MXPA96005312A - Deposipeptidos ciclicos antifungal - Google Patents
Deposipeptidos ciclicos antifungalInfo
- Publication number
- MXPA96005312A MXPA96005312A MXPA/A/1996/005312A MX9605312A MXPA96005312A MX PA96005312 A MXPA96005312 A MX PA96005312A MX 9605312 A MX9605312 A MX 9605312A MX PA96005312 A MXPA96005312 A MX PA96005312A
- Authority
- MX
- Mexico
- Prior art keywords
- group
- ethyl
- methyl
- reaction
- independently selected
- Prior art date
Links
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- 235000012970 cakes Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229950008597 drug INN Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000005469 ethylenyl group Chemical group 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960003136 leucine Drugs 0.000 description 1
- 239000004571 lime Substances 0.000 description 1
- 238000011068 load Methods 0.000 description 1
- 150000004702 methyl esters Chemical group 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 235000020070 mezcal Nutrition 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 150000002790 naphthalenes Chemical class 0.000 description 1
- 239000004533 oil dispersion Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000010802 sludge Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 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
- 239000007921 spray Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 101700065432 talA Proteins 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 239000006208 topical dosage form Substances 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229960001475 zolpidem Drugs 0.000 description 1
Abstract
Described are compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein R 1, R 2, X 1, X 2, X 3, X 4, X 5, X 6, X 7 and X 8 are as proposed herein. These compounds are useful as agents for the treatment of fungal infections. (See Formula
Description
DFPSTPEPTIDOS CTCLTCOB ANTTFUNCALES COMPENDIUM OF THE INVENTION L invention refers to compounds of the formula
1 r > ? lt "jDH» f (? j 1 nt »- '» --i? | - Rl PC? m> »Jo -t». »», »'»;) »• Í» JI »ÍI:» .: I IJIH > J »?" > > I '- ij »-". TJ "or» > > > »> :
- * indua amtioi »isomers or b (> -? n Pl RC jijiibo 25 form R3 is H, methyl, ethyl, propyl or acyl; XI and X6, are independently selected within the group
»: Who is a
* indicates both possible isomers in this center > of carbon; X2 and X3 in »:: a» gives one independently is selected 'within' of the group consisting of
0 R4 is H, • = > r; i lo, m & you lo, or p rop 13; P5 is H, OH, 0- lqu 1 l < Cl -C3), Cl, F, or Br; Pó and P7 are selected J entro > 1e1 »jr po
• that »: ns? Ste» of H, methyl, ti il, propyl, hi rp: i, etoM, e uiv 1 and own 1;
P.1.8 and R19 are independently selected "within the group
. consisting of H, C1-C6 alkyl,
where X "is Cl, F, Br, OH or to COK i C1-C6; X4 is seleo: iopa inside the> jrup>:> which consists of
. { 4
dort »i» - X is HH > T ien NHC -t roml? »-? on > "| ue? H» I NHC n > "--íl- p uni'j» j-5 =? a »; • < rbono that joins a he r'jto o ini 11; 15 RR e =? H or hi- ^ n ilqui ln C1-C4; R9 and RIO a »?. Sl > =» > :: ci un ??? independently den rg>: iei group that consists of H, met J lo, ethyl, pr »op? l > 3; *
and p are independently at 4 a »z» -jnd i »" i ón ue »n + μ n» D 10 is greater than 4; 5 and X7 will be output i ndepend i eni »-ip > > - > > .group "consisting of ue
m
* indicates both possible isomers in this carbon center; 25 XB is selected within »: .the group consisting of
where Rll is H, methyl, ethyl, propyl, or phenyl; R12 is H, methyl, ethyl or proplo; 13 e H, me t ilo, e t i 1 es, or p op i 1 o;
P15 is H, methyl or ethyl; R16 and R17 are independently selected from the group consisting of H, CH3, C1-C6 alkyl,
where X 'is m, F, Br, OH or at 3 > or J Cl-C ?, n b J in a - 1 farin céu t i diwp te ace able > .1el m? -5? I! »3»? > an »_! o e s in 1 -i lé ulcí» > n '_ > rnp »? L > A- > H-O n a group 5 ». ? > ! > > »Je
> : \) ?? u < ?? » a »ji.?e -nr-t?». ie »Ja iiífti1 > »Na al; a ndici on > | i »e when XR is Í3-H0- e» i l val ina, RC is not
with f i IJUGÍL ion í R >; and on condition to »i icionately > that X6 is not D-MeVa 1; and > : on Li i.appropriate additional »how much? X8 s treomna,
R, O I II «, R2- C- C-? Or I and «??? is H p, n can not be 2. It is preferred »=»! composed of formula I > j > tn »of R * is c i > r 1 oh; < 11 o, and R 1 H.
Co or used here, MeVal denotes tM-met i 1 va 1 i na, Phe indicates
T * ^ phenylalanine. MePhe indicates N-met i 1 feni la lanin. Pro indicates proline. Ale indicates loisoleucine. Leu indicates le? Cina, MeThr in ica N-met i l treonip. i-Pr indicates i ap opi lo. n-Pr indicates n-propyl. BOP indicates he? Acloraphospha or »benzotria :: ol-l- iiax i tris (»: iimet i lamino) phosphoni. > : .. PyBOP means BOP of pyridyl. BÜP-Cl means c1 > jruro Bi s (2-o: < o-3- 0 4:01 i »1 i n i l) f» n f í n i o.-). Rent refers to > : »:: ienat» of straight hydrocarbons to
»J 40 r-» i M ada; -, »? Which are between 1-carbon dioxide. • 7. Jemp los re r sin a los os til til, e i .-., pr > : »? Il».), T-butyl, decyl, dode i. It and the like. Alternately, the number »ie carbon s in a particular chain > "ie rent can be specified." For example, the uilo C1-C6
refers to an alkyl which may have at least 6 carbon s. Alcoyí refers to alkyl-O where alkyl is as above
*? "- *» esc r i ta As it is used here, Osu indicates N-a; - 'i succi ida, HOsu.
indicates N-hydroxysuccin i ni i. > .J, DCC indicates 1.3-ic. i > - 1ohe; Icarbod i imida, HOB t in ica N-h i r »:. iben: triaso 1, DMF indicates N, N-ime il formamide (BOC) 20 indi a di tert "but i. Id i arbon BOC indicates, ter tbuto < icarbani lo; and Cb; v indicates benc i. the; < icarboni la 5 and Bn indic benzyl.
As used here, a link _ ^^ indi »:: to a link that s. it leaves the plane of the page. A link of stripes ••• mu indicates a link that reaches below the plane of the page. A curved link, W »A» indicates a racemic mixture. As can be seen, formula I has been made with arrows between each of the amino acid portions, XI to XB, and between the -OC (Rl, R2) C0- portion of the molecule and between XI and X8. The "tail" "ie the arrow between the - *. OCRI, P2) C0> portion of the XI molecule connects to the 1-carbon bon bon
^ 10 portion -OC (Rl, P2) CO > He's the molecule. The tip e of the arrow between the -QC (Rl, R2) C0 portion of the molecule X8 is connected to the other oxygen > ie the portion -OC (R 1, R2 CD of the molecule.) The other parts »ie the» -> Dla »of each arrow are connected to the acid end of the amino acid portion, and the
other "tip" parts of each arrow are connected to the N-terminus of the amino acid portion. In certain chemical structures in this specific ion,
If "* CH3" has been eliminated by greater ease of reading, even when it is understood that it is present. For example, a
times the structure
is used to indicate Compounds »ie formula I of the invention include l» .: > s that 25 appear in the following list No. RC n l C. l he i lo C C Ciclohe: li 1
7 Fe »? I l» J 2 8 Ci lpJp ropil »3 C In all the abovementioned table, Rl is
H. vs, C > > "Additional features" of the invention together with physical and ionic coughs) ion
FABMS M + 1 = 1099.5 and M + Na 1121.5. MIC of Candida tf * albicans and tropic lis = 0.30.
? ^ - FABM8 M + 1 = 1111.5. MIC »from Candi 'to albi» ans and tropicali * \ 1 \, (FAB), MH + 11 MIC = 0.16 Ca fSDB)
The most preferred compound? - J »: > »E the invention is the compound» »-» l, > sn l i lab l =? previous, where P2 is »-?» rl »3he; \\ or > ) i na 5 1 f ar acéi 111 »ament acceptable» the same. I. i n n i laughed at amb ien a c mposic i »?» I »s far acéu 11 ca = - that comprise a one or more of formula I in
CO comb i n-t ». Ion with a pharmaceutical vehicle
H »r t a b 1. L-3 invention also relates to a method for treating fungi > What comprises the idminis trac ion to a mammal does not require such treatment of a > "-? nt i>: l ant? f» »gal
effective > d a c > tax > ~ »E formula T pa a > This is you.
^ DETAILED DESCRIPTION OF THE INVENTION Asymmetric centers e: < I have compounds of formula I of the invention »::? on Accordingly, the compounds of formula I include shallow stereoisomers. All of these isomeric forms and mixtures thereof are within the scope of the present invention. At ore *, which is intro duced, the methods of preparation indicated here can > »Result in f» Je Je Je Je Je pr que que que que que los los los los los los los los los los los los los los los los los
-. 10 - < ? '? n > lia or -in 'IH | I »J» J »??» =? A rs uesta fi s? »" > lo »;» i > _- = »op de - • aria» according to 1-3 su ura e cereoqu i »rti>: a. Í» DS is me sun e-.i =? r know »->!» o »-, i.» ».)» nw i'ií conven »: I on l f.» _ »-?» N »:) > -? R example» D »: ris tal i: a»: i op f,? C? On = »1, cromj togra f í to instantaneous, or bi n HPI.C (rom ografí liquid high
11performance). Compounds of formula I can exist in solvated form as well as in solvated form, including forms * > hydrated, for example the hem? h idrato. In general, the sun forms are tared, with pharmaceutically solvents
acceptable as for example water, etan »jl and similar s» on eqi L va lenses to the forms na sun and tied for the pr "npós? of the invention. These »compounds of formula I having l > The basic approved functional groups, form salts
fat ar.éu 11 »iment acceptable. The most preferred "preferred acceptable" salts: > n addition acidic acid addition salts formed by adduction to a compound of the invention in an approximately equivalent amount of a mineral acid, for example HCl, HBr, HCS04 or H3P04 >;:? or of organic acid such as, for example, acetic, propionic, malaric, oleate, palmitic, stearic, arinate, benzoic, lactic acid, > , pa al oluensí 11 f óm rn, metan-iul phonic, clique, evil, fnm? r »» ro, -5u? ín and similar, "" res 1 t. 10 l »» s curnpi 'es I ») -,» e the formula T an io e ¡.i rep-. ra r-s or j m lo, »es r i ¡os a > . '"(> ti» tua. »- i ón opt mé d» -3 an l go- -!] »? ^ > pl - ¡e < do- = >in l» o-- examples -> i.. L L ma ma ma ma ma ma ma ma ma ma ma ma ma ma ma ma ma ma ma s s s &&&&&&&&s &&s &s s &&&&&&&&&&&&&&&&. ?) n > > »?» L »:» t,? I bie - > u prepare i n = »e describe here, F. REACTION SCHEME 1
r- 1) coupling agent Remover Jf P2XOH ^ PaXrXaOPí > 2X2 * X3CH 2JHX30P, 0 1) coupling agent 2JHX40P,
Remove P ^ P2 2- 3- 4OH 1) Remover agent P \ P2X5OH aC9plamienlOP2Xs-Xß0P? PaXs-XßOH 1) coupling agent 2) HX7? P,
Remove P2 HXrX < r 7? , - P2X5-XS-XTOP,
coupling agent p1 Remove * i p
In. is it a previous reaction, is a block group, ie a methyl or benzyl ester? PC is an amine blocking group such as BOC or X1, X2, X3, X4, XT > , Xí > , X7, and X8, are as described here, and Rl and PC are co or described here. Coupling agents as for example > 3 BOP, DCC, DEC, and pivaloyl chloride are added to the solution. As shown in the schema > : reaction 1, a compound PCXCOH reacts with a coupling agent and a compound of HX30P1 under a dry inert atmosphere, for example, of argon, or with a greater degree of preference, pyrogen, in a solvent Inert organic, such as, for example, tetrahydrofuran, or formamide, or, with a higher degree of preference, than that of wood, at a temperature in the range of approximately -20 ° C to approximately 73 ° C. preferably ~~ 0 ° C, to obtain a compound of the formula P2X2X30P1. The coupling reagent can be selected within the
The group consisting of B0P-C1, DCC, BOP, or, with a higher degree of preference, pivaloyl chloride and N-me and Imorfol ina (NMM). the termination of the reaction can be monitored by means of thin layer chromatography (tick) or by other conventional media. After the reaction is completed, the temperature is allowed to rise slowly until it reaches a temperature within the range of about -10 * 0 to about 2 * 3 * 0, more preferably up to about 0 ° C.
The reaction mixtures are stirred at 0 ° C for approximately 1 to approximately 3 days, prepared by conventional means and made by conventional means such as chromatography, for example, the carboxylic blocking group Pl is removed from the product.
Resulting, P2X2X30P1, by reaction of P7X2X30P1 in a practical, polar solvent such as methanol, propanol, or, with a greater degree of preference, ethanol of normal gradation 200 with a hydrogenation catalyst such as PdOH, Pd-black, or with greater degree of preference, 5 Pd / C at 10 * 4, under a hydrogen atmosphere. The final product, P2X2X30H, can be prepared and isolated by conventional means 1. By means of this use: ie the above or similar coupling and releasing reactions, it is possible to perform the same. 0 the conversion of P2X2X30H -t. P2X2X3X40P \, and espu s a PCX2X3X4DH, D li »? i man > »R-t, \ n ... inversion .Je PC 0H =? P2X5 60F1, and d ^ μ,, _ < - • :. = ¡PCX5X60H can be read. 5 L i larment »-,; > ? can convert the conversion of P2 5X6CH to P2X5X6X70P1. 15 R i mi 1 armen t, e can perform the conversion > e P2X80H a
and then to
To remove the amine blocking group P2, to convert a compound > of formula PCX5X6X70P1 the compound with 1 »DS two protecting groups react with an acid, such as for example trichloroacetic acid in an aprotic solvent, organic with or for example meth. log.
1?
Using a reaction > : similar deprotection, you can convert a compound of formula
P? 0 CO-X, -OP, in a formula compue
REACTION SCHEME C
.0
In the above reaction scheme, Pl is a blocking group of carboxylic acid co or for example a methyl or benzyl ester? P2 is an amine blocking group such as BOC or Cb¿; and Pl, P2, XI, X2, X3, X4, X5, X? > , X7, and X8 are as described to »qui, and R1 and R2 are as described here. Using the first reaction or the second reaction to the immediate arrivals, and the second reaction. 3 is shown on the screen »| e C oller reaction, PCXCX3X40H 1 d b! or of formula P2X2X3XJ-X'3X. X7nPl and after the removal of Pl can be coupled with a compound »_" formula to get a co puest > e formula
starting with a formula ompueslo
PaX? X? XsXjXeO
Pl and PC are removed by reactions as shown in C5 above. For example, deprotection is carried out by reaction with H2 on the reaction of Pd / C to tOVi with trifluoracetic acid in methylene chloride at a temperature within the range of approximately -10 * C to approximately 25 ° C, with greater degree of preference approximately O'C, and then the reaction with 1N HCl in ether. In the same reaction vessel where the deprotection was performed, the resulting compound
HX2X3X4XsX6X7X80 is treated with a coupling agent such as
FyBrOP, OCC, or BOP-Cl, with greater preference of di met i 1 ai nop id in * hexafluorofo fato »tie ben ot r * *•:» .. »1-1 -i lox i tris' dime i lamino) fos onio (BOP) in a polar aprotic solvent with, for example, methylene chloride or ether a »_ > At a temperature within the range of approximately
0 ° C approximately 25 ° C, with a majority »degree» preferably around 25 ° C. The reaction is stirred for approximately 3 days, and then prepared and isolated by conventional means. for
• obtain a cyclic peptide with the formula. I REACTION SCHEME 3
Remove Pi P2X5-Xß-X7? ?
In the scheme of the above reaction P 1. is a blocking group J i is carboxylic such as e < methyl or benzyl ester; P2 is an amine blocking group as per-for example, a BOC to Cbz; and Rl, P.2, XI, X2, X3, X4, X5, X > , X7, X8, and XI, are as described herein. Alt n tively, as shown in the scheme 3 above, by the use of reaction conditions analogous to those described for the reactions of the plant and plant. As described above, a compound of formula P2X5XOX70P1 can be converted to a compound of formula P2X5XOX70H; and a compound of formula
pourable in a comp estr.
The last two compounds partially clesproteg i. can be coupled to form a compound "Je formula
P2 can be removed from
split this last product or to obtain a competitions t »o» Je the formula
HXsXßX7X80 •• «« «• The latter product may be connected to a compound of the formula P2X2X3X40H (whose preparation was described above) to obtain a composition of the formula
The deprotection and cyclization of the compound just above to form compounds of formula I of the invention has already been described. / "" v Below we present biological data for compounds 10 of m la 7 »1e the esen invention» "i n. ! AC Mo. Medium of MTCi- Geo» necl ia Ge »:» (μg / ml) (μ / ml) Ca, fEMEM) Ca. (SDB) ló ". 1 0 0..28888 0, 018 < - * O.353 0.062 4 0.500 0, 32 I - 0.195 O. 15 6 0.500 0.090 20 7"7 00..771100 0.170 8 0.780 0.133 9 0.475 0.290 The geometrical me is taken from the following strains Candida albicans C4 25 Candida alb?» Aus C41 Candida lbi »~ ans C42 V * * Candida albicans C43 Candida lbi »zans C & O Candida albicans C79 5 Candida tropic lis C44 Can &dt. C184 F? ^ Ca nd i da pa raps ilis C5.3 1 0 Ca i id i cia pa raps i 1 is C91 Ca nd i da k ruse i C245 C »J i da r» < C24ó> These compounds are also active against all yeasts and other opportunistic fungi. 15 RESULTS Minimum inhibition concentrations (GMMICs-R (μg / ml) for Ca (SDB) Ca (EMEM) (Derm) and (Asp) for Compounds of the formula I of the present invention are as shown in Table 2 above, The minimum inhibition concentrations were determined in accordance with the procedure set out in TEST PROCEDURES The antifungal activity i.n vi tro was determined in tests of minimum inhibition concentration (MJC) »ie icrot i tu '« tion. ^ using Yeast Nitrogen Br > Dth (YYNB without amino acids, Difco.,
Detroit, Michigan) with a pH of 5.4. The yeasts were grown overnight in a Sabouraud dextrose broth at 28'C with shaking, and the concentrations were adjusted
a sterile saline solution using a spectrophotometer
540 mμ. The compounds were dissolved in several vehicles and diluted in media up to 2 times the final concentrations. The Pro / Pette Cetus system was used to "dilute Q in series 50 μl in plates of 96" "j¿;» Ds of round inn
'10 (Fpl on, Li.n';;; Dln Park, NJ.). The suspensions of adjusted yeast turbometry were diluted 1: 3,000 in YNB.
These dilutions when added to the sludge produced a final in > of 3 K 1000 / ml. The plates were incubated at 37 ° C for -3-8 hours. MICs were defined
as the lowest concentrations of compound compounds that prevented visible growth. The MICs were carried out against the following organisms and expressed in the table ** above: orno la med i.a geamé t r i.ca. These compounds are active against all yeasts and
other opportunistic fungi. Antifungal activity in vivo > of the compounds of formula I of the invention was determined by the use of the test protocol established in ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Vol. 36, No. 1, January 1992, p- 64-67, which
incorporates »by reference. The specific test protocol used p3, ra.a obtain the data presented to
Then they appear in the article mentioned above on pages 64 and 65 under the heading "C. albicans mfection stu ies". The data obtained from this test protocol is 1 > DS following: C pd MP Guide to '/, from CFUs to »1? ni s r ^ c i on u P i a l e 1 1 40 PO 100 6.52 i PO l OO or .38 -? O 1 PO 1 6,01 O 7 i ó. 6 or TV 7"t. Ll T oO .10
40 P0 t? 0 5"80 20 P0 70 6.50 10 Pü 0 7.50 f- 5 P? 0 5f-
Vehí ulo * PC 40 8.28 Vehicle P0 40 8.2 The numbering of the compounds tested is the same as the numbering shown for the compounds in the rest of the application. The mice used in the previous e: ep enta
were Charles River mice, white, > T? a? ~ hos, with a weight between 18 and 20 grams. The agency used
• "to infect the mice was C. lbicans, C-43, 1XE6 CFU / mice, 0.1 Ml IV, treatment was once a day for 4 days starting 4 hours after infection 5 for compounds that have a # near In the case of compounds that do not have cerera from them, the treatment was once: - daily for 4 days starting 24 hours after the infection. The 'dose was 0.1 l / mouse in any case. The vehicle used with the »r» d »tpuets, 10 was Tü.e in 80 j Ethanol: PBS (1: 9: 40 n well 2.? 18 * Í 80 'The pharmaceutical compositions» .ie the present invention can be formulated by the combination of a compound of the invention or a pharmaceutically acceptable salt thereof with any suitable diluent, is
In other words, a pharmaceutically inert vehicle or diluent adapted for oral administration, is 1, top, lime, vaginal or rectal. Examples of suitable compositions include liquid or solid compositions for oral administration such as, for example,
tablets, capsules, pills, powders, granules, solutions, suspensions or emulsions. They can be manufactured in the form of sterile, solid compositions that can be dissolved in sterile water, solution-physiological saline or some sterile, injectable media immediately before use.
? Q
»* Topical dosage forms can be prepared according to procedures well known in the art and can contain various ingredients, excipients and additives. The formula ": ions for topical use include
ointments, creams, lotions, powders, sprays, weigh them, and prayers. Among these, lotions, ointments and creams may contain water, ac-utes, fats, oils, polyesters, alcohols or polyols, or other lenses such as * • > j m what fragrances, e ú 3 si f i cantes y ». onservators. L s
Í O p "» 3? J-, se 1 ^ b "» ran me »11 = • n u] -_? Wn ¿> ]? »Je" »i grediente a >" tj-j ron ij n agent of "powder distribution, unarmed,
> i i 3pon i h 1 e co o by e _? em 1 o ico, < z.? rb > ina t.- > of > -" 1":. i »> , 1-r? cAc? co phosphate or A boric A. Cumbersome suspensions of previous polyees can also be elaborated. HE
can also iv yes-ír t > There are also inert emulsions or solvents which are preferably non-flammable, without oligoes, ions, and toxic solvents, for example, vegetable oils, i -propanol, sulfo, ? »D» j »of di ethyl, hydrogenated naphthanes and alkylated naphthalene. In the same way, it
0 can be prepared aerosolized and non-aerosol sprayed using solutions to suspensions in appropriate solvents, for example, difluorochlorethane for aerosols. Parenteral forms to be injected intravenously, intramuscularly or subcutaneously generally have the form of a sterile solution and may contain salts or glucose to render the solution isstonic. Compounds of the invention can also be incorporated in vaginal or rectal suppositories. The suppositories can be prepared by conventional methods in the art. In addition to including a compound of the invention, the suppositories may contain a suppository base made of biocountable polymers, a surfactant and an absorbent in a. vegetable phase. 1 A »slogans,] > "&sup> suppositories can be modified by inclusion by means of inclusion: When an agent is used orally or parenterally, the compounds of the present invention can be administered in an amount approximately 0.02 mg / g. kg of body weight
to about 4.0 mg / kg > of body weight, preferably "of about 0.1 mg / kg of body weight to about 20 mg / kg of body weight per > day. The determination of the appropriate digestion of a compound of the present invention for a particular situation is
employs within the reach »of experts in the field. In general, treatment starts with lower dosages that are less than the optimum dose of the compound. Then, the dosage is increased in small increments until the optimum effect is achieved under the circumstances. For greater convenience, the total daily dosage can be divided and administered in portions during the day if desired. The amount and frequency of administration of the compounds of the formula I and the pharmaceutically acceptable salts of
they will be regulated in accordance with the doctor's criteria taking into consideration factors such as the e ad, condition, size »of the patient, severity of the > of the symptom to be treated and 1? pharmacos i pé t i. as »of the compound
/ *. particular »u.e s is using. 10 L-i invention in a to c is shown in the following examples of a country that do not owe c &g; > ns i > ierar se coi] i itii I -i I.! o-'j »lel. scope of the u ion. Gulas.-An > a s alternatives to í. as analogous structures within the scope of the present invention may be apparent to the
1. 5 e: ert in the subject, EXAMPLE 1 PREPARATION OF BOC-N-METHYL-VALINE and
N (ß) B0C
60 g of BOC- were dissolved in ina in 1 L of dry tetrahydrofuran (THF) under an atmosphere of dry nitrogen. The reaction mixture was cooled in a bath of ice csnn agitation
by the top and addition in divided parts of 34 q t fe fe, of sodium hydride (NaH) (dispersion of oil to 60). The temperature was debited by 25 ßC. After the addition was complete, 141 ml of methyl iodide was added dropwise over 30 minutes. When the reaction became too viscous, another 200 to 300 additional ml of THF were added. After 1 hour, it was determined that the reaction to the ambient temperature would be disturbed and stirred for 18 hours (during the night) A small sample was prepared to add water and by washing l i.le 1, < f - '. pa A fns ** with H »:: et-3'" .- > et l »t. The water was identified as a citrusy aquatic ida (10 * 5) and x with full met chloride. Fl espero »magnetic resonance i > -.-. of proton (PMP) was measured and showed the correct ratio between the N-me "3o and the 3 i n-met i. (note: the chrom tography in
elgad layer (TLC) showed no separation of the initial B0C- v lma and product). Preparing a large amount of water to stop the bubbling caused by the ex-io-that of NaH (ie, approximately 30 ml of water) was added. It vanished
the THF at approximately 20 ml. 1 L of water was added and the mixture was washed with 2 x 500 ml of ethyl acetate. The aqueous layer was acidified with solid citric acid to a pH of approximately 3 to 3.5. The mixture of the reaction was extracted with 3 x 500 ml of
I mixed wood, dried in MgSO4, filtered and evaporated to dryness. The compound was eventually crystallized in the form of a tan-colored solid of semigoma. FAB-MS m / z
EXAMPLE 2 PREPARATION OF N-METHYL ESTER HIDP0CL0PUR0 -VAL IN-0- BENCILO
f ^ > 1 Se »d J sol v lei'iin» ~ of BOC- -met 11- a 1 i na in 300 ml > of toluene 'dry. 29.3 ml of DMF-iodine were reacted and the reaction was carried out in a dry nitrogen atmosphere for 18 hours (overnight). TLC (30 * 5 ETOCAc / hexane) was used to observe if the reaction y, > In addition, the reflux continued and the reaction was monitored ad hoc by TLC.
When it was finished, the mixture of the rear was evaporated until an oil was obtained. The oil was dissolved in 10O ml of methylene chloride and an ice bath cooled. 10 ml > The temperature was slowly raised to room temperature. After 3 hours, the reaction was reversed by TLC to see v,? It has reached its culmination. It has been made
1"! TLC with two solvent systems, 5V, MeOH / CH2C12 and 30 '/" EtPAc / hexane.) When the reaction was complete, it was prepared by evaporation to an oil, addition of hexanes and stirring. The hexane supernatant layer was decanted and this step was repeated two see A. The resulting syrup material was dissolved in SOO> ni> ie ether and 40 ml of HCl in cyanoxane, drop 3 O were added. ) a, to obtain a pre ipi White side, the r 4 pre-poll -ido u il rado y lavado »:». ether, dried in an oven »Je •, '- >»: [>. > a 4 T to obtain 1 20.56 g of product FAB-MS m / z 222 (M + H), EXAMPLE 3
• *
PREPARATION OF B0C-ALL0I50LEUCINE? 0 L-al-isoleucine (20.0 g, 0.152 mol) was suspended in 200 ml of MeOH at 5 y, / H2O. The pH was adjusted to 9-9.5 with 4N NaOH. The reaction mixture was cooled to 10 °} C. and di-tert-butox i-d icarbonate (39.8 g, 0.184 mol) was added. The pH was maintained at 9-9.5 with NaQH, after approximately 0.5
hours, the cooling bath was removed. The reaction mixture was stirred at room temperature for 3-4 hours.
T? < 'MeOH / CH2C12 at 5 * / was subjected to TLC. When the
The reaction mixture was acidified to a pH of 3 with 20 * / 5 cyclic acid, extracted with 3 X 500 measured CH2C12, dried over MgSO4, filtered and evaporated to give a gum. They added 200 mi. of toluene and the reaction mixture was evaporated. This last pass was repeated, which is additional until a gum was obtained which was weighed under high vacuum for two days to provide a
1. 0 só 1 i > do (37, 53 g). EXAMPLE 4
PREPARATION OF BOC-ALL0ISOLEUICIL-N-METIL-VALI L- • Q-BENC? L0 BOC-ile esters (2.7.06 g, 0.117 mol) in 150 ml of dry CH2C12
an atmosphere of dry nitrogen and N-me I: lmorfctl i was added. Na (NMM) (25.73 ml, 0.234 mol). The reaction mixture was cooled to -20 degrees C, and arsenyl chloride (15.85 ml, 0.129 mol) was added dropwise at -20 degrees C. The reaction mixture was stirred for 4-5 hours at - 20 degrees C.
Activation was determined by TLC (MeOH al
** 54? / CH2C12 / H0Ac at 0.5 * 4) in the following manner: (To a small aliquot, n-bu-lamin was added and citric acid was quickly added and the resulting mixture was stirred. layer of CH2C12 and compared with the initial BOC-aile., absence of BOC-aile or a very small amount was observed). In a separate, dry 250 ml round-bottomed flask, N-meval-OBn HCl (30.1 g, 0.117 mol) and nn (25.75 r ~ H? Ml, 0.234 mol) were dissolved in 150, -? L of 0¡ - »2C12 dry. The above reaction was added dropwise to this suspension at a temperature comprised between -1.0 and -20 degrees C to ba or a nitrogen atmosphere -sec, Se »let rise slowly at a temperature of 0 degrees C, The mixture >15 of the reaction was stirred at 0 degrees C for 36 hours. The reaction was determined by TLC (MeOH at 54/./CH2C12 / 0.5% H0Ac). When the reaction was completed, the mixture f ~ of the reaction was washed with citric acid at 20 * /, the CH2C12 layer in MgSO4, and filtered, and the solvent was evaporated
0 under reduced pressure to obtain a gum (55.1 g). The gum was dissolved in 500 ml of hexane, loaded on a flash silica column of a little more than 1 g of silica packed in hexane, and eluted first > : op 9 liter »of hexanes. Fractions were collected from ÍL, then
eluted with 91% EtOAc 5% / he? Anoj 9L EtOAc at 7.55 / hexanes and finally 91% EtOAc at lOV./hexana. He
? The product containing the fractions was collected and evaporated to obtain 12.5 g of a slightly impure product and 21.15 g of a pure product. EXAMPLE 5
and 0 PREPARATION OF BOC-ALL TOSOLELICI LN-METT L-VAL TNA BOC ester was dissolved in the soli-lN-et 11 -va 1 and 1-0-benzyl (21 g, 48.3 mol) in 200 ml of EtOH in normal graduation 200. Under nitrogen, 1.25> g of P »d / C was added to 10 '/' was stirred under an atmosphere of" H2. After 18 hours,
The catalyst was removed by filtration and the residue was washed with EtOH and the solvent was evaporated to dryness and co-triturated with dry 3X toluene (to remove the
/ or * - EtOA) ps. pa obtain 16.8 * 9 g of a solid of tip »D gorn. FAB-MS m / z 345 (M + H). EXAMPLE 6
Ts * 58
PREPARATION OF BOC-ALLOISOl EUCIL-N-METIL-VALIL-LEUCIL-OBn
BOC-loisoleuci 1-N-met 11 -val i na (16.53 g, 48 mol) > = > p 1 1 Dry CH2C12 itro under dry nitrogen. Benthyl ester tosylate was added L-leucine (94.43 g, 240 mol), followed by the addition of n m (26.4 ml, 240 mol). The mixture > of the reaction was ag? ta »da at room temperature ^ 10 mol * > . The z the > of the reaction was eii -J »-20» jra »i» ps C and added 1, 3-d i c ic loosi l arbndi imi > the (DCC'J (18.4 g, ^ h mol * in small portions (during a laps »D of 0.5 hours to maintain the temperature at -" - ^ g ados C. After finishing
the address, was allowed or that l a. The temperature of the reaction rose to 0 degrees C. The reaction temperature was stirred at 0 degrees C during the course of the reaction. night. TLC (MeOH at 5 * / 5 / CH2C12 / H0Ac * 10.0% \ and EtOA at 30 * / ./year) was performed to detect and complete reaction. When finished the
After drying, CH2C12 was evaporated under vacuum to obtain an oil. The oil was washed in liter of EtOAc washed with 1 liter of 1N HCl and then with 2 X 21. of distilled water (notes the reaction mixture did not remain in a solution aia due to the inability of the group. BOC e?
rido). The reaction mixture was washed immediately in saturated NaHC03 followed by water again, dried in water.
/ ^ > Mg2S04, filtered and evaporated to obtain a viscous pull. The reaction mixture was cured to 1.5 kg of silica gel (instantaneous grade) by loading the
Compound in CH2C12 (approximately 300 ml) followed by elution as follows, collecting fractions of 0.5 liters: 4 liters of hexane, 10 liters of 5% EtOAc / hexapo,
16 l? Tr »os» of EtOAc at 7,55 / hexans, 10 liters of EtOa at
-. 10 * / hex na, 10 liters of EtOac at 1 .5 / hexane, 10 liters of FtOa ». at 1"V / 5 / hr., The compound was eluted in EL0A, at about 1 / hex years, to fractions containing the product were collected and evaporated to obtain a viscous syrup (20.4 g). -MSm / z 584 (M + H) EXAMPLE 7 1
PREPARATION OF B0C-N-METT L-0-Bn-TPE0NINA 60 g (0.194 mol) of L-N-B0C-0-B-reonin was dissolved in 1 liter of dry THF under an atmosphere of dry nitrogen. The reaction mixture was placed in an ice bath with stirring at the top and 23.28 g were added.
(0.582 mol) of sodium hydride in a 60% oil dispersion, in portions. The temperature was maintained by default of 25 degrees C. After determining the addition, 141 ml of methyl hydrate was added, drop by drop, during 30 minutes. When the reaction became too viscous, an additional 5 200 to 300 ml of THF was added. After 1 hour, it was allowed > The reaction was brought to room temperature and stirred for 18 hours (overnight). A small sample was prepared by the addition of water and the layer of water was washed with ethyl acetate. The layer "of a" was r "-" or labeled with Scido ítrico a uo- ?? (10 * 5) and extracted with chloride >1e met full. The TMP was taken. The PMP showed the pfppnrpon > -.- > rre.-l? between N-ilo and va 1 i na- et i 1""> (Note: the TLC did not show the evolution of the reaction, in such a way that PMR had to be used).
Large scale preparation: 3 ml of a > : Ua > drop by drop. The THF was evaporated to approximately 200 ml. 1] r of water was added and the reaction mixture was washed with 2 X r ~ 50O ml of ethyl acetate. The aqueous layer was acidified with solid citric acid to 1 pH of about 3 to
approximately 3.5. The aqueous layer was extracted with 3 X 500 ml of chloride > of wood, dried in MgSO4, filtered, and evaporated to dryness to obtain 56.4 g of an oil v i coss. EXAMPLE 8 25
PREPARATION OF LN-BOC-N-METHYLPHENYLALANIN In a 3-liter bottle, under an N2 atmosphere, LN-BOC-pheni was dissolved in the 1-year-old (70.00 g, 26.4 mol) in 1 liter of THF. The solution was cooled in an ice bath and sodium hydride (dispersion in 60 * 5 oil) was added (31.70
- i or g, 1320 mol) to the cooled solution in portions or stirring. The increase in weight was increased, and an additional 350 ml of THF was added to the series, thus "} The mixture of the reaction was lowered so that the reaction mixture could be stirred again. '"Se" "' observed
bubbling and the reaction mixture turned gray. The mixture was stirred for 10 minutes, iately (299.?, 2.11 mol) was added to the reaction mixture, and the reaction mixture was stirred for 10 minutes at 0-5 degrees C. was then stirred at room temperature during
8-15 hours (during the night). The reaction was monitored by PMP in CDC13. Approximately 2 nl of the reaction mixture was left and stirred in a mixture of CH2C12 (2 L) and H20 (2 mL). The aqueous layer was acidified using an acid solution
citric acid to IQ'A (weight / weight) and extracted with CH2C12. The layer? ».- ^ of CH2C12 was dried (MgSO4) and evaporated. The PMR of the residue was taken and the peak integration of the N-methyla group (2.76 &2.69 ppm) and the phenyl group (7.10-7.40 ppm) was checked. When the ratio was less than 3 to 5, the reaction mixture was stirred for an additional 4 hours and the PMR of the reaction mixture was checked again. When the ratio was 3 a, the reaction was complete. After completing the reaction, 20 ml of HoO were added. to the jar slowly to 'destroy the excess NaH. The
mez '-] a > of 1? react ». i OII was evaporated until obtaining a syrup
(most of it was removed »Je THP) and 300 L > from
H20 The aqueous mixture was washed with CH2C12 (3 X 200 ml), cooled in an ice bath and acidified using a
"" "* citric acid solution (approx. 160 g in 200 L
of H20). The pH value of the solution was checked. The solution was extracted with CH2C12 (3 X 200 L). The organic solution was dried (MgSO 4) and evaporated until a
«*« • », syrup ama illo-c fe (75.33 g). The syrup was seeded with crystals of L-N-BOC-N-met i lf or lalanine (previously
elabora »do) to obtain 1 CDS crystals (a mixture of long crystals and yellow-brown oil). This product was used for the following reaction if additional purification, FAB-MS m / z 280 (M + H) As used herein, rt means room temperature 25 EXAMPLE 9
PREPARATION OF THE PTSA SALT BENCYLIC ESTER OF LN-METHYLPHENYLLIN INILO L-N-BOC-N-me 111 pheny1 = tlame (40.0 g, 143 mmol), benzyl alcohol (BnOH) (68.2 g, 631 mmol) and monohydrate "from j > 3-p-toluenesulfonyl acid (pTSA) (49.0 g, 258 mmol) in "00
- '1 ml of oluene at temperature' of reflux or a Dean-Start trap under an atmosphere of N2 overnight (15 hours).
The reaction mixture was allowed to cool. White solids were pressed. The solids were removed by filtration and rinsed with toluene. The filtrate was evaporated
until obtaining a syrup. Et20 (approximately 300 mL) was added to the syrup and the syrup was swirled. the saltation of Et20 was seeded with some "pTSA salt crystals" of benzyl ester "of L-N-met 11 fem lalan mi lo
(previously prepared). The white prices were
.0 collected by filtration and filtration cake -was rinsed with cold Et20 sn. The filter cake was dried under house vacuum overnight to provide 55.05 g
(yield »of 87., * /,) of salt pTSA of benzyl ester» ie L- N-me 11-fem 1 am lo. the filtrate was evaporated at 1 OO, »L and
mL of 4M HCl in dioxane (anhydrous) was added. A precipitate was formed. The precipitate was recovered by filtration and rinsed with Et20. The precipitate was dried under a vacuum box to provide 2.15 g (yield of 4.93 *?) Of an HCl salt of benzyl ester of L-N-meth i 1 phenylalanine.
(MOLECULAR WEIGHT, 304.84). FAB-MS m / z 270 (M + H). EXAMPLE 10 1) Piv-CI, NMM __
NMM, CH2CI2, -20 ° C
PREPARATION OF ESTER. BENCYLIC OF L-N-BOC-PHENYLALANINYL L-y-. N-METHYLPHENYLALANINYL LN-BOC-pheni was dissolved in the lanin (20.2 g, 76.1 mmol) and N-20 methylmorphol ina (NMM), 16.74 mL, (152.2 mmol) in 200 mL of CH2C12 in a bottle of 1 liter dry at a temperature of -20 degrees C under an N2 atmosphere. Pivalenyl chloride (PIV-Cl), (9.85 ml., 79.9 ml) was added dropwise to the solution (to keep the reaction mixture at -20.
degree O and the reaction mixture was stirred for 4 *. hours at -20 degrees C under one atmosphere > Je N2. After 4 hours (formation of anhydride, myxo, reaction 1) the reaction mixture was reduced by TIC (silica gel) by the use of an N-butyl amine. 5 Prepare TLC ion: A few drops of the reaction mixture that was reacted with a cat of amine of N-b? T? La were taken. After 1 my myth was added - I went to 10% cy to l a. solution ».ie butyl amine adduct. The resulting mixture
^ was extracted with a small amount of ELOAc. The material
? N? »?? A» lp fin-- d te > "ta» lo, the> --tpa »the EtOAc was" de tec 1 a »J, - e-, 1 a -s > 3s as were spliced.The plaque was revealed in a -ji-j ßim de solven »of 30 * / 4 .Jet EtOAc / year The" disappearance> of the initial material and the formation "of amide» N-butyl was monitored.
of starting material, 5 to 10 * 5 of Piv-Cl was added again and the reaction mixture was stirred for an additional 4 hours in the same reaction conditions. After
The reaction was again carried out by TLC until complete: it was complete. O After completion of the reaction (at least one reaction of approximately 90-95 * /.), A mixture of p-TSA salt of LN-methyl phenyl lamne (21.4 g, 48.7 mmol), NMM 5.36 ml was added. (48.7 mmol), and 20 ml of CH2C12 to the flask. The resulting mezcal was stirred for 8 hours at -20 degrees C or N? Atmosphere. Coupling reaction was monitored by TLC (silica gel). PREPARATION OF TLC: A few drops of the reaction mixture were taken and said mixtures reacted with a drop of 5 N-butyl amine. After 2 minutes, citric acid at 10 * 5 was added to the n-butyl amine adduct solution. The resulting mixture was extracted with a small amount of EtOAc. After a few drops of the reaction mixture reacted ».on ¿> »_?» Jo citric to 10 * 4, U resulting mixture • id fnu extracted > : ») N a small amount»: le EtOAc, These two et tas > of Ti C were compiled ». "n-to-1": n-butyl "to" of n-butyl by the "developing" of the plate n < < n solvent system »of 30 * 5» of FtOAc / hexane. The amine-free mixture of n-but? L > -? was the coupled product and the sample with n-butyl amine was the adduct of the n-butyl amine. When the coupling ended, there was no n-butyl amine adduct formation in the TLC sample. The disappearance of adduct from butyl amine was also revised because it indicated the ending > of the coupling reaction. Once the coupling was complete, a solution of citric acid at l0 * 5 was added to the reaction mixture and the reaction mixture was extracted with CH2C12 (3 X 100 mL). The organic layer was concentrated by rotary evaporation at 2 0 m. The residue was washed with a solution of NaHCO3
saturated. The mixture was extracted with CH2C12 (3 X 100 L). The organic layer was dried with MgSO4. The CH2C12 filtrate was evaporated until a syrup was obtained: Djo-coffee. The product was isolated by the use of flash chromatography (silica gel, 45.72 »:: m X 30.48 cm). The crude product was charged in a minimum amount of CH2C12 to the column and the column was washed with 2 liters > of hexane. The column was eluted with a mixture of EtOAc at 5 * / h, anus (4 liters), and then with 10 * EtOAc / hexa no. The column was monitored by TLC (silica, EtOA) at 70 ° / h x r). 10 pués-s, (μa pin i f ipp the column, S n i i - er On ^, 8 »j
(r nniment »iel 95.0 *> 5)» of ¿ÍI UP lt ni.i l < > : > iJ »-1! - - OC- feml al an i n > 1 l -N-met i 1 fen »1 to 1 to n» u i 1 > > . FAP-MSi.n '' 51"(M + H * <.) EXAMPLE 11
PREPARATION OF L-N-B C-FENI LALANINI L L-N-ETHYLPHENIL AI.ANI A S dissolved L-N-BOC-phen t 1 in the kid (23.3 g, 45. mmol) in 500 ml of EtOH under N2 atmosphere. Two grams of palladium were added to the l »4 n activated carbon to the solution. The bottle was equipped with an H2 balloon and the bottle was evacuated using a home vacuum. The H2 was released into the bottle and the .5 bottle was evacuated. This procedure was repeated two times. The black mixture was stirred under H2 at room temperature overnight (15 hours). The mixture was filtered through celite under N2 atmosphere. Cell a was rinsed with hot EtOAc under an N2 atmosphere. The filter cake was preserved until all of the product had been recovered (the final product tended to last for the duration of the product). The filtrate was evaporated until it was obtained to obtain 16.5 g.
J * bm (yield »Jel 86.0 * 4) > | nna L-N-BOC-feni 1 to 1 anini 1 L-N- »> ? »~ - 1 i 1 f > -n? 1 -i 1 -i ni na e = .p ?? »n -.a, white. ^ reaction was ground by the TLC »» »of sil '» .. »*, EbCAc at 30/5 / he - year) - FAB-MS / • 4" (M + H), EXAMPLE 12
NMM, CH2CI2, -20 ° C
^ PREPARATION OF ESTER L-PROLINI LBENCILICO OF L-N-BOC- \ PHENYLALANINIL L-N-METILFENILALANINI LO L-N-BOC-feni were dissolved. lalanini 1 L-met i 1 phenylalanine (16.6 g, 39.0 mmol), and N-methylmorpholine (8.57 m, 78.0 mmol) 5 in 200 ml of CH2C12 in a dry 1 liter flask at a temperature> 0. He -20 degrees C drops »3 an atmosphere of N2. Pivasonyl chloride (8.57 mL, 42.9 mmol) was added dropwise to the solution (to maintain the temperature of the
, -I reaction to -20 »ra» two C) the reaction mixture was i 1 > This was carried out for 8 hours at -20 degrees C under an N2 atmosphere. During the active ion (mixed anhydride formation, reaction 1) TLC was used (ice gel) using amine > n-butyl »3 to check the reaction mixture. Preparation of TLC: A few drops of the reaction mixture »
reacted with a "drop" of butyl amine.After 2 minutes, 1.0 * 5 citric acid was added to the solution.
_ Butyl amine adduct. The resulting mixture was extracted with a small amount of EtOAc. The layers of EtOAc and 3 as L-N-BOC-pheni lalanini 1 L-me i 1 phenylalanine were detected and
these two samples were spliced. The plate was developed in solvent systems of 30 * 5 EtOAc / hexane and 5 *? of MeOH / CH2C12 (with HOAc to .IX). The disappearance of L-N-B0C-feni lalanini.1 L-met i 1 phenylane and the formation of butyl amine adduct was monitored. When L-N-B0C-25 pheni lalanini 1 L-met i Ifeni lalanin was observed, an additional 5-10 * 4 r of Piv-Cl was added and the reaction mixture was stirred for an additional 4 hours under the same conditions. Then the reaction mixture was checked again by
TLC 5 After finishing the acti ation (at least one reaction of approximately 90-95 * - :) s added a mixture of benzyl ester salt of L-prol mi let (9.4 g, 39.0 mmol) to the flask. NMM (4.28 ml., 3. mmol) and 200 l of CH2C12.
^, The mixture re - =, u] t =? It was Í I tsda for 24 hours =, to -2"10 gradne; C in one to l-.nó-> f de de,". I a resn-i? N »de a.-.jo 1 even nl o was moni o a? p > ) r TLC (gel of - * 11? .- e ^. P paraci el TLC; l) na < -? ueñ - = drops of the .. »the» of 1 ^ reaction reaction with a ga k? »Ie butyl amine. After 2 minutes, citric acid was added at 10 * 5 to 15% solution. t »: > Min and butyl, the resulting mixture was extracted with a small amount of EtOAc. Some 'jotas of the mixture' reaction reacted with acid and citrus at 1 *. I__? The resulting mixture was extracted with a small amount "Je EtOAc. These» do < - > samples »Je TLC were
0 compared > : o? t - * al »de h i rocl aruro > Benzyl benzene »by L-prolinyl me > before the development > of the plates in solvent systems of 30 * /, of EtOA / hexapa and MeOH to 5 / CH2C12 (with HOAc al .1 * 5). The butylamine butyl mixture was the coupling product and the mixture with butyl amine was the
amine adduct > Je butyl. When the coupling ended.
"No formation of butyl amine adduct was observed in the TLC sample. The disappearance of the L-prolyl benzyl ester hydrochloride salt was also checked when the coupling reaction was nearing completion. After the addition was complete, a solution of citric acid was added to? * A to the reaction mixture and the mixture H was extracted with CH2C12 (3 X 100 mL). The organic layer was washed with a saturated NaHCO 3 solution and washed. w6 the organic layer > : on brine The layer »- > rg m »_. a was
1 dry '»with MgSO4 and the filtrate» Je CH2C12 was pored until a solid (24.6 g) was obtained, foamy, yellow. FAB-MS -'z 614 (M-H-P, EXAMPLE 13
»- PREPARATION OF L-N-BOC-PHENYLALANINIL L-N-METHYLPHENILALANINI L-PROL INA Benzyl ester of L-N-BOC-phenylalaninyl L-N-et i 1 phenylalanine 1 L-prolinil (16.9 g, 27.6 mmol in 300 ml was dissolved.
of EtOH under an atmosphere of N2. Palladium was added at 10 * /. in activated carbon to the solution. The bottle was equipped with a balloon of H2 and the bottle was evacuated using the vacuum. home. The H2 to the bottle was released and evacuated. This * ^ procedure was repeated twice. The black mixture was
After stirring under H2 at room temperature overnight (20 hours), the reaction mixture was filtered through cel i and the filtrate was worked up to obtain 1.4.6 g of L-N-BOC-fepi laine. neither the LM-met i 1 feni, the lanini, the frothy L-proline, white.The reaction was monitored by TLC (gel
of silica, MeOH at 5 * / 5 / CH2C12 with HOAc at .1%). FAB-MS m / z
524 (M + H). EXAMPLE 14
3
PREPARATION OF BOC-FENILALANI I LA-METI LFENI LALANI ILA- ~, PPOL I L-ALOISOLEUC I L-METI L '-' AL I L-LEUC T l.-BENCI LESTER 10 Se d i. - ?? 1 i. L-N-BOC- f n i 1 a 1 a n i. n i 1 to L-W-me t i 1. in 11 a i a n 1 n 11 a L-prol ina (20 g, 38.2 mmol) in 200 ml of methylene chloride
? e 1; > D b a t o 01. na a tí J '> i. 1; Róijei 10 a r g ó NMM
(8.8 ml, 80.22 mmol) and the reaction mixture was cooled to -20 ° C. Pivalayl chloride was added (5 ml, 40.11
1. 5 mmol) and the mixture > of the reaction was stirred 'for 18 hours at -20 ° C. In a 500 ml round bottom flask
After separating with flame, the ester was dissolved in loisoleuci 1-N-ethyl-1-i-1-leucyl-1-benzyl ester (21.54 g, 38.2 mmol) in 200 ml of dry methylene chloride and 4.6 ml (42.02 mmol) of NMM.
This clear solution was added to the above reaction and stirred at -20 * G for 48 hours. The cold bath was removed and, while it was cold, the reaction mixture was acidified with 10 * 4 citric acid until reaching a pH of 3 to 2.5. The reaction mixture was extracted with 3 × 500 ml of methyl chloride, the extracts of methylene chloride were dried in magnesium sulfate, filtered and evaporated to dryness. The oil was added to a 1.25 kg instant silica column packed in hexane, and eluted with 3 L of benzenes, followed by 9L of ethyl acetate at 254.4 / bexane, followed by 91. ethyl acetate. at 30 * 4 / hexanes, followed by p »3r 9L of ethyl acetate at 0 * 4 / hexa, followed by 3 L. ethyl acetate at 50 * /, / he'- ano -?, and finally 9L» J »j ethyl acetate
and * - "O *, 5 / he - an" t. l -, fractions containing the product ".- 1» were
1 . gid: > evap > »R-_da-a h - > t ^ e.-? i »-». . I-rr -i ob n r 2 £? . 3 g »J > -.- l p i »l» l? i ", i> d l ith E TEMPLE 15 ACTDO BENC TI (R - HEXAHIDPOMAMDEL ICO The carbonate of ces i o (solution up to 20 *) is added to a
fifteen - . 15 -solution e A ulo (R) -hexah idromancJél i > ~ »(3 g, 19 mmol) in" O. ni each of H20 and methanol until the pH> of the solution reaches "7.0. All the sun vents were removed in vacuum. The residue was dried, dried DMF, evaporated to dryness, and the p &or > etion was met once. He
2 residue obtained from ^ > The manner was redissolved in 7% dry dtmethyl sulfoxide (DMSO). Benzyl bromide (2.4 ml, 19.6 mmol at room temperature was added and the solution was stirred for 4 hours.The mixture was divided between H20 and ethyl acetate.
sequentially on H20 (twice) and brine, dried over Na2SO4 and concentrated. The residue was chromatographed on a silica gel * (5 * 4 EtOAc / hexane) to give an ester (4.47 g, 95 * 4) as a white solid: (al fa) 25D + 2.46 (CHC13); FAB-MS m / z 248 (M + H) -.-. EXAMPLE 16
ESTFR OF L-0-Bn-N ~ Boc-TRE0NIL- (R -HEXAHIDR0MANDELIC0-ACID0- 0-BFNCI OA stirred solution of N-Boc-0-benzyl lo-N-met i 1 threonine - < 13.3 g, 41.2 mmol) f - "- benzyl ester (9.9 g, 40 mmol) 4-15 (N, N-ime i the i no) pi idine (4.88 g, 40 mmol in 200 ml of dry CH2C12, was added 1, 3-di »: ic lohex and Icarbod i imide (8.73 g 42.4 mmol) at the temperature of 0 ° C. The temperature was maintained at 0 ° C. for 5 hours and then slowly reached 20 ° C. overnight. removed by
Filtration was carried out and the filtrate was di.vicii.do between citric acid at 1 * 4 and ethyl acetate. The gano layer was washed with H20, brine, dried in Na2SO4 and concentrated. The residue was chromatographed on silica gel (20 * 4 isapropyl ether / hexane) to provide an acid peptide (18.2 g, 82 * 4 * e oil) (al f) 25D + 220.61 ICHC13 'FAB-MS m / z EXAMPLE 17
ESTEP DE -O-Bn-N-F. »? C - TBEONT L - IR) -HEXAHTDPOMANDELATO-L - 1 METIVAI TNA-0-EE CTl.n / E3 depsid Ipeio i eta eta eta ? 5.4 was »? ? drog "» swim b-! ..or one sphere> H2 f. 1 r »'/, Pd / C (7 * 4 that / p ^ n1 dm > n» -e 4 hydras to generate * <lynx>, a olu ión a l »": a »da> g of this free acid (11, 57, 25 mmol1, N-met i 1-0-ben 11 -va l ma (6.67? j, 30 mmol) and i.N-ii op »'or? 11 el-1 lamina (9.56? i> 3, 55 imitol) in 1 ml of CH2C12, -sulfur (2- a? -3- axazol id 11) -fosf 1 ni (7.65, 30 mmol) at 0 ° C. The mixture was added at 0 ° C. for 4 hours and then it was determined between citric acid. to 1 * 4 and check it in> ethyl.
Organic was washed with H20, brine, dried over Na2SO4 and concentrated. The residue was chromatographed on silica and (ethyl acetate at 15 * 4 / hexane) to provide depsipeptide (12.36 g, 74.4) in the form of an acetyl-1alpha) 25D-37.8 (CHC13) s FAB-MS m / z (M + H> +. EXAMPLE 18
ESTER. N-Boc-FENI LANAL I LN-METI LFENI LANAL I L-PROP IL-AL »3- ISOLEUCIL-N-METILVALIL-LEUCIL-L-0-Bn-TREONIL- (R) - HEXAHIDROMANDELATO-L-METIVALINA-0 -BENCIL To a solution of N-Bac-feni anal ini iN-met i 1 phene lana 1 ini 1- pr »ol i. nor 1-alo-isoleuc ini 1-N-met i. Iva 1 ini 1-leucine (4.9 »g, 5.68
mmol) and 4-met i. Iorfolin (1.37 ml, 12.5 mmol) in 90 ml of CH2C12 was added with methyl chloride (0.77 ml, 6.25 g).
/ * mmol) at -20ßC. It was stirred at this temperature overnight. The depsi tripeptide base (3.8 g, 6.7 mmol, obtained by the treatment of tripeptide depsi with trifluoroacetic acid in CH2C12 a ßC and then saturated NaHC03) was added in 15 ml of CH2C12. The solution was stirred at 0 ° C for 18 hours and at room temperature for 3 > dlair ». It was divided between citric acid ti 1 * 4 and ethyl acetate. I. Organic r-layer was rinsed H20, brine, dried in Na2S04
_-? -onc entriila. The re > if n »7 was cr or a! For the preparation of silica gel (2 * 5 CH30H-'CH7C12) for the preparation of the depot-nonapépted '1 2 * g, 61 * 4) n form (a 1 fa '< 25D-104 (CHC1); FAB-MS m / z 1411 iM + H) +. EXAMPLE ! < ?
CYCLE-DEFSI-N-METHYL-0-BENCIL-TBEONIL- (2-HYDROXY-2-CYCLOHEX I LACETILE) -N-METILVAL 11.-PHENYLANALTL-N- and METI LFENI LANAL I L-PPOL I L-ALO- ISOLEUCI LN-METI LVAL I L-LEUC INA
To a solution of the double salt of r.p »a t eg i» .ia of HC1 »deponaneppetite (3.5» ^, 2.7C? Mmol) obtained by the sequencing t! »Of > densi-nonapép t i »do roteni < -: not an atmosphere (atm) of H2 in 10 * 4 Pd / C (3 * 4 weight / weight) trifluoroacetic acid in CH2C12 at O'C and then with dry HC1 1 N
1 in ether) in 2.5 L of dry CH2C12 were added ime i i i ir i ina (2.03, 16.71 mmol)
* I have afflicted fato of benzotr iazol-1- i. lo i ris (d imet i lamina) f »3sphonium (BOP) (6.16 g, 13.93 mmol). The mixture was stirred for 3 days and then divided into 1 * 4 cyclic acid.
and acetate of il.j. The organic layer was washed with H20, brine, dried over Na2SO4 and concentrated, the residue was chromatographed on silica gel (ethyl acetate ai 60 * 4 / hexapos) to give 0-benzyl->: i-depsi - nonapeptide (0.52 g, 16 * 4) as a white solid:
7 < ñ (alf) 25D-166 (CHC13)? FAB-MS m / z 1203 (M + H) +.
EXAMPLE 20
C 1CL0-DEPSI-N-MET I L-TREONIL- í -HIDR0XIL-2-CICL0HE I LACETIL) - N-MET I LVAL I L-FENI LANAL I LN-MET I LFENI LANAL I L-PROP I L-ALO- ^ ISOLEUCI LN-MET I LVAL I Ll. EUCI A O-benc 11 -c i 'lo- »deps? -nonapéptyl (500 mg, 0.416 mmol) in
20 ml > of t nol and 0.83 ml of HC1 1 was hydrogenated (1 atmosphere of H2, 120 mg of 10 * 4 Pd / C) for 6 hours. After the removal of "Pd / C and the evaporation" of the solvents, the crude product was chrome togrs on the silica gel side (ethyl acetate at 80 * 4 / heman) to prepare the cyclone. - ..D? - | ep < i-nonapép t i do (302 m, 65 * 4) in the form of a white base: (alf) 25D (CHC13) 5 FAB-MS m / z 1113 (M + H) +. HPMSÍFAB) calculated for C61H93N8011 (M + H) + 1113.6964, found in
1 13.6944. EXAMPLE 21
PREPARATION OF ACID L-N-BOC-ACETYDINE-2-CAPBO T l. TCO L-ac acid was suspended? »D ma-2-c rb» -j? The ion (5 g, 0.00495 mol'l in 50? \ 1 of MeOH at 5 *; / H20- The pH was jus aoa 8 with 4N NaOH. The mixture »of the r» ea »'inu em at 10 ° C and added > d 1 -t-hut, 1 > - | 1 r 3 rbona tp (1. 7 »j., 0.OO519 mol.) The ph \ remained at 9-9.5 with After> about 0.5 hours, the cooling bath was stirred, the mixture was stirred at room temperature for 3-4 hours, and TLC was made in 5 * 4 MeOH / CH2C12. the reaction was terminated, the reaction mixture was acidified to a pH> 3 with 10 * 4 acetic acid and extracted with 7 x 150 ml EtOAc dried in MgSO 4, filtered and evaporated to give a compound semi-cr j tal 1 na (9.9 \ FAB m / z 292 (M + HH-) EXAMPLE 22
o PREPARATION OF BENCYLIC ACTDE DF ACID l -N-BOC-ACETIDTN-2- / r \ CAPBO ILICO LN-Boc-acet? din-2-c rbo 3 ico acid (9.0 g., 0.045 mol) was dissolved in dimethy Dry formamide (DMF) (90 ml) and stirred with cesium carbonate (21.87 g, 0.067 mol 5 for 5 hours) Benzyl bromide (7.98 ml, 0.067 mol) and 3rd mixture were added: the reaction was stirred overnight at room temperature, and the reaction was evaluated to determine its completion by TLC in the OAc at r * \ or 4! / b - year. Approximately 20 ml is added, and the residue is treated with EtOAc (7 15 ml) washed with r > cyclohexane at 1 * 4 and * - > »In MgSQ4 and evaporated to dry» Ja »J to give u gum (12." ^ 8 g) FAB m / z 292 (M + H) +. - > 1 EXAMPLE "
PREPARATION OF SALT TFA OF BENCYLIC ESTER DF. ACID L- ACETIDIN-2-CARBOX II. ICO 10 grams of benzyl ester of L-N-Boc-acet? D? N-2-carboxylic acid was dissolved in CH2C12 (100 ml) and cooled to 10 * C. 15 ml of TFA and the mixture in the reaction were added
was stirred for 3 hours. The FTA was taken to evaluate the disappearance of the initial material. The reaction mixture was evaporated to dryness and aceotroped with dry toluene to give an oil, 10.2 g. EXAMPLE 24
PREPARATION OF BENCYL ESTER OF LN-BOC-FENI LALANILI L I ..-- N- METHYLPHENYLALANININ L-ACETIDINIL0 25 REAGENTS weight (Molecular weight, nmol) SPs - 1) 1 LN-BOC-Fenilalanini 1 L-met i 3 feni 3 alam na 2.16 g (426.61, 5.06) 2 N-meti Imorpholine (NMM), d-.920 5 1.12 mL (101. 15, 10. 12) 7 Pivallous chloride (P? v-C3), d = .979 0.69 mi (120.58, 5.56) 4 CH2C12
to? '? 5 = .a 1 TFA ».le ester benc (1 i» - »» of | --nti> I ini 1 n 1.55 g 5., 5.Có)) 6 NMM 0.56 mL (1.01.15, 5, 6) 7 CH2C12 15 25 ml 1 and 2 were diluted with 0H2T12 in a flask > of 1 liter dry at a temperature of -20ßC ba or an atmosphere of N 2. HE ? added 7 drop to ota to the sun u > . i ón (for antenei the temperature »reaction to - 'C) and the reaction mixture
was agitated for 8 hrs:. Tra-^ -i -7 * 0 b or an atmosphere »of N2. During the activation (formation »of mixed anhydride, reaction 1), the TIC (silica gel) of the reaction mixture was evaluated using amine» ie n-butyl. Preparation > of TLC: a few drops > He mix > of the reaction
reacted with a drop »ie butyl amine. After 2 minutes, citric acid at 10 * 4 was added to the solution of
> The resulting mixture was extracted with a small amount of EtOAc.The 1 and the EtOAc layer were detected and these two samples were spliced.The plate was developed in 30 * 4 EtOAc / solvent systems. hexane and 5 * 4 MeOH / CH2C1.2 (can HOAc al .1 * 4) The disappearance of 1 and the adduct formation of butyl amine was monitored.When 1 was observed, another 5-10 * was added. 4
f of Piv-Cl and the reaction mixture was acidified during
additional hours in the same conditions. When the TLC was revised again, it was determined that activation Br ^ x co pl eta. After completing the activation (at least one reaction of approximately 90-95 * 4) the mixture of
5, 6 and 7 to the bottle. The resulting mixture was stirred for 24 hours at -20 ° C under an atmosphere of N2. The reaction > coupling was moni. bulldozed by silica gel TLC). **, Preparation of TLCI some drops of the reaction mixture reacted with a drop of butyl amine. Within 2
minutes, the 10 * 4 was added to the butyl amine adduct solution. The resulting mixture was extracted with a small amount of EtOAc. Some drops of the reaction mixture reacted with 10 * 4 citric acid. The resulting mixture was extracted with a small amount
EtOAc. These two samples of TLC were compared to 5 by developing the plate in solvent systems that were 30 * 4 EtOAc / hexane and 5 * 4 MeOH / CH2C12 (with HOAc al .1 * 4). The non-butyl amine sample was the coupling product and the butyl amine sample was the butyl amine adduct 5. When the coupling was terminated, there was no ion-butylated form of butyl amine in the TLC sample. The disappearance was also reviewed > of 5 when the -coupling reaction ended, -. After "finishing the" of the coupling, a
solution of Ári o »-. í! ? > ~ > ~ > at 1 * 5 -t? To mp. The reaction was 1 -3 »t" e ": > ™ 1 ad the reaction was ex con with CUrd" "1 (3 10 mL) I: t - 'i or A í»: - * unua soluci The water was saturated and the organic layer was washed with brine. The organic was dried with MgSO4. The CH2C17 filtrate was
evaporated until obtenet a foamy, yellow solid, The product was isolated by instant chromatography. The oil was dropped in a can! » minimum > of CH2C12 to the y-column and the column »» »e washed with 1 L of hexane.The solution was diluted with 10-40 * 4 EtOAc / he auo.
were monitored by TLC (silica gel, 40 * 4 EtOAc / hexane). After purification of the column, 1.81 g (60 * 4) of benzyl ester of L-N-Boc-f or laninyl L-N-m-t-phhenylalaninyl-L-acetidinyl; FAB-MS m / z 600 (M + H) +. 25 EXAMPLE 25
H2 (1atm), Pa7C EtOH, rt
? - / L
PREPARATION OF L-N-BOC-PHENYLALANINI L-N-METHYLPHENYLALANINI L-ACETYDINE Benzyl ester was dissolved > of L-N-BOC-pheni lalanini 1 L-N- * ethylphenylalkidl L-acefe J dini lo (1.8 g, 3.0 rrtmol) > = t > 50 / r > > of EtOH ba or an N2 atmosphere. Palladium added to l 10%
in activated carbon on the solution. The bottle was equipped with a balloon of H2 and the bottle, in atmosphere (under N2) was evacuated using the home vacuum. The H2 to the bottle was released and the bottle was evacuated. This procedure was repeated twice. The black mixture was shaken ba
atmosphere "of H2 at room temperature overnight (20 hours). The reaction mixture was filtered through
-H »celite and the filtrate was evaporated to obtain 1.4 g of L-N-BOC-geni lani ni 1 L-N-meti ifeni lalanini 1 White, frothy L-acet idine. The reaction was monitored by TLC (silica salt, 5 * 4 MeOH / CH2C12 with .1 * 4 HOAc); FAB-MS m / z 510 < M + H) +. As used in the. previous example »3r and throughout this specific ion, rt indicates ambient temperature. EXAMPLE 26 1
r
PREPARATION OF ESTER SALT TFA OF ALLO-ISOLEUCIL-N- METI LVAL I L-LEUCIL-L-0-Bn-TREO I L- (R) -HEXAH IDROMANDEL T-L ~
METÍ LVAL IN-Q-BENCILO Dissolve BOC-1 lo-isoleuc i 1-N-met i 1-val i 3.-1euc i. na (0.83
** - g, 1.81 mmol) in 20 ml of dry methylene chloride under an atmosphere of dry nitrogen. NMM (0.4 mL, 3.62 mmol) was added and the reaction mixture was cooled to -20 degrees C. 5 Pi chloride was added. Value (0.25 ml, 1.99 mmol) and the reaction mixture was stirred for 18 hours at -20 degrees C. In a separate 100 ml round bottom flask dried with flames, sl TFA of L-0-Bn was dissolved. -treani l- (R) - hedah i.dromen »from a to-L.- > t? et il va 1 ina (1.23 g, 1.81 mmol i in 20
1 > ttl of non-dried methyl chloride and 0.23 ml (2.0 mmol "NMM.) This clear solution was added to the previous reaction and stirred at -20 ° C to 8 ° C. The clear solution was added to the previous reaction and agitated at -20 degrees C for 48 hours.The cold bath was removed and, while
was cold, the reaction mixture was acidified with citric acid at 10 * 4 at a pH > from 3 to 2.5. The reaction mixture was extracted with 3 X 100 ml of methylene chloride. F. The extracts, ie methylene chloride, were dried over magnesium sulphate, filtered and evaporated to dryness.
The resulting gum was cured on an instantaneous grade »silica» column packed in hexanes, eluted with hexanes, then by ethyl acetate at 10 * 4 / hexanes; followed by ethyl acetate at 20 * 4 / hexane 5 followed by ethyl acetate at 30 * 4/5 years followed by acetate.
Ethyl at 40 * 4 / henias 5 and finally ethyl acetate at 70 * 4 / hexanes. The fractions containing the product were collected and evaporated to dryness to obtain 1.3 g of the title product which was dissolved in methylene chloride (30 ml) cooled to 10 degrees C. Acid was added
The reaction mixture was stirred for 3 hours and evaporated to dryness to provide the title compound, FAB-MS m / z 1.006 (M + H) +. EXAMPLE 27
PREPARATION OF ESTER OF N-BOC-FENILALANI LN-25 METILFENILALANIL-ACETIDINIL-ALLO-ISOLEIJCIL-N-METILVA IL-LEUCI LLQ-BN-TPEONI L- (R.) -HE AHIDROMENDALATO-L-METI LVAL INA- and- Q -BENCIL LN-met ilfeni lalanini 1 L-acetidine (0.949 g, 1.86 mmol) was dissolved in 50 ml of dry methylene chloride under an atmosphere of dry nitrogen. NMM (0.41 ml, 3.75 mmol) was added and the mixture was cooled to -20 degrees C. Pivaloyl chloride (0.25 ml, 2.04 mmol) was added and the mixture was stirred for 24 hours at -20 degrees C. In a separate 100 ml round-bottomed flask, dried with a further one, it was dissolved in the TFA of the ester of the loisoleuclN-met i 1-v 1 i-leuc i nt.-O- n- I; reo i l- (R) -hexah and romandela to-L-met i 1 v 1 i 1-0-benzyl (1.9 g, 1.86 mmol) in 30 ml and chloride > of dry methylene and 0.25 l (2.23 mmol) of NMM. This solution was added "'the previous solution and the mixture of the reaction
was stirred at 1.0 degrees C for 48 hours. The cold bath was removed and, while cold, it was acidified with citric acid at 10 * 4 until it reached a pH of 3 to 2.5. The reaction mixture was extracted with 3 X 500 ml of methylene chloride. Methylene chloride extracts were
dried over magnesium sulphate, filtered and evaporated to dryness. The resulting gum was chroma tography on an instant-grade silica column packed in hexanes. Elution was with hexanes followed by ethyl acetate at 25 * 4 / hexanes 5 followed by ethyl acetate at
30! 4 / hex. 5 followed by acetate "from ethyl to 4? V, / hexanes;
followed by ethyl acetate at 50 * 4 / hexanes 5 and finally followed by ethyl acetate at 60 * 4 / hexanes. The fractions containing the product were collected and evaporated to dryness to obtain 1.85 g of the title product. FAB-MS m / z 1420 (M + Na) +. EXAMPLE 28
PREPARATION OF CYCLE-DEPSI-N-METHYL-O-BENCIL-TPONYL- (2- V * v. HIDP0XI-2-CICL0HEXILACETID-N-METILVALIL-PHENYLALANIL-N-METHYLPHENYLALANIL-ACETYDINYL-ALLO-ISOLEUCIL-N-METHYL-LEUKINE To a salt solution of double deprotected depsinane-peptide HCl (0.5 g, 0.36 mmol, obtained by sequential treatment of nonapépfcido with an atmosphere of H2 in Pd / C (5 * 4 weight / weight), acid tr if 1? oroacetic in CH2C12 to degrees C then with dry HCl l N in ether) in 400
T ** ^ mi l »-, ác do? N CH2C] was set di?»? I 11 = »mi nop ipdi na (0. ^ > -», "> and he¡ af 1 uorofos fa tc > »de li n ,:") r L zol -1 -i 1 o, itris (d a I, ¡-mu no '• (0.76 y), la me: ». la f hj agi atJ 3 »- | í- < and 'id idide id ítrica to 1 * 4 and ethyl acetate, the organic layer was washed ccfn H2t), brine, dried in Na ^ 0 and concentrated. 'He
1. • esiduo was c roma tagra > ia »d» "on silica gel (ethyl acetate) at 60 * 4 / hexane) to vaporize 0-benzyl-1-depsine nonapeptide-1 (0.252 g,) as a white solid : FAB-MS m / z 1189 (M + H) + "EXAMPLE 29
PREPARATION OF CYCLE-DEPSI-N-METHYL-TREONYL- (2-HIDP.0XI-2- - CICLOHE ILACETID-N-METHYLVALIL-PHENYLALANYL-N- 10 METHYLPHENYLALANIL-ACETYDINYL-ALLO-ISOLEUCIL-N-METHYLVALIL- LEUCI A. The O-benzyl 1-cyclo-depsy-nonapeptide (200 mg,) in 15 ml of ethanol and 0.35 ml of 1 N HCL was hydrogenated (1 atmosphere of H2, 50 mg of 10 * 4 Pd / C -) * during 6 hours later "it was removed
Pd / C and the solvents were evaporated, the crude product was chromatographed on silica gel (ethyl acetate ai 804 / hexane) to give cyclo-depsy-nonapeptide gone (109-mg,) as a white solid FAB -MS m / z 1099 (M + H) +. EXAMPLE 30
r - * - More specifically, a »z» :) nt i. An example of this reaction and product is given.
CTCL0-DEPSI-N-METHYLTRE0NIL- (2-HIDR0XT-3-METHYLPENTAN0IL) -N-METHYLVALYL-PHENYLANALYL-N-METHYLPHENYLANALYL-PROLIL-ALLO-ISOLEUCIL-N-METHYLVALYL-LEUCINE To a solution > of ciclo-depsi-sarcosini 1- (2-h? drox -3- and i 1 penta no i 1) -N-met i 1 v l i 1-fen? the nal i 1 -Nm ti lfem la nal i 1-prol i 1-al lo-i soleuc i 1-N-me i 1 val i l-leucine (50 m, 0.047 mm l) in 6 ml of THF - > and added lithium chloride (57 mg, 1.3 iti ol). It was cooled to -78 ° C under an atmosphere of dry nitrogen and added drop by drop. l »u:? ón 1M» le b i st i t i] i i i i a i> of the mixture (O.27 > nl, O, 7 mmol). After stirring for 4 hours, - ^ e 1 > The reaction was stirred at -3 ° C. for 3 min. (20 μl, 0.4 mmol). The solution was washed with an aolyte or 1% citric acid, after chromatography on silica gel using 1 * 4 to 5'4 methanol / ethylene chloride, 11 mg was obtained. (22 * 4) of the title product FAB-MS m / z 1088 (M + H) + EXAMPLE 31
s e-spec í f ica efite, here is an example of this reaction and product. ? * ¡CIGLO-DEPSI- -METILTREONTI -ÍG-HTDBOXTL-G-OTOLOHEXTLA? ETTI -.- -METII VAL TI -FFNTI ANAL T LDN-MFTT I.FENILA AL r I.-PROL TL-ALLO- SOL IC TL -N-MET IL AL 11 -L EUC T NA
To a solution of 83 mg of the initial non-benzylated compound (0.081 mmol) and 95 mg of LiCl (2.24 mmol) in 6 ml of THF, 0.45 ml of bis < tpmet i lsi 111) lithium amide (1 M THF solution) at a temperature of -78 degrees C. After stirring for 4 hours, 0.6 ml of DMPU was added, followed by 0.137 ml of benzylamine bromide (1.49 mmol) to? a temperature of -78 degrees C. The solution was stirred for 3 »days at the same temperature. The reaction was quenched by a buffer of 1M phosphate buffer (pH = 7) at a temperature of -78 ° C, ethyl acetate. The organic layer was concentrated in Na 2 SOO and concentrated, the residue was separated on a preparative silica gel TLC plate, developed with 50 * 4 ». of acetone / he ano.The compound, venti side resulting
was obtained in 44 m (rennion of 49 * 4), N0SEY NMR conf confted the stereochemistry, m / z (FAB), 1113 (MH +). The initial materials in the above examples are known or can be prepared in a convenient manner with conforming methods. The following table illustrates other compounds of the formula I of the invention that can be prepared by the use of analogous procedures presented above. Exemplary compounds of the present invention include
No, R2 n Mate ia] Ini ia] P, M. i > z i lohe; - 'i 1 or 2 a gone R-he;; ah idromandél ico 1113.4
2 CJ c.1 ohe¡ i i »- > 1 Acid P-he; -ah i'dromandél} .- or 109"
1 4 í-Pr 7 * - »? - (? L")? - (R) -hi dr > #! - i -3-me 1, 3] - 10 '- .. 4 butan ico ¡nn J »-1,! Di- -«> ... »» »R he, ah i drom -?» VJé] i cu ci lope t, i 1 > > 1 '? »:?» Jo -% í-R) - 1 Í_185.4 il opent i 1 acé ico instead of 15 ác? »I» D R-he; ah i dromandél co icl pent i lo do 2- (R) ~ 1 99.4 cil open i 1 acét i co instead of - »» .: i »i> R-hexah i dromandél ico feni lo acid mandé] co instead of 1107.4
Ac i "d > i R - he K ahidr orna n» d 1 i »o cc oprocess i tic acid 2-5-hi 'ro? I -2- 1071.3 c icloprop i 1 acetic instead of Ac i »do P-hexa idromandél ico jcl ohe¡ < i 1 > .. Acid R-he: < ah ídromandél ico ¡7.4
In all the compounds of the previous table, R1 is H.
Claims (1)
- REI INDICATIONS /?, - 1. A compound of the formula where »za» da Rl. and R.2 attached to a particular carbon is independent of each Rl and R.2 linked to another carbon? and where Rl is H and P.2 is selected within the group and 10 with i * indicates both possible isomers in this carbon center? or Rl and P.2 together with the carbon to which they are both bound form V a Rl and R2 are both ethyl; R3 is H, methyl, ethyl, propyl or ac i. the; XI and X6, are independently selected within the group q u e c o n s i s t e d 10 * indicates both possible isomers in this carbon center; and * X2 and; 2 are independently selected within »the group consisting of R 4 is H, ethyl, methyl, or p-pyl yl * R 5 is H, OH, 0- (C 1 -C 3), Cl, F, or Br; P.6 and R7 are independently selected from the group consisting of H, methyl, ethyl, prapil, hydraxy, ethaxy, ethoxy and propoxy; R18 and R19 are independently selected from the group consisting of H, C1-C6 alkyl, 1 where X "is 01, P, Br, OH, u to Ico and CI-C 5 j (4 is selected from the group consisting of» l where 'e-, OH n NH2 = < > ondición »-u > - »OH or WH2 nn s n bonded to a carbon > It is attached to a hetero-tune in the ring; R8 is H -i C1-C4 alkyl; 11 R9 PlO = e independ independ independ independ independ independ independ el el el el el el el 11 11 11 11 11 11 11 11 11 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9lec. _ n is 1 to 5 «y. i and p s »-. n 1 ndeperi'iently 0 to 4 on condition that m + p is not greater than 4; 5 and X7 are independently selected within the group consisting > from * indicates both possible isomers in this carbon center; < ** X8 is selected within the group consisting of twenty where R.1. is H, me t ilo, et i lo, propyl, or phenyl; R.12 is H, methyl, ethyl, or propyl; 20 P.13 is H, methyl, ethyl, or propyl »D. R.l4 is OH, or NHP.15; P.15 is H, methyl, or ethyl; P.16 and P.17 are independently selected from the group consisting of H, CF3, C1-C6 alkyl, 25 8 ' where X 'is Cl, F, Br, OH, or lCaxi Cl to C6, to a pharmaceutically acceptable salt thereof when a basic group or acid group is in the molecule such that a salt can be formed; provided that when X8 is beta-HO-mefc i l to ina, R2 is not conf i gu ion (P); and i condi ión besides that it is not D-Me'v'a 1: and a »rondici'ón also when X.8 s threonine, R, O 1 R2-C-C- 5 is Hmp, n can not be 2,! Jn composed of the formula Xr Xs where Rl is H, and P.2 is selected within the group consisting of 10 * indicates both possible isomers at this carbon center; or bi n Rl and R2 together with the carbon to which they are both bound fo man 15 to R1 and R2 are both ethyl; R3 is H, met i. lo, et i 1o, o p rop i 1o; XI C ?, are independently selected within the group *** 'that c o ns i s t e d * indicates both possible isomers in this center? of carbon; X2 and X3 are each independently selected within d l. rupo qu cofis i. st 20 b P.4 is H, ethyl, methyl, or prop i lo; tr ^. R5 is H, OH, alkyl 0- (Cl-C3), Cl, F, or Br; R6 and R.7 are independently selected from the group consisting of H, methyl, ethyl »3, prspilo, hydroxy, methoxy, 5 ethoxy and propo i X4 is selected within »the group consisting of where X is OH or NH2; R8 is H or C1-C4 alkyl; R9 and RIO are independently selected from the group consisting of H, methyl, ethyl, or propyl; n is 1 to 5; X5 and X7 are independently selected within the group 5 which consists of * indicates both possible isomers in this carbon »center; and- X8 is selected within the group consisting of 9 ^ Where R 1 is H, methyl, ethyl, p rop i lo, or phenyl; R 12 is H, methyl 1, 3, ethyl propyl; P13 is H, methyl, ethyl propyl; R14"to QH, O NHR15; »10 1 s H, me ilo,» 5 e it »is not pharmaceutically acceptable» when the molecule is a basic group or a group Acid so that it can form a s l; provided that when X8 is beta-OH-met i 1 goes 3 in, P2 is not with f i > ju r a ».: i ó n í #); and provided that X6 is not D-MeVal; 20 and provided further that when X8 is threonine, Ri 0 \ II ^ R2-C-C- > I O Y -? V? V * t * 3 Hmpa, n can not be 2. 3. A compound according to claim 2, of 25 the formula 5 'where XI is 6 is , t is 7 4. A compound according to the claim selected from the group consisting of ft 1 No, R2 1 c i »: lo! ? i i lo * - ^ c icloh x i lo 4 i-Pr 5 c iclopent i lo 6 c i. c 1opent ilo 7 phei lo 8 cyclopr »pi lo 9 c iclohex ilo where Rl is H. 5. Compound 9 of claim 4. 6. The compound according to claim 1, of formula: The: conformance stamp with the. re indication 1 di : Ormula: 8. The compound according to claim 1, from fó mul: 9. The compound in accordance with the re vindication 1, of formulas 1o, The compound in accordance with the rei indication 1, di f mul 11. The compound according to claim 1, of formula: 12. A pharmaceutical composition comprising a compound * - in accordance with that defined in claim 1, in combination with a pharmaceutically acceptable carrier. 13. A method for the treatment of a fungal infection in a mammal comprising administering to the mammal an effective an effective amount of a compound according to claim 1. 14. A process for the production of a The compound of claim 1 comprising the repletion of the 10 REACTION SCHEME, and then the REACTION SCHEME 2 or REACTION SCHEME 3. fifteen twenty 25
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US237794 | 1994-05-04 | ||
| PCT/US1995/005020 WO1995030692A1 (en) | 1994-05-04 | 1995-05-01 | Anti-fungal cyclic depsipeptides |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MXPA96005312A true MXPA96005312A (en) | 1998-02-01 |
| MX9605312A MX9605312A (en) | 1998-02-28 |
Family
ID=39165075
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MX9605312A MX9605312A (en) | 1995-05-01 | 1995-05-01 | Anti-fungal cyclic depsipeptides. |
Country Status (1)
| Country | Link |
|---|---|
| MX (1) | MX9605312A (en) |
-
1995
- 1995-05-01 MX MX9605312A patent/MX9605312A/en unknown
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