DERIVES DE 2-GUANIDINOTHIAZOLE

2-GUANIDINOTHIAZOLE DERIVATIVES

Abrégé anglais

2-GUANIDIMITHIAZOLE DERIVATIVES
Abstract:
A compound of the formula:
<IMG>
[wherein n is an integer from 2 to 4;
R is hydrogen, C1-C6 alkyl (optionally substituted by hydroxy,
cyano, amino, or phenoxy), C3-C6 cyclonlkyl, C2-C6 alkenyl
(optionally substituted by phenyl or C2-C7 alkoxycarbonyl),
C4-C7 alkadienyl, C6-C12 aryl (optionally substituted by
one to three members selected from halogen, cyano, nitro,
amino, C2-C10 dialkylamino, tetrazolyl, hydroxy, C1-C6 alkoxy,
benzoyloxy, C2-C7 alkoxycarbonyl, sulfamoyl, C1-C6 alkyl-
sulfonyl, C1-C6 alkanesulfonamido, and C1-C6 alkanoyl), or
5- or 6-membered heterocycle (optionally substituted by
halogen, C1-C6 alkyl, or phenyl); and
X is a single bond or thia]
and its pharmaceutically acceptable acid addition salts,
being useful as anti-peptic ulcer agents or histamine H2
receptor antagonists.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of the
formula (I):
<IMG> (I)
(wherein
n is an integer from 2 to 4;
R is hydrogen, C1-C6 alkyl (optionally substituted by hydroxy,
cyano, amino, or phenoxy), C3-C6 cycloalkyl, C2-C6 alkenyl
(optionally substituted by phenyl or C2-C7 alkoxycarbonyl),
C4-C7 alkadienyl, C6-C12 aryl (optionally substituted by
one to three members selected from halogen, cyano, nitro,
amino, C2-C10 dialkylamino, tetrazolyl, hydroxy, C1-C6
alkylsulfonyl, C1-C6 alkanesulfonamido, and C1-C6 alkanoyl),
or 5- or 6-membered heterocycle (optionally substituted by
halogen, C1-C6 alkyl, or phenyl); and
X is a single bond or thia) or a pharmaceutically acceptable
acid addition salt thereof
which comprises a) reacting an amine of the formula:
<IMG>
(wherein n, and X each is as defined above)
28

with a carboxylic acid of the formula:
RCOOH
(wherein R is as defined above)
or its reactive derivative in an inert solvent, if
necessary, in the presence of a base or a condensing agent,
at a temperature from -20°C to 60°C;
b) reacting a 2-guanidino-4-(activated)methyl-
thiazole of the formula:
<IMG>
(wherein B is reactive group)
with a mercaptan of the formula:
HS(CH2)nNHCOR
(wherein n and R each is as defined above)
in the presence of a base in an inert solvent at a tempera-
ture from 0°C to 60°C; or
c) reacting guanylthiourea of the formula:
<IMG>
with a ketone derivatives of the formula:
A-CH2COCH2S(CH2)nNHCOR
(wherein A is reactive group and n and R each is as defined
above)
29

in the presence of a base in an inert solvent at a tempera-
ture from 0°C to the boiling point of the solvent used; or
d) optionally converting a compound of formula
I to the corresponding pharmaceutically acceptable acid
addition salt.
2. A process according to claim 1, wherein n is an
integer from 2 to 3, R is phenyl optionally substituted by
one to three members selected from halogen, cyano, nitro,
amino, C2-C10 dialkylamino, tetrazolyl, hydroxy, C1-C6 alkoxy,
benzoyloxy, C2-C7 alkoxycarbonyl, sulfamoyl, C1-C6 alkylsulfonyl
C1-C6 alkanesulfonamido, and C1-C6 alkanoyl, and X is thia.
3. A process according to claim 1, wherein n is an
integer from 2 to 3, R is 5-membered heterocycle optionally
substituted by halogen, C1-C6 alkyl, or phenyl, and X is thia.
4. A process according to claim 1, wherein n is an
integer from 2 to 3, R is 6-membered heterocycle optionally
substituted by halogen, C1-C6 alkyl, or phenyl, and X is
thia.
5. A process according to claim 1, wherein n is an
integer from 2 to 3, R is hydrogen, C1-C6 alkyl (optionally
substituted by cyano, amino, or phenoxy), C3-C6 cycloalkyl,
C2-C7 alkenyl (optionally substituted by phenyl or C2-C7
alkoxycarbonyl), or C4-C7 alkadienyl, and X is thia.
6. A process according to claim 5 for the preparation
of 2-guanidino-4-[2-(formamido)ethylthiomethyl]thiazole and
the pharmaceutically acceptable acid addition salts thereof,
wherein n=2 and R is hydrogen.

7. A process according to claim 5 for the preparation
of 2-guanidino-4-[2-(acetamido)ethylthiomethyl]thiazole and
the pharmaceutically acceptable acid addition salts thereof,
wherein n=2 and R is methyl.
8. A process according to claim 4, for the preparation
of 2-guanidino-4-[2-(nicotinamido)ethylthiomethyl]thiazole
and the pharmaceutically acceptable acid addition salts thereof,
wherein n=2 and R is pyridyl.
9. A process according to claim 5, for the preparation
of 2-guanidino-4-[3-(formamido)propylthiomethyl thiazole and
the pharmaceutically acceptable acid addition salts thereof,
wherein n=3 and R is hydrogen.
10. A process according to claim 5, for the preparation
of 2-guanidino-4[3-(acetamido)propylthiomethyl]thiazole and
the pharmaceutically acceptable acid addition salts thereof,
wherein n=3 and R is methyl.
11. A process according to claim 4, for the preparation
of 2-guanidino-4-[3-(nicotinamido)propylthiomethyl]thiazole
and the pharmaceutically acceptable acid addition salts thereof,
wherein n=3 and R is pyridyl.
12. A process according to claim 2, for the preparation
of 2-guanidino-4-[2-(benzamido)ethylthiomethyl]thiazole and
the pharmaceutically acceptable acid addition salts thereof,
wherein n=2 and R is phenyl.
13. A process according to claim 2, for the preparation
of 2-guanidino-4-[2-(4-sulfamoylbenzamido)ethylthiomethyl]-
thiazole and the pharmaceutically acceptable acid addition
31

salts thereof, wherein n=2 and R is 4- sulfamoylphenyl.
14. A process according to claim 2, for the preparation
of 2-guanidino-4-[2-(4- aminobenzamido ) ethylthiomethyl ] thiazole
and the pharmaceutically acceptable acid addition salts thereof,
wherein n=2 and R is 4-aminophenyl.
15. A process according to claim 2, for the preparation
of 2-guanidino-4-[2-(3- aminobenzamido ) ethylthiomethyl ]thiazole
and the pharmaceutically acceptable acid addition salts there-
of, wherein n=2 and R is 3- aminophenyl.
16. A process according to claim 3, for the preparation
of 2-guanidino- [2-(2- thiophenecarboxamido ) ethylthiomethyl]-
thiazole and the pharmaceutically acceptable acid addition
salts thereof, wherein n=2 and R is thiophene.
17. A process according to claim 3, for the preparation
of 2-guanidino-4-[2-(2-furancarboxamido)ethylthiomethyl]-
thiazole and the pharmaceutically acceptable acid addition
salts thereof, wherein n=2 and R is furan.
18. A process according to claim 2, for the preparation
of 2-guanidino-4-[2-(4-(N)-tetrazolylbenzamido)ethylthiomethyl]-
thiazole and the pharmaceutically acceptable acid addition
salts thereof, wherein n=2 and R is tetrazolylphenyl.
19. The process of claim 1, wherein the prepared com-
pound is mixed with a pharmaceutically acceptable
carrier.
20. The process of claim 2, wherein the prepared com-
pound is mixed with a pharmaceutically acceptable carrier.
32

21. The process of claim 3, wherein the prepared com-
pound is mixed with a pharmaceutically acceptable carrier.
22. The process of claim 4, wherein the prepared com-
pound is mixed with a pharmaceutically acceptable carrier.
23. The process of claim 5, wherein the prepared com-
pound is mixed with a pharmaceutically acceptable carrier.
24. The process of claim 6, wherein the prepared com-
pound, 2-guanidino-4-[2-(formamido)ethylthiomethyl]thiazole
or the pharmaceutically acceptable acid addition salts
thereof, is mixed with a pharmaceutically acceptable carrier.
25. The process of claim 7, wherein the prepared com-
pound, 2-guanidino-4[2-(acetamido)ethylthiomethyl]thiazole
or the pharmaceutically acceptable acid addition salts
thereof, is mixed with a pharmaceutically acceptable carrier.
26. The process of claim 8, wherein the prepared com-
pound, 2-guanidino-4-[2-(nicotinamido)ethylthiomethyl]thiazole
or the pharmaceutically acceptable acid addition salts
thereof, is mixed with a pharmaceutically acceptable carrier.
27. The process of claim 9, wherein the prepared com-
pound, 2-guanidino-4-[3-(formamido)propylthiomethyl]thiazo]e
or the pharmaceutically acceptable acid addition salts
thereof, is mixed with a pharmaceutically acceptable carrier.
28. The process of claim 10, wherein the prepared com-
pound, 2-guanidino-4-[3-(acetamido)propylthiomethyl]thiazole
or the pharmaceutically acceptable acid addition salts
thereof, is mixed with a pharmaceutically acceptable carrier.
33

29. The process of claim 11, wherein the prepared com-
pound, 2-guanidino-4-[3-(nicotinamido)propylthiomethyl]thiazole
or the pharmaceutically acceptable acid addition salts
thereof, is mixed with a pharmaceutically acceptable carrier.
30. The process of claim 12, wherein the prepared com-
pound, 2-guanidino-4-[2-(benzamido)ethylthiomethyl]thiazole
or the pharmaceutically acceptable acid addition salts
thereof, is mixed with a pharmaceutically acceptable carrier.
31. The process of claim 13, wherein the prepared com-
pound, 2-guanidino-4 [2-(4-sulfamoylbenzamido)ethylthiomethyl]-
thiazole or the pharmaceutically acceptable acid addition salts
thereof, is mixed with a pharmaceutically acceptable carrier.
32. The process of claim 14, wherein the prepared com-
pound, 2-guanidino-4-[2-(4-aminobenzamido)ethylthiomethyl]-
thiazole or the pharmaceutically acceptable acid addition
salts thereof, is mixed with a pharmaceutically acceptable
carrier.
33. The process of claim 15, wherein the prepared com-
pound, 2-guanidino-4-[2-(3 aminobenzamido)ethylthiomethyl]-
thiazole or the pharmaceutically acceptable acid addition
salts thereof, is mixed with a pharmaceutically acceptable
carrier.
34. The process of claim 16, wherein the prepared com-
pound, 2-guanidino-[2-(2-thiophenecarboxamido)ethylthiomethyl]-
thiazole or the pharmaceutically acceptable acid addition
salts thereof, is mixed with a pharmaceutically acceptable
carrier.
34

35. The process of claim 17, wherein the prepared com-
pound, 2-guanidino-4-[2-(2-furancarboxamido)ethylthiomethyl]-
thiazole or the pharmaceutically acceptable acid addition
salts thereof, is mixed with a pharmaceutically acceptable
carrier.
36. The process of claim 18, wherein the prepared com-
pound, 2-guanidino-4-[2-(4-(N)-tetrazolylbenzamido)ethylthio-
methyl]thiazole or the pharmaceutically acceptable acid addi-
tion salts thereof, is mixed with a pharmaceutically accept-
able carrier.
37. A compound of the formula (I):
<IMG>
(wherein
n is an integer from 2 to 4;
R is hydrogen, C1-C6 alkyl (optionally substituted by hydroxy,
cyano, amino, or phenoxy), C3-C6 cycloalkyl, C2-C6 alkenyl
(optionally substituted by phenyl or C2-C7 alkoxycarbonyl),
C4-C7 alkadienyl, C6-C12 aryl (optionally substituted by
one to three members selected from halogen, cyano, nitro,
amino, C2-C10 dialkylamino, tetrazolyl, hydroxy, C1-C6 alkoxy,
benzoyloxy, C2-C7 alkoxycarbonyl, sulfamoyl, C1-C6 alkyl-
sulfonyl, C1-C6 alkanesulfonamido, or C1-C6 alkanoyl), or
5- or 6-membered heterocycle (optionally substituted by
halogen, C1-C6 alkyl, or phenyl); and

X is a single bond or thia) or a pharmaceutically acceptable
acid addition salt thereof when prepared by the process of
claim 1.
38. A compound according to claim 37, wherein n
is an integer from 2 to 3, R is phenyl optionally substi-
tuted by one to three members selected from halogen, cyano,
nitro, amino, C2-C10 dialkylamino, tetrazolyl, hydroxy,
C1-C6 alkoxy, benzoyloxy, C2-C7 alkoxycarbonyl, sulfamoyl,
C1-C6 alkylsulfonyl, C1-C6 alkanesulfonamido, and C1-C6
alkanoyl, and X is thia when prepared by the process of
claim 2.
39. A compound according to claim 37, wherein n
is an integer from 2 to 3, R is 5-membered heterocycle
optionally substituted by halogen, C1-C6 alkyl, or phenyl,
and X is thia when prepared by the process of claim 3.
40. A compound according to claim 37, wherein n is
an integer from 2 to 3, R is 6-membered heterocycle optionally
substituted by halogen, C1-C6 alkyl, or phenyl, and X is
thia when prepared by the process of claim 4.
41. A compound according to claim 37, wherein n is an
integer from 2 to 3, R is hydrogen, C1-C6 alkyl (optionally
substituted by cyano, amino, or phenoxy), C3-C6 cycloalkyl,
C2-C7 alkenyl (optionally substituted by phenyl or C2-C7
alkoxycarbonyl), or C4-C7 alkadienyl, and X is thia when
prepared by the process of claim 5.
42. A compound according to claim 37, namely 2-guanidino-
4-[2-(formamido)ethylthiomethyl]thiazole and the pharmaceuti-
cally acceptable salts thereof when prepared by the process
of claim 6.
36

43. A compound according to claim 37, namely 2-guanidino-
4-[2-(acetamidolethylthiomethyl]thiazole and the pharmaceuti-
cally acceptable acid addition salts thereof when prepared
by the process of claim 7.
44. A compound according to claim 37, namely 2-guanidino-
4-[2-(nicotinamido)ethylthiomethyl]thiazole and the pharma-
ceutically acceptable acid addition salts thereof when pre-
pared by the process of claim 8.
45. A compound according to claim 37, namely 2-guanidino-
4-[3-(formamido)propylthiomethyl]thiazole and the pharmaceuti-
cally acceptable acid addition salts thereof when prepared
by the process of claim 9.
46. A compound according to claim 37, namely 2-guanidino-
4-[3-(acetamido)propylthiomethyl]thiazole and the pharma-
ceutically acceptable acid addition salts thereof when pre-
pared by the process of claim 10.
47. A compound according to clai.m 37, namely 2-guanidino-
4-[3-(nicotinamido)propylthiomethyl]thiazole and the pharma-
ceutically acceptable acid addition salts thereof when pre-
pared by the process of claim 11.
48. A compound according to claim 37, namely 2-guanidino-
4-[2-(benzamido)ethylthiomethyl]thiazole and the pharmaceuti-
cally acceptable acid addition salts thereof when prepared
by the process of claim 12.
49. A compound according to claim 37, namely 2-guanidino-
4-[2-(4-sulfamoylbenzamido)ethylthiomethyl]thiazole and the
pharmaceutically acceptable acid addition salts thereof when
prepared by the process of claim 13.
37

50. A compound according to claim 37, namely 2-guanidino-
4-[2-(4-aminobenzamido)ethylthiomethyl]thiazole and the
pharmaceutically acceptable acid addition salts thereof when
prepared by the process of claim 14.
51. A compound according to claim 37, namely 2-guanidino-
4-[2-(3-aminobenzamido)ethylthiomethyl]thiazole and the
pharmaceutically acceptable acid addition salts thereof when
prepared by the process of claim 15.
52. A compound according to claim 37, namely 2-guanidino-
[2-(2-thiophenecarboxamido)ethylthiomethyl]thiazole and the
pharmaceutically acceptable acid addition salts thereof when
prepared by the process of claim 16.
53. A compound according to claim 37, namely 2-guanidino-
4-[2-(2-furancarboxamido)ethylthiomethyl]thiazole and the
pharmaceutically acceptable acid addition salts thereof when
prepared by the process of claim 17.
54. A compound according to claim 37, namely 2-guanidino-
4-[2-(4-(N)-tetrazolylbenzamido)ethylthiomethyl]thiazole and
the pharmaceutically acceptable acid addition salts thereof
whem prepared by the process of claim 18.
38

Description

~1S82~
The present invention relates to 2-guanidino~
thiazole derivatives of the formula: ;
HN=C -NH2
NH
S N
CH2X(CH2)nNH-CO-R (I)
(wherein n is an integer from 2 to 4;
R i~s hydrogen, Cl-C6 alkyl (optionally substituted by hydroxy,
cyano, amino, or phenoxy), C3-C6 cycloalkyl, C2-C6 alkenyl
(optionally substituted by phenyl or C2-C7 alkoxycarbonyl),
C4-C7 alkadienyl, C6-C12 aryl (optionally substituted by
one to three members selected from halogen, cyano, nitro,
amino 9 C2-C10 dialkylamino, tetrazolyl, hydroxy, Cl-C6
alkoxy, benzoyloxy, C2-C7 alkoxycarbonyl, sulfamoyl, Cl-C6
alkylsulfonyl, Cl-C6alkanesulfonamido, and Cl-C6 alkanoyl),
or 5- or 6-membered heterocycle (optionally substituted by
halogen, Cl-C6 alkyl,.or phenyl); and ~:
X is a sln~le bond or thia)
and the pharmaceutically accep:table acid addition salts
thereof, being useful as anti-peptic ulcer agents or hist-
amlne M2 receptor antagonists.
In the above formula (I) the terms used above
have the following signlficance:~
Cl-C alkyl includes methyl, ethyl 9 propyl, isopropyl,
- 2 -

~ ~8~3
butyl, isobutyl, t~butyl, pentyl, isopentyl, and hexyl;
C3-C6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclo-
pentyl, and cyclohexyl;
C2-C6 alkenyl inclucles vinyl, allyl, bu-tenyl, pentenyl,
and hexenyl,
~4-C7 alkadienyl includes butadienyl, pentadienyl, hexa-
dienyl, and heptadienyl;
Cl-C6 alkoxy-includes methoxy, ethoxy, propoxy, isopropoxy,
butoxy, pentyloxy, and hexyloxy;
C2-C7 alkoxycarbonyl includes methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, and
hexyloxycarbonyl;
Cl-C6 alkanoyl includes formyl, acetyl, propionyl, butyryl,
pentanoyl, and hexanoyl;
Cl-C6 alkanesulfonamido includes methanesulfonamido, ethane
sulfonamido, propanesulfonamido, isopropanesulfonamido,
butanesulfonamido, isobutanesulfonamido, pentanesulfonamido,
and hexanesulfonamido;
Cl-C6 alkylsulfonyl includes methylsulfonyl, ethylsulfonyl,
propylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentyl-
sulfonyl, and hexylsulfonyl;
C2-C10 dialkylamino includes dimethylamino, diethylamino,
dipropylamino, dibutylamino, dipentylamino, methylethylamino,
methylpropylami.no, ethylpropylamino, ethylbutylamino, ancl
methylbutylamino;

~1~8~3
C6-C12 aryl includes phenyl, tolyl, xylyl, naphthyl, methyl-
naphthyl,and ethylnaphthyl;
5-membered heterocycle includes thienyl, furyl, isoxazolyl,
and isothiazolyl;
6-membered heterocycle includes pyridyl; and
halogen includes chlorine, bromine, and iodine.
As such 2-guanidinothiazole type H2 receptor
antagonists, U.S. pat. 4,165,377 (1979) has disclosed tio-
tidine, which has N-methylcyanoguanidino group, potentially
changeable into the carcinogenic nitroso N-methylcyanogua-
nidino group in the mammalian body [Pool, et al., Toxicology,
15, 69 (1979)]. Further Japanese Unexamined Patent Publn.
17271/1978 has dlsclosed N-[2-((2--pyridyl)methylthio)-
ethyl]acetamide which has no activity as the histamine H2
receptor antagonist.
The first preferred compounds of Formula 1 are
those in which n is an integer from~2 to 3, R is phenyl
:
optionally substituted by one to three members selected
from halogen, cyano, nitro, amino, C2-C10 dialkylamino,
tetrazolyl, hydroxy, Cl-C6 alkoxy, benzoyloxy, C2-C7 alkoxy-
carbonyl, sulfamoyl, Cl-C6 aIkylsul~onyl, Cl-C6 alkane-
sulfonamido, and Cl-C6 alkanoyl, and X is thia.
. The secondly preferred compounds of Formula I
are those in which n is an integer from 2 to 3 9 R is 5-
membered heterocycle optionàlly substituted by~halbgen,

~5~2~3
Cl-C6 alkyl, or phenyl, and ~ is thia.
The thirdly preferred compounds of Formula I are
those in which n is an integer from 2 to 3, R is 6-membered
heterocycle optionally subs-tituted by halogen, Cl-C6 alkyl,
or phenyl, and X is thia.
The fourthly preferred compounds of Formula I are
those in which n i5 an integer: from2 to 3, R is hydrogen,
Cl-C6 alkyl (optionally subs-tituted by cyano, amino, or
phenoxy)~ C3-C6 cycloalkyl, C2-C7 alkenyl ~optionally sub-
stituted by phenyl or C2-C7 alkoxycarbonyl) or C4-C7
alkadienyl, and X is thia.
The 2-guanidinothiazole derivatives (I) can be
prepared in accordance wlth the following scheme:
.:

~:IL582~3
E~N =CI -NE~2
NH
S N RCOOH (III)
Route A
~--~CH2X(CH2)nN 2
(II) \
\
.
HN=C-NH
NH 2 HN=IC-NH2
~ NH
S ~ N HS(CH2)nNHcOR(v)
CH2-B (Route B)(X=S)~ S
(IV) 2 ( 2)n
, ~
~' .
HN=C-NH2 A-cH2cocH2s(cH2)nNHco~ (VII)
NH (Rou~e C)(X=S)
s =b -NH2
, (~I)
wherein A and B each is reactive group such as halogen or
residue o~ active ester (e.g. tosyloxy), and n, R, and X
each is as defined above].
Route A
:
The objective compounds (I) can,be prepared by
~: :
reacting the amine (II) with the carboxylic acid (III) or
its reactive derivative (e.g. halide, mixed acid anhydride,
or active ester such as tosylate) in an inert solvent, if

2l4 3
necessary, in -the presence of a base or a condensing agent
(e.g DCC, triphenylphosphine/2,2'-dipyridyl disulfide).
This acylation is performed in a conventional manner such
as mixed acid anhydride method, acid halide mathod, DCC
method or triphenylphosphine method, as follows:
(1) Mixed acid anhydride method:
The amine (II) i9 reacted with a mixed acid .
anhydride containing an acyl moiety (RC0) of the carboxylic
acid (III) preliminarily prepared. The reaction may gene-
rally be performed at a temperature from -20C to 60C.
Further preparation o~ the mixed acid anhydride is performed
by reacting the carboxylic acid (III) with alkyl chloro-
carbonate such as methyl chlorocarbonate, ethyl chloro-
carbonate, or the li~e in the presence of a base such as
triethylamine, pyridine, or the like in an inert solvent
at a temperature from -30C to 0C. Examples of the solvent
are tetrahydro~uran, methylene chloride, dioxane, dimethyl-
sulfoxide, dimethyl~ormamide, acetonitrile, hexamethyl-
phosphoric triamide, or the like.
(2) Acid halide method:
The amine ~II) is reacted with an acid halide of
the carboxylic acid (III) in the presence of a base such
as triethylamine, pyridine, or the like. This reaction
may be performed in an appropriate solvent such as dimethyl-
formamide, acetonitrile, he~amethylphosphoric triamide,

1~82~13
tetrahydrofuran, or the like at a temperature from -20C
to 60C.
(3) DCC method:
The amine (II) is reacted with the carboxylic
acid (III) in the presence of DCC (dicyclohexylcarbodiimide)
in an appropriate solvent such as chloroform, dimethyl-
formamide, dimethylsul~oxide, or the like. This reaction
may be performed at a temperature from -20C to 60C.
(4) Triphenylphosphine method:
The amine (II) is reacted with the carbo~ylic
acid (III) in the presence of triphenylphosphine and
2,2'-dipyridyl disulfide in an appropriate solvent such
as dimethylformamide or the like at a temperature from -20~C
to 60C.
The starting amlne (II) is prepared in accordance
with the method disclosed in U.S. pat. 4,165,377.
~ oute ~
The objective compounds (I) can be prepared by
reacting the 2-guanidino-4-(activated)methylthiazole (IV)
~ : ~
with the mercaptan (V) in -the presence of a base. The
reaction is carried out in an inert solvent (e.g. methanol,
~ .:
ethanol, diethyl ether, tetrahydrofuran, dimethylformamide,
dimethylsulfoxide, acetone, chloroform) at a temperature
from 0C to 60C. Examples of the base are alkali metal
hydroxides (e.g. sodium hydroxlde~, alkali metal carbonates

~ 15~243
(e.g. potassium carbonate, sodium carbonate), and alkali
metal alkoxides (e.g. sodium methoxide, potassium ethoxide).
The starting thiazole (IV) is prepared,for exam-
ple, by treating guanylthiourea with l,3-dichloroacetone
in an iner-t solvent such as acetone [U.S. pat. 4,165,377].
Another starting mercaptan (V) is prepared by
treating a disulfide (VIII) with the carboxylic acid (III)
or its reactive derivative according to the acylation step
as above disclosed and reducing the resulting acylamino-
alkyl disul-fi.de (IX) with sodium borohydride in an inert
solvent (e.g. ethanol or methanol), as follows:
~S(CH ) NH ~ ~ ~S(CH ) NXCOR]
2 n 2 2 2 n 2
(VIII) (IX)
4 _ > HS(CH2)nNHCOR
(V~ .
(wherein n and R each is as de-fined~above).
Route C
The objective compound (I) can be prepared by
reacting guan~lthiourea (VI) with the ketone derivative
(VII) in the presence of a base such as triethylamine,
pyridine or the like. The reaction is performed in an
inert solvent such as ethanol, tetrahydrofuran, dimethyl-
sulfoxide, dimethylformamide, chloroform, or the like at
a temperature from O~C to the boiling point of the solvent

~158243
used.
The starting ketone derivative (VII) is prepared
by reacting L,3-di(activated)ketone (X) with the mercaptan
(V) in the presence of a base such as triethylamine, pyridine
or ion exchange resin (OH type), preferably ion exchange
resin (OH type) in an inert solvent such as ethanol, ace-
tone, dimethylsulfoxide or the like at a temperature from
-20C to 30C.
A-CH2COCH2-A + ~IS(CH2)nNHCOR
(X) (V)
> ~CH2COCH2S(CH2)~NHCOR
(VII)
(wherein A, n, and R each is as de~ined above).
If necessary, the nitro group on the benzene
ring of the compounds (I) (R=aryl) can be reduced with a
mild reducing agent such as titanium trichloride or the
like in aqueous acetic acid at room temperature for con-
verting into the corresponding amino group. Any amino-
protecting group such as carbobenzoxy or trityl which has
been necessarily introduced into the product (I) through
the above routes may be deprotected therefrom in a conven-
tional manner.
The product (I) can be converted into pharma-
ceutically acceptable ac,id addition salts such as those
-- 10 --

11582~3
.
with inorganic acid (e.g. hydrochloric acid, sulfuric acid,
nitro acid, phosphoric acid, thiocyanic acid) or those
with organic acid (e.g. acetic acid, succinic acid, oxalic
acicl, maleic acid, malic acid, phthalic acid, methanesul-
fonic acid) ~or the necessi-ty of preparation, crystalli-
zation, solubilization, or improvement of stability.
Thus obtained 2-guanidinothiazole derivatives
(I) and their pharmaceutically acceptable acid addition
salts are useful as antipeptic ulcer agents or histamine
H2 receptor antagonists. For example, 2-guanidino-4-
[2-(formamido)ethylthiomethyl]thiazole maleate sho~ed the
following pharmacological activities:
a) Histamine H2 antagonism in vitro using extracted guinea
pig atrium owing to pretreatment with the test compound:
PA2 = 7~5
[Ariens, Molecular Pharmacology, vol. 1, Academi.c Press,
New York, 1964];
b) Inhibition to peptic secretion d-te to histamine in vivo
using Donryu strain male rats:
ED 0 25 mg/kg (i v )
[~Ghosh, et al. Brit.J.Pharmacol., (1958), 13, 54];
c) Lethal dose in mice:
LD50 148 mg/kg (i.v-)i 7691 mg/kg (p-o-)
[Bliss; Ann.Appl.Biol., 22, 134-307 (1935); Qant.J.Pharma-
col., 11, 192 (1938)].

11582~3
The other compounds showed similar pharmacolo-
gical activities.
The 2-guanidinothiazole derivatives (I) and their
pharmaceutically acceptable acid addition salts are applied
singly or in combination with pharmaceutically appropria-te
carriers such as wheat starch, cor~ starch, potaro starch,
gelatin, etc. The choice of carriers is determined by the
preferred route of administration, the solubility of the
substance and standard pharmaceutical practice. Examples
of pharmaceutical preparations are tablets, capsules, pills,
suspensions, syrups, powders, and solutions. These compo-
sitions can be prepared in a conventional manner.
A suitable daily dosage of the 2-guanidinothiazole deriva-
tives (I) or their pharmaceutically acceptable acid addition
saIts for human adults is in the order of about 1.0 to about
40.0 mg/kg, preferably about 1.0 to about 15.0 mg/kg in a
single or divi.ded portions.
Histamine H2 receptor antagonism was reported by
Black et al. [Black et al., Nature, 236, 385 (1972)].
Presently preferred and practical embodlments
of the present invention are illustratively shown in the
following examples.
- 12 -

~115~2~3
A ~ixture of p-sulfamoylbenzoic acid (201 mg),
triphenylphosphine (262 mg) and 2,2'-dipyridyl disulfide
(220 mg) in dry dimethylfomamide (4 ml) was stirred at
room temperature ~or 1 hour. To the resulting solution
were added 2-guanidino-4-(2-aminoethylthiomethyl)thiazole
dihydrochloride (304 mg) ~U.S. pat. 4,165,377) arld
triethylamine (0.4 ml). After stirring was continued at
room temperature for 20 hours, the solvent was evaporated
in ~acuum, and the residue was subjected to silica gel
(50 g) column chromatography eluting ~ith ethyl acetate/
methanol (20/5 v/~) to afford 2-guanidino-4-[2~(4-sulfamoyl-
benzamido)ethylthiomethyl]thiazole (274 mg) in 67 % yield.
Treatment of the product with maleic acid (300 mg) in
acetone yielded the monomaleate (297 mg) as crystals melt-
ing at 215-217C decO (methanol).
Anal Calcd for C18H2207 6 3
N? 15084 (~)0 Found: C, 40,63; H, 4,08; N, 15.74 (~0)O
:
The monohydrochloride, mpO 220C (decO).
Example 20
Using p-(N)-tetrazolylbenzoic acid in lieu of
p-sulfamoylbenzoic acid, the reaction was carried out as
in Example 1, whereby 2-guanidino-4-~2-(4-(N)-tetrazolyl-
benzamido)ethylthiomethyl]thiazole was obtained in 28 %
yield. The monomaleate, m.pO 211C (dec.) (methanol).

2 '~ 3
`:`
19 21 5 9 2 ; 7 ( )
Found: C, 43.85; H, 4.15 (~o)~
To a solution of p-~methyl~ul~onyl)benzoic acid
(352 mg) i.n dry tetrahydrofuran (10 ml) were added triethyl-
ami.ne (0.24 ml) and ethyl chlorocarbonate (191 mg) at 0C
under stirring. After stirring at that temperature for 30
minu$es, the resulting suspension was treated with 2-guanidino-
4-(2-aminoethylthiomethyl)thiazole dihydrochloride (500 mg)
and triethylamine (0.5 ml) and allowed to come to room
temperature o~ernight under stirring. The precipitated solid
was filtered off and the filtrate wa~ evaporated in vacuum to
leave an oil, which was puri~ied by silica gel (40 g) chroma-
tography eluting with ethyl acetate/methanol (20:5) to give
2-guanidino-~-[2-(4-methylsul~onylbenzamido)ethylthiometh~l]-
thiazole (154 mg) in 82 % yi01d. Treatment o~ the product
with maleic acid (500 mg) in acetone ga~e the monomaleate
(600 mg) as crystals melting at 192-194C (dec.) (methanol).
.
Anal. Calcd. for Cl~H230753N5: C, 43-08; H, 4 38;
N, 13.~22:(qo). Found: G, 42~81; H, 4..20; N, 13.33 (%j.
Using the carboxylic acid (III), th0 reaction was
carried out as in Example 3, whereby the product (I) was
obtained as shown in Table 1.
_ 14 _

~ 15~3
HN=CI-NH2 ,HN=C-NH2
NH
S N RCOOH(III) S ~ N
O
CH~S(CH2)2NH2 CH2S(CH2)N~CR
(II) (I)
Table 1.
~ . .
Ex~ _ . _ I _
No. R Salt; ~ m.p-(C) Yield (~)
_ . : . _--
_
4 - ~ CN maleate 175-176 80.2
_ , __ _ ~
5~ OCH3 maleate 161-163 87~4
__ _ ~-
6-CH=C(CH3)2 1/2aH2ate 175-176d. 91
~ ~ , _ . __
~ 7~ Ph~ maleate 212-214d. 43~3
-- . _
8 ~ ~ NHSO2CH3 maleate 197-198 35
_ _ ..................... _ ~ _
9 ~ 1 maleate 183-185 63 ~
. _ _
~ F
- 15
,' ' ' ~ ~ .

1 15~243
~ ,
Ex. ~ _
No. R ~Salt m.p,(C) Yield ~)
.~ _ . __ ,
11 ~ OOCH3 maleate 173-175 76
_ . . _
1 ~ 0 maleaLe 181-183 55
_ _
13 ~ O-CO-Ph maleate 207-209 34
14 CH3 maleate 134-136 1 62~5
_ _ I _ _
: 15 -CH=CH2 1/2H2o95-98d~ 30~5
. _~ _ _ ~
maleate j
16 ~ OCH3- 1/2H20 l154-156d. 58-5
OCH3 .
_ ~ ~
17 -CH=CH-CH=CHCH3 1/4H o ~l79-l8od~ 81.6
~ _ . _ _ . ~_ _.
19 ~ maleate 168-170d. 66.3 ,
_ 16 _

115~243
. . , .
Ex.
No~ ~Salt m.p-(C) Yield (~o)
-CH=CH COOBu ml/a2H~Oe 99-lOld. 54.4
__. _ __
1.25male _-
t~ 2 ate 141-145d. 11.1
i ' _ _ . ~
!
maleate ~179-181 ¦ 39
Note: The abbreviation has the following significance:
Bu (butyl), Ph (phenyl), d (clecomposition).
Example_23
To a suspension o~ 2-guanidino-4-[2-(amino)ethyl-
thiomethyl]thiazole dihydrochloride (500 mg) in dry dimethyl-
~ormamide (5 ml) were added p-nitrobenzoyl chloride (300 mg)
and triethylamine (0.74 ml) at 0C ~nder stirring.
The resultant suspension was stirred and allowed to come to
room temperature overnight. The solvent was evaporated in
vacuum and the residue was subjected to chromatography on
silica gel (40 g) column, eluting with ethyl acetate-methanol
(20:5 v/v) to afford 2-guanidino-4-[2-(4 nitrobenzamido)-
ethylthiomethyl]thiazole (614 mg) in 98 % yield. The mono-
maleate, m.p. 180 181C (sintering at 170C) (recrystallized
from methanol).

1 ~582~3
' ":
Anal- Calcd- for C18H207N6S2 C, 43.43; H~ 4.o6;
N, 16.92 (~o). ~ound: C) 43.08; ~, 4.14; N, 16.76 (~o).
Examples 24-34.
Using the carboxylic acid chloride (III), the
reaction was carried out as in Example 23, whereby the product
(I) was obtained as shown in Table 2.
~ Table 2.
~ ____ l
: Ex R ¦Salt Im-p-(c) I Yield (~o)
_ . _ __ . _
24 ~ COOCH3 maleate 189-190 22
: 25 ~maleate 188-189 73-8
.... _ ._ _.. _ _ j ____ _
26 ~-naphthyl ¦maleate 175-177d 89
. ~ - ~~ - - - 151-152d.
27 -CH2 ~ Iat 145C)
: 28 ~maleate 200-202d. 69.8
: ~ = la~eate 182-184d. 77-8
30 ~ Cl maleate 177-178 ' 48.4
- 18 -
.i

1~5~2~3
-- .TI . . ,, ,
Ex. -_ I
No. . ~ . Salt m,p.(C) ~ Yield (~o)
31 ~ V maleate l9l-lg2d~ 62.1
. - ~ _
maleate
32~ OCH3 H20 141-145d. 60.4
I 33-CH=~H-Ph maleate 183-185d. 55~5
: 34~ N(CH3)2 ¦maleate 188-190 21
~3~ - .
To a mixture of 2-guanidino-4-[2-(amino)ethyl-
thiomethyl]thiazole (800 mg), ~ormic acid (132 mg) and DCC
(590 mg) in dry dimethyl~ormamide (15 ml) was added trie-thyl-
amine (0,8 ml) under stirring. Afte:r the resulting mixture
was stirred a-t room temperature for 16 hours, the precipi-
tated solid was filtered off and the filtrate was evaporated
in vacuum to leave an oily residue, which was chromatographed
on a column of silica gel (70 g) eluting with ethyl acetate-
methanol 20:5 v/v) to give a mixture (706 mg) o~ the ~ree
base and the carbona,te of 2-guanidino-4-[2-(formamido)-
ethylthiomethyl]thiazole~ It was dissolved in methanol and
carbon dioxide gas was passed through the solution.
Evaporation of the solvent gave the carbonate (720 mg) in
_ 19 _

2 ~ 3
85 ~o yield as crystals melting at 138-140C.
Anal. Calcd- for CgH1504N5S2-1~5 ~2C 3 2 2
30.41; H, 4.82 (~p). Found: C, 30.55; H, 4.66 (~).
Example 36.
To a solution of metallic sodium (about 70 mg) in
ethanol (5 ml) was added dropwise a solution of N-benzoyl~
cysteamine (268 mg) in ethanol (5 ml) at 0C with stirring,
and the resul-tant mixture was stirred at 0C ~or 2 hours.
A solution o~ 2-guanidino-4-chloromethylthiazole (239 mg) in
ethanol (5 ml) was dropwise added to the mixture, which was
stirred at room temperature for 15 hours. The reaction
mixture was concentrated in vacuum, and the mixture was mixed
with acetone. The insoluble material was filtered o~ and the
filtrate was mixed with maleic acid/acetone to give 2-guanidino-
4-C2-(benzamido)ethylthiomethyl~thiazole maleate (414 mg) in
91.4 ~o as crystals melting at 200-202C (dec.)-
Example 37
Using N~nicotinoylcysteamine (273 mg), the reactionwas carried out as in Example 36 9 whereby ~-guanidino-4~
C2 (nicotinamido)ethylthiomethyl]thiazole maleate (0.35 g)
was obtained in 77.4 ~p yield.
Example 38.
Using 3, 4 9 5 trimethoxybenzoic acid, the reaction
was carried out as in Example 3, whereby 2-guanidino-4-[2-
(3, 4, 5-trimethoxybenzamido)ethylthiomethyl]thiazole maleate
- 20 -

115~2~3
was obtained as crystals melting at 163-165C (dec.) in 66 ~o
yield.
Example 39.
Using p-methylsulfonylbenzoic acid, the reac-tion
was carried out as in Example 3, whereby 2-guanidino-4-[2-
(4-methylsulfonylbenzamido)ethylthiomethyl]thiazole hydro-
chloride was obtained as crystal melting at 196-198C,
Example 40.
To a solution of l-chloro-3-[2-(acetamido)ethylthio]-
2-propanone (607 mg) in absolute ethanol (25 ml) was added
guan~lthiourea (320 mg), and the resultant mixture was
refluxed under stirring for 3 hours. After cooling, the
reaction mixture was mixed with triethylamine (1.5 ml) and
concentrated in vacuum. The residue was chromatographed on
a column of silica gel (25 ~), which was eluted with ethyl
acetate-methanQl (20:5 v/v). The eluate was concentrated t,o
give 2-guanidino-4~[2-(acetamido)eth~lthiomethyl]thiazole
(196 mg), which was identical with the product in E~ample 14.
The yield was 25 ~o.
Production of l-chloro-3-[2-(acetamido)eth~lthio]-
2-propanone:
To a solution o~ 2-acetamidoethanethiol (667 mg) in
absolute ethanol (2S ml) was added Amberlite IR4B (OH type)
(2 g). The resultant mixture was cooled at 0C, mixed with
1,3 dichloroacetone (908 mg), stirred at 0C ~or 1 hour, then

~Lt~82~3
allowed to stand at 3-5C overnight. The resin was filtered
off, and the filtrate was concentrated in vacuum at a temper-
ature below 35C. The oily residue was chromatographed on a
colum~ of silica gel, which was eluted with ethyl acetate-
methanol (20:5 v/v). The eluate was concentrated in ~acuum
to give l-chloro-3-[2-(acetamido)ethylthio]-2 propanone
(607 mg) as an oil. The yield was 52 ~.
! NMR, O 3: 1.98 ~3Hs), 2.65 (2Ht, J=7 Hz),
3.45 (2Hs), 4.28 (2~s), 6.22 (lH brs).
xample 41.
To a suspension of 2-guanidino-4-[2-(amino)ethyl-
thiomethyl]thiazole dihydrochloride (30 g) and N,N-dimçthyl-
formamide dimethyl acetal (13 g) in dry tetrahydrofuran (550 ml)
was added triethylamine (30 g). The resultant mixture was
refluxed under stirring for 5 hours and concentrated in vacuum
The residue was mixed with 10 ~o aqueous potassium carbonate
solution (300 ml) and stirred at room temperature for 3 days.
The reaction mixture was neutralized with dilute h~drochloric
acid approximately to Ph 7 and chromatographed on a column of
Amberlite IRC-50 (H type), which was eluted with 10 % aqueous
ammonia solution. The eluate was concentrated in vacuum to
give 2-guanidino-4-[2-(formamido)ethylthiomethyl]thiazole
(11.6 g) as a viscous oil The oil was dissolved in acetone
and mixed with a solution of maleic acid (11 g) in acetone to
give the crude maleate (15.3 g) as crystals, which were
- 22 -

1~$~2~3
recrystallized from ethanol to give the monomaleate (11,8 g).
m.p. 146-148C. The yield was 32 %.
A~lal~ Calcd~ for C8Hl3~5os2~c4H4o4: C~ 38~3~i
H, 4.56; N, 18.66; S, 17.08 (~). Found: C, 38.58; H, 4.47;
N9 18.45; S, 16.74 (~o~
~=
To a solution of 2-guanidino-4-[2-(4-nitrobenz-
amido)ethylthiomethyl]thiazole monomaleate (7.2 g) in 50
acetic acid (200 ml) was added 20 ~o aqueous titanium tri-
chloride solution (89 ml) at room tempera-ture and the
resultant mixture was stirred at room temperature for 45
minutes. The reaction mixture was basified with 10 ~o
aqueous sodium hydroxide solution and extracted with ethyl
acetate. The precipitated resinous material was dissolved
in methanol and the solution was combined with the ethyl
acetate layer. The mi~ture was dried over anhydrous sodium
.ulfate and concentrated. The residue was chromatographed
on a column o~ silica gel, which was eluted with ethyl acetate-
methanol (20:5 v/v). The eluate was concentrated to give an
oil, which was treated with a solution of maleic acid
(4,6 g) in acetone. The resultant crude maleate was crys-
tallized from ethanol to give 2-guanidino-4-[2-(4-aminobenz-
amido)ethylthiomethyl]thiazole monomaleate (3,1 g). m.p. 171-
172C (dec.). The yield was 46 ~
Anal- Calcd~ for C14Hl~N60S2 C, 46-34; H~ 4.75;

~$~2~3
N, 18.02; S, 13.75 (~). Found: C, 46.35; H, 4.82; N, 17.63;
S, 13.55 (~o)~
Example 43.
To a solution of N-carbobenzoxy-~-aminobutyric acid
(7.8 g) in dry tetrahydrofuran (200 ml~ were added triethyl-
amine(3.4 g) and methyl chlorocar~bonate (3.1 g) at -10C and
the resultant mixture was stirred for 30 minutes at the same
temperature. Triethylamine (7.0 g) and 2-guanidino-4-C2-
(amino)ethylthiomethyl]thiazole dihydrochloride (10 g) were
added to the mixture, which was stirred at room temperature
overnight. The precipitate was filtered and sufficiently
washed with tetrahydrofuran. The filtrate was combined with
the washings and concentrated in ~acuum. The residue was
mixed with 30 ~ hydrobromic acid-acetic acid (50 ml~ and
stirred at room temperature ~or 12 hours. The reaction
mixture was diluted with dry ether (1 L). ~he resultant
hygroscopic precipitate was rapidly filtered, dissolved in
water (50 ml) and neutralized with solid sodium carbonate.
The solution was concentrated in vacuum to dryness. The
residue was extracted ~ith ethanol, and the extract was
concentrated to give a viscous oil (3.0 g). The oil was
treated with a solution of maleic acid (3.0 g) in ethanol to
give 2~guanidino-4-[2-(4-aminobut~ramido)ethylthiomethyl]-
thiazole monomaleate (1.5 g). m.p. 87-89C (recrystallized
from 95 ~ ethanol),
- 2~ _

5~243
Anal~ Calcd~ for CllH20N60S2 2C4 4 4 2
C, 40.92; H, 5.24; N, 15,07; S, 11.50 (%). Found: C, 40.30;
H, 5.19; N, 15.22; S, 11.86 (~o)~
Example 44~
To a solution of 2-guanidino-4-(3-aminopropyl)
thiazole (U.S.pat. 4,165,377) (472 mg) and trieth~lamine
(0.8 ml) in dry dimethylformàmide (8 ml) was added nicotinyl
chloride hydrochloride (500 mg) at -20C. The resultant
mixture was stirred at room temperature overnight and
concentrated in vacuum. The residue was mixed with water
(3 ml), and basified with 5 % aqueous sodium hydrogen
carbonate solution. The resultant precipitate was filtered,
sufficiently washed with water and dried to give crude product~
The crude product was treated with a solution of maleic acid
(300 mg) in methanol and diluted with acetone to give 2-
guanidino-4-[3-(nicotinamido)propyl]thiazole monomaleate
(300 mg). m.p. 176C (dec.) (ethanol).
nal Calcd ~or C13H16N60S C4H404 C~ 48 56;
~ . .
H, 4.79; N, 19.99; S, 7.63 (%). Found: C, 48.31; H, 4.59;
N, 19.73; S, 7.80 (%~.
Example 45.
To a solution of sodium hydride (50 ~p suspension
in mineral oil, 590 mg) in absolute ethanol (20 ml) was
dropwise added a solution of 2-acetamidoethanethiol (733 mg)
in absolute ethanol (3 ml) at ~20C and the resultant mixture
_ 25 _

~ 1~82~3
was stirred at -20C ~or 10 minutes~ Solid 2-guanidino-4-
chloromethylthiazole hydrochloride (U,S.pat. 4,165,377)
(1.88 g) was added to the mixture, which was stirred at room
temperature overnight. The resultant precipitate ~a~ filtered
and washed with ethanol, The filtrate was combined with the
washings and concentrated in vacuum to dryness. The residue
was chromatographed on a column of silica gel, which was
eluted with ethyl acetate-methanol (20:5 v/v). The eluate
was concentrated in vacuum to give 2-guanidino-4-C2-(acet-
amido~ethylthiomethyl]thiazole (1.5 g) as an oil, The yield
was 89 %,
Examples 46-50-.
The following compounds were obtained in accordance
with Route B as in Example 3:
~ 2
S~ .
CH2S(C~I2)nNHcOR
,
_ ~ .: .. .. ~ . , .. . ~.. .... ...... . . ,
Ex n _ Saltm.p.(~C) Yield(~)
leate
48 3 -CH3 ¦ -158-159 74.4
. ~ ._ _ ~. . . .
49 3l~ 127-129 39.8
. ~ _ ~ . ,
_ 26 -

:~5~2~3
,
E~ ~ m . p, ( C ) S~ )
5 1 4 ~<~ 'I Monomaleat~ 135-137 ~ 33 . 3
I . _ ., _ I . _ ,
l~ LC 3 160-162 1 55-8
: ,
~, ,
27
'
'~