JPS63211272A - Intermediate compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Japanese Patent Application No. 121855/1985 discloses a novel 3,4-disubstituted compound which is an effective inhibitor of gastric acid secretion in animals (including humans).
1゜2.5-thiadiazole-1-oxide and -1
, 1-dioxide compounds are described. The present invention provides novel intermediates useful for producing the novel compounds described above. The novel compound described in the above Japanese Patent Application No. 121855/1985 (original patent application M) has the following formula l
or a non-toxic pharmaceutically usable salt, hydrate, solvate or N-oxide thereof.

[In the formula, p is 1 or VJi2: R1 is hydroxy or NR"Rj: R8 and R
1 each independently represents hydrogen, (lower) alkyl, (lower)
Alkenyl, (lower)alkynyl, cyclo(lower)alkyl, cyclo(lower)alkyl(lower)alkyl, and droxy(lower)alkyl, (lower)alkoxy(lower)
Alkyl, (lower)alkylthio(lower)alkyl, amino(lower)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-) Lifluoroethyl, 2-fluoroethyl, hydroxy, (lower) alkoxy, 2,3-dihydroxypropyl, cyan, cyano (lower) alkyl, amidino, (lower) alkylamidino, A/-(CH2), , Z' (
CH2) %I-, phenyl, phenyl(lower)alkyl, substituted phenyl or substituted phenyl(lower)alkyl (phenyl ring is (lower i)alkyl, hydroxy, (lower)
may have one or two substituents selected from alkoxy and halogen or one substituent selected from methylenedioxy, trifluoromethyl and di(lower)alkylamino) with the proviso that R8 and BaFi , both cyclo(lower) alkyl, phenyl, substituted phenyl, amine,
(lower) alkylamino, di(lower) alkylamino,
Hydroxy, (lower) alkoxy, cyanide, amidino,
(lower) alkylamidino or A'-(CHz)J
' (CHz ) , /-; or R1 and R1 together must not be CHz CH2X(CH
z) - may be; r is an integer from 1 to 3: XFi, methylene, sulfur, oxygen or N-R', provided that when r is 1, X is methylene; R4 is , hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower) alkanoyl or benzoyl; Ta and Ta' are each independently an integer from 0 to 2; each independently an integer from 2 to 4: Z and Z
' are each independently sulfur, oxygen or methylene; A and A' are each independently phenyl, imidazolyl,
Thiazolyl, inthiazolyl, oxasilyl, inxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, chenyl or pyridyl: However, A
and A' may independently have 1 or 2 substituents, the first substituent being (lower) alkyl, hydroxy,
The second [9 minutes is selected from trifluoromethyl, halogen, amino, hydroxymethyl, (lower alkoxy, selected from:
q is an integer from 0 to 6; each 84 may be independently as defined above or the two R groups together may be ethylene; Ri and Ro are each , independently hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cyclo(
(lower) alkyl or phenyl, with the proviso that RI and R
6 must not both be cyclo(lower)alkyl or phenyl: or All and R together with the nitrogen atom to which they are attached may be pyrrolidino, morpholino, piperidino, methylpiperidino, N-methylpiperazino or homopiperidino The present invention relates to novel intermediates useful in the preparation of compounds of formula I above.

According to the present invention, the formula [where p is l or 1-t2; R7 is halogen, (lower) alkoxy, (lower) alkylthio, phenoxy, phenylthio, phenyl/I/f
RI2 is a leaving group selected from substituted phenylthio and substituted phenylthio, optionally with one or two substitution valves selected from 11 carahalogen, (lower a)argyl, (lower)alkoxy and nitro; , the above R? , A (CHz) -Z (C
Hz)%NH-1R'R3N- or HS (CHz
)? LNH (where R2 and R3 are each independently hydrogen, (lower) alkyl, (lower) alkenyl, (lower)
Alkynyl, cyclo(lower)alkyl, cyclo(lower R)
Alkyl (lower) alkyl, hydroxy (lower) alkyl, (lower) alkoxy (lower) alkyl, (lower) alkylthio (lower) alkyl, amine (lower) alkyl, (lower) alkylamino (lower) alkyl, di (lower) ) alkylamino (lower) alkyl, pyrrolidino (lower) alkyl, piperidino (lower) alkyl, morpholino (lower) alkyl, piperazino (lower) alkyl, pyridyl (lower) alkyl, amine, (lower) alkylamino, di(lower) alkyl Amino, 212.2-trifluoroether, 2-70 loedel, hydroxy, (lower) alkoxy, 2,3-dihydroxypropyl, cyano, 7
7-(lower) alkyl, amidino, (low g) alkylamidino, A'-(CB, )-/Z' (0%)
%/-, phenyl, phenyl (low M) alkyl, phenyl ring 2>((lower) alkyl, hydroxy, (lower)
Substituted phenyl or substituted phenyl optionally having one or two substituents independently selected from alkoxy and halogen, or one substituent selected from mesolodioxy, trifluoromethyl and di(lower)alkylamino. (
Lower) alkyl: Provided that both R2 and Hs are (lower alkyl, phenyl, substituted phenyl,
Amine, (lower) alkylamino, di(lower) alkylamino, hydroxy, (lower alkoxy, cyano, amidino, (lower) alkylamidino or A'-(C1
h＞−rZ(CHt)%l−; or R” and CFR”Fi, joint wa<”(, CH2CBz
X (CHz), Th may be: r is an integer from 1 to 3: X is methylene, VL yellow, oxygen or N-R', provided that p is 2 and R7 is methoxy7 When R
1 and R3 together with the nitrogen to which they are attached cannot be morpholino and when r is 1, X is methylene; R4 is hydrogen, (lower) alkyl, (lower) alkenyl , (lower)alkynyl, (lower)alkanoyl, or benzoyl; and m' are each independently an integer of θ to 2; n and 9' 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, inthiazolyl, oxasilyl, inxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, chenyl or pyridyl: provided that A
and A' independently have one or two substituents (the first substituent being (lower) alkyl, hydroxy,
The second substituent is selected from (lower) alkyl, hydroxy, trifluoromethyl, halogen, amine, hydroxymethyl, and (lower) alkoxy. selected from;
q is an integer from θ to 6; each R4 can be independently as defined above or the two R4 groups together can be ethylene; B
m and R. each independently represent hydrogen, (lower) alkyl,
(lower)alkenyl, (lower)alkynyl, cyclo(lower)alkyl or phenyl, provided that R1 and R6
must not both be cyclo(lower)alkyl or phenyl: or BS and R together with the nitrogen atom to which they are attached may be pyrrolidino, morpholino,
or a salt, hydrate, solvate or N-oxide thereof.

Furthermore, according to the present invention, [in the formula, p is 1 or 2; , (lower) alkynyl, cyclo(
(lower) alkyl, cyclo (lower) alkyl (lower) alkyl, hydroxy (lower) alkyl, (lower) alkoxy (lower i) alkyl, (lower) alkylthio (lower) alkyl, amino (lower) alkyl, (lower) alkylamino (lower) alkyl, di(lower) alkylamino (lower) alkyl, pyrrolidino (lower) alkyl, piperidino (lower) alkyl, morpholino (lower) alkyl, piperazino (lower) alkyl, pyridyl (lower) alkyl, amine, (lower) ) alkylamino, di(lower) alkylamino, 2,2.2-)IJ fluoroethyl, 2-70
loethyl, hydroxy, (lower) alkoxy, 2,
3-dihydroxypropyl, cyan, cyan (lower) alkyl, amidino, (lower) alkylamidino, A'
(CHt)tyt'Z'(CHt)% l-, phenyl, phenyl (lower) alkylphenyl ring is independently selected from (lower) alkyl, hydroxy, (lower) alkoxy and halogen, without substitution of l or 2 , or a substituted phenyl or substituted phenyl(lower)alkyl optionally containing an extra substituent selected from methylenedioxy, trifluoromethyl and di(lower)alkylamino; provided that both R2 and R3 are both cyclo (lower) alkyl, phenyl, substituted phenyl, amine, (lower) alkylamino, di(lower) alkylamino, and doroxy, (lower) alkoxy, cyanide, amidino, (lower) alkylamidino or A'-(CH,) ,,/Z'-(CH2
)%l-: or R2 and Ha are
together may be CHtCHJ(CHt)r-; de is an integer from 1 to 3; X is methylene, sulfur, oxygen or N-R'; provided that when r is 1, is methylene; R4 is
hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower) alkanoyl or benzoyl; 2' is sulfur, oxygen or methylene; A' is phenyl, imidazoyl, thiazolyl, inthiazolyl, oxasilyl, inxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, chenyl or pyridyl; provided that A' is 1 or 2; The first non-substitute is selected from (lower) alkyl, hydroxy, trifluoromethyl, halogen, amine, hydroxymethyl, (lower) alkoxy, and the second non-substitute is , (lower) alkyl, hydroxy, trifluoromethyl, halogen, amine, hydroxymethyl and (lower) alkoxy;
q is an integer from 0 to 6; each 84 may be independently as defined above or the two 84 groups together may be ethylene; R
5 and R6 are each independently hydrogen, (lower) alkyl,
(lower)alkenyl, (lower)alkynyl, cyclo(lower)alkyl or phenyl; with the proviso that Rs and R6
must not both be cyclo(lower)alkyl or phenyl; or Bs and R6, together with the nitrogen atom to which they are attached, can be pyrrolidino, morpholino,
or a salt, hydrate, solvate or N-oxide thereof.

Compounds of formula I are prepared using the intermediate compounds of the invention, preferably with a compound of formula C in which R' is a compound with good releasability, such as halogen, phenoxy, substituted phenoxy, phenylthio, substituted phenylthio, alkoxy, alkylthio, etc. can be prepared starting from the compound (which is a group of ). Suitable leaving groups are well known to those skilled in the art. Preferably, R7 is
(lower) alkoxy (especially methoxy).

Starting materials of formula 1, in which p is 2 and each BY is chloro, methoxy or ethoxy, are known and their preparation is described in J, Org, Cham, 40.2743 (19
75). A starting material of formula 2 in which p is 2 and each R is alkoxy, alkylthio, phenoxy, phenylthio, substituted phenoxy or substituted phenylthio (compounds of formulas suitable alkanol, alkylthio,
The reaction can be performed with phenol, thiophenol, substituted phenol or substituted thiophenol to produce the corresponding compound of formula ■ or V, in which R1 is alkyl, phenyl or substituted phenyl: ■ This reaction It is carried out in an inert organic solvent such as ether, dimethylformamide, etc. When the reactant R"OH or Ra5H is a liquid, for example methanol, ethanol, ethyl mercaptan or thiophenol, the reaction can be carried out in an excess of that solvent as solvent. The starting materials (compounds of formula (1) and 3) can be prepared in a similar manner from a compound of formula (compound Vl) in which each 87 is chloro.

■ Compound ■ is a new compound, but the same procedure (/, Org, Chum, , 40.27
43 (1975)] and the known compound 1-oxide 3,4-dihydroxy-1,2,5-thiadiazole [per se O deg, p dea.

Proagd., 1.255 (1969)]. The starting materials of formulas 1 and 2 are new compounds not previously described in the literature.

Alternatively, the starting materials of formulas IV and 1 can be obtained by reaction of the corresponding 3, It can be produced by forming a 4-disubstituted 1,2,5-thiadiazole and then oxidizing it to the corresponding 1-oxide of formula (1) or 1,1-dioxide of formula (2).

The oxaldiimidates of the formula 1, which are X IV -butyl and 9-pentyl, are known and their preparation has been described by Chum
Bar・.

U.S., 3121 (1974). R6 is.

Corresponding compounds which are phenyl, optionally substituted by (lower) alkyl, (lower) alkoxy, halogen or nitro, can be prepared by analogous operations.

Compounds of formula X, where R6 is methyl or ethyl, have J,0
Deg.

Cham, 40.2749 (1975).

The literature is! , that the 2,5-thiadiazole nucleus is sensitive to oxidation, that oxidation of thiadiazole with peracids usually involves ring decomposition and the production of sulfate ions, and that peracetic acid oxidation of the tetracycle produces 1,1-dioxide. It has been reported that attempts to prepare 1,2,5-thiadiazole resulted in cleaving of the mass. Surprisingly, we found that the corresponding 3,4-disubstitution of formula
,2,5-thiadiazole in good yield by oxidation of the formula ■
It has been found that 1-oxides of 3°1 4-disubstituted-1,2,5-thiadiazole and 1°-aged oxides of formula N can be readily prepared. l-oxide 3.4-
The preparation of dimethoxy-1,2,5-thiadiazole is shown below in Example 4, Step A; the preparation of the corresponding 1,1-dioxide is shown below.

Example [I] 1.1-dioxide 3,4-dimethoxy-1,2,5-
Thiadiazole chloroform 6〇-chujo-chloroperbenzoic acid w < 4.
11t; 20.3 mmol; quantitative value 85%) in chloroform 20-3,4-dimethoxy-
1,2,5-thiadiazole (1,48f: 10.1 mmol) (J, Org, cA#&.

A solution prepared according to the procedure described in Kudan, 2749 (1975) was added over a period of 1 minute. After stirring for 1 hour at ambient temperature, the mixture was heated to reflux for 8 hours and then stirred for 1 hour at ambient temperature. The reaction mixture was diluted with aqueous bicarbonate and water, and the organic layer was dried over sodium sulfate, washed and evaporated under reduced pressure. The residue was treated with methanol and filtered to give 1.03 r of product. Recrystallization from methanol yields the title compound, tnp200~
202°C was obtained.

Analysis Calculated value as C, H, N, O, S: C, 26, 9
7; H, 3, 39: #, 15.72; S, is, oo.

Go hard [I straight: C, 26, 82: H, 3, 18 2N, 1
6-09: S, 18.00° The present inventors have discovered that the compound of formula (1) can be directly produced from the compound of formula (2) by reaction of the latter with thionyl chloride in a one-step reaction fc .

This reaction is carried out in an inert organic solvent such as methylene chloride, chloroporm, and the like. This reaction can be carried out without the addition of base as an acid scavenger, but
The inventor prefers to add about 2 equivalents of base to remove HCl generated during the reaction. Higher yields of compound (2) are thereby obtained. A suitable base is
Includes inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate, as well as organic bases such as triethylamine, pyridine, and the like. This method is much more economical in that it not only saves one step, but also avoids the use of expensive oxidizing agents such as -di-chloroperbenzoic acid. This reaction is about -20°
at a temperature of ~25°, preferably from about 00° to about 10°
It can be carried out in Example [11] shows the preparation of a compound of formula (1) in which R8 is methyl by this method.

Example [River] Sol CH, CL, 18-medium thionyl chloride (2,61s/,
4.25t; 70.6 mmol) in a cold solution of CH, CL
, dimethyloxal diimide in 8d) (4, (1
:34.5 mmol) and pyridine (5.71m, 5.
A solution of 5El (70.6 mmol) was added in a nitrogen stream at such a rate that the reaction temperature remained between 0 and 15°. After stirring for 20 minutes at ambient temperature, the reaction mixture was washed twice with 1 ml portions of aqueous 0.055N HCl. The aqueous phase was extracted twice with 20 wt each of CH*C1v and the organic phases were combined, dried and evaporated to dryness under reduced pressure. The solid residue was recrystallized from inpropyl alcohol to give the title compound, m
p137-139°C, 3.02 was obtained.

Compounds of formula I can be prepared from compounds of formula (I) via a variety of alternative reaction schemes via several types of novel intermediates according to the invention.

Reaction scheme 1 % formula % In reaction scheme 1, R9 is -NR"E" or -
yH(cg, >, tz' (cH,), tA'. When A', Z', chicken' and outside' are the same as A, Z, s and calculation, this reaction is Of course, it can also be carried out in one step by reacting a compound of formula (■) with two equivalents of A (CH,) and Z (CX, )□!.Formula X
All intermediates of I are new. The intermediate of formula X is
Novel except for compounds where p is 2, R7 is methoxy and R9 is morpholino.

This compound has been approved by J, Org, Chatyc, +
40.2743 (1975). This reaction is carried out in an inert organic solvent; the inventors have found methanol to be a convenient and readily available solvent. Reaction temperature is not critical. Most of the starting materials are reactive and we prefer to carry out the reaction at temperatures below room temperature, e.g. 0-10°. Sometimes we then raise the temperature of the reaction mixture. It is desirable to allow the reaction to proceed to completion (for example, at 50-60°C).

Reaction Scheme 2 %Formula % In Reaction Scheme 2, y is a metal cation, which is preferably Ni+, L(+ or Ha+. Reaction conditions and solvents are as described for Reaction Scheme 1. All intermediates of formula XI are new compounds.

Reaction Scheme 3 Compound ■ In Reaction Scheme 3, RIO is -NR"R" or -NH(CHt)%'Z'(CHt)g
'A' and X is a commonly used leaving group.

Suitable leaving groups are, for example, fluoro, chloro, bromo, iodo, □5SR11 (R11 is (lower) alkyl (for example methanesulfonate), aryl or ha-substituted 7
! 0. SF, acetoxy and 2,4-dinitrophenoxy are included. For reasons of convenience and economy, we prefer to utilize compounds where X is chloro. The reaction conditions for the preparation of compounds 2, 2 and Xv are as described for Reaction Scheme 1. The reaction of the compound of formula X■ with A(CHt)tsX can be carried out in any inert organic solvent such as alkanols, acetonitrile, dimethylformamide, dimethylsulfoxide, acetone, and the like. We prefer to carry out the reaction in an alkanol such as methanol, ethanol or impropatol.

The reaction temperature is not critical; the reaction is approximately 0 (approximately 20
It can be carried out at a temperature of 0.00.

At low temperatures, the reaction is slow, while high temperatures usually result in relatively less pure products due to decomposition and by-product formation.

We generally prefer to carry out the reaction at room temperature. A of the compound of formula Xv to obtain the compound of formula 16
The reaction with (CH2),.X is preferably carried out in the presence of a base, which facilitates the reaction by acting as an acid acceptor. Suitable bases include, for example, N
aOH, KOH.

LiOH, ) ethylamine, dimethylaniline, sodium ethoxylate, and the like. When X is hydroxyl, the reaction can be carried out in concentrated mineral acids, such as HC1 (see Example 25). All intermediates of formula X[[[, XIV and Xv are new compounds.

One preferred embodiment of the invention is that p is 1 and R1
A novel intermediate compound of the above formula in which 2 is 8 units, that is, the following formula ■ α [In the formula, 87 is halogen, (lower) alkoxy, (lower) alkylthio, and optionally halogen, (lower) alkyl, (lower)
a leaving group selected from phenoxy or phenylthio with one or two substituents selected from alkoxy and nitro.

In yet another aspect, the present invention provides a compound of the formula [where p is 1 or 2; R'' is halogen, (lower 2-aralkoxy, (low i)
A releasable compound selected from alkylthio, phenoxy, phenylthio, substituted phenoxy and substituted phenylthio in which the phenyl ring may have one or two substituents selected from halogen, (lower) alkyl, (lower) alkoxy and nitro. is a group; R” is A(CHI) Z CCHz ) NH
-1R means R”N- or ηt tS HE(CH2)%NH-; however, R1 and R1 are each independently hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cyclo(lower) )alkyl, cyclo((a-M)alkyl(lower)alkyl, hydroxy(lower)alkyl, (lower)alkoxy(lower)
Alkyl, (lower)alkylthio(lower)alkyl, amine(lower)alkyl, (lower)alkylamino(lower)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,
21212-) J fluoroethyl, 2-70 loenal, hydroxy, (lower) alkoxy, 3,4-dihydroxypropyl, cyano, cyano (lower) alkyl, amidino, (lower) alkylamidino, A' - (CHz
), (Z'(CHz)%/ -, phenyl, phenyl (
lower s)alkyl, phenyl ring with 1 or 2 substituents independently selected from (lower)alkyl, hydroxy, (lower)alkoxy and halogen, or methylenedioxy, trifluoromethyl and di(lower)alkylamino monosubstituted phenyl or substituted phenyl (lower) alkyl which may have a substituent selected from alkylamino, di(lower) alkylamino, hydroxy, (lower) alkoxy,
Cyano, amidino, (lower)alkylamidino or A'
(CHz), &lt (CHz)%/-; rJtinR" and UR"F'! ,
Together, it may be -CHz CHx When lysed and R7 is methoxy,
R2 and Ba together with the nitrogen to which they are attached must not be morpholino and when r is 1, X is methylene; R4 is hydrogen, (lower) alkyl, (lower) alkenyl , (lower) alkynyl, (lower) alkanoyl or benzoyl; 5 and h' are each independently an integer of 2 to 4; 5 and h' are each independently an integer of 2 to 4; Yes; Z and 2
' are each independently sulfur, oxygen or methylene; A and A' are each independently phenyl, imidazolyl,
Thiazolyl, inthiazolyl, oxasilyl, inxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, chenyl or pyridyl; provided that A
and A' may independently have 1 to 2 substituents, the first substituent being (lower) alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, (lower) alkyl, and the second substituent is selected from (lower) alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl and (lower) alkoxy; q is an integer from 0 to 6; each R4 may be independently as defined above or the two R4 groups together may be ethylene;
RI and R6 each independently represent hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cyclo(
(lower) alkyl or phenyl, provided that R5 and R
”Fi, neither of which may be chloro(lower)alkyl or phenyl; or FiRS and R together with the nitrogen atom to which they are attached are pyrrolidino, morpholino, piperidino, methylpiperidino, N-methylpiperazino or homopiperidino; or a salt, hydrate, solvate or N-oxide thereof.

In a further preferred embodiment of the compound of formula xvI, R
” is A(CHz) IICCHz)%NH [where AFi, phenyl, imidazolyl, thiazolyl, furyl, chenyl or pyridyl, each of which may have 1 or 2 substituents, and the first a substituent is selected from (lower) alkyl; a second substituent is selected from (lower) alkyl; Z is sulfur, oxygen or methylene; m
is 0 or 1; duck is 2 or 3; each R'
Fi, independently hydrogen or (lower) alkyl, or the two R4 groups together may be ethylene; R5 and R6 are each independently hydrogen or (lower) alkyl ; or 85 and R6, together with the nitrogen atom to which they are attached, are pyrrolidino, morpholino,
It may be piperidino, methylpiperidino, N-methylpiperazino or homopiperidino; R7 is (lower) alkoxy.

In another more preferred embodiment of the compound of formula
independently hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cyclo(lower) alkyl, (lower) alkyl, pyridyl (lower) alkyl, A'-(
CHz ) nl r (C1k ) @'-, phenyl(lower)alkyl or 3,4-methylenedioxybenzyl; however, Bt and R3 are co-KA'-(CHz
), (2' (CHz)%l- must not be exceeded; groove' is 0 or l; 5' is 2 or 3;
Z' is sulfur, oxygen or methylene; Al is phenyl, imidazolyl, thiazolyl, furyl, chenyl or pyridyl, each of which may have 1 or 2 substituents, the first substituent being (lower) alkyl; each R4 is independently hydrogen or (lower) alkyl;
is alkyl, or the two R4 groups together are
may be ethylene; Rs and R6 are each independently hydrogen or (lower) alkyl; or R6 and R6
together with the nitrogen atoms they are attached to, are pyrrolidino, morpholino, piperidino, methylpiperidino,
It may be N-methylpiperazino or homopiperidino; R'Fi, (lower) alkoxy.

In another more preferred embodiment of the compound of formula XVI, R12 is H8(CH2)%NH-; where 1 is an integer from 2 to 4; R7 is It is.

In one particularly preferred embodiment of the compound of formula X■, R
" is [in the formula, Z is sulfur or methylene, and R" is hydrogen or methyl: R? is (lower) alkoxy]
It is.

In another particularly preferred embodiment of the compound of formula XVI, RI! is HUn2ALn2LnzlVn- [where R'' is hydrogen or methyl; Z is sulfur or methylene; R7 is lower (alkoxy)
It is.

In another particularly preferred embodiment of the compound of formula XvI, RI! [where R1 and R6 are each independently hydrogen or (lower) alkyl; 2 is sulfur or methylene; 8
Ding is.

(lower) alkoxy].

In another particularly preferred embodiment of the compound of formula Xvl, R'' is R may also be (lower) alkenyl or (lower) alkynyl; or R5 and R" Fi, together with the nitrogen to which they are attached, may be pyrrolidino, morpholino, piperidino or homopiperidino; R
7 is (lower) alkoxy].

In one aspect, the present invention relates to the formula [where pri is represented by 1 or 2; f& is represented by an integer from 2 to 4; R2 and R3 are each independently hydrogen, (lower) Alkyl, (lower) alkenyl, (lower) alkynyl, cyclo(
(lower) alkyl, cyclo (lower) alkyl (lower) alkyl, hydroxy (lower) alkyl, (lower) alkoxy (lower M) alkyl, (lower) alkylthio (lower) alkyl, amino (lower) alkyl, (lower) alkylamino (lower)alkyl, di(lower)alkylamino(lower)alkyl, pyrrolidino(lower)alkyl, piperidino(lower)alkyl, morpholino(lower)alkyl, piperazino(lower)alkyl, pyridino(lower)alkyl, amine, (lower) ) alkylamino, di(low li &) alkylamino, 2.2.2-)lifluoroethyl, 2-fluoroethyl, hydroxy, (lower) alkoxy, 2,3
-dihydroxypropyl, cyano, cyan (lower) alkyl, amidino, (lower) alkylamidino, A'
(' R2) ' Z (CH2) n '-, phenyl, phenyl (lower) alkyl, substituted phenyl or substituted phenyl (lower) alkyl (however, the phenyl ring is (
(lower) alkyl, hydroxy, (lower alkoxy) and halogen, or with an It substitute selected from methylenedioxy, trifluoromethyl and di(lower)alkylamino. provided that R2 and R3 are both cyclo(lower) alkyl, phenyl, substituted phenyl, amino, (lower) alkylamino, di(lower) alkylamino, hydroxy, (lower) alkoxy, cyanide. , amidino, (lower) alkylamidino or A'-(CH2) tr force 1 (CH,)%/-; (CH
z) may be -; r is an integer from 1 to 3; Xij, methylene, sulfur, oxygen or N-R'; provided that when De is 1, X is methylene :R4
is hydrogen, (lower) alkyl, (lower R) alkenyl, (
Z' is sulfur, oxygen or methylene; ' is phenyl, imidazolyl, thiazolyl, inthiazolyl, oxasilyl, inxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, chenyl or pyridyl; however, A' may have 1 to 2 substituents, and the first The second substitute is selected from (lower) alkyl, hydroxy, trifluoromethyl, halogen, amine, hydroxymethyl, (lower) alkoxy, and the second substitute is (lower) alkyl, hydroxy, trifluoromethyl, selected from halogen, amino, hydroxymethyl and (lower) alkoxy;
q is an integer from 0 to 6; each 84 may be independently as defined above or the two R4 groups together may be ethylene;
R5 and R6 are each hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, cyclo(lower)alkyl or phenyl; or R5 and R6 together, together with the nitrogen atom to which they are attached, are pyrrolidino , morpholino, piperidino, methylpiperidino, N-methylpiperazino or homopiperidino]; or a salt, hydrate, solvate or N-oxide thereof.

In a further preferred embodiment of the compound of formula ) alkyl, phenyl (lower)
Alkyl, pyridyl (lower) alkyl, 3,4-methylenedioxybenzyl or A' (CHx ), (Z(C
Hz), t-tea; Tatashi R" and HiR3 are both A'(CH2)-tZ'(CH2),t-tea")
shall not be an integer from 0 to 2;
each ' is independently an integer from 2 to 4; Z' is sulfur, oxygen, or methylene; A' is phenyl, imidazolyl, thiazolyl, furyl, chenyl, or pyridyl, each of which is 1 may have ~2 substitutions,
The first unsubstituted is selected from (lower) alkyl, and the second unsubstituted is selected from (lower) alkyl; Rs and R6 are each independently hydrogen or (
(lower) alkyl.

In another more preferred embodiment of the compound of formula
)A/? selected from phenyl and phenyl(lower)alkyl, or when R2 is hydrogen, R3 may be: with Z being sulfur or methylene;
R'' is hydrogen or methyl.

Examples and Reference Examples The method for producing a compound and the physical properties (rnp, etc.) of the product when both the 3- and 5-positions are leaving groups (R7) were described above as Examples fIII] and [nl, The following describes the method for producing intermediate compounds within the scope of the present invention and their physical properties (Examples), as well as the final compound of formula (1) from the intermediate compound (objective of Japanese Patent Application No. The method for producing the compound (Reference Example) will also be explained. In these examples, all temperatures are expressed in "°C".

Example l.

midazol-4-yl)methylthio]ethylamine)-
4 ゛1,1- in methanol 2001ffJ at room temperature
Dioxidized 3°4-dimethoxy-1,2,5-thiadiazole (2-(1; 11.2 mmol) (J, Org, C
Hmm, 40, 2743 (1975)] was added with good stirring to a suspension of 2-((5-methyl-1H-imidazol-4-yl)methylthio]ethylamine (prepared according to the procedure described in 1975) in 25 ml of methanol. From the dihydrochloride, 2.732; 11.2 mmol) (prepared according to Belgian Special Rod 779.775) was added.

After stirring for 30 minutes, a methanol solution of the title compound was obtained.

TLC [Silica/CHzCL*: CHsOH (90”
10)) Ef-0.44 was obtained.

To the methanolic solution of the product of Sol Step A was added 7 rsl of 2-propynylamine. After stirring for 20 minutes at room temperature, the reaction mixture was evaporated under reduced pressure and the residual oil was placed on silica gel and chromatographed by gradient elution using methylene chloride-methanol. Combining the appropriate fractions gave 2.74t of the title compound as an oil.

Further purification was achieved by combining the above material with that obtained during a second identical experiment, and the mixture was placed on silica gel and chromatographed by gradient elution using methylene chloride-methanol. The appropriate fractions were combined with methanol and evaporated under reduced pressure to give a brittle solid, m
The title compound (2,9:l') as p82-103@
NMR spectrum (100 MHz) in d6 dimethyl sulfoxide showed the presence of 1/3 mole methanol.

Analysis CI, Hl-N60. Calculated value as S: C,
42,19; H, 4,97; N, 23.95; S, 1B
, 27° Experimental value: C, 42,05; H, 5,05', N, 24.
01”.

S, 18.45゜Example 2゜ice water bath 250% dry methanol cooled in water 1,
A solution of 2-((5 r;
-Methyl-IH-imidazol-4-yl)methylthio]ethylamine (from dihydrochloride, 3.42f; 14.0
A solution of 1 mmol) was added over a period of 25 minutes. After stirring for 20 minutes at 2°, anhydrous methylamine was bubbled into the solution for 6 minutes and stirring continued for 30 minutes at ambient temperature. The reaction mixture was evaporated under reduced pressure and chromatographed by gradient elution using methylene chloride-methanol. The appropriate portions were combined to give the title compound 3.21. The product was further purified using column chromatography to provide an analytical sample of the title compound as an amorphous solid, mp9B~100°. The NMR spectrum (100MZrg) in d6 dimethyl sulfoxide showed the following resonances: δ near, 46 (a, IH); 3.70 (a, 2
H); 2.53 (t, 2ff); 2.86 (s, 3ff
); 2.76 (t.

2B); 2.15 (a, 3#).

Analysis Calculated value as C1oH1aNsOzsz: C, 3
7,96", H, 5,09", N, 26.56; S, 2
0.27° Experimental value: C, 37,79', H, 5,16; N, 26.
52;S, 20.24゜Example 3゜1.1-dioxide 3-(2-((5-methyl-IH-
imidazol-4-yl]methylthio]etheramino)
-4-Methoxy-1,2,5-thiadiazole [dihydrochloride of 2-((5-methyl-IB-imidazol-4-yl)methylthio)ethylamine (2,7:NF ; 11.2 mmol) was added with methanol 3 at -10° while stirring well.
2-[(2-guanidinothiazol-4-yl) in 5ν
Methylthio]ethylamine (from dihydrochloride, 3.41f
; 11.2 mmol) [prepared according to the procedure described in South African Patent No. 78/2129] was quickly added.

After stirring for 30 minutes at -10@, the solution was allowed to reach ambient temperature. The reaction mixture was evaporated under reduced pressure and the residue was placed on silica gel 45 and diluted with methylene chloride/-methanol (4:l
) 1 liter was used for chromatography. The appropriate fractions were combined and evaporated and the residue (5,822) was placed on aluminum oxide 80f and chromatographed using a gradient elution of ethyl acetate-methanol.

The appropriate fractions were combined, filtered through Celite and evaporated under high vacuum to give the title compound as an amorphous solid containing approximately 273 moles of ethyl acetate [as confirmed by NMR spectroscopy in d6 dimethyl sulfoxide (100 mph)]. (2
, 5t) was obtained.

Analysis (16H24N 1602S4 ・2/3C
Calculated value as 4H@02: C, 38,96; H, 5,1
4; N, 24.34; S, 22.29° Experimental value: C, 39,08; H, 4,96; /l/,
24.48; S, 22.26゜Example 4゜Adiasol 20'' in 900 g of chloroform to a solution of aa perbenzoate [(50,7?; 25.0 mmol) in 100 l of chloroform under stirring. 4-dimethoxy-1,2
,5-thiadiazole (35,2f; 24.1 mmol) (J, Org-ch-Ind., 40.2749 (19
A solution prepared according to the procedure described in 75) was added over a period of 3 minutes. A cooling bath was used to suppress this exothermic reaction by increasing the temperature above 32°. 3 at ectotherm
After stirring for an hour, the excess peracid was further reacted with 2.01 portions of 3,4-dimethoxy-i,2,5-thiadiazole and stirred for 1 hour.

The organic solution was diluted with 300μ of a 1% solution of Na HC03.
Extracted twice, washed with water 250111j, dried and evaporated under reduced pressure to yield product 47. I got Or. Recrystallization from inpropyl alcohol gave the title compound (34-(1)). Further recrystallization from inpropyl alcohol gave an analytical sample, mp 135-137°.

Analysis Calculated value as C4H6Nz03S: C, 29,6
3;H, 3,72;N, 17.27;S, 19.7
7° Experimental value: (1', 29.53; H, 3,75; #, 17
．． 26; S, 19.83° A solution of 1-oxide 3,4-dimethoxy-1,2,5-thiadiazole obtained from step A above was added to an equimolar amount of 2
-[(5-methyl-ig-imidazol-4-yl)-
The resulting 1-oxide 3-(2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethylamine)-4-methoxy-1,2゜5-thiadiazole was reacted with methylthio]ethylamine in excess. of methylamine, thereby giving the title compound.

EXAMPLE 5 By the general procedure of Example 12, step A, 1,1-dioxide 3-[2-((5-methyl-IH-imidazole-4-
yl)methylthio]ethylamino)-4-methoxy-1
, 2° When a methanolic solution of 5-deadiazole [prepared by the procedure of Example 1, Step A] is treated with a solution of caustic soda in methanol, the title compound, 5p263-2
65° (resolution) is obtained.

Analysis Calculated value as CgH13N5StOs: C, 35
, 64", H, 4, 32; N, 23.09; S, 21.
13° Experimental value: C, 35,56; H, 4,38; N, 23.0
1; S, 21.13° Example 6° 2-[(5-dimethylaminemethyl-2-furyl)methylthio]ethylamine (2,
41? ; 11.2 mmol) [Belgian patent 8523
A solution of 1,1-dioxide 3,4-dimethoxy-1,2,5-thiadiazole (2,0f; 11.2 mol) in methanol 200°C was prepared according to the procedure described in Section 8g. ) was added in its entirety to the suspension with good stirring. After stirring for 15 minutes at 8-10°, a methanolic solution of the title compound is obtained.

Anhydrous methylamine was bubbled into the cold (1°) methanolic solution of the product of Step A for 6 minutes. Stirring was continued for 10 minutes and the mixture was evaporated under reduced pressure. The residue was placed on silica gel 45f and chromatographed using a methylene chloride-methanol gradient elution. The appropriate portions were combined in methanol using methylene chloride-methanol (95:5), passed through Celite, and then concentrated under reduced pressure to give the product. Recrystallization from methanol gave the title compound (1,76F), 5p82-90@;
NMR spectrum in d6 dimethyl sulfoxide (l O
OhlHg) showed the presence of 273 moles of methanol.

Analysis Calculated value as C13H21NSO1S2・2/3CHsOH: C, 43, 10; #, 6.26; #, 18
．． 38; S, 16.83° Experimental value: C, 43, 30; H, 6, 12; N, 1B, 5
7; S, 16.96° The slowly eluting component from the middle chromatography in step B was eluted onto aluminum oxide 45f using methylene chloride-methanol (9:1), t'a, ethyl acetate-methanol gradient elution. Chromatographed using. Evaporation of the appropriate fractions and trituration of the residue with ether-acetonitrile gave a colorless solid, which was collected by filtration to give the title compound (4
28η) was obtained.

Analysis CHHuN, calculated value as 5304-H2O: C
,47,12;H,6,47;N,14.99;S,1
7.15゜ Actual value: C, 47, 2B; H, 6, 48: N, 15.0
9; Calculated value for S, 17.39° H2O -3.21%; Experimental value for H2O -3.32%.

Example 7゜del-2-furyl)methylthio]ethylamino)-4-
1,1-dioxide 3,4-dimethoxy-1,2,5-thiadiazole (2,0f; 1
1.2 mmol) of 2-((5-dimethylaminomethyl-2-furyl)methylthio]ethylamine (2
, 41P; 11.2 mmol) was added all at once. After drying for 15 min at 1-5°, ethylamine (4,0d) was added and stirring continued for 20 min at approx.
Lasted for minutes. The reaction mixture was evaporated under reduced pressure and the residue was placed on silica gel 46f and chromatographed using gradient elution using methylene chloride-methanol. The appropriate fractions were combined and evaporated, the gelatinous residue triturated under ether and filtered to give a colorless solid (2-814).
The product was obtained as Recrystallized twice from methanol and dried over 17 hours p2o at ambient temperature to give the title product,
NMR spectra (100 MHz) in sd6 dimethyl sulfoxide obtained mp 155-160@(94-96'') showed the presence of about 0.8 moles of methanol.

Analysis C1aHtsNsOsSz ・0.8 CH30
Calculated value as H: (:', 44.54; H, 6,62;
N, 17.55; S, 16.07° Experimental value: C, 44,35; H, 6,58; N, 17.4
4”.

S, 16.18° Example 8° 1,1-dioxide 3,4- in methanol 2001Rt
Dimethoxy-1,2,5-thiadiazole (2,(H'
2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine (2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine (
A solution of 2,41r; 11.2 mmol) was added over a period of 25 minutes. After stirring for 15 minutes at 1-2@, 2-propynylamine (4,
0!16) was added all at once and stirring was then continued for 1 hour at external temperature. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in silica gel 50? Place methylene chloride on top
Chromatographed using methanol gradient elution. Appropriate fractions were combined, evaporated and crystallized from methanol to give product 4.07. Recrystallization from methanol and then from isopropyl alcohol gave the title compound (
2,901), mp 92-100@; NMR spectrum in d6 dimedelsulfoxide (100 MHz) n
, showed that the product was solvated with 1 mol of methanol.

Analysis Calculated value as 015H2lN503Sz-CH30H: C, 46,25", H, 6,06:N, 16.8
5; S, 15.43° Experimental value: C, 46,36; H, 6,22; N, 16.9
5”.

S, 15.73° Example 9° Furfuryl alcohol (2,4
9? ; 25.4 mmol), salt rRN-methylpropylamine (4,0r; 37.9 mmol) and 40
% formalin (3.13u; 41.7 mi!j mole)
was added and the mixture was stirred while allowing it to reach ectotherm. After stirring for 1 hour, the solution was left at ambient temperature for 4-A days. The reaction mixture was poured into ice water and diluted with 4° aqueous NaOH.
The mixture was made strongly basic and extracted five times with methylene chloride. The combined organic phases were dried, filtered and evaporated under reduced pressure to give the product as an oil (quantitative yield). The title compound, b, 102-106@10.3 fat Hg was obtained by vacuum distillation.

Analysis Calculated value as CIof113No2: C, 67,
02; H, 7,31", N, 7.82 Experimental value: C, 66
,80;H,7,44;#,7.93Amine Cysteamine hydrochloride (27,'l;24
．． 6 mmol) of hydrochloric acid made into a cold (5°) solution under stirring and water-cooled.
00! 5-(CN-methyl-N-(2-propynyl)aminocomethyl)-2-furanmethanol (40,
233 mmol) [produced during step A] was added. The solution was left at 0° for 2-A days and then at ambient temperature for 7 hours to complete the reaction. The reaction mixture was cooled in a water bath, diluted with 200 d of water and diluted with 40% aqueous NaO.
The mixture was made strongly alkaline with H and then extracted three times with methylene chloride. The combined organic phases were dried, filtered and evaporated under reduced pressure to give the product as a thick oil (46,4F). This oil was quickly vacuum distilled to give the title compound, bp 136-14.
0.2 hours Hg was obtained.

Analysis Calculated value with c' as H1@N, Q3: C, 60
,47;H,7,61;/l/,11.76;S,13
-46° Experimental value: C, 59,82; H, 7,68; 7V, 11.
61; S, 13.27° 1,1-dioxide 3.4- in dry methanol 20ON
Dimethoxy-1,2,5-thiadiazole (2,0P;
11.2 mmol) into a cold (3°) suspension of 2-[
(5-((#-methyl-N-(2-propynyl)aminocomethyl)-2-furyl)methylthio]ethelamine (
2,68t; 11.2 mmol) [Process BCf' production]
A solution of was added. After stirring for 15 minutes at 3-7'', methylamine was bubbled into the solution for 15 minutes.

The reaction mixture was evaporated under reduced pressure and the oily residue was placed on silica gel 1002 and chromatographed using an acetonitrile-methanol gradient. Appropriate fractions were combined and rechromatographed on silica gel 1002 using a methylene chloride-methanol gradient. The appropriate fractions were dissolved in methylene chloride and extracted with 1% aqueous NaOH.

The aqueous phase was brought to pH 9 with 5% aqueous HCl and the separated oil was extracted three times with methylene chloride. The combined extracts were dried, filtered and evaporated under reduced pressure to give the product as a foam. Recrystallization from inpropyl alcohol gave the title compound, −
p50~51@, transparent melt 54~56'1 was obtained; D
6 NME in dimethyl sulfoxide (100MHz)
indicated the presence of about 1/4 mole of inpropyl alcohol.

Analysis C15li21N, 03:S, -174C3H,
Calculated value as 0: (1”, 47.47; ff, 5.82
;#, 17.57; 5j16.09° Experimental value: C, 47,51; H, 6,21; N, 16.4
0;S, 15.97゜Example 10 methanol 3-methyl-2-furfuryl alcohol (11,2f
; 0.1 mol [1, 9 hits, mue,, deaf, 2195 (1
950)], dimethylamine hydrochloride (12,23P; 0.15 mol) and 37
% aqueous formaldehyde (12jlj; 0.15 mol)
The mixture was stirred at about 5° for 2.5 hours and then at ambient temperature overnight. The solution was heated on a steam bath for 10 minutes, diluted with 12 ml of water and made basic with soda carbonate. The mixture was extracted with ethyl acetate and the organic phase was dried, filtered and evaporated under reduced pressure to yield the title compound, hp 8
8-96/0.05-0.08tnwHt was obtained.

5-dimethylaminomethyl-3-methyl-2-furanmethanol (3 . After 17 hours the cold solution was made strongly basic with aqueous KOH solution and then extracted five times with methylene chloride.

The combined organic phases were dried, filtered and evaporated under reduced pressure to give the title compound (4,16F), &p110-120 0.1
Obtained Dragon Hg.

3,4-dimethoxy-1,2,5-
Thiadiazole was reacted with an equimolar amount of 2-((5-dimethylaminomethyl-3-methyl-2-furyl)methylthio]ethylamine [produced in step B] to obtain 1,1
-When treating 3-(2-((5-dimethylaminemethyl-3-methyl-2-furyl)methylthio]ethylamine)-4-methoxy-1,2,5-thiadiazole with excess methylamine, it gives the title compound.

Example 11 A solution of 3-methyl-2-furfuryl alcohol (25,2r; 22.5 mmol) and triethylamine (27,3f; 27.0 mmol) in 20011 Ll of methylene chloride was brought to -15° in an ice-salt bath. Cool and lower the temperature to -10=
-15", a solution of methylene chloride (30 red thionyl chloride + 18.0 IRt; 24.8 mmol) was added dropwise. After 15 minutes, the mixture was poured into ice water and the organic phase was separated. - The methylene chloride phase containing methyl-2-chloromethylfuran is added to a solution of dimethylamine (137, (1; 3.04 mol) in 400 ml of absolute ethanol under stirring at 0° and the resulting solution is Stirred at external temperature for 17 hours. The reaction mixture was evaporated under reduced pressure and the residue was mixed with water 4001, made strongly basic with 40% aqueous NaOH and extracted five times with methylene chloride. The extracts were combined and dried. and evaporated under reduced pressure to give the title compound 26.(
I got 1,6p64-70n 20kg. TLCI Nijirika/CHCl3:CH30H (85:15)] is
Rf-Q, 50 was given.

-2-dimethylaminomethyl-3 in methylfuran chloroform 2501
-To a solution of methylfuran (6,5r; 37.0 mmol) [produced during step A] paraformaldehyde (1,67r)
; 55.7 mmol) and zinc chloride (312119) were added and a slow stream of HCt gas was bubbled in while stirring at ambient temperature for 15 minutes. Stirring was continued for 2 hours, then HCt gas was bubbled in for 15 minutes and the mixture was stirred for 1 hour. Additional paraformaldehyde (1,67r; 55.7 mmol) was added to the reaction mixture at this time and 1
A slow flow of HCt gas was bubbled in for 5 minutes. After stirring for 18 hours at external temperature, the reaction mixture was filtered through Celite and solution F was evaporated under reduced pressure to give the title compound (4,9
7f), which crystallized on standing and was used in Step C without further purification.

The NMR spectrum in CDCl3 gave the following resonances δ
:6.33ts, IH);4.55(a,2H1;4.
30 (d.

2H): 2.83(d, 6H); 2.13Ca, 3H)
.

2-Chloromethyl-5-dimetelaminomether-3-methylfuran (77
2-aminoethanethiol hydrochloride (392119; 3.45 mmol) was added to a solution of 3#; 3.45 mmol) and the mixture was stirred for 30 minutes. The solution was left at 0° C. for 3 days, then made strongly basic with 50% aqueous KOH, diluted with water, and extracted five times with methylene chloride. The combined extracts were dried, filtered and evaporated under reduced pressure to give the title compound as an oil.

The product was dissolved in absolute ethanol, treated with anhydrous hydrogen chloride and evaporated under reduced pressure. The residue was dissolved in hot isopropyl alcohol, treated with charcoal, filtered and concentrated to crystallize the hydrochloride salt. The title compound as the dihydrochloride salt by recrystallization from inpropyl alcohol, mplB5-190
” (decomposition) was obtained.

:l21,1-dioxide 3,4-dimethoxy-1,2,5-
A methanolic suspension of thiadiazole was added to an equimolar amount of 2-
1,1-dioxide 3-(2-[(5-
dimethylaminomethyl-4-methyl-2-furyl)methylthio]ethelamino)-4-methoxy-1,2,5-
When thiadiazole is reacted with excess methylamine,
The title compound is obtained.

Example 1 in 180 ν of dry methanol cooled to 10 in a 12° ice-water bath
．． A suspension of 1-dioxide 3,4-dimethoxy-1,2,5-thiadiazole (1,78f; 10.0 mmol) was added with dry methanol while stirring well. L6 middle school 2
A solution of -[:(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine (2,14P; 10.0 mmol) was added dropwise over 35 minutes. 1 at 0@
After 5 minutes, a methanolic solution of the title compound is obtained. TL
C(Silica/CHz Ct2: CHs 0H(9:
1)] gave Rf-0.48.

Part of this solution 2. Turn on 6. Acidified with HCl ON and evaporated under reduced pressure without heating to give the title compound as the salt rI&salt. The null spectrum in D20 is
δ that gave the following resonance: 6.45Cd, lH); 6.19
(d, Iff); 4.14 (a, 2ff); 4.0 (j
, 3i; 3.64 (s, 2ff); 3.37 (t, 2J
IN; 2-65 (s, 6H): 2.61 (t.

2H).

To a methanolic solution of the product of Step A, cooled to 0°C in an ice-water bath, was added a bath solution of caustic soda pellets (2.10 f; 52.5 mmol) in 25 IL of dry methanol. After drying for 2 hours at 0° and 68 hours at ambient temperature, the reaction mixture was converted to an aqueous 6. ON HCl 8.75μ(
52.5 mmol) and, after stirring for 10 minutes, evaporated under reduced pressure. The residue was crystallized under 95% E t OH to give the crude product, which was dissolved in methanol, filtered to remove the common salt, and placed on silica gel 601 using a methylene chloride-methanol gradient elution. Chromatographed. Appropriate fractions were combined and evaporated under reduced pressure to yield 3.1'l of product. Recrystallization from aqueous methanol gave the title compound, fij) 109-122°.

Analysis Calculated value as Cl2H,, N404S: C,4
L61; H, 5, 24; N, 16.17; 5f, 18.
51° Experimental value (corrected for 1.15% H,0): C', 4
1.59 near; 7, 5.32; #, 16.33; S, 1
8.81° Example 13° 1-oxide 3,4- cooled to 12-15° in an ice water bath
Dimethoxy-1,2,5-thiadiazole (2,50)
; 15.4 milJ mol) (prepared according to the procedure of Example 4, Step A) was added dropwise over a period of 14 minutes with good stirring. This solution was stirred at ambient temperature for 1.5 hours to obtain a methanolic solution of the title compound.

B, 1-oxide 3-(2-[:(5-dimethylamythate) Anhydrous methylamine was added for 8 min to a methanolic solution of the product of step A cooled to 5° in an ice-water bath. The reaction mixture was allowed to cool to an external temperature. Stirred for 17 hours at and then evaporated under reduced pressure to give the product as a yellow oil, which was purified by silica gel 5F.
1 and chromatographed using a methylene chloride-methanol gradient elution. Evaporation of appropriate fractions, dissolution in methanol, and dilution with diethyl ether afforded the title compound (2,32r) as a solid, which was vacuum dried at ambient temperature at p2o for 3 h to m p 86~
92°.

Analysis Calculated value as CIJt@N5QtSt: C, 45
, 46:H, 6, 16:N, 20.39:S, 18.6
7° Experimental value: C, 45,24:H, 6,24:N, 20.
41 ; S, 18.90° Example 14° 1.1- in methanol 200- cooled to θ° in an ice-water bath
A partial suspension of 3,4-dimethoxy-1,2,5-thiadiazole dioxide (2,08t: 11.7 mmol) in methanol 3o-((5-dimethylaminomethyl-
A solution of 2-furyl)methylthio]ethylamine was fed over a period of 45 minutes. When the addition was complete, allylamine 10.5- was added and the solution was stirred at ambient temperature for 18 hours. The reaction mixture was evaporated under reduced pressure and the residue was chromatographed on silica gel 120 using a methylene chloride-methanol gradient elution. Appropriate fractions were combined, evaporated under reduced pressure and the residue was crystallized from isopropyl alcohol to give the title compound, 83-86°; d, NMR spectrum in dimethyl sulfoxide (1
0ONHg ) indicated the presence of approximately 0.9 moles of isopropyl alcohol.

Analysis C,,HJsO,S, -0,9C, Calculated value as H8O: C, 48,36:H, 6,92:N, 15.
93; S, 14.59° Experimental value IC, 48, 46', H, 6, 96; N, 16.
13;S, 14.5B.

Example 3,4-dimethoxy-1,2,5-thiadiazole (1,89f; 10.
5 mmol) in 2111 t of methanol.
A solution of -((5-methylaminomethylaminomethyl-2-furyl)methylthio]ethylamine (0,7r; 3.51 mmol) [prepared according to the procedure described in Belgian patent 857.388] was added all at once. The mixture was stirred for 15 minutes, cooled to 1° in an ice-water bath, and then anhydrous methylamine was bubbled through the solution for 6 minutes. After stirring for 15 minutes, the reaction mixture was evaporated under reduced pressure and the residue was poured onto 110R of silica gel. and chromatographed using a gradient elution of acetonitrile to acetonitrile-methanol-glacial acetic acid (50:50:0.5).

Rf=0.50CTLC-Silica/CH, CM:CM,
OH:CM.

Appropriate fractions containing the first eluting component with coon (s O: 50:1)) were combined and evaporated under reduced pressure to give the title product as a form, sp 50-566.

NMR spectrum in d6 dimethyl sulfoxide (100
MHz) gave the following resonance δ: 6.20 (m, 2H
); 3.80 (s, 2H); 3.62 (g, 2H)
;3, so (22M): 2.90 (s, 3H);2.
70(t, 2H); 228(s*3H); it also indicated the presence of about 0.2 mol of methanol.

Analysis C□H0゜N603S2・0.2 Calculated value as CH30H: C, 41,65; H, 5,65: #, 19
．． 96; &, 18.28° Experimental value: C, 4L, 98:H, 5, 69:N, 19.5
4:8.18.54°Rf=0.47 [TLC-Silica/CH,CN:CH
, OH:CHsCOOH (50:50:l)] containing the slowly eluting components from the chromatography in step A were combined and evaporated, leaving a residue of 2.5Nα
Partitioned between OH and ethyl acetate. The aqueous phase was extracted several times with ethyl acetate and the organic phases were combined, dried and evaporated under reduced pressure to give the title compound as an oil.

NMR spectrum in d6 dimethyl sulfoxide (100
MHz) gave the following resonance δ: 6.22 (groove,
4H); 3-82 (a, 4H); 3.65 (a, 4H)
;3.50 (g.

4H); 2.72 (t, 4H): 2.30 (a, 6H)
.

Example 16 In a solution of 1°1-dioxidized 3,4-dimethoxy-1,2,5-thiadiazole (1,36f; 7.64 ml J mol) in 200° dry methanol cooled to 3° in an ice-water bath 4-(5-dimethylaminomethyl-2-furyl)butylamine (1,5r Nia, 6ml) in 40ml dry methanol under stirring.
A solution of 4 mmol) (prepared according to the procedure described in US Pat. No. 4,128,658) was added over a period of 45 minutes. After 15 minutes at 3°, anhydrous methylamine was bubbled into the cold solution for 10 minutes. The reaction mixture was evaporated under reduced pressure and the residue was placed on silica gel 60r and chromatographed using acetonitrile-methanol gradient elution. The appropriate fractions were combined to give product 2.16F. Recrystallize the title compound from acetonitrile, ?
I% 2152-153' was obtained.

Analysis C., HuN50. Calculated value as S: C, 49,
25;ff, 6.79;N, 20.51;S,
59.39° Experimental value: (1', 49.411.6.87; N, 20.
61;S, 9.2B.

Example 1,1 in 250 wt methanol cooled to 1° in a 17° ice-water bath
- 2-aminoethanethiol (hydrochloride to A solution of .91r; 16.8 mmol) was added over a period of 15 minutes. After 10 minutes at 2-4°, methylamine was bubbled into the solution for 6 minutes while cooling.
Stirring was continued for an additional 30 minutes at external temperature. The reaction mixture was evaporated under reduced pressure and the residue was chromatographed on silica gel 45 using a methylene chloride-methanol gradient elution. Appropriate fractions were combined and evaporated and the product (2,43r) was crystallized from absolute ethanol. Recrystallization from absolute ethanol gave the title compound, sp.
259-260' (decomposition) was obtained.

Analysis Calculated value as C'5HION40t'D: C,2
7,03; H, 4,54: N, 25.20° Experimental value: C
,27,13;H,4,55;#,24.86°B,1
．． 1-dioxide 3-(2-((5-dimethyla, a
1,1-dioxide 3-methylamino-4 in 20 d of hydrochloric acid
-(2-mercaptoethyl-1,2,5-thiadiazole (1,0f; 4.5 mmol) [produced during step A] and 5
-dimethylaminomethyl-2-furanmethanol (o,
52tH4,5 mmol) CJ, Chatyh, Hoe
, 4728 (1958)] was stirred in a water bath for 2 hours and then left at 00 for 64 hours. The reaction mixture was stirred at ambient temperature for 23 hours, evaporated under reduced pressure without heating and the residue was partitioned between water and methylene chloride. Make the aqueous phase basic with baking soda;
Extracted with methylene chloride/. The combined organic phases were washed with saturated brine solution, dried and evaporated under reduced pressure.

The residue was placed on silica gel 252 and chromatographed using a methylene chloride-methanol gradient elution. Appropriate fractions were evaporated and the product crystallized from methanol. Recrystallization from methanol gave the title compound, m
p 92-96° was obtained.

Example 1-oxidation 3,4-dimethoxy-1,2,5-thiadiazole (2
.
Aminoethanethiol (from hydrochloride, 2.04f; 1B
, 0 mmol) was added. After 10 minutes, anhydrous methylamine was bubbled through the solution for 6 minutes and stirring was continued for an additional 20 minutes at ambient temperature. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in silica gel 45? and chromatographed using a methylene chloride-methanol gradient elution. Combine the appropriate parts and evaporate to give the product 2.74
I got f. Recrystallization from methanol and then 95% ethanol gave the title compound, % 2191-193°.

1-oxide 3-methylamino-4-(2-mercaptoethyl)-1,2,5-thiadiazole [prepared in Step A] was prepared in concentrated hydrochloric acid according to the procedure described in Example 17, Step B.
When treated with an equivalent amount of 5-dimethylaminomethyl-2-furanmethanol, the title compound is thereby obtained; identical to the product of Example 13.

Example 19° 1,1-dioxide 3,4-dimethoxy-1,2,5-thiadiazole (2,08f; 1
2-[:(5-dimethylaminomethyl-
2-furyl)methylthio]ethylamine (2,5P; 1
1.7 mmol) was added over a period of 45 minutes.

When the addition was complete, methylamine was bubbled into the solution for 10 minutes while maintaining the temperature at 6°. After stirring for 18 hours at ambient temperature, the reaction mixture was evaporated under reduced pressure and the residue was chromatographed on silica gel 200 using a methylene chloride-methanol gradient elution.

The appropriate portions were combined, evaporated and the residue rechromatographed on aluminum oxide using a methylene chloride-methanol gradient elution over 75R. Combine appropriate fractions,
Evaporate under pressure to obtain the title compound, f% 2139-142
Got °.

Analysis Subtracted value as C□H,4NIO5S:C,44
,90:H,6,462N,18.70;S,17.1
2° Experimental value (corrected for 0.51% water) C, 44,77
:H, 6,25:N, 1B, 89:S, 17.42° Example 206 Ruamino-1,2,5-thiadiazole 1,1-dioxidized 3,4-dimethoxy-1 in methanol 250 at 10° ,2,5-thiadiazole (2,50r; 1
2-(:(2-guanidinothiazole-4-
yl)methylthio]ethylamine (from dihydrochloride, 4.
2ry: 14°O mmol) was added. 10°
After 15 minutes at , the solution was cooled to 1° in a cooling bath and anhydrous methylamine was bubbled into the solution for 10 minutes. The reaction mixture was evaporated under reduced pressure and the residue was placed on silica gel 6 (l) and chromatographed using a methylene chloride-methanol gradient elution. Product 4.539
Aluminum oxide 80? and rechromatographed using an ethyl acetate-methanol gradient elution. The appropriate fractions were combined and evaporated to give a form which was crystallized from methanol to give the title compound, m p 196-1980 (decomposition) (2,3
8F) was obtained.

Analysis Cl0H16N80.8! Calculated value: C, 3
1,90:H, 4,28:N, 29.77:S, 25.
55° Experimental value: C, 31, 85: H, 4, 24: N, 29.7
9:S, 25.45゜Example 21゜1,1-dioxide 3,4-dimethoxy-1,2,5-thiadiazole-&(2,Oy;
2-C(2-guanidinothiazol-4-yl)methylthio]ethylamine (from dihydrochloride, 3.42 r After 15 minutes at 8-10', the solution was cooled to 1° in an ice bath and a solution of 6.0-2 in methanol 151 nt was added.
-Propylamine was added. Remove the water bath and stir for 15 minutes.
Lasted for minutes. The reaction mixture was evaporated under reduced pressure and the residue was placed on silica gel 501 and chromatographed using a methylene chloride-methanol gradient elution. Fraction 2 gives the crystalline product (1,74r') from methanol
occurred. The product was dissolved in hot methanol, filtered through Celite, cooled, and filtered to give the title compound, m
p176-178° was obtained.

Analysis C1,H,,N,0. Calculated value as Fl: C,
35,99:H, 4,03:N, 27.98:S, 24
．． 02° Experimental value: C, 35, 82; H, 4, 12: N, 28.4
1:S, 24.28° Example 22° Tolyl A suspension of methylaminoacetonitrile hydrochloride (10 (1; 0.94 mol) in 1 liter of methylene chloride (cooled in a water bath) with triethylamine (260d: 1.88 mmol)
and phenyl chloroformate (is
s, or; 0.99 mol) was added. The reaction mixture was heated to reflux for 18 hours and then evaporated under reduced pressure to give a semi-solid which was triturated with 1 IJ liter of diethyl ether and filtered. The F solution was evaporated under reduced pressure, and the residual oil was vacuum distilled to give the title compound (123?), bpHl~113γ0.
．． 25 *w+Hf was obtained: CDCL, medium NMR spectrum (60 MHz) with L-order resonance, δ near, 2
3 (vortex, 5H); 4.30 (g, 2ff): 3.13 (
s, 3ff).

A solution of N-carbophenoxy-N-methylaminoacetonitrile (131,0f; 0.69 mol) [prepared in step A] in acetamide-dried DMF 917- was heated with H until an exothermic reaction occurred.
Treated with Ct gas and then heated on a steam bath for 20 minutes. The reaction mixture was partially evaporated under reduced pressure to remove some of the solvent, then basified with saturated aqueous NaHCO, solution and partitioned between ether and water. Extract the aqueous phase with ether,
The combined ethereal phases were washed with water, saturated aqueous NaCl solution and dried. Filtration and evaporation of the solvent gave an oil which was triturated with methylcyclohexane to give the product as a solid. Recrystallization from isopropyl alcohol gave the title compound, %9101-103°.

Analysis C, f, Hl, N, 0. Calculated value as S: C, 5
3,55; H, 5,40: N, 12.49; S, 14.
30° Experimental value 2G, 53.65; H, 5,51; N, 12.6
9; S, 14.41° (N-carbophenoxy-N-methylamino)thioacetamide (10t; 4.46 in absolute ethanol 6-
1,3 mmol) and dry pyridine (0,36d: 4.46 mmol) in 3 ml of absolute ethanol under cooling.
-dichloropropane (0.57f: 4.49 mmol)
A solution of was added. The mixture was heated to reflux for 1.5 hours, then evaporated under reduced pressure and the oil residue was partitioned between water and ether. The aqueous phase was extracted with ether, and the ether phases were combined, washed with water and a saturated saline solution, and dried. Filter and evaporate to a viscous oil to give the title compound 1.029
Obtained: TLC [Silica/CH,CL, :CH,CM
(85:15)) gave Rf=0.82.

The NME spectrum (60MB g) in CDC'ts is
δ near which gave the next resonance, 16 (inertia, sH); t77 (
Broad 8° 2H); 4.60 (a, 2ff)
; 3.07 (broad a, 3ff).

and sodium methoxylate (2,
Cysteamine hydrochloride (27,6f; 0.24 mol) in a nitrogen stream at 00 to a solution of 61t; 0.48 mol)
And an additional 218 g of absolute ethanol was added. After stirring for 1 hour at 0°, 4-
A solution of chloromethyl-2-(N-carbophenoxy-N-methylamino)methylthiazole (72.5t: 0.24 mol) was added over 15 minutes. The reaction mixture was stirred at ambient temperature for 18 hours, filtered and evaporated under reduced pressure to give an oil which was partitioned between methylene chloride and water.

The aqueous phase was extracted with methylene chloride, the organic phases were combined and washed with water,
Dry, filter and evaporate under reduced pressure to give the product (6
8,5P) was obtained, which was dissolved in fumaric acid (8,5P) in exo-propanol (
23,6F) to obtain the salt (47,0?). Recrystallized from absolute ethanol to give fumarate salt, mp145-1
The title compound was obtained as 46°.

Analysis C,sH,,N,0. S, -C,H,O, calculated values: C, 50, 31: H, 5, 11; N, 9.
27;-S, 14.14° Experimental value 2C, 50,02:H, 5,16:N, 9.47
:S, 14.22°2-([2-(N-
Carbophenoxy-N-methylamino)methyl-4-thiazolylcomethylthio)ethylamine (0,50P; 1
．． Lithium aluminum hydride (0.17 t: 4.48 mmol) was added to a solution of (48 mmol) [produced during the process] in a nitrogen stream, and the mixture was heated under reflux for 0.5 hour. Further add 10% of tetrahydrofuran and heat for 3
Lasted for an hour. The reaction mixture was treated with H,OO, 17wd,
15% aqueous Na0HO,17wt and H,00,51-
, filtered through Celite, and dried.

The lachrymal fluid was collected and evaporated under reduced pressure to obtain an oil, which was dissolved in absolute ethanol, diluted with diethyl ether, and dried in H.
Acidified with C1. The hygroscopic hydrochloride salt of the title compound was collected and partitioned between 2,5 N NaOH and methylene chloride. The organic phase was washed with water, dried and filtered. The lachrymal fluid was evaporated under reduced pressure to give the free base of the title compound (0,
221t: 0.95 mmol) was obtained, which was dissolved in oxalic anhydride (0.24P; 1.90
mmol) and the next. This mixture was evaporated from hot absolute ethanol to yield the title compound bis-oxalate, Ka216.
8-171° was obtained.

Analysis Calculated value as C1H1,N,04S,・2C,H,0,: C,37,951,5,15;#,10.21
:, 5', 15.59° Experimental value: C, 37,95; H, 5,04: N, 9.81
:S, 15.27°-4-methylamino-1,2,5-thiadiazole in methanol 80++t/1,1-dioxide 3,4-dimethoxy-1,2,5-thiadiazole (0,745';
4.17 mmol) 2-((
2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamine (0,91'; 4.17 mmol) [
1. The solution manufactured in Step E] was added for 45 minutes.
1-dioxide 3-(2-[(2-dimethylaminemethyl-4-thiazolyl)methylthio]ethylamino)-4
-Methoxy-1,2,5-thiadiazole, R/=0.
64 (Silica/CH, C1,: CM, 0H (9:1)
:l was obtained. The temperature was kept at 6° and anhydrous methylamine was bubbled into this solution for 8 minutes. The reaction mixture was evaporated under reduced pressure and the residue was placed on silica gel 80f and chromatographed using a methylene chloride-methanol gradient elution. The appropriate fractions were combined and the residue was purified using aluminum oxide 2 using a methylene chloride-methanol gradient elution.
5 was up-chromatographed. Recrystallization from isopropyl alcohol/ether gave the title compound, m p
144-148° (foaming) was obtained.

Analysis CI! Calculated value as H=N6Q, S: C, 3
8,28:H,5,35;N,22.32;&,25.
55° Experimental value: C, 37,89; H, 5,43; #, 22.1
9; S, 25.40° Example 23° Triethylamine (5.2 sg; 37.6 mmol) was added to a suspension of hydrochloric acid methylaminoacetonitrile (2.0f; 18.8 mmol) in 20-methylene chloride. friend. The resulting suspension was cooled in a water bath and diluted with methylene chloride 10
- A solution of ethyl chloroformate (2,14f: 19.8 mmol) in medium was added over 0.5 h and the mixture was then heated under reflux for 18 h. The reaction mixture was evaporated under reduced pressure to give a semi-solid residue which was triturated with diethyl ether, filtered and Part F was evaporated under reduced pressure to an oil, bp 96-98.
'/5.2 Obtain the title compound as txHy Asahi B
, (N-carbethoxy-N-methylamino)thioacetamide N-carbethoxyaminoacetonitrile (9,8 t; 6.9 mmol) in 175 m dry DMF
[Produced during step A] and thioacetamide (10,35r
; 13.8 mmol) was treated with hydrogen chloride until a strongly exothermic reaction occurred and then heated on a steam bath for 15 minutes. The reaction mixture was made basic with saturated NaHCO, solution, then extracted with ether, washed with water, and dried. The ether phase was evaporated under reduced pressure to obtain a solid residue, which was dissolved in methylene chloride, washed with water, and the organic phase was dried, treated with F, and evaporated under reduced pressure to obtain the product (2,5P). . Ethyl acetate
Recrystallization from hexane yielded the title compound, Ina 791-93.
Got °.

Analysis Calculated values as C, HI, N, O, S: C, 40,
89; H, 6, 87; #, 15.96;, 9, 18.9
2° Experimental value: C, 40,73; H, 6,85; N, 16.1
3; S, 18.86° in absolute ethanol 1801Rt (N-carbetoxy-N
-methylamino)thioacetamide (30,7t;
0.17 mol) [produced in step B] was added with dimethyl bromopyruvate (25.0 d
; 0.20 mol) solution was added. The reaction mixture was heated to reflux for 17 hours, then evaporated under reduced pressure and the residue was partitioned between ether and water. The organic phase was washed with water and saturated saline solution, dried, washed and evaporated under reduced pressure to give an oil, which was placed on silica gel and chromatographed using diethyl ether as the eluting solvent. The title compound was obtained as an oil from the appropriate fraction; TLC [CI on silica gel: CH,CN (85:15)
] gave Rf=0.50. The NMR spectrum (60 MHz) in dimethyl sulfoxide gave the following resonances δ: 8.49 (s, If); 4.79 (s
, 2H); 4.23 (s.

4H);3.00(a,aH):ll-30(,6H
).

Thiazole 2-(N-carbetoxy-N-methylamino)methyl-4 in 160% dry tetrahydrofuran was added to a suspension of lithium aluminum hydride (8,4f; 0.22 mol) in 80% dry tetrahydrofuran under cooling. -Carbetoxythiazole (20.0f: 0.07 mol) [Produced during step C]
solution was added over a period of 1 hour. The reaction mixture was heated at reflux for 8 hours, then cooled and decomposed with Na2SO4 and 40% aqueous caustic potash. The mixture was filtered, dried and evaporated under reduced pressure to yield the title compound 4 as an oil.
．． 2t was obtained; TLC (aluminum oxide/CM, C
M) gave Rf=0.45.

CDCL, medium NMft spectrum/' (60MH*) is
Gives the following resonance, next δ near, 17(s, IH); 4,73
(d, 2ff); 3.43 (a, 2Jf); 3.35 (
g, 6ff).

) Methylthio]ethylamine 2-dimethylamine methyl-4-hydroxymethylthiazole [manufactured during the process] is reacted with thionyl chloride, and the resulting 2-dimethylaminomethyl-4-chloromethylthiazole is mixed with an equimolar amount of cysteamine hydrochloride. and 2 equivalents of base (according to the general procedure of Example 22), thereby giving the title compound.

A methanol suspension of 1-oxide 3,4-dimethoxy-1,2,5-thiadiazole [Example 4, prepared in step A] was added to an equimolar amount of 2-((2-dimethylaminomethyl-4-thiazolyl)methylthio). ] Ethylamine [Example 22, Step E
1-oxide 3-(2-
((2-di-methylaminomethyl-4-thiazolyl)methylthio]ethylamino)-4-methoxy-1,2,5
- When thiadiazole is treated with methylamine, the title compound is thereby obtained.

Example 24゜1,1-dioxide 3,4-dimeth*cy in 220 wt of methanol 1,2,5-? 7 Diazo IL/(2
, 12f; 11.9 mmol) in 30 wt of methanol with good stirring. [Dihydrochloric acid 2-((
2-guanidinothiazol-4-yl)methylthio]ethylamine (4,0r; 13.0 mmol).
[obtained by neutralizing with 5N aqueous caustic soda and extracting with ethyl acetate] was added over a period of 1 hour.

Anhydrous ammonia was bubbled into this solution for 6 minutes while maintaining the temperature at 0.000 C, and stirring was continued for 0.5 hour at external temperature.

The reaction mixture was evaporated under reduced pressure and the residue was purified with silica gel 1
202 and chromatographed using a methylene chloride-methanol gradient elution. The appropriate portions were combined, evaporated and the residue chromatographed on silica gel 40f using a methylene chloride-methanol gradient elution.

Appropriate fractions were combined, flkimed under vacuum and dried under vacuum to give the title compound, 134-139° (foaming);
The NME spectrum (100 MHz) in 6 dimethyl sulfoxide/D, 0/DC1 gave the following resonances, δ near,
16 (i, IH); 3.84 (a, 2H); 3.52
(t, 2H); 2-75 (t.

2H); also indicated the presence of about 1.2 moles of methanol.

Analysis C@H14N@02 Ss ” 1.2 CH
Calculated value as 30H: C, 30,561,4,72;N
, 27.95; S, 23.99° experimental value (corrected for 1,31% H,0) C, 30,
19;7f, 4.32:N, 27.91;S, 24.7
1° Example A suspension of 1,1-dioxide 3,4-dimethoxy-1,2,5-thiadiazole (2,05P; 11.5 mmol) in 200° dry methanol was stirred well at 25°. 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine (2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine (
A solution of 3.5 f, 11.5 mmol) was added dropwise over 30 minutes. After 15 min at 3°, ethanolamine (1,03 m,
A solution of 17.3 mmol) was immediately added dropwise and stirred for 15 minutes. The reaction mixture was evaporated under reduced pressure to give the product as a brittle foam, which was crystallized from methanol.

Recrystallized twice from methanol to obtain the title compound, pseudop==
Slowly turns into resin from tis° and decomposes from 175'.

Analysis C,,H,,N,0. Calculated value as S: C,3
2,50:H,4,46;71/,27.57;,9
, 23.66° Experimental value (corrected for 3,85% H2O): C, 32
,77:H,4,21;#,27.90;S,24.
39° Example 26° 1,1-dioxidized 3,4-dimethoxy-1,2,5-thiadiazole (2, (1; 11.2
2-[:(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine (2,4
1t; 11.2 mmol) was added dropwise over a period of 45 minutes. After stirring for 15 minutes at Oo, a solution of anhydrous hydrazine (1,8f: 56.13 mmol) in 30° dry methanol was added all at once and stirring continued for 30 minutes. The reaction mixture was evaporated under reduced pressure, the solid residue was treated with chloroform, filtered and mj! 11 compounds, s
p 170° (decomposition) 3.28 ft was obtained.

Example 27° Thiadiazole A suspension of 1,1-dioxidized 3,4-dimethoxy-1,2,5-thiadiazole in 200 d of dry methanol cooled to 0 to 5° in an ice water bath was added with good stirring to 25° of dry methanol. 2-((2-pyridyl)methylthio]ethylamine (from dihydrobromide, 3.5 t; 10.6
solution Y (prepared according to the procedure described in Belgian patent 779,775) was added dropwise over a period of 30 minutes. After stirring the cold ameliorate for 15 minutes, anhydrous methylamine was bubbled into the solution for 15 minutes. The reaction mixture was stirred at external temperature for 45 minutes, evaporated under reduced pressure and the residue was crystallized from methanol. Recrystallization twice from methanol gave the title compound, % p 168-171°.

Analysis C,, H,, NsO, Calculated value as mind: C, 42
,xs;H,4,82;#,22.35;,S+,20
．． 46° Experiment 1 [:C, 42,07;H,4,75;#, 22
．． 28 ; S, 20.73° Example 28° Solution of 3-methyl-4-7 Razancarvone fi (27,0 r; o, 21 mol) in tetrahydrofuran 180-
1.02 j/a (825 sd; 0.84 mol) of borane in tetrahydrofuran was added in a stirred room under stirring (cooling in a water bath) in a stream of elementary gas. When the addition was complete, the mixture was stirred at ambient temperature overnight.

After 20 hours, 1 part of 6N HCl was added until hydrogen evolution ceased, and the reaction mixture was evaporated under reduced pressure. The residue was partitioned between methylene chloride and water, made basic with potassium carbonate, and the combined methylene chloride extracts were dried and evaporated under reduced pressure to give the product 21. I got Of. Eri title compound, 6p in vacuum distillation
99°/1 By was obtained.

48% aqueous hydrofluoric acid 60-3-hydroxymethyl-
4-Methylamine (2,49r; 21.8 mmol) [prepared during step A] and salt I! A solution of 122-aminoethanethiol (2-48r; 21.8 mmol) was stirred and heated at reflux temperature for 23 hours and then stirred at ambient temperature for 40 hours. Excess hydrobromic acid was removed under reduced pressure, the oil residue was dissolved in inpropyl alcohol, filtered through Celite, and the product was crystallized from liquid P. Recrystallized from isopropyl alcohol to give hydrobromide, m
The title compound was obtained as p142-143°.

1, z By the general procedure of Example 2, 1,1-dioxide 3,4-dimethoxy-1,2,5-thiadiazole was prepared in an equimolar amount of 2
-[(4-methyl-1,2,5-oxadiazole-3
When treated sequentially with -yl)methylthio]ethylamine [prepared in Step B] and excess methylamine, the title compound is thereby obtained.

Example 29゜1,1-dioxide 3-(2-C(5-methyl-1,2
゜4-Oxazol-3-yl)methylthio]ethylamine)-4-methylamino-1,2,5-thiadiazole Sodium methylate (2,89'?; 53.4 mmol) in 5QMl of methanol at 0@ Cysteamine hydrochloride (3,03P; 26.7 mmol) was added to the solution in several portions over 10 minutes while stirring. After stirring for 70 min at 0°, a solution of 3-chloromethyl-5-methyl-1°2,4-oxadiazole (3,54jF; 26.7 mmol) in 15aj methanol was added in portions over 15 min. and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was filtered, evaporated, redissolved in isopropyl alcohol, then treated with KF and evaporated under reduced pressure to give the title compound as a yellow oil. CDC1° Medium NM
The R spectrum (60MHz) gave the following resonances δ:
3.77 (a-2H); 2.77 (m*4ff); 2.
63('-3H).

-l 1,1-dioxide 3,4-dimethoxy-1,2,5-
Thiadiazole was prepared by the general procedure of Example 2 to form 2-[(5
-methyl-1,2,5-oxadiazol-3-yl)
When treated sequentially with methylthio]ethylamine [step Al1IP preparation] and methylamine, the title compound is thereby obtained.

4-Oxadiazol-5-yl methylthio etelamino-4-methylamino-1,2,5-thiadiazole 0 @ in methanol 20 d Sodium methyl V-
) (1,08f; 0.02 mol) was added with cysteamine hydrochloride (1,13f; 0.01 mol) in an argon stream with stirring.

This mixture was stirred for 1 hour at O@ and the resulting suspension was dissolved in methanol 1511 at O@.
1,32f; 0.01 mol) [Earν, Chi poison, A
eta, 55, 1979 (1972)] dropwise over a period of 25 minutes with stirring. The reaction mixture was stirred at ambient temperature for 45 minutes, concentrated to near dryness, then diluted with metele/chloride, filtered and evaporated under reduced pressure to give the title compound (1,9Sl) as a yellow oil. Ta. The NMR spectrum (60 MHz) in CD Ct gave the following resonances δ:
3.87 (a, 2H); 2.8 (Raku, 4H
); 2.53h3H).

: So 1,1-dioxide 3,4-dimethoxy-1,2,5-
A suspension of thiadiazole was prepared by the general procedure described in Example 2 to prepare an equimolar amount of 2-[(2-methyl-1,3,
When treated with 4-oxadiazol-5-yl)methylthio]ethylamine [Step ACF' backing] and excess methylamine, the title compound is thereby obtained.

Example 31゜1.1-Dioxide 3-(2-[(5-dimethylamizume) 159 m of dry methanol cooled to 0-3 in an ice-water bath
1, 1,1-dioxide 3,4-dimethoxy-1,2,
5-thiadiazole (0,77f; 4.34 mmol)
A solution of 2-((5
-dimethylaminomethyl-2-chenyl)methylthio]
A solution of ethylamine (i,or; 4.34 mmol) [prepared according to the procedure described in Belgian patent 867.105] 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 chromatographed on silica gel 50 using acetonitrile-methanol gradient elution. Excess fractions were combined to give product 1. O? I got it. Recrystallization from methanol gave the title compound, mp60.
5 to 66'' were obtained.

Example 32° 1 in 15 ynt of dry methanol cooled to 8 in an ice water bath
- oxidized 3,4-dimethoxy-1,2,5-thiadiazole (2,0t; 12.3 mmol)) in 25N dry methanol with good stirring. -furyl)methylthio]ethylamine (2,64r; 12.3 mmol) was added over a period of 30 minutes. After 15 minutes, ethylamine 4.Olj was added and the mixture was stirred for 1 hour at external temperature. .

The reaction mixture was evaporated under reduced pressure and the residue was purified with silica gel 55
? and chromatographed using a methylene chloride-methanol gradient elution. The appropriate portions 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, m
p 68-74° was obtained.

Analysis Calculated value as C14H23N502Sz: C, 4
7,04; H, 6,48; N, 19.59; S, 17.
94° Experimental value (corrected for 1.24% HIO): C, 46
,54;H,6,33;N,19.37;S,17.9
6° Example 33° 1° 1-dioxide 3,4-dimethoxy-1,2,5- in 200 IIt of dry methanol cooled to 2° in an ice-water bath
A suspension of thiadiazole (2-Of; 11-2 mmol) was added with good stirring to a suspension of thiadiazole (2-Of; 11-2 mmol) in 251 Lt of dry methanol.
A solution of -((5-dimethylaminomethyl-2-furyl)methyldeo]ethylamine (2,41t; 11.2 mmol) was added over a period of 30 minutes.

After 15 minutes, 4.0!11j of exo-probylamine were added all at once and the mixture was stirred for 30 minutes at ambient temperature. The reaction mixture was evaporated under reduced pressure and the residue was placed on silica gel 55f and chromatographed using a medelene chloride-methanol gradient elution. The appropriate portions were combined, evaporated under reduced pressure, and the syrup was crystallized from ether to yield the title compound, mp 164-166"3.79;
NMR spectrum in d6 dimethyl sulfoxide (100
MHz) indicated the presence of approximately 0.9 moles of methanol.

Analysis C15H2sNsOsSz・0.9 Calculated value as CH40: C, 45-86; ff, 6.92; N, 1
6.82; S, 15.40° Experimental value: C, 45,60; H, 6,93; N, 17.0
3; S, 15.47° Example 34° 1-oxide 3,4-dimethoxy-1,2,5-thiadiazole (
2-[(5-dimethylaminomethyl-2-furyl→methylthio]ethylamine (
3.3f; 15.4 mmol] was added over a period of 30 minutes. After 1.5 hours, anhydrous ammonia was bubbled into the solution for 8 minutes, and the mixture was heated on the outside for 30 minutes.
Stir for a minute. The reaction mixture was evaporated under reduced pressure and the residue was placed on silica gel 60f and chromatographed using a methylene chloride-methanol gradient elution. The appropriate portions were combined, evaporated and the product crystallized from acetonitrile. Recrystallization from inpropyl alcohol gave the title compound, mp 139-142°2.59f.

l Cl2H1, N502S, h Calculated value: C, 43
,75;j7.5.81;/l/,2126;S,19
．． 46° Experimental value: Cl43.71; H, 6,05; A/, 21.
32; S, 19.510 in dry methanol cooled to 5°C in an ice water bath 1.
To a suspension of 1-dioxide 3.4-dimethoxy-1,2,5-thiadiazole (2,08f; 11.8 mmol) was added 2-((5
A solution of -dimethylaminomethyl-2-furyl)methylthio]ethylamine (2,5P; 11.7 mlJ mol) was added dropwise over a period of 45 minutes.

After 30 minutes, 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 purified with silica gel 200
P and chromatographed using a methylene chloride-methanol gradient elution. Appropriate fractions were combined and evaporated to yield 3.6t of product. Recrystallization from methanol-ether gave the title compound, mp156-158@ Analysis Calculated as CI, Hl, N, 03g: C
, 4L72; H, 5,54", N, 20.28".

S, 18.56° Experimental value: (ll', 41.50; H, 5, 52; #, 2
1-oxide 3,4-dimethoxy-1,2,5-theadiazole-/I' (3,24r
2-[(guanidinothiazol-4-yl)methylthio]ethylamine (from dihydrochloride, 6.08 r; 20.0 mmol) in methanol 50 V with good stirring into a cold (5°) solution of solution was added dropwise over a period of 45 minutes. After stirring at 5-101 for 1.5 hours, anhydrous ammonia was bubbled into the solution for 10 minutes and continued for 18 hours at external temperature with stirring. The reaction mixture was evaporated under reduced pressure and the residue was placed on silica gel 65f.
Chromatographed using a methylene chloride-methanol gradient elution. Appropriate fractions were combined and evaporated to yield product 4.16f from methanol. Recrystallization from methanol yields the title compound, mp 167-170” (decomposition)
I got it.

Analysis CJ14Nsc) B, Calculated value: C, 31,
20; H, 4,07; #, 32.35; S, 27.7
6° Experimental value (corrected for 0.48% H, O): 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, 5p136-138@ (decomposition).

Analysis Calculated value as C@H14NmO8@・H,0: □
2 C, 29,66; J7, 4.42; N, 30.75;
S', 26.39° Experimental value: C, 29,92; H, 4,42; N, 30.8
4:S, 26.58° A sample of this product as the free base was suspended in 95% ethanol and 1 equivalent of aqueous 6.58° was suspended in 95% ethanol. Treatment with ON hydrochloric acid and filtration gave the hydrochloride salt, mp200-201@ (decomposed).

Bon standing C, H, C1N, O8, calculated value: C, 28
,23;H,3,95;#,29.26;CL,9.
26 Experimental value (corrected for 1.02% H2O1/C): C,
2B, 26; H, 3-83; N, 29.41: C1,9
,53 t-1'l・1,1-dioxide 3-benzylamino-4-2-5-
Dimethylaminomethyl-2-furyl methylthio ethylamino-1,2,5-thiadiazole in ice water bath 1-3
2-((5 -dimethylaminomethyl-2-furyl)methylthio]ethylamine (2,4r
; 11.2 mmol) was added dropwise over a period of 35 minutes. After 15 minutes in 1-3@, benzylamine (1,
83rnt; 16.8 mmol) was added and the solution was stirred for 1 hour at ambient temperature. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in silica gel 50? and chromatographed using a methylene chloride-methanol gradient elution. Appropriate fractions were combined to give product *4.1f.

Recrystallization from aqueous methanol and then methanol gave the title compound, 5p152° (decomposed); NMR spectrum in d6 dimethyl sulfoxide (100 Mffg) showed the presence of about 1.0 mole methanol.

Analysis C1*Ih5NsOsS z ・Calculated value as CH40: C, 51,37; H, 6,25; #, 14.9
8° Experimental value: C, 51,51; H, 6,05", N, 1
4-78° Example 38° 1 in 200xj of dry methanol cooled to 2° in an ice-water bath
．． A suspension of 1-dioxide 3,4-dimethoxy-1,2,5-thiadiazole (2,(1; 11.2 mmol)) was added with good stirring to a suspension of 2-(2,(1; 11.2 mmol)) in dry methanol 2Srxl.
A solution of (3-(dimethylaminomethyl)phenyl)methylthio]ethylamine (2,51f; 112 mmol) [prepared according to the procedure described in Belgian patent 862106] was added dropwise over a period of 30 minutes. After 15 minutes at 2-5, anhydrous methylamine was bubbled into the solution for 10 minutes, then the solution was stirred at external temperature for 30 minutes. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in silica gel 60? and chromatographed using a methylene chloride-methanol gradient elution. The appropriate fractions were combined to give product 2.96f. Recrystallization from acetonitrile then methanol gave the title compound, m4p152.
~158° was obtained; NMR in d6 dimethyl sulfoxide
The spectrum showed the presence of about 0.6 moles of methanol.

Analysis Calculated value as C15H, NsO, S2-0.6CH, 0: C, 48, 20; H, 6, 59; #, 18-0
2; S, 16.49° Experimental value: C, 4'L99; H, 6,78: N, 17.8
1; S, 16.09° Example 39° 1-oxide 3-amino-4-[2-[(3-(1- in 100 ml of dry methanol cooled to 5° in a dimethyl water bath)
To a solution of the oxide 3,4-dimethoxy-1,2,5-thiadiazole (2,0f; 12.3 mmol) was added 2-C(3-(
A solution of dimethylaminomethyl)phenyl)methylthio]ethylamine (2-77r; 12.3 mmol) was added to 4
It was added dropwise over a period of 5 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 external temperature, the reaction mixture was evaporated under reduced pressure and
The residue was placed on silica gel 55f and chromatographed using a methylene chloride-methanol gradient elution. The appropriate fractions were combined to obtain the product 3. from acetonitrile. O
I got v. Recrystallization from acetone yielded the title compound, mp
122-125@ was obtained.

Analysis C1aH21N50S2 and Ltt calculation (ilL
:C, 49,53; H, 6,23; /l/, 20.63
; S, 18.89° Experimental value: C, 49, 18: H, 6,08; N, 20.9
3:, S', 19.25° Example 40 1-oxide 3,4-dimethoxy-1,2,5-thiadiazole (1,06f; 6.5 mmol) in anhydrous methanol 15Q [1,06f; 6.5 mmol], trap-cooled at 3° in a water bath To a solution of 2-[(5-dimethylaminomethyl-2-chenylunmethyltheo)]ethylamine (1,5
A solution of P; 6.5 mmol) was added dropwise over a period of 45 minutes. After 15 minutes at 31, 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 silica gel 752 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 Calculated value as C13H21NsO83: C, 43
,42;H,5,89;#,19.48;,! ? , 26
．． 76° Experimental value: C, 43,70; H, 5,58; #, 19.7
1; S, 26.79° Example 41° 1.1-dioxide 3-amino-4-(4-(5-dimethe) 1.1-dioxide 3, in dry methanol 150ν cooled to 0 to 3° in an ice bath 4-dimethoxy-1* 2.5
-Thiadiazole (1,46f; 8.2 mmol) was added to a suspension of 4-(
A solution of 5-dimethylaminomethyl-2-furyl)butylamine (1,611; 8.2 mmol) was added dropwise over a period of 35 minutes. After 15 minutes, anhydrous ammonia was bubbled into the solution for 5 minutes and the solution was stirred for 30 minutes. The reaction mixture was evaporated under reduced pressure and the residue was chromatographed on silica gel 60 using acetonitrile-methanol gradient elution. Appropriate fractions were combined and evaporated to yield product 1.68F.

Crystallization from acetonitrile gives the title compound, mp1
54-156° (obtained decomposition.

Analysis Calculated value as C13H21N503S: C, 47
,69;H,6,47;#,21.39;S,9.
80° Experimental value: C, 47,73; H, 6,28: N, 21.4
3 ; S, 9.84° Example 1,1-dioxide 3,4-dimethoxy-1,2,5-thiadiazole (0
, 69f; 3.89 mmol) in dry methanol 2011.
-Deazolyl)methylthio]ethylamine (0,9?:
A solution of 3.89 mmol) was fed over a period of 40 minutes,
Anhydrous ammonia was bubbled into the solution for 8 minutes, then the solution was stirred at ambient temperature for 18 hours. The reaction mixture was evaporated under reduced pressure and the residue was placed on a 7S gel 1502 and chromatographed using acetonitrile-methanol gradient elution. The appropriate portions were combined and evaporated to give 0.66 P of product. This form was dissolved in 2-propanol and evaporated to dryness to yield the title compound, my
60-65° was obtained; NM in d6 dimethyl sulfoxide
The R spectrum (100A□g) shows approximately 0.16 moles of 2
- Indicated the presence of propanol.

Analysis Values calculated as CHHll, N6S302・C, HsO: (:', 37.02; H, 5, 21; #, 22.
62; S, 25.89° Experimental value (corrected as 2.79% HIO): C, 36,
75; H, 5, 13; N, 21.75; S, 25.03
゜Example 43゜Amidinothiourea (1
A solution of 17f; 0.99 mol) and hychloro-alpha-formylacetic ether (150r; 1.0 mol) was stirred at ambient temperature for 18 hours, then heated to reflux for 1 hour. At this time, additional ethyl chloro-α-formylacetate (20.0f; 0.0f) was added.
13 mol) was added, and after 1 hour, an additional 20 mol of chloro-α-formylacetic acid was added. (l was added. After further heating and refluxing for 2 hours,
The reaction mixture was evaporated under reduced pressure and the residue was dissolved in 1.5 ml of acetone.
Trituration and filtration gave product 103f. 2
- the title compound recrystallized from propatool, mp 2
Obtained 04-206@.

Analysis Calculated value as C7HHCIJ'J40zS: C,
33,53", H, 1L43; N, 22.35; C1,
14,14; S, 12.79° Experimental value: C, 33,38: H, 4,40; N, 22.5
4; C1,13,97; P;, 12.92° (B) 2-
Guanidino-5-hydroxymethylteasheet - Cooled in a suspension of tetrahydrofuran 25 lithium aluminum hydride (0.46r; 12.1 mmol) (
2-guanidino-5-thiazolecarboxylic acid ether hydrochloride (1.0 r; 3.99 mmol) [prepared during step A] was added to the mixture (ice-water bath).

The reaction mixture was then heated to reflux for 2 hours, cooled and 0.46
j! t Hzo, 0.46 15% NaOH and 1.
Digested with 38 ml of H2O and filtered. Solution F was dried and evaporated under reduced pressure to obtain 0.61r of product. Recrystallization from acetonitrile yielded the title compound, p168-170°
I got it.

Analysis Calculated value as CsH@N40S: C, 34, 87
; H, 4,68; #, 32.54; S, 1g, 62° Experimental value: C, 34,55; H, 4,52; N, 32.6
3; S, 1 g, 54° cysteamine hydrochloride (10,6 t; 9.3 mmol) and 2-guanidino-5-hydroxymethylthiazole (1
6,Ot; 9.3 mmol) [produced in step B] was dissolved in concentrated hydrochloric acid 801, stirred at an external temperature of this solution for 1 hour, and then heated under reflux for 3 hours. The reaction mixture was cooled to 40
% aqueous NaOH (pH 11) and filtered to give product 159. Recrystallization from acetonitrile gave the title compound, 5p150-153@.

Analysis Calculated value as CrH1sNs82: C, 36,3
4; H, 5, 66; /l/, 30.27; S, 27
．． 72° Experimental value: C', 36.29; ff, 5.70; N, 30
．． 40;S, 27.64° 1,1- in methanol 1601 cooled to 80°C in an ice-water bath
To a suspension of 3,4-dimethoxy-1,2,5-thiadiazole (1,54P; 8.64 mmol) in methanol 601 was added 2-[(2-guanidinothiazol-5-yl) dioxide with good stirring. Methylthio]ethylamine (2.0f; 8.64 mmol) [Step CI'l'1
lia solution] 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 dissolved in silica gel 175? and chromatographed using acetonitrile-methanol gradient elution. Appropriate fractions combined product 1.3? I got it. Recrystallization from methanol gave the title compound, mp225-226@ (decomposition).

Analysis C1,H,,N,0. Calculated value as S3: C, 3
L, 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-oxide 3-amino-4-[2-[(2-guanidino 1-oxide 3° 4-dimethoxy-1,2,5 in 200 lj methanol cooled to 8° -thiadiazole (
2-((2-guanidinothiazol-5-yl)methylthio]ethylamine (3,Of
; 13.0 mmol) [Example 43, prepared in Step C] was added dropwise over a period of 40 minutes, and then anhydrous ammonia was bubbled into this solution for 8 minutes. After stirring for 18 hours at ambient temperature, the reaction mixture was evaporated under reduced pressure and the residue was placed on silica gel 225f and chromatographed using acetonitrile-methanol gradient elution. Combine appropriate fractions to obtain the title compound, mp85-132@3.61F
Obtained: wptp spectrum in d6 dimethelsulfoxide (100 MHtl showed the presence of about 0.3 moles of acetonitrile.

Analysis C, H14NsO83・Q, 3 Calculated value as CtHsN: C, 32, 24; H, 4, 22; #, 32
．． 41 ; S, 26.71° Experimental value (corrected as 1,84% H2O): (1', 3
2-63: H, 4, 33; #, 32-55; S, 26.
62° Example 45° The general procedure of Example 8 was repeated, 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 title compound 3 was obtained by recrystallization from inpropyl alcohol.
．． 511 regular p 194-195” (min P#) was obtained;
NMR spectrum in d6 dimethyl sulfoxide (100
MHz) indicated the presence of approximately 1.0 moles of inpropyl alcohol.

Analysis C15H-N503S, -C3H,O Calculated value: C, 48,52: H, 7,01; N, 15.72° Experimental value: C, 4B, 36; H, 6,95: #, 14. 87
゜Example 46゜? The general procedure of Example 8 was repeated, except that the 2-propynylamine used in IJS was replaced with equimolar cyclopropylmethylamine and the product was crystallized from methanol. Recrystallization from methanol gave the title compound 1.6f, mp 86-89°C (decomposed): d, NME spectrum in dimethyl methyl oxide (100Aff
g) showed the presence of about 1.25 mol of methanol.

Analysis C++*HmNsOsSz・1.25 Calculated value as CH40: C, 47,13; H, 6,88; N, 15.9
3° Experimental value: C, 47, 40; H, 6, 49; N, 15
．． 77° Example 47° The general procedure of Example 19 was repeated, except that the dimethylamine used in Example 19 was replaced with an equimolar amount of morpholine. After column chromatography, the product was crystallized from inpropyl alcohol. This mixture was diluted with Skellin Lub B and filtered to give the title compound, 5p1.
22-127° was obtained.

Analysis C1, H, N, 04;, drunkenness gL:C', 4
6.24: ff, 6.06; N, 16.86° experimental value (
(corrected as 0.61% H, O): C, 45,82; H
, 6,06; N, 16.62° Example 48° Example 8 except that the 2-propynylamine used in Example 8 was replaced with equimolar 2-methoxyethylamine.
The general operations were repeated. After column chromatography, the residue was treated with inpropyl alcohol, evaporated to near dryness, and cooled to yield product 3.79F. Recrystallization from isopropyl alcohol gave the title compound, mp 56-58''; NME spectrum (100 MHz) in d6 dimethyl sulfoxide showed the presence of about 0.6 moles of inpropyl alcohol.

Analysis C+sHmNsO4s z ・0.6 C5HaO
Calculated values: C, 45,90; H, 6,83", N,
15.93° Experimental value (corrected as 0.74% H,O)
:C, 45,50:H, 6,72:N, 15.63° Example 49° General procedure of Example 19, except that dimethylamine used in Example 19 was replaced with an equimolar amount of pyrrolidine. I repeated. The crude reaction mixture was evaporated under reduced pressure, treated with inopropyl alcohol and filtered to give the title product 3.92
%spl 51-1521 was obtained.

Analysis C1 @ HBN 603 S @ Calculated value: C
', 48.09: H, 6,31; #, 17.53° Experimental value: C, 48,00; H, 6,10; N, 17.7
1° Example 50° The general procedure of Example 19 was repeated, except that the dimethylamine used in Example 19 was replaced with an equimolar amount of piperidine. Chromatography yielded product 3.87.

Recrystallization from hydrothermal ethanol gave the title compound, m1p.
106-108@ was obtained.

Calculated value as analysis C, H revision N103S: C, 49,
37: H, 6,58", N, 16.94° experimental value (0,
(corrected as 2% H, O); C, 49, 17", H, 6
, 52:N, 17.14° Example 51° The general procedure of Example 8 was repeated, except that the 2-propynylamine used in Example 8 was replaced with an equimolar amount of butylamine. The crude product was chromatographed three times and heated to dryness under high vacuum for 3.5 hours to yield 1.81 t of the title compound as a somewhat rubbery foam. Calculated value as N503S: C, 47
, 86; H, 6, 78; N, 17.44° experimental value (1,
(corrected as 34% H, O): C, 47, 60: ff,
6.81; #, 17.81° Example 52° Example 8 except that the 2-propynylamine used in Example 8 was replaced with an equimolar amount of 2-aminomethylpyridine.
The general operations were repeated. Combine appropriate fractions from column chromatography to produce $3.9? I got it. Recrystallization twice from isopropyl alcohol gave the title compound, m
p43-45@ were obtained. The sample was recrystallized from absolute ethanol and the solid was heated under vacuum to 60°C for 6 hours to obtain a melt. Dissolved in this melt hot isopropyl alcohol,
Collected by filtration at ambient temperature and dried under high vacuum to give the title compound, 5p45-47@; NMR spectrum in d6 dimethyl sulfoxide (100 MHz) showed ca.
It showed the presence of 25 moles of inpropyl alcohol.

Analysis Calculated as Cx5HuNaO3Sx 1.25C3HBO: C, 51,05; H, 6,70; #, 16.
42° Experimental value (corrected as 0.58% H2O): C,
51,08:H, 6,32;N, 16.03゜Example
53° Example 8 A The general procedure of Example 8 was repeated, except that the 2-propynylamine used was replaced by 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 the title compound 2.595', inert p20.
I got 3~205@.

Calculated value as analysis C12H1gNC12H1: C, 39
,87:H,5,30;A',19.38;S,17.
74° Experimental value (corrected as 1.18% H2O): C, 39,
53; H, 5, 04; #, 19.61; S, 17.6
1,1-dioxide 3,4-dimethoxy-1,2,5-thiadiazole (2,0r; 1
A cold suspension of 2-((5-dimethylaminomethyl-2
-furyl)methylthio]ethylamine (2,4xr; 1
A solution of t, 2 mmol) was added. After stirring for 15 minutes at 2-5', a solution of dodecylamine (4,15F'; 22.4 mmol) in 25 mt of methanol was added all at once and stirring continued for 18 hours at ambient temperature. The reaction mixture was evaporated under reduced pressure and the residue was
The appropriate fractions were combined, evaporated and the residue was chromatographed on Rica gel 6 (l) using a gradient elution of methylene chloride/-methanol. Silica gel 60 was ascending chromatographed. The appropriate fractions from the second chromatography were combined and concentrated under reduced pressure 11!! and the crystallized product was collected by filtration and dried to yield the title compound 2. 13
f%mp 136-139° was obtained.

Analysis C24H4sNs03S, # Calculated value: C, 55
,89;H,&79;N,13.58;S,12.
43° Experimental value: C', 56.16; H, 8,57; #, 13.
38; S, 12.61° Example 55° The general procedure of Example 8 was repeated, except that the 2-propynylamine used in Example 8 was replaced with an equimolar amount of methoxyamine. The reaction mixture was stirred at ambient temperature overnight, during which time a crystalline precipitate formed. The solution was cooled, filtered and the solid collected was dried to yield the title compound 3.82, mp
224-226 (decomposition) was obtained.

Analysis: C, 3H21Ns04S, calculated value: C, 41
,59:ff, 5.64;/l/, 18.65
;S, 17.0B.

Experimental value (corrected as 0.79% H,O): C, 41,
25:H, 5, 54; A/, 18.50; S, 17
．． 16° Example 56° The general procedure of Example 31 was repeated, except that the methylamine used in Example 31 was replaced with an equimolar amount of propylamine. 3. Crystalline product by chromatography.
I got 52. Recrystallization from acetonitrile gave the title compound, mp 194-196° (decomposed).

Calculated value as analysis C15HHNs0283: C, 44,
64; H, 6,24; /l/, 17.35; S, 23° 84° Experimental value: C, 44,66; H, 6,02; N, 17.8
8; S, 23.87゜Example 57゜To a solution of 1-oxide 3,4-dimethoxy-1,2,5-thiadiazole in 200 ν of methanol cooled to 3 in an ice-water bath was added 2-chloride 5 in 25 ILt of methanol under stirring. A solution of -dimethylaminomethyl-2-chenyl)methylthio]ethelamine (2,84P; 12.3 mmol)
The feeding was carried out over a period of 5 minutes. After stirring for 15 minutes, anhydrous ammonia was bubbled into the solution for 5 minutes. The reaction mixture was evaporated under reduced pressure and the residue was chromatographed on silica gel 60 using a methylene chloride-methanol gradient elution. Adding the excess parts gives a product of 1.7
I got 3r. Recrystallization from acetonitrile gave the title compound, mp 149-152° (dec.).

Example 58゜Azole The methylamine used in Example 31 was added in an equimolar amount of 3-
The general procedure of Example 31 was repeated, except that aminomethylpyridine was substituted. The title compound 3.1Of was obtained as an oil from both ends of column chromatography. The product was dissolved in excess 5% HClK, evaporated and then triturated with inpropyl alcohol to give a solid product. Recrystallized from 95% aqueous ethanol to give dihydrochloride, mz
The title compound was obtained as +143-146.5'.

Analysis 01@H2sC14N 60 z Calculated as S s: C', 41.13; H, 4,99; A/, 15.
99; S, 18.30° Experimental value (corrected as 2,04% H, 0): C, 41,
25;H,4,90;#,16.18;5l18.52
1 in 200 Iit of methanol cooled to 3 in an ice water bath
To a solution of 1-dioxide 3.4-dimethoxy-1,2,5-thiadiazole (1,55r; 8.68 mmol) in methanol 25R3 was added 2-((5-dimethylaminemethyl-2-chenyl) Methylthio]ethylamine (
2,0? , 8.68 mmol) was added dropwise over a period of 35 minutes. After stirring for 15 minutes, add 1 portion of anhydrous ammonia to the solution.
Bubbled for 0 minutes. The reaction mixture was evaporated under reduced pressure to give the title compound 3.32.

d6 NMR spectrum in dimethyl sulfoxide (10
0MHz) f′i, δ that gave the following resonance: 6.88(d
, If); 6.78 (d, IH); 4.03 (a, 2
B); 3.61 (s.

2H); 3.54 (t, 2H); 2.74 (t, 2H)
;2.22(a,6H); It also showed the presence of about 273 moles of methanol.

EXAMPLE 60 The general procedure of Example 31 was repeated, except that the methylamine used in Example 31 was replaced by an equimolar amount of benzylamine. The reaction mixture was evaporated under reduced pressure to obtain the product.

Recrystallization from methanol and subsequent work-up yielded the title compound 2.
63? , ml 203-205.5@(decomposition) was obtained.

Calculated value as analysis C1gH25Ns02S3: C, 50
,53;H,5,58;#,15.51;S,21.
30° Experimental value: C, 50,79; H, 5,34; #, 15.7
8:S, 20.94° Example 61° 1,1 in methanol 250 red cooled in 09 in an ice water bath
A suspension of 3,4-dimethoxy-1,2,5-thiadiazole (2,5P; 14.0 mmol) was added to a suspension of 3-(:3-(dimethylaminomethyl)phenoxy]propyl siloxide in methanol for 50 minutes with stirring. Amine (2,73P:1
A solution of 4.0 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 placed on silica gel 752 and chromatographed using a methylene chloride-methanol gradient elution. The appropriate fractions were combined, evaporated, dissolved in 1-propanol, treated with 1 charge of HCL, and salted! ! j!
The product was obtained as a salt. Recrystallization from aqueous ethanol gave the title compound as the hydrochloride salt, 5p140-145°.

Calculated value as analysis C15H, 4N503S: C, 46,
20:H, 6, 20:#, 17.96;S, 8.
38; C1,9,05° experimental value (3,79% H,
(corrected as O): C, 46, 21; H, 6, 06; N,
18.24; S, 8.38: CL, 9.05
゜Example 62゜(N-carbophenoxy-N-methylamino)thioacetamide (46,7P: 0.21 mol) was combined with 1,2-dichloroethano2(0.20 mol) and heated under reflux for 2 hours. did. Additional amount of α-formyl ethyl chloroacetate (3,(1; 0.02 mol) was added and heating was continued for 1.5 hours. The reaction mixture was extracted twice with 300a each of cold 5% aqueous sodium carbonate and It was then washed twice with 300v of water and dried over Na2SO4. Evaporation gave the product as an oil which slowly crystallized. Recrystallization from 2-propanol gave the title compound 21'% vnp. Obtained 81-83@.

Calculated value as analysis C + BH1aN204S 2C, 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°E, 2-Hydroxymethyl-5-dimethylaminomethylthiazole Cold (5
5-carbetoxy-2-(N-carbophenoxy-N-methylamine)methylthiazole (1
9.8f; 0.62 mol) [manufactured during step A] was added. The reaction mixture was heated to reflux for 0.5 h, then cooled to room temperature, decomposed, passed through Celite, and evaporated under reduced pressure. The residue was dissolved in 180 ml of 3N HC and extracted with ether. The aqueous phase was adjusted to pH 8 and extracted with methylene chloride. The organic phase is dried, filtered and evaporated in vacuo to yield the title compound 6. Of was obtained as an oil. NM in CDCl5
The R spectrum (60MZrg) gave the following resonances δ = 7.50 (a, IH); 4.85 (a, 2H); 4
．． 15 (g.

IH); 3.75 (a, 2H); 2.35 (a
, 6H).

C12-Chloromethyl-5-dimethylaminomethylthiazole To a cold (ice-water bath) solution of 5-hydroxymethyl-2-dimethylaminothiazole (8,9f; 52.0 mmol) [prepared in step B] in 300a of methylene chloride Thionyl (27,4f:o, 16 moles) was fed. The mixture was heated to reflux for 2 hours, then cooled and evaporated under reduced pressure to yield product 12.3f. Crystallization from acetonitrile gave the title compound, %p143-144@.

Calculated value as analysis C11H1sct, N, S: C, 37
,01:ff,5.32:N,12.33;CL,
31.63° Experimental value (corrected as 0.9% H, O): C, 36,88
; H, 5, 11; N, 12.14: CL, 31.65° cysteamine hydrochloride (0,2r: 1.furimimole) and 5-chloromethyl-2-dimethylaminomethylthiazole hydrochloride (0,4P; 1. (produced in step C) was dissolved in #2.5114 hydrochloric acid, and the solution was heated at 100°
was heated at an oil bath temperature of . 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 the title compound 0.32 as an oil. CDC1, medium NMR spectrum (60mg)
T! , near which gave the following resonance δ, 50(a, 1ff);
3.95 (s, 2ff); 3.76 (a, 2#); 2.
85 (s, 4Zf); 2.40 (a, 6H); 1.8
5(a.

2H).

1,1-dioxide 3,4-dimethoxy-1,2,5-thiadiazole (
2-((2-dimethylaminomethylthiazol-5-yl)methylthio]ethylamine (1,55
f; 6.7 mmol) [manufactured in Step 8D] 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
Silica gel 150? using acetonitrile-methanol gradient elution. Top chromatographed. The appropriate fractions were combined to give 1.05f of product. Precious crystallization from 2-propanol gave the title compound, p170-172°. Analysis C1, H2oN60.83, calculated value: C, 38
,28;H,5,36;#, 22.33;,Sr,
25.56° Experimental value: C', 38.31; H, 5, 32; #, 22.
13:S, 25.96゜Example 63゜The 1,1-dioxide 3,4-dimethoxy-1,2,5-thiadiazole used in Example 20 was replaced with an equimolar amount of the corresponding 1-[ The general procedure of Example 20 was otherwise repeated. Excess fractions from column chromatography were combined to give product @4.5f. Crystallization from absolute ethanol gives the title compound 3.05F, inert p175.
~177@ was obtained.

Calculated value as analysis C16H16NBO3z: C, 33,
32:H, 4, 47:N, 3L, 09:S, 26.6B
.

Experimental value: (1', 33.10; H, 4, 42; /l/,
31.00; S, 26.51° 1-oxide 3° 4-dimethoxy-1,2,5-thiadiazole (2
, 91r; 17.9 mmol) in methanol 50
2-((2-geanidinotheazol-4-yl) in xl
A solution of methylthio]ethylamine (4,15r; 17.9 mmol) was added dropwise over a period of 30 minutes. The reaction mixture was diluted with casein in methanol (3,58r; 8
9.5 mmol) solution.

After stirring overnight at ambient temperature, the mixture was diluted with aqueous 6.0N H
Neutralized with CL14.9N (89.5 mmol) and 1
Evaporated under pressure for 0 min. The solid residue was L-filtered with 70 Mt water at ambient temperature for 2 hours to obtain the product. Recrystallized from water to give the title compound, mp 148-151°
I got it.

Analysis C, H1, calculated value as NyO2S2: C, 31,
11:H, 3,77:N, 28.22:S, 27.
69° Experimental value (5.52% H, O and °C correction): C, 30,
95; H, 3, 76; #, 28.27; S, 28.1
1° Example 65°-4-ylcomethylthio)ethylamine Cysteamine hydrochloride (1,8'l; 16.6 mmol) and 2-(2-
Methylguanidino)-4-chloromethylthiazole (4
,0r; 16.6 mmol) [(N-methylamidino)
[produced from thiourea and 1,3-dichloro-2-propane] was mixed in 20 nl 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 NaOH. The aqueous phase was extracted several times with methyl acetate and the organic phase was dried, filtered and evaporated to give the title compound 3.35F. D.
OI:' pNMR spectrum (60 MHz) gave the following characteristic resonances δ: 6.52 (a, 1#); 3.60 (
s, 2H); 2.70 (fI%, 7H).

Etheramino)-1,2,5-thiadiazole 1-oxide 3° 4- in 1701 Wt of methanol cooled to 7°
Dimethoxy-1,2,5-thiadiazole (1,399
; 8.56 mmol) in methanol 5 QmJ
4-yl)methylthio]ethylamine (2,11;8.
A solution of 56 mmol) [Process 1, produced in A] was poured over a period of 30 minutes. Add 7% of anhydrous ammonia to this solution.
Bubble for a minute and then stir overnight at ectotherm. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in acetonitrile-
Chromatographed on 10 (l) silica gel (230-400 mesh) by flash chromatography using a gradient elution of methanol. The appropriate aliquots were combined, evaporated and the residue was chromatographed on μm boracyl silica gel. It was used for chromatography on a preparative HPLC system.

The appropriate fractions were combined and concentrated to a small fraction, yielding the title compound, tnp86-91@; the NMR spectrum in d6 dimethyl sulfoxide (100 MZrg) showed the presence of about 0.8 moles of ethanol. showed that.

Analysis C1 (, calculated value as H16NB08B: C, 35
,06:H,5,28:N,2B,20:S,24.2
1° Experimental value (corrected as 1.64% H2O): C, 35,
66; H, 5, 05: N, 28.33; S, 23.9
6° Example 66° Diazole To a solution of 1-oxide 3,4-dimethoxy-1,2,5-thiadiazole in 200 v methanol cooled to 2°C in an ice-water bath was added 3-(3-(diy) in 35 mj methanol under stirring.
'aminomethyl)phenoxyprobylamine (2,
A solution of 5P (12.9 mmol) was added 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.

Recrystallization twice from methanol yielded the title compound, fILl.
165.5-166.5° (decomposition) was obtained.

Analysis H, 4H! Calculated value as 1N, O, S: c, 51.
99:H, 6,55;N, 21.66;S, 9
．． 92° Experimental value: C, 51,58; H, 6,49; #, 22.0
3;110.19゜Example 67゜A, 2-((2-methylaminothiazol-4-yl)
Cysteamine hydrochloride (2,8f: 24.6 mmol) and 2
-Methylamino-4-chloromethylthiazole (4-O
24.6 mmol) CN-methylthiourea and 1.
3-dichloro-2-propane] in concentrated hydrochloric acid 2Q
The solution was heated at an oil bath temperature of 100". After 30 hours of heating, the reaction mixture was evaporated under reduced pressure and the residue was made basic with 40% aqueous NaOH. The aqueous phase was Extraction with methyl acetate, drying, filtering and evaporation afforded 1.75 t of the title compound as an oil, which was used in Step B without further purification.

The product of Step A above was converted to '1:1-oxide 3,4-dimethoxy-1,2,5' according to the general procedure of Example 65, Step B.
- sequential reaction with thiadiazole and anhydrous ammonia,
Chromatography was performed as described there.

Excess fractions from the flood cyclomography were combined and evaporated to give 0.51 of the product as 7 ohms. Crystallization from acetone gives the title compound, mp 180-1
83@ (decomposition) was obtained.

Analysis C, H14N@O8, calculated value: C, 33,9
4; H, 4, 43; N, 26.39; S, 30.21
゜Experimental value (corrected as 1,41% H, O): C, 33,
96; H, 4, 11; #, 26.27; S, 30.44
゜Example 68゜1-oxide 3-amino-4-(2-((2-(2,3
- cysteamine hydrochloride (2,2!M'; 19.6 mmol) and 4-chloromethyl-2-(2,3-dimethylguanidino)thiazole (5P: 19.6 mmol) [:1.
3-dichloro-2-propanone and (N,N'-dimethylamidino)thiourea (itself prepared from dimethyl cyanodithioiminocarboxylate and methylamine)] was dissolved in 17.5M concentrated @acid to give 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, 243-245°.

8, 1-oxide 3-amino-4-2-(: 2-
The product of Step A on (2°3-dimethylguanidino)thiazol-4-yl)methyl was converted to 1-oxide 3.4-dimethoxy-1,2 according to the general procedure of Example 65, Step B.
, 5-thiadiazole and anhydrous ammonia. The crude reaction mixture was evaporated under reduced pressure and the residue was crystallized from methanol to give the title compound, mp201-20.
3° (decomposition) was obtained.

Analysis CIIH1117V! Calculated value as Q S3: C,
35,28;H,4,84:N,29.92:&,25
．． 69° Experimental value (corrected as 0.88% H2O): C, 34,
93", H, 4°56; #, 30.27; S, 2
5.92° Name-At first glance, the mu-1-oxide 3,4-bis-(2-((2-guanidinothiazole) In a solution of sodium methoxylate (2,16f; 40.0 mmol) in 00 u of CHsOHl cooled to 0 Dihydrochloric acid 2-((2-guanidinothiazole-4-
yl)methythio]ethylamine (6,09P; 20.
After adding 0 mmol) and stirring for 20 minutes, the solution was treated with 1-oxide 3,4-dimethoxy-1,2,5-thiadiazole (1,62f; 10 mmol). The reaction mixture was stirred at ambient temperature for 65 hours and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (230-400 mesh) using a gradient elution of acetonitrile-methanol at 100? After chromatography, the appropriate fractions were combined, evaporated, and the residue was subjected to preparative HPLC using μm Porasil silica gel.
On-system chromatography Appropriate fractions were combined and evaporated under reduced pressure to yield the title compound as an amorphous solid;
NME spectrum in d6 dimethyl sulfoxide (100
MHg)tl, indicating the presence of approximately 0.11 mol of ethanol.

Analysis C, 6H,, N120! ls-0,11C2H,O
Calculated value: C, 34, 42; ff, 4.39; N,
29.71; S, 28.33° Experimental value (corrected as 1,86% H, O): C, 34,
95:H,4,41;jV,29.04;5j27.7
1゜Example 70゜A, dihydrochloric acid 2-((2-aminothiazol-4-yl)
Cysteamine hydrochloride (5,65f; 50.0 mmol) and 2-amino-4-chloromethylthiazole hydrochloride (9,2
5f: 50.0 mmol) was dissolved in concentrated hydrochloric acid 7ON,
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 crushed again with ethanol,
Filter and dry to give the title compound, mp 170-200.
Got °.

Analysis C, H 凰3Ct2#3S2 Calculated value: C, 27
,48;7f,4.90;N,16.02;S,2
4.46 ; Ct, 27.04° Experimental value: C, 27,2
9:ff, 5.07;#, 15.91:S, 24.
15: C1,27,24°B, 1-dioxide 3
-2-2-aminothiazol-4-yl)methylthio]
Stir into a cold (5 part suspension) 1,1-dioxide 3,4-dimethoxy-1,2,5-thiadiazole (2,03f; 11.4 mmol) in ethylamino-1,2° methanol 55 A solution of 2-((2-aminothiazol-4-yl)methylthio]ethylamine (from the dihydrochloride, 3.0 r; 11.4 mmol) [prepared in step A] in 25 μm of methanol was added over 1.5 h. After 15 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 fP of silica gel.
Chromatographed using acetone-methylene chloride (7:3). Appropriate fractions were combined and evaporated to give the product.

Recrystallization from 95% ethanol yielded the title compound, mp2
00 to 2011 were obtained.

Calculated value as analysis C9H14N@02S3: C, 32,
32: H, 4, 32; #, 25.13; S, 28.76
゜Experimental value: C, 32, 25", H, 4, 20: N, 25.
06”.

S, 29.14° Example 71° 1-oxide 3,4-dimethoxy-1,2,5-deadiazole (1,41'; 8-88
mmol) of methanol 70 II under stirring to a solution of cold (8
2-((2-dimethylaminomethyltheazole-5) in t
-yl)methylthio]ethylamine (2,05r;8.
A solution of 86 mmol) [Example 62, prepared in process] was added dropwise. Anhydrous ammonia was bubbled into this solution at 8 minute intervals and then stirred at external temperature for 0.5 hours. The reaction mixture was evaporated under reduced pressure and the residue was triturated with acetonitrile to give the product 1.76P. This product was purified using silica gel 100f (230~
400 mesh) was purified by flash chromatography. The appropriate portions were combined, evaporated and the residue crystallized from acetone to give the title compound, mp131.
~133° was obtained.

Calculated value for all types p11H, γN60S: C, 3B,
13;II, 5.24;N, 24.26:S, 2'17
6° Experimental value (corrected as 0.49% H2O): C, 37,
86; H, 5, 06; N, 24.34; S, 27.6
8゜Uヱ.

1-oxide 3-amino-4-(2-C(2-aminothiamethanol) 1-oxide 3,4-dimethoxy-1,2,5-thiadiazole (1,62P; 10.0
A cold (5°) solution of methanol (20 mmol) in 2-
A solution of ((2-aminothiazol-4-yl)methylthio]ethylamine (from dihydrochloride, 2.62r; 10.0 mmol) [Example 70, prepared in step A] was added dropwise over 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 purified using μm boracyl silica gel. Chromatography on HPLC system The appropriate fractions were combined and evaporated under reduced pressure to give the title compound as an amorphous solid; the NMR spectrum (100 MHz) in d6 dimethyl sulfoxide was:
It showed the presence of about 0.4 moles of ethanol.

Analysis CaHuA'rro S3 ・0.4 Cd160
As, its value: C, 32, 74; H, 4, 50; N
, 26.03: S, 29.80° Experimental value (corrected as 1,39% H2O): C, 32,
39', H, 4, 28:N, 28.39:S, 30.0
2゜Example 73゜1,1-dioxide 3,4 in 121 methanol 27orILt
-dimethoxy-1,2,5-thiadiazole (1,72
9.62 mmol) in methanol under stirring with 2-((2-(2,3-dimethylguanidino)thiazol-4-yl)methylthio]ethylamine (2,5r; 9. 64 mmol) [Example 68, prepared in Step A] was fed over a period of 40 minutes. Anhydrous methylamine was bubbled into this solution for 7 minutes and the solution was then evaporated under reduced pressure. Residue by flash chromatography on silica gel (230-400 mesh) 1
00f, the appropriate fractions were combined and evaporated to give the product 2.52 in the form. Crystallization from aqueous ethanol gave the title compound, inert p132-1.
I got 37”.

Analysis C! Calculated value as 2H26N 602 S 3: C
,35,63;H,4,98",N,27.70:&,
23.78° Experimental value (corrected as 4.78% H, 0): C, 35,
74;H,5,04;N,2S,87:S,23.56
Example 74 Cysteamine hydrochloride (5,21'; 45.9 mmol) and 2-dimethylamino-4-chloromethylthiazole hydrochloride (9,8f; 45.9 mmol) r-N,N-dimethylthiourea and 1° 3-dichloro-2-propanone] was dissolved in concentrated hydrochloric acid and heated at an oil bath temperature of 100° for 96 hours. The mixture was evaporated under reduced pressure,
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 spectrum in D20 (6071□g) gave arrow resonance δ: 6.97 (g, If); 3.94 (a
, 2ff): 3.67 (a, 377); 3.15 (s,
3ff): 3.05 (s.

4H).

1-oxide 3,4-dimethoxy-1,2,5-thiadiazole (2,61P; 16.1
mmol) in methanol with stirring to a cold (7°) solution. QW
2-(:(2-dimethylaminothiazole-4-
yl)methylthio]ethylamine (3,5f; 16.1
mmol) [prepared during step A] was added 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, filtered and evaporated to give the product. The product was purified by flash chromatography on 100f of silica gel (230-400 mesh) using methylene chloride-methanol. Appropriate fractions were combined and rechromatographed by HPLC on a μm Porasil silica gel column. The appropriate portions were combined and evaporated under reduced pressure to give the title compound, up 116-122°; NMR spectrum in d6 dimethyl sulfoxide (100 MHg) #:t, indicating the presence of about 173 moles of ethanol.

Analysis (II'toHtaA'go S3 ・1 /
3 Calculated value as Cdl@0: C, 36, 83”, H,
5,22', N, 24.16° Experimental value (corrected as 11,92% H, O): C, 36,61: H, 4,06;
1,1-dioxide 3,4-dimethoxy-1,2,5-thiadiazole (2,05?;
11.5 mmol) of 2-(((
2-dimethylaminothiazol-4-yl)methylthio]ethylamine (2,5P; 11.5 mmol) [Example 7
4. The solution produced during step A] was added dropwise over 30 minutes. Bubble anhydrous methylamine into this solution for 7 minutes,
After stirring for 30 minutes, the mixture was evaporated under reduced pressure. The residue was crystallized from methanol to give product 1.6f. Recrystallization twice from 2-methoxyethanol gave the title compound, mp227-229@.

Example 76゜cysteamine hydrochloride (2,22r; 19.5 mmol) and 2-((2-imidazolidinyl)imino]-4-glolomethylthiazole hydrochloride (4,94r; 19.51 mmol) [:1. 3-cyclo-2-propanone and N-(2
-imidazolidin-2-yl)thiourea (per se 2-
(manufactured from (cyanimino)imidazolidine)] was dissolved in 20 rILt of concentrated hydrochloric acid and heated at an oil bath temperature of 100° for 5.5 hours. The reaction mixture was evaporated under reduced pressure and the residue was made basic with 40% NaOH. The aqueous phase was extracted with methyl acetate, dried and evaporated to yield the title compound 2.
．． 02t'l was obtained, which was used in the next step without further manufacturing M.

2-( (2-(2-imidazolidinyl)
iminothiazol-4-yl)methylthio]ethylamine (2,02fNia, 85 mmol) [Produced during Step A]
solution was added dropwise over 40 minutes. Anhydrous methylamine was stirred into this solution for 7 minutes and after 30 minutes at ambient temperature the mixture was evaporated under reduced pressure to give product 3.52. This product was chromatographed on a preparative HPLC system using μm boracyl silica gel. The appropriate fractions were combined, evaporated and the residue crystallized from ethanol to give the title compound, 5p229-231. Got @. Recrystallization from aqueous ethanol gave the title compound with mp 136-140°, which resolidified with mp 219-140°.
Remelted at 224°.

Separation C,,H,,N80. Calculated value as S3: C, 35
,81;H,4,51;#,27.84 :S,23.
90° Experimental value (corrected as 4,59% H,O): C, 35,
51; H, 4, 43: #, 27.98; S, 23.
56゜Example 77゜Tyl-2-chenyl)methylthio]ethylamine)-4
- methylamine used in Azole Example 31 in an equimolar amount of 2-
The general procedure of Example 31 was repeated except that aminomethylpyridine was substituted. Column chromatography of the crude solid yielded product 3.08F. Recrystallized from inpropyl alcohol to obtain the title compound, mp162~
164@(decomposition) was obtained.

Calculated value as analysis C1aH24N 60233: C,4
7,76; ff, 5.34; #, 18.57° Experimental value: C, 47,80; 77.5.32; N, 18.75° Example 78° [(4-pyridyl)methylamino)- 1,2,5-Thiadiazole The methylamine used in Example 31 was mixed with an equimolar amount of 4-thiadiazole.
The general procedure of the example was repeated except that aminomethylpyridine was substituted. After chromatography, the crude product was dissolved in hot inpropyl alcohol, the insoluble material was decanted, and the solution was treated with anhydrous HCl to give 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 was prepared as free base, 5
The title compound was obtained as p88-90''.

Analysis C1, H24N60. Calculated value as S3: C, 47
, 76; ff, 5.34; jV, 18.57° experimental value (
(corrected as 3,73 H2O): C, 47,54; f
f, 5.32; The general procedure of Example 31 was repeated with the exception that the appropriate aliquots from the column chromatography were dissolved in warm inpropyl alcohol and saturated with anhydrous HCl.

A crystalline solid was collected by filtration and dissolved in acetone as Fc#L.
, to give the title compound 2,92 as its hydrochloride salt, tph
Obtained as p246-247@ (degraded).

Calculated value as %Ct4HuN s Oz S s: C,
39,47; H, 5,68; #, 16.44; C1,
8,32° Experimental value: C, 39,81; H, 5,74; /'/, 16
．． 62; C1,8,20° Example 1,1-dioxide 3,4-dimethoxy-1,2,5-thiadiazole (1,68r
; 9.45 mmol) in methanol 301 under stirring under stirring. 23.133] was fed over a period of 40 minutes. After 15 minutes, anhydrous methylamine 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,
The residue was chromatographed by flattening chromatography on 100 r of silica gel (230-400 mesh) using mechnol-acetonitrile. Appropriate fractions were combined and evaporated to give product 2.22. Recrystallization from acetonitrile with animal charcoal treatment provided the title compound, fFLj1182-184°.

Analysis C1, H27N503: Calculated value as l: C, 54
,94;H,6,92:N,17.80;S,8.1
5° Experimental value: C, 54, 90; 77.7.07; #, 18.
14; S, 8.29° Azole Methanol to a solution of 1-oxide 3,4-dimethoxy-1,2,5-thiadiazole (2,01f: 12.4 mmol) in methanol 2001 cooled to 0° in an ice-water bath 3-(3-Piperidinomethylphenoxy)propylamine (from dihydrochloride, 4-Of: 12.4 mlJ)
mol) solution was added dropwise over a period of 50 minutes. 15 minutes later,
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 purified using silica gel (230-400 mesh) using methanol-acetonitrile.
00? Chromatographed by top flash chromatography. Appropriate fractions were combined and evaporated to give the product 4.18r'. Recrystallization from 95% ethanol gave the title compound, trLp155-157@(decomposed).

Calculated value as analysis C17H25N502S: C, 56,
17', H, 6,93", N, 19.27; S, 8.8
2° Experimental value: (:”, 55.97; H, 7, 04: #, 19
．． 57; 5', 8.63° Example 82° Thiadiazole 1-oxide 3,4-dimethoxy-1,2,5-thiadiazole (2,22r: 12.4 mi!) in methanol zoomt cooled to 2@ in an ice water bath. 3-(3-piperidinomethylphenoxy)propylamine (from the dihydrochloride salt, 4.
After 15 minutes, anhydrous ammonia was bubbled into the solution for 30 minutes, and then the solution was stirred at an external temperature for 30 minutes. The reaction mixture was evaporated under reduced pressure, and the residue was dissolved in silica gel (230-400 mesh) at 100 °C. The mixture was placed on top and chromatographed using methanol-acetonitrile on a 7-Lassini chromatography. Appropriate fractions were combined and evaporated to give product 3.22.

NMR spectrum in d6 dimethyl sulfoxide (100
MHt) is near, 2 (7X,
IH): 6.9 (Jō, 3H); 4.1 (t, 2Zf)
;3.5(t,2H):3.4(a,2H):2.3(
m, 4H): 2.0 (m, 2H): 1.4 (broad s
, 6H).

1. in 200 lt of methanol cooled to 0° in an ice water bath.
2-((5-dimethylaminomethyl-2- chenyl)methylthio]ethylamine (
A solution of 2.02r; 8.8 mmol) was added dropwise over a period of 40 minutes. After 20 minutes, piperonylamine (1,46f
; 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 the product 3.47? I got it. Recrystallization from methanol gave the title compound, mp180-182@.

Calculated value as 5 CHH5N50483: C, 48, 46
; H, 5,08; N, 14.13° experimental value (0,38%
(corrected as H2O): C, 4B, 92: H, 4, 88
:N, 14.52° Example 84° - 1,2,5-thiadiazole A solution of 6-carpomethoxy-2-picolinic acid (22,8f; 0.13 mol) in thionyl chloride 80d at an oil bath temperature of 100° heated for an hour. The solution was evaporated under reduced pressure and the residue was evaporated under reduced pressure. -Ten 2001! jK was dissolved and this was then added dropwise to a solution of dimethylamine (70?) in diochitin. The reaction mixture was stirred for 2 hours, then 4'
'' overnight, filtered and evaporated under reduced pressure. The residue was dissolved in toluene, diluted with methylcyclohexane and filtered to give the title compound 20.7?, tnp 90-9.
I got 2@.

+9? Calculated value as C1oHlzN z Os: C,
57,68; ff, 5.81; /l/, 13.46° Experimental value: C, 57,64; ff, 5.85; A/, 13.
77°B, 6-dimethylaminomethyl-2-hydroxymethylpyridine To a suspension of lithium aluminum hydride (9,6P: 0.25 mol) in tetrahydrofuran 5001R1 was added 6-(N,N-dimethylcarbamate) in tetrahydrofuran 200M. Mil-2-carbomethoxypyridine (20,3f';9
7.5 mmol) solution was added. The mixture was stirred and heated to reflux under nitrogen for 3 hours, then left at ambient temperature overnight. The mixture was decomposed with a saturated aqueous solution of N tH804, dried and evaporated under reduced pressure. The residue was placed on aluminum oxide 275v and eluted with methylene chloride. Appropriate fractions were combined and evaporated to give the title compound 5.22.

NMR spectrum in CDCts (60A□g) showed the following resonances δ: 7.38 (m, 37?); 4
．． 75 (a, 2H); 3.58 (s, 2H):
2.27(a, 6Zf).

C,2-((6-dimethylaminomethyl-2-pyridyl)cysteamine hydrochloride (3,58f; 31.5 mmol)
and 6-dimethylaminomethyl-2-hydroxymethylpyridine (5.0f; 30.1 mmol) [produced in step B] were dissolved in 48% hydrobromic acid, and the solution was heated under reflux for 12 hours. It was left at external temperature for 8 hours. The reaction mixture was evaporated to half volume under reduced pressure, basified with 40% aqueous NaOH and extracted several times with methylene chloride. The combined organic phases were washed with a little water and saturated prine solution, dried and evaporated under reduced pressure to give 3.14t of the title compound.

The NMR spectrum (60 MHz) in CDCLs gave the resonance δ of the arrow near-5 (3H); 3.83 (s,
2Z/); 3.56 (g, 2ff); 2.7 (m, 4f
f); 2.28 (s, 6H).

A methanolic solution of n,i-oxide 3-amino-4-(2-((6-dime-1-oxide 3,4-dimethoxy-1,2,5-thiadiazole) was added to an equimolar amount of 2-((6
-dimetelaminomethyl-2-pyridyl)methylthio]
When treated sequentially with ethylamine (prepared in Step C) and excess ammonia, the title compound is thereby obtained.

Patent Applicant: Pristreux Meyers Company
Agent Ryoji Kawase (Toni, :J)

Claims (1)

[Claims] 1. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, p is 1 or 2; R^7 is halogen, (lower) alkoxy, (lower) alkylthio, phenoxy, phenylthio, a leaving group selected from substituted phenoxy and substituted phenylthio, in which the phenyl ring may bear one or two substituents selected from halogen, (lower) alkyl, (lower) alkoxy and nitro; R^1^2 is the above R^7, A(CH_2)_mZ(
CH_2)_nNH-, R^2R^3N- or HS(C
H_2)_nNH- (where 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) alkylamino (lower) 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)_m'Z'(C
H_2)_n'-, phenyl, phenyl (lower) alkyl, 1 in which the phenyl ring is independently selected from (lower) alkyl, hydroxy, (lower) alkoxy and halogen
or 2 substituents, or 1 selected from methylenedioxy, trifluoromethyl and di(lower)alkylamino
Substituted phenyl or substituted phenyl (lower) alkyl which may have a substituent; provided that both R^2 and R^3 are cyclo(lower) alkyl, phenyl, substituted phenyl, amino, (lower) alkylamino , di(lower)alkylamino, hydroxy, (lower)alkoxy, cyano, amidino, (lower)alkylamidino or A'-(
CH_2)_m'Z(CH_2)_n'; or R^2 and R^3 together must be -CH_
2CH_2X(CH_2)_r-; r is an integer from 1 to 3; X is methylene, sulfur, oxygen or N-R^4, provided that p is 2 and R^7 When is methoxy,
R^2 and R^3 together with the nitrogen to which they are attached cannot be morpholino, and when r is 1, X is methylene; R^4 is hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower) alkanoyl or benzoyl; m and m' are each independently an integer of 0 to 2; n and n' are each independently 2 is an integer of ~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' may independently have one or two substituents, the first substituent being (lower) alkyl, hydroxy,
Trifluoromethyl, halogen, amino, hydroxymethyl, (lower) alkoxy, ▲Mathematical formulas, chemical formulas, tables, etc.▼ and -(CH_2)
_qNR^5R^6, and the second substitution is (
(lower)alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl and (lower)alkoxy; q is an integer from 0 to 6; each R^4 independently as defined above or the two R^4 groups together can be ethylene; R^5 and R^6 are each independently hydrogen, (lower) alkyl, (lower) alkenyl, (lower) ) alkynyl, cyclo(lower)alkyl or phenyl, with the proviso that R^
5 and R^6 cannot both be cyclo(lower)alkyl or phenyl; or R^5 and R^6 are
Together with the nitrogen atoms to which they are attached, pyrrolidino, morpholino, piperidino, methylpiperidino, N-
or a salt, hydrate, solvate or N-oxide thereof. 2. The compound according to claim 1, wherein p is 1 and R^1^2 is R^7. 3,1-oxide-3,4-dimethoxy-1,2,5-
The compound according to claim 2, which is a thiadiazole. 4. Formulas ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, p is 1 or 2; n is an integer from 2 to 4; R^2 and R^3 each independently represent 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) alkylamino (lower) 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)_m'Z'(CH_2)_n'-, phenyl, phenyl(lower)alkyl, one or two substituents in which the phenyl ring is independently selected from (lower)alkyl, hydroxy, (lower)alkoxy and halogen , or substituted phenyl or substituted phenyl(lower)alkyl which may contain one substitution selected from methylenedioxy, trifluoromethyl and di(lower)alkylamino;
However, both R^2 and R^3 are cyclo(lower)alkyl, phenyl, substituted phenyl, amino, (lower)alkylamino, di(lower)alkylamino, hydroxy, (lower)alkoxy, cyano, amidino, ( lower) alkylamidino or A'-(CH_2)_m'Z'(C
H_2)_n'-; or R^2 and R^3 together must be -CH_2CH_2X(CH_
2) may be _r-; r is an integer from 1 to 3; X is methylene, sulfur, oxygen, or N-R^4; provided that when r is 1, X is methylene ;R^4
is hydrogen, (lower) alkyl, (lower) alkenyl, (
(lower) alkynyl, (lower) alkanoyl or benzoyl; 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, imidazole, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl; provided that A' may contain one or two substituents and the first Substituents include (lower) alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, (lower) alkoxy, ▲numerical formula, chemical formula, table, etc.▼ and -(CH_2)
_qNR^5R^6, and the second substitution is (
(lower)alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl and (lower)alkoxy; q is an integer from 0 to 6; each R^4 independently as defined above or the two R^4 groups together can be ethylene; 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 are
Together with the nitrogen atoms to which they are attached, pyrrolidino, morpholino, piperidino, methylpiperidino, N-
or a salt, hydrate, solvate or N-oxide thereof.