -4-yl)methyl] Imidazole- 4-carboxaldehyde and 2-n-propyl-l-[(2,-(N- tr1phenyl»ethyl-(lH-tetrazol-5-yl))b1phenyl-4 yl)methyl]1m1dazole-4,5-d1carboxaldehyde. , 5-D1 hyd o xymethyl -2-n-propy 1 -1 - [ (2 * - (N-trlphenylmethyl (lH-tetrazol-5-yl))b1phenyl-4-yl)methyl]1m1dazole (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 CelUe™, the cake washed with THF, and the solvent of the filtrate removed In vacuo. The residue was flash chromatographed 1n 1:1 hexane/ethyl acetate to 100% ethyl acetate over s111 ca gel to yield the d I aldehyde which eluted first; 1.25 g (15¾) of a tan glass. NMR (DMS0-d6) 6 10.27 (s.lH); 10.17 (s.lH); 7.81 (d, IH, 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 C 1H34N6O2: C, 76.62; H, 5.33; N, 13.07. Found: C, 76.46; H, 5.54; N, 12.94.
Continued elutlon yielded the 4-hydroxymethyl1m1dazole-5-carboxaldehyde product as a light yellow solid: mp 164.5-166.0eC. NMR (DMSO-dg) 6 9.86 (s, IH); 7.80 (d, IH, J-9Hz) ; 7.63 (t, IH, 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, IH, 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, calcd. for 0 ^3^502» (H20)o.i: C, 76.16; 110 Ill H, 5.64; N, 12.84. Found: C, 76.02; H, 5.36; N, 12.84.
Preparation of 5-hydroxymethyl-2-n-propyl-l [ (2 ' - (N-tr1pheny 1 methyl - ( ΙΗ-tet razol -5- yl))b1phenyl-4-yl)methyl] -4- vinyl -Imidazole n-BuL1 (2.5 M 1n THF) (1.70 niL, 4.3 mmol, 2.1 eq) was added dropwlse to a suspension of methyltrl-phenylphosphonlum bromide (1.53 g, 4.3 mmol, 2.1 eq) 1n 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-tr1phenylmethyl-(lH-tetrazol-5-yl))b1phenyl-4-yl)methyl]1m1dazole-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 (MgSO.}), the solvent removed In vacuo, and the residue flash chro atographed over silica gel In 1:1 hexane/ethyl acetate to yield 620 mg (48¾) of a white glass: NMR (DMSO-d ) 6 7.79 (d,lH,J=7Hz); 7.62 (t, 1H, J=7Hz) ; 7.55 (t, 1H, 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 (m.lH); 5.73 (d of d,lH,J=17,3 Hz); 5.17 (s,2H); 5.10 (t, 1H,J»7Hz) ; 5.05 (d of d,lH,J=12,3Hz); 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 0 2Η3β 6θ·Η2θ: 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- tr1 henylmethyl-(lH-tetrazol-5- yl ))b1phenyl -4-yl )methyl]-4- inyl-1m1dazole- 5-carboxaldehyde. 5-hyd oxymethyl -2-n-propy1 -1- [(2 ' - (N- tr1phenylmethyl-(lH-tetrazol-5-yl))b1phen l-4- yl)methyl]-4-v1nyl1m1dazole (470 mg, 0.73 mmol, 1 eq), Dess-Marlln perlodlnane (J. Pro. Chem. (1983) £8, 4155) (341 mg, 0.80 mmol, 1.1 eq) and methylene chloride (lOniL) were mixed and stirred under nitrogen overnight. The solvent was removed in vacuo and the residue flash chromatographed 1n 3:2 hexane ethyl acetate over s1 Hca gel to yield 310 mg (66%) of a white glass. NMR (DMSO- d6) 69.91 (s.lH); 7.80 (d, 1H,J=7Hz) ; 7.61 (t.lH, J*7Hz); 7.54 (t, 1H, 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 112 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) . I (neat) 1658 cm"1. Anal, calcd. for 042^6^0· (H20)n.5: 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-y1 )b1phenyl -4-yl)methyl]-4-v1nyl-1m1dazole- 5-carboxaldehyde. 2-n-propyl-l-[(2'-(N-tr1phenylmethyl-(lH-tetrazol-5-yl))b1phenyl -4-yl )methyl]-4-v1nyl -Imidazole' 5-carboxaldehyde (330 mg), trl fluoroacetlc 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 In vacuo. The residue was flash chromatographed 1n 1:1 hexane/ethyl acetate to 100% ethanol to yield 270 mg of a white glass. NMR (DMSO-d6) 69.92 (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 (N jol) 1680 cm"1. 113 Example 2 PART A: Preparation of 5-hydroxymethyl-4-1odo-2-n propyl Imidazole.
A solution of 31.5 g of 4(5)-hydroxymethyl-2- n-propyl Imidazole and 50.6 g of N-1odosucc1nlm1de 1n 560 mL of l,4-d1oxane and 480 niL 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 169-170eC. NMR (DMSO-de) δ 12.06 (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 4-1odo-2-n-propy11m1dazole-5 carboxaldehyde To a solution of 35.8 g of 5-hydroxymethyl-4- 1odo-2-n-propyl Imidazole 1n 325 mL of glacial acetic 114 add at 20eC was added dropwlse over 1 h 290 mL of 1.0 N aqueous cerlc ammonium nitrate solution. The resulting mixture was stirred at 20eC 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 recrystalllzed from 1-chlorobutane to furnish 29.9 g of product as a light yellow solid; mp 141-142eC. NM (CDCI3) 6 11.51 (br s.lH); 9.43 (s.lH); 2.81 (t,2H); 1.81 (sext., 2H); 0.97 (t,3H).
Preparation of 3-n-propyl-4- (phenylethynyl)1ni1dazole-5-carboxaldehyde.
A solution of 2.64 g (0.01 mol) of 4-1odo-2-n-propyl1m1dazole-5-carboxaldehyde, 25 mL of dry DMF, 2.5 mL of tr1ethylam1ne, 1.00 g (0.001426 mol) of b1s(trtpheny1phosph1ne)pallad1um chloride and 5.00 g (0.017 mol) of (phenylethynyl)tr1butylt1n was heated to 70eC 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 115 residue was dissolved In 200 mL of methylene chloride and extracted three times with 100 mL of 10% HC . 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 ol, 23%) of 3-n-propyl-4- (phenylethynyl)1m1dazole-5-carboxaldehyde. NMR (CDC13) 69.89 (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). 116 The following intermediates could be prepared by the procedure described in example 2, part C: Preparation of 4-phenylethyny1-3-n-propyl-l [(2'-(lH-tetrazol-5-yl)b1phenyl-4-yl) methyl ]1m1dazole-5-carboxaldehyde. 3-n-Propyl -4- (phenyl ethynyl ) 1m1dazole-5-carboxaldehyde was alkylated with 4-bromomethyl-2'-(N-tr1 phenyl met hyl -(lH-tetrazol-5-yl))b1phenyl by the procedure described 1n example 1, parts D and I, to yield the entitled product. NMR (CDCI3) 6 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. 118 Table 1 Example No. mp (°C) 3 n-propyl 4-CF3 4 n-propyl 4-O e 5 n-propyl 4-COOH 6 n-propyl 4-CON(Me)2 7 n-propyl 4-SO2CH3 8 n-propyl 4-S02NMe2 9 n-propyl 3-CF3 10 n-propyl 3-OMe 1 1 n-propyl 3-COOH 12 n-propyl 3-CON(Me)2 13 n-propyl 3-SO2CH3 14 n-propyl 3-S02NMe2 15 n-butyl 4-CF3 16 n-butyl 4-OMe 17 n-butyl 4-COOH 18 n-butyl 4-CON(Me)2 19 n-butyl 4-SO2CH3 20 n-butyl 4-S02N e2 21 n-butyl 3-CF3 22 n-butyl 3-OMe 23 n-butyl 3-COOH 24 n-butyl 3-CON(Me)2 25 n-butyl 3-SO2CH3 26 n-butvi 3-S02NMe2 Example 27 PART A: Preparation of 4-(furan-2-yl)-2-n- propyl1midazo)e-5-carboxaldehyde.
A solution of 2.64 g (0.01 ol) of 4-1odo-3-n-propyl 1m1dazole-5-carboxaldehyde, 60 mL of toluene, and 0.33 g (0.00029 mol) of tetrak1str1phenylphosph1ne palladium (0) was stirred at room temperature under nitrogen, while a solution of 2.34 g (0.0174 mol) of furan-2-ylboronlc add 1n 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 1n 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% HC1. The HC1 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, 120 5-carboxaldehyde. NM (CDCI3) 6 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 1n Example 27, part A: Table 2 R6 R7 mp (OC) n-propyl glassa n-propyl wax D n-propyl n-propyl n-propyl n-propyl n-propyl 122 Table 2, continued.
R6 R7 mp (OC) N n-propyl . l A s n-propyl n-propyl n-propyl n-propyl n-propyl *0 123 Table 2, continued.
R6 R7 n-propyl n-propyl n-propyl n-propyl n-propyl 124 Table 2, continued.
Table 2, continued.
R6 R7 mp (OC) n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl Table 2, continued.
R7 mp (°C) n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl Table 2, continued.
R6 R7 mp (OC) n-butyi n -butyl n-butyl aN R (CDCI3) 910.25 (s,1H); 9.85 (s, 1H);7.B5 (m, 2H);7.65 (m, 3H); 7.25 (m, 4H); 2.83 (t, 2H); 1.85 (m, 2H); 1.05 (t, 3H). bNMR (CDCI3) d 11.45 (bs,1H);9.88 (s, 1H);7.55 (m, 1H);7.37 (m, 1H);7.13 (m, 1H); 2.73 (t, 2H); 1.80 (m, 2HJ;0.91 (t, 3H).
CNMR (D SO-D6) 39.66 (s, 1H), 7.70 (m, 1H), 7.38 (m.2H), 7.11 (m, 2H), 7.04 (m, 4H), 2.70 )t, 2H), .80 (m, 2H), 0.97 (t, 3H). 129 PART Β: Preparation of 4-(furan-2-y1)-2-n-propyl-l- [(2'-(lH-tetrazo1-5-yl)b1phenyl-4- yl )niethyl] 1m1dazole-5-carboxa1dehyde. 4-(furan-2-yl)-2-n-propyl1m1dazole-5 carboxaldeliyde was transformed Into the entitled product by the procedures described 1n Example 1, parts D and I: mp 129 (dec). NMR (CDCI3) 6 10.15 (s, 1H) ; 7.95 (d.lH); 7.55 (m,2H); 7.38 (m,2H); 7.10 (d,2H); 6.98 (d,2H); 6.85 (d.lH); 6.45 (m.lH); 5.55 (s,2H); 2.55 (t,2H); 1.70 (m,2H); 0.91 (t,3H).
The examples In Table 3 could be prepared by the procedures described In example 27 using the appropriate starting materials: 130 Table 3, continued. mp (°C) Table 3, continued.
Example No. mp (OC) 41 n-propyl 42 n-propyl 43 n-propyl 44 n-propyl 45 n-propyl 133 1 Table 3, continued. mp (OC) Table 3, continued.
Example No. mp (OC) aNMR (CDCI3) d 9.81 (s, 1 H), 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). bNMR (CDCI3) 9 9.69 (s, 1H), 8.10 (m, 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 In 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. 139 93 π ■propyl 4-CF3 COOH single bond CN4H 94 η ■propyl 4-OMe COOH single bond CN4H 95 η •propyl 4-COOH COOH single bond CN4H 96 π ■propyl 4-CON(Me)2 COOH single bond CN4H 97 η •propyl 4-SO2CH3 COOH single bond CN4H 98 η •propyl 4-S02NMe2 COOH single bond CN4H 99 η •propyl 3-CF3 COOH single bond CN4H 100 η •propyl 3-OMe COOH single bond CN4H 101 η ■propyl 3-COOH COOH single bond CN4H 102 η •propyl 3-CON(Me)2 COOH single bond CN4H 103 η •propyl 3-SO2CH3 COOH single bond CN4H 104 π •propyl 3- S02NMe2 COOH single bond CN4H 105 n-butyl 4- CF3 COOH single bond CN4H 106 n-butyl 4-OMe COOH single bond CN4H 107 n-butyl 4-COOH COOH single bond CN4H 108 n-butyl 4-CON(Me)2 COOH single bond CN4H 109 n-butyl 4-SO2CH3 COOH single bond CN4H 1 10 n-butyl 4-S02NMe2 COOH single bond CN4H 11 1 n-butyl 3-CF3 COOH single bond CN4H 1 12 n-butyl 3-OMe COOH single bond CN4H 1 13 n-butyl 3-COOH COOH single bond CN4H 1 14 n-butyl 3-S02NMe2 COOH single bond CN4H Tabl e 4 (conti nued) Ex. No. R6 R R8 A mp (OC) 15 n-propyl 4-CF3 CHO single bond NHSO2CF3 16 n-propyl 4-OMe CHO single bond NHSO2CF3 17 n-propyl 4-COOH CHO single bond NHSO2CF3 1 8 n-propyl 4-CON(Me)2 CHO single bond NHSO2CF3 19 n-propyl 4-SO2CH3 CHO single bond NHSO2CF3 20 n-propyl 4-S02NMe2 CHO single bond NHSO2CF3 21 n-propyl 3-CF3 CHO single bond NHSO2CF3 22 n-propyl 3-OMe CHO single bond NHSO2CF3 23 n-propyl 3-COOH CHO single bond NHSO2CF3 24 n-propyl 3-CON(Me)2 CHO single bond NHSO2CF3 25 n-propyl 3-SO2CH3 CHO single bond NHSO2CF3 26 n-propyl 3-S02NMe2 CHO single bond NHSO2CF3 27 n-butyl 4-CF3 CHO single bond NHSO2CF3 28 n-butyl 4-OMe CHO single bond NHSO2CF3 29 n-butyl 4-COOH CHO single bond NHSO2CF3 30 n-butyl 4-CON( e)2 CHO single bond NHSO2CF3 31 n-butyl 4-SO2CH3 CHO single bond NHSO2CF3 32 n-butyl 4-S02NMe2 CHO single bond NHSO2CF3 33 n-butyl 3-CF3 CHO single bond NHSO2CF3 34 n-butyl 3-OMe CHO single bond NHSO2CF3 35 n-butyl 3-COOH CHO single bond NHSO2CF3 36 n-butyl 3-S02N e2 CHO single bond NHSO2CF3 4 (continued) n-propyl 4-CF3 CHO -NHCO- n-propyl 4-O e CHO -O- n-propyl 4-COOH CHO -S- n-propyl 4-CON(Me)2 CHO -NH- n-propyl 4-SO2CH3 CHO -OCH2- n-propyl 4-S02NMe2 CHO -SCH2- n-propyl 3-CF3 CHO -CH2O- n-propyl 3-OMe CHO -NHSO2 n-propyl 3-COOH CHO -SO2NH n-propyl 3-CON( e)2 CHO -CH=CH n-propyl 3-SO2CH3 CHO -CO- n-propyl 3- S02N e2 CHO -CH2- n-butyl 4- CF3 CHO -NHCO- n-butyl 4-OMe CHO -O- n-butyl 4-CON(Me)2 CHO -S- n-butyl 4-SO2CH3 CHO -NH- n-butyl 4-S02NMe2 CHO -CH2S- n-butyl 3-CF3 CHO -SCH2- n-butyl 3-OMe CHO -SO2NH n-butyl 3-COOH CHO -CO- n-butyl 3-S02NMe2 CHO -CH2- 143 Ex. No. R6 A mp (OC) 158 n-propy) * J COOH single bond CN4H AT 159 n-propyl C00H 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 COOH single bond CN4H 164 n-propyl COOH single bond CN4H » 5 con nue 167 n-propyl . l CHO single bond COOH 168 n-propyl CH0 single bond COOH 169 n-propyl iJCy cho sin9,ebond cooh 170 n-propyl CH0 sin9,e bond C00H Tabl e 5 (continued) 171 n-propyl CHO single bond NHS<¾CF3 172 n-propyl CHO single bond NHSO2CF3 173 n-propyl CHO single bond NHSO2CF3 174 n-propyl cho single bond NHSO2CF3 175 n-propyl CHO single bond NHSOJCFJ Table 5 (contl Table 5 (continued) 83 n-propyl T1 CHO single bond CN4H CH3 CHO single bond CN4H n-propyl N { CH3 CHO single bond CN4H 185 n-propyi Tabl e 5 (conti nued) CHO single bond CN4H n-propyl n-propyl CHO single bond CN4H CHO single bond CN4H 188 n-propyl CHO single bond CN4H 189 n-propyl Tabl e 5 (contl 190 n-propyl CHO single bond CN4H 191 n-propyl CHO single bond CN4H CHO single bond CN4H 193 n-propyl CHO single bond CN4H Tabl e 5 (conti nued) CHO single bond CN4H n-propyl CHO single bond CN4H 196 n-propyl COOH single bond CN4H 197 n-propyl C00H single bond CN4H CH2OH single bond CN4H CH2OH single bond CN4H CH2OH single bond CN4H CH2OH single bond CN4H 202 n-propyl JO CH2OH single bond CN4H 203 n-propyl CH2OH single bond CN4H 204 n-propyl CH2OH single bond CN4H Tabl e 5 (contl t 205 n-propyl C=C-H CHO single bond CN4H 206 n-propyl ¾-CHC-CH3 CHO single bond CN4H 207 n-propyl — C s C - CHJ*CH3 CHO single bond CN4H 208 n-propyl •¾-C=C-CH2-Ph CHO single bond CN4H 209 n-propyl CHO single bond CN4H 21 0 n-propyl CHO single bond CN4H 21 1 n-propyl CH0 SING,E BOND C ,4H 21 2 n-propyl <ζ Se CHO single bond CN4H Table 5 (continued) 213 n-propyl jQf iQ) CHO single bond CN4H 214 n-propyl CHO single bond CN4H 215 n-propyl CHO single bond CN4H 216 n-propyl CHO single bond CN4H CHO single bond CN4H 217 n-propyl CHO single bond CN4H 218 n-propyl 219 n-propyl CHO single bond CN4H Table 5 (contl 20 25 30 35 155 The following compounds in Table 6 were prepared or could be prepared by the procedure in example 1 : Table 6 Re A mp (°C) 221 n-butyl CHO CN4H cls 222 n-butyl CHO CN4H 223 n-butyl CHO CN4H 224 n-butyl CHO CN H 225 n-butyl yQ CHO CN4H Table 6, continued.
Ex. No. R6 R7 Re A mp (oC) 226 n-butyl JO CHO CN4H 227 n-propyl CHO CN4H cls 228 n-propyl CHO CN4H 229 n-propyl CHO CN4H 230 n-propyl COOH CN4H 231 n-propyl CHO COOH 232 n-propyl JO COOH CN4H 157 Table 6, continued.
Ex. No. R6 Re mp (oC) 158 Table 6, continued.
Ex. No. Re R7 Re A mp (oC) 239 n-propyl CN4H 240 n-propyl COOH 241 n-butyl CHO CN4H Example 242 Preparation of 2-n-Buty 1 -4-pheny 1 th1 o-l- [(2 ' - (1H-tetrazol-5-yl )b1 phenyl -4-yl ) methyl] Imidazol e-5-carboxyaldehyde 2-n-Butyl -4-chloro-l-[ (2' -N-tr1 phenyl -methyl (lH-tetrazol -5-yl )b1 phenyl -4-yl )methyl]-imidazol e-5-carboxyaldehyde (synthesized as described in European Published Application Number 0 324 377, 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 methoxlde 1n methanol (sodium: 205 mg,8.9 mmol, 10 eq; methanol, 40 mL) and the mixture refluxed overnight under Ng. The solvent was removed 1n 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 mL) . 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 redlssolved 1n water (50 mL) . The pH was adjusted to 1 with cone. HC1. 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-butylchlor1de yielded a white solid (142 mg): mp 1435-145.5eC. NMR (DMS0-d6) δ 9.82 (s, 1H); 7.80-761 (m, 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 C28H26N60S,(H20)o.4'- C 6 -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 European Published Application 0 324 377 (published 7.19.89) or by other methods familiar to one skilled in the art.
Tabl e 7 Ex. No. R6 R7 Re A mp (oC) 243 n-butyl C00H 142.5-143.5 244 n-butyl COOH a 245 n-butyl CN4H 246 n-butyl CHO COOH c 247 n-butyl CHO CN4H 248 n-butyl CHO CN4H 162 3 Tabl e 7 (conti nued) Ex. No. R6 R7 Re A mp (oC) 249 n-propyl -NHCOCH3 CHO CN4H 250 n-propyl CHO NHS02CF3 CN4H 251 n-propyl CHO COOH 252 n-propyl COOH COOH 253 n-propyl CH2OH COOH 254 n-propyl CH2OH CN4H Table 7 (continued) Ex. No. R6 R? Re mp (oC) 255 n-propyl CHO COOH 256 n-butyl CHO CN4H 257 n-butyl CHO CN4H 258 n-butyl CH2OH CN4H 164 Ex. No. R6 R? Re mp (oC) 259 n-propyl CHO COOH 260 n-propyl CHO CN4H 261 n-butyl CHO CN4H 262 n-butyl CHO CN4H 263 n-butyl CHO CN4H 264 n-propyl CHO CN4H CH2OH COOH CHO COOH CHO CN4H H); 7.59 (d, 1H, J=8Hz); &.50-7.10(m, (d, 2H, J=8Hz); 5.32 (s,2H); 2.66 (t, 2H, Hz); 1.28 (t of q, 2H, J=7,7Hz); 0.82 (t, bNMR (DMSO-d6) 39.80 (s, 1H); 8.41 (d, 1H, J=7Hz); 7.72 (d, 1H, J=7Hz); 7.55 (d, 1H, J=7Hz); 7.49-7.25 (m, 3H); 7.19 (t, 2H, J=7Hz); 7.09 (d, 2H, J=7Hz); 6.95 (d, 2H, J=7Hz); 5.63 (s, 2H); 2.70 (t, 2H, J=7Hz); 1.57(toft,2H,J=7,7Hz); 1.29 (t of q, 2H, J=7,7Hz); 0.81 (t, 3H, J=7Hz).
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 (t of q, 2H, J=7,7Hz); 0.78 (t, 3H, J*7Hz).
Example 268 Preparation of 2-n-propy I -4-cyclobutyl 1 deny 1 - 5-hydroxymethyl-l-[(2'-(N-tr1phenylmethyl-(lH tetrazol -5-yl ) )bi phenyl -4-yl ) methyl] Imidazole (δ-Bromo-n -butyl ) trl phenyl phosphonl urn bromide (7.42 g, 0.0155 mmol , 2 eq) was suspended 1n THF (125 mL) and 0.75 potassium hexamethyldl si lazane (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-hydroxymethyl -l-[(2 ' - (N-triphenylmethyl- (lH-tetrazol - 5- l ) )bi phenyl -4-yl -methyl ] 1midazole-4-carboxaldehyde (5.00 g, 7.75 mmol, 1 eq) as a slurry 1n 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 (DMSO-ds) δ 7.78 (rn.lH); 7.61 (t,lH, J=7Hz); 7.54 (t , 1H, J=7Hz) ; 7.48-7.20 (m.lOH); 7.03 167 (d,2H,J=8Hz); 6.96-6.70 (m,8H); 5.99 (s.lH); 5.13 (s,2H); 4.97 (t, IH, 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. ((C45H 2N60*(H20)o.75) C. H, N.
PART B: Preparation of 2-n-propyl -4-cyclobutyl idenyl 5-hydroxymethyl-l-[(2'-(lH-tetrazol-5- yl )b1 phenyl -4-yl ) methyl] Imidazole. 2-n- Propyl -4-cyclobutyl Idenyl -5-hydroxymethyl -l-[(2'-(N-triphenylmethyl-(lH-tetrazol-5-yl))b1phenyl-4-yl )methyl] imidazole (1.00 g), methanol (25 mL) and THF (15 mL) were mixed and refluxed for 24 h. The solvents were removed In vacuo and the residue Immediately flash chromatographed quickly 1n 1:1 pentane/ethyl acetate to 100% Isopropanol and eventually to 100% ethanol to yield 320 mg of a light yellow glass: NMR (DMS0-d6) 6 7.59 (d, IH, J=7Hz) ; 7.54 (t,lH,J=7Hz); 7.46 (t, IH, J=7Hz) ; 7.42 (d, IH, 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. (C26H28N60) c- H. Ν· 168 Utility The hormone angiotensin II (All) produces numerous biological responses (e.g. vasoconstriction) 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 1 igand-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) 1n Tr1s buffer and 2 nM of 3H-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 3H-AII trapped In filter was quantitated by scintillation counting. The inhibitory concentration (IC50) of potential All antagonist which gives 50% displacement of the total specifically bound 3H-AII 1s 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"5M or less (Table 8). 169 Table 8 Angiotensin II Antihypertensive Receptor Effects 1n renal Binding Hypertensive Rats IC50 Intravenous Oral Ex. No. (/jmolar) Activity1 Activit 0.013 + ♦ 2 0.021 + ml 27 0.17 + NT3 28 0.35 NA NT 47 0.21 NA NT 242 0.024 + + 243 0.28 NA NT 244 0.37 NA NT 245 0.024 + + 246 0.27 + NT 268 0.044 NT NT Significant decrease 1n blood pressure at 3.0 mg/kg or less Significant decrease 1n blood pressure at 30 mg/kg or less - 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.
Not tested.
Not tested at 30 mg/kg p.o. 170 The potential antihypertensi e 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 [Canglano 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 1s 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 pretreatment levels to determine the antihypertensive 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, 1n some cases administration can be by the oral route.
The compounds can be administered by any conventional means available for use 1n conjunction with pharmaceuticals, either as Individual therapeutic agents or 1n 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 warmblooded animal Is a member of the animal kingdom possessed of a homeostatlc 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 hemodynamic burden on the heart to relieve the congestion.
The active Ingredient can be administered orally 1n solid dosage forms, such as capsules, tablets, and powders, or 1n liquid dosage forms, such as elixirs syrups, and suspensions. It can also be administered parenteral ly, 1n sterile liquid dosage forms.
Gelatin capsules contain the active Ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be 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 If necessary, buffer substances. Antioxidi zing agents such as sodium bisulfite, sodium sulfite, or ascorbic add, 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 preservati es, such as benzal koniuni 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 173 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 mlcrocrystal 11ne cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase pa 1 tab 111 ty or delay absorption.
Injectable A parenteral composition suitable for administration by Injection Is prepared by stirring 1.5% by weight of active Ingredient In 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 milliliters 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 milliliters 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 In 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. 174 Examples of NSAID's that can be combined with All blockers of this Invention: Dose Drug Formulation Route Indomethacln 25 Tablet Oral (2/3 times dally) Meclofenamate 50-100 Tablet Oral (2/3 times dally) Ibuprofen 300-400 Tablet (3/4 times dally) Pi oxl cam 10-20 Tablet (1/2 times dally) Sul 1ndac 150-200 Tablet Oral (2 times dally) Azapropazone 200-500 Tablet Oral (3/4 times dally) 175 Examples of diuretics that can be combined with All blockers of this Invention: Dose Drug Formulation Route Benzothladlzldes 25-100 (dally) Tablet Oral (e.g. hydrochlorothl Loop diuretics 50-80 (dally) Tablet Oral (e.g. furosemlde) When used with an NSAID, the dosage of All blockers will generally be the same as when the All blocker is 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 In the treatment of chronic renal failure. 176
Claims (58)
1. An antihypertensive compound of the formula 95258/2 178 Is H; CI; Br; I; F; NO2; CN; alkyl of 1 to 4 carbon atoms; acyloxy of 1 to 4 carbon atoms; alkoxy of t to 4 carbon atoms; C02H; C02R9; NHS02CH3; NHSO2CF3; C0NH0R * aryl ; or furyl ; R4 is CN, N02 or C02Rn; 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; R5 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 C0 R14; cycloalkyl of 3 to 8 carbon atoms, cycloal kyl al kyl of 4 to 10 carbon atoms; cycloalkyl lkenyi or cycioalkylalkynyl of 5 to 10 carbon atoms; (CH2) sZ(CH2)mR:) optionally substituted with F or C02R14; 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; 95258/2 179 1s vinyl; cycloal kyl ί deny 1 ; aikynyl of 2-10 carbon atoms; phenylalkynyl where the aikynyl portion 1s 2-6 carbon atoms; heteroaryl selected from 2- and 3-thlenyl, 2- and 3-furyl , 2-, 3-, and 4-pyrldyl, 2-pyrazlnyl, 2-, 4-, and 5-pyrim1d1nyl , 3- and 4-pyrldazlnyl, 2-, 4- and 5-thiazolyl , .2-, 4-, and 5-selenazolyl, and 2-, 4-, and 5-oxazolyl, 2- or 3-pyrrolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl; o-, m- or p-bi phenyl l ; o-, m- or p-phenoxyphenyl ; 2-oxazol 1 n 1 ; 2-th 1 azol 1 nyl ; said . phenylalkynyl, heteroaryl, blphenylyl or plienoxyphenyl being optionally substituted with 1 or 2 substltuents selected from halogen, hydroxy, mercapto, alkoxy of 1-5 carbon atoms, alkyl of 1-5 carbon atoms, -N02, -CN, -CF3, -COR16, -CH2OR17, 95258/2 180 -NHC0R17, -C0NR18R19, S(0)RR17, and S02NR18R19; pyrrolyl, pyrazolyl or Imldazolyl as defined above substituted on ring nitrogen with alkyl of 1-5 carbon atoms, phenyl or benzyl; or alkyl, alkenyl, or alkynyi of 1 to 10 carbon atoms optionally substituted with a . _ _.-· — -heteroaryl, b,1phenylyl or phenoxyphenyl group as defined above; -S(0)r-heteroaryl , -S-(0)r-biphenylyl ,/-S(0)r-phenoxypheny1 , -S-tetrazole, -S(0)rR17,,;-NR18R19, -NR18-heteroaryl, -NR18-phenyl , -NR18-b1phenylyl , -NR18-phenoxyphenyl , -N-phthal 1m1do, -NH-SO?-phenoxyphenyl , -NH-S02-heteroaryl, -NH-S02-b1pheny1yl , -NH-S02-R17, ÷ _: -S-(C=0)-R17, N-1midazolyl , N-l,2,3-tr1azoly1', . N-l,2,4-triazolyl , where heteroaryl 1s a heterocycle defined 1n the scope of R7 and where the phenyl grou 1n R17 of -S-(0)rR17, the N-1m1dazolyl , N-1,2,3-triazolyl . and N-l,2,4-tr1azolyls may be substituted with one or two substltuents as described above for heteroaryl; Is R14; -(CH2)nSR15; R14 0 0 -CH=CH(CH2)sCHOR15; -CH=CH(CH2) SCR16; -CR16; 0 -CH=CH(CH2)sOCRU; -(CH2)m-tetrazolyl ; 0 Y (CH2)s-CH-C0R16; -(CH2)nCR16; -(CH2)n0CNHR10; I CH3 Y 0 -(CH2)nNRnC0R10; -(CH2)nNR11CNHR10; -(CH2)nNR11S02R10; Y -(CH2)nNRUCR10; R24 O R9 Is -CH-OCR21; R10 1s alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6 carbon atoms, 1-adamantyl, 1-naphthyl, l-(l-naphthyl)ethyl , or (CH2)pC6H5; R11 Is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R12 is H, methyl or benzyl; Rn 1s -C02H; -C02R9; -CH2C02H, -CH2C02R9; or 181 R14 1s H, alkyl or perf luoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl ; R15 1s 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; R16 1s H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH2)pC6H5, OR17, or NR18R19; R17 Is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R18 and R19 Independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, a-methylbenzyl , or taken together with the nitrogen form a ring of the formula Q is NR20, 0 or CH2; R20 1s H, alkyl of 1-4 carbon atoms, or phenyl; R21 Is a!kyl of 1 to 6 carbon atoms, -NR22R23, or -CHCH9C09CH.; R22 and R23 Independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together as (CH2)U where u is 3-6; R24 Is H, CH3 or -C6H5; R25 1s NR27R28, OR28, NHC0NH2, NHCSNH2, R26 Is hydrogen, alkyl with from 1 to 6 carbon atoms, benzyl , or allyl ; R27 and R28 are independently hydrogen, alkyl with from 1 to 5 carbon atoms, or phenyl; 182 95258/2 183 R^J and RJU are Independently alkyl of 1-4 carbon atoms or taken together are -(CH2)q-; R31 or. R32 Is H, N02, NH2l OH or 0CH3; X Is a carbon-carbon single bond, -CO-, -CH2-, -0-, -S-, -NH-, - , -CON- , - -, -0CH2-, -CH 0-, -SCH2-, -CH2S-( -NHC(R27) (R28)-, -NR23S02-, -S02NR23-, -C(R27) (R28)NH-, -CH=CH-, -CF-CF-, -CH=CF-, 14 17 25 OR OCOR NR R290 OR30 \ / -CH- , -CH ■C- or -C- Y is 0 or S; z is 0, NR11, m 1s 1 to 5; n Is 1 to 10; P Is 0 to 3; q 1s 2 to 3; r i s 0 to 2; s 1s 0 to 5; t 1s 0 or 1; or a pharmaceutically acceptable salt thereof; provided that: (l) when R1 1s , X Is a single bond, 95258/2 184 N-N 13 and R13 Is C02H, or N , then R must. be 1n the ortho or meta position; or when R1 and X are as above and R13 1s NHSO2CF3 or NHSO2CH3, R13 must be ortho; when R1 1s . X 1s a single bond, a single bond, then R1J must be ortho except when X = NR23CO and R13 Is NHS02CF3 or NHS02CH3, then R13 must be ortho or meta; (3) when R1 1s !-CC^H or a salt thereof, R6 cannot be S-alkyl; (4) when R1 1s -CO2H or a salt thereof, the s bstl tuent on the 4-pos1t1on of the Imidazole cannot be CH20H, CH2OCOCH3, or CH2C02H; (5) when R1 is R° 1s not methoxy- benzyl ; tlie R6 group 1s not -CHCH2CH2CH3 or CH2OH; \
2. A compound of Claim 1 having the formul (Π) 95258/2 185 wherein R and R are as defined in Claim 1, R6 is 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 R8 is -(CH2)m-tetrazolyl, -(CH2)n0Ru; -(CH )n0CR14; -CH=CH(CH2)S ?CR16, -CH=CH(CH2)s fCHOR15; 0 0 -(CH2)nCR16; -(CH2)nNHC0R10; -(CH2)nNHS02R10; 0 or -CR16; N-N R13 1s -C02H, -C02R9, NHS02CF3; S03H; or N I N H R16 is H, alkyl of 1 to 5 carbon atoms, OR17, or NR18R19; X 1s carbon-carbon single bond, -CO-, -CH2CH2-, -NC0-, -0CH2-, -CH20-, -0-, -SCH2-, R23 -CH2S-, -NHCH2-, -CH2NH- or -CH=CH-; or a pharmaceutically acceptable salt thereof.
3. A compound of Claim 2 wherein: IS H, alkyl of 1 to 4 carbon atoms, halogen, or alkoxy of 1 to 4 carbon atoms; ' R6 1s alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms; R7 is heteroaryl selected from 2- and 3-thlenyl, 2- and 3-furyl, 2-, 3-, and 4-pyrldyl, or p-b1phenylyl R8 is -(CH2)m0Rn; - (CH2)m0CR14; -CH=CH-CH0R15; 0 0 -(CH2)mCR16; -CH2NHC0R10; -(CH2)mNHS02R10; or -COR16; R10 is CF3 , alkyl of 1 to 6 carbon atoms or phenyl; R11 is H, or alkyl of 1 to 4 carbon atoms; R13 Is C02H; C02CH2OCOC(CH3)3; NHS02CF3 Riq is H, or alkyl of 1 to 4 carbon atoms; R1^ 1s H, alkyl of 1 to 4 carbon atoms, or acyl of 1 to 4 carbon atoms; 186 95258/2 187 R16 1s H, alkyl of 1 to 5 carbon atoms; OR17; or m 1s 1 to 5; X = single bond, -0-; -CO-; -NHC0-; or -OCH2-; or a pharmaceutically acceptable salt thereof..
4. A compound of Claim 3 wherein R* 1s and X is a single bond, or a pharmaceutical ly suitable salt thereof,
5. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a compound of any one of Claims 1 through 4,
6. Pharmaceutical composition of 'Claim 5 which additionally contains a diuretic or a non-steroidal antiinflammatory drug.
7. A method of preventing renal failure 1n a non-human warm blooded animal resulting from administration of a non-steroidal anti-inflammatory drug (NSAID) which comprises administering, stepwise or 1n physical combination with the NSAID, a compound of any of Claims 1 through 4 in an amount effective' to prevent renal failure.
8. A method of treating hypertension 1n anon-human warm blooded animal comprising administering to the animal 1n an amount effective to lower the animal 's blood pressure a compound of any of Claims 1 through 4. 95258/2 188
9. Method of Claim 8 wherein a diuretic is administered to the animal prior to or simultaneously with the Imidazole compound.
10. A method of treating congestive heart failure in a non-human warm-blooded animal comprising administering to the animal a compound of any one of Claims 1 through 4 In an amount effective to correct the hemodynamic burden on the heart to relieve the congestion.
11. A process for the preparation of a compound of Claim 1 wherein r is 1 whic comprises contacting an imidazole derivative of Formula 1 with a benzyl derivative of Formula 2 1n a solvent 1n the presence of a base for about 1 to about 10 hours at a temperature in the range of about 20eC to the" reflux temperature of the solvent to form a benzyl imidazole of Formula 3: 3 wherein each of R1, R7 and R is stable under the reaction conditions and 1s a group as defined in Claim 1 or an intermediate or protected form thereof which can be transformed to such a group and wherein X1 is halogen, p-toluenesul fonyloxy or methyl sul fonylox ; and thereafter as necessary transforming said Intermediate or protected forms of the R groups to R groups as defined in Claim 1. 95258/2 189
12. Process of Claim 11 wherein compounds 1 and 2 are contacted 1n the presence of a base selected from the group consisting of a metal hydride (HH) , a metal -alkoxide (MOR) , sodium carbonate, potassium carbonate, t r1 ethyl ami ne and pyridine, 1n a dipolar aprotlc solvent or, where the base 1s MOR, the solvent can be an alcohol, ROH, where M 1s lithium, sodium or potassium and R is methyl, ethyl or t-butyl.
13. Process of Claim 11 wherein a two-phase solvent system, one an organic phase such as methylene chloride and the other an aqueous phase, Is used in the presence of a phase transfer catalyst such as tri capryl methyl ammonium chloride.
14. Process of Claim 12 wherein: R1 is X 1s a carbon-carbon single bond, -CO-, -0-, -S- -NH-; R2 and R3 are each independently H, Clr Br, I, CO2R14 , -F.( O2, alkyl of 1 to 4 carbon atoms, alkoxy o.f 1 to 4 carbon atoms, aryl or furyl; R6 and R7 are as defined 1n Claim 1; R8 is -(CH2)nORn; -(CH2)nSR15; or -(CH2)nCN; R11 Is as defined In Claim 1; R13 is C02R14, CN, N02, trlalkyl tin tetrazole, or trityltetrazole; and R14 and R15 are as defined in Claim 1.
15. Process of Claim 14 wherein R13 1s -CO2R14 and the product of Formula 3 1s contacted with an alkali In an aqueous alcoholic solvent or with CF3CO2H at a temperature In the range of about 20CC to the reflux temperature of the solvent for about 1-24 hours, followed by adjustment of the pH of the mixture to a value In the range of 3 to 7, to convert the product to the corresponding product wherein R13 1s -CO2H.
16. Process of Claim 15 wherein at least one of R2, R3 or R13 In Formula 1 is -CO2R1 and 1s converted to -CO2H.
17. Process of Claim 15 wherein R14 1s t-butyl and the reaction 1s conducted 1n CF3CO2H.
18. Process of Claim 14 wherein R13 1s -CN and the product of Formula 3 1s contacted with (1) a strong acid at reflux temperature of the solvent for about 2-96 hours or (1i) a strong alkali 1n an alcohol solvent at a temperature 1n the range of about 20°C and the reflux temperature of the solvent for about 2-96 hours followed by adjustment of the pH to about 3-7, or (Iii) sulfuric acid followed by add or alkali, to convert the product to the corresponding compound wherein R13 is -CO2H.
19. Process of Claim 18 wherein at least one of R2, R3 or R13 1s -CO2R14 and is converted to -CO2H.
20. Process of Claim 18 wherein R8 Is -(CH2)nC and is converted to -(CH2)nC02H, or Is -(CH2)nORn and Is converted to (CH2)nOH when R13 Is converted to -CO2H. 190
21. Process of Claim 14 wherein R13 is -CN and the product of Formula 3 1s contacted with a mixture of eq linolar amounts of sodium azide and ammonium chloride In a polar aprotlc solvent at a temperature in the range of about 30°C to the reflux temperature of the solvent, for about 1 hour to 10 days, to convert the product to the corresponding compound wherein R* 1s 5-tetrazolyl .
22. Process of Claim 21 wherein R8 Is -(CH2)m N and 1s converted to -(CH2)m-tetrazolyl when R13 1s converted to 5-tetrazolyl.
23. Process of Claim 14 wherein R13 1s -CN and the product of Formula 3 Is reacted with trial kyl t 1 n azide or trlaryltin azide followed by acidic or basic hydrolysis to convert the product to the corresponding compound wherein R*3 Is 5-tetrazolyl.
24. Process of Claim 14 wherein R13 1s -CN and the product of Formula 3 1s reacted with trlalkyltln azide or trlaryltin azide to produce a compound of Formula 3 wherein R^3 1s trialkyl or trlaryl stannyl tetrazol -5-yl , the latter compound 1s reacted with triphenylmethyl chloride to produce a compound of Formula 3 wherein R13 1s triphenylmethyl -tetrazol -5-yl , and the latter compound 1s hydrolyzed to produce a compound of Formula 3 wherein R13 is 5-tetrazolyl.
25. Process of Claim 23 wherein R8 1s -(CH2)nC and is converted to - (CH2)m-tetrazolyl when R*3 is converted to 5-tetrazolyl.
26. Process of Claim 14 wherein R1J 1s -NO2 and the product of Formula 3 Is contacted with a reducing 191 agent to form a second Intermediate of Formula 3 1n which R13 1s H , and the latter 1s contacted with an anhydride (CH3S02)20 or (CF3S02)20 or a chloride CH3SO2CI or CF3SO2CI of sulfonic acid In a solvent to produce a compound In which R* is -NHSO2CH3 or -NHSO2CF3.
27. Process of Claim 26 wherein at least one of R2, R3, or R13 Is - O2 and is converted to -NHSO2CH3 or -NHSO2CF3.
28. Process of Claim 15 or 18 wherein the compound of Formula 3 with R13=CC>2H either (a) 1s contacted with about 1-4 equivalents of thlonyl chloride 1n excess th1 on 1 chloride or another solvent at a temperature in the range of about 20°C to the reflux temperature of the solvent for a period of about 5 minutes to about 2 hours to form an intermediate of Formula 3 wherein R13 Is C0C1, and the latter Is contacted with about 2-10 equivalents of hydroxyla ine derivative H2NOR12 1n excess liydroxylamine derivative H2 OR12 or other solvent, at a temperature In the range of about 25-80°C for about 2-18 hours, or (b) 1s contacted the hydroxylamine derivative H2 0R12, dicyclohexylcarbodl 1m1de and 1-hydroxybenzotriazole 1n a solvent at a temperature in the range of about 0-30°C for about 1-24 hours; to provide a compound In which R13 1s CONHOR12. 192 95258/2 193
29. Process of Claim 11 wherein: R1 1s X is a carbon-carbon single bond, -CO-, -0-, -S-, or - H-; R2, R3, R6 and R7 are as defined 1n Claim 1; and Ra is (CH2)n0Rn, (CH2) n0CQR14 , (CH2)nCH(0H)R16, (CH2)nC0R16 (CH2)nC1, (CH2)„CN, CHO.
30. Process of Claim 29 wherein R8 is (CH2)n0H and the product of Formula 3 is contacted with an a cohol R^OH in the anhydrous state 1n the presence of a strong acid or a Lewis acid, followed by saponification of any C02R^ groups concomitantly formed or present in Intermediate 2, to form the corresponding compound of Formula 3 wherein R8 1s (CH )n0RH and R11 is not H.
31. Process of Claim 29 wherein R8 1s (CH2)n0Rn and R1J is not H and the product of Formula 3 Is contacted with an aqueous acidic medium at a temperature 1n the range of about 25°C and the reflux temperature of the solvent for a period of about 0,5-24 hours to form the corresponding compound of Formula 3 wherein R8 is (CH2)n0H.
32. Process of Claim 29 wherein R8 1s (CH2)„0H and the product of Formula 3 1s contacted with (a) a carboxyllc acid anhydride (R14C0)20 or chloride R14C0C1 1n a solvent 1n presence of a base at a temperature In the range of about 0°C and the reflux temperature of the solvent for about 0.5-24 hours or (b) a carboxyllc add R14C02H under anhydrous conditions In presence of a strong add or Lewis add at about 0°-100°C for about 0.5 to 24 hours, to form the corresponding compound 1n which R8 Is (CH2)nOCOR14.
33. Process of Claim 29 wherein R8 1s (CH2)nOCOR14 and the product of Formula 3 1s contacted with aqueous add or alkali to form the corresponding compound wherein R8 1s (CH2)n0H.
34. Process of Claim 29 wherein R8 Is (CH2)n0H and the product of Formula 3 1s contacted with an oxidizing agent at a temperature of about 25-45°C for about 1-200 hours to produce a corresponding compound of Formula 3 In which R8 Is (CH2)n-lC0R16 and R16 1s H.
35. Process of Claim 29 wherein R8 1s (CH2)nC0R16 and R16 1s H and the product of Formula 3 is contacted with an organometal 11c compound R16P In which P is MgBr or L1 1n a solvent at a temperature In the range of about -78°C to 100°C for about 0.5-24 hours to form a compound of Formula 3 1n which R8 Is (CH2)nCH(0H)R16 and R16 1s not H.
36. Process of Claim 29. wherein R8 1s (CH2)nCH(0H)R16 and R16 1s not H and the product of Formula 3 Is contacted with an oxidizing agent 1n a solvent to form a corresponding compound of Formula 3 1n which R8 1s (CH2)nC0R16 and R16 1s not H. 194
37. Process of Claim 29 wherein R8 Is (CH2)nC0R16 and R16 1s H and the compound of Formula 3 Is contacted with an oxidizing agent In a solvent to form a corresponding compound of Formula 3 in which R8 Is (CH2)nC0R16 and R16 Is OH.
38. Process of Claim 29 wherein R8 1s (CH2)nC0R16 and R16 is OH and the compound of Formula 3 Is contacted with thlonyl chloride in excess or 1n another solvent at a temperature In the range of about 0°C to the reflux temperature of the solvent for about 5 minutes to about 24 hours to form a corresponding compound of Formula 3 1n which R8 1s (CH2)nCOCl followed by contact of the latter with an amine NH l8Rl in excess or 1n a solvent at temperatures In the range of about 0°C and reflux temperature of the solvent for about 5 minutes to about 24 hours to form a corresponding compound of Formula 3 1n which R8 1s (CH2)nC0NR18R19.
39. Process of Claim 29 wherein R8 1s (Cl^nOR11 and R11 Is H and the product of Formula 3 1s contacted with thionyl chloride 1n excess or In a solvent at a temperature in the range of about 20°C to the reflux temperature of the solvent for about 0.5-24 hours to form an Intermediate compound of Formula 3 1n which R8 1s (CH2)nCl.
40. Process of Claim 39 wherein the compound of Formula 3 in which R8 is (CH2)nCl 1s contacted with sodium or potassium salt of a mercaptan R^SH 1n a solvent at a temperature 1n the range of about 25-100°C for about 1-24 hours to form a compound of Formula 3 1n which R8 Is (CH2)nSR15. 195
41. Process of Claim 29 wherein the compound of Formula 3 1n which Re 1s (CH2) ncl is contacted with an alkali metal cyanide In a solvent at a temperature in the range of about 20-100°C for about 1-24 hours to form a compound of Formula 3 In which R8 1s (CH2)nCN and the latter compound Is hydrolyzed to the corresponding compound of Formula 3 In which R8 Is (CH2)nC0R16 and R16 1s OH.
42. Process of Claim 29 wherein the compound of Formula 3 1n which R8 Is (CH2)n-lcl 1s contacted with the sodium or potassium salt of a dlalkyl malonate In a solvent at a temperature In the range of about 20-100°C for about 0.5-24 hours to form a compound of Formula 3 In which R8 Is (CH2)n_iCH(C02al kyl )2 followed by saponification of the latter with aqueous alkali at a temperature in the range of about 25°C to the reflux temperature of the solvent followed by acidification with mineral add to form a compound of Formula 3 1n which R8 is (CH2)n_iCH(C02H)2 followed by heating the latter to about 120°C or 1n dilute mineral add at reflux temperature to form a product of Formula 3 1n which R8 Is (CH2)nCOR16 and R16 Is OH.
43. Process of Claim 29 wherein R8 1s -CH0 and the compound of Formula 3 1s contacted with a methylene phosphorane (C6H5) 3P=CH(CH2) sCHR14OR15 or ( 6H5)3P=CH(CH2)SC0R16 in a solvent at a temperature 1ii the range of about 25eC to the reflux temperature of the solvent for about 1-24 hours to form a compound of Formula 3 in which R8 Is -CH=CH(CH2) sCHR140R15 or -CH=CH(CH2)sC0R16, except where R15 Is H and R16 Is OH, and optionally then contacting the compound of Formula 3 in which R8 Is -CH=CH(CH2)sC0R16 with a reducing agent In a solvent at a temperature of about 0°-25eC 196 for about 0.5-24 hours to form a product of Formula 3 In which 8 Is -CH=CH(CH2) sCHR140H.
44. Process of Claim 29 wherein R8 Is (CH2)n0H and the compound of Formula 3 1s contacted with an Isocyanate of Formula R10NCO In a solvent at a temperature in the range of about 25°C to the reflux temperature of the solvent for a period of about 5 minutes to about 24 hours to form a compound of Formula 3 In which R8 is (CH2)n0C0NHR10.
45. Process of Claim 29 wherein the compound 1n which R8 1s (CH2)nCl 1s contacted with an amine RUNH2 in excess amine or another solvent for a period of about 1-24 hours at a temperature In the range of about 0°C to the reflux temperature of the solvent to form an intermediate of Formula 3 1n which R8 1s (CH2)nNHRn.
46. Process of Claim 29 1n which R8 1s (CH2)nCl and the compound of Formula 3 Is contacted with an alkali metal azide In an aprotlc solvent at a temperature in the range of about 25-80°C for about 1-24 hours to form a compound of Formula 3 1n which R8 is (CH2)n 3 and the latter 1s contacted with a reducing agent to form an Intermediate of Formula 3 1n which R8 is (CH2)nNH2.
47. Process of Claim 45 or 46 1n which R8 1s (CH2)|1 H 11 or (CH2)nNH2 and the compound of Formula 3 Is contacted with a chloroformate of Formula R10OCOC1 or a sulfonyl derivative of Formula R10S02C1, or (R10SO )2O 1n * solvent in the presence of a base at a temperature In the range of about 0°C to the reflux temperature of a solvent for about 5 minutes to about ' 197 95258/2 198 24 hours to form a compound of Formula 3 1n which R8 1s -(CH2),1NR11C02R10 or -(CH2)n nS02R10.
48. Process of Claim 45 or 46 1n which the compound of Formula 3 with R8 equal to -(CH2)nNHR11 or (CH2)|-]NH2 is contacted with an Isocyanate or isothiocyanate R10NCY 1n a solvent at a temperature 1n the range of about 25°C to the reflux temperature of the solvent for about 5 minutes to about 24 hours to form a compound of the Formula 3 1n which R8 is -(CH2)nNR11CYNHR10.
49. Process of Claim 11 wherein R1 1s NO2 and R2, R3, R6, R7, and R8 are as defined 1n Claim 34 1n which the compound of Formula 3 wherein R1 1s O2 is reduced by means of Iron and acetic add, stannous chloride, or hydrogen and palladium to a compound of Formula 3 wherein R1 1s NH2 and the latter Is reacted with an appropriate add anhydride such as phthaiic anhydride or a substituted phthaiic anhydride in a solvent or with an appropriate add chloride such as substituted anthranlUc add chloride In the presence of aqueous alkali or a base or with an appropriately substituted phthaiic or. anthranl 1 ic add in the presence of dlcyclohexylcarbodl lmide 1n a solvent to produce a compound of the Formula 3 In which R1 1s and X is NHCO. 95258/2 199
50. Process of Claim 11 wherein R1 1s OCH2C6H5, R2 and R3 are H and R6, R7, and R8 are as defined 1n Claim 11 and the resulting compound of Formula 3 with R1 equal to OCH2C5H5 1s contacted with tri fluoroacetlc acid at reflux temperature for a period of about 0.2-1 hour or with hydrogen and palladium to form the corresponding compound of. Formula 3 1n which R* 1s OH and the latte is contacted with a base at about 25eC and a suitable bei yl allde of the formula: to produce the~correspond1ng compound of Formula 3 wherein R* is and X is -OCH2-.
51. Process of Claim 11 wherein R8 1s -CHO, whereby the benzyl derivative of Formula 2 attaches to the imidazole derivative of Formula 1 preferentially at the nitrogen atom adjacent the carbon atom of the imidazole ring to which R8 1s attached.
52. A process for the preparation of a compound of Claim 1 wherein r Is 0 which comprises contacting an Imidazole derivative of Formula 1 or its metallic salt with 4-f luoro-l-n1 trobenzene 1n a solvent, 1n the presence of a base 1f the free Imidazole 1s used, for 1-10 days at a temperature of 25-150°C to form an N-p enyl Imidazole followed by elaboration to compounds wherein X=NHC0 by the process described In Claim 49.
53. A process of Claim 29 wherein R8 1s CHO, and X 1s a carbon-carbon single bond, and the product of Formula 3 Is contacted with an organometal 11c reagent such as R^MgBr or R11 L1 1n the presence of an anhydrous nonhydroxyl 1c solvent such as ether, THF or dimethoxyethane at -78 to 25°C followed by aqueous work-up followed by add hydrolysis of any CO ^ groups where Is t-butyl or hydrolysis of any tri tyl -protected tetrazole groups to form the corresponding compound of Forumula 3 wherein R8 1s -(CH2)n-rCH-Rl1. wnere rU ≠ Η·
54. A process for the preparation of the compounds of claim 1 where R7 = substituted or unsubstUuted blphenylyl, phenoxyphenyl , or heteroaryl, characterized 1n that halolmldazoie 237 1s coupled with an arylmetal derivative ArM, where M=ZnBr, t^Sn, B(0H)2, etc. 1n the presence of a transition metal catalyst such as palladium, platinum, nickel, or zirconium, to form an aryl Imidazole 238: 200 95258/2 201 237 238 i 6 where 1, R R and r have the meanings given in Claim 1, X 1s Br or I, H 1s ZnBr, Me3Sn, B(0H)2, etc., and Ar 1s substituted or unsubsti tuted biphenylyl , phenoxyphenyl , or heteroaryl .
55. A process for the preparation of the compounds of Claim 1 where R7=subst1tuted or unsubsti tuted blphenylylmethyl , phenoxyphenylmethyl , or heteroarylmethyl characterized in that a halolmldazole 237 is coupled with an arylmethylmetal derivative ArCh^M' 1n the presence of a transition metal catalyst to form an ar Imeth 11m1 dazol e 240: 237 240 95258/2 202 where R1, R5, R8 and r have the meanings given In Claim 1, X 1s Br or Ι,'Η' Is ZnBr, etc., and Ar Is substituted or unsubs L I ttited heteroarylmethyl , biphenylmethyl , phenoxyphenylmethyl .
56. A process for the preparation of the compounds of Claim 1 where R7=v1ny1, alkynyl, substituted alkenyl, or substituted alkynyl characterized in that a halolmidazole 23 Is coupled with an ] -al kenylmetal or an 1-al kynylmetal derivative (AM) , or an 1-alkene, or an 1-alkyne (AH) In the presence of a transition metal catalyst to form a 1-alkeiiyl- or 1-al kynyl imldazol e 241: where R1, . . . R6, R8 and r have the meanings given in Claim 1,' X Is Br or I, M Is a metal , A is vinyl , CH=CH(CH2)xAr, C=C (CH2)yCH3 , C5C(CH2)zPh\ or C=C(CH2)xAr, Ph ' 1s phenyl or substituted phenyl, 95258/2 203 and Ar 1s substituted or imsubstl t ted blplenylyl, phenoxyphenyl or heteroaryl, x=0-8, y=0-7 and 2=0-4.
57. A process for the preparation of the compounds of claim 1 where ^=v1nyl or substituted alkenyl characterized In that Imidazole aldehyde 253. 1 s reacted with methylenetrlphenylphosphorane or a substituted niethylenetrlphenylphosphorane to form a vi nyl imidazole or a substituted al kenyl 1 ml dazo 1 e 254 : or n=0-5 where R1, R6, R8 and r have the meanings given In Claim 1, Ar 1s substituted or unsubstl tuted biphenylyl, phenoxyphenyl or heteroaryl, and u + v = 0 to 8. 95258/2 204
58. A process for the preparation of the compounds of Formula I wherein R7 1s -S (0) r-heteroaryl , -S-(0)r-biphenylyl , -S (0) r-phenoxyphenyl , -S-tetra2ol e, -S(0),-R17, -NR18R19, -MR18-heteroary1 , -NR18-pheny1 , - R18-bi phenylyl , -NR18phenoxyphenyl , -N-p thal 1mido, -NH-S02-plienoxyphenyl , -NH-S02~heteroaryl , -NH- S02-biphenylyl , -NH-S02-R17, and -S- (C=0) -R17 , N- imldazolyl, N-l,2,3-tr1azolyl , and N-1 ,2, 4-triazolyl , characterl zed 1n that Imidazole containing compounds 255 substituted with an electron withdrawing group E are reacted with n cl eophl 1 es 1n a suitable solvent at room temperature to the reflux temperature of the solvent resulting 1n an aromatic substitution reaction whereby the leaving group X is substituted with a nucleophile Nu where Nu is -S (0) r-heteroaryl ; -S (0)r-biphenylyl; -S (0) r-phenoxyphenyl ; -S-tetrazole ; -S(0)rR17,-NR18R19; -NR18-heteroaryl ; -NR18-phenyl ; -NR-^-biphenylyl ; -NR-^-phenoxyphenyl -N-phthalimido ; -NH-S02-phenoxyphenyl -NH-S02-heteroaryl ; -NH-S02-biphenylyl ; -NH-S02-R17; -S- (C=0) -R17 ; N-imidazolyl ; N-1 , 2 , 3-triazolyl ; or N-1 , 2 , 4-triazolyl , to produce compounds of structure 256 : 255 256
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IL9525890A IL95258A (en) | 1990-08-01 | 1990-08-01 | Substituted imidazoles, their preparation and pharmaceutical compositions containing them |
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IL9525890A IL95258A (en) | 1990-08-01 | 1990-08-01 | Substituted imidazoles, their preparation and pharmaceutical compositions containing them |
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IL95258A0 IL95258A0 (en) | 1991-06-30 |
IL95258A true IL95258A (en) | 1994-08-26 |
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IL9525890A IL95258A (en) | 1990-08-01 | 1990-08-01 | Substituted imidazoles, their preparation and pharmaceutical compositions containing them |
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