248282-01-1

Usage

Uses

Used in Pharmaceutical Industry:
Paquinimod is used as an anti-inflammatory agent for reducing pathology in experimental collagenase-induced osteoarthritis (CIOA). It has been shown to significantly reduce synovial thickening, osteophyte size, and cartilage damage in affected areas.
Additionally, Paquinimod is used as an immunomodulator for reducing leukocyte recruitment during sterile inflammation. It has demonstrated the ability to decrease the priming of proinflammatory effector CD4(+) T cells, which can contribute to a more balanced immune response in certain conditions.

InChI:InChI=1/C21H22N2O3/c1-4-14-10-9-13-16-17(14)19(24)18(20(25)22(16)3)21(26)23(5-2)15-11-7-6-8-12-15/h6-13,24H,4-5H2,1-3H3

Synthetic route

1,2-dihydro-4-hydroxy-5-ethyl-1-methyl-2-oxo-quinoline-3-carboxylic acid methyl ester (1354639-60-3) + N-ethyl-N-phenylamine (103-69-5) → N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-ethyl-1-methyl-2-oxo-quinoline-3-carboxamide (248282-01-1)

Conditions	Yield
In n-heptane for 2h; Product distribution / selectivity; Reflux; Molecular sieve;	93%

N-ethyl-N-phenylamine (103-69-5) + 5-ethyl-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid → N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-ethyl-1-methyl-2-oxo-quinoline-3-carboxamide (248282-01-1)

Conditions	Yield
With thionyl chloride; triethylamine In dichloromethane at 0 - 20℃; for 4.5h;

5-ethyl-1H-benzo[d][1,3]oxazine-2,4-dione (34934-06-0) → N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-ethyl-1-methyl-2-oxo-quinoline-3-carboxamide (248282-01-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: NaH / dimethylformamide / 5 h / 20 °C 2: NaH / dimethylformamide / 5 h / 85 °C 3: HCl / acetic acid / 6 h / 60 °C 4: SOCl2; Et3N / CH2Cl2 / 4.5 h / 0 - 20 °C View Scheme
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide 2: sodium methylate / N,N-dimethyl-formamide 3: n-heptane / 2 h / Reflux; Molecular sieve View Scheme

6-ethyl-anthranilic acid (66232-56-2) → N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-ethyl-1-methyl-2-oxo-quinoline-3-carboxamide (248282-01-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: dioxane / 1 h / 20 °C 2: NaH / dimethylformamide / 5 h / 20 °C 3: NaH / dimethylformamide / 5 h / 85 °C 4: HCl / acetic acid / 6 h / 60 °C 5: SOCl2; Et3N / CH2Cl2 / 4.5 h / 0 - 20 °C View Scheme
Multi-step reaction with 4 steps 1: chloroformic acid ethyl ester / 1,4-dioxane 2: potassium carbonate / N,N-dimethyl-formamide 3: sodium methylate / N,N-dimethyl-formamide 4: n-heptane / 2 h / Reflux; Molecular sieve View Scheme

5-ethyl-1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione → N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-ethyl-1-methyl-2-oxo-quinoline-3-carboxamide (248282-01-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: NaH / dimethylformamide / 5 h / 85 °C 2: HCl / acetic acid / 6 h / 60 °C 3: SOCl2; Et3N / CH2Cl2 / 4.5 h / 0 - 20 °C View Scheme

ethyl 5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-1-oxo-3-quinolinecarboxylate (675574-87-5) → N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-ethyl-1-methyl-2-oxo-quinoline-3-carboxamide (248282-01-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: HCl / acetic acid / 6 h / 60 °C 2: SOCl2; Et3N / CH2Cl2 / 4.5 h / 0 - 20 °C View Scheme

N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-ethyl-1-methyl-2-oxo-quinoline-3-carboxamide (248282-01-1) → N-ethyl-N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide calcium salt

Conditions	Yield
With sodium hydroxide; calcium acetate In ethanol; water at 20 - 70℃; for 1.08333h; pH=7.5;	98%
Stage #1: N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-ethyl-1-methyl-2-oxo-quinoline-3-carboxamide With sodium hydroxide In ethanol; water pH=7.5; Stage #2: With calcium acetate In ethanol; water	98%

N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-ethyl-1-methyl-2-oxo-quinoline-3-carboxamide (248282-01-1) → N-ethyl-N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide lithium salt (862462-44-0)

Conditions	Yield
With lithium hydroxide In ethanol; water for 4h;	84%
With lithium hydroxide In ethanol; water for 4h;	84%

N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-ethyl-1-methyl-2-oxo-quinoline-3-carboxamide (248282-01-1) → N-ethyl-N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide zinc salt

Conditions	Yield
With sodium hydroxide; zinc diacetate In ethanol; chloroform; water for 0.166667h;	76%
Stage #1: N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-ethyl-1-methyl-2-oxo-quinoline-3-carboxamide With sodium hydroxide In ethanol; water Stage #2: With zinc diacetate In ethanol; chloroform; water for 0.166667h;	76%

propan-1-ol (71-23-8) + N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-ethyl-1-methyl-2-oxo-quinoline-3-carboxamide (248282-01-1) → C16H19NO4

Conditions	Yield
With hydrogenchloride In water at 45 - 60℃; for 4h; Reactivity;
With hydrogenchloride at 45 - 60℃; for 4h; Reactivity;

ethanol (64-17-5) + N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-ethyl-1-methyl-2-oxo-quinoline-3-carboxamide (248282-01-1) → ethyl 5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-1-oxo-3-quinolinecarboxylate (675574-87-5)

Conditions	Yield
Reflux;

Upstream product

• 103-69-5 N-ethyl-N-phenylamine 
• 1354639-60-3 1,2-dihydro-4-hydroxy-5-ethyl-1-methyl-2-oxo-quinoline-3-carboxylic acid methyl ester 
• 66232-56-2 6-ethyl-anthranilic acid 
• 675574-87-5 ethyl 5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-1-oxo-3-quinolinecarboxylate 
• 34934-06-0 5-ethyl-1H-benzo[d][1,3]oxazine-2,4-dione 

Downstream Products

• 862462-44-0 N-ethyl-N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide lithium salt 

Relevant academic research and scientific papers

METHOD FOR MANUFACTURING OF QUINOLINE-3-CARBOXAMIDES

A method for preparing a compound of formula (I) by reacting the appropriate alkyl ester and an aniline derivative, in a refluxing mixture containing an aliphatic solvent or a mixture of aliphatic solvents having a boiling point in the range of 68-191 °C; condensing vapors of the refluxing mixture; treating the condensed vapors with an alcohol scavenging agent or a mixture of alcohol scavenging agents; and returning the condensed vapors back to the reaction mixture.

1,2-DIHYDRO-4-HYDROXY-2-OXO-QUINOLINE-3-CARBOXANILIDES AS AHR ACTIVATORS.

The present invention relates to compounds which are 1, 2-dihydro-4- hydroxy-2-oxo-quinoline-3-carboxanilides, their thieno-pyridone analogs, and prodrugs thereof. This invention specifically relates to such derivatives containing an N-hydrogen in the carboxanilide moiety and which exhibit modulating activity towards the aromatic hydrocarbon receptor (AhR), and, specifically, also to prodrugs thereof. The present invention also relates to use of said compounds as a medicament, and for the treatment of cancer, autoimmune disorders and other disorders with an immunological component, and a pharmaceutical composition comprising one or more of said compounds and a method of treatment.

Synthesis and Biological Evaluation of New 1,2-Dihydro-4-hydroxy-2-oxo-3-quinolinecarboxamides for Treatment of Autoimmune Disorders: Structure-Activity Relationship

Roquinimex-related 3-quinolinecarboxamide derivatives were prepared and evaluated for treatment of autoimmune disorders. The compounds were tested in mice for their inhibitory effects on disease development in the acute experimental autoimmune encephalomyelitis model and selected compounds in the beagle dog for induction of proinflammatory reaction. Structure-activity relationships are discussed. Compound 8c, laquinimod, showed improved potency and superior toxicological profile compared to the lead compound roquinimex (1b, Linomide) and was selected for clinical studies (currently in phase II).

Quinoline derivatives

The invention relates to compounds of general formula (I) wherein R is selected from ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec.-butyl and allyl; R4 is selected from hydrogen and pharmaceutically acceptable inorganic and organic cations; R5 is selected from methyl, ethyl, n-propyl, iso-propyl, methoxy, ethoxy, chloro, bromo, CF3, and OCHxFy; wherein x=0-2, y=1-3 with the proviso that x+y=3; R6 is hydrogen; or R5 and R6 taken together are methylenedioxy; and any tautomer hereof. The invention also relates to pharmaceutical compositions containing a compound of the general formula (I) together with a pharmaceutically acceptable carrier. Included are also processes for the preparation of the compounds of formula (I), as well as methods of treating mammals suffering from diseases resulting from autoimmunity and pathological inflammation by administering a compound having the formula (I) to said mammal.