WO2022123336A1 - Composés de chromeno [4,3-b] quinoléine et leur synthèse à l'aide d'acide silicotungstique [h4siw12o40] - Google Patents

Composés de chromeno [4,3-b] quinoléine et leur synthèse à l'aide d'acide silicotungstique [h4siw12o40] Download PDF

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Publication number
WO2022123336A1
WO2022123336A1 PCT/IB2021/058086 IB2021058086W WO2022123336A1 WO 2022123336 A1 WO2022123336 A1 WO 2022123336A1 IB 2021058086 W IB2021058086 W IB 2021058086W WO 2022123336 A1 WO2022123336 A1 WO 2022123336A1
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WIPO (PCT)
Prior art keywords
compound
quinolone
dimethyl
formula
thiochromeno
Prior art date
Application number
PCT/IB2021/058086
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English (en)
Inventor
Subramanya Gopal Hegde
Koodlur Sannegowda LOKESH
Jayachamarajapura Pranesh SHUBHA
Nurani Viswanathan SUSHMA
Girish Basavaraju
Ananda Danagoudar
Vijay Kumar Boda
Original Assignee
Subramanya Gopal Hegde
Lokesh Koodlur Sannegowda
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Application filed by Subramanya Gopal Hegde, Lokesh Koodlur Sannegowda filed Critical Subramanya Gopal Hegde
Publication of WO2022123336A1 publication Critical patent/WO2022123336A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the development of novel compounds of chromeno [4,3-b] quinolone derivatives. It particularly relates to the development of novel compounds of thiochromeno [4,3-b] quinolone derivatives for the treatment of coronary artery diseases, dyslipidemia, and metabolic syndrome.
  • the present invention also relates to the first synthesis of Silicotungstic -catalyzed Aza-Diels-Alder-reactions (ADAR) with s-prenyl derivatives of a- tetralone, 4-chromanone and Thiochroman-4-one and various substituted amines to deliver cycloadducts in good yield and excellent diastereoselectivity under mild reaction conditions.
  • the invention further relates to the method for the treatment of coronary artery diseases, dyslipidemia, and metabolic syndrome by using synthesized compounds of thiochromeno [4,3-b] quinolone derivatives.
  • ADAR Aza-Diels-Alder-reactions
  • Diels-Alder reaction was carried out by using Metal aqua complexes, and the water as an auxiliary ligand impacts the diastereo- and enantioselectivity of the reaction.
  • Jan B. F. N. Engberts et al [J. Am. Chem. Soc. 1991, 113, 11, 4241-4246] have reported Carbo- Diels-Alder reactions by studying the effect of different Lewis acid catalysts on the diastereoselective of endo-exo between diene and dienophile.
  • the primary object of the present invention is the development of novel compounds of chromeno [4,3-b] quinolone derivatives for the treatment of coronary artery diseases, dyslipidemia, and metabolic syndrome.
  • the specific object of the present invention is the development of thiochromeno [4,3-b] quinolone derivatives for the treatment of coronary artery diseases, dyslipidemia, and metabolic syndrome.
  • the other object of the present invention is the development of a synthetic method for compounds of chromeno [4,3-b] quinolone derivatives.
  • the other object of the present invention is the development of a synthetic method for compounds of thiochromeno [4,3-b] quinolone derivatives.
  • the other object of the present invention is the development of pharmaceutical compositions of chromeno [4,3-b] quinolone derivatives for the treatment of coronary artery diseases, dyslipidemia, and metabolic syndrome.
  • the other object of the present invention is the development of chromeno [4,3-b] quinolone derivatives for the treatment of coronary artery diseases, dyslipidemia, and metabolic syndrome.
  • the other object of the present invention is the development of chromeno [4,3-b] quinolone derivatives for the treatment of coronary artery diseases, dyslipidemia, and metabolic syndrome.
  • the other object of the present invention is the development of chromeno [4,3-b] quinolone derivatives for the treatment of coronary artery diseases, dyslipidemia, and metabolic syndrome, which are safe and practical to use.
  • the present invention provides compounds of Formula I that can be useful for pharmaceutical importance for the treatment of coronary artery diseases, dyslipidemia, and metabolic syndrome.
  • Ri is H, Cl, -CN, Ci-4 alkyl, Cl-3fluoroalkyl, C1.3 hydroxy fluoroalkyl, C3.6 cycloalkyl, or tetrahydopyranyl ;
  • R2 is independently halo, -CN, -OH, -NO2 + , Cl -3 alkyl, Cl-2fluoro alkyl, Cl -2 cyanoalkyl, C1.3 hydroxyalkyl, C1.3 aminoalkyl, C1.3 fluoro alkoxy, -cyclopropyl, cycloalkyl, morpholinyl, methylpyridine, imidazolyl, triazolyl, or thiazolyl.
  • the present invention provides the use of Silicotungstic acid as Lewis acid for Aza-Diels-Alder- reactions to get a mixture of diastereomers are the first examples.
  • the catalyst is very cheap and only a small amount (10 mol%) is needed.
  • Intramolecular cyclization was carried out very conveniently as a one-pot reaction starting from the S-prenyl chromene-3-carbaldehyde and arylamines without isolation of the intermediate imines.
  • X is CH 2 , Oxygen, or Sulphur
  • Ri is H, Cl, -CN, Ci-4 alkyl, Cl-3fluoroalkyl, Ci-shydroxy fluoroalkyl, C3.6 cycloalkyl, or tetrahydopyranyl;
  • R2 is independently halo, -CN, -OH, -NO2 + , Cl -3 alkyl, Cl-2fluoro alkyl, Cl -2 cyanoalkyl, C1.3 hydroxyalkyl, C1.3 aminoalkyl, C1.3 fluoro alkoxy, -cyclopropyl, cycloalkyl, morpholinyl, methylpyridine, imidazolyl, triazolyl, or thiazolyl.
  • the compound is selected from group consisting of
  • the compound is selected from group consisting of
  • the compound is selected from group consisting of
  • a pharmaceutical composition for treatment of coronary artery diseases, dyslipidemia, and metabolic syndrome comprising a compound of Formula I or its pharmaceutically acceptable salt thereof and pharmaceutically suitable excipient or carrier.
  • a process for preparation of compound of Formula I comprising: a. preparation of compound Formula IV by reacting the compound Formula III with phosphorous tribromide and DMF in the presence of chloroform; b. then treating the compound of Formula IV with sodium hydrosulfide/sodium bisulfide and prenyl bromide to synthesize allyl thioether compound of Formula V by allylation; and c.
  • X is CH 2 , Oxygen, or Sulphur
  • Ri is H, Cl, -CN, Ci-4 alkyl, Cl-3fluoroalkyl, Ci-shydroxy fluoroalkyl, C3.6 cycloalkyl, or tetrahydopyranyl;
  • R2 is independently halo, -CN, -OH, -NO2 + , Cl -3 alkyl, Cl-2fluoro alkyl, Cl -2 cyanoalkyl, C1.3 hydroxyalkyl, C1.3 aminoalkyl, C1.3 fluoro alkoxy, -cyclopropyl, cycloalkyl, morpholinyl, methylpyridine, imidazolyl, triazolyl, or thiazolyl.
  • Ri is H, Cl, -CN, Ci-4 alkyl, Cl-3fluoroalkyl, Ci ⁇ hydroxy fluoroalkyl, C3.6 cycloalkyl, or tetrahydopyranyl;
  • R2 is independently halo, -CN, -OH, -NO2 + , Cl -3 alkyl, Cl-2fluoro alkyl, Cl -2 cyanoalkyl, Ci-3 hydroxyalkyl, C1.3 amino alkyl, C1.3 fluoro alkoxy, -cyclopropyl, cycloalkyl, morpholinyl, methylpyridine, imidazolyl, triazolyl, or thiazolyl.
  • reaction proceeded one pot without the isolation of P-thiolo enal to afford l-((3-methylbut-2-en-l-yl) thio)-3,4- dihydronaphthalene-2-carbaldehyde 4 in 70% yield.
  • a series of optimization was performed to choose the Lewis acid for ADAR.
  • HPLC The synthesized compounds, the reaction mixtures for the reaction monitoring, and the purity were analyzed by high-performance liquid chromatography.
  • HPLC in a Shimadzu LC 8A, an instrument using an Ascentis Express Cl 8 (50X2, 1mm, 2.7pm) and acetonitrile: water in 80:20 (v/v) as the mobile phase at a flow rate of 1 mL/min using refractive index detector. Conversion yields can also be determined by comparison with starting material from the HPLC peak areas. Error measurements in HPLC yields will be ⁇ 5-10%.
  • Infrared spectroscopy Infrared spectroscopy: Infrared spectra were recorded on a Nicolet-FTIR spectrophotometer. Isolated solid glycoside samples (5-8 mg) were prepared as KBr pellets and employed for spectral recording. Liquid alcohol standards were employed as such between salt plates to obtain the IR spectra.
  • 13 C NMR 13C NMR spectra were recorded on a Bruker DRX 400 MHz NMR spectrometer (100MHz). Carbon 90° pulse widths were 10.5 ms. The sample concentration of around 20 mg dissolved in DMSO-d6 was used for recording the spectra at 35 °C. About 500 to 2000 scans were accumulated for each spectrum in the 0-200 ppm region. Chemical shift values were expressed in ppm and tetramethylsilane (TMS) was used as the internal standard.
  • TMS tetramethylsilane
  • 2D-HSQCT Two-dimensional Heteronuclear Single Quantum Coherence Transfer Spectra (2-D HSQCT) were recorded on a Bruker DRX 400 MHz NMR spectrometer. A sample concentration of about 20 mg in DMSO-d6 was used for recording the spectrum. Spectra were recorded in magnitude mode with the sinusoidal shaped Z gradients of strength 25.7, 15.42, and 20.56 G/cm in the ratio of 5:3:4 applied for a duration of 1 ms each with a gradient recovery delay of 100 ms to defocus unwanted coherences. Then it was incremented in 256 steps. The size of the computer memory used to accumulate the 2D data was 4K. The spectra were processed using unshifted and p/4 shifted sine bell window function in Fl and F2 dimensions respectively.
  • Mass spectroscopy Mass spectra were recorded from the Q-TOF Waters Ultima instrument (Q- Tof GAA 082, Waters Corporation, Manchester, UK) with an integral electron spray ionization (ESI) source. Software version 4.0 was used for data acquisition. The positive ion mode using a spray voltage at 3.5 kV and a source temperature of 80°C was employed for recording the spectra. Mass spectra were recorded under electron impact ionization at 70 eV electron energy. Compounds were dissolved in the concentration range of 0.5- 1.0 mg/mL in methanol and injected by flow injection analysis at a flow rate of 10 pL/ min. The recorded mass of the sample was in the range of 100-1500. Table-2: Silicotungstic acid- catalyzed synthesis of tetralone derived thiochromeno[4,3-b] quinolines via ADAR
  • Step-II Preparation of l-((3-methyl but-2-en-l-yl) thio)-3,4-dihydro naphthalene-2-
  • step-1 intermediate l-Bromo-3,4-dihydro naphthalene-2-carbaldehyde (2) was dissolved in a mixture of isopropanol and water (3:4), containing sodium thiol (2 mmol), and the mixture was stirred 15mins at room temperature. After prenyl bromide (3 mmol) was added slowly to the reaction mixture and the completion of the reaction was monitored as indicated by TLC.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Vascular Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

La présente invention concerne le développement de nouveaux composés de dérivés de chromeno [4,3-b] quinolone. Elle concerne en particulier le développement de nouveaux composés de dérivés de thiochromeno [4,3-b] quinolone pour le traitement des maladies artérielles coronaires, de la dyslipidémie et du syndrome métabolique. La présente invention concerne également la première synthèse de réactions d'Aza-Diels-Alder (ADAR) catalysées silicotungstiques avec des dérivés de s-prényle d'α-tétralone, de 4-chromanone et de Thiochroman-4-one et de diverses amines substituées pour administrer des cycloadduits avec un bon rendement et une excellente diastéréosélectivité dans des conditions douces de réaction. L'invention concerne en outre le procédé pour le traitement de maladies artérielles coronaires, de la dyslipidémie et du syndrome métabolique en utilisant des composés synthétisés de dérivés de thiochromeno [4,3-b] quinolone. La présente invention concerne l'utilisation d'acide silicotungstique en tant qu'acide de Lewis pour des réactions d'Aza-Diels-Alder pour obtenir un mélange de diastéréomères qui sont les premiers exemples. En plus de son efficacité, de sa simplicité et de conditions douces de réaction, le catalyseur est très bon marché et seule une petite quantité (10 % en moles) est nécessaire. La cyclisation intramoléculaire a été réalisée très commodément en tant que réaction monotope à partir du S-prényl chromène-3-carbaldéhyde et d'arylamines sans isolement des imines intermédiaires.
PCT/IB2021/058086 2020-12-07 2021-09-05 Composés de chromeno [4,3-b] quinoléine et leur synthèse à l'aide d'acide silicotungstique [h4siw12o40] WO2022123336A1 (fr)

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IN202041053100 2020-12-07

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007002867A1 (fr) * 2005-06-28 2007-01-04 Cv Therapeutics, Inc. Composés augmentant le taux en abca1
WO2009009417A2 (fr) * 2007-07-06 2009-01-15 Wyeth Compositions pharmaceutiques et procédés pour prévenir, traiter ou inhiber des maladies, des troubles ou des affections inflammatoires cutanés et des maladies, des troubles ou des affections associés à un appauvrissement en collagène

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007002867A1 (fr) * 2005-06-28 2007-01-04 Cv Therapeutics, Inc. Composés augmentant le taux en abca1
WO2009009417A2 (fr) * 2007-07-06 2009-01-15 Wyeth Compositions pharmaceutiques et procédés pour prévenir, traiter ou inhiber des maladies, des troubles ou des affections inflammatoires cutanés et des maladies, des troubles ou des affections associés à un appauvrissement en collagène

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PAL ET AL.: "Recent doveloments and multiple biological activites available with 1,8-naphthyridine derivatives", INT J PHARM PHARM SCI, vol. 11, 2019, pages 17 - 37, XP055944097, Retrieved from the Internet <URL:http://dx.doi.org/10.22159/ijpps.2019v11i1.304> *

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