CA2417408A1 - N-benzyldioxothiazolidybenzamide derivatives and process for producing the same - Google Patents

Abstract

The invention of this divisional application relates to processes for preparing compounds of the following formulae (4), (5) and (7)

Description

The present divisional application is divided out of parent application Serial No. 2,220,698 filed on May 30, 1996.
The invention of the parent applicat=ion relates to compounds of the formula (1), processes for the preparation of compounds of the formulae (1), (lb) and (ld) (hereinafter defined) and their use.
The invention of the present first divisional application relates to processes for preparing compounds of the formulae (4) , (5) , (7) and (7a) (he:reinafter defined) .
A second divisional application has been filed which relates to a process for preparing compounds of the formula (10) (hereinafter defined).
The invention of the parent application relates to novel N-benzyldioxothiazolidylbenzamide derivatives that improve diabetes mellitus and hyperlipidemia, and processes for preparing the same.
So far, as oral therapeutic drugs for diabetes mellitus, biguanide type and sulfonylurea type compounds have been used. However, with biguanide type compounds, lactic acidosis or hypoglycemia is caused and, with sulfonylurea type compounds, serious and prolonged hypoglycemia is caused, and the adverse effect thereof :is posing a problem, hence the appearance of new therapeutic drug for diabetes mellitus without such defects is desired. It is also known that some of thiazolidine-2,4-dione derivatives exhibit hypoglycemic and lipid-lowering effects (Journal of Medicinal Chemistry, Vol. 35, P. 1853 (1992), Published Unexamined Patent Application No. Hei 1-272573), but, in all of these compounds, the substituted position of middle benzene ring that connects thiazolidine-2,4-dione ring and aromatic ring is p-position, or the middle benzene ring has no substituent, further the arornatic ring of the former is oxazol ring, the linkage of the latter is through sulfonamide, and the like, which differ structurally from compounds of the invention, N-benzyldioxothiazolidyl- ;
f benzamide derivatives.
For the non-insulin dependent diabetes mellitus (NIDDM) accounting for the majority of diabetic~~, a blood sugar-lowering drug that improves the insulin resistance and has high safety and effectiveness is strongly desired.
As a result of diligent studies on a drug that improves the insulin resistance and has potent hypoglycemic effects and high safety, the inventors have found that novel N-benzyldioxothiazolidylbenzamide derivatives represented by a following general formula (1) have excellent hypoglycemic and lipid-lowering effects.
In accordance with one aspect of the parent application, there is provided an N-benzyldioxothiazolidylbenzamide derivative represented by the general formula (1) [wherein R1 and R2 are identical or different and represent hydrogen, lower alkyl with 1 to 4 carbon atoms, lower alkoxy with 1 to 3 carbon atoms, lower haloalkyl with 1 to 3 carbon atoms, lower haloalkoxy with 1 to 3 carbon atoms, halogen, hydroxyl, nitro, amino which may be substituted with lower alkyl with 1 to 3 carbon atoms, or R~and R~ together represent methylenedioxy, R~ represents lower alkoxy with 1 to 3 carbon atoms, hydroxyl or halogen, and the dotted line indicates a double bond or a single bond in combination with the solid line], or a pharmaceutically acceptable salt thereof .
In accordance with another aspect of the parent application there is provided a process for preparing an N-benzyldioxothiazolidylbenzamide derivative represented by the general formula (l) as defined above wherein R1, R~, R3 and the dotted line are as defined in claim 1, or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of the general formula (7) O
s--.~
I ~H cap ~o2c [wherein R3 and the dotted line are as defined above , with a compound of the general formula (11) t CFi~NHz (9 i~
O

[wherein Ri and R2 are as defined above and, where required, forming a pharmaceutically acceptable sa:Lt thereof].
In accordance with another aspect of the parent application there is provided a process for preparing an N-benzyldioxothiazolidylbenzamide derivative of the general formula (lb) Rt Ra !VH 4db) 'w:/ ~/' ~ r ~2 wherein R'', Rz and R3 are as defined above, or a pharma~eutically acceptable salt thereof, which process comprises reducing a compound of the general formula (la) [wherein R1, R2, and R3 are as defined above] .
In accordance with another aspect of the parent application there is provided a process for preparing an N-benzyl.dioxothiazolidylbenzamide derivative of the general formula (ld) Rt /~
C
NH t, ~) R

wherein Rl, R2 and the dotted line are as defined above, or a pharmaceutically acceptable salt thereof, which process comprises reducing a compound of the general formula (7c) [wherein R1, R2 and the dotted line are as defined above], with a Lewis acid.
The invention of the parent application also relates to pharmaceutical compositions comprising compounds of formula (1) as defined above, or pharmaceutically acceptable salts thereof, uses of compounds of formula (1) as defined above, or pharmaceutically acceptable salts thereof, in the treatment of diabetes mellitus or hyperlipidemia, and commercial packages comprising compounds of formula (1) as defined above, or pharmaceutically acceptable salts thereof, together with instructions for the treatment of diabetes mellitus or hyperlipidemia.
The salts of compounds represented by the general formula (1) are of common use, and pharmacologically acceptable metal salts such as alkali metal salts (e. g.
sodium salt, potassium salt, etc.), alka:Line earth metal salts (e. g. calcium salt, magnesium salt, etc.) and aluminum salt can be mentioned.
-4a-Moreover, the general formula (1) sometimes includes stereoisomers based on double bond and optical isomers based on thiazolidine portion. Such isomers and their mixtures are all to be included.
In the general formula (1), for "lower alkyl group", straight or branched chain groups with carbon atoms of 1 to 4 such as methyl, ethyl, propyl and butyl are mentioned.
For "lower alkoxy group", straight or branched chain groups with carbon atoms of 1 to 3 such as methoxy, ethoxy and propoxy are mentioned.
For "lower haloalkyl group", straight or branched chain groups with carbon atoms of 1 to 3 such as trifluoromethyl are mentioned.
For "lower haloalkoxy group" straight or branched chain groups with carbon atoms of l to 3 such as trifluoromethoxy are mentioned.
For "halogen atom°°, fluorine atom, chlorine atom, bromine atom and iodine atom are mentioned.
For "amino group which may be substituted with lower alkyl group", amino group, or methylamino group, ethylamino group, dimethylamino group, diethylamino group, etc., in which one or two hydrogen atoms are substituted with straight or branched chain lower alkyl group with carbon atoms of 1 to 3 such as methyl, ethyl and propyl, are mentioned.
Compounds of said general formula (1) can be prepared -4b-C ;
through following processes.
Compounds of general formula (1) can. be prepared by reacting compounds of general formula (7) with compounds of general formula (11) [wherein R1 and R2 denote identically or differently hydrogen atoms, lower alkyl groups with carbon atoms of 1 to 4, lower alkoxy groups with carbon atoms of 1 to 3, lower haloalkyl groups with carbon atoms of 1 to 3, lower haloalkoxy groups with carbon atoms of 1 to 3, halogen atoms, hydroxyl groups, nitro groups, amino groups which may be substituted with lower alkyl groups) with carbon atoms of 1 to 3 or hetero rings, or -4c-R1 and R2 link to form a methylenedioxy group, R3 denotes a lower alkoxy group with carbon atoms of 1 to 3, hydroxyl group or halogen atom, and dotted line indicates double bond or single bond in combination with solid line) O

NH d7) [wherein R and dotted line are as described above]
~t i ~~-~(~NN2 ( B 1 ~2 [wherein Rl and R2 are as described above) The reaction can be conducted by treating with condensing agent, for example, 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide, diethyl cyanophosphate or the like in an organic solvent, for example, dimethyl sulfoxide, N,N-dimethylformamide or the like. Moreover, if need be, an organic base, for example, triethylamine or the like may be added.
As the reaction temperature, ice cooling to room temperature can be used.
Compounds of general formula (lb) can be prepared by reducing compounds of general formula (la).

1 ?
NH ( Ib) /.
~2 [wherein R1, R2 and R3 are as described above]
NHI
C
p2 (wherein R1, R2 and R3 are as descried abovel 'Fhe reaction can be conducted by hydrogenating at ambient pressure to 4 kg/cmz in the presence of catalyst such as palladium/carbon in an organic solvent, for example, ethanol, ethyl acetate, N.N-dimethylformamide or the like or in a mixed solvent thereof at room temperature to heating. Or, it can be conducted by treating with sodium amalgam in an organic solvent. for example, alcohol such as ethanol or in a mixed solvent with water at room temperature to heating.
Compounds of following general formula (ld) can be prepared by reacting general formula (lc) with Lewis acid0 N~ (td~
~2 [wherein R , R and dotted lane are as described above]

[wherein R , R and dotted line are as described above]
The reaction can be conducted by treating with Lewis acid. for example, boron tribromide, boron trichloride or the like in an organic solvent, for example, dichloromethane, chloroform or the like at -78 °C to room temperature.
Compounds of general formula (7) can be prepared by hydrolyzing compounds of following general formula (6) [wherein R3 and dotted line are as described above, and R5 denotes a lower alkyl group with carbon atoms of 1 to 3) The reaction can be conducted under acidic or alkaline condition employing cooling to solvent r efluxing as reaction temperature and, for example, refluxing under heat in a mixed solvent of acetic acid with concentrated hydrochloric acid is preferable.
Compounds of general formula (4) can be prepared by reacting compounds of following general. formula (2) with compound of formula (3).
O
[wherein R3 is as described above, and R4 denotes a hydrogen atom or lower alkyl group with carbon atoms of 1 to 3]
~3 r r tz) MHO
[wherein R3 and R4 are as described above]
S
O (3) The reaction can be conducted in an organic solvent, for example, benzene, toluene, xylene or the like at room temperature to solvent-re.fluxing temperature as reaction temperature, but the solvent-refluxing i:empe.rature is preferable. Moreover, as a catalyst, addition of secondary amine (piperidine or the like) or acetic acid salt (ammonium acetate or the like) and acetic acid is suitable.
Also, it can be conducted by heating together with base (sodium acetate, piperidine or the, like) without solvent.
Compounds of general formula (5) can be prepared by reducing compounds of general formula (4).

pdo C NH (s) z [wherein R3 and R~ are as described above]
The reaction can be conducted by hydrogenating at ambient pressure to 4 kg/cm2 in the presence of catalyst such as palladium/carbon in an organic solvent, for example, ethanol, ethyl acetate, N,N-dimethylformamide or the like or in a mixed solvent thereof at room temperature to heating.
Or, it can be conducted by treating with sodium amalgam in an organic solvent, for example, alcohol such as ethanol or in a mixed solvent with water at room temperature to heating.
Compounds of general formula (7a) can be prepared by reacting compounds of following general formula (10) with thiourea, followed by hydrolysis.

[wherein R3 is as described above]
R~
)( ( ll?) R5~2C COZR&
[wherein R3 and R5 are as described above. R6 denotes a lower alkyl group with carbon atoms of 1 to 3,. and X denotes a halogen atom) The reaction between compounds of general formula (10) and thiourea can be conducted in an organic solvent, for example, alcohol such as ethanol at morn temperature to solvent refluxing temperature, but the solvent refluxing temperature is preferable~ If need be, a base (sodium acetate or the like) may be added. Successive hydrolysis reaction can be conducted under acidic condition and. for example, it is preferable to reflux under heat in hydrochloric acid or in a mixed solvent of hydrochloric acid with organic solvent (sulforane or the like).
Compounds of general formula {IO) can be prepared by converting compounds of general formula (8) to diazonium salts and then conducting Meerwein arylation with compouiads of general formula (9).

(8) [wherein R3 and R5 are as described above) /~.CO~Rs (~) [wherein R6 is as described above]
The reaction can be conducted by diazotizing compounds of general formula (8) with nitrite such as sodium nitrite in an organic solvent, for example, alcohol such as methanol or ethanol, ketone such as acetone or methyl ethyl ketone or water or in a mixed solvent thereof in the presence of hydrogen halide such as hydrochloric acid or hydrobromic acid, and then reacting with catalyta~c amount of cuprous salt such as cuprous oxide or cuprous chloride in the presence of compounds of general formula (9).
In following, the invention of the parent and divisional applications will be illustrated based on concrete examples, but the inventions are not confined to these examples. The abbreviated terms used in examples represent following meanings.
1H NMR Proton nuclear magnetic resonance spectrum MS_ Mass spectrum CDC13 Deuterated chloroform DMF N,N-dimethylformamide DMSO Dimethyl sulfoxide THF Tetrahydrofuran d6-DMSO Deuterated dimethyl sulfoxide Example 1 Methyl 5-(2,4-dioxothiazolidin-5-yl.idene)methyl-2-methoxybenzoate A mixture of methyl 5-formyl-2-methoxybenzoate (490 mg), thiazolidine-2,4-dione (358 mg), ammonium acetate (401 mg), acetic acid (0.8 ml) and benzene (10 ml) was submitted to Dean-Stark dewatering apparatus to reflux for 4 hours under heat. After cooling, the crystals deposited were collected by filtration, washed with benzene and with 20 o aqueous solution of acetone, and then dried to obtain 634 mg (86 0) of aimed compound as crystals.
1H NMR (d6-DMSO), 5:3.83(3H, s), 3.90(3H, s), 7.34(1H, d, J -9.3Hz), 7.79(1H, s), 7.76-7.83(1H, m), 7.87-7.92(1H, m), 12.59(1H, s) Examples 2 and 3 Similarly to Example 1. compounds in Table 1 were obtained.
[Table 1]

Example R3 R4 Property MS(m/z):M+

2 Et0 Et Crystal -3 i-Pr0 H Crystal 307 Example 4 Methyl 5-(2,4-dioxothiazolidin-5-yl)methyl-2-methoxy-benzoate Methyl 5-(2,4-dioxothiazolidin-5-ylidene)methyl-2-methoxy-benzoate (9.52 g) was suspended into DMF (250 ml) and hydrogenated with 20 o palladium/carbon (10.0 g) at room temperature under a hydrogen pressure of 3.5 kg/cm2. After the reaction, the solution was filtered and concentrated and water was added to the residue, which was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by means of silica gel column chromatography (developing solvent; methylene chloride: acetone = 50:1) to obtain 5.88 g (~1 0) of aimed compound as an amorphous material.
MS(m/z):295(M+) Example 5 5-(2,4-Dioxothiazolidin-5-ylidene)methyl-2-methoxy-benzoic acid A suspension of methyl 5-(2,4-dioxothiazolidin-5-ylidene)-methyl-2-methoxybenzoate (629 mg} :in acetic acid-concentrated hydrochloric acid (I:1, 18.0 ml) was refluxed for 6 hours under heat. After cooling, wat~Sr (36 ml) was added and the crystals were collected by filtration,~washed with water and dried to obtain 599 mg (100 0) of aimed compound as crystals.
1H NMR (d6-DMSO), 5:3.89(3H, s), 7.31(1H, d, J - 8.8 Hz), 7.76(1H, dd, J - 2.4, 8.8Hz), 7.79(1H, s), 7.89(1H, d, J -2.4E1z), 12.58( 1H, s), 12.91( 1H, br) Example 6 and 7 Similarly to Example 5, compounds in Table 2 were obtained.
[Table 2]
Example R3 Dotted line property MS(m/z):M+

portion 6 Me0 ~ Single bond Crystal -7 ~ Eto Double bond Crystal 293 Example 8 Methyl 2-bromo-3-(3-methoxycarbonyl-4-i:luorophenyl}-propionate To a solution of methyl 5-amino-2-fluor_obenzoate (4.I2 g) in 47 o hydrobromic acid ( 11 .4 rnl ) , methano_~ ( 20 ml ) and acetone (50 ml), a solution of sodium nitrite (1.88 g) in water (3 ml) was slowly added dropwise under cooling with salt-ice and stirring so as to keep an internal temperature of not higher than -5 °C. After stirred for 30 minutes as it was, ice bath was removed, methyl acrylate (13.3 ml) was added, and cuprous oxide (225 mg) was added little by little while stirring vigorously. After no nitrogen became to generate, the reaction liquor was concentrated under reduced pressure. The residue was dissolved into ethyl acetate, washed with water, saturated aqueous solution of sodium hydrogencarbonate and water in order. dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by means of silica gei column chromatography (developing solvent; n-hexane:ethyl acetate =
10:2) to obtain 3.48 g (45 0) of aimed compound as an oily material.
IH NMR (CDC13), 8:3.25(1H, dd, J = 7.3, 14.6Hz), 3.46(1H, dd, J - 7.8, 14.2Hz), 3.75(3H, s); 3.93(3H, s), 4.38(1H, t, J -7.8Hz), 7.09(1H, dd, J - 8.8, I0.8Hz), 7.38(1H, ddd, J - 2.4, 4.4, 8.8Hz), 7.80(IH, dd, J - 2.4, 6.3Hz) MS(m/z):318. 320(M+) Examples 9 and 10 Similarly to Example 8, compounds in Table 3 were obtained.
[Table 3]

6 gf R~~2~~3 ~ ~ ~C~xRB

Example R3 R5 R6 Property M~S(m/z):Mt 9 6-Meo Et Me ~ 344 aterial 2-Me0 Me Me Oily 330, 332 material Example 11 5-(2,4-Dioxothiazolidin-5-yl)methyl-2-fluorobenzoic acid To a solution of methyl 2-bromo-3-(3-methoxycarbonyl-4-fluorophenyl)propionate (1.22 g) in ethanol (40 ml), thiourea (356 mg) was added and the mixture was r~~fluxed for 11 hours under heat. After cooling, this was concentrated under reduced pressure and water (50 ml) was added to the residue.
After pH was adjusted to around 8 with saturated aqueous solution of sodium bicarbonate under stirring, ether (20 ml) and n-hexane (40 ml} were added, which was stirred for 10 minutes as it was. The crystals were collected by filtration, washed with water, and then dried. The solids thus obtained were dissolved into sulforane (10 ml) and, after 6N
hydrochloric acid (20 ml) was added, the mixture was refluxed for 8 hours under heat. After cooling, this was poured into ice water and the crystals deposited were collected by filtration, washed with water, and then dried to obtain 403 mg (39 $) of aimed compound as crystals.
1H NMR (d6-DMSO), 8:3.22(1H, dd, J - 8.3, 14.2Hz}, 3.51(1H, dd, J - 4.4, 14.2Hz}, 4.95(1H, dd, J - 4.4, 8.3Hz), 7.27(1H, dd, J - 8.3, 10.8Hz), 7.51(1H, ddd, J - 2.5, 4.9, 8.3Hz), 7.74(1H, dd,.J = 2.5, 6.8Hz), 12.05(1H, s), 13.28(1H, s) MS(m/z):269(M+) Examples 12 and 13 Similarly to Example 11, compounds in Table 4 were obtained.
[Table 4]
Example R3 Property MS(m/z):M+

12 4-Me0 Crystal 281 13 2-Meo Crystal 281 Example 14 N-(4-Trifluoromethylbenzyl)-5-(2,4-dioxothiazolidin-5-ylidene)methyl-2-methoxybenzamide To a solution of 5-(2,4-dioxothiazolidin-5-ylidene)methyl-2-methoxybenzoic acid (1.00 g) and 4-trifluoromethylbenzylamine (627 mg) in DMF (10 ml), diethyl cyanophosphate (615 mg) and tri.ethylami.ne (370 mg) were added at room temperature in an argon atmosphere under stirring, and the mixture was stirred for 5 hours as it was. The reaction liquor was poured into ice water and the crystals deposited were collected by filtration, washed with water, and then dried to obtain 1.31 g (84 0) of aimed compound as crystals.
Further. these were recrystalli.zed from ethanol to obtain purified aimed compound as yellow prismatic crystals. Melting point 210.0 ~ 211.5 °C
Elemental analysis (o): For C20H15F3N2~4S
C H N
Calculated 55.04 3.4~ 6.42 Found 55.30 3.36 6.48 Examples 15 through 38 Similarly to Example 14, compounds in Table 5 and Table 6 were obtained.
[Table 5]

.__-__ ~ In .-a oo rn r- r- oo rn o tn t-- cD m r-- N m an a~ oo m m ~r In ow lnm cDd' mc~ rirr mm mm d'd' tnm mrr .-im oo terra . . . . . . . . . . . . . . . . . . . . .
t~- t- r- ~- cD cn cn ~t~ cn cD cD cn In tn cD cD cD ca rD In ~- r- cn cD
O O GO O r-1 In r- C\1 ri O~ In N tn r4 d' r-1 N ~r d' (X~ tn In ri d' a~ r-r c~ sn a~ m r- t~- a~ rn en d' a~ o re m rn a~ m cD cn tn c~mt' d' In -i' d' m cn ch ~~ r7 m m m N m cD ca en In cn m d' -1' In w b .-d d' °1' C~i Qo cY, C~ t7« Cn c7O r- O C\1 °a' t~- ('._ CvD tn CJ) m Cn tn Ot n1 v cD a~ cn m r-- cD oo r- : t- 1 n d: cD .-a o t- a~ cD ~ c~ cm N m a~ o --1 rr rr cV ~I' d~ cV c.g ~y' d' d° d' Cn a~ -9' rt' ca nt c'~ W o o t-«~
cD cD co cD an In tn In In tn In tn d' ~r cD co cD cD tn In cD cD In tn _ ___ -O ~. ~ O ~ O O ~ O
cn cn O O ~ ~ 0 O . ~ J O ~: ~ ~ m ~: ~ C7.~ ~ , m ~ j O -d. --, ~. ~., ~ ~, N ~ ~., s' _.. ."
w O O ~ 7. 7 '.7,. ;~ 7. '~' O . O 7, O~ U ._ ..., ~ ° . , .~, , , °
Z ;T, ts-. rs. ice. Cs. ~ '7, ~~.~ !s. '.T 7 O x x x~ ~-~ ~ _ ~~ x x°, ,~ °
v, , o o _ ° _~ .~., ..-° , _ , c"
U U U U U U U U U U U U
_ o o O o 0 o o 0 0 0 CJ p o .,~ N pr'. O r-1 a CI) . Ch tD i OO fb .-1 P-d ~ d' ~ ~ 00 ~ C7~ m ~ m ~ 00 r.D .--I ~
N N - ri (Lj .-! .-1 f(f .-I CV ,-t .--1 ~ .-i r-i N r4 U
UW a C o °d N o ~ ~ ~ rIO o ro ~ o p o ~ O ~ N o O o O o .t-1 O
r;
x tn x co rn r_- r- tn ~ tn cD as O ~ N d' ~ op r- CJ1 m m ~ 00 PD O
fx uWl).~ W.~ W W.~ W ~ W W W
N .---r ~ .-4 ...~ r-i ..~ .--1 .... N ~. r-d ~. .--i ~ .-8 ~ CV .~
N N ~ QJ N ~ ~ ~ Qt N N
.-I '-1 r1 r-t .--I ~-1 °-1 r-1 r r-i .- 1 8 ~ ~, ~~.8 8~ ~~.~ 8~ ~ 8 8~ ~.8~ ~~~ 8 8 8~ ~~ ~ S
0 0 0 0 0 0 0 ~ 0 0 0 0 H '-1 ~".
I I I I I t ! ! o a a !
fo r., o ~.,, Is, ~ ~ O
~. cs. r~ ~. U m m O
_ x x U U c ~ U ! I ! r.~ a~ I
I ! i i In » ~ c.~ "~''-', ~r m m ~~ N 1 I ! 1 .
m d' d' °~' d' m In co t- m o o ~ N --_ -- --._ -___._ .-t ,-i ra .-a .-a cu c~ cd cv cu cm cm [Table 6) cn o r n ~° m n cn -r m t- a~ cn o 0o r- o c~ c~ ~-- cu ~ r- c~ o c~ c~ ~ n C- t- m r~ m e~ ,-, o~ arJ t- o o en co _, o~ .,._., . . . . . . . . . . . . . . . . . . . .
cn cn c- ~- co cn c~ cn t- ~- co cn cn tn cD cn co cn cn co =' cV
.--r oo cD .-r ~ ~r ~ ~-r rn r~ ,-a ~t° cry c~~ m cwt .-~ ,-r c~ c~
o~ ~ rn cn a~ o~ m <3° o ~ a~ ~ a~ oo cu m .--a .-r c~~ c~
-i ~ c~ r~ r3° d° co m ~r <~~ m i.r~ m cn ~~ c-o -~°
d° W W° m c~ N
b .--t c~ rn co cn co ire o~ a~ o o c-o W° cn c'n cx~ c~ co ~~ .-r <~° .-a r- r-- rn r- cx> t- t- rc- o~ oo ,-a rn ao co m m cn 0o co r- t- <i~ e9~ r- r- ap rn v~ d' ~ d' cIo o~ ccoc~ cn cT7 ~n r~ ~r~ cn rn ire r.n erg crmn en ~n are try sn in sr~ t.~ cn ~n O en Q cn cn O rn cn ,.
C cn y. ~: O cn rn x ' O O ~ ~ r r3 O O cn cn O ~ , -~,- ~ ~, ~ ...
-r+'i ~U O ~ , ~ 7, p~' o ~.~ j ;z. ._' O
07 ~-i ,-, '7. ° ~-~ ~, ." ~ ., 7- t3, c=. '_7, 7 t~ rs.' ;~. , ~a M ."
;T T.
r- m ~-- e~ m ~-. m x~ x x x~ x~ ~ x~' ~ x~ x' x a a U , ~_. ~ , U ., ~_. U = ~ ' C.) ' U U U ~ O
U O ° 0 0 0 0 0 0 0 0 0 0 o .,-I .
-- -r-r ,--r r- _ ~- m a> amr~ c~ cD oo cu ro i-~ N ~1' -, O Qy c~J (J~ ~ CV ~ r-1 ~. m ef' O r--_ ~ CV O G~7 ~ ,--1 .--1 GV ~ GV ~ C~l .--r Chi ~ r-1 t ~ ~ t ~ d ~ ~ t r-, t ~ l .~ ~ ~ r :-r d ~ ~d t . ~ r-s t -~ ~ 5 . i .r-r O , ~ . ~ a W 1 .~ O .C
s-r ° .~ m ~ d; N ~. ~ in ~ N r c~ ~ .-a~ n +' c~ ~ o -G
w a~ o ~ o ° a~ ~ -~ ~ ~ +~ v ~ ~ +~
Ix tn m ~ o ~ c-o ~ U a> W o~ W cW ~ m W d° ~' U o ~ ~ r- W
'-' .-- t '~ ~y-- cW 'l cV ~' , -r ~'' ~ '' ~ ~..
p ~ ~ ~ N N N N dl N ~ ~ U7 r-i r-i r-i r-1 >--1 r-I r-1 r-1 .-1 .--1 .-V .--I
N +~ ~ °i~ ~ 'L3 U~ b tr~ b is 'Lf U~ °tii .O 'Lf .O b .~ 'Z5 tr b ~ 'd .Q 't~
.r~ C ~ ~ C C C C C G C C C C C ~ C ~ C ~ C G C ~ C ~ G
8 ~ ~, 8 .~ ~ .S ~~ .8 ~ ~ ~ .~ ~ .~ 8 .~ 8 .8 8 .~ ~ ~ 8 ~ 8 .~

0 0 o c~ 0 0 0 0 ~. 0 0 vvvvvv~-~.~p_,~,vcu c~ ~ ~ ~ 2; ~ ~ W W I i I ! I I I 1 f I ~--~ cn I t cn cry ~t° V° d° cw co co ( cn co cfl r r r 5, 5. y, ~. 5. P.
.C DS .f: >C ,~ -c: SG _ >-' O (z, a O W La, ~ O f~ Cs. ~ v _ w-~ ts. U v ..-. U U cv --> U U v S' i I ~ -b ~' I i ~ Ts I I ~ i CY, I v d° ~° I v rr° ~t° I v d°
V' G rt° G ~r ~ I
. v _ as d.
m -° m __.
r- c0 07 CJ .-I . cW t' 11~ c0 C-cu cw m m co m m m co m m _ 20 _ * 1H NMR (d6-DMSO), 5:2.86(6H, s), 3.94(3H, s), 4.38(2H, d, J = 5.9Hz), 6.69(2H, d. J - 8.8Hz), 7.18(2H: d, J - 8.8Hz), 7.28(1H, d, J - 7.9Hz), 7.74(1H, dd, J - 2B2r7.9Hz), 7.78(1H, s), 7.95(1H, d, J - 2.2Hz), 8.59(1H, t, J - 5.9Hz), 12.30(1H, br}
Example 39 N-(4-Trifluoromethylbenzyl)-5-(2,4-dioxothiazolidin-5-yl)methyl-2-methoxybenzamide N-(4-Trifluoromethylbenzyl)-5-(2,4-dioxothiazolidin-5-ylidene)methyl-2-methoxybenzamide (500 mg} was suspended into ethanol (70 ml) and hydrogenated with 10 o palladium/carbon (500 mg) at room temperature under a hydlrogen pressure of 3.0 kg/cm2. The reaction liquor was filtered and concentrated and the residue was purified by means of silica gel column chromatography (developing solvent; meth~ylene chloride: methanol = 5a:1) to obtain 403 mg (80 ~) of aimed compound as crystals. Further, these were recrystallized from ethyl acetate to obtain purified aimed compound as colorless powdery crystals. Melting point 176.0 ~ 177.5 °C
Elemental analysis (o): For C20H17F3N2~4s C H N
Calculated 54.79 3.91 6..39 Found 54.75 3,84 f.40 Examples 40 through 48 Similarly to Example 39, compounds in Table 7 were obtained.
[Table 7]

m d' o~ O ~ u~ cV ~I' a~ o~ In m cn d' ~' c~ --r co a n a r~ cm m r-o d' a~ o~ cfl o0 0 .---o .-~ m a n c- o cs~
o'o ~ .
an a n t- r-- co c~ ca cn ca co o O co ca cn co cn a n ,~ ,~ .-, ,-a rn cn d' m t-~ o .-i m co 00 0o co m m .--a cn d' d' w .--a o cv cV r- co .~ o d' m cc3 cn cva cu ~- oo a n d' . . . . . . . . . .
m m an an m m an an ei~ d~ an an d' d' d' d' d' d' a>y b 0 0 00 o cc~ oo .-a ~y~ m o m oo ~r on t~- cT) an o C:
0.'7 0 ~:1~ C~3 00 cD m CW m r-o m ~I. f- cD Cn an -t3 l~ .
r-1 U 07 O N N CV N c7~ ~ H~- P- o o an an cxa oo cn cry W d' an ca <v an an an on m an co cD an an an an an on cn cn O O O cn cn 0 . ~f, cn ~ , en ,~ ~ cn ~: ' O cn O
., , > ~ ~ W, . .
-rat act %T. O T. [~ -~ o ..~ ~ _ . ;~., OQ 7.
C=-. f? LL. :T ;T :l t=. , 7. ta, o r-- 0 00 ~.-a w. o U v~-a x ~ ~ ~: ~C ~ ' x a a ~i' c~' ~' ~., ~. ~ U' v ° co -- C o ~ an U O
o -r-1 .
~- +~ rn N o0 0 ~, N cD co en ai .-s rr r-s ~
~a ~ d a~a-a a ~ a) v ~ v a~ 0.. ~ a.
c~ ~ ~ ~ ~ ~ ~ w w i i l a l s i l i cr7 co cn cn eo en cc~ co 1 ~. >, O ~: ~.., .~ SC
Y

fs ~ ~ , W_ . O _ O

U N Cia N 4) 4J (s.. N -.
.-.

I > U ~ ~ ~ U ~ b U
-cJ

tY ~n I I I 1 " 1 1 ~ I
~

d' d' ~r d' 1 d' d' ~ d' ~

m ~ d' m o r-a N - a -_ -._ ~

d' d' d' d' d' d' d d' d' Example 49 N-(4-Trifluoromethylbenzyl)-5-(2,4-dioxatYiiazolidin-5-yl)methyl-2-hydroxybenzamide To a suspension of N-(4-trifluoromethylbenzyl)-5-(2,4-di-oxothiazolidin-5-yl)methyl-2-methaxybenzamide (800 mg) in anhydrous methylene chloride {30 ml), a 1. ON boron tribromide-methylene chloride solution (2.20 ml) was slawly added dropwise in an argon atmosphere under cooling with dry ice-acetone and stirring. After stirred for 6 haurs at room temperature, the reaction liquor was allowed to stand for 3 days. After water was added and the mixture was stirred for 30 minutes, this was concentrated under reduced pressure.
Ethyl acetate was added to the residue, which was washed with water and then dried over anhydrous sodium sulfate. This was concentrated under reduced pressure and the x-esidue was purified by means of silica gel column chromatography {developing solvent; methylene chloride:methanol = 40:1) to obtain 618 mg (80 0) of aimed compound a.s crystals. These were recrystallized from ethanol-water to obtain purified aimed compound as a light brown powdery crystals. Melting point 146.0 ~ 148.0 °C
Elemental analysis (o): For C19H15F3N2G4S
C H N
Calculated 53.77 3.56 6.60 Found 53.92 3.88 6.49 Example 50 (-)-N-(4-Trifluoromethylbenzyl)-5-(2,4-dioxothiazolidin-5-yl)methyl-2-methoxybenzamide - 24 _ Into 20 ml of ethyl acetate, I.00 g of (~)-N-(4-trifluoromethylbenzyl)-5-(2,4-dp_oxothiazolidin~5-yl)methyl-2-methoxybenzamide obtained in Example 39 was dissolved under heat. After cooling, 0.276 g of L(-)-ptlenethylamine were added and the mixture was allowed to stand for a week at room temperature. The crystals deposited were filtered, washed with ethyl acetate and dried to obtain 0.753 g of L(-)-phenethylamine salt as white flaky crystals. Further, these were recrystallized from ethyl acetate i~o obtain 0.142 g of second crystals and 0.0908 g of third crystals. Melting point 191 ~ 193 °C, Optical rotation [a]D = -87° (C = 0.24, THF) Elemental analysis (o): For C28H28F3N3O4S
C H N
Calculated 60.10 5.04 7.51 Found 60.24 5.05 '7.43 To 20 ml of IN hydrochloric acid, 0.753 g of first crystals were added under ice cooling. The mixture was stirred for 5 minutes and then filtered, and the crystals were washed with water and dried by heating. The crystals thus obtained were recrystallized from ethanol to obtain 0.532 g of aimed product as white powdery crystals. Melting point 194 195 °C, Optical rotation [o!JD = -100° ((~ - 0.24, THF) Elemental analysis (o): For C20H17F3N2(~4S
C H N
Calculated 54.79 3.91 6.39 Found 54.72 3.90 6.35 For measuring the optical purity, part of crystals obtained (ca. 1 mg) was sampled and dissolved into 3 ml of methanol. After cooling, 0.2 ml of diazometlZane-ether solution were added and, after stirred for 5 minutes at room temperature, solvent was distilled off under reduced prssure.
Further, after distilled off the residual solvent for one hour with pump for distillation under reduced pressure, the residue was dissolved into methanol, and the optical purity was measured by me~Y~s of liquid chromatography (column; chiral cell AD (Daicel), eluting solvent; hexane:isopropanol = 70:30, flow rate; 1.0 ml/min, measuring wavelength; a - 230 nm, retention time; 22.31 min) to obtain 99.2 o ee.
Example 51 (+)-N-(4-Trifluoromethylbenzyl)-5-(2,4-dioxothiazolidin-5-yl)methyl-2-methoxybenzamide Similarly to Example 50, 1.00 g of (~)-N-(4-trifluoromethylbenzyl)-5-(2,4-dioxothiazolidine-5-yl)methyl-2-methoxybenzamide obtained in Example 39 was submitted to the optical resolution with D(+)-phenethylamine to obtain 0.742 g of first crystals, 0.143 g of second crystals and 0.0587 g of third crystals as white flaky crystals for D(+)-phenethylamine salt. Melting point 191 ~ 193 °C, Optical rotation [~~D - 87°
(C = 0.24, THF) Elemental analysis (o): For C28H28F3N304S
C H N
Calculated 60.10 5.04 7.51 Found 59.95 5.19 T.49 Similarly to Example 50, 0.742 g of first crystals were treated with 1N hydrochloric acid and recrystallized from ethanol to obtain 0.510 g of aimed product as white powdery * Trade-mark crystals. Melting point 194 ~ 195 °C, Crptical rotation [a]D =
100° (C = 0.24, THF) '' Elemental analysis (o): for C20H17F3N2G4S
C H N
Calculated 54.79 3.91 6.39 Found 54.88 4.03 6.42 For measuring the optical purity, N-methylation was made with diazomethane similarly to Example 50, and then the optical purity was measured by means of liquid chromatography (column; chiral cell ~D (Daicel), eluting solvent;
hexane:isopropanol = 70:30, flow rate; 1.0 ml/min, measuring wavelength; a = 230 nm, retention time; 30.64 min) to obtain 99.2 % cc.
Test example 1 Employing inherited obese mice (C57BL ob/ob), the value of blood sugar was determined by collecting blood from caudal vein prior to testing. They were grouped so as not to cause any difference in the values of blood sugar, and the compounds of Example 36, 39, 46 and 48 were administered orally for 5 days at a dosage of 10 mg/kg, respectively. For the glucose resistance test, 2 g/kg of glucose were administered orally after fasted overnight and the values of blood sugar at 0 minute, 30 minutes and 60 minutes were determined. The blood sugar-lowering rate was calculated from following formula.
Blood sugar-lowering rate (o) -[(Sum of values of blood sugar of vehicle control group at 0, 30 and 60 minutes after administration of glucose)-(Sum of values of blood sugar of each group at 0, 30 and 60 minutes after adma.nistration of glucose)]
x 100 (Scan of values of blood sugar of vehicle control group at 0. 30 and 60 minutes after administration of glucose) Results are shown in Table 8. Frorn these results, it was shown that the compounds had potent hypoglycemic effects.
Blood sugar-~

Compound Dosage lowering rate (mg/kg) ( ~) Example 36 10 43 Example 39 10 47 Example 46 10 37 Example 48 10 45 Test example 2 Employing inherited obese mice (C5'7BL ob/ob), value of triglyceride in blood and value of free fatty acid in blood were determined by collecting blood from caudal vein prior to testing and they were grouped. After the compound of Example 39 was administered orally for 2 weeks at following dosages, the value of triglyceride in blood and the value of free fatty acid in blood were determined. The lowering rate of each parameter was calculated from following formula.
Lowering rate (o) -m _ .
[(Value measured for vehicle control group)-(Value measured for each group of carrpound administration)]
x 100 (Value measured for vehicle control group) Results are shown in Table 9. From these results, it was shown that the compound had potent lipid-lowering effects.
", Table 9]
Lowering rate of Lowering rate of tri- free Compound Dosage glyceride in blood fatty acid in blood ~mg~kg) t~) l F~camp e As above, with the above N-benzyldio:~othiazolidyl-benzamide derivatives, drugs that improve the insulin resistance in the non-insulin dependent 'type diabetes mellitus and have potent hypoglycemic effects and high safety can be obtained.

Claims (10)

1. A process for preparing a compound of the general formula (4) [wherein R3 represents lower alkoxy with 1 to 3 carbon atoms, hydroxyl or halogen, and R4 represents hydrogen or lower alkyl with 1 to 3 carbon atoms, which process comprises reacting a compound of the general formula (2) [wherein R3 and R4 are as defined above , with a compound of the general formula (3).

2. A process for preparing a compound of the general formula (5) [wherein R3 represents lower alkoxy with 1 to 3 carbon atoms, hydroxyl or halogen, and R4 represents hydrogen or lower alkyl with 1 to 3 carbon atoms, which process comprises reducing a compound of the general formula (4) [wherein R3 and R4 are as defined above].

3. A process for preparing a compound of the general formula (7) [wherein R3 represents lower alkoxy with 1 to 3 carbon atoms, hydroxyl or halogen, and the dotted line indicates a double bond or a single bond in combination with the solid line], which process comprises hydrolyzing a compound of the general formula (6) [wherein R3 and the dotted line are as defined above, and R5 represents lower alkyl with 1 to 3 carbon atoms].

4. A process for preparing a compound of the general formula (7a) [wherein R3 represents lower alkoxy with 1 to 3 carbon atoms, hydroxyl or halogen], which process comprises reacting a compound of the general formula (10) [wherein R3 is as defined above, R5 represents lower alkyl with 1 to 3 carbon atoms, R6 represents lower alkyl with 1 to 3 carbon atoms, and x represents halogen, with thiourea, and hydrolyzing the product so obtained.

5. A process according to claim 3 wherein, in the starting materials, the dotted line in combination with the solid line is a double bond.

6. A process according to claim 3 wherein, in the starting materials, the dotted line in combination with the solid line is a single bond.

7. A process according to any one of claims 1 to 6 wherein, in the starting materials, R3 is fluoro.

8. A process according to any one of claims 1 to 6 wherein, in the starting materials, R3 is methoxy.

9. A process according to any one of claims 1 to 6 wherein, in the starting materials, R3 is ethoxy.

10. A process according to any one of claims 1 to 6 wherein, in the starting materials, R3 is isopropoxy.