JPH0141154B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel thiazolo[3,2,-a]pyryls.
Midins and their derivatives and their production methods and
Concerning its pharmaceutical use. For more details, see 6th place
A novel thiazolo[3,2-
a] Pyrimidines or acid addition salts thereof, and the same
methods of manufacturing and their pharmaceutical uses, especially
and its use as an immunomodulator. Conventionally, thiazolopyrimidines include 2-a
Diethyl malonate equivalent to minothiazoline and
The following formula obtained from [Here, R is H or an ethyl group, and
R¹When R is H, methyl group, ethyl group, iso-propylene
Ropyl group, phenyl group or benzyl group, R
When is an ethyl group, ethyl group, iso-propyl group,
n-butyl group, phenyl group or benzyl group
Ru. ] 6-mono- or 6,6-di-substituted- represented by
2,3,6,7-tetrahydro-5,7-dioxy
So-5-thiazolo[3,2-a]pyrimidine is known
(Journal of American chemical
Society, vol. 64, 1942, pages 2709-2712). This literature states that the above thiazolopyrimidines are hypnotic.
expected to have a paralytic effect or a paralytic effect)
Are listed. In addition, in Japanese Patent Application Laid-open No. 55-64591, the following formula [In the formula, R is a substituted or unsubstituted alicyclic group, a substituted
Phenyl group, substituted aralkyl group, or carbon number 8 or more
represents an unsubstituted aralkyl group. ] Thiazolo[3,2-a]pyrimidine represented by
Derivatives are claimed. Furthermore, in Japanese Patent Application Laid-Open No. 55-66592, the following formula [In the formula, R₁is a substituted or unsubstituted alicyclic group,
substituted or unsubstituted phenyl group, or substituted or unsubstituted
represents an aralkyl group, R₂is a lower alkyl group
The dotted line cooperates with the solid line to represent a single bond or a double bond.
Represents a double bond. ] 7-alkoxythiazolo [3,2-
a] Pyrimidine derivatives are claimed. The above two publications include the above-mentioned thiazolo
[3,2-a]pyrimidine derivative is a delayed allele
Immunomodulatory effects, especially immunotherapy, as assessed by the
It is disclosed that it has a promoting effect. One of the above two disclosed in the above two public gazettes
Thiazolo[3,2-a]pirimi represented by the general formula
Zine derivatives have a substituent at position 6 that is a hydrocarbon group.
The novel thiazolo[3,2-a]pyri of the present invention
The molecular structure is different from midins. Moreover, the present invention has a substituted amino group at the 6-position.
The compound has a hydrocarbon group at the above-known 6-position.
It has different immunomodulatory effects than other compounds. In other words, the evaluation of immunomodulatory effects is generally based on the evaluation system.
different evaluations even for the same compound
system, the compound exhibits immunostimulatory effects, and other evaluations
In the valent system, the compound has an immunosuppressive effect.
is often observed. Therefore, more
Evaluation using an evaluation system determines the immunity of the compound.
This is desirable for more accurate evaluation of epidemic-controlling effects.
Needless to say. According to the research of the present inventor, the above two publications
The compound having a hydrocarbon at the 6th position disclosed in
Evaluated by Plaquc Forming Calls (PFC) test
If the value of
It was revealed that it was for production use. Compounds having a substituted amino group at the 6-position of the present invention
On the other hand, as detailed later, the delayed array
evaluated by both the energy test and the PFC test.
In this respect, the above-mentioned known
The immunomodulatory effect is different from that of other compounds. Therefore, the object of the present invention is to create a novel 6-substituted atom.
Thiazolo[3,2-a]pyrimidine with mino group
or their acid addition salts.
Ru. Another object of the present invention is to have a hydrocarbon group at the 6-position.
What are thiazolo[3,2-a]pyrimidine derivatives?
Novel thiazolo with different immunomodulatory effects
[3,2-a] Pyrimidines or their acid addition salts
It is about providing. Still another object of the present invention is to improve immunity by promoting immunity.
Comprising the above-mentioned novel compounds that exhibit disease-regulating effects.
The purpose of the present invention is to provide an immunomodulating agent that can improve the immune system. Still another object of the present invention is to provide the above-mentioned novel compounds.
The purpose is to provide a manufacturing method. Further objects and advantages of the present invention are described below.
It will become clear from this. Such objects and advantages of the invention are part of the invention.
According to the surface, the following general formula () [Here, R¹and R²are the same or different,
hydrogen atom, C₁-C_Tenalkyl group, C₃-C_TenAl of
Kenyl group, substituted or unsubstituted phenyl group,
Replaced or unreplaced C₃-C₈Alicyclic group, substitution also
or unsubstituted phenylalkyl group or substituted
or unsubstituted C₂-C₇represents an acyl group (this
Here, the phenyl group, alicyclic group, phenylal
The substituents for the kill group and acyl group are halogen, respectively.
Substituted with an atom, a hydroxyl group, or a halogen atom.
Moyoi C₁~C_FourAlkyl group, substituted with halogen atom
C may have been₁~C_Fouralkoxy group, nitri
group, carboxyl group or (C₁-C₆)Arco
It is a oxycarbonyl group. ). However, R¹and R²but
Both are hydrogen atoms or both are substituted or unsubstituted.
C of substitution₂-C₇It is not an acyl group, or
taR¹and R²are joined together and they are combined
Even if it contains an additional heteroatom along with the nitrogen atom
It may form a 5- to 6-membered ring. ] Thiazolo[3,2-a]pyrimidine represented by
or its acid addition salts.
achieved. C above₁~C_TenAs an alkyl group, straight chain or branched
It may be branched, for example, methyl,
Ethyl, n-propyl, iso-propyl, n-butyl
chill, iso-butyl, tert-butyl, n-pliers
n-hexyl, n-octyl, n-nonyl,
Examples include n-decyl. These utensils
C, C₁~C₆Alkyl groups, especially methyl, ethyl,
Lopyl and butyl are preferred. C above₃-C_TenAs the alkenyl group, straight chain or
may be branched, for example, ant
2-butenyl, 3-butenyl, 3-methyl-
2-butenyl, 3-hexenyl, 7-octenyl
and geranyl. these
Of which, C₁~C₆Alkenyl group especially allyl is preferred
stomach. C above₃-C₈The alicyclic group may be saturated or unsaturated.
Can be either saturated, e.g. cyclopropylene
pill, cyclopentyl, cyclohexyl, cyclo
heptyl, cyclooctyl, cyclopentenyl,
Examples include cyclohexenyl. this
Of these, C_Five-C₆Alicyclic groups, especially cyclopentyl,
Cyclohexyl is preferred. Examples of the above phenyl alkyl include benzyl
Examples include phenyl, phenethyl, phenylpropyl, etc.
I can do it. Among these, for example, benzyl, α
- Phenyl like phenethyl (C₁-C₂) alki
is preferred. C above₂-C₇As an acyl group, for example, acetyl
propionyl, n-butyryl, iso-butyl,
n-valeryl, iso-valeryl, caproyl,
Examples include nanthyl and benzoyl.
Of these, C₂-C₆Aliphatic acyl groups such as a
Cetyl, n- or iso-butyryl, caproyl or
is preferably benzoyl. Above R¹and R²come together and they combine
Formed together with nitrogen atoms. Furthermore, heteroatoms
As the 5- to 6-membered ring which may contain
Preferably further 1 to 2 nitrogen, oxygen or sulfur atoms
I can list things that contain. example
For example, pyrrolidyl, thiazolyl, piperidyl, mole
Horyl, piperazyl, etc. can be mentioned. C above₃-C₈alicyclic group, phenylalkyl group
and C₂-C₇The acyl group may be substituted.
Substitution of these substituents and the above substituted phenyl groups
Examples of groups include halides such as fluorine, chlorine, and bromine.
rogen atom; hydroxyl group; methyl, ethyl, n-propylene
pill, isopropyl, n-butyl, trifluoro
Substituted with halogen atoms such as methyl, chloromethyl, etc.
C that may be replaced₁~C_FourAlkyl group; methoxy
cy, ethoxy, n-proboxy, iso-proboxy
cy, n-butoxy, trifluoromethoxy, chloro
Substituted with a halogen atom such as lomethoxy
Moyoi C₁-C_FourAlkoxy group; Nitrile group; Cal
Boxyl group; methoxycarbonyl, ethoxyl
Bonyl, butoxycarbonyl, hexyloxycarbonyl
(C₁-C₆) alkoxy carboni
Preferred examples include
Ru. Thiazolo [3,
2-a] Pyrimidines are oxo at the 5th or 7th position.
may be enol derivatives based on such groups, but such
For example, the following general formula ()-a [Here R¹and R²The definition of is in the above formula ()
is the same as R³is R¹or R²same as if
C₁-C_TenAlkyl group, C₃-C_TenArche
Nyl group, substituted or unsubstituted C₃-C₈cycloaliphatic
group, substituted or unsubstituted phenyl alkyl group,
Substituted or unsubstituted C₂-C₇Acyl group or a
alkali metal, provided that R¹and R²together with hydrogen field
are never children and are both substituted or unsubstituted
C₂-C₇It cannot be an acyl group. ] Or the following general formula ()-b [Here, R¹and R²The definition of is the above formula ()
is the same as in R³The definition of is the above formula ()
- Same as in a. ] There is. Alka in the above formulas ()-a and ()-b
Examples of metals include sodium or potassium.
There is. Thiazo represented by the above general formula () of the present invention
B[3,2-a]pyrimidines or acid addition thereof
Salts are inorganic acids, organic carboxylic acids or organic sulfones.
salts with acids, especially salts with inorganic acids, among others
Salts with mineral acids are also particularly preferred. Here as mineral acid
For example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.
Examples of organic carboxylic acids include vinegar.
Acid, propionic acid, oxalic acid, citric acid, mandel
Acid, maleic acid, fumaric acid, lactic acid, glutamic acid
Examples of organic sulfonic acids include
Methanesulfonic acid, ethanesulfonic acid, benzene
sulfonic acid, p-toluenesulfonic acid, cumyl
Examples include sulfonic acid. Among these, especially mineral acids such as hydrochloric acid and sulfuric acid
Salt is preferred. Expressed by the above general formula () provided by the present invention
Examples of compounds that can be used include the following thia
Zolo[3,2-a]pyrimidines are mentioned. (100) 5H-2,3,6,7-tetrahydro-
6-methylamino-5,7-dioxothiazolo
[3,2-a]pyrimidine, (102) 6-ethylamino-5H-2,3,6,
7-tetrahydro-5,7-dioxothiazolo
[3,2-a]pyrimidine, (104) 6-n-hexylamino-5H-2,3,
6,7-tetrahydro-5,7-dioxothia
Zolo[3,2-a]pyrimidine, (106) 6-allylamino-5H-2,3,6,
7-tetrahydro-5,7-dioxothiazolo
[3,2-a]pyrimidine, (108) 6-(3-hexenylamino)-5H-
2,3,6,7-tetrahydro-5,7-dio
xothiazolo[3,2-a]pyrimidine, (110) 6-anilino-5H-2,3,6,7-
Tetrahydro-5,7-dioxothiazolo
[3,2-a]pyrimidine, (112) 6-p-chloroanilino-5H-2,3,
6,7-tetrahydro-5,7-dioxothia
Zolo[3,2-a]pyrimidine, (114) 6-o-chloroanilino-5H-2,3,
6,7-tetrahydro-5,7-dioxothia
Zolo[3,2-a]pyrimidine, (116) 6-m-chloroanilino-5H-2,3,
6,7-tetrahydro-5,7-dioxothia
Zolo[3,2-a]pyrimidine, (118) 5H-2,3,6,7-tetrahydro-
6-p-hydroxyphenylamino-5,7-
dioxothiazolo[3,2-a]pyrimidine, (120) 5H-2,3,6,7-tetrahydro-
5,7-dioxo-6-p-tolylaminothi
Azolo[3,2-a]pyrimidine, (122) 6-p-trifluoromethylphenyla
Mino-5H-2,3,6,7-tetrahydro-
5,7-dioxothiazolo[3,2-a]pyri
Mijin, (124) 5H-2,3,6,7-tetrahydro-
6-p-methoxyphenylamino-5,7-di
oxothiazolo[3,2-a]pyrimidine, (126) 6-p-trifluoromethoxyphenyl
Amino-5H-2,3,6,7-tetrahydro
-5,7-dioxothiazolo[3,2-a]pi
Limidine, (128) 6-p-cyanophenylamino-5H-
2,3,6,7-tetrahydro-5,7-dio
xothiazolo[3,2-a]pyrimidine, (130) 6-p-carboxyphenylamino-
5H-2,3,6,7-tetrahydro-5,7
-Dioxothiazolo[3,2-a]pyrimidi
hmm, (132) 6-p-ethoxycarbonylphenyla
Mino-5H-2,3,6,7-tetrahydro-
5,7-dioxothiazolo[3,2-a]pyri
Mijin, (134) 6-cyclopentylamino-5H-2,
3,6,7-tetrahydro-5,7-dioxo
thiazolo[3,2-a]pyrimidine, (136) 6-cyclohexylamino-5H-2,
3,6,7-tetrahydro-5,7-dioxo
thiazolo[3,2-a]pyrimidine, (138) 6-benzylamino-5H-2,3,6,
7-tetrahydro-5,7-dioxothiazolo
[3,2-a]pyrimidine, (140) 6-p-chlorobenzylamino-5H-
2,3,6,7-tetrahydro-5,7-dio
xothiazolo[3,2-a]pyrimidine, (142) 5H-2,3,6,7-tetrahydro-
5,7-dioxo-6-α-phenethylthiazo
B[3,2-a]pyrimidine (144) 6-acetamide-5H-2,3,6,
7-tetrahydro-5,7-dioxothiazolo
[3,2-a]pyrimidine, (146) 6-n-butyrylamino-5H-2,3,
6,7-tetrahydro-5,7-dioxothia
Zolo[3,2-a]pyrimidine, (148) 6-caproylamino-5H-2,3,
6,7-tetrahydro-5,7-dioxothia
Zolo[3,2-a]pyrimidine, (150) 6-Benzoylamino-5H-2,3,
6,7-tetrahydro-5,7-dioxothia
Zolo[3,2-a]pyrimidine, (152) 6-p-chlorobenzoylamino-5H
-2,3,6,7-tetrahydro-5,7-di
oxothiazolo[3,2-a]pyrimidine, (160) 5H-2,3,6,7-tetrahydro-
6-dimethylamino-5,7-dioxothiazo
b [3,2-a]pyrimidine, (161) 6-diethylamino-5H-2,3,6,
7-tetrahydro-5,7-dioxothiazolo
[3,2-a]pyrimidine, (162) 5H-2,3,6,7-tetrahydro-
5,7-dioxo-6-dipropylaminothia
Zolo[3,2-a]pyrimidine, (164) 5H-2,3,6,7-tetrahydro-
6-(N-methylanilino)-5,7-dioki
sothiazolo[3,2-a]pyrimidine, (166) 6-p-chloro-N-methylanilino)
-5H-2,3,6,7-tetrahydro-5,
7-Dioxothiazolo[3,2-a]pyrimidine
hmm, (168) 6-(N-cyclohexyl-N-methyl
amino)-5H-2,3,6,7-tetrahydride
rho-5,7-dioxothiazolo[3,2-a]
pyrimidine, (170) 6-benzylmethylamino-5H-2,
3,6,7-tetrahydro-5,7-dioxo
thiazolo[3,2-a]pyrimidine, (172) 6-benzoylmethylamino-5H-2,
3,6,7-tetrahydro-5,7-dioxo
thiazolo[3,2-a]pyrimidine, (174) 6-(N-allylanilino)-5H-2,
3,6,7-tetrahydro-5,7-dioxo
thiazolo[3,2-a]pyrimidine, (176) 6-(N-benzyl-N-phenylamine
-5H-2,3,6,7-tetrahydro-
5,7-dioxothiazolo[3,2-a]pyri
Mijin, (178) 6-(N-benzoyl-N-phenyla
Mino)-5H-2,3,6,7-tetrahydro
-5,7-dioxothiazolo[3,2-a]pi
Limidine, (180) 6-dicyclohexylamino-5H-2,
3,6,7-tetrahydro-5,7-dioxo
thiazolo[3,2-a]pyrimidine, (182) 6-dibenzylamino-5H-2,3,
6,7-tetrahydro-5,7-dioxothia
Zolo[3,2-a]pyrimidine, (184) 5H-2,3,6,7-tetrahydro-
5,7-dioxo-6-(1-pyrrolidyl)thi
Azolo[3,2-a]pyrimidine, (186) 5H-2,3,6,7-tetrahydro-
5,7-dioxo-6-(3-thiazolyl)thi
Azolo[3,2-a]pyrimidine, (188) 5H-2,3,6,7-tetrahydro-
5,7-dioxo-6-piperidylthiazolo
[3,2-a]pyrimidine, (190) 5H-2,3,6,7-tetrahydro-
6-morpholino-5,7-dioxothiazolo
[3,2-a]pyrimidine, (192) 5H-2,3,6,7-tetrahydro-
5,7-dioxo-6-piperazinothiazolo
[3,2-a]pyrimidine, (193) 6-p-chloroanilino-5H-2,3,
6,7-tetrahydro-5,7-dioxothia
Zolo[3,2-a]pyrimidine hydrochloride (194) 6-p-chloroanilino-5H-2,3,
6,7-tetrahydro-5,7-dioxothia
Zolo[3,2-a]pyrimidine sulfate (195) 6-anilino-5H-2,3,6,7-
Tetrahydro-5,7-dioxothiazolo
[3,2-a] Pyrimidine hydrochloride Enol derivative represented by the above formula ()-a
Examples include the following compounds:
Can be done. (200) 5H-2,3-dihydro-7-methoxy
-6-dimethylamino-5-oxothiazolo
[3,2-a]pyrimidine (202) 5H-2,3-dihydro-7-methoxy
-5-oxo-6-di-n-propylaminothi
Azolo[3,2-a]pyrimidine (204) 6-anilino-5H-2,3-dihydro
-7-methoxy-5-oxothiazolo[3,2
-a] Pyrimidine (206) 6-p-chloroanilino-5H-2,3
-dihydro-7-methoxy-5-oxothiazo
B[3,2-a]pyrimidine (208) 5H-2,3-dihydro-7-methoxy
C-6-(N-methylanilino)-5-oxo
Thiazolo[3,2-a]pyrimidine (210) 5H-2,3-dihydro-7-methoxy
-6-(N-methyl-p-chloroanilino)-
5-oxothiazolo[3,2-a]pyrimidine (212) 7-n-butoxy-6-(Nn-butoxy
luanilino)-5H-2,3-dihydro-5-
Oxothiazolo[3,2-a]pyrimidine (214) 6-anilino-7-n-butoxy-5H
-2,3-dihydro-5-oxothiazolo
[3,2-a]pyrimidine (216) 6-Benzylamino-5H-2,3-di
Hydro-7-methoxy-5-oxothiazolo
[3,2-a]pyrimidine (218) 6-(N-benzyl-N-methylamine
-5H-2,3-dihydro-7-methoxy
-5-oxothiazolo[3,2-a]pyrimidi
hmm (220) 6-(N-allylanilino)-7-eth
Oxy-5H-2,3-dihydro-5-oxothi
Azolo[3,2-a]pyrimidine (222) 6-(N-cyclohexyl-N-methyl
amino)-5H-2,3-dihydro-7-meth
xy-5-oxothiazolo[3,2-a]pyri
Mijin (224) 6-(N-benzoyl-N-phenyla
Mino)-5H-2,3-dihydro-7-methoxy
C-5-oxothiazolo[3,2-a]pirimi
gin (226) 7-Ethoxy-5H-2,3-dihydro
-5-oxo-6-piperidylthiazolo [3,
2-a] Pyrimidine (230) 7-allyloxy-5H-2,3-dihi
Dro-5-oxo-6-di-n-propylthia
Zoro[3,2-a]pyrimidine (232) 6-(N-allylanilino)-7-aryl
5H-2,3-dihydro-5-oxy
Cythiazolo[3,2-a]pyrimidine (234) -7-allyloxy-6-anilino-
5H-2,3-dihydro-5-oxothiazolo
[3,2-a]pyrimidine (236) 7-allyloxy-6-(N-cyclohe
xyl-N-methylamino)-5H-2,3-
Dihydro-5-oxothiazolo[3,2-a]
pyrimidine (238) 7-allyloxy-6-(N-benzoy
Ru-N-phenylamino)-5H-2,3-di
Hydro-5-oxothiazolo[3,2-a]pi
Limidine (240) 7-allyloxy-5H-2,3-dihi
Dro-6-morpholino-5-oxothiazolo
[3,2-a]pyrimidine (242) 7-(3-hexyloxy)-5H-2,
3-dihydro-6-dimethylamino-5-ox
Sothiazolo[3,2-a]pyrimidine (250) 7-benzyloxy-6-diethylamide
No-5H-2,3-dihydro-5-oxothia
Zoro[3,2-a]pyrimidine (252) 6-(N-allyl-N-phenylamine
-7-benzyloxy-5H-2,3-di
Hydro-5-oxothiazolo[3,2-a]pi
Limidine (256) 7-benzyloxy-6-(N-cyclo
hexyl-N-methylamino)-5H-2,3
-dihydro-5-oxothiazolo[3,2-
a] Pyrimidine (258) 6-anilino-benzyloxy-5H
-2,3-dihydro-5-oxothiazolo
[3,2-a]pyrimidine (260) 7-benzyloxy-6-(N-benzi
Ru-N-phenylamino)-5H-2,3-di
Hydro-5-oxothiazolo[3,2-a]pi
Limidine (262) 6-benzylamino-7-benzyloki
C-5H-2,3-dihydro-5-oxothia
Zoro[3,2-a]pyrimidine (264) 6-(N-benzoyl-N-phenyla
Mino)-7-benzyloxy-5H-2,3-
Dihydro-5-oxothiazolo[3,2-a]
pyrimidine (266) 5H-2,3-dihydro-5-oxo-
7-α-phenethyloxy-6-piperazinothi
Azolo[3,2-a]pyrimidine (267) 6-(N-cyclohexyl-N-methyl
Amino)-5H-2,3-dihydro-7-hy
Droxy-5-oxothiazolo [3,2-a]
Sodium salt of pyrimidine (268) 5H-2,3-dihydro-7-hydroxy
C-5-oxo-6-di-n-propylamino
Thiazolo[3,2-a]pyrimidine sodium
mu salt (269) 6-p-chloroanilino-5H-2,3
-dihydro-7-hydroxy-5-oxothia
Sodium salt of zolo[3,2-a]pyrimidine (270) 7-acetoxy-5H-2,3-dihyde
Lo-5-oxo-6-di-n-propylamino
Thiazolo[3,2-a]pyrimidine (272) 7-acetoxy-6-(N-acetoxy
-N-methylamino)-5H-2,3-dihyde
lo-5-oxothiazolo[3,2-a]pirimi
gin (274) 7-acetoxy-6-(N-allyl-N
-phenylamino)-5H-2,3-dihydro
-5-oxothiazolo[3,2-a]pyrimidi
hmm (276) 7-acetoxy-6-(N-cyclohexyl
sil-N-methylamino)-5H-2,3-di
Hydro-5-oxothiazolo[3,2-a]pi
Limidine (278) 7-acetoxy-6-(N-acetyl-
N-phenylamino)-5H-2,3-dihyde
lo-5-oxothiazolo[3,2-a]pirimi
gin (280) 7-acetoxy-5H-2,3-dihyde
rho-6-(N-methylanilino)-5-oxo
Thiazolo[3,2-a]pyrimidine (282) 7-acetoxy-6-(N-benzyl-
N-methylamino)-5H-2,3-dihydro
-5-oxothiazolo[3,2-a]pyrimidi
hmm (284) 7-acetoxy-5H-2,3-dihyde
Rho-5-oxo-6-(3-thiazolyl)thia
Zoro[3,2-a]pyrimidine (286) 7-benzoyloxy-5H-2,3-
Dihydro-6-dimethylamino-5-oxothi
Azolo[3,2-a]pyrimidine (288) 6-(N-allyl-N-phenylamine
-7-benzoyloxy-5H-2,3-
Dihydro-5-oxothiazolo[3,2-a]
pyrimidine (290) 7-benzoyloxy-6-(N-sic
lohexyl-N-methylamino)-5H-2,
3-dihydro-5-oxothiazolo [3,2-
a] Pyrimidine (292) 7-benzoyloxy-5H-2,3-
Dihydro-6-(N-methylanilino)-5-
Oxothiazolo[3,2-a]pyrimidine (294) 7-benzoyloxy-6-(N-ben
Zyl-N-methylamino)-5H-2,3-di
Hydro-5-oxothiazolo[3,2-a]pi
Limidine (296) 7-benzoyloxy-5H-2,3-
dihydro-5-oxo-6-(1-pyrrolidi
) Thiazolo[3,2-a]pyrimidine (298) 7-cyclohexyloxy-5H-2,
3-dihydro-6-(N-methylanilino)-
5-oxothiazolo[3,2-a]pyrimidine (299) 6-anilino-5H-2,3-dihydro
-7-hydroxy-5-oxothiazolo [3,
2-a] Sodium salt of pyrimidine Enol derivative represented by the above formula ()-b
For example, the above compounds can be mentioned.
Can be done. (300) 5H-2,3-dihydro-5-methoxy
-6-dimethylamino-7-oxothiazolo
[3,2-a]pyrimidine (302) 6-anilino-5H-2,3-dihydro
-5-methoxy-7-oxothiazolo[3,2
-a] Pyrimidine (304) 5H-2,3-dihydro-5-methoxy
-6-(N-methylanilino)-7-oxothy
Azolo[3,2-a]pyrimidine (306) 5H-2,3-dihydro-5-methoxy
-6-(N-methyl-p-chloroanilino)-
7-oxothiazolo[3,2-a]pyrimidine (308) 6-Benzylamino-5H-2,3-di
Hydro-5-methoxy-7-oxothiazolo
[3,2-a]pyrimidine (310) 5-allyloxy-5H-2,3-dihi
Dro-7-oxo-6-di-n-propylthia
Zoro[3,2-a]pyrimidine (312) 5-benzyloxy-6-diethylamide
No-5H-2,3-dihydro-7-oxothia
Zoro[3,2-a]pyrimidine (314) 6-anilino-5-benzyloxy-
5H-2,3-dihydro-7-oxothiazolo
[3,2-a]pyrimidine (316) 5-acetoxy-6-(N-acetyl-
N-methylamino)-5H-2,3-dihydro
-7-oxothiazolo[3,2-a]pyrimidi
hmm (318) 5-acetoxy-5H-2,3-dihyde
rho-6-(N-methylanilino)-7-oxo
Thiazolo[3,2-a]pyrimidine (320) 5-benzoyloxy-5H-2,3-
Dihydro-6-dimethylamino-7-oxothi
Azolo[3,2-a]pyrimidine (322) 5-benzoyloxy-5H-2,3-
Dihydro-6-(N-methylanilino)-7-
Oxothiazolo[3,2-a]pyrimidine (324) 5-benzoyloxy-5H-2,3-
dihydro-7-oxo-6-(1-pyrrolidi
) Thiazolo[3,2-a]pyrimidine Thiazo represented by the above general formula () of the present invention
b [3,2-a]pyrimidines according to the present invention.
For example, the following general formula () [Here, R¹and R²The definition of is the above formula ()
is the same as R^Fourand R^Fiveare the same or different
RiC₁-C₆It is an alkyl group] The malonic acid derivative represented by 2-aminothiazo
and (a) a condensation cyclization reaction under heating, or
(b) Condensation reaction in the presence of alkali metal alkoxide
Alkali metal salt of enol obtained
neutralized with acid and optionally the resulting reaction
Manufactured by addition reaction of reaction product with acid
can do. R in the above formula ()¹and R²The definition of is the expression
Same as in (). R^Fourand R^Fiveare the same or differentC₁-C₆Al
Kill group, such as methyl, ethyl, n-propylene
pill, iso-propyl, n-butyl, iso-butyl
, sec-butyl, tert-butyl, n-pentyl,
Examples include n-hexyl. these
Of which C₁-C_FiveAlkyl, especially methyl, ethyl, especially
R^Fourand R^FiveIt is preferred that both are methyl or ethyl.
Delicious. As a malonic acid derivative represented by the above formula ()
For example, N-methylaminomalonic acid, N-
Ethylaminomalonic acid, N-n-hexylamino
Malonic acid, N-allylaminomalonic acid, N-3-
hexenylaminomalonic acid, anilinomalonic acid,
p-Chloranilinomalonomaronic acid, o-chloranili
Nomalonic acid, m-chloroanilimalonic acid, p-hyperoxychloride
Droxyphenylaminomalonic acid, p-toluyl
Aminomalonic acid, p-trifluoromethylphenylene
Ruaminomalonic acid, p-methoxyphenylamino
Malonic acid, p-trifluoromethoxyphenyla
Minomalonic acid, p-cyanophenylaminomalon
Acid, p-ethoxycarbonylphenylaminomalo
acid, N-cyclopentylaminomalonic acid, N-
Cyclohexylaminomalonic acid, N-benzylua
Minomaronic acid, N-p-chlorobenzylaminomer
ronic acid, N-α-phenethylaminomalonic acid, N
-dimethylaminomalonic acid, N-di-ethylamide
Nomalonic acid, N-di-n-propylaminomalon
acid, N-methylanilinomalonic acid, p-chloro-
N-methyl-anilinomalonic acid, N-cyclohex
Sil-N-methylaminomalonic acid, N-benzyl
-N-methylaminomalonic acid, N-allylamino
Malonic acid, N-benzyl-N-phenylaminomer
rononic acid, N-dicyclohexylaminomalonic acid,
N-dibenzylaminomalonic acid, 1-pyrrolidyl
Malonic acid, 3-thiazolylmalonic acid, piperidyl
Malonic acid, morpholinomalonic acid and piperazino
Di(C) such as malonic acid_1-6) alkyl esters, preferred
Examples include dimethyl ester and diethyl ester.
can be given. Such malonic acid derivatives () have the corresponding halo
Genated malonic acid diester, preferably bromma
Ronic acid diester or chlormalonic acid diester
and the corresponding amine in an inert organic solvent, e.g.
in benzene, toluene, xylene, preferably with filtration.
Heating in the presence of a surplus of the amine or tertiary amine
It can be produced by reaction.
This manufacturing method has been described, for example, in the Journal of Organic
Described in Chemistry vol 20 1454-1457 (1955)
It is. As the other starting material, the following formula 2-aminothiazoline represented by
Ru. The method of the present invention comprises the above malonic acid derivative () and 2
- Condensation and cyclization reaction with aminothiazoline
This is done by The condensation cyclization reaction is caused by malonic acid
This is an equimolar reaction between a conductor and 2-aminothiazoline.
Ru. According to the method of the present invention, preferably malonic acid-induced
Approximately 0.8-1.2 moles of 2-aminothia per mole of body
Zolin can be used. The condensation cyclization reaction can be carried out under (a) heating.
and (b) carried out in the presence of an alkali metal alkoxide.
You can also do it. It is preferably carried out under heating. a
The reaction is carried out in the presence of alkali metal alkoxide.
If the cyclocondensation reaction product is an alkali metal
Since it is obtained as a salt, it is then neutralized with an acid.
There is a need. The condensation cyclization reaction carried out under heating is preferably carried out using an inert
It is carried out in the presence of a sterile organic solvent. inert organic solvent
An aprotic inert organic solvent is used as the medium.
is advantageous. Such inert organic solvents include, for example, toluene.
xylene, cumene, cymene, tetralin, de
Karin, diethylene glycol diethyl ether
diethylene glycol diethyl ether, diethylene glycol diethyl ether,
Ethylene glycol dibutyl ether, dipheni
ether, dimethyl sulfoxide, dimethyl ether
Aprotic such as lumamide, nitrobenzene
Inert organic solvent or ethanol, butanol
Like C_1-4lower alcohols, etc. Such inert organic solvents are suitable for the malonic acid derivative used.
The total amount of conductor () and 2-aminothiazoline
About 1 to about 50 times the weight, especially about 2 to about 20 times the weight.
Preferably used. The reaction temperature and reaction time depend on the type of starting materials used.
depending on the type, whether or not a solvent is used, and the type of solvent used.
It's different. Usually at 80-320℃ for 1 minute to 48 hours.
Especially preferred is 100 to 300℃ for 10 minutes to 24 hours.
It will be implemented as soon as possible. The reaction can be preferably carried out under normal pressure or elevated pressure. When using lower alcohol as a reaction solvent
is preferably carried out under pressure to increase the reaction temperature.
Yes. The reaction produced by the condensation cyclization reaction according to the above procedure
The reaction product is a thiazolo compound represented by the above formula ().
[3,2-a] pyrimidines. This reaction mixture
Isolation and purification from compounds are performed by recrystallization and chromatography.
Easily carried out by conventional methods such as extraction and separation.
can become. On the other hand, alkali gold as a catalyst for cyclocondensation reaction
relatively low when carried out in the presence of genus alkoxides.
The reaction can be carried out at low temperatures. As an alkali metal alkoxide, lithium
C of mum, sodium or potassium_1-C_FourAlkoxy
is preferably used. Such alkali metal a
For example, lithium methoxy
Lithium ethoxide, Lithium propoxy
sodium methoxide, sodium ethoxy
sodium propoxide, sodium isopoxide
Ropoxide, sodium gotoxide, sodium
isogotoxide, sodium sec-butoxide,
Examples include sodium t-butoxide. especially
Sodium methoxide, sodium ethoxide, etc.
is preferably used. Such alkali metal alkoxides are commonly used
1 to 10 mol per mol of malonic acid derivative, preferably
Preferably, it can be used in a range of 1 to 2 mol.
Ru. Condensation reaction of alkali metal alkoxides
When carried out in the presence of
C_1-4Lower alcohols are preferably used. Such lower alcohols include, for example, meth.
alcohol, ethanol, propanol, isopropanol
Nol, butanol, isobutanol, sec-butanol
Examples include tanol, t-butanol, etc.
Ru. In addition, as a reaction solvent, C_1-4lower alcohol
and other inert organic solvents (e.g.
(Tonic inert solvents) may also be used.
can. The reaction solvent depends on the malonic acid derivative and
and 2-aminothiazoline, usually 1~
Used at 50 times the weight, preferably 2 to 10 times the weight.
Ru. The reaction time and reaction temperature depend on the starting materials and the solvent used.
medium, type of alkali metal alkoxide used
The reaction usually takes place at 40° to 150°C, depending on
1 for 30 minutes to 72 hours, more preferably at 60 to 120°C.
It will be held for ~10 hours. The reaction takes place under normal pressure to increased pressure.
It can be carried out. The steps for actually carrying out the reaction are as described above.
Alkali metals such as sodium are added to lower alcohols.
In addition to the lower alkali metal alkoxides,
A kohl solution is prepared, and then the above formula is added into this.
[] Malonic acid derivative and 2-aminothiazoli
It is preferable to carry out the condensation cyclization reaction by adding a compound. The above condensation reaction using an alkali metal alkoxide
The reaction product produced by the reaction is an enol atom.
It is a metal salt. This enol salt is then converted into an acid
By being neutralized by
gives thiazolo[3,2-a]pyrimidines
I can do it. Such a neutralization reaction involves the reaction obtained by a condensation reaction.
a given amount of acid required for the neutralization reaction in the reaction mixture.
or simply remove the enol from the reaction mixture.
After separating, for example, add a certain amount of acid in water.
You can also do that. As acids, various inorganic acids, organic sulfonic acids,
Organic carboxylic acids can be used. preferably
is an inorganic acid such as hydrochloric acid, hydrobromic acid, vinegar
Organic carboxylic acids such as acids are used. The product thus obtained is recrystallized and chromatographed.
Simply by conventional means such as graphie, extraction and separation.
Separated and purified. The product of the present invention obtained through the above condensation cyclization reaction
Thiazolo [3,2-a] represented by the formula ()
Pyrimidines can then undergo an addition reaction with an acid.
to give its acid addition salt. The addition reaction is performed using isolated thiazolo[3,2-a]
What can be done about pyrimidines is
Ron, other thiazolo[3,2-a]pyrimidines
The acid is added to the reaction mixture containing the
Alternatively, it can be carried out simultaneously with the above neutralization reaction.
It can also be done. Thiazolo [3,
2-a] Enol derivatives of pyrimidines are
It can be manufactured as follows. That is, the above general formulas ()-a and ()
- Among the enol derivatives represented by b, the general formula
R in ()-a or ()-b³is C_1-10Al
kill group, C_3-10alkenyl group, substituted or unsubstituted
C of exchange_3-8Alicyclic groups or substituted or unsubstituted groups
Enol derivatives, which are enyl alkyl groups, are as follows:
General formula ()-1 [Here, R¹¹and R^{twenty two}are the same or different
Nari, C₁-C_Tenalkyl group, C₃-C_TenArkeni of
phenyl group, substituted or unsubstituted phenyl group, substituted
or unsubstituted C₃-C₈alicyclic group, substituted or
is unsubstituted phenylalkyl or substituted or
unsubstituted C₂-C₇is an acyl group, provided that R¹¹and
R^{twenty two}are both substituted or unsubstituted C₂-C₇Acyl group
and R¹¹and R^{twenty two}are together
and further along with the nitrogen atoms to which they are bonded.
A 5- to 6-membered ring that may contain a heteroatom
It may be formed. Thiazolo[3,2-a]pyrimidine represented by
The following general formula () R⁶-X...() R⁶is C₁-C_TenAlkyl group, C₃-C_Tenalkenyl
group, substituted or unsubstituted C₃-C₈Alicyclic group,
or a substituted or unsubstituted phenyl alkyl group.
be. ] Halogen compounds and basic compounds represented by
reaction in a polar organic solvent in the presence of
The reaction product obtained by the reaction is reacted with an acid.
It can be manufactured by R in the above formula ()₆is C_1-10Alkyl group, C_3-10
Alkenyl group, substituted or unsubstituted C_3-8alicyclic
group or substituted or unsubstituted phenylalkyl
Examples of these groups include the above formula ()
I can give you the same example as the one exemplified in
can. In addition, X is a halogen atom, for example, a salt
bromine or iodine. As a halogen compound represented by the above formula ()
For example, methyl chloride, methyl bromide, methyl iodide
, ethyl bromide, ethyl iodide, n-propyl bromide
isopropyl bromide, n-butyl bromide, sec bromide
Butyl, n-pentyl bromide, iso-pentyl bromide,
n-hexyl bromide, n-decyl bromide, ant bromide
3-hexenyl chloride, cyclohexyl bromide,
4-methylcyclohexyl bromide, benzyl chloride,
Benzyl odor, benzyl iodide, p-chlorobene bromide
Gill et al. Thiazolo [3,
2-a] Pyrimidines represented by the above formula ()
The halogen compounds are stoichiometrically equimolar.
react. Usually thiazolo[3,2-a]pyrimidi
About 1 to about 1 mole of halogen compound ()
It is desirable to use 10 times the mole amount. Unresponsive halogen
The compound () is collected and reused after the reaction is completed.
be able to. The reaction takes place in the presence of a basic compound in an inert organic solvent.
It takes place inside. Examples of basic compounds include sodium hydride.
sodium amide; or sodium hydroxide;
Potassium hydroxide, sodium carbonate, potassium carbonate
Mu, Sodium Bicarbonate, Potassium Bicarbonate, Water
Alkali gold such as calcium oxide and calcium carbonate
hydroxides of genus or alkaline earth metals, bicarbonate
salt or carbonate; sodium methoxide, nat.
Lium ethoxide, potassium methoxide, potassium
Muethoxide, sodium isopropoxide, carbon
Lithium isopropoxide, potassium t-butoxide
Metal alkoxides such as cid; trimethylamine,
Triethylamine, diethylamine, diisopropylene
Pyramine, pyridyl, lutidine, collidine, i
Organic bases such as midazole, especially sodium hydride
pyridine, triethylamine, etc. are preferably used.
I can stay. The basic compound used is thiazolo[3,2-
a] Usually about 1 to 3 mole per mole of pyrimidine
mol, preferably 1.1 to 2 mol. Examples of inert organic solvents include methanol,
Ethanol, dimethyl sulfoxide, dimethyl fluoride
Protic or non-protic such as lumamide, pyridine
Protic polar solvents, methylene chloride, chlorophore
Lum, benzene, toluene, xylene, ether
Aprotic solvents such as
etc. are preferably used. Such organic solvents are suitable for the starting materials and bases used.
Preferably about 1 to about 50 times the weight of the total amount of the compound.
It is used in an amount of about 2 to about 20 times the weight. The reaction temperature is usually about 10°C to about 100°C, preferably about 15°C.
It is carried out at temperatures ranging from ~50°C. The reaction is usually
It is completed in about 1 to about 72 hours. The reaction takes place at normal pressure to
It can be carried out under pressure, but is preferably carried out at normal pressure.
Yes. Thus, according to the above reaction, the following general formula ()
-a₁ and/or the following general formula () - b₁ [Here, R⁶,R¹¹and R^{twenty two}is defined above
It's the same. ] An enol derivative represented by is produced. The above formula
()―a₁and the above formula () - b₁expressed as
Usually produced as a mixture of enol derivatives. The enol derivative thus obtained is recrystallized,
Chromatography e.g. column chromatography
Mixture as appropriate by methods such as e.g., extraction and separation.
or separated, isolated and purified.
Ru. The enol derivatives mentioned above are also the same as those already mentioned above.
It can be converted into its acid addition salt by similar methods. Represented by the above general formulas ()-a and ()-b
Among the enol derivatives, general formula ()-a
or R in ()-b³is substituted or unsubstituted
C_2-7The enol derivative which is an acyl group has the above formula
Thiazolo [3,2-a] represented by ()-1
Pyrimidines can be expressed by the following general formula () R⁷-OH...() Here, R⁷is substituted or unsubstituted C₂-C₇Asil
It is the basis. ] Acid halide or acid of carboxylic acid represented by
Reaction with anhydride in an aprotic inert organic solvent
and optionally the reaction product obtained with acid.
It is produced by reacting with R in the above general formula ()⁷is substituted or unsubstituted
C_2-7Acyl groups, examples of which are the above formulas
I can give the examples shown in ().
Ru. As a carboxylic acid represented by the above general formula ()
These include acetic acid, propionic acid, butyric acid, iso-butyric acid,
n-valeric acid, iso-valeric acid, caproic acid, capri
chloric acid, benzoic acid, trifluoroacetic acid, p-chloric acid
Examples include benzoic acid. The method of the present invention
In many cases, these carboxylic acids are reactive derivatives,
That is, acid halides such as acid chloride, acid but
Used as lomid or acid anhydride. Thiazolo[3,2-
a] Pyrimidines and the above acid halides or acid-free
It reacts with hydrates in equimolar amounts stoichiometrically. General
To 1 mole of thiazolo[3,2-a]pyrimidines
about 1 to about 3 mol, preferably about 1.1 to about 2 mol
It is preferable to use it in a file. The reaction is preferably carried out in an aprotic inert organic solvent.
The method is carried out in the presence of a basic compound. Examples of aprotic inert organic solvents include
Examples: methylene chloride, chloroform, dichloroetha
carbon, carbon tetrachloride, chlorobenzene, benzene,
Luene, xylene, diethyl ether, tetrahylene
Dorofuran, dimethylformamide, dimethyla
Cetamide and the like are preferably used. The basic compounds are the same as those mentioned above.
can be used. Aprotic inert organic solvents and basic compounds
The amount of materials used can also be set in the same proportion as mentioned above.
can. The reaction temperature is usually about 0° to about 100°C, preferably about 5° to
It is carried out at approximately 50°C. The reaction is usually carried out at normal pressure.
Ru. The reaction usually completes in a few minutes to about 12 hours. Thus, according to the above reaction, The following general formula () - a₂ and/or the following formula () - b₂ [Here, R⁷,R¹¹and R^{twenty two}is defined above
It's the same. ] An enol derivative represented by is produced. The above formula () - a₂and ()—b₂represented by
Enol derivatives are usually produced as a mixture. The enol derivative thus obtained is as described above.
by similar means, as a mixture or individually.
It is isolated, purified, and converted into acid addition salts.
It can be done. Above ()-a₁and ()—b₁expressed in
The enol derivative represented by the following general formula ()-2 [Here, R¹¹The definition of is the above formula () - a₁same as
It is the same. ] Thiazolo[3,2-a]pyrimidine represented by
halogenated by the above general formula ()
compound in a polar organic solvent in the presence of a basic compound
and then optionally the reaction product obtained
It is also produced by reacting a compound with an acid.
be able to. Halogen compounds used in the above reaction, basic
The compounds, polar solvents and reaction conditions for their reactions are:
General formula () - a₁and/or ()—b₁Table with
The above-described method for producing an enol derivative
It can be exactly the same as in . According to the above reaction, general formula ()-a and
() - R in b²is a hydrogen atom.
It is also possible to produce roll derivatives. That is, according to the above reaction, the following general formula
()―a₃ and/or the following general formula ()-b₃ [The above formula () - a₃and ()—b₃Medium, R⁶
and R¹¹The definition of is the above formula () - a₁is the same as
R, R⁶¹is a hydrogen atom or R⁶is the same as ] Thiazolo[3,2-a]pyrimidine represented by
enol derivatives or their acid addition salts are produced.
Ru. The above general formula () - a₂and ()—b₂in
The enol derivative represented by the above formula ()-2
Thiazolo[3,2-a]pyrimidine represented by
of the carboxylic acid represented by the above formula ().
Logenides or acid anhydrides and aprotic inerts
in an organic solvent, preferably in the presence of a basic compound,
react and then optionally the resulting reaction product
It can also be produced by reacting a substance with an acid.
I can do it. Acid halide or non-acid used in the above reaction
Aquatic substances, aprotic inert organic solvents, basic compounds
The reaction conditions for the compound and its reaction are expressed by the general formula () -
a₂and/or general formula ()—b₂expressed as
In the above method for producing enol derivatives
It can be done exactly the same. According to the above reaction, in the general formula ()-a,
R²is a hydrogen atom and/or
In the general formula (), R²is replaced or unreplaced
C_2-7Producing a compound corresponding to an acyl group
Can be done. That is, according to the above reaction, the following general formula
()―a_Four and/or the following general formula () - b_Four and/or the following general formula ()-1₁ [The above formula () - a_Four,()―b_Fourand()
-1₁Medium, R⁷and R¹¹The definition of is the above formula () - a₂
is the same as R⁷¹is a hydrogen atom or R⁷is the same as
Ru. ] Thiazolo[3,2-a]pyrimidine represented by
and/or enol derivatives are produced. According to the research of the present inventor, the present invention provides
Among the enol derivatives, the above general formula () -
The compound represented by a further has its S-oxy
It was revealed that it can be converted into a code. Sunawa
The following general formula () [In the above formula, R¹,R²and R³The definition of is the expression ()
- Same as in a. ] Thiazolo[3,2-a]pyrimidi, represented by
Also provided are S-oxides of enol derivatives of
Ru. Such S-oxides include, for example, the following compounds:
I can give you a compound. (400) 5H-2,3-dihydro-7-methoxy
-6-dimethylamino-5-oxothiazolo
[3,2-a]pyrimidine-1-oxide (402) 5H-2,3-dihydro-7-methoxy
-5-oxo-6-di-n-propylaminothi
Azolo[3,2-a]pyrimidine-1-oxy
de (404) 6-anilino-5H-2,3-dihydro
-7-methoxy-5-oxothiazolo[3,2
-a] Pyrimidine-1-oxide (406) 6-p-chloroanilino-5H-2,3
-dihydro-7-methoxy-5-oxothiazo
B[3,2-a]pyrimidine-1-oxide (408) 5H-2,3-dihydro-7-methoxy
-6-(N-methyl-p-chloroanilino)-
5-oxothiazolo[3,2-a]pyrimidine
-1-oxide (410) 6-anilino-7-n-butoxy-5H
-2,3-dihydro-5-oxothiazolo
[3,2-a]pyrimidine-1-oxide (412) 6-[N-allylanilino)-7-ant
5H-2,3-dihydro-5-oxy
Sothiazolo[3,2-a]pyrimidine-1-o
oxido (414) 7-allyloxy-6-anilino-5H
-2,3-dihydro-5-oxo-thiazolo
[3,2-a]pyrimidine-1-oxide (416) 6-anilino-7-benzyloxy-
5H-2,3-dihydro-5-oxothiazolo
[3,2-a]pyrimidine-1-oxide (418) 7-benzyloxy-6-(N-benzi
Ru-N-phenylamino)-5H-2,3-di
Hydro-5-oxothiazolo[3,2-a]pi
Limidine-1-oxide (420) 7-acetoxy-6-(N-acetyl-
N-methylamino)-5H-2,3-dihydro
-5-oxothiazolo[3,2-a]pyrimidi
-1-oxide (422) 7-acetoxy-6-(N-acetyl-
N-phenylamino)-5H-2,3-dihyde
lo-5-oxothiazolo[3,2-a]pirimi
Gin-1-oxide (424) 7-benzoyloxy-5H-2,3-
Dihydro-6-dimethylamino-5-oxothi
Azolo[3,2-a]pyrimidine-1-oxy
de (426) 6-(N-allyl-N-phenylamine
-7-benzoyloxy-5H-2,3-
dihydro-5-oxothiazolo[3,2-a]pi
Limidine-1-oxide (428) 7-benzoyloxy-5H-2,3-
dihydro-5-oxo-6-(1-pyrrolidi
) Thiazolo[3,2-a]pyrimidine-1-
oxide (430) 5H-2,3-dihydro-7-methoxy
-6-(N-methylanilino)-5-oxothy
Azolo[3,2-a]pyrimidine-1-oxy
de The above S-oxide has the above formula ()-a
The enol derivative represented by
It is produced by oxidizing it with an oxidizing agent in
Ru. Such oxidizing agents include, for example, peracetic acid,
acid, perbenzoic acid, m-chloroperbenzoic acid, etc.
Acid; iso-butyl hydroperoxide, sec-
Butyl hydroperoxide, t-butyl high
Alkyl hydroperoxide such as droperoxide
Oxide; Sodium perchlorate, Sodium periodate
Peracids such as Lithium; N-bromosuccinimide,
Imide compounds such as N-chlorosuccinimide;
Alternatively, hydrogen peroxide and the like are preferably used. Kaka
The oxidizing agent used is usually
Used in an amount of 1 to 100 equivalents, preferably 0.5 to 3 equivalents.
Ru. Inert organic solvents include, for example, acetic acid, chloride
Methylene, chloroform, 1,2-dichloroetha
Preferably used are chlorine, benzene, ethyl acetate, etc.
Ru. Such a solvent is usually used in an amount of 1 to
Used at 100 times capacity, preferably 2 to 20 times capacity.
Ru. The reaction temperature is preferably in the range of -78°C to 50°C, and -
A range of 20°C to 30°C is particularly preferred. The reaction time depends on the raw material compound, reaction temperature, and type of oxidant.
Although it varies depending on the type, it is usually 30 minutes to 48 hours. Separation and purification of sulfoxides from reaction mixtures
is done in the usual way, e.g.
This can be done by chromatography, recrystallization, etc.
I can do it. According to the research of the present inventor, the present invention provides
Thiazolo represented by the above general formula ()
[3,2-a] Pyrimidines, their eler derivatives
bodies and their acid addition salts, i.e., pharmaceutically acceptable
Its acid addition salts, which can tolerate delayed allergy testing.
and Plaque Forming Cells test.
It also shows immunostimulatory effects and is useful as an immunomodulator.
It was revealed that this compound is useful for many purposes. Therefore, according to the present invention, in the above general formula (),
Thiazolo[3,2-a]pyrimidines represented
and its pharmaceutically acceptable acid addition salts.
pharmaceutically acceptable compounds as active ingredients
There is provided a pharmaceutical composition comprising, together with a carrier,
It will be done. According to the invention, the dosage of the active ingredient is approximately
0.1 to about 50 mg/Kg - body weight/day, preferably about 1 to
It can be about 10mg/Kg - body weight/day. The active ingredients of the invention are administered alone as such.
It can also be used as a pharmaceutical composition as described above or
Conveniently administered as a drug in unit dosage form
It is. The active ingredient of the present invention can be administered orally or parenterally.
(e.g. intravenously, subcutaneously or intramuscularly)
Alternatively, it can be administered rectally. in
It is also advantageous to administer orally. For oral administration, solid or liquid formulations are available.
be done. Such solid preparations include, for example, tablets, pills, etc.
This includes dosage forms such as tablets, powders, granules, and sugar coatings.
Ru. Such solid preparations contain one or more types of the present invention.
The active ingredients of light, such as calcium carbonate and potato
Diluents such as starch, alginic acid, lactose and
and if necessary e.g. magnesium stearate.
Mix intimately with a lubricant such as
It can be prepared by Liquid formulations include e.g.
Emulsions, solutions, suspensions, syrups, elixirs
This includes dosage forms such as tablets. Such liquid formulations are
One or more active ingredients of the invention may be added to, e.g.
Vehicles such as water or liquid paraffin, and
Wetting agents, suspension aids, sweeteners, and co-flavoring agents may be added as required.
Mix thoroughly with preservatives and formulate by conventional methods.
It can be prepared by For rectal administration, when making suppositories,
The carrier used and one or two of the active ingredients of the present invention
Suppositories and
It is prepared by Available in liquid formulations for intravenous, subcutaneous, and intramuscular administration.
It will be done. Such liquid formulations include sterile aqueous or
Solutions, suspensions, and emulsions using non-aqueous media are included.
Included. Examples of non-aqueous solvents include propylene glyco
alcohol, polyethylene glycol, vegetable oil, e.g.
Olive oil, available for injection
Examples of organic acid esters include ethyl oleate, etc.
It will be done. These liquid formulations may contain protective
Contains adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants.
You can also have it. Sterilization means bacteria
filtration through a retention filter, combination of sterilizers, or
This can be done by irradiation. Also, like this
For liquid preparations, prepare sterile solid preparations and use them immediately.
Dissolve in sterile water or sterile injection solvent before
It can also be prepared by The active ingredients of the invention are suitable for warm-blooded animals in need of e.g.
administered to humans to modulate the immune function of the warm-blooded animal.
Ru. For example, the active compounds of the invention may be used to treat chronic rheumatoid arthritis.
gore, systemic lupus erythematosus, scleroderma, multifocal
Diseases such as arteritis and dermatomyositis; cancer; infection
Disease; primary or severe infectious disease, steroid treatment,
Immune deficiency associated with lymphoma, etc.; steroids, anti-inflammatory drugs
Drugs that lower immunity, such as cancer drugs and immunosuppressants
Combination therapy when using; to enhance antibacterial activity
Combination therapy with antibiotics to reduce age-related immunity
It is effective for diseases etc. Hereinafter, the present invention will be explained in further detail with reference to Examples. Example 1 6-p-chloroanilino-5H-2,3,6,
7-tetrahydro-5,7-dioxothiazolo
Synthesis of [3,2-a]pyrimidine (112) (1) Synthesis of diethyl p-chloroanilinomalonate p-Chloraniline (2g) in dry benzene
(20 ml) and diethyl brommalonate (3.8
g) Then add dry pyridine (1.3ml) and
The mixture was stirred and heated to reflux overnight. After removing the solvent under reduced pressure, add water.
After extracting twice with chloroform, remove the chloroform layer.
Wash twice with water, dry with sodium sulfate, and remove the solution.
The solvent was distilled off under reduced pressure. Sift the resulting residue (3.34g)
Purify by licage gel column chromatography
and p-chloranilinomalo in the benzene elution area.
1.56 g (yield: 35%) of diethyl phosphate was obtained. this
The physical properties of the material were as follows. NMR(δ^CDCl3 _TMS): 1.26 (6H, t, J = 7Hz), 4.2
8
(4H, q, J=7Hz), 4.6~5.0 (2H, m,
D₂Adding O makes 1H. ), 6.63 (2H, d,
J=7H₂), 7.19 (2H, d, J = 9Hz). (2) 6-p-chloroanilino-5H-2,3,6,
7-tetrahydro-5,7-dioxothiazolo
Synthesis of [3,2-a]pyrimidine Sodium metal (120mg) in absolute ethanol
(3 ml) and add p-chloranilinoma to it.
Diethyl lonate (700 mg) in absolute ethanol (6
ml) suspension, then 2-aminothiazoline (265
mg) in absolute ethanol (2 ml) and stir.
The mixture was heated under reflux for 5 hours while stirring. Add water (50ml)
After washing with ether (30 ml), concentrated hydrochloric acid was added to the aqueous layer.
Set the pH to around 2. Add it to ethyl acetate (50ml)
Extract the combined ethyl acetate layer twice with saturated salt.
After washing with water (50ml), dry with sodium sulfate.
Ta. When the solvent was distilled off under reduced pressure, 6-p-chlorani
Rino-5H-2,3,6,7-tetrahydro-5,
7-dioxothiazolo[3,2-a]pyrimidine
440 mg (yield: 61%) was obtained. this thing's thing
The sexual values were as follows. Melting point (mp); 258-261℃ IR(ν^KBr _nax)cm^-1;3380, 3200~2200 (enol
type), 1660, 1624, 1592, 1542, 1490,
1433, 1257, 1128, 826. NMR(δ^DMSO-D6 _TMS); 3.58 (2H, t, J=8Hz),
4.37 (2H, t, J=8Hz), 6.58 (2H, d,
J = 9Hz), 6.90 (1H, br, D₂(delete with O),
7.14 (2H, d, J=9Hz), 10.3~12.0
(1H,br,D₂Eliminate with O, enol form). Example 2 6-o-chloroanilino-5H-2,3,6,
7-tetrahydro-5,7-dioxothiazolo
[3,2-a]pyrimidine (114) (1) Synthesis of diethyl o-chloroanilinomalonate o-Chloraniline (15.9g) in dry toluene
(20ml) and diethyl brommalonate.
(12.0 g) was added, stirred for 10 hours, and heated under reflux.
The reaction solution was washed with diluted hydrochloric acid and then with water three times.
It was dried over sodium sulfate and the solvent was distilled off under reduced pressure. profit
The resulting residue was subjected to silica gel column chromatography.
When purified with
Obtained 5.1 g (yield: 36%) of diethyl linomalonate.
Ta. The physical properties of this product were as follows. NMR(δ^CDCl3 _TMS); 1.20 (6H, t, J = 8Hz), 4.1
7
(4H, q, J=7Hz), 4.57, (1H, d,
J=7Hz), 5.40 (1H, d, J=7Hz), 6.3
~7.3 (4H, m) (2) 6-o-chloroanilino-5H-2,3,6,
7-tetrahydro-5,7-dioxothiazolo
Synthesis of [3,2-a]pyrimidine Sodium metal (0.28g) in absolute ethanol
(10ml) and add o-chloranilinoma to it.
Diethyl lonate (2.86 g) followed by 2-aminothi
Add azoline (1.02g) and stir for 5 hours.
The mixture was heated to reflux. Water (50ml), ethyl acetate (30ml)
and then add dilute hydrochloric acid to bring the pH to around 4.
Ru. After filtering the precipitated solid and washing with water,
Recrystallize with 6-o-chloroanilinol-5H
-2,3,6,7-tetrahydro-5,7-dio
Xothiazolo[3,2-a]pyrimidine (114)
0.92g (yield: 31%) was obtained. Physical properties of this thing
was as follows. Melting point (mp); 247.0-249.5℃ IR(ν^KBr _nax)cm^-1;3380, 3100~2000 (enol
type), 1635, 1598, 1580, 1530, 1400,
1355, 1313, 1257, 758 NMR (δCDCl₃ DMSO-d₆ TMS) ppm; 3.53 (2H, t, J=7Hz) 4.40 (2H, t,
J = 7Hz), 5.53 (1H, br, D₂add O
and disappearance) 6.3 to 7.4 (4H, m) 10.5 to 12.0
(1H,br,D₂disappears when O is added) Example 3 6-m-chloroanilino-5H-2,3,6,
7-tetrahydro-5,7-dioxothiazolo
[3,2-a]pyrimidine (116) (1) Synthesis of diethyl m-chloroanilinomalonate m-Chloraniline (12.8g) and Brommarone
Add diethyl acid (9.6g) to dry toluene (20ml)
The mixture was stirred for 3 hours and heated under reflux. reaction solution
was washed with dilute hydrochloric acid, then three times with water, and then washed with sulfuric acid.
It was dried over sodium and the solvent was distilled off under reduced pressure. Obtained
The resulting residue was washed with n-hexane to remove m-chloride.
Diethyl anilinomalonate 3.3g (yield: 29%)
I got it. The physical properties of this material are as follows.
Ta. NMR(δ^CDCl _3TMR) ppm; 1.25 (6H, t, J=7Hz),
4.20 (4H, q, J = 7Hz), 4.5~4.7 (2H,
br、D₂When O is added 1H) 6.2 to 7.3 (4H,
m) (2) 6-m-chloroanilino-5H-2,3,6,
7-tetrahydro-5,7-dioxothiazolo
Synthesis of [3,2-a]pyrimidine Sodium metal (0.29g) in absolute ethanol
(10 ml) and add m-chloranilinoma to it.
Diethyl lonate (2.86 g) followed by 2-aminothi
Add azoline (1.02g) and stir until 5 o'clock.
The mixture was heated to reflux for a while. Water (50ml) and ethyl acetate (30ml)
ml), then add dilute hydrochloric acid to bring the pH to around 4.
Ru. The precipitated solid was filtered, washed with water, and then washed with ethanol.
6-m-chloroanilino-5H
-2,3,6,7-tetrahydro-5,7-dio
Xothiazolo[3,2-a]pyrimidine (116)
0.76g (yield: 26%) was obtained. Physical properties of this thing
was as follows. Melting point (mp); 269.0-271.0℃ IR(ν^KBr _nax)cm^-1;3300, 3150~2000 (enol
type), 1635, 1600, 1530, 1515, 1425,
1410, 1395, 1360, 1135, 770 NMR (δCDCl₃ DMSO-d₆ TMS) ppm: 3.57 (2H, t, J=7Hz), 4.40 (2H, t,
J = 7Hz), 5.43 (1H, br, D₂add O
and disappearance), 6.7-7.1 (4H, m), 10.5-12.0
(1H,br,D₂disappears when O is added) Example 4 6-anilino-5H-2,3,6,7-tetra
Hydro-5,7-dioxothiazolo[3,2-
a] Synthesis of pyrimidine (110) (1) Synthesis of diethyl anilinomalonate Aniline (18.6g) was mixed with dry benzene (12.5g).
diethyl brommalonate (23.9 ml)
g) was added, and the mixture was stirred and heated under reflux for 37 hours. reaction solution
Wash with dilute hydrochloric acid to remove unreacted aniline. benzene
Wash the layer three times with water and dry with magnesium sulfate.
The solvent was then distilled off under reduced pressure. The resulting residue is silica
Hexa-vinegar when purified by gel chromatography
Ethyl acid (10:1) eluate contains dianilinomalonate.
7.5 g (yield 30%) of ethyl was obtained. this thing's thing
The sexual values were as follows. NMR(δ^CDCl4 _TMS): 1.20 (6H, t, J=7Hz), 4.2
0
(4H, q, J=7Hz), 4.66 (2H, s, br,
D₂1H with O), 6.5-7.3 (5H, m). (2) 6-anilino-5H-2,3,6,7-tet
lahydro-5,7-dioxothiazolo[3,2
-a] Synthesis of pyrimidine Sodium metal (0.80g) in absolute ethanol
(30 ml) and add the anilinomalonic acid diethyl
A solution of chill (3.75 g) in absolute ethanol (15 ml),
Then 2-aminothiazoline (1.52g) was added,
The mixture was heated to reflux for 2.5 hours while stirring. Release the reaction solution.
When cooled, a solid precipitated out, so this was separated.
(3.7g). Dissolve the separated solid (1.20g) in water,
Adjust the pH to around 4 with acetic acid to precipitate a solid. this
Separated, washed with water and dried, 6-anilino-5H-2,
3,6,7-tetrahisolo-5,7-dioxothi
Azolo[3,2-a]pyrimidine 0.26g (yield:
24%). The physical properties of this material are as follows.
be. Melting point (mp): 226.0~228.0℃ IR(ν^KBr _nax)cm^-1:3020, 1680, 1500, 1390,
1340, 1300, 1258, 1122 NMR(δ^CCl4 _TMS) ppm: 3.60 (2H, t, J = 7Hz),
4.37 (2H, t, J=7Hz), 6.4~7.5 (6H,
m, D₂1H disappears with O), 10.0-11.5 (1H, br,
D₂Disappears with O, enol form). Example 5 6-Benzylamino-5H-2,3,6,7-
Tetrahydro-5,7-dioxothiazolo
Synthesis of [3,2-a]pyrimidine (138) (1) Synthesis of diethyl benzylaminomalonate Benzylamine (18.3g) and brommalonic acid di
Ethyl (20.3g) to dry benzene (100ml)
The mixture was dissolved and stirred and heated to reflux for 14 hours. Separated from reaction solution
Remove the salt through a sieve and wash the liquid with dilute hydrochloric acid.
Unreacted benzelamine was removed. This benzene
Wash the layer three times with water and dry with magnesium sulfate.
The solvent was then distilled off under reduced pressure. The resulting residue is silica
When purified by gel chromatography, hexane
-Benzylamino in the ethyl acetate (4:1) eluate
4.7 g (yield: 21%) of diethyl malonate was obtained.
The physical properties of this product were as follows. NMR(δ^CCl4 _TMS): 1.22 (6H, t, J = 7Hz), 3.20
(2H, s), 4.10 (4H, q, J=7Hz),
4.70 (2H, s, br, D₂When O is added, 1H),
7.15-7.5 (5H, m). (2) 6-benzylamino-5H-2,3,6,7
-Tetrahydro-5,7-dioxothiazolo
Synthesis of [3,2-a]pyrimidine Sodium metal (0.46g), benzylaminomer
Diethyl ronate (2.65g), 2-aminothiazoli
(1.02g) and absolute ethanol (20ml).
Then, perform the same operation as in Example (110)-(2),
Furthermore, the residue was subjected to silica gel column chromatography.
and diluted with methylene chloride-methanol (19:1).
From the exit part 6-benzylamino-5H-2,3,6,
7-tetrahydro-5,7-dioxothiazolo
[3,2-a]pyrimidine 0.8g (yield: 29%)
Obtained. The physical properties of this product were as follows. Melting point (mp): 196.0~198.0℃ IR(ν^KBr _nax)cm^-13200-2000 (enol type), 1600
，
1590, 1375, 1240, 1120, 1070 NMR(δ^CCl4 _TMS) ppm: 3.30 (2H, t, J=7Hz),
4.23 (2H, t, J=7Hz), 4.23 (2H, s),
7.1~7.5 (6H, m, D₂Adding O gives 5H.
) 10.0 to 11.5 (1H, br, D₂Adding O
disappearance, enol form) Example 6 5H-2,3,6,7-tetrahydro-6-
(N-methylanilino)-5,7-dioxothi
Synthesis of azolo[3,2-a]pyrimidine (164)
Growth (1) Synthesis of diethyl N-methylanilinomalonate N-methylaniline (15.1g) and brommalone
Diethyl acid (16.9g) and dry benzene (90ml)
The mixture was stirred and heated under reflux for 16 hours. Example 2 (1)
Washing, drying, and concentration were performed in the same manner as above. Residue
Purify the residue using silica gel column chromatography.
Then, N- is added to the benzene-hexane (2:1) elution area.
Diethyl methylanilinomalonate 10.2g (yield:
54%). The physical properties of this material are as follows.
It was hot. NMR(δ^CCl4 _TMS) ppm: 1.23 (6H, t, J = 7Hz)
3.02 (3H, s), 4.20 (4H, q, J=7Hz),
5.03 (1H, s), 6.6~7.45 (5H, m), (2) 5H-2,3,6,7-tetrahydro-6-
(N-methylanilino)-5,7-dioxothi
Synthesis of azolo[3,2-a]pyrimidine Diethyl N-methylanilinomalonate (1.58
g) and 2-aminothiazoline (0.71g) and diphene
Mix Nyl ether (2 ml) and add under nitrogen atmosphere.
Heat to 175°C with stirring and react for 1.5 hours. reaction mixture
The compound was subjected to silica gel column chromatography.
and methylene chloride-methanol (19:1) elution part
to 5H-2,3,6,7-tetrahydro-6-
(N-methylanilino)-5,7-dioxothia
Zoro[3,2-a]pyrimidine 0.43g (yield: 27
%) was obtained. The physical properties of this material are as follows.
Ivy. Melting point (mp): 100.0~102.0℃ IR(ν^KBr _nax)cm^-1:3700~2000 (enol), 1635
，
1602, 1505, 1400 NMR(δ^CDCl3 _TMS) ppm: 3.03 (3H, s), 3.35 (2H,
t, J = 7Hz), 4.30 (2H, t, J = 7
Hz), 6.45-7.5 (5H, m), 10.0-11.5 (1H,
br、D₂When O is added, it disappears, enol form). Example 7 6-(p-chloro-N-methylanilino)-
5H-2,3,6,7-tetrahydro-5,7
-Dioxothiazolo[3,2-a]pyrimidine
Synthesis of (166) (1) p-chloro-N-methylanilinomalonate di
Synthesis of ethyl p-chloro-N-methylaniline (10.1g) and
Diethyl brommalonate (8.5g) and dryben
Mix Zen (60 ml) and stir and heat to reflux for 7 hours.
Ta. Washing, drying, and concentration in the same manner as in Example 2 (1)
I did this. The resulting residue was placed in a silica gel column.
Benzene-hexane
(1:1) From the elution part, p-chloro-N-methyl
Diethyl anilinomalonate 3.5g (yield: 33%)
I got it. The physical properties of this product are as follows. NMR(δ^CCl4 _TMS): 1.30 (6H, t, J = 7Hz), 3.00
(3H, s), 4.25 (4H, q, J=7Hz),
4.95 (1H, s), 6.72 (2H, d, J=9H₂),
7.21 (2H, d, J = 9Hz). (2) 6-(p-chloro-N-methylanilino)-
5H-2,3,6,7-tetrahydro-5,7
-Dioxothiazolo[3,2-a]pyrimidine
synthesis of p-chloro-N-methylanilinomalonate diene
Chill (2.40g) and 2-aminothiazoline (0.98g)
g) and diphenyl ether (5 ml), and
Stir under elementary atmosphere, heat to 180℃, and react for 2 hours.
let The residue was washed with methylene chloride and 6-(p
-Chlor-N-methylanilino)-5H-2,3,
6,7-tetrahydro-5,7-dioxothiazo
B[3,2-a]pyrimidine 0.99g (yield: 36
%) was obtained. The physical properties of this material are as follows.
Ru. Melting point (mp): 228.0~230.5℃ IR(ν^KBr _nax)cm^-1:3700~2000 (enol), 1620
，
1600, 1525, 1497, 1405, 1360, 1250,
1120 NMR(δ^{CDCl3+DMSO-D6} _TMS) ppm: 3.03 (3H, s) 3.53
(2H, t, J = 7Hz), 4.37 (2H, t, J
=7Hz), 6.50 (2H, d, J = 9Hz) 7.06
(2H, d, J=9Hz), 10.0~11.5 (1H,
br、D₂When O is added, it disappears, enol form). Reference example 1 5H-2,3-dihydro-7-methoxy-6-
(N-methylanilino)-5-oxothiazolo
[3,2-a]pyrimidine (208) and 6-ani
Rino-5H-2,3-dihydro-7-methoxy
-5-oxothiazolo[3,2-a]pyrimidi
Synthesis of (204) Add sodium hydride (0.2g) to anhydrous dimethyl fluoride.
Suspend in Lumamide (10 ml) and add anhydrous
6-aniline dissolved in chillformamide (5 ml)
No-5H-2,3,6,7-tetrahydro-5,
7-dioxothiazolo[3,2-a]pyrimidine
(1.7g), then methyl iodide (3.0g)
was added and stirred at room temperature for 8 hours. Concentrate the solvent under reduced pressure
and the residue was extracted with chloroform.
Wash the chloroform layer with water and dilute with anhydrous sodium sulfate.
The solvent was distilled off. Silica gel residue
Subjected to column chromatography, chloroform
-Elute with methanol (20:0~1), low polarity
From the fraction, 5H-2,3-dihydro-7-methoxy
-6-(N-methylanilino)-5-oxothia
Zoro[3,2-a]pyrimidine (206) 0.26g
(yield: 15%) and 6-anilino from the highly polar fraction.
-5H-2,3-dihydro-7-methoxy-5-
Oxothiazolo[3,2-a]pyrimidine (204)
0.18g (yield: 10%) was obtained. these things things
The gender values are as follows. 5H-2,3-dihydro-7-methoxy-6-
(N-methylanilino)-5-oxothiazolo
Physical properties of [3,2-a]pyrimidine: Melting point (mp); 234.5-237.0℃ IR(ν^KBr _nax)cm^-1;1658, 1580, 1520, 1503,
1468, 1395, 1360, 1345, 1238, 1125,
760 NMR(δ^CDCl3 _TMS) ppm: 3.13 (3H, s), 3.46 (2H,
t, J=7Hz), 3.90 (3H, s), 3.50 (2H,
t, J=7Hz), 6.6-7.5 (5H, m) 6-anilino-5H-2,3-dihydro-7-
Methoxy-5-oxothiazolo[3,2-a]pi
Physical properties of Limidine: IR(ν^KBr _nax)cm^-1;1655, 1595, 1525, 1497,
1460, 1393, 1345, 1320, 1265, 1145,
963,741 NMR(δ^CDCl3 _TMS) ppm; 3.44 (2H, t, J=7Hz),
3.93 (3H, s), 4.45 (2H, t, J=7Hz),
5.3(1H,br,s,D₂disappears when O is added),
6.6~7.5 (5H, m) Reference example 2 5H-2,3-dihydro-7-methoxy-6-
(N-methyl-p-chloroanilino)-5-o
Xothiazolo[3,2-a]pyrimidine (210)
and 6-p-chloroanilino-5H-2,3-
Dihydro-7-methoxy-5-oxothiazolo
Synthesis of [3,2-a]pyrimidine (206) 6-(p-chloranili obtained in Example 4)
g) 5H-2,3,6,7-tetrahydro-5,
7-dioxothiazolo[3,2-a]pyrimidine
Sodium salt (390mg) of anhydrous dimethylform
Dissolved in 5 ml of amide, then dissolved in methyl iodide (1
ml) and stirred at room temperature for 12 hours. After the reaction
The same post-processing operation as in Reference Example 1 was performed. thin the residue
Subjected to layer chromatography, methylene chloride
Developed with tanol (19:1) and fractionated with Rf value 0.47.
5H-2,3-dihydro-7-methoxy-6-
(N-methyl-p-chloroanilino)-5-oxy
Sothiazolo[3,2-a]pyrimidine (210)85
mg (yield: 23%) and Rf value 0.4 fraction, 6-p
Chloranilino-5H-2,3-dihydro-7-
Methoxy-5-oxothiazolo[3,2-a]pi
25 mg (yield: 7%) of rimidine (206) was obtained. child
The physical properties of these materials are as follows. 5H-2,3-dihydro-7-methoxy-6-
(N-methyl-p-chloroanilino)-5-oxy
Physical properties of sothiazolo[3,2-a]pyrimidine: Melting point (mp); 165.5-165.6℃ IR(ν^KBr _nax)cm^-1;1645, 1580, 1523, 1498,
1460, 1400, 1350, 1238, 1120, 820 NMR(δ^CDCl3 _TMS) ppm; 3.07 (3H, s), 3.43 (2H,
t, J=7Hz), 3.86 (3H, s), 4.43 (2H,
t, J=7Hz), 6.75-7.3 (4H, m) 6-p-chloranilino-5H-2,3-dihi
Dro-7-methoxy-5-oxothiazolo [3,
2-a] Physical properties of pyrimidine: Melting point (mp); 184.0-186.5℃ IR(ν^KBr _nax)cm^-1;1640, 1580, 1495, 1448,
1390, 1345, 1320, 1260, 1200, 1148,
962,815 NMR(δ^CDCl3 _TMS) ppm; 3.45 (2H, t, J=7Hz),
3.88 (3H, s), 4.45 (2H, t, J=7Hz),
5.35 (1H, s, D₂disappears when O is added), 6.45
~7.3 (4H, m) Reference example 3 7-n-butoxy-6-(N-n-butylani
Reno)-5H-2,3-dihydro-5-oxo
Thiazolo[3,2-a]pyrimidine (212) and
and 6-anilino-7-n-butoxy-5H-2,
3-dihydro-5-oxothiazolo [3,2-
a] Synthesis of pyrimidine (214) Sodium hydride (0.17g) was dissolved in anhydrous dimethyl fluoride.
Suspend in Lumamide (20 ml) and add anhydrous
In Example 4 dissolved in chillformamide (5 ml)
The resulting 6-anilino-5H-2,3,6,7-
Tetrahydro-5,7-dioxothiazolo[3,
2-a] Add pyrimidine (1.50g) and then remove the odor.
Add n-butyl chloride (1.38g) and heat at 15-20℃ for 8 o'clock.
Stir for a while. Post-treatment similar to Reference Example 1 after completion of reaction
I performed the operation. Silica gel column chromatography of the residue
Attached to graphite, methylene chloride-hexane (1:
1 to 0), and 7-n-butane was eluted from the low polarity fraction.
Toxi-6-(N-n-butylanilino)-5H
-2,3-dihydro-5-oxothiazolo [3,
2-a] Pyrimidine (212) 0.09g (yield: 4%)
6-anilino-7-n-butoki from the highly polar fraction
C-5H-2,3-dihydro-5-oxothiazo
B[3,2-a]pyrimidine (214) 0.76g (yield
rate: 42%). The physical properties of these things are as follows
That's right. 7-n-butoxy-6-(N-n-butylani
Rino)-5H-2,3-dihydro-5-oxothi
Physical properties of Azolo[3,2-a]pyrimidine: Acid point (mp); 119.0-121.5℃ IR (^KBr _nax)cm^-1;1650, 1577, 1513, 1498,
1395, 1338, 1240, 735 NMR(δ^CDCl3 _TMS) ppm; 3.46 (4H, t, J=7Hz),
4.20 (2H, t, J=7Hz), 4.46 (2H, t,
J=7Hz), 0.6~2.0 (14H, m), 6.43~7.4
(5H, m). 6-anilino-7-n-butoxy-5H-2,
3-dihydro-5-oxothiazolo [3,2-
a] Physical properties of pyrimidine: Melting point (mp); 97.0-98.5℃ IR (^KBr _nax)cm^-1；1640，1590，1500，1460，
1390, 1325, 1260, 1148 NMR(δ^CDCl3 _TMS) ppm; 0.6 to 1.9 (7H, m), 3.41
(2H, t, J = 8Hz), 4.30 (2H, t, J
= 7Hz), 4.43 (2H, t, J = 8Hz), 5.38
(1H,s,D₂disappears when O is added), 6.6 to 7.5
(5H, m). Reference example 4 6-(N-allylanilino)-7-allyluoki
C-5H-2,3-dihydro-5-oxothia
Zoro[3,2-a]pyrimidine (232) and 7
-Allyloxy-6-anilino-5H-2,3
-dihydro-5-oxothiazolo[3,2-
a] Synthesis of pyrimidine (234) Add sodium hydride (0.12g) to anhydrous dimethyl fluoride.
Suspend in Lumamide (10 ml) and add anhydrous
In Example 4 dissolved in chillformamide (5 ml)
The resulting 6-anilino-5H-2,3,6,7-
Tetrahydro-5,7-dioxothiazolo[3,2
-a] Add pyrimidine (0.52g), then bromide
Add allyl (0.29g) and stir at 15-20℃ for 30 hours.
did. After the reaction is complete, post-processing operations are the same as in Reference Example 1.
I went to Silica gel thin layer chromatography of the residue
methylene chloride-methanol (19:
1), and the 6-(N allele) was extracted from the low polarity fraction.
Anilino)-7-allyloxy-5H-2,3-
Dihydro-5-oxothiazolo[3,2-a]pi
Limidine (232) 0.15g (yield: 25%) and high polarity
From the fraction of 7-allyloxy-6-anilino-
5H-2,3-dihydro-5-oxothiazolo
[3,2-a]pyrimidine (234) 0.07g (yield:
11%). The physical properties of these things are as follows
It is. 6-(N-allylanilino)-7-allyluoki
C-5H-2,3-dihydro-5-oxothiazo
B Physical properties of [3,2-a]pyrimidine: Melting point (mp); 134.0-136.0℃ IR (^KBr _nax)cm^-1;1650, 1578, 1515, 1500,
1392, 1335, 1298, 1227, 1143, 755 NMR(δ^CDCl3 _TMS) ppm; 3.40 (2H, t, J=7Hz),
4.06 (2H, d, J = 4Hz), 4.40 (2H, d,
J = 7Hz), 4.70 (2H, d, J = 4Hz),
4.73~5.50 (4H, m), 6.5~7.33 (5H, m) 7-allyloxy-6-anilino-5H-2,
3-dihydro-5-oxothiazolo [3,2-
a] Physical properties of pyrimidine Melting point (mp); 123.0-1245℃ IR (^KBr _nax)cm^-1;1655, 1595, 1515, 1498,
1395, 1335, 1320, 1260, 1140 NMR(δ^CDCl3 _TMS) ppm; 3.40 (2H, t, J=8Hz),
4.43 (2H, t, J=8Hz), 4.85 (2H, d,
J=5Hz), 5.0~5.6(3H, m, D₂add O
and 2H), 5.65-6.5 (1H, m), 6.6-7.4
(5H, m) By the above reaction, 6-(N-allyl
nilino)-5H-2,3,6,7-tetrahydro
-5,7-dioxothiazolo[3,2-a]pyri
Midin (174) was also obtained. The physical properties of this thing are
It was as follows. Melting point (mp): 108.5~112.0℃ IR(ν^KBr _nax)cm^-1:3700~2000 (enol), 1640
，
1602, 1503, 1402, 1240, 1225, 1022 NMR(δ^CDCl3 _TMS) ppm: 3.41 (2H, t, J=8Hz),
4.15 (2H, d, J = 7Hz), 4.40 (2H, t,
J=8Hz), 5.0~5.6 (2H, m), 5.7~6.4
(1H, m), 6.6-7.9 (5H, m), 10.5-12.0
(1H,br,D₂disappears when O is added, enol
type). Reference example 5 7-benzyloxy-6-(N-benzyl-N
-phenylamino)-5H-2,3-dihydro
-5-oxothiazolo[3,2-a]pyrimidi
(260) and 6-anilino-7-benzylo
Oxy-5H-2,3-dihydro-5-oxothi
Synthesis of azolo[3,2-a]pyrimidine (258)
Growth Add sodium hydride (0.28g) to anhydrous dimethyl fluoride.
Suspend in Lumamide (20 ml) and add anhydrous
In Example 4 dissolved in chillformamide (10ml)
The resulting 6-anilino-5H-2,3,6,7-
Tetrahydro-5,7-dioxothiazolo[3,
2-a] Add pyrimidine (2.50g), then salt
Add benzyl chloride (2.48g) and heat at 15-20℃ for 8 hours.
Stirred. After completion of the reaction, post-treatment similar to Reference Example 1
I performed the operation. Silica gel column chromatography of the residue
Methylene chloride-methanol
(15:0 to 1), and 7-
Benzyloxy-6-(N-benzyl-N-hue
nylamino)-5H-2,3-dihydro-5-o
Xothiazolo[3,2-a]pyrimidine (260)
0.32g (yield: 8%) and 6-a from the highly polar fraction.
Nilino-7-benzyloxy-5H-2,3-di
Hydro-5-oxothiazolo[3,2-a]pyri
0.94 g (yield: 28%) of midine (258) was obtained. child
The physical properties of these materials are as follows. 7-benzyloxy-6-(N-benzyl-N
-phenylamino)-5H-2,3-dihydro-
5-oxothiazolo[3,2-a]pyrimidine
Physical property values: Melting point (mp); 156.0-158.0℃ IR(ν^KBr _nax)cm^-1;1650, 1583, 1518, 1500,
1392, 1355, 1228, 1143, 758 NMR(δ^CDCl3 _TMS) ppm; 3.30 (2H, t, J=7.5
Hz), 4.35 (2H, t, J=7.5Hz), 4.75
(2H, s), 5.29 (2H, s), 6.45~7.6
(15H, m), 6-anilino-7-benzyloxy-5H-2,
3-dihydro-5-oxothiazolo [3,2-
a] Physical properties of pyrimidine: Melting point (mp); 160.6-161.0℃ IR (^KBr _nax)cm^-1；1640，1603，1585，1505，
1440, 1392, 1345, 1265, 1150 NMR(δ^CDCl3 _TMS) ppm; 3.36 (2H, t, J=8Hz),
4.40 (2H, t, J=8Hz), 5.4 (3H, s,
D₂2H when adding O), 6.57 to 7.5 (10H, m) Reference example 6 5H-2,3-dihydro-5-methoxy-6-
(N-methylanilino)-7-oxothiazolo
Synthesis of [3,2-a]pyrimidine (304) 6-anilino-5H-2,3,6,7-tetra
Hydro-5,7-dioxothiazolo[3,2-
a] Pyrimidine enolide sodium salt
(0.97g) in anhydrous NN-dimethylformamide
(25 ml) and add methyl iodide (2.0 g) to it.
Add. The reaction was stirred at 15°C for 22 hours. melt
The medium was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography.
Subjected to matography, methylene chloride-methanol
Elute with 5H-2,3-di
Hydro-5-methoxy-6-(N-methylanili
B)-7-oxothiazolo[3,2-a]pirimi
0.32 g (yield: 13%) of gin was obtained. this thing's thing
The gender values are as follows. Melting point (mp): 124.0~127.5℃ IR(ν^KBr _nax)cm^-1:1640, 1600, 1555, 1505,
1325, 1250, 753 NMR(δ^CDCl3 _TMS) ppm: 3.13 (3H, s), 3.33 (2H,
t, J=8Hz), 3.43 (3H, s), 4.47 (2H,
t, J=8Hz), 6.5-7.2 (5H, m), Reference example 7 6-anilino-5-benzyloxy-5H-2,
3-dihydro-7-oxothiazolo[3,2-
a] Synthesis of pyrimidine (314) 6-anilino-5H-2,3,6,7-tetra
Hydro-5,7-dioxothiazolo[3,2-
a] Add pyrimidine (2.50g) to sodium hydride
(0.28g) of anhydrous N,N-dimethylformamide
(20 ml) added to the suspension. Furthermore, add benzyl chloride (248g) to this,
The mixture was stirred and reacted at ℃ for 14 hours. Distill the solvent under reduced pressure
The residue was extracted with ethyl acetate, washed with water, and extracted with anhydrous sulfur.
After drying with sodium chloride, it was concentrated. Remove residue
The chloride solution was subjected to Kagel column chromatography.
Elute with tyrene and 6-anilino-5-benzyl
Oxy-5H-2,3-dihydro-7-oxothi
Azolo[3,2-a]pyrimidine 0.30g (yield:
9%). The physical properties of this material are as follows.
Ru. Melting point (mp): 198~200.5℃ IR(ν^KBr _nax)cm^-1:1623, 1540, 1470, 1447, 1425,
1320, 1293, 1240, 766, 715 NMR(δ^CDCl3 _TMS) ppm: 3.20 (2H, t, J=7Hz),
4.33 (2H, t, J=7Hz), 5.00 (2H, s),
6.4-7.4 (11H, m). Reference example 8 7-acetoxy-6-(N-acetyl-N-ph)
enylamino)-5H-2,3-dihydro-5
-Oxothiazolo[3,2-a]pyrimidine
Synthesis of (278) 6-anilino-5H-2 obtained in Example 4,
3,6,7-tetrahydro-5,7-dioxothi
Azolo[3,2-a]pyrimidine (1.0g) and nothing
Hydroacetic acid (0.47g) and triethylamine (0.58g)
and methylene chloride (50ml) and heat at 15-20°C.
Stir for hours. Add the reaction solution to saturated sodium bicarbonate solution, then water.
(3 times) and dried with anhydrous sodium sulfate.
The solvent was distilled off. Chroma the residue on a silica gel column.
Methylene chloride-methanol
(25:0-1) elution, 7-acetoxy-6-
(N-acetyl-N-phenylamino)-5H-
2,3-dihydro-5-oxothiazolo[3,2
-a] 0.10 g (yield: 8%) of pyrimidine was obtained.
The physical properties of this product are as follows. IR (^KBr _nax)cm^-1;1793, 1665, 1600, 1530,
1395, 1345, 1320, 1180, 1008 NMR(δ^CDCl3 _TMS) ppm; 2.06 (3H, s), 2.20 (3H,
s), 3.52 (2H, t, J=7Hz), 4.50 (2H,
t, J = 7Hz), 7.4 (5H, br, s). Example 8 6-(N-benzoyl-N-phenylamino)
-5H-2,3,6,7-tetrahydro-5,
7-Dioxothiazolo[3,2-a]pyrimidine
Synthesis of (178) 6-anilino-5H-2,3,6,7-tetra
Hydro-5,7-dioxothiazolo[3,2-
a] Add pyrimidine (1.67 g) to methylene chloride (20
ml), and here triethylamine (1.52
Add g). Followed by benzoyl chloride (1.83g)
and stirred at 10-20℃ for 15 hours to carry out the reaction.
Closed. Wash the reaction solution with dilute hydrochloric acid and then with saturated sodium bicarbonate solution.
After cleaning, it was washed three times with water. This methylene chloride
The solution was dried over magnesium sulfate and the solvent was removed under reduced pressure.
I left. Silica gel column chromatography of the residue
methylene chloride-methanol (49:
1) 6-(N-benzoylanilino)- in the elution area
5H-2,3,6,7-tetrahydro-5,7-
Dioxothiazolo[3,2-a]pyrimidine 1.19
g (yield: 51%) was obtained. The physical properties of this material are as follows.
It is as below. Melting point (mp): 100.0~102.0℃ IR(ν^KBr _nax)cm^-1:3700~2050 (enol), 1758
，
1685, 1660, 1600, 1530, 1498, 1396,
1342, 1243, 1100. NMR(δ^CDCl3 _TMS) ppm: 3.50 (2H, t, J=7Hz),
4.50 (2H, t, J=7Hz), 7.1~7.8 (8H,
m), 7.9-8.3 (2H, m), 10.5-12.0 (1H,
br、D₂When O is added, it disappears, enol form). Reference example 9 6-(N-cyclohexyl-N-methylamine
-5H-2,3-dihydro-7-hydro
C-5-oxothiazolo[3,2-a]pirimi
Gin sodium salt (267) (1) (N-cyclohexyl-N-methylamino)
Synthesis of diethyl malonate Diethyl brommalonate (17.0g), triethyl
Mix lamine (9.1g) and dry toluene (10ml).
Combine and heat to reflux while stirring. here
N-cyclohexane diluted with light toluene (5 ml)
Add sil-N-methylamine (8.1 g) dropwise and add 2.5
The mixture was stirred for hours and heated under reflux. Add the reaction solution to water
After washing three times with
The solvent was distilled off under reduced pressure. The remaining liquid is distilled under reduced pressure.
Tute (N-cyclohexyl-N-methylamino)
5.5 g (yield: 29%) of diethyl malonate was obtained.
The physical properties of this product were as follows. Boiling point (b.p.): 124-128℃ (0.4mmHg) NMR(δ^CDCl3 _TMS) ppm: 1.23 (6H, t, J = 7Hz),
0.9~2.1 (10H, m), 2.42 (3H, s), 2.3~
3.0 (1H, m), 4.31 (4H, q, J = 7Hz),
4.06 (1H, s). (2) 6-(N-cyclohexyl-N-methylamine
-5H-2,3-dihydro-7-hydro
C-5-oxothiazolo[3,2-a]pirimi
gin sodium salt Sodium metal (0.30g) in absolute ethanol
(10ml). in absolute ethanol (10ml)
Dissolved N-cyclohexyl N-methylaminomer
Add diethyl lonate (2.7 g), then add 2-a
Add minothiazoline (1.0g) and stir for 3 hours.
It was heated to reflux. Filter the precipitated solid and add ethanol.
6-(N-cyclohexyl-N-
methylamino)-5H-2,3-dihydro-7-
Hydroxy-5-oxothiazolo[3,2-a]
Pyrimidine sodium salt (267) 0.86 g (yield:
31%). The physical properties of this material are as follows.
It was hot. IR(ν^KBr _nax)cm^-11635, 1562, 1505, 1400, 1238 NMR(δ^D2O _DSS): ppm: 0.9 to 2.1 (10H, m), 2.90
(3H, s), 2.8~3.0 (1H, br), 3.50 (2H,
t, J = 8Hz), 4.35 (2H, t, J = 8
Hz). Reference example 10 5H-2,3-dihydro-7-hydroxy-5
-oxo-6-di-n-propylaminothiazo
B[3,2-a]pyrimidine sodium salt
(268) () Diethyl di-n-propylaminomalonic acid
Synthesis of esters D-n-propylamine (15.2g) and bromic acid
Dissolve 17.9g of diethyl in dry benzene (90ml)
The mixture was stirred for 7 hours and heated to reflux. fruit after this
The residue obtained by performing the same operation as in Example 2 (1)
was subjected to silica gel column chromatography,
From the benzene-ethyl acetate (20:1) eluate, di-
n-propylaminomalonic acid diethyl ester
16.9g (yield: 87%) was obtained. () 5H-2,3-dihydro-7-hydroxy
C-5-oxo-6-di-n-propylamino
Thiazolo[3,2-a]pyrimidine sodium
salt synthesis Sodium metal (0.28g) in absolute ethanol
(10ml) plus sodium ethoxide ether
Prepare a nol solution. Absolute ethanol here
G-n-propylaminomalo dissolved in (10ml)
Add phosphoric acid diethyl ester (2.74g) and
- Add aminothiazoline (1.02g) and leave for 3 hours.
The mixture was stirred and heated to reflux. Pour the precipitated solid
Twist and take out, 5H-2,3-dihydro-7-
Hydroxy-5-oxo-6-d-n-propyl
Minothiazolo[3,2-a]pyrimidine sodium
0.74 g (yield: 26%) of mu salt (268) was obtained. this
The physical properties of the material were as follows. IR(ν^KBr _nax)cm^-1:1637, 1563, 1518, 1415,
1400, 1225, 797 NMR(δ^D2O _DSS) ppm: 0.80 (3H, t, J=7Hz),
1.15 (3H, t, J=7Hz), 0.5~1.6 (4H,
m), 2.9 (2H, t, J=8Hz), 3.45 (2H,
t, J = 8Hz), 3.57 (2H, t, J = 7
Hz), 4.30 (2H, t, J = 7Hz). Reference example 11 6-anilino-5H-2,3-dihydro-7-
Hydroxy-5-oxothiazolo[3,2-
a] Pyrimidine sodium salt (299) 6-anilino-5H-2,3,6,7-tetra
Hydro-5,7-dioxothiazolo[3,2-
a] Pyrimidine (110) (1.31g) in sodium hydroxide
(0.2 g) and water (3 ml) at room temperature for 1 hour.
Stir briefly to dissolve. Distill water under reduced pressure and
6-anilino-5H-2,3-dihydro-7
-Hydroxy-5-oxothiazolo[3,2-
a] 1.4 g (yield) of sodium salt of pyrimidine (299)
rate: 100%). The physical properties of this material are as follows.
It was hot on the street. NMR(δ^D2O _DSS) ppm: 3.53 (2H, t, J=7Hz),
4.27 (2H, t, J=7Hz), 6.5~7.4 (5H,
m). Reference example 12 6-p-chloranilino-5H-2,3-dihi
Dro-7-hydroxy-5-oxothiazolo
[3,2-a]Pyrimidine sodium salt (269) 6-p-chloroanilino-5H-2,3,6,
7-tetrahydro-5,7-dioxothiazolo
[3,2-a]Pyrimidine (112) (1.48g) in water
In addition to sodium oxide (0.2 g) and water (3 ml),
Stir for 1 hour at room temperature to dissolve. Distill water under reduced pressure
target 6-p-chloroanilino-5H
-2,3-dihydro-7-hydroxy-5-ox
sothiazolo[3,2-a]pyrimidine sodium
1.58 g (yield: 100%) of mu salt (269) was obtained. this
The physical properties of the material were as follows. NMR(δ^D2O _DSS) ppm: 3.40 (2H, t, J=7Hz),
4.27 (2H, t, J=7Hz), 6.4~7.3 (4H,
m). Reference example 13 6-anilino-7-n-butoxy-5H-2,
3-dihydro-5-oxothiazolo [3,2-
a] Synthesis of pyrimidine-1-oxide (410) 6-anilino-7-n-butoxy-5H-2,
3-dihydro-5-oxothiazolo [3,2-
a] Pyrimidine (450 mg) and m-chlorperbenzoin
Dissolve the acid (430 mg) in methylene chloride (15 ml),
Stirred at 20°C for 21 hours. Then heated under reflux for 3 hours.
Add m-chloroperbenzoic acid (230 mg),
The mixture was further heated under reflux for 2 hours to react. methylene chloride
Wash the solution twice with saturated sodium bicarbonate solution, followed by three times with water.
Washed twice. dried with anhydrous magnesium sulfate
Afterwards, the solvent was concentrated under reduced pressure, and the resulting residue was filtered onto silica gel.
The mixture was subjected to column chromatography. Methi chloride
Elute with ren-methanol (13:0-1),
-Anilino-7-n-butoxy-5H-2,3-
Dihydro-5-oxothiazolo[3,2-a]pi
44 mg (yield: 9%) of rimidine-1-oxide was obtained.
Ta. The physical properties of this product are as follows. IR(ν^KBr _nax)cm^-1:1640, 1660, 1500, 1440,
1407, 1345, 1153, 1062, 740 NMR(δ^CDCl3 _TMS) ppm: 0.6 to 1.85 (7H, m), 3.40
(2H, t, J = 7Hz), 4.43 (2H, t, J
= 6Hz), 4.73 (2H, t, J = 7Hz), 6.6~
7.6 (6H, m). Reference example 14 6-p-chloranilino-5H-2,3-dihi
Dro-7-methoxy-5-oxothiazolo
[3,2-a]pyrimidine-1-oxide
Synthesis of (406) 6-p-chloranilino-5H-2,3-dihi
Dro-7-methoxy-5-oxothiazolo [3,
2-a] Pyrimidine (300mg) and m-chloride overconsumption
Dissolve zoic acid (200mg) in methylene chloride (20ml)
The mixture was stirred at 20°C for 6 hours to cause a reaction.
After this, the same post-processing operation as in Example 1 was performed.
Ta. The residue thus obtained was transferred to a silica gel column.
Subjected to chromatography and eluted with methylene chloride.
Se,6-p-chloroanilino-5H-2,3-di
Hydro-7-methoxy-5-oxothiazolo
[3,2-a]pyrimidine-1-oxide 103mg
(yield: 33%). The physical properties of this material are as follows.
It is. NMR(δ^CDCl3 _TMS) ppm; 3.47 (2H, t, J=7Hz),
4.00 (3H, s), 4.77 (2H, t, J=7Hz),
6.05 (1H, br, s), 6.6-7.4 (4H, m). Reference example 15 5H-2,3-dihydro-7-methoxy-6-
(N-methylanilino)-5-oxothiazolo
[3,2-a]pyrimidine-1-oxide
Synthesis of (430) 5H-2,3-dihydro-7-methoxy-6-
(N-methylanilino)-5-oxothiazolo
[3,2-a]pyrimidine (257mg) and m-chlor
Perbenzoic acid (270mg) in methylene chloride (30ml)
Dissolve and stir at 20℃ for 3 hours to initiate a reaction.
Ta. After this, a saturated aqueous solution of sodium bicarbonate
(30ml) and continue stirring at the same temperature for 30 minutes.
Ta. After this, the methylene chloride solution was separated, washed with water,
After drying with anhydrous sodium sulfate, methylene chloride was added under reduced pressure.
Removed. Silica gel column chromatography of the residue
Elute with methylene chloride, 5H-
2,3-dihydro-7-methoxy-6-(N-methoxy)
tylanilino)-5-oxothiazolo[3,2-
a] 13 mg of pyrimidine-1-oxide was obtained (harvested
Rate: 5%). The physical properties of this product are as follows. NMR(δ^CDCl3 _TMS) ppm: 3.06 (3H, s), 3.33 (2H,
t, J=6Hz), 3.90 (3H, s), 4.60 (2H,
t, J = 6Hz), 6.4-7.3 (5H, m). Reference example 16 5H-2,3-dihydro-7-methoxy-6-
(N-methyl-p-chloroanilino)-5-o
Xothiazolo[3,2-a]pyrimidine-1-
Synthesis of oxide (408) 5H-2,3-dihydro-7-methoxy-6-
(N-methyl-p-chloroanilino)-5-oxy
Sothiazolo[3,2-a]pyrimidine (104mg)
and m-chloroperbenzoic acid (65 mg) in methylene chloride.
(10ml) and stirred at 20℃ for 6 hours to stop the reaction.
I made it difficult. After this, perform the same post-processing operations as in the reference example.
I applied it. The residue thus obtained is converted into silica gel.
Subjected to preparative thin layer chromatography, methylene chloride
5H-2,3-dihydro-7-methane
Toxi-6-(N-methyl-p-chloroanili
B)-5-oxothiazolo[3,2-a]pirimi
30 mg of gin-1-oxide was obtained (yield: 27%).
The physical properties of this product are as follows. NMR(δ^CDCl3 _TMS) ppm: 3.13 (3H, s), 3.46 (2H,
t, J=7Hz), 4.01 (3H, s), 4.70 (2H,
t, J = 7Hz) 6.5 to 7.3 (4H, m) Example 25 Delayed allergy measurement (i) C3H/He male mice (7 weeks old), 5 mice per group
5 x 10 sheep red blood cells^FiveCells were sensitized by intravenous injection. Suspension of test drug in 5% gum arabic solution
Immediately after sensitization, 1 day, 2 days, and 3 days after sensitization.
Each was administered orally. Then, 4 days after sensitization, the right hind leg
10 sheep red blood cells in the skin⁸Allergy by injecting cells
- provoked a reaction. 24 hours after allergy induction, micro thickening of the feet
Measure with a meter, and from this value sheep red blood cells 10⁸
Subtract the value before cell injection and calculate the foot pat reaction (0.1
Delayed allergy was measured as mm).
The results are shown in Table 1.

[Table] (ii) Bordetella pertusis (5 × 10 ⁹
The mice were sensitized by intradermally injecting the bacteria into the right anterior paw and left hind paw. A suspension of the test drug in a 5% gum arabic solution was orally administered once a day in the amount shown in Table 2 from 9 to 12 days after sensitization. Then, 12 days after sensitization, the same antigen (5 x 10 ⁹ organisms) was injected into the skin of the right hind footpad to induce an allergic reaction. 24 hours after allergy induction, paw volume was measured by water displacement method.
Delayed allergy was measured by calculating the edema rate (swelling percent) from the value obtained before antigen injection. The results are shown in Table 2.

[Table] Example 26 (i) The influence on antibody production was investigated as follows. Specifically, the spleen was removed from a 12-week-old BALB/c female mouse, and a suspension of splenic fat was prepared. To these 6 x 10 ⁶ splenocytes, sheep red blood cells (SRBC, 2 x 10 ⁶ ) were added as an antigen, and Mischell was added in 10% fetal bovine serum and RPMI-1640 medium.
Dutton's modified method for 5 days (Mischell, RIand
Dutton, R.W.: J.Exp.Med.126:423 (1967)
Culture and calculate the number of distinct PFCs that appear using Jerene's method (Jerne, NKand Nardin, AA: Science
140:405 (1963)). The test compound was dissolved in dimethyl sulfoxide to a final concentration of 0.1 M, diluted with culture medium, and then added at the same time as the antigen. The results are shown in Table 3.

【table】

[Table] Example 27 Manufacture of tablets Tablets each having the following composition were manufactured. Active ingredient compound (112) 50mg Lactose 115mg Potato starch 24mg Polyvinylpyrrolidone 10mg Magnesium stearate 1mg Mix the active ingredient, lactose and potato starch, moisten it evenly with a 20% ethanol solution of polyvinylpyrrolidone, and mix it into a 20mm mesh. The mixture was passed through a sieve, dried at 45°C, and passed through a 1.5 mm mesh sieve again. The granules thus obtained were mixed with magnesium stearate and compressed into tablets. Compound (112) was used as the active ingredient. Example 28 Preparation of Hard Gelatin Capsules Hard gelatin capsules were prepared, one capsule containing the following composition. Active Ingredient Compound (110) 50mg Microcrystalline Cellulose 75mg Lactose 74mg Magnesium Stearate 1mg The active ingredient in finely powdered form, microcrystalline cellulose and unpressed amorphous silicic acid are thoroughly mixed and packed into hard gelatin capsules and encapsulated. was manufactured. Compound (110) was used as the active ingredient.

Claims (1)

[Claims] 1. The following general formula () [In the formula, R ¹ and R ² are the same or different,
Hydrogen atom, C ₁ - C ₁₀ alkyl group, C ₃ - _{C 10} alkenyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted C ₃ - _{C 8} alicyclic group, substituted or unsubstituted phenyl group, It represents an enyl alkyl group or a substituted or unsubstituted C ₂ - C ₇ acyl group (here, the substituents of the phenyl group, alicyclic group, phenyl alkyl group, and acyl group are a halogen atom, a hydroxyl group, respectively) , C ₁ - C ₄ alkyl group which may be substituted with a halogen atom, C ₁ - _{C 4} alkoxy group which may be substituted with a halogen atom, nitrile group, carboxyl group or (C ₁ - _{C 6} ) alkoxycarbonyl ). However, R ₁ and R ² are not both hydrogen atoms or substituted or unsubstituted C ₂ - C ₇ acyl groups,
Further, R ¹ and R ² may be combined together with the nitrogen atom to which they are bonded to form a 5- to 6-membered ring which may further contain a heteroatom. ] Thiazolo[3,2-a]pyrimidines or acid addition salts thereof. 2 In the above general formula (), R ¹ and R ² are the same or different, and are a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ alkenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenyl group, Substitution of C _5
-C6 alicyclic group, substituted or unsubstituted phenyl ( _C1 - _C2 ) alkyl group, substituted or unsubstituted C2 _{-C6 aliphatic} acyl group, or substituted or unsubstituted benzoyl group; , provided that R ¹ and R ² are both hydrogen atoms or neither are the above aliphatic acyl group or benzoyl group, and R ¹ and R ² together are the nitrogen atom to which they are bonded. The thiazolo[3 ,2-a]
Pyrimidines or their acid addition salts. 3. The acid addition salt of thiazolo[3,2-a]pyrimidines according to claim 1 or 2, wherein the acid addition salt is a mineral acid salt. 4. The acid addition salt of thiazolo[3,2-a]pyrimidines according to claim 3, wherein the mineral salt is a hydrochloride or a sulfate. 5 General formula below () [In the formula, R ¹ and R ² are the same or different,
Hydrogen atom, C ₁ - C ₁₀ alkyl group, C ₃ - _{C 10} alkenyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted C ₃ - _{C 8} alicyclic group, substituted or unsubstituted represents a phenyl alkyl group or a substituted or unsubstituted _C2 - _C7 acyl group (here, the substituents of the phenyl group, alicyclic group, phenyl alkyl group, and acyl group are halogen atoms, Hydroxyl group, _C1 - _C4 alkyl group optionally substituted with halogen atom, _C1 - _C4 alkoxy group optionally substituted with halogen atom, nitrile group, carboxyl group or ( _C1 - _C6 ) alkoxy carbonyl group). However, R ¹ and R ²
are not both hydrogen atoms or substituted or unsubstituted C ₂ - C ₇ acyl groups,
Further, R ¹ and R ² may be combined together with the nitrogen atom to which they are bonded to form a 5- to 6-membered ring which may further contain a heteroatom.
R ⁴ and R ⁵ are the same or different and are C ₁ -C ₆ alkyl groups. ] A malonic acid derivative 2-aminothiazoline represented by (a) is subjected to a condensation cyclization reaction under heating, or
(b) carrying out a condensation cyclization reaction in the presence of an alkali metal alkoxide, then neutralizing the obtained alkali metal salt of the enol with an acid, and then optionally subjecting the obtained reaction product to an addition reaction with an acid; The following general formula () [In the formula, R ¹ and R ² are the same as defined in the above formula (). ] A method for producing thiazolo[3,2-a]pyrimidines or acid addition salts thereof. 6 Claim 5, wherein the alkali metal alkoxide is a C ₁ -C ₄ alkali metal alkoxide
Manufacturing method described in section. 7. The production method according to claim 5, wherein the condensation cyclization reaction is carried out in the presence of an inert organic solvent, in the absence of an alkali metal alkoxide, and under heating. 8. The method of claim 7, wherein the cyclocondensation reaction is carried out at a temperature of about 80° to about 320°C. 9 General formula below () [In the formula, R ¹ and R ² are the same or different,
Hydrogen atom, C ₁ - C ₁₀ alkyl group, C ₃ - _{C 10} alkenyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted C ₃ - _{C 8} alicyclic group, substituted or unsubstituted represents a phenyl alkyl group or a substituted or unsubstituted _C2 - _C7 acyl group (here, the substituents of the phenyl group, alicyclic group, phenyl alkyl group, and acyl group are halogen atoms, Hydroxyl group, _C1 - _C4 alkyl group optionally substituted with halogen atom, _C1 - _C4 alkoxy group optionally substituted with halogen atom, nitrile group, carboxyl group or ( _C1 - _C6 ) alkoxy carbonyl group). However, R ¹ and R ²
are not both hydrogen atoms or substituted or unsubstituted C ₂ - C ₇ acyl groups,
Further, R ¹ and R ² may be combined together with the nitrogen atom to which they are bonded to form a 5- to 6-membered ring which may further contain a heteroatom. 1. An immunomodulator comprising a thiazolo[3,2-a]pyrimidine represented by the formula or an acid addition salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.