JPS603080B2 - S-triazolo[3,4-α][5,6,7,8]tetrahydrophthalazines - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel s-triazolo[3,41a][5,6
, 7, 8] relating to tetrahydrophthalazines. More specifically, the present invention provides novel s
-Relating to triazolo[3,4a][5,6,.7,8]tetrahydrophthalazines. To explain the present invention in detail, the compound of the present invention is represented by the following formula (1). In the above general formula (1), R is a hydrogen atom, an alkyl group having 10 or less carbon atoms, preferably 5 or less carbon atoms (for example, a methyl group,
Ethyl group, propyl group, isopropyl group, butyl group, t
-butyl group, etc.), a halogenated alkyl group having 10 or less carbon atoms, preferably 5 or less carbon atoms (for example, chloromethyl group, dichloromethyl group, trichloromethyl group, bromomethyl group,
tripromomethyl group, trifluoromethyl group, etc.) or an aryl group having 20 or less carbon atoms, preferably 10 or less carbon atoms (for example, phenyl group, naphthyl group, etc.). R2 is a hydrogen atom, a halogen atom, an alkoxy group having 10 or less carbon atoms, preferably 5 or less carbon atoms (e.g., methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, t-butoxy group, etc.), 10 carbon atoms or less, Preferably 5 or less alkylthio groups (e.g. methylthio group, ethylthio group, propylthio group, isoprobylthio group, butylthio group, etc.), carbon number 20 or less, preferably 10
The following aryloxy groups (e.g. phenoxy group, naphthyloxy group, etc.), azide group, hydrazino group or N2
-substituted hydrazino group (the substituent is an alkylidene having up to 10 carbon atoms, preferably up to 8 carbon atoms) (for example, N2
-(1,3-dimethyl-2-butenyridine)hydrazino group, etc.). Specific examples of the compounds of the present invention are listed below, but the compounds of the present invention are not limited to the following compounds. 6-
Chloro-3-trifluoromethyl-s-triazolo[3
,41a][5,6,7,8]tetrahydrophthalazine 6-chloro-s triazolo[3,41a][5,6,
7,8] Tetrahydrophthalazine 6-chloro-3-phenyl-s triazolo[3,4-a][5,6,7,8
] Tetrahydrophthalazine 6-chloro 3-trichloromethyl-s triazolo [3,41a] [5,6,7,
8] Tetrahydrophthalazine 6-chloro-3-methyl-
s-triazolo[3,4-a][5,6,7,8]tetrahydrophthalazine 6-methoxy-3-trifluoromethyl-s-triazolo[3,4-a][5,6,7,8]
] Tetrahydrophthalazine 6-methoxy-s-triazolo[3,4-a][5,6,7,8] Tetrahydrophthalazine 6-methoxy-3-methyl-s-triazolo[3
,4-a](5,6,7,8)tetrahydrophthalazine 6-methoxy-3-phenyl-s triazolo[3,4
1a] [5,6,7,8]tetrahydride. Phthalazine 6-ethoxy-3-trifluoromethyl-s
Triazolo[3,41a][5,6,7,8]tetrahydrophthalazine 6-phenoxy3-trifluoromethyl-s-triazolo[3,41a][5,6,7,8
] Tetrahydrophthalazine 6-methylthio 3-trifluoromethyl-s triazolo[3,41a][5,6
,7,8]tetrahydrophthalazine-3-trifluoromethyl-s triazolo[3,41a][5,6,7,8
] Tetrahydrophthalazine 6-hydrazino-3-trifluoromethyl-sH triazolo[3,4-a][5.6
,7,8]tetrahydrophthalazine6-{N2-(1,
3-dimethyl-2-butenylidene)hydrazino}-3-trifluoromethyl Hs-triazolo[3,41a][
5,6,7.8] Tetrahydrophthalazine 6-azido-3-trifluoromethyl-s-triazolo[3,41a
] [5”6,7,8]tetrahydrophthalazine s-triazolo[3,4-a][5,6,7
, 8] Tetrahydrophthalazines can be manufactured by various methods, and the manufacturing methods will be explained below by giving some examples.

[1' When R2 in the general formula (1) is a halogen atom, carboxylic acid (R, -C02H) or its derivative, or nitrile (R.
), and X is a halogen atom. As shown in the above reaction formula, 1-hydrazino 4-halogeno 5,6,7,8-tetrahydrophthalazine (0
) with a carboxylic acid or its derivative or a nitrile in the absence of a solvent or in the presence of a solvent to produce 6-halogeno s-triazolo[3,4-a][5,6,7] represented by the general formula (1'). , 8] tetrahydrophthalazines can be produced. 1-hydrazino-4-halogeno 5,6,7, represented by the above general formula (b),
8-Tetrahydrophthalazines are prepared by mixing 1,4-dihalogeno 5,6,7,8-tetrahydrophthalazines and hydrazine (e.g. 80% hydrazine hydrate) in a solvent (e.g. ethanol) at a certain temperature (e.g. ethanol). (reflux temperature). Examples of the carboxylic acid or its derivative used in the above reaction include aliphatic and aromatic carboxylic acids, carboxylic acid esters, carboxylic acid anhydrides, carboxylic acid halides, orthoformic acid esters, and specific examples include formic acid, Acetic acid, propionic acid, butyric acid, hexanoic acid, chloroacetic acid, trichloroacetic acid, tribromoacetic acid, trifluoroacetic acid, benzoic acid, o-chlorobenzoic acid, p-chlorobenzoic acid, p-methoxybenzoic acid, p-cyanobenzoic acid, p-hydroxy Benzoic acid, p-methylbenzoic acid, methyl formate, ethyl formate, methyl acetate, ethyl acetate, butyl acetate, pendyl acetate, ethyl propionate, ethyl trifluoroacetate, methyl benzoate, acetic anhydride, propionic anhydride, trifluoroacetic anhydride , acetyl chloride, trichloroacetyl chloride, propionyl chloride, t-butyryl chloride, methyl orthoformate, orthoformate, and the like. Further, as the nitrile, trichloroacetonitrile, benzonitrile, etc. are used. When an acid halide is used as a carboxylic acid or its derivative, a base is used as a catalyst in an amount equal to or more than the equivalent molar amount of the solvent based on the amount (0) of 1-hydrazino-4-halogeno-5,6,7,8-tetrahydrophthalazine. You can also do that. As a base, trimethylamine, triethylamine,
Tertiary bases such as pyridine, picoline, lutidine, and N,N-dimethylaniline are used. The reaction proceeds without a solvent, but if necessary, a solvent such as aromatic hydrocarbons such as benzene and toluene; chlorinated hydrocarbons such as chloroform, carbon tetrachloride, and dichloromethane; dioxane, water, etc. can be used. . Generally the reaction involves 1-hydrazino-4-halogeno-5,6
, 7,8-tetrahydrophthalazines (0) or a solvent solution thereof and a carboxylic acid or its derivative or nitrile in an amount equal to or more than the equimolar amount of the solvent (if an acid halide is used as the carboxylic acid or its derivative, a base is added). Mix and concentrate (add all three ingredients) and leave at room temperature or 1500
This is done by heating to temperatures down to 0. The reaction time is 1 - hydrazino 4 - halogeno 5
, 6,7,8-tetrahydrophthalazines, carboxylic acid or its derivative, or the type of nitrile, but is selected from a range of several minutes to several hours. After the reaction is complete, remove the solvent, excess acids, bases, etc. to obtain a residue, which is clean enough as it is, but if necessary, it can be purified by means such as recrystallization, distillation, chromatography, etc. Further purification is also possible. '21 In the above reaction formula where R2 is other than a halogen atom in the general formula (1), R and R2 are as defined in the general formula (1), and X is a halogen atom. That is, 6-halogen/-s obtained by the production method of [11]
Triazolo[3,4-a][5,6,7,8]tetrahydrophthalazine (1') is reacted with a nucleophile to form s-triazolo[3,4-a] represented by the above general formula (1'').
-a][5,6,7,8]tetrahydrophthalazines can be produced. Specific examples of nucleophilic reagents used in the above reaction include hydrogen, methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, t-butyl alcohol, n-octyl alcohol, etc. Alkali metal salts of alcohols with 10 or less carbon atoms (i.e., lithium, sodium, potassium, etc.), methyl mercaptan, ethyl mercaptan, n-butyl mercaptan, etc., alkali metal salts of mercaptans with 10 carbon atoms or less: alkali metals such as phenol, naphthol, etc. Salt: Sodium azide; hydrazine, hydrazine hydrate; N2-substituted hydrazine (N2-
Specific examples of the substituents are as described above. ) etc. The reaction proceeds without a solvent, but if necessary, water, alcohols such as methyl alcohol, ethyl alcohol, and propyl alcohol; aromatic hydrocarbons such as benzene, toluene, and xylene; and chloroform, dichloromethane, carbon tetrachloride, etc. Chlorinated hydrocarbons: Ethers such as diethyl ether, tetrahydrofuran, and dioxane can be used, but alcohols are preferred. The reaction is 6-halogeno-s-triazolo[3,
41a] [5,6,7,8] Tetrahydrophthalazines or their solvent solution and at least the equivalent molar amount (preferably 1.1
~1.3 somolar) of the nucleophile and either left at room temperature or heated to temperatures up to 200°C. The preferred reaction temperature is the reflux temperature of the solvent when a solvent is used, and 160 to 190°C when no solvent is used. The reaction time is determined by the 6-halogeno-s-triazolo[3,4
1a] [5,6,7,8] Although it varies depending on the type of tetrahydrophthalazines and nucleophilic reagent, the time is selected from a range of several tens of minutes to several hours (preferably 2 to 5 hours). After the reaction is completed, the solvent is distilled off to obtain Zenizumi, which is washed with water to give triazolo[3,41a][5,6,7,
8] Tetrahydrophthalazines are bound. This is sufficiently clean as it is, but if necessary, it can be further purified by means such as recrystallization, distillation, and chromatography. Among the compounds synthesized by the above production method '21, the compound in which R2 is an N2-(1,3-dimethyl-2-butenylidene)hydrazino group is 6-hydrazino-s-triazolo[3,4-a][5,6,7 ，
8] It can also be produced by heating tetrahydrophthalazines and mesityl oxide in a solvent such as benzene. In addition, the compound in which R2 is an azide group is as shown in the reaction formula below, 6-hydrazino-s triazolo[3,4a
[5,6,7,8] It can also be synthesized by reacting tetrahydrophthalazines with sodium sulfite. That is, in hydrochloric acid with or without glacial acetic acid, 6-hydrazinose triazolo[3 , '4-a] [5,6,7,8] It is prepared by adding tetrahydrophthalazines and incubating for several minutes to several hours. Next, the compound of the present invention, s-triazolo[3,41a]
[5,6,7,8] The pharmacological actions of tetrahydrophthalazines will be explained. Inhibitory effect on carrageenan mammoma Eight female Wistar rats weighing 130-150 mm were used as one group. The drug was orally administered one hour before subcutaneous injection of 1% lambda carrageenin 0.05' next to the right hind leg. The mammary tumor rate was determined from the volume of the right hind paw before and 3 hours after lambda carrageenan injection, and the inhibition rate was calculated using the following formula.
Suppression rate (%) = E Mitomi X,. . Ec and Et are the 3-hour average milk production rates of the control group and the drug-administered group, respectively. As shown in Table 1 below, each compound showed a remarkable carrageenan breast tumor suppressing effect. Table 11 Next, the method for producing the compounds of the present invention will be specifically explained using Examples, but the present invention is not limited to the compounds synthesized in these Examples unless the gist thereof is exceeded. (In the following examples, elemental analysis is in weight % and yield is in mol %.) Example 1 6-chloro-3-trifluoromethyl-s-triazolo[3,4-a][5,6,7.8 ] Synthesis of tetrahydrophthalazine 1-hydrazino 4-chloro 5,6,7,
8-Tetrahydrophthalazine 1. Scale 5 Yu (IWmmol
) was added to 20 parts of trifluoroacetic acid, heated for 7 hours, and the excess trifluoroacetic acid was removed. The resulting crystals were reconstituted with inpropyl alcohol. Melting point: 142-3°C. Yield 2.37mm (yield 86%) Elemental analysis value: C, oH8N4Cso F3 ○ H N
CZ calculated value Phosphorus 43.42 2.91 20.25
12.81 Experimental value association 43.38 2.91 20.
16 12.85 Example 26-Chloro s-triazolo[3,4-a](5,6,7,8]Synthesis of tetrahydrophthalazine 1-hydrazino-4-chloro-5,6,7
, 8-tetrahydrophthalazine 1.99 ml (Mhmol
) in 17' of formic acid and heated under reflux for 3 hours. After refluxing, excess formic acid was distilled off and water was added to the kojisumi to form white crystals. This is recrystallized from methanol water. Melting point 114-5°C. Yield: 1.91% (yield percentage) Elemental analysis value: C Rainbow QN4C as a final ○ H N OZ Calculated value ■ 51.80 4.35 26.85 16.
99 Experimental Value Association 51.83 4.32 26.54 1
6.71 Example 36-chloro-3-phenyl-triazolo[3,41a][5,6,7,8]Synthesis of tetrahydrophthalazine 1-hydrazino-4-chloro-5,
6.7,8-tetrahydrophthalazine 720 mol (3 mol) and penzoyl chloride 560 mol (4. mol)
l) and pyridine 15 in the skin 2. Immediately heat to reflux, remove the pyridine, remove the benzene-soluble portion, distill off the benzene, and reconsolidate with ethanol. Kuzukan points 191-300. Yield 41 products 9 (yield 40%) Elemental analysis value: C, 5 days, ○ H N as 3N4C
C multi-calculation value ■ 63.27 4.60 19.68 12.
45 Experimental value Phosphorus 62.82 4.51 19.70 1
2.64 Example Synthesis of 46-chloro-3-trichloromethyl-striazolo[3,41a][5,6,7,8]tetrahydrophthalazine In the same manner as in Example 3, 1
-Hydrazino-4-k. Rho-5,6,7,8-tetrahydrophthalazine 1. scales 5
(IQhmol) and trichloroacetyl chloride 2.2
(12 hmol) and triethylamine 4 in benzene
．． The reaction was carried out using Ogawa as a catalyst to obtain 18 cc of product. Reconstitute with inpropyl alcohol. Melting point 175~6℃
. Elemental analysis value: C, oH8N4Cso4○H
NOZ Calculated value (fence 36.84 2.47 17.19 43
．． 50 experimental value (fence 37.19 2.52 17.30
43.41 Proposed Example 56-Chloro 3-methyl-s triazolo [3,41a] [5,6,7,8) Synthesis of tetrahydrophthalazine 1-hydrazino 4-chloro 5
, 6, 7, 8m tetrahydrophthalazine 1.0 evening (9h
1 mol) of acetic anhydride was added to 10 mol of acetic anhydride, and 1 mol of
After heating for an hour, excess acetic anhydride is distilled off, washed with water, and the residue is reconsolidated from a small amount of ethanol and water. Melting point: 19 0. Yield 782 p (yield 70%) Weight cost analysis value: C, oH, . As N4C evening ○ H N
OZ Calculation Value Association 53.94 4.98 25.16 1
5.92 Experimental value association 53.60 4.79 25.32
16.35 Example 66-Methoxy-3-trifluoromethyl-s triazolo[3,4-a][5,6,7
, 8] Synthesis of tetrahydrophthalazine 6-chloro-3-trifluoromethyl-s-triazolo[3,4-a][
5,6,7,8] Tetrahydrophthalazine 1. Ball Yu (5
7 mmol) and sodium methoxide 370 females (6 losses m
mol) was heated for 4 hours in 30 methanol, washed with water, and reconsolidated with ethanol. Melting point: 121-2°C. Elemental analysis value: C,. Day,. ON4F
3 as C Japan/N-Calculation Value Association 4 Crab. 53 4.07 20.58 Experimental value Phosphorus 48.
44 4.03 20.61 In the same manner as in Example 6, 6-alkoxystriazolo[3,
4-a] [5,6,7.8) Tetrahydrophthalazines were obtained. Table 2* Upper row: calculated values, lower row: experimental values Example 7 6-phe/xy-3-trifluoromethyl-s-triazo. [3,41a] [5,6,7,8] Synthesis of tetrahydrophthalazine 6-chloro-3-trifluoromethyl-s-
Triazolo [3,41a] [5.6,7,8]tetrahydrophthalazine 97 o (3.0 mol), phenol 500 (5.2 mol) and potassium carbonate 730
Female (5.28hmo) was heated to 160-175℃ without solvent.
Heat for 1.5 hours. After cooling, 30 parts of chloroform is added, and the chloroform layer is washed with 30 parts of 2N caustic soda and then with water. After drying, the chloroform is distilled off, and the residue is reconsolidated with ethanol and then with inpropyl alcohol. Melting point 131.5-132
．． 5℃. Yield 8$ imitation (yield 76%) Elemental analysis value: C, 6
○ H N calculated value phosphorus as 30N4F3 57.
49 3.92 16.76 Experimental value association 57.1
6 3.96 16.57 Example 86-methylthio-3-trifluoromethyl-s triazolo[3,
41a] Synthesis of [5,6,7,8]tetrahydrophthalazine 6-chloro-3-trifluoromethyl-striazolo[3,4-a][5,6,7,8]tetrahydrophthalazine 434 .7 female (1.57 mmol) and methylcaptan sodium 20% aqueous solution 1.19 (1.57
After heating and refluxing 15 mmol of methanol for 35 hours and distilling off the methanol and water, the solution was reconsolidated with isopropyl alcohol. Melting point 112-5°C. Yield: 412 copy (yield 91%) Elemental analysis value: C,. Day,. As 04SF3 ○ H NF calculation value association 45.83 3.85 19.43 19.7
7 Aoi test value 45.79 3.79 19.46 2
0.07 Example 9 Synthesis of 3-trifluoromethyl-s-triazolo[3,41a][5,6,7,8]tetrahydrophthalazine 6-chloromethyl 3-trifluoromethyl-s
Triazolo [3,4-a] [5,6,7,8] Tetrahydrophthalazine 553.3 (2.hmol) and triethylamine 242.4-9 (2.hmol) and 1
0% palladium-carbon 100% and ethanol 35'
Catalytic reduction is carried out under medium mixing, room temperature, and normal pressure. After 1 hour, the reaction is stopped, the solvent of the palladium-carbon solution is removed, and the residue is reconsolidated from ethanol. Melting point: 170-2°C. Yield 29 muo (yield 56%) Elemental analysis value: C, oH9N4F3 ○ H N Calculated value Phosphorus 49.59 3.74 23.13
Experimental data 49.56 3.69 23.47 Example 106-hydrazino-3-trifluoromethyl-
Synthesis of s-triazolo[3,4-a][5,6,7,8]tetrahydrophthalazine 6-chloro-3-trifluoromethyl-s-triazolo[3,4-a][5,6,7]
．． 8] Tetrahydrophthalazine 922.2-9 (3. Madaramisaki mol) and 80% l hydrazine hydrate 1.0 mol (
8.0 hmol) was heated under reflux for 7 hours in 20ml of ethanol, and after the solvent was removed, water was added and the insoluble portion was separated in a furnace and reconsolidated with ethanol. Melting point 248-9°C, yield unevenness 5 o (yield 92%) elemental analysis values: C, oH, . As N6F3 C day N F Calculated value Phosphorus 44.12 4.07 30.87 20.
94 experimental value candle 44.25 4.02 31.40 2
0.91 Example 116m{N2-(1,3-dimethyl-2-putenylidene)hydrazino}-3-trifluoromethyl-s triazolo[3,41a][5,6,7,
8] Synthesis of tetrahydrophthalazine 6-hydrazino-3-trifluoromethyl-s triazolo[3,4-a][5,6,7,8]tetrahydrophthalazine 272.2-pan,9( 1 mmol) and 176.8 mmol of mesityl oxide (1.8 mmol) were heated in benzene on a water bath for 3 hours, and after distilling off the benzene, the residue was recrystallized from ethanol. Yield 207.3 female (yield 59%) Elemental analysis value: C, 6E, 9N6F3, ○ H N F
Calculated value: 54.54 5.44 23.85 16.
18 Experimental value Phosphorus 54.55 5.24 24.27
16.40 Example 126-azido-3-trifluoromethyl-s triazolo[3,41a][5,6,7,
8] Synthesis of Tetrahydrophthalazine 2807 units (1.08 hmol) of 6-hydrazino-3-trifluoromethyl-striazolo[3,41a][5,6,7,8]tetrahydrophthalazine synthesized in Example 10 were concentrated. Hydrochloric acid 1
Add 10 parts of water, 1 part of glacial acetic acid to a mixture of ice-
Under water cooling, sodium nitrite 72. Iso p (1.0 shoes mol
) on top of this little by little to increase the IQ concentration. After further incubating at room temperature for 2 hours, the resulting crystals are stabbed in a furnace and mackereled again with ethanol. Melting point 135-6℃, yield 2
52o (yield 86%) Elemental analysis value: C, oH8N7F
○ H N as 3

Claims (1)

[Claims] 1 The following general formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. are included ▼ (In the above formula, R_1 is a hydrogen atom, an alkyl group having 10 or less carbon atoms, a halogenated alkyl group, or a halogenated alkyl group having 20 carbon atoms)
R_2 represents the following aryl group, and R_2 is a hydrogen atom, a halogen atom, an alkoxy group or alkylthio group having 10 or less carbon atoms, an aryloxy group having 20 or less carbon atoms, an azide group, a hydrazino group, or an N^2-substituted hydrazino group (such as The substituent is an alkylidene group having 10 or less carbon atoms. ) represented by s-triazolo[3,4-
a] [5,6,7,8] Tetrahydrophthalazines 2
In claim 1, R_1 is a hydrogen atom, an alkyl group having 5 or less carbon atoms, a halogenated alkyl group, or an aryl group having 10 or less carbon atoms, and R_2 is a hydrogen atom, a halogen atom, or an alkyl group having 5 or less carbon atoms. alkoxy group,
Alkylthio group, aryloxy group having 10 or less carbon atoms,
Compound 3 according to claim 1, which is an azide group, hydrazino group or N^2-substituted hydrazino group (the substituent is an alkylidene group having 8 or less carbon atoms) , R_1 is a hydrogen atom, trichloromethyl group, trifluoromethyl group, methyl group or phenyl group, and R_2 is a hydrogen atom, chloro group, methoxy group, ethoxy group, methylthio group, phenoxy group, azide group, hydrazino group or N Compound 4 according to claim 2, which is a ^2-(1,3-dimethyl-2-butenylidene)hydrazino group In claim 3, R_1 is a trifluoromethyl group and R_2 is hydrogen Compound 5 according to claim 3, which is an atom, methoxy group, ethoxy group, methylthio group, azide group or hydrazino group In claim 3, R_1
is a methyl group, and R_2 is a chloro group or a methoxy group.