CA1305136C - Derivatives of all-trans- and 13-cis retinoic acid and methods for preparing same - Google Patents
Derivatives of all-trans- and 13-cis retinoic acid and methods for preparing sameInfo
- Publication number
- CA1305136C CA1305136C CA000538880A CA538880A CA1305136C CA 1305136 C CA1305136 C CA 1305136C CA 000538880 A CA000538880 A CA 000538880A CA 538880 A CA538880 A CA 538880A CA 1305136 C CA1305136 C CA 1305136C
- Authority
- CA
- Canada
- Prior art keywords
- trans
- retinoic acid
- coa
- cis
- retinoyl
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired - Lifetime
Links
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical class OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 title claims abstract description 24
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 title claims abstract description 8
- 229960005280 isotretinoin Drugs 0.000 title claims abstract description 7
- 238000000034 method Methods 0.000 title claims abstract description 7
- 150000002148 esters Chemical class 0.000 claims abstract description 15
- 229930002330 retinoic acid Natural products 0.000 claims abstract description 15
- RGJOEKWQDUBAIZ-IBOSZNHHSA-N CoASH Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCS)O[C@H]1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-IBOSZNHHSA-N 0.000 claims abstract description 7
- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000005516 coenzyme A Substances 0.000 claims abstract description 5
- 229940093530 coenzyme a Drugs 0.000 claims abstract description 5
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 4
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 claims description 3
- 150000008064 anhydrides Chemical class 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 229960001727 tretinoin Drugs 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 101100170172 Caenorhabditis elegans del-10 gene Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000009786 epithelial differentiation Effects 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- KCWYOFZQRFCIIE-UHFFFAOYSA-N ethylsilane Chemical compound CC[SiH3] KCWYOFZQRFCIIE-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229930182480 glucuronide Natural products 0.000 description 1
- 150000002314 glycerols Chemical class 0.000 description 1
- 206010021198 ichthyosis Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- HVFSJXUIRWUHRG-UHFFFAOYSA-N oic acid Natural products C1CC2C3CC=C4CC(OC5C(C(O)C(O)C(CO)O5)O)CC(O)C4(C)C3CCC2(C)C1C(C)C(O)CC(C)=C(C)C(=O)OC1OC(COC(C)=O)C(O)C(O)C1OC(C(C1O)O)OC(COC(C)=O)C1OC1OC(CO)C(O)C(O)C1O HVFSJXUIRWUHRG-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- CMXPERZAMAQXSF-UHFFFAOYSA-M sodium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate;1,8-dihydroxyanthracene-9,10-dione Chemical compound [Na+].O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O.CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC CMXPERZAMAQXSF-UHFFFAOYSA-M 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Abstract of the Disclosure The invention relates to new coenzyme A and N-hydroxysuccinimidyl esters of all-trans- and 13-cis-retinoic acid and to methods for preparing the same. A new method for preparing all-trans-retinoic acid anhydride is also disclosed.
Description
L3~
Description Derivatives of All-trans- nd 13-cis P~tinoic ~cid and thods for PreFaring ~e Field o~ Lh~ Invention . . _ . .
Ihe presen-t invention relates to ncvel derivatives of al7-trans- and 13~cis-retinoic acid.
Backgrou~d o~ the Inv nt on In 1967 r 13~cis-retino.ic acid was iæ n-tified in rat tissue ex*rzcts and it was postulated to be a natural me~bolite of all-trans-retinoic acid.l Ihe 13-cis-retinoic aci~ has ~een found to be at least as efiective as all-trars-retinoic acid in promo-ting vitamin A-~ependent growth as well as in controlling epithelial cell differentia-tion.
Recent ~rk s~ggests that 13-c retinoic acid is not solely '~ 15 pro~u oed as c~n artifact of isolation but ~hat all trans-re inoic acid is iscmerized in mammals to scme extent to 13-cis-retLnoic acid.2 The utlity of 13-cis-retinoic acid in treatiny den~atological conditions, i~s t~Imor inhibitory prcperties, a~ its reduced toxicity relat_ve to all-trans-re, ~oic acid are kncwn.
Disclo~ure of the Invention .
I~e pr.esent invention relates to ~cve1 derivatives of a1l-trans- and 13-cis-retinoic acid. k~re specifically, this irventicn re1~t~s to N-hydroxysuccini~idyl and coenzyme A
esters of all-trans- and 13-cis-retinoic acid.
Ihe der-~ative of the present i~Jention can be represented by the following foDmula:
\
13a~s~3~
wherein ~ and ~ are each selected frGm the f~G~ crnsisting of:
(a~ hydrcgen, O ~
(b) - C - O ~ and (c) ~ ~ C o ~
.
where CQ~ represents cc~nzym~ A, except that both of ~ anc~ R2 cannot be (a), but one of ~ and R2 must be (a).
The compounds of the present invention can be p ~pared :in S accordance with the following schematic c~iac~ram and descrip~tic~. ~ ~ - o- H~
co~7 y.~,te A
A/ hy~%y~ de 2 ~ o ~Co~ft ~ c-s - c f~h \~/ d;~ cLahe~ L-~d;"~;~o aOe ~ E A
~c~
where 1 = all tran~-retinoic acid 2 = N-hydroxysucclnimldyl all trans-retinoa~
Description Derivatives of All-trans- nd 13-cis P~tinoic ~cid and thods for PreFaring ~e Field o~ Lh~ Invention . . _ . .
Ihe presen-t invention relates to ncvel derivatives of al7-trans- and 13~cis-retinoic acid.
Backgrou~d o~ the Inv nt on In 1967 r 13~cis-retino.ic acid was iæ n-tified in rat tissue ex*rzcts and it was postulated to be a natural me~bolite of all-trans-retinoic acid.l Ihe 13-cis-retinoic aci~ has ~een found to be at least as efiective as all-trars-retinoic acid in promo-ting vitamin A-~ependent growth as well as in controlling epithelial cell differentia-tion.
Recent ~rk s~ggests that 13-c retinoic acid is not solely '~ 15 pro~u oed as c~n artifact of isolation but ~hat all trans-re inoic acid is iscmerized in mammals to scme extent to 13-cis-retLnoic acid.2 The utlity of 13-cis-retinoic acid in treatiny den~atological conditions, i~s t~Imor inhibitory prcperties, a~ its reduced toxicity relat_ve to all-trans-re, ~oic acid are kncwn.
Disclo~ure of the Invention .
I~e pr.esent invention relates to ~cve1 derivatives of a1l-trans- and 13-cis-retinoic acid. k~re specifically, this irventicn re1~t~s to N-hydroxysuccini~idyl and coenzyme A
esters of all-trans- and 13-cis-retinoic acid.
Ihe der-~ative of the present i~Jention can be represented by the following foDmula:
\
13a~s~3~
wherein ~ and ~ are each selected frGm the f~G~ crnsisting of:
(a~ hydrcgen, O ~
(b) - C - O ~ and (c) ~ ~ C o ~
.
where CQ~ represents cc~nzym~ A, except that both of ~ anc~ R2 cannot be (a), but one of ~ and R2 must be (a).
The compounds of the present invention can be p ~pared :in S accordance with the following schematic c~iac~ram and descrip~tic~. ~ ~ - o- H~
co~7 y.~,te A
A/ hy~%y~ de 2 ~ o ~Co~ft ~ c-s - c f~h \~/ d;~ cLahe~ L-~d;"~;~o aOe ~ E A
~c~
where 1 = all tran~-retinoic acid 2 = N-hydroxysucclnimldyl all trans-retinoa~
3 = all trans-retinoic acid anh~dride 104 = all trans-retinc~l CoA
~3~5136 ~U~ ~ - O~
s ~ /o o .
C~ ~e A
(-5 co~
wr~ e 5 = 13-cis~retinoic acid 6 = N-hydroxysuccinimidyl 13- _ -reti~ate 7 = 13~cis-retir.cyl CoA
De~ailed Description of Processes C~ icals All _rans-retinoic acid and the sodium salt of coenzyme A
we~e purchased from Sigma Chemical Co. (St. Louis, ~).
M-~droxysuccinimicle ~nd N,N'-dicyclohexylcarbodii~ide were f~om the Aldrich Chemical Co. (Milwaukee, ~ Disposable silica gel Sep-Pak cartridges ~Waters Pssociates, ~lilford, MA) we-e used for purification of synthetic intermRdiates.
All operations irvolving the use of retinoic acid analogs e~2 perfor~d under yellow light in a nitrogen a~mosphere.
Gl3ssware silanized ~th aimethyldichlorosilane was used for ~r~ synthesis, handling and storage of retinoic acid CoA
t~oesters~ All reac*ions were done using l and 5 ml Reacti-Vials (Pierce Chen. Corp., Rockford, IL).
Ch~cmato~raphic ~ e Analytical and preparatlv~ thin-layer chromatography (~C) was done usiny pre ate alu~inum silica gel sheets wi-~h W indica~or and glass pre-coated silica gel plates (20~20 cm, 2 m~ thick) without fluorescence indicator, respectively, c~,ained fro~ EM Science (Gibbstown, NJ). Plates were c~eloped using sol~ent sys-t~ms: A; hexane-ethyl acetate l:l ~-~ B; n-butanol-acetic acid-watex 5:2:3.
~L3 sæc =
~ . .
Electron i~pact mass spectra (EI-~S) were recorded at 70 eV with al~ AEI l'~-9 spectrGme-ter coupled to a DS-50 data system.
Ultraviolet (W) absorp-tio~ spectra were recorded in absolute ethanol or dioxane with a Hitachi Ik~del 10~-60 W -visible spectrcphoto~eter~
~nfrared spectra (IR~ t~iere recorded on a Nicolet ~
Fm-lR spec~rGmeter in CC14 solution or using i~ns of oily substances.
Proton magnetic resonance spectra (~I-NMR) were taken t~th a Bruker ~ 270 FT spectr~eter in acetone-d6 solutions containing tetra~ethylsilane (T~LS) as internal standard.
Bec]~N~l m~del 4500 pH meter equipped with Bech~an C~B
p~-electrode was used for pH adjus-tments.
PREPARATIONS
Preparation of N-hydroxy~succininLidyl ester of all-trans-retinoic acid (2) Pll-tr -retinoic acid (1) (20 mg, 64 ~M) in 0.8 ml of dioxane was trea ed with N-hydroxysuccin~nide (7.6 mg, 64 ~M) in 0.4 ml of dioxare and dicyclohexylcarbodiimide (13.6 mg, 64 ~i) in 0.4 ml of dioxane. ~ne resulting solution was ragnetically stirred at room temF~rature for 5 hours and then diluted with 10 ml of ethyl ether. The precipitated dicyclohexylurea was separated by filtration and the filtrate evaporated to dryness under reduced pressure. me oily residue was dissolved in warm metnanol (10 ml) and the solution concen~rated under reduced pressure until a slight prec~pitate becare apparent. After standing overnight at -20C, crystals t~--ere filtered off and washed with cold ~ethanol. Chro~tographically pure product (2) showed TLC Rf 0.47 (solvent syst~m A~. W (ethanol) ~max 377 (36.400); IR
1758, 1734 cm 1; ~ (acetone-d6) ~ 1.05 ~s, 6,(CH3)2C), l.S
(m, 2, 2 ~ I2), 1.6 (m, 2j 3-CH2), 1.72 Is, 3, 5-~13), 2.01 (s, 3, 9{~I3), 2.02 ~2, 4{~l2~ ~ 2.37 (s, 3, 13 CF13), 2.97 (s, 4, ~3CP~;3L36 ~ 12 2l-Gn~2); ~ m/e (relative intensity~ ~M3~ 397 (65) ~
3~2 (5) 1 299 ~12) r 2~;3 (40) ~ 267 (19) ~ 255 (10) r 239 (17) ~ ~;9 (lC0).
~ all~_rans-retinoie acid anydride (3) ALl trans-ret7~oie acid (10 m~, 33 yM) in 0.2 ml o*
tetrahydrofuran ~ias treated with dicyclohexylcarbcdiimide (7.2 ~, 34 ~M) in 0.2 ~L of acetonitrile. The _olution was stirred at ro~ te~~ ature for 2 hours and then diLuted with ethyl ether. P~ee_?itated dic~clohexylurea was re-~oved by filtration ~rd solven~ evaporated under reduced pr~ssure. rrhe residue was susper~a in hexane and chrc~natographed on a Sep~Pak ear~-c'ge. Anhydride 3 was eluted frc~ the cartridse with the m~xt~re o 1.5% propanol~2 in hexane (20 ml).
Further elu~i~n wit`n the same ~uxt~re afforded the unreaeted substrate cx~'~L~.~ed wi~h the produet of condensation of dieyelohe~yLc~Lrboliimide wi-th all-trans-retinoic acid. rrhe pure anhydr~e 3 (_olvent system A) ~as obtained as an oily substance (~ro~ hexa~e). l~C, R~ 0.81 (solven-t system A). W
(eth~nol~ ~rax 38~ ~E 76,0C~3 ~maX 385, 68,300 ~ethanol)~;
IR 1701, 1767 cm ~ (acetc~ne-d6) 0 l.Q4 (S, 12, (CH332C), 1.5 (m, 4, 2-CH2), 1.6 ~m, 4, 3-CH2), 1.74 ~6, S, 5-CH3~, 2.1 (m, 10, 4-C~.2, 9-CE3), 2.44 (S, 6, 13-CH3), MS, m/e ~relative intensity) (~I)* 582 (7), 444 (3.6), 404 (5~4)~ 381 (9.4), 366 (4.61, 2~3 ~7), 177 (7), 159 (26), 145 (17), 44 (lC0)~
Prèparation o' all-trans-retinoic acid CoA ester ~4) N-hydro~succirimidyl ester of all-trans-retinoic acid (2) (1.5 mg, 3.7 ~ in 0.4 ml of tetrahydrofuran was added to a stirred solUtion O~ coenzyme A (2.5 m~, 2.8 ~M) in 0.2 ml of water. The ~H o' ~e solution was adjusted to 8.0 - 8.5 wi~h 1% NaHC03. Ih2 re~ction mixture was stirred under nitrogen atm~sphere at 35C _or 20 hours until most of the CoA was consumed as ~eterm~d by TIC using the solvent system B.
Ester 4 ~las s~ar2'~ed from the crude reaction mixture by preparative T~.C us~ng the solvent system B. Product was extracted fro~ the ~LC adsorbent using a mixture of acetic ~3~3~
acid and ~ter. ~ .ilization o:E the extract afforded pure es~r 4 as dete~.~ '. by 'FLC using the solvent system B (Rf 1 0.43, cc~par.~g ~r h ~~ 0.40 and 0.41 for ~-methylcroto.nyl and ¦ r~yris'~l esters ~~ C~). W tH20) AmaX ~5~ (~ lO,S00 and ~'~r~Rx 393 (~ 32rCC~
Ester 4 ~,~.~s ~lso obtained starting fr~n anhydride 3 usi~g the sar~e proc~ure and separation me~hod as a~e. In this prep~ration, 'r~ er, the fonmation of ester 4 cculd not ke cc~pleted e~en ^~hen coenzym~ A was exposed to a 2-3-fold molar excess of 3r~ydride 3 for double the time .in above pr~paration.
Preparation of N-h~r~ysuccinir~id~l ester o 13-cis-retinolc acid ~6~
The compcun~ 6 ~as prepared by the rnethod esse~tial'ly the same as for pr_~ahra'_ion of ester 2 starting fram 13~c s-retinoic aci~ 5. TLC of chrGmatographically pure ca~pound 6 sh~el ?~ 0.53 ~solvent systern A). W (ethanol) 380 (~ 35 r0~3~; IP~ 1760, 1747 c~n , ~ (acetone-d6) ~
1.05 (s, 6, (~3~2C~, 1.5 (m, 2, 2-CH2), 1.65 (m, 2, 3-CH2), 1.76 ~s, 3, 5 ~ }, 2.05 ~m, 2, 4-CH2~, 2.1 (S, 3t 9~CH3), 2-88 ts, 4~ {~12, 2'-OE12); ~, ~/e (relative intensity~ (M) 3~7 (36), 382 (2), 3~3 ~7), 283 (17), 267 (10], 255 (8), 23g ~19), 41 (100).
Preparation o 13-c~s-retinoic acid CoA ester (7) Ester 7 ~,~s p~ared and purified by the method described for the prepa atiç~ or ester 4. TIC of chrcmatographically pure product S~Y~ _ 0.42 in solvent system B.
T~.e compcun~a O this invention find utility in the treat~ent of ~e~o~ogical conditions such as acne and ichthyosis, ar~1 Ga ~bstitutes for all-trans-retinoic acid and 13-cis-retinolc ~^d in their various known applications.
I~y ~ay al~o ~e uced as a substrate for bioche~ical reactions, such ~s, the transfer of retinoic acid to glycerol derivatives o~ g'~oe rldes or in the B and omega oxidation of retinoic acid.
~L3~ 31~i eferences 1. Zile, M., R. J. E~erick, H. F. DeLuca, "Iclentification of 13-cis-Retinoic ~cid in Tissue Extracts in .-Lts Biological Activity in Ra~s," Biochi~. Bicp~ 5. Acta, Vol. 141r PP-639-641, 1967.
2. Zile, M., R. C. Inhorn, H. F. DeLuca, "~tabolites o:E
All-trans Reti Qic Acid in Bile: Identificat.ion of Pll trans and 13~cis-Retinoyl Glucuronides," J. Biol. Chem., Vol. 257, pp. 3537-35~3, lg82.
.
.
~3~5136 ~U~ ~ - O~
s ~ /o o .
C~ ~e A
(-5 co~
wr~ e 5 = 13-cis~retinoic acid 6 = N-hydroxysuccinimidyl 13- _ -reti~ate 7 = 13~cis-retir.cyl CoA
De~ailed Description of Processes C~ icals All _rans-retinoic acid and the sodium salt of coenzyme A
we~e purchased from Sigma Chemical Co. (St. Louis, ~).
M-~droxysuccinimicle ~nd N,N'-dicyclohexylcarbodii~ide were f~om the Aldrich Chemical Co. (Milwaukee, ~ Disposable silica gel Sep-Pak cartridges ~Waters Pssociates, ~lilford, MA) we-e used for purification of synthetic intermRdiates.
All operations irvolving the use of retinoic acid analogs e~2 perfor~d under yellow light in a nitrogen a~mosphere.
Gl3ssware silanized ~th aimethyldichlorosilane was used for ~r~ synthesis, handling and storage of retinoic acid CoA
t~oesters~ All reac*ions were done using l and 5 ml Reacti-Vials (Pierce Chen. Corp., Rockford, IL).
Ch~cmato~raphic ~ e Analytical and preparatlv~ thin-layer chromatography (~C) was done usiny pre ate alu~inum silica gel sheets wi-~h W indica~or and glass pre-coated silica gel plates (20~20 cm, 2 m~ thick) without fluorescence indicator, respectively, c~,ained fro~ EM Science (Gibbstown, NJ). Plates were c~eloped using sol~ent sys-t~ms: A; hexane-ethyl acetate l:l ~-~ B; n-butanol-acetic acid-watex 5:2:3.
~L3 sæc =
~ . .
Electron i~pact mass spectra (EI-~S) were recorded at 70 eV with al~ AEI l'~-9 spectrGme-ter coupled to a DS-50 data system.
Ultraviolet (W) absorp-tio~ spectra were recorded in absolute ethanol or dioxane with a Hitachi Ik~del 10~-60 W -visible spectrcphoto~eter~
~nfrared spectra (IR~ t~iere recorded on a Nicolet ~
Fm-lR spec~rGmeter in CC14 solution or using i~ns of oily substances.
Proton magnetic resonance spectra (~I-NMR) were taken t~th a Bruker ~ 270 FT spectr~eter in acetone-d6 solutions containing tetra~ethylsilane (T~LS) as internal standard.
Bec]~N~l m~del 4500 pH meter equipped with Bech~an C~B
p~-electrode was used for pH adjus-tments.
PREPARATIONS
Preparation of N-hydroxy~succininLidyl ester of all-trans-retinoic acid (2) Pll-tr -retinoic acid (1) (20 mg, 64 ~M) in 0.8 ml of dioxane was trea ed with N-hydroxysuccin~nide (7.6 mg, 64 ~M) in 0.4 ml of dioxare and dicyclohexylcarbodiimide (13.6 mg, 64 ~i) in 0.4 ml of dioxane. ~ne resulting solution was ragnetically stirred at room temF~rature for 5 hours and then diluted with 10 ml of ethyl ether. The precipitated dicyclohexylurea was separated by filtration and the filtrate evaporated to dryness under reduced pressure. me oily residue was dissolved in warm metnanol (10 ml) and the solution concen~rated under reduced pressure until a slight prec~pitate becare apparent. After standing overnight at -20C, crystals t~--ere filtered off and washed with cold ~ethanol. Chro~tographically pure product (2) showed TLC Rf 0.47 (solvent syst~m A~. W (ethanol) ~max 377 (36.400); IR
1758, 1734 cm 1; ~ (acetone-d6) ~ 1.05 ~s, 6,(CH3)2C), l.S
(m, 2, 2 ~ I2), 1.6 (m, 2j 3-CH2), 1.72 Is, 3, 5-~13), 2.01 (s, 3, 9{~I3), 2.02 ~2, 4{~l2~ ~ 2.37 (s, 3, 13 CF13), 2.97 (s, 4, ~3CP~;3L36 ~ 12 2l-Gn~2); ~ m/e (relative intensity~ ~M3~ 397 (65) ~
3~2 (5) 1 299 ~12) r 2~;3 (40) ~ 267 (19) ~ 255 (10) r 239 (17) ~ ~;9 (lC0).
~ all~_rans-retinoie acid anydride (3) ALl trans-ret7~oie acid (10 m~, 33 yM) in 0.2 ml o*
tetrahydrofuran ~ias treated with dicyclohexylcarbcdiimide (7.2 ~, 34 ~M) in 0.2 ~L of acetonitrile. The _olution was stirred at ro~ te~~ ature for 2 hours and then diLuted with ethyl ether. P~ee_?itated dic~clohexylurea was re-~oved by filtration ~rd solven~ evaporated under reduced pr~ssure. rrhe residue was susper~a in hexane and chrc~natographed on a Sep~Pak ear~-c'ge. Anhydride 3 was eluted frc~ the cartridse with the m~xt~re o 1.5% propanol~2 in hexane (20 ml).
Further elu~i~n wit`n the same ~uxt~re afforded the unreaeted substrate cx~'~L~.~ed wi~h the produet of condensation of dieyelohe~yLc~Lrboliimide wi-th all-trans-retinoic acid. rrhe pure anhydr~e 3 (_olvent system A) ~as obtained as an oily substance (~ro~ hexa~e). l~C, R~ 0.81 (solven-t system A). W
(eth~nol~ ~rax 38~ ~E 76,0C~3 ~maX 385, 68,300 ~ethanol)~;
IR 1701, 1767 cm ~ (acetc~ne-d6) 0 l.Q4 (S, 12, (CH332C), 1.5 (m, 4, 2-CH2), 1.6 ~m, 4, 3-CH2), 1.74 ~6, S, 5-CH3~, 2.1 (m, 10, 4-C~.2, 9-CE3), 2.44 (S, 6, 13-CH3), MS, m/e ~relative intensity) (~I)* 582 (7), 444 (3.6), 404 (5~4)~ 381 (9.4), 366 (4.61, 2~3 ~7), 177 (7), 159 (26), 145 (17), 44 (lC0)~
Prèparation o' all-trans-retinoic acid CoA ester ~4) N-hydro~succirimidyl ester of all-trans-retinoic acid (2) (1.5 mg, 3.7 ~ in 0.4 ml of tetrahydrofuran was added to a stirred solUtion O~ coenzyme A (2.5 m~, 2.8 ~M) in 0.2 ml of water. The ~H o' ~e solution was adjusted to 8.0 - 8.5 wi~h 1% NaHC03. Ih2 re~ction mixture was stirred under nitrogen atm~sphere at 35C _or 20 hours until most of the CoA was consumed as ~eterm~d by TIC using the solvent system B.
Ester 4 ~las s~ar2'~ed from the crude reaction mixture by preparative T~.C us~ng the solvent system B. Product was extracted fro~ the ~LC adsorbent using a mixture of acetic ~3~3~
acid and ~ter. ~ .ilization o:E the extract afforded pure es~r 4 as dete~.~ '. by 'FLC using the solvent system B (Rf 1 0.43, cc~par.~g ~r h ~~ 0.40 and 0.41 for ~-methylcroto.nyl and ¦ r~yris'~l esters ~~ C~). W tH20) AmaX ~5~ (~ lO,S00 and ~'~r~Rx 393 (~ 32rCC~
Ester 4 ~,~.~s ~lso obtained starting fr~n anhydride 3 usi~g the sar~e proc~ure and separation me~hod as a~e. In this prep~ration, 'r~ er, the fonmation of ester 4 cculd not ke cc~pleted e~en ^~hen coenzym~ A was exposed to a 2-3-fold molar excess of 3r~ydride 3 for double the time .in above pr~paration.
Preparation of N-h~r~ysuccinir~id~l ester o 13-cis-retinolc acid ~6~
The compcun~ 6 ~as prepared by the rnethod esse~tial'ly the same as for pr_~ahra'_ion of ester 2 starting fram 13~c s-retinoic aci~ 5. TLC of chrGmatographically pure ca~pound 6 sh~el ?~ 0.53 ~solvent systern A). W (ethanol) 380 (~ 35 r0~3~; IP~ 1760, 1747 c~n , ~ (acetone-d6) ~
1.05 (s, 6, (~3~2C~, 1.5 (m, 2, 2-CH2), 1.65 (m, 2, 3-CH2), 1.76 ~s, 3, 5 ~ }, 2.05 ~m, 2, 4-CH2~, 2.1 (S, 3t 9~CH3), 2-88 ts, 4~ {~12, 2'-OE12); ~, ~/e (relative intensity~ (M) 3~7 (36), 382 (2), 3~3 ~7), 283 (17), 267 (10], 255 (8), 23g ~19), 41 (100).
Preparation o 13-c~s-retinoic acid CoA ester (7) Ester 7 ~,~s p~ared and purified by the method described for the prepa atiç~ or ester 4. TIC of chrcmatographically pure product S~Y~ _ 0.42 in solvent system B.
T~.e compcun~a O this invention find utility in the treat~ent of ~e~o~ogical conditions such as acne and ichthyosis, ar~1 Ga ~bstitutes for all-trans-retinoic acid and 13-cis-retinolc ~^d in their various known applications.
I~y ~ay al~o ~e uced as a substrate for bioche~ical reactions, such ~s, the transfer of retinoic acid to glycerol derivatives o~ g'~oe rldes or in the B and omega oxidation of retinoic acid.
~L3~ 31~i eferences 1. Zile, M., R. J. E~erick, H. F. DeLuca, "Iclentification of 13-cis-Retinoic ~cid in Tissue Extracts in .-Lts Biological Activity in Ra~s," Biochi~. Bicp~ 5. Acta, Vol. 141r PP-639-641, 1967.
2. Zile, M., R. C. Inhorn, H. F. DeLuca, "~tabolites o:E
All-trans Reti Qic Acid in Bile: Identificat.ion of Pll trans and 13~cis-Retinoyl Glucuronides," J. Biol. Chem., Vol. 257, pp. 3537-35~3, lg82.
.
.
Claims (8)
1. A compound having the formula:
wherein R1 and R2 are each selected from the group consisting of a) hydrogen, and b) , wherein X represents Coenzyme A residue;
except that both of R1 and R2 cannot be (a), but one of R1 and R2 must be (a).
wherein R1 and R2 are each selected from the group consisting of a) hydrogen, and b) , wherein X represents Coenzyme A residue;
except that both of R1 and R2 cannot be (a), but one of R1 and R2 must be (a).
2. A compound according to claim 1 wherein R1 is (a) and R2 is (b).
3. A compound according to claim 1 wherein R2 is (a) and R
is (b).
is (b).
4. A method for preparing all-trans and 13-cis-retinoyl CoA
which comprises treating, respectively, all-trans or 13-cis-reti-noic acid with N-hydroxysuccinimide, separating formed dicyclohex-ylurea from the reaction mixture, recovering the respective N-suc-cinimidyl esters of all-trans or 13-cis-retinoic acid, reacting said respective esters with a solution of Coenzyme A and recover-ing all-trans-retinoyl CoA or 13-cis-retinoyl CoA.
which comprises treating, respectively, all-trans or 13-cis-reti-noic acid with N-hydroxysuccinimide, separating formed dicyclohex-ylurea from the reaction mixture, recovering the respective N-suc-cinimidyl esters of all-trans or 13-cis-retinoic acid, reacting said respective esters with a solution of Coenzyme A and recover-ing all-trans-retinoyl CoA or 13-cis-retinoyl CoA.
5. A method for preparing all-trans-retinoyl CoA which com-prises condensing all-trans-retinoic acid with dicyclohexylcarbo-diimide, separating formed dicyclohexylurea from the reaction mix-ture, recovering pure all-trans-retinoic acid anhydride, reacting the recovered anhydride with a solution of Coenzyme A and recover-ing all-trans-retinoyl CoA.
6. A pharmaceutical composition comprising a compound having the formula:
together with a pharmaceutically acceptable carrier therefor, wherein R1 and R2 are each selected from the group consisting of a) hydrogen, and b) ?-S-CoA;
except that both of R1 and R2 cannot be (a), but one of R1 and R2 must be (a).
together with a pharmaceutically acceptable carrier therefor, wherein R1 and R2 are each selected from the group consisting of a) hydrogen, and b) ?-S-CoA;
except that both of R1 and R2 cannot be (a), but one of R1 and R2 must be (a).
7. A composition according to claim 6 wherein R1 is (a) and R2 is (b).
8. A composition according to claim 6 wherein R2 is (a) and R1 is (b).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000538880A CA1305136C (en) | 1987-06-04 | 1987-06-04 | Derivatives of all-trans- and 13-cis retinoic acid and methods for preparing same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000538880A CA1305136C (en) | 1987-06-04 | 1987-06-04 | Derivatives of all-trans- and 13-cis retinoic acid and methods for preparing same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1305136C true CA1305136C (en) | 1992-07-14 |
Family
ID=4135826
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000538880A Expired - Lifetime CA1305136C (en) | 1987-06-04 | 1987-06-04 | Derivatives of all-trans- and 13-cis retinoic acid and methods for preparing same |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1305136C (en) |
-
1987
- 1987-06-04 CA CA000538880A patent/CA1305136C/en not_active Expired - Lifetime
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