Method of producing derivatives of thiazole or their additive salts with organic or inorganic acids

专利摘要:
L'invention concerne des nouveaux dérivés du thiazole repondant à la formule générale dans laquelle: - R1 et R2 représentent chacun indépendamment l'hydrogène ; un groupe alkyle en Ci-C4 ; un groupe phényle ; un groupe phényle substitué une ou plusieurs fois par un atome d'halogène, un groupe alkyle en Ci-C4, un groupe alcoxy en Ci-C4, un groupe nitro, ou un groupe hydroxy ; ou l'un des groupes R1 et R2 désigne l'hydrogène et l'autre représente: un groupe naphtyle ; un groupe benzyle ; un groupe aa-diméthyl-benzyle ; un groupe cyclohexyle ; un groupe biphényle ; un groupe thiényle ; un groupe adamantyle, ou encore Ri et R2 considérés ensemble représentent un groupe : où le groupe phényle est lié en position 4 du thiazole et le groupe (CH2)m en position 5 et dans lequel m représente un nombre entier égal à 2 ou 3 et R5 désigne l'hydrogène ou un groupe nitro occupant l'une des positions libres du cycle ; - R3 représente l'hydrogène ou un groupe alkyle en Ci-C4 - R4 représente notamment un alkyle substitué par un groupe amino, pyrrolidino ou pyridino.
公开号:SU1604157A3
申请号:SU884355377
申请日:1988-03-11
公开日:1990-10-30
发明作者:Бизьер Катлин；Олльеро Доминик；Вормс Поль
申请人:Санофи (Фирма)；
IPC主号:

专利说明:

the action of substituted thiourea f-ly HjN-C (S) -NR5R4l where Rj is indicated above; R p provided that when. has a free first, or second, amino group, then it is protected by a carbonyl-containing group with a compound R, -CHBr-C (0) -R2, where R, and R are above, or its corresponding compound, where carbonyl is protected in acetal by heating and pH 1-6, followed, if necessary, by removing the carbonyl-containing group and isolating the target product as a base or an acid addition salt. -New compounds with LD4o toxicity of 60-450 mg / kg are antagonists of type M cholinergic muscarinic receptors / and some of them have antagonistic activity to the action of causative agents of amino acids in the brain. 8,
The invention relates to a process for the preparation of new chemical compounds, namely, derivatives of thiazole or their addition salts with inorganic or organic acids, which have activity against the cholinergic system and can be used in medicine for the treatment of degenerative syndromes associated with aging.
The aim of the invention is to obtain new compounds of the thiazole series, possessing a new type of biological effect for this class of compounds.
Example 1 Preparation of 2- (2-α-diethylaminoethyl) amino-5-fenshthiazole dihydrochloride (compound SR 44318A).
A) Preparation of K-benzoyl - - (diethyl aminoethyl) thiourea.
To a suspension of 51 g of potassium thiocyanate in 300 ml of anhydrous acetone at room temperature, a solution of 70 ml of benzoyl chloride in 100 ml of anhydrous acetone is added dropwise. After the addition is complete, the reaction mixture is heated to reflux for 5 minutes. To the resulting hot solution, a solution of 85 ml of 2-diethylaminoethylamine in 100 ml of methylene chloride is slowly added with vigorous stirring so that the mixture is maintained at reflux. After the addition is complete, stir for 1 h at room temperature, then the solvents are evaporated off and the residue is treated with ice water. Extract 2 times with 200 ml of methylene chloride and dry the solution over magnesium sulfate. The solvent is evaporated to dryness and the resulting
The oily product is purified by chromatography on a silica column. The elution with a mixture of methylene chloride and ethyl acetate 80:20 (by volume) removes the low polarity.
Then, elution with a mixture of methylene chloride and methanol 95: 5 (by volume) gives the product. Weight 78 g; T. pl. 54 - 56 ° C ..
B) Preparation of the compound SR 44 318 A.
In nitrogen atmosphere for
For 30 minutes under reflux, 3.5 g of the sodium hydroxide obtained in A) 7 or 18 ml of 2.5 N sodium hydroxide solution are boiled. After cooling, concentrated hydrochloric acid is added up to a pH of about 6. A solution of 2.48 g of o-bromophenyl acetaldehyde in 25 ml of 95% ethanol is added and the mixture is heated under reflux.
for 1 h under nitrogen.
Extract under vacuum and add aqueous 10% sodium carbonate solution. Extract 2 times with 4-ethylene chloride and dry the solution over magnesium sulfate. The solvent is evaporated and the residue is chromatographed on a silica column, eluting with a 95: 5 mixture of methylene chloride and methanol. An oil is obtained (1.46 g).
This oil is dissolved in anhydrous ether and a gas solution is added. hydrogen chloride in anhydrous ether and left to crystallize, the crystals are sucked off, rinsed with anhydrous ether, and dried under vacuum. T. pl,,
Examples 2-108, A) Work as in Example 1-A, but the amino compounds used,
15
20
25
thirty
receive the corresponding substituted thioureas presented in table. one . B) Work as in the example, using thiourea from table. 1 and the men-oxo-halogenated derivative, the thiazoles are obtained, presented in Table. 2 ..
Example 109. Preparation of α-aminopropyl) amino-5-methyl-4-phenyl thiazole dihydrochloride (compound
SR 44 514 A).
A) Preparation of N-Boc-3-aminopropionitrile (Boe is benzyloxycarbonyl).
To a solution of 25 g of 3-aminopropionitrile fumarate in 100 ml of water is added 56 ml of triethylamine, then heated to 50 ° C. Then, with vigorous stirring, 46 g of bis- tert-butyl ester of () dicarboxylic acid are added as a solution in 100 ml of dioxane.
After evaporation, the solvent is treated with dichloromethane. The organic solution is rinsed with aqueous 5%
sodium carbonate solution, then
pH 2 sulfate buffer. The solution is dried over magnesium sulfate and the solvent is evaporated. The residue (38.8 g) is crystallized.
B) Preparation of K-Boc-3-aminopropylamine.
20 g of the product obtained above are dissolved in a mixture of 400 ml of water, 40 ml of ammonia and 50 ml of ethanol. Add35
Rene's nickel and hydrogen at the lung temperature and pressure.
After filtering off the catalyst, the solvents are evaporated under vacuum. The residue is taken up in saline water and extracted with ethyl acetate. The solution is dried over magnesium sulfate and the solvent is evaporated. 12.6 g of product are obtained.
B) Preparation of K-benzoyl-K - (N-Boc-45 -3-aminopropyl) -tourea.
To a suspension of 70.6 g of potassium thiocyanate and 50 ml of anhydrous acetone, a solution of 6.38 ml of benzoyl chloride in 20 ml of anhydrous acetone was added, then was boiled under reflux for 5 minutes.
A solution of 12.6 g of N-Boc-3-aminopropyl-55 amine in 20 ml of methylene chloride is slowly added to the hot solution with vigorous stirring.
After the addition is complete, leave for 1 hour with stirring, then the solvents are evaporated and the residue is approx.
15
20
25
thirty






35
40
bath 100 ml of cold anhydrous
the ether.
Crystals are isolated which are scrubbed and cooled with cold ether and dried with an oven at 70 ° C. Weight 8.3 g; T. pl. 104-105 C. D) Preparation of Compound SR 44 514 A. For 15 minutes, 3.37 g of the product obtained above are boiled under reflux in 14 ml 2.5 n. sodium hydroxide solution. After cooling, concentrated hydrochloric acid d6 pH1 is added. 2.13 g of 2-bromopropiophenone, dissolved in 20 ml of ethanol, are added and the mixture is heated under reflux for 1 h under a nitrogen atmosphere. The mixture is treated as indicated in Example IB and an oil is obtained. By adding hydrochloric ether, dihydrochloride is obtained in the form of a solution in methanol. T. pl. YuO-PO S.
Examples 110 and 111. From behind. of the melted thiourea obtained in Example 109, and operation as in Example 109-G, but changing the bromo-derivative used, 2-r3-aminopropyl) amino-4- (4-fluorophenyl) -thiazole (SR 44886 A ), allocated in the form of fumarate (0.5), T. pl. 162- (example software), and 2- (3-aminopropyl) -aminoZ-4- (2,4,6-trimethylphenyl) -thiazole (compound SR 44949), isolated as fumarate, T. pl. 163- (example 11).
Example 112. Preparation of α-methyl-K- (3-pyridylmethyl) -amino-4 (2, 4,6-trimethylphenyl-thiazole oxalate (compound SR 45206 A).
H;
SNS
/
snsn
R
R

A) Preparation of K-methyl-K (3-pyridylmethyl) -thiourea.
To a suspension of 16.2 g of sodium thiocyanate in 90 ml of anhydrous acetone, cooled to, with good stirring, 24.6 ml of pivaloyl chloride are added dropwise. Allow to stir for 3 hours at, then add 25 g of 3-methylaminomethylpyridine so that the temperature is maintained at 0-4 ° C. Leave the temperature to rise and stir for 15 hours at this temperature. The mixture is evaporated under vacuum and the residue is treated to 100 ml of concentrated hydrochloric acid. Heat for 1 h at 95 ° C. After cooling, it is extracted 2 times with methylene chloride, then the aqueous phase is made alkaline with concentrated sodium hydroxide solution. The organic extracts are combined and dried over magnesium sulphate. The solvent is evaporated and the residue is crystallized. Triturate the crystals with 100 ml of ether and suck. After drying, 26.7 g of product are obtained;
T. pl. 119-120 C.
B) Preparation of SR 45206 A Compound
A mixture of 3.6 g of the thiourea obtained above, 6 g of phenacyl-2.4, 6-trimethyl bromide, 20 ml of water, 50 ml of ethanol and 2 ml of concentrated hydrochloric acid are boiled under reflux for 4 hours.
After evaporation under vacuum, the residue is treated with 150 ml of methylene chloride and extracted with 150 ml of aqueous 1N. hydrochloric acid solution. The organic phase is again extracted 3 times with 100 ml of 1N. hydrochloric acid and acid extracts are combined. Alkalinize with sodium hydroxide solution and extract 4 times with 150 ml of methylene chloride. The organic extracts are combined, dried over magnesium sulphate and the solvent is evaporated. The oily residue is chromatographed on a silica column (100 g). Elution with a methylene chloride / methanol mixture 97: 3 by volume gave 4.5 g of an oily product.
Oxalate.
4.5 g of the above product was dissolved in 30 ml of acetone and a solution of 1.4 g of oxalic acid in 40 ml of acetone was added. Light yellow crystals are formed, which are removed, dried with a small amount of acetone and dried. 4.3 g of product are obtained. T. pl. 160-161 ° C.
Examples 113-117. Work As in example 112-A), get such
0
five
0
five
0
five
40
45
50
five
the same way substituted thioureas, combined by Et tab. 3
B) Of these different thioureas, the work, as in Example 1 1 2-B), is obtained from the thiazoles presented in Table. four.
Example 118. Preparation of 2- - (2-morpholinoethylamino) -4,5-dihydronaphtho (1,2-d) thiazolone dihydrochloride (compound SR 44 273 A).
 Under nitrogen for 15 minutes, 3.66 g of M-benzoyl-K - (morpholinoethyl) - thiourea in 17.5 ml of 2.5 and sodium hydroxide solution are heated under reflux. After cooling, concentrated hydrochloric acid is added to pH 7. A solution of 3 g of 2-bromo-1,2,3,4-tetrahydrin naphthalin-1-one in 20 Mji ethanol is added and the mixture is refluxed for 1 h. . After evaporation, the solvent is neutralized by the addition of sodium bicarbonate and extracted 2 times with dichloromethane. The organic phase is dried over magnesium sulphate and chromatographed on a silica column. Elute with a mixture of dichloromethane and methanol (95: 5 by volume). After evaporation of the solvents, the oily residue is treated with ether and the hydrochloride is precipitated with ether. 0t-C.sub.shut and recrystallized from a mixture of isopropanol with ethanol 95. So pl. 255-257 ° C.
Examples 119-124. Working as in Example 118, but changing the bromo derivatives and / or benzoylthioureas, the thiazoles given in c. tab. five.
Example 125v Preparation of 2 (2-diethylaminoethyl.) - amino1-9-nitro-5,6-dihydro-4H-benz: o (6,7) -cyclohepta (1, 2-d) thiazolone dihydrochloride (compound SR 44 411 A).
Operating as in Example 118, starting from K-benzoyltK- (3-diethylaminopropyl) -thiourea, on the one hand, and 2-bromo-8-nitrobenzocycloheptan-1-one, on the other hand, the expected product is obtained in the form of dihydrochloride. T. pl. 192-195 C (isopropanol - ethanol 95).
For the products obtained according to the proposed method, their pharmacological properties, in particular, their affinity for cholinergic muscarinic receptors, were studied.
The study was carried out in vitro with biochemical tests, as well as with pharmacological tests carried out on animals.
Biochemical study in vitro. In mammals, there are two classes of cholinergic muscarinic receptors: the receptors H and Mj.
Type M receptors are concentrated in certain areas of the brain, such as the hippocampus, cerebral cortex, and the striatum, as well as in the sympathetic ganglia. These sites can be selectively labeled with tritium-containing prenzepin (Hl-PZ). Type M2 receptors. prevail in the heart and ileum and can be labeled with tritium N-methylscopolamine (H-NMS). In order to determine the selectivity of the products according to the proposed method with respect to sites M and M, their interaction was studied in vitro with the high affinity of H-PZ to the membranes of the rat hippocampus and smooth of the ileum of the guinea pig, respectively, about Metrology.
A) Affinity study for cholinergic muscarinic receptor type M ,.
The interaction of molecules with muscarinic receptors of the Mj type was studied by measuring in vitro on the hippocampal rat shift homogenate containing tritium pyrenzepine from its specific fixed positions. Aliquots (10 µl) of rat hippocampus homogenate (w / v) in buffer Ka, HP04 (50tM, pH 7.40) were incubated for 2 hours at 4 ° C in the presence of H-PZ (76 Ci) mmol; final 1 nM) and with increasing concentrations of the product studied. Final volume 2 ml. The reaction was stopped by centrifuging for 10 minutes at 50,000 xg. After decantation and precipitation, the fixed radioactivity was resolved by scintillation of the liquid. Non-specific fixation was determined in the presence of 10 (UM atropine sulfate. The inhibitory concentration 50 (CIj (j) was determined graphically.
B) Affinity study for cholinergic muscarinic receptor type MI.
0
five
0
five
0
five
0
five
The interaction with type N2 muscarinic receptors was studied by measuring in vitro on the homogenate of the ileum ileum of the guinea pig ileum, containing tritium N-methylscopolamine, its specific fixed positions. Aliquots (50 µl) of the smooth guinea pig ileum homogenate at a concentration of 0.625% (weight / volume) in 20 mM HEPES buffer: 2- (2-hydroxy-4- -ethyl-1-piperazinyl) -ethanesulfide containing NaCl (100 tM) and MgCl4 (10 pM) (final pH 7.5), isosubated for 20 min at 30 ° C in the presence of H-NMS (85 Ci) mmol; 0.3 NM final) and with increasing concentrations of the product under investigation. The final volume is 1 ml. The reaction was terminated by centrifugation for 5 minutes at 15,000 xg. Non-specific fixation was determined in the presence of atropine sulphate 1O. Results:
Tab. 6 shows the affinity of the products obtained by the proposed method for the receptors M and M. The results are expressed in inhibitory concentrations of 50 (C1, or in concentration (mM), which leads to a 50% shift in the tritium-containing ligand fixed to membrane H-PZ Shift Receptors - Affinity for Mj Receptor; H-NMS Shift Clgo - Affinity for M Receptor
In addition, in the next column table. 6 shows the ratio of R between Cljo FOR receptors M and M, which expresses the selectivity of products with respect to one of the types of receptors.
As a comparison, in the table. 6 shows the results obtained with three standard products.
The results show that the compounds obtained according to the proposed method have a strong affinity for cholinergic muscarinic receptors with labeled specificity for central MI receptors.
Pharmacological study of the virus. Pirenzepine (PZ) is a specific antagonist of the cholinergic muscarinic centers of M. Intrastria and injected with PZ myppie leads to rotational behavior. We studied antagonism of this behavior due to the products obtained according to the invention.
The products were carried out either intraperitoneally (i.p.) or orally (P.O.) after being dissolved in distilled water or suspended in a 5% solution of gum arabic. Control was implemented by introducing pure solvent under the same conditions.
Used smaller females (Swiss CD 1, Chearles River, France) weighing 25-30 g.
Pyrenezepine was dissolved in phosphate buffer, pH of the solution 6..
The studied products or their solvents were administered either by injection, either intraperitoneally or orally using an esophageal probe, in a volume of 0.4 ml per 20 g of body weight. The administration was carried out either 15 minutes (intraperitoneally) or 30 minutes (oral) before direct injection of pyrhenepine at a dose of 1 µg in µl of solvent into the straight striatum of the mouse. The number of contralateral rotations (in the opposite direction of the injection) was counted in for three periods of 2 min after injection of pirenzepine: minutes 2-4, 8-10 and 13-15. Each treatment consisted of 3-4 doses and 10 animals per dose. For each treatment, the total number of rotations and the percentage of antagonism with respect to the control lot were calculated.
For each product, an effective dose of 50 (EDD g dose, which reduces by 50% the number of rotations caused by pirenzepine) is graphically determined.
The results are presented in the scoreboard 7 "
Tab. 7 Displays for each test product an effective dose of 50 (ED) in mg / kg in mouse for antago U
Uniform rotations caused by pyreneepine, either intraperitoneally or orally.
As a comparison, the results obtained were correlated with three standard products. .
According to the table. 7 „
Strong induction of secondary effects (tremor, drooling, varnish
e
Q
five
0 5 o
o

five,
rimaci, defecation, piloerection, hypothermia, sedatatsiya) in doses close to the active doses in these tests.
The results table. 7 shows that the compounds according to the invention have an activity that stimulates cholinergic central transmission and, therefore, can be used as agonists of muscarinic receptors.
 In addition, some of the products exhibit antagonistic activity to the action of pathogens of amino acids in the brain. This activity was measured by an acetylcholine release test induced by L-methyl-B-aspartic acid (NMDA) on rat striatal sections.
Acute toxicity was determined for various products according to the method of the invention. The products were administered intraperitoneally in high doses in batches of 10 female mice (Swiss CD 1, Charles River, France) weighing 20 g each.
1) The death caused by the use of food products, was noted within 24 hours in accordance with the introduction of the product. For each of the products, a lethal dose of 50 was determined (N, i.e., the dose that causes death of 50% of the animals.
The results are summarized in table. eight..
The products according to the method of the invention are low toxic and show no sign of toxicity at the doses in which they are active. Therefore, they can be used as medicaments for treating degenerative syndromes associated with aging, and especially memory and senile dementia disorders.
In pharmaceutical compositions for oral, transdermal, transdermal, 1-time rectal administration, the new active ingredients can be administered in a mixture with the pharmaceutical bases of people for the treatment of senile dementia.
In order to achieve the desired effect, the dose of the active principle can vary from 20 to 500 mg per day.
Each dose may contain 5–200 mg of active ingredient in combination with a pharmaceutical base.
This dose may be administered 1-4 times per day.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining the thiazole derivatives of the general formula
R
 N "2
Rde R is hydrogen, C, -C4-alkyl, phenyl or benzyl; hydrogen. C, -C4-alkyl, phenyl, mono- or disubstituted with halogen, preferably chlorine or fluorine, phenyl, mono- or tr, and substituted with C, -C4-alkyl phenyl or monosubstituted With a j-C-alkoxy group, nitro - or a hydroxyl group, phenyl or hydrogen; naphthyl, benzyl, oi, 0 -Dimethy benzyl, cyclohexyl, biphenylyl, thienyl, or adathyl; whether R t and R2 together mean a group
L-R is associated with position 4 of the thiazole ring through a direct bond of phenyl and position 5 of the thiazole ring through an alkylene chain - (CH ,,, - in which m is an integer equal to 2 or 3,
RC - hydrogen or nitro group,
occupying one of the free positions of the benzene to the OL,
provided that one of the groups R and R is hydrogen, then the other cannot mean hydrogen or methyl;
RI is hydrogen or C -C alkyl; R4. - Group
/ Re-A.-
where AJ is my pr or branched
C-C-alkylene;
RgHR-7 independently of one another is hydrogen or C4-C4-alkyl,
or one of R and Ry is hydrogen, and the other is cyclopropyl or a group
.R
-N
6
means a pyrrolidine, piperidine, morpholino or N-methylpiperizine cycle, or R4 group
-BUT
"
where A 2 is a direct bond or straight C —C-alkylene, wherein A is bound to the pyridine ring in the 2,3 or 4 position, or the R4 group
- (CH2) 2-lf
sn,
or
O-RI
where Rg is C, -C4-alkyl, or a group
 . -
four
o - means group
where Re has the indicated meaning, under the condition 1I, that in this case, if R is hydrogen or 0 -64-alkyl, then is C, -C4-alky or cyclohexyl,
or their addition salts with inorganic or organic acids, characterized in that in an acidic medium with a pH of 1-6, substituted thiourea of the general formula
-N
R3 R
where Ra has the indicated value;
R has the meanings for R provided that the substituent R4 has a free primary or secondary amino group, then it is protected by a carbonyl-containing protecting group,
when heated, interact with a compound of the general formula
RI-CH-C-R.
I
7 Vg about
where R and RJ have the indicated meanings, de free base or as or with a corresponding compound, an additive salt with an inorganic one in which the carbonyl group or organic acids ..
T a b. l and c and 1 Structural characteristic of the initial thioureas formula
S V-CO-OT-d-NH-R
- (CH2)
(CHab-N
X
X
, s, n
2 5
,
- (CH2)
sn
{CH2)
(dn 2) 2-0
l zlz-l Z
T. PL T. PL T. PD
(CH2) 2-N
(SNg)
(CH2) CHF
(СН2) ЗСНз СН (СНз) 2
CH (CHS) 2
 ,
(,
gdn - (CHa) z-I
SNS
 protected in the form of acetal, followed in the case of the removal of a carbonyl-containing protective group and the separation of the target product into nit. square 119 - 120 С
Oil, thin layer matography (TLC) Rf 0.51 С% С12. - MeON 90/10 (by volume)
T. pl. 67-69 s
m.p. 98 - T. pl. 70 - 71 ° С T. pd. 48-49 0
T. pl. 93 -
Butter
T. pl. 65 - 67 seconds
17
CH2)
.V / CH (CH3) 2
lCH7l N Oil
  ch (sn,) g
SNS
T. pl
CHj-C-CH-N
/
2
SNS t. PL
CH:
- (CH2) zK
-about
If
- {CH,) 3-N
- (
- (CHj) -N
Z t. Pl. 74 - 75 С
SNS
 m.p. 31 -
SNS SNZ
- (SNG) sp
- (CH,)) -CH,
 -fcT
N
- HE . square 158-159 ° С
- (
(CH2 2- / LT. Yl. 118 - 119 C
 .
160415718
Continued table. one
T. pl. 55-57 С
SNS t. PL. 57 - 58 seconds
CH:
m.p. 73 - 75 С
Butter
T. pl. 72 -
Bos
Z t. Pl. 74 - 75 С
SNS SNZ
Butter
square 45 - 48 ° C
T. pl. 152 - 153 С
T. pl. 98 - 100 С
T. pl. 146-147 seconds
- (SNG)
N
(SNOW
N
(sn,), 1G)
Table 2 Structure and characteristics. Derivatives of thiazole formula /
.
or their additive salts
44244 A
44234 A
44285 A
44286 A
44345 A
44346 A
sn.
844347 A
sn,
SNS
Continuation of table 1
T. pl. 142 -
T; square 81 - 82 С
T. pl. 118 -
/ hf and ftDichlorohydrate
) 2 v 220-221
(iPrOH-EtjO)
- (CH, -j-N ODH
 ZJJ j216-217
(iPrOH)
- (CH2)
Dihydrochloride 264 - 265 (lPrOH-EtOH95)
- (CH2) 4-N:
- (CH2) sp:
.SgNd
CiHs. СНз
SNSU
110-111
(iPrOH-iPrjO)
Dihydrochloride
181-182
()
CjHs 1СНг) з
General Staff
®2) W
Dihydrochloride
0.5 H20; I43-444
acetone
Dihydrochloride 199-200, cyclohexane EtjO
28 44490
- -
- (Dglorgiprat 2JZ / 250 (decomposed
out) (BtjO)
Continued table. 2
29
1604157
30 "Continued tab, 2
. Continuation of the table. 2
, lU C (Et, 0)
SNS
814A8S6 A
Continuation of table 2
sn.
Chong) aC
phoslorgndrat 225-22b with ()
Extension table. 2
39
1604157
106 45255 A
J07 45264 A
NCS CHS
sn.
108 45258 A
Note. iPrOH - isopropanol; Proton - propanol; EtOH 95 ° - ethanol 95 °;
 - anhydrous diethyl ether; - diisopropyl ether.
Tabli
The structure and characteristics of the formula
 xx
HjN-C-
R4
.-I and-СНз 174-175 with
N
-WITH
(CH2) hr
sn,
  , 40-44 0
V
-to
Continuation of table 2
Monochlorde (0.5HzO)
200-201 s (EtjO)
Dihydrochloride
221-223 С
(iPrOH-Et ,, 0)
- (CH, 3-NH-C1Oxalate
V 170 - UZ C
(acetone).
sn,
3
V
141-143 ° С
Structure and characteristics of the thiazole derivatives of the formula
,, J-
in the form of additive salts
117 45257 AH
Table 4
-N
/
Dichlorohydrate
224-22b with
(iPrOH-iPr O)
Structure and characteristics of condensed thiazoles of the formula
C W- (CH,)
and
in the form of their additive salts
119
44317 A
3 2
12044323 A
32-K
121 .44326 A
3 3
122
44327 A
3 3
12344392 A
3 3
124
44393 A
2 2 --N
Table 5
-N About
217 ° C dihydrochloride (iPrOH-EtOH 95)
Dihydrochloride
70 ° C
(iPr.OH-Et20)
Dichlorohydrate 0.5 192 ° C (iPrOH-iPrgO)
N
.
3-3
Dichlrrg Hydra t 1 198 ° C
()
(
f
O
Dihydrochloride
0.5 HgO
245 C (decomposition)
(ECO)
Sgnz
WITH
Dichlorohydrate 0.5 HjO (Etj O-PrOH)
45
The affinity of thiazole derivatives for receptors M (and Mg
16041.5746
Table
49
Table 7
Studying the effect of thiazols on pirenzepine-induced rotation
SR 44244 And SR 44284 And SR 44285 And SR 44286 And SR 44318 And SR 44323 And SR 44326 And SR 44327 And SR 44345 And SR 44346 And SR 44347 And SR 44372 And SR 44373 And SR 44374 And SR 44392 And SR 44393 And SR 44411 A SR 44421 A SR 44435 A
160415750
X "
Continuation of table 6
20
10 3
0.20
3 1
0.2

类似技术:

---

公开号 | 公开日 | 专利标题

---

SU1604157A3|1990-10-30|Method of producing derivatives of thiazole or their additive salts with organic or inorganic acids

---

US3994974A|1976-11-30|α-Aminomethylbenzyl alcohol derivatives

---

KR100341683B1|2002-11-30|Aza spiro compounds acting on the cholinergic system with muscarinic agonist activity

---

US5073560A|1991-12-17|Spiro-isoxazolidine derivatives as cholinergic agents

---

EP0470127A1|1992-02-12|Pcp receptor ligands and the use thereof

---

PL116437B1|1981-06-30|Process for preparing novel phthalazine derivatives

---

DE69530706T2|2004-03-25|HUPERZINE DERIVATIVES, THEIR PRODUCTION AND THEIR USE

---

RU2069662C1|1996-11-27|Derivatives of pyrazolo-[1,5-a]-pyridine or their pharmaceutical acceptable salts and method of their synthesis

---

EP0517852A1|1992-12-16|Tri- and tetra-substituted guanidines and their use as excitatory amino acid antagonists

---

EP0319429A2|1989-06-07|9-Acylamino-tetrahydroacridine derivatives and memory enhancing agent containing said derivative as active ingredient

---

EP0427636B1|1996-05-29|4-Acylaminopyridine derivatives

---

AU767923B2|2003-11-27|Novel 2-|thiazolidin-4-one derivatives

---

US5786364A|1998-07-28|Bicyclic isothiourea derivatives useful in therapy

---

US4970301A|1990-11-13|2-|-2-oxoethylene-substituted flavonoid compounds

---

SU1342415A3|1987-09-30|Method of producing derivatives of pyridazine

---

FI88162B|1992-12-31|FREQUENCY REQUIREMENT FOR THERAPEUTIC USE OF THERAPEUTIC SOLUTION SULFONYLDEKAHYDRO-8H-ISOKINO / 2,1-G // 1,6 / NAPHTHYRIDINE, DERAS OPTICAL ISOMERER SAMT PHARMACEUTICAL FORMAL SODIUM SALTER

---

AU2006220097A1|2006-09-08|Derivatives of aminobutanoic acid inhibiting CPT

---

US5405848A|1995-04-11|Substituted thiazolylaminotetrahydropyridopyrimidines derivatives useful as platelet aggregation inhibitors

---

CN101253146A|2008-08-27|Novel derivatives of amino acids for treatment of obesity and related disorders

---

JP4781362B2|2011-09-28|Quinuclidine compound having a quaternary ammonium group, its preparation method, and use as an acetylcholine blocker

---

US3888983A|1975-06-10|Derivatives of thiazolino-pyrimidin-6-ones, in inducing analgesia

---

DK153149B|1988-06-20|METHOD OF ANALOGUE FOR THE PREPARATION OF HYDROXYAMINOEBURNAND DERIVATIVES OR PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS OR OPTIC ACTIVALLY ISOMERATED ANGERA DERIVATED ANOSTERANE DERIVATED ANOSTERIVES

---

RU2075477C1|1997-03-20|1-[[2-|alkyl]amino]-4-substituted thioxanthene-9-ones and pharmaceutical composition showing antitumor activity

---

US6017910A|2000-01-25|PCP receptor ligands and the use thereof

---

CA2048959C|2003-07-29|3-|-4-pyridinamines and derivatives

同族专利:

---

公开号 | 公开日

---

DD274028A5|1989-12-06|

---

MA21207A1|1988-10-01|

---

HU198916B|1989-12-28|

---

JPS63243080A|1988-10-07|

---

DK170162B1|1995-06-06|

---

PT86952A|1988-04-01|

---

EP0283390A2|1988-09-21|

---

OA08871A|1989-10-31|

---

FR2612187B1|1989-07-21|

---

FI881152A0|1988-03-11|

---

AU1266288A|1988-09-15|

---

AU612350B2|1991-07-11|

---

HUT47261A|1989-02-28|

---

KR880011135A|1988-10-26|

---

MY103233A|1993-05-29|

---

ZA881764B|1988-08-31|

---

DE3878708D1|1993-04-08|

---

FR2612187A1|1988-09-16|

---

NO881093L|1988-09-13|

---

DE3878708T2|1993-09-02|

---

YU49688A|1989-10-31|

---

IE60173B1|1994-06-15|

---

NO881093D0|1988-03-11|

---

DK128688D0|1988-03-09|

---

IE880721L|1988-09-12|

---

IL85704A|1992-11-15|

---

TNSN88020A1|1990-07-10|

---

PT86952B|1992-05-29|

---

IL85704D0|1988-08-31|

---

PL271132A1|1988-11-24|

---

NZ223845A|1990-11-27|

---

PH25389A|1991-06-03|

---

NO170081C|1992-09-09|

---

AT86249T|1993-03-15|

---

ES2053778T3|1994-08-01|

---

FI881152A|1988-09-13|

---

AR243515A1|1993-08-31|

---

EP0283390A3|1988-09-28|

---

EP0283390B1|1993-03-03|

---

DK128688A|1988-09-13|

---

PL151889B1|1990-10-31|

---

NO170081B|1992-06-01|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US2975182A|1959-11-16|1961-03-14|Paul A J Janssen|1--4- piperazines|

---

FR2092714B1|1970-06-11|1974-03-22|Melle Bezons|

---

CH583232A5|1973-02-02|1976-12-31|Wander Ag Dr A|

---

DE3135250A1|1981-09-05|1983-03-17|Basf Ag, 6700 Ludwigshafen|TRICYCLIC THIAZOLYLOXAMATES, METHOD FOR THE PRODUCTION THEREOF AND THERAPEUTIC AGENTS CONTAINING THEM|

---

US4552886A|1982-06-07|1985-11-12|Eli Lilly And Company|Fungicidal pyridylmethyl-amines|

---

FR2581063B1|1985-04-30|1987-07-17|Chauvin Blache Lab|AMINO-2 THIAZOLES N-SUBSTITUTED, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN THERAPEUTICS|

---

HUT43600A|1985-06-22|1987-11-30|Sandoz Ag|Process for production of new thiazole derivatives and medical compound containing those|JPS6440474A|1987-08-04|1989-02-10|Hisamitsu Pharmaceutical Co|Novel 2-substituted aminothiazole derivative|

---

JPH0753666B2|1987-09-14|1995-06-07|久光製薬株式会社|Anti-inflammatory agent consisting of substituted diphenylthiazole derivative|

---

FR2656610B1|1989-12-29|1992-05-07|Sanofi Sa|DERIVATIVES OF 2-AMINO PHENYL-4 THIAZOLE, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION.|

---

WO1991018882A1|1990-05-29|1991-12-12|Nippon Soda Co., Ltd.|N-substituted heterocyclic amidine derivative|

---

WO1992021666A1|1991-05-31|1992-12-10|Laboratoires Upsa|Angiotensin ii receptor antagonist thiazole devivatives|

---

FR2677021B1|1991-05-31|1993-10-01|Upsa Laboratoires|NOVEL THIAZOLE DERIVATIVES ANTAGONISTS OF ANGIOTENSIN II RECEPTORS; THEIR PREPARATION METHODS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.|

---

AU4982293A|1993-03-02|1994-09-26|Fujisawa Pharmaceutical Co., Ltd.|Novel heterocyclic compound|

---

FR2692893B1|1992-06-24|1994-09-02|Sanofi Elf|Branched alkylamino thiazole derivatives, processes for their preparation and pharmaceutical compositions containing them.|

---

FR2714059B1|1993-12-21|1996-03-08|Sanofi Elf|Branched amino derivatives of thiazole, processes for their preparation and pharmaceutical compositions containing them.|

---

FR2735777B1|1995-06-21|1997-09-12|Sanofi Sa|4-PHENYLAMINOTHIAZOLE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

---

FR2754258B1|1996-10-08|1998-12-31|Sanofi Sa|AMINOTHIAZOLE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

---

GB9705428D0|1997-03-15|1997-04-30|Knoll Ag|Therapeutic agents|

---

AU768751B2|1998-06-18|2004-01-08|Bristol-Myers Squibb Company|Carbon substituted aminothiazole inhibitors of cyclin dependent kinases|

---

US6989379B1|1999-04-22|2006-01-24|H. Lundbick A/S|Selective NPYantagonists|

---

US6340683B1|1999-04-22|2002-01-22|Synaptic Pharmaceutical Corporation|Selective NPYantagonists |

---

EP1183245B1|1999-04-22|2007-05-09|H. Lundbeck A/S|Selective npyantagonists|

---

US6218408B1|1999-06-30|2001-04-17|Synaptic Pharmaceutical Corporation|Selective NPYantagonists |

---

US6214853B1|1999-06-30|2001-04-10|Synaptic Pharmaceutical Corporation|Selective NPYantagonists |

---

US6225330B1|1999-06-30|2001-05-01|Synaptic Pharmaceutical Corporation|Selective NPYantagonists |

---

US7273880B2|1999-06-30|2007-09-25|H. Lunbeck A/S|Selective NPYantagonists|

---

US6222040B1|1999-06-30|2001-04-24|Synaptic Pharmaceutical Corporation|Selective NPYantagonists |

---

US6699866B2|2001-04-17|2004-03-02|Sepracor Inc.|Thiazole and other heterocyclic ligands for mammalian dopamine, muscarinic and serotonin receptors and transporters, and methods of use thereof|

---

WO2003061655A1|2002-01-16|2003-07-31|University Of Virginia Patent Foundation|2-aminothiazole allosteric enhancers of a1 adenosine receptors|

---

DE10251513A1|2002-11-04|2004-05-19|Basf Ag|Compounds with 5-membered heterocycle linked by amino- or phosphino-methyl to a benzene ring with an ortho-hydroxy, alkoxy, thiol or amino group, used as multidentate ligands in olefin polymerization catalysts|

---

US7880008B2|2005-05-31|2011-02-01|Vertex Pharmaceuticals Incorporated|Heterocycles useful as modulators of ion channels|

---

KR20110137941A|2010-06-18|2011-12-26| 에빅스젠|Novel thiourea or urea derivative, process for preparing the same and pharmaceutical composition for preventing or treating aids comprising the same|

---

RU2456284C1|2011-04-12|2012-07-20|Федеральное государственное автономное образовательное учреждение высшего профессионального образования "Уральский федеральный университет имени первого Президента России Б.Н. Ельцина"|2-aminopropylmorpholino-5-aryl-6h-1,3,4-thiadiazines, dihydrobromides and 2-aminopropylmorpholino-4-arylthiazoles, hydrobromides showing antiaggregant action|

---

WO2016077232A2|2014-11-10|2016-05-19|Forge Life Science, Llc|Anti-hcmv compositions and methods|

法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

FR8703398A|FR2612187B1|1987-03-12|1987-03-12|THIAZOLE DERIVATIVES ACTIVE IN THE CHOLINERGIC SYSTEM, THEIR PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME|

---