IE55560B1 - Substituted diamino thiadiazole intermediates - Google Patents

Description

2 5 5 5 6 0 The present Application has been divided out of our Patent Specification No. 5^5% referred to below as our “primary" Application).

As disclosed in our primary Application, certain 5 3-(amino or substituted amino)-4-(substituted amino)- 1,2,5-thiadiazoles having the formula wherein A, m, Z, n and are as defined below, and their nontoxic pharmaceutically acceptable salts, 10 hydrates and solvates, are potent histamine H2-receptor antagonists which inhibit gastric acid secretion and are useful in the treatment of peptic ulcers and other pathological hypersecretory conditions. The compounds are prepared by ring closure of the correspondingly 15 substituted ethanediimidamide of the formula A- (CH-) Z(CH,) NH-C-C-NHR1 2 .m 2 n /y ^ I1N NH II 3 Our published United Kingdom Patent Application No. 2,067,987 discloses 3,4-disubstituted-1,2,5-thiadiazole 1-oxides and 1,1-dioxides having the formula and processes for their preparation, wherein the variables A, m, z, n and R^ are similar to the corresponding substituents of the compounds disclosed and claimed herein. However, the compounds disclosed therein are 1-oxides or 1,1-dioxides (p is 1 or 2), and the compounds of the present invention cannot be prepared by any of the processes described therein for the preparation of the prior art compounds.

Published European Patent Application No. 0,040,696 discloses inter alia 3,4-disubstituted-l,2,5-thiadiazole 1-oxides and 1,1-dioxides having the formula z*1 R-®- and processes for their preparation, wherein the variables R, ¢), η, X, m, R and R are similar to the corresponding substituents of the compounds disclosed and claimed herein. However, the compounds disclosed therein also are 1-oxides or 1,1-dioxides (p .is 1 or 2) and the compounds of the present invention cannot be prepared by any of the processes described therein for the preparation of the prior art compounds. 4 In the two publications cited above, each o£ the processes described for preparation o£ the prior art compounds involves the use (as a starting material or intermediate) of a 1,2,5-thiadiazole 1-oxide or 1,1-dioxide having either amino 5 groups or suitable "leaving groups" on the 3- and 4-positions. The desired substituents on the 3- and 4-positions are then obtained by substitution on the amino groups or by replacement of the "leaving groups”. We have made extensive attempts to prepare the compounds of the present invention by similar 10 procedures, i.e. by utilizing 1,2,5-thiadiazole having amino groups or suitable "leaving groups" on the 3- and 4-positions as starting materials or intermediates. Although numerous variations were tried, along with varying reaction conditions, we were not able to isolate the compounds of this invention 15 by that route.

The subject matter of the present invention comprises primarily the above-mentioned substituted ethanediimidamides of the formula HN II and salts, hydrates and solvates thereof.

In formulae I and II, the symbols A, m, Z, n and R1 have the following meanings: R1 is hydrogen, (lower) alkyl, 2-fluoroethyl, 2,2,2-trifluoro-ethyl, allyl, propargyl, 5 in which p is 1 or 2, R2 and R3 each are independently hydrogen, (lower)alkyl, (lower)alkoxy or halogen, and, when 2 3 2 3 R is hydrogen, R also may be trifluoromethyl, or R and R , 4 5 taken together, may be methylenedioxy, and R is hydrogen, (lower)alkyl o.r (lower)alkoxy; m is an integer of from 0 to 2 inclusive; n is an integer of from 2 to 5 inclusive; Z is oxygen, sulfur or methylene; and 10 A is in which R5 is hydrogen, (lower)alkyl or (lower)alkoxy, q is an integer of from 1 to 4 inclusive and R® and R7 each are 15 independently (lower)alkyl, (lower)alkoxy (lower)alkyl in which the (lower) alkoxy moiety is at least two carbon atoms removed from the nitrogen atom, or phenyl (lower)alkyl, and, when R6 is hydrogen, R7 also may be cyclo(lower)alkyl, or R6 and R7, taken together with the nitrogen atom to which they are 20 attached, may be pyrrolidino, methylpyrrolidino, dimethyl-pyrrolidino, morpholino, thiomorpholino, piperidino, methyl-piperidino, diroethylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octa-methyleneinino, 3-azabicyclot3.2.23non-3-yl or 3-pyrrolino. 6 This invention also relates to processes for the preparation of the intermediate compounds of Formula II.

The present invention includes within its scope all possible tautomeric forms, di&stereoisomeric forms and optically 5 active isomers of the compounds of Formula I as well as mixtures thereof. As used herein and in the claims, the term "(lowerj-alkyl" means a straight or branched chain alkyl group containing from 1 to 6 carbon atoms. The term " (lower)alkoxy" means a straight or branched chain alkoxy group containing from 1 to 4 10 carbon atoms. "Cyclo(lower) alkyl" means a cycloalkyl group containing from 3 to 6 carbon atoms. The term "nontoxic pharmaceutically acceptable salts" means acid addition salts formed with acids such as, for example, hydrochloric, hydrohromic, nitric, sulfuric, acetic, propionic, fumaric, methanesulfonic, maleic, 15 tartaric, citric, levulinic, benzoic and succinic.

The intermediates of Formula II may be prepared by various procedures. In one procedure, the corresponding 7 3-(amino or substituted amino)-4-(substituted amino)-1,2,5-thiadia2ole l^oxide of Formula III is treated with a strong mineral acid (preferably HC1) to produce the compound of Formula IX. 7 5 III HC1 Ψ II The reaction may be conducted in an inert solvent and preferably is conducted in methanol. Reaction temperature is not critical; it most conveniently is conducted at room temperature. The compounds of Formula III are known or may readily be prepared by the 10 procedures described in our Patent Specification No. 50997.

In an alternate procedure, the compounds of Formula II may be prepared by the following reaction scheme. The A-(CH2)ra2(CH2)nNH2 + V IV V Ill A“ lCH25 ra2 {CH2) nNH\ yHHR1 reaction nay be conducted in an inert solvent and preferably is conducted in methanol. The starting materials of formula IV are known or may be readily prepared by known procedures, e.g. as by procedures described in our Patent Specification No. 50997.

Broadly, as already implied, this invention is directed to novel intermediates of the formula A- (CH2)nZ (CH2)nNH. _ khr1 J~% 11 wherein R1 is hydrogen, (lower)alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, allyl, propargyl, 2 3 in which p is 1 or 2, R and R each are independently hydrogen, (lower)alkyl, (lower)alkoxy or halogen, and, when 9 2 3 ’3 R is hydrogen, R also may be trifluoromethyl, or R“ and R , A taken together, may be methylenedioxy, and R is hydrogen, (lower)alkyl or (lower)alkoxy; m is an integer of from 0 to 2 inclusive; 5 n is an integer of from 2 to 5 inclusive; Z is oxygen, sulfur or methylene; and Λ is in which R is hydrogen, (lower)alkyl or (lower)alkoxy, q is 10 an integer of from 1 to 4 inclusive and R® and V? each are independently (lower)alkyl, (lower)alkoxy(lower)alkyl in which the (lower)alkoxy moibty is at least two carbon atoms removed from the nitrogen atom, or phenyl (lower)alkyl, and, when R® 7 6 7 is hydrogen, R also may be cyclo(lower)alkyl, or R and R , 15 taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethyl- pyrrolidino, roorpholino, thiomorpholino, piperidino, methyl- piperidino, dimethylpiperidino, N-methylpiperazino, 1,2,3,6- tetrahydropyridyl, homopiperidino, heptamethyleneimino, octa- 2o methyleneimino , 3-azabicyclo[3.2.2]non-3-yl or 3-pyrrolino? and salts, hydrates and solvates thereof.

In a preferred embodiment, the intermediates of Formula II have the structure NHR // w iN NH II wherein R^ is hydrogen or (lower)alkyl, m is 0 or 1, n is 2 or 3, Z is oxygen or sulfur and λ is in which !R5 is hydrogen or methyl, and R® and R7 each are 5 independently methyl or ethyl, or when taken together with the nitrogen to which they are attached, R® and R7 represent a pyrrolidino or piperidino ring; or a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof.

In another preferred embodiment, the intermediates 10 of Formula IX have the structure wherein R* is hydrogen or methyl, and R® and R7 each are methyl or, when taken together with the nitrogen atom to which they are attached, R® and R7 represent a pyrrolidino or piperidino -15 ring·; or a salt, hydrate or solvate thereof.

In another preferred embodiment, the intermediates of Formula XX have the structure 11 wherein R7- and R® each are independently hydrogen or methyl', and R® and R7 each are independently methyl or ethyl? or a salt, hydrate or solvate thereof.

In another preferred embodiment, the intermediates of Formula II have the structure HN NH wherein R7, and R1 2 3 4 5 each are independently hydrogen or methyl, and R6 and R7 each are independently methyl or ethyl? or a salt, 10 hydrate or solvate thereof.

In another preferred embodiment, the intermediates of Formula II have the structure 5 2 wherein R and R each are independently hydrogen or methyl, and 3 R6 and R7 each are independently methyl or ethyl, or, when taken 4 together with the nitrogen to which they are attached, R6 and R7 5 represent piperidino? or a salt, hydrate or solvate thereof. 12 As presently envisaged, the most preferred intermediates of Formula XI are 1) N-13-(3-plperidinomethylphenoxy)propyl]ethane-diimidamide, 5 2) N-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]- ethyUethanediimidaraide, 3) N-{2-t(5-dimethylaminomethyl-4-methyl-2-thienyl)-methylthio] ethyl Jethanediimidamide, 4) U-[3-(3-pyrrolidinomethylphenoxy)propyl]ethane- 10 diimidamide, 5) N-{3—[3—{1,2,3,5-tetrahydro-1-pyridyl)methyl-phenoxy ] propyl}ethanediimidamide; or a salt, hydrate or solvate thereof. 13 Example 1 N-[3-(3-Piperidinomethylphenoxy)propyl]ethanedilmidamlde trihydrochloride A suspension of 3-amino-4-[3-(3-piperidinoraethyl-5 phenoxy)propylamino]-l,2,5-thiadiazole 1-oxide (17.1 g; 47.0 mmoles) [prepared according to Patent Specification No. 50997] in 450 ml· of methanol was treated with 38 mL of concentrated HCl, The resultant solution was stirred for 3 hours at ambient temperature. Concentration of lO the solution followed by azeotropic removal of water with absolute ethanol gave colorless crystals. These were suspended in 200 mL of absolute ethanol, filtered and dried under vacuum to give 16.6 g (82.61) of the title compound, m.p. 205-222*C (dec.). Recrystallization from 501 methanol-15 ethyl acetate gave an analytical sample, m.p. 206-216*C (dec.) Anal. Calc'd for C17H27H50*3BC1: C, 47.84; H, 7.08; N, 16.41 Found; C, 47.56; H, 7.18; N, 16.75 Example 2 M— C2— t (5-Dimethylaminomethyl-2-furyl)methylthiol ethyl)-2o ethanedilmidamlde trihydrochloride hydrate A suspension of 3-amino-4-{2-((5-dimethylaminoroethyl 2-furylJmethylthio]ethylamino)-l,2,5-thiadiazole 1-oxide (6.59 g; 20.0 mmoles) [prepared according to Patent Specification No. 50997] in 200 ml· of 25 methanol was warmed slightly to achieve complete solution, then treated with 13.3 mL of concentrated HCl. After Stirring at ambient temperature for 2.5 hours, the solution was concentrated and the residue was triturated with 70 mL of absolute ethanol. The crystals were collected by filtration and dried 30 under vacuum to_ give 4.3 g (52%) of the title compound, sup.. 166-169‘C (dee.).

Anal. Calc'd for C1,H,1N=0S*3HCl*H,0s c, 35.08; H, 6.38; N, 17.05; s, 7.80 Found: c, 34.85; H, 6.24; 35 N, 17.45; s, 7.97 14 Example 3 H-(2-[ (S-Dimethyl&mlncntethYl-4-methyl-2-thienyl)methvlthlol-ethyl)ethanedlimldamlde trlhvdrochlorlde A stirred solution of 3-araino-4-{2-((5-diraethylamino-methyl-4-methyl-2-thienyl)methylthio] ethylamino)-l,2,5-thiadiazole 1-oxide (17.9 g, 50.0 mmoles) (prepared according to the general procedure described in Patent Specification Ho. 50997] in 500 mL of methanol was treated with 33.3 mL of concentrated HC1. After stirring for 3 hours, the reaction mixture was concentrated and excess water was removed by azeotropic concentration with absolute ethanol to give an almost colorless crystalline residue. The residue was triturated with 200 mL of absolute ethanol at 0*C, filtered and dried, to give 16.9 g (801) of the title compound, m.p. 206-220*C (dec.). Recrystallisation from 50% methanol-ethyl acetate gave a product having m.p. 210-221»C (dee.).

Anal. Calc'd for C13H23H5S2*3HCls C, 36.92,· H, 6.20; M, 16.56} S, 15.17 Founds C, 36.76; H, 6.33; N, 16.97» S, 15.54 Example 4 H- [3- (3-Fyrrolidinomethylphenoxy)propyl) ethanediinidamide trihydrochloride A suspension of 3-amino-4-l3-(3-pyrrolidinomethyl-phenoxy)propylamine]-1,2,5-thiadiazole 1-oxide (13.4 g; 38.3 mmoles) (prepared according to Patent Specification Ho. 50997] in 350 mL of methanol was treated with 25.5 mL of concentrated HC1. The resultant solution was stirred for 3 hours at ambient temperature. Concentration of the solution followed by azeotropic removal of water with absolute ethanol gave the product. The crystalline residue was triturated with 150 mL of absolute ethanol, filtered and dried to give '10.8 g of the title compound, m.p. 195-203*C (dee.).

Anal. Calc'd for C16H25NsO*3HCl! C, 46.55; H, 6.84; H, 16.97 Found: C, 46.55; H, 6.93; N, 16.93 IS Example 5 The general procedure of Sample 1 is repeated except that the 3-amino-4-[3-(3-piperidinomethyl-phenoxy}propylamino)-l,2,5-thiadiazole 1-oxide utilized therein 5 is replaced by an equimolar amount of (a) 3-amino-4-[3- (3-dimethylaminomethylphenoxy) propylamino) - 1.2.5- thiadiazole 1-oxide, (b) 3-amino-4-[3-(3-diethylaminomethylphenoxy) propylamino]- 1.2.5- thiadiazole 1-oxide, 10 15 20 (c) 3-amino-4-{3-[3-(2-methylpyrrolidino)methylphenoxy)-propylamino)-1,2,5-thiadiazole 1-oxide, (d) 3-amino-4-{3-[3-(3-methylpyrrolidino)methylphenoxy]-propylamino)-l,2,5-thiadiazole 1-oxide, (e) 3-amino-4-{3-[3-(4-methylpiperidino)methylphenoxy]-propylamino)-1,2,5-thiadiazole 1-oxide, (f) 3-amino-4- [3- (3-morpholinomethylphenoxy) propylamino] -1,2,5-thiadiazole 1-oxide, (g) 3-aminc-4-{3-[3-(N-methylpiperazino)methylphenoxy) -propylamino)-1,2,5-thiadiazole 1-oxide, (h) 3-amino-4-[3-(3-hexamethyleneiminomethylphenoxy)propylamino]- 1.2.5- thiadiazole 1-oxide, (i) 3-amino-4-(3-(3-heptamethyleneiminomethylphenoxy)propyl-amino]-1,2,5-thiadiazole 1-oxide, {j ) 3-amino-4-{3-13- (3-azabicyclo (3.2.2]non-3-yl)methylphenoxy]-propylamino}-l,2,5-thiadiazole 1-oxide and (k) 3-amino-4-{3- [3- (3-pyrrolino)methylphenoxy) propylamino)- 1.2.5- thiadiazole 1-oxide, respectively, and there is thereby produced 25 16 (a) N- [3- (3-dimethylaminomethy lphenoxy) propyl]-ethanediimidamide trihydrochloride, (b) N- [ 3 - (3 -diethylaminomethy lphenoxy) propyl ] -ethanediimidamide trihydrochloride, 5 (c) N-{ 3-[3- (2 -methylpyrrol idino) methylphenoxy ] - propyl} ethanediimidamide trihydrochloride, (d) N-{3-[3-(3 -methylpyrrol idino) methylphenoxy ] -propyl}ethanediimidamide trihydrochloride, (e) N-{3-[3-( 4-methylpiperidino) methylphenoxy] - 10 propyl)ethanediimidamide trihydrochloride, (f) N- [3- (3-morpholinomethy lphenoxy) propyl]-ethanediimidamide trihydrochloride, (g) N-{3-[3- (N-methylpiperazino) methylphenoxy] -propyl)ethanediimidamide trihydrochloride, 15 (h) N-[3-(3-hexamethyleneiminomethylphenoxy)- propyl ] ethanediimidamide trihydrochloride, (i) N- [3- (3-heptamethyleneiminomethylphenoxy) propyl] -ethanediimidamide trihydrochloride, (j) N-{3-[3-(3 -azabioyclo [3.2.2.] non-3 -yl) methyl- 20 phenoxy]propyl)ethanediimidamide trihydrochloride, and » (H) N-{3-[3-(3-pyrrolino)methylphenoxy]propyl}- ethanediimidamide trihydrochloride, respectively.

Claims (8)

1. 7

2. 1. A compound of the formula A-(CH2)mZ(CH2)nN < img-format="tif" img-content="drawing" /> HN HH II wherein R"*- is hydrogen, (lower)alkyl, 2-fluoroethyl, 2,2,2-5 trifluoroethyl, allyl, propargyl, R 2 \\ R 3. (CH2)p- or < img-format="tif" img-content="drawing" /> ICVp- 2 3 in which p is 1 or 2, R and R each are independently hydrogen, (lower)alkyl, (lower)alkoxy or halogen, and, when 2 3 2 3 R is hydrogen, R also may be trifluororaethyl, or R and R , 4 10 taken together, may be methylenedioxy, and R is hydrogen, (lower)alkyl or (lower)alkoxy,· m is an integer of from 0 to 2 inclusive; n is an integer of from 2 to 5 inclusive; Z is oxygen, sulfur or methylene; and 15 A is < img-format="tif" img-content="drawing" /> 18 in which RS is hydrogen# (lover)alkyl or (lower)alkoxy, q is an integer of from 1 to 4 inclusive and R6 and R7 each are independently (lower)alkyl, (lower)alkoxy(lower)alkyl in which the (lower)alkoxy moiety is at least two carbon atoms removed 5 from the nitrogen atom, or phenyl (lower)alkyl, and, when R® 7 fi 7 is hydrogen, R also may be cyelo(lover)alkyl, or R and R , taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidlno, dimethyl- pyrrolidino, morpholine, thiomorpholino, piperidino, methyl- 10 piperidino, dimethylpiperidino, N-methylpiperazino, 1,2,3,6- tetrahydropyridyl, homopiper id ino, heptamethyleneimino, octa- methyleneimino, 3-azabicyclo(3.2.2]non-3-yl or 3-pyrrolinoj or a salt, hydrate or solvate thereof; "(lower)alkyl", "(lower)alkoxy" •and "cyclo (lower) alkyl" in the foregoing definitions having in all 15 occurences the significations "(lower)alkyl, as herein defined " "(lower)alkoxy, as herein defined", and "cyclo(lower)alkyl, as herein defined", respectively. IrC HN NH λ compound of Claim 1 A~(CH2,raZ(CH2,nNH having the formula HHR1 II 20 wherein R* is hydrogen or (lower) alkyl, m is 0 or 1, n is 2 or 3, Z is oxygen or sulfur and λ is < img-format="tif" img-content="drawing" /> in which R® is hydrogen or methyl, and R® and R7 each are 25 independently methyl or ethyl, or when taken together with the 19 6 7 nitrogen to which they are attached, R and R represent a pyrrolidino or piperidino ring; or a salt, hydrate or solvate thereof.

3. A compound of Claim 1 having the formula 5 < img-format="tif" img-content="drawing" /> ^N^dch 2CH2CH2NH < img-format="tif" img-content="drawing" /> Ila wherein R^ is hydrogen or methyl, and R® and R7 each are methyl or, when taken together with the nitrogen atom to which they are attached, R6 and R7 represent a pyrrolidino or piperidino ring; or a salt, hydrate or solvate thereof. A compound of Claim 1 having the formula < img-format="tif" img-content="drawing" /> lib wherein R^ and R^ each are independently hydrogen or methyl, 6 7 and R and R each are independently methyl or ethyl; or a salt , hydrate or solvate thereof. 15 5. A compound of Claim 1 having the formula id N/NCH2 *6/ 2 < img-format="tif" img-content="drawing" /> H2SeH2CH2NH Ύ HN NH NHR lie wherein R^· and R5 each are independently hydrogen or methyl, and R® and R^ each are independently methyl or ethyl; or a salt, hydrate or solvate thereof. 5 6. NCH < img-format="tif" img-content="drawing" /> A compound of Claim 1 having the formula ,5 IXd och2ch2ch2nh NHRa Ύλ HN NH wherein R^· and R5 each are independently hydrogen or methyl, and R® and R^ each are independently methyl or ethyl, or, when taken together with the nitrogen to which they are attached, R® and R^ 10 represent piperidino; or a salt, hydrate or solvate thereof. 21

4. 7. N-[3-(3-Piperidinomethylphenoxy)propyl]-ethanediimidamide, or a salt, hydrate or solvate thereof.

5. 8. N-{2-[(5-Dimethylaminomethyl-2-furyl)- 5 methylthio]ethyl}ethanediimidamide, or a salt, hydrate or solvate thereof.

6. 9. N- {2- [ (5-Dimethylaminomethyl-4-methyl-2-thienyl) -methylthio]ethyl}ethanediimidamide, or a salt, hydrate or solvate thereof. 10 10. N-[3-(3-Pyrrolidinomethylphenoxy) propyl]- ethanediimidamide, or a salt, hydrate or solvate thereof.

7. 11. N-{3-[3-(1,2,3,6-Tetrahydro-l-pyridyl)methyl-phenoxy]propyl}ethanediimidamide, or a salt, hydrate or 15 solvate thereof.

8. 12. A process for preparing a compound of the formula XI according to claim 1, comprising reacting a compound of formula < img-format="tif" img-content="drawing" /> 20 with a strong mineral acid, or reacting a compound of formula A-(CH2)mZ(CH2)nNH2 IV V with a compound of formula < img-format="tif" img-content="drawing" /> to produce a compound of formula \ J A-(CH2)mZ(CH2)nNH < img-format="tif" img-content="drawing" /> VI then reacting said compound of formula VI with a compound of formula R^NH2· 13 . & process according to claim 12, wherein the reaction of a compound of formula III with a mineral acid is carried out in an inert solvent and at room temperature. 14. a process according to claim J 2 or 13, wherein the mineral acid is hydrochloric acid. 15. a compound of the formula II given and defined in claim 1 or a salt, hydrate or solvate thereof, which is any one of those specifically hereinbefore mentioned other than those claimed in claims 7-11. 16. a process for preparing a compound of the formula II given and defined in claim 1 or a salt, hydrate or solvate therof, substantially as hereinbefore described with particular reference to the accompanying Examples. 17. a compound of the formula II given and defined in claim 1 or a salt, hydrate or solvate thereof, whenever prepared by a process claimed in any one of claims 12-14 or claim 16. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS.