JPH03223280A - New production of indazole-3-carboxamide derivative - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as an excellent serotonin 3(5-HT3) antagonistic agent by reacting a specific aldehyde compound with a specific diamino compound and reducing the resultant product. CONSTITUTION:A compound expressed by formula I [R1 is acyl, lower alkylfulfonyl, (substituted) arylsulfonyl, lower alkoxycarbonyl or aralkyloxycarbonyl; R2 is H or halogen; Z is =CH2 or CH2X (X is reactive ester residue of an alcohol) [e.g. 2-(1-benzyloxycarbonylindazole-3-carbonylamino) propenal] is subjected to a reaction with a compound expressed by formula II [R3 is lower alkyl; R4 is (substituted) aryl(lower)alkyl; (n) is 2 or 3] (e.g. N-benzyl-N'-methylethylenediamine) and the resultant product is then reduced to afford the objective compound expressed by formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is applicable to serotonin 3 (5HT 3
) The following general formula (1) useful as an antagonist [wherein R2
means a hydrogen atom or a halogen atom, R and I mean a lower alkyl group, R4 means an unsubstituted or substituted aryl (lower) alkyl group, and n means 2 or 3. The present invention relates to a method for producing an indazole-3-carboxamide derivative represented by the following.

PRIOR ART A method for producing an indazole-3-carboxamide derivative having a 7- or 8-membered cyclic diamine structure as a partial structure has not been known so far.

OBJECTS OF THE INVENTION The present invention provides a novel method for producing indazole-3-carboxamide derivatives having excellent serotonin 3 (5-1 (T, .) antagonistic activity).

The present invention relates to the formula (11) (wherein R1 is an acyl group, a lower alkylsulfonyl group,
means an unsubstituted or substituted arylsulfonyl group, lower alkoxycarbonyl group, or aralkyloxycarbonyl group, R2 means a hydrogen atom or a halogen atom, Z means =CH2 or -CH2X, where X is a reaction of alcohol ester residue. ) A compound represented by the general formula: [wherein R3 means a lower alkyl group, R4 means an unsubstituted or substituted aryl (lower) alkyl group, and n
means 2 or 3. ] A method for producing a compound of formula (1), which comprises reacting with a compound represented by formula (IVa) or (IVb) (IVa) 5 (IVb) (in the formula , R5 means an unsubstituted or substituted phenyl group or a lower alkyl group, and R1 and Z mean the same as defined above.) is reacted with the compound represented by the above formula (Ill). The compound represented by the general formula (V) 4 (wherein R3, R- and n have the same meanings as defined above) is obtained by hydrolyzing the resulting compound.

General formula (■1) H (wherein, R2 means the same as mentioned above). This invention relates to a method for producing a compound.

Terms used in this specification will be explained below.

"Lower" means 1 to 6 carbon atoms unless otherwise specified. The lower alkyl group or lower alkyl moiety may be linear or branched.

Examples of the aryl moiety include phenyl, naphthyl, and the like. What is a “halogen atom”? Fluorine.

means a chlorine, bromine or iodine atom. "Unsubstituted or substituted aryl (lower) alkyl group" refers to one in which the aryl moiety is unsubstituted or has 1 to 2 halogen atoms, lower alkyl group, trifluoromethyl group, hydroxy group,
It means one substituted with a lower alkoxy group, a cyano group, or an amino group, and specific examples thereof include benzyl, 2-fluorobenzyl, 3-methylbenzyl, 4-methoxybenzyl, and the like. "Acyl group" means an unsubstituted or substituted saturated aliphatic carboxylic acid residue or an unsubstituted or substituted aromatic carboxylic acid residue or a portion thereof, such as formyl, acedel, propionyl, butyryl. , isobutyl, 2-methyl-2-phenoxyacetyl, acryloyl.

Examples include methacryloyl, cinnamoyl, benzoyl, chlorobenzoyl, methylbenzoyl, methoxybenzoyl, nitrobenzoyl and the like.

Examples of the "lower alkylsulfonyl group" include those in which the lower alkyl moiety is methyl, ethyl, propyl, butyl, etc., and specific examples include methanesulfonyl, ethanesulfonyl, and the like. Examples of the "unsubstituted or substituted arylsulfonyl group" include p-methylbenzenesulfonyl and benzenesulfonyl. Specific examples of the [lower alkoxycarbonyl group] include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and the like. Specific examples of the "aralkyloxycarbonyl group" include benzyloxycarbonyl and the like.

As a "reactive ester residue of alcohol".

For example, halogen atoms such as chlorine, bromine, and iodine, lower alkylsulfonyloxy groups such as methanesulfonyloxy, and benzenesulfonyloxy.

Examples include arylsulfonyloxy groups such as p-toluenesulfonyloxy.

The compound reaction between the compound of formula (11) and formula (l11) is
It is carried out in a solvent or without a solvent, and after the reaction is completed, the produced iminium salt is reduced using a metal hydride such as sodium borohydride or palladium on carbon.

By performing catalytic reduction using a catalyst such as platinum oxide,
A compound of formula (1) can be produced.

The solvent used is mainly alcohols such as methyl alcohol and ethyl alcohol, to which are added ethers such as diethyl ether and tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, ethylene glycol, water, etc. , can be used in combination. The reaction is usually -10 to IOD
'c.

The reaction between the compound of formula (IVa) or (IVb) and the compound of formula (Ill) can be carried out under the same conditions as the reaction between the above-mentioned formula (11) and the compound of formula (III). Alternatively, the compound of formula (V) can be obtained by carrying out hydrolysis using a base according to a specific method.

Examples of reactive derivatives of the compound of formula (Vl) include lower alkyl esters, active esters, acid anhydrides, acid halides (especially acid chlorides), and the like. Specific examples of active esters include p-nitrophenyl ester, 2,4.5-)cyclophenyl ester, pentachlorophenyl ester, cyan methyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, I-hydroxy Benztriazole ester, N-hydroxy-5-norporenedi-2,3
-dicarboximide ester, N-hydroxypiperidine ester, 8-hydroxyquinoline ester, 2-
Hydroxyphenyl ester, 2-hydroxy-4,5
-dichlorophenyl ester, 2-hydroxypyridine ester.

Examples include 2-pyridylthiol ester.

As the acid anhydride, a symmetrical mixed acid anhydride or a mixed acid anhydride is used. Specific examples of the mixed acid anhydride include a mixed acid anhydride with an alkyl chlorocarbonate, and an aralkyl chloride carbonate such as benzyl chlorocarbonate. Mixed acid anhydrides with aryl rorocarbonate such as phenyl chlorocarbonate, mixed acid anhydrides with alkanoic acids such as isovaleric acid and pivalic acid, and the like.

The reaction between the compound of formula (V) and the compound of (■1) involves dicyclohexylcarbodiimide, 1-edy-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N
' -Carbonyldiimidazole, 1-ethoxycarbonyl-2-ethoxy-■.

It can be carried out in the presence of a condensing agent such as 2-dihydroquinoline. When using dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride as a condensing agent, pyridine, 4-dimethylaminopyridine, 4-pyrrolidinopyridine, N-hydroxysuccinimide , l-hydroxybenztriazole, 3-hydroxy-4-oxo-3,
4-dihydro-1,2,3-benztriazine, N-hydroxy-5-norbornene-2,3-dicarboximide, etc. may be added and reacted.

The reaction between the compound of formula (V) and formula (Vl) is carried out in a solvent or without a solvent. The solvent to be used should be appropriately selected according to the type of raw material compound, etc., but for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc.
diethyl ether.

Ethers such as tetrahydrofuran and dioxane,
Examples include halogenated hydrocarbons such as methylene chloride and chloroform, ethyl acetate, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, ethylene glycol, and water, and these solvents may be used alone or in combination of two or more. It is used as This reaction is carried out in the presence of a base if necessary, and specific examples of the base include alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali carbonates such as sodium carbonate and potassium carbonate, triethylamine, triethylamine, and triethylamine. butylamine,
Organic bases such as diisopropylethylamine and N-methylmorpholine can be used, but an excess amount of the compound of formula (V) can also serve as the base. The reaction temperature varies depending on the type of raw material compound used, but generally ranges from -30°C to 20°C.
0°C1 is preferably -10°C to 150°C.

The compounds of formulas (!I) and (IVa) can be produced by the methods of Reference Examples 1 and 2 or a method analogous thereto, respectively. Further, the compound of formula (IVb) is P, Tk
aczuk and E, Thornton [J, Org, C
bem,,4Ei.

4393-4398 (+981)) or a method similar thereto.

In the present invention, the compound represented by formula (I) is:

A pharmaceutically acceptable acid addition salt can be obtained by treatment with a suitable inorganic or organic acid according to a conventional method. Examples of the inorganic acid include hydrochloride, hydrobromide, hydroiodide, and sulfate.

Non-acid salts, etc., and organic acid salts include oxalate, maleate, fumarate, lactate, and malate.

Examples include citrate, tartrate, benzoate, methanesulfonate, and the like.

In order to explain the present invention more specifically, reference examples and examples are given below, but the present invention is not limited to these examples. Compound identification is done through elemental analysis, mass spectra, and IR spectra.

The analysis was carried out using U■ spectrum, NMR spectrum, etc. In Examples and Reference Examples, the solvent in parentheses indicated at melting point means a recrystallization solvent.

Furthermore, in the following Reference Examples and Examples, the following abbreviations may be used to simplify the description.

Ph: phenyl group J: bond constant S knee doublet d: doublet triplet: quartet: polyperpendicular br nibrod (below the margins) reference 1 2-(1-benzyloxycarbonyl indazole-3
-Carbonylamino)propenal production: (1) diindazolo(2,3-a,2'3'-d)pyrazine-
A mixture of 20 g of 7,14-dione, 19 g of 2-amino-1,3-propanediol, and 200 ml of N,N-dimethylformamide is stirred at room temperature for 12 hours. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel chromatography and eluted with chloroform-methanol (10:1).
Purified to give N-(1<3-dihydroxyprob-2-yl)-1H-indazole-3-carboxamide 12
．． Obtain 7 g.

Melting point 128-130°C (ethanol)'H-NMR spectrum (DMSO-d, δppm): 3, 37-
3.73 [411,m, 2 (-C1l,,0n)
l, 4. DO(III, m, -CONIIC
II) 4.80 [2B, t, J=1111z, 2(-0
tl) 1,7.25(10,t, J=9I(z,ti-
H) 7, 42 (ltl, t, J=9tlz, 5
-TI), 7. ti2 (IH, d, J=91
1z, 7-8>7,73 (1B, d, J=9[
1z, -CONB), 8.18 (1B, d,
J=9 [IZ, 4-! 13, 59 (IH,s
, -Nu-).

(2) N-(1,3-dihydroxyprob-2-yl)
-1H-indazole-3-carboxamide 11.7
g was suspended in 500 ml of chloroform, 6.0 g of triethylamine was added, and 9.0 g of benzyl chlorocarbonate was added under water cooling.
Add 3g dropwise. After stirring at room temperature for 12 hours, the organic layer is washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography and eluted with chloroform-methanol (10:1) to obtain N-(1°3-dihydroxyprob-2-yl).
11.7 g of -1-benzyloxycarbonylindazole-3-carboxamide are obtained.

Melting point 162-164°C (ethanol)'H-NMR
Spectrum (DMSO-d, δppm): 3, 42
-3.70 [4H, m, 2 (-1Jtl)]
, 4. Old (IH, m, -CONHCp) 4.82
[2fl, t, J=I IHz, 2(-011)],
5.61 (2) I, s, -COOCII,, Ph)7
, 354.75 (71, m, 5-H, 8-H, -C
[IzPh), 8.02 (III, d, J=
9) Iz, -CONB), 8.18 (1 mouth, d, J=9
11z, 4-)I), 8.30 (III, d, J=90
z, 7-H).

(3) Oxalyl chloride 5.9 to 601 methylene chloride
Dissolve 7.3 g of dimethyl sulfoxide at -60 °C.
After stirring for 2 minutes, 5.8 g of N-(1,3-dihydroxyprob-2-yl)-1-benzyloxycarbonylindazole-3-carboxamide was dissolved in 50 ml of dimethyl sulfoxide and 30 ml of methylene chloride. , dropped at −60°C. After stirring for 15 minutes, 24 g of triethylamine is added and stirred until the reaction mixture reaches room temperature. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain 4.7 g of the desired product.

Melting point 150-152°C (ethanol)'H-NMR
Spectrum (CDCl2.δppm): 5.62 (2
11,s, -COOCR,Ph), 5.75(IH,d
, J=1[1z, -C=CU2)7.36 (1 mouth, s,
-C=CL), 7.39-7.70 (70, m, 5-t
l, 6-! ! .

-CI(2Ph), 8.26 (In, d, J
=911z, 4-H), 8.43 (Ill,
d, J=911z.

7-H) 9.30 (1B, s, -CtlO), 9.40
(ltl, br, -CONH).

Box No. 1-1 Preparation of 2-acetylamino-2-propenal A solution of 9.52 g of oxalyl chloride in methylene chloride (60 ml) cooled to about -70°C with dry ice-acetone and dimethyl sulfoxide-methylene chloride (1: After dropping 70 ml of the mixed solution of 1), the mixture was stirred for 10 minutes.

To this, 2-acetylamino-1,3-propanediol e, ae g dimethyl sulfoxide-methylene chloride (
2:1) mixed solution 901 was added dropwise, and after stirring for 20 minutes, 34 ml of triethylamine was added dropwise.

After stirring for 20 minutes, the temperature of the solution was raised to -15°C, 150 ml of water was added, and the mixture was extracted with chloroform. The extract is sequentially washed with 10% citric acid, water, and saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain 3.65 g of the desired product as an oil.

'H-NMR spectrum (CDCI engineering 1.δppm):
2.17 (3n.

s, -COC! Lri, 5.67 (Ill, d
, J=1.511z, -C=CL), 7.15
(III.

S, −[;=C! ! 2), 7.72 (In,
br, -CONIri, 9.27 (Itl, s
, -CtlO).

Box No. 1-1 Production of 2-benzyloxycarbonylamino-2-propenal: 2-benzyloxycarbonylamino-1 instead of 2-acetylamino-1,3-propanediol in Reference Example 2
, 3-propanediol and the same reaction as in Reference Example 2.
Process to obtain the desired product.

'H-NMR spectrum (CIIC13, δppm)
:5, 19 (2H,s, -CH5+Ph), 7
．． 30-7.46 (5tl, m, -(:H2Ph
).

Production of reference IL-ma 2-benzoylamino-2-propenal: Using 2-benzoylamino-1,3-propanediol in place of 2-acetylamino-1,3-propanediol in Reference Example 2, Reference Example React and process in the same manner as in 2 to obtain the desired product.

'H-NMR spectrum (CDC13, δppm) Near, 38-7.86 (3[1,m, -[:0Pb
), 7.82-7.93 (2H,m,-COPh
).

Hisejo-YuN-(1-benzyl-4-methylhexahydro-IH-
Production of 1,4-diazepin-6-yl)-1H-indazole-3-carboxamide = 500 mg of 2-(1-benzyloxycarbonylindazole-3-carbonylamino)propenal was dissolved in 20 ml of methanol and 20 ml of terahydrofuran. Add 250 mg of N-benzyl-No-methylethylenediamine. continue,
Add 52 mg of sodium borohydride little by little and stir at room temperature for 1 hour. The solvent is removed under reduced pressure and the residue is dissolved in chloroform. The chloroform layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.

The residue was purified by silica gel chromatography and eluted with chloroform-methanol (10:1) to obtain 230 mg of the desired product as an oil.

'H-NMR spectrum (C[1C13, δppm)
:2,35 (31,S, -NCH3), 2.4
0-2.95 (8■, ra, ), 3.67 (2
11゜q, -C11,Pb), 4, 18 (1
1, m, -C! ! NHCO1,), 7.12-7
．． 48 (7rl.

m), 7.65 (III, d, J=9Hz)
, 8.17 (211,d, J=9Hz, -[
;0N11°4-11), +3. En (In, s, -
Nll).

Example 2 N-(1-benzyl-4-methylhexahydro-IH-
Production of 1,4-diazepin-6-yl)-〇-fluoroindazole-3-carboxamide: (1) 2-acetylamino-2-propenal 2.6
N-benzyl-No- to 30 ml of methanol solution of
3.77 g of methylethylenediamine is added dropwise under water cooling. After stirring for 5 minutes, 2.18 g of sodium borohydride
Add little by little. After stirring this solution at room temperature for 2 hours, the solvent was distilled off under reduced pressure, and ethyl acetate and water were added to the residue to separate the layers. The ethyl acetate layer is washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent is distilled off under reduced pressure. The residue was purified by silica gel chromatography and eluted with a mixed solvent of chloroform-methanol (15:1) to obtain an oily 6
2.1 g of -acetylamino-1-benzyl-4-methylhexahydro-IH-1,4-diazepine are obtained.

(2) Dissolve 0.9 g of 6-acetylamino-1-benzyl-4-methylhexahydro-IH-1,4-diazepine in 10 ml of 10% hydrochloric acid and heat under reflux for 2 hours.

After cooling, the mixture is made alkaline with a 48% aqueous sodium hydroxide solution and extracted with chloroform. After washing the organic layer with water and drying with anhydrous magnesium sulfate.

The solvent was removed under reduced pressure to obtain an oil. Dissolve this in 20 ml of methylene chloride and add 6-fluoroindazole-3
-450 mg of carboxylic acid and 518 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
mg and stirred at room temperature for 2 hours. Add the reaction solution to water, 10
% sodium hydroxide and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The residue is subjected to medium pressure silica gel column chromatography and purified by elution with acetone to obtain 0.5 g of the desired product. This product was treated with fumaric acid in a conventional manner to obtain 0.0% dioxalate of the target product.
Obtain 39g.

Melting point 126~+30°C (ethanol-acetone) -1 N-[1-(3-methylbenzyl)-4-methyl-hexahydro-IH-1,4-diazepin-6-yl]-1
Production of H-indazole-3-carboxamide: Using 2-benzyloxycarbonylamino-2-propenal, N-(3-methylbenzyl)-N'-methylethylenediamine and indazole-3-carboxylic acid,
The reaction and treatment are carried out in the same manner as in Example 2 to obtain the desired product. This material was treated with ethanol-hydrochloric acid in a conventional manner to obtain the desired product.
Obtain the hydrochloride.

Melting point 241-244°C (methanol-water) resistant to fire
1 N-(1-benzyl-4-methyl-hexahydro-IH
-1,4-Diazepin-6-yl)-111-indazole-3-carboxamide production: using 2-benzoylamino-2-propenal, N-benzyl-N'-methylethylenediamine and indazole-3-carboxylic acid, The desired product of Example 1 was obtained by reacting and treating in the same manner as in Example 2.

Claims (2)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 means an acyl group, lower alkylsulfonyl group, unsubstituted or substituted arylsulfonyl group, lower alkoxycarbonyl group, aralkyloxycarbonyl group, R_2 means a hydrogen atom or a halogen atom,
Z means =CH_2 or -CH_2X, where X
means a reactive ester residue of alcohol. ) A compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_3 means a lower alkyl group, R_4 means an unsubstituted or substituted aryl (lower) alkyl group, n means 2 or 3. ] There are general formulas ▲mathematical formulas, chemical formulas, tables, etc.▼ (wherein R_3, R_4 and n have the meanings defined above). ) A method for producing an indazole-3-carboxamide derivative and an acid addition salt thereof. (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 is an acyl group, lower alkylsulfonyl group, unsubstituted or substituted arylsulfonyl group, lower alkoxy means a carbonyl group, an aralkyloxycarbonyl group, R_5 means an unsubstituted or substituted phenyl group or a lower alkyl group, Z is =CH_2 or -CH_2
X, where X means a reactive ester residue of an alcohol. ) A compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_3 means a lower alkyl group, R_4 means an unsubstituted or substituted aryl (lower) alkyl group, n means 2 or 3. ], reduce the product, hydrolyze the resulting compound,
The resulting general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_3, R_4 and n mean those defined above.) ▼ (In the formula, R_2 means a hydrogen atom or a halogen atom.) General formula ▲ Numerical formula, chemical formula characterized by reacting with indazole-3-carboxylic acid or its reactive derivative represented by , tables, etc. ▼ (In the formula, R_2, R_3, R_4 and n mean what is defined above.) A method for producing an indazole-3-carboxamide derivative and its acid addition salt.