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WO2018199797A1 - 2-methyliden-5-(phénylamino)-2,3-dihydrothiophen-3-ones substitués pour traiter des leucémies aiguës avec une translocation du gène mm et d'autres maladies cancéreuses - Google Patents

2-methyliden-5-(phénylamino)-2,3-dihydrothiophen-3-ones substitués pour traiter des leucémies aiguës avec une translocation du gène mm et d'autres maladies cancéreuses Download PDF

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WO2018199797A1
WO2018199797A1 PCT/RU2017/000276 RU2017000276W WO2018199797A1 WO 2018199797 A1 WO2018199797 A1 WO 2018199797A1 RU 2017000276 W RU2017000276 W RU 2017000276W WO 2018199797 A1 WO2018199797 A1 WO 2018199797A1
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Денис Николаевич КАЗЮЛЬКИН
Любовь Корочкина
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"oncotartis" LLC
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    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/36—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • This invention relates to the chemistry of organic compounds, pharmacology and medicine and relates to the prevention and treatment of cancer, in particular leukemia with translations of the MLL gene using a new class of chemical compounds with increased efficiency, as well as increased selectivity and bioavailability.
  • MLL ixed Lineage Leukemia, multilinear leukemia
  • AML acute myeloid leukemia
  • BRD2 / 3/4 bromodomain inhibitors are known to have antitumor activity in animal models of MLL leukemia [Nature 2011; 478 (7370): 529-533]. It has also been shown that low molecular weight inhibitors of certain protein kinases, such as GSK-3 [Nature 2008; 455: 1205-1209], FLT3 [Front Oncol 2014; 4: 263], CDK6 [Blood 2014; 124: 5-6], EPHA7 [Proc Natl Acad Sci U S A. 2007; 104: 14442-14447] may be new effective drugs for the treatment of leukemia with MLL translocations.
  • GSK-3 Nature 2008; 455: 1205-1209
  • FLT3 FLT3 [Front Oncol 2014; 4: 263]
  • CDK6 [Blood 2014; 124: 5-6]
  • EPHA7 Proc Natl Acad Sci U S A. 2007; 104: 14442-14447
  • MLL-menin protein-protein interaction inhibitors exhibit high selective cytotoxicity against malignant cell lines with translocation of the MLL gene and also exhibit significant antitumor activity in xenograft models [Cancer Cell 2015; 27: 1-14].
  • hCE1 carboxyl esterase-1
  • hCE1 is characteristic of leukemia cell lines with translations of the MLL gene widely used in experimental biology, such as THP-1, U937 and MV-411 rhttp: //www.proteinatlas.orq/ENSG00000198848-CES1/cein.
  • HepG2 hepatocellular carcinoma cell lines and A549 lung adenocarcinomas also express hCE1 [RSC Adv., 2016, 6: 4302-4309].
  • the objective of the present invention is to develop and create new compounds effective for the treatment of cancer, namely cancer, associated with malignant transformation of cells, expressing the enzyme hCE1 (carboxyl esterase-1), in particular, in the treatment of leukemia with translocation of the MLL gene.
  • cancer namely cancer, associated with malignant transformation of cells, expressing the enzyme hCE1 (carboxyl esterase-1), in particular, in the treatment of leukemia with translocation of the MLL gene.
  • the technical result of the invention is the development and preparation of new chemical compounds that are highly effective for the treatment of cancer, namely for the treatment of cancer associated with malignant transformation of cells expressing the enzyme carboxyl esterase pSE1, as well as high selectivity for tumor diseases associated with malignant transformation cells expressing the carboxylesterase hCE1 enzyme, in particular tumors with translocation of the MLL gene, in particular leukemia with translocation of the MLL gene.
  • These compounds are promising for use in the treatment of cancer, including cancer in translocation of the MLL gene, for example leukemia with translocation of the MLL gene.
  • R 1 , R 2 are independently selected and are —H, substituted or unsubstituted —C ! -Cb-alkyl, substituted or unsubstituted -C 3 -C 9 -cycloalkyl, substituted or unsubstituted -C 2 -Cb-alkenyl, substituted or unsubstituted -C 2 -C 6 - alkynyl, wherein the substituents R 1 and R 2 , together with the carbon atom to which they are attached can form substituted or unsubstituted —C3 — C ⁇ cycloalkyl, substituted or unsubstituted —C 5 -C 12 cycloalkenyl;
  • X 2 is independently selected and represents an unsubstituted or substituted alkylene chain - (CH 2 ) P -, where n takes values from 1 to 4;
  • Y 2 is independently selected and is —C (R b ) 2 -;
  • R a is independently selected and is —H, halogen, —OH, —CN, —C 6 —alkyl, —O — C — C 6 -alkyl, —Cz-C 9 -cycloalkyl, phenyl, five or six membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, 3-I 2-membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, with two substituents R a , together with the carbon atom to which they are attached, they can form —C 3 -C 6 cycloalkyl, a 3-I2 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O;
  • R b is independently selected and is —H, —C g C 6 -alkyl, —C 3 -C 9 — cycloalkyl, 5-HO membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, or a 3-I2-membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, the two substituents R b , together with the carbon atom to which they are attached, can form -C 3 -C 6 - cycloalkyl;
  • R c is independently selected and is —H, halogen, substituted or unsubstituted —Ci — C b alkyl;
  • R 3 is independently selected and is —H, substituted or unsubstituted —C ⁇ —C b -alkyl, substituted or unsubstituted —C 3 -C 9 cycloalkyl, substituted or unsubstituted —C 6 -C 0 aryl, substituted or unsubstituted 5 -IO-membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, 3-H 2-membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, or represents Rd
  • R d , R d ′ are independently selected and are —H, substituted or unsubstituted —C Ce alkyl, substituted or unsubstituted —C 6 -C 10 aryl, substituted or unsubstituted 5 + 6 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and O, substituted or unsubstituted 3-I and 2-membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, with two substituents R d and R d ', together with the carbon atom to which they are attached, may form a substituted or unsubstituted c 3 -C 12 -cycloalkyl, substituted or n substituted -C1 2 -C 5 cycloalkenyl, substituted or unsubstituted 3-I2-membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O;
  • Y 3 is independently selected and is —F, —CN, —OR e , —N (R e ) 2 or a substituted or unsubstituted 3-I and 2-membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O;
  • X 3 is independently selected and is —0—, —S—, —C (R a ) 2 - or —NR b -;
  • R 4 is independently selected and is halogenated —Ci-C b- alkyl, substituted or unsubstituted 5 * 6 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, or substituted or unsubstituted 3- And a 2-membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and O;
  • X 4 is independently selected and is —O—, —S—, —C (R a ) 2 or —NR 15 -;
  • X s represents an unsubstituted or substituted alkylene chain - (CH 2 ) P -, where n takes values from 1 + 4;
  • X 6 is independently selected and is —O— or —S—;
  • R 5 is independently selected and is —H, substituted or unsubstituted —C ⁇ C b- alkyl, substituted or unsubstituted —C 2 -C 6 alkenyl, substituted or unsubstituted —C 6 -C 10 aryl, substituted or unsubstituted 5+ 6-membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O substituted or unsubstituted 3-I and 2-membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O;
  • X 7 , X 9 are independently selected and are —N— or —CR f -;
  • X 8 is independently selected and is —O— or —S—;
  • R f is independently selected and is —H, halogen, —N (R b ) 2 , —CN, —N0 2 , substituted or unsubstituted substituted or unsubstituted -Od-Sb-alkyl, substituted or unsubstituted -C 6 -C 10 aryl, substituted or unsubstituted 5-K5-membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, substituted or unsubstituted ZI 2-membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O;
  • X 10 is independently selected and is N or —CR 9 -;
  • R 9 is independently selected and is —H, halogen, —CN, —N0 2 , —OR e , —N (R b ) 2 , substituted or unsubstituted —C 6 alkyl, substituted or unsubstituted — C 2 —C 6 -alkynyl, substituted or unsubstituted -0-C1-C6 alkyl, substituted or unsubstituted C 6 -C 10 -aryl, substituted or unsubstituted -O-phenyl, unsubstituted or substituted with b-G-membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and O, substituted or unsubstituted Z-H 2-membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O;
  • R h is independently selected and is —H, halogen, —CN, —NO 2 , —OR b , —
  • N (R b ) 2 substituted or unsubstituted -C 6 -alkyl, substituted or unsubstituted — Sb-Cyu-aryl, substituted or unsubstituted 5 + 6-membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, or a substituted or unsubstituted Z-H 2-membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O;
  • R 6 is independently selected and is —H, substituted or unsubstituted —C 6 alkyl, substituted or unsubstituted — C 2 -C 6 alkenyl, substituted or unsubstituted —C 2 -C 6 alkynyl, substituted or unsubstituted —Cb- Syuaryl, substituted or unsubstituted 5-6 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, substituted or unsubstituted 3-5-12 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O;
  • X 11 is independently selected and is —N— or —CR j -;
  • X 12 is independently selected and is —N— or —CR j -;
  • R j is independently selected and is —H, halogen, —CN, —CF 3 , —CHF 2 , -
  • Alkynyl substituted or unsubstituted -C 3 -C 2 -cycloalkyl, substituted or unsubstituted - Sb-Cyu-aryl, substituted or unsubstituted 5- membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S, O, substituted or unsubstituted cyclic-3-membered heterocyclyl containing from 1 to 4 heteroatoms, independently selected from N, S, and O;
  • R 7 is independently selected and is —F, —CN, —CF 3 , —CHF 2 , - (CH 2 ) tO (CH2) s, substituted or unsubstituted —C B-alkyl, substituted or unsubstituted —C 2 -C 4 -alkenyl, substituted or unsubstituted -C 2 -C 4 -alkynyl, substituted or unsubstituted-C 3 -C 12 -cycloalkyl, substituted or unsubstituted - C b -Cyu-aryl, 5-IZ membered heterocycle containing from 1 to 4 heteroatoms independently selected from N, S and / or O, substituted or unsubstituted 3-I2-membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O;
  • t and s take values from 1 to 10;
  • B is independently selected and represents:
  • each substituent R k is independently selected and is —H, halogen, —CN, —N0 2 , —CF 3 , —CHF 2 , CH 2 F, substituted or unsubstituted —d-Ce-alkyl, substituted or unsubstituted —0 — C C 6 -alkyl, substituted or unsubstituted -C 2 -C 4 alkenyl, substituted or unsubstituted -C 2 -C 4 -alkynyl or substituted or unsubstituted -C 3 -C 12 -cycloalkyl;
  • R L is independently selected and is —N (R b ) 2 , substituted or unsubstituted —d-Ce-alkyl, substituted or unsubstituted —C 6 -C 10 aryl, substituted or unsubstituted 5-C3 membered heteroaryl containing from 1 up to 4 heteroatoms independently selected from N, S and / or O, or a substituted or unsubstituted 3-12 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O.
  • a separate subclass of compounds of interest includes compounds of general formula (la), general formula (Ma), or general formula (Ilia): formula (la),
  • R 1 , R 2 are independently selected and are —H, or substituted or unsubstituted —Ct-Cb-alkyl, with substituents R 1 and R 2 , together with the carbon atom to which they are attached, can form a substituted or unsubstituted —C 3 -C 9 is cycloalkyl;
  • each substituent R k is independently selected and is —H, —F, —CI, —CN, —Ci-Cb-alkyl, —C 3 -C 6 cycloalkyl;
  • R 8 is independently selected and is —H, substituted or unsubstituted —C 6 -alkyl, substituted or unsubstituted — C 3 -C 9 cycloalkyl, substituted or unsubstituted —C 6 -C 10 aryl, substituted or unsubstituted 5 + 6 - a membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, a substituted or unsubstituted 3-IO membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O; R is independently selected and is —H or substituted or unsubstituted —C 6 alkyl.
  • a separate subclass of compounds of interest includes compounds of general formula (lb), general formula (lib), or general formula (lllb):
  • R represents: and the asterisk indicates the place of attachment of the substituent
  • R 1 , R 2 are independently selected and are —H, substituted or unsubstituted —C 6 alkyl, with substituents R 1 and R 2 , together with the carbon atom to which they are attached, can form a substituted or unsubstituted —C 3 - C ⁇ cycloalkyl;
  • each substituent R k is independently selected and is —H, —F, —CI, —C 1 -C 4 alkyl;
  • Y 4 is independently selected and is —C (R n ) 2 -;
  • R is independently selected and is —H, —F, —CI, substituted or unsubstituted —d-Ce-alkyl, —OR b , —N (R b ) 2 ; m, v are selected independently take values from 1 + 6;
  • R b is independently selected and is —H, substituted or unsubstituted —Ci-Sb-alkyl, substituted or unsubstituted — C3-Cd-cycloalkyl, substituted or unsubstituted 5 + 6 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, or a substituted or unsubstituted 3 + E-membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O.
  • a separate subclass of compounds of interest includes compounds of general formula (lc), general formula (lie), or general formula (Cc):
  • R 1 , R 2 are independently selected and are —H, substituted or unsubstituted —C ⁇ C b -alkyl, wherein R 1 and R 2 , together with the carbon atom, are to which they are attached, may form substituted or unsubstituted -C 3 - C ⁇ -Cyloalkyl;
  • each substituent R k is independently selected and is —H, —F, —CI, —C-hC 4 -alkyl;
  • R h is independently selected and is —H, halogen, —CHF 2 , —CF 3 , substituted or unsubstituted —CrCe alkyl, substituted or unsubstituted —C 3 -C 6 cycloalkyl;
  • R 6 is independently selected and is substituted or unsubstituted-d-C b -alkyl
  • X 10 is —CR 9 -;
  • R 9 is independently selected and is H, —CI, —OR b , —N (R b ) 2 , substituted or unsubstituted substituted or unsubstituted 4-I 0-membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O;
  • R b is independently selected and is —H, substituted or unsubstituted —Ci-C b- alkyl, substituted or unsubstituted —C 3 -C 9 cycloalkyl, substituted or unsubstituted —0-C 6 aryl, substituted or unsubstituted —5+ 6-membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, or substituted or unsubstituted 4- ; -9 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O.
  • the compounds of interest may be selected from the group:
  • the present invention also relates to the use of the subject compounds for the manufacture of a pharmaceutical composition for the treatment and / or prevention of cancer.
  • the cancer is associated with a malignant transformation of cells expressing the enzyme pCE1 (carboxyl esterase-1).
  • the disease is leukemia, a cancer of the liver, bladder, bronchi, lungs, nasopharynx, stomach, colon, pancreas or thyroid, head, neck, smooth muscle, urothelial cancer, or carcinoid tumor.
  • the tumor is characterized by translocation of the MLL gene.
  • the tumor with translocation of the MLL gene is leukemia.
  • the invention provides pharmaceutical compositions for treating and / or preventing cancer in a subject, comprising an effective amount of a compound of the invention and at least one pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient is a carrier, excipient and / or solvent.
  • the subject is a human or animal.
  • the invention also relates to a method for treating and / or preventing an oncological disease, comprising administering an effective amount of a compound of the invention.
  • the invention also includes the preparation of compounds of general formula (I), general formula (II), or general formula (III).
  • hCE1 as used herein means the carboxyl esterase-1 enzyme.
  • alkyl refers to straight or branched chain saturated hydrocarbon groups, including hydrocarbon groups having the indicated number of carbon atoms (that is, C 1-6 alkyl means from one to six atoms carbon). Examples of alkyls include methyl, ethyl, n-propyl, iso-propyl.
  • alkynyl alone or as part of another substituent refers to hydrocarbon groups in which at least one carbon-carbon bond is a triple bond, while the remaining bonds can be simple, double or additional triple bonds, including hydrocarbon groups, from 2 to 6 carbon atoms.
  • alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, etc.
  • alkenyl by itself or as part of another substituent refers to hydrocarbon groups in which at least one carbon-carbon bond is a double bond, while the remaining bonds can be either single bonds or additional double bonds, including hydrocarbon groups containing from 2 to 6 carbon atoms.
  • alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, and the like.
  • halogen by itself or in part of another term refers to an atom of fluorine, chlorine, bromine or iodine.
  • cycloalkyl refers to groups having from 3 to 12 carbon atoms in a mono- or polycyclic structure, including spirocycles.
  • cycloalkyls include, but are not limited to, the following radicals: cyclopropyl, cyclopentyl, cyclohexyl, bicyclo [2.2.2] octanyl, spiro [5.5] undecanyl, which, as with other aliphatic or heteroaliphatic or heterocyclic substituents, may be substituted .
  • heterocycle means herein non-aromatic mono- or polycyclic systems (saturated or partially unsaturated) having from three to twelve atoms containing heteroatoms of N, O or S.
  • the heterocycle can be attached to the main a fragment of a molecule through a nitrogen atom ( ⁇ -heterocyclyl) or through a carbon atom. Heterocycles may also be substituted.
  • cycloalkenyl means in this document a partially unsaturated cycloalkyl containing from 5 to 12 carbon atoms, having in its composition from one to two double carbon-carbon bonds.
  • aryl as used herein means groups containing an aromatic ring having from five to ten carbon atoms.
  • An example of aryl ring groups is phenyl.
  • heteroaryl means a stable heterocyclic and polyheterocyclic aromatic moiety having 5-10 atoms in the ring.
  • a heteroaryl group may be substituted or unsubstituted and may consist of one or more rings.
  • Possible substituents include, but are not limited to, any of the previously mentioned substituents.
  • heteroaryl rings are five- and six-membered monocyclic groups such as thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazolyl and the like; as well as polycyclic heterocyclic groups such as benzo [b] thienyl, isobenzofuranyl, isoindolyl, benzimidazolyl, and the like.
  • heteroaryl can be used equivalently with the terms “heteroaryl ring” or “heteroaromatic”.
  • An aryl group or heteroaryl group may contain one or more substituents.
  • substituents include, but are not limited to, halogen (F, CI, Br or I), d-3-alkyl, —CN, —OH, —C 1-3 alkyl and others.
  • substituted should mean that one or more hydrogen atoms in an atom or group referred to as “substituted” are replaced by any of the listed groups, provided that the said atom has a normal valency or that the valency of the substituted corresponding atom of the group is not excessive, and that substitution leads to a stable connection.
  • substituted or unsubstituted means that the compound or substructure is either unsubstituted or substituted, as defined in the application, by one or more substituents, as mentioned or as defined below.
  • alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl groups, as well as other substructures containing at least one hydrogen atom, can be replaced by one or more substituents:
  • a stable or chemically feasible compound is a compound whose stability is sufficient for its synthesis and analytical detection.
  • Preferred compounds of this invention are sufficiently stable and do not decompose at temperatures up to 40 ° C in the absence of chemically active conditions, for at least one week.
  • Certain compounds of this invention may exist in tautomeric forms, and this invention includes all such tautomeric forms of such compounds, unless otherwise indicated.
  • the compounds of the present invention may exist as tautomers A and B in a state of dynamic equilibrium. Under normal conditions, their separation is not possible, therefore, the pharmacological properties of the compounds of the present invention are a combination of the effects of tautomers.
  • the structures depicted herein also include all stereoisomers, i.e., R- and S-isomers for each asymmetric center.
  • individual stereochemical isomers, as well as enantiomers and diastereomeric mixtures of the present compounds, are also the subject of this invention.
  • this invention encompasses each diastereomer or enantiomer substantially free of other isomers (> 90%, and preferably> 95% molar purity), the same as a mixture of such isomers.
  • a particular optical isomer can be obtained by resolving the racemic mixture in accordance with a standard procedure, for example, by preparing diastereoisomeric salts by treatment with an optically active acid or base, followed by crystallization of the diastereomer mixture, followed by isolation of the optically active bases from these salts.
  • suitable acids are tartaric, diacetyl tartaric, dibenzoyl tartaric, ditoluolvic and camphorsulfonic acid.
  • Another technique for separating optical isomers is to use a chiral chromatographic column.
  • another separation method involves the synthesis of covalent diastereomeric molecules by reacting the compounds of the invention with optically pure acid in an activated form or optically pure isocyanate.
  • the resulting diastereomers can be separated by conventional methods, for example, chromatography, distillation, crystallization or sublimation, and then hydrolyzed to obtain an enantiomerically pure compound.
  • optically active compounds of this invention can be prepared using optically active starting materials.
  • Such isomers may be in the form of a free acid, free base, ester or salt.
  • the present invention includes all pharmaceutically acceptable isotopically labeled compounds of the present invention, in which one or more atoms is replaced by atoms having the same atomic number, but an atomic mass or mass number other than the atomic mass or mass number commonly found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include hydrogen isotopes such as 2 H and 3 H, carbon such as 11 C, 13 C and 1 C, chlorine such as 36 CI, fluorine such as 18 F, iodine, such as 123 1 and 125 1, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphor, such as 32 P, and sulfur, such as 35 S.
  • Radioactive isotopes such as tritium, that is, 3 N, and carbon-14, that is, 14 C, in view of the ease of their introduction and the availability of detection tools.
  • Substitution with heavier isotopes such as deuterium, i.e. 2 N, can provide certain therapeutic effects due to metabolic stability, for example, an increase in half-life in vivo or a decrease in dosing rates, and therefore may be preferred in some cases.
  • Isotopically labeled compounds of the invention can be prepared by conventional methods known to one skilled in the art or by methods similar to those described in the accompanying examples of synthetic methods using appropriate isotopically labeled reagents instead of the unlabeled previously used reagent.
  • solvates in accordance with the invention include solvates where the crystallization solvent may be isotopically substituted, for example, D 2 0, c16-acetone, (.6-DMSO.
  • solvate refers to an association or complex of one or more solvent molecules and a compound of the invention.
  • solvate forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • hydrate refers to a complex wherein the solvent molecules are water.
  • the compounds of the present invention may exist in free form or, if desired, in the form of a pharmaceutically acceptable salt or other derivative.
  • pharmaceutically acceptable salt refers to those salts which, within the framework of a medical opinion, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, etc., and correspond to a reasonable balance of benefits and risk.
  • Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates and other types of compounds are well known in medicine. Salts can be prepared in situ during the isolation or purification of the compounds of the invention, and can also be prepared separately by reacting the free acid or free base of the compound of the invention with a suitable base or acid, respectively.
  • An example of pharmaceutically acceptable, non-toxic acid salts is the amino group formed by inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or organic acids such as acetic, oxalic, maleic, tartaric, succinic or malonic acids, or the resulting other methods used in this field, for example, using ion exchange.
  • inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids
  • organic acids such as acetic, oxalic, maleic, tartaric, succinic or malonic acids, or the resulting other methods used in this field, for example, using ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorite, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucohexanoate heptane, heptoacetate heptoacetate, glycohexanoate heptane, heptoacetate heptoacetate, glycohexanoate heptanoate, heptoacetate heptoacetate, glycohexanoate heptanoate, heptoacetate heptoacetate, glycohexanoate heptanoate, heptoacetate heptohydrate, heptoacetate, heptoacetate, heptohydrogen
  • Typical alkali and alkaline earth metal salts contain sodium, lithium, potassium, calcium, magnesium and others.
  • pharmaceutically acceptable salts may contain, if desired, non-toxic cations of ammonium, quaternary ammonium and amine obtained using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.
  • Figure 1 Effect of a specific carboxyl esterase-1 BNPP inhibitor ((bis (4-nitrophenyl) phosphate) on the selectivity profile of the compound of Example 50 on a panel of malignant cell lines with expression of hCE1 (MV4-11, U937) and hCE1-negative (CCRF-) carboxylesterase CEM, SK-Mel-SW)
  • hCE1 MV4-11, U937
  • CCRF- hCE1-negative carboxylesterase CEM, SK-Mel-SW
  • the cytotoxicity of the test compound was determined using a standard fluorimetric method after 72 hours of incubation in the absence or presence of BNPP (100 ⁇ mol / L):
  • Example 50 The cytotoxicity profile of the compound of Example 50 on a panel of 4 cell lines: MV4-11 and U937 (hCE1-positive), CCRF-CEM and SK-Mel-103 (hCE1-negative) when incubated with 0.3% DMSO in the presence of 100 ⁇ mol / L BNPP, a specific inhibitor of carboxyl esterase hCE1.
  • FIG. 1 The cytotoxicity profile of the compound of Example 36 on a panel of 4 cell lines: MV4-11 and U937 (hCE1-positive), CCRF-CEM and SK-Mel-103 (hCE1-negative) when incubated with 0.3% DMSO (the control).
  • FIG. 3 The cytotoxicity profile of the compound of Example 36 on a panel of 4 cell lines: MV4-11 and U937 (ISE1-positive), CCRF-CEM and SK-Mel-103 (hCE1-negative) after incubation in human plasma (10 min.incubation in human plasma (pCE1 -negative).
  • Figure 4 Cytotoxicity of the compounds of formula (I) with respect to non-cancerous macrophages (monocytic cells expressing carboxyl esterase) isolated from the abdominal cavity of mice.
  • the volume of the subcutaneous tumor on the first day of measurement is taken as 100%. all tumor volumes in subsequent measurements correlated with this value.
  • no obvious signs of toxicity were observed in animals.
  • the volume of the subcutaneous tumor on the first day of measurement is taken as 100%. all tumor volumes in subsequent measurements correlated with this value.
  • T / C 41% (p ⁇ 0.0001).
  • no obvious signs of toxicity were observed in animals.
  • the compounds of the present invention can be prepared using the synthetic methods described below. The listed methods are not exhaustive and allow the introduction of reasonable modifications. These reactions should be carried out using suitable solvents and materials. When implementing these general procedures for the synthesis of specific substances, it is necessary to take into account the functional groups present in the substances and their influence on the course of the reaction. To obtain some substances, it is necessary to change the order of the stages or give preference to one of several alternative synthesis schemes. It should be understood that these and all examples cited in the application materials are not limiting and are provided merely to illustrate the present invention.
  • Compounds of general formula (I) can be prepared in two synthetic steps as indicated in Scheme 1.
  • Compounds 1 can be prepared by reacting available alkyl 4-haloacetoacetates A and phenylisothiocyanates B in the presence of a strong base, for example sodium hydride, in a suitable aprotic solvent , for example, THF with yields of 20-80%.
  • a strong base for example sodium hydride
  • a suitable aprotic solvent for example, THF with yields of 20-80%.
  • Compounds of general formula (II) can be prepared by controlled alkaline hydrolysis of compounds (I) in an aqueous medium, for example, using lithium hydroxide in a water-THF system, followed by acidification of the reaction medium.
  • Compounds of general formula (III) can be prepared by thermal decarboxylation of compounds of general formula (II) in a suitable solvent, for example, DMSO.
  • compounds of formula (I) can be obtained in high yields according to Scheme 2 directly from acids (II) and the corresponding readily available alcohols R 1 R 2 CHOH using various condensing agents such as CDI, EEDQ, BOP, TBTU, HBTU, etc. in the presence of an organic base (e.g. triethylamine or diisopropylamine) in a suitable organic solvent, e.g. dichloromethane, DMF, DMSO or acetonitrile.
  • esters of general formula (I) can be prepared from acids of general formula (II) via an intermediate synthesis of acid halides, for example acid chlorides, followed by their reaction with alcohols R 1 R 2 CHOH in the presence of a base.
  • Reaction conditions a) a condensing agent (for example, CDI, EEDQ, BOP, TBTU, HBTU), an organic base (Et 3 N, DBU); or SOCI 2 heating, then R 1 R 2 CHOH, Et 3 N in an organic solvent.
  • a condensing agent for example, CDI, EEDQ, BOP, TBTU, HBTU
  • organic base for example, Et 3 N, DBU
  • SOCI 2 heating then R 1 R 2 CHOH, Et 3 N in an organic solvent.
  • HPLC analysis was performed on an Agilent 1200 instrument under the following conditions:
  • HPLC / MS analysis was performed using an Agilent 1100 chromatograph with a tandem mass spectrometer with a chemical ionization detector at atmospheric pressure in positive and negative ion fixation mode (APCI):
  • DAD LED matrix
  • NMR spectra on 1 H and 13 C nuclei were recorded on a Bruker Advance 400 instrument with operating purities of 400 and 100 MHz, respectively.
  • s singlet
  • d doublet
  • t triplet
  • q quartet
  • quint quintet
  • m multiplet
  • br wide.
  • the compounds were purified by preparative high performance liquid chromatography using an Agilent 1200 HPLC Preparative instrument;
  • Solvent for dissolving samples 50% DMSO, 50% acetonitrile;
  • Mobile phase 0.1% solution of formic acid in a mixture of acetonitrile / water
  • a solution of the target compound in DCM was applied to dry silica gel and eluted with ethyl acetate (in in the case of polar compounds, a DCM / methanol mixture 10: 1) was used as an eluent.
  • a portion of the target compounds (I) was purified by preparative HPLC.
  • Aldehyde 4 (3.16 g, 0.02 mol) was dissolved in a solution of aqueous dimethylamine (40% w / w, 30 ml). The resulting mixture was heated at 80 ° C in a glass thick-walled reactor for 7 hours. After that, the reactor was cooled to rt, overpressure was vented, and the reaction mixture was extracted with ethyl acetate (3x100 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated to dryness on a rotary evaporator under reduced pressure. In the residue, the desired aldehyde 5b was obtained as a yellow oil, which was used in the next step without further purification. Yield: 2.66 g (84%).
  • Target compound 9b was purified by silica gel column chromatography using 5: 1 n-hexane / ethyl acetate mixture as an eluent. Yield: 31 g (93%).
  • Example 2 The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1a-1 and 1- (but-2-in-1-yl) -5-chloro-1 H-pyrrole-2-carbaldehyde, which was synthesized by alkylation 5 -chloro-1 H-pyrrole-2-carbaldehyde 1-bromobut-2-in in the presence of sodium hydride (1.1 eq.) in anhydrous THF at RT. Yield: 86.7 mg (21%).
  • the specified compound was obtained according to the General scheme of synthesis (I) from compound 1L-4 and aldehyde 10s on a scale of 0.2 mmol. Yield: 22.0 mg (19%).
  • the specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1A-2 and commercially available 2- (pyridin-2-ylmethoxy) benzaldehyde. Yield: 229.3 mg (50%).
  • the specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1L-4 and aldehyde South in a scale of 0.2 mmol. Yield: 17.3 mg (15%).
  • the specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1b-4 and aldehyde 10q on a scale of 0.2 mmol. Yield: 9.0 mg (8%).
  • the specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1A-2 and commercially available 2- (prop-2-en-1-yloxy) benzaldehyde. Yield: 228.2 mg (56%).
  • the specified compound was obtained according to General scheme 1 for the synthesis of (I) from compound 1a-2 and 2- (but-2-in-1-yloxy) benzaldehyde, which was synthesized by alkylation of salicylic aldehyde 1-bromobut-2-in (1.3 equiv. ) in the presence of potassium carbonate in boiling acetonitrile. Yield: 268.5 mg (64%).
  • the specified compound was obtained according to General scheme 1 for the synthesis of (I) from compound 1a-2 and 2 - [(2E) -but-2-en-1-yloxy] benzaldehyde, which was synthesized by alkylation of salicylic aldehyde (2E) -1-bromobut 2-ene (1.3 equiv.) In the presence of potassium carbonate in boiling acetonitrile. Yield: 311.9 mg (74%).
  • the specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1L-4 and aldehyde Ju in a scale of 0.2 mmol. Yield: 19.8 mg (18%).
  • the specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1L-1 and 2 - [(4-methylpent-2-yn-1-yl) oxy] benzaldehyde, which was synthesized by alkylation of salicylic aldehyde 1-bromo-4- methylpent-2-in in the presence of potassium carbonate in boiling acetonitrile. Yield: 203.2 mg (45%).
  • Example 21 The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1A-1 and commercially available 1, 3,5-trimethyl-1 H-pyrazole-4-carbaldehyde. Yield: 140.4 mg (38%).
  • the specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1A-1 and commercially available 5-chloro-1, 3-dimethyl-1 H-pyrazole-4-carbaldehyde. Yield: 70.7 mg (13%).
  • the specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1a-1 and 2 - [(3-fluoropyridin-2-yl) methoxy] benzaldehyde, which was synthesized by alkylation of salicylic aldehyde 2- (chloromethyl) -3-fluoropyridine in the presence of potassium carbonate in acetonitrile. Yield: 180.4 mg (39%).
  • the specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1a-1 and 2 - [(5-fluoropyridin-2-yl) methoxy] benzaldehyde, which was synthesized by alkylation of salicylic aldehyde 2- (chloromethyl) -5-fluoropyridine in the presence of potassium carbonate in acetonitrile. Yield: 254.4 mg (55%).
  • the specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1a-1 and 2 - [(1-methyl-1H-pyrazol-3-yl) methoxy] benzaldehyde, which was synthesized by the Mitsunobu reaction from salicylic aldehyde with 1-methyl-1 H-pyrazol-3-yl-methanol in the presence of DIAD (diethyl azodicarboxylate), triphenylphosphine in anhydrous THF. Yield: 281.9 mg (63%).
  • the specified compound was obtained according to the General scheme of synthesis (I) from compound 1a-1 and 2 - [(6-chloropyridin-3-yl) methoxy] benzaldehyde, which was synthesized by alkylation of salicylic aldehyde 2-chloro-5- (chloromethyl) pyridine in the presence of potassium carbonate in boiling acetonitrile. Yield: 344.8 mg (72%).
  • the specified compound was obtained according to the general scheme 1 of synthesis (I) from compound 1b-1 and 2- (3-methoxypropoxy) benzaldehyde, which was synthesized by alkylation of salicylic aldehyde 1-chloro-3-methoxypropane in the presence of potassium carbonate in boiling acetonitrile.
  • the specified compound was obtained according to an alternative synthesis scheme 2 (I) from compound M7 (Table 2) and cyclopentanol. Yield: 81.7 mg (29%).
  • the specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1L-4 and aldehyde 10p in a scale of 0.2 mmol. Yield: 35.2 mg (31%).
  • the specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1a-1 and 1, 3-dimethyl-5-phenyl-1 H-pyrazole-4-carbaldehyde, which was synthesized by the Suzuki reaction from 5-chloro-1, 3-dimethyl-1 H-pyrazole-4-carbaldehyde and phenylboronic acid (2 equiv.)
  • a catalyst 5 mol%
  • Yield 146.7 mg (34%).
  • the specified compound was obtained according to the General scheme 1 of synthesis (I) from compounds 1L-1 and 1, 3-dimethyl-5- (2-phenylethynyl) -H-pyrazole-4-carbaldehyde, which was synthesized by the Sonogashira reaction from
  • Example 33 The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1a-1 and 1 - (3-methoxypropyl) -1 N-pyrrole-2-carbaldehyde, which was synthesized by alkylation of pyrrole-2-carbaldehyde 1-chloro-3- methoxypropane in the presence of sodium hydride (1.1 equiv.) in anhydrous THF.
  • the specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1L-4 and aldehyde 10d in a scale of 0.2 mmol. Yield: 17.7 mg (17%).
  • the specified compound was obtained according to General scheme 1 for the synthesis of (I) from compound 1a-1 and 1 - (2-methoxyethyl) -1 H-pyrrole-2-carbaldehyde, which was synthesized by alkylation of pyrrole-2-carbaldehyde 1-chloro-2- methoxyethane in the presence of sodium hydride (1.1 eq.) in anhydrous THF.
  • the specified compound was obtained according to General scheme 1 for the synthesis of (I) from compound 1a-1 and 1 - (but-2-in-1-yl) -1 H-pyrrole-2-carbaldehyde, which was synthesized by alkylation of commercially available pyrrole-2 ⁇ -carbaldehyde 1-bromobut-2-in in the presence of sodium hydride (1.1 eq.) in anhydrous THF.
  • the specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1L-1 and aldehyde 10e on a scale of 10 mmol (purified column chromatography on silica gel, eluent n-nexane / ethyl acetate 1: 5). Yield: 4.26 g (70%).
  • Example 53 The compound from Example 53 (4.26 g, 7 mmol) was dissolved in anhydrous DCM (50 ml), cooled to 0 ° C, and trifluoroacetic acid (5.2 ml, 70 mmol) was added dropwise with vigorous stirring. The reaction mixture was stirred for 12 hours at rt, then diluted with 10% aqueous potassium carbonate solution (200 ml), the organic layer was separated, the aqueous layer was extracted with DCM (3x50 ml). The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure on a rotary evaporator, obtaining the target compound (3.27 g, 92%) as a clear glassy mass.
  • the target compound was prepared as described above for Example 56 using methyl chloroformate (0.4 mmol) as the acylating agent. Yield of target compound: 200 mg (88%).
  • Ethyl isocyanate (0.44 mmol) was added to a solution of the compound from Example 54 (200 mg, 0.4 mmol) in anhydrous THF (5 ml) with vigorous stirring. The reaction mixture was stirred for 2 hours at the boil, diluted with water (20 ml), extracted with ethyl acetate (3x10 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure on a rotary evaporator. The evaporation residue was purified by preparative HPLC to obtain the desired compound (220.3 g, 95%).
  • N-Boc glycine (70 mg, 0.4 mmol, 1 equiv.) was suspended in anhydrous DCM (5 ml), then BOP (212 mg, 0.48 mmol, 1.2 equiv.) was added in one portion with stirring and the reaction was stirred for 10 minutes at .t .; then a secondary amine was sequentially added to the reaction mixture — the compound from Example 54 (200 mg, 0.4 mmol, 1 equiv.) and DIPEA (0.6 mmol, 1.5 equiv.). The resulting mixture was stirred 24 hours at rt, then washed successively with saturated aqueous solutions of hydrogen carbonate and sodium chloride (10 ml each).
  • the target compound was prepared as described above for Example 56 using 3-methoxypropionic acid chloride (0.4 mmol) as the acylating agent. Yield of target compound: 128.5 mg (54%).
  • the specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1L-4 and aldehyde 10 and on a scale of 0.2 mmol. Yield: 10.1 mg (9%).
  • the specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1A-3 and aldehyde 5b. Yield: 81.0 mg (19%).
  • Example 71 (racemic mixture) The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1a-3 and aldehyde 101 Yield: 149.3 mg (31%).
  • Example 76 (racemic mixture) The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1 b-1 and aldehyde 13k. Yield: 101.0 mg (20%).
  • the specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1 L-1 and aldehyde 131. Yield: 55.7 mg (10%).
  • the specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1A-1 and commercially available 2-methylthiophene-3-carbaldehyde. Yield: 193.0 mg (54%).
  • Example 80 (mixture of cis-impac isomers)
  • the specified compound was obtained according to an alternative synthesis scheme 2 (I) from compound 9 (1.45 g, 3 mmol, Table 2) and cyclopentanol. Yield: 480.0 mg (29%).
  • Example 88 (racemic mixture) The specified compound was obtained according to an alternative synthesis scheme 2 (I) from compound M9 (table 2) and cyclohexanol. Yield: 84.8 mg (30%).
  • Example 90 (a mixture of cis - / - trans isomers of decahydroquinoline)
  • the specified compound was obtained from the compound of Example 1 according to the following procedure: The compound from Example 1 (145 mg, 0.25 mmol) was dissolved in DCM (10 ml) and at rt. and stirring, meta-chloroperbenzoic acid (0.5 mmol, 3 equiv.) was added in one portion. The resulting mixture was stirred 24 hours at rt, then washed successively with saturated aqueous solutions of hydrogen carbonate and sodium chloride (10 ml each) and extracted with DCM (3x10 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure on a rotary evaporator. The evaporation residue was purified by preparative HPLC to obtain the title compound. Yield: 123.7 mg (81%).
  • Example 92 The specified compound was obtained according to the alternative scheme 2 of synthesis (I) from compound 7 (table 2) and cyclohexanol. Yield: 132.9 mg (46%).
  • the specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1b-4 and aldehyde 10v in a scale of 0.2 mmol. Yield: 28.4 mg (24%).
  • the specified compound was obtained from the compound of Example 1 according to the following procedure: The compound from Example 1 (145 mg, 0.25 mmol) was dissolved in DCM (10 ml) and at rt. and stirring, meta-chloroperbenzoic acid (0.25 mmol, 1 equiv.) was added in one portion. The resulting mixture was stirred for 4 hours at rt. (monitoring the conversion of the starting compound by TLC), then washed successively with saturated aqueous solutions of bicarbonate and sodium chloride (10 ml each) and extracted with DCM (3x10 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure on a rotary evaporator. The evaporation residue was purified by preparative HPLC to obtain the title compound. Yield: 40.2 mg (27%).
  • the specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1b-1 and 1- (but-2-yn-1-yl) -5-chloro-1 H-pyrrole-2-carbaldehyde, which was synthesized by alkylation 5 -chloro-1 H-pyrrole-2-carbaldehyde [Journal of Organic Chemistry, 1975, 40 (22): 3161-9] 1-bromobut-2-in in the presence of sodium hydride (1.1 eq.) in anhydrous THF.
  • the specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1a-1 and 2- (3-methoxypropoxy) benzaldehyde, which was synthesized by alkylation of salicylic aldehyde 1-chloro-3-methoxypropane in the presence of potassium carbonate in boiling acetonitrile. Yield: 297.9 mg (70%).
  • the specified compound was obtained according to the General scheme 1 of synthesis (II) from the compound of Example 50. Yield: 277.5 mg (56%).
  • the specified compound was obtained from 8 (20 mg, 0.045 mmol) by reaction with acetyl chloride (2 equivalents) in the presence of triethylamine (2 equivalents) in acetonitrile (200 ⁇ l) at room temperature.
  • the product was isolated by preparative HPLC. Yield: 23.0 mg (80%).
  • the compounds described in this invention can be used for the treatment and / or prevention of cancer, in particular cancer associated with increased expression of the enzyme hCE1, in particular, for the treatment of leukemia with translations of MLL-geia.
  • the subject of the invention also includes administering to a subject in need of appropriate treatment a therapeutically effective amount of a compound of general formula (I), a compound of general formula (II) or compounds of general formula (III).
  • a therapeutically effective amount is meant an amount of a compound administered or delivered to a patient in which the patient is most likely to exhibit the desired response to treatment (prophylaxis).
  • the exact amount required can vary from subject to subject, depending on the age, body weight and general condition of the patient, the severity of the disease, the method of administration of the drug, combined treatment with other drugs, etc.
  • the compound of the invention or a pharmaceutical composition comprising the compound can be administered to the patient in any amount and by any route of administration effective for treating or preventing a disease.
  • compositions comprising the essence of the invention can be administered orally, parenterally, topically, and the like to the human or other animals.
  • a dose of each of the components of the combination therapy is administered during the desired treatment period.
  • the compounds that make up the combination therapy can be administered into the patient's body both at a time, in the form of a dosage containing all the components, and in the form of individual dosages of the components.
  • the invention also relates to pharmaceutical compositions which comprise a compound of general formula (I), general formula (II) or a compound of general formula (III) (or a prodrug, a pharmaceutically acceptable salt, solvate, hydrate or other pharmaceutically acceptable derivative thereof) and one or several pharmaceutically acceptable carriers, adjuvants, solvents and / or excipients, such as can be introduced into the patient’s body together with the compound of the invention and which do not destroy the pharmacological activity of this compound and are non-toxic when administered in doses sufficient to delivering a therapeutic amount of a compound.
  • pharmaceutical compositions which comprise a compound of general formula (I), general formula (II) or a compound of general formula (III) (or a prodrug, a pharmaceutically acceptable salt, solvate, hydrate or other pharmaceutically acceptable derivative thereof) and one or several pharmaceutically acceptable carriers, adjuvants, solvents and / or excipients, such as can be introduced into the patient’s body together with the compound of the invention and which do not destroy
  • compositions of this invention comprise the compounds of this invention together with pharmaceutically acceptable carriers, which may include any solvents, diluents, dispersions or suspensions, surfactants, isotonic agents, thickeners and emulsifiers, preservatives, astringents, lubricants materials, etc., suitable for a particular dosage form.
  • pharmaceutically acceptable carriers may include any solvents, diluents, dispersions or suspensions, surfactants, isotonic agents, thickeners and emulsifiers, preservatives, astringents, lubricants materials, etc.
  • Materials that may serve as pharmaceutically acceptable carriers include, but are not limited to, mono- and oligosaccharides, as well as their derivatives; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut, cottonseed, safrole, sesame, olive, corn and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic solution, Ringer's solution; ethyl alcohol and phosphate buffers.
  • excipients such as cocoa butter and suppository wax
  • oils such as peanut, cottonseed, safrole, sesame, olive, corn and soybean oil
  • glycols such as propylene glycol
  • esters such as ethyl oleate and ethyl laur
  • composition of the composition may be other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as dyes, release fluids, film-forming agents, sweeteners, flavors and fragrances, preservatives and antioxidants.
  • non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate
  • dyes such as sodium lauryl sulfate and magnesium stearate
  • release fluids such as sodium lauryl sulfate and magnesium stearate
  • film-forming agents such as sodium lauryl sulfate and magnesium stearate
  • sweeteners such as sodium lauryl sulfate and magnesium stearate
  • flavors and fragrances such as sodium lauryl sulfate and magnesium stearate
  • preservatives and antioxidants such as sodium lauryl sulfate and magnesium stearate
  • the subject of the present invention is also dosage forms — a class of pharmaceutical compositions whose composition is optimized for a particular route of administration into the body in a therapeutically effective dose, for example, for oral, topical, intraocular, pulmonary, for example, inhalation spray, or intravascular routes the method, intranasally, subcutaneously, intraperitoneally, intramuscularly, as well as the infusion method, in the recommended dosages.
  • a therapeutically effective dose for example, for oral, topical, intraocular, pulmonary, for example, inhalation spray, or intravascular routes the method, intranasally, subcutaneously, intraperitoneally, intramuscularly, as well as the infusion method, in the recommended dosages.
  • Dosage forms of the present invention may contain formulations prepared using liposome methods, microencapsulation methods, methods for preparing nanoforms of the preparation, or other methods known in the pharmaceutical art.
  • the active principle is mixed with one or more pharmaceutical excipients, such as, for example, gelatin, starch, lactose, magnesium stearate, talc, silica, gum arabic, mannitol, microcrystalline cellulose, hypromellose or the like. Tablets may be coated with sucrose, a cellulosic derivative, or other suitable coating materials. Tablets can be prepared in various ways, such as direct compression, dry or wet granulation, or hot fusion.
  • pharmaceutical excipients such as, for example, gelatin, starch, lactose, magnesium stearate, talc, silica, gum arabic, mannitol, microcrystalline cellulose, hypromellose or the like.
  • Tablets may be coated with sucrose, a cellulosic derivative, or other suitable coating materials. Tablets can be prepared in various ways, such as direct compression, dry or wet granulation, or hot fusion.
  • a pharmaceutical composition in the form of a gelatin capsule can be prepared by mixing the active principle with a solvent and filling the mixture with soft or hard capsules.
  • aqueous suspensions, isotonic saline solutions or sterile injectable solutions which contain pharmacologically compatible agents, for example propylene glycol or butylene glycol.
  • the tested chemical compounds were prepared in the form of 10 mmol DMSO effluents and stored in the dark at -20 ° C, thawing immediately before the experiment.
  • Cytotoxicity of the compounds was determined using a commercially available alamarBlue assay® fluorescence assay (ThermoFisher Scientific, USA) according to the manufacturer's instructions in 384-well plates. Cells were scattered into the wells on a plate, incubated for 24 hours in a C0 2 incubator at 100% humidity at 37 ° C; after that, serially diluted DMSO stocks of the test compounds in the concentration range of 0.0015-30 ⁇ mol / L (two repetitions for each concentration of the compound), the final concentration of DMSO in the medium 0.3%) were added and incubated for 72 hours under the conditions described above. A culture medium with 0.3% DMSO was used as a negative control.
  • Non-toxic ester compounds of the general formula (I) exhibit high selective cytotoxicity only in relation to human malignant cell lines expressing the carboxyl esterase-1 enzyme (hCE1) and are not toxic to hCE1 - negative cell lines.
  • Non-toxic ester compounds of the general formula (I) which are more resistant to hydrolyzing enzymes other than hCE1, for example, acetylcholinesterase, butyrylcholinesterase and carboxyl esterase isoform hCE2, hCE3, will selectively hydrolyze to the corresponding cytotoxic carboxylic acid only in cells expressing hCE1 -positive cells, under physiological conditions, are negatively charged particles, which complicates their reverse passive diffusion through cell w membrane. This leads to the accumulation of active drug acids in the intracellular space and, as a consequence, to an increase in the pharmacological effect, prolonged action and a decrease in the applied dose of the compound of general formula (I).
  • the compounds M1 and M8 of the general formulas (II) and (III) respectively exhibit high cytotoxicity (1C 50 ⁇ 110 nmol / L) only with respect to proliferating malignant cell lines of SK-Mel melanoma -103 and lung adenocarcinomas A549, but are absolutely indifferent (IC 50 > 10 ⁇ mol / L) with respect to the same cell lines in a senescent state (irreversible arrest of the cell cycle). It doesn’t matter in what way the state of senescence was initiated.
  • Test compounds were incubated in plasma at a concentration of 100 ⁇ mol / L at 37 ° C.
  • plasma aliquots were taken from the incubation mixture, after which they were diluted 10 times with the culture medium and used to determine cytotoxicity, as described above.
  • the compound of example 50 is highly toxic to cell lines with expression of carboxyl esterase-1 hCE1 (leukemia with translocations of the MLL gene MV4-11 and U937, IC 50 36-40 nmol / l), but indifferent to hCE1-negative cell lines (CCRF-CEM lymphoma and SK-Mel-103 melanoma, IC 50 8.8-10 ⁇ mol / L).
  • mice derived from vivarium RPCI Female SCID mice derived from vivarium RPCI (LAR RPCI) were used in the study. At the time of the start of the experiment, the animals were 9 weeks old. Mice were kept 5 animals per cage. The animals were kept on a standard diet for rodents (2018S, Harlan) and free access to sterile drinking water under controlled conditions (temperature 18-26 ° C, humidity 30-70%, 12-hour light-dark cycle). Before the experiment, the animals were acclimatized for 3-5 days.
  • MV4-1 1 was cultured in RPMI medium supplemented with phenol red, 10% fetal calf serum, 100 units / ml penicillin, 100 ⁇ g / ml streptomycin and 2 mmol L-glutamine.
  • the compounds of the invention were administered intraperitoneally once a day in accordance with the schedules and doses shown in Figures 6 and 7.
  • the compound of Example 29 was administered at a dose of 80 mg / kg in a mixture of 10% DMSO, 10% Cremaphor ELP and 80% saline .
  • the compound of example 87 was administered at a dose of 100 mg / kg in a mixture of 10% ethanol, 10% Cremaphor ELP and 80% saline, the same formulation was used for the control group.
  • the injected volumes of the test compound solutions (10 ml / kg) were calculated based on the weight of each animal; solutions were injected for 10 seconds.
  • T / C% x 100%.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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Abstract

L'invention concerne la chimie des compositions organiques, de la pharmacologie et de la médecine et porte sur la prévention et/ou le traitement de maladies hyperprolifératives liés à la transformation maligne de cellules exprimant le ferment carboxylestérase hCE1 et notamment des leucémies aiguës avec une translocation du gène MM, des carcinomes hépatocellullaire et adénocarcinomes du poumon. A cet effet, on a proposé des composés ayant la formule générale (I), la formule générale (II) ou la formule générale (III) dans lesquelles R1, R2, А, В et Q ont des valeurs décrites dans le descriptif. L'invention concerne également des compositions pharmaceutiques contenant ces composés et l'utilisation de ces composés pour traiter et/ou prévenir des maladies hyperprolifératives.
PCT/RU2017/000276 2017-04-27 2017-04-27 2-methyliden-5-(phénylamino)-2,3-dihydrothiophen-3-ones substitués pour traiter des leucémies aiguës avec une translocation du gène mm et d'autres maladies cancéreuses Ceased WO2018199797A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2025172368A1 (fr) 2024-02-13 2025-08-21 Syngenta Crop Protection Ag Dérivés de (5-isoxazol-3-yl)-[4-(pyrazol-4-yl)-3,4-dihydro-1h-isoquinolin-2-yl]méthanone destinés à être utilisés en tant que fongicides

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