EP2139860A2 - Dérivés de la classe des hydroxyquinoléines aminées pour le traitement de cancers. - Google Patents

Dérivés de la classe des hydroxyquinoléines aminées pour le traitement de cancers.

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Publication number
EP2139860A2
EP2139860A2 EP08787845A EP08787845A EP2139860A2 EP 2139860 A2 EP2139860 A2 EP 2139860A2 EP 08787845 A EP08787845 A EP 08787845A EP 08787845 A EP08787845 A EP 08787845A EP 2139860 A2 EP2139860 A2 EP 2139860A2
Authority
EP
European Patent Office
Prior art keywords
group
methylene
hydroxyquinoline
substituted
alkyl
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.)
Withdrawn
Application number
EP08787845A
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German (de)
English (en)
French (fr)
Inventor
Jean-Louis Kraus
Olivier Blin
Frédéric CHAMPAVERE
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Biopharmed A Responsabilite Ltee Ste
Original Assignee
Biopharmed A Responsabilite Ltee Ste
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Application filed by Biopharmed A Responsabilite Ltee Ste filed Critical Biopharmed A Responsabilite Ltee Ste
Publication of EP2139860A2 publication Critical patent/EP2139860A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to derivatives of the class of hydroxyquinoline amines for the treatment of cancers.
  • glioblastoma multiforme a type of aggressive brain tumor. Temodal 'is used in newly diagnosed patients: it is first associated with radiotherapy, then it is used alone;
  • malignant gliomas such as glioblastoma multiforme or anaplastic astrocytoma, when the tumor recurred or worsened after standard treatment.
  • This drug is based on its ability to cross the blood-brain barrier. This limits access to brain tissue by the joint action of cerebrospinal fluid renewal and several active selective transport systems. Inhibition of these systems may increase the cerebral penetration of the corresponding substrates, explaining the occurrence of drug interactions with central manifestations; it can also improve the access of antibiotics, anticancer drugs or psychotropic drugs to the brain.
  • the Applicant first sought to develop a new family of compounds having the ability to treat tumors, such as prostate and colon, very effectively, and in particular Gioglastomas. . Indeed, it is highly desirable to provide products that can be administered at the lowest possible doses but having an anti-cancer efficacy at least comparable or better than the products of the prior art, while by limiting cytotoxicity on healthy cells.
  • glioblastomas In the particular case of glioblastomas, the evaluation of the ability to treat by such compounds has consisted in evaluating their effectiveness by the implementation of preliminary tests on glioblastoma cell lines on which the active principles commonly used have almost no effect.
  • the human cell lines were trans-glomerated U87 / GFPs, which express the GFP ("Green Fluore ⁇ cent Protein") protein.
  • GFP Green Fluore ⁇ cent Protein
  • the GFP protein is known as a very effective fluorescence marker, which can be used in a living medium.
  • a first series of trials was based on survival tests of the treated cells, such as carcinoma cells (KB3). The tests consist in measuring the number of surviving cells after contact with these compounds under appropriate operating conditions. Reference tests are carried out in the absence of such compounds.
  • a second series of tests consisted in determining the ability of these compounds to inhibit the proliferation and migration of U87 / GFP cells defined above. Such inhibition of migration and proliferation can reduce or even prevent the process of metastasis, which is one of the most important factors in the development of many cancers in humans.
  • this family of compounds can not only present the skills listed above, but also act on other types of cancer cells and tumors.
  • Such cells represent, in particular, carcinomas, adenocarcinomas, hepatocarcinomas, lymphoblastomas and also sarcomas, myelomas, melanomas and mesotheliomas. Therefore, one of the aims of the present invention has been to provide novel compounds for treating or preventing diseases associated with proliferation, migration of metastases and cell survival, or more general, tumor cells, while affecting only very moderately healthy cells. They must therefore be very advantageously effective for the treatment of cancer cells mentioned above while limiting the toxicity of these comoose.
  • the new class of amine hydroxyguinolines-derived compounds has the properties listed above.
  • the present invention therefore relates to compounds of formula (I),
  • the group -CH 2 -NRiR 2 being: in the ortho, meta or para position relative to the -OH group
  • Ri and R 2 represents a hydrogen atom, an alkyl group Ci-Ci 0, alkenyl or alkynyl, C 2 -C 4 or 5- procedurathyiène-8-hydroxyquinoline group; the other represents 5-methylene-8-hydroxyquinoline, an aryl group, - (CH 2 ) n -heteroaryl comprising one or more heteroatoms selected from N, O and S, n being an integer from 0 to 4, a - (CH 2 ) n - C 4 -C 6 heterocycloalkyl group wherein the heteroatom is N, O or S, n being an integer of 0 to 4, or alkylphenyl where the alkyl is C 1 to C 10 , the phenyl which is unsubstituted or substituted by 1 or 2 halogen atoms selected from F, Br, I and Cl or -CF 3 •
  • R 1 and R 2 represents a group of formula (II) linked to asymmetric carbon
  • R 3 , R 4 , R 5 , Re and R 7 independently of each other represent a hydrogen atom, a C 1 -C 10 alkyl group, -CF 3 , -NO 2 , the N-5-methylene group - 8-hydroxyquinoline, 1 or 2 halogen atoms selected from F, Br, I and Cl or a group -0-R where R is alkyl to C 4, or -CF 3,
  • X or Y represents a hydrogen atom, an alkyl group of C 1 -C 10 aryl that is unsubstituted or substituted by an alkyl group in Ci 0, -CF 3 or -NO 2 and the other of Ri and R2 H, tert-butyloxycarbonyl (Boc), 5-methylene-8-hydroxyquinoline or - (CH 2 ) n -phenyl, n being an integer from 1 to 5; or, in the case where one of R 1 and R 2 is YNY 'where Y is selected from the group consisting of - (CH 2 ) n -, n being an integer from 1 to 10, - ( CH 2) r-phenyl- i.
  • R 1 and R 2 represent a - (CH 2 ) n -naphthalene group, n being an integer between 1 and 10, the naphthalene group being unsubstituted or substituted by one or more groups selected from C 1 -C 10 alkyl, -CF 3 and -O-R where R is C 1 -C 10 alkyl, the other is selected from the group consisting of hydrogen, group 5 methylene-8-hydroxyquinoline and the Boc group; or R 1 and R 2 form a piperazine in which at least one of the ring carbon atoms is substituted by a C 1 -C 6 alky
  • N of the ring at positions 1,4 and 8 are unsubstituted or are each independently substituted by the group
  • Ri ez R 2 represents a group of formula (II) linked to asymmetric carbon
  • R 3 , R 4 , R 5 , Re and R 7 independently of each other represent: a hydrogen atom, a C 1 -C 6 alkyl group, -CF 3 , -NO 2 , the group N-5 methylene-8-hydroxyquinoline, 1 or 2 halogen atoms selected from F, Br, I and Cl or a -O-R group, R being a C 1 -C 3 alkyl group or -CF 3
  • X or Y represents a hydrogen atom, a C 1 -C 6 alkyl group, aryl unsubstituted or substituted by a C 1 -C 6 alkyl group, -CF 3 or -NO 2 , the other of R 1 and R 2 representing an H atom; Boc group, 5-methylene-8-nydroxy ⁇ uolinine or - (CH 2 ) n -phenyl, n being an integer ranging from 1 to 5; or, in the case where one of R 1 and R 2 is YNY
  • the compounds of formula (I) are those wherein one of R and R 2 represents a hydrogen atom, an alkyl group C 1 -C 4 alkenyl or alkynyl, C 2 -C 4 or the 5-methylene-8-hydroxyquinoline group; the other represents the 5-methylene-8-hydroxyquinoline group, an aryl group, - (CH 2 ) r -heteroaryl comprising one or more heteroatoms selected from N, O and S, n being an integer from 0 to 3, a group - (CHo) n - heterocycloalkyl C 4 to Ce in which the heteroatom is N, O or S, n being an integer between 0 and 3, or alkylphenyl wherein the alkyl is Ci to C 4, phenyl group is unsubstituted or 'substituted by 1 or 2 halogen atoms selected from F , and I or -CF 3 ;
  • R 1 and R 2 represents a group of formula (II) linked to asymmetric carbon
  • R 3 , R 4 , R 5 , R 6 and R 7 represents the N-5-methylene-8-hydroxyquinoline group and the others a hydrogen atom
  • X or Y represents a hydrogen atom, a C 1 -C 4 alkyl group, aryl unsubstituted or substituted by a C 1 -C 4 alkyl group, -CF 3 or -NO 2 , the other of R 1 and R 2 H, certiobutyloxycarbonyl (Boc) or 5-methylene-8-hydroxyquinoline; or, in the case where one of R 1 and R 2 is YNY 'where Y is selected from the group consisting of - (CH 2 ) n -, n being an integer from 1 to 4, - ( CH 2 ) m -phenyl- (CH 2 ) p -, the phenylant unsubstituted or substituted with 1 or 2 halogen atoms selected from F, Br and Cl or by a Ci-C 4 alkyl group, m and p being respectively numbers between 1 and 3, and wherein Y 'is 5-methylene-8-hydroxyquinoline, the other is a hydrogen atom
  • the compounds of formula (I) are chosen from the group consisting of
  • aryl means a mono or polycyclic aromatic carbon ring comprising between 5 and 14 carbon aromas, such as phenyl, naphthyl or cresyl, and "heteroaryl", an aryl comprising one or more heteroatoms selected from N, O and S, such as pyridine, pyrimidine, pyrazine, furan, pyran, thipyran, thiophene.
  • the invention also relates to the compounds of formula (I) and, preferably, pharmaceutical compositions containing them for use as a medicament.
  • the group -CH 2 -NRiR 2 is in the orcho, meta or para position relative to the -OH group
  • R 1 and R 2 represents a hydrogen atom, a C 1 -C 10 alkyl group, a C 2 -C 4 alkenyl or alkynyl group or the 5-methylene-8-hydroxyquinoline group; the other represents the 5-methylene-8-hydroxyquinoline group, an aryl group, - (CH 2 ) n -heteroaryl comprising one or more heteroatoms selected from N, O and S, n being an integer from 0 to 4, a - (CH 2 ) n - C 4 -C 6 heterocycloalkyl group wherein the heteroatom is N, O or S, n being an integer of 0 to 4, or alkylphenyl where the alkyl is C 1 to Cio, the the phenyl group being unsubstituted or substituted with 1 or 2 halogen atoms selected from F, Br, 1 and Cl or -CF 3 ; or one of R 1 and R 2 is a group of formula (II) linked to asymmetric carbon
  • R 3, R 4, R 5, Re and R 7, independently of one another, represent a hydrogen atom, a C 1 -C 10 alkyl group, -CF 3 , -NO 2 , the N-5-methylene group; hydroxyquinoline, 1 or 2 halogen atoms selected from F, Br, I and Cl or a -O-R group, R being a C 1 -C 4 alkyl group or -CF 3 , X or Y represents a hydrogen atom , C 1 -C 10 alkyl, aryl unsubstituted or substituted by C 1 -C 10 alkyl, -CF 3 or -NO 2 , the other of R 1 and R 2 representing H, tert-butyloxycarbonyl (Boc) ), 5-methylene-8-hydroxyquinoline or - (CH 2 ) n -phenyl, n being an integer from 1 to 5; or, in the case where one of R 1 and R 2 is YNY 'where Y is selected
  • the compounds of formula (I) for the manufacture of a medicament intended for use as anti-cancer agents, where one of the R : and R 2 represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 2 -C 1 alkenyl or alkynyl group or the 5- methylene-8-hydroxyquinoline; the other represents the 5-methylene-8-hydroxyguinoline group, an aryl group, - (CH 2 ) n -heteroaryl comprising one or more heteroatoms selected from N, O and S, n being an integer between 0 and 4, a - (CH 2 ) n - C 4 -C 6 heterocycloalkyl group wherein the heteroatom is N, O or S, where n is an integer from 0 to 4, or alkylphenyl where the alkyl is Ci to Ce, the phenyl group being unsubstituted or substituted by 1 or 2 halogen atoms selected from
  • R 1 and R 2 represents a group of formula (II) linked to asymmetric carbon
  • R 3 , R 4, R 5 , R 6 and R 7 independently of each other represent a hydrogen atom, a C 1 -C 6 alkyl group, -CF 3 , -NO 2 , the N-5-methylene group; 8-hydroxyquinoline, 1 or 2 halogen atoms selected from F, Br, I or Cl and -OR, wherein R is alkyl to C 3 or -CF 3,
  • X or Y represents a hydrogen atom, a C 1 -C 6 alkyl group, aryl unsubstituted or substituted by a C 1 -C 6 alkyl, -CF 3 or -NO 2 group , the other of R x and R 2 representing an H atom, the Boc group, 5-methylene-8-hydroxyquinoline or - (CH 2 ) n-phenyl, n being an integer between 1 and 5; or, in the case where one of R 1 and R 2 is YNY 'where Y is selected from the group consisting of - (CH 2 ) n -, n being an integer from 1 to 6, - (CH 2 ) m -phenyl- (CH 2 ) p -, the phenyl being unsubstituted or substituted by 1 or 2 halogen atoms selected from F, Br and Cl or by a Ci-C f alkyl group, m and p being respectively numbers from 1 to 4, and wherein Y
  • n is an integer from 1 to 6, where Z represents one of the N atoms of a 1,4, 8,12-tetraazacyclopentadecane or a 1,4, 8,11 tetraazacyclotetradecane wherein the other ring N atoms at the 1,4- and 8-position are unsubstituted or are each independently substituted by the Boc group, and their enantiomers,
  • the compounds of formula (I) are used for the manufacture of a medicament for use as cancer control agents, wherein one of R 1 and R 2 represents a hydrogen atom, a alkyl group -C 4 alkenyl or alkynyl, C 2 -C 4 or 5- methylene-8-hydroxyquinoline; the other represents the 5-methylene-8-hydroxyquinoline group, an aryl group, - (CH 2 ) n -heteroaryl comprising one or more heteroatoms selected from N, O and S, n being an integer comprising 0 and 3, a - (CH 2 ) n - C 4 -C 6 heterocycloalkyl group wherein the heteroatom is N, O or S, where n is an integer from 0 to 3, or alkylphenyl where 1 'is C 1 to C 4 the phenyl group being unsubstituted or substituted with 1 or 2 halogen atoms selected from F, and I or -CF 3 ;
  • R 1 and R 2 represents a group of formula (II) linked to asymmetric carbon
  • R 3 , R 4 , R 5 , R 7 and R 7 represents the group N-5-methylene-8-hydoxoxyguinoline and the others a hydrogen atom
  • X or Y represents a hydrogen atom, a C 1 -C 4 alkyl group, aryl unsubstituted or substituted by a C 1 -C 4 alkyl group, -CF 3 or -NO 2 , the other of R 1 and R 2 H, tert-butyloxycarbonyl (Boc) or 5-methylene-8-hydroxyquinoline; or, in the case where one of the groups R 1 and R 2 is a group YNY 'where Y is chosen from the group consisting of - (CH 2 ) ⁇ -, n being an integer between 1 and 4, - ( CH 2 ) m -phenyl- (CH 2 ) p -, the phenyl being unsubstituted or substituted by 1 or 2 halogen atoms selected from F, Br and Cl or by a C 1 -C 4 alkyl group, m and p being respectively numbers between 1 and 3, and wherein Y 'is 5-methylene-8-hydroxyquinoline
  • R 1 and R 2 form an unsubstituted piperazine or wherein at least one of the ring carbon atoms is substituted by a C 1-3 alkyl group and wherein the N atom which is not part of the group -CH 2 -NR 1 R 2 is substituted with a 5-methylene-8-hydroxyquinoline group; or R 1 and R 2 form a polyazamacrocycle (cyclam) representing 1, 4, 8, 12-tetraazacyclopentadecane or unsubstituted 1, 4, 8, 11-tetraazacyclotetradecane wherein at least one of the ring N atoms at position 1,4 and 8 is independently substituted by the Boc group by a 5-methylene-8-hydroxyquinoline group or with - (CH 2 ) r -phenyl- (CH 2 ) n -Z, n being an integer between 1 and 4, where Z represents one of the N atoms of a 1, 4, 8, 12-tetraazacyclopentadecane or a 1,4,8,11
  • the compounds of formula (I) are used for the manufacture of a medicament for use as cancer control agents selected from the group consisting of
  • the therapeutic activity of these compounds lies in their ability to prevent the migration and proliferation of metastases or tumor cells, such as gliobla ⁇ come ⁇ , carcinomas, sarcomas, myeloma ⁇ , melanoma ⁇ and mesothelioma ⁇ .
  • metastases or tumor cells such as gliobla ⁇ come ⁇ , carcinomas, sarcomas, myeloma ⁇ , melanoma ⁇ and mesothelioma ⁇ .
  • tumor cells such as gliobla ⁇ come ⁇ , carcinomas, sarcomas, myeloma ⁇ , melanoma ⁇ and mesothelioma ⁇ .
  • cytotoxicity induced on certain cells is also proven.
  • these compounds can be used in the treatment of numerous cancers selected from the group consisting of oral carcinomas, carcinomas of the colon, breast carcinomas, pulmonary carcinomas, prostate carcinomas, glioblastomas, ovarian adenocarcinomas and the like. hepatocarcinoma and lymphoblastoma.
  • oral carcinoma KB
  • carcinoma of the colon HTC116, HT29 and HTC15.
  • MCF7 and MCF7R breast carcinoma
  • PC3 proestate carcinoma
  • SF268 proestate carcinoma
  • SK-OV-3 ovarian adenocarcinoma
  • HepG2 hepatocarcinoma
  • HDO and K562 lee lymphoblastoma
  • non-tumoral VERO eel kidney cells non-tumoral VERO eel kidney cells
  • the compounds of the invention have the capacity to induce the activation of caspases, since It is well known that caspases play an important role in apoptosis induced by genotoxic stress, and that certain drugs cause the permeabilization of the outer mei ⁇ bran of the mithocondria which leads to the release of cytochrome C and the activation of caspases.
  • the Applicant has furthermore shown that the presence of two substituents of 5-methylene-8-hydroxyquinoline type in these compounds has a major influence on the anti-cancer activity.
  • bi ⁇ -5-methylene-8-hydroxyquinolines compounds of formula (I) in which one of R 1 and R 2 represent the group 5- methylene-8-hydroxyquinoline
  • IC50 values concentration of the compounds in the reaction medium for which one of R 1 and R 2 represent the group 5- methylene-8-hydroxyquinoline
  • the mechanism of action of the compounds of the invention comprises the following steps of protonation of the tertiary amine (N carrying the groups R 1 and R 2 ) followed by addition of a nucleophilic agent (Nu " ), which may be chemical or biological, to the K atom of the hydroxyquinoline group which generates a carbanionic entity, the addition being followed by a resonance stabilization resulting in an entity called" intermediate quinone methide >> by breaking the CN bond (N carrying the groups R: and R 2).
  • This intermediate would be an alkylating chemical substrates or biological, such as nucleic acids or proteins.
  • the starting material to be considered is 5-chloromethyl-8-hydro ⁇ uinoline hydrochloride which is suspended in a suitable solvent, such as ethyl acetate. To this suspension is added the appropriate amino compounds for defining the groups R 1 and R 2 above.
  • amines comprising C 1 -C 10 alkanes, a - (CH 2) n -C 4 -C 6 heterocycloalkyl group in which the heteroatom represents N, O or S, an alkene or alkyne.
  • an aryl, a - (CH 2 ) n -heteroaryl group comprising one or more heteroatoms chosen from N, O and S, n being an integer between 0 and 4, alkylphenyl, the phenyl group being unsubstituted or substituted by 1 or 2 halogen atoms selected from F, Br, 1 and Cl or -CF 3 , a 5-methylene-8-group; hydroxyquinoline.
  • the mixture obtained is heated in a water bath with gentle stirring.
  • the reaction product is then filtered and washed with the solvent, which is then removed by evaporation.
  • the residue thus obtained is then recrystallized with an alkane solvent, such as petroleum ether.
  • Ri and R2 represents a group of formula (II) wherein R3, R4, R 5, Re and R 7 independently of each other represent a hydrogen atom, a C 1 -C 10 alkyl group, -CF 3 , -NO 2 , the N-5-methylene-8-hydroxyquinoline group, 1 or 2 halogen atoms selected from F, Br, 1 and Cl or a group - oR where R is alkyl to C 4, or -CF 3,
  • X or Y represents a hydrogen atom, an alkyl group in C 1 0, aryl is unsubstituted or substituted by an alkyl group Ci-Ci 0, -CF 3 or -NO 2 and the other of R and R 2 represents an H atom, tert-butyloxycarbonyl (Boc), 5-methylene-8-hydroxyquinoline or - (CH 2 ) n -phenyl, n being an integer from 1 to 5; and, on the other hand, where in the case where one of Ri and R 2 is - (CH 2) r -naphthalene, naphthalene group being unsubstituted or substituted by one or more groups selected from the groups C 1 -C 10 alkyl, -CF 3 and -O-R wherein R is C 1 -C 10 alkyl, n being an integer from 1 to 10, the other is selected from the group consisting of hydrogen, 5-methylene-8-hydroxyquinoline group, tert-butyloxycarbonyl
  • Method 1 The precursor amine substrate, corresponding to the compounds making it possible to define the groups R 1 and R 2 above, is reacted with 5-chloromethyl-8-hydroxyquinoline in acetonitrile, in the presence of a weak inorganic base, such as K2CO3. After filtration and evaporation, the residue is washed with a citric acid solution and the aqueous phase is extracted several times with a suitable solvent, such as ethyl acetate, and is then dried over magnesium sulfate and then evaporated.
  • a weak inorganic base such as K2CO3.
  • the compounds mono- and ⁇ -substituted by the 8-hydroxyquinoline group resulting from the condensation are then separated and isolated by chromatographic separation on silica gel, using: various solvent mixtures usually used in this chromatography, such as methylene chloride, various alkanes, in particular iodooctane, and isopropyl ether.
  • the separation of the mono- and disubstituted derivatives with the 8-hydroxyquinoline groups is carried out after a protection step with a tert-butyloxycarbonyl (Boc) group.
  • the disubstituted derivative which is more polar, is easily separated from the monosubstituted derivative by the Boc group by silica gel chromatography.
  • the monosubstituted derivative protected by the isolated Boc group is then deprotected in an acid medium in a manner known to those skilled in the art.
  • the protected mono derivative is obtained in the form of chlorhydrate, which is isolated by precipitated in ethyl ether, and isolated pure after filtration.
  • one of the groups R 1 and R 2 is a group YNY 'where Y is - (CH 2 ) n -, n being an integer between 1 and 10, and where Y 'is 5-methylene-8-hydroxyquinoline, the other is a hydrogen atom, and
  • R 1 and R 2 form a polyazamacrocycle (cyclam) representing 1, 4, 8, 12-tetraazacyclopentadecane or unsubstituted 1, 4, 8, 11-tetraazacyclotetradecane or one of the ring N atoms in the 1,4-position and 8 is, independently, substituted by the Boc group, 5-methylene-8-hydroxyquinoline or - (CH 2 ) n -phenyl- (CH 2 ) n -Z, where n is an integer from 1 to 10, where Z represents one of the N atoms of a 1,4,8,12-tetraazacyclopentadecane or a 1,4,8,11-tetraazacyclotetradecane in which the other N atoms of the ring in position 1,4 and 8 are unsubstituted or are each independently substituted by the Boc group, and their enantiomers, these can be prepared according to the different synthetic routes described in V. Moret et al., Biorganic & Medecinal
  • R 1 and R 2 form a polyazamacrocycle representing the 1,4,8,11-tetraazacyclotetradecane group
  • one of the ring N atoms at the 1,4 and 8 positions is, independently, substituted with - (CH 2 n -phenyl- (CH 2 ) n -Z, n being an integer between 1 and 10, where Z represents one of the N atoms of a 1, 4, 8, 12-tetraazacyclopentadecane in which the other N atoms of the cycle in position 1,4 and 8 are no substituted or are each independently substituted by the Boc group
  • the synthesis is carried out as follows.
  • the starting material is 1,4,8,11-tetraazacyclotetradecane (3 equivalents) which is reacted with di-terbutyldicarbonate (1 equivalent) in the presence of methylene chloride at room temperature overnight. After chromatographic purification, 1,1-di-tert-butoxy-1,4,8,11-tetraazacyclotetradecane was obtained. It is possible to promote the sorting or tetra protection of the nitrogen atom of cyclam by the Boc group, according to the methodology described in Dessolin J. et al, J.Med.Chem, 1999, 42, 229-241.
  • the selective triprotection of the cyclam or bicyclam derivative by Boc groups is achieved by employing 1.8 equivalents of the diterbutyloxycarbonyl reagent per 1 equivalent of cyclam in methylene chloride, as indicated above.
  • the triple protection of cyclam by Boc is predominant compared to mono, di-, tetra-protected compounds.
  • a 1,4,8,11-tetraazacyclorradecane compound (1 equivalent) in which one of the nitrogen atoms is substituted by a Boc group undergoes a condensation reaction with the compound Br- (CH 2 ) n - phenyl- (CK 2 ) n -Br (1 equivalent) in the presence of a weak base, such as K 2 CO 3 , in dimethylformamide (DMF) for three days at room temperature.
  • a weak base such as K 2 CO 3
  • DMF dimethylformamide
  • the product thus obtained is reacted with 1,1-di-tert-butoxy-1,4,8,11-tetraazacyclotetradecane in acetonitrile in the presence of a weak base such as K 2 CO 3 .
  • This latter intermediate product is then reacted with 5-chloromethyl-8-hydroxyquinoline in acetonitrile in the presence of a weak base, such as K 2 CO 3.
  • R 1 and R 2 form a polyazamacrocycle (cyclam) representing the 1,4,8,11-tetraazacyclotetradecane group where at least one of the N atoms of the ring in the 1,4-position and 8 is substituted with - (CH 2 ) n -phenyl- (CH 2 ) n -Z where Z represents one of the N atoms of a 1, 4, 8, 11-tetraazacyclotetradecane, the other nitrogen atoms being substituted by the Boc group.
  • cyclam representing the 1,4,8,11-tetraazacyclotetradecane group where at least one of the N atoms of the ring in the 1,4-position and 8 is substituted with - (CH 2 ) n -phenyl- (CH 2 ) n -Z
  • Z represents one of the N atoms of a 1, 4, 8, 11-tetraazacyclotetradecane, the other nitrogen atoms being substituted by the Boc group.
  • the Boc groups present on these compounds can be removed by contacting these compounds in an acidic medium, in the presence of ethyl ether and at a temperature between 25 ° C. and 70 ° C., according to conventional implementations.
  • the deprotection of the protected derivative is carried out in acid medium, the protected mono derivative is thus obtained in the form of hydrochloride which is isolated by precipitation in
  • N of the ring at positions 1,4 and 8 are unsubstituted or are each independently substituted by the group
  • R 1 and R 2 form an unsubstituted piperazine or wherein at least one of the ring carbon atoms is substituted by a C 1 -C 6 alkyl group and wherein the other N atom is substituted by a 5-methylene-8-hydroxyquinoline group
  • one of R 1 and R 2 is YNY 'where Y is - (CH) 2 ) n -, where n is an integer from 1 to 10, and wherein Y 'is 5-methylene-8-hydroxyquinoline, the other is hydrogen
  • such compounds can be prepared as follows.
  • the compounds of formula (I) wherein R 1 and R 2 form a polyazamacrocycle representing the unsubstituted 1,4,8,12-tetraazacyclopentadecane group or one of the ring N atoms at position 1,4 and 8 is substituted by the Boc group may be prepared by re-admixing unsubstituted 1,4,8-tetraazacyclopentadecane, or wherein one of the ring N atoms at the 1,4- and 8-position is substituted by the Boc group with 5-chloromethyl-8- hydroxyquinoline in chloroform or methylene chloride in the presence of an excess of di-isopropylethylamine overnight at a temperature between 25 0 C and 70 0 C.
  • Such compounds where the Boc group is absent are obtained by placing in contact with these compounds in an acidic medium, in the presence of ethyl ether and at a temperature of between 25 ° C. and 70 ° C., according to conventional implementations defined above.
  • R 1 and R 2 form a polyazamacrocycle representing the 1,4,8,12-tetraazacyclopentadecane group, one of the ring N atoms at position 1,4 and 8 being substituted by the Boc group and another N atom is substituted with the 5-methylene-8-hydroxyquinoline group before: Agonically synthesized as indicated above.
  • R 1 and R 2 form a 5- or 6-membered cyclic polyamine
  • one of the groups R 1 and R 2 is - (CH 2 ) m -phenyl- (CH 2 ) p -, the phenyl being unsubstituted or substituted with 1 or 2 halogen atoms selected from F, Br and Cl or by a C 1 -C 6 alkyl group, m and p being respectively numbers from 1 to 4, and wherein Y 'is 5-methylene -8-hydroxyquinoline, the other represents a hydrogen atom, and when R and R 2 form an aliphatic ring of 4 to 8-membered unsubstituted or substituted by one alkyl group -C O or by a group -0-
  • R is a C 1 to C 10 alkyl group, or an aryl, optionally hydrogenated, unsubstituted or substituted by a C 1 to C 6 alkyl group or a halogen selected from F, Br and Cl
  • the control of proliferation and cell migration in the presence of the compounds (I) of the invention is carried out by a colorimetric method (MTS) and is implemented according to known standard protocols.
  • MTS colorimetric method
  • the methodologies used use a flash cytometer (Trophos SA - Marseille - France).
  • the Flash cytometry technique involves fluorescence which consists of irradiating a compound at a fixed wavelength and recording the fluorescence emitted at another wavelength. This is implemented with a flash cytometer suitable for 96-well test plates.
  • the excitation and emission wavelengths in the context of the implementation of this fluorescence are in the range of 485-495 nm.
  • the measured fluorescence expresses the amount of surviving cells after treatment with the compounds of the invention.
  • the determination of the anti-migratory activity of the compounds (I) of the invention on these same cell lines, grown in MEM ("Minimum Essential Medium”) medium, is carried out by the so-called "scratch” technique which consists in carrying out a scratch on a cellular carpet using a cone of micropipettes.
  • the anti-migratory effect is determined.
  • a migration of 100% is attributed to the untreated cells, whereas according to the concentration of the compounds (T) of the invention, the total stopping of migration is determined by the observation of the "scratch” remaining unmet by cell migration, using computer software.
  • the cells of the U87 / GFP lines are cultured in 96-well plates according to a standard methodology described by Bajetto et al., Neurochemistry International, 2006, 43, 31-38 in the presence of different concentrations of the compounds of the invention.
  • Cell proliferation is determined and quantified according to standard methods known to those skilled in the art. A 100% proliferation is attributed to the untreated cells and less than 100% is obtained when the same cells are treated with the compounds of the invention.
  • Proliferation and cell migration are determined by imaging using a flash cytometer (Trophos SA - Marseille - France), and calculations are performed using the "MetaMorph 4.6" signal processing software. imaging (Molecular Devices, USA) whose use, known in the art, makes it possible to determine the two effects above independently of one another.
  • Cancerous KB cells are also considered to determine cell viability (or survival rate). This cell viability is determined according to the teachings of Nicholson KM et al, British Journal or Cancer, 1999, 81, 423-430.
  • KB cells are human carcinoma cell lines, KB-3-1. These cells are maintained in "Dulbecco's Modified Eagle's Medium” (DMEM-Sigma) culture medium, which contains 0.11 g / l of sodium puryvate and 4.5 g / l of glucose, supplemented with fetal calf serum. 10% (v: v), penicillin (32 ⁇ g / ml) and streptomycin (50 ⁇ g / ml). The cells are cultured in monolayers and are incubated at 37 ° C. in a humid atmosphere (95% air / 5% CO 2 ).
  • DMEM-Sigma "Dulbecco's Modified Eagle's Medium”
  • the previous KB cells are then incubated in 6 or 96 well plates in the presence of the compounds of the invention to be tested, dissolved in dimethylsulfoxide (DMSO).
  • DMSO dimethylsulfoxide
  • the level of the surviving cells is measured by the "colony formm ⁇ assay" test, in which the cells are redistributed with a density of 100 to 300 cells per well in 24-well plates, for a duration of 8 days, then staining with Leishman reagent (0.2% in methanol) is performed. Colonies with more than 50 cells are counted visually under a microscope, the survival rate being expressed on the colonies formed in the presence of the compounds of the invention relative to cell colonies not treated with the said compounds. The determination of IC50
  • Example 2 From the results obtained in Example 1, it was possible to determine the IC50 on the KB cell lines (Table 3), according to the protocol described above.
  • Table 3 indicates that it is possible to obtain a cellular cytotoxicity, expressed by IC50, for nanomolar concentrations, although values of the order of ten micromoles are still acceptable.
  • R 1 is a 5-methylene-8-hydroxyquinoline group and R 2 is a group (II) where X and Y represent an H atom, or X is H and Y is -CH 3 , R 3 to R 7 have different substituents, the nature and position of these substituents have an influence on their activity.
  • a mouse toxicity study has shown that the LD50 value of derivative 120 is 100 mg / kg, which demonstrates a relatively low toxicity for derivative 120, knowing that for anticancer drugs such as Taxol LD50 in mice is of the order of 10 mg / kg.
  • Example 4 This example is intended to show that the cytotoxic activity of the compounds of the invention on HLoO (lymphoblastoma) cell lines is dependent on the induction of caspases.

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EP08787845A 2007-03-23 2008-03-25 Dérivés de la classe des hydroxyquinoléines aminées pour le traitement de cancers. Withdrawn EP2139860A2 (fr)

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FR0702154A FR2913976B1 (fr) 2007-03-23 2007-03-23 Derives de la classe des hydroxyquinoleines aminees pour le traitement de cancers.
PCT/FR2008/000399 WO2008135671A2 (fr) 2007-03-23 2008-03-25 Dérivés de la classe des hydroxyquinoléines aminées pour le traitement de cancers.

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EP2149567A1 (en) * 2008-07-18 2010-02-03 Bayer Schering Pharma Aktiengesellschaft Cyclic polyamines for binding phosphatidylserine
FR2940289B1 (fr) * 2008-12-23 2014-09-12 Biopharmed Derives de la classe des hydroxyquinoleines aminees pour le traitement du cancer du pancreas
KR101514285B1 (ko) 2013-08-09 2015-04-22 숙명여자대학교산학협력단 아미노다이하이드로퀴놀린 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암 질환의 예방 또는 치료용 약학적 조성물

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US8058442B2 (en) * 2002-11-07 2011-11-15 Technion Research And Development Foundation Ltd. Neuroprotective iron chelators and pharmaceutical compositions comprising them
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AU2008248475A1 (en) 2008-11-13
CN101641332A (zh) 2010-02-03
US20130102630A1 (en) 2013-04-25
CA2680803A1 (en) 2008-11-13
AU2008248475B2 (en) 2013-10-03
WO2008135671A3 (fr) 2009-05-22
CN101641332B (zh) 2014-03-12
FR2913976B1 (fr) 2013-04-26
JP5555494B2 (ja) 2014-07-23
JP2010522147A (ja) 2010-07-01
FR2913976A1 (fr) 2008-09-26
US8324243B2 (en) 2012-12-04
WO2008135671A2 (fr) 2008-11-13
US20100120856A1 (en) 2010-05-13

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