IL96268A - מקרולידים טריציקליים המכילים הטרואטומים, מותמרים ע" י ציקלואלקיל,הכנתם ותכשירי רוקחות המכילים אותם - Google Patents

מקרולידים טריציקליים המכילים הטרואטומים, מותמרים ע" י ציקלואלקיל,הכנתם ותכשירי רוקחות המכילים אותם

Info

Publication number: IL96268A
Authority: IL; Israel
Prior art keywords: hydroxy; compound; group; single bond; formula
Prior art date: 1989-11-09

Application number

IL9626890A

Other languages

English (en)

Original Assignee

Sandoz Ag

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1989-11-09

Filing date

1990-11-07

Publication date

1996-07-23

1990-11-07 Application filed by Sandoz Ag filed Critical Sandoz Ag

1996-07-23 Publication of IL96268A publication Critical patent/IL96268A/he

Links

238000002360 preparation method Methods 0.000 title claims description 14
239000008194 pharmaceutical composition Substances 0.000 title claims description 6
239000003120 macrolide antibiotic agent Substances 0.000 title description 3
229940041033 macrolides Drugs 0.000 title description 3
125000005842 heteroatom Chemical group 0.000 title description 2
125000005346 substituted cycloalkyl group Chemical group 0.000 title 1
150000001875 compounds Chemical class 0.000 claims description 213
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 109
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 59
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 49
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 25
238000000034 method Methods 0.000 claims description 22
150000003839 salts Chemical group 0.000 claims description 22
-1 chloro, bromo, iodo Chemical group 0.000 claims description 19
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 15
125000006239 protecting group Chemical group 0.000 claims description 10
125000001309 chloro group Chemical group Cl* 0.000 claims description 9
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
239000002253 acid Substances 0.000 claims description 5
125000001246 bromo group Chemical group Br* 0.000 claims description 5
239000003085 diluting agent Substances 0.000 claims description 5
ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 claims description 5
150000001450 anions Chemical class 0.000 claims description 4
ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 claims description 4
239000003937 drug carrier Substances 0.000 claims description 4
238000006345 epimerization reaction Methods 0.000 claims description 4
230000000269 nucleophilic effect Effects 0.000 claims 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 claims description 4
CKOZVEHVVHCMGD-UHFFFAOYSA-N 5-[(4-fluorophenyl)methyl]-n,n-dimethyltetrazole-1-carboxamide Chemical compound CN(C)C(=O)N1N=NN=C1CC1=CC=C(F)C=C1 CKOZVEHVVHCMGD-UHFFFAOYSA-N 0.000 claims description 3
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
150000001540 azides Chemical class 0.000 claims description 3
229910052740 iodine Inorganic materials 0.000 claims description 3
239000011630 iodine Substances 0.000 claims description 3
238000002156 mixing Methods 0.000 claims description 3
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
229910052794 bromium Inorganic materials 0.000 claims description 2
239000000460 chlorine Substances 0.000 claims description 2
229910052801 chlorine Inorganic materials 0.000 claims description 2
125000002346 iodo group Chemical group I* 0.000 claims 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 64
239000000203 mixture Substances 0.000 description 58
238000005160 1H NMR spectroscopy Methods 0.000 description 51
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 32
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 description 27
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
239000000741 silica gel Substances 0.000 description 16
229910002027 silica gel Inorganic materials 0.000 description 16
229960001866 silicon dioxide Drugs 0.000 description 16
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
229910052938 sodium sulfate Inorganic materials 0.000 description 15
235000011152 sodium sulphate Nutrition 0.000 description 15
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 14
KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 14
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
239000011541 reaction mixture Substances 0.000 description 13
229920006395 saturated elastomer Polymers 0.000 description 13
238000006243 chemical reaction Methods 0.000 description 12
239000012074 organic phase Substances 0.000 description 12
239000011347 resin Substances 0.000 description 12
229920005989 resin Polymers 0.000 description 12
238000005481 NMR spectroscopy Methods 0.000 description 10
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
238000004440 column chromatography Methods 0.000 description 10
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
239000002904 solvent Substances 0.000 description 8
238000010998 test method Methods 0.000 description 7
PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
238000010511 deprotection reaction Methods 0.000 description 6
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
235000017557 sodium bicarbonate Nutrition 0.000 description 6
238000003756 stirring Methods 0.000 description 6
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 6
230000003110 anti-inflammatory effect Effects 0.000 description 5
230000000694 effects Effects 0.000 description 5
230000001861 immunosuppressant effect Effects 0.000 description 5
239000012442 inert solvent Substances 0.000 description 5
239000011780 sodium chloride Substances 0.000 description 5
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
230000001028 anti-proliverative effect Effects 0.000 description 4
239000006260 foam Substances 0.000 description 4
229960003444 immunosuppressant agent Drugs 0.000 description 4
239000003018 immunosuppressive agent Substances 0.000 description 4
230000005764 inhibitory process Effects 0.000 description 4
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
238000011200 topical administration Methods 0.000 description 4
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
239000002246 antineoplastic agent Substances 0.000 description 3
229910052799 carbon Inorganic materials 0.000 description 3
125000004432 carbon atom Chemical group C* 0.000 description 3
238000002651 drug therapy Methods 0.000 description 3
125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
238000007799 mixed lymphocyte reaction assay Methods 0.000 description 3
239000007858 starting material Substances 0.000 description 3
238000006467 substitution reaction Methods 0.000 description 3
230000000699 topical effect Effects 0.000 description 3
239000003981 vehicle Substances 0.000 description 3
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
208000023275 Autoimmune disease Diseases 0.000 description 2
201000004624 Dermatitis Diseases 0.000 description 2
206010012442 Dermatitis contact Diseases 0.000 description 2
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206010020751 Hypersensitivity Diseases 0.000 description 2
206010046851 Uveitis Diseases 0.000 description 2
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238000011097 chromatography purification Methods 0.000 description 2
239000006071 cream Substances 0.000 description 2
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
239000000499 gel Substances 0.000 description 2
229910052739 hydrogen Inorganic materials 0.000 description 2
JUINSXZKUKVTMD-UHFFFAOYSA-N hydrogen azide Chemical compound N=[N+]=[N-] JUINSXZKUKVTMD-UHFFFAOYSA-N 0.000 description 2
238000000338 in vitro Methods 0.000 description 2
230000004968 inflammatory condition Effects 0.000 description 2
239000000543 intermediate Substances 0.000 description 2
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
239000006210 lotion Substances 0.000 description 2
210000004698 lymphocyte Anatomy 0.000 description 2
230000001404 mediated effect Effects 0.000 description 2
KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
230000003647 oxidation Effects 0.000 description 2
238000007254 oxidation reaction Methods 0.000 description 2
239000012071 phase Substances 0.000 description 2
230000002265 prevention Effects 0.000 description 2
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
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210000003491 skin Anatomy 0.000 description 2
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BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
210000004127 vitreous body Anatomy 0.000 description 2
NBKZGRPRTQELKX-UHFFFAOYSA-N (2-methylpropan-2-yl)oxymethanone Chemical compound CC(C)(C)O[C]=O NBKZGRPRTQELKX-UHFFFAOYSA-N 0.000 description 1
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YIWGJFPJRAEKMK-UHFFFAOYSA-N 1-(2H-benzotriazol-5-yl)-3-methyl-8-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carbonyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound CN1C(=O)N(c2ccc3n[nH]nc3c2)C2(CCN(CC2)C(=O)c2cnc(NCc3cccc(OC(F)(F)F)c3)nc2)C1=O YIWGJFPJRAEKMK-UHFFFAOYSA-N 0.000 description 1
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FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
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229910052757 nitrogen Inorganic materials 0.000 description 1
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
UNCAXIZUVRKBMN-UHFFFAOYSA-N o-(4-methylphenyl) chloromethanethioate Chemical compound CC1=CC=C(OC(Cl)=S)C=C1 UNCAXIZUVRKBMN-UHFFFAOYSA-N 0.000 description 1
239000002674 ointment Substances 0.000 description 1
238000005580 one pot reaction Methods 0.000 description 1
210000000056 organ Anatomy 0.000 description 1
230000000144 pharmacologic effect Effects 0.000 description 1
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
239000002244 precipitate Substances 0.000 description 1
239000000047 product Substances 0.000 description 1
230000035755 proliferation Effects 0.000 description 1
230000009696 proliferative response Effects 0.000 description 1
239000002516 radical scavenger Substances 0.000 description 1
239000012429 reaction media Substances 0.000 description 1
210000001525 retina Anatomy 0.000 description 1
206010039073 rheumatoid arthritis Diseases 0.000 description 1
238000007157 ring contraction reaction Methods 0.000 description 1
210000003786 sclera Anatomy 0.000 description 1
208000008742 seborrheic dermatitis Diseases 0.000 description 1
208000017520 skin disease Diseases 0.000 description 1
URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
230000000638 stimulation Effects 0.000 description 1
239000012258 stirred mixture Substances 0.000 description 1
239000000126 substance Substances 0.000 description 1
229910052717 sulfur Inorganic materials 0.000 description 1
239000011593 sulfur Substances 0.000 description 1
230000001629 suppression Effects 0.000 description 1
201000000596 systemic lupus erythematosus Diseases 0.000 description 1
HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 1
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
210000001519 tissue Anatomy 0.000 description 1
231100000419 toxicity Toxicity 0.000 description 1
230000001988 toxicity Effects 0.000 description 1
238000002054 transplantation Methods 0.000 description 1
125000004665 trialkylsilyl group Chemical group 0.000 description 1
235000015112 vegetable and seed oil Nutrition 0.000 description 1
239000008158 vegetable oil Substances 0.000 description 1
201000005539 vernal conjunctivitis Diseases 0.000 description 1
229920002554 vinyl polymer Polymers 0.000 description 1

Landscapes

Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

IL9626890A 1989-11-09 1990-11-07 מקרולידים טריציקליים המכילים הטרואטומים, מותמרים ע" י ציקלואלקיל,הכנתם ותכשירי רוקחות המכילים אותם IL96268A (he)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
DE3937336		1989-11-09
DE3942833		1989-12-23
DE3942831		1989-12-23

Publications (1)

Publication Number	Publication Date
IL96268A true IL96268A (he)	1996-07-23

Family

ID=27200427

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
IL9626890A IL96268A (he)	1989-11-09	1990-11-07	מקרולידים טריציקליים המכילים הטרואטומים, מותמרים ע" י ציקלואלקיל,הכנתם ותכשירי רוקחות המכילים אותם

Country Status (1)

Country	Link
IL (1)	IL96268A (he)

1990
- 1990-11-07 IL IL9626890A patent/IL96268A/he active Protection Beyond IP Right Term

Legal Events

Date	Code	Title
1996-12-05	FF	Patent granted
1997-02-18	KB	Patent renewed
1997-11-20	HC	Change of name of proprietor(s)
2001-04-30	KB	Patent renewed
2005-01-24	EXTP	Application for extension order is pending
2005-02-20	KB	Patent renewed
2005-06-19	PEL	Intention of commissioner to extend period of protection
2006-01-15	EXTG	Extension of patent term granted
2010-10-31	EXTN	Extension order renewed
2011-05-31	EXTN	Extension order renewed
2012-06-28	EXTN	Extension order renewed
2013-06-27	EXTN	Extension order renewed
2014-05-28	EXTN	Extension order renewed

Publication	Publication Date	Title
EP0427680B1 (en)	1995-08-23	Heteroatoms-containing tricyclic compounds
US5352671A (en)	1994-10-04	Heteroatoms-containing tricyclic compounds
AU641410B2 (en)	1993-09-23	Antiinflammatory and immunosuppressant triheterocyclic FK506-like compounds and processes for their preparation
US5493019A (en)	1996-02-20	Tetrahydropyran derivatives
US5514685A (en)	1996-05-07	Heteroatom-containing tricyclic compounds
US5508290A (en)	1996-04-16	Hindered N-oxide esters of rapamycin
EP0629203B1 (en)	2001-09-12	Desosamino derivatives of macrolides as immunosuppressants and antifungal agents
AU648806B2 (en)	1994-05-05	Cyclopentylvinyl substituted macrolides
GB2225576A (en)	1990-06-06	Substituted azatricyclo derivatives and metabolites
KR100317009B1 (ko)	2002-02-19	테트라하이드로피란유도체
HK1011684B (en)	2004-06-18	Tetrahydropyran derivatives
PT98175A (pt)	1993-07-30	Processo para a preparacao de compostos triciclicoscontendo heteroatomos e produtos intermediarios