JPH0925268A - 2-nitroimidazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new 2-nitroimidazole derivative excellent in inhibitory action on ariterialization and radiation sensitizing action, effective for treating various inflammatory diseases, diabetic retinopathy or cancers. SOLUTION: This 2-nitroimidazole derivative is shown by formula I (R is a lower alkyl, an aralkyl, a hydroxyalkyl, an alkoxyalkyl, etc.) and its optically active substance such as 2-bromoacetylcarbamoyl-1-(2-nitroimidazolyl)-3- methoxypropane. The compound of formula I, for example, is obtained by reacting a 3-alkoxy-1-(2-nitroimidazolyl)-2-propanol derivative of formula II with bromoacetylisocyanate of formula III. The reaction is preferably carried out by using a solvent such as dichloromethane, tetrachloromethane, etc. The amount of the compound of formula III used is preferably 1.5-3mols based on 1mol of the compound of formula II.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a 2-nitroimidazole derivative having an angiogenesis inhibitory action and a radiosensitizing action and effective for treating various inflammatory diseases, diabetic retinopathy or cancer, and an optically active substance thereof.

[0002]

2. Description of the Related Art As a compound similar to the 2-nitroimidazole derivative of the present invention, a compound in which the bromine atom part of the compound of the present invention is replaced by a chlorine atom is disclosed in JP-A-7-3365.
It is disclosed as a compound having an angiogenesis inhibitory action in Japanese Patent No. 8 and Abstracts 2 of the 115th Annual Meeting of the Pharmaceutical Society of Japan [Published by the Pharmaceutical Society of Japan on March 5, 1995].

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel compound which exhibits an angiogenesis-inhibiting action and a radiosensitizing action which are superior to those of the compound described in JP-A-7-33658.

[0004]

The present invention relates to a 2-nitroimidazole derivative represented by the general formula (1) and an optically active substance thereof.

Embedded image (In the formula, R represents a lower alkyl group, an aralkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a substituted or unsubstituted aminoalkyl group, or a lower alkyl-substituted aryl group.)

The inventors of the present invention represented by the general formula (2)
It was clarified in JP-A-7-33658 that the nitroimidazole compound has an excellent angiogenesis-inhibiting effect, and a diligent research was conducted to find out a compound having a further superior effect. It was found that by replacing the chlorine atom of the compound with a bromine atom, the angiogenesis-inhibiting effect and radiosensitizing effect are dramatically increased.

Embedded image (In the formula, R ₃ represents a lower alkyl group or a phenyl group which may be substituted with a lower alkyl group.)

In the above general formula, R is defined as follows. Lower alkyl group: a linear or branched alkyl group having 1 to 6 carbon atoms (methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.) Aralkyl group: phenyl, naphthyl, etc. Aryl groups 1 to
C1-C4 lower alkyl group substituted with 3 (phenyl-substituted lower alkyl group: benzyl, benzhydryl,
Naphthyl-substituted lower alkyl groups such as phenethyl and phenylpropyl: α-naphthylmethyl, α-naphthylethyl,
β-naphthylmethyl etc.) Hydroxyalkyl group: a linear or branched hydroxyalkyl group having 1 to 6 carbon atoms (hydroxymethyl, hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 2 -Hydroxy-2-methylpropyl, 5-hydroxypentyl, etc.) Alkoxyalkyl group: a group in which a lower alkoxy group having 1 to 6 carbon atoms is substituted with an alkyl group having 1 to 6 carbon atoms (methoxymethyl, ethoxymethyl, propyloxymethyl). , Tert
-Butoxymethyl, methoxyethyl, ethoxyethyl,
iso-propyloxyethyl, butoxyethyl, n-hexyloxyethyl, methoxypropyl, ethoxypropyl, 2,2-dimethyl-3-ethoxypropyl, propyloxypropyl, n-butoxypropyl, methoxybutyl, ethoxybutyl, propyloxybutyl , Tert
-Butoxybutyl etc.)

Substituted or unsubstituted aminoalkyl group: a group in which an amino group of a lower aminoalkyl group having 1 to 6 carbon atoms is substituted, and the substituent includes a lower alkyl group having 1 to 6 carbon atoms [methyl, ethyl, propyl , Isopropyl, butyl,
Isobutyl, tert-butyl, pentyl, hexyl, etc.] Acyl group having 1 to 6 carbon atoms [formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, etc.] Aryl group [phenyl, naphthyl, etc.] Specific examples ( 1) amino lower alkyl group: (aminomethyl, aminoethyl, aminopropyl, aminobutyl, etc.) (2) mono-, di-lower alkyl amino lower alkyl group:
(N, N-dimethylaminomethyl, N-methylaminopropyl, N, N-dimethylaminobutyl, etc.) (3) Lower acylaminoalkyl group: (acetylaminomethyl, butyrylaminoethyl, valerylaminobutyl, etc.) ( 4) Arylamino lower alkyl group: (phenylaminomethyl, phenylaminobutyl, etc.) Lower alkyl-substituted aryl group: Monoalkylaryl group or dialkylaryl group obtained by substituting 1 to 3 aryl groups in which the lower alkyl group is phenyl or naphthyl. , Trialkylaryl groups (toluyl, xylyl, 2,4,6-trimethylphenyl, ethylphenyl, propylphenyl, isopropylphenyl, tert-butylphenyl, 2
-Methyl-1-naphthyl, 3-ethyl-1-naphthyl,
1-methyl-2-naphthyl etc.)

The compound of the present invention has an asymmetric carbon atom represented by * and includes all optical isomers based on this.

Embedded image

More specific examples of the compound of the present invention include: 2-bromoacetylcarbamoyl-1- (2-nitroimidazolyl) -3-methoxypropane (TX-184)
4) R-(+)-2-bromoacetylcarbamoyl-1-
(2-Nitroimidazolyl) -3-methoxypropane (TX-1866) -2-Bromoacetylcarbamoyl-1- (2-nitroimidazolyl) -3-ethoxypropane-2-Bromoacetylcarbamoyl-1- (2-nitroimidazolyl) ) -3-Propyloxypropane-R-(+)-2-bromoacetylcarbamoyl-1-
(2-Nitroimidazolyl) -3-benzyloxypropane (TX-1867) S-(-)-2-bromoacetylcarbamoyl-1-
(2-Nitroimidazolyl) -3-benzyloxypropane (TX-1868) * 2-Bromoacetylcarbamoyl-1- (2-nitroimidazolyl) -3-tert-butoxypropane (TX-
1845) 2-Bromoacetylcarbamoyl-1- (2-nitroimidazolyl) -3- (2-methylphenoxy) propane 2-Bromoacetylcarbamoyl-1- (2-nitroimidazolyl) -3- (4-ethylphenoxy) ) Propane 2-bromoacetylcarbamoyl-1- (2-nitroimidazolyl) -3- (4-tert-butylphenoxy)
Propane (TX-1846) etc. are illustrated.

The compound of the present invention is produced, for example, by the following method.

Embedded image That is, 3-alkoxy-1-represented by the general formula (2)
It is produced by reacting a (2-nitroimidazolyl) -2-propanol derivative with bromoacetylisocyanate represented by the general formula (3). This reaction proceeds in the presence or absence of a solvent, but it is usually preferable to use a solvent such as dichloromethane, tetrahydrofuran, dioxane or the like. The compound (2) and (3) are used in an amount of usually 1.5 to 3 mol of the compound (3) per 1 mol of the compound (2). The reaction temperature is 35 ° C to 65 ° C, and the mixture is usually heated under reflux in a solvent.
The reaction is not constant depending on the solvent and temperature used, but is usually completed in 0.5 to 8 hours. The compound (2) is a known compound and is disclosed in JP-B-43-16384 and JP-A-63.
The manufacturing method is described in JP-A-310873. Further, the optically active compound of the present invention can be synthesized by reacting the optically active compound (2) in the same manner as described above. The optically active compound (1 ′) is produced by the following reaction process formula.

[0011]

[Chemical 6] A compound (2 ′ that is optically active by reacting 2-nitroimidazole represented by the general formula (4) with a chiral glycidyl ether represented by the general formula (5) in the presence or absence of a solvent. ) Is manufactured. The reaction ratio of the above compound is usually 9 to 63 mol of glycidyl ether (5) per 1 mol of 2-nitroimidazole (4). The reaction temperature and reaction time are usually 25 to 60 ° C. and 5
~ 65 hours. Any solvent may be used as long as it does not affect the reaction, for example, methanol,
Examples thereof include alcohols such as ethanol. (1 ′) is produced by reacting the bromoacetyl isocyanate represented by the general formula (3) with the general formula (2 ′) as described above. The chiral compound (1 ′) thus obtained can be isolated by a usual separation and purification means such as recrystallization and column chromatography. The compound (5) is commercially available and can be easily obtained.

The 2-nitroimidazole derivative of the present invention has an excellent angiogenesis-inhibiting action and radiosensitizing action, and is effective in many diseases due to abnormal growth of angiogenesis, such as diabetic retinal detachment, rheumatoid arthritis and cancer. It is useful as a therapeutic agent and a radiosensitizer that enhances the cell killing effect of radiation in radiotherapy for malignant tumors. The compound can be orally or parenterally administered to mammals including human.
The dosage unit form of the preparation of the present invention is not particularly limited and can be appropriately selected according to the purpose of treatment, and specifically, tablets, pills, powders,
Examples include liquids, suspensions, emulsions, granules, capsules, suppositories, injections, ointments, patches, eye drops, nasal drops and the like.
Examples of the formulation carrier used herein include various types commonly used for ordinary drugs, for example, diluents or excipients such as fillers, extenders, binders, disintegrants, surfactants, and lubricants. it can.

In the case of molding into tablets, as carriers, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc., excipients, water, ethanol, propanol, Simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, poly Disintegrators such as oxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch and lactose, disintegration inhibitors such as sucrose, stearic acid, cocoa butter and hydrogenated oils, quaternary ammonium bases, la Absorption promoters such as sodium rill sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid; lubricating agents such as purified talc, stearates, boric acid powder, and polyethylene glycol Sourcing agents and the like can be used. Further, the tablet is a tablet coated with a usual coating as necessary, for example, a sugar-coated tablet,
Gelatin-coated tablets, enteric-coated tablets, film-coated tablets,
Double tablets, multilayer tablets and the like can be used.

In the case of molding in the form of pills, as carriers, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, tragacanth powder, gelatin, ethanol and the like are bound. Agent,
Disintegrators such as laminaran and agar can be used. Capsules are prepared by mixing the 2-nitroimidazole derivative with the various carriers exemplified above and filling hard gelatin capsules, soft capsules, or the like. In molding into a suppository form, for example, polyethylene glycol, cocoa butter, esters of higher alcohols, gelatin, semisynthetic glyceride and the like can be used as carriers. When prepared as an injection, the solution, emulsion and suspension are preferably sterilized and isotonic with blood. When molded into these forms, for example, water, a lactic acid aqueous solution as a diluent,
Ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be included in the pharmaceutical preparation, and a usual solubilizer, buffer, soothing agent and the like may be added. You may. Ointment,
For example, when prepared in the form of paste, cream and gel, as a diluent, for example, white petrolatum, paraffin,
Glycerin, a cellulose derivative, polyethylene glycol, silicone, bentonite, etc. can be used. Further, colorants, preservatives, flavors, flavors, sweeteners and other pharmaceuticals may be added to the above-mentioned preparations, if necessary.

The amount of the 2-nitroimidazole derivative contained in the preparation of the present invention is not particularly limited and may be appropriately selected, but it is usually about 1 to 70% by weight in the preparation. The administration method of the preparation of the present invention is not particularly limited, and is determined according to various preparation forms, patient's age, sex and other conditions, patient's symptom level, and the like. For example tablets, pills, powders,
Solutions, suspensions, emulsions, granules and capsules are administered orally. Suppositories are administered rectally. Injections are administered alone or mixed intravenously with glucose, amino acids, etc., and are administered intravenously, and further, if necessary, alone intraarterially, intramuscularly, intradermally,
It is administered subcutaneously or intraperitoneally. The ointment is applied to skin, oral mucosa, and the like. The amount of the compound of the present invention to be blended in each dosage unit form is not constant depending on the symptoms of the patient to which it is applied or the dosage form thereof, but generally it is about 100 to 2000 m in an oral preparation per dosage unit form.
g, about 10-500 mg for injections, about 100-for suppositories
It is preferably 2000 mg.

The dosage of the active ingredient of the preparation of the present invention is as follows:
It can be appropriately selected according to the age, sex and other conditions of the patient, the degree of disease and the like. Usually, the compound of the present invention is 0.1 to 100 mg /
The amount should be in the range of about kg / day, preferably 0.5 to 50 mg / kg / day. These preparations of the present invention
It can be administered once or twice or four times a day.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail with reference to the following examples.

Example 1 2-Bromoacetylcarbamoyl-1- (2-nitroimidazolyl) -3-tert-butoxypropane (TX-1
Synthesis of 845) (1) Synthesis of 3-tert-butoxy-1- (2-nitroimidazolyl) -2-propanol tert-butyl glycidyl ether (2.09 g, 16.4 m
mol) to 2-nitroimidazole (904 mg, 8 mmol)
Was added to the anhydrous ethanol suspension (30 ml) and the mixture was stirred under reflux for 7 hours. The reaction mixture was filtered and the filtrate was washed with a little dichloromethane. The solvent was distilled off from the obtained filtrate and washing solution under reduced pressure to obtain a semi-solid residue. The residue was subjected to silica gel column chromatography and eluted with dichloromethane-methanol to give the title compound (1.08 g, yield 55.5%) as pale yellow crystals with a melting point of 75 to 77 ° C. IR (KBr) ν: 3341, 2972, 1532, 1
489, 1360, 1280, 1190, 1162, 1
^{100,918,836,798cm -1 1 H-NMR (CDCl} 3) δ: 1.15,1.19 (s,
9H, tert-Butyl-C H 3), 1.63 (s, 1H, O
H), 3.36,3.51 (each s, 2H, C H = C H) 13 C-NMR (CDCl 3) δ: 27.3 (tert-Butyl
_{- C H 3), 73.8 (} tert-Butyl- C), 52.7
( C- 1), 62.6 ( C- 3), 69.4 ( C- 2),
127.2, 128.0 (imidazole- C = C- )

(2) Synthesis of TX-1845 3-tert-butoxy-1- (2-nitroimidazolyl)
Bromoacetylisocyanate (328 mg, 2 mmol) was added to a solution of 2-propanol (234 mg, 1 mmol) in anhydrous dichloromethane (10 ml), and the mixture was stirred under reflux for 2 hours.
The reaction mixture was evaporated under reduced pressure to give a semi-solid residue. The residue was subjected to silica gel column chromatography and eluted with dichloromethane-ethyl acetate to give a melting point of 98.
~ 99 ° C pale yellow crystalline title compound (284 mg, yield 7
0.0%) was obtained. IR (KBr) ν: 3427, 2977, 1720, 1
539, 1488, 1362, 1287, 1219, 1
^{190,1092,1026,839,770cm -1 1 H-NMR (CDCl} 3) δ: 1.19,1.20 (each
s, 6H, 3H, tert- Butyl-C H 3), 3.51,
3.60 (dd, 2H, H- 1), 4.22, 4.92 (d
d, 2H, Br-C H 2), 5.25 (m, 1H, C H),
5.30 (s, 1H, NH ), 7.16, 7.28 (each d
d, 2H, C H = C H) 13 C-NMR (CDCl 3) δ: 27.3 (tert-Butyl
_{- C H 3), 73.9 (} tert-Butyl- C), 28.0 (B
_{r- C H 2), 49.7 (} C -1), 60.0 (O C H 2),
74.1 (C -2), 126.8,128.4 ( C H = C
_{H), 150.3 (C -NO 2} )

Example 2 2-Bromoacetylcarbamoyl-1- (2-nitroimidazolyl) -3-methoxypropane (TX-184)
Synthesis of 4) Bromoacetyl isocyanate (983 mg, 6 mmol) was added to anhydrous dichloromethane (20 ml) in which misonidazole (402 mg, 2 mmol) was dissolved. After refluxing for 8 hours, the orange semi-solid residue obtained by evaporating the solvent was separated and purified by silica gel column chromatography (dichloromethane-ethyl acetate), and the melting point was 108 to 110 ° C., and the title compound (616 mg, yield) was obtained as a pale yellow crystal. Rate 84.4%). IR (KBr) ν cm ^-1 : 3177, 2989, 178
3,1719,1542,1484,1360,123
1,1008,837,761,596 cm ^{-1 1} H-NMR (CDCl ₃ ) δ: 3.32 (s, 3H, OC
H ₃ ), 3.62 (m, 2H, OC H ₂ ), 4.13 (d, 2
H, J = 6.4Hz, Br- C H 2), 4.59,4.93
(Each dd, each 1H, J = 14.4, 14.8Hz, N
_{-C H 2), 5.32 (m} , 1H, C H), 7.14,7.
24 (each s, each 1H, imidazole- H ) MS (HRFAB) m / z: 365.0079 [calcd f
or C ₁₀ H ₁₃ BrN ₄ O ₆ (M ⁺ ): 365.0097]

Example 3 Synthesis of 2-bromoacetylcarbamoyl-1- (2-nitroimidazolyl) -3- (4-tert-butylphenoxy) propane (TX-1846) 3- (4-tert-butylphenoxy)- 1- (2-Nitroimidazolyl) -2-propanol (478 mg, 1.
Bromoacetylisocyanate (492 mg, 3 mmol) was added to a solution of 5 mmol) in anhydrous dichloromethane (15 ml),
Refluxed for 10 hours. The reaction mixture is filtered and washed with dichloromethane. The solvent was distilled off under reduced pressure to obtain a semi-solid residue. The residue was subjected to silica gel column chromatography and eluted with dichloromethane-ethyl acetate to give a melting point of 94.
˜95 ° C. pale yellow crystalline title compound (672 mg, yield 9
2.7%) was obtained. IR (KBr) ν: 3435, 2962, 1784, 1
702, 1539, 1513, 1488, 1364, 1
^{211,834,766,553cm -1 1 H-NMR (CDCl} 3 / CD 3 OD) δ: 1.31 (s,
9H, tert-Butyl-C H 3), 4.15 (s, 2H, O
_{-C H 2), 4.20 (s} , 2H, Br-C H 2), 4.7
7, 5.05 (each d, each 1H, J = 14.4, 14.
_{4H z, N-C H 2} ), 5.34 (s, 1H, N H), 5.
48 (m, 1H, C H ), 6.83, 7.32 (each d, e
ach 2H, J = 8.8, 8.8Hz, arom- H ), 7.1
4,7.40 (each s, each 1H, imidazole- H ) MS (HRFAB) m / z: 483.0892 [calcd f
or C ₁₉ H ₂₃ BrN ₄ O ₆ (M ⁺ ): 483.0879]

Example 4 R-(+)-2-Bromoacetylcarbamoyl-1-
Synthesis of (2-nitroimidazolyl) -3-benzyloxypropane (TX-1867) R-(−)-3-benzyloxy-1- (2-nitroimidazolyl) -2-propanol (277 mg, 1 mmol) in anhydrous dichloromethane Bromoacetyl isocyanate (492 mg, 3 mmol) was added to (8 ml), and the mixture was refluxed for 30 minutes. The reaction mixture was evaporated under reduced pressure to give a semi-solid residue. The residue was subjected to silica gel column chromatography and eluted with dichloromethane-ethyl acetate to give the title compound (278 mg, yield 63%) as a yellow hygroscopic semi-solid. [Α] _D ²⁸ = + 49.399 ° (c = 0.3, CH ₃ OH) IR (KBr) ν: 3423, 2925, 1782, 1
717, 1540, 1490, 1363, 1219, 1
^{099,838,742,699,597cm -1 1 H-NMR (CDCl} 3 / CD 3 OD) δ: 3.37,3.
72 (each dd, each 1H, J = 3.6, 4.4Hz, O
_{C H 2), 4.11 (d} , 2H, J = 4.4Hz, Br-C H
_{2), 4.58 (s, 2H} , Ar-C H 2), 4.61,4.
94 (each dd, each 1H, J = 12.8, 14.8H
_{z, N-C H 2)} , 5.35 (m, 1H, C H), 7.1
2,7.24 (each s, each 1H, imidazole- H ),
7.37 (m, 4H, arom- H ) MS (HRFAB) m / z: 441.0434 [calcd f
or C ₁₆ H ₁₈ BrN ₄ O ₆ (MH ⁺ ): 441.0410]

Example 5 S-(-)-2-Bromoacetylcarbamoyl-1-
Synthesis of (2-nitroimidazolyl) -3-benzyloxypropane (TX-1868) Bromoacetylisocyanate (492 mg, 3 mmol) and S-(+)-benzyloxy-1- (2-nitroimidazolyl) -2-propanol (227 mg). , 1 mmol) was used to obtain the title compound (283 mg, yield 64%) as a yellow hygroscopic semi-solid in the same manner as in Example 4. [Α] _D ²⁸ = −50.666 ° (c = 0.3 CH ₃ OH) IR (KBr) ν: 3449, 2963, 1785, 1
717, 1540, 1489, 1363, 1219, 8
^{38,740,699,597cm -1 1 H-NMR (CDCl} 3 / CD 3 OD) δ: 3.68,3.
73 (each dd, each 1H, J = 6.4, 6.8Hz, O
_{C H 2), 4.10 (d} , 2H, J = 4.4Hz, Br-C H
_{2), 4.54 (s, 2H} , Ar-C H 2), 4.57,4.
93 (each dd, each 1H, J = 13.6, 14.4H
_{z, N-C H 2)} , 5.35 (m, 1H, C H), 7.1
1,7.24 (each s, each 1H, imidazole- H ),
7.36 (m, 4H, arom- H ) MS (HRFAB) m / z: 441.0430 [calcd f
or C ₁₆ H ₁₈ BrN ₄ O ₆ (MH ⁺ ): 441.0410]

Example 6 R-(+)-2-Bromoacetylcarbamoyl-1-
Synthesis of (2-nitroimidazolyl) -3-methoxypropane (TX-1866) Example 4 except using bromoacetylisocyanate and R-(+)-methoxy-1- (2-nitroimidazolyl) -2-propanol. The semi-solid title compound (yield 72%) was obtained in the same manner as in. [Α] _D ²⁸ = 37.199 ° (c = 0.3 CH ₃ OH) IR (KBr) ν: 3439, 2934,1783,1
719, 1542, 1490, 1363, 1220, 1
^{102,839,668cm -1 1 H-NMR (CDCl} 3 / CD 3 OD) δ: 3.39 (m,
_{3H, -OC H 3), 3.63} (m, 2H, O-C H 2),
4.12 (dd, 2H, J = 4.40Hz, Br-C H 2),
4.60, 4.92 (each dd, each 1H, J = 14.
_{4,14.8Hz, N-C H 2)} , 5.33 (m, 1H, C
H ), 7.13, 7.29 (each s, each 1H, imidazo
le− H ) MS (HRFAB) m / z: 365.0097 [calcd f
or C ₁₀ H ₁₃ BrN ₄ O ₆ (MH ⁺ ): 365.0080] The following are pharmacological test examples and prescription examples.

Pharmacological test 1 (Measurement of angiogenesis inhibitory activity) Fertilized eggs were placed in an incubator at 37 ° C., which was saturated with water, and four days later, the upper and lower sides of the egg were opened with a syringe from the hole on the air chamber side. Then, 2 ml of egg white was extracted from the lower hole with a syringe. Then, suck the air inside the egg through the hole in the upper part using the rubber cap of the pipette to facilitate the peeling of the eggshell membrane,
Aseptic adhesive film OpSite (Smith Nep
The egg shell membrane was removed by opening a window of about 2 cm ² above the egg and blocking it with a hew company. The sample was dissolved in physiological saline containing 1% methylcellulose, and a silicon ring (diameter 3 mm, internal diameter 2) was placed on the CAM that had grown to a diameter of 1-2 mm.
mm) and 10 μl of each solution was added dropwise. Then I capped the egg and re-egged it. On the 6th day after the start of inoculation, after injecting an appropriate amount of Intralipos into the CAM so that the blood vessels can be clearly seen,
Photographs were taken to determine the degree of blood vessel formation. Judgment was made positive for inhibitory activity when the avascular region on the CAM had a diameter of 3 mm or more,
The positive rate of inhibition of angiogenesis in the group treated with the inhibitor was calculated. The data for actinonin as a control drug is shown. The results are shown in Table 1 below.

[0026]

[Table 1] * Comparative 1-3 (JP-A-7-33658) The compound of the present invention showed an excellent angiogenesis inhibitory effect at a low dose as compared with the compound of Comparative 1-3 described in JP-A-7-33658.

Pharmacological test 2 (radiosensitizing effect) BalbC / mouse-derived MT6 / KU cells were used for screening. a) Primary screening by single cele Each cell was used in a logarithmic growth phase in a drug solution having a concentration that did not cause toxicity, and irradiation was carried out in a suspended state in a test tube. In the case of low oxygen conditions, mixed nitrogen gas (5% CO ₂ ) was flowed in the test tube for 60 minutes, and then ⁶⁰ Co-γ rays (dose rate; 1.1).
7 Gy / min). After irradiation, the drug solution was removed, and after dilution, the mixture was spread on a petri dish and the survival rate was determined by a colony forming method. The sensitizing effect (ER) was calculated by the dose required to obtain a survival rate of 1%. b) Secondary screening with spheroids Cells in the logarithmic growth phase were cultured on soft agar for 3 days and then transferred to a spinner culture bottle to form spheroids. After culturing for 21 to 25 days, the diameter of spheroid is 600 to 7
It was used in the experiment when it reached 00 μm. Irradiation ( ⁶⁰ Co-
Gamma ray; dose rate 0.85 Gy / min) was performed in an Erlenmeyer flask. After irradiation, the spheroid will be supplemented with 0.24% trypsin solution 15-
After allowing it to act for 20 minutes to make it a single cell, the number of cells was counted, and the dish was spread on a petri dish to determine the survival rate by the colony forming method. Table 2 shows the results.

[0028]

[Table 2] * Comparative 1-3 (JP-A-7-33658) The compound of the present invention is about 1 / 10-1 / 1 compared to Comparative 1-3.
A concentration of 00 showed the same radiosensitizing effect.

Formulation Example 1 Tablet TX-1844 40 mg Starch 100 mg Magnesium stearate 15 mg Lactose 45 mg Total 200 mg According to the conventional method, 200 mg of each tablet was prepared in the above blending ratio. Formulation Example 2 Granules TX-1845 200 mg Lactose 340 mg Corn starch 450 mg Hydroxypropyl methylcellulose 10 mg Total 1000 mg Granules were prepared according to a conventional method at the above blending ratio. Prescription example 3 Capsule TX-1845 100 mg Lactose 170 mg Crystalline cellulose 77 mg Magnesium stearate 3 mg Total 350 mg Capsules were prepared according to a conventional method at the above blending ratio. An injection was prepared according to a conventional method in the above mixing ratio.

[0030]

INDUSTRIAL APPLICABILITY The 2-nitroimidazole derivative of the present invention and its optically active substance exhibit excellent angiogenesis-inhibiting action and radiosensitizing action.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/415 AGZ A61K 31/415 AGZ C07M 7:00

Claims (5)

[Claims] 1. A 2-nitroimidazole derivative represented by the general formula (1) and an optically active substance thereof. Embedded image (In the formula, R represents a lower alkyl group, an aralkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a substituted or unsubstituted aminoalkyl group, or a lower alkyl-substituted aryl group.) 2. The derivative according to claim 1, wherein R is a lower alkyl group, a phenyl-substituted lower alkyl group, or a lower alkyl-substituted phenyl group, and an optically active form thereof. 3. The derivative according to claim 1, wherein R is a lower alkyl group, a benzyl group or a lower alkyl-substituted phenyl group, and an optically active form thereof. 4. The derivative according to claim 1, wherein R is a methyl group, a tert-butyl group, a benzyl group or a tert-butylphenyl group, and an optically active form thereof. 5. 2-Bromoacetylcarbamoyl-1-
(2-nitroimidazolyl) -3-methoxypropane,
2-Bromoacetylcarbamoyl-1- (2-nitroimidazolyl) -3-benzyloxypropane, 2-bromoacetylcarbamoyl-1- (2-nitroimidazolyl) -3-tert-butoxypropane or 2-bromoacetylcarbamoyl-1 -(2-Nitroimidazolyl)-
The derivative according to claim 1, which is 3- (4-tert-butylphenoxy) propane, and its optically active substance.