JPS5970685A - Benzoylthiophene derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I {R<1> is (substituted) 1-8C straight or branched-chain alkyl, 2-8C straight- or branched-chain alkenyl, etc.; R<2> and R<3> are H, (substituted) lower alkyl, lower alkoxy, etc.; R<4> and R<5> are H, lower alkyl, lower alkenyl, lower aliphatic acyl, OH, etc.; Z is oxo or =N-OR<6> [R<6> is H, (substituted) lower alkyl, lower alkenyl, etc.]}. EXAMPLE:4-(5-Benzoylthiophen-2-yl)-butan-2-one. USE:Drug having antiphlogistic and analgesic activities. PROCESS:The objective compound of e.g. formula IV can be prepared by reacting the thiophene derivative of formula II with the benzoic acid halide derivative of formula III (X is halogen).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel benzoylthiophene cavity conductor represented by the general formula that exhibits anti-inflammatory and analgesic effects and is useful as a medicine, and a method for producing the same.

In the above formula, R is a linear or branched alkyl group having 1 to 8 carbon atoms, a linear or branched alkenyl group having 2 to 8 carbon atoms, or a linear or branched alkenyl group having 1 to 8 carbon atoms. The figure shows an aliphatic acyl group having 8 groups, and each group further includes an ogiso group, a hydroxyl group, a lower alkoxy group, a lower aliphatic acyloxy group, a carboxy group, a lower alkoxycarbonyl group, an amine group, a mono-lower alkylamino group, a di- R2 and R3 are the same or different and may be substituted with a lower alkylamino group or a cyclic amine group,
Lower alkoxy group as a substituent. lower alkylthio group,
An amino group, a mono-lower alkylamino group, a di-lower alkylamino group, or a lower alkyl group or lower alkoxy group which may have a halogen atom.

Indicates a lower alkylthio group or a halogen atom.

R4 and R5 are the same or different hydrogen atoms.

Lower alkyl group, lower alkenyl group, lower aliphatic acyl group, hydroxyl group, lower alkoxy group, lower NH NG group acyloxy group, mercapto group, lower alkylthio group, amino group, mono- or di-lower alkylamino group, cyclic amino group , halogen atom or nitro group, 2 is an oxo group or: Base.

It may be substituted with a hydroxyl group, a lower alkoxy group, a lower aliphatic acyloxy group, a carboxy group, a lower alkoxycarbonyl group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, or a cyclic amine group. ) is shown. however.

When R1 is an unsubstituted alkyl group, VC has 3 or more carbon atoms.

In the general formula (I+), R1 is preferably methyl.

Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sub-butyl*'e13rt-butyl.

Lowhentill. A linear or branched alkyl group having 1 to 8 carbon atoms such as impentyl, n-hexyl-isohexyl, n-heptyl, n-octyl,
vinyl, allyl, mesoflobenyl e 2-futhynyl, 3
-Pentenyl.

3-hexenyl, 1-methyl-2-hexenyl.

A linear or branched alkenyl group having 2 to 8 carbon atoms such as 3-octenyl, formyl, acetyl, propionyl. Butyryl, isobutyryl, valeryl, isovaleryl.

It represents an aliphatic acyl group having 1 to 8 carbon atoms such as hexanoyl, heptanoyl, and octanoyl, and each group further includes an ogiso group and a hydroxyl group.

Lower alkoxy groups such as methoxy, ethoxy, n-propoxy, impropoxy, n-butoxy, imbutoxy, lower aliphatic acyloxy groups such as acetoxy, probionyloxy, n-butyryloxy, imbutyryloxy, carboxy groups , methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, lower alkoxycarbonyl groups such as impropoxycarbonyl, amino group, monomethylamino, monoethyl ag), mono n
- mono-lower alkylamino groups such as propylamine, mono-n-propylamine, dimethylamino, diethylamino.

may be substituted with a di-lower alkylamino group such as diisopropylamino, diisopropylamino, or a cyclic amino group such as 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl; 9R2 and R3 are the same but different; 71 (X atom, methoxy, ethoxy as a substituent.

Lower alkoxy groups such as lowpropoxy, isopropoxy, methylthio, nigerthio, n-propylthio,
Lower alkylthio groups such as isopropyldio, amine groups, monomethylamine.

Mono-lower alkyl such as ethylamino, n-propylamino, and isopropylamine.

di-lower alkylamino groups such as dimethylamino, diethylamino, dilaufurobylamine, diisopropylamine, or fluorine, chlorine.

Methyl which may have a halogen atom such as bromine,
Ethyl, n-propyl, isopropyl.

Lower alkyl groups such as n-butyl, isobutyl, methoxy, ethoxy, n-propoxy, isobropoxy, n
- lower alkoxy groups such as butoxy, isobutoxy,
Methylthio, ethylthio, n-propylthio, isopropylthio.

Represents a lower alkylthio215 such as n-butylthio, ~isobutylthio, or a halogen atom such as fluorine, chlorine, or bromine, and R4 and R5 are the same or different and represent a hydrogen atom, methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, 5 or lower alkyl/1
7 units, view 2. Alli/Ll Lower alkenyl groups such as isopropenyl, 2-butenyl, 3-butenyl, formyl, acetyl A1. Lower aliphatic acyl groups and hydroxyl groups such as propionyl, lobetyryl, and isobutyryl.

Lower alkoxy groups such as methoxy, ethoxy, n-propoxy, -f-sobroboxy, n-butoxy, isobutoxy, lower aliphatic acyloxy groups such as acetoxy, propionyloxy, n-buty-lyloxy, isobutyryloxy, mercapto Group 9 methylthio, ethylthio,
n-Provirthio. Lower alkylthio groups such as isopropylthio, n-butylthio, isobutylthio. Amino group, mono-lower alkylamino group such as monomethylamino, monoethylamino, mono n-propylamine, monoisopropylamino, di-lower alkylamino group such as dimethylamino, diethylamino, dilowpropylamine, diisopropylamino, 1- Pyrrolidinyl.

It represents a cyclic amine group such as piperidino, morpholino, 1-biverazini A, (7), a halogen atom such as fluorine, chlorine, bromine, or a nitro group, and 2 is an oxo group or =N
-OR6 group (where H6 is a hydrogen atom or a lower alkyl group such as methyl, ethyl, n-propyl, isopropyl, 0-butyl, isobutyl, vinyl, allyl, impropenyl, 2-butenyl, 3-butenyl) It represents a lower alkenyl group or a lower aliphatic acyl group such as formyl, acetyl, propionyl, n-butyryl, and isobutyryl, and each group is a ranioxo group, a hydroxyl group, methoxy, or ethoxy.

Lower alkoxy groups such as n-propoxy and isopropoxy, lower aliphatic acyloxy groups such as acetoxy, propionyloxy, n-phthyryloxy and imbutyryloxy, and carboxy groups. Lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, amine groups, monomethylamino, monoethylamino,
Mono-lower alkylamino groups such as mono-n-propylamino, monoisopropylamine, di-lower alkylamino groups such as dimethylamino, diethylamino, dilopropylamine, diisopropylamino, or 1-pyrrolidinyl, piperazino, morpholino, 1-piperazinyl. may be substituted with a cyclic amine group such as ) is shown.

Specific examples of the compound having the general formula [I3] obtained by the present invention are shown below.

(1) 2-isopropyl-5-pensoyl-J-offene (212-n-butyl-5-benzoylthiophene (3) 2-n-heptyl-5-benzoylthiophene (4) 2-n-butyl-5-(4-methyl benzoyl)-thiophene (5) 2-n-n-butyl-5-(4-chlorobenzoyl)-thiophene (6) 2-n-n-butyl-5-(4-methoxybenzoyl)-thiophene (7) 3-(5-benzoylthiophene -2-yl)-
Propan-2-one (8) 4-(5-benzoylthiophen-2-yl)-
Butan-2-one (9) 4-(5-benzoylthiophen-2-yl)-
Butan-3-one (10) 1-bromo-4-(5-benzoylthiophen-2-yl)-butan-2-one (11) 1-fluoro-4-(5-benzoylthiophen-2- yl)-butan-2-one (12) 4-
(s-(4-methylben,]°iaL)-”offen-2-yl)-butan-2-one (13) 4-(5-
(4-chlorobenzoyl)-thiophen-2-yl)-
Butan-2-one (14) 4-(5-(4-methoxybenzoyl)-thiophen-2-yl)-butane-2
-one (15) 4- (5-benzoylthiophene-
2-yl)-butan-2-ol (16) 4-(5-(4-methylbenzoyl)-thiophen-2-y/l/)-butan-2-ol (17
) 4- (5-(4-chlorobenzoyl)-thiophen-2-yl)-butan-2-ol (1 g) 4-
(5-(4-methoxybenzoyl)-thiophene-2-
yl)-butan-2-ol (19) 2-acetoxy-4-(5-benzoylthiophen-2-yl)-butane (20) 4-(5-benzoylthiophen-2-yl)-2-methoxy-butane (21) 4-'(5-(4-methylbenzoyl)-
Thiophen-2-yl)-2-methoxybutane (22)
4-(5-benzoylthiophen-2-yl)-but-3-en-2-one (23) 4-(5-benzoylthiophen-2-yl)-1-fluoro-but-3-en-2- one (24) 4- (5-(4-methylbenzoyl)-thiophen-2-yl)-but-3-en-2-one (25) 4- (5-(4-chlorobenzoyl)-thiophene-2 -yl)-but-3-en-2-one (26) 4- (5-benzoylthiophen-2-yl)-1-promobuter-3-en-2-one (27) 4- (5-(4- fluorobenzoyl)−
Thiophene)-phth-3-en-2-one (7,8)
4-(5-(3-methoxybenzoyl)-thiophene)
-phth-3-en-2-one (29) 4- (5-benzoylthiophen-2-yl)-2-(1-morpholino)-butane (30) 4- (5-benzoylthiophen-2-yl) -3-(1-morpholino)-butane (
31) 4-(4-Methyl-5-benzoylthiophen-2-yl)butan-2-one (32) 4-(4'-trifluoromethyl-5-
pensoylthiophen-2-yl)butan-2-one (33) 4-(4-methyl-5-benzoylthiophen-2-yl)butan-2-ol (34) 4-(4-methyl-5-( 4-fluorobenzoyl)thiophen-2-yl)butan-2-one (35) 4-(4-methyl-5-(4-fluorobenzoyl)thiophen-2-yl)butan-2-ol (36) 4 - (5-benzoylthiophen-2-yl)-butan-2-one oxime (37) 4- (5-benzoylthiophen-2-yl)-butan-2-one oxime methyl ether (3B), 4-(5 -benzoylthiophen-2-yl)-butan-2-one oxime normal butyl ether (39) 4- (5-benzoylthiophen-2-yl)-butan-2-one oxime normal heptyl ether (40) 4- (5- benzoylthiophen-2-yl)-butan-2-one oxime-(2-dimethylamine-ethyl)-ether (41) 4-(5-benzoylthiophen-2-yl)-butan-2-one oxime-(°2- Carboxymethyl)ether (42) 4-(5-benzoylthiophen-2-yl)butan-2-ol oxime-methyl ether The novel compound according to the present invention can be prepared by the method shown below.

Manufacturing method (1) General formula (in the formula, R', R2, R', R' and R5
has the same meaning as above. ) is a benzoylthiophene derivative.

A thiophene derivative having the general formula (wherein R1, R2 and R3 have the same meanings as above) is added to a thiophene derivative having the general formula (wherein R4 and R5 have the same meanings as above, or chlorine, bromine, etc.) It is obtained by reacting a benzoic acid halide derivative having a halogen atom).

To explain the above production method in detail, the raw material thiophene (1)
and benzoyl halide +1) in an anhydrous solvent.

Obtained by Friedel-Crafts reaction under acid catalyst.

The reaction solvent may be solvent-free, but it is usually preferable to use an inert solvent to facilitate stirring. Examples of solvents include halogenated hydrocarbon compounds such as carbon disulfide, chloroform, methylene chloride, dichloroethane, and trichloroethane, aliphatic hydrocarbons such as pentane, hexane, and heptane, nitromethane, and ether.

Ethers such as tetrahydrofuran can be used.

Further, as the acid catalyst, metal halides such as boron trifluoride, aluminum chloride, stannic chloride, and ordinary salts of chloride, and mineral acids such as sulfuric acid and phosphoric acid can be used.

The reaction temperature is not particularly limited, but is usually around 90°C to 20°C.
It is 0°C.

The reaction time varies depending on the reaction temperature and the reactivity of the raw materials, but is usually within 24 hours.

Post-treatment of the reaction involves adding water, extracting with an organic solvent such as ether, toluene, benzene, or ethyl acetate, washing the solvent with 1-layer aqueous solution, and drying using a desiccant such as sodium sulfate or magnesium sulfate. After distilling off the solvent, the residue 9 can be further purified by distillation, recrystallization, column chromatography, etc. to obtain the target compound.

Production method (2) A benzoylthiophene oxime derivative having the general formula (wherein B1, R2, R5, R4, and R5 have the same meanings as described above) is produced by the benzoylthiophene oxime derivative having the general formula (wherein R1, R4, and R5 have the same meanings as described above). R1゜a
a Same meaning except that the aliphatic acyl group and oxo group in R and R are protected.

R2 and R5 have the same meanings as described above. ) is reacted with hydroxylamine, and the protecting group contained in the resulting compound is removed.

The protecting group for the aliphatic acyl group and oxo group in the above general formula (IC) is not particularly limited as long as it is commonly used, but alkylene dioxylic acid that forms a ketal such as ethylenedioxy and trimethylene dioxy Oxy groups or alkylene dithio groups forming thioketals such as ethylenedithio are preferred.

The reaction rate can be further increased by using hydroxylamine, which is used in the above reaction.

Usually hytroxylamines are benzoylthiophene 1
1 to 100 moles are used per mole.

Although the reaction proceeds satisfactorily even in the absence of a solvent, an inert solvent may be used to carry out the nine reactions homogeneously. As a solvent,
A vehicle such as water, ethers such as dioxane and tetrahydrofuran, and lower alcohols such as dimethyl sulfoxide, methanol, and ethanol is used.

The reaction temperature is not particularly limited, but usually ranges from room temperature to 150°C.
It is.

Reaction time varies depending on reaction temperature and reactivity of raw materials.
However, it is usually less than 5 days.

Also, to increase the reaction rate, acids such as acetic acid, hydrochloric acid, toluenesulfonic acid, camphorsulfonic acid, pyridine, and triethylamine 9-pyrrolidine are used.

Base catalysts such as hyheridine can be used.

After completion of the oximation reaction, the above-mentioned protecting group can be removed according to a conventional method. For example, the ketal 2G can be easily removed using a catalyst such as acetic acid, oxalic acid, toluenesulfonic acid, dilute hydrochloric acid, etc. to obtain the target compound.

The target compound can be obtained by contacting the thioketal protecting group with 1 unit of mercuric chloride.

After completion of the above reaction, the target compound of this production method can be obtained by processing according to a conventional method and further purifying by distillation, recrystallization, chromatography, etc.

Production method (3) General formula (wherein Rb represents a lower alkyl group, a lower alkenyl group, or an aliphatic butyl group, each group further contains an oxo group 9
Hydroxyl group, lower alkoxy group.

B
, j, R2, R3, R4 and R5 have the same meanings as described above. ) The benzoylthiophene oxime ether derivative having the general formula (in the formula, R; They have the same meanings except that the amino group, cyclic amino group and mercapto group are protected. ) is a benzoylthiophene oxime derivative having the general formula %% () (in the formula, R6 is a lower alkyl group, the lower alkenyl group is further an oxo group, a hydroxyl group which may be modified, a lower alkoxy group, a lower aliphatic acyl group). 8. Carboxy group which may be protected.

Lower alkoxycarbonyl group. An amino group that may be protected, a mono-lower alkyl amyle group that may also be protected. may be substituted with a di-lower alkylamino group or an optionally protected cyclic amine group, y is chlorine. It represents a halogen atom such as bromine, a lower alkanesulfonyloxy group such as methanesulfonyloxy and ethanesulfonyloxy, or a 7-arylsulfonyloxy group such as benzenesulfonyloxy and p-toluenesulfonyloxy. ) can be obtained by reacting a compound having W and removing the protecting group contained in the resulting compound.

The protecting groups present in the above general formulas (Ie) and (W) are not particularly limited as long as they are commonly used, but examples of protecting groups for the 9-hydroxyl group include evarocetyl, trifluoroacetyl, benzoyl, and benzyloxy. Acyl groups such as carbonyl, p-nitrobenzyloxyca/+/bonyl.

trialkylsilyl groups such as trimethylsilyl, dimethyl-tert-butylsilyl, dihydropyran-2-
yl group, etc. are preferable, and groups that form esters such as + tert-butyl, p-nitrobenzyl, benzhydryl, and trichloroethyl are preferable as protecting groups for carboxy groups, and as protecting groups for matathiol groups. is an acyl group such as acetyl or trifluoroacetyl.

The above reaction can be carried out by reacting the oxime (Ie) with an etherification agent (Ivl, etc.) in the presence of a base.

Organic bases such as sodium methoxide, sodium etrethylamine, and pyridine can be used.

Although the reaction proceeds satisfactorily even in the absence of a solvent, a solvent may be used to carry out the reaction homogeneously. As the solvent, ethers such as dioxane and tetrahydrofuran, lower alcohols such as dimethyl sulfoxide, dimethylformamide, methanol, and ethanol are used.

The reaction temperature is not particularly limited, but usually ranges from room temperature to 150°C.
It is.

The reaction time varies depending on the reaction temperature and the reactivity of the raw materials, but is usually 40 hours or less.

After the completion of the neethylation reaction, the above-mentioned protecting group can be removed according to a conventional method. For example, aliphatic acyl groups such as acetyl, +7 fluoroacetyl, and benzoyl, which are protective groups for hydroxyl groups, can be converted to aralkyloxy groups such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc. by treating with dilute aqueous sodium hydroxide or potassium hydroxide solution. The carbonyl group can be converted into a trialkylsilyl group such as trimethylsilyl, dimethyl-tert-butylsilyl, or hydrogen fluoride water by a catalytic reduction method using a palladium-carbon catalyst.

By fluoro compounds such as boron trifluoride,
Alternatively, it can be removed with acetic acid, hydrochloric acid, etc., and the dihydrobilan-2-yl group can be removed with a mineral acid such as hydrochloric acid, 9-hydrobromic acid, or an organic acid such as formic acid or acetic acid.

tert-butyl group, which is a protecting group for carboxyl group.

By treating the benzhydryl group with a mineral acid such as hydrochloric acid or hydrobromic acid or an organic acid such as trifluoroacetic acid,
The trichloroethyl group can be removed by treatment with zinc and acetic acid, and the p-nitrobenzyl group can be removed by catalytic reduction using a palladium-carbon catalyst.

Further, an acyl group such as acetyl or trifluoroacetyl which is a protecting group for a thiol group can be removed in the same manner as the corresponding acyl group of a hydroxyl group.

After the completion of the above reaction, the target compound of the one-step production method was treated according to a conventional method and further distilled. It can be obtained by purification by recrystallization, chromatography, etc.

The benzoylthiophene derivative having the general formula (1) synthesized by the above production method can be subjected to pharmacologically acceptable salt pressure, if necessary. For example, amine derivatives can be made into acid addition salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid or salts of organic acids such as tartaric acid, citric acid, lactic acid, maleic acid, and carboxylic acid derivatives can be made into salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, etc. salts of alkali metals or alkaline earth metals such as potassium, calcium, aluminum salts, ammonium salts, salts of organic bases such as triethylamine, dicyclohexylamine, morpholine, piperidine, or salts of basic amino acids such as lysine, arginine. It can be done.

It is clear that the compound having the general formula (I) of the present invention has excellent anti-inflammatory or analgesic effects, and the pharmacological effects thereof are illustrated below.

The pharmacological test was conducted using the following method.

Anti-inflammatory activity was tested using the carrageenan edema method using Wlster rats. (e, A, wintθr.

Fi, A, R15ley, G, W, Nuss: J
, Pharmacol, Exp, Therap-+14
1, 369 (1963)) Analgesic effect was tested by the Randall-Selicito method using Wistar rats. (L.O., Randal
leJ, J, 5elitto: Arch, int,
Pharmacodyn, 111 * 409 (19
57)).

As is clear from the results of the above pharmacological tests, the compound having the general formula CI) is useful as an analgesic and anti-inflammatory agent. The dosage form is, for example, two tablets, a capsule,
Examples include oral administration in the form of granules, powders, etc., and parenteral administration in the form of external preparations such as topical preparations, ointments, and creams. The dosage varies depending on the symptoms, age, weight, etc., but is normal when administered orally.

Approximately 50■ to 200,011 per day for adults? Yes.

It can be administered once or in several doses.

Next, the present invention will be explained in more detail with reference to Examples.

Example 1 4-(5-benzoylthiophene 2,71
of aluminum chloride [30] of methylene chloride is added, and 1.91 of benzoyl bromide is added under water cooling. After stirring for 30 minutes, 1.54 liters of 4-(thiophen-2-yl)-butan-2-one was added, followed by stirring for 30 minutes.

After that, it was poured into cold water and extracted with ether, and the ether layer was washed with sodium hydrogen sulfate water and dried over anhydrous sodium sulfate.The ether was distilled off and purified by silica gel column chromatography to obtain 1.4 g of the target compound. Ta. Recrystallization from n-hexane gave 9 crystals with a melting point of 40-42°C.

The following compounds were synthesized in the same manner.

1 Example RRR substitution position Melting point (C) Ma, s
s(M”)2 H-0H(C!H5)2
2 olt 2303 H-0
4H920112444H-08H17232-353
00 54-Ol-CJ411q
2 50-51 2786 4-0H5
-04H9255-725874-OT(,,O-0,
R9236-38274H 8'H/Heme~ 2 0i1260H g HI3 Table 3 //
26000H.

1 o Ht! (2//27400
H.

11 Ht9(3//274000
H5 12H□ 2 //
302000H5 13Ht9 (3//30214
H, -yll, 3 52-54
25815 H/Y'-262-642
581B ) (c [ 2 θB
-64 2440 17 H△person 4 0it258
1114-F Han 2 80-82 27
719 H△person) 2 83-85 2
7620 H 2 109-111
25621 1 [(△person)]” 2 91
-93 33622 HW' 2
60-62 336T 5-benzoyl-2-butylthiophene (2,2,9)
and 1.2 g of hytroxylamine hydrochloride in methanol 2
Dissolve in 0ml and store at room temperature overnight. Methanol was distilled off, water was added, and the mixture was extracted with ether. After drying over anhydrous sodium sulfate, the ether was concentrated to obtain 1.3511 of the target compound. Melting point 126-128°C Same as actual MU example 23. -The target compound was obtained by reaction using methylhydroxylamine hydrochloride.

Similarly, the following compounds were synthesized.

25 H-04H92o:tz 27326
4-○t -04H92tt 30727
H Chichi 2 tt 289104
l! 5-benzoyl-2-butylthiophene oxime and 0.2 g of sodium hydride were stirred in 20 ml of dimethylformamide for 1 hour under water cooling. Butyl bromide (o, eg) f was added to this, and the mixture was further stirred at room temperature for 1 hour, poured into ice water, acidified with hydrochloric acid, extracted with ether, the solvent was distilled off, and the mixture was purified by silica gel column chromatography.

1°II of the target compound was obtained as an oil.

29 n-Bu, n-Bu2 01t3
153Q -CH2CH2N(C!H5)2 n-B
u2t/ 33Q31 -0H2000Hn-B
But-2-ol (1,3y) hydrochloride is dissolved in pyridine and 1.0 g of methanesulfonyl chloride is added under water cooling. After stirring for 2 hours, ice water is added and extracted with ether. After distilling off, add 1.4 g of morpholine and react at 90° C. for 2 hours. Add water, extract with ether, distill off the solvent, purify by column chromatography, and add ether hydrochloric acid.

When recrystallized from ethanol-ether, the melting point is 131~
0.61 of the target compound was obtained at 135°C.

The target compound having a melting point of 91-93°C was obtained in the same manner as in Example 32.

Patent Applicant Sankyo Co., Ltd. Agent Patent Attorney Shoji Kashi Procedural Amendment (Voluntary) Date of November 1982 Commissioner of the Patent Office Wakasugi OIJ Husband 1, Indication of Case 1979 Patent Application No. 180381 2 , Title of the invention: benzoylthiophene derivatives and their manufacturing process 3, Relationship with the person making the amendment Patent applicant address: 6 Name, 3-1 Nihonbashi Honmachi, Chuo-ku, Tokyo 103 (185) Sankyo Co., Ltd. Representative Director and President Kawamura Letter 4, Agent residence: Sankyo Co., Ltd., 1-2-58 Hiromachi, Honmonagawa-ku, Tokyo 140 Detailed explanation column 7, Contents of amendment Attachment Circular 1, Specification 1, the scope of claims hf as below
Press.

[(11-1) In the formula 1, R1 is a chain-like or branched alkyl group having 1 to 8 carbon atoms, and lIl is a chain-like or branched alkyl group having 2 to 8 carbon atoms. represents an alkenyl group or an aliphatic acyl group having 1 to 8 carbon atoms, and each group further includes an oxo group, a hydroxyl group, a lower alkoxy group, a lower aliphatic acyloxy group, a carboxyne group, a lower alkoxycarbonyl group, a halogen atom, It may be substituted with an amine group, a mono-lower alkylamino group, a di-lower alkylamino group, or a cyclic amine group, R2 and R3 are the same or different, and hydrogen atoms are substituted, and the substituent is a lower alkoxy group, a lower alkylthio group, or an amino group. R represents a lower alkyl group, a lower alkoxy group, a lower alkylthio group, or a halogen atom, which may contain a mono-lower alkylamino group, a di-lower alkylamino group, or a halogen atom.
4 and R5 are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower aliphatic acyl group, a hydroxyl group, a lower mechanical alkoxy group, a 1-class aliphatic acyloxy group, a mercapto group, a lower alkylthio group, an amine 7 group, mono- or di-lower alkylamino group, cyclic amine group, halogen atom or nitro group, Z is an oxo group or -
N-OR6 group (in the formula, R6 is a hydrogen atom or a lower alkyl group, a lower alkenyl group or a lower aliphatic acyl group, and each group further represents an oxo group, a hydroxyl group, a primary alkoxy group, a lower aliphatic group) It may be substituted with an acyloxy group, carboxy a, +aS alkoxycarbonyl group, amine group, mono-lower alkylamino group, di-lower alkylamino group or cyclic amine group.) Of course.

However, if R is a non-direct alkyl group, does it have 3 or more carbon atoms? clothe ” A benzoylthiophene derivative.

(2) General formula (wherein R1 is a linear or branched alkyl group having 1 to 8 carbon atoms, a linear or branched alkenyl group having 2 to 8 carbon atoms) or an aliphatic acyl group having 1 to 8 carbon atoms, and each group roughly refers to an oxo group, a hydroxyl group, a lower alkoxy group, a lower aliphatic acyloxy group, a carboxy group, a lower alkoxycarbonyl group, a halogen atom, an amino R2 and R3 are the same or different and may be substituted with a limescale atom, a lower alkoxy group, a lower alkylthio group, an amino group as a substituent. Lower alkylamino group, di-lower alkylamino group or halogen, ', 'jl +
k Indicates a lower alkyl group, a lower alkokene group, a 1-degree alkylthio group, or a halogen atom, which may be crushed. However, when R1 is an unsubstituted alkyl group, the number of carbon atoms is 3 or more. ) to a thiophene visiting conductor with the general formula (wherein R4 and R5 are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower aliphatic acyl group, a hydroxyl group, a lower alkoxy group, a lower aliphatic acyloxy group, (representing a mercapto group, lower alkylthio group, amine group, mono- or di-lower alkylamino group, cyclic amine group, halogen atom or nitro group, where X represents all halogen atoms). The general formula (where R', R2+ R', R' and R5
shows the same behavior as mentioned above. ) A method for producing a benzoylthiophene derivative having the following.

(3) General formula (wherein R; t is a linear or branched alkyl group having 1 to 8 carbon atoms; 1IfI C0i or branched chain having 2 to 8 carbon atoms; The alkenyl group or 7ζ represents an aliphatic acyl group having 1 to 8 carbon atoms, and each group further includes a protected oxo group,
R2 and R3 is the same or different and is a hydrogen atom, a lower alkoxy group, a lower alkylthio group, an amine group, a mono-lower alkylamino group, a di-lower alkylamino group, or a lower alkyl group which may have a halogen atom as a substituent; an alkoxy group or) 10 atoms, and Rz and Rz are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkenyl group, a protected lower aliphatic acyl group, a hydroxyl group, a lower alkoxy group, a lower aliphatic acyloxy group, mercapto group, +hm alkylthio group, amine group, mono- or di-lower alkylamino group, cyclic amine group, halogen atom or nitro group.However, when Rz is an unsubstituted alkyl group, VC is its IAT, number I Represents 3 or more. ) is reacted with hydroxylamine to benzoylthiophene 844, and the binding group contained in the resulting compound is removed. A method for producing a benzoylthiophene oxime derivative having the same meanings as those obtained by removing the included retaining group, and R2 and R3 having the same meanings as described above.

(4) General formula (wherein R4 is a linear or branched alkyl group having 1 to 8 carbon atoms, a linear or branched alkenyl group having 2 to 8 carbon atoms, or It represents an aliphatic acyl group having 1 to 8 carbon atoms, and each group further includes an oxo group, a protected hydroxyl group, a lower alkoxy group, a lower aliphatic acyloxy group, a protected carboxy group, a lower alkoxycarbonyl group. , may be substituted with a halogen atom, a protected amine group, a protected mono-lower alkylamino group, a di-lower alkylamino group or a protected cyclic amine group, and R and R are the same or different and are hydrogen atoms, A lower alkoxy group, a lower alkylthio group, a protected amine group, a protected mono-lower alkylamino group, a di-lower alkylamino group, or a lower alkyl group, a lower alkoxy group, which may have a halogen atom as a substituent, a primary represents a class alkylthio group or a halogen atom, and R4 and the tag are the same or different and represent a hydrogen atom,
Lower alkyl group, lower alkenyl group, lower aliphatic acyl group, protected hydroxyl group, lower alkoxy group, lower aliphatic acyloxy group, protected mercapto group, lower alkylthio group, protected amine group, protected mono-lower Indicates an alkylamino group, a di-lower alkylamino group, a protected cyclic amino group, a halogen atom, or a nitro group. However, when Rb is an unsubstituted alkyl group, the number of carbon atoms is 3 or more. ) A benzoylthiophene oxime derivative having the general formula (where R6 is of course a lower alkyl group, a lower alkenyl group, or a lower aliphatic acyl group, and each group may further include an oxo group, an optionally protected hydroxyl group, or a lower alkoxy group) ,
Lower aliphatic acyloxy group, optionally protected carboxy group, lower alkoxycarbonyl group, optionally protected amine group, optionally protected mono-lower alkylamino group, di-lower alkylamino group or unprotected optionally substituted with a cyclic amine group <,
/% represents a rogen atom, a lower vulcanulphonyloxy group or an arylsulfonyloxy group. ) is characterized by reacting a compound having the following, and removing the hokoshi group contained in the resulting compound - (wherein R1, R
2, RA, R4, R5 and R6 are the above-mentioned R4
, R: , R: , R8, R: and RaVc
It has the same meaning as removing the protective group contained in @. ) Process for producing benzoylthiophene oxime ether derivatives. 2. On page 11, line 8, "amine group" is corrected to "halogen atom, amine group."

3 In the third line from the bottom of the 13th member, "amine group," is corrected to "fluorine, chlorine, bromine, chlorine, etc... rogene atom, amino group."

4. Insert the following words between the 5th and 4th lines from the 22nd Sadashi.

r (43) 1.1.1-) refluoro-4-(
5-benzoylthiophen-2-yl)-butane-2-
On (44) 1.1.1-) Refluor0-4-(5-
(4-fluorobenzoyl)thiophen-2-yl)-
Butan-2-one (45) tl, 1-trifluoro-4-(s-(4
-chlorobenzoyl)thiophen-2-yl)-butan-2-one (46) 1,1.1-)lifluoro-4-(5-(
2-fluorobenzoyl)thiophen-2-yl)-butan-2-one
tar) J and d" Correct 06 3rd T member Correct "R4, Lee R1" in the bottom row to ○ "R4-(C "4μm1゛").

1, page 38, line 1 "Example R2R1" [Corrected as Example R4' RI J.

8 Insert the following statement between line γ and line 8 on page 39.

r23 4-F △人ay397-99 3302
44-C1△person. F3110-112 34625 2
-F △person OF 73-76 33026
H△person. F379-81 312" or more

Claims (4)

[Claims] (1) General formula [wherein Hj is a linear or branched alkyl group having 1 to 8 carbon atoms, a linear or branched alkenyl group having 2 to 8 carbon atoms, or carbon Indicates an aliphatic acyl group having number 1 to 8, and each group further includes an oxo hydroxyl group, a lower alkoxy group, a lower aliphatic acyloxy group, a carboxy group, a lower alkoxycarbonyl group, an amino group, a mono-lower alkylamino group 9 It may be substituted with a di-lower alkylamino group or a cyclic amino group, R2 and R3 are the same or different and are hydrogen atoms, and the substituent is a lower alkoxy group, a lower alkylthio group, or an amino group. A mono-lower alkylamino group, a di-lower alkylamino group, or a lower alkyl group which may have a halogen atom, a lower alkoxy group 9 A lower alkylthio group or a halogen atom, H4 and R5 are the same or different and are a hydrogen atom, lower alkyl group, lower alkenyl group, lower aliphatic acyl group, hydroxyl group, lower alkoxy group, lower aliphatic acyloxy group, mercapto group, lower alkylthio group,
An amine group, a mono- or di-lower alkylamino group, a cyclic amine group, a halogen atom or a nitro group, 2 is an oxo group or) 2 = N-0R6 group (in the formula, R6 is a hydrogen atom, a lower alkyl group, a lower alkenyl group) or a lower aliphatic acyl group, and each group further includes an oxo group. Hydroxyl group, lower alkoxy group, lower aliphatic acyloxy group, carboxyl group, lower alkoxycarbonyl group, amine group, mono-lower alkylamino group, di-lower alkylamino group. or presently may be substituted with an amine group). however. When 1R is an unsubstituted alkyl group, the number of carbon atoms is 3 or more. ] A benzoylthiophene derivative having the following. (2) General formula (wherein R1 is a linear or branched alkyl group having 1 to 8 carbon atoms, a linear or branched alkyl group having 2 to 8 carbon atoms, Alkenyl group or 1 carbon number
An aliphatic acyl group having 8 to 8 aliphatic acyl groups, each of which is further an oxo group. R2 and R5 may be substituted with a hydroxyl group, a lower alkoxy group, a lower aliphatic acyloxy group, a carboxy group, a lower alkoxycarbonyl group, an amine group, a mono-lower alkylamino group, a di-lower alkylamino group, or a cyclic amino group, and R2 and R5 are Same or different hydrogen atom, lower alkoxy group, lower alkylthio group, amine group as a substituent. Indicates a lower alkylamino group, a di-lower alkylamino group, a lower alkyl group that may have a halogen atom, a lower alkoxy group, a lower alkylthio group, or a halogen atom. However, when R1 is an unsubstituted alkyl group, the number of carbon atoms is 3 or more. ) A thiophene derivative having the general formula) (wherein R4 and R5 are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkenyl group. A similar aliphatic acyl group, a hydroxyl group, a lower alkoxy group, a lower aliphatic acyloxy group, Mercapto group (represents a lower alkylthio group, an amino group, a mono- or di-lower alkylamino group, a cyclic amino group, a halogen atom or a nitro group, where X represents a halogen atom). A method for producing a benzoylthiophene derivative having the general formula (wherein H+, R2, R5, R4 and R5 have the same meanings as described above). (3) General formula (wherein R is a linear or branched alkyl group having 1 to 8 carbon atoms, a linear or branched alkenyl group having 2 to 8 carbon atoms) or a protected aliphatic acyl group having 1 to 8 carbon atoms, each of which is further protected as an oxo group, hydroxyl group, lower alkoxy group, lower aliphatic acyloxy group, or carboxy group; lower alkoxycarbonyl group; Amine group, mono-lower alkylamino group. May be substituted with di-lower akylamino group or cyclic amino group. R2 and R3 are the same and different hydrogen atoms. As a substituent, lower alkoxy group, lower alkylthio group ,
Amine group, mono-lower alkylamino group. It represents a lower alkyl group, a lower alkoxy group, or a halogen atom which may have a di-lower alkylamino group or )/rogen atom, and R and R5 are the same or different and represent a hydrogen atom, a lower alkyl group, or a lower alkenyl group 9
Protected lower aliphatic acyl group, hydroxyl group, lower alkoxy group, lower aliphatic acyloxy group, mercapto group, lower alkylthio group. It represents an amine group, a mono- or di-lower alkylamino group, a cyclic amino group, a nitrogen atom, or a nitro group. However, when Ra is an unsubstituted alkyl group, the number of carbon atoms is 3 or more. Patent W, which is characterized in that a benzoylthiophene derivative dihydroxylamine having the following formula is reacted and the protecting group contained in the resulting compound is removed, has the same meaning as described above. ) A method for producing a benzoylthiophene oxime derivative having (4) General formula (in the formula, R1) is a linear or branched alkyl group having 1 to 8 carbon atoms, or a linear or branched alkenyl group having 2 to 8 carbon atoms. group or carbon number 1
An aliphatic acyl group having 8 to 8 aliphatic acyl groups, each of which is further an oxo group. Protected hydroxyl group, lower alkoxy group, lower aliphatic acyloxy group, protected carboxy group. Lower alkoxycarbonyl group, protected amine group, protected mono-lower alkylamino group. It may be substituted with a di-lower alkylamino group or a protected cyclic amine group. group, a protected mono-lower alkylamino group, a di-lower alkylamino group, or a lower alkyl group which may have a halogen atom. It represents a lower alkoxy group, a lower alkylthio group, or a halogen atom, and R8 and R8 are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower aliphatic acyl group, a protected hydroxyl group, a lower alkoxy group, a lower aliphatic group. Indicates an acyloxy group, protected mercapto group, lower alkylthio group, protected amino group, protected mono-lower alkylamino group, di-lower alkylamino group, protected cyclic amino group, norogen atom or nitro group. . However, when Rb is an unsubstituted alkyl group, the number of carbon atoms is 3 or more. ) A benzoylthiophene oxime derivative having the general formula (wherein R represents a lower alkyl group, a lower alkenyl group, or a lower aliphatic acyl group, each group further includes an oxyne group, an optionally protected hydroxyl group, Lower alkoxy group, lower aliphatic acyloxy group, optionally protected carboxy group. Lower alkoxycarbonyl group, optionally protected amine group, optionally protected mono-lower alkylamino group, di-lower alkylamino group or may be substituted with an optionally protected cyclic amine group, and Y represents a halogen atom, a lower alkanesulfonyloxy group, or an alkane sulfonyloxy group). (wherein R1, R2, R5, R4, R5 and R6 are the aforementioned Rb, Ra, Ra, Rh, Rb and R
It has the same meaning as a with the protecting group removed. ) A method for producing benzoylthiophene oxime ether derivatives.