JPS5939892A - Novel pyrimidone derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound (acid addition salt) shown by the formula I {R<1> is H, lower alkyl, lower alkynyl, or group shown by the formula II [Ar is (halogen-, tert-butyl-, or methylenedioxy-substituted) phenyl, naphthyl, pyridine, or benzimidazolyl]; R<2> is H, or lower alkyl}. EXAMPLE:2-{-2-[ 5-(Dimethylaminomethyl)furfurylthio ]ethyl}-6-methyl-4(1H)-pyrimidone.dihydrochloride. USE:An inhibitor for secretion of acid in the stomach. Useful as an antiphlogistic, and a cardiovascular drug, as well. PROCESS:For example, an amidine derivative (acid addition salt) shown by the formula III is reacted with an acylacetic ester derivative shown by the formula IV(R<3> is lower alkyl) in an organic solvent such as methanol, etc. in equimolar amounts at room temperature - under heating, and, if necessary, in the presence of a base such as potassium hydroxide, etc. The raw material compound shown by the formula III is a novel substance, and obtained by reacting a compound shown by the formula V with ammonium chloride and hydrochloric acid.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel pyrimidone conductor represented by the following general formula (1), an acid addition salt thereof, 112, and a method for producing them.

[In the formula, R1 is a hydrogen atom, lower alkyl formula -CH2-
Ar (wherein, Ar means a phenyl group optionally substituted with a rogen atom, a tert-butyl group or a methylenedioxy group, or a naphthyl group, a pyridyl group, or a benzimida lylyl group). +
12 means a hydrogen atom or a lower alkyl group. The same applies hereinafter] In the definition of the group in the general formula of this specification, the word ``lower'' or ``month'' means a straight or branched carbon chain having 1 to 4 carbon atoms. In the general formula (D) and the general formula below, specific examples of lower alkyl groups include methyl group, ethyl group, propyl group, isopropyl group, butyl group, inobutyl group, sec-butyl group, tert
-butyl group.

Further, specific examples of the halokene atom which may be substituted with the phenyl group represented by Ar include a fluorine atom, a chlorine atom, a bromine atom, and the like.

The compound of the present invention is represented by the above general formula (1).

Forms acid ++ salt. The present invention also encompasses the pharmacologically acceptable salts of the compounds of general formula (1).

Specific examples of such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfuric acid, and organic acids such as maleic acid, fumaric acid, and Vikuri 7. can do.

In addition, the compound (1) of the present invention exists as IH and 3H tautomers, and a small amount also exists as the hydroxy 7 tautomer3, and the present invention does not include all of these iso-t1 forms. be.

According to the present invention, the compound (1) and its acid salts provided by -) have a histamine I'I, = receptor agonist action.
The moon (j') 5su.Useful as a gastric acid secretion suppressant1
It is.

Furthermore, some of these compounds also have histamine 111 receptor 1'+'i anti-activity. Such compounds are useful not only as gastric acid content suppressants, but also as anti-inflammatory agents and drugs that act on the cardiovascular system.
Volume 5, No. 4:3-61 Sada, +9/15),
It has been confirmed that gastric acidity is effectively suppressed at doses below 10-5 (Ing/kg).

Preparations containing the compound represented by general formula (1) or its acid addition salt as a 4-component are 714
The drug may be prepared in a conventional manner using the body, excipients, etc., and administration may be in either the oral or non-prescription form. The dosage is determined depending on the individual case, taking into consideration the symptoms, the age and gender of the recipient, etc.9, but it is usually 100 to 800 Ir1g per day for adults, and this is administered in 1 to 4 doses. is preferable.

Compound (1) of the present invention and acid addition salts can be produced by various methods. The present invention also includes methods for producing these compounds. Typical methods are illustrated below.

First manufacturing method (I) (R3 in the reaction formula means a lower alkyl group.

The same applies hereinafter) As shown in the above reaction formula, one of the present invention compounds (1)
Alternatively, the acid addition salt thereof can be obtained by condensing the Romidine derivative represented by the formula (It) or the acid addition salt thereof with the a/allacetate ester represented by the general formula (1). can be manufactured.

This reaction is advantageously carried out usually in an organic solvent at room temperature or at room temperature. Examples of solvents that can be used here include methanol, ethanol, alcohols such as infropanol, dimethylformamide, methylsulfochloride/oxane, methyl cellosolve, and ethyl cellonorb.

Ngrim et al. During the reaction, a base may be added if necessary, and suitable examples of such bases include alkali metal alcolades such as sodium, potassium hydroxide, sodium hydroxide, and the like.

Note that the amounts of raw material compounds (11) and (1) to be used may be equimolar, and one may be slightly excess than the other.

Second production method (In the reaction formula, R4 and R5 are the same or different and mean a lower alkyl group. The same applies hereinafter) The compound (1) of the present invention is an imidate derivative represented by the general formula (IV) and a general formula ( It can also be produced by condensing and cyclizing a 3-a,minoacrylic acid ester derivative represented by V).

The reaction can be carried out under substantially the same reaction conditions as in the first production method. That is, in this condensation cyclization reaction, the starting compounds (fV) and (V).

Equal moles of each or a slight excess of one, the first
Compound 9 of the present invention (1) can be produced by dissolving in the same organic solvent as in the production method, adding the same base as in the first production method if necessary, and reacting under heating or heating under reflux.

The compounds of the present invention thus produced are isolated as free compounds or their acid addition salts, if necessary, and subjected to column chromatography.

It is purified by means commonly known in the art, such as recrystallization.

In addition, the raw material compound (1v) can be produced by the method described in JP-A-55-115877 filed by the present applicant. The raw material compound (11) is a new substance, and the raw material compound (Ill) also contains a new substance, and when these substances are produced by the method of the reference example below, it is possible to have t+i'-. .

EXAMPLES The present invention will be described in further detail with reference to Examples and Reference Examples below.

In addition, among the symbols indicating the physical and chemical properties of the products in the examples, NMR means nuclear magnetic resonance spectrum, IR means infrared absorption spectrum + m, p means melting point, Mass means mass spectrum, and Anal means elemental analysis value. 1゜Also, the compound of Reference Example 1 is the raw material compound (II) of the first production method described in -.
As, the compounds of Reference Examples 2 to 6 are the raw material compound (Ill)
8 to Reference Example 1 3-[5-(dimethylaminemethyl)furfurylthiopropionamidine dibasic acid salt ethyl salt 34g of 3-(5-(dimethylaminemethyl)furfurylthio]propionimidate was dissolved in dry methanol. After adding 6 g of ammonium chloride and stirring at room temperature for 1 hour, add an ethanol solution containing hydrochloric acid to obtain the dihydrochloride, and remove the solvent under reduced pressure. When recrystallized from a mixed solvent, 31 g of 3-[s-(dimethylaminemethyl)furfurylthio]propionavazine dihydrochloride having a melting point of 134 to 136C is obtained0 Reference Example 2 Ethyl α-(:3-pyridylmethyl) Acetoacetate-1
・Metals in a nitrogen stream]・Riuno. 8.4 g was dissolved in 500 mt of absolute ethanol, 238 g of ethyl acetoacetate was added, and the mixture was stirred at room temperature for 1 hour.
Add 30 g of methylpyridine hydrochloride and heat to reflux for 20 hours. After removing the salt formed by 11.

The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography using rolopolmoethyl acetate as a developing solvent to obtain 12.0 g of the target product in the form of an oil.・NMR (
. in DC1B) δ(pprn); 1. +8 (3Il+t
) 2, 20 (311・S) 3, 13 (211, d) 3, 78 (+u, t) 4, 13 (2H+q) 7, 04 - 76o (2H+m) 8, 40 (2+1, m) Mass (m /e) 221 (M Reference Examples 3 to 6 The following raw material compounds were obtained in the same manner as in Reference Example 2.

Reference Example 3 Methyl)/cet/cet 1/7. 2-8.2 (7H
,m)Mass(m/e)270(M+),2
27, l 81 Reference Example 4 CH3 Co CHCOOC2 H2 C Cetate Reference Example 5 NMR (in CDCIA) δ (rlllm); 1. +8 (t, 3 11
)・+ 1.1 (q, 2+1) -1-chill α-(p-cert-;/chi
7 (18 (d, 2 11) rune/ru) no'pito/pinault 728 (d・211) 7,0
0~? ．． :3fi (m, 411) IR (neat) ν; 1735, 17H1cm ' Mass (m/e) ' 27fi (M"), 261 (M' +5) 2; U3 (M
4.'3) Reference Example 6 NMR (CI) in Cl3) 1-v; l735, 1710 cm-'
Mass (m/e) 298 (M″), 25 5 (M″-4 3) Example 1 After adding 1.24 g of ethyl acetoacetate to 30 ml of ethanol containing 0044 g of metallic sodium,
- Add 3.0 g of [5-(dimethylaminomethyl)furfurylthio]propionamidino dihydrochloride, and
After stirring for 0 hours, the solvent was distilled off under reduced pressure to make the dihydrochloride salt with ethanol containing hydrochloric acid, and when recrystallized with ethanol, the melting point was 16.
2-[2-C3-(dimethylaminemethyl)furfurylthio]ethyl]-6-methyl-4(
1.7 g of IH)-pyrimidone dihydrochloride are obtained.

m, p, 163-165 C (ethanol) An
al (as C15H23N302 S CI2)C
(%] ) [%) N (%) Calculated value 47
．． 37 6.10 11.05 Actual value lI7.14
5.91 10.98 Examples 2 to 7 The following compounds were produced by the same reaction procedure as in Example 1.

Example 2 Target compound 2-[2-[5-(/methylaminomethyl)furfurylthio]ethyl]-5,6-methyl-4(group)-pyrimidone dihydrochloride Physicochemical properties m, p, 172-177C ( Ethanol-ethyl acetate) Anal, (C,6H,,5N3028C1
,, ) C (%) H (%1 N (%) Calculated value 48,73 6.39 10.66 Actual value 48
,44 6.27 10.49 Example 3 Target compound 5 (P Lert-butylbenzyl)-2-[2
-[5-(dimethylaminemethyl)furfurylthio]ethyl]-6-methyl-4(IH)-pyrimidone dihydrochloride Physicochemical properties m, p, 171-175c (ethanol) Ana
l, (C,,6H37N,O,,S C1,,)C (%) H (%1 N1%) Calculated value 5
9.31 7,08 7.98 Actual value 59,1
2 7,14 7.94 Example 4 Target compound 5-[(6-chloro-1,3-benzonoquinol-5
-yl)methyl]-2-42-[5-(dimethylaminomethyl)furfurylthio]ethyl l -6-methyl-1
+(+n)-pyrimidone dihydrochloric acid Geochemical properties m, p, 158-162tZ' (ethanol) An
al, (as C23H2BN3048 C13)C
(%) H (%) N (%) Calculated value 50,
33 5,14 7.66 Actual value 50,27
5,07 7.55 Example 5 Target compound 2-[2-45-(dimethylaminomethyl)furfurylthio]ethylco-6-methyl-5-(1-naphthylmethyl)-4(lH)-pyrimidone dihydrochloride Physicochemical symptoms m, p, 178-181r (-[-tanol) Anal
, (as C26H31N302S C12mV2H20) C (%) H (%) N (%) divided value
58.97 6.09 7.94 Actual value 59.
155.97794 Example 6 Target compound 2-[2-4s-(dimethylaminemethyl)furfurylthio]ethyl]-6-methyl-5-(3-pyridylmethyl)-4(IH)-pyrimidone trihydrochloride Physicochemical Properties m, p,' 164-166c (ethanol) Ana
l, (as C21H2gN402 S C13)
C(%i H(%1 N(%) Calculated value 49
,66 5.75 11.03 Actual value 49.26
5.83 10.78 Example 7 Target compound 5-(2-benzimidazolylmethyl)-2-[245
-(dimethylaminomethyl)furfurylthio]ethyl]
-6-Methyl-4(IH)-pyrimidone trihydrochloride 3HC1 Physical and chemical properties m, p, 18-5 to 189 C (ethanol) An
al, (as C23H3oN502SC13)C
(%) H (%) N (%) Calculated value 50,
51 5.53 12.80 Actual value 50.22
'5.56 12.64 Patent applicant Akira Sasaki, agent of Yamanouchi Pharmaceutical Co., Ltd. - Procedural proof (spontaneous) Commissioner of the Japan Patent Office Kazuo Wakasugi 1 Indication of case Patent application No. 14891i of 1982
No. 7 No. 2 Name of the invention: New method for producing pyrimidone derivatives 3. Relationship with the case of the person who made the hli correction Patent applicant's address: 21, 5-kuchi, 1', Nihonmachihonmachi, Chuo-ku, Tokyo.

4. Column 5, "Detailed Description of 1 Invention of the Specification Subject to Amendment" Contents of the Amendment (1) The following passage is inserted between the third line and the fourth line of page 16 of the specification.

[Example 2 0 50 m of ethanol in which 029 g of metallic sodium was dissolved
To l.

3-(5-(dimethyl7minomethyl)furfurylthio]
゛Stir at room temperature for 24 hours. After removing the generated sodium chloride, it is concentrated and the remaining residue is mixed with PCR form and methanol, which produces the desired product with a melting point of 150 to 155"C.
．． 9 g is obtained.

Mass, (”/, ) 350 (M”+1),
304 (M” 45) Anal, (C, 6H
2gN302SC]2 ・'/4 as H2O)C(
Shock H (%j NI'f4 S hook C1 (Tao = +1
'il i1 white 50.6.16,969,847.511
6.61 real Rou] value 50.56 7,14 9.9
0 7.31 16.81 J(2) On the same page, lines 4 to 6, "Examples 2 to 7 Example 1 . . . -1 was produced."

[Examples 3 to 9 Reaction operation similar to Example 1 or Example 2 e(,1: The following compounds were produced.] is corrected.

(3) Same negative 7th line, 17th Sada 1st line, 18th Sada 1st line
line.

"Example 2", "Example 3", "Example 41゜""Example5","Example6" in the 1st row of 19fA, the 1st row of 20th mouth, and the 1st row of 211jJ [Example 7].

"Example 3", "Example 4J, l-Example 5-" respectively.
1° “Example 6” and “Example 7” [Example 8-1 is closed.

(4) Insert the following verse between the third line and the second line from the 21st Sadakata.

[Example 9 Target compound 5n-butyl-2-(2-(5-(dimethylamino/methyl)furfurylthio]ethyl]-6-methyl-4(IH
)-pyrimidone dihydrochloride physicochemical properties m, p, +58-162'C Mash, (m/e) 364 (M++1),
318 (M” 45) A nal , (C1gH
31N302 S C12) C (9'=l H
□ N F4 S eel CI 1%)it)
1 i]1'i 52,29 7.
+6 9,63 7.35 +6.2
5 real 1l II direct 52,03 7.45
9,64 7.29 16.22 j and above ・Superior procedure ili official document (spontaneous) ri++1 1 Indication of case Patent application No. 1 of 1989 □189
ii No. 7 2. Title of the invention Novel pyrimidone derivative manufacturing method 3 Relationship with the case of the person making the amendment Patent applicant address 21-5-14 Nihon Yuhonmachi, Chuo-ku, Tokyo Subject of amendment (1) Patent claim Correct the range by 1 as shown in the attached sheet.

(2) The description in the specification is changed to crystal-1' +
Do E.

(Insert ``lower arginyl group'' after ``1 lower alkyl group'' in line 8 from the 4th line of the Book of Meiyo I.

(2) Side stop "1 to 4 pieces" in the second row of the fifth car to "11 to 5 pieces".

■ After the "tert-notyl group" in the seventh line of the same negative [.

n-pentyl group, impe/tyl group, neopentyl group, etc.
Insert 1.

θ) Insert the following verse between the 7th and 8th lines of the Emperor.

“Also, the lower fulginyl group is the ethynyl group.

2-propynyl group, l-propynyl group, 3-butynyl group, 2-futhynyl &+1' thynyl group, x-, I thyl-2-propynyl group, pentynyl group ring list ψ, et al. λ Example of row 1 of vm Insert the following verses at the end of section 9.

[Example IO Aim 1 Compound 2-(2-(5-(dimethyl7:/methyl)tuno1-norylthio]ethyl]-6-methyl-5-n-benzo-1(Ill)-pyriStone・2144 acid physicochemical properties rn,, p, +53-156'C Mass, , (m/e) 378 (M+-1-
1), 332 (M″-45) Anal, (C
2oH33N302SCI2)C (%)
H (To) N%l S (%i C1 pregnancy) Calculation value 5
3,33 7,38 9.33 712 1574 Actual value 53,28 7,56 9,38 7.2615
．． 57 J Example 11 Target compound 2-(2-1: 5-(dimethyl/minomethyl)-/rufurylthio]ethyl]-6-methyl-5-noIJ hynyl-4(IH)-pyrimidone Physical and chemical properties □, 9. 98~98.5"C Mass, (Sh.), 346 (M"+1),
300(M”-45) Anal, (cur(23
As 1”3o2s) C (possible H (g) N (g) S open t )9 Value 62,58
6.71 12.16 9.28 Actual 31H1
+'t 62,67 6.43
12.20 9.25 J or above Claim 1 General formula [wherein R1 is a hydrogen atom, a lower fluoro]-small group, a lower 7
1 quinyl group or the formula -CH2Ar (in the formula, r Ar is a hargt atom, a tert-butyl group or a mebre/
) Tsunyl group optionally substituted with an okino group, ■ Hari-phthyl group, (.

A new pyrimidone derivative or an acid thereof (2 means a hydrogen atom or a lower fluorine group) is substituted with a group represented by , (7min/g4 body shown by formula 2 or its acid f (no addition, cise).

General formula R2Co CHCOOR3 [wherein R1 is a hydrogen atom, a lower alkyl group, a lower arginyl group, or the formula -
CH2-Ar (wherein, Ar is a halogen atom.

a phenyl group optionally substituted with a tert-butyl group or a methylenedioxy group, or a naphthyl group, a pyridyl group, or a benzimidazolyl group) R2 is a hydrogen atom or a lower furkyl group BS is a lower means an alkyl group. A method for producing a novel pyrimidone derivative represented by the general formula or an acid addition salt thereof, which is characterized by reacting a pyrimidone derivative represented by the formula [hereinafter the same applies] with an acetic ester derivative represented by the following formula.

3 general formula (in the formula, R4 means a lower argyl group. The same applies hereinafter)
An imitate derivative represented by the general formula % [wherein R' is a hydrogen atom, a lower furkyl group, or a lower]'
ruquinyl group or formula -C1l, Ar (wherein, Ar
)・■ Nokunjiji, a phenyl group which may be substituted with a tert-butyl group or a methylenedioxy group,
Or naphthyl group.

pyrinol group or benzimidazolyl group) R2 is a hydrogen atom or a lower alkyl group R
5 means a lower fulgyl group. The same applies below] A general formula characterized by reacting with a 3-7 minoacryl acid derivative represented by

Claims (1)

[Claims] 1 General formula [wherein R1 is a hydrogen atom, lower alkyl-°CH2-]
Ar (wherein, Ar is /-rogen atom, tert-
] A group represented by a phenyl group which may be substituted with a methylenedioquine group, or a naphthyl group, a pyridyl group or a penzimidanolyl group.
R2 means a hydrogen atom or a lower alkyl group]-. Novel pyrimidone derivatives represented by the following formulas or amidine derivatives represented by the formula 2 or acid addition salts thereof [wherein R1 is a hydrogen atom, a lower alkyl group, or a formula -CH2]
-Ar (wherein, Ar means a phenyl group optionally substituted with a halogen atom, a tert-butyl group or a methylene dioxy group, or a naphthyl group, a pyridyl group or a benzimidazolyl group); R2 is a group represented by R3 represents a hydrogen atom or a lower alkyl group. 1. A method for producing a novel pyrimidone derivative represented by the general formula or an acid addition salt thereof, which comprises reacting the pyrimidone derivative with an aryl acetate derivative represented by [the same applies hereinafter]. 3. An imidate derivative represented by the general formula (in the formula, R4 means a lower alkyl group, the same applies hereinafter) and the general formula % formula % [wherein R1 is a hydrogen atom, a lower alkyl group, or the formula -CH
2-Ar (wherein, Ar is a 7% rogen atom, ter
a phenyl group optionally substituted with a t-butyl group or methylenedioxy group, or a naphthyl group, a pyridyl group, or a benzimidazolyl group)
R2 means a hydrogen atom or a lower alkyl group, and R5 means a lower alkyl group. The same applies hereinafter] A method for producing a novel pyrimidone visiting conductor represented by the general formula, characterized by reacting it with a 3-anoacrylic acid derivative represented by