GB2092130A - 4-Oximino-1,2,3,4- tetrahydroquinoline Derivatives - Google Patents
4-Oximino-1,2,3,4- tetrahydroquinoline Derivatives Download PDFInfo
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- GB2092130A GB2092130A GB8120931A GB8120931A GB2092130A GB 2092130 A GB2092130 A GB 2092130A GB 8120931 A GB8120931 A GB 8120931A GB 8120931 A GB8120931 A GB 8120931A GB 2092130 A GB2092130 A GB 2092130A
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- tetrahydroquinoline
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
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Abstract
A 4-oximino-1,2,3,4- tetrahydroquinoline derivatives of the formula (I): <IMAGE> 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. These compounds have anti- oedemic, diuretic and hypotensive effects.
Description
SPECIFICATION 4oxi mino- 1 ,2,3,4tetrn hydroquinol ine Derivatives 1. Field of the Invention
This invention relates to a novel 4-oximino-l ,2,3,4-tetrahydroquinoline derivative having antiedemic, diuretic and hypotensive effects.
2. Description of the Prior Art
Extensive researches has been continued for developing efficient antiphlogistic analgesics which are neutral or basic and therefor do not cause gastrointestinal disorders, ever since non-steroid antiinflammatory agents, particulariy acidic non-steroid anti-inflammatory agents had been found to cause severe gastrointestinal disorders.
The present inventors, after many years of research, have found a novel 4-oximino-1,2,3,4tetrahydroquinoline derivative which exhibits strong antiedemic, diuretic and hypotensive effects without causing appreciable gastrointestinal disorders, thus achieving this invention.
Summary of the Invention
Accordingly, this invention provides a novel 4-oximino-l ,2,3,4-tetrahydroquinoline derivative of the general formula:
wherein X represents a halogen atom and Y represents a hydrogen atom, a straight-chain or branchedchain 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.
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 by a known method, such as a method described in J. Medicinal Chem., 8, 566571, as follows:
A p-halogen-substituted aniline of the formula:
wherein X represents a halogen atom; and an acrylic acid ester of the formula:
CH2=CHCOOR wherein R is an ester forming 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 halogen-substituted phenylamino)propionic acid ester of the formula:
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 or xylene etc., whereby a 6-halogen-substituted-4-oxo-1 ,2,3,4- tetrahvdroauinoline of the formula::
Alternatively, p-propiolactone is condensed with a p-halogen-substituted aniline with or without a Lewis acid catalyst such as zinc chloride, or aluminum chloride in the presence of a solvent such as acetonitrile, to produce a 3-(p-halogen-substituted phenylamino)propionic acid, which is then cyclized with dehydration using phosphorus pentoxide, polyphosphoric acid 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- ,2,3,4-tetrahydroquinoline can be obtained as the intermediate.
Thereafter, in order to effect the N-acylation of the above-obtained intermediate, 6-halogen substituted-4-oxo-l ,2,3,4-tetrahydroquinoline, it 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:: (Y'CO),A wherein Y' represents a hydrogen atom, a straight-chain or branched-chain alkyl group, a halogensubstituted lower alkyl group, a phenylalkyl group, a phenylalkenyl group, an unsubstituted or halogensubstituted phenyl group or a nitrogen-containing aromatic group, A represents -01,-Br; or --OO-, and n represents 2 when A is --OO- or 1 when A is-Cl or -Br; in the presence of an organic base such as triethylamine, pyridine etc. in a solvent such as ether, tetrahydrofuran, dioxane, chloroform, benzene etc., to obtain an N-substituted-6-halogen-substituted-4-oxo- 1 ,2,3,4-tetrahydroquinoline derivative of the formula:
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-i ,2,3,4- tetrahydroquinoline derivatives.
In order to introduce a carbamoyl group in said intermediate, phosgene gas is passed into said
intermediate in the presence of a solvent such as tetrahydrofuran dioxa e, ether, chloroform, etc. or, after the introduction of phosgene gas, an organic base such as triethylamine, pyridine etc. is added dropwise to the mixture to give a 6-halogen-substituted-4-oxo-i -chloroformyl-i 2,3,4- tetrahydroquinoline, which product is then reacted 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 obtain a N-substituted-6-haiogen-substituted-4-ox ,2,3,4- tetrahydroquinoline derivative of the formula:
wherein X represents a halogen atom and R' and R" are as defined above.
When N-alkoxycarbonylation of the above-described intermediate is desired, this is reacted with a chloroformate of the formula:
ROCOCI 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, dichloromethane, chloroform, benzene etc., to obtain a N-substituted-6-halogen-substituted-4-oxo- 1 2,3,4- tetrahydroquinoline derivative of the formula:
wherein X represents a halogen atom and R is as defined above.
Alternatively, it is also possible to react said chloroformate with an alkali metal amide (e.g.
sodium potassium or lithium amide 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, pyridinetetrahydrofuran, pyridine-dioxane, and triethanolamine-alcohol, thereby the N-substituted-6-halogen substituted-4-oximino-1 ,2,3,4-tetrahydrnquinoline derivative of this invention may be obtained.
The term "halogen atom" as used herein means a chlorine atom, a bromine atom or a fluorine atom.
The thus obtained compounds according to this invention which are represented by the general formula I have strong antiedemic, diuretic and hypotensive effects and cause little gastrointestinal disorder; they are, therefore, excellent as pharmaceutical drugs.
Accordingly, the compounds of this invention may be formulated into pharmaceutical products, either alone or in combination with other pharmacologically active compounds, and if desired, also with binding agents, fillers, flavors, etc. commonly employed in the pharmaceutical field in a suitable conventional manner.
This invention is illustrated by the following examples, in which the parts and % represent parts by weight and % by weight respectively.
Example 1
Synthesis of 6-chlorn-4oximino-I -formyl-I ,2,3,4tetrehydroquinoline 18.16 parts of 6-chloro-4-oxo-1 ,2,3,4-tetrahydroquinoline and 150 parts of formic acid (purity of 98% or higher) 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 precipitated 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 1 5.0 parts of hydroxylamine hydrochloride and 1 7.0 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-l -formyl-1,2,3,4- tetrahydroquinoline as white crystals.
This product showed a melting point of 1 92-1 930C when measured by the method specified in the Japanese Pharmacopeia, and the results of its elemental analysis were as follows:
Elemental Analysis:
C H CI N
Calculated: 53.45 4.01 15.81 12.47
Found: 53.41 4.00 15.79 12.50
Example 2
Synthesis of 6-chloro-oximinoI -acetyl-I ,2,3,4-tetrahydroquinoline 18.16 parts of 6-chloro-4-oxo-l ,2,3,4-tetrahydroquinoline and 11.23 parts of acetic anhydride were mixed and reacted at 900C 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-1,2,3,4tetrahydroquinoline.
Then, the above product was dissolved in 300 ml of ethanol, to which were added 1 5.64 parts of hydroxylamine hydrochloride and 1 7.8 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-4oximino-1 -acetyl-1 ,2,3,4-tetrahydroquinoline as white crystals.
This product showed a melting point of 214--21 5.50C 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: 55.35 4.61 14.88 11.74
Found: 55.40 4.65 14.85 11.71
Example 3
Synthesis of 6-chloro-4-oximino-I -propionyl1 ,2,3,4-tetrahydroquinoline 18.16 parts of 6-chloro-4-oxo-1 ,2,3,4-tetrahydroquinoline, 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--5 0 C. After addition, the reaction was conducted at room temperature for 5 hours.
The reaction mixture was poured into one liter of water, the precipitated cystals were filtered out, washed with water and then with petroleum ether, and dried to obtain 20.4 parts of 6-chloro-4-oxo-1 propionyl-1 ,2,3,4-tetrahydroquinoline.
Thereafter, the above product was converted to the oxime as in Example 1 thereby obtaining 20.6 parts of white 6-chloro-4-oximino-1 -propionyl-1 ,2,3,4-tetrahydroquinoline.This product showed a melting point of 1 66-1 690C when measured by the method specified in the Japanese
Pharmacopeia, and the results of its elemental analysis were as follows:
Elemental Analysis
C H C/ N
Calculated: 57.03 5.15 14.06 11.09
Found: 56.98 5.09 14.01 11.10
Example 4--15 In each example, the desired product was obtained by the method described in Example 3, except that the propion 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-I -methylcarbamoyl-I ,2,3,4-tetrahydroquinoline a) 54.5 parts of 6-chloro-4-oxo-1 ,2,3,4-tetrahydroquinoline 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 20-250C. After the introduction, the temperature was raised gradually, and the reaction was effected at 40-450Cfor 2.5 hours, after which the temperature was further raised to 700C, 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 70.3 parts of 6-chloro-4-oxo-1 -chloro-formyl-1 ,2,3,4-tetrahydroquinoline (m.p. 114- 116"C).
b) 2.6 Parts of the above product was dissolved in 30 ml of dioxane, and this solution was added dropwise to 10 ml of dioxane solution containing 1.0 part of monomethylamine in while maintaining 0--5 0 C. After the addition, stirring was conducted at room temperature for 4 hours.
The reaction mixture was poured into water, and the precipitated 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 added 2.0 parts of hydroxylamine hydrochloride and 2.2 parts of pyridine, and 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 211-21 20C when measured by the method specified in the Japanese
Pharmacopeia, and the results of its elemental analysis were as follows:
Elemental Analysis:
C H CI N
Calculated: 52.07 4.73 14.00 16.57
Found: 52.05 4.75 13.97 16.49
Examples 17-19 In each example, the 6-chloro-4-oxo-1 -chloroformyl-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 1 6 was replaced by the corresponding amine or aniline, to obtain the desired product.The properties of the products are given in Table 1 below.
Table 1
Example Melting
No. Compound Appearance point ( C) 4 6-Chloro-4-oximino-1-butyryl-1,2,3,4-tetrahydroquinoline White crystal 141-142 5 6-Chloro-4-oximino-1-isobutyryl-1,2,3,4-tetrahydroquinoline White crystal 185-186 6 6-Chloro-4-oximino-1-valeryl-1,2,3,4-tetrahydroquinoline White crystal 118-120 7 6-Chloro-4-oximino-1-isovalerylacetyl-1,2,3,4-tetrahydroquinoline White crystal 142-143 8 6-Chloro-4-oximino-1-trimethylacetyl-1,2,3,4-tetrahydroquinoline White crystal 204-208 9 6-Chloro-4-oximino-1-hexanoyl-1,2,3,4-tetrahydroquinoline White crystal 153-154 10 6-Chloro-4-oximino-1-heptanoyl-1,2,3,4-tetrahydroquinoline White crystal 156-158 11 6-Chloro-4-oximino-1-octanoyl-1,2,3,4-tetrahydroquinoline White crystal 147-149 12 6-Chloro-4-oximino-1-phenylacetyl-1,2,3,4-tetrahydroquinoline White crystal 181-183 13 6-Chloro-4-oximino-1-cinnamoyl-1,2,3,4-tetrahydroquinoline White crystal 216-217 14 6-Chloro-4-oximino-1-trifluoroacetyl-1,2,3,4-tetrahydroquinoline White crystal 158-159 15 6-Chloro-4-oximino-1-nicotinyl-1,2,3,4-tetrahydroquinoline White crystal 227-228 17 6-Chloro-4-oximino-1-ethylcarbamoyl-1,2,3,4-tetrahydroquinoline White crystal 183-184 18 6-Chloro-4-oximino-1-dimethylcarbamoyl-1,2,3,4-tetrahydroquinoline White crystal 150-152 19 6-Chloro-4-oximino-1-phenylcarbamoyl-1,2,3,4-tetrahydroquinoline White crystal 182.5-183.5 Example 20
18.16 Parts of 6-chloro-4-oxo-l ,2,3,4-tetrahydroquinoline, 10.3 parts of pyridine and 100 ml of 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--50C. 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-l ,2,3,4-tetrahydroquinoline.
Thereafter, the above product was dissolved in 330 ml of ethanol, to which were added 1 5.0 parts of hydroxylamine hydrochloride and 17.0 parts of pyridine, and the reaction was conducted 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 1 9.9 parts of white crystals of 6-chloro-4-oximino-1 methoxycarbonyl-1 ,2,3,4-tetrahydroquinoline. The product showed a melting point of 162-1 630C when measured by the method specified in the Japanese Pharmacopeia, and the results of its elemental analysis were as follows:
Elemental Analysis:
C H CI N
Calculated: 51.87 4.32 13.95 11.00
Found: 51.85 4.35 13.88 11.02
Example 21
16.51 parts of 6-fluoro-4-oxo-l ,2,3,4-tetrahydroquinoline, 10.3 parts of pyridine and 100 ml of dichloromethane were mixed, and 14.2 parts of ethyl chloroformate was added dropwise to the mixture with stirring while the temperature was maintained at 0--50C. After the addition, the reaction was conducted at room temperature for 5 hours.
500 ml of cold water was poured into the reaction mixture, and the layers were separated. The organic phase was washed once with 100 ml of 1 N aqueous hydrochloric acid and then twice with 100 ml each of water, and dried over anhydrous Glauber's salt. The solvent (dichloromethane) was distilled off under reduced pressure, and 100 ml of ethanol was added to the residue and heated to dissolve it. After cooling, the precipitated crystals were filtered out, and dried to obtain 20.8 parts of 6fluoro-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 hydrochloride and 1 6.2 parts of pyridine, and the reaction was conducted under reflux for 2 hours. Thereafter, the product was treated similarly as in Example 20 to obtain 20.2 parts of white crystals of 6-fluoro-4-oximino- 1 -ethoxycarbonyl-1 ,2,3 ,4-tetrahydroquinoline.This product showed a melting point of 122-1 240C 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 5.16 7.54 11.11
Found: 57.18 5.18 7.55 11.08
Example 22
Similarly as in Example 20, 6-bromo-4-oxo-1 ,2,3,4-tetrahydroquinoline was reacted with methyl chloroformate and subsequently converted into the oxime thereby obtaining white crystals of 6-bromo4-oximino-1 -methoxycarbonyl-1 ,2,3,4-tetrahydroquinoline. The properties of the product are given in
Table 2 below.
Example 23
Similarly as in Example 21, 6-fluoro-4-oxo-1 ,2,3,4-tetrahydroquinoline was reacted with methyl chloroformate and subsequently converted into the oxime thereby obtaining white 6-fluoro-4-oximino1-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-tetrahydroquinoline was reacted with ethyl chloroformate and subsequently converted into the oxime thereby obtaining 6-chloro-4-oximino-1 ethoxycarbonyl-1 ,2,3,4-tetrahydroquinoline. The properties of the product are given in Table 2.
Example 25
Similarly as in Example 20, 6-chloro-4-oxo-1 ,2,3,4-tetrahydroquinoline was reacted with isopropyl chloroform ate 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-tetrahydroquinoline was reacted with isopropyl chloroformate and subsequently converted to the oxime thereby obtaining the desired 6 bromo-4-oximino-1 -isopropoxycarbonyl-1 ,2,3,4-tetrahydroquinoline. The properties of the product are given in Table 2.
Table 2
Example Melting
No. Compound Appearance point ( C) 22 6-bromo-4-oximino-1-methoxycarbonyl-1,2,3,4-tetrahydroquinoline White crystal 155.5-158.5 23 6-fluoro4-oximino-1-methoxycarbonyl-1,2,3,4-tetrahydroquinoline White crystal 145-148 24 6-chloro-4-oximino-1-ethoxycarbonyl-1,2,3,4-tetrahydroquinoline White crystal 112-113 25 6-chloro-4-oximino-1-isopropoxycarbonyl-1,2,3,4-tetrahydroquinoline White crystal 165.5-167.5 26 6-bromo-4-oximino-1-isopropoxycarbonyl-1,2,3,4-tetrahydroquinoline White crystal 160-162.5 Example 27
Synthesis of 64luoro-4oximino-1 -formyl-1 ,2,3,4-tetrahydroquinoline 16.51 parts of 6-fluoro-4-oxo-1,2,3,4-tetrahydroquinoline and 150 parts of formic acid (purity of 98% or higher) 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 precipitated crystals were filtered out, and dried to obtain 1 6.2 parts of 6-fluoro-4-oxo-1 -formyl-1 2,3,4-tetrahydro- quinoline.
Then, the above product was dissolved in 250 ml of ethanol, to which were added 15.0 parts of hydroxylamine hydrochloride and 17.0 parts of pyridine, and the reaction was conducted 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 melting point of 175.5-1 76.50C 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: 57.69 4.33 9.13 13.46
Found: 57.63 4.30 9.17 13.48
Example 28
Synthesis of 6-bromo-4-oximino-1 -acetyl-1 ,2,3,4-tetrahydroquinoline 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 900C 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-tetra- hydroquinoline.
Then, the above product was dissolved in 350 ml of ethanol, to which were added 14.6 parts of hydroxylamine hydrochloride and 1 6.1 -parts of pyridine, and the reaction was effected 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 ,2,3,4-tetrahydroquinoline.
This product showed a melting point of 200-202.50C when measured by the method specified in the Japanese Pharmacopeia, and the results of the elemental analysis were as follows:
Elemental Analysis:
O H Br N
Calculated: 46.64 3.89 28.27 9.89
Found: 46.67 3.84 28.24 9.92
Example 29
Synthesis of 6-fluoro-4-oximino-l -propiony-l .2.3.4-tetrahydroquinoline 16.51 parts of 6-fluoro-4-oxo-l ,2,3,4-tetrahydroquinoline, 1 1.9 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 maintained at 0--50C.
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 -propionyi-l ,2,3,4-tetrahydroquinoline. This product showed a melting point of 126.5-1 280C when measured by the method specified by the Japanese
Pharmacopeia, and the results of its elemental analysis were as follows:
Elemental Analysis:
C H F N
Calculated: 61.02 5.51 8.05 11.86
Found: 61.04 5.55 8.02 11.82
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-oxim ino-1 -dimethylcarbamoyl-1 ,2,3,4-tetrahydroquinoline
a) 33.0 parts of 6-fluoro-4-oxo-l ,2,3 .4-tetrahydroquinoline 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 20-250C. After the introduction, the temperature was raised
gradually, and the reaction was effected at 40-450C for 2.5 hours, after which the temperature was further raised to 70"C, 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-tetra- hydroquinoline.
b) 2.3 Parts of the above product was dissolved in 30 ml of dioxane, and this solution was added dropwise to 10 ml of dioxane solution containing 1.5 parts of dimethylamine while the temperature was maintained at 0--50C. After the addition, stirring was continued at room temperature for 4 hours.
The reaction mixture was poured into water, and the precipitated 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 2.0 parts of 6-fluoro-4-oxo-1 -dimethylcarbamoyl- 1 ,2 3,4-tetra hydro- quinoline. This product was dissolved in 30 ml of ethanol, to which were added 1.8 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-tetrahydroquinoline. This product showed a melting of 147-1 49.50C 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: 57.37 5.58 7.57 16.73
Found: 57.34 5.53 7.56 16.78
Example 38
The 6-fluoro-4-oxo-l -chloroformyl-l ,2,3,4-tetrahydroquinoline obtained in Example 37a) was treated similarly as in Example 37b) 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-l -methylcarbamoyl-l ,2,3.4-tetrahydroquinoline a) 45.2 Parts of 6-bromo-4-oxo-1,2,3,4-tetrahydroquinoline and 200 parts of dioxane were mixed, and 39.4 parts of phosgene was introduced to the stirred mixture while the temperature was maintained at 20-250C over about 30 minutes. After the introduction, the reaction was effected at 40--45 OC for 2.5 hours, and thereafter the mixture was treated as in Example 37a) 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--50C. After the addition, stirring was continued at room temperature for 4 hours, and thereafter the mixture was treated as in Example 37b) to obtain 2.4 parts of 6-bromo-4-oxo- 1 -methylcarbamoyl- 1 2,3,4-tetra hydroquinoline.
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-tetrahydro- quinoline. This product showed a melting point of 206.50C (dec.) when measured by the method specified in the Japanese Pharmacopeia, and the results of its elemental analysis were as follows:
Elemental Analysis:
C H Br N
Calculated: 44.30 4.03 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-tetrahydroquinoline obtained in Example 39a) was treated similarly as in Example 39b) except that the monomethylamine was replaced by dimethylamine, to obtain the desired product. The properties of the product are given in Table 3. Table 3
Example Melting
No.Compound Appearance point ( C) 30 6-bromo-4-oximino-1-propionyl-1,2,3,4-tetrahydroquinoline White crystal 151.5-152.5 31 6-bromo-4-oximino-1-isoutyryl-1,2,3,4-tetrahydroquinoline White crystal 195-197 32 6-fluoro-4-oximino-1-trimethylacetyl-1,2,3,4-tetrahydroquinoline White crystal 211-212.5 33 6-bromo-4-oximino-1-hexenoyl-1,2,3,4-tetrahydroquinoline White crystal 208.5-210.5 34 6-bromo-4-oximino-1-benzoyl-1,2,3,4-tetrahydroquinoline White crystal 185.5-187.5 35 6-bromo-4-oximino-1-(2,4-dichlorobenzoyl)-1,2,3,4-tetrahydroquinoline White crystal 178.5-181.5 36 6-bromo-4-oximino-1-cinnamoyl-1,2,3,4-tetrahydroquinoline White crystal 208.5-210.5 38 6-fluoro-4-oximino-1-phenylcarbamoyl-1,2,3,4-tetrahydroquinoline White crystal 195.5(dec.) 40 6-bromo-4-oximino-1-dimethylcarbamoyl-1,2,3,4-tetrahydroquinoline White crystal 113-115 The compounds of this invention have strong antiedemic, diuretic and hypotensive effects and further hardly cause gastrointestinal disorder. By way of example, when the diuretic effect of the compounds obtained in Examples 3, 20, 23, 29 and 30 were tested in rats, each showed a diuretic effect about 4 times stronger as that of furosemide which was the control agent. Further, it was confirmed that their toxicity was negligible at dosages commonly employed in medical treatment.
Claims (9)
1. A 4-oximino-1 ,2,3,4-tetrahydroquinoline derivative of the formula (I):
wherein X represents a halogen atom and Y represents a hydrogen atom, a straight-chain or branchedchain 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 straightchain or branched-chain alkoxy group or an alkyl-substituted or phenyl-substituted amino group.
2. A 4-oximino-1 ,2,3,4-tetrahydroquinoline derivative according to Claim 1 which is of the formula (la):
wherein Y1 represents a hydrogen atom, a straight-chain or branched-chain alkyl group, a halogensubstituted lower alkyl group, a phenyl-substituted lower alkyl group, a phenylalkenyl group, a nitrogen-containing aromatic group or an alkyl-substituted or phenyl-substituted amino group.
3. A 4-oximino- 1 ,2,3,4-tetrahydroquinoline derivative according to Claim 1 which is of the formula (Ib):
wherein Y2 represents a hydrogen atom, a straight-chain or branched-chain alkyl group, a phenylalkenyl group, an unsubstituted or halogen-substituted phenyl group or an alkyl-substituted or phenyl-substituted amino group and X represents a fluorine atom or a bromine atom.
4. A 4-oximino-1 ,2,3,4-tetrahydroquinoline derivative according to Claim 1 which is of the formula (Ic):
wherein R represents a straight-chain or branched-chain alkyl group and X represents a fluorine atom, a chlorine atom or a bromine atom.
5. A 4-oximino-1 ,2,3,4-tetrahydroquinoline derivative according to Claim 1 which is 6-chloro-4 oximino-1 -propionyl-1 ,2,3,4-tetrahydroquinoline, 6-chloro-4-oximino-1 -methoxycarbonyl-1 ,2,3,4- tetrahydroquinoline,6-fluoro-4-oximino-1-methoxycarbonyl-1,2,3,4-tetrahydroquinoline. 6-fluoro-4 oximino-1 -propionyl-1 ,2,3,4-tetrahydroquinoline or 6-bromo-4-oximino-1 -propionyl-1,2,3,4- tetrahydroquinoline.
6. A process for producing a 4-oximino-1 ,2,3,4-tetrahydroquinoline derivative of the formula (Id):
wherein Y' represents a hydrogen atom, a straight-chain or branched-chain alkyl group, a halogensubstituted lower alkyl group, a phenylalkyl group, a phenylalkenyl group, an unsubstituted or halogensubstituted 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 -01,-Br or -0- and n represents 2 when A is -0- 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.
7. A process for producing a 4-oximino-1 ,2,3,4-tetrahydroquinoline derivative of the formula (le):
wherein X represents halogen atom and R' represents an alkyl group or a phenyl group and R1, 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 -chloroformyl1 ,2,3,4-tetrahydroquinoline, 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-tetra- hydroquinoline 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.
8. A process for producing a 4-oximino-1 ,2,3,4-tetrahydroquinoline derivative of the formula (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;epresents a hydrogen atom or an alkali metal atom; with a chloroformate of the formula:
ROCOCI 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.
9. A process for producing 4-oximino-1 ,2,3,4-tetrahydroquinoline derivatives as claimed in anyone of claims 6 to 8 and substantially as described in anyone of the specific examples hereinbefore set forth.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10327280A JPS5728052A (en) | 1980-07-28 | 1980-07-28 | Novel 4-hydroxyimino-1,2,3,4-tetrahydroquinoline derivative |
| JP3991081A JPS57154168A (en) | 1981-03-19 | 1981-03-19 | Novel 4-oximino-1,2,3,4-tetrahydroquinoline derivative |
| JP3991181A JPS57154169A (en) | 1981-03-19 | 1981-03-19 | Novel 4-oximino-1,2,3,4-tetrahydroquinoline derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2092130A true GB2092130A (en) | 1982-08-11 |
| GB2092130B GB2092130B (en) | 1984-05-10 |
Family
ID=27290305
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8120931A Expired GB2092130B (en) | 1980-07-28 | 1981-07-07 | 4-oximino-1,2,3,4-tetrahydroquinoline derivatives |
Country Status (3)
| Country | Link |
|---|---|
| DE (1) | DE3129718A1 (en) |
| FR (1) | FR2487346A1 (en) |
| GB (1) | GB2092130B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1851739A2 (en) * | 2004-12-29 | 2007-11-07 | Naturon, Inc. | Xanthurenic acid derivative pharmaceutical compositoins and methods related thereto |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2552430B1 (en) * | 1983-09-22 | 1985-10-25 | Rhone Poulenc Sante | PROCESS FOR THE PREPARATION OF QUINOLINONES-4 |
| JPS6160682A (en) * | 1984-08-30 | 1986-03-28 | Nippon Tokushu Noyaku Seizo Kk | Tetrahydroquinolin-1-ylcarbonylimidazole derivative, its intermediate, its production, herbicide, agricultural and horticultural fungicide |
| US4839368A (en) * | 1986-05-02 | 1989-06-13 | Mochida Pharmaceutical Co., Ltd. | 1-acyl-2,3-dihydro-4(1H)-quinolinone-4-oxime derivatives |
| JP2602037B2 (en) * | 1987-10-31 | 1997-04-23 | 持田製薬株式会社 | 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime derivatives, process for preparing the same, and pharmaceutical compositions containing diuretic, antihypertensive, anti-edema and ascites removal based on them |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3075984A (en) * | 1958-05-09 | 1963-01-29 | Sterling Drug Inc | 1-[(lower-aromatic)-(lower-alkyl)]-4-[(lower-aromatic)-(lower-alkyl) imino]-1, 4-dihydroquinolines and their preparation |
| US3406176A (en) * | 1964-08-24 | 1968-10-15 | Sterling Drug Inc | 7-halo-4-carbamylimino-1, 4-dihydroquinolines |
-
1981
- 1981-07-07 GB GB8120931A patent/GB2092130B/en not_active Expired
- 1981-07-24 FR FR8114436A patent/FR2487346A1/en active Granted
- 1981-07-28 DE DE19813129718 patent/DE3129718A1/en active Granted
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1851739A2 (en) * | 2004-12-29 | 2007-11-07 | Naturon, Inc. | Xanthurenic acid derivative pharmaceutical compositoins and methods related thereto |
| EP1851739A4 (en) * | 2004-12-29 | 2012-08-29 | Naturon Inc | Xanthurenic acid derivative pharmaceutical compositoins and methods related thereto |
| US8361734B2 (en) | 2004-12-29 | 2013-01-29 | Naturon, Inc. | Xanthurenic acid derivative pharmaceutical compositions and methods related thereto |
| US8697674B2 (en) | 2004-12-29 | 2014-04-15 | Naturon, Inc. | Xanthurenic acid derivative pharmaceutical compositions and methods related thereto |
| EP3379506A1 (en) * | 2004-12-29 | 2018-09-26 | Naturon, Inc. | Xanthurenic acid derivative pharmaceutical compositions and methods related thereto |
| US10370335B2 (en) | 2004-12-29 | 2019-08-06 | Naturon, Inc. | Xanthurenic acid derivative pharmaceutical compositions and methods related thereto |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2487346A1 (en) | 1982-01-29 |
| DE3129718C2 (en) | 1988-08-18 |
| GB2092130B (en) | 1984-05-10 |
| FR2487346B1 (en) | 1984-12-28 |
| DE3129718A1 (en) | 1982-04-15 |
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