WO2004024058A2 - Molecules a activite antitumorale, et procede de synthese chimique - Google Patents

Molecules a activite antitumorale, et procede de synthese chimique Download PDF

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Publication number
WO2004024058A2
WO2004024058A2 PCT/BR2003/000128 BR0300128W WO2004024058A2 WO 2004024058 A2 WO2004024058 A2 WO 2004024058A2 BR 0300128 W BR0300128 W BR 0300128W WO 2004024058 A2 WO2004024058 A2 WO 2004024058A2
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WO
WIPO (PCT)
Prior art keywords
acridin
methylene
thiazolidine
dione
benzyl
Prior art date
Application number
PCT/BR2003/000128
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English (en)
Other versions
WO2004024058A3 (fr
Inventor
Ivan Da Rocha Pitta
Maria Do Carmo Alves De Lima
Suely Lins Galdino
Jacques Barbe
Original Assignee
Conselho Nacional De Desenvolvimento Científico E Tecnológico - Cnpq
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 Conselho Nacional De Desenvolvimento Científico E Tecnológico - Cnpq filed Critical Conselho Nacional De Desenvolvimento Científico E Tecnológico - Cnpq
Publication of WO2004024058A2 publication Critical patent/WO2004024058A2/fr
Publication of WO2004024058A3 publication Critical patent/WO2004024058A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention is related to acridine-thiazolidine and acridine- imidazolidine compounds denominated, respectively, thiazacridine and imidazacridine, which displayed an antitumor activity, and the respective processes for their chemical synthesis as well as their therapeutic use as anticancer agents.
  • STATE OF THE TECHNIQUE It is known that the azolidines and the acridines are effective compounds against infectious diseases. LHOMME et al., PCT Int. Appl. WO 94 25,439 (Cl. C07D219/08), 10 Nov 1994, FR. Appl.
  • the synthesized compounds described in this invention belong to a new series of thiazacridine derivatives, 5-(acridin-9-yl-methylene)-3-(benzyl)- thiazolidine-2,4-dione substituted or not at the aromatic ring in position 3; 5- (acridin-9-yl-methylene)-3-(2-phenyl-2-oxo-ethyl)-thiazolidine-2,4-dione substituted at the aromatic ring in position 3; 5-(acridin-9-yl-methylene)-3-(4- bromo-benzyl)-4-thio-thiazolidin-2-one substituted or not at the aromatic ring in position 3. All these compound possess pharmacological and antitumor activities.
  • the synthesis of the thiazolidine part takes place through the benzylation or phenacylation of the thiazolidine-2,4-dione followed or not by the thionation in position 4 in presence of phosphorous pentasulfide.
  • the preparation of the imidazolidine part of the molecule was obtained by the benzylation of the imidazoline-2,4-dione followed by the thionation in position 4 in presence of phosphorous pentasulfide.
  • Fig. 1 represents the general formula of thiazacridine compounds, 5-(acridin- 9-yl-methylene)-3-(benzyl)-thiazolidine-2,4-dione.
  • the R radical corresponds to the substituants: hydrogen (AC24), chlorine (AC10) and fluorine (AC23), all in para position.
  • the IUPAC nomenclature, the configuration of the isolated product, the code of the compound, their empirical formula and the melting point are specified below:
  • Fig. 2 represents the general formula of the thiazacridine compounds, 5- (acridin-9-yl-methylene)-3-(2-phenyl-2-oxo-ethyl)-thiazolidine-2,4-dione.
  • the R, radical corresponds to the substituants: nitro (AC8), phenyl (AC12), chlorine (AC14), fluorine (AC15) and bromine (AC16), all in para position.
  • Fig. 3 represents the formula of the thiazacridine compound, 5-(acridin-9-yl- methylene)-3-(4-bromo-benzyl)-4-thio-thiazolidin-2-one (AC18).
  • IUPAC nomenclature the configuration of the isolated product, the code of the compound, their empirical formula and the melting point are specified below: 5-(acridin-9-yl-methylene)-3-(4-bromo-benzyl)-4-thio- thiazolidin-2-one, (Z), (AC-18), C 24 H 16 BrN 2 OS 2 , F213-215 9 C.
  • Fig. 4 represents the general formula of the imidazacridine compounds, 5- (acridin-9-yl-methylene)-3-benzyl-4-thio-imidazolidin-2-one.
  • the R 2 radical corresponds to the substituants: hydrogen (AC28), chlorine (AC26), nitro (AC27), all in para position.
  • the IUPAC nomenclature, the configuration of the isolated product, the code of the compound, their empirical formula and the melting point are specified below:
  • mice were used for the in vivo evaluation of the antitumor activity of the invented compounds. They were infected by implant of the solid tumor sarcoma 180. Ten to twelve days later, they were anesthetized and sacrificed with diethyl ether. Thereafter, an incision was performed, the mass of the tumor was removed under aseptic conditions and placed in plate of Petri. Selected fragments with approximately 3 mm of diameter were then implanted in the right axillary area of the receiver animals. The latter animals were divided into two groups: one group received the invented compound (treated group) and the other, used as control, received only the isotonic saline (0.9%) solution.
  • Procedure of preparation of the acridin-9-carboxaldehvde The diphenylamine, the acetic acid and the zinc chloride were heated at a temperature of 220 9 C, for 8 hours. The mixture was treated initially with a solution of sulfuric acid at 10% and, after, alkaline was made with a solution of ammonia at 30%. The 9-methyl-acridine was firstly isolated through an extraction with benzene and later purified through flash chromatography on silica.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

L'invention porte sur la synthèse et la structure de nouveaux composés d'acridine-thiazolidine-thiazacridine et d'acridine-imidaziolidine-imidazacridine à activité antitumorale, et sur leur utilisation thérapeutique comme agents anticancéreux.
PCT/BR2003/000128 2002-09-10 2003-09-09 Molecules a activite antitumorale, et procede de synthese chimique WO2004024058A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
BRPI0203747-5 2002-09-10
BR0203747-5A BR0203747A (pt) 2002-09-10 2002-09-10 Moléculas com atividade antitumoral e processo para a sua obtenção

Publications (2)

Publication Number Publication Date
WO2004024058A2 true WO2004024058A2 (fr) 2004-03-25
WO2004024058A3 WO2004024058A3 (fr) 2004-05-27

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/BR2003/000128 WO2004024058A2 (fr) 2002-09-10 2003-09-09 Molecules a activite antitumorale, et procede de synthese chimique

Country Status (2)

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BR (1) BR0203747A (fr)
WO (1) WO2004024058A2 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006066846A1 (fr) * 2004-12-23 2006-06-29 Cell Therapeutics Europe S.R.L. Utilisation de derives de thiazolidinone comme agents antiangiogeniques
WO2007109871A2 (fr) * 2006-03-24 2007-10-04 Universidade Federal De Pernambuco - Ufpe Dérives d'acridine a activite antitumorale
EP1959958A1 (fr) * 2005-11-14 2008-08-27 University Of Southern California USC Stevens Petites molecules de liaison a une integrine
WO2012119212A1 (fr) * 2011-03-10 2012-09-13 Universidade Federal De Pernambuco Molécules imidazolidiniques et thiazolidiniques à activité anti-t.cruzi
WO2013053034A2 (fr) * 2011-10-10 2013-04-18 Universidade Federal De Pernambuco - Ufpe Thiazacridines utilisées dans la thérapie anticancéreuse
CN107954938A (zh) * 2017-12-01 2018-04-24 苏州艾缇克药物化学有限公司 一种1h-咪唑-4-甲酸的合成方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SILVA, T.G. ET AL.: 'Synthesis and structural elucidation of new benzylidene imidazolidines and acridinylidene thiazolidines' HETEROCYCL. COMMUN. vol. 7, no. 6, 2001, pages 523 - 528, XP002975509 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006066846A1 (fr) * 2004-12-23 2006-06-29 Cell Therapeutics Europe S.R.L. Utilisation de derives de thiazolidinone comme agents antiangiogeniques
JP2008525340A (ja) * 2004-12-23 2008-07-17 チェル テラペウティクス ユーロペ ソシエタ ア レスポンサビリタ リミタータ 抗血管新生薬としてのチアゾリジノン誘導体の使用
EP1959958A1 (fr) * 2005-11-14 2008-08-27 University Of Southern California USC Stevens Petites molecules de liaison a une integrine
EP1959958A4 (fr) * 2005-11-14 2010-07-14 Univ Southern California Petites molecules de liaison a une integrine
WO2007109871A2 (fr) * 2006-03-24 2007-10-04 Universidade Federal De Pernambuco - Ufpe Dérives d'acridine a activite antitumorale
WO2007109871A3 (fr) * 2006-03-24 2009-06-11 Univ Fed De Pernambuco Ufpe Dérives d'acridine a activite antitumorale
WO2012119212A1 (fr) * 2011-03-10 2012-09-13 Universidade Federal De Pernambuco Molécules imidazolidiniques et thiazolidiniques à activité anti-t.cruzi
WO2013053034A2 (fr) * 2011-10-10 2013-04-18 Universidade Federal De Pernambuco - Ufpe Thiazacridines utilisées dans la thérapie anticancéreuse
WO2013053034A3 (fr) * 2011-10-10 2013-06-27 Universidade Federal De Pernambuco - Ufpe Thiazacridines utilisées dans la thérapie anticancéreuse
CN107954938A (zh) * 2017-12-01 2018-04-24 苏州艾缇克药物化学有限公司 一种1h-咪唑-4-甲酸的合成方法

Also Published As

Publication number Publication date
WO2004024058A3 (fr) 2004-05-27
BR0203747A (pt) 2004-05-25

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