CA3025866A1

CA3025866A1 - Alpha-d-galactoside inhibitors of galectins

Alpha-d-galactoside inhibitors of galectins Download PDF

Info

Publication number: CA3025866A1
Authority: CA; Canada
Prior art keywords: deoxy; galactopyranoside; thio; triazol; optionally substituted
Prior art date: 2016-07-12
Legal status : Pending

Application number

CA3025866A

Other languages

English (en)

French (fr)

Inventor

Fredrik Zetterberg

Hakon Leffler

Ulf Nilsson

Current Assignee

Galecto Biotech AB

Original Assignee

Galecto Biotech AB

Priority date

2016-07-12

Filing date

2017-07-09

Publication date

2018-01-18

2017-07-09 Application filed by Galecto Biotech AB filed Critical Galecto Biotech AB

2018-01-18 Publication of CA3025866A1 publication Critical patent/CA3025866A1/en

Status Pending legal-status Critical Current

Links

WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 title claims description 16
102000007563 Galectins Human genes 0.000 title abstract description 53
108010046569 Galectins Proteins 0.000 title abstract description 53
239000003112 inhibitor Substances 0.000 title description 35
150000001875 compounds Chemical class 0.000 claims abstract description 242
108010001498 Galectin 1 Proteins 0.000 claims abstract description 58
238000000034 method Methods 0.000 claims abstract description 35
238000011282 treatment Methods 0.000 claims abstract description 24
239000003446 ligand Substances 0.000 claims abstract description 17
241000124008 Mammalia Species 0.000 claims abstract description 16
230000027455 binding Effects 0.000 claims abstract description 13
102000000795 Galectin 1 Human genes 0.000 claims abstract 4
-1 D-galactopyranose compound Chemical class 0.000 claims description 63
125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 60
229910052736 halogen Inorganic materials 0.000 claims description 59
150000002367 halogens Chemical class 0.000 claims description 59
206010028980 Neoplasm Diseases 0.000 claims description 54
125000000217 alkyl group Chemical group 0.000 claims description 50
201000011510 cancer Diseases 0.000 claims description 35
125000001424 substituent group Chemical group 0.000 claims description 29
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 27
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 25
125000001072 heteroaryl group Chemical group 0.000 claims description 23
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 21
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 21
206010016654 Fibrosis Diseases 0.000 claims description 20
230000004761 fibrosis Effects 0.000 claims description 20
239000003814 drug Substances 0.000 claims description 17
125000004076 pyridyl group Chemical group 0.000 claims description 17
239000008194 pharmaceutical composition Substances 0.000 claims description 16
230000033115 angiogenesis Effects 0.000 claims description 15
208000035475 disorder Diseases 0.000 claims description 15
229910052801 chlorine Inorganic materials 0.000 claims description 12
201000010099 disease Diseases 0.000 claims description 12
229910052794 bromium Inorganic materials 0.000 claims description 11
206010029113 Neovascularisation Diseases 0.000 claims description 10
125000000623 heterocyclic group Chemical group 0.000 claims description 10
208000030159 metabolic disease Diseases 0.000 claims description 10
125000000592 heterocycloalkyl group Chemical group 0.000 claims description 9
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150000003839 salts Chemical class 0.000 claims description 8
206010025323 Lymphomas Diseases 0.000 claims description 7
125000003118 aryl group Chemical group 0.000 claims description 7
229910052731 fluorine Inorganic materials 0.000 claims description 7
239000012453 solvate Substances 0.000 claims description 7
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208000031737 Tissue Adhesions Diseases 0.000 claims description 6
206010052779 Transplant rejections Diseases 0.000 claims description 6
230000001594 aberrant effect Effects 0.000 claims description 6
125000004432 carbon atom Chemical group C* 0.000 claims description 6
208000030533 eye disease Diseases 0.000 claims description 6
208000011379 keloid formation Diseases 0.000 claims description 6
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
230000036573 scar formation Effects 0.000 claims description 6
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206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 5
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208000011231 Crohn disease Diseases 0.000 claims description 5
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208000006933 Hermanski-Pudlak Syndrome Diseases 0.000 claims description 5
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206010039710 Scleroderma Diseases 0.000 claims description 5
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206010040070 Septic Shock Diseases 0.000 claims description 5
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208000002780 macular degeneration Diseases 0.000 claims description 5
125000001624 naphthyl group Chemical group 0.000 claims description 5
208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 5
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239000000654 additive Substances 0.000 claims description 4
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125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims description 3
150000003214 pyranose derivatives Chemical group 0.000 claims description 3
229910052799 carbon Inorganic materials 0.000 claims description 2
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 3
RETCGUYVIXHAIY-YNIRGQLTSA-N (2R,3R,4S,5R,6R)-2-(3,4-dichlorophenyl)sulfanyl-6-(hydroxymethyl)-4-[4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]triazol-1-yl]oxane-3,5-diol Chemical compound OC[C@H]1O[C@H](SC2=CC(Cl)=C(Cl)C=C2)[C@H](O)[C@H]([C@H]1O)N1C=C(N=N1)C1=NC(=CS1)C(F)(F)F RETCGUYVIXHAIY-YNIRGQLTSA-N 0.000 claims 1
PUBCIQPVAYGFEN-UVLCOCDESA-N (2R,3R,4S,5R,6R)-2-(3,5-dichloro-4-fluorophenyl)sulfanyl-6-(hydroxymethyl)-4-[4-(1,3-thiazol-4-yl)triazol-1-yl]oxane-3,5-diol Chemical compound OC[C@H]1O[C@H](SC2=CC(Cl)=C(F)C(Cl)=C2)[C@H](O)[C@H]([C@H]1O)N1C=C(N=N1)C1=CSC=N1 PUBCIQPVAYGFEN-UVLCOCDESA-N 0.000 claims 1
ANVSQEIVWHEGGC-WZYWGQKZSA-N (2R,3R,4S,5R,6R)-2-(5-bromopyridin-3-yl)sulfanyl-6-(hydroxymethyl)-4-[4-(1,3-thiazol-2-yl)triazol-1-yl]oxane-3,5-diol Chemical compound OC[C@H]1O[C@H](SC2=CC(Br)=CN=C2)[C@H](O)[C@H]([C@H]1O)N1C=C(N=N1)C1=NC=CS1 ANVSQEIVWHEGGC-WZYWGQKZSA-N 0.000 claims 1
UQIQKTGRGJCQQJ-DRRXZNNHSA-N (2R,3R,4S,5R,6R)-2-(5-bromopyridin-3-yl)sulfanyl-6-(hydroxymethyl)-4-[4-(2-methyl-1,3-thiazol-4-yl)triazol-1-yl]oxane-3,5-diol Chemical compound CC1=NC(=CS1)C1=CN(N=N1)[C@H]1[C@@H](O)[C@@H](CO)O[C@H](SC2=CC(Br)=CN=C2)[C@@H]1O UQIQKTGRGJCQQJ-DRRXZNNHSA-N 0.000 claims 1
LWZXKSIPVXQFGN-YNIRGQLTSA-N (2R,3R,4S,5R,6R)-4-[4-(4-bromo-1,3-thiazol-2-yl)triazol-1-yl]-2-(3,4-dichlorophenyl)sulfanyl-6-(hydroxymethyl)oxane-3,5-diol Chemical compound OC[C@H]1O[C@H](SC2=CC(Cl)=C(Cl)C=C2)[C@H](O)[C@H]([C@H]1O)N1C=C(N=N1)C1=NC(Br)=CS1 LWZXKSIPVXQFGN-YNIRGQLTSA-N 0.000 claims 1
DQGVHLYQXAQQBT-AHXITHOBSA-N (2R,4S,5R)-2-(2,5-dichlorophenyl)sulfanyl-6-(hydroxymethyl)-4-[4-(1,3-thiazol-2-yl)triazol-1-yl]oxane-3,5-diol Chemical compound C1=CC(=C(C=C1Cl)S[C@@H]2C([C@H]([C@H](C(O2)CO)O)N3C=C(N=N3)C4=NC=CS4)O)Cl DQGVHLYQXAQQBT-AHXITHOBSA-N 0.000 claims 1
ISLKHLAJYHLAKA-AHXITHOBSA-N (2R,4S,5R)-2-(3,4-dichlorophenyl)sulfanyl-4-[4-(5-fluoro-1,3-thiazol-2-yl)triazol-1-yl]-6-(hydroxymethyl)oxane-3,5-diol Chemical compound C1=CC(=C(C=C1S[C@@H]2C([C@H]([C@H](C(O2)CO)O)N3C=C(N=N3)C4=NC=C(S4)F)O)Cl)Cl ISLKHLAJYHLAKA-AHXITHOBSA-N 0.000 claims 1
UXFIYTXCLJLNTP-YQDVBHNYSA-N (2R,4S,5R)-2-(3,4-dichlorophenyl)sulfanyl-6-(hydroxymethyl)-4-[4-(1,3-thiazol-2-yl)triazol-1-yl]oxane-3,5-diol Chemical compound C1=CC(=C(C=C1S[C@@H]2C([C@H]([C@H](C(O2)CO)O)N3C=C(N=N3)C4=NC=CS4)O)Cl)Cl UXFIYTXCLJLNTP-YQDVBHNYSA-N 0.000 claims 1
GTARISNSLWRIAA-LAYQYYCJSA-N (2R,4S,5R)-2-(3,4-dichlorophenyl)sulfanyl-6-(hydroxymethyl)-4-[4-(1,3-thiazol-4-yl)triazol-1-yl]oxane-3,5-diol Chemical compound C1=CC(=C(C=C1S[C@@H]2C([C@H]([C@H](C(O2)CO)O)N3C=C(N=N3)C4=CSC=N4)O)Cl)Cl GTARISNSLWRIAA-LAYQYYCJSA-N 0.000 claims 1
GJARXSUVLGPOSU-YQDVBHNYSA-N (2R,4S,5R)-2-(3,5-dichlorophenyl)sulfanyl-6-(hydroxymethyl)-4-[4-(1,3-thiazol-2-yl)triazol-1-yl]oxane-3,5-diol Chemical compound C1=CSC(=N1)C2=CN(N=N2)[C@H]3[C@H](C(O[C@@H](C3O)SC4=CC(=CC(=C4)Cl)Cl)CO)O GJARXSUVLGPOSU-YQDVBHNYSA-N 0.000 claims 1
DNENTQOFXMLIPJ-YQDVBHNYSA-N (2R,4S,5R)-2-(3-bromo-4-chlorophenyl)sulfanyl-6-(hydroxymethyl)-4-[4-(1,3-thiazol-2-yl)triazol-1-yl]oxane-3,5-diol Chemical compound C1=CC(=C(C=C1S[C@@H]2C([C@H]([C@H](C(O2)CO)O)N3C=C(N=N3)C4=NC=CS4)O)Br)Cl DNENTQOFXMLIPJ-YQDVBHNYSA-N 0.000 claims 1
KQSLNGFNPKREHT-YQDVBHNYSA-N (2R,4S,5R)-2-(3-bromo-4-fluorophenyl)sulfanyl-6-(hydroxymethyl)-4-[4-(1,3-thiazol-2-yl)triazol-1-yl]oxane-3,5-diol Chemical compound C1=CC(=C(C=C1S[C@@H]2C([C@H]([C@H](C(O2)CO)O)N3C=C(N=N3)C4=NC=CS4)O)Br)F KQSLNGFNPKREHT-YQDVBHNYSA-N 0.000 claims 1
FEDXCIOMXFWCDX-UENKNZSUSA-N (2R,4S,5R)-2-(5-bromo-2-isocyanopyridin-3-yl)sulfanyl-6-(hydroxymethyl)-4-[4-(1,3-thiazol-2-yl)triazol-1-yl]oxane-3,5-diol Chemical compound [C-]#[N+]C1=C(C=C(C=N1)Br)S[C@@H]2C([C@H]([C@H](C(O2)CO)O)N3C=C(N=N3)C4=NC=CS4)O FEDXCIOMXFWCDX-UENKNZSUSA-N 0.000 claims 1
YTXRGVYGGMRUNR-BEBHXBEKSA-N (2R,4S,5R)-2-(5-bromopyridin-3-yl)sulfanyl-6-(hydroxymethyl)-4-[4-(1,3-thiazol-4-yl)triazol-1-yl]oxane-3,5-diol Chemical compound C1=C(C=NC=C1Br)S[C@@H]2C([C@H]([C@H](C(O2)CO)O)N3C=C(N=N3)C4=CSC=N4)O YTXRGVYGGMRUNR-BEBHXBEKSA-N 0.000 claims 1
CUGAKXHNQPJMNW-SAHXZQTASA-N (2R,4S,5R)-2-(5-chloropyridin-3-yl)sulfanyl-6-(hydroxymethyl)-4-[4-(1,3-thiazol-2-yl)triazol-1-yl]oxane-3,5-diol Chemical compound C1=CSC(=N1)C2=CN(N=N2)[C@H]3[C@H](C(O[C@@H](C3O)SC4=CC(=CN=C4)Cl)CO)O CUGAKXHNQPJMNW-SAHXZQTASA-N 0.000 claims 1
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TTWAWDQEFOJURU-GIMKSSNDSA-N (2R,4S,5R)-4-[4-(4-chloro-1,3-thiazol-2-yl)triazol-1-yl]-2-[(1E,3E,5E)-1,6-dichlorohexa-1,3,5-trien-3-yl]sulfanyl-6-(hydroxymethyl)oxane-3,5-diol Chemical compound C1=C(N=NN1[C@H]2[C@H](C(O[C@@H](C2O)S/C(=C/C=C/Cl)/C=C/Cl)CO)O)C3=NC(=CS3)Cl TTWAWDQEFOJURU-GIMKSSNDSA-N 0.000 claims 1
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MAVHNZOGQVPBLP-AHXITHOBSA-N (3R,4S,6R)-2-(hydroxymethyl)-4-[4-(1,3-thiazol-2-yl)triazol-1-yl]-6-(3,4,5-trichlorophenyl)sulfanyloxane-3,5-diol Chemical compound C1=CSC(=N1)C2=CN(N=N2)[C@H]3[C@H](C(O[C@@H](C3O)SC4=CC(=C(C(=C4)Cl)Cl)Cl)CO)O MAVHNZOGQVPBLP-AHXITHOBSA-N 0.000 claims 1
JESDPLFOKAYMQB-HBWZYELFSA-N 2-chloro-4-[(2R,4S,5R)-3,5-dihydroxy-6-(hydroxymethyl)-4-[4-(1,3-thiazol-4-yl)triazol-1-yl]oxan-2-yl]sulfanylbenzonitrile Chemical compound C1=CC(=C(C=C1S[C@@H]2C([C@H]([C@H](C(O2)CO)O)N3C=C(N=N3)C4=CSC=N4)O)Cl)C#N JESDPLFOKAYMQB-HBWZYELFSA-N 0.000 claims 1
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