CA1045136A - Thiazole derivatives - Google Patents
Thiazole derivativesInfo
- Publication number
- CA1045136A CA1045136A CA213,282A CA213282A CA1045136A CA 1045136 A CA1045136 A CA 1045136A CA 213282 A CA213282 A CA 213282A CA 1045136 A CA1045136 A CA 1045136A
- Authority
- CA
- Canada
- Prior art keywords
- hydrogen
- formula
- lower alkyl
- thiazole
- process according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/36—Sulfur atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Novel thiazole derivatives of the formula (I);
(I) wherein R1 and R2 are each hydrogen, lower alkyl, cycloalkyl, optionally substituted aryl or optionally substituted hetero-aromatic ring containing any one or more of oxygen, sulfur, or nitrogen, and R3 and R4 are each hydrogen or lower alkyl, and salts thereof, may be prepared by reacting a thiazole derivative of the formula (II) (II) wherein R1 and R2 have the same meanings as defined above and A is or
Novel thiazole derivatives of the formula (I);
(I) wherein R1 and R2 are each hydrogen, lower alkyl, cycloalkyl, optionally substituted aryl or optionally substituted hetero-aromatic ring containing any one or more of oxygen, sulfur, or nitrogen, and R3 and R4 are each hydrogen or lower alkyl, and salts thereof, may be prepared by reacting a thiazole derivative of the formula (II) (II) wherein R1 and R2 have the same meanings as defined above and A is or
Description
~04513~ -This invention relates to a process ~or producing novel thiazole de~ivatives of the formula (I);
R2 ~ ~
S SCH2C~cH2NR3R4 ~ .
wherein Rl and R2 are each hydrogen, lower alkyl, cycloalkyl, optionally substituted aryl or optionally substituted hetero- :
aromatic ring containing any one or more of oxygen~ sulfur, .
or nitrogen, and R3 and R4 are each hydrogen or lower alkyl,and salts thereof, and the invention also relates to the production ~.
thereofO , ;, . .
The term, "lower alkyl" as used herein includes C - C ~ ::
alkyl (for example, methyl, ethyl, n-propyl, iso-propylg n- ~ :
butyl, iso-butyl, t-butyl); methyl,ethyl, iso~propyl and t-butyl ~.
are preferredO
The term "optionally substituted aryl" as used herein ..
includes phenyl, substituted phenyl, naphthyl and substituted ~ `
':, ..
naphthyl with the substituents being Cl - C4 alkyl (for example, ~ ;
. methyl, ethyl, n~propyl, iso-propyl, n-butylg iso-butyl, sec- : .
butyl, t-butyl), C1 - C4 alkoxy (for example, m~thoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso--butoxy, t-butoxy), hydroxyl, C3 -~C5 alkenyl (for example, propenyl, butenyl, hexenyl), , C3 - C5 alkenyloxy (for example,~propenyloxy, butenyloxy, - `:
hexenyloxy), halogeno (for example, iodo, chloro, bromo, 1uoro), cyano, aminoj nitro, aryloxy (for example, phenoxy, naphthoxy) ~ and acylamino (or example, acetamido, propionamido, benzamido)0 : ~ ~The term "cycloalkyl" includes C3 - C6 cycloakyls, among ~-~ which cyclohexyl is preferred;
:;~ ''" ~ ~'.'' ::
- ~45~3~
h~ teIm ~optionally substituted heteroaromatic ring"
includes 5 and 6 membered rings containing any one or more of oxygen, sul~ur, or nitrogen and rings formed by the condensation of these with benzene rings, preferably furyl, thienyl, pyrrolyl, thiazolyl, iso-thiazoLyl, imidazolyl, pyra~olyl, oxazolylJ
isoxazolyl, pyridyl, pyrLmidinyl, pyrazinyl, benzothienyl~
benzoLmidazolyl, indolyl, and qui.nolylO Among these, furyl, thienyl, thiazolyl, pyrrolyl, pyridyl are most preferred. As the substitutents of these heteroaromatic rings, there may be exemplified lower alkyl, lower alkoxy, halogen, amino~ nitro, cyano, phenyl, acylamino, groups of the formula . .
-- C -- Y
(wherein Y is hydroxy, lower alkyl, lower alkoxy or lower ~ :
alkenyloxy) and groups of the formula ..
- C - N - R ~:~
(wherein R5 and R6 are each hydrogen, amino, lower alkyl, cyclo- : ;.
alkyl, optionally substituted aryl and, when taken together with ; :.
20 adjacent nitrogen, may form a heterocyclic group). In the above :
the term "acylamino" may include C2 - C8 acylamino, (for example, - acetamido, propionamido, benzamide), and the.term "lower alkenyl- . . :
~ . .,: .
loxyl' includes C3 - C5 alkenyloxy (for example, propenyloxy, butenyloxy, hexenyloxy~, and the term "cycloalkyl" include~ .
C3 ~ & cycloalkyl wherein cyclopropyl, cyclopentyl and cyclohexyl are preferred, and the term "heterocyclic groups" includes 5 and ..
6 membered heterocyclic groups, in which morpholinyl, pyrrolidinyl, piperidyl and thiomorpholinyl are preferred. The other terms "lower alkyl", "lower alkoxy", "halogen" and "optionally .
: .
1C~45136 substituted aryl" hav~ the same meanings as aboveO
A principal object of the present invention is to provide .
a process for preparing novel thiazole derivatives of the formula (I).
.i .
The thiazole derivatives of the formula (I) hav~ excellent pharmacological properties, such as ~-adrenergic receptor blocking effect, with low toxicity, and are valuable compounds exerting preventive or therapeutic effect on heart diseases, for example, arrhythmia, angina pectoris and other coronary heart disease In order to show these properties of ~-adrenergic receptor , blocking activity and low toxicity, thiazole derivatives of the formula (I) are compared with propranolol and practolol, which are commercially available compounds, and are known as two of ~;
the most effective compounds in the field of this inventionO As can be seen from the following Tables, thiazole derivatives of the formula (I) have stronger or the same ~-adrenerglc receptor blocking activity but less toxi.city than propranolol and practolol .:
TabIe Compound ~-adrenergic receptor blocking .
: 20 activity in open chest dog : .
- (propranolol = 1~
DPC DPI DDE .~ ;:
:: compd O of Example 22 2 1~5 4 ;` compd. of :
. -: Example 37 : 15 15 8 - compdO of ~ ~I Example 35 2 3 oO 8 ; ~ ~
`~ ~Propranolol 1 l l ~ ` :
, . .~ -~Practolol 0~5 0O7 oO
Note: The determination of ~~adrenergic receptor blocking , activity of the test compounds in open chest dogs ~as as follows. .:
. ~ 3 ~ .:~
' ': ' -~04513~
- The dogs were anesthetized with pentbarbital sodium (ad-ministrated 30 - 40 my./kg. intraveneously). Heart rate, myocardial contractile force and blood pressure were recorded with NIHON KODEN RM-150* polygraph. The depressive effect of test compounds on positive chronotropic (DPC), positive : intropic (DPI) and depresser effect (DDE) induced by :~ .
isoproterenol injected intraveneously at a quarter hour ~' intervals~ was determinedO :
Table 2 Acute toxicity Compound Acute toxicity ~:
LD50 (mg./k compdO of Example 22 46 compd. of Example 37 86 . : .
compd. of Example 35 60 Propranolol 23 .
Note: For the determination of the intraveneous LD50, 10 male mice were used, and the method of up and down was used for .:
calculation of the LD50.
According to the present invention, the thiazole derlvatlves of the formula (I) : ', Rl ~ OH . (I) : : 2CHFE2~R3R4 :., ~ . :
`~ ~ *Trade Mark ~ 4 -~lO4~S~L36 wherein Rl~ R2, R3 and R4 have the same meanings as defined before, are prepared by reacting a thiazole dexivative of the formula (II) ' R2 ~ ~ (II) ~
.. " ',, wherein Rl and R2 have the same meanings as defined above and ~
A is R
_ CH2CHCH2 or ~
- C ~ ~HCH2X
where X is a halogen, with an amine of the formula (III) .
j H~R3R4 (III) wherein R3 and Rl~ have the same meanings as defined above. ~.
More particularly, the thiazole derivatives of the formula :~;
(I) are prepared by reacting a thiazole derivative of the formula (~I) wlth an amine of the formula (III) in a sealed tube by .~ ~:
heating to a temperature of from 30~co to 150~C~, or by heating ,.. ~
to a temperature of from 30~C. to 150C. in the presence of an : :
organic solvent (-for example, methanol, ethanol, n-propanol, iso~
: . . :
propanol, n-butanol, iso-butanol, sec-butanol, t-butanol~ dio~ane, : dimethyl formamide, dimethyl acetamlde, dimethylsulfoxide, acetone), or a water-organic solvent system (for example, water-methanol~
water-ethanol, water-n-propanol, water-iso-propanol, water~n~
.,: :.:
butanol, water-iso-butanol, water-sec-butanol, water-t-butanol)0 ..
It is preferred to carry out the reaction under reflux in an~alcoholic solution. The reaction can be carried out using a .::
- 5 - :
:. :, ,, , -- --~045136 mixture of the compound of the formula (IIa)O
-S ~ (IIa) ` S - CH2 - C~-&H2 O '.
wherein Rl and R2 are each as defined above, and the compound of the formula (Ilb), R N
R2 ~ ~
S SCH2C~cH2NR3R4 ~ .
wherein Rl and R2 are each hydrogen, lower alkyl, cycloalkyl, optionally substituted aryl or optionally substituted hetero- :
aromatic ring containing any one or more of oxygen~ sulfur, .
or nitrogen, and R3 and R4 are each hydrogen or lower alkyl,and salts thereof, and the invention also relates to the production ~.
thereofO , ;, . .
The term, "lower alkyl" as used herein includes C - C ~ ::
alkyl (for example, methyl, ethyl, n-propyl, iso-propylg n- ~ :
butyl, iso-butyl, t-butyl); methyl,ethyl, iso~propyl and t-butyl ~.
are preferredO
The term "optionally substituted aryl" as used herein ..
includes phenyl, substituted phenyl, naphthyl and substituted ~ `
':, ..
naphthyl with the substituents being Cl - C4 alkyl (for example, ~ ;
. methyl, ethyl, n~propyl, iso-propyl, n-butylg iso-butyl, sec- : .
butyl, t-butyl), C1 - C4 alkoxy (for example, m~thoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso--butoxy, t-butoxy), hydroxyl, C3 -~C5 alkenyl (for example, propenyl, butenyl, hexenyl), , C3 - C5 alkenyloxy (for example,~propenyloxy, butenyloxy, - `:
hexenyloxy), halogeno (for example, iodo, chloro, bromo, 1uoro), cyano, aminoj nitro, aryloxy (for example, phenoxy, naphthoxy) ~ and acylamino (or example, acetamido, propionamido, benzamido)0 : ~ ~The term "cycloalkyl" includes C3 - C6 cycloakyls, among ~-~ which cyclohexyl is preferred;
:;~ ''" ~ ~'.'' ::
- ~45~3~
h~ teIm ~optionally substituted heteroaromatic ring"
includes 5 and 6 membered rings containing any one or more of oxygen, sul~ur, or nitrogen and rings formed by the condensation of these with benzene rings, preferably furyl, thienyl, pyrrolyl, thiazolyl, iso-thiazoLyl, imidazolyl, pyra~olyl, oxazolylJ
isoxazolyl, pyridyl, pyrLmidinyl, pyrazinyl, benzothienyl~
benzoLmidazolyl, indolyl, and qui.nolylO Among these, furyl, thienyl, thiazolyl, pyrrolyl, pyridyl are most preferred. As the substitutents of these heteroaromatic rings, there may be exemplified lower alkyl, lower alkoxy, halogen, amino~ nitro, cyano, phenyl, acylamino, groups of the formula . .
-- C -- Y
(wherein Y is hydroxy, lower alkyl, lower alkoxy or lower ~ :
alkenyloxy) and groups of the formula ..
- C - N - R ~:~
(wherein R5 and R6 are each hydrogen, amino, lower alkyl, cyclo- : ;.
alkyl, optionally substituted aryl and, when taken together with ; :.
20 adjacent nitrogen, may form a heterocyclic group). In the above :
the term "acylamino" may include C2 - C8 acylamino, (for example, - acetamido, propionamido, benzamide), and the.term "lower alkenyl- . . :
~ . .,: .
loxyl' includes C3 - C5 alkenyloxy (for example, propenyloxy, butenyloxy, hexenyloxy~, and the term "cycloalkyl" include~ .
C3 ~ & cycloalkyl wherein cyclopropyl, cyclopentyl and cyclohexyl are preferred, and the term "heterocyclic groups" includes 5 and ..
6 membered heterocyclic groups, in which morpholinyl, pyrrolidinyl, piperidyl and thiomorpholinyl are preferred. The other terms "lower alkyl", "lower alkoxy", "halogen" and "optionally .
: .
1C~45136 substituted aryl" hav~ the same meanings as aboveO
A principal object of the present invention is to provide .
a process for preparing novel thiazole derivatives of the formula (I).
.i .
The thiazole derivatives of the formula (I) hav~ excellent pharmacological properties, such as ~-adrenergic receptor blocking effect, with low toxicity, and are valuable compounds exerting preventive or therapeutic effect on heart diseases, for example, arrhythmia, angina pectoris and other coronary heart disease In order to show these properties of ~-adrenergic receptor , blocking activity and low toxicity, thiazole derivatives of the formula (I) are compared with propranolol and practolol, which are commercially available compounds, and are known as two of ~;
the most effective compounds in the field of this inventionO As can be seen from the following Tables, thiazole derivatives of the formula (I) have stronger or the same ~-adrenerglc receptor blocking activity but less toxi.city than propranolol and practolol .:
TabIe Compound ~-adrenergic receptor blocking .
: 20 activity in open chest dog : .
- (propranolol = 1~
DPC DPI DDE .~ ;:
:: compd O of Example 22 2 1~5 4 ;` compd. of :
. -: Example 37 : 15 15 8 - compdO of ~ ~I Example 35 2 3 oO 8 ; ~ ~
`~ ~Propranolol 1 l l ~ ` :
, . .~ -~Practolol 0~5 0O7 oO
Note: The determination of ~~adrenergic receptor blocking , activity of the test compounds in open chest dogs ~as as follows. .:
. ~ 3 ~ .:~
' ': ' -~04513~
- The dogs were anesthetized with pentbarbital sodium (ad-ministrated 30 - 40 my./kg. intraveneously). Heart rate, myocardial contractile force and blood pressure were recorded with NIHON KODEN RM-150* polygraph. The depressive effect of test compounds on positive chronotropic (DPC), positive : intropic (DPI) and depresser effect (DDE) induced by :~ .
isoproterenol injected intraveneously at a quarter hour ~' intervals~ was determinedO :
Table 2 Acute toxicity Compound Acute toxicity ~:
LD50 (mg./k compdO of Example 22 46 compd. of Example 37 86 . : .
compd. of Example 35 60 Propranolol 23 .
Note: For the determination of the intraveneous LD50, 10 male mice were used, and the method of up and down was used for .:
calculation of the LD50.
According to the present invention, the thiazole derlvatlves of the formula (I) : ', Rl ~ OH . (I) : : 2CHFE2~R3R4 :., ~ . :
`~ ~ *Trade Mark ~ 4 -~lO4~S~L36 wherein Rl~ R2, R3 and R4 have the same meanings as defined before, are prepared by reacting a thiazole dexivative of the formula (II) ' R2 ~ ~ (II) ~
.. " ',, wherein Rl and R2 have the same meanings as defined above and ~
A is R
_ CH2CHCH2 or ~
- C ~ ~HCH2X
where X is a halogen, with an amine of the formula (III) .
j H~R3R4 (III) wherein R3 and Rl~ have the same meanings as defined above. ~.
More particularly, the thiazole derivatives of the formula :~;
(I) are prepared by reacting a thiazole derivative of the formula (~I) wlth an amine of the formula (III) in a sealed tube by .~ ~:
heating to a temperature of from 30~co to 150~C~, or by heating ,.. ~
to a temperature of from 30~C. to 150C. in the presence of an : :
organic solvent (-for example, methanol, ethanol, n-propanol, iso~
: . . :
propanol, n-butanol, iso-butanol, sec-butanol, t-butanol~ dio~ane, : dimethyl formamide, dimethyl acetamlde, dimethylsulfoxide, acetone), or a water-organic solvent system (for example, water-methanol~
water-ethanol, water-n-propanol, water-iso-propanol, water~n~
.,: :.:
butanol, water-iso-butanol, water-sec-butanol, water-t-butanol)0 ..
It is preferred to carry out the reaction under reflux in an~alcoholic solution. The reaction can be carried out using a .::
- 5 - :
:. :, ,, , -- --~045136 mixture of the compound of the formula (IIa)O
-S ~ (IIa) ` S - CH2 - C~-&H2 O '.
wherein Rl and R2 are each as defined above, and the compound of the formula (Ilb), R N
2 ~ S 1 f (IIb) 0~ . . '' :'-:
wherein Rl, R2 and X are each as defined aboveO .
However, the method of reacting an halohydxin derivative (IIb) 10 with an amine (III) is rather advantageous for commerci.al pro- . .
duction of the thiazoie derivative (I) than that of rea~ting a propoxide derivative (IIa) with an amine (III), because several ! ~
of the latter reactions produce some polymerized products in some cases. And, in order to prevent production of a by-product, ~ :
for example a pol~nerlzation produot, this reaction is preferably carried out in a nitrogen gas atmosphereO
:~ The reaction can preferably be conducted by using an .
excess~ amount of the amine of the formula (III) defined above, but it ~can also be carried out by using the amine (III) in amount j-.
subatantially equivalent to the compound of the ~ormula (II). ~ : :
, Thiazole derivatives thus obtained and salts thereo~ can : ~ .
:~ be isolated and refined by conven!tional procedures such as ex- ~ ::
. .
traotion, recrystallization, reprecipitation, column chromatography or treatment with active carbon, and can be converted to their pharmaceutically acceptable salts with inorganic or oxganic acid - ~04S136 ~ :
(for example, hydrochloric acid, sulfuric acid~ phosphoric acid, tartaric acid, mandelic acid, citric acid) according to con~
ventional procedures.
: 2-(2',3'-epoxypropylthio)-thiazole derivatives (IIa) and 2-(3'-choro-2'-hydroxypropylthio)-thiazole derivatives (IIb) :
can be prepared by reacting 2-mercaptothiazole derivatives (IV), :-wherein Rl and ~2 are defined above, with epichlorohydrin (V) in the presence of a base. ~; .-'. .
- O :. :
R r~ 2CHcH2 ~
....
Rl R ~ ; :
I . . p 1 11 OH l:
R2 1 ~ 5 ~ ~ SCH2CHCH2 2 ~ S ~ ~ SCH21HCH2Cl ... .
: (IIa) (Ilb) .;. .~:
: .
: ~ ~ In this case, 2-mercaptothiazole derivatives (IV) can be prepared by reacting a haloketone of the formula (VI) ~ ..
~ RlCOCHY
~ R2 (VI) ; ~ whexein Rl and R2 have the same.meanings as mentioned above, and ~ Y i8 halogen, with dithiocarbc~mic acid derivatives of the formula .
. ,: - ..
: (VII) H NCSR ; ~ (VII) wherein R6 is preferably sodium potassium ammonium, lower- ~`.:/
~: ~; alkyl and acyl group~ at a temperature of from -lO^C~ to 140C. - :.
,: . . : :
~ in the presence oL water or an organic solvent (for example, - 7 ~
.~ .
~LS~.3~
: alcohol, hydrocarbon, ether, ethyl acetate, tetxahydrofuran, and dioxane)0 It is preferred to add haloketone (VI) to dithiocarbamic acid derivatives under cooling and complete the reaction under reflux because most of this reaction is exothermicO
Among these intermediate compounds of the for~ula (IV)~
2-mercaptothiazole derivatives of the formula (VIII) .
~8 ~ S 1 SH (VIII) '~
wherein R7 is nitro, acylamino, cyano~ lower alkylamino- .
- carbonyl, lower alkoxycarbonyl, lower alkylcarbonyl,or hydrazino-carbonyl and R8 is hydrogen, cyano, or lower alkylaminocarbonyl ~ ~ :
and X is oxygen, sulfur~ or nitrogen atom, are newO
Alternatively, its carbamoyl derivatives (VIIIa) (~7 or R8 = carbamoyl) and its carboxy dexivatives (VIIIb) -(R7 or R8 = carboxy) are also obtained in high yield by hydrolysis of its cyano derivatives (VIIIc) (~ or R8 = cyano)0 ';,':
' ~, ' ' .' ";
,:
: . :
' -:
~ -., . ~ .
: lO~S136 .
H _ C ~ N H2NCC F~
S ~ SH X ~ S ~ SH
(VIIIc) \ (VIIIa) ~;
\ 3 x OH
HOOC ~ X = O, ~ orS) S SH ~ :
(~IIIb) And additionally, carboxy derivatives (VIIIb) .
(R7 or R8 = c~rboxy) are also prepared in high yield by : `
- hydrblysis of ester derivatives (VIIld) (R7 or R8 - alkoxy- : -carbonyl).
,. t . ~:
ROOC t~ / 1~ . ~ .~.. r . . .. ... -S SH acid or base ::
(VIIId) ~ ~ -HOOC ~ N ` .
X ~ ~ = N, O or S) ` ~ ;
S SH . : :
: (VIIIb) : . i ~.
~: ': . ~ . - . ,.; . ' ~ In order to illustxate the invention ih details, :~ - the following E~amples are given,but not by way of limita- :-~ ~ tlon. ~ `' ' .. .. .
xample 1 ~;`
2-(3'-t-but~lamino-2'-hydroxypropylthio)-4- .: .:
: phenyl thiazole hy~rochloride :
A solution of 1.25 g. o~ 2-(2',3'-epoxypropylthio)~
4-phenyl thiazole and lO~ml. of t-butylamine in 20 ml. o~ ~ .
~:~ methanol was refluxed ~or 4.6 hours~ ~fter the reaction ~vas ;:' ~ :........... ' ~ ' ' "' 1~)4S~36 over, the reactlon solution wa~ evaporated in vacuo to ~ive an oil, which was dissolved in chloroform and the chloroform solution was extracted with hydrochloric acid ' solution. ~he aqueous layer was made alkaline with 10 N ~;
aqueous so'dium hydroæiae solution and extracted with chloroform. " "'~
, ~he chloroform extract was aried over anhydrous magnesium sul~a~e and evaporated in vacuo to give an oil, ' ~ ,~
which was converted to its hydrochloride.
The hydrochloride was recrys-tallized from a ', ~' mixture of acetone and methanol to yield 2-(3'-t-butyl-amino-2'-hydroxypropylthio)-4-phenyl thiazole hydrochloride: , white solid, m.pO 169 - 174C;~ 0.7 g. ~ ' ' ~ound: C9 48.~4; H, 6.15; N, 6.83; S, 15.11, Cl, 17.00(%) ~ ;, C16H220N2S2~2HCl require~ C, 48.~8; H, 6.o6; N, 7.07; ~ ~
S, 16~16; Cl, 18.43 (%) ~ ',''~' 2-(2',7'-epoxypropylthio)-4-phenyl thiazole used as starting ma-terial wa~ prepared by the following~method desoribed below.
- ~
Four grc~m~ of 2-mercapto-4-phenyl thia'zoleJ 2.0 g.
of piperidine and 20 ml. of epichlorohydrin were mixed ~elow ' and heated at 8CC.~for 1 hour. APter cooling, the vola~
tile material wa~ removed in ~acuo, and the residue was dis- ~' solved in chloro~orm. ~he solutlon was washed with N a~ueou~
sodium hydroxide solution, dried~over anhydrou~ magnesium sulfate and evaporated under reduced pressure to give 7.22 g.
.:. ~ , . . .
~o~ an oil, which was purified~by column chromatography on silica gel to yield 2-(2',3'-epoxypropylthio)-4-phenyl ' ', ~'~ thiazole; colourle~s oil, n24 6 1.5678. ' ;; ~ ' , ~ ' Aocording to the method o~ Example 1, the following , ~ ..
10 ~ `' ''' ' ~ ', ' , .' ~... .
~ . ., , , " . , .~ ...... , . ., . , - . . .
1~5136 . :
compounds were prepared.
.
2 ~ S l SCH2C~2~IC - CH
C~3 -~ . .
Ex. R isolated NoO 1 R2 ~orm physical const. . .
..... _ ... .. _ . . . ~ . .
H hydro- m.p. 169-74a. ~:
chloride (acetone-methanol) 2 CH ~ hydro- m~p. 205-6C. -
wherein Rl, R2 and X are each as defined aboveO .
However, the method of reacting an halohydxin derivative (IIb) 10 with an amine (III) is rather advantageous for commerci.al pro- . .
duction of the thiazoie derivative (I) than that of rea~ting a propoxide derivative (IIa) with an amine (III), because several ! ~
of the latter reactions produce some polymerized products in some cases. And, in order to prevent production of a by-product, ~ :
for example a pol~nerlzation produot, this reaction is preferably carried out in a nitrogen gas atmosphereO
:~ The reaction can preferably be conducted by using an .
excess~ amount of the amine of the formula (III) defined above, but it ~can also be carried out by using the amine (III) in amount j-.
subatantially equivalent to the compound of the ~ormula (II). ~ : :
, Thiazole derivatives thus obtained and salts thereo~ can : ~ .
:~ be isolated and refined by conven!tional procedures such as ex- ~ ::
. .
traotion, recrystallization, reprecipitation, column chromatography or treatment with active carbon, and can be converted to their pharmaceutically acceptable salts with inorganic or oxganic acid - ~04S136 ~ :
(for example, hydrochloric acid, sulfuric acid~ phosphoric acid, tartaric acid, mandelic acid, citric acid) according to con~
ventional procedures.
: 2-(2',3'-epoxypropylthio)-thiazole derivatives (IIa) and 2-(3'-choro-2'-hydroxypropylthio)-thiazole derivatives (IIb) :
can be prepared by reacting 2-mercaptothiazole derivatives (IV), :-wherein Rl and ~2 are defined above, with epichlorohydrin (V) in the presence of a base. ~; .-'. .
- O :. :
R r~ 2CHcH2 ~
....
Rl R ~ ; :
I . . p 1 11 OH l:
R2 1 ~ 5 ~ ~ SCH2CHCH2 2 ~ S ~ ~ SCH21HCH2Cl ... .
: (IIa) (Ilb) .;. .~:
: .
: ~ ~ In this case, 2-mercaptothiazole derivatives (IV) can be prepared by reacting a haloketone of the formula (VI) ~ ..
~ RlCOCHY
~ R2 (VI) ; ~ whexein Rl and R2 have the same.meanings as mentioned above, and ~ Y i8 halogen, with dithiocarbc~mic acid derivatives of the formula .
. ,: - ..
: (VII) H NCSR ; ~ (VII) wherein R6 is preferably sodium potassium ammonium, lower- ~`.:/
~: ~; alkyl and acyl group~ at a temperature of from -lO^C~ to 140C. - :.
,: . . : :
~ in the presence oL water or an organic solvent (for example, - 7 ~
.~ .
~LS~.3~
: alcohol, hydrocarbon, ether, ethyl acetate, tetxahydrofuran, and dioxane)0 It is preferred to add haloketone (VI) to dithiocarbamic acid derivatives under cooling and complete the reaction under reflux because most of this reaction is exothermicO
Among these intermediate compounds of the for~ula (IV)~
2-mercaptothiazole derivatives of the formula (VIII) .
~8 ~ S 1 SH (VIII) '~
wherein R7 is nitro, acylamino, cyano~ lower alkylamino- .
- carbonyl, lower alkoxycarbonyl, lower alkylcarbonyl,or hydrazino-carbonyl and R8 is hydrogen, cyano, or lower alkylaminocarbonyl ~ ~ :
and X is oxygen, sulfur~ or nitrogen atom, are newO
Alternatively, its carbamoyl derivatives (VIIIa) (~7 or R8 = carbamoyl) and its carboxy dexivatives (VIIIb) -(R7 or R8 = carboxy) are also obtained in high yield by hydrolysis of its cyano derivatives (VIIIc) (~ or R8 = cyano)0 ';,':
' ~, ' ' .' ";
,:
: . :
' -:
~ -., . ~ .
: lO~S136 .
H _ C ~ N H2NCC F~
S ~ SH X ~ S ~ SH
(VIIIc) \ (VIIIa) ~;
\ 3 x OH
HOOC ~ X = O, ~ orS) S SH ~ :
(~IIIb) And additionally, carboxy derivatives (VIIIb) .
(R7 or R8 = c~rboxy) are also prepared in high yield by : `
- hydrblysis of ester derivatives (VIIld) (R7 or R8 - alkoxy- : -carbonyl).
,. t . ~:
ROOC t~ / 1~ . ~ .~.. r . . .. ... -S SH acid or base ::
(VIIId) ~ ~ -HOOC ~ N ` .
X ~ ~ = N, O or S) ` ~ ;
S SH . : :
: (VIIIb) : . i ~.
~: ': . ~ . - . ,.; . ' ~ In order to illustxate the invention ih details, :~ - the following E~amples are given,but not by way of limita- :-~ ~ tlon. ~ `' ' .. .. .
xample 1 ~;`
2-(3'-t-but~lamino-2'-hydroxypropylthio)-4- .: .:
: phenyl thiazole hy~rochloride :
A solution of 1.25 g. o~ 2-(2',3'-epoxypropylthio)~
4-phenyl thiazole and lO~ml. of t-butylamine in 20 ml. o~ ~ .
~:~ methanol was refluxed ~or 4.6 hours~ ~fter the reaction ~vas ;:' ~ :........... ' ~ ' ' "' 1~)4S~36 over, the reactlon solution wa~ evaporated in vacuo to ~ive an oil, which was dissolved in chloroform and the chloroform solution was extracted with hydrochloric acid ' solution. ~he aqueous layer was made alkaline with 10 N ~;
aqueous so'dium hydroæiae solution and extracted with chloroform. " "'~
, ~he chloroform extract was aried over anhydrous magnesium sul~a~e and evaporated in vacuo to give an oil, ' ~ ,~
which was converted to its hydrochloride.
The hydrochloride was recrys-tallized from a ', ~' mixture of acetone and methanol to yield 2-(3'-t-butyl-amino-2'-hydroxypropylthio)-4-phenyl thiazole hydrochloride: , white solid, m.pO 169 - 174C;~ 0.7 g. ~ ' ' ~ound: C9 48.~4; H, 6.15; N, 6.83; S, 15.11, Cl, 17.00(%) ~ ;, C16H220N2S2~2HCl require~ C, 48.~8; H, 6.o6; N, 7.07; ~ ~
S, 16~16; Cl, 18.43 (%) ~ ',''~' 2-(2',7'-epoxypropylthio)-4-phenyl thiazole used as starting ma-terial wa~ prepared by the following~method desoribed below.
- ~
Four grc~m~ of 2-mercapto-4-phenyl thia'zoleJ 2.0 g.
of piperidine and 20 ml. of epichlorohydrin were mixed ~elow ' and heated at 8CC.~for 1 hour. APter cooling, the vola~
tile material wa~ removed in ~acuo, and the residue was dis- ~' solved in chloro~orm. ~he solutlon was washed with N a~ueou~
sodium hydroxide solution, dried~over anhydrou~ magnesium sulfate and evaporated under reduced pressure to give 7.22 g.
.:. ~ , . . .
~o~ an oil, which was purified~by column chromatography on silica gel to yield 2-(2',3'-epoxypropylthio)-4-phenyl ' ', ~'~ thiazole; colourle~s oil, n24 6 1.5678. ' ;; ~ ' , ~ ' Aocording to the method o~ Example 1, the following , ~ ..
10 ~ `' ''' ' ~ ', ' , .' ~... .
~ . ., , , " . , .~ ...... , . ., . , - . . .
1~5136 . :
compounds were prepared.
.
2 ~ S l SCH2C~2~IC - CH
C~3 -~ . .
Ex. R isolated NoO 1 R2 ~orm physical const. . .
..... _ ... .. _ . . . ~ . .
H hydro- m.p. 169-74a. ~:
chloride (acetone-methanol) 2 CH ~ hydro- m~p. 205-6C. -
3 ~IY chloride (acetone-methanol) .- .
3 ~ H hydro- m,p. 204-5C. . ; ;
W chloride ~ace-tone) : .
3 ~ H hydro- m,p. 204-5C. . ; ;
W chloride ~ace-tone) : .
4 CH H hydro m.p 210-214C l: :
3 chloride (acetone) ~ C~ ree (ben~ene-light 3 base petroleum) ;~:
6 ~- ~ H hydro_ m.p. 180-183C.
chloride (acetone-methanol) . ' , - , ' ;
7 C~30- ~ - H brage nd8 1.5936 8 CH - ~ - H h~dro- m.p. 158--161C. :1 chloride (acetone-methanol) 9 8 H base nd5 1.6162 : ~ , ' ~ ~, '' .
~ hydro- m.p. 150-153C.
~ ~ chloride (acetone-methanol) : ~ .
,' ;' ' ',: ~' ,; , . .. , ,, ;, , ., .,. . . ". .. :, : .. , .. , ., . , :, . ~,.. ,.. ,., ., .. ,, .. ~. .. .. . ... . . .. . .. . .
1~45~36 ., , 11 Br- ~ - H hydro_ m.p. 178-180~.
chloride (acetone-methanol) ':
,~, .
12 ~ _ H base nd9 1.5968 ,. : , . F:" ' ' :
13 NC~ - H hydro_ m.p. 138-143G.
~ chloride (acetone-ethanol) ., . ~ .
. OCH2CH=C~
14 ~ ~ 2 H hydro- m.p. 169-171C
chloride ~acetone-methanol) .:.
:
~ baseee- nd~'5 1.5745 ~ :
.
16 - ~ ~ hydro- m.p. 171-174a chloride (acetone-methanal) ~ .
~1 17 ~ H hydro- . m.p. 176-177C. ~ ;
chloride (aoetone-met~anol) .
18 ~ H hydro- m.p. 140-143~C.
" ~ chloride (acetone-methanol) aH3 -:
ba~e n26 1.5979 ,~ .
~ : : . . ;~ .
: 20 ~ ~ N ~ C~3 H hydro_ m.p. 278-279C
CH3 ~ 5 ~ chloride (methanol-water) ,.
: 21 ~ ~J H free: m.p. 146-147C.
J~ ll base (benæene-light ~" , . -' ~ S ~ \ ~ : petroleum) .~
: . : ~,~ . .. :
. :
. .
........ . . . .
~)4S~3~i 2 D 11 3 "~
l S ~ N OH CX3 S SCH2CHCH2i~C - CH3 3 . :.
No Rl R2 R3 solated ph~sical cons-t. .
22 H H H free base nd6 1.5970 . 23 H X H picrate m.p. 153-154C. .
(chloroform) :; .
24 CH H H h~dro- m.p. 122-124C.
3 chloride (acetone) H H CH3 free base n25 1.6030 : ,... . ..
26 Br CH hydro~ m.p. 176-177C. -k -: -:
3 H chloride (aceto~e_ ; . .
27 CH3 , CH3 ~ h dro- m(apet229-230 C
.:
28 CH3CH2-~ H H chloride (m p l48-149C. ~ ;
29 3, C~ H H hydro- m.pl 145-146C.
: CH3 chlorid~ (chl~roform- . ~ :
methanol) , ,'.
: 30 ~ - H H ~base ~5 lr5966 hy~ro- ~ p D 173-173.5a.
Br H H chloride (acetone-methanol) ~. :
~2 I ~ H H h dro- (aPetone- , 33 CN H H free base ndl 5 1.6009 ~ .
.
~' ' .
~)45~3~
., -.
34 H H CN chloride (acetone-methanol) N02 H H chloride m p 236-237 C.
methanol) 36 H N02 H hydro_ ( P t~7~ 75 C. ;.
- methanol) RC0 ~ ~ ~ , , 3 2 2NH,C - CH3 ..: ,.,:
No R isolated physical const.
37 H2N- ~ree base m-p- 148-149C
. (acetone) 38 CH3NH- hydrochloriae (acpetone2 144 C~
metha~ol) .
39CH3(~H2)3NX- ydrochloride (aPetol06~108 C.
methanol) : ~ m.p. 163-165C
C N- hydrochloride (acet-one-methanol) , . r--~ m.p. 165~166C.
41 ~ N- hydrochloride (acetone-. methanol) :~ :
, . -.:
m.p. 178-179Co 42 0 ~- hydrochloride (acetone-~ methanol) ... -m.p~ 202~207C. ::
43 ~ H2NNH- h~drochloride (acetone- .
: ~ methanol) ~:~
: ~ ' : : '' ' ,` ~ ' '-14- -- ' . !
~ , ' . . ':
''~ , ' '"
'' ' ' , "' .
~04S~36 - ~
(CH3C1~2)2N- hYdrochlOride(aPe.~;l52-l53c. "
methanol). .~
.. ..
r-~ m.p. 140-141C. .:
4~ ~ -NH- free base (ligh-t petro-leum-benzene) 46 ( 3)3C O h~drochloride (aPet25l-252 metha~ol) 47 CH3- free base ~ 5 1.6032 ~ `
48 EtO- h d hl (m p 118-119QC.
49 ~eO- hydrochloride m^p- 124-126~
. . (aceto~e) (.~.
3 chloride (acetone) ~ C~ ree (ben~ene-light 3 base petroleum) ;~:
6 ~- ~ H hydro_ m.p. 180-183C.
chloride (acetone-methanol) . ' , - , ' ;
7 C~30- ~ - H brage nd8 1.5936 8 CH - ~ - H h~dro- m.p. 158--161C. :1 chloride (acetone-methanol) 9 8 H base nd5 1.6162 : ~ , ' ~ ~, '' .
~ hydro- m.p. 150-153C.
~ ~ chloride (acetone-methanol) : ~ .
,' ;' ' ',: ~' ,; , . .. , ,, ;, , ., .,. . . ". .. :, : .. , .. , ., . , :, . ~,.. ,.. ,., ., .. ,, .. ~. .. .. . ... . . .. . .. . .
1~45~36 ., , 11 Br- ~ - H hydro_ m.p. 178-180~.
chloride (acetone-methanol) ':
,~, .
12 ~ _ H base nd9 1.5968 ,. : , . F:" ' ' :
13 NC~ - H hydro_ m.p. 138-143G.
~ chloride (acetone-ethanol) ., . ~ .
. OCH2CH=C~
14 ~ ~ 2 H hydro- m.p. 169-171C
chloride ~acetone-methanol) .:.
:
~ baseee- nd~'5 1.5745 ~ :
.
16 - ~ ~ hydro- m.p. 171-174a chloride (acetone-methanal) ~ .
~1 17 ~ H hydro- . m.p. 176-177C. ~ ;
chloride (aoetone-met~anol) .
18 ~ H hydro- m.p. 140-143~C.
" ~ chloride (acetone-methanol) aH3 -:
ba~e n26 1.5979 ,~ .
~ : : . . ;~ .
: 20 ~ ~ N ~ C~3 H hydro_ m.p. 278-279C
CH3 ~ 5 ~ chloride (methanol-water) ,.
: 21 ~ ~J H free: m.p. 146-147C.
J~ ll base (benæene-light ~" , . -' ~ S ~ \ ~ : petroleum) .~
: . : ~,~ . .. :
. :
. .
........ . . . .
~)4S~3~i 2 D 11 3 "~
l S ~ N OH CX3 S SCH2CHCH2i~C - CH3 3 . :.
No Rl R2 R3 solated ph~sical cons-t. .
22 H H H free base nd6 1.5970 . 23 H X H picrate m.p. 153-154C. .
(chloroform) :; .
24 CH H H h~dro- m.p. 122-124C.
3 chloride (acetone) H H CH3 free base n25 1.6030 : ,... . ..
26 Br CH hydro~ m.p. 176-177C. -k -: -:
3 H chloride (aceto~e_ ; . .
27 CH3 , CH3 ~ h dro- m(apet229-230 C
.:
28 CH3CH2-~ H H chloride (m p l48-149C. ~ ;
29 3, C~ H H hydro- m.pl 145-146C.
: CH3 chlorid~ (chl~roform- . ~ :
methanol) , ,'.
: 30 ~ - H H ~base ~5 lr5966 hy~ro- ~ p D 173-173.5a.
Br H H chloride (acetone-methanol) ~. :
~2 I ~ H H h dro- (aPetone- , 33 CN H H free base ndl 5 1.6009 ~ .
.
~' ' .
~)45~3~
., -.
34 H H CN chloride (acetone-methanol) N02 H H chloride m p 236-237 C.
methanol) 36 H N02 H hydro_ ( P t~7~ 75 C. ;.
- methanol) RC0 ~ ~ ~ , , 3 2 2NH,C - CH3 ..: ,.,:
No R isolated physical const.
37 H2N- ~ree base m-p- 148-149C
. (acetone) 38 CH3NH- hydrochloriae (acpetone2 144 C~
metha~ol) .
39CH3(~H2)3NX- ydrochloride (aPetol06~108 C.
methanol) : ~ m.p. 163-165C
C N- hydrochloride (acet-one-methanol) , . r--~ m.p. 165~166C.
41 ~ N- hydrochloride (acetone-. methanol) :~ :
, . -.:
m.p. 178-179Co 42 0 ~- hydrochloride (acetone-~ methanol) ... -m.p~ 202~207C. ::
43 ~ H2NNH- h~drochloride (acetone- .
: ~ methanol) ~:~
: ~ ' : : '' ' ,` ~ ' '-14- -- ' . !
~ , ' . . ':
''~ , ' '"
'' ' ' , "' .
~04S~36 - ~
(CH3C1~2)2N- hYdrochlOride(aPe.~;l52-l53c. "
methanol). .~
.. ..
r-~ m.p. 140-141C. .:
4~ ~ -NH- free base (ligh-t petro-leum-benzene) 46 ( 3)3C O h~drochloride (aPet25l-252 metha~ol) 47 CH3- free base ~ 5 1.6032 ~ `
48 EtO- h d hl (m p 118-119QC.
49 ~eO- hydrochloride m^p- 124-126~
. . (aceto~e) (.~.
5 CH2=CHCH20- hydrochloride m~p. 135-l36oc~ .
. . (acetone) : 51 . HO- hydrochloride ( P 251)Z5ZC~
Referred hxample :: 2-mercapto-4-(5'.-~itro-2l~thie~yl)-thiazole o a suspension of 1.6 g. of ammonium dithiocarba-mate in 20~ml. of ethanol, 3.0 g. of 2-bromoacetyl-5-nitro- ~.
thiophene was added below~10C.
;; The reaction mixture was stir~ed at room~tempera~
ture overnight,:and then heated under re~lux for 2.5 hours, :.:
followed b~evaporation in vacuo.
o~the~resldue, dilute aqueous ammonia was added, and~the filtrate was acidified with dilute aqueous hydro- ;.,:. '..
; ~ . . .
: chloric acid solu-tion.
he precipita-te was collected and .recr~stallized .;~
from acetone-methanol t~o give 2.8 g. of ~-mercapto-4-(5'- ; .
. . .
..
~045~36 :' ' nitro-2'-thietnyl)-thiazole; needles, m.p. 214C.
~ouna: c, 34.27; H, 1.59; I~, 11.50; S, 39.10 (%).
C7H902N2~3 requires C, 34.43; H, 1.64; N, 11.48; S~
39~34 (%)-Accordin~ to the method of Re~erred EXample 1, the following compou~ds were prepared.
Rb~lrRc '`1 Ra - S S:EI: . ' ,' Re~rd.
Ex m.pO sol~e~t No. Ra RbRc (C-) tfllizrY~ Y(yO) tion `
: 2 ~:X2NC0- ,- iH H 259 methanol 87 .-:
3 CN H H 225-6 aethan0el 91.7 4 H N02 ~ E 211-2 ~cxcha~l~ 97 : 5 ~ H3CCo_` H acetone- 60 ~
. . - . ether :.
. . (acetone) : 51 . HO- hydrochloride ( P 251)Z5ZC~
Referred hxample :: 2-mercapto-4-(5'.-~itro-2l~thie~yl)-thiazole o a suspension of 1.6 g. of ammonium dithiocarba-mate in 20~ml. of ethanol, 3.0 g. of 2-bromoacetyl-5-nitro- ~.
thiophene was added below~10C.
;; The reaction mixture was stir~ed at room~tempera~
ture overnight,:and then heated under re~lux for 2.5 hours, :.:
followed b~evaporation in vacuo.
o~the~resldue, dilute aqueous ammonia was added, and~the filtrate was acidified with dilute aqueous hydro- ;.,:. '..
; ~ . . .
: chloric acid solu-tion.
he precipita-te was collected and .recr~stallized .;~
from acetone-methanol t~o give 2.8 g. of ~-mercapto-4-(5'- ; .
. . .
..
~045~36 :' ' nitro-2'-thietnyl)-thiazole; needles, m.p. 214C.
~ouna: c, 34.27; H, 1.59; I~, 11.50; S, 39.10 (%).
C7H902N2~3 requires C, 34.43; H, 1.64; N, 11.48; S~
39~34 (%)-Accordin~ to the method of Re~erred EXample 1, the following compou~ds were prepared.
Rb~lrRc '`1 Ra - S S:EI: . ' ,' Re~rd.
Ex m.pO sol~e~t No. Ra RbRc (C-) tfllizrY~ Y(yO) tion `
: 2 ~:X2NC0- ,- iH H 259 methanol 87 .-:
3 CN H H 225-6 aethan0el 91.7 4 H N02 ~ E 211-2 ~cxcha~l~ 97 : 5 ~ H3CCo_` H acetone- 60 ~
. . - . ether :.
6 ~ t2~cc- ~ H H 1~9-90 ~Ct1ne 81 '
7 t-BuNEC0- H H~ 227-8 acetone 79 . ;
H2~HCC- ~ H~ ~ 282-3 methano1 84 9 ~ NCC- H H 211-3 acetone 83 ;:~ ~ NC0- ~ H ~ H ~212-3 acetone 80 ~: ~ . . , : . i : . ' - .
: ::
~)45~31~
., . - ~ :
11 ~ NC0- H H 141-2 0Hctone- 77 12CH~NHC0 H H 253-4 methanol 82 .
13 n-~uNHC0- H ~-I 157-8 petroleum 64.4 . ether 14 ~ -NHC0- H H 235-6 actetone B3.6 3 H H 219_20 benzene- 78O5 ~ (:
. . :. , .
16t-BuOOC- H H 182-3 ethanol 89.1 17t-BuOOCCH2NHC0 H H 180-1 acetone 87 . .
. ,. ~ ... .
. . acetone-18 H CN H 195-6 petroleum 65 ~
benzine ~.
.19CH3CONH H H 300 ethanol 83.3 . .
20 ~: ~ C~ CN 207-8 ethanol 70 Referred Example 21 :' . .
~ 2-mercapto-4-(2'-N-methylp~xrolyl)-thiazole ... ...
~ o a suspension of 5.8 g. of ammonium dithio- :.
: ~ .
carbamate in 50 m:L. of absolute ethanol, 7.6 g. of 2- ..
chloroacetyl-N-methylpyrrol ~as added below 20C. ~he ", .:
reaction~mixture was stirred at room temperature and heated under reflux ~or 2 hours, followed by evaporation in ~acuo. .
The residue was treated with 100 ml. of water, :~ ~
: precipltated product was collected and recrystalli~ed from . .-::
ethanol to yield 6.8 g. of 2-mercapto-4-(2'-N-methylpyrxol)-~ ~
j,~, .:
~ thiazole; white solid, m.p. 110 ~ 111.5C~
.:: .
. -~ . , ~ . ' ''"''.
. . .
~L0~5~L36 ..
Found: C, 48,75; H, 4.01; N, 14.60; S, 32.61 (~
C8H8N2S2 requlres C, 48.98; H, ~.08; N, 14.29; S, 32.65 (%).
Re~erred Example_ 22 2-mercapto-4-(5'-carboxy-2'-thienyl)-thiazole A solution of 1.5 g. of 2-mercapto-4~(5'-t-buto-xycarbonyl-2'-thieny1)-thiazole in 5 % ethanolic hydrochloric acid was refluxed for 1 hour.
After cooling, the solution was evaporated to -~ . - ..
dr~ess. ~he residue was washed with water and recrystal-lized from methanol to yield 1.2 g. of 2-mercapto-4-(5'-carboxy-2'-thienyl)-thiazole;~Yhite solid, m.p. 249-250C.
Found: C, 39.65; H, 2.01; N, 5.70; S, 39.95 (%).
C8E502NS3 re~uires C, 39.51; H, 2.06; N, 5.76; S~ 39.51 (%).
:
Re erred Exemple _3 According to the Referred Example 22, 2-mercapto~
4-(5'-carboxymeth~laminocarbon~1-2'-thienyl)-thiazole; ~ -- - m.p. 153-155C. (recrystalli~æed from acetone) was pre-pared~from 2-mercapto-4-(5'-t-butoxycarbo~ylmethylamino~
carbonJ1-2'-thienyl)-thiazole.~
Re~erred Example~ 24 o the solution of 1.2 g. o~ sodium dithiocar-~- -bamate 1n 20~ ml. oP mixture of ~7ater and ethanol (1 ~2~.3 g.~ o~5-c~ano-2-bromoacet~1 thiophene was added por- -~
tionwise.~
The react1on mixbure was~stirred at room tempera- ;
;~ ~ ture~overnight~, heated at 60C~ for 2 hours and cooled.
fter a~ld1fication, the~precipltates were collected~
~dried~and~recrystallized from mixed sol~ent o~ acetone 18~-45~3~ -...,..., .. ~ ,...
, .,:~!
and metha~ol to yield 1.9 g. of 2-mercapto-4-(5'-cyano-2'-thienyl)-thiazole; pale yellow powder, m.p. 225-226C.
~ ound: C, 42.17; H, 1.90; N, 12.56; S, 42.50 (%).
C~X4N2S3 requires C, 42.86; H, 1.79; N, 12.50; S, 42.86 (%).
Re~erred Example 25 A solution of 57.6 g. o~ 2-mercapto-4-~5'-cyano-2'-thienyl)-thiazole in an aqueous alkaline solution, pre-pared ~rom 20.4 g. of sodium hydroxide and 1.4 liters of water, was stood at room temperature overnight.
~ he solution was acidi~ied with hydrochloric acid, and precipitate was recr~stallization ~rom methanol to yield 52.7 g. o~ 2-mercapto-4-(5'-carbamo~1-2'-thienyl)-thiazole; pale yellow needles9 m.p. 259C.
. . .
~ .,:, . . .
"~ :'.:.' : .
., ,i .. .
:. '~. .
. .: !
' i ' -; ' ' ,, ,'~ ,'.,"'" '; ~
:~ ' '; ,' ''''' ~ ' ' ", . . ' :, :.
i: ': '::
- , ', '. ~ ' ~'' '~' "' ''' : ~ ' , ~ " ' ;':
: ' . ' '." '' . ' :~ ~ ' ` . . ' ' ',:
';
, , - 19 ~ , ':' ' : .
'~
~)45136 Example 52. 2-(3'-t-butylamino-2'-hydroxypropylthio)-4-(5/-carbamoyl-2'-thienyl)thiazole A solution of 2-(3'-chloro-2'-hydroxypropylthio)-4-(5'-carbamoyl-2'-thienyl)thiazole,4.0g(0.012 mol) and t-butylamine 70 g(large excess) was heated at 100 D in a sealed tube for 3 hrs. After cooling, t-butylamine was removed and residue was treated with methanolic hydrochloric acid solution.
Recrystallization of the crude hydrochloride from methanol provided 4.55g(93 %) of 2-(3'-t-butylamino-2'-hydroxypropylthio) -4-(5--carbamoyl-2'-thienyl)thiazole hydrochloride,mp 234-235.5, which was identified with the hydrochloride of the compound ~n Example 37 (i.r., n.m.r. and mixed melting point determination).
' ': . ::
2-(3'-chloro-2'-hydroxypropylthio)-4-(5'-carbamoyl-2'-thienyl)thiazole employed as the starting material was prepared by the following method described below.
2-Mercapto4-(5'-carbamoyl-2'-thienyl)thiazole, 12.lg (0.05 mol) was dissolved in an aqueous sodium hydroxide(2.2g= ` -0.055 mol) soIution(200 ml) and stirred with 5.0 g(0.054 mol) -~
Of epichlorohydrin at room temperature for 2.5 hrs. The visid product separated from the reaction solution was taken out -by decantation, dissolved in ethyl acetate, washed with an 10 %
~sodium hydroxlde solution, dried and evaporated.~ Column chro-matography of this residue(15.5g) on silica gel(200g) was carried out. Eluate with acetone-chloroform(1-5) provided 2-(3'-chloro-2'-hydroxypropylthio)-4-(5'-càrbamoyl-2'-thienyl)thiazole,m.p. ;
143-5~(recrystallized from methanol).
Found: C,44.I2; H,3.60; N,9.41; 5,32.15(~) Cl1HloN2O2S3 requires C,44.30; H,3.36; N,9.40; S,32~21(%).
: :, :.
~ ` - 20 1C)45136 Example 53. 2-(3'-t-butylamino-2'-hydroxypropylthio)-4-(5'-methyl-2'-thienyl)thiazole hydrochloride To a solution of 2-mercapto-4-(5'-methyl-2'-thienyl)thiazole
H2~HCC- ~ H~ ~ 282-3 methano1 84 9 ~ NCC- H H 211-3 acetone 83 ;:~ ~ NC0- ~ H ~ H ~212-3 acetone 80 ~: ~ . . , : . i : . ' - .
: ::
~)45~31~
., . - ~ :
11 ~ NC0- H H 141-2 0Hctone- 77 12CH~NHC0 H H 253-4 methanol 82 .
13 n-~uNHC0- H ~-I 157-8 petroleum 64.4 . ether 14 ~ -NHC0- H H 235-6 actetone B3.6 3 H H 219_20 benzene- 78O5 ~ (:
. . :. , .
16t-BuOOC- H H 182-3 ethanol 89.1 17t-BuOOCCH2NHC0 H H 180-1 acetone 87 . .
. ,. ~ ... .
. . acetone-18 H CN H 195-6 petroleum 65 ~
benzine ~.
.19CH3CONH H H 300 ethanol 83.3 . .
20 ~: ~ C~ CN 207-8 ethanol 70 Referred Example 21 :' . .
~ 2-mercapto-4-(2'-N-methylp~xrolyl)-thiazole ... ...
~ o a suspension of 5.8 g. of ammonium dithio- :.
: ~ .
carbamate in 50 m:L. of absolute ethanol, 7.6 g. of 2- ..
chloroacetyl-N-methylpyrrol ~as added below 20C. ~he ", .:
reaction~mixture was stirred at room temperature and heated under reflux ~or 2 hours, followed by evaporation in ~acuo. .
The residue was treated with 100 ml. of water, :~ ~
: precipltated product was collected and recrystalli~ed from . .-::
ethanol to yield 6.8 g. of 2-mercapto-4-(2'-N-methylpyrxol)-~ ~
j,~, .:
~ thiazole; white solid, m.p. 110 ~ 111.5C~
.:: .
. -~ . , ~ . ' ''"''.
. . .
~L0~5~L36 ..
Found: C, 48,75; H, 4.01; N, 14.60; S, 32.61 (~
C8H8N2S2 requlres C, 48.98; H, ~.08; N, 14.29; S, 32.65 (%).
Re~erred Example_ 22 2-mercapto-4-(5'-carboxy-2'-thienyl)-thiazole A solution of 1.5 g. of 2-mercapto-4~(5'-t-buto-xycarbonyl-2'-thieny1)-thiazole in 5 % ethanolic hydrochloric acid was refluxed for 1 hour.
After cooling, the solution was evaporated to -~ . - ..
dr~ess. ~he residue was washed with water and recrystal-lized from methanol to yield 1.2 g. of 2-mercapto-4-(5'-carboxy-2'-thienyl)-thiazole;~Yhite solid, m.p. 249-250C.
Found: C, 39.65; H, 2.01; N, 5.70; S, 39.95 (%).
C8E502NS3 re~uires C, 39.51; H, 2.06; N, 5.76; S~ 39.51 (%).
:
Re erred Exemple _3 According to the Referred Example 22, 2-mercapto~
4-(5'-carboxymeth~laminocarbon~1-2'-thienyl)-thiazole; ~ -- - m.p. 153-155C. (recrystalli~æed from acetone) was pre-pared~from 2-mercapto-4-(5'-t-butoxycarbo~ylmethylamino~
carbonJ1-2'-thienyl)-thiazole.~
Re~erred Example~ 24 o the solution of 1.2 g. o~ sodium dithiocar-~- -bamate 1n 20~ ml. oP mixture of ~7ater and ethanol (1 ~2~.3 g.~ o~5-c~ano-2-bromoacet~1 thiophene was added por- -~
tionwise.~
The react1on mixbure was~stirred at room tempera- ;
;~ ~ ture~overnight~, heated at 60C~ for 2 hours and cooled.
fter a~ld1fication, the~precipltates were collected~
~dried~and~recrystallized from mixed sol~ent o~ acetone 18~-45~3~ -...,..., .. ~ ,...
, .,:~!
and metha~ol to yield 1.9 g. of 2-mercapto-4-(5'-cyano-2'-thienyl)-thiazole; pale yellow powder, m.p. 225-226C.
~ ound: C, 42.17; H, 1.90; N, 12.56; S, 42.50 (%).
C~X4N2S3 requires C, 42.86; H, 1.79; N, 12.50; S, 42.86 (%).
Re~erred Example 25 A solution of 57.6 g. o~ 2-mercapto-4-~5'-cyano-2'-thienyl)-thiazole in an aqueous alkaline solution, pre-pared ~rom 20.4 g. of sodium hydroxide and 1.4 liters of water, was stood at room temperature overnight.
~ he solution was acidi~ied with hydrochloric acid, and precipitate was recr~stallization ~rom methanol to yield 52.7 g. o~ 2-mercapto-4-(5'-carbamo~1-2'-thienyl)-thiazole; pale yellow needles9 m.p. 259C.
. . .
~ .,:, . . .
"~ :'.:.' : .
., ,i .. .
:. '~. .
. .: !
' i ' -; ' ' ,, ,'~ ,'.,"'" '; ~
:~ ' '; ,' ''''' ~ ' ' ", . . ' :, :.
i: ': '::
- , ', '. ~ ' ~'' '~' "' ''' : ~ ' , ~ " ' ;':
: ' . ' '." '' . ' :~ ~ ' ` . . ' ' ',:
';
, , - 19 ~ , ':' ' : .
'~
~)45136 Example 52. 2-(3'-t-butylamino-2'-hydroxypropylthio)-4-(5/-carbamoyl-2'-thienyl)thiazole A solution of 2-(3'-chloro-2'-hydroxypropylthio)-4-(5'-carbamoyl-2'-thienyl)thiazole,4.0g(0.012 mol) and t-butylamine 70 g(large excess) was heated at 100 D in a sealed tube for 3 hrs. After cooling, t-butylamine was removed and residue was treated with methanolic hydrochloric acid solution.
Recrystallization of the crude hydrochloride from methanol provided 4.55g(93 %) of 2-(3'-t-butylamino-2'-hydroxypropylthio) -4-(5--carbamoyl-2'-thienyl)thiazole hydrochloride,mp 234-235.5, which was identified with the hydrochloride of the compound ~n Example 37 (i.r., n.m.r. and mixed melting point determination).
' ': . ::
2-(3'-chloro-2'-hydroxypropylthio)-4-(5'-carbamoyl-2'-thienyl)thiazole employed as the starting material was prepared by the following method described below.
2-Mercapto4-(5'-carbamoyl-2'-thienyl)thiazole, 12.lg (0.05 mol) was dissolved in an aqueous sodium hydroxide(2.2g= ` -0.055 mol) soIution(200 ml) and stirred with 5.0 g(0.054 mol) -~
Of epichlorohydrin at room temperature for 2.5 hrs. The visid product separated from the reaction solution was taken out -by decantation, dissolved in ethyl acetate, washed with an 10 %
~sodium hydroxlde solution, dried and evaporated.~ Column chro-matography of this residue(15.5g) on silica gel(200g) was carried out. Eluate with acetone-chloroform(1-5) provided 2-(3'-chloro-2'-hydroxypropylthio)-4-(5'-càrbamoyl-2'-thienyl)thiazole,m.p. ;
143-5~(recrystallized from methanol).
Found: C,44.I2; H,3.60; N,9.41; 5,32.15(~) Cl1HloN2O2S3 requires C,44.30; H,3.36; N,9.40; S,32~21(%).
: :, :.
~ ` - 20 1C)45136 Example 53. 2-(3'-t-butylamino-2'-hydroxypropylthio)-4-(5'-methyl-2'-thienyl)thiazole hydrochloride To a solution of 2-mercapto-4-(5'-methyl-2'-thienyl)thiazole
8.lg(0.038 mol) in an aqueous sodium hydroxide solution prepared from sodium hydroxide,3.5g(0.088 mol) and 100 ml of water,was added 4.22 g(0.0456 mol) of epichlorohydrin in one potion at room temperature. The resulting solution was allowed to stand at room temperature for 3 hrs, ahd extracted with methylene chloride. The organic phase was dried and evaporated in vacuo.
The residue , without purification, and 30 g(large excess) of `
t-butylamine were heated at 70 for 3 hrs. Excess t-butylamine , was removed and residue was dissolved in 100 ml of methylene - ;
chloride followed by treatment with dry HCl gas. Precipitate was collected and recrystallized from acetone to yield 2-(3'- `
t-butylamino-2'-hydroxypropylthio)-4-(5'-methyl-2'-thienyl) thiazole hydrochloride, mp 123-5 , which was identified with the compound on Experiment 24. (i.r., n.m.r., and mixed meltin~
point determination) ~;
According to the method of Example 2, all compounds listed in the ~able (Ex. No.1-50) are also prepared : ; :
.
- ..
- 21 - ~
~, - :' :~ ' ~ ~ ' . ...... , ....... ... ... ~ ~ - - ~
The residue , without purification, and 30 g(large excess) of `
t-butylamine were heated at 70 for 3 hrs. Excess t-butylamine , was removed and residue was dissolved in 100 ml of methylene - ;
chloride followed by treatment with dry HCl gas. Precipitate was collected and recrystallized from acetone to yield 2-(3'- `
t-butylamino-2'-hydroxypropylthio)-4-(5'-methyl-2'-thienyl) thiazole hydrochloride, mp 123-5 , which was identified with the compound on Experiment 24. (i.r., n.m.r., and mixed meltin~
point determination) ~;
According to the method of Example 2, all compounds listed in the ~able (Ex. No.1-50) are also prepared : ; :
.
- ..
- 21 - ~
~, - :' :~ ' ~ ~ ' . ...... , ....... ... ... ~ ~ - - ~
Claims (14)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing thiazole derivatives of the formula (I) (I) wherein R1 is hydrogen, lower alkyl, C3-C6 cycloalkyl, aryl or heteroaromatic ring, said aryl being selected from the group consisting of phenyl and naphthyl each of which may optionally be substituted with C1-C4 alkyl, C1-4 alkoxy, C3-C5 alkenoxy, halogen or cyano, said heteroaromatic ring being selected from the group consisting of thienyl, furyl, pyridyl, pyrrolyl, thiazolyl, and benzothiazolyl each of which may optionally be substituted with lower alkyl, halogen, cyano, phenyl, C2-C8 acylamino, a group of the formula, [wherein Y is hydroxy, lower alkyl, lower alkoxy or lower alkenyloxy], or a group of the formula [wherein R5 and R6 are each hydrogen, amino, lower alkyl, C3-C6 cycloalkyl, or R5 and R6 may form a morpholino piperidino, or pyrrolydino group], R2 is hydrogen, lower alkyl, phenyl, or lower alkyl-substituted phenyl, R3 is hydrogen and R4 is t-butyl which comprises reacting thiazole ?ivatives of the formula (II) (II) wherein R1 and R2 have the same meanings as defined above, and A is or and X is halogen with an amine of the formula (III) HNR3R4 (III) wherein R3 and R4 have the same meanings as defined above.
2. A process for producing thiazole derivatives of the formula (I) (I) wherein R1, R2, R3 and R4 have the same meanings as defined above which comprises reacting halohydrin derivatives of the formula (IIa) (IIa) wherein X is halogen, with an amine of the formula (III) HNR3R4 (III) wherein R3 and R4 have the same meanings as defined above.
3. A process according to claim 1, wherein the reaction is carried out by heating within a temperature range of from 30°C.
to 150°C.
to 150°C.
4. A process according to claim 1, wherein the reaction is carried out in the presence of an organic solvent.
5. A process according to claim 1, wherein the reaction is carried out by heating under reflux in an alcoholic solution
6. A process according to claim 1, wherein the reaction is carried out in a nitrogen gas atmosphere.
7. A process according to claim 1 wherein R1 is hydrogen, lower alkyl, C3-C6 cycloalkyl, phenyl, naphthyl, phenyl which is substituted with lower alkyl, lower alkoxy, halogen, cyano, hydroxy or C3-C5 lower alkenyloxy, R2 and R3 are hydrogen and R4 is t-butyl.
8. A process according to claim 1 wherein R1 is thienyl or substituted thienyl having one or more substituents selected from lower alkyl, halogen, cyano, nitro, phenyl, a group of the formula [in which R5 is hydrogen or lower alkyl, and R6 is hydrogen, lower alkyl, amino, or C3-C6 cycloalkyl.], or a group of the formula [in which Y is hydroxy, lower alkoxy, lower alkyl or C3-C5 alkenyloxy.] R2 and R3 are hydrogen and R4 is t-butyl.
9. A process according to claim 1 wherein R1 is furyl, pyridyl, pyrrolyl, thiazole, or benzothiazolyl, each of which may optionally be substituted with lower alkyl, R2 and R3 are hydrogen and R4 is t-butyl.
10. A process according to claim 1 for producing a thiazole derivative of the formula wherein R1 is R2 is hydrogen, R3 is hydrogen and R4 is t-butyl.
11. A process according to claim 1 for producing a thiazole derivative of the formula wherein R1 is R2 is hydrogen, R3 is hydrogen and R4 is t-butyl.
12. A process according to claim 1 for producing a thiazole derivative of the formula wherein R1 is R2 is hydrogen, R3 is hydrogen and R4 is t-butyl.
13. A process according to claim 1 for producing a thiazole derivative of the formula wherein R1 is R2 is hydrogen, R3 is hydrogen and R4 is t-butyl.
14. A process according to claim 1 for producing a thiazole derivative of the formula wherein: R1 is R2 is hydrogen, R3 is hydrogen and R4 is t-butyl.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12607073A JPS5239827B2 (en) | 1973-11-08 | 1973-11-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1045136A true CA1045136A (en) | 1978-12-26 |
Family
ID=14925858
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA213,282A Expired CA1045136A (en) | 1973-11-08 | 1974-11-07 | Thiazole derivatives |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPS5239827B2 (en) |
| CA (1) | CA1045136A (en) |
| CH (1) | CH605867A5 (en) |
| HU (1) | HU168452B (en) |
| NL (1) | NL7414537A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7514566B2 (en) | 2006-01-18 | 2009-04-07 | Amgen, Inc. | Thiazole compounds and methods of use |
| US7897619B2 (en) | 2007-07-17 | 2011-03-01 | Amgen Inc. | Heterocyclic modulators of PKB |
| US7919504B2 (en) | 2007-07-17 | 2011-04-05 | Amgen Inc. | Thiadiazole modulators of PKB |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8302591D0 (en) * | 1983-01-31 | 1983-03-02 | Fujisawa Pharmaceutical Co | Thiazole derivatives |
-
1973
- 1973-11-08 JP JP12607073A patent/JPS5239827B2/ja not_active Expired
-
1974
- 1974-11-06 HU HUSU000879 patent/HU168452B/hu unknown
- 1974-11-07 CH CH1490074A patent/CH605867A5/en not_active IP Right Cessation
- 1974-11-07 CA CA213,282A patent/CA1045136A/en not_active Expired
- 1974-11-07 NL NL7414537A patent/NL7414537A/en not_active Application Discontinuation
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7514566B2 (en) | 2006-01-18 | 2009-04-07 | Amgen, Inc. | Thiazole compounds and methods of use |
| US8084479B2 (en) | 2006-01-18 | 2011-12-27 | Amgen Inc. | Thiazole compounds and methods of use |
| US7897619B2 (en) | 2007-07-17 | 2011-03-01 | Amgen Inc. | Heterocyclic modulators of PKB |
| US7919504B2 (en) | 2007-07-17 | 2011-04-05 | Amgen Inc. | Thiadiazole modulators of PKB |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5239827B2 (en) | 1977-10-07 |
| HU168452B (en) | 1976-04-28 |
| NL7414537A (en) | 1975-05-12 |
| CH605867A5 (en) | 1978-10-13 |
| JPS5076069A (en) | 1975-06-21 |
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