[go: up one dir, main page]

WO2012099453A1 - Pyrrolothiazole containing curcumin compounds - Google Patents

Pyrrolothiazole containing curcumin compounds Download PDF

Info

Publication number
WO2012099453A1
WO2012099453A1 PCT/MY2011/000176 MY2011000176W WO2012099453A1 WO 2012099453 A1 WO2012099453 A1 WO 2012099453A1 MY 2011000176 W MY2011000176 W MY 2011000176W WO 2012099453 A1 WO2012099453 A1 WO 2012099453A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydroxy
methoxyphenyl
tetrahydro
pyrrolo
mmol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/MY2011/000176
Other languages
French (fr)
Inventor
Rusli Ismail
Mohamed Ashraf Ali
Soo Choon Tan
Keng Yoon YEONG
Chee Wei Ang
Raju SURESH KUMAR
Hasnah OSMAN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Universiti Sains Malaysia (USM)
Original Assignee
Universiti Sains Malaysia (USM)
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Universiti Sains Malaysia (USM) filed Critical Universiti Sains Malaysia (USM)
Publication of WO2012099453A1 publication Critical patent/WO2012099453A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/20—Spiro-condensed systems

Definitions

  • the present invention relates to compounds for treatment of HIV, TB, Alzheimer or anti-cancer and the processes thereof, particularly curcumin compounds and processes for their preparation.
  • heterocycles are a research area of ever-increasing importance, as heterocycles are widely prevalent in nature and play a pivotal role in the pharmaceutical and drug industry. Because of their ability to mimic the structure of peptides and binding to proteins, functionalized heterocycles are interesting scaffolds for the preparation of diversity-oriented compound libraries for medicinal and pharmaceutical applications.
  • Curcumin a polyphenolic compound derived from dietary spice turmeric, possesses diverse pharmacologic effects including anti-HIV, anti-TB, antioxidant, antiproliferative and alzheimer diseases. Phase I clinical trials have shown that curcumin is safe even at high doses (12 g/day) in humans but exhibit poor bioavailability.
  • curcumin Major reasons contributing to the low plasma and tissue levels of curcumin appear to be due to poor absorption, rapid metabolism, and rapid systemic elimination.
  • approaches involve, first, the use of adjuvant like piperdine that interferes with glucuronidation; second, the use of liposomal curcumin; third, curcumin nanoparticles; fourth, the use of curcumin phospholipid complex; and fifth, the use of structural analogues of curcumin like indolizine with isatin.
  • curcumin Despite the lower bioavailability, therapeutic efficacy of curcumin against various human diseases, including cancer, cardiovascular diseases, diabetes, arthritis, neurological diseases and Crohn's disease, has been documented.
  • curcumin compounds with enhanced bioavailability for the treatment of anti-HIV, anti-TB, anti-Alzheimer, and anti-cancer.
  • the curcumin compounds would have enhanced bioavailability and stability. Besides that, these curcumin compounds are soluble in water.
  • the invention discloses compounds of pyrrolothiazole moiety containing with mono bis substituted curcumin molecules which improves solubility of curcumin which has the following formulas:
  • the invention also discloses the method in synthesizing these compounds wherein the steps includes mixing curcumin, isatin derivatives or ninhydrin and thioproline (thiazolidine-4-carboxylic acid) in 20 mL methanol. The mixture was then refluxed with a solvent on a water bath and excess solvent was removed under vacuum. The residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1) as eluent to afford the product. The ratio for curcumin: isatin derivative/ninhydrin: thioproline (thiazolidine-4-carboxylic acid) is 1 :1 :2 and 1 :2:4.
  • the present invention provides compounds with enhanced bioavailability for the prevention and treatment of anti-human immunodeficiency virus (HIV), anti-tuberculosis (TB), anti-Alzheimer or anti-cancer.
  • HIV anti-human immunodeficiency virus
  • TB anti-tuberculosis
  • anti-Alzheimer or anti-cancer anti-cancer.
  • the making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 1 mmol of isatin derivative and 2 mmol of thioproline (thiazolidine-4-carboxylic acid)in 20 mL of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product.
  • TLC thin layer chromatography
  • the making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 1 mmol of ninhydrin and 2 mmol of thioproline (thiazolidine-4-carboxylic acid) in 20 mL of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1) as eluent to afford the product.
  • TLC thin layer chromatography
  • the making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 2 mmol of isatin derivative and 4 mmol of thioproline (thiazolidine-4-carboxylic acid) in 20 mL of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1) as eluent to afford the product.
  • TLC thin layer chromatography
  • the making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 2 mmol of isatin derivative or ninhydrin and 4 mmol of thioproline (thiazolidine- 4-carboxylic acid) in 20 mL of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1) as eluent to afford the product.
  • TLC thin layer chromatography
  • the making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 1 mmol of isatin derivative and 2 mmol of thioproline (thiazolidine-4-carboxylic acid) in 20 mL of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product.
  • TLC thin layer chromatography
  • the making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 1 mmol of chloroisatin derivative and 2 mmol of thioproline (thiazolidine-4- carboxylic acid) in 20 mL of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product.
  • TLC thin layer chromatography
  • the making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 2 mmol of chloroisatin and 4 mmol of thioproline (thiazolidine-4-carboxylic acid) in 20 mL of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product.
  • TLC thin layer chromatography
  • the making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 2 mmol of nitroisatin and 4 mmol of thioproline (thiazolidine-4-carboxylic acid) in 20 ml_ of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC) the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product.
  • TLC thin layer chromatography
  • the making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 2 mmol of ninhydrin and 4 mmol of thioproline (thiazolidine-4-carboxylic acid) in 20 mL of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC) the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product.
  • TLC thin layer chromatography

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Virology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pulmonology (AREA)
  • Hospice & Palliative Care (AREA)
  • AIDS & HIV (AREA)
  • Molecular Biology (AREA)
  • Psychiatry (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Accordingly, the invention discloses compounds of pyrrolothiazole moiety containing with mono bis substituted curcumin molecules which improves solubility of curcumin. The invention also discloses the method in synthesizing these compounds wherein the steps includes mixing curcumin, isatin derivatives or ninhydrin and thioproline (thiazolidine-4-carboxylic acid) in 20 mL methanol. The mixture was then refiuxed with a solvent on a water bath and excess solvent was removed under vacuum. The residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1) as eluent to afford the product. The ratio for curcumin: isatin derivative/ninhydrin:thioproline (thiazolidine-4-carboxylic acid) is 1:1:2 and 1:2:4.

Description

PYRROLOTHIAZOLE CONTAINING CURCUMIN COMPOUNDS
FIELD OF THE INVENTION
The present invention relates to compounds for treatment of HIV, TB, Alzheimer or anti-cancer and the processes thereof, particularly curcumin compounds and processes for their preparation.
BACKGROUND OF THE INVENTION
Synthesis of heterocycles is a research area of ever-increasing importance, as heterocycles are widely prevalent in nature and play a pivotal role in the pharmaceutical and drug industry. Because of their ability to mimic the structure of peptides and binding to proteins, functionalized heterocycles are interesting scaffolds for the preparation of diversity-oriented compound libraries for medicinal and pharmaceutical applications. Curcumin, a polyphenolic compound derived from dietary spice turmeric, possesses diverse pharmacologic effects including anti-HIV, anti-TB, antioxidant, antiproliferative and alzheimer diseases. Phase I clinical trials have shown that curcumin is safe even at high doses (12 g/day) in humans but exhibit poor bioavailability. Major reasons contributing to the low plasma and tissue levels of curcumin appear to be due to poor absorption, rapid metabolism, and rapid systemic elimination. To improve the bioavailability of curcumin numerous approaches have been undertaken. These approaches involve, first, the use of adjuvant like piperdine that interferes with glucuronidation; second, the use of liposomal curcumin; third, curcumin nanoparticles; fourth, the use of curcumin phospholipid complex; and fifth, the use of structural analogues of curcumin like indolizine with isatin. Despite the lower bioavailability, therapeutic efficacy of curcumin against various human diseases, including cancer, cardiovascular diseases, diabetes, arthritis, neurological diseases and Crohn's disease, has been documented.
However, there is the need for better curcumin compounds with enhanced bioavailability for the treatment of anti-HIV, anti-TB, anti-Alzheimer, and anti-cancer. The curcumin compounds would have enhanced bioavailability and stability. Besides that, these curcumin compounds are soluble in water.
SUMMARY OF THE INVENTION
Accordingly, the invention discloses compounds of pyrrolothiazole moiety containing with mono bis substituted curcumin molecules which improves solubility of curcumin which has the following formulas:
Figure imgf000003_0001
6'-(4-hydroxy-3-methoxyphenyl)-7'((2Z,4E)-3-hydroxy-5-(4-hydroxy-3- methoxyphenyl)penta-2,4-dienoyl)-3',6',7,,7a'-tetrahydro-1 'H-spiro[indoline-3,5'- pyrrolo[1 ,2-c]-2-one
H3CO
5-chloro-6'-(4-hydroxy-3-methoxyphenyl)-7'-((2Z,4£)-3-hydroxy-5-(4-hydroxy-3- methoxyphenyl)penta-2,4-dienoyl)-3',6',7,,7a,-tetrahydro-1 ,H-spiro[indoline-3,5'- pyrrolo[1 ,2-c]thiazol]-2-one
Figure imgf000004_0001
6'-(4-hydroxy-3-methoxyphenyl)-7'-((2Z,4£)-3-hydroxy-5-(4-hydroxy-3- methoxyphenyl)penta-2,4-dienoyl)-5-nitro-3',6',7',7a'-tetrahydro-1 'H-spiro[indoline-3,5'- pyrrolo[1 ,2-c]thiazol]-2-one
6'-(4-hydroxy-3-methoxyphenyl)-7'-((2Z,4-E)-3-hydroxy-5-(3-hydroxy-4- methoxyphenyl)penta-2,4-dienoyl)- 3',6',7',7a'-tetrahydro-1 'H-spiro[indene-2,5'-pyrrolo[1 ,2- c]thiazol]-1 ,3(3aH,7aH)-dione
Figure imgf000005_0001
(Z)-7,-(3-hydroxy-3-(7'-(3-hydroxy-4-methoxyphenyl)-2-oxo-3,,6',7',7a,-tetrahydro-2'H- spiro[indoline-3,5'-pyrrolo[2,1-b]thiazole]-6'-yl)acryloyl)-6'-(4-hydroxy-3-methoxyphenyl)- 3',6',7',7a'-tetrahydro-1 ,A spiro[indoline-3,5'-pyrrolo[1 ,2-c]thiazol]-2-one
(^-S-chloro-y'^S-iS-chloro-T'-iS-hydroxy^-methoxyphenylJ^-oxo-S'.e'J'.Ta'-tetrahydro- 2' V-spiro[indoline-3,5'-pyrrolo[2,1 -b]thiazole]-6'-yl)-3-hydroxyacryloyl)-6,-(4-hydroxy-3- met oxyphenyl)-3',6',7',7a'-tetrahydro-1 'H-spiro[indoline-3>5'-pyrrolo[1 ,2-c]thiazol]-2-one
Figure imgf000006_0001
(2)-7'-(3-hydroxy-3-(7,-(3-hydroxy-4-methoxyp enyl)-5-nitro-2-oxo-3',6,,7',7a'-tetrahydro-
1 ,W-spiro[indoline-3,5,-pyrrolo[1 ,2-c]thiazole]-6'-yl)acryloyl)-6'-(4-hydroxy-3- methoxypheny -S-nitro-S'.e'J'Ja'-tetrahydro-l 'H-spiroIindoline-S.S'-pyrrolofl ^-clthiazole]-
2-one
(ZJ-T'-iS-hydroxy-S-iT'-iS-hydroxy^-methoxypheny -I .S-dioxo-I .S.a'.e'.yja'- hexahydro-1 'H-spiro[indene-2,5'-pyrrolo[1 ,2-c]thiazole]-6'-yl)acryloyl)-6'-(4-hydroxy-3- methoxyphenyl)-3',6',7',7a'-tetrahydro-1 'H-spiro[indene-2,5'-pyrrolo[1 ,2-c]thiazole]-1 ,3- dione
The invention also discloses the method in synthesizing these compounds wherein the steps includes mixing curcumin, isatin derivatives or ninhydrin and thioproline (thiazolidine-4-carboxylic acid) in 20 mL methanol. The mixture was then refluxed with a solvent on a water bath and excess solvent was removed under vacuum. The residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1) as eluent to afford the product. The ratio for curcumin: isatin derivative/ninhydrin: thioproline (thiazolidine-4-carboxylic acid) is 1 :1 :2 and 1 :2:4.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds with enhanced bioavailability for the prevention and treatment of anti-human immunodeficiency virus (HIV), anti-tuberculosis (TB), anti-Alzheimer or anti-cancer. Hereinafter, this specification will describe the present invention according to the preferred embodiments of the present invention. However, it is to be understood that limiting the description to the preferred embodiments of the invention is merely to facilitate discussion of the present invention and it is envisioned that those skilled in the art may devise various modifications and equivalents without departing from the scope of the appended claims.
General procedure for synthesis of substituted 6'-(4-hvdroxy-3-methoxyphenylV7'((2Z.4E)-
3-hvdroxy-5-(4-hvdroxy-3-methoxyphenyl)penta-2.4-dienoyl)-3'.6'.7'.7a'-tetrahvdro-1 'H- spironndoline-3.5'-pyrroloi1.2-cl-2-one
The making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 1 mmol of isatin derivative and 2 mmol of thioproline (thiazolidine-4-carboxylic acid)in 20 mL of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product.
General methods in synthesizing substituted 6'-(4-hvdroxy-3-methoxyphenylV7'-(2Z4B-3- hvdroxy-5-(3-hvdroxy-4-methoxyphenvhpenta-2.4-dienoyl)- 3'.6'.7'.7a'-tetrahvdro-1 'H- spirofindene-2.5'-pyrrolof1 ,2-clthiazoll-1.3(3aH.7aH)-dione
The making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 1 mmol of ninhydrin and 2 mmol of thioproline (thiazolidine-4-carboxylic acid) in 20 mL of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1) as eluent to afford the product.
General methods in synthesizing substituted (ZV7'-(3-hvdroxy-3-(7'-(3-hvdroxy-4- methoxyphenyl)-2-oxo-3'.6'.7'.7a'-tetrahvdro-2'H-spironndoline-3.5'-pyrrolof2.1-b1thiazolel-
6'-yl)acryloyl)-6'-(4-hvdroxy-3-methoxyphenyl)-3'.6'.7'.7a'-tetrahvdro-1'A -spirorindoline- 3.5'-pyrrolof1.2-clthiazol1-2-one
The making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 2 mmol of isatin derivative and 4 mmol of thioproline (thiazolidine-4-carboxylic acid) in 20 mL of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1) as eluent to afford the product.
General methods in synthesizing substituted (Z)-7'-(3-hvdroxy-3-(7'-(3-hvdroxy-4- methoxyphenyl)-1.3-dioxo-1.3.3'.6'.7'.7a'-hexahvdro-1 'H-spirorindene-2.5'-pyrroloM .2- clthiazole1-6'-yl)acryloyl)-6'-(4-hvdroxy-3-methoxyphenvn-3'.6'.7'.7a'-tetrahvdro-1'H- spiro[indene-2.5'-pyrrolof 1.2-clthiazole1-1 ,3-dione
The making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 2 mmol of isatin derivative or ninhydrin and 4 mmol of thioproline (thiazolidine- 4-carboxylic acid) in 20 mL of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1) as eluent to afford the product. EXAMPLES
Example 1
Synthesis of 6'-(4-hydroxy-3-methoxyphenyl)-7'((2Z,4E)-3-hydroxy-5-(4-hydroxy-3- methoxypheny penta^^-dienoy -S'.e'.T'.Ta'-tetrahydro-l'H-spiroIindoline-S.S'- pyrrolo[1 ,2-c]-2-one
Figure imgf000010_0001
Chemical Formula: C32 H30 N2 07 S
Exact Mass: 586
Molecular Weight: 587
m/z: 586 (100.0%), 587 (36.8%), 588 (12.5%), 589 (2.9%)
Elemental Analysis: C, 65.51 ; H, 5.15; N, 4.78; O, 19.09; S, 5.47.
The making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 1 mmol of isatin derivative and 2 mmol of thioproline (thiazolidine-4-carboxylic acid) in 20 mL of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product.
Example 2
Synthesis of 5-chloro-6'-(4-hydroxy-3-methoxyphenyl)-7'-((2Z,4E)-3-hydroxy-5-(4-hydroxy- 3-methoxyphenyl)penta-2,4-dienoyl)-3',6',7,,7a,-tetrahydro-1 'H-spiro[indoline-3,5'- pyrrolo[1 ,2-c]thiazol]-2-one
Figure imgf000011_0001
Chemical Formula: C 32H 29CIN 207S
Exact Mass: 620
Molecular Weight: 621
m/z: 620 (100.0%), 622 (44.5%), 621 (36.7%), 623 (14.7%), 624 (4.5%), 625 (1.0%) Elemental Analysis: C, 61.88; H, 4.71 ; CI, 5.71 ; N, 4.51 ; O, 18.03; S, 5.16
The making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 1 mmol of chloroisatin derivative and 2 mmol of thioproline (thiazolidine-4- carboxylic acid) in 20 mL of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product.
Example 3
Synthesis of 6'-(4-hydroxy-3-methoxyphenyl)-7'-((2Z,4£)-3-hydroxy-5-(4-hydroxy-3- methoxyphenyl)penta-2,4-dienoyl)-5-nitro-3',6',7',7a'-tetrahydro-1 'H-spiro[indoline-3,5'- pyrrolo[1 ,2-c]thiazol]-2-one
Figure imgf000012_0001
Chemical Formula: C32 H29 N3O 9S
Exact Mass: 631
Molecular Weight: 632
m/z: 631 (100.0%), 632 (37.2%), 633 (13.1 %), 634 (3.1 %)
Elemental Analysis: C, 60.85; H, 4.63; N, 6.65; O, 22.80; S, 5.08 The making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 1 mmol of nitroisatin derivative and 2 mmol of thioproline (thiazolidine-4- carboxylic acid) in 20 ml_ of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product.
Example 4
Synthesis of 6'-(4-hydroxy-3-methoxyphenyl)-7'-((2Z,4£)-3-hydroxy-5-(3-hydroxy-4- methoxyphenyl)penta-2,4-dienoyl)- ^'J'^a'-tetrahydro-l 'H-spiro[indene-2,5'-pyrrolo[1 ,2- c]thiazol]-1 ,3(3aH,7aH)-dione
Figure imgf000013_0001
Chemical Formula: C33H3iN08S
Exact Mass: 601
Molecular Weight: 602
m/z: 601 (100.0%), 602 (37.5%), 603 (13.0%), 604 (3.1 %)
Elemental Analysis: C, 65.88; H, 5.19; N, 2.33; O, 21.27; S, 5.33 The making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 1 mmol of ninhydrin and 2 mmol of thioproline (thiazolidine-4-carboxylic acid) in 20 ml_ of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product.
Example 5
Synthesis of (2)-7,-(3-hydroxy-3-(7'-(3-hydroxy-4-methoxyphenyl)-2-oxo-3',6,,7,,7a'- tetrahydro-2'H-spiro[indoline-3,5,-pyrrolo[2,1 -b]thiazole]-6'-yl)acryloyl)-6'-(4-hydroxy-3- methoxyphenyl)-3',6',7',7a'-tetrahydro-1 'H-spiro[indoline-3,5'-pyrrolo[1 ,2-c]thiazol]-2-one
Figure imgf000014_0001
Chemical Formula: C43H40 4O8S2
Exact Mass: 804
Molecular Weight: 805
m/z: 804 (100.0%), 805 (50.4%), 806 (23.1 %), 807 (7.3%), 808 (1.9%)
Elemental Analysis: C, 64.16; H, 5.01 ; N, 6.96; 0, 15.90; S, 7.97 The making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 2 mmol of isatin and 4 mmol of thioproline (thiazolidine-4-carboxylic acid) in 20 ml. of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product. Example 6
Synthesis of (Z)-5-chloro-7'-(3-(5-chloro-7,-(3-hydroxy-4-methoxyphenyl)-2-oxo-3',6',7,,7a'- tetrahydro-2' V-spiro[indoline-3,5'-pyrrolo[2,1 -b]thiazole]-6'-yl)-3-hydroxyacryloyl)-6'-(4- hydroxy-3-methoxyphenyl)-3',6',7',7a'-tetrahydro-1 'H-spiro[indoline-3,5'-pyrrolo[1 ,2- c]thiazol]-2-one
Figure imgf000015_0001
Chemical Formula: C43H38Cl2N408S2
Exact Mass: 872
Molecular Weight: 874
m/z: 872 (100.0%), 874 (87.0%), 873 (50.3%), 875 (39.5%), 876 (26.9%), 877 (10.2%), 878 (3.7%), 879 (1.0%)
Elemental Analysis: C, 59.10; H, 4.38; CI, 8.1 1 ; N, 6.41 ; O, 14.65; S, 7.34
The making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 2 mmol of chloroisatin and 4 mmol of thioproline (thiazolidine-4-carboxylic acid) in 20 mL of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC), the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product. Example 7
Synthesis of (2)-7'-(3-hydroxy-3-(7,-(3-hydroxy-4-methoxyphenyl)-5-nitro-2-oxo-3',6,,7',7a'- tetrahydro-1 'H-spiro[indoline-3)5'-pyrrolo[1 ,2-c]thiazole]-6'-yl)acryloyl)-6'-(4-hydroxy-3- methoxypheny -S-nitro-S'.e'J'Ja'-tetrahydro-l 'H-spiroIindoline-S.S'-pyrroloII ^-clthiazole]- 2-one
Figure imgf000016_0001
Chemical Formula: C43H38N6Oi2S2
Exact Mass: 894
Molecular Weight: 895
m/z: 894 (100.0%), 895 (51.2%), 896 (24.4%), 897 (7.9%), 898 (2.2%)
Elemental Analysis: C, 57.71 ; H, 4.28; N, 9.39; O, 21.45; S, 7.17.
The making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 2 mmol of nitroisatin and 4 mmol of thioproline (thiazolidine-4-carboxylic acid) in 20 ml_ of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC) the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product. Example 8
Synthesis of (Z)-7 3-hydroxy-3-(7'-(3-hydroxy-4-methoxyphenyl)-1 ,3-dioxo-1 ,3,3',6',7·,73·- hexahydro-1 'H-spiro[indene-2,5'-pyrrolo[1 ,2-c]thiazole]-6'-yl)acryloyl)-6'-(4-hydroxy-3- methoxyphenyl)-3',6',7',7a'-tetrahydro-1 'H-spiro[indene-2,5'-pyrrolo[1 ,2-c]thiazole]-1 ,3- dione
Figure imgf000017_0001
Chemical Formula: C 5H38 2O10S2
Exact Mass: 830
Molecular Weight: 831
m/z: 830 (100.0%), 831 (51.8%), 832 (24.3%), 833 (7.9%), 834 (2.1 %)
Elemental Analysis: C, 65.05; H, 4.61 ; N, 3.37; 0, 19.26; S, 7.72
The making of these compounds can be generally represented by a mixture of 1 mmol of curcumin, 2 mmol of ninhydrin and 4 mmol of thioproline (thiazolidine-4-carboxylic acid) in 20 mL of methanol which were refluxed on a water bath for 3 to 5 hours. After the completion of the reflux reaction as monitored by thin layer chromatography (TLC) the excess solvent was removed under vacuum and the residue subjected to flash column chromatography using petroleum ether: ethyl acetate mixture (4:1 ) as eluent to afford the product.

Claims

1. A 6,-(4-hydroxy-3-methoxyphenyl)-7'((2Z,4E)-3-hyclroxy-5-(4-hydroxy-3- methoxyphenyl)penta-2,4-dienoyl)-3',6,,7',7a'-tetrahydro-1,l-l-spiro[indoline-3,5'-
Figure imgf000018_0001
A 5-chloro-6'-(4-hydroxy-3-methoxyphenyl)-7'-((2Z,4£)-3-hydroxy-5-(4-hydroxy-3- methoxyphenyl)penta-2,4-dienoyl)-3\6',7',7a'-tetrahydro-1 ,H-spiro[indoline-3,5'- pyrrolo[1 ,
2-c]thiazol]-2-one compound represented by the formula
Figure imgf000018_0002
3. A 6'-(4-hydroxy-3-methoxyphenyl)-7'-((2Z,4£)-3-hydroxy-5-(4-hydroxy-3- methoxyphenyl)penta-2,4-dienoyl)-5-nitro-3',6',7',7a'-tetrahydro-1'Hspiro[indoline- 3,5'-pyrrolo[1 ,2-c]thiazol]-2-one compound represented by the formula
Figure imgf000019_0001
4. A 6'-(4-hydroxy-3-methoxyphenyl)-7'-((2Z,4.=)-3-hyclroxy-5-(3-hydroxy-4- methoxyphenyl)penta-2,4-dienoyl)- 3',6',7',7a'-tetrahydro-1 'H-spiro[indene-2,5'- pyrrolo[1 ,2-c]thiazol]-1 ,3(3aH,7aH)-dione compound represented by the formula
Figure imgf000019_0002
5. A (2)-7,-(3-hydroxy-3-(7'-(3-hydroxy-4-methoxyphenyl)-2-oxo-3,,6',7,,7a'-tetrahydro- 2'H-spiro[indoline-3,5'-pyrrolo[2,1 -b]thiazole]-6'-yl)acryloyl)-6,-(4-hydroxy-3- methoxyphenyl)-3',6',7',7a'-tetrahydro-1 ' V-spiro[indoline-3,5'-pyrrolo[1 ,2-c]thiazol]-2- one compound represented by the formula
Figure imgf000020_0001
6. A i^-S-chloro-y-iS-iS-chloro-T'-ia-h droxy^-methoxypheny ^-oxo-a'.e'.y.ya'- tetrahydro-2'H-spiro[indoline-3,5'-pyrrolo[2,1-b]thiazole]-6'-yl)-3-hydroxyacryloyl)-6'-
Figure imgf000020_0002
A (2)-7'-(3-hydroxy-3-(7,-(3-hydroxy-4-methoxyphenyl)-5-nitro-2-oxo-3',6',
7,,7a'- tetrahydro-1'H-spiro[indoline-3,5'-pyrrolo[1 ,2-c]thiazole]-6'-yl)acryloyl)-6'-(4-hydroxy- S-methoxyp eny -S-nitro-S'.e'J' a'-tetrahydro-l'H-spirolindoline-S.S'-pyrroloII ^- c]thiazole]-2-one compound represented by the formula
Figure imgf000021_0001
8. A (2)-7'-(3-hydroxy-3-(7'-(3-hydroxy-4-methoxyphenyl)-1 ,3-dioxo-1 ^^'.ff^^a'- hexahydro-1'H-spiro[indene-2,5'-pyrrolo[1 ,2-c]thiazole]-6'-yl)acryloyl)-6'-(4-hydroxy- 3-methoxyphenyl)-3',6',7',7a'-tetrahydro-1 'H-spiro[indene-2,5'-pyrrolo[1 ,2-c]thiazole]-
1 ,3-dione compound represented by the formula
Figure imgf000021_0002
A use of 6'-(4-hydroxy-3-methoxyphenyl)-7'((2Z,4E)-3-hydroxy-5-(4-hydroxy-3- methoxypheny penta^^-dienoy -S'.e'J' a'-tetrahydro-l 'H-spirofindoline-S.S'- pyrrolo[1 ,2-c]-2-one compound represented by the formula
Figure imgf000022_0001
for preventing or treating a patient having human immunodeficiency virus, tuberculosis, Alzheimer or cancer.
10. A use of 5-chloro-6'-(4-hydroxy-3-methoxyphenyl)-7'-((2Z,4E)-3-hydroxy-5-(4- hydroxy-3-methoxyphenyl)penta-2,4-dienoyl)-3',6',7',7a,-tetrahydro-1 'H- spiro[indoline-3,5'-pyrrolo[1 ,2-c]thiazol]-2-one compound represented by the formula
Figure imgf000022_0002
for preventing or treating a patient having human immunodeficiency virus, tuberculosis, Alzheimer or cancer.
11. A use of 6'-(4-hydroxy-3-methoxyphenyl)-7'-((2Z,4£)-3-hydroxy-5-(4-hydroxy-3- methoxypheny penta^^-dienoy -S-nitro-S'.B'J'Ja'-tetrahydro-l 'H-spiroIindoline- 3,5'-pyrrolo[1 ,2-c]thiazol]-2-one compound represented by the formula
Figure imgf000023_0001
for preventing or treating a patient having human immunodeficiency virus, tuberculosis, Alzheimer or cancer.
12. A use of 6'-(4-hydroxy-3-methoxyphenyl)-7'-((2Z,4£)-3-hydroxy-5-(3-hydroxy-4- methoxyphenyl)penta-2,4-dienoyl)- 3,,6,,7',7a'-tetrahydro- H-spiro[indene-2,5'- pyrrolo[1 ,2-c]thiazol]-1 ,3(3aH,7aH)-dione compound represented by the formula
Figure imgf000023_0002
for preventing or treating a patient having human immunodeficiency virus, tuberculosis, Alzheimer or cancer.
13. A use of (Zj-^-iS-hydroxy-S-i^-iS-hydroxy^-methoxypheny ^-oxo-S'.e' 'Ja'- tetrahydro-2'H-spiro[indoline-3,5'-pyrrolo[2,1 -b]thiazole]-6'-yl)acryloyl)-6'-(4-hydroxy- S-methoxypheny -S'.e'J' a'-tetrahydro-l 'H-spirotindoline-S.S'-pyrrololl ^-clthiazol]- 2-one compound represented by the formula
Figure imgf000024_0001
for preventing or treating a patient having human immunodeficiency virus, tuberculosis, Alzheimer or cancer.
14. A use of (2)-5-chloro-7'-(3-(5-chloro-7'-(3-hydroxy-4-methoxyphenyl)-2-oxo- S'.e'y^a'-tetrahydro-a'H-spiroIindoline-S.S'-pyrrolo^.l-blthiazoleJ-e'-y -S- hydroxyacryloyl)-6'-(4-hydroxy-3-methoxyphenyl)-3,,6',7',7a'-tetrahydro-1 'H- spiro[indoline-3,5'-pyrrolo[1 ,2-c]thiazol]-2-one compound represented by the formula
Figure imgf000024_0002
for preventing or treating a patient having human immunodeficiency virus, tuberculosis, Alzheimer or cancer.
15. A use of (2)-7'-(3-hydroxy-3-(7'-(3-hydroxy-4-methoxyphenyl)-5-nitro-2-oxo-
S'.e'J'Ja'-tetrahydro-l 'W-spirofindoline-S.S'-pyrrolotl ^-cJthiazolel-e'-y acryloy -e'- (4-hydroxy-3-methoxyphenyl)-5-nitro-3 6\7\7a'-tetrahydro-1 ,W-spiro[indoline-3,5'- pyrrolo[1 ,2-c]thiazole]-2-one compound represented by the formula
Figure imgf000025_0001
for preventing or treating a patient having human immunodeficiency virus, tuberculosis, Alzheimer or cancer.
16. A use of (2)-7'-(3-hydroxy-3-(7'-(3-hydroxy-4-methoxyphenyl)-1 ,3-dioxo-
1.S.S'.e'J'Ja'-hexahydro-l 'H-spiro[indene-2,5'-pyrrolo[1 ,2-c]thiazole]-6'-yl)acryloyl)- 6'-(4-hydroxy-3-methoxyphenyl)-3,,6',7,,7a,-tetrahydro-1 ,H-spiro[indene-2,5'- pyrrolo[1 ,2-c]thiazole]-1 ,3-dione compound represented by the formula
Figure imgf000025_0002
for preventing or treating a patient having human immunodeficiency virus, tuberculosis, Alzheimer or cancer.
17. A method of synthesizing 6'-(4-hydroxy-3-methoxyphenyl)-7'((2Z,4E)-3-hydroxy-5-(4- hydroxy-3-methoxyphenyl)penta-2,4-dienoyl)-3',6',7',7a'-tetrahydro-1 'H- spiro[indoline-3,5'-pyrrolo[1 ,2-c]-2-one
Figure imgf000026_0001
wherein the method includes the steps of
a. mixing 1 mmol of curcumin, 1 mmol of isatin derivative and 2 mmol of
thioproline (thiazolidine-4-carboxylic acid);
b. refluxing the mixture from step (a) with an organic solvent.
18. A method of synthesizing 5-chloro-6'-(4-hydroxy-3-methoxyphenyl)-7,-((2Z,4£)-3- hydroxy-5-(4-hydroxy-3-methoxyphenyl)penta-2,4-dienoyl)-3',6',7, )7a,-tetrahydro-1 ,H- spiro[indoline-3,5'-pyrrolo[1 ,2-c]thiazol]-2-one
Figure imgf000026_0002
wherein the method includes the steps of mixing 1 mmol of curcumin, 1 mmol of chloroisatin derivative and 2 mmol of thioproline (thiazolidine-4-carboxylic acid);
refluxing the mixture from step (a) with an organic solvent.
19. A method of synthesizing 6'-(4-hydroxy-3-methoxyphenyl)-7'-((2Z,4i≡)-3-hydroxy-5- (4-hydroxy-3-methoxyphenyl)penta-2,4-dienoyl)-5-nitro-3',6',7',7a'-tetrahydro-1 'H- spiro[indoline-3,5'-pyrrolo[1 ,2-c]thiazol]-2-one
Figure imgf000027_0001
wherein the method includes the steps of
a. mixing 1 mmol of curcumin, 1 mmol of nitroisatin derivative and 2 mmol of thioproline (thiazolidine-4-carboxylic acid);
b. refluxing the mixture from step (a) with an organic solvent.
20. A method synthesizing 6'-(4-hydroxy-3-methoxyphenyl)-7'-((2Z,4£)-3-hydroxy-5-(3- hydroxy-4-methoxyphenyl)penta-2,4-dienoyl)- S'.e'J'Ja'-tetrahydro-l 'H- spiro[indene-2,5'-pyrrolo[1 ,2-c]thiazol]-1 ,3(3aH,7aH)-dione
Figure imgf000028_0001
wherein the method includes the steps of
a. mixing 1 mmol of curcumin, 1 mmol of ninhydrin and 2 mmol of thioproline (thiazolidine-4-carboxylic acid) ;
b. refluxing the mixture from step (a) with an organic solvent.
21. A method of synthesizing (2)-7'-(3-hydroxy-3-(7'-(3-hydroxy-4-methoxyphenyl)-2- oxo-S'.e'yja'-tetrahydro-^H-spiroIindoline-S.S'-pyrrolo^.l -blthiazolel-e'- yl)acryloyl)-6'-(4-hydroxy-3-methoxyphenyl)-3',6',7',7a'-tetrahydro-1'H-spiro[indoline-
Figure imgf000028_0002
wherein the method includes the steps of
a. mixing 1 mmol of curcumin, 2 mmol of isatin and 4 mmol of thioproline
(thiazolidine-4-carboxylic acid); b. refluxing the mixture from step (a) with an organic solvent.
22. A method of synthesizing (Z)-5-chloro-7'-(3-(5-chloro-7'-(3-hydroxy-4- methoxyphenyl)-2-oxo-3',6',7',7a'-tetrahydro-2'H-spiro[indoline-3,5,-pyrrolo[2,1-
Figure imgf000029_0001
wherein the method includes the steps of
a. mixing mmol of curcumin, 2 mmol of chloroisatin and 4 mmol of thioproline (thiazolidine-4-carboxylic acid);
b. refluxing the mixture from step (a) with an organic solvent.
23. A method of synthesizing (2)-7'-(3-hydroxy-3-(7'-(3-hydroxy-4-methoxyphenyl)-5- nitro-2-oxo-3',6',7, )7a'-tetrahydro-1 ,H-spiro[indoline-3,5'-pyrrolo[1 ,2-c]thiazole]-6'- yl)acryloyl)-6,-(4-hydroxy-3-methoxyphenyl)-5-nitro-3',6',7,,7a'-tetrahydro-1'H- spiro[indoline-3,5'-pyrrolo[1 ,2-c]thiazole]-2-one
Figure imgf000030_0001
wherein the method includes the steps of
c. mixing 1 mmol of curcumin, 2 mmol of nitroisatin and 4 mmol of thioproline
(thiazolidine-4-carboxylic acid) ;
a. refiuxing the mixture from step (a) with an organic solvent.
24. A method of synthesizing (Z)-7'-(3-hydroxy-3-(7'-(3-hydroxy-4-methoxyphenyl)-1 ,3- dioxo-1 ,3,3\6\7\7a'-hexahydro-1 W-spiro[indene-2,5'-pyrrolo[1 ,2-c]thiazole]-6'- yl)acryloyl)-6'-(4-hydroxy-3-methoxyphenyl)-3',6',7',7a'-tetrahydro-1 'H-spiro[indene- 2,5'-pyrrolo[1 ,2-c]thiazole]-1 ,3-dione
Figure imgf000030_0002
wherein the method includes the steps of a. mixing 1 mmol of curcumin, 2 mmol of ninhydrin and 4 mmol of thioproline (thiazolidine-4-carboxylic acid);
b. refluxing the mixture from step (a) with an organic solvent.
25. The method as claimed in claims 17 to 24 wherein the organic solvent is preferably methanol.
PCT/MY2011/000176 2011-01-21 2011-07-22 Pyrrolothiazole containing curcumin compounds Ceased WO2012099453A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
MYPI2011000319 2011-01-21
MYPI2011000319 MY153034A (en) 2011-01-21 2011-01-21 Pyrrolothiazole containing curcumin compounds

Publications (1)

Publication Number Publication Date
WO2012099453A1 true WO2012099453A1 (en) 2012-07-26

Family

ID=46515924

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/MY2011/000176 Ceased WO2012099453A1 (en) 2011-01-21 2011-07-22 Pyrrolothiazole containing curcumin compounds

Country Status (2)

Country Link
MY (1) MY153034A (en)
WO (1) WO2012099453A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10590147B1 (en) 2019-09-10 2020-03-17 King Saud University Spirooxindole-pyrrolothiazole heterocyclic hybrids
CN112010932A (en) * 2019-05-30 2020-12-01 首都医科大学 curcumin-4-O-acetyl-Arg-Gly-Asp-Val strontium salt, and synthesis, activity and application thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ALI M.A. ET AL.: "Substituted spiro [2.3'] oxindolespiro [3.2'']-5,6-dimethoxy-indane- 1 ''-one-pyrrolidine analogue as inhibitors of acetylcholinesterase", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 20, 2010, pages 7064 - 7066 *
ANAND P. ET AL.: "Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature", BIOCHEMICAL PHARMACOLOGY, vol. 76, 2008, pages 1590 - 1611 *
BISHT S. ET AL.: "Systemic Delivery of Curcumin: 21st Century Solutions for an Ancient Conundrum", CURRENT DRUG DISCOVERY TECHNOLOGIES, vol. 6, 2009, pages 192 - 199 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112010932A (en) * 2019-05-30 2020-12-01 首都医科大学 curcumin-4-O-acetyl-Arg-Gly-Asp-Val strontium salt, and synthesis, activity and application thereof
CN112010932B (en) * 2019-05-30 2022-08-05 首都医科大学 curcumin-4-O-acetyl-Arg-Gly-Asp-Val strontium salt, and synthesis, activity and application thereof
US10590147B1 (en) 2019-09-10 2020-03-17 King Saud University Spirooxindole-pyrrolothiazole heterocyclic hybrids

Also Published As

Publication number Publication date
MY153034A (en) 2014-12-31

Similar Documents

Publication Publication Date Title
WO2012099454A1 (en) Curcumin compounds and their preparations thereof
AU2019222911B2 (en) Berberine salts, ursodeoxycholic salts and combinations, methods of prepration and application thereof
FI82940B (en) FOERFARANDE FOER FRAMSTAELLNING AV SOM LAEKEMEDEL ANVAENDBARA KOMPLEX AV EN ELLER FLERA FLAVANOLIGNANER MED EN ELLER FLERA FOSFOLIPIDER.
EP2275419B1 (en) A lubiprostone crystal, its preparation process and its use
EP2395007A1 (en) Fractionated products obtained from gamboge resin, and medical uses of the same
CN107635993A (en) Substituted tricyclic heterocyclic compounds
Kazakova et al. Diastereoselective synthesis of triterpenoid 1, 2, 4-trioxolanes by griesbaum co-ozonolysis
CN102276621B (en) Compounds isolated from gamboge resin and derivatives thereof, and pharmaceutical compositions containing these compounds and derivatives
CN108341829B (en) Artemisinin ester compound with cardiovascular and cerebrovascular disease prevention and treatment activity, preparation method and application thereof
Chen et al. Ursodeoxycholic acid platinum (IV) conjugates as antiproliferative and antimetastatic agents: remodel the tumor microenvironment through suppressing JAK2/STAT3 signaling
WO2012099453A1 (en) Pyrrolothiazole containing curcumin compounds
Chapman et al. 9, 10-Dehydroanthracene. A derivative of 1, 4-dehydrobenzene
RU2393160C2 (en) Pharmaceutical composition containing temozolomide ester
Cazelles et al. Alkylating properties of synthetic trioxanes related to artemisinin
CA2570961C (en) Anticancer and antiprotozoal dihydroartemisinene and dihydroartemisitene dimers with desirable chemical functionalities
WO2012099452A1 (en) Curcumin compounds with superior structural stability and processes for their preparation
WO2012099451A1 (en) Curcumin compounds containing indolizine and their preparations thereof
WO2008052352A1 (en) Substituted quinone indoleamine 2,3-dioxygenase (ido) inhibitors and syntheses and uses therefor
US12414960B2 (en) Analogues of oleuropein and oleacein and uses thereof
Bhalla et al. Crystal engineering of fisetin: a step towards improved biopharmaceutical parameters
CN1365278A (en) Water soluble trioxanes as potent and safe anti-malarial agents
de Lourdes Betancourt-Mendiola et al. Concentration depending fluorescence of 8-(di-(2-picolyl)) aminoBODIPY in solution
WO2017130156A1 (en) Ingenol analogs, pharmaceutical compositions and methods of use thereof
Zherdev et al. Experimental pharmacokinetics of the new neurotensine-derived antipsychotic drug dilept
JP5994059B2 (en) Azaartemisinin derivative having antimalarial activity and method for producing the same

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11856607

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11856607

Country of ref document: EP

Kind code of ref document: A1