JPS5995276A - Novel imidazole compound - Google Patents

Abstract

NEW MATERIAL:A imidazole compound shown by the formula I [R1 is H, lower alkyl; X1 is carbonyl, or sulfonyl; n is 0 or 1; Y is lower alkyl, cycloalkyl, (substituted)phenyl, (substituted)heterocyclic group] and its acid addition salt. EXAMPLE:4-Benzoylcarbamoyloximidazole-5-carboxyamide. USE:Having cell growth inhibitory action on tumor cell such as sarcoma 180, L1210, Lewis Lung Carcinoma, etc., useful as a carcinostatic agent. PROCESS:A 4-hydroxyimidazole-4-carboxyamide which is replaced with a lower alkyl group at the 1-psotion or not is brought into contact with an isocyanic acid derivative shown by the formula III in a solvent preferably in the presence of a base to give a compound shown by the formula I . A compound shown by the formula IV may be used instead of the compound shown by the formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel imidazole compound represented by the following general formula and an acid addition salt thereof.

R.

However, the symbols in formula 2 have the following meanings.

R1: hydrogen atom or lower alkyl group X: carbonyl group <-Co-) or sulfonyl group (
-8O□-) n: 0 or I Y: lower alkyl group, cycloalkyl group.

Substituted or unsubstituted phenyl group or substituted or unsubstituted heterocyclic group To further explain the meaning of the symbols in the above formula, lower alkyl groups include straight chain or branched carbon atoms having 1 to 5 carbon atoms. chains, such as methyl, ethyl, propyl, isopropyl groups.

It includes a butyl group, a 5ee-butyl group, an amyl group, and the like. The cycloalkyl group is a cyclic alkyl group having 3 to 7 carbon atoms, and is a 2-cyclopropyl group.

Examples include cyclope/tyl group and cyclohexyl group. Examples of the heterocyclic group include a 5- to 6-membered aromatic heterocyclic group having an oxygen atom, sulfur atom, or nitrogen atom as a hetero atom, such as a furyl group, a chenyl group, a pyrazolyl group, a 2-pyridyl group, and a pyrimidyl group. Contains groups. Substituents for phenyl groups or heterocyclic groups include nologeno atoms (fluoro atoms, chloro atoms, bromine atoms, iodo atoms, etc.), nitro groups, lower alkyl groups (methyl groups, ethyl groups, 2-propyl groups, inglovir groups, etc.) , lower alkokino groups (methoxy, ethoxy, propoxy, etc.), trihalogenmethyl groups (trifluoromethyl, etc.), unsubstituted or lower alkyl-substituted amine groups (methylamino, dimethylamino, etc.) can be mentioned. These substituents can be substituted one or two times.

When two lower alkyl groups are adjacent as substituents, these groups together form a butadienylene group (-CH
=CH-CH=C[(-) can be formed. In other words, when the substituent of the fer group is buta, the whole forms a naphthyl group, and when the substituent of a heterocyclic group, for example hahiridino, is a butano group, the whole forms a quinolyl group or isoquinolyl group. .

Next, the acid addition salt of the above compound (1) is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples of salts with inorganic acids include hydrochloride, sulfate, dinitrate, etc. As a salt with, penzenosulfonoic acid! , p-) Luenesulfonate, tartrate.

Examples include lactate, maleinoate, and the like.

Note that when R1 of the compound (1) of the present invention is a hydrogen atom, tautomers exist.

The compound (1) of the present invention or its acid addition salt is Sarc
oma 180°L1210. Lewis Lun
g Carcinoma, Ehrlich Carc
It exhibits a cell proliferation inhibiting effect on tumor cells such as inoma and P-388. Therefore, the compounds of the present invention or acid addition salts thereof are useful as anticancer agents.

Based on the results of animal experiments, the dosage of the target compound of the present invention for anticancer effects for humans is 5 to 500 doses per day.
Administration is carried out orally or parenterally. Oral administration can be in any dosage form such as 2 tablets, capsules, powders, or liquids.

These pharmaceutical dosage forms can be prepared by conventional methods using appropriate pharmaceutical carriers.

According to the present invention, the above compound (1) can be produced by the following method.

1st manufacturing method This manufacturing method uses 4-hydroxyimidazole-5-carboxamide (also known as 4-carbamoylimidazolium-5-oleate) (■), which is substituted with a lower alkyl group at the 1st position or unsubstituted, or a salt thereof. and isocyano acid derivative (■) to form imidazole compound (I).
It manufactures. As the salt of the above compound (II), for example, a salt with a base such as an alkali metal salt such as a quaternary ammonium salt disodium salt can be used.

In carrying out this production method, two compounds (II) or their salts and a corresponding amount of compound (■) are brought into contact with each other in a solvent, preferably in the presence of a base. As the solvent, any ordinary organic solvent that does not participate in the reaction can be used.

Preferably, aprotic solvents such as dimethylformamide (DMF), dimethylsulfoquine (DMSO), hexamethylphosphorylamide (HEMPA), etc. are suitable. Further, as the base, preferably a tertiary amine such as triethylamine is used.

Although the reaction easily proceeds at room temperature, it can also be carried out under heating or cooling.

In this production method, a corresponding azide derivative represented by N5-(X)ny can also be used instead of the upper isocyanic acid derivative (I).

Second production method (1,) (1) This method alkylates the compound (11) in which R3 is a hydrogen atom among the target compounds of the present invention to produce the corresponding compound in which RI is a lower alkyl group. It's a method. Alkylation can be carried out by a conventional method using a diazoalkane such as diazomethane, an alkylnolide such as methyl iodide, a dialkyl sulfate such as dimethyl sulfate, etc. as an alkylating agent.

Next, in order to further explain the present invention, the general formula (1
) Examples are listed below for the compounds included in K in the table below. In addition, among the symbols in the examples.

mp is melting point, Anal is elemental analysis value, IR is infrared absorption spectrum, NMR is nuclear magnetic resonance spectrum, Example 1゜4-Hydroxyimidazole-5-carboxamide 0
．． 635 g was suspended in 20 ml of dimethylformamide, 0.7 ml of triethylamine was added, and 0.625 g of cyclohexyl diisocyanate was added dropwise to give a solution of 35 to 40 g.
The mixture was stirred at C for 1 hour and left at room temperature overnight. 180 ml of ice water was added to the reaction solution, followed by neutralization with 5 ml of 1N hydrochloric acid, and one precipitate was taken. Recrystallized from an ethyl acetate-methanol mixture to obtain a powder of 4-cyclohexylcarbamoyloquinoimidazole-5-carboxamide (0.6%).
I got g. This material exhibits the following physical and chemical properties.

mp: Does not show a clear melting point and decomposes into color and carbonizes at temperatures above about '250 C.

Anal, f%): (as Cl1H16N403)
CHN Calculated value 52,37 6.39 22.21 Actual value 52,29 6.33 22.35IR (K
Br, cm')': 3380.3140.2
900.1730.1610°500 NM, R (DMSO-d, , δ): 1.0
'2.1 (m, 10B), 3.7 (m.

LH), 6.9 (m, 3H).

8.48 (8, IH), 9.6 (d, IH)
Example 2 4-hydroxyimidazole-5-carboxamide 0
．． After suspending 635 g in 20 ml of dimethylformamide and adding 0.7 ml of triethylamine, 5-
0.29 g of methyl incyanate was added dropwise at 10C, and the mixture was stirred at room temperature for 30 minutes. 100 mt of ice water was added to the reaction solution, followed by neutralization with 5 ml of 1N hydrochloric acid, precipitated crystals were collected, and 4-methylcarbamoyloxyimidazole-
0.7 g of 5-carboxamide powder was obtained.

This powder was dissolved in an aqueous potassium carbonate solution and neutralized with hydrochloric acid to obtain colorless needle crystals. This material exhibits the following physical and chemical properties.

mp: Does not show a clear melting point and carbonizes and decomposes at temperatures above about 200C.

Anal, f%): (C6H3N403 0.4 H
2O) CHN Calculated value 37,66 4.63 29.2'8 Actual value 37,56 4.53 29.54IR(
KBr, am'): 3370.3260,1
725, 1620, 1570°505 NMR (DMSO-da, δ): 2.84 (d
, 3H), 5.3(m).

6.93 (m, 2H), 8.50 (s, IH).

9.3 (d, LH).

Example 3 4-Hydroquinimidazole-5-carboxamide 1
After suspending 27 g in 20 ml of dimethylpolamide and adding 1.4 ml of triethylamine, 0.85 g of inglovir incyanate was added, and 1
The mixture was stirred for an hour and left overnight at room temperature. Add 18 ml of ice water to the reaction solution.
0 ml was added, followed by neutralization with 10 mt of 1N hydrochloric acid, and a lot of precipitated crystals were collected. The crystals were dissolved in an aqueous potassium carbonate solution and neutralized with hydrochloric acid to obtain a colorless powder of 4-isopropylcarbamoyloxyimidazole-5-carboxamide.1.
1g was obtained. This product exhibits the same physical and chemical properties.

mp: Does not show a clear melting point 2, and carbonizes and decomposes at temperatures above about 200C.

Anal, (@: (C8H+2N40s' (
13t120) CHN Calculated value 44.16 5.84 25.75 Actual value 44.06 6.23 25.94IR (K
Br, am'): 3380.3280,30
90.1730.1645°55O NMR (DMSOdo, δC1,24(d, 6H)
, 3.96 (m, IH).

Approximately 6.5 (m, IH), 6.93 (m, 2H).

8.50 (s, IH), 9.5'0 (d, IH)
.

Mass'(r+1/zC212(M+), 127,
85.70 The following compound was produced by the same reaction procedure as in Example 3.

Example 4 4-phenylcarbamoyloxyimitasole-5-carboxamide.

This compound exhibits the following physical and chemical properties.

mp,: Gradually decomposes above about 250C (crystallized from potassium carbonate solution with hydrochloric acid) Anal, f%): (as Cl1HION403) CHN Calculated value 53,66 3.93 22.51 Actual value 53,66 4. 09 22.75IR(K
Br, cm'): 3350.3110,28
90.1735.1590°56O NMR (D20+, Co3.δ): 8.1~8
．． 6 (m)Mass (FD method, rrV/z)
: 246(M+), 127,119゜Example 5 4-benozoylcarbamoylogiciimidazole-5-
Carboxamide.

This material exhibits the following physical and chemical properties.

mp,: Gradually carbonized and decomposed at about 250C or higher Anal, (
9f9: (as Cl2H, oN404) CHN Calculated value 52,56 3.68 20.43 Actual value 52,77 3.59 20.57IR (K
Br, am'): 3410, 3290, 31
30,2850.1765°1620.150O NMR (DMSO-d,,δ): 6.8 (m)
, 7.4-7.6 (m).

7.8-7.9 (m) Mass (FD method, rrI//z), : 27
5 (M++ 1), 274 (M”).

147.127゜Example 6゜4-Tosylcarbamoyloxyimidazole-5-carboxamide.

This compound exhibits the same physical and chemical properties.

mp,: gradual carbonization decomposition at about 200C or higher;
(919: (as C12H12N405 S) Calculated value 9.89 Actual value 9.88 IR (KBr, cm'): 3140.172
0.1600.1430.135ONMR(DMSOd
o, δ): 2.38(s, 3H), 7.4(
d, 2H).

7.9 (d, 2H), 8.4 (s, IH)
.

10.3 (m, 2H), 12-13 (m, 2H) Mas
s (FD method, rr1//z): 197,12
7゜Example 7゜1-Methyl-4-methylcarbamoyloxyimidazole-5-carboxamide.

11 g of 4-methylcarbamoyloxyimidazole-5-carboxamide 50 obtained in Example 2 was dissolved in 5 ml of dimethyl sulfoxide at room temperature.

An ether solution of diazomethane was added dropwise until one reaction solution turned yellow. Low-boiling substances were distilled off under reduced pressure, a mixture of chloroform and hexano was added, and one portion of the precipitated crystals was collected to give 1-methyl-4-methylcarbamoyloxyimidazole-5.
- 15 mg of carboxamide powder was obtained. This material exhibits the following physical and chemical properties.

mp,: gradual carbonization decomposition Anal at about 200C or higher;
(@” (as C7HION403) CHN Calculated value 42,42 5.09 28.27 Actual value 42.45 5.03 28.02IR (K
Br, cm-'): 3370, 3160, 310
0,1730,1670°565 NMR (DMSO-ci, δ): 2.87Cd,
2B), 3.88 (s, 3H).

7.1 (d, 2H), 8.72 (s, LH).

9.2 (d, IH).

Mass (rrV/z): 198 (M”),
141,124゜Example 8゜4-hydroxyimidazole-5-carboxamide 1
．． 3 g of dry dimethylamide 5 containing 1.54 g of p-chlorophenylinocyanate in a mixture of 1.0 g of l-ethylamine and 30 ml of dry dimethylamide.
ml was added dropwise at room temperature. After further stirring at room temperature for 3 hours, the precipitated solid was separated. 300 ml of RGVC water was added, and the precipitated solid was separated. The resulting 1 liquid was acidified with water-cooled hydrochloric acid water. , 3-4) The precipitated crystal is f
take. The obtained solid was dissolved in an aqueous solution of potassium carbonate to remove insoluble materials, and then acidified with hydrochloric acid (pH #3) while cooling with water.
~4) Collect the precipitated crystals, wash with water, and dry under reduced pressure.
1.5 g of powder of (p-chlorophenylcarbamoyloxy)imidazole-5-carboxamide was obtained. This material exhibits the following physical and chemical properties.

mp: Gradually becomes colored and carbonized, showing no clear decomposition point at °C.

IR (KBr, cm-'): 3475, 3325, 31
00 2650,1735°1650.1595 NMR (DMSO-a6.δ): 7.48 (LH
,s), 7.25(4H,)Anal,f%):
(as CIl 89N403 C1) CHN
C1 Calculated value 47.07 3.23 19.96. 12.
63 actual value 46,80 3.18 19.92 12
．． 59 Example 9゜4-hydroxyimidazole-5-carboxamide 1
．． After adding dropwise 5 ml of dry dimethylformamide containing 2.25 g of 3,4-dichlorophenylisocyanate to a mixture of 3 g of triethylamine, 1.2 g of triethylamine, and 30 ml of dry dimethylformamide, the same treatment as in Example 8 was carried out. 4-(3,4-cyclophenylcarnogmoyl-ogisi)imidazole-5-carboxamide powder 1
．． 5g was obtained. This material exhibits the following physical and chemical properties.

mp: Gradually becomes colored and carbonized, showing no clear decomposition point.

IR (KBr, cm'): 3470.333
0.3100~2700.1725°1640.

NMR (DMSO-d, , δ): 7.84 (I
H,s)Anal,f%): (c,,H8N4o3
ct) CHN Cl Calculated value 41.93 2.56 17.78 22.
50 Actual value 41.66 2.56 17.43 2
2.87 Example 10 4-Hydroxyimidazole-5-carboxamide 1
．． 9 g, ) p-nitroisocinate 2 in a mixture of 1.8 g ethylamine and 50 ml dry dimethylamide
．． After dropping 10 mZ of dry dimethylformamide containing 95 g, the same treatment as in Example 8 was carried out to obtain 4-(p-=l
-o phenylcarbamoyloxy)imidazole-5-
1.7 g of carboxamide powder was obtained.

This material exhibits the following physical and chemical properties.

mp: Gradually becomes colored and carbonized, showing no clear decomposition point.
.

IR (KBr, cm'): 3520,335
0,3125.1735,1590°1560, 14
90.

NMR (DMSOd6=δ): 8.72 (LH,
s), 8.28 (2H, d).

7.80 (2H, d) Anal, (LfA: (CHHgN505, 0.5
H20) CHN Calculated value 44,01 3.36 23.33 Actual value 44,00 3.22 23.27 Example 1
1 4-hydroxyimidazole-5-carboxamide 1
．． To a mixed solution of 9 g of triethylamine, 18 g of triethylamine, and 50 ml of dry dimethylformamide, 2.4 g of m-tolyl incyane was added dropwise, followed by the same treatment as in Example 8 to obtain 4-(m-)lylcarbamoyloxy)imidazole. 3.5 g of -5-carboxamide powder was obtained.

This material exhibits the following physical and chemical properties.

mp: Gradually becomes colored and carbonized, showing no clear decomposition point.
.

IR (KBr, cm'): 3350,310
0,2900.1730.1600゜1560゜NMR (DMSOd6.δ): 7.45 (IH,s
), 2.23(3H,5)Anal, f%):
(As Cl2H12N403) CHN Calculated value 55,38 4.65 21.53 Actual value 55,44 4.54 21.66 Example 1
2 4-hydroxyimidazole-5-carboxamide i
, c+g, t To a mixed solution of 18 g of ethylamine and 50 ml of dry dimethylformamide, 2.7 g of p-methoxyphenylisocyanate was added dropwise, followed by the same treatment as in Example 8 to obtain 4-(p-methoxyphenylcarbamoyloxy). Imidazole-5-carboxamide powder 22
I got g. This material exhibits the following physical and chemical properties.

mp: Gradually becomes colored and carbonized, showing no clear decomposition point.
.

IR (KBr, cm'): 3450,333
0,3120.1720.1590°NMR (DMSO
d6. δ): 8.64 (IH,s), 7.48
(2H, d).

6.96 (2H, d), 3.76 (3H, s) A
nal, (919: (C21H12N404)
0.8 H20) C, HN Calculated value 49,59 4.72 19.28 Practical value 49,52 4.66 19.09 Example 13 4-Hydroxyimidazole-5-carboxamide 1
．． After dropping 2 g of furano-2-incyanate into a mixture of 18 g of ethyl amino and 50 ml of dry dimethylformamide, the same treatment as in Example 8 was carried out to obtain 4-(2-)Ylcarbamoyloxy)imidazole-5. - 2.5 g of carboxamide powder was obtained.

This material exhibits the following physical and chemical properties.

mp: Gradually becomes colored and carbonized, showing no clear decomposition point (
・.

IR (KBr, cm'): 3360. ．． 31
20.1730.161ONMR (2CO3 in D20+
, δ) : 7.6.4(LH,s), 7.28(I
H).

6.48 (LH), 6.24 (LH) Anal, (%): (CoH8N404・0.2H2
0) c HN Calculated value 45,08 3.53 23.36 Actual value 45,13 3.39 23.05 Example
14゜4-hydroxyimidazole-5-carboxamide 1
．． Thiopheno-2-
After dropping 2.25 g of 4-(2-thimcarbamoyloxy)imidazole-5-carboxamide, 2.7 g of 4-(2-thimcarbamoyloxy)imidazole-5-carboxamide powder was obtained. This product exhibits the same physical and chemical properties.

mp: Gradually becomes colored and carbonized, showing no clear decomposition point ℃・
.

IR(KBrlcm'): 3400.3100
．． 1720.162ONMR (2CO3 in D20+, δ
): 7.45 (LH, a), 6.70-6.92
(3)1) Anal, f%j: (CoHgN40
3 S ” 0.4 H20)CHN
S Calculated value 41.66 3.43 21.59 12.
36 Actual value 41,78 3.72 21.33 1
2.78 Example 15゜4-hydroxyimidazole-5-carboxamide 1
．． Add 2.7 g of pyridine-4-carboxyazide to a mixture of 9 g of triethylamine, 18 g of triethylamine, and 50 ml of dry dimethylformamide. After heating to 70 to 80 C for 2 hours, the same treatment as in Example 8 was carried out to obtain 05 g of 4-(4-pyridylcarbamoyloxy)imidazole-5-carboxamide powder. This material exhibits the following physical and chemical properties.

mp: Gradually colored, showing no clear decomposition point.

IR (KBr, cm-'): 3380.308
0.172ONMR (2Co3.δ on D20-1-)
: 7.30 (IH, s), 8.12 (2H, d).

7.24(2H,d) Anal, (@: (Cl0H9N503 ・0.58
20) CHN Calculated value /16,88 3.93 27.33 Actual value 46,80 4.25 27.44 Example 16° 4-Hydroxyimidazole-5-carboxamide 1
．． Add 2.7 g of pyridino-3-carboxyazide to a mixed solution of 18 g of ) ethylamine and 50 ml of dry dimethylformamide. After heating to 70-80 υ for 3 hours, the same treatment as in Example 8 was carried out to obtain 4-(3 05 g of powder of -pyridylcarbamoyloxy)imidazole-5-carboxamide was obtained. Konomo's shows the following physical and chemical properties.

mp: Gradually colored, showing no clear decomposition point.

IR (KBr, am'): 3400,310
0,1730.158ONMR(D20+K2C
O3, δ): 7.30 (IH), 7. /18(I
H,s).

7.90 (11 (), 8.16 (LH).

8.54 (IH) Anal, f%'l: (Cl0H9N503 e
O,4H20)Cl(N Calculated value 47,21 3.88 27.53 Actual 6
11j value 47,41 3.80 27.54 Example 17 4-Hydroxyimidazole-5-carboxinamide 3
Add 4.4 g of pyridino-2-carbogine to a mixture of 3 g of l-ethylamine and 80 ml of dry dimethylforma and heat to 70 to 80 CK for 2 hours, then process in the same manner as in Example 8. 14 g of powder of -(2-pyridylcarbamoyloxy)imidazole-5-carboxinamide was obtained. This material exhibits the following physical and chemical properties.

mp: Gradually colored, showing no clear decomposition point.

IR (KBr, 'cm-'): 3350.31
00, 1740.164ONMR (2Co in D20+
3. δ): 7.66 (II-1, s), 8.2
8 (IH).

7.88 (2H), 7.20 (IH) Anal, (
%): (as Cl0HON503) CHN Calculated value 48,59 3.67 28.33 Actual value 48,37 3.73 28.47 Example
18 From 1.3 g of 4-hydroxyimidazole-5-carboxamide, 1.2 g of triethylamine, 2.25 g of m-)lifluoromethylphenylisocyanate, and 30 ml of dry dimethylformamide, 4-(m-) -trinololomethylphenyl(rubamoyloxy)imidazole-5-carboxamide 1.3
I got g. This material exhibits the following physical and chemical properties.

mp: Gradually becomes colored and carbonized, showing no clear decomposition point.

TR (KBr, am'): 3400,312
0,1740,1670,1600°57O NMR (DMSOd6.δ): 8.72 (IH,s
), 8.05 (IH).

8.65 (3H, m) Anal, (%l: (as Cl289N403F3) CHN Calculated value 45,87 2.89 17.83 Actual value 45,86 2.63 17.63 Example
19゜4-hydroxyimidazole-5-carboxamide 2
．． 5 g, itoethylamine 725 g, naphthalene-1
-Incyane-) and 70ml of dry dinotylpolamide were treated in the same manner as in Example 8 to obtain 4-(1
4.5 g of powder of -naphthylcarbamoyloxy)imidazole-5-carboxamide was obtained. This thing does not show the same physical and chemical properties.

mp: Gradually becomes colored and carbonized, with no clear decomposition point.

IR (KBr, cm-'): 3400.330
0.1740.1660.162ONMR(DMSOd
a, δ): 8.76 (IH, s), 8.22'
-7,56(7H,m)Anal, (%): (C
l5812N403” 0.4 as H2O)c
HN Calculated value 59,36 4.25 18.46 Actual value 59,38 4.24 18.44 Example
20 4-hydroxyimidazole-5-carboxamide 0
．． 42 g, ) ethylamine 0.4 g, p-dimethylaminophenyl-carboxyazide 0.75 g, and 70 to 80 cK heated for 2 hours with 50 ml of dry dimethylformamide. Carbamoyloxy)imidazole-
0.2 g of 5-carboxamide was obtained.

This product exhibits the same physical and chemical properties.

mp: Gradually becomes colored and carbonized, showing no clear decomposition point.

IR (KRr, cm-'): 3350,311
0,2900,1730,1590°51O NMR (D20 + K2 CO3, δ): 7.4
8 (IH, s), 7.24 (2H, d).

2.72 (6H,s) Anal, (n: (C+3H+5NsOa ・0.
I H2O) CHN Calculated value 53,64 5.26 24.06 Actual value 53.7,1 5.40 23.78 Patent applicant Yamanouchi Pharmaceutical Co., Ltd. Agent Akira Sasaki -

Claims (1)

[Claims] A novel imidazole compound represented by the general formula 3゜1 and an acid addition salt thereof. However, the symbols in formula 2 have the following meanings. R8: Hydrogen atom or lower alkyl group X: Carbonyl group (-CO-) or sulfonyl group <
-302-) n: 0 or I Y: lower alkyl group, cycloalkyl group. 2.4-benzoylcarbamoyloximidazole-
The compound according to claim 1, which is a 5-carboxamide, and an acid addition salt thereof.