IE45035B1 - Process for preparing 4-substituted imidazole compounds - Google Patents

Process for preparing 4-substituted imidazole compounds

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Publication number
IE45035B1
IE45035B1 IE839/77A IE83977A IE45035B1 IE 45035 B1 IE45035 B1 IE 45035B1 IE 839/77 A IE839/77 A IE 839/77A IE 83977 A IE83977 A IE 83977A IE 45035 B1 IE45035 B1 IE 45035B1
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Ireland
Prior art keywords
process according
formula
compound
hydrogen
methyl
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IE839/77A
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IE45035L (en
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Smithkline Corp
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Priority claimed from US05/771,044 external-priority patent/US4119781A/en
Application filed by Smithkline Corp filed Critical Smithkline Corp
Publication of IE45035L publication Critical patent/IE45035L/en
Publication of IE45035B1 publication Critical patent/IE45035B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/84—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The imidazole compounds of the general formula II represent valuable intermediates for preparing pharmacologically active compounds. They are obtained by reacting a compound of the formula I in an organic solvent under basic conditions with a compound of formula R<2>-H. The symbols used in the general formulae I and II are defined in Claim 1.

Description

This invention relates to a process for preparing substituted imidazole compounds which are useful intermediates in the preparation of compounds having pharmacological activity.
According to the present invention there is provided a process for 5 ' preparing a compound of the formula: (where R is hydrogen or lower alkyl; is NCN -sch2ch2nhc TO nhch3 fi 7 fi 7 or -NR R (where R and R are each hydrogen, lower alkyl or together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine or q morpholine ring); and R is hydrogen, lower alkyl, trifluoromethyl, benzyl, amino or -SR^ (where R4 is lower alkyl, phenyl, benzyl or chlorobenzyl) which comprises reacting a compound of the formula: - 2 «3035 CH2P(Ra)3 II 13· 6 (where R and R are as hereinbefore defined; R“ is lower alkyl or phenyl; 2 and X is halo) with a compound of the formula R -H (where R is as hereinbefore defined) under basic conditions.
When R2 3 is -SR4,, R4 is preferably methyl, R5 is preferably phenyl, and X is preferably chloro or bromo, is preferably -sch2ch2nhc NHOH, The starting materials of formula II and a process for their preparation are described in Patent Specification No. 443S5. Certain compounds of formula I are described and claimed in Patent Specification No. 38353.
As used herein, the term lower alkyl refers to groups containing from one to four carbon atoms.
Displacement of the trisubstituted phosphonium group Γ -P(R V of a compound of formula II is effected by reaction of a compound of formula II 2 2P with R H under basic conditions, that is with R H in the form of its anion R .
The anion can be formed in situ by reacting a compound of the formula R H with a strong base. Among the bases which can be used in the process of this invention are those which are capable of removing the proton from a compound of the 2 2S 2 formula R H to form the anion R where R is defined as above. Such bases are those having a pKa greater than 12, for example the alkali meta- alkoxides, such as sodium methoxide or ethoxide, or the metal hydrides such as sodium hydride which ? are preferred. When R H is itself sufficiently basic, for example when R H is 43O3S piperidine, no additional base need be used. In those cases where R H is extremely volatile, such as when R2 is -NrV and one or both of R3 and R? are hydrogen, it is preferable that R H be in the form of a metalate, for example a sodium or lithium metalate, such as sodium amide. Preferably, a slight excess I f of R H is present.
The reaction’will' usually be carried out in an organic solvent with solvents such as methanol ethanol, propanol, butanol, acetone, acetonitrile, dimethylformamide and dimethylsulfoxide being preferred. Preferably, the reaction is carried out at a temperature ranging from about ambient temperature to the reflux temperature of the solvent used in the reaction, viz. from 25°C to 200°C, 55°C to 100°C being advantageous, for from 20 minutes to 24 hours, advantageously from 20 minutes to 3 hours.
Preferably, the reaction mixture is worked up by dilution with water and removal of the trialkyl- or triphenylphosphine by-product by filtration. Extraction of the filtrate when necessary followed by evaporation gives the compounds of formula I. It is often desirable to convert the compounds of formula I into their corresponding salts, preferably hydrochloride salts. Such salts can be prepared by treating a solution of an imidazole of formula I with ah acid or acid solution, for example with an ethereal or ethanolic solutioh of hydrochloric acid, and crystallizing the salt produced from an appropriate solvent.
The 4-(trisubstituted phosphonium)-methylimidazoles of formula II can be prepared by reacting a trisubstituted A-acylvinylphosphonium halide, preferably bromide or chloride, of the formula ' 0 (r5)3p —-r1 X θ where R , R and X are defined as above with an amidine of the formula R3 HgN^^NH where R is defined as above and is other than hydrogen, according to the procedure described by Zbiral, Synthesis 11:775 (1974) and Zbiral and Hugl, Phosphorus 2:29 (1972). When R is hydrogen, the corresponding 4-(trisubstituted phosphonium)methylimidazoles of formula II can be prepared by reaction of - 4 ¢3033 tri chioroacetamidine or formamidine sulfinic acid with a tri phenyl β -acylvinylphosphonium halide. In the formamidine sulf.inic acid process, a base is used, preferably a non-nucleophilic base such as a tertiary amine.
To prepare the trisubstituted β -acylvinylphosphonium halides not known to the art, a halovinyl alkyl ketone such as chlorovinyl metal ketone can be reacted with a trialkyl or triphenylphosphine. When R1 is hydrogen, the trisubstituted β -formylvinylphosphonium halides can be prepared by oxidation of a β -haloalkyl alcohol such as β -chloroallyl alcohol and reaction of the product thus formed with a trialkyl- or triphenylphosphine.
The process of this invention provides an inexpensive, efficient and high yield method for preparing certain imidazoles useful as intermediates in the preparation of pharmacologically active compounds. A further advantage of this process for the conversion of compounds of formula II into those of formula I is that tne trisubstituted phosphines, P(R )^, formed during the course of the reaction can be easily removed from the reaction mixture and recycled or Otherwise reused.
Histamine Hg-antagonists N-cyano-N'methyl-N”-/__2-(5-R1-imidazolyl0 methylthio)ethyl7guanidines are prepared by the present invention when R is NCN SCKgCHgNHC 'NHCH, and R is hydrogen.
However, these compounds and other Hg-antagonists, for example N-methyl-N'-7_2-(5-R1-imidazolylmethylthio)ethy27thiourea compounds can be prepared from compounds of formula I. Histamine Hg-antagonists act as histamine Hg-receptors which, as described by Black et.al_. /Nature 236:385 (1972)_7, are defined as those histamine receptors which are not blocked by “antihistamines such as mepyramine but are blocked by burimamide. Blockade - 5 ¢3033 of histamine H2~receptors is of utility in inhibiting the biological actions of histamine which are not inhibited by antihistamines. Histamine H,,-antagonists are useful, for example, as inhibitors of gastric acid secretion.
Conversion of the compounds of formula I into pharmacologically active guanidine and thiourea products can be accomplished in a variety of ways. When R2 is NCN -sch2ch2nhc NHCHand R is hydrogen, lower alkyl, trifluoromethyl, benzyl or amino, guanidines are prepared directly by the process of this invention.
When R2 is NCN -sch2ch2nhc 'NHCHj and R3 is -SR^, the compounds of formula I produced can be reduced with a suitable reducing agent to give a guanidine product where R is hydrogen.
When R2 is -NR6R7 and R3 is -SR4 (where R4 is as defined above), the -SR4 group of the compounds of formula I can be removed as described above and the products thus formed can then be treated with cysteamine to give 4-(23 aminoethylJthiomethylimidazole compounds where R is hydrogen. These can then be reacted with methyl isothiocyanate to give the corresponding N-methyl-N’-ZZ(5-R^-imidazol-4-y1methylthio)ethyl7thioureas. Reaction of the same 4-(2aminomethyl)thiomethylimidazole compounds with N-cyano-N',S-dimethylisothiourea gives the corresponding N-cyano-N'-methyl-N-Z2-(5-R1-imidazol-4-ylmethylthfto) ethyl7-guanidines. The guanidine products can also be prepared by reacting the 4-(2-aminoethyl)-thiomethylimidazole with dimethyl-N-cyano-imidodithiocarbonate, and subsequently reacting the resulting N-cyano-N'-Z2-(5-R1-imidazol-4-ylmethylthio)ethyT7-S-methylisothiourea with methylamine. 6 7 3 When R is -NR R and R is hydrogen, the compounds of formula I can be reacted with cysteamine to give the 4-(2-aminoethy1)-thiomethylimidazo1es which can then be converted into guanidine and thiourea products as previously described.
Thioureas and cyanoguanidines prepared from the compounds of formula I are described tin U.S. Patent Specifications Nos. 3,950,333 and 3,950,353. - 6 <5 3 Ο 3 s The following Examples are given by way of illustration. Temperatures are in degrees Centigrade (°C) unless otherwise indicated.
EXAMPLE 1. (a) Trichloroacetamidine (1.62 g., 0.1 mole) was dissolved in 20 ml. of 5 dry dimethylsulfoxide, and 4.1 g. (0.1 mole) of triphenyl fi -acetylvinylphosphonium bromide in 40 ml. of dimethylsulfoxide were added in one portion with stirring. The exothermic reaction mixture gradually - 7 - 45Ο 3 ' • the mixture lightened in coloq and/was heated at 100 for 10 minutes.
Evaporation of the solvent gave [(5-methylimidazolyl)-4methyl]triphenylphosphonium bromide.
Alternatively, and preferably, the phosphonium 5 bromide is prepared using trichloroacetamidine by the following procedure^: Triphenyl β-acetylvinylphosphonium bromide (8.0 g., 0.019 mole) was dissolved in a minimum amount of dry acetonitrile (about 100 ml.) and trichloroacetamidine (4.0 g., 0.025 mole) was added in one portion. The resulting mixture was stirred at room temperature and the material which crystallized out was filtered off to give [(2-trichloromethyl5-methylimidazolyl)-4-methyl]triphenylphosphonium bromide.
This phosphonium salt (15.0 g., 0.027 mole) was added to 150 ml. of methanol and the resulting mixture was -.,refluxed for three hours. The mixture was concentrated to about 15 ml. and the solid material was filtered off to give [(2-methoxycarbonyl-5-methylimidazolyl)-4-methyl]triphenylphosphonium bromide.
The above prepared phosphonium salt is heated to o its melting point (approximately 170 ) and held at this temperature until the evolution of gas is complete. On cooling, the solid product is triturated with chloroform to - give ((5-methylimidazoiyl)-4-methyl]triphenylphosphonium bromide. ?5 Triphenyl β-acetylvinylphosphonium chloride (36 g., mole) and trichloroacetamidine (16.1 g., 0.1 mole) were stirred in 200 ml. of methanol for one hour. The solution s was was heated to reflux, cooled and the methanol/evaporated to leave [(2-methoxycarbonyl-5-methylimidazolyl)-4-methyl]30 -8triphenylphosphonium chloride. Heating this phosphonium chloride salt at 170° until evolution of gas is complete, and then cooling and triturating with chloroform gives ((5-methylimidazolyl)-4-methyl]triphenylphosphonium chloride. (b, Formamidine sulfinic acid (11.0 g., 0.1 mole) was suspended in 250 ml. of dry dimethylsulfoxide and 2.4 g. (0.1 mole) of sodium hydride was added. After cessation Of hydrogen gas evolution 36.5 g. (0.1 mole) of triphenyl β-acetylvinylphosphonium chloride were added The - mixture was stirred for one hour at ambient and o temperature,/then heated at 100 for 10 minutes. After cooling, the dimethylsulfoxide was evaporated and the residue was dissolved in 300 ml. of 1:1 chloroform-methanol was and che solution/filtered. The filtrate was evaporated to dryness and the residue was recrystallized from chloroformacetone to give 20 g. (50¾) of [(5-methylimidazolyl)-4methyl]triphenylphosphonium chloride, m.p. 223-225°.
Alternatively, and preferably, [{5-methylimidazolyl)-4-methylJtriphenylphosphonium chloride and bromide are prepared using formamidine sulfinic acid bythe following procedures: Triphenyl 6-acetylvinylphosphonium chloride (3.65 g., 0.01 mole) and formamidine sulfinic acid (1.1 g., 0.01 mole) were dissolved in 50 ml. of dimethylsulfoxide. 1,8-bis(Dimethylamino)naphthalene (proton sponge) (2.14 g., was 0.01 mole) was added, and the mixture/warmed to 80°. After cooling, evaporating the dimethylsulfoxide, precipitating the inorganic salts with chloroform, filtering, evaporating to dryness and recrystallizing the residue from chloroformacetone, an essentially guantitative yield of ί(5-methylimidazolyl)-4-methyl]triphenylphosphonium chloride was obtained. ; 4 3 Ο 3 5 \ Triphenyl β.-acetylvinylphosphonium bromide (20.6 g., 0.05 mole) and formamidine sulfinic acid (6.0 g., slight excess over 0.05 mole) were dissolved in 100 ml. of dimethylsulfoxide. l,5-Diazabicyclo[5.4.0]undec-5-ene (DBU)(7.6 g., 0,05 mole) was added dropwise wj.th stirring. The mixture was maintained at 80° for 20 minutes and the dimethylsulfoxide was evaporated off. The residue was taken up in chloroform and inorganic salts were removed by filtration. The filtrate was evaporated / to dryness and the residue was recrystallized from chloroformacetone to give [(5-methylimidazolyl)-4-methyl]triphenylphosphonium bromide in 80S yield.
Sodium amide (0.39 g., 0.01 mole) was dissolved in 40 ml. of liquid ammonia and 4.11 g'<, (0.01 mole) of [(5-methylimidazolyl)-4-methyl]triphenylphosphonium bromide was added. The suspension was stirred at -40°C. for one 15 hour and then allowed to warm to room temperature as the ammonia evaporated. The triphenyl phosphine was extracted from the residue with benzene and the remaining solids were taken up in water and extracted with chloroform. The chloroform extracts were dried and evaporated to give 4-ammomethyl-5-methylimidazole in 70S yield. This amine was refluxed with a molar equivalent of cysteamine in acetic acid and treated with hydrochloric acid to give 4-(2-aminoethyl) thiomethyl-5-methylimidazole dihydrochloride.
EXAMPLE 2 -3 [(5-Methyl-2-methylthioimidazolyl)-4-methyl]triphenylphosphonium bromide (4.83 g., 0.01 mole) was stirred in 20 ml. of piperidine at room temperature for 30 minutes, then refluxed for one hour, cooled and filtered. The filtrate was evaporated under reduced pressure and chromatographed -10«3035 on a silica gel column using chloroform/methanol as eluant to yield 5-methyl-2-methylthio-4-piperidinomethylimidazole. Treating with hydrochloric aoid and refluxing the resulting dihydrochloride salt with one molar equivalent of cysteamine in acetic acid gave 4-(2-aminoethyl)thiomethyl-5-methyl-2methylthioimidazole dihydrochloride.
By the same procedure, using pyrrolidine in place of piperidine, 5-methyl~2-methylthio-4-pyrrolidinomethylimidazole is prepared.' IQ Similarly, using morpholine in place of piperidine -methyl-2~methylthio-.4-morpholinomethylimidazole is prepared Converting these pyrrolidine and morpholine compounds to the dihydroohloride salts and treating with cysteamine in acetic acid gives 4-(2-aminoethyl)thiomethyl5-methyl-2-methylthioimidazole dihydrochloride.
* EXAMPLE 3 Dimethylamine (0.5 g., 0.01 mole) was dissolved in 35 ml. of tetrahydrofuran, stirred and cooled in an ice bath while 5 ml. (0.01 mole) of 2M butyl lithium in hexane were added dropwise with stirring. After stirring the mixture for 15 minutes in the cold, 3.93 g. (0.01 mole) of [(5-methyl· imidazolyl)-4-methyl]triphenylphosphonium chloride were added and the solution allowed to warm to room temperature. After stirring for two hours at room temperature, the solvents were evaporated and the residue treated with 50 ml. of water. ?5 Filtration yielded diphenyl phosphine. The aqueous filtrate and the extract was was extracted with chloroform,/ dried and evaporated to afford 4-(Ν,Ν-dimethylaminomethyl)-5-methylimidazole. This amine was then refluxed with a molar equivalent of cysteamine in acetic acid and treated with hydrochloric acid to give 4-(2-aminoethyl)thiomethyl-5-methylimidazole dihydrochloride. -111 4503s; By the same procedure, using methylamine in place of dimethylamine, 4-(N-methylaminomethyl)-5-methyliraidazole is prepared. In the same way, using butylamine and dibutylamine, 4-(N-butylaminomethyl)-5-methylimidazole and 4-(N,N-dibutylaminomethyl)-5-methylimidazole are prepared. Refluxing these intermediates with cysteamine by the above procedure and treating with hydrochloric acid gives 4-(2-aminoethyl)thiomethyl)-5-methylimidazole dihydroehloride.
- EXAMPLE 4 .
N-Cyano-N’-methyl-N''-mercaptoetny Iguanidine (1.58 g., 0.01 mole) was dissolved in 15 ml. of methanol and 2.3 ml. of sodium methoxide (0.01 mole) in methanol was-added.
After stirring at room temperature .for five minutes, a suspension of 3.93 g. of [(5-methylimidazolyl)-4-methylItriphenylphosphonium chloride in 10 ml. of methanol was added. The solution was heated to reflux·. An equal volume of water was added and most of the methanol was removed by evaporation.
Filtration and water washing afforded triphenylphosphine. . The and it was filtrate was treated with charcoal,/ filtered and concentrated. Filtration gave N-cyano-N’-methyl-N-[2-(5-methy1-4imidazolyImethylthio)ethyl]guanidine.
EXAMPLE 5 · Using /7(2-methylthio-5-methy1imidazolyl)-4-methyl7triphenylphosphonium bromide in place of the phosphonium compound in the procedure of Example 4 gives N-cyano-N'-methyl-N-/-2-(2-methylthio-5-methyl-425 imidazolylmethylthio)ethyT7guanidine, The 2-methylthio group is removed by refluxing a mixture of the compound and 50:50 nickel-aluminium alloy in formic acid and working up by the procedure of Example 12 of Patent Specification No. 44395 to give N-cyano-N'-methyl-N-/2-(5-methyl-4imidazolylmethylthio)ethyl7-guanidine. . -,.

Claims (16)

1. 3 where R and R are as defined in Claim 1, whenever prepared by a process according to any one of Claims 1 to 4 and 6 to 12. 1 in which 1 ih which to provide the 1 3 R and R are as hereinbefore defined; R is lower alkyl or phenyl; and X is halq),
1. A process for preparing a compound of the formula: R 1 CH 2 R 2 N. N (where R 1 is hydrogen or lower alkyl; .NCN R 2 is -SCH O CH O NHC Z or -NR 6 R 7 2. Rf R is -SCH 2 CH 2 NHC ' s nhch 3
2. A process according to claim 1 in which R 5 is phenyl. 2 2 with a compound of the formula R-H( where R is as hereinbefore defined) under basic conditions. 2 2 v NHCH 3 z· 7 where R and R are each hydrogen, lower alkyl or together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine or morpholine ring);and □ R is hydrogen, lower alkyl, A. 4 « trifluoromethyl, benzyl, amino or -SR (where R xs lower alkyl, phenyl, benzyl or chlorobenzyl), which comprises reacting a compound of the formula:
3. A process according to claim 1 in which NCN
4. A process according to claim 3 in which 5 R is phenyl.
5. A process according to claim 1 in which R^ is -NR^R? and R^ and R? are each hydrogen, lower alkyl or together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine or morpholine ring.
6. A process according to claim 2 in which is rf >SCH 2 CH 2 NHC\ NCN nhch 3 and r3 is hydrogen.
7. A process according to claim sodium methoxide or sodium hydride are used basic conditions.
8. A process according to claim the reactionis carried out in en organic solvent.
9. A process according to Ciaim 1, in which the reaction is effected in methanol, ethanol, propanol, butanol, acetone, acetonitrile, dimethylformamide or dimethylsulfoxide as solvent. 10. 13. A process according to Claim 1, substantially as hereinbefore illustrated in any one of the Examples.
10. A process according to Claim 1, in which the reaction is carried out at 5 a temperature of from 25°C to 200°C for from 20 minutes to 24 hours.
11. A process according to Claim 10, in which the reaction is carried out at a temperature of 65°C to 100°C for from 20 minutes to 3 hours.
12. A process according to Claim 3, substantially as hereinbefore illustrated in Example 4 or Example 7.
13. - 13 430 35 (where
14. A compound of the formula I, as defined in Claim 1, whenever prepared by a process according to any one of Claims 1 to 13. - 14 «3035
15. A compound of the formula ,K N V 7 CH 2 SCH 2 CH 2 NHCNHCH 3 NH
16. N-Cyano-N*-methyl-N-/ _ 2-(5-methyl-4-imidazolylmethylthio)ethyl7guanidine whenever prepared by a process according to any one of Claims 1 to 4 and 6 to 12.
IE839/77A 1977-02-22 1977-04-26 Process for preparing 4-substituted imidazole compounds IE45035B1 (en)

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IE45035B1 true IE45035B1 (en) 1982-06-02

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IE (1) IE45035B1 (en)
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GB1582865A (en) 1981-01-14
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SE7704870L (en) 1978-08-23
IN148285B (en) 1981-01-03
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CH631167A5 (en) 1982-07-30
SE442199B (en) 1985-12-09
IE45035L (en) 1978-08-22
CH631168A5 (en) 1982-07-30
MX4663E (en) 1982-07-21
AT355015B (en) 1980-02-11
DE2718715A1 (en) 1978-08-31
IL51898A0 (en) 1977-06-30
FI771291A (en) 1978-08-23
ATA289577A (en) 1979-07-15
PT66446A (en) 1977-05-01
HU174840B (en) 1980-03-28
SE8008935L (en) 1980-12-18
SE452887B (en) 1987-12-21
CA1084052A (en) 1980-08-19
BE853954R (en) 1977-10-26
PT66446B (en) 1978-09-22

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