CA1247108A - Process for the preparation of heterocyclylphenylformamidines - Google Patents
Process for the preparation of heterocyclylphenylformamidinesInfo
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- CA1247108A CA1247108A CA000484268A CA484268A CA1247108A CA 1247108 A CA1247108 A CA 1247108A CA 000484268 A CA000484268 A CA 000484268A CA 484268 A CA484268 A CA 484268A CA 1247108 A CA1247108 A CA 1247108A
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- phenyl
- imidazol
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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
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/06—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
- C07D233/08—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms with alkyl radicals, containing more than four carbon atoms, directly attached to ring carbon atoms
- C07D233/12—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms with alkyl radicals, containing more than four carbon atoms, directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen 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
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/06—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Abstract New process for the preparation of heterocyclylphenylformamidines of general formula I
(I) wherein B represents a guanidino group or a hydrogen atom;
R represents a linear or branched alkyl group which may optionally contain one heteroatom such as oxygen or nitrogen atom, an alkenyl group, a cycloalkyl or cycloaliphatic alkyl group having 3 to 6 carbon atoms; R1 represents a hydrogen atom, a C1-3 alkyl or alkoxy group or halogen atom; Het represents a substituted or unsubstituted five-membered heterocyclic ring containing from 1 to 3 heteroatoms; tautomers thereof and acid addition salts of the aforesaid compounds, which comprises desulphurizing the corresponding thioureas.
(I) wherein B represents a guanidino group or a hydrogen atom;
R represents a linear or branched alkyl group which may optionally contain one heteroatom such as oxygen or nitrogen atom, an alkenyl group, a cycloalkyl or cycloaliphatic alkyl group having 3 to 6 carbon atoms; R1 represents a hydrogen atom, a C1-3 alkyl or alkoxy group or halogen atom; Het represents a substituted or unsubstituted five-membered heterocyclic ring containing from 1 to 3 heteroatoms; tautomers thereof and acid addition salts of the aforesaid compounds, which comprises desulphurizing the corresponding thioureas.
Description
The present invention relates to a novel process for the preparation of heterocyclylphenylformamidines which have histamine H2 antagonist activity.
These formamidines are already disclosed in our Italian Patent Application No. 26323 A/80 corresponding to Canadian Patent 1,171,092 No.
20356 A/82, corresponding to Canadian Application I~O. 424,307 filed March 23, 1983 No. 21331 A/82 and No. 22110 A/83 corresponding to Canadian Application No. 459,030 filed July 17, 1984 as compounds endowed with good H2-receptor blocking activity and inhibitory activity of gastric acid secretion and are use-ful antiulcer agents, as well as their processes of preparation.
Some processes for producing heterocyclylphenylformamidines have been described in the above mentioned Italian Patent applications, e.g. reaction of a suitable heterocyclyl aniline with a reactive derivative of a carboxamide, for instance a N-alkylformimidate or formimidoyl chloride, or alternatively, reaction of an appropriate substituted N-phenyl formimidate with the proper amine, or reaction of a particular amine with a N-heterocyclylphenyl-N'-sub-stituted formamidine, where the N'-substituent is an electron withdrawing group such as cyano or carbethoxy. By these processes the formamidines, described in said applications, may be prepared in convenient yields. However, some are obtained in better yields ~Ising a particular process than another and the choice of the method depends on the particular case under consideration.
Now, we have found that heterocyclylphenylformamidines may be pre-pared smoothly and economically in good yields and in high purity by desulphuriz-ing the corresponding precursor thioureas. One of the main advantages of the new process, according to the present invention, is that it is general in scope and applicable to the preparation of all heterocyclylphenyl formamidines dis-closed in the previous applications. The new process involves a particularly simple procedure alld it is very useful in practice. F~lrthermore, it allows to ~2~'7~
- la -obtain the desired formamidine as its sulphate salt directly when in the desul-phurizing reaction an oxidizing agent is used.
These formamidines are already disclosed in our Italian Patent Application No. 26323 A/80 corresponding to Canadian Patent 1,171,092 No.
20356 A/82, corresponding to Canadian Application I~O. 424,307 filed March 23, 1983 No. 21331 A/82 and No. 22110 A/83 corresponding to Canadian Application No. 459,030 filed July 17, 1984 as compounds endowed with good H2-receptor blocking activity and inhibitory activity of gastric acid secretion and are use-ful antiulcer agents, as well as their processes of preparation.
Some processes for producing heterocyclylphenylformamidines have been described in the above mentioned Italian Patent applications, e.g. reaction of a suitable heterocyclyl aniline with a reactive derivative of a carboxamide, for instance a N-alkylformimidate or formimidoyl chloride, or alternatively, reaction of an appropriate substituted N-phenyl formimidate with the proper amine, or reaction of a particular amine with a N-heterocyclylphenyl-N'-sub-stituted formamidine, where the N'-substituent is an electron withdrawing group such as cyano or carbethoxy. By these processes the formamidines, described in said applications, may be prepared in convenient yields. However, some are obtained in better yields ~Ising a particular process than another and the choice of the method depends on the particular case under consideration.
Now, we have found that heterocyclylphenylformamidines may be pre-pared smoothly and economically in good yields and in high purity by desulphuriz-ing the corresponding precursor thioureas. One of the main advantages of the new process, according to the present invention, is that it is general in scope and applicable to the preparation of all heterocyclylphenyl formamidines dis-closed in the previous applications. The new process involves a particularly simple procedure alld it is very useful in practice. F~lrthermore, it allows to ~2~'7~
- la -obtain the desired formamidine as its sulphate salt directly when in the desul-phurizing reaction an oxidizing agent is used.
-2- ~7~ 27086-7 The object of the present invention is to provide a new process for the preparation of heterocyclylphenylformamidines of ~eneral formula I
B - ~et ~
N~ - C~l= N - R (I) R
wherein B Tepresents a guanidino group or a hydrogen atom;
R represents a linear or branched alkyl group which may optionally contain one heteroatom such as oxygen or nitrogen atom, an alkenyl group~ a cycloalkyl or cycloaliphatic alkyl group having 3 to 6 carbon atoms;
Rl represents a hydrogen atom, a Cl 3 alkyl or alkoxy group or halogen atom;
Het represents a substituted or unsubstituted ring of imidazol, thia~ol, thiadiazol, tria~ol or pyrazol; tautomers thereof; and acid addition salts of the aforesaid compounds.
The acid addition salts referred to the above will of course be physiologically compatible acid addition salts. The term "acid addition salts" includes salts with inorganic or organic acids. Suitable physiologically compati'ole acid addition salts include, for example, salts formed with hydrochloric, acetic, nitric, maleic~ fumaric, citric, tartaric or sulphuric acid.
It is to be understood that although in the formula ~I) given above the double bond in the formamidine radical has been inserted in a particulaT position, other tautomeric forms are possible and that in the heterocyclic ring different ~automeric forms are also possible. The presen-t invention includes such ,.. ,;
~Z~
-2a- 27086-7 tautomeric forms within its scope.
In the above mentioned formula (I) the formamidine radical may be in ortho, meta or para position of the benzene ring with respect to the Het group~ and the group Rl is in any position in the benzene ring.
!` ~ j~3;
~Z~7
B - ~et ~
N~ - C~l= N - R (I) R
wherein B Tepresents a guanidino group or a hydrogen atom;
R represents a linear or branched alkyl group which may optionally contain one heteroatom such as oxygen or nitrogen atom, an alkenyl group~ a cycloalkyl or cycloaliphatic alkyl group having 3 to 6 carbon atoms;
Rl represents a hydrogen atom, a Cl 3 alkyl or alkoxy group or halogen atom;
Het represents a substituted or unsubstituted ring of imidazol, thia~ol, thiadiazol, tria~ol or pyrazol; tautomers thereof; and acid addition salts of the aforesaid compounds.
The acid addition salts referred to the above will of course be physiologically compatible acid addition salts. The term "acid addition salts" includes salts with inorganic or organic acids. Suitable physiologically compati'ole acid addition salts include, for example, salts formed with hydrochloric, acetic, nitric, maleic~ fumaric, citric, tartaric or sulphuric acid.
It is to be understood that although in the formula ~I) given above the double bond in the formamidine radical has been inserted in a particulaT position, other tautomeric forms are possible and that in the heterocyclic ring different ~automeric forms are also possible. The presen-t invention includes such ,.. ,;
~Z~
-2a- 27086-7 tautomeric forms within its scope.
In the above mentioned formula (I) the formamidine radical may be in ortho, meta or para position of the benzene ring with respect to the Het group~ and the group Rl is in any position in the benzene ring.
!` ~ j~3;
~Z~7
- 3 -According to the present inventiol) tllere is provided a process for the preparation of compounds of formula (I) which comprises desulphurizing the corresponding thioureas of general formula 11 B - Het -\= ~
NH - C - NHR (Il) S
Rl ;n which R, R1, B and Het are as above defined to give the compounds of formula (1).
The reaction is advantageously carried out by oxidizing or reducing agents in the presence of a suitable solven-t at an appropriate temperature.
Oxidizing and reducing agents which may be used include hydrogen peroxide,. peroxy acids such as peracetic or perbenzoic acid, and Raney nickel.
Hydrogen peroxide and Raney nickel are preferred as oxidizing and reducing acJents, respectively. The reaction is preferably carried out in the presence of a solvent which may be selected from alcohols, esters, chlorinated hyclrocarbons and polar aprotic solvents, according to the nature of the oxidizing and reducing agents used. The reaction is generally effected at room temperature.
A higher or lower temperature maysometimes be found more satisfactory.
When the desulphurizatioll is carried out using hydrogen peroxide the reaction is usually performed by dissolving a compound of general formula (Il) in -the alcoholic solvents, preferably methanol.
Hydrogell peroxide is then added thereto under stirring by keeping the temperature ullder 40UC. The reaction may be optionally per-formed ~2~7 in the presence of slight quantities oF a catalyst, e.g. ammonium molybdate. The reaction is completed within few hours. The desired compound of formula (I) can be separated from the reaction mixture in a crude form as a sulphate salt by fiItration. The product may be purified, if desired, by recrystallization from an ;appropriate solvent such as ethanol in a standard manner or by purifica-tion of the isolated base. The sulphate salt may be converted into the cor-responding free base by conventional treatment with suitable bases. The base so obtained may be optionally converted with inorganic or organic acids into physiologically compatible acid addition salts, for example, by conventional method, such as by reacting it with a solution of the corresponding acid in a suitable solvent.
When the desulphurization is carried out using Raney nickel the reaction is usually performed by dissolving a compound of general formula (Il) in a suitable solvent such as alcohols or dimethylforma-mide. Raney nickel is then added under stirring, generally at room temperature, and in Few cases at 50C. The reaction is completed in a period of 1-2~ hours. The desired compounds are usually obtained as bases and may be optionally converted with inorganic or organic acids into physiologically compatible acid addition salts according to conventional methods.
The compounds of general formula (Il) used as starting material in the process, object of the present invention, may be obtained by conventional methods, -for example by reacting an amine of formula 111 R - NH7 (111) -in which R is as above defined, with an isothiocyanate of general formula IY
B - llet- ~
1 NCS (IV) 5 ~L~471V~
in wl~ich l~l, B ~lnd ~let are as above defined. The reactioll is generally carried out in the presellce of a suitable solvent such as acetolle or alcohols at a temperature from 20 C to the boiling point of the solvent used.
Instead of the compound of formula (IV) there may be used in the above reaction a compound of formula V
B - Het - ~
~ ~ .
~H - C - S - C - OR~ (V) F
S O
in which Rl, B and Het are as above defined and R2 is a lower alkyl (1-3 C atoms) or a phenyl group.
Alternatively the compound of formula (I() may also be prepared by reacting an amine of formula Vl B - Het -~-- (Vl) Rl where Rl, B and Het are as above-defined, with a isothiocyanate of formllla Vll R - N C S (Vll) in which R is above defined, following the same procedure as above described.
The c~llpo~ ds of formula (IV) and (V ) are new compoullds and constitllte Furtller featules of the presellt inventioll.
1;~4~
The compounds of formula ~IV) in their turn may be obtained by methods that are known per se in the literature, for example, by reacting the appropriate aniline derivative with carbon disulfide and ammonium hydroxide, and treating this mixture with ethyl chloroformate.
In an analogous manner are obtained the compounds of formula (V).
These compounds are the intermediates for the corresponding isothiocyanates, which precipitate from the reaction mixture and may be isolated as such. Thus, for instance, referring to Examples lO and ll below, it can be seen that time is a factor ~hich distinguishes whether the product of the reaction is a com-pound of formula IV or formula V. In Example 10, after 15 minutes stirring there was obtained a compound of formula V. In Example 11, after 2 hours stir-ring there was obtained a compound of formula IV
- 7 ~ 7~
The following examples illustrate some oF the new compounds accord-ing to the present invention; these exarnples are not to be in any way considered limitative of the scope o-f the invention itself:
Example 1 N-lsopropyl-N'-/ 4-(imidazol-4-yl)-phenyl 7-formamidine A suspension of N-lsopropyl-N'-/ 4-(imidazol-4-yl)-phenyl_/ thio-urea (13 y) and Raney-nick~l (39 9) in methanol (600 ml) is stirred at room temperature for 1 hour. The fiItered solution is evaporated to dryness and the crude residue is crystallized from ethyl acetate and diethyl ether to give 6.6 9 of the title compound. M. p . 18~-189C .
Analysis C13H16N4 Found % C 68.20 H 7.13 N 24.41 Calc. % C 68.39 H 7.06 N 24.5 Analogously the following compounds were prepared:
- N-Ethyl-N'/ 4-~imida7O1-4-yl)-phenyl_7-formamidine. M.p. 163-166C.
Analysis Cl~H14N4 Foulld % C 67.01 H 6.63 N 26.28 Calc. % C 67.26 H 6. 59 N 26.15 - N-AlIyl-N'-/ 4-( imidazol-4-yl)-phenyl_7-formamidine. M.p. 190-191C.
Analysis I3 l4 4 Fourld '~', C 68.~l H 6.30 N 24.65 C.llc. ','~ C 6~.00 H 6~24 N 24.76 - 8- ~L247~
- N-tert-Butyl-N'-~ 4-(imidazol-4-yl)-phenyl_/-formamidine, thick ol I .
Analysis C14H18N4 Found % C 69.56 H 7.54 N 23.02 Calc. % C 69.38 H 7.48 N 23.12 - N-(1,1-Dime-thyl-2-hydroxy-ethyl)-N' { 4-(imidazol-4-yl)-phenyl~ -formamidine, thick oil.
Analysis 14 18N4 Found % C 65.21 H 7.12 N 21.74 Calc. % C 65.Q9 H 7.02 N 21.69 - N-lsopropyl-N'-/ 2-methoxy-4-(imidazol-4-yl)-phenyl_7-formamidine.
M.p. 190-193C. ~ - -Analysis 14 18 4 Found % C 65.31 H 7.09 N 21.40 Calc. % C 65.09 h 7.02 N 21.09 Example 2 N-Methyl-N'-/ 3-(2-guanidino-4-thiazolyl)-phenyl_/--formamidine .
Raney Ni (6 9) was added to a solution of N-methyl-N'-/ 3-(2-guanidi-no-4-thia~olyl)-pllenyl_/ thiourea (1.53 9) in dimethylFormamido ~Z47 (20 ml). AFter 2 hours stirring, the catalyst was filtered and the solution was diluted with ether. The oil which separated was collected and triturated with ether. The solid base was pwrified by conversion to the maleate salt in ethanol. This process yielded 0.46 9 of the title compound as maleate.
Maleate salt (ethanol). M.p. 180-2C (dec.).
Analysis 20 22 68S Found % C 47.09 H 4.54 N 16.38 Calc. % C 47.43 H 4.38 N 16.59 Example 3 N-tert-Butyl-N'-/ 2-methoxy-4-(imidazoi-4-yl)-phenyl_/-formamidine A solution of 30Yo hydrogen peroxyde (18.6 ml) in ethanol was added dropwise to a stirred suspension of N-tert-~utyl-N'-/ 2-methoxy-4-(imidazol-4-yl)-phenyl_7-thiourea (10.5 9) in ethanol (170 ml). The temperature was kept below 20C during the reaction time. From the resulting solution, after -few minutes a white solid crystallized-out,-and after 30 minutes stirring the solid was collected by fiItration to give 9.9 9 of the title compound, as sulphate salt.
Sulphate salt (ethanol). M.p. 260C (dec.).
Analysis .
15 22 405S Found % C 48.95 H 5 oS N 15.23 Calc. ~ C 48.63 H 5.98 N 15.12 In the same manner, starting from the suitable N-substituted thiourea the ~ollowing compDLInd~ were obtained.
lZ47~
- N-/ 4-(imidazol-4-yl)-phenyl_/-formamidire Maleate salt (acetone). M.p. 169-70C (dec.).
Analysis 18 18 48 Found % C 50.76 H 4.43 N 13.18 Calc. % C 51.07 H 4.34 N 13.39 - N-Ethyl-N'-/ 4-(imidazol-4-y l)-phenyl_/-formamidine Sulphate salt ~ethanol). M.p. 254-2560C ( dec.).
Analysis N404S Found % C 46.31 H 5.22 N 18.05 Calc. % C 46.1~ ~ 5.16 N 17.94 - N-lsopropyl-N'-/ a - ( i midazol-4-yl)-phenyl_/-formamidine Sulphate salt (ethanol). M.p. 235C ( dec.).
Analysis 13 18 4 4 Found % C 48.o9 H 5.61 N 17.02 Calc. % C 47.83 H 5. j6 N 17.17 - N-Allyl-N'-/ 4-(imidazol-4-yl)-?henyl_7-formamidine Sulphate salt (ethanol). M.p. 270C ( dec.).
Analysis 13 16 4 4S Found % C 48.26 H 5.04 N 17.32 Calc. ~/o C 48.14 H 4.97 N 17.27 I.
" lZ~7~C~8 - N-Cyclohexyl-N'-/ 4-(imidazol-4-yl)-phenyl_7-formamidine Sulphate salt (ethano'). M.p. 225-227C (dec.).
Analysis 16 22 404S Found % C 52.18 H 6.11 N 15.34 Calc. ~o C 52.~4 H 6.05 N 15.29 - N-tert-Butyl-N'-/ 4-~imidazol-4-yl)-phenyi_7-formamidine .
Sulphate salt (ethanol). M.p. 261-262C (dec.).
Analysis 14 20N4C4S Found % C 49.67 H 5.49 N 16.39 Calc. % C 49.54 H 5.64 N 16.51 - N-tert-Amyl-N'-/ 4-(imidazol-4-yl)-phenyl 7-formamidine Sulphate salt (ethanol). M.p. 256-2670C (dec.).
Analysis 15~22N44S Found % C 49.84 H 6.18 N 15.70 Calc. % C 50.83 H 6.26 N 15.81 - N-~1,l-Dimethyl-2-hydro~y-ethyl)-N'-/ 4-(imidazol-4-yl)-phenyl_7-formamidine Sulphate salt (ethanol). M.p. 193-194C (dec.).
Analysis 14 20 405S Found % C 47.39 H 5.71 N 14.83 Calc. ~/o C 47.18 !-l 5.65 N 14.72 12g~7~
- N-(l,l-Dimethyl-propen-2-yl)-N'-/ 4-(imidazol-4-yl)-phenyl 7--formamidine Sulphate salt (ethanol). M.p. 229-230C (dec.).
Anaiysis C15H20N44S Found % C 51.48 H 5.86 N 15.75 Calc. % C 51.12 H 5.72 N 15.90 N-lsopropyl-N'-/ 2-methoxy-4-(imidazol-4-yl)-phenyl_7-formamidine Sulphate salt (ethanol). M.p. 204-205C (dec.).
Analysis 1~ 20N404S Found % C 47.29 H 5.70 N 15.58 Calc. % C 47.18 H 5.65 N 15.72 N-tert-Butyl-N'-/ 2-fluoro-4-(imidazol-4-yl)-phenyl_/-formamidine Sulphate salt (ethanol). M.p. 249-250C (dec.).
Analysis C14H19FN404S Found % C 47.11 H 5.41 N 15.80 Calc. % C 46.91 H 5.34 N 15.63 N-lsopropyl-N'-/ 2-chloro-4-(imidazol-4-yl)-phenyl_/-formamidine Sulphate salt (ethanol~ .p. 218-220C (dec.).
Analysis C13H17CIN40~S Found % C 43.54 H 4.88 N 15.40 Calc. % C 43.2G H 4.74 N 1~.52 t3 ~L~ 7 1 ~3 Example 4 N-Ethyl-N -/ 3-(5-guanidino-1,2,4-thiadiazol-3-yl)-phenyl~ -formamidine To a stirred solution of N-ethyl-N -/ 3-(5-guanidino-1,2,4-thiodia-zol-3-yl)-phenyl_/-thiourea (5 9) in methanol (600 ml) containing a cataiytic amount o-f ammonium molybdate, a solution of 30% hydrogen peroxice (8.3 ml) in methanol (8 ml) was dropped slowly during 45 minutes. A-fter adoitional 4 hours stirring, the solid which separa-ted was fiItered, suspended in water and the suspension was made alkaiine with 10% sodium carbonate. The free base was fiItered, washed with water and dried to give 3.5 9 of the title compound.
Maleate salt (etnanol). M.p. 174-177C (dec.).
Analysis 20 23 7 8 Found % C 46.13 H 4.52 N i9.01 Ca!c. % C 46.o6 H 4.45 N 18.80 The following compounds were prepared in a similar manner, starting from the appropriate thiourea derivatives.
N-Methyl-N -/ 3-(2-guanidino-4-thiazolyl)-phenyl_/-Formamidine Hydrochloride salt (ethanol). M.p. 210-212C (dec.).
Analysis 12 l6CI2N6S Found % C 41.27 H 4.67 N 23.98 Calc. % C 41.50 H 4.64 N 24.20 N-tert-Butyl-N -/ 3-(2-~uanidino-4-thiazolyl)-phenyl_7--Formamidine Hydrochlorioe salt (methanol). M.p. 234-236C tdec.).
Analysis 15 2 CI2 6S Fouild % C 46.69 H 5.55 N 21.32 Calc. % G 46. 27 H 5.69 N 21. 58 12~73~
N-Allyl-N'-/ 3-(2-guani~ino-4-thiazolyl)-phenyl_/-Forrnarnidine Maleate salt (ethanol). M.p. 168-170C (dec.).
Analysis 22 24 6 8 Found % C 49.54 H 4.47 N 15.89 Calc. % C 49.62 H 4.54 N 15.78 N-(l,l-Dimethyl-propyl)-N'-/ 3-(2-guanidino-4-thiazolyl)-phenyl_7-formamidine Hydrochloride salt (ethanol). M.p. 216-218C (dec.).
Analysis 16 24 2 6 Found % C 47.38 H 6.25 N 20.~8 Calc. % C 47.64 H 6.oo N 20.83 N-lsopropyl-N'-/ 4-(1,2,4-triazol-3-yl)-phenyl_/-formami~ine .
Maleate salt (ethanol). M.p. 155-157C (dec.).
Analysis 20 23 58 Found % C 51.87 ~ 4.98 N 15.23 Calc. % C 52.06 H 5.02 N 15.18 N-lsopropyl-N'-/ 4-(pyrazol-3-yl)-phenyl_7-formamidine Hydrochloride salt (acetone). M.p. 202-203C (dec.).
Analysis l3 18 2 L~ Fourld % C 51.70 H 6.18 N 18.41 Calc. iy~ C 51.83 ll 6.Q2 N 18.Go i ~ 7 N-lsopropyl-N'-/ 4-(imidazol-2-yl)-phenyl_/-formamidirle Fumarate (ethanol). M.p. 138-140C (dec.).
Analysis 21 24 4 8 Found % C 55.02 H 5.17 N 11.85 Calc. % C 54.77 H 5.25 N 12.17 N-tert-Butyl-N'-/ 4-(2-methyl-imidazol-4-yl)-phenyl_/-formamidine Sulphate salt (methanol). M.p. 276-2780C (dec.).
Analysis 15 22N4 4S Found % C 50.50 H S.06 N 15.77 Calc. % C 50.84 h' 6.26 N 15.81 Exan~le 5 N-lsopropyl-N'-/ 4-(~.-imidazolyl3-phenyl_/-formamidine Raney Ni (8.v 9) was added to a suspension o~ N-isopropyl-N'-/ 4-(2-mercapto-imidazol-4-yl)-phenyl_7-thiourea (1.1 9) in dimethyl formamide (22 ml).The mixture was heated at 50C for 24 hours, cooled and fiItered. The solution was diluted ~ith water and the gummy solid which separated was dissolved in ethanol and purified ~y conversion to the maleate salt (0.4 9).
Maleate salt (ethanol). ~II.p. 195-197C (dec.).
Analysis 21 24 4 8 Found ~u C 54.41 H 5.33 N 12.00 Calc. % C 54.78 H 5.25 N 12.t7 ~2~7 Example 6 N-lsopropyl-N'-~ 4-(imidazol-4-yl)-phenyl~ -thiourea A solution of 4-(4-aminophenyl)-1-H-imidazole (15.9 9) and isopropyl isothiocyanate (15.2 9) in ethanol (L50 ml) was refluxed for 90 minutes and evaporated to dryness. From the crude residue the title compound was obtained after crystalliza'ion from 70~o ethanol (8.2 9).
M.p. 204-205C.
In the same manner, from the suitable amino derivatives and the isothiocyanate the following thioureas were prepared:
- N-Ethyl-N'-/ 4-(imidazol-4-yl)-phenyl_7-thiourea. M.p. 125-126C
_ . .
- N-AlIyl-N'-/ 4-(imidazol-4-yl)-phenyl~ -thiourea. M.p. 140-142C
_ _ _ - N-Cyclohexyl-N'-~ 4-(imidazol-4-yl)-phenyl 7-thiourea.
M.p. 162-163C
- N-lsopropyl-N'-_ 4-(1,2,4-triazol-3-yl)-phenyl 7-thiourea.
M.p. 184-185~C
;- - N-lsopropyl-N'-/ ~ 1-3-yl)-phenyl_/-thiourea. M;p; 1 59-i60c - N-lsopropyl-N'-/ 4-(imidazol-2-yl)-phenyl~ -thiourea.
~.I.p~ 187-188C (dec.) Example 7 N-tert-~utyl-N'-~ 2-methoxy-~-(imiaazol-4-yl)-phenyl_7-~hiourea _ A solution oF N { 2-methoxy-4-(imidazol-4-yl)-phenyl_7-carbethoxy dithiocarbamate ( 12 . 5 9) and t-butylainine (13.5 9) in methanol was ~L24 stirred at room temperature overnight and then evaporated to dryness.
After crystallization From diethyl ether of the residue, the title compound was obtained (10.8 9). M.p. 156-157C.
Analogously the following compounds were obtained:
- N-lsopropyl-N'-/ 4-(imidazol-4-yl)-phenyl_7-thiourea.
M.p. 185-187C (dec.) - N-Ethyl-N'-~ 4-(imidazol-4-yl)-phenyl_7-thiourea.
M.p. 125-126C (dec.) - N-Allyl-N'-/ 4-(imidazol-4-yl)-phenyl_7-thiourea.
M.p. 140-142C (dec.) - N-Cyclohexyl-N'-_ 4-(imidazol-4-yl)-phenyl_7-thiourea.
M.p. 162-163C (dec.) - N-tert-Butyl-N'-/ 4-(imidazol-4-yl)-phenyl_7-thiourea.
M.p. 147-149C
- N-tert-Amyl-N'-/ 4-(imidazol-4-yl)-phenyl_7-thiourea.
M.p. 159-160C (dec.) - N-(l~l-Dimethyl-2-~ydroxye~hyll~N~-/4-(imidazol-4-yl)-phenyl7-thiourea.
-M.p. 171-172C (dec.) - N-(1,1-Dimethyl-propen-2-yl)-N'-/4-(imidazol-4-yl)-phenyl7-thiourea-M.p. 163-L64C (dec.) - N-lsopropyl-N'-/ 2-methoxy-4-(imidazol-4-yl)-phenyl_7-thiourea.
M.p. 156-157C (dec.) - N-tert-Butyl-N'-/ 2-fluoro-4-(imidazol-4-yl)-phenyl_7-thiourea.
M.p. 148-149C (dec.) - N-lsopropyl-N' { 2-chloro-4-(imidazol-4-yl)-pllenyl_7-tlliotlrea.
M.p. lS5-15~C (dec.) E,xamp I e $
N-Methyl-N'-/ 3-(2-guanidino-4-thiazolyl)-phenyl~ -thiourea A mixture oF 3-(2-guanidino-4-thiazolyl)-phenyl isothiocyanate hydrobromide (6 9) and 35~ aqueous methylamine (6 ml) in acetone (80 ml) was stirred overnight. The resulting solution was filtered with charcoal and evaporated to dryness. The residual gum was washed with water and recrystallized from ethanol to give 4 9 of the title compound. M.p. 192-195C.
The following compounds were prepared in a simiiar manner starting from the appropriate isothiocyanate derivatives:
- N-tert-Butyl-N'-/ 3-(2-guanidino-4-thiazolyl)-phenyl_/-thiourea.
M.p. 160-162C (dec.) - N-AlIyl-N'-/ 3-(2-guanidino-4-thiazolyl)-phenyl_7-thiourea.
M.p. 184-187C (dec.) - N-(1,1-Dimethyl-propyl)-N'-/ 3-(2-guanidino-4-thiazolyl)-phenyl_7-thiourea. M.p. 168-170C (dec.~
- N-Ethyl-N'-/ 3-(5-guanidino-1,2,4-thiadiazol-3-yl)-phenyl_7-thiourea.
-M.p. 214-215C (dec.) N-tert-Butyl-N' { 4-(2-methyl-imidazol-4-yl)-phenyl_7-thiourea.
M.p. 142-l43C (dec.) N-tert-Butyl-N' f 4-(imidazol-4-yl)-phenyl_7-thiourea M.p. 150-153C (dec.) N-lsopropyl-N'-/ 4-(Nnidazol-4-yl)-phenyl_7-thiourea.
~l.p. -lS5-187C (dec.) ~L~ 7 ~L~3 _ l9 _ - N-Allyl-N'-/ 4-(imidazol-4-yl)-phenyl~ -thiourea.
M.p. 140-142~C (dec.) - N-Ethyl-N'-/ 4-(imidazol-4-yl)-phenyl_7-thiourea.
M.p. 125-126~C (dec.) Example 9 N { 4-(imidazol-4-yl)-phenyl_7-thiourea A) Benzoyl chloride ~28 9) was added dropwise to a solution of ammonium thiocyanate (16.7 9) in acetone (120 ml) at room temperature. After 10 minutes stirring, the solution was refluxed for 5 minutes, cooled and 4-(4-aminophenyl)-1-~l-imidazole (31.8 9) in acetone (200 ml) was dropped in. The reaction mixture was refluxed for 45 minutes and diluted with water (550 ml). The solid which separated was filtered and dried to give 36.1 9 of N-Benzoyl-N'-/ 4-(imidazol-~-yl)-phenyl_7-thiourea. M.p. 166-167C (dec.).
B) A solution of this intermediate (36 9) in methanol (150 ml) and 8% NaOH (150 ml) was stirred a~ room ~emperature for 45 minutes, and poured into water (600 ml). The solid was filtered and dried to give the title compound (18.3 9).
M.p. 208-210~C (dec.).
1~47~
Example lO
N-/ 2-methoxy-4-(irnidazol-4-yl)-phenyl_/-carbethoxy-dithiocarbamate To a cooled solution (0C) of 4-(3-methoxy-4-amino-phenyl)-1-~1-imidazole (13.2 9) in acetone (100 ml) and 30~ ammonium hydroxyde (24.5 9) was added dropwise, carbon disulfide (8 9). The reaction mixture was stirred overni~ht at 0C and then ethylchtoroformate (17.5 9) was added, Iceeping the temperature at 0C. After 15 minutes stirring, water (50 ml) was introduced and the solid which crystalli-zed out was filtered and dried to give 12~5 9 of the titl~ compound.M.p. 125-126C (dec.).
Similarly the following compounds were prepared:
- N { 4-(imidazol-4-yl)-phenyl_7-carbethoxy-dithiocarbamate.
M.p. 123-124C
- N-_ 2--fluoro-4-(imidazol-4-yl)-phenyl 7-carbethoxy-dithiocarbamate.
M.p. 132-133C.
Exampie 11
NH - C - NHR (Il) S
Rl ;n which R, R1, B and Het are as above defined to give the compounds of formula (1).
The reaction is advantageously carried out by oxidizing or reducing agents in the presence of a suitable solven-t at an appropriate temperature.
Oxidizing and reducing agents which may be used include hydrogen peroxide,. peroxy acids such as peracetic or perbenzoic acid, and Raney nickel.
Hydrogen peroxide and Raney nickel are preferred as oxidizing and reducing acJents, respectively. The reaction is preferably carried out in the presence of a solvent which may be selected from alcohols, esters, chlorinated hyclrocarbons and polar aprotic solvents, according to the nature of the oxidizing and reducing agents used. The reaction is generally effected at room temperature.
A higher or lower temperature maysometimes be found more satisfactory.
When the desulphurizatioll is carried out using hydrogen peroxide the reaction is usually performed by dissolving a compound of general formula (Il) in -the alcoholic solvents, preferably methanol.
Hydrogell peroxide is then added thereto under stirring by keeping the temperature ullder 40UC. The reaction may be optionally per-formed ~2~7 in the presence of slight quantities oF a catalyst, e.g. ammonium molybdate. The reaction is completed within few hours. The desired compound of formula (I) can be separated from the reaction mixture in a crude form as a sulphate salt by fiItration. The product may be purified, if desired, by recrystallization from an ;appropriate solvent such as ethanol in a standard manner or by purifica-tion of the isolated base. The sulphate salt may be converted into the cor-responding free base by conventional treatment with suitable bases. The base so obtained may be optionally converted with inorganic or organic acids into physiologically compatible acid addition salts, for example, by conventional method, such as by reacting it with a solution of the corresponding acid in a suitable solvent.
When the desulphurization is carried out using Raney nickel the reaction is usually performed by dissolving a compound of general formula (Il) in a suitable solvent such as alcohols or dimethylforma-mide. Raney nickel is then added under stirring, generally at room temperature, and in Few cases at 50C. The reaction is completed in a period of 1-2~ hours. The desired compounds are usually obtained as bases and may be optionally converted with inorganic or organic acids into physiologically compatible acid addition salts according to conventional methods.
The compounds of general formula (Il) used as starting material in the process, object of the present invention, may be obtained by conventional methods, -for example by reacting an amine of formula 111 R - NH7 (111) -in which R is as above defined, with an isothiocyanate of general formula IY
B - llet- ~
1 NCS (IV) 5 ~L~471V~
in wl~ich l~l, B ~lnd ~let are as above defined. The reactioll is generally carried out in the presellce of a suitable solvent such as acetolle or alcohols at a temperature from 20 C to the boiling point of the solvent used.
Instead of the compound of formula (IV) there may be used in the above reaction a compound of formula V
B - Het - ~
~ ~ .
~H - C - S - C - OR~ (V) F
S O
in which Rl, B and Het are as above defined and R2 is a lower alkyl (1-3 C atoms) or a phenyl group.
Alternatively the compound of formula (I() may also be prepared by reacting an amine of formula Vl B - Het -~-- (Vl) Rl where Rl, B and Het are as above-defined, with a isothiocyanate of formllla Vll R - N C S (Vll) in which R is above defined, following the same procedure as above described.
The c~llpo~ ds of formula (IV) and (V ) are new compoullds and constitllte Furtller featules of the presellt inventioll.
1;~4~
The compounds of formula ~IV) in their turn may be obtained by methods that are known per se in the literature, for example, by reacting the appropriate aniline derivative with carbon disulfide and ammonium hydroxide, and treating this mixture with ethyl chloroformate.
In an analogous manner are obtained the compounds of formula (V).
These compounds are the intermediates for the corresponding isothiocyanates, which precipitate from the reaction mixture and may be isolated as such. Thus, for instance, referring to Examples lO and ll below, it can be seen that time is a factor ~hich distinguishes whether the product of the reaction is a com-pound of formula IV or formula V. In Example 10, after 15 minutes stirring there was obtained a compound of formula V. In Example 11, after 2 hours stir-ring there was obtained a compound of formula IV
- 7 ~ 7~
The following examples illustrate some oF the new compounds accord-ing to the present invention; these exarnples are not to be in any way considered limitative of the scope o-f the invention itself:
Example 1 N-lsopropyl-N'-/ 4-(imidazol-4-yl)-phenyl 7-formamidine A suspension of N-lsopropyl-N'-/ 4-(imidazol-4-yl)-phenyl_/ thio-urea (13 y) and Raney-nick~l (39 9) in methanol (600 ml) is stirred at room temperature for 1 hour. The fiItered solution is evaporated to dryness and the crude residue is crystallized from ethyl acetate and diethyl ether to give 6.6 9 of the title compound. M. p . 18~-189C .
Analysis C13H16N4 Found % C 68.20 H 7.13 N 24.41 Calc. % C 68.39 H 7.06 N 24.5 Analogously the following compounds were prepared:
- N-Ethyl-N'/ 4-~imida7O1-4-yl)-phenyl_7-formamidine. M.p. 163-166C.
Analysis Cl~H14N4 Foulld % C 67.01 H 6.63 N 26.28 Calc. % C 67.26 H 6. 59 N 26.15 - N-AlIyl-N'-/ 4-( imidazol-4-yl)-phenyl_7-formamidine. M.p. 190-191C.
Analysis I3 l4 4 Fourld '~', C 68.~l H 6.30 N 24.65 C.llc. ','~ C 6~.00 H 6~24 N 24.76 - 8- ~L247~
- N-tert-Butyl-N'-~ 4-(imidazol-4-yl)-phenyl_/-formamidine, thick ol I .
Analysis C14H18N4 Found % C 69.56 H 7.54 N 23.02 Calc. % C 69.38 H 7.48 N 23.12 - N-(1,1-Dime-thyl-2-hydroxy-ethyl)-N' { 4-(imidazol-4-yl)-phenyl~ -formamidine, thick oil.
Analysis 14 18N4 Found % C 65.21 H 7.12 N 21.74 Calc. % C 65.Q9 H 7.02 N 21.69 - N-lsopropyl-N'-/ 2-methoxy-4-(imidazol-4-yl)-phenyl_7-formamidine.
M.p. 190-193C. ~ - -Analysis 14 18 4 Found % C 65.31 H 7.09 N 21.40 Calc. % C 65.09 h 7.02 N 21.09 Example 2 N-Methyl-N'-/ 3-(2-guanidino-4-thiazolyl)-phenyl_/--formamidine .
Raney Ni (6 9) was added to a solution of N-methyl-N'-/ 3-(2-guanidi-no-4-thia~olyl)-pllenyl_/ thiourea (1.53 9) in dimethylFormamido ~Z47 (20 ml). AFter 2 hours stirring, the catalyst was filtered and the solution was diluted with ether. The oil which separated was collected and triturated with ether. The solid base was pwrified by conversion to the maleate salt in ethanol. This process yielded 0.46 9 of the title compound as maleate.
Maleate salt (ethanol). M.p. 180-2C (dec.).
Analysis 20 22 68S Found % C 47.09 H 4.54 N 16.38 Calc. % C 47.43 H 4.38 N 16.59 Example 3 N-tert-Butyl-N'-/ 2-methoxy-4-(imidazoi-4-yl)-phenyl_/-formamidine A solution of 30Yo hydrogen peroxyde (18.6 ml) in ethanol was added dropwise to a stirred suspension of N-tert-~utyl-N'-/ 2-methoxy-4-(imidazol-4-yl)-phenyl_7-thiourea (10.5 9) in ethanol (170 ml). The temperature was kept below 20C during the reaction time. From the resulting solution, after -few minutes a white solid crystallized-out,-and after 30 minutes stirring the solid was collected by fiItration to give 9.9 9 of the title compound, as sulphate salt.
Sulphate salt (ethanol). M.p. 260C (dec.).
Analysis .
15 22 405S Found % C 48.95 H 5 oS N 15.23 Calc. ~ C 48.63 H 5.98 N 15.12 In the same manner, starting from the suitable N-substituted thiourea the ~ollowing compDLInd~ were obtained.
lZ47~
- N-/ 4-(imidazol-4-yl)-phenyl_/-formamidire Maleate salt (acetone). M.p. 169-70C (dec.).
Analysis 18 18 48 Found % C 50.76 H 4.43 N 13.18 Calc. % C 51.07 H 4.34 N 13.39 - N-Ethyl-N'-/ 4-(imidazol-4-y l)-phenyl_/-formamidine Sulphate salt ~ethanol). M.p. 254-2560C ( dec.).
Analysis N404S Found % C 46.31 H 5.22 N 18.05 Calc. % C 46.1~ ~ 5.16 N 17.94 - N-lsopropyl-N'-/ a - ( i midazol-4-yl)-phenyl_/-formamidine Sulphate salt (ethanol). M.p. 235C ( dec.).
Analysis 13 18 4 4 Found % C 48.o9 H 5.61 N 17.02 Calc. % C 47.83 H 5. j6 N 17.17 - N-Allyl-N'-/ 4-(imidazol-4-yl)-?henyl_7-formamidine Sulphate salt (ethanol). M.p. 270C ( dec.).
Analysis 13 16 4 4S Found % C 48.26 H 5.04 N 17.32 Calc. ~/o C 48.14 H 4.97 N 17.27 I.
" lZ~7~C~8 - N-Cyclohexyl-N'-/ 4-(imidazol-4-yl)-phenyl_7-formamidine Sulphate salt (ethano'). M.p. 225-227C (dec.).
Analysis 16 22 404S Found % C 52.18 H 6.11 N 15.34 Calc. ~o C 52.~4 H 6.05 N 15.29 - N-tert-Butyl-N'-/ 4-~imidazol-4-yl)-phenyi_7-formamidine .
Sulphate salt (ethanol). M.p. 261-262C (dec.).
Analysis 14 20N4C4S Found % C 49.67 H 5.49 N 16.39 Calc. % C 49.54 H 5.64 N 16.51 - N-tert-Amyl-N'-/ 4-(imidazol-4-yl)-phenyl 7-formamidine Sulphate salt (ethanol). M.p. 256-2670C (dec.).
Analysis 15~22N44S Found % C 49.84 H 6.18 N 15.70 Calc. % C 50.83 H 6.26 N 15.81 - N-~1,l-Dimethyl-2-hydro~y-ethyl)-N'-/ 4-(imidazol-4-yl)-phenyl_7-formamidine Sulphate salt (ethanol). M.p. 193-194C (dec.).
Analysis 14 20 405S Found % C 47.39 H 5.71 N 14.83 Calc. ~/o C 47.18 !-l 5.65 N 14.72 12g~7~
- N-(l,l-Dimethyl-propen-2-yl)-N'-/ 4-(imidazol-4-yl)-phenyl 7--formamidine Sulphate salt (ethanol). M.p. 229-230C (dec.).
Anaiysis C15H20N44S Found % C 51.48 H 5.86 N 15.75 Calc. % C 51.12 H 5.72 N 15.90 N-lsopropyl-N'-/ 2-methoxy-4-(imidazol-4-yl)-phenyl_7-formamidine Sulphate salt (ethanol). M.p. 204-205C (dec.).
Analysis 1~ 20N404S Found % C 47.29 H 5.70 N 15.58 Calc. % C 47.18 H 5.65 N 15.72 N-tert-Butyl-N'-/ 2-fluoro-4-(imidazol-4-yl)-phenyl_/-formamidine Sulphate salt (ethanol). M.p. 249-250C (dec.).
Analysis C14H19FN404S Found % C 47.11 H 5.41 N 15.80 Calc. % C 46.91 H 5.34 N 15.63 N-lsopropyl-N'-/ 2-chloro-4-(imidazol-4-yl)-phenyl_/-formamidine Sulphate salt (ethanol~ .p. 218-220C (dec.).
Analysis C13H17CIN40~S Found % C 43.54 H 4.88 N 15.40 Calc. % C 43.2G H 4.74 N 1~.52 t3 ~L~ 7 1 ~3 Example 4 N-Ethyl-N -/ 3-(5-guanidino-1,2,4-thiadiazol-3-yl)-phenyl~ -formamidine To a stirred solution of N-ethyl-N -/ 3-(5-guanidino-1,2,4-thiodia-zol-3-yl)-phenyl_/-thiourea (5 9) in methanol (600 ml) containing a cataiytic amount o-f ammonium molybdate, a solution of 30% hydrogen peroxice (8.3 ml) in methanol (8 ml) was dropped slowly during 45 minutes. A-fter adoitional 4 hours stirring, the solid which separa-ted was fiItered, suspended in water and the suspension was made alkaiine with 10% sodium carbonate. The free base was fiItered, washed with water and dried to give 3.5 9 of the title compound.
Maleate salt (etnanol). M.p. 174-177C (dec.).
Analysis 20 23 7 8 Found % C 46.13 H 4.52 N i9.01 Ca!c. % C 46.o6 H 4.45 N 18.80 The following compounds were prepared in a similar manner, starting from the appropriate thiourea derivatives.
N-Methyl-N -/ 3-(2-guanidino-4-thiazolyl)-phenyl_/-Formamidine Hydrochloride salt (ethanol). M.p. 210-212C (dec.).
Analysis 12 l6CI2N6S Found % C 41.27 H 4.67 N 23.98 Calc. % C 41.50 H 4.64 N 24.20 N-tert-Butyl-N -/ 3-(2-~uanidino-4-thiazolyl)-phenyl_7--Formamidine Hydrochlorioe salt (methanol). M.p. 234-236C tdec.).
Analysis 15 2 CI2 6S Fouild % C 46.69 H 5.55 N 21.32 Calc. % G 46. 27 H 5.69 N 21. 58 12~73~
N-Allyl-N'-/ 3-(2-guani~ino-4-thiazolyl)-phenyl_/-Forrnarnidine Maleate salt (ethanol). M.p. 168-170C (dec.).
Analysis 22 24 6 8 Found % C 49.54 H 4.47 N 15.89 Calc. % C 49.62 H 4.54 N 15.78 N-(l,l-Dimethyl-propyl)-N'-/ 3-(2-guanidino-4-thiazolyl)-phenyl_7-formamidine Hydrochloride salt (ethanol). M.p. 216-218C (dec.).
Analysis 16 24 2 6 Found % C 47.38 H 6.25 N 20.~8 Calc. % C 47.64 H 6.oo N 20.83 N-lsopropyl-N'-/ 4-(1,2,4-triazol-3-yl)-phenyl_/-formami~ine .
Maleate salt (ethanol). M.p. 155-157C (dec.).
Analysis 20 23 58 Found % C 51.87 ~ 4.98 N 15.23 Calc. % C 52.06 H 5.02 N 15.18 N-lsopropyl-N'-/ 4-(pyrazol-3-yl)-phenyl_7-formamidine Hydrochloride salt (acetone). M.p. 202-203C (dec.).
Analysis l3 18 2 L~ Fourld % C 51.70 H 6.18 N 18.41 Calc. iy~ C 51.83 ll 6.Q2 N 18.Go i ~ 7 N-lsopropyl-N'-/ 4-(imidazol-2-yl)-phenyl_/-formamidirle Fumarate (ethanol). M.p. 138-140C (dec.).
Analysis 21 24 4 8 Found % C 55.02 H 5.17 N 11.85 Calc. % C 54.77 H 5.25 N 12.17 N-tert-Butyl-N'-/ 4-(2-methyl-imidazol-4-yl)-phenyl_/-formamidine Sulphate salt (methanol). M.p. 276-2780C (dec.).
Analysis 15 22N4 4S Found % C 50.50 H S.06 N 15.77 Calc. % C 50.84 h' 6.26 N 15.81 Exan~le 5 N-lsopropyl-N'-/ 4-(~.-imidazolyl3-phenyl_/-formamidine Raney Ni (8.v 9) was added to a suspension o~ N-isopropyl-N'-/ 4-(2-mercapto-imidazol-4-yl)-phenyl_7-thiourea (1.1 9) in dimethyl formamide (22 ml).The mixture was heated at 50C for 24 hours, cooled and fiItered. The solution was diluted ~ith water and the gummy solid which separated was dissolved in ethanol and purified ~y conversion to the maleate salt (0.4 9).
Maleate salt (ethanol). ~II.p. 195-197C (dec.).
Analysis 21 24 4 8 Found ~u C 54.41 H 5.33 N 12.00 Calc. % C 54.78 H 5.25 N 12.t7 ~2~7 Example 6 N-lsopropyl-N'-~ 4-(imidazol-4-yl)-phenyl~ -thiourea A solution of 4-(4-aminophenyl)-1-H-imidazole (15.9 9) and isopropyl isothiocyanate (15.2 9) in ethanol (L50 ml) was refluxed for 90 minutes and evaporated to dryness. From the crude residue the title compound was obtained after crystalliza'ion from 70~o ethanol (8.2 9).
M.p. 204-205C.
In the same manner, from the suitable amino derivatives and the isothiocyanate the following thioureas were prepared:
- N-Ethyl-N'-/ 4-(imidazol-4-yl)-phenyl_7-thiourea. M.p. 125-126C
_ . .
- N-AlIyl-N'-/ 4-(imidazol-4-yl)-phenyl~ -thiourea. M.p. 140-142C
_ _ _ - N-Cyclohexyl-N'-~ 4-(imidazol-4-yl)-phenyl 7-thiourea.
M.p. 162-163C
- N-lsopropyl-N'-_ 4-(1,2,4-triazol-3-yl)-phenyl 7-thiourea.
M.p. 184-185~C
;- - N-lsopropyl-N'-/ ~ 1-3-yl)-phenyl_/-thiourea. M;p; 1 59-i60c - N-lsopropyl-N'-/ 4-(imidazol-2-yl)-phenyl~ -thiourea.
~.I.p~ 187-188C (dec.) Example 7 N-tert-~utyl-N'-~ 2-methoxy-~-(imiaazol-4-yl)-phenyl_7-~hiourea _ A solution oF N { 2-methoxy-4-(imidazol-4-yl)-phenyl_7-carbethoxy dithiocarbamate ( 12 . 5 9) and t-butylainine (13.5 9) in methanol was ~L24 stirred at room temperature overnight and then evaporated to dryness.
After crystallization From diethyl ether of the residue, the title compound was obtained (10.8 9). M.p. 156-157C.
Analogously the following compounds were obtained:
- N-lsopropyl-N'-/ 4-(imidazol-4-yl)-phenyl_7-thiourea.
M.p. 185-187C (dec.) - N-Ethyl-N'-~ 4-(imidazol-4-yl)-phenyl_7-thiourea.
M.p. 125-126C (dec.) - N-Allyl-N'-/ 4-(imidazol-4-yl)-phenyl_7-thiourea.
M.p. 140-142C (dec.) - N-Cyclohexyl-N'-_ 4-(imidazol-4-yl)-phenyl_7-thiourea.
M.p. 162-163C (dec.) - N-tert-Butyl-N'-/ 4-(imidazol-4-yl)-phenyl_7-thiourea.
M.p. 147-149C
- N-tert-Amyl-N'-/ 4-(imidazol-4-yl)-phenyl_7-thiourea.
M.p. 159-160C (dec.) - N-(l~l-Dimethyl-2-~ydroxye~hyll~N~-/4-(imidazol-4-yl)-phenyl7-thiourea.
-M.p. 171-172C (dec.) - N-(1,1-Dimethyl-propen-2-yl)-N'-/4-(imidazol-4-yl)-phenyl7-thiourea-M.p. 163-L64C (dec.) - N-lsopropyl-N'-/ 2-methoxy-4-(imidazol-4-yl)-phenyl_7-thiourea.
M.p. 156-157C (dec.) - N-tert-Butyl-N'-/ 2-fluoro-4-(imidazol-4-yl)-phenyl_7-thiourea.
M.p. 148-149C (dec.) - N-lsopropyl-N' { 2-chloro-4-(imidazol-4-yl)-pllenyl_7-tlliotlrea.
M.p. lS5-15~C (dec.) E,xamp I e $
N-Methyl-N'-/ 3-(2-guanidino-4-thiazolyl)-phenyl~ -thiourea A mixture oF 3-(2-guanidino-4-thiazolyl)-phenyl isothiocyanate hydrobromide (6 9) and 35~ aqueous methylamine (6 ml) in acetone (80 ml) was stirred overnight. The resulting solution was filtered with charcoal and evaporated to dryness. The residual gum was washed with water and recrystallized from ethanol to give 4 9 of the title compound. M.p. 192-195C.
The following compounds were prepared in a simiiar manner starting from the appropriate isothiocyanate derivatives:
- N-tert-Butyl-N'-/ 3-(2-guanidino-4-thiazolyl)-phenyl_/-thiourea.
M.p. 160-162C (dec.) - N-AlIyl-N'-/ 3-(2-guanidino-4-thiazolyl)-phenyl_7-thiourea.
M.p. 184-187C (dec.) - N-(1,1-Dimethyl-propyl)-N'-/ 3-(2-guanidino-4-thiazolyl)-phenyl_7-thiourea. M.p. 168-170C (dec.~
- N-Ethyl-N'-/ 3-(5-guanidino-1,2,4-thiadiazol-3-yl)-phenyl_7-thiourea.
-M.p. 214-215C (dec.) N-tert-Butyl-N' { 4-(2-methyl-imidazol-4-yl)-phenyl_7-thiourea.
M.p. 142-l43C (dec.) N-tert-Butyl-N' f 4-(imidazol-4-yl)-phenyl_7-thiourea M.p. 150-153C (dec.) N-lsopropyl-N'-/ 4-(Nnidazol-4-yl)-phenyl_7-thiourea.
~l.p. -lS5-187C (dec.) ~L~ 7 ~L~3 _ l9 _ - N-Allyl-N'-/ 4-(imidazol-4-yl)-phenyl~ -thiourea.
M.p. 140-142~C (dec.) - N-Ethyl-N'-/ 4-(imidazol-4-yl)-phenyl_7-thiourea.
M.p. 125-126~C (dec.) Example 9 N { 4-(imidazol-4-yl)-phenyl_7-thiourea A) Benzoyl chloride ~28 9) was added dropwise to a solution of ammonium thiocyanate (16.7 9) in acetone (120 ml) at room temperature. After 10 minutes stirring, the solution was refluxed for 5 minutes, cooled and 4-(4-aminophenyl)-1-~l-imidazole (31.8 9) in acetone (200 ml) was dropped in. The reaction mixture was refluxed for 45 minutes and diluted with water (550 ml). The solid which separated was filtered and dried to give 36.1 9 of N-Benzoyl-N'-/ 4-(imidazol-~-yl)-phenyl_7-thiourea. M.p. 166-167C (dec.).
B) A solution of this intermediate (36 9) in methanol (150 ml) and 8% NaOH (150 ml) was stirred a~ room ~emperature for 45 minutes, and poured into water (600 ml). The solid was filtered and dried to give the title compound (18.3 9).
M.p. 208-210~C (dec.).
1~47~
Example lO
N-/ 2-methoxy-4-(irnidazol-4-yl)-phenyl_/-carbethoxy-dithiocarbamate To a cooled solution (0C) of 4-(3-methoxy-4-amino-phenyl)-1-~1-imidazole (13.2 9) in acetone (100 ml) and 30~ ammonium hydroxyde (24.5 9) was added dropwise, carbon disulfide (8 9). The reaction mixture was stirred overni~ht at 0C and then ethylchtoroformate (17.5 9) was added, Iceeping the temperature at 0C. After 15 minutes stirring, water (50 ml) was introduced and the solid which crystalli-zed out was filtered and dried to give 12~5 9 of the titl~ compound.M.p. 125-126C (dec.).
Similarly the following compounds were prepared:
- N { 4-(imidazol-4-yl)-phenyl_7-carbethoxy-dithiocarbamate.
M.p. 123-124C
- N-_ 2--fluoro-4-(imidazol-4-yl)-phenyl 7-carbethoxy-dithiocarbamate.
M.p. 132-133C.
Exampie 11
4-~2-Methyl-imidazol-4-yl)-phenyl isothiocyanate Carbon disul-fide (6.~5 9) was added ~o a solution of 2-methyl-4-(4-aminophenyl)-1-.~-imidazole (10.39 9) and 30% ammonium hydroxide (9 21.03) in methanol (105 ml) cooled at 0C over a period of 15 minutes. AFter 24 hours stirring at 0C, e~hylchloroformate (21.54 9) was dropped to the mixture at 0C. After 2 hours stirring, the mixture was diluted with cold water (60 ml) and the solid was fiItered, washed with water ana dried to give 12.3 9 of the title compound . M.p. 233-235C.
- 21 - ~24'7~
S;milarly the l`ollowing cornpound was prepared:
- 4-(lmidazol-4-yl)-phenyl isothiocyanate. M.p. 139-142C (dec.) Example 12 3-Bromoacetyl-phenyl isothiocyanate Bromine (17.23 9) was dropped to a stirred solution of 3-acetyl-phenyl isothiocyanate (17.4 9) and 1,4-dioxane (9.52 9) in diethyl ether (15~ ml) with U.V. Iight irradiation. After addi--tional 2 hours stirring, the reaction mixture was evaporated to small volume, cooled and the crystalline product was fiitered, washed with isopropanol and dried to give 17.5 9 of the title compound. M.p. 62-4C.
3-(2-Guanidino-4=thia~olyl)-phenyl isothiocyanate A solution of 3-bromoacetyl-phenyl isothiocyanate (6.4 9) and amidinothiourea (2.95 9) in acetone (35 mi) was heated under reflux for 5 hours.
The mi~ture was cooled and the prodwct was fiItered and dried to give 8~l8 9 of the title compound as hydrobromide.
M.p. 230-3C.
- 21 - ~24'7~
S;milarly the l`ollowing cornpound was prepared:
- 4-(lmidazol-4-yl)-phenyl isothiocyanate. M.p. 139-142C (dec.) Example 12 3-Bromoacetyl-phenyl isothiocyanate Bromine (17.23 9) was dropped to a stirred solution of 3-acetyl-phenyl isothiocyanate (17.4 9) and 1,4-dioxane (9.52 9) in diethyl ether (15~ ml) with U.V. Iight irradiation. After addi--tional 2 hours stirring, the reaction mixture was evaporated to small volume, cooled and the crystalline product was fiitered, washed with isopropanol and dried to give 17.5 9 of the title compound. M.p. 62-4C.
3-(2-Guanidino-4=thia~olyl)-phenyl isothiocyanate A solution of 3-bromoacetyl-phenyl isothiocyanate (6.4 9) and amidinothiourea (2.95 9) in acetone (35 mi) was heated under reflux for 5 hours.
The mi~ture was cooled and the prodwct was fiItered and dried to give 8~l8 9 of the title compound as hydrobromide.
M.p. 230-3C.
Claims (16)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of general formula I
(I) in which B represents a guanidino group or a hydrogen atom;
R represents a linear or branched alkyl group which may optionally contain one heteroatom, an alkenyl group, a cycloalkyl or cycloaliphatic alkyl group having 3 to 6 carbon atoms;
R1 represents a hydrogen atom, a C1-3 alkyl or alkoxy group or halogen atom;
Het represents a substituted or unsubstituted ring of imidazol, thiazol, thiadiazol, triazol or pyrazol; tautomers thereof and physiologically compatible acid addition salts thereof, which comprises desulphurizing a corresponding thiourea of general formula II
(II) in which R, R1, B and Het are as above defined, to give a compound of formula (I) and, if required, converting the compound of formula (I) into a physiologically compatible acid addition salt thereof.
(I) in which B represents a guanidino group or a hydrogen atom;
R represents a linear or branched alkyl group which may optionally contain one heteroatom, an alkenyl group, a cycloalkyl or cycloaliphatic alkyl group having 3 to 6 carbon atoms;
R1 represents a hydrogen atom, a C1-3 alkyl or alkoxy group or halogen atom;
Het represents a substituted or unsubstituted ring of imidazol, thiazol, thiadiazol, triazol or pyrazol; tautomers thereof and physiologically compatible acid addition salts thereof, which comprises desulphurizing a corresponding thiourea of general formula II
(II) in which R, R1, B and Het are as above defined, to give a compound of formula (I) and, if required, converting the compound of formula (I) into a physiologically compatible acid addition salt thereof.
2. A process as claimed in claim 1 wherein a compound of general formula II is obtained by a) reacting an amine of formula III
R - NH2 (III) in which R is as defined in claim 1, with an isothiocyanate of general formula IV
(IV) in which R1, B and Het are as defined in claim 1, or b) reacting an amine of formula III as defined above with a compound of formula V
(VI) in which R1, B and Het are as defined in claim 1 and R2 is a lower alkyl (1-3 C atoms) or a phenyl group; or c) reacting an amine of formula VI
(VI) where R1, B and Het are as defined in claim 1, with an isothio-cyanate of formula VII
R - N C S (VII) in which R is as defined in claim 1.
R - NH2 (III) in which R is as defined in claim 1, with an isothiocyanate of general formula IV
(IV) in which R1, B and Het are as defined in claim 1, or b) reacting an amine of formula III as defined above with a compound of formula V
(VI) in which R1, B and Het are as defined in claim 1 and R2 is a lower alkyl (1-3 C atoms) or a phenyl group; or c) reacting an amine of formula VI
(VI) where R1, B and Het are as defined in claim 1, with an isothio-cyanate of formula VII
R - N C S (VII) in which R is as defined in claim 1.
3. A process as claimed in claim 2 wherein the compound of formula V is obtained by reacting a corresponding aniline compound with carbon disulfide and subsequently treating the reaction mixture with ClCOOR2 in which R2 is as defined in claim 2.
4. A process as claimed in claim 2 wherein the compound of formula IV is obtained by reacting a corresponding aniline compound with carbon disulfide, subsequently treating the reaction mixture with ClCOOR2 in which R2 is as defined in claim 2 and continuing the reaction for a period of time sufficient to obtain a compound of formula IV.
5. A process as claimed in claim 1, 2 or 3 in which the desulphurization is carried out by oxidizing or reducing agents.
6. A process as claimed in claim 1, 2 or 3 in which the desulphurization is carried out by oxidizing with an oxidizing agent.
7. A process as claimed in claim 1, 2 or 3 in which the desulphurization is carried out by oxidizing with hydrogen peroxide.
8. A process as claimed in claim 1, 2 or 3 in which the desulphurization is carried out by reducing with a reducing agent.
9. A process as claimed in claim 1, 2 or 3 in which the desulphurization is carried out by reducing with Raney nickel.
10. A process as claimed in claim 1, 2 or 3 in which the reaction is carried out in the presence of a suitable organic solvent.
11. A process as claimed in claim 1, 2 or 3 in which the reaction is carried out in the presence of a suitable organic solvent which comprises methanol or dimethylformamide.
12. A process as claimed in claim 1, 2 or 3 in which the reaction is performed at a temperature from 20° to 50°C.
13. A process as claimed in claim 1, 2 or 3 wherein R
represents a linear or branched alkyl group which contains an oxygen atom or nitrogen atom as a heteroatom.
represents a linear or branched alkyl group which contains an oxygen atom or nitrogen atom as a heteroatom.
14. A process as claimed in claim 1, 2 or 3 in which Het is an imidazol-4-yl group, B is hydrogen, R is isopropyl and R1 is hydrogen and the imidazol-4-yl group is in the para position with respect to the formamidine group.
15. A process for preparing N-isopropyl-N'-[4-(imidazol-4-yl)-phenyl]-formamidine which comprises hydrogenating N-isopropyl-N'-[4-(imidazol-4-yl)-phenyl] thiourea with Raney nickel to desulphurize.
16. A process as claimed in claim 13 wherein the N-isopropyl-N'-[4-(imidazol-4-yl)-phenyl] thiourea is obtained by reacting 4-(4-aminophenyl)-1-H-imidazol with isopropylisothio-cyanate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT21508A/84 | 1984-06-20 | ||
| IT8421508A IT1209558B (en) | 1984-06-20 | 1984-06-20 | PROCEDURE FOR THE PREPARATION OF HETEROCYCLYLPHENYLFORMAMIDINS. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1247108A true CA1247108A (en) | 1988-12-20 |
Family
ID=11182840
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000484268A Expired CA1247108A (en) | 1984-06-20 | 1985-06-18 | Process for the preparation of heterocyclylphenylformamidines |
Country Status (8)
| Country | Link |
|---|---|
| KR (1) | KR860000266A (en) |
| CA (1) | CA1247108A (en) |
| ES (1) | ES8606287A1 (en) |
| FI (1) | FI852428L (en) |
| GR (1) | GR851444B (en) |
| IT (1) | IT1209558B (en) |
| NO (1) | NO852471L (en) |
| PT (1) | PT80647B (en) |
-
1984
- 1984-06-20 IT IT8421508A patent/IT1209558B/en active
-
1985
- 1985-06-13 GR GR851444A patent/GR851444B/el unknown
- 1985-06-17 PT PT80647A patent/PT80647B/en not_active IP Right Cessation
- 1985-06-18 CA CA000484268A patent/CA1247108A/en not_active Expired
- 1985-06-19 KR KR1019850004330A patent/KR860000266A/en not_active Application Discontinuation
- 1985-06-19 NO NO852471A patent/NO852471L/en unknown
- 1985-06-19 ES ES544357A patent/ES8606287A1/en not_active Expired
- 1985-06-19 FI FI852428A patent/FI852428L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| FI852428L (en) | 1985-12-21 |
| ES8606287A1 (en) | 1986-04-01 |
| IT8421508A0 (en) | 1984-06-20 |
| FI852428A0 (en) | 1985-06-19 |
| ES544357A0 (en) | 1986-04-01 |
| PT80647B (en) | 1987-05-04 |
| KR860000266A (en) | 1986-01-27 |
| IT1209558B (en) | 1989-08-30 |
| NO852471L (en) | 1985-12-23 |
| PT80647A (en) | 1985-07-01 |
| GR851444B (en) | 1985-11-25 |
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