CA2155573A1 - Process for production of an imidazole derivative - Google Patents
Process for production of an imidazole derivativeInfo
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- CA2155573A1 CA2155573A1 CA002155573A CA2155573A CA2155573A1 CA 2155573 A1 CA2155573 A1 CA 2155573A1 CA 002155573 A CA002155573 A CA 002155573A CA 2155573 A CA2155573 A CA 2155573A CA 2155573 A1 CA2155573 A1 CA 2155573A1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The object of the present invention is to improve the selectivity on reduction of the C ring double bond of an imidazole derivative having the hydrazine cross-linking structure by formula (I). The imidazole derivative is subjected to the reaction with a diimide (HN=NH).
Description
WO 94/21641 215 5 ~ 7 3 PCTIUS94/01949 PROCESS FOR PRODUCTION OF AN IMIDAZOLE DERIYATIYE
BACKGROUND OF THE INVENTION
The present invention relates to a process for producing an imidazole derivative. More particularly, the present invention relates to a process for producing an imidazole derivative 5 useful for hypertension, congestive heart failure, renal failure, glaucoma, hyperuricemia and the like and an intermediate therefor.
The present inventors have aimed at angiotensin II antagonist as an agent for preventing or treating hy~lellsion, congestive heart failure, renal failure, glaucoma, hyperuricemia and the like, and studied intensively the drugs which have longer shelf life, higher activity, rapid 10 m~nife.st~tion of action upon intravenous injection, good absorbability into the body upon oral ~riminictration, lower toxicity and long-lasting action. As the result, we found the novel imidazole derivatives having the hydl~ille cross-linking structure ,tp,~st;~lled by the formula:
15 N~N
and filed applications ~l~imjng the derivatives (JP-A 3-277537, JP-A 3-323474. JP-A 4-095191, 20 JP-A 4-216809 and published PCT application WO 93/08193).
In the process for producing the above imidazole co",puul-d, when the C ring double bond of a colllpuulld produced by Diels Alder reaction is reduced (see the below Reaction Scheme), in particular when R is a protecting group such as benzyl group and the like, the reducing reaction is usually carried out in meth~nnl under hydrogen gas atmosphere using a 25 pa~ m hydroxide catalyst which makes possible a simultaneous deprotecting reaction such as debenzylation and the like. However, in this reducing reaction, in particular in the case of the co,l,pùulld (I) in which C ring represented by -P- forms bicyclo, 10 to 60% of a ring cleavaged side product (3) is produced in addition to the end col.lpoulld (2) depending upon the kind and size of R13 group and R17 group as well as the reaction conditions. Therefore, the purification 30 by column chromatography is indispensable. Such a reduction reaction is not s~ti~f~rtory, both in terms of the yield and of the ecomonics of mass production-21~5S73 WO 94/21641 ' PCT/US94/01949 R2 R3 R13 R2 R3 Rl3 R2 R3 R13 R1~ R1~ +R1~
R R4 Rs Rl7 R R4 R5 R17 RR4 R5 R17 (1) (2) (3) N ~ N ~ ~ R1 ~ / ~ N
BACKGROUND OF THE INVENTION
The present invention relates to a process for producing an imidazole derivative. More particularly, the present invention relates to a process for producing an imidazole derivative 5 useful for hypertension, congestive heart failure, renal failure, glaucoma, hyperuricemia and the like and an intermediate therefor.
The present inventors have aimed at angiotensin II antagonist as an agent for preventing or treating hy~lellsion, congestive heart failure, renal failure, glaucoma, hyperuricemia and the like, and studied intensively the drugs which have longer shelf life, higher activity, rapid 10 m~nife.st~tion of action upon intravenous injection, good absorbability into the body upon oral ~riminictration, lower toxicity and long-lasting action. As the result, we found the novel imidazole derivatives having the hydl~ille cross-linking structure ,tp,~st;~lled by the formula:
15 N~N
and filed applications ~l~imjng the derivatives (JP-A 3-277537, JP-A 3-323474. JP-A 4-095191, 20 JP-A 4-216809 and published PCT application WO 93/08193).
In the process for producing the above imidazole co",puul-d, when the C ring double bond of a colllpuulld produced by Diels Alder reaction is reduced (see the below Reaction Scheme), in particular when R is a protecting group such as benzyl group and the like, the reducing reaction is usually carried out in meth~nnl under hydrogen gas atmosphere using a 25 pa~ m hydroxide catalyst which makes possible a simultaneous deprotecting reaction such as debenzylation and the like. However, in this reducing reaction, in particular in the case of the co,l,pùulld (I) in which C ring represented by -P- forms bicyclo, 10 to 60% of a ring cleavaged side product (3) is produced in addition to the end col.lpoulld (2) depending upon the kind and size of R13 group and R17 group as well as the reaction conditions. Therefore, the purification 30 by column chromatography is indispensable. Such a reduction reaction is not s~ti~f~rtory, both in terms of the yield and of the ecomonics of mass production-21~5S73 WO 94/21641 ' PCT/US94/01949 R2 R3 R13 R2 R3 Rl3 R2 R3 R13 R1~ R1~ +R1~
R R4 Rs Rl7 R R4 R5 R17 RR4 R5 R17 (1) (2) (3) N ~ N ~ ~ R1 ~ / ~ N
(2) (4) N ~ N
~ Tr (5) In addition, it is thought that there is the possibility that the formation of 7~-allyl-25 palladium complex participates in this side reaction. However, the similar side reaction is also observed when platinum oxide and p~ m carbon are used in place of p~ rlillm hydroxide.
Therefore, the detailed meçh~ni~m is not known. And it was found that this side reaction rarely occurs in the case of Lindlar catalyst. However, in the case of this catalyst, the desired reaction does not proceed in some cases, probably due to the impurities cont~in~.d in the raw materials ~0 upon mass production, and there is a problem with reprocl~-ct;~ility.
~4 -WO 94/21641 215 ~ 5 7 3 PCT/US94/01949 INFORMATION DISCLOSI~RE
The prior route to the synthesis of the compounds produced by the process of this invention is described in WO 93/08193.
' SUMMARY OF THE INVENTION
5 The Problems to be Solved by the Invention The object of the present invention is to improve the selectivity on the reduction of C
ring double bond of the above imidazole derivative in order to achieve the high yield even in mass production and exclude the necessity of cl mplic~t~d purific~tion steps.
The Means to Solve the Problems In order to solve the above problems, the present inventors have studied intensively and, as a result, found that C ring double bond can be reduced selectively without the C ring cleavage reaction.
That is, the present invention provides a process for producing an imidazole derivative represented by the formula (II):
wherein R R1 R2 R3 R4 R5 R13, R14, R15, R16, R17 and R18 are as defined below. or a pharmacologically acceptable ester or salt thereof which compri~es reacting a compound represented by the formula (I):
\ /R13 R16 wherein R1 is hydrogen atom, lower alkyl group, lower alkoxy group, lower alkylthio group, lower alkylamino group, lower alkenyl group, -CF3 group, aryl group or aralkyl group;
R is hydrogen atom, or a group selected from the group co~ li"g of 215S~73 ~` ~
WO 94/21641 ~ PCT/US94/01949 --CH2 ~ --Ct 12 ~ --CH2 ~3 wherein X is -CH2-, -NR'-, oxygen atom or ~S(O)n~~ wherein R' is hydrogen atom or lower alkyl group, wherein n is 0, 1 or 2;
- wherein X1, x2 and X3 are independently hydrogen atom, halogen atom. Iower alkyl group, lower alkoxy group, nitro group, cyano group, lH-tetræol-5-yl group or alk~li metal salt 10 thereof, -Co2R7 group, -CONR'R" group, -CONHS02R8 group, amino group, -NHSO2CF3 group or -S03H group, or a group selected from the group con~ ing of Co2R7 R10 --NH--C ~--NH--C--CH--NH--C--R6 --N~( Y Y
Co2R7 R10 --O--CH~R11 Y is lH-tetrazol-5-yl group or alkali metal salt thereof optionally ~.ubslilllled with cyano group, benzyl group, tosyl group, methoxymethyl group, ethoxymethyl group, methoxyethoxymethyl group or trirnethylsilylethoxymethyl group, -Co2R7 group, -CONR'R"
group, -CONHSO2R8 group, amino group, -NHSO2CF3 group or -S03H group;
R2, R3, R4 and R5 are independently hydrogen atom or lower alkyl group, or R2 and R3, or R4 and R5 are taken together to form =O bond;
R6 is hydrogen atom, halogen atom, lower alkyl group, -CF3 group or -CF2CF3 group;
R7 is hydrogen atom, alkali metal atom or lower a~kyl group; ,, R' and R" are independently hydrogen atom or lower alkyl group, or R' and R" aretaken together to form the alicyclic structure; !, R8 is lower alkyl group, cycloalkyl group or aryl group;
R9 is lower ~lkyl group, lower alkoxy group, cycloalkyl group, cycloalkoxy group, aryl ~5 group or aryloxy group;
R10, R11 and R12 are independently hydrogen atom, halogen atom, lower a'kyl group, ~ 2~573 lower alkoxy group, nitro group, cyano group, -Co2R7 group or -CONR'R" group;
R13, R14, R15, R16, R17 and R18 are independently hydrogen atom, lower alkyl group, lower fluoroalkyl group, -C(R')iR")-oR19 group, -(CH2)j-Co2R7 group, -(CH2)j-CN group, -(CH2)j-C(=O)R' group, -(CH2)j-CONR'R'I group or -(CH2)j-Aryl group, wherein j is 0, 1 or 2, 5 wherein R16 and R18 may be taken together to form -(CH2)i- group, wherein i is 1, 2 or 3, wherein Aryl is phenyl group, pyridyl group, pyrimidyl group, pyridazinyl group, furyl group, thenyl group, pyrazolyl group, oxazolyl group, thiazolyl group, oxadiazolyl group or isooxazolyl group optionally ~ubsliillled with halogen atom, lower alkyl group, hydroxy group, lower alkoxy group, nitro group or cyano group;
R19 is hydrogen atom, or lower alkyl group optionally ~ul ~ llPd with hydroxy group or ether group, with a diimide (HN=NH).
First, variable substituents used in the general formula of the compounds herein are expl~inP,I
As the lower alkyl group represented by Rl, there are the alkyls having 1 to 8 carbon 15 atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isoamyl, n-hexyl, n-heptyl, n-octyl and the like. As the lower alkoxy group represented by R1, there are methoxy, ethoxy, n-p~upo~y, isop.ul)o~y~ n-butoxy, isob,llo~y, t-butoxy, n-pentoxy, isoamyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy and the like. As the lower alkylthio group ,~p,~se~led by R1, there are methylthio, ethylthio, n-p,ul~ylLllio, isuulupyllllio, n-butylthio, n-20 pentylthio, n-hexylthio, n-he~Lylil~io, n-octylthio and the like. As the lower alkylamino group re~ ;sel,led by Rl, there are methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino, di(n-propyl)amino, isol,lu~ylamino, n-butylamino, n-pentylamino, pyrrolidino, piperidino, ~ip~ o, morpholino and the like. As the lower alkenyl group represented by R1, there are vinyl, I-~lupt;llyl, 2-~lu~tillyl, 2-methyl-1-~,upenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 25 2-pellienyl, I-hexenyl, I-heptenyl, I-octenyl and the like. As the lower alkynyl group ,t;p,~sellled by Rl, there are acetylene group, l-pluL~yllyl, 2-Llrul~yllyl, l-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, l-heptynyl, l-octynyl and the like. As the aryl group or aralkyl group It;~ulcswlled by Rl, there are aryl or aralkyl group having 6 to 10 carbon atoms, for example, phenyl, naphthyl, benzyl, phenethyl, 3-phellyllJIul)yl, 4-phenylbutyl and the like.
30 These aryl and aralkyl groups are optionally ~ub~ llPd with the sllbstitlle.nt(s) such as the above described lower alkyl group, or lower alkoxy group, halogen atom, nitro group, cyano group and the like.
When R is substill~tPd or Im~ubslil"led ph~llylmethyl group, as the halogen atom defined hy X1, x2 and X3, there are fluorine atom, chlorine atom, bromine atom and iodine atom. As 35 the lower alkyl group and lower alkoxy group, there are above defined lower alkyl group and alkoxy group. When X1, x2 and X3 are lH-tetrazol-5-yl group, as the alkali metal salt thereof, 21~5~7~ ~
~ . .. .
there are sodium salt, potassium salt and the like. When Xl, x2 and X3 are -Co2R7 group, as the examples of R7 in the group, there are hydrogen atom, alkali metal atom such as lithium, sodium, potassium and the like, alcohol ester of the above defined lower alkyl group. When X1, x2 and X3 are -CONR'R", the examples of -NR'R" in the group, there are amino, r 5 methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino, di(n-propyl)amino;
dii~uplupylamino, dibutylamino, pyrrolidyl, pi~ uillO, morpholino and the like. As the examples of R8 in -CONHSO2R8 group, there are methyl, trifluoromethyl, ethyl, n-propyl, n-butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl, phenyl and the like. When X1, x2 and X3 are the group selected from the following:
Co2R7 R11 --NH--C ~ --NH--C--CH--NH--C--R6 --N~
Y Y
Co2R7 R10 --O--1H 4~
~=J R11 , Y and R7 are the same as defined above. The lower alkyl group and lower alkoxy group represented by R9 are as defined above. When R9 is cycloalkyl group or cycloalkoxy group, the examples are 5 to 7 membered cyclic compounds such as cyclopentyl, cyclohexyl, cyclopentyl and the like. As the e~mples of aryl group or aryloxy group represented by R9, 25 there are substit lt~d or ~ d phenyl coll-puunds such as phenyl, p-hydroxyphenyl, p-carboxyphenyl, o-ll-lluph~llyl and the like. The examples of lower alkyl group, lower alkoxy group, -Co2R7 group or -CONR'R" group represented by RlU, Rll or R12 are as defined above. When R is s~lbstit--t~d biphenylmethyl group, as the examples of the aLkali metal salt of substituent lH-tetrazol-5-yl, there are sodium salt, pol~iulll salt and the like. When Y is -30 Co2R7 group, -CONR'R" group or -CONHS02R8 grûup~ the e~mp'~s ûf R7, -NR'R" and R8 in the groups are as defined above. When R is represented by the following formula:
--CH2~R6 X
Y~
2~5~7~
, the example of halogen and lower alkyl group l~pl~s~ ed by R6, the examples of alkali metal salts of lH-tetrazol-5-yl represented by Y, and the examples of R7, NR'R" and R8 in -Co2R7 group, -CONR'R" group or -CONHSO2R8 group represented by Y are as defined above.When R2, R3, R4 and R5 are lower alkyl group, the examples of them are the alkylgroups having 1 to 8 carbon atoms, for ~x~mple, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isoamyl, n-hexyl, n-heptyl, n-octyl and the like.
When R13, R14, R15, R16, R17 and R18 are lower alkyl group, the example of them are the alkyls having 1 to 8 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isoamyl, n-hexyl, n-heptyl, n-octyl and the like. When R13, R14, R15, R16, R17 and R18 are lower fluoroalkyl group, the examples of them are trifluoromethyl, 2,2,2,-trifluoroethyl, pentafluoroethyl and the like. When R13 R14 R15 R16 R17 and R18 are -(CH2)j-Co2R7, -(CH2)j-C(=O)R', -C(R')(R")-OR19, or -(CH2)j-CONR'R", the examples of R7, R' and R" are as defined above.
The diimide used in the process of the present invention can be generated by various methorl~, for e~mrle, by oxid~tinn of hyd,a~u,e, decomposition of the dipotassium salt of azodicarboxylic acid by an acid, the decomposition of arylsulLol,yd,~ide by a base, the hydroxylamine-acetic acid ester method, and the like (Organic Reactions, 40, 91-155 (1991)).
Among them, the use of deco",po~ilion of p-tohlen~slllfohydrazide by sodium acetate is suitable in view of ~implirity of the operations and high safety.
The reaction between the diimide and the colllLJuulld of the general formula (I) proceeds effectively at room ~ ...e to 120 C. The reaction is carried out in a solvent. As the solvent, there are the alcoholic solvents such as methanol, ethanol, propanol and the like, and the etheric solvent such as lel~ ydlorul~l, dimetho~yt;~ le and the like. When p-toluenesulfohydrazide is used to generate the diimide, it is desirable to react the diimide and the 25 compound of the formula (I) while g~,le,~illg the diimide in ~nu~illg dimethoxyethane.
According to the previous process, 10 to 60 % of ring opened products are produced as side products. However, the above described reaction affords ~lu~ ely a product having the reduced C ring double bond without side products.
In addition, when R is a protecting group such as benzyl group and the like, after 30 reduction of C ring double bond according to the present method, the reduced product is reacted in methanol in the presence of the catalytic amount of 20 % p~ m hydroxide-carbon under 1 to 3 atmospheric l"~s~u~e hydrogen by a conventional method to easily effect the deprotection such as debenzylation and the like. Therefore, a process of the present invention is also useful for ~ ;paling an intermediate (4) for ~yllllle~is (see the above Reaction Scheme). Further, the 35 end imidazole derivative (5) can be obtained as crystals almost without side products by ching the biphenyltetrazole part to the interm~ te according to the method described in JP-21~S~73 A 3-277537, JP-A 3-323474, JP-A 4-095191 and JP-A 4-216809 and WO 93/08193 (see the above Reaction Scheme). Thereby, the purification by column chromatography which was indispensable to the previous process becomes llnnPcec~ry, and it was found that the present process can be applied to the mass production in the good reproductivity.
S If desired, the co"ll,uu"ds produced by the present process can be converted into the ester or salt thereof by a conventional method. The esters or salts are pharmacologically acceptable and non-toxic ones. Suitable esters include esters of lower alcohol having a straight or branched chain such as methanol, ethanol and the like. Suitable salts include alkali metal salts such as sodium salt, puLas~iulll salt and the like, and alkaline earth metal salts, hydrogen halide salts such as hydrogen fluoride, hydrogen chloride and the like, inorganic acid salts such as nitrate, sulfate and the like, lower alkylsulfonate salts such as meth~npslllfonate and the like, organic acid salts such as maleate, fumarate and the like, and amino acid salts such as aspartate and the like.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following F.Y:lmplP~s further illustrate the present invention in detail.
EXAMPLE 1 Synthesis of 1-benzyl-2-n-butyl-5,8-dimethyl-5,8-ethano-5,6,7,8-tetrahydro-lH-1,3,4a,8a-tetraæa-cyclop~ lPnP4,9-dione lc;~ s~llted by the formula:
o CH3 H3C ~/ ~N~
1-Benzyl-2-n-butyl-5,8-dimethyl-5,8-ethano-5,8-dihydro-lH-1,3,4a,8a-tetraaza-cyclopent~n~rhth~lene-4,9-dione (58 g, 0.14 mol) and p-toluPnPslllfonylhydrazide (187 g, 1.0 mol) were dissolved in dimethoxyethane (400 ml), and the mixture was heated to reflux. An aqueous solution (400 ml) of sodium acetate (165 g, 2.0 mol) was added dropwise to this 30 solution over 4 hours. The mixture was cooled to room lelllpel~Lule, further cooled to 0 C, and the precipit~tPd crystals were filtered. The crystals were dissolved in methylene chloride, washed with water and brine, dried over ~ulhydluu~ sodium sulfate, and the solvent was distilled off under reduced pressure. The residue combined with another residue (l-benzyl-2-n-butyl-5,8-dimethyl-5,8-ethano-5,8-dihydro-1H-1,3,4a,8a-tetraaza-cyclop~ lprup4~8-dione~ 56.5 g) ~5 obtained by the similar procedures was purified by silica gel column chromatography (acetone:
hex~ne: methylene chloride=5:1:40) for the purpose of removing the impurities derived from the 215~57~
WO 94t21641 PCTIUS94101949 g reagents to give the titled compound (105 g, 91%) as colorless solid. In this reduction of the diimide, only the titled co~ )ou-ld can be obtained as a sole product and no side products which were produced in the reduction by palladium hydroxide were recognized. The titled compound has the following NMR spectrum.
S lH-NMR (CDC13) ~ppm: 0.84 (3H, t, J=7.3Hz), 1.25-1.38 (2H, m), 1.63-1.80 (6H, m), 1.82 (3H, s), 1.89 (3H, s), 2.13-2.24 (4H, m), 2.65 (2H, t, J=8.0Hz), 5.69 (2H, s), 7.09-7.15 (2H, m), 7.24-7.36 (3H, m) EXAMPLE 2 Synthesis of 2-n-butyl-5,8-dimethyl-5,8-ethano-5,6,7,8-tetrahydro-lH-1,3,4a,8a-tetraaza-cyclope, .l AnAl hll~AIPnP4~9-dione r~pl~sell~ed by the formula:
o CH3 H3C ~<~ 3~N~3 1-Benzyl-2-n-butyl-5,8-dimethyl-5,8-ethano-5,6,7,8-letlal1ydlu-1H-1,3,4a,8a-tetraaza-cyclope,~ Al l~ AlPnP-4,9-dione (53 g, 0.13 mol) was dissolved in a mixed solvent of mPthAn (300 ml) and methylene chloride (80ml). 20% palladium hydroxide (cont~inin~ 50% water, 10 g) was added to this solution, and the mixture was stirred at 3 normal atmospheres at room 20 temperature for 4 hours under hydrogen atmosphere. The catalyst was filtered off, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in a mixed solvent of ethanol and toluene, and the solvent was distilled off under reduced pressure. These procedures were repeated three times to give the titled colllpoulld (41.1 g, 100%) as colorless solid. The titled cc~lllpoulld has the following NMR spectrum.
lH-NMR (CDC13+CD30D) oppm: 0.97 (3H, t, J=7.2Hz), 1.34-1.49 (2H, m), 1.80-1.94 (6H, m), 1.86 (6H, s), 2.10-2.21 (4H, m), 3.17 (2H, t, J=7.4Hz) ~ffects of the Invention According to the present invention, there is provided a process for selectively reducing the C ring double bond of an imidazole derivative having the hyd~ille cross-linking structure 30 and, thereby, there becomes possible the production of the useful imidazole derivative in high yield even in the mass production and without complic~tPd p~lrific~tion steps.
~ Tr (5) In addition, it is thought that there is the possibility that the formation of 7~-allyl-25 palladium complex participates in this side reaction. However, the similar side reaction is also observed when platinum oxide and p~ m carbon are used in place of p~ rlillm hydroxide.
Therefore, the detailed meçh~ni~m is not known. And it was found that this side reaction rarely occurs in the case of Lindlar catalyst. However, in the case of this catalyst, the desired reaction does not proceed in some cases, probably due to the impurities cont~in~.d in the raw materials ~0 upon mass production, and there is a problem with reprocl~-ct;~ility.
~4 -WO 94/21641 215 ~ 5 7 3 PCT/US94/01949 INFORMATION DISCLOSI~RE
The prior route to the synthesis of the compounds produced by the process of this invention is described in WO 93/08193.
' SUMMARY OF THE INVENTION
5 The Problems to be Solved by the Invention The object of the present invention is to improve the selectivity on the reduction of C
ring double bond of the above imidazole derivative in order to achieve the high yield even in mass production and exclude the necessity of cl mplic~t~d purific~tion steps.
The Means to Solve the Problems In order to solve the above problems, the present inventors have studied intensively and, as a result, found that C ring double bond can be reduced selectively without the C ring cleavage reaction.
That is, the present invention provides a process for producing an imidazole derivative represented by the formula (II):
wherein R R1 R2 R3 R4 R5 R13, R14, R15, R16, R17 and R18 are as defined below. or a pharmacologically acceptable ester or salt thereof which compri~es reacting a compound represented by the formula (I):
\ /R13 R16 wherein R1 is hydrogen atom, lower alkyl group, lower alkoxy group, lower alkylthio group, lower alkylamino group, lower alkenyl group, -CF3 group, aryl group or aralkyl group;
R is hydrogen atom, or a group selected from the group co~ li"g of 215S~73 ~` ~
WO 94/21641 ~ PCT/US94/01949 --CH2 ~ --Ct 12 ~ --CH2 ~3 wherein X is -CH2-, -NR'-, oxygen atom or ~S(O)n~~ wherein R' is hydrogen atom or lower alkyl group, wherein n is 0, 1 or 2;
- wherein X1, x2 and X3 are independently hydrogen atom, halogen atom. Iower alkyl group, lower alkoxy group, nitro group, cyano group, lH-tetræol-5-yl group or alk~li metal salt 10 thereof, -Co2R7 group, -CONR'R" group, -CONHS02R8 group, amino group, -NHSO2CF3 group or -S03H group, or a group selected from the group con~ ing of Co2R7 R10 --NH--C ~--NH--C--CH--NH--C--R6 --N~( Y Y
Co2R7 R10 --O--CH~R11 Y is lH-tetrazol-5-yl group or alkali metal salt thereof optionally ~.ubslilllled with cyano group, benzyl group, tosyl group, methoxymethyl group, ethoxymethyl group, methoxyethoxymethyl group or trirnethylsilylethoxymethyl group, -Co2R7 group, -CONR'R"
group, -CONHSO2R8 group, amino group, -NHSO2CF3 group or -S03H group;
R2, R3, R4 and R5 are independently hydrogen atom or lower alkyl group, or R2 and R3, or R4 and R5 are taken together to form =O bond;
R6 is hydrogen atom, halogen atom, lower alkyl group, -CF3 group or -CF2CF3 group;
R7 is hydrogen atom, alkali metal atom or lower a~kyl group; ,, R' and R" are independently hydrogen atom or lower alkyl group, or R' and R" aretaken together to form the alicyclic structure; !, R8 is lower alkyl group, cycloalkyl group or aryl group;
R9 is lower ~lkyl group, lower alkoxy group, cycloalkyl group, cycloalkoxy group, aryl ~5 group or aryloxy group;
R10, R11 and R12 are independently hydrogen atom, halogen atom, lower a'kyl group, ~ 2~573 lower alkoxy group, nitro group, cyano group, -Co2R7 group or -CONR'R" group;
R13, R14, R15, R16, R17 and R18 are independently hydrogen atom, lower alkyl group, lower fluoroalkyl group, -C(R')iR")-oR19 group, -(CH2)j-Co2R7 group, -(CH2)j-CN group, -(CH2)j-C(=O)R' group, -(CH2)j-CONR'R'I group or -(CH2)j-Aryl group, wherein j is 0, 1 or 2, 5 wherein R16 and R18 may be taken together to form -(CH2)i- group, wherein i is 1, 2 or 3, wherein Aryl is phenyl group, pyridyl group, pyrimidyl group, pyridazinyl group, furyl group, thenyl group, pyrazolyl group, oxazolyl group, thiazolyl group, oxadiazolyl group or isooxazolyl group optionally ~ubsliillled with halogen atom, lower alkyl group, hydroxy group, lower alkoxy group, nitro group or cyano group;
R19 is hydrogen atom, or lower alkyl group optionally ~ul ~ llPd with hydroxy group or ether group, with a diimide (HN=NH).
First, variable substituents used in the general formula of the compounds herein are expl~inP,I
As the lower alkyl group represented by Rl, there are the alkyls having 1 to 8 carbon 15 atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isoamyl, n-hexyl, n-heptyl, n-octyl and the like. As the lower alkoxy group represented by R1, there are methoxy, ethoxy, n-p~upo~y, isop.ul)o~y~ n-butoxy, isob,llo~y, t-butoxy, n-pentoxy, isoamyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy and the like. As the lower alkylthio group ,~p,~se~led by R1, there are methylthio, ethylthio, n-p,ul~ylLllio, isuulupyllllio, n-butylthio, n-20 pentylthio, n-hexylthio, n-he~Lylil~io, n-octylthio and the like. As the lower alkylamino group re~ ;sel,led by Rl, there are methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino, di(n-propyl)amino, isol,lu~ylamino, n-butylamino, n-pentylamino, pyrrolidino, piperidino, ~ip~ o, morpholino and the like. As the lower alkenyl group represented by R1, there are vinyl, I-~lupt;llyl, 2-~lu~tillyl, 2-methyl-1-~,upenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 25 2-pellienyl, I-hexenyl, I-heptenyl, I-octenyl and the like. As the lower alkynyl group ,t;p,~sellled by Rl, there are acetylene group, l-pluL~yllyl, 2-Llrul~yllyl, l-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, l-heptynyl, l-octynyl and the like. As the aryl group or aralkyl group It;~ulcswlled by Rl, there are aryl or aralkyl group having 6 to 10 carbon atoms, for example, phenyl, naphthyl, benzyl, phenethyl, 3-phellyllJIul)yl, 4-phenylbutyl and the like.
30 These aryl and aralkyl groups are optionally ~ub~ llPd with the sllbstitlle.nt(s) such as the above described lower alkyl group, or lower alkoxy group, halogen atom, nitro group, cyano group and the like.
When R is substill~tPd or Im~ubslil"led ph~llylmethyl group, as the halogen atom defined hy X1, x2 and X3, there are fluorine atom, chlorine atom, bromine atom and iodine atom. As 35 the lower alkyl group and lower alkoxy group, there are above defined lower alkyl group and alkoxy group. When X1, x2 and X3 are lH-tetrazol-5-yl group, as the alkali metal salt thereof, 21~5~7~ ~
~ . .. .
there are sodium salt, potassium salt and the like. When Xl, x2 and X3 are -Co2R7 group, as the examples of R7 in the group, there are hydrogen atom, alkali metal atom such as lithium, sodium, potassium and the like, alcohol ester of the above defined lower alkyl group. When X1, x2 and X3 are -CONR'R", the examples of -NR'R" in the group, there are amino, r 5 methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino, di(n-propyl)amino;
dii~uplupylamino, dibutylamino, pyrrolidyl, pi~ uillO, morpholino and the like. As the examples of R8 in -CONHSO2R8 group, there are methyl, trifluoromethyl, ethyl, n-propyl, n-butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl, phenyl and the like. When X1, x2 and X3 are the group selected from the following:
Co2R7 R11 --NH--C ~ --NH--C--CH--NH--C--R6 --N~
Y Y
Co2R7 R10 --O--1H 4~
~=J R11 , Y and R7 are the same as defined above. The lower alkyl group and lower alkoxy group represented by R9 are as defined above. When R9 is cycloalkyl group or cycloalkoxy group, the examples are 5 to 7 membered cyclic compounds such as cyclopentyl, cyclohexyl, cyclopentyl and the like. As the e~mples of aryl group or aryloxy group represented by R9, 25 there are substit lt~d or ~ d phenyl coll-puunds such as phenyl, p-hydroxyphenyl, p-carboxyphenyl, o-ll-lluph~llyl and the like. The examples of lower alkyl group, lower alkoxy group, -Co2R7 group or -CONR'R" group represented by RlU, Rll or R12 are as defined above. When R is s~lbstit--t~d biphenylmethyl group, as the examples of the aLkali metal salt of substituent lH-tetrazol-5-yl, there are sodium salt, pol~iulll salt and the like. When Y is -30 Co2R7 group, -CONR'R" group or -CONHS02R8 grûup~ the e~mp'~s ûf R7, -NR'R" and R8 in the groups are as defined above. When R is represented by the following formula:
--CH2~R6 X
Y~
2~5~7~
, the example of halogen and lower alkyl group l~pl~s~ ed by R6, the examples of alkali metal salts of lH-tetrazol-5-yl represented by Y, and the examples of R7, NR'R" and R8 in -Co2R7 group, -CONR'R" group or -CONHSO2R8 group represented by Y are as defined above.When R2, R3, R4 and R5 are lower alkyl group, the examples of them are the alkylgroups having 1 to 8 carbon atoms, for ~x~mple, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isoamyl, n-hexyl, n-heptyl, n-octyl and the like.
When R13, R14, R15, R16, R17 and R18 are lower alkyl group, the example of them are the alkyls having 1 to 8 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isoamyl, n-hexyl, n-heptyl, n-octyl and the like. When R13, R14, R15, R16, R17 and R18 are lower fluoroalkyl group, the examples of them are trifluoromethyl, 2,2,2,-trifluoroethyl, pentafluoroethyl and the like. When R13 R14 R15 R16 R17 and R18 are -(CH2)j-Co2R7, -(CH2)j-C(=O)R', -C(R')(R")-OR19, or -(CH2)j-CONR'R", the examples of R7, R' and R" are as defined above.
The diimide used in the process of the present invention can be generated by various methorl~, for e~mrle, by oxid~tinn of hyd,a~u,e, decomposition of the dipotassium salt of azodicarboxylic acid by an acid, the decomposition of arylsulLol,yd,~ide by a base, the hydroxylamine-acetic acid ester method, and the like (Organic Reactions, 40, 91-155 (1991)).
Among them, the use of deco",po~ilion of p-tohlen~slllfohydrazide by sodium acetate is suitable in view of ~implirity of the operations and high safety.
The reaction between the diimide and the colllLJuulld of the general formula (I) proceeds effectively at room ~ ...e to 120 C. The reaction is carried out in a solvent. As the solvent, there are the alcoholic solvents such as methanol, ethanol, propanol and the like, and the etheric solvent such as lel~ ydlorul~l, dimetho~yt;~ le and the like. When p-toluenesulfohydrazide is used to generate the diimide, it is desirable to react the diimide and the 25 compound of the formula (I) while g~,le,~illg the diimide in ~nu~illg dimethoxyethane.
According to the previous process, 10 to 60 % of ring opened products are produced as side products. However, the above described reaction affords ~lu~ ely a product having the reduced C ring double bond without side products.
In addition, when R is a protecting group such as benzyl group and the like, after 30 reduction of C ring double bond according to the present method, the reduced product is reacted in methanol in the presence of the catalytic amount of 20 % p~ m hydroxide-carbon under 1 to 3 atmospheric l"~s~u~e hydrogen by a conventional method to easily effect the deprotection such as debenzylation and the like. Therefore, a process of the present invention is also useful for ~ ;paling an intermediate (4) for ~yllllle~is (see the above Reaction Scheme). Further, the 35 end imidazole derivative (5) can be obtained as crystals almost without side products by ching the biphenyltetrazole part to the interm~ te according to the method described in JP-21~S~73 A 3-277537, JP-A 3-323474, JP-A 4-095191 and JP-A 4-216809 and WO 93/08193 (see the above Reaction Scheme). Thereby, the purification by column chromatography which was indispensable to the previous process becomes llnnPcec~ry, and it was found that the present process can be applied to the mass production in the good reproductivity.
S If desired, the co"ll,uu"ds produced by the present process can be converted into the ester or salt thereof by a conventional method. The esters or salts are pharmacologically acceptable and non-toxic ones. Suitable esters include esters of lower alcohol having a straight or branched chain such as methanol, ethanol and the like. Suitable salts include alkali metal salts such as sodium salt, puLas~iulll salt and the like, and alkaline earth metal salts, hydrogen halide salts such as hydrogen fluoride, hydrogen chloride and the like, inorganic acid salts such as nitrate, sulfate and the like, lower alkylsulfonate salts such as meth~npslllfonate and the like, organic acid salts such as maleate, fumarate and the like, and amino acid salts such as aspartate and the like.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following F.Y:lmplP~s further illustrate the present invention in detail.
EXAMPLE 1 Synthesis of 1-benzyl-2-n-butyl-5,8-dimethyl-5,8-ethano-5,6,7,8-tetrahydro-lH-1,3,4a,8a-tetraæa-cyclop~ lPnP4,9-dione lc;~ s~llted by the formula:
o CH3 H3C ~/ ~N~
1-Benzyl-2-n-butyl-5,8-dimethyl-5,8-ethano-5,8-dihydro-lH-1,3,4a,8a-tetraaza-cyclopent~n~rhth~lene-4,9-dione (58 g, 0.14 mol) and p-toluPnPslllfonylhydrazide (187 g, 1.0 mol) were dissolved in dimethoxyethane (400 ml), and the mixture was heated to reflux. An aqueous solution (400 ml) of sodium acetate (165 g, 2.0 mol) was added dropwise to this 30 solution over 4 hours. The mixture was cooled to room lelllpel~Lule, further cooled to 0 C, and the precipit~tPd crystals were filtered. The crystals were dissolved in methylene chloride, washed with water and brine, dried over ~ulhydluu~ sodium sulfate, and the solvent was distilled off under reduced pressure. The residue combined with another residue (l-benzyl-2-n-butyl-5,8-dimethyl-5,8-ethano-5,8-dihydro-1H-1,3,4a,8a-tetraaza-cyclop~ lprup4~8-dione~ 56.5 g) ~5 obtained by the similar procedures was purified by silica gel column chromatography (acetone:
hex~ne: methylene chloride=5:1:40) for the purpose of removing the impurities derived from the 215~57~
WO 94t21641 PCTIUS94101949 g reagents to give the titled compound (105 g, 91%) as colorless solid. In this reduction of the diimide, only the titled co~ )ou-ld can be obtained as a sole product and no side products which were produced in the reduction by palladium hydroxide were recognized. The titled compound has the following NMR spectrum.
S lH-NMR (CDC13) ~ppm: 0.84 (3H, t, J=7.3Hz), 1.25-1.38 (2H, m), 1.63-1.80 (6H, m), 1.82 (3H, s), 1.89 (3H, s), 2.13-2.24 (4H, m), 2.65 (2H, t, J=8.0Hz), 5.69 (2H, s), 7.09-7.15 (2H, m), 7.24-7.36 (3H, m) EXAMPLE 2 Synthesis of 2-n-butyl-5,8-dimethyl-5,8-ethano-5,6,7,8-tetrahydro-lH-1,3,4a,8a-tetraaza-cyclope, .l AnAl hll~AIPnP4~9-dione r~pl~sell~ed by the formula:
o CH3 H3C ~<~ 3~N~3 1-Benzyl-2-n-butyl-5,8-dimethyl-5,8-ethano-5,6,7,8-letlal1ydlu-1H-1,3,4a,8a-tetraaza-cyclope,~ Al l~ AlPnP-4,9-dione (53 g, 0.13 mol) was dissolved in a mixed solvent of mPthAn (300 ml) and methylene chloride (80ml). 20% palladium hydroxide (cont~inin~ 50% water, 10 g) was added to this solution, and the mixture was stirred at 3 normal atmospheres at room 20 temperature for 4 hours under hydrogen atmosphere. The catalyst was filtered off, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in a mixed solvent of ethanol and toluene, and the solvent was distilled off under reduced pressure. These procedures were repeated three times to give the titled colllpoulld (41.1 g, 100%) as colorless solid. The titled cc~lllpoulld has the following NMR spectrum.
lH-NMR (CDC13+CD30D) oppm: 0.97 (3H, t, J=7.2Hz), 1.34-1.49 (2H, m), 1.80-1.94 (6H, m), 1.86 (6H, s), 2.10-2.21 (4H, m), 3.17 (2H, t, J=7.4Hz) ~ffects of the Invention According to the present invention, there is provided a process for selectively reducing the C ring double bond of an imidazole derivative having the hyd~ille cross-linking structure 30 and, thereby, there becomes possible the production of the useful imidazole derivative in high yield even in the mass production and without complic~tPd p~lrific~tion steps.
Claims (3)
1. A process for producing an imidazole derivative represented by the formula:
wherein R R1 R2 R3 R4 R5 R13 R14, R15, R16, R17 and R18 are as defined below, or a pharmacologically acceptable ester or salt thereof which comprises reacting a compound represented by the formula:
wherein R1 is hydrogen atom, lower alkyl group, lower alkoxy group, lower alkylthio group, lower alkylamino group, lower alkenyl group, -CF3 group, aryl group or aralkyl group;
R is hydrogen atom, or a group selected from the group consisting of wherein X is -CH2-, -NR'-, oxygen atom or -S(O)n-, wherein R' is hydrogen atom or lower alkyl group, wherein n is 0, 1 or 2;
wherein X1, x2 and X3 are independently hydrogen atom, halogen atom, lower alkylgroup, lower alkoxy group, nitro group, cyano group, 1H-tetrazol-5-yl group or alkali metal salt thereof, -CO2R7 group, -CONR'R" group, -CONHSO2R8 group, amino group, -NHSO2CF3 group or -SO3H group, or a group selected from the group consisting of wherein Y is 1H-tetrazol-5-yl group or alkali metal salt thereof optionally substituted with cyano group, benzyl group, tosyl group, methoxymethyl group, ethoxymethyl group, methoxyethoxymethyl group or trimethylsilylethoxymethyl group, -CO2R7 group, -CONR'R" group, -CONHSO2R8 group, amino group, -NHSO2CF3 group or-SO3H group;
R2, R3, R4 and R5 are independently hydrogen atom or lower alkyl group, or R2 and R3, or R4 and R5 are taken together to form =O bond;
R6 is hydrogen atom, halogen atom, lower alkyl group, -CF3 group or -CF2CF3 group;
R7 is hydrogen atom, alkali metal atom or lower alkyl group;
R' and R" are independently hydrogen atom or lower alkyl group, or R' and R" aretaken together to form the alicyclic structure;
R8 is lower alkyl group, cycloalkyl group or aryl group;
R9 is lower alkyl group, lower alkoxy group, cycloalkyl group, cycloalkoxy group, aryl group or aryloxy group;
R10, R11 and R12 are independently hydrogen atom, halogen atom, lower alkyl group, lower alkoxy group, nitro group, cyano group, -CO2R7 group or -CONR'R" group;
R13,R14,R15,R16 R17 and R18 are independently hydrogen atom, lower alkyl group, lower fluoroalkyl group, -C(R')(R")-OR19 group, -(CH2)j-CO2R7 group, -(CH2)j-CN group, -(CH2)j-C(=O)R' group, -(CH2)j-CONR'R" group or -(CH2)j-Aryl group, wherein j is 0, 1 or 2, wherein R16 and R18 may be taken together to form -(CH2)i- group, wherein i is 1, 2 or 3, wherein Aryl is phenyl group, pyridyl group, pyrimidyl group, pyridazinyl group, furyl group, thenyl group, pyrazolyl group, oxazolyl group, thiazolyl group, oxadiazolyl group or isooxazolyl group optionally substituted with halogen atom, lower alkyl group, hydroxy group, lower alkoxy group, nitro group or cyano group;
R19 is hydrogen atom, or lower alkyl group optionally substituted with hydroxy group or ether group, with a diimide (HN=NH).
wherein R R1 R2 R3 R4 R5 R13 R14, R15, R16, R17 and R18 are as defined below, or a pharmacologically acceptable ester or salt thereof which comprises reacting a compound represented by the formula:
wherein R1 is hydrogen atom, lower alkyl group, lower alkoxy group, lower alkylthio group, lower alkylamino group, lower alkenyl group, -CF3 group, aryl group or aralkyl group;
R is hydrogen atom, or a group selected from the group consisting of wherein X is -CH2-, -NR'-, oxygen atom or -S(O)n-, wherein R' is hydrogen atom or lower alkyl group, wherein n is 0, 1 or 2;
wherein X1, x2 and X3 are independently hydrogen atom, halogen atom, lower alkylgroup, lower alkoxy group, nitro group, cyano group, 1H-tetrazol-5-yl group or alkali metal salt thereof, -CO2R7 group, -CONR'R" group, -CONHSO2R8 group, amino group, -NHSO2CF3 group or -SO3H group, or a group selected from the group consisting of wherein Y is 1H-tetrazol-5-yl group or alkali metal salt thereof optionally substituted with cyano group, benzyl group, tosyl group, methoxymethyl group, ethoxymethyl group, methoxyethoxymethyl group or trimethylsilylethoxymethyl group, -CO2R7 group, -CONR'R" group, -CONHSO2R8 group, amino group, -NHSO2CF3 group or-SO3H group;
R2, R3, R4 and R5 are independently hydrogen atom or lower alkyl group, or R2 and R3, or R4 and R5 are taken together to form =O bond;
R6 is hydrogen atom, halogen atom, lower alkyl group, -CF3 group or -CF2CF3 group;
R7 is hydrogen atom, alkali metal atom or lower alkyl group;
R' and R" are independently hydrogen atom or lower alkyl group, or R' and R" aretaken together to form the alicyclic structure;
R8 is lower alkyl group, cycloalkyl group or aryl group;
R9 is lower alkyl group, lower alkoxy group, cycloalkyl group, cycloalkoxy group, aryl group or aryloxy group;
R10, R11 and R12 are independently hydrogen atom, halogen atom, lower alkyl group, lower alkoxy group, nitro group, cyano group, -CO2R7 group or -CONR'R" group;
R13,R14,R15,R16 R17 and R18 are independently hydrogen atom, lower alkyl group, lower fluoroalkyl group, -C(R')(R")-OR19 group, -(CH2)j-CO2R7 group, -(CH2)j-CN group, -(CH2)j-C(=O)R' group, -(CH2)j-CONR'R" group or -(CH2)j-Aryl group, wherein j is 0, 1 or 2, wherein R16 and R18 may be taken together to form -(CH2)i- group, wherein i is 1, 2 or 3, wherein Aryl is phenyl group, pyridyl group, pyrimidyl group, pyridazinyl group, furyl group, thenyl group, pyrazolyl group, oxazolyl group, thiazolyl group, oxadiazolyl group or isooxazolyl group optionally substituted with halogen atom, lower alkyl group, hydroxy group, lower alkoxy group, nitro group or cyano group;
R19 is hydrogen atom, or lower alkyl group optionally substituted with hydroxy group or ether group, with a diimide (HN=NH).
2. A process for producing an imidazole derivative represented by the formula:
wherein R1, R2, R3, R4, R5, R13 and R17 are as deflned above, or a pharmacologically acceptable ester or salt thereof which comprises reacting a compound represented by the formula:
wherein R1, R2, R3, R4, R5, R13 and R17 are as defined above, with a diimide (HN=NH), the subjecting the product to hydrogenolysis.
wherein R1, R2, R3, R4, R5, R13 and R17 are as deflned above, or a pharmacologically acceptable ester or salt thereof which comprises reacting a compound represented by the formula:
wherein R1, R2, R3, R4, R5, R13 and R17 are as defined above, with a diimide (HN=NH), the subjecting the product to hydrogenolysis.
3. A process for producing an imidazole derivative represented by the formula:
wherein R1, R2, R3, R4, R5, R13, R17 and Y are as defined above, or a pharmacologically acceptable ester or salt thereof which comprises reacting a compound represented by the formula:
wherein R1, R2, R3, R4, R5, R13, R17 and Y are as defined above, with a diimide (HN=NH).
wherein R1, R2, R3, R4, R5, R13, R17 and Y are as defined above, or a pharmacologically acceptable ester or salt thereof which comprises reacting a compound represented by the formula:
wherein R1, R2, R3, R4, R5, R13, R17 and Y are as defined above, with a diimide (HN=NH).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60067/1993 | 1993-03-19 | ||
| JP5060067A JPH06271576A (en) | 1993-03-19 | 1993-03-19 | Manufacturing of imidazole derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2155573A1 true CA2155573A1 (en) | 1994-09-29 |
Family
ID=13131379
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002155573A Abandoned CA2155573A1 (en) | 1993-03-19 | 1994-03-04 | Process for production of an imidazole derivative |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0689544A1 (en) |
| JP (2) | JPH06271576A (en) |
| CN (1) | CN1120337A (en) |
| AU (1) | AU6351994A (en) |
| CA (1) | CA2155573A1 (en) |
| NZ (1) | NZ263008A (en) |
| WO (1) | WO1994021641A1 (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE146474T1 (en) * | 1991-09-10 | 1997-01-15 | Tanabe Seiyaku Co | IMIDAZOINDOLIZINE DERIVATIVES WITH ANGIOTENSIN-II INHIBITING EFFECT |
| JPH06107661A (en) * | 1991-10-24 | 1994-04-19 | Upjohn Co:The | Imidazole derivative and medicinal composition having same as effective component |
-
1993
- 1993-03-19 JP JP5060067A patent/JPH06271576A/en active Pending
-
1994
- 1994-03-04 CA CA002155573A patent/CA2155573A1/en not_active Abandoned
- 1994-03-04 CN CN94191674A patent/CN1120337A/en active Pending
- 1994-03-04 EP EP94910736A patent/EP0689544A1/en not_active Withdrawn
- 1994-03-04 JP JP6521039A patent/JPH08508468A/en active Pending
- 1994-03-04 NZ NZ263008A patent/NZ263008A/en unknown
- 1994-03-04 WO PCT/US1994/001949 patent/WO1994021641A1/en not_active Application Discontinuation
- 1994-03-04 AU AU63519/94A patent/AU6351994A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| JPH08508468A (en) | 1996-09-10 |
| CN1120337A (en) | 1996-04-10 |
| WO1994021641A1 (en) | 1994-09-29 |
| AU6351994A (en) | 1994-10-11 |
| JPH06271576A (en) | 1994-09-27 |
| NZ263008A (en) | 1996-12-20 |
| EP0689544A1 (en) | 1996-01-03 |
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