THERAPEUTICALLY ACTIVE COMPOSITIONS AND THEIR METHODS OF USE

• US 20130184222A1
• Filed: 07/15/2011
• Published: 07/18/2013
• Est. Priority Date: 07/16/2010
• Status: Abandoned Application

• Current Assignee: Servier Pharmaceuticals LLC (Servier Sas)
• Original Assignee: Agios Pharmaceuticals Inc.
• Inventors: Popovici-Muller, Janeta, Salituro, Francesco G., Saunders, Jeffrey, Yan, Shunqi, Travins, Jeremy
• Application Number:
  US13/810,410
• Publication Number:
  US 20130184222A1
• Time in Patent Office: Days
• US Class Current: 514/19.3
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 237/22 having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated peptides C07K
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/04 with a four-membered ring
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 271/22 to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 271/44 to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
• CPC Class Codes: C07C 271/58 with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/06 to acyclic carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 311/13 the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 311/19 to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 317/36 with the nitrogen atoms of the amino groups bound to hydrogen atoms or to carbon atoms
• CPC Class Codes: C07C 335/32 having sulfur atoms of isothiourea groups bound to acyclic carbon atoms
• CPC Class Codes: C07D 207/10 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
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/08 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 209/14 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 209/26 : with an acyl radical attached to the ring nitrogen atom
• CPC Class Codes: C07D 209/42 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/44 : Iso-indoles; Hydrogenated iso-indoles
• CPC Class Codes: C07D 211/14 : with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/38 : Halogen atoms or nitro radicals
• CPC Class Codes: C07D 211/54 : Sulfur atoms
• CPC Class Codes: C07D 211/60 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 213/30 : Oxygen atoms
• CPC Class Codes: C07D 213/38 : having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: C07D 213/56 : Amides
• CPC Class Codes: C07D 213/64 : attached in position 2 or 6
• CPC Class Codes: C07D 213/65 : attached in position 3 or 5
• CPC Class Codes: C07D 213/68 : attached in position 4
• CPC Class Codes: C07D 213/74 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 217/04 : with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 221/18 : Ring systems of four or more rings
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/42 : Benzene-sulfonamido pyrazoles
• CPC Class Codes: C07D 231/56 : Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 233/61 : with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
• CPC Class Codes: C07D 233/64 : with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 233/70 : One oxygen atom
• CPC Class Codes: C07D 233/88 : Nitrogen atoms, e.g. allantoin
• CPC Class Codes: C07D 235/04 : Benzimidazoles; Hydrogenated benzimidazoles
• CPC Class Codes: C07D 237/14 : Oxygen atoms
• CPC Class Codes: C07D 239/26 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 241/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 249/04 : 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
• CPC Class Codes: C07D 249/18 : Benzotriazoles
• CPC Class Codes: C07D 253/06 : 1,2,4-Triazines
• CPC Class Codes: C07D 257/04 : Five-membered rings
• CPC Class Codes: C07D 261/18 : Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
• CPC Class Codes: C07D 265/36 : condensed with one six-membered ring
• CPC Class Codes: C07D 271/06 : 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
• CPC Class Codes: C07D 271/10 : 1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
• CPC Class Codes: C07D 277/28 : Radicals substituted by nitrogen atoms
• CPC Class Codes: C07D 277/30 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 277/56 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 295/04 : with substituted hydrocarbon radicals attached to ring nitrogen atoms
• CPC Class Codes: C07D 295/205 : Radicals derived from carbonic acid
• CPC Class Codes: C07D 305/08 : 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 atoms
• CPC Class Codes: C07D 307/20 : Oxygen atoms
• CPC Class Codes: C07D 307/22 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 309/12 : only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
• CPC Class Codes: C07D 309/14 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 317/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 319/20 : with substituents attached to the hetero ring
• CPC Class Codes: C07D 333/24 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07K 5/06078 : and aromatic or cycloaliphatic

Abstract

Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1 comprising administering to a subject in need thereof a compound described here.

Claims

1. A compound of Formula II:

2. The compound of claim 1, wherein R³ is 3-fluorophenyl.

3. The compound of claim 1 or 2, wherein:

R¹ is selected from cyclohexyl, cyclopentyl, cycloheptyl, 3,3-difluorocyclobutyl, 4,4,-difluorocyclohexyl, and bicyclo[2.2.1]heptanyl; and

R⁴ is selected from 1-(methylmethoxycarbonylamino)ethyl, 1,2,3,4-tetrahydroquinolin-1-yl, 1-ethoxycarbonylpiperidin-2-yl, 1-ethoxycarbonylpyrrolidin-2-yl, 1H-benzimidazol-1-ylmethyl, 1H-indazol-3-ylmethyl, indolin-1-ylmethyl, 1H-indol-3-ylmethyl, 1H-indol-5-ylmethyl, 1H-pyrrolo[2,3-b]pyridine-3-ylmethyl, 1H-pyrrolo[3,2-b]pyridin-3-ylmethyl, 1-methoxycarbonylpiperidin-2-yl, 1-methoxycarbonylpyrrolidin-2-yl, 2-fluoropyridin-3-ylaminomethyl, 2-imino-4-fluoropyridin-1-ylmethyl, 2-methoxyphenylaminomethyl, 2-methyl-1H-benzimidazol-1-ylmethyl, 2-methylimidazol-1-ylmethyl, 2-trifluoromethyl-1H-imidazol-1-yl, 3-cyanophenylaminomethyl, 3-fluoropyridin-2-ylaminomethyl, 3-methoxyphenylaminomethyl, 4-(1,3,4-oxadiazole-2-yl)phenylaminomethyl, 4-(dimethylaminocarbonyloxy)phenylmethyl, 4,5-dichloroimidazol-1-ylmethyl, 4-cyanophenylaminomethyl, 4-fluorophenylaminomethyl, 4-fluoropyridin-2-ylaminomethyl, 4-hydroxyphenylmethyl, 4-methoxycarbonylmorpholin-3-yl, 4-methoxycarbonylpiperazin-1-ylmethyl, 4-methoxyphenylaminomethyl, 4-methylcarbonyloxyphenylmethyl, 5-fluoropyridin-2-aminomethyl, 5-fluoropyridin-2-oxymethyl, 6-fluoropyridin-3-ylaminomethyl, benzomorpholin-4-ylmethyl, methoxycarbonylaminomethyl, methylmethoxycarbonylaminomethyl, methylphenylaminomethyl, phenylaminomethyl, pyridin-2-oxymethyl, pyridin-2-ylaminomethyl, pyridin-2-yloxymethyl, pyridin-3-oxymethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, thiazol-4-ylmethyl, and thien-2-ylmethyl.

4. The compound of claim 1, wherein the compound is selected from any one of Compound numbers 104, 126, 135, 140, 150, 155, 160, 161, 165, 173, 185, 186, 197, 198, 201, 202, 203, 210, 212, 213, 217, 218, 227, 228, 237, 240, 247, 253, 260, 265, 271, 272, 275, 276, 287, 288, 289, 290, 291, 293, 297, 301, 306, 307, 311, 313, 314, 316, 320, 321, 322, 331, 334, 341, 344, 348, 351, 356, 359, 361, 366, 378, 381, and 385 from Table 2.

11. The method of claim 5, wherein the compound is a compound of any one of claims 1-4.

17. A pharmaceutical composition comprising a compound of any one of claims 1 to 4;

and a pharmaceutically acceptable carrier.

5. A method of treating a cancer characterized as having an R132X IDH1 mutation, the method comprising administering to a subject a therapeutically effective amount of a compound of formula A:

6. The method of claim 5, wherein the compound is a compound of formula I,

7. The method of claim 5, wherein the compound is a compound of Formula I-c.

8. The method of claim 7, wherein R¹ is selected from cyclohexyl, cyclopentyl, cycloheptyl, cyclobutyl, 3,3-difluorocyclobutyl, 4,4,-difluorocyclohexyl, bicyclo[2.2.1]heptanyl, tertahydropyran-3-yl, tertahydropyran-4-yl, 1-t-butoxycarbonylpyrrolidin-3-yl, t-butyl, 2-bromophenyl, 2-methylphenyl, and bicyclo[3.1.0]hexan-3-yl.

9. The method of claim 7 or 8, wherein R² is selected from phenyl, 2-methylphenyl, 2-fluorphenyl, 2-chlorophenyl, 2-bromophenyl, 2-bromo-5-fluorophenyl, 2,5-dichlorophenyl, 2-fluoro-5-methylphenyl, thien-2-yl, 4-fluorophenyl, 5-bromofuran-2-yl, 3-methylthien-2-yl, 2,4,5-trifluorophenyl, 3-fluoro-5-chlorophenyl, 2,5-difluoro-6-chlorophenyl, 3-chlorophenyl, 3-fluorophenyl, 3-methylphenyl, 2,6-dimethylphenyl, 3-bromopohenyl, 2-ethylphenyl, 2-nitrophenyl, 3′

-methoxybiphenyl-3-yl, 2,5-dibromo-6-fluorophenyl, 2-trifluoromethylphenyl, 4-hydroxyphenyl, 3-hydroxyphenyl, 2-hydroxyphenyl, 2-methoxyphenyl, and 2-fluoro-5-methoxyphenyl.

10. The method of any of claims 7-9, wherein R³ is selected from 3-fluorophenyl, 3-methylphenyl, 3-chlorophenyl, thien-2-ylmethyl, 3-(1-methyl-1H-pyrazol-4-yl)phenyl, 1-methyl-1H-pyrazol-3-yl, 4-chlorophenyl, 3-acetylaminophenyl, 3′

-trifluoromethoxy-biphenyl-3-yl, pyridin-3-yl, 4-fluorophenyl, thiazol-2-ylmethyl, cyclohexyl, 2-methylphenyl, 3-fluoro-4-methylphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, phenyl, 3-bromophenyl, 2-fluorophenyl, 3-chloro-4-methylphenyl, 3-(pyriminidin-5-yl)phenyl, biphenyl-3-yl, 3-trifluoromethylphenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3-aminophenyl, 3-ethylcarbonylaminophenyl, 3-t-butoxycarbonylaminophenyl, 3-chloro-4-bromophenyl, 4-methlyphenyl, 3-methoxyphenyl, 3-(1-methyl-1H-pyrazol-5-yl)phenyl, 3-methoxycarbonylaminophenyl, 3-cetylphenyl, 3-(morpholin-4-yl)phenyl, 3,4-difluorophenyl, and 3-(4-t-butoxycarbonylpiperazin-1-yl)phenyl.

12. The method of any one of claims 5 to 11, wherein the compound or a pharmaceutically acceptable salt thereof is formulated into a pharmaceutical composition together with a pharmaceutically acceptable carrier.

13. The method of any one of claims 5 to 12, wherein the subject is evaluated for the presence of an IDH1 R132X mutant allele prior to administration of the compound.

14. The method of any one of claims 5 to 12, wherein the subject is evaluated for the presence of an elevated level of 2HG prior to administration of the compound.

15. The method of any one of claims 5 to 12, wherein efficacy of treatment of cancer comprises monitoring the level of 2HG in a subject during treatment.

16. The method of any one of claims 5 to 12, wherein efficacy of treatment of cancer comprises monitoring the level of 2HG in a subject following termination of treatment.