JPS6067450A - 2-phenylethylamine derivative, manufacture and medicinal composition - 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 [Industrial Application Field] The present invention relates to derivatives of 2-phenylethylamine having anti-obesity and/or anti-hyperglycemic activity, methods for their production and their use in medicine.

[Conventional technology]

EP6766, EP6735, EP23385゜E
P70133. and EP 70134 discloses derivatives of 2-phenylethylamine having anti-obesity and/or anti-hypertensive activity.

[Problem that the invention seeks to solve]

Other groups of compounds have been found that have anti-obesity and/or hyperglycemic activity.

[Means for solving problems]

According to the present invention, the formula (1) % formula % [wherein Ar Lri is benzofuran-2-yl or the group R1 and/or HR'' (wherein R1 is halogen, trifluoromethyl or hydroxy and R2 is halogen is phenyl which may be substituted by: R3 is hydrogen or methyl; and b is 2~
is an integer of 7, and M is hydroxy, C1-6 alkoxy, phenyl C, -6 alkoxy, or -NR4R5 (wherein R4 and R5 are each hydrogen or 01-6 alkyl, or - together are 5-membered or (forming a 6-membered heterocyclic ring): Y is 02-6 straight-chain or branched alkylene and at least 42 carbon atoms are 10- and 10H and n is 1 or 2] or a pharmaceutically acceptable salt, ester or amide thereof.

Ar is each halogen or trifluoromethyl 11,
B fK II-k rV&-+9-)711-*n
There is a group of compounds within formula (1) where fAZR1 and R2 are phenyl optionally substituted and R'', X, Y and n are as defined in formula (1).

Ar is R1 (halogen or trifluoromethyl at the meta-(or 3-) position on the phenyl ring) and/
or R2 (which is ortho (or 2-) fluoro) is phenyl which may be substituted by K, and X is 10 (0
M2) a CO, I-1 or -〇(C)12) bM(
In the formula, a, b, and M are the same as above), and R, Y, and n
There is another group of compounds within formula (1) in which the force defined in formula (1) is exactly as defined in formula (1).

When Ar is substituted phenyl, 1 is preferably a halogen at the meta-(or 3-) position on the aromatic ring. Preferably R1 is chlorine. Preferably a is 1. Yes, b is 2. Preferably, n is l.

Particularly preferred compounds are those in which R3 is methyl.

When M is -NR4R5, one of R4 and R5 is preferably purple and C1-6 alkyl is preferably methyl or ethyl0 NR4R5 together form a 5- or 6-membered heterocyclic ring Examples include piperidinyl, piperidinyl and morpholinyl.

Yfl is preferably ethylene or n-propylene.

Pharmaceutically acceptable compounds of formula (1) include pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, orthophosphoric acid, sulfuric acid, methanesulfonic acid, toluenesulfonic acid, acetic acid, propionic acid, lactic acid, citric acid. , fumaric acid, malic acid, succinic acid, salicylic acid or acetylsalicylic acid.

The clever ester Hx of the compound of formula (1) is -CO2H
Also u-0(CH2)ac02)i TC1 of a certain compound
-6 alkyl ester. Particularly preferred esters are methyl and ethyl esters.

A preferred amide of the compound of formula (1) is one in which X is of the formula -C0NR
4R' or -0 (0M2)a C0NR4R' (wherein R4 and R5 are as defined in formula (1)).

When R3 is methyl, compounds of formula (1) have two asymmetric carbon atoms in the formula, indicated by one and two asterisks. The compound of Kone et al. would therefore exist in the form of four stereoisomers. The present invention encompasses all stereoisomers of the compounds of formula (1), whether free from other stereoisomers or mixed with other stereoisomers in any proportion, and therefore includes, for example, mirror images. It also includes racemic mixtures of isomers.

Preferably the carbon atom marked with one asterisk has the R configuration.

The most effective compounds of formula (1) are those in which both asymmetric carbon atoms are in the R configuration.

The absolute configuration of any compound of formula (1) may be determined by conventional X-ray crystallographic techniques.

The present invention provides a method for producing the compound of Wenmu (1) or its salt, ester or amide, which method comprises formula (II) -Y-OH + R9R3 ++ CH-C-N-C-(C) (2 )n where R3, Y and n are as defined for formula (1): At' is a group as defined for formula (1) or convertible thereto: RIOd formula (1) is a group X defined with respect to, or is a group convertible into a group X: R6 together with hydrogen or R7 forms a bond; R7
is hydrogen or together with R6 or R8 to form a bond; R8 is hydrogen or together with R7 to form a bond or together with R9 to form an oxo group; R9 is hydrogen or together with R8, the oxo group forms m1- and R6~
When R% nRlG is X, not all of it is hydrogen. ) or its ester or amide by reducing the oxo group or double bond and then converting the resulting compound in which Ar' is other than Ar and/or RIO is other than X to a compound of formula (1). may be formed and/or may form a compound of formula (1) formed and/or may be formed of a compound of formula (1)
) may be converted to other compounds of formula (1).

Provided that there are two reducing functional groups in a compound of formula (...), these may be reduced separately or simultaneously in any order.

The above reductions may be carried out by conventional chemical or catalytic methods. Preferably the chemical reduction will be carried out with lithium aluminum hydride, sodium cyanoborohydride, sodium borohydride or borane methyl sulfide. Catalytic hydrogenation may be carried out using a catalyst such as palladium or platinum on charcoal, such as reduced platinum oxide.

The reduction with sodium borohydride is advantageously carried out in a lower alkanolic solvent, such as methanol or ethanol, and is generally carried out at 0 to 20°C.

The reduction with lithium aluminum hydride is preferably carried out at room temperature or elevated temperature in a dry ethereal solvent such as diethyl ether or tetrahydrofuran.

The catalytic reduction is advantageously carried out in customary hydrogenation solvents such as lower alkanols such as ethanol.

Hydrogenation is generally carried out under hydrogen gas at ambient or elevated temperatures and about 1 to JO atmosphere.

An example when Ar' is other than Ar is protected hydroxy-substituted phenyl (when Ar is hydroxy-substituted phenyl).

Suitable protecting groups are those which can be removed by conventional hydrogenolysis, such as benzyl.

A preferred embodiment of the method of the invention is to reduce a compound of formula (IIA)-Y-OR or to reduce a compound of formula ('nB)0-Y-0)1 or to reduce a compound of formula (IIC)-Y -OH or reduce the compound of formula (IID) 0- Y -0
To reduce the compound of [1] [where R3, X, Y and n are as defined for formula (II) and Ar// is Ar
or (when Ar in formula (1) is phenyl substituted by R1 hydroxy group) and W is a truncated group that can be reduced by X] and Ar'' may be converted to Ar. .

The present invention provides another method for producing the compound of Bunmu (1), where f'L is the formula (R1) A-N13 (■) [wherein A is the formula (IIIA) or (III B ) (II
IA) (IITB) (In the formula, At", R3, X, Y and n are the formula ())
and (as defined for (IIA-D)) and length (IV) B-Z (■U [wherein B is the formula (IVA) or (IVB) (CH2)
CH-0-Y-OH halogen or tosyloxy group), provided that when A is a group of formula (I[lA), B is a group of formula (IVA
) and when A is a group of formula (IB), B is a group of formula (IB)
IVB) and then converting Ar'' to Ar, forming a salt of the compound of formula (I) formed and/or The expression (
The compound of 1) may be converted to other compounds of formula (I).

The reaction of a compound of formula (III) with a compound of formula (IV) is advantageously carried out for about 2 to 3 days at an elevated temperature, such as 50'0, in a solvent, preferably dimethyl sulfoxide.

Salts of compounds of formula (1) may be prepared by treating compounds of formula (υ) with associated acids.

F) The compound of formula (1) and its salts produced by the above-described method may be recovered by conventional methods.

The compound of formula (II) is itself a combination of an amine of the above-mentioned formula (I[[) (in which the person represents a moiety of formula (CH□)n Cl -) and formula (V) o -y -o ti ■ C11CO □) I (V) At' is reacted with an amine of formula (Ill)' (in the formula % represents a part of the formula %) and an amine of the formula CM) (i: R3 (in the formula Ar' , R'', X, Y and n are the formula (If)
(as defined for).

Conventional conditions compatible with the particular compound of formula (V) or (Vi'') will be used for this reaction.

Therefore, the formula (If ri (in the formula A14 formula (n+A) ノM−
The reaction between a compound of c h ) and a compound of formula (■) is advantageously carried out at elevated temperatures under conditions which result in the removal of the water formed during the reaction. A particularly preferred method is to carry out the reaction under reflux in an inert solvent such as benzene and remove water azeotropically using a Diller and Stark trap.

The reaction between a compound of formula (■) in which AFi is a group of formula (RIB) and a compound of formula (V) is advantageously carried out under standard peptide-forming reaction conditions.

In the latter reaction, it may be desirable to protect the --OH$; of Y of formula (V) with a conventional protecting group such as acetate, followed by reaction-deprotection.

It is often advantageous to prepare the compound of formula (1) and reduce it in situ to obtain the desired compound of formula (1) without isolation of the compound of formula (Ir).

Stereospecific synthesis of compounds of formula (nc) is achieved by using single bell isomers of compounds of formulas (■]) and (V). The compound of formula (nc) is then reduced to the compound of formula (1) without changing the configuration of the two asymmetric carbon atoms. Therefore, for example, the formula (
+n) and a compound of formula (V) having an R-absolute configuration to give a compound of formula (IIC) and by subsequent reduction a compound of formula (1) in R,R-absolute Annex I line 4
Let's see.

The compound of formula (1) or its pharmaceutically acceptable salt, ester or amide (hereinafter referred to as drug) may be administered as a pure drug, but the drug may also be a pharmaceutical composition comprising a pharmaceutically acceptable carrier. It is preferable to administer it as a drug.

Accordingly, the present invention provides a pharmaceutical composition comprising a compound of Wenmu (1) or a pharmaceutically acceptable salt, ester or amide thereof and a pharmaceutically acceptable carrier therefor.

As used herein, "pharmaceutical composition" and "pharmaceutically acceptable composition" include compositions and ingredients for use in humans and animals.

Generally, the compositions of the present invention are adapted for oral administration, although compositions that can be administered by other routes, such as by injection, are also contemplated.
Good morning.

Compositions particularly suitable for oral administration are unit dosage forms such as tablets and capsules. Other fixed unit dosage forms, such as bag-packed powders, may also be used.

In accordance with normal pharmaceutical practice, the ingredients may include diluents, fillers, disintegrants, humectants, lubricants, colorants or flavoring agents.

Typical carriers are therefore microcrystalline cellulose, starch, sodium starch glycolate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate,
It consists of agents such as sodium lauryl sulfate and sucrose.

Most preferably the composition will be presented in unit dosage form. This unit dose usually contains 0.1 to 0007Q of the drug, more usually 0.1 to 550 and preferably 0.1 to 250
Consists of mg.

The present invention further provides a method for treating and/or preventing obesity in humans or non-human animals, which method comprises administering an effective and non-toxic amount of a compound of formula (1) or a pharmaceutically acceptable amount thereof to a mammal. It consists of administering a salt, ester or amide.

The present invention further provides a method for treating and/or preventing hyperglycemia in mammals, including humans, which method uses a compound of formula (1) or a pharmaceutical thereof that is effective and non-infectious in mammals. and administering an acceptable salt, ester or amide.

Advantageously, the medicament is administered as a pharmaceutical composition as described above, and this forms a special aspect of the invention.

To treat people with hyperglycemia or obesity, the drug is generally administered at a total daily dose of about 0.1 to 6000 m9 for a 70 kg adult.
and more usually about 1 to 1500 m9, taken from 1 to 6 times a day with the above-mentioned doses. Preferred compounds that are more effective generally range from 0.1 to 2001
It would be a unit dose containing n9. The daily dosage of soroki is generally about 0.5 to 500 mg ζ and usually 1 to 2
It would be 0.001 ng.

To treat hyperglycemic or obese animals, especially dogs, the drug is approximately 0.
．． n 25 mL2/9 to 25 m97 kg, for example 0.1 m9/kg to 20 Tn/kg, usually 1 day
Administer orally in ~2 doses.

The invention will be described with respect to the following examples.

In the examples, the substituents of formula (1) are as shown in the table below.

〔Example〕

Example I N-(2-(4-carbomethoxymethoxyphenyl)-
1-methylethyl)-2-(2-hydroxyethoxy)
-2-(3-chlorophenyl)ethanamine hydrochloride methanol (1-(4-carbomethoxymethoxyphenyl)propan-2-one (4,4 g in 10 m7)
) and 2-(2-hydroxyethoxy)-2-(3-chlorophenyl)ethanamine (4,39) were hydrogenated in the presence of platinum (from platinum oxide, 5omcI) until absorption of hydrogen ceased. The solution was filtered through diatomaceous earth and the solvent was removed in vacuo.

Chromatography on silica gel of 25% methanol in dichloromethane gave an oil. Treatment of this oil with an ethereal solution of hydrogen chloride produces the diastereoisomer 56
:44 mixture as the title compound [melting point 72-75°C (
acetone-diethyl ether)] was obtained.

'H-nmr δ (DMSO=d6) 1.20 (3) 1. d):2.6-2.9(]H,m)
:3.0-3.8 (9H, 8H by D20 wash)
Complex m ) ; 3.70 (3H,
s): 4.78 (2H, S): 4.9-5.2 (IH,
m) 6.90 (2H, d) near, 24 (2H, d
) Near, 3-7.6 (4H, m): 9, (1-9
, 5 (IH, brcl m, exchange by D20):
9. fi-10,2 (In, brd m, exchanged with D20), Example 2 N-(2-(4-carbomethoxymethoxyphenyl)-
]-]methylethyl]-2-3-hydroxypropoxy)-2-(3-chlorophenyl)ethanamine hydrochloride The title compound described in Example 1 was prepared in a similar manner to 1-(4- Diastereoisomer 56 from carbomethoxymethoxyphenyl)propan-2-one (43θ) and 2-(3-hydroxypropoxy)-2-(3-chlorophenyl)ethanamine (4,59):
44 mixture [melting point 11-Q' to 114. °C (ethyl acetate-cyclohexane)].

'H-nmr δ (DMSO-d,) 1.0-1.3 (3H, m): 1. ．． 5-1.9(
2H, rn): 2.6-2.9 (IH, rr+) 3,
n -3,8 (FD-1, complex m): 3.7
0(3H,s):4.5-4.8(IH,brd m,
D,, exchange by O)': 4.78 (2H, s): 4,
Fl-5,1 (ltl, in): 6.9+1 (2, H,
d) Near, 2] (2H, d); 7.3-7.6 (4):
l, m): 8.8-9.3 (IH, brd m, D20
9.810.3 (11-1,brd r
n, exchange by D20).

Example 3 N-(2-(4-Methylaminocarbonylmethoxyphenyl)-1-methylethyl)-27(2-hydroxyethoxy)-2-(3-chlorophenyl)ethanamine hydrochloride N- in ethanol (50 nTl) (2-(4-rubomethoxymethoxyphenyl)-1-methylethyl)-
2-(2-hydroxyethoxy)-2-(3-chlorophenyl)ethanamine (4.0 g) and No. 33 methylamine were heated under reflux for 1.5 hours. The mixture was evaporated under reduced pressure and the residue converted to its hydrochloride salt by addition of ethereal hydrogen chloride.

Recrystallization from ethyl acetate-methanol gave the title metal as a 56:44 mixture of diastereoisomers (melting point 1
17-121°C).

"H-nmr δ (DMSO-d6) 1.0-1..3 (3H, m): 2.6B (3I-1,
d): 2.5-2.9 (IH, m): 3.0-3.7 (
8) i, :l:/plex m):4.33(21→
+S): 4.5-4.9 (replaced with IH, m, D20):
4. ．． 8-5. (1(II-1,m); 6.92(21
"d); 7.23 (2, FJ, d) near, 3-7.8 (
4H, m);8. n-8,3(] II.

m, replaced with D20); 8.9-9.4 (II (,brd
m, I) 20): 9.5-10.0 (1) 1.
brd r+1. (Exchanged with D20).

Actual sister example 4 N-(2-(4-(2-hydroxyethoxy)phenyl)-1-methylethyl)-2-(2-hydroxyethoxy)=2-(3-chlorophenyl)ethanamine hydrochloride Dry tetrahydrofuran (30me) N-(2-
(4-Carbota I ximethoxyphenyl)=1-methylethyl]-2-(2-hydroxyethoxy)-2-(
3-chlorophenyl)ethanamine (3,09) was added dropwise with stirring to a suspension of lithium hydride (1,0j9) in dry tetrahydrofuran (30d) and the resulting mixture was heated under reflux for 3 hours. did. After cooling, water (1 mj 10% aqueous sodium hydroxide (1 d)
and water (2me) were added carefully. An oil was obtained by filtration and evaporation of the furnace liquor to dryness, which was converted to its hydrochloride by treatment with ethereal hydrogen chloride. Recrystallization from ethyl acetate-methanol-diethyl ether gave the title compound as a 49:51 mixture of diastereoisomers (mp 8
6-90°C).

'H, nmr δ(DMSO-d6) 1, (1-1,3(3H,m):2.6-2.9(])
1. rn): 3.0-4.1 (12H.

Complex m): 4.7-4.9 (2I-1, m
, D, Oa exchange); 4.41-5.2 (II(, m)
;6.90 (2M, d) ;7.23 (2H, d)
Near, 3-7.7 (4H, m); 8.8-9.4 (IH
,brd m,D,Q? : Exchange): 9.5-10.00
(IH,brd m,exchanged with D20).

Example 5 N-(2-(4-(2-methylaminoethoxy)phenyl)-1-methylethyl)-2-(2-e hydroxyethoxy)-2-(3-chlorophenyl)ethanamine dihydrochloride hydrate drying N-(2-
(4-methylaminocarbonylmethoxyphenyl)-1
-methylethyl]-2-(2-hydroxyethoxy)-
2-(3-chlorophenyl)ethanamine (2,'09
) was added 9 times a day of poran dimethyl sulfide complex (6d) to the stirred solution. The solution was heated under sieve for 3 hours and after cooling to room temperature methanol (20ml) was added.

The solution was allowed to stand overnight at room temperature, heated under reflux for 1 hour, cooled, and passed with hydrogen chloride gas for 10 minutes. After dilution with diethyl ether, cooling to 0 °C and filtration, the title compound (mp 204-208 °C) was separated into 5 diastereoisomers.
Obtained as a 8:42 mixture.

lHnmr δ(DMSO-d6+D20)1.20
(3HId);2.70(3H,s);2.6-
2.9 (1-H, m): 3.0-3.8 (1011
-1, complex m): 4.2-4.5 (2H, m
): 4.7-5.1 (1B, m) near, 00 (2I (,
d) Near, 29 (2H,, d) Near, 4-7.7 (4H
, m).

Example 6 N-(2-(4-carbomethoxymethoxyphenyl)-
1-methylethyl)-2-(2-hydroxyethoxy)
-2-(3-)lifluoromethylphenyl)ethanamine hydrochloride 1-(4-)
-Carbomethoxymethoxyphenyl)propan-2-one (4,405') and 2-(-2-hydroxyethoxy)-2-(3-)lifluoromethylphenyl)ethanamine (4,989) as diastereoisomers 66
:34 mixture as the title compound (melting point 93-97°C)
(Ethyl acetate diethyl ether) was obtained.

IHnmr δ (■] MSO-d6) 1.0-1.4 (31-1, m), 2.6-3.0 (I
H, m), 3. lo-4,0 (8H.

m), 3.70(3)1. s), 4.80 (2fi, s
), 4.9-5.4 (2H, m.

IH, D, exchanged with 0), 6.91 (2) i, d), 7
．． 23(2)1. d).

7.6-80 (4FL, rn), 9.0-9.6 (II
(, m, replaced with D20).

9.6-. 10. ](]lI-1.m, exchanged for D2).

Example 7 N-[2-(4-carbomethoxyphenyl)-1-methylethyl]-2-(2-hydroxyethoxy)-2-(
3-chlorophenyl)ethanamine hydrochloride 1-(4-
carbomethoxyphenyl)brobazi-2-one (3,
579) and 2-(2-hydroxyethoxy)-2-(
3-chlorophenyl)ethanamine (4,009) gave the title compound as a 65:35 mixture of diastereoisomers (mp 84-87°C) (ethyl acetate-cyclohexane).

IHnmr δ (DMSO-d6) 1.0-1.3 (3H, m), 2.6-3.0 (]
H, m), 3.0-3.8 (811, m) 3.8
5 (3H,, s), 4.0-4.5 (] month, m, D20
%'l), 4.96 (IH, t), 7.2-7.6
(6H, m), 7.91 (2H, d), 9. (1-9,
5 (IH, broad m, replaced with D20), 9.6-'1
0.1 (IH, Broad m, replaced with D20).

Example 8 N-(2-(4-carbomethoxymethoxyphenyl)-
1-methylethyl)-2-(2-hydroxyethoxy)
-2-phenylgotanamine hydrochloride J-(4-
Carbomethoxymethoxyphenyl)propan-2-one (4,409) and 2-(2-hydroxyethoxy)-
The title compound (mp 128-1320C) (ethyl acetate-diethyl ether) was obtained as a 51:49 mixture of diastereoisomers from 2-phenylethanamine (3,62 g).

'Hnmr δ(DMSO-d6) 1,+1-1.5 (3,H,m), 2.6-3.
0(-1H,m), 3.0-4.0(P,H,r
n) 3.70 (31-1, s), 4.78 (2H, s)
, 4.7-5.2 (2H, m, IH.

(exchanged with D20), 6.92 (2H, d), 7.23 (2
H, d), 7.3-7.6 (51-Lm), 8.9-9
．． 5(1)1. m, replaced with D20), 9.6-10.3
(1)1. m, I) exchanged with 20).

Example 9 N-(2-('4-carbomethoxymethoxyphenyl)
-1-Methylethyl]-2-(2-hydroxyethoxy)-2-(2-benzofuranyl)ethanamine hydrochloride was loaded onto the ae in a similar manner to η.
-carbomethoxymethoxyphenyl)propan-2-one (1,,79) and 2-(2-benzofuranyl)-
2-(2-hydroxyethoxy)ethanamine (1,7
The title compound (mp 125-143°C (ethyl acetate)) was prepared from 9) as a 52:48 mixture of diastereoisomers.

"Hnmr δ(DMS O-d6) 1.16(3H,m), 2.6]-2,72(IH
, rn): 3.28-3.55 (8H, m), 3
．． 7 (1 (3H, s); 4.77 (2H, s);
4.93 (IH.

Broad, replaced with D20): 5.14-5.17 (IH
, m), 6.88 (2Hd) near, ]0 (IH, s) near, 18 (2H, d) near, 20-7.38 (2H.

m);7.61(1)1. d) Near, 68 (IH, d)
:9.09 (IH, replaced with broad D20):9.66
(Replaced with IH, Broad, D20).

Example 1O N-(2-(4-aminocarbonylmethoxyphenyl)
-1-methylethyl)-2-(2-hydroxyethoxy)-2-(4-hydroxyphenyl)ethanamine N-(2-(4-aminocarbonylmethoxyphenyl)-1-methyl in wood vinegar e' (30me) ethyl)−
2-(4-benzyloxyphenyl)-2-(2-hydroxyethoxy)ethanamine (3,5!?) was hydrogenated in the presence of 10% palladium on carbon at atmospheric pressure and room temperature until hydrogen absorption was complete. The solution was filtered through diatomaceous earth and the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, the organic layer was separated, dried (#S, 04) and evaporated to an oil. The oil was crystallized from ethyl acetate to obtain the diastereoisomer 4Q.
:60 mixture as the title compound (melting point 145-160
℃) ↓Fist=.

"Hnmrδ (DMSO-d,) 0.85 (3H, d): 2.2-2.95 (5H, m+
2H, exchanged with D20); 2.95-3.55 (41-1
, m): 4.2 (IH, m): 4.35 (2H, s);
6.6-7.3(8)1. m+]H, exchanged with D20) near, 45 (2H, ba.

(exchanged with D20).

Example 11 N-(2-(4-carbomethoxymethoxyphenyl)-
1-methylethyl)-2-(2-hydroxyethoxy)
-2-(4-hydroxyphenyl)ethanamine hydrochloride N-(
2-(4-carbomethoxymethoxyphenyl)-1-methylethyl)-2-(4-benzyloxyphenyl)-
2-(2-hydroxyethoxy)ethanamine (5g)
The title compound was prepared as a 60:40 mixture of diastereoisomers, mp 138-145[deg.]l (ethyl acetate-methanol).

"Hnmr δ(DMSO-d,) 1,,I2(3H,d):2.6-2.7(1,H
, m); 2.7-3.7 (replaced with FIH, m+2HD20); 3.7 (3H, s): 4.5-4.8 (IH
, m): 4.75 (2H, s): 6.68-7. +1
5 (4H, m) Near, 05-7.35 (4H.

d): 8.5-10.2 (IH, bs, replaced with D20)
:9J5(IH.

bs, exchanged with D20).

Reference Example 1 3-chlorobenzaldehyde (311!?) in 2-(3-chlorophenyl)-1,3-diosalantoluene (2+1 (l1 mg)), ethylene glycol (20/nI
The 4-toluenesulfonic acid hydrate was boiled under centrifugal flow for 5 hours and the water formed during the reaction was removed with the aid of a Diller and Stark trap. The solvent was evaporated and the residue was distilled under reduced pressure at 90-100° C. to give the title compound as a colorless oil (1 loaf).

'H-nmr δ (CDC13) 3.7-4. J(4H,brd m), 5.67(1,
H,brd s) near, 1-7.4(3H,m) near,
45(IH,s) Reference Example 2 l-(2-hydroxyethoxy)-1-(3-chlorophenyl)acetonitrile 2-(3-chlorophenyl)-1,3-dioxalan (10 g) in dry diethyl ether (150 m) and zinc iodide (19) was added with stirring to a solution of trimethylsilyl cyanide (7 m
J) was added dropwise. After 18 hours at room temperature diethyl ether was added and the resulting solution was washed with sodium carbonate solution, dried, filtered and evaporated to give the title compound as an oil.

11ll-1-n δ(CDCl2) 3.4-3.8(5,H,'brd m): 5.28
(3M, s) near, 1-7.3 (3H, m) near,
40(IH,s)n Reference Example 3 2-(2-Hydroxyethoxy)-2-(3-chlorophenyl)ethanamine 1-( in dry diethyl ether (4 (l ml!))
2-Hydroxyethoxy)-1-C3-chlorophenyl)acetonitrile (12 g) was added dropwise with stirring to a mixture of lithium aluminum hydride (5 g) in dry diethyl ether (1 (10 me)).

After boiling under reflux for 3 hours, the mixture was cooled and water (5 ml
), 10% sodium hydroxide solution (5 ml!) and water (10 d) were added one after another. The mixture was filtered and the filtrate was washed twice with dichloromethane. The combined organic solutions were dried and evaporated to give the title compound as an oil, which was used without further purification.

"H-nmr δ (CDCl2) 3.86 (d, 2H): 3.O-3,4 (3H, m, D
20) ; 3.4-4.0 (4H,) emblem m): 4.31 (IH, t) near, 0-7.5 (4
H.

m).

Reference Example 4 2-(3-Chlorphenyl)1,3-dioxane - 3-chlorobenzaldehyde (249) and 1,3-propanediol (20 g) were obtained by the same method as described in Reference Example 1. Colorless oil (boiling point 95-102°C/0
．． The title compound was prepared as 2).

'H-nmr δ (CDCl2) 1.33 (IH, m): 1.8-2.4 (IH, m)
:3.84(2H,m) :4.18(21-1,m
): 5.40 (II-J, s); 7.1 -7.4
(3H, m); 7.49 (IH.

S) Reference Example 5 1-(3-hydroxypropoxy)-1-(3-chlorophenyl)acetonitrile 2-(3-hydroxypropoxy)-1-(3-chlorophenyl)acetonitrile
-chlorophenyl)-1,3-dioxane(,10&
) and trimethylsilyl cyanide (7 mA') and used in the next step without further purification.

Reference Example 6 2-(3-hydroxypropoxy)-2-(3-chlorophenyl)ethanamine 1-(3-
Hydroxypropoxy)-1-(3-chlorophenyl)
The title compound was prepared from acetonitrile (II9) and lithium aluminum hydride (5g).

'H-nmr δ(CJ)C13) 1.5-1.8(2H,m):2.4-2.6(3)1
．． brd m Replaced with D20) 02.70 (2H, d)
:3. I-3,5(2Fl,m): 3.5-3
．． 8(2)1. m)”.

4.09 (IH, t): 6.9-7.4 (4H,
m).

Reference Example 7 2-phenyl-1,3-dioxalan As described in Reference Example 1, benzaldehyde and 1,2-
Dihydroxyethane to the title compound (boiling point I03-10
5°O/2 trrm) and f(.

Reference Example 8 J-(2-Hydroxyethoxy)-1-phenylacetonitrile 2-phenyl-1,3-dioxalan (1(1) and trimethylsilylsia) in the presence of zinc iodide as described in Reference 9112. The title compound was prepared from nido (8,92) and used without further purification. Reference Example 9 2-(2-Hydroxyethoxy)-2-phenylethanamine 1-( The title compound was created from 2-hydroxyethoxy)-1-phenylacetonitrile (10!9) and lithium aluminum hydride (4g).

'Hnmr δ (CDCl2) 2.90 (2) i, d), 3.08 (31-1, broad s, replaced with D20); 3.3-3.8 (4H,, m)
, 4.33 (IH, t), 7.1-7.7 (5H, m)
Reference Example 10 2-(3-Trifluoromethylphenyl)-1,3-Dioxalane The title compound (boiling point 85-90°C) was prepared from 3-trifluoromethylbenzaldehyde and 1,2-dihydroxyethane as described in / 0.5 m) was produced.

Reference Example 11 1-(2-hydroxyethoxy)-1-(3-trifluoromethylphenyl)acetonitrile 2-(3-trifluoromethylphenyl) as described in Reference Example 2
The title compound was prepared from -1,3-dioxalan and trimethylsilyl cyanide'fc.

Reference Example 12 2-(2-hydroxyethoxy)-2-(3-trifluoromethylphenyl)ethanamine 1-(2-hydroxyethoxy)-1-(3
-trifluoromethylphenyl)acetonitrile (12
&) and lithium aluminum hydride (4g) to prepare the title compound.

')t-nmr δ(CDCl2) 2.86 (21(,d); 2.9-3.3 (3H, broad m, replaced with D20); 3.4-3.9 (4H, complex m) :4.41 (IH, t) near, 2-7.
8(4)1. Complex m) Reference Example 13 2-(2-Benzofuranyl)-1,3-dioxala As described in Reference Example 1, 2-formylbenzofuran and 1
．． From 2-dihydroxyethane to the title compound (boiling a)
Onm104°O/0.3 m) produced 0 1H nmr δ (CDC13) 4.10 (4H, +n): 6.10 (]H, s): 6.
83 (IH, s) near, 15-7.65 (4) l, rn
) Reference Example 14 2-(2-Benzofuranyl)-2-(2-hydroxyethoxy)ethanamine 2-(2-
benzofuranyl)-1,3-dioxalan (21,38
Trimethylsilyl cyanide (15 m) was added dropwise to the solution of g) and zinc iodide (0,-'5 g) while stirring. After 18 hours at room temperature, lithium aluminum hydride (
5g) of the mixture. After boiling under reflux for 3 hours, the mixture was cooled and ice (5 ml, 104 NaOH solution (5d) and water (15 mA') were added successively. The mixture was diluted with dichloromethane (50 ml) and filtered. The liquid was dried and evaporated, and the oil and salt were purified by column chromatography on silica gel.Acetonitrile:methanol:ammonium hydroxide (15:2:
Elution with l) gave the title compound as an oil.

'1 (nmr δ (CDC13) 3.20 (2H, d); 3.45-4.0 (rn, 4H
+3H, exchanged with D20); 4.55 (IH, t): 6
．． 65 (IH, s) Near, 0-7.60 (4H,, m
) Reference Example 15 2-(4-Benzyloxyphenyl)-1,3-dioxalan The title compound was prepared as an oil that crystallized on standing from 4-benzyloxybenzaldehyde and 1,2-dihydroxyethane as described in Reference Example 1. Manufactured.

"Hnmr δ (CDCl2) 3.8-4.2 (4H, broad m); 5.0 (21L
! 'ri: 5.7 (IH+8) 6.9 (2H, d) near,
2-7.7 (7H, m) Reference Example 16 2-(4-pencyloxyphenyl) = 2-(2-hydroxyethoxy)ethanamine 2-(4-benzyloxyphenyl) as listed in Reference Example J4 The title compound was prepared as a yellow solid as -1,3-dioxalan.

'Hnmr δ (CDCl2) 2.4 (3H, bs, replaced with D20); 2.87 (2
B, d); 3.3-3.9 (411, m): 4.28
(IH, t): 5.05 (2H, s): 6.8-7
．． 6(9H,m) Reference Example 17 N-(2-(4-carbomethoxymethoxyphenyl)-
g?1-methylethyl)-2-(4-benzyloxyphenyl)-2-(2-hydroxyethoxy)ethanamine in Example 1? From 1-(4-carbomethoxymethoxyphenyl)propan-2-one (4,529) and 2-(4-benzyloxyphenyl)-2-(2-hydroxyethoxy)ethanamine (5,84 g) as listed above. The title compound was prepared as an oil 'Hnrnr δ(CDCl2) 1.05(3H,d):2.5-3.1(7H-,rn
):3.3-3.7. (4H,,m');3.8(3H
, s): 4.4 (IH, m): 4. fi(2H,s):
5. (1(21-1,s)6.65-7.55(] 3
H, rI+) Reference Example 18 N-(2-(4-aminocarbonylmethoxyphenyl)
-1-Methylethyl)-2-(4-pendino1.oxyphenyl)-2-(,2-hydroxyethoxy)ethanamine Ammonia gas was dissolved in N in methanol (5oy) for 10 min.
-(2-(4-Rikito, bomethoxymethoxyphenyl)-
J-methylethyl)-2-(4-benzyloxyphenyl)-2-(2-hydroxyethoxy)ethanamine (
/1.2 g) in a water-cooled solution. The resulting solution was left at temperature overnight and then the solvent was evaporated to yield a white solid (a, s9).

"Hnrnr δ (DMSO-d6') 0.95 (3H
,d) ;2.3-3.0(5H,m) :3.3-3
°7 (41-11m): 3.9 (replaced with 2H, bs, D20): 4. ]5-4.5(2)1. s+IH,rn)
5.10 (2H, s): 6.75-7.75 (13H
, m+2H, D, O) [Effect] Demonstration of compound efficacy (a) Antidiabetic activity Female CFLP mice weighing approximately 259 kg were fasted for 24 hours before the study. The compound under study was administered orally as an aqueous solution to each of six mice.

After 30 minutes, a sample (10 μe) of working fluid was obtained from the tail for blood glucose analysis. Immediately after collection of this blood sample, glucose (19/kg body weight) was injected subcutaneously into each mouse. Six mice received water as a control. Blood samples were then obtained from each mouse at 30 minute intervals for 120 minutes.

Compounds that produced a significant (P(0,05) decrease in white sugar compared to control mice given filtrate at arbitrary time intervals were designated as active. Area under the blood glucose curve 2 hours after glucose administration. was calculated for each compound and compared to the value of control animals.

Example tooth Dosage deposit / Blood sugar curve below] 2.5 53 3 2.5 41 42.5 38 5 25.0 31 6 2.5 21 7 25.0 36 8 25.0 36 10 25.0 19 11 25, (139) (b) Effect on energy expenditure The effect of the compounds on energy expenditure in mice was demonstrated by the method of fertilization.

Approximately 249 female CFLP mice each prefer food and water before and during the experiment! Ft [given. Compounds were dissolved in water by addition of 1 mole of hydrochloric acid per mole of compound and these solutions were administered orally to each of 12 mice. The other 12 mice received water orally. Mice were placed in a box with air passing through it, and the oxygen content of the air leaving the box was measured. Mouse energy consumption J, B, deV, We
ir, J, phy-siol, (London), 1
09.1-9 (1949), calculated for 3 hours after administration from the volume of air leaving the box and its oxygen content.

What level of implementation Dosage Average energy consumption 1 22
．． 9 147 2 23.6 170 3 22.8 167 4 21.5 158 5 24.9 121 6 24.6 113 7 21.4 134 8 21.2 159 9 23.2 125 Responsibility In the above test, toxicity was I couldn't admit it.

Agent Patent attorney Masaaki Aki Sawa Mitsunobu 1Continued from page 1Priority claim [Sen] December 22, 1983[Shi] United Kingdom ■Inventor John Burge Lee (GB) [Shi] 34293 Greece , Red Hill, Ospawn Road 1:1, Incident display area Gansho Tata No. 17 o/ri No. 8 3, Relationship with the 6 cases to be amended Tazami Kano 4, generation η 11 people

Claims (1)

[Claims] (1) Formula (1) %Formula%) [In the formula, Ar hapenzofuran-2-yl or a group R
1 and/or R2 (wherein R1 is halogen, trifluoromethyl or hydroxy and R2 is halogen); R3 is hydrogen or methyl; (wherein a is 1 is an integer of ~6, b is an integer of 2~7, and M is hydroxy, C1~6 alkoxy, phenyl C1~
6 alkoxy or -NR4R5 (wherein R4 and R5 are each hydrogen or C1-6 alkyl, or - together form a 5- or 6-membered heterocyclic ring); Y is 10 02-6 straight chain or branched alkylene having at least 2 carbon atoms between - and -OH: and n is l or 2] or a pharmaceutically acceptable salt thereof; ester or amide. (2) The compound according to claim (1), wherein Ar is phenyl substituted with R1, which is a halogen, at the meta-(or 3-) position on the phenyl ring. (3) Claim No. (1) or 0 in which R1 is chlorine
) Compounds described in section 2. (4) Claims (1) to 3 in which R3 is methyl
(3)(5) A compound according to any one of claims (1) to (4), wherein a is 1 and b is 2. (6) A compound according to any one of claims (1) to (5), wherein n is 1. (7) The compound according to any one of claims (1) to (6), wherein Y is ethylene or nn-propylene. (8) The compound is N-(2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-hydroxyethoxy)=2-(3-chlorophenyl)ethanamine. -carbomethoxymethoxyphenyl)-
]-methylethyl)-2-(3-hydroxypropoxy)-2-(3-chlorophenyl)ethanamine. N-(2-(4-methylaminocarbonylmethoxyphenyl)-1-methylethyl]-2-(2-hydroxyethoxy)-2-(3-chlorophenyl)ethanamine. N-(2-(4-(2- hydroxyethoxy)phenyl)-・1-methylethyl)-2-(2-hydroxyethoxy)-2-(3-chlorophenyl)ethanamine, -N-(2-(4-(2-methylaminoethoxy)phenyl)- J-methylethyl: l-2-(2-hydroxyethoxy)-2=(3-chlorophenyl)ethanamine. N-(2-(4-carbomethoxymethoxyphenyl)-
1-methylethyl)-2-(2-hydroxyethoxy)
-2-(3-trifluoromethylphenyl)ethanamine. N-(2-(4-carbomethoxyphenyl)-1-methylethyl)-2-(2-hydroxyethoxy)-2-(
3-chlorophenyl)ethanamine. N-(2-(4dicarbomethoxymethoxyphenyl)-
1-methylethyl)-2-(2-hydroxyethoxy)
-2-phenylethanamine. N-(2-(4-carbomethoxymethoxyphenyl)-
1-methylethyl)-2-(2-hydroxyethoxy)
-2-(2-Benzofuranyl)ethanamine. N-(2-(4-aminocarbonylmethoxyphenyl)
-1-methylethyl)-2-(2-hydroxyethoxy)-2-(4-hydroxyphenyl)ethanamine. N-(2-(4-carbomethoxymethoxyphenyl)-
1-methylethyl)-2-(2-hydroxyethoxy)
-2-(4-hydroxyphenyl)ethanamine or a pharmaceutically acceptable salt thereof; (9) Formula (11) (wherein R'i, Y and n are as defined in claim (1); Ar is t- as defined in claim (0)); or a group convertible thereto: R10 is a group X defined in claim (1), or a group X
is a group that can be converted into; R6 is hydrogen or R7
together with R7 forms a bond: R7 is hydrogen or together with R6 or R8 forms a bond; R8 is hydrogen or together with R7 forms a bond or together with R9 to form an oxo group; R9 is hydrogen or together with R'' to form an oxo group, provided that when R6-R9 is X, all It doesn't have to be hydrogen. ) or its ester or amide, and then convert the obtained compound (wherein Ar' is other than Ar and/or RIG is other than X) into a compound of formula (1). and/or may form a salt of the compound of formula (1) formed and/or may convert the compound of formula (1) formed into another compound of formula (1). A method for producing the compound, or its compound, ester or amide, according to any one of claims (1) to (8), which may be made of Japanese cypress. QOI a! A complete pharmaceutical composition comprising a compound according to any one of claims (1) to (8), or a pharmaceutically acceptable salt, ester or amide thereof, together with an acceptable phase. (11) A compound according to any one of claims 0) to (8), or a pharmaceutically acceptable salt, ester or amide thereof, for use as an active therapeutic substance. 02 Compound or pharmaceutically acceptable salt or ester thereof according to any one of claims (1) to (8) for use in the treatment and/or prevention of obesity and/or hyperglycemia 7 Stain amide.