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WO2018167801A1 - Nouveaux composés tricycliques, leur procédé de préparation et leur utilisation - Google Patents

Nouveaux composés tricycliques, leur procédé de préparation et leur utilisation Download PDF

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Publication number
WO2018167801A1
WO2018167801A1 PCT/IN2018/050137 IN2018050137W WO2018167801A1 WO 2018167801 A1 WO2018167801 A1 WO 2018167801A1 IN 2018050137 W IN2018050137 W IN 2018050137W WO 2018167801 A1 WO2018167801 A1 WO 2018167801A1
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compound
formula
cancer
afford
alkyne
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Chepuri Venkata RAMANA
Dinesh Jagannath PAYMODE
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Council of Scientific and Industrial Research CSIR
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/23—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/52—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen

Definitions

  • the present invention relates to novel compound of formula (I) and (II). More particularly, the present invention relates to novel tricyclic compound of formula (I), process for preparation and use thereof for treating or preventing cancer. The present invention further relates to novel compound of formula (I I ) which is used as intermediate for the preparation of compounds of formula (I) and process for preparation thereof.
  • Colchicine (1) is an alkaloid having a tricyclic ring structure.
  • Colchicine (1) isolated as the major alkaloid in Colchicum autumnale, is one of the oldest known natural product which leads in the search for new antitumor agents. It was used as effective medicine in keen gout attacks and in familial Mediterranean fever.
  • Colchicine is very well known for its selective binding to tubulin which disturbs the microtubule-dependent functions in the cell and thereby inhibits cellular mitosis. It binds to the cytoskeletal protein tubulin, disrupting the microtubule-dependent functions in the cell resulting in suppressing the cell division process.
  • another naturally occurring allocolchicines 2 is isolated and resembles to the colchicine.
  • AUocolchicine has been a prominent target in natural produc synthesis, and several distinct synthetic approaches are reported. These synthetic methodologies include the transformation of natural colchicines, Diels- Alder reactions, biaryl oxidative couplings, direct arylations and Nicolas reactions, Elegant routes to several variants of allocolchicines are also reported,
  • EP2952501 discloses a compound of formula (I), which may permit for a method or use in treating or preventing a cancer, such as pancreatic cancer or leukemia.
  • a method of preparing a compound of formula (la) including conducting a cyclization reaction of a compound of formula (III) to obtain a compound of formula (IV), wherein conducting the cyclization reaction comprises conducting a Michael reaction in the presence of a Lewis acid.
  • R 1 and R 2 are independently of each other H, OH, OR', C(0)OR', OP(0)(OH) 2 or a halogen atom, or R 3 ⁇ 4 and R together with adjacent phenyl carbon atoms form a ring structure selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl having one or more of N, O and S, aryl and heteroaryl having one or more of N, O and S, wherein the ring structure is optionally substituted;
  • R 3 to R 5 are independently of each other H or R';R b is R", NHR", O, OH or N 3 in the formula (I) and R6 is O or OH in the formula ⁇ II);R ' ' is H, OH or OR';R s is optionally substituted aryl, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; and R" is optionally
  • the main objective of the present invention is to provide novel tricyclic compound of formula (I) and process for preparation thereof.
  • Another objective of the present invention is to provide novel compound of formula (II), which is used as intermediate for the preparation of compounds of formula (I) and process for preparation thereof.
  • Yet another objective of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a tricyclic compound of formula (I), or a stereoisomer, or ester or pharmaceutically acceptable salt thereof, and a pharmaceutical ly acceptable carrier, diluent or excipient.
  • Still another objective of the present invention is to provide a method for treating or preventing cancer in a subject in need thereof; comprising administering to the said subject a therapeutically effective amount of the tricyclic compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • Ri and R 2 may be same or different and each is independently selected from the group consisting of H, C0 2 Me, CH 2 CH 2 CH 3, CH 2 OAc, CH 2 (CH 2 ) 2 CH 3 or Ph; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the tricyclic compound of formula (I) is selected from Methyl (l laR)-5- acetarrddo-2-butyl-9,10,l l-trimethoxy-6,7-dihydro-5H-dibenzo[a,c][7]an-nulene-3- carboxylate (21 ), Methyl ( 1 laR)-5-acetamido-3-buty 1-9, 10,1 l-trimethoxy-6,7-dihydro-5H- dibenzo[a,c][7]-aunulene-2-carboxylate (22), Dimethyl (1 laR)-5-acetamido-9,10,l 1- trimethoxy-6,7-dihydro-5H-dibenzo[a,c][7Jajnnulene-2,3-dicarboxylate (23), (5-Acetamido- 9,10,1 l-tiimethoxy-6,7-dihydro-5H-
  • the present invention provides a process for the preparation of tricyclic compound of formula (I) from dialkyne compound of formula (II) comprising the steps of: a) reacting dialkyne (15) with p-methoxy benzyl amine in presence of suitable base in acetonitrile for the period ranging from 70-80 hrs to afford alkyne (17);
  • step (a) protecting acetate group of the alkyne (17) compound of step (a) by stirring the reaction mixture comprising alkyne (17) of step (a) in dichloromethane (CH 2 C1 2 ), NEt 3 , dimethylaminopyridine (DMAP) and acetic anhydride (Ac 2 0) for the period in the range of 3-5 h to afford N-(5-(2-Ethynyl-3,4,5-trimethoxyphenyl)pent-l-yn-3-yl)-N-(4- methoxybenzyl)acetamide (18);
  • step (b) reacting the acetamide (18) of step (b) with alkyne in presence of cyclopentadienylcobalt dicarbonyl [CpCO(CO) 2 ] under light for the period in the range of 10- 12 h to afford mixture of regioisomers followed by subjecting said mixture deprotection of p- methoxybenzyl group of amine by using trifluoroacetic acid/CH 2 Cl 2 to afford compound of formula (I) .
  • the process is carried out at temperature in the range of 25 to 30°C.
  • the suitable base in step (a) is caesium carbonate or calcium carbonate.
  • the alkyne in step (c) is selected from methyl propiolate, acetylene, Methyl 2-heptynoate, dimethyl acetylenedicarboxylate, ester of butyne diol, 4-Octyne or Methyl 3- ph en y Ipropi ol ate .
  • the present invention provides novel compound of formula (II) which are used as intermediate for the reparation of compounds of formula (I);
  • R 1 is selected from CI, NHPMB or N(Ac)PMB.
  • the compound of formula (II) is l-(3-Chloropent-4-yn-l-yl)-2- ethynyl-3,4,5-trimethoxybenzene (15), 5-(2-Ethynyl-3,4,5-trimethoxyphenyl)-N-(4- methoxybenzyl)pent-l-yn-3-amine (17) or N-(5-(2-Ethynyl-3,4,5-trimethoxyphenyl)pent-l- yn-3-yl)-N-(4-methoxybenzyl)acetamide (18).
  • the present invention provides a process for the preparation of novel compound of formula (II) from 3, 4, 5, trimethoxybenzaldehyde comprising the steps of:
  • step (b) deoxygenating alcohol (7) of step (a) with suitable deoxygenating agent in presence of boron trifluoride diethyl etherate to afford aikene (8);
  • step (b) subjecting aikene compound of step (b) for oxidative cleavage to afford aldehyde
  • step (d) subjecting iodo compound (11) of step (d) to sonogashira cross-coupling with trimethylsilylacetylene in the presence of bis(triphenylphosphine)palladium(II) dichloride and copper iodide in dimethylformam de/diethy] amine at temperature ranging from 70 to 90 °C to afford protected compound (12) followed by one pot silyi and acetate deprotection using potassium carbonate as a base in methanol to afford alcohol (13); f) oxidizing alcohol (13) of step (e) with suitable oxidizing agent to afford aldehyde (14);
  • step (g) reacting compound of formula (II) of step (g) with >-methoxybenzyl amine in presence of suitable base in acetonitrile for the period ranging from 70-80 hrs to afford the desired compound of formula (II) wherein R 1 is -NHPMB; and i) protecting acetate group of compound of step (h) by stirring the reaction mixture comprising compound of step (h) in dichloromethane (CH 2 C1 2 ), NEt 3 , dimethylaminopyridine (D AP) and acetic anhydride (Ac 2 0) for the period in the range of 3-5 h to afford desired compound of formula (II) wherein R 1 is - N(Ac)PMB;
  • the suitable deoxygenating agent in step (b) is triethylsilane (Et 3 SiH).
  • the suitable oxidizing agent in step (f) is Dess-Martin periodinane.
  • the suitable chlorinating agent in step (g) is n- chl oro s ucc inamide (NC S ) .
  • the present invention provides a pharmaceutical composition comprising a tricyclic compound of formula (I), or a stereoisomer, or ester or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention provides a method for treating or preventing cancer in a subject in need thereof; comprising administering to the said subject a therapeutically effective amount of the tricyclic compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the cancer is lung cancer, breast cancer, colorectal cancer, prostate cancer, a leukemia, a lymphoma, non-Hodgkin's lymphoma, skin cancer, a brain cancer, a cancer of the central nervous system, ovarian cancer, uterine cancer, stomach cancer, pancreatic cancer, esophageal cancer, kidney cancer, liver cancer, or a head and neck cancer.
  • Fig. 1 depicts the graph which shows the cytotoxic effect of Compound 2 on A431 , LN229, HEK293T and SiHa.
  • Fig. 2 depicts the graph which shows the cytotoxic effect of Compound 19 on A431, LN229, HEK293T and SiHa,
  • Fig. 3 depicts the graph which shows the cytotoxic effect of Compound 20 on A431 , LN229, HEK293T and SiHa.
  • Fig. 4 depicts the graph which shows the cytotoxic effect of Compound 22 on A431, LN229, HEK293T and SiHa,
  • Fig. 5 depicts the graph which shows the cytotoxic effect of Compound 23 on A431 , LN229, HEK293T (with IC 50: 189.596) and SiHa ,
  • Fig. 6 depicts the graph which shows the cytotoxic effect of Compound 25 on A431, LN229, HEK293T and SiHa.
  • phrases "pharmaceutically acceptable salt,” as used herein, is a salt formed from an acid and a base, for example an acidic or a basic salt of a molecule.
  • An "effective amount" when used in connection with a compound of the invention is an amount of the compound of the invention, individually or in combination, that is effective for treating or preventing a condition individually or in combination with another compound of the invention.
  • the present invention provides novel tricyclic compounds of formula (I) and process for the preparation thereof.
  • the present invention further provides novel compounds of formula (II) which are used as intermediate for the preparation of compounds of formula (I) and process for preparation thereof.
  • the present invention provides a novel tricyclic compound of formula (I);
  • R. and R 2 may be same or different and each is independently selected from H, C0 2 Me, CH2CH2CH3, CH 2 OAc, CH 2 (CH 2 )2CH 3 , Ph.
  • the tricyclic compound of formula (I) is selected from
  • the present invention provides a process for the preparation of compounds of formula (I) from compound of formula (II) comprising the steps of:
  • dialkyne (15) with p-methoxy benzyl amine in presence of suitable base in acetonitrile for the period ranging from 70-80 hrs to afford alkyne (17).
  • step (a) protecting acetate group of compound of step (a) by stirring the reaction mixture comprising alkyne (17) in dichloromethane (CH 2 C1 2 ), NEt 3 , dimethylaminopyridine (DMAP) and acetic anhydride (Ac 2 0) for the period in the range of 3-5 h to afford N-(5- (2-Ethynyl-3,4,5-trimethoxyphenyl)pent-l-yn-3-yl)-N-(4-methoxybenzyl)acetamide (18);
  • step (a) reacting 18 of step (b) with alkyne in presence of cyclopentadienylcobalt dicarbonyl [CpCO(CO) 2 ] under light for the period in the range of 10-12 h to afford mixture of regioisomers followed by subjecting said mixture deprotection of p-methoxybenzyl group of amine by using trifluoroacetic acid/CH 2 Cl 2 to afford compound of formula (I).
  • the suitable base in step (a) is caesium carbonate, calcium carbonate.
  • the aikyne in step (c) is selected from methyl propiolate, acetylene, Methyl 2-hept noate, dimethyl acetyienedicarboxylate, ester of butyne dial, 4-Octyne or Methyl 3- pheny lpropiolate .
  • the process is carried out at temperature in the range of 25 to 30°C.
  • R 3 ⁇ 4 and R 2 may be same or different and each is independently selected from H, C0 2 Me, CH 2 CH2CH3, CH 2 OAc, CH 2 (CH 2 )2CH 3 , Ph.
  • the present invention provides a novel compound of formula (II) which is used for the preparation of compounds of formula (I);
  • R-. is selected from CI, NHPMB or N(Ac)PMB.
  • the compound of formula (II) is l-(3-Chloropent-4-yn-l-yl)-2- ethynyl-3,4,5-trirnethoxybenzene (15), 5-(2-Ethyny 1-3,4, 5-trimethoxyphenyl)-N-(4- methoxybenzyI)pent- l-yn-3-amine ( 17) or N-(5-(2-Etiiynyl-3,4,5-trimethoxyphenyl)pent-l- yn-3-yl)-N-(4-methoxybenzyl)acetamide (18).
  • the present invention provides a process for the preparation of novel compounds of formula (II) from 3, 4, 5, trimethoxybenzaldehyde comprising the steps of: a) subjecting 3, 4, 5, trimethoxybenzaldehyde (6) for grignard reaction with A- bromobut-l-ene to afford alcohol (7);
  • step (b) deoxygenating alcohol (7) of step (a) with suitable deoxygenating agent in presence of boron trifluoride diethyl etherate to afford aikene (8);
  • step (b) subjecting aikene compound of step (b) for oxidative cleavage to afford aldehyde
  • step (d) subjecting iodo compound (11) of step (d) to sonogashira cross-coupling with trimethylsilylacetylene in the presence of bis(triphenylphosphine)palladium(II) dichloride and copper iodide in dimethylformamide/diethyl amine at temperature ranging from 70 to 90 °C to afford protected compound (12) followed by one pot silyl and acetate deprotection using potassium carbonate as a base in methanol to afford alcohol (13);
  • step (e) oxidizing alcohol (13) of step (e) with suitable oxidizing agent to afford aldehyde (14);
  • N(A ⁇ :)PM B The suitable deoxygenating agent in step (b) is triethylsilane (Et 3 SiH).
  • the suitable oxidizing agent in step (f) is Dess-Martin periodinane.
  • the suitable chlorinating agent in step (g) is n- chlorosuccinamide (NCS).
  • the resulting ester 10 is then treated with I 2 /CF 3 COOAg in CHC1 3 , afford iodo compound 1 1 with 85% yield.
  • the stage is set for the installation of first alkyne required for cyclotrimerisation.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer, or ester or pharmaceut cally acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient known in the art.
  • excipients or carriers are selected from the group such as diluents, disintegrants, crosslinked polymers, binders, lubricants, coatings layer.
  • the present invention relates to administering 'an effective amount' of the 'composition of invention' to the subject suffering from cancer.
  • compound of the invention and pharmaceutical compositions containing them may be administered using any amount, any form of pharmaceutical composition via any route of administration effective for treating the disease.
  • Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal.
  • compositions can be administered to a subject or patient may take the form of one or more dosage units.
  • dosage forms can also be prepared as sustained, controlled, modified and immediate dosage forms.
  • compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid, such as tablets, capsules, powders, granules, ointments, solutions, injections, gels and microspheres.
  • compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient.
  • Compositions that will be administered to a subject or patient may take the form of one or more dosage units.
  • the dosage forms can also be prepared as sustained, controlled, modified and immediate dosage forms.
  • the present invention provides a method for the treating or preventing cancer in a subject in need thereof; comprising administering to the said subject a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for treating or preventing cancer comprising administering to a subject in need thereof an effective amount of said composition.
  • the present invention provides a method, wherein the cancer is lung cancer, breast cancer, colorectal cancer, prostate cancer, a leukemia, a lymphoma, non- Hodgkin's lymphoma, skin cancer, a brain cancer, a cancer of the central nervous system, ovarian cancer, uterine cancer, stomach cancer, pancreatic cancer, esophageal cancer, kidney cancer, liver cancer, or a head and neck cancer.
  • the cancer is lung cancer, breast cancer, colorectal cancer, prostate cancer, a leukemia, a lymphoma, non- Hodgkin's lymphoma, skin cancer, a brain cancer, a cancer of the central nervous system, ovarian cancer, uterine cancer, stomach cancer, pancreatic cancer, esophageal cancer, kidney cancer, liver cancer, or a head and neck cancer.
  • compositions of compounds of formula (I) are used as antimitotic agent, anti- microtubule agents.
  • compositions of compounds of formula (I) shows the cytotoxic effect against cell lines selected from A431 (epidermoid carcinoma), LN229 (brain cancer), HEK293T (control/normal) and SiHa (cervical cancer).
  • Fig. 1 depicts the graph which shows the cytotoxic effect of molecule (compound 2) on A431 (with IC 50: 128.8452 ⁇ ig/ml), LN229 (with IC 50: 220.0269 .ug/ml), HE 293T (with IC 50: 171.9255 p.g/ml) and SiHa (with IC 50: 488.8137 .ug/ml).
  • compound 2 shows the graph which shows the cytotoxic effect of molecule (compound 2) on A431 (with IC 50: 128.8452 ⁇ ig/ml), LN229 (with IC 50: 220.0269 .ug/ml), HE 293T (with IC 50: 171.9255 p.g/ml) and SiHa (with IC 50: 488.8137 .ug/ml).
  • Fig. 1 depicts the graph which shows the cytotoxic effect of molecule (compound 2) on A431 (with
  • Fig. 3 depicts the graph which shows the cytotoxic effect of molecule (compound 20) on A431 (with IC 50: 128.3682 p.g/ml), LN229 (with IC 50: 149.7078 g/ml), HEK293T (with IC 50: 167.3332 ⁇ ) and SiHa (with IC 50: 194.8697 ⁇ g/ml).
  • Fig. 4 depicts the graph which shows the cytotoxic effect of molecule (compound 22) on A431 (with IC 50: 150.4805 ⁇ ), LN229 (with IC 50: 195.8868 ⁇ / ⁇ ), HEK293T (with IC 50: 219.9398 ⁇ g/ml) and SiHa (with IC 50: 216.9956 ⁇ ).
  • Fig. 5 shows the cytotoxic effect of molecule (compound 23) on A431 (with IC 50: 161.304), L 229 (with IC 50: 202.105 g/ml), HEK293T (with IC 50: 189.596 ⁇ g/ml) and SiHa (with IC 50: 155.583 ⁇ g/ml).
  • Fig. 6 shows the cytotoxic effect of molecule (compound 25) on A431 (with IC 50: 145.36), LN229 (with IC 50: 166.835 ⁇ g/rnl), HEK293T (with IC 50: 151.768 ⁇ g/mi) and SiHa (with IC 50: 151.52 ⁇ ).
  • Example 2 Synthesis ofl-(3,4,5-Trimethoxyphenyl)pent-4-en-l-ol (8): To a cooled solution of the alcohol 7 (23.0 g, 91.16 mmol) in anhydrous CH 2 C1 2 (400 mL), triethylsilane (18.9 mL, 118.51 mmol) and boron trifluoride diethyl etherate (16.9 mL, 136.74 mmol) was added slowly one by one and stirring was continued at 25 °C for 6 h. The reaction mixture was quenched with saturated NaHC0 3 solution (200 mL) and the aqueous layer was extracted with CH 2 CI 2 (2 x 300 mL).
  • Example 3 Synthesis of 4-(3,4,5-Trimethoxyphenyl)butyl acetate (10): To a solution of 8 (20.0 g, 84.63 mmol) in 1,4-dioxane/water (9: 1, 400 mL), Mn0 4 (14.7 g, 93.10 mmol) was added and the contents were stirred at 25 °C for 4h. The reaction mixture was filtered through celite pad and crude was extracted with EtOAc (3 x 300 mL). The combined organic layer was dried (Na 2 SC1 ⁇ 4), and concentrated under vacuum. The crude was used for next step as such without purification.
  • the diyne 18 (1 equiv) and alkyne (2.5 equiv) were placed in a screw-capped pressure tube and dissolved in anhydrous toluene (2 mL), which was then evacuated and back-filled with argon.
  • CpCo(CO)? (20 mol %) was added to the reaction vessel.
  • the solution was then stirred under light (200 W) until consumption of the starting material.
  • the reaction mixture was cooled to 25 °C and the crude filtered through Celite pad and concentrated, and the crude product was subjected to N-PMB group deprotection.
  • the alkyne 18 (30 mg, 0.069 mmol) and methyl propiolate (0.02 mL, 0.207 mmol) was placed in a screw cap pressure tube and dissolved in anhydrous toluene (2 mL), which was then evacuated and back filled with argon.
  • CpCo(CO) 2 (0.69 mL, 0.2 M, 20 mol%) was added. The solution was then stirred under light (200 W) for 12 h. The reaction mixture was cooled to 25 °C. The crude filtered through Celite pad, solvent was evaporated and the crude was subjected to further reaction.
  • Example 17 Synthesis of (5-Acetamido-9,10,ll-trimethoxy-6,7-dihydro-5H- dibenzo[a,c] [7]annulene-2,3-diyl)bis(me-thylene) diacetate (24) : The reaction was carried out similar to general procedure for trimerization with alkyne 18 (40 mg, 0.092 mmol) and ester of butyne diol. The analogue 24 (31 mg, 69%) was obtained as white solid. 0.2 (80% EtOAc in pet. ether); 1H NMR (400 MHz, CDCI 3 ): ⁇ 1.78-1.85 (m. i l l ).
  • MTT cytotoxicity assay was performed for estimation of dosages, and determination of bioactivity of compounds.
  • MTT assay which is based on formation of formazan crystals upon addition of MTT salt, indirectly represents cell viability as reduction of MTT can only occur in metaboiicaily active cells.
  • the formazan crystals were dissolved in isopropanol which gives purple color and the intensity of color directly represent cell vibility w.r.t control cells.
  • NCL molecules cytotoxic potential of all three molecules were measured after 48 hours and dose response curves were made as shown below by reading the absorbance of purple color at 570nm in a microplate reader.

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  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau composé tricyclique de formule (I), son procédé de préparation et son utilisation dans le traitement du cancer. La présente invention concerne en outre un nouveau composé de formule (II) qui est utilisé comme intermédiaire pour la préparation de composés de formule (I) et son procédé de préparation.
PCT/IN2018/050137 2017-03-14 2018-03-14 Nouveaux composés tricycliques, leur procédé de préparation et leur utilisation Ceased WO2018167801A1 (fr)

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IN201711008764 2017-03-14
IN201711008764 2017-03-14

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150344411A1 (en) * 2014-06-03 2015-12-03 University Of Windsor Catalytic Method for Dibenzocycloheptane Synthesis and Allocolchicinoid Synthesis

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150344411A1 (en) * 2014-06-03 2015-12-03 University Of Windsor Catalytic Method for Dibenzocycloheptane Synthesis and Allocolchicinoid Synthesis

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEPURI V. RAMANA ET AL.: "An Alkyne [2+2+2]-Cyclotrimerization Approach for Synthesis of 6,7-Cyclopropylallocolchicinoids", J. ORG. CHEM., vol. 81, no. 8, 2016, pages 3400 - 3406, XP055556969 *

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