JPS60130572A - 5-(p-nitrophenyl)tetrazole derivative - Google Patents

Abstract

NEW MATERIAL:The 5-(p-nitrophenyl)tetrazole derivative of formula (R is lower alkyl substituted with a substituent group selected from carboxyl, hydroxyl and lower alkoxy). EXAMPLE:2-[5-(p-Nitrophenyl)tetrazol-2-yl]acetic acid. USE:It has strong radiation sensitizing effect and is useful as a drug. It has no side effect such as central toxicity. PREPARATION:The compound of formula can be produced by reacting the compound of formula RX (X is halogen or its equivalent reactive group) with 5-(p- nitrophenyl)tetrazole in a solvent such as methanol in the presence of an acid acceptor base. The base is e.g. sodium hydroxide, and the reaction is carried out under ice-cooling - at the boiling point of the solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 5-(p-nitrophenyl)tetrazole derivatives.

The novel 5-(p-nitrophenyl)tetrazole derivatives of the present invention are represented by the general formula (I) [Formula hole 1 is a lower alkyl group substituted with a substituent selected from carboxy, hydroxy and lower alkoxy groups] means. ] It is expressed as .

Here, examples of the alkyl group moiety in the lower alkyl group substituted with a lower alkoxy group include alkyl groups having a carbon atom such as methyl, ethyl, n-propyl, isopropyl, and n-butyl. can.

The substituted lower alkyl group may be -substituted or disubstituted, or may have more substituents, and in the case of polysubstitution, the substituents may be the same or different. When the group represented by a has a carboxyl group, the compounds of the present invention include salts thereof.

In general, tumor cells in a hypoxic environment are less sensitive to radiation than when the same cells are in a normoxic (aerobic) environment. When a mass-type tumor reaches a certain diameter,
The center of the tumor has fallen into so-called central necrosis, and the outermost edge of the tumor has good oxygen partial pressure and nutritional support due to blood circulation, and tumor cells are actively proliferating. In the middle between the center and the outermost edge there are cells that survive under hypoxia. Because these intermediate cells are under a hypoxic environment, they are more radioresistant than the outermost cells, and therefore cause tumor recurrence after radiotherapy. There is a strong desire to strengthen this.

2-nitroimidazole derivatives such as misonidazole are known as representative drugs having such effects (J. O. Asquith).

M., Watts, etal., Rodiat, R.
es, 60, 108-118 (1974)), but at present its radiosensitizing effect cannot be said to be sufficient.

The compound obtained by the present invention has a strong radiosensitizing effect, and is also expected to reduce side effects such as central toxicity of nitroimidazole derivatives.

The compound represented by the general formula (I) has the general formula (n)RX
(ml [In the formula, R is the same as above, and X means a halogen atom or a reactive equivalent group thereof.] 5-(p-nitrophenyl)tetrasol (m) Synthesized by reaction.

The halogen atom here is, for example, a chlorine atom, a bromine atom, etc., and the reactive equivalent group is one that shows the same reactivity as these substituents, such as evamethanesulfonyloxy &, p7 toluenesulfonyloxy group. etc.

The starting material is a compound known in the literature.
It can be synthesized by the reaction of p-nitrobenzonitrile and azide (W, G).

Finnegan, R.A., Henry and R.
, Lofquist, J. Am.

Ohem, soc,, 80, 8908, (19
58)).

The reaction between compound (nI) and compound (rl) is generally carried out in a solvent in the presence of a deoxidizing base. Examples of such solvents include alcohol solvents such as methanol, ethanol and isopropanol, aprotic polar solvents such as dimethylformamide, and ether solvents such as tetrahydrofuran and dioxane. Examples of the base used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, anhydrous sodium carbonate, and anhydrous potassium carbonate, and organic bases such as triethylamine, N-methylmorpholine, and pyridine. Although the reaction temperature is not particularly limited, it is generally carried out under water cooling or below the boiling point of the solvent.

In general formula (I), when producing the compound of the present invention in which the group represented by B is a group having a hydroxy group at the β-position of the nitrogen atom, the compound ( It can also be synthesized by reacting with m). Examples of such solvents include alcohol solvents such as methanol, ethanol, and isopropanol, aprotic polar solvents such as dimethylformamide, halogenated hydrocarbon solvents such as chloroform and dichloromethane, and ether solvents such as tetrahydrofuran and dioxane. .

Examples of the base used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, anhydrous sodium carbonate, and anhydrous potassium carbonate, and organic bases such as triethylamine, N-methylmorpholine, and pyridine. Although the reaction temperature is not particularly limited, it is generally carried out under water cooling or below the boiling point of the solvent.

When producing the compound of the present invention in which all the groups shown in general formula (1) are groups having hydroxy groups at the β and γ positions of the nitrogen atom, the compound consisting of the compound (m) and the shrimp halohydride derivative The reaction between compound (I) and the shrimp halohydrin derivative is generally carried out in a solvent in the presence of a base, and the solvent may be an alcoholic solvent such as methanol, ethanol, isopropanol, or an aprotic polar solvent such as dimethylpolamide. , tetrahydrofuran, dioxane, and other ether solvents.

Examples of the base used in this reaction include inorganic bases such as anhydrous sodium carbonate and anhydrous potassium carbonate, and organic bases such as triethylamine and N-methylmorpholine. Although the reaction temperature is not particularly limited, it is generally carried out under water cooling or below the boiling point of the solvent.

Further, the ring-opening reaction of the 1,2-epoxy-8-(5-(p-nitrophenyl)tetrazolyl)propane derivative is generally carried out by hydrolysis in a solvent in the presence of an acid catalyst.

As such a solvent, water or a mixed solvent of water and an organic solvent is used, and examples of the organic solvent include alcohol solvents such as methanol and ethanol, aprotic polar solvents such as dimethylformamide and dimethyl sulfoxide,
Examples include acetone.

Examples of acid catalysts include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid and trinitrobenzenesulfonic acid.

Although the reaction temperature is not particularly limited, it is generally carried out under water cooling or below the boiling point of the solvent.

5-(p-nitrophenyl) represented by general formula (f)
In the tetrazole derivative, the substituent hole is located at one of the tetrazole rings.
There are compounds bonded to the 2-position and compounds bonded to the 2-position. Although the present invention includes these two positional isomers, the two isomers can be separated as necessary by methods such as column chromatography and recrystallization.

Furthermore, when the group represented by 几 in general formula (1) has a carboxyl group, the compound can be obtained as a salt if necessary. Examples of such salts include salts with inorganic bases such as sodium, potassium, calcium, and magnesium salts, and salts with pharmaceutically acceptable amines.

The compounds provided by the present invention can be administered in solid or liquid form in admixture with organic or inorganic inert carrier substances and auxiliary substances suitable for oral or parenteral administration. Administration as a sensitizer, usage,
Although the amount of the active ingredient is selected as appropriate depending on the patient's age, gender and other conditions, and the severity of the disease, the amount of the active ingredient is usually given per body weight per day.
It is good to set it as about 0.1-100q per kg.

The following examples illustrate methods for making the compounds provided by this invention.

[Example 1] 2-[5-(P-nitrophenyl)tetrazol-2-yl] Acetic acid and its sodium salt 5-(p-nitrophenyl)tetrazole 5.7011
was dissolved in 100 ml of ethanol, potassium hydroxide 1.68F and ethyl 2-bromoacetate 8-88
Add 1 mL of the mixture and heat under reflux for 15 hours. After returning to room temperature, the solvent was distilled off from the reaction solution under reduced pressure, and the residue was separated and purified by silica gel column chromatography using chloroform as an eluent. -yl] acetate 8.
I got 829.

Melting point 104-105℃ NMR (ODOzs) δ (p, p, m,) 1.81 (8H1L (J = 7Hz)), 4.27 (
2B, +(J=7'Hz) )5.49(2H,s)
8.82 (4H,s) Ethyl 2-[5-(p-nitrophenyl)tetrazole-2 thus obtained
-yl] acetate-1-1,88N in methanol 80 m
The mixture was dissolved in A and 0.241 of sodium hydroxide was added, and the mixture was stirred at 40 to 50°C for 1 hour.

The precipitated crystals were dried several times, and the title compound was 1.01%
I got g.

Melting point: 297° to 308°C After dissolving this in distilled water and adjusting the pH to 1 to 2 with concentrated hydrochloric acid, the precipitated crystals were collected and dried to obtain 2-(
5-(p-nitrophenyl)tetrazol-2-yl]
O, sog of acetic acid was obtained.

Melting point 187~iss°C NMR (d6-DM80) δ (p, p, m,) 6.78
(2H,s) 8.84 (4H1s) [Example 21 a
-[5-(p-nitrophenyl)tetrazol-2-yl] -1-methoxypropanol-2-ol 5-(p-nitrophenyl)tetrazole 8.82f/
was dissolved in 50 mL of ethanol, 0.281 g of anhydrous potassium carbonate and 2.61 f of 1,2-epoxy-3-methoxypropane were added, and the mixture was heated under reflux for 2 hours. After returning the temperature to room temperature, insoluble matter was removed, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using chloroform-methanol (98/2=v/V) as an eluent to obtain the title compound 2. 'I got 15f/.

Melting point 80-81°C NMR (ODOza) J (p, 1), m, ) 8, 47
(8H, s), 8.57 (2H, d (J=5Hz)).

4, 21-4.77 (LH, m).

4,86 (2H, d(J=5Hz)), 8.81
(4H,s) [Example 8] 2-[5-(p-nitrophenyl)tetrazol-2-yl] Ethanol 5-(p-nitrophenyl)tetrazole 0.951 was dissolved in 15 ml of ethanol, and water Potassium oxide 0
．． After adding 28 II and heating under reflux for 1 hour, 0.854 m4 of 2-bromoethanol was added dropwise and the mixture was further heated under reflux for 9 hours. After returning to room temperature, insoluble materials were removed, the solvent was distilled off under reduced pressure, and the 98-residue was purified by silica gel column chromatography using chloroform-methanol (/2-v/V) as an eluent. The title compound 0,84 II was obtained, melting point 125-126°C NMR (d6-DM80) J(P-P-m, )
8.85-4.15 (2H, m).

4.56-4.91 (2H, m).

5.69 (1H,s), 8.80 (4H,8) [Example 41 8-[5'-(P-tetrophenyl)tetrazol-2-yl] Propan-1-ol 5-(p-nitro Dissolve 8.809 phenyl)tetrazole in 50 mL of ethanol and add 1.809 g of potassium hydroxide.
After adding 45N and heating to 75°C, 2.2'7f of 8-chloropropanol and 8.61ml of sodium iodide were added and stirred at the same temperature for 26 hours. After returning the temperature to room temperature, insoluble matter was removed, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using chloroform-methanol (98/2=V/v) as an eluent to obtain the title compound 1.
Obtained 65F.

Melting point 77.5-78.5°C NMR (d6-DM80) a(1), Il, m, )1
．． 98~2.42 (2H, m) 8.52 (2H, t (J=6H7,)) 4.05 (
1H, 11) 4.79 (2ff, t (J=7.5H7))
8.25(4H,s) [Example 5') -8-15-(1)-nitrophenyl)tetrazol-2-yl) propane-1,2-diol 5-(p-nitrophenyl)tetrazole 8.0f, 180q of anhydrous potassium carbonate and 60 m of epichlorohydrin
1, and then heat under reflux for 80 minutes. After returning to room temperature, insoluble matter was removed, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using chloroform-methanol (98/2 = V/v) as an eluent.
-Epoxy-8-(5-(p-nitrophenyl)tetrazol-2-yl)propane 2.2g was obtained.

The 1,2-epoxy-8-(5-
Add 10 ml of 6N acid to 246 capes of (p-nitrophenyl)tetrazol-2-yrunpropane and mix 60-6
The mixture was stirred at 5°C for 8 hours. After cooling on ice, the mixture was neutralized with aqueous ammonia, extracted with ethyl acetate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using chloroform-methanol (9515) as an eluent to obtain the title compound 129 Misaki. Obtained.

Melting point 108-109°C NMR (d6-DMSO) J (p, p, +n,) 18
7-8.57 (2H, ml) 3.98-4.25 (1H, m)

Claims (1)

[Claims] General formula [The middle hole in the formula represents a lower alkyl group substituted with a substituent selected from carboxy, hydroxy and lower alkoxy groups. ] A 5-(p-nitrophenyl)tetrazole derivative represented by the following.