JPH0568472B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to substituted 3,4-diamino-1,2,5-thiadiazoles with histamine _H2 -receptor antagonistic activity. A certain 3-(amino or substituted amino) having the formula: where A, m, Z, n and R ¹ are defined below
4-(Substituted amino)-1,2,5-thiadiazole and its pharmaceutically acceptable non-toxic salts, hydrates and solvates are effective histamine _H2 -receptor antagonists that suppress gastric acid secretion and are effective in treating gastric ulcers and other diseases. It is useful for treating abnormal hypersecretion conditions. This compound is prepared by ring closure of the corresponding substituted ethanediimidamide having the formula: Applicants' UK Patent Application No. 2067987 has the formula:
3 having the formula: (in the above formula, A, m, Z, n and R ¹ are the same as the corresponding substituents of the compound of the present invention),
4-2-substituted-1,2,5-thiadiazole 1-oxides and 1,1-dioxides and their production methods have been published. However, the compounds disclosed therein are 1-oxide and 1,1-dioxide (p is 1 or 2), and the compounds of the present invention cannot be prepared by any of the methods for preparing conventional compounds described therein. Published European Patent Application No. 40696 inter alia has the formula: where R, , n, X, m, R ¹ and R ² are the same as the corresponding substituents of the compounds of the invention. 3,4-2-substituted-1,2,5-thiadiazole 1
- oxide and 1,1-dioxide. However, the compounds are also 1-oxides or 1,1-dioxides (p is 1 or 2), and the compounds of the present invention cannot be prepared by the methods for preparing conventional compounds described therein. Each of the methods for preparing the conventional compounds in the above two documents uses 1,2,5-thiadiazole 1-oxide or 1,1-dioxide having an amino group or an appropriate "leaving group" in the 3- and 4-substitutions. I am using it. The desired substituents on the 3- and 4-positions are subsequently obtained by substitution on the amino group or by substitution of "leaving groups". Applicants have prepared the present invention using the same method, ie, 1,2,5-thiadiazole with an amino group or a suitable "leaving group" in the 3- or 4-position as starting material or intermediate, but also varying the reaction conditions. Although various efforts were made to develop the compound, the compound of the present invention could not be isolated using the above methods. Applicants now believe that the compounds of the present invention have the formula:
They discovered that they could be prepared by ring closure of the corresponding substituted ethanediimidamide having the formula. The intermediate itself can be produced in various ways. The present invention has the formula: [Formula] [In the above formula, R ¹ is hydrogen, lower alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,
Allyl, propargyl, [Formula] or [Formula] (where p is 1 or 2, R ² and R ³ are independently hydrogen, lower alkyl, lower alkoxy or halogen, and when R ² is hydrogen, R ³ is (or R ² and R ³ may both be methylenedioxy and R ⁴ is hydrogen, lower alkyl or lower alkoxy), and m is 0 to 2.
n is an integer of 2 to 5, Z represents oxygen, sulfur, or methylene, and A is [Formula] [Formula] [Formula] or [Formula] (In the above formula, R ⁵ is hydrogen, lower alkyl, or Lower alkoxy, q is an integer from 1 to 4, and
R ⁶ and R ⁷ are independently lower alkyl, lower alkoxy lower alkyl in which the lower alkoxy moiety is at least two carbon atoms removed from the nitrogen atom, or phenyl lower alkyl, and if R ⁶ is hydrogen then R ⁷ may be cyclolower alkyl, or
R ⁶ and R ⁷ together with the nitrogen atoms to which they are bonded include pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, N
- methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino, 3-azabicyclo[3.2.2.]non-3-yl or 3-pyrrolino,
The present invention relates to a histamine H ₂ -receptor antagonist represented by the following formula (forming a compound) and its pharmaceutically acceptable non-toxic salts, hydrates and solvates. The present invention also relates to processes for preparing compounds having the formula and intermediate compounds having the formula. Also included within the scope of the present invention are all possible tautomers, diastereoisomers and optically active isomers of the compounds having the formula and mixtures thereof.
As used herein and in the claims, "lower alkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms. "Lower alkoxy" means a straight or branched alkoxy group having 1 to 4 carbon atoms. "Cyclolower alkoxy" means a cycloalkyl group having 3 to 6 carbon atoms. “Pharmaceutically acceptable non-toxic salts” are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, acetic acid, propionic acid, fumaric acid, methanesulfonic acid, maleic acid, tartaric acid, citric acid, levulinic acid, benzoic acid, and succinic acid. refers to acid addition salts formed with acids such as R ¹ in compounds having the formula is preferably hydrogen or lower alkyl, preferably hydrogen or methyl, and most preferably hydrogen. Substituent A is preferably the above substituted phenyl moiety, substituted furyl moiety or substituted thienyl moiety,
Substituted phenyl moieties are best. Substituent Z is preferably oxygen or oxygen, and if A is a substituted phenyl moiety, Z is preferably oxygen. It is preferable that m is 0 or 1 and n is 2 or 3, and even if A is a substituted phenyl moiety, it is preferable that m is 0 or n is 3. ^R5
is preferably hydrogen or methyl, with hydrogen being most preferred.
q is preferably 1. Preferably R ⁶ and R ⁷ are lower alkyl or together with the nitrogen atom to which they are attached form pyrrolidino or piperidino. Compounds with the formula can be prepared by reacting compounds with the formula with sulfur monochloride (S ₂ Cl ₂ ), sulfur dichloride (SCl ₂ ), or their chemical equivalents as follows: ] In the above formula, A, m, Z, n and R ¹ are as defined above. It is necessary to use at least about 1 mole of S ₂ Cl ₂ or SCl ₂ per mole of compound. Excess of S ₂ Cl ₂ or SCl ₂ , for example about 2 per mole of compound
It is preferred to use from to about 3 moles of S ₂ Cl ₂ or SCl ₂ .
S _{2 Cl 2} is usually preferred for reactions as it has been shown to often produce crude products and poor yields of purified products. Reaction temperature is not critical;
The reaction is carried out at temperatures of from about 0°C to about 50°C, although it is most convenient to carry out the reaction at room temperature. The reaction time usually takes about 30 minutes to about 6 hours depending on the temperature. Reaction times of about 1.5 to 4 hours, usually at room temperature, are preferred. The reaction can be carried out in an inert organic catalyst, preferably a mixture of an inert organic catalyst and dimethylformamide. It is best to carry out the reaction in dimethylformamide. A compound of a preferred embodiment of the invention has the formula:
[Formula] or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof. In the above formula, R ¹ represents hydrogen or lower alkyl, m is 0 or 1, and n is 2 or 3.
, Z represents oxygen or sulfur, and A is [formula] [formula] [formula] or [formula] (in the above formula, R ⁵ represents hydrogen or methyl, and R ⁶ and
R ⁷ independently represents methyl or ethyl, or R ⁶ and R ⁷ together with their bonding nitrogen form a pyrrolidino or piperidino ring. In a more preferred embodiment, the compound has the structure a: where R ¹ represents hydrogen or methyl and R ⁶
and R ⁷ are each methyl, or form a pyrrolidino or piperidino ring with the nitrogen to which they are bonded, or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof It is. In another more preferred embodiment, a compound having the formula b: [Image Omitted] wherein R ¹ and R ⁵ each independently represent hydrogen or methyl, and R ⁶ and R ⁷ each independently represent methyl or ethyl. or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof. In another more preferred embodiment, the compound has the structure c: where R ¹ and R ⁵ independently represent hydrogen or methyl and R ⁶ and R ⁷ independently represent methyl or ethyl. or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof. In another more preferred embodiment, the compound has the structure d: where R ¹ and R ⁵ independently represent hydrogen or methyl and R ⁶ and R ⁷ independently represent methyl or ethyl. or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof. The most preferred compounds having the formula as shown above are: 1 3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5
-thiadiazole, 2 3-amino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole, 3 3-amino-4-{2-[ (5-dimethylaminomethyl-4-methyl-2-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole, 4 3-amino-4-[3-(3-pyrrolidinomethylphenoxy)propyl Amino]-1,2,5
-thiadiazole, 5 3-methylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,
2,5-thiadiazole, 6 3-benzylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,
2,5-thiadiazole, 7 3-amino-4-{2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole, 8 3-amino-4-{ 2-[(5-piperidinomethyl-3-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole, 9 3-amino-4-[3-(6-piperidinomethyl-2-pyridyloxy)propylamino]-
1,2,5-thiadiazole, and 10 3-amino-4-[3-(4-piperidinomethyl-2-pyridyloxy)propylamino]-
1,2,5-thiadiazole, and pharmaceutically acceptable non-toxic salts, hydrates and solvates thereof. The intermediates of the formula used in the preparation of the compounds of the formula can themselves be prepared in a variety of ways. One method is to treat 3-(amino or substituted amino)-4-(substituted amino)-1,2,5-thiadiazole 1-oxide with the corresponding formula with strong phosphoric acid (preferably HCl) to give the formula It is made into a compound. [Chemical formula] [Chemical formula] The reaction is preferably carried out in an inert solvent, preferably methanol. The reaction temperature is not critical and is most conveniently carried out at room temperature. Compounds with the formula are well known and are described in Applicants' UK Patent Application No.
It can be easily produced by the method described in No. 2067987. An alternative method for producing a compound having the formula is as follows. [C] [C] [C] The reaction is carried out in an inert solvent, preferably methanol. Starting materials having the formula are known and can be readily prepared, for example, by the method described in Applicants' UK Patent Application No. 2067987. Another aspect of the invention relates to novel intermediates having the formula: embedded image or salts, hydrates or solvates thereof. In the above formula, R ¹ is hydrogen, lower alkyl,
2-fluoroethyl, 2,2,2-thiofluoroethyl, allyl, propargyl,
[Formula] or [Formula] (In the formula, p is 1 or 2, R ² and R ³ independently represent hydrogen, lower alkyl, lower alkoxy, or halogen, and when R ² is hydrogen, R ³ is trifluoromethyl or both R ² and R ³ may be methylenedioxy, and R ⁴ represents hydrogen, lower alkyl, or lower alkoxy), m is an integer from 0 to 2, and n is an integer from 2 to 5. ,
Z represents oxygen, sulfur or methylene, and A
is [Formula] [Formula] [Formula] or [Formula] (In the above formula, R ⁵ represents hydrogen, lower alkyl or lower alkoxy, p is an integer from 1 to 4,
and R ⁶ and R ⁷ independently represent 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 R ⁶ is hydrogen, R ⁷ may be cyclo-lower alkyl, or R ⁶ and R ⁷ together with the nitrogen atom to which they are attached include pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, N- Methylpiperazino, 1,2,3,
6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino, 3
-Azabicyclo[3.2.2.] forming non-3-yl or 3-pyrrolino). In a preferred embodiment, the intermediate has the structure: [Formula] where R ¹ is hydrogen or lower alkyl, m is 0 or 1, n is 2 or 3, and Z is oxygen or A is [Formula] [Formula] [Formula] or [Formula] (In the above formula, R ⁵ is hydrogen or methyl, and R ⁶ and
or ^{pharmaceutically} acceptable non-toxic ^{salt ,} water compound or solvate. In other preferred embodiments, intermediates having the formula a: where R ¹ is hydrogen or methyl, and R ⁶ and
R ⁷ is each methyl or a compound having a pyrrolidino or piperidino ring (together with the nitrogen atom to which they are bonded), or a salt, hydrate or solvate thereof. In another preferred embodiment, the intermediate has the structure b: where R ¹ and R ⁵ are independently hydrogen or methyl and R ⁶ and R ⁷ are independently methyl or ethyl. ) or its salt, hydrate or solvate. In another preferred embodiment, the intermediate having the formula c: where R ¹ and R ⁵ are independently hydrogen or methyl and R ⁶ and R ⁷ are independently methyl or ethyl. ) or its salt, hydrate or solvate. In another preferred embodiment, the intermediate having the formula d: where R ¹ and R ⁵ are each independently hydrogen or methyl and R ⁶ and R ⁷ are each independently methyl or ethyl. or their salts, hydrates or solvates. The most preferred intermediates having the formula as shown above are: 1 N-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamide, 2 N-{2-[(5 -dimethylaminomethyl-2
-furyl)methylthio]ethyl}ethanediimidamide, 3N-{2-[(5-dimethylaminomethyl-4
-Methyl-2-thienyl)methylthio]ethyl}ethanediimidamide, 4N-[3-(3-pyrrolidinomethylphenoxy)propyl]ethanediimidamide, 5N-{2-[(5-dimethyl Aminomethyl-3
-thienyl)methylthio]ethyl}ethanediimidamide, 6 N-{2-[(5-piperidinomethyl-3-thienyl)methylthio]ethyl}ethanediimidamide, 7 N-[3-(6-piperidinomethyl-2- pyridyloxy)propyl]ethanediimidamide,
and 8 N-[3-(4-piperidinomethyl-2-pyridyloxy)propyl]ethanediimidamide, or a salt, hydrate or solvate thereof. Pharmacologically active compounds with formulas for therapeutic use are usually prepared as pharmaceutical compositions consisting of the base form or pharmaceutically acceptable non-toxic acid addition salt form of at least one of the above compounds as the essential active ingredient together with a pharmaceutically acceptable carrier. administered. Pharmaceutical compositions can be administered orally, parenterally or by rectal suppository. Various pharmaceutical forms are used. Thus, if a solid carrier is used, the preparation may be in the form of a powder, a tablet or pellet placed in a hard gelatin capsule, or a troche or buccal tablet. If liquid carriers are used, the preparations may be in the form of syrups, emulsions, soft gelatin capsules, sterile injectable solutions, or aqueous or non-aqueous suspensions. Pharmaceutical compositions are manufactured in any conventional manner appropriate to the desired formulation. The dosage of the compounds of this invention will depend on factors such as patient weight, as well as the degree of acid suppression desired and the efficacy of the particular compound used. Instructions as to the particular amount of drug to be used (and the number of daily doses) are at the discretion of the physician and will vary as the dosage is titrated to the particular condition of the particular patient. Each oral dosage unit of the preferred compounds of this invention will contain from about 2 to about 300 mg of active ingredient, preferably from about 4 to 100 mg. The active ingredient is 1
It is recommended to administer the same amount 1 to 4 times a day. Histamine H ₂ -receptor antagonists have been shown to be effective in suppressing gastric acid secretion in animals and humans.
(Brimblecombe et al. 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)) Some of the preferred compounds of the present invention were compared with cimetidine in various tests to determine the effect of histamine in the right atrium of guinea pigs isolated.
It has been found to be more potent than cimetidine both as an _H2 -receptor antagonist and as an inhibitor of gastric acid secretion in mice and dogs. Measurement of gastric acid secretion suppressing activity in rats with gastric fistulas Male long-even rats weighing approximately 240-260 g at the time of implantation of the drainage tube were used. The specification of the stainless steel drainage canal and its endografting into the anterior wall of the proventriculus is essentially as described by Baer et al. [ Laboratory Animal Science, 27 , p.
244 (1977)].
The planned surgical procedure inside the fistula (inside the tube placed in the stomach) was performed exactly as described in the above-mentioned literature. After surgery, the animals were individually placed in cages with bottom plates containing sawdust and were given food and occasional water during their recovery. Animals were not used for testing purposes for at least 15 days after surgery. Animals were fasted for 20 hours before the start of the test and given occasional access to water. Immediately before gastric juice collection, the drain tube was opened and the stomach was gently washed with 30-40 ml of warm saline or distilled water to remove all residue. The catheter was then screwed into the drainage tube instead of the stopper, and the mouse was placed in a transparent plastic rectangular box 40 cm long, 15 cm wide, and 13 cm high.The bottom of the box was about 1.5 cm wide enough for the catheter to hang from. , length 25
The cm slit was open towards the center. The rats were thus restrained and allowed free movement within the cage during the collection period. Other analyzes can be found in Ridley et al. [ Lasearch Comm.Chem.Path.Pharm . , 17 , 365
(1977)]. Gastric secretions collected during the first hour after gastric lavage were discarded due to possible contamination. For oral evaluation, the catheter was removed from the drainage canal and replaced with a plug. Water (2 ml/Kg) was administered orally via gastric intubation and the animals were returned to the cage for 45 minutes. After this time, the stopper was removed, the catheter was reinserted, and a small plastic bottle was attached to it to collect gastric secretions. A 2 hour sample was taken (this represents a control secretion) and the catheter was removed and re-stopped. Now, the test drug was orally administered in a volume of 2 ml/kg through gastric intubation. After 45 minutes, the stopper was removed and the catheter with the small plastic bottle was reattached and samples were collected for an additional 2 hours. In order to examine the effect of the test drug, the second sample secretion fluid was compared with that of the control sample. If the test compound is to be evaluated parenterally, administer 2 ml/Kg to the animal immediately after discarding the first 69-minute collection solution.
A volume of test compound vehicle was injected ip or se. 2
A time sample was collected (control secretions) and the animal was
Kg volumes of test compounds were injected either ip or se. Samples are collected for an additional 2 hours and the secretions are compared with those from a control period to examine drug effects. Samples were centrifuged and placed in graduated centrifuge tubes for volume measurements. 0.02N of 1ml sample using automatic biuret and electric PH meter (radiometer)
The titratable acidity was measured by titration with NaOH solution. The microequivalent titratable acid amount was calculated by multiplying the milliliter volume by the milliequivalent acid concentration per liter. The results were expressed as inhibition rates relative to control reading. Create a dose-response curve and use regression analysis
_ED50 values were calculated. At least three rats were used for each dose and the minimum of three doses was used for dose response curve determination. Table: Histamine _H2 - Receptor Antagonism - Isolated Guinea Pig Atrium Study Histamine shows a concentration-related increase in the rate of contraction of isolated naturally beating guinea pig atria. Bratzk et al. , Nature, 236 , 385 (1972).
Properties of the Competitive Antagonist of the H ₂ -Receptor Primamide This effective receptor of histamine is described in the report as the histamine H ₂ -receptor. Followed by Hyuse and Collets Proc, Soc.Exp.Biol.
Mod. , 148 , 127 (1975) and Vuama and Matsuknail, J.Pharmacol.Exp.Ther . , 200 , 352
(1977) study showed that the chronotropic effects of histamine in the isolated guinea pig right atrium showed that histamine
This supports the conclusion of Black et al. that it is transmitted by H ₂ -receptors. Agents of Bratsk et al.
and Action, 3, 133 (1973) and Brimblecombe et al., Eed. Proc . , 35 , 1931 (1971) used isolated guinea pig right atrium as a means of comparing the activity of histamine _H2 -receptor antagonists.
The current comparative study is Reinhardt et al.'s Agents and
A modified method was used as reported in Actions, 4 , 217 (1974). Male Hartley guinea pigs (350-450 g) were killed by hitting them on the head. The heart was removed and oxidized (95%
O ₂ , 5% CO ₂ ) modified Krebs solution (per liter
NaCl6.6g, KCl0.35g, _MgSO4・_7H2O0.295g ,
KH ₂ PO ₄ 0.162g, CaCl ₂ 0.238g, NaHCO ₃ 2.1g
and 2.09 g of dextrose). The naturally beating right atrium was cut away from other tissues and silk thread (4-0) was attached to both ends. 32℃
Added oxidized modified Krebs solution kept at 20
The atrium was suspended in the ml muscle chamber. Glass atrial contractions
ET0.03 force transfer transducer
Contractile forces and velocities were recorded using a Beckman RP dynograph recorded isometrically. A resting tension of 1 g was applied to the atrium and allowed to equilibrate for 1 hour. A final maximum concentration (3 x 10 ^-6 M) histamine dihydrochloride solution for 1 hour was added to the bath to prime the washed tissue. Histamine was then added to the bath cumulatively using 1/2 log10 intervals.
A final bath molarity of 3×10 ⁻⁵ of ×10 ⁻⁷ was used. The increase in atrial velocity caused by histamine was allowed to plateau before the next velocity concentration was added. The maximum response always occurred at a concentration of 3×10 ⁻⁵ M. Several histamine washes were performed to return the atrium to accommodative speed. Test compounds were then added at appropriate molar concentrations and after 30 minutes of incubation, the required higher concentrations were added to repeat the histamine level response. The difficulty constant (K _B ) was calculated using at least three doses by Alan Lakshiana O. and Schild HO [ Br.J.
Pharmacol. 14 , 48 (1959) from the Sehild plot. Table 2 shows the results obtained by parallel shifting the dose-response curve without depressing the maximum response at the antagonist concentration used.
Shown below. [Table] Compounds with the formula are also:
It can be prepared by ring closure of a compound having the formula using N,N'-thiobisphthalimide having the formula. If SCl ₂ or N,N'-thiobisphthalimide is used in place of SCl ₂ in the ring-closing reaction, the crude compound having the formula can be obtained more purly and in higher yield. The crude product having the formula thus produced is usually of sufficient purity to directly produce the crystalline salt without prior chromatographic purification. In this process, a starting diimidamide having the formula is reacted with approximately equimolar amounts of N,N'-thiobisphthalimide in an inert predominant solvent such as CH ₂ Cl ₂ . The starting diimidamide may be used in the form of its trihydrochloride salt, in which case three molar equivalents of an amine such as triethylamine are added to the reaction mixture to neutralize the trihydrochloride salt. The reaction is stirred at room temperature for about 1 hour to complete the reaction. The phthalimide precipitated from the reaction mixture can be washed with a strong base (e.g. 10-20% KOH aqueous solution).
The organic solvent layer is dried, filtered and concentrated to give a crude mixture having the formula: N used in the reaction,
N′-thiobisphthalimide is a known compound
Canadian Journal of Chem. , 44 , 2111−2113
(1966) or as described in Production Method No. 1 below. Production Method 1 N,N'-Thiobisphthalimide A solution of 14.7 g (0.1 mol) of phthalimide in 80 ml of dimethylformamide (DMF) was cooled to 0°C, and 5.15 g (0.05 mol) of sulfur dichloride was added dropwise. After the addition, the mixture was warmed to 20°C and stirred for 4 hours. The resulting solid was collected and dried to yield 12.5 g of the title compound as a DMF solvate. Melting point 301−315
℃. Both IR and NMR spectra were consistent with the structural formula. Analytical values for C ₁₆ H ₈ N ₂ O ₄ S and C ₃ H ₇ NO: Calculated values: C, 57.42; N, 3.80; N, 10.57; S, 8.07. Measured value: C, 57.50; H, 3.80; N,
10.29; S, 8.57. The DMF solvate can be removed by recrystallizing the substance from chloroform. The melting point of the product without DMF was 320-325°C. NMR spectrum showed that DMF was removed. Analytical values for C ₁₆ H ₈ N ₂ O ₄ S: Calculated values: C, 59.25; H, 2.49; N, 8.64; S,
9.89. Measured value: C, 59.21; H, 2.21; N, 8.91; S,
10.14. Example 1 3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-
Thiadiazole, AN-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamide trihydrochloride 3-amino-4-[3- in 450 ml methanol
After suspension of 17.1 g (47.0 mmol) of (3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1-oxide [prepared according to published UK Patent Application No. 2067987] ]
was treated with 38 ml of concentrated HCl. After stirring the resulting solution at ambient temperature for 3 hours, the solution was concentrated and water was azeotropically removed with absolute ethanol to obtain colorless crystals. 200ml of this
The residue was suspended in absolute ethanol, filtered and dried under vacuum to obtain 16.6 g (82.6%) of the title compound. melting point 205
Analytical samples were obtained by recrystallization from -222°C (decomposed) methanol 50%-ethyl acetate. Melting point 206−216
°C (decomposition). Analytical values _{for C17H27N5O.3HCl} : Calculated values: C, 47.84; H, 7.08; _N , 16.41. Measured values: C, 47.56; H, 7.18; N, 16.75. B 3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5
-thiadiazole, N- in 20 ml of dimethylformamide (DMF)
A suspension of 2.13 g (5.0 mmol) of [3-(3-piperidinomethylphenoxy)propyl]ethanediimidamide trihydrochloride (prepared in step A) was mixed with 2.02 g (15.0 mmol) of sulfur monochloride. The mixture was treated and stirred for 4 hours. Carefully pour the mixture into 200ml of water and add K ₂
Made basic with _CO3 . Add this to 50ml of methylene chloride
3, dried over MgSO ₄ and concentrated to give 2.1 g of a dark gum containing the product. as a fluid phase
CH ₂ Cl ₂ (100): 2-propanol (10): NH ₄
Purified by preparative high pressure liquid chromatography on silica using OH (0.5). 0.89 g of the title compound was obtained from the appropriate fractions and treated with fumaric acid in n-propanol to yield 0.76 g (21.4%) of the crystalline title compound fumarate salt. Melting point 187-187.5℃.
Purity as determined by HPL was >99%. (C ₁₇ H ₂₅ N ₅ OS) Analysis values for ₂・C ₄ H ₄ O ₄ : Calculated values: C, 56.27; H, 6.71; N, 17.27; S,
7.90. Measured value: C, 56.09; H, 6.36; N, 16.98; S,
8.08. A small amount of the fumarate salt was suspended in water, neutralized with K ₂ CO ₃ and extracted with CH ₂ Cl ₂ . The free base of the title compound was crystallized by concentrating the CH ₂ Cl ₂ . Melting point 43-47℃. A small amount of the free base was converted to the hydrochloride salt. Melting point 138−140
℃. Analysis values for C ₁₇ H ₂₅ N ₅ OS/HCl: Calculated values: C, 53.18; H, 6.83; N, 18.24; S,
8.35. Measured value: C, 53.14; H, 6.88; N, 18.49; S,
8.74. Example 2 3-Amino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole A N-{2-[(5-dimethylaminomethyl -2
-furyl)methylthio]ethyl}ethanediimidamide trihydrochloride hydrate 3-amino-4-{2-
[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxide 6.59 g (20.0 mmol)
The suspension [prepared in accordance with published UK Patent Application No. 2,067,987] was warmed slightly to become completely in solution and then treated with 13.3 ml of concentrated HCl. After stirring for 2.5 hours at ambient temperature, the solution was concentrated and the residue was triturated with 70 ml of absolute methanol. The crystals were collected and dried under vacuum to obtain 4.3 g (52%) of the title compound. Melting point 166-169℃
(Disassembly). Analysis values for C ₁₂ H ₂₁ N ₅ OS・3HC1・H ₂ O: Calculated values: C, 35.08; H, 6.38; N, 17.05; S,
7.80. Measured value: C, 34.85; H, 6.24; N, 17.45; S,
7.97. B 3-Amino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole N-{2-[(5-dimethylaminomethyl -2-furyl)methylthio]ethyl}
Ethanediimidamide trihydrochloride hydrate 12.3g (30.0
7.2 ml of 12.1 g (90 mmol) of sulfur monochloride was added to the suspension of sulfur monochloride (prepared in step A) with stirring. After stirring at ambient temperature for 4 hours, about half of the DMF was removed under reduced pressure. The residual black solution was poured into 1 water, made basic with K ₂ CO ₃ and extracted first with ethyl acetate and then with chloroform. 9.0 g of black rubber containing product after drying over MgSO ₄ and overconcentration
I got it. This was purified by preparative high pressure liquid chromatography on silica using ethyl chloride (100):2-propanol (10): _NH4OH (0.5) as the fluid phase. Rubbery title compound from appropriate parts
I gained 1.24g. A portion of this product was dissolved in methanol to an equivalent of 2N
Treatment with HCl gave the hydrochloride salt of the title compound. Analytical values for C ₁₂ H ₁₉ N ₅ S ₂ O.HCl: Calculated values: C, 41.18; H, 5.76; N, 20.02; S, 18.33. Measured values (corrected for 1.65% _H2O ): C, 40.54; H, 5.70; N, 19.39; S, 18.44. The product was treated with an equivalent amount of cyclohexylsulfamic acid in acetone to yield the cyclohexylsulfamic acid salt of the title compound. Melting point 93-95℃. Analytical _{values for C12H19N5S2O.C6H13NO3S} : _Calculated values: C, _43.88 ; _H , 6.55; _N , 17.06; S, 19.53. Measured value: C, 43.77; H, 6.17; N, 17.21; S,
19.58. Example 3 3-Amino-4-{2-[(5-dimethylaminomethyl-4-methyl-2-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole A N-{2-[(5 -dimethylaminomethyl-4
-Methyl-2-thienyl)methylthio]ethyl}ethanediimidamide trihydrochloride 3-Amino-4-{2-
[(5-dimethylaminomethyl-4-methyl-2-
thienyl)methylthio]-ethylamino}-1,
2,5-thiadiazole 1-oxide 17.9g
(50.0 mmol) [Published UK Patent Application No.
33.3 ml of concentrated HCl was added to a stirred solution of [prepared by the general method described in No. 2067987], stirred for 3 hours, the reaction mixture was concentrated, and the excess water was azeotropically concentrated with absolute ethanol to give an almost colorless crystalline residue. I got it. The residue was triturated with 200 ml of absolute ethanol at 0°C and dried to yield 16.9 g (80%) of the title compound. melting point
Recrystallization from 50% ethanol-ethyl acetate at 206-220°C (decomposition) gave the product with a melting point of 210-221°C (decomposition). Analytical _{values for C13H23N5S2.3HCl} : Calculated values: C, 36.92; H, 6.20; _N , 16.56; S, 15.17. Measured values: C, 36.76; H, 6.33; N, 16.97; S, 15.54. B 3-Amino-4-{2-[(5-dimethylaminomethyl-4-methyl-2-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole N-{2-[(5 -dimethylaminomethyl-4-methyl-2-thienyl)methylthio]ethyl}ethanediimidamide (prepared in step A) in a stirred suspension of 6.34 g (15.0 mmol) of
After adding 6.1 g (45.0 mmol) of sulfur chloride and stirring at ambient temperature for 4 hours, the reaction mixture was poured into 800 ml of water.
The mixture was made alkaline with K ₂ CO ₃ and extracted several times with 100 ml portions of methylene chloride. The extract was dried over MgSO ₄ and overconcentrated to yield 3.4 g of a black gum containing the product. The product was purified by preparative high pressure liquid chromatography on silica using _CH2Cl2 (100):2-propanol ₍ 10): _NH4OH (0.5) as the fluid phase. Furthermore, by preliminary high pressure liquid chromatography on silica, CH ₂ Cl ₂ (100): CH ₃ OH (2.5): NH ₄ OH (0.5)
was purified as a fluid phase. The title compound (purity up to 98%) was obtained from appropriate fractionation. equivalent of the product
Treatment with 2NHCl gave the hydrochloride salt of the title compound. Analysis values for C ₁₃ H ₂₁ N ₅ S ₃・HCl: Calculated values: C, 41.09; H, 5.84; N, 18.43; S,
25.32. Measured value (corrected for 0.51% H ₂ O): C, 40.78;
H, 5.63; N, 18.31; S, 25.44. Example 4 3-amino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5-
Thiadiazole A N-[3-(3-pyrrolidinomethylphenoxy)propyl]ethanediimidamide trihydrochloride 3-amino-4-[3-
In a suspension of 13.4 g (38.3 mmol) of (3-pyrrolidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1-oxide [prepared in accordance with published British Patent Application No. 2067987]
25.5 ml of concentrated HCl was added and stirred at ambient temperature for 3 hours. The liquid was concentrated and the water was removed azeotropically with absolute ethanol to give the product. The crystalline residue was triturated with 150 ml of absolute ethanol and overdried to give the title compound 10.8
I got g. Melting point 195-203°C (decomposed). Analytical values _{for C16H25N5O.3HCl} : Calculated values: C, 46.55; H, 6.84; _N , 16.97. Measured values: C, 46.55; H, 6.93; N, 16.93. B 3-amino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5
- Thiadiazole 8.25 g (20 mmol) of N-[3-(3-pyrrolidinomethyl-phenoxy)propyl]ethanediimidamide trihydrochloride in 80 ml of DMF (produced in step A)
5.4 g (40.0 mmol) of sulfur monochloride was added to the stirred suspension and stirred for 3 hours under a nitrogen atmosphere.
The reaction mixture was concentrated, the dark colored gum was suspended in 500 ml of water, made alkaline with K ₂ CO ₃ and diluted with methylene chloride.
Extracted with 100ml x 3. The extract was dried over MgSO ₄ , filtered and concentrated to give 7.5 g of a dark gum containing the product. The product was purified by preparative high pressure liquid chromatography on silica using _CH2Cl2 (100):2-propanol ₍ 5): _NH4OH (0.5) as the fluid phase.
The portions containing the desired product were combined and concentrated to yield 1.64 g (24.6%) of the purified title compound. The product was treated with an equivalent amount of 2N HCl in absolute ethanol to yield 1.13 g of the title compound hydrochloride. Melting point 138-140℃. Analysis values for C ₁₆ H ₂₃ N ₅ OS/HCl: Calculated values: C, 51.95; H, 6.54; N, 18.93; S,
8.67. Measured value: C, 51.97; H, 6.36; N, 18.63; S,
8.76. Example 5 3-Amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1-oxide used in the general method of Example 1 Steps A and B. in place of equimolar amounts of the following compounds: (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, (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}-1,2,5-thiadiazole 1-oxide, (e) 3-amino-4-{3-[3- (4-methylpiperidino)methylphenoxypropylamino}-1,2,5-thiadiazole 1-oxide, (f) 3-amino-4-[3-(3-morpholimethylphenoxy)propylamino]-1, 2,5
-thiadiazole 1-oxide, (g) 3-amino-4-{3-[3-N-methylpiperazino)methylphenoxy]propylamino}
-1,2,5-thiadiazole 1-oxide, (h) 3-amino-4-[3-(3-diallylaminomethylphenoxy)propylamino]-1,2,
5-thiadiazole 1-oxide, (i) 3-amino-4-[3-(3-hexamethyleneiminomethylphenoxy)propylamino]-
1,2,5-thiadiazole 1-oxide, (j) 3-amino-4-[3-(3-heptamethyleneiminomethylphenoxy)propylamino]-
1,2,5-thiadiazole 1-oxide, (k) 3-amino-4-{3-[3-(3-azabicyclo[3.2.2]non-3-yl)methylphenoxy]propylamino}-1,2 ,5-thiadiazole 1-oxide and (l) 3-amino-4-{3-[3-(3-pyrrolino)
Methylphenoxypropylamino}-1,2,
The general method was repeated using 5-thiadiazole 1-oxide to prepare (a) 3-amino-4-[3-(3-dimethylaminomethylphenoxy)propylamino]-1,2, respectively;
5-thiadiazole, (b) 3-amino-4-[3-(3-diethylaminomethylphenoxy)propylamino]-1,2,
5-thiadiazole, (c) 3-amino-4-{3-[3-(2-methylpyrrolidino)methylphenoxy]propylamino}-1,2,5-thiadiazole, (d) 3-amino-4-{ 3-[3-(3-methylpyrrolidino)methylphenoxy]propylamino}-1,2,5-thiadiazole, (e) 3-amino-4-{3-[3-(4-methylpiperidino)methylphenoxy]propylamino }-1,2,5-thiadiazole, (f) 3-amino-4-[3-(3-morpholinomethylphenoxy)propylamino]-1,2,
5-thiadiazole, (g) 3-amino-4-{3-[3-N-methylpiperazino)methylphenoxy]propylamino}
-1,2,5-thiadiazole, (h) 3-amino-4-[3-(3-diallylaminomethylphenoxy)propylamino]-1,2,
5-thiadiazole, (i) 3-amino-4-[3-(3-hexamethyleneiminomethylphenoxy)propylamino]-
1,2,5-thiadiazole, (j) 3-amino-4-[3-(3-heptamethyleneiminomethylphenoxy)propylamino]-
1,2,5-thiadiazole, (k) 3-amino-4-{3-[3-(3-azabicyclo[3.2.2]non-3-yl)methylphenoxy]propylamino}-1,2,5- Thiadiazole, and (l) 3-amino-4-{3-[3-(3-pyrrolino)
Methylphenoxypropylamino}-1,2,
5-thiadiazole was produced. Example 6 3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-
Thiadiazole This is a modification of Example 1, Step B, which uses a smaller amount of sulfur monochloride and a shorter reaction time. N-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamide 3 in 120 ml of DMF
7.64 g (56.6 mmol) of sulfur monochloride was added to a stirred suspension of 12.08 g (28.3 mmol) of hydrochloride, and N ₂
Stirred under atmosphere for 3 hours. The black rubber from which DMF had been removed under reduced pressure was suspended in water, made alkaline with K ₂ CO ₃ and extracted with 3×100 ml of CH ₂ Cl ₂ . The combined extracts were dried over MgSO ₄ and overconcentrated to a black gum. This was purified using preparative high pressure liquid chromatography on silica using CH ₂ Cl ₂ (100):2-propanol (5):NH ₄ OH (0.5) as a fluid phase. The appropriate portions were combined to yield 3.1 g of the title compound as a dark oil. This was treated with fumaric acid in n-propanol to give 2.66 g (23.2%) of the crystalline fumarate salt of the title compound. Purity by HPLC
It turned out to be 99%. ( _C17H25N5OS ) Analytical values for _2.C4H4O4 : _{Calculated values} : C, _{56.27 ;} H, 6.71; _N , 17.27; S, 7.90. Measured values: C, 56.27; H, 6.96; N, 17.31; S, 7.98. Example 7 3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-
Thiadiazole This is a variation of Example 1, Step B, using sulfur dichloride instead of sulfur monochloride. SCl in 2 ml of DMF under an atmosphere of N2 in a stirred suspension of 854 mg ( ₂ mmol) of N-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamide trihydrochloride in 6 ml of DMF. ₂ 206 mg (2 mmol)
liquid was added. The reaction mixture was stirred at ambient temperature to yield the title compound. Example 8 3-Methylamino-4-[3-(3-piperidinomethylphenoxy)propylamino)-1,2,
5-thiadiazole A N-methyl-N'-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamide trihydrochloride 3-methylamino-4- in 95 ml of methanol
A suspension of 4.13 g (10.9 mmol) of [3-(3-piperidinomethylphenoxy)propylamino)-1,2,5-thiadiazole 1-oxide [prepared in accordance with published UK patent application no. 2067987]. After adding 7.2 ml of concentrated HCl to the cloudy solution and stirring for 3 hours at ambient temperature, the solution was concentrated and the residue was triturated with acetone and overdried to yield 4.35 g (90.4%) of the product.
A sample was recrystallized from aqueous isopropyl alcohol to give the title compound. Melting point 207-225°C (decomposition). Analytical values _{for C18H29N5O.3HCl} : Calculated values _: C, 49.03; H, 7.33; N, 15.89. Measured values (corrected for 0.94% _H2O ): C, 49.37; H, 7.35; N, 15.71. B 3-methylamino-4-[3-(3-piperidinomethylphenoxy)propylamino)-1,
2,5-thiadiazole N-methyl-N'-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamide 3
3.47 g (8.47 mmol) of hydrochloride [produced in step A],
A mixture of 34 ml CH ₂ Cl ₂ and 3.5 ml triethylamine was stirred for 1 hour. The mixture was washed with 30 ml of 10% KOH, dried over _MgSO4 , diluted with filtered toluene, and concentrated to yield 3.6 g of product. The product was purified by flash chromatography on 90 g of silica gel (230-400 mesh) with ethyl acetate-methanol (95:
5) was purified as an eluent to obtain 1.9 g (62
%) was obtained. The product was treated with an equivalent solution of hydrochloric acid in 1-propanol to give the hydrochloride salt of the title compound. Melting point 163.5-164.5°C C ₁₈ H ₂₇ N ₅ Analytical values for OS/HCl: Calculated values: C, 54.32; H, 7.04; N, 17.60; S, 8.06; Cl, 8.91. Measured values: C, 54.35; H, 7.07; N, 17.64; S, 36; Cl, 8.8 6. Example 9 3-benzylamino-4-[3-(3-piperazinomethylphenoxy)propylamino)-1,
2,5-thiadiazole A N-benzyl-N'-[3-(3-piperazinomethylphenoxy)propyl]ethanediimidamide trihydrochloride 3-benzylamino-4 in 100 ml of methanol
-[3-(3-piperazinomethylphenoxy)propylamino)-1,2,5-thiadiazole 1-
To a suspension of 5.14 g (11.3 mmol) oxide (prepared in accordance with published UK Patent Application No. 2,067,987) was added 7.55 ml of concentrated HCl and stirred for 3 hours at ambient temperature. The solution was concentrated and the residue was triturated with acetone and overdried to yield 5.16 g (88%) of the title compound. melting point
187−205℃ (decomposition). Analytical values _{for C24H33N5O.3HCl :} Calculated values: C, 55.75; H, 7.03; _N , 13.55; Cl, 20.57. Measured values: C, 54.88; H, 6.75; N, 13.33; Cl, 20.20. B 3-benzylamino-4-[3-(3-piperidinomethylphenoxy)propylamino)-1,
2,5-thiadiazole N-benzyl-N'-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamide trihydrochloride 4.73 g (9.16 mmol) [produced in step A], CH ₂ 45ml _Cl2 and 3.8ml triethylamine
3.64 g (9.16 mmol) of N,N'-thiobisphthalimide (DMF solvate) was added to the mixture and stirred for 1 hour. Wash the mixture with 44ml of 10% KOH
It was dried with _MgSO4 , diluted with filtered toluene, and concentrated. Apply the residue to silica gel (230-400 mesh)
Purified by flash chromatography on 110 g, eluting with ethyl acetate, yielding 3.1 g (77%) of the title compound.
I got it. The product was dissolved in an equivalent amount of HCl in 2-propanol.
Treatment with the solution gave the title compound hydrochloride. melting point
138°-141°C C ₂₄ H ₃₁ N ₅ Analytical values for OS/HCl: Calculated values: C, 60.80; H, 6.80; N, 14.77; S, 6.76; Cl, 7.48. Measured values: C, 60.53; H, 6.64; N, 14.99; S, 6.91; Cl, 7.47. Example 10 3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-
Thiadiazole This is a modification of Example 1, step B, in which N,N'-thiobisphthalimide is used in place of sulfur monochloride. N-[3-(3-piperidinomethylphenoxy)
Propyl ethanediimidamide trihydrochloride 27.3g
(64.0 mmol) [Produced in Example 1, Step A],
_{250ml CH2Cl2} and 26.6ml triethylamine
25.4 g (64.0 mmol) of N,N'-thiobisphthalimide (DMF solvate) was added little by little to a mixture of (192.0 mmol) and stirred at ambient temperature for 1 hour. The mixture was washed with 120 ml of 20% KOH, dried over _MgSO4 , overconcentrated, taken up in 150 ml of toluene and concentrated again.
The product was mixed with 250 ml of 1-propanol and 10.7 ml of 6N HCl.
ml, treated with decolorizing carbon, and passed through Celite. This solution was concentrated to a volume of 100 ml, diluted with 175 ml of dry 1-propanol and left at 0°C to yield 20.2 g (82.1%) of the crystalline hydrochloride salt of the title compound.
Melting point: 137-138℃ C ₁₇ H ₂₅ N ₅ Analytical values for OS/HCl: Calculated values: C, 53.18; H, 6.83; N, 18.24; S,
8.35. Measured value: C, 52.78; H, 6.74; N, 18.52; S,
8.66. Example 11 3-amino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5-
Thiadiazole This is a variation of Example 4, step B, in which N,N'-thiobisphthalimide is used in place of sulfur monochloride. N-[3-(3-pyrrolidinomethylphenoxy)
Propyl ethanediimidamide trihydrochloride 22.0g
(53.0 mmol) [Produced in Example 4, Step A],
21.2 g (53.0 mmol) of N,N'-thiobisphthalimide (DMF solvate) was added to a mixture of 200 ml of CH ₂ Cl ₂ and 22 ml of triethylamine at ambient temperature.
After stirring for an hour, wash the mixture with 100ml of 20% KOH.
It was dried with MgSO ₄ , filtered, diluted with 100 ml of toluene, and concentrated. 1 equivalent of product in 1-propanol
After treatment with aqueous HCl solution, 13.2 g of the title compound hydrochloride (67
%) was obtained. Melting point 135-137℃ C ₁₆ H ₂₃ N ₅ Analytical values for OS・HCl: Calculated values: C, 51.95; H, 6.54; N, 18.29; S,
8.67. Measured value: C, 51.92; H, 6.55; N, 19.30; S,
9.06. Example 12 3-Amino-4-{2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethylamino-1,2,5-thiadiazole A N-{2-[(5-dimethylaminomethyl- 3
-thienyl)methylthio]ethyl}ethanediimidamide trihydrochloride 3-amino-4-{2-
[(5-dimethylaminomethyl-3-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxide 7.8 g (22.6 mmol)
15.0 ml of concentrated HCl was added to the suspension of [produced in accordance with published British patent application no. 2067987] at ambient temperature
After stirring for an hour, the solution was concentrated and the residue was triturated with 1-propanol and dried to yield 7.38 g of product.
(80%). A sample was recrystallized from methanol-acetitone to give the title compound. Melting point 190−
205℃ (decomposition). Analytical _{values for C12H21N5S2.3HCl} : Calculated _values : C, 35.25; H, 5.92; N, 17.13. Measured values: C, 35.03; H, 5.93; N, 17.39. B 3-amino-4-{2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole N-{2-[(5-dimethylaminomethyl-3-
6.13 g (15.0 mmol) of thienyl)methylthio]ethyl}ethanediimidamide trihydrochloride [prepared in step A], 60 ml of CH ₂ Cl ₂ and triethylamine
Add 5.96 g (15 mmol) of N,N'-thiobisphthalimide (DMF solvate) to 6.3 ml of the mixture.
Stir for hours. Wash the mixture with 100ml of 10% KOH
Dry with MgSO ₄ , filter, dilute with toluene and concentrate to give 5.1 g of product. The product was treated with 0.5 molar equivalents of fumaric acid in 1-propanol to yield the fumarate salt of the compound. Melting point 141-143℃. DMSO−
The NMR spectrum in _d6 showed the presence of about 0.12 moles of 1-propanol. Analytical values for (C ₁₂ H ₁₉ N ₅ S ₃ )・C ₄ H ₄ O ₄・0.12C ₃ H ₈ O: Calculated values: C, 43.68; H, 5.61; N, 17.75; S, 24.38. Measured values: C, 43.41; H, 5.53; N, 17.54; S, 24.24. Example 13 3-amino-4-{2-[(5-piperidinomethyl-3-thienyl)methylthio]ethylamino-1,2,5-thiadiazole A N-{2-[(5-piperidinomethyl-3-thienyl) Methylthio]ethyl}ethanediimidamide trihydrochloride 3-amino-4-{2-
6.1 g (15.8 mmol) of [(5-piperidinomethyl-3-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxide [prepared in accordance with published UK patent application no. 2067987]. Add 10.5 ml of concentrated HCl to the turbid solution, stir at ambient temperature for 3 hours, concentrate the solution, triturate the residue with 50 ml of 1-propanol, and dry to obtain the product 5.86
g (83%). A sample was recrystallized from methanol-acetitone to give the title compound. melting point 201
-214℃ (decomposition). Analytical _{values for C15H25N5S2.3HCl} : _Calculated values: C, 40.13; H, 6.29; N, 15.60; S, 14.29. Measured values: C, 39.97; H, 6.47; N, 15.28; S, 14.39. B 3-amino-4-{2-[(5-piperidinomethyl-3-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole N-{2-[(5-piperidinomethyl-3-thienyl)methylthio] 5.17 g (11.5 mmol) of ethanediimidamide trihydrochloride [prepared in step A], 48 ml of CH ₂ Cl ₂ and 4.8 ml of triethylamine
ml of the mixture was stirred for 1 hour with 4.57 g (11.5 mmol) of N,N'-thiobisphthalimide (DMF solvate). Wash the mixture with 90ml of 10% KOH
Dry over MgSO ₄ , filter, dilute with toluene and concentrate to give 4.5 g of product. The product was treated with 1 equivalent of cyclohexylsulfamic acid in ethanol to yield the cyclohexylsulfamic acid salt of the title compound. Melting point 143-143℃. Analytical values for C ₁₅ H ₂₃ N ₅ S ₃ and C ₆ H ₁₃ NO ₃ S: Calculated values: C, 45.96; H, 6.61; N, 15.31; S, 23.38. Measured values: C, 45.61; H, 6.41; N, 15.46; S, 23.48. Example 14 3- used in the general method of Example 1, Step A and either Example 1, Step B or Example 10
Amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1-oxide is replaced by equimolar amounts of the following compounds: (a) 3-ethylamino -4-[3-(3-piperidinomethylphenoxy)propylamino]-1,
2,5-thiadiazole 1-oxide, (b) 3-allylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,
2,5-thiadiazole 1-oxide, (c) 3-(2-propynyl)-4-[3-(3-piperidinomethylphenoxy)propylamino]-
1,2,-5-thiadiazole 1-oxide, (d) 3-(3-pyridylmethylamino)-4-[3
-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1-
oxide, (e) 3-6-methyl-pyridyl)methylamino-
4-[3-(3-piperidinomethylphenoxy)
propylamino]-1,2,5-thiadiazole 1-oxide, (f) 3-(3,4-methylenedioxybenzylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino ]-1,2,5-thiadiazole 1-oxide, respectively, to prepare the following compounds: (a) 3-ethylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]- 1,
2,5-thiadiazole, (b) 3-allylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,
2,5-thiadiazole, (c) 3-(2-propynyl)-4-[3-(3-piperidinomethylphenoxy)propylamino]-
1,2,5-thiadiazole, (d) 3-(3-pyridylmethylamino)-4-[3
-(3-piperidinomethylphenoxy]propylamino]-1,2,5-thiadiazole, (e) 3-(6-methyl-3-pyridyl)methylamino-4-[3-(3-pyridyl) peridinomethylphenoxy)propylamino]-1,2,5-thiadiazole, and (f) 3-(3,4-methylenedioxybenzylamino)-4-[3-(3-piperidinomethylphenoxy) Example 15 3-amino-4-[3-(6-piperidinomethyl-2-pyridyloxy)propylamino]-1,
2,5-thiadiazole A 3-amino-4-[3-(6-piperidinomethyl-2-pyridyloxy)propylamino]-
1,2,5-thiadiazole 1-oxide 4.65 g of 3-(6-piperidinomethyl-2-pyridyloxy)propylamine in 50 ml of methanol
(18.6 mmol) [prepared in accordance with UK Patent Application No. 2098988] was dissolved in a solution of
3-amino-4-methoxy-1,2,5
3-amino-4-[3-(6
-piperidinomethyl-2-pyridyloxy)propylamino]-1,2,5-thiadiazole 1-
A solution containing oxide was obtained. The melting point of the purified compound was 145-147°C. B N-3-(6-piperidinomethyl-2-pyridyloxy)propyl]ethanediimidamide 3
Hydrochloride A methanolic solution of the product prepared in step A
12.4 ml of dilute concentrated HCl was added to 100 ml. The solution was stirred at ambient temperature for 18 hours, then concentrated, and the residue was dissolved in 80 ml of water and extracted twice with CH ₂ Cl ₂ . The aqueous layer was concentrated, treated with n -propanol, and concentrated under high vacuum to give the title compound as a foam. C 3-amino-4[3-(6-piperidinomethyl-2-pyridyloxy)propylamino]-1,
2,5-thiadiazole The crude product prepared in step B was mixed with 7.69 ml of triethylamine in 80 ml of CH ₂ Cl ₂ and brought to ambient temperature with 7.35 g (18.5 mmol) of N,N'-thiobisphthalimide (DMF solvate). The mixture was stirred for 1 hour. The mixture was washed successively with 50 ml of 4N NaOH, water, saturated aqueous NaCl, dried over _NaSO4 , filtered and evaporated under reduced pressure to give the crude product. The product was purified by silica gel (230−400
Purified by flash chromatography on 100 g of ethyl acetate-methanol (95:
5) 3.63 g of the title compound as a viscous oil eluted with
I got it. The product was treated with 1 equivalent of cyclohexylsulfamic acid in acetone to give the cyclohexylsulfamic acid salt of the title compound. melting point
125.5−131℃. Analytical values for C ₁₆ H ₂₄ N ₆ OS・C ₆ H ₁₃ NO ₃ S: Calculated values: C, 50.07; H, 7.07; N, 18.58; S, 12.15. Measured values: C, 50.02; H, 7.03; N, 18.54; S, 12.15. Example 16 3-amino-4-[3-(6-dimethylaminomethyl-2-pyridyloxy)propylamino]
-1,2,5-Thiadiazole 3-(6-dimethylaminomethyl-2-pyridyloxy)propylamino is also described in methanolic solution [prepared according to UK Patent Application No. 2098988] in UK Patent Application No. 2067987 3-amino-4[3-(6-piperidinomethyl-2-pyridyloxy)propylamino]-1 obtained by reacting with 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide by the general method of , 2,5-thiadiazole 1-oxide followed by Example 1, Step A and Example 1 Step B or Example 10
The title compound was prepared by successive reactions by any of the following general methods. Example 17 3-amino-4-{2-[(6-dimethylaminomethyl-2-pyridyl)methylthio]ethylamino]-1,2,5-thiadiazole 3-amino-4-{2-[6-dimethyl Aminomethyl-2-pyridyl)methylthio]ethylamino]-1,2,5-thiadiazole 1-oxide [prepared in accordance with UK Patent Application No. 2067987]
The title compound was prepared by reacting a suspension of the following in sequence according to the method of Example 1, Step A, and then either the method of Example 1, Step B or Example 10. Example 18 3-amino-4-{2-[(6-piperidinomethyl-2-pyridyl)methylthio]ethylamino]-1,2,5-thiadiazole 3-amino-4-{2-[(6-piperidinomethyl- 2-pyridyl)methylthio]ethylamino]
A suspension of -1,2,5-thiadiazole 1-oxide [prepared in accordance with UK patent application no. The title compound was prepared by reaction method. Example 19 3-amino-4-[3-(3-piperidinodimethylphenoxy)propylamino]-1,2,5
- Thiadiazole 1-oxide is replaced by equimolar amounts of the following compounds: (a) 3-amino-4-[3-(3-piperidinomethylthiophenoxy)propylamino]-1,2,
5-thiadiazole 1-oxide, (b) 3-amino-4-[3-(3-dimethylaminomethylthiophenoxy)propylamino]-1,
2,5-thiadiazole 1-oxide, (c) 3-amino-4-[3-(3-pyrrolidinomethylthiophenoxy)propylamino]-1,2,
-5-thiadiazole 1-oxide, (d) 3-amino-4-[3-(4-dimethylaminomethyl-2-pyridyloxy)propylamino]-1,2,5-thiadiazole 1-oxide, (e) 3-amino-4-[3-(5-dimethylaminomethyl-3-thienyloxy)propylamino]-1,2,5-thiadiazole 1-oxide, (f) 3-amino-4-[3-(5 -piperidinomethyl-3-thienyloxy)propylamino]-
1,2,5-thiadiazole 1-oxide, (g) 3-amino-4-{2-[(4-dimethylaminomethyl-2-pyridyl)methylthio]ethylamino-1,2,5-thiadiazole 1-oxide , and (h) 3-amino-4-{2-[(4-piperidinomethyl-2-pyridyl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxide, respectively. A and then the following compound according to either Example 1, Step B or Example 10: (a) 3-amino-4-[3-(3-piperidinomethylthiophenoxy)propylamino]-1 ,2,
5-thiadiazole, (b) 3-amino-4-[3-(3-dimethylaminomethylthiophenoxy)propylamino]-1,
2,5-thiadiazole, (c) 3-amino-4-[3-(3-pyrrolidinomethylthiophenoxy)propylamino]-1,2,
-5-thiadiazole, (d) 3-amino-4-[3-(4-dimethylaminomethyl-2-pyridyloxy)propylamino]-1,2,5-thiadiazole, (e) 3-amino-4- [3-(5-dimethylaminomethyl-3-thienyloxy)propylamino]-1,2,5-thiadiazole, (f) 3-amino-4-[3-(5-piperidinomethyl-3-thienyloxy)propyl Amino〕-
1,2,5-thiadiazole, (g) 3-amino-4-{2-[(4-dimethylaminomethyl-2-pyridyl)methylthio]ethylamino-1,2,5-thiadiazole, and (h) 3 -Amino-4-{2-[(4-piperidinomethyl-2-pyridylmethyl)methylthio]ethylamino}-1,2,5-thiadiazole were obtained, respectively. The above starting compounds are listed in published UK patent application no.
Manufactured by the general method described in No. 2067987. The precursors of the starting materials are UK Patent Application No. 2067987,
2098988 and 2063875 and published European Patent Application No. 49173 and similar general methods. Example 20 3-amino-4-[3-(4-piperidinomethyl-2-pyridyloxy)propylamino]-1,
2,5-thiadiazole A 3-(4-piperidinomethyl-2-pyridyloxy)propylamine 2 used in the general process for the preparation of 3-(6-piperidinomethyl-2-pyridyloxy)propylamine described in UK Patent Application No. 2098988 -2-bromo-4-methylpyridine was used in place of chloro-6-methylpyridine to produce the oily title compound. Analytical values _{for C14H23N3O} : Calculated _: C, 67.44; H, 9.30; N, 16.85. Measured values: C, 67.54; H, 8.98; N, 16.55. B 3-amino-4-[3-(4-piperidinomethyl-2-pyridyloxy)propylamino]-
1,2,5-Thiadiazole 1-oxide A solution of 6.5 g (26.0 mmol) of the product of the step in 90 ml of methanol was prepared by the general method described in British Patent Application No. 2067987 to 3-amino-4-methoxy-
1,2,5-thiadiazole 1-oxide 3.84
g (26.0 mmol) to yield 6.33 g of product. Recrystallization from methanol-acetonitrile gave the title compound. Melting point 154-158℃. Analysis values for C ₁₆ H ₂₄ N ₆ OS: Calculated values: C, 52.73; H, 6.64; N, 23.96; S,
8.80. Measured value: C, 52.72; H, 6.30; N, 23.32; S,
8.74. C N-[3-(4-piperidinomethyl-2-pyridyloxy)propyl]trihydrochloride 5.0 g of Step B product (13.7
mmol) was dissolved and 9.1 ml of concentrated HCl was added. After stirring at ambient temperature for 4.5 hours, the solution was evaporated to dryness under reduced pressure to yield the title compound. D 3-amino-4[3-(4-piperidinomethyl-2-pyridyloxy)propylamino]-1,
2,5 _- Thiadiazole N, _N'-
Thiobisphthalimide (DMF solvate) 5.44g
(13.7 mmol) and stirred for 1 hour at ambient temperature, the mixture was diluted with 40 ml of 4N NaOH, water and saturated NaCl.
Washed sequentially with aqueous solutions, dried over Na ₂ SO ₄ and filtered.
The crude product was obtained by concentration under reduced pressure. The product was purified by flash chromatography on 90 g of silica gel (230-400 mesh) and eluted with ethyl acetate-methanol (96:4) to give 3.44 g of the title compound as a viscous oil. The product in acetone at 1
Treatment with an equivalent amount of cyclohexylsulfamic acid gave the cyclohexylsulfamic acid salt of the title compound. Melting point 124.5-126℃. Analytical values for C ₁₆ H ₂₄ N ₆ OS・C ₆ H ₁₃ NO ₃ S: Calculated values: C, 50.07; H, 7.07; N, 18.58; S, 12.15. Measured values: C, 50.47; H, 7.12; N, 18.33; S, 11.87. Example 21 3-Amino-4-{3-[3-(1,2,3,6
-tetrahydro-1-pyridyl)methylphenoxy]propylamino}-1,2,5-thiadiazole Instead of the 3-(6-piperidinomethyl-2-pyridyloxy)propylamino used in Example 15, an equimolar amount of 3-[ 3-(1,2,3,6-
The general procedure was repeated using tetrahydro-1-pyridyl)methylphenoxy]propylamine to give 2.31 g of product. Recrystallization from toluene gave the title compound. Melting point 99.5-104℃. Analytical values _{for C17H23N5OS} : Calculated values _: C, 59.10; H, 6.71; N, 20.27; S, 9.28. Measured values: (corrected for 2.19% _H2O ) C, 58.78; H, 6.71; N, 19.90; S, 9.26. In connection with the present invention, the following embodiments are also proposed. 1 Formula: [Formula R ¹ is hydrogen, lower alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, allyl, propargyl,
[Formula] or [Formula] (where p is 1 or 2, R ² and R ³ independently represent hydrogen, lower alkyl, lower alkoxy or halogen, and when R ² is hydrogen, R ³ is May be trifluoromethyl, or
R ² and R ³ are both methylenedioxy, and
R ⁴ represents hydrogen, lower alkyl or lower alkoxy), m is an integer from 0 to 2, n is an integer from 2 to 5, Z represents oxygen, sulfur or methylene, and A is [Formula] [Formula] [Formula] or [Formula] (In the above formula, R ⁵ represents hydrogen, lower alkyl, or lower alkoxy, q is an integer from 1 to 4, and R ⁶ and R ⁷ independently represent lower alkyl,
represents lower alkoxy lower alkyl, or phenyl lower alkyl, in which the lower alkoxy moiety is at least two carbon atoms removed from the nitrogen atom, and when R ⁶ is hydrogen, R ⁷ may be cyclo-lower alkyl or R ⁶ and ^R7 together with the nitrogen atom to which they are bonded is pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, N-methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino, 3-azabicyclo [3.2.2.] non-3-yl or 3-pyrrolino) or a salt thereof; Hydrate or solvate. 2 Formula: In the formula, R ¹ is hydrogen or lower alkyl,
m is 0 or 1, n is 2 or 3, and Z
is oxygen or sulfur, and A is [formula], [formula], [formula] or [formula] (in the above formula, R ⁵ is hydrogen or methyl, and R ⁶
and R ⁷ are each independently methyl or ethyl, or together with the nitrogen to which they are bonded form a pyrrolidino or piperidino ring) or a salt thereof, water compound or solvate. 3 Formula a: In which R ¹ is hydrogen or methyl, and R ⁶ and
A compound according to item 1 above, or a salt, hydrate or solvate thereof, having formula a, wherein R ⁷ is each methyl, or together with the nitrogen to which they are attached, forms a pyrrolidino or piperidino ring. 4 Formula b: A compound according to item 1 above, having the formula b, wherein R ¹ and R ⁵ are each independently hydrogen or methyl, and R ⁶ and R ⁷ are each independently methyl or ethyl, or its salts, hydrates or solvates; 5. Formula c: The compound according to item 1 above, having formula c, wherein R ¹ and R ⁵ are independently hydrogen or methyl, and R ⁶ and R ⁷ are independently methyl or ethyl. or a salt, hydrate or solvate thereof. 6 Formula d: A compound according to item 1 above, having formula d, wherein R ¹ and R ⁵ are each independently hydrogen or methyl, and R ⁶ and R ⁷ are each independently methyl or ethyl, or its salts, hydrates or solvates; 7. The compound according to item 1 above, which is N-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamide, or a salt, hydrate or solvate thereof. 8 N-{2-[(5-dimethylaminomethyl-2
-furyl)methylthio]ethyl}ethanediimidamide, or a salt, hydrate or solvate thereof, according to item 1 above. 9 N-{2-[(5-dimethylaminomethyl-4
-Methyl-2-thienyl)methylthio]ethyl}ethanediimidamide, or a salt, hydrate or solvate thereof, according to item 1 above. 10 The compound according to item 1 above, which is N-[3-(3-pyrrolidinomethylphenoxy)propyl]ethanediimidamide, or a salt, hydrate or solvate thereof. 11 N-{2-[(5-dimethylaminomethyl-3
-thienyl)methylthio]ethyl}ethanediimidamide, or a salt, hydrate or solvate thereof, according to item 1 above. 12 The compound according to item 1 above, which is N-{2-[(5-piperidinomethyl-3-thienyl)methylthio]ethyl}ethanediimidamide, or a salt, hydrate or solvate thereof. 13 The compound according to item 1 above, which is N-[3-(6-piperidinomethyl-2-pyridyloxy)propyl]ethanediimidamide, or a salt, hydrate or solvate thereof. 14 The compound according to item 1 above, which is N-[3-(4-piperidinomethyl-2-pyridyloxy)propyl]ethanediimidamide, or a salt, hydrate or solvate thereof. 15 The compound according to item 1 above, which is N-[3-(3-(1,2,3,6-tetrahydro-1pyridyl)methylphenoxy]ethanediimidamide, or a salt, hydrate or solvate thereof. 16 Formula: [Formula] [In the above formula, R ¹ is hydrogen, lower alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, allyl, propargyl [Formula] or [Formula] (In the above formula, p is 1 or 2, R ² and R ³ are each independently hydrogen, lower alkyl, lower alkoxy or halogen, and when R ² is hydrogen, R ³ may be trifluoromethyl, or
R ² and R ³ may both be methylenedioxy and R ⁴ is hydrogen, lower alkyl or lower alkoxy), m is an integer from 0 to 2, n is an integer from 2 to 5, Z represents oxygen, sulfur or methylene, and A is [Formula] [Formula] [Formula] or [Formula] (In the above formula, R ⁵ is hydrogen, lower alkyl or lower alkoxy, and q is an integer of 1 to 4. and R ⁶ and R ⁷ are independently lower alkyl,
lower alkoxy lower alkyl or phenyl lower alkyl in which the lower alkoxy moiety is at least two carbon atoms removed from the nitrogen atom, and
When R ⁶ is hydrogen, R ⁷ may be cyclolower alkyl, or R ⁶ and R ⁷ together with the nitrogen atom to which they are attached may be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino. , dimethylpiperidino, N-methylpiperidino, 1,2,3,6-tetrahydropyridyl,
homopiperidino, heptamethyleneimino, octamethyleneimino, 3-azabicyclo[3.2.2. acid, preferably hydrochloric acid to produce a compound of the formula: A-( _CH2 ) _nZ ( _CH2 ) _{oNH2 ,} where A, m, Z, and n are as above. after reacting a compound with the formula: [formula] with a compound having the formula: [formula] to form a _compound with ^{the formula} : by reacting with a compound having the formula: [in which A, m, Z, n and R ¹ have the meanings as defined above]. A method for producing a compound having the above formula, characterized by producing a compound.

Claims (1)

[Scope of Claims] 1 Formula: [Formula R ¹ is hydrogen, lower alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, allyl, propargyl, [Formula] or [Formula] ( However, p is 1 or 2, R ² and R ³ are hydrogen, lower alkyl, lower alkoxy, or halogen, and when R ² is hydrogen, R ³ may be trifluoromethyl, or R ² and R ³ are both methylenedioxy, and R ⁴ is hydrogen, lower alkyl, or lower alkoxy), m is an integer of 0 to 2, n is an integer of 2 to 5, and Z is oxygen, sulfur, or methylene. and A is [Formula] [Formula] [Formula] or [Formula] (In the above formula, R ⁵ is hydrogen, lower alkyl or lower alkoxy, q is an integer from 1 to 4, and
R ⁶ and R ⁷ are each independently lower alkyl or at least two lower alkoxy moieties removed from the nitrogen atom.
lower alkoxy lower alkyl or phenyl lower alkyl which is a carbon atom, and if R ⁶ is hydrogen, R ⁷ may be cyclo lower alkyl or R ⁶
and R ⁷ together with their bonded nitrogen atoms are pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, N
- methylpiperazino, 1,2,3,6-tetrahydropyridyl, homopiperazino, heptamethyleneimino, octamethyleneimino, 3-azabicyclo[3.2.2.]non-3-yl or 3-pyrrolino) ] or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof. 2 Formula: In the formula, R ¹ is hydrogen or lower alkyl, and m
is 0 or 1, n is 2 or 3, Z is oxygen or sulfur, and A is [formula] [formula] [formula] or [formula] (in the above formula, R ⁵ is hydrogen or methyl Yes, and R ⁶
and R ⁷ are each independently methyl or ethyl, or together with their bonding nitrogen form a pyrrolidino or piperidino ring, or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof The compound according to claim 1, which is a compound. 3 Formula a: In the formula, R ¹ is hydrogen or methyl, and R ⁶ and
Claims in which R ⁷ is each methyl or a compound of formula a forming a pyrrolidino or piperidino ring together with the nitrogen to which they are attached, or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof A compound according to scope 1. 4 Formula b: A compound of formula b, or a pharmaceutically acceptable compound thereof, wherein R ¹ and R ⁵ are independently hydrogen or methyl, and R ⁶ and R ⁷ are independently methyl or ethyl. The compound according to claim 1, which is a non-toxic salt, hydrate or solvate. 5. Formula c: A compound of formula c, where R ¹ and R ⁵ are independently hydrogen or methyl, and R ⁶ and R ⁷ are independently methyl or ethyl, or a pharmaceutically acceptable non-toxic compound thereof The compound according to claim 1, which is a salt, hydrate or solvate. 6 Formula: [In the above formula, R ¹ and R ⁵ are each independently hydrogen or methyl, and R ⁶ and R ⁷ are each independently methyl or ethyl, or together with the nitrogen atom to which they are attached 2. The compound according to claim 1, which is a compound having a compound (forming pyrrolidino) or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof. 7 3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-
The compound according to claim 1, which is thiadiazole or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof. 8 3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-
Claim 1 which is thiadiazole hydrochloride
Compounds described in Section. 9 3-amino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof The compound according to claim 1, which is a compound. 10 3-amino-4-{2-[(5-dimethylaminomethyl-4-methyl-2-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole or a pharmaceutically acceptable non-toxic salt thereof, water The compound according to claim 1, which is a compound or a solvate. 11 3-Amino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5
- The compound according to claim 1, which is thiadiazole or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof. 12 3-methylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,
The compound according to claim 1, which is 2,5-thiadiazole or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof. 13 3-benzylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,
The compound according to claim 1, which is 2,5-thiadiazole or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof. 14 3-Amino-4-{2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof The compound according to claim 1, which is a compound. 15 3-Amino-4-{2-[(5-piperidinomethyl-3-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof A compound according to certain claim 1. 16 3-amino-4-[3-(6-piperidinomethyl-2-pyridyloxy)propylamino]-
The compound according to claim 1, which is 1,2,5-thiadiazole or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof. 17 3-amino-4-[3-(4-piperidinomethyl-2-pyridyloxy)propylamino]-
The compound according to claim 1, which is 1,2,5-thiadiazole or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof. 18 3-amino-4-{-[3-(1,2,3,
The compound according to claim 1, which is 6-tetrahydro-1-pyridyl)methylphenoxypropylamino}-1,2,5-thiadiazole or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof. . 19 Formula: [In the above formula, R ¹ is hydrogen, lower alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,
Allyl, propargyl, [Formula] or [Formula] (However, in the above formula, p is 1 or 2, R ² and R ³ are independently hydrogen, lower alkyl, lower alkoxy, or halogen, and R ² is hydrogen Sometimes
R ³ may be trifluoromethyl, or R ² and R ³
may both be methylenedioxy, and
R ⁴ is hydrogen, lower alkyl or lower alkoxy), m is an integer from 0 to 2, n is an integer from 2 to 5, Z represents oxygen, sulfur or methylene, and A is [Formula] Formula] [Formula] or [Formula] (In the above formula, R ⁵ is hydrogen, lower alkyl or lower alkoxy, q is an integer from 1 to 4,
and R ⁶ and R ⁷ are each 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 R ⁶ is hydrogen; R ⁷ may be cyclo-lower alkyl, or R ⁶ and R ⁷ together with the nitrogen atom to which they are bonded may be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino,
piperidino, methylpiperidino, dimethylpiperidino, N-methylpiperidino, 1,2,3,6-
Tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino, 3-azabicyclo[3.2.2.]non-3-yl or 3-
pyrrolino) in an organic solvent inert to the reaction at a temperature of 0°C to 50°C.
A compound, or a pharmaceutically acceptable non-toxic salt or hydrate thereof ^, which is reacted with sulfur chloride and has the formula: or a method for producing a compound having the above formula, or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof, which is characterized by producing a solvate.