CA2585353A1

CA2585353A1 - Phosphonate derivatives of mycophenolic acid

Phosphonate derivatives of mycophenolic acid Download PDF

Info

Publication number: CA2585353A1
Authority: CA; Canada
Prior art keywords: compound; formula; alkyl; independently; substituted
Prior art date: 2004-10-26
Legal status : Abandoned

Application number

CA002585353A

Other languages

English (en)

French (fr)

Inventor

William J. Watkins

Aesop Cho

Current Assignee

Gilead Sciences Inc

Original Assignee

Individual

Priority date

2004-10-26

Filing date

2005-10-26

Publication date

2006-05-04

2005-10-26 Application filed by Individual filed Critical Individual

2006-05-04 Publication of CA2585353A1 publication Critical patent/CA2585353A1/en

Status Abandoned legal-status Critical Current

Links

HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 title abstract description 12
ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 title description 46
229960000951 mycophenolic acid Drugs 0.000 title description 10
-1 mycophenolate oxime Chemical class 0.000 claims abstract description 338
239000000203 mixture Substances 0.000 claims abstract description 124
239000003814 drug Substances 0.000 claims abstract description 43
206010061218 Inflammation Diseases 0.000 claims abstract description 30
206010028980 Neoplasm Diseases 0.000 claims abstract description 29
238000011282 treatment Methods 0.000 claims abstract description 29
210000000056 organ Anatomy 0.000 claims abstract description 28
230000004054 inflammatory process Effects 0.000 claims abstract description 27
206010052779 Transplant rejections Diseases 0.000 claims abstract description 18
230000009385 viral infection Effects 0.000 claims abstract description 18
201000011510 cancer Diseases 0.000 claims abstract description 17
208000036142 Viral infection Diseases 0.000 claims abstract description 16
230000002265 prevention Effects 0.000 claims abstract description 10
230000004614 tumor growth Effects 0.000 claims abstract description 9
150000001875 compounds Chemical class 0.000 claims description 447
238000000034 method Methods 0.000 claims description 208
125000000217 alkyl group Chemical group 0.000 claims description 141
UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 98
125000004432 carbon atom Chemical group C* 0.000 claims description 83
229910052760 oxygen Inorganic materials 0.000 claims description 78
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 60
229910052757 nitrogen Inorganic materials 0.000 claims description 60
239000004480 active ingredient Substances 0.000 claims description 58
239000001257 hydrogen Substances 0.000 claims description 54
229910052739 hydrogen Inorganic materials 0.000 claims description 54
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 54
125000003118 aryl group Chemical group 0.000 claims description 49
238000009472 formulation Methods 0.000 claims description 49
125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 48
125000006239 protecting group Chemical group 0.000 claims description 47
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 42
125000000623 heterocyclic group Chemical group 0.000 claims description 42
229910052717 sulfur Inorganic materials 0.000 claims description 41
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 38
125000005843 halogen group Chemical group 0.000 claims description 32
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 28
230000000694 effects Effects 0.000 claims description 27
229920002554 vinyl polymer Polymers 0.000 claims description 27
241001465754 Metazoa Species 0.000 claims description 24
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 24
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 23
125000003710 aryl alkyl group Chemical group 0.000 claims description 21
238000001727 in vivo Methods 0.000 claims description 21
241000700605 Viruses Species 0.000 claims description 18
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 18
229910052799 carbon Inorganic materials 0.000 claims description 18
125000005842 heteroatom Chemical group 0.000 claims description 18
239000001301 oxygen Substances 0.000 claims description 18
125000003342 alkenyl group Chemical group 0.000 claims description 17
125000002947 alkylene group Chemical group 0.000 claims description 16
230000002401 inhibitory effect Effects 0.000 claims description 16
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
125000003107 substituted aryl group Chemical group 0.000 claims description 15
125000000547 substituted alkyl group Chemical group 0.000 claims description 14
125000003545 alkoxy group Chemical group 0.000 claims description 12
239000003937 drug carrier Substances 0.000 claims description 12
239000008194 pharmaceutical composition Substances 0.000 claims description 12
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 11
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 10
229920006395 saturated elastomer Polymers 0.000 claims description 10
239000011593 sulfur Chemical group 0.000 claims description 10
229910052794 bromium Inorganic materials 0.000 claims description 9
125000001188 haloalkyl group Chemical group 0.000 claims description 9
208000024891 symptom Diseases 0.000 claims description 9
125000002252 acyl group Chemical group 0.000 claims description 8
125000000304 alkynyl group Chemical group 0.000 claims description 8
229910052801 chlorine Inorganic materials 0.000 claims description 8
239000002552 dosage form Substances 0.000 claims description 8
229910052731 fluorine Inorganic materials 0.000 claims description 8
229910052740 iodine Inorganic materials 0.000 claims description 8
125000004429 atom Chemical group 0.000 claims description 7
125000000753 cycloalkyl group Chemical group 0.000 claims description 7
125000004437 phosphorous atom Chemical group 0.000 claims description 7
229910052736 halogen Inorganic materials 0.000 claims description 6
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
125000004663 dialkyl amino group Chemical group 0.000 claims description 5
125000004442 acylamino group Chemical group 0.000 claims description 3
125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 2
125000002837 carbocyclic group Chemical group 0.000 claims description 2
125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims description 2
125000004001 thioalkyl group Chemical group 0.000 claims description 2
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 abstract description 13
230000001093 anti-cancer Effects 0.000 abstract description 7
230000000840 anti-viral effect Effects 0.000 abstract description 7
238000003556 assay Methods 0.000 abstract description 6
229910052698 phosphorus Inorganic materials 0.000 abstract description 6
230000003110 anti-inflammatory effect Effects 0.000 abstract description 5
230000012010 growth Effects 0.000 abstract description 3
239000011574 phosphorus Substances 0.000 abstract description 3
238000001514 detection method Methods 0.000 abstract description 2
229940014456 mycophenolate Drugs 0.000 abstract description 2
230000003612 virological effect Effects 0.000 abstract description 2
239000000047 product Substances 0.000 description 127
238000006243 chemical reaction Methods 0.000 description 122
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 91
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 64
238000002360 preparation method Methods 0.000 description 54
239000000651 prodrug Substances 0.000 description 53
229940002612 prodrug Drugs 0.000 description 53
150000002148 esters Chemical class 0.000 description 48
229940024606 amino acid Drugs 0.000 description 46
235000001014 amino acid Nutrition 0.000 description 45
150000001413 amino acids Chemical class 0.000 description 45
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 43
239000000243 solution Substances 0.000 description 41
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
239000002585 base Substances 0.000 description 36
108090000765 processed proteins & peptides Proteins 0.000 description 36
102000004196 processed proteins & peptides Human genes 0.000 description 34
239000000543 intermediate Substances 0.000 description 33
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 32
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 32
229940079593 drug Drugs 0.000 description 30
229920001184 polypeptide Polymers 0.000 description 30
239000002253 acid Substances 0.000 description 29
210000004027 cell Anatomy 0.000 description 29
150000003839 salts Chemical class 0.000 description 29
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
238000003786 synthesis reaction Methods 0.000 description 28
150000005690 diesters Chemical class 0.000 description 27
150000001412 amines Chemical class 0.000 description 25
210000001519 tissue Anatomy 0.000 description 25
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
230000015572 biosynthetic process Effects 0.000 description 24
239000002904 solvent Substances 0.000 description 24
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 23
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 23
125000002887 hydroxy group Chemical group [H]O* 0.000 description 23
239000003153 chemical reaction reagent Substances 0.000 description 22
125000000524 functional group Chemical group 0.000 description 22
DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 22
125000001424 substituent group Chemical group 0.000 description 21
OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 20
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 20
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
230000002378 acidificating effect Effects 0.000 description 19
238000003776 cleavage reaction Methods 0.000 description 19
238000004007 reversed phase HPLC Methods 0.000 description 19
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
150000003009 phosphonic acids Chemical class 0.000 description 18
230000007017 scission Effects 0.000 description 18
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 18
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 18
YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
229940059260 amidate Drugs 0.000 description 16
239000003795 chemical substances by application Substances 0.000 description 16
239000000463 material Substances 0.000 description 16
KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 15
102000004190 Enzymes Human genes 0.000 description 15
108090000790 Enzymes Proteins 0.000 description 15
150000004657 carbamic acid derivatives Chemical class 0.000 description 15
238000005859 coupling reaction Methods 0.000 description 15
239000000126 substance Substances 0.000 description 15
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 14
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 description 14
HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 14
125000006413 ring segment Chemical group 0.000 description 14
238000006460 hydrolysis reaction Methods 0.000 description 13
150000002440 hydroxy compounds Chemical class 0.000 description 13
239000003112 inhibitor Substances 0.000 description 13
239000003960 organic solvent Substances 0.000 description 13
239000003826 tablet Substances 0.000 description 13
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 13
OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 12
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
241000282414 Homo sapiens Species 0.000 description 12
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
125000000539 amino acid group Chemical group 0.000 description 12
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 12
230000007062 hydrolysis Effects 0.000 description 12
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
239000000546 pharmaceutical excipient Substances 0.000 description 12
230000008569 process Effects 0.000 description 12
239000000523 sample Substances 0.000 description 12
238000000926 separation method Methods 0.000 description 12
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 11
150000001408 amides Chemical class 0.000 description 11
239000007788 liquid Substances 0.000 description 11
239000002207 metabolite Substances 0.000 description 11
210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 11
XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 11
238000004587 chromatography analysis Methods 0.000 description 10
230000002255 enzymatic effect Effects 0.000 description 10
ROBXZHNBBCHEIQ-BYPYZUCNSA-N ethyl (2s)-2-aminopropanoate Chemical compound CCOC(=O)[C@H](C)N ROBXZHNBBCHEIQ-BYPYZUCNSA-N 0.000 description 10
230000003834 intracellular effect Effects 0.000 description 10
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 10
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
239000000376 reactant Substances 0.000 description 10
239000000758 substrate Substances 0.000 description 10
230000001225 therapeutic effect Effects 0.000 description 10
101150041968 CDC13 gene Proteins 0.000 description 9
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
230000008878 coupling Effects 0.000 description 9
238000010168 coupling process Methods 0.000 description 9
239000003921 oil Substances 0.000 description 9
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 8
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
238000006751 Mitsunobu reaction Methods 0.000 description 8
150000007513 acids Chemical class 0.000 description 8
125000003158 alcohol group Chemical group 0.000 description 8
239000012620 biological material Substances 0.000 description 8
210000004369 blood Anatomy 0.000 description 8
239000008280 blood Substances 0.000 description 8
239000007822 coupling agent Substances 0.000 description 8
235000014113 dietary fatty acids Nutrition 0.000 description 8
125000004185 ester group Chemical group 0.000 description 8
LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 description 8
229930195729 fatty acid Natural products 0.000 description 8
239000000194 fatty acid Substances 0.000 description 8
150000004665 fatty acids Chemical class 0.000 description 8
BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 8
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
235000019198 oils Nutrition 0.000 description 8
230000003287 optical effect Effects 0.000 description 8
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
235000018102 proteins Nutrition 0.000 description 8
102000004169 proteins and genes Human genes 0.000 description 8
108090000623 proteins and genes Proteins 0.000 description 8
PXAJQJMDEXJWFB-UHFFFAOYSA-N acetone oxime Chemical compound CC(C)=NO PXAJQJMDEXJWFB-UHFFFAOYSA-N 0.000 description 7
150000008064 anhydrides Chemical class 0.000 description 7
ITVPBBDAZKBMRP-UHFFFAOYSA-N chloro-dioxido-oxo-$l^{5}-phosphane;hydron Chemical compound OP(O)(Cl)=O ITVPBBDAZKBMRP-UHFFFAOYSA-N 0.000 description 7
239000000839 emulsion Substances 0.000 description 7
125000002883 imidazolyl group Chemical group 0.000 description 7
238000000338 in vitro Methods 0.000 description 7
239000004615 ingredient Substances 0.000 description 7
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 7
RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 7
239000002777 nucleoside Substances 0.000 description 7
150000007530 organic bases Chemical group 0.000 description 7
239000000725 suspension Substances 0.000 description 7
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
PRXGMEURJXGKOP-UHFFFAOYSA-N NP(N)=O Chemical class NP(N)=O PRXGMEURJXGKOP-UHFFFAOYSA-N 0.000 description 6
XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 6
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
HAXFWIACAGNFHA-UHFFFAOYSA-N aldrithiol Chemical compound C=1C=CC=NC=1SSC1=CC=CC=N1 HAXFWIACAGNFHA-UHFFFAOYSA-N 0.000 description 6
XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 6
150000001718 carbodiimides Chemical class 0.000 description 6
239000000969 carrier Substances 0.000 description 6
239000003054 catalyst Substances 0.000 description 6
239000006071 cream Substances 0.000 description 6
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
238000006073 displacement reaction Methods 0.000 description 6
239000003995 emulsifying agent Substances 0.000 description 6
125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 6
239000000796 flavoring agent Substances 0.000 description 6
210000001035 gastrointestinal tract Anatomy 0.000 description 6
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 6
230000002503 metabolic effect Effects 0.000 description 6
230000004048 modification Effects 0.000 description 6
238000012986 modification Methods 0.000 description 6
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
239000012044 organic layer Substances 0.000 description 6
230000003647 oxidation Effects 0.000 description 6
238000007254 oxidation reaction Methods 0.000 description 6
239000012071 phase Substances 0.000 description 6
239000000843 powder Substances 0.000 description 6
239000002243 precursor Substances 0.000 description 6
150000003254 radicals Chemical class 0.000 description 6
238000006722 reduction reaction Methods 0.000 description 6
239000007858 starting material Substances 0.000 description 6
239000003765 sweetening agent Substances 0.000 description 6
230000008685 targeting Effects 0.000 description 6
230000032258 transport Effects 0.000 description 6
238000012384 transportation and delivery Methods 0.000 description 6
125000004400 (C1-C12) alkyl group Chemical group 0.000 description 5
NFDXQGNDWIPXQL-UHFFFAOYSA-N 1-cyclooctyldiazocane Chemical compound C1CCCCCCC1N1NCCCCCC1 NFDXQGNDWIPXQL-UHFFFAOYSA-N 0.000 description 5
238000005160 1H NMR spectroscopy Methods 0.000 description 5
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 5
SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
238000005481 NMR spectroscopy Methods 0.000 description 5
229910019142 PO4 Inorganic materials 0.000 description 5
ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 5
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical group CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 5
AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 5
239000013543 active substance Substances 0.000 description 5
238000005804 alkylation reaction Methods 0.000 description 5
125000003277 amino group Chemical group 0.000 description 5
239000007900 aqueous suspension Substances 0.000 description 5
230000037396 body weight Effects 0.000 description 5
150000001721 carbon Chemical group 0.000 description 5
150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
230000003197 catalytic effect Effects 0.000 description 5
238000002648 combination therapy Methods 0.000 description 5
125000004093 cyano group Chemical group *C#N 0.000 description 5
239000012973 diazabicyclooctane Substances 0.000 description 5
201000010099 disease Diseases 0.000 description 5
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