JPH0710857B2 - Intermediate compound - Google Patents

Description

Detailed Description of the Invention

Japanese Patent Application No. 55-121855 (Japanese Patent Publication No. 63-63)
No. 42624) , a novel 3,4-disubstituted-1,2,5 which is an effective inhibitor of gastric acid secretion in animals (including humans).
-Thiadiazole-1-oxide and -1,1-dioxide compounds are described. The present invention provides novel intermediates useful in preparing the novel compounds described above. The above-mentioned Japanese Patent Application No. 55-121855 (Japanese Patent Publication No. 6-6
The novel compound described in JP-A-3-42624) is a compound represented by the following formula I, or a non-toxic pharmaceutically usable salt, hydrate, solvate or N-oxide thereof.

[0002]

[Wherein p is 1 or 2; R ¹ is hydroxy or NR ² R ³ ; R ² and R ³ are each
Independently hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cyclo (lower) alkyl, cyclo (lower) alkyl (lower) alkyl, hydroxy (lower) alkyl, (lower) alkoxy (lower) alkyl , (Lower) alkylthio (lower) alkyl, amino (lower) alkyl, (lower) alkylamino (lower) alkyl, di (lower) alkyl (lower) alkyl, pyrrolidino (lower) alkyl, piperidino (lower) alkyl,
Morpholino (lower) alkyl, piperazino (lower) alkyl, pyridyl (lower) alkyl, amino, (lower) alkylamino, di (lower) alkylamino, 2,2,2
-Trifluoroethyl, 2-fluoroethyl, hydroxy,
(Lower) alkoxy, 2,3-dihydroxypropyl,
Cyano, cyano (lower) alkyl, amidino, (lower)
Alkyl _{amidino, A '- (CH 2)} m'Z' (C
H ₂ ) n′-, phenyl, phenyl (lower) alkyl,
Substituted phenyl or substituted phenyl (lower) alkyl (the phenyl ring is 1 or 2 substituents selected from (lower) alkyl, hydroxy, (lower) alkoxy and halogen or methylenedioxy, trifluoromethyl and di (lower) Which may have 1 substituent selected from alkylamino), wherein R ² and R ³ are both cyclo (lower) alkyl, phenyl, substituted phenyl, amino,
(Lower) alkylamino, di (lower) alkylamino,
Hydroxy, (lower) alkoxy, cyano, amidino,
(Lower) alkyl amidino or _{A '- (CH 2) m} '
Z _'(CH 2) a n'- have it; or ^{R 2}
And R ³ together represent —CH ₂ CH ₂ X (CH ₂ ) r.
-May be;

R is an integer from 1 to 3; X is methylene, sulfur, oxygen or N--R ⁴ , provided that when r is 1, X is methylene; R ⁴ is hydrogen; (Lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower) alkanoyl or benzoyl; m and m ′ are each independently an integer of 0 to 2; n and n ′ are each independently And is an integer of 2 to 4; Z and Z '.
Are each independently sulfur, oxygen or methylene;

A and A'are each independently phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl,
Oxadiazolyl, furyl, thienyl or pyridyl; provided that A and A ′ may independently have 1 or 2 substituents, the first substituent being (lower) alkyl,
Hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, (lower) alkoxy,

[0006]

The second replacement is selected from (lower)
Alkyl, hydroxy, trifluoromethyl, halogen,
Selected from amino, hydroxymethyl and (lower) alkoxy;

Q is an integer from 0 to 6; each R ⁴ is independently as defined above or two R ^{4 s.}
The groups together may be ethylene; R ⁵ and R ⁶
Are each independently hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cyclo (lower) alkyl or phenyl, provided that R ⁵ and R ⁶ are both cyclo (lower) alkyl or phenyl. Or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached may be pyrrolidino, morpholino, piperidino, methylpiperidino, N-methylpiperazino or homopiperidino]

The present invention relates to novel intermediates useful in the preparation of compounds of formula I above. Production of the intermediate of the present invention
As a useful compound for

[0010]

[Wherein p is 1 or 2; R ⁷ is halogen, (lower) alkoxy, (lower) alkylthio,
Phenoxy, phenylthio, phenyl ring is halogen,
A leaving group selected from substituted phenoxy and substituted phenylthio, which may have 1 or 2 substituents selected from (lower) alkyl, (lower) alkoxy and nitro;

R ¹² is the above R ⁷ , A '(CH ₂ ) m
^{_{Z '(CH 2) nNH-,}} R 2 R 3 N- or HS (CH
₂ ) nNH- (wherein R ² and R ³ are each independently hydrogen, (lower) alkyl, (lower) alkenyl, (lower)
Alkynyl, cyclo (lower) alkyl, cyclo (lower)
Alkyl (lower) alkyl, hydroxy (lower) alkyl, (lower) alkoxy (lower) alkyl, (lower) alkylthio (lower) alkyl, amino (lower) alkyl, (lower) alkylamino (lower) alkyl, di (lower) Alkylamino (lower) alkyl, pyrrolidino (lower) alkyl, piperidino (lower) alkyl, morpholino (lower) alkyl, piperazino (lower) alkyl, pyridyl (lower) alkyl, amino, (lower) alkylamino, di (lower) alkyl Amino, 2,2,2-trifluoroethyl, 2-fluoroethyl, hydroxy, (lower)
Alkoxy, 2,3-dihydroxypropyl, cyano,
Cyano (lower) alkyl, amidino, (lower) alkyl _{amidino, A '- (CH 2)} m'Z' (CH 2) n '
-, Phenyl, phenyl (lower) alkyl, 1 or 2 substituents independently selected from (lower) alkyl, hydroxy, (lower) alkoxy and halogen in the phenyl ring, or methylenedioxy, trifluoromethyl and di A substituted phenyl or substituted phenyl (lower) alkyl optionally having 1 substituent selected from (lower) alkylamino; provided that both R ² and R ³ are both cyclo (lower) alkyl, phenyl, substituted phenyl ,amino,
(Lower) alkylamino, di (lower) alkylamino,
Hydroxy, (lower) alkoxy, cyano, amidino,
(Lower) alkyl amidino or _{A '- (CH 2) m} '
Z _(CH 2) a n'- have it; or ^{R 2} and ^{R 3,} _{together, -CH 2 CH 2 X (CH} 2) r-
May be;

R is an integer from 1 to 3; X is methylene, sulfur, oxygen or NR ⁴ , provided that p is 2 and R ⁷ is methoxy, then R ² and R ³ is
Together with the nitrogen to which they are attached, must not be morpholino, and when r is 1, X is methylene;

R ⁴ is hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower) alkanoyl or benzoyl; m and m ′ are each independently an integer from 0 to 2. N and n ′ are each independently an integer from 2 to 4; Z and Z ′ are each independently sulfur, oxygen or methylene;

A and A'are each independently phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl,
Oxadiazolyl, furyl, thienyl or pyridyl; provided that A and A ′ may independently have 1 or 2 substituents, the first substituent being (lower) alkyl,
Hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, (lower) alkoxy,

[0016]

The second substitution is selected from (lower)
Alkyl, hydroxy, trifluoromethyl, halogen,
Selected from amino, hydroxymethyl and (lower) alkoxy; q is an integer from 0 to 6; each R ⁴ is independently as defined above or two R ⁴
The groups together may be ethylene;

R ⁵ and R ⁶ are each independently hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cyclo (lower) alkyl or phenyl, provided that R ⁵ and R ⁶ are both It must not be cyclo (lower) alkyl or phenyl; or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached are pyrrolidino, morpholino, piperidino, methylpiperidino, N-
Methylpiperidino, N-methylpiperazino or homopiperidino)).

Alternatively, its salt, hydrate, solvate or N-
An oxide is provided. Further according to the invention,

[0020]

[Wherein p is 1 or 2; n is 2 to 2]
Is an integer of 4; R ² and R ³ are each independently hydrogen,
(Lower) alkyl, (lower) alkenyl, (lower) alkynyl, cyclo (lower) alkyl, cyclo (lower) alkyl (lower) alkyl, hydroxy (lower) alkyl,
(Lower) alkoxy (lower) alkyl, (lower) alkylthio (lower) alkyl, amino (lower) alkyl,
(Lower) alkylamino (lower) alkyl, di (lower)
Alkylamino (lower) alkyl, pyrrolidino (lower)
Alkyl, piperidino (lower) alkyl, morpholino (lower) alkyl, piperazino (lower) alkyl, pyridyl (lower) alkyl, amino, (lower) alkylamino, di (lower) alkylamino, 2,2,2-trifluoroethyl , 2-Furoroechiru, hydroxy, (lower) alkoxy, 2,3-dihydroxypropyl, cyano, cyano (lower) alkyl, amidino, (lower) alkyl _{amidino, A '- (CH 2)} m'Z' (CH 2) n'-,
Phenyl, phenyl (lower) alkyl phenyl ring has 1 or 2 substituents independently selected from (lower) alkyl, hydroxy, (lower) alkoxy and halogen, or methylenedioxy, trifluoromethyl and di (lower) )
A substituted phenyl or substituted phenyl (lower) alkyl which may contain one substituent selected from alkylamino; provided that both R ² and R ³ are both cyclo (lower)
Alkyl, phenyl, substituted phenyl, amino, (lower)
Alkylamino, di (lower) alkylamino, hydroxy, (lower) alkoxy, cyano, amidino, (lower)
Alkyl amidino or _{A '- (CH 2) m'Z} ' - (C
H ₂₎ A n'- have it; or ^{R 2} and ^{R 3}
Are _combined, it may be _{-CH 2 CH 2 X (CH 2} ) r-;

R is an integer from 1 to 3; X is methylene, sulfur, oxygen or N--R ⁴ ; provided that when r is 1, X is methylene; R ⁴ is hydrogen; (Lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower) alkanoyl or benzoyl; m '
Is an integer from 0 to 2; n'is an integer from 2 to 4; Z'is sulfur, oxygen or methylene;

A'is phenyl, imidazoyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl; provided that A '
May contain 1 or 2 substituents, the first substituent being (lower) alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, (lower) alkoxy,

[0024]

The second substitution is selected from (lower)
Alkyl, hydroxy, trifluoromethyl, halogen,
Selected from amino, hydroxymethyl and (lower) alkoxy; q is an integer from 0 to 6; each R ⁴ is independently as defined above or two R ⁴
The groups together may be ethylene;

R ⁵ and R ⁶ are each independently hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cyclo (lower) alkyl or phenyl; provided that R ⁵ and R ⁶ are both It must not be cyclo (lower) alkyl or phenyl; or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached are pyrrolidino, morpholino, piperidino, methylpiperidino, N-
Which may be methylpiperazino or homopiperidino]; or a salt, hydrate, solvate or N-oxide thereof. The compound of formula I is preferably a compound of formula

[0027]

It can be prepared by starting from a compound of the formula: wherein R ⁷ is a good leaving group such as halogen, phenoxy, substituted phenoxy, phenylthio, substituted phenylthio, alkoxy, alkylthio and the like. Suitable leaving groups are well known to those skilled in the art. Suitably R ⁷ is (lower) alkoxy (especially methoxy).

Preparation of Intermediate Compounds of the Invention Formula I wherein p is 2 and R ⁷ is chloro, methoxy or ethoxy.
The starting materials for I are known and their preparation is described in J. O
rg. Chem. , 40, 2743 (1975). p is 2 and each R ⁷ is alkoxy,
The starting material of formula II, which is an alkylthio, phenoxy, phenylthio, substituted phenoxy or substituted phenylthio (compounds of formula IV and V), is prepared by converting a dichloro compound of formula III into a suitable alkanol, alkylthio, phenol, thiophenol, substituted It can be reacted with a phenol or a substituted thiophenol to produce the corresponding compound of formula IV or V, wherein R ⁸ is alkyl, phenyl or substituted phenyl:

[0030]

The reaction is carried out in an inert organic solvent such as atech, dimethylformamide and the like. When the reagent R ⁸ OH or R ⁸ SH is a liquid, for example methanol, ethanol, ethyl mercaptan or thiophenol, the reaction can be carried out in excess of that solvent as solvent. Corresponding starting materials of formula II where p is 1 (compounds of formula VII and VIH) can be similarly prepared from compounds of formula II where R ⁷ is chloro (compound VI).

[0032]

Compound VI is a novel compound,
The same procedure utilized to prepare compounds of formula III from 1-dioxide 3,4-dihydroxy-1,2,5-thiadiazole [J. Org. Chem. ，
40, 2743 (1975)], the known compound 1-oxide 3,4-dihydroxy-1,2,5-
Thiadiazole [as such Org, Prep. Proc
ed. , 1, 255 (1969)]
Can be manufactured from. The starting materials of the formulas VII and VIII are new compounds not mentioned previously in the literature.

Alternatively, the starting materials of formulas IV and VII are SCl of a suitable substituted oxaldiimidate ester of formula IX in an inert solvent such as dimethylformamide.
₂ or the corresponding 3, of formula X by reaction with S ₂ Cl ₂ .
It can be prepared by forming a 4-disubstituted 1,2,5-thiadiazole, which is then oxidized to the corresponding 1-oxide of formula VII or 1,1-dioxide of formula IV.

[0035]

Formula IX wherein R ⁸ is methyl, ethyl, n-propyl, isopropyl, n-butyl and n-pentyl.
Oxaldiimidates are known and their preparation is described in Chem. Ber. , 107, 3121 (197)
4). The corresponding compound wherein R ⁸ is phenyl, optionally substituted with (lower) alkyl, (lower) alkoxy, halogen or nitro can be prepared by similar procedures. Compounds of formula X where R ⁸ is methyl or ethyl are described in J. Org. Che
m. , 40, 2749 (1975).

The literature indicates that the 1,2,5-thiadiazole nucleus is sensitive to oxidation, that the oxidation of thiadiazole by peracid usually accompanies ring decomposition and sulfate ion formation,
It has also been reported that an attempt to produce 1,1-dioxide 1,2,5-thiadiazole by peracetic acid oxidation of a mother ring leads to ring cleavage. Surprisingly, we have found that the corresponding 3,4 of formula X with a peracid such as m-chloroperbenzoic acid in an inert solvent such as chloroform.
1-oxide 3,4-disubstituted-1, of formula VII, in good yield by oxidation of disubstituted-1,2,5-thiadiazole,
It has been found that 2,5-thiadiazole and the 1,1-dioxide of formula IV can be easily prepared . The production of the corresponding 1,1-dioxide is shown below.

Reference Example [1] 1,1-dioxide 3,4-
Dimethoxy-1,2,5-thiadiazole m-chloroperbenzoic acid (4.11 g;
3 mmol; quantified value 85%) with stirring under stirring in chloroform 20 ml 3,4-dimethoxy-1,2,5-thiadiazole (1.48 g; 10.1 mmol) [J. O
rg. Chem. , 40, 2749 (1975).] Was added over 1 minute. After stirring for 1 hour at ambient temperature, the mixture was heated at reflux for 8 hours and then for 1 hour at ambient temperature. The reaction mixture was extracted with aqueous sodium bicarbonate and water, the organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure.
The residue is treated with methanol and filtered to give the product 1.03
g was obtained. Recrystallize from methanol to give the title compound, m
p200-202 ° C was obtained.

Analysis Calculated for C ₄ H ₆ N ₂ O ₄ S:
C, 26.97; H, 3.39; N, 15.72; S,
18.00. Experimental value: C, 26.82; H, 3.18;
N, 16.09; S, 18.00.

We have identified compounds of formula VII with the formula IX
From the compound of 1 by reaction of the latter with thionyl chloride
It has been found that it can be produced directly in the process reaction.

[0041]

This reaction is carried out in an inert organic solvent such as methylene chloride, chloroform and the like. This reaction is
Although it can be carried out as an acid scavenger without the addition of a base, the inventor prefers to add about 2 equivalents of base to remove the HCl formed during the reaction. Thereby a higher yield of compound VII is obtained. Suitable bases are inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate,
And organic bases such as triethylamine, pyridine and the like. This method is much more economical in that it not only saves one step, but avoids the use of expensive oxidizing agents such as m-chloroperbenzoic acid. The reaction can be carried out at a temperature of about -20 ° to about 25 °, preferably about 0 ° to about 10 °. Reference Example [I] is a compound of formula V in which R ⁸ is methyl by this method.
11 shows the preparation of compound II.

Reference Example [II] 1-oxide 3,4-dimethoxy-1,2,5-thiadiazole CH ₂ Cl ₂ 18
Thionyl chloride in ml (2.61 ml, 4.25 g; 7
0.6 mmol) in a cold solution of dimethyl oxaldiimidate (4.0 g; 34.5 mmol) and pyridine (5.71 ml, 5.58 g; 7) in 8 ml of CH ₂ Cl _2.
(0.6 mmol) in a nitrogen stream at a reaction temperature of 0
Droplet was added at a rate such that it remained between ~ 15 °. After stirring at ambient temperature for 20 minutes, the reaction mixture was treated with aqueous 0.055N.
It was washed twice with 11 ml each of Hcl. The aqueous phase is CH ₂ Cl
_2. Extract twice with 20 ml each, combine the organic phases and dry,
Evaporated to dryness under reduced pressure. Recrystallize the solid residue from isopropyl alcohol to give the title compound, mp 137-139.
C., 3.0 g was obtained. The compounds of formula I can be prepared from the compounds of formula II by various alternative reaction schemes via several types of novel intermediates according to the invention.

[0044]

In Reaction Scheme 1, R ⁹ is --NR ²
R ³ or _{-NH (CH 2) n'Z '(} CH 2) m'
It may be A '. A ', Z', m'and n'are A,
This reaction, of course, when Z, m and n are the same,
The compound of formula II is treated with 2 equivalents of A (CH ₂ ) mZ (CH ₂ )
It can be carried out in one step by reacting with nNH ₂ . The intermediates of formula XI are all novel. The intermediates of formula XII are new except for compounds where p is 2, R ⁷ is methoxy and R ⁹ is morpholino. This compound is described in J. Org. Chem. , 40,
2743 (1975). This reaction is
Performed in an inert organic solvent; the inventors have found that methanol is a convenient and readily available solvent. The reaction temperature is not critical. Most starting materials are quite reactive and we prefer to carry out the reaction at temperatures below room temperature, eg 0-10 °. It is sometimes desirable to then raise the temperature of the reaction mixture (eg to 50-60 ° C) to complete the reaction.

[0046]

In Reaction Scheme 2, M is a metal cation, which is preferably K ⁺ , Li ⁺ or Na ⁺ . Reaction conditions and solvents are as described for Reaction Scheme 1. All intermediates of formula XI are novel compounds.

[0048]

In Reaction Scheme 3, R ¹⁰ is --NR ²
R ³ is or is _{-NH (CH 2) n'Z '(} CH 2)
m'A 'and X is a conventional leaving group. Suitable leaving groups are, for example, fluoro, chloro, bromo, iodo, —O ₃ SR ¹¹ [R ¹¹ is (lower) alkyl (eg methanesulfonate), aryl or substituted aryl (eg benzenesulfonate, p-bromo). Benzene sulfonate or p-toluene sulfonate), O ₃ SF, acetoxy and 2,4-dinitrophenoxy. For convenience and economy, we prefer to utilize compounds where X is chloro. The reaction conditions for the preparation of compounds of Formula XIII, XIV and XV are as described for Reaction Scheme 1. The reaction of the compound of formula XV with A (CH ₂ ) mX can be carried out in any inert organic solvent such as alkanol, acetonitrile, dimethylformamide, dimethylsulfoxide, acetone and the like. We prefer to carry out the reaction in an alkanol such as methanol, ethanol or isopropanol. The reaction temperature is not critical; the reaction is from about 0 °
It can be carried out at a temperature of about 200 °. Reactions are slower at lower temperatures, while higher temperatures usually give relatively less pure products due to decomposition and byproduct formation.
We usually prefer to carry out the reaction at room temperature. A of a compound of formula XV to obtain a compound of formula Ic
The reaction with (CH ₂ ) mX is preferably carried out in the presence of a base, which facilitates the reaction by acting as an acid acceptor. Suitable bases are, for example, Na
OH, KOH, LiOH, triethylamine, dimethylaniline, sodium ethoxylate and the like are included. When X is hydroxyl, the reaction is concentrated mineral acid, such as HC
Ru can be carried out in l. XIII, XIV and XV
All of the intermediates are novel compounds. One preferred embodiment of the present invention is the above formula wherein p is 1 and R ¹² is R ^7.

[0050]

A novel intermediate compound of the formula II
a

Wherein R ⁷ is halogen, (lower) alkoxy, (lower) alkylthio and optionally halogen,
Is a leaving group selected from phenoxy or phenylthio having 1 or 2 substituents selected from (lower) alkyl, (lower) alkoxy and nitro].

In yet another aspect, the present invention provides a formula

[Wherein p is 1 or 2; R ⁷ is halogen, (lower) alkoxy, (lower) alkylthio, phenoxy, phenylthio, phenyl ring is halogen, (lower) alkyl, (lower) alkoxy) And a leaving group selected from substituted phenoxy and substituted phenylthio optionally having 1 or 2 substituents selected from nitro;

R ¹² is A (CH ₂ ) mZ (CH ₂ ) n
^NH-, R ^{2 R} 3 N-or _HS (CH 2) a NNH-; proviso ^{R 2} and ^{R 3} each is independently hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cyclo (Lower) alkyl, cyclo (lower) alkyl (lower) alkyl, hydroxy (lower) alkyl, (lower) alkoxy (lower) alkyl, (lower) alkylthio (lower) alkyl, amino (lower) alkyl, (lower) alkylamino (Lower) alkyl, di (lower) alkylamino (lower) alkyl, pyrrolidino (lower) alkyl, piperidino (lower) alkyl, morpholino (lower) alkyl, piperazino (lower) alkyl, pyridyl (lower) alkyl, amino, (lower) ) Alkylamino,
Di (lower) alkylamino, 2,2,2-trifluoroethyl, 2-fluoroethyl, hydroxy, (lower) alkoxy, 3,4-dihydroxypropyl, cyano, cyano (lower) alkyl, amidino, (lower) alkylamidino _{, A '- (CH 2)} m'Z' (CH 2) n'-, phenyl, phenyl (lower) alkyl, phenyl rings (lower) alkyl, hydroxy, is independently selected from (lower) alkoxy and halogen 1 or 2 substituents, or methylenedioxy, trifluoromethyl and di (lower)
It is a substituted phenyl or substituted phenyl (lower) alkyl which may have one substituent selected from alkylamino; provided that R ² and R ³ are both cyclo (lower) alkyl, phenyl, substituted phenyl, amino, ( Lower) alkylamino, di (lower) alkylamino, hydroxy,
(Lower) alkoxy, cyano, amidino, (lower) alkyl amidino or _{A '- (CH 2) m'Z} ' (CH 2)
A n'- have it; or ^{R 2} and ^{R 3,} _together, may be _{-CH 2 CH 2 X (CH 2} ) r-;

R is an integer from 1 to 3; X is methylene, sulfur, oxygen or N--R ⁴ ; provided that p is 2 and R ⁷ is methoxy, then R ² and R ^2.
3 must not be morpholino, together with the nitrogen to which they are attached, and when r is 1, X is methylene. ;

R ⁴ is hydrogen, (lower) alkyl, (lower)
Alkenyl, (lower) alkynyl, (lower) alkanoyl or benzoyl; m and m ′ are each independently an integer from 0 to 2; n and n ′ are each independently 2 to
Is an integer of 4; Z and Z ′ are each independently sulfur, oxygen or methylene; A and A ′ are each independently phenyl, imidazolyl, thiazolyl, isothiazolyl,
Is oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl; provided that A and A ′ may independently have 1 to 2 substituents and the first substituent is (lower ) Alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, (lower) alkoxy,

[0058]

The second substitution is selected from (lower)
Alkyl, hydroxy, trifluoromethyl, halogen,
Selected from amino, hydroxymethyl and (lower) alkoxy; q is an integer from 0 to 6; each R ⁴ is independently as defined above or two R ⁴
The groups together may be ethylene; R ⁵ and R ⁶
Are each independently hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cyclo (lower) alkyl or phenyl, provided that R ⁵ and R ⁶ are both chloro (lower) alkyl or phenyl. Must not be;
Alternatively, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached are pyrrolidino, morpholino, piperidino,
Methylpiperidino, N-methylpiperazino or homopiperidino], or a salt, hydrate, solvate or N-oxide thereof.

In a further preferred embodiment of the compound of formula XVI, R ¹² is A (CH ₂ ) mZ (CH ₂ ) nN
H [wherein A is phenyl, imidazolyl, thiazolyl, furyl, thienyl or pyridyl, each of which may have 1 or 2 substituents, the first substituent being (lower) alkyl,

[0061]

The second substitution is selected from (lower)
Selected from alkyl; Z is sulfur, oxygen or methylene; m is 0 or 1; n is 2 or 3; each R ⁴ is independently hydrogen or (lower) alkyl. Or alternatively two R ⁴ groups may together be ethylene; R ⁵ and R ⁶ are each independently hydrogen or (lower) alkyl; or R ⁵ and R ⁶ are combined. Together with the nitrogen atom to which they are attached, pyrrolidino, morpholino, piperidino, methylpiperidino, N-methylpiperazino or homopiperidino; R ⁷ is
(Lower) alkoxy.

In another more preferred embodiment of the compound of formula XVI, R ¹² is R ² R ³ N- [wherein R ²
And R ³ are each independently hydrogen, (lower) alkyl,
(Lower) alkenyl, (lower) alkynyl, cyclo (lower) alkyl, (lower) alkyl, pyridyl (lower) _{alkyl, A '- (CH 2)} m'Z' (CH 2) n'-,
Phenyl (lower) alkyl or 3,4-methylenedioxybenzyl; R ² and R ³ are both A′-
_{(CH 2) m'Z '(CH} 2) a n'- have it; m' is 0 or 1; n 'is 2 or 3; Z' is sulfur, oxygen or methylene A'is
Phenyl, imidazolyl, thiazolyl, furyl, thienyl or pyridyl, each of which may have 1 or 2 substituents, the first substituent being (lower) alkyl,

[0064]

Each R ⁴ is independently hydrogen or (lower) alkyl, or the two R ⁴ groups may together be ethylene; R ⁵ and R ⁶ are Each independently hydrogen or (lower) alkyl; or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached may be pyrrolidino, morpholino, piperidino, methylpiperidino, N-methylpiperazino or homopiperidino; R ⁷ is (lower) alkoxy.

In another more preferred embodiment of the compound of formula XVI, R ¹² is HS (CH ₂ ) nNH—; n is an integer from 2-4; R ⁷ is ( Lower) alkoxy.

In a particularly preferred embodiment of the compound of formula XVI, R ¹² is

[Wherein Z is sulfur or methylene, and R is
¹³ is hydrogen or methyl; R ⁷ is (lower) alkoxy].

In another particularly preferred embodiment of the compound of formula XVI, R ¹² is

[Wherein R ¹³ is hydrogen or methyl; Z is sulfur or methylene; R ⁷ is (lower)
It is alkoxy].

In another particularly preferred embodiment of the compound of formula XVI, R ¹² is

[Wherein R ⁵ and R ⁶ are each independently hydrogen or (lower) alkyl; Z is sulfur or methylene; R ⁷ is (lower) alkoxy].

In another particularly preferred embodiment of the compound of formula XVI, R ¹² is

[Wherein R ⁵ and R ⁶ are each independently hydrogen or (lower) alkyl, or when R ⁵ is hydrogen, R ⁶ is also (lower) alkenyl or (lower) alkynyl. Or R ⁵ and R
⁶ together with the nitrogen to which they are attached may be pyrrolidino, morpholino, piperidino or homopiperidino; R ⁷ is (lower) alkoxy].

In yet another aspect, the invention provides the formula

[Wherein p is 1 or 2; n is 2 to 2]
Is an integer of 4; R ² and R ³ are each independently hydrogen,
(Lower) alkyl, (lower) alkenyl, (lower) alkynyl, cyclo (lower) alkyl, cyclo (lower) alkyl (lower) alkyl, hydroxy (lower) alkyl,
(Lower) alkoxy (lower) alkyl, (lower) alkylthio (lower) alkyl, amino (lower) alkyl,
(Lower) alkylamino (lower) alkyl, di (lower)
Alkylamino (lower) alkyl, pyrrolidino (lower)
Alkyl, piperidino (lower) alkyl, morpholino (lower) alkyl, piperazino (lower) alkyl, pyridino (lower) alkyl, amino, (lower) alkylamino, di (lower) alkylamino, 2,2,2-trifluoroethyl , 2-Furoroechiru, hydroxy, (lower) alkoxy, 2,3-dihydroxypropyl, cyano, cyano (lower) alkyl, amidino, (lower) alkyl _{amidino, A '- (CH 2)} m'Z (CH 2) n ′-, Phenyl, phenyl (lower) alkyl, substituted phenyl or substituted phenyl (lower) alkyl (wherein the phenyl ring is
1 or 2 substituents independently selected from (lower) alkyl, hydroxy, (lower) alkoxy and halogen,
Or optionally substituted with one substituent selected from methylenedioxy, trifluoromethyl and di (lower) alkylamino), where R ² and R ³ are both cyclo (lower) alkyl, phenyl, substituted Phenyl, amino,
(Lower) alkylamino, di (lower) alkylamino,
Hydroxy, (lower) alkoxy, cyano, amidino,
(Lower) alkyl amidino or _{A '- (CH 2) m} '
Z _'(CH 2) a n'- have it; or ^{R 2}
And R ³ together represent —CH ₂ CH ₂ X (CH ₂ ) r.
-May be;

R is an integer from 1 to 3; X is methylene, sulfur, oxygen or N--R ⁴ ; provided that when r is 1, X is methylene; R ⁴ is hydrogen. , (Lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower) alkanoyl or benzoyl; m ′
Is an integer from 0 to 2; n'is an integer from 2 to 4; Z'is sulfur, oxygen or methylene; A'is
Phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl; where A'may have 1 to 2 substituents, the first substituent being , (Lower) alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, (lower) alkoxy,

[0078]

And the second substitution is (lower)
Alkyl, hydroxy, trifluoromethyl, halogen,
Selected from amino, hydroxymethyl and (lower) alkoxy;

Q is an integer from 0 to 6; each R ⁴ is independently as defined above or two R ^{4 s.}
The groups together may be ethylene; R ⁵ and R ⁶
Are each hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cyclo (lower) alkyl or phenyl; or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached, pyrrolidino, Morpholino, piperidino, methylpiperidino, N-methylpiperazino or homopiperidino]; or a salt, hydrate, solvate or N-oxide thereof.

In a further preferred embodiment of the compound of formula XVII, R ² and R ³ are each independently hydrogen,
(Lower) alkyl, (lower) alkenyl, (lower) alkynyl, cyclo (lower) alkyl (lower) alkyl, phenyl (lower) alkyl, pyridyl (lower) alkyl,
3,4-methylenedioxyphenyl benzyl or A _'(CH 2)
m′Z (CH ₂ ) n ′, where R ² and R ³ are
Both _{A '- (CH 2) m'Z} ' (CH 2) a n'- have it; m 'is an integer of 0 to 2; n and n' each is independently 2-4 Z'is sulfur, oxygen or methylene; A'is phenyl, imidazolyl, thiazolyl, furyl, thienyl or pyridyl, each of which has 1 to 2 substituents. Often, the first substituent is (lower) alkyl,

[0082]

And the second substitution is (lower)
Selected from alkyl; R ⁵ and R ⁶ are each independently hydrogen or (lower) alkyl.

In another more preferred embodiment of the compound of formula XVII, n is 2; R ² and R ³ are each independently hydrogen, (lower) alkyl, (lower) alkenyl, (lower ) Is selected from alkynyl and phenyl (lower) alkyl, or when R ² is hydrogen, R ³ is

[0085]

May be: where Z is sulfur or methylene and R ¹³ is hydrogen or methyl.

Example The production method of the compound and the physical properties (mp etc.) of the product when both the 3-position and the 5-position are releasable groups (R ₇ ) are described as Reference Examples [I] and (II). However, the following will describe the preparation method and physical properties of intermediate compounds within the scope of the present invention, and in these examples, all temperatures are indicated in "° C".

Example 1. 1,1-dioxide 3- {2-
[(5-Dimethylaminomethyl-2-furyl) methylthio
O] ethylamino} -4-methylamino-1,2,5-
Thiadiazole A. 1,1-dioxide 3-methylami
No-4- (2-mercaptoethylamino) -1,2,5
-Thiadiazole methanol 2 cooled to 1 ° in an ice-water bath
1,1-dioxidized 3,4-dimethoxy-1, in 50 ml
2,5-thiadiazole (3.0 g; 16.8 mm)
Solution) in 20 ml of methanol with good stirring
2-aminoethanethiol (1.91 g from the hydrochloride; 1
6.8 mmol) solution was added dropwise over 15 minutes.
After 10 minutes at 2-4 ° the solution was cooled to methylamine.
Bubble for 6 minutes and stir at ambient temperature for another 30 minutes
Continued for a while. The reaction mixture was evaporated under reduced pressure and the residue was filtered.
Place on 45 g of Rica gel and add methylene chloride-methanol
Chromatographed using gradient elution. Suitable picture
The contents were combined and evaporated to give the product (2.43 g) with anhydrous ethanol.
Crystallized from Nol. Recrystallized from absolute ethanol
To give the title compound, mp 259-260 ° (decomposition)
It was

Analysis Calculated as C ₅ H ₁₀ N ₄ O ₂ S _2.
Values: C, 27.03; H, 4.54; N, 25.20.
Experimental value: C, 27.13; H, 4.55; N, 24.8
6.

B. 1,1-dioxide 3- {2-[(5
-Dimethylaminomethyl-2-furyl) methylthio] d
Tylamino} -4-methylamino-1,2,5-thiadi
1,1-dioxide 3-methyl in 20 ml of concentrated azole hydrochloric acid
Luamino-4- (2-mercaptoethylamino) -1,
2,5-thiadiazole (1.0 g; 4.5 mmol)
[Manufacturing in step A] and 5-dimethylaminomethyl-2-fu
Run methanol (0.82 g; 4.5 mmol) [J.
Chem. Soc. , 4728 (1958)
Therefore, the mixture with [Preparation] is stirred in an ice bath for 2 hours, then 0
It was left for 64 hours at °. Smell reaction mixture to ambient temperature
Stirred for 23 hours, evaporated under reduced pressure without heating,
The residue was partitioned between water and methylene chloride. Heavy water phase
It was made basic with sodium hydroxide and extracted with methylene chloride. Combine the organic phases
Washed with saturated brine solution, dried and evaporated under reduced pressure.
Let Place the residue on 25 g of silica gel and
Chromatography using gradient elution of methanol-methanol
I understood Evaporate the appropriate fractions to remove the product from methanol.
It was crystallized. Recrystallize from methanol to give the title compound.
, Mp 92-96 °.

Example 2 1-oxide 3- {2-[(5-di
Methylaminomethyl-2-furyl) methylthio] ethyl
Amino} -4-methylamino-1,2,5-thiadiazo
Lumpur A. 1-oxide 3-methylamino-4- (2-me
Lucaptoethyl) -1,2,5-thiadiazole ice water bath
1-Oxide 3, in 150 ml of methanol cooled to 3 °
4-dimethoxy-1,2,5-thiadiazole (2.9
2 g; 18.0 mmol) with good stirring
2-Aminoethanethiol (base
A solution of 2.04 g; 18.0 mmol) was added dropwise from the salt.
did. After 10 minutes, add anhydrous methylamine to this solution for 6 minutes.
Bubble and continue stirring at ambient temperature for another 20 minutes.
It was The reaction mixture was evaporated under reduced pressure and the residue was silica gel.
Place on 45 g, gradient elution with methylene chloride-methanol
Was chromatographed using. Combine the appropriate fractions
And evaporated to give 2.74 g of product. methanol,
Then recrystallize from 95% ethanol to give the title compound, m
p191-193 ° was obtained.

B. 1-oxide 3- {2-[(5-dimme
Cylaminomethyl-2-furyl) methylthio] ethyla
Mino} -4-methylamino-1,2,5-thiadiazo
Le 1-oxide 3-methylamino-4- (2-mercapto
Toethyl) -1,2,5 -thiadiazole [Process A intermediate production
Example 1) in concentrated hydrochloric acid according to the procedure described in Example 1, Step B.
Equivalent amount of 5-dimethylaminomethyl-2-furanmethanoe
When treated with silane, it gave the title compound.
It

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location C07D 417/12 271 275 277 307 333

Claims (1)

[Claims] 1. A formula [Wherein p is 1 or 2; n is an integer of 2 to 4; R ² and R ³ are each independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, Cyclo lower alkyl, cyclo lower alkyl lower alkyl, hydroxy low
Grade alkyl, lower alkoxy-lower alkyl, lower alkyl <br/> heteroarylthio lower alkyl, amino-lower alkyl, lower alkyl <br/> arylamino-lower alkyl, di-lower alkylamino-lower al <br/> kill, pyrrolidino-lower alkyl, piperidino-lower alkyl <br/> Le, morpholino-lower alkyl, piperazino-lower alkyl <br/> Le, pyridyl lower alkyl, amino, lower alkylamino, di-lower alkylamino, 2,2,2-trifluoroethyl, 2-Furoroechiru, hydroxy , Lower alkoxy, 2,3-dihydroxypropyl, cyano, cyano low
Grade alkyl, amidino, lower alkyl amino Gino, A'-
(CH ₂ ) m′Z ′ (CH ₂ ) n ′, -phenyl, phenyl lower alkyl, 1 or 2 substituents in which the phenyl ring is independently selected from lower alkyl, hydroxy, lower alkoxy and halogen, or methylene. Substituted phenyl or substituted phenyl lower alkyl which may contain one substituent selected from dioxy, trifluoromethyl and di lower alkylamino; provided that both R ² and R ³ are both cyclo lower alkyl, phenyl, substituted phenyl, amino, lower alkylamino, di-lower alkylamino, hydroxy, lower alkoxy, cyano, amidino, lower A <br/> Rukiruamijino or _{A '- (CH 2) m'Z} ' (C
H ₂₎ A n'- have it; or ^{R 2} and ^{R 3}
Are _{combined, -CH 2 CH 2 X (CH} 2) may be a r-; r is an integer from 1 to 3; X is methylene,
Sulfur, oxygen or N—R ⁴ ; provided that when r is 1, X is methylene; R ⁴ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl. > L or benzoyl; m'is an integer from 0 to 2; n'is an integer from 2 to 4; Z'is sulfur, oxygen or methylene; A'is phenyl, imidazoyl , Thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl; provided that A ′ may contain 1 or 2 substituents,
Substituents include lower alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, lower alkoxy, The second substituent is selected from lower alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl and lower alkoxy; q is 0
Is an integer from 6 to 6; each R ⁴ is independently as defined above, or the two R ⁴ groups may together be ethylene; R ⁵ and R ⁶ are each independently Then hydrogen,
Lower alkyl, lower alkenyl, is lower alkynyl, lower cycloalkyl or phenyl; with the proviso ^{R 5} and R
⁶ should not be both a lower cycloalkyl or phenyl; or R ⁵ and R ^6, together with the nitrogen atom marked with their combined, pyrrolidino, morpholino, piperidino, methylpiperidino, may be N- methylpiperazino or homopiperidino ] The compound or its salt, hydrate, solvate, or N-oxide.