JPS6342624B2 - - Google Patents

Description

[Detailed description of the invention] Burimamide (a) is initially
clinically effective H₂-It is a receptor antagonist.
It suppresses gastric secretions in animals and humans, but oral
Absorption is not good. a;R²=H, Z=CH₂,X=S Briamide b;R²＝CH₃, Z=S, X=S methamide c;R²＝CH₃, Z=S, X=NCN cimetidine Metiamide (b) is then evaluated.
valued H₂-Antagonist, stronger than Briamide
active and orally active in humans. However, clinical
Utilization is limited due to toxicity (agranulocytosis)
ing. Cimetidine (c) is a medicinal
H as effective as thiamide₂- is an antagonist;
It does not cause agranulocytosis and is used as an anti-ulcer drug.
was recently released on the market. The half-life of cimetidine is relatively
Short and multiple doses of 200-300 mg tablets per day
Requires dosage treatment regimen. Thus Shimechiji
anti-ulcer that is more durable and/or more potent than
There is a need for agents. The present invention aims to improve the effectiveness of gastric acid secretion in animals (including humans).
Histamine H, an inhibitor₂- Concerning antagonists
and it is useful for peptic ulcer disease.
ri, ceremony [In the formula, p is 1 or 2; R¹is hydroxy or NR²R³is; R²and R³are each independently hydrogen and (lower) alkali.
Kyl, (lower) alkenyl, (lower) alkynyl,
cyclo(lower)alkyl, cyclo(lower)alkyl
(lower) alkyl, hydroxy (lower) alkyl
(lower) alkoxy, (lower) alkyl, (lower)
(grade) alkylthio (lower) alkyl, amino (lower)
class) alkyl, (lower) alkylamino (lower)
Alkyl, di(lower)alkyl(lower)alkyl
, pyrrolidino (lower) alkyl, piperidino
(lower) alkyl, morpholino (lower) alkyl,
piperazino (lower) alkyl, pyridyl (lower)
Alkyl, amino, (lower) alkylamino, di
(lower) alkylamino, 2,2,2-trifluor
loethyl, 2-fluoroethyl, hydroxy, (low
class) alkoxy, 2,3-dihydroxypropyl
cyano, cyano (lower) alkyl, amidi
ノ, (lower) alkylamidino, A′-(CH₂)_n′
Z′(CH₂)_o′-, phenyl, phenyl (lower) al
phenyl, substituted phenyl or substituted phenyl (lower) a
alkyl (phenyl ring is a (lower) alkyl, hydrogen
Selected from oxy, (lower) alkoxy and halogen.
1 or 2 selected substituents or methylene dioxy
trifluoromethyl and di(lower)alkyla
may have one substitution selected from mino)
is; however, R²and R³are both cyclo (low grade)
Alkyl, phenyl, substituted phenyl, amino,
(lower) alkylamino, di(lower) alkylua
Mino, hydroxy, (lower) alkoxy, cyano,
Amidino, (lower)alkylamidino or A′-
(CH₂)_n′Z′(CH₂)_o'- must not be; or
is R²and R³Together, -CH₂CH₂X(CH₂)_r
- may be; r is an integer from 1 to 3; X is methylene, sulfur, oxygen or N-R^FourAnd
However, when r is 1, X is methylene
be; R^Fouris hydrogen, (lower) alkyl, (lower) alkyl
Kenyl, (lower)alkynyl, (lower)alkanoy
benzoyl or benzoyl; m and m' are each independently an integer of 0 to 2.
be; n and n' are each independently an integer of 2 to 4.
Ru; Z and Z′ are each independently sulfur, oxygen or methane.
It's Ren; A and A′ each independently represent phenyl, imida
Zolyl, thiazolyl, isothiazolyl, oxazo
Lyle, isoxazolyl, triazolyl, thiazia
Zolyl, oxadiazolyl, furyl, thienyl or
is pyridyl; however, A and A' are independently
may have one or two substitutions, and the first
The conversion is (lower) alkyl, hydroxy, trif
lolomethyl, halogen, amino, hydroxymethy
(lower) alkoxy,
[Formula] and - (CH₂)_qNR^FiveR⁶ and the second substituent is a (lower) alkyl
, hydroxy, trifluoromethyl, halogen,
Amino, hydroxymethyl and (lower) alkoxy
selected from; q is an integer from 0 to 6; R^Fouris independently
as defined above or two R^Four
The groups may together be ethylene; R^Fiveand R⁶are each independently hydrogen and (lower) alkali.
Kyl, (lower) alkenyl, (lower) alkynyl,
cyclo(lower)alkyl or phenyl,
Dashi R^Fiveand R⁶are both cyclo(lower) alkyl
or phenyl; or R^FiveReach
BiR⁶are the nitrogen atoms to which they are attached together.
Along with pyrrolidino, morpholino, piperidino,
Methylpiperidino, N-methylpiperazino or
mopiperidino]; or a non-toxic pharmaceutically usable salt thereof;
It is a hydrate, solvate or N-oxide. The invention also relates to a process for preparing compounds of formula
It is. This invention includes within its scope all compounds of formula
Possible tautomeric forms, geometric isomers, and optical isomers
and zwitterionic systems, as well as mixtures thereof.
include. As used herein and in the claims.
the terms “(lower) alkyl”, “(lower) alkyl”
"(lower)alkynyl", "(lower)alkynyl", "(lower)alkenyl", "(lower)alkynyl", "(lower)alkynyl"
"(lower)alkylthio" and "(lower) alkylthio"
In its broadest sense, 1 to 12 carbon atoms
Straight-chain and branched alkyl, alkeni
alkynyl, alkoxy and alkylthio groups
means. Preferably, these groups include 1 to 8
carbon atoms, and most preferably 1 to 6 carbon atoms
have a child The term “non-toxic, medicinally usable”
"salts" are not only acid addition salts, but also alkali metal salts.
and alkaline earth metal salts. compound of formula
potassium, sodium and calcium salts
It has been found that metal salts such as
These salts contain a hydroxy group (R¹is hydroxy
) or adjacent to the thiadiazole ring
Formed by replacement of a proton from one nitrogen atom
It is believed that this is possible, but this is only a theory.
However, the present invention is not limited thereto in any way.
stomach. In the compound of formula, A and A' are independently
preferably optionally substituted phenyl,
imidazolyl, thiazolyl, oxazolyl, thia
Diazolyl, Oxadiazolyl, Frill, Thieni
or pyridyl ring; most preferably A and
A′ is independently an optionally substituted fe
Nyl, imidazolyl, thiazolyl, furil, thi
Nyl or pyridyl ring. Particularly suitable A and
The A′ group is guanidino-substituted thiadiazolyl, di
(lower) alkylamino (lower) alkyl-substituted
(and especially dimethylaminomethyl-substituted)
(lower) alkyl-substituted (and especially methyl
-Substituted) imidazolyl, di(lower)alkylamide
(lower)alkyl-substituted (and especially dimethyl
(aminomethyl substituted) thiazolyl, di(lower)al
Kylamino(lower)alkyl-substituted (and especially
dimethylaminomethyl-substituted) phenyl and dimethyl
(lower) alkylamino (lower) alkyl-substituted
(and especially dimethylaminomethyl-substituted) thie
This is the nil part. m is 0 or 1 and n is 2 to 3
It is preferable that Preferably, X is sulfur, oxygen
or methylene (most preferably sulfur or oxygen)
Ru. R¹is preferably NR²R³(R²and R³is preferably
are each independently hydrogen, (lower) alkyl, (lower)
Alkenyl, (lower) alkynyl or A′-
(CH₂)_n′Z′(CH₂)_o’-).
In a particularly preferred embodiment, R²and R³teeth,
Both are hydrogen or methyl. Other particularly preferred implementations
In the aspect R²is hydrogen and R³is hydrogen,
(lower) alkyl (especially methyl, ethyl or pro-
pills), (lower) alkenyls, (especially 2-propenyl)
), (lower) alkynyl (especially 2-propynyl)
or A′-(CH₂)_n′Z′(CH₂)_o′—[m′ is preferably
0 or 1, and n′ is preferably 2 or 3;
Z′ is preferably sulfur or oxygen; A′ is preferably
is a substituted thiazolyl, phenyl or furyl ring (especially
guanidino-substituted thiazolyl or dimethylamine
methyl-substituted phenyl or furyl)
be. Compounds of formula can be prepared by various manipulations, preferably
formula (R in the formula⁷is a halogen, phenoxy, substituted phenol.
enoxy, phenylthio, substituted phenylthio, a
with good release properties such as rukoxy, alkylthio, etc.
to produce starting from a compound (which is a group)
Can be done. A suitable releasable group can be determined by a person skilled in the art.
It is well known. Preferably, R⁷is (lower) arco
xy (especially methoxy). Production of starting materials p is 2 and each R⁷is chloro, methoxy
or ethoxy starting materials of the formula are known
and their manufacturingJ．．Org．．Chem．． ，40,2743
(1975). p is 2 and
Each R⁷is alkoxy, alkylthio, phenoxy,
phenylthio, substituted phenoxy or substituted phenyl
Starting material of formula which is thio (compound of formula and)
The quality is as follows, appropriate dichloro compound of the formula
alkanol, alkylthio, phenol,
Ofenol, substituted phenol or substituted thiophene
Compounds of the corresponding formula or by reacting with nor
(R in the formula⁸is alkyl, phenyl or substituted phenyl
) can be manufactured: This reaction is performed using ether, dimethylformamide
It is carried out in an inert organic solvent such as. reaction
Agent R⁸OH or R⁸SH is a liquid, e.g. methanol,
Ethanol, ethyl mercaptan or thiopheno
When the solvent is
It can be carried out in a solvent of formula where p is 1
The corresponding starting materials (compounds of formula and )
is each R⁷is chloro (compound
) can be produced in the same manner. Although the compound is a new compound, it is a 1,1-o
oxide 3,4-dihydroxy-1,2,5-thia
Used to prepare compounds of formula from diazole.
The same operation used [J．．Org．．Ohem．． ，
40, 2743 (1975)].
1-oxide 3,4-dihydroxy-1,2,5
-Thiadiazole [as such]Org．．Prep．．
Proced. ，1, 255 (1969)]
It can be manufactured from. Formula and starting materials
quality is a novel compound not previously described in the literature.
Ru. Alternatively, the starting materials of formula and
in an inert solvent such as formamide.
Substituted oxal diimidate ester of SCl₂or
is S₂Cl₂3,4 of the corresponding formula X by reaction with
-Produces disubstituted 1,2,5-thiadiazole
and then oxidize it to form the 1-oxygen of the corresponding formula.
1,1-dioxide of the formula
It can be manufactured by R⁸are methyl, ethyl,n-propyl, isop
Lopyl, n-butyl andn-Formula that is pentyl
The oxal diimidate is known and it
The production ofChem．．Ber．．107, 3121 (1974)
Are listed. R⁸but optionally (lower) al
Kill, (lower) alkoxy, halogen or nitro
The corresponding phenyl is substituted by
The compound can be produced by similar operations.
Wear. R⁸is methyl or ethyl
The thing isJ．．Org．．Ohem．． ，40, 2749 (1975).
It is listed. The literature states that the 1,2,5-thiadiazole nucleus is oxidized.
be sensitive to thiadiazole due to peracid
Oxidation is usually accompanied by ring decomposition and the formation of sulfate ions.
1,1 by peracetic acid oxidation of the parent ring.
- Manufacture of 1,2,5-thiadiazole dioxide
It has been reported that attempts to do so result in ring cleavage.
Ru. Surprisingly, the inventors found that chloroform
in an inert solvent such asm- of chloroperbenzoic acid
3,4-disubstitution of the corresponding formula by a peracid such as
oxidation of -1,2,5-thiadiazole
The yield of 1-oxide 3,4-disubstituted-1,
2,5-thiadiazole and 1,1-dio of the formula
discovered that oxides can be easily produced.
did. 1-oxide 3,4-dimethoxy-1,
Preparation of 2,5-thiadiazole is carried out in Example 4, Step A.
shown in; Preparation of the corresponding 1,1-dioxide
is shown below. Example operation No. 1 1,1-dioxide 3,4-dimethoxy-1,
2,5-thiadiazole in 60ml of chloroformm-Chloroperbenzoic acid
(4.11 g; 20.3 mmol; quantitative value 85%) in a solution of
3,4-dimethoxy in 20 ml of chloroform under stirring.
-1,2,5-thiadiazole (1.48 g; 10.1 mi
Rimor) [J．．Org．．Chem．． ，40, 2749 (1975)
[produced according to the procedure described] for 1 minute.
It was added over time. Stir for 1 hour at external temperature
Afterwards, the mixture was heated to reflux for 8 hours and then evaporated to ectotherm.
The mixture was stirred for 1 hour. Add reaction mixture to aqueous sodium bicarbonate
extracted with sodium hydroxide and water, and the organic layer was extracted with sodium sulfate.
Dry, filter and evaporate under reduced pressure. Remove residue
Treated with tanol and filtered to obtain 1.03g of product.
Ta. Recrystallization from methanol yields the title compound,
Obtained mp200~202°. Analysis C_FourH₆N₂O_FourCalculated value as S: C, 26.97 ;H, 3.39;N, 15.72 ;S, 18.00. Experimental value: C, 26.82; H, 3.18; H, 16.09 ;S, 18.00. The inventors have determined that the compound of formula
By reaction of the latter with thionyl chloride, one step
found that it is possible to directly produce the reaction of
Ta. This reaction is performed using methylene chloride, chloroform, etc.
The method is carried out in an inert organic solvent such as this reaction
is effective as an acid scavenger without addition of base.
However, the inventor has determined that the
Add approximately 2 equivalents of base to remove HCl
It is preferable to do so. This results in higher yields.
amount of compound is obtained. A suitable base is sodium carbonate.
Thorium, potassium carbonate, sodium bicarbonate and
Inorganic bases such as potassium bicarbonate, as well as
Including organic bases like thylamine, pyridine, etc.
do. This method does not just omit one step.
Ku,m- Expensive oxidizing agents such as chloroperbenzoic acid
much more economical in that the use of
be. This reaction takes place at a temperature of about -20° to about 25°.
Therefore, it is preferably carried out at about 0° to about 10°.
Can be done. Example operation No. 2 is based on this method,
R⁸illustrates the preparation of a compound of formula where is methyl. Example operation No. 2 1-oxide 3,4-dimethoxy-1,2,5
-thiadiazole CH₂Cl₂Thionyl chloride in 18 ml (2.61 ml, 4.25 g;
70.6 mmol) in a cold solution of CH₂Cl₂Dimethyl in 8ml
Oxaldiimidate (4.0g; 34.5mmol)
and pyridine (5.71 ml, 5.58 g; 70.6 mmol)
A solution of is heated in a nitrogen stream at a reaction temperature of 0 to 15°.
It was added dropwise at such a rate that it remained at . 20 at ectotherm
After stirring for min, the reaction mixture was diluted with 11 ml of aqueous 0.055N HCl.
Washed twice with each. CH the aqueous phase₂Cl₂20ml each
Extracted twice, combined organic phases, dried and evaporated under reduced pressure.
It was dried and solidified. Isopropyl alcohol to remove solid residue
Recrystallized the title compound, mp137-139゜3.0g.
I got it. Compounds of formula form several classes of novel intermediates.
From the compound of formula by various alternative reaction schemes
can be manufactured. In reaction scheme 1, R⁹――NR²R³Kamata
H-NH(CH₂)_o′Z′(CH₂)_nIt may be 'A'.
A', Z', m' and n' are the same as A, Z, m and n.
This reaction, of course, converts the compound of formula 2
Equivalent amount of A(CH₂)_nZ(CH₂)_oN.H.₂to react with
It can be carried out in one step. Formula XI
All intermediates are new. The intermediate of formula XII is
p is 2 and R⁷is methoxy and R⁹but
This compound is novel except for compounds that are morpholinos.
The compound isJ．．Org．．Chem．． ，40, 2743 (1975)
Are listed. This reaction is carried out in an inert organic solvent.
carried out; the inventors have determined whether methanol is convenient
We have discovered that there are two readily available solvents.
Ru. Reaction temperature is not critical. departure of most
The substance is quite reactive and we
Carry out the reaction at a lower temperature, e.g. 0-10°.
It is preferable to apply Sometimes then the reaction mixture
Start the reaction by increasing the temperature (e.g. to 50-60 °C) of
It is desirable to complete it. In reaction scheme 2, M is a metal cation.
, which is preferably K⁺, Li⁺Or Na⁺It is. anti
The reaction conditions and solvent were as described for reaction scheme 1.
That's right. All intermediates of formula XI are new compounds
It is. In reaction scheme 3, R^Ten――NR²R³is
Kamata-NH(CH₂)_o′Z′(CH₂)_n′A′ and X
is a commonly used leaving group. A suitable leaving group
For example, fluoro, chloro, bromo, iodo,
-O₃S.R.¹¹[R¹¹is a (lower) alkyl (e.g. meth)
sulfonate) aryl or substituted aryl (e.g.
For example, benzene sulfonate, p-bromobenzene
sulfonate or p-toluenesulfonate)
], O³SF, acetoxy and 2,4-dinitro
Includes phenoxy. For convenience and economy
In this case, the present inventors utilized a compound in which X is chloro.
It is preferable to use formula, and
The reaction conditions for the production of the compound are shown in reaction scheme 1.
As described above. compound with formula
A(CH₂)_nThe reaction with X is alkanol, acetic acid.
tonitrile, dimethylformamide, dimethyls
Any inert agent like sulfoxide, acetone etc.
It can be carried out in an organic solvent. The inventors
is methanol, ethanol or isopropanol
It is recommended to carry out the reaction in an alkanol such as
Suitable. The reaction temperature is not critical;
The reaction should be carried out at a temperature of approximately 0° to approximately 200°.
Can be done. The reaction is slow at low temperatures, while the reaction is slow at low temperatures.
Temperatures are usually relatively low due to decomposition and by-product formation.
Produces less pure product. We typically
Preference is given to carrying out the reaction at room temperature.
A(CH₂)
_nThe reaction with X is preferably carried out in the presence of a base.
, it acts as an acid acceptor.
This facilitates the reaction. A suitable base is
For example, NaOH, KOH, LiOH, triethylamine,
Contains dimethylaniline, sodium ethoxylate, etc.
Contains. When X is hydroxyl, the reaction
can be carried out in concentrated mineral acids, e.g. HCl
(See Example 25). The intermediates of the formula, and
All of them are new compounds. In a preferred embodiment of the present invention, the expression
The compound has a structure [In the formula, p is 1 or 2; R²and R³are each independently hydrogen and (lower) alkali.
Kyl, (lower) alkenyl, (lower) alkynyl,
Cyclo(lower)alkyl(lower)alkyl, Pyri
Zyl (lower) alkyl, A′-(CH₂)_n′Z′(CH₂)
_o'-, phenyl (lower) alkyl or 3,4-methane
is tylene dioxybenzyl; where R²as well as
R³are both A′-(CH₂)_n′Z′(CH₂)_o′-and
Must not be; m and m' are each independently 0 or 1; n and n' are each independently 2 or 3; Z and Z′ are each independently sulfur, oxygen or methane.
It's Ren; A and A′ each independently represent phenyl, imida
Zolyl, thiazolyl, furyl, thienyl or pyryl
where A and A' are independently one or
may have two substitutions, the first substitution
is (lower) alkyl, [formula] and - CH₂NR^FiveR⁶ and the second substituent is a (lower) alkyl
selected from; Each R^Fouris independently hydrogen or (lower) alkyl
or two R^FourThe base is
May be tyrene; R^Fiveand R⁶are each independently hydrogen or (lower)
is alkyl; or R^Fiveand R⁶together with
Along with the nitrogen atoms to which they are attached, pyrrolidine
No, morpholino, piperidino, methylpiperidino
, N-methylpiperazino or homopiperidino
Warm enough] Does it have; or its salts and water that can be used as non-toxic medicines.
They are hydrates, solvates, or N-oxides. In another preferred embodiment of the invention, the formula
The compound has the structure [In the formula, p is 1 or 2; Z is sulfur or
is methylene;R²and R³are each independently
or (lower) alkyl, or R²
When is hydrogen, R³Also, (lower) alkeni
(lower) alkynyl, (lower) phenyl
Kyl, cyclo(lower) alkyl(lower) alkyl
pyridylmethyl or may be ;R¹³is hydrogen or methyl
or used as a non-toxic medicine.
Possible salts, hydrates, solvates or N-oxides thereof
It is. In another preferred embodiment of the invention, the formula
The compound has the structure [In the formula, p is 1 or 2; Z is sulfur or
is methylene; each R^Fouris independently hydrogen or metal.
Chill or 2 R^FourTogether, the base is
May be ethylene; R²and R³are each independent
is hydrogen or (lower) alkyl, or
is R²When is hydrogen, R³Also, (lower) a
Lukenyl, (lower) alkynyl, pyridylmethyl,
[Formula] or ] or can be used as a non-toxic medicine
salts, hydrates, solvates or N-oxides of
Ru. In another preferred embodiment of the invention, the formula
The compound has the structure [In the formula, p is 1 or 2; Z is sulfur or
is methylene;R²and R³are each independently
elementary or (lower) alkyl, or R²but
When it is hydrogen, R³Also, (lower) alkeni
(lower) alkynyl or It may be ;R¹³is hydrogen or methyl
] or used as a medicine as non-toxic
Possible salts, hydrates, solvates or N-oxides thereof
It is. In another preferred embodiment of the invention, the formula
The compound has the structure [In the formula, p is 1 or 2; Z is sulfur or
is methylene;R²and R³are each independently
or (lower) alkyl, or R²
When is hydrogen, R³Also, (lower) alkeni
(lower) alkynyl, (lower) phenyl
Kir, pyridylmethyl, 3,4-methylene dioxy
Shibenzil or It may be ;R¹³is hydrogen or methyl
] or can be used as a non-toxic medicine
salts, hydrates, solvates or N-oxides of
Ru. In another preferred embodiment of the invention, the formula
The compound has the structure [In the formula, p is 1 or 2; R²and R³teeth
each independently hydrogen or (lower) alkyl
or R²When is hydrogen, R³Also,
(lower) alkenyl, (lower) alkynyl or ] or can be used as a non-toxic medicine
salts, hydrates, solvates or N-oxides of
Ru. In another preferred embodiment of the invention, the odor is of the formula
Compound structure [In the formula, p is 1 or 2; Z is sulfur or
is methylene;R²and R³are each independently
or (lower) alkyl, or R²
When is hydrogen, R³Also, (lower) alkeni
(lower) alkynyl or may be ;R^Fiveand R⁶are each independently
is elementary or (lower) alkyl] or can be used as a non-toxic medicine
salts, hydrates, solvates or N-oxides of
Ru. In another preferred embodiment of the invention, the formula
The compound has the structure [In the formula, p is 1 or 2; R²and R³teeth
each independently hydrogen or (lower) alkyl
or R²When is hydrogen, R³Also,
(lower) alkenyl, (lower) alkynyl or is ;R^Fiveand R⁶are each independently hydrogen or
(lower) alkyl, or R^Fiveis hydrogen
Sometimes R⁶Also, (lower) alkenyl or
(lower)alkynyl; or R^FiveReach
BiR⁶together with the nitrogen they are attached to.
pyridino, morpholino, piperidino or homo
It may be piperidino.] or can be used as a non-toxic medicine
salts, hydrates, solvates or N-oxides of
Ru. As currently contemplated, the invention particularly
Suitable compounds are as follows. Furthermore, these
In compounds, "oxidation" refers to "oxide".
means. a 1,1-dioxide 3-{2-[(5-dimethyl
Aminomethyl-2-furyl)methylthio]ethyl
Ruamino}-4-methylamino-1,2,5-
Thiadiazole, b 1-oxidation 3-{2-[(5-dimethylamino
Methyl-2-furyl)methylthio]ethylamide
No}-4-methylamino-1,2,5-thiazi
Azor, c 1-1-dioxide 3-{2-[(5-dimethyl
Aminomethyl-2-furyl)methylthio]ethyl
Ruamino}-4-ethylamino-1,2,5-
Thiadiazole, d 1,1-dioxide 3-{2-[(5-dimethyl
Aminomethyl-2-furyl)methylthio]ethyl
Ruamino}-4-(n-propyl)amino-
1,2,5-thiadiazole, e 1,1-dioxidized 3-allylamino-4-{2
- [(5-dimethylaminomethyl-2-furyl)
Methylthio]ethylamino}-1,2,5-thi
Asiazole, f 1,1-dioxidized 3-{2-[(5-dimethyl
Aminomethyl-2-furyl)methylthio]ethyl
Ruamino}-4-(2-propynyl)amino-
1,2,5-thiadiazole, g 1,1-dioxide 3-{2-[(5-dimethyl
Aminomethyl-2-furyl)methylthio]ethyl
Ruamino}-4-amino-1,2,5-thiazi
Azor, h 1-oxidation 3-{2-[(5-dimethylamino
Methyl-2-furyl)methylthio]ethylamide
No}-4-amino-1,2,5-thiadiazole
le, i 1,1-dioxide 3-{2-[(5-dimethyl
Aminomethyl-2-furyl)-2-furyl)
Chilthio]ethylamino}-4-dimethylamino
no-1,2,5-thiadiazole, j 1,1-dioxide 3-{4-(5-dimethyla
mino-2-furyl)butylamino}-4-methy
Ruamino-1,2,5-thiadiazole, k 1,1-dioxide 3,4-bis-{2-[(5
-dimethylaminomethyl-2-furyl)methyl
Thio]ethylamino}-1,2,5-thiadia
Zor, l 1,1-dioxide 3-{2-[(2-guanidi
Nothiazol-4-yl)methylthio]ethyl
amino}-4-methylamino-1,2,5-thi
Asiazole, m 1,1-dioxide 3-{2-[(2-guanidi
Nothiazol-4-yl)methylthio]ethyl
amino}-4-(2-propynyl)amino-
1,2,5-thiadiazole, n 1,1-dioxide 3-{2-[(2-guanidi
Nothiazol-4-yl)methylthio]ethyl
amino}-4-{2-[(5-methyl-1-H
-imidazol-4-yl)methylthio]ethyl
Ruamino-1,2,5-thiadiazole, o 1,1-dioxide 3-{2-[(2-guanidi
Nothiazol-4-yl)methylthio]ethyl
amino}-4-amino-1,2,5-thiasia
Zor, p 1,1-dioxidized 3-{2-[(2-dimethyl
Aminomethyl-4-thiazolyl)methylthio]
ethylamino}-4-methylamino-1,2,
5-thiadiazole, q 1,1-dioxide 3-{2-[(5-dimethyl
Aminomethyl-2-thienyl)methylthio]et
thylamino}-4-methylamino-1,2,5
-thiadiazole, r 1-oxidation 3-{2-[(5-dimethylamino
Methyl-2-furyl)methylthio]ethylamide
No}-4-ethylamino-1,2,5-thiazi
Azor, s 1,1-dioxide 3-{2-[(5-methyla
Minomethyl-2-furyl)methylthio]ethyl
amino}-4-methylamino-1,2,5-thi
Asiazole, t 1-oxidation 3-amino-4-{2-[(2-g
Anidinothiazol-4-yl)methylthio]
ethylamino}-1,2,5-thiadiazole
le, u 1,1-dioxidized 3-benzylamino-4-
{[(5-dimethylaminomethyl-2-furyl)
Methylthio]ethylamino}-1,2,5-thi
Asiazole, v 1,1-dioxidized 3-{2-[(3-dimethyl
aminomethyl}phenyl)methylthio]ethyl
amino}-4-methylamino-1,2,5-thi
Asiazole, w 1-oxidation 3-amino-4-{2-[(3-
{dimethylaminomethyl)phenyl)methylthi
[o]ethylamino}-1,2,5-thiadiazole
rule, x 1-oxidation 3-{2-[(5-dimethylamino
Methyl-2-thienyl)methylthio]ethylua
Mino}-4-methylamino-1,2,5-thia
diazole, y 1,1-dioxidized 3-amino-4-{4-(5
-dimethylaminomethyl-2-furyl)butyl
amino}-1,2,5-thiadiazole, z 1,1-dioxidized 3-amino-4-{2-
[(2-dimethylaminomethyl-4-thiazoli
) methylthio]ethylamino}-1,2,5
-thiadiazole, aa 1,1-dioxidized 3-butylamino-4-
{2-[(5-dimethylaminomethyl-2-furi
) methylthio]ethylamino}-1,2,5
-thiadiazole, bb 1,1-3-cyclopropylmethyl dioxide
-4-{2-[(5-dimethylaminomethyl-
2-furyl)methylthio]ethylamino}-
1,2,5-thiadiazole, cc 1,1-dioxide 3-{2-[(5-dimethyl
Aminomethyl-2-furyl)methylthio]ethyl
Ruamino}-4-[(2-pyridyl)methyla
Mino]-1,2,5-thiadiazole, dd 1,1-dioxidized 3-amino-4-{2-
[5-dimethylaminomethyl-2-thienyl]
Methylthio]ethylamino}-1,2,5-thi
Asiazole, ee 1,1-dioxide 4-{2-[(5-dimethyl
Aminomethyl-2-thienyl)methylthio]et
thylamino}-3-(1-propylamino)-
1,2,5-thiadiazole, ff 1-oxidation 3-{2-[(2-guanidinothia
sol-4-yl)methylthio]ethylamide
No}-4-methylamino-1,2,5-thiazi
Azor, gg 1-oxidation 3-amino-4-{2-[(5-di
methylaminomethyl-2-thienyl) methylthi
[o]ethylamino}-1,2,5-thiadiazole
rule, hh 1,1-dioxide 3-[3-(3-dimethyl
Aminomethylphenoxy)propylamino]-
4-Methylamino-1,2,5-thiadiazole
le, ii 1,1-dioxidized 3-benzylamino-4-
{2-[(5-dimethylaminomethyl-2-thie
methylthio]ethylamino}-1,2,
5-thiadiazole, jj 1,1-dioxide 4-{2-[(5-dimethyl
Aminomethyl-2-thienyl)methylthio]et
thylamino}-3-(3-pyridyl)methyla
mino-1,2,5-thiadiazole, kk 1,1-dioxidation 3-{2-[(2-{2,3
-dimethylguanidino}thiazole-4-i
) methylthio]ethylamino}-4-methyl
amino-1,2,5-thiadiazole, ll 1-oxidation 3-amino-4-{2-[(2-
{2,3-dimethylguanidino}thiazole-
4-yl)methylthio]ethylamino}-1,
2,5-thiadiazole, mm 1-oxidized 3-amino-4-[3-(3-di
Methylaminomethylphenoxy)propylamide
]-1,2,5-thiadiazole, nn 1,1-dioxide 3-{2-[(5-dimethyl
Aminomethyl-2-thienyl)methylthio]et
thylamino}-4-[(2-pyridyl)methyl
amino]-1,2,5-thiadiazole, oo 1-3,4-bis oxide {2-[(2-guani
dinothiazol-4-yl)methyl]ethylua
Mino}-1,2,5-thiadiazole, pp 1-oxidation 3-amino-4-{2-[(2-
{2-methylguanidino}thiazole-4-y
) methylthio]ethylamino}-1,2,5
-thiadiazole, qq 1,1-dioxidized 3-methylamino-4-
[3-(3-piperidinomethylphenoxy)]
Lopylamino]-1,2,5-thiadiazole
le, rr 1-oxidation 3-amino-4-[3-(3-pipe
lysinomethylphenoxy)propylamino〕-
1,2,5-thiadiazole, ss 1,1-dioxide 3-{2-[(5-dimethyl
Aminomethyl-2-thienyl)methylthio]et
thylamino}-4-ethylamino-1,2,5
-thiadiazole, tt 1,1-dioxidized 3-amino-4-[3-(3
-Piperidinomethylphenoxy)propylamide
]-1,2,5-thiadiazole, uu 1,1-dioxide 3-{2-[(5-dimethyl
Aminomethyl-2-thienyl)methylthio]et
thylamino}-4-[(4-pyridyl)methyl
Amino]-1,2,5-thiadiazole As used in the present invention, the term non-toxic drug
The salts can be used as non-toxic medicines.
Salts of compounds of formula with possible organic or inorganic acids
Taste. Such acids are well known and include hydrochloric acid, bromide
Hydrogen acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid,
Leic acid, fumaric acid, succinic acid, oxalic acid, benzoic acid
Fragrance acid, methanesulfonic acid, ethanedisulfonic acid,
Benzesulfonic acid, acetic acid, propionic acid, flamlite
acids, including citric acid, camphorsulfonic acid, etc.
Ru. These salts can be prepared by any method known in the art.
made by. Formulas disclosed in the present invention
Some of the compounds and intermediates of
A person skilled in the art can produce salt, tri-salt, etc.
recognized by. Also, the intermediate itself is a drug.
Intermediate salts are non-toxic when not used as
Not limited to salts that can be used as sexual medicines
should be understood. The inventors have discovered that the compounds of formula prepared in the present invention
Many of the substances retain solidly the solvent in which they are crystallized.
I found out that it holds. In some cases the product is true
, while in other cases the product is a solvate of
Simply having unfixed solvent or solvate plus young
It is a mixture of dry and unfixed solvents. The solvent is hot
can be removed by drying in
However, this results in a product that is nicely crystalline.
It is often converted into a rubbery solid. The solvate is
It usually has a very sharp melting point.
Therefore, in the present invention, drying is normally carried out at room temperature.
Ta. The solvent was retained even after long drying, but NMR
The amount of solvent was determined by e.g. Example below
indicates the amount of solvent (if appropriate) and
Points are for solvated products unless otherwise noted.
be. For therapeutic use, the pharmacologically active compounds of the invention are typically
A base along with a non-toxic pharmaceutically acceptable carrier.
in the form of acidified or non-toxic pharmaceutically usable
One of this compound in salted form as an essential active ingredient
Administered as a pharmaceutical composition comprising: Pharmaceutical compositions can be administered orally, parenterally or rectally.
Administered by suppository. Uses various medicinal forms
I can be there. Thus, solid carriers are used
If the preparation is to be made into tablets, powder or
is in the form of pellets in hard gelatin capsules.
or in the form of a troche or lozenge
be able to. When using a liquid carrier,
Agents include syrup, emulsion, and hard gelatin.
sterile liquid for injection, or aqueous or non-aqueous liquid
It may be in the form of a suspension. Pharmaceutical set
The composition can be manufactured by any technique suitable for the desired pharmaceutical product.
will be built. Suitably, each dosage unit contains about 0.5 mg to about 150 mg,
Most preferably it contains an amount of active ingredient from about 2 mg to about 50 mg.
have The active ingredient is preferably used 2 to 4 times a day.
amount is administered. The daily dose is suitably between 1 mg and approx.
600 mg, most preferably about 4 mg to about 200 mg. Histamine H₂-Receptor antagonists are used in animals and
has been shown to be an effective inhibitor of gastric secretion in humans.
As shown [Bryblecomb et al.J．．Int．．
Med.Res．． ，3, 86 (1975)]. Histamine H₂―
The clinical evaluation of the receptor antagonist cimetidine
is an effective therapeutic agent in the treatment of peptic ulcers.
[Gray et al.Lancet，1,8001
(1977)]. Histamine H₂- Antigastric secretory activity of antagonists
One of the standard animal models for determining
It is. Table 1 below shows that many of the compounds of the invention
Anti-gastric secretion in rats with pylorus ligation₅₀(Ma
(unit: icromol/Kg). Determination of antigastric secretion activity in rats with pylorus ligation for 2 hours.
fixed Pyloric ligation in rats causes perforated gastric ulcers.
For the study of Xie et al.Gastroenterology，5，
53 (1945); however, this method
As the gastric secretion of rats became known,
It was also used as a research tool [Xie et al.
Gastroenterology26, 906 (1954), Broday
-, D.A.Am．．J．．Dig．．Dis．． ，11, 231 (1966)].
Here we use a variation of this procedure to demonstrate antigastric secretion activity.
Evaluate compounds for their properties. Use male Long Evans rats, 280-300 mg.
do. Place the animals one at a time in a cage and keep them in a cage for 24 hours.
Food and water are provided ad libitum. under ether anesthesia,
The stomach is reached through a midline incision and cotton suture is placed around the pylorus.
to perform ligation. After closing the wound, stop the ether treatment and
ml/Kg of test compound or control vehicle in a
or subcutaneously. All compounds were dissolved in an equivalent amount of HCl.
Solubilize and make compatible with water. animals, water bottles
Return to the removed cage and kill with ether after 2 hours.
do. Remove the stomach and do a 2 hour stomach collection.
Drain into a graduated test tube to determine the volume. auto
Viewlet and potential type PH meter (radiometer)
Using the
To measure titratable activity by titrating with
Ru. Do not multiply the volume (ml) by the acid concentration (milliequivalent per liter).
Acid emissions microequivalents titratable by
Calculate. Calculate the suppression % of acid emissions as follows:
do. Acid emission suppression% = Acid excretion (control) - Acid excretion (drug) / Acid excretion (
control) x 100 At least 5 rats at each dose level
to determine the dose-response curve using the lowest dose level.
Set. Initial intraperitoneal injection of test compound or control vehicle
This test was conducted using a ray. However, subcutaneous injection
This test is also somewhat more sensitive when using
Subsequently, all subsequent tests were conducted using the subcutaneous route.
I decided to implement it. Note in Table 1 the route of administration of each compound.
Write down. 【table】 【table】 Some of the compounds of the present invention were added to the right heart of a guinea pig.
Cell test, gastrostomy dog test (in the quiet room) and Heiden High
Tested and active in the poach dog test (oral)
showed that. The first two tests were conducted in collaboration with the inventors.
The operation described in the powerful US patent 4112234
Therefore, it was carried out. heidenhain pouch dog test
Grossman and Konturek,
Gastroenterology66, 517 (1974) general operations.
I followed. Celite is a Johnsman against diatomaceous earth.
Registered Trader of Bill Products Corporation
It is a sign. Skerisoleb B is mainly n-hexane
For the petroleum ether fraction with bp 60-68° consisting of
is a registered trademark of Skelli Oil Company.
Ru. The term "flash" used in some of the examples
``Yu Chromatography'' means w.c. still etc.
by J.Org.Chem.43, 2923-2925 (1978)
Relatively new chromatographic techniques described
refers to technology. It is a finer chromatograph
using an e-medium and a pressure somewhat higher than atmospheric pressure.
and obtain faster chromatographic separations. In the following examples, all temperatures are expressed in degrees Celsius.
It will be done. In addition, the compound names described in these examples
"oxidation" means "oxide". Example 1 1,1-dioxide 3-{2-[(5-methyl-1H
-imidazol-4-yl)methylthio]ethyl
Ruamino}-4-(2-propynyl)amino-
1,2,5-thiadiazole A 1,1-dioxide 3-{2-[(5-methyl-
1H-imidazol-4-yl)methylthio]
ethylamino}-4-methoxy-1,2,5-
Thiadiazole 1,1-diacid in 200 ml of methanol at room temperature
3,4-dimethoxy-1,2,5-thiadiazole
(2.0 g; 11.2 mmol) [J．．Org．．Chem．． ，
40, 2743 (1975)
Add methanol 25% to the suspension of [Production] while stirring well.
2-[(5-methyl-1H-imidazole-4) in ml
-yl) methylthio]ethylamine (dihydrochloride?
et al., 2.73 g; 11.2 mmol) [Belgian patent
779775] was added. After stirring for 30 minutes,
A methanol solution of the title compound was obtained. TLC
Rika/CH₂Cl₂:CH₃OH (90:10)], Rf=
I got 0.44. B 1,1-dioxide 3-{2-[(5-methyl-
1H-imidazol-4-yl)methylthio]
ethylamino}-4-(2-propynyl)ami
No-1,2,5-thiadiazole Add 2-Pro to the methanolic solution of Step A product.
7 ml of pinylamine was added. 20 minutes at room temperature
After stirring for a while, the reaction mixture was evaporated under reduced pressure to remove the residual
Place the oil on silica gel and add methylene chloride-methano
Chromatography by gradient elution using a
E-processed. Combine appropriate fractions and prepare as oil
2.74 g of the compound was obtained. The above material was obtained during the same second experiment.
Further purification is achieved by combining and this mixture
Place the material on silica gel and add methylene chloride-methano
Chromatography by gradient elution using a
E-processed. Combine appropriate fractions with methanol,
Evaporate under reduced pressure as a brittle solid, mp82~103°
The title compound (2.93g) was obtained; d₆dimethylsu
The NMR spectrum (100MHz) in sulfoxide is
It showed the presence of 1/3 mole of methanol. Analysis C₁₂H₁₆N₆O₂S₂as Calculated value: C, 42.19; H, 4.97; N, 23.95: S, 18.27 Experimental values: C, 42.05; H, 5.05; N, 24.01; S, 18.45 Example 2 1,1-dioxide 3-{2-[(5-methyl-1H
-imidazol-4-yl)methylthio]ethyl
Ruamino}-4-methylamino-1,2,5-
Thiadiazole In 250 ml of dry methanol cooled to 2° in ice water bath water
1,1-dioxidized 3,4-dimethoxy-1,2,
5-thiadiazole (2.5 g; 1.40 mmol)
2- in 25 ml of methanol while stirring well
([5-methyl-1H-imidazol-4-yl)
Methylthio]ethylamine (from dihydrochloride, 3.42
g; 14.0 mmol) was added dropwise over 25 minutes.
did. After stirring for 20 minutes at 2°, add
Bubble anhydrous methylamine for 6 minutes and remove stirring.
Continued for 30 minutes at room temperature. Reaction mixture under reduced pressure
Evaporate and use methylene chloride-methanol
Chromatographed by gradient elution. suitable
The fractions were combined to obtain 3.2 g of the title compound. Kara
Further purify the product using mucochromatography.
Manufactured as an amorphous solid, mp98~100°
Samples for compound analysis were obtained. d₆dimethyl sulfoki
The NMR spectrum (100MHz) in CID is the following common
δ that showed ringing: 7.46 (s, 1H); 3.70 (s, 2H);
2.53 (t, 2H); 2.86 (s, 3H); 2.76 (t, 2H);
2.15 (s, 3H). Analysis C_TenH₁₆N₆O₂S₂as Calculated value: C, 37.96; H, 5.09; N, 26.56; S, 20.27 Experimental values: C, 37.79; H, 5.16; N, 26.52; S, 20.24 Example 3 1,1-dioxide 3-{2-[(2-guanidino
Thiazol-4-yl)methylthio]ethylua
mino}-4-{2-[(5-methyl-1H-imi
dazol-4-yl)methylthio]ethylamide
No-1,2,5-thiadiazole 1,1-dioxide 3-{2-[(5-methyl-1H
-imidazol-4-yl)methylthio]ethyl
Amino}-4-methoxy-1,2,5-thiadia
Sol [2-{(5
-Methyl-1H-imidazol-4-yl)methy
ruthio}ethylamine dihydrochloride (2.73g; 11.2
(manufactured from millimoles) at -10°.
2-[(2-g) in 35 ml of methanol with vigorous stirring.
Anidinothiazol-4-yl)methylthio]et
Thylamine (from dihydrochloride, 3.41 g; 11.2 mmol
) [According to the operations described in South African Patent No. 7812129
[Manufacturing] solution was quickly added. At −10°
After stirring for 30 minutes, the solution was allowed to reach ambient temperature. reaction mixture
The mixture was evaporated under reduced pressure, and the residue was poured into 45 g of silica gel.
Place on top, methylene chloride-methanol (4:1)
1 liter was used for chromatography.
The appropriate fractions were combined and evaporated to a residue (5.82 g).
was placed on 80 g of aluminum oxide, and ethyl acetate was added.
Chromatograph using methanol gradient elution
Processed. Combine appropriate fractions and pass through Celite.
Filter and evaporate under high vacuum to about 2/3 mole of ethyl acetate.
As an amorphous solid containing [d₆Dimethylsu
NMR spectrum in sulfoxide (100MHz)
[Confirmation] The title compound (2.5 g) was obtained. Analysis C₁₆H_{twenty four}N_TenO₂S_Four・2/3C_FourH₈O₂as Calculated value: C, 38.96; H, 5.14; N, 24.34; S, 22.29 Experimental values: C, 39.08; H, 4.96; N, 24.48; S, 22.26 Example 4 1-oxidation 3-{2-[(5-methyl-1H-imi
dazol-4-yl)methylthio]ethylamide
No}-4-methylamino-1,2,5-thiazi
Azor A 1-oxidized 3,4-dimethoxy-1,2,5-
Thiadiazole M-chlorofiltration in 900 ml of chloroform at 20°
Stir into a solution of benzoic acid (50.7 g; 25.0 mmol)
3,4-dimethoxy-1 in 100 ml of chloroform,
2,5-thiadiazole (35.2 g; 24.1 mmol
(described in J.Org.Chem., 40, 2749 (1975))
[produced according to the procedure] was applied for 3 minutes.
added. Use a cooling bath to rise above 32°
Therefore, this exothermic reaction was suppressed. 3 at ectotherm
After stirring for an hour, add an additional 2.0 g of 3,4-
Reacts with dimethoxy-1,2,5-thiadiazole
and stirred for 1 hour. Organic solution with NaHCO₃2 with 300ml each of 1% solution of
Extracted twice, washed with 250ml of water, dried and evaporated under reduced pressure.
Evaporation yielded 47.0 g of product. Isopropyl alcohol
The title compound (34.0g) was recrystallized from coal.
Obtained. Further recrystallization from isopropyl alcohol
A sample for analysis, mp135-137°, was obtained. Analysis C_FourH₆N₂O₃as S Calculated value: C, 29.63; H, 3.72; N, 17.27; S, 19.77 Experimental values: C, 29.53; H, 3.75; N, 17.26; S, 19.83 B 1-oxidation 3-{2-[(5-methyl-1H-i
midazol-4-yl)methylthio]ethylua
Mino}-4-methylamino-1,2,5-thia
diazole 1-3,4-dimethyl oxide obtained from step A above
A solution of toxy-1,2,5-thiadiazole, etc.
molar amount of 2-[(5-methyl-1H-imidazole
-4-yl)methylthio]reacts with ethylamine
The obtained 1-oxidized 3-{2-[(5-methyl
-1H-imidazol-4-yl)methylthio]
ethylamino}-4-methoxy-1,2,5-thi
Treating diazole with excess methylamine
This gives the title compound. Example 5 1,1-dioxidized 3-hydroxy-4-{2-
[(5-methyl-1H-imidazol-4-yl)
Methylthio]ethylamino}-1,2,5-thi
Asiazole Example 12, 1,1-diacid by the general procedure of step A
Chemical formula 3-{2-[(5-methyl-1H-imidazole
-4-yl)methylthio]ethylamino}-4-
Methoxy-1,2,5-thiadiazole [Example 1,
Methanolic solution of [produced by the operation of step A]
treated with a solution of caustic soda in methanol
At this time, the title compound, mp263-265° (decomposition) was obtained.
Ru. Analysis C₉H₁₃N_FiveS₂O₃as Calculated value: C, 35.64; H, 4.32; N, 23.09; S, 21.13 Experimental values: C, 35.56; H, 4.38; N, 23.01; S, 21.13 Example 6 1,1-dioxide 3-{2-[(5-dimethyla
Minomethyl-2-furyl)methylthio]ethyl
amino}-4-methylamino-1,2,5-thi
Asiazole and 3,4-bis 1,1-dioxide
{2-[(5-dimethylaminomethyl-2-furi
) methylthio]ethylamino}-1,2,5
-thiadiazole A 1,1-dioxide 3-{2-[(5-dimethyl
Aminomethyl-2-furyl)methylthio]ethyl
Ruamino}-4-methoxy-1,2,5-thia
diazole 2-[(5-dimethyl acetate) in 20 ml of dry methanol
Minomethyl-2-furyl)methylthio]ethylua
Min (2.41 g; 11.2 mmol) [Belgian patent
857388]
1,1-dioxidized 3,4- in 200 ml of methanol
Dimethoxy-1,2,5-thiadiazole (2.0
Stir well into a cold (8°) suspension of
Added everything at once. At 8~10°
After stirring for 15 minutes, a methanolic solution of the title compound
get. B 1,1-dioxide 3-{2-[(5-dimethyl
Aminomethyl-2-furyl)methylthio]ethyl
Ruamino}-4-methylamino-1,2,5-
Thiadiazole Product of Step A in cold (1°) methanolic solution
Then anhydrous methylamine was bubbled in for 6 minutes. 10 minutes
Continue stirring for a while and evaporate the mixture under reduced pressure.
Ta. Place the residue on top and bottom of 45g of silica gel and add chloride solution.
Chromatography using tyrene-methanol gradient elution
Tograph treated. Methylene chloride-methanol
(95:5) to remove appropriate fractions in methanol.
Neutralize, filter through Celite, then concentrate under reduced pressure.
The product was obtained by condensation. recrystallized from methanol
The title compound (1.76 g), mp 82-90° was obtained. d₆Ji
NMR spectrum in methyl sulfoxide (100M
Hz) indicated the presence of 2/3 mole methanol. Analysis C₁₃H_{twenty one}N_FiveO₃S₂・2/3CH₃As OH Calculated value: C, 43.10; H, 6.26; N, 18.38; S, 16.83 Experimental value: C, 43.30; H, 6.12; N, 18.57; S, 16.96 C 1,1-dioxidized 3,4-bis{2-[(5-
dimethylaminomethyl-2-furyl) methylthi
[o]ethylamino}-1,2,5-thiadiazole
rule Methylene chloride from chromatography in step B
Slow elution using methanol-methanol (9:1)
Place the ingredients on 45g of aluminum oxide and add acetic acid.
Chromatography using ethyl-methanol gradient elution
Tograph treated. Evaporate the appropriate fractions and leave the remaining
Crush the material with ether-acetonitrile to make it colorless.
Obtain a solid and collect it by filtration to obtain 1 hydrate,
The title compound (428 mg) was obtained as mp92.5-96°.
Ta. Analysis C_{twenty two}H₃₄N₆S₃O_Four・H₂as O Calculated value: C, 42.12; H, 6.47; N, 14.99; S, 17.15 Experimental value: C, 47.28; H, 6.48; N, 15.09; S, 17.39 H₂Calculated value for O = 3.21%; H₂O experimental value = 3.32%. Example 7 1,1-dioxide 3-{2-[(5-dimethyla
Minomethyl-2-furyl)methylthio]ethyl
amino}-4-methylamino-1,2,5-thi
Asiazole 1,1-dioxide 3,4-di in 200 ml of methanol
Methoxy-1,2,5-thiadiazole (2.0
Stir well into a cold (1°) suspension of
2-[(5-dime) in 20 ml of dry methanol while
thylaminomethyl-2-furyl)methylthio]et
Add a solution of thylamine (2.41 g; 11.2 mmol) to the
parts were added at once. Dry at 1-5 degrees for 15 minutes.
After that, add ethylamine (4.0ml) and continue stirring.
It lasted for 20 minutes at about 5°. Vacuum the reaction mixture
Evaporate and place the residue on 46g of silica gel.
Gradient elution using methylene chloride-methanol
Chromatography was performed using appropriate fraction
Combine, evaporate and remove gelatinous residue under ether.
Crush and strain to give a colorless solid (2.81g)
The product was obtained. Recrystallized twice from methanol and
17 hours at temperature₂O_FiveDry over to give the title product,
mp155~160° (various half melting at 94~96°)
T;d₆NMR spectrum in dimethyl sulfoxide
(100MHz) indicates the presence of about 0.8 moles of methanol.
Indicated. Analysis C₁₄H_{twenty three}N_FiveO₃S₂・0.8CH₃As OH Calculated value: C, 44.54; H, 6.62; N, 17.55; S, 16.07 Experimental values: C, 44.35; H, 6.58; N, 17.44; S, 16.18 Example 8 1,1-dioxide 3-{2-[(5-dimethyla
Minomethyl-2-furyl)methylthio]ethyl
amino}-4-(2-propynyl)amino-
1,2,5-thiadiazole 1,1-dioxide 3,4-di in 200ml of methanol
Methoxy-1,2,5-thiadiazole (2.0
Stir well into a cold (1°) suspension of
2-[(5-dime) in 20 ml of dry methanol while
thylaminomethyl-2-furyl)methylthio]et
A solution of thylamine (2.41 g; 11.2 mmol)
It was added dropwise over a period of minutes. Stir at 1-2° for 15 minutes.
After stirring, add 2-propynylamine in 10 ml of dry methanol.
(4.0ml) of the solution all at once, then
Stirring was continued for 1 hour at room temperature. reaction mixture
Evaporate under reduced pressure and place the residue on 50 g of silica gel.
using methylene chloride-methanol gradient elution.
and chromatographed. Combine appropriate fractions
produced by evaporation and crystallization from methanol.
4.0g of material was obtained. From methanol, then isopropyl
The title compound was recrystallized from pyrual alcohol.
(2.90g), mp92~100° obtained; d₆dimethyl sulfo
The NMR spectrum (100MHz) in oxide is 1 mo
The product is solvated with methanol
showed that. Analysis C₁₅H_{twenty one}N_FiveO₃S₂・CH₃As OH Calculated value: C, 46.25; H, 6.06; N, 16.85; S, 15.43 Experimental value: C, 46.36; H, 6.22; N, 16.95; S, 15.73 Example 9 1,1-dioxidized 3-methylamino-4-{2-
[(5-{[N-methyl-N-(2-propynyl)
[amino]methyl}-2-furyl)methylthio]
ethylamino}-1,2,5-thiadiazole A 5-{[N-methyl-N-(2-propynyl)
Amino]methyl}-2-furan methanol Furfuryl alcohol cooled to 5° in an ice water bath
(2.49 g; 25.4 mmol) with N-methylpropylene hydrochloride
pakylamin (4.0 g; 37.9 mmol) and 40%
Formalin (3.13 ml; 41.7 mmol) was added;
Stir the mixture while allowing it to reach ectotherm.
Ta. After stirring for 1 hour, the solution was kept at external temperature for 4-1/2 hours.
I left it for days. Pour the reaction mixture into ice water and reduce to 40%
Make strongly basic with aqueous NaOH, and add 55% with methylene chloride.
Extracted twice. The organic phases are combined, dried, filtered and reduced.
Evaporation under pressure gave the product as an oil (quantitative yield
amount). The title compound, bp102 ~ by vacuum distillation
106°/0.3mmHg was obtained. Analysis C_TenH₁₃NO.₂as Calculated value: C, 67.02; H, 7.31; N, 7.82 Experimental value: C, 66.80; H, 7.44; N, 7.93 B 2-[(5-{[N-methyl-N-(2-pro
pinyl)amino]methyl}-2-furyl)methy
Lucio]ethylamine Cysteamine hydrochloride (27.9 g; in 125 ml of concentrated hydrochloric acid;
Add ice-cold concentrated salt to a cold (5°) solution of 24.6 mmol) with stirring.
5-{[N-methyl-N-(2-propylene) in 100 ml of acid
Nyl)amino]methyl}-2-furan methanol
(40.0g; 233 mmol) Solution of [manufactured during step A]
was added. This solution was kept at 0° for 21/2 days.
Then leave it at outside temperature for 7 hours to complete the reaction.
Ta. Cool the reaction mixture in an ice bath and dilute with 200 ml of water.
and made strongly alkaline with 40% aqueous NaOH, then
Extracted three times with methylene chloride. Combine the organic phases and dry
Dry, filter and evaporate under reduced pressure to a thick oil (46.4
The product was obtained as g). This oil can be quickly vacuum evaporated.
Dilute the title compound, bp136-140°/0.2mmHg.
Obtained. Analysis C₁₂H₁₈N₂As an OS Calculated value: C, 60.47; H, 7.61; N, 11.76; S, 13.46 Experimental values: C, 59, 82; H, 7.68; N, 11.61; S, 13.27 C 1,1-dioxidized 3-methylamino-4-{2
-[(5-{[(N-methyl-N-(2-propylene)
Nyl)amino]methyl-2-furyl)methylthi
[o]ethylamino}-1,2,5-thiadiazole
rule 1,1-dioxidation 3,4 in 200ml dry methanol
-dimethoxy-1,2,5-thiadiazole
Stir into a cold (3°) suspension of (2.0 g; 11.2 mmol)
Lower 2-[(5-{[N-methyl-N-(2-propylene)
Nyl)amino]methyl}-2-furyl)methylthi
Ethylamine (2.68 g; 11.2 mmol)
The solution prepared in Step B] was added. At 3~7°
After stirring for 15 minutes, add methylamine to this solution for 15 minutes.
I made a valve for a while. The reaction mixture was evaporated under reduced pressure,
Place the oily residue on 100g of silica gel and add acetate.
Chromatography using a nitrile-methanol gradient
Graph processed. Combine appropriate fractions and add methylene chloride.
Silica gel 100% using a methanol-methanol gradient
Rechromatographed on g.g. Salt appropriate fractions
Dissolved in methylene chloride and extracted with 1% aqueous NaOH.
Ta. The aqueous phase was brought to pH 9 with 5% aqueous HCl and the oil separated.
was extracted three times with methylene chloride. Combine the extracts
Dry, filter and evaporate under reduced pressure to form a foam.
A product was obtained. Reconstituted from isopropyl alcohol
Crystallizes the title compound, mp50~51°, transparent meth
Obtained 54-56°;D₆in dimethyl sulfoxide
NMR (100MHz) is approximately 1/4 mole of isopropyl
Indicated the presence of alcohol. Analysis C₁₅H_{twenty one}N_FiveO₃S₂・1/4C₃H₈as O Calculated value: C, 47.47; H, 5.82; N, 17.57; S, 16.09 Experimental value: C, 47.51; H, 6.21; N, 16.40; S, 15.97 Example 10 1,1-dioxide 3-{2-[(5-dimethyla
Minomethyl-3-methyl-2-furyl)methyl
thio]ethylamino}-4-methylamino-
1,2,5-thiadiazole A 5-dimethylaminomethyl-3-methyl-2
-Furan methanol 3-Methyl-2-furfuryl alcohol (11.2
g; 0.1 mol [J．．Am．．Chem．．Soc．． ，72,2195
(1950)], salt
acid dimethylamine (12.23 g; 0.15 mol) and 37
Contains % aqueous formaldehyde (12 ml; 0.15 mol)
The mixture was kept at about 5° for 2.5 hours, then brought to ambient temperature.
The mixture was left to stir overnight. Place this solution on a steam bath for 10 minutes
Heat, dilute with 12 ml of water, and make basic with soda carbonate.
did. This mixture was extracted with ethyl acetate and the organic phase
was dried, filtered and evaporated under reduced pressure to give the title compound.
BP88-96/0.05-0.08 mmHg was obtained. B 2-[(5-dimethylaminomethyl-3-methane)
methyl-2-furyl)methylthio]ethylamine Ice-salt bath - Hydrochloric acid in 120ml of concentrated HC cooled to 10°
2-aminoethanethiol (2.27 g; 20.0 mm
5-dimethylaminomethyl-3-methane solution of
Chill-2-furan methanol (3.38g; 20.0ml
mol) [produced during step A] was added dropwise, and the mixture was
Stir for 15 minutes and then leave in the cold (0°) overnight.
After 17 hours, make this cold solution strongly basic with an aqueous KOH solution.
and then extracted five times with methylene chloride. organic phase
were combined, dried, filtered and evaporated under reduced pressure to give the title
compound of (4.16 g), bp 110-120°/0.1 mmHg was obtained. C 1,1-dioxide 3-{2-[(5-dimethyl
aminomethyl-3-methyl-2-furyl)methy
Lucio]ethylamino}-4-methylamino-
1,2,5-thiadiazole 1,1-dioxidized 3,4-dimethoxy-1,2,
5-thiadiazole was added to an equimolar amount of 2-[(5-di
methylaminomethyl-3-methyl-2-furyl)
Methylthio]ethylamine [produced during step B] and
The obtained 1,1-dioxidized 3-{2-
[(5-dimethylaminomethyl-3-methyl-2-
furyl) methylthio]ethylamino}-4-meth
Excess methoxy-1,2,5-thiadiazole
When treated with amine, the title compound is thereby
You can get things. Example 11 1,1-dioxide 3-{2-[(5-dimethyla
Minomethyl-4-methyl-2-furyl)methyl
Thio]ethylamino}-1,2,5-thiadia
sol A 2-dimethylaminomethyl-3-methylfura
hmm 3-Methyl-2-furuf in 200ml of methylene chloride
Lyru alcohol (25.2 g; 22.5 mmol) and
Solution of ethylamine (27.3 g; 27.0 mmol)
Cool to -15° in an ice-salt bath and bring the temperature to -10 to 15°.
Keep thionyl chloride (18.0
ml; 24.8 mmol) was added dropwise. 15 minutes later,
The mixture was poured into ice water and the organic phase was separated.
Contains 3-methyl-2-chloromethylfuran
Dimethylene chloride phase in 400 ml of absolute ethanol
In a solution of Lamine (137.0; 3.04 mol) under stirring,
, and the resulting solution was kept at an external temperature.
Stirred for 17 hours. The reaction mixture was evaporated under reduced pressure,
The residue was mixed with 400 ml of water and strengthened with 40% aqueous NaOH.
The mixture was made basic and extracted five times with methylene chloride. extraction
The combined solutions were dried and evaporated under reduced pressure to yield the title compound.
26.0 g of material, bp 64-70°/20 mmHg was obtained. TLC
Rica/CHCl₃:CH₃OH (85:15)] is Rf=0.50
gave. B 2-chloromethyl-5-dimethylaminomethy
Leu-3-methylfuran 2-dimethylaminomethy in 250 ml of chloroform
Leu-3-methylfuran (6.5 g; 37.0 mmol)
Add paraformaldehyde to the solution [manufactured during step A]
(1.67 g; 55.7 mmol) and zinc chloride (312 mg)
HCl while stirring for 15 min at external temperature.
The slow flow of gas was valved. Stir for 2 hours
Continue and then bubble HCl gas for 15 minutes, this
The mixture was stirred for 1 hour. At this time, add
Paraformaldehyde (1.67 g; 55.7 mmol)
) and stop the slow flow of HCl gas for 15 minutes.
It made me fly. After stirring for 18 hours at external temperature, the reaction mixture was
The mixture was filtered through Celite and the liquid was evaporated under reduced pressure.
The title compound (4.97g) was obtained.
If left untreated, it will crystallize and will not be purified further.
Used in step C. CDCl₃The middle NMR spectrum then gives resonances
δ: 6.33 (s, 1H); 4.55 (s, 2H); 4.30 (d,
2H); 2.83 (d, 6H); 2.13 (s, 3H). C 2-[(5-dimethylaminomethyl-4-methyl
methyl-2-furyl)methylthio]ethylamine 2-Chloromethylene in 20 ml of concentrated hydrochloric acid cooled in an ice-water bath.
Ru-5-dimethylaminomethyl-3-methylfura
(773 mg; 3.45 mmol) was added with 2-arne hydrochloric acid.
Minoethanethiol (392 mg; 3.45 mmol)
was added and the mixture was stirred for 30 minutes. This solution
was left at 0° for 3 days, then 50% aqueous KOH
Make it a strong base, dilute with water, and dilute with methylene chloride.
Extracted twice. Combine the extracts, dry, filter, and reduce.
Evaporation under pressure gave the title compound as an oil. Dissolve this product in absolute ethanol and remove the anhydrous salts.
Treated with hydrogen chloride and evaporated under reduced pressure. residue
Dissolve in hot isopropyl alcohol and treat with charcoal
The solution was filtered and concentrated to crystallize the hydrochloride. stomach
Recrystallized from sopropyl alcohol to form dihydrochloride.
The title compound, mp185-190° (decomposition) was obtained. D 1,1-dioxide 3-{2-[(5-dimethyl
aminomethyl-4-methyl-2-furyl)methy
Lucio]ethylamino}-4-methylamino-
1,2,5-thiadiazole 1,1-dioxidized 3,4-dimethoxy-1,2,
A methanolic suspension of 5-thiadiazole was
of 2-[(5-dimethylaminomethyl-4-
Methyl-2-furyl)methylthio]ethylamine
1,1- obtained by reacting with [manufactured in step C]
Dioxide 3-{2-[(5-dimethylaminomethyl
-4-methyl-2-furyl)methylthio]ethyl
Amino}-4-methoxy-1,2,5-thiadia
When reacting the sol with excess methylamine, the target
The title compound is obtained. Example 12 1,1-dioxide 3-{2-[(5-dimethyla
Minomethyl-2-furyl)methylthio]ethyl
Amino-4-hydroxy-1,2,5-thiazi
Azor A 1,1-dioxide 3-{2-[(5-dimethyl
Aminomethyl-2-furyl)methylthio]ethyl
Ruamino}-4-methoxy-1,2,5-thia
diazole 180 ml of dry methanol cooled to 1° in ice water
1,1-dioxidized 3,4-dimethoxy-1,2,
5-thiadiazole (1.78 g; 10.0 mmol)
Suspend in 25 ml of dry methanol with good stirring.
2-[(5-dimethylaminomethyl-2-furyl)
Methylthio]ethylamine (2.14 g; 10.0 mm
A solution of (1) was added dropwise over a period of 35 minutes. 0゜odor
After 15 minutes, a methanolic solution of the title compound was obtained.
Ru. TLC (Silica/CH₂Cl₂:CH₂OH (9:1)]
gave Rf=0.48. A 2.0 ml portion of this solution was acidified with 6.0 N HCl,
Evaporate under reduced pressure without heating to form hydrochloride
The title compound was obtained. D₂NMR spectrum in O
gave the following resonance δ: 6.45 (d, 1H); 6.19
(d, 1H); 4.14 (s, 2H); 4.0 (s, 3H); 3.64
(s, 2H); 3.37 (t, 2H); 2.65 (s, 6H); 2.61
(t, 2H). B 1,1-dioxide 3-{2-[(5-dimethyl
Aminomethyl-2-furyl)methylthio]ethyl
Ruamino}-4-hydroxy-1,2,5-thi
Asiazole Add the methanolic solution of the product of Step A to an ice-water bath.
Cool to 0° and dissolve in 25 ml of dry methanol.
A solution of pellets (2.10 g; 52.5 mmol)
Added. 2 hours at 0°, 68 hours at external temperature
After drying for a while, the reaction mixture was diluted with 8.75 ml of aqueous 6.0NHCl.
(52.5 mmol) and reduced after 10 min of stirring.
Evaporated under pressure. Crystallize the residue under 96% EtOH
to obtain the crude product, which was dissolved in methanol.
Filter it to remove the salt and place it on 60g of silica gel.
using methylene chloride-methanol gradient elution.
and chromatographed. Combine appropriate fractions
and evaporated under reduced pressure to obtain 3.19 g of product. aqueous
Recrystallization from methanol yields the title compound, mp109
~122° was obtained. Analysis C₁₂H₁₈N_FourO_FourS₂as Calculated value: C, 41.61; H, 5.24; N, 16.17; S, 18.51 Experimental value (1.15% H₂(corrected for O): C, 41.59; H, 5.32; N, 16.33; S, 18.81 Example 13 1-oxidation 3-{2-[(5-dimethylaminomethyl
methyl-2-furyl)methylthio]ethylamide
No}-4-methylamino-1,2,5-thiazi
Azor A 1-oxidation 3-{2-[(5-dimethylamino
Methyl-2-furyl)methylthio]ethylamide
No}-4-methoxy-1,2,5-thiadiazole
rule 1-oxidation, 3,4- cooled at 12-15° in an ice water bath
Dimexy-1,2,5-thiadiazole (2.50
g; 15.4 mmol) Suspension [prepared according to the procedure of Example 4, Step A]
The mixture was added dropwise over 14 minutes with good stirring. child
The solution was stirred at external temperature for 1.5 hours to obtain the title
A methanolic solution of the compound was obtained. B 1-oxidation 3-{2-[(5-dimethylamino
methylfuryl) methylthio]ethylamino}
-4-methylamino-1,2,5-thiadiazo
rule Methanol of the product of step A cooled to 5° in an ice water bath.
Anhydrous methylamine was added to the solution for 8 minutes.
Ta. The reaction mixture was stirred at external temperature for 17 h and then
Evaporation under reduced pressure to give the product as a yellow oil;
Place this on 55g of silica gel and add methylene chloride.
Chromatographed using tanol gradient elution.
I understood. Evaporate appropriate fractions and dissolve in methanol.
diluted with diethyl ether and labeled as a solid.
The title compound (2.32 g) was obtained, which was heated at external temperature.
P₂O_FiveVacuum dry for 3 hours and mp86~92° Analysis C₁₃H_{twenty one}N_FiveO₂S₂as Calculated value: C, 45.46; H, 6.16; N, 20.39; S, 18.67 Experimental values: C, 45.24; H, 6.24; N, 20.41; S, 18.90 Example 14 1,1-dioxidized 3-allylamino-4-{2-
[(5-dimethylaminomethyl-2-furyl)methane
Chilthio]ethylamino}-1,2,5-thia
diazole 1 in 200 ml of methanol cooled to 0° in an ice water bath.
1-dioxidized 3,4-dimethoxy-1,2,5-thi
Partial suspension of Asiazole (2.08 g 11.7 mmol)
Add 2-[(5-dimethylamine) to the solution in 30 ml of methanol.
methyl-2-furyl)methylthio]ethylamide
The solution was added dropwise over a period of 45 minutes. Addition complete
Add 10.5ml of allylamine and add this solution.
was stirred at ambient temperature for 18 hours. Reduce reaction mixture
Evaporate under pressure and place the residue on 120 g of silica gel.
using methylene chloride-methanol gradient elution.
and chromatographed. Combine appropriate fractions
evaporated under reduced pressure and the residue was dissolved in isopropyl alcohol.
Crystallize with coal to obtain the title compound, 83-86°
Got it ;d₆NMR spectrum in dimethyl sulfoxide
(100MHz) is approximately 0.9 moles of isopropyl alcohol.
showed the presence of a call. Analysis C₁₅H_{twenty three}N_FiveO₃S₂・0.9C₃H₈as O Calculated value: C, 48.36; H, 6.92; N, 15.93; S, 14.59 Experimental value: C, 48.46; H, 6.96; N, 16.13; S, 14.58 Example 15 1,1-dioxidized 3-methylamino-4-{2-
[(5-methylaminomethyl-2-furyl)methy
ruthio]ethylamino}-1,2,5-thiazidi
Azole and 1,1-dioxidized 3,4-bis-
{2-[(5-methylaminomethyl-2-furi
) methylthio]ethylamino}-1,2,5
-thiadiazole A 1,1-dioxidized 3-methylamino-4-{2
- [(5-methylaminomethyl-2-furyl)
Methylthio]ethylamino}-1,2,5-thi
Asiazole 3,4-dimethyl in 210 ml of methanol cooled to 8°
Toxi-1,2,5-thiadiazole (1.89g;
10.5 mmol) in 21 ml of methanol.
2-[(5-methylaminomethylaminomethyl-
2-furyl)methylthio]ethylamine (0.7
g; 3.51 mmol) [described in Belgian patent 857388
(prepared according to the procedure) added all at once.
Ta. Stir the mixture for 15 minutes and cool to 1° in an ice-water bath.
Cool and then add anhydrous methylamine to this solution for 6 minutes.
Made it bubble. After stirring for 15 min, the reaction mixture was placed under vacuum.
Evaporate and place the residue on 110g of silica gel.
Acetonitrile to acetontrile-methanol
- using a gradient elution of glacial acetic acid (50:50:0.5)
Chromatographed. Rf=0.50 [TLC-Siri
Ka/CH₃CN:CH₃OH：CH₃COOH (50:50:
1)] containing the first eluting component.
The fractions were combined and evaporated under reduced pressure to form a form.
The title product was obtained as mp 50-56°. d₆NMR spectrum in dimethyl sulfoxide
(100MHz) gave the following resonance δ: 6.20(m,
2H); 3.80 (s, 2H); 3.62 (s, 2H); 3.50 (t,
2H); 2.90 (s, 3H); 2.70 (t, 2H); 2.28 (s,
3H); it is also the presence of about 0.2 moles of methanol
showed that. Analysis C₁₂H₁₉N_FiveO₃S₂・0.2CH₃As OH Calculated value: C, 41.65; H, 5.65; N, 19.96; S, 18.28 Experimental values: C, 41.98; H, 5.69; N, 19.54; S, 18.54 B 1,1-dioxide 3,4-bis-{2-[(5
-methylaminomethyl-2-furyl) methylthi
[o]ethylamino}-1,2,5-thiadiazole
rule Rf=0.47 [TLC-Silica/CH₃CN:CH₃OH:
CH₃COOH (50:50:1)] in process A
Contains components that elute slowly from matography
Combine the fractions, evaporate and remove the residue.
Partitioned between 2.5N NaOH and ethyl acetate. water
The phases were extracted several times with ethyl acetate and the organic phases were combined and dried.
Dry and evaporate under reduced pressure to yield the title compound as an oil.
Obtained. d₆NMR spectrum in dimethyl sulfoxide
(100MHz) gave the following resonance δ: 6.22 (m,
4H); 3.82 (s, 4H); 3.65 (s, 4H); 3.50 (t,
4H); 2.72 (s, 4H); 2.30 (s, 6H). Example 16 1,1-dioxidized 3-{4-(5-dimethylamino)
methyl-2-furyl)butylamino}-4-
Methylamino-1,2,5-thiadiazole in 200 ml of dry methanol cooled to 3° in an ice water bath.
1,1-dioxidized 3,4-dimethoxy-1,2,5
-Dissolution of thiadiazole (1.36 g; 7.64 mmol)
4-(5-dimethyl) in 40 ml of dry methanol under stirring.
tylaminomethyl-2-furyl)butylamine
(1.5 g; 7.64 mmol) [described in U.S. Pat. No. 4,128,658
solution] for 45 minutes.
Added over time. After 15 minutes at 3°, this cold solution
was bubbled with anhydrous methylamine for 10 min. reaction
The mixture was evaporated under reduced pressure and the residue was purified with silica gel 60
acetonitrile-methanol gradient
Chromatographed using elution. Appropriate
The fractions were combined to give product 2.16. acetonitrile
The title compound, mp152-153°, was obtained by recrystallization from
Ta. Analysis C₁₄H_{twenty three}N_FiveO₃as S Calculated value: C, 49.25; H, 6.79; N, 20.51; S, 9.39 Experimental values: C, 49.41; H, 6.87; N, 20.61; S, 9.28 Example 17 1,1-dioxide 3-{2-[(5-dimethyla
Minomethyl-2-furyl)methylthio]ethyl
amino}-4-methylamino-1,2,5-thi
Asiazole A 1,1-dioxidized 3-methylamino-4-(2
-Mercaptoethyl)-1,2,5-Thiasia
sol 1 in 250 ml of methanol cooled to 1° in an ice water bath.
1-dioxidized 3,4-dimethoxy-1,2,5-thi
Suspension of Asiazole (3.0 g; 16.8 mmol)
2-Amino in 20 ml of methanol while stirring well.
Ethanethiol (1.91 g from hydrochloride; 16.8 mm
A solution of 1) was added dropwise over a period of 15 minutes. 2 to 4 degrees
After 10 minutes, add 6 methylamine to this solution under cooling.
Bubble for a minute and stir at external temperature for an additional 30 minutes.
Continued. The reaction mixture was evaporated under reduced pressure and the residue
on 45 g of silica gel, methylene chloride-meth
Chromatographed using nol gradient elution.
Ta. Appropriate fractions were combined and evaporated to yield the product (2.43
g) was crystallized from absolute ethanol. Anhydrous
Recrystallized from tanol to obtain the title compound, mp259~
260° (decomposition) was obtained. Analysis C_FiveH_TenN_FourO₂S₂as Calculated value: C, 27.03; H, 4.54; N, 25.20 Experimental value: C, 27.13; H, 4.55; N, 24.86 B 1,1-dioxide 3-{2-[(5-dimethyl
Aminomethyl-2-furyl)methylthio]ethyl
Ruamino}-4-methylamino-1,2,5-
Thiadiazole 1,1-dioxidized 3-methylamino in 20 ml of concentrated hydrochloric acid
-4-(2-mercaptoethyl-1,2,5-thi
Asiazole (1.0 g; 4.5 mmol) [in step A
production] and 5-dimethylaminomethyl-2-furan
Methanol (0.82 g; 4.5 mmol) [J.Chcm.
Soc., 4728 (1958)
The mixture was stirred in an ice bath for 2 hours and then heated at 0°64
I left it for a while. The reaction mixture was kept at external temperature for 23 hours.
Stir and evaporate under reduced pressure without heating to remove the remaining
The material was extracted with water and methylene chloride. Combine the organic phases
Washed with saturated prine solution, dried and evaporated under reduced pressure.
I let it emanate. Place the residue on 25g of silica gel and add salt.
Clean using methylene chloride-methanol gradient elution.
Romatographed. Evaporate the appropriate fractions,
The product was crystallized from methanol. methanol
The title compound, mp92-96°, was obtained by recrystallization from
Ta. Example 18 1-oxidation 3-{2-[(5-dimethylaminomethyl
methyl-2-furyl)methylthio]ethylamide
No}-4-methylamino-1,2,5-thiazi
Azor A 1-oxidized 3-methylamino-4-(2-mer
captoethyl)-1,2,5-thiadiazole 1 in 150 ml of methanol cooled to 3° in an ice water bath.
3,4-dimethoxy-1,2,5-thiadias oxide
Sol (2.92 g; 18.0 mmol) [Example 4, Step A
While stirring well, add methanol to the suspension of
2-aminoethanethiol (from hydrochloride,
A solution of 2.04 g; 18.0 mmol) was added dropwise. 10 minutes
Then, bubble anhydrous methylamine into this solution for 6 minutes.
and stirring continued for an additional 20 minutes at external temperature.
The reaction mixture was evaporated under reduced pressure and the residue was filtered onto silica gel.
of methylene chloride-methanol.
Chromatographed using distributive elution. suitable
The fractions were combined and evaporated to give 2.74 g of product.
Recrystallize from methanol and then 95% ethanol.
The title compound, mp 191-193°, was obtained. B 1-oxidation 3-{2-[(5-dimethylamino
Methyl-2-furyl)methylthio]ethylamide
No}-4-methylamino 1,2,5-thiadia
sol 1-oxidized 3-methylamino-4-(2-merca
ethyl)-1,2,5-thiadiazole
[Manufacture in Step A] according to the procedure described in Example 17, Step B.
About 1 equivalent of 5-dimethylaminomethyl in concentrated hydrochloric acid
-2- When processing with furan methanol,
The title compound is obtained; similar to the product of Example 13.
one. Example 19 1,1-dioxide 3-{2-[(5-dimethyla
Minomethyl-2-furyl)methylthio]ethyl
amino}-4-dimethylamino-1,2,5-
Thiadiazole 1,1-dioxide 3,4-di in 200 ml of methanol
Methoxy-1,2,5-thiadiazole (2.08
g; 11.7 mmol) under cooling (6°).
2-[(5-dimethylaminomethyl) in 50 ml of methanol
methyl-2-furyl)methylthio]ethylamino
(2.5 g; 11.7 mmol) over 45 minutes.
Added. When the addition is complete, keep the temperature at 6°.
Bubble the methylamino into this solution for 10 min while
I let it happen. After stirring for 18 hours at external temperature, the reaction mixture
was evaporated under reduced pressure, and the residue was poured onto 200 g of silica gel.
and methylene chloride-methanol gradient elution.
Chromatography was performed using appropriate fraction
Combine, evaporate and pour the residue onto aluminum oxide 75
g using methylene chloride-methanol gradient elution.
and rechromatographed. Combine appropriate fractions
and evaporated under reduced pressure to obtain the title compound, mp139~
Obtained 142°. Analysis C₁₉H_{twenty four}N_FiveO₃S₂as Calculated value: C, 44.90; H, 6.46; N, 18.70; S, 17.12 Experimental values (corrected for 0.51% water): C, 44.77; H, 6.25; N, 18.89; S, 17.42 Example 20 1,1-dioxide 3-{2-[(2-guanidino
Thiazol-4-yl)methylthio]ethylua
Mino}-4-methylamino-1,2,5-thia
diazole 1,1-dioxidation in 250 ml of methanol at 10°
3,4-dimethoxy-1,2,5-thiadiazole
(2.50 g; 14.0 mmol) and stir well.
2- [(2-guanidine) in 30 ml of methanol while
Nothiazol-4-yl)methylthio]ethylua
Min (from dihydrochloride, 4.27 g; 14.0 mmol dissolved)
liquid was added. After 15 minutes at 10°, in cooling bath
This solution was cooled to 1°, and anhydrous methyl was added to the solution.
Amine was bubbled for 10 minutes. Vacuum the reaction mixture
Evaporate and place the residue on 60g of silica gel.
using methylene chloride-methanol gradient elution.
Chromatographed. Containing 4.53g of product
Place the appropriate fraction on 80 g of aluminum oxide,
Re-evaluate using ethyl acetate-methanol gradient elution.
Combine appropriate chromatographed fractions and evaporate
This is then crystallized from methanol.
The title compound, mp196-198゜(decomposition)
(2.38g) was obtained. Analysis C_TenH₁₆N₈O₂S₃as Calculated value: C, 31.90; H, 4.28; N, 29.77; S, 25.55 Experimental values: C, 31.85; H, 4.24; N, 29.79; S, 25.45 Example 21 1,1-dioxide 3-{2-[(2-guanidino
Thiazol-4-yl)methylthio]ethylua
mino}-4-(2-propynyl)amino-1,
2,5-thiadiazole 1,1-dioxide 3,4-di in 200 ml of methanol
Methoxy-1,2,5-thiadiazole (2.0
Stir well into a cold (8°) suspension of
2-[(2-guanidine) in 25 ml of methanol while
Nothiadiazol-4-yl)methylthio]ethyl
Ruamine (from dihydrochloride, 3.42 g; 11.2 mmol
) was added. After 15 minutes at 8-10°,
This solution was cooled to 1° in an ice bath and dissolved in 15 ml of methanol.
6.0 ml of 2-propylamine was added. ice bath
Remove, stir, evaporate under reduced pressure, and transfer the residue to silica gel.
of methylene chloride-methanol.
Chromatographed using distributive elution. fraction
2, crystalline product (1.74g) from methanol
occurred. Dissolve this product in hot methanol and
Pass through celite, cool, and strain
A compound with a mp of 176-178° was obtained. Analysis C₁₂H₁₆N₈O₂S₃as Calculated value: C, 35.99; H, 4.03; N, 27.98; S, 24.02 Experimental values: C, 35.82; H, 4.12; N, 28.41; S, 24.28 Example 22 1,1-dioxide 3-{2-[(2-dimethyla
Minomethylthi-4-thiazolyl)methylthio]
ethylamino}-4-methylamino-1,2,
5-thiadiazole A N-carbophenoxy-N-methylaminoa
Setonitrile Methylaminol hydrochloride in 1 liter of methylene chloride
A suspension of cetontril (100 g; 0.94 mol) on ice
triethylamine (260 ml; 1.88 ml)
700 pheniformic acid in 500 ml of methylene chloride
(155.0 g; 0.99 mol) was added. anti
The reaction mixture was heated to reflux for 18 hours, then evaporated under reduced pressure.
A semi-solid was obtained, which was diluted with 1 liter of diethyl ether.
Mash and strain. Evaporate the liquid under reduced pressure
and the residual oil was vacuum distilled to give the title compound (123
g), bp111~113°/0.25mmHg was obtained; CDCl₃During ~
NMR spectrum (60MHz) gives the following resonances
δ: 7.23 (m, 5H); 4.30 (s, 2H): 3.13 (s,
3H). B (N-carbophenoxy-N-methylamine
c) Thioacetamide N-carbophenoxy-N- in dry DMF 917ml
Methylaminoacetonitrile (131.0g; 0.69mol)
) The solution [manufactured during step A] is
treated with HCl gas until solid, then heated on a steam bath for 20 minutes.
It was hot. The reaction mixture was partially evaporated under reduced pressure.
Remove some of the solvent and then add saturated aqueous NaHCO₃melt
The liquid is made basic and distributed between ether and water.
Ta. Extract the aqueous phase with ether and combine the ether phases.
Washed with water, saturated aqueous NaCl solution and dried.
filtration and evaporation of the solvent to obtain an oil, which was methylated.
Triturate with cyclohexane to obtain the product as a solid.
Ta. Recrystallized from isopropyl alcohol to obtain the title
A compound with mp 101-103° was obtained. Analysis C_TenH₁₂N₂O₂as S Calculated value: C, 53.55; H, 5.40; N, 12.49; S, 14.30 Experimental values: C, 53.65; H, 5.51; N, 12.69; S, 14.41 C 4-chloromethyl-2-(N-carbopheno
xy-N-methylamino)methylthiazole In 6 ml of absolute ethanol (N-carbophenoxy
-N-methylamino)thioacetamide (1.0
g; 4.46 mmol) and dry pyridine (0.36 ml;
4.46 mmol) in absolute ethanol under cooling to a solution of 3
1,3-dichloropropane (0.57g; 4.49ml)
A solution of 100 ml of mol. Add this mixture for 1.5 hours
Heat to reflux for a while, then evaporate under reduced pressure to remove oil residue.
was partitioned between water and ether. aqueous phase
Combine the ether phases, add water and saturated sodium chloride.
Washed with aqueous solution and dried. filter and evaporate
1.02 g of the title compound was obtained as a viscous oil;
TLC [Silica/CH₂Cl₂:CH₃CN (85:15)] is
Rf=0.82 was given. CDCl₃Medium NMR spectrum
(60MHz) gave the following resonance δ: 7.16 (m,
6H); 4.77 (broad s, 2H); 4.60 (s, 2H);
3.07 (Broad s, 3H). D 2-{[2-(N-carbophenoxy-N-
Methylamino) methyl-4-thiazolyl]
Chilthio}ethylamine Sodium methoxylate in 290 ml of absolute ethanol
(26.1 g; 0.48 mol) in a nitrogen stream at 0°
Cysteamine hydrochloride (27.6 g; 0.24 mol) and
218 ml of absolute ethanol was added to the solution. At 0°
After stirring for 1 hour, 4-
Chlorolmethyl-2-(N-carbophenoxy-
N-methylamino)methylthiazole (72.5g;
0.24 mol) was added over 15 minutes. anti
The reaction mixture was stirred at ambient temperature for 18 hours, filtered,
Evaporation under reduced pressure gave an oil, which was mixed with methylene chloride.
distributed between water. Extract the aqueous phase with methylene chloride
Combine the organic phases, wash with water, dry, filter and reduce.
Evaporation under pressure gave the product (68.5 g) as an oil;
This was treated with 23.6 g of fumaric acid in n-propanol.
Salt (47.0g) was obtained by processing. From absolute ethanol
Recrystallized as fumarate, mp145~146°
The compound was obtained. Analysis C₁₅H₁₉N₃O₂S₂・C_FourH_FourO_Fouras Calculated value: C, 50.31: H, 5.11; N, 9.27; S, 14.14 Experimental values: C, 50.02; H, 5.16; N, 9.47; S, 14.22 E 2-[(2-dimethylaminomethyl-4-thi
azolyl)methylthio]ethylamine 2-{[2- in 10 ml of dry tetrahydrofuran
(N-carbophenoxy-N-methylamino)methane
methyl-4-thiazolyl]methylthio}ethylamide
(0.50 g; 1.48 mmol) [manufactured during step D]
Lithium aluminum hydride in a nitrogen stream in solution
(0.17 g; 4.48 mmol) was added to this mixture.
was heated to reflux for 0.5 h. Furthermore, tetrahydrof
10 ml of run was added and heating continued for 3 hours. reaction
H the mixture₂O0.17ml, 15% aqueous NaOH0.17ml and
H₂Treated with 0.51 ml of O, passed through Celite,
Dry. Filter the liquid and evaporate under reduced pressure to remove the oil.
This was dissolved in absolute ethanol and diluted with diethyl ethyl ethyl ether.
and acidified with dry HCl. of the title
Collect the hygroscopic hydrochloride of the compound, 2.5NNaOH
and methylene chloride. water the organic phase
Washed, dried and strained. Evaporate the liquid under reduced pressure
The free base of the title compound as an oil (0.22 g;
0.95 mmol) and heat it in acetonitrile for 30 min.
Combined with oxalic anhydride (0.24 g; 1.90 mmol) in ml.
did. Heat this mixture evaporated from absolute ethanol.
The title compound bis-oxalate, mp168~
Obtained 171°. Analysis C₉H₁₇N₃O_FourS₂・2C₂H₂O_Fouras Calculated value: C, 37.95; H, 5.15; N, 10.21; S, 15.59 Experimental values: C, 37.95; H, 5.04; N, 9.81; S, 15.27 F 1,1-dioxidized 3-{2-[(2-dimethyl
Aminomethyl-4-thiazolyl)methylthio]
ethylamino}-4-methylamino-1,2,
5-thiadiazole 3,4-dimethyl 1,1-dioxide in 80 ml of methanol
Toxi-1,2,5-thiadiazole (0.74g;
4.17 mmol) under cooling (6°) to a suspension of 2-
[(2-dimethylaminomethyl-4-thiazolyl)
Methylthio]ethylamine (0.96 g; 4.17 mmol
) solution [produced during step E] dropwise for 45 minutes.
In addition, 1,1-dioxidized 3-{2-[(2-dimethyl
ruaminomethyl-4-thiazolyl)methylthio〕〕
ethylamino}-4-methoxy-1,2,5-thi
Asiazole, Rf=0.64 [Silica/CH₂Cl₂:
CH₃OH (9:1)] was obtained. Keep the temperature at 6° and
Bubble anhydrous methylamine into the solution for 8 minutes.
Ta. The reaction mixture was evaporated under reduced pressure and the residual oil was siphoned off.
Place on 80g of licagel, methylene chloride-methanol
Chromatographed using gradient elution with
Ta. Combine the appropriate fractions and remove the residual oil with methylene chloride.
-Aluminum oxide using methanol gradient elution
The sample was rechromatographed on 25 g of aluminum. isopro
Recrystallize from pyrualcohol/ether to obtain the title
A compound, mp 144-148° (foaming) was obtained. Analysis C₁₂H₂₀N₆O₂S₃as Calculated value: C, 38.28; H, 5.35; N, 22.32; S, 25.55 Experimental value: C, 37.89; H, 5.43; N, 22.19; S, 25.40 Example 23 1-oxidation 3-{2-[(2-dimethylaminomethyl
methyl-4-thiazolyl)methylthio]ethylua
Mino}-4-methylamino-1,2,5-thia
diazole A N-carbetoxy-N-methylaminoacetate
Nitrile Methylaminoacetoni hydrochloride in 20 ml of methylene chloride
A suspension of tolyl (2.0 g; 18.8 mmol)
Add ethylamine (5.2 ml; 37.6 mmol)
Ta. The resulting suspension was cooled in an ice bath and diluted with methylene chloride.
Ethyl chloroformate (2.14 g; 19.8 mmol in 10 ml)
solution) was added over a period of 0.5 h, then this
The mixture was heated to reflux for 18 hours. Vacuum the reaction mixture
Evaporation under water gave a semi-solid residue, which was dissolved in diethyl
Triturate with ether, filter and evaporate the liquid under reduced pressure.
Compound of the title as lettuce oil, bp96~98°/5.2mmHg
I got something. B (N-carbetoxy-N-methylamino)thi
oacetamide N-Carbetoxy-N-Methi in 175ml dry DMF
Ruaminoacetonitrile (9.8g; 6.9mmol)
(manufactured during step A) and thioacetamide (10.35
g; 13.8 mmol) in a violently exothermic reaction.
treated with hydrogen chloride until
Heated for minutes. Saturate the reaction mixture with NaHCO₃solution
, then extracted with ether, washed with water,
Dry. The ether phase was evaporated under reduced pressure to leave a solid residue.
The distillate was obtained, dissolved in methylene chloride, and washed with water.
Ta. The organic phase was dried, filtered and evaporated under reduced pressure.
The product (2.5g) was obtained. Ethyl acetate-hexane
The title compound, mp91-93°, was obtained by recrystallization from
Ta. Analysis C₆H₁₂N₂O₂as S Calculated value: C, 40.89; H, 6.87; N, 15.96; S, 18.92 Experimental values: C, 40.73; H, 6.85; N, 16.13; S, 18.86 C 2-(N-carbetoxy-N-methylamine
c) Methyl-4-carbetoxythiazole In 180 ml of absolute ethanol (N-carbetoxy)
N-methylamino)thioacetamide (30.7g;
0.17 mol) [produced during step B] to the solution of anhydrous ethanol.
Ethyl bromopyruvate (25.0ml;
0.20 mol) solution was added. Reaction mixture at 17:00
Heat to reflux for a while, then evaporate under reduced pressure and remove the residue.
and water. The organic phase is saturated with water.
Washed with Japanese salt solution, dried, filtered and evaporated under reduced pressure.
to obtain an oil, which was placed on silica gel and eluted.
chroma using diethyl ether as the solvent for
Tograph treated. Titled as oil from appropriate fractions
The compound was obtained; TLC [Silica/CH₂Cl₂:
CH₃CN (85:15)] gave Rf = 0.50. d₆Ji
NMR spectrum in methyl sulfoxide (60M
Hz) gave the following resonance δ: 8.49 (s, 1H);
4.79 (s, 2H); 4.23 (m, 4H); 3.00 (s, 3H);
1.30 (q, 6H). D 2-dimethylaminomethyl-4-hydroxy
Methylthiazole Lithium hydride in 80ml dry tetrahydrofuran
A suspension of aluminum (8.4 g; 0.22 mol) was
Discard 2-(N-) in 160 ml of dry tetrahydrofuran.
Carbethoxy-N-methylamino)methyl-4-
Carbethoxythiazole (20.0g; 0.07mol)
Add the solution [produced during step C] over a period of 1 hour.
Ta. Heat the reaction mixture at reflux temperature for 8 hours.
then cooled and Na₂S.O._Fourand 40% aqueous caustic soda
I disassembled it with li. Filter, dry and reduce this mixture.
Evaporation under pressure gave 4.2 g of the title compound as an oil.
TLC (aluminum oxide/CH₃CN) is Rf
=0.45 was given. CDCl₃Medium NMR spectrum
(60MHz) gave the following resonance δ: 7.17(s,
1H); 4.73 (d, 2H); 3.43 (s, 2H); 3.35 (s,
6H). E 2-[(2-dimethylaminomethyl-4-thi
azolyl)methylthio]ethylamine 2-dimethylaminomethyl-4-hydroxymeth
Tilthiazole [manufactured in step D] is converted into thionyl chloride.
2-dimethylaminomethyl obtained by reacting with
-4-chloromethylthiazole in an equimolar amount of hydrochloric acid
React with cysteamine and 2 equivalents of base (e.g.
22, according to the general operation of step D), thereby
The title compound is obtained. F 1-oxidation 3-{2-[(2-dimethylamino
Methyl-4-thiazolyl)methylthio]ethyl
amino}-4-methylamino-1,2,5-thi
Asiazole 1-oxidized 3,4-dimethoxy-1,2,5-thi
Methanol of Asiazole [Example 4, manufactured during step A]
2-[(2-dimethylamino)]
Nomethyl-4-thiazolyl)methylthio]ethyl
React with amine [Example 22, prepared during step E] to obtain
1-oxidized 3-{2-[(2-dimethylamino
Methyl-4-thiazolyl) methylthioethylamide
No}-4-methoxy-1,2,5-thiadiazole
When treated with methylamine, it thereby
The title compound is obtained. Example 24 1,1-dioxidized 3-amino-4-{2-[(2
-guanidinothiazol-4-yl)methylthi
Ethylamino-1,2,5-thiadiazole
le 1,1-dioxide 3,4-di in 220 ml of methanol
Methoxy-1,2,5-thiadiazole (2.12
Stir well into a cold (0°) suspension of
2- [(2-guanidine) in 30 ml of methanol while
Nothiazol-4-yl)methylthio]ethylua
Min (2.75 g; 11.9 mmol) [dihydrochloric acid 2-[(2
-guanidinothiazol-4-yl)methylthi
Ethylamine (4.0 g; 13.0 mmol)
Neutralize with 2.5N aqueous caustic soda and ethyl acetate.
[obtained by extraction] solution for 1 hour.
It was added over a period of time. While keeping the temperature at 0°,
Bubble anhydrous ammonia into the solution for 6 minutes and remove
Stirring was continued for 0.5 h at room temperature. reaction mixture
was evaporated under reduced pressure, and the residue was dissolved in 120 g of silica gel.
Methylene chloride-methanol gradient elution
Chromatographed using. appropriate fraction
were combined, evaporated and the residue was dissolved in methylene chloride.
on 40 g of silica gel using tanol gradient elution.
Chromatographed. Combine appropriate fractions and
Concentrate in the air and dry in vacuo to obtain the title compound, mp134~
Obtained 139° (foaming); d₆Dimethyl sulfoxide/
D₂The NMR spectrum (100MHz) in O/DCl is as follows:
δ that gave resonance: 7.16 (s, 1H); 3.84 (s,
2H); 3.52 (t, 2H); 2.75 (t, 2H); and approximately 1.2 mo
showed the presence of methanol. Analysis C₉H₁₄N₈O₂S₃・1.2CH₃As OH Calculated value: C, 30.56; H, 4.72; N, 27.95; S, 23.99 Experimental value (1.31% H₂(corrected for O) C, 30.19; H, 4.32; N, 27.91; S, 24.71 Example 25 1,1-dioxide 3-{2-[(2-guanidino
Thiazol-4-yl)methylthio]ethylua
Mino}-4-(2-hydroxyethylamino)
-1,2,5-thiadiazole 1,1-di in 200 ml of dry methanol at 3°
3,4-dimethoxy-1,2,5-thiadias oxide
Good for suspension of sol (2.05 g; 11.5 mmol)
2- [(2-
Guanidinothiazol-4-yl)methylthio]
Ethylamine (from dihydrochloride; 3.5g, 11.5ml)
mol) solution was added dropwise over 30 minutes. to 3°
After 15 minutes, remove ethanolamine in 10 ml of methanol.
(1.03ml, 17.3ml mmol) solution immediately
Add dropwise and stir for 15 minutes. Reaction mixture under reduced pressure
Evaporation yields the product as a brittle foam and
Crystallized from tanol. 2 times from methanol
Crystallizes the title compound, slowly making it from mp=115°
Converts into resin and decomposes from 175°. Analysis C₁₁H₁₈N₈O₃S₃as Calculated value: C, 32.50: H, 4.46; N, 27.57; S, 23.66 Experimental value (3.85% H₂(corrected for O) C, 32.77; H, 4.21; N, 27.90; S, 24.39 Example 26 1,1-dioxide 3-{2-[(5-dimethyla
Minomethyl-2-furyl)methylthio]ethyl
Amino-4-hydrazino-1,2,5-thiazino
Azor 1,1-dioxide 3,4-di in 250 ml of methanol
Methoxy-1,2,5-thiadiazole (2.0
g; 11.2 mmol)) in a cold (ice-water bath) suspension.
2- [(5
-dimethylaminomethyl-2-furyl)methylthi
Dissolution of ethylamine (2.41 g; 11.2 mmol)
The liquid was added dropwise over 45 minutes. 15 minutes at 0°
After stirring, anhydrous hydrazine in 30 ml of dry methanol.
(1.8 g; 56.13 mmol) was added all at once.
and stirring continued for 30 minutes. Vacuum the reaction mixture
Evaporate under and treat the solid residue with chloroform.
Then, the title compound, mp170゜(decomposition) 3.28
I got g. Example 27 1,1-dioxidized 3-methylamino-4-{2-
[(2-pyridyl)methylthio]]ethylamino}
-1,2,5-thiadiazole Dry methanol cooled to 0-5° in an ice water bath 200
1,1-dioxidized 3,4-dimethoxy-1 in mm,
Stir well into the suspension of 2,5-thiadiazole.
2-[(2-pyridyl) in 25ml of dry methanol
Methylthio]ethylamine (dihydrobromide)
et al., 3.5 g; 10.6 mmol) [Belgian patent 779775
Prepared according to the procedure described in 30
It was added dropwise over a period of minutes. Stir this cold solution for 15 minutes
Then add anhydrous methylamine to this solution for 15 minutes.
Made it bubble. Stir the reaction mixture at external temperature for 45 minutes.
Stir, evaporate under reduced pressure and concentrate the residue with methanol.
crystallized. Recrystallized twice from methanol to obtain the title
A compound with a mp of 168-171° was obtained. Analysis C₁₁H₁₅N_FiveO₂S₂as Calculated value: C, 42.15: H, 4.82; N, 22.35; S, 20.46 Experimental values: C, 42.07; H, 4.75; N, 22.28; S, 20.73 Example 28 1,1-dioxide 3-{2-[(4-methyl-1,
2,5-oxadiazol-3-yl)methyl
thio]ethylamino}-4-methylamino-
1,2,5-thiadiazole A 3-hydroxymethyl-4-methylfurazane 3-Methyl-4- in 180ml of tetrahydrofuran
Solution of furazancarboxylic acid (27.0 g; 0.21 mol)
Tetrahydrochloride in a nitrogen stream under stirring (cooled in an ice bath)
1.02M solution of borane in furan (825ml; 0.84mol)
was added dropwise. When addition is complete, remove this mixture.
Stir overnight at room temperature. After 20 hours, hydrogen generation
Add 6NHCl until the reaction stops and vacuum the reaction mixture.
Evaporated down. The residue is mixed between methylene chloride and water.
made basic with potassium carbonate and diluted with methylene chloride.
The combined extracts were dried and evaporated under reduced pressure to obtain the product.
21.0g was obtained. The title compound is obtained by vacuum distillation,
bp99°/1 mmHg was obtained. B 2-[(4-methyl-1,2,5-oxadi
azol-3-yl)methylthio]ethylamide
hmm 3-Hydroxymethy in 60 ml of 48% aqueous hydrobromic acid
Leu-4-methylfuran (2.49 g; 21.8 mmol)
[Production during step A] and 2-aminoethanethio hydrochloride
A solution of mol (2.48 g; 21.8 mmol) was refluxed for 23 hours.
Stir and heat at ambient temperature, then at external temperature for 40 min.
Stir for hours. Remove excess hydrobromic acid under reduced pressure
and dissolve the oil residue in isopropyl alcohol.
and filter the product from the liquid by passing it through celite.
crystallized. Recondensation from isopropyl alcohol
Crystallized as hydrobromide, mp142-143°
The compound was obtained. C 1,1-dioxide 3-{2-[(4-methyl-
1,2,5-oxadiazol-3-yl)methane
Chilthio]ethylamino}-4-methylamino
-1,2,5-thiadiazole 1,1-dioxidation 3,4 by the general procedure of Example 2
- dimethoxy 1,2,5-thiadiazole
amount of 2-[(4-methyl-1,2,5-oxa
diazol-3-yl)methylthio]ethylamide
[produced during step B] and excess methylamine.
Upon further treatment, it yields the title compound.
It will be done. Example 29 1,1-dioxide 3-{2-[(5-methyl-1,
2,4-oxazol-3-yl)methylthi
o]ethylamino}-4-methylamino-1,
2,5-thiadiazole A 2-[(5-methyl-1,2,4-oxadi
azol-3-yl)methylthio]ethylamide
hmm Sodium methylene in 50 ml of methanol at 0°
salt (2.89 g; 53.4 mmol) with stirring.
acid cysteamine (3.03 g; 26.7 mmol) for 10 minutes.
It was added in several portions over time. 70 at 0°
After stirring for a minute, 3-chloroform in 15 ml of methanol was added.
Mumethyl-5-methyl-1,2,4-oxydia
solution of sol (3.54 g; 26.7 mmol) for 15 minutes.
and the reaction mixture was kept at external temperature for 16 h.
Stir for a while. The mixture was filtered, evaporated and
Redissolved in sopropyl alcohol and then filtered.
Evaporation under reduced pressure gave the title compound as a yellow oil.
Obtained. CDCl₃The medium KNMR spectrum (60MHz) is
δ that gave the following resonance: 3.77 (s, 2H); 2.77 (m,
4H); 2.63 (s, 3H). B 1,1-dioxide 3-{2-[(5-methyl-
1,2,4-oxadiazol-3-yl)methane
Chilthio]ethylamino}-4-methylamino
-1,2,5-thiadiazole 1,1-dioxidized 3,4-dimethoxy-1,2,
5-Thiadiazole was prepared by the general procedure of Example 2.
2-[(5-methyl-1,2,5-oxazole
-3-yl)methylthio]ethylamine [Step A
When sequentially treated with methylamine) and methylamine, the
This gives the title compound. Example 30 1,1-dioxide 3-{2-[(2-methyl-1,
3,4-oxadiazol-5-yl)methyl
thio]ethylamino-4-methylamino-1,
2,5-thiadiazole A 2-[(2-methyl-1,3,4-oxadi
azol-5-yl)methylthio]ethylamide
hmm Sodium methylene in 20 ml of methanol at 0°
(1.08 g; 0.02 mol) was added with stirring to a solution of
Cysteamine hydrochloride (1.13 g; 0.01 mol) in air stream
was added. Stir this mixture at 0° for 1 hour.
The resulting suspension was diluted with methanol 15°C at 0°.
2-methyl-5-chloromethyl-1,3,4- in ml
Oxadiazole (1.32g; 0.01mol) [Helv.
Chim. Acta, 55 , 1979 (1972)] dropwise over 25 minutes with stirring. The reaction mixture was stirred at ambient temperature for 45 minutes, concentrated to near dryness, then diluted with methylene chloride, filtered and evaporated under reduced pressure to give the title compound (1.92g) as a yellow oil. CDCl ₃
The medium NMR spectrum (60MHz) gave the following resonances δ: 3.87 (s, 2H); 2.8 (m, 4H); 2.53 (s,
3H). B 1,1-dioxide 3-{2-[(2-methyl-
1,3,4-oxadiazol-5-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole 1,1-dioxidized 3,4-dimethoxy-1,2,
A suspension of 5-thiadiazole was prepared by the general procedure described in Example 2 to prepare an equimolar amount of 2-[(2-
Methyl-1,3,4-oxadiazol-5-yl)methylthio]ethylamino [manufactured during step A]
and excess methylamine, thereby obtaining the title compound. Example 31 1,1-dioxide 3-{2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-methylamino-1,2,5-
Thiadiazole 150ml dry methanol cooled to 0-3° in an ice water bath
1,1-dioxidized 3,4-dimethoxy-1,2,
A solution of 5-thiadiazole (0.77 g; 4.34 mmol) was added with stirring to a solution of 2-[(5-
A solution of methylaminomethyl-2-thienyl)methylthio]ethylamine (1.0 g; 4.34 mmol) [prepared according to the procedure described in Belgian patent 867105] was added dropwise over a period of 35 minutes. After the addition was complete, anhydrous methylamine was bubbled into the solution for 10 minutes and stirring continued for 15 minutes. The reaction mixture was evaporated under reduced pressure and the residue was placed on 50 g of silica gel and chromatographed using acetonitrile-methanol gradient elution. Appropriate fractions were combined to yield 1.0 g of product. Recrystallization from methanol gave the title compound, mp 60.5-66°. Example 32 1-oxidation 3-{2-[(5-dimethylaminomethyl-furyl)methylthio]ethylamino}-
4-ethylamino-1,2,5-thiadiazole 1 in 75 ml of dry methanol cooled to 8° in an ice-water bath
-To a solution of oxidized 3,4-dimethoxy-1,2,5-thiadiazole (2.0 g; 12.3 mmol) was added 2-[(5-
A solution of dimethylaminomethyl-2-furyl)methylthio]ethylamine (2.64 g; 12.3 mmol) was added dropwise over 30 minutes. After 15 minutes, 4.0 ml of ethylamine was added and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was evaporated under reduced pressure,
The residue was placed on 55 g of silica gel and chromatographed using a methylene chloride-methanol gradient elution. Appropriate fractions were combined and evaporated under reduced pressure, and the residue was treated with ether and decanted. Treatment of the residue with fresh ether gave the title compound,
I got mp68~74°. Analysis Calculated for C ₁₄ H ₂₃ N ₅ O ₂ S ₂ : C, 47.04; H, 6.48; N, 19.59; S, 17.94 Experimental: (corrected for 1.24% H ₂ O): C, 46.54; H, 6.33; N, 19.37; S, 17.96 Example 33 1,1-dioxidized 3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-propylamino-1,2,5 ―
Thiadiazole 3,4-dimethoxy-1,1-dioxide in 200 ml of dry methanol cooled to 2° in an ice-water bath.
-To a suspension of thiadiazole (2.0 g; 11.2 mmol) in 25 ml of dry methanol with good stirring
- [(5-dimethylaminomethyl-2-furyl)
A solution of methylthio]ethylamine (2.41 g; 11.2 mmol) was added dropwise over 30 minutes. 15 minutes later,
Add 4.0ml of n-propylamine all at once,
The mixture was stirred at external temperature for 30 minutes. The reaction mixture was evaporated under reduced pressure and the residue was purified on silica gel 55
chromatographed using a methylene chloride-methanol gradient elution. The appropriate fractions were combined, evaporated under reduced pressure, and the syrup was crystallized with ether to yield the title compound, mp164-166°3.7g.
NMR spectrum (100 MHz) in d ₆ dimethyl sulfoxide showed the presence of about 0.9 mol of methanol. Analysis As C ₁₅ H ₂₅ N ₅ O ₃ S ₂・0.9CH ₄ O Calculated value: C, 45.86; H, 6.92; N, 16.82; S, 15.40 Experimental value: C, 45.60; H, 6.93; N, 17.03; S, 15.47 Example 34 1-oxidized 3-amino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]
Ethylamino}-1,2,5-thiadiazole Add a well-stirred solution of 1-3,4-dimethoxy-1,2,5-thiadiazole (2.5 g; 15.4 mmol) in 75 ml of methanol cooled to 8° in an ice-water bath. A solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine (3.3 g; 15.4 mmol) in 25 ml of methanol was added dropwise over a period of 30 minutes. After 1.5 hours, anhydrous ammonia was bubbled into the solution for 8 minutes and the mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was evaporated under reduced pressure and the residue was placed on 60 g of silica gel.
Chromatographed using a methylene chloride-methanol gradient elution. Appropriate fractions were combined, evaporated and the product recrystallized from acetonitrile. Recrystallization from isopropyl alcohol gave 2.59 g of the title compound, mp139-142°. Analysis C ₁₂ H ₁₉ N ₅ O ₂ S As ₂ Calculated value: C, 43.75; H, 5.81; N, 21.26; S, 19.46 Experimental value: C, 43.71; H, 6.05; N, 21.32; S, 19.51 Example 35 1,1-dioxidized 3-amino-4-{2-[(5
-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole 1,1-dioxidized 3,4-dimethoxy-1,2, in 200 ml of dry methanol cooled to 5° in an ice-water bath. 5
-To a suspension of thiadiazole (2.08 g; 11.8 mmol) in 50 ml of dry methanol with good stirring
- [(5-dimethylaminomethyl-2-furyl)
A solution of methylthio]ethylamine (2.5 g; 11.7 mmol) was added dropwise over 45 minutes. 30 minutes later,
Anhydrous ammonia was bubbled into the solution for 10 minutes and the mixture was stirred at ambient temperature for 8 hours.
The reaction mixture was evaporated under reduced pressure and the residue was placed on 200 g of silica gel and chromatographed using a methylene chloride-methanol gradient elution. Appropriate fractions were combined and evaporated to yield 3.6 g of product.
Recrystallization from methanol ether gave the title compound, mp 156-158°. Analysis C ₁₂ H ₁₉ N ₅ O ₃ S As ₂ Calculated value: C, 41.72; H, 5.54; N, 20.28; S, 18.56 Experimental value: C, 41.50; H, 5.52; N, 20.33; S, 18.74 Example 36 1-oxidation 3-amino-4-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxidation 3,4-dimethoxy-1, in 150 ml of methanol 2,5-thiadiazole (3.24g; 20.0
2-[(guanidinothiazole-) in 50 ml of methanol with good stirring.
A solution of 4-yl)methylthio]ethylamine (from the dihydrochloride, 6.08 g; 20.0 mmol) was added dropwise over a period of 45 minutes. After stirring for 1.5 hours at 5-10°, anhydrous ammonia was bubbled into the solution for 10 minutes and stirring continued for 18 hours at ambient temperature. The reaction mixture was evaporated under reduced pressure and the residue was purified with silica gel 65.
chromatographed using a methylene chloride-methanol gradient elution. The appropriate fractions were combined and evaporated to give the product 4.16 from methanol.
I got g. Recrystallization from methanol gave the title compound, mp 167-170° (decomposed). Analysis C ₉ H ₁₄ N ₈ OS Calculated as ₃ : C, 31.20: H, 4.07; N, 32.35; S, 27.76 Experimental: (corrected for 0.48% _H2O ): C, 30.39; H, 3.97; N, 32.25; S, 27.91 This crude product was recrystallized from 95% ethanol to give the title compound as a monohydrate, mp 136-138° (decomposed). Analysis C ₉ H ₁₄ N ₈ OS ₃・H ₂ O Calculated value: C, 29.66; H, 4.42; N, 30.75; S, 26.39 Experimental value: C, 29.92; H, 4.42; N, 30.84; S, 26.58 A sample of this product as the free base was suspended in 95% ethanol, treated with 1 equivalent of aqueous 6.0N hydrochloric acid, and filtered to give the hydrochloride salt, mp 200-201° (dec). Analysis C ₉ H ₁₅ ClN ₈ OS Calculated as ₃ : C, 28.23; H, 3.95; N, 29.26; Cl, 9.26 Experimental values: (corrected for 1.02% H ₂ O): C, 28.26; H, 3.83; N, 29.41; Cl, 9.53 Example 37 1,1-dioxidized 3-benzylamino-4-{2
- [(5-dimethylaminomethyl-2-furyl)
Methylthio]ethylamino-1,2,5-thiadiazole Dry methanol cooled to 1-3° in an ice-water bath 200
1,1-dioxidized 3,4-dimethoxy-1 in ml,
2,5-thiadiazole (2.0 g; 11.2 mmol)
A solution of 2-[(5
A solution of -dimethylaminomethyl-2-furyl)methylthio]ethylamine (2.4 g; 11.2 mmol) was added dropwise over a period of 35 minutes. 15 at 1~3°
After min, benzylamine (1.83 ml; 16.8 mmol)
was added and the solution was stirred at ambient temperature for 1 hour. The reaction mixture was evaporated under reduced pressure and the residue was placed on 50 g of silica gel and chromatographed using a methylene chloride-methanol gradient elution.
Appropriate fractions were combined to yield 4.1 g of product. Recrystallization from aqueous methanol and then methanol gave the title compound, _mp152 ° (decomposed);
It showed the presence of 1.0 mol of methanol. Analysis As C ₁₉ H ₂₅ N ₅ O ₃ S ₂・CH ₄ O Calculated value: C, 51.37; H, 6.25; N, 14.98 Experimental value: C, 51.51; H, 6.05; N, 14.78 Example 38 1,1- 3-{2-[(3-{dimethylaminomethyl}phenyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole in 200 ml of dry methanol cooled to 2° in an ice-water bath. 1-dioxidized 3,4-dimethoxy-1,2,5
-To a suspension of thiadiazole (2.0 g; 11.2 mmol) in 25 ml of dry methanol with good stirring
- [(3-{dimethylaminomethyl}phenyl)
A solution of methylthio]ethylamine (2.51 g; 11.2 mmol) [prepared according to the procedure described in Belgian patent 867106] was added dropwise over a period of 30 minutes. After 15 minutes at 2-5 degrees, anhydrous methylamine was bubbled into the solution for 10 minutes, then the solution was stirred at ambient temperature for 30 minutes. The reaction mixture was evaporated under reduced pressure and the residue was placed on 60 g of silica gel.
Chromatographed using a methylene chloride-methanol gradient elution. Appropriate fractions were combined to yield 2.96 g of product. Recrystallization from acetonitrile and then methanol gave the title compound, mp 152-158°; NMR spectrum in _d6 dimethyl sulfoxide showed the presence of about 0.6 moles of methanol. Analysis As C ₁₅ H ₂₃ N ₅ O ₂ S ₂・0.6CH ₄ O Calculated value: C, 48.20; H, 6.59; N, 18.02; S, 16.49 Experimental value: C, 47.99; H, 6.78; N, 17.81; S, 16.09 Example 39 1-oxidized 3-amino-4-{2-[(3-{dimethylaminomethyl}phenyl)methylthio]
ethylamino}-1,2,5-thiadiazole 1 in 100 ml of dry methanol cooled to 5° in an ice bath
-To a solution of oxidized 3,4-dimethoxy-1,2,5-thiadiazole (2.0 g; 12.3 mmol) was added 2-[(3-
{dimethylaminomethyl}phenyl)methylthio]
A solution of ethylamine (2.77 g; 12.3 mmol)
It was added dropwise over a period of 45 minutes. When the addition was complete, the solution was stirred at ambient temperature for 1.5 hours, then cooled to 5° and anhydrous ammonia was bubbled into the solution for 8 minutes. After stirring for 16 hours at ambient temperature, the reaction mixture was evaporated under reduced pressure and the residue was placed on 55 g of silica gel and chromatographed using a methylene chloride-methanol gradient elution. Appropriate fractions were combined to yield 3.0 g of product from acetonitrile.
Recrystallize from acetone to obtain the title compound, mp122~
Obtained 125°. Analysis C ₁₄ H ₂₁ N ₅ As OS ₂ Calculated value: C, 49.53; H, 6.23; N, 20.63; S, 18.89 Experimental value: C, 49.18; H, 6.08; N, 20.93; S, 19.25 Example 40 1- Oxidation 3-{2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole 1 in 150 ml of anhydrous methanol cooled to 3° in an ice bath
-To a solution of 3,4-dimethoxy-1,2,5-thiadiazole oxide (1.06 g; 6.5 mmol) in 25 ml of dry methanol with stirring was added 2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamine (1.5 g; 6.5 mmol) was added over a period of 45 minutes. After 15 minutes at 3°, anhydrous methylamine was bubbled into the solution for 5 minutes and the solution was stirred for 15 minutes. After standing overnight at ambient temperature, the reaction mixture was evaporated under reduced pressure and the residue was placed on 75 g of silica gel and chromatographed using acetonitrile-methanol gradient elution.
The appropriate fractions were combined to give a crystalline product from acetonitrile. Recrystallization from acetonitrile gave the title compound, mp 98.5-102°. Analysis C ₁₃ H ₂₁ N ₅ As OS ₃ Calculated value: C, 43.42; H, 5.89; N, 19.48; S, 26.76 Experimental value: C, 43.70; H, 5.58; N, 19.71; S, 26.79 Example 41 1. 1-dioxidized 3-amino-4-{4-(5-
dimethylaminomethyl-2-furyl)butylamino}-1,2,5-thiadiazole 1500 ml of dry methanol cooled to 0-3° in an ice bath
1,1-dioxidized 3,4-dimethoxy-1,2,
A suspension of 5-thiadiazole (1.46 g; 8.2 mmol) was added to a suspension of 4-(5-dimethylaminomethyl-2-furyl) in 25 ml of dry methanol with good stirring.
A solution of butylamine (1.61 g; 8.2 mmol)
It was added dropwise over a period of 35 minutes. After 15 minutes, bubble anhydrous ammonia into the solution for 5 minutes;
Stir for 30 minutes. The reaction mixture was evaporated under reduced pressure,
The residue was placed on 60 g of silica gel and chromatographed using acetonitrile-methanol gradient elution. Appropriate fractions were combined and evaporated to yield 1.68 g of product. Crystallization from acetonitrile gave the title compound, mp 154-156° (resolved). Analysis as C ₁₃ H ₂₁ N ₅ O ₃ S Calculated value: C, 47.69; H, 6.47; N, 21.39; S, 9.80 Experimental value: C, 47.73; H, 6.28; N, 21.43; S, 9.84 Example 42 1 ,1-dioxidized 3-amino-4-{2-[(2
-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-1,2,5-thiadiazole 1,1-dioxidized 3,4-methoxy-1,2,5-thiadiazole ( 0.69 g; 3.89 mmol) in 20 ml of dry methanol.
A solution of 4-thiazolyl)methylthio]ethylamine (0.9 g; 3.89 mmol) was added dropwise over 40 minutes, anhydrous ammonia was bubbled into the solution for 8 minutes, and the solution was then stirred at ambient temperature for 18 hours. The reaction mixture was evaporated under reduced pressure and the residue was placed on 150 g of silica gel and chromatographed using an acetonitrile-methanol gradient elution. The appropriate fractions were combined and evaporated to give the product 0.66
I got g. This form was dissolved in 2-propanol and evaporated to dryness to give the title compound, mp 60-65°; d NMR spectrum in _dimethyl sulfoxide (100 MHz) showed the presence of about 0.16 moles of 2-propanol. Ta. Analysis As C ₁₁ H ₁₈ N ₆ S ₃ O ₂・C ₃ H ₈ O Calculated value: C, 37.02; H, 5.21; N, 22.62; S, 25.89 Experimental value (corrected as 2.79% H ₂ O): C , 36.75; H, 5.13; N, 21.75; S, 25.03 Example 43 1,1-dioxidized 3-{2-[(2-guanidinothiazol-5-yl)methylthio]ethylamino-4-methylamino-1, 2,5-thiadiazole (A) Ethyl 2-guanidino-5-thiazolecarboxylate hydrochloride A solution of amidinothiourea (117 g; 0.99 mol) and ethyl chloro-α-formylacetate (150 g; 1.0 mol) in 3.5 liters of absolute ethanol is removed. Stir at room temperature for 18 hours, then heat to reflux for 1 hour. At this time, additional ethyl chloro-α-formylacetate (20.0 g; 0.13 mol) was added, and after 1 hour, another 20.0 g of chloro-α-formylacetic acid was added. After further heating under reflux for 2 hours, the reaction mixture was evaporated under reduced pressure, and the residue was triturated with 1.5 liters of acetone and filtered to obtain 103 g of product. 2
-Recrystallized from propanol to give the title compound,
I got mp204~206°. Analysis as C ₇ H ₁₁ ClN ₄ O ₂ S Calculated value: C, 33.53; H, 4.43; N, 22.35; Cl, 14.14; S, 12.79 Experimental value: C, 33.38; H, 4.40; N, 22.54; Cl, 13.97; S, 12.92 (B) 2-guanidino-5-hydroxymethylthiazole A suspension of lithium aluminum hydride (0.46 g; 12.1 mmol) in 25 ml of tetrahydrofuran was diluted with 2-guanidino-hydrochloric acid under cooling (ice-water bath).
Ethyl 5-thiazolecarboxylate (1.0g;
3.99 mmol) [manufactured during step A] was added.
The reaction mixture was then heated to reflux for 2 hours, cooled,
0.46ml _H2O , 0.46 15% NaOH and 1.38ml
of _H2O and filtered. Dry the filtrate;
Evaporation under reduced pressure gave 0.61 g of product. Recrystallization from acetonitrile yields the title compound, mp168
~170° was obtained. Analysis C ₅ H ₈ N ₄ As OS Calculated value: C, 34.87; H, 4.68; N, 32.54; S, 18.62 Experimental value: C, 34.55; H, 4.52; N, 32.63; S, 18.54 (C) 2- [(2-guanidinothiazol-5-yl)methylth]ethylamine Cysteamine hydrochloride (10.6 g; 9.3 mmol)
and 2-guanidino-5-hydroxymethylthiazole (16.0 g; 9.3 mmol) [prepared in step B] were dissolved in 80 ml of concentrated hydrochloric acid, and the solution was stirred at ambient temperature for 1 hour and then heated under reflux for 3 hours. The reaction mixture was cooled, made basic (PH 11) with 40% aqueous NaOH, and filtered to yield 15 g of product. Recrystallization from acetonitrile gave the title compound, mp 150-153°. Analysis C ₇ H ₁₃ N ₅ S As ₂ Calculated value: C, 36.34; H, 5.66; N, 30.27; S, 27.72 Experimental value: C, 36.29; H, 5.70; N, 30.40; S, 27.64 (D) 1 , 1-dioxidized 3-{2-[(2-guanidinothiazol-5-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole in 160 ml of methanol cooled to 8° in an ice-water bath. 1,
1-dioxidized 3,4-dimethoxy-1,2,5-
A suspension of thiadiazole (1.54 g; 8.64 mmol) was dissolved in 60 ml of methanol with good stirring.
[(2-guanidinothiazol-5-yl)methylthio]ethylamine (2.0 g; 8.64 mmol)
The solution [prepared in step C] was added dropwise over a period of 40 minutes. Methylamine was bubbled into this solution for 8 minutes while maintaining the temperature at 8°. After stirring for 18 hours at ambient temperature, the reaction mixture was evaporated under reduced pressure and the residue was placed on 175 g of silica gel and chromatographed using an acetonitrile-methanol gradient elution. Appropriate fractions were combined to yield 1.3 g of product. Recrystallization from methanol yields the title compound,
mp225-226° (decomposition) was obtained. Analysis C ₁₀ H ₁₆ N ₈ O ₂ S As ₃ Calculated value: C, 31.90; H, 4.28; N, 29.76; S, 25.55 Experimental value: C, 32.07; H, 4.14; N, 29.91; S, 25.60 Example 44 1-oxidation 3-amino-4-{2-[(2-guanidinothiazol-5-yl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxidation 3, in 200 ml of methanol cooled to 8°
To a solution of 4-dimethoxy-1,2,5-thiadiazole (2.1 g; 13.0 mmol) in 70 ml of methanol was added 2-[(2-guanidinothiazol-5-yl)methylthio]ethylamine (3.0 g; 13.0 mmol) with good stirring. ) [Example 43, production during step C]
solution was added dropwise over 40 minutes, then anhydrous ammonia was bubbled into the solution for 8 minutes. After stirring for 18 hours at external temperature, the reaction mixture was evaporated under reduced pressure, the residue placed on 225 g of silica gel and chromatographed using acetomethyl-methanol gradient elution. Appropriate fractions were combined to yield 3.6 g of the title compound, mp 85-132°; NMR spectrum in _d6 dimethyl sulfoxide (100 MHz) showed approx.
It showed the presence of 0.3 moles of acetonitrile. Analysis C ₉ H ₁₄ N ₈ OS ₃・0.3C ₂ H ₃ N Calculated value: C, 32.24; H, 4.22; N, 32.41; S, 26.71 Experimental value (corrected as 1.84% H ₂ O): C, 32.63; H, 4.33; N, 32.55; S, 26.62 Example 45 1,1-dioxidized 3-cyclopropylamino-4
-{2-[(5-dimethylaminomethyl-2-
furyl) methylthio]ethylamino}-1,
2,5-Thiadiazole Example 8 except that the 2-propynylamine used in Example 8 was replaced with an equimolar amount of cyclopropylamine and the product was crystallized from methanol.
The general operations were repeated. Recrystallize from isopropyl alcohol to obtain 3.5 g of the title compound, mp194~
195° (decomposition) was obtained; d ₆ in dimethyl sulfoxide
NMR spectrum (100MHz) showed the presence of approximately 1.0 moles of isopropyl alcohol. Analysis As C ₁₅ H ₂₃ N ₅ O ₃ S ₂・C ₃ H ₈ O Calculated value: C, 48.55; H, 7.01; N, 15.72; Experimental value: C, 48.36; H, 6.95; N, 14.87; Example 46 1,1-dioxidized 3-cyclopropylmethylamino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino-
1,2,5-Thiadiazole Replace the 2-propynylamine used in Example 8 with an equimolar amount of cyclopropylmethylamine,
The general procedure of Example 8 was repeated except that the product was crystallized from methanol. Recrystallized from methanol to yield 1.6 g of the title compound, mp 86-89°C.
(decomposition) was obtained; d ₆ in dimethyl sulfoxide
NMR spectrum (100MHz) showed the presence of about 1.25 moles of methanol. Analysis As C ₁₆ H ₂₅ N ₅ O ₃ S ₂・1.25CH ₄ O Calculated value: C, 47.13; H, 6.88; N, 15.93; Experimental value: C, 47.40; H, 6.49; N, 15.77; Example 47 1 ,1-dioxidized 3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-morpholino-1,2,5-thiadiazole The dimethylamine used in Example 19, etc. The general procedure of Example 19 was repeated except that molar amounts of morpholine were substituted. After column chromatography, the product was crystallized from isopropyl alcohol. Dilute this mixture with Skellisolve B,
Filtration gave the title compound, mp 122-127°. Analysis Calculated as C ₁₆ H ₂₅ N ₅ O ₄ S ₂ Calculated: C, 46.24; H, 6.06; N, 16.86 Experimental (corrected as 0.61% H ₂ O): C, 45.82; H, 6.06; N, 16.62 Example 48 1,1-Dioxide 3-{2-[(5-dimethylaminomethyl-2furyl)methylthio]ethylamino}-4-(2-methoxyethylamino)-
1,2,5-Thiadiazole The general procedure of Example 8 was repeated, except that the 2-propynylamine used in Example 8 was replaced with an equimolar amount of 2-methoxyethylamine. After column chromatography, the residue was treated with isopropyl alcohol, evaporated to near dryness and cooled to yield 3.79 g of product. Recrystallization from isopropyl alcohol yields the title compound, mp56
~58° was obtained; d ₆ NMR spectrum in dimethyl sulfoxide (100 MHz) showed the presence of about 0.6 moles of isopropyl alcohol. Analysis As C ₁₅ H ₂₅ N ₅ O ₄ S ₂・0.6C ₃ H ₈ O Calculated value: C, 45.90; H, 6.83; N, 15.93 Experimental value: (corrected as 0.74% H ₂ O): C, 45.50 ;H, 6.72;N, 15.63 Example 49 1,1-dioxidized 3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-pyrrolidino-1,2,5-thiadiazole The general procedure of Example 19 was repeated, except that the dimethylamine used in Example 19 was replaced with an equimolar amount of pyrrolidine. The crude reaction mixture was evaporated under reduced pressure, treated with isopropyl alcohol and filtered to yield 3.9 g of the title product, mp 151-152°. Analysis As C ₁₆ H ₂₅ N ₅ O ₃ S ₂ Calculated value: C, 48.09; H, 6.31; N, 17.53 Experimental value: C, 48.00; H, 6.10; N, 17.71 Example 50 1,1-dioxidation 3- {2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-piperidino-1,2,5-thiadiazole The dimethylamine used in Example 19 was replaced with an equimolar amount of piperidine. Other than that, the general operations of Example 19 were repeated. 3.8 g of product were obtained by chromatography. Recrystallization from hydrothermal ethanol gave the title compound, mp 106-108°. Analysis As C ₁₈ H ₂₇ N ₅ O ₃ S ₂ Calculated value: C, 49.37; H, 6.58; N, 16.94 Experimental value: (corrected as 0.2% H ₂ O): C, 49.17; H, 6.52; N, 17.14 Example 51 1,1-dioxidized 3-butylamino-4-{2-
[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino-1,2,5-thiadiazole Example 8 except that the 2-propynylamine used in Example 8 was replaced with an equimolar amount of butylamine. Repeated general operations. The crude product was chromatographed three times and heated to dryness under high vacuum for 3.5 hours to give the title compound 1.81 as a somewhat rubbery foam.
I got g. Analysis as C ₁₆ H ₂₇ N ₅ O ₃ S ₂ Calculated value: C, 47.86; H, 6.78; N, 17.44 Experimental value: (corrected as 1.34% H ₂ O): C, 47.60; H, 6.81; N, 17.81 Example 52 1,1-dioxide 3{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-[(2-pyridine)methylamino]
-1,2,5-Thiadiazole The general procedure of Example 8 was repeated, except that the 2-propynylamine used in Example 8 was replaced by an equimolar amount of 2-aminomethylpyridine. Appropriate fractions from column chromatography were combined to yield 3.9 g of product. Recrystallization twice from isopropyl alcohol gave the title compound, mp 43-45°. The sample was recrystallized from absolute ethanol and the solid was heated to 60° under vacuum for 6 hours to obtain a melt. This melt was dissolved in hot isopropyl alcohol, collected by filtration at ambient temperature, and dried under high vacuum to give the title compound, mp _45-47 °;
It showed the presence of 1.25 moles of isopropyl alcohol. Analysis As C ₁₈ H ₂₄ N ₆ O ₃ S ₂・1.25C ₃ H ₈ O Calculated value: C, 51.05; H, 6.70; N, 16.42 Experimental value: (corrected as 0.58% H ₂ O): C, 51.08 ;H, 6.32;N, 16.03 Example 53 1,1-dioxidized 3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-hydroxylamino-1,2,
5-Thiadiazole The general procedure of Example 8 was repeated, except that the 2-propynylamine used in Example 8 was replaced with an equimolar amount of hydroxylamine. The crude reaction mixture, in which the product was precipitated as an oil, was heated to reflux until all the product crystallized, then filtered and dried to yield 2.59 g of the title compound, mp 203-205°. Analysis C ₁₂ H ₁₉ N ₅ O ₄ S as ₂ Calculated value: C, 39.87; H, 5.30; N, 19.38; S, 17.74 Experimental value: (corrected as 1.18% H ₂ O): C, 39.53; H, 5.04; N, 19.61; S, 17.62 Example 54 1,1-dioxidized 3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-dodecylamino-1,2,5 ―
Thiadiazole 1,1-dioxidized 3,4-dimethoxy-1,2,5-thiadiazole (2.0
A solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine (2.41 g; 11.2 mmol) in 25 ml of methanol was added dropwise with good stirring to a cold suspension of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine (2.41 g; 11.2 mmol). 2
After stirring for 15 minutes at ~5°, add 25 ml of methanol.
A solution of medium dodecylamine (4.15 g; 22.4 mmol) was added all at once and stirring continued at ambient temperature for 18 hours. The reaction mixture was filtered, evaporated under reduced pressure and the residue was placed on 60 g of silica gel and chromatographed using a methylene chloride-methanol gradient elution. Combine appropriate fractions, evaporate,
The residue was rechromatographed on 60 g of silica gel using acetonitrile-methanol gradient elution. Appropriate fractions from the second chromatography were combined and concentrated under reduced pressure, and the crystallized product was collected by filtration and dried to yield 2.13 g of the title compound.
Obtained mp136-139°. Analysis C ₂₄ H ₄₅ N ₅ O ₃ S As ₂ Calculated value: C, 55.89; H, 8.79; N, 13.58; S, 12.43 Experimental value: C, 56.16; H, 8.57; N, 13.38; S, 12.61 Example 55 1,1-dioxidized 3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-methoxyamino-1,2,5-
Thiadiazole Except for replacing the 2-propynylamine used in Example 8 with an equimolar amount of methoxyamine,
The general procedure of Example 8 was repeated. The reaction mixture was stirred at ambient temperature overnight, during which time a crystalline precipitate formed. The solution was cooled, filtered, and the collected solid was dried to yield 3.8 g of the title compound, mp 224-226 (dec). Analysis C ₁₃ H ₂₁ N ₅ O ₄ S as ₂ Calculated value: C, 41.59; H, 5.64; N, 18.65; S, 17.08 Experimental value (corrected as 0.79% H ₂ O): C,
41.25; H, 5.54; N, 18.50; S, 17.16 Example 56 1,1-dioxidized 3-{2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-propylamino-1 ,2,5
-Thiadiazole The general procedure of Example 31 was repeated, except that the methylamino used in Example 31 was replaced by an equimolar amount of propylamine. Chromatography yielded 3.5 g of crystalline product. Recrystallized from acetonitrile to obtain the title compound, mp194-196° (decomposition)
I got it. Analysis As C ₁₅ H ₂₅ N ₅ O ₂ S ₃ Calculated value: C, 44.64; H, 6.24; N, 17.35; S, 23.84 Experimental value: C, 44.66; H, 6.02; N, 17.88; S, 23.87 Example 57 1-oxidation 3-amino-4-{2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole 200 ml methanol cooled to 3° in an ice-water bath 1-oxidation 3 ,4-dimethoxy-1,2,5-thiadiazole in 25 ml of methanol with stirring.
A solution of -dimethylaminomethyl-2-thienyl)methylthio]ethylamine (2.84 g; 12.3 mmol) was added dropwise over a period of 35 minutes. After stirring for 15 minutes,
Anhydrous ammonia was bubbled into this solution for 5 minutes. The reaction mixture was evaporated under reduced pressure and the residue was placed on 60 g of silica gel and chromatographed using a methylene chloride-methanol gradient elution. Appropriate fractions were combined to yield 1.73 g of product. Recrystallization from acetonitrile yields the title compound,
mp149-152° (decomposition) was obtained. Example 58 1,1-Dioxide 3-{2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-[(3-pyridyl)methylamino)-1,2,5-thiadiazole The general procedure of Example 31 was repeated, except that the methylamine used in Example 31 was replaced with an equimolar amount of 3-aminomethylpyridine. 3.10 g of the title compound was obtained as an oil from appropriate fractions of column chromatography. This product was dissolved in excess 5% HCl.
Dissolved in solution, evaporated and then triturated with isopropyl alcohol to obtain a solid product. Recrystallized from 95% aqueous ethanol to dihydrochloride, mp143~
The title compound was obtained as 146.5°. Analysis as C ₁₈ H ₂₆ Cl ₂ N ₆ O ₂ S ₃ Calculated: C, 41.13; H, 4.99; N, 15.99; S, 18.30 Experimental: (corrected as 2.04% H ₂ O): C, 41.25; H, 4.90; N, 16.18; S, 18.52 Example 59 1,1-dioxidized 3-amino-4-{2-[(5
-dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole 1 in 200 ml of methanol cooled to 3° in an ice-water bath.
To a solution of 1-dioxidized 3,4-dimethoxy-1,2,5-thiadiazole (1.55 g; 8.68 mmol) in 25 ml of methanol was added 2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamine ( 2.0 g, 8.68 mmol) was added dropwise over 35 minutes. After stirring for 15 minutes, anhydrous ammonia was bubbled through the solution for 10 minutes. The reaction mixture was evaporated under reduced pressure to yield 3.3 g of the title compound. The NMR spectrum (100MHz) in _d6 dimethyl sulfoxide gave the following resonance δ: 6.88 (d,
1H); 6.78 (d, 1H); 4.03 (s, 2H); 3.61 (s,
2H); 3.54 (t, 2H); 2.74 (t, 2H); 2.22 (s,
6H); it also showed the presence of about 2/3 mole methanol. Example 60 1,1-dioxidized 3-benzylamino-4-{2
-[(5-dimethylaminomethyl-2-thienyl)methylthio]]ethylamino}-1,2,
5-Thiadiazole The general procedure of Example 31 was repeated, except that the methylamine used in Example 31 was replaced with an equimolar amount of benzylamine. The reaction mixture was evaporated under reduced pressure to obtain the product. Recrystallized from methanol,
Charcoal treatment yielded 2.63 g of the title compound, mp 203-205.5° (decomposition). Analysis As C ₁₉ H ₂₅ N ₅ O ₂ S ₃ Calculated value: C, 50.53; H, 5.58; N, 15.51; S, 21.30 Experimental value: C, 50.79; H, 5.34; N, 15.78; S, 20.94 Example 61 1,1-dioxide 3-[3-(3-dimethylaminomethylephenoxy)propylamine]-4-
Methylamino-1,2,5-thiadiazole 1 in 250 ml of methanol cooled to 0° in an ice-water bath
A suspension of 1-dioxidized 3,4-dimethoxy-1,2,5-thiadiazole (2.5 g; 14.0 mmol) was added with 3-[3-(dimethylaminomethyl)phenoxy]propylamine ( A solution of 2.73 g; 14.0 mmol) (prepared according to the procedure described in Belgian patent 867106) was added dropwise over a period of 60 minutes. After stirring for 20 minutes, anhydrous methylamine was bubbled into the solution for 10 minutes. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in 5 g of silica gel.
and chromatographed using a methylene chloride-methanol gradient elution. Appropriate fractions were combined, evaporated, then dissolved in n-propanol and treated with 1 equivalent of HCl to give the product as the hydrochloride salt. hydrochloride by recrystallization from aqueous ethanol,
The title compound was obtained as mp 140-145°. Analysis Calculated as C ₁₅ H ₂₄ N ₅ O ₃ S: C, 46.20; H, 6.20; N, 17.96; S, 8.38; Cl, 9.05 Experimental value: (corrected as 3.79% H ₂ O): C, 46.21 ; H, 6.06; N, 18.24; S, 8.38; Cl, 9.05 Example 62 1,1-dioxide 3-{2-[(2-dimethylaminomethylthiazol-5-yl)methylthio]ethylamino}-4- methylamino-1,
2,5-thiadiazole A 5-carbetoxy-2-(N-carboxenoxy-N-methylamino)methylthiazole (N-carbophenoxy-N-methylamino)
1,2 thioacetamide (46.7 g; 0.21 mol)
The mixture was combined with ethyl formylchloroacetate (30.0 g; 0.20 mol) in 270 ml of dichloroethane and heated under reflux for 2 hours. Additional amount of α-formyl 700 ethyl acetate (3.0 g; 0.02 mole) was added and heating continued for 1.5 hours. Cool the reaction mixture with 5% aqueous soda carbonate.
Extracted twice with 300 ml each, then washed twice with 300 ml each of water and dried over Na ₂ SO ₄ . Evaporation gave the product as an oil that slowly crystallized.
Recrystallize from 2-propanol to obtain the title compound 26
g, mp 81-83° were obtained. Analysis As C ₁₅ H ₁₆ N ₂ O ₄ S Calculated value: C, 56.24; H, 5.03; N, 8.74; S, 10.01 Experimental value: C, 56.48; H, 4.97; N, 8.54; S, 10.17 B 2- Hydroxymethyl-5-dimethylaminomethylthiazole Cooled (5°) lithium aluminum hydride (6.12 g; 0.16 mol) in 544 ml of dry tetrahydrofuran
5-carbethoxy-2-(N-carbophenoxy-N-methylamino)methylthiazole (19.8 g; 0.62 mol) [prepared in step A] was added to the suspension with stirring. The reaction mixture was heated to reflux for 0.5 h, then cooled to room temperature, decomposed, poured through Celite, and evaporated under reduced pressure. Residue 3NHCl180
ml and extracted with ether. The aqueous phase was adjusted to pH 8 and extracted with methylene chloride. The organic phase was dried, concentrated and evaporated under vacuum to yield the title compound 6.0.
g was obtained as an oil. NMR spectra (60 MHz) in CDCl ₃ gave the following resonance δ: 7.50 (s,
1H); 4.85 (s, 2H); 4.15 (s, 1H); 3.75 (s,
2H); 2.35 (s, 6H). C 2-chloromethyl-5-dimethylaminomethylthiazole hydrochloride 5-hydroxymethyl in 300ml of methylene chloride
To a cold (ice-water bath) solution of 2-dimethylaminothiazole (8.9 g; 52.0 mmol) [prepared in Step B] was added dropwise thionyl chloride (27.4 g; 0.16 mole).
The mixture was heated to reflux for 2 hours, then cooled and evaporated under reduced pressure to yield 12.3 g of product. Crystallization from acetonetrile yields the title compound, mp143~
Obtained 144°. Analysis As C ₁₁ H ₁₂ Cl ₂ N ₂ S Calculated values: C, 37.01; H, 5.32; N, 12.33; Cl, 31.63 Experimental values: (corrected as 0.91% H ₂ O): C, 36.88; H, 5.11; N, 12.14; Cl, 31.65 D 2-[(2-dimethylaminomethylthiazol-5-yl)methylthio]]ethylamine Cysteamine hydrochloride (0.2 g; 1.76 mmol) and 5-chloromethyl-2-dimethylaminomethylthiazole hydrochloride ( 0.4g; 1.76 mmol) [Step C
2.5 ml of concentrated hydrochloric acid, and this solution was
Heated at an oil bath temperature of 100°. After 2 hours, the mixture was evaporated under reduced pressure and the residue was made basic with 40% aqueous caustic soda solution. The aqueous phase was extracted with methyl acetate and the organic phase was dried, filtered and evaporated to give 0.3 g of the title compound as an oil. CDCl ₃ medium
NMR spectrum (60MHz) gave the following resonances δ: 7.50 (s, 1H); 3.95 (s, 2H); 3.76 (s,
2H); 2.85 (m, 4H); 2.40 (s, 6H); 1.85 (s,
2H). E 1,1-dioxidized 3-{2-[(2-dimethylaminomethylthiazol-5-yl)methylthio]ethylamino}-4-methylamino-1,
2,5-Thiadiazole A partial suspension of 1,1-dioxidized 3,4-dimethoxy-1,2,5-thiadiazole (1.19 g; 6.7 mmol) in 130 ml of methanol cooled to δ° contains 2-thiadiazole in 60 ml of methanol. A solution of [(2-dimethylaminomethylthiazol-5-yl)methylthio]ethylamine (1.55 g; 6.7 mmol) [prepared in step D] was added dropwise over 40 minutes. When the addition was complete, anhydrous methylamine was bubbled into the solution for 8 minutes and then stirred overnight at ambient temperature. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in acetonitrile.
Silica gel 150 using methanol gradient elution
Chromatographed on g.g. Appropriate fractions were combined to yield 1.05 g of product. Recrystallization from 2-propanol gave the title compound, mp 170-172°. Analysis As C ₁₂ H ₂₀ N ₆ O ₂ S ₃ Calculated value: C, 38.28; H, 5.36; N, 22.33; S, 25.56 Experimental value: C, 38.31; H, 5.32; N, 22.13; S, 25.96 Example 63 1-oxidation 3-{2-[(2-guazinothiazol-4-yl)methylthio]ethylamino}-
4-Methylamino-1,2,5-thiadiazole 1,1-dioxidized 3,4- used in Example 20
Examples except that dimethoxy 1,2,5-thiadiazole was replaced by an equimolar amount of the corresponding 1-oxide.
20 general operations were repeated. Appropriate fractions from column chromatography were combined to yield 4.5 g of product. Crystallization from absolute ethanol gave 3.05 g of the title compound, mp 175-177°. Analysis C ₁₀ H ₁₆ N ₈ As OS ₃ Calculated value: C, 33.32; H, 4.47; N, 31.09; S, 26.68 Experimental value: C, 33.10; H, 4.42; N, 31.00; S, 26.51 Example 64 1- Oxide 3-{2-[(2-guanidinothiazol-4-yl))methylthio]]ethylamino}-4-hydroxy-1,2,5-thiadiazole 1-oxidation 3,4 in 350 ml of methanol cooled in an ice-water bath. -Dimethoxy-1,2,5-thiadiazole (2.91 g; 17.9 mmol) in methanol
2-[(2-guandinothiazole-4-
yl)methylthio]ethylamine (4.15g; 17.9
(mmol) solution was added dropwise over a period of 30 minutes. The reaction mixture was treated with a solution of caustic soda pellets (3.58 g; 89.5 mmol) in methanol. After stirring overnight at ambient temperature, the mixture was evaporated into an aqueous solution.
It was neutralized with 14.9 ml (89.5 mmol) of 6.0NHCl and evaporated under reduced pressure after 10 minutes. The solid residue was triturated with 70 ml of water at ambient temperature for 2 hours and filtered to give the product. Recrystallize the title compound from water, mp148~
Obtained 151°. Analysis As C ₉ H ₁₃ N ₇ O ₂ S ₃ Calculated values: C, 31.11; H, 3.77; N, 28.22; S, 27.69 Experimental values: (corrected as 5.52% H ₂ O): C,
30.95; H, 3.76; N, 28.27; S, 28.11 Example 65 1-oxidized 3-amino-4-{2-[(2-methylguanidino}thiazol-4-yl)methylthio]ethylamino-1,2,5 -Thiadiazole A 2-[(2-(2-methylguanidino)thiazol-4-yl]methylthio}ethylamine Cysteamine hydrochloride (1.89 g; 16.6 mmol) and 2-(2-methylguanidino)-4-chloromethylthiazole hydrochloride ( 4.0g; 16.6 mmol) [N-
methylamidino)thiourea and 1,3-dichloro-
2-propane] with 20 ml of concentrated hydrochloric acid,
This solution was heated at an oil bath temperature of 100°. 2
After an hour the mixture was evaporated under reduced pressure and the residue was
% NaOH aqueous solution. The aqueous phase was extracted several times with methyl acetate and the organic phase was dried, filtered and evaporated to give 3.35 g of the title compound. In _D2O
The NMR spectrum (60MHz) has the following characteristic resonance δ
gave: 6.52 (s, 1H); 3.60 (s, 2H); 2.70
(m, 7H). B 1-oxidation 3-amino-4-{2-[(2-
{2-methylguannidino}thiazole-4-
yl)methylthio]ethylamino}-1,2,
5-thiadiazole 1-oxidation 3, in 170 ml of methanol cooled to 7°
50 methanol to a solution of 4-dimethoxy-1,2,5-thiadiazole (1.39 g: 8.56 mmol)
A solution of 2-[(2-{2-methylguanidino}thiazol-4-yl)methylthio]ethylamine (2.1 g; 8.56 mmol) [prepared in Step A] in ml was added dropwise over 30 minutes. Anhydrous ammonia was bubbled into the solution for 7 minutes and then stirred overnight at ambient temperature. The reaction mixture was evaporated under reduced pressure and the residue was chromatographed on 100 g of silica gel (230-400 mesh) by flash chromatography using acetone tolyl-methanol gradient elution. Appropriate fractions were combined, evaporated and the residue chromatographed on a preparative HPLC system using μ-Porasil silica gel.
Appropriate fractions were combined, concentrated to a small volume, and filtered to give the title compound, mp 86-91°; NMR spectrum (100 MHz) in _d6 dimethyl sulfoxide:
It showed the presence of about 0.8 moles of ethanol. Analysis C ₁₀ H ₁₆ N ₈ OS Calculated as ₃ : C, 35.06; H, 5.28; N, 28.20; S, 24.21 Experimental (corrected as 1.64% _H2O ): C, 35.66; H, 5.05; N , 28.33; S, 23.96 Example 66 1-oxidized 3-amino-4-[3-dimethylaminomethylphenoxy)propylamino]-1,
2,5-thiadiazole 1- in 200 ml of methanol cooled to 2° in an ice-water bath
A solution of 3,4-dimethoxy-1,2,5-thiadiazole oxide was added with stirring in 35 ml of methanol.
A solution of -(dimethylaminomethyl)phenoxypropylamine (2.5 g; 12.9 mmol) was added dropwise over a period of 30 minutes. After stirring for 15 minutes, anhydrous ammonia was bubbled into the solution for 5 minutes. The reaction mixture was evaporated under reduced pressure to give a crystalline product. Recrystallized twice from methanol to obtain the title compound,
mp165.5~166.5° (decomposition) was obtained. Analysis as C ₁₄ H ₂₁ N ₅ O ₂ S Calculated value: C, 51.99; H, 6.55; N, 21.66; S, 9.92 Experimental value: C, 51.58; H, 6.49; N, 22.03; S, 10.19 Example 67 1 -Oxidized 3-amino-4-{2-[(2-methylaminothiazol-4-yl)methylthio]
ethylamino}-1,2,5-thiadiazole A 2-[(2-methylaminothiazole-4-
yl) methylthio]ethylamine Cysteamine hydrochloride (2.8 g; 24.6 mmol) and 2-methylamino-4-chloromethylazole (4.0 g; 24.6 mmol) [manufactured from N-methylthiourea and 1,3-dichloro-2-propane ] was dissolved in 20 ml of concentrated hydrochloric acid, and the solution was heated at 100° oil bath temperature. After heating for 30 hours, the reaction mixture was evaporated under reduced pressure and the residue was made basic with 40% NaOH solution. The aqueous phase was extracted with methyl acetate, dried, filtered and evaporated to give 1.75 g of the title compound as an oil, which was used in Step B without further purification. B 1-oxidized 3-amino-4-{2-[(2-methylaminothiazol-4-yl)methylthio]ethylamino-1,2,5-thiadiazole The product of Step A above was converted to Example 65 Step B 1-oxidized 3,4-dimethoxy-1,2, according to the general procedure of
It was reacted sequentially with 5-thiadiazole and anhydrous ammonia and chromatographed as described therein. Appropriate fractions from flash chromatography were combined and evaporated to yield 0.5
g was obtained as a foam. Crystallization from acetone gave the title compound, mp 180-183° (decomposed). Analysis C ₉ H ₁₄ N ₆ OS Calculated as ₃ : C, 33.94; H, 4.43; N, 26.39; S, 30.21 Experimental (corrected as 1.41% _H2O ): C, 33.96; H, 4.11; N , 26.27; S, 30.44 Example 68 1-oxidation 3-amino-4-{2-[(2-{2,
3-dimethylguanidino}thiazol-4-yl)methylthio]ethylamino}-1,2,5
-Thiadiazole A dihydrochloride 2- [(2-{2,3-dimethylguanidino}thiazol-4-yl)methylthio]
Ethylamine Cysteamine hydrochloride (2.25 g; 19.6 mmol) and 4-chloromethyl-2-(2,3-dimethylguanidino)thiazole (5 g; 19.6 mmol) [1.3
- prepared from dichloro-2-propanone and (N,N'-dimethylamidino)thiourea (itself prepared from dimethyl cyanodithioiminocarboxylate and methylamine)] was dissolved in 17.5 ml of concentrated hydrochloric acid,
Heated at an oil bath temperature of 100°. After 24 hours the reaction mixture was evaporated under reduced pressure and the residue was crystallized from absolute ethanol to give the title compound, mp 243-245°. B 1-oxidation 3-amino-4-{2-[(2-
{2,3-dimethylguanidino}thiazole-
4-yl)methylthio]ethylamino}-1,
2,5-Asiazole The product of Step A above was converted to 3,4-dimethoxy-1, 1-oxidation according to the general procedure of Example 65, Step B.
It was reacted sequentially with 2,5-thiadiazole and anhydrous ammonia. The crude reaction mixture was evaporated under reduced pressure,
The residue was crystallized from methanol to give the title compound, mp 201-203° (resolved). Analysis C ₁₁ H ₁₈ N ₈ OS Calculated as ₃ : C, 35.28; H, 4.84; N, 29.92; S, 25.69 Experimental (corrected for 0.88% _H2O ): C, 34.93; H, 4.56; N , 30.27; S, 25.92 Example 69 1-oxidized 3,4-bis-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole at 0° in an ice water bath Dihydrochloric acid 2-[(2 _- guanidinothiazole-4-
yl)methylthio]ethylamine (6.09g; 20.0
After stirring for 20 minutes, the solution was treated with 1-oxidized 3,4-dimethoxy-1,2,5-thiadiazole (1.62 g; 10 mmol). The reaction mixture was stirred at ambient temperature for 65 hours and evaporated under reduced pressure. The residue was chromatographed on 100 g of silica gel (230-400 mesh) by flash chromatography using acetonitrile-methanol gradient elution. Appropriate fractions were combined, evaporated and the residue was purified by μ-Poracil.
Chromatographed on a preparative HPLC system using silica gel. Appropriate fractions were combined and evaporated under reduced pressure to yield the title compound as an amorphous solid;
NMR spectrum (100 MHz) in d ₆ dimethyl sulfoxide showed the presence of about 0.11 mol of ethanol. Analysis C ₁₆ H ₂₄ N ₁₂ OS ₅・0.11C ₂ H ₆ O Calculated value: C, 34.42; H, 4.39; N, 29.71; S, 28.33 Experimental value (corrected as 1.8% H ₂ O): C, 34.95; H, 4.41; N, 29.04; S, 27.71 Example 70 1,1-dioxidized 3-{2-[(2-aminothiazol-4-yl)methylthio]ethylamino}-4-methylamino-1, 2,5- A Dihydrochloric acid 2-[(2-aminothiazole-4-
Cysteamine hydrochloride (5.65 g; 50.0 mmol) and 2-amino-4-chloromethylthiazole hydrochloride (9.25 g; 50.0 mmol) were dissolved in 70 ml of concentrated hydrochloric acid and heated at an oil bath temperature of 105°. . After heating for 64 hours, the mixture was evaporated under reduced pressure and the residue was triturated with acetone. The collected product was retriturated with ethanol, filtered and dried to give the title compound, mp 170-200°. Analysis As C ₆ H ₁₃ Cl ₂ N ₃ S ₂ Calculated value: C, 27.48; H, 4.90; N, 16.02; S, 24.46; Cl, 27.04 Experimental value: C, 27.29; H, 5.07; N, 15.91; S , 24.15; Cl, 27.24 B 1,1-dioxidized 3-{2-[(2-aminothiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole in 55 ml of methanol 1,1-dioxidized 3,4-dimethoxy-1,2,5-thiadiazole (2.03g;
A cold (5°) partial suspension of 11.4 mmol) of 2-[(2-aminothiazole-
A solution of 4-yl)methylthio]ethylamine (from dihydrochloride, 3.0 g; 11.4 mmol) [prepared in step A] was added dropwise over 1.5 hours. After 1.5 hours, anhydrous methylamine was bubbled into the solution for 30 minutes and stirred at 5° for 19 hours. The reaction mixture was evaporated under reduced pressure and the residue was placed on 400 g of silica gel and chromatographed using acetone-methylene chloride (7:3). Combine appropriate fractions,
Evaporation gave the product. Recrystallization from 95% ethanol gave the title compound, mp 200-201°. Analysis C ₉ H ₁₄ N ₆ O ₂ S As ₃ Calculated value: C, 32.32; H, 4.32; N, 25.13; S, 28.76 Experimental value: C, 32.25; H, 4.20; N, 25.06; S, 29.14 Example 71 1-oxidation 3-amino-4-{2-[(2-dimethylaminomethylthiazol-5-yl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxidation 3,4-dimethoxy- in 170 ml of methanol 1,2,5-thiadiazole (1.44g; 8.88
70 mmol) of methanol under stirring into a cold (8°) solution of
2-[(2-dimethylaminomethylthiazol-5-yl)methylthio]ethylamine (2.05 in ml)
g; 8.86 mmol) [Example 62, prepared during step D] was added dropwise. Add 8% of anhydrous ammonia to this solution.
Bubbled for a minute and then stirred at external temperature for 0.5 hour. The reaction mixture was evaporated under reduced pressure and the residue was triturated with acetonitrile to yield 1.76 g of product. The product was purified by flash chromatography on 100 g (230-400 mesh) of silica gel using acetonitrile-methanol. Appropriate fractions were combined, evaporated and the residue crystallized from acetone to give the title compound, mp 131-133°. Analysis C ₁₁ H ₁₇ N ₆ OS Calculated as ₃ : C, 38.13; H, 5.24; N, 24.26; S, 27.76 Experimental (corrected for 0.49% _H2O ): C, 37.86; H, 5.06; N , 24.34; S, 27.68 Example 72 1-oxidation 3-amino-4-{2-[(2-aminothiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxidation in 50 ml of methanol A cold (5°) solution of 3,4-dimethoxy-1,2,5-thiadiazole (1.62 g; 10.0 mmol) in 20 ml of methanol was
[(2-aminothiazol-4-yl)methylthio]ethylamine (from dihydrochloride, 2.62 g; 10.0
A solution of Example 70 (prepared during step A) was added dropwise over a period of 30 minutes. After stirring for 1.5 hours, anhydrous ammonia was bubbled into the solution and the solution was kept at 5° for 17 hours. The reaction mixture was evaporated under reduced pressure and the residue was chromatographed on a preparative HPLC system using μ-Poracil silica gel. Appropriate fractions were combined and evaporated under reduced pressure to give the title compound as an amorphous solid; _d6 in dimethyl sulfoxide.
NMR spectrum (100MHz) showed the presence of approximately 0.4 moles of ethanol. Analysis C ₈ H ₁₂ N ₆ OS ₃・0.4C ₂ H ₆ O Calculated value: C, 32.74; H, 4.50; N, 26.03; S, 29.80 Experimental value (corrected as 1.39% H ₂ O): C, 32.39; H, 4.28; N, 28.39; S, 30.02 Example 73 1,1-dioxidized 3-methylamino-4-{2-
[(2-{2,3-dimethylguanidino}thiazol-4-yl)methylthio]ethylamino}
-1,2,5-Thiadiazole 1,1-dioxidized 3,4-dimethoxy-1,2,5-thiadiazole (1.72
2-[(2-{2,3-dimethylguanidino}thiazol-4-yl)methylthio]ethylamine (2.5 g; 9.64 mmol) in methanol with stirring. Example 68, prepared during step A] was added dropwise over a period of 40 minutes. Anhydrous methylamine was bubbled into the solution for 7 minutes, then the solution was evaporated under reduced pressure. The residue was chromatographed on 100 g of silica gel (230-400 mesh) by flash chromatography, and the appropriate fractions were combined and evaporated to give the product.
2.5 g was obtained as a foam. Crystallization from aqueous ethanol gave the title compound, mp 132-137°. Analysis Calculated as C ₁₂ H ₂₀ N ₈ O ₂ S ₃ : C, 35.63; H, 4.98; N, 27.70; S, 23.78 Experimental (corrected as 4.78% H ₂ O): C, 35.74; H, 5.04 ;N, 27.87; S, 23.56 Example 74 1-oxidized 3-{2-[(2-dimethylaminothiazol-4-yl)methylthio]ethylamino}-4-amino-1,2,5-thiadiazole A 2- [(2-dimethylamithiazole-4-
Cysteamine hydrochloride (5.24 g; 45.9 mmol) and 2-dimethylamino-4-chloromethylthiazole hydrochloride (9.8 g; 45.9 mmol) [N,N-dimethylthiourea 1,3-dichloro-2-propanone and ] was dissolved in 45 ml of concentrated hydrochloric acid and heated at an oil bath temperature of 100° for 96 hours. The mixture was evaporated under reduced pressure and the residue was made basic with 40% aqueous NaOH. The aqueous phase was extracted with methyl acetate, dried and evaporated to give the title compound as an oil, which was used in Step B without further purification. NMR spectra (60MHz) in D ₂ O gave the following resonances δ: 6.97 (s, 1H); 3.94 (s, 2H);
3.67 (s, 3H); 3.15 (s, 3H); 3.05 (m, 4H). B 1-oxidation 3-{2-[(2-dimethylaminothiazol-4-yl)methylthio]ethylamino}-4-amino-1,2,5-thiadiazole 1-oxidation 3,4-dimethoxy- in 200 ml of methanol 1,2,5-thiadiazole (2.61g; 16.1
70 mmol) of methanol under stirring into a cold (7°) solution of
2-[(2-dimethylaminothiazole-4) in ml
-yl)methylthio]ethylamine (3.5g;
A solution of 16.1 mmol (prepared during step A) was added dropwise over a period of 30 minutes. Anhydrous ammonia was bubbled into the solution for 8 minutes and after stirring for 30 minutes the mixture was evaporated under reduced pressure. The residue was triturated with isopropyl alcohol, then dissolved in methanol,
Filtration and evaporation gave the product. The product was purified by flash chromatography on 100 g of silica gel (230-400 mesh) using methylene chloride-methanol. Appropriate fractions were combined and rechromatographed by HPLC on a μ-Poracil silica gel column. Appropriate fractions were combined and evaporated under reduced pressure to yield the title compound, mp116~
122° was obtained; d ₆ NMR spectrum in dimethyl sulfoxide (100 MHz) showed the presence of about 1/3 mole of ethanol. Analysis C ₁₀ H ₁₆ N ₆ OS ₃・1/3C ₂ H ₆ Calculated value: C, 36.83; H, 5.22; N, 24.16; Experimental value (corrected as 11.92% H ₂ O): C, 36.61; H , 4.06; N, 24.22 Example 75 1,1-Dioxidized 3-{2-[(2-dimethylaminothiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole Methanol 200ml Medium 1,1-dioxidized 3,4-dimethoxy-1,2,5-thiadiazole (2.05
11.5 mmol) under stirring into a cold (7°) suspension of
- [(2-dimethylaminothiazol-4-yl)
A solution of methylthio]ethylamine (2.5 g; 11.5 mmol, prepared in Example 74, Step A) was added dropwise over 30 minutes. Add 7% of anhydrous methylamine to this solution.
After bubbling for a minute and stirring for 30 minutes, the mixture was evaporated under reduced pressure. The residue was crystallized from methanol to obtain 1.6 g of compound. Recrystallized twice from 2-methoxyethanol to obtain the title compound, mp227~
Obtained 229°. Example 76 1,1-dioxide 3-{2-[(2-{2-imidazolidinyl}iminothiazol-4-yl)
methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole A 2-[(2-{2-imidazolidinyl}iminothiazol-4-yl)methylthio]ethylamine cysteamine hydrochloride (2.22 g; 19.5 mmol) and Hydrochloric acid 2-[(2-imidazolidinyl)imino]-
4-Chloromethylthiazole (4.94 g; 19.51 mmol) [prepared from 1,3-dichloro-2-propanone and N-(2-imidazolidin-2-yl)thiourea (itself 2-(cyanimino)imidazolidine)] [manufactured from ] in 20 ml of concentrated hydrochloric acid,
Heated for 5.5 hours at an oil bath temperature of 100°. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in 40% NaOH.
Make it basic. The aqueous phase was extracted with methyl acetate, dried and evaporated to give 2.02 g of the title compound, which was used in the next step without further purification. B 1,1-dioxidized 3-{2-[(2-{2-imidazolidinyl}iminothiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole 1 in 190 ml of methanol , 1-dioxidized 3,4-dimethoxy-1,2,5-thiadiazole (1.4
2-[(2-{2-imidazolidinyl}iminothiazol-4-yl)methylthio]ethylamino (2.02 g; 7.85 mmol) in 85 ml of methanol with stirring. The solution prepared during step A] was added dropwise over a period of 40 minutes.
Anhydrous ammonia was bubbled into the solution for 7 minutes, and after 30 minutes at ambient temperature, the mixture was evaporated under reduced pressure to yield 3.5 g of product. This product is μ
-HPLC for production using Porasil silica gel
The system was chromatographed. Appropriate fractions were combined, evaporated and the residue crystallized from methanol to give the title compound, mp 229-231°. Recrystallization from aqueous ethanol gave the title compound with mp 136-140°, which resolidified and remelted at mp 219-224°. Analysis Calculated as C ₁₂ H ₁₈ N ₈ O ₂ S ₃ : C, 35.81; H, 4.51; N, 27.84; S, 23.90 Experimental (corrected as 4.59% H ₂ O): C, 35.51; H, 4.43 ; N, 27.98; S, 23.56 Example 77 1,1-Dioxide 3-{2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-[(pyridyl)methylamino]
-1,2,5-Thiadiazole The general procedure of Example 31 was repeated, except that the methylamine used in Example 31 was replaced by an equimolar amount of 2-aminomethylpyridine. Column chromatography of the crude solid yielded 3.08 g of product.
I got it. Recrystallization from isopropyl alcohol gave the title compound, mp 162-164° (decomposed). Analysis As C ₁₈ H ₂₄ N ₆ O ₂ S ₃ Calculated value: C, 47.76; H, 5.34; N, 18.57 Experimental value: C, 47.80; H, 5.32; N, 18.75 Example 78 1,1-dioxidation 3- {2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-[(4-pyridyl)methylamino]-1,2,5-thiadiazole The methylamine used in Example 31 The general procedure of the example was repeated except that an equimolar amount of 4-aminomethylpyridine was substituted. After chromatography, the crude product was dissolved in hot isopropyl alcohol, decanted from the insoluble material, and the solution was dried.
Treatment with HCl gave the title compound as the hydrochloride salt. After dissolving this salt in water, making basic with saturated aqueous sodium bicarbonate solution, and filtering, the title compound is converted to the free base,
The title compound was obtained as mp 88-90°. Analysis Calculated as C ₁₈ H ₂₄ N ₆ O ₂ S ₃ : C, 47.76; H, 5.34; N, 18.57; Experimental value (corrected as 3.73% H ₂ O): C, 47.54; H, 5.32; N, 19.09; Example 79 1,1-dioxidized 3-{2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-ethylamino-1,2,5-
Thiadiazole The general procedure of Example 31 was repeated, except that the methylamine used in Example 31 was replaced with an equimolar amount of ethylamine. Appropriate fractions from column chromatography were dissolved in warm isopropyl alcohol and saturated with anhydrous HCl. A crystalline solid was collected by filtration, washed with acetone, and dried to give 2.9 g of the title compound as the hydrochloride salt, mp 246-247° (resolved). Analysis As C ₁₄ H ₂₄ N ₅ O ₂ S ₃ Calculated value: C, 39.47; H, 5.68; N, 16.44; Cl, 8.32 Experimental value: C, 39.81; H, 5.74; N, 16.62; Cl, 8.20 Example 80 1,1-dioxidized 3-methylamino-4-[3-
(3-Piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 3,4-1,1-dioxide cooled to 1° in an ice water bath
Dimethoxy-1,2,5-thiadiazole (1.68
g; 9.45 mmol) in 30 ml of methanol with stirring.
The solution [manufactured in accordance with published UK patent application no. 2023133] was added dropwise over a period of 40 minutes. After 15 minutes, anhydrous thylamine was bubbled into the solution and the solution was then stirred at ambient temperature for 30 minutes. The reaction mixture was evaporated under reduced pressure and the residue was purified on silica gel (230-400 mesh) using methanol-acetonitrile.
Chromatographed on 100 g flash chromatography. Appropriate fractions were combined and evaporated to yield 2.2 g of product. Recrystallization from acetonitrile and charcoal treatment yielded the title compound, mp182~
Obtained 184°. Analysis As C ₁₈ H ₂₇ N ₅ O ₃ S Calculated value: C, 54.94; H, 6.92; N, 17.80; S, 8.15 Experimental value: C, 54.90; H, 7.07; N, 18.14; S, 8.29 Example 81 1 -Oxidized 3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-
1,2,5-thiadiazole 1- in 200 ml of methanol cooled to 0° in an ice-water bath
To a solution of 3,4-dimethoxy-1,2,5-thiadiazole oxide (2.01 g; 12.4 mmol) in 40 ml of methanol was added 4.0 g of 3-(3-piperidinomethylphenoxy)propylamine (from dihydrochloride). ;
12.4 mmol) was added dropwise over a period of 50 minutes. After 15 minutes, anhydrous ammonia was bubbled into the solution for 5 minutes, then the solution was stirred at ambient temperature for 17 hours. The reaction mixture was evaporated under reduced pressure and the residue was flushed onto 100 g of silica gel (230-400 mesh) using methanol acetonitrile.
Chromatographed by chromatography. The appropriate fractions were combined and evaporated to yield 4.18 g of product.
I got it. Recrystallization from 95% ethanol gave the title compound, mp 155-157° (decomposed). Analysis As C ₁₇ H ₂₅ N ₅ O ₂ S Calculated value: C, 56.17; H, 6.93; N, 19.27; S, 8.82 Experimental value: C, 55.97; H, 7.04; N, 19.57; S, 8.63 Example 82 1 ,1-dioxidized 3-amino-4-[3-(3-
Piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1- in 200 ml of methanol cooled to 2° in an ice-water bath
A partial suspension of 3,4-dimethoxy-1,2,5-thiadiazole oxide (2.22 g; 12.4 mmol) in 35 ml of methanol with stirring was added to 3-(3-piperidinomethylphenoxy)propylamine (dihydrochloric acid). A solution of 4.0 g (12.4 mmol) of the salt was added dropwise over a period of 65 minutes. After 15 minutes, anhydrous ammonia was bubbled into the solution for a minute, and then the solution was stirred at ambient temperature for 30 minutes. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in silica gel (230-400 mesh).
100 g and chromatographed by flash chromatography using methanol-acetonitrile. Appropriate fractions were combined and evaporated to yield 3.2 g of product. NMR spectrum (100 MHz) in d ₆ dimethyl sulfoxide showed the following resonances δ; 7.2 (m, 1H); 6.9 (m, 3H);
4.1 (t, 2H); 3.5 (t, 2H); 3.4 (s, 2H); 2.3
(m, 4H); 2.0 (m, 2H); 1.4 (broad s.6H). Example 83 1,1-Dioxide 3-{2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-(3,4-methylenedioxybenzylamino)-1,2,5 - Thiadiazole 1 in 200 ml of methanol cooled to 0° in an ice water bath
To a solution of 1-dioxidized 3,4-dimethoxy-1,2,5-thiadiazole (1.56 g; 8.8 mmol) in 30 ml of methanol with stirring was added 2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamine ( A solution of 2.02 g (8.8 mmol) was added dropwise over a period of 40 minutes. After 20 minutes, piperonylamine (1.46 g; 9.6 mmol) was added and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was evaporated to near dryness, ether was added and the mixture was filtered to give 3.47 g of product. Recrystallization from methanol gave the title compound, mp 180-182°. Analysis Calculated as C ₂₀ H ₂₅ N ₅ O ₄ S ₃ : C, 48.46; H, 5.08; N, 14.13; Experimental value (corrected as 0.38% H ₂ O): C, 48.92; H, 4.88; N, 14.52 Example 84 1-oxidized 3-amino-4-{2-[(6-dimethylaminomethyl-2-pyridine)methylthio]ethylamino}-1,2,5-thiadiazole A 6-(N,N dimethylcarbamyl )-2-carbomethoxypyridine 6-carbomethoxy-2- in thionyl chloride 80ml
A solution of picolinic acid (22.8 g; 0.13 mol) was heated at an oil bath temperature of 100° for 3 hours. The solution was evaporated under reduced pressure and the residue was dissolved in 200 ml of dioxane, which was then dissolved in dimethylamine (70 ml) in dioxane.
g) was added dropwise to the solution. The reaction mixture was stirred for 2 hours, then left at 4° overnight, filtered and evaporated under reduced pressure. The residue was dissolved in toluene, diluted with methylcyclohexane, and filtered to give the title compound.
Obtained 20.7g, mp90-92°. Analysis As C ₁₀ H ₁₂ N ₂ O ₃ Calculated value: C, 57.68; H, 5.81; N, 13.46; Experimental value: C, 57.64; H, 5.85; N, 13.77 B 6-dimethylaminomethyl-2-hydroxymethyl Pyridine 6-(N,N-dimethylcarbamyl-2-carbomethoxypyridine (20.3
g; 92.5 mmol) was added. The mixture was stirred and heated to reflux under nitrogen for 3 hours, then left at ambient temperature overnight. The mixture was diluted with a saturated aqueous solution of Na ₂ SO ₄ , dried and evaporated under reduced pressure. Place the residue on 275g of aluminum oxide,
Eluted with methylene chloride. Appropriate fractions were combined and evaporated to give 5.2g of the title compound. NMR spectrum (60MHz) in _CDCl3 showed the following resonances δ: 7.38 (m, 3H); 4.75 (s,
2H); 3.58 (s, 2H); 2.27 (s, 6H). C 2-[(6-dimethylaminomethyl-2-pyridyl)methylthio]ethylamine Cysteamine hydrochloride (3.58 g; 31.5 mmol) and 6-dimethylaminomethyl-2-hydroxymethylpyridine (5.0 g; 30.0 mmol) [in step B [Preparation] was dissolved in 48% hydrobromic acid, and the solution was heated under reflux for 12 hours, then left at ambient temperature for 8 hours. The reaction mixture was evaporated under reduced pressure to half volume and 40%
Made basic with aqueous NaOH and extracted several times with methylene chloride. The combined organic phases were washed with a small amount of water and a saturated brine solution, dried and evaporated under reduced pressure to yield 3.14 g of the title compound. NMR spectrum in CDCl ₃ (60MHz) gave the following resonances δ: 7.5 (m, 3H); 3.83 (s, 2H);
3.56 (s, 2H); 2.7 (m, 4H); 2.28 (s, 6H). D 1-oxidized 3-amino-4-{2-[(6-dimethylaminomethyl-2-pyridyl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxidized 3,4-dimethoxy-1,2 , 5-thiadiazole was added to an equimolar amount of 2-[(6-dimethylaminomethyl-2-pyridyl)methylthio]ethylamine [produced during step C].
and excess ammonia, thereby yielding the title compound. The results of acute toxicity tests of the compounds of the invention in comparison with other known compounds (such as cimetidine) are shown in the table below. [Table] Table B Acute toxicity test results by intravenous injection in mice Compound LD50 (mg/Kg, iv) Cimetidine 172 Examples 6 43 Example 7 65 Example 8 74 Example 13 85 Example 16 44 Example 20 113 Examples 21 170 Examples 33 44

Claims (1)

[Claims] 1 formula [In the formula, p is 1 or 2; R ¹ is hydroxy or NR ² R ³ ; R ² and R ³ are each independently hydrogen, (lower) alkyl, (lower) alkenyl, (lower) ) alkynyl,
Cyclo (lower) alkyl, cyclo (lower) alkyl (lower) alkyl, hydroxy (lower) alkyl, (lower) alkoxy (lower) alkyl, (lower) alkylthio (lower) alkyl, amino (lower) alkyl, (lower) alkyl Amino (low grade)
Alkyl, di(lower)alkylamino(lower)alkyl, pyrrolidino(lower)alkyl, piperidino(lower)alkyl, morpholino(lower)alkyl, piperazino(lower)alkyl, pyridyl(lower)alkyl, amino(lower)alkylamino,
Di(lower) alkylamino, 2,2,2,-trifluoroethyl, 2-fluoroethyl, hydroxy,
(lower) alkoxy, 2,3-dihydroxypropyl, cyano, cyano (lower) alkyl, amidino, (lower) alkylamidino, A'-(CH ₂ ) _n '
-Z'(CH ₂ ) _o '-, phenyl, phenyl (lower) alkyl, substituted phenyl or substituted phenyl (lower)
Alkyl (provided that the phenyl ring has one or two substituents independently selected from (lower) alkyl, hydroxy, (lower) alkoxy and halogen, or selected from methylenedioxy, trifluoromethyl and di(lower) alkylamino provided that R ² and R ³ are both cyclo(lower) alkyl, phenyl, substituted phenyl, amino, (lower) alkylamino, di(lower) alkylamino, must not be hydroxy, (lower)alkoxy, cyano, amidino, (lower)alkylamidino or A'-( _CH2 ) _n'Z ( _CH2 ) _o'- ; or ^R2 and ^R3 taken together ,-
CH ₂ CH ₂ X(CH ₂ ) _r - may be; r is an integer from 1 to ³ ; , X is methylene; R ⁴ is hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower) alkanoyl or benzoyl; m and m' are each independently 0 to is an integer of 2; n and n' are each independently an integer of 2 to 4; Z and Z' are each independently sulfur, oxygen, or methylene; A and A' are each independently is phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl; however, A and A' may independently have one or two substituents. , the first substituent is (lower) alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, (lower) alkoxy,
and _{the second} substituent is ( ^lower ) alkyl, ^hydroxy , trifluoromethyl, halogen,
selected from amino, hydroxymethyl and (lower) alkoxy; q is an integer from 0 to 6; R ⁴ is independently as defined above or two R ⁴
The groups together may be ethylene; and R ⁵ and R ⁶ are each independently hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl,
cyclo(lower)alkyl or phenyl, provided that R ⁵ and R ⁶ cannot both be cyclo(lower)alkyl or phenyl; or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached; pyrrolidino, morpholino, piperidino,
methylpiperidino, N-methylpiperidino or homopiperidino; or a non-toxic, pharmaceutically acceptable salt thereof;
Hydrates, solvates or N-oxides. 2. The compound according to claim 1, wherein R ¹ is NR ² R ³ . 3 p is 1 or 2; R ¹ is NR ² R ³ ; R ² and R ³ are each independently hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cyclo (lower) Alkyl (lower) alkyl, pyridyl (lower) alkyl, A′—(CH ₂ ) _n ′Z′ (CH ₂ ) _o ′
-, phenyl (lower) alkyl or 3,4-dimethylenedioxybenzyl (provided that R ² and
R ³ must not both be A′-(CH ₂ ) _n ′Z′ (CH ₂ ) _o ′-); m and m′ are each independently 0 or 1; n and n′ are each independently is 2 or 3; Z and Z' are each independently sulfur, oxygen or methylene; A and A' are each independently phenyl, imidazolyl, thiazolyl, furyl, thienyl or pyridyl ( However, A and A' may independently have one or two substituents, and the first substituent is
(lower) alkyl, CH ₂ NR ⁵ R ⁶ and the second substituent is selected from (lower) alkyl); each R ⁴ is independently hydrogen or (lower) alkyl, or the two R ⁴ groups together may be ethylene; R ⁵ and 6 ⁶ are each independently hydrogen or (lower) alkyl; or R ⁵ and R ⁶ are Together with the nitrogen atoms to which they are attached, pyrrolidino,
Morpholino, piperidino, methylpiperidino, N
- The compound according to claim 1 or 2, which may be methylpiperazino or homopiperidino. 4 Any one of claims 1 to 3
The formula described in section [wherein p is 1 or 2; Z is sulfur or methylene; R ² and R ³ are each independently hydrogen or (lower) alkyl, or R ²
is hydrogen, R ³ is (lower) alkenyl, (lower) alkynyl, phenyl (lower) alkyl, cyclo (lower) alkyl (lower) alkyl, pyridylmethyl or and R ¹³ is hydrogen or methyl. 5 Any one of claims 1 to 3
The formula described in section [wherein p is 1 or 2; Z is sulfur or methylene; each R ⁴ is independently hydrogen or methyl, or the two R ⁴ groups together are
may be ethylene; R ² and R ³ are each independently hydrogen or (lower) alkyl, or when R ² is hydrogen, (lower) alkenyl, (lower) alkynyl, pyridylmethyl,
[Formula] or A compound of 6 Any one of claims 1 to 3
The formula described in section [wherein p is 1 or 2; Z is sulfur or methylene; R ² and R ³ are each independently hydrogen or (lower) alkyl, or when R ² is hydrogen , R ³ is (lower) alkenyl,
(lower) alkynyl or and R ¹³ is hydrogen or methyl. 7 Any one of claims 1 to 3
The formula described in section [wherein p is 1 or 2; Z is sulfur or methylene; R ² and R ³ are each independently hydrogen or (lower) alkyl, or R ²
is hydrogen, R ³ is (lower) alkenyl, (lower) alkynyl, phenyl (lower) alkyl, pyridylmethyl, 3,4-methylenedioxybenzyl or and R ¹³ is hydrogen or methyl. 8 Any one of claims 1 to 3
The formula described in section [wherein p is 1 or 2; R ² and R ³ are each independently hydrogen or (lower) alkyl, or when R ² is hydrogen, R ³ is (lower) alkenyl, (lower) alkynyl or A compound of 9 Any one of claims 1 to 3
The formula described in section [wherein p is 1 or 2; Z is sulfur or methylene; R ² and R ³ are each independently hydrogen or (lower) alkyl, or R ²
is hydrogen, R ³ is (lower) alkenyl, (lower) alkynyl or and R ⁵ and R ⁶ are each independently hydrogen or (lower) alkyl. 10 Formula according to any one of claims 1 to 3 [wherein p is 1 or 2; R ² and R ³ are each independently hydrogen or (lower) alkyl, or when R ² is hydrogen, R ³ is (lower) alkenyl , (lower) alkynyl or and R ⁵ and R ⁶ are each independently hydrogen or (lower) alkyl, or R ⁵
When is hydrogen, R ⁶ may be (lower) alkenyl or (lower) alkynyl; or
R ⁵ and R ⁶ together with the nitrogen to which they are attached may be pyrrolidino, morpholino, piperidino or homopiperidino. 11 1,1-dioxide-3-{2-[(5-
The compound according to claim 1, which is dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-(n-propylamino-1,2,5-thiadiazole. 12 1,1-dioxide-3 -{2-[(5-
dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-amino-1,2,5-
A compound according to claim 1 which is a thiadiazole. 13 1,1-dioxide-3-{2-[(2-
Guanidinothiazol-4-yl)methylthio]
The compound according to claim 1, which is ethylamino}-4-amino-1,2,5-thiadiazole. 14 1,1-dioxide-3-{2-[(5-
dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-methylamino-1,
The compound according to claim 1, which is 2,5-thiadiazole. 15 1-oxide-3-amino-4-{2-
The compound according to claim 1, which is [(2-guanidinothiazol-4-yl)-methylthio]ethylamino}-1,2,5-thiadiazole. 16 Monohydrate 1-oxide-3-amino-4-
{2-[(2-guanidinothiazol-4-yl-
The compound according to claim 1, which is methylthio]ethylamino}-1,2,5-thiadiazole. 17 Hydrochloric acid 1-oxide-3-amino-4-{2
- [(2-guanidinothiazol-4-yl) -
The compound according to claim 1, which is methylthio]ethylamino}-1,2,5-thiadiazole. 18 1,1-dioxide-3-amino-4-
{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-1,2,5
- The compound according to claim 1, which is thiadiazole. 19 1-oxide-3-amino-4-[3-
The compound according to claim 1, which is (3-dimethylaminomethylphenoxypropylamino)-1,2,5-thiadiazole. 20 1,1-dioxide-3-methylamino-
4-[3-(3-piperidinomethylphenoxy)
The compound according to claim 1, which is propylamino]-1,2,5-thiadiazole. 21 1-oxide-3-amino-4-[3-
The compound according to claim 1, which is (3-piperidinomethylphenoxy)propylamino)-1,2,5-thiadiazole. 22 Anti-digestive agents comprising a compound of the following formula as an essential active ingredient, or a non-toxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof, in combination with a pharmaceutically acceptable carrier. Ulcer agent. [In the formula, p is 1 or 2; R ¹ is hydroxy or NR ² R ³ ; R ² and R ³ are each independently hydrogen, (lower) alkyl, (lower) alkenyl, (lower) ) alkynyl,
Cyclo (lower) alkyl, cyclo (lower) alkyl (lower) alkyl, hydroxy (lower) alkyl, (lower) alkoxy (lower) alkyl, (lower) alkylthio (lower) alkyl, amino (lower) alkyl, (lower) alkyl Amino (low grade)
Alkyl, di(lower)alkylamino(lower)alkyl, pyrrolidino(lower)alkyl, piperidino(lower)alkyl, morpholino(lower)alkyl, piperazino(lower)alkyl, pyridyl(lower)alkyl, amino,(lower)alkylamino ,
Di(lower) alkylamino, 2,2,2-trifluoroethyl, 2-fluoroethyl, hydroxy,
(lower) alkoxy, 2,3-dihydroxypropyl, cyano, cyano (lower) alkyl, amidino, (lower) alkylamidino, A'-(CH ₂ ) _n '
-Z'(CH ₂ ) _o '-, phenyl, phenyl (lower) alkyl, substituted phenyl or substituted phenyl (lower)
Alkyl (provided that the phenyl ring has one or two substituents independently selected from (lower) alkyl, hydroxy, (lower) alkoxy and halogen, or selected from methylenedioxy, trifluoromethyl and di(lower) alkylamino provided that R ² and R ³ are both cyclo(lower) alkyl, phenyl, substituted phenyl, amino, (lower) alkylamino, di(lower) alkylamino, must not be hydroxy, (lower)alkoxy, cyano, amidino, (lower)alkylamidino or A'-( _CH2 ) _n'Z '( _CH2 ) _o- '; or ^R2 and ^R3 together hand,-
CH ₂ CH ₂ X(CH ₂ ) _r - may be; r is an integer from 1 to ³ ; , X is methylene; R ⁴ is hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower) alkanoyl or benzoyl; m and m' are each independently 0 to is an integer of 2; n and n' are each independently an integer of 2 to 4; Z and Z' are each independently sulfur, oxygen, or methylene; A and A' are each independently phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl; provided that A and A′ independently have one or two substituents; Often the first substituent is (lower) alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, (lower) alkoxy,
and _{the second} substituent is ( ^lower ) alkyl, ^hydroxy , trifluoromethyl, halogen,
selected from amino, hydroxymethyl and (lower) alkoxy; q is an integer from 0 to 6; R ⁴ is independently as defined above or two R ⁴
The groups together may be ethylene; and R ⁵ and R ⁶ are each independently hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl,
cyclo(lower)alkyl or phenyl, provided that R ⁵ and R ⁶ cannot both be cyclo(lower)alkyl or phenyl; or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached; pyrrolidino, morpholino, piperidino,
may be methylpiperidino, N-methylpiperidino or homopiperidino]. 23 The active ingredient is monohydrated 1-oxide-3-amino-4-{2-[(2-guanidinothiazol-4-yl)-methylthio]ethylamino}-
The anti-peptic ulcer agent according to claim 22, which is 1,2,5-thiadiazole. 24 The active ingredient is hydrochloric acid 1-oxide-3-amino-4-{2-[(2-guanidinothiazole-4
-yl)-methylthio]ethylamino}-1,
The anti-peptic ulcer agent according to claim 22, which is 2,5-thiadiazole. 25 formula [In the formula, p is 1 or 2; R ¹ is NR ² R ³ ; R ² and R ³ are each independently hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl,
Cyclo (lower) alkyl, cyclo (lower) alkyl (lower) alkyl, hydroxy (lower) alkyl, (lower) alkoxy (lower) alkyl, (lower) alkylthio (lower) alkyl, amino (lower) alkyl, (lower) alkyl Amino (low grade)
Alkyl, di(lower)alkylamino(lower)alkyl, pyrrolidino(lower)alkyl, piperidino(lower)alkyl, morpholino(lower)alkyl, piperazino(lower)alkyl, pyridyl(lower)alkyl, amino,(lower)alkylamino ,
Di(lower) alkylamino, 2,2,2-trifluoroethyl, 2-fluoroethyl, hydroxy,
(lower) alkoxy, 2,3-dihydroxypropyl, cyano, cyano (lower) alkyl, amidino, (lower) alkylamidino, A'-(CH ₂ ) _n '
-Z'(CH ₂ ) _o '-, phenyl, phenyl (lower) alkyl, substituted phenyl or substituted phenyl (lower)
Alkyl (provided that the phenyl ring has one or two substituents independently selected from (lower) alkyl, hydroxy, (lower) alkoxy and halogen, or selected from methylenedioxy, trifluoromethyl and di(lower) alkylamino provided that R ² and R ³ are both cyclo(lower) alkyl, phenyl, substituted phenyl, amino, (lower) alkylamino, di(lower) alkylamino, must not be hydroxy, (lower)alkoxy, cyano, amidino, (lower)alkylamidino or A′-(CH ₂ ) _n ′Z′(CH ₂ ) _o ′-; or R ² and R ³ together hand,-
CH ₂ CH ₂ X(CH ₂ ) _r - may be; r is an integer from 1 to ³ ; , X is methylene; R ⁴ is hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower) alkanoyl or benzoyl; m and m' are each independently 0 to is an integer of 2; n and n' are each independently an integer of 2 to 4; Z and Z' are each independently sulfur, oxygen, or methylene; A and A' are each independently is phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl; however, A and A' may independently have one or two substituents. , the first substituent is (lower) alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, (lower) alkoxy,
and _{the second} substituent is ( ^lower ) alkyl, ^hydroxy , trifluoromethyl, halogen,
selected from amino, hydroxymethyl, and (lower) alkoxy; q is an integer from 0 to 6; R ⁴ is independently as defined above or two R ⁴
The groups together may be ethylene; and R ⁵ and R ⁶ are each independently hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl,
cyclo(lower)alkyl or phenyl, provided that R ⁵ and R ⁶ cannot both be cyclo(lower)alkyl or phenyl; or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached; pyrrolidino, morpholino, piperidino,
methylpiperidino, N-methylpiperidino or homopiperidino; or a non-toxic, pharmaceutically usable salt, hydrate, solvate or N-oxide thereof, comprising: In solvent [In the formula, p is 1 or 2, and R ⁷ is halogen, (lower) alkoxy, (lower) alkylthio, phenoxy or phenylthio (halogen,
(optional) having one or two substituents selected from (lower) alkyl, (lower) alkoxy and nitro) of the formula A(CH ₂ ) _n Z(CH ₂ ) _o
NH ₂ or A′(CH ₂ ) _n ′Z′(CH ₂ ) _o ′NH ₂ and then a compound of the formula R ⁹ H, where R ⁹ is —NR ² R ³
or in the reverse order and, if desired, the product obtained in a manner known per se, into non-toxic pharmaceutically usable salts, hydrates, A method characterized in that it is converted into a solvate or an N-oxide. 26 R ⁹ H is characterized in _{that the} reaction _is carried out in one step with 2 equivalents of A(CH ₂ ) _n Z( _{CH 2 ) o NH 2} 26. The method of claim 25. 27 formula is treated with approximately equimolar amounts of HNR ² R ³ ,
26. The method of claim 25, which is then treated with approximately equimolar amounts _of A( _CH2 ) _nZ ( _CH2 ) _oNH2 . The intermediate product obtained by treatment with 28 HNR ² R ³ is isolated, and then the intermediate product is converted to A(CH ₂ ) _n Z(CH ₂ ) _o
26. The method according to claim 25, wherein the method is treated with _NH2 . 29 formula [In the formula, p is 1 or 2; R ¹ is hydroxy; m is an integer of 0 to 2; n is an integer of 2 to 4; Z is sulfur, oxygen or methylene; A is phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,
triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl; with the proviso that A may independently have one or two substituents, the first substituent being (lower) alkyl, hydroxy, trifluoro. Methyl, halogen, amino,
Hydroxymethyl, (lower) alkoxy,
and _{the second} substituent is ( ^lower ) alkyl, ^hydroxy , trifluoromethyl, halogen,
selected from amino, hydroxymethyl and (lower) alkoxy; q is an integer from 0 to 6; each R ⁴ is independently hydrogen, (lower) alkyl, (lower) alkenyl,
(lower) alkynyl, (lower) alkanoyl or benzoyl, or the two R ⁴ groups together may be ethylene; and R ⁵ and R ⁶ are each independently hydrogen, (lower) Alkyl, (lower) alkenyl, (lower) alkynyl,
cyclo(lower)alkyl or phenyl, provided that R ⁵ and R ⁶ cannot both be cyclo(lower)alkyl or phenyl; or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached; pyrrolidino, morpholino, piperidino,
methylpiperidino, N-methylpiperidino or homopiperidino; or a non-toxic, pharmaceutically usable salt, hydrate, solvate or N-oxide thereof, comprising the formula: [In the formula, p is 1 or 2, and R ⁷ is halogen, (lower) alkoxy, (lower) alkylthio, phenoxy or phenylthio (halogen,
(optional) with one or two substituents selected from (lower) alkyl, (lower) alkoxy and nitro) is initially mixed with one equivalent of formula A (CH ₂ ) in an inert organic solvent. _n Z(CH ₂ ) _o NH ₂ and the product obtained is treated with potassium, lithium or sodium hydroxide and, if desired, the product obtained in a manner known per se. 1. A process characterized by converting a compound into a non-toxic pharmaceutically usable salt, hydrate, solvate or N-oxide thereof. 30 formula [In the formula, p is 1 or 2; R ¹ is NR ² R ³ ; R ² and R ³ are each independently hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl ,
Cyclo (lower) alkyl, cyclo (lower) alkyl (lower) alkyl, hydroxy (lower) alkyl, (lower) alkoxy (lower) alkyl, (lower) alkylthio (lower) alkyl, amino (lower) alkyl, (lower) alkyl Amino (low grade)
Alkyl, di(lower)alkylamino(lower)alkyl, pyrrolidino(lower)alkyl, piperidino(lower)alkyl, morpholino(lower)alkyl, piperazino(lower)alkyl, pyridyl(lower)alkyl, amino(lower)alkylamino,
Di(lower) alkylamino, 2,2,2-trifluoroethyl, 2-fluoroethyl, hydroxy,
(lower) alkoxy, 2,3-dihydroxypropyl, cyano, cyano (lower) alkyl, amidino, (lower) alkylamidino, A'-(CH ₂ ) _n '
-Z'(CH ₂ ) _o '-, phenyl, phenyl (lower) alkyl, substituted phenyl or substituted phenyl (lower)
Alkyl (provided that the phenyl ring has one or two substituents independently selected from (lower) alkyl, hydroxy, (lower) alkoxy and halogen, or selected from methylenedioxy, trifluoromethyl and di(lower) alkylamino provided that R ² and R ³ are both cyclo(lower) alkyl, phenyl, substituted phenyl, amino, (lower) alkylamino, di(lower) alkylamino, must not be hydroxy, (lower)alkoxy, cyano, amidino, (lower)alkylamidino or A′-(CH ₂ ) _n ′Z′(CH ₂ ) _o ′-; or R ² and R ³ together hand,-
CH ₂ CH ₂ X(CH ₂ ) _r - may be; r is an integer from 1 to ³ ; , X is methylene; R ⁴ is hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower) alkanoyl or benzoyl; m and m' are each independently 0 to is an integer of 2; n and n' are each independently an integer of 2 to 4; Z and Z' are each independently sulfur, oxygen, or methylene; A and A' are each independently is phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl; however, A and A' may independently have one or two substituents. , the first substituent is (lower) alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, (lower) alkoxy,
and _{the second} substituent is ( ^lower ) alkyl, ^hydroxy , trifluoromethyl, halogen,
selected from amino, hydroxymethyl and (lower) alkoxy; q is an integer from 0 to 6; R ⁴ is independently as defined above or two R ⁴
The groups together may be ethylene; and R ⁵ and R ⁶ are each independently hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl,
cyclo(lower)alkyl or phenyl, provided that R ⁵ and R ⁶ cannot both be cyclo(lower)alkyl or phenyl; or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached; pyrrolidino, morpholino, piperidino,
methylpiperidino, N-methylpiperidino or homopiperidino; or a non-toxic, pharmaceutically usable salt, hydrate, solvate or N-oxide thereof, comprising the formula: [In the formula, p is 1 or 2, and R ⁷ is halogen, (lower) alkoxy, (lower) alkylthio, phenoxy or phenylthio (halogen,
(1) may have one or two substituents selected from (lower) alkyl, (lower) alkoxy and nitro) in an inert organic solvent.
Treatment with compounds HS(CH ₂ ) _o NH ₂ and R ¹⁰ H in which n is 2 or 3 and R ¹⁰ is -NR ² R ³ in two steps without regard to order; 2) The product obtained in the presence of a base is converted to a product of formula A (CH ₂ ) _n X [wherein X is fluoro,
chloro, bromo, iodo, -O ₃ SR ¹¹ (R ¹¹ is phenyl substituted by (lower) alkyl, phenyl or methyl or bromo), O ₃ SF, acetoxy or 2,4-dinitrophphenoxy and, if desired,
A process characterized in that the product obtained in a manner known per se is converted into its non-toxic pharmaceutically usable salts, hydrates, solvates or N-oxides.