GB2147899A - Chemical intermediates derived from cyclobutene - Google Patents

Chemical intermediates derived from cyclobutene Download PDF

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GB2147899A
GB2147899A GB08429389A GB8429389A GB2147899A GB 2147899 A GB2147899 A GB 2147899A GB 08429389 A GB08429389 A GB 08429389A GB 8429389 A GB8429389 A GB 8429389A GB 2147899 A GB2147899 A GB 2147899A
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dione
alkyl
integer
inclusive
cyclobutene
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Aldo Antonio Algieri
Ronnie Ray Crenshaw
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Bristol Myers Co
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Bristol Myers Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms

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Description

SPECI FICATION Chemical intermediates derived from cyclobutene The present Application has been divided out of Application No. 82.14351 (2098988), referred to below as our "primary"Application.
As disclosed in our primary Application, certain substituted 1,2-diaminocyclobutene-3, 4-diones of the formula
wherein A is substituted phenyl, furyl, thienyl or pyridyl, Z is sulfur, oxygen or methylene, m is 0-2, n is 2-5 and R1 and R2 are as defined below, are potent histamine H2-antagonists, inhibit gastric acid secretion and are useful in the treatment of peptic ulcers.
Burimamide (Ila) was the first clinically effective H2-receptor antagonist. It inhibits gastric secretion in animals, including man, but oral absorption is poor.
Ila ; R=H, Z=CH2, X=S Burimamide b; R=CH3, Z=S, X=S Metiamide c; R=CH3, Z=S, X=NCN Cimetidine Metiamide (lob), a subsequently evaluated H2-antagonist, is more potent than burimamide and is orally active in man. Clinical utility was limited, however, owing to toxicity (agranulocytosis). Cimetidine (Ilc) is as effective an H2-antagonist as metiamide, without producing agranulocytosis, and has recently been marketed as an anti-ulcer drug.
Reviews on the development of H2-antagonists, including those discussed in the preceding paragraph, may be found in C. R. Ganellin, et al., Federation Proceedings, 35, 1924 (1976), in Drugs of the Future, 1, 13 (1976) and in references cited therein.
U. S. Patent 4,062,863 discloses histamine H2-antagonists of the formula
wherein R is hydrogen, (lower) alkyl or (CH2) 2Z'CH2-HET'; Z and Z'each are sulfur or methylene ; and HET and HET'each are an imidazole ring optionally substituted by methyl or bromo, a pyridine ring optionally substituted by hydroxy, methoxy, chloro or bromo, a thiazole ring or an isothiazole ring, and pharmaceutically acceptable acid addition salts thereof. U. S. Patents 4,120,968,4,120,973 and 4,166,857 are divisionals thereof which have substantially the same disclosure.
U. K. Published Patent Application 2,023,133 discloses histamine H2-antagonists of the formula
wherein Ri and R2 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, trifluoroalkyl or alkyl substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino or cycloalkyl, or Ri and R2, taken together with the nitrogen to which they are attached, may be a 5-to 1 0-membered alicyclic heterocyclic ring which may be saturated or may contain at least one double bond, which may be substituted by one or more alkyl groups or a hydroxy group and/or which may contain another heteroatom; Alk is a straight or branched alkylene chain of 1-6 carbon atoms; Q is a furan or thiophene ring incorporated into the molecule via the 2and 5-positions, the furan ring optionally bearing a further substituent R7 adjacent the R1R2N-Alk-group, or Q is a benzene ring incorporated into the molecule via its 1-and 3-or 1-and 4-positions ; R7 is halogen, alkyl (which may be substituted by hydroxy or alkoxy) ; X is methylene, oxygen, sulfur or N-R in which R6 is hydrogen or methyl ; n is 0,1 or 2; m is 2,3 or 4; R3 is hydrogen, alkyl, alkenyl, aralkyl, hydroxyalkyl having at least two carbon atoms, alkoxyalkyl or aryl ; and R4 and R5 are independently hydrogen, alkyl, alkyl substituted by hydroxy or C1 3 alkoxy, alkenyl, aralkyl or heteroaralkyl, or R4 and R5 taken together with the nitrogen to which they are attached, may be a 5-to 7-membered saturated heterocyclic ring which may contain another heteroatom orthe group NR6, or R and R5 taken together may be the group CR$R9 wherein Rg is aryl or heteroaryl and Rg is hydrogen or alkyl ; and physiologically acceptable salts and hydrates thereof.
Published European Patent Application No. 30,092 discloses histamine H2-antagonists of the formula
in which R'and R2 are hydrogen or optionally halogen-substituted alkyl, cycloalkyl or cycloalkylalkyl, provided that at least one of R'and R2is halogen-substituted alkyl, cycloalkyl or cycloalkylalkyl ; X is a phenyl ring with 1 or 2 optional substituents or a 5-or 6-membered heterocyclic aromatic ring containing 1,2 or 3 heteroatoms selected from 0, N and S, the heterocyclic ring, where possible, having 1 optional substituent, which optional substituents are halogen, alkyl, alkoxy, alkylthio, trifluoromethyl, hydroxy and amino; Y is O, S, a direct bond, methylene, cis or trans vinylene, sulfinyl or NR4 in which R4 is H or alkyl ; m is 0 to 4 and n is 1 to 5 ; R3 is interalia AB in which A is interalia a 3,4-dioxocyclobuten-1,2-diyl radical and B is interalia the radical NR7R3 in which R and R3 are interalia hydrogen, alkyl, haloalkyl, alkoxycarbonyl, alkenyl, alkynyl, (primary hydroxy) atkyl or (primary amino) alkyl, or R6 and R9, together with the nitrogen atom to which they are attached, may be a 5-or 6-membered ring which optionally contains O or NR9 in which R9 is H or alkyl.
Complete disclosure This application relates to histamine H2-antagonists which are effective inhibitors of gastric acid secretion in animals, including man, which are useful in the treatment of peptic ulcers and other conditions caused or exacerbated by gastric acidity, and which have the formula
wherein R'and R2 each are independently hydrogen or (lower) alkyl, and, when R'is hydrogen, R2 also may be allyl, propargyl, cyclo (lower) alkyl (lower) alkyl, cyclo (lower) alkyl, cyano (lower) alkyl, 2-fluoroethyl, 2,2,2trifluoroethyl, hydroxy, 2,3-dihydroxypropyl,
in which p is an integer of from 1 to 6, q is an integer of from 1 to 6, R3 and R4 each are independently hydrogen, (lower) alkyl, 4 hydroxy, (lower) alkoxy or halogen, and, when R3 is hydrogen, R4 also may be trifluoromethyl, or R3 and R4, taken together, may be methylenedioxy, R5 is hydrogen, (lower) alkyl, (lower) alkoxy, hydroxy, amino or halogen; m is an integer of from 0 to 2; n is an integer of from 2 to 5; Z is sulfur, oxygen or methylene ; and Ais
in which R8 is hydrogen, (lower) alkyl, (lower) alkoxy or halogen ; r is an integer of from 1 to 4; and R8 and R9 each are independently hydrogen, (lower) alkyl, allyl, propargyl, (lower) alkoxy (lower) alkyl in which the (lower) alkoxy moiety is at least two carbon atoms removed from the nitrogen atom, cyclo (lower) alkyl, or phenyl (lower) alkyl, provided that R3 and R9 may not both be cyclo (lower) alkyl, or RI and R9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, 3-pyrrolino, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo [3.2.2] nonane; or a nontoxic, pharmaceutically acceptable salt, hydrate or solvate thereof.
Also disclosed herein are processes for the preparation of the compounds of Formula I and intermediates in the preparation of the compounds of Formula I.
The present invention includes within its scope all possible tautomeric forms, geometric isomers, optical isomers and zwitterionic forms of the compounds of Formula I, as well as mixtures thereof. As used herein and in the claims, the terms"(lower) alkyl"and"(lower) alkoxy"mean straight or branched chain alkyl or alkoxy groups containing from 1 to 6 carbon atoms. Preferably these groups contain from 1 to 4 carbon atoms and, most preferably, they contain 1 or 2 carbon atoms. The term"cyclo (lower) alkyl", as used herein and in the claims, means a cycloalkyl ring containing from 3 to 7 carbon atoms and preferably from 3 to 6 carbon atoms. Unless otherwise specified in the particular instance, the term"halogen"as used herein and in the claims is intended to include chloride, fluorine, bromine and iodine. The term"nontoxic pharmaceutically acceptable salts"is intended to include salts of the compounds of Formula I with any nontoxic pharmaceutically acceptable acid. Such acids are well-known and include hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, maleic, fumaric, succinic, oxalic, benzoic, methanesulfonic, tartaric, citric, camphorsulfonic, and levulinic. The salts are made by methods known in the art.
The compounds of Formula I may be prevented by various alternative procedures, utilizing as a starting material a compound of the formula
in which R12 is a good leaving group such as halogen, phenoxy, substituted phenoxy, or alkoxy. Suitable leaving groups are well-known to those skilled in the art. Preferably, R12 is (lower) alkoxy, and especially methoxy and ethoxy.
The compounds of Formula I may be prepared from a compound of Formula II by various alternative reaction schemes. Some of the intermediate compounds are themselves novel.
Reaction Scheme 1
CompoundAjCHZtCH AtCHZfCHHHR B 0 0 R R 2 NH RZ NN g12 NzR AlCH2XmZICH2) nNH N uR2 AICHZjmZICH2pNH2 ro---00 n I The reactions are conducted in an inert organic solvent; we find methanol to be a convenient and readily available solvent. The reaction temperature is not critical. Most starting materials are quite reactive and we prefer to conduct the reaction at a temperature below room temperature, e. g. 0-10 C. With some less reactive compounds it is convenient to conduct the reaction at room temperature. Sometimes it is desirable to subsequently raise the temperature of the reaction mixture (e. g. to 50-60 C) to complete the reaction.
Reaction Scheme 2
Compound '"I NH \HS) CH2) A /"\ / R12 N a'NH R12 n i 0 0 0 0 oo oo \hui/2/ HSf~) M IT o o
In Reaction Scheme 2, X is a conventional leaving group such as fluoro, chloro, bromo, iodo,-03SR3 in which R13 is (lower) alkyl [e. g. methanesulfonate], aryl orsubstituted aryl [e. g. benzenesulfonate, p-bromobenzenesulfonate or p-toluenesulfonate],-03SF, acetoxy or 2,4-dinitrophenoxy. For convenience and economy we prefer to utilize a compound in which X is chloro. The reaction conditions for the preparation of the compounds of Formula IV, V and VI are as described for Reaction Scheme 1. The reaction of the compound of Formula VI with A (CH2) mX may be conducted in any inert organic solvent such as an alkanol, acetonitrile, dimethylformamide, dimethylsulfoxide, or acetone. We prefer to conduct the reaction is an alkanol such as methanol, ethanol or isopropanol. The reaction temperature is not critical ; thus it may be 0 to 200 C. At low temperatures the reaction is slow, while high temperatures normally lead to less pure products due to decomposition and the formation of side-products. We normally prefer to conduct the reaction at room temperature. The reaction of the compound of Formula VI with A (CH2) mX to produce the compound of Formula I preferably is conducted in the presence of a base, which facilitates the reaction by acting as an acid acceptor. Suitable bases include, for example, NaOH, KOH, LiOH, triethylamine, dimethylaniline, and sodium ethoxide.
In a preferred embodiment of the invention the compounds of Formula I have the structure
wherein R2 is hydrogen, (lower) alkyl, allyl, propargyl, 3-pyridylmethyl or 6-methyl-3-pyridylmethyl ; m is an integer of from 0 to 2; n is an integer of from 2 to 5; Z is sulfur, oxygen or methylene ; R6 is hydrogen or (lower) alkyl ; r is an integer of from 1 to 4; and R and R9 each are independently hydrogen or (lower) alkyl, or R8 and R9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, hepta methyleneimino, octamethyleneimino or 3-azabicyclo [3.2.2]-nonane; or a nontoxic, pharmaceutically acceptable salt, hydrate or solvate thereof.
In another preferred embodiment of the invention, the compounds of Formula I have the structure
wherein R is hydrogen, (lower) alkyl, allyl, propargyl, 3-pyridylmethyl or 6-methyl-3-pyridylmethyl ; m is an integer of from 0 to 2; n is an integer of from 2 to 5; Z is sulfur, oxygen or methylene ; RI is hydrogen or (lower) alkyl ; r is an integer of from 1 to 4; and RI and Ro each are independently hydrogen or (lower) alkyl, or R8 and R9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, hepta methyleneimino, octamethyleneimino or3-azabicyclo [3.2.2] nonane; or a nontoxic, pharmaceutically acceptable salt, hydrate or solvate thereof.
In another preferred embodiment of the invention the compounds of Formula I have the structure
wherein R2 is hydrogen or (lower) alkyl, allyl, propargyl, 3-pyridylmethyl or 6-methyl-3-pyridylmethyl ; m is an integer of from 0 to 2; n is an integer of from 2 to 5; Z is sulfur, oxygen or methylene ; R6 is hydrogen or (lower) alkyl ; r is an integer of from 1 to 4 ; and R8 and R9 each are independently hydrogen or (lower) alkyl, or R8 and R9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, hepta methyleneimino, octamethyleneimino or 3-azabicyclo [3. 2.2] nonane ; or a nontoxic, pharmaceutically acceptable salt, hydrate or solvate thereof.
In another preferred embodiment of the invention, the compounds of Formula I have the structure
wherein R2 is hydrogen or (lower) alkyl, allyl, propargyl, 3-pyridylmethyl or 6-methyl-3-pyridylmethyl ; m is an integer of from 0 to 2; n is an integer of from 2 to 5; Z is sulfur, oxygen or methylene ; R6 is hydrogen or (lower) alkyl ; r is an integer of from 1 to 4; and R8 and R9 each are independently hydrogen or (lower) alkyl, or R8 and R9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or3-azabicyclo [3.2.2] nonane; or a nontoxic, pharmaceutically acceptable salt, hydrate or solvate thereof.
As presently envisaged, the particularly preferred compounds of Formula I are a) 1-Amino-2- [3- (3-piperidinomethylphenoxy) propylamino] cyclobutene-3, 4-dione, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. b) 1-Amino-2-[-piperidinomethylphenoxy) propylamino] cyclobutene-3, 4-dione hydrochloride. c) 1-Amino-2-, 2-[(5-dimethylaminomethyl-2-fu ryl) methylthio] ethyla minoicyclobutene-3, 4-dione, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. d) 1-Amino-2-2-[(5-dimethylam i nomethyl-3-th ienyl) methylthio] ethylamino, cyclobutene-3, 4-dione. or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. e) 1-Amino-2-2- [ (5-piperidinomethyl-3-thienyl) methylthio] ethylamino) cyclobutene-3, 4-dione, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. f) 1-Amino-2- [3- (3-dimethylaminomethylphenoxy) propylamino] cyclobutene-3, 4-dione, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. g) 1-Amino-2- [3- (3-pyrrolidinomethylphenoxy) propylaminol]-cyclobutene-3, 4-dione, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. h) 1-Amino-2- ;3- [3- (3-methylpyrrolidino) methylphenoxyl]-propylamino) cyclobutene-3, 4-dione, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. i) 1-Methylamino-2- [3- (3-piperidinomethylphenoxy) propylamino] cyclobutene-3, 4-dione, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. j) 2- [3- (3-Piperidinomethylphenoxy) propylamino]-1- (2-propynylamino) cyclobutene-3, 4-dione, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. k) 2- [3- (3-Piperidinomethylphenoxy) propylamino]-1- (3-pyridyl) methylaminocyclobutene-3, 4-dione, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.
I) 1-Amino-2- [3- (3-hexamethyleneiminomethylphenoxy)-propylamino] cyclobutene-3, 4-dione, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. m) 1-Amino-2- [3- (3-piperidinomethylthiophenoxy) propylamino] cyclobutene-3, 4-dione, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. n) 1-Amino-2- [3- (3-heptamethyleneiminomethylphenoxy) propylamino] cyclobutene-3, 4-dione, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof. o) 1-Amino-2- [3-octamethyleneiminomethylphenoxy) propylamino] cyclobutene-3, 4-dione, or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.
Useful for this invention are novel intermediates of the formula
wherein R12 is a conventional leaving group selected from halogen, phenoxy, substituted phenoxy and alkoxy ; m is an integer of from 0 to 2; n is an integer of from 2 to 5; Z is sulfur, oxygen or methylene ; and Ais
in which R6 is hydrogen, (lower) alkyl, (lower) alkoxy or halogen ; r is an integer of from 1 to 4; and R8 and R9 each are independently hydrogen, (lower) alkyl, allyl, propargyl, (lower) alkoxy (lower) alkyl in which the (lower) alkoxy moiety is at least two carbon atoms removed from the nitrogen atom, cyclo (lower) alkyl, or phenyl (lower) alkyl, provided that R8 and R9 may not both be cyclo (lower) alkyl, or R8 and R9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, 3-pyrrolino, homopiperidino, hepta methyleneimino, octamethyleneimino or 3-azabicyclo [3. 2.2] nonane.
A preferred embodiment of the intermediates of Formula III are those having the structure
wherein R12 is a conventional leaving group selected from halogen, phenoxy, substituted phenoxy and (lower) alkoxy ; m is an integer of from 0 to 2; n is an integer of from 2 to 5; Z is sulfur, oxygen or methylene ; R6 is hydrogen or (lower) alkyl ; r is an integer of from 1 to 4; and R8 and R9 each are independently hydrogen (lower) alkyl, or RI and R9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo [3.2.2] nonane.
Another preferred embodiment of the intermediates of Formula III are those having the structure
wherein R12 is a conventional leaving group selected from halogen, phenoxy, substituted phenoxy and (lower) alkoxy ; m is an integer of from 0 to 2; n is an integer of from 2 to 5; Z is sulfur, oxygen or methylene ; R6 is hydrogen or (lower) alkyl ; r is an integer of from 1 to 4; and R8 and R9 each are independently hydrogen or (lower) alkyl, or R'and R', taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or3-azabicyclo [3.2.2] nonane.
'Another preferred embodiment of the intermediates of Formula III are those having the structure
wherein R12 is a conventional leaving group selected from halogen, phenoxy, substituted phenoxy and (lower) alkoxy ; m is an integer of from 0 to 2 ; n is an integer of from 2 to 5; Z is sulfur, oxygen or methylene ; R6 is hydrogen or (lower) alkyl ; r is an integer of from 1 to 4; and R'3 and R9 each are independently hydrogen or (lower) alkyl, or R'and R', taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo [3.2.2] nonane.
Another preferred embodiment of the intermediates of Formula III are those having the structure
wherein R12 is a conventional leaving group selected from halogen, phenoxy, substituted phenoxy and (lower) alkoxy ; m is an integer of from 0 to 2 ; n is an integer of from 2 to 5; Z is sulfur, oxygen or methylene ; R6 is hydrogen or (lower) alkyl ; r is an integer of from 1 to 4; and R8 and R9 each are independently hydrogen or (lower) alkyl ; or R8 and R9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, hepta methyleneimino, octamethyleneimino or 3-azabicyclo [3.2.2] nonane.
As presently envisaged, the most preferred intermediates of Formula III are a) 1-Methoxy-2- [3- (3-piperidinomethylphenoxy) propylamino] cyclobutene-3, 4-dione. b) 1-Methoxy-2-รง2-[(5-dimethyla minomethyl-2-fu ryl) methylthio] ethylam inocyclobutene-3, 4-dione. c) 1-Methoxy-2-F2-[(5-dimethylaminomethyl-3-thienyl) methylthio] ethylaminoEcyclobutene-3, 4-dione. d) 1-Methoxy-2-i2-[(5-piperidinomethyl-3-thienyl) methylthio] ethylaminolcyclobutene-3, 4-dione. e) 1-Methoxy-2- [3- (3-dimethylaminomethylphenoxy) propylamino] cyclobutene-3, 4-dione. f) 1-Methoxy-2- [3- (3-pyrrolidinomethylphenoxy) propylamino] cyclobutene-3, 4-dione. g) 1-Methoxy-2- ! 3- [3- (3-methylpyrrolidino) methylphenoxy] propylamino ; cyclobutene-3, 4-dione. h) 1-Methoxy-2- [3- (3-hexamethyleneiminomethylphenoxy) propylamino] cyclobutene-3, 4-dione. i) 1-Methoxy-2- [3- (3-piperidinomethylthiophenoxy) propylamino] cyclobutene-3, 4-dione. j) 1-Methoxy-2- [3- (3-heptamethyleneiminomethylphenoxy) propylamino] cyclobutene-3, 4-dione. k) 1-Methoxy-2- [3- (3-octamethyleneiminomethylphenoxy) propylamino] cyclobutene-3, 4-dione.
The starting materials of Formula II used in the preparation of the compounds of this invention are either known or are prepared by methods known in the art. See, for example, the extensive review article by A. H.
Schmidt in Synthesis, Pages 961-994 (December 1980) and references cited therein.
For therapeutic use, the pharmacologically active compounds of Formula I will normally be administered as a pharmaceutical composition comprising as the (or an) essential active ingredient at least one such compound in its basic form or in the form of a nontoxic pharmaceutically acceptable acid addition salt, in association with a pharmaceutically acceptable carrier.
The pharmaceutical compositions may be administered orally, parenterally 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 of a syrup, mulsion, soft gelatin capsule, sterile solution for injection, or an aqueous or non-aqueous liquid suspension. the pharmaceutical compositions are prepared by conventional techniques appropriate to the desired preparation.
The dosage of the compounds of this invention will depend not only on such factors as the weight of the patient, but also on the degree of gastric acid inhibition desired and the potency of the particular compound being utilized. The decision as to the particular dosage to be employed is within the discretion of the physician. In the Heidenhain Pouch Dog test described below, cimetidine has an oral ED50 of approximately 3.3 Amoles/kg. The usual human adult oral dose of cimetidine is 300 mg, given fourtimes a day. The usual human adult starting oral dosages of the compounds of this invention are readily determined from their oral EDS0 in this same test. Thus, if the oral ED50 is 0.33 Fmoles/kg, the usual starting oral dosage woufd be approximately 30 mg, given four times a day. Similar calculations may be made for iv dosages. These starting dosages (and the number of times administered per day) may, of course, be varied by titration of the dosage to the particular circumstances of the specific patient. With the preferred compounds of this invention, each oral dosage unit will contain the active ingredient in an amount of from 5 mg to 300 mg, and most preferably from 10 mg to 100 mg. The active ingredient will preferably be administered in equal doses from one to fourtimes a day.
Histamine H2-receptor antagonists have been shown to be effective inhibitors of gastric secretion in animals including man, Brimblecombe etal., J. Int Med. Res., 3,86 (1975). Clinical evaluation of the histamine H2-receptor antagonist cimetidine has shown it to be an effective therapeutic agent in the treatment of peptic ulcer disease, Gray et al., Lancet, 1, 8001 (1977). Two of the standard animal models for determining gastric antisecretory activity of histamine H2-antagonists are the Gastric Fistula Rat and the Heidenhain Pouch Dog. The EDS0's for some of the compounds of this invention in these two animal models are given in Tables 1 and 2, below.
Determination of gastric antisecretory activity in the Gastric Fistula Rat Maie Long Evans rats weighing about 240-260 grams at the time of cannula implantation are used. The design and implantation of the stainless steel cannula into the anterior wall of the fore-stomach are carried out essentially as described by Pare et aL [Laboratory Animal Science, 27,244 (1977)]. The fistula components are designed and the operative procedure is carried out exactly as described in the above reference. Post operatively the animals are individually housed in solid bottom 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 allowed water ad libitumfor 20 hours before the testing procedure isto begin.
Immediately prior to collection, the cannula is opened and the stomach washed gently with 30-40 ml of warm saline or distilled water to remove any residual contents. The catheter is then screwed into the cannula in place of the plugging screw and the rat is placed in a clear plastic rectangular cage measuring 40 cm long, 15 cm wide and 13 cm high. The bottom of the cage has a slit approximately 1.5 cm wide and 25 cm long running down the center to accommodate the catheterwhich hangs through it. In this way the rat is not restricted and can move freely about the cage during collection periods. The remainder of the assay is carried out as described by Ridley etal. [Research Comm. Chem. Path. Pharm., 17, 365 (1977)].
Gastric secretions collecte during the first hour after washing the stomach are discarded as they may be contaminated. For oral evaluation, the catheter is then removed from the cannula and replaced with the plugging screw. Water (2 ml/kg) is administered orallyvia gastric intubation adn the animal is returned to the cage for 45 minutes. After this time the plugging screw is removed and replaced with a catheter to which a small plasticvial has been attached to collect the gastric secretions. Atwo hour sample is collected (this represents the control secretion), the catheter 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 attached to a small plastic vial and another 2 hour sample is collecte. The secretions in the second sample are compared to those of the control sample in order to determine the effects of the test drug.
When 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 after discarding the initial 60 minute collection. Atwo hour sample is collecte (control secretion) and the animals are injected either ip or sc with the test compound in a volume of 2 ml/kg. An addition two hour sample is collecte and its secretions are compared to those of the control period to determine drug effets.
The samples are centrifuged and placed in a graduated centrifuge tube for volume determination.
Titratable acidity is measured by titrating a one ml sample to pH 7.0 with 0.02N NaOH, using an Autoburet and an electrometric pH meter (Radiometer). Titratable acid output is calculated in microequivalents by multiplying the volume in milliliters by the acid concentration in milliequivalents per liter.
Results are expressed as percent inhibition relativeto control readings. Dose response curves are constructed and EDro values are calculated by regression analyses. At least three rats are used at each dosage level and a minimum of three dosage levels are utilized for determination of a dose responsive curve.
Determination of gastric antisecretoryactivityin the Heidenhain Pouch Dog Priorto surgery, hematology and blood chemistry profiles are obtained and an assessment made as to the general helth of selected female dogs. Dogs are vaccinated with Tissue Vax 5 (DHLP-Pitman-Moore) and housed in general animal quarters for four weeks'observation so incipient diseases may become apparent.
Dogs are fasted with water ad libitum 24 hours prior to surgery.
Anesthesia is induced with Sodium Pentothal (Abbott) 25-30 mg/kg iv. Subsequent anesthesia is maintained with methoxyflurane (Pitman-Moore). A mid-line linea alba incision from xiphoid to umbilicus provides good exposure and ease of closure. The stomach is pulled up into the operative field, the greater curvature stretched out at multiple points and clamps placed along the selected line of incision. The pouch is made from the corpus of the stomach so that true parietal cell juice is obtained. About 30% of the corpus volume is resected. The cannula is made of light-weight, biologically-inert material such as nylon or Deirin* (* Registered Trade mark) with dimensions and attachments after DeVito and Harkins [J. Appl. Physiol., 14, 138 (1959)]. Post operatively, dogs are medicated with antibiotics and an analgesic. They are allowed 2-3 months for recovery. Experiments are carried out in the following way: Dogs are fasted overnight-18 hours) with water ad libitum prior to each experiment. The dogs are placed in a sling and a saphenous vein cannulated for drug administration. Histamine as the base (100 Fg/kg/hr) and chlorpheniramine maieate (0.25 mg/kg/hr) are infused continuously (in a volume of 6 ml/hr) with a Harvard infusion pump.
Ninety minutes'infusion are allowed for the dogs to reach a steady state of acid output. At this time the drug or normal saline (control) is administered concomitantly with the secretagogue in a volume of 0.5 ml/kg over a 30 second period. When oral studies are to be carried out, the drug is administered via gastric gavage in a volume of 5 ml/kg. Infusion of the secretagogue is continued and 15 minute samples of the gastric juice are taken for 4.5 hours. Each sample is measured to the nearest 0.5 ml and titratable acidity is determined by titrating a 1 mi sample to pH 7.0 with 0.2N NaOH, using an Autoburet and an electrometric pH meter (Radiometer). Titratable acid output is calculated in microequivalents by multiplying the volume in milliliters by the acid concentration in milliequivalents per liter.
Results are expressed as percent inhibition relative to control readings. Dose response curves are constructed and ED50 values are calculated by regression analyses. From 3 to 5 dogs are used at each dose level and a minimum of three dosage levels are utilized for determination of a dose response curve.
Celite is a registered trademark of the Johns-Manville Products Corporation for diatomaceous earth.
In the following examples, all temperatures are given in degrees Centigrade.
TABLE 1 Gastric antisecretory activity in the Gastric Fistula Rat ED50 sc Potency Ratio Compound ( moleslkgl [cimetidine = 7. 0/ Cimetidine 3.8 1.0 (2.3-5.5)* Compound of Example 1 0.023 162 (0.011-0.037) (77-328) * Compound of Example 2 < 1 > 4 Compound of Example 3-4-1 Compound of Example 9 0.055 61 (0.016-0.14) (20-204) Compound of Example 10i 0.08 48 (0.04-0.16) (21-97) Compound of Example 10j 0.044 88 (0.019-0.09) (36-211) Compound of Example 10m 0.7 5.4 (0.36-1.4) (2.1-12) Compound of Example 11 0.067 50 (0.02-0.18) (15-169) Compound of Example 12 0.094 44 (0.046-0.17) (22-90) Compound of Example 14d 0.031 124 (0.016-0.056) (62-243) *numbers in parentheses are 95% confidence limits TABLE 2 Gastric antisecretory activity in the Heidenhain Pouch Dog ED5o Potency Ratio Compound [limoleslkgj [cimetidine = 1. 01 (INTRAVENOUS) Cimetidine 2.18 1.0 (1.48-2.95) * Compound of Example 1 0.024 87 (0.019-0.029) (62-117) * Compound of Example 2-20 Compound of Example 9-40 Compound of Example 10i > 40 (ORAL) Cimetidine 3.29 1.0 (1.05-5.19) Compound of Example 1 0.16 25 (0.10-0.22) (14-40) Compound of Example 9-20 *numbers in parentheses are 95% confidence limits Example 1 1-Amino-2- 3- (3-piperidinomethylphenoxy) propylaminoJcyclobutene-3, 4-dione A solution of 3- (3-piperidinomethylphenoxy) propylamine (from the dihydrochloride, 4.46 g; 13.9 mmoles) [prepared according to published U. K. Patent Application 2,023,133] in 40 mL of methanol was added all at once to a solution of 1, 2-dimethoxy-cyclobutene-3, 4-dione (1.97 g; 13.9 mmoles) in 40 mL of methanol that had been cooled to 5 in an ice-water bath. After 2 hours at ambient temperature, the solution was cooled to 5 and excess anhydrous ammonia was bubbled into the solution for 5 minutes. The mixture was stirred at ambient temperature for 18 hours and then filtered to give 4.35 g of product.
The product (4.20 g; 12.2 mmoles) was suspended in 40 mL of 95% aqueous ethanol and 6.11 mL (12.2 mmoles) of aqueous 2.0 N HCI was added with stirring. The solution was filtered through Celite, cooled at 0 for 17 hours, and then filtered to give 4.33 g of the title compound as its hydrochloride salt, mp 254-257 .
Anal. Calc'd. for C1gH26CIN303 ; C, 60.08; H, 6.90, N, 11.06; Cl, 9.33.
Found (corr. for 0.28% H20) : C, 59.73; H, 6.97; N, 11.14; CI, 9.36.
Example 2 1-Amino-2-t2- [65-dimethylaminomethyl-2-furylJmethylthiolethylaminolcyclobutene-3, 4dione A solution of 2- [ (5-dimethylaminomethyl-2-furyl) methylthio] ethylamine (2.89 g; 13.5 mmoles) [prepared according to the procedure described in Belgian Patent 857,388] in 30 mL of methanol was added dropwise over a period of 30 minutes to a cold (5 ) stirred solution of 1, 2-dimethoxycyclobutene-3, 4-dione (1.92 g; 13.5 mmoles) in 50 mL of methanol. After 3 hours at ambient temperature, the solution was cooled to 5 and excess anhydrous ammonia was bubbled into the solution for 5 minutes. The mixture was stirred at ambient temperature for 18 hours and then filtered to give 2.48 g of the title compound, mp 227-230 (dec.).
An analytical sample was prepared by recrystallization from 95% aqueous ethanol and then from methanol, and was dried in vacuo over PZOS for 18 hours to give the title compound as a non-friable sticky solid ; the NMR spectrum (100 MHz) in d6 dimethylsulfoxide showed the presence of approximately 0.2 moles of methanol.
AnaL Calc'd. for C14H1gN303S-0. 2 CH40 : C, 54. 01; H, 6.32; N, 13.31; S, 10.15.
Found (corr. for0. 54% H2O) : C, 53.72; H, 6.07; N, 14.01; S, 10.51.
Example 3 1-Amino-2-X2- [{5-dimethylam nomethyl-2-thienyl) methylthiolethylaminolcyclobutene-3, 4dione A solution of 2- [ (5-dimethylaminomethyl-2-thienyl) methylthio] ethylamine (2.06 g; 8.94 mmoles) [prepared according to the procedure described in Belgian Patent 867,105] in 20 mL of methanol was added all at once to a cold (5 ) solution of 1, 2-dimethoxycyclobutene-3, 4-dione (1.27 g; 8.94 mmoles) in 20 mL of methanol.
After 3.5 hours at ambient temperature, the solution was cooled to 5 and excess anhydrous ammonia was bubbled into the solution for 5 minutes. The mixture was stirred for 18 hours at ambient temperature and then filtered to give 2.66 g of product. Recrystallization from 95% aqueous ethanol yielded the title compound, mp 240-243 (dec.).
AnaL Calc'd. for C14Hl9N302S2 : C, 51.67; H, 5.88; N, 12.91; S, 19.70.
Found: C, 51.60; H, 5.76; N, 12.97; S, 19.69.
Example 4 2-I2-5-Dimeth ylaminomethyl-2-furylJmethylthiolethylamino-1-methylaminocyclobutene-3, 4-dione A solution of 2- [ (5-dimethylaminomethyl-2-furyl) methylthio] ethylamine (2.89 g; 13.5 mmoles) in 30 mL of methanol was added all at once to a cold (5 ) solution of 1,2-dimethoxy-cyclobutene-3,4-dione (1.92 g; 13.5 mmoles) in 50 mL of methanol. After 3 hours at ambient temperature, the solution was cooled to 5 and excess anhydrous methylamine was bubbled into the solution for 5 minutes. The mixture was stirred for 18 hours at ambient temperature, evaporated under reduced pressure and then triturated with acetonitrile and filtered to give 2.9 g of crude product. The product was placed on 40 g of silica gel (230-400 mesh) and chromatographed by flash chromatography using a gradient elution of methanol-acetonitrile. The appropriate fractions were evaporated, then combined in methanol, treated with charcoal, filtered and evaporated to near dryness. The solid was triturated with acetonitrile and filtered to give the title compound, m. p. 176-177.5 .
Anal Calc'd for C, 5H21 N303S : C, 55.71; H, 6.54; N, 12.99; S, 9.91 Found (corr. for 1.86% H20) : C, 55.46; H, 6.39; N, 13.14; S, 10.30 Example 5 2-12- (5-Dimefh ylaminomethyl-2-thienylJmethylthiolethylamino -1-methylaminocyclobutene-3, 4-dione A solution of 2- [ (5-dimethylaminomethyl-2-thienyl) methylthio] ethylamine (1.32 g; 5.73 mmoles) in 20 mL of methanol was added to a cold (5 ) solution of 1, 2-dimethoxycyclobutene-3, 4-dione (814 mg; 5.73 mmoles) in 15 mL of methanol. After 3. 5 hours at ambient temperature, the solution was cooled to 5 and excess anhydrous methylamine was bubbled into the solution for 5 minutes. The mixture was stirred for 70 hours at ambient temperature and then filtered to give 1.38 g of product. Recrystallization from ethanol yielded the title compound, m. p. 185-187 .
Anal. Calc'd for C15H21N302S2 : C, 53.07; H, 6.23; N, 12.38; S, 18.89 Found: C, 53. 18; H, 6.21; N, 12.25; S, 18.94 Example 6 l-Amino-2-t2- [{5-dimethylaminomethyl-4-methyl-2-thienyl) methylthiolethylaminolcyclobutene-3, 4dione A mixture of 2- [ (5-dimethylaminomethyl-4-methyl-2-thienyl) methylthio] ethylamine (3.0 g; 12.3 mmoles) [prepared according to the procedure described in published United Kingdom Patent Application 2,063,875] and 1-amino-2-methoxycyclobutene-3, 4-dione (1.56 g; 12.3 mmoles) in 50 mL of methanol was stirred at ambient temperature for 18 hours and then filtered to give 3.72 g of product. Recrystallization from 95% aqueous ethanol gave 3.1 g of the title compound.
The product (3.1 g; 9.13 mmoles) was suspended in 40 mL of methanol and 1.52 mL of aqueous 6. ON HCI was added with stirring. The mixture was filtered and the solid was recrystallized from aqueous methanol to give the title compound as its hydrochloride salt, m. p. 202-205 .
Anal. Calc'd for C15H21 N302S2HCI : C, 47.93; H, 5.90; N, 11.18; S, 17.06; CI, 9.43 Found (corr. for 0.38% H2O) : C, 47.74; H, 5.79; N, 11.41; S, 17.21; Cl, 9.42 Example 7 l-Amino-2-02- [{5-piperidinomethyl-4methyl-2-thienyl) methylthiolethylaminotcyclobutene-3, 4dione The general procedure of Example 6 was repeated exceptthatthe 2- [ (5-dimethylaminomethyl-4-methyl-2- thienyl) methylthio] ethylamine utilized therein was replaced by an equimolar amount of 2- [ (5- piperidinomethyl-4-methyl-2-thienyl) methylthio] ethylamine [prepared according to the procedure described in published United Kingdom Patent Application 2,063,875]. The product (3.64 g; 9.6 mmoles) was suspended in 50 mL of ethanol and 4.8 mL of aqueous 2. ON HCI was added with stirring. The mixture was filtered and the solid was recrystallized from aqueous ethanol to give the title compound as its hydrochloride salt, m. p. 150-157 .
Anal. Calc'dforC13H25N303S2HCI : C, 51.97; H, 6.30; N, 10.10; S, 15.41; CI, 8.52 Found (corr. for 1.58% H20) : C, 52.05; H, 6.33; N, 10.37; S, 15.24; Cl, 8.16 Example 8 1-Amino-2- [3-83-piperidinomethylphenoxy) propylaminolcyclobutene 3, 4dione A solution of 3- (3-piperidinomethylphenoxy) propylamine (from the dihydrochloride, 43.37 g; 0.135 moles) in 250 mL of methanol was added to a suspension of 1-amino-2-methoxycyclobutene-3, 4-dione (17.16 g; 0.135 moles) in 350 mL of methanol and stirred at ambient temperature. After 22 hours, the mixture was filtered to give 38.0 g of product.
The product (38.0 g ; 0.111 moles) was suspended in 375 mL of aqueous 95% ethanol and 55.3 mL of aqueous 2. ON HCI was added with stirring. The mixture was filtered to give 40.5 g of the title compound as its hydrochloride salt, which is identical to the product prepared in Example 1.
The product was further purified by dissolving in 30% aqueous ethanol then filtered through a pad of silica gel and carbon, evaporated and the solid recrystallized from aqueous ethanol to yield a colorless hydrochloride salt of the title compound, m. p. 257-259 .
Anal. Calc'd for C19H25N303HCI : C, 60.08; H, 6.90; N, 11.06; Cl, 9.33' Found: C, 59.82; H, 7.10; N, 10.87; Cl, 9.47 Example 9 1-Amino-2- (3- (3-dimethylaminomethylphenoxy) propylaminoJcyclobutene-3, 4-dione A mixture of 3- (3-dimethylaminomethylphenoxy) propylamine (1.41 g ; 6.77 mmoles) [prepared according to the procedure described in Belgian Patent 867,106] and 1-amino-2-methoxy-cyclobutene-3, 4-dione (0.86 g ; 6.77 mmoles) in 40 mL of methanol was stirred at ambient temperature for 20 hours and then filtered to give 1.95 g of the title compound.
The product (1.95 g ; 6.43 mmoles) was suspended in 35 mL of ethanol and 3.21 mL of 2. ON aqueous HCI was added with stirring. The mixture was filtered and the solid was recrystallized from aqueous ethanol to give the hydrochloride salt of the title compound, m. p. 205-207 .
AnaL Calc'dforC, 6H21N303HCI : C, 56.55; H, 6.52; N, 12.37 ; Cl, 10.43 Found: C, 56.25; H, 6.56; N, 12.36; Cl, 10.27 Example 10 The general procedure of Example 9 is repeated, except that the 3- (3-dimethylaminomethylphenoxy) propylamine utilized therein is replaced by an equimolar amount of (a) 3- (3-pyrrolidinomethylphenoxy) propylamine.
(b) 3- [3- (2-methylpyrrolidino) methylphenoxy] propylamine, (c) 3- [3- (3-methylpyrrolidino) methyl phenoxy] propylamine, (d) 3- [3- (4-methylpiperidino) methylphenoxy] propylamine, (e) 3- (3-morpholinomethylphenoxy) propylamine, (f) 3- [3- (4-hydroxypiperidino) methylphenoxy] propylamine, (g) 3- [3- (N-methylpiperazino) methylphenoxy] propylamine, (h) 3- [3- (1, 2,3,6-tetrahydro-1-pyridyl) methy) phenoxyipropy) amine, (i) 3- (3-hexamethyleneiminomethylphenoxy) propylamine, (j) 3- (3-heptamethyleneiminomethylphenoxy) propylamine, (k) 4- (3-piperidinomethylphenoxy) butylamine, (I) 5- (3-piperidinomethylphenoxy) pentylamine, (m) 3- (3-octamethyleneiminomethylphenoxy) propylamine, (n) 3- [3- (3-azabicyclo [3.2.2] non-3-yl) methylphenoxy] propylamine and (o) 3- [3- (3-pyrrolino) methylphenoxy) propylamine, respectively, and there is thereby produced (a) 1-amino-2- [3- (3-pyrrolidinomethylphenoxy) propylamino] cyclobutene-3, 4-dione as its hydrochloride salt, m. p. 192.5-195 .
Anal. Calc'd for C18H23N303HCi : C, 59.10; H, 6.61; N, 11.49; Cl, 9.69 Found (corr. for 0. 55% H2O) : C, 58.92; H, 6.73; N, 11.61; Cl, 9.41 (b) 1-amino-2-3- [3- (2-methyl pyrrolidino) methylphenoxy] propylaminocyclobutene-3, 4-dione as its hydrochloride salt, m. p. 210-212 .
Anal. Calc'd for C19H25N303HCI : C, 60.08; H, 6.90; N, 11.06; Cl, 9,33 Found: C, 59.97; H, 6.92; N, 10.88; Cl, 9.46 (c) 1-amino-2- (3- [3- (3-methylpyrrolidino) methylphenoxy] propylamino-cyclobutene-3, 4-dione as its hydrochloride salt, m. p. 184.5-187 .
Anal. Calc'd for C19H25N303HCI : C, 60.08; H, 6.90; N, 11.06 Cl, 9.33 Found (corr. for 0.26% H20) : C, 60.43; H, 7.02; N, 11.03; Cl, 9.31 (d) 1-amino-2-3- [3- (4-methylpiperidino) methylphenoxy] propylaminocyclobutene-3, 4-dione, (e) 1-amino-2- [3- (3-morpholinomethylphenoxy) propylamino] cyclobutene-3, 4-dione.
(f) 1-amino-2- 3- [3- (4-hydroxypiperidino) methylphenoxy] propylamino} cyclobutene-3, 4-dione, (g) 1-amino-2-13- [3- (N-methylpiperazino) methylphenoxy] propylaminolcyclobutene-3, 4-dione, (h) 1-amino-2- ; 3- [3- (1, 2,3,6-tetrahydro-1-pyridyl) methyl phenoxy] propylaminoEcyclobutene-3, 4-dione, m. p.
213-215 (dec.), (i) 1-amino-2- [3- (3-hexamethyleneiminomethylphenoxy) propylamino] cyclobutene-3, 4-dione as its hydrochloride salt, m. p. 200-202 .
Anal. Caic'd for C2oH27N303HCI : C, 60.98; H, 7.16; N, 10.67; Cl, 9.00 Found (corr. for 0. 28% H20) : C, 61.25; H, 7.14; N, 10.55; Cl, 8.61 (j) 1-amino-2- [3- (3-heptamethyleneiminomethylphenoxy) propylamino] cyclobutene-3, 4-dione, m. p. undefined, gradual decomposition-200-240 .
Anal. Calc'd for C21 H29N303 : C, 67.90; H, 7.87; N, 11.31 Found: C, 66.44; H, 7.74; N, 11.33 (k) 1-amino-2- [4- (3-piperidinomethylphenoxy) butylamino] cyclobutene-3, 4-dione, (I) 1-amino-2- [5- (3-piperidinomethylphenoxy) pentylamino] cyclobutene-3, 4-dione, (m) 1-amino-2- [3- (3-octamethyleneiminomethylphenoxy) propylamino] cyclobutene-3, 4-dione, m. p. undefined.
Anal. Calc'd for C22H31N3C3 : C, 68.54; H, 8.11; N, 10.90 Found: C, 68.42; H, 8.42; N, 11.10 (n) 1-amino-2- ; 3- [3- (3-azabicyclo [3.2.2] non-3-yl) methylphenoxy] propylaminoncyclobutene-3, 4-dione as its hydrochloride salt, m. p. 162-164 and (o) 1-amino-2- ; 3- [3- (3-pyrrolino) methylphenoxy] propylaminolcyclobutene-3, 4-dione, respectively.
Example 11 1-Methylamino-2- [3- (3-piperidinomethylphenoxy) propylamino] cyclobutene-3, 4-dione A solution of 3- (3-piperidinomethylphenoxy) propylamine (from the dihydrochloride, 3.21 g ; 10.0 mmoles) in 40 mL of methanol was added to a solution of 1, 2-dimethoxycyclobutene-3, 4-dione (1.42 g; 10.0 mmoles) in 40 mL of methanol. After 1 hour at 10 and 30 minutes at ambient temperature, the solution was cooled to 5 and excess anhydrous methylamine was bubbled into the solution for 5 minutes. The mixture was stirred for 17 hours at ambient temperature and then filtered to give 2.77 9 of product.
The product (2.77 g) was suspended in 40 mL of ethanol and 4.07 mL (8.1 mmoles) of aqueous 2N HCI was added with stirring to yield the hydrochloride salt of the title compound, m. p. 194-198 .
Anal. Calc'd for C2oH27N303-HCI : C, 60.99; H, 7.16; N, 10.67 Found (corr. for 1.35% H2O) : C, 60.63; H, 6.96; N, 10.71 Example 12 2- propylamino] 3-pyridyl, methylaminocyclobutene-3, 4dione The general procedure of Example 11 was repeated, except that the methylamine utilized therein was replaced by 1.08 g (10.0 mmoles) of 3-aminomethylpyridine. The crude product was placed on 65 g of silica gel (230-400 mesh) and chromatographed by flash chromatography using a gradient elution of methanol-methylene chloride containing 1 % NH40H. The appropriate fractions were combined, evaporated and the solid residue recrystallized from methanol to give the title compound, m. p. 174-178.5 .
Anal. Calc'dforC25H30N403 : C, 69.10; H, 6.96; N, 12.89 Found (corr. for 0-52% H2O) : C, 68.80; H, 7.03; N, 12.74 Example 13 2-3- (3-PiperidinomethylphenoxyJpropylaminoJ 1-propylaminocyclobutene-3, 4-dione The general procedure of Examples 11 was repeated, except that the methylamine utilized therein was replaced by 4.0 mL (48.7 mmoles) of propylamine. The crude product was placed on 60 g of silica gel (230-400 mesh) and chromatographed by flash chromatography using a gradient elution of methanolmethylene chloride. The appropriate fractions were combined and the solid residue recrystallized from methanol to yield the title compound, m. p. 158-160 .
Anal. Caic'd for C22H31 N303 : C, 68.54; H, 8.11; N, 10.90 Found: C, 68.11; H, 8.25; N, 11.21 Example 74 The general procedure of Example 12 is repeated, except that the 3-aminomethylpyridine utilized therein is replaced by an excess molar amount of (a) ethylamine, (b) n-butylamine, (c) allylamine, (d) propargylamine, (e) benzylamine and (f)6-methyl-3-aminomethylpyridine, respectively, and there is thereby produced (a) 1-ethylamino-2- [3- (3-piperidinomethylphenoxy) propylamino] cyclobutene-3, 4-dione, (b) 1-butylamino-2- [3- (3-piperidinomethylphenoxy) propylamino] cyclobutene-3, 4-dione, (c) 1-allylamino-2- [3- 3-piperidinomethylphenoxy) propylamino] cyclobutene-3, 4-dione, m. p. 158-159.5 .
Anal. Calc'd for C22H29N303 : C, 68.90; H, 7.62; N, 10.96 Found: C, 68.81; H, 7.70; N, 10.72 (d) 2- [3- (3-piperidinomethylphenoxy) propylamino]-1- (2-propynylamino) cyclobutene-3, 4-dione, m. p. 158 160 .
Anal. Calc'd for C22H27N303 : C, 69.27; H, 7.13; N, 11. 02 Found: C, 69.26; H, 7.25; N, 10.78 (e) 1-benzylamino-2- [3- (3-piperidinomethylphenoxy) propylamino] cyclobutene-3, 4-dione hydrochloride, m. p. 136-140 .
Anal. Calc'd for C26H31N303HCI : C, 66.44; H, 6.86; N, 8.94; CI, 7.54 Found: C, 65.41; H, 7.08; N, 8.83; Cl, 7.67 and (f) 1- (6-methyl-3-pyridyl) methylamino-2- [3- (3-piperidinomethylphenoxy) propylamino] cyclobutene-3, 4dione, respectively.
Example 15 1-Amino-2-j3- (6-piperidinomethyl-2-pyridyloxy) propylaminojcyclobutene-3, 4-dione A. 2-Chloro-6-piperidinomethylpyridine To 2-chloro-6-methylpyridine (50.0 g, 0.392 mole) in 393 mL of carbon tetrachloride was added N-bromosuccinimide (87.2 g, 0.49 mole) and 1.0 g of benzoyl peroxide. The mixture was stirred at reflux for 22 hours, cooled to 10 and filtered. The chilled filtrate then was treated slowly with piperidine (83.5 g, 0.98 mole) and allowed to stir at ambient temperature for 18 hours. After removal of the piperidine hydrobromide by filtration, the filtrate was concentrated to about half volume and extracted with 6N HCI (65 mL) and 3N HCI (40 mL). The acid extracts were made basic with 40% sodium hydroxide and the product was extracted into methylene chloride. The solvent was evaporated and the residue distilled to yield 41 % of the title compound as a colorless oil, b. p. 101-103 /0. 45 mm Hg.
Anal. Calc'dforC11H15CIN2 : C, 62.71; H, 7.18; 13.29; Cl, 16.82 Found: C, 61.71; H, 7.31; 13. 63; Cl, 17.20 B. N-3- (6-Piperidinomethyl-2-pyridyloxyJpropyllformamide 3-Aminopropanol (12.84 g, 0.171 mole) was added to a suspension of 50% sodium hydride in mineral oil (7.96 g, 0.166 mole) in 180 mL of dry DMF and the mixture was warmed to 80-83 . A solution of 2-chloro-6-piperidinomethylpyridine (34.0 g, 0.161 mole) [prepared in Step A] in 180 mL of dry DMF was then added dropwise and when complete, the temperature was raised to 125-128 for 3 hours followed by 17 hours at ambient temperature. The precipitated salts were removed by filtration and the solvent stripped under vacuum. The oily residue was dissolved in methylene chloride, washed with water, dried and the solvent evaporated. This residue was redissolved in acetonitrile and extracted with skelly B. After removing the solvent the crude oil was purified by flash chromatography on 270 g of silica gel (230-400 mesh) using a gradient elution of methanol-methylene chloride and evaporated to give the title product as a yellow oil, 21.63 g (48.4%).
C. 3- (6-Piperidinomethyl-2-pyridyloxy) propylamine N- [3- (6-Piperidinomethyl-2-pyridyloxy) propyl] formamide (19.6 g, 70.7 mmoles) [prepared in Step B] was added to a solution of 85% potassium hydroxide pellets (18.63 g, 0. 332 mole) dissolved in 180 mL of methanol and the solution was heated at gentle reflux for 20 hours. The solvent was stripped in vacuum and the residue partially purified by redissolving in about 180 mL of 20% methanol-methylene chloride and passing through a pad of 38 g of silica gel. The silica was washed with an additional 120 mL of eluant and the combined filtrates were evaporated to an amber oil. Final purification was effected by flash chromatography on 120 g of silica gel (230-400 mesh) using a gradient elution of methanol-methylene chloride containing 0.5% NH40H. The title compound was obtained as a yellow oil in 63% yield.
D. 1-Amino-2- 3- (6-piperidinomethyl-2-pyridyloxy) propylaminolcyclobutene-3, 4-dione A mixture of 3- (6-piperidinomethyl-2-pyridyloxy) propylamine (2.5 g, 10 mmoles) [prepared in Step C] and 1-amino-2-methoxycyclobutene-3, 4-dione (1. 27g, 10 mmoles) in 35 mL of methanol was stirred at ambient temperature for 18 hours and filtered to give 2.71 g of product.
The product (2.71 g, 7.87 mmoles) was suspended in 35 mL of absolute ethanol and 7.87 mL of aqueous 6. ON HCI was added with stirring. After 64 hours at 0 the salt was collected by filtration and recrystallized from aqueous ethanol to give the hydrochloride salt of the title compound, m. p. 225-258 .
Anal. Calc'd for C18H24N403HCI : C, 56.77; H, 6.61; N, 14.71; Cl, 9.31 Found: C, 56.71; H, 6.80; N, 14.41; Cl, 9.98 Example 16 1-Amino-2- (3- (6-dimethylaminomethyl-2-pyridyloxy) propylaminolcyclobutene-3, 4-dione The general procedure of Example 15 was repeated, except that the piperidine utilized in Step A was replaced with an excess of anhydrous dimethylamine. The product (2.26 g, 7.43 mmoles) was suspended in 40 mL of 95% ethanol and 7.43 mL of aqueous 2. ON HCI was added with stirring. After evaporating most of the solvent, the residue was triturated under isopropyl alcohol and recrystallized from aqueous ethanol to give the hydrochloride salt of the title compound, m. p. 230-234 (dec.).
Anal. Calc'dforC15H20N403HCI : C, 52.87; H, 6.21; N, 16.44; Cl, 10.40 Found: C, 51.52; H, 5.98; N, 16.64; Cl, 10.88 Example 17 1-Amino-2- [2- (3-piperidinomethylthiophenoxy) ethylaminolcyclobutene-3, 4-dione A. m-Dithiobenzoyl chloride A mixture of m-dithiobenzoic acid (20.8 g, 67.9 mmoles) [prepared according to the procedure described in J. Chem. Soc., London, 119, 1792 (1921)] and thionyl chloride (200 mL) was refluxed for four hours, filtered and the excess SOCI2 removed in vacuum.
B. Dithio bis-3, 3'-NN-di (piperidino) benzenecarboxamide The crude product from Step A, dissolved in 100 mL of tetrahydrofuran, was added dropwise at 3 to a solution of piperidine (25.1 g, 0.29 mole) in 500 mL of tetrahydrofuran. The mixture was stirred at ambient temperature for 76 hours and poured into 1500 mL of dilute HCI (ca. 2N). After one hour the product was extracted into ether and washed sequentially with water, aqueous 1 N NaOH and water. The solvent was evaporated to leave 26.4 g of the title compound.
C. 3- (Piperidinomethyl) thiophenol To a suspension of lithium aluminum hydride (45.3 g, 1. 19 moles) in 2200 mL of ether was added, dropwise under nitrogen, a solution of dithio bis-3, 3'-N, N-di) piperidino) benzenecarboxamide (141.5 g, 0.32 mole) [preferred in Step B] in 2200 mL of ether and the mixture was stirred at ambient temperature for 20 hours. The mixture was decomposed by the addition of saturated sodium sulfate solution and filtered. The filter cake was stirred with 3000 mL of water and a solution of citric acid monohydrate (550 g, 2.62 moles) in 550 mL of water was added. The pH of the solution was adjusted to about 2 with 12N HCI and then to pH 8 with concentrated ammonium hydroxide. The solution was exhaustively extracted with ether to yield 120 g of product.
An aliquot of the title compound was recrystallized from isopropyl alcohol, m. p. 121-123 ; Mass spectrum 206 M+).
Anal. Calc'dforCa2Ha7NS : C, 69.56; H, 8.21; N, 6.76; S, 15.46 Found: C, 69.02; H, 8.03; N, 6.67; S, 15.06 D. N-f2- 3- (Piperidinomethyl) thiophenoxyJefhylphthalimide A mixture of 3- (piperidinomethyl) thiophenol (2.07 g, 10 mmoles) [prepared in Step C] and N- (2- bromoethyl) phthalimide (2.41 g, 9.5 mmoles) in 10 mL of dry DMF was stirred at ambient temperature for 84 hours. The solvent was evaporated under reduced pressure and the crude oil was flask chromatographed on 100 g of silica gel (230-400 mesh) using 2.5% methanol in methylene chloride witn 0.2% NH40H as the eluant.
The appropriate fractions were combined and evaporated to give an oil that crystallized under ether.
Recrystallization from acetonitrile yielded 1.2 g of the hydrobromide salt of the title compound, m. p.
180-181.5 .
Anal. Calc'd for C22H24N202SHBr : C, 57.26; H, 5.46; N, 6.07; Br, 17.32; S, 6.95 Found: C, 56.98; H, 5.43; N, 6.30; Br, 17.51; S, 7.10 E. 2- (3-Piperidinomethylthiophenoxy) ethylamine Anhydrous hydrazine (1.79 g, 56.0 mmoles) was added to a suspension of N- ; 2- [3- (piperidinomethyl) thiophenoxy] ethyl,-phthalimide hydrobromide (5.17 g, 11.2 mmoles) [prepared in Step D] in 200 mL of 95% ethanol, stirred at ambient temperature for 18 hours and filtered. The filtrate was stripped and the semi-solid residue was stirred with several portions of ether. Evaporation of the solvent gave 2.8 g of title compound as a yellow oil.
F. 1-Amino-2- (2- (3-piperidinomethylthiophenoxy) ethylaminol-cyclobutene-3, 4dione The crude amine prepared in Step E (1.4 g, 4.05 mmoles) in 40 mL of methanol was added to a suspension of 1-amino-2-methoxycyclobutene-3, 4-dione (0.515 g, 4.05 mmoles) in 100 mL of methanol. The mixture was stirred for 20 hours at ambient temperature and then filtered to give 0.8136 g of product. A second crop was obtained from the concentrated mother liquor and the combined lots were recrystallized from methanol to yield 0.786 g (56%) of the title compound, m. p. 228-230 (dec.).
Anal. Calc'dforC18H23N302S : C, 62.58; H, 6.71; N, 12. 16 ; S, 9.28 Found: C, 62.17; H, 6.36; N, 12.59; S, 9.60 Exa/np/e/5 1-Amino-2- 3- (3-piperidinomethylthiophenoxy) propylaminoJcyclobutene-3, 4-dione A. N-3- {3-{Piperidinomethyl) thiophenoxylpropyliphthatimide The general procedure of Example 17, Step D, was repeated, exceptthe N- (2-bromoethyl) phthalimide utilized therein was replaced with an equimolar amount of N- (3-bromopropyl) phthalimide. The chromatographed product was recrystallized from isopropyl alcohol to give the title compound as its hydrobromide salt, m. p. 188-192 .
Anal Calc'dforC23H26N202SHBr : C, 58.10; H, 5.72; N, 5.89; Br, 16.81 Found: C, 57.79; H, 5.41; N, 5.73; Br, 16.80 B. 3- (3-Piperidinomethylthiophenoxy) propylamine To a solution of N- 3- [3- (piperidinomethyl) thiophenoxy]-propyllphthalimide hydrobromide (58.0 g, 0.12 mole) [prepared in Step A] in 1650 mL of 95% ethanol was added hydrazine hydrate (26.9 g, 0.54 mole) and the reaction mixture was heated at 45 for 4.5 hours. The mixture was diluted with 500 mL of ether, filtered and the filtrate evaporated to dryness to give the title compound as an amber oil (14.1 g). An aliquot was distilled to a colorless oil, b. p. 154-155 /0. 15 mm Hg.
Anal. Calc'd for C, 5H24N2S : C, 68.13; H, 9.15; N, 10.59 Found: C, 67.37; H, 9.07; N, 10.94 C. 1-Amino-2- (3- (3-piperidinomethylthiophenoxy) propylaminoJcyclobutene-3, 4-dione 1-Amino-2-methoxycyclobutene-3, 4-dione (1.20 g, 9.5 mmoles) was added to a solution of the crude amine prepared in Step B (2.50 g, 9.5 mmoles) in 75 mL of methanol and the mixture was stirred at ambient temperature for 16 hours. The precipitate was filtered to give 2.82 g of crude product.
The crude solid (2.82 g, 7.84 mmoles) was suspended in 30 mL of 95% ethanol and 4.0 mL of aqueous 2. ON HCI was added with stirring. After ca. 15 minutes 40 mL of acetone was added and the mixture stored at ambient temperature for 16 hours. The precipitate was recrystallized from aqueous ethanol to yield 1.64 g of the hydrochloride salt of the title compound, m. p. 236-237.5 .
Anal. Calc'd for C19H25N303S-HCI : C, 57.64; H, 6.62; N, 10.61; S, 8.10 ; Cl, 8.95 Found: C, 57.72; H, 6.56; N, 10.66; S, 8.49; Cl, 8.88 Example 19 1-Amino-2-2- ( (5-dimethylaminomefhyl-3-thienyl) methylthioJethylaminolcyclobutene-3, 4-dione A mixture of 2- [ (5-dimethylaminomethyl-3-thienyl) methylthio] ethylamine (2.11 g, 8.68 mmoles) [prepared according to the procedure described in published European Patent Application 27,744] and 1-amino-2- methoxycyclobutene-3, 4-dione (1.10 g, 8.68 mmoles) in methanol was stirred at ambient temperature for 18 hours and filtered. The crude product was recrystallized from 2-methoxyethanol to yield 1. 30 g of the title compound as a colorless solid, m. p. 234-236 .
AnaL Caic'd for C14Hl9N302S2 : C, 51.66; H, 5.88; N, 12.91; S, 19.71 Found: C, 51.53; H, 5.64; N, 12.62; S, 19.91 Example 20 1-Amino-2-12- methylthiolethylaminolcyclobutene-3, 4-dione The general procedure of Example 19 was repeated except that the 2- [ (5-dimethylaminomethyl-3- thienyl) methylthio] ethylamine utilized therein was replaced by an equimolar amount of 2- [ (5- piperidinomethyl-3-thienyl) methylthio] ethylamine [prepared according to the procedure described in published European Patent Application 27,744]. The crude solid was recrystallized from 2-methoxyethanol to give the title compound (1.27 g), m. p. 236-238 .
Anal. Calc'd for C17H23N302S2 : C, 55.86; H, 6.34; N, 11.50; S, 17.54 Found: C, 55.59; H, 6.23; N, 11.75; S, 17.62 Example 21 1-Amino-2- (3- (5-dimethylaminomethyl-3-thienyloxy) propylaminoJcyclobutene-3, 4-dione An equimolar mixture of4- [3- (amino) propoxy]-N, N-dimethyl-2-thiophenemethanamine [prepared according to the procedure described in published European Patent Application 27,744] and 1-amino-2 methoxycyclobutene-3, 4-dione is reacted according to the general procedure of Example 19 to yield the title compound.

Claims (16)

1. A compound of the formula
ici wherein R12 is a conventional leaving group selected from halogen, phenoxy, substituted phenoxy and alkoxy ; m is an integer of from 0 to 2 inclusive ; n is an integer of from 2 to 5 inclusive ; Z is sulfur, oxygen or methylene ; and Ais
in which R6 is hydrogen, (lower) aikyl, (lower) alkoxy or halogen ; r is an integer of from 1 to 4 inclusive; and R8 and R9 each are independently hydrogen, (lower) alkyl, allyl, propargyl, (lower) alkoxy (lower) alkyl in which the (lower) alkoxy moiety is at leasttwo carbon atoms removed from the nitrogen atom, cyclo (lower) alkyl, or phenyl (lower) alkyl, provided that RI and R9 may not both be cyclo (lower) alkyl, or R9 and R9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, 3-pyrrolino, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo [3.2.2] nonane.
2. A compound of Claim 1 having the formula
wherein R12 is a conventional leaving group selected from halogen, phenoxy, substituted phenoxy and (lower) alkoxy ; m is an integer of from 0 to 2 inclusive; n is an integer of from 2 to 5 inclusive ; Z is sulfur, oxygen or methylene ; R6 is hydrogen or (lower) alkyl ; r is an integer of from 1 to 4 inclusive; and R and R9 each are independently hydrogen or (lower) alkyl, or RI and R9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, hep tamethyleneimino, octamethyleneimino or 3-azabicyclo [3.2.2] nonane.
3. A compound of Claim 1 having the formula
wherein R12 is a conventional leaving group selected from halogen, phenoxy, substituted phenoxy and (lower) alkoxy ; m is an integer of from 0 to 2 inclusive; n is an integer of from 2 to 5 inclusive ; Z is sulfur, oxygen or methylene ; R6 is hydrogen or (lower) alkyl ; r is an integer of from 1 to 4 inclusive; and R8 and R9 each are independently hydrogen or (lower) alkyl, or R8 and R9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo [3.2.2] nonane.
4. A compound of Claim 1 having the formula
wherein R12 is a conventional leaving group selected from halogen, phenoxy, substituted phenoxy and (lower) alkoxy ; m is an integer of from 0 to 2 inclusive; n is an integer of from 2 to 5 inclusive; Z is sulfur, oxygen or methylene ; R6 is hydrogen or (lower) alkyl ; r is an integer of from 1 to 4 inclusive ; and R8 and R9 each are independently hydrogen or (lower) alkyl, or RI and R9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino or 3-azabicyclo [3.2.2] nonane.
5. A compound of Claim 1 having the formula
wherein R12 is a conventional leaving group selected from halogen, phenoxy, substituted phenoxy and (lower) alkoxy ; m is an integer of from 0 to 2 inclusive; n is an integer of from 2 to 5 inclusive; Z is sulfur, oxygen or methylene ; R6 is hydrogen or (lower) alkyl ; r is an integer of from 1 to 4 inclusive ; and R8 and R9 each are independently hydrogen or (lower) alkyl ; or R'and R9, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, hep tamethyleneimino, octamethyleneimino or 3-azabicyclo [3.2.2] nonane.
6.1-Methoxy-2- [3- (3-piperidinomethylphenoxy) propylamino]-cyclobutene-3,4-dione.
7.1-Methoxy-2-f2-[(5-dimethylaminomethyl-2-furyl) methylthio] ethylaminoTcyclobutene-3, 4-dione.
8.1-Methoxy-2-l2-[(5-dimethylami nomethyl-3-thienyl) methylthio] ethylamino, cyclobutene-3,4-dione.
9.1-Methoxy-2-t2-[(5-piperidinomethyl-3-thienyl) methylthio] ethylaminolcyclobutene-3,4-dione.
10.1-Methoxy-2- [3- (3-dimethylaminomethylphenoxy) propylamino] cyclobutene-3, 4-dione.
11.1-Methoxy-2- [3- (3-pyrrolidinomethylphenoxy) propylamino] cyclobutene-3, 4-dione.
12.1-Methoxy-2- 3- [3- (3-methylpyrrolidino) methyl phenoxy]-propylaminolcyclobutene-3, 4-dione.
13.1-Methoxy-2- [3- (3-hexamethyleneiminomethylphenoxy) propylamino] cyclobutene-3, 4-dione.
14.1-Methoxy-2- [3- (3-piperidinomethylthiophenoxy) propylamino] cyclobutene-3,4-dione.
15.1-Methoxy-2- [3- (3-heptamethyleneiminomethylphenoxy) propylamino] cyclobutene-3,4-dione.
16.1-Methoxy-2- [3- (3-octamethyleneiminomethylphenoxy) propylamino] cyclobutene-3, 4-dione.
GB08429389A 1981-05-18 1984-11-21 Chemical intermediates derived from cyclobutene Expired GB2147899B (en)

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GB08429389A GB2147899B (en) 1981-05-18 1984-11-21 Chemical intermediates derived from cyclobutene
CY144889A CY1448A (en) 1981-05-18 1989-03-10 Chemical intermediates derived from cyclobutene

Applications Claiming Priority (3)

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US06/264,533 US4390701A (en) 1981-05-18 1981-05-18 1-Amino-2-[3-(3-piperidinomethylphenoxy)propylamino]cyclobutene-3,4-dione
GB8214351A GB2098988B (en) 1981-05-18 1982-05-17 1,2-diamino-cyclobutene-3,4-dione derivatives
GB08429389A GB2147899B (en) 1981-05-18 1984-11-21 Chemical intermediates derived from cyclobutene

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GB8429389D0 GB8429389D0 (en) 1985-01-03
GB2147899A true GB2147899A (en) 1985-05-22
GB2147899B GB2147899B (en) 1985-11-06

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GB2147899B (en) 1985-11-06
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