JPS584760A - 1-phenylthio-2-aminopropane derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formulaI(R<1> is halogen; R<2> is H or halogen; R<3> is methyl, ethyl, or hydroxyethyl). EXAMPLE:1-(4-Chlorophenylthio)-2-methylaminopropane fumarate. USE:Preventive and remedy for obesity and diabetes. It has low toxicity and is free from stimulating action to central vervous system. It can be administered safely for a long period. PROCESS:The compound of formulaIis prepared by reacting the thiophenol derivative of formula II with chloroacetone according to the reaction formula, and subjecting the resultant compound of formula III to the reductive amination reaction with R<3>NH2 using LiBH3CN or NaBH3CN as a reducing agent. The reaction is carried out in a solvent such as methanol, in the presence of 1-3mol of an acid such as HCl, using 2-20mol of R<3>NH2 based on 1mol of the compound of formula III.

Description

[Detailed Description of the Invention] The present invention provides a novel compound having excellent mulberry field action, = phenylthio 2-aminophylamide #K If (seki-
do.

The present inventors have proposed a novel compound represented by the formula c, in which R1 is a halogen, R2 is a hydrogen-spanning 118 halogen, and R3 is methyl, ethyl/l' or hydroxyethyl/L/Ashit=respectively. - Succeeded in the synthesis of phenylthio-2-aminopropane derivative <r>, and found that the compound and its acid addition salt exhibit remarkable anti-obesity and anti-diabetic effects 1r: Obtained,
Further research led to the completion of the present invention.

That is, the present invention provides a prophylactic and therapeutic agent for obesity or diabetes containing (1) the compound (1) and its acid addition salt, and (2) one or more of these compounds.
It is something to do.

In compound (I), examples of the halogen represented by 2 include fluorine, chlorine, or bromine, and when R2 is a halogen, the halogen may be the same as or different from the halogen represented by Hl. The compound (I) of the present invention can be easily synthesized, for example, according to the reaction formula shown below.

Pr0CeSB 1 , process 11 Process III [In the formula, R1, R2 and 83 have the same meanings as above, [<4 represents hydrogen or formyl group, R5 represents lower alkyl or arafurekyl group, and X represents a salivary group] In "Rosenu ■ 1:, S 1 JpA], thiophenol derivative 29 (II) is reacted with chloroacetone. This reaction is carried out by a method known per se, using an aqueous solution of sodium hydroxide, potassium hydroxide, etc. The reaction can be carried out at θ to 20° C. in the presence of methanol, ethanol, etc. as a solvent.The produced (Ill) can be easily obtained as a product of any purity by distillation or recrystallization.

In (St, p B ), (Ill) is synthesized as an example of a reductive amination reaction I)'e 3. This recombinant amination reaction is particularly performed with lithium or sodium cyanopolyhydride F.
(between LIBH3 and Nmafl Id NaBH301)
It is best to use
- (using 2 to 20 moles of , and the presence of 1 to 3 moles of an acid such as acetic acid, dihydric acid, acetic acid, etc.). It may be added to the reaction system in the form of LiBH.
3(,;I'] or N and the circle of H3CN is usually (I
[l) 0.5 to 2 moles per mole, and the reaction temperature is generally preferably in the range from room temperature to the solvent's precipitating point. In this reductive amination reaction, first, the ureroimine (IX) represented by the formula (all symbols in the formula have the same meanings as above) is produced, and then this is reduced to produce (I). Therefore, first, (ill) and 1 ("NH, 2 to imine CYX) may be synthesized, and then this may be converted into IM. In this case, in addition to the above-mentioned reducing agent, N
a, BH4, IL]-AlH3 etc. 1:
Wear.

In step C), (Ill) and the primary amine are combined with N-formyl. Illegality is caused by the so-called Leucard reaction (Lθucka.
rt.

This method utilizes a reaction known per se called ``reacti○n''. This reaction is carried out with respect to 1 mole of (III), primary amine or its N-formyl base: 1 to
20 mol, preferably 5-10 mol, formic acid'tl-10
Hot melt 111TI 2 0-1 8 0
'C, if-1 or i ao'~1 7 0
The resulting compound (1■) can be purified or subjected to the hydrolysis reaction of Tokuyamachini (St; e, p I'). The target compound (I) is synthesized.

This hydrolysis is preferably carried out easily by heating using mineral acids such as hydrochloric acid and sulfuric acid.

Process■ [1 liter, 6 liters of country] is a thiophenol derivative (
(2) This is carried out by reacting 1) with compound (V). The leaving group for X in the compound (V) is preferably halogen, such as salts or bromine.

Either yellow or purple is fine. This reaction is generally preferably carried out in a suitable solvent in the presence of a base, and examples of such bases include sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxy F, and the like.

Any solvent may be used as the solubilizer as long as it does not inhibit the reaction, such as methanol and ethanol.

Tetrahydrofuran, dimethoxyethane, dioxane,
The reaction can be carried out by appropriately selecting a water-containing solvent such as dimethylformamide or silica.

Reaction Q: [Although it proceeds at 0 to 80°C, it may be heated to around the boiling point of the solvent to accelerate the reaction. The amount of (11) and CV) in the present J reaction may be in a molar ratio of 1:I, and either one may be used in a small excess as appropriate. The stool dosage of the base is (if) 1 to 1.
2 mol of compound (V) is used, but when compound (V) is used in the form of an acid addition salt (e.g., hydrochloride, hydrobromide, iodide salt), the acid is neutralized/C. Add extra if necessary. −
1 of the JSL responses to enter again.

When there is relatively little chlorine or bromine, sodium iodide is used to accelerate the reaction (when there is relatively little chlorine or bromine), potassium iodide is added to the compound (
The reaction may be carried out by adding 0.1-1-f:/l/toasahi to v).

In (Step F,) of fluorescene, the thionoenol derivative (1) and the compound (Vl) are reacted to form (
■). Before removing *XX from the compound (vl), in addition to self (Vl), alkyl or aryl such as methanosulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group, etc. A nulfonyloxy group is preferably used. Examples of the γrugyl group represented by R5 include methyl, ethyl/I/I butyl, isopropyl, n-)ethyl, vlt-butyl, etc. having 1 carbon number. ~4 is preferable,
Aralkyl groups include benzyl, p-methylbenzyl,
Examples include p-methoxybenzyl group. The reaction between (II) and (Vl) can be carried out under the same reaction conditions as in (5tep E) above.

In the alkylation reaction of compound (■) in [St, ep G), first, (Vll) is converted into an anion using an appropriate base in an anhydrous solvent, and then a common alkylating agent is reacted with the anion. Examples of such bases include sodium hydride, sodium amide, sodium methoxy F, sodium ethoxide, potassium t-butoxy F, and examples of solvents include dimethylformamide, dimethyl nurefoxide,
Tetrahydrofuran, dimethoxyethane, etc. are used as appropriate.

As the alkylating agent, those used in ordinary alkylation reactions can be used, such as R3(') alkyl halide (eg, chloride).

Furomi F, iodite), KIt acid entel, nulphonic acid ester, etc. The reaction is usually carried out at a temperature of 0 to 40°C, but in order to control the reaction rate, it is possible to conduct the reaction at a temperature of less than this or more than this.

The thus generated (■) can then be led to compound (I) by subjecting it to a deprotection reaction [5te
pH). For this deprotection reaction, in addition to the hydrolysis reaction using acid and alkali, if 17'5 is an aralgi fi7 group or a t-buty/l/ group, a deprotection reaction known per se from Bebuti F chemistry may be used. This can be easily done. That is, by reacting the main bromide with acetic acid, those in which R5 is an aralkyl group or a °C-butyl group, trifluoroacetic acid or hydrogen chloride with a Zontsuki solvent,
When hydrogen chloride-acetic acid is used, p-methoxybenzyl groups and t-butyl groups where 1<5 are removed, respectively. Note that these R5 are Aworki) L/-4 Takeshichi-
During the deprotection reaction when represented by (buty)v group, then,
Anisole, mercaptoethanol to suppress side reactions
Good results may be obtained by adding 1 ml of methyl ethyl nurphyto.

The target compound (I) thus produced can be isolated in the form of a free base or in the form of an acid salt by means known per se. For example, the free base can be removed by distillation, and the acid addition salt can be removed by distillation, and the acid addition salt can be removed by distillation. Acid addition salts are preferably those which can be physiologically measured, such as inorganic acid salts such as hydrochloride, hydrobromide, 1IIIc salt, phosphate, and for example acetate, maleate, fumarate. Examples include organic acid salts such as salts, acid fumarates, succinates, alcoholates, citrates, and malates.

In the compound (,T), Q, there exists an optical viscosity substance in which the feeding configuration of * in the general formula (I) is S configuration, and an isomer in which *'s Zetsutairoku 8 is F (12I121 kidney). However, each isomer and a mixture thereof are naturally included in the scope of the present invention, and if desired, the isomers can be individually refined.For example, as the raw material compound (V) or (■) Optically active substance (S configuration ff-=) or R
By carrying out the reaction of fluorene 1[ or 111 using configuration), (I) can be obtained with the corresponding isomer (7). In the case of a mixture, it is subjected to extraction optical resolution methods such as optically active carboxylic acids, d- and l-tartaric acids,
d- and l-') malic acid.

d-camphor carboxylic acid, etc.) or an optically active sulfonic acid (e.g., d-camphor sulfonic acid, etc.), which are first separated into both isomers by recrystallization, and then separated into free optically active forms. It is also possible to separate and purify each isomer by means such as converting it into (I) and then converting it into an appropriate acid salt.

Among the optically active (I) thus obtained, compounds with S configuration generally exhibit more preferable physiological activity than the corresponding isomer with R configuration. 1. Compound (I) of the present invention and its acid Addition salts can be added to animals, especially mammals (e.g. mice, rats, guinea pigs, rabbits, cats, dogs,
(su/l/, humans), suppressing feeding behavior (feeding suppressing effect), enhancing ear moss resistance, suppressing inulin hypersecretion,
It has very specific effects such as inhibiting the biosynthesis of fatty acids from carbohydrates, and inhibits the effects of old 111. 1 Obesity or Ellllll! It is known that diabetes associated with obesity causes an undue increase in body fat 8h, a decrease in inulin blood 16m, 1lli Jl, lJ power, etc. Therefore, the compounds of the present invention are useful for treating obesity and 1. :It is an effective preventive or therapeutic agent for h-urinary disease. In addition, the compound of the present invention has low toxicity and does not cause the central nervous system stimulation effect, which is a serious side effect generally seen in drugs, so it can be safely used for long-term treatment1, and it can also be used orally. When administered, it is easy to inhale and has excellent stability, so when used in the medical practice described in (G) above, it can be used as a powder, by itself or mixed with appropriate pharmaceutically acceptable carriers, excipients, and diluents. It can be safely administered orally or parenterally in the form of tablets, capsules, injections, etc.3, and the dosage depends on the type and condition of the mammal.

For example, when administered orally to adults as a preventive treatment for obesity or diabetes, the daily inclination is approximately 0.1 to 6 (+ '
9/kq, especially about 0.2~20~/kti is good, and this throw! 5- It is preferable to divide the tablet into divided doses and take it around mealtime.

As a compound similar to the compound of the present invention, Belgian patent No. 658101 has a benzene ring iQ! '; 11(
.

Only the substituted 1-phenylthio-2-aminopropane compound (hereinafter abbreviated as compound CX) is circumferentially (described as C,
Although it is described as having a blood pressure increasing effect, a blood pressure increasing effect, 1)1'','r irritability effect, it has an anti-obesity effect, an anti-hypertensive effect,
There is no description of the urinary effect, and there is no description of the antidepressant effect of 1-(4-chloronoenylth)-2-aminopropane (1-(4-chloronoenyl))-2-aminopropane (13), which is expressed by the formula (Xl) in 12 in the Rain Africa Patent FF167A108. However, it is also anti-obesity,
No mention has been made regarding anti-diabetic effects11 According to the σf study conducted by the present inventors, compound (X) has no anti-obesity or anti-diabetic effects;
Compound I) exhibits only a weak, temporary feeding-inhibiting effect and has no stimulant value.2 However, the compound (I) of the invention has a specific halogen at the para-position of the benzene ring. By having one substituent group and having a specific secondary amine type structure, it exhibits powerful and long-lasting anti-obesity and anti-diabetic effects.

The raw material compound (V) of Brosene ■ or Brosene ■
Alternatively, (VI) can be easily synthesized using alanine as a starting material. For example, the amino alcohol produced by reducing the alanine derivative represented by the formula (Xll)
tv (X'fu) k A raw material compound (V') in which R3 is converted to a menal group by treatment with a halogenating agent
) is obtained as an acid salt, and (Xll) is partially reduced to (XIV) and then converted into a nulphonic acid to give (■') 3, (ShH30[■3 (Xll) (
XIV) (XM,) (Vl'
)0H3NHCHCH2Y, BY H3 (V) [In the formula, R5 is the same as above, R6 is hydrogen, lower alkyl or benzylv group, Y is halogen, Z is alkyl #
or an allylsulfonyluogish group, respectively] When (X1ll) is synthesized by the reduction reaction of compound (Xll), this reaction proceeds advantageously by using lithium aluminum hydride, and usually ethyl ether.

The reaction can be carried out in a solvent such as tetrahydrofuran or dimethoxyethane at a temperature ranging from room temperature to the boiling point of the solvent.

Examples of the halogenating agent used for halogenating the obtained compound (XJII) include hydrobromic acid, thionyl salt, phosphorus tribromide, etc. 1. When using hydrogen bromide 1adk, use the water bath solution as is. can be obtained, thionyl chloride,
When using phosphorus tribromide, use an anhydrous inert solvent, such as chloroform.

Iobium for dichloromethane, benzene, and toluene
Chemistry, Vol. 49, p. 1968 (1971) or the same magazine, Vol. 51, p. 1915 (1973), or by reduction of N-alkylalanine or its ester synthesized by a method similar thereto; -It can also be synthesized by reduction of acylalanine or its ester. Lithium 7'/reminium hydride can also be advantageously used in these reduction reactions.

When synthesizing (XIV) by partial reduction of alanine derivative (Xll), reduction with sodium borohydride is advantageous when (Xll) is an ester, and reduction with diborane is advantageous when (■) is a free carboxylic acid. be.

Methanol for reduction with sodium hydride.

Reduction proceeds advantageously in a temperature range from room temperature to the boiling point of the solvent in a solvent such as ethanol, and in the case of reduction with diborane, proceeds advantageously at 0 to 40°C in a solvent such as tetrahydrofuran, dioxane, dimethoxyethane, diglyme, etc. The target (XIV) can be obtained.

As shown in the above formula, alanine/l/ (XV ), which is one reduced alanine, is halogenated to (XVI ) in the same way as (x'nt), and then this is converted to urethane. By doing so, (Vl'') can be synthesized.

Such (■“) can also be used as a raw material in the present invention.

(XV) (XVI)C) (■〃) [In the formula ht5. y has the same meaning as above.] In any case, L-alanine is converted into S-absorbed 4' [substituted raw material compounds (V'), (Vl'),
(Vl〃) or D-alanine R narrow mouth l:・111
) Raw material compounds with (V'), (Vi'),
(Vi") are obtained, respectively, and t) is optically inactive when L is used (V').

(■Self, (Vl”) is generated.

The results of pharmacological tests demonstrating the excellent usefulness of the compound (I) of the present invention are illustrated below.

(ξ)) Feeding suppressive effect on mice: 111 ((2E-2pWder, Nippon Talea)) was fed for 6 hours a day to 11J11 for 7 days. (Nil' 6 animals), on the 8th day of feeding li++ 0.5 hours 1111, 50q/g of the test compound was dissolved in 5% arabic gum lz M solution and orally administered, and 5% arabic gum alone was administered. The intake amount was compared between the control group and the control group V.1 The results are as shown in Table 11.The number 11u in the table is 1!!4 when control/L/ is 100. Eating rate (percentage).

In Table 1, NS in parentheses indicates that there is no significant difference in terms of scale. All other values are -j゛P<0
．． It was significant at 02 o, ooi.

Cb) Ingestion suppressive effect of Jl on rats 24:1i1
'l Fasted 7 male S prable ζ11 (-J -
L) Administered to 4 & 11 rats (14,446 rats) by force orally after dissolving 20 IQ/kgf in distilled water, and feeding (41 (CE-2-powder)
), and 1 and 2 hours after the start, the amount of food intake was measured and compared with the control/l/group to which only distilled water was administered. The results were as shown in Table 2. The values in the table are the feeding rate (percentage) when the control is set as 100.7 Table 2 (0) 1ml Glycopotency enhancing effect in rats [2]
7-week-old male S' [) fed with 0 ti', + #11
1”a(:Lu t]-1-1a, wl+!3' rough 1・h and fa, tty rats (5 animals per group) were given 1-(4-chlorophenylthio)-2-methyl dissolved in distilled water. 20 or 50 q/kg of Aminopropane/L'r Toshiki was administered orally, and glucose (
ay/kq) was orally administered, immediately before administration of dulcose, an
, 60 and 120 minutes, the glucose of plasma collected in bales was measured, and the glucose area was calculated. The results are shown in Table 8.

Table 3 Each control) v (Administering only distilled water) *P
<0.05. ※※P<0.01 n) 7-week-old mujl' fasted for 20 hours: 5pra
The test compound dissolved in distilled water was orally administered at 20q/kQ to gue-Dawley rats F (5 animals per group) at 7.8o.
minutes later) v:1-nu (3F!/kti) was orally administered, and 30 minutes after the blood glucose reached @+fi, the glucose of the blood collected was measured. The results are shown in Table 4.
.

Table 4 Against control *P<0.01゜※※P<0.0
01 ■) 7 year old male Sprague-1) fasted for 24 hours
A, Wle7 rats) (5 animals per group) were orally administered the test compound dissolved in distilled water, and 80 minutes later, Dalcone Caf1
kgVt was orally administered, and the blood glucose taken 80 minutes later was measured. For the control group to which only distilled water was administered, (+M[ is expressed as 100, and the results are
Shown in the table.

99- Table 5 + (13 Insulin hypersecretion suppressive effect in rats■)
7-week-old male 5prafu, fasted for 20 hours], e-o
awley rats) and fatty rats (5 rats per group) 1-(4-chlorophenylthio)-2-methylaminopropane fumarate dissolved in KillC
0.20 or 50 W/kQ was administered orally, and insulin in plasma collected immediately before, 80,60 and 120 minutes after glucose administration was measured, and the inulin area was calculated. The results are shown in Table 6.

9A- Table 6 Each control) V (administration of distilled water only) *P
<0.05. ※※P<0.02. ※※※P＜0.0
11f) 7 week old male 5pra, fasted for 24 hours, Hue
-DaWle, YF1- (5 animals per group) (S)-1-(4-chlorophenylthio)-2- dissolved in distilled water.
Methylaminopropane fumarate 'e1.5゜10
, 20 Q/kQ oral administration, aO minutes later t/Cf1V
1-nu C8F! /kL;l) was orally administered, and 80 minutes later, plasma was separated from the blood collected and insulin was measured.
3° expressed as 0 ※※P<0.001. *1″<0.(11(0) Fatty acid synthesis inhibitory effect 6 hours a day feeding (OE -2pOwder, 84
A 7-week-old male 5prsν was kept on IO day 11 (Claire).
3-Dawley rats (5 rats per group) were given 1-(4-chlorophenylthio)-2-methylaminopropane fumarate dissolved in distilled water at a rate of 20q/^q [1 time, 80 minutes later]. Curcose-U-(shi(85μ(shiYy)
9) was orally administered to ``3117'', and 60 minutes later, the layer was sacrificed, and the radioactivity to fatty acids in the liver and parasardine adipose tissue was measured in total.A control group in which distilled water was administered instead of the test compound. (The inhibition rate was 46.6% in the liver and 58.8% in the epihidimal adipose tissue.

(0 acute sex (LD5o)) (S)-1-(4
-chlorophenylthio)-2-methylaminopropane
Oral administration of fumarate as an aqueous solution (500,750
, 1000, 1250 and 15001F1/kQ)
did. The animals were reared and observed for 5 days, and LD5oilk was calculated by the probit method.

LD50-10704/N& The present invention will be explained in more detail below using reference examples and examples, but the scope of the present invention is not limited thereto.

Reference Example 1 4-chlorothiopheno-)v (22,8f/
Chloracetone (1a, 9 g) was added to the mixture under water cooling and stirring. After cooling, the mixture was further stirred for 1.6 hours under water cooling, water a00 resistant was added, and after cooling with water, the precipitated crystals were collected by filtration to obtain 1-(4-chlorophenylthio)-2=propanone (aO, 6f). Melting point a6-87°C Reference example 2 4-fluorothiophenol (2,561i1)e ethanol-yVc 20ml), 2N-NaOH (12ml)
(Dissolved in mixture D, and added chloroacetone (1.8 g 7) to it while stirring under water cooling. After mixing, stir under water cooling for another 2 hours, and frost with water < 50 ml).
-Extracted with thyl ether. The ethyl ether layer was washed with water, dried over anhydrous magnesium sulfate, and the ethyl ether was distilled off to obtain 1-(4-fluorophenylthio)-2-propanone as an oil.

Yield a, ry0 This product was used as a raw material for the next step without further purification.

The following compounds were obtained by the same method: 1゜1- (
4-y-romophenylthio)-2-furobanone; melting point 6 a-64°C 1-(a,4-dichlorophenylthio)-2-propanone one point a6-a7°C Reference example 3 ■) N-carbo Benzyloxy-thi-alanine (55g
) of dry tetrahydrofuran C50 with lithium aluminum hydride (28 g) and dry tetrahydrofuran C50.
0 tsl) under reflux. The bale was refluxed for an additional 2 hours, cooled with water, and acetone (60#lt) was added without stirring to decompose excess lithium aluminum hydride. Next, water (100 s/) was added under water cooling, and after vigorous stirring at room temperature, the precipitate was filtered, and the solid matter was washed with ether and tetrahydrofuran. 1Mh
After drying with anhydrous potassium carbonate and distilling off RJ, the residue was distilled under reduced pressure to obtain (εE)-2-methylaminopropane-
) v18.45g? I got l+-. Boiling point 67-80°C (
(S)-2-methylaminopropanol was obtained by similarly reducing N-carboethoxy-thi-alanine (1, If) (S)-2-methylaminopropanol (10,
4f) was dissolved in CHC soil 3 (50 tnl), thionyl chloride (10,2*J) was added dropwise under water cooling, and then refluxed for 2 hours.
Isopropyl ether! Crystal L (S)
, Of) was partially purified by total sublimation, and crystallized from Saranietano μm isopropyl ether to give colorless needle crystals f.
@+ta. Melting point 149-150, 5°C [α] Eup 2+2
．． 9° (C=2.(+, methanol) Elemental analysis i1 c, HIQ CilN-H01 calculated value C aa.a5. f (7.70, N 9.7
2 induce you 1 tlk O aB. 29,H
7.70, N 9.72N-capopenzyloxy-D-alanine Purple As the starting material, (di-2-2-methylamitubeppi7rechloride hydrochloride was obtained in the same manner as in I) and n) above. .mi) 149.5-151.5℃
(α) 24-2.6° (0=2.0, fifi/
-A/) Reference Example 4 ■) Into a mixture of sodium borohydride (1.86 g) and dry dioxane (20 g), add water-cooled water to a mixture of sodium borohydride (1.86 g) and dry dioxane (20 g).
6f) CD dry di-v-y-one (l O Hl
) The solution was mixed. This was then added with dry dioxane (10*
l) The solution was added dropwise and stirred for 1 hour while cooling with water. After making the mixture acidic by adding water and acetic acid, the solvent was distilled off, and the ethyl acetate layer (3) was extracted with ethyl acetate. Melting 101
1: was distilled off and crystallized from isopropyl ether cooled with water to obtain (S)-2-penzyloxycarboniμ aminopropano-/I/(2,70fI). Recrystallized from isobrobyl ether to give a colorless -4.7° (C=2.O
, methanol-/L/) elemental analysis 1m eilH15NO
3 Calculated value C6a, 14. H7, 2a, N 6.69
Experimental value e 6B, 08. H7,09,N 6.54
If) (S)-2-bendi p-oquine carbonyl μ-aminopropano-/I/ (2,09 g), dichloromethane (20
Mesyl chloride (0.92 g+/) was added dropwise to a mixed solution of ethylamine (1.68 g/) while cooling with ice-salt. After stirring in a refrigerator for 40 minutes, the mixture was washed with water, dried over anhydrous magnesila sulfate (11 ml), and the solvent was distilled off.

The remaining crystals were collected by filtration and washed with isofurobyl ether to obtain 5)-N-benzyloxycarbonyl-(2-mesyloxy-1-methy)ethylamine (2.4 g). 1, melting point 104-106°C (a) 2a-19,a
o (C=2.1.meta) -ru) Elemental analysis value Cl2H17No5S Calculation 11 C50,16,H5,96,N 4.87
Experimental test C50,04,H5,71,N 4.59 Example 1 l-(4-chlorophenylthio)-2-propanone (2
Of), methylamine hydrochloride (13,51i').

In a mixed solution consisting of 40% methylamine methanol RN&<62'l) and methanol (100 g/),
“””H3ON(4y) @ was added while stirring and the whole mixture was stirred at room temperature for 5 days. 8N-NaOH
(100 m/), concentrated under reduced pressure, and extracted with ethyl ether. Ethyl ether After drying over anhydrous magnesium sulfate, all ethyl ether remained. The residue was dissolved in ethanol (20%), washed with fumaric acid (6,59) in ethanol/l/(80%) and diluted with ethyl ether to form crystals.
-I was happy. This is total ethanol-isofolvanol (
Recrystallized from 1-(4-chlorophenylthio)-2-methylaminopropane/"[4(1
1,2FI) obtained 1, melting point 160-161℃ Elemental analysis value C1oH1, UINS-1/2C,H,0° Calculated value C52,64,H5,89,N 5.12 actual m
Value (S 52.60.
A mixture of 5,5F), N-methylformamide (16,5g) and formic acid (5,06g) was heated on an oil bath at 145-150<0>C for 8 hours. After cooling, the mixture was diluted with 150 ml of water and extracted with ethyl ether. Ethylamine) After washing the V layer with water, the solvent was distilled off and the residue was mixed with 6N-HCl (20 #l/).
was added and heated under reflux for 2 hours. After diluting with water (60*l), wash with ethyl ether to remove soluble components, and remove the aqueous layer with 6N-N
Make alkaline with aOH (aOme) and extract with ethyl ether. The ethyl ether layer was washed with water, dried over anhydrous magnesium sulfate, and then the ethyl ether was distilled off. Residual oil r reduction +] E distillation 1. ．． 14Il of 1-(4-chlorophenylthio)-2-methylaminopropane: salt% (
3,82y) was obtained. Boiling point 10a-104℃ (0,2
pxwHg) Elemental analysis fin Cto HI3 C
l-NS calculated value 055.67, )l 6.54.
N 6.49 Experimental value c 65.4a, H6,66,
N6.42 free base 2f was dissolved in ethyl ether (10s+
t) Dissolve K, add excess methanolic hydrogen chloride, further dilute with ethyl ether, and collect the precipitated crystals by filtration.
Recrystallized from ethanol-ethyl ether to give 1-(4-
Chlorophenylthio)-2-methylaminof”lopane
Hydrochloric acid*(2,041)+3k.

Melting point: 127-128°C Elemental analysis: C1oH1, ClN5. HC soil calculation value 04
7.62. H6,00,N 5.55 Experimental value C4'
1.72. E (5,97, N 5.56 Also, the above free base 1f is converted into isopropanol of fumaric acid (0,27 da).
/L/(4ml) was added to the hot solution and left to cool.
-chlorophenylthio)-2-methylaminopropane
Fumaric acid 4 (1,18f) was obtained. Melting point 160
-161'C0 This product completely matched the compound obtained in Example 1 using infrared absorption Nuvector.

Example 3 l-(4-10lophenylthio)-2-7'lovanone (
2f) taM ethylamine methanol-μ solution (20m
/) and add 15% HCI・Meta/-IV (4
(4 ml) and NaBH3CN (0,49) were added and the whole mixture was stirred at room temperature for 4 days. 8N-Na
After adding 0H (10 tnl), the mixture was extracted with reduced Ifte concentrated diethyl ether. The ethyl ether layer was washed with water, dried over anhydrous II #11 magnesium, and the ethyl ether was distilled off. Residue ethanol/l/ (5tel)
x p / -IV of fumaric acid (0, sy) in solution
(12ml) solution was added, concentrated, and crystals obtained by adding a7ton were recrystallized from total ethanol, 1-(4-
Chlorophenylthio)-2-ethylaminopropane fumarate was crystallized 0, yield 1, Of
o +9・IK l 5 0 = 1 5
a °C elemental analysis value C1, H1601NS-1
/2 (J, H, O.

Calculated value C54,25, H6, aO, N 4.87 Experimental value C54,00, H6, a9. N 5.02 Example 4 Monoethanolamine (3.7 g) was used instead of the ethylamine methano-)V bath solution in Example 8.
(20 wtt) solution was used in exactly the same manner as in Example 3.
-hydroxyethylamino)ph.

Crystals of lopane fumarate were obtained II″!, amount 1.
25go melting point lag-189℃ Original cumulative analysis group C□, H, 6elNUS-'AC, H, 0
4 Calculated value C51,40,H5,97,N 4.61Estimated value c 51.26. H5,91,H4,82 Example 5 1-(4-fluorophenylthio)-2-propanone C
8,7 g), 40% methylamine methano-/I/bath solution C169), methane-yv (20 ml) and 15
%ldC in a mixture of methanol-1"6i& (8 ml)], BYl:S in a mixture of N (0,81/)?
c-add lc, oaN-NaO and stir for 4 days at room temperature
H (20 wtt) was added to the mixture at a pressure of 1 m and extracted with ethyl ether. The ethyl ether/L' layer was washed with water, dried over anhydrous magnesium silicate, and then the bath (2) was distilled off.

In the residue, the effect of V acid (1,7 da) is added to the residue.
5*t) After adding the solution and filtering off a small amount of insoluble matter, ethanol/
The crystals obtained by distilling off L/ and adding ethyl ether to the residue were recrystallized from ethanol-ethyl/'l/ether to obtain 1-(4-fluorophenylthio)-2-methylaminopropane acidic fumarate. of? →It is. Yield 2.2
8f, melting point 12a-12480 Elemental analysis 17C101 (14, Ii'NS, C4H40
4th edition'8 餉 (35a, a2. l-15, 75, LQ
4.44 Experiment 41'u C,: 5a, 12
．． Fl 5.68. N 4.65 Example 6 l-(4-Zolothousenylthio)-2--y” Lovanone (2,45N), Methylamine hydrochloride (1,35LJ40
% Methylamine Methanol/L'Vl& (6,21/
) and methanol/L/(lONt),
NaBH3CN (0.4 L) was added and stirred at room temperature for 4 days. After adding aN-NaOH (10 rats), the mixture was condensed under reduced pressure and extracted with ethyl ether. Ethylamine) V layer was washed with water, dried over anhydrous magnesium sulfate, ethyl ether was distilled off, and to the residue was added a bath solution of ethanol (18*1) of Zuma-) V acid (1,2 F/).
After removing a small amount of insoluble materials by filtration, the crystals obtained by filtration and ethyl ether/reggae processing were reconstituted with ethanol and ethyl ether to give 1-(4-bromophenylthio)-2-methylaminopropane and acidic fumaric acid. Salt 1.4'lFI was obtained. Melting point 126-128" 0 Yuan cumulative analysis group 010H1
4BrNS-C4H404 calculated value e 44.69.
H4, 82, Na, 72 trial 111k C44, 76
, H4,86, Na, 86 Example 7 1-(a,4-dichlorophenylthio)-2-7"
Lovanone (1,88g), methylamine hydrochloride (1,85g)
N), 40% methylamine methanol solution (6.2g
) and meta/1 in a mixed solution of −1 L (10 vre) O
fCNaBH30N (0.4f) was added and stirred at room temperature for 7 days. 4, N-N/1. OH(10#11
) was added, the mixture was concentrated under reduced pressure, and extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and chloroform was distilled off. Fumaric acid (0,7
y) (Dxp)-/l/(10ml) solution was added and decanted, the precipitated crystals were collected by filtration and reconstituted from ethanol +n+Lte1
- (a, 4-dichlorophenylthio)-2-methylaminopropane acidic fumarate (1.05 g)/ζ. Melting point 14a-145°C Original cumulative analysis 11f C]o
H13C12NS-C4H404 calculated value C45,91
,H4,68,,N L82 test cake C45,89,H
4,65,N 4.00 Example 8 (S)-2-Methylaminoprobyl chloride F hydrochloride (
11,5F) in methanol-zlz (80 ml), p
-chlorothiopheno-/”(11,59), methanol-
tv (80 byt) and 28% sodium methoxy F/methanol ('a 2 +tte) under reflux for 1 hour and 20 minutes, followed by a further 2 hours of reflux. Add water (50 tons) and distill off methanol/l/] ~,
Acidify with 1 to 6 N-salts, wash with ethyl/+7 ether, and make the aqueous layer alkaline with 6N-sodium hydroxide (7
Extracted with ethyl ether. Extract # was washed sequentially with ll'J-sodium hydroxide and brine, dried over anhydrous potassium carbonate, and the solvent was distilled off.
[I,,(S)-1-(4-chlorophenylthio)-
Fumaric acid (4,1'l) was added to ethanol (2 (ls/J) and heated under heating. Drop the above oil while stirring,
After heating for a while, isopropyl knee was added and allowed to cool. The precipitated crystals were collected by filtration and recrystallized from EtOH-isopropyl ether to give Kl, (S)-1-(4-
Chlorophenylthio)-2-methylaminopropane fumarate (16.2 g)'Ik was obtained. Melting point 140.5
-142℃ [α] 25+12.2° (C= 2.0
, )Tano=yLi)■] Elemental analysis Jim C1oH1,C]N5-V2C,1
1404ifl 1+fi (: 52.(iL
115.891 N 5.12 trial 1'1 ke
(-+ 52.8G,,tl 5.84.N 5.89
], I
Minoblovir chloride hydrochloride and p-fluorothio7'l-/-/l/, l: Total reaction, then humer/
(S)-1-(4
-fluorophenylthio)-2-methylaminopropane acid fumarate was obtained. Yield 94.4% M11. a
127-128°C [a) 23+8. (io (c
= [] 2.0. Methanol-7L') Elemental analysis 11k 010 H14FNS ・C41■
404 total: El: 1+m C5a, 82. H5,7
5, N 4.44 dick experience 1+ii c 58
．． 16. H5,82,N 4.51 Example 1O Same as Inusei], (S)-2-methylaminopropyl chloride hydrochloride and 8,4-dichlorothiophe,
(S)-1-(a,4-dichlorophenylthio)-2-)yvaminopropane (acidic salt) by reacting the metal and then forming a salt with fumaric acid.
A V acid group was obtained. Yield 3 68.3% 1 point 120-121 ”t: (α)
1°+9.10<C=2. o, methanol) 7G
Cumulative analysis (1[Cl0H1311JC12Sl-:4)i
4j, ]4 Calculation II C45,9L H4,68,l
Harvest 3.82 seeds 1ul C45,92,114,68
, I < a, 99 Example 11 Similarly to the side 8, (R)-2-methy/l/γminof"ropyl chloride hydrochloride])-chlorothioph x /
-1V Toi reaction awn, then Tsuma-)vW4 To(
7) By forming a fund (R) -1-(4-
Chlorophenylthio)-2-methylamino 750 Pano 9
Fumer/L/acid was obtained. Yield 74% Melting point 140.5
-141.5℃ [α)25-12.8' (C=2
．． 0.

Methanol/L/) Elemental content h's clo Hl, cllXJs 'A
C4H404 calculation 11 good C52,64,H5,89
,N 5.12 Trial C52,7a, H5,72,N
5.09 Example 12 I) p-Chlorothiophenol (0,72f).

(S)-N-benzyloxycarbonyl-(2-mesyloxy-1-methy/I/)ethylamine (1,44 g, sodium iodide C0,2f), methanol (15 m
+&) and 28% sodium methoxide/methanol-/
The mixture of I/(1,0y) was stirred at room temperature for 4 hours and then under reflux for 2 hours, and then methanol was distilled off. Add water, extract with ethylamine μ, wash the ethyl ether layer with sodium hydroxide solution and water, and add anhydrous tiIIcm.
3 was dried over magnesium, the solvent was distilled off, and hecan was added to give (S)-2-pencyloxycapbonylamino-1.
-(4-chlorophenylthio)fluoropane crystals (1,
aOg) was obtained. A colorless film was obtained by recrystallization from isofropylether.One point 66-67℃ [α)2
a+58.7° (C=2.O, methanol elemental analysis value C17HIB 01NO2S calculation 1111c 60
．． 80. [(5,40,N 4.17ri(Experiment 11n
c 60.81. Iko 5.24. N
4.0911)(S)-2-Benzyloxycarbonylamino-1-(4-chlorophenylthio9propane(1
, 11f) of N,N-dimethylformamide FC,
6ml) Add sodium hydride (
60% oily, 012f) was added and stirred for 40 minutes.

Next, this was cooled with water, and methyl iodide (0.2 ml) was added dropwise, and the mixture was stirred for 15 minutes while cooling with water and for 30 minutes at room temperature. Water was added and extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate.

Distilling off the salt gave an oily substance (0.90f) of (S)-2-(N-pendyloquine carboni/L/)methylamino-1-(4-chlorophenylthio)propane.

m)(S)-2-(N-penzyloxycarponi)V)
Methylamino-1-(4-chlorophenylthio)propane (0,0), acetic acid (Igt)', anisole (1g/
) 25% hydrogen bromide/acetic acid (8.5 g/) was added dropwise to the mixture while stirring under water cooling.

The drained water stirred for 2.5 hours was added, and the mixture was extracted with ethyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solution was distilled off to obtain an oily product C0.4f) of 5J-1-(4-chlorophenylthio)-2-methylaminopropane. Dissolve this oil in ethanol/L/(5N/),
Ethano-N (a ml) of fumaric acid (0.12 g)
) solution, further isopropylether was added, and the precipitated crystals were collected by filtration to give (S)-1,-(4-chlorophenylthio)-2-methylaminopropane fumarate (
0,50&) was obtained. Isopropano-p-ethyl ether was recrystallized to give colored crystals. Melting point 1 as-ia 9
°C [α] is also a+12.4° <C=2. o. The infrared absorption Nuvector and nuclear magnetic resonance spectra of this product containing methanol completely matched the compound obtained in Example 8.

Example 13 When the compound (I) of the present invention is used as an agent for treating obesity or as an agent for preventing or treating diabetes, it can be used, for example, in the following formulation.

Tablets (1) 1-(4-chlorophenylthio)-2-methylaminophyllopane fumarate 0fI (2) Lactose 90Ii (3) Corn flour 29FI (4
) machinenium stearate 1y100
0 tablets 1aOf (1), (2> and l'l corn starch - 1 powder is mixed together, and a paste made from 7y of corn flour is mixed with granules, 5g of corn starch and (4) are added to the granules. is added and the mixture is compressed using a compression tablet machine to produce 100 tablets with a diameter of 7 hm and each tablet has a name of 10 mf.

B Capsule (1) (S) -1-(4-chlorophenylthio)=2-methylaminopropane zuma-)v acid salt
1Ov (2) Lactose
1a5f (3) Cellulose starch powder 'toy (4
) Magnesium stearate 5y100
0 Cuff Cell 220 g Mix all ingredients and fill 1000 gelatin capsules No. 3 (9th revised Japanese Pharmacopoeia).
) Manufacture and consume the cabbage containing 1 Oq.

C Injection (1) I-(4-chlorof''L-nylthio)-2-methylaminopropane fumar sto 1y (2) Sodium chloride 9g All ingredients in distilled water 10
Dissolve in 00 ml and add brown amplifier lvl to 000 pieces.
Dispense each ml, replace with nitrogen gas, and use 4'S for 1 person. The entire process is performed under sterile conditions.

47- 407-

Claims (1)

[Scope of Claims] (υ Formula [wherein R is halogen, R is hydrogen or halogen
3 represents a methyl, ethyl, or hydroquinethyl group, respectively]; or an acid addition salt thereof. (2) Formula [In the formula, R is halogen, R is hydrogen or halogen, R
represents a methyl, ethyl group or a hydroxyethyl group, respectively.
11! t1υVIA treatment for diabetes, 11.1