CA1075689A - Substituted imidazoles, their preparation and use - Google Patents
Substituted imidazoles, their preparation and useInfo
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- CA1075689A CA1075689A CA257,658A CA257658A CA1075689A CA 1075689 A CA1075689 A CA 1075689A CA 257658 A CA257658 A CA 257658A CA 1075689 A CA1075689 A CA 1075689A
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Abstract
ABSTRACT OF THE DISCLOSURE
The invention relates to novel imidazoles of the formula:
wherelr. R and R1 are independently selected from hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl having 1-3 substituents, aryl, substituted aryl having 1-5 substituents, heterocyclic group having 5-6 ring atoms, halogen, cyano, carboxy and carboxy derivatives, and wherein Ra is H or C1-C6 alkyl, R2 is selected from hydrogen, C1-C10 alkyl, hydroxy-C1-C10-alkyl and C3-C6 alkeny1, R3 is aryl having 6 ring atoms of which 0-2 are non-carbon, substituted aryl having 1-4 substit-uents, fused ring aryl havlng 9-10 ring atoms of which 0-2 are non-carbon and substituted fused ring aryl having 1-4 substit-uents, R4 is selected from hydroxy and
The invention relates to novel imidazoles of the formula:
wherelr. R and R1 are independently selected from hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl having 1-3 substituents, aryl, substituted aryl having 1-5 substituents, heterocyclic group having 5-6 ring atoms, halogen, cyano, carboxy and carboxy derivatives, and wherein Ra is H or C1-C6 alkyl, R2 is selected from hydrogen, C1-C10 alkyl, hydroxy-C1-C10-alkyl and C3-C6 alkeny1, R3 is aryl having 6 ring atoms of which 0-2 are non-carbon, substituted aryl having 1-4 substit-uents, fused ring aryl havlng 9-10 ring atoms of which 0-2 are non-carbon and substituted fused ring aryl having 1-4 substit-uents, R4 is selected from hydroxy and
Description
~07~
1 Background_of the Invention 3 The present invent:ion involves novel imidazoles 4 which have antihyper~ensive and ~-adrenergic blocking activity.
6 Various chemical agents axe available for treating 7 hypertension i~ man and animals. Certain tri~luoromethyl 8 imidazoles are known to have substantial antihypertensive 9 activity. These imidazoles are disclosed in U.S. 3,786,061.
Another class of agents known as ~-adrenergic 11 blocking agents, are also available. These ~-blocking 12 agents a~ect cardiac, vascular and pulmonary unctions ; ;
13 and can be mild antihypertensives. Specifically, these 14 agents have the capability o~ reducing heart rate, counterac~ing vasodepression and suppressing bronchodilata-16 tion. ~-adrenergic blocking agents, their ~hemucal structrue 17 and activity, are disclosed in "Clinical Pharmacology and 18 Therapeutics" 10, 292~306 ~1969). Various ~-adren~rgic 1~ blocking agents are also described in the following patents:
U.S. 3,048,3~7; U.S. 3,337,628; U.S. 3,655,663;
; 21 U.5. 3,794,650; U.S. 3,832,470; U.S. 3~836,666;
22 U.S. 3,850,945; U.S. 3,850,9~6; U.S. 3,850,947;
23 U.S~ 3,852,291 and British 1,1~4,548.
24 Where an antihypertensive agent acts pxincipally via vasodilation, it may cause undesirable side effeats 26 such as substantially increased heart rate (tachycardia).
27 Novel imidazoles characterized by having ~mino-28 substituted propoxyaryl su~stitution have been disco~ered.
29 These imidazoles have unexpected antihypertensive activity ~and ~ adrenergic bLocking activity.
, .
.. , . . . - ~ . . .
-~ ` 15524 IA
~7~
1 Summary of the Invention 3 Novel imidazoles having amino substituted ~ropoxy 4 aryl substitution and salts thereof; their preparation;
S pharmaceutical composition containing said Lmidazoles; and 6 method of treatment of animals e.g. those having hypertension 7 or angina pectoris, using said imidazoles.
8 Description of Prefsrred Embodlments An embodiment of the present invention is 11 compounds having the formula 12 R ~4 ~ 5 L3 Rl ~ ~ R3-O-CH2-C~CH2-N
14 ~ 6 17 wherein 18 R and Rl are independently selected from hydrogen, 19 Cl-C10 alkyl, substituted CI-C10 alkyl having 1-3 substituents, cycloalkyl, aryl, substituted 21 axyl having 1-5 ~ubstituents, heterocyclic group 22 having 5-6 ring atoms, halogen, cyano, carboxy and 23 carboxy derivatives and -C~ wherein Ra is H
24 or Cl-C6 alkyl, a 25 R2 is select~d from hydrogen, Cl-C10 alkyl, hydroxy-26 Cl-C10-alkyl and C3 C~ alkenyl, 27 R3 is selected from aryl having 6 ring at~ms of 28 which 0-2 are non-carbon, substituted aryl having 29 1-4 su~stituents, fussd ring aryl having 9-:L0 ring atoms of which 0-2 are non-carbon, a~d 31 ~ubstituted fused ring aryl having 1-4 substituents, .
;; 15524 IA
~075~
1 R4 is selected from hydroxy and -O-~-Rb wherein ~ :
1 Background_of the Invention 3 The present invent:ion involves novel imidazoles 4 which have antihyper~ensive and ~-adrenergic blocking activity.
6 Various chemical agents axe available for treating 7 hypertension i~ man and animals. Certain tri~luoromethyl 8 imidazoles are known to have substantial antihypertensive 9 activity. These imidazoles are disclosed in U.S. 3,786,061.
Another class of agents known as ~-adrenergic 11 blocking agents, are also available. These ~-blocking 12 agents a~ect cardiac, vascular and pulmonary unctions ; ;
13 and can be mild antihypertensives. Specifically, these 14 agents have the capability o~ reducing heart rate, counterac~ing vasodepression and suppressing bronchodilata-16 tion. ~-adrenergic blocking agents, their ~hemucal structrue 17 and activity, are disclosed in "Clinical Pharmacology and 18 Therapeutics" 10, 292~306 ~1969). Various ~-adren~rgic 1~ blocking agents are also described in the following patents:
U.S. 3,048,3~7; U.S. 3,337,628; U.S. 3,655,663;
; 21 U.5. 3,794,650; U.S. 3,832,470; U.S. 3~836,666;
22 U.S. 3,850,945; U.S. 3,850,9~6; U.S. 3,850,947;
23 U.S~ 3,852,291 and British 1,1~4,548.
24 Where an antihypertensive agent acts pxincipally via vasodilation, it may cause undesirable side effeats 26 such as substantially increased heart rate (tachycardia).
27 Novel imidazoles characterized by having ~mino-28 substituted propoxyaryl su~stitution have been disco~ered.
29 These imidazoles have unexpected antihypertensive activity ~and ~ adrenergic bLocking activity.
, .
.. , . . . - ~ . . .
-~ ` 15524 IA
~7~
1 Summary of the Invention 3 Novel imidazoles having amino substituted ~ropoxy 4 aryl substitution and salts thereof; their preparation;
S pharmaceutical composition containing said Lmidazoles; and 6 method of treatment of animals e.g. those having hypertension 7 or angina pectoris, using said imidazoles.
8 Description of Prefsrred Embodlments An embodiment of the present invention is 11 compounds having the formula 12 R ~4 ~ 5 L3 Rl ~ ~ R3-O-CH2-C~CH2-N
14 ~ 6 17 wherein 18 R and Rl are independently selected from hydrogen, 19 Cl-C10 alkyl, substituted CI-C10 alkyl having 1-3 substituents, cycloalkyl, aryl, substituted 21 axyl having 1-5 ~ubstituents, heterocyclic group 22 having 5-6 ring atoms, halogen, cyano, carboxy and 23 carboxy derivatives and -C~ wherein Ra is H
24 or Cl-C6 alkyl, a 25 R2 is select~d from hydrogen, Cl-C10 alkyl, hydroxy-26 Cl-C10-alkyl and C3 C~ alkenyl, 27 R3 is selected from aryl having 6 ring at~ms of 28 which 0-2 are non-carbon, substituted aryl having 29 1-4 su~stituents, fussd ring aryl having 9-:L0 ring atoms of which 0-2 are non-carbon, a~d 31 ~ubstituted fused ring aryl having 1-4 substituents, .
;; 15524 IA
~075~
1 R4 is selected from hydroxy and -O-~-Rb wherein ~ :
2 is Cl-C6 alkyl, and
3 R5 and R6 when separate, are independently selected from
4 hydrogen, Cl-C6 alkyl and substituted Cl~C6 alkyl having 1-3 substituents and, when joined, form a 6 5-6 membered N-alicyclic ring 7 and pharmacologically acceptable acid addition and q~later-8 nary ammonium salts ~hereofO
9 Compounds o particular interest have the formulae: :
13 1 ~ R3-O-CH2-C8-C~ -N
IA
18 ~ N-C~2- ~-C~2 O R3 ~ 1 22 Use~ul R and Rl alkyl groups include unsubstltuted 23 as well as substituted alkyl, cycloalkyl as well as branched 24 and linear alkyl gxoups. These alkyl groups may contain` ``
2$ up to 10 alkyl carbons, preerably up to 8 alkyl carbon 26 atom~ and more pre~erably from 1 to 6 alkyl carbons. Exam-27 ples of sui~able R and Rl unsubstituted alkyl groups are 28 methyl, isopropyl, cyclopropyl, cyclopentyl, 2-methyl-n-2~ butyl, decyl, 2-ethyl-n-hexyl ~uitable R and Rl substituted alkyl group~ have 1 3 substituents such as halo (Cl,Br,I,F) 31 hydroxy, phenyl, Cl-C4 alkoxy,-exemplified by -CC13, bromo-~ .
~ 15524 IA
~L~756~
1 hexyl, CH3-O-C~2-CH2-, hydroxypropyl, dliodethyl, trifluoro-2 methyl, benzyl, chlorodecyl and the like.
3 Useful R and Rl aryl groups inclucle aryl groups 4 having up to 10 ring carbon atoms~ These aryl groups include single ring as well as fused ring aryls, unsubstituted 6 aryls as well as substituted aryls havir~ from l-S sub-7 stituents. These ubstituents include alkyl, preerably 8 C~-C6 alkyl, alkoxy preferably Cl-C6 alkoxy, cyano, halo 9 (Cl, I, Br and F), nitro, amino, carboxy, hydroxy, carb~nyl, -SH, sulfamoyl, thioalkyl, phenyl and the like.
11 Examples of suitable aryl R and Rl groups are phe~yl, 12 chlorophenyl, dibromophenyl, fluorophenyl, toluyl, xylyl, 13 hexylphenyl, dodecylphenyl, tert butylphenyl, methoxyphenyl, 14 C6H13-O-phenyl, HO-C6H4-, carboxyphenyl, H-~-C6H4, sulfamoylphenyl, N,N-dimethylsul~amoylphenyl, naphthyl, 16 indanyl, chloronaphthyl, trichlorophenyl, ~O-CH2-C6H~-, 17 pentafluorophenyl, the tetralin ~roup, cyanophenyl, chloro-18 hydroxyphenyl, Cl-C6-alkyl-S-C6H~-, ~ -SH and the .
19 like.
Useful R and Rl heterocyclic groups have S-6 21 ring atoms of which 1-3 and preferably 1-2 are hetero atoms 22 and the quinolyl group. Substituted a~ well as unsu}:~-23 stituted hetexocycllc groups are included. The hetero atoms 24 are O,S and N. Examples of suitable R and Rl heterocyclic ~5 groups are pyridyl, pyrazinyl, pyrimidinyl, pyrida2inyl 26 sub~tituted pyridyl such a~ dimethylpyridyl, methylpyridylr 27 chloropyridyl, dichlor~pyridyl, diethylpyridyl, trimethyl-28 pyridyl, methylethylpyridyl, et~ylpyridyl, bromopyridyl, 29 and analogous substituted pyrazinyl pyrimidinyl and pyridaz~nyl groups; pyridyl-~-oxide, methylpyridyl-N-oxide, 31 furyl, thienyl a~d the like.
.
.
~17~i~i8~
1 Other useful R and Rl group~ are cyano, carboxy, 2 carboxy derivatives such as -~-O-Cl-C6~alkyl, -~-N~2, 3 N-mono-Cl-C6-alkyl- and N,N-di-Cl-C6 al]cylcarbamoyl;
4 halogen preferably Br, Cl and F; and ~~~Ra wherein Ra is S hydrogen or Cl-C6 alkyl and the like.
6 It is preferred tha~ at least one of R and R
7 is hydrogen.
8 Useful R2 alkyl groups have up to 10 carbons, 9 are unsubstituted or monohydroxysubstituted and include cycloalkyl as well as branched and straight chain alkyl.
11 R2 alkyl groups having 1-6 carbons are preferred, with 1~4 12 carbon atoms more preferred. Examples of sui~able R2 alkyl 13 yroups are methyl, ethyl, decyl, tert-butyl, isopropyl, 14 2,2,4-trimethyl-n-butyl, cyclohexyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxybutyl and the like. Useful R2 16 alkenyl groups have 3-6 carbon atoms and ara examplified by . . .
17 allyl, -CH2 CH2-CH2-C~-C~YCH~ and the like.
18 Preferred compounds are those where R2 is H.
L9 R3 is an aryl group. The aryl group include~
single ring ~6-ring atoms) and fused ring (9-10 ring atoms~
21 groups, having 0-2 nitrogen ring atoms, both substituted as 22 well as unsub~tituted moieties. The R3 heterocyclic groups 23 contain 1 or 2 nitrogen atoms. Examples of such useful 24 heterocyclic groups axe 2-pyridyl, 3-pyridyl, 4-pyridyl, halopyridyl, Cl-C3 alkylpyridyls, pyridyl N-oxide~ Epidyl, 26 pyrazinyl, pyridazinylJpyrimidinyl, quinolyl, and the like.
27 Pre~erred R3 heterocyclic groups are pyridyl, substituted 28 pyridyl e.g. chloropyridyl, methylethylpyridyl, methyl-29 pyridyl~ 2-chloro-4-methylpyridyl, bromopyridyl, 2,4,6 trimethylpyridyl, dlmethylpyridyl, and the N~oxides e.g~
31 pyridyl-N-Qxide, me~hylpyridyl-N-oxide and the like.
.:. . ~ :
` 15524 IA
~L~7~8g 1 Useful R3 carbocyclic aryl groups include phenyl 2 groups and fused ring groups such as naphthyl, tetrahydro-3 naphthyl, indanyl and the like.
4 Preferred R3 carbocyclic aryl groups are those ha~ing the ~ormula 8 (R ) II
where x is 0, 1,2,3 or 4 and Rc includes alkyl groups, both 11 linear and branched, and preferably Cl-C4 alkyl groups, 12 C3-C6 cycloalkyl groups, halogen such as Cl, I, Br or F, 13 alkoxy preferably Cl-C4 alkoxy, hydroxy, nitro, cyano, 14 carbamoyl, N-Cl~C6-alkyl- and N,N-di-Cl-C6-alkylcarbamoyl, and the like. Examples of suitable pr~ferred caxbocyclic 16 aryl groups of Foxmula II are phenyl, tetrahydronaphthyl, 17 fluorophenyl, dibromophenyl, trichlorophenyl, iodophenyl, 18 hydroxyphenyl, toluyl, cresyl, nitrophenyl, carboxyphenyl, 1~ methoxyphenyl, cyclohexylphenyl, aminophenyl, dimethyl-chlorophenyL, butoxyphenyl, dichlorophenyl, cyanophenyl, 21 nitrophenyl, tetramethylphenyl, dimethylphenyl~ carbamoyl-22 phenyl, N,N~dimethylcarbamoylphenyl and the like.
23 An especially pre~erred R3 group is the carbocyclic 24 group having the ormula 26 ~
27 ~Rc)~ :
28 rI A
29 A more preferred R3 carbocyclic group is formula II A where x is 0, 1, 2 or 3. An especially preferred carbocyclic .
. . .~ : . .
756~3~
1 R3 group is formula II A where x is O, 1 or 2. A most 2 preferred carbocyclic group is ~ .
R4 includes the hydroxy group and the ester group Rb-~-O- where ~ is Cl-C6 alkyl such as methyl, isopropyl,~t-butyl, hexyl, ethyl and the like. Compounds where R4 is OH are preferred.
The R5 a~d R6 groups are hydrogen or alkyl groups.
8 The alkyl groups preferably have from 1-6 alkyl carboIl atoms 9 and may be branched, linear, or cyclic; substituted or unsubstitutedO Examples of suitable alkyl groups are methyl, 11 n-hexyl, isopropyl, 2,2,4-trimethyl-n-butyl, cyclopropyl, 12 cyclohexyl, chlorobutyl, tert-butyl, -CH2 ~ , ~ H3 13 -CH2-~CH2)4-cH2 ~ and the like. The R5 and R6 14 groups may also be ioined to fo~m a 5-6 membered N-alicyclic ring such as -N ~ -N ~ -N o - ~ -Z
16 where Z is H or Cl-C10 alkyl, and the like-17 It is preerred tha~ one of R5 and R6 is hydrogen 18 while the othar is Cl C6 alkyl, and preferably C3-C~
19 branched hydrocarbon alkyl.
Compounds of formula I which are pxeferred are ~1 tho~e in which R is hydxogen, represented by the formula 22 1 ~ ~ R3-O-CH~ CH2-N~
26 II~
27 A~other series of pre~erred compounds is that in 28 which R and R2 are each hydrogen~ These compounds have the 29 formula :
.
~1756 3 ~, J~3 -O-C~ 2-C~I-CH 2-N~
IV
6 When R2 is hydrogen, the 4 and 5 positions in the imidazol~
7 are substantially equivalent.
8 A more preferred series of compounds is that of 9 formula IV where Rl i~ selec~ed from hydrogen, trihaloalkyl, preferably -CF3, cyano, -CH3, phen~l, substituted phenyl 11 havlng 1-5 substituents preferably selected from halogen 12 (Cl, Br, F), and heterocyclic group such as thienyl, furyl, 13 methylpyridyl, pyridyl, pyridyl-N-oxide and ~he liXe.
14 Another more preerred series o~ compounds is that having the formula 18 ~ ~ _ O-ch2-c~-c~-N /
19 ,:
' ' :
where Rl is selected from CH3, H, phenyl, pentafluorophenyl, 21 p-chlorophenyl, p-fluorophenyl, p-methoxyphenyl, ~h~nyl,-CF3-22 and pyridyl; x i5 O, 1, 2 or 3 and R~ is halo preferably 23 chloro, Cl~C3 alkyl preferably -CH3, and cyano.
24 Another series of preferred compounds are those ha~ing ~he ~ormula Y where R4 is -O~.
26 ~n a particularly pre~erred series o~ oompound$
27 havi~g formula V, R4 is OH and only one o~ R5 and R6 is 2~ Cl C6 alkyl, preferably cyclic or branched C3-C~ alkyl such 29 as tert-bu~yl, cyclopropyl, 1-methyl-3-phenylpropyl, l-methyl-2-phenyle~hyl a~d the lik~o '.
. .
- -~ 15524 IA
1~7~ii8g 1 An especially preferred series of compounds is 2 one having formula V where Rl is -CF3, R~ is OH and one of 3 R5 and R~ is hydrogen while the other i~; Cl-C6 alkyl, 4 preferably C3-C4 cyclic or branchad hydrocarbon alkyl, especially tert-butyl.
6 The compounds of the present i.nvention include 7 all the optical isomer forms. In o~her words, the 8 compounds include mixtures containing the optical isomers 9 such as racemic mixtures, as well as the individual optical isomers.
11 The compounds of the present invention also include 12 the non-toxic phaxmacologically acceptable acid addition 13 and quaternary ammonium salts of the present lmidazoles.
14 The acid addition salts are prepared by reating the imidazole with an appropriate amount of a suitable organic 16 or inorganic acid. Examples of useful organic acias are 17 carboxylic acids such as maleic acid, tartaric acid, acetic 18 acid, pamoic acid, oxalic acid, propionic acid, salicyclic 1~ acid, succinic acid, citric acid, malic acid, isethionic a~id and the like; useful inorganic acids are hydrohalo 21 acids such as HCl, HBr and HI, suluric acid, H3PO4 and the 22 like.
23 The quaternary salts are characterized by the 24 group R5 ( ~.
2 6 --N-- Rd L
~8 wherein R5 and R6 are Cl-C6 alkyl, Rd is Cl-C6 alkyl and 29 L is the anion of a non-toxic aci.d, preferably a halide such as the iodide. These salt~ axe prepared by any suitable ~ g _ ~75~
1 method - for example, by reacting any i~idazole of the 2 present invention having the tertiary amine group -N ~ 5 , ~ with an alkyl halide, preferably the iodide such as ethyl-iodide or methyliodide, in a suitable solvent such as 6 methanol, ethanol or dimethylormamide (DME). The 7 reaction is generally carried out at room temperature. The 8 quaternary salt is obtained directly on removing the 9 solvent.
Compounds of the present invention may be 11 prepared b~ any convenient method.
12 One method (~ethod A) of preparing the present }3 compounds i9 by amination of a compound having the formula R ~ R3-0-CH2- ~-CH2~X
; 17 R2 18 V~
lq where X is a halogen, preferably Br, I or Cl. When NH3 is 2a the aminating agent, X is replaced by -NH2 while when a 21 primary or secondary, acyclic or alicyclic amine is used, 22 X is replaced by the corresponding -NR5R6 group. Typically, 23 the amination can be carxied out by heating a mixture of the 24 halo campound VI and the amine e.g. t-butylamine for a suf-icient period of time and then isolating the aminat@d 26 pxoduct. U.S. 3,337,628 disclosed such procedures.
27 An especially us~ful method of preparin~ ~midazoles 28 of the pre~ent invention wherein R4 is -OH is by reaction 29 of ammonia or a suitable amine reactant with an epoxy compound as illus~rated by the following general reaction 31 equation:
.. ~ - . ,. -- l~ 15524 IA
~56~3 4 Rl ~ 3 o C~2-HC--C~I2 + R5R6NH
R
7 Rl ~ R3-0-C~ -Ch-Ch -N ~ S
..
11 The reaction is generally carried out in solution with excess 12 amine reactant serving as the solvent. However, other 13 solvents may be used such as triethylamine, pyxidine, tetra-14 hydrofuran and the like. The reaction is conveniently 14 conducted at reflux temperature. However, the reaction temperature can ~e varied ~rom room tempe~ature to temper-16 atures above reflux. The reaction may be carried out at 17 atmospheric pre~sure but it can be carried out at pressures 18 above atmospheric, if desired.
19 A method of preparing compounds of formula I where-in R and R2 are H, Rl is trihaloalkyl and 21 -R -O-CH2-C~ - CH2-N 5 is in the 2 position in the 22 imidazole ring involves the reaction o 1,1,1 trlhalo-3, 23 3-dihaloacetone, aryl aldehyde and N~3. Depending on the 24 type aryl aldehyde u~e~, diferent sequencas of reactions are utilized, these are illustrated by the following sets of 26 equations. In these equations X and Xl are halogen selected 27 from F, Br and Cl - and it is preferred that X is F and 28 X is Br.
.
-~ 15524 IA
~07S~89 ME~HOD C
o xl ~1) X-C-C-l-H WEAK BASE ~ [INTERMEI:)IATE]
x Xl ~ 4 (2) [INTERMEDIATE] ~ H-C-R3-O-CH2-CH-CH2-NR5R6 + NH3 --l~L R3-0-C~2-CEl-C32 NR5R6 l o l 1 (1) X- ~-C-C-H WEA~ BASE [INTERMEDIA~F.
X
O OH Cl (2) ] 3 O CH2 CH CH2 ~ NH3 X-C ~R3-0-C32-c~l-clH
~3 ) 1 STRONG BASE
X-C ~1 R - - Ç \
~N~ 3 C~2 -C -CH2 ( 4 ) ~¦~ HMR5R6 .~ ' .
.:
~ 15524 IA
S~
1 ~ R3-0-CH2-CH-C~2- NR5R6 H
4 The intermediate in the above equations is believed to be a glyoxal (X-~ -H) or a hydra~ed ~ o OH
6 glyoxal (X-l-C- -~). This intermediate is generally X
7 prepared as an aqueous mixture by treating the halogenated 8 acetone with a aqueous solution o~ a weak base such as 9 sodium acetate trihydrate. This solution is heated for a period o~ time and at a temperature sufficient to form the 11 intermediate. On cooling, the intermediate containing 12 solution is added to a solution of the appropriate aryl-13 aldehyde and aqueous ammonia. An~ suitable water miscible 14 301vent may be used. Methanol is conveniently used. The reaction to yield the substitu~ed imida~ole is generaLly 16 conducted at room temperature, although elevated tem-17 peratures may be used. The solvent is then stripped and 18 the product imidazole is reco~ered.
19 ~here the imidazole intermediate has the ~H Cl -R3-0-CH2-C~-~H2 substituent, this intermediate is txeated 21 with a suitable strong base such as KOH, potassium butoxide, 22 ~aO~, or the like, in a solvent such as methanol, to ef~ect 23 conver~ion to the epoxy ~R3-0-CH2-C~_~H2) group~ This epoxy 24 derivati~e is then converted to the desired amine inal product as illustrated abov 26 Still anothe~ method for preparing compounds o~
27 ~ormula I where R2 Ls H and -R3-0-CH2- ~-CH2-N~ 5 is in the 28 2 position in the imidazole is by the reaction of6aryl -~ 15524 IA
~L~75~
1 aldehyde with a glyoxal or acetal thereof and NH3. When 2 the acetal is used, it must first be hyclrolyzed e.g. by 3 treatment with a strong acid solution such as aqueous H2S04.
4 This reaction scheme is illustxated by the ollowing equations:
7 O O O Rg R
Il ll ll I ~ 5 Rl-C-C-R ~ H-C-R3-O-CH~-CH-CH2 N ~ R ~ NH3 12 Rl ~ ~ ~3 O C~2-C~-C~2-N /
13 If, in Method D, the aryl aldehyde used has the formula 14 O OH ~1 ~-R3-O-CH2-C~CH2, the imidazole product would require 16 }I
17 dehydrochlorination and treatmen~ with amine, as shown in 18 Method C sequence 2, steps (3) and (4), to afford the imida-19 zole of the present invention.
The process o~ Method D is generally carried out in 21 solution and at temperatures ranging from about room tempera-22 ture to about 100C. Pressure is not required. 5Olvents 23 used will vary depending on the type of reactants used.
24 Generally, this reaction is carried out in an aqueous solution e.g. H2O or H2O/miscible alkanol.
26 Another method or prepariny Formula I compou~ds 27 ~here R~- i9 other than H is by treating the corresponding 28 aompound whsre R2 is H with a suitable reagent using a 29 recogni ed technique.
Where the R2 group i~ to be an alkyl group, the 31 corresponding Formula I compound whexe R2 is H is alkylated , .. .
~s6~
1 using a suita~le reagent such as diazomethane, an alkyl 2 halide e.g. C~H5-Br, C6H13-I, n-butylchloride and the 3 like, or a dialkylsulfate.
4 Where the R2 group is to be an alkenyl group, recognized alkenylating reagents and techniques axe used.
6 Illustrative of these techniques is the reaction of the - 7 imidazole having R2=H, with NaH followad by treatment with 8 an alkenyl halide e.g. allylbromide to produce the 9 corresponding imidazole having R2=alkenyl.
Where the R2 group is to be hydroxyalkyl, the 11 imidazole wherein R2 is H is reacted with an epoxy compound 12 e.g. 1,2-epoxyethane, 1,2-epoxypropane, 1,2-epoxyhexane 13 to produce the corresponding imidazole where R2 is mono-14 hydroxyalkyl. Conditions (temperature, catalysts, solvents etc.) for this type of reaction are disclosed in 16 U.S. 3,786,061.
18 The aryl aldehyde intermediates having the 19 ~ormula1l OIH hlal VII
22 where hal is Cl or Br, are conveniently prepared by reacting 23 the corresponding hydroxyaryl aldehyde with epihalohydrin 24 as illustrated by the following reaction equation:
o / O
H-~-R3-OH ~ CH2- CH-cH
26 1 NaOH/H2o-27 ~ HCl/~I2O
R ~ C,l 28 H-c-R3-o-cH2-cH-c~2 29 The aryl aldehyde intermediates ha~ing formula ~ 15524 IA
A O=CH-R3-0 CH2-cHoH-cH2-NR5-R6 (VIII) 1 are conveniently prepared by reacting the corresponding 2 hydroxyarylaldehyde with an epihalohydrin as the following 3 equations illustrate:
4 1l /o~
H-C-R -oX + ~r-CH2-CH - C`H2 6 ~ XOH~H20 7 H-c-R3-o-cH2-cH - CH2 ~ HNR5R6 H-C----R3-0-CH2-CH-CH2-NR5~6 11 ~ HCl O OH
U
12 H_C_R3-0-CH~-CH-C~2 NR5R6 13 Reaction conditions are similar to those used to prepare 14 the VII compound.
The aryl aldehydes VIII can also be prepared by 16 reacting an aryl aldehyde with an oxa olidine as illustrated 17 ~y the following equations:
ç~ , .
18 H C R3 ~H + R70-CH ~
19 0~fN-R5 . I H R8 1~ IX
21 ~-C-R3-0-C~2 ~
22 o~J~-R5 23 ~ ~ R8 1O OH ~ HYDROLYSIS `
26 H-C R3-o-cH2-cH-cx2 NHR5 ~ 15524 IA
.
~L~375~8~
1 R8 is the residue of an aldehyde as will be described below.
2 R7 is an alkyl or aryl sulfonyl group e.g. benzene sul~onyl, 3 toluene sulfonyl, methane sulfonyl and the like. This 4 coupling reaction of the oxazolidine IX and the aryl S aldehyde is generally carried out in su:itable solvent 6 such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), 7 hexamethylenephosphoramide (HMPP), alkanols such as 8 methano~, ethanol and the like. While the reaction can be 9 carried out at temperatures ranging from 0C. to 200C., it iq conveniently carried out at the reflux temperature 11 o~ the ~olution. Conventional tech~iques and reagents 12 e.g. HCl, H2SO4, are used to effect khe hydrolysis.
13 The oxaæolidine IX is o~tained from the reac~ion 14 o an aldehyde with a 1-amino-2,3-dihydroxypropane followed by treatment with an appropriate alkyl or aryl 16 sulonyl halide. This reaction is illustrated by the 17 following equations:
o ; 18 ~1) Rg-~-H ~ HO-~I2C-CHOH-CH2-NHR~ HO-CH2~ `
~N-R5 ~R8 22 ~2) HO-CH2 ~ ~ R7-Cl~ R7 C~2 24 H R8 ~ R8 AnY ~ ~ aldehyde may be used provided that it does not H
26 adversely a~fect ~he oxazolidlnc preparation~ -Examples of 27 suitable aldehydes are aryl aldehydes such as benzaldehyde, ~8 substituted benzaldehyde~, napthylaldehyde, and the like, 29 and alkanals such as acetaldehyde, fo~maldehyde, bul:y:raldehyde and the like. Commercially availabla aldehydes are most ~ ; , 756~3~
1 conveniently used. Processes for preparing oxazolidines 3 are disclosed in U.S. 3,718,647 and U.S. 3,657,237.
The Lmidazoles o~ the present invention wherein 6 R4 is the ester group ~-~-O-, are conveniently prepared 7 by treating the corresponding imidazole wherein R4 is OH
8 with the desired organic acid anhydride or halide, preferably 9 the chloride. This reaction can be càrried out at ambient temperature or at elevated temperature up to about 100C.
11 When R2 in the starting imidazole is hydrogen, then in 12 order to avoid acylating the l-nitrogen in the imidazole 13 the reaction is carried out under acidic conditions. The 14 . general reaction is illustrated by the following equation:
16 R ~ R3-O-CH2-CH-CH2 NR5R6 18 R2 or lg ' .
/ ~O
21 Rb-22 O-C-R.
23 Rl ~ 3 O CH2 ~H-C~2-NR5R6 -h The presen~ imidazoles encompass all optical 26 isomer forms tha~ is mixtures of isomers e.g. racemates as 27 well as ~he individual optical isomers. These indi~idual 28 isomers are commonly designated, according to the optical 2~ rotation they effect, by (-) and (~), (L~ and (D) or a combinatlon of these signs and letters. These optical 31 isomers may also he designated according to their absolute - ~8 -.. .. . . . . . . . . .. .. . ..
~ ` 15524 IA
S6~
1 spatial configuration, by the symbols (S) for sinister and 2 (R) for rectus.
3 Ordinarily, the imidazoles of the present invention 4 are obtained as racemates. These racemates can be separated into the individual optical isomers uqing techniques 6 available in the axt. These methods are nonmally tedious, 7 time consuming and rarely efect a complete separation of 8 isomexs~ This separation of isomers can be circumvented g and one or the other optical isomer of the pressnt imidazoles can be directly preparad by utilizing a single enantiomer 11 of the oxazolidine IX to prepare a single optical isomer of 12 the aryl aldehyde intexmediate VIII. By using this single 13 isomer intermediate, a single optical isomer form of the 14 desired Lmidazole inal product can be obtained. The single optical isomer of the oxazolidine IX is conveniently obtained 16 by using a single optical isomer of the 1-amino-2,3-dihydroxy-17 propane reactant in the oxazolidine preparation disclosed 18 above.
H
19 Compoundc of formula I wherein the -~-O-CEI2- H-CH2-N-R5-R6 is in the 4-po~ition in the imidazole ring can 21 be prepared according to the method illustrated by the 22 following equations:
24 (1) H3-CO-R -~-C ~ R-~-H ~ NH
~6 28 H3-CO-R ~ ~ R
H
31 ¦HI
~ .
~ 15524 IA
~7~6l3~
HO R3 rN~ L R
3 H C~2 ~ 2 C
R70-CE12~_~ /
O ~ R5 7 H ~ R8 ROUTE A ROUTE B
11 ~ CH2- O-R ~ ~~ ~ ~ ~ N
12 R5- ~ 0 3 ~ -R C~2-C~-C82-0-R3 ~ ~ -R
14 ~ hydrolysis NR5 6 2 C~ CH2--R3 ~ -R ~5-~-~ C-l~_C~ -O R~
18 Method E, as the e~uation illustrated, involve~
19 the reaction o~ alkoxyarylacetal with an aldehyde in the presence of ammonia. This ammonia may be liquid ammonia 21 wherein the reaction t~mperature would range from about 22 -33C up to about 70C, the r action being carried out under 23 pres~ure where the temperature re~uires. The ammonia may .~. . .
24 also be provided as aqueous solution i.e. ammonia ::.
hydroxide, in which case reaction temperatures of ~ro~ about 26 the freeziny point of the reaction mixture to about }OO:!C can : 27 be used. With the aqueous ammonia syste~, room t~mperature .
28 is c~nveniently usad. Other watar miscible aquèous solvents 29 such a~ the lower alkanol e.g. CH30H, or DME' may also be .~
. .......
~ 20 -'75~
1 used as necessary. The ether cleavage, step (2), may be 2 accomplished using any suitable reagents and procedure 3 such as aqueous HI or a~ueous HBr;or AlC13 in a hydrocarbon 4 solvent (hexane, benzene etc.). The Met:hod E route A
of course permits preparation of a single optical isomer -6 while the route B reqults in a racemate.
7 The compounds of the present invention are 8 ac~ive (1) as antihypertensives, i.e. they have an i~nediate 9 blood pressure lowering efect in hypertensive anLmals and (2) as ~-adrenergic blocking agents. Many o~ the present 11 imidazoles also are active vasodilators.
12 The antihypertensive effect was determined by 13 administering (orally or intraperitoneally) the present 14 compounds to spontaneously hypertensive (SEI) rats and mea~uring the effect on the blood pressure. Representative 16 im1dazoles, generally administe~ed as salts e.g. the hydro-17 chloride, were fou~d to lower the SH rat's blood pressure.
18 The ~-adrenergic blocking activity (~-blockade) 19 of th~ present compounds was determined by measuring the ability o~ representative compounds to block isoproterenol 21 induced tachychardia, vasodepression and bronchodilatation 22 in animals. Intravenous administration o~ the imidazole, 23 (generally as an acid addition salt) was u~ed for this 24 ~valuation. Representat~ve imidazoles showed ability to ~5 effect ~-blockade in addition to havin~ the aforesaid anti-26 hypertenslve ef~ect of immedia~e onse~.
27 R~presentative compounds which were tested and 28 found to have antihypertensive and ~-adrenergic blockiny 29 activity are listed below. The compounds were race~ates except where otherwise indicated.
.
-``` ~ 15524 IA
~L~75~
llo . COMPOUND
3 3~0-(: H 2-CH-CH2-N-C (CH3 ) 3 2 r__N OH ~1 CH
6 3 \~L~O--CH2-~ ~ CH2 `~CH
8 3 N OH H ~. CH2-CEI2 ~3 3 ~N ~<~O--CH2-CH-CH2-N--C
H
12 3 ~N~o-cH2-cH-cE~2-l-cÉ
14 5 ~ OI H H
3 ~N~O-CH2-CH-CH2-N C (CH3 ) 3 3 P3C r~_o-~l~2 - c:~-cE~2-N - c(c~3)3 ( S ) ISOMER
22 H3CO-C r~_e~O-CH2-cH-cH2-~-c (CH3 ) 3 2 4 8 ~ H
3 ~N J ~_~O~CH2-CH-CH2-N C (CH3 ) 3 26 CH3 , .
2 7 9 ~ H ~1 28 ~N~:3--o-CH2-CH~CH2 N C (CEI3 ~ 3 .: .
` . ` . : ` ` : . . . : `
75~
COMPOUND
NO.
~ N OH H
NC ~ ~ o-CH2-L -CH2 N C(C~3)3 H
ll 1- N OH H
3 ~ N ~ O-CH2-CH-CH2 ~ C(CH3)3 H
.:
F3C r ~ ~ O-CH2-CH-CH2-~-CH
~ 3 H ~
P3c~o-cH2-cH--cH2~ c(cH3)3 H
F3C ~ ~ - O-CH2-CH-CH2-N C(CH3)3 ~ OH
F3C ~ ~ ~ O-CH2-C!H-CH2-~-C(CH3)3 H Cl Cl 16 r~-_N OH H
F3C ~ ~ O-CH2-~H-CH~ C~CH3)3 H
: 17 ~ OH H
F3 ~ O-CH2-CH-CH2-N C~CH3)3 H
18 2-~4-(3- ert.~bu~yl-2-hydroxypropoxy)phenyl]-` 4-(3-pyridyl)imidazole 19 i-methyl-2-~4-(3-tert.-butyl-2-hydroxypropoxy)pheny].]-4(and 5)-tri1uoromethylimidazole ... ., , . .. ~ , ,~ .. . , . . ,:
~ - 15524 IA
~7568~
1 In evaluating the ~-blocking ef~ectiveness of 2 the present compounds, it was noted that: many of the 3 compounds exhibit some cardioselectivity that is the 4 compound is more ef~ective in reducing the heart rate e~fects of isoproterenol than it is in blocking the iso-6 proterenol effects on the bronchiO Expressed in 7 different terms, a smaller amount o~ the compound is 8 required to block isoproterenol-induced elevation in heart 9 rate than is required to block the isopxoterenol-induced relaxation of the bronchi. This cardioselectivity ~actor 11 can be expressed as the ratio of ED50 ~or pulmonary effect 12 (~2) :ED50 ~or cardiac effect (~1) Where the ~2:~1 ratio 13 is over 1, then the compound would be considered to have 14 cardioselective activi~y. The tested compounds numbered 1-11 above are examples of compounds having ~2 ~1 ratios 16 greater than 1.
17 The ability o~ the compounds of the present .:
18 inven~ion to xeduce blood pressure in the SH rat indicates 19 that the compounds and their salts may be useful to treat essantial hypertension in h~mans.
21 The ~-adrenergic blocking effectivenes~ of the 22 compounds of the present invention indicates that they are 23 also useful to treat humans suf~ering from undesirable 24 conditions such as angina pectoris or certain arrhythmias which are known to be amenable to treatment with ~-adrenergic 26 bloc~ing agents. Furthermore~ the cardioselective nature of 27 some of the present compounds oers the advan~age of limit-28 ing blockade to only the ~1 receptors, iOe. those which 2g control heart rate.
For use as antihyper~ensives and/or ~ adre.nergic 31 blocking agents, the present compounds can be admi.ni.stered ~ 15524 IA
~7~39 1 orally or parenterally i.e. intravenously, in~erperit-2 oneally, etc. and in any suitable dosage orm. The com-3 pounds may be offered in a form (a) for oral adminis~ration 4 e.g. as tablets in combination with other compounding ingredients customarily used such as talc, vegetable oils, 6 polyols, benzyl alcohols, gums, gelatine, starches and 7 other carriers; dissolved or dispersed or emulsified in a 8 suitabla liquid carrier; in capsules or encapsulated in a 9 suitable encapsulating material or (b) ~or parent~ral administration e.g. dissolved or aispersed in a suitabl;e 11 liquid carrier or emulsified or (c) as an aerosol. The 12 ratio o~ active compound to compounding ingredients i.e.
13 carrier, diluent etc. will vary as the dosage fonn requires.
14 Whatever dosage form is used, the amount of compound o the present invention administered should be su~ficient to 16 e~fect (a) a reduction in blood pressure of the patient 17 suffering from hypertension and/or (b) desirable }evel of 18 ~-~lockade in ~he patient. Generally, doses of the present 19 compounds of from about 0.01 to about 50 mg/kg and preferably rom about 0.1 to about 10 mg/kg of body weight per day may 21 be used. Dosage may be single or multiple depending on the 22 daily total re~uired and the unit dosage.
Z3 FoIlowing are example~ illustrating representative 24 pharmaceutical ormulations containing imidazoles oE the present i~vention. Conventional techniques are used to 26 prepare ~hese formulations 27 rA0~ ro~ruL~
28INGREDIENT AMOUNT (M~
29(S) 2~4-(3 tert-kutylamino-2- 5.0 hydroxyprQpoxy)phenyl]-4-30methylimida201e 31calcium phosphate 120.0 ~ 15524 IA
~75~
1 TABLET FORMULATIONI(cont.) 2 INGREDIENT AMO~NT (M~.) ~ , ....
3 lacto e 50.0 4 starch 23.5
9 Compounds o particular interest have the formulae: :
13 1 ~ R3-O-CH2-C8-C~ -N
IA
18 ~ N-C~2- ~-C~2 O R3 ~ 1 22 Use~ul R and Rl alkyl groups include unsubstltuted 23 as well as substituted alkyl, cycloalkyl as well as branched 24 and linear alkyl gxoups. These alkyl groups may contain` ``
2$ up to 10 alkyl carbons, preerably up to 8 alkyl carbon 26 atom~ and more pre~erably from 1 to 6 alkyl carbons. Exam-27 ples of sui~able R and Rl unsubstituted alkyl groups are 28 methyl, isopropyl, cyclopropyl, cyclopentyl, 2-methyl-n-2~ butyl, decyl, 2-ethyl-n-hexyl ~uitable R and Rl substituted alkyl group~ have 1 3 substituents such as halo (Cl,Br,I,F) 31 hydroxy, phenyl, Cl-C4 alkoxy,-exemplified by -CC13, bromo-~ .
~ 15524 IA
~L~756~
1 hexyl, CH3-O-C~2-CH2-, hydroxypropyl, dliodethyl, trifluoro-2 methyl, benzyl, chlorodecyl and the like.
3 Useful R and Rl aryl groups inclucle aryl groups 4 having up to 10 ring carbon atoms~ These aryl groups include single ring as well as fused ring aryls, unsubstituted 6 aryls as well as substituted aryls havir~ from l-S sub-7 stituents. These ubstituents include alkyl, preerably 8 C~-C6 alkyl, alkoxy preferably Cl-C6 alkoxy, cyano, halo 9 (Cl, I, Br and F), nitro, amino, carboxy, hydroxy, carb~nyl, -SH, sulfamoyl, thioalkyl, phenyl and the like.
11 Examples of suitable aryl R and Rl groups are phe~yl, 12 chlorophenyl, dibromophenyl, fluorophenyl, toluyl, xylyl, 13 hexylphenyl, dodecylphenyl, tert butylphenyl, methoxyphenyl, 14 C6H13-O-phenyl, HO-C6H4-, carboxyphenyl, H-~-C6H4, sulfamoylphenyl, N,N-dimethylsul~amoylphenyl, naphthyl, 16 indanyl, chloronaphthyl, trichlorophenyl, ~O-CH2-C6H~-, 17 pentafluorophenyl, the tetralin ~roup, cyanophenyl, chloro-18 hydroxyphenyl, Cl-C6-alkyl-S-C6H~-, ~ -SH and the .
19 like.
Useful R and Rl heterocyclic groups have S-6 21 ring atoms of which 1-3 and preferably 1-2 are hetero atoms 22 and the quinolyl group. Substituted a~ well as unsu}:~-23 stituted hetexocycllc groups are included. The hetero atoms 24 are O,S and N. Examples of suitable R and Rl heterocyclic ~5 groups are pyridyl, pyrazinyl, pyrimidinyl, pyrida2inyl 26 sub~tituted pyridyl such a~ dimethylpyridyl, methylpyridylr 27 chloropyridyl, dichlor~pyridyl, diethylpyridyl, trimethyl-28 pyridyl, methylethylpyridyl, et~ylpyridyl, bromopyridyl, 29 and analogous substituted pyrazinyl pyrimidinyl and pyridaz~nyl groups; pyridyl-~-oxide, methylpyridyl-N-oxide, 31 furyl, thienyl a~d the like.
.
.
~17~i~i8~
1 Other useful R and Rl group~ are cyano, carboxy, 2 carboxy derivatives such as -~-O-Cl-C6~alkyl, -~-N~2, 3 N-mono-Cl-C6-alkyl- and N,N-di-Cl-C6 al]cylcarbamoyl;
4 halogen preferably Br, Cl and F; and ~~~Ra wherein Ra is S hydrogen or Cl-C6 alkyl and the like.
6 It is preferred tha~ at least one of R and R
7 is hydrogen.
8 Useful R2 alkyl groups have up to 10 carbons, 9 are unsubstituted or monohydroxysubstituted and include cycloalkyl as well as branched and straight chain alkyl.
11 R2 alkyl groups having 1-6 carbons are preferred, with 1~4 12 carbon atoms more preferred. Examples of sui~able R2 alkyl 13 yroups are methyl, ethyl, decyl, tert-butyl, isopropyl, 14 2,2,4-trimethyl-n-butyl, cyclohexyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxybutyl and the like. Useful R2 16 alkenyl groups have 3-6 carbon atoms and ara examplified by . . .
17 allyl, -CH2 CH2-CH2-C~-C~YCH~ and the like.
18 Preferred compounds are those where R2 is H.
L9 R3 is an aryl group. The aryl group include~
single ring ~6-ring atoms) and fused ring (9-10 ring atoms~
21 groups, having 0-2 nitrogen ring atoms, both substituted as 22 well as unsub~tituted moieties. The R3 heterocyclic groups 23 contain 1 or 2 nitrogen atoms. Examples of such useful 24 heterocyclic groups axe 2-pyridyl, 3-pyridyl, 4-pyridyl, halopyridyl, Cl-C3 alkylpyridyls, pyridyl N-oxide~ Epidyl, 26 pyrazinyl, pyridazinylJpyrimidinyl, quinolyl, and the like.
27 Pre~erred R3 heterocyclic groups are pyridyl, substituted 28 pyridyl e.g. chloropyridyl, methylethylpyridyl, methyl-29 pyridyl~ 2-chloro-4-methylpyridyl, bromopyridyl, 2,4,6 trimethylpyridyl, dlmethylpyridyl, and the N~oxides e.g~
31 pyridyl-N-Qxide, me~hylpyridyl-N-oxide and the like.
.:. . ~ :
` 15524 IA
~L~7~8g 1 Useful R3 carbocyclic aryl groups include phenyl 2 groups and fused ring groups such as naphthyl, tetrahydro-3 naphthyl, indanyl and the like.
4 Preferred R3 carbocyclic aryl groups are those ha~ing the ~ormula 8 (R ) II
where x is 0, 1,2,3 or 4 and Rc includes alkyl groups, both 11 linear and branched, and preferably Cl-C4 alkyl groups, 12 C3-C6 cycloalkyl groups, halogen such as Cl, I, Br or F, 13 alkoxy preferably Cl-C4 alkoxy, hydroxy, nitro, cyano, 14 carbamoyl, N-Cl~C6-alkyl- and N,N-di-Cl-C6-alkylcarbamoyl, and the like. Examples of suitable pr~ferred caxbocyclic 16 aryl groups of Foxmula II are phenyl, tetrahydronaphthyl, 17 fluorophenyl, dibromophenyl, trichlorophenyl, iodophenyl, 18 hydroxyphenyl, toluyl, cresyl, nitrophenyl, carboxyphenyl, 1~ methoxyphenyl, cyclohexylphenyl, aminophenyl, dimethyl-chlorophenyL, butoxyphenyl, dichlorophenyl, cyanophenyl, 21 nitrophenyl, tetramethylphenyl, dimethylphenyl~ carbamoyl-22 phenyl, N,N~dimethylcarbamoylphenyl and the like.
23 An especially pre~erred R3 group is the carbocyclic 24 group having the ormula 26 ~
27 ~Rc)~ :
28 rI A
29 A more preferred R3 carbocyclic group is formula II A where x is 0, 1, 2 or 3. An especially preferred carbocyclic .
. . .~ : . .
756~3~
1 R3 group is formula II A where x is O, 1 or 2. A most 2 preferred carbocyclic group is ~ .
R4 includes the hydroxy group and the ester group Rb-~-O- where ~ is Cl-C6 alkyl such as methyl, isopropyl,~t-butyl, hexyl, ethyl and the like. Compounds where R4 is OH are preferred.
The R5 a~d R6 groups are hydrogen or alkyl groups.
8 The alkyl groups preferably have from 1-6 alkyl carboIl atoms 9 and may be branched, linear, or cyclic; substituted or unsubstitutedO Examples of suitable alkyl groups are methyl, 11 n-hexyl, isopropyl, 2,2,4-trimethyl-n-butyl, cyclopropyl, 12 cyclohexyl, chlorobutyl, tert-butyl, -CH2 ~ , ~ H3 13 -CH2-~CH2)4-cH2 ~ and the like. The R5 and R6 14 groups may also be ioined to fo~m a 5-6 membered N-alicyclic ring such as -N ~ -N ~ -N o - ~ -Z
16 where Z is H or Cl-C10 alkyl, and the like-17 It is preerred tha~ one of R5 and R6 is hydrogen 18 while the othar is Cl C6 alkyl, and preferably C3-C~
19 branched hydrocarbon alkyl.
Compounds of formula I which are pxeferred are ~1 tho~e in which R is hydxogen, represented by the formula 22 1 ~ ~ R3-O-CH~ CH2-N~
26 II~
27 A~other series of pre~erred compounds is that in 28 which R and R2 are each hydrogen~ These compounds have the 29 formula :
.
~1756 3 ~, J~3 -O-C~ 2-C~I-CH 2-N~
IV
6 When R2 is hydrogen, the 4 and 5 positions in the imidazol~
7 are substantially equivalent.
8 A more preferred series of compounds is that of 9 formula IV where Rl i~ selec~ed from hydrogen, trihaloalkyl, preferably -CF3, cyano, -CH3, phen~l, substituted phenyl 11 havlng 1-5 substituents preferably selected from halogen 12 (Cl, Br, F), and heterocyclic group such as thienyl, furyl, 13 methylpyridyl, pyridyl, pyridyl-N-oxide and ~he liXe.
14 Another more preerred series o~ compounds is that having the formula 18 ~ ~ _ O-ch2-c~-c~-N /
19 ,:
' ' :
where Rl is selected from CH3, H, phenyl, pentafluorophenyl, 21 p-chlorophenyl, p-fluorophenyl, p-methoxyphenyl, ~h~nyl,-CF3-22 and pyridyl; x i5 O, 1, 2 or 3 and R~ is halo preferably 23 chloro, Cl~C3 alkyl preferably -CH3, and cyano.
24 Another series of preferred compounds are those ha~ing ~he ~ormula Y where R4 is -O~.
26 ~n a particularly pre~erred series o~ oompound$
27 havi~g formula V, R4 is OH and only one o~ R5 and R6 is 2~ Cl C6 alkyl, preferably cyclic or branched C3-C~ alkyl such 29 as tert-bu~yl, cyclopropyl, 1-methyl-3-phenylpropyl, l-methyl-2-phenyle~hyl a~d the lik~o '.
. .
- -~ 15524 IA
1~7~ii8g 1 An especially preferred series of compounds is 2 one having formula V where Rl is -CF3, R~ is OH and one of 3 R5 and R~ is hydrogen while the other i~; Cl-C6 alkyl, 4 preferably C3-C4 cyclic or branchad hydrocarbon alkyl, especially tert-butyl.
6 The compounds of the present i.nvention include 7 all the optical isomer forms. In o~her words, the 8 compounds include mixtures containing the optical isomers 9 such as racemic mixtures, as well as the individual optical isomers.
11 The compounds of the present invention also include 12 the non-toxic phaxmacologically acceptable acid addition 13 and quaternary ammonium salts of the present lmidazoles.
14 The acid addition salts are prepared by reating the imidazole with an appropriate amount of a suitable organic 16 or inorganic acid. Examples of useful organic acias are 17 carboxylic acids such as maleic acid, tartaric acid, acetic 18 acid, pamoic acid, oxalic acid, propionic acid, salicyclic 1~ acid, succinic acid, citric acid, malic acid, isethionic a~id and the like; useful inorganic acids are hydrohalo 21 acids such as HCl, HBr and HI, suluric acid, H3PO4 and the 22 like.
23 The quaternary salts are characterized by the 24 group R5 ( ~.
2 6 --N-- Rd L
~8 wherein R5 and R6 are Cl-C6 alkyl, Rd is Cl-C6 alkyl and 29 L is the anion of a non-toxic aci.d, preferably a halide such as the iodide. These salt~ axe prepared by any suitable ~ g _ ~75~
1 method - for example, by reacting any i~idazole of the 2 present invention having the tertiary amine group -N ~ 5 , ~ with an alkyl halide, preferably the iodide such as ethyl-iodide or methyliodide, in a suitable solvent such as 6 methanol, ethanol or dimethylormamide (DME). The 7 reaction is generally carried out at room temperature. The 8 quaternary salt is obtained directly on removing the 9 solvent.
Compounds of the present invention may be 11 prepared b~ any convenient method.
12 One method (~ethod A) of preparing the present }3 compounds i9 by amination of a compound having the formula R ~ R3-0-CH2- ~-CH2~X
; 17 R2 18 V~
lq where X is a halogen, preferably Br, I or Cl. When NH3 is 2a the aminating agent, X is replaced by -NH2 while when a 21 primary or secondary, acyclic or alicyclic amine is used, 22 X is replaced by the corresponding -NR5R6 group. Typically, 23 the amination can be carxied out by heating a mixture of the 24 halo campound VI and the amine e.g. t-butylamine for a suf-icient period of time and then isolating the aminat@d 26 pxoduct. U.S. 3,337,628 disclosed such procedures.
27 An especially us~ful method of preparin~ ~midazoles 28 of the pre~ent invention wherein R4 is -OH is by reaction 29 of ammonia or a suitable amine reactant with an epoxy compound as illus~rated by the following general reaction 31 equation:
.. ~ - . ,. -- l~ 15524 IA
~56~3 4 Rl ~ 3 o C~2-HC--C~I2 + R5R6NH
R
7 Rl ~ R3-0-C~ -Ch-Ch -N ~ S
..
11 The reaction is generally carried out in solution with excess 12 amine reactant serving as the solvent. However, other 13 solvents may be used such as triethylamine, pyxidine, tetra-14 hydrofuran and the like. The reaction is conveniently 14 conducted at reflux temperature. However, the reaction temperature can ~e varied ~rom room tempe~ature to temper-16 atures above reflux. The reaction may be carried out at 17 atmospheric pre~sure but it can be carried out at pressures 18 above atmospheric, if desired.
19 A method of preparing compounds of formula I where-in R and R2 are H, Rl is trihaloalkyl and 21 -R -O-CH2-C~ - CH2-N 5 is in the 2 position in the 22 imidazole ring involves the reaction o 1,1,1 trlhalo-3, 23 3-dihaloacetone, aryl aldehyde and N~3. Depending on the 24 type aryl aldehyde u~e~, diferent sequencas of reactions are utilized, these are illustrated by the following sets of 26 equations. In these equations X and Xl are halogen selected 27 from F, Br and Cl - and it is preferred that X is F and 28 X is Br.
.
-~ 15524 IA
~07S~89 ME~HOD C
o xl ~1) X-C-C-l-H WEAK BASE ~ [INTERMEI:)IATE]
x Xl ~ 4 (2) [INTERMEDIATE] ~ H-C-R3-O-CH2-CH-CH2-NR5R6 + NH3 --l~L R3-0-C~2-CEl-C32 NR5R6 l o l 1 (1) X- ~-C-C-H WEA~ BASE [INTERMEDIA~F.
X
O OH Cl (2) ] 3 O CH2 CH CH2 ~ NH3 X-C ~R3-0-C32-c~l-clH
~3 ) 1 STRONG BASE
X-C ~1 R - - Ç \
~N~ 3 C~2 -C -CH2 ( 4 ) ~¦~ HMR5R6 .~ ' .
.:
~ 15524 IA
S~
1 ~ R3-0-CH2-CH-C~2- NR5R6 H
4 The intermediate in the above equations is believed to be a glyoxal (X-~ -H) or a hydra~ed ~ o OH
6 glyoxal (X-l-C- -~). This intermediate is generally X
7 prepared as an aqueous mixture by treating the halogenated 8 acetone with a aqueous solution o~ a weak base such as 9 sodium acetate trihydrate. This solution is heated for a period o~ time and at a temperature sufficient to form the 11 intermediate. On cooling, the intermediate containing 12 solution is added to a solution of the appropriate aryl-13 aldehyde and aqueous ammonia. An~ suitable water miscible 14 301vent may be used. Methanol is conveniently used. The reaction to yield the substitu~ed imida~ole is generaLly 16 conducted at room temperature, although elevated tem-17 peratures may be used. The solvent is then stripped and 18 the product imidazole is reco~ered.
19 ~here the imidazole intermediate has the ~H Cl -R3-0-CH2-C~-~H2 substituent, this intermediate is txeated 21 with a suitable strong base such as KOH, potassium butoxide, 22 ~aO~, or the like, in a solvent such as methanol, to ef~ect 23 conver~ion to the epoxy ~R3-0-CH2-C~_~H2) group~ This epoxy 24 derivati~e is then converted to the desired amine inal product as illustrated abov 26 Still anothe~ method for preparing compounds o~
27 ~ormula I where R2 Ls H and -R3-0-CH2- ~-CH2-N~ 5 is in the 28 2 position in the imidazole is by the reaction of6aryl -~ 15524 IA
~L~75~
1 aldehyde with a glyoxal or acetal thereof and NH3. When 2 the acetal is used, it must first be hyclrolyzed e.g. by 3 treatment with a strong acid solution such as aqueous H2S04.
4 This reaction scheme is illustxated by the ollowing equations:
7 O O O Rg R
Il ll ll I ~ 5 Rl-C-C-R ~ H-C-R3-O-CH~-CH-CH2 N ~ R ~ NH3 12 Rl ~ ~ ~3 O C~2-C~-C~2-N /
13 If, in Method D, the aryl aldehyde used has the formula 14 O OH ~1 ~-R3-O-CH2-C~CH2, the imidazole product would require 16 }I
17 dehydrochlorination and treatmen~ with amine, as shown in 18 Method C sequence 2, steps (3) and (4), to afford the imida-19 zole of the present invention.
The process o~ Method D is generally carried out in 21 solution and at temperatures ranging from about room tempera-22 ture to about 100C. Pressure is not required. 5Olvents 23 used will vary depending on the type of reactants used.
24 Generally, this reaction is carried out in an aqueous solution e.g. H2O or H2O/miscible alkanol.
26 Another method or prepariny Formula I compou~ds 27 ~here R~- i9 other than H is by treating the corresponding 28 aompound whsre R2 is H with a suitable reagent using a 29 recogni ed technique.
Where the R2 group i~ to be an alkyl group, the 31 corresponding Formula I compound whexe R2 is H is alkylated , .. .
~s6~
1 using a suita~le reagent such as diazomethane, an alkyl 2 halide e.g. C~H5-Br, C6H13-I, n-butylchloride and the 3 like, or a dialkylsulfate.
4 Where the R2 group is to be an alkenyl group, recognized alkenylating reagents and techniques axe used.
6 Illustrative of these techniques is the reaction of the - 7 imidazole having R2=H, with NaH followad by treatment with 8 an alkenyl halide e.g. allylbromide to produce the 9 corresponding imidazole having R2=alkenyl.
Where the R2 group is to be hydroxyalkyl, the 11 imidazole wherein R2 is H is reacted with an epoxy compound 12 e.g. 1,2-epoxyethane, 1,2-epoxypropane, 1,2-epoxyhexane 13 to produce the corresponding imidazole where R2 is mono-14 hydroxyalkyl. Conditions (temperature, catalysts, solvents etc.) for this type of reaction are disclosed in 16 U.S. 3,786,061.
18 The aryl aldehyde intermediates having the 19 ~ormula1l OIH hlal VII
22 where hal is Cl or Br, are conveniently prepared by reacting 23 the corresponding hydroxyaryl aldehyde with epihalohydrin 24 as illustrated by the following reaction equation:
o / O
H-~-R3-OH ~ CH2- CH-cH
26 1 NaOH/H2o-27 ~ HCl/~I2O
R ~ C,l 28 H-c-R3-o-cH2-cH-c~2 29 The aryl aldehyde intermediates ha~ing formula ~ 15524 IA
A O=CH-R3-0 CH2-cHoH-cH2-NR5-R6 (VIII) 1 are conveniently prepared by reacting the corresponding 2 hydroxyarylaldehyde with an epihalohydrin as the following 3 equations illustrate:
4 1l /o~
H-C-R -oX + ~r-CH2-CH - C`H2 6 ~ XOH~H20 7 H-c-R3-o-cH2-cH - CH2 ~ HNR5R6 H-C----R3-0-CH2-CH-CH2-NR5~6 11 ~ HCl O OH
U
12 H_C_R3-0-CH~-CH-C~2 NR5R6 13 Reaction conditions are similar to those used to prepare 14 the VII compound.
The aryl aldehydes VIII can also be prepared by 16 reacting an aryl aldehyde with an oxa olidine as illustrated 17 ~y the following equations:
ç~ , .
18 H C R3 ~H + R70-CH ~
19 0~fN-R5 . I H R8 1~ IX
21 ~-C-R3-0-C~2 ~
22 o~J~-R5 23 ~ ~ R8 1O OH ~ HYDROLYSIS `
26 H-C R3-o-cH2-cH-cx2 NHR5 ~ 15524 IA
.
~L~375~8~
1 R8 is the residue of an aldehyde as will be described below.
2 R7 is an alkyl or aryl sulfonyl group e.g. benzene sul~onyl, 3 toluene sulfonyl, methane sulfonyl and the like. This 4 coupling reaction of the oxazolidine IX and the aryl S aldehyde is generally carried out in su:itable solvent 6 such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), 7 hexamethylenephosphoramide (HMPP), alkanols such as 8 methano~, ethanol and the like. While the reaction can be 9 carried out at temperatures ranging from 0C. to 200C., it iq conveniently carried out at the reflux temperature 11 o~ the ~olution. Conventional tech~iques and reagents 12 e.g. HCl, H2SO4, are used to effect khe hydrolysis.
13 The oxaæolidine IX is o~tained from the reac~ion 14 o an aldehyde with a 1-amino-2,3-dihydroxypropane followed by treatment with an appropriate alkyl or aryl 16 sulonyl halide. This reaction is illustrated by the 17 following equations:
o ; 18 ~1) Rg-~-H ~ HO-~I2C-CHOH-CH2-NHR~ HO-CH2~ `
~N-R5 ~R8 22 ~2) HO-CH2 ~ ~ R7-Cl~ R7 C~2 24 H R8 ~ R8 AnY ~ ~ aldehyde may be used provided that it does not H
26 adversely a~fect ~he oxazolidlnc preparation~ -Examples of 27 suitable aldehydes are aryl aldehydes such as benzaldehyde, ~8 substituted benzaldehyde~, napthylaldehyde, and the like, 29 and alkanals such as acetaldehyde, fo~maldehyde, bul:y:raldehyde and the like. Commercially availabla aldehydes are most ~ ; , 756~3~
1 conveniently used. Processes for preparing oxazolidines 3 are disclosed in U.S. 3,718,647 and U.S. 3,657,237.
The Lmidazoles o~ the present invention wherein 6 R4 is the ester group ~-~-O-, are conveniently prepared 7 by treating the corresponding imidazole wherein R4 is OH
8 with the desired organic acid anhydride or halide, preferably 9 the chloride. This reaction can be càrried out at ambient temperature or at elevated temperature up to about 100C.
11 When R2 in the starting imidazole is hydrogen, then in 12 order to avoid acylating the l-nitrogen in the imidazole 13 the reaction is carried out under acidic conditions. The 14 . general reaction is illustrated by the following equation:
16 R ~ R3-O-CH2-CH-CH2 NR5R6 18 R2 or lg ' .
/ ~O
21 Rb-22 O-C-R.
23 Rl ~ 3 O CH2 ~H-C~2-NR5R6 -h The presen~ imidazoles encompass all optical 26 isomer forms tha~ is mixtures of isomers e.g. racemates as 27 well as ~he individual optical isomers. These indi~idual 28 isomers are commonly designated, according to the optical 2~ rotation they effect, by (-) and (~), (L~ and (D) or a combinatlon of these signs and letters. These optical 31 isomers may also he designated according to their absolute - ~8 -.. .. . . . . . . . . .. .. . ..
~ ` 15524 IA
S6~
1 spatial configuration, by the symbols (S) for sinister and 2 (R) for rectus.
3 Ordinarily, the imidazoles of the present invention 4 are obtained as racemates. These racemates can be separated into the individual optical isomers uqing techniques 6 available in the axt. These methods are nonmally tedious, 7 time consuming and rarely efect a complete separation of 8 isomexs~ This separation of isomers can be circumvented g and one or the other optical isomer of the pressnt imidazoles can be directly preparad by utilizing a single enantiomer 11 of the oxazolidine IX to prepare a single optical isomer of 12 the aryl aldehyde intexmediate VIII. By using this single 13 isomer intermediate, a single optical isomer form of the 14 desired Lmidazole inal product can be obtained. The single optical isomer of the oxazolidine IX is conveniently obtained 16 by using a single optical isomer of the 1-amino-2,3-dihydroxy-17 propane reactant in the oxazolidine preparation disclosed 18 above.
H
19 Compoundc of formula I wherein the -~-O-CEI2- H-CH2-N-R5-R6 is in the 4-po~ition in the imidazole ring can 21 be prepared according to the method illustrated by the 22 following equations:
24 (1) H3-CO-R -~-C ~ R-~-H ~ NH
~6 28 H3-CO-R ~ ~ R
H
31 ¦HI
~ .
~ 15524 IA
~7~6l3~
HO R3 rN~ L R
3 H C~2 ~ 2 C
R70-CE12~_~ /
O ~ R5 7 H ~ R8 ROUTE A ROUTE B
11 ~ CH2- O-R ~ ~~ ~ ~ ~ N
12 R5- ~ 0 3 ~ -R C~2-C~-C82-0-R3 ~ ~ -R
14 ~ hydrolysis NR5 6 2 C~ CH2--R3 ~ -R ~5-~-~ C-l~_C~ -O R~
18 Method E, as the e~uation illustrated, involve~
19 the reaction o~ alkoxyarylacetal with an aldehyde in the presence of ammonia. This ammonia may be liquid ammonia 21 wherein the reaction t~mperature would range from about 22 -33C up to about 70C, the r action being carried out under 23 pres~ure where the temperature re~uires. The ammonia may .~. . .
24 also be provided as aqueous solution i.e. ammonia ::.
hydroxide, in which case reaction temperatures of ~ro~ about 26 the freeziny point of the reaction mixture to about }OO:!C can : 27 be used. With the aqueous ammonia syste~, room t~mperature .
28 is c~nveniently usad. Other watar miscible aquèous solvents 29 such a~ the lower alkanol e.g. CH30H, or DME' may also be .~
. .......
~ 20 -'75~
1 used as necessary. The ether cleavage, step (2), may be 2 accomplished using any suitable reagents and procedure 3 such as aqueous HI or a~ueous HBr;or AlC13 in a hydrocarbon 4 solvent (hexane, benzene etc.). The Met:hod E route A
of course permits preparation of a single optical isomer -6 while the route B reqults in a racemate.
7 The compounds of the present invention are 8 ac~ive (1) as antihypertensives, i.e. they have an i~nediate 9 blood pressure lowering efect in hypertensive anLmals and (2) as ~-adrenergic blocking agents. Many o~ the present 11 imidazoles also are active vasodilators.
12 The antihypertensive effect was determined by 13 administering (orally or intraperitoneally) the present 14 compounds to spontaneously hypertensive (SEI) rats and mea~uring the effect on the blood pressure. Representative 16 im1dazoles, generally administe~ed as salts e.g. the hydro-17 chloride, were fou~d to lower the SH rat's blood pressure.
18 The ~-adrenergic blocking activity (~-blockade) 19 of th~ present compounds was determined by measuring the ability o~ representative compounds to block isoproterenol 21 induced tachychardia, vasodepression and bronchodilatation 22 in animals. Intravenous administration o~ the imidazole, 23 (generally as an acid addition salt) was u~ed for this 24 ~valuation. Representat~ve imidazoles showed ability to ~5 effect ~-blockade in addition to havin~ the aforesaid anti-26 hypertenslve ef~ect of immedia~e onse~.
27 R~presentative compounds which were tested and 28 found to have antihypertensive and ~-adrenergic blockiny 29 activity are listed below. The compounds were race~ates except where otherwise indicated.
.
-``` ~ 15524 IA
~L~75~
llo . COMPOUND
3 3~0-(: H 2-CH-CH2-N-C (CH3 ) 3 2 r__N OH ~1 CH
6 3 \~L~O--CH2-~ ~ CH2 `~CH
8 3 N OH H ~. CH2-CEI2 ~3 3 ~N ~<~O--CH2-CH-CH2-N--C
H
12 3 ~N~o-cH2-cH-cE~2-l-cÉ
14 5 ~ OI H H
3 ~N~O-CH2-CH-CH2-N C (CH3 ) 3 3 P3C r~_o-~l~2 - c:~-cE~2-N - c(c~3)3 ( S ) ISOMER
22 H3CO-C r~_e~O-CH2-cH-cH2-~-c (CH3 ) 3 2 4 8 ~ H
3 ~N J ~_~O~CH2-CH-CH2-N C (CH3 ) 3 26 CH3 , .
2 7 9 ~ H ~1 28 ~N~:3--o-CH2-CH~CH2 N C (CEI3 ~ 3 .: .
` . ` . : ` ` : . . . : `
75~
COMPOUND
NO.
~ N OH H
NC ~ ~ o-CH2-L -CH2 N C(C~3)3 H
ll 1- N OH H
3 ~ N ~ O-CH2-CH-CH2 ~ C(CH3)3 H
.:
F3C r ~ ~ O-CH2-CH-CH2-~-CH
~ 3 H ~
P3c~o-cH2-cH--cH2~ c(cH3)3 H
F3C ~ ~ - O-CH2-CH-CH2-N C(CH3)3 ~ OH
F3C ~ ~ ~ O-CH2-C!H-CH2-~-C(CH3)3 H Cl Cl 16 r~-_N OH H
F3C ~ ~ O-CH2-~H-CH~ C~CH3)3 H
: 17 ~ OH H
F3 ~ O-CH2-CH-CH2-N C~CH3)3 H
18 2-~4-(3- ert.~bu~yl-2-hydroxypropoxy)phenyl]-` 4-(3-pyridyl)imidazole 19 i-methyl-2-~4-(3-tert.-butyl-2-hydroxypropoxy)pheny].]-4(and 5)-tri1uoromethylimidazole ... ., , . .. ~ , ,~ .. . , . . ,:
~ - 15524 IA
~7568~
1 In evaluating the ~-blocking ef~ectiveness of 2 the present compounds, it was noted that: many of the 3 compounds exhibit some cardioselectivity that is the 4 compound is more ef~ective in reducing the heart rate e~fects of isoproterenol than it is in blocking the iso-6 proterenol effects on the bronchiO Expressed in 7 different terms, a smaller amount o~ the compound is 8 required to block isoproterenol-induced elevation in heart 9 rate than is required to block the isopxoterenol-induced relaxation of the bronchi. This cardioselectivity ~actor 11 can be expressed as the ratio of ED50 ~or pulmonary effect 12 (~2) :ED50 ~or cardiac effect (~1) Where the ~2:~1 ratio 13 is over 1, then the compound would be considered to have 14 cardioselective activi~y. The tested compounds numbered 1-11 above are examples of compounds having ~2 ~1 ratios 16 greater than 1.
17 The ability o~ the compounds of the present .:
18 inven~ion to xeduce blood pressure in the SH rat indicates 19 that the compounds and their salts may be useful to treat essantial hypertension in h~mans.
21 The ~-adrenergic blocking effectivenes~ of the 22 compounds of the present invention indicates that they are 23 also useful to treat humans suf~ering from undesirable 24 conditions such as angina pectoris or certain arrhythmias which are known to be amenable to treatment with ~-adrenergic 26 bloc~ing agents. Furthermore~ the cardioselective nature of 27 some of the present compounds oers the advan~age of limit-28 ing blockade to only the ~1 receptors, iOe. those which 2g control heart rate.
For use as antihyper~ensives and/or ~ adre.nergic 31 blocking agents, the present compounds can be admi.ni.stered ~ 15524 IA
~7~39 1 orally or parenterally i.e. intravenously, in~erperit-2 oneally, etc. and in any suitable dosage orm. The com-3 pounds may be offered in a form (a) for oral adminis~ration 4 e.g. as tablets in combination with other compounding ingredients customarily used such as talc, vegetable oils, 6 polyols, benzyl alcohols, gums, gelatine, starches and 7 other carriers; dissolved or dispersed or emulsified in a 8 suitabla liquid carrier; in capsules or encapsulated in a 9 suitable encapsulating material or (b) ~or parent~ral administration e.g. dissolved or aispersed in a suitabl;e 11 liquid carrier or emulsified or (c) as an aerosol. The 12 ratio o~ active compound to compounding ingredients i.e.
13 carrier, diluent etc. will vary as the dosage fonn requires.
14 Whatever dosage form is used, the amount of compound o the present invention administered should be su~ficient to 16 e~fect (a) a reduction in blood pressure of the patient 17 suffering from hypertension and/or (b) desirable }evel of 18 ~-~lockade in ~he patient. Generally, doses of the present 19 compounds of from about 0.01 to about 50 mg/kg and preferably rom about 0.1 to about 10 mg/kg of body weight per day may 21 be used. Dosage may be single or multiple depending on the 22 daily total re~uired and the unit dosage.
Z3 FoIlowing are example~ illustrating representative 24 pharmaceutical ormulations containing imidazoles oE the present i~vention. Conventional techniques are used to 26 prepare ~hese formulations 27 rA0~ ro~ruL~
28INGREDIENT AMOUNT (M~
29(S) 2~4-(3 tert-kutylamino-2- 5.0 hydroxyprQpoxy)phenyl]-4-30methylimida201e 31calcium phosphate 120.0 ~ 15524 IA
~75~
1 TABLET FORMULATIONI(cont.) 2 INGREDIENT AMO~NT (M~.) ~ , ....
3 lacto e 50.0 4 starch 23.5
5 magnesium stearate 1.5
6 ~BLE~ FORMULATION II
7 ING~EDIENT AMOUNT (Mg.)
8 2-[4-(3-cyclopropylamino-2-hydroxy- 500.0 propoxy)phenyl]-4-tri1uoromethyl-
9 imidazole Starch paste -12 1/2%, 100 cc allon. 12.s 11 .
12 Starch, U.S.P. corn 25.0 13 Magnesium stearate 5.5 14 C~9~D~ ro~D~$IO~ . . .
INGREDIENT AMOUNT (M~.) 16 ~S)-2[4~(3-tert-butylamino-2-hydroxy- 250 propoxy)p ~ 1]-4-p-methoxyphenyl-17 imidazole dihydrochloride dihydrate 18 lac~ose~ U.S.P. 93 19 talc 7 INJECTABLE SOLU~ION
.
21 ING~EDTENT AMOUNT~
22 2~[4-(3-isopropylamino-2-hydroxy-propoxy)phenyl] 4-cya~oLmidazol~
23 hydroc~loride 24 sodium chloride 9 2S dis~illed wa~er, q.s. 1.0 ml.
.:
.
.
.. . 15524 IA
~7~
2 IN~REDIENT AMOUNT (~/1) 3 (S)-2-[4-(3-methylamino-2~hydroxy- 5.0 propoxy)phenyl]-4-(4-pyridyl) 4 imidazole Veegum H.V. 3.0 6 methyl parable 1.0 7 kaolin 10.0 8 glycerin 250.0 9 water, q.s. ~ 1 liter 12 The following examples illustrate preparation of 13 representative imidazoles of the present invention. A11 14 par~ and percentages are ~y weight unless otherwise indicated.
. .
~ 15524 IA
~75~89 1 EXA~LE 1 -2 A. Preparation of 3-(3-C~loro-2-hydroxypropoxy)-Benzaldehyde 3 A mixture of m-hydroxybenzaldehyde (24.4 ~
4 epichlorohydrin (55.2 g.), and pyridine (0.4 ml.) is heated 5 hours at 100C. and then concentrated under reduced 6 pressure (2~ mm. Hg.) over steamO The xesidual oil i~
7 taken up in chloroform (200 ml.), concentrated hydrochloxic 8 acid (50 ml.) is added, and the mixture is stirred 0.5 hours 9 at room temperature. The chloroform layer is separated, washed with water, and the chloroform ramoved under reduced 11 pressure (20 mm. Hg.) over steam. Distillation of the L2 residual oil yields 28.9 g. of 3--(3-chloro-2-hydroxypropoxy)-13 benzaldehyde as a yellow-brown oil, b.p. 166C./0.25 mm. Hg.
5 ~. Preparation of 2-[3-~3-Chloro-2-hydroxypropoxy)-phenyl]-4-trifluoromethylimldaæole 16 To a solution o~ sodium acetate trihydrate (11.6 17 g.) in water (40 ml.) is added trifluorodibromoacetone (11.6 18 g.) and the resulting solution is heated 0.5 hours at 100C.
19 A~ter cooling to room temperature, it is added to one pox-20 tion to a solution of 3-(3-chloro-2~hydroxypropoxy)benzal-21 dehyde t9.45 g.) in methanol (100 ml.~ and aqueou~ ammonia 22 50 ml.~. The resulting cloudy solution is allowed to stand 23 5 hours at room temperature and the methanol is removed 24 under reduced pressure (20 mm Hg. ) over steam. An oil 25 separates and cry~;tallizes. The supernatant liquid is 26 decan ed and the residue is triturated with benzene and 27 isola~ed by filtra~io~ to yield 6.97 g. of solid. After 28 recrystaIlization from toluene, the solid is suspended in 29 warm water and acetonitrile added to cau~e solution. Upon :
.
~7~613~
l cooling, 2-~3-(3-chloro 2-hydroxypropoxy~phenyl]-4-tri-2 fluorome~hylimidazole is obtained as a white ~olid, m.p.
3 181-183C.
S C. Preparation o~ 2-~3-~2,3-Epoxypropo~)phenyl]-4-trifluoromethylimidazole 6 To a solution o 2-~3-(3-chloro-2-hydroxypro-7 poxy)phenyl]-4-trifluoromethylimidazole (3.8 g.) in methanol 8 (lS0 ml.) is added powdered potassium hydroxide (3.g.) and 9 the mixture is allowed to stir 4 hours at room temperature.
Glacial acetic acid (2.75 ml.) i5 addPd and the mixture 11 concentrat0d under reduced pressure (20 mm. Hg.) ovsr steam.
12 The resulting residue is stirred with water, filtered and 13 recry~tallized from xylene to yield 2.5 g. of 2-l3-t2,3-14 epoxypropoxy)phenyl]-4-tri~luoromethylLmidazole i~ obtained, m.p. 145-146.5C.
7 D. Preparation of 2-[3-(3-Isopropylamino-2-hydroxy propoxy)~ tri~luoromethylimidazole 18 A solution o~ 2-~3 (2,3-epoxypropoxy)phenyl]-4-~ tri~luoromethylimidazole (0.9 g.) in isopropylamine (lO ml.) i~ heated 6 hours at ref].ux. The excess isopropylamine is 1 removed by distillation at atmospheric pressure over steam.
22 The residue i5 triturated with nitromethane (5 ml~) and the 23 resulting solid removed by ~iltration. After recrystal-24 lization ~rom nitromethane 0.65 g. of 2~[3-(3-isopropyl-amino-2-hydroxypropoxy3phenyl~4-trifluorvmethylLmidazole 26 is obtained, m.pO 162.5-163.5C.
j~ ~
. .
~75689 2 Preparation of 2-[4-(3-isopropylamino-2-hydroxypropoxy)-phenyl]-4-trifluoromethylimidazole 3 A solution of 2-[4-(2.3-epoxypropoxy)phenyl]-4-4 trifluoromethylimidazole (1 g) in isopropylamine (10 ml.) is heated 7 hours at reflux and then allowed to stand 16 6 hours at room temperature. The ~xcess isopropylamine is 7 removed by distillation at atmospheric pressure and the 8 residue is triturated with nitromethane to yield a solid.
9 A~ter filtration and recrystallization from acetonitrile, 0.6 g. of 2-~4-(3-isopropylamino-2~hydroxypropoxy)phenyl]-11 4-trifluoromethylimidazole is obtained, m.p. 173~-173.5C.
4 A. Preparation of 2-methyl-4-(2,3-epoxypropoxy)-benzaldehYde To epichlorohydrin ~20 g., 0.216 mole) h~ated 16 at 55C. is added dropwise a solution of 2-methyl 4-17 hydroxybenzaldehyde (9.0 g., .066 mole) in 2.5 N sodium 18 hydroxide solution (40 ml.). After the addition, ~he 19 solution is allowed to stir an additional 3 hours at 55C. and then at room temperature overnight. The oil 21 is distilled to give 8.3 g. of 2-methyl-4-(2,3-epoxy-22 propyl)benzaldehyde, m.p. 160-170C. at 1 mm. Hg.
4 B. Prepaxation of 2-methyl~4-(3-ter~-butylamino-2-hydroxypropoxy)benzaldeh~de To a methyl-4-(2,3-epoxypropoxy~benzaldehyde 26 (8.3 g~, .043 mole) is added~text-butylamine (10 g~, 27 0.137 mole) ana the resulting ~olution refluxed for 28 2 hours and allowed to stand overnight at room tempera-29 ture. The excess text ~utylamine is removed under ~7~ti8~
1 reduced pressure (20 mm. Xg.), the residue is heated on a 2 steam bath with 6 N hydrochloric acid ~50 ml.) for 5 3 hours, and then basified while hot with solid sodium 4 hydroxide. The mixture is cooled to room temperature, extracted with chloroform (3x50 ml.), dried over sodium 6 sulfate, filtered and concentrated to dryness. The 7 residual oil is crys~allized from hexane to give 8.75 g.
8 of 2-methyl-4-(3-tert.butylamino-2-hydroxypropoxy)benz-9 aldehyde, m.p. 82-84C.
11 C. Preparation of 2-[2-methyl 4~(3-tert~butylamino-2-hydroxY~ro~oxv)phenYl]-4-trifluoromethYl~nidazole 12 To ~odium acetate trihydrate (6.26 g., .046 13 mole) in water (26 ml.) is added dibromotrifluoroacetone 14 (6.26 g., .023 mole). The solution is heated for 45 minutes on a steam bath, cooled, and added to a solution 16 of 2-methyl-4 (3-tert,butylamino-2-hydroxypropoxy)-17 benzaldehyde (3.05 g., 0115 mole) in methanol (60 ml.) 18 and concentrated aqueous ammonia (20 ml.)~ The ~olution L9 is allowed to stand for 5 hours at room temperature. The methanol is removed under reduced pressure (20 mm. Hg.) 21 over steam and the residue treated with chloroform (3 x 22 50 ml.) and sa~urated sodium carbonate (50 ml.). The 23 organic layer is concentrated to dryness and the residue 24 crystallized from acetonitrile to give 1.2 g. o 2-[2-methyl-4~ ~ter~-butylamino-2-hydroxypropoxy)phenyl]-26 4-trifluoromethylimidazole, m.p. 162-164C.
` ~ 15524 IA -~L6)7S68~
1 Example 4 2 Preparation of 2-[4-(3-tert. butylamino-2 hydroxy~
propoxy)phenyl]-4-pheny~ dazole 3 A solution of p-(3-tert. butylamino-2-hydroxy-4 propyl)benzaldehyde (5.0 ~., O.Q2 moleI, p~enylglyoxal monohydrate (6.04 g., 0.04 mole), concentrated aqueous 6 ammonia (50 ml.), water (50 ml.) and methanol (200 ml.) 7 is allowed to stand at room temperature for 5 hours.
8 The solution is concentrated to a residual o-l under 9 reduced pressure (20 mm. Hg.) over steam and treated with satura~ed sodium carbonate (50 ml.) and chloroform 11 (3 x 50 ml.). The oryanic layer is concentrated to 12 dryness and chromatographed on neutral alumina (500 g.) 13 using a gradient elution technique starti~ with chloro-14 ~orm. The product is eluted with 10~ methanol-90~
chloroform. Final purification is accomplished by pass-16 ing through a column of silica gel (150 g.) and eluted 17 with 20% methanol-80% chloroform. The solvent is 18 removed under reduced pressure (20 mm. Hg.) over steam 19 and the residue crystallized from acetonitrile to give 0.7 g. o~ 2-[4-(3-tert. butylamino-2-hydroxypropoxy)-21 phenyl~-4-phenylimidazole, m.p. 176~178C.
24 A. Preparation o~ S-4~3-tert. butylamino-2-hydroxy-prol~oxY)benzaldehYde To a solution of S-2-phenyl-3-tert. butyl-5-26 hydroxymethyloxazolidine (47 g., 0.2 mole) in pyridine 27 (75 ml.) is added portionwise p-toluenesulfonyl chloride 28 keeping the internal temperature between 25 and 30C.
.' ~ - 32 -~7S6~1~
1 The mixture is stirred 2 hours after addition is complete 2 keeping the temperature between 25 and 30C. Ice water 3 (150 ml.) and potassium carbonate (27.6 g.) are added and 4 the mixture is extracted with chlorofonn (3 x 100 ml.).
The organic extract is dried over sodiwn sulfate and con-6 centrated first at 20 mm. ~g. and then at 1 mm. Hg. keep-7 ing the temperature below 50C. The re~idual oil is dis-8 solved in N,N-dimethylformamide (150 ml.) and added drop-9 wi~e to a refluxing solution of the sodium salt of p-hydroxybenzaldehyde (0.2 mole) in N,N-dimethylformamide 11 (200 ml.). After refluxing 10 hours, the reaction mix-12 ture is concentrated first at 20 mm. Hg. and then at 13 1 mm. Hg. over steam. The residue is treated with 5~
14 sodium hydroxide soltuion and extracted with chloroform (3 x 100 mlJ). The organic extract is dried over sodium 16 sulfate and the residue chromatographed on alumina 17 (500 g. activity grade II). The chromatographic frac-18 tions are concentrated and the residue distilled at 19 240C. at 0.3 mm. Hg. The distillate (21 g.) is treated with 1 N hydrochloric acid (75 ml.), heated 1/2 hour 21 over ~eam, cooled and extracted with ether. The 22 aqueous layer is made basic to pH 10 by the addition of 23 2~ sodium hydroxide solution and extracted with chloro-24 form (3 x 100 ml.). The organic extract is dried over sodium sulfate and concentrated to an oil which after 26 crystallization from hexane yields 14.5 gO of S 4-(3-27 tert. butylamino~2-hydroxypropoxy)benzaldehyde, m.p.
28 60-62C.
~ 33 -.. . . - .
~ 15524 IA
~L~7S689 - 1 B. Preparation of S-2-[4-t3-tert. buty]amino-2-hydroxy-propoxy)phen~l]-4 trifluoromethylimidazole _ . , 2 To sodium acetate trihydrate (20.2 g., 0.15 3 mole) in water ~100 ml.) is added dibro~lotrifluoro-4acetone (20.2 g., 0.075 mole). The solution is heated 45 minutes on a steam bath, cooled and is added to a 6 solution of S~p-(3-tert. butylamino-2-hydroxypropoxy)-7benzaldehyde (12.5 g., 0.05 mole) in methanol ~200 ml.) 8 and concentrated aqueous ammonia (75 ml.). The solut:ion 9 is allowed to stand 5 hours at room temperature. The methanol is removed by distillation under reduced 11 pressure (20 mm. Hg.) over steam. The mixture is made 12 ba~ic with saturated aqueous sodium carbonate solution 13 and extracted with ethyl acetate (3 x 100 ml.). The 14 organic ex~ract is dried over sodium sulfate and con-centrated at 20 mm. Hg. over s~eam. The resulting resi-16 due is recrystallized from acetonitrile to yield 7.6 g.
17 of S-2-[4-(3-tert. butylamino-2-hydroxypropoxy)phenyl]-134-trifluoromethylimidazole, m.p. 181-182C.
19Other Formula I imidazoles prepared using the procedures su~stantially as described in Examples 1-5 21 are listed in the following table. It is to be understood 22 that analogous reactants are used to obtain the particular 23 iridazole produc~s.
'.
.
..
- 3~ --~ 15524 IA
~L~75~3g PREPARED IMIDAZOLES OF FORMULA
--~N~N-- R3-o-cH2-cH-cH2-N- R6 H
... . . .
Imlda201e Using Substituents Example of 6 1 H -CF3 ~ t-butyl 207-210 ___ 7 2 H -CF3 ~ t~butyl 139-141 8 2 H -CF3 ~ IH CH2 C~2 ~ 159-170 ~3 2 H -CF3 ~ n-propyl - 153-155 9 2 H -CF3 ~ -~H-CH2CH2- ~ 120-133 11 2 H -CF3 ~ cyclo- 163.5-165 propyl C ~ H3 12 3 H -CF3 ~ t-butyl 187-190 C~3 1~ 3 H ~CF3 ~ t-butyl 183-185 C~
13a 3 H -CF3 ~ t-butyl 159~162 . C~3 14 3 H -CF3 ~ isopropyl 210-213 ~ ' ~
- 35 - ~;
~j, ... .
' ~.~756~
TABLE 1 (Contd.) PREPARED IMIDAZOLES OF FORMUL~
OI R
. Imldazole Substituents Using Procedure ~ M.P.
Example of ~ Rl R3 R ~
No. _ Example ~ C C1 6 ~ (C)_ 3 H -CF3~ t-but~l 181 182 Cl 16 3 H -CF3~ ~ t-butyl 167-171 ~ . .
17 3 H -CF3~ t-butyl 207210 / \
Cl 18 3 H -CF3~ ~ t-butyl 174-177 19 4 ~ ~ _ ~ t~butyl 180-181 4 H H ~ t-butyl 162-164 ~ .
~ ' 21 4 H H ~ t-butyl 133O5-196 22 4 HC1 ~ ~ t-butyl 186-188 .
~: 23 4 H ~ ~ t-butyl 167-169O
~ '.:
24 4 H r~ ~ t-butyl 179~'-181 ' TABLE 1 (Co~td.) PREPARED lMIDAZOLES OF FORMULA
Rl ~ ~ R8-O-CHz~CH~CH -I-R
Using Imidazole Procedure Substituents Exampleo~ ~ ~;~~ ]!a P
Wo.ExamPlel 3 6 ~ , O
Cl . 1,~ ~
4 H Cl ~ ~ t-butyl 189-190 .
26 4 H ~ ~ t-butyl 101-105 (~
27 4 H H ~ t-butyl 158-162 28 4 ~ ~ ~ t-butyl 172-173 29 4 H~ ~ t-butyl 1?8-180 F F
4 HF ~ ~ t-butyl 168-170 F F
31 5 H -CF3 ~ t-butyl 178-179~5 32 5 H -CF3 ~ t-butyl 141-143 ~
33 5 H -CF3 ~ t-butyl 110-120 .
-~ 0 The glyoxal reagent used Wa~s ~ ~
HCl Salt Q R-isomg~ ;
S~isomer ~ O-CH2-~2-CH2~R6 attached at this position Monohydrate : S-Isomer - 37 - :
107~689 15524 IA
1 Additional Examples illustrating preparation 2 of other imidazoles of the present invention follow. All 3 parts and percentages are by weight unless otherwise 4 indicated.
6 A. Preparation of 2-[4-(3-Chloro-2-hydroxypropoxy)-phenyl]-4-~rifluoromethylimidazole _ _ 8 To sodium acetate trihydrate ~5.8 g.) in water (20 9 ml.) is added tri~luorodibromoacetone (5.8 g.); the xesult ing mixture is heated 0.5 hours on a steam bath. A~ter 11 cooling, the ~olution is added to p-(3-chloro-2-hydroxy-12 propoxy)benzaldehyde (4.2 g.) in methanol (100 ml.) and 13 concentrated aqueous ammonia (25 ml.). After standing 4.5 14 hours at room temperature, the methanol is removed by distillation at 20 mm. Hg. over ste~; a solid separates and 16 is filtered. After recrystallization from nitromethane, 17 1.65 g. of 2-[4-(3-chloro-2-hydroxypropoxy)phenyl]-4-tri-18 fluoromethylimidazole is obtained, m.p. 181-183C.
B. Preparation of 2-[4-(2,3-Epoxypropoxy)phenyl]-4 21 trifluoromethylimidazole 22 To a Rolution o 2-~p-(3-chloro-2-hydroxypro-23 poxy~phenyl]-4-trifluoromethylimidazole (1.92 ~.) in meth-24 anol (100 ml.) Ls added crushed potassium hydroxide (1.5 g.)~
The mixture is stirred 3 hours at room temperature, neu-26 tralized with acetic acid and concentra~ed under recluced 27 pres~ure ~20 mm. Hg.) over steam. Th~ residue LS triturated 28 with water (25 ml.), filtered and xecrystalli2ed by dis- ~ .
2~ solving in benzene and adding hexane until turbid.
' , .
. ' ' ' ' , : ' . . .
~ ~ 15524 IA
~L~75~
1 A yield of 1.2 g. of 2-[4-(2,3-epoxypropoxy)phenyl]-4-2 trifluoromethyLimidazole is obtained, m.p. 152-153.5~C~
3 C. Preparation of ~-[4-(3-tert. Butylamino-2 hydroxy-propoxy)~henx1]-4-trifluorometh~limldazole_ _ A solution of 2-[4-(2,3-epoxypropoxy)phenyl]-6 tri~luoromethylimidazole (2.5 g.) in tert. butylamine 7 (20 ml.) is heated 6 hours at reflux. The excess tert.
8 butylamine is removed by distillation at atmospheric 9 pressure over steam. The residue is triturated with nitromethane (5 ml.) and the resulting solid removed by 11 filtration. After recrystallization from acetonitrile, 12 (1.2 g.) of 2-[4~(3-tert. butylamino-2-hydroxypropoxy)-13 phenyl]-4-tri~luoromethylimidazole is obtained, m.p.
14 ~ 185.5-186.5CC.
.
17 A. Preparation of 4-(3-tert. Butylamino-2-hydroxy-Dro~oxv)benzaldehvde 18 ~
19 To 4-(2,3-epoxypropoxy)benzaldehyde (20 g.) is added tert. butylamine (50 ml.) and the resulting solu-21 tion is refluxed 17 hours. The excess tert. butylamine ~ -22 i9 removed by heating at atmospheric pressure to yield a 23 solid residue. To this residue is added 6 N hydrochloric 24 acid (200 ml.) and the resulting mixture i~ h~ated 5 hours 2S on a steam bath. The solution is cooled and concentrated 26 to 100 ml. on a steam bath under reduced pressure (20 mm.
27 Hg.). The concentrated solution is made basic to pH lO
28 with saturated aqueous sodium carbonate and extracted 29 with chloroform. The chloroform extract is concentrated - 39 ~
' .
~ 15524 IA
~756il5~
1 to a solid which after recrystallization from acetonitrile 2 yields 18 g. of 4-(3-tert.butylamino-2-hydroxypropoxy)-3 benzaldehyde, m.p. 123-125.5C.
B. Preparation of 2-[4-(3~tert.Butylam:Lno-2-hydroxypropoxy)-pheny~]-4-trifluorometh ~ idazole __ __ 6 To sodium acetate trihydrate (11.8 g., 7 0.088 moles) in water (40 ml.) is added dibromotri-8 fluoroacetone (11.8 g., 0.044 moles). The solution i5 9 heated 45 minutes on a steam bath, cooled and added to a solution of 4-(3-tert. butylamino-2-hydroxypropoxy)-11 benazldehyde (5 g., 0.02 moles) in methanol (200 ml.) and 12 concentrated aqueous ammonia (25 ml.). The solution is 13 allowed to stand 5 hours at room temperature. The methanol 14 is rem~ved under reduced pressure (20 mm. Hg.) o~er steam and chloroform (50 ml~) and saturated aqueous sodium 16 carbonate (25 ml.) are added to the residue. After stir-17 ring a solid separa~es is filtered and washed with water.
18 After recrystallization from acetonitrile, 3 g. of 19 2-[4-(3-tert.butylamino-2-hydroxypropoxy)phenyl]-4-tri~luoromethylimidazole is obtained, m.p. 189-l91~C.
~ - 40 -:
~L~75~
2 A. Preparation of Salicylaldehyde Diethyl acetal 3 A mixture of salicylaldehyde (80 g., 0.0655 4 mole), triethylorthoformate (110 g., 0.765 mole), absolute ethanol (40 ml.) and concentrated sulfuric acid (3 drops) 6 is heated to reflux overnight. The volatiles are re~
7 mov~d under reduced pressure (20 mm. Hg.) over steam to 8 give diethyl acetal of salicylaldehyde which i9 used 9 without furthex purification.
11 B. Preparation of 2-(2,3-Epoxypropoxy)benzaldehyde DiethYl acetal 12 - _ 13 To epichlorohydrin (37 g., 0.4 mole~ heated at 14 50C. is added dropwise a solution of salicylaldehyde diethyl acetal (25 g., 0.13 mole) in 2 N sodium hydroxide 16 solution (200 ml.) and the mixture allowed to st~r over-17 night at 50JC. The reaction mLxture is extracted with 18 chloroform (3 x 100 ml.~, dried over potas~ium carbonate, 19 and concentrated to dxyness to give 34.3 g. of 2-(2,3-epoxypropoxy)benzaldehyde diethyl acetal.
22 C. Preparation o 2-(3-tert. butylamino~2-hydroxy-~ro~oxv)benæaldehvde 24 A solution of 2-(2,3-epoxypropoxy)banzal-?5 dehyde diethyl acetal (53 g., 2.1 mole) and tert. butyl-26 amine (100 ml.) is heated to reflux for 2 hours and 27 allowed to stand at rosm temperature overnight. The ex-28 cess tert. butylamine is remo~ed under reduced pressure 29 ~20 mm. Hg.) and the residue heated on a steam ~ath with . . ..
~ 15524 IA
5~
1 6 N hydrochloric acid (300 ml.). After cooling, the 2 solution is neutrali2ed with solid sodium bicar~onate, 3 extracted with chloroform (3 x 100 ml.), dried over 4 sodium sul~ate, filtered and concentrated to dryness.
The residue is chromatographed on silica gel (500 ml.) 6 using gradient elution techniques starting with chloro-7 form and the product is obtained with 10% methanol 90%
8 chloroform. After removal of the solvent under reduced 9 pressure (20 mm. Hg.), the xesidue is crystallized from acetonitrile to give 13.8 g. of 2-(3-tert. butylamino-11 2-hydroxypropoxy)benzaldehyde, m.p. 156-160C.
13 D. Preparation of 2-[2 (3-tert. butylamino-2-hydroxy-14 pro~oxy)phenyl]-4-tri1uorom thylimidazole _ _ To sodium acetate trihydrate (5.4 g., O.0396 16 mole) in water (20 ml.) is added dibromotrifluoroacetone 17 (5.4 g., 0.02 mole). The solution is heated for 45 18 minutes on a steam bath, cooled and added to a solution 19 of 2-(3-tert. butylamino-2-hydroxypropoxy)benzaldehyde (3.6 g., 0.0143 mole) in methanol (100 ml.) and con-21 centrated aqueous ammonia (25 ml.). The solution is 22 allowed to stand overnight at room temperature. The ~3 methanol is removed by distillation under reduced pres-24 sure (20 mm. Hg.) and the residue treated with saturated sodium carkonate (50 ml ~, extracted with chloroform 26 (3 x 50 ml.) and separated. The organic layer is dried 27 over sodium sul~ate, ~iltered and concentrated to dry-28 ness. The residue is chromatographed on silica gel 29 (400 ml.) and the product eluted with 20~ methanol-80~
chloroform. Recrystallization of the product from nitro-t ~ ~ 15524 IA
~756~
1 methane gives 700 mg. of 2-[2-(3-tert. butylamino-2-2 hydroxypropoxy)phenyl]-4-trifluoromethylimidazole, m.p.
3 105-107C.
6 2-~4-(-3-tert. butylamino-2-hydroxypropoxy)phenyl]-4-meth~limi~ le .. . .. _ 7 To a mixture of cupric acetate (5.0 g., .0~5 8 mole), acetoxyacetone (1.5 g., .013 mole), concentrated - 9 agueous ammQnium t2S ml.) is added a solution of p-(3-tert. butylamino-2-hydroxypropoxy)benzaldehyde (3.2 g., 11 .0127 mole) in methanol (25 ml.). After the addition, 12 the mixture is heated at re~lux overnight. The methanol 13 i9 removed by dis~illation under reduced pressure (20 mm.
14 Hg.) over steam and water (200 ml.) is added to the residue. The resulting solution is treated with 16 hydrogen sulfide, filtered through a filter aid, treated 17 with solid potassium carbonate until basic and extracted L8 with chloroform (3 x 50 ml.). The chloroform is con-19 centrated to dryness and the residue chromatographed on neutral alumina tl70 g.) using a gradient elution 21 technique star~ing with chloroorm. ~he material i~
22 eluted off the column using 5~ methanol-95% chloroform.
23 The organic solvent is removed by dis~illation under 24 reduced pressure (20 mm. Hg.) and the residue crystal-lized rom acetonitrile to give 0.79 g. of 2-[4-(3-26 tert. butylamino-2-hydroxypropoxy)phenyl]-4-methylimida-~ 27 zol~, m.p. 202-203C.
: _ 43 _ ~ - 15524 IA
10756~39 -2 ~ Pyridylglyoxal-dimethylacetal 3 To a solution of butyl lithi~n (129 ml., 193N, 4 0.25 m.) in ether (300 ml.) cooled below -50C. is added 3-bromopyridine (33.02, 0.209 m.) in ether (60 ml.). The 6 yellow suspension which results is allowed to stir an 7 additional 1/2 hour at -50C. and dimethoxyacetic acid 8 piperidide (33.6 gO, 0.179 m.) in ether (90 ml.) is 9 added over 1 hour at -50C. After complete addition, the react~on mixture is allowed to warm to room -~empera-11 ture and heated to reflux for 1/2 hour. After cooling, 12 a solution of ammonium chloride (500 ml.) is addecl 13 separated and the aqueous layer extracted with 2x100 mlO
14 ether. The ether layer is washed with 3N ~SO4, acid;
the aqueou~ layer is neutralized with KOH and extracted 16 with 3x100 ml. CH2C12,dried over Na2SO4, filtered ancl 17 concentrated to dryness. The remainder is distilled at 18 95-100/0.4 mm. to give l3.8 g. o~ ~-pyridylglyoxal-lg dimethylacetal.`
21 B. 4~ Pyridyl)-2-[4-(3-tert-butylamino-2-hydroxypro-~oxY)PhenYl]-imidazole 23 To concentrated sulfuric acid (15 g.) cooled to 24 0-4 is added ~-pyridyl~lyoxal-dimethylacetal (5.4 g., 0.03 m) and the solution allowed to stand at room tempera-26 ture. After 3 days, the mixture is cooled and neutrali~ed 27 with Na~CO3 (26 g., 0.30m).
28 To this qolution is added water (2S ml.), 29 37% aqueous ammonia (75 ml.), methanol (25 ml.) and a solution of p-(3-tert-butylamino-2-hydroxypropoxy)benzal-'~.
.
~ 15524 IA
lL~9756~
1 dehyde (5.1 g., 0.02 m) in methanol (200 ml.). After 2 standing at room temperature for 3 days, the methanol is 3 removed under reduced pressure (20 mm) over steam, the 4 residue covered with saturated Na2CO3 ~100 ml.), ex-tracted with CHC13 (3xlS0 mlO), dried over Na2SO4, 6 filtered and concentrated to dryness. The residue is 7 chromatographed on silica gel (600 ml.~ and the product 8 eluted with 50% CHC13/MeOH. The crude product is fuxther ; 9 puri~ied by chromatography on NoO 2 neutral alumina (90 g.) and eluted with 2~ MeOH/CHC13. Recrystallization from 11 acetonitrile/chloroform gave 125 mg. of 4-(3-pyridyl)-12 [4-(3-tert-butylamino 2-hydroxypropoxy)phenyl]-imidazole.
(S) Methyl-2-[4-(3-tert-butylamino~2-hyd~oxypropoxy)-16 phenyl~imldazol~ carboxylate 17 To lN sodium hydroxide solution (20 ml.) is 18 added (S)-2-[4-(3-tert-butylamino-2-hydroxypropoxy~phenyl]-19 4-trifluoromethylimidazole (1 g.) and the mixture is heated 0.5 hour over steam. The resulting solution is neutralized 21 to pH 7 with concentrated hydrochloric acid and concentrated 22 on a steam bath over a stream of nitrogen. The resulting 23 solid is suspended in methanol (25 ml.) saturated with 24 hydrogen chloride. The mixture is re~luxed three hours with hydrogen chloride ~eing added after the first and second 26 hour. A~t~r being concentrated under reduced pressure (20 27 mm.) over steam, saturated aqueous solid carbonate solution 28 is added (25 ml.) and the mixture extracted with ethyl 29 acetate. The organic extract was concentrat~d to a gum which on trituration with aqueous sodium carbonate Crude S-2-[4-(3-tert.-butylamino-2-hydroxy~ropoxy)phenyl]-4-carboxy-imidaæ~
" 15524 IA
~LCl 7~8~D
1 solidifies and is filtered. After recrystalliæation from 2 acekonitrile 200 mg. of (S)-methyl 2-[4-(3-tert. butylamino-3 2-hydroxypropoxy)phenyl]imidazole 4-carboxylate melting 4 at 159-161C. is obtained.
...
7 A. S-2-Phenyl-3-Tert. butyl 5-(3-cyano-6~pyridyl-oxymethYl)oxazolidine 8 To a solution of S-2-phe~yl~3-tert. butyl-5-9 hydroxymethyloxazolidine (12.35 g., O.0526 mole) in dime~hyl-formamide (65 ml.) is added sodium hydride 11 (2.22 g., 0.0526 mole of 57%. A~ter heating 25 minutes 12 on a steam bath, the mixture is stirred and cooled to room 13 temperature in 30 minutes and added to a ~olution of 14 6-chloronicotinonitrile (7.28 g., 0.0526 mole) in dimethyl-~ormamide (35 ml.). The reaction mixture ~ stirred at 16 room temperature for 4 1/2 hours and then is concentrated 17 under reduced pressure. The 1uid residue is taken up in 18 ether and washed with water. The ether solution is dried }9 and concentrated under reduced pressure to yield 18~5 g.
of S-2-phenyl-3~tert. butyl--5-(3-cyano-6-pyridyl~oxymethyl) 21 oxazolidine as an oil.
22 B. S=6-(3-Tert.butylamino-2-h~droxypropoxy~nicotinonitrile 23 A su~pension of S-2-phenyl-3-tert. butyl-5-24 (3-cyano-6-pyridyloxymethyl) oxa201idine (18.5 g.) in lN
hydrochloric acid (60 ml.) is heated 5 minutes on a steam 26 bath and then stirred at room temperature for 1~2 houx.
27 The mixture is extracted with chloroorm and the aqueous 28 layer is made basic with 40% sodium hydroxide solution.
2~ The basic solu~ion is extracted with e~hyl acetate ancl the extract is dried and concentrated under reduced pressure.
31 The residual white solid is recrystallized from hexane-n-- ~6 -.~
~756~3~
1 butyl chloride to yield 5.14 g. of S-6-(3-tert. butylamino-2 2-hydroxypropoxy~ nicotinonitrile, m.p. 103-105C.
3 C. S-6-(3-Tert. butylamino-2-hydroxypropoxy) nicotinalde-hyde 4 A suspension of S-6-(3-tert. butyLamino-2-S hydroxypropoxy) nicotinonitrile (5.14 g. 0.0204 mole) in 6 toluene (128 ml.) in a flamed flask is heated with stirring 7 until a solution is ob~ained. The toluene is allowed to 8 distill until a total o~ 21 ml. is collected. ~eating is 9 discontinued and the reaction solution is cooled in a dry ice- acetone bath causing the staxting material to 11 reprecipitate. To the cold reaction mixture is added 12 diisobutylaluminum hydride in toluene (62.6 ml. 0.075 mole 13 of 0.17 g./ml.) dropwise under nitrogen with stirring. The 14 yellow reaction mixture is stirred cold ~or 1 hour, and then the acetone bath is removed as methanol (22 drops) is added 16 followed by the addition of water (22 drops). Chloroform 17 is added to the mixture and then water (43 ml.), and after 18 good stirring the mixture is ~iltered. The filtrate ~
19 shaken in a separatory funnel and the organic layer is sep arated, dried, and concentrated under reduced pressuxe. To 21 the residual oil is add~d 1% hydrochloxic acid (43 ml.) and 22 the mixture is heated on a steam bath for 1/2 hour. At this 23 point the pH is basic. Concentrated hydrochloric acid is 24 added until the pH is acid and heating is continued for 15 minutes. The mixture is cooled and made basic with 40%
26 odium hydroxide solution and then extracted with chloroform.
27 The extract is dried and concentrated under reduced p~essure 28 to yield 5.1 gO o~ S-6 (3-tert. butylamino-2-hydroxypropoxy) 29 nicotinaldehyde as an oil which solidifies.
: ' ~1~75~
1 D. S-2-[2-(3-te~ Butylamino-2-hydroxypropoxy)-5-pyridyll-4-trifluoromethxlimidazole _ _ _ 2 To sodium acetate trihydrate (2.16 g., 0.016 moles) 3 in H2O (15 ml.) is added dibromotrifluoroacetone (2.16 g., 4 0.008 moles) and the mixture is heated 1/2 hour on a steam bath. After cooling the solution is added to 6-(3-tert.-6 butylamino-2-hydroxypropoxy) nicotinaldehyde (1 g.) in 7 methanol (50 ml.) and concentrated aqueous ammonium 8 hydroxide (15 ml.~. After standing 20 hours at room temp-9 erature, the methanol is xemoved under reduced pressuxe (20 mm.) over steam. Concentration aqueous sodium carbonate 11 (10 ml.) and ethyl acetate (50 ml.) are added to the concen-12 trated solution. A~ter extracting the organic layer is 13 separated dried over sodium sulfate and concentrated to 14 a gum whic~ is chromatographed on activity grade II alumina with chlorofonm methanol using a gradient elution technique.
16 The fractions containing product are combined and concen~
17 trated to a gum which is dissolved in ethyl acetate. The 18 ethyl acetate solution is washed with saturated sodium 19 carbonate solution, dried and concentrated to yield 2 ~2-(3-text.-butylamino-2~hydroxypropoxy)-5-pyridyl]-4-21 krifluoromethylimidazole as a non-crystalline solid ~650 mg).
22 This non-crystalline solid was covered with 23 hexane and allowed to stand at about OC. for 7 days. The 24 h~xane was ~hen decanted and the residue triturated with ether to yi~ld a solid. The ether filtrate also yielded 26 solid on ~tanding at room temperature. These solids were 27 combined and di~solved in benzene. Hexane was added to the 2B point of turbidity, which on cooling yielded a solid. The 2g solid was dried at 66-73~C. and 0.2 mm ~or about 4~ hours.
The dried solid was S-2-[2-(3-tert. butylamino-2-hydroxypro-31 poxy~-5-pyridyl~-4-tri~luoromethylimidazole monohyclrclte (NMR
. .
A and Mass Spectroscopic analysis), melting at 110-120C.
2 A. 4-(p-metho~hs~ __ __ pyridyl)imidazole 3 A solution of sodium acetate trihydrate (5.8 g, 4 0.04 m), 3-pyridinecarboxaldehyde (2.3 g., 0.02 m3, p-S methoxyphenylglyoxal monohydrate (3.92 g., 0.02 m), water ~~ 6 (20 ml.), concentrated aqueous a~monia (25 ml.), and 7 methanol (75 ml.) is allowed to stand at room temperature 8 overnight. The solution is concentrated to dxyness 9 under reduced pressure (20 mm) over steam, treated wi.th saturated Na2cO3 (100 ml.) and extracted with chloro~orm 11 (3 x 100 ml.). The organic layer is dried over Na2SO4, 12 filtered and concentrated to dryness. The residue i~
13 chromatographed on silica gel (300 ml.) and the product 14 eluted with 3--5% MeOH/CHC13. The material is crystallized from acetonitrile to give 2.3 g. of 4-(p-methoxyphenyl~-16 2-(3-pyridyl)imidazole of m.p. 184-186.
17 B. 2-(3-pyridyl)-4-(4-hydroxyphenyl)imidazole 18 A mixture of 4-tp-methoxyphenyl)-2-(3-pyridyl)-19 imidazole (2.0 g.) and 48~ HBr (100 ml.) is heated to re~lux for 20 hrs. After cooling, the precipitate is ~ -21 filtered off and crystallized from isopropanol-methanol 22 to give 2.05 g. o 2-(3-pyridyl)-4-(4-hydroxyphenyl)-23 imidazole of m.p. 315-318C.
24 C. 4--[4-(3-tert-butylamino-2-hydroxypropoxy)phenyl]-2-~. (3-~Yrid~T rmidaæole ; 25 A ~olution of 2-phenyl-3~tert-butyl-5-hydroxy-26 methyloxazolidine (2.4 g., 0.01 m) in pyridine t3 ml,) is ~7 cooled to 0-4C. and treated portionwise with p-toluene-28 sulfonylchloride t2.0 g., 0.01 m). The cooled solution 29 i9 slowly warm~d to room temperature while not allowing - . : . . . .:
1 the reac~ion mixture to exceed 30C. After 2.5 hrs., the 2 mixture is treated with a solution of ~2CO3 (1.4 g.) in 3 water (20 ml.~ and extracted with chloro~orm (3 x 50 ml.).
4 The organic layer is dried over Na2SO4 r ~iltered, and concentrated to dryness under reduced pressure (20 ~m) 6 over steam and finally at 60C. and 1 mm. Tha residual 7 oil is dissolved in dry N,N dimethylformamide (DMF) (20 ml.) 8 and added dropwise to a mixture of 2-(3-pyridyl)-4-~4-9 hydroxyphenyl)imidazole:2HBr:H2O (4.0 ~., .0095 m) in DMF (20 ml.~ and sodium hydride (57% oil suspension, 11 1.3 g., .031 m). After refluxing for 11 hours, the 12 mixture is concentrated to dryness under reduced pressure 13 (1-2 mm Hg.) over steam. The residue is treated with 14 lN HCl (100 ml.), heated for 1/2 hr. on a steam bath, cooled, and extracted with ether~ The aqueous layer is 16 neutra~ized with 10N NaOH (12 ml.), extracted with 17 C~C13 (3 x 50 ml.), dried over Na2SO4, filtexed and 18 concentrated to dryness.
19 The residue is chromatographed on No. 2 neutral alumina (200 g.) and eluted with 4~ MeOH/CHC13. The crude 21 product is further purified by chromatography on silica 22 gel t20Q ml.) and eluted with 40-50% MeO~/CHC13. The 23 material is crystallized from acetonitrile to give 0~425 g.
24 ~f4-[4~(3-tert-butylamino-2-hydroxypropoxy)phenylJ-2-(3-pyridyl)imidazole o~ m.p. 163-165C.
27 Methyl 2-~4 (3-tert-butyla~ino-2-hydroxypropoxy)phenyl]-28 A solution of crude 2-~4-(3-tert~utylamino-2 29 hydroxypropoxylp~enyl~-4~carboxyimidazole (30 g.) in prepared from the corresponding 4-tr~fluoro~ethyl-imidazole per Example 39 ~rocedure.
` 15524 IA
~75~
1 methanol (600 ml.) is heated to reflux, and then heating 2 is discontinued as hydrogen chloride is bubbled rapidly 3 through the solution with stirring for a half hour, ~ol-4 lowed by two and a half hours a~ reflux. Bubbling of hydrogen chloride is continued for another two hours ~ol-6 lowed by another hour at reflux and then the reaation 7 mixture is stirred at room temperature overnight. The 8 mixture is filtered and the filtrate is then concentrated 9 to dryness underAreduced pressure. The residue is dis-solved in water (150 ml.) and the pH is adjusted to 8 11 with saturated sodium carbonate solution. The basic 12 mixture is extracted with ethyl aaetate and the extracts 13 are dried, ~iltered, and concentrated under reduced }4 pre~sure to yield a solid which is recrystallized rom acetonitrile to yield the methyl 2-~4-(3-tert.butylamino-16 2-hydroxypropoxy)phenyl]-imidazole-4-carboxylate as a 17 cream-colored solid, m.p. 168-172C.
A. 2-~4-(3-Tert. butylamino-2-hydroxypropoxy)phenyl]-4-carbamo~limidazole ~ , .............. . _ _ . ......................... .
21 A solution o~ methyl 2-~4-(3-tert. butylamino-22 2-hydroxypropoxy)phenyl]imidazole-4 carboxylate ~10 g.~ in 23 methanol (100 ml.) is reacted in a bomb wi~h ammonia (44 g.) 24 at 100C. for 24 hoursO The reaction mixture is concentrated under reduced pressure and the residue is chromatographed on 26 silica g~l. The product is aluted with chloroform that is 27 wa hed with concentrated a~ueous ammonia ~0%) and methanol 28 (10~) and is recrystallized from acetonitrile to yield the 29 2~[4-(3-tert. butylamino-2~hydroxxpropoxy)phenyl]-4-carbamoylimidazole as a white solid, m.p. 149-154~C.
~51-~~ ~ 15524 IA
75613~
l B. 2-[4-(3-tert.-butylamino-2-hydroxypropoxy)phenyl]-4-cvanoimidazole _ _ , . ~ . . . _ . _ . . _ 2 To a solution of 2-[4-(3-tert.-butylamino-2~
3 hydroxypropoxy)phenyl]-4-carbamoylimidazole (0.5 g.) in 4 dry pyridine (lO ml.) is added trifluoroacetic anhydride (l.26 g.) portionwise with stirring. The reaction 6 solution is refluxed with stirring for four hours and 7 then concentra~ed under reduced pressure. The residual 8 gum is taken up in ethanol and saturated sodium carbonate 9 solution (lS ml.~ and stirred at room temperature for 20 hours. The ethanol is removed under reduced pressure ll and the remaining aqueous mixture is extracted with ethyl 12 acetate. The extract is dried over sodium sulfate, 13 filtered, and concentrated under reduced pressure. The~
14 residual gla~s is converted to its hydrochloride salt with ethanolic HCl and is recrystallized from ethanol-16 ether. The resulting tan solid is converted back to its 17 ~ree base by trituration with saturated sodium carbonate 18 solution. The free base is extracted into ethyl acetate l9 and the extract i3 dried over sodium sulate, filtered and concentrated under reduced pressure. The resldual 21 gum i9 recrystallized from acetonitrile to yield 40 mg~
22 of 2-[4-(3-tert.-butylamino-2-hydroxypropoxy)phenyl]-4 23 cyancimLdazo1e, m.p. 174-177~C.
- . . , ~-- 15524 IA
~375E;~
.
2 A. 4 Hydroxy-5,6,7,8-tetrahydronapthalclehyde 3 Step ~:
4 Dry hydrogen chloride gas is bubbled into a suspension of 5.O gms. of 5,6,7,8-tetrahydronaphthol and 6 6.0 gm. æinc cyanide in 60 ml. of dry ethyl ether for two 7 hours. To the mixture is added cautiously 50 ml. of water 8 and lO ml. 95% ethanol, and the resulting mixture is 9 refluxed l/2 hourO After cooling, the mixture is extracted with ethyl ether. The ether layer is washed 11 with water and dried over anhydrous sodium sulfate. The 12 ether is filtered and concentrated to an oil. The oil is 13 dissolved in benzene, and 4-hydroxy-5,6,7,8 tetrahydro-14 napththaldehyde crystallizes and is ~ ered.
16 B. 4=(2,3-Epoxypropox~)-5,6,7,8-tetrah~dronapthaldehyde 18 To a solution of 4-hydroxy-5,6,7,3-tetrahydro-19 napthaldehyde (20 gms., 0.012 m) in 1.5N sodium hydroxide (20 mlO) at 50C. is added epichlorohydrin (3.3 gms., 21 0.036 m) dropwis2. After 3 hours at 50C., the solution 22 i3 cooled and extracted with chloroform. The chloroform 23 is dried over anhydrous sodium sul~ate, filtered and con-24 centxated to an oil. The oil is purified by column chromatography to give 2.4 gm. of 4-(2,3-epoxypxopoxy)-26 5~6,7,8-tetrahydronapthaldehyde 4 '.
~' :
~751~9 1 C. 4(3-tert.-Butylamino-2 hydroxypropoxy)-5,6,7,8-tetrahydronapthaldehyd-e ..
3 To 4-(2,3-epoxypropoxy)-5,6,7,8-tetrahydronapth-4 aldehyde (2.4 gms) is added tert.-butylamine (15 ml.). The S resulting solution is heated at 45C. for 15 hours. The 6 excess tert.-butylamine is removed at reduced pressure 7 (20 mm). To the residue is added 30 ml. 6N hydrochloric 8 acid, and the resulting mixture is re~luxed ~or three 9 hours. The acidic mixture is poured into a satuxated solution of sodium carbonate which is heated on a steam 11 bath with nitrogen bubbling through it. The basic mixture 12 is extracted with chloroform, which i5 dried over anhydrous 13 sodium sul~ate, iltered and concentrated to give 2.3 g 14 of 4-(3-tert.butylamino-2-hydroxypropoxy)-5,6,7,8-tetrahydronapthaldehyde as an oil.
17 D. 2~ 3-tert.-Butylamino-2-hydroxypropoxy~-5,6,7,8-tetrahydronapthyl]-4-trifluoromethylimidazole 18 Step D:
19 To ~odium acetate trihydrate (2~07 gm., 0.015 m) in water (20 ml.) is added dibromotrifluoroacetone 21 (2.07 g., 0.0075 m). The solution is heated for 40 minutes 22 on a steam bath, cooled and added to a solution of 4-(3-tert.
23 -butylamino-2-hydroxypropoxy)-5,6/7,8-tetrahydronapth-~ 54 ~
.
~756~9 1 aldehyde (2.3 mgs., 0.0075 m) in methanol (1~0 ml.) with 2 concentrated aqueous ammonium hydroxide (15 ml.). The 3 solution is allowed to stand at room t~perature for 17 4 hours. The methanol is removed under rleduced pressure (20 mm) over steam and ethyl acetate (100 ml.) and 6 saturated aqueous sodium carbonate are added to the residue.
7 The ethyl acetate is separated, dried oE anhydrous sodium 8 sulfa~e, filtered and concentrated. The oil ~s crystallized 9 from acetonitrile to give 500 mg. of 2-~(3-tert-butyl-amino-2-hydroxypropoxy)-5,6,7,8-tetrahydronaphthyl]-4 11 tri1uoromethyl-imidazole. Melting point 203-205C.
13 A. 4-(3-n-Butylamino-2-hydroxypropoxy)benzaldehyde 14 Step A:
To 4-(2,3-epoxypropoxy)benz~ldehyde (8.9 gms., 16 0.05 m) is added n-butylamine (30 ml.) and the resulting 17 solution i9 refluxed 17 hourc. The excess n-butylamine 18 is removed under reduced pressure (20 mm). The oil is 19 dissolved in 6N hydrochloric acid (30 ml.) and the solu-tion is heated on a steam bath for 40 minutes. The hot 21 acidic solution is poured into a hot saturated aqueous 22 sodium carhonate solution with nitrogen bubbling thxough 23 it. The basic solution is extracted with chloroform.
24 The chloroform is dried over sodium sulfate and concen-trated to yield 4-(3~ butylamino-2-hydroxypropoxy) 26 benzaldehyde, as an oil.
:
~L~7~68~
1 B. 2-[4-(3-n-But~lamino-2-hydroxypropoxy)phenyl] 4 trifluoromethYlimidazole 3 To a solution of sodium acetat:e trihydrate 4 (5.0 g.) in water (20 ml.) is added dibromotrifluoro-acetone (S.0 g.). The solution is heated on a steam 6 bath for 30 minutes. After cooling to room temperature, 7 this solution is added to the methanolic solution of 8 4-(3-n-butylaminv-2-hydroxypropoxy)-benzaldehyde and 9 concentrated aqueous ammonium hydroxide (25 ml.).
After standing at room temperature for 48 hours, the 11 methanol is removed under reduced pressure (20 mm). The 12 residue is dissolved in ~thyl acetate and saturated 13 aqueous sodi~m carbonate, dried over anhydrous sodium 14 sulfate and concentrated under reducad pxessure. The oil is placed in acetonitrile to yield 800 mg. of 2-~4-(3-n-16 butylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethyl-17 imidazole, melting at 151~154C.
19 S-4-(4-methoxyphenyl)-2-[4-(3-tert-butylamino-2-hydroxy-_pro~oxy)- ~ idazole d ~ rochloride dih~drate A heterogeneous solution o~ p-methoxypheny~-21 glyoxal monohydrate (3.19 g. 0.018 m) sodium acetate 22 (2.90 g., 0.036 m), water (23 ml), 37~ aqueous ammonia 23 (23 ml) and (S)-p-(3-tert-butylamino-2-hydroxypropoxy)-24 benzaldehyde (2.90 g~, 0.012 m) in methanol (75 ml) is stirred at 25C. for 72 hours. The reaction mixture ~6 i concentrated to drynes~ under reduced pressure (15 mm) 27 at 80C. The residual solid is treated with saturated 28 aquaous Na2C03 (75 ml), extracted with chloroform (4x75 ml), .. ..
-.~ ~ 15524 IA
~L~75689 l dried over anhydrous MgSO4, filtered and concentrated to ~ dryness. The residue is dissolved in chloroform (50 ml) - 3 and absorbed on an alumina pad ~200 g). The pad is eluted 4 with chloroform (2 l), 5% methanol/chloroform (1 liter),
12 Starch, U.S.P. corn 25.0 13 Magnesium stearate 5.5 14 C~9~D~ ro~D~$IO~ . . .
INGREDIENT AMOUNT (M~.) 16 ~S)-2[4~(3-tert-butylamino-2-hydroxy- 250 propoxy)p ~ 1]-4-p-methoxyphenyl-17 imidazole dihydrochloride dihydrate 18 lac~ose~ U.S.P. 93 19 talc 7 INJECTABLE SOLU~ION
.
21 ING~EDTENT AMOUNT~
22 2~[4-(3-isopropylamino-2-hydroxy-propoxy)phenyl] 4-cya~oLmidazol~
23 hydroc~loride 24 sodium chloride 9 2S dis~illed wa~er, q.s. 1.0 ml.
.:
.
.
.. . 15524 IA
~7~
2 IN~REDIENT AMOUNT (~/1) 3 (S)-2-[4-(3-methylamino-2~hydroxy- 5.0 propoxy)phenyl]-4-(4-pyridyl) 4 imidazole Veegum H.V. 3.0 6 methyl parable 1.0 7 kaolin 10.0 8 glycerin 250.0 9 water, q.s. ~ 1 liter 12 The following examples illustrate preparation of 13 representative imidazoles of the present invention. A11 14 par~ and percentages are ~y weight unless otherwise indicated.
. .
~ 15524 IA
~75~89 1 EXA~LE 1 -2 A. Preparation of 3-(3-C~loro-2-hydroxypropoxy)-Benzaldehyde 3 A mixture of m-hydroxybenzaldehyde (24.4 ~
4 epichlorohydrin (55.2 g.), and pyridine (0.4 ml.) is heated 5 hours at 100C. and then concentrated under reduced 6 pressure (2~ mm. Hg.) over steamO The xesidual oil i~
7 taken up in chloroform (200 ml.), concentrated hydrochloxic 8 acid (50 ml.) is added, and the mixture is stirred 0.5 hours 9 at room temperature. The chloroform layer is separated, washed with water, and the chloroform ramoved under reduced 11 pressure (20 mm. Hg.) over steam. Distillation of the L2 residual oil yields 28.9 g. of 3--(3-chloro-2-hydroxypropoxy)-13 benzaldehyde as a yellow-brown oil, b.p. 166C./0.25 mm. Hg.
5 ~. Preparation of 2-[3-~3-Chloro-2-hydroxypropoxy)-phenyl]-4-trifluoromethylimldaæole 16 To a solution o~ sodium acetate trihydrate (11.6 17 g.) in water (40 ml.) is added trifluorodibromoacetone (11.6 18 g.) and the resulting solution is heated 0.5 hours at 100C.
19 A~ter cooling to room temperature, it is added to one pox-20 tion to a solution of 3-(3-chloro-2~hydroxypropoxy)benzal-21 dehyde t9.45 g.) in methanol (100 ml.~ and aqueou~ ammonia 22 50 ml.~. The resulting cloudy solution is allowed to stand 23 5 hours at room temperature and the methanol is removed 24 under reduced pressure (20 mm Hg. ) over steam. An oil 25 separates and cry~;tallizes. The supernatant liquid is 26 decan ed and the residue is triturated with benzene and 27 isola~ed by filtra~io~ to yield 6.97 g. of solid. After 28 recrystaIlization from toluene, the solid is suspended in 29 warm water and acetonitrile added to cau~e solution. Upon :
.
~7~613~
l cooling, 2-~3-(3-chloro 2-hydroxypropoxy~phenyl]-4-tri-2 fluorome~hylimidazole is obtained as a white ~olid, m.p.
3 181-183C.
S C. Preparation o~ 2-~3-~2,3-Epoxypropo~)phenyl]-4-trifluoromethylimidazole 6 To a solution o 2-~3-(3-chloro-2-hydroxypro-7 poxy)phenyl]-4-trifluoromethylimidazole (3.8 g.) in methanol 8 (lS0 ml.) is added powdered potassium hydroxide (3.g.) and 9 the mixture is allowed to stir 4 hours at room temperature.
Glacial acetic acid (2.75 ml.) i5 addPd and the mixture 11 concentrat0d under reduced pressure (20 mm. Hg.) ovsr steam.
12 The resulting residue is stirred with water, filtered and 13 recry~tallized from xylene to yield 2.5 g. of 2-l3-t2,3-14 epoxypropoxy)phenyl]-4-tri~luoromethylLmidazole i~ obtained, m.p. 145-146.5C.
7 D. Preparation of 2-[3-(3-Isopropylamino-2-hydroxy propoxy)~ tri~luoromethylimidazole 18 A solution o~ 2-~3 (2,3-epoxypropoxy)phenyl]-4-~ tri~luoromethylimidazole (0.9 g.) in isopropylamine (lO ml.) i~ heated 6 hours at ref].ux. The excess isopropylamine is 1 removed by distillation at atmospheric pressure over steam.
22 The residue i5 triturated with nitromethane (5 ml~) and the 23 resulting solid removed by ~iltration. After recrystal-24 lization ~rom nitromethane 0.65 g. of 2~[3-(3-isopropyl-amino-2-hydroxypropoxy3phenyl~4-trifluorvmethylLmidazole 26 is obtained, m.pO 162.5-163.5C.
j~ ~
. .
~75689 2 Preparation of 2-[4-(3-isopropylamino-2-hydroxypropoxy)-phenyl]-4-trifluoromethylimidazole 3 A solution of 2-[4-(2.3-epoxypropoxy)phenyl]-4-4 trifluoromethylimidazole (1 g) in isopropylamine (10 ml.) is heated 7 hours at reflux and then allowed to stand 16 6 hours at room temperature. The ~xcess isopropylamine is 7 removed by distillation at atmospheric pressure and the 8 residue is triturated with nitromethane to yield a solid.
9 A~ter filtration and recrystallization from acetonitrile, 0.6 g. of 2-~4-(3-isopropylamino-2~hydroxypropoxy)phenyl]-11 4-trifluoromethylimidazole is obtained, m.p. 173~-173.5C.
4 A. Preparation of 2-methyl-4-(2,3-epoxypropoxy)-benzaldehYde To epichlorohydrin ~20 g., 0.216 mole) h~ated 16 at 55C. is added dropwise a solution of 2-methyl 4-17 hydroxybenzaldehyde (9.0 g., .066 mole) in 2.5 N sodium 18 hydroxide solution (40 ml.). After the addition, ~he 19 solution is allowed to stir an additional 3 hours at 55C. and then at room temperature overnight. The oil 21 is distilled to give 8.3 g. of 2-methyl-4-(2,3-epoxy-22 propyl)benzaldehyde, m.p. 160-170C. at 1 mm. Hg.
4 B. Prepaxation of 2-methyl~4-(3-ter~-butylamino-2-hydroxypropoxy)benzaldeh~de To a methyl-4-(2,3-epoxypropoxy~benzaldehyde 26 (8.3 g~, .043 mole) is added~text-butylamine (10 g~, 27 0.137 mole) ana the resulting ~olution refluxed for 28 2 hours and allowed to stand overnight at room tempera-29 ture. The excess text ~utylamine is removed under ~7~ti8~
1 reduced pressure (20 mm. Xg.), the residue is heated on a 2 steam bath with 6 N hydrochloric acid ~50 ml.) for 5 3 hours, and then basified while hot with solid sodium 4 hydroxide. The mixture is cooled to room temperature, extracted with chloroform (3x50 ml.), dried over sodium 6 sulfate, filtered and concentrated to dryness. The 7 residual oil is crys~allized from hexane to give 8.75 g.
8 of 2-methyl-4-(3-tert.butylamino-2-hydroxypropoxy)benz-9 aldehyde, m.p. 82-84C.
11 C. Preparation of 2-[2-methyl 4~(3-tert~butylamino-2-hydroxY~ro~oxv)phenYl]-4-trifluoromethYl~nidazole 12 To ~odium acetate trihydrate (6.26 g., .046 13 mole) in water (26 ml.) is added dibromotrifluoroacetone 14 (6.26 g., .023 mole). The solution is heated for 45 minutes on a steam bath, cooled, and added to a solution 16 of 2-methyl-4 (3-tert,butylamino-2-hydroxypropoxy)-17 benzaldehyde (3.05 g., 0115 mole) in methanol (60 ml.) 18 and concentrated aqueous ammonia (20 ml.)~ The ~olution L9 is allowed to stand for 5 hours at room temperature. The methanol is removed under reduced pressure (20 mm. Hg.) 21 over steam and the residue treated with chloroform (3 x 22 50 ml.) and sa~urated sodium carbonate (50 ml.). The 23 organic layer is concentrated to dryness and the residue 24 crystallized from acetonitrile to give 1.2 g. o 2-[2-methyl-4~ ~ter~-butylamino-2-hydroxypropoxy)phenyl]-26 4-trifluoromethylimidazole, m.p. 162-164C.
` ~ 15524 IA -~L6)7S68~
1 Example 4 2 Preparation of 2-[4-(3-tert. butylamino-2 hydroxy~
propoxy)phenyl]-4-pheny~ dazole 3 A solution of p-(3-tert. butylamino-2-hydroxy-4 propyl)benzaldehyde (5.0 ~., O.Q2 moleI, p~enylglyoxal monohydrate (6.04 g., 0.04 mole), concentrated aqueous 6 ammonia (50 ml.), water (50 ml.) and methanol (200 ml.) 7 is allowed to stand at room temperature for 5 hours.
8 The solution is concentrated to a residual o-l under 9 reduced pressure (20 mm. Hg.) over steam and treated with satura~ed sodium carbonate (50 ml.) and chloroform 11 (3 x 50 ml.). The oryanic layer is concentrated to 12 dryness and chromatographed on neutral alumina (500 g.) 13 using a gradient elution technique starti~ with chloro-14 ~orm. The product is eluted with 10~ methanol-90~
chloroform. Final purification is accomplished by pass-16 ing through a column of silica gel (150 g.) and eluted 17 with 20% methanol-80% chloroform. The solvent is 18 removed under reduced pressure (20 mm. Hg.) over steam 19 and the residue crystallized from acetonitrile to give 0.7 g. o~ 2-[4-(3-tert. butylamino-2-hydroxypropoxy)-21 phenyl~-4-phenylimidazole, m.p. 176~178C.
24 A. Preparation o~ S-4~3-tert. butylamino-2-hydroxy-prol~oxY)benzaldehYde To a solution of S-2-phenyl-3-tert. butyl-5-26 hydroxymethyloxazolidine (47 g., 0.2 mole) in pyridine 27 (75 ml.) is added portionwise p-toluenesulfonyl chloride 28 keeping the internal temperature between 25 and 30C.
.' ~ - 32 -~7S6~1~
1 The mixture is stirred 2 hours after addition is complete 2 keeping the temperature between 25 and 30C. Ice water 3 (150 ml.) and potassium carbonate (27.6 g.) are added and 4 the mixture is extracted with chlorofonn (3 x 100 ml.).
The organic extract is dried over sodiwn sulfate and con-6 centrated first at 20 mm. ~g. and then at 1 mm. Hg. keep-7 ing the temperature below 50C. The re~idual oil is dis-8 solved in N,N-dimethylformamide (150 ml.) and added drop-9 wi~e to a refluxing solution of the sodium salt of p-hydroxybenzaldehyde (0.2 mole) in N,N-dimethylformamide 11 (200 ml.). After refluxing 10 hours, the reaction mix-12 ture is concentrated first at 20 mm. Hg. and then at 13 1 mm. Hg. over steam. The residue is treated with 5~
14 sodium hydroxide soltuion and extracted with chloroform (3 x 100 mlJ). The organic extract is dried over sodium 16 sulfate and the residue chromatographed on alumina 17 (500 g. activity grade II). The chromatographic frac-18 tions are concentrated and the residue distilled at 19 240C. at 0.3 mm. Hg. The distillate (21 g.) is treated with 1 N hydrochloric acid (75 ml.), heated 1/2 hour 21 over ~eam, cooled and extracted with ether. The 22 aqueous layer is made basic to pH 10 by the addition of 23 2~ sodium hydroxide solution and extracted with chloro-24 form (3 x 100 ml.). The organic extract is dried over sodium sulfate and concentrated to an oil which after 26 crystallization from hexane yields 14.5 gO of S 4-(3-27 tert. butylamino~2-hydroxypropoxy)benzaldehyde, m.p.
28 60-62C.
~ 33 -.. . . - .
~ 15524 IA
~L~7S689 - 1 B. Preparation of S-2-[4-t3-tert. buty]amino-2-hydroxy-propoxy)phen~l]-4 trifluoromethylimidazole _ . , 2 To sodium acetate trihydrate (20.2 g., 0.15 3 mole) in water ~100 ml.) is added dibro~lotrifluoro-4acetone (20.2 g., 0.075 mole). The solution is heated 45 minutes on a steam bath, cooled and is added to a 6 solution of S~p-(3-tert. butylamino-2-hydroxypropoxy)-7benzaldehyde (12.5 g., 0.05 mole) in methanol ~200 ml.) 8 and concentrated aqueous ammonia (75 ml.). The solut:ion 9 is allowed to stand 5 hours at room temperature. The methanol is removed by distillation under reduced 11 pressure (20 mm. Hg.) over steam. The mixture is made 12 ba~ic with saturated aqueous sodium carbonate solution 13 and extracted with ethyl acetate (3 x 100 ml.). The 14 organic ex~ract is dried over sodium sulfate and con-centrated at 20 mm. Hg. over s~eam. The resulting resi-16 due is recrystallized from acetonitrile to yield 7.6 g.
17 of S-2-[4-(3-tert. butylamino-2-hydroxypropoxy)phenyl]-134-trifluoromethylimidazole, m.p. 181-182C.
19Other Formula I imidazoles prepared using the procedures su~stantially as described in Examples 1-5 21 are listed in the following table. It is to be understood 22 that analogous reactants are used to obtain the particular 23 iridazole produc~s.
'.
.
..
- 3~ --~ 15524 IA
~L~75~3g PREPARED IMIDAZOLES OF FORMULA
--~N~N-- R3-o-cH2-cH-cH2-N- R6 H
... . . .
Imlda201e Using Substituents Example of 6 1 H -CF3 ~ t-butyl 207-210 ___ 7 2 H -CF3 ~ t~butyl 139-141 8 2 H -CF3 ~ IH CH2 C~2 ~ 159-170 ~3 2 H -CF3 ~ n-propyl - 153-155 9 2 H -CF3 ~ -~H-CH2CH2- ~ 120-133 11 2 H -CF3 ~ cyclo- 163.5-165 propyl C ~ H3 12 3 H -CF3 ~ t-butyl 187-190 C~3 1~ 3 H ~CF3 ~ t-butyl 183-185 C~
13a 3 H -CF3 ~ t-butyl 159~162 . C~3 14 3 H -CF3 ~ isopropyl 210-213 ~ ' ~
- 35 - ~;
~j, ... .
' ~.~756~
TABLE 1 (Contd.) PREPARED IMIDAZOLES OF FORMUL~
OI R
. Imldazole Substituents Using Procedure ~ M.P.
Example of ~ Rl R3 R ~
No. _ Example ~ C C1 6 ~ (C)_ 3 H -CF3~ t-but~l 181 182 Cl 16 3 H -CF3~ ~ t-butyl 167-171 ~ . .
17 3 H -CF3~ t-butyl 207210 / \
Cl 18 3 H -CF3~ ~ t-butyl 174-177 19 4 ~ ~ _ ~ t~butyl 180-181 4 H H ~ t-butyl 162-164 ~ .
~ ' 21 4 H H ~ t-butyl 133O5-196 22 4 HC1 ~ ~ t-butyl 186-188 .
~: 23 4 H ~ ~ t-butyl 167-169O
~ '.:
24 4 H r~ ~ t-butyl 179~'-181 ' TABLE 1 (Co~td.) PREPARED lMIDAZOLES OF FORMULA
Rl ~ ~ R8-O-CHz~CH~CH -I-R
Using Imidazole Procedure Substituents Exampleo~ ~ ~;~~ ]!a P
Wo.ExamPlel 3 6 ~ , O
Cl . 1,~ ~
4 H Cl ~ ~ t-butyl 189-190 .
26 4 H ~ ~ t-butyl 101-105 (~
27 4 H H ~ t-butyl 158-162 28 4 ~ ~ ~ t-butyl 172-173 29 4 H~ ~ t-butyl 1?8-180 F F
4 HF ~ ~ t-butyl 168-170 F F
31 5 H -CF3 ~ t-butyl 178-179~5 32 5 H -CF3 ~ t-butyl 141-143 ~
33 5 H -CF3 ~ t-butyl 110-120 .
-~ 0 The glyoxal reagent used Wa~s ~ ~
HCl Salt Q R-isomg~ ;
S~isomer ~ O-CH2-~2-CH2~R6 attached at this position Monohydrate : S-Isomer - 37 - :
107~689 15524 IA
1 Additional Examples illustrating preparation 2 of other imidazoles of the present invention follow. All 3 parts and percentages are by weight unless otherwise 4 indicated.
6 A. Preparation of 2-[4-(3-Chloro-2-hydroxypropoxy)-phenyl]-4-~rifluoromethylimidazole _ _ 8 To sodium acetate trihydrate ~5.8 g.) in water (20 9 ml.) is added tri~luorodibromoacetone (5.8 g.); the xesult ing mixture is heated 0.5 hours on a steam bath. A~ter 11 cooling, the ~olution is added to p-(3-chloro-2-hydroxy-12 propoxy)benzaldehyde (4.2 g.) in methanol (100 ml.) and 13 concentrated aqueous ammonia (25 ml.). After standing 4.5 14 hours at room temperature, the methanol is removed by distillation at 20 mm. Hg. over ste~; a solid separates and 16 is filtered. After recrystallization from nitromethane, 17 1.65 g. of 2-[4-(3-chloro-2-hydroxypropoxy)phenyl]-4-tri-18 fluoromethylimidazole is obtained, m.p. 181-183C.
B. Preparation of 2-[4-(2,3-Epoxypropoxy)phenyl]-4 21 trifluoromethylimidazole 22 To a Rolution o 2-~p-(3-chloro-2-hydroxypro-23 poxy~phenyl]-4-trifluoromethylimidazole (1.92 ~.) in meth-24 anol (100 ml.) Ls added crushed potassium hydroxide (1.5 g.)~
The mixture is stirred 3 hours at room temperature, neu-26 tralized with acetic acid and concentra~ed under recluced 27 pres~ure ~20 mm. Hg.) over steam. Th~ residue LS triturated 28 with water (25 ml.), filtered and xecrystalli2ed by dis- ~ .
2~ solving in benzene and adding hexane until turbid.
' , .
. ' ' ' ' , : ' . . .
~ ~ 15524 IA
~L~75~
1 A yield of 1.2 g. of 2-[4-(2,3-epoxypropoxy)phenyl]-4-2 trifluoromethyLimidazole is obtained, m.p. 152-153.5~C~
3 C. Preparation of ~-[4-(3-tert. Butylamino-2 hydroxy-propoxy)~henx1]-4-trifluorometh~limldazole_ _ A solution of 2-[4-(2,3-epoxypropoxy)phenyl]-6 tri~luoromethylimidazole (2.5 g.) in tert. butylamine 7 (20 ml.) is heated 6 hours at reflux. The excess tert.
8 butylamine is removed by distillation at atmospheric 9 pressure over steam. The residue is triturated with nitromethane (5 ml.) and the resulting solid removed by 11 filtration. After recrystallization from acetonitrile, 12 (1.2 g.) of 2-[4~(3-tert. butylamino-2-hydroxypropoxy)-13 phenyl]-4-tri~luoromethylimidazole is obtained, m.p.
14 ~ 185.5-186.5CC.
.
17 A. Preparation of 4-(3-tert. Butylamino-2-hydroxy-Dro~oxv)benzaldehvde 18 ~
19 To 4-(2,3-epoxypropoxy)benzaldehyde (20 g.) is added tert. butylamine (50 ml.) and the resulting solu-21 tion is refluxed 17 hours. The excess tert. butylamine ~ -22 i9 removed by heating at atmospheric pressure to yield a 23 solid residue. To this residue is added 6 N hydrochloric 24 acid (200 ml.) and the resulting mixture i~ h~ated 5 hours 2S on a steam bath. The solution is cooled and concentrated 26 to 100 ml. on a steam bath under reduced pressure (20 mm.
27 Hg.). The concentrated solution is made basic to pH lO
28 with saturated aqueous sodium carbonate and extracted 29 with chloroform. The chloroform extract is concentrated - 39 ~
' .
~ 15524 IA
~756il5~
1 to a solid which after recrystallization from acetonitrile 2 yields 18 g. of 4-(3-tert.butylamino-2-hydroxypropoxy)-3 benzaldehyde, m.p. 123-125.5C.
B. Preparation of 2-[4-(3~tert.Butylam:Lno-2-hydroxypropoxy)-pheny~]-4-trifluorometh ~ idazole __ __ 6 To sodium acetate trihydrate (11.8 g., 7 0.088 moles) in water (40 ml.) is added dibromotri-8 fluoroacetone (11.8 g., 0.044 moles). The solution i5 9 heated 45 minutes on a steam bath, cooled and added to a solution of 4-(3-tert. butylamino-2-hydroxypropoxy)-11 benazldehyde (5 g., 0.02 moles) in methanol (200 ml.) and 12 concentrated aqueous ammonia (25 ml.). The solution is 13 allowed to stand 5 hours at room temperature. The methanol 14 is rem~ved under reduced pressure (20 mm. Hg.) o~er steam and chloroform (50 ml~) and saturated aqueous sodium 16 carbonate (25 ml.) are added to the residue. After stir-17 ring a solid separa~es is filtered and washed with water.
18 After recrystallization from acetonitrile, 3 g. of 19 2-[4-(3-tert.butylamino-2-hydroxypropoxy)phenyl]-4-tri~luoromethylimidazole is obtained, m.p. 189-l91~C.
~ - 40 -:
~L~75~
2 A. Preparation of Salicylaldehyde Diethyl acetal 3 A mixture of salicylaldehyde (80 g., 0.0655 4 mole), triethylorthoformate (110 g., 0.765 mole), absolute ethanol (40 ml.) and concentrated sulfuric acid (3 drops) 6 is heated to reflux overnight. The volatiles are re~
7 mov~d under reduced pressure (20 mm. Hg.) over steam to 8 give diethyl acetal of salicylaldehyde which i9 used 9 without furthex purification.
11 B. Preparation of 2-(2,3-Epoxypropoxy)benzaldehyde DiethYl acetal 12 - _ 13 To epichlorohydrin (37 g., 0.4 mole~ heated at 14 50C. is added dropwise a solution of salicylaldehyde diethyl acetal (25 g., 0.13 mole) in 2 N sodium hydroxide 16 solution (200 ml.) and the mixture allowed to st~r over-17 night at 50JC. The reaction mLxture is extracted with 18 chloroform (3 x 100 ml.~, dried over potas~ium carbonate, 19 and concentrated to dxyness to give 34.3 g. of 2-(2,3-epoxypropoxy)benzaldehyde diethyl acetal.
22 C. Preparation o 2-(3-tert. butylamino~2-hydroxy-~ro~oxv)benæaldehvde 24 A solution of 2-(2,3-epoxypropoxy)banzal-?5 dehyde diethyl acetal (53 g., 2.1 mole) and tert. butyl-26 amine (100 ml.) is heated to reflux for 2 hours and 27 allowed to stand at rosm temperature overnight. The ex-28 cess tert. butylamine is remo~ed under reduced pressure 29 ~20 mm. Hg.) and the residue heated on a steam ~ath with . . ..
~ 15524 IA
5~
1 6 N hydrochloric acid (300 ml.). After cooling, the 2 solution is neutrali2ed with solid sodium bicar~onate, 3 extracted with chloroform (3 x 100 ml.), dried over 4 sodium sul~ate, filtered and concentrated to dryness.
The residue is chromatographed on silica gel (500 ml.) 6 using gradient elution techniques starting with chloro-7 form and the product is obtained with 10% methanol 90%
8 chloroform. After removal of the solvent under reduced 9 pressure (20 mm. Hg.), the xesidue is crystallized from acetonitrile to give 13.8 g. of 2-(3-tert. butylamino-11 2-hydroxypropoxy)benzaldehyde, m.p. 156-160C.
13 D. Preparation of 2-[2 (3-tert. butylamino-2-hydroxy-14 pro~oxy)phenyl]-4-tri1uorom thylimidazole _ _ To sodium acetate trihydrate (5.4 g., O.0396 16 mole) in water (20 ml.) is added dibromotrifluoroacetone 17 (5.4 g., 0.02 mole). The solution is heated for 45 18 minutes on a steam bath, cooled and added to a solution 19 of 2-(3-tert. butylamino-2-hydroxypropoxy)benzaldehyde (3.6 g., 0.0143 mole) in methanol (100 ml.) and con-21 centrated aqueous ammonia (25 ml.). The solution is 22 allowed to stand overnight at room temperature. The ~3 methanol is removed by distillation under reduced pres-24 sure (20 mm. Hg.) and the residue treated with saturated sodium carkonate (50 ml ~, extracted with chloroform 26 (3 x 50 ml.) and separated. The organic layer is dried 27 over sodium sul~ate, ~iltered and concentrated to dry-28 ness. The residue is chromatographed on silica gel 29 (400 ml.) and the product eluted with 20~ methanol-80~
chloroform. Recrystallization of the product from nitro-t ~ ~ 15524 IA
~756~
1 methane gives 700 mg. of 2-[2-(3-tert. butylamino-2-2 hydroxypropoxy)phenyl]-4-trifluoromethylimidazole, m.p.
3 105-107C.
6 2-~4-(-3-tert. butylamino-2-hydroxypropoxy)phenyl]-4-meth~limi~ le .. . .. _ 7 To a mixture of cupric acetate (5.0 g., .0~5 8 mole), acetoxyacetone (1.5 g., .013 mole), concentrated - 9 agueous ammQnium t2S ml.) is added a solution of p-(3-tert. butylamino-2-hydroxypropoxy)benzaldehyde (3.2 g., 11 .0127 mole) in methanol (25 ml.). After the addition, 12 the mixture is heated at re~lux overnight. The methanol 13 i9 removed by dis~illation under reduced pressure (20 mm.
14 Hg.) over steam and water (200 ml.) is added to the residue. The resulting solution is treated with 16 hydrogen sulfide, filtered through a filter aid, treated 17 with solid potassium carbonate until basic and extracted L8 with chloroform (3 x 50 ml.). The chloroform is con-19 centrated to dryness and the residue chromatographed on neutral alumina tl70 g.) using a gradient elution 21 technique star~ing with chloroorm. ~he material i~
22 eluted off the column using 5~ methanol-95% chloroform.
23 The organic solvent is removed by dis~illation under 24 reduced pressure (20 mm. Hg.) and the residue crystal-lized rom acetonitrile to give 0.79 g. of 2-[4-(3-26 tert. butylamino-2-hydroxypropoxy)phenyl]-4-methylimida-~ 27 zol~, m.p. 202-203C.
: _ 43 _ ~ - 15524 IA
10756~39 -2 ~ Pyridylglyoxal-dimethylacetal 3 To a solution of butyl lithi~n (129 ml., 193N, 4 0.25 m.) in ether (300 ml.) cooled below -50C. is added 3-bromopyridine (33.02, 0.209 m.) in ether (60 ml.). The 6 yellow suspension which results is allowed to stir an 7 additional 1/2 hour at -50C. and dimethoxyacetic acid 8 piperidide (33.6 gO, 0.179 m.) in ether (90 ml.) is 9 added over 1 hour at -50C. After complete addition, the react~on mixture is allowed to warm to room -~empera-11 ture and heated to reflux for 1/2 hour. After cooling, 12 a solution of ammonium chloride (500 ml.) is addecl 13 separated and the aqueous layer extracted with 2x100 mlO
14 ether. The ether layer is washed with 3N ~SO4, acid;
the aqueou~ layer is neutralized with KOH and extracted 16 with 3x100 ml. CH2C12,dried over Na2SO4, filtered ancl 17 concentrated to dryness. The remainder is distilled at 18 95-100/0.4 mm. to give l3.8 g. o~ ~-pyridylglyoxal-lg dimethylacetal.`
21 B. 4~ Pyridyl)-2-[4-(3-tert-butylamino-2-hydroxypro-~oxY)PhenYl]-imidazole 23 To concentrated sulfuric acid (15 g.) cooled to 24 0-4 is added ~-pyridyl~lyoxal-dimethylacetal (5.4 g., 0.03 m) and the solution allowed to stand at room tempera-26 ture. After 3 days, the mixture is cooled and neutrali~ed 27 with Na~CO3 (26 g., 0.30m).
28 To this qolution is added water (2S ml.), 29 37% aqueous ammonia (75 ml.), methanol (25 ml.) and a solution of p-(3-tert-butylamino-2-hydroxypropoxy)benzal-'~.
.
~ 15524 IA
lL~9756~
1 dehyde (5.1 g., 0.02 m) in methanol (200 ml.). After 2 standing at room temperature for 3 days, the methanol is 3 removed under reduced pressure (20 mm) over steam, the 4 residue covered with saturated Na2CO3 ~100 ml.), ex-tracted with CHC13 (3xlS0 mlO), dried over Na2SO4, 6 filtered and concentrated to dryness. The residue is 7 chromatographed on silica gel (600 ml.~ and the product 8 eluted with 50% CHC13/MeOH. The crude product is fuxther ; 9 puri~ied by chromatography on NoO 2 neutral alumina (90 g.) and eluted with 2~ MeOH/CHC13. Recrystallization from 11 acetonitrile/chloroform gave 125 mg. of 4-(3-pyridyl)-12 [4-(3-tert-butylamino 2-hydroxypropoxy)phenyl]-imidazole.
(S) Methyl-2-[4-(3-tert-butylamino~2-hyd~oxypropoxy)-16 phenyl~imldazol~ carboxylate 17 To lN sodium hydroxide solution (20 ml.) is 18 added (S)-2-[4-(3-tert-butylamino-2-hydroxypropoxy~phenyl]-19 4-trifluoromethylimidazole (1 g.) and the mixture is heated 0.5 hour over steam. The resulting solution is neutralized 21 to pH 7 with concentrated hydrochloric acid and concentrated 22 on a steam bath over a stream of nitrogen. The resulting 23 solid is suspended in methanol (25 ml.) saturated with 24 hydrogen chloride. The mixture is re~luxed three hours with hydrogen chloride ~eing added after the first and second 26 hour. A~t~r being concentrated under reduced pressure (20 27 mm.) over steam, saturated aqueous solid carbonate solution 28 is added (25 ml.) and the mixture extracted with ethyl 29 acetate. The organic extract was concentrat~d to a gum which on trituration with aqueous sodium carbonate Crude S-2-[4-(3-tert.-butylamino-2-hydroxy~ropoxy)phenyl]-4-carboxy-imidaæ~
" 15524 IA
~LCl 7~8~D
1 solidifies and is filtered. After recrystalliæation from 2 acekonitrile 200 mg. of (S)-methyl 2-[4-(3-tert. butylamino-3 2-hydroxypropoxy)phenyl]imidazole 4-carboxylate melting 4 at 159-161C. is obtained.
...
7 A. S-2-Phenyl-3-Tert. butyl 5-(3-cyano-6~pyridyl-oxymethYl)oxazolidine 8 To a solution of S-2-phe~yl~3-tert. butyl-5-9 hydroxymethyloxazolidine (12.35 g., O.0526 mole) in dime~hyl-formamide (65 ml.) is added sodium hydride 11 (2.22 g., 0.0526 mole of 57%. A~ter heating 25 minutes 12 on a steam bath, the mixture is stirred and cooled to room 13 temperature in 30 minutes and added to a ~olution of 14 6-chloronicotinonitrile (7.28 g., 0.0526 mole) in dimethyl-~ormamide (35 ml.). The reaction mixture ~ stirred at 16 room temperature for 4 1/2 hours and then is concentrated 17 under reduced pressure. The 1uid residue is taken up in 18 ether and washed with water. The ether solution is dried }9 and concentrated under reduced pressure to yield 18~5 g.
of S-2-phenyl-3~tert. butyl--5-(3-cyano-6-pyridyl~oxymethyl) 21 oxazolidine as an oil.
22 B. S=6-(3-Tert.butylamino-2-h~droxypropoxy~nicotinonitrile 23 A su~pension of S-2-phenyl-3-tert. butyl-5-24 (3-cyano-6-pyridyloxymethyl) oxa201idine (18.5 g.) in lN
hydrochloric acid (60 ml.) is heated 5 minutes on a steam 26 bath and then stirred at room temperature for 1~2 houx.
27 The mixture is extracted with chloroorm and the aqueous 28 layer is made basic with 40% sodium hydroxide solution.
2~ The basic solu~ion is extracted with e~hyl acetate ancl the extract is dried and concentrated under reduced pressure.
31 The residual white solid is recrystallized from hexane-n-- ~6 -.~
~756~3~
1 butyl chloride to yield 5.14 g. of S-6-(3-tert. butylamino-2 2-hydroxypropoxy~ nicotinonitrile, m.p. 103-105C.
3 C. S-6-(3-Tert. butylamino-2-hydroxypropoxy) nicotinalde-hyde 4 A suspension of S-6-(3-tert. butyLamino-2-S hydroxypropoxy) nicotinonitrile (5.14 g. 0.0204 mole) in 6 toluene (128 ml.) in a flamed flask is heated with stirring 7 until a solution is ob~ained. The toluene is allowed to 8 distill until a total o~ 21 ml. is collected. ~eating is 9 discontinued and the reaction solution is cooled in a dry ice- acetone bath causing the staxting material to 11 reprecipitate. To the cold reaction mixture is added 12 diisobutylaluminum hydride in toluene (62.6 ml. 0.075 mole 13 of 0.17 g./ml.) dropwise under nitrogen with stirring. The 14 yellow reaction mixture is stirred cold ~or 1 hour, and then the acetone bath is removed as methanol (22 drops) is added 16 followed by the addition of water (22 drops). Chloroform 17 is added to the mixture and then water (43 ml.), and after 18 good stirring the mixture is ~iltered. The filtrate ~
19 shaken in a separatory funnel and the organic layer is sep arated, dried, and concentrated under reduced pressuxe. To 21 the residual oil is add~d 1% hydrochloxic acid (43 ml.) and 22 the mixture is heated on a steam bath for 1/2 hour. At this 23 point the pH is basic. Concentrated hydrochloric acid is 24 added until the pH is acid and heating is continued for 15 minutes. The mixture is cooled and made basic with 40%
26 odium hydroxide solution and then extracted with chloroform.
27 The extract is dried and concentrated under reduced p~essure 28 to yield 5.1 gO o~ S-6 (3-tert. butylamino-2-hydroxypropoxy) 29 nicotinaldehyde as an oil which solidifies.
: ' ~1~75~
1 D. S-2-[2-(3-te~ Butylamino-2-hydroxypropoxy)-5-pyridyll-4-trifluoromethxlimidazole _ _ _ 2 To sodium acetate trihydrate (2.16 g., 0.016 moles) 3 in H2O (15 ml.) is added dibromotrifluoroacetone (2.16 g., 4 0.008 moles) and the mixture is heated 1/2 hour on a steam bath. After cooling the solution is added to 6-(3-tert.-6 butylamino-2-hydroxypropoxy) nicotinaldehyde (1 g.) in 7 methanol (50 ml.) and concentrated aqueous ammonium 8 hydroxide (15 ml.~. After standing 20 hours at room temp-9 erature, the methanol is xemoved under reduced pressuxe (20 mm.) over steam. Concentration aqueous sodium carbonate 11 (10 ml.) and ethyl acetate (50 ml.) are added to the concen-12 trated solution. A~ter extracting the organic layer is 13 separated dried over sodium sulfate and concentrated to 14 a gum whic~ is chromatographed on activity grade II alumina with chlorofonm methanol using a gradient elution technique.
16 The fractions containing product are combined and concen~
17 trated to a gum which is dissolved in ethyl acetate. The 18 ethyl acetate solution is washed with saturated sodium 19 carbonate solution, dried and concentrated to yield 2 ~2-(3-text.-butylamino-2~hydroxypropoxy)-5-pyridyl]-4-21 krifluoromethylimidazole as a non-crystalline solid ~650 mg).
22 This non-crystalline solid was covered with 23 hexane and allowed to stand at about OC. for 7 days. The 24 h~xane was ~hen decanted and the residue triturated with ether to yi~ld a solid. The ether filtrate also yielded 26 solid on ~tanding at room temperature. These solids were 27 combined and di~solved in benzene. Hexane was added to the 2B point of turbidity, which on cooling yielded a solid. The 2g solid was dried at 66-73~C. and 0.2 mm ~or about 4~ hours.
The dried solid was S-2-[2-(3-tert. butylamino-2-hydroxypro-31 poxy~-5-pyridyl~-4-tri~luoromethylimidazole monohyclrclte (NMR
. .
A and Mass Spectroscopic analysis), melting at 110-120C.
2 A. 4-(p-metho~hs~ __ __ pyridyl)imidazole 3 A solution of sodium acetate trihydrate (5.8 g, 4 0.04 m), 3-pyridinecarboxaldehyde (2.3 g., 0.02 m3, p-S methoxyphenylglyoxal monohydrate (3.92 g., 0.02 m), water ~~ 6 (20 ml.), concentrated aqueous a~monia (25 ml.), and 7 methanol (75 ml.) is allowed to stand at room temperature 8 overnight. The solution is concentrated to dxyness 9 under reduced pressure (20 mm) over steam, treated wi.th saturated Na2cO3 (100 ml.) and extracted with chloro~orm 11 (3 x 100 ml.). The organic layer is dried over Na2SO4, 12 filtered and concentrated to dryness. The residue i~
13 chromatographed on silica gel (300 ml.) and the product 14 eluted with 3--5% MeOH/CHC13. The material is crystallized from acetonitrile to give 2.3 g. of 4-(p-methoxyphenyl~-16 2-(3-pyridyl)imidazole of m.p. 184-186.
17 B. 2-(3-pyridyl)-4-(4-hydroxyphenyl)imidazole 18 A mixture of 4-tp-methoxyphenyl)-2-(3-pyridyl)-19 imidazole (2.0 g.) and 48~ HBr (100 ml.) is heated to re~lux for 20 hrs. After cooling, the precipitate is ~ -21 filtered off and crystallized from isopropanol-methanol 22 to give 2.05 g. o 2-(3-pyridyl)-4-(4-hydroxyphenyl)-23 imidazole of m.p. 315-318C.
24 C. 4--[4-(3-tert-butylamino-2-hydroxypropoxy)phenyl]-2-~. (3-~Yrid~T rmidaæole ; 25 A ~olution of 2-phenyl-3~tert-butyl-5-hydroxy-26 methyloxazolidine (2.4 g., 0.01 m) in pyridine t3 ml,) is ~7 cooled to 0-4C. and treated portionwise with p-toluene-28 sulfonylchloride t2.0 g., 0.01 m). The cooled solution 29 i9 slowly warm~d to room temperature while not allowing - . : . . . .:
1 the reac~ion mixture to exceed 30C. After 2.5 hrs., the 2 mixture is treated with a solution of ~2CO3 (1.4 g.) in 3 water (20 ml.~ and extracted with chloro~orm (3 x 50 ml.).
4 The organic layer is dried over Na2SO4 r ~iltered, and concentrated to dryness under reduced pressure (20 ~m) 6 over steam and finally at 60C. and 1 mm. Tha residual 7 oil is dissolved in dry N,N dimethylformamide (DMF) (20 ml.) 8 and added dropwise to a mixture of 2-(3-pyridyl)-4-~4-9 hydroxyphenyl)imidazole:2HBr:H2O (4.0 ~., .0095 m) in DMF (20 ml.~ and sodium hydride (57% oil suspension, 11 1.3 g., .031 m). After refluxing for 11 hours, the 12 mixture is concentrated to dryness under reduced pressure 13 (1-2 mm Hg.) over steam. The residue is treated with 14 lN HCl (100 ml.), heated for 1/2 hr. on a steam bath, cooled, and extracted with ether~ The aqueous layer is 16 neutra~ized with 10N NaOH (12 ml.), extracted with 17 C~C13 (3 x 50 ml.), dried over Na2SO4, filtexed and 18 concentrated to dryness.
19 The residue is chromatographed on No. 2 neutral alumina (200 g.) and eluted with 4~ MeOH/CHC13. The crude 21 product is further purified by chromatography on silica 22 gel t20Q ml.) and eluted with 40-50% MeO~/CHC13. The 23 material is crystallized from acetonitrile to give 0~425 g.
24 ~f4-[4~(3-tert-butylamino-2-hydroxypropoxy)phenylJ-2-(3-pyridyl)imidazole o~ m.p. 163-165C.
27 Methyl 2-~4 (3-tert-butyla~ino-2-hydroxypropoxy)phenyl]-28 A solution of crude 2-~4-(3-tert~utylamino-2 29 hydroxypropoxylp~enyl~-4~carboxyimidazole (30 g.) in prepared from the corresponding 4-tr~fluoro~ethyl-imidazole per Example 39 ~rocedure.
` 15524 IA
~75~
1 methanol (600 ml.) is heated to reflux, and then heating 2 is discontinued as hydrogen chloride is bubbled rapidly 3 through the solution with stirring for a half hour, ~ol-4 lowed by two and a half hours a~ reflux. Bubbling of hydrogen chloride is continued for another two hours ~ol-6 lowed by another hour at reflux and then the reaation 7 mixture is stirred at room temperature overnight. The 8 mixture is filtered and the filtrate is then concentrated 9 to dryness underAreduced pressure. The residue is dis-solved in water (150 ml.) and the pH is adjusted to 8 11 with saturated sodium carbonate solution. The basic 12 mixture is extracted with ethyl aaetate and the extracts 13 are dried, ~iltered, and concentrated under reduced }4 pre~sure to yield a solid which is recrystallized rom acetonitrile to yield the methyl 2-~4-(3-tert.butylamino-16 2-hydroxypropoxy)phenyl]-imidazole-4-carboxylate as a 17 cream-colored solid, m.p. 168-172C.
A. 2-~4-(3-Tert. butylamino-2-hydroxypropoxy)phenyl]-4-carbamo~limidazole ~ , .............. . _ _ . ......................... .
21 A solution o~ methyl 2-~4-(3-tert. butylamino-22 2-hydroxypropoxy)phenyl]imidazole-4 carboxylate ~10 g.~ in 23 methanol (100 ml.) is reacted in a bomb wi~h ammonia (44 g.) 24 at 100C. for 24 hoursO The reaction mixture is concentrated under reduced pressure and the residue is chromatographed on 26 silica g~l. The product is aluted with chloroform that is 27 wa hed with concentrated a~ueous ammonia ~0%) and methanol 28 (10~) and is recrystallized from acetonitrile to yield the 29 2~[4-(3-tert. butylamino-2~hydroxxpropoxy)phenyl]-4-carbamoylimidazole as a white solid, m.p. 149-154~C.
~51-~~ ~ 15524 IA
75613~
l B. 2-[4-(3-tert.-butylamino-2-hydroxypropoxy)phenyl]-4-cvanoimidazole _ _ , . ~ . . . _ . _ . . _ 2 To a solution of 2-[4-(3-tert.-butylamino-2~
3 hydroxypropoxy)phenyl]-4-carbamoylimidazole (0.5 g.) in 4 dry pyridine (lO ml.) is added trifluoroacetic anhydride (l.26 g.) portionwise with stirring. The reaction 6 solution is refluxed with stirring for four hours and 7 then concentra~ed under reduced pressure. The residual 8 gum is taken up in ethanol and saturated sodium carbonate 9 solution (lS ml.~ and stirred at room temperature for 20 hours. The ethanol is removed under reduced pressure ll and the remaining aqueous mixture is extracted with ethyl 12 acetate. The extract is dried over sodium sulfate, 13 filtered, and concentrated under reduced pressure. The~
14 residual gla~s is converted to its hydrochloride salt with ethanolic HCl and is recrystallized from ethanol-16 ether. The resulting tan solid is converted back to its 17 ~ree base by trituration with saturated sodium carbonate 18 solution. The free base is extracted into ethyl acetate l9 and the extract i3 dried over sodium sulate, filtered and concentrated under reduced pressure. The resldual 21 gum i9 recrystallized from acetonitrile to yield 40 mg~
22 of 2-[4-(3-tert.-butylamino-2-hydroxypropoxy)phenyl]-4 23 cyancimLdazo1e, m.p. 174-177~C.
- . . , ~-- 15524 IA
~375E;~
.
2 A. 4 Hydroxy-5,6,7,8-tetrahydronapthalclehyde 3 Step ~:
4 Dry hydrogen chloride gas is bubbled into a suspension of 5.O gms. of 5,6,7,8-tetrahydronaphthol and 6 6.0 gm. æinc cyanide in 60 ml. of dry ethyl ether for two 7 hours. To the mixture is added cautiously 50 ml. of water 8 and lO ml. 95% ethanol, and the resulting mixture is 9 refluxed l/2 hourO After cooling, the mixture is extracted with ethyl ether. The ether layer is washed 11 with water and dried over anhydrous sodium sulfate. The 12 ether is filtered and concentrated to an oil. The oil is 13 dissolved in benzene, and 4-hydroxy-5,6,7,8 tetrahydro-14 napththaldehyde crystallizes and is ~ ered.
16 B. 4=(2,3-Epoxypropox~)-5,6,7,8-tetrah~dronapthaldehyde 18 To a solution of 4-hydroxy-5,6,7,3-tetrahydro-19 napthaldehyde (20 gms., 0.012 m) in 1.5N sodium hydroxide (20 mlO) at 50C. is added epichlorohydrin (3.3 gms., 21 0.036 m) dropwis2. After 3 hours at 50C., the solution 22 i3 cooled and extracted with chloroform. The chloroform 23 is dried over anhydrous sodium sul~ate, filtered and con-24 centxated to an oil. The oil is purified by column chromatography to give 2.4 gm. of 4-(2,3-epoxypxopoxy)-26 5~6,7,8-tetrahydronapthaldehyde 4 '.
~' :
~751~9 1 C. 4(3-tert.-Butylamino-2 hydroxypropoxy)-5,6,7,8-tetrahydronapthaldehyd-e ..
3 To 4-(2,3-epoxypropoxy)-5,6,7,8-tetrahydronapth-4 aldehyde (2.4 gms) is added tert.-butylamine (15 ml.). The S resulting solution is heated at 45C. for 15 hours. The 6 excess tert.-butylamine is removed at reduced pressure 7 (20 mm). To the residue is added 30 ml. 6N hydrochloric 8 acid, and the resulting mixture is re~luxed ~or three 9 hours. The acidic mixture is poured into a satuxated solution of sodium carbonate which is heated on a steam 11 bath with nitrogen bubbling through it. The basic mixture 12 is extracted with chloroform, which i5 dried over anhydrous 13 sodium sul~ate, iltered and concentrated to give 2.3 g 14 of 4-(3-tert.butylamino-2-hydroxypropoxy)-5,6,7,8-tetrahydronapthaldehyde as an oil.
17 D. 2~ 3-tert.-Butylamino-2-hydroxypropoxy~-5,6,7,8-tetrahydronapthyl]-4-trifluoromethylimidazole 18 Step D:
19 To ~odium acetate trihydrate (2~07 gm., 0.015 m) in water (20 ml.) is added dibromotrifluoroacetone 21 (2.07 g., 0.0075 m). The solution is heated for 40 minutes 22 on a steam bath, cooled and added to a solution of 4-(3-tert.
23 -butylamino-2-hydroxypropoxy)-5,6/7,8-tetrahydronapth-~ 54 ~
.
~756~9 1 aldehyde (2.3 mgs., 0.0075 m) in methanol (1~0 ml.) with 2 concentrated aqueous ammonium hydroxide (15 ml.). The 3 solution is allowed to stand at room t~perature for 17 4 hours. The methanol is removed under rleduced pressure (20 mm) over steam and ethyl acetate (100 ml.) and 6 saturated aqueous sodium carbonate are added to the residue.
7 The ethyl acetate is separated, dried oE anhydrous sodium 8 sulfa~e, filtered and concentrated. The oil ~s crystallized 9 from acetonitrile to give 500 mg. of 2-~(3-tert-butyl-amino-2-hydroxypropoxy)-5,6,7,8-tetrahydronaphthyl]-4 11 tri1uoromethyl-imidazole. Melting point 203-205C.
13 A. 4-(3-n-Butylamino-2-hydroxypropoxy)benzaldehyde 14 Step A:
To 4-(2,3-epoxypropoxy)benz~ldehyde (8.9 gms., 16 0.05 m) is added n-butylamine (30 ml.) and the resulting 17 solution i9 refluxed 17 hourc. The excess n-butylamine 18 is removed under reduced pressure (20 mm). The oil is 19 dissolved in 6N hydrochloric acid (30 ml.) and the solu-tion is heated on a steam bath for 40 minutes. The hot 21 acidic solution is poured into a hot saturated aqueous 22 sodium carhonate solution with nitrogen bubbling thxough 23 it. The basic solution is extracted with chloroform.
24 The chloroform is dried over sodium sulfate and concen-trated to yield 4-(3~ butylamino-2-hydroxypropoxy) 26 benzaldehyde, as an oil.
:
~L~7~68~
1 B. 2-[4-(3-n-But~lamino-2-hydroxypropoxy)phenyl] 4 trifluoromethYlimidazole 3 To a solution of sodium acetat:e trihydrate 4 (5.0 g.) in water (20 ml.) is added dibromotrifluoro-acetone (S.0 g.). The solution is heated on a steam 6 bath for 30 minutes. After cooling to room temperature, 7 this solution is added to the methanolic solution of 8 4-(3-n-butylaminv-2-hydroxypropoxy)-benzaldehyde and 9 concentrated aqueous ammonium hydroxide (25 ml.).
After standing at room temperature for 48 hours, the 11 methanol is removed under reduced pressure (20 mm). The 12 residue is dissolved in ~thyl acetate and saturated 13 aqueous sodi~m carbonate, dried over anhydrous sodium 14 sulfate and concentrated under reducad pxessure. The oil is placed in acetonitrile to yield 800 mg. of 2-~4-(3-n-16 butylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethyl-17 imidazole, melting at 151~154C.
19 S-4-(4-methoxyphenyl)-2-[4-(3-tert-butylamino-2-hydroxy-_pro~oxy)- ~ idazole d ~ rochloride dih~drate A heterogeneous solution o~ p-methoxypheny~-21 glyoxal monohydrate (3.19 g. 0.018 m) sodium acetate 22 (2.90 g., 0.036 m), water (23 ml), 37~ aqueous ammonia 23 (23 ml) and (S)-p-(3-tert-butylamino-2-hydroxypropoxy)-24 benzaldehyde (2.90 g~, 0.012 m) in methanol (75 ml) is stirred at 25C. for 72 hours. The reaction mixture ~6 i concentrated to drynes~ under reduced pressure (15 mm) 27 at 80C. The residual solid is treated with saturated 28 aquaous Na2C03 (75 ml), extracted with chloroform (4x75 ml), .. ..
-.~ ~ 15524 IA
~L~75689 l dried over anhydrous MgSO4, filtered and concentrated to ~ dryness. The residue is dissolved in chloroform (50 ml) - 3 and absorbed on an alumina pad ~200 g). The pad is eluted 4 with chloroform (2 l), 5% methanol/chloroform (1 liter),
10% methanol/chloroform (l), 20% methanol/chloroorm (l), 6 40% me~hanol/chloroform (l l) and methanol (1 liter), 7 Concentration of the 20~ methanol/chloroform, 40% methanol/
8 chloroform a~d methanol solu~ions gives 1.5 g of crude 9 (S)-4-(4-methoxyphenyl)-2-[4-~3-tert-butylamino-2-hydroxy-propoxy)-phenyl]-imidazole. This treatment of this crude ll product with 8N ethanolic hydrogen chloride (l ml) yields 12 the hydrochloride salt which is puri~ied by three 13 precipitations from isopropyl alcohol/ethyl acetate to give 14 810 mg of (S)-4-t4-methoxyphenyl)-2-[4-(3-tert-butylamino-2-hydroxypropoxy)-phe~yl]-imidazole dihydrochloride dihydrate, 16 m.p. 132.0-135.0C.
19 A. 2,6-Dichloro-~-b~rox~benzaldeh~de To a stirred suspension of calcium hydroxide ; 21 (61 gm), sodium car~onate (69.7 gm), and 3,5 dichlorophenol 22 (20.~7 gm) in water (436 ml) at 74 is added chloroform 23 (45.3 gm) over 90 minutes. The solution is refluxed for 24 3 1/2 hours. Ater the 510w addition of co~centrated hydro-chloric acid (170 ml), the acidic solution is steam distilled 26 the aqueous residue is cooled and the solid which separates 27 is ~iltered. RecrystaIlization from toluene gives l.l ~m of 28 2,~-dichloro-4-hydroxybenzaldehyde.
- 57 ~
-~ 15524 IA
~L~17~689 1 B. 2,6-Dichloro-4-(2,3 epoxypropox~? benzaldehyde 2 To a stirred solution of 2,6~dichloro-4-hydroxy 3 benzaldehyde (3.0 gm 0.0167 m) in 1.5 N sodium hydroxide 4 (25 m) at 50 is added epichlorohydrin (4.4 gm, 0.048 m).
After stirring at 50 for 3 houxs, the solution is cooled 6 and extracted with chloroform. The chloroform is dried 7 over anhydrous sodium ~ulfate, filtered and concentrated 8 to 2,6-dichloro-4-(2,3~epoxypropoxy~-benzaldehyde (3 g) 9 which is u~ed without further purification.
8 chloroform a~d methanol solu~ions gives 1.5 g of crude 9 (S)-4-(4-methoxyphenyl)-2-[4-~3-tert-butylamino-2-hydroxy-propoxy)-phenyl]-imidazole. This treatment of this crude ll product with 8N ethanolic hydrogen chloride (l ml) yields 12 the hydrochloride salt which is puri~ied by three 13 precipitations from isopropyl alcohol/ethyl acetate to give 14 810 mg of (S)-4-t4-methoxyphenyl)-2-[4-(3-tert-butylamino-2-hydroxypropoxy)-phe~yl]-imidazole dihydrochloride dihydrate, 16 m.p. 132.0-135.0C.
19 A. 2,6-Dichloro-~-b~rox~benzaldeh~de To a stirred suspension of calcium hydroxide ; 21 (61 gm), sodium car~onate (69.7 gm), and 3,5 dichlorophenol 22 (20.~7 gm) in water (436 ml) at 74 is added chloroform 23 (45.3 gm) over 90 minutes. The solution is refluxed for 24 3 1/2 hours. Ater the 510w addition of co~centrated hydro-chloric acid (170 ml), the acidic solution is steam distilled 26 the aqueous residue is cooled and the solid which separates 27 is ~iltered. RecrystaIlization from toluene gives l.l ~m of 28 2,~-dichloro-4-hydroxybenzaldehyde.
- 57 ~
-~ 15524 IA
~L~17~689 1 B. 2,6-Dichloro-4-(2,3 epoxypropox~? benzaldehyde 2 To a stirred solution of 2,6~dichloro-4-hydroxy 3 benzaldehyde (3.0 gm 0.0167 m) in 1.5 N sodium hydroxide 4 (25 m) at 50 is added epichlorohydrin (4.4 gm, 0.048 m).
After stirring at 50 for 3 houxs, the solution is cooled 6 and extracted with chloroform. The chloroform is dried 7 over anhydrous sodium ~ulfate, filtered and concentrated 8 to 2,6-dichloro-4-(2,3~epoxypropoxy~-benzaldehyde (3 g) 9 which is u~ed without further purification.
11 C. 2,6-Dichloro-4-(3-tert-butylamino-2-hydroxypropoxy)-benzaldehYde ~ ~ _ , . . .
12 A mixture o~ 2,6-dichloro-4-(2,3-epoxypropoxy)~
13 benzaldehyde (3 gm) and tert-butylamine (20 ml) ls heated
14 at 45 for 17 hours. ~he excess tert-butylamine i5 lS removed under reduced pressure (20 mm). The oil is dissol-16 ved in 6 N hydrochloric acid (25 ml) and heated for 1 hour.
17 The acid solution is added to boiling saturated aqueous 18 qodium carbonate with nitrogen ebullition. The ~asic 19 solution is extracted with chloroform. The chloro~orm is dried over anhydrous sodium sulfate, filtered and 21 aoncentrated to 2,6-dichloro-4-(3-tert~b~tylamino-2-22 hydroxypropoxy)benzaldehyde which is used without further 23 purification.
Do 2-~2,6-Dichloro-4-~tert-butylamino-2-hydroxypropoxy)-phenYl~-4-txifluoromethYl imidazole 26 A solution of sodium acetate trihydrate (2.7 gm 27 0.02 m) and dibromotrifluoroacetone (276 gm (0.01 m) in 28 water (20 ml) is refluxed for 45 minutes. It is cooled 29 and added to a solution of 2,6-dichloro-4-(3-tert-butylamino-.
, . , . . .
, - , .
~ 15524 IA
~1~756~39 1 2-hydroxypropoxy)benzaldehyde (3.0 gm, 0.009 m) in methanol 2 (200 ml) and saturate aqueous ammonia (:30 ml). After stand-3 ing at room temperature for 17 hours, the solution is 4 concentrated to an oil. The oil is dissolved in ethyl-acetate and washed with saturated aqueous sodium carhonate.
6 The ethylacetate is dried over anhydrous sodium sulfate, 7 filtered and concentrated. The gu~ is purified by chromato-8 graph o~ qilica gel with chloroform, washed with ammonium 9 hydroxide and methanol as solvents. After purification 1090 mg of 2-[2,6-dichloro-4(3-tert~butylamino-2-hyclroxypro-11 poxy)-phenyl]-4-trifluoromethyl imidazole is obtained.
141-Methyl-2-[4-(3-tert-butylamino-2 hydroxypropoxy)phenyl]-4 ~and 5)-trifluoromethyl imidazole
17 The acid solution is added to boiling saturated aqueous 18 qodium carbonate with nitrogen ebullition. The ~asic 19 solution is extracted with chloroform. The chloro~orm is dried over anhydrous sodium sulfate, filtered and 21 aoncentrated to 2,6-dichloro-4-(3-tert~b~tylamino-2-22 hydroxypropoxy)benzaldehyde which is used without further 23 purification.
Do 2-~2,6-Dichloro-4-~tert-butylamino-2-hydroxypropoxy)-phenYl~-4-txifluoromethYl imidazole 26 A solution of sodium acetate trihydrate (2.7 gm 27 0.02 m) and dibromotrifluoroacetone (276 gm (0.01 m) in 28 water (20 ml) is refluxed for 45 minutes. It is cooled 29 and added to a solution of 2,6-dichloro-4-(3-tert-butylamino-.
, . , . . .
, - , .
~ 15524 IA
~1~756~39 1 2-hydroxypropoxy)benzaldehyde (3.0 gm, 0.009 m) in methanol 2 (200 ml) and saturate aqueous ammonia (:30 ml). After stand-3 ing at room temperature for 17 hours, the solution is 4 concentrated to an oil. The oil is dissolved in ethyl-acetate and washed with saturated aqueous sodium carhonate.
6 The ethylacetate is dried over anhydrous sodium sulfate, 7 filtered and concentrated. The gu~ is purified by chromato-8 graph o~ qilica gel with chloroform, washed with ammonium 9 hydroxide and methanol as solvents. After purification 1090 mg of 2-[2,6-dichloro-4(3-tert~butylamino-2-hyclroxypro-11 poxy)-phenyl]-4-trifluoromethyl imidazole is obtained.
141-Methyl-2-[4-(3-tert-butylamino-2 hydroxypropoxy)phenyl]-4 ~and 5)-trifluoromethyl imidazole
15` An ether solution of diazomethane ~1.5 gm) is
16 added to a sol~tion of 2-[4-t3-tert-butylamino 2-hydroxy-
17 propoxy)phenyl] 4-trifluoromethylimidazole in ether (100
18 ml) and methanol (50 ml). The solution is allowed to stand
19 at room temperature until the yellow color has disappeared.
The solvents are removed under reduced pressure. The 21 resulting gum is chromatographed on silica gel with 2~ chloro~orm treated with a~ueous ammonium hydroxide and 23 methanol to yi~ld 1-mathyl-2-[4-(tert-butylamino~2 hydroxy-24 propoxy)phenyl];;4-(and 5)-txifluoromethyl imidazole, whlch is a 50-50 mixture o~ th~ two N-methyl isomers.
26 ~NALYSIS:
27 NMR (d DMSO) N-C~3 double~. 3.72 3.74 28 (CH3) t~t-butyl 1OO4 29 ~ass spec 371 m~ peak 356 m - 15 ~1.7 gm3 ~756~3~
1 ExAMæLE4g 2 2-[4-(3-dimethylamino-2-hydroxypropoxy)phenyl]-4-tri-fluoromethylimidazole -3 A solution of 2-[4-(2,3-epoxypropoxy)phenyl-4-4 trifluoromethylimidazole in triethylamine ~15 ml) is added 1.1 equivalents of a dimethylamine. This solution is 6 refluxed until reaction is complete as indicated by TLC.
7 The solvent is removed under reduced pressure and the 8 residue recrystallized to yield 2-[4-(3-dimethylamino-2-9 hydroxypropoxy~phenyl]-4-trifluoromethylimidazole.
' 11 The methods illustrated in the examples l~9 12 above are readily utilized to prepare other analogous 13 imidazoles which are encompassed by the present invention.
i"~
:' ' ' :, ~.
~ - 60 -' .
~756~
2 S-2-[2-(3-tert. bu~ylamino-2-hydro~ypropoxy)-3-chloro-5-pyridyl]-4-trifl ~ hydr~en maleate 3 A. A mixture of 57% sodium hydride in mineral oil 4 (0.53 g., equivalent to 0O30 g., 0.0126 m, of active sodium hydride) is added over a period of ten minutes to a 6 stixred solution of S-2-phenyl-3-tert. butyl-5-hydroxy-7 methyLoxazolidine (2.97g, 0.0126 m) in 25 ml of anhydrous 8 toluene under nitrogen. The reaction mixture is allowed 9 to stir at 25C for 15 minutes, 100C for 15 mi~utes and L0 finally at 25C for 30 minutes. The homogeneous solution 11 obtained is added dropwise over a period of 60 minutes to 12 a rapidly stirred solution of 2,3-dichloro-5-cyanopyridine 13 (2.0 g, 0.0126 m~ in 20 ml of anhydrous toluene at 0C
14 under nitrogen. The heterogenous reaction mixture is stlrred rapidly at 0-5C for 60 minutes and at 25C for 16 16 hours. This reaction mixtur~ is then poured into 50 ml 17 of water and the toluene layer separated. The aqueous 18 phase is extracted with additional toluene 3x25 ml). The 19 toluene extracts are combined, washed with saturated aqueous sodium chloride (50 ~1), dried over anhydrous sodium 21 sul~ate, ~iltered and concentrated under reduced pressure 22 (25 m~). The residue i~ diluted with 60 ml of ~N aqueou~
23 hydrochloric acid and ~tirred on a steam bath for 5 24 minutes and at 25C for 30 minutes. The acidic reaction mixture is extracted with diethylether (5x50 ml) and chilled 26 in a~ ice bath. 10 M aqueous sodium hydroxide is added 27 dropwi~e until the pH is approximately 12-140 The basic 28 reaction mixture is extracted with chloroform (4x50ml).
~756~
1 The chloroform extracts are combined, dried over anhydrous 2 sodium sulfate, filtered and concentrated at reduced 3 pressure (25 mm). The remaining oil is dissolved in 4 re~luxing petroleum ether (400 ml), and on cooling to 25C., 1.38 y of S-2-~tert. butylamino-2-hydl-oxypropoxy)-3-chloro-6 5-cyanopyridine is isolated melting at 62.0-63.0C.
7 B. A solution of S-2-(3-tert. butylamino-2-hydroxy-8 propoxy)-3-chloro-5-cyanopyridine (11.19 g, 0.0394 m) in 9 anhydrous toluene (100 ml) is stirred rapidly at -73 C.
under nitrogen. A solution o~ diisobutylaluminum hydride 11 in ~oluene (66.3 ml, (Q.0394 m) of a 9.37 M solution) is 12 added dropwise over a ten minute period. The heterogeneous 13 reaction mixture is stirxed at -73C for 6 hours and then 14 allowed to stand at 0C. for 16 hours. The reaction mixture is stirred at 0C. and treated dropwise with methanol 16 ~50 ml) fol~owed by water (200 ml). The turbid solution is 17 extracted with chloro~onm (3x200 ml). Chloroform extracts 18 are combined, dried over anhydrous sodium sulfate, filtered 19 and concentrated under reduced pressure (25 mm)~ The residual oil (11.4g) is diluted with 60 ml of 6N a~ueous 21 hydrochloxic acid and stirred at lOO~C for 30 minutes. The 22 homogeneous acid solution is cooled to 0-5C. and treated 23 with 10 M aquaous sodium hydroxide until the pH is 2~ approximately 12-14. The basic solution is saturated with sodium chloride and extracted with chloroform (3x150 ml).
26 The chloroform eætracts are combined, dried over anhydrous 27 odium sulfate, ~iltered and concentrated at reduced pressura 28 (25 mm) to yield 11.66 g o~ S-2--~3 tert. butylamino-2-hydroxy 29 propoxy)-3-chloxonicotinaldehyde as a light brown oil.
- 62 _ .. ..
. . .
~L~7~6~
1 C. Sodium acetate ~8.66 g., O.0636m) is ~reated 2 with 60 ml of water and the homogeneous solution stirred 3 rapidly at 25C. Trifluorodibromoacetone (8.58g, 0.0318m) 4 is added in one portion and the mixture heated at 100C
for 40 minutes and cooled to 25C. This solution is 6 immediately added to a homogeneous mixture of S-2-(3-tert.
7 butylamino-2-hydroxypropoxy)~3-chloronicotinaldehyde 8 (6.09g, 0.0212m), methanol ~150 ml~ and concentrated aqueous 9 ammonium hydroxide ~60 ml). The reaction mix~ure is allowed to stir at 25C for 16 hrs., and concen~rated at 11 reduced pre~sure (25 mm) to remove the methanol. The 12 aqueous solution i~ extracted with 3% methanol/chloroform 13 ~2xlO0 ml) and 5% methanol/chloroform (2xlO0 ml). All 14 extract~ are combined, dried over anhydrous sodium sulfate, ~iltered and concentrated at reduced pressure (25 mm) to 16 yield 6.98g of glassy foam. This foam is dissol~ed in 17 absolute ethanol and the soLution filtered through a 150g 18 silica pad. The filtrate is concentrated to a small volume, 19 treated with a 10% excess of maleic acid and chilled. Upon dilution with diethyl ether, 1.82 g of S~2-~2-(3-tert.
21 bu~ylamino-2 hydroxyp~opoxy~-3-chloro-5-pyridyl]-4-tri-22 ~luoromethylimidazole hydrogen maleate wa~ isolated melting 23 at 80.0-35C.
24 ~he ~ree base may bs obtained by con~entional neutralization of the hydrogen maleate salt.
26 Claims to the in~ntion follow.
The solvents are removed under reduced pressure. The 21 resulting gum is chromatographed on silica gel with 2~ chloro~orm treated with a~ueous ammonium hydroxide and 23 methanol to yi~ld 1-mathyl-2-[4-(tert-butylamino~2 hydroxy-24 propoxy)phenyl];;4-(and 5)-txifluoromethyl imidazole, whlch is a 50-50 mixture o~ th~ two N-methyl isomers.
26 ~NALYSIS:
27 NMR (d DMSO) N-C~3 double~. 3.72 3.74 28 (CH3) t~t-butyl 1OO4 29 ~ass spec 371 m~ peak 356 m - 15 ~1.7 gm3 ~756~3~
1 ExAMæLE4g 2 2-[4-(3-dimethylamino-2-hydroxypropoxy)phenyl]-4-tri-fluoromethylimidazole -3 A solution of 2-[4-(2,3-epoxypropoxy)phenyl-4-4 trifluoromethylimidazole in triethylamine ~15 ml) is added 1.1 equivalents of a dimethylamine. This solution is 6 refluxed until reaction is complete as indicated by TLC.
7 The solvent is removed under reduced pressure and the 8 residue recrystallized to yield 2-[4-(3-dimethylamino-2-9 hydroxypropoxy~phenyl]-4-trifluoromethylimidazole.
' 11 The methods illustrated in the examples l~9 12 above are readily utilized to prepare other analogous 13 imidazoles which are encompassed by the present invention.
i"~
:' ' ' :, ~.
~ - 60 -' .
~756~
2 S-2-[2-(3-tert. bu~ylamino-2-hydro~ypropoxy)-3-chloro-5-pyridyl]-4-trifl ~ hydr~en maleate 3 A. A mixture of 57% sodium hydride in mineral oil 4 (0.53 g., equivalent to 0O30 g., 0.0126 m, of active sodium hydride) is added over a period of ten minutes to a 6 stixred solution of S-2-phenyl-3-tert. butyl-5-hydroxy-7 methyLoxazolidine (2.97g, 0.0126 m) in 25 ml of anhydrous 8 toluene under nitrogen. The reaction mixture is allowed 9 to stir at 25C for 15 minutes, 100C for 15 mi~utes and L0 finally at 25C for 30 minutes. The homogeneous solution 11 obtained is added dropwise over a period of 60 minutes to 12 a rapidly stirred solution of 2,3-dichloro-5-cyanopyridine 13 (2.0 g, 0.0126 m~ in 20 ml of anhydrous toluene at 0C
14 under nitrogen. The heterogenous reaction mixture is stlrred rapidly at 0-5C for 60 minutes and at 25C for 16 16 hours. This reaction mixtur~ is then poured into 50 ml 17 of water and the toluene layer separated. The aqueous 18 phase is extracted with additional toluene 3x25 ml). The 19 toluene extracts are combined, washed with saturated aqueous sodium chloride (50 ~1), dried over anhydrous sodium 21 sul~ate, ~iltered and concentrated under reduced pressure 22 (25 m~). The residue i~ diluted with 60 ml of ~N aqueou~
23 hydrochloric acid and ~tirred on a steam bath for 5 24 minutes and at 25C for 30 minutes. The acidic reaction mixture is extracted with diethylether (5x50 ml) and chilled 26 in a~ ice bath. 10 M aqueous sodium hydroxide is added 27 dropwi~e until the pH is approximately 12-140 The basic 28 reaction mixture is extracted with chloroform (4x50ml).
~756~
1 The chloroform extracts are combined, dried over anhydrous 2 sodium sulfate, filtered and concentrated at reduced 3 pressure (25 mm). The remaining oil is dissolved in 4 re~luxing petroleum ether (400 ml), and on cooling to 25C., 1.38 y of S-2-~tert. butylamino-2-hydl-oxypropoxy)-3-chloro-6 5-cyanopyridine is isolated melting at 62.0-63.0C.
7 B. A solution of S-2-(3-tert. butylamino-2-hydroxy-8 propoxy)-3-chloro-5-cyanopyridine (11.19 g, 0.0394 m) in 9 anhydrous toluene (100 ml) is stirred rapidly at -73 C.
under nitrogen. A solution o~ diisobutylaluminum hydride 11 in ~oluene (66.3 ml, (Q.0394 m) of a 9.37 M solution) is 12 added dropwise over a ten minute period. The heterogeneous 13 reaction mixture is stirxed at -73C for 6 hours and then 14 allowed to stand at 0C. for 16 hours. The reaction mixture is stirred at 0C. and treated dropwise with methanol 16 ~50 ml) fol~owed by water (200 ml). The turbid solution is 17 extracted with chloro~onm (3x200 ml). Chloroform extracts 18 are combined, dried over anhydrous sodium sulfate, filtered 19 and concentrated under reduced pressure (25 mm)~ The residual oil (11.4g) is diluted with 60 ml of 6N a~ueous 21 hydrochloxic acid and stirred at lOO~C for 30 minutes. The 22 homogeneous acid solution is cooled to 0-5C. and treated 23 with 10 M aquaous sodium hydroxide until the pH is 2~ approximately 12-14. The basic solution is saturated with sodium chloride and extracted with chloroform (3x150 ml).
26 The chloroform eætracts are combined, dried over anhydrous 27 odium sulfate, ~iltered and concentrated at reduced pressura 28 (25 mm) to yield 11.66 g o~ S-2--~3 tert. butylamino-2-hydroxy 29 propoxy)-3-chloxonicotinaldehyde as a light brown oil.
- 62 _ .. ..
. . .
~L~7~6~
1 C. Sodium acetate ~8.66 g., O.0636m) is ~reated 2 with 60 ml of water and the homogeneous solution stirred 3 rapidly at 25C. Trifluorodibromoacetone (8.58g, 0.0318m) 4 is added in one portion and the mixture heated at 100C
for 40 minutes and cooled to 25C. This solution is 6 immediately added to a homogeneous mixture of S-2-(3-tert.
7 butylamino-2-hydroxypropoxy)~3-chloronicotinaldehyde 8 (6.09g, 0.0212m), methanol ~150 ml~ and concentrated aqueous 9 ammonium hydroxide ~60 ml). The reaction mix~ure is allowed to stir at 25C for 16 hrs., and concen~rated at 11 reduced pre~sure (25 mm) to remove the methanol. The 12 aqueous solution i~ extracted with 3% methanol/chloroform 13 ~2xlO0 ml) and 5% methanol/chloroform (2xlO0 ml). All 14 extract~ are combined, dried over anhydrous sodium sulfate, ~iltered and concentrated at reduced pressure (25 mm) to 16 yield 6.98g of glassy foam. This foam is dissol~ed in 17 absolute ethanol and the soLution filtered through a 150g 18 silica pad. The filtrate is concentrated to a small volume, 19 treated with a 10% excess of maleic acid and chilled. Upon dilution with diethyl ether, 1.82 g of S~2-~2-(3-tert.
21 bu~ylamino-2 hydroxyp~opoxy~-3-chloro-5-pyridyl]-4-tri-22 ~luoromethylimidazole hydrogen maleate wa~ isolated melting 23 at 80.0-35C.
24 ~he ~ree base may bs obtained by con~entional neutralization of the hydrogen maleate salt.
26 Claims to the in~ntion follow.
Claims (15)
1. A process for preparing im:idazoles having the formula:
wherein:
R and R1 are independently selected from hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl having 1-3 sub-stituents selected from halo, hydroxy, phenyl and C1-C4 alkyl, aryl, substituted aryl having 1-5 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, cyano, halo, nitro, amino, carboxy, carbonyl, -SH, sulfamoyl, thioalkyl and phenyl, heterocyclic group having 5-6 ring atoms selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl and substituted pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl wherein the substituents are selected from methyl, ethyl, chloro and bromo, halogen, cyano, carboxy and carboxy derivatives, and wherein Ra is H or C1-C6 alkyl, R2 is selected from hydrogen, C1-C10 alkyl, hydroxy-C1-C10 alkyl and C3-C6 alkenyl, R3 is aryl having 6 ring atoms of which 0-2 are non-carbon selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, substituted aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen C1-C4 alkoxy, OH, NO2, CN
carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkyl-carbamoyl, fused ring aryl having 9-10 ring atoms of which 0-2 are non-carbon selected from quinolyl, naphthyl, tetrahydronaphthyl and indanyl and substituted fused ring aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen, C1-C4 alkoxy, OH, NO2, CN carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkylcarbamoyl, R5 and R6 when separate are independently selected from hydrogen, C1-C6 alkyl and substitu-ted C1-C6 alkyl wherein the substituent is selected from , and and when joined form a 5-6 membered -N-alicyclic ring selected from , , and wherein Z is H or C1-10 alkyl which comprises (a) the reaction of compounds having the formula:
wherein X is Br, I or Cl with compounds having the formula:
(b) the reaction of epoxide having the formula:
with amine having the formula:
(c) reacting compounds having the formula:
(a) with compounds having the formula:
(b) wherein L is halogen in the presence of ammonia wherein said (a) compound may be prepared by (1) reacting oxazolidine having the formula:
wherein R7 is aryl or alkyl sulfonyl, and R8 is alkyl or aryl with aldehyde having the formula:
and (2) hydrolyzing the reaction product from (1) (d) (1) reaction of compounds having the formula:
(a) with compound having the formula:
(b) wherein L is halogen, in the presence of ammonia (2) treating the product from (1) with strong base, and (3) finally reacting the product from (2) with amine having the formula:
provided that R is H, or (e) reacting compound having the formula:
with compounds having the formula:
in the presence of NH3.
wherein:
R and R1 are independently selected from hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl having 1-3 sub-stituents selected from halo, hydroxy, phenyl and C1-C4 alkyl, aryl, substituted aryl having 1-5 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, cyano, halo, nitro, amino, carboxy, carbonyl, -SH, sulfamoyl, thioalkyl and phenyl, heterocyclic group having 5-6 ring atoms selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl and substituted pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl wherein the substituents are selected from methyl, ethyl, chloro and bromo, halogen, cyano, carboxy and carboxy derivatives, and wherein Ra is H or C1-C6 alkyl, R2 is selected from hydrogen, C1-C10 alkyl, hydroxy-C1-C10 alkyl and C3-C6 alkenyl, R3 is aryl having 6 ring atoms of which 0-2 are non-carbon selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, substituted aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen C1-C4 alkoxy, OH, NO2, CN
carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkyl-carbamoyl, fused ring aryl having 9-10 ring atoms of which 0-2 are non-carbon selected from quinolyl, naphthyl, tetrahydronaphthyl and indanyl and substituted fused ring aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen, C1-C4 alkoxy, OH, NO2, CN carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkylcarbamoyl, R5 and R6 when separate are independently selected from hydrogen, C1-C6 alkyl and substitu-ted C1-C6 alkyl wherein the substituent is selected from , and and when joined form a 5-6 membered -N-alicyclic ring selected from , , and wherein Z is H or C1-10 alkyl which comprises (a) the reaction of compounds having the formula:
wherein X is Br, I or Cl with compounds having the formula:
(b) the reaction of epoxide having the formula:
with amine having the formula:
(c) reacting compounds having the formula:
(a) with compounds having the formula:
(b) wherein L is halogen in the presence of ammonia wherein said (a) compound may be prepared by (1) reacting oxazolidine having the formula:
wherein R7 is aryl or alkyl sulfonyl, and R8 is alkyl or aryl with aldehyde having the formula:
and (2) hydrolyzing the reaction product from (1) (d) (1) reaction of compounds having the formula:
(a) with compound having the formula:
(b) wherein L is halogen, in the presence of ammonia (2) treating the product from (1) with strong base, and (3) finally reacting the product from (2) with amine having the formula:
provided that R is H, or (e) reacting compound having the formula:
with compounds having the formula:
in the presence of NH3.
2. Process for preparing imidazoles having the formula:
wherein:
R and R1 are independently selected from hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl having 1-3 sub-stituents selected from halo, hydroxy, phenyl and C1-C4 alkyl, aryl, substituted aryl having 1-5 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, cyano, halo, nitro, amino, carboxy, carbonyl, -SH, sulfamoyl, thioalkyl and phenyl, heterocyclic group having 5-6 ring atoms selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl and substituted pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl wherein the substituents are selected from methyl, ethyl, chloro and bromo, halogen, cyano, carboxy and carboxy derivatives, and wherein Ra is H or C1-C6 alkyl, R2 is selected from hydrogen, C1-C10 alkyl, hydroxy-C1-C10 alkyl and C3-C6 alkenyl, R3 is aryl having 6 ring atoms of which 0-2 are non-carbon selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, substituted aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen C1-C4 alkoxy, OH, NO2, CN
carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkyl-carbamoyl, fused ring aryl having 9-10 ring atoms of which 0-2 are non-carbon selected from quinolyl, naphthyl, tetrahydronaphthyl and indanyl and substituted fused ring aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen, C1-C4 alkoxy, OH, NO2, CN carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkylcarbamoyl, R5 and R6 when separate are independently selected from hydrogen, C1-C6 alkyl and substituted C1-C6 alkyl wherein the substituent is selected from , and and when joined form a 5-6 membered -N-alicyclic ring selected from , , and wherein Z is H or C1-C10 alkyl which comprises the reaction of epoxide having the formula:
with amine having the formula:
wherein:
R and R1 are independently selected from hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl having 1-3 sub-stituents selected from halo, hydroxy, phenyl and C1-C4 alkyl, aryl, substituted aryl having 1-5 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, cyano, halo, nitro, amino, carboxy, carbonyl, -SH, sulfamoyl, thioalkyl and phenyl, heterocyclic group having 5-6 ring atoms selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl and substituted pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl wherein the substituents are selected from methyl, ethyl, chloro and bromo, halogen, cyano, carboxy and carboxy derivatives, and wherein Ra is H or C1-C6 alkyl, R2 is selected from hydrogen, C1-C10 alkyl, hydroxy-C1-C10 alkyl and C3-C6 alkenyl, R3 is aryl having 6 ring atoms of which 0-2 are non-carbon selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, substituted aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen C1-C4 alkoxy, OH, NO2, CN
carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkyl-carbamoyl, fused ring aryl having 9-10 ring atoms of which 0-2 are non-carbon selected from quinolyl, naphthyl, tetrahydronaphthyl and indanyl and substituted fused ring aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen, C1-C4 alkoxy, OH, NO2, CN carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkylcarbamoyl, R5 and R6 when separate are independently selected from hydrogen, C1-C6 alkyl and substituted C1-C6 alkyl wherein the substituent is selected from , and and when joined form a 5-6 membered -N-alicyclic ring selected from , , and wherein Z is H or C1-C10 alkyl which comprises the reaction of epoxide having the formula:
with amine having the formula:
3. Process for preparing imidazoles having the formula:
wherein:
R1 is selected from hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl having 1-3 substituents selected from halo, hydroxy, phenyl and C1-C4 alkyl, aryl, substi-tuted aryl having 1-5 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, cyano, halo, nitro, amino, carboxy, carbonyl, -SH, sulfamoyl thioalkyl and phenyl, heterocyclic group having 5-6 ring atoms selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl and substituted pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl wherein the substituents are selected from methyl, ethyl, chloro and bromo, halogen, cyano, carboxy and carboxy derivatives, and wherein Ra is H or C1-C6 alkyl, R3 is aryl having 6 ring atoms of which 0-2 are non-carbon selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, substituted aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen C1-C4 alkoxy, OH, NO2, CN
carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkyl-carbamoyl, fused ring aryl having 9-10 ring atoms of which 0-2 are non-carbon selected from quinolyl, naphthyl, tetrahydronaphthyl and indanyl and substituted fused ring aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen, C1-C4 alkoxy, OH, NO2, CN carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkylcarbamoyl, R5 and R6 when separate are independently selected from hydrogen, C1-C6 alkyl and substituted C1-C6 alkyl wherein the substituent is selected from , and and when joined form a 5-6 membered -N-alicyclic ring selected from , , and wherein Z is H or C1-C10 alkyl which comprises reacting compounds having the formula:
(a) with compounds having the formula:
(b) wherein L is halogen in the presence of ammonia.
wherein:
R1 is selected from hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl having 1-3 substituents selected from halo, hydroxy, phenyl and C1-C4 alkyl, aryl, substi-tuted aryl having 1-5 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, cyano, halo, nitro, amino, carboxy, carbonyl, -SH, sulfamoyl thioalkyl and phenyl, heterocyclic group having 5-6 ring atoms selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl and substituted pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl wherein the substituents are selected from methyl, ethyl, chloro and bromo, halogen, cyano, carboxy and carboxy derivatives, and wherein Ra is H or C1-C6 alkyl, R3 is aryl having 6 ring atoms of which 0-2 are non-carbon selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, substituted aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen C1-C4 alkoxy, OH, NO2, CN
carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkyl-carbamoyl, fused ring aryl having 9-10 ring atoms of which 0-2 are non-carbon selected from quinolyl, naphthyl, tetrahydronaphthyl and indanyl and substituted fused ring aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen, C1-C4 alkoxy, OH, NO2, CN carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkylcarbamoyl, R5 and R6 when separate are independently selected from hydrogen, C1-C6 alkyl and substituted C1-C6 alkyl wherein the substituent is selected from , and and when joined form a 5-6 membered -N-alicyclic ring selected from , , and wherein Z is H or C1-C10 alkyl which comprises reacting compounds having the formula:
(a) with compounds having the formula:
(b) wherein L is halogen in the presence of ammonia.
4. Process of Claim 3, wherein as a first step said compound (b) is treated with a weak base and the resultant reaction product is then reacted with compound (a).
5. Process of Claim 4, wherein said compound (b) is
6. The process of Claim 5, wherein said compound (a) has the formula:
wherein R6 is C1-C6 alkyl-
wherein R6 is C1-C6 alkyl-
7. Process for preparing imidazoles having the formula:
wherein:
R1 is selected from hydrogen, C1-C1O alkyl, substituted C1-C10 alkyl having 1-3 substituents selected from halo, hydroxy, phenyl and C1-C4 alkyl, aryl, substi-tuted aryl having 1-5 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, cyano, halo, nitro, amino, carboxy, carbonyl, -SH, sulfamoyl, thioalkyl and phenyl, heterocyclic group having 5-6 ring atoms selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl and substituted pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl wherein the substituents are selected from methyl, ethyl, chloro and bromo, halogen, cyano, carboxy and carboxy derivatives, and wherein Ra is H or C1-C6 alkyl, R3 is aryl having 6 ring atoms of which 0-2 are non-carbon selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, substituted aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen C1-C4 alkoxy, OH, NO2, CN
carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkyl-carbamoyl, fused ring aryl having 9-10 ring atoms of which 0-2 are non-carbon selected from quinolyl, naphthyl, tetrahydronaphthyl and indanyl and substituted fused ring aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen, C1-C4 alkoxy, OH, NO2, CN carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkylcarbamoyl, R5 and R6 when separate are independently selected from hydrogen, C1-C6 alkyl and substituted C1-C6 alkyl wherein the substituent is selected from , and and when joined form a 5-6 membered -N-alicyclic ring selected from , , and wherein Z is H or C1-C10 alkyl which comprises (1) reaction of compounds having the formula:
(a) with compound having the formula:
(b) wherein L is halogen, in the presence of ammonia (2) treating the product from (1) with strong base, and (3) finally reacting the product from (2) with amine having the formula:
wherein:
R1 is selected from hydrogen, C1-C1O alkyl, substituted C1-C10 alkyl having 1-3 substituents selected from halo, hydroxy, phenyl and C1-C4 alkyl, aryl, substi-tuted aryl having 1-5 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, cyano, halo, nitro, amino, carboxy, carbonyl, -SH, sulfamoyl, thioalkyl and phenyl, heterocyclic group having 5-6 ring atoms selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl and substituted pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl wherein the substituents are selected from methyl, ethyl, chloro and bromo, halogen, cyano, carboxy and carboxy derivatives, and wherein Ra is H or C1-C6 alkyl, R3 is aryl having 6 ring atoms of which 0-2 are non-carbon selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, substituted aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen C1-C4 alkoxy, OH, NO2, CN
carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkyl-carbamoyl, fused ring aryl having 9-10 ring atoms of which 0-2 are non-carbon selected from quinolyl, naphthyl, tetrahydronaphthyl and indanyl and substituted fused ring aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen, C1-C4 alkoxy, OH, NO2, CN carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkylcarbamoyl, R5 and R6 when separate are independently selected from hydrogen, C1-C6 alkyl and substituted C1-C6 alkyl wherein the substituent is selected from , and and when joined form a 5-6 membered -N-alicyclic ring selected from , , and wherein Z is H or C1-C10 alkyl which comprises (1) reaction of compounds having the formula:
(a) with compound having the formula:
(b) wherein L is halogen, in the presence of ammonia (2) treating the product from (1) with strong base, and (3) finally reacting the product from (2) with amine having the formula:
8. Process for preparing imidazoles having the formula:
wherein:
R and R1 are independently selected from hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl having 1-3 sub-stituents selected from halo, hydroxy, phenyl and C1-C4 alkyl, aryl, substituted aryl having 1-5 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, cyano, halo, nitro, amino, carboxy, carbonyl, -SH, sulfamoyl, thioalkyl and phenyl, heterocyclic group having 5-6 ring atoms selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl and substituted pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl wherein the substituents are selected from methyl, ethyl, chloro and bromo, halogen, cyano, carboxy and carboxy derivatives, and wherein Ra is H or C1-C6 alkyl, R3 is aryl having 6 ring atoms of which 0-2 are non-carbon selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, substituted aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen C1-C4 alkoxy, OH, NO2, CN
carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkyl-carbamoyl, fused ring aryl having 9-10 ring atoms of which 0-2 are non-carbon selected from quinolyl, naphthyl, tetrahydronaphthyl and indanyl and substituted fused ring aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen, C1-C4 alkoxy, OH, NO2, CN carbamoyl, N-C1-C6 alkyl and N,N-di-C1 -C6 and alkylcarbamoyl, R5 and R6 when separate are independently selected from hydrogen, C1-C6 alkyl and substituted C1-C6 alkyl wherein the substituent is selected from , and and when joined form a 5-6 membered -N-alicyclic ring selected from , , and wherein Z is H or C1-C10 alkyl whieh comprises reacting compound having the formula:
with compounds having the formula:
in the presence of NH3.
wherein:
R and R1 are independently selected from hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl having 1-3 sub-stituents selected from halo, hydroxy, phenyl and C1-C4 alkyl, aryl, substituted aryl having 1-5 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, cyano, halo, nitro, amino, carboxy, carbonyl, -SH, sulfamoyl, thioalkyl and phenyl, heterocyclic group having 5-6 ring atoms selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl and substituted pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl wherein the substituents are selected from methyl, ethyl, chloro and bromo, halogen, cyano, carboxy and carboxy derivatives, and wherein Ra is H or C1-C6 alkyl, R3 is aryl having 6 ring atoms of which 0-2 are non-carbon selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, substituted aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen C1-C4 alkoxy, OH, NO2, CN
carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkyl-carbamoyl, fused ring aryl having 9-10 ring atoms of which 0-2 are non-carbon selected from quinolyl, naphthyl, tetrahydronaphthyl and indanyl and substituted fused ring aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen, C1-C4 alkoxy, OH, NO2, CN carbamoyl, N-C1-C6 alkyl and N,N-di-C1 -C6 and alkylcarbamoyl, R5 and R6 when separate are independently selected from hydrogen, C1-C6 alkyl and substituted C1-C6 alkyl wherein the substituent is selected from , and and when joined form a 5-6 membered -N-alicyclic ring selected from , , and wherein Z is H or C1-C10 alkyl whieh comprises reacting compound having the formula:
with compounds having the formula:
in the presence of NH3.
9. Process for preparing acid addition salts of imidazole having the formula:
wherein:
R and R1 are independently selected from hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl having 1-3 sub-stituents selected from halo, hydroxy, phenyl and C1-C4 alkyl, aryl, substituted aryl having 1-5 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, cyano, halo, nitro, amino, carboxy, carbonyl, -SH, sulfamoyl, thioalkyl and phenyl, heterocyclic group having 5-6 ring atoms selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl and substituted pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl wherein the substituents are selected from methyl, ethyl, chloro and bromo, halogen, cyano, carboxy and carboxy derivatives, and wherein Ra is H or C1-C6 alkyl, R2 is selected from hydrogen, C1-C10 alkyl, hydroxy-C1-C10 alkyl and C3-C6 alkenyl, R3 is aryl having 6 ring atoms of which 0-2 are non-carbon selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, substituted aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen C1-C4 alkoxy, OH, NO2, CN
carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkyl-carbamoyl, fused ring aryl having 9-10 ring atoms of which 0-2 are non-carbon selected from quinolyl, naphthyl, tetrahydronaphthyl and indanyl and substituted fused ring aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen, C1-C4 alkoxy, OH, NO2, CN carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkylcarbamoyl, R5 and R6 when separate are independently selected from hydrogen, C1-C6 alkyl and substituted C1-C6 alkyl wherein the substituent is selected from , and and when joined form a 5-6 membered -N-alicyclic ring selected from , , and wherein Z is H or C1-C10 alkyl which comprises treating said imidazole with organic or inorganic acid.
wherein:
R and R1 are independently selected from hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl having 1-3 sub-stituents selected from halo, hydroxy, phenyl and C1-C4 alkyl, aryl, substituted aryl having 1-5 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, cyano, halo, nitro, amino, carboxy, carbonyl, -SH, sulfamoyl, thioalkyl and phenyl, heterocyclic group having 5-6 ring atoms selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl and substituted pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl wherein the substituents are selected from methyl, ethyl, chloro and bromo, halogen, cyano, carboxy and carboxy derivatives, and wherein Ra is H or C1-C6 alkyl, R2 is selected from hydrogen, C1-C10 alkyl, hydroxy-C1-C10 alkyl and C3-C6 alkenyl, R3 is aryl having 6 ring atoms of which 0-2 are non-carbon selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, substituted aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen C1-C4 alkoxy, OH, NO2, CN
carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkyl-carbamoyl, fused ring aryl having 9-10 ring atoms of which 0-2 are non-carbon selected from quinolyl, naphthyl, tetrahydronaphthyl and indanyl and substituted fused ring aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen, C1-C4 alkoxy, OH, NO2, CN carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkylcarbamoyl, R5 and R6 when separate are independently selected from hydrogen, C1-C6 alkyl and substituted C1-C6 alkyl wherein the substituent is selected from , and and when joined form a 5-6 membered -N-alicyclic ring selected from , , and wherein Z is H or C1-C10 alkyl which comprises treating said imidazole with organic or inorganic acid.
10. Process for the preparation of S-2-[2-(3-tert.
butylamino-2-hydroxypropoxy)-3-chloro-5-pyridyl]-4-trifluoro-methylimidazole which comprises reacting S-2-(3-tert. butyl-amino-2-hydroxypropoxy)-3-chloronicotinaldehyde with tri-fluorodibromoacetone in the presence of ammonia.
butylamino-2-hydroxypropoxy)-3-chloro-5-pyridyl]-4-trifluoro-methylimidazole which comprises reacting S-2-(3-tert. butyl-amino-2-hydroxypropoxy)-3-chloronicotinaldehyde with tri-fluorodibromoacetone in the presence of ammonia.
11. The process of Claim 10, wherein the compound obtained is treated with maleic acid to form the corresponding S-2-[2-(3-tert. butylamino-2-hydroxypropoxy)-3-chloro-5-pyridyl]-4-trifluoromethylimidazole hydrogen maleate.
12. Imidazoles having the formula:
wherein:
R and R1 are independently selected from hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl having 1-3 sub-stituents selected from halo, hydroxy, phenyl and C1-C4 alkyl, aryl, substituted aryl having 1-5 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, cyano, halo, nitro, amino, carboxy, carbonyl, -SH, sulfamoyl, thioalkyl and phenyl, heterocyclic group having 5-6 ring atoms selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl and substituted pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl wherein the substituents are selected from methyl, ethyl, chloro and bromo, halogen, cyano, carboxy and carboxy derivatives, and wherein Ra is H or C1-C6 alkyl, R2 is selected from hydrogen, C1-C10 alkyl, hydroxy-C1-C10 alkyl and C3-C6 alkenyl, R3 is aryl having 6 ring atoms of which 0-2 are non-carbon selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, substituted aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen C1-C4 alkoxy, OH, NO2, CN
carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkyl-carbamoyl, fused ring aryl having 9-10 ring atoms of which 0-2 are non-carbon selected from quinolyl, naphthyl, tetrahydronaphthyl and indanyl and substituted fused ring aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen, C1-C4 alkoxy, OH, NO2, CN carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkylcarbamoyl, R5 and R6 when separate are independently selected from hydrogen, C1-C6 alkyl and substituted C1-C6 alkyl wherein the substituent is selected from , and and when joined form a 5-6 membered -N-alicyclic ring selected from , , and wherein Z is H or C1-C10 alkyl when prepared by the process defined in Claim 1, 2 or 3 or by an obvious chemical equivalent.
wherein:
R and R1 are independently selected from hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl having 1-3 sub-stituents selected from halo, hydroxy, phenyl and C1-C4 alkyl, aryl, substituted aryl having 1-5 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, cyano, halo, nitro, amino, carboxy, carbonyl, -SH, sulfamoyl, thioalkyl and phenyl, heterocyclic group having 5-6 ring atoms selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl and substituted pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl wherein the substituents are selected from methyl, ethyl, chloro and bromo, halogen, cyano, carboxy and carboxy derivatives, and wherein Ra is H or C1-C6 alkyl, R2 is selected from hydrogen, C1-C10 alkyl, hydroxy-C1-C10 alkyl and C3-C6 alkenyl, R3 is aryl having 6 ring atoms of which 0-2 are non-carbon selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, substituted aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen C1-C4 alkoxy, OH, NO2, CN
carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkyl-carbamoyl, fused ring aryl having 9-10 ring atoms of which 0-2 are non-carbon selected from quinolyl, naphthyl, tetrahydronaphthyl and indanyl and substituted fused ring aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen, C1-C4 alkoxy, OH, NO2, CN carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkylcarbamoyl, R5 and R6 when separate are independently selected from hydrogen, C1-C6 alkyl and substituted C1-C6 alkyl wherein the substituent is selected from , and and when joined form a 5-6 membered -N-alicyclic ring selected from , , and wherein Z is H or C1-C10 alkyl when prepared by the process defined in Claim 1, 2 or 3 or by an obvious chemical equivalent.
13. Imidazoles having the formula:
wherein:
R1 is selected from hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl having 1-3 substituents selected from halo, hydroxy, phenyl and C1-C4 alkyl, aryl, substi-tuted aryl having 1-5 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, cyano, halo, nitro, amino, carboxy, carbonyl, -SH, sulfamoyl, thioalkyl and phenyl, heterocyclic group having 5-6 ring atoms selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl and substituted pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl wherein the substituents are selected from methyl, ethyl, chloro and bromo, halogen, cyano, carboxy and carboxy derivatives, and wherein Ra is H or C1-C6 alkyl, R3 is aryl having 6 ring atoms of which 0-2 are non-carbon selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, substituted aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen C1-C4 alkoxy, OH, NO2, CN
carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkyl-carbamoyl, fused ring aryl having 9-10 ring atoms of which 0-2 are non-carbon selected from quinolyl, naphthyl, tetrahydronaphthyl and indanyl and substituted fused ring aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen, C1-C4 alkoxy, OH, NO2, CN carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkylcarbamoyl, R5 and R6 when separate are independently selected from hydrogen, C1-C6 alkyl and substituted C1-C6 alkyl wherein the substituent is selected from , and and when joined form a 5-6 membered -N-alicyclic ring selected from , , and wherein Z is H or C1-C10 alkyl when prepared by the process defined in Claim 7, 8 or 9 or by an obvious chemical equivalent.
wherein:
R1 is selected from hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl having 1-3 substituents selected from halo, hydroxy, phenyl and C1-C4 alkyl, aryl, substi-tuted aryl having 1-5 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, cyano, halo, nitro, amino, carboxy, carbonyl, -SH, sulfamoyl, thioalkyl and phenyl, heterocyclic group having 5-6 ring atoms selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl and substituted pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl wherein the substituents are selected from methyl, ethyl, chloro and bromo, halogen, cyano, carboxy and carboxy derivatives, and wherein Ra is H or C1-C6 alkyl, R3 is aryl having 6 ring atoms of which 0-2 are non-carbon selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, substituted aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen C1-C4 alkoxy, OH, NO2, CN
carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkyl-carbamoyl, fused ring aryl having 9-10 ring atoms of which 0-2 are non-carbon selected from quinolyl, naphthyl, tetrahydronaphthyl and indanyl and substituted fused ring aryl having 1-4 substituents selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen, C1-C4 alkoxy, OH, NO2, CN carbamoyl, N-C1-C6 alkyl and N,N-di-C1-C6 and alkylcarbamoyl, R5 and R6 when separate are independently selected from hydrogen, C1-C6 alkyl and substituted C1-C6 alkyl wherein the substituent is selected from , and and when joined form a 5-6 membered -N-alicyclic ring selected from , , and wherein Z is H or C1-C10 alkyl when prepared by the process defined in Claim 7, 8 or 9 or by an obvious chemical equivalent.
14. The S-2- [2-(3-tert. butylamino-2-hydroxy-propoxy)-3-chloro-5-pyridyl]-4-trifluoromethylimidazole, when prepared by the process defined in Claim 10 or by an obvious chemical equivalent.
15. The S-2-[2-(3-tert. butylamino-2-hydroxy-propoxy)-3-chloro-5-pyridyl]-4-trifluoromethylimidazole hydrogen maleate, when prepared by the process defined in Claim 11 or by an obvious chemical equivalent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA257,658A CA1075689A (en) | 1976-07-23 | 1976-07-23 | Substituted imidazoles, their preparation and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA257,658A CA1075689A (en) | 1976-07-23 | 1976-07-23 | Substituted imidazoles, their preparation and use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1075689A true CA1075689A (en) | 1980-04-15 |
Family
ID=4106493
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA257,658A Expired CA1075689A (en) | 1976-07-23 | 1976-07-23 | Substituted imidazoles, their preparation and use |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1075689A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0018568A2 (en) * | 1979-04-28 | 1980-11-12 | BASF Aktiengesellschaft | Process for preparing imidazoles |
| WO2017110237A1 (en) * | 2015-12-25 | 2017-06-29 | 株式会社大塚製薬工場 | Phenylimidazole compound |
| RU2788966C2 (en) * | 2015-12-25 | 2023-01-26 | Оцука Фармасьютикал Фэктори, Инк. | Phenyl imidazole compound |
-
1976
- 1976-07-23 CA CA257,658A patent/CA1075689A/en not_active Expired
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0018568A2 (en) * | 1979-04-28 | 1980-11-12 | BASF Aktiengesellschaft | Process for preparing imidazoles |
| EP0018568A3 (en) * | 1979-04-28 | 1981-03-25 | Basf Aktiengesellschaft | Process for preparing imidazoles |
| WO2017110237A1 (en) * | 2015-12-25 | 2017-06-29 | 株式会社大塚製薬工場 | Phenylimidazole compound |
| CN108430977A (en) * | 2015-12-25 | 2018-08-21 | 株式会社大塚制药工场 | Phenyl imidazole compounds |
| JPWO2017110237A1 (en) * | 2015-12-25 | 2018-10-11 | 株式会社大塚製薬工場 | Phenylimidazole compound |
| US10570117B2 (en) | 2015-12-25 | 2020-02-25 | Otsuka Pharmaceutical Factory, Inc. | Phenylimidazole compound |
| CN108430977B (en) * | 2015-12-25 | 2021-06-08 | 株式会社大塚制药工场 | Phenylimidazole compounds |
| RU2788966C2 (en) * | 2015-12-25 | 2023-01-26 | Оцука Фармасьютикал Фэктори, Инк. | Phenyl imidazole compound |
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