# US 4,394,508 A · Chemical compounds > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 4,394,508 A - Document ID: US4394508A - Status: Granted - Kind: A - Application number: 06/240,034 - Filed: 1981-03-03 - Granted: 1983-07-19 - Earliest claimed: 1979-09-04 - Assignees: Bristol-Myers Company - Inventors: Ronnie R. Crenshaw; Aldo A. Algieri - Web page: https://patentgrep.com/patent/US4394508A ## CPC - C07D 213/81: Amides; Imides - C07D 213/38: having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom - C07D 271/06: 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles - C07D 271/08: 1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles - C07D 271/10: 1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles - C07D 277/28: Radicals substituted by nitrogen atoms - C07D 277/40: Unsubstituted amino or imino radicals - C07D 277/42: Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals - C07D 277/48: by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines - C07D 277/56: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen - C07D 285/10: 1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles - C07D 307/52: Radicals substituted by nitrogen atoms not forming part of a nitro radical - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) ## Abstract Histamine H.sub.2 -antagonists of the formula ##STR1## wherein p is 1 or 2; R.sup.1 is hydroxy, amino, substituted amino or a 5- to 9-membered fully saturated nitrogen-containing heterocyclic ring attached via its nitrogen atom; m is an integer of from 0 to 2; n is an integer of from 2 to 4; Z is sulfur, oxygen or methylene; and A is an optionally substituted phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl ring; and nontoxic pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof are novel anti-ulcer agents. Intermediates and processes for their preparation are disclosed. ## Claims ### Claim 1 A compound of the formula ##STR60## wherein p is 1 or 2; R.sup.1 is hydroxy or NR.sup.2 R.sup.3 ; R.sup.2 and R.sup.3 each are independently hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, cyclo(lower)alkyl(lower)alkyl, hydroxy(lower)alkyl, (lower)alkoxy(lower)alkyl, (lower)alkylthio(lower)alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl or cyano(lower)alkyl, or, when R.sup.2 is hydrogen, R.sup.3 may also be cyclo(lower)alkyl, amino(lower)alkyl, (lower)alkylamino(lower)alkyl, di(lower)alkylamino(lower)alkyl, pyrrolidino(lower)alkyl, piperidino(lower)alkyl, piperazino(lower)alkyl, substituted pyridyl(lower)alkyl wherein the pyridyl ring may contain one substituent selected from (lower)alkyl, (lower)alkoxy, hydroxy, amino and halogen, amino, (lower)alkylamino, di(lower)alkylamino, hydroxy, (lower)alkoxy, 2,3-dihydroxypropyl, cyano, amidino, (lower)alkylamidino, A'--(CH.sub.2).sub.m' Z'(CH.sub.2).sub.n' --, phenyl, phenyl(lower)alkyl, substituted phenyl or substituted phenyl(lower)alkyl, wherein the phenyl ring may contain one or two substituents independently selected from (lower)alkyl, hydroxy, (lower)alkoxy and halogen or one substituent selected from methylenedioxy, trifluoromethyl and di(lower)alkylamino; or R.sup.2 and R.sup.3, taken together, may be --CH.sub.2 CH.sub.2 X(CH.sub.2).sub.r --; r is an integer of from 1 to 3, inclusive; X is methylene, sulfur, oxygen or N-R.sup.4, provided that, when r is 1, X is methylene; R.sup.4 is hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, (lower)alkanoyl or benzoyl; m and m' each are independently an integer of from zero to 2, inclusive; n and n' each are independently an integer of from 2 to 4, inclusive; Z and Z' each are independently sulfur, oxygen or methylene; A and A' each are independently phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl; provided that A and A' independently may contain one or two substituents, the first substituent being selected from (lower)alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, (lower)alkoxy, ##STR61## and --(CH.sub.2).sub.q NR.sup.5 R.sup.6, and the second substituent being selected from (lower)alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl and (lower)alkoxy; q is an integer of from 0 to 6, inclusive; R.sup.14 and R.sup.15 independently are hydrogen or (lower)alkyl, or, if R.sup.14 is hydrogen, R.sup.15 also may be (lower)alkanoyl or benzoyl, or R.sup.14 and R.sup.15, taken together, may be ethylene; and R.sup.5 and R.sup.6 each are independently hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, (lower)alkoxy(lower)alkyl, cyclo(lower)alkyl or phenyl, provided that R.sup.5 and R.sup.6 may not both be cyclo(lower)alkyl or phenyl; or R.sup.5 and R.sup.6, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino, homopiperidino, heptamethyleneimino or octamethyleneimino; or a nontoxic, pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 2 (depends on 1) A compound of claim 1 having the formula ##STR62## wherein p is 1 or 2; R.sup.2 and R.sup.3 each are independently hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, cyclo(lower)alkyl(lower)alkyl, hydroxy(lower)alkyl, (lower)alkoxy(lower)alkyl, (lower)alkylthio(lower)alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl or cyano(lower)alkyl, or, when R.sup.2 is hydrogen, R.sup.3 may also be cyclo(lower)alkyl, amino(lower)alkyl, (lower)alkylamino(lower)alkyl, di(lower)alkylamino(lower)alkyl, pyrrolidino(lower)alkyl, piperidino(lower)alkyl, piperazino(lower)alkyl, substituted pyridyl(lower)alkyl wherein the pyridyl ring may contain one substituent selected from (lower)alkyl, (lower)alkoxy, hydroxy, amino and halogen, amino, (lower)alkylamino, di(lower)alkylamino, hydroxy, (lower)alkoxy, 2,3-dihydroxypropyl, cyano, amidino, (lower)alkylamidino, A'--(CH.sub.2).sub.m' Z'(CH.sub.2).sub.n' --, phenyl, phenyl(lower)alkyl, substituted phenyl or substituted phenyl(lower)alkyl, wherein the phenyl ring may contain one or two substituents independently selected from (lower)alkyl, hydroxy, (lower)alkoxy and halogen or one substituent selected from methylenedioxy, trifluoromethyl and di(lower)alkylamino; or R.sup.2 and R.sup.3, taken together, may be --CH.sub.2 CH.sub.2 X(CH.sub.2).sub.r --; r is an integer of from 1 to 3, inclusive; X is methylene, sulfur, oxygen or N-R.sup.4, provided that, when r is 1, X is methylene; R.sup.4 is hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, (lower)alkanoyl or benzoyl; m and m' each are independently an integer of from zero to 2, inclusive; n and n' each are independently an integer of from 2 to 4, inclusive; Z and Z' each are independently sulfur, oxygen or methylene; A and A' each are independently phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl; provided that A and A' independently may contain one or two substituents, the first substituent being selected from (lower)alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, (lower)alkoxy, ##STR63## and --(CH.sub.2).sub.q NR.sup.5 R.sup.6, and the second substituent being selected from (lower)alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl and (lower)alkoxy; q is an integer of from 0 to 6, inclusive; R.sup.14 and R.sup.15 independently are hydrogen or (lower)alkyl, or, if R.sup.14 is hydrogen, R.sup.15 also may be (lower)alkanoyl or benzoyl, or R.sup.14 and R.sup.15, taken together, may be ethylene; and R.sup.5 and R.sup.6 each are independently hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, (lower)alkoxy(lower)alkyl, cyclo(lower)alkyl or phenyl provided that R.sup.5 and R.sup.6 may not both be cyclo(lower)alkyl or phenyl; or R.sup.5 and R.sup.6, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino, homopiperidino, heptamethyleneimino or octamethyleneimino; or a nontoxic, pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 3 (depends on 1) A compound of claim 1 having the formula ##STR64## wherein p is 1 or 2; R.sup.2 and R.sup.3 each are independently hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, cyclo(lower)alkyl(lower)alkyl, hydroxy(lower)alkyl, (lower)alkoxy(lower)alkyl, 2-fluoroethyl or 2,2,2-trifluoroethyl, or, when R.sup.2 is hydrogen, R.sup.3 also may be pyrrolidino(lower)alkyl, piperidino(lower)alkyl, piperazino(lower)alkyl, substituted pyridyl(lower)alkyl wherein the pyridyl ring may contain one substituent selected from (lower)alkyl, (lower)alkoxy, hydroxy, amino and halogen, hydroxy, A'--(CH.sub.2).sub.m' Z'(CH.sub.2).sub.n' --, phenyl(lower)alkyl or substituted phenyl(lower)alkyl, wherein the phenyl ring may contain one or two substituents independently selected from (lower)alkyl, hydroxy, (lower)alkoxy and halogen or one substituent selected from methylenedioxy, trifluoromethyl and di(lower)alkylamino; m and m' each are independently an integer of from zero to 2, inclusive; n and n' each are independently an integer of from 2 to 4, inclusive; Z and Z' each are independently sulfur, oxygen or methylene; A and A' each are independently phenyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl; provided that A and A' independently may contain one or two substituents, the first substituent being selected from (lower)alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, (lower)alkoxy, ##STR65## and --(CH.sub.2).sub.q NR.sup.5 R.sup.6, and the second substituent being selected from (lower)alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl and (lower)alkoxy; q is an integer of from 0 to 6, inclusive; R.sup.14 and R.sup.15 independently are hydrogen or (lower)alkyl, or R.sup.14 and R.sup.15, taken together, may be ethylene; and R.sup.5 and R.sup.6 each are independently hydrogen, (lower)alkyl, (lower)alkenyl or (lower)alkynyl; or R.sup.5 and R.sup.6, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino, homopiperidino, heptamethyleneimino or octamethyleneimino; or a nontoxic, pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 4 (depends on 1) A compound of claim 1 having the formula ##STR66## wherein p is 1 or 2; R.sup.2 and R.sup.3 each are independently hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl or cyclo(lower)alkyl(lower)alkyl, or, when R.sup.2 is hydrogen, R.sup.3 also may be substituted pyridyl(lower)alkyl wherein the pyridyl ring may contain one substituent selected from (lower)alkyl, (lower)alkoxy, hydroxy, amino and halogen, A'--(CH.sub.2).sub.m' Z'(CH.sub.2).sub.n' --, phenyl(lower)alkyl or 3,4-methylenedioxybenzyl; m and m' each are independently zero or 1; n and n' each are independently 2 or 3; Z and Z' each are independently sulfur, oxygen or methylene; A and A' each are independently phenyl, imidazolyl, thiazolyl, furyl, thienyl or pyridyl; provided that A and A' independently may contain one or two substituents, the first substituent being selected from (lower)alkyl, ##STR67## and --CH.sub.2 NR.sup.5 R.sup.6, and the second substituent being selected from (lower)alkyl; R.sup.14 and R.sup.15 independently are hydrogen or (lower)alkyl, or R.sup.14 and R.sup.15, taken together, may be ethylene; and R.sup.5 and R.sup.6 each are independently hydrogen or (lower)alkyl; or R.sup.5 and R.sup.6, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino, homopiperidino, heptamethyleneimino or octamethyleneimino; or a nontoxic, pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 5 (depends on 1) A compound of claim 1 having the formula ##STR68## wherein p is 1 or 2; Z is sulfur or methylene; R.sup.2 and R.sup.3 each are independently hydrogen or (lower)alkyl, or, when R.sup.2 is hydrogen, R.sup.3 also may be (lower)alkenyl, (lower)alkynyl, phenyl(lower)alkyl, cyclo(lower)alkyl(lower)alkyl, or ##STR69## R.sup.16 is methyl and R.sup.13 is hydrogen or methyl, or R.sup.16 and R.sup.13, taken together with the nitrogen atom to which they are attached, may be piperidino; or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 6 (depends on 1) A compound of claim 1 having the formula ##STR70## wherein p is 1 or 2; Z is sulfur or methylene; R.sup.14 and R.sup.15 independently are hydrogen or methyl, or, R.sup.14 and R.sup.15, taken together, may be ethylene; and R.sup.2 and R.sup.3 each are independently hydrogen or (lower)alkyl, or, when R.sup.2 is hydrogen, R.sup.3 may also be (lower)alkenyl, (lower)alkynyl, ##STR71## or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 7 (depends on 1) A compound of claim 1 having the formula ##STR72## wherein p is 1 or 2; Z is sulfur or methylene; R.sup.2 and R.sup.3 each are independently hydrogen or (lower)alkyl, or when R.sup.2 is hydrogen, R.sup.3 also may be (lower)alkenyl, (lower)alkynyl or ##STR73## and R.sup.13 is hydrogen or methyl; or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 8 (depends on 1) A compound of claim 1 having the formula ##STR74## wherein p is 1 or 2; Z is sulfur or methylene; R.sup.2 and R.sup.3 each are independently hydrogen or (lower)alkyl, or, when R.sup.2 is hydrogen, R.sup.3 also may be (lower)alkenyl, (lower)alkynyl, phenyl(lower)alkyl, 3,4-methylenedioxybenzyl or ##STR75## and R.sup.13 is hydrogen or methyl; or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 9 (depends on 1) A compound of claim 1 having the formula ##STR76## wherein p is 1 or 2; and R.sup.2 and R.sup.3 each are independently hydrogen or (lower)alkyl, or, when R.sup.2 is hydrogen, R.sup.3 also may be (lower)alkenyl, (lower)alkynyl or ##STR77## or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 10 (depends on 1) A compound of claim 1 having the formula ##STR78## wherein p is 1 or 2; Z is sulfur or methylene; R.sup.2 and R.sup.3 each are independently hydrogen or (lower)alkyl, or, when R.sup.2 is hydrogen, R.sup.3 also may be (lower)alkenyl, (lower)alkynyl or ##STR79## and R.sup.5 and R.sup.6 each are independently hydrogen or (lower)alkyl, or, R.sup.5 and R.sup.6, taken together with the nitrogen atom to which they are attached, may be piperidino; or a nontoxic, pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 11 (depends on 1) A compound of claim 1 having the formula ##STR80## wherein p is 1 or 2; Z is oxygen or sulfur; R.sup.2 and R.sup.3 each are independently hydrogen or (lower)alkyl, or, when R.sup.2 is hydrogen, R.sup.3 also may be (lower)alkenyl, (lower)alkynyl or ##STR81## and R.sup.5 and R.sup.6 each are independently hydrogen or (lower)alkyl, or, when R.sup.5 is hydrogen, R.sup.6 also may be (lower)alkenyl or (lower)alkynyl; or R.sup.5 and R.sup.6, taken together with the nitrogen to which they are attached, may be pyrrolidino, methylpyrrolidino, piperidino, methylpiperidino, dimethylpiperidino, homopiperidino or heptamethyleneimino; or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 12 (depends on 1) A compound of claim 1 having the formula ##STR82## wherein p is 1 or 2; Z is oxygen or sulfur; R.sup.2 and R.sup.3 each are independently hydrogen or (lower)alkyl, or, when R.sup.2 is hydrogen, R.sup.3 may be (lower)alkenyl, (lower)alkynyl, or ##STR83## or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 13 (depends on 1) The compound of claim 1 which is 3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-methylamino- 1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 14 (depends on 1) The compound of claim 1 which is 3-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-methylamino-1,2 ,5-thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 15 (depends on 1) The compound of claim 1 which is 3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-ethylamino-1 ,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 16 (depends on 1) The compound of claim 1 which is 3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-(n-propyl)am ino-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 17 (depends on 1) The compound of claim 1 which is 3-allylamino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1 ,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 18 (depends on 1) The compound of claim 1 which is 3-{2-[(5-dimethylaminomethyl-2-furyl(methylthio]ethylamino}-4-(2-propynyl) amino-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 19 (depends on 1) The compound of claim 1 which is 3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-amino-1,2,5- thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 20 (depends on 1) The compound of claim 1 which is 3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-amino-1,2,5- thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 21 (depends on 1) The compound of claim 1 which is 3-amino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 22 (depends on 1) The compound of claim 1 which is 3-{4-(5-dimethylaminomethyl-2-furyl)butylamino}-4-methylamino-1,2,5-thiadi azole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 23 (depends on 1) The compound of claim 1 which is 3-methylamino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5-thiadiaz ole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 24 (depends on 1) The compound of claim 1 which is 3-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5- thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 25 (depends on 1) The compound of claim 1 which is 3-{2-[(2-guanidinothiazol-3-yl)methylthio]ethylamino}-4-(2-propynyl)amino- 1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 26 (depends on 1) The compound of claim 1 which is 3-amino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 27 (depends on 1) The compound of claim 1 which is 3-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-4-amino-1,2,5-thiadi azole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 28 (depends on 1) The compound of claim 1 which is 3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methylam ino-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 29 (depends on 1) The compound of claim 1 which is 3-{2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-methylamin o-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 30 (depends on 1) The compound of claim 1 which is 3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-ethylamino-1 ,2,5-thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 31 (depends on 1) The compound of claim 1 which is 3-amino-4-{3-[3-(4-methylpiperidinomethyl)phenoxy]propylamino}-1,2,5-thiad iazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 32 3-Amino-4-{2-[(2-guanidi nothiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 33 3-Ami no-4-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-2-1,2,5-thiadiazol e 1-oxide monohydrate. ### Claim 34 3-Amino-4-{2-[(2-g uanidinothiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxide hydrochloride. ### Claim 35 (depends on 1) The compound of claim 1 which is 3-benzylamino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}- 1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 36 (depends on 1) The compound of claim 1 which is 3-{2-[(3-{dimethylaminomethyl}phenyl)methylthio]ethylamino}-4-methylamino- 1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 37 (depends on 1) The compound of claim 1 which is 3-amino-4-{2-[(3-{dimethylaminomethyl}phenyl)methylthio]ethylamino}-1,2,5- thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 38 (depends on 1) The compound of claim 1 which is 3-{2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-methylamin o-1,2,5-thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 39 (depends on 1) The compound of claim 1 which is 3-amino-4-{4-(5-dimethylaminomethyl-2-furyl)butylamino}-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 40 (depends on 1) The compound of claim 1 which is 3-amino-4-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-1, 2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 41 (depends on 1) The compound of claim 1 which is 3-butylamino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1 ,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 42 (depends on 1) The compound of claim 1 which is 3-cyclopropylmethylamino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]e thylamino}-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 43 (depends on 1) The compound of claim 1 which is 3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-[(2-pyridyl) methylamino]-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 44 (depends on 1) The compound of claim 1 which is 3-amino-4-{3-[3-(4-methylpiperidinomethyl)phenoxy]propylamino}-1,2,5-thiad iazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 45 (depends on 1) The compound of claim 1 which is 4-{2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-3-(1-propyla mino)-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 46 (depends on 1) The compound of claim 1 which is 3-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5- thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 47 (depends on 1) The compound of claim 1 which is 3-{3-[3-(hexamethyleneiminomethyl)phenoxy]propylamino}-4-methylamino-1,2,5 -thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 48 (depends on 1) The compound of claim 1 which is 3-[3-(3-dimetylaminomethylphenoxy)propylamino]-4-methylamino-1,2,5-thiadia zole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 49 (depends on 1) The compound of claim 1 which is 3-amino-4-{3-[3-(hexamethyleneiminomethyl)phenoxy]propylamino}-1,2,5-thiad iazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 50 (depends on 1) The compound of claim 1 which is 3-amino-4-[3-(3-dimethylaminomethylphenoxy)propylamino]-1,2,5-thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 51 (depends on 1) The compound of claim 1 which is 3-amino-4-{3-[3-(heptamethyleneiminomethyl)phenoxy]propylamino}-1,2,5-thia diazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 52 (depends on 1) The compound of claim 1 which is 3-amino-4-{2-[(2-{2-methylguanidino}thiazol-4-yl)methylthio]ethylamino}-1, 2,5-thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 53 (depends on 1) The compound of claim 1 which is 3-methylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazo le 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 54 (depends on 1) The compound of claim 1 which is 3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 55 (depends on 1) The compound of claim 1 which is 3-{2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-ethylamino -1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 56 (depends on 1) The compound of claim 1 which is 3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 57 (depends on 1) The compound of claim 1 which is 3-amino-4-[3-(3-guanidinophenoxy)propylamino]-1,2,5-thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. ### Claim 58 (depends on 1) A compound of claim 1 having the formula ##STR84## wherein p is 1 or 2; Z is sulfur or methylene; R.sup.2 and R.sup.3 each are independently hydrogen or (lower)alkyl, or, when R.sup.2 is hydrogen, R.sup.3 also may be (lower)alkenyl, (lower)alkynyl, phenyl(lower)alkyl, 3,4-methylenedioxybenzyl or ##STR85## R.sup.16 is methyl and R.sup.13 is hydrogen or methyl, or R.sup.16 and R.sup.13, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, morpholino, piperidino, methylpiperidino, homopiperidino or heptamethyleneimino; or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof.