Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • 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
  • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• • 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
  • 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
  • C07D401/12—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 chain containing hetero atoms as chain links
• • 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
  • C07D401/14—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 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
  • C07D407/14—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 three or more hetero rings

Definitions

• the present invention relates to anticancer derivatives, the compositions containing them and their therapeutic application.
• the invention also relates to the process for preparing these compounds and to some of the intermediate products used.
• R 5 represents a hydrogen atom, F, Cl, Br, OH, NO 2 , CN, a (C 1 -C 6 ) alkyl group or - (Cr C 6 ) alkoxy optionally substituted with F, Cl or Br:
• Application EP 0978516 describes compounds of formula (B) in which R 4 represents a hydrogen atom, an optionally substituted alkyl group or a halogen atom:
• Japanese application JP 4077488 describes compounds of formula (C) in which X 1 represents a halogen atom and R 3 represents a halogen atom, an alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyl or arylsulfonyl group:
• Z represents an optionally substituted aryl or heteroaryl group, a phenyl-alkyl, heterocycloalkyl group, etc.
• a halogen atom a fluorine, chlorine, bromine or iodine atom (advantageously fluorine);
• An alkyl group a saturated aliphatic hydrocarbon group comprising from 1 to 6 carbon atoms (advantageously, from 1 to 4 carbon atoms) linear or branched obtained by removing a hydrogen atom from an alkane.
• alkoxy group a -O-alkyl group, wherein the alkyl group is as defined above;
• a heteroatom a nitrogen, oxygen or sulfur atom
• a cycloalkyl group a cyclic alkyl group comprising between 3 and 8 carbon atoms engaged in the cyclic structure.
• cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups An aryl group: a monocyclic or bicyclic aromatic group comprising 6 to 10 members, for example a phenyl or naphthyl group;
• a heteroaryl group a mono-, bi- or tricyclic aromatic group comprising between 5 and 14 members and comprising one or more heteroatoms;
• a heterocycloalkyl group a cycloalkyl group as defined above, further comprising 1 to 4 heteroatoms engaged in the cyclic structure.
• protecting group a group intended to protect a chemical function of unwanted chemical reactions introduced during a protection step and which is released during a subsequent step. Examples of protective groups can be found in
• each of the preceding groups may be substituted by one or more groups, which are identical to or different from each other, chosen from: hydroxy, (C 1 -C 6 ) alkoxy, preferably (dC 4 ) alkoxy (C 1 -C 6 ) alkyl, preferably (d-C 4 ) alkyl e or halogen atom.
• the present invention relates to a compound of formula (I):
• R 1 represents: a (drd) cycloalkyl group or
• R a and R b independently of one another represent a hydrogen atom or a group (dd) alkyl or
• A represents a group -NR 2 R 3 ;
• B represents a group -NR 4 R 5 or -OR 6 ;
• R 2 and R 3 are such that: R 2 and R 3 represent, independently of one another, a hydrogen atom or a (C 1 -C 6 ) alkyl group; where R 2 represents a hydrogen atom and R 3 represents a (C 6 -C 6 ) alkyl group substituted with:
• R c and R d represent, independently of one another, a hydrogen atom or a (dd) alkyl group; or (ii) R c and R d form together with the nitrogen atom to which they are attached, a heterocycloalkyl group optionally comprising in the ring another heteroatom and optionally substituted;
• R 4 and R 5 are such that: R 4 and R 5 represent, independently of one another, a hydrogen atom or a (C 1 -C 4 ) alkyl group or together with the atom of nitrogen to which they are attached an optionally substituted heterocycloalkyl group; o or R 4 represents a hydrogen atom and R 5 represents a (C 1 -C 6 ) alkyl group substituted with:
• R 6 represents a hydrogen atom or a (C 1 -C 4 ) alkyl group
• Z represents N or CH
• X is an integer ranging from 0 to 4.
• R 7 represents a hydrogen atom or a (C 1 -C 4 ) alkyl group
• Ar represents a group chosen from:
• R 1 represents a (C 3 -C 7 ) cycloalkyl group or a (C 1 -C 6 ) alkyl group optionally substituted with a group -NR a R b R a and R b may represent independently of one another an atom of hydrogen or a group
• R a and R b may also form together with the nitrogen atom to which they are attached, a heterocycloalkyl group optionally comprising in the ring another heteroatom and optionally substituted.
• This heterocycloalkyl group may for example be group A-
• R a may also represent a hydrogen atom and R b a -COO (C 1 -C 4 ) alkyl group, for example the group -COO'Bu.
• R 1 can be one of those in Table I.
• A can represent a group -NR 2 R 3 .
• R 2 and R 3 may independently of one another be a hydrogen atom or a (C 1 -C 6 ) alkyl group.
• R 2 and R 3 may both represent a hydrogen atom or R 2 may represent a hydrogen atom and R 3 a (C 1 -C 6 ) alkyl group.
• R 2 may also represent a hydrogen atom and R 3 a (C 1 -C 6 ) alkyl group substituted by a heterocycloalkyl group,
• piperidinyl e.g. 4-N-methyl-piperidinyl, or 2-tetrahydrofuryl
• R 2 may also represent a hydrogen atom and R 3 a (C 1 -C 6 ) alkyl group substituted with a group -NR c R d .
• R c and R d may independently of one another represent a hydrogen atom or a (dC 4 ) alkyl group.
• R c and R d may also form together with the nitrogen atom to which they are attached, a heterocycloalkyl group optionally comprising in the ring another heteroatom and optionally substituted: for example the 4-morpholinyl group
• substituted heterocycloalkyl groups there may be mentioned the following groups: 2-methyl-pyrrolidinyl
• B can represent a group -NR 4 R 5 .
• R 4 and R 5 may independently of one another represent a hydrogen atom or a group (C 1 -C 6 ) alkyl.
• R 4 and R 5 may both represent a hydrogen atom or a (C 1 -C 6 ) alkyl group or R 4 may represent a hydrogen atom and R 5 a (C 1 -C 6 ) alkyl group.
• R 4 and R 5 may also together with the nitrogen atom to which they are attached form a group
• heterocycloalkyl such as piperazinyl or N-
• alkyl-piperazinyl e.g. N-methyl-piperazinyl.
• R 4 may represent a hydrogen atom and R 5 may be an optionally substituted heterocycloalkyl group (C 1 -C 6 ) alkyl, such as, for example, 4-piperidinyl or 4-N-alkyl-piperidinyl, eg. 4-N-methyl-piperidinyl, or 2-tetrahydrofuryl.
• C 1 -C 6 optionally substituted heterocycloalkyl group
• R 4 may represent a hydrogen atom and R 5 a (C 1 -C 6 ) alkyl group substituted with a group -NR e R f .
• R e and R f may represent a hydrogen atom or a (Ci-C 4 ) alkyl group.
• R e and R f may also together with the nitrogen atom to which they are attached form a heterocycloalkyl group optionally comprising in the ring another heteroatom and being optionally substituted: for example 4-morpholinyl, pyrrolidinyl, piperazinyl or N-group; alkyl-piperazinyl, e.g. N-methyl-piperazinyl, piperidinyl.
• substituted heterocycloalkyl groups there may be mentioned the following groups: 2-methyl-pyrrolidinyl, 4-hydroxy-piperidinyl or 4,4'-difluoropiperidinyl.
• R e may also represent a hydrogen atom and R f a -COO (C 1 -C 4 ) alkyl group, such as the group -COO'Bu.
• R 4 may represent a hydrogen atom and R 5 may be one of the following groups: -C (CH 2 OH) 3 ; - [(CH 2 ) 2 O] m CH 2 NH 2 or - [(CH 2 ) 3 NH] m -H in which m is an integer ranging from 3 to 10.
• B can represent a group -OR 6 in which R 6 represents a hydrogen atom or a group (dC 4 ) alkyl.
• R 6 represents a hydrogen atom or a group (dC 4 ) alkyl.
• R 6 in Table I.
• Z is N or CH and Z 'is N or CH if Z is N and CH if Z is CH.
• the cycle comprising Z and Z 'is therefore one of the following 3 cycles:
• x represents the number of fluorine atoms (s) as a ring substituent; this integer varies from 0 (no fluorine atom) to 4.
• R 7 represents a hydrogen atom or a (C 1 -C 4 ) alkyl group. Preferably, it is a hydrogen atom. R 7 can be chosen from Table I.
• R 7 or R 8 groups is a hydrogen atom.
• L can be one of those described in Table I.
• Ar represents a group chosen from:
• R 1 represents a (C 1 -C 6 ) alkyl group
• A represents a group -NHR 3 in which R 3 represents a hydrogen atom or a (dC 4 ) alkyl group;
• R 4 represents a hydrogen atom or a (C 1 -C 6 ) alkyl group and R 5 represents: a hydrogen atom; o or a (C 1 -C 6 ) alkyl group optionally substituted with:
• R 1 represents a (C 1 -C 6 ) alkyl group substituted with a group -NR a R b as defined above;
• A represents an -NH 2 group
• B represents a group -NR 4 R 5 in which R 4 represents a hydrogen atom or a (C 1 -C 6 ) alkyl group.
• R 1 represents a (C 1 -C 6 ) alkyl group
• a and B represent a group -NHR 3 in which R 3 represents a (C 1 -C 6 ) alkyl group substituted by a heterocycloalkyl group or by a group -NR c R d as defined above.
• Q is an optionally substituted heterocycloalkyl group or the group -NR c R d .
• the heterocycloalkyl group may be more particularly the morpholinyl, pyrrolidinyl, piperazinyl or N-alkyl-piperazinyl group, e.g. N-methyl-piperazinyl, piperidinyl, 2-methyl-pyrrolidinyl, 4-hydroxy-piperidinyl, 4,4'-difluoropiperidinyl, 2-tetrahydrofuryl.
• Ar, L, R 7 , R 8 , Z, Z 'and x have the same meanings as before. More particularly, for the compounds of formula (I) as well as for the subgroups:
• Ar represents the group Ar 1 ;
• the compounds of the invention may exist in the form of bases or addition salts with an acid. These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds also form part of the invention.
• the compounds according to the invention may also exist in the form of hydrates or solvates, namely in the form of combinations or combinations with one or more molecules of water or with solvent.
• the compounds may optionally comprise one or more asymmetric carbon atoms and may therefore exist in the form of enantiomers and / or diastereoisomers, or mixtures of these forms.
• the invention relates to the process for preparing the compounds of the invention and some of the reaction intermediates.
• the compound of formula (I) is obtained according to Scheme 1 by a Suzuki type coupling of P 1 and P 2 .
• HaI represents a halogen atom (chlorine, bromine, iodine).
• Z and Z 'are both CH the coupling is favored if HaI is a bromine or iodine atom.
• Z and Z 'are both N or respectively N and CH HaI may be a chlorine atom.
• the coupling is carried out in the presence of a palladium complex (in the oxidation state (O) or (M)) such as, for example, Pd (PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , Pd (OAc) ) 2 or PDCI 2 (dppf).
• the most frequently used complexes are palladium (O) complexes.
• the coupling is also favored in the presence of a base, which may be for example K 2 CO 3 , NaHCO 3 , and 3 N, K 3 PO 4 , Ba (OH) 2 , NaOH, KF, CsF, Cs 2 CO 3
• the coupling can be carried out in a mixture of an ethereal solvent and an alcohol, for example a dimethoxyethane (DME) / ethanol mixture.
• the temperature at which is the reaction can be between 50 and 120 ° C.
• K and K ' represent a hydrogen atom, an alkyl or aryl group, optionally linked together to form together with the boron atom and the two oxygen atoms a 5- to 7-membered ring optionally substituted by one or more group (s) alkyl or optionally attached to a phenyl group.
• group (s) alkyl or optionally attached to a phenyl group can be used:
• This agent may be, for example, phosgene, triphosgene or N, N'-disuccinimidyl carbonate (DSC).
• the reaction is conducted in the presence of triphosgene. It is also preferably carried out in the presence of a base such as, for example, triethylamine and at a temperature of between -5 ° C.
• Example 1.5 illustrates the preparation of P 1 in the case where P 4 represents 3- (aminomethyl) pyridine.
• An example of P 7 which is advantageously used in Scheme 3 and in the following is 4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenylamine (commercial product).
• Example 2.1 illustrates the preparation of a P 1 where P 5 represents 3- (3-pyridyl) acrylic acid.
• step (i) the reaction with the amine R 1 NH 2 can take place at room temperature, in a protic solvent such as alcohol or water (see ex.1.1); step (N): conversion of P 9 acid to P 10 acid fluoride, for example using cyanuric fluoride and optionally a base such as pyridine.
• the reaction can take place at ambient temperature in dichloromethane (DCM) (see Example 1.2).
• DCM dichloromethane
• the strong base can be NaH or NaH associated with t-
• a solution of P 10 is preferably added in small quantities to a solution of P 11 (see Example 1.4).
• step (i) reaction of P 12 with triphosgene to obtain P 13 .
• the reaction can be conducted in refluxing dioxane (see ex.7.1);
• the halide is more particularly an iodide (eg ethyl iodide); step (iii): reaction between P 11 and P 14 in the presence of a strong base, e.g. NaH, in a polar solvent, e.g. DMF (see ex.7.3).
• a strong base e.g. NaH
• a polar solvent e.g. DMF
• P 2 is obtained from 2,4-dihydroxy-pyrimidine-5-carboxylic acid P 15 .
• the skilled person may be inspired by the conditions given in ex. 9 and apply them to other groups R 1 and R 5 : step (i): preparation of P 16 acid chloride.
• the reaction can take place in a polar solvent such as THF (see ex.9.3); step (iv): conversion of the ester function -COOEt to acid function -COOH.
• a base such as lithium hydroxide can be used in water and then acidified (see ex.9.4); step (v): preparation of the acid fluoride.
• Cyanuric fluoride can be used in DCM
• the reaction can be carried out in the presence of a concentrated ammonia solution, room temperature (see ex.3.5).
• P 7 is replaced by P 7 '.
• P 7 ' is obtained by introducing the R 7 group by alkylation of the amine function of P 7 previously protected by the protective group PG (PG may be for example the tert-butyloxycarbonyl group BOC).
• a and B both represent the group -NH- (C-rC 6 ) alkyl-Q
• P 3 is obtained according to Scheme 6 "by a Suzuki type coupling between P 7 and P 20 to give P 2 i followed by the reaction of P 21 with the compound of formula H 2 N- (C-1) -C 6 ) alkyl-Q ', Q' has the same definition as Q except when Q is -NH 2 , in which case Q 'is -NH-PG in which PG is a protecting group for the amino function ( eg BOC) and the coupling is then followed by a deprotection step to form the -NH 2 function.
• reaction between P 21 and H 2 N- (C 1 -C 6) alkyl-Q ' is preferably carried out at above 100 ° C temperature (see ex.8.7 or 4.2) and preferably for an extended period ( > 10 h).
• P 2 O is prepared from P ' 8 according to Scheme 7:
• COCI oxalyl chloride
• This step (iv) can be carried out at one time (see ex.3.4) or by isolating an intermediate compound (see ex.8.4).
• the fluorinated compounds P 7 for which K and K 'represent a hydrogen atom can be prepared from fluorinated bromoaniline by the reactions described in Tetrahedron Letters 2003, 44, 7719-7722.
• Amines are commercial products or already described in published documents; for example :
• 6-amino-3-pyridinepropanoic acid CAS No. 446263-96-3, described in EP 1394159 (Preparation 6, page 27);
• 5-thiazolepropanoic acid CAS No. 933724-95-9, available from CHEMSTEP, 20, av.V.Hugo, 33560 France.
• the salts are obtained by contacting the acid and the compound in its base form. They can also be obtained during a deprotection step in acidic medium.
• the invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising a compound as defined above in combination with a pharmaceutically acceptable excipient.
• the excipient is selected according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
• the mode of administration may be oral or intravenous.
• the invention relates to a medicament which comprises a compound as defined above and the use of a compound as defined above for the manufacture of a medicament. It can be useful for treating a pathological condition, especially cancer. This drug may find use in the treatment or prevention of diseases caused or exacerbated by the proliferation of cells and especially tumor cells.
• the drug may be administered in combination with one or more other anticancer drugs, in particular selected from:
• Chemotherapeutic agents such as alkylating agents, platinum derivatives, antibiotic agents, antimicrotubule agents, taxoids, anthracyclines, group I and II topoisomerase inhibitors, fluoropyrimidines, cytidine analogues, analogs adenosine, enzymes, as well as estrogenic and androgenic hormones;
• the invention also relates to a method for treating the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention or a pharmaceutically acceptable salt thereof or hydrates or solvates.
• the compounds were analyzed by HPLC-UV-MS coupling (liquid chromatography, ultraviolet (UV) detection and mass detection).
• the apparatus used consists of an Agilent chromatographic chain equipped with an Agilent diode array detector and a ZQ Waters single quadrupole mass spectrometer or a Quattro-MicroWaters triple quadrupole mass spectrometer.
• the liquid phase chromatography / mass spectrometer (LC / MS) spectra were recorded in electrospray (ESI) positive mode, in order to observe the ions resulting from the protonation of analyzed compounds (MH + ), or the formation of adducts with other cations such as Na + , K + , etc.
• the ionization parameters are as follows: cone voltage: 20 V; capillary voltage: 3 kV; source temperature: 12OoC; desolvation temperature: 45OoC; gas desolvation: N 2 at 450 L / h.
• the compounds are analyzed by HPLC-UV-MS coupling (liquid chromatography-UV detection and mass detection).
• the apparatus used consists of a Gilson chromatographic chain equipped with an Agilent diode array detector and a Thermo Finnigan AQA single quadrupole mass spectrometer.
• the recording of the mass spectra is carried out in electrospray (ESI) mode positive at a cone voltage of 20 kV, in order to observe the ions resulting from the protonation of analyzed compounds (MH +), or the formation of adducts with other cations such as Na +, K +, etc.
• ESI electrospray
• the conditions of the LCMS are chosen from one of the following methods:
• N-methylcyanoacetamide (variant)
• a stream of methylamine (gas) is passed through for 2 hours while maintaining the temperature below 25 ° C.
• the THF is evaporated and 25.86 g of white solid is obtained.
• IC 50 (HCT116) 0.2-0.5 nM.
• Example 2 2-Amino-1-ethyl-4-oxo-7- [4 - ((E) -3-pyridin-3-yl-acryloylannino) -phenyl] -1,4-dihydro- [1, 8] naphthyridine-3-carboxylic acid methylamide (No. 7) 2.1: (E) -3-pyridin-3-yl- ⁇ / - [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan) 2-yl) -phenyl1-acrylamide
• IC 50 (HCT116) 2 nM
• Example 4 1-Ethyl-2- [2- (4-methyl-piperazin-1-yl) -ethylamino] -4-oxo-7- [4- (3-pyridin-3-ylmethyl-ureido) -phenyl] -1,4-Dihydro- [1,8] naphthyridine-3-carboxylic acid [2- (4-methyl-piperazin-1-yl) ethyl] -amide (46)
• step 7.3 750 mg (2.4 mmol) of step 7.3 are dissolved in 20 mL of THF. 530 mg (2.4 mmol) of p-aniline boronic ester are added followed by 3 ml (6.0 mmol) of a 2M aqueous solution of Na 2 CO 3 . The mixture is degassed with a stream of nitrogen, then 280 mg (0.2 mmol) of Pd (PPh 3 ) 4 are added and the mixture is heated for 16 hours under reflux. After returning to ambient temperature, the mixture is filtered on filter paper and the solvents are evaporated under reduced pressure.
• Example 8 1-Ethyl-4-oxo-7- [4- (3-pyridin-3-ylmethyl-ureido) -phenyl] -2- (2-pyrrolidin-1-yl-ethylamino) -1,4-hydrochloride Dihydroquinoline-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl) -amide (No. 61)
• IC 50 refers to the concentration of compound that leads to 50% loss of proliferation and cell viability.

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