JPS58110595A - Novel thiazolo(3,2-a)pyrimidines, their derivatives, their preparation, and immunoregulator containing said compound as active component - Google Patents

Abstract

NEW MATERIAL:The compound of formulaI[R<1> and R<2> are H, 1-10C alkyl, 2-10C alkenyl, (substituted) phenyl, (substituted) 3-8C alicyclic group, (substituted) phenylalkyl or (substituted) 2-7C acyl, provided that R<1> and R<2> are not H or 2-7C acyl at the same time; R<1> and R<2> may together with N atom form a 5-6-membered ring which may contain hetero atom]. EXAMPLE:6-p-Chloroanilino-5H-2,3,6,7-tetrahydro-5,7-dioxothiazolo-[3,2 -a]pyrimidine. USE:Immunoregulator. PROCESS:The objective compound can be prepared by (1) condensing and cyclizing the malonic acid derivative of formula II (R<4> and R<5> are 1-6C alkyl) with 2-aminothiazoline under heating or in the presence of an alkali metal alkoxide, (2) neutralizing the resultant enol alkali metal salt with an acid, and if necessary, (3) carrying out the addition reaction of the reaction product with an acid.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel thiazolo[λ2-a]py114dines and derivatives thereof, their preparation and their pharmaceutical uses. More specifically, novel cyanoro[λ2-a]bi-13i-dines having a substituted 7-mino group at the 6-position, enol derivatives thereof or acid addition salts thereof, as well as their production methods and their pharmaceutical uses, % regarding their use as immunomodulators.

Conventionally, cyanolopyrimidines include 6-molar or 6-di-substituted-λ turtle-7- which is obtained from z-7j nopyrimidine and the corresponding diethyl maprate.
Tetrahydro-5,fusioxo-5-thia/mouth [λ2
-a] Pyrimidine is known (Jrural o
f Arnerian Ch@m1calSocie
ty, vol, 64.194L paq8a 27
09-2712).

This document describes that the above-mentioned thiatropyrimidines have a hypnotic or anesthetic effect.

Further, JP-A-55-64591 claims a thiazolo(&2-,!L)pyrimidine derivative represented by the following formula.

Further, 1% Japanese Patent Publication No. 55-66592 claims a 7-flufoxythianoro[λto1]pyrimidine cod conductor represented by the following formula.

The above two publications are as follows: Chia/1ic3.
2-a) The pyrimidine derivative was tested in the delay layer Anrugy test @P
It has been disclosed that it has an immunostimulating effect, particularly an immunostimulating effect, as evaluated by the immunostimulatory effect.

The cyanoro[λ2-a]pyrimidine derivatives represented by the above two general formulas disclosed in the above two publications are novel cyanoro[λ2-a] of the present invention in that the substituent at the 6-position is a hydrocarbon group. It has a different molecular structure from pyrimidine or its enol derivative.

Moreover, the compound of the present invention having a 1-7 amino group at the 6-position has an immunomodulatory effect different from that of the above-mentioned known compounds having a hydrocarbon group at the 6-position.

That is, in general, the evaluation of immunomodulatory effects differs depending on the evaluation system, and even if the same compound is used in one evaluation system, the compound exhibits an immunostimulatory effect.

In other evaluation systems, it is often observed that the compound exhibits immunosuppressive effects. Therefore.

Needless to say, it is desirable to use more evaluation systems for evaluation in order to more accurately evaluate the immunomodulatory effects of the compound.

According to the research of the present inventor, it was disclosed in the above two publications. A compound with carbon and hydrogen at the 6th position is Plaque.
When evaluated by the Forming Cells (PFC) test, it was revealed that it exhibits an immunosuppressive effect rather than an immunostimulatory effect.

As will be explained in detail later, the compound of the present invention having a Kl-substituted amino group at the 6-position exhibits an immunostimulatory effect when evaluated by both the delayed potato allergy test and the PFC test, and in this respect, the above-mentioned known compounds have an immunostimulatory effect. The immunomodulatory effect is different from that of other compounds.

Therefore, one object of the present invention is to provide a novel group [λ2-a]pyrimine having a substituted amino group at the 6-position, an enol derivative thereof, or an acid addition salt thereof.

Another object of the present invention is to provide thia/
An object of the present invention is to provide novel thiazolo[λ2-a) pyrimidines, enol derivatives thereof, or acid addition salts thereof, which have an immune function different from that of (3,2-a) pyrimidine derivatives. Yet another object of the present invention is to exert immunoregulatory effects by promoting immunity. An object of the present invention is to provide an immunomodulator comprising the above-mentioned novel compound.

1 of the present invention! Another object of the invention is to provide a method for producing the above novel compounds.

1 of the present invention! Other objects and advantages will become apparent from the description below.

According to one aspect of the present invention, these objects and advantages of the present invention are obtained from 7 thiazolo(s,2-a)pyrimidis represented by the following general formula (I), their enol derivatives, and their acid addition salts. This is achieved by selected compounds.

The above q-C1 alkyl group may be either linear or branched, such as mer.

Ethyl, n-propyl + 1so-propyl, tl-
Butyl, i.O-butyl-tert-pukyl, n-pentyl, rhohexyl, n-octyl, n-nonyl, n
- Decyl, etc. can be mentioned. Among these, at
-Q alkyl group, particularly methyl, ethyl, propyl and butyl are preferred.

The above C, -C, alkenyl group may be linear or branched, such as allyl, 2-/
/butenyl 3-butenyl, 1-7,000-2-butenyl,
Examples include 3-hexenyl, 7-octenyl, geranyl, and the like. Among these, C, -C, and alkenyl groups, particularly allyl, are preferred.

The above-mentioned alicyclic group may be saturated or unsaturated, and examples thereof include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, and the like. Among these, C5-Q alicyclic groups are particularly preferred, such as pentyl and cyclohexyl.

Examples of the above-mentioned phenylalkyl include pendel, phenethyl, 7enylpropyl, and the like. Among these, kyphenyl (cl-C,) alkyl such as benzyl and α-7enethyl is preferred.

Examples of the above q-97 syl group include 7cetyl, propionyl, n-butyryl* 1so-butyl, n-valerylψ 1so-valeryl, caproyl, enantyl.
Examples include benzoyl. Among these, CI
"* aliphatic acyl group e.g. 7 cetyl, n-714
Preference is given to 1so-butyryl, caproyl or benzoyl.

+1 formed by the above R1 and R8 together with the nitrogen atom to which they are bonded! I! As the S~6-membered ring which may contain a hede atom.

Preferably, those further containing 1 to 2 nitrogen, oxygen or sulfur atoms can be mentioned.

Examples include pyrrolidyl, thiazolyl, piperi94morpholine, I-''peradyl, and the like.

Alicyclic group, phenylalkyl group and C,
The acyl group of -C, may be substituted.

These substituents and the substituents of the above-mentioned substituted phenyl group include 1, for example, halogen atoms such as fluorine, chlorine, and bromine:
Hydroxylic acid; Methyl, ethyl, ゛--propylene Amount 1C1 to C which may be substituted with a halogen atom such as O-propyl, n-butyl-trifluoromethyl, chloromethyl, etc.
4 alkyl group: methoxy-ethoxy, n-propoxy*
Cr-Q y alkoxy group optionally substituted with a halogen atom such as imo-propoxy, n-butoxy, triple ocmethoxy, clodimethoxy, etc.: nitrile group: carboxyl group: ethoxycarbonyl.

Preferred examples include (cl-Cs)alkoxycarbonyl groups such as ethoxycarbonyl, ethoxycarbonyl/hexyloxycarbonyl, and the like.

Thia/σ(&2
-a) The enol derivative of pyrimidines is preferably represented by the following general formula (1)-a or the following general formula (1)-b.

The alkali metal in the above formulas (1)-a and (I)-b is preferably, for example, sodium 17ium or potassium.

Thiazolo [λ2] represented by the above general formula (I) of the present invention
-8] The fused salts of pyrimidines or their enol derivatives include salts with inorganic acids, organic carboxylic acids, or organic sulfonic acids, especially salts with inorganic acids, especially salts with mineral acids. Preferred mineral acids include 1, for example hydrochloric acid,
Examples of organic carboxylic acids include hydrogen bromide, sulfuric acid, and phosphoric acid. Examples of organic carboxylic acids include vinegar and propionic acid.

蓚木, Kuen's beak, Mandel m, maleic acid, 7kelic acid,
Examples include lactic acid and glutamic acid.

Examples of organic sulfonic acids include methanesulfonic acid, ethanesulfonic acid, and benzenesulfonic acid.

p-) Luenesulfonic acid, cumylsulfonic acid, and the like.

Among these, salts with mineral acids such as +am and arIl are particularly preferred.

Acid addition salts of enol derivatives according to the present invention include those which react with an acid during their production and return to dioxo compounds of general formula +1), such as those of general formulas (I) -11 and (1) -b.
It should be understood that acid addition salts of enol derivatives in which Hs is an alkali metal are not included.

The compounds represented by the above general formula (I) provided by the present invention include 1, for example, the following thia/mouth [λ2-a
] Pyrimidines are mentioned.

(too) 5 H-λ into 7-tetrahydro 6-・
Methyl 7-dioxothiazolo(3,2-a)pyrimidine.

(1Gri 6-e5- to 7!/-5H-&&&?-?trahydro-5.7-thioxothiazo(&2-a) pyrimidine.

(104) @-n-hexyl 7mi/-5H-4 & d-
Tetrahydro-7-thioxothiazo a(λ2-a)pyrimidine.

(106) 6-allyl7/-5H-2,”A,
6.7-titrahydro-7-dioxothi7;/
a(,,12-a)
.

(1os) s -(3-hexanyl Z)) -sH-
&&a7-titrahydrokan7-sioquinthia/mouth [tortoise 2-a] pyrimidine.

(1to) 6-7 Nilino 5H-a&he7-thitrahydro 7-thioxothiazo w (34-a) pyrimidine.

(112) 6-P-coolanilino-5H-λkame (7
-Titrahydro & 7-Sioquinthiazolo [λ2-a]
Pirimidji/.

(!14) '6-0-Chloranilino-5H-λλ to 7-detrahydro-7-thioxothi7pro(&g-a
) Pill! gin.

('116) 6- m -fP a /reaeri/-
5R-L&a fuchitrahydrokan7-shiokisochi71
Mouth [&2-a) Pyrimidine.

(1111) 5 H-λ turtle 7-titrahydro R-
p-human σxyphenylamino\7-thioxothiazolo[λ2-1]pyrimidine.

(12G) S H-λ&hetutetrahydro-5,fusioxo-6-p-) lyylaminothiazolo[λ2-
a] Pyrimidine.

(lz2)s-p-)lifluoromethylphenylamino-5H-λKamehe7-titrahydro-7-shiokinch7noro[λ2-a] birimidine.

(124) 5 H-λλ to 7-detra and draw 6-
p-methoxyphenylamino-\7-sioquinthiazole [containing 2-a] Biri! gin.

(146) Is -p -) Rifurt lomethoxyphenyl 7! No 5H-Z&&? -tetrahydro-47-:
) oxothia/ri(&!-i)pyrimidine, (128) 6-p-Schiff/7znyl7mi/-5R-2
, Xa7-titrahydro47-:)oxothia/mouth(
3,2-a) Pyrimidine.

(13G) @ -P-carboxyphenylami/-5
R&&a7-Ttrahit a-! L7-dioxothiazolo[3,2-a) py11midine9 (132) s -p-ethoxycarponylphenyl 4nor 15H- & turtle 7-titrahydro 7-:) oxothyano σ (> t - * ') bi y mijin.

(134) s-cyclopentyl 7 minnow 5H-R & 7-titrahydro rod? -:) Oxothia In(3,2
-a) Pirimidi/.

(131B) @-cyclohexyl 7! No 6H-λ turtle to 7-titrahydro-5,γ-dioquinthia/mouth [\
2-a] pyrimidine.

(138) 6-benzylamine/-,5H-2L 3
．． 6.7-Tetrahydro-to-7-thioxothi7-containing 2-a]pyrimidine.

(140) 6-p-chlorpennru7mino-5T (
-2,3,6,)-tetrahydro-5,7-dioxothia/(3,2-a)pyrimidine.

(142) 5H-2,3,6,7-titrahydro S,
7-Jisukin-6-α-phenetyl typhoid 1 mouthful [λ2-a
] Pyrimidine.

(144) 6-7 Cetamide 5) I-2, 3, to 7
-tetrahydro-5, Fusioquintifunoro [λ2-a
] Bi11 Mijin.

(1411) 6- n-butyryl 7mi 7-5 H-2
, 16° 7-Chitrahydro Mr. 7-Shiokisochi 7/mouth [
λ2-a] Pi1 + Mijin.

(148) 6--h Broyl 7 i 7-5 H-Z
:L 6.7-tetrahydro to 7-2 occhinthia/
(3,2-a)pyrimidine.

(150) 6-bennyyl 7 minnow 5H-43,6,
7-Tetrahydro to 7-dioxothiazoo (a,
2-a) Pyrimidine.

(152) 6-p-chloroben/ylamino-5H
-7-titrahydro to λλ -5,7-dioxothia/
Mouth [Enter 2-a] Biri ξnnnn.

(160) 5 H-2, 7-titrahydro a-6 to λ
-Shimethyl 7 minnow 5.7-Shioxothi 7/fung (3,2
-a) Pyrimidine.

(O61) 6-dimethyl 7 minnow 5H-λλ to 7-titrahydro σ- to 7-dioxothia/mouth [λ 2-3 ]
Pili Mi Shinn.

(162) 5H-Zla7 f Trahito a-Kan 1
-diokiy-6-:)propylaminothia/mouth(3,z
-a) Pyrimidine.

(164) SH-Z&&? - To Tetra = Draw 6 - (N
-Methylanili/)-5,7-:)oxothyanoro(&
2-a) Pyrimidine.

(166) 6-(p-ri-q-N-methylanilino)-5H-&&a7-fto5human a-5,7-dioxothia/(&2-1)pyrimidine.

(16s) 6-(N-cyclohexyl-N-methylylamino)-s 7-tetrahydrogen to H-2,1.

Low to 7-dioxoa/mouth [λ2-a]pyrimidine.

(1)0)6-benzylmethylamino/-5H-2,λ7-te)lahydro5.7-thioxothi7no[λ2-
a] Pyrimidine.

(172) Fl-ben/ilme sheep 7 rareminor 5H-
43, ξ7-thitrahydro-hiki7-thioxothyanolo (
3,2-a) Pyrimidine.

(174) 6- (N-allyl amyrif) -5H-
λλ6,7-chitrahitrow5.7-shioxochi7no1
[龜2-a] Pirimin 2in.

(176) 6-(N-benzyl-N-phenylamino)-5H-λλ6.7-tet→hydro7-thioxothyanolo(3,2-a)pyrimidine.

(17B) 6- (N-bennoyl-N-phenylamino) -51 (-λ3,6 futetrahydro to 1-
Dioxothia/(&2-a) pyrimidine.

(180) 6-2cyclohexylamino-5H-λ3
, he7-tetrahydro-5, Fudioyasochi 710 (3
, 2-a) pyrimidine.

(182) 6-shihe7jiru7j/-5H-Z
&ft, ? -Tetrahydro to 7-dioxothia/mouth [3,2-a] Virimicin.

(184) 5 H-λλ6,7-detrahydro47
-Siokin-6-(l-bi-a-riji?shi) 1,000/mouth (3,
2-a) Pyrimidine.

(186) S H-S λ6.7-Chitrahi Draw 1
7-thioxo6-(3-thyanolyl)thyanolo(:&
z-a) Pyrimidine.

(188) 5 H-2,L &? -Tetrahuman,-
7% 7-dioxo-6-piveridilthia la (&2-a
] Pyrimidine.

(1110) 5H-21 & 6.7-titrahydro a −
8-Morphorif-5,7-dioxothia/mouth [Gourd 2-
a] Pyrimidine.

(192) 5H-λ&6,7-titrahydride! -Fudioxo-6-piperazinotyanoro[λ2-a]pyrimidine.

(193) 6-P-chloroanilino-sii-λ
λ6゜7-tetrahydro-5, Fusioquintifunoro C
l2-a) Pyrimidine salt acid salt (194) 6-p-chloroanilino-5H-43,
6゜7-tetrahydro-51fusioquinthia/aCλ
2-a] Pyrimidine sulfate (195) 6-7 Nilino S H-Z :L 6.7
-Tetrahydro5.7-dioquinthia 1 mouthful [λ2-a
) lJ of pyrimidine! MI Hanawaki Present Invention Chia/mouth [λ2] represented by the above general formula (I)
-a] Pyrimidines should be understood to also include tautomers based on the quinine group at the 5- or 7-position, that is, enol forms.

Examples of the enol rust conductor represented by the above formula (1)-a provided by the present invention include the following compounds.

(200) 5-H-λ3-dihydro 7-medoxy-6-dimethyl 7 minnow 5-size xoxochi 7 zoro [λ2-a
]Pyrimidine (202) 5 H-2,3-dihydry-7-medoxy5-oxo-6-di-n-propyla ξnotifzolo(3,2-a)pyrimidine (204) 4$ -7ni/-5H- 43-dihydro a
--7-MediliSea 5-Oxothia 1 sip (&2-a) Pyrimidine (20g) 6-p-Pol72')/-5H-! 3-
Dihydro-7-nodoxy-S-oxothiazo a (3
,2-a) Pyrimidine (20g) 1 mouthful of 5H-λ3-dihydro-7-methoxy-6-(N-methylanilino)-s-oxothia (
&2-a) Pyrimidine (21G) 5H-23-dihydro-7-medoxy 6-
(N-methyl-p-chloroanilino)-5-oxothia/(3,2-a)pyrimidine (212)? -n-ptoxy6- (N-n-butylanilino)-5H-zs-dihydro-5-oxothiac(&2-a)pyrimidine (214) 6-7 Ni/-7-n-butoxy-5H
-λ3-dihydro-5-okinthi7no[λto1]pyrimidine (216) 8-benzylamino-5H-13-dihydro-7-medoxy5-oxothia/mouth(&2-a)pyrimidine (218) s -(N -benzyl-N-methylamino)-5H-43-dihydro-7-medoxy 5-oxothia/mouth[λ2-a]pyrimidicine (22G) 6- (N-7lyl7nilino)-7-1 Toxi SH-λ3 -Dihydro 5-Okinchi 7 no Kuchi (:
L2-a) Pyrimidine (222) 6- (N-cyclohexyl-N-methyl 7!))-5R-43-dihydro-7-medoxy 5-
Oxothyanolo(3,2-a)pyrimidine (224) 6-(N-bennoyl-N-phenylamino)-5H-λ3-dihydro -7-medoxy5-oxothyanolo(&!-a)pyrimidine (22g) t -ethoxy-5H-λ3-dihydro5
-oxo-6-biperidylthi7no(&2-a)pyrimidine (23G) 7-7lyloxy-5H-2,3-9 human ty-5-oxo-6-di-0-propylcyano(1
2-a) Pyrimidine (232) s -(N-7lylanilino)-7-allyloxy-! 1H-2,3-dihydro-5-oxythia 1o (3,2-a)pyrimidine (234) 7-7
Lil T Kishi-6-72! j/-5H-λ3-dihydro b-5-ochinethiazolo(&2-a)pyrimidine (23g)? -7lyloxy-6-(N-Schif-hexyl-N-methyl74))-! iH-λ3-dihydro
-5-oxothiazolo[λ2-a]pyrimidine (23g)? -7lyloxy-6-(N-penyl-N-phenyl7!)) -5H-λ3-dihydro-5
-Oxothiazolo (&2-a) pyrimidine (240) 7-allyloxy-5H-λ3-dihydro 6-morpholino 5-oxothyano a (λ2-a) pyrimidine (242) 7-(3-hexyloxy) -s )I
-λ3-dihydro -1+-dimethylamino-5-oxothia/mouth (&2-a) pyrimidine (2so) 7-penzyloxy-6-diethylamino-5H-43-dihydro a-5-oxothia/mouth [&2-a) Pyrimidine (2sz) s -(N-allyl-N-phenyla5)
)-7-benzyloxy-5H-23-dihydro-5-
Oxothyanolo (&2-a) pyrimidine (251) l-benzyloxy-6-(N-cyclohexyl-N-methylamino) -5H-λ3-dihydro 5-oxothiazolo[λ2-a] pyrimidine (25 g) 6-7 7-penzyloxy-5H
-43-dihydro-5-oxothia/(&2-a)pyrimidine (260) 7-benzyloxy-6-(N-benzyl-N-phenylamino)-5H-λ3-dihydro -5
-Oxothyanolo[λ2-1]pyrimidine (262) 6-benzylamino-7-penzyloxy-5H-λ3-dihydro 5-oxothia/mouth[λ2-
&] Pyrimidine (264) 6- (N-penlyl-N-phenylamino)-7-benzyloxy-5H-λ3-dihydro 5-oxothia 1o(λ2-a) pyrimidine (266) 5 H-λ3-dihydro a-5-oxo-
7-α-7enethyloxy-6-pipe5') noti7/a
(λ2-a) pyrimidine (26'l) @ -(N-Schif-hexyl-N-methylamino)-5H-2,3-dihydro-7-hydroxy-5-oxothia/(l!-a) pyrimidine Sodium salt of (268) 5H-λ3-dihydro-7-hydroxy-5-oxo-6-di-n-propylaminothiazolo [
λ2-a] Sodium pyrimidine 1 (21H) 6- p-chloroanilino-5H-λ3-
Dihydro a-7-hydroxy-5-oxothyano [λ
2-a] Sodium salt of pyrimidine (2) o) y-7 Setoxy5 T (-2,3-dihydro-5-oxo-6-di-n-propylaminothiazolo C52-a) Pyrimidine (2) 2) 7-7 Setoxy 6-(N-7 Setoxy N
-methylamino)-5H-13-dihydrog-s-oxothia/[λ2-a]pyrimidine (274) 7-acedoxy6-(N-allyl-N-
phenylamino)-stt-λ3-dihydro a -5-oxothyanolo(3,2-a)pyrimidine (276) 'I-7 Setoxy6-(N-cyclohexyl-N-methylamino)-5H-23-dihydro-5
-Oxothyanolo(λ2-a)pyrimidine (27g) 7-7cetoxy6-(N-acetyl-N
-phenyl7mino)-5H-43-dihydro-5-oxothia/[λto1]pyrimidine (280) fu7setoxy5 jl-λ3-dihydro-6-(N-methylanilino)-5-oxothia/(
12-a) Pyrimidine (282) 7-7setoxy6-(N-benzyl-N
-Methylamino)-5H-L3-dihydro-5-oxothi7/(3,z-a)pyrimidine (284)'! Norcetoxy 5H-&3-dihydro-5-o xo-6-(3-thiazolyl)thyanoro(&
2-a) Pyrimidine (286)? -pen/yloxy-5H-λ3-dihydro-6-dimethylamino-5-oxothiazolo C&X
-a) Pyrimidine (288) 6- (N-allyl-N-phenylamino)-7-pen/yloxy-s 1t-2 to 3-dihydro-5-dexothia/Jλ2-a] birimylene (290) 7- pen/yloxy-6-(N-cycloto+sil-N-methylamino)-5H-λ3-dihydro-5-oyasothia/a (&2-'a) Piri
Machine (2sz) 7-Pen! Iloxy-5
H-43-dihydro-6-(N-methylanilino)-5
-Oxothyanolo[λ2-3]pyrimidine (294) 7-penzoyloxy-6-(N-benzyl-N-methylamine)-5H-λ3-dihydro5-
Oxothyano a[λ2-a]pyrimidine (296) 7-Pentyloxy-5H-su3-dihydro-5-okine-6-(l-pyrrolidyl)thiazolo(
&2-a]Pyrimidine (298) 7-cyclohexyloxy-5H-su3-dihydrocy-6-(N-methyl7nilino)-5-oxothyanolo(3,2-a)pyrimidine (29G) 6-7nilino 5H-43-Ninhydro 7-Hydoku°Shi 5-Oxothyanoro (&2-a)
Sodium salt of pyrimidine The above formula (
T) Examples of the enol derivative represented by -b include the following compounds.

(300) 5H-2,3-dihyde a-5-7+toxi-6-dimethylamino-7-oxocyanolo (IL2
-a) Pyrimidine (302) 6-7 Nilino 5 II-λ3-dihydro-5-methoxy-7-oxothia 1 mouth [λ2-a) Pyrimidine (3G4) 5 H-Z 3-dihydro-5-methoxy-6-( N-methyl7nilino)-1-oxocyanolo(
12-IL) pyrimidine (306) 5H-λ3-
Dihydro E7-5-methoxy-(N-methyl-p-ralanirif)-7-oxothyanolo(12-a) pyrimidine (aos) s-benzylamino-5H-λ3-dihydro 5-methoxyf-oxothyanolo+: 3.2 −
a) Pyrimidine (310) 5-7lyloxy-5H-λ3-dihydro-7-oxofi-1-n-pill/mouth [λ
2-a] Pyrimidine (312) 5-pendyloxy6-ethylamino-5H-λ3-dihyde I: I-7-oxothyanoro(3
,2-a) Pyrimidine (314) 6-7nilino-5-benzyloxy-5H
-2,3-dihydrocy -7-oxothia 1 mouthful [λ2-
a] Pyrimidine (316) 5-7 Cetoxy 6-(N-7 Cetyl-N
-methylamino)-5H-43-dihydro-7-oxothyanolo(3,2-a)pyrimidine (31 g) 5-7cetoxy5H-λ3-dihydro 6-(N-methylanilino)-7-oxothyanolo(
3,2-a) Pyrimidine (32G) 5-pentyloxy-5H-43-dihyFa -6-dimethylamino-fuoxothyanoro [
λ2-a]Pyrimidine (322) 5-benzoyloxy-5H-λ3-dihydro-6-(N-methylanilino)-7-oxothia 1
0(3,2-a)pyrimidine (324) 5-pen/yloxy-5H-43-dihydro-7-oxo-6-(l-pyrrolidyl)thyanolo(
3,2-A 1Pyrimidine According to the present invention, the above cyanoro[λ2-a]pyrimidine represented by the general formula (I) is a malonic acid derivative compounded by the following general formula (II). 2-7 minothiazoly/ and (a) subjected to a condensation cyclization reaction under heating, or (b) subjected to a KM-combination reaction in the presence of an alkali metal flukoxide, and then neutralized the alkali metal salt of the obtained enol with an acid. , and optionally by addition reaction of the reaction product obtained with an acid.

The definitions of R1 and D in the above formula (6) are the same as in formula (1).

R4 and are the same or different C, -C, l furkyl groups, for example methyl-ethyl on-propyl@
1so-propyl-n-butyl m 1so-butyl, f&-butyl-tert-glutyl on-pentyl, n
- Examples include hexyl.

Methyl, ethyl,
It is particularly preferred that R4 and Ftm are both methyl or ethyl.

As the malonic acid conductor represented by the above formula (D), for example, %N-methylaminomalonic acid, N-ethyl7! N-n-hexylaminomalonic acid, N-7
lyl-7minomalonic acid, N-3-hexylaξnomalonic acid, anilinomalonic acid,
- Chlor 7 nirifuma a7Rmm - chlor 7 nilinomalonic acid, p-human mixiphenylamitumaron*.

1)-) Ruyl 7mi/ma7ryo, p-trifluoro amethylphenylaminomalonic acid, p-methoxyphenylaminomalonic acid 07a, p-trifluoromethoxyphenylaminomalonic acid, p-cyanophenylaminomalonic acid, p- Ethoxy 7 enylaminomalonic acid, N-cyclopentyl 7
Minomalonic acid, N-cyclohexylaminomalonic acid.

N-benzyl 7-minomaric acid, N-p-chlorobensylamitumaronic acid @N-a-7enethyl 7-minomacunic acid, N-dimethylamitumaronic acid.

N-di-ethyl 7minomalonic acid, N-di-n-propylaminomalonic acid, N-methylanilinomalonomalic acid/p-
Chlor-N-methyl-7-nilinomanic acid, N-chlorhexyl-N-methyl-7-minomalonic acid #N-benzyl-N
-methylaminomalonic acid, N-allylaminomalonic acid,
N-benzyl-N-7enyl 7minomacuic acid, N-dicyclohexylamitumaron F? *N) Benzyl 7ξ tumaronic acid, 1-biarydylma a7 acid.

3-thiazolylmalonic acid, piperidylmalonic acid.

Di(
C+-s) furkyl esters, preferably dimethyl esters and diethyl esters.

Such a malon fR11 conductor (2) is made of a corresponding halogenated malonic acid diester, preferably a chlormalonic acid diester or a chlormalonic acid diester.
can be produced by heating and reacting them in an inert organic solvent such as benzene, toluene, or xylene, preferably in the presence of an excess amount of the 7ξone or tertiary amine. This manufacturing method is described, for example, in the Journal of
Organie Chemistry Vo120.1
454-1457 (1955).

As the other starting material, the following formula A 2-7 minothiazoline represented by is used.

The method of the present invention is carried out by subjecting the above malonic acid derivative (6) and 2-7 minothiazoline to a condensation cyclization reaction. The condensation cyclization reaction is an equimolar reaction of the Ma0/II conductor and 2-7 minothiazoline.

According to the method of the invention, preferably about 0.8 to 12 moles of 2-arole/tizoline can be used per mole of malonic acid derivative.

The condensation cyclization reaction can be carried out in row 5 (a) under heating and (
b) 7 It can also be carried out in the presence of alkali metal alkoxide. It is preferably carried out under heating. Alkali gold [if the reaction is carried out in the presence of flukoxide, m
Since the gold cyclization reaction product is obtained as an alkali metal salt, it is then necessary to neutralize it by spraying.

The condensation cyclization reaction carried out under heating is preferably carried out in the presence of an inert organic solvent. Preference is given to using aprotic inert organic solvents as inert organic solvents.

Examples of such inert organic solvents include toluene, xylene, cumene, cymene, and tetralin.

Decalin, diethylene glycol dimethyl ether, diethylene glycol diethyl ether.

Aprotic inert organic solvents such as diethylene glycol dibutyl ether, diphinyl ether, dimethyl sulfoxide, dimethyl formamide, nitrobenzene, or ethanol.

Examples include q-4 lower alcohols such as butanol.

Such an inert organic solvent may be used in an amount of about 1 to 1 to
It is preferably used at a concentration of about 50 times by weight, particularly about 2 to about 2 oIt weight.

Reaction temperature 1 Reaction time varies depending on the type of starting materials used, whether or not a solvent is used, and the type of solvent used. Normally 1 minute to 48 hours at 80 to 32 G'C, Special VC10o
It is preferably carried out at ~300°C for 10 minutes to 24 hours.

The reaction is often carried out under normal or elevated pressure.

When using a lower alcohol as a reaction solvent, ff
It is preferable to hold the ceremony under pressure in order to increase the warmth of the guests.

The reaction product produced by the condensation It 4F reaction according to the above procedure is expressed by the above formula (1).
8) It is a pyrimidine fist. Isolation and purification from this reaction mixture can be easily carried out by conventional methods such as recrystallization, chromatography, extraction and separation.

On the other hand, when the cyclization reaction is carried out in the presence of an alkali metal alkoxide as a catalyst, the reaction can be carried out at a relatively low temperature.

As the alkali metal alkoxide, lithium, sodium or potassium C1-6 flukoxide is preferably used. As such alkali gold m-flukoxide,
For example, Su+rum methoxide. Lithium ethoxide, lithium propoxide, sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, sodium butoxide.

Examples include sodium isobutoxide, sodium formula-butoxide, sodium t-butoxide, and the like. 4? Sodium methoxide, sodium ethoxide, etc. are preferably used.

Such alkali metal alkoxide is used in an amount of 1 to 10 mol, preferably 1 mol, per 1 mol of the commonly used malonic acid derivative.
It can be used in the range of ~2 moles.

When the condensation reaction is carried out in the presence of such an alkali metal alkoxide, the reaction solvent is c, -4 lower 7
Lecor is preferably used.

Examples of such lower alcohols include methanol,
Ethanol, propatool iisoprop. Examples of the reaction solvent include panol, getanol, insitanol, formula-butanol, t-butanol, etc. In addition, q-4 lower alcohols and other inert organic solvents (for example, the above-mentioned non-pketonic inert solvents) The reaction solvent, which can also be used as a mixture with ), is usually used in an amount of 1 to 50 times by weight, preferably 2 to 10 times by weight, based on the total amount of malonic acid derivative and 2-7 minothiazoline used.

Reaction time 1 The reaction temperature varies depending on the starting materials, the solvent used, the type of alkali metal alkoxide used, etc., but 1 reaction is usually carried out at 40° to 150°C for 30 minutes to 72 hours, more preferably at 60 to 120°C. The reaction, which is carried out for 1 hour to 10 hours, can be carried out under normal pressure to increased pressure.

The procedure for actually carrying out the reaction is to add an alkali metal such as sodium to the top of the above-mentioned lower alcohol to prepare a lower furfur solution of the alkali metal alkoxide.
Then, in this, the malonic acid derivative of the above formula (n) and 2-
It is preferred to carry out the condensation cyclization reaction by adding 7-minothiazoline.

The reaction product produced by the above-mentioned combination reaction using an alkali metal alkoxide is an alkali metal salt of an enol. This enol salt is then neutralized with an acid.
Give pyrimidines.

Such a neutralization reaction can be carried out by adding a predetermined amount of beak required for the neutralization reaction into the reaction mixture obtained by the condensation reaction, or by removing a predetermined amount of acid from the reaction mixture, for example, in water. You can also do this in addition.

As alcohol, there are a wide range of inorganic acids and organic sulfonic acids.

Organic carboxylic acids can be used. Preferably inorganic acids such as hydrochloric acid, hydrobromic acid and the like.

Organic carboxylic acids such as acetic acid are used.

The product thus obtained is isolated and purified by conventional means such as recrystallization, chromatography, extraction and separation.

The above formula (I) of the present invention obtained through the above condensation rationalization reaction
The thiazolo(3,2-a)pyrimidine represented by ) is then subjected to an addition reaction with an acid to give its acid addition salt.

The addition reaction can be carried out on isolated thiazo-[λ2-a]pyrimidines, but it can also be carried out in a heated reaction mixture containing other thiano[lambda]pyrimidines. Alternatively, it can also be carried out simultaneously with the above neutralization reaction.

1,71 units (&2 units) represented by the above general formula (r) of the present invention
-a) 1-Nol derivatives of pyrimidines can be produced according to the invention as follows.

That is, among the enol derivatives represented by the above general formulas (I)-a and (I)-, the general formula (D-Hatake or (I)-
1) In -b, W is q-1°alkyl.

The enol derivative is a q-8°fulkenyl group, a substituted or unsubstituted he-1 alicyclic group, or a substituted or unsubstituted phenylfurkyl group.

Thiazo cr(&2-8)pyrimidines represented by the following general formula (I) -'1,
It is the following general formula (m) R'-X... (m) or a substituted or unsubstituted 7enylfurkyl group.

It can be produced by reacting a halogen compound represented by the formula in a polar organic solvent in the presence of a basic compound, and then optionally reacting the resulting reaction product with an acid.

Thia la [λ2-
a] Pyrimidines are compounds included in the above general formula (I) IC (in the above formula (I), both 71 and R2 are groups other than hydrogen atoms).

Peng in the above formula (1) is a q-1° alkyl group* Q −
@@Flukenyl group base weight Substituted or unsubstituted ra 1 alicyclic group or substituted or unsubstituted phenylalkyl group, examples of these groups are the same as those exemplified in the above formula (I) I can give things away. Also, X
is a halogen atom, such as chlorine, bromine or oxygen.

Examples of the halogen compound represented by the above formula (E) include methyl chloride, methyl bromide, methyl alumide, ethyl bromide, ethyl oxide, n-propyl bromide, 1so-bupyl bromide, n-butyl bromide, Bromide-butyl-n-pentyl bromide-1so-pentyl bromide, Ohiherohexyl, n-decyl bromide, allyl bromide, 3-hexenyl chloride,
Cyclohexyl odorant/4-megylcyclohexyl bromide.

Benzyl chloride, benzyl bromide, benzyl acid.

Examples include p-chlorobenzyl bromide.

A hand represented by the above formula (I)'-1, Cλ2-a
] The pyrimidine and the halogen compound represented by the above formula (product) react in equimolar amounts stoichiometrically.

Usually, it is desirable to use about 1 to about 10 moles of halogen compound (e) per mole of cyanolo (!L2-a) pyrimidine. Unreacted halogen compound (6) is collected and reused after the reaction is completed. can do.

The reaction is carried out in the presence of a basic compound in an inert organic solvent.

Basic compounds include, for example, sodium hydride, sodium hydride: or alkali metals such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, calcium hydroxide, calcium carbonate, etc. Alkaline earth metal hydroxide monobicarbonate or carbonate: sodium methoxide,
Metal alkogides such as sodium ethoxide, potassium metomeside, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, potassium t-butoxide: trimethylamine, triethylamine-
Organic bases such as diethylamine, diimpropylamine, pyridyl, lutidine, collidine, imidanol, etc., especially sodium hydride, pyridine.

Triethylamine and the like are preferably used.

The basic compound is usually used in an amount of about 1 to 3' mol per mol of the pyrimidine used.

Preferably L1 to 2 moles are used.

Examples of inert organic solvents include methanol.

Protic or aprotic polar solvents such as ethanol, dimethyl sulfoxide, :) methylformamide, pyridine, methylene chloride, chloroform, benzene,
Toluene, xylene.

11:Protic solvents such as ether and tetrahydrofuran are preferably used.

Such an organic solvent is used in an amount of about 1 to about sol@ times, preferably about 2 to about 20 times by weight, based on the total amount of starting materials and basic compounds used.

The reaction temperature is usually about 10°C to about 100°C, preferably about 15°C.
The process is carried out at temperatures ranging from 0.degree. to about 50.degree.

The reaction is usually complete in about 1 to about 72 hours.

The reaction can be carried out under normal pressure to elevated pressure, but it is preferable to carry out the reaction under normal pressure.

Thus, by the above reaction, the following general formula (t)-"
t and/or an enol derivative represented by the following general formula (:) b+ is produced - the above formula (I) -1L+
and an enol-conductor mixture represented by the above formula (i)-b+.

The enol derivative thus obtained is recrystallized.

Chromatography e.g. column chromatography,
By methods such as extraction and separation, they are appropriately separated into a mixture or into individual components, and then isolated and purified.

The enol derivatives mentioned above can also be converted into their acid addition salts by methods similar to those already described above.

According to the present invention, furthermore, among the enol derivatives represented by the general formulas (I)-a and (I)-b, in the general formula (1)-a or (I)-b (. The enol derivative which is a substituted or unsubstituted C, +, 7 sil group is a thiazolo [λ2
- Steam] pyrimidine is combined with an acid halide or acid anhydride of a carboxylic acid represented by the following general formula (EV) R7 in the above general formula (IV) by reacting in an active organic solvent and then reacting the optionally obtained reaction product with an acid.
is substituted or unsubstituted q-.

It is an acyl group, and examples thereof include those exemplified in the above formula +1).

As the carboxylic acid represented by the above general formula (IT),
Vinegar 111. Propionic acid, butyric acid, 180-butyric acid.

N-valeric acid, imo-valeric acid, caproic acid, caprylic acid, benzoic acid, trifluoroacetic acid, p-coolbenzoic acid, etc. can be mentioned. That is, it is used as an acid-loginide such as an acid chloride, an acid bromide or an acid anhydride.

A thiazolo (a, z-s) biridine represented by the formula (I) 7t reacts with the above acid halide or anhydride in an equimolar amount in terms of scientific theory.
-a] It is desirable to use the pyrimidine in an amount of about 1 to about 3 mol, preferably about 1.1 to about 2 mol, per mol of the pyrimidine.

The reaction is carried out in an aprotic inert organic solvent, preferably in the presence of basic compounds.

Examples of the aprotic inert organic solvent include iii, hymethylene salt, lyoform, di〃σloethane, carbon tetrachloride, and dichlorobenzene. benzene.

Toluene, xylene, diethyl ether, tetrahydrofuran, dimethylformamide, dimethylacetamide and the like are preferably used.

As the basic compound, the same ones as mentioned above can be used.

The amounts of the aprotic inert organic solvent and the basic compound used can also be in the same proportions as described above.

The reaction is usually carried out at about 0 DEG to about 100 DEG C., preferably about 5 DEG to about 50 DEG C.The reaction is usually carried out at normal pressure.The reaction is usually completed in several minutes to about 12 hours.

Thus, according to the above reaction.

General formula (I)-9 below.

υ and/or lower fertilizer type (I)-b.

OR' An enol derivative represented by is produced.

The enol derivatives represented by the above formulas σ)-a and (1)'-bt are usually produced as a mixture.

The enol derivatives thus obtained can be isolated and purified as a mixture or individually, or modified into partial addition salts, by the same means as described above.

According to the present invention, the above-mentioned dinopre derivatives represented by (I) -ai and (I)-1 can be further combined with thial(&2-a) pyrimidines represented by the following general formula (I) -2. can also be produced by reacting a halogen compound represented by the above general formula (to) in a polar organic solvent in the presence of a basic compound, and then optionally reacting the obtained reaction product with an acid. I can do it.

The I-rogen compound, basic compound, polar solvent used in the above reaction, and the reaction conditions are shown in the general formula (■).
The method for producing the enol derivative represented by - and/or (I) -b can be exactly the same as in the above-mentioned method.

According to the above reaction, general formulas (I) -a and (■)-
It is also possible to produce corresponding enol derivatives in which R2 is a hydrogen atom.

That is, according to the above reaction, the following general formula % formula % and/or the following general formula (I)-b.

A thiazolo[λ2-a]pyrimidi/enol derivative or an acid addition salt thereof is produced.

According to the present invention, enol derivatives represented by the general formulas (■) and (1) are as follows.

Thia/cy(λ2-a
[1] When a pyrimidine is reacted with an acid halide or acid anhydride having a carton concentration of e and t (IV) in an aprotic inert organic solvent, preferably in the presence of a basic compound. It can also be produced by reacting the reaction product obtained by K with an acid.

The acid halide or acid anhydride, aprotic inert organic solvent, basic compound, and reaction conditions for the reaction used in the above reaction are general formula (1) -am and/or general formula (1) -bt. In the above-described method of producing the enol derivative represented, all (can be similar).

According to the above reaction, a compound in which R1 corresponds to a hydrogen atom in general formula (1)-a and/'' or general formula (I)
, in which V is substituted or unsubstituted.

Compounds corresponding to acyl groups can be prepared.

That is, according to the above reaction.

The following general formula (I) -z and/or the following general formula (I)-b.

And/or pyrimidines and/or enol derivatives represented by the following general formula (D-"t, thiazoloC&!-a) are produced.

According to the method of the present invention, the thiazolo[λ2-1]pyridine of the present invention represented by the general formula (I), its enol derivative, and its acid addition salt are produced by the above-described method.

According to the research of the present inventor, among the enol derivatives provided by the present invention, k expressed by the above general formula (1) -a
It has been shown that the compound can be further converted to its S-oxide. That is, according to the present invention, there is also provided an S-oxide of a dinolic derivative represented by the following general formula (V).

Examples of such S-oxides include the following compounds.

(40G) 5 H-&! 4-dihydro c1-7-71
Toxi-6-dimethylamino-5-oxothiazolo (&
2-a) Pyrimidine-1-oxide (402) 5H-λ3-dihydro7-medoxyb-okine-6-:) -n-propyl7! Nochi7 Zoro [λ2-Otori] Pyrimidine-1-oxide (404) 6-7 Nilino 5H-λ3-dihydro 4-7
-Methoxy5-oxothia/IJ2-a) Pyrimidine-1-Oyoshir (406) 6-P-R-R7Nilino5H-λ3-
Dihydrocy-7-medoxy5-oxothia/mouth(&
! -a) Pyrimidine-1-oxide (40 g) S H-su3-dihydro a -7-medoxy6-(N-methyl-p-chloroanilino)-5-oxothia/mouth [Tool 2-1] Pyridine-1 -Oxide (410) 6-7nilino7-t+-butoxy-5H
-λ3-:) Hido-5-okinthia,'/mouth [λ2-
a] Biriξdine-1-oxide (412) @ -(N-
7lylanilino)-1-allyloxy-5H-λ3-dihydro-5-ochinethiazolo(λ2-a)pyrimidine-
1-oxide (414)? -7ri and oxy-6-72! j/-5
H- & 3-:) Human a-5-oxo-thial [enter 1] pyrimidine-1-oxide (416) 6-7-7-7-pen') le*'t'/
-1n-&3-dihydro5-oyanthiano-[λto1]pyridξdine-1-oxide (418) t-benzyloxy-6-(N-benzyl-N-phenylamino)-5H-λ3-dihydro5-
oxothiazocap', &2-a) Birigin-1-Oquindo (42G) 7-7 Setoxy 6-(N-1 Cetyl-N
-Methylamino)-5H-λ3-dihydro-5-ochinethiazolo[&Hiroshi-a]pyrimidine-1-oxide (OX)? -acetoxy-6-(N-1 cetyl-N-
Phenylamino)-5H-23-dihydro-5-oxothia/Pyridξdine-1-oxyto(424)2pendiyloxy-5H-43-dihydro-6-dimethyl7minor 5-oxothia-/ ν(!L
2-a) Pyrimidine-1-oxide (4tg) 4-(N-allyl-N-phenylamino)-7-penyloxy-5H-2,3-dihyde a
-5-oxythiazop(λ2-1]pyrimidine-1-oxide(4!II)twopendiyloxy-5H-λ3-dihydro-5-okine-6-(1-biridyl)thiazolo(
tz-a) Pyrimidine-1-oxide (430) 5 H-43-dihydrodi-7-methoxy-
6-(N-methylanilino)-S-oxothia/mouth(&
! -a) Pyrididine-heavy-oxide The above S-oxide is produced by oxidizing the enol derivative represented by the above formula (1) -& with a preservative in an inert organic solvent. .

Examples of such oxidizing agents include peracids such as peracetic acid, peracid, perbenzoic acid, 0m-chloroperbenzoic acid, 1ao-butyl hydroperoxide, 5lIc-butylhydroperoxide, t-methyl hydroperoxide, and the like. Furkyl hydride peroxide: Sodium perchlorate A,
Too much! - Peracids such as sodium chlorate; imide compounds such as N-promolar helicyl imide and N-lyuk-succinimide; or hydrogen peroxide, etc. are preferably used. On the other hand, usually 1~Zoo
It is used in an equivalent amount, preferably α5 to 3 equivalents.

As the inert organic solvent, for example, acetic acid, methylene chloride, σa form, 1,2-dichloroethane, benzene-ethyl acetate, etc. are preferably used. Such a solvent is usually used in an amount of 1 to 100 times the volume of the raw material compound, preferably 2 to 100 times the volume of the raw material compound.
Used at 20 times the capacity.

The reaction temperature is preferably in the range of -78°C to 50°C, and -20°C
Particularly preferred is a temperature range of .degree. C. to 30.degree.

The reaction time varies depending on the reaction temperature of the raw material compound and the type of oxidizing agent, but is usually 30 minutes to 48 hours.

Separation and purification of the sulfoxide from the reaction mixture can be carried out by conventional methods, eg, color chromatography, recrystallization, and the like.

According to the research of the present inventors, 1. Thia la(:L2-a) pyrimidine compound represented by the above general formula (1) provided by the present invention, its enol derivatives and acid addition salts thereof, i.e., pharmaceutically acceptable Its acid addition salts can be used in delayed allergy tests and Plaqu porm1+tg
It was also shown to have an immunostimulatory effect in the cl\'1 crow test and was found to be a useful compound as an immunomodulator.

Therefore, according to the present invention, thiazolo[λ2-a]bilimidines represented by the above general formula (1) are provided.

A pharmaceutical composition is provided comprising a compound selected from enol derivatives thereof and pharmaceutically acceptable acid addition salts thereof as an active ingredient together with a pharmaceutically acceptable carrier.

According to the invention, the dosage of the active ingredient ranges from about 1 to 100 m
oat/kl weight/d+ay % preferably about 1~
It can be about 10 IIf/kf/day.

Although the active ingredients of the invention can be administered alone, they are conveniently administered as pharmaceutical compositions as described above or as medicaments in unit dosage form.

The active ingredients of the invention can be administered orally, non-E4u (eg intravenously, subcutaneously or intramuscularly) or rectally. Among these, it is advantageous to administer by mouth.

For oral administration, K is in solid or liquid formulations.

Such solid preparations include, for example, tablets.

Dosage forms such as pills, powders, jaw granules, and sugar coatings are included. Such solid preparations contain one or more active ingredients of the present invention, such as Tanakuma calcium.

It can be prepared by mixing intimately with a diluent such as potato starch, alginic acid, lactose, and optionally a lubricant such as magnesium stearate, and formulating it in a conventional manner. Liquid preparations include 1, such as emulsions, FA liquids,
Dosage forms such as suspensions, syrups, and elixirs are included.

Such liquid formulations include one or more active ingredients of the invention in intimate contact with a vehicle such as water or liquid paraffin, and optionally wetting agents, clouding agents, sweeteners, co-flavourings or preservatives. It can be prepared by mixing the mixture with the following and formulating it by a conventional method.

For rectal administration, whole steel is prepared by intimately mixing one or more of the active ingredients of the present invention with the carrier normally used in preparing whole steel.

K is a liquid preparation for intravenous, subcutaneous, or intramuscular administration. Such a liquid preparation contains a *1 agent S suspension or emulsion agent using a sterile aqueous or non-aqueous medium.

Examples of non-aqueous solvents include propylene glycol, polyethylene glycol, vegetable oil, olive oil, organic acid esters that can be used for injection, and the like.
Examples include ethyl oleate. These liquid preparations may also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersants, if necessary. Sterilization can be performed by filtration with a bacteria retention filter, addition of a sterilizing agent, or irradiation. Such a liquid preparation can also be prepared by preparing a sterile solid preparation and dissolving it in sterile water or a sterile injectable medium in a front electric key.

The active ingredients of the invention are administered to a warm-blooded animal in need, such as a human, to modulate the immune function of the warm-blooded animal.

For example, one active compound of the invention may be used for rheumatoid arthritis,
Systemic lupus erythematosus, scleroderma.

Diseases such as polyarteritis and dermatomyositis: Cancer: Infectious diseases; Primary or severe infectious diseases, steroid treatment, immunodeficiency associated with lymphoma, etc.; Steroids, anticancer drugs, immunosuppressants, etc. that reduce immunity Combination method when using drugs: Combination therapy with antibiotics to enhance antibacterial activity: Effective for 5 immune diseases associated with aging.

Hereinafter, the present invention will be explained with reference to Examples. Details are given below.

Example 1 (Synthesis of 11p-Cool Anilinomasin Kuma Diethyl
diethyl acetate (119
) Dry pyridine (tS-) was then added, and the mixture was stirred and heated to reflux overnight. After the phosphorus medium was distilled off under reduced pressure, the water was poured off, and after extraction twice with lya form, the ryo form layer was washed twice with water, dried over sodium balate, and the solvent was distilled off under reduced pressure. Obtained/
When the residue (134 g) was purified by silica gel column chromatography, 1.58 F of p-alaniliphmalonate was found in the benzene eluate (yield: 35%).
I got it.

The physical properties of this product were as follows.

CDCj.

NMR (J): 126 (6H, t, J=7
Hz).

M.S. 44g (4H, q, J=7Hz).

4'6~! LO (If you add 2 ru 1 ring O, it will become II)
.

&s3 (2H, d, J=9Hz).

7.113 (2 d, J=ilHz).

+21 6- p -I a k 7 Nili/-5H-
1117-tetrahydroku~kan1-dioxothia1゜(&
2-a,) Synthesis of pyridine Sodium metal (12039) was dissolved in absolute ethanol (3d
), to which was added a suspension of p-chlor 7 diethyl linomacunate (yooiy) in absolute ethanol (s d ), then a solution of 2-7 minothiazo'line (265 m9) in absolute ethanol (2 d), and stirred. The mixture was heated under reflux for 5 hours while stirring. Add water (S 0sl) and ether (3oSl)
After washing with d), add ICl1 acid to the aqueous layer to adjust the pH to 2. It was extracted twice with ethyl acetate (soRl), and the combined ethyl acetate layers were washed with saturated brine (50 iu), and then 5! dried with sodium chloride. When the solvent was distilled off under reduced pressure, 6-p-rialanilino-5H-2, Kamehe7-
Tetrahydrogen 7-cyoxothia/cy(&2-IL
7440 tq of I pyrimidine (yield: 61%) was obtained. The physical properties of this product were as follows.

Melting point (mp): 258-261℃ (enol type), ll’! 80° 1624, 1592. 1541 14110, 1433. 125? .

11'28. 826 + 437 (2H, t, J==11Hi).

a! i 8 (2H-d-J=9HsL&90(lH,
br, disappears at 010).

7.14 (2H, d-J=9Hs Ll 0, 3~I
LO (IH, br, disappears in QO, enol W).

Example 2 s-o-alanilino-5H-λ& to 7-tetrahydro to 7-dioquinthiazolo(12-alpyridζdine(
114) (1) Synthesis of diethyl O-chloroanilinomalonate O-chloroanilino (14IN) was mixed with dry toluene (2
od) and diethyl brommalonate (lλ0II
) was added, stirred and heated under reflux for 10 hours. The reaction solution was washed with diluted JJiffi, then washed three times with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography. When purified by graphy, 0-chloro-7-nilinomazif-adsorbed diethyl 5-1J was added to the benzene eluate.
I (yield: 36%) was obtained. The physical properties of this product were as follows.

CDCj.

NMRCa): 7Mg tzo (in, t, Jz8Hz).

417 (4H, qs J=7 Hz).

tsy (iH, d, J=7Hz)-14G(I
H, d, J = 7Hz).

eLs ~7.3 (4H, m) Synthesis of 7-dioxoty7no[λto1]pyrimidi/ to (211i-o-ralanili/-8R-2147-tetrahydro) Metallic sodium (0,28,9) Anhydrous ethanol (1
0114), to which Co-Cool 7 diethyl malonate (teal) and then 2-7R Noti 7 Zoline (1 oz #) were added and heated under reflux for 5 hours with stirring. Add water (say) and ethyl vinegar (30ml).

Next, add diluted salt to bring the pH to 4#. The precipitated solid was filtered, washed with water, and FIN crystallized with ethanol.
-o-Chloranilino 5H-λS to 7-tetrahydro 7-dioxothi7zoa(12-a)pyrimidine (
114>αe2# (yield: 31%) was obtained. The physical properties of this product were as follows.

Melting point (mp): t 47.0~2495℃KBr
-1@1K(ν)1.

m&x 5aso, 3100-2000 (!/-lell).

1@35,1591 15!16,1530.1400
゜13! Is, 1313.1257. Ti1lass(
*H, t, Jx7Hz) 440 (2H, to J=?HS).

5.57 (Disappears when IH, br, and DIO are added)
&3~7.4(4)1. m) Heavy a fi ~Z 10 (Z H-br -T)*O
t' addition t6 M loss) Example 3 5-m-chlor7nili/-5R-λ3.6.7-tetrahydro & 7-dioquinthyanoro [λ2-a) pyrimidine (***) 111 m-chlor7 Synthesis of diethyl nilinomalonate I-Chlor 7 niline (1118,9) and diethyl brommalonate (9,@II) in dry toluene<201d)
) lcflj, stirred for 3 hours, and heated under reflux. The reaction solution was washed with dilute hydrochloric acid, then washed with water three times, and diluted with 1lal.
! Dry with sodium.

The solvent was removed under reduced pressure. The resulting residue was washed with raw hexane to give rIll-ral7nirifumaronate diethyl λ.
3.9 (yield: 29%) was obtained.

The physical properties of this product were as follows.

Table 20 (4 ge, q, J = 7 tit).

44-47 (18 when adding !H, br, D, ρ) L2
-L,S (4H,m) (2) 7-tetrahydro to 6-m-chloroanilino-5R-λλ! 1.7-dioxothi 71 mouths [λ2-a]
Synthesis of pyrimidine Metal sodium (azsy) is mixed with anhydrous kool (1 oi
d), and therein was added diethyl m-chloroanilinomalonate (λ5sJl), followed by 2-7 minothialine (L
ORE) was added thereto, and the mixture was heated to reflux for 5 hours while stirring.

Add water (sollj) and ethyl acetate (30ml).

Next, dilute hydrochloric acid is added to adjust the pH to 4 Kff1K. The precipitated solid was filtered, washed with water, and then recrystallized with ethanol.
6-m-Chloranilino 5H-2λ6,7-tetrahydro-fudioxothia-/j(λ2-a]pyrimidine (1111) α76I (yield: 26%) was obtained.The physical properties of this product were as follows. Ta.

Melting point ("p): 26 East 0 ~ 271.0℃ 3300.31
50-2000 (!/-le Wi).

1635, 11t00.1530.1!515°112
5.1410.139g, j, 360°113S@, 7
FuO! ! ? (2H, t, J=yHz).

10 (28, t, J=7 Hz).

! L43 (disappears when IH, br, D, and O are added).

[7-7.1 (4H, rn).

1 (1s ~ 1'Lo (1f (disappears when adding +br, D, O)) Example 4 6-7 Nilinolll-5LI (7-tetrahydro-5
1 fusioxothi71a(3,2-a)pyrimidine(t
(1) Synthesis of diethyl 7nilinomalonate 7nilin (1&
Dissolve 6,9) in dry benzene (1λ5IM), add diethyl bromo70phosphate (219I), stir and heat under reflux for 37 hours. Wash the reaction solution with dilute hydrochloric acid to remove unreacted aniyne. The benzene layer was washed three times with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.The resulting residue was purified with silica gel 01 togelafy, and 7-nylinomalonic acid was found in the hexane-ethyl acetate (10:1) eluate. Diethyl?, 51i (yield: 30%) was obtained.The physical properties of this product were as follows.

NMR (J””’): M.S. i, 20 (aH, L J = 7Hz).

420 (4H, q, J=7F(z).

4L66 (2 turtles a, br, D, O make 1) 1)
.

& 5”-7,3(5H-rn) *(2) 6-
7 Nilino 5 H-2, 7-tetrahydro to λ -! l
, r-dioquinthia/synthetic sodium metal (asoy) of biridine was dissolved in anhydrous ethanol (30 m
) and diethyl anilinomalonate (175
g) in absolute ethanol (151117) 1 and 2
-Add 7 minochi 7 zolin (tszy) and while stirring? When the upstream reaction solution was heated for 5 hours and allowed to cool, a solid precipitated, which was separated by P (&ri) aP separated solid (
L! Of) was dissolved in water and PH4IIlled with acetic acid,
A solid is precipitated. Separate this from P, wash it with water and dry it.6-
7 Nilino 5H-λ3. He7-tetrahydro! 1.7
- Shiokisochi 7zoo [$2-a) Pirimidi 7Q, 26.
9 (yield: 24%) was obtained. The physical properties of this product are as follows.

Melting point (mp) lzao ~22&O℃ KBr -1m IR (ν)1 ・m&X 3020.1680.1600.1390°1340.
1300.1258,1122C4 NMR (J) ppm: M8 i60 (!H,t, J=7Hz).

tsy(zH, to J=rHz)a 6, 4-7.5 (6H, m, IH disappears at D!0).

1 ao ~ 115 (disappeared with I H, br, D, O,
! / -le type).

Example 5 To 6-pendylamino-5H-@l to 7-tetrahydro 7-thioxothi7zoloC&2-a) Pyrimidine (13
Synthesis of benzylamine (1&3I?) and diethyl benzylaminomalonate (1%)
203JF) in dry benzene (100m),
The platform precipitated from the 0 reaction solution stirred and heated under reflux for 14 hours was
The solution F was washed with dilute hydrochloric acid to remove unreacted benzylamine. This benzene layer was washed three times with water, dried over magnesila sulfate, and the WI medium was distilled off under reduced pressure. The resulting residue was purified by silica gel chromatography to obtain diethyl benzylaminomalonate 477' (yield: 21%) in the hexane-ethyl acetate (4:1) eluate. The physical properties of this product were as follows.

142 (ISH, t, J=7Hz).

′ λ20C2H,s).

410 (4B, q, J='lH*).

Table γO(2He-so br-1) When 10 is added, 1■).

7.25-7.5 (51H* n1L (216-benzylamino-5H-λλ to 7-tetrahydro-7-dioxothia/[3,2-a) Synthesis of pyrimidine metal sodium (046,9), benzyl The same operation as in Example (110)-(2) was carried out using diethyl aminomalonate (zss-jl), 2-7 minocyanomeline (IO2,9), and anhydrous ethanol (20m), and the residue was obtained in 9! was subjected to silica gel chromatography,
From the methylene chloride-methanol (**:t) elution part, 6-
benzylamino-5-H-2, λ to 7-tetrahydro-7-dioxo-7/[kato 1] pyrimidine o, a
g (yield: 29%) was obtained.

The physical properties of this product were as follows.

Melting point (mp): 1S60~19&O℃ KBr-s.

IR(ν)1・la x 3200~2000(!/-MJ), 1! (10°15
90.1375.1240.1120°07G CCt.

NMR(a>pprn: M.S. 130 (2H, to Jx7Hz).

423 (2H, t, J=7 Hz).

42! (2H, l).

7, 1-7.5 (SH, m, when DlO is added, sH
K)1αo ~ILs (Disappears when IH*bre0.0 is added.

Enol type) Example 6 +1) Synthesis of diethyl N-methylanilinomalonate N
- Methylaniline (1alg), diethyl brommalonate (la (Jg)) and dry benzene (90ml) were mixed and stirred and heated under reflux for 16 hours. Washed in the same manner as in Example 2 (1).

Drying and concentration were performed. When the residual liquid was purified by silica gel column chromatography, benzene-hexane (2:l)
Diethyl N-methylanilinomalonate 1o, 2 in the elution area
JP (yield: 54%) was obtained. The physical properties of this product were as follows.

143 (@H, to J=7H to) λ02(SH,s).

L2 G (4H, q, J=7Hz).

! L03(IH,s).

& @ ~ 7.45 (5H, m).

1215H-λλ6.7-titrahydro6-(N-methyl7nilino)-gourd 7-dioquinthiazolo [λ2-1]
Synthesis of pyrimidine diethyl N-methylanilinomalonate (1,581) and 2-7 minothianoline (ays, 9)
and diphenyl ether (2d), heated and stirred at 175°C under a nitrogen atmosphere, and reacted for 1.5 hours. The reaction mixture was subjected to silica gel chromatography, and the #i methylene-methanol (19:1) eluate was obtained. From 5H-2
, λ to 1-tetrahydro-6-(N-mekyl 7 di-alternate/
)-5,7-dioxothia/cy[&2-a) pyrimidine α4311 (yield: 27%) was obtained.

The physical properties of this product were as follows.

-Melting point (mp): 10Q, 0-102. Or・
KBr −1@IR(ν)儂.

m&X 3700~200G (enol), 11i35°160
2.1505.1400 DC4 NMR (J) ppm: M8 103 (3H, easy).

135 (2H, t, J=7Hz).

:IO(21(, t, J=1Hz).

6L4 S~7.1 (5H, rn).

1α0~115 (Disappears when I H, br, D, and O are added.

enol type).

Synthesis of Example 7 to Synthesis of p-chloro-N-methyl7nylinomalonate diethyl p-ri1N-methylaniline (10,111) to/romomalonate diethyl (as,p) and dry benzene (60Ml) The mixture was stirred and heated to reflux for 7 hours. Washing, drying, and concentration were performed in the same manner as in Example 2 (1). The obtained residue was subjected to silica glucidography.

From the benzene-hexane (1:1) eluate.

p-chloro-N-methyl 7-diethyl malonate 15
g (Yield: 33%) was obtained. The physical properties of this product are as follows.

L30 (@H, ta J=7Hz).

λoO(3H,s).

42 B (4H, q, J = 7Hx).

tos(*H,5)e t72 (2H, d, J-9) 1z).

711 (2H, d, J=9 Hz).

+216-(p-ral-N-methylaniline)-5H
-2,:Synthesis of Li2-tetrahydro a-7-dioxothyanolo(3,2-a)pyrimidine p-chloro-N-methylanilinomalon-diethyl (λ
40j), 2-7 minothiazoli 7 ((L981I), Schiffeni/L, and ether (5m) were mixed, stirred under an atmosphere of *subson, heated with tsO'CK, and reacted for 2 hours.

The residue was washed with conditioned methylene chloride and @-(p-chloro-N-
methylanilino)-5H-λλ to 7-tetrahydrocyano1-dioxothyano[λ2-a]pyrimidi7al#J
F (yield: s@%) was obtained.

The physical properties of this product are as follows.

Melting point (mp) 121o ~ 230.5℃ 3700 ~ 20
0G (enol), 1620°160G, 1525
．． 1497. 1405°1360.1250.13
20 to3 (sH, 5) 153 (2H, to J=7Hz).

4! ? (2H, t, J=7Hz).

Li0 (2H, d, J=9Hz).

t, os (2H, d, J=9Hz).

1αO~IL5(eye(,br,D!Disappears when adding O.

Enol W).

Example 8 Bisnor-5H-λ3-dihydro-7-medoxy-5-oxothiazolo[λ2-a]pyrimidine Sodium hydride (02g) was suspended in anhydrous dimethylformamide (10Ml), and anhydrous dimethylformamide (7ξ) was suspended in anhydrous dimethylformamide (10Ml). 5117
) K#-resolved 6-7 nilinosH-λλ yield 7-titrahya-5,7-thioxothi7zoa(zz-a)pyrimidine (L7J7) was added, then Nikka methyl CILOI
) and stirred at room temperature for 8 hours. The AS medium was removed by concentration under reduced pressure, and the residue was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate.

The solvent was distilled off. The residue was subjected to silica gel chromatography and gelatinized with alcohol-methanol (20:'0-1).
), and from the low polarity fraction SH-λ3-dihydra
-7-Medoxy6-(N-methyl7nilino)-5-oxothiazoo(3,2'-a)pyrimidine (2(11!
l) a! eII (yield: 1s%) and the highly polar fraction I) 6-7 nilino + 1H-λ3-dihyFlow 1-methoxy-5-oxothiazolo(&2-a)pyridzdiy(z
oa)aiaII (yield: 10%) was obtained. The physical property values of these materials are as follows.

5H-λ1-dihydro a-7-medoxy 6-(N-methylanilino)-5-oxothia/g(λ2-a] bili S
Physical properties of gin: Melting point (mp): 23415-23
7.0℃16S8.1580.1520.1503,1
41'18゜1m95.1360.1345.1238
．． 1125゜ra.

xxs(sH,s).

14 B (2H, to J=7Hz).

190 (3H, a).

150 (!H, t, J=7Hz)e6@~7.5(
Physical properties of pyrimidine: KBr -1°IR (ν)01°a x 1ssc 1595, 1525.14117,1411
0°1393.1345,1320,1268,114
L963, 742 144 (2B, t, J=7Hz) * λ93 (3H, s).

445 (2H, t, J=7Hj).

翫3 (disappears when adding eye 1 e b r -s + 5o).

as~y,5(sH,m) Example - 5H-13-dihydro-7-medoxy6-(N-methyl-p-chloroanilino)-S- and 6-p-lylanilino-sH-λ3-dihyde a-7-Medoxy 5
-Synthesis of xisothi7zo-(x*-a)pyrimidine (gos) 4i-(p-chloroanilino) obtained in Actual Example 4
-5)i-L&&? -Tetrahuman σ- -Sodium salt of 7-dioxothy7zoa (λ2-a) pyrimidine (3somP) was dissolved in anhydrous dimethylformamide)'s-, then methyl iodide (1aj) was added, and the solution was dissolved at room temperature for 1
After the completion of the 0 reaction which was stirred for 2 hours, the same post-treatment as in Example 8 (ml)
performed the operation. The residue was subjected to thin layer chromatography,
Developed with methylene chloride-methanol (IS: t),
From the fraction with Rf value α47, 5H-λ3-dihydro a-,'
l-Methoxy-6-(N-methyl-p-chloro7nilino)-5-oxothia1cICL2-a) Pyrimidine (2
10), 6-p-Rialanilino-5H-λ3-dihydro was obtained from the fractions of 85K (yield: 23%) and Rfiiα4.
-7-Medoxy 5-oxothiazolo[λ2-a]pyrimidine (zos) 25TI9 (jtslE near %) was obtained. The physical property values of these materials are as follows.

5H-λ3-dihydrono\-7-medoxy6-(N-methyl-p-chloroanilino)-5-okinthi7:/E
l (&2-a) Physical properties of pyrimidine fli: Melting point (mp): 16 翫 5-161 LIS ℃ 16418,
158G, 1523.1498.1460°1400
, 1350.123R, 1120, 8203 LOT (3
H, l).

14m (2H, to J=7Hz).

5ss(sH,s).

443 (2H, t, J=7HS).

6.75-7.3 (4H, m) 4G-p-chloroanilino-5R-λ3-dihyde c1-
Physical properties of 7-medoxy 5-oxothiazo a(&!-a) pyrimidine: Melting point (mp): 1840-18 Yield 5°C 1640, 1511 (1,1495,1448,116
0° 145.13! 0.1260.1! Go, 11
411°91SL811 CDC4 NMR (J) I) pHl: 7M8 145 (2H,t, J=7Hz).

111B (3H, s).

tns(zH, t, J=-7Hz).

&35 (disappears by adding 〇 to eye (e - m)).

&4S ~7.3 (4H, r+s) Example 10 Sodium hydride (as77F) is suspended in anhydrous dimethylformamide (z Od ), and obtained in Example 4 where it is dissolved in anhydrous dimethylformamide (S-) 6
-7 Nilino 5H-λλ to 7-tetrahydro-7-thioxoty7-(a,z-a)pyrimidine (t s o
Add I).

Next, n-butyl bromide was added and stirred for 8 hours at is~zo''c.After the reaction was completed, the same post-treatment operation as in Example 8 was performed.The residue was subjected to silica gel chromatography and diluted with methylene chloride-hexane. (1:1~O), and from the low polarity fraction, 6-7-n-butoxy-6-(N-a-butylanilino)-5R-λ3-dihyde a-5-oxothiazolo(&2-a) Pyrimidine (212) αO I (yield: 4%) From the highly polar fraction, 6-7nilino7-n-butoxy-5H-λ3-dihVgy-6-okituchi7
zo*(12-a), pyrimidine (214) 0.7@, 9
(yield: 42%). The physical property values of these materials are as follows.

7-n-butoxy-8-(N-n-butylanidiVz)
-! ! H-λ3-dihydro 5-year-old Kinch 7-(&!
-a) Physical properties of pyrimidine: 1-1 points (fflP):
Heavy 1 ta LO ~ 1'211 ℃KBr -4・IR()z.

a x 11850, 1577, 151 3. 1418.
11111゜1338, 1240. 753 14 g (4H, t, J=tHz).

42G (2H, t, J=7Hz).

448 (!H, t, Jz7Hz).

a@~! 0(14)I#　　m).

IL43~D: 4 (5H, m).

6-anirif'l-n-butoxy-5H-43-dihyF
Physical properties of rho-5-oxothiazolo (>z-a) pyrimidine: @4 (mp): *t, o ~ sas°C 164G, 1590.1500.146G, 1390°18! S, 1260.1148 01-L9 (? H, m).

λ41 (2H, t, J=8kls)
tH, t, J=THz).

*3 (tH, t, Jz8Hz).

! L$8 (jH, m, D, Ot and Elt disappear).

6.8-7.5 (5H, m') @ Example 11 Sodium hydride (0,1271') was converted into anhydrous dimethylformamide (SOSD) K! ! 7-tetrahydro to 6-anili/-5H-λλ was dissolved in anhydrous dimethylformamide (5 m).
-dioxothia 1a (3,2-a) pyrimidi 7 (as
! Add F), then add allyl bromide (away),
After the completion of the 0 reaction, which was stirred at 1 s to 20°C for 30 hours, the actual Nl
The same post-treatment procedure as for Nll8 was performed.The residue was subjected to silica gel thin layer chromatography, developed with methylene chloride-methanol (19:1), and 5-(
N-7lylanilino)-7-allyloxy-sH-λ3
-dihydro-5-oxothiazolo[12-a]pyrimidine (232) 0.159 (yield: 25%) and 7-allyloxy-6-7nilino 5H-λ
3-dihydro-5-oxothyanolo(3,2-a)pyrimidine (234) 0.07.9 (Yield: l1%)
I got it. The physical properties of these materials are as follows.

6-(N-7lylanilino)-7-7lyloxy-SR
Physical properties of -λ3-dihydro-5-okintianok (12-a) pyrimidine: Melting point (mp), 'la 40
~t s s, o ℃ KBr l.

IR()m.

a x 1g50.1578.1515.150G, 1392
゜1335, 1298.1227.1143.755D
C4 NMR (J) ppm: M8 14G (2H,t, J=7Hz).

406 (21H0da J=4Hz)-L40(2
H, t, J = 7Hz).

47G (2H, d, J=4Hz).

473~5.50 (4H, m) # &5~7.3 s (s H, m).

7-7 Lylox-6-7 Nilino 5tt-λ3-dihydro 5-oxothyanoro(&nee a) pyrimidine Melting point (rnp): 1210-12 Table 5℃ 1655, 15
95.1515.1498.1398°1335, 1
320. 1260. 1140140 (2H, to
J=g8Hz)eshi43(2H,t, J=x8H
z).

L@S (2H, d, J=Si(z LLO~16
(3H, m, L) Adding 10 gives 2H).

165~&5(IH,m)e 6.6~7.4(liH,m) By the above reaction, FiaKs-(N-ylylanilino)-5H-Zλ6,7-tetrahydro-7-dioxothyanolo[λ2- &] Pyridξdine (174) was also obtained. The physical properties of this product were as follows.

Melting point (mp): 1G8.5-112LO℃KBr -
1.IR(ν)α.

1 x 3100-2000 (enol), 1640. 160
15G3.1402.1240.1225.1022
141(IH, t, J=Flr(z).

41 g (2H, d, J=7 Hz) -4,4
0 (2H, t, J=8Hz).

! LO~ILI(2T(,m).

! L7-6.4 (IH, m).

6.6-7.9 (SH, m).

10.5-1λO (disappears when I H, br, D, and O are added.

enol type).

Example-12, Sodium xy-5H-λ3-dihydro-5-oxothiahydride (0,281i) was suspended in anhydrous dimethylformamide (20m/), and: K11l water dimethylformamide (xod) 6-7 nilinosH-λλa7-titrahydro7 obtained in K-dissolved real example 4
-dioxothi7zocy(L2-a)pyrimidine(λ5o
y) was added, followed by the addition of ichpenzyl salt (248 g), and the reaction was stirred at 15-20° C. for 8 hours. After completion of the reaction, the same post-treatment operation as in Example 8 was carried out. The residue was subjected to silica gel chromatography and purified with methylene chloride/methylene chloride (
Is: 0 to 1), and 7-benzyloxy-6-(N-benzyl-N-phenylamino) was extracted from the low polar fraction.
-5H-λ3-dihydro-5-oxothiazocy(12
-a) From pyrimidine (260) α32I (yield: 8%) and the highly polar fraction, 6-7nilino-7-penzyloxy-5H-2h3-dihydro-5-oxothiazolo
a) 94 g (yield: 28%) of pyrimidine (258) α was obtained. The physical property values of these materials are as follows.

7-benzyloxy-r,-(N-benzyl-N-phenylamino)-5H-13-dihydro a-S-saikinch 7
Physical properties of Noguchi [λ2-a) pyrimidine: Melting point (mp): 154LO ~ IFi5 at 1 sao
0. tssa, 1518.1500.1392゜1
355, 122g, 1143.758130 (2H,
t, J==7.5Hz).

435 (!H, t, J=7.5Hz).

cys(2H,s).

翫29 (2H, 飄).

&45~7.6(15H-mL 6-7nilino7-penzyloxy-5H-λ3-dihydro 5-year-old xoti7-[λ2-a]pyrimidine physical properties: Melting point (mp): 6α0~16LO℃1g40 .1
603. 1585. 1505. 144G.

1392, 1345. 1265. 115013g
(2H, t, J=8Hz).

Peep 4G (2L t, J=8Hz).

Rod 4 (3H, m, 2H if you add DID).

457-7.5 (10H, rn) Example 13 6-7 Nilino 5R-2 to λ to 7-tetrahydro 7
- Sodium enolide of dioquine thiazo a(kame 2-a) pyrimidine (a97,9) was dissolved in anhydrous NN-dimethylformamide (200%, and truncated methyl
Add toe). The mixture was stirred and reacted at 15° C. for 22 hours. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and the salt ichmethylene-methanol (
2o: eluted at t~2), SH-λ3-dihydra
-5-methoxy-6-(N-methylanilino)-fuokinthiazolo(xz-a)pyrimidine 0.32 Jl
(Yield: 13%) was obtained. The physical properties of this product are as follows.

Melting point (mp): 12 Table 0-127.5℃ KBr -1
・IR(ν) ・nam! 1G40.1800.1555.1505.1325°125G, 753 DC1s NMR (J) ppm: MS 113 (SR, 1).

133 (2H, t, J=sHz).

gLts(3H,a).

47 (!H, to J=8Hz).

t S ”-7,2 (5H@Ill) @Example 1
4 6-7 Nilino 5H-1 & a7-te) Unido ex-5
，? -dioki7,700 la (&2-a) pyrimidine (2,50,9) with sodium hydride (a28f
) of anhydrous N,N-dimethylformamide (20 Ml 3
Add to suspension.

Furthermore, benzyl chloride (jL48 #) was added to this, and 20
The mixture was stirred and reacted at ℃ for 14 hours. The solvent was distilled off under reduced pressure,
The residue was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and then condensed. The residue was subjected to silica gel coomadography and eluted with methylene chloride to give 6-7nilino-5-benzyloxy-8H-13-dihydro-7-
oxinthiazo a1λ2-a]pyrimidine o, 30.9(
Yield: 9%) was obtained. The physical properties of this product are as follows.

Melting point ('mp)Nio9B-4005℃ IR (yKB')m-': max 1@! 3. 154G, 1470.1447.1425
゜13!0. 1213.1240. 766, 71
5120 (tH, to Jz7Hz).

LSN(2H* to J”7Hg)*40G(!
H, I).

tL4~? , +(118-m)e Example 1s 6-7nilino5H-λ&he1-tetrahyto-5,7-dioquinthiazo o(L!-a)pyrimidy(toII) obtained in Example 4 and acetic anhydride ((147N), triethyl 7I (o, s s 11) and methylene chloride (
50 m/ ) and stirred at 1 s to 20°C for 8 hours. The reaction solution was washed with saturated hydrogenated water*1, then water (3 times), dried over anhydrous sodium sulfate, the S medium was distilled off, and the residue was It was subjected to silica gel column chromatography and eluted with methylene chloride-methanol (ZS: O~1), and 7-7 setoxy@-(N-7 cetyl-N-phenylaminotide-5H-
43-dihydroc-5-oxothiazolo[λto1]pyrimidine 6to, 9 (yield: 8%) was obtained. The physical properties of this product are as follows.

1793.1665.1600,1530.凰39S.

1345.1320.1180.1001008Nδc
oc4TMS) ppr'': ILO@(3H,I).

! 2G (3H, 1).

152 (2H, ta J+ = 7Hz).

4go(zH,t,J=7H1).

Synthesis of 7.4(SR,br*I)@Example 16 6-aniso/-SH-2,16,7-f) to 7-dioxoty7no[λ2-a]pyrimidine (L@7# ) to methylene chloride (zoiu) VCF! ! The mixture is made cloudy and triethylamine (1,52, IF) is added thereto. After adding benzoyl chloride (>5 sl) to #4e and stirring at 10 to 20°C for 1 s to carry out decontamination, the reaction solution was washed with dilute hydrochloric acid and then with saturated sodium bicarbonate solution.

Washed three times with water. This methylene chloride solution was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography and diluted with methylene chloride (49:1) #! 6-(N-pen/yl7nilino)-S-HL&a7-f)5hi)' at the exit part
a −'j47-dioxoti7noIf[λ2-a]
Pyrimidine/1sel (yield: 51%) was obtained. The physical properties of this product are as follows.

Melting point (mp): 1G 0.0~101G℃37
00-2050 (enol), 1758. 1g5
s.

t1160. 1600. 1530. 1498.
339L1342, 1243. 1100°150 (2H, to J=7Hz).

4.50 (28, t, J==7Hz).

7, 1-7.8 (8H, rn).

7.9~&3 (2H, rn).

10.5~l to (disappears when br, D, and O are added to 1.

enol type).

Example 17 s-(N-cyclohexy5r-N-methylaζ)-IH
-λ3-Dihydroc-7-hydroxy-S-oxothi7zo[Turtle 2-a] Pyrimidine sodium salt (267) +11 (N-Sif-a-hexyl-N-methylamino) Synthesis of diethyl malonate Diethyl bromomalonate (17, 0Jil),) ethylamine (S, 1μ), dry toluene (1017)
Mix and reflux while stirring. Here, dry toluene (N-cyclohexyl-N diluted with 5 liters)
- Add methylamine (&III) dropwise and stir for 25 hours.

The 0 reaction solution heated under reflux was washed three times with water, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. From the remaining liquid, (N-hexyl-N-
diethyl (methylamino) malonate 5.59 (yield: 29
%) was obtained. The physical properties of this product were as follows.

Boiling point (b, p,): tz4-128℃ (0.4mHy)
Lza (gH, t, J=7Hz).

0,') A-Zl (10H, tn).

-4! (3H, s).

23~&0 (IH, m).

431 (4H, q, J=7Hz).

Table 06 (IH, g) e (2) 6-(N-cyclohexyl-N-methylamino)-8H-λ3-dihydro7-hydroxy-5-oxothia/a(λ2-a]pyridξdine sodium salt metal Sodium (0,*O#) was dissolved in absolute ethanol (
to WIl). Anhydrous ethanol (101
Diethyl N-cyclohexyl-N-methylamitumacinate (!7,9) dissolved in Ij) was added, followed by 2-aminothia/phosphorus (toe), and the mixture was stirred and heated under reflux for 3 hours. The solid precipitated out was filtered and washed with ethanol.

@-(N-cyclohexyl-N-methylaξ))-8R
-λ3-dihydro7-hydroxy-5-oxothiazolo[λ2-1]biliξ9:/+) U151A salt (2g7
) (L81iI (Q: 31%) was obtained. The physical properties of this product were as follows.

11135i, 1s62, 1505.1400.123
8α meeting ~ 11 (IOH, rn).

190 (mH, a), 18-1 G (IH, br).

Al1o(IL to J=8H$ Li2S(
jH-t-J=8Hz L Practical example 18 sH-43-dihydro-7-hydroxy-5-oxo-6-di-n-propylacetate (&2-a) pyrimidine sodium salt (268) (I) di -Synthesis of low-propyl azeta-tumaronic acid diethyl ester 7 mg of di-butyl (ta2F) and 17.9 jl of diethyl bromate were dissolved in dry benzene (Goad) K, stirred for 7 hours, and heated to reflux. After this, Example 2 (
The same operation as in 1) was carried out, and the obtained residual liquid was subjected to silica gel column chromatography, and from the benzene-ethyl acetate (2G:1) eluate, 1 and 9 g of di-n-propyl 7j tumaronic acid diethyl ester ( Yield: 87%) was obtained.

([r) 5H-λ3-dihydro-7-hydroxy-5
-oxo-6-di-n-propylaminothia 1 mouthful [λ2
-a] Synthesis of pyrimidine sodium salt Sodium metal (α28p) was dissolved in absolute ethanol (10 m
) Add IC to prepare an ethanol solution of sodium ethoxide. Here, di-i-propylaminomanic acid diethyl ester (
λ74I) and further 2-7 minothiazoline (LO2
, 9) and stirred for 3 hours.

Heat to reflux. The precipitated solid was removed by filtration, and! ) 1kl-dihydro a-7-hydrodixy 5-
Oxo-6-celopropylaξnotiazoo (12m
) Pyrimidine sodium salt (2@II) (L74jl(
Yield: -%) was obtained. The physical properties of this material are as follows:
Met.

1637. 15g3. ! 518. 141
5. 140G.

1225.7117 oso(sH,i,J=yHz).

115 (sH, t, J=7Hz)*0.5-1.
6 (4H, m).

19 (2H, t, J=8Hz).

145 (28,t, J=8Hz).

3.57 (2H, t, J=7Hz).

430 (2H, t, J=7Hz).

Example! 9 6-7 Nilino 5H-λ3-dihydro 7-hydroxy-5-oxothiazolo [λ2-a) pyrimidine sodium salt (299) 6-7 Nilino 5 H-su 16.7-tetrahydroku 7-shiokinch 7 zoro (&2-a ) Pirimidji 7 (11G
) (1,31 Jl), sodium hydroxide (021) and water (351 Jl) were added and stirred at room temperature for 1 hour to dissolve. Water was distilled off under reduced pressure, and the desired 6-7 nylinol lH-
λ3-dihydro 7-hydroxy-5-oxothiazog
y (127m) Sodium salt of pyrimidine (29G) L
4JF (yield: 1o, 6%) was obtained. The physical properties of this product were as follows.

11s3 (2H, t, J=7Hz).

427 (2H, to J=7Hz).

115-7.4 (5Hal!I) mExample 20 6-p-chloroanilino-5H-λ3-dihydro 7
-hydro axy 5-oxothiazolo(1c2-a) pyrimidine sodium salt (2as) fi-p-chloroanilino-5H-λ&he7-tetrahydro a-IJ? -Dioxothiazo a(&2-a)pyrimidine (112) (x4@9
) to sodium hydroxide (α2II) and water (3d)K, and stirred at room temperature for 1 hour to dissolve. Water was distilled off under reduced pressure, and the target 6-p-chloroanilino-5H-λ3-dihydro 7-hydroxy-5-oxothiazolo[λ2-
Color] Sodium salt of pyrimidine (269) hssg (
Yield: 100%). The physical properties of this material are as follows:
Met.

x4o (2H, t, J=7Hz).

427 (2H, t, J=7Hz).

IL4-7.3 (4H, mL Example 21 6-7nilino7-rosetoxy5H-λ3-dihydro-5-ochinethiazo0(&2-1)pyrimidine(45
0m9) and m-chloroperbenzoic acid (4s ov) were dissolved in Hanihimetin/(1glIj)K and pressed at 20°C for 21 hours. Thereafter, the mixture was heated under reflux for 3 hours, and 1m-4-4ylperbenzoic acid (230119) was added thereto, and the mixture was further heated under reflux for 3 hours to react. The methylene chloride solution was diluted with saturated tW water.
Washed twice, followed by three washes with water. After drying over anhydrous magnesium sulfate, the solvent was reduced to 11 aL, and the resulting residue was subjected to silica gel column chromatography, eluted with methylene chloride-methanol (13:0-1),
-7nilino7-n-butoxy-5H-43-dishdraw 5-oxothia1OC-2-a]pyrimidine-1-oxide 44 (yield: 9%) was obtained. The physical properties of this product are as follows.

KBr, -1・IR(ν)1-ax 1fi40.160G, 1500.1440.140
Ding.

134!1. 1153. 1061. 740a6~
185 (7H, to).

xio(zu, t, J=7Hz).

L43 (SH, t, J=6Hz).

473 (2H, J=7Hz)e as~y,s(gH,re).

Example 22 Synthesis of 6-p-rialanilino-5H-λ3-dihy)o-7
-Medoxy 5-oxothyanolo(3,2-a)pyrimidine (30019) to m-chloroperbenzoic acid (200M
Dissolve g) in methylene chloride (!Om)) and add 20
The reaction was stirred at ℃ for 6 hours. This trowel was subjected to the same post-processing operation as in Example 1. The residue thus obtained was subjected to silica gel column chromatography and eluted with itomethylene salt to obtain 6-p-chloroanilino-5.
1(-'L3-dihydro-7-medoxy-5-oxothiazolo[tortoise 2-a] piri! gin-1-oxide 103
Drops were obtained (yield: 33%), and the physical properties of this product are as follows.

147 (21(, t, J=7Hz).

460 (3H1l).

47? (2H, tlJ=7Hz) *& 05 (I
H+ br @I) +Na ~7.4 (4H,
m).

Example 23 Synthesis of SH-λ3-dihydro-7-medoxy6-(N-methylanilino)-5-oxothiazolo(zz-a)pyrimidine-1-oxide (43G) 5H-43-dihydro-7-medoxy6-( N-Methyl 7nilino)-5-year-old
Dissolve p) in salt fhimethylene(30wj))C,
The mixture was stirred at 0°C for 3 hours to cause a reaction. After this, a saturated aqueous solution of 7 Um hydrogen carbonate (SOSD) was added and stirring continued for 30 minutes in the same greenhouse. Thereafter, the methylene chloride solution was separated, washed with water, dried over anhydrous sodium sulfate, and then removed under pressure in the dichloromethane region. The residue was subjected to silica gel column chromatography, eluted with the salt ichmethylene, and 5H-2,3-dihydro a-7-medoxy 6-
(N-methylanilino)-5-oxothyanolo[λ2-
&] Pyrimidine-1-oxide 13 was immediately obtained (yield: 5
%), and the physical properties of this product are as follows.

10s (sH*s)e ′ λ33 (2H* t # J==5 Hz
) 1zso(si(+sj.

4sO(2Hrt*J=6Hz).

t4-7.3 (S H, mL Example 24 5H-43-dihydro-7-medoxy6-(N-methyl-p-rimylanilino)-1-oxothiazolo (ZZ
-a) Pyrimidine (104119) and m-chloroperbenzoic acid (6-) were dissolved in methylene chloride (10 Il/) and 2
The reaction was stirred at 0° C. for 6 hours. Thereafter, the same post-treatment operation as in Example 8 was performed.

The residual liquid thus obtained was subjected to silica gel preparative thin layer chromatography, developed with itomethylene chloride, and sH-λ
3-dihydro-a-7-medoxy-5-(N-methyl-p
-chloroanilino)-5-oxothiazolo[λ2-a]
3011 g of pyrimidine-1-oxide was obtained (yield: 2
7%), and its physical properties are as follows.

CDC4 NIvla(a) ppm: M8 λ* a (s He s) - x4s (!H, t, J=7Hz).

Table 01 (3H* 1) * two (2H, teJ=+=7Hz) &s-y, 5 (4H, m) tI/Afl12s (1) 1NS C3H/H@ strain male mice (7 weeks old)
K sheep red blood cells were sensitized by intravenous injection of 5 x 101 cells.

A suspension made by dissolving S% gum arabic into a turbid suspension.
Immediately after sensitization, 1 day, 12 days after sensitization, and 3 days after sensitization, sheep red blood cells 1'O cells were administered orally. Then, 4 days after sensitization, sheep red blood cell 1'O cells were injected into the skin of the right hind leg to induce a single 7-allergy reaction. Ta.

At 24 hours of allergy induction, the thickening of one bale and one foot was measured with a micrometer, and from this wax, sheep red blood cells 1G"#
Subtract the foot before injecting the footpat.
On (01m), delayed allergy was measured. The results are shown in table s1.

Table 1 (I Group of 7 to 11 SD male rats (1 week old)
ICFreundm complete adjut
Bord@t@lla p@ mixed and suspended in equal amount with ant
rtumim (!I X 10・organlmms
) was injected into the right forelimb and left hindlimb for sensitization. Sensitize with a 5% gum arabic solution KJI suspension of the test drug.
The animals were administered orally once a day until day 12 in children as listed in Table 2.

Then, 12 days after sensitization, the same antigen (s
24 hours after allergy induction, the volume of one foot was measured volumetrically (water dis-pla*e).
m@tIt m@thods), and the edema rate (swelling perc.
ent) was calculated to measure delayed allergy.

The results are shown in Table 2.

Table 2 Example 26 (1) The effect on antibody haze was investigated as follows. That is, the pancreas was removed from a 12-week-old BALII/e strain mouse, and a suspension of lung cells was prepared. Sheep red blood cells (SRBC,
Add x x s o・).

Mi in RPMI-1640 medium with 10% fetal bovine serum.
5 days using a modified method of meh@ll and Dutton (Mischsll*R, I, and Dutton+
R,W,:J,Exp,Mad.

126:423 (19g?)) Dim that appears after culturing
@et The number of PFC is determined by J@r*ne method (Jerne+
N.K.

and Nardin, A.A.:5science 1
40:405 (1963)).

The test compound was dissolved in dimethyl sulfoxide to a final concentration of 01M, diluted with culture solution, and then added at the same time as the antigen.

The results are shown in Table 3.

Table 3 Example 27 Manufacture of mulch agent A tablet was prepared with the following composition.

Active ingredient compound (112) 50#9 Lactose 1
j 5I#p potato starch
24 drops polyvinylpyrrolidone 10
M9 Magnesium stearate 1~
The active ingredient, lactose and potato starch were mixed, evenly moistened with a 20% ethanol solution of polyvinylpyrrolidone, and passed through a 20-inch mesh through a 45' mesh.
It was dried at C and passed through a 15 m mesh again. The granules thus obtained were mixed with magnesium stearate and compressed into one tablet.

Compound (112) was used as the active ingredient.

Example 28 Hard gelatin capsules were made, one capsule containing the following composition:

Active ingredient compound (110) 5019 microcrystalline cell a
-su yssy lactose
749 Sacrificial Magnesium Stearin 1q The active ingredient in finely powdered form, microcrystalline cellulose and unpressed amorphous silicic acid were thoroughly mixed and filled into hard gelatin capsules to produce capsules.

The compound (11'0) was used as the active ingredient.

Continuation of page 1 0 shots clear person Tatsuyuki Seichi 5-20-2 Tamadaira, Hino City 0 shots Akira Keiji Komoriya 1532-117 Uchikoshicho, Hachioji City

Claims (1)

[Claims] 1. Thiazolo(3,2-a)pyrimidines represented by the following general formula (I),
Compounds selected from enol derivatives thereof and addition salts thereof. 2 In the above general formula (I), R1 and W are the same or different, and are an alkyl group with a hydrogen atom "l"*,
Rahe's fulkenyl group, substituted or unsubstituted phenyl group, fl-substituted or unsubstituted alicyclic group, substituted or unsubstituted phenyl (C, -C,) alkyl or substituted or unsubstituted C, -C, is an aliphatic acyl group or a substituted or unsubstituted benzoyl group, provided that R1
and R1 are not both hydrogen atoms or both aliphatic 7syl groups or ben/yl groups, and R
1 and V may be taken together with the nitrogen atom to which they are bonded to form a 5- to 6-membered ring that may further contain 1 to 2 nitrogen, atom, or sulfur. . The compound according to claim 1, which is A C,-Q alkyl group, a -q alkoxy group optionally substituted with a norogen atom, a nitrile group, a carboxyl group, or a (C,-(,)alkoxycarbonyl group.Claim 1) The compound according to item 1 or item 2.Table is an enol derivative of cyanoro[\2-a]pyrimidine 7 represented by the following general formula (I)-8, or an acid addition salt thereof when R3 is other than an alkali metal. .A compound according to any one of claims 1 to 3.B An enol derivative of thiazolo(&!-m) bildine represented by the following general formula (I)-b, or R1 The compound according to any one of claims 1 to 3, which is an acid addition salt of a metal other than an alkali metal. Item 1~
The compound according to any one of Item 5 xf14. 7. The compound according to claim 6, wherein the mineral acid salt is a Chapter #1 salt or a sulfate. A malonic acid derivative represented by the following general formula (U) Peng is subjected to a condensation and cyclization reaction with 2-aminothiazoline (a) under heating, or (b) in the presence of an alkali metal flukoxy.
Next, the obtained dinolic alkali metal salt is neutralized with an acid, and the reaction product optionally obtained is subjected to an addition reaction with an acid. ,!-a) Method for producing birid ζ zine or an acid addition salt thereof. Manufacturing method described in section. 10. The above condensation cyclization reaction is carried out in the presence of an inert organic solvent and in the absence of an alkali metal alkoxide. The manufacturing method according to claim 8, which is carried out under heating. 11. The above condensation cyclization reaction is carried out at about so' to about 320°C.
The manufacturing method according to claim 1O, which is carried out at a warm temperature. 12 Thia/mouth (!L2-a) pyrimidines represented by the following general formula (1)-1,
General formula (■) below. R.-X River... React with the Hapgun compound represented by (III) in a polar organic solvent in the presence of a basic compound. Then, optionally, the obtained reaction product is reacted with an acid to form an enol of thiazolo[λ2-a]pyrimidines represented by the following general formula (%) and/or the following general formula (1)-blW. Method for producing derivatives or acid addition salts. 1λ Thia/kuchi (turtle 2-a) pyrimidines represented by the following general formula (1)-1 are represented by the following general formula (IV) an acid halide or acid anhydride of a carboxylic acid;
The following general formula (t)-a is characterized in that the reaction is carried out in an aprotic inert organic solvent, and then the reaction product obtained is optionally reacted with an acid. and/or the following formula (■) -su. A method for producing an enol derivative of 3,2-1' pyrimidines represented by OR' or an acid addition salt thereof. 1 melon Thiazo a(λ2-a)pyrimidine represented by the following general formula (1)-2, the following general formula (III) R, -X ...... (IIT
) and the following general formula (), which is characterized by reacting the compound represented by the formula () in a polar organic solvent in the presence of a basic compound, and then optionally reacting the obtained reaction product with an acid. and/or the following general formula (1)-b. A method for producing an enol derivative of thia/(3,2-a) pyrimidines represented by or an acid addition station thereof. IN Thiazo a(λ2-yl)pyrimidines represented by the following general formula (I)-2H are combined with carboboxyl pyrimidines represented by the following general formula (rV) 8-OH... (IV) The following general formula (I) is characterized by reacting with an acid halogenide or an acid anhydride in an aprotic inert organic solvent, and then reacting the optionally obtained reaction product with an acid. -A4 and/or cyanolo[λ2-] represented by the following general formula (I)-b4 and/or the following general formula (I)-11
a) Method for producing pyrimidines and/or enol derivatives thereof. 1 & Thiazolo (ZZ-
a) A pharmaceutical composition comprising a compound selected from pyrimidines, enol derivatives thereof and acid addition salts thereof as an active ingredient together with a pharmaceutically acceptable carrier. 17. Cyanoro [λ] represented by the above general formula CI>
2-a) A drug in unit dosage form comprising a pharmaceutical composition comprising a compound selected from pyrimidines, enol derivatives thereof and acid addition salts thereof as active ingredient together with a pharmaceutically acceptable carrier. . 1 & Claims FI in dosage form for oral administration
B. The drug according to item 17. 11 Represented by the following general formula (V) ↑. Thiazolo (: (2-, a) S-oxide of enol derivative of pyrimidines.