Classifications

• • 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
• • 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
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/56—Amides

Definitions

• the present invention relates to novel anticancer compounds, the compositions containing them and their therapeutic application, especially as anticancer agents.
• the invention also relates to the process for the preparation of these compounds as well as to some of the intermediate products.
• WO 99/31064 discloses compounds of formula (A):
• G represents especially the group - (CRgRioWRs in which m is 0 or 1
• R 9 and R 10 may represent a hydrogen atom or an alkyl group and R 8 represents an aralkyl group, a monocyclic aromatic or heteroaromatic group which may contain 1 to 3 heteroatoms (N, O or S) or a bicyclic or tricyclic aromatic group
• R 8 may be optionally substituted by: halogen, - CN, alkyl, fluoroalkyl, cycloalkyl, aralkyl, aryl, -OH, hydroxyalkyl, alkoxy (- Oalkyl), aryloxy (-Oaryl), mercapto (-SH), alkylthio (-Salkyl), arylthio (-Saryl), carboxy (-COOH), carboxyalkyl (-alkyl-COOH), carboxyalkenyl (-alkenyl-COOH), alkoxycarbonyl (- COOal
• a halogen atom a fluorine, chlorine, bromine or iodine atom
• An alkyl group a saturated aliphatic hydrocarbon group comprising from 1 to 6 carbon atoms (advantageously 1 to 4 carbon atoms) of formula C n H 2n + I -, obtained by removing a hydrogen atom from an alkane.
• the alkyl group can be linear or branched.
• An alkylene group a divalent group of formula -CH 2n -, obtained by removing two hydrogen atoms of an alkane on two different carbon atoms of said alkane;
• alkoxy group a -O-alkyl group, wherein the alkyl group is as defined above;
• a cycloalkyl group a cyclic alkyl group comprising between 3 and 8 carbon atoms, all the carbon atoms being involved in the cyclic structure.
• heterocycloalkyl group a cycloalkyl group comprising at least one heteroatom (O, S, N) engaged in the ring and connected to the carbon atoms forming the ring.
• heteroatom O, S, N
• pyrrolidinyl piperidinyl, piperazinyl or N- (C 1 -C 4 ) alkyl-piperazinyl, azepanyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1, 1-dioxothiomorpholinyl groups.
• the present invention relates to a compound of formula (I):
• W represents a - (CrC 4 ) alkylene-CH 2 CH 2 - group
• R 1 represents a hydrogen atom, a (C 1 -C 6 alkyl), (C 3 -C 6 ) cycloalkyl or phenyl group; R 1 represents a hydrogen atom or a group (C 1 -C 6 alkyl);
• Z and Z ' represent N or CH. More particularly, Z and Z 'may respectively represent N and CH; CH and CH or N and N:
• R 1 represents a hydrogen atom, a (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl group, for example cyclopropyl, a phenyl group.
• R ' 1 represents a hydrogen atom or a group (CrC 6 ) alkyl. More particularly, R 1 represents a hydrogen atom.
• R 1 and / or R ' 1 may be chosen from those described in Table I.
• R 2 represents:
• a (C 3 -C 6) cycloalkyl group such as for example the cyclopropyl or cyclopentyl group;
• the heterocycloalkyl group formed by R 3 and R b may be, for example, the pyrrolidinyl group
• the heterocycloalkyl group formed by R a and R b may be optionally substituted by one or more substituents, which are identical to or different from each other when there are several of them, chosen from: -OH; (CrC 4 ) alkoxy: for example methoxy; (CrC 4 ) alkyl: for example methyl.
• the substituted heterocycloalkyl may be the 3-hydroxypiperidinyl group
• the pyridine ring may comprise from 1 to 4 substituents R 3 chosen from a hydrogen or fluorine atom, a (dC 4 ) alkyl group or -NR c R d in which R c and R d represent an atom of hydrogen or a (CrC 4 ) alkyl group.
• R3 is in the 5 and / or 6 position on the pyridine ring.
• the number of substituents R3 is 1 and / or R3 is in the 5 or 6 position on the pyridine ring as shown below: position 6 position 5
• R3 is even more preferentially in the 6-position.
• R3 represents a hydrogen atom or -NH 2 .
• W represents a group - (C 1 -C 4 ) alkylene-CH 2 CH 2 -, in particular the group - (CH 2 ) m -, m being an integer between 1 and 6.
• R 1 is (C 1 -C 6 ) alkyl
• the double bond on the pyridine ring may be in E or Z form. Preferably, they are in E form.
• the compounds of the invention may exist in the form of bases or addition salts with acids. Such addition salts are also part of the invention. 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 a solvent. Such hydrates and solvates are also part of the invention.
• the compounds may have one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures are part of the invention.
• the subject of the invention is the process for preparing the compounds of the invention as well as some of the reaction intermediates.
• step (i) a Sonogashira type coupling between Pi and P 2 is performed to obtain P 3 .
• HaI represents a halogen atom (chlorine, bromine, iodine)
• ALK represents the (Cr C 4 ) alkylene group, in particular the group - (CH 2 ) m -
• PG represents a group protecting the amine function, for example the BOC
• U represents OH or a halogen atom, such as chlorine.
• the coupling is carried out in the presence of a palladium complex (in the oxidation state (O) or (N)) in a solvent in basic medium.
• the palladium complex may be for example Pd (PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , Pd (OAc) 2 , PdCl 2 (dppf) or bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II).
• a copper (I) salt such as cuprous chloride, is generally required as a cocatalyst of the palladium complex.
• a copper salt such as, for example, the Pd 2 (dba) 3 , P (t-Bu) 3 , and 3 N system in THF (Eur J. Org Chem 2000, 3679).
• the coupling is carried out in the presence in a basic medium, 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 conducted in a mixture of a polar solvent, for example DMF.
• the temperature is between 50 and 120 ° C. The duration of the reaction may in certain cases exceed long (see conditions of ex.1).
• step (ii) the -C ⁇ C- bond is hydrogenated.
• Hydrogen can be used in the presence of a metal catalyst, for example palladium deposited on a solid support (eg Pd / C).
• the hydrogenation can be carried out for example at room temperature, with hydrogen under a pressure of the order of 1 atm in the presence of palladium on carbon, for a period of about 20-30 min. See for example the conditions of ex.1.5.
• There are other techniques for hydrogenating -C ⁇ C- bonds into -CH 2 CH 2 - bonds which are known to those skilled in the art.
• step (iii) P 4 is deprotected, for example by acid treatment when PG is BOC.
• U represents an acid
• the amidification can be carried out advantageously in the presence of an acid activator (also called
• Coupling agent such as, for example, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (or BOP, CAS No. 56602-33-6, see also Castro, B.,
• Ps is obtained from P 7 acid by monosubstitution with an amine of formula R 1 R 1 NH.
• the reaction may be carried out at room temperature and in a protic solvent such as an alcohol or water or in an aprotic solvent such as THF (see also ex.1.1. ).
• a strong base such as for example LiHMDS (((CH 3 ) 3 Si) 2 NLi) is added and the reaction is carried out under heat.
• P 7 is a 2,6-dihalogenonicotinic acid, for example 2,6-dichloronicotinic acid which is commercial;
• Ps can also be obtained from the commercial compound 5-pyrimidinecarboxylic acid, 2,4-dichloroethyl ester:
• Pi is obtained from Ps acid by amidification using the amine R 2 NH 2 or a salt of this amine, for example the hydrochloride.
• Amidification can advantageously be carried out in the presence of an acid activator (also called “coupling agent”) such as for example benzotriazol-1-yloxytris (dimethylamino) -phosphonium hexafluorophosphate (or BOP, CAS No. 56602-33- 6, see also Castro, B., Dormoy, JR Tetrahedron Letter 1975, 16, 1219).
• the reaction is preferably carried out in the presence of a base (such as triethylamine) at room temperature, in a solvent such as tetrahydrofuran (THF) or dimethylformamide (DMF).
• a base such as triethylamine
• solvent such as tetrahydrofuran (THF) or dimethylformamide (DMF).
• Scheme 4 is obtained from Pg according to Scheme 4 by conversion of the alcohol functional group to the amine function via the intermediate P 10 carrying the mesyl leaving group, followed by protection of Pu with PG. It is also possible to use sodium azide in place of NH 3 to azide function, which is then converted to amine function (see Tetrahedron Scheme II 1987, 43 (21), 5145-58 and Tetrahedron 2008 Scheme 1, 64, 3578-3588).
• N- (2-aminoethyl) thiamorpholin-1-oxide CAS No. 1017791-77-3, sold by Sinova Inc. 3 Bethesda Metro Center, Suite 700, Bethesda, MD, 20814, USA.
• a method for obtaining compounds for which R 2 represents a group (CrC ⁇ ) alkyl substituted with the group -NR a R b in which R 3 and R b together with the nitrogen atom to which they are connected form the group (C 4 -C 6 ) heterocycloalkyl optionally comprising in the ring the group -S (O) q with q 0, 1 or 2 or the group -NH- or -N (CrC 4 ) alkyl is described in Scheme 5 and is inspired of Scheme 3 of Bioorg, Chem Chem 2007, 15, 365-373 or Scheme 2 of Bioorg, Chem Chem Lett 2008, 18, 1378-1381:
• Figure 5 Another method described in Figure 6 is based on Figure 2 of Bioorg. Med. Chem. Lett. 2006, 16, 1938-1940: Ba gg hydrogenation NC- (C 1 -C 5 ) Alk-Br + NHR a R b "NC- (C 1 -C 5 ) Alk-NR 3 R, - NH 2 - (C 1 -C 5 ) AIk-NR 3 R,
• trans-3- (3-pyridyl) acrylic acid is marketed by Sigma-Aldrich.
• (6-Aminopyridin-3-yl) acrylic acid (CAS No. 234098-57-8, compound E: CAS No. 167837-43-6) is described in J.Med.Chem. 2002, 45 (15), 3246-3256 (see diagram 4).
• P 6 can be prepared from bromoaniline and acrylic acid according to the teachings of J.Med.Chem. 2002, 45 (15), 3246-3256.
• P 6 can also be prepared according to J.Org.Chem. 1998, 63, 8785-8789 from the corresponding beta-formylpyridine or according to J.Med.Chem. 1989, 32 (3), 583-93 from 2-chloro-5-nitro-pyridine.
• an acylating agent such as, for example, SOCI 2 or (COCI) 2 .
• Pg can be either commercially available (for example, 3-butyn-1-ol CAS No. 927-74-2 or 2-propyn-1-ol CAS No. 107-19-7) is prepared according to the known methods of the skilled person.
• a protecting group to protect one or more chemical function (s), including a primary or secondary amine function.
• R 3 and R b both represent a hydrogen atom
• the amidification of Scheme 2 is carried out using for R 2 NH 2 the compound 2 HN- (d-C ⁇ ) alkyl-NH-PG, where PG represents advantageously BOC (tert-butoxycarbonyl) .
• PG represents advantageously BOC (tert-butoxycarbonyl) .
• the heterocycloalkyl group formed by R 3 and R b represents the group piperazinyl
• the function -NH- can advantageously be protected by using
• the chemical function (s) is / are then obtained by a deprotection step (final or intermediate) whose conditions depend on the nature of the protected function (s) and protective group used.
• a deprotection step final or intermediate
• the deprotection step is carried out in acidic medium using, for example, HCl or trifluoroacetic acid (TFA).
• the deprotection step is carried out in acidic medium using, for example, HCl or trifluoroacetic acid (TFA).
• TFA trifluoroacetic acid
• 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 from the usual excipients known to those skilled in the art according to the pharmaceutical form and the desired mode of administration.
• the mode of administration may be, for example, orally or intravenously.
• the subject of the invention is a medicinal product 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.
• the drug (as well as a compound according to the invention) may be administered in combination with one (or more) anticancer drugs. This treatment can be administered simultaneously, separately or sequentially. The treatment will be adapted by the practitioner according to the patient and the tumor to be treated.
• 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. 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 chromatography / mass spectrometry (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: 120 ° C. desolvation temperature: 450 ° C .; gas desolvation: N 2 at 450 L / h.
• HPLC conditions are chosen from one of the following methods:
• HCT116 ATCC-CCL247
• PC3 ATCC-CRL1435.
• MTS 3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium.
• MTS mitochondrial capacity of living cells is measured to transform MTS into a colored compound after 72 hours of incubation of the test compound. The concentration of compound which leads to 50% loss of proliferation and cell viability is noted as IC 5 O.

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