Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
  • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
  • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
  • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
  • C07D493/10—Spiro-condensed systems
• • 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
  • C07D495/02—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 two hetero rings
  • C07D495/10—Spiro-condensed systems

Definitions

• the present invention relates to griseofulvin derivatives and their use for the treatment of cancerous and pre-cancerous hyperproliferative pathologies.
• Griseofulvin 1 is a natural molecule isolated from filamentous fungus cultures Penicilium griseofulvum [J. Chem. Soc. 1958, 360-365]. It is used in the treatment of fungal diseases of the skin in humans and is also used in veterinary medicine. It is administered primarily orally at doses of 0.5 to 1.0 grams per day in humans.
• griseofulvin derivatives substituted at 2 'with oxygen or sulfur groups [J. Med. Chem. 2009, 3342-3347] have been synthesized. However, none of these products has demonstrated the potential to be used as a drug in the treatment of cancerous and pre-cancerous hyperproliferative diseases.
• the inventors have thus surprisingly discovered that the addition of a particular 2 'and / or 3' group makes it possible to obtain more potent cytotoxic derivatives than griseofulvin and that its analogs previously described have remarkable activity on cancerous lines. particularly resistant to known cytotoxic agents.
• the present invention thus relates to a compound of general formula (I) below:
• rrrr represents a single or double bond
• Z represents a group -S (O) R 7 or -S (O) 2 R 7
• Z represents a hydrogen atom or a group R 9 and X represents a group CH-Rio when rrrr represents a single bond or C-Rio when rrrr represents a double bond,
• ⁇ Ri to R 5 representing, independently of each other, a hydrogen atom or a (Ci-C 6) alkyl, aryl, (Ci-C 6) alkyl-aryl, aryl- (Ci-C 6) alkyl or 5- or 6-membered heterocycle,
• ⁇ R O is a hydrogen atom or a (Ci-Ce) alkyl, aryl, (Cl- C6) alkyl-aryl, aryl- (Ci-C 6) alkyl, C (0) NH 2, C ( S) NH 2 or 5- or 6-membered heterocycle,
• R 7 is (C 1 -C 6) alkyl, aryl, (C 1 -C 6 ) alkyl-aryl, aryl (C 1 -C 6 ) alkyl or 5- or 6-membered heterocycle,
• R 9 is a group -R 4, -NHRi, -CH 2 -NHRi 4, -CH 2 -CH 2 -NH-C (O) -Rn, -NH-CH 2 -Rn, -NH-NH-Rn, -NH-C ( 0) -Rn, -NH-C (O) -CH 2 -Rn, -NH-CH 2 -C (O) -Rn, -NH-CH 2 -C (O) -O-Rn, -NH-CH 2 -C (O) -NH-Rn, -NH-S0 2 -Rn, -S (O) -Rn, -SO 2 -Rn, -S (O) -CH 2 -R n , -SO 2 -CH 2 -R n , or -NRi 2 Ri 3
• ⁇ R 9 is a group -R 4, -NHRi, -CH 2 -NHRi
• ⁇ Ru represents a hydrogen atom or a (Ci-Ce) alkyl, carbocycle, heterocycle, biaryl, carbocycle- (Ci-C6) alkyl or heterocycle (Ci-C6) alkyl optionally substituted,
• ⁇ R12 and R13 form, together with the nitrogen atom which carries them, a heterocycle optionally substituted with one -rU group, or -ORn -NHRn,
• R 4 is (C 1 -C 6) alkyl, carbocycle, heterocycle, biaryl, carbocycle (C 1 -C 6) alkyl or optionally substituted (C 1 -C 6) alkyl heterocycle,
• R 15 is optionally substituted (C 1 -C 6 ) alkyl, optionally substituted aryl, (C 1 -C 6 ) alkyl aryl, aryl (C 1 -C 6) alkyl, carbocycle, optionally substituted heterocycle, biaryl, carbocycle (C 1 -C 6 ) C6) alkyl or heterocycle (Ci-C 6) alkyl, and
• Ri6 and Ri 7 together with the nitrogen atom carrying them a heterocycle optionally substituted with a group -Ri 4 , -ORi 4 or -NHRi.
• part Y of the molecule of formula (I) mentioned above may comprise one or more asymmetric carbon atoms which may each be present in the R or S configuration or in the form of a mixture of the two configurations R and S in all proportions, especially in equimolar proportions.
• the term "pharmaceutically acceptable” means that which is useful in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither biologically nor otherwise undesirable and which is acceptable for veterinary as well as pharmaceutical use. human.
• pharmaceutically acceptable salts of a compound is meant in the present invention salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity of the parent compound.
• inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulphonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-acid toluenesulphonic acid, trimethylacetic acid, trifluoroacetic acid and the like.
• organic acids such as acetic acid, benz
• halogen atom means the fluorine, chlorine, bromine and iodine atoms.
• (Ci-C 6) alkyl is understood within the meaning of the present invention, a saturated hydrocarbon chain, linear or branched, having 1 to 6 carbon atoms. It may be in particular a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl group.
• (C 1 -C 6 ) alkoxy means a (C 1 -C 6 ) alkyl group as defined above bonded to the remainder of the molecule via an atom. oxygen. It may be in particular a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy or n-hexoxy group.
• aryl means an aromatic hydrocarbon group preferably comprising from 5 to 10 carbon atoms and comprising one or more contiguous rings, preferably 1 or 2 rings, for example a grouping. phenyl or naphthyl. Advantageously, it is phenyl.
• (Ci-C 6 ) alkyl-aryl means a (C 1 -C 6 ) alkyl group as defined above bonded to the remainder of the molecule by via an aryl group as defined above. It may be in particular a tolyl group.
• aryl- (Ci-C 6) alkyl is understood within the meaning of the present invention, an aryl group as defined above bound to the rest of the molecule via a (Ci-C 6 ) alkyl as defined above. It may be in particular a benzyl group.
• biasing is meant, within the meaning of the present invention, an aryl group as defined above linked to the remainder of the molecule through an aryl group as defined above. It may be in particular a biphenyl group.
• heteroaryl group is meant, in the sense of the present invention, an aryl group as defined above in which one or more carbon atoms have been replaced by one or more heteroatoms, advantageously 1 to 4, preferably 1 to or 2.
• heteroaryl groups are pyridine, pyrimidine, pyrazine, pyridazine, furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, triazole, tetrazole, benzo furan, benzothiophene, indole, benzimidazole, indazole, quinoline, isoquinoline, quinazoline or quinoxaline.
• heteroatom in particular an atom of sulfur, nitrogen or oxygen.
• the term "carbocycle” means one or more contiguous rings, preferably 1 or 2 fused, hydrocarbon, saturated, unsaturated or aromatic rings, each ring advantageously having 3 to 8 ring members, preferably 3, 5, 6 or 7 members, and more preferably 5 or 6 members. It may be in particular cycloalkyl, such as cyclopentyl or cyclohexyl.
• the term "unsaturated" means that the ring comprises one or more double bonds.
• the term "carbocycle- (C 1 -C 6 ) alkyl” is intended to mean a carbocycle group as defined above bonded to the remainder of the molecule via a (Ci-C) group. 6 ) alkyl as defined above, and preferably via a group -CH 2 -. It may be in particular a cyclopentylmethyl or cyclohexylmethyl group.
• heterocycle is intended to mean a carbocycle group as defined above in which one or more carbon atoms have have been replaced by one or more heteroatoms, advantageously 1 to 4, preferably 1 or 2.
• heterocycle comprising a single ring are epoxide rings, aziridine, furan, dihydrofuran, tetrahydrofuran, pyrrole, pyroline, pyrrolidine, thiophene, dihydrothiophene , tetrahydrothiophene, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline, imizadolidine, thiazole, dihydrothiazole, tétrahydrothiazole, oxazole, dihydrooxazole, tétrahydrooxazole, triazoles, dihydrotriazoles, tétrahydrotriazoles, pyridine, dihydropyridine, tetrahydr
• heterocycles comprising two fused rings are the aforementioned 1-ringed heterocycles fused with one phenyl ring, such as indole, benzofuran, benzopyrans including chromene and isochromene, and dihydrobenzopyrans including chroman and quinoline. dihydroquinolines, tetrahydroquinoline, isoquinoline, dihydroisoquinolines and tetrahydroisoquinoline.
• (C 1 -C 6 ) -cyclo-heterocycle means a heterocycle group as defined above bonded to the remainder of the molecule via a (C 1 -C 4) group. 6 ) alkyl as defined above, and preferably via a group -CH 2 -.
• cycloalkyl is intended to mean a saturated hydrocarbon monocycle, advantageously comprising 3 to 8 carbon atoms, in particular 5 or 6. This may especially be cyclohexyl.
• R 1 to R 5 represent, independently of one another, a hydrogen atom or a (C 1 -C 6 ) alkyl, aryl, (C 1 -C 6 ) alkyl-aryl or aryl- (C 1 -C 6 ) alkyl group ,
• ⁇ R O represents a hydrogen atom or a (Ci-C 6) alkyl, aryl, (Cl- C6) alkyl-aryl, aryl- (Ci-C 6) alkyl, C (0) NH 2 or C (S) NH 2
• ⁇ R 7 represents a (Ci-Ce) alkyl, aryl, (Ci-C6) alkyl-aryl or aryl- (Cl- C6) alkyl.
• rrrr will advantageously represent a double bond.
• Z represents a group -S (O) R 7 or -S (O) 2 R 7
• R 7 represents a (C 1 -C 6) alkyl, aryl, (C 1 -C 6) alkylaryl or aryl (C 1 -C 6) group;
• C 6 alkyl, preferably an aryl or (C 1 -C 6 ) alkyl-aryl group.
• Ru will advantageously represent a hydrogen atom or a (C 1 -C 6 ) alkyl, carbocycle, heterocycle, biaryl, carbocycle- (C 1 -C 6 ) alkyl or optionally substituted (C 1 -C 6 ) alkyl heterocycle; in particular a hydrogen atom or a (C 1 -C 6) alkyl, carbocycle, heterocycle or optionally substituted biaryl group; preferentially a hydrogen atom or a (C 1 -C 6 ) alkyl group such as a CH 3 group; for example a hydrogen atom,
• the carbocycle being advantageously a cycloalkyl such as cyclohexyl or an aryl such as phenyl or naphthyl,
• the heterocycle being advantageously pyridine, pyrimidine, pyridazine, pyrazine, furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, oxazole, triazoles, benzo furan, benzothiophene, indole, 1,3-benzodioxolane, piperidine, morpholine or piperazine; more particularly pyridine, furan, thiophene, pyrrole, benzofuran, benzothiophene, indole, 1,3-benzodioxolane or piperidine; and especially pyridine, furan, thiophene, benzofuran, 1,3-benzodioxolane or piperidine, and the biaryl being advantageously biphenyl.
• Z preferably represents a hydrogen atom.
• R9 preferably represents a group R14
• R 14 then preferably representing a hydrogen atom or a (C 1 -C 6 ) alkyl, carbocycle, heterocycle, biaryl, carbocycle- (C 1 -C 6 ) alkyl or optionally substituted (C 1 -C 6 ) alkyl heterocycle; in particular a (C 1 -C 6) alkyl, carbocycle, heterocycle or optionally substituted baryl group; preferentially a (C 1 -C 6 ) alkyl group such as a CH 3 group,
• the carbocycle being advantageously a cycloalkyl such as cyclohexyl or an aryl such as phenyl or naphthyl,
• the heterocycle being advantageously pyridine, pyrimidine, pyridazine, pyrazine, furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, oxazole, triazoles, benzo furan, benzothiophene, indole, 1,3-benzodioxolane, piperidine, morpholine or piperazine; more particularly pyridine, furan, thiophene, pyrrole, benzofuran, benzothiophene, indole, 1,3-benzodioxolane or piperidine; and especially pyridine, furan, thiophene, benzofuran, 1,3-benzodioxolane or piperidine, and
• the biaryl being advantageously biphenyl.
• the groups R 22 to R 25 representing, independently of one another, a hydrogen atom or a (C 1 -C 6 ) alkyl or aryl group, and
• heterocycles being optionally substituted by an oxo, (C 1 -C 6 ) alkyl or C0 2 - (C 1 -C 6 ) alkyl group.
• Rio will preferably represent a group -S (O) 2 Ris.
• Ris is (Ci-C 6) optionally substituted alkyl, optionally substituted aryl, (Ci-C 6) alkyl-aryl, aryl- (Ci-C 6) alkyl, carbocycle, heterocycle optionally substitute, biaryl, carbocycle- (Ci -C 6 ) alkyl or heterocycle- (C 1 -C 6 ) alkyl.
• R 26 to R 29 representing, independently of each other, a hydrogen atom or a (C 1 -C 6) alkyl or aryl group.
• Ris preferably represents a group (Ci-C 6) alkyl optionally substituted with one or more groups (including one) selected from C0 2 R 26, OR 27, and NR 2 SR 2 9, in particular from OR 27 and NR 2 SR 2 ; aryl; (C1-C6) alkyl-aryl; or aryl (C 1 -C 6 ) alkyl.
• the compounds of the invention may be chosen from the following examples:
• the subject of the present invention is also a compound according to the invention of formula (I) as defined above, for its use as a medicament, in particular intended for the treatment of cancerous and precancerous hyperproliferative pathologies.
• the present invention also relates to the use of a compound of formula (I) as defined above, for the manufacture of a medicament, in particular for the treatment of cancerous and pre-cancerous hyperproliferative pathologies.
• the present invention also relates to a method for treating cancerous and pre-cancerous hyperproliferative pathologies, comprising administering to a person in need of an effective dose of a compound of formula (I) as defined above.
• cancerous or precancerous hyperproliferative pathologies is intended to mean all types of cancerous or pre-cancerous hyperproliferative pathologies, in particular cancer of the lung, breast, brain and cutaneous cancers.
• the term "skin cancer” is intended to mean, in particular, actinic keratosis, solar keratosis, keratinocyte intraepithelial neoplasia, cutaneous papillomas, squamous cell carcinomas in situ, squamous cell carcinomas, precancerous skin lesions, basal cell carcinoma including superficial and nodular forms, Bowen's disease, Dubreuilh's melanoma, condylomas, Merkel's tumor, Paget's disease, or mucocutaneous lesions induced by the human papillomavirus.
• the present invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising at least one compound of formula (I) as defined above, and at least one pharmaceutically acceptable excipient.
• compositions according to the invention may be formulated especially for oral administration, for topical administration or by injection, said compositions being intended more particularly for mammals, including humans.
• the active ingredient can be administered in unit dosage forms, in admixture with conventional pharmaceutical carriers, to animals including humans.
• the compounds of the invention as active ingredients can be used at doses of between 0.01 mg and 1000 mg per day, given as a single dose once a day or administered in several doses throughout the day, for example twice a day in equal doses.
• the dose administered per day is advantageously between 5 mg and 500 mg, more advantageously between 10 mg and 200 mg. It may be necessary to use doses out of these ranges which the skilled person can realize himself.
• compositions according to the invention may also comprise at least one other active ingredient, such as an anticancer agent.
• the present invention also relates to a pharmaceutical composition as defined above for its use as a medicament, in particular for the treatment of cancerous and pre-cancerous hyperproliferative pathologies.
• the compounds according to the invention have often been obtained in the form of two diastereoisomers which have been separated. However, it was not determined to which of the two NMR spectra obtained corresponded each of these two diastereoisomers.
• the mixture is heated at 100 ° C. for 16 hours.
• the reaction mixture is then cooled to room temperature and diluted with water and dichloromethane.
• the sentence The organic material is washed with saturated NaHCO 3 solution , dried over MgSO 4, filtered and concentrated under reduced pressure.
• the residue is purified by chromatography on silica gel (eluent dichloromethane / methanol).
• N1E115 (ATCC, CRL2263), MDA-MB-231 (ATCC, HTB26) and HSC-1 (Health Science Research Resources Bank, JCRB1015) lines were grown in DMEM (Dulbecco's Modified Eagle Medium) supplemented with 2 mM L Glutamine (Sigma, G7513) and 10% fetal calf serum (Hyclone, SH30109.03) or 20% in the case of HSC-1 cells.
• Lines HCC-1937 (ATCC, CRL2336) and A549 (ATCC, CCL185) were cultured in RPMI medium (Roswell Park Memorial Institute medium) supplemented with 10% fetal calf serum and 2 mM L-Glutamine.
• the SCO 14 line (DSMZ, ACC662) was cultured in MEM (Essential Essential Medium Eagle) supplemented with 10% fetal calf serum and 2 mM L-Glutamine.
• MEM Essential Essential Medium Eagle
• the cells are seeded into their respective culture media with 750 cells per well for N1E115; 1000 cells per well for SCC114 and A549; 2000 cells per well for HCC-1937 and HSC-1; 2500 cells per well for MDA-MB-231.
• a cascade dilution of each compound was made in dimethylsulfoxide (DMSO) (Sigma, D8418) from stock solutions at 10 mM in 100% DMSO.
• DMSO dimethylsulfoxide
• the cytotoxic properties of some compounds of the invention evaluated on lines A549 lung cancer cell line
• MDA-MB-231 mimmary adenocarcinoma cell line
• N1E115 neuroroblastoma cell line
• murine brain HCC-1937
• HSC-1 cutaneous squamous cell carcinoma cell line
• SCC114 squamous cell carcinoma cell line
• the activity of the compounds according to the invention on the HCC line 1997 was compared with that of known cytotoxics (Epotilone B and Vinflunine).
• the compounds according to the invention exhibit a particularly remarkable activity on this particularly resistant breast cancer cell line.

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• 2013
  • 2013-08-01 US US14/418,892 patent/US9416143B2/en not_active Expired - Fee Related
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