SUBSTITUTED 3,4-DIAMINO-1,2,5-THIADIAZOLES HAVING HISTAMINE H.SUB.2-RECEPTOR ANTAGONIST ACTIVITY

DERIVES DE SUBSTITUTION DE 3,4-DIAMINO-1,2,5- THIADIAZOLES, INHIBITEURS DES RECEPTEURS H.SUB.2 A L'HISTAMINE

English Abstract

Abstract of the isclosure
Substituted ethanediimidamide compounds of the
formula
<IMG> II
wherein A, m, Z, n and R1 are as defined herein. The compounds
of formula II are useful in the preparation of histamine H2-
receptor antagonists of the formula
<IMG>

Claims

-46-
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 II
<IMG> II
wherein R1 is hydrogen, (lower)alkyl, 2-fluoroethyl, 2,2,2-
trifluoroethyl, allyl, propargyl,
<IMG> or <IMG>
in which p is 1 or 2, R2 and R3 each are independently
hydrogen, (lower)alkyl,(lower)alkoxy or halogen, and, when
R2 is hydrogen, R3 also may be trifluoromethyl, or R2 and R3,
taken together, may be methylenedioxy, and R4 is hydrogen,
(lower)alkyl or (lower)alkoxy;
m is an integer of from 0 to 2 inclusive;
n is an integer of from 2 to 5 inclusive;
Z is oxygen, sulfur or methylene; and
A is
<IMG>
<IMG> or <IMG>

47
in which R5 is hydrogen, (lower)alkyl or (lower)alkoxy, q is
an integer of from 1 to 4 inclusive and R6 and R7 each are
independently (lower)alkyl, (lower)alkoxy (lower)alkyl in which
the (lower)alkoxy moiety is at least two carbon atoms removed
from the nitrogen atom, or phenyl(lower)alkyl, and, when R6
is hydrogen, R7 also may be cyclo(lower)alkyl, or R6 and R7,
taken together with the nitrogen atom to which they are
attached, may be pyrrolidino, methylpyrrolidino, dimethyl-
pyrrolidino, morpholino, thiomorpholino, piperidino, methyl-
piperidino, dimethylpiperidino, N-methylpiperazino, 1,2,3,6-
tetrahydropyridyl, homopiperidino, heptamethyleneimino, octa-
methyleneimino, 3-azabicyclo[3.2.2]non-3-yl or 3-pyrrolino; or
a salt, hydrate or solvate thereof, which process comprises
a) reacting in an inert solvent and at room temperature, a
compound of Formula III
III
<IMG>
wherein R1, m, n, Z and A are as defined above, with a strong
mineral acid and, if desired, converting the resultant compound
of Formula II to a suitable salt, hydrate or solvate; or
b) reacting a compound of Formula IV
A-(CH2)mZ(CH2)nNH2 IV
wherein m, n, Z and A are as defined above, with a compound
of Formula V

48
<IMG> V
to produce a compound of Formula VI
<IMG>
then reacting said compound of Formula VI with a compound of
Formula R1NH2, and, if desired, converting the resultant
compound of Formula II to a suitable salt, hydrate or solvate.
2. A process for preparing a compound of the Formula II
<IMG>
wherein R1 is hydrogen or (lower)alkyl, m is 0 or 1, n is 2
or 3, Z is oxygen or sulfur and A is
<IMG> or <IMG>

49
in which R5 is hydrogen or methyl, and R6 and R7 each are
independently methyl or ethyl, or when taken together with
the nitrogen to which they are attached, R6 and R7 represent
a pyrrolidino or piperidino ring; or a salt, hydrate or
solvate thereof, which process comprises
a) reacting in an inert solvent and at room temperature, a
compound of Formula III
<IMG> III
wherein R1, m, n, Z and A are as defined above, with a strong
mineral acid and, if desired, converting the resultant compound
of Formula II to a suitable salt, hydrate or solvate; or
b) reacting a compound of Formula IV
A-(CH2)mz(CH2)nNH2 IV
wherein m, n, Z and A ara as defined above, with a compound
of Formula V
<IMG> V
to produce a compound of Formula VI
<IMG>
the reacting said compound of Formula VI with a compound of

Formula R1NH2, and, if desired, converting the resultant
compound of Formula II to a suitable salt, hydrate or solvate.
3. A Process for preparing a compound of the Formula IIa
<IMG> IIa
wherein R1 is hydrogen or methyl, and R6 and R7 each are
methyl or, when taken together with the nitrogen atom to
which they are attached, R6 and R7 represent a pyrrolidino
or piperidino ring; or a salt, hydrate or solvate thereof,
which process comprises
a) reacting, in an inert solvent and at room temperature, a
compound of Formula IIIa
<IMG> IIIa
wherein R1, R6 and R7 are as defined above, with a strong
mineral acid and, if desired, converting the resultant compound
of Formula IIa to a suitable salt, hydrate or solvate; or
b) reacting a compound of Formula IVa
<IMG> IVa

51
wherein R6 and R7 are as defined above, with a compound of
Formula V
<IMG> V
to produce a compound of Formula VIa
<IMG> VIa
wherein R6 and R7 are as defined above, then reacting said
compound of Formula VIa with a compound of Formula R1NH2 and,
if desired, converting the resultant compound of Formula IIa
to a suitable salt, hydrate or solvate.
4. A process for preparing a compound of the Formula IIb
<IMG> IIb
wherein R1 and R5 each are independently hydrogen or methyl,
and R6 and R7 each are independently methyl or ethyl; or
a salt, hydrate or solvate thereof, which process comprises
a) reacting in an inert solvent and at room temperature,
a compound of Formula IIIb

-52-
<IMG> IIIb
wherein R1, R5 R6 and R7 are as defined above, with a strong
mineral acid and, if desired, converting the resultant compound
of Formula IIb to a suitable salt, hydrate or solvate; or
b) reacting a compound of Formula IVb
<IMG> IVb
wherein R5, R6 and R7 are as defined above, with a compound of
Formula V
<IMG> V
to produce a compound of Formula VIb
<IMG> VIb
wherein R5, R6 and R7 are as defined above, then reacting said
compound of Formula VIb with a compound of Formula R1NH2 and,
if desired, converting the resultant compound of Formula IIb to
a suitable salt, hydrate or solvate.

53
5. A process for preparing a compound of the Formula IIc
<IMG> IIc
wherein R1 and R5 each are independently hydrogen or methyl
and R6 and R7 each are independently methyl or ethyl, or
a salt, hydrate or solvate thereof, which process comprises
a) reacting in an inert solvent and at room temperature, a
compound of Formula IIIc
<IMG>
wherein R1, R5, R6 and R7 are as defined above, with a strong
mineral acid and, if desired, converting the resultant compound
of Forumula IIc to a suitable salt, hydrate or solvate; or
b) reacting a compound of Formula IVc
<IMG> IVC
wherein R5, R6 and R7 are as defined above, with a compound
of Formula V
<IMG> V

54
to produce a compound of Formula VIc
<IMG> VIc
wherein R5, R6 and R7 are as defined above, then reacting
said compound of Formula VIc with a compound of Formula R1NH2
and, if desired, converting the resultant compound of Formula
IIc to a suitable salt, hydrate or solvate.
6. A process for preparing a compound of the Formula IId
<IMG>
wherein R1 and R5 each are independently hydrogen or methyl,
and R6 and R7 each are independently methyl or ethyl, or, when
taken together with the nitrogen to which they are attached, R6
and R7 represent piperidino, or a salt, hydrate or solvate
thereof, which process comprises
a) reacting in an inert solvent and at room temperature, a
compound of Formula IIId
IIId
<IMG>

-55-
wherein R1, R5, R6 and R7 are as defined above, with a strong
mineral acid and, if desired, converting the resultant compound
of Formula IId to a suitable salt, hydrate or solvate; or
b) reacting a compound of Formula IVd
<IMG>
IVd
wherein R5, R6 and R7 are as defined above, with a compound of
Formula V
<IMG> V
to produce a compound of Formula VId
<IMG> VId
wherein R5, R6 and R7 are as defined above, then reacting said
compound of Formula VId with a compound of Formula R1NH2 and,
if desired, converting the resultant compound of Formula IId to
a suitahle salt, hydrate or solvate.
7. The process of claim 3 wherein R1 is hydrogen,
and R6 and R7 taken together is piperidino.
8. The process of claim 4 wherein R1 and R5 are both hydrogen
and R6 and R7 are both methyl.

-56-
9. The process of claim 5 wherein R1 is hydrogen and R5,
R6 and R7 are each methyl.
10. The process of claim 3, wherein R1 is hydrogen, and R6
and R7 taken together is pyrrolidino.
11. The process of claim 5 wherein R1 and R5 are both hydrogen
and R6 and R7 are both methyl.
12. The process of claim 5 wherein R1 is hydrogen, R5 is
methyl and R6 and R7 taken together is piperidino.
13. The process of claim 6 wherein R1 is hydrogen, R5 is
methyl, and R6 and R7 taken together is piperidino.
14. The process of claim 6 wherein R1 is hydrogen, R5 is
methyl, and R6 and R7 taken together is piperidino.
15. The process of claim 3 wherein R1 is hydrogen and R6
and R7 taken together is 3-(1,2,3,6-tetrahydro-1-pyridyl).
16. A compound of the formula
<IMG> II
wherein R1 is hydrogen, (lower)alkyl, 2-fluoroethyl, 2,2,2-
trifluoroethyl, allyl, propargyl,

<IMG> or <IMG>
in which p is 1 or 2, R2 and R3 each are independtly hydrogen,
(lower)alkyl, (lower)alkoxy or halogen, and, when R2 is hydrogen,
R3 also may be trifluoromethyl, or R2 and R3, taken together,
may be methylenedioxy, and R4 is hydrogen, (lower)alkyl or
(lower)alkoxy;
m is an integer of from 0 to 2 inclusive;
n is an integer of from 2 to 5 inclusive;
Z is oxygen, sulfer or methylene; and
A is
<IMG>
<IMG> or <IMG>
in which R5 is hydrogen, (lower)alkyl or (lower)alkoxy, q is
an integer of from 1 to 4 inclusive and R6 and R7 each are
indepently (lower)alkyl, (lower)alkoxy(lower)alkyl in which
57

the (lower)alkoxy moiety is at least two carbon atoms removed
from the nitrogen atom, or phenyl(lower)alkyl, and, when R6
is hydrogen, R7 also may be cyclo(lower)alkyl, or R6 and R7,
taken together with the nitrogen atom to which they are
attached, may be pyrrolidino, methylpyrrolidino, dimethyl-
pyrrolidino, morpholino, thiomorpholino, piperidino, methyl-
piperidino, dimethylpiperidino, N-methylpiperazino, 1,2,3,6-
tetrahydropyridyl, homopiperidino, heptamethyleneimino, octa-
methyleneimino, 3-azabicyclo[3.2.2]non-3-yl or 3-pyrrolino; or
a salt, hydrate or solvate thereof, whenever prepared by the
process of claim 1 or by an obvious chemical equivalent thereof.
17. A compound of claim 16 having the formula
<IMG> II
wherein R1 is hydrogen or (lower)alkyl, m is 0 or 1, n is 2 or
3, Z is oxygen or sulfur and A is
<IMG>
<IMG> or <IMG>
58

in which R5 is hydrogen or methyl, and R6 and R7 each are
independently methyl or ethyl, or when taken together with
the nitrogen to which they are attached, R6 and R7 represent
a pyrrolidino or piperidino ring; or a salt, hydrate or
solvate thereof, whenever prepared by the process of claim
2 or by an obvious chemical equivalent thereof.
18. A compound of claim 16 having the formula
<IMG> IIa
wherein R1 is hydrogen or methyl, and R6 and R7 each are methyl
or, when taken together with the nitrogen atom to which they
are attached, R6 and R7 represent a pyrrolidino or piperidino
ring; or a salt, hydrate or solvate thereof, whenever prepared
by the process of claim 3 or by an obvious chemical equivalent
thereof.
19. A compound of claim 16 having the formula
<IMG> IIb
59

wherein R1 and R5 each are independently hydrogen or methyl,
and R6 and R7 each are independently methyl or ethyl; or a
salt, hydrate or solvate thereof, whenever prepared by the
process of claim 4 or by an obvious chemical equivalent
thereof.
20. A compound of claim 16 having the formula
<IMG> IId
wherein R1 and R5 each are independently hydrogen or methyl,
and R6 and R7 each are independently methyl or ethyl; or a
salt, hydrate or solvate thereof. whenever prepared by the
process of claim 5 or by an obvious chemical equivalent thereof.
21. A compound of claim 16 having the formula
<IMG> IId
wherein R1 and R5 each are independently hydrogen or methyl, and
R6 and R7 each are independently methyl or ethyl, or, when
taken together with the nitrogen to which they are attached,
R6 and R7 represent piperidino; or a salt, hydrate or solvate
thereof, whenever prepared by the process of claim 6 or by
an obvious chemical equivalent thereof.

-61-
22. The compound N-[3-(3-piperidino-
methylphenoxy)propyl]ethanediimidamide, or a salt, hydrate or
solvate thereof, whenever prepared by the process of claim 7
or by an obvious chemical equivalent thereof.
23. The compound N-[2-[(5-dimethyl-
aminomethyl-2-furyl)methylthio]ethyl]ethanediimidamide, or a
salt, hydrate or solvate thereof, whenever prepared by the
process of claim 8 or by an obvious chemical equivalent thereof.
24. The compound N-[2-[(5-dimethyl-
aminomethyl-4-methyl-2-thienyl)methylthio]ethyl]ethanediimidamide,
or a salt, hydrate or solvate thereof, whenever prepared by
the process of claim 9 or by an obvious chemical equivalent
thereof.
25. The compound N-[3-(3-pyrrolidino-
methylphenoxy)propyl]ethanediimidamide, or a salt, hydrate
or solvate thereof, whenever prepared by the process of claim
10 or by an obvious chemical equivalent thereof.
26. The compound N-[2-[5-dimethyl-
aminomethyl-3-thienyl)methylthio]ethyl]ethanediimidamide, or
a salt, hydrate or solvate thereof, whenever prepared by the
process of claim 11 or by an obvious chemical equivalent
thereof.
27. The compound N-[2-[(5-piperidino-
methyl-3-thienyl)methylthio]ethyl]ethanediimidamide, or a
salt, hydrate or solvate thereof, whenever prepared by the
process of claim 12 or by an obvious chemical equivalent
thereof.

-62-
28. The compound N-[3-(6-piperidino-
methyl-2-pyridyloxy)propyl]ethanediimidamide, or a salt,
hydrate or solvate thereof, whenever prepared by the process
of claim 13 or by an obvious chemical equivalent thereof.
29. The compound N-[3-(4-piperidino-
methyl-2-pyridyloxy)propyl]ethanediimidamide, or a salt,
hydrate or solvate thereof, whenever prepared by the process
of claim 14 or by an obvious chemical equivalent thereof.
30. The compound N-[3-[3-(1,2,3,6-
tetrahydro-1-pyridyl)methylphenoxy]propyl]ethanediiimidamide,
or a salt, hydrate or solvate thereof, whenever prepared by
the process of claim 15 or by an obvious chemical equivalent
thereof.
31. A compound of the formula
<IMG> II
wherein R1 is hydrogen, (lower)alkyl, 2-fluoroethyl, 2,2,2-
trifluoroethyl, allyl, propargyl,

-63-
<IMG> or <IMG>
in which p is 1 or 2, R2 and R3 each are independtly hydrogen,
(lower)alkyl, (lower)alkoxy or halogen, and, when R2 is hydrogen,
R3 also may be trifluoromethyl, or R2 and R3, taken together,
may be methylenedioxy, and R4 is hydrogen, (lower)alkyl or
(lower)alkoxy;
m is an integer of from 0 to 2 inclusive;
n is an integer of from 2 to 5 inclusive;
Z is oxygen, sulfer or methylene; and
A is
<IMG> or <IMG>
in which R5 is hydrogen, (lower)alkyl or (lower)alkoxy, q is
an integer of from 1 to 4 inclusive and R6 and R7 each are
indepently (lower)alkyl, (lower)alkoxy(lower)alkyl in which

-64-
the (lower)alkoxy moiety is at least two carbon atoms removed
from the nitrogen atom, or phenyl(lower)alkyl, and, when R6
is hydrogen, R7 also may be cyclo(lower)alkyl, or R6 and R7,
taken together with the nitrogen atom to which they are
attached, may be pyrrolidino, methylpyrrolidino, dimethyl-
pyrrolidino, morpholino, thiomorpholino, piperidino, methyl-
piperidino, dimethylpiperidino, N-methylpiperazino, 1,2,3,6-
tetrahydropyridyl, homopiperidino, heptamethyleneimino, octa-
methyleneimino, 3-azabicyclo[3.2.2]non-3-yl or 3-pyrrolino; or
a salt, hydrate or solvate thereof.
32. A compound of claim 31 having the formula
<IMG> II
wherein R1 is hydrogen or (lower)alkyl, m is 0 or 1, n is 2 or
3, Z is oxygen or sulfur and A is
<IMG>
<IMG> or <IMG>

-65-
in which R5 is hydrogen or methyl, and R6 and R7 each are
independently methyl or ethyl, or when taken together with
the nitrogen to which they are attached, R6 and R7 represent
a pyrrolidino or piperidino ring; or a salt, hydrate or
solvate thereof.
33. A compound of claim 31 having the formula
<IMG> IIa
wherein R1 is hydrogen or methyl, and R6 and R7 each are methyl
or, when taken together with the nitrogen atom to which they
are attached, R6 and R7 represent a pyrrolidino or piperidino
ring; or a salt, hydrate or solvate thereof.
34. A compound of claim 31 having the formula
<IMG> IIb

-66-
wherein R1 and R5 each are independently hydrogen or methyl,
and R6 and R7 each are independently methyl or ethyl or a
salt, hydrate or solvate thereof.
35. A compound of claim 31 having the formula
<IMG> IIc
wherein R1 and R5 each are independently hydrogen or methyl,
and R6 and R7 each are independently methyl or ethyl; or a
salt, hydrate or solvate thereof.
36. A compound of claim 31 having the formula
<IMG> IId
wherein R1 and R5 each are independently hydrogen or methyl, and
R6 and R7 each are independently methyl or ethyl, or, when
taken together with the nitrogen to which they are attached,
R6 and R7 represent piperidino; or a salt, hydrate or solvate
thereof.

-67-
37. The compound N-[3-(3-piperidino-
methylphenoxy)propyl]ethanediimidamide, or a salt, hydrate or
solvate thereof.
38. The compound N-[2-[(5-dimethyl-
aminomethyl-2-furyl)methylthio]ethyl}ethanediimidamide, or a
salt, hydrate or solvate thereof.
39. The compound N-[2-[(5-dimethyl-
aminomethyl-4-methyl-2-thienyl)methylthio]ethyl}ethanediimidamide,
or a salt, hydrate or solvate thereof.
40. The compound N-[3-(3-pyrrolidino-
methylphenoxy)propyl]ethanediimidamide, or a salt, hydrate
or solvate thereof.
41. The compound N-[2-[5-dimethyl-
aminomethyl-3-thienyl)methylthio]ethyl}ethanediimidamide, or
a salt, hydrate or solvate thereof.
42. The compound N-[2-[(5-piperidino-
methyl-3-thienyl)methylthio]ethyl}ethanediimidamide, or a
salt, hydrate or solvate thereof-

-68-
43. The compound N-[3-(6-piperidino-
methyl-2-pyridyloxy)propyl]ethanediimidamide, or a salt,
hydrate or solvate thereof.
44. The compound N-[3-(4-piperidino-
methyl-2-pyridyloxy)propyl]ethanediimidamide, or a salt,
hydrate or solvate thereof.
45. The compound N-[3-[3-(1,2,3,6-
tetrahydro-1-pyridyl)methylphenoxy]propyl}ethanediimidamide,
or a salt, hydrate or solvate thereof.

Description

1.25~
SY-l7o6A
SUBSTIII~TE~3 3, 4-DIAMIN~-1, 2, 5-THIADIAZOLES
HAVING HISTAMINE H;~-RECFPTOR ANTAGONIST ACTIVITY
Summa~y of the Invention
Certain 3-(ami~o or substituted amino)-4-(su~sti~ute
amino~-1,2,5-thiadiazoles having the formula
A-(CH2)mZ~CH2)nNH~ NHR
~Ç/ \~!1
~S~
wherein ~, m, Z, n and Rl are as defined below, and the~r
non.oxic pharmaceutically acceptable salts, hydrates and
solva.es, zre potent histamine H2-receptor antagonists.
which inhibit gastric acid secretion and are use-ul in the
treatment of peptic ulcers and other pathological hypersecre.ory
conditions. The compounds are prepared by ring closure o~
the correspondingly substituted ethanediimidamide of the
formula
A-(CH2)~Z(CH2)nNH~ ~ NHRl . lI

Back~round and ~rior Art
Our published ~nited Xinqdo~ Patent Application No.
2,067,987 discloses 3,4-disubstituted-1,2,5-~hiadiazole 1-
oxides and l,l-dioxides having the formula
A-(C~2)mZ(CH2)~NH ~ 1
// \\
~S
(O) p
and processes for their preparation, wherein the ~ariables ~,
m, Z, n and Rl are s~milar to the corres~onding substituents
of the compounds disclosed and clai~ned herein. However, the
compounds disclosed therein are l-oxides or l,l-dioxides (p is
1 or 2), and the compounds of the present inYention cannot be
prepared by any of the processes described therein f~r the
prepz_a~ion of the prior art compounds .
~ ub1ished ~uropean Pa tent Application No. 40,696
discloses inter alia 3,4-disubstituted-1,2,5-thiadiaæole 1-
oxices and 1,1-dioxides having the formula
~1
R- ~ - (CH2)n-x-(cH2)mN~ ~ \ R2
N ~ ~
(~)p
and processes for their preparation, wherein the variab~es ~,
, n, X, m, Rl and R2 are similar to the corresponding
su~stituents of the compounds disclosed znd claimed herein.
~owe~er, the compounds disclosed therein also are l-oxides
or l,l-dioxides (p is 1 or 2) and the compounds of the present
invention cannot be prepared by any of the processes described
therein for ~he preparation of the prior art compoundsO

~i3~
In the two publications cited above, e~ch of the
processes described for preparation of the prior art compounds
involves the use (as a starting material or intermediate) of
a 1,2,5-thiadiazole l~oxide or l,l-dioxide having either amino
groups or suitable "lea~ing groups" on the 3- and 4~positions.
The desired substituents on the 3- and 4-positions are hen
obtained by substitution on the amino groups or by replacement
of the "leaving groups". We have made extensive attempts to
prepare the compounds of the pres~nt invention by similar
procedures, i.e. by utilizing 1,2,5-thiadiazole having amir.o
groups or suitable "leaving sroups" on the 3- and 4-positions
as starting ~aterials or int~rmediates. Although numerous
vasiations were tried, along with ~arying reaction conditions,
we were not able to isolate the compounds of this invention
~y thzt route.
We have no~ found that the compounds of.the present
invention may be prepared by ring closure of the co~respondingly
substituted ethanediimidamide of the formula
A-(CH2)mZ(CH2)nNH/I ~\ II
HN HN
Intermediate II, itself, may ~e prepared by various procedures.
Complete Description
This invention relates to histamine H2-receptor
antagonists of the formula
.- (CH2)mZ (CH2)nNH~NH}~,l
// \\ I
wherein Rl is hydrogen, (lower)alkyl, 2-fluoroethyl, 2,2,2-
trifluoroethyl, allyl, propargyl,

~3~
--4--
R3 ~ (C~2 ) p~ or R4--~ (C~2 ) p~
in which p is 1 or 2, R2 and R3 each are independently
hydrogen , (lower) alkyl, (lower) alkoxy or halogen, ~nd, when
R2 is hydrogen, R3 also may be trifluoro~ethyl, or R2 and R ,
t~.ken together, may be methylenedioxy, and R4 is hydrogen,
(lower)alkyl or (lower) alkoxy;
m is an integer o~ from O to 2 inclusive;
n is an integer of from 2 to 5 inclusive;
~ is oxygen, sulfur or methylene; and
A is
~(C~)q~ / (CH
/N (CH2 ) q ~ or 6/ (C112)q ~
in which R5 is ~ydrogen, tlower)alkyl or (lower)alkoxy, q is
an integer ~f from 1 to 4 inclusive and R6 and R7 each are
independently tlower)alkyl, (lower)alkoxy(lowcr)al~yl in which
~ the (lower)alkoxy moiety is at least two carbon atoms re~oved
from the nitrogen atom, or phenyl(lower)alkyl, and, when R
is hydrogen, R7 also may be cyclo~lower)alkyl, or R6 and R7,
taken together with the nitrogen atom to which they are
attached, may be pyrro:Lidino, ~ethylpyrrolidino, ~methyl-
pyrrolidino t morpholino, thiomorpholino, piperidino, methyl-
piperidino, dimethylpiperidino, N-methylpiperazino, 1,2,3,6-
tetrahydropyridyl, homopiperidino, heptamethyleneimino, octa
methyleneLmino, 3-azabicyclot3.2.2~non-3-yl or 3-pyirolino;
and nontoxic, pharmaceutically acceptable s~lts, hydrat~s and
solv2tes thereof.

:~253~
--5--
This invention also relates to processes for the
preparation of the compounds of Formula I and to the intermediate
compounds of Formula II.
The present invention includes within its scope all
possible tautomeric forms, diastereoisomeric forms and optically
active isomers of the compounds of Formula I as well as mixtures
thereo~. ~s used herein and in the claims, th~ term ~(lower)-
alkyl~ means a straight or branched chain alkyl sroup conta~ning
from 1 to 6 carbon atoms. The tenm ~(lower)alkoxy~ me~ns a
skraight or branched chain alkoxy group containing from 1 to 4
carbon atomsO ~Cyclo(lower)al~oxy" me ns a cycloalkyl group
containing from 3 to ~ carbon atoms. The term "nontoxic pharma-
ceutically acceptable salts~ means acid addition salts formed
with a~ids such as hydrochloric, hydrobromic, nitric, sulfuric,
acetic, pr~pionic, fumaric, methanesulfonic, maleic, tartaric,
citric, levulinic, benzoic, succinic and the like.
In the compounds of Fo~mula I, Rl preferably is
hydrogen or (lower)alkyl, more preferably is hydrogen or methyl
and most preferably is hydrogen. Substituent A pre erably is
the substituted phenyl moiety, substituted furyl moiety or
substituted thienyl moiety shown above, and most preferably is
the substituted phenyl moiety. Substituent Z preferably is
sul.ur or oxygen and, when A is the substituted phenyl moiety,
Z preferably is oxygen. It is preferred that m is zero or 1
and n is 2 or 3, a~d that, when A is the substituted phenyl
moiety, m is zero and n is 3. R5 pre.erably is hydrogen or
methyl and most preferably is hydrogen. It is preferred that
q is 1. R6 and R7 preferably are (lower)alXyl or, taken
together with the nitrogen atom to which they are attached, are
pyrrolidino o~ piperidino.
The compounds of Formula I may be prepared by
reaction of a compound of Formula II with sulfur monochlorid~
~52C123, sulfur dichloride 5SCl~) or chemical equivalents
thereof, as follows:

-6-
A-(cH2)mz(cH2)nN~ C~NHR II
HN }I
¦ 52C12
SC12
V
A_(C~2)mZ(CH2)nN ~ N~Rl
~t ~ I
~S~
wherein ~, m, Z, n and Rl are as defined above. At least about
1 mole of 52C12 or SC12 should be used per mole of Compound II;
it is preferred to use an excess of S2C12 or SC12, e.g. from
about 2 to about 3 moles of S2C12 or SC12 per mole of Compound
II. It has been found that SC12 often give~ a cruder product
and lower yiel~ of purified product, and we usually prefer to
use S2C12 for the reaction. The reaction tempe_ature is not
critical; we prefer to conduct the reaction at a temperature of
'rom about 0C to about 50C, and it is most convenient to
conduct the reaction at ambient temperature. The reaction time
is not critical and is dependent on temperature. We normally
utilize a reaction time of from about 30 minutes to about 6
hours. At ambient temperature, reaction times of from about
1 1/2 to 4 hours usually are preferred. The reaction may be
conducted in an inert organic solvent, preferably a mixture of
an inert organic solvænt and dimethylformamide. Most preerably
the reaction is conducted in dimethylformamide.

~L2~
--7--
Ln a preferred embodlment of the invention, the
compounds of Formula I have khe structure
A (CH2)mZ(c 2)n NHRl I
?~
~S~
wherein Rl is hydrogen or (lower)alkyl, ~ is O or 1, n is 2 or
3, ~. is oxygen or sulfur and A is
'2 ~_ ' 6~NC1:
R5
6~ 2 ~ ~ NC~ ~
in which R5 is hydrogen or methyl, and R6 and R7 each are
i~dependently methyl or ethyl, or when taken together with the
nitrogen to which they are attached, R6 and ~7 represent a
pyrrolidino or piperidino ring; or a nontoxic pharmaceutically
acceptable salt, hydrate or solvate thereof.
In a more preferred embodiment, the compounds of
Formula I have the structure
R \ ~
/~CH2 ~ I Ia
R6 ~ CH2CH2 2 ~t~ Rl
// \\ .
~ S

-
--8--
wherein Rl is hydrogen or methyl, and R~ and R7 each are methyl
or/ when taken together with the nitrogen atom to which they
are at~ached, R6 and R7 represent a pyrrolidino or piperidino
riny; or a nontoxic pharmaceutically acceptable salt, hydrate
or solvate thereoC
In another more preferred embodiment, the compounds
of Formula I have the structure
7 R5
NCH,,~CX25CH2CH2 ~HRl Ib
N ~ ~
wherein Rl and R5 each are in~ependently hydrogen or methyl,
nd R6 and R7 each are independently methyl or ethyl; or a
nontoxic pharmaceutically ac~eptable salt, hydrate or sol~ate
khereof.
In another more preferred embodiment, the compounds
of Formula I have the structure
R5
R6/ ~ ~2scll2c~2N~ ~ N~Rl Ic
wherein Rl and RS each are independently hydrogen or methyl,
and R6 and R7 each are independently methyl or ethyl; or a
nontoxic pharmaceutically accepta~le salt, hydrate or solvate
thereof.
In another more preferred embodiment, 'he compounds
of Formula I have the structure

~L2~3~
9--
R5
R6/ ~ CH2c~2c 2 ~ NHRl Id
N
~S~
wherein Rl and R5 each are independently hydrogen or methyl, and
R6 and R7 each are independently methyl or ethyl, or, when taken
together with the nitrogen to which they are attached, R6 and R7
represent piperidino; or a nontoxic pharmaceutically acceptable
salt, hydrate or solvate thereof.
As presently envisaged, the most preferred compounds
of Formula I are
1) 3-~mino-4-130(~-piperidinomethylphenoxy)propyl-
æmino~-l,2,5-thiadiazole;
2) ~-amino-4-~2-1(5-dimethylaminomethyl-2-~uryl)-
methyl~hio]ethylamino~l,2,5-thiadi2zole;
33 3-~mino-4-{2-1(5-dimethylaminome~hyl-4-methyl-
2-thi~nyl)methylthio~ethylamino}-l,2,5-~hiadiazole,
4) 3-~mino-4-13-(3-pyrrolidinomethylphenoxy~-
propylamino~-~,2,5~thiadiazole,
5) 3-methylamino-4-13-(3-piperidinomethylphenoxy)-
propylamino~-l,2,5-thiadiazole,
6) 3-benzylamino-4-[3-(3-piperidinomethylphenoxy)-
propylamino~-l,2,5-thiadia~ole,
7) 3-amino-4-~2-1~5-dimethylaminomethyl-3-thienyl)-
methylthio~ethylamino}-l,2,5-thiadiazole,
8) 3-amino-4-{2-[(5-piperidinomethyl-3-thienyl)-
methyl~hiolethylamino}-l,2,~-thiadiazole,
9) 3 ~mino-4-[3-~6-piperidi~o~ethyl-2-pyridyloxy)-
propyl~mino~-l,2,5-thiadiazole ~nd
10) 3-amino-~4-~3-~4-piperidinomethyl-2-pyridyloxy)-
propyli~minol-l,2,5-thiadiazole; i~nd their nontoxic, pharma-
ceutically accepti~ble salts, hydrates and solvatesL
The intenmediates of Formula II used in the prepara-
tio~ o~ ~he compounds of Formula I may themselves be prepared
hy various procedures. In one procedure, ~he corresponding

~3~
--10--
3-(amino or substituted amino)~4-(substituted am~no)-1,2,5-
thiadiazole l-oxide of Formula III is treated with a strong
mineral acid (preferably HCl) to produce ~he compound of Formula
II.
A- (CH2 ) mZ (CH2) nNH NHRl
III
~ HCl
A-(CR2~mZ(c~2)nNH ~ NHRl II
The reaction m~y be conducted in an ~nert solvent ~nd preferably
is conducted in methanol. Reaction temperature is not critic~l;
it most conveniently is conducted at room temperatureO The com-
pounds of Formula III ~re known or may read~ly be prepared by the
procedures described in our published United Xing~om Patent
Application No. 2,067,987.
In an alternate procedure, the compounds of Formula
II may be prepared by the following reaction scheme. The
CH30 \ / OCH3
A-(cH2)mz(c~2)nN~2 /C - ~
~f ~H
I~7 V

~.%~
A-~C~2)mZ(c~2)n \ OCH3 VI
C --~/
¦~R1N~2
A-(CH2)~Z(CH2)nNH \JNHRl III
reaction may be conducted in an inert sol~ent and preferably
is conducted in methanol~ The start mg matexials of Formula TY
are kn~wn or may be seadily prepared by ~nown procedures, e.g.
as by procedures described in our publlshed Uni~ed Kingdom
Paten~ ~pplication No. 2,067,987.
In another aspect, ~hls invention relates to novel
intermediates of the formula
A-(C~2)mZ(cH2)nMH ~ ~Rl
H~/ ~H II
wherein Rl is hydrogen, (lower)alkyl, 2-fluoroethyl, 2,2,2-
tri~luoroethyl, allyl, propargyl,
~3 ~ (CN2)p- or R ~ ~ r ~CH2)p-
in which p is 1 or 2, R2 and R3 ea~h are independently
hydrogen, (lower)alkyl, tlower~al~oxy or halogen, and, when

;
~Z~3~
-12-
R2 is hydrogen, R3 also may be trifluoro~ethyl, or R~ and R3,
taken together, may be methylenedioxy, and R4 is hydrogen,
(lower)alkyl or (lower)alkoxy; .
m is an integer of from 0 to 2 inclusive;
n is an integer of from 2 to 5 incl~sive;
Z is oxygen, sulfur or methylene; and
A is
N~C}12)q~ /n(C~2)q~
/~C~2)q ~ or N(Cl~2)q ~
in which R is hydrogen, ~lower)alkyl or (lower)alkoxy, q is
an integer of from 1 to 4 inclusive and R6 and R7 each are
independently ~lower)al~yl, ~lower)alkoxy~lower)alkyl in which
the (lower)alkoxy moiety is at least two carbon atoms re~oved
~rom the nitrosen atom, or phenyl~lower)alkyl, and, when R6
is hydrogen, R7 also may be cyclo(lower)alkyl, or R6 and R7,
ta~en together.with the nitrogen atom to which they are
attached, may be pyrrolidino, methylpyrrolidino, dimethyl-
pyrrolidino, morpholino, thiomorpholino, piperidino, methyl-
piperidino, dimethylpiperidino, N-methylpiperazino, 1,2,3,6-
tetrahydropyridyl, homopiperidino, heptamethyleneimino, octa-
methyleneimino, 3-azabicyclol~02.2)non-3-y~ or 3-pyrrolino;
or a s~lt, hydrat~ or solvate thereo~.
I~ a preferred embodiment, the intermediates of
Formula I~ have ~he structure
~-(CH~1mZ(CH2)nNH ~NHR
~ II
HN NH

~.25;~
-13-
wherein Rl is hydrogen or (lower)alkyl, ~ is O or 1, ~ is 2 or
3, Z is oxygen or sulfur and A is
R5 7 R5
6~ 2 ~ , 6/NCH
R5 R7 R5
/N~2 ~ ~ or 6/ NC~2 ~
in which R5 is hydroqen or methyl, and R6 and R7 ea~h are
ndependently methyl or ethyl, or when take~ together with the
nit_oqen to which they are ~ttached, R6 and R7 represent a
pyrrolidino ~r piperidino ring; or a nontoxic pharmaceutically
acce?table salt, hydrate or sol~ate thereof.
In another preferred embodiment, the intermediates
of Formula I~ have the structure
2 ~ C~2CH2CI~2
}~N NH
wherein Rl is hydrogen or methyl, and R6 and R7 each are methyl
or, when taken together with the nitrogen ~tom to which they
are attached, R6 and R7 .re~resent a pyrrolidino or piperidino
ring; or a salt, hydrate or solvate thereof.
In another preferred embodiment, the intermediates
of Formula II have the structure

~3~
7 R5
NCH2- ~ H2scH2c~2NH ~ ~Rl IIb
~N N~
wherein Rl and R5 each are independ~ntly hydrogen or methyl, and
R6 and R7 each are independently methyl or ethyl; or a salt,
hydrate or solvate thereof.
In another preferred embodiment, the intermediates
of Formula II have ~he structure
NC82 ~ ~ ~2sCrl2c 2 ~ ~HRl IIc
XN NH
wherein Rl and R5 each are independently hydrogen or ~ethyl,
and R6 and R7 each are independently methyl or ethyl; or a salt,
hydrate or solvate thereof.
~ n another preferred embodiment, the intermediates of
Formula II have the structure
- /NCH~ OCH2C~2 2 ~ HRl IId
NH
wherein Rl and R5 each are independently hydrogen or me~hyl, and
R6 and R7 each are independently methyl or ethyl, or, when taken
tosether with the nitrogen to which they are at~ached, ~ and R
represent pi~eridino; or a salt, hydrate or solvate thereof.

~253~
-15-
As presently envisaged, ~he most pre rerred intermediates
of Formula II are
1) N-~3-(3-piperidinomethylphenoxy)propyl~ethane-
diimidamide,
2) N-{2-~(5-dimethylaminomethyl-2-furyl)methylthio]-
ethyl}ethanedii~idamide,
3) N-{2-~(5-dime~hylami~omethyl-4-methyl-2-thienyl)-
methylthio)ethyl~ethanediimidamide,
4) N-~3-(3-pyrrolidinome~hylphenoxy)propyl]ethane-
di~midamide~
5) N-{2-l(5-dimethyl~minomethyl-3-thienyl)~ethylthio]-
ethyl}e~hanediimidamide,
6) N~12-l(5-piperidinom~thyl-3-thienyl)methylthio]-
P~hyl}ethanediimidamide,
7) N-~3-(6-piperidinomethyl-2-pyridyloxy)propyl~-
ethanediimidamide and
8) N-~3-t4-piperidinomethyl-2-pyridyloxy~propyl~
ethanediimidamide;
or a salt, hydrate or solvate thereof.
For therapeutic use, the pharmacologlcally active
compounds of ~ormula I will normally be administered as a
pharmaceutical composition comprising as the ~or an) esse2,ial
acti~e ingredient at least one such compound in its basic form
or in the for~ of a nontoxic pharmaceutically acceptable acid
addition salt, in association with a phanmaceutically acceptable
carrier.
The pharmaceutical compositions may be administered
or211y, pare~terally or by rectal suppository. A wide variety
of pharmaceutical forms may be employed. Thus, if a solid
carrier is used, the preparation may be tableted, placed in a
hard gelatin capsule in powder or pellet form, or in the form
of a troche or lozenge. If a liquid carrier is employed, the
preparation may be in the form ~f a syrup, ~mulsion, soft
gelatin capsule, sterile solution for ~njection, or an aqueous
or non-aqueous liquld suspension. The pharmaceutical compositions
are prepared by ~onventional techniques appropriate to ~he

-16-
desired preparation.
The dosage of ~he compounds of thi in~ention will
depend not only on such factors as the weight of the patient;
but also on the degree of gastri~ acid inhibition desired and
the potency of the particular compound being utilized. The
decision as to the particular dosage to be employed (and the
number of times to be admLnistered per day) is within the
discretion of the physician, and may be varied by titration of
the dosage t~ the particular circumstances of the specific
patient. ~ith the preferred compounds of this in~ention, each
oral dosage unit will contain the ~ctive ingredient in an amount of
from about 2 mg to about 300 mg, and most preferably from about
4 mg to about 100 my. The active ingredient will preferably be
administered in equal doses from one to four times a day.
Histamine H2-receptor antagonists have ~e~n shown t~
be effective inhibitors of gastric secretion in animals ~nd ~an,
Brimblecombe et al., J. Int. Med. ~es., 3, 86 (1975)~ Clinical
evaluation of the histamine H2-receptor antag~nist cimetidine
has shown it to be an effecti~e therapeutic agent in the treatment
of peptic ulcer disease, G~ay et al , ~ancet, 1, ROOl (1977).
Some of the preferred compounds of this invention hav~ be~n
compared with cimetidine in various tests and ha~e b2en found to
be more potent than cimetidine both as an histamine H2-receptor
antagonist in isolated guinea pig right atria and as an inhibitor
o gastric acid secretion in rats and doss.
Determination of Gastric Antisecretory
Activlty_in the Gastric ~istula Rat
Male Long Evans rats weighing about 240~260 grams ak
the time of cannula implantation are use~. The design and
implantation of the stainless s~eel cannula into ~he anterior
wall of the fore-stomach are carried out essentially as described
by Pare et al. ~Labor~tory ~nimal Science, 27, 244 (1977)~. The
fistula components a_~ designed and the operative procedure is
carried out exactly as described in the above refere~ce. Post
operati~ely the an~mals are individually housed in solid bottom

-17-
cages with sawdust and are allowed food and water ad libitum
throughout the entire recovery period. Animals are not used
for test purposes for at least 15 days after the operative
procedure.
The animals are fasted but allowe~ water ad libitum
for 20 hours before the testing procedure is to begin. Immed-
iately ~rior to collection, the cannula is opened and the
stomach washed gently with 30-40 mL of w~rm saline or distilled
wa~er to remove any residual contents. m e catheter is then
scre~ed into the cannula in place of ~he plugging screw and the
rat is pla~ed in a clear plastic rectangular cage measuring
40 cm long, lS cm wide and 13 ~m high. The bottom of ~he cage
has a slit approximately 1.5 ~ wide and 25 cm long runnins
down the center to ac~ommodate the catheter which hangs ~hrough
it. In this way the rat is not restricted and can move freely
about the cage during collectio~ periods. The remainder of the
assay is car~ied out as des~ribed by Ridley et al. [Research
Comm. Chem. Path. Pharm., 17, 365 (1977)].
Gastric secretions collected during the first hour
after washing the stomach are discarded as they may be contam-
inated. Por oral evaluation, the catheter is then removed from
the cannula and replaced with the plugging screw. Water (2 mL/
kg) is administered orally via gastric intubation and ~he
animal is returned to the cage for 45 minutes. A~ter this
time the plugging screw is removed and replaced with a catheter
to which a small plasti~ vial has been attached to collect ~he
gastric secretions~ A two-hour sample is collected (this
represents the control secretion), the catheter is removed and
replaced with the plugging screw. The test drug is now
administered orally in a volume of 2 mL/kg via gastric
intubation. Forty-five minutes later the plugging screw is
again removed, replaced with the catheter zttached to a small
plastic ~ial and another 2-hour sample is collected. The
secretions in the second sample are compared to ~hose of ~he
con~rol sample in order to determine the effects of the test
dru~.

~53~
18-
l~en test compounds are to be evaluated parenterally,
the animal is injected ip or sc with the test compound vehicle
in a volume of 2 mL~kg immediately af ter discarding the initial
60-minute collection. A two-hour sample is collected (eontrol
secretion) and the animals are injected either ip or sc with
the test compound in a volume of 2 mL/kg. ~n zdditional two-
hour sample is collected and its secretions are compared to
those of the control period to determine drug ef f ects .
The ~amples are centrifuged and placed in a graduated
centrifuge tube for volume deter~inatlon. Titratable aci~ity
is measured by titrating a one~mL sample to pH 7.0 wi~h 0.02N
NaOH, using an AutoburPt and a~ electrometric pH meter
~Radiometer). Ti~ratahle acid output is calculated in micro~
equivalents by multiplying the ~olume in milliliters by ~he
acid concentration in milliequivalents per liter.
Results are expressed as percent i~hibition relati~e
to control readings. Dose response curves are constructed a~d
ED50 values are calculated ~y regressio~ analyses, At least
~hree rats are used at each dosage leve~ and a minimum of three
dosage levels are utilized for determination of a dose response
cur~e.

- ` ~%53~
Table 1
_ _
Gastric Antis~cretory Activity in the Gastric Fistula Rat
._ ~
ED50 sc Potency Ratio
Compound ~moles/kg (cimetidine = 1.0)
_ _ _ _ . _
cimetidine 3.48 1.0
(1.68-5.70 *
__ , _ __ _ ___
Example 1 0.094 37
(0.043~0.20)
I ._ . _ __ _ _ . ,.
Example 2 O.77 4.5
(0.45-1~4)
. _ . _
Example 3 ~0~5 ~7
_ _ _ _ __ _ _ _ _ _
Example 4 0.18 20
(0.10-0.36) _ i
. _
*95% confidence limits
~istamine H -Receptor Antagonism-Isolated
_ 2
Guinea Pig Atria Assay
Histamine produces co~centration-related increases
in the contractile rate of isolated, spontaneo~sly beating
guinea pi$ right atriaO Black et al-, Nature, 236, 385 (1972),
described the receptors involved in this effect of histamine
as histamine H2-r2ceptors when they reported the properties o~
burimamide, a eompetit.ive antayonist of these receptors. Subse~
quent inves~igatior.s by Hughes and Coret, Proc. Soc. Exp. Biol.
Med., 148, 127 (1975) and Verma and McNeill, J. Pharmacol.
Exp. Ther., 200, 352 ~1977) support the conclusion of Bla~k and
coworkers ~ha~ the positive chrono~ropic effect of histamine ~n

-20-
isolated guinea pig right atria is mediated via histamine ~2-
receptors. Black et al., Agents and Actions, 3, 133 (19~3)
and Brimblecombe et al., Fed. Proc., 35, 1931 (1976) have~_.
utilized isolated guinea pig right atria as a means or compar-
ing the activities of histamine Y.2-receptor antagonists. The
present comparative studies were carried out using a modifi
cation of the procedure reported by Reinhardt et al., Agents
and Actions, 4, 217 (1974).
~ ale Hartley stra m guinea pigs (350-450 gml wese
sacrificed ~y a ~low on the head~ The heart was excised and
placed in a Petri dish of oxygenated (95% 2~ 5% C02) modified
Krebs solution (g/liter: NaCl 6.6, XCl 0.35, MsS~4-7~20 0.295,
~X2P04 0.162, CaC12 0.238, NaHCO3 2.1 and dextrose ~.99). The
spontaneously beating right atrium was dissected free from
other tissues and a silk t~read (4-0) attached to each end.
The atrium was suspended in a 20 ml muscle chamber containing
o~ygenated modified Krebs solution maintained at 32C. Atrial
contractions were recorded isometrically by means of a Grass
FT 0.03 force displacement transducer and rec~rdings of
contractile force and rate were made with a ~eckman RP
D~nosraph .
A res~ing tension o~ 1 g was applied to the atrium and
it was allowed to equilibrate for 1 hour. At the end of the
equilibration period a su~maximal concentrationrof histamine
dihydrochloride (3 x 10 6M) was added to the bath and washed out
to prLme the tissue. Histamine was then added to the bath in
a cumulative ~ashion using 1/2 log 10 intervals to give final
molar bath concentrations of 1 x 10 7 to 3 x 10 5. The
histamine-induced increase in atrial rate was allowed to plateau
befo~e the next successi~e concen ration was added. The
maximal response invaria~ly occurred at the 3 x 10 ~M concen-
tration. The histamine was washed out several times and the
atrium allowed to return to control rate. The test compound
was then added at appropriate molar concentrations and, after
a 30-minute incubation, the histamine dose response was repeated

-21- ~ 2
adding higher concentratibns as needed~
The dissocia~ion consta~t~ ~X~) were derived from
Schild plots by the method of ~runlakshana, O. and Schild, H. O~
lBr. J Pharmacol. 14, 48 (l9591~ using at least three dose
levels. Parallel shifts in dose-response curves were obtained
without depressing the maximal response at the antagonis~
concen~rations utilized, and the results are shown in Table 2.
Table 2
A tivit in Isolated Guinea Pi Ri ht Atria
c y g g
_ _
Potency Ratio
Compound N KB (~moles) (cimetidine=l.0)
_ _ _
cimetidine 20 O.41 ~.21-.64)* l.0
Example 1 12 0.003 ~.OOl-.004) 137
Exampl 4 ll 0.004 ~.OOl-.OlO) 102
*95% confidence limits
The compounds ~f Formula ~ als~ ma~
be prepared by ring closure of a compound of Formula II with
N~N'-thiobisphthalimide having the formula
O ~
~;tS
The use of N,N'-thiobisphthalimide ~nstead of S2C12or SCl~ for
the ring closure reaction results in both purer and higher crude
yields of the compounds of Formula I. The crude products

-22-
of Formula I thereby produced normally are pure enough to form
crystalline salts directly without prior chromato~raphic purifi-
cation. - ~
In this process, the starting diimidamide of ~ormula II
is reacted with about an equimolar amount of N,N'-thiobis-
phthalimide in an inert organic solvent such as CH2C12. Prefer-
ably the starting diimidamide is used in the form of its tri-
hydrochloride salt, in which case three molar equivalents of
an amine, such as trlethyl~mine, are added to the reaction mix-
ture ~o neutral~ze the trihydrochloride salt. The reaction may
be conducted by stirring at room temperature for about an hour
to insure completene~s of the reaction. ~he phthalimide which
precipitates rom the reaction mixture i5 then extracted with a
strong base (e.g. 10-20~ aqueous XOH), and the organic solvent
layer is dried, filtered and concentrated to yield the csude
compound of Formula I. The N,N'-thiGbisphthalimide used in the
reaction is a known compound which may be prepared as described
in the Canadian Journal of Chemistry, 44, 2111-2113 (1966), or
as described below in Preparation No. 1.
~9~
N,N'-Thiobisphthali _de
A cooled (0C) solution of phthalimide (14.7 g, 0.1
mole) in 80 ml of dimethylformamide (DMF) was treated dropwise
with sul~ur dichloride (5.15 g, 0.05 mole). After the addition,
the mixture was allowed to warm to 20C with stirring over four
hours. ~he solid was collected and dried to give 12.5 g of the
title compound as a DMF solvate, mp 301-315C. Both ir and nmr
spectra are consistant or structure.
Anal. Calc d. for Cl~jH8N2O~S-C3H7NO: C, 57.42; H, 3.80; N, 10.57;
$, ~.07
Found: C, 57.50; H, 3.80; N, 10.29;
S, 8.57

~2~3~
-~3-
The DME solvate can be removed by recrystallization of the above
material from chloroform; mp of the DMF-free produck was 320-
325C. The ~mr spectrum shows that the D~ has been removed. r
Anal. Calc'd. for C16H~N204S: C, 59.25; H, 2.49; N, 8.64; S, 9.89
Found: C, ~9.~ , 2.21; N, 8.91; S, 10.14

3~
-24-
~xa~ple 1
thiadiazole
A. N-[3-(3-Piperidinomethylphenoxy)pro~yl~ethanediimidamide
trihvdrochloride
A suspension of 3-amino-4-[3-(3-piperidinomethyl-
phenoxy)propyl~m mo]-1,2,5-thiadiazole l-oxide (17.1 g; 47.0
mmoles) ~prepared accordi~g to published ~nited Xingdom Patent
Application No. 2,067,9873 ln ~50 mL of methanol was treated
with 38 mL o ~oncentrated ~Cl. The resultant solution was
stirred f~r 3 hours at ambient t~mperaturer Concentration of
the solution followed by a2eotropi~ remo~al of water with
absolute ethanol gave colorless ~rystals. ~he~e were
suspended i~ ~00 ~ of absolute ethanol, filtered and dried
und~r ~2cuum to give 16.6 g (82~6~) v~ the title compound,
m.p. 205-222C (dec.). Recrystallization from 50~ methanol-
e~hyl acetate ga~e an analytical sample, m.p. 206-216DC (dec.) J
Anal- Cal~d for Cl7H27~so-3~cl: C, 47-84; H~ 7-08; N~ 16-41
Found: C, 47.56; ~, 7.18; N, 16.75
B. 3-Amino-4-~3-(3-piperidinometh~lp_enoxy)pro~yl2m~no~-
1,2,5-thiadiazole
-
A s~irred suspension of M-[3-(3-piperidinome.thyl-
phenoxy)propyl~ethanediimidamide trihydrochloride (2.13 g, ,.
5.0 mmoles) [prepared in Step A~ in 20 m~ o dimethylformamide
(DME) was treated with sulfur monochloride (2.02 g, 15.0 mmoles)
and stirred for 4 hours,. The resultant mixture was poured
cautiously into 200 mL of water and made basic with ~CO3.
Tnis was extracte~ with 3 x 50 mL portions of methylene
chloride and, after drying over .~gSO4 ~nd concentration, 2 .1 g
of a dar~ gum containing the product was obtained. The product
was purified by pxepa~ative high press~re liq~id chromatography

~i3~4~
-25-
on silica using CH2C12tlOO):2-propanol(lO):NH40H(0.5) as the
mobile phase. The appropriate fractions yielded 0.89 g of
the title compound which gave, with fumaric acid in n-propanol,
0.76 g (21.4~) of the title compound as a crystalline ~umarate
salt, m.p. 187-187.5C. ~PLC indicated a purity of ~99~.
Anal. Calc'd for (Cl7~25N50s~2 C4H404~ C~
N, i7.27; S, 7.90
Found: C, 56.09; ~, 6.36;
N, 16.98; 5, 8.08
A portion o~ the fumarate was suspended in water,
neutralized with X2C03 and extracted wi~h CH2Cl~. The CH2C12
was con~entrated and the free base of the title compound
crystallized out; m.p. 43-47~C. A por~ion of the free base
was converted to the hydrochloride salt, m,p. ~38-140JC.
A~al calc~d fr Cl7H25Nsos-~cl: C~ 53-18; H~ 6-83; N~ 18-2~;
S, 8.35
Found: C, 53.14; H, 6.88; N, 18.49;
S, 8.74
Ex æ le 2
3-Ammo-4-{2- ~ t5-dimethYlaminomethx~-2-furyl)rnethylthio] =
ethylamino}-1,2,5-thiadiazole
A. N-~2-~(5-Dimethylæminome yl-2-furyl)methylthio]ethyl}-
ethanediimidamide trihydrochloride hYdrate
A suspension o~ 3-amino-4-{2-l(5-d~methylamino~ethyl-
2-fusyl)methylthiolethylamino}-1,2,5-thiadiazole l-oxide
(6.59 g; 20~0 mmoles) lprepared according to published United
Ringdom Patent Application No. 2,067,987] in 200 mL o
methanol was warmed slightly to achieve complete solution,
then treated with 13.3 mL o~ concentrated HCl. After ~tirring
at ambient temperature ~or 2.5 hours, the solution ~as concen-

~L2~3~
-26-
trated and the residue was triturated with 70 mL of absolute
ethanol. The crystals were collected by filtration and dried
under vacuum to give 4.3 g (52%) of the title compoun~, m.~.
166-169C (dec.).
Anal. Calc'd for Cl2H21N5S-3HCl H2O
N, 17.05; S, 7.80
Found: C, 34.8~; ~, 6.24;
N, 17.45; S, 7.97
B. 3 Amino 4-{2-[(5-dimethylæm1nomethyl-2-furyl)methylthio~_
ethylamino~-1,2,5-thiadiazo~e
To a stirred suspension of N-{2-l(5-dimethylamino-
methyl-2-furyl)~e~hylthio]ethyl~ethanediimidamide trihydro-
chloride hydrat~ ~12.3 g; 30.0 rnmoles) Iprepared in Step A]
in 150 mI. of DMF was added 7 . 2 mL of sulfur monochloside
(12.1 y; 90 mmoles~. After stirring for 4 hours at ambient
t~mperature, approximately half of the DMF was r2moved at
reduced pressure. The ~emai~ing blac~ solution was poured
into 1 liter of water, made basic with K2CO3 and extracted
first with ethyl acetate and then with chloroform. After
drying over MgS04, filtration and concen~ration, 9.0 g of a
black gum oontaining the product was obtained. This was
purified by preparative high pressu~ liquid chromatography
on silica using ethyl acetate(lO0~:2-propa~ol(lO):NH4OH(0.5)
as the mobile phase. The appropriate fractions yielded 1.~4 g
of the title compound as a gum.
Treatment ~f part of ~his product with an e~uivalent
a~ount of 2N HCl in methanol yielded the hydrochloride salt of
the title compound.
Anal. Calc d for Cl~HlgN552O-HCl: C, 41.18; Ho 5.76; N, 20.02;
S, 18.33
Found (corr. for 1.65~ H2O): C, 40.54; H, 5.7~; N, 19.3~;
5, 18,44

-27-
Treatment of the product with an equivalent amount of
cyclohexylsulfamic acid in acetone yielded the cyclohexyl--
sulfamate salt of the title compound, m.p. 93-95C.
Anal. CalC'd for C12HlgN552 C6H13 3
N, 17.06; S, 19.53
Found: C, 43.77; H, 6~17;
N, 17.21; S, 19.58
~x~mple 3
3-.~mino-4-{2~ d~meth~laminometh~ 4-methyl-2-thienyl)-
methylthio?ethylamino-}-1,2,5-thiadiazole
A. N-{2-[(5-Dimethylaminomethyl-4-methyl-2-th enyl?methy_thio~-
ethy~}ethanediimidamide trihydsochloride
A stirred solution o~ 3-amino-4-i2-l(5~dimethylamino-
methyl-4-methyl~2-thienyl)methylthio~ethylamino3-1,2,5-
thiadiazole l-oxide (17.9 g, 50.0 mmoles) [prepared according
to the general procedure described in published United Kingdom
Patent Application No. 2,067,987~ in 500 mL of methanol
was treated with 33.3 mL of concent~ated HCl. After stirring
for 3 hours, the reaction mixture was concentrated and excess
water was removed by azeotropic concentration with absolute
ethanol to give an almost colorless crystalline residue. The
residue was triturated with 200 mL of absolute ethanol.at 0C,
filtered and dried to give 16.9 g ~80~) of the title compound,
m.p. 206-220C (dec.). Recrystallization from 50% methanol-
~thyl acPtate gave a product having m.p. 210-2~1C (dec.).
Anal- ealc d ~or Cl3~23M5s2~3Hcl C, 36 g2; H~ 6-20; N~ 16-56;
Found: C, 36.76; H, 6.33; N, 16.97;
S, 15.54

3~
-28-
3. 3-Amino-4 ~2-[(S-dlmethylaminomethv
methYl~hio]eth~lamino}-1,2,5- h _diazole
To a stirred suspension of N- { 2- [ ( 5-dimethylamino-
methyl-4-methyl-2-thienyl)methylthio~ethyl}ethanediimidamide
trihydrochloride (6.34 g; 15.0 mmoles) ~prepared in Step A]
in 60 mL of DMF was added 6.1 g (45.0 mmoles) of sulfur mono-
chloride. After stirring for 4 hours at ambient temperature,
the reaction mixture was poured into 800 mL of water, made
basic with ~C03, and extracted seYeral tLmes with 100 ~L-
portions o~ methylene chloride. The extracts were dried over
MsS04, filtered, a~d concentrated to give 3.4 g o~ a black gum
containing the product. The product was p~rified by preparative
high pressure liquid chromatography on silica using CH2Cl~(100):
2-propanol510):NB~OH(0.5) as the mobile phase. ~urther
purification was achieved by an additional preparative high
pre sure li~uid chromatography on silica usins CH2cl2tloo):
C~.30~(2.5):NH40H(005) as the mobile phase. The appropriate
fractions yielded the title co~pound (purity ~98~). Treatment
of the product with an equivalent amount of 2N HCl gave the
hydro~hloride salt of the title compound.
C lc~d ~r C ~21N553 HCl: C~ 41-09; ~ 5-
S, Z5.32
Found (corr. for 0.51% H20): C, 40078; ~, 5.63; ~, 18.31;
S, 25.44
Exampl e 4
3-Amino-4-[3-~3-pyrrolidinome~hyl~henoxy~propylamino~-1,2,5-
~hiadiazole
A. N-~3-(3-Pyrrolidinomethyl~henoxy)pro~yl]ethanedii~idamide
rihydrochlor~de
A suspension of 3-amino~4-[3-(3-pyrrolidinomethyl-
phenoxy)propyl~nino~-1,2,5-thiadiazole l-oxide (13.~ g; 38~3
~moles) ~prepared accordins to puhlished United ~ingdom Patent

-29-
Application No. 2,067,987] in 350 mL of methanol was treated
with 25.5 mL of concentrated HCl. The resultant solution was
stirred for 3 hours at ,~mbient temperature. Concentration of
the solution ~ollowed by azeotropic removal of water with
absolute ethanol gave the product. The crystalline residue was
triturated with 150 mL of absolute ethanol, filtered ,~nd dried
to g ~e 10.8 g of the title compound, m.p. 195-203C (dec.).
Anal calc~d for C16~25N5o~3~cl: C, 46.55; H, 6-84; N~
Found: C, 46.55; B, Ç.93; N, 16093
B, 3-Amino-4-~3-~3-pyrrol~dinomethylphenoxy)propylamino]-
1,2,5-thiadiazole
A s'irred suspension of N-~3~(3-pyrrolidinomethyl
phenoxy)propyl~ethanediimidamide trihydrochloride (8.25 g: 20.0
~moles) [prepared ~n 5tep A~ in 80 mL of DMF was treated wi~h
sulfur monochloride (5.4 g; 40.0 mmoles) and stirred under a
nitrogen a~mosphere for 3 hours. Concentration o~ the reaction
mixture gave a dark sum which was suspended in 500 ml of water,
made basic with X~C03 and extracted with 3 x 100 mL of methylene
chloride. The extracts were dried over MgS0~, filtered and
concentrated to giv~ 7.5 g of a dark gum containing the product.
The product wa~ purified by preparative high pressure liquid
chromatography on silica using CH2C12(100):2-propanol~5):
NH40H(0.5) as the mobile phase. Fractions containing the
desired product were combined and concentrated to give 1~64 g
(~4.6%) of the purified title product. Treatment of the
product in absolute ethanol with an equivalent a~ount of 2N ~Cl
g2ve the hydrochloride salt o~ ~he title compound (1.13 g);
m.p. 138-140C.
Anal, Calc~d ~or Cl6H23N5os-Hcl: C, 51-95; H~ 6-54; N~ 18-93;
S, 8.67
Found: C, 51.97; H, 6~36; N! 18.63;
5, 8.76

-30-
Example 5
The general procedure of Example 1, S~eps A and~B,
is repeated except that ~he 3-amino-4-[3-~3-piperidinomethyl~
phenoxy)propylami~o]-1,2,5-thiadiazole l-oxide u~ilized ~herein
is replaced by an equimolar amount of
~a) 3--amino-4-~3-(3-dimethylaminomethylphenoxy)propylamino~-
1,2,5-~hiadiazole l-oxide,
(b) 3-amino-4-l3-(3-diethylaminomethylphenoxy)propylamino~-
1,2,5-thiadiazole l-oxide,
(c) 3-amino~4-~3 ~3-~2-methylpyrrolidino)me~hylphenoxy]-
propylamino~-1,2,5-thiadiazole ~-~xide,
(d) 3-amino-4-{3-l3-(3-methylpyrrolidino)methylphenoxy~-
propylamino} 1,2,5-thiadiazole l-oxide,
(e) 3-amino-4-{3~3-(4-methylpiperidilo)methylphenoxy]~
propylamino~-1,2,5-thiadiazole l-oxid~,
(f) 3-amino-4-~3-( 3-morpholinomethylphenoxy) propylamino)-1,2,~
~hiadiazole l-oxide,
(g) 3-amino-4-{3-l3~ methylpiperazino)methy~pheno~y~-
propylamino}-1,2,5-thiadiaz~le l-oxide,
(h) 3-amino-4-13-(3-diallylaminomethylphenoxy)propylamino~-1,2,5-
thiadiazole l-oxide,
(i) 3-~mino-4-[3-(3-hexamethyle~eiminomethylphenoxy)propylamino)-
1,2,5-thiadiazole 1-oxide,
(j) 3-amino-4-l3-(3~heptamethyleneiminomethylphenoxy)~ropyl-
amino~-1,2,5-~hiadiazole l-oxide,
(k) 3-amino-4-{3-L3-(3-azabicyclo~3.2.2lnon-3-yl)methylph~oxy~-
propylamino} 1,2,5-thiadiazole l-oxide and
(1) 3-amino-4-;3~3-(3-pyrrolino)methylphenoxy]propyl~mino~-
1,2,5-thiadiazole l-oxide, respectively,
and there is thereby produced

-31-
(a) 3-amino-4-~3-(3-dimethylaminomethylphenoxy)propylamino~
1,2,5-thiadiazole,
(b) 3 amino-4-[3-(3-diethylaminomethylphenoxy)propylamino~-
1,2,5-thiadiazole,
(c) 3-amino-4-{3-~3-(2-methylpyrrolidino)methylphenoxy~-
propylamino~-1,2,5-thiadiazole,
(d) 3-amino-4-{3-~3~(3-methylpyrrolidino)methylphenoxy]-
propylamino ? -1,2,5-thiadiazole,
(e) 3-amino-4-~3-[3-(4-methylpiperidino)methylphenoxy~-
propylamino)-1,2,5-thiadiazole,
(f) 3-amino-4-13-(3-mor~holinome~hylphenoxy)propylamino~-1,2,5-
thiadiazole,
(g) 3-amino-4-{3-~3-(N-methylpiperazino)methylphenoxy)
propylamino)-1,2,5-~hiadiazole,
(h) 3-amino-4-13-(3-diallylaminomethylPh~oXy)prOpylamino]-1~2,5-
thiadiazole,
(i) 3-amino-4-13-~3-hexamethyleneiminomethylphenoxy)propyl~mino~
1,~,S-thiadiazole,
(j) 3 amino-4-~3-~3-heptamethyleneiminDmethylphenoxy)propylamino]-
1,2,5-thiadiazole,
(k) 3-amino-4-{3-[3-(3-azabicyclo[3.2.2.)non-3-yl)methylphenoxy]-
propylzmino}-1,2,5-thiadiazole and
(1) 3-amino-4-{3-[3-~3-pyrrolino)methylphenoxy~propylami~o~-
1,2,5-thiadiazole, respectively.
Exam~le 6
3-Amino-4-[3-(3-Piperidino ethyl~henoxy)propylamino]-l~2
thiadiazole
This is a variation of Example 1, Step B, utilizing
le~s sulfur monochloride and a shorter reaction tlme.
To a stirred suspension of N-~3-(3-piperidino~ethyl- J
phenoxy)propyl~ethanediimidamide trihydrochloride (12.08 g;
28.3 mmoles) in-120 mL of DMF was added sulfur monochloride
(7.64 g; 56.6 mmoles) and the mixture was stirred under an
N2 atmosphere for 3 hours. The DM~ was removed at reduced

~L~253~
-32-
pressure to leave a black gum which was suspended in water,
made basic with K2C03 and extracted with 3 x 100 mL portions
of CH2C12. The combined extracts were dried o~e- MgS04, .
f iltexed and concentrated to a blacX gum. This gum was
purified by prepara~ive high pressure liquid chromatography
on silica using CH2C12(100):2-propanol(5):1~H40H(O~S) as the
mobile phase~ The appropriate fractions yielded 3.1 g o' the
title product as a dark oil which gav~, with fumaric acid in
n-propanol, 2.66 g (23.2~) of the title compound as a cry~tal-
~ine fumarate sal , m.p. 186-1~6.5C. HPLC indicated a purity
of 99%.
Anal. Calc'd. for (C17H25~50S)2 C4 4 4
N, 17,27; S, 7.90
Found: C, 56.27; H, 6.96;
N, 17.31; S, 7.98
Example 7
3-Amino-4-~3-(3-piperid~no~ethylphenoxy~pro-pylamino~ 2!5
thiadi2zol~
This is a variation of Example 1, Step B, utilizing
sulfur dichloride instead of sulfur monochloride.
To a stirred suspension of N-~3-(3-piperidinomethyl-
pheno~y)propyl~ethanediimidamide trihydrochloride (854 mg; 2
mmoles) in 6 mL of D~ under N2 in an ice bath was added SC12
(206 ~g; 2 mmoles) in 2 mL o. DMF. The reaction mixture was
stirred at ambient temperature and the title compound was
produced.
3-Methylam~no-4-~3-~ piperidinomet~phenoxy)~ropylamino]-1,2,~-
thiadiazole
A. ~ _

~253~4L~
-33-
di~midamide trih drochloride
. Y
A suspensio~ of 3~methylamino-4-I3-13-piperidinomethyl-
phenoxy)propylamino]-1,2,5-thiadiazole l-oxide (4.13 g; 10.9
mmoles) Iprepared according to published United Ringdom Patent
Application No. 2,067,987] in 9S ml of methanol was treated
with 7~2 ml of concentrated HCl. After stirring at ambient
temperature for 3 hours, the solution was concentrated and the
residue was triturated with acetone, filtered and dried to gi~e
4.35 g (90.4%) of product. A sample was recrystallized from
aqueous i opropyl alcohol to give the title compound, mp 207-
225C (dec.).
Anal. Calcld. for Cl H29N5O-3HCl: C, 49.03; B, 7.33; N, 15.89
Found (corr. for 0-94% ~2) C, 49.37; ~, 7.35; N, 15.71
B. 3-Methyla_ino-4-~3-~3 ~iperidinometh~lpheno~y)propylamino]-
1,2,5-thiadiazole
A mixt~re of ~-methyl-N'-~3-(3-piperidinomethyl-
phenoxy)propyllethanedilmidamide trihydrochloride (3.74 g; 8.47
~moles) [prepared in Step A~, 34 ml of C~2C12 and 3.5 ml of
triethylamine was treated with N,N'-thiobisph~halimide (D~
solvate) (3.36 g; 8.46 mmoles) and stirred for one hour. The
mixture was washed with 30 ml o 10% KOH, dried (MsSO4),
filtered, diluted with toluene and ooncentrated to give 3.6 g
of the product. The product was purified by flash chromatography
on 90 g of silica gel (230-400 mesh) using ethyl acetate
methanol (95:5) as the eluent to give 1.9 g (62~) of the title
compound. Treatment o~ the product with an equivalent amnunt
o~ aqueous HCl in l-propanol gave the hydrochloride salt of
the title compound, mp 163.5-164.5C.
Anal. Calc'd. for C18H27N5OS~HCl: C, 54.32; H, 7.04, ~, 17.60;
S, 8.06; Cl, 8.91
Found: C, S4.35; H, 7.07; N, 17.64;
S, 8.3~; Cl, ~.8~

~ ~ 3*~
-3~-
Example 9
3-Benzylamino-4~[3-(3-piperidinometh~lphenox~)proEy~mino]
1,2,5-thiadiazole
_
. N-Benzyl-N'-I3-(3-piperidinometh~l~henoxy)~op~l~ethane-
diimidamide trihydrochlorlde
A suspension of 3-benzylæmino-4-[3-(3-piperidinomethyl-
phenoxy)propylamino]-~,2,5-thiadiazole l-oxide ~.14 g; 11.3
mmoles) [prepared according to publi~hed United Kingdom Pa~ent
Application No. 2,067,987~ in 100 ml of methanol was treated
with 7O55 ml of concentratea HCl A~ter stirring at ambient
temperature for 3 hours, ~he solution was concentrated and ~he
residue was triturated with acetone, filtered and dried to give
5.16 g (88%) of the title compound, mp 187-205~C (dec.)~
Anal Calc'd for C24~33N50-3HCl: C, ~5.75; H, 7.03; N, 3.55;
-
Cl, 20.57
Found: C, 54.88; ~1, 6.75; N, 13.33;
C~, 20.20
B. 3-Benzylamino-4-~3-(3-~iperidinomethylphenoxy)propylamino~-
1,2,5-thiadiazole
A mixture of N-benzyl-N'-13-(3-piperidinomethylphenoxy)
propyl]ethanediimidamide trihydrochloride (4.73 g; 9.16 mmoles)
[prepared in Step A], 45 ml of CH2C12 and 3.8 ml of triethylamine
was treated with N,N'-thiobisphthalimide (DMF solvate) (3.64 g;
9.16 mmoles) and stirred for one hour. The mixture was washed
with 44 ml of 10~ ROH, dried (~gSO4), filtered, diluted with
toluene and concentrated. The residue wa~ chromatographed by
flash chromatography o~ 110 g of silica gel (230-400 mesh) using
ethyl acetate as ~he eluènt to give 3~1 g ~77~) of the ti~le
compourld. Treatment: of the product with an equivalent amount of
aqueous HCl in 2-propanol gave the hydrochloride salt of the
title compound, mp 138-141C.

~;3~
nal. Calc'dO for C24H31N5OS~HCl: C, 60.80; H, 6.80; N, 14.77;
S, 6.76; Cl, 7.48
Found: C, 60.53; H, ~.64; N, 14~99;
S, 6.91; Cl, 7.~7
Exam~le 10
3-Amino-4-¦3-(3-piperidinometh ~ e oxy)propylamino~-1,2,5-
~hiadiazole
This is a variation of Example 1, s~ep B, u~ilizing
N,NI-thio~isphthalimide instead of sulfur monochloride .
A mixture of N- E3- (3-piperidinomethylphenoxy)propyl]-
ethanediimidamide trihydroohloride (27.3 g; 64.0 mmoles)
~prepared in Example 1, Step A), 250 ml of CH2C12 nd 26.6 ml
(192.0 mmoles) of triethylamine was treated portionwise with
N,N'-thiobisphthalimide (DMF solvate) S25.4 g; 6400 mmoles).
After tirring at ambient temperature for one hour, the mixture
was wa~hed with 120 ml of 20~ KOH, dried (~gSO4~, filtered and
concentrated, then taken up ~n 150 ml of toluene and reconcen-
traked. The product was taken up in 250 ml of l-propanol and
10.7 ml of 6N HCl, treated with decoloriziny carbon and ~iltered
through Celite* This solution was concentrated to 10a ml volume,
diluted with 175 ml of dry l-propanol and stored at 0C to give
20.2 g (82.1%) of crystalline hydrochloride salt of the title
compound, mp 137-138C.
nal. Calc d. ~ox C17H25N5O5 HCl: C, 53-18; H, 6-83 N~ 18-24;
S, 8.35
Found: C, 52.78; H, 6.74; N, 18.52;
S, 8.~6
Example 11
3-Amino-4-l3-(3-~yrrolidinomethylphenox~)pro~ mino]-1,2,5-
thiadiazole
This is a variation of Example 4, Step B, utilizing
N,N'-thiobisphthalimide instead of sul.ur monochlorideO
*T~ade Mark

3~
-36-
A mixture of N-~3-(3-pyrrolidinomethylphenoxy)propyl]-
ethanediimidamide trihydrochloride (22.0 g; 53.0 mmoles)
[prepared in Example 4, Step A~, 200 ml of CH2Cl~ and 22 ~1 of
triethylamine was treated with N,N'-thiobisphthalimide ~DMF
solvate) (21.2 g; 53.0 mmoles). After stirring at ambient
temperature for one hour, the m~xture was washed with 100 ml of
20~ KOH, dried (MgSO4), filtered, diluted with 100 ml of toluene
and concentrated. The product was treated with one equivalent
of aqueous HCl in l-propanol to give 13.2 g (67%) of the hydro-
chloride salt of the title compour.d, mp 135-137C.
Anal. Calc'd. for C16H23N5OS~HCl: C, 51.95; H, 6.54; N, 18~93;
S, B.67
~und: C, 51.92; H, 6.55; N, 19.30;
S, 9.06
3-.~mino-4-{2-[~5-dimethylaminomethyl-3-thie~yl)methvlthio]-
ethylamino}-1,2,5-thiadiazole
A. N-{2-~(5-dimeth~laminomethyl-3-thien~l)methylthioJethyl}-
ethanediimidamide trihydrochloride
A suspension of 3-amino-4-{2-[15-dimethylaminomethyl-3-
thienyl)methylthio]ethylamino}-1,2,5-thiadiazole l-oxide (7.8 g;
22.6 mmoles) [prepared according to published ~nited Xingdom
Patent Application No. 2,067,987] in 150 ml of methanol was
treated with 15.0 ml of concer.trated HCl. After stirring at
ambient temperature for 3 hours, the solution was concentrated
and the residue triturated with l-propanol, filtered and dried to
give 7.38 g t80~) of product. A sample was recrystallized from
methanol acetone to give the title compound, mp 190-205~C (dec.~.
Anal. Calc~d- or C12N21N5S2~3Hcl C, 35.25; H, 5-92; N~ 17-13
Found: C, 35.03; H, 5.g3; N, 17.39

-37-
B. 3-Amino-4-{2-~(5-dimethylaminomethyl-3-thienyl~meth~lthio~-
ethylamino~l,2,5-thiadiazole
A mixture of N-{2-[(5-dimethylaminomethyl-3-thienyl)-
methylthio]ethyl}ethanediimidamid0 trihydrochlor~de ~6.i~ g;
15.0 mmoles~ [prepared in Step A~, 60 ml of CH2C12 and 6.3 ml of
triethylamine was trea~ed with N,N'-thiobisphthalimide ~DMP
solvate) (5.96 g; 15.0 mmol~s) and stirred ~or one hour. Th~
mixture was washed with 100 ml of 10~ XOH, dried (MgSO4),
filtered, diluted with toluene and concentrated to give S.l g of
product. Treatme~t of the product with 0.5 molar equivalent o
fumaric acid in l-propanol ga-~e the fumaric acid salt of ~he
compound, mp 141-143C. The nmr spectrum in D~SO-d6 shows the
presence of approximately 0~12 moles of l-propanol.
nal~ Calc~d. f~r (Cl2~lgNss3)2-c4H4O4Dool2c3~8o C, 43~68;
H, 5~61;
N, 17.75;
S, 24~38
Found: C, 43.41;
H, 5.53;
N, 17.54;
S, 24.24
Example 13
3-Amino-4 {2-[(5-2~peridinomethyl-3-thienyl)methylthio]ethylamino}-
1,2,5-thiadiazole
A. N-{2-[(5-piperidinomethyl-3-thi~nyl)methylthio]ethyl}ethane-
diimidamide trih~drochloride
A suspension of 3-amino-4-{2-[(5-piperidinomethyl 3-
~hienyl)methylthio~ethylamino}-1,2,5-thiadiazole l-oxide (6.1 g;
15.8 mmoles) IprPpared according to published United ~ingdom
Patent Application No. 2,067,987~ in 80 m' of methanol was
treated with 10.5 ml of concer.trated HC1. After stirring at
ambient tempera~ure for 3 hours, the solution was concentrated

5 ~ LLi~
~38-
and the residue triturated with 50 ml of l-propanol, filtered and
dried to give 5.86 g (83%) o~ product. A cample was recrystal-
lized from methanol-acetone to give the title compound, mp 201-
214C (dec.).
Anal. Calc'd. for C15H25N5S2-~HCl: C, 40,13; H, 6.29; N, 15.60;
~, 14.29
Found: C, 39.97; H, 6.47; N, 15.28;
S, 14.63
B. 3-Rmino-4-{2-[(5-piperidinomethyl-3-thienyl)methylthiol-
eth lamino}-1,2,5-thiadiazole
.
~ mixture of N-{2-t(5-piperidinomethyl-3-thienyl)-
methylthio]ethyl}ethanediimidamide trihydrochloride (5.17 g;
11.5 mmoles) Iprepared in Step A], 48 ml of CH2C12 and 4.8 ml
of triethylamine was treated with N,N'-thiobisphthalimide ~DMP
solvate) (4.57 g; 11.5 mmoles) and stirred for one hour. The
mixture was washed with 90 ml of 10% ~OH, dried (MgSO4), filtered,
diluted with toluene and concentrated to give 4.5 g of product.
Treatment of the product with one equivalent of cyclohexyl
slllfamic acid in methanol gave the cyclohexyl sulamate salt
of the title compound, mp 142-143C.
Anal Calc'd- for C15H23~5S3 C6H13 3
N, 15.31; S, 23.38
Found: C, 45.61, H, 6.41;
N, 15.46; S, 23.48
Example 14
The gene~al procedures of Example 1, Step A, and then
either Example 1, Step B, or Example 10 is repeated except that
the 3-amino-4-[3-(3-piperidinomethylphenoxy)propylaminol-1,2,5-
thiadiazole l-oxide utilized the_ein is repla~ed by a~ equimolar
amount of
(a~ 3-ethylamino-4-13-t3-piperidinomethylphenoxy)propylamino]-
1,2,5-thiadiazole l--oxide,

~ l
~ 2~ 3
-39
(b) 3-allylamino-4-i3-(3-piperid momethylphenoxy)propylamlno]-
1,2,5-thladiazole l-oxide,
(c) 3-(2-p~opynyl)-4-~3-(3-piperidinomethylphenoxy)propyla~ino3-
1,2,5-thiadiazole 1-oxide,
(d) 3-(3-pyridylmethylamino)-4-l3-t3-piperidinomethylphenoxy)-
propylamino]-1,2,5-thiadiazole l-oxide,
(e) 3-(6-methyl-3-pyridyl)methylamino-4-l3-(3-piperidinomethyl-
phenoxy)propylamino]-1,2,5-thiadiazole l-oxide and
(f) 3-(3,4-methylenedioxybenzylamino)-4-~3-~3-piperidinomethyl~
phenoxy)propylamino]-1,2,5-thiadiazole l-oxide, respectively,
and there is therPby produced
(a) 3-e.thylamino-4-[3 (3-piperidinomethylphenoxy)propylamino]-
1,2,5-thiadiazole,
(b) 3-allylamino-4-[3-(3-pip2ridinomethylphenoxy)propylamino]-
1,2,5-thia~iazole,
(c) 3 (2-propynyl)-4-[3-(3-piperidinomethylphenoxy)propylamino]-
1,2,5-thiadiazole,
(d) 3-(3-pyridylmethylamino~-4-[3-(3-piperidinomethylphenoxy)-
propylamino~-1,2,5-thiadiazole,
(e) 3-(6-methyl-3-pyridyl)~ethylamino-4-~3-(3-piperidinomethyl-
phenoxy3propylamino]-1,2,5-thiadiazole and
(f) 3-(3,4-methylenedioxybenzylamino)-4-~3-(3-piperidinomethyl-
phenoxy)propylamino]-1,2,5-thiadia~ole, respectively.
Exam~le 15
-
3-Amino-4-[3-(6-piperidinomethyl-2-pyridyloxy)propyl~m~
1,2,5-thiadiazole
A. 3-~mino-4-~3-(6-piperidinomethyl-2-pyridyloxy)propylamino~-
1,2,5-thiadiazole l-oxide
A solution of 3-(6-piperidinomethyl-2-pyridyloxy)-
propylamine (4.6S g; 18.6 n~oles) [prepared according to
published United Ki~gdom Patent Application No. 2,098,988~ in
50 ml of methanol was reacted wi~h 3-amino-4-methoxy-1,2,5-

~253~
~40-
thiadiazole l-oxide (2.74 gi 18.6 mmoles) according to the
general procedure described in United Xingdom Patent Applica~ion
No. 2,067,987 to give a solution containing 3-amino-4-~3-(6-
piperidinomethyl-2-pyridyloxy)propylamino]-1,2,5-thiadiazole 1-
oxide. A purified sample melted at 145-147C.
B. N
trih drochloride
Y
A methanolic solution of the product prepared in Step
A was diluted to 100 ml and 12.4 ml of co~centrated HCl was
added. The ~olution was stirred at ambien~ temperature 'or 18
hours, concentrated, and the residue was dissolved in 80 ml of
water and extracted twice with CH2C12. The aqueous layer was
concentrated, treated with n-propanol and concentrated under high
vacuum to give the title compound as a foam.
C. 3-Amino 4-~3 _6-piperidmomethyl-2-~yridylo ~ ropylamino~-
1,2,5-thiadiazole
A mixture of the crude product prepared in Step B in 80
ml of CH~C12 and containing 7.69 ml of triethylamine was ~rea~ed
with N,N'-thiobisphthalimide tDMF solvate) (7.35 g; 18.5 mmoles)~
After stirring at ambient temperature for one hour, the mixture
was washed ~ith 50 ml of 4N NaOH, water, saturated aqueous NaCl
solution, dried (Na2SO4), flltered and evaporated under reduced
pressure to give ~he crude product. The product was purified by
~lash chromatography on 100 g of silica gel (230-400 mesh~ using
ethyl acetate-methanol (95:5) as the eluent to give 3.63 9 of the
title compo-md as a viscous oil. Treatment of the product with
one e~uivalent o~ cyclohexyl sulfamic acid in acetone gave the
cyclohexyl sulfamate salt of the title compound, mp 125.5-131C.
Anal. Calc'd. for C16H~4N60S C6H13N03S: C, 50.07; H, 7.07;
N, 18.58; S, 12.~5
Found: C, 50.02; H, 7.03;
~, 18.54; S, 12.14

~253~
-41-
Example 16
3-Amino-4-[3-(6-dimet~laminomethyl-2-pyridyloxy)propylamino]-
1,2,5-thiadiazole
_ _
When a methanolic solution of 3 (6-dimethylaminomethyl-
2-pyridyloxy)propylamine [prepared according to published United
Kingdom Patent Application No. 2,098,988~ is rPacted with 3-
amino-4-methoxy-1,2,5-~hiadiazole l-oxide according to the
general procedure described in United Kingdom Patent Application
No. 2,067,987 and the resulting 3-amino-4-[3-(6-piperidinomethyl-
2-pyridyloxy)propylamino]-1,2,5-thiadiazole l-oxlde is succes-
sively reacted by ~he general procedure described in Example 1,
Step A, and then by either Example 1, Step B, or Example 10 r the
title compound is thereby produced.
Example 17
3-Amino-4-{2-[(6-dimethylaminomethyl-2-pyriZ~l)methylthio~
ethylam~no}-1,2,5-thiadiazole
When a suspension of 3-amino-4-~2-[~6-dimethylamino-
methyl-2-pyridyl)methylthio~ethylamino}-1,2,5-thiadiazole 1-
oxide [prepared according to published United Kingdom Patent
Application No. 2,067,987] is succes~ively reacted according to
the procedures of Example 1, Step A, ~nd then by either Example 1,
Step B, or Example 10, the title compound is thereby produced.
3-Amino-4-{2- [ (6-piperidinomethyl-2-pyrid~l)methylthio~ eth
amino}-1,2,5-thiadiazole
When a suspension of 3-amino-4-{2 ~(6-piperidino-
methyl-2~pyridyl~methylthio~ethylamino}-1,2,5-thiadiazole 1-
oxide ~prepared according to published ~nited gingdom Patent
Application No. 2,067,9871 is successively reacted according to
the procedures of ExamplP 1, Step A, and then by either Example 1,

~253~l4~
-42-
Step B, or Example 10, the title compound is thereby produced.
Example 19
The genexal procedure of Example 1, Step Ar and then
either Example 1, Step B, or Example 10 is repeated except that
the 3-amino-4-13-(3-piperidinomethylphenoxy)propylamino]~ ,5-
thiadiazole l-oxide utilized therein is replaced by an equimolar
amount of
(a) 3-amino-4-13-(3-piperidinomethylthiophenoxy)propylamino]-
1,2,5-thiadiazole l-oxide,
~b) 3-amino-4-13-(3-dimethylaminomethylthiophenoxy)pxopylamino]-
1,2,5-thiadiazole l-oxide,
(c) 3-amino-4-13-(3-pyrrolidinomethylthiophenoxy)propylamino~_
1,2,5-thiadiazole l-oxide,
(d) 3-amino-4-[3-~4-dimethylaminomethyl~2-pyridyloxy)-
propylam~no]-1,2,5-thiadiazole l-oxide,
(e) 3-amino-4-[3-(5-dimethylaminomethyl-3-thienyloxy)propyl-
amino]-1,2,5-~hiadiazole l-oxide,
(f) 3-amino-4-~3-(5-piperidinomethyl-3-thienyloxy)propylamino~-
1,2,5-thiadiazole l-oxide,
(g) 3-amino-4-{2-1(4-dimethylaminomethyl-2-pyridyl)methylthio]-
ethylamino}-1,2,5-thiadiazole l-oxide and
(h) 3-amino-4-{2-~(4-piperidinomethyl-2-pyridyl)methylthio~-
ethylamino}-1,2,5-thiadiazole l-oxide, respectively,
and therP is thereby produced
(a) 3-amino-4-13-(3-piperidinomethylthiophenoxy)propylamino]-
1,2,5-thiadiazole,
(b) 3-amino-4-[3-(3-dimethylaminomethylthiophenoxy)propylamino]
1,2,5-thiadiazole,
(c) 3-amino-4-[3-(3-pyrrolidinomethylthiophenoY.y)propylamino~-
1,2,5-thiadiazole,
(d) 3-amino-4-~3-(4-dimethylaminomethyl-2-pyriGyloxy)-
propylamino]-1,2,5-thiadiazole,
~e) 3-amino-4-13-(5-dimethylaminomethyl-3-thienyloxy)propyl-
amino]~l,2,5-thiadiazole,
,

:~ ;
_43- ~.253~4~
(f) 3-amino-4-~3~(5-piperidinomethyl- -thienyloxy)propylamino~-
1,2,5-thiadiazole,
(g) 3-amino-4-{2-[(4-dimethylaminomethyl 2-pyridyl)methylthio~-
ethylamino}-1,2,5-thiadiazole and
(h1 3-amino-4-{2-1(4-piperidinomethyl-2-pyridyl)methylthio~-
ethylamino}-1,2,5-thiadiazole, respectively~
The above starting materials are prepared according to the
general procedures described in published U.K. Patent Application
No. ~,067,987. The precursors of the starting materials are
prepared by the procedures and analogous general procedures
described in U.K. Patent Application Nos. 2,067,987, 2,098,988,
2,063,875 and published European Patent Application No. 49,173.
Example 20
3-Amino-4-[3-54-piperidinometh~1-2-pyridyloxy)propylamino]-1,2,5-
thiadiazole
A. 3-(4-Piperidinomethyl-2-pyridyloxy)propylamine
When the general procedure for the preparation of 3~~6-
piperidinomethyl-~-pyridyloxy)propylamine described in U.K.
Patent Application NoO 2,098,988 was followed except that the 2-
chloro-6-methylpyridine utilized therein was replaced by ~-
bromo-4-methylpyridine, then the title compound was produced as
an oil.
Anal. Calc'd. for C H N30: C, 67.44; El, 9.30; N, 16.85
14 23
Found: C, 67.54; H, 8.98; N, 16.55
B. 3-Amino-4-[3-(4-~iperidinomethy1 2-pyridyloxy)propylamino]-
1,2,5-thiadiazole l-oxide
A solution o the product of Step A (6.5 g; 2~.0 mmoles~
in 90 ml of methanol was reacted with 3-amino-4-methoxy-1,2,5-
thiadiazole l-oxide (3.84 g; 26.0 mmoles) according to the
general procedures described in U.K. P~tent Application 2,067,987
to give 6.33 g of product. Recrystallization from methanol-
acetonitrile yielded the title compound, ~p 154-158C.
Anal. Calc d. for C16H24N6OS: C, 52-73; H~ 6-64; N~ 23-06; S, 8-80
Found: C, 52.72; H, 6.30; N, 23.32; S, 8.74

~2~3~
~44
C. N-[3-(4-Piperidinomethyl-2-~yridyloxy)~ropvl~ethanediimid~ide
trihydroohloride
The product of Step B (5.0 g; 13.7 mmoles~ was dissolved
in 80 ml of methanol and treated with 9.1 ml of concentrated HCl.
After stirring at ambient t~mperature for 4.5 hours, the solution
was evaporated to dryness under reduced pressure to give the title
compound.
D. 3-Amino-4-[3-~4-pi~eridinomethyl-2-pyridyloxy)propylamino]-
1,2,5-thiadiazole
A mixture o~ the product prepared in Step C in 50 ml of
CH2C12 and 5.7 ml of triethylamine was treated with N,N'-thio-
bisphthallmide (DMF solvate) (5.44 g; 13.7 mmoles). After stir-
ring at ambient temperature for one hour, the mixture was
washed with 40 ml of 4N NaO~, water, saturated aqueous NaCl
solution, dried tNa2so4)~ filtered and evaporated under redu~ed
pressure to give the crude product. The product was purified by
flash chromatography on 90 g of silica gel (230-400 mesh) using
ethyl acetate-methanol (96:4) as the eluent to give 3.44 g of
the title compound as a viscous oil. Treatment of the product
with one equivalent of cyclohexyl sulfamic acid in acetone gave
the cyclohexyl sulfamate o~ the title compound, mp 124.5-126C.
AnalO Calc'd. for C16H2~N6OS-C6H13NO35: C, 50.07; H, 7.07;
N, 18.58; S, 12.15
Fvund: C, 50.47; H, 7.12;
N~ 18.33; S, 11.87
Exam~le 21
3_~mino-4-{3-t3-(1,2,3,6-tetrah~dro-1-pyridyl)methvlpnenoxy~=
ro~vlamino}-1,2,5-thiadiazole
The general procedure of Example 15 was repeated, except
th~t the 3-(6-piperidinomethyl-2-pyridyloxy)propylamine utilized
th~rein was replaGed by an equivalent amount of 3-l3-(1,2,3,6

~S ! i
'~
~253~L~4
-45-
tetrahydro-l-pyridyl)methylphenoxy~propylamine, to give 2.31 g
of product. Crystallization from toluene yielded the title com-
pound, mp 99.5-104C. ~_,
Anal. Calc'd. for C17N23N50S: C, 59-10; H, 6-71; N~ 20-27; S~ 9-2
Found (corr. for 2.19~ H2O): C, 58.78; ~, 6.71; N, 19.90; S, 9.26