JPS63225383A - Fused ring thienopyrimidine derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R1-R6 represent H or lower alkyl; either of X or Y represents S, and the other represents C; A represents alkylene expressed by -(CH2)n- (n is 2-6); B represents S or methylene] or acid addition salt thereof. EXAMPLE:2,3-Dihydrothiazolo[3,2-a]thieno[3,2-d]pyrimidin-5-one. USE:A gastric juice secretion inhibitory agent or antiulcer agent, having no toxicity and capable of being readily synthesized. PREPARATION:A compound expressed by formula II is reacted with an aminoethanol derivative expressed by formula IV preferably at 20-50 deg.C to form a compound expressed by formula III. The resulting compound is reacted with a dehydrating agent, such as sulfuric acid, or with a halogenating agent, such as thionyl chloride, preferably at 20-150 deg.C to afford the compound expressed by formula V.

Description

DETAILED DESCRIPTION OF THE INVENTION (Objectives) The present invention relates to a novel fused ring-fused chenopyrimidine derivative tx having excellent gastric juice secretion suppressing action and anti-ulcer action, and its pharmaceutically acceptable acid addition salt.

The present inventors have conducted intensive research over many years on the synthesis of derivatives that have gastric juice secretion suppressing effects and antiulcer effects. As a result, a new compound, a fused chenopyrimidine derivative, has an excellent suppressive effect on gastric juice secretion. The present invention was completed based on the discovery that it has anti-ulcer and anti-ulcer effects, is non-toxic, and can be easily synthesized.

(Structure) The novel fused chenopyrimidine derivative of the present invention is a compound represented by the general formula, and is a pharmaceutically acceptable acid addition salt thereof.

In the above formula, R1'R2'R3"4" 5 and R
6 is the same or t is different and represents a hydrogen atom or a lower alkyl group, either X or Y represents a sulfur atom and the other represents a carbon atom, A represents the formula -(CH2)n- (in the formula, n is 2
Indicates an integer from 6 to 6. ), and B represents a sulfur atom or a methylene group.

In the above general formula (1), R1, R2, R3, R4,
The lower alkyl group represented by R5 or R6 is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, S-butyl, t-butyl, pentyl, impentyl, 8-pentyl, t-pentyl, neopentyl. , hexyl, and isohexyl, and preferably an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, n-butyl, and isobutyl. A is -(Ca,)
It represents an alkylene group represented by n-, where n represents 2 to 6, preferably 2 to 4. B represents a sulfur atom or a methylene group.

Specific examples of the compound having the general formula (1) of the present invention include the compounds listed in the following Tables 1 to 4, but the present invention is limited to these compounds. It's not a thing.

In addition, in the table, Me represents a methyl group, El represents an ethyl group,
Pr is a propyl group, iPr is an isopropyl group, Bu
Butyl, J! , iBu represents an isobutyl group.

Furthermore, the substitution positions of the alkyl substituents R and R4 in Tables 3 and 4 are as shown below.

33 PrHHHEtH34PrHHH
PrH 35PrHE H1BuH 36Pr HMe HMe H37Pr
HEt HMe H38Pr HMe
Me HH39Pr HMe Et
Et H40Me Me HHHH 41Me Me Me HFf H4
2Me Me Bt HHH43MeMeH
HMs H 44MeMe HHRtH 45Me Me HHPr H46MeMe
HHBuH 47Me Me HH1BuH 48Me Et HHHH 49Me Et Me HFI H5
0Me Et Me HMe H51
MePrHHHH 52MePrMeHH)H 53Me Pr Me HMe H54Me
Pr Me Me HH55FjtM
e MeHHH 56Et Me Me HMe H57EtM
sHHMeH 58Et Me Me Me Me H
59Kt Me Me Me iBu H
60Rt Bt HHHH 61Kt Et Me HHH 62Et Fit FI HMe H6
3EtiPrHHHH 64Et iPrMe HHH65Et
1PrHHMe H66EtPrHHHH 67It Pr Me HHH68It
Pr HHMe H69Kt Pr
Me Me Me H70PrMeHHHH 71Pr1(e Me HHH 72PrMeHHMeH 73iPrMeHHHH F2 iPrMe Me HHHI3゜ iPrMe HHMe H76PrEt
HHHH 77PrEt MeHHH 78Pr Pr HHHH 79PrPrMeHHH 80HMe HHHH 81HMe HHMe H 82HMeHHKtF! 83 HMe HHPrH 84HMeHH1BuH 85HMe Me HMe H 86HMe Et HMe H 87HMe Me Me HH 88HMe Me Et EtH89HEtHH
HH 90HEtMeHHH 91HEtHHMeH 92HEtHHPt H 93HBt HHPr H 94HEtHH1BuH 95HEtMe HMe H 96HEt Me Me Me H8
7HPr FI HHH 98HPrMeHHH 99HPr HHMe H loo HPrMeHMeHlol
H1PrHHHH102HiPrMe H
HH 103H1PrHHMe H 104HiPr Me Me Ms H
Table 2 105 HHIII HHH 2O2HHMe HHH 2O2HHlit HHH 2O2HHHHMe H 2O2HHHHIt H llo HHHII Pr H lll HHIII HBu H II2 TI HHHiBuIi m MeHHII HH 114MaHMaHIII H II5 Me l'f H11Me HII6 M
e HHH11t H II7 MeHII HEtH River MsHHHBuH 119Me Fi HB iBu! (12
0Men MsHMeH 121MeHKtHMeH 122Me HMe Me HH123M
e HMe Me Et H124E
t HHHHH 125EtHMeHHH 126Et HHHMe H lll ICt HHH1BuH1
28RtHMaHMeH j29 1! tHMe HMeH13
0] lit HMe Me TI H13
1KtHMe Et Et I'1132
Pr HHHHHH133Pr
HMe HHH 134PrHHHMeH 135Pr HHH1PrH 136PrHMe HMe H137Pr
HIt HMe H2Se P
rHMeMeHH2Se MeMeHHH
H140Me Me Me HHH141
Me Me KtHHH 142Me Me Me Me PI
H143M6 Me HHBu H144Me
Ht HHHT1 145 MeEtMeHHH146Me
Kt Me HMe 11147
Me Pr HHHH148MePr Me
H'E H149Me Pr Me Me
HH2SOBt Me HHHH 151ICtMe Me HHH152Et
Et HHHH 153Et Et Me HH1(154Et
It HHMe H155Pr Pr
HHHH 2Se Pr Pr Mis HH
H157HMe HHHH 2Se HMeHHMeH1511HMa
HHEtE 160 HMe HHPr H16
1HMet HFI 1BuH162HMe
Me FI H'H163HMe
It HMe HII4 HMe
Me Me HH165HMe Me
Et Et H1Se H
Et PI HHHII7 HE
t Me HHHII8 E
1! it Me HMe H2Se
HEt Et HMe H170
HE(MeMeHH 171HEt HHMe H II2 HEt HH1BuH173H
Pr HTi HH 174HPrMsE HH 175HPrHHMeH 176 HPrMe HMet(17
7HPr Me Ms Me H2T
e H1PrHHHH2Te
HiPrMe HHH2SOH1PrHHMe
H 181HiPr Me Ms Me H
Table 3 182 2 HH--1832HHM
e(61, - 1842HHMe(8) - 1852HHMe(6) Me(6)186
2 HH11t(7) -1873HII
! -188 3 HFi Me19)
-1894HH-- 1904HHMe(61- 1915HH-- 1925HHMe(61Me(6) 193 6 HH--1946HHB
ulm-1952Me H-- 11162Me HMet61 -197
2 Me HMe(8) -1982
Me HMe(61Me(6)199 2
Me H1et (71-2003Me H-- 2013Me HMet9) -2024Me
H--2034Me HMet6) -2045Me
H--2055Me HPr(6) -2066Me
H-- 2076Me HMen -2082KtH
-- 2092It HMe (61- 21G 2 It HMe (8)
-21121it HMe(6) Me(6
)212 2 Kt HMe(7)
-2133EiH-- 2144g1a -- 21551]:t H-1216 61etH-- 2172PrH-- 2182Me Me -- 2192Me Ms Me (61-2202Me
MeMe1(8) -2212Me
Me Me (6) Me (612222Me
Me Me () -2233Me
Me -- 2244Me Me -- 2255Me Me -- 226$MeMe -- 2272Me It -- 2283MeEt -- 2292Me Pr -1230 5MePr --2312K
t ue -- 2322Kt Me Me(8) -23
34KtMe -- 2342PrEtM・(8) -- 2353Et iPr -- 2365gtPr -- 2372PrMe -- 2382Pr Me Me (6) Me (6
12394KtMe -- 2402iPrMe -- 2413PrEt -- 2422Pr Pr Me(8) -24
32HMe -- 2442FI Me Met6) -2
452HMe Me[8) -248
2 HMe Me(6) Me(6)2
4γ 2 HMe Me(7) −2
483HMs -- 2494HMe -- 2505HMe -- 2518HMe -- 2522HEt -- 2532HEt Me (61- 2545HB1 -- 255 2 HPr --256
2HIPr -- 2572n iPr Me(fl Me(
6) 258 2 Ht H--25
92Bit B no<61 -260
2 I! lt HMe (81-261
2ICt HMe(61Me(6126233t
H-- 2g3 411tH-- 21i4 51et! I--2656
gt, a -- 2662PrH -- 26γ 2 ヱPr HM
e (6) Me fil No. 4 Table 261 2 HH-- 2702d HMe(67- 2712HHMe(81- 2722HHMete1 Me(61 2732HHgtf'y) - 2743HH-- 2753HHMgI2) - 2764HH-- 2774H HMete) - 2785HH-- 27+ 5 HHMete )
Mete) 280 6 HH--28
12Me H-- 2822Me HMe (61- 2832Me HMe(8) -2842Me
HMe(6) Me(612852Me HM
e(7) −2863Me H−− 2873MeHMe(61− 2884Me Tl −− 2894Me HPr(6) −2905Me
Fl -- 2H5Me HMe(61Me(612926Me
H-- 2932m1 H-- 2942Et HMe (61- 2953mt a-- 291i 2 Pr H--
2975PrH -- 2982MeMa -- H92Me Me Mete) -300
2MeMeMe<81 -301
2 Me Me Me (61 Me (6
13022Me Me Me (71-3033Me
Me -- 3043Me Me Et(61-3054Me
Me -- 3085MeMe -- 3076MeMe -- 3082Mallt -- 3092Me Et Me (61-3103M
eEt -- 3H6Malt -- 3122M5Pr -- 3134MePr -- 3142EtMe -- 315 2 gt Me Me[6]
Me (613163Kt Me Me (61
-3174FitMe -- 318' 2 Et xt
--3192Et Et Me(6) Me
(613206EtKt -- 3212PrPr -- 3224PrPr -- 3232HMe -- 3242HMe Mef6) -3252HM
e Me(8) -3262HMe Me(
61Mef6) 327 2 HMe M
ef71328 3 HMe
--3293HMe ]1Ctf6J -330
4HMe -- 3315HMs -- 3326HMe -- 3332HEt -- 3342HEt Me(61- 3352HKt Me(8) -3362HK
t Mef6) -3372HRt Mef
6) Mef6) 338 2 Hl
it Me(7) -3393Hgt-- 3403HBt Pr(61- 3414H11t-- 3424HEt Mef6) -3435Hg
i-- 3446Hgt -- 3452HPr -- 34B 2 HPr ICt
(6) -3474H'Pr -- 3482HiPr -1 The novel fused ring-fused chenopyrimidine derivative (1) of the present invention can be produced by the method described below.

(G) In the above formula, X, Y, R1, R2, R,, R4,
R5 and R have the same meanings as above. R2 represents a hydrogen atom or a group similar to the lower alkyl group defined above.

In the first step, a compound having the general formula (1) is converted into a compound having the general formula (■)
This is a process for producing a compound having the general formula ([) by reacting it with an aminoethanol derivative having the formula ([). The compound (1) was prepared by the method of Kienz et al. (F, Kienz et al.
le, He1v, Chin, Acta, 66, 1
48 (1983)).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but aromatic hydrocarbons such as benzene, toluene, and xylene; methylene chloride; Examples include halogenated hydrocarbons such as chloroform; esters such as ethyl acetate and propyl acetate; ethers such as ether, tetrahydrofuran and dioxane; and excess aminoethanol (a).

The reaction temperature is from -10°C to 70°C, preferably from 20°C to 50°C. The reaction time varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used, but is usually 5 minutes to 5 hours. After completion of the reaction, the target compound (1) of this reaction is collected from the reaction mixture according to a conventional method.

In the second step, a compound having the general formula (1) is treated with a dehydrating agent such as sulfuric acid, methanesulfonic acid, polyphosphoric acid, or diethyl cyanophosphate, or thionyl chloride, thionyl bromide, phosphorus chloride, oxybromide, etc. This is a process of producing a compound having the general formula (-) by reacting with a halogenating agent such as phosphorus.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferred are amides such as dimethylformamide, dimethylacetamide, and samethylphosphorotriamide. Alternatively, an excess of a dehydrating agent or a halogenating agent may be used.

The reaction temperature is from -10°C to 170°C, preferably from 20°C to 150°C. The reaction time varies mainly depending on the reaction quality, the raw material compound, or the class a of the solvent used, but is usually from 1 hour to 5 days. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method.

[Production method 2 ] In the above formula, X, Y, RRRR and R7 1' 21 5th Lieutenant 4 indicates the same meaning as above.

The third steps A and B involve reacting a compound having the general formula (vD) with an allyl isothiocyanate derivative having the general formula (■a), or reacting a compound having the general formula (vD) with an allyl isothiocyanate derivative having the general formula ([). This is a process for producing a compound having the general formula (-) by reacting it with an allylamine derivative having the formula (■,).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but benzene and toluene are preferably used.

Aromatic hydrocarbons such as xylene; Norogenated hydrocarbons such as methylene chloride and chloroform; Esters such as ethyl acetate and propyl acetate: Ethers and ethers such as tetrahydrofurandioxene;
Mention may be made of alcohols such as methanol, ethanol, n-propanol, impropanol, n-butanol, imbutanol, isoamyl alcohol. The reaction temperature is from -10°C to 170°C,
Preferably, the temperature is 60C to 100C. The reaction time varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used, but is usually from 30 minutes to 5 days. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that is immiscible with water to the reaction mixture, washing with water, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by conventional methods such as recrystallization, reprecipitation, or chromatography.

The fourth step is a step of producing a compound Ill having the general formula (K) by reacting the compound having the general formula (Vli) with hydrogen halide.

As a halogenated water system, chloride water ac or chloride water x
i can list.

Solvents used include reaction t-inhibitor, starting material
There is no particular limitation on the type of hydrocarbons that can be dissolved to some extent, but suitable examples include aromatic hydrocarbons X such as benzene, toluene, and xylene; halogenated hydrocarbons such as methylene chloride and chloroform; methanol, ethanol, n-
Alcohols such as gropanol, ingropanol, n-butanol, inbutanol, and inamyl alcohol; organic #R@'Cs such as acetic acid and propionic acid.

The reaction temperature is from -10°C to 170°C.

Preferably, the temperature is 50°C to 100°C. During reaction #,
The time required for one cycle is 5 minutes to 2 hours, depending mainly on the reaction temperature, raw material compound, or type of solvent used. After completion of the reaction, the target compound (K) for one reaction is collected from the nine reaction mixtures according to a conventional method. If necessary, the obtained target compound may be prepared using a conventional method.

For example, it can be further purified by recrystallization, reprecipitation, chromatography, or the like.

[Production method 3] (1) (v) In the above formula, X# Y# RI I R2 and R1 have the same meanings as above. W represents a halogen atom, preferably gold such as chloro, bromine or iodine.

The fifth step is a step of producing a compound having the general formula (V)k by reacting the compound having the general formula (I[) with the ethylamine derivative (3).

The solvent used does not inhibit the reaction at all.

There is no particular limitation as long as it dissolves the starting material JX to a certain extent, but benzene and toluene are preferred.

Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride and chloroform; esters such as ethyl acetate and propyl acetate; ethers,
Ethers such as tetrahydrofuran and dioxane;
Alcohols such as methanol, ethanol, n-d-panol, isopropanol, n-butanol, imbutanol, inamyl alcohol; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide; dimethyl sulfoxide; Examples include sulfoxides such as

The warping temperature is 110°C to 170°C.

Preferably, the temperature is 50°C to 100°C. The reaction time mainly depends on the reaction temperature, the la of the raw material compound or the solvent used.
It varies depending on the class, but each line takes from 10 minutes to 5 days.

After completion of the reaction, the target compound (V) of one reaction is collected from one reaction mixture Rikishima according to a conventional method. For example, it can be obtained by adding a water-immiscible solvent to a reaction mixture, washing with water, and then completely distilling off the solvent. The obtained target compound can be further purified by conventional methods such as crystallization, reprecipitation, or chromatography.

[Production method 4] (W) (XI) In the above formula, X* Ys R1e R2# R5# R4# R5e
R6 and R7 have the same meanings as above. n is 2 to 6t-
show.

In the sixth step, a compound having the general formula (W) is converted into a compound having the general formula (XX
) through a condensation reaction with the lactams shown.

This is a method for producing compound 0CIi)'t-.

Condensing agents used include halogenating agents such as thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus oxybromide, and phosphorus pentachloride.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but aromatic hydrocarbons such as benzene, toluene, and xylene; methylene chloride are preferred. , halogenated hydrocarbons Th' such as chloroform.

The reaction temperature is from -110°C to 110°C.

The temperature is preferably 90°C to 150°C. The reaction time varies mainly depending on the reaction temperature, the starting material, or the type of solvent used, but is usually from 1 hour to 5 days. anti-l
After the completion of the reaction, the target compound (Kari) for one reaction was prepared using the conventional method.
taken from the reaction mixture. For example, it can be obtained by adding an organic solvent that does not mix with water to the reaction mixture, neutralizing it, washing with water, and then distilling off the bath agent. The obtained target compound can be further purified, if necessary, by conventional methods such as recrystallization, reprecipitation, or chromatography.

[Dyeing method 5] In the above formula, x* Y * R1* R2* R4* R4
#R5#R6 and R7 have the same meanings as above. R8
represents the same group as the nine lower alkyl group defined above.

In the seventh step, a compound having the general formula (4) is converted into a compound having the general formula (XI
II) with the iminoethers shown in condensed ash,
This is a method for producing compound (■).

The solvent used should be one that does not inhibit the reaction and that does not inhibit the starting material it.
There is no particular limitation as long as it dissolves to some extent, but benzene and toluene are preferred.

Aromatic hydrocarbons such as silane; amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide; and ethers such as tonyl ether and dowsum. It is also possible to react without using.

The reaction temperature is 50°C to 220°C.

The temperature is preferably 90°C to 180°C. The reaction time varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used, but is usually from 1 hour to 5 days. After completion of the reaction, the target compound (XI) of this reaction is collected from one reaction mixture according to a conventional method. The obtained target compound can be further purified, if necessary, by conventional methods such as recrystallization, reprecipitation, or chromatography.

The compound of the present invention having the general formula (1) obtained by the above reaction can be made into a pharmaceutically acceptable acid addition salt form, if necessary.

Such acid addition salts mean salts with acids that do not increase the toxicity of the basic compound; examples of these acid addition salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, methaline Mention may be made of mineral acids such as acid, nitric acid, and sulfuric acid, as well as #i of acetic acid, oxalic acid, tartaric acid, citric acid, benzoic acid, glycolic acid, glucic acid.

(Effect) The novel fused chenopyridine brocade conductor of the present invention has excellent gastric juice secretion suppressing action and wiping action.
Examples include oral administration using granules, powders, syrups, etc., and parenteral administration using injections, layered preparations, etc. These preparations are manufactured by well-known methods using additives such as excipients, binders, disintegrants, lubricants, stabilizers, and flavoring agents. The amount of violet used varies depending on the symptoms, age, etc., but the usual dosage for adults is 10-2000119 per day.
It can be administered once a day or in several divided doses.

The present invention will be explained in more detail below by giving examples, test examples, and reference examples.

Example 1 a) 3-[2-hydroxyethyl]-2-mercaptocheno[3,2-d]]pyrimidin-5-one 1 s
yr Added to methanesulfonic acid 15d 12G -13
Heated at 0°C for 30 minutes. Pour into ice water and neutralize with 1(l) sodium hydroxide to collect precipitated crystals, wash with water and recrystallize from ethanol to obtain colorless needle crystals of 1.00 # (7
2%).

mp 187-189°C IR(KBr)ax-' 7 16!10. 167
0. 1548. 1495b) 3-[2-Hydroxyethyl]-2-mercaptocheno[3,2-d]pyrimidin-5-one 3081 was added to sulfuric acid 3 (ld) at 20°C.
The mixture was stirred for 2 hours. The mixture was poured into ice water, neutralized, and the precipitated crystals were collected, washed with water, and recrystallized from ethanol to obtain colorless needle-like crystals (1.9211C68).

mp 187-190℃ (αa?llchi1rb
zIRs4t)Is Shida match]C) Methyl 3-isothiocyanato-2-thiophenecarboxylate) 4
．． 93,F g) Add 12.5 ethylamine and 10- to dichloromethane to obtain 2-chloroethylamine hydrochloride! Added 3011e. After stirring at 20° C. for 1 hour, the mixture was heated under reflux for 1 hour. After pouring into ice water and extracting with dichloromethane, 445 liters (86%) of colorless needle crystals were obtained.

mp111! -11! AT ℃(a) MiF-dezui~OJjitkacr'Ftx<'ylr-=I
IP43 Example 2-6 Compound S* was obtained in the same manner as in Example 1.

Table 5 2M HHHHIII 193-19411i110,
1688,1520 953 Me Me HFi
l(, H180-1821880, 16684528
Ta2 1% [! ti KEI H13
8-131116110, 181iS, 1518 1i
t5 Bird-,s HHHMe H177
-1110166845209 words umbrella)
Umbrella) II Me HHHiBu H19
7-111918110,18Da, 1551 94 trihydrochloride Axis) KBr Example 7-8 Compounds in Table 6 were obtained in the same manner as in Example 1.

@6Table 7 HHIII H)I EI IIJI-2
001675,159083II MeMe HEI
EI H00-1721865, 1598H3-
Allyl-2-mercaptocheno[龜2-d]pyrimidy:
/ -4-t-LOOI t-acetic acid 20-,
The chlorinated leaves were introduced for 3 hours while heating under reflux. The material obtained by neutralizing in water and extracting with chloroform was subjected to silica gel chromatography, eluted with ethyl acetate-nihexane (1:1), and recrystallized from n-hexane to form colorless needles. A crystal of 1.38 N (69 t) was obtained.

mp 85-97℃ IR(Br)cm, 1672, 1
550, 14911 Example 11-H Compounds in Table 1 were obtained in the same manner as in Example 10.

Table 1 11 Me HH182-1841665,151
59312Me Me H156-1581668,1
5226413EI Me H110-112167
0j560j52080) KBr Examples 15-20 The compounds shown in Table 8 were obtained in the same manner as in Example 10.

Table 8 15 a a a 107-109 1680,1
588 8516 HMe H113-414167
0,15808817Me HH95-1161(17
5,15888518MaMe H09-12118
70, 15888819I (It H82-84167
0, 158292*) 2g HFitMe 5←57 1675, 15
78 100 KBr Example 21 Cheno (S, 2-d) pyrimidin-4-one 1.31 of 3-amino-2-thiophenecarboxylic acid was added to 4-phosphorus oxychloride and 1,2 N'i of α-pyrrolidone was added. did.

After heating under reflux for 1 hour and cooling, the mixture was poured into ice water and neutralized with aqueous ammonia. The crystals obtained by extraction with dichloromethane were recrystallized from ethyl acetate to give pale yellow flaky crystals a, γg (
4 (I got 1 Chino.

mp 15G-152℃ IR (CHC4) (1111, 1670, 1598, 1
502 Example 22 The target compound was extracted with ethyl acetate using ashes in the same manner as in Example 21.
Recrystallization from n-hexane gave pale yellow needles in 61% yield.
I got it.

mp 1B7-'169℃ IR(C1(C'ts) ax: 1gg!0
, 1592, 1530 Example 23 (onmethyl 3-amino-2-thiophenecarboxylate)
1.51 and α-piperidone tlN and t-/chloroethane 8- and phosphorus oxychloride 1- was added. 15
After heating under reflux for a minute, the mixture was poured into ice water for neutralization, extracted with methylene chloride, and the resulting crystals were recrystallized from ethyl acetate to obtain colorless needle crystals of 1.4, p (71).

mp 102-103℃ XR(C:Hcts)C1l, 1675, 16
60 Examples 24-34 The compounds in Table 9 were obtained in the same manner as in Example 23.

Table 9 2a HH4110-1111685, 158581
25Me H396-971665, 15308626
Me H4113-1151662, 15308227
MeMa 2157-159 1665, 1595
84211 MeMa 3164-168 1665
, 1530 7129 MeMe 4 154-1
56 1660, 1538 8230 1tH289
-901665,15!13,15286331 E
t H378-791665, 15286432Kz
H4To-731662, 1570, 15327833
Me H5120-1211660j530 B6
34 Me H6113-1141682, 1530
72 Examples 35-45 The compounds shown in Table 10 were obtained in the same manner as in Example 23.

Table 10 35 HH2144-1481685,1610,1
5925036HH3126-1281680,163
2,1550823γ HH4153-1551875
,15957038HMe 3 108-109 1
665,1582 5039 EI Me
4 116-117 1665,1592 5
T40 MeMe 2 77-79 1668,16
32j572 8041MeM+s3 γ2-73
16γ2,1595 5042 Me Me
4 103-104 1665,1598' 3
943 Hn-190-911668, 162550
45HR1467-701665,1590 [tertiary hydrochloride axis] KBr Example 46 The target compound was obtained by reacting in the same manner as in Example 21.

Recrystallization from ethyl acetate gave golden yellow needles in a yield of 6T.

mp Zu2B -129℃ IR (CHCts)cR, 1670, 1628, 156
0 Example 4T 2-a]cheno(3,2-d)pyrimidin-4-onemethyl 3-amino-2-thiophenecarboxylate 1
．． 57.9 and Toazor 2-methoxy-1-cycloheptene 1.52II were heated and stirred at 180° C. for 7 hours. After cooling, the oil obtained by pouring into ice water and extracting with ethyl acetate was subjected to silica gel chromatography and eluted with hexane-ethyl acetate (2M) to give light yellow needles of 0.7/(
321) was obtained.

mp 11G-112℃ Test Example 1 Gastric juice secretion suppressing effect Bhay method [H, 13hay: Gaatroent
The following procedure was carried out based on the volume 5, page 43 (190) of erology*.

SD male with a weight of about 180I)? A group of 5 friends.

The animals were fasted for 24 hours before the experiment and had free access to water. The abdomen was opened under ether anesthesia, the pylorus was opened, and the test compound suspended in 0.5 tcarboxymethylcellulose solution was administered into the duodenum. After 4 hours, the rats were sacrificed with deep ether anesthesia, and the gastric fluid was extracted and measured. The suppression wheel (R) for the control group was calculated using the following formula.

R-(1-B/A)×100 A: Gastric juice II of control group (sg/100 f7 body weight) B
: Gastric juice volume (m/100.9 body weight) of sample administration group 11th
Table Examples of preparations with gastric juice secretion suppressing action Capsules 7,8-dihydro-2-methyl-4H-pyrrolo-[1,
2-a]cheno[3,2-cl:] ]pyrimidin-4-one Example 22 Compound)
...2589 milk J bird
・・・・・・・・・・・・
・・・・・・ 1091g wheat flour starch
・・・・・・・・・・・・・・・ 15 M Magnesium Stearate ・・・・・・・・・・・・・・・
1 q total of 150 irises 9 or more is filled to make capsules.

Reference Example 1-3 Kinintsuru et al.'s method (F, K15nile, He1v,
Chim.

Ada, 66, 148 (1!183)) to obtain the compounds shown in Table 12.

Table 12 1 Me H63-642070, 1700702M
e Me 70-71 20110.1705 16
3 Hl H60-442070, 170575 Reference Example 4-6 Compounds in Table 13 in the same manner as Reference Example 1-3 Table 13 4 HH103-1042110, 1715745M
e Me 30-35 2110, 1715 7
3 Reference Example T A solution of methyl 3-isothiocyanato-2-thiophenecarboxylate 5I in tetrahydrofuran slaw was added to a mixed solution of ethanolamine z3- and 130 m of tetrahydrofuran, and the mixture was stirred at 20°C for 20 minutes. Pour into water and stir for 5 minutes to precipitate crystals.After drying, recrystallize from dimethylformamide to form colorless needle crystals!
L! T & (obtained 831.

mp 255-257℃ IR (KBrJ tx: 11iS1,
15113, 1552 Reference Examples 8-14 Compounds shown in Table 14 were obtained in the same manner as in Reference Example 1.

Table 14 II HII B% HHB 17M
72 (Yuin Ginba) 11152,154g 511
1 [(HHHMeF1171i-17111613
,15414110Me HHHHH253-255
11!44,1512 1911 MsM@HHFi
HIst 153 1662.14711 T
412 Es HHHEI H235-2371
647,15587113M・HHHMeH21G-
21316Hj555 7!114 MeHHHiB
u H172-1741851, 1553100 Reference Example 15-17 Compound gold shown in Table 15 was obtained in the same manner as in Reference Example 1.

Table 15 15 II HHHH11232-234186
0,16007fJ1@M@M@HHH■ 210
-H2f680.11!12 14 Reference Example 18 Methyl 3-amino-2-thiophene force A boxylene)
26.0. P and allyl intiocyaner) 32.68-
and heated under reflux for 18 hours in total n-propertool 200-. After cooling, the precipitated crystals are crushed and dried to give orange needle-like crystals I.
T, 52 # (4T%)@jmp H&-H9
°C

Table 16 Reference Examples 21-25 Compounds in Table 1T were obtained in the same manner as Reference Example 1B.
Nine.

Table 17 21 a HH201-2031656,160
56822HMe E'l 177-179
1687.1606 6923 Me HH2
12-2131702, 16077924M@Me
H209-H31&! 12.26+31 3425
HEt H172-1751708, 15986
9 Reference Example 26 2H5 Methyl 5-ethyl-4-thiocyanate-3-thiophenecarboxylate) 2.0J and 2-methyl-2-
Propenylamine! Add 1 g of acid salt and 20 kg of gold ethanol, add 0.94 g of triethylamine, F? Add 2
The mixture was stirred at 0°C for 2 hours.

Dissolve the residue in 10% sodium hydroxide under reduced pressure.
Crystals precipitated by acidification t Filtered to give colorless needle crystals 2.25
．． ! i+(96 chin obtained 9.

mp 172-173°C IR (CHC44 μm': 1700, 1805 Reference Example 2T Captothieno[3,2-d]pyrimidine-4-O) The desired product was obtained by reacting in the same manner as in Reference Example 26 in a yield of T2T.

mp　207-210℃

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) [In the formula, R_1, R_2, R_3, R_4, R_5 and R_6 are the same or different and represent a hydrogen atom or a lower alkyl group. , either X or Y represents a sulfur atom, the other represents a carbon atom, A represents an alkylene group represented by the formula -(CH_2)_n- (wherein n represents an integer of 2 to 6), B represents a sulfur atom or a methylene group. ] or a pharmaceutically acceptable acid addition salt thereof.