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WO2018175954A1 - Synthèse d'un dérivé d'imidazo[5,1-a]isoindole utile en tant qu'inhibiteurs d'ido - Google Patents

Synthèse d'un dérivé d'imidazo[5,1-a]isoindole utile en tant qu'inhibiteurs d'ido Download PDF

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Publication number
WO2018175954A1
WO2018175954A1 PCT/US2018/024127 US2018024127W WO2018175954A1 WO 2018175954 A1 WO2018175954 A1 WO 2018175954A1 US 2018024127 W US2018024127 W US 2018024127W WO 2018175954 A1 WO2018175954 A1 WO 2018175954A1
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Prior art keywords
compound
formula
mixture
added
mmol
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Inventor
Remy Angelaud
Stephan Bachmann
Andreas BEYELER
Diane CARRERA
Rolf Fischer
Maud GUILLEMONT-PLASS
Haiyun HOU
Hans Iding
Anne Katrin KRAFT
Andreas Manns
Roland Meier
Karin Monika NIEDERMANN
Martin OLBRICH
Katarzyna PIECHOWICZ
Pankaj Rege
Travis Paul Remarchuk
Lauren SIROIS
Frederic St-Jean
Jie Xu
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F Hoffmann La Roche AG
Genentech Inc
Hoffmann La Roche Inc
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F Hoffmann La Roche AG
Genentech Inc
Hoffmann La Roche Inc
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Publication of WO2018175954A1 publication Critical patent/WO2018175954A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to the synthesis of compounds for inhibition of indoleamine 2,3-dioxygenase.
  • Tryptophan is an essential amino acid required for the biosynthesis of proteins, niacin and the neurotransmitter 5-hydroxytryptamine (serotonin).
  • the enzyme indoleamine 2,3-dioxygenase also known as INDO or IDO
  • IDO indoleamine 2,3-dioxygenase
  • IFN-y stimulation induces activation of IDO, which leads to a depletion of Trp, thereby arresting the growth of Trp-dependent intracellular pathogens such as Toxoplasma gondii and Chlamydia trachomatis.
  • IDO activity also has an antiproliferative effect on many tumor cells, and IDO induction has been observed in vivo during rejection of allogeneic tumors, indicating a possible role for this enzyme in the tumor rejection process.
  • IDO is involved in induction of immune tolerance.
  • Studies of mammalian pregnancy, tumor resistance, chronic infections and autoimmune diseases have shown that cells expressing IDO can suppress T-cell responses and promote tolerance. Accelerated Trp catabolism has been observed in diseases and disorders associated with cellular immune activation, such as infection, malignancy, autoimmune diseases and AIDS, as well as during pregnancy. It was proposed that IDO is induced chronically by HIV infection, and is further increased by opportunistic infections, and that the chronic loss of Trp initiates mechanisms responsible for cachexia, dementia and diarrhea and possibly immunosuppression of AIDS patients (Brown, et al, 1991, Adv. Exp. Med. Biol., 294: 425-35).
  • IDO inhibition can enhance the levels of virus-specific T cells and, concomitantly, reduce the number of virally infected macrophages in a mouse model of HIV (Portula et al, 2005, Blood, 106:2382-90).
  • IDO-related diseases such as those described above.
  • PCT Publication WO 99/29310 reports methods for altering T cell-mediated immunity comprising altering local extracellular concentrations of tryptophan and tryptophan metabolites, using an inhibitor of IDO such as 1-m ethyl -DL-tryptophan, p-(3-benzofuranyl)-DL-alanine, p-[3-benzo(b)thienyl]-DL-alanine, and 6-nitro-L-tryptophan) (Munn, 1999).
  • Reported in WO 03/087347 also published as European Patent 1501918, are methods of making
  • IDO indoleamine-2,3-dioxygenase
  • IDO Inhibitors of IDO can be used to activate T cells and therefore enhance T cell activation when the T cells are suppressed by pregnancy, malignancy or a virus such as HIV. Inhibition of IDO may also be an important treatment strategy for patients with neurological or neuropsychiatric diseases or disorders such as depression.
  • the invention provides a method for making a compound of the Formula (I)
  • the method includes converting a compound of Formula (IX)
  • the method involves
  • Figure 1 shows the Di-silyl sequence. Two silyl protecting groups are introduced sequentially. Compounds in square brackets are not isolated.
  • Figure 2 shows the Direct sequence. Only one silyl protecting group is introduced. No additional protecting group is employed in position 1.
  • FIG 3 shows the Mono-silyl sequence. A second TBS-group is introduced in position 1, followed by the removal of the TBS-group at position 4'. Compounds in square brackets are not isolated.
  • Figure 4 shows the synthesis of a compound of Formula (I) according to an example embodiment.
  • Figure 5 shows the synthesis of a compound of Formula (I) according to an example embodiment.
  • Figure 6 shows the synthesis of a compound of Formula (I) according to an example embodiment.
  • Figure 7 shows the synthesis of a compound of Formula (I) according to an example embodiment.
  • Figure 8 shows the synthesis of a compound of Formula (I) according to an example embodiment.
  • Figure 9 shows the synthesis of a compound of Formula (I) according to an example embodiment.
  • convert means performing a single or multi-step process to transform a first molecule into a second.
  • the step or steps of the process may include, e.g., chemical reactions, purifications, crystallizations, or any other techniques known to one of skill in the art.
  • PG may be any suitable hydroxyl protecting group.
  • the hydroxyl can be protected with a TBS group.
  • Other exemplary protecting groups include, without limitation, alkyl ethers, such as methyl, trityl, triphenylmethyl, methoxymethyl, benzyl, p- methoxybenzyl, tetrahydropyranyl (THP); silyl ethers, such as triethylsilyl (TES), tnisopropylsilyl (TIPS), t-Butyldimethylsilyl (TBS) or t-Butyldiphenylsilyl (TBDPS); or esters, such as trifluoroacetyl (TFA), acetyl (Ac), trimethylacetyl (Piv) or benzoyl (Bz).
  • Protecting groups may be selected from suitable protecting groups known in the art, such as those described in “Greene's protective groups in organic synthesis” Wiley-Interscience,
  • the invention presents a method for making a compound of the Formula (I)
  • the method may include converting a compound of Formula (IX)
  • the invention provides a method for making a compound of the Formula (I), wherein the method involves
  • the compound of Formula (II) can be provided by protecting the 4'-hydroxy group of the corresponding unprotected compound.
  • the 4'-Hydroxy-ketone can be protected with a TBS group.
  • the synthetic procedure can be carried out with other protecting groups and in a manner known in the art, such as described in "Greene's protective groups in organic synthesis” Wiley-Interscience, New Jersey 2007, 4 th Edition. 189-196.
  • the protecting group may be an alkyl ether, such as methyl, trityl, triphenylmethyl, methoxymethyl, benzyl, p-methoxybenzyl, tetrahydropyranyl (TUP); a silyl ether, such as triethylsilyl (TES), triisopropyl silyl (TIPS), t-Butyldimethylsilyl (TBS) or t-Butyldiphenylsilyl (TBDPS); or an ester, such as trifluoroacetyl (TFA), acetyl (Ac), trimethylacetyl (Piv) or benzoyl (Bz).
  • TES triethylsilyl
  • TIPS triisopropyl silyl
  • TBS t-Butyldimethylsilyl
  • TDPS t-Butyldiphenylsilyl
  • ester such as trifluoroacetyl (TF
  • oxidizing the compound of Formula (II) may comprise contacting the compound of Formula (II) with an oxidizing composition comprising a periodate.
  • the oxidizing composition may also comprise LiBr, NaBr, or I.
  • the components of the oxidizing composition may be mixed before addition to the reaction mixture or added sequentially.
  • the oxidizing composition comprises sodium periodate and iodine in acetic acid.
  • lithium bromide is added to the reaction or to the oxidizing composition.
  • the ratio of NaI0 4 /LiBr may be 0.3/0.6 to 1.1/0.005 molar equivalents of the compound of Formula (II), preferably 0.4/0.05 equivalents of the compound of Formula (II).
  • the solvent of the oxidation may also include a mixture of AcOH with other solvents (e.g., 2- MeTHF or ACN), and the oxidation may be performed at a temperature of 20-80 °C, preferably 50-60 °C.
  • a halogenation/elimination sequence may also be used to provide the compound of Formula (III). Oxidation can be accomplished with other oxidizing groups according to known procedures. Step 3.1 Asymmetric Ketone Hydrogenation
  • the compound of Formula (rV) can be provided by reducing the ketone of a compound of Formula (III).
  • reducing the ketone of a compound of Formula (III) comprises contacting the ketone with a Ruthenium catalyst in an atmosphere of hydrogen.
  • the Ruthenium catalyst can be a Ruthenabicyclic complex with chiral diphosphine of type [Ru(daipena)(diphosphine)X] of the formula
  • daipena anion of DAIPEN at the 2-position of an anisyl group
  • X anionic ligand, e.g., CI “ , Br “ , ⁇ , CH 3 SO 3 " , CF 3 CO 2 " , TfO "
  • diphosphine atropisomeric biarylphosphines (e.g., SEGPHOS, BINAP, and MeOBIPHEP)
  • R N1 , R N2 , R N3 , and R N4 are each independently a hydrogen atom, an optionally substituted C1-C20 alkyl group, an optionally substituted C2- C20 alkenyl group, an optionally substituted C7-C20 alkylaryl group, or an optionally
  • R a , and R are each independently a hydrogen atom, an optionally substituted C1-C20 alkyl group, an optionally substituted C2-C20 alkenyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C7-C20 alkylaryl group, an optionally substituted aryl group, or an optionally substituted heterocyclic group, or R a , R and R c combine to form
  • the compound is an alkylene group or an alkylenedioxy group;
  • n is an integer of 0 to 3; and
  • R is a methoxy group.
  • the compound is
  • the complexes may be in part commercially available or prepared in analogy to literature from [Ru(p-cym)Cl 2 ] 2 (K. Matsumura, N. Arai, K. Hon, T. Saito, N. Sayo, T. Ohkuma, J. Am. Chem. Soc. 2011, J 33, 10696-10699; H. Nara, T. Yokozawa, US9079931B2 July 14, 2015 to Takasago Int. Corp.).
  • the Ruthenium catalyst may contain a chiral diphosphine of the formula
  • R 1 is lower-alkyl, lower-alkoxy, hydroxy or lower-alkyl-C(0)0-;
  • R 2 and R 3 are each independently hydrogen, lower-alkyl, lower-alkoxy or di(lower- alkyl)amino; or
  • R 1 and R 2 which are attached to the same phenyl group, or R 2 and R 3 which are
  • X-(CH 2 ) r -Y- attached to the same phenyl group taken together are -X-(CH 2 ) r -Y-, wherein X is - O- or -C(0)0-, Y is -O- or -N(lower-alkyl)- and r is an integer from 1 to 6, or a CF 2 group,
  • R 1 taken together, are -0-(CH 2 ) r -0- or 0-CH(CH 3 )-(CH 2 ) r -CH(CH 3 )-0-, wherein r is an integer from 1 to 6, or
  • R 1 and R 2 , or R 2 and R 3 together with the carbon atoms to which they are attached, form a naphthyl, tetrahydronaphthyl or dibenzofuran ring;
  • R 4 and R 5 are each independently lower alkyl, cycloalkyl, phenyl, naphthyl or
  • heteroaryl substituted with 0 to 7 substituents independently selected from the group consisting of lower-alkyl, lower-alkoxy, di(lower-alkyl)amino, morpholino, phenyl and tri(lower-alkyl)silyl, carboxy, lower-alkoxycarbonyl;
  • R 4 is phenyl, it is substituted with 0 to 5, preferably 0 to 3 substituents as described above.
  • the chiral diphosphine in the ruthenium complex may be BINAP, MeOBIPHEP or SegPhos.
  • a more highly active catalyst e.g., the triflate
  • the triflate can be formed in situ by treatment of the chloro ruthenium complex with sodium triflate
  • the desired configuration of the product at the CH(OH) chiral in position 1 center is (S).
  • Obtaining the (S) configuration of the product at the CH(OH) chiral center at position 1 is achieved by using catalyst containing the (R) configuration at the phosphine ligand (Rp).
  • the configuration of the diamine ligand can be (R) or (S) ((RN) or (S N )). The experiments conducted with catalysts of the opposite configuration at the phosphine ligand afforded the (R)-product.
  • the solvent in the ketone reduction may be methanol, ethanol, 2-propanol, dichloromethane, THF, ethyl acetate, toluene or a combination thereof.
  • the solvent is a 2-propanol/dichlorom ethane mixture.
  • the base in the ketone reduction may be KOtBu, DBU (K. Matsumura, N. Arai, K. Hori, T. Saito, N. Sayo, T. Ohkuma, J. Am. Chem. Soc. 2011, 133, 10696-10699), KOtBu, LiOH, triethylamine, DBU (H. Nara, T. Yokozawa, US9079931B2 July 14, 2015 to Takasago Int. Corp), Cs 2 C0 3 , K 2 C0 3 , K 3 P0 4 , TMG, N- Ethyldiisopropylamine, Dicyclohexylamine, DABCO, DBN.
  • the amount of cisltrans isomerization on the cyclohexyl ring may depend on the base used. In specific examples, the base is Cs 2 C0 3 , K 2 C0 3 or TMG.
  • the amount of base added can vary between 0.0005 and 5.0 molar equivalents to substrate. The amount can be adjusted depending on the base type and the substrate quality. In some examples, the molar equivalents of base to substrate is 0.005-0.5.
  • the enantiomeric ratio (e.r.) of the product of the ketone reduction is greater or equal to 97.5:2.5. In other embodiments, the e.r. is greater than or equal to 99.5:0.5.
  • the compound of Formula (IV) is crystallized to provide a compound of Formula (IV) in greater than 90: 10, 95:5, 96:4, 97:3, 98:2, or 99: 1 enantiomeric ratio (e.r.) before reducing the alkene and deprotecting the 4'-hydroxy group of the compound of Formula (IV) to provide a compound of Formula (I).
  • reducing the alkene and deprotecting the 4'-hydroxy group of the compound of Formula (IV) is conducted by
  • the product of the asymmetric hydrogenation may be protected with one of following groups: TBS ("Greene's protective groups in organic synthesis” Wiley-Interscience, New Jersey 2007, 4 th Edition. 189-196) (see Example 4), TES ("Greene's protective groups in organic synthesis” Wiley-Interscience, New Jersey 2007, 4 th Edition. 178-180) (see Example 5), Piv (“Greene's protective groups in organic synthesis” Wiley-Interscience, New Jersey 2007, 4 th Edition. 250-252) (see Example 6), Ac (“Greene's protective groups in organic synthesis” Wiley-Interscience, New Jersey 2007, 4 th Edition. 223-224) (see Example 7).
  • TBS Greene's protective groups in organic synthesis
  • TES Greene's protective groups in organic synthesis” Wiley-Interscience, New Jersey 2007, 4 th Edition. 178-180
  • Piv Greene's protective groups in organic synthesis” Wiley-Interscience, New Jersey 2007, 4 th Edition. 250-252
  • Ac Greene's protective groups in
  • the exocyclic double bond can be reduced selectively if the allylic hydroxy function in position 1 is protected with a sterically demanding protecting group (e.g., acetyl, pivaloyl, triethylsilyl, tert-butyldimethylsilyl).
  • a sterically demanding protecting group e.g., acetyl, pivaloyl, triethylsilyl, tert-butyldimethylsilyl.
  • the catalyst used in the heterogeneous hydrogenation of the alkene can be Pd, Pt, Rh or Ni. In some embodiments, the catalyst is Pd or Pt, while in other embodiment, the catalyst is Pd.
  • the solvent used in the heterogeneous hydrogenation of the alkene can be cpme, tbme, iPrOAc, EtOAc, MeOH, iPrOH, THF, 2-MeTHF. In some embodiments, the solvent is cpme.
  • the temperature of the heterogeneous hydrogenation of the alkene can be about 25 to about 40 °C, at a hydrogen pressure of about 1 to about 50 bar.
  • the addition of a base may improve the diastereo selectivity of the heterogeneous reduction of the alkene.
  • the base may be 2,6-lutidine, 3,5-lutidine, 1,8- diazabicyclo[5.4.0]undec-7-ene, pyridine, imidazole, triethylamine, tetramethylguanidine, diisopropylethylamine, diisopropylamine, dicylohexylmethylamine, aniline, benzylamine, l,4-diazobicyclo[2.2.2]octane, ammonia.
  • the base is selected from 2,6-lutidine, pyridine and l,8-diazabicyclo[5.4.0]undec-7-ene. (see Example Het3.01-3.03).
  • DiTBS- API The deprotection of DiTBS- API may be performed in analogy to classic methods. ("Greene's protective groups in organic synthesis” Wiley-Interscience, New Jersey 2007, 4 th Edition. 196-206).
  • the deprotection conditions may include 1-5 NHC1 aq.
  • the exocyclic double bond is reduced in step 5a.1 with a diastereomeric ratio (d.r.) of greater than or equal to 93 :7.
  • d.r. enrichment may be achieved by crystallization.
  • reducing the alkene and deprotecting the 4'-hydroxy group of the compound of Formula (rV) are performed simultaneously to provide a compound of Formula (I).
  • Reducing the alkene of the compound of Formula (VI) may include contacting the alkene with a catalyst in an atmosphere of hydrogen. Under comparable conditions as in step 5a. l 4 -TBS-En-ol is reduced to API as a mixture of the desired (1R,5 " S) and the undesired (1R,5 “ R) diastereomer in a ratio of 1 :2. This unfavorable ratio can be reversed and the desired diastereoisomer formed as major product (in a ratio up to 84: 16) if acids are added to the heterogeneous hydrogenation or the reaction is run in acetic acid as solvent, (see Example Het4.01-Het4.05)
  • the catalyst used in the heterogeneous reduction of the alkene can be Pd, Pt, Rh, Ni or Co. In some embodiments, the catalyst is Pd or Pt, while in other embodiment, the catalyst is Pd.
  • the solvent used in the heterogeneous reduction of the alkene can be i-PrOAc, iPrOH, 2-MeTHF, methanol, AcOH, ethanol, methanol/H 2 0 or MeOH.
  • the temperature of the heterogeneous reduction of the alkene can be about 25 to about 80 °C. In some embodiments, the temperature of the heterogeneous reduction of the alkene can be about 25 to about 40 °C.
  • the pressure of the heterogeneous reduction of the alkene can be about 2 to about 250 bar. In some embodiments, the pressure of the heterogeneous reduction of the alkene can be about 80 to about 120 bar.
  • the acid used in the heterogeneous reduction of the alkene can be AcOH, phosphoric acid, ascorbic acid, citric acid, tartaric acid, camphor- 10-sulfonic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid, p- toluenesulfonic acid.
  • the acid used in the heterogeneous reduction of the alkene is methanesulfonic acid.
  • the protecting group stays intact or is (partially) cleaved during the reaction. In some embodiments, using
  • methansulfonic acid provides the best di stereo selctivity and the TBS-group is completely removed. Thus, an additional deprotection step is not necessary.
  • Free base API can be obtained by the addition of aqueous sodium hydroxide to the mesylate salt (or alternatively aqueous ammonium hydroxide could also been used). See Example 13.
  • DiTBS-En-ol is not isolated, but in a one-pot procedure is converted to intermediate 1-TBS-En-ol by the addition of phosphoric acid.
  • the solvent used can be cpme, 2-MeTHF, iPrOAc, MeOH, iPrOH, 1-propanol. In some embodiments, the solvent is MeOH.
  • the heterogeneous reduction of the alkene may also include a base.
  • the base can be DBU, 2,6-lutidine or triethylamine.
  • the heterogeneous reduction of the alkene is performed at about 40 °C.
  • TBS-deprotection of the 4' position in MeOH with methanesulfonic acid and d.r. enrichment through crystallization of the mesylate salt can be performed (see Example 12).
  • the method may further include crystallizing the compound of Formula (I) from a solution to provide a crystalline salt of a compound of Formula (I).
  • the crystalline salt may be formed from any pharmaceutically acceptable salt known in the art.
  • the crystalline salt of Formula (I) may be a phosphoric acid salt or a methanesulfonic acid salt.
  • the method may further include forming a free base of the compound of Formula (I).
  • This method may include contacting the crystalline salt of a compound of Formula (I) with a base in solution to provide a free base of a compound of Formula (I).
  • the compound of Formula (I) is isolated as a mixture of diastereomers in a ratio of 90: 10 or greater.
  • the compound of Formula (I) is isolated in an overall yield of 30 % or greater.
  • the compound of Formula (I) has a purity of 90 % or greater.
  • the compound of Formula (I) has a purity of 91 % or greater, 92 % or greater, 93 % or greater, 94 % or greater, 95 % or greater, 96 % or greater, 97 % or greater, 98 % or greater or 99 % or greater.
  • PG is a protecting group that remains intact during the manipulation of the chemical structure, and is easily removed without significantly affecting the other functional groups of the molecule.
  • PG is acetyl, pivaloyl or a silyl protecting group.
  • PG can be triethylsilyl or a tert- butydimethylsilyl.
  • the reducing agent used to reduce the carbonyl in the compound of Formula (IX) to provide a mixture of a compound of Formula (I) and a compound of Formula ( ⁇ ) may be any boron or aluminum reducing agent known in the art, such as NaBH 4 , BH 3 , Li A1H 4 , RedAl, LiAlH(OtBu) 3 , selectride, as well as any other suitable reducing agent known in the art.
  • LiAlH(OtBu) 3 may be used, and may result in diastereoselectivities of >97%.
  • the solvent may be MeOH, EtOH, i-PrOH, n-PrOH, THF, 2-Me-THF, DCM, TBME, CPME, dioxane, toluene or mixtures thereof.
  • the solvent may be THF, 2-Me-THF, CPME, TBME, dioxane, DCM, toluene or mixtures thereof.
  • a mixture of THF/2-Me-THF may be used, and may improve the diastereoselectivity of the reaction. For example, a reduction in THF may provide a diastereoselectivity of 94-95%, where a reduction performed in THF/2-Me-THF may provide a diastereoselectivity of >97%.
  • the stoichiometry of the reducing agent may range from about 0.3-5 equiv. for boron reducing reagents, and about 1.0-5.0 equiv. for aluminum reducing reagents. In some embodiments, about 0.3-1 equiv. of boron reducing reagent may be used. In other embodiments, about 1.0-1.3 equiv. or about 1.1 equiv. of aluminum reducing may be used.
  • the temperature of the reduction may range from about -30 °C to about 50 °C. In some embodiments, the temperature may range from about -15 °C to about 25 °C, or from about -15 °C to about 0 °C.
  • the method further includes (a) treating the mixture of the compound of Formula (I) and the compound of
  • diastereomeric salt formation may be accomplished by using various chiral acids.
  • the chiral acid may be tartaric acid or derivatives thereof, such as dibenzoyl tartaric acid or ditoluoyl tartaric acid.
  • the chiral acid may be mandelic acid or camphorsulfonic acid.
  • the chiral acid may be used in about 0.9-10 equiv., or about 0.95-1.5 equiv. or about 1.0-1.2 equiv.
  • the solvents use for the diastereomeric salt formation include alcohols such as MeOH, EtOH, n-PrOH, 2-PrOH, n- BuOH, s-BuOH, tBuOH, t-Amyl alcohol or mixtures thereof.
  • the diastereomeric salt formation may be performed at a temperature of about 0-100 °C, or about 40-70 °C, or about
  • treating the diastereoselective salt with a base to provide the compound of Formula (I) may be performed with any free basing reagent known in the art.
  • the free basing agent may be an aqueous solution of an inorganic base, such as NaOH, KOH, Li OH, Ca(OH) 2 ,Na/K/LiHC0 3 , Na/K/Li 2 C0 3 , NaAmberlyst A21 Resin, etc.
  • the free basing may be performed in any organic solvent, water, or any aqueous inorganic base described above.
  • the free basing may be performed in aqueous NaOH.
  • the free basing agent may be used in about 1.95-10 equiv., about 2-3 equiv., or about 2.5 equiv.
  • the free basing may be performed at a temperature of about 0- 50°C, about 5-25°C, or about 15-20°C.
  • the method further includes cleaving a hydroxyl protecting group, PG, from a compound of Formula (II)
  • the method further includes reacting a compound of Formula (V)
  • PG is a hydroxyl protecting group
  • each R" is independently a Ci-C 6 alkyl group, a compound of Formula (VI)
  • the method further includes
  • R is a Ci-C 6 alkyl group
  • esterification may be performed with an acid, such as HC1, MsOH or TsOH, in an alcoholic solvent, such as ethanol.
  • Toluene may be used for the workup following the esterification, as well as for the subsequent protection of the 4'- hydroxyl group.
  • the protecting group (PG) of the compound of Formula (Vb) may be a silyl group, such as TBS.
  • the esterification may be performed at about 30-40°, and the subsequent silylation at about 70-80°C.
  • the compound of Formula (Vb) may be obtained by short-path distillation.
  • the converting of the compound of Formula (Vb) to a compound of Formula (V) involves treating the compound of Formula (Vb) with an alkyl phosphonate (e.g., dimethylmethyl phosphonate) under basic conditions.
  • an alkyl phosphonate e.g., dimethylmethyl phosphonate
  • low temperatures may not be needed.
  • the phosphonate (compound of Formula (V)) may not be isolated and the crude product may be taken on to react with a compound of Formula (VI).
  • the protecting group on the compound of Formula (II) may be cleaved in situ to provide a compound of Formula (IX). Under these conditions, the compound of Formula (IX) may be provided from a compound of Formula (Vb) without the isolation of any intermediates.
  • the method further includes
  • Converting a compound of Formula (IX) to a compound of Formula (IXa) may include
  • diastereomeric salt formation may be accomplished by using various chiral acids.
  • the chiral acid may be tartaric acid or derivatives thereof, such as dibenzoyl tartaric acid or ditoluoyl tartaric acid.
  • the chiral acid may be mandelic acid or camphorsulfonic acid.
  • the chiral acid may be used in about 0.9-10 equiv., or about 0.95-1.5 equiv. or about 1.0-1.2 equiv.
  • the solvents use for the diastereomeric salt formation include alcohols such as MeOH, EtOH, n-PrOH, 2-PrOH, n- BuOH, s-BuOH, tBuOH, t-Amyl alcohol or mixtures thereof.
  • the diastereomeric salt formation may be performed at a temperature of about 0-100 °C, or about 40-70 °C, or about 45-55 °C.
  • the diastereomeric salt formation may be carried out in EtOH or IPA at a temperature from about 60 °C to 80 °C.
  • treating the diastereoselective salt with a base to provide the compound of Formula (IXa) may be performed with any free basing reagent known in the art.
  • the free basing agent may be an aqueous solution of an inorganic base, such as NaOH, KOH, Li OH, Ca(OH) 2 ,Na/K/LiHC0 3 , Na/K/Li 2 C0 3 , NaAmberlyst A21 Resin, etc.
  • the free basing may be performed in any organic solvent, water, or any aqueous inorganic base described above.
  • the free basing may be performed in aqueous NaOH.
  • the free basing agent may be used in about 1.95-10 equiv., about 2-3 equiv., or about 2.5 equiv.
  • the free basing may be performed at a temperature of about 0- 50°C, about 5-25°C, or about 15-20°C.
  • the free basing may be carried out in DCM with an aqueous solution of Na/Li/KHC0 3 or Na/Li/KH x P0 4 at a temperature of about 0 °C to about 40 °C.
  • slurrying of the free base in MeTHF, toluene, IP Ac or EtOAc may increase the resulting enantiomeric excess.
  • converting the compound of Formula (IX) to the compound of Formula (IXa) may involve treating the compound of Formula (IX) with (L)- Dibenzoyl tartaric acid salt and K 2 HP0 4 .
  • converting the compound of Formula (IXa) to a compound of Formula (I) may involve reducing the carbonyl in the compound of Formula (IXa).
  • reducing the carbonyl in the compound of Formula (IXa) may involve treating the compound of Formula (IXa) with an aluminum or boron reducing agent.
  • the reducing agent may include BH 3 /(R)-2-methyl-CBS-oxazaborolidine, NaBH 4 , LiAlH 4 , RedAl, Li AlH(OtBu) 3 , selectride, etc.
  • using LiAlH(OtBu) 3 as the reducing reagent may provide a compound of Formula (I) in a diastereo selectivity of about >97%.
  • the solvent may be MeOH, EtOH, i-PrOH, n-PrOH, THF, 2-Me-THF, DCM, TBME, CPME, dioxane, toluene or mixtures thereof.
  • the solvent may be THF, 2-Me-THF, CPME, TBME, dioxane, DCM, toluene or mixtures thereof.
  • a mixture of THF/2-Me-THF may be used, and may improve the diastereoselectivity of the reaction. For example, a reduction in THF may provide a diastereoselectivity of 94-95%, where a reduction performed in TFIF/2-Me-TFIF may provide a diastereoselectivity of >97%.
  • the stoichiometry of the reducing agent may range from about 0.3-5 equiv. for boron reducing reagents, and about 1.0-5.0 equiv. for aluminum reducing reagents. In some embodiments, about 0.3-1 equiv. of boron reducing reagent may be used. In other embodiments, about 1.0-1.3 equiv. or about 1.1 equiv. of aluminum reducing may be used.
  • the temperature of the reduction may range from about -30 °C to about 50 °C. In some embodiments, the temperature may range from about -15 °C to about 25 °C, or from about -15 °C to about 0 °C.
  • the method may further include reducing the 4'-carbonyl group of a compound of Formula (VIII)
  • reducing the 4'-carbonyl group of the compound of Formula (VIII) to provide the compound of Formula (IX) may involve treating the compound of Formula (VIII) with a ketoreductase.
  • the stereoselective reduction provides the trans-product in 95% yield with a purity >95a%.
  • a low enzyme loading (substrate /enzyme up to 200 [w/w]) and low NAD cofactor loading (substrate /cofactor up to 2000 [w/w]) may be used, and the pH of the reaction may range from about 6.0 to about 8.0.
  • the reduction may also include a buffer, such as phosphate buffer of about 50-250 mM.
  • the reduction may be performed at a temperature of about 20 °C to about 50 °C, and may include a beneficial additive, such as 2-propanol, butanol and glycine.
  • a beneficial additive such as 2-propanol, butanol and glycine.
  • the additive is 2-Propanol in about 5 to about 25 weight percent.
  • the method may further include reacting a compound of Formula (VII)
  • each R' is independently Ci-C 6 alkyl or both R' combine with the oxygen atoms to which they are attached to form a 5- or 6-membered dioxanyl ring, and
  • each R" is independently a Ci-C 6 alkyl group
  • the compound of Formula (VII) is formed from an alkyl 4- oxocyclohexanecarboxylate.
  • the ketone of the alkyl 4-oxocyclohexanecarboxylate e.g., ethyl 4-oxocyclohexanecarboxylate
  • the reaction may be run in EtOH, THF, MTBE or toluene with or without alkylorthoformate and in presence of a strong acid, such as H 2 SO 4 , HQ or pTsOH, and at a temperature of about 20 to about 80 °C.
  • the compound of Formula (VII) can then be formed by treating the protected alkyl 4-oxocyclohexanecarboxylate with an alkyl phosphonate (e.g.,
  • the protected alkyl 4- oxocyclohexanecarboxylate may be treated with a base at a temperature of about -80 °C to about -20 °C, in a solvent such as MeTHF, THF or toluene.
  • Suitable bases include, but are not limited to BuLi, LDA and LHMDS.
  • reacting a compound of Formula (VII) with reacting a compound of Formula (VI) to provide a compound of Formula (VIII) is performed in a solvent (e.g., THF, MeTHF, toluene, etc.) in the presence of a base (e.g., NaOH, or
  • Li/K/Na 2 C0 3 Li/K/Na 2 C0 3 ) at a temperature of about 40 °C to about 80 °C.
  • an acid e.g., H 2 S0 4 , HC1, AcOH, etc.
  • water can be used for the deprotection of the acetal.
  • the method may further include converting a compound of Formula (Via)
  • the conversion of a compound of Formula (Via) to a compound of Formula (VIb) is performed at about -40 °C to about 0 °C, in MeTHF, TUF or toluene.
  • reacting of the compound of Formula (VIb) and the compound of Formula (Vic) to provide the compound of Formula (VI) may be performed through a palladium catalyzed cross-coupling, such as the Suzuki-Miyaura cross-coupling reaction.
  • a zero valent palladium species (Pd(0)) is used, which may be applied directly (e.g.
  • Pd(0) complexes such as Pd(PPh 3 ) 4 , Pd(PCy 3 ) 2 , Pd(PtBu 3 ) 2 or similar Pd(0) complexes) or may be formed from a palladium source in combination with either a phosphine ligand and/or a base such as (KOtBu, KOH, NaOAc, K 3 P0 4 , K 2 C0 3 , Hiinig's base, Et 3 , Pr 3 , etc.).
  • a phosphine ligand and/or a base such as (KOtBu, KOH, NaOAc, K 3 P0 4 , K 2 C0 3 , Hiinig's base, Et 3 , Pr 3 , etc.).
  • the palladium catalyzed cross-coupling may also employ a ligand, which may be used in combination with [PdCl(allyl)] 2 or as a Pd pre-catalyst.
  • the ligand is Amphos or di-tert-butylphenylphospine.
  • the catalyst system is an in situ formed Pd complex from Pd2(dba)3/Amphos
  • the catalytic system may be further refined by exploring different palladium pre-catalysts in oxidation state 0 and II with and without pre-bound ligand.
  • the solvent used in the palladium catalyzed cross-coupling may include methanol, ethanol, iso-propanol, dioxane, 2-methyltetrahydrofuran, tetrahydrofuran, toluene, tert- butylmethyl ether, acetone, dimethyl carbonate, acetonitrile, N-methyl-2-pyrrolidone, isopropyl acetate, propylene carbonate, mixtures thereof and water mixtures thereof.
  • the solvent may be a mixture of methanol, water and a co-solvent selected from any of the solvents listed directly above.
  • the solvent for the palladium catalyzed cross-coupling may be methanol/water/THF.
  • the base used in the palladium catalyzed cross-coupling may include an inorganic base, such as M 2 C0 3 , MO Ac, MHC0 3 , M 3 P0 4 , MH 2 P0 4 , MOH, tBuOM or MPiv (where "M” is a alkali earth metal), an organic base, such as tetramethylguanidine, N,N- diisopropylethylamine, triethylamine, l,4-diazobicyclo[2.2.2]octane, tripropylamine, triphenylamine, lutidine, pyridine, tributylamine, NMM, or tert-butylamine, or a combination thereof.
  • the base is present in about 1.0 to about 2.5 molar
  • the base is 1.3 equivalents of N,N- dii sopropyl ethyl amine .
  • the palladium catalyzed cross-coupling may be performed at a temperature of about 60-80 °C, for up to about 24h, and at a substrate/catalyst ratio of up to about 200.
  • the method may further include
  • each R' is independently Ci-C 6 alkyl or both R' combine with the oxygen atoms to which they are attached to form a 5- or 6- membered dioxanyl ring, and
  • each R" is independently a Ci-C 6 alkyl group
  • the method may further include
  • PG is a hydroxyl protecting group
  • each R" is independently a Ci-C 6 alkyl group
  • X is F, CI, or Br. In certain embodiments, X is F.
  • PG may be TBS.
  • the compound of Formula (I) is isolated as a mixture of diastereomers in a ratio of about 90: 10 or greater, about 91 :9 or greater, about 92:8 or greater, about 93 :7 or greater, about 94:6 or greater, about 95:5 or greater, about 96:4 or greater, about 97:3 or greater, about 98:2 or greater, or about 99: 1 or greater.
  • the compound of Formula (I) is N-(2-aminoethyl)-2-aminoethyl
  • wet-milling of the compound of Formula (I) is performed to control (and diminish) particle size control.
  • Wet-milling may be performed by single-pass or multiple-pass of a suspension through rotor-stator equipment typically controlled by a pump. The suspension temperature increases to a certain degree.
  • This suspension a) may be isolated directly, or b) may be tempered at a certain (potentially elevated) temperature in order to manipulate particle size distribution. The resulting suspension is then cooled and isolated.
  • 4'-Hydroxy-ketone of general Formula II is an intermediate of the current synthesis of the API according to International Patent Application Publication No.
  • Example 1 l-[4-[fert-butyl(dimethyl)silyl]oxycvclohexyl1-2-(6-fluoroimidazol[L5- b]i soindol -5 -yPethanone (4'-TBS-ketone)
  • the residue was filtered over silica (eluent: toluene, toluene/EtOAc) and the solvent removed under reduced pressure.
  • the residue was extracted with toluene/water, and the toluene phase was washed with aq. Na 2 S0 4 .
  • the residue was filtered over silica (eluent: toluene, toluene/EtOAc) to obtain the crude intermediate product [RuCl((5)-daipena)((5)-3,5-Me-4-MeO-MeOBIPHEP)] after removal of the solvent.
  • In-situ catalyst preparation In a glove box (0 2 content ⁇ 2 ppm ) 21.83 mg (0.016 mmol) of [RuCl((R)-daipena)((R)-3,5-iPr-MeOBIPHEP)] and 28.15 mg (160 ⁇ ) NaOTf were added in 5 ml of toluene in a 10 ml flask. The resulting suspension was stirred for 1.5 h. (In-situ preparation of [RuOTf((R)-daipena)((R)-3,5-iPr-MeOBIPHEP] has not been described in K. Matsumura, N. Arai, K. Hon, T. Saito, N. Sayo, T. Ohkuma J. Am. Chem. Soc. 2011, J 33, 10696-10699).
  • the asymmetric hydrogenation was run for 19 h at 25 °C under 40 bar of hydrogen. Afterwards the pressure was released from the autoclave and the reaction mixture was analyzed as described in Example AH1 to determine the conversion and the ee of the resulting TBS-En- ol. The conversion was 99.8 a%, 97.3 a% yield, 91 :9 e.r. R.
  • the autoclave was sealed and the hydrogenation was run at 40 °C under 10 bar of hydrogen. After 1.5 h the autoclave was cooled to ambient temperature and the pressure released. The catalyst was filtered off, rinsed with total 60 mL methanol and the filtrate was concentrated. The solution was heated to 55 °C and a total of 90 mL water was added dropwise, the resulting suspension was allowed to cool to room temperature, the crystals were filtered off, washed with H 2 0/MeOH 7/3 and dried to obtain 8.69 g (86%) of the titled compound in 99.1% purity (HPLC area).
  • the compound of Formula (V) may be prepared in accordance with the methods of the '237 PCT publication, Tetrahedron, Asymmetry 16 (2005) 3682-3689, methods known to one of skill in the art, and/or the following synthetic schemes:
  • the compound of Formula (VI) may be prepared in accordance with the following synthetic scheme:
  • the compound of Formula (VIb) may be prepared in accordance with the following synthetic scheme:
  • the compound of Formula (II) may be prepared in accordance with the methods of the '237 PCT publication, methods known to one of skill in the art, and/or the following synthetic scheme:
  • the compound of Formula (I) may be prepared in accordance with the methods of the '237 PCT publication, methods known to one of skill in the art, and/or the following synthetic scheme: Formula (IX) Chiral
  • the reaction mixture was cooled to 20-30 °C and then aqueous acetic acid (5%, 120 mL) was added. Then the phases were separated, the organic phase was washed twice with water (134 mL) and the organic phase was concentrated to dryness under vacuum (50 °C, ⁇ 0.1 mbar) to yield the crude product (53.53 g, 87.5% yield) as yellow oil.
  • the pH was adjusted to pH 6.0-7.0 with additional acetic acid if necessary and the phases were separated.
  • the organic phase was washed with water (90 mL), the phases were separated and the organic phase was concentrated to dryness under vacuum.
  • THF 156 mL was added and this THF solution was added under stirring at ambient temperature to a mixture of 2-fluoro-6-(lH-imidazol-4-yl)benzaldehyde (25.4 g) in THF (106 mL) and K 2 C0 3 (73.9 g) in water.
  • the resulting bi-phasic mixture was heated to 50 °C and stirred for 15h. Then the reaction mixture was cooled to 20-30 °C and the phases were separated.
  • the suspension was heated to 40-45 °C, 35% (35 mL) of the D-(+)-Dibenzoyl tartaric acid monohydrate solution was added and the mixture was stirred until a yellow-orange solution was obtained. Then, seeding crystals (lg in 7.9 g iPrOH) were added and the resulting suspension was stirred for 15-45 min and the remaining 55% (55 mL) of the D-(+)-Dibenzoyl tartaric acid monohydrate solution was added. The suspension was stirred for 30-60 min and then cooled to 15-25 °C within 1-2 h. The suspension was stirred for lh, the crystals were filtered off, washed with iPrOH (200 mL) and dried at 50 °C under vacuum to yield the title compound as white solid (90.6 g, 41% yield).
  • methyllithium (3.1 M in diethoxymethane, 1.2 equiv., 483 mmol, 155.9 mL) was added at -20 °C over 30 min, then the reaction mixture was allowed to warm to 0 °C and stirred for 16h. Then the mixture was cooled to -20°C, trimethylb orate (3.0 equiv., 1208 mmol, 138 mL) was added over a period of 1 h and the slurry was then warmed to 0 °C and stirred for 2.5h.
  • This reaction mixture was added at 10 °C to water (500 mL), the resulting bi-phasic slurry was aged for 30 min, allowed to warm to ambient temperature, the solids were filtered off washed with water (200 mL). From the bi-phasic filtrate the layers were allowed to separate and to the aqueous layer MTBE (250 mL) was added. This biphasic mixture was stirred at internal temperature 20-25 °C for 30 min and the phases were separated. The aqueous layer was acidified with sulfuric acid in water (50 wt%, 200mL) to pH 2.3, MBTE (250 mL) was added and the bi-phasic mixture was stirred for 30 min at ambient temperature.
  • the aqueous phase was extracted with MTBE (250 mL) twice.
  • the combined organic phases were washed with water (100 mL) and the bi-phasic mixture was stirred for 30 min at ambient temperature.
  • the phases were separated and the organic phase was heated to 45°C and the mixture was concentrated to ca. 5V under vacuum.
  • toluene 500 mL was added and the mixture was concentrated to a content of ⁇ 5 w% of TBME in toluene.
  • water (100 mL) was added and the mixture was allowed to stir for 1 h at 45 °C.
  • the mixture was warmed to 60 °C and allowed to stir for an additional 1 h.
  • the mixture was cooled to 25 °C, and the stirring solids were aged for 1 h then filtered.
  • the wet cake was dried at ambient temperature under a stream of nitrogen overnight yielding the product as off- white solid (48.0% yield).
  • the reactor was evaporated and refiled with argon 3 times, heated to 80 °C and stirred for 16-20 h. Then, the mixture was cooled to 55 °C over a period of 2h, the solids were filtered over a charcoal filter pad, and washed with methanol (400 mL).
  • N-acetyl cysteine (1.67 g) was added and the mixture was stirred for 2-16h at 50- 55 °C.
  • methanol was continuously exchanged under vacuum with 2-Me-THF (500 mL), the volume was adjusted to ca. 250 mL, 2-Me-THF (250 mL) and water (190 mL) were added and the mixture was stirred for 15-30 min at 55 °C.
  • the phases were separated and the aqueous layer was washed three times with 2-Me-THF (240 mL). The combined organic layers were treated with water and the biphasic mixture was stirred for 15-30 min at 55 °C.
  • the phases were separated, the organic phase was cooled to 20-25 °C and treated with water (150 mL). Afterwards, the pH was adjusted to >13.6 upon addition of NaOH (30%, ca. 43.6 g) and the bi-phasic mixture was stirred for 15-30 min. The layers were separated, the organic phase was treated with water (100 mL) and NaOH (30%, ca. 9.1 g) to adjust the pH to >13.6 and the bi-phasic mixture was stirred for 15-30 min. The phases were separated and the organic phase was treated with water (100 mL) and NaOH (30%, ca. 6.1 g) to adjust the pH to >13.6 and the bi-phasic mixture was stirred for 15-30 min.
  • the bi-phasic mixture was cooled to 20-25 °C, the layers were separated and the organic phase was washed twice with sodium chloride solution (18 w%, 320 mL).
  • the organic phase was washed twice at 20-25 °C with sulfuric acid (3 M, 260 mL), the layers were separated and the combined aqueous phases were diluted with water (325 mL) and 2- Me-THF (24 mL).
  • the pH was adjusted at 25-30 °C with ammonium hydroxide in water (15 w% solution, 325 mL) to pH 4-4.5.
  • Example 7 Synthesis of trans- l-(4-hydroxycyclohexyl)-2-[(5S)-6-fluoro-5H- imidazo[l,5-b]isoindol-5-yl]ethanone (L)-Dibenzoyl tartaric acid salt
  • This reaction mixture was added at 0 °C to H2S04 (20 wt% aqu., 214.5 g) over a period of 15 min and the reaction mixture was allowed to warm to 23° C and stirred for lh. Then, the phases were separated, the organic layer was cooled to 15 °C and H2S04 (96 wt% aqu., 3.9 g) in water (100 mL) was added. The bi-phasic mixture was stirred for 15 min, the phases were separated. To the combined aqueous phases, citric acid (38.2 g) in water (100 mL) and 2-Me- THF (500 mL) was added and the pH was adjusted upon addition of NaOH (28% aqu.
  • Reactor 1 (2 L) was charged under inert atmosphere with trans- 1 -(4- hydroxycyclohexyl)-2-[(5S)-6-fluoro-5H-imidazo[l,5-b]isoindol-5-yl]ethanone (80 g, 254.5 mmol, 1.0 equiv.) and tetrahydrofuran (15 vol, 1200 mL).
  • Reactor 2 (2.5 L) with overhead stirrer was charged under inert atmosphere with borane-THF complex in THF (2.2 equiv., 559.8 mmol, 1 mol/L, 560 mL) followed by a solution of (R)-2-methyl-CBS-oxazaborolidine (0.1 equiv., 25.45 mmol, 7.053g) in THF (0.35 vol, 28 mL), and mixed for 15 min at r.t., then cooled down to -20 °C.
  • reactor 1 Contents of reactor 1 were added via pump to the reactor 2 over 5h, at -20 °C and then aged at -20 °C overnight (the reaction is usually complete at the end of addition, but can be let for 18 h at -20 °C). Reaction was quenched with methanol (3 vol, 240 mL) added dropwise at -15 °C over lh, followed by aqueous H2S04 (4 vol, 2 mol/L, 320 mL) added dropwise at -10 °C over 40 min. Next the reaction was warmed to r.t. and concentrated under vacuum to -350 mL (-35 °C jacket temperature) and water (250 mL) was added to reach a final volume of -600 mL.
  • aqueous NH40H (3.15 vol, ⁇ 15w%, 255 mL) was added at 10-15 °C until pH reached -8 (measure with a pH meter probe) and the title compound crystallized out.
  • the slurry was aged for 45 min at r.t., solid was filtered, cake washed with water (7 vol, 560 mL), and dried to provide 78 g (88.8% corrected yield).
  • Example 32 Synthesis of (lR,5S)-2-(6-fluoro-5H-imidazo[5,l-a]isoindol-5-yl)-l-(trans)- 4-hydroxycyclohexyl)ethanol monophosphate mono hydrate salt Crystallization procedure without milling.

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Abstract

La présente invention concerne un procédé de fabrication d'un composé de formule (I) dans laquelle X est un halogène, qui est utile pour moduler l'activité de l'indoléamine 2,3-dioxygénase (IDO), pour traiter des maladies et des états pathologiques dans lesquels l'inhibition de l'immunosuppression induite par IDO est bénéfique.
PCT/US2018/024127 2017-03-23 2018-03-23 Synthèse d'un dérivé d'imidazo[5,1-a]isoindole utile en tant qu'inhibiteurs d'ido Ceased WO2018175954A1 (fr)

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Citations (7)

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WO1999029310A2 (fr) 1997-12-05 1999-06-17 Medical College Of Georgia Research Institute, Inc. Regulation de l'immunite a mediation lymphocytaire, au moyen du tryptophane
WO2003087347A1 (fr) 2002-04-12 2003-10-23 Medical College Of Georgia Research Institute, Inc. Populations de cellules presentatrices de l'antigene et leur utilisation comme reactifs pour renforcer ou diminuer la tolerance immunitaire
WO2004094409A1 (fr) 2003-03-27 2004-11-04 Lankenau Institute For Medical Research Inhibiteurs de ido et procedes d'utilisation de ceux-ci
US20040234623A1 (en) 2003-04-01 2004-11-25 Medical College Of Georgia Research Institute, Inc. Use of inhibitors of indoleamine-2,3-dioxygenase in combination with other therapeutic modalities
WO2012142237A1 (fr) 2011-04-15 2012-10-18 Newlink Geneticks Corporation Dérivés d'imidazole fusionnés pouvant être employés en tant qu'inhibiteurs d'ido
US9079931B2 (en) 2010-04-28 2015-07-14 Takasago International Corporation Ruthenium complex and method for preparing optically active alcohol compound
WO2016037026A1 (fr) * 2014-09-05 2016-03-10 Merck Patent Gmbh Composés diaza et triaza tricycliques à substitution cyclohexyl-éthyle utilisés comme antagonistes de l'indoleamine-2,3-dioxygénase (ido) pour le traitement du cancer

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Publication number Priority date Publication date Assignee Title
WO1999029310A2 (fr) 1997-12-05 1999-06-17 Medical College Of Georgia Research Institute, Inc. Regulation de l'immunite a mediation lymphocytaire, au moyen du tryptophane
WO2003087347A1 (fr) 2002-04-12 2003-10-23 Medical College Of Georgia Research Institute, Inc. Populations de cellules presentatrices de l'antigene et leur utilisation comme reactifs pour renforcer ou diminuer la tolerance immunitaire
EP1501918A1 (fr) 2002-04-12 2005-02-02 Medical College Of Georgia Research Institute, Inc. Populations de cellules presentatrices de l'antigene et leur utilisation comme reactifs pour renforcer ou diminuer la tolerance immunitaire
WO2004094409A1 (fr) 2003-03-27 2004-11-04 Lankenau Institute For Medical Research Inhibiteurs de ido et procedes d'utilisation de ceux-ci
US20040234623A1 (en) 2003-04-01 2004-11-25 Medical College Of Georgia Research Institute, Inc. Use of inhibitors of indoleamine-2,3-dioxygenase in combination with other therapeutic modalities
US9079931B2 (en) 2010-04-28 2015-07-14 Takasago International Corporation Ruthenium complex and method for preparing optically active alcohol compound
WO2012142237A1 (fr) 2011-04-15 2012-10-18 Newlink Geneticks Corporation Dérivés d'imidazole fusionnés pouvant être employés en tant qu'inhibiteurs d'ido
WO2016037026A1 (fr) * 2014-09-05 2016-03-10 Merck Patent Gmbh Composés diaza et triaza tricycliques à substitution cyclohexyl-éthyle utilisés comme antagonistes de l'indoleamine-2,3-dioxygénase (ido) pour le traitement du cancer

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