WO2021231335A1 - Novel intermediates and synthesis for endochin-like quinolone compounds - Google Patents
Novel intermediates and synthesis for endochin-like quinolone compounds Download PDFInfo
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- WO2021231335A1 WO2021231335A1 PCT/US2021/031651 US2021031651W WO2021231335A1 WO 2021231335 A1 WO2021231335 A1 WO 2021231335A1 US 2021031651 W US2021031651 W US 2021031651W WO 2021231335 A1 WO2021231335 A1 WO 2021231335A1
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- 239000000543 intermediate Substances 0.000 title abstract description 8
- 230000015572 biosynthetic process Effects 0.000 title description 6
- 238000003786 synthesis reaction Methods 0.000 title description 6
- 150000007660 quinolones Chemical class 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 83
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- -1 nitro, cyano, amino Chemical group 0.000 claims description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- 229910052794 bromium Inorganic materials 0.000 claims description 20
- 229910052731 fluorine Inorganic materials 0.000 claims description 19
- 229910052740 iodine Inorganic materials 0.000 claims description 19
- 229910052801 chlorine Inorganic materials 0.000 claims description 18
- 125000001188 haloalkyl group Chemical group 0.000 claims description 13
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 9
- 229960000583 acetic acid Drugs 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- WZDNKHCQIZRDKW-UHFFFAOYSA-N elq-300 Chemical compound O=C1C=2C=C(Cl)C(OC)=CC=2NC(C)=C1C(C=C1)=CC=C1OC1=CC=C(OC(F)(F)F)C=C1 WZDNKHCQIZRDKW-UHFFFAOYSA-N 0.000 claims description 8
- 239000012362 glacial acetic acid Substances 0.000 claims description 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- ZOAIGCHJWKDIPJ-UHFFFAOYSA-M caesium acetate Chemical compound [Cs+].CC([O-])=O ZOAIGCHJWKDIPJ-UHFFFAOYSA-M 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 239000011630 iodine Substances 0.000 claims description 7
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 6
- VHUGESOJEBDHSY-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-[4-[4-(trifluoromethoxy)phenoxy]phenyl]-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C(C=C1)=CC=C1OC1=CC=C(OC(F)(F)F)C=C1 VHUGESOJEBDHSY-UHFFFAOYSA-N 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- SUFFMIUELDDRLM-UHFFFAOYSA-N 6-fluoro-7-methoxy-2-methyl-3-[4-[4-(trifluoromethoxy)phenoxy]phenyl]-1h-quinolin-4-one Chemical compound O=C1C=2C=C(F)C(OC)=CC=2NC(C)=C1C(C=C1)=CC=C1OC1=CC=C(OC(F)(F)F)C=C1 SUFFMIUELDDRLM-UHFFFAOYSA-N 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 3
- 239000001257 hydrogen Substances 0.000 claims 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 abstract description 11
- 238000010189 synthetic method Methods 0.000 abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 150000003839 salts Chemical class 0.000 description 20
- 235000002639 sodium chloride Nutrition 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 201000004792 malaria Diseases 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- PBFVXFWZNBAEPU-UHFFFAOYSA-N 3-bromo-6-chloro-7-methoxy-2-methyl-1h-quinolin-4-one Chemical compound N1C(C)=C(Br)C(=O)C2=C1C=C(OC)C(Cl)=C2 PBFVXFWZNBAEPU-UHFFFAOYSA-N 0.000 description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- GPCPUKDQSWVZHE-UHFFFAOYSA-N 3-bromo-4,6-dichloro-7-methoxy-2-methylquinoline Chemical compound CC(C(Br)=C(C1=C2)Cl)=NC1=CC(OC)=C2Cl GPCPUKDQSWVZHE-UHFFFAOYSA-N 0.000 description 5
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 201000005485 Toxoplasmosis Diseases 0.000 description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 230000000155 isotopic effect Effects 0.000 description 4
- 244000045947 parasite Species 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- PMZDQRJGMBOQBF-UHFFFAOYSA-N quinolin-4-ol Chemical class C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 0 *C(C(c(c(*)c(*)c(I=*)c1*)c1N1)Cl)=C1[Re] Chemical compound *C(C(c(c(*)c(*)c(I=*)c1*)c1N1)Cl)=C1[Re] 0.000 description 3
- YJXTZWWKNXVRHA-UHFFFAOYSA-N 4-chloro-1h-quinolin-2-one Chemical class C1=CC=CC2=NC(O)=CC(Cl)=C21 YJXTZWWKNXVRHA-UHFFFAOYSA-N 0.000 description 3
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
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- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 2
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- 125000004918 2-methyl-2-pentyl group Chemical group CC(C)(CCC)* 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 2
- ORONNQYGONYNFL-UHFFFAOYSA-N 4,6-dichloro-3-iodo-7-methoxy-2-methylquinoline Chemical compound CC(C(I)=C(C1=C2)Cl)=NC1=CC(OC)=C2Cl ORONNQYGONYNFL-UHFFFAOYSA-N 0.000 description 2
- 150000005653 4-chloroquinolines Chemical class 0.000 description 2
- JNNYJVHRRGBMOU-UHFFFAOYSA-N 6-chloro-3-iodo-7-methoxy-2-methyl-1h-quinolin-4-one Chemical compound N1C(C)=C(I)C(=O)C2=C1C=C(OC)C(Cl)=C2 JNNYJVHRRGBMOU-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 241000224482 Apicomplexa Species 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical class C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
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- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
Definitions
- the present invention provides synthetic methods and novel intermediates in the preparation of 3-aryl Endochin-like quinolone (ELQ) compounds.
- Endochin-like quinolone (ELQ) compounds have been developed for the treatment of diseases caused by organisms of the phylum Apicomplexa include malaria, toxoplasmosis and coccidiosis.
- the present invention provides synthetic methods and novel intermediates in the preparation of 3-aryl Endochin-like quinolone (ELQ) compounds, particularly including 6- chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one (ELQ-300) and 6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl) quinolin-4(1H)-one (ELQ-316) that are amenable to industrial scale-up production.
- ELQ 3-aryl Endochin-like quinolone
- R a , R b , R c , and R d are each independently selected from the group of H, halogen, Ci- C 6 alkyl, Ci-C 6 alkoxy, C1-C3 haloalkyl, aryl, nitro, cyano, amino, amido, acyl, carboxyl, substituted carboxyl, and -S0 2 R h ;
- R h is selected from the group of H, Ci-C 6 alkyl, amino, or C1-C3 haloalkyl;
- R e is selected from the group of methyl, C 1 -C 3 haloalkyl, and heteroaryl;
- R f and Ra are independently selected from the group of H, Ci-C 6 alkyl, Ci-C 6 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, methylsulfonyl, and halogen; n1 is integer selected from the group of 0, 1 , 2, 3, 4, and 5; and n2 is integer selected from the group of 0, 1 , 2, 3, 4, and 5.
- the new synthetic methods presented herein take advantage of the known conversion of 4-chloro quinolines to their respective 4-(1H)-quinolones and demonstrates a previously unknown selective Suzuki reaction. Taken together in one embodiment it comprises, as depicted in Scheme 1 , a new method for the synthesis of 3-aryl functionalized 4-(1H)- quinolones, including ELQ-300 and ELQ-316, that is amenable to industrial scale production.
- Ri is selected from the group of F and Cl; and R 2 is selected from the group of Br and I; with the proviso that, when Ri is Cl, R 2 is not Br.
- Ri is selected from F and Cl; and R 2 is selected from Br and I.
- Ri is selected from F and Cl.
- GC-MS was obtained using an Agilent Technologies 7890B gas chromatography machine (30 m, DBS column set at either 100 °C or 200 °C for 2 min, then at 30 °C /min to 300 °C with inlet temperature set at 250 °C) with an Agilent Technologies 5977A mass-selective detector operating at 70 eV. Flash column chromatographies were performed with the TLC plate measurement method implemented by the machine, using an automated flash chromatography Isolera One from Biotage, Uppsala, Sweden. 1 H-NMR spectra were obtained using a Bruker AMX-400 NMR spectrometer operating at 400.14 MHz in CDCI 3 or DMSO-d 6 .
- High resolution mass spectra were collected using a high-resolution (30,000) Thermo LTQ-Orbitrap Discovery hybrid mass spectrometry instrument (San Jose, CA) equipped with an electrospray ionization source operating in the positive or negative mode.
- the Orbitrap was externally calibrated prior to data acquisition allowing accurate mass measurements for [M+H] + ions to be obtained to within 4 ppm.
- the compounds and pharmaceutical compositions disclosed herein can be used for inhibiting or preventing parasitic diseases.
- human or animal parasitic diseases include malaria, toxoplasmosis, amebiasis, giardiasis, leishmaniasis, trypanosomiasis, and coccidiosis, caused by organisms such as Toxoplasma sp., Eimeria sp., Babesia bovis, Theileria sp., and also includes infections by helminths, such as ascaris, schistosomes and filarial worms.
- the compounds and compositions are also effective in the inhibition of fungal pathogens including Pneumocystis carinii, Aspergillus fumigatus, and others.
- the parasitic diseases may be caused by parasites that cause malaria.
- Particular species of parasites that are included within this group include all species that are capable of causing human or animal infection.
- Illustrative species include Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium knowiesi, and Plasmodium malariae.
- the compounds and compositions disclosed herein are particularly useful for inhibiting drug-resistant malaria such as chloroquine-resistant malaria or multidrug- resistant malaria that is caused by organisms harboring resistance to chloroquine, quinine, mefloquine, pyrimethamine, dapsone, and/or atovaquone.
- Toxoplasmosis is caused by a sporozoan parasite of the Apicomplexa called Toxoplasma gondii. It a common tissue parasite of humans and animals. Most of the infections appear to be asymptomatic (90%), however toxoplasmosis poses a serious health risk for immuno-compromised individuals, such as organ transplant recipients, cancer and AIDS patients, and the unborn children of infected mothers.
- the compounds disclosed herein may be used alone to treat toxoplasmosis or they may be co-administered with “antifolates” such as sulfonamides, pyrimethamine, tirmethoprim, biguanides and/or atovaquone.
- alkyl refers to a straight or branched hydrocarbon.
- an alkyl group can 1 to 6 carbon atoms (i.e., Ci-C 6 alkyl).
- suitable alkyl groups include, but are not limited to, methyl (Me, --CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, - CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1 -propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2- methyl-2-propyl (t-Bu
- alkoxy refers to a group having the formula -O-alkyl, in which an alkyl group, as defined above, is attached to the parent molecule via an oxygen atom.
- the alkyl portion of an alkoxy group can have 1 to 6 carbon atoms (i.e., Ci-C 6 alkoxy).
- suitable alkoxy groups include, but are not limited to, methoxy (-0-CH 3 or --OMe), ethoxy (-OCH 2 CH 3 or - OEt), t-butoxy (-0-C(CH 3 ) 3 or -OtBu) and the like.
- haloalkyl refers to an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group is replaced with a halogen atom.
- the alkyl portion of a haloalkyl group can have, for instance, 1 to 3 carbon atoms (i.e., Ci-C 3 haloalkyl).
- suitable haloalkyl groups include halofluoro groups, such as, but are not limited to, -CF 3 , -CHF 2 , -CFH 2 , -CH 2 CF 3 , and the like.
- haloalkoxy refers to a haloalkyl group bridged through an oxygen atom, such as seen in a trifluoromethoxy, 2,2,2-trifluoroethoxy, and 1 ,1- difluoroethoxy groups.
- aryl refers to an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
- an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms.
- Typical aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), benzyl (-CH 2 -phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like.
- aryl groups include phenyl, benzyl, and naphthyl groups.
- aryl refers to phenyl and benzyl substituents.
- heteroaryl refers to an aromatic heterocyclyl having at least one heteroatom in the ring.
- suitable heteroatoms which can be included in the aromatic ring include oxygen, sulfur, and nitrogen.
- suitable heteroatoms include oxygen, sulfur, and nitrogen.
- suitable heteroatoms include oxygen, sulfur, and nitrogen.
- Non-limiting examples of heteroaryl rings include aromatic rings pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, etc.
- pharmaceutically acceptable salt or “therapeutically acceptable salt” refer to a salt form of a compound of Formula (!) which is, within the scope of sound medical evaluation, suitable for use in contact with the tissues and organs of humans and/or animals such that any resulting toxicity, irritation, allergic response, and the like and are commensurate with a reasonable benefit/risk ratio.
- An additional step may be included to each of the processes herein that result in a compound of Formula (I) to produce a pharmaceutically acceptable salt of a compound of Formula (I).
- This may include, for example, salts with inorganic acids and salts with an organic acid.
- salts may include hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate (mesylate), benzenesuflonate (besylate), p-toluenesulfonate (tosylate), 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and alkanoate (such as acetate, HOOC--(CH 2 ) n --COOH where n is 0-4).
- the free base can be obtained by basifying a solution of the acid salt.
- an addition salt particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
- Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. These salts may be prepared by standard procedures, for example by reaction of the free acid with a suitable organic or inorganic base. Any chemical isotopic compound recited in this specification may alternatively be administered as a pharmaceutically acceptable salt thereof.
- compositions are also inclusive of the free acid, base, and zwitterionic forms of the disclosed isotopic compounds.
- Descriptions of exemplary pharmaceutically acceptable salts can be found in Stahl and Wermuth, Eds., Handbook of Pharmaceutical Salts; Properties, Selection and Use, Wiley VCH (2008).
- suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include, without limitation, alkaline, alkaline earth, ammonium, and quaternary ammonium cations.
- Such salts are known to those of skill in the art.
- isotopic compounds disclosed herein include a basic group such as an amino group
- suitable pharmaceutically acceptable anion pairs for the basic group are similarly well known and include halide, hydroxide, perhalate, halite, hypohalite, sulfate, sulfite, phosphate, phosphite, nitrate, nitrite, and others known to those of skill in the art.
- pharmacologically acceptable salts see Berge et al, J. Pharm. Sci. 66, 1 (1977).
Abstract
Description
Claims
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US17/998,018 US20230167065A1 (en) | 2020-05-11 | 2021-05-10 | Novel intermediates and synthesis for endochin-like quinolone compounds |
BR112022022984A BR112022022984A2 (en) | 2020-05-11 | 2021-05-10 | INTERMEDIATES AND SYNTHESIS FOR ENDOQUIN-TYPE QUINOLONE COMPOUNDS |
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US20140045888A1 (en) * | 2008-12-05 | 2014-02-13 | Oregon Health & Science University | Compounds having antiparasitic or anti-infectious activity |
US20190031613A1 (en) * | 2016-01-22 | 2019-01-31 | University Of South Florida | Compounds and methods for their use in the treatment of malaria |
US20190202766A1 (en) * | 2016-06-20 | 2019-07-04 | The California Institute For Biomedical | Antimalarial compositions and uses thereof |
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- 2021-05-10 US US17/998,018 patent/US20230167065A1/en active Pending
- 2021-05-10 EP EP21804723.1A patent/EP4149510A1/en active Pending
- 2021-05-10 WO PCT/US2021/031651 patent/WO2021231335A1/en unknown
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US20140045888A1 (en) * | 2008-12-05 | 2014-02-13 | Oregon Health & Science University | Compounds having antiparasitic or anti-infectious activity |
US20190031613A1 (en) * | 2016-01-22 | 2019-01-31 | University Of South Florida | Compounds and methods for their use in the treatment of malaria |
US20190202766A1 (en) * | 2016-06-20 | 2019-07-04 | The California Institute For Biomedical | Antimalarial compositions and uses thereof |
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EP4149510A1 (en) | 2023-03-22 |
US20230167065A1 (en) | 2023-06-01 |
BR112022022984A2 (en) | 2022-12-20 |
AR125006A1 (en) | 2023-05-31 |
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