BR112019009293A2 - pirrol amidas como inibidores de integrina alfa v - Google Patents

Info

Publication number

BR112019009293A2

BR112019009293A2 BR112019009293A BR112019009293A BR112019009293A2 BR 112019009293 A2 BR112019009293 A2 BR 112019009293A2 BR 112019009293 A BR112019009293 A BR 112019009293A BR 112019009293 A BR112019009293 A BR 112019009293A BR 112019009293 A2 BR112019009293 A2 BR 112019009293A2

Authority

BR

Brazil

Prior art keywords

alkyl

membered

heterocyclyl

carbocyclyl

petition

Prior art date

2016-11-08

Links

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• Global Dossier
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• -1 pyrrol amides Chemical class 0.000 title claims description 199
• 102000006495 integrins Human genes 0.000 title abstract description 30
• 108010044426 integrins Proteins 0.000 title abstract description 30
• 239000003112 inhibitor Substances 0.000 title abstract description 21
• KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 title description 17
• 150000001875 compounds Chemical class 0.000 claims abstract description 147
• 150000003839 salts Chemical class 0.000 claims abstract description 44
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 23
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 19
• 206010016654 Fibrosis Diseases 0.000 claims abstract description 17
• 230000004761 fibrosis Effects 0.000 claims abstract description 17
• 201000011510 cancer Diseases 0.000 claims abstract description 13
• 208000027866 inflammatory disease Diseases 0.000 claims abstract description 9
• 230000001575 pathological effect Effects 0.000 claims abstract description 7
• 208000001132 Osteoporosis Diseases 0.000 claims abstract description 3
• 206010052779 Transplant rejections Diseases 0.000 claims abstract 2
• 125000000217 alkyl group Chemical group 0.000 claims description 88
• 125000000623 heterocyclic group Chemical group 0.000 claims description 70
• 125000003118 aryl group Chemical group 0.000 claims description 52
• 125000004452 carbocyclyl group Chemical group 0.000 claims description 47
• 229910052739 hydrogen Inorganic materials 0.000 claims description 43
• 125000003545 alkoxy group Chemical group 0.000 claims description 41
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 41
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 41
• 239000003814 drug Substances 0.000 claims description 40
• 125000001072 heteroaryl group Chemical group 0.000 claims description 37
• 125000001188 haloalkyl group Chemical group 0.000 claims description 36
• 125000005843 halogen group Chemical group 0.000 claims description 35
• 239000001257 hydrogen Substances 0.000 claims description 32
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 29
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 27
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 27
• 229940124530 sulfonamide Drugs 0.000 claims description 27
• 150000003456 sulfonamides Chemical class 0.000 claims description 27
• 229920002472 Starch Polymers 0.000 claims description 24
• 239000008107 starch Substances 0.000 claims description 24
• 235000019698 starch Nutrition 0.000 claims description 24
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 22
• 125000004429 atom Chemical group 0.000 claims description 22
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
• 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 18
• 239000004475 Arginine Substances 0.000 claims description 17
• 125000002947 alkylene group Chemical group 0.000 claims description 17
• ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 17
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
• 229910052717 sulfur Inorganic materials 0.000 claims description 15
• 229910052760 oxygen Inorganic materials 0.000 claims description 14
• 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 13
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 13
• 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 13
• 125000004043 oxo group Chemical group O=* 0.000 claims description 12
• 229940079593 drug Drugs 0.000 claims description 11
• 238000004519 manufacturing process Methods 0.000 claims description 11
• 239000000463 material Substances 0.000 claims description 10
• 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 10
• 125000003282 alkyl amino group Chemical group 0.000 claims description 8
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
• 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 7
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 7
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
• 201000009594 Systemic Scleroderma Diseases 0.000 claims description 6
• 206010042953 Systemic sclerosis Diseases 0.000 claims description 6
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
• 125000005884 carbocyclylalkyl group Chemical group 0.000 claims description 6
• 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 6
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
• 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 4
• 208000033679 diabetic kidney disease Diseases 0.000 claims description 4
• 230000002440 hepatic effect Effects 0.000 claims description 4
• 210000004185 liver Anatomy 0.000 claims description 4
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
• 210000004369 blood Anatomy 0.000 claims description 3
• 239000008280 blood Substances 0.000 claims description 3
• 208000020832 chronic kidney disease Diseases 0.000 claims description 3
• 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 3
• 210000003734 kidney Anatomy 0.000 claims description 3
• 210000004072 lung Anatomy 0.000 claims description 3
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
• 210000002784 stomach Anatomy 0.000 claims description 3
• 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 2
• 210000000988 bone and bone Anatomy 0.000 claims description 2
• 210000004556 brain Anatomy 0.000 claims description 2
• 210000000481 breast Anatomy 0.000 claims description 2
• 230000000747 cardiac effect Effects 0.000 claims description 2
• 210000003169 central nervous system Anatomy 0.000 claims description 2
• 210000003679 cervix uteri Anatomy 0.000 claims description 2
• 210000001072 colon Anatomy 0.000 claims description 2
• 230000002500 effect on skin Effects 0.000 claims description 2
• 210000004696 endometrium Anatomy 0.000 claims description 2
• 210000003238 esophagus Anatomy 0.000 claims description 2
• 210000000232 gallbladder Anatomy 0.000 claims description 2
• 210000004392 genitalia Anatomy 0.000 claims description 2
• 210000003128 head Anatomy 0.000 claims description 2
• 210000002429 large intestine Anatomy 0.000 claims description 2
• 210000000867 larynx Anatomy 0.000 claims description 2
• 210000002200 mouth mucosa Anatomy 0.000 claims description 2
• 210000003205 muscle Anatomy 0.000 claims description 2
• 210000002850 nasal mucosa Anatomy 0.000 claims description 2
• 210000003739 neck Anatomy 0.000 claims description 2
• 210000001672 ovary Anatomy 0.000 claims description 2
• 210000000496 pancreas Anatomy 0.000 claims description 2
• 210000002307 prostate Anatomy 0.000 claims description 2
• 230000002685 pulmonary effect Effects 0.000 claims description 2
• 210000003491 skin Anatomy 0.000 claims description 2
• 210000000813 small intestine Anatomy 0.000 claims description 2
• SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 2
• 210000000952 spleen Anatomy 0.000 claims description 2
• 210000001550 testis Anatomy 0.000 claims description 2
• 210000001685 thyroid gland Anatomy 0.000 claims description 2
• 210000003932 urinary bladder Anatomy 0.000 claims description 2
• 150000002431 hydrogen Chemical class 0.000 claims 5
• 238000000034 method Methods 0.000 abstract description 115
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 53
• 239000000203 mixture Substances 0.000 abstract description 35
• 208000035475 disorder Diseases 0.000 abstract description 34
• 239000012453 solvate Substances 0.000 abstract description 22
• 201000010099 disease Diseases 0.000 abstract description 18
• 230000008482 dysregulation Effects 0.000 abstract description 3
• 239000000543 intermediate Substances 0.000 description 97
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 94
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 88
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 84
• 238000005481 NMR spectroscopy Methods 0.000 description 82
• 238000004128 high performance liquid chromatography Methods 0.000 description 51
• HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 47
• 230000014759 maintenance of location Effects 0.000 description 43
• 239000000243 solution Substances 0.000 description 41
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
• 239000007787 solid Substances 0.000 description 33
• 239000002253 acid Substances 0.000 description 32
• 239000011541 reaction mixture Substances 0.000 description 31
• 239000002904 solvent Substances 0.000 description 29
• 238000006243 chemical reaction Methods 0.000 description 26
• 150000002148 esters Chemical class 0.000 description 26
• 125000004432 carbon atom Chemical group C* 0.000 description 25
• 238000011282 treatment Methods 0.000 description 24
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
• 229910052757 nitrogen Inorganic materials 0.000 description 22
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
• 229940124597 therapeutic agent Drugs 0.000 description 21
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 21
• YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
• 239000000651 prodrug Substances 0.000 description 20
• 229940002612 prodrug Drugs 0.000 description 20
• 229910052799 carbon Inorganic materials 0.000 description 19
• 125000001424 substituent group Chemical group 0.000 description 19
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
• RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
• 235000019439 ethyl acetate Nutrition 0.000 description 17
• ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 15
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
• 238000010511 deprotection reaction Methods 0.000 description 13
• 238000003818 flash chromatography Methods 0.000 description 13
• 239000012071 phase Substances 0.000 description 13
• 238000002360 preparation method Methods 0.000 description 13
• 239000000741 silica gel Substances 0.000 description 13
• 229910002027 silica gel Inorganic materials 0.000 description 13
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 12
• 238000001914 filtration Methods 0.000 description 12
• 125000005842 heteroatom Chemical group 0.000 description 12
• 229920006395 saturated elastomer Polymers 0.000 description 12
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
• 239000004480 active ingredient Substances 0.000 description 11
• 150000001721 carbon Chemical group 0.000 description 11
• 239000003153 chemical reaction reagent Substances 0.000 description 11
• WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical compound OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 description 11
• 238000004808 supercritical fluid chromatography Methods 0.000 description 11
• 210000004027 cell Anatomy 0.000 description 10
• 230000003176 fibrotic effect Effects 0.000 description 10
• 239000000706 filtrate Substances 0.000 description 10
• 125000004433 nitrogen atom Chemical group N* 0.000 description 10
• 239000012044 organic layer Substances 0.000 description 10
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
• 238000003786 synthesis reaction Methods 0.000 description 10
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
• 239000003921 oil Substances 0.000 description 9
• 235000019198 oils Nutrition 0.000 description 9
• 239000011734 sodium Substances 0.000 description 9
• 239000000126 substance Substances 0.000 description 9
• 230000009466 transformation Effects 0.000 description 9
• 239000012267 brine Substances 0.000 description 8
• 239000003937 drug carrier Substances 0.000 description 8
• 125000004404 heteroalkyl group Chemical group 0.000 description 8
• 125000002950 monocyclic group Chemical group 0.000 description 8
• 239000002244 precipitate Substances 0.000 description 8
• 230000002062 proliferating effect Effects 0.000 description 8
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 7
• XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 7
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
• 230000015572 biosynthetic process Effects 0.000 description 7
• 239000003795 chemical substances by application Substances 0.000 description 7
• 239000000460 chlorine Substances 0.000 description 7
• 229910052801 chlorine Inorganic materials 0.000 description 7
• 230000008878 coupling Effects 0.000 description 7
• 238000010168 coupling process Methods 0.000 description 7
• 238000005859 coupling reaction Methods 0.000 description 7
• 229910052731 fluorine Inorganic materials 0.000 description 7
• VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
• 238000002953 preparative HPLC Methods 0.000 description 7
• 239000000725 suspension Substances 0.000 description 7
• 238000012360 testing method Methods 0.000 description 7
• 238000000844 transformation Methods 0.000 description 7
• WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 6
• USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 6
• 239000005695 Ammonium acetate Substances 0.000 description 6
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
• DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
• 239000000556 agonist Substances 0.000 description 6
• 235000019257 ammonium acetate Nutrition 0.000 description 6
• 229940043376 ammonium acetate Drugs 0.000 description 6
• 238000003556 assay Methods 0.000 description 6
• 239000002585 base Substances 0.000 description 6
• 229910052796 boron Inorganic materials 0.000 description 6
• 125000002837 carbocyclic group Chemical group 0.000 description 6
• 230000000694 effects Effects 0.000 description 6
• 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 6
• 238000002347 injection Methods 0.000 description 6
• 239000007924 injection Substances 0.000 description 6
• DOYOPBSXEIZLRE-UHFFFAOYSA-N pyrrole-3-carboxylic acid Natural products OC(=O)C=1C=CNC=1 DOYOPBSXEIZLRE-UHFFFAOYSA-N 0.000 description 6
• 125000001544 thienyl group Chemical group 0.000 description 6
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
• 238000005406 washing Methods 0.000 description 6
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
• 125000003342 alkenyl group Chemical group 0.000 description 5
• 125000004448 alkyl carbonyl group Chemical group 0.000 description 5
• 230000003042 antagnostic effect Effects 0.000 description 5
• 125000002618 bicyclic heterocycle group Chemical group 0.000 description 5
• 150000001733 carboxylic acid esters Chemical class 0.000 description 5
• HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 5
• 229910052736 halogen Inorganic materials 0.000 description 5
• 150000002367 halogens Chemical class 0.000 description 5
• 229910052740 iodine Inorganic materials 0.000 description 5
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 5
• 125000004430 oxygen atom Chemical group O* 0.000 description 5
• 230000008569 process Effects 0.000 description 5
• 239000000047 product Substances 0.000 description 5
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
• 125000004076 pyridyl group Chemical group 0.000 description 5
• 238000002560 therapeutic procedure Methods 0.000 description 5
• 239000003981 vehicle Substances 0.000 description 5
• ZCZVGQCBSJLDDS-UHFFFAOYSA-N 1,2,3,4-tetrahydro-1,8-naphthyridine Chemical class C1=CC=C2CCCNC2=N1 ZCZVGQCBSJLDDS-UHFFFAOYSA-N 0.000 description 4
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
• PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 4
• ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 4
• NXMFJCRMSDRXLD-UHFFFAOYSA-N 2-aminopyridine-3-carbaldehyde Chemical compound NC1=NC=CC=C1C=O NXMFJCRMSDRXLD-UHFFFAOYSA-N 0.000 description 4
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
• OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
• 150000001204 N-oxides Chemical class 0.000 description 4
• 229910017917 NH4 Cl Inorganic materials 0.000 description 4
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
• 102000004887 Transforming Growth Factor beta Human genes 0.000 description 4
• 108090001012 Transforming Growth Factor beta Proteins 0.000 description 4
• 239000013543 active substance Substances 0.000 description 4
• 238000007605 air drying Methods 0.000 description 4
• 125000001931 aliphatic group Chemical group 0.000 description 4
• 125000004414 alkyl thio group Chemical group 0.000 description 4
• 125000000304 alkynyl group Chemical group 0.000 description 4
• 150000001412 amines Chemical class 0.000 description 4
• 150000003927 aminopyridines Chemical class 0.000 description 4
• 229910021529 ammonia Inorganic materials 0.000 description 4
• 125000004104 aryloxy group Chemical group 0.000 description 4
• 125000002527 bicyclic carbocyclic group Chemical group 0.000 description 4
• 229910052794 bromium Inorganic materials 0.000 description 4
• 229910002091 carbon monoxide Inorganic materials 0.000 description 4
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
• 208000019425 cirrhosis of liver Diseases 0.000 description 4
• 239000012043 crude product Substances 0.000 description 4
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
• NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 4
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
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