CA2156067A1

CA2156067A1 - Heterocycle-containing macrocyclic immunomodulators

Heterocycle-containing macrocyclic immunomodulators

Info

Publication number: CA2156067A1
Authority: CA; Canada
Prior art keywords: group; hydrogen; compound according; hydroxy; compound
Prior art date: 1993-03-17
Legal status : Abandoned

Application number

CA002156067A

Other languages

English (en)

French (fr)

Inventor

Megumi Kawai

Yat Sun Or

Jay R. Luly

Current Assignee

Abbott Laboratories

Original Assignee

Individual

Priority date

1993-03-17

Filing date

1994-03-14

Publication date

1994-09-29

1994-03-14 Application filed by Individual filed Critical Individual

1994-09-29 Publication of CA2156067A1 publication Critical patent/CA2156067A1/en

Status Abandoned legal-status Critical Current

Links

125000000623 heterocyclic group Chemical group 0.000 title claims description 12
239000002955 immunomodulating agent Substances 0.000 title description 2
229940121354 immunomodulator Drugs 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims abstract description 208
238000000034 method Methods 0.000 claims abstract description 94
150000002148 esters Chemical class 0.000 claims abstract description 13
150000003839 salts Chemical class 0.000 claims abstract description 13
239000000651 prodrug Substances 0.000 claims abstract description 10
229940002612 prodrug Drugs 0.000 claims abstract description 10
150000001408 amides Chemical class 0.000 claims abstract description 8
230000002519 immonomodulatory effect Effects 0.000 claims abstract description 7
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 76
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 69
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 64
239000001257 hydrogen Substances 0.000 claims description 53
229910052739 hydrogen Inorganic materials 0.000 claims description 53
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 30
125000003118 aryl group Chemical group 0.000 claims description 20
125000000217 alkyl group Chemical group 0.000 claims description 16
KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 10
125000003710 aryl alkyl group Chemical group 0.000 claims description 8
150000002431 hydrogen Chemical class 0.000 claims description 8
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
125000004432 carbon atom Chemical group C* 0.000 claims description 7
125000003342 alkenyl group Chemical group 0.000 claims description 6
229910052736 halogen Inorganic materials 0.000 claims description 6
150000002367 halogens Chemical class 0.000 claims description 6
229910052757 nitrogen Inorganic materials 0.000 claims description 6
239000001301 oxygen Substances 0.000 claims description 6
229910052760 oxygen Inorganic materials 0.000 claims description 6
125000004442 acylamino group Chemical group 0.000 claims description 5
125000003282 alkyl amino group Chemical group 0.000 claims description 5
125000001691 aryl alkyl amino group Chemical group 0.000 claims description 5
125000001769 aryl amino group Chemical group 0.000 claims description 5
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
125000000753 cycloalkyl group Chemical group 0.000 claims description 5
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 4
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
239000008194 pharmaceutical composition Substances 0.000 claims description 4
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
229910052717 sulfur Chemical group 0.000 claims description 4
125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 3
239000003937 drug carrier Substances 0.000 claims description 3
125000005842 heteroatom Chemical group 0.000 claims description 3
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 3
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
239000011593 sulfur Chemical group 0.000 claims description 3
125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
125000002837 carbocyclic group Chemical group 0.000 claims description 2
125000004966 cyanoalkyl group Chemical group 0.000 claims description 2
125000005356 cycloalkylalkenyl group Chemical group 0.000 claims description 2
125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
125000006413 ring segment Chemical group 0.000 claims description 2
229920006395 saturated elastomer Polymers 0.000 claims description 2
125000004945 acylaminoalkyl group Chemical group 0.000 claims 1
239000000203 mixture Substances 0.000 abstract description 24
150000002678 macrocyclic compounds Chemical class 0.000 abstract description 4
238000002560 therapeutic procedure Methods 0.000 abstract description 2
-1 azole radical Chemical class 0.000 description 90
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 81
238000006243 chemical reaction Methods 0.000 description 64
125000004043 oxo group Chemical group O=* 0.000 description 63
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 62
239000000047 product Substances 0.000 description 62
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 46
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 45
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 31
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 29
238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 26
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 23
230000000694 effects Effects 0.000 description 21
125000001033 ether group Chemical group 0.000 description 21
238000004305 normal phase HPLC Methods 0.000 description 19
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
125000001145 hydrido group Chemical group *[H] 0.000 description 17
230000008569 process Effects 0.000 description 16
239000002904 solvent Substances 0.000 description 16
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
ZDQSOHOQTUFQEM-NURRSENYSA-N ascomycin Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](O)[C@H](OC)C1 ZDQSOHOQTUFQEM-NURRSENYSA-N 0.000 description 15
125000004435 hydrogen atom Chemical group [H]* 0.000 description 15
239000000741 silica gel Substances 0.000 description 15
229910002027 silica gel Inorganic materials 0.000 description 15
QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 14
239000007787 solid Substances 0.000 description 14
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
239000003153 chemical reaction reagent Substances 0.000 description 13
QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 12
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
229940079593 drug Drugs 0.000 description 12
239000003814 drug Substances 0.000 description 12
238000005481 NMR spectroscopy Methods 0.000 description 11
238000000746 purification Methods 0.000 description 11
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
230000004913 activation Effects 0.000 description 10
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
239000012267 brine Substances 0.000 description 9
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
235000019441 ethanol Nutrition 0.000 description 9
125000006239 protecting group Chemical group 0.000 description 9
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
230000015572 biosynthetic process Effects 0.000 description 8
238000003786 synthesis reaction Methods 0.000 description 8
OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 7
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
239000003795 chemical substances by application Substances 0.000 description 7
238000001816 cooling Methods 0.000 description 7
239000002502 liposome Substances 0.000 description 7
239000000546 pharmaceutical excipient Substances 0.000 description 7
238000010898 silica gel chromatography Methods 0.000 description 7
229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
239000000243 solution Substances 0.000 description 7
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-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
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
238000010521 absorption reaction Methods 0.000 description 6
230000002411 adverse Effects 0.000 description 6
239000000460 chlorine Substances 0.000 description 6
210000001508 eye Anatomy 0.000 description 6
150000002500 ions Chemical class 0.000 description 6
231100000252 nontoxic Toxicity 0.000 description 6
230000003000 nontoxic effect Effects 0.000 description 6
150000007530 organic bases Chemical class 0.000 description 6
239000000126 substance Substances 0.000 description 6
239000004094 surface-active agent Substances 0.000 description 6
150000003852 triazoles Chemical class 0.000 description 6
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
241001674048 Phthiraptera Species 0.000 description 5
239000004480 active ingredient Substances 0.000 description 5
235000001014 amino acid Nutrition 0.000 description 5
150000001413 amino acids Chemical group 0.000 description 5
125000003277 amino group Chemical group 0.000 description 5
ZDQSOHOQTUFQEM-XCXYXIJFSA-N ascomycin Natural products CC[C@H]1C=C(C)C[C@@H](C)C[C@@H](OC)[C@H]2O[C@@](O)([C@@H](C)C[C@H]2OC)C(=O)C(=O)N3CCCC[C@@H]3C(=O)O[C@H]([C@H](C)[C@@H](O)CC1=O)C(=C[C@@H]4CC[C@@H](O)[C@H](C4)OC)C ZDQSOHOQTUFQEM-XCXYXIJFSA-N 0.000 description 5
208000006673 asthma Diseases 0.000 description 5
230000001684 chronic effect Effects 0.000 description 5
WICQXESQFGXSKV-UHFFFAOYSA-N disulfuryl fluoride Chemical compound FS(=O)(=O)OS(F)(=O)=O WICQXESQFGXSKV-UHFFFAOYSA-N 0.000 description 5
239000007788 liquid Substances 0.000 description 5
210000004185 liver Anatomy 0.000 description 5
230000000813 microbial effect Effects 0.000 description 5
210000000056 organ Anatomy 0.000 description 5
229920001223 polyethylene glycol Polymers 0.000 description 5
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235000017557 sodium bicarbonate Nutrition 0.000 description 5
UBQBKOBGHRTZRG-UPAXIQFWSA-N 104987-09-9 Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 UBQBKOBGHRTZRG-UPAXIQFWSA-N 0.000 description 4
BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 4
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
206010019663 Hepatic failure Diseases 0.000 description 4
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
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229910052783 alkali metal Inorganic materials 0.000 description 4
239000007864 aqueous solution Substances 0.000 description 4
208000010668 atopic eczema Diseases 0.000 description 4
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150000007529 inorganic bases Chemical class 0.000 description 4
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210000004072 lung Anatomy 0.000 description 4
239000003120 macrolide antibiotic agent Substances 0.000 description 4
CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical group C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 4
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150000003254 radicals Chemical class 0.000 description 4
102220315634 rs1196125127 Human genes 0.000 description 4
125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
210000001519 tissue Anatomy 0.000 description 4
238000002054 transplantation Methods 0.000 description 4
WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
239000003981 vehicle Substances 0.000 description 4
NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 3
AOPMJTXVTVQAGD-KNLBXDFQSA-N 5,6,8,11,12,13,14,15,16,17,18,19,23,24,25,25a-hexadecahydro-5,19-dihydroxy-3-(2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl)-14,16-dimethoxy-4,10,12,18-tetramethyl-8-15,19-epoxy-1h,3h-pyrrolo(2,1-c)(1,4)oxaazacyclotricosine-1,7,20,21(4h)-tetrone Chemical compound C1CC(O)C(OC)CC1\C=C(/C)C1C(C)C(O)CC(=O)C(CC=C)\C=C(C)/CC(C)CC(OC)C(C(CC2C)OC)OC2(O)C(=O)C(=O)N2CCCC2C(=O)O1 AOPMJTXVTVQAGD-KNLBXDFQSA-N 0.000 description 3
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
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OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
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PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 3
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125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
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KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
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RUQGXFJIPMDCFD-UHFFFAOYSA-N (5-Phenyl-1,2,4-triazol-3-yl)urea Chemical compound NC(=O)NC1=NNC(C=2C=CC=CC=2)=N1 RUQGXFJIPMDCFD-UHFFFAOYSA-N 0.000 description 2
VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
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