Aminothiadiazoles as gastric secretion inhibitors

Claim 2

Compounds having the formulae: wherein R is hydrogen, loweralkyl: wherein R 3 and R 4 are independently hydrogen, loweralkyl, cycloloweralkyl, or phenylloweralkyl, or R 3 and R 4 may be joined to form, along with the nitrogen to which they are attached, a 5- or 6-membered heterocycle, which may also contain an oxygen, sulfur or N-R 7 heteroatom, wherein R 7 is hydrogen, loweralkyl of from 1 to 3 carbon atoms or benzyl; R 5 and R 6 are independently hydrogen or loweralkyl; n is O or 1; m is 2 to 4; k is 1 to 4; X is oxygen, sulfur or methylene; p is 1 or 2; R 1 and R 2 are independently hydrogen, loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, phenyl, pyridyl and substituted loweralkyl wherein the substituent is phenyl, cycloloweralkyl, pyridyl, imidazolyl, morpholino, hydroxy, loweralkoxy, loweralkylthio or di(loweralkyl)amino, or R 1 and R 2 may be joined to form, along with the nitrogen to which they are attached, a 5- or 6-membered heterocycle which may also contain an oxygen, sulfur or N-R 7 heteroatom wherein R 7 is as defined above; Ⓐ is phenylene or a 5- or 6-membered heterocycle containing one to three heteroatoms selected from oxygen, sulfur or nitrogen, which may optionally have a benzo ring fused thereon; provided that when Ⓐ is a 5-membered heterocycle or benzo fused 5-membered heterocycle, n is 1; Ar is aryl; R 10 is lower alkanoyl, aroyl, substituted aroyl, hetaroyl, lower alkylsulfonyl, arylsulfonyl, hetarylsulfonyl, cyano, amidino, dialkylcarbamoyl, dialkylsulfamoyl, alkoxycarbonyl, -(CH 2 )yCOR 11 wherein y is 1 or 2; R 11 is loweralkyl, hydroxy, alkoxy, amino, loweralkylamino, diloweralkylamino; R 12 is aralkylidene, diarylmethylidene; and, the physiologically acceptable salts thereof.

Claim 3

The compounds of Claim 1 which are members selected from the group consisting of: 3-N-[3-[3-(dimethylaminomethyl)phenoxy]propyl]amino-4-amino-1,2,5-thiadiazole-1-oxide; 3-N-[3-(1-piperidinyimethyl)phenoxy]propyl]amino-4-amino-l,2,5-thiadiazole-l-oxide; 3-N-[3-[3-(dimethylaminomethyl)phenoxy]propyl]amino-4-methylamino-1,2,5-thiadiazoie-1-oxide; 3-N-[3-[3-(dimethylaminomethyl)phenoxy]propyl]amino-4-amino-1,2,5-thiadiazole-1,1-dioxide; 3-N-[2-[(2-furanyl)methylthio]ethyl]amino-4-amino-1,2,5-thiadiazole-1-oxide; 3-N-[2-[(5-dimethylaminomethyl-2-thienyl)methylthio] ethyl]amino-4-amino-1,2,5-thiadiazole-l-oxide; 3-N-[2-[(4-methyl-5-oxazolyl)methylthio]ethyl]amino-4-amino-1,2,5-thiadiazole-l-oxide; 3-N-[2-[(2-furanyl)methylthio]ethyl]amino-4-amino-1,2,5-thiadiazole-1,1-dioxide; 3-N-[2-[[5-(1-piperidinylmethyl)-2-furanyl]methylthio]ethyl]amino-4-amino-1,2,5-thiadiazole-1- oxide; 3-N-[2-[(5-dimethylaminomethyl-2-furanyl)methylthio] ethyl]amino-4-amino-1,2,5-thiadiazole-1-oxide; 3-N-[2-[(5-dimethylaminomethyl-2-furanyl)methylthioI ethyl]amino-4-methylamino-1,2,5-thiadiazole-1-oxide; 3-N-[2-[(5-dimethylaminomethyl-2-furanyl)methylthio] ethyl]amino-4-methylamino-1,2,5-thiadiazole-1,1-dioxide; 3-N-[2-[(5-dimethylaminomethyl-2-furanyl)methylthio] ethyl]-amino-4-amino-1,2,5-thiadiazole-1,1-dioxide; 3-N-[2-[(5-methylaminomethyl-2-furanyl)methylthio] ethyl]amino-4-amino-1,2,5-thiadiazole-1-oxide; 3-N-[2-[(5-methylaminomethyl-2-furanyl)methylthio] ethyl]amino-4-amino-1,2,5-thiadiazole-1,1-dioxide; 3-N-[2-[(2-guanidino-4-thiazolyl)methylthio]ethyl] amino-4-methylamino-1,2,5-thiadiazole-1,1-dioxid:e; 3-N-[2-[(2-guanidino-4-thiazolyl)methylthio]ethyl] amino-4-amino-1,2,5-thiadiazole-1-oxide; 3-N-[2-[(2-guanidino-4-thiazolyl)methylthio]ethyl] amino-4-methylamino-1,2,5-thiadiazole-1-oxide; and, 3-N-[2-[[(6-(4-morpholinylmethyl-2-benzofuranyl) methylthio]ethyl]amino-4-amino-1,2,5-thiadiazole-1- oxide.

Claim 4

Compounds having the formulae: and wherein R, Ⓐ, n, X, and m are as defined in Claim 1; p is 1 or 2; L 2 is loweralkoxy, loweralkylthio, phenoxy, phenylthio or halogen; and, the physiologically acceptable salts thereof.

Claim 5

The compounds of Claim 3 which are members selected from the group consisting of : 3-N-[2-[(5-dimethylaminomethyl-2-furanyl)methylthio] ethyl]amino-4-ethoxy-1,2,5-thiadiazole-l-oxide; 3-N-[2-[(5-dimethylaminomethyl-2-furanyl)methylthio] ethyl]amino-4-ethoxy-1,2,5-thiadiazole-1,1-dioxide; 3-N-[3-(2-guanidino-4-thiazolyl)phenyl]amino-4-methyl amino-1,2,5-thiadiazole-1-oxide; 3-N-[3-(2-guanidino-4-thiazolyl)phenyl]amino-4-amino-1,2,5-thiadiazole-1-oxide;

Claim 6

Compounds having the formulae: wherein R1 and R 2 are members selected from the following groups: a) wherein R 1 an R 2 are the same and are loweralkoxy, loweralkylthio, phenoxy or phenylthio; or, b) wherein R 1 and R 2 are different and one of R 1 or R 2 is amino or loweralkylamino and the other is halo or loweralkylthio; or, c) wherein R 1 and R 2 are different and one of R 1 and R 2 is as defined in a) above and the other is: wherein R 3 and R 4 are independently hydrogen, loweralkyl, loweralkenyl, loweralkynyl, cycloloweralkyl, phenyl, pyridyl, or substituted loweralkyl wherein the substituent is phenyl cycloloweralkyl, pyridyl, imidazolyl, morpholino, hydroxy, loweralkoxy, lower alkylthio, di (loweralkyl)amino; or, R 3 and R 4 may be connected to form , along with the nitrogen to which they are attached, a 5- or 6-membered heterocyclic ring which may also contain an oxygen, sulfur or an N-R 5 heteroatom selected from morpholine, thiomorpholine, piperidine, piperazine, N-loweralkyl piperazine, and pyrrolidine wherein R 5 is hydrogen or loweralkyl of from 1 to 3 carbon atoms; and, wherein R 1 , R 2 , R 3 and R 4 can each independently be hydrogen, alkyl, loweralkenyl, loweralkynyl, cycloloweralkyl, aryl, phenyl, pyridyl or substituted loweralkyl wherein the substituent is amino, phenyl, substituted phenyl, cycloloweralkyl, pyridyl, loweralkoxy, imidazolyl, morpholino, hydroxy, di(loweralkyl)amino; or, R 3 and R 4 may be connected to form, along with the nitrogen to which they are attached a 5- or 6-membered heterocyclic ring, which may also contain an oxygen, sulfur or N-R 5 heteroatom, said heterocyclic ring being a member selected from morpholine, thiomorpholine, piperazine, piperidine, N-loweralkyl-piperazine, and pyrrolidine, and wherein R 5 is hydrogen or loweralkyl of from 1 to 3 carbon atoms.

Claim 7

Compounds having the formulae: wherein R1 and R 2 are members selected from the following groups: a) wherein R 1 an R 2 are the same and are loweralkoxy, loweralkylthio, phenoxy or phenylthio; or, b) wherein R 1 and R 2 are different and one of R 1 or R 2 is amino or loweralkylamino and the other is halo or loweralkylthio; or, c) wherein R 1 and R 2 are different and one of R 1 and R 2 is as defined in a) above and the other is: wherein R 3 and R 4 are independently hydrogen, loweralkyl, loweralkenyl, loweralkynyl, cycloloweralkyl, phenyl, pyridyl, or substituted loweralkyl wherein the substituent is phenyl cycloloweralkyl, pyridyl, imidazolyl, morpholino, hydroxy, loweralkoxy, lower alkylthio, di (loweralkyl)amino; or, R 3 and R 4 may be connected to form , along with the nitrogen to which they are attached, a 5- or 6-membered heterocyclic ring which may also contain an oxygen, sulfur or an N-R 5 heteroatom selected from morpholine, thiomorpholine, piperidine, piperazine, N-loweralkyl piperazine, and pyrrolidine wherein R 5 is hydrogen or loweralkyl of from 1 to 3 carbon atoms; and, wherein R 1 , R 2 , R 3 and R 4 can each independently be hydrogen, alkyl, loweralkenyl, loweralkynyl, cycloloweralkyl, aryl, phenyl, pyridyl or substituted loweralkyl wherein the substituent is amino, phenyl, substituted phenyl, cycloloweralkyl, pyridyl, loweralkoxy, imidazolyl, morpholino, hydroxy, di(loweralkyl)amino; or, R 3 and R 4 may be connected to form, along with the nitrogen to which they are attached a 5- or 6-membered heterocyclic ring, which may also contain an oxygen, sulfur or N-R 5 heteroatom, said heterocyclic ring being a member selected from morpholine, thiomorpholine, piperazine, piperidine, N-loweralkyl-piperazine, and pyrrolidine, and wherein R 5 is hydrogen or loweralkyl of from 1 to 3 carbon atoms.

Claim 8

Compounds of Claim 5 which are members of the group consisting of: 3,4-diethoxy-1,2,5-thiadiazole-l-oxide; 3,4-bis-methylthio-1,2,5-thiadiazole-1-oxide; 3-methylamino-4-methylthio-1,2,5-thiadiazole-1-oxide; 3-amino-4-methylthio-1,2,5-thiadiazole-1-oxide; 3-isopropylamino-4-methylthio-1,2,5-thiadiazole-1- oxide; 3-ethoxy-4-amino-1,2,5-thiadiazole-1-oxide; 3-ethoxy-4-methylamino-1,2,5-thiadiazole-1-oxide; 3-ethoxy-4-(l-pyrrolidinyl)-1,2,5-thiadiazole-l-oxide; 3-ethoxy-4-(4-morpholino)-1,2,5-thiadiazole-l-oxide; 5(aimethylaminomethyl)furfuryl mercaptan. 3,4-diamino-1,2,5-thiadiazole-1-oxide; 3-amino-4-(2-dimethylaminoethyl)amino-1,2,5-thiadiazole-l-oxide; 3-amino-4-methylamino-1,2,5-thiadiazole-1-oxide; 3-amino-4-dodecylamino-1,2,5-thiadiazole-1-oxide; 3-amino-4-(4-fiuoroanilino)-1,2,5-thiadiazole-1-oxide; 3-amino-4-morpholino-1,2,5-thiadiazole-1-oxide; and, 3-morpholino-4-(2-pyridinomethyl)amino-1,2,5-thiadiazole-l-oxide.

Claim 9

A process for the preparation of a compound of Claim 1 which comprises treating a compound having the formula: wherein p is 1 or 2 and L 1 and L 2 are leaving groups, sequentially with either of the amines: or or wherein R, Ⓐ, n, X, m, R 1 and R 2 are as defined in Claim 1, followed by treatment of the resulting compound with the other of said amines; or where Ⓐ is furan, treating the resulting compound with the other of said amines to obtain a furan intermediate compound; reacting said furan intermediate compound with either or wherein Hal is halo and R 3 and R 4 are as defined . in Claim 1 to produce the compounds of Claim 1; or, reacting an intermediate compound having the formula: wherein R, Ⓐ, X, m, n and p are as defined in Claim 1 and L 2 is a leaving group with an imine such as or (aryl) 2 C= NH wherein R 5 is as defined in Claim 1 to produce derivatives having the formula: wherein R, Ⓐ, X, m, n and p are as defined in Claim 1; R 12 is aralkylidene, diarylmethylidene; or, reacting said intermediate witl wherein R 5 is as defined in Claim 1 to produce derivatives having the formula: wherein R, R 5 , Ⓐ, X, m, n and p are as defined in Claim 1; and, the physiologically acceptable salts of said compounds and said derivatives.

Claim 10

A process for the preparation of compounds of Claim 1 which comprises reacting an alcohol having the formula: wherein R 1 , R 2 and p are as defined in Claim 1 and m>2, with an acylating agent to obtain an activated ester intermediate; reacting said ester intermediate with an alkali metal salt of 3-hydroxy benzaldehyde to obtain an intermediate having the formula: wherein X is 0; and, reducing said intermediate in the presence of amine R 3 NHR 4 , wherein R 3 and R 4 are as defined in Claim 1; or, reacting said ester intermediate when m=2 with a mercaptan having the formula R- Ⓐ -(CH 2 ) n -SH wherein R, Ⓐ and n are as defined in Claim 1; or reacting an alcohol having the formula wherein R, Ⓐ , X and n are as defined in Claim 1 with, after activation of said alcohol toward nucleophiles, an amino compound having the formula: wherein R 1 , R 2 and p are as defined in Claim 1; or, reacting a mercaptan having the formula: wherein R 1 , R 2 and p are as defined in Claim 1, with an alcohol having the formula R- Ⓐ -(CH 2 ) n -OH wherein R, Ⓐ and n are as defined in Claim 1, in the presence of a mineral acid to afford the compounds of Claim 1; and the physiologically acceptable salts thereof; or, reacting the compounds defined in Claim 1 and tautomers thereof with an alkylating reagent, an acylating agent or a sulfonating agent to produce derivatives having the formulae: and wherein R, R 1 , Ⓐ , X, m, n and p are as defined in Claim 1; R 10 is lower alkanoyl, aroyl, substituted aroyl, hetaroyl, lower alkylsulfonyl, arylsulfonyl, hetarylsulfonyl, cyano, amidino, dialkylcarbamoyl, dialkylsulfamoyl, alkoxycarbonyl, -(CH 2 ) y COR 11 wherein y is 1 or 2 and R 11 is loweralkyl, hydroxy, alkoxy, amino, loweralkylamino, diloweralkylamino; and, the physiologically acceptable salts thereof.

Claim 11

A process for the preparation of compounds of Claim 5 which comprises treating a compound having the formula: wherein R1 and R 2 are as defined in a) or b) in Claim 5, with thionyl chloride in the presence of a base to form a compound having the formula: which is treated with an amine having the formula: wherein R 3 and R 4 is as defined in Claim 5 to form the compounds wherein R 1 and R 2 are as defined in c) in Claim 5; or, treating a compound having the formula: wherein L 1 and L 2 are leaving groups selected from the group consisting of loweralkoxy, loweralkylthio, phenoxy, or phenylthio, with thionyl chloride in the presence of a base to form an intermediate compound having the formula: which is reacted with amines having the formulae: wherein R 1 , R 2 , R 3 and R 4 are as defined in Claim 5 to form the compounds having the formula: wherein R 1 , R 2 , R 3 and R 4 are as defined in Claim 5.

Claim 13

A composition useful for suppressing gastric acid secretions in an animal with excess gastric acid secretions which comprises an inert carrier and an effective amount of a compound of Claims 1, 3 or 5.