CA1189078A - Process for producing 4-oximino-1,2,3,4- tetrahydroquinoline derivatives and said derivatives produced thereby - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Process for producing 4-oximino-1,2,3,4-tetrahydro-quinoline derivatives of the formula (I):

(I) wherein X represents a halogen atom and Y represents a hydrogen atom, a straight-chain or branched-chain alkyl group, a halogen-substituted lower alkyl group, a phenylalkyl group, a phenyl-alkenyl group, an unsubstituted or halogen-substituted phenyl group, a nitrogen-containing aromatic group, a straight-chain or branched-chain alkoxy group or an alkyl-substituted or phenyl-substituted amino group, and said derivatives produced thereby.
These compounds exhibit strong antiedemic, diuretic and hypo-tensive effects.

Description

B~CKGROUND OF TME INVENTION
1. Field of the Invention This invention relates to a process for producing novel 4-oximino 1,2,3,4-tetrahydroquinoline derivative having anti-edemic, diuretic and hypotensive effects. It also relates to novel 4-oximino- 1,2,3,4-tetrahydroquinoline derivative produced by said process.

2. Descr~ption of the Prior Art Extensive researches has been continued for developlng efficient antiphlogistic analgesics which are neutral or basic and therefor do not cause gastrointestinal clisorclers, ever since non-steroid anti-inflammatory agents, particularly acidlc non-steroid anti-inflammatory agents had been found to cause severe gastrointestinal disorders.
The present inventors, after many year of research, have found a novel 4-oximino-1,2,3,4-tetrahydroquinoline derivative which exhibits strong antiedemic, diuretic and hypotensive effects without causing appreciable gastrointestinal disorders, thus achieving this invention.
SUMMARY OF TME INVENTION
. _ .
Accordingly, this invention provides a process for produclng novel 4-oximino-1,2,3,4-tetrahydroquinoline derivative of the general formula:

_ ~ _ Z~

N-OH

(I) 0~ ~Y

wherein X represents a halogen atom and Y represents a hydrogen atom, a straight-chain or branched-chain alkyl group, a halogen-substituted lower alkyl group, a phenylalkyl group, a phenyl-alkenyl group, an unsubstituted or halogen-substituted phenyl group, a nitrogen-containing aromatic group, a straight-chain or branched-chain al]~oxy group or an alkyl-substituted or phenyl-substituted amino group and said derivative produced thereby.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The compounds of this invention having the formula (I) may be generally produced as follows:
6-Halogen-substituted-4-oxo-1,2,3,4-tetrahydroquinolines, the intermediates in the production of the compounds of this invention, may be produced as follows:
A p-halogen-substituted aniline of the formula:

X _~--NH2 wherein X represents a halogen atom; and an acrylic acid ester of the formula:
CH2=CHCOOR
wherein R is an ester forminy group are subjected to Michael condensation reaction under heating in a solvent such as benzene, toluene, ethyl acetate, ethanol etc or, if desired, using a base such as sodium hydride, a sodium alkoxide etc. at room temperature or at an elevated temperature, to obtain a 3-(p-halogen-substi-tuted phenylamino)propionic acid ester of the formula:

X~_~H_CH2_c~l2cooR

The ester compound thus obtained is hydrolyzed and subsequently heated using phosphorus pentoxide, polyphosphoric acid or the like as a dehydrating agent in the presence or the absence of a solvent such as benzene, toluene, xylene etc., thereby a 6-halogen-substituted-~-oxo-1,2,3,~-tetrahyclroquinoline o~ the Eormllla:

` ~
H
is synthesized.
Alternatively, p-propiolaetone is condensed with a p-halogen-substituted aniline with or without a Lewis aeid catalyst such as zinc chloride, aluminum chloride etc. in the presence of a solvent such as acetonitrile, to produee a 3-(p-halo~en-substituted phenylamino)propionic acid, which is then cyclized with dehydration using phosphorus pentoxide, polyphosphoric acicl or the like or, after converting the carboxyl group to the acid chloride, and subjecting to cyclization by Friedel-Crafts reaction, the 6-halogen-substituted-4-oxo-1,2,3,~-tetrahydro-quinoline can be obtained as the intermediate.

~ 8~1~

Thereafter, in order to effect the N-acylation of the above-obtained intermediate, 6-halogen-substituted-4-oxo-1,2,3,4-tetrahydroquinoline, this is reacted with a reactive derivative of a carboxylic acid for example, an acid anhydride, acid chloride or acid bromide of a carboxylic acid of the formula:

(Y7co)nA
wherein Y' represents a hydrogen atom, a straight-chain or branched-chain alkyl group, a halogen-substituted lower alkyl group, a phenylalkyl group, a phenylalkenyl group, an unsubsti-tuted or halogen-substituted phenyl group or a nitrogen-contain-ing aromatic group, A represents -Cl, -Br; or -O-, and n repre-sents 2 when A is -O- or 1 when ~ i9 -Cl or -Br; in the pres.~nce of an organic base such as triethylamine, pyridine etc. in a solvent such as ether, a tetrahydrofuran, dioxane, chloroform, benzene etc., to obtain an N-substituted-6-halogen-substituted-4-oxo-1,2,3,4-tetrahydroquinoline derivative of the formula:
X~

O~ ~Y' wherein X represents a halogen atom and Y' is as defined above.
Alternatively, it is also possible to react said reactive derivative of the carboxylic acid with an alkali metal amide of the above-described intermediate (e.g. sodium, potassium or lithium amide etc.) in such a solvent as described above to obtain ;~

the N-substituted-6-halogen-substituted-4-oxo-1,2,3,4-tetrahydro-quinoline derivatives.
In order to introduce a carbamoyl group in said inter-mediate, phosgene gas is passed into said intermediate in the presence of a solvent such as tetrahydrofuran, dioxane, ether, chloroform etc. or, after the introduction of phosgene gas, an organic base such as triethylamine, pyridine etc. is added drop-wise to the mixture to give a 6-halogen-substituted-4-oxo-1-chloroformyl-1,2,3,4-tetrahydroquinoline, which product is then reacted with an amine of the formula:

R'\
/ H
R"
wherein R' represents an alkyl group or a phenyl group and R"
represents a hydrogen atom or the same meaning as assigned to R';
to obtain a N-substituted-6-halogen-substituted-4-oxo-1,2,3,4-tetrahydroquinoline derivative of the formula:
G~
X~

O/~c~N /R
R"

wherein X represents a halogen atom and R' and R" are as defined above.
When N-alkoxycarbonylation of the above-described inter-mediate is desired, this is reacted with a chloroformate of the formula:

~ 8 ROCOCl wherein R is a straight-chain or branched-chain alkyl group; in the presence of an organic base such as triethylamine, pyridine etc. in a solvent such as ether, tetrahydrofuran, dioxane, di-chloromethane, chloroform, benzene etc., to obtain a N-substi-tuted-6-halogen-substituted-4-oxo-1,2,3,4-tetrahydroquinoline derivative of the formula:
X~

~/ \OR

wherein X represents a halogen atom and R is as defined above.
Alternatively, it is also possible to react said chloro-formate with an alkali metal amide (e.g. sodium, potassium or lithium amid etc.) of the 6-halogen-substituted-4-oxo-1,2,3,4-tetrahydroquinoline.
The N-substituted-6-halogen-substituted-4-oxo-1,2,3,4-tetrahydroquinoline derivative thus synthesized is then heated together with hydroxylamine hydrochloride in an appropriate organic solvent, for example, a mixed solvent of pyridine -alcohol, triethylamine-alcohol, pyridlne-tetrahydrofuran, pyridine-dioxane, and triethanolamine-alcohol, therehy the N-substituted-6-halogen-substituted-4-oximino-1,2,3,4-tetrahydro-quinoline derivative of this invention may be obtained.

The term "halogen atoml' as used herein means a chlorine atom, a bromine atom or a fluorine atom.
The thus obtained compounds according to this invention whieh are represented by the general formula I have strong anti~
edemic, diuretie and hypotensive effects and hardly cause gastro-intenstinal disorder, and therefore they are exeellent as pharma-ceutical drugs.
Aceordingly, the compounds of this invention may be formulated into pharmaceutical produets, either alone or in eombination with other pharmacologieally aetive compounds, and if desired, also with binding agents, fillers, Elavors ete. commonly employed in the pharmaeeutical field in a suitable eonven~ion~l manner.
This invention is illustrated by the following examples, in whieh the parts and ~ represent parts by weight and ~ by weight respectively.
Example 1 Synthesis of 6-chloro-4-oximino-1-formyl-1,2,3,4-tetra-hydroquinoline 18.16 parts of 6-chloro-4-oxo-1,2,3,4-tetrahydroquinoline and 15~ parts of formic acid (purity of 98~ or higher) were mixed and reaeted under reflux with stirring for 3 hours.
The reaction mixture was distilled under redueed pressure to remove the exeess formic acid, 100 ml of ethanol was added to the residue and heated to dissolve it. After cooling, the pre-cipitated crystals were filtered out, and dried to obtain 18.03 parts of 6-chloro-4-oxo-1-formyl-1,2,3,4-tetrahydroquinoline.

Then, the above product was dissolved in 270 ml of ethanol, to which were added 15.0 parts of hydroxylamine hydro-chloride and 17.0 parts of pyridine, and the reaction was effected under reflux for 1.5 hours.
The reaction mixture was poured into one liter of water, filtered out,washed with water, dried, and recrystallized from ethanol to obtain 18.3 parts of 6-chloro-4-oximino-1-formul-1,2,3, 4-tetrahydroquinoline as white crystals.
This product showed a melting point of 192 - 193 C when measured by the method specified in the Japanese Pharmacopeia, and the results of its elemental analysis were as follows:
Elemental Analysis:
C H Cl N
Calculated: 53.45 4.01 15.81 12.47 Found: 53.41 4.00 15.7912.50 Example 2 .
Synthesis of 6-chloro-4-oximino-1-acetyl-1,2,3,4-tetra-~ydroquinoline 18.16 parts of 6-chloro-4-oxo-1,2,3,4-tetrahydroquinollne and 11.23 parts of acetic anhydride were mixed and reacted at 90 C with stirring for 3 hours.
The reaction mixture was poured into 300 ml of water, and the precipitated crystals were filtered out, washed with water, and dried to obtain 20.1 parts of 6-chloro-4-oxo-1-acetyl-1,2,3,4-tetrahydroquinoline.
Then, the above product was dissolved in 300 ml of ethanol, to which were added 15.64 parts of hydroxylamine , hydrochloride and 17.8 parts of pyridine, and the reaction was effected under reflux for 1.5 hours. Thereafter, the product was treated as in Examples 1 to obtain 20.4 parts of 6-chloro-4-oximino-l-acetyl-1,2,3,4-tetrahydroquinoline as white crystals.
This product showecl a melting point of 214 - 215.5C
when measured by the method specified in the Japanese Pharmacopeia, and the results of lts elemental analysis were as follows:
Elemental Analysis:
C H Cl N
Calculatecl: 55.35 4.61 14.88 11.74 Found: 55.40 4.65 lA.~511.71 Example 3 Synthesis of 6-chloro-4-oximino-1-propiOny~ 2v3~4 tetrahydroquinoline 18.16 parts of 6-chloro-4-oxo-1,2,3,4-tetrahydroquino-line, 24.0 parts of pyridine and 100 ml of dioxane were mixed, and 11.1 parts of propionyl chloride was added dropwise to the mixture with stirring while the temperature was maintained at 0 - 5C. After addition, the reaction was conducted at room temperature for 5 hours.
The reaction mixture was pourecl into one liter of water, the precipitated crystals were filtered out, washed with water and then with petroleum ether, ancl dried to obtain 20.4 parts of 6-chloro-4-oxo-1-propionyl-1,2,3,4-tetraphydroquinoline.
Thereafter, the above product was converted to the oxime as in Example 1 thereby obtainin~ 20.6 parts of white 6-chloro-4-oximino-1-propionyl-1,2,3,4,-tetrahydroquinoline. This product g showed a melting point o~ 166 - 169C when measured by the method specified in the Japanese Pharmacopeia, and the results of its elemental analysis were as follows:
Elemental Analysis:
C H Cl N
Calculated: 57.03 5.1514.06 11.09 Found:56.98 5.09 14.0111.10 Examples 4 - 15 In each example, the desired product was obtained by the method described in Example 3, except that the propionyl chloride was replaced by the corresponding acid chloride.
The properties of the products are given in Table 1 below.
Example 16 Synthesis of 6-chloro-4-oximino-1-methylcarbamoyl-1,2,3, 4-tetrahydroquinoline a) 54.5 parts of 6-chloro-4-oxo-1,2,3,4-tetrahydroquino-line and 300 parts of dioxane were mixed, and 44.6 parts of phosgene was introduced to the stirred mixture over about 30 minutes while the temperature was maintained at 20 - 25C. After the introduction, the temperature was raised gradually, and the reaction was effected at 40-45C for 2.5 hours, after which the temperature was further raised to 70C, nitrogen gas was passed throuyh the mixture, and the solvent (dioxane) was distilled off under reduced pressure.
Petroleum ether was added to the residue followed by filtration, washing and drying, there was obtained 70.3 parts of 6-ch]oro-4-oxo-l-chloro-formyl-1,2,3,4-tetrahydroquinoline (m.p. 114-116C)~

~B

b) 2.6 Parts of the above product was dissolved in 30 ml of dioxane, and this solu~ion was added dropwise to 10 ml of dioxane solution containing 1.0 part of monomethylamine in while maintaining 0 - 5C. After the addition, stirring was conducted at room temperature for 4 hours.
The reaction mixture was poured into water, and the pre-cipitated crystals were filtered out, washed with water and then with petroleum ether, dried, and recrystallized from a mixed solvent of ethanol - n-hexane to obtain 2.2 parts of 6-chloro-4-oxo-1-methylcarbamoyl-1,2,3,4-tetrahydroquinoline. This product was dissolved in 30 ml of ethanol, to which were addecl 2.0 p~rts of hydroxylamine hydrochloricle ~nd 2.2 p~rts oE pyridine, ~ncl the reaction was conducted under reflux for 2 hours. Thereafter, the mixture was treated as described in Example 1 to obtain 2.2 parts of white crystals of 6-chloro-4-oximino-1-methylcarbamoyl-1,2,3, 4-tetrahydroquinoline. This product showed a melting point of 211 - 212C when measured by the method specified in the Japanese Pharmacopeia, and the results of its elemental analysis were as follows:
20 Elemental Analysis:
C H Cl N
Calculated: 52.07 4.73 14.00 16.57 Found:52.05 4.75 13.9716.49 Examples 17 - 19 In each example, the 6-chloro-4-oxo-1-chloroEormyl-1,2,-

3,4-tetrahydroquinoline obtained in a) of Example 16a) was treated as described in Example 16b) except that the monomethylamine in b) of Example 16 was replaced by the corresponding amine or aniline, to obtain the desired product. The properties of the products are given in Table 1 below.

- lla -O ~ ro utu~ ~u~ ~~o,r~ co IJ ~ ~ U~ Cl) ~ ~' ~ ~ 1-- ~ ~D 0~ r~ ~ o Lr~
~ O ~ ro U~u~ ~u~ ~cou~

Q) r~ I
C~ JJ
~ u~
5~ LJ
~t~ : = = - = = = = = - - = -L~ a) ~ .LJ

I
O
.
O
S
~ I
~ !
Q~ I i , I ~
~r ~ ~ ~ ~ 0 ~1 1 E-~ ~ (I) ~ I .L) ~>1 (1 l ~ ~ O R E~
~ r~ ~r-~ I r-~ o ,~ R
O I ~-I I L~~ r~ r it.) ~ !_~ ~Ll r~
Q rl >~ r I a S >1 0 ? ~ ~ O O C (IS ~I O
~ ~ r-~~) O C O ~ .. ) s r^I
O Ll ~ Ll (~ 3 C~1 ~r-l ~-r-I -~
t.. ) ~ c ~ O
r-l O r~ XQ~ rl t~ S
~ n L~ ) C) S ~rl LIrI .~J r~
Q r~ ~) S S OC~ Ca) ~ t!~
l l l l l l l l l l l l l l l l r~ r-l r-l r-lr-l r~r-l r-lrl r I r-lr-l r1 r-l r~
b ' ' ' ' ' l ' ' ' ' ' ' ' I
C
.

.,, o ,~
s C) ~ !
.~ ~
C l er u~ ~D r co c~ c ,~ ^ r oa c~
~3 Z rt r-l r~ ~ r-l r r-~
X

Example 20 18.16 Parts of 6-chloro-4-oxo-1,2,3,4-tetrahydroquino-line, 10.3 parts oE pyridine and 100 ml o~ dioxane were mixed, and 12.3 parts of methyl chloroformate was added dropwise to the mixture with stirring while the temperature was maintained at 0 - 5C. After the addition, the reaction was conducted at room temperature for 5 hours.
The reaction mixture was poured into one liter of water, the precipitated crystals were filtered out, washed with water and then with n-hexane, and dried to obtain 22.0 parts of 6--chloro-4-oxo-1-methoxycarbonyl-1,2,3,4-tetrallydroquinoline.
Thereafter, the above product was clissolved ln 33n ml oE
ethanol, to which were added 15.0 parts oE hyclroxylamine hydro-chloride and 17.0 parts of pyridine, and the reaction was con-ducted under reflux for 2 hours.
The reaction mixture was poured into one liter of water, filtered out, washed with water, dried, and recrystallized from ethanol to obtain 19.9 parts of white crystals of 6-chloro-4-oximino-l-methoxycarbonyl-1,2,3,4-tetrahydroquinoline. The product showed a meltin~ point of 162 - 163C when measured hy the method specified in the Japanese Pharmacopeia, and the results of its elemental analysis were as follows:
Elemental Analysis:
C H Cl N
Calculated: 51.87 4.32 13.9511.00 Found: 51.85 4.35 13.8811.02 ~8~

Example 21 16.51 parts of 6-fluoro-4-oxo-1,2,3,4-tetrahydroquino-line, 10.3 parts of pyridine and 100 ml of dichloromethane were mixed, and 14.2 parts of ethyl cllloroformate was added dropwise to the mixture with stirring while the temperature was maintained at 0 - 5C. After the addition, the reaction was conducted at room temperature for 5 hours.
500 ml of cold water was poured into the reaction mix-ture, and the layers were separated. The organic phase was washed once with 100 ml of a 1 N aqueous hydrochloric acid and then twice with 100 ml each of water, and dried over anhydrous Glauber's salt. The solvent (clichloromethane) was dis~ d off under reduced pressure, and 100 ml of ethanol was added to the residue and heated to dissolve it. After cooling, the precipi-tated crystals were filtered out, and dried to obtain 20.8 parts of 6-fluoro-4-oxo-1-ethoxycarbonyl-1,2,3,4-tetrahydroquinoline.
Then, the above product was dissolved in 310 ml of ethanol, to which were added 14.3 parts of hydroxylamine hydro-chloride and 16.2 parts of pyridine, and the reaction was con-ducted under reflux for 2 hours. Thereafter, the product wastreated similarly as in Ex~ple 20 to obtain 20.2 parts of white crystals of 6-fluoro-4-oximino-1-ethoxycarbonyl-1,2,3,4-tetra-hydroquinoline. This product showed a melting point of 122 -124C when measured by the method specified in the Japanese Pharmacopeia, and the results of its elemental analysis were as follows:

, .

Elemental Analysis:
C H F N
Calculated: 57.14 5.167.54 11.11 Found:57.18 5~18 7.5511.08 Example 22 Similarly as in Example 20, 6-bromo-4-oxo-1,2,3,4-tetra-hydroquinoline was reacted with methyl chloroformate and subse-quently converted into the oxime thereby obtaining white crystals of 6-bromo-4-oximino-1-methoxycarbonyl-1,2,3,4-tetrahydroquino-line. The properties of the product are given in Table 2 below.Example 23 Similarly as in Example 21, 6-fluoro-~-oxo-1,2,3,4-tetra-hydroquinoline was reacted with methyl chloroformate and subse-quently converted into the oxime thereby obtaining white 6-~luoro-

4-oximino-1-methoxycarbonyl-1,2,3,4-tetrahydroquinoline. The properties of the product are given in Table 2.
Example 24 Similarly as in Example 20, 6-chloro-4-oxo-1,2,3,4-tetra-hydroquinoline was reacted with ethyl chloroformate and subse-quently converted into the oxime thereby obtaining 6-chloro-4-oximino-l-ethoxycarbonyl-1,2,3,4-tetrahydroquinoline. The pro-perties of the product are given in Table 2.
Example 25 Similarly as in Example 20, 6-chloro-4-oxo-1,2,3,4-tetra-hydroquinoline was reacted with isopropyl chloroformate and subsequently converted into the oxime -thereby obtaining 6-chloro-4-oximino-1-isopropoxycarbonyl-1,2,3,4-tetrahydroquinoline. The properties of the product are given in Table 2.
Example 26 Similarly as in Example 20, 6-bromo-4-oxo-1,2,3,4-tetra-hydroquinoline was reacted with isopropyl chloroformate and sub-sequently converted to the oxime thereby obtaining the desired 6-bromo-4-oximino-1-isopropoxycarbonyl-1,2,3,4-tetrahydroquino-line. The properties of the product are given in Table 2.

Lr~
~ tX) tXl .~ ~-- N
oIl') 1U' ~ o ~ ~ ~ ~ ,_, a S~ aJ
~.~
~1 L!, S
~~ U
O

~, : : : _ I~
1.
r~
~ I I
~1 ~I >1 t~ I I C C
E~ ~ ~, I Q QO
1:1 C ~ ~ h C O O S: t~
Q Q O C~C) O ~ 1_1 Q >`, Q~ ~ x x E o o 1~ 0 0 O X X`` ~ O O
O O X ~ ~
rC S S O O
.

E _ :
O
I O O O
O ~ L~ ~ O
~ o O O
o ~ ~ ~ O
~ ~ s ~ s~
,~ t,~ C)C) a Q, E O
~ z L:l Example 27 Synthesis of 6-fluoro-4-oximino-1-formyl-1,2,3,4-tetra-hydroquinoline 16.51 parts of 6-fluoro-4-oxo-1,2,3,4-tetrahydroquino-line and 150 parts of formic acid (purity of 9S~ or hi~her) were mixed and reacted under reflux with stirring for 3 hours.
The reaction mixture was distilled under reduced pressure to remove the excess formic acid, 100 ml of ethanol was added to the residue and heated to dissolve it. After cooling, the pre-cipitated crystals were filtered out, and dried to obtain 16.2 parts of 6-fluoro-4-oxo-1-formyl-1,2,3,4-tetrahydroquino:Line.
Then, the above product was dlssolved in 250 ml o~
ethanol, to which were added 15.0 parts of hydroxylamine hydro-chloride and 17.0 parts of pyridine, and the reaction was con-ducted under reflux for 2 hours.
The reaction mixture was poured into one liter of water, filtered out, washed with water, dried and then recrystallized from ethanol to obtain 16.1 parts of white crystals of 6-fluoro-4-oximino-1-formyl-1,2,3,4-tetrahydroquinoline.
This product showed a meltin~ point of :L75.5 - 176.5C
when measured by the method specified in the Japanese Pharma-copeia, and the results of its elemental analysis were as follows:
Elemental Analysis:
C ~ F N
Calculated: 57.69 4.33 9.13 13.46 Found: 57.63 4.30 9.17 13.48 Example 28 Synthesis of 6-bromo-4-oximino-1-ace-tyl-1,2,3,4-tetra-hydroquinoline 22.61 parts of 6-bromo-4-oxo-1,2,3,4-tetrahydroquinoline and 13.3 parts of acetic anhydride were mixed and reacted at 90C
with stirring for 3 hours.
The reaction mixture was poured into 500 ml of water, and the precipitated crystals were filtered out, washed with water, and dried to obtain 23.9 parts of 6-bromo~4-oxo-1-acetyl-1,2,3,4-tetrahydroquinoline.
Then, the above product was dissolved in 350 ml of ethanol, to which were added 14.6 parts of hyclroxylamine hydro-chloride and 16.1 parts of pyridine, and the reaction was ef~ected under reflux for 2 hours. Thereafter, the mixture was treated as in Example 27 to obtain 24.1 parts of white crystals of 6-bromo-4-oximino-1-acetyl-1,2,3,4-tetrahydroquinoline.
This product showed a meltin~ point of 200 - 202.5C
when measured by the method specified in the Japanese Pharmacopeia, and the results of the elemental analysis were as follows:
20 Elemental Analysis:
O H Br N
Calculated: 46.643.89 28.27 9.89 Found:46.67 3.8428.24 9.92 Example 29 Synthesis of 6-fluoro-4-oximino-1-propionyl-1,2,3,4-tetrahydroquinoline 16.51 parts of 6-fluoro-4-oxo-1,2,3,4-tetrahydroquinoline, 11.9 parts of pyridine and 100 ml of dioxane were mixed and 12.0 parts of propionyl chloride was added dropwise to the stirred mixture while the temperature was maintain~d at 0 - 5 C.
The reaction mixture was poured into one liter of water, and the precipitated crystals were filtered out, washed with water and then with petroleum ether, and dried to obtain 20.4 parts of 6-fluoro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline.
Then, the above product was converted to the oxime as in Example 27, thereby obtaining 19.5 parts of white 6-fluoro-4-oximino-1-propionyl-1,2,3,4-tetrahydroquinoline. This product showed a melting point of 126.5 - 128C when measured by the method specified by the Japanese Pharmacopeia, and the res~llts of its elemental analysis were as follows:
Elemental Analysis:
C H F N
Calculated: 61.02 5.518.05 11.86 Found:61.04 5.55 8.0211.82 Examples 30 - 36 -In each example, the desired product was obtained by the method similar to that in Example 29, except that the propionyl chloride was replaced by the corresponding acid chloride. The properties of the products are given in Table 3 below.
Example 37 Synthesis of 6-fluoro-4-oximino-1-dimethylcarbamoyl-1,2,3,4-te-trahydroquinoline a) 33.0 parts of 6-fluoro-4-oxo-1,2,3,4-tetrahydroquino-line and 200 parts of dioxane were mixed, and 39.6 parts of /

phosgene was introduced to the stirred mixture over about 30 minutes while the temperature was maintained at 20 - 25C. After the introduction, the temperature was raised gradually, and the reaction was effected at 40 - 45C for 2.5 hours, after which the temperature was further raised to 70C, nitrogen gas was passed through the mixture, and the solvent (dioxane) was distilled off under reduced pressure. Petroleum ether was added to the residue followed by filtration, washing and drying, there was obtained 43.7 parts of 6-fluoro-4-oxo-1-chloroformyl-1,2,3,4-tetrahydro-quinoline.
b) 2.3 Parts of the above product was clissolved ln 30 ml of dioxane, and this solution was added dropwise to 10 ml of dioxane solution containing 1.5 p~rts of dimethylamine whil~ the temperature was maintained at 0 - 5C. ~fter the addition, stir-ring was continued at room temperature for 4 hours.
The reaction mixture was poured into water, and the pre-cipitated crystals were filtered out, washed with water and then with petroleum ether, dried and recrystallized from a mixed sol-vent of ethanol - n-hexane to obtain 2.0 parts of 6-fluoro-4-oxo-20 1-dimethylcarbamoyl-1,2,3,4-tetrahydroquinoline. This product was dissolved in 30 ml of ethanol, to which were added 1.3 parts of hydroxylamine hydrochloride and 1.9 parts of pyridine, and the reaction was conducted under reflux for 2 hours. Thereafter, the mixture was treated as in Example 27 to obtain 2.0 parts of white crystals of 6-fluoro-4-oximino-1-dimethylcarbamoyl-1,2,3,4-tetra-hydroquinoline. This product showed a melting point of 147 -``~ 89,~l 149.5C when measured by the method specified in the Japanese Pharmacopeia, and the results of its elemental analysis were as follows:
Elemental Analysis:
C H ~ N
Calculated: 57.37 5.58 7.57 16.73 Found:57.34 5.53 7.56 16.78 Example 38 The 6-fluoro-4-oxo-1-chloroformyl-1,2,3,4-tetrahydro-quinoline obtained in Example 37 a) was treated similarly as in Example 37 b) except that the dimethylamine was replaced by aniline, to obtain the desired product. The properties of the product are given in Table 3.
Example 39 Synthesis of 6-bromo-4-oximino-1-methylcarbamoyl-1,2,3,4-tetrahydroquinoline a) 45.2 Parts of 6-bromo-4-oxo-1,2,3,4-tetrahydroquino-line and 200 parts of dioxane were mixed, and 39.4 parts of phos-gene was introduced to the stirred mixture while the temperature was maintained at 20 - 25C over about 30 minutes. After the introduction, the reaction was effected at 40 - ~SC for 2.5 hours, and thereafter the mixture was treated as in Example 37 a) to obtain 55.9 parts of 6-bromo-4-oxo-1-chloroformyl-1,2,3,4-tetrahydroquinoline.
b) 2.9 Parts of the above compound was dissolved in 30 ml of dioxane, and this solution was added dropwise to 10 ml of dioxane solution containing 1.1 parts of monomethylamine while the ~' temperature was maintained at 0 - 5C. After the addition, stir ring was continued at room temperature for 4 hours, and thereafter the mixture was treated as in Example 37 b) to obtain 2.4 parts of 6-bromo-4-oxo-1-methylcarbamoyl-1,2,3,4-tetrahydroauinoline.
Then, the above product was treated similarly as in Example 27 to convert it into the oxime, thereby obtaining 2.3 parts of white 6-bromo-4-oximino-1-methylcarbamoyl-1,2,3,4-tetra-hydroquinolineO This product showed a melting point of 206.5C
(dec.) when measured by the method specified in the Japanese Pharmacopeia, and the results of its elemental analysis were as follows:
Elemental Analysis:
C ~I Br N
Calculated: 44.304.03 26.85 14.09 Found:44.28 4.05 26.81 14.11 Example 40 The 6-bromo-4-oxo-1-chloroformyl-1,2,3,4-tetrahydro~
quinoline obtained in Example 39 a) was treated similarly as in Example 39 b) except that the monomethylamine was replaced by dimethylamine, to obtain the desired product. The properties of the product are given in Table 3.

s- `1 ,n Ln Ln Ln Ln n -- ~n r~
O ~ ~ ~ ~ ~ ~ ~ ~ ~

L' Ln ~ I Ln Ln Ln Ln Lr~ I
~j Ln ~ CO Ln CO C~
a) o Ln a~ ~ o co 1` 0 Ln LI ~ ~ ~ ~ ~1 t) U~

Q
Q
~ .~

~0 L
., 0~
_ , _ _ _ ~ =

~ I
J~
r~ I O
N ~
a~ ~ o ~) 'a ~ ~ Q >~ E~
~ ~ ~ O O
Q O ~ ~ g o ~ .a E~ Q I~It~ ,~ I Q ~IJ
~~1:>~ ~1 1 .C ~1 ~ O
O ~ ~ ~ ~ IC) CJ s~ 0 C :~
O ~J~ O
o I(1~ >`1 Q~ N ~
O O.-1 X C ~L~ G
~rl Q~ -~ ~ S ~ ~(,~ C-' I ~
l l l l l l l l l l l l l l l l l l CO

X = - ~ :
~0 I I O I O I I O
O O~-I O~I O O ~ O
E~ ~ O E~ OE~E~ O E~
O O ~ O ~ O O ~ O

Q Q4-1 ,0C~l Q ~ CH ~0 Q) QJ -~ O o ~ f~ rLn ~ Cx) O
(3 z ~~Y) ~ ~ ~ ~ ~ ~ ~r X

The pharmacological effect, toxicity, method for use and dosage of each of the active compounds used in the composi-tions of this invention are illustrated by the following Experi-mental Examples.
Experimental Exa_~le 1 Diuretic Effect in Rats Wister strain male rats weighing about 200 g were starved overnight and each compound of this invention suspended in 25 ml/kg of physiological saline were administered orally to the

5 animals in each group, and the diuretic effect up to 5 hours after the administration was measured. The diuretic effect is expressed as the average urine volume (QO) of the treated group divided by that of the control group. The results are given in Tables 4 and 5 below.

Table 4 Diuretic Effect in Rats _--~
Compound to DosageDiuretic `
be 're sted mg/kgEf f ec t ~ % ) . .. . ..- _ ~
Control 1 0 0 __ 2 1 0 1 8 ~
2 a2 ~ 0 ~ ~ . ~, ,.
2.5 253 ~ n ~1 a . I
__ . I __ . . I I . . ~.
5 ~ 22 2 ~ 2 4 D
. . I i ~
5 . . ~0 ~1 ~
_ ~ .. .

6 5 0 2 0 ~
_ __,~_ ~ .,

7 5 a 1 ~ ~
_ . _ . . . .
12 5 a 2 0 2 _ ~__ .

Furosemide 1 1~ 1 ~ 7 . ~ 2 ~ _ 3 ~ 4 B

Table 5 _ . _ ___ _.
CompoundDosage D iure t ic ComE ound Dosage Diure tic to be m~/kgEf f ect to be mg/kg Eff ect Tested ( 9~ ~ Tested ~ % ) ~ _ _ ~ ~ , . _ ~ 5 2 5 129 1 0 4 2 5 .
23 5 3 0 ~~ _ 5 7 4 3 1 8 83l 5 0 1.7 ~--.
__ ___ _ . .
~ ~ 36 5 2 0 3 . __ 1 Q 3 7 1 ~;6 __ ¦ 5 0 1 8 0 .
__ ____ 1 5 7 1 39 5 ~1 1~~ 7 l . ~
22 ¦ 1 0 2 ~ 3 37 1 0 1 2 a _ l 0 1 8 0 I _ ~ ~ _7 0 Y
21 2 0 2 ~ 5 r ~ O 1 ~ ~
_ . ~ ~ . 2 ~ 4 I :L8 . 2 ~ 2 6 . . I .

___ __ I .
282 0 ~ ~ 4. . . . 5 1 1 ~
2 0 ~ Furosemid 1 0 Z 1 S
5 3 4 ~ 7 0 27 7_ __ .__ ~ _ ._ A diuretic effect was observed in each of Compounds.

~ 27 --Exper imental Example 2 ~Iypotensive Ef~ect in ra~s v~ith Spontan~ou3 ~rtensi-r ( 9EI¦
.5 Male S~R's ~eighi~g 250 - 300 g ~ith blood pressure of 170 - 190 mm ~Ig were used.i~ each group.
Each compound of this lnvention ~as suspended i~ a 5% aqueous arabic gum solution and the blood pressure was measured before adm~nistration and 2 hours ai~ter daily admini~;tratiorl by usi~g a plethysmograph. The results are given i~ Tables 6 and 7 below.

Table 6 EIypotensive E3~fect in S~R' s _ ~ _ . , ~
o Compound Dosage Blood Pressure (mm Hg) to be mg/kg I~Before ~ h~ter After IA~ter _~_ ... - __ Control 180 . 177 ~78 175 _ 2 5Q 178 170.167 . 164 ., _ . . _, .
3 ~ 182 167 16~ 158 __ ___ I+ 50 179 166 165 157 _ ._ _ . , _ _ _ ..

_ . _ __ 6 200 181 _ 169 _ 165_ 166 _ _ ~ .. _ , ___ _ _ _ 3 100_ 1 18.1 ~ 169 1 164 15g I .

Table 7 .

Compound Dosage_ Blood Pressure (rmD ~q?
to be m~/kg Before A~ter Afte.r ¦ After Tested Administ- 2 days 4 days ¦ 8 days ~__ ra lon ___ 5521!~ ~ 1 R 1 1 7 ~ 1 8 2 1 8 0 23 ~o 1 1 81 1 64 1 5,3 1 57 . _ _ __ ___ . .
2~ 2t) 1 80 1 ~ 1 58 1 SS
~__ ~_ _ . . ,,.~. ,_ 22 2 0 1 8 1 1 7 6 1 7 l 1 ~ 5 ~ ___ _ ~ , ,. ._ . , ___ _ 21 5 0 1 7 ~ 1 7 4 1 7 0 l 6 0 . _ " .~...,~. _, . ,, 24 5 0 ! 1 8 2 1 7 0 1 6 5 1 6 2 ----__ __ 28 S a 1 8 0t 7 5 1 6 ~ 1 6 3 __ _ ___ 29 20 1 81 I h6 1 5~ 1 54 .
_ _. ,"..... ,., _,, ,, . _ _ 3 2 0 1 8 3 1 7 1 1 cS 3 1 5 8 31 ' oa 181 17~ 178 17 _ _ ........................ . . .,, _ 36 l Q 0 1 8 ?. l 7 7 1 7 5 -1 6 7 ~ ., .. _.. ,,. ._ ~- ~ --_, .. , _ .. ~ . .. ,............. _ ~
39 1 0 0 1 7 ~ l 7 3 1 7 3 1 6 7 _ , _. , ., , ___ 37 5 ~ 1 8 3 1 7 5 1 6 71 6 6 .. , . ~ . - .... . .... _ 18 5 0 1 6 l 1 7 0 1 6 ~ 1 6 3 -- ' ' ~ ,. __ _ , _ 40 1 0 0 1 8 0 t 7 2 1 6 6 1 ~ 7 ..,_ , ~ _ _~
.

... .

= 29 -Experiment Examle 3 Inhibition for Carrageenin-Induced Foot Edema in ~tats 10 Wister strain male rats weighing about 120 g were used in each gr3up. Each compound of -this invention was suspended in a 5~ aqueous arabic g~n solu-tion and administered orally to the animals. One hour after the admi~i.stration7 0.1 ml o~
a 1% solution of carrageenin in physiological saline as a phlogistic agent wa~ subcutaneously injected into the right hind paw of the rats which had been shaven previously. The volume of the right hind paw was measured before the administra-tion of the phlogis-tic agen-t and 3 hours after the administra-tion. The intensity of edema expressed as percent increase in the foot volume was calculated from the equa-tion (1~ and the percent inhibition of edema was calcula-ted from the equa-tion (2).
Equation (1) ~oot Volume 3 hrs. after ~ Administra-tion (ml)- 1 I x 100 Percent Edema (v/OJ = Foot VoIu~e bef'ore ~ I
Administration (ml) J
Equation (2) Percent Edema in Percent Inhibition Treated Grou~ (50) of Edema (o~O)_ 1 ~ Percent Edema ln Ix 100 Control Group (%) The effective dosage of each compound for inhibiting edema was expressed as ED30 (mg/kg) by calculating the dosage for 30 ~ inhibition from -the percent inhibition of edema according to the probit me-thod. The results are given in Tables 8 and 30 ~ below, Table 8 ~__ ¦ Compound ¦ ED30 (m~Jkg) ~_ .

! 3 8.g :--_ ..... .. ... __ .

---- a7 .
6 14~
. ._ . . ,. _~ .
, 105 , ....

... ~ .. ~ .

__ ~, -- .
Phenylbutazone 65 ---~. . _ .. . . - .. .. .
Table 9 _ , ~ ~ __ Compound to ~D~o Compound ~o ~ ~0 be Tes~ed (mg /Ic~)- be Tested ( m g/ kg) _ " _____ ................. '._ ~ , 23 2 2 31 1 0 2 . , .. .,~ ~ - _ 1 4 36 . t 3 _ . - . . . ~ ~
22 8 3 16 ~ 2 .. ~_ _ ~ ~ . .. __ , . 21 a O 39 . ~ ~ .
.. ,. -._ ~ .. ~ ~ _ ~ ~
24 4 ~ 37 t 4 1 ~ . _ . _ . ~ ~ . . . ____.
29 ~.3 40 5 1 _~ ~ ~__ 1 6 ~ 6 ~ `

118~7B

~ he inhibitor~ effect for carrageenin-induced foot edema Ln ~ats was observed in each of the CompoundS, Experimental Exam~le 4 10 ddY Strai~ male mice weighing abou~ ~0 g were used in each group. Each compound of this i~ve~tion waS suspended in a 5% aqueou~ gum arabic solution and adminis~ered orally. The mortality rste (%~ was determined from the ~umber of dead arlimal9 7 days after t~e administratior~, and the dosage corre~pondi~g to 50~ mortality was calculated and expressed as ID50 (mg/kg). ~he ~esults are gi~re~ i~ ~ablelO below.

Table 3.0 Acute oral Toxicity in Mice Compound to L X) so be Te s ted, ~ mg / k g ) - -- . , . . ~
2 . ~ ~ O O O
3 . ~ 4 8 8 ~ __ __ ,_ 4 ~ o O O
5-: ~ ~ O D 0, __I_ _ 6 >5~0 0 0 .~ ~
7 ~ 5, 0 0 U
.,. . _ .~ . , , _.__ _ _ 12 ~ ~ O 0 0 ' ~ ~ O O. ~
'.' . - 32 - .

Table 10 ( cont ~ d) ComPound to L D,~.~g / k~) ¦ < n . 23 ~ S,~ 0 0 31 > 510 0 0 _~ ~ ., . _ ,~
2~ ~,4 7 0 36 ~ 5,0 0 ~
___ ~ ~__ 22 ~? 5~0 ~ I 16 ~> ~,0 0 ~
21 ~ 5,0 0 ~ 11 39 ~ 5, 0 0 0 24 > s,a o o ~ 37 ~ 5,0 0 p _ ._ ~ ~_ _ ,.......... ........
28 ~ ~,0 ~ 0 18 ~ 5,0 0 n ~ - ~ ~
29 3,4 4 0 ¦ 40 ~ ~,0 a D
__ _ ~ ~ _ 30 4,7 1 0 . .. ,.. ........ . _ All of the LD50 values of Compounds aIe g.r~ter than ~he levels which show a pahrmaceutical e~fect and thus the co~pounds are o~ sufficient safety.
As evident ~rom the above-described experi~ental exa~ple~, all of the compounds o~ the forrnula (I) according to this inve~-tion have remar~able diure~ic and antiedemic e~ects as well as a mild hypotensitve effe~ Yurther, these compounds ar~ o~
very low toxicity and are adequa~.ely sa~e at ~he dosage at which a phar~.aceuticaL effect is mani~ested. The~efore, the compounds 20 of thi~ invention are not only-usefuL or ~he treatment of hypertensio~ b~-t also extremely useful ~Qr the treatment of edem~L result~ng from the localized rete~tio~l of water a~d electrolytes genera~ed by the Xu~ctional depression o~ the liver, the heart or ~he like or the metabolic disorder.
While the compounds o this anvention are usually a~minis~e~-ed orally or .intraLec~ally, they-can also be administered as an .' ' . I

~i8~7~

injectable composition or as a ~opical composition. The dose of each compound for a human adult is given in Table 11, but this may be out o:~
the exempliied range as appropriate dependi~g on the seve~ity of ~he disease or the administration route, arld on therapeutiC 1 demand.
Table 11 Dose for Treating ~Iuman Adults _ I . - . . , ~
~omp~und Dose (mg/aay~ ¦ Compoun~ Dos;e ~m~/day~
~__ 1~ _~ .
2 2C. ~ 2 9000 1 6 80 - 6 ,000 _ I_ _ 3 5 - 1,000 I .7 80 - 6,000 _~ _ .___ 4 20 - 2,000 12 80 - 6,000 .

. ., . ~ _ lo 5 25 - 29'500 :L3 ~0 - /.~,000 . _ .., ,. ,_ _ 23 ~ 2. 0 0 0 3] û 0~~, 0 0 a _ _ _ .
~ 0 - 2. 0 0 0 1 - 36 _ /1 ~
22 3 0~-2,5 0 0 16 5 0~4,5 0 0 _ ~_ ~_. _ 21 3 0~-2,5 0 0 39 ~ 0~-~,S 0 0 _ .. ~.. ,.. ~.... ." _ _ 24 3 0~~ 2, 5 0 0 37 8 o~ ~ a o o 28 4 0~~,0 a o '18 2 0~2.0 0 0 ____ 29 5~1.0 a 0 1 4O ~0~4,0 0 0 __ _ ~ 34 --~ ~D7~

Generally speaking, peroral or intrarectal administration of 0.02 - 200 mg, in particuiar ~.1 - 100 mg of -the compound per day per one kg of the patient's body weight would be desirable for the purpose of achieving the expected effect. In the general case of an adult a daily administration of 1 to 10 units of a composition containing 5 - 600 mg of the composition according to the present in~ention will suffice. For injection, about the same to 1/10 of the above dosage will have approximately the same effect.
The compounds of this invention may be formulated into pharmaceutical preparations in a conventional manner with conven-tional additives, i.e. a pharmaceutical carrier, base material or excipient.
As the pharmaceutical carrier or the base materia:l, there may be employed lactose, mannitol, corn starch, potato starch etc.
Examples of the excipient which can be used are crystalline cellu-lose, cellulose derivatives, gum arabic, corn starch, gelatin etc.
In addition, a disintegrant such as calcium carboxymethyl cellu-lose and a lubricant such as talc, magnesium stearate etc. as well as polyvinylalcohol etc. may also be employed as the additive. As the liquid carrier when formulated into an injectable composition, there may be employed distilled water for injection, physiological saline, aqueous dextrose, vegetable oils for injection, glycols such as propylene glycol, polyethylene glycol etc.and so forth.
Preferred oral compositions are in the form of capsules, tablets, powders and oral liquid preparations, and preferred in-trarectal compositions are rectal suppositories. The injectable composition i~ preferably a suspension contai~ing a p~a;rmaceutically acceptabae ~sper i~g agent such as Tvve~ 80~ aqueous gum arabic at~.~, and the -topical composition is preferably prese~ted as an o:i~tme~
The amoun t o the active compound o~ the formula ( I ) in the compositio~ is 1 - ~g.,go~ by vveight, preferably 1 - 99.05~o by weight and especially 5 - ?09~ by ~eight.
Thas . ~vention i5 more partic:ularly described by the following examples.

~xamDle 1 Capsules o Compound 2 500 ~actose 485 g Magnesium stearate 15 g 10~0 g-The abol~e components are weighed respectively and mixed together uni~orTnly. Each o~ 500 mg o~ the m~xed powder is filled in~o bard gelatirL capsules ~o. 1 to prepare. capsule~.

~ablets Compound 29 500 g Lac~ose 320 g Potato s~arch 150 g -Pol~rinylalcchol 15 . g Magnesium stearate 15 g 1~00 g The a~ove components are weighed respectively, and Compoand 29, lactose and pota~o starch are mixed toge~her uniformly. To this mixture is added an aqueous solu ion of poly~inylalcohol, and granu}es a~e prepared by a we~ pelletization method. The granules are dried, magnesium stearate is added and compressed on a tabletting machine ~o prepare tablets w~ighing 200 mg each.
Powder Compound 24 100 g Lactose 8gO g o Magnesium stearate 10 g 1000 g The above components are weighed respectively, and mixed together uni~ormly, ~o pre~are a 10% powder.
Suppository Compound 21 100 g Polye~hylene glycol 1500 180 g Polyethylen~ glyool 4000 720 g 10~0 g Compound 21 i~ pulverized on a mortar ~o a fine-powder, and made into a rectal suppository ~y a mel~ing method.

Claims (22)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR PRIVILEGE
IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of compounds of the formula (I) (I) wherein X represents a halogen atom and Y represents a hydrogen atom, a straight-chain or branched-chain alkyl group, a halogen-substituted lower alkyl group, a phenylalkyl group, a phenylalkenyl group, an unsubstituted or halogen-substituted phenyl group, a nitrogen-containing aromatic group, a straight-chain or branched-chain alkoxy group or an alkyl-substituted or phenyl-substituted amino group, which comprises when a compound of the formula (I) is required wherein Y is Y' and represents a hydrogen atom, a straight-chain or branched-chain alkyl group, a halogen-substituted lower alkyl group, a phenylalkyl group, a phenylalkenyl group, an unsubstituted or halogen-substituted phenyl group or a nitrogen-containing aromatic group and X
represents a halogen atom; which comprises reacting a 6-halogen-substituted-4-oxo-1,2,3,4-tetrahydroquinoline of the formula:

or an alkali metal amide thereof, wherein X is as defined above and Z
represents a hydrogen atom or an alkali metal atom; with a reactive derivative of a carboxylic acid of the formula:

(Y'CO)nA

wherein Y' is as defined above, A represents -Cl, -Br or -O- and n represents 2 when A is -O- or 1 when A is -Cl or -Br; in an organic solvent, to produce an N-substituted-6-halogen-substituted-4-oxo-1,2,3,4-tetrahydroquinoline derivative of the formula:

wherein X and Y' are as defined above, and subsequently heating the resulting derivative with hydroxylamine hydrochloride in an organic solvent; when a compound of formula (I) is required wherein Y is NHR' and X represents halogen atom and R' represents an alkyl group or a phenyl group; introducing phosgene gas into a 6-halogen-substituted 4-oxo-1,2,3,4-tetrahydroquinoline of the formula:

wherein X is as defined above; in the presence of an organic solvent and, if desired, adding dropwise an organic base to convert the quinoline compound into the 6-halogen-substituted-4-oxo-1-chloroformyl-1,2,3,4-tetrahydro-quinoline, reacting thus obtained product with an amine of the formula:

wherein R' represents an alkyl group or a phenyl group and R" represents a hydrogen atom or the same meaning as assigned to R'; to produce an N-substituted-6-halogen-substituted-4-oxo-1,2,3,4,-tetrahydroquinoline derivative of the formula:

wherein X, R' and R" are as defined above, and subsequently heating the resulting derivative with hydroxylamine hydrochloride in an organic solvent;
and when a compound of the formula (I) is required wherein Y is -O-R and R
represents a straight-chain or branched-chain alkyl group and X represents a halogen atom; reacting a 6-halogen-substituted-4-oxo-1,2,3,4,-tetrahydro-quinoline derivative of the formula:

or an alkali metal amide thereof, wherein X is as defined above and Z
represents a hydrogen atom or an alkali metal atom; with a chloroformate of the formula:

ROCOCl wherein R is as defined above; in an organic solvent, to produce an N-substituted-6-halogen-substituted-4-oxo-1,2,3,4-tetrahydroquinoline derivative of the formula:

wherein X and R are as defined above, and subsequently heating the resulting derivative with hydroxylamine hydrochloride in an organic solvent.

2. A process for producing a 4-oximino-1,2,3,4-tetrahydroquinoline derivative of the formula (Id):

(Id) wherein Y' represents a hydrogen atom, a straight-chain or branched-chain alkyl group, a halogen-substituted lower alkyl group, a phenylalkyl group, a phenylalkenyl group, an unsubstituted or halogen-substituted phenyl group or a nitrogen-containing aromatic group and X represents a halogen atom; which comprises reacting a 6-halogen-substituted-4-oxo-1,2,3,4-tetrahydroquinoline of the formula:

or an alkali metal amide thereof, wherein X is as defined above and Z
represents a hydrogen atom or an alkali metal atom; with a reactive derivative of a carboxylic acid of the formula:

(Y'CO)nA

wherein Y' is as defined above, A represents -Cl, -Br or -O- and n represents 2 when A is -O- or 1 when A is -Cl or -Br; in an organic solvent, to produce an N-substituted-6-halogen-substituted-4-oxo-1,2,3,4-tetrahydroquinoline derivative of the formula:

wherein X and Y' are as defined above, and subsequently heating the resulting derivative with hydroxylamine hydrochloride in an organic solvent.

3. A process for producing a 4-oximino-1,2,3,4-tetrahydroquinoline derivative of the formula (Ie):

(Ie) wherein X represents halogen atom and R' represents an alkyl group or a phenyl group and R" represents a hydrogen atom or the same as assigned to R', which comprises introducing phosgene gas into a 6-halogen-substituted 4-oxo-1,2,3,4-tetrahydroquinoline of the formula:

wherein X is as defined above, in the presence of an organic solvent, and if desired, adding dropwise an organic base to convert the quinoline compound into the 6-halogen-substituted-4-oxo-1-chloroformyl-1,2,3,4-tetrahydro-quinoline, reacting thus obtained product with an amine of the formula wherein R' represents an alkyl group or a phenyl group and R" represents a hydrogen atom or the same meaning as assigned to R'; to produce an N-substituted-6-halogen-substituted-4-oxo-1,2,3,4-tetrahydroquinoline derivative of the formula:

wherein X, R' and R" are as defined above, and subsequently heating the resulting derivative with hydroxylamine hydrochloride in an organic solvent.

4. A process for producing a 4-oximino-1,2,3,4-tetrahydroquinoline derivative of the formula (Ic):

(Ic) wherein R represents a straight-chain or branched-chain alkyl group and X
represents a halogen atom; which comprises reacting a 6-halogen-substituted-4-oxo-1,2,3,4-tetrahydroquinoline derivative of the formula:

or an alkali metal amide thereof, wherein X is as defined above and Z
represents a hydrogen atom or an alkali metal atom; with a chloroformate of the formula:

ROCOCl wherein R is as defined above; in an organic solvent, to produce an N-substituted-6-halogen-substituted-4-oxo-1,2,3,4-tetrahydroquinoline derivative of the formula:

wherein X and R are as defined above, and subsequently heating the resulting derivative with hydroxylamine hydrochloride in an organic solvent.

5. A process as claimed in claim 1 for the preparation of compounds of the formula (I) wherein X is chloro, fluoro or bromo and Y is selected such that the combined group is formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, trimethylacetyl, hexanoyl, heptanoyl, octanoyl, phenylacetyl, cinnamoyl, trifluoroacetyl, nicotinyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, phenylcarbamoyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, benzoyl or 2,4-dichlorobenzoyl wherein the reactants are chosen such that X has the values given above, Z is as defined in claim 1, Y' is chosen so that in combination with CO it has the meanings given above for Y and n, A, R, R' and R" are as defined in claim 1.

6. A process for the preparation of 6-chloro-4-oximino-1-propionyl-1,2,3,4-tetrahydroquinoline which comprises reacting 6-chloro-4-oxo-1,2,3,4-tetrahydroquinoline, pyridine, dioxane and propionyl chloride to obtain 6-chloro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline which is then converted by reaction in ethanol, hydroxylamine hydrochloride and pyridine to the title compound.

7. A process for the preparation of 6-chloro-4-oximino-1-methoxy-carbonyl-1,2,3,4-tetrahydroquinoline which comprises reacting 6-chloro-4-oxo-1,2,3,4-tetrahydroquinoline, pyridine, dioxane and methyl chloroformate to obtain 6-chloro-4-oxo-1-methoxycarbonyl-1,2,3,4-tetrahydroquinoline which is then reacted with ethanol, hydroxylamine hydrochloride and pyridine to obtain the title compound.

8. A process for the preparation of 6-bromo-4-oximino-1-methoxycarbonyl-1,2,3,4-tetrahydroquinoline which comprises reacting 6-bromo-4-oxo-1,2,3,4-tetrahydroquinoline, pyridine, dioxane and methyl chloroformate to obtain 6-bromo-4-oxo-1-methoxycarbonyl-1,2,3,4-tetrahydroquinoline which is then reacted with ethanol, hydroxylamine hydrochloride and pyridine to obtain the title compound.

9. A process for the preparation of 6-fluoro-4-oximino-1-methoxy-carbonyl-1,2,3,4-tetrahydroquinoline which comprises reacting 6-fluoro-4-oxo-1,2,3,4-tetrahydroquinoline, pyridine, dioxane and methyl chloroformate to obtain 6-fluoro-4-oxo-1-methoxycarbonyl-1,2,3,4-tetrahydroquinoline which is then reacted with ethanol, hydroxylamine hydrochloride and pyridine to obtain the title compound.

10. A process for the preparation of 6-fluoro-4-oximino-1-propionyl-1,2,3,4-tetrahydroquinoline which comprises reacting 6-fluoro-4-oxo-1,2,3,4-tetrahydroquinoline, pyridine, dioxane and propionyl chloride to obtain 6-fluoro-4-oxo-1-propionyl-1,2,3,4-tetrahydroguinoline which is then reacted with ethanol, hydroxylamine hydrochloride and pyridine to obtain the title compound.

11. A process for the preparation of 6-bromo-4-oximino-1-propionyl-1,2,3,4-tetrahydroquinoline which comprises reacting 6-bromo-4-oxo-1,2,3,4-tetrahydroquinoline, pyridine, dioxane and propionyl chloride to obtain 6-bromo-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline which is then reacted with ethanol, hydroxylamine hydrochloride and pyridine to obtain the title compound.

12. Compounds of the formula (I) as defined in claim 1 whenever prepared by the process of claim 1 or an obvious chemical equivalent thereof.

13. Compounds of the formula (Id) as defined in claim 2 whenever prepared by the process of claim 2 or an obvious chemical equivalent thereof.

14. Compounds of the formula (Ie) as defined in claim 3 whenever prepared by the process of claim 3 or an obvious chemical equivalent thereof.

15. Compounds of the formula (Ic) as defined in claim 4 whenever prepared by the process of claim 4 or an obvious chemical equivalent thereof.

16. Compounds of the formula (I) as defined in claim 5 whenever prepared by the process of claim 5 or an obvious chemical equivalent thereof.

17. 6-Chloro-4-oximino-1-propionyl-1,2,3,4-tetrahydroquinoline whenever prepared by the process of claim 6 or an obvious chemical equivalent thereof.

18. 6-Chloro-4-oximino-1-methoxycarbonyl-1,2,3,4-tetrahydroquinoline whenever prepared by the process of claim 7 or an obvious chemical equivalent thereof.

19. 6-Bromo-4-oximino-1-methoxycarbonyl-1,2,3,4-tetrahydroquinoline whenever prepared by the process of claim 8 or an obvious chemical equivalent thereof.

20. 6-Fluoro-4-oximino-1-methoxycarbonyl-1,2,3,4-tetrahydroquinoline whenever prepared by the process of claim 9 or an obvious chemical equivalent thereof.

21. 6-Fluoro-4-oximino-1-propionyl-1,2,3,4-tetrahydroquinoline whenever prepared by the process of claim 10 or an obvious chemical equivalent thereof.

22. 6-Bromo-4-oximino-1-propionyl- 1,2,3,4-tetrahydroquinoline whenever prepared by the process of claim 11 or an obvious chemical equivalent thereof.