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EP2411368A1 - Nicotinamidderivate, deren herstellung und deren therapeutische verwendung als antikrebsmittel - Google Patents

Nicotinamidderivate, deren herstellung und deren therapeutische verwendung als antikrebsmittel

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Publication number
EP2411368A1
EP2411368A1 EP10716566A EP10716566A EP2411368A1 EP 2411368 A1 EP2411368 A1 EP 2411368A1 EP 10716566 A EP10716566 A EP 10716566A EP 10716566 A EP10716566 A EP 10716566A EP 2411368 A1 EP2411368 A1 EP 2411368A1
Authority
EP
European Patent Office
Prior art keywords
phenyl
fluoro
ureido
nicotinamide
ylmethyl
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Withdrawn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
EP10716566A
Other languages
English (en)
French (fr)
Inventor
Jérôme ARIGON
Claude Bernhart
Monsif Bouaboula
Romain Combet
Sandrine Hilairet
Samir Jegham
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi SA
Original Assignee
Sanofi SA
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Filing date
Publication date
Application filed by Sanofi SA filed Critical Sanofi SA
Publication of EP2411368A1 publication Critical patent/EP2411368A1/de
Withdrawn legal-status Critical Current

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    • 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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • C07D213/60—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 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • 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
    • C07D213/60—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 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to nicotinamide derivatives, the compositions containing them and their therapeutic application, especially as anti-cancer agents.
  • the invention also relates to the process for the preparation of these compounds as well as to some of the intermediate products.
  • Z represents a phenyl or indanyl group and not a pyridinyl group.
  • R 1 3 may be a 2-, 3- or 4-pyridinyl group
  • R 4 and R 5 represent a hydrogen atom, a group alkyl, alkoxy, -OH, -CF 3 or -CN.
  • halogen atom a fluorine, chlorine, bromine or iodine atom
  • Alkyl group a saturated aliphatic hydrocarbon group comprising from 1 to 6 carbon atoms (advantageously from 1 to 4 carbon atoms) obtained by removing a hydrogen atom from an alkane.
  • the alkyl group can be linear or branched.
  • alkoxy group a -O-alkyl group, where the alkyl group is as defined above; cycloalkyl group: a cyclic alkyl group comprising between 3 and 8 carbon atoms, all the carbon atoms being engaged in the ring 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.
  • 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.
  • 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):
  • X is an integer equal to 1 or 2, representing the number of fluorine atom (s) attached to the central phenyl ring;
  • R 1 represents a hydrogen atom, a (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, phenyl group;
  • R 1 represents a hydrogen atom or a (C 1 -C 6 ) alkyl group
  • R 2 represents:
  • R 3 represents at least one substituent of the pyridine ring chosen from a hydrogen or fluorine atom, a (C 1 -C 4 ) alkyl group or -NR c R d in which R c and R d represent a hydrogen atom or a (C 1 -C 4 ) alkyl group;
  • 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 (C 1 -C 4 ) alkyl group. 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;
  • q 1 or 2.
  • the heterocycloalkyl group formed by R 3 and R b may be, for example, the pyrrolidinyl group
  • 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; (C 1 -C 4 ) alkoxy: for example methoxy; (C 1 -C 4 ) alkyl: for example methyl.
  • substituents which are identical to or different from each other when there are several of them, chosen from: -OH; (C 1 -C 4 ) alkoxy: for example methoxy; (C 1 -C 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 (C 1 -C 4 ) alkyl group or -NR c R d in which R c and R d represent a hydrogen atom or a (dC 4 ) alkyl group.
  • R 3 may be chosen from those described in Table I.
  • R 3 is in the 5 and / or 6 position on the pyridine ring.
  • the number of substituents R 3 is 1 and / or R 3 is in the 5 or 6 position on the pyridine ring as shown below:
  • R 3 is even more preferably in the 6-position.
  • R 3 represents a hydrogen atom or -NH 2 .
  • n is 1.
  • Z and Z ' represent N or CH.
  • Z and Z ' may respectively represent N and CH; CH and CH or N and N:
  • x is an integer of 1 or 2, representing the number of fluorine atom (s) attached to the central phenyl ring. More particularly, x is 1.
  • R 1, R 1 , R 2 , R 3 and x are as previously defined.
  • R 1 represents a (C 1 -C 4 ) alkyl group
  • 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 N-oxides of compounds containing an amine or a nitrogen atom are also part of the invention.
  • the invention provides the process for preparing compounds of to the invention as well as some of the reaction intermediates.
  • HaI represents a halogen atom (chlorine, bromine, iodine).
  • the coupling is carried out in the presence of a palladium complex (in the oxidation state (O) or (M)) in a basic medium.
  • the 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 ( ll).
  • the most frequently used complexes are palladium (O) complexes.
  • the base can 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 an ethereal solvent and an alcohol, for example a dimethoxyethane (DME) / ethanol mixture; it can also be a toluene / water mixture.
  • the temperature is between 50 and 120oC.
  • the duration of the reaction can in some cases be long (see ex.1.3.).
  • 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 at least one (C 1 -C 4 ) alkyl group or to which is optionally attached to two consecutive carbon atoms of said ring a phenyl group.
  • one of the following groups can be used:
  • the compound of formula (I) is obtained by an amidification reaction starting from P 6 and the amine R 2 NH 2 or a salt of this amine, for example the hydrochloride (see ex .3.2).
  • the amidification can be carried out advantageously in the presence of an activator of acid (also called “coupling agent”) such as benzotriazol-1-yloxytris (dimethylamino) -phosphonium hexafluorophosphate (or BOP, CAS No. 56602-33-6, see also B.Castro., 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).
  • 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 ambient temperature and in a protic solvent such as an alcohol or water or in an aprotic solvent such as
  • P 7 is a 2,6-dihalogenonicotinic acid, for example 2,6-dichloronicotinic acid which is commercially available (see example 1.1);
  • Ps can also be obtained from the commercial compound 5-pyrimidinecarboxylic acid, 2,4- dichloro-, ethyl 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). See ex.1 .2.
  • 2007/064931 3-F (4-amino-3-fluorophenylboronic acid pinacol ester, CAS No. 819058-34-9, Boron Molecular Inc., PO Box 12592, Research Triangle Park, NC 27709); 2-F (4-amino-2-fluorophenylboronic acid pinacol ester, CAS No. 819057-45-9, Boron Molecular, described on page 185 of WO 2007/064931); 2-F, 5-F (CAS No. 939807-75-7, compound described on page 184 of WO 2007/064931); 3-F, 5-F (CAS No. 939968-08-8, described on page 182 of WO
  • Amines R 2 NH 2 are commercial products or already described in published documents; for example :
  • Pyrrolidineethanamine CAS No. 7154-73-6, described in Anales de Quimica 1974, 70 (9-10), 733-737, sold by International Laboratory Ltd, 1067 Sneath Ln, San Bruno, CA94066, USA;
  • 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 (C 1 -C 6 ) alkyl group substituted by the group -NR a R b in which R 3 and R b together with the nitrogen atom to which they are heterocycloalkyl (C 4 -C 6 ) group optionally comprising in the ring the group -S (O) q with q 0, 1 or 2 or the group -NH- or -N (C 1 -C 4 ) alkyl is described on Figure 6 which is inspired by scheme 3 of Bioorg. Med. Chem. 2007, 15, 365-373 or diagram 2 of Bioorg. Med. Chem. Lett. 2008, 18, 1378-1381:
  • P 5 can be either commercial or prepared according to methods known to those skilled in the art.
  • the hydrogenation conditions may be those described in ex.19 and 20 of WO 00/46179 or in Synlett 2001, 10, 1623-1625.
  • the compounds 3-picolylamine (CAS No. 3731-52-0), 3- (2-aminoethyl) pyridine (CAS No. 20173-24-4), 2-amino-5-aminomethylpyridine (CAS No. 156973-09- 0), 2-methyl-5-aminomethylpyridine (CAS No. 56622-54-9), 3-methyl-5-aminomethylpyridine (CAS No. 771574-45-9), 2- (BOC-amino) -5-aminomethyl -pyridine (CAS No. 187237-37-2), 2,5-diaminopyridine (CAS No. 4318-76-7) are commercial products.
  • 2-amino-5-aminomethylpyridine can also be prepared according to EP 0607804.
  • 5-Aminomethyl-2- (dimethylamino) pyridine (CAS No. 354824-17-2) is commercially available or can be prepared according to J.Agr.Food Chem . 2008, 56 (1), 204-212.
  • 2-Amino-3-methyl-5-aminomethylpyridine (CAS No. 187163-76-4) can be obtained by catalytic hydrogenation of the 6-amino-5-methyl-nicotinonitrile compound (CAS No. 183428-91-3), the amino function being doubly protected by the BOC.
  • Catalytic hydrogenation 6-methylamino-3-pyridinecarbonitrile (CAS No. 261715-36-0) provides access to 2-methylamino-5-aminomethylpyridine.
  • P 10 can be either commercial or prepared according to methods known to those skilled in the art.
  • 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 10 can be prepared from bromoaniline and acrylic acid according to the teachings of J.Med.Chem. 2002, 45 (15), 3246-3256.
  • P 10 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.
  • the acyl halide P '10 is obtained by a reaction known to those skilled in the art from the acid P 10 and an acylating agent such as for example SOCb or (COCI) 2 .
  • SOCb acylating agent
  • COCI COCI
  • P 4 is reacted with acryloyl chloride in the presence of a base such as, for example, triethylamine and at a temperature of between 0 ° C. and room temperature to obtain P 11 .
  • a base such as, for example, triethylamine
  • the solvent may be dichloromethane (DCM) (see Example 4.1).
  • P 11 is reacted with P 12 (Hal represents a halogen atom), in the presence of a palladium complex such as for example Pd (OAc) 2 , tri-orthotolylphosphine and a base such as for example diisopropylethylamine.
  • the solvent may be, for example, propionitrile.
  • the temperature is between room temperature and the reflux temperature of the solvent.
  • 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 3 is carried out using for R 2 NH 2 the compound 2 HN- (Cr C ⁇ ) alkyl-NH-PG, where PG represents advantageously BOC (tert-butoxycarbonyl).
  • the heterocycloalkyl group formed by R 3 and R b represents the group piperazinyl can advantageously protect the function -NH- using
  • R 3 represents the group -NH 2 or -NHR C
  • the amine function can advantageously be protected by one or two PG group (s), preferably BOC or FMOC (9-fluorenylmethyl carbamate).
  • the compound P 5 can be used
  • 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 HCl or trifluoroacetic acid
  • the salts are obtained during the deprotection step described above or by contacting the acid and the compound in its base form.
  • N-oxides of the compounds containing an amine or a nitrogen atom are prepared according to the methods known to those skilled in the art by reaction of the amine with peracids organic such as peracetic, trifluoroperacetic, performic, perbenzoic acids or its derivatives such as 3-chloroperbenzoic acid, at temperatures between 0oC and 90oC, preferably at temperatures below 50oC.
  • peracids organic such as peracetic, trifluoroperacetic, performic, perbenzoic acids or its derivatives such as 3-chloroperbenzoic 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 can be, for example, orally or intravenously.
  • the subject of the invention is a medicinal product which comprises a compound as defined above as well as 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 of treatment of pathologies indicated above which comprises administering to a patient an effective dose of a compound of the invention or a pharmaceutically acceptable salt or hydrates or solvates.
  • the compounds were analyzed by HPLC-UV-MS coupling (liquid chromatography, ultraviolet (UV) detection and mass detection).
  • the apparatus used is composed of a Agilent chromatographic system equipped with an Agilent diode array detector and a ZQ Waters single quadrupole mass spectrometer or a Quattro-Micro Waters triple quadrupole mass spectrometer.
  • the compounds were analyzed by HPLC-UV-MS coupling (liquid chromatography, ultraviolet (UV) detection and mass detection).
  • the apparatus used is composed of a chromatographic chain equipped with a diode array detector (HP1 1 10 Agilent or UPLC Acquity Waters) and a quadrupole mass spectrometer (ZQ, QM or SQD Waters).
  • 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 HPLC conditions are selected from one of the following methods:
  • Example 3 6- ⁇ 4-r3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl ⁇ -N- (2-azepan-1-yl-ethyl) -2-ethylamino-nicotinamide (Compound No. 15 prepared according to Scheme 3) 3.1. 6- (4 - ⁇ [( ⁇ 6-rbis (tert-butoxycarbonyl) amino] pyridin-3-yl ⁇ methyl) carbamoyamino ⁇ -3-fluorophenyl) -2- (ethylamino) nicotinic acid
  • compound no. 28 (250 MHz) 1, 22 (t, 3), 1, 23 - 1, 6 (m, 6), 2.30 - 2.50 (m, 6), 2.75 (d, 3), 3.34 (m, 2), 3.52 (which, 2), 4.13 (d, 2), 6.39 (q, 1), 6.43 (d, 1), 6, 98 (t, 1), 7.16 (d, 1), 7.37 (dd, 1), 7.80 - 8.02 (m, 4), 8.28 (t, 1), 8.37 (t, 1), 8.41 (t, 1), 8.49 (d, 1).
  • compound no. 40 (400 MHz) 1, 22 (t, 3), 1, 30 - 1, 59 (m, 10), 2.23 (t, 2), 2.28 (s, 4), 3 23 (q, 2); 3.52 (which, 2), 4.13 (d, 2), 5.83 (s, 2), 6.43 (d, 1), 6.99 (t, 1), 7.14 (d, 1), , 1), 7.34 (dd, 1), 7.82 - 8.00 (m, 4), 8.26 (t, 1), 8.43 (m, 2), 8.51 (if, 1).
  • the compounds described in Table I have been the subject of pharmacological tests for determining anticancer activity. They were tested in vitro on the tumor line HCT116 (ATCC-CCL247). Proliferation and cell viability were determined in a test using 3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium (MTS) according to Fujishita T. et al. Oncology 2003, 64 (4), 399-406. In this test, the 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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  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP10716566A 2009-03-24 2010-03-22 Nicotinamidderivate, deren herstellung und deren therapeutische verwendung als antikrebsmittel Withdrawn EP2411368A1 (de)

Applications Claiming Priority (2)

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FR0901365A FR2943669B1 (fr) 2009-03-24 2009-03-24 Derives de nicotinamide,leur preparation et leur application en therapeutique
PCT/FR2010/050511 WO2010109122A1 (fr) 2009-03-24 2010-03-22 Derives de nicotinamide, leur preparation et leur application en therapeutique comme anticancereux

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EP2411368A1 true EP2411368A1 (de) 2012-02-01

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JP (1) JP2012521396A (de)
KR (1) KR20110133049A (de)
CN (1) CN102448939A (de)
AR (1) AR075920A1 (de)
AU (1) AU2010227402A1 (de)
BR (1) BRPI1013553A2 (de)
CA (1) CA2756099A1 (de)
FR (1) FR2943669B1 (de)
IL (1) IL215285A0 (de)
MX (1) MX2011010052A (de)
RU (1) RU2011142753A (de)
SG (1) SG174902A1 (de)
TW (1) TW201038554A (de)
UY (1) UY32517A (de)
WO (1) WO2010109122A1 (de)

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EP2611777B1 (de) 2010-09-03 2016-05-11 Forma TM, LLC. 4- {[(pyridin- 3 -yl-methyl) aminocarbonyl] amino}-benzolsulfonderivate als nampt-inhibitoren zur behandlung von krankheiten wie krebs
RU2617988C2 (ru) 2010-09-03 2017-05-02 ФОРМА ТиЭм, ЭлЭлСИ Новые соединения и композиции для ингибирования nampt
US9169209B2 (en) 2011-05-04 2015-10-27 Forma Tm, Llc Compounds and compositions for the inhibition of NAMPT
CN103929961A (zh) * 2011-06-20 2014-07-16 美国阿尔茨海默病研究所公司 化合物及其治疗应用
EP2712862A1 (de) * 2012-09-28 2014-04-02 Splicos Neue anti-invasive Derivate
US9938258B2 (en) 2012-11-29 2018-04-10 Karyopharm Therapeutics Inc. Substituted 2,3-dihydrobenzofuranyl compounds and uses thereof
FI3016946T3 (fi) 2013-07-03 2023-01-13 Substituoituja bentsofuranyyli- ja bentsoksatsolyyliyhdisteitä ja niiden farmaseuttisia käyttöjä
WO2015042414A1 (en) 2013-09-20 2015-03-26 Karyopharm Therapeutics Inc. Multicyclic compounds and methods of using same
WO2016191547A1 (en) * 2015-05-26 2016-12-01 Comfort Care For Animals Llc Liposome loading
EA201890524A1 (ru) 2015-08-18 2018-07-31 Кариофарм Терапевтикс Инк. (s,e)-3-(6-аминопиридин-3-ил)-n-((5-(4-(3-фтор-3-метилпирролидин-1-карбонил)фенил)-7-(4-фторфенил)бензофуран-2-ил)метил)акриламид для лечения рака
US10858347B2 (en) 2015-12-31 2020-12-08 Karyopharm Therapeutics Inc. Multicyclic compounds and uses thereof
WO2023119230A1 (en) 2021-12-22 2023-06-29 L'oreal Coagulation pathway and nicotinamide-adenine dinucleotide pathway modulating compositions and methods of their use

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GB0327734D0 (en) * 2003-11-28 2003-12-31 Novartis Ag Organic compounds
AU2004292773A1 (en) * 2003-11-28 2005-06-09 Novartis Ag Diaryl urea derivatives in the treatment of protein kinase dependent diseases
KR20130083488A (ko) * 2004-09-02 2013-07-22 제넨테크, 인크. 헤지호그 신호전달에 대한 피리딜 억제제
FR2921657A1 (fr) * 2007-09-28 2009-04-03 Sanofi Aventis Sa Derives de nicotinamide, leur preparation et leur application en therapeutique

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IL215285A0 (en) 2011-11-30
UY32517A (es) 2010-10-29
US20120053170A1 (en) 2012-03-01
KR20110133049A (ko) 2011-12-09
CN102448939A (zh) 2012-05-09
SG174902A1 (en) 2011-11-28
CA2756099A1 (fr) 2010-09-30
FR2943669B1 (fr) 2011-05-06
RU2011142753A (ru) 2013-04-27
AR075920A1 (es) 2011-05-04
BRPI1013553A2 (pt) 2016-04-12
WO2010109122A1 (fr) 2010-09-30
JP2012521396A (ja) 2012-09-13
FR2943669A1 (fr) 2010-10-01
TW201038554A (en) 2010-11-01
AU2010227402A1 (en) 2011-10-20
MX2011010052A (es) 2012-01-12

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