JPS58180477A - Histamine h2-acceptor antagonistic substituted 3,4-diamino-1,2,5-thiadiazole - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides substitutions 6 with histamine H2-receptor antagonistic activity.
．． It relates to 4-diamino-1,2,5-thiadiazole.

A certain 3-(amine or amino)-4 of formula I: where I's rns Z, n and R are defined below.
-C-substituted amine)-1,2,5-thiadiazole and its pharmaceutically acceptable non-toxic forms, hydrates and solvates are effective histamine H2-receptor antagonists that suppress gastric acid secretion and cause gastric ulcers and other abnormal secretions. Useful for treating overload conditions. This compound] is prepared by ring closure of the corresponding substituted ethanediimidamide having the formula (1).

Applicants' UK Patent Application No. 2.067987 has the formula: (
3.4-2 slightly substituted-1 having the above formula, A, m, Z, n and R1 are the same as the corresponding substituents of the compound of the present invention
, 2,5-thiadiazole 1-oxide and 1.1
-Dioxide 25- and its production method have been announced. However, the compounds announced there were 1-oxide and 1,1-dioxide (pH
1 or 2), and the compound of the present invention is the conventional compound described therein! It cannot be manufactured using any of the methods described in Example 1.

Published European Patent Application No. 40.696 specifically describes the formula: (0) in which R1, n, Motsu 3.4-
29-methylated-1,2,5-thiadiazole 1-oxide and 1
, 1-dioxide, but the compounds are also 1-oxides or 1,1-dioxides (p 1 or 2), and the compounds of the present invention can be prepared by the methods of preparing conventional compounds described therein. cannot be manufactured.

26- Each method for producing the conventional compound in the above formula "2" is 6- and 4
1,2,5-thiadiazole 1-oxide or 1,1 with an amino slow or suitable leaving group in the - position
- Dioxide is used. Desired substituents on the 3- and 4-positions can later be replaced on the amine group or "leaving group"
obtained by replacing . Applicants have prepared the present invention using the same method, ie, 1,2,5-thiadiazole with an amino group or a suitable "leaving group" on 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, it was not possible to isolate the compound v/1 of the present invention using the above method.

Applicants have now discovered that compounds of the invention can be prepared by ring closure of the corresponding substituted ethanediimidamide having the formula: Intermediate (1) itself can be produced by various methods.

The present invention relates to formula I: [In the above formula, R1 is hydrogen, lower alkyl, 2-fluoroethyl, 2.2.2-] IJ fluoroethyl, allyl,
flopargyl, (where p is 1 or 2, R2 and R3 are independently hydrogen, lower alkyl, lower alkoxy, or halogen, and when R2 is hydrogen, R3 may be trifluoromethyl, or both R2 and R3 are methylene) (may be dioxy and R4 is hydrogen, lower alkyl or lower alkoxy), m is an integer of O to 2, n is an integer of 2 to 5, 2 is oxygen, sulfur or methylene, and A is (In the above formula, R5 is hydrogen, lower alkyl, or lower alkoxy, q is an integer from 1 to 4, and R6 and R7 are independently lower alkyl or at least two carbon atoms from which the lower alkoxy moiety is removed from the nitrogen atom. is lower alkoxy lower alkyl, or C phenyl lower alkyl, and if R6 is hydrogen, R7 may be cyclo-lower alkyl, or R6 and R7 together with the nitrogen atom to which they are bonded are pyrrolidino, methylpyrrolidino, dimethyl Pyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, N-methylpiperazino, 1,2,3,6-titrahydropyridyl, homopiperidino, heptamethyleneimino, off-29-tamethyleneimino, 3-azabicyclo [3, 2, 2]
] Non-3-yl represents 6-viroline)] and pharmaceutically acceptable non-toxic compounds, hydrates and solvates thereof.

The invention also relates to processes for preparing compounds of formula I and intermediate compounds of formula n.

Also included within the scope of the invention are all possible tautomers, diastereoisomers and optically active isomers of the compounds of formula I and mixtures thereof. As used herein and in the claims, "lower alkyl" means a straight chain or branched alkyl group having 1 to 6 carbon atoms. "Lower alkoxy" means a straight chain or branched alkyl group having 1 to 4 carbon atoms. Refers to a branched alkoxy group. "Cyclolower alkoxy" refers to a cycloalkyl group having 6 to 6 carbon atoms.

“Pharmaceutically acceptable non-toxic” means hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, acetic acid, 30-propionic acid, fumaric acid, methanesulfonic acid, maleic acid, tartaric acid, citric acid, l/vric acid, benzoic acid. Refer to acid addition salts formed with acids, such as succinic acid.

R1 in compounds of formula I may be hydrogen or lower alkyl, preferably hydrogen or methyl, and most preferably hydrogen. The W substituent A is preferably the above substituted phenyl moiety, substituted furyl moiety or substituted chenyl moiety, and most preferably the substituted phenyl moiety. Substituent 2 is preferably oxygen or oxygen, and if A is a substituted phenyl moiety, 2 is preferably oxygen. It is preferable that m is 0 or 1 and n is 2 or 6, and when A is a substituted phenyl moiety, it is preferable that m is 0 and n is 3. R5 is preferably hydrogen or methyl, most preferably hydrogen. q is preferably 1. Preferably R6 and R are lower alkyl or together with the 9 atoms to which they are attached form pyrrolidino or piperidino.

A compound of formula I is a compound of formula
S2C]2), di-filled sulfur (sci, As defined. About 1 mole of 52c per mole of compound ■
12 or 5C12 must be used. excess 82C1,
or 5C12, such as from about 2 to about 6 moles of 52C12 or 5C12 per mole of compound. 5C12
Since it is known that Hashiba removes the crude product and has a poor yield of the purified product, 82C12 is preferably used for the Kazu reaction. The reaction temperature is important, and the reaction is carried out at a temperature of about 0 to about 50°C, although it is most convenient to carry out the reaction at room temperature. The reaction time depends on the temperature and is usually about 30 minutes.
It takes about 6 hours. Reaction times of about 1.5 to 4 hours, usually at room temperature, are preferred. The reaction is carried out in an inert organic solvent,
Preferably, it can be carried out in a mixture of an inert organic solvent and dimethylformamide. The reaction is best carried out in dimethylformamide.

The compounds of a preferred embodiment of the invention have formula I: or a pharmaceutically acceptable non-toxic form, hydrate or solvate thereof. In the above formula, R1 represents hydrogen or lower alkyl,
m is 0 or 1, n is 2 or 6, and 2 represents oxygen or sulfur; 8 represents ethyl, or R6 and R7 together with their attached nitrogen form a pyrrolidino or piperidino ring. In a highly preferred embodiment, compounds of formula I are of structure Ia: R1 represents hydrogen or methyl; R6 and R7
is methyl or forms a pyrrolidino or piperidino ring with its bonding nitrogen), or is a pharmaceutically acceptable crude, hydrate or solvate thereof.

In a more preferred embodiment, the compound having formula I has the structural formula Ib: or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof.

In another more preferred embodiment, the compound with formula 1 has the structural formula Ic: 5 in which R1 and R5 independently represent hydrogen or methyl and R6 and R7 independently represent methyl or ethyl. compound or a pharmaceutically acceptable non-toxic compound, hydrate or solvate thereof.

In another more preferred embodiment, the compound having formula I is of structural formula Id: where R1 and R5 independently represent hydrogen or methyl; or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof.

The most preferred compounds having formula I as described above are:

1) 3-amino-4-[3-(3-piperidinomethylphenoxy)propylamine]-1,2,5-thiadiazole, 2) 3-amino-4-(2-((5-dimethylaminemethyl) -2-furyl)methylthio]ethylamino) -1,2゜5-thiadiazole, 3)6-amino-4-(2-((5-dimethylaminemethyl-4-methyl-2-chenyl)methylthio]ethylamino )-1,2,5-thiadiazole, 3-amino-4-[3-(3-pyrrolidinomethylphenoxycoupropylamino]-1,2,5-thiadiazole, 5
) 3-Methylamino-4-[3-(3-piperidinomethylphenoxy]propylamine)-1,2,5-thiacyazole, 6) 3-benzylamino-4-(3-(j-piperidino methylphenoxy)propylamine]-i, 2.5-thiadiazole, 7]6-amino-4-(2-[(5-dimethylaminomethylo7-ru-3-chenyl)methylthio]ethylamino)-1
,2゜5-thiadiazole, 8)3-amino-4-(2-((5-piperidinomethyl-3-chenyl)-methylthio]ethylamine)-1,
2,5-thiadiazole, 9) 6-amino-4-(3-(j-piperidinomethyl-
2=pyridyloxy)propylamine)-1,2,5-
thiadiazole, and 10) 6-amino-4-(3-(4-piperidinomethyl-2-pyridyloxy)propylamine)-1,2,5
- thiadiazole, and pharmaceutically acceptable non-toxic salts, hydrates and solvates thereof.

The intermediates of formula (1) used in the preparation of compounds of formula I can themselves be prepared in various ways. 1 method is the corresponding formula ■
3-(amino or substituted amino)-4-(fF7 substituted amino)-1,2,5-thiadiazole 1-oxide having 68- is treated with a strong mineral acid (HCI is preferred) to form a compound of formula That's what I do.

The reaction is preferably carried out in an inert solvent, preferably methanol. Since the reaction polarity is less than 1, it is most convenient to carry out the reaction at room temperature. Compounds of formula (1) are well known and can be easily prepared by the method described in United Kingdom Patent Application No. 2,06Z9B7 of the same applicant.

Another method for making cloth from the compound having formula (■) is as follows.

The reaction is carried out in an inert solvent, preferably methanol.

Starting materials having the formula (1) are known and can be readily prepared, for example, by the method described in Applicants' GB Patent Application No. 2,067.987.

Another aspect of the present invention relates to a new intermediate having the formula (1): or a salt, hydrate or solvate thereof. In the above formula, R1 is hydrogen, lower alkyl, 2-fluoroethyl, 2,2.2-thiofluoroethyl, allyl,
Propargyl, (wherein p is 1 or 2, R2 and R3 independently represent hydrogen, lower alkyl, lower alkoxy or) rogene - and when R2 is hydrogen, R3 may be trifluoromethyl or R2 and R3 may both be methylenedioxy, and R4 represents hydrogen, lower alkyl, or lower alkoxy), m is an integer from 0 to 2, and n is 2.
An integer from 1 to 5, 2 represents oxygen, sulfur, or methylene, and A is 41- (in the above formula, R5 represents hydrogen, lower alkyl, or lower alkoxy, p is an integer from 1 to 4, and R6 and R7
independently represents 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 9-group atom, and when R6 is hydrogen, R7 may also be cyclo-lower alkyl. pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, N-methylpiperazino; 3.6'-tetrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino, 3-azabicyclo[3°2.2]
forming non-3-yl or 3-viroline].

In a preferred embodiment, the intermediate having the formula ■ has the structural formula ■
: [In the above formula, R1 is hydrogen or lower alkyl, m is 0 or 1, n is 2 or 6, Z is oxygen or an atom, and A is (in the above formula, R5 is hydrogen or methyl, and R6
and R7 are each independently methyl or ethyl, or R6 and R
A preferred embodiment is a compound or a pharmaceutically acceptable solid, hydrate or solvate, wherein 7 forms a pyrrolidino or piperidino ring with the nitrogen to which they are bonded. The intermediate having the formula ■ is structural formula ■a: (wherein R1 is hydrogen or methyl, and R6 and R7 are each methyl, or together with the nitrogen atom to which they are bonded, they form a pyrrolidino or piperidino ring. ) or its salt, hydrate or solvate.

In another preferred embodiment, the intermediate having formula (1) has the structure (2) b = 5, where R1 and R5 are each independently hydrogen or methyl and R6 and R7 are each independently methyl or ethyl. A compound or its derivatives, hydrates or solvates.

In a preferred embodiment of Sen, the intermediate having the formula ■ has the formula ■
C: (In the above formula, R1 and R5 are each independently hydrogen or methyl, and R6 and R7 are each independently methyl or ethyl) or a salt, hydrate or solvate thereof; Other preferred In embodiments, the intermediate having the formula ■ has the formula ■
d: having (in the above formula, R1 and R5 are each independently hydrogen or methyl, and R6 and R7 are each independently methyl or ethyl, or together with the molecules to which they are attached form piperidino) A compound or a salt, hydrate or solvate thereof.

45- The most likely intermediates with formula ■ as arranged are: 1) N-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamide, 2) N-(2 -[(5-dimethylaminemethyl-2-furyl9methylthio]ethyl)ethanediimidamide, 3
)N-(2-[(5-dimethylaminomethyl-4-methyl-2-thenyl)methylthio]ethyl)ethanediimidamide, liN-[3-(3-pyrrolidinomethylphenoxy)propyl]ethanediimide 5) N-(2-[(5-dimethylaminemethyl-6-chenyl)methylthio]ethyl)ethanediimidamide, 5) N-(2-[(5-piperidinomethyl-3-chenyl)methylthio]ethyl) ethanediimidamide, 46-7)N-[3-(6-piveridinomethyl-2-pyridyloxy]propyl]ethanediimidamide, and 8)N
-[j-(4-piperidinomethyl-2-pyridyloxy)propyl]ethanediimidamide, or a hydrate or solvate thereof.

Pharmacologically active compounds of formula I for therapeutic use are usually pharmaceutical preparations consisting of at least one of the above compounds in cyclic form or in the form of a pharmaceutically acceptable non-toxic acid salt as the essential active ingredient together with pharmaceutically acceptable carriers. Administered as a composition.

The pharmaceutical composition can be administered parenterally or rectally for gauze purposes. A pharmaceutical form of glaze is used. Thus, if a solid phase 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, they 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 the patient's weight, the degree of gastric acid suppression desired, and the efficacy of the particular compound used.

Instructions as to the specific amount of drug to be used (and the number of daily doses) are at the discretion of the physician and will vary depending on the titration of the drug for the particular condition of the individual. Preferred oral dosage units for the use of the compounds of this invention contain from about 2 to about 300 mg of active ingredient.
, will preferably contain from 4 to about 100 cm. The active ingredient may be administered in equal doses 1 to 4 times a day.

Histamine H2-receptor antagonists have been shown to be effective in suppressing secretion in both animals and humans. (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., 8001 (1977)) Histamine H2-receptor antagonist in the right atrium of Guinean pigs and mice isolated by comparing some of the preferred compounds of the present invention with cimetidine in a single test. It has been found to be more potent than cimetidine both as a gastric acid secretion suppressant and in dogs.

Measurement of gastric gland secretion suppressing activity during gastric anaphylaxis Male Long Evens rats weighing approximately 240-2609 kg at the time of intracanal transplantation 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 5science, 2m, 244 (19
77)). The planned surgical procedure for the stomach thinning component was performed exactly as described in the above literature. After surgery, animals were individually placed in a bottom plate cage filled with sawdust and provided with food and occasional water during the recovery period. At least 1 after surgery
No animals were used for testing purposes on day 5.

49- Animals were fasted for 20 hours before the start of the test and given only occasional access to water.

Immediately before gastric juice collection, the drain tube was opened and all the juice residue was gently removed from the stomach with 3030-4O warm water or distilled water. Next, screw the catheter into the drainage tube with the plug upside down and tighten the mouse to a length of 4.
ocrn, placed in a transparent plastic rectangular box with a width of 15t1n and a height of 13crn, with a slit of about 1.5cm in width and 25cm in length facing the center at the bottom of the box, suitable for the catheter to hang down from. Ta. In this way, the mouse was not restrained and could move freely within the cage during the collection period.

Other analyzes include Radley et al.
Chem, Path, Pharrn, is, 365 (
(1977)].

Gastric secretions collected during the first hour after gastric lavage were discarded due to possible contamination. For oral measurements, the catheter was removed from the drainage tube and the stopper was replaced. Water (2 me/Kq) was administered orally via gastric intubation and the animals were returned to the cage for 45 minutes.

After this time, the 50-mm stopper was removed and 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 it's time to administer the test drug via gastric intubation to a volume of 2 me/
Only Kq was orally administered. The 45-minute crest stopper was removed, 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 secretion solution of the second sample was compared with that of the control sample.

If test compounds were to be evaluated parenterally, animals were injected 1p or 8c with 2/K9 volumes of test compound vehicle immediately after discarding the first 60 minute extract. After collecting samples for 2 hours (control secretions), animals were injected either ip or lie with a 2-/Kq volume of test compound. Samples are collected for an additional 2 hours and the secretions are compared with those from a control period to examine drug effects.

゛The sample was centrifuged and placed in a graduated centrifuge tube for volume measurement. The titratable acidity was measured by titrating the 1πE sample with 0.02 N NaOH solution using an automatic biuret and an electric pH meter (radiometer). The microequivalent amount of titratable acid was calculated by multiplying the milliliter volume by the milliliter folic acid concentration per liter.

The results were expressed as inhibition rates relative to control reading. A dose-response curve was created and the EDso value was estimated by regression analysis.

At least 3 mice were used for each dose and the minimum of 3 doses was used for dose response curve determination.

Table 1 Cimetidine 3.48 (1,68-5,7 blue) 1
0 Example 1 0.094 (0,043-0,20)
37 Example 2 0.77 (0,45-
1, 4) 4.5 Example 3 ~0.
5 to 77 implementation 4 01B (0,
1O-036) 20*...confidence limit 9
5% Histamine H2-Receptor Antagonism - Isolated Guinea Pig Atrial Test Histamine shows a concentration-related increase in the rate of contraction of isolated naturally beating Guinea pig right atrium. This effective receptor of histamine is described as the histamine H,-receptor in Black et al., Nature, 236.385 (1972), in a report on the properties of the competitive antagonist primamide of the H2-receptor. Followed by Hughes and Colette's Proc and Soc.

EXP, Biol. M'ed,, 148.127(
1975) and Phar of Vuma and Matsuknail.
maco1. Ex, Ther.

The study of ζ00.352 (1977) supports the conclusion of Black et al. that the chronotropic effects of histamine in the isolated Guinea pig right atrium are mediated by histamine H2-receptors. Agents of Black et al.
dAction, 3° 133 (1973) and Primprekom et al., Proc.

53-ΣRep., 1931 (1976) uses isolated Guinean pig right atrium as a means of comparing the activity of histamine H2-receptor antagonists. The current comparative study is Reinhardt et al., Agents and Actions, 4.217
(1974) was used with modifications.

Male Hartley Guinea pigs (350-45Of) were killed by bashing on the head. The heart was removed and oxidized (95%02.
5% CO2) modified Krebs solution (NaC1 per liter)
6,6f'.

KCI 0.35f, MgSO4-7H200,29
591KH2PO40, 162f, CaCl2 0.2
389, NaHCO32,1? and dextrose 2.099
) was placed in a Petri dish containing The naturally beating right atrium was cut away from other tissues and silk thread (4-0) was attached to both ends. The atria were suspended in a 20 ml muscle tube containing oxidized modified Krebs solution maintained at 62°C. Atrial contractions were recorded isometrically with a Grass FTα03 force transfer transducer-54 and contraction force and velocity were recorded using a Beckman RP dynograph. A resting tension of 1 V was applied to the atrium and allowed to equilibrate for 1 h. Ta. Maximum concentration (3X10””M) at the end of 1 hour
Histamine dihydrochloride solution was added to the bath to prime the washed tissue. Histamine was then added to the bath cumulatively using 2 log 10 intervals.
The final bath molarity of X 10-'! It was set as 1×10-'. The increase in atrial velocity caused by histamine was allowed to plateau before the next serial concentration was added. The maximum response occurred at a concentration of −f 3 × 10 −′M. Several histamine washes were performed to return the atrium to accommodative speed. A test compound was then added at an appropriate molar concentration and after incubation for 60 minutes, a concentration higher than the required force was added to reverse the histamine level response.

The dissociation constant (Kn) was calculated using at least 3 doses of Alanrakshana O0 and Schild H, Oo [Br, J, Pha
rmacol, 14.

4B (1959)].
) determined from the plot. Table 2 shows the results obtained by moving the dose-part response curves in parallel to reduce the maximum response at the antagonist concentrations used.

Table 2 Cimetidine 20 0.41 (0,21-0
, 6 blue) 1.0 Example 1 12 0.005 (0,0
01-0,004) 137 Example 4 11 0.00
4 (0,001-0,010) 102*...Confidence limit 95% (at the same time) Colleagues of application Tortus A, M. Compounds of formula I can also be prepared by ring closure of compounds of formula (1) using N,N'-thiobisphthalimides of formula: as described in U.S. Patent Application Serial No. (SY-1751). By using N,N'-thiobisphthalimide in place of 5C12 or 5C12 in the ring-closing reaction, the crude compound of formula I can be obtained more conveniently, elegantly and in higher yields.

The crude product of formula I thus produced is usually of sufficient purity to directly produce the crystalline salt without prior chromatographic purification.

In this method, the starting diimidamide with the formula ■ is CH,
Approximately equimolar amounts of N, N in an inert organic solvent such as C12
' - reacted with thiobisphthalimide. The starting diimidamide may be used in its 3 molar form, in which case a 3 molar portion of an amine such as triethylamine is added to the reaction mixture to neutralize the hydrochloride salt. The reaction is brought to full completion by stirring the mixture for about 1 hour at room temperature. The phthalimide precipitated from the reaction mixture is extracted with a strong base (e.g., 10-20 KOH aqueous solution), and the organic solvent layer is dried and concentrated over F4 to yield a crude mixture having formula I.

N,N'-thiobisphthalimide used in the reaction is a known compound and was published in Canadian Journal o
f Chem, 44.2111-2113 (19
66) or can be produced as described in Production Method No. 1 below.

Production method 111 A solution of phthalimide 14.71 (0.1 mol) in 80 fnl of N,N'-thiobisphthalimide dimethylformamide (DMF) was cooled to 0°C and 2
5.15 f (0.05 mol) of sulfur 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 the title compound 12.5r as a DMF solvate. Melting point 301-315℃o
Both IR and NMR spectra were 58- Analytical values for 2°C,6H8N204S*c3H,No which matched the structural formula: Calculated values: C,5Z42;N, 3.80
;N, 10.57;S, 8.07°Measured value:
C, 57,50; H, 3,80; N, 10.29;
S,B57°DMF solvate can be removed by recrystallizing the above substance from chloroform. The melting point of the DMF'-containing shell product was 320-325°C. NMR spectrum showed that DMF was removed.

Analysis value for C161 (6N204 S: total η value:
C, 59, 25; N12.49; N, B64; S
19.89° Measured value: C, 59,21; H, 2,21;
N1B, 91;S, 10.14゜Example 1 3-amino-4-(3-(
3-piperidinomethylphenoxy)propylamine)-
1,2,5-thiadiazole 1-oxide 17.1
? (47,0 mmol) [prepared in accordance with published British Patent Application No. 2.067.987]
8m7! Processed with @HCI. The resulting solution was stirred at ambient temperature for 3 hours, the solution was concentrated, and water was azeotropically removed with absolute ethanol to obtain colorless crystals. This was suspended in 200-g of absolute ethanol, filtered and dried under vacuum to obtain the title compound 16.
．． I got 69 (B2.6ch). Melting point 205-222℃ (
An analytical sample was obtained by recrystallization from methanol 50%-ethyl acetate. Melting point 206-216°C (min M).

Analysis value of C1fuH2,N50・3HcL; Calculated value: C
, 47, 84; H, 7, 08; N, 16.41° Measured value: C, 47, 56; H, 7, 18; N, 16.75
゜B, N in 5-amino-4-(3-(3-piveridinomethylphedimethylformamide (DMF) 20-
A suspension of -(:3-(3-piperidinomethylphenoxy)propyl]ethanediimidamide trihydrochloride 213y (5.0 mmol) (prepared in step A) was prepared using sulfur monochloride2.
02r (15.0 mmol) and stirred for 4 hours.

Carefully pour the mixture into 200ml of water and add 2Co.
It was made basic by . This was extracted with methylene chloride 5O-X3, dried over MgSO4 and concentrated to give 2.12 dark gums containing the product. CM2C1 as fluid phase
z (100): 2-proper tool (10): N
H40H (05) was purified by preparative high pressure liquid chromatography on silica. The title compound 0.B9f was obtained from the appropriate fractions and treated with 7-maric acid in n-propanol to give the crystalline title compound fumaric acid. salt 0.769
(21.4%). Melting point 61 187-1875°C. Purity measured by HPLC is >9
It was 9chi.

(C10Hzs Ns OS )2・C4H404 analysis value: Calculated value: C, 56,27; H, 6,71
;N, 17.27 ;S, 7.90° Measured value: C
,56,09;H,6,56;N116.9B;S,
A small amount of B08° fumarate was suspended in water, neutralized with 2CO3 and extracted with CH2Cl2. The free base of the title compound was crystallized by concentrating the CH2Cl2. Melting point 43-47℃
. A small amount of the free base was converted to the hydrochloride salt. Melting point 138-1
40℃.

C1, H25N60S * Analysis value for HCI:
Calculated value: C, 55, 1B; N16.83; N, IEl
, 24; S%B, 35° Measured value: C, 55, 14; H
, 6, 88; N, 1 B49; S, B74° Example 2 62- Diazole salt hydrate methanol 200 m7! 3-amino-4-(2-(
(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino l-1,2,5-thiadiazole 1-
After slightly warming a suspension of oxide 6,599 (20,0 mmol) [prepared in accordance with published British Patent Application No. 2.067.987] to complete solution, 13
, 6- of concentrated HCl. After stirring for 25 hours at ambient temperature, the solution was concentrated and the residue was triturated with 70-g dry methanol. The crystals were filtered and dried in vacuum to give the compound 4.31.
(52%). Melting point 166-169°C (decomposition) O C1□H2,N, Analysis value for OS・3HC1-H2O: Calculated value: C, 35,08; H, 6,5B; N
, 17.05 ; S, 7.80° Measured value: C, 5
4,85;H16,24;N, 17.45;S,
7.97° N-(2-(:(5
-dimethylaminomethyl-2-furyl)methylthio]
Ethyl)ethanediimidamide 6 salt Kiji hydrate 12.39
(30.0 mIJmol) [produced in step A] while stirring 7.2rn1. Sulfur chloride 12.1
S' (90 mmol) was added. 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 t of water, basified with 2CO3 and extracted first with ethyl acetate and then with chloroform. Mg So4
After drying on top, filter and concentrate the black gum containing the product9. O
I got v. This was purified by preparative high pressure liquid chromatography on silica using ethyl acetate (100):2-propanol (10):NH40H (0,5) as the fluid phase. 1.249 gummy title compound was obtained from the appropriate portion.

A portion of this product was diluted with an equivalent of 2N HCl in methanol.
The hydrochloride salt of the title compound was obtained.

Analysis value for C12Hte N5 S20・HCI: Calculated value: C, 41, 18;)],, 5°76;N
, 20.02; 511a33° measurement value (1,65%H,
Corrected for O): C, 4054; H, 5, 70; N,
19.39;S, 1 B, 44° The product was treated with an equivalent amount of cyclohexylsulfamic acid in acetone to give the cyclohexylsulfamic acid salt of the title compound. Melting point 93-95°C.

Analysis value for C12H1gC12H1・C6Hl3NO3S: Calculated value: C143,88; H, 6,55; N,
17.06 ; S, 19.53° Measured value: C, 43
,77;H16,17;N,17.21;S, 19
．． 58゜65 Example 3 5-amino-4-(2-(:
(5-dimethylaminemethyl-4-methyl-2-chenyl)methylthio]-ethelamino l-1,2,5-thiadiazole 1-oxide 17.99 (50,0 mmol) [Published British Patent Application No. 2, 067.987
[produced by the general method described in the issue] to a stirred solution of
After adding 3.3 ml of HC and stirring for 3 hours, the reaction mixture was concentrated and excess water was azeotropically concentrated with absolute ethanol to give an almost colorless crystalline residue. The residue was soaked in absolute ethanol 200ml at 0℃66-! Trituration, filtration and drying yielded 16.9f (80%) of the title compound. Melting point 20
/) Recrystallization from 50% ethanol-ethyl acetate at -220°C (decomposition) gave a product with a melting point of 210-221°C (min M).

Analysis value for C13N23 NS 82.3HC1:
Calculated value: C13692; N16.20; N11656
; S115.17° measurement 46: C, 3/), 76
;N16.33;N, 16.97;S, 1
5.54° N-(2-((5-dimethylaminomethyl-4-methyl-2-chenyl)methylthio]ethyl)ethanediimidamide 6.34f(15,0
6.11F (45.0 mmol) of sulfur monochloride was added to the stirred suspension of sulfur monochloride (45.0 mmol) [produced in step A], and after stirring at ambient temperature for 4 hours, the reaction mixture was poured into 80% water and diluted with 2C.
The mixture was made alkaline with 0.03 and extracted several times with 100mfi of Hanawaji methylene each time. The extract was dried over Mg SO, filtered and concentrated to yield black gum 347 containing the product. The product was purified by preparative high pressure liquid chromatography on silica using CH2Cl2(100):2-propanol(1) as the fluid phase.
0): Purified using NH4OH (0,5). Furthermore, CH2
Cl2 (100): CH30H (2,5): N
Purification was carried out using H4OH(0,5) as the fluid phase. The title compound (98% purity) was obtained from appropriate fractions. The product was treated with an equivalent amount of 2N HCl to give the hydrochloride salt of the title compound.

Analysis value for C13H21N5S, *HCI:
Calculated value: C, 41, Oq; N2.5.84; N, 1
8.43; 5125.32° Measured value (corrected for 051% N20): C, 40,78; H, 5,63; N, 1
C31;S, 25.44゜Example 4 5-Amino-4-[3-(3-
pyrrolidinomethylphenoxy)propylaminoyo 1,
2,5-thiadiazole 1-oxide 13.42 (3
F3.3mm Monolith [Published UK Patent Application No. 2.0
6S No. 987] was added with 25.5-concentrated HCl 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-m of absolute ethanol, filtered and dried to yield the title product, 10.8F. Melting point 195-203
°C (decomposition) O Analysis value for C16H25NS0.3HC1: 69- Calculated value: c, +6. ss; ■, 6.84; N, 16
．． 97° measurement value: C, 46, 55; N1693; N11
6.95゜DMF80ml! N-[:3-(3-pyrrolidinomethyl-phenoxy)propyl]ethanediimidamide 3-hydrochloric acid a2. 5.4S' (4
0.0 mil J mol] was added thereto, and the mixture was stirred for 3 hours under a nitrogen atmosphere. 500 ml of dark colored rubber that was able to concentrate the reaction mixture
The suspension was suspended in water, made alkaline with 2CO3, and extracted with 100dX3 methylene chloride. The extract was dried over MgSO4, filtered and concentrated to give a dark gum 7,59 containing the product. The product was purified by preparative high pressure liquid chromatography on silica in CH2Cl2(100):2-propyl(5
): Purified using NH40H(0,5) as a fluid phase. The fractions containing the desired product were combined and concentrated to give the purified title compound 1.649 (24.6%)
jC.

The product was treated with an equivalent amount of 2N) ICI in absolute ethanol to give the title compound, zt1sy. Melting point 138-
140℃0C, 6H23NS0S * Analysis value for HC1: Candle value: C, 51,95; H, 654; N,
18.93; S, a67° measurement value: C, 51,
97; H, 6, 56; N, 1 a63; S, 8.
76° Example 5 3-Amino-4-[3-(3-piperidinomethylphenoxy) used in the general method of Example 1 Steps A and B
(a) 3-Amino-4-[3-(3-dimethylaminomethylphenoxy]propylamine]-1 in place of equimolar amounts of the following compounds in place of 1,2,5-thiadiazole 1-oxide): ,2,5-thiadiazole 1-oxide, (b) 6-amino-4-[3-(3-diethylaminomethylphenoxy)propylamine]-1,2,5-aminothiazole 1-oxide, (c) 6- Amino-4-(3-(3-(2-methylpyrrolidino)methylphenoxy]propylamine) -1,
2,5-thiadiazole 1-oxide, (d) 6-amino-4-(3-[3-(3-methylpyrrolidino]methylphenoxy]propylamino) -1,
2,5-thiadiazole 1-oxide, (e) 3-amino-4-(s-[-(4-methylpiperidino]methylphenoxy]propylamino l-1,2,
5-thiadiazole 1-oxide, (f) 3-amino-4-(3-(3-morpholinomethylphenoxy)propylamino)-1,2,s-thiadiazole 1-oxide, (g) 3-amino-4 -(3-[3-(N-methylpiperazino]methylphenoxy]propylamine)-1,2
, 5-thiadiazole 1-oxide, (h) 6-amino-4-[3-(3-diallylaminomethylphenoxy]propylamine, ll-1,2,5-
Thiadiazole 1-oxide, (1) 3-amino-4-(3-(3-hexamethyleneiminomethylphenoxy)propylamine)-1,2,5
-thiadiazole 1-oxide, (j) 3-amino-4-(3-(3-hebutamethyleneiminomethylphenoxy)propylamine)-1,2,5
-thiadiazole 1-oxide, (k)5-amino-4-(6-[-(3-azabicyclo[3°2.2]non-3-yl)methylphenoxy]
propylamino)-1,2,5-thiadiazole 1-oxide and 73-(1)3-amino-4-(s-(s-(s-viroline)
The general method was repeated using each of (a) 3-
Amino-4-(3-(3-dimethylaminomethylphenoxy)propylamine)-1,2,5-thiadiazole, (b) 3-amino-4-43-(3-diethylaminomethylphenoxy)propylamine':] -1,2,5-
Thiadiazole, (C)3-amino-4-(3-(3-(2-methylbip
lysino]methylphenoxy]glopylamine)-1,z
, s-thiadiazole, (d) 3-amino-4-(3-[:3-(3-methylpyrrolidino)methylphenoxy]propylamino)-1,
2,5-thia 4-diazole, (e) 3-amino-4-(3-[3-(4-methylpiperidino)methylphenoxy]propylamine)-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]propylamine) -1,2,5-thiadiazole, (h) 3-amino-4-[5-(5-diallylaminomethylphenoxy)propylamino]-1,2,5-thiadiazole, ( i) 6-amino-4-[-(3-hexamethyleneiminomethylphenoxy)propylamino]-1,2,5-
Thiadiazole, (j) 3-amino-4-[3-(3-hebutamethyleneiminomethylphenoxy)propylamine]-1,2,5
-thiadiazole, (k) 3-amino-4-(5-[5-(5-azabicyclo[3,2,2]]non-3-ylmethylphenoxy]propylamine)-1,2,5-thiadiazole, and (1) 3-Amino-4-(3-[3-(3-pyrodine)methylphenoxy]propylamine)-1,2,5
-Produced thiadiazole.

EXAMPLE Nire is a modification of Example 1, Step B, which uses a smaller amount of unicarbonized iori and requires a shorter reaction time.

To a stirred suspension of 12.08 f (2a3 mmol) of N-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamito 6-hydrochloride (2a3 mmol) in 12 mA of DMF was added 1
Add 7.641 (56.6 mmol) of sulfur chloride and N
The mixture was stirred under two atmospheres for 6 hours. The black rubber from which DMF had been removed under reduced pressure was suspended in water, made alkaline with C03, and extracted with C1 (2C12100dX3).The combined extracts were dried over MgSO, and then overconcentrated to obtain black rubber. This was converted into CH2Cl2 (100): 2 using preliminary high pressure liquid chromatography on silica.
-Proper tool (s): NH40H (o, s)
was purified as a fluid phase. The appropriate portions were combined to give the title product 6.12 as a dark oil which was treated with fumaric acid in n-propanol to give the crystalline fumarate salt of the title compound 2.669 (25.2%).

The purity was found to be 99% by HPLC.

(C,, H25N50S)2・c4H4o, analytical value near 7- Calculated value: C, 56, 27; H, 6, 71; N, 17
．． 27; S, 7.90° measurement value SC, 56, 27;
)(,6,96;N,17.51;S17.9B.

Example 7 This is a modification of Example 1, step B, in which 2-layer sulfur is used instead of 1-layer sulfur.

N-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamide 5' hydrochloride 85 in DMF6-
To a stirred suspension of 4mf/(2mmol) 80122 (16mg(
2 mmol) of the solution was added. The reaction mixture was stirred at ambient temperature to yield the title compound. Example 8 78- A, N-methyl-N'-[3-(3-methylamino-4 in 3-piperidinomethylfemethanol 95me)
-[3-(3-piperidinomethylphenoxy)propylamine]-1,2゜5-thiadiazole 1-oxide 4.15r (10,9 mmol) [Published British Patent Application Box 2.06s 987 After adding concentrated HCI 7.2- to a suspension of [produced by 4%).

A sample was recrystallized from aqueous isopropyl alcohol to give the title compound. Melting point 207-225°C (branch).

C, 8H2, N50・3) Analysis value for icl: Calculated value: C, 49,03; H, 7,33; N, 15.89
° Measured value (corrected for 0.94% H20): C, 49,
37;N17.35;N, 15.71°B, 3
-Methylamino-4-[3-(3-piperidinomethyl?N-methyl-N'-(3-(3-piperidinomethylphenoxy)propyl)ethanediimidamide 3-hydrochloric acid 43.4
7f (a47 mmol) [produced in step A], CH2Cl
A mixture of 54ml of 2 and 3.5ml of triethylamine was stirred for 1 hour.

The mixture was washed with 10% KOH30, dried over MgSO4, diluted with toluene and concentrated to give product 362. Convert the product into silica gel (230-400 mesh) 9
Purification by flash chromatography over 0 f using ethyl acetate-methanol (95:5) as eluent afforded 1.99 (62%) of the title compound. The product was treated with an equivalent solution of hydrochloric acid in 1-propatol to give the hydrochloride salt of the title compound. Melting point 163.5-164.5℃0 C, 8H27N50S # Analysis value for HC1: Subtraction value: C, 54,32; H, 7,04; N, 17.
60; S, a06; C1, 8, 91° Measured value: C, 54, 35: H, 7, 07; N, 17.6
4;S, 36;C1,8,86゜Example 9 3-benzylamino-4-[3
-(6-piperidinomethylphenoxy)propylamine]-1,2,5-thiadiazole 1-oxide 5.1
4F (11,3 mmol [prepared in accordance with published British Patent Application No. 2,067.987]) with concentrated H
CI 7.55- was added, and the mixture was stirred for 3 hours at an atmospheric temperature of 81-. The solution was concentrated, the residue was triturated with acetone, and the supernatant was dried overnight to give the title compound 5.16f (88%).
I got it.

Melting point 187-205°C (decomposed).

Analysis value for C24H33N50・3HC1: Measured value: C, 55,75; N17.03; N, 13.5
5; CL 20.57-1 Measured value: C, 54, 88
;H,6,75;N,13.33;C1,20,20
゜Zol N-benzyl-N'-C3-(3-piperidinomethylphenoxy)propyl]ethanediimidamide 6-hydroacid j74
．． 73 ri (916 mmol) [produced in step A], C) 1
3.64? (9.16 mmol) of N,N'-thiobisphthalimide (DMIi" solvate) was added to a mixture of 2C1245- and triethylamine 38- and stirred for 1 hour. The mixture was washed with 44rnl of 10% KOH82
- Dry over MgSO4, filter, dilute with toluene and concentrate. Silica gel (250-400 mesh) 1
The title compound 3.1 was purified by flash chromatography at 10 fJ and eluted with ethyl acetate. (77%). The product was treated with an aqueous solution of HCI in 2-propanol to give the title compound hydrochloride. Melting point 138°-14
Analysis value for 1℃0 C24H31N, O8@HC1: Initial value: C,6[11,80;)L 6.80;N, 1
477;S, 6.76;C1,7,48° measurement @: C,60,53;H,6,64;N, 14
．． 99;S, 6.91;C1,7,47゜Example 10 This is Example 1, N, N instead of sulfur monochloride in IB.
This is a modified method using '-thiobisphthalimide.

N-(3-(3-,piperidinomethylphenoxy)propyl]ethanediimidamide 3i acid salt 27.59 (64
,0 mmol) [Produced in Example 1, Step A], C)
-I2C12250m7! and triethylamine 26
．． 6me (j 92.0 mmol) N, N'
-thiobisphthalimide (DMF solvate) 25, 4
Add f (64, Omi IJ mole) little by little at atmospheric temperature.
I pressed my finger on the time. Mixture with 20% KOH1207! Wash with water, dry over MgSO4, overconcentrate, and add 150 ml of toluene.
It was then concentrated again. Product 1-proper tool 25
The mixture was taken up in 10.7 ml of 6N HCl, treated with decolorizing carbon, and passed through Celite for 1 hour. 100% of this solution
Concentrate to 1 mg volume and 175ml! The crystalline hydrochloride salt of the title compound was diluted with dry 1-propanol and allowed to stand at 0°C for 20 minutes.
29 (82.1%). Melting point 137-138°C.

Analysis value for Cl7H26N50S @ HCI: Subtraction value: C, 53, 18; I16.83; N, 18
．． 24; S, F3.35° measurement value: C152,7
8; I16.74; N, 18.52; S, B, 66
゜Example 11 This is Example 4, and in step B, N, N
This is a modified method using '-thiobisphthalimide.

N-[3-(3-pyrrolidinomethylphenoxy)propyl]ethanediimidamide 3i@Kan22. Oy (53,
0 mmol], [produced in Example 4, Step A], CH
N,N'-thiobisphthalimide (DMF solvate) 2t2f (53.0 mmol) was added to a mixture of 2Cl2200- and triethylamine 22-2, and after stirring at ambient temperature for 1 hour, the mixture was diluted with 20% KOH100m
7! The mixture was washed with water, dried with MgSO, diluted with 85-5-100 toluene, and concentrated. The product was treated with 1 equivalent aqueous MCI in 1-propanol to give the title compound hydrochloride 13.
2v (67%).Melting point 135-137℃0CI6
Analysis value for H23N50S @ HCI: Calculated value:
C151,95; I16.54; N, 18.93
, s% a670 measurement value: C, 51,92; II, 6.
55:N, 19.30;S, 9.06° Example 1
2. 3-Amino-4-(2-[:(
s-Dimethylaminomethyl-3-thenyl)methylthio]et86-thylamino)-1,2,5-thiadiazole 1-oxide 7,89 (22,6 mmol) [Published UK Patent Application No. 2067,987 15. After adding Ome and stirring at ambient temperature for 3 hours, the solution was concentrated, and the residue was triturated with 1-propatool, filtered for 1 time, and dried to yield product 7, 389 (80%). A sample was recrystallized from methanol-acetone to give the title compound. Melting point 190-205℃ (decomposed) O Analysis value for CI2HHN5S2・3HC1: t+
1-1L Iyama: C, 35, 25; Hl 5.92
;N, 1 7.13.

Measured value: C, 35,03; H, 5,93; N117.3
9°N-(2-[(5-dimethylaminomethyl-3-chenyl)methylthio]ethyl)ethanediimidamide 6 salt 6.13 g (15.0 mmol) [produced in step A], CH2Cl260rn7! 5.96 r (j5 mmol) of N,N'-thiobisphthalimide (DMF solvate) was added to a mixture of 6,3 me and triethylamine, and the mixture was stirred for 1 hour. The mixture was washed with 10% KOH100-, dried over MgSO4, filtered, diluted with toluene and concentrated to give raw h'! I got 5.12 items. The product was treated with 1.5 moles of fumaric acid in 1-propanol to give the fumarate salt of the compound, OE point 141-143 °C o DMSO.
The NMR spectrum in -d6 showed the presence of about 0.12 moles of 1-propanol.

(C1□H19H583) 2・C,H404・012
Analytical values for C3H80: Calculated values: C, 43,68; H, 5,61; N, 17
．． 75 ; S, 24.38° Measured value: C, 45, 41
;H, 5,53;N, 17.54;S, 24.24
゜Example 1'5 3-Amino-4-(2-((
5-piperidinomethyl-6-chenyl)methylthio]ethylamine)-1,2,5-thiadiazole 1-oxide 612 (15,8 mmol) [prepared in accordance with published British El Patent Application No. 2.06S987] After adding 10.5 mA' of concentrated HCI to the suspension and stirring at ambient temperature for 3 hours, the solution was concentrated and the residue was ground with 50 ml of 1-propatool, filtered through d4 and dried to give a product of 5.869 g (
83%). sample from methanol-acetone]
Crystallization gave the title compound. Melting point 201-21489
- °C (decomposition) O C15H26H5S Analysis value for 2.3HC1: Calculated value: C, 4o, 13; II, 629; N115.6
0; S, 14.29° Measured value: C, 39,97;
H, 6,47; N, 15.28; S114. /)3
゜Thiadiazole N-(2-[(5-piperidinomethyl-3-chenyl)
Methylthio]ethyl)ethanediimidamide trisalt ifi
5.17F (11.5 mmol) [Produced in step A]
, CH201248ml and triethylamine 4.8
me mixture with N,N'-thiobisphthalimide (D
MF solvate) 4.57f (11.5 mmol) and stirred for 1 hour. Wash the mixture with 10% KOH90-M
Dried over gSO4, filtered once, diluted with toluene and concentrated to give product 4.57. sieve the product in methanol
〇- Treatment with 1 equivalent of chlorohexylsulfamic acid afforded the cyclohexylsulfamate salt of the title compound. 8 points 1
42-146℃.

Analysis value for Cl5H23N5 s3・C,H,3NO3S: Calculated value: C145,96;H,6,61;N
, 15.31 ; S, 23.38° Measured value: C14
5,lS1;H,6,41;N, 15.46;S,
23.48° Example 14 3-amino-4-[ used in the general method of Example 1, Step A and either Example 1, Step B or Example 10
(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)propylamine]-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-3-pyridylmethylamino-4-
[3-(j-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1-oxide, (f) 3-(5,4-methylenedioxybenzylamino)-4-[3-( 3-piperidinomethylphenoxy)
propylamine]-1,2,5-thiadiazole 1-
oxide, respectively: (a) 3-ethylamino-4-(3-(3-piperidinomethylphenoxy)propylamine)-1,2,5-thiadiazole, (b) 3- Allylamino-4-[3-(3-biveridinomethylphenoxinebrobylamino]-1,2,5-
Thiadiazole, (c)3-(2-propynyl)-4-(:5-(S-piperidinomethylphenoxy)propylamine)-1,2
,5-thiadiazole, (d)3-(j-pyridylmethylamino)-4-(3-
(3-piperidinomethylphenoxy)propylamine)
-1゜2.5-thiadiazole, (e) 3-(6-methyl-3-pyridyl)methylamino-4-(3-(3-piperidinomethylphenoxy)propyl96-amine]-1,2, 5-thiadiazole, and (f)
3-(3,4-methylenedioxybenzylamino)-4
-(:3-(3-piperidinomethylphenoxy)propylamino)-1,2,5-thiadiazole was produced.

Example 15 3-(6-piperidinomethyl-
2-pyridyloxy)propylamine 4.659 (1a
A solution of 3-amino-4-methoxy-1,2,5-thiadiazole (prepared by British Patent Application Box 2,068,987) 1-oxide 2.74f (18.6 mmol) to give 3-amino-4-(3-(6-biperidinomethyl-2-pyridyloxy)propylamine': l-1,
A solution containing 2,5-thiadiazole 1-oxide was obtained. The melting point of the purified compound was 145-147°C.

The methanolic solution of the product produced in step A was diluted with 100-
12.4-mg of diluted HCI was added to the mixture. The solution was stirred at ambient temperature for 18 hours, then concentrated, and the residue was dissolved in 80 mA of water and extracted twice with CH2Cl2. The aqueous layer was concentrated and treated with knee propatool and concentrated under high vacuum to give the title compound as a foam.

C,3-amino-4-[,3-(6-biperidinomethyl-2-pyridyloxy)propylamine')-1,2,
5-Thiadiazole CH2Cl2 Mix the crude product prepared in step B with triethylamine '169- in 80+++/N,N'-
Thiobisphthalimide (DMF solvate) 7.359
(18.5 mmol) at ambient temperature for 1 hour. The mixture was diluted with 50 ml of 4 N NaOH, water, saturated Na
Washing with aqueous C1 solution, drying over Na SOa, filtration and evaporation in vacuo afforded the crude product. The product was purified by flash chromatography on silica gel (250-400 mesh) 1009, eluting with ethyl acetate-methanol (95:5) to give the title compound A6 as a viscous oil.
Got 3F. The product was treated with 1 equivalent of cyclohexylsulfamic acid in acetone to yield the cyclohexylsulfamic acid salt of the title compound. Melting point 125.5-131
℃.

Analysis value for C1,H24N60S @C6H,3No3S: Calculated value: C, 50,07; H, 7,07;
N, 18.58; S, 12.15° Measured value: C, 50,
02;H, 7,03;N, 1a54;S, 12.14゜Example 16 Methanolic solution of 3-(6-dimethylaminemethyl-2-pyridyloxy)propylamine [UK Patent Application No. 2 No. 098.988] was reacted with 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide by the general method described in British Patent Application No. 2,067.987. -amino-4-[3-(6
-biperidinomethyl-2-pyridyloxy)propylamino)-1,2,5-thiadiazole 1-oxide by the general method of either Example 1, Step A and Example 1 Step B or Example 10, 97- The title compound was prepared by sequential reactions.

Example 17 Asiazole 3-amino-4-(2-((6-dimethylaminemethyl-2-pyridyl)methylthio]ethylamino)-1,2
, 5-thiadiazole 1-oxide [prepared in accordance with British Patent Application No. 2.06S987] was prepared sequentially in Example 1 Step A and then in Example 1 Step B or Example 1.
The title compound was prepared by reaction according to any of the following methods.

Example 18 Azole 98-3-amino-4-(2-((6-biperidinomethyl-2
-pyridyl)methylthio]ethylamine)-1,2,5
-Thiadiazole 1-oxide [UK Patent Application No. 2,
No. 067.987] was reacted sequentially by the method of Example 1, Step A, and then by any of the methods of Example 1, Step B or Example 10 to prepare the title compound.

Traditional example 19 Instead of 6-amino-4-(3-(3-piperidinodimethylphenoxy)propylamino)-1,2,S-thiadiazole 1-oxide, equimolar amounts of the following compound: (a
) 3-amino-4-(3-(3-piperidinomethylthiophenoxy)propylamine)-1,2,5-thiadiazole 1-oxide, (b) 5-amino-4-(3-(3-dimethyl aminomethylthiophenoxy)propylamine] -1,2,5
-thiadiazole 1-oxide, (c) 3-amino-4-(3-(3-pyrrolidinomethylthiophenoxy)propylamine)-1,2,5-thiadiazole 1-oxide, (d) 3-amino-4- (3-(4-dimethylaminomethyl-2-pyridyloxy)propylamino'll-1
,2,5-thiadiazole 1-oxide, (e)3-amino-4-[-(5-dimethylaminemethyl-6-chenyloxy)propylamino)-1,2,
5-thiadiazole 1-oxide, (f) 3-amino-4-1j-(5-piperidinomethyl-6-chenyloxy)propylamine]-1,2,5
-thiadiazole 1-oxide, (g) 3-amino-4-(2-[(4-dimethylaminemethyl-2-pyridyl)methylthio]ethylamine)
-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 by the general method of Example 1, Step A and then Example 1, Step B or Example 10: (a) 3-Amino-4 -[3-(3-piperidinomethylthiophenoxy)propylamine]-1,2,5-thiadiazole, (b) 3-amino-4-(5-(5-dimethylaminomethylthiophenoxy)propylamine)-
1,2,5-thiadiazole, (c) 3-amino-4-[3-(3-pyrrolidinomethylthiophenoxy)propylamino]-1,2,5-thiadiazole, 101- (d) 3-amino-4 -[3-(4-dimethylaminemethyl-2-pyridyloxylapropylamine]-j, 2
．． 5-thiadiazole, (e) 3-amino-4-[3-(5-dimethylaminomethyl-3-chenyloxylapropylamine:]-1,
2,5-thiadiazole, (f) 3-amino-4-[3-(5-piperidinomethyl-3-chenyloxy)propylamino)-1,2,5
-thiadiazole, (g) 3-amino-4-(2-((4-dimethylaminomethyl-2-pyridyl)methylthio]ethylamine)-
1,2,s-thiadiazole, and (h) 3-amino-4-[-((4-piperidinomethyl-2-pyridylmethyl)methylthio]ethylamine)-
1,2,5-thiadiazole 102- were obtained.

The above starting compounds were published in British Patent Application No. 2.0:
0 created by the general law described in No. 6.7.9.87
The precursor of the subject substance is UK Patent Application No. 2,067.98.
7, 2.09a988 and 2,063,875 and published European Patent Application No. 49.173 and similar general methods.

Example 20 Lysyloxy)propylamine]-1,2,5-thiadiazo-earth A, 3-(4-piperidinomethyl-2-pyridyloxy)propylamine 3-( as described in UK Patent Application No. 2,098,988 6
The oily title compound was produced by substituting 2-bromo-4-methylpyridine for the 2-chloro-6-methylpyridine used in the general procedure for -biperidinomethyl-2-pyridyloxy)propylamine.

Analytical values for Cl4H23N30: Calculated values: C, 67,44; H, 9,30; N, 16
．． 85° measurement value: C, 67, 54; H, a98; N
, 16.55°Product of Step A6.5 S' (26
, 0 mmol) in methanol 90 - by the general method described in British Patent Application No. 2,067.9B7.
Reaction with 3.849 (26.0 mmol) of -amino-4-methoxy-1,2,5-thiadiazole 1-oxide gave 6.33 r of product. Recrystallization from methanol-acetonitrile gave the title compound. Melting point 1
54-158°C.

Analysis value for C16H24N60S: Calculated value: C,
52,73; H, 6,64; N, 23.06; S,
a80° measurement value: C, 52,72; H, 6,50;
Step B product 5.N, 23.32; S, a74° methanol 80- (1 (13.7 mmol)) was dissolved and 9.1- of concentrated HCl was added. After stirring for 4.5 hours at ambient temperature, the solution was evaporated to dryness under reduced pressure to give the title compound in azole CH2Cl250- and triethylamine 5.7- N,N'-thiobisphthalimide group DMF solvate) 5.449 (13
, 7 mmol) was added and stirred for 1 hour with Daeduderu.
Washing sequentially with H40-1 water and saturated NaCl aqueous solution,
It was dried with Na2SO4-h to 1PIi% and concentrated under pressure to obtain a crude product. The product was purified by silica gel (230-4
The title compound 3442 was purified by flash chromatography on Mesh 902 and eluted with ethyl acetate-methanol (96:4) to give the title compound 3442 as a viscous oil.
ζ. The product was treated with 1 mole of cyclohexyl sulfamic acid in acetone to provide the cyclohexyl sulfamic acid base of Table M compounds. Melting point 124.5-126°C.

Analysis value for C,6H24N60SeC6H,3No,8: Calculated value: C,50,07;H,7,07;N
, 1a58; S, 12.15° Measured value: C, 50, 47
;H,7,12;N,1B,33;S,11.87゜Example 21 106-1,2.5-thiadiazole 3-(6-biperidinomethyl-2-pyridyloxy used in Example 15) ) propylamine instead of equimolar 5-(3-(1,2,3,6-tetrahydro-
Reversing the general procedure using 1-pyridyl)methylpropylamine gave product 2.31f. Recrystallization from toluene yielded the title compound. Melting point 99.5-
104℃.

Analysis value for C, 7H, 3N50S: Calculated value: C1
59,10;H16,71;N, 20.27;S,
9.28° Measured value: (2,1996'f (corrected to 20) C, 51178; H, 6,71; N, 19.9
0;S, 9.26°107-Continued from page 1 295108 6917-4 C307
1527043-4C 333/20 8214-4 C285
1007330-4C 2851007330-4C 333100) 8214-4C (C0
7D 417/12 -28510
0 7330-4 C213100)
7138-4C@Inventor Aldo
Antonio Alchery 113 Vanida Lane, Huyetteville, New York 13066

Claims (1)

[Claims] 1. Formula I: In the formula C, R1 is hydrogen, lower alkyl, 2-fluoroethyl, 2.2.2-)lifluoroethyl, allyl, propargyl, (provided that p is 1 or 2, R2 and R3 are independently hydrogen, lower alkyl, lower alkoxy, or rogene, and when R2 is hydrogen, R3 may be trifluoromethyl, or both R2 and R3 are methylenedioxy and potassium, and R4 is hydrogen. , low alkyl or lower alkoxy), m is an integer from 0 to 2, and n is 2
Z represents oxygen, sulfur, or methylene, and A is (in the above formula, R6 is hydrogen, lower alkyl, or lower alkoxy, q is an integer of 1 to 4, and R
6 and R7 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 if R6 is hydrogen, R7 is cyclo lower alkyl. or R6 and R7 together with their bonded nitrogen atoms, pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, N-
Methylpiperazino, 1.2.3.6-titrahydropyridyl, homopiperazino, heptamethyleneimino, octamethyleneimino, 3-azabicyclo[3,2,2]]
non-3-yl represents 3-viroline) or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof. 2, Formula I: in which R1 is hydrogen or lower alkyl, m is O or 1, n is 2 or 3, Z is oxygen or and R6 and R7
are each independently methyl or ethyl, or together with their bonding nitrogen form a pyrrolidino or piperidino ring) or a pharmaceutically acceptable non-toxic compound thereof; Salt, hydrate or solvate Q 3, formula Ia; in which R1 is hydrogen or methyl, and Desired and R7 are each methyl, or together with the nitrogen to which they are bonded, they form a pyrrolidino or piperidino ring 1a or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof. 4. A compound according to claim 1, or a pharmaceutical thereof, having the formula 1b, in which R1 and R5 are each independently hydrogen or methyl, and R6 and R7 are each independently methyl or ethyl. Acceptable non-toxic salts, hydrates or solvates of the above. 5 Formula Ic: 5- A compound according to the range P1 of the crystal search having the formula c, in which R1 and R5 are independently hydrogen, and R6 and R7 are independently methyl or ethyl, or Pharmaceutically acceptable non-toxic salts, hydrates or solvates. 6 Formula: (In the above formula, R, l and R11 are each independently hydrogen or methyl, and R6 and R7 are each independently methyl or ethyl, or together with the g atom to which they are bonded form piperidino) or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof. Z 3-Amino-4-(3-(3-piperidinomethylphenoxy)glohylamino) to 1.2.5-thiadiazole and 6- According to claim 1; Acceptable non-toxic salts, hydrates or solvates. A compound according to Range 1. 9.6-amino-4-(2-[:(5-dimethylaminemethyl-2-furyl]methylthio]ethylamino)
-1,2°5-thiadiazole, or a pharmaceutically acceptable non-toxic salt, hydrate or solvate of the compound according to claim 1. 103-Amino-4-(2-((s-dimethylaminomethyl-4-methyl-2-chenyl)methylthio]ethylamino)-1,2,5-thiadiazole according to claim 1 Compound or pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof. 113-amino-4-(3-(3-pyrrolidinomethylphenoxy)propylamine': l-1,2,5-thiadiazole) The compound listed in claim 1 or a pharmaceutically acceptable compound, hydrate or solvate thereof. 123-Methylamino-4-[3-(3-piperidinomethylphenoxy)] 133-benzylamino-4-[133-benzylamino-4-[133-benzylamino-4-[ 3-(3-Piperidinomethylphenoxy]propylamine]-1,2,5-thiadiazole, the compound according to % permissible range item 1 or its pharmaceutically acceptable non-toxic salt, hydrate or Solvate. 143-amino-4-(2-((5-dimethylaminemethyl-6-chenyl)methylthio]ethylamino) -
Claim 1 which is 1,2゜5-thiadiazole
Compounds or pharmaceutically acceptable non-toxic salts, hydrates or solvates thereof. 156-amino-4-(Z-((S-piperidinomethyl-6-chenyl)methylthio)ethylamino11,2,
The compound according to claim 1, which is 5-thiadiazole, or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof. 163-amino-4-(3-(6-biperidinomethyl-2-pyridyloxy)propylamine)-1,2,5-
A compound according to claim 1, or a pharmaceutically acceptable compound, hydrate or solvate thereof, which is superior to thiadiazole. 175-amino-4-1j-(4-piperidinomethyl-
2-pyridyloxy)propylamino': l-1,2,
The compound according to claim 1, which is 5-thiadiazole, or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof. 9-1a 3-amino-4-(3-[3-(1,2,3,
6-tetrahydro-1-pyridyl)methylphenoxy]
The compound according to claim 1, which is propylamine)-12,5-thiadiazole, or a pharmaceutically acceptable non-toxic salt, hydrate or solvate thereof. Formula 19 ■; [In the formula, R1 is hydrogen, lower alkyl, 2-fluoroethyl, 2.2.2-)lifluoroethinoparyl, flopargyl, (however, p is 1 or 2, and R2 and R3i are independent of each other) represents hydrogen, lower alkyl, lower alkoxy or halogen, and when R2 is hydrogen, R3 may be trifluoromethyl 10-, or R2 and R3 are both methylene dioxy, and R4 is hydrogen, lower alkyl or lower alkoxy ), m is an integer from 0 to 2, and n is 2
Z is an integer from 1 to 5, and A represents oxygen, sulfur, or methylene; represents lower alkyl, lower alkoxy lower alkyl in which the lower alkoxy moiety is at least two carbon atoms removed from the silicon atom, or phenyl lower alkyl, and when R6 is hydrogen, R7 may be cyclolower alkyl, or R6 and R7 together with the nitrogen atom to which they are bonded are pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino, N-methylpiperazino, 1,2,3.6- titrahydropyridyl, homopiperidino, heptamethyleneimino, octamethyleneimino, 3-azabicyclo[3,2,2]]non-3-yl forms 6-viroline]
A compound, or a salt, hydrate or solvate thereof, characterized by: 20 Formula ■: In which R1 is hydrogen or lower alkyl, m is 0 or 1, n is 2 or 3, 2 is oxygen or sulfur, and A is (in the above formula, R5 is hydrogen or methyl) Claim 19 has the formula (2) in which R6 and R7 are each independently methyl or ethyl, or together with the nitrogen to which they are attached, form a pyrrolidino or piperidino ring. Compound or salt, hydrate or solvate thereof. 21. Formula ■a: In which R1 is hydrogen or methyl, R6 and R7 are each methyl, or together with the 9 atoms to which they are bonded, 13-pyrrolidine is The compound according to claim 19 having the formula Tla forming a piperidino ring, or a salt, hydrate or solvate thereof.22Formula (b): In which R1 and R5 are independently hydrogen or methyl The compound according to claim 19, or a salt, hydrate or solvate thereof, having the formula Ilb, wherein R6 and R7 are each independently methyl or ethyl. The compound according to item 19 of the scope of the claim, having the formula 1c, in which R5 is independently hydrogen or methyl, and R6 and R7 are independently methyl or ethyl, or a salt or hydrate thereof or a solvate. 24. d: according to claim 19 having the formula 11d, in which R1 and R6 are each independently hydrogen or methyl, and R6 and R7 are each independently methyl or ethyl. Compound or substance, hydrate or solvate. 25, N-(3-(3-piperidinomethylphenoxy)
20. The compound according to claim 19, which is [propyl]ethanediimidamide, or its derivatives, hydrates or solvates. 26, N-(2-((5-dimethylaminemethyl-2-
20. The compound according to claim 19, which is freel)methylthio]ethyl)ethanediimidamide, or its hydrate, hydrate or solvate. 27, N-(2-((5-dimethylaminemethyl-4
-Methyl-2-chenyl)methylthio]ethyl)ethanediimidamide, or its derivatives, hydrates or solvates. Claim 1 which is 2aN-(3-(3-pyrrolidinomethylphenoxy)propyl)ethanediimidamide
The compound according to item 9 or its derivative, hydrate or solvate. 29, N-(2-[(5-dimethylaminemethyl-3-
The compound according to claim 19, which is chenyl)methylthio]ethyl)ethanediimidamide, or a salt, hydrate or solvate thereof. 3o N-(2-1:(5-piperidinomethyl-3-
The compound according to claim 19, which is chenyl)methylthio]ethyl)ethanediimidamide, or a salt, hydrate or solvate thereof. 31, N-[3-(6-biperidinomethyl-2-pyridyloxy)propyl]ethanediimidamide, or the compound, hydrate, or solvate thereof according to claim 19. 32, N-[3-(4-piperidinomethyl-2-pyridyloxy)propyl]ethanediimidamide, or its in situ, hydrate or solvate. 65N-(3-(3-(12,3,6-tetrahydro-
20. The compound according to claim 19, which is 1-pyridyl)methylphenoxy]propyl)ethanediimidamide, or a salt, hydrate or solubilized product thereof. 34, Formula ■: 17- [In the above formula, R1 is hydrogen, lower alkyl, 2-fluoroethyl 2,2.2-)! J fluoroethyl, allyl, flopargyl, (in the above formula, p is 1 or 2, R2 and R3 are independently hydrogen, lower alkyl, low viscosity alkoxy or halogen), and when R2 is hydrogen, R3 may be trifluoromethyl, or both R2 and R3 may be methylenedioxy, and R4 is hydrogen, lower alkyl, or lower alkoxy], m is an integer from 0 to 2, and n is 2. an integer from 1 to 5, Z represents oxygen, sulfur, or methylene, and A is 18- (in the above formula, R5 is hydrogen, lower alkyl, or lower alkoxy, q is an integer from 1 to 4, and R6 and R7 are each independently lower alkyl, lower alkoxy lower alkyl or phenyl lower alkyl in which the lower alkoxy moiety is two carbon atoms removed from the nitrogen atom;
Furthermore, when R6 is hydrogen, R7 may be cyclolower alkyl, or R6 and R7 together with the nitrogen atom to which they are bonded are pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino, methylpiperidino, dimethyl piperidino, N-methylpiperazino, 1.2.5.6-titrahydrobiridyl,
homopiperidino, heptamethyleneimino, octamethyleneimino, 3-azabicyclo[5,2,2]]non-3-yl represents 3-pyrrolino] in an inert organic solvent. about 0 to about 5
at a temperature of 0° C. a small amount of arachnoid, preferably in molar excess, most preferably in 2-3 molar excess, of sulfur, sulfur dichloride or chemically equivalent compounds thereof;
Preferably, the above formula is characterized in that it is reacted with a sulfur compound to form a compound having the formula I: in which R', A, m, Z and n have the meanings defined above. ■A compound or a pharmaceutically acceptable non-toxic salt thereof,
Process for producing hydrates or solvates. Formula 35 ■: [In the above formula, R1 is hydrogen, lower alkyl, 2-fluoroethyl, 2,2.2-] IJ fluoroethyl, allyl,
flopargyl (in the above formula, p is 1 or 2, R2 and R3 are independently hydrogen, lower alkyl, lower alkoxy or halogen, and when R2 is hydrogen, R3 may be trifluoromethyl, or R2 and R3 may both be methylenedioxy and R4 is hydrogen, lower alkyl or lower alkoxy], m is an integer from 0 to 2, n is an integer from 2 to 5, Z is oxygen, or methylene, and A is (in the above formula, R5 is hydrogen, lower alkyl, or lower alkoxy, an integer from qdl to 4, and R6 and R7 are independently lower alkyl, and the lower alkoxy moiety is nitrogen lower alkoxy-lower alkyl or phenyl-lower alkyl with at least two carbon atoms removed from the atom, and when R6 is hydrogen, R7 may be cyclo-lower alkyl, or R6 and R7 are the bond thereof; Along with the nitrogen atom, pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino, piperidino,
Methylpiperidino, dimethylpiperidino, N-methylpiperazino, 22-1,2.3.6-titrahydropyridyl, homopiperidi6hebutamethyleneimino, octamethyleneimino, 5-
azabicyclo[3,2,2]non-6-yl or 6-
Forming viroline) is reacted with a strong mineral acid, preferably hydrochloric acid, in an inert solvent at room temperature, or a compound of the formula 2: A -(CH2)mZ (CH2)nNH2 (forming A -(CH2)mZ (CH2)nNH2)
, m, Z and n have the meanings as defined above)
After reacting the compound with the formula ■; with the compound having the formula 2■: to produce the compound having the formula %, the compound with the formula % formula % ((Ell, R' have the meanings as defined above)
A compound having the above formula (■), which is characterized in that by reacting with a compound having the above, a compound having the formula n: (in the above formula, ks ms Zs n and R1 have the meanings as defined above) manufacturing method.