JPH1025280A - Nitroimidazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new derivative which is a specific nitroimidazole derivative, useful for treating cancers, etc., excellent in action on malignant tumor, action on radiosensitization and controlling action on metastasis free from neurotoxic as an adverse effect, improved in water solubility. SOLUTION: This derivative is shown by formula I [R is a lower alkyl or a lower acyl; R' is a group of the formula (CH2 )n OR1 (R1 is H, a lower alkyl, a lower acyl, etc.; (n) is an integer of 1-5) or a group of the formula (CH2 )n NR2 R3 (R2 and R3 are each H, a lower alkyl or a lower acyl)], has action on malignant tumor and immunopotentiative action and is effective for treating cancers. The compound is obtained by reacting 2-nitroimidazole-1-acetic acid of formula II or its methyl ester with an amine derivative of the formula RR'NH.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD [0001] The present invention relates to an antineoplastic effect,
The present invention relates to a novel nitroimidazole derivative which has a radiosensitizing effect, a metastasis suppressing effect, and an immunostimulating effect and is effective for treating cancer.

[0002]

2. Description of the Related Art As a compound relating to the nitroimidazole derivative of the present invention, for example, JP-B-46-32266 discloses a compound of the present invention wherein R is a lower alkyl group, R 'is hydroxy lower alkyl, lower alkoxy lower alkyl,
A compound which is an amino lower alkyl group is disclosed in JP-A-7-33.
No. 658 discloses compounds in which R is a lower alkyl group and R 'is a hydroxy lower alkyl group, but there is no specific description of these compounds. Also,
The compounds described in JP-B-46-32266 are useful as fungicides and antibacterial agents.
The article only describes the usefulness as an angiogenesis inhibitor, but does not describe a radiosensitizing effect or a metastasis suppressing effect.

As a 2-nitroimidazole derivative having a radiosensitizing effect, US Pat. No. 4,371,540
The compound of the present invention wherein R is a hydrogen atom and R ′ is a hydroxyethyl group (SR-2508),
Compounds in which both R and R ′ are hydroxyethyl groups are 2-nitroimidazole derivatives having a radiosensitizing effect and a metastasis suppressing effect as disclosed in JP-A-7-10186.
No. 0 describes compounds such as N, N-dimethyl-2-nitro-1-imidazoleacetamide (KIN806). However, SR-2508 has been observed to exhibit neurotoxicity in large doses in clinical trials.
It has been pointed out that IN806 has a problem in solubility in water.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide an anti-malignant tumor effect, a radiosensitizing effect and a metastasis suppressing effect which are superior to those of the conventional compounds as described above, and to reduce the side effect of neurotoxicity. Another object of the present invention is to provide a novel nitroimidazole derivative having no water solubility and improved water solubility.

[0005]

Means for Solving the Problems The present invention relates to a nitroimidazole derivative represented by the general formula (1).

[0006]

Embedded image Wherein R is a lower alkyl group or a lower acyl group, R ′ is a — (CH ₂ ) _n OR ₁ group or — (CH ₂ ) _n NR ₂ R ₃ group, R ₁ is a hydrogen atom, a lower alkyl group, Lower acyl group, -CONR
_{A 4} R ₅ group (R ₄ and R ₅ are the same or different and each represent a hydrogen atom or a lower alkyl group) or a —SO ₂ R ₆ group (R ₆ may be substituted with a lower alkyl group or a lower alkyl group; R ₂ and R ₃ are the same or different and represent a hydrogen atom, a lower alkyl group or a lower acyl group, and n represents an integer of 1 to 5. ]

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula, R ′ is — (CH ₂ ) _n
OR ₁ group or — (CH ₂ ) _n NR ₂ R ₃ group. R ₁ is a hydrogen atom, a lower alkyl group, a lower acyl group, a —CONR ₄ R ₅ group (R ₄ and R ₅ are the same or different and represent a hydrogen atom or a lower alkyl group), or a —SO ₂ R ₆ group (R ₆ represents a lower alkyl group, a phenyl group which may be substituted with a lower alkyl group or a hydroxyl group). R ₂ and R ₃ are the same or different and represent a hydrogen atom, a lower alkyl group or a lower acyl group. Examples of the lower alkyl group represented by R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,
A linear or branched alkyl group having 1 to 6 carbon atoms such as a pentyl and hexyl group is a lower acyl group represented by R, R ₁ , R ₂ and R ₃ , and formyl, acetyl, propionyl and isopropionyl. , Butyryl, isobutyryl,
1 to 1 carbon atoms such as valeryl, isovaleryl and pivaloyl groups
And 6 linear or branched acyl groups. R
Is preferably a lower alkyl group, particularly preferably a methyl group. R ′ is preferably a — (CH ₂ ) _n OR ₁ group, wherein R ₁ is particularly preferably a hydrogen atom. Further, n is preferably from 1 to 3, and particularly preferably 2. Therefore, it is particularly preferable that R ′ is a hydroxyethyl group.

More specific compounds included in the compounds of the present invention include, for example, N-hydroxyethyl-N-methyl-2- (2-nitro-1-imidazolyl) -acetamide (compound 1) N-hydroxymethyl- N-methyl-2- (2-nitro-1-imidazolyl) -acetamide (compound 2) N-hydroxyethyl-N-ethyl-2- (2-nitro-1-imidazolyl) -acetamide (compound 3) N-methoxy Ethyl-N-methyl-2- (2-nitro-
1-imidazolyl) -acetamide (compound 4) N-acetoxyethyl-N-methyl-2- (2-nitro-1-imidazolyl) -acetamide (compound 5) N-mesyloxyethyl-N-methyl-2- (2 -Nitro-1-imidazolyl) -acetamide (Compound 6) N-Tosyloxyethyl-N-methyl-2- (2-nitro-1-imidazolyl) -acetamide (Compound 7) N-aminoethyl-N-methyl-2 -(2-nitro-1
-Imidazolyl) -acetamide (compound 8) N-methylaminoethyl-N-methyl-2- (2-nitro-1-imidazolyl) -acetamide (compound 9) N-dimethylaminoethyl-N-methyl-2- (2 -Nitro-1-imidazolyl) -acetamide (Compound 1
0) N-acetylaminoethyl-N-methyl-2- (2-nitro-1-imidazolyl) -acetamide (Compound 1)
1)

The compound of the present invention is disclosed in JP-B-46-32266.
Gazette, US Pat. No. 3,679,698,
Can be produced by the methods described in JP-A-79158, JP-A-4-66575, JP-A-7-33658 and JP-A-7-33745, and a method analogous thereto. Manufactured according to the formula.

[0010]

Embedded image (Wherein R and R ′ are the same as above)

2-nitroimidazole of the general formula (2)
The compound (1) of the present invention can be produced by reacting 1-acetic acid or its methyl ester with an amine derivative represented by the general formula (3) in a solvent. The reaction ratio is 1 to 1 mole of the compound of the general formula (2).
Preferably it is 5 mol. Any solvent may be used as long as it does not affect the reaction. For example, alcohols such as methanol and ethanol are preferable. Reaction temperature is -3
0 ° C to + 50 ° C, preferably around room temperature. The reaction time is about 0.5 to 48 hours. The compound (1) of the present invention thus obtained can be isolated by ordinary separation and purification means such as recrystallization and column chromatography. The nitroimidazole derivative of the present invention has excellent antineoplastic action, radiosensitizing action, metastasis suppressing action and immunostimulating action, and is useful as a therapeutic drug for cancer. The compounds of the present invention can be administered orally or parenterally to mammals, including humans. The dosage unit form of the preparation of the present invention is not particularly limited,
It can be appropriately selected according to the purpose of treatment, and specifically, tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules,
Examples include 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, carriers such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and other excipients, water, ethanol, propanol, Simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, and other binders, dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, poly Disintegrating agents such as oxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegrating inhibitors such as sucrose, stearic acid, cocoa butter, hydrogenated oil, quaternary ammonium base, 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 tablets are tablets coated with ordinary skin as required, such as sugar-coated tablets,
Gelatin-coated tablets, enteric-coated tablets, film-coated tablets,
Double tablets, multilayer tablets and the like can be used.

In the case of molding into pill form, carriers such as excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, tragacanth powder, gelatin, ethanol, etc. Agent,
Disintegrators such as laminaran and agar can be used. Capsules are prepared by mixing with the various carriers described above and filling in hard gelatin capsules, soft capsules, and 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 liquid preparations, emulsions and suspensions are preferably sterilized and isotonic with blood, and when formed into these forms, diluents such as water, aqueous lactic acid, ethyl alcohol , Propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation,
Further, ordinary solubilizers, buffers, soothing agents and the like may be added. For preparing an ointment such as paste, cream and gel, for example, white vaseline, paraffin, glycerin, cellulose derivative, polyethylene glycol, silicone, bentonite and the like can be used as a diluent. Further, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent and the like and other pharmaceuticals may be added to each of the above-mentioned preparations as needed. The amount of the nitroimidazole derivative contained in the preparation of the present invention is not particularly limited and may be appropriately selected, and it is generally preferable that the amount is usually about 1 to 70% by weight in the preparation.

The method of administration of the preparation of the present invention is not particularly limited.
It is determined according to various formulation forms, the age of the patient, gender and other conditions, the degree of symptoms of the patient, and the like. For example, tablets, pills,
Powders, solutions, suspensions, emulsions, granules and capsules are administered orally. Suppositories are administered rectally. The injection is administered intravenously, alone or mixed with a normal replenisher such as glucose, amino acids, etc.
It is administered intradermally, subcutaneously or intraperitoneally. The ointment is applied to skin, oral mucosa, and the like. The dose of the active ingredient of the preparation of the present invention can be appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease and the like. Usually, the compound of the present invention is used in an amount of about 0.1 to 100 mg / kg / day, preferably 0.5 to 5 mg / kg / day.
It is better to use an amount in the range of about 0 mg / kg / day as a guide. These preparations of the present invention can be administered once or twice or four times a day.

[0015]

The present invention will be described below with reference to examples and pharmacological test examples. Example 1 Synthesis of N-hydroxyethyl-N-methyl-2- (2-nitro-1-imidazolyl) -acetamide (compound 1) 3.72 g of 2-nitro-1-imidazole-1-acetic acid methyl ester and 2- After dissolving 4.5 g of methylaminoethanol in 20 ml of anhydrous methanol and reacting at room temperature for 18 hours, methanol was distilled off to obtain a brown oily residue.
Next, this was subjected to silica gel column chromatography, and the obtained brown oil was crystallized from diethyl ether to obtain 2.65 g of the title compound 1 (yield: 58%). still,
Compound 1 was a mixture of two conformers by ¹ H-NMR, and the ratio was Z: E = 54%: 46%. Melting point: 83-85 ° C ¹ H-NMR (CD ₃ OD) δ: 2.983 (3H,
s), 3.208 (3H, s), 3.509 (2H, t,
J = 5.6 Hz), 3.552 (2H, t, J = 5.2H)
z), 3.668 (2H, t, J = 5.6 Hz), 3.78
5 (2H, t, J = 5.2 Hz), 4.893 (1H,
s), 7.150 (1H, s), 7.160 (1H,
s), 7.372 (1 H, s), 7.399 (1 H, s) ¹³ C-NMR (CD ₃ OD) δ: 34.260, 36.2
53, 51.986, 52.237, 52.420, 59.
735, 60.430, 128.169, 129.04
7, 167.817, 168.146, 188.373 IR (KBr) cm ^-1 : ν 3549, 1661, 1367, 1292, 1137,
802

Pharmacological test 1 Examination of anti-malignant tumor effect, metastasis suppressing effect, radiation-induced anti-malignant tumor effect enhancing effect and immunostimulatory effect An 8-week-old C3H / He mouse female was subjected to control group, 30 Gy irradiation group, KIN806 administration group. (0.4 mg / g), Compound 1 administration group (0.4 mg / g), 30 Gy irradiation group + KIN806 administration group (0.4 mg / g)
g), 30 Gy irradiation group + compound 1 administration group (0.4 mg / g) 6
And 20 animals were assigned to each group. After transplanting 10 ⁵ SCCVII tumor cells into the right hind limb of the mouse, on the 15th day, a local irradiation of 30 Gy of ⁶⁰ Co-γ-ray was performed once at the site where the tumor was present. In the group in which the compound was used in combination with the radiation treatment, the compound was administered intraperitoneally 30 minutes before the irradiation.
Fluctuations in tumor volume were observed every 2 to 3 days and were performed until day 19. The effect was determined by setting the tumor volume on the day of the treatment start to 1, and then evaluating the tumor volume ratio. Twenty days after the treatment, all mice were sacrificed, tumor tissues and lungs were excised, and the number of metastatic nodules on the lung surface was counted using a loupe with a magnification of 7 times. These tissues should be stored immediately in liquid nitrogen,
ABC immunization (immunostaining) was performed. In addition, regarding the tumor tissue, the same procedure was performed on the 7th and 14th days after the treatment.
saved. Table 1 shows the results on the 19th day after the treatment for the anti-malignant tumor, and Table 2 shows the results of the lung metastasis inhibitory action.

[0017]

[Table 1]

[0018]

[Table 2]

From the above results, it has been clarified that the compound of the present invention shows a tumor reducing effect by itself, but shows a remarkable tumor reducing effect when used in combination with 30 Gy of radiation. In addition, it was shown that the lung metastasis inhibitory effect was exhibited irrespective of the presence or absence of radiation irradiation. Furthermore, administration of the compound of the present invention showed moderate or more infiltration of helper T cells and suppressor / killer T cells into the infiltrating mononuclear cells in tumor tissues, and it was also revealed that the mononuclear cells had an immunostimulatory effect.

Formulation Example 1 Tablets Compound 1 40 mg Starch 100 mg Magnesium stearate 15 mg Lactose 45 mg Total 200 mg Tablets of 200 mg per tablet were prepared in the above-mentioned mixing ratio according to a conventional method. Formulation Example 2 Granules Compound 1 200 mg Lactose 340 mg Cornstarch 450 mg Hydroxypropylmethylcellulose 10 mg Total 1000 mg Granules were prepared according to a conventional method in the above mixing ratio. Formulation Example 3 Capsule Compound 1 100 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 mixing ratio. Formulation Example 4 Injection Compound 1 200 mg Distilled water for injection qs 5 ml per ampoule Injection was prepared in the above mixing ratio according to a conventional method.

[0021]

Industrial Applicability The nitroimidazole derivative of the present invention has excellent antineoplastic activity, radiosensitizing effect, metastasis suppressing effect and immunostimulating effect, has no neurotoxicity which is a side effect, and has excellent water solubility. .

Claims (6)

[Claims] 1. A nitroimidazole derivative represented by the general formula (1). Embedded image Wherein R is a lower alkyl group or a lower acyl group, R ′ is a — (CH ₂ ) _n OR ₁ group or — (CH ₂ ) _n NR ₂ R ₃ group, R ₁ is a hydrogen atom, a lower alkyl group, Lower acyl group, -CONR
_{A 4} R ₅ group (R ₄ and R ₅ are the same or different and each represent a hydrogen atom or a lower alkyl group) or a —SO ₂ R ₆ group (R ₆ may be substituted with a lower alkyl group or a lower alkyl group; R ₂ and R ₃ are the same or different and represent a hydrogen atom, a lower alkyl group or a lower acyl group, and n represents an integer of 1 to 5. ] 2. The compound according to claim 1, wherein R ′ is a — (CH ₂ ) _n OR ₁ group.
The nitroimidazole derivative according to the above. 3. The nitroimidazole derivative according to claim _{2, wherein} R ′ is — (CH ₂ ) _n OH. 4. The nitroimidazole derivative according to claim 3, wherein R ′ is a hydroxyethyl group. 5. The nitroimidazole derivative according to claim 1, wherein R is a lower alkyl group. 6. The nitroimidazole derivative according to claim 1, wherein R is a methyl group and R ′ is a hydroxyethyl group.