SI9300289A - Hydroxamic acid derivatives - Google Patents
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- SI9300289A SI9300289A SI9300289A SI9300289A SI9300289A SI 9300289 A SI9300289 A SI 9300289A SI 9300289 A SI9300289 A SI 9300289A SI 9300289 A SI9300289 A SI 9300289A SI 9300289 A SI9300289 A SI 9300289A
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- methylvaleryl
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/43—Indoles; Hydrogenated indoles with an —OCH2CH(OH)CH2NH2 radical, which may be further substituted, attached in positions 4, 5, 6 or 7
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Description
DERIVATI HIDROKSAMSKE KISLINEDERIVATIVE HYDROXAMIC ACIDS
Predloženi izum se nanaša na derivate hidroksamske kisline.The present invention relates to hydroxamic acid derivatives.
Derivati hidroksamske kisline, kijih nudi predloženi izum, so spojine s splošno formuloThe hydroxamic acid derivatives of the present invention are compounds of the general formula
v kateri predstavljajoin which they represent
Rl 5- ali 6- členski N-heterocikličen obroč, ki je (a) vezan preko N-atoma, (b) v danem primeru vsebuje N,O in/ali S kot dodatni ali dodatne heteroatome v položaju ali položajih, različnih od sosednjega k veznemu N-atomu, (c) je substituiran z okso na enem ali obeh C-atomih, sosednjih k veznemu N-atomu in (d) je v danem primeru benz-sklenjen ali v danem primeru substituiran na enem ali več drugih C atomih z nižjim alkilom ali okso in/ali na morebitnem ali morebitnih dodatnih N atomih z nižjim alkilom ali arilom;R1 is a 5- or 6-membered N-heterocyclic ring which is (a) bonded via the N atom, (b) optionally contains N, O and / or S as additional or additional heteroatoms in a position or positions different from the adjacent to the N bond atom, (c) is substituted by oxo on one or both C atoms adjacent to the N bond atom, and (d) is optionally benzene coupled or optionally substituted on one or more other C atoms with lower alkyl or oxo and / or on the possible or possibly additional N atoms with lower alkyl or aryl;
R^ nižji alkil in R^ predstavlja nižji alkil ali aril, aliR ^ is lower alkyl and R ^ represents lower alkyl or aryl, or
NR^R^ nasičen 5-, 6- ali 7- členski heterocikličen obroč, ki v danem primeru vsebujeNR ^ R ^ is a saturated 5-, 6- or 7-membered heterocyclic ring, optionally containing
-NRa, -Ο-, -S-, -SO- ali -SO2- kot obročni člen in/ali je v danem primeru substituiran s hidroksi, nižjim alkoksi, okso ketaliziranim okso, amino, mono(nižji alkiljamino, di(nižji alkiljamino, karboksi, nižjim alkoksikarbonilom, hidroksimetilom, nižjim alkoksimetilom, karbamoilom, mono(nižji alkil)karbamoilom, di(nižji alkiljkarbamoilom ali hidroksiimino;-NR a , -Ο-, -S-, -SO- or -SO2- as the ring member and / or optionally substituted by hydroxy, lower alkoxy, oxo ketalized oxo, amino, mono (lower alkylamino, di (lower alkylamino, carboxy, lower alkoxycarbonyl, hydroxymethyl, lower alkoxymethyl, carbamoyl, mono (lower alkyl) carbamoyl, di (lower alkylcarbamoyl or hydroxyimino;
Ra vodik, nižji alkil, nižji alkanoil, aril-nižji alkanoil, nižji alkoksikarbonil, aril-nižji alkoksikarbonil ali mono(nižji alkiljkarbamoil;R a is hydrogen, lower alkyl, lower alkanoyl, aryl-lower alkanoyl, lower alkoxycarbonyl, aryl-lower alkoxycarbonyl or mono (lower alkylcarbamoyl;
R4, R5, R6 in R^ vsakokrat predstavlja vodik ali metil, s pridržkom, da vsaj dva izmed teh simbolov predstavljata vodik; in n stoji za 1- 4;R 4 , R 5 , R 6 and R 6 each represent hydrogen or methyl, with the proviso that at least two of these symbols represent hydrogen; and n stands for 1- 4;
in njihove farmacevtsko sprejemljive soli.and pharmaceutically acceptable salts thereof.
Spojine s formulo I imajo dragocene farmakološke lastnosti. So zlasti inhibitorji kolagenaze in se jih da uporabiti pri kontroli ali preventivi degenerativnih sklepnih bolezni, kot revmatoidnega artritisa in osteoartritisa, ali pri zdravljenju invazivnih tumorjev, ateroskleroze ali multiple skleroze.The compounds of formula I have valuable pharmacological properties. In particular, they are collagenase inhibitors and can be used to control or prevent degenerative joint disease, such as rheumatoid arthritis and osteoarthritis, or in the treatment of invasive tumors, atherosclerosis, or multiple sclerosis.
Predmeti predloženega izuma so spojine s formulo I in njihove farmacevtsko sprejemljive soli same in za uporabo kot terapevtsko učinkovite snovi; postopek za pripravo navedenih spojin in soli; intermediati, ki so koristni pri navedenem postopku; zdravila, ki vsebujejo navedene spojine in soli ter priprava teh zdravil; ter uporaba navedenih spojin in soli pri kontroli ali preventivi bolezni ali pri izboljšanju zdravja, zlasti pri kontroli ali preventivi degenerativnih sklepnih bolezni, ali pri zdravljenju invazivnih tumorjev ali ateroskleroze, ali za pripravo zdravila za kontrolo ali preventivo degenerativnih sklepnih bolezni ali za zdravljenje invazivnih tumorjev, ateroskleroze ali multiple skleroze.The objects of the present invention are the compounds of formula I and their pharmaceutically acceptable salts, alone and for use as therapeutically effective substances; a process for preparing said compounds and salts; intermediates useful in the said process; medicines containing said compounds and salts and the preparation of these medicines; and the use of said compounds and salts in the control or prevention of disease or in improving health, in particular in the control or prevention of degenerative joint disease, or in the treatment of invasive tumors or atherosclerosis, or in the preparation of a medicament for the control or prevention of degenerative joint disease or for the treatment of invasive tumors, atherosclerosis or multiple sclerosis.
Kot ga uporabljamo v predloženem opisu, pomeni izraz nižji alkil sam ali v kombinaciji, ravno ali razvejeno alkilno skupino, ki vsebuje največ 6, prednostno 1 do 4 atome ogljika, kot metil, etil, n-propil, izopropil, n-butil, sek.butil, izobutil, terc.butil, n-pentil, n-heksil ipd. Izraz nižji alkoksi, sam ali v kombinaciji, pomeni ravno ali razvejeno alkoksi skupino, ki vsebuje največ 6, prednostno 1 do 4 atome ogljika, kot metoksi, etoksi, n-propoksi, izopropoksi, n-butoksi, terc.butoksi ipd. Izraz aril pomeni fenil, ki je v danem primeru substituiran npr. z nižjim alkilom, nižjim alkoksi in/ali halogenom, npr. fluorom, klorom, bromom ali jodom. Izraz nižji alkanoil sam ali v kombinaciji, pomeni acilno skupino, izvedeno iz alkanojske kisline, ki vsebuje do 6 atomov ogljika, npr. acetil, propionil, butiril, izobutiril ipd. Ketalizirana okso skupina je lahko npr. etilendioksi.As used herein, the term lower alkyl alone or in combination, is a straight or branched alkyl group containing not more than 6, preferably 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec .butyl, isobutyl, tert.butyl, n-pentyl, n-hexyl and the like. The term lower alkoxy, alone or in combination, means a straight or branched alkoxy group containing not more than 6, preferably 1 to 4, carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like. The term aryl means phenyl optionally substituted e.g. with lower alkyl, lower alkoxy and / or halogen, e.g. fluorine, chlorine, bromine or iodine. The term lower alkanoyl alone or in combination, means an acyl group derived from alkanoic acid containing up to 6 carbon atoms, e.g. acetyl, propionyl, butyryl, isobutyryl and the like. The ketalized oxo group may be e.g. ethylenedioxy.
Spojine s formulo I tvorijo farmacevtsko sprejemljive soli z bazami, kot so hidroksidi alkalijskih kovin (npr. natrijev hidroksid in kalijev hidroksid), hidroksidi zemljoalkalijskih kovin (npr. kalcijev hidroksid in magnezijev hidroksid), amonijev hidroksid ipd. Spojine s formulo I, ki so bazične, tvorijo farmacevtsko sprejemljive soli s kislinami. Kot take soli ne pridejo v poštev samo soli z anorganskimi kislinami kot hidrohalogenidne kisline (npr. klorovodikova in bromovodikova kislina), žveplova kislina, solitrna kislina, fosforova kislina itd., ampak tudi soli z organskimi kislinami kot ocetno, vinsko, jantarno, fumarovo, maleinsko, jabolčno, salicilno, citronsko, metansulfonsko in p-toluensulfonsko kislino itd.The compounds of formula I form pharmaceutically acceptable salts with bases such as alkali metal hydroxides (eg sodium hydroxide and potassium hydroxide), alkaline earth metal hydroxides (eg calcium hydroxide and magnesium hydroxide), ammonium hydroxide and the like. The compounds of formula I, which are basic, form pharmaceutically acceptable salts with acids. As such, salts not only include salts with inorganic acids such as hydrohalic acids (eg hydrochloric and hydrobromic acid), sulfuric acid, hydrochloric acid, phosphoric acid, etc., but also salts with organic acids such as acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulfonic and p-toluenesulfonic acid, etc.
Spojine s formulo I vsebujejo vsaj dva asimetrična atoma ogljika in zato lahko obstajajo kot optično aktivni enantiomeri, kot diastereoizomeri ali kot racemati. S predloženim izumom naj bodo obsežene vse te oblike.The compounds of formula I contain at least two asymmetric carbon atoms and may therefore exist as optically active enantiomers, as diastereoisomers or as racemates. The present invention should cover all of these forms.
Spojine s formulo I, v kateri vsebuje N- heterociklični obroč RA v danem primeru kot dodaten ali dodatne hetero atom(e) enega ali dva N atoma, en N atom in en O atom ali en O atom, so prednostne. Posebno prednostni obroči, označeni z Rl, so tisti s formulamiCompounds of formula I in which the N-heterocyclic ring contains RA, optionally as additional or additional hetero atom (s) of one or two N atoms, one N atom and one O atom or one O atom, are preferred. Particularly preferred rings denoted by R1 are those of formulas
v katerihin which
R8 in vsakokrat pomenita vodik ali skupaj predstavljata dodatno vez ali preostanek sklenjenega benzenskega obroča;R8 and in each case represent hydrogen or together represent an additional bond or the remainder of a closed benzene ring;
RlO vodik, nižji alkil ali aril;R10 is hydrogen, lower alkyl or aryl;
X -CO-, -CH2-, -CH(nižji alkil)-, -C(nižji alkil)2~, -NH-, -N(nižji alkil)- ali -O-; in Y -0-, -NH- ali -N(nižji alkil)-.X -CO-, -CH2-, -CH (lower alkyl) -, -C (lower alkyl) 2 ~, -NH-, -N (lower alkyl) - or -O-; and Y is -O-, -NH- or -N (lower alkyl) -.
Primeri za take obroče so 2-okso-l-pirolidinil, 2,5-diokso-l-pirolidino, ftalimido, 1,2dimetil-3,5-diokso-l,2,4-triazolidin-4-il, 3-metil-2,5-diokso-l-imidazolidinil, 3,4,4-trimetil-2,5-diokso-l-imidazolidinil, 2-metil-3,5-diokso-1,2,4-oksadiaksol-4-il, 3-metil2,4,5-triokso-l-imidazolidinil, 2,5-diokso-3-fenil-1 -im idazolidi n il in 2,6-dioksopiperidino. Ti obroči s formulama (b) in (c), zlasti ftalimido, l,2-dimetil-3,5-diokso-l,2,4triazolidin-4-il, 3-meti1-2,5-diokso-l-imidazolidinil ali 3,4,4-trimetil-2,5-diokso-limidazolidinil, so posebno prednostni.Examples of such rings are 2-oxo-1-pyrrolidinyl, 2,5-dioxo-1-pyrrolidino, phthalimido, 1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl, 3-methyl -2,5-dioxo-1-imidazolidinyl, 3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl, 2-methyl-3,5-dioxo-1,2,4-oxadiaxol-4-yl , 3-methyl2,4,5-trioxo-1-imidazolidinyl, 2,5-dioxo-3-phenyl-1-imidazolidinyl and 2,6-dioxopiperidino. These rings of formulas (b) and (c), in particular phthalimido, 1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl, 3-methyl-2,5-dioxo-1-imidazolidinyl or 3,4,4-trimethyl-2,5-dioxo-limidazolidinyl are particularly preferred.
Spojine s formulo 1, v kateri NR^R^ predstavlja 5-, 6- ali 7- členski nasičen heterocikličen obroč, kot smo že prej definirali, so prednostne. Taki obroči vključujejo l-pirolidinil, piperidino, 1-piperazinil, 4-metiI-l-piperazinil, heksahidro-l-piridazinil, morfolino, tetrahidro-l,4-tiazin-4-il, tetrahidro-1,4-tiazin-4-il 1-oksid, tetrahidro-1,4tiazin-4-il 1,1-dioksid in oktahidro-l-azocinil, ki so lahko substituirani na zgoraj navedeni način; npr. 2-(metilkarbamoil)-l-pirolidinil, 2-(hidroksimetil)-l-pirolidinil, 4-hidroksipiperidino, 2-(metilkarbamoil)piperidino, 4-hidroksiiminopiperidino, 4-metoksipiperidino, l,4-dioksa-8-azaspiro-[4.5]dekan-8-il, heksahidro-3-(metilkarbamoil)-2-piridazinil in heksahidro-l-(benziloksikarbonil)-2-piridazinil. Posebno so prednostne spojine s formulo 1, kjer predstavlja NR2R2 6-členski nasičen heterocikličen obroč, zlasti morfolino, tetrahidro-l,4-tiazin-4-il, 4-hidroksipiperidino ali heksahidro-3-(metilkarbamoil)-2-piridazinil.Compounds of formula I in which NR 1 R 2 represents a 5-, 6- or 7-membered saturated heterocyclic ring, as previously defined, are preferred. Such rings include 1-pyrrolidinyl, piperidino, 1-piperazinyl, 4-methyl-1-piperazinyl, hexahydro-1-pyridazinyl, morpholino, tetrahydro-1,4-thiazin-4-yl, tetrahydro-1,4-thiazin-4 -yl 1-oxide, tetrahydro-1,4-thiazin-4-yl 1,1-dioxide and octahydro-1-azocinyl, which may be substituted as indicated above; e.g. 2- (methylcarbamoyl) -1-pyrrolidinyl, 2- (hydroxymethyl) -1-pyrrolidinyl, 4-hydroxypiperidino, 2- (methylcarbamoyl) piperidino, 4-hydroxyiminopiperidino, 4-methoxypiperidino, 1,4-dioxa-8-azaspiro- [ 4.5] decan-8-yl, hexahydro-3- (methylcarbamoyl) -2-pyridazinyl and hexahydro-1- (benzyloxycarbonyl) -2-pyridazinyl. Particularly preferred are compounds of formula I wherein NR 2 R 2 represents a 6-membered saturated heterocyclic ring, in particular morpholino, tetrahydro-1,4-thiazin-4-yl, 4-hydroxypiperidino or hexahydro-3- (methylcarbamoyl) -2- pyridazinyl.
Spojine s formulo I, v kateri R^ r5 jn r7 vsakokrat predstavljajo vodik in R6 predstavlja metil, so tudi prednostne.Compounds of formula I in which R ^ r5 j n R7 each represent hydrogen, and R 6 represents methyl, are also preferred.
Nadalje so prednostne spojine s formulo I, v kateri n stoji za 1 ali 2.Further preferred are compounds of formula I wherein n is 1 or 2.
Najbolj prednostne spojine s formulo I so:The most preferred compounds of formula I are:
4-[2(R)-[l(R ali S)-(hidroksikarbamoil)-2-ftalimidoetil]-4-metilvaleril]morfolin, 4-[2(R)-[l(R ali S)-(hidroksikarbamoil)-2-ftalimidoetil]-4-metilvaleril]tetrahidro-l,4-tiazin,4- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] morpholine, 4- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] tetrahydro-1,4-thiazine,
1-[2(R)-[1(R ali S)-(hidroksikarbamoil)-2-ftalimido-etil]-4-metilvaleril]4-piperidinol,1- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimido-ethyl] -4-methylvaleryl] 4-piperidinol,
1-[2(R)-[1(R ali S)-(hidroksikarbamoii)-2-(l,2-dimetil-3,5-diokso-l,2,4-triazolidin-4il)etil]-4-metilvaleril]piperidin,1- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4yl) ethyl] -4- methylvaleryl] piperidine,
4-[2(R)-[l(R ali S)-(hidroksikarbamoil)-2-(3-meti!-2,5'diokso-l-imidazolidinil)etil]-4metilvaleril]tetrahidro’l,4-tiazin, heksahidro-2-[2(R)'[l(R ali S)-(hidroksikarbamoil)-2-ftalimidoetil]-4-metflvaleril]-Nmetil-3(S)-piridazinkarboksamid in4- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3-methyl-2,5'-dioxo-1-imidazolidinyl) ethyl] -4methyl valeryl] tetrahydro-1,4-thiazine , hexahydro-2- [2 (R) '[1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methylphenyl] -Nmethyl-3 (S) -pyridazinecarboxamide and
1-[2(R)-[1(R ali S)-(hidroksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-l-imidazolidinil)etil]-4-metilvalerilJ-4-piperidinol.1- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -4-methylvaleryl-4- piperidinol.
V skladu s postopkom, ki ga nudi predloženi izum, pripravimo spojine s formulo I in njihove farmacevtsko sprejemljive soli tako, da (a) kislina s splošno formuloIn accordance with the method provided by the present invention, the compounds of formula I and their pharmaceutically acceptable salts are prepared such that (a) an acid of the general formula
v kateri imajo R1, R2, R3, R4, R5, R6, R7 in n prej navedeni pomen, reagira s spojino s splošno formuloin which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and n have the aforementioned meaning, reacts with a compound of the general formula
H2N-OZ (III) v kateri Z predstavlja vodik, tri(nižji alkil)silil ali difenil(nižji alkil)silil, in po potrebi odcepimo morebitno difenil(nižji alkil)sililno skupino, prisotno v reakcijskem produktu, aliH 2 N-OZ (III) in which Z represents hydrogen, tri (lower alkyl) silyl or diphenyl (lower alkyl) silyl, and optionally cleaving any diphenyl (lower alkyl) silyl group present in the reaction product, or
b) katalitsko hidrogeniramo spojino s splošno formulob) catalytically hydrogenate a compound of the general formula
v kateri imajo Rl, R^, r3, r4, r5, r6, r7 jn n prej navedeni pomen in Bz predstavlja benzil, in po želji pretvorimo dobljeno spojino s formulo Ϊ v farmacevtsko sprejemljivo sol.where Rl, R ^, R3, R4, R5, R6, R7, j nn p re j as defined above and Bz represents benzyl, and, if desired, converting the resulting compound of formula Ϊ into a pharmaceutically acceptable salt thereof.
Reakcijo kisline s formulo II s spojino s formulo lil v skladu z izvedbo (a) postopka lahko izvedemo na znan način, npr. v inertnem organskem topilu kot dimetilformamidu ipd., ob uporabi hidroksibenzotriazola v prisotnosti kondenzacijskega sredstva kot l-etil-3-(3-dimetilamino-propil)karbodiimid hidroklorida pri okoli 0 °C do okoli sobne temperature. Prednostne spojine s formulo III so tiste, v katerih Z predstavlja vodik, terc.butil-dimetilsilil ali terc.butil difenilsilil. Če uporabimo spojino s formulo III, v kateri Z predstavlja tri(nižji alkil)silil, to skupino odcepimo med reakcijo in obdelavo ter direktno dobimo spojino s formulo I. Po drugi strani pa pri uporabi spojine s formulo 111, v kateri Z predstavlja diaril-(nižji alkil)silil, ta skupina ostane v reakcijskem produktu in jo je naknadno treba odcepiti na znan način, npr. s pomočjo fluoridnih ionov.The reaction of an acid of formula II with a compound of formula lil according to embodiment (a) of the process can be carried out in a known manner, e.g. in an inert organic solvent such as dimethylformamide and the like, using hydroxybenzotriazole in the presence of a condensing agent such as l-ethyl-3- (3-dimethylamino-propyl) carbodiimide hydrochloride at about 0 ° C to about room temperature. Preferred compounds of formula III are those wherein Z represents hydrogen, tert-butyl-dimethylsilyl or tert-butyl diphenylsilyl. If a compound of formula III is used in which Z represents three (lower alkyl) silyl, this group is cleaved during the reaction and treatment and directly obtained is a compound of formula I. On the other hand, when using a compound of formula 111 in which Z represents diaryl- (lower alkyl) silyl, this group remains in the reaction product and must subsequently be cleaved in a known manner, e.g. using fluoride ions.
Katalitsko hidrogeniraje spojine s formulo IV v skladu z izvedbo (b) postopka lahko izvedemo na sam po sebi znan način, npr. v inertnem organskem topilu ob uporabi vodika v prisotnosti katalizatorja plemenite kovine. Primerna inertna organska topila so npr. nižji alkanoli kot metanol, etanol itd. Katalizator pa je lahko npr. platinov, paladijev ali rodijev katalizator, ki je lahko nanešen na primernem noslinem materialu. Prednosten katalizatorje paladij na oglju. Temperatura in tlak nista kritična, čeprav zaradi prikladnosti izvedemo katalitsko hidrogeniranje prednostno pri sobni temperaturi in pri atmosferskem tlaku.The catalytic hydrogenation of compounds of formula IV in accordance with embodiment (b) of the process can be carried out in a manner known per se, e.g. in an inert organic solvent using hydrogen in the presence of a precious metal catalyst. Suitable inert organic solvents are e.g. lower alkanols than methanol, ethanol, etc. However, the catalyst may be e.g. platinum, palladium or rhodium catalyst, which may be applied on suitable nostril material. Preferred palladium catalysts on charcoal. Temperature and pressure are not critical, although catalytic hydrogenation is preferably carried out at room temperature and atmospheric pressure for convenience.
Spojine s formulo I lahko pretvorimo v farmacevtsko sprejemljive soli z obdelavo z bazami in bazične spojine s formulo I se dajo pretvoriti v farmacevtsko sprejemljive soli z obdelavo s kislinami, take obdelave lahko izvedemo na običajen način.Compounds of formula I can be converted to pharmaceutically acceptable salts by treatment with bases, and basic compounds of formula I can be converted into pharmaceutically acceptable salts by treatment with acids, such treatment can be carried out in the usual way.
Kisline s formulo II, uporabljene kot izhodni materiali pri izvedbi (a) postopka, so nove spojine in tvorijo nadaljnji predmet predloženega izuma.The acids of formula II used as starting materials in carrying out (a) of the process are novel compounds and form a further object of the present invention.
Kisline s formulo II se da pripraviti npr. tako, kot je prikazano na naslednji Reakcijski shemi, v kateri imajo Rl, R^, R-\ r4 r5, r7, gz jn n prej navedeni pomen in tBu predstavlja terc.butil.The acids of formula II can be prepared e.g. as shown in the following Reaction Scheme in which R1, R4, R- \ r4 r5, r7, g with j nn p re j have the indicated meaning and tBu represents tert.butyl.
Reakcijska shemaReaction scheme
Z ozirom na zgornjo Reakcijsko shemo pri prvi stopnji aIkantrikarboksilat s formulo V reagira z bromoalkil-substituiranim N-heterociklom s formulo VI, da dobimo spojino s formulo VIL To reakcijo lahko izvedemo na splošno znan način, npr. z obdelavo alkantrikarboksilta v inertnem organskem topilu kot dimetilformamidu z močno bazo, npr. hidridom alkalijske kovine kot natrijevim hidridom, nakar dodamo bromoalkilsubstituiran N-heterocikel in pustimo, da se reakcija odvija, prednostno pri sobni temperaturi.In view of the above Reaction Scheme, in the first step, αIcantricarboxylate of formula V is reacted with a bromoalkyl-substituted N-heterocycle of formula VI to give a compound of formula VIL This reaction can be carried out in a conventional manner, e.g. by treating alkantricarboxylate in an inert organic solvent as dimethylformamide with a strong base, e.g. alkali metal hydride as sodium hydride, then bromoalkylsubstituted N-heterocycle is added and the reaction is allowed to proceed, preferably at room temperature.
Dobljeno spojino s formulo VII nato debenziliramo v spojino s formulo VIII na sam po sebi znan način, npr. s hidrogeniranjem v inertnem organskem topilu, npr. v nižjem alkanolu kot metanolu ali etanolu, v prisotnosti katalizatorja kot paladija na oglju.The resulting compound of formula VII is then debenzylated into the compound of formula VIII in a manner known per se, e.g. by hydrogenation in an inert organic solvent, e.g. in lower alkanol than methanol or ethanol, in the presence of a catalyst as palladium on charcoal.
Sledeče dekarboksiliranje spojine s formulo VIII v spojino s formulo IX tudi izvedemo na znan način, npr. s segrevanjem v aromatskem topilu kot benzenu ali toluenu, v prisotnosti baze kot N-metilmorfolina.The following decarboxylation of the compound of formula VIII into the compound of formula IX is also carried out in a known manner, e.g. by heating in an aromatic solvent such as benzene or toluene, in the presence of a base such as N-methylmorpholine.
Pri naslednji stopnji spojina s formulo IX reagira z aminom s formulo X, da dobimo spojino s formulo XI. To reakcijo lahko izvedemo na sam po sebi znan način. Tako npr. reakcijo prikladno izvedemo v inertnem organskem topilu kot dimetilformamidu ipd. ob uporabi hidroksibenzotriazola v prisotnosti kondenzacijskega sredstva kot 1etil-3-(3-dimetilaminopropil)karbodiimid hidroklorida, ali s pretvorbo spojine s formulo IX z oksalilkloridom v ustrezni klorid in reakcijo le-tega z aminom, smotrno v prisotnosti baze kot trietilamina pri okoli 0 do 25 °C.In a further step, a compound of formula IX is reacted with an amine of formula X to yield a compound of formula XI. This reaction can be carried out in a manner known per se. So e.g. the reaction is conveniently carried out in an inert organic solvent such as dimethylformamide and the like. using hydroxybenzotriazole in the presence of a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, or by converting a compound of formula IX with oxalyl chloride into a suitable chloride and reacting it with an amine, preferably in the presence of a base such as triethylamine, at about 0 to triethylamine 25 ° C.
Pri končni stopnji odstranimo zaščito pri spojini s formulo XI, da dobimo želeni kislinski izhodni material s formulo II. To odstranitev zaščite lahko izvedemo na sam po sebi znan način, npr. z obdelavo s trifluorocetno kislino.At the final step, the protection of the compound of formula XI is removed to obtain the desired acid starting material of formula II. This deprotection can be carried out in a manner known per se, e.g. by treatment with trifluoroacetic acid.
Po želji lahko spojino s formulo XI funkcionalno modificiramo pred stopnjo odstranitve zaščite. Tako npr. spojino s formulo XI. v kateri NR^R^ predstavlja nasičen 5-, 6- ali 7-členski heterocikličen obroč, ki vsebuje -S- kot obročni člen, oksidiramo na sam po sebi znan način, npr. z uporabo perkisline kot mkloroperbenzojske kisline, v ustrezno spojno, ki vsebuje -SO- ali -SO2- kot obročni člen.If desired, the compound of formula XI can be functionally modified prior to the deprotection step. So e.g. a compound of formula XI. in which NR ^ R ^ represents a saturated 5-, 6- or 7-membered heterocyclic ring containing -S- as a ring member, is oxidized in a manner known per se, e.g. using peracid as mChloroperbenzoic acid, into a suitable compound containing -SO- or -SO2- as a ring member.
Spojine s formulo IV, kijih uporabimo kot izhodne materiale pri izvedbi (b) postopka, so nove in tvorijo nadaljnji predmet predloženega izuma.The compounds of formula IV to be used as starting materials in carrying out (b) of the process are novel and form a further object of the present invention.
Spojine s formulo IV lahko pripravimo, npr., z reakcijo kisline s formulo II z Obenzilhidroksilaminom. To reakcijo lahko izvedemo na znan način, npr. v inertnem organskem topilu kot dimetilformamidu ob uporabi hidroksibenzotriazola v prisotnosti kondenzacijskega sredstva kot l-etil-3-(3-dimetilaminopropil)karbodiimid hidroklorida.Compounds of formula IV can be prepared, for example, by reaction of an acid of formula II with Obenzylhydroxylamine. This reaction can be carried out in a known manner, e.g. in an inert organic solvent such as dimethylformamide using hydroxybenzotriazole in the presence of a condensing agent such as l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride.
Ostale spojine, ki jih uporabimo kot intermediate ali reagente pri pripravi spojin s formulo I, so znane spojine ali analogi znanih spojin, ki se jih da pripraviti na podoben način kot znane spojine.Other compounds used as intermediates or reagents in the preparation of compounds of formula I are known compounds or analogs of known compounds which can be prepared in a similar manner to known compounds.
Kot smo že prej omenili, so spojine s formulo I in njihove farmacevtsko sprejemljive soli inhibitorji kolagenaze. Aktivnost predloženih spojin in soli za in vitro inhibiranje kolagenaze se da prikazati z uporabo kolagenaze, dobljene iz kulture humanih sinovialnih fibroblastov po metodi Dayer J-M et. al, Proč. Natl. Acad.Sci. USa (1976), 73 945, ki sledi aktiviranju pro-kolagenaze v kondicioniranem mediju z obdelovo s tripsinom. Kolagenazno aktivnost smo izmerili z uporabo ,4C-acetiliranega kolagena tipa I iz tendonov podganjega repa kot substrata in ob uporabi testne metode z mikrotitrirno ploščo (Jonson-Wint, B, Anal. Biochem. (1980), 104, 175). IC5q je tista koncentracija spojine ali soli v smislu predloženega izuma, pri digestiji encima, ki zmanjša cepitev substrata in solubilizacijo na 50 % vrednosti, dosežne s samim encimom.As mentioned earlier, the compounds of formula I and their pharmaceutically acceptable salts are collagenase inhibitors. The activity of the present compounds and salts for in vitro inhibition of collagenase can be demonstrated using collagenase obtained from culture of human synovial fibroblasts according to the method of Dayer JM et. al., Contd. Natl. Acad.Sci. USa (1976), 73 945, following the activation of pro-collagenase in conditioned medium by trypsin treatment. Collagenase activity was measured using 4 C-acetylated type I collagen from rat tail tendons as substrate and using a microtiter plate assay method (Jonson-Wint, B, Anal. Biochem. (1980), 104, 175). IC5q is that concentration of a compound or salt of the present invention in the digestion of an enzyme that reduces substrate cleavage and solubilization to 50% of the value achieved by the enzyme itself.
Rezultati, dobljeni pri zgornjem testu z reprezentativnimi spojinami in solmi v smislu predloženega izuma, so zbrani v naslednji tabeli 1:The results obtained in the above test with representative compounds and salts of the present invention are summarized in the following Table 1:
Tabela ITable I
Spojina A: 4-[2(R)-[ 1 (R ali S)-(hidroksikarbamoil)-2-ftalim idoetil]4-metilvaleril]morfolin.Compound A: 4- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalim idoethyl] 4-methylvaleryl] morpholine.
Spojina B: 4-[2(R)-[l(R ali S)-(hidroksikarbamoil)-2-ftalimidoetil]4-metilvaleril]tetrahidro-1,4-tiazin.Compound B: 4- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] 4-methylvaleryl] tetrahydro-1,4-thiazine.
Spojina C: 1-[2(R)-[1(R ali S)-(hidroksikarbamoil)-2-t'talimidoetilj4-metilvaleril]-4-piperidinol.Compound C: 1- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-thalimidoethyl 4-methylvaleryl] -4-piperidinol.
Spojina D: 1-[2(R)-[1(R ali S)-(hidroksikarbamoil)-2-( 1,2-dimetil-3,5-diokso-l,2,4triazolidin-4-il)]-4-metilvaleril]piperidin.Compound D: 1- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl)] - 4-methylvaleryl] piperidine.
Spojina E: 4-[2(R)-[ 1(R ali S)-(hidroksikarbamoil)-2-(3-metil-2,5-dioksoCompound E: 4- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3-methyl-2,5-dioxo)
-l-imidazolidinil)etil]-4-metilvaleril]tetrahidro-l ,4-tiazin.-1-imidazolidinyl) ethyl] -4-methylvaleryl] tetrahydro-1,4-thiazine.
Spojina F: heksahidro-2-[2(R)-[l(R ali S)-(hidroksikarbamoil)-2-ftalimidoetil]4-metilvaleril]-N-metil-3(S)piridazinkarboksamid.Compound F: Hexahydro-2- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] 4-methylvaleryl] -N-methyl-3 (S) pyridazinecarboxamide.
Spojina G: 1-[2(R)-[1(R ali S)-(hidroksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-l imidazolidinil)etil]-4-metilvaleril]-4-piperidinol.Compound G: 1- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -4-methylvaleryl] -4-Piperidinol.
Spojine s formulo I in njihove farmacevtsko sprejemljive soli lahko uporabimo kot zdravila, npr. v obliki farmacevtskih pripravkov. Farmacevtske pripravke lahko dajemo oralno, npr. v obliki tablet, prevlečenih tablet, dražejev, trdih in mehkih želatinskih kapsul, raztopin, emulzij ali suspenzij. Vendar pa se jih da dajati tudi rektalno, npr. v obliki supozitorijev, ali parenteralno, npr. v obliki injekcijskih raztopin.The compounds of formula I and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical compositions can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, they can also be administered rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
Za pripravo farmacevtskih pripravkov lahko formuliramo spojine s formulo I in njihove farmacevtsko sprejemljive soli s terapevtsko inertnimi anorganskimi ali organskimi nosilci. Kot take nosilce za tablete, prevlečene tablete, dražeje in trde želatinske kapsule, lahko uporabimo npr. laktozo, koruzni škrob ali njihove derivate, smukec, stearinsko kislino ali njene soli. Primerni nosilci za mehke želatiske kapsule so npr. rastlinska olja, voski, maščobe, poltrdni in tekoči polioli ipd. V odvisnosti od narave učinkovite sestavine na splošno niso potrebni nosilci pri mehkih želatinskih kapsulah. Primerni nosilci za pripravo raztopin in sirupov so npr. voda, polioli, saharoza, invertni sladkor, glukoza ipd. Primerni nosilci za pripravo injekcijskih raztopin so npr. voda, alkoholi, polioli, glicerin, rastlinska olja ipd. Naravna in strjena olja, voski, maščobe, poltekoči polioli ipd. so primerni nosilci za pripravo supozitorijev.For the preparation of the pharmaceutical compositions, the compounds of formula I and their pharmaceutically acceptable salts may be formulated with therapeutically inert inorganic or organic carriers. As such, carriers for tablets, coated tablets, dragees and hard gelatin capsules can be used e.g. lactose, maize starch or derivatives thereof, talc, stearic acid or its salts. Suitable carriers for soft gelatin capsules are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. Depending on the nature of the effective ingredient, carriers in soft gelatin capsules are generally not required. Suitable carriers for the preparation of solutions and syrups are e.g. water, polyols, sucrose, invert sugar, glucose and the like. Suitable carriers for the preparation of injection solutions are e.g. water, alcohols, polyols, glycerin, vegetable oils, etc. Natural and solid oils, waxes, fats, semi-liquid polyols and the like. are suitable carriers for the preparation of suppositories.
Farmacevtski pripravki lahko vsebujejo tudi konzervanse, stabilizatorje, omakala, emulgatorje, sladila, barvila, snovi za izboljšanje arome, soli za nastavitev osmotskega tlaka, pufre, prevlečna sredstva ali antioksidante.Pharmaceutical preparations may also contain preservatives, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, osmotic pressure adjusting salts, buffers, coating agents or antioxidants.
Zdravila, ki vsebujejo spojino s formulo 1 ali njeno farmacevtsko sprejemljivo sol in terapevtsko sprejemljiv nosilec, kot tudi postopek za pripravo takih zdravil, so prav tako predmeti predloženega izuma. Ta postopek obsega pomešanje spojine s formulo I ali njene farmacevtsko sprejemljive soli s terapevtsko inertnim nosilnim materialom in formuliranje zmesi v pripravek za galensko dajanje.Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically acceptable carrier as well as a process for the preparation of such medicaments are also objects of the present invention. This process involves mixing a compound of formula I or a pharmaceutically acceptable salt thereof with a therapeutically inert carrier material and formulating the mixture into a galenic preparation.
Kot smo že omenili, se da spojine s formulo I in njihove farmacevtsko sprejemljive soli uporabiti pri kontroli ali preventivi bolezni, zlasti pri kontroli ali preventivi degenerativnih bolezni sklepov ali pri zdravljenju invazivnih tumorjev, ateroskleroze ali multiple skleroze. Doziranje lahko variira v širokih mejah in bo seveda prilagojeno individualnim potrebam v vsakem posameznem primeru. Na splošno bo pri dajanju odraslim primerna dnevna doza od okoli 5 mg do okoli 30 mg, prednostno od okoli mg do okoli 15 mg, čeprav se da zgornjo mejo tudi preseči, če bi se to izkazalo kot koristno. Dnevno dozo lahko dajemo v enem samem doziranju ali s porazdeljenimi doziranji.As mentioned above, the compounds of formula I and their pharmaceutically acceptable salts may be used in the control or prevention of diseases, especially in the control or prevention of degenerative joint diseases or in the treatment of invasive tumors, atherosclerosis or multiple sclerosis. Dosage can vary within wide limits and will, of course, be tailored to the individual needs of each case. In general, a daily dose of about 5 mg to about 30 mg, preferably from about mg to about 15 mg, will be appropriate when administered to adults, although the upper limit may also be exceeded if this would prove useful. The daily dose can be given in a single dose or in divided doses.
Naslednji Primeri podrobneje pojasnjujejo predloženi izum. Pri vseh teh Primerih so temperature navedene v °C.The following Examples explain the present invention in more detail. In all these Examples, temperatures are indicated in ° C.
Primer 1Example 1
Raztopino 0.15 g 1-[2(R)-[1(R ali S)-karboksi-2-ftalimidoetil]-4-metilvaleril]-pirolidina (diastereoizomer 1) v 3 ml suhega dimetilformamida smo ohladili na 0 °C ob mešanju pod dušikom in zapored obdelali z 0.075 g 1-hidroksibenzotriazola, 0.12 g O(terc.butildimetilsilil)-hidroksilamina, 0.075 ml N-metilmorfolina in 0.094 g l-etil-3-(3dimetilaminopropil)karbodiimid hidroklorida. Zmes smo pustili ogreti na sobno temperaturo in mešali čez noč. Topilo smo uparili in ostanek obdelali s 5 ml 5 % vodne raztopine natrijevega hidrogen karbonata. Produkt smo ekstrahirali s 3 deleži etil acetata in združene ekstrakte izprali z 1.0 M klorovodikovo kislino in vodno raztopino natrijevega klorida. Po sušenju nad brezvodnim magnezijevim sulfatom smo topilo uparili in ostanek zdrgnili z zmesjo etra in heksana. Trdno snov smo odfiltrirali in sušili, da smo dobili 0.09 g 1-[2(R)-[1(R ali S)-(hidroksikarbamoil)-2-ftalimidoetil]-4metilvaleriljpirolidina (diastereoizomer 1) v obliki belega prahu: nmr (MeOD): 7.847.71 (m,4H); 3.78-3.70 (m,3H); 3.54-3.43 (m,IH); 3.23-3.15 (m,IH); 3.05-2.90 (m,3H); 2.06-1.86(m,2H); 1.83-1.71 (m, 2H), 1.58-1.49 (m,IH); 1.43-1.32 (m,IH); 1.23-1.14 (m, IH); 0.87 (d,3H,J=6); 0.81 (d,3H,J=6);A solution of 0.15 g of 1- [2 (R) - [1 (R or S) -carboxy-2-phthalimidoethyl] -4-methylvaleryl] -pyrrolidine (diastereoisomer 1) in 3 ml of dry dimethylformamide was cooled to 0 ° C with stirring under was treated with nitrogen and sequentially treated with 0.075 g of 1-hydroxybenzotriazole, 0.12 g of O (tert-butyldimethylsilyl) -hydroxylamine, 0.075 ml of N-methylmorpholine and 0.094 g of l-ethyl-3- (3dimethylaminopropyl) carbodiimide hydrochloride. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was treated with 5 ml of 5% aqueous sodium hydrogen carbonate solution. The product was extracted with 3 parts of ethyl acetate and the combined extracts were washed with 1.0 M hydrochloric acid and aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was triturated with a mixture of ether and hexane. The solid was filtered off and dried to give 0.09 g of 1- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4methylvalerylpyrrolidine (diastereoisomer 1) as a white powder: nmr (MeOD ): 7,847.71 (m, 4H); 3.78-3.70 (m, 3H); 3.54-3.43 (m, 1H); 3.23-3.15 (m, 1H); 3.05-2.90 (m, 3H); 2.06-1.86 (m, 2H); 1.83-1.71 (m, 2H), 1.58-1.49 (m, 1H); 1.43-1.32 (m, 1H); 1.23-1.14 (m, 1H); 0.87 (d, 3H, J = 6); 0.81 (d, 3H, J = 6);
MS 402 (M + H) + .MS 402 (M + H) < + >.
Izhodni material smo pripravili kot sledi:The starting material was prepared as follows:
(i) Raztopino 0.41 g približno 6 : 1 zmesi diastereoizomera 1 in diastereoizomera 2 [2(R)-[.1(R ali S)-(terc.butoksikarbonil)-2-ftalimidoetil]-4-metilva]erianske kisline ) v 5 ml suhega dimetilformamida smo ohladili na 0 °C ob mešanju pod dušikom in zapored obdelali z 0.16 g 1-hidroksibenzotriazola, 0.1 g pirolidina, 0.13 ml Nmetilmorfolina in 0.23 g l-etil-3-(3-dimetilaminopropil)karbodiimid hidroklorida. Zmes smo pustili ogreti na sobno temperaturo in mešali čez noč. Topilo smo uparili in ostanek obdelali z 20 ml 5 % vodne raztopine natrijevega hidrogen karbonata. Produkt smo ekstrahirali s 3 deleži etil acetata in združene ekstrakte izprali s 5 % citronsko kislino in vodno raztopino natrijevega klorida. Po sušenju nad brezvodnim magnezijevim sulfatom smo topilo uparili, da smo dobili 0.5 g brezbarvne gume, ki smo jo očistili s flash kromatografijo na silikagelu ob uporabi heksana/etil acetata (5 : 4) za elucijo. Po eluciji produkta (diastereoizomer 2), ki je hitreje potoval, smo dobili 0.365 g 1-[2(R)-[1(R ali S)-(ter.butoksikarbonil)-2-ftalimidoetil]-4-metil-valeril]pirolidina (diastereoizomer 1) v obliki brezbarvne gume: nmr (MeOD): 7.88-7.79 (m,4H); 3.99-3.93 (m.IH); 3.78-3.66 (m,2H); 3.60-3.53 (m,IH); 3.39-3.30 (m,IH); 3.273.21 (m,IH); 3.19-3.13 (m, IH), 3.06-2.99 (m,IH); 2.10-1.96 (m,2H); 1.92-1.83 (m,2H);(i) A solution of 0.41 g of approximately 6: 1 mixture of diastereoisomer 1 and diastereoisomer 2 [2 (R) - [. 1 (R or S) - (tert-butoxycarbonyl) -2-phthalimidoethyl] -4-methyl] eric acid) in 5 ml of dry dimethylformamide was cooled to 0 ° C under stirring under nitrogen and treated sequentially with 0.16 g of 1-hydroxybenzotriazole, 0.1 g of pyrrolidine, 0.13 ml of N-methylmorpholine and 0.23 g of l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was treated with 20 ml of 5% aqueous sodium hydrogen carbonate solution. The product was extracted with 3 parts of ethyl acetate and the combined extracts were washed with 5% citric acid and aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated to give 0.5 g of colorless gum, which was purified by flash chromatography on silica gel using hexane / ethyl acetate (5: 4) for elution. Elution of the faster-traveling product (diastereoisomer 2) gave 0.365 g of 1- [2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2-phthalimidoethyl] -4-methyl-valeryl] pyrrolidine (diastereoisomer 1) as a colorless gum: nmr (MeOD): 7.88-7.79 (m, 4H); 3.99-3.93 (m.IH); 3.78-3.66 (m, 2H); 3.60-3.53 (m, 1H); 3.39-3.30 (m, 1H); 3.273.21 (m, 1H); 3.19-3.13 (m, 1H), 3.06-2.99 (m, 1H); 2.10-1.96 (m, 2H); 1.92-1.83 (m, 2H);
1.76-1.68 (m,IH), 1.53-1.42 (m,IH), 1.33 (s,9H); 1.30-1.20 (m,IH); 0.95 (d,3H,J=6);1.76-1.68 (m, 1H), 1.53-1.42 (m, 1H), 1.33 (s, 9H); 1.30-1.20 (m, 1H); 0.95 (d, 3H, J = 6);
0.88 (d,3H,J=6).0.88 (d, 3H, J = 6).
(ii) Raztopino 0.35 g 1-[2(R)-[1(R ali S)-(ter.butoksikarbonil)-2-ftalimidoetil]-4-metilvaleriljpirolidina (diastereoizomer 1) v 10 ml diklormetana smo obdelali s 3ml trifluorocetne kisline. Zmes smo mešali pri sobni temperaturi 2 uri in dodali 10 ml toluena. Topilo smo uparili in ostanek uparili še trikrat z 20 ml deleži toluena. Ostanek smo kristalizirali iz etra, da smo dobili 0.161 g 1-[2(R)-[1(R ali S)-karboksi-2ftalimidoetil]-4-metilvaleril]pirolidina (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 7.86-7.75 (m,4H); 3.92-(dd,1H,J = 11.6); 3.80 (dd,lH,J = 11.6); 3.74-3.67 (m,IH); 3.55-3.46 (m,IH); 3.32-3.18 (m,2H); 3.13-2.99(m,2H); 2.06-1.90 (m,2H); 1.871.77 (m,2H); 1.71-1.62 (m,IH), 1.52-1.40 (m,IH); 1.33-1.25 (m,IH); 0.92 (d,3H,J=6); 0.86 (d,3H,J=6); MS: 387 (M + H) + .(ii) A solution of 0.35 g of 1- [2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2-phthalimidoethyl] -4-methylvalerylpyrrolidine (diastereoisomer 1) in 10 ml of dichloromethane was treated with 3 ml of trifluoroacetic acid . The mixture was stirred at room temperature for 2 hours and 10 ml of toluene was added. The solvent was evaporated and the residue was evaporated three more times with 20 ml portions of toluene. The residue was crystallized from ether to give 0.161 g of 1- [2 (R) - [1 (R or S) -carboxy-2-phthalimidoethyl] -4-methylvaleryl] pyrrolidine (diastereoisomer 1) as a white solid; nmr (MeOD): 7.86-7.75 (m, 4H); 3.92- (dd, 1H, J = 11.6); 3.80 (dd, 1H, J = 11.6); 3.74-3.67 (m, 1H); 3.55-3.46 (m, 1H); 3.32-3.18 (m, 2H); 3.13-2.99 (m, 2H); 2.06-1.90 (m, 2H); 1,871.77 (m, 2H); 1.71-1.62 (m, 1H), 1.52-1.40 (m, 1H); 1.33-1.25 (m, 1H); 0.92 (d, 3H, J = 6); 0.86 (d, 3H, J = 6); MS: 387 (M + H) < + >.
Primer 2Example 2
Na analogen način, kot smo opisali v prvem odstavku Primera 1, smo iz 0.155 g 1-[2(R)-[1(R ali S)-karboksi-2-ftalimidoetil]-4-metilvaleril]piperidina (diastereoizomer 1), pripravljenega na analogen način, kot je opisano v Primeru 1 (i) - (ii), dobili 0.1 g 1-[2(R)-[1(R ali S)-(hidroksikarbamoil)-2-ftalimidoetil]-4-metilvaleril]piperidina (diastereoizomer 1) v obliki belega prahu; nmr (MeOD): 7.88-7.76 (m,4H); 3.89 (dd,lH,J = 11.6); 3.86-3.77 (m,IH); 3.70-3.58 (m,3H); 3.37-3.24 (m,2H); 2.99-2.93 (m,IH); 1.78-1.53 (m,6H); 1.52-1.36 (m,2H), 1.23-1.14 (m,IH); 0.93-0.85 (m,6H);In an analogous manner as described in the first paragraph of Example 1, 0.155 g of 1- [2 (R) - [1 (R or S) -carboxy-2-phthalimidoethyl] -4-methylvaleryl] piperidine (diastereoisomer 1) was obtained. prepared in an analogous manner as described in Example 1 (i) - (ii) gave 0.1 g of 1- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl ] piperidine (diastereoisomer 1) in the form of a white powder; nmr (MeOD): 7.88-7.76 (m, 4H); 3.89 (dd, 1H, J = 11.6); 3.86-3.77 (m, 1H); 3.70-3.58 (m, 3H); 3.37-3.24 (m, 2H); 2.99-2.93 (m, 1H); 1.78-1.53 (m, 6H); 1.52-1.36 (m, 2H), 1.23-1.14 (m, 1H); 0.93-0.85 (m, 6H);
MS: 416 (M+H)+ .MS: 416 (M + H) < + >.
Primer 3Example 3
Na analogen način, kot smo opisali v prvem odstavku Primera 1, smo iz 0.283 g 4[2(R)-[1(R ali S)-karboksi-2-ftalimidoetil]-4-metilvaleril] morfolina (diastereoizomer 1), pripravljenega na analogen način, kot je opisano v Primeru 1 (i) - (ii), dobili 0.12 g 4-[2(R)-[l(R ali S)-(hidroksikarbamoil)-2-ftalimidoetil]-4-metilvaleril]morfolina (diastereoizomer 1) v obliki belega prahu; nmr (MeOD): 7.87-7.76 (m,4H); 3.87 (dd,lH,J=11.6); 3.83-3.70 (m,3H); 3.68-3.60 (m,3H); 3.59-3.51 (m,2H); 3.47-3.39 (m,IH); 3.32-3.23 (m,lH), 2.99-2.92 (m,IH); 1.66-1.58 (m,IH); 1.47-1.36 (m,IH); 1.241.14 (m,IH); 0.91 -0.84 (m,6H); MS: 418 (M + H) +.In an analogous manner as described in the first paragraph of Example 1, 0.283 g of 4 [2 (R) - [1 (R or S) -carboxy-2-phthalimidoethyl] -4-methylvaleryl] morpholine (diastereoisomer 1) was prepared in an analogous manner as described in Example 1 (i) - (ii), 0.12 g of 4- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] was obtained white powder morpholine (diastereoisomer 1); nmr (MeOD): 7.87-7.76 (m, 4H); 3.87 (dd, 1H, J = 11.6); 3.83-3.70 (m, 3H); 3.68-3.60 (m, 3H); 3.59-3.51 (m, 2H); 3.47-3.39 (m, 1H); 3.32-3.23 (m, 1H), 2.99-2.92 (m, 1H); 1.66-1.58 (m, 1H); 1.47-1.36 (m, 1H); 1.241.14 (m, 1H); 0.91 -0.84 (m, 6H); MS: 418 (M + H) < + >.
Primer 4Example 4
Na analogen način, kot smo opisali v prvem odstavku Primera 1, smo iz 0.16 g 1-[2(R)-[1(R ali S)-karboksi-2-ftalimidoetil]-4-metilvaleril]heksahidroazepina (diastereoizomer 1), pripravljenega na analogen način, kot je opisano v Primeru 1 (i) - (ii), dobili 0.13 g 1-[2(R)-[1 (R ali S)-(hidroksikarbamoil)-2-ftalimidoetil]-4-metilvaleriljheksahidroazepina (diastereoizomer 1) v obliki belega prahu; nmr (MeOD): 7.88-7.76 (m,4H); 3.95 (dd,lH,J = 11.6); 3.84-3.76 (m,IH); 3.70-3.54 (m,3H); 3.37-3.25 (m,2H); 2.97-2.89 (m,IH); 1.94-1.77 (m,2H); 1.75-1.53 (m,7H), 1.51-1.40 (m,IH); 1.271.19 (m,IH); 0.92 (d,3H,J=6); 0.88 (d,3H,J = 6); MS: 430 (M + H) + .In an analogous manner as described in the first paragraph of Example 1, 0.16 g of 1- [2 (R) - [1 (R or S) -carboxy-2-phthalimidoethyl] -4-methylvaleryl] hexahydroazepine (diastereoisomer 1) are obtained. prepared in an analogous manner as described in Example 1 (i) - (ii) gave 0.13 g of 1- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methylvalerylhexahydroazepine (diastereoisomer 1) in the form of a white powder; nmr (MeOD): 7.88-7.76 (m, 4H); 3.95 (dd, 1H, J = 11.6); 3.84-3.76 (m, 1H); 3.70-3.54 (m, 3H); 3.37-3.25 (m, 2H); 2.97-2.89 (m, 1H); 1.94-1.77 (m, 2H); 1.75-1.53 (m, 7H), 1.51-1.40 (m, 1H); 1.271.19 (m, 1H); 0.92 (d, 3H, J = 6); 0.88 (d, 3H, J = 6); MS: 430 (M + H) < + >.
Primer 5Example 5
Na analogen način, kot smo opisali v prvem odstavku Primera 3, smo iz 0.28 g 4-[2(R)-[l(R ali S)-karboksi-2-ftalimidoetil]-4-metilvaleril]tetrahidro- 1,4-tiazina (diastereoizomer 1), pripravljenega na analogen način, kot je opisano v Primeru 1 (i) - (ii), dobili 0.14 g 4-[2(R)-[l(R ali S)-(hidroksikarbamoil)-2-ftalimidoetil]-4metilvaleriljtetrahidro-1,4-tiazina (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD); 7.84-7.73 (m,4H); 4.09-4.01 (m,IH); 3.93-3.81 (m,3H); 3.63-3.53 (m,2H); 3.29-3.21 (m,IH); 2.95-2.87 (m,IH); 2.76-2.69 (m,IH), 2.67-2.59 (m,IH); 2.572.46 (m,2H); 1.63-1.55 (m,IH); 1.43-1.32 (m,IH); 1.20-1.12 (m,IH); 0.86 (d,3H,J=6); 0.83 (d,3H,J=6); MS: 434 (M + H)+.In an analogous manner to that described in the first paragraph of Example 3, 0.28 g of 4- [2 (R) - [1 (R or S) -carboxy-2-phthalimidoethyl] -4-methylvaleryl] tetrahydro-1,4- of the thiazine (diastereoisomer 1) prepared in an analogous manner as described in Example 1 (i) - (ii) gave 0.14 g of 4- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- phthalimidoethyl] -4methylvaleryltetrahydro-1,4-thiazine (diastereoisomer 1) as a white solid; nmr (MeOD); 7.84-7.73 (m, 4H); 4.09-4.01 (m, 1H); 3.93-3. 81 (m, 3H); 3.63-3.53 (m, 2H); 3.29-3.21 (m, 1H); 2.95-2.87 (m, 1H); 2.76-2.69 (m, 1H), 2.67-2.59 (m, 1H); 2,572.46 (m, 2H); 1.63-1.55 (m, 1H); 1.43-1.32 (m, 1H); 1.20-1.12 (m, 1H); 0.86 (d, 3H, J = 6); 0.83 (d, 3H, J = 6); MS: 434 (M + H) < + >.
Primer 6Example 6
Na analogen način, kot smo opisali v prvem odstavku Primera 1, smo iz 0.36 g 1-[2(R)[1(R ali S)-karboksi-2-ftalimidoetil]-4-metilvaleril]-4-piperidinola (diastereoizomer 1), pripravljenega na analogen način, kot je opisano v Primeru 1 (i) - (ii), dobili po čiščenju surovega produkta s flash kromatografijo na silikagelu ob uporabi diklormetana/metanola (16 : 1) za elucijo, 0.053 g 1 -[2(R)-[ 1 (R ali S)-(hidroksikarbamoil)-2-ftalimidoetil]-4-metilvaleril]-4-piperidinola (diastereoizomer 1) v obliki belega prahu; nmr (MeOD): 7.88-7.76 (m,4H); 4.15-3.79 (m,4H); 3.67-2.84 (m,5H); 2.06-1.73 (m,2H); 1.70-1.14 (m,5H); 0.95-0.84 (m,6H); MS: 432 (M + H) + .In the analogous manner as described in the first paragraph of Example 1, 0.36 g of 1- [2 (R) [1 (R or S) -carboxy-2-phthalimidoethyl] -4-methylvaleryl] -4-piperidinol (diastereoisomer 1) ) prepared in an analogous manner as described in Example 1 (i) - (ii), obtained after purification of the crude product by flash chromatography on silica gel using dichloromethane / methanol (16: 1) for elution, 0.053 g 1 - [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] -4-piperidinol (diastereoisomer 1) as a white powder; nmr (MeOD): 7.88-7.76 (m, 4H); 4.15-3.79 (m, 4H); 3.67-2.84 (m, 5H); 2.06-1.73 (m, 2H); 1.70-1.14 (m, 5H); 0.95-0.84 (m, 6H); MS: 432 (M + H) < + >.
Primer ΊExample Ί
Na analogen način, kot smo opisali v Primeru 1, smo iz 0.557 g 2(R)-[1(R ali S)karboksi-2-ftalimidoetil]-N,N,4-trimetilvaleramida (diastereoizomer 1), pripravljenega na analogen način, kot je opisano v Primeru 1 (i) - (ii), dobili po čiščenju produkta s flash kromatografijo ob uporabi 2 % metanola v diklorometanu za elucijo 0.053 g 2(R)-[1(R ali S)-(hidroksikarbamoil)-2-ftalimidoetil]-N,N,4-trimetilvaleramida v obliki belega prahu; nmr (MeOD): 7.85-7.75 (m,4H); 3.84 (dd,J= 14.7,IH); 3.68 (dd,J= 14.10,IH); 3.18 (s,3H); 2.98-2.93 (m,IH); 2.75 (s,3H); 1.6-1.53 (m,IH); 1.4-1.3 (m,IH); 1.23-1.14 (m,lH); 0.88 (d,J=8.3H); 0.84 (d,J = 8,3H). MS: 376 (M+H)+.In an analogous manner as described in Example 1, 0.557 g of 2 (R) - [1 (R or S) carboxy-2-phthalimidoethyl] -N, N, 4-trimethylvaleramide (diastereoisomer 1) is prepared in an analogous manner , as described in Example 1 (i) - (ii), obtained after purification of the product by flash chromatography using 2% methanol in dichloromethane to elute 0.053 g of 2 (R) - [1 (R or S) - (hydroxycarbamoyl) - 2-phthalimidoethyl] -N, N, 4-trimethylvaleramide as a white powder; nmr (MeOD): 7.85-7.75 (m, 4H); 3.84 (dd, J = 14.7, 1H); 3.68 (dd, J = 14.10, 1H); 3.18 (s, 3H); 2.98-2.93 (m, 1H); 2.75 (s, 3H); 1.6-1.53 (m, 1H); 1.4-1.3 (m, 1H); 1.23-1.14 (m, 1H); 0.88 (d, J = 8.3H); 0.84 (d, J = 8.3H). MS: 376 (M + H) < + >.
Primer 8Example 8
Na analogen način, kot smo opisali v prvem odstavku Primera 1, smo iz 0.59 g približno 6 : 1 zmesi diastereoizomera 1 in diastereoizomera 2 N2-[2(R)-[1(R ali S)-karboksi-2ftalimidoetil]-4-metilvaleril]-N1-metil-L-prolinamida, pripravljenega na analogen način, kot je opisano v Primeru 1 (i) - (ii), dobili po kristalizaciji produkta iz zmesi diklorometana in etra 0.12 g diastereoizomera 1 N2-[2(R)-[1(R ali S)-(hidroksikarbamoil)-2-ftalimidoeti]]-4-metilvaleril]-N 1-metil-L-prolinamida v obliki bele trdne snovi; nmr (MeOD): 7.86-7.75 (m,4H); 4.12-4.07 (m,IH); 3.92-3.83 (m,2H); 3.74-3.64 (m,2H); 3.13-3.04 (m,IH); 2.93-2.86 (m,IH); 2.67 (s,3H), 2.19-1.96 (m,3H); 1.91-1.82 (m,IH); 1.75-1.65 (m,IH); 1.64-1.55 (m,IH); 1.23-1.14 (m,IH); 0.93 (d,3H,J=6); 0.86 (d,3H,J = 6); MS:458(M) + .In an analogous manner as described in the first paragraph of Example 1, 0.59 g of about 6: 1 is a mixture of diastereoisomer 1 and diastereoisomer 2 N 2 - [2 (R) - [1 (R or S) -carboxy-2-phthalimidoethyl] -4 -methylvaleryl] -N 1 -methyl-L-prolinamide, prepared in an analogous manner as described in Example 1 (i) - (ii), obtained after crystallization of the product from a mixture of dichloromethane and ether 0.12 g of diastereoisomer 1 N 2 - [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl]] - 4-methylvaleryl] -N 1-methyl-L-prolinamide as a white solid; nmr (MeOD): 7.86-7.75 (m, 4H); 4.12-4.07 (m, 1H); 3.92-3.83 (m, 2H); 3.74-3.64 (m, 2H); 3.13-3.04 (m, 1H); 2.93-2.86 (m, 1H); 2.67 (s, 3H), 2.19-1.96 (m, 3H); 1.91-1.82 (m, 1H); 1.75-1.65 (m, 1H); 1.64-1.55 (m, 1H); 1.23-1.14 (m, 1H); 0.93 (d, 3H, J = 6); 0.86 (d, 3H, J = 6); MS: 458 (M) < + >.
Primer 9Example 9
Na analogen način, kot smo opisali v prvem odstavku Primera 1, le da da je reakcija potekala samo 3 ure, smo iz 0.31 g 1-[2(R)-[1(R ali S)-karboksi-2-ftalimidoetil]-4metilvaleril]-2(S)-pirolidinmetanola (diastereoizomer 1) po očiščenju produkta s flash kromatografijo ob uporabi diklorometana/metanola (12 : 1) za elucijo in s kristalizacijo iz zmesi etil acetata in etra, dobili 0.06 g 1-[2(R)-[1 (R ali S)-(hidroksikarbamoil)-2-ftalimidoetil]-4-metilvaleril]-2(S)-pirolidinmetanola (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD); 7.88-7.77 (m,4H); 3.86 -3.73 (m,4H); 3.63-3.50 (m,2H); 3.98-3.27 (m,IH); 3.10-2.92 (m,2H); 2.07-1.83 (m,4H); 1.62-1.43 (m,2H); 1.281.17 (m,IH), 0.97-0.83 (m,6H); MS: 432 (M + H) + .In the analogous manner as described in the first paragraph of Example 1, except that the reaction took only 3 hours, 0.31 g of 1- [2 (R) - [1 (R or S) -carboxy-2-phthalimidoethyl] was obtained from 0.31 g. 4methylvaleryl] -2 (S) -pyrrolidinmethanol (diastereoisomer 1) after purification of the product by flash chromatography using dichloromethane / methanol (12: 1) for elution and crystallization from ethyl acetate / ether mixture, 0.06 g of 1- [2 (R ) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] -2 (S) -pyrrolidinethanol (diastereoisomer 1) as a white solid; nmr (MeOD); 7.88-7.77 (m, 4H); 3.86 -3.73 (m, 4H); 3.63-3.50 (m, 2H); 3.98-3.27 (m, 1H); 3.10-2.92 (m, 2H); 2.07-1.83 (m, 4H); 1.62-1.43 (m, 2H); 1.281.17 (m, 1H), 0.97-0.83 (m, 6H); MS: 432 (M + H) < + >.
Izhodni material smo pripravili kot sledi:The starting material was prepared as follows:
Raztopino 0.355 g 1-[2(R)-[1(R ali S)-(terc.butoksikarbonil)-2-ftalimidoetil]-4metilvaleril]-2(S)-pirolidinmetanola (diastereoizomer 1), pripravljeno na analogen način kot smo opisali v Primeru l(i), v 7 ml toluena, smo obdelali z 0.07 g 3-metil-3pentenola in 0.7 ml trimetilsilil bromida. Zmes smo mešali v atmosferi suhega dušika 1.5 ur in nato topilo uparili. Po 3 nadaljnjih uparjenjih iz vsakokrat 10 ml toluena smo dobili 0.31 g bledorjave pene, ki je vsebovala 1-[2(R)-[1(R ali S)-(karboksi-2ftalimidoetil]-4-metilvaleril]-2(S)-pirolidinmetanola (diastereoizomer 1), ki smo ga uporabili brez nadaljnjega čiščenja.A solution of 0.355 g of 1- [2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2-phthalimidoethyl] -4methyl valeryl] -2 (S) -pyrrolidinmethanol (diastereoisomer 1) prepared in an analogous manner as in described in Example l (i), in 7 ml of toluene, was treated with 0.07 g of 3-methyl-3pentenol and 0.7 ml of trimethylsilyl bromide. The mixture was stirred under a dry nitrogen atmosphere for 1.5 hours and then the solvent was evaporated. After 3 further evaporations from each 10 ml of toluene, 0.31 g of a pale brown foam containing 1- [2 (R) - [1 (R or S) - (carboxy-2-phthalimidoethyl) -4-methylvaleryl] -2 (S) was obtained -Pyrrolidinmethanol (diastereoisomer 1), which was used without further purification.
Primer 10Example 10
Na analogen način, kot smo opisali v prvem odstavku Primera 1, smo iz 0.568 g približno 6:1 zmesi diastereoizomera 1 in diastereoizomera 2 1-[2(R)-[1(R ali S)karboksi-2-ftalimidoetil]-4-metilvaleril)-4-metilpiperazin hidrobromida, pripravljenega na analogen način, kot smo opisali v Primeru 9(i), dobili po čiščenju produkta s flash kromatografijo na silikagelu ob uporabi diklorometana/metanola (12 : 1) za elucijo in obarjanjem hidroklorida z dodatkom hidrogen klorida v etil acetatu, 0.105 g 1-[2(R)[1(R ali S)-(hidroksikarbamoil)-2-ftalimidoetil]-4-metilvaleril]-4-metilpiperazin hidroklorida (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 7.89-7.79 (m,4H); 4.18 -3.80 (m,4H); 3.74 (dd,lH,J= 11.5); 3.48-3.18 (br m,6H); 2.93-2.84 (m,4H); 1.761.67 (m,IH); 1.52-1.42 (m,IH); 1.35-1.27 (m,lH), 0.93 (d,3H,J=6); 0.89 (d,3H,J=5.5); MS: 431 (M+H)+.In an analogous manner, as described in the first paragraph of Example 1, from 0.568 g, approximately 6: 1 is a mixture of diastereoisomer 1 and diastereoisomer 2 1- [2 (R) - [1 (R or S) carboxy-2-phthalimidoethyl] -4 -methylvaleryl) -4-methylpiperazine hydrobromide, prepared in an analogous manner as described in Example 9 (i), obtained after purification of the product by flash chromatography on silica gel using dichloromethane / methanol (12: 1) to elute and precipitate the hydrochloride with the addition of hydrogen chloride in ethyl acetate, 0.105 g 1- [2 (R) [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] -4-methylpiperazine hydrochloride (diastereoisomer 1) as a white solid ; nmr (MeOD): 7.89-7.79 (m, 4H); 4.18 -3.80 (m, 4H); 3.74 (dd, 1H, J = 11.5); 3.48-3.18 (br m, 6H); 2.93-2.84 (m, 4H); 1.761.67 (m, 1H); 1.52-1.42 (m, 1H); 1.35-1.27 (m, 1H), 0.93 (d, 3H, J = 6); 0.89 (d, 3H, J = 5.5); MS: 431 (M + H) < + >.
Primer 11Example 11
Na analogen način, kot smo opisali v prvem odstavku Primera 1, smo iz 0.29 g 4-[2(R)-[l(R ali S)-karboksi-2-ftalimidoetil]-4-metilvaleril]tetrahidro-1,4-tiazinIn an analogous manner to that described in the first paragraph of Example 1, 0.29 g of 4- [2 (R) - [1 (R or S) -carboxy-2-phthalimidoethyl] -4-methylvaleryl] tetrahydro-1,4- thiazine
1,1-dioksida (diastereoizomer 1) dobili 0.13 g 4-[2(R)-[ 1 (R ali S)-(hidroksikarbamoil)2-ftalimidoetil]-4-metilvaleril]tetrahidro-1,4-tiazin 1,1-dioksida (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 7.88-7.75 (m,4H); 4.33-4.23 (m,IH); 4.20-4.04 (m,2H); 3.93 (dd,lH,J= 11.6); 3.87-3.78 (m,lH); 3.73 (dd,lH,J= 11.5); 3.44-3.28 (m,3H); 3.22-3.03 (m,3H); 2.97-2.90 (m,IH); 1.67-1.57 (m,IH); 1.51-1.38 (m,IH); 1.341.25 (m,IH), 0.93-0.84 (m,6H); MS: 466 (M + H) + .1,1-dioxide (diastereoisomer 1) gave 0.13 g of 4- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) 2-phthalimidoethyl] -4-methylvaleryl] tetrahydro-1,4-thiazine 1,1 -dioxide (diastereoisomer 1) as a white solid; nmr (MeOD): 7.88-7.75 (m, 4H); 4.33-4.23 (m, 1H); 4.20-4.04 (m, 2H); 3.93 (dd, 1H, J = 11.6); 3.87-3.78 (m, 1H); 3.73 (dd, 1H, J = 11.5); 3.44-3.28 (m, 3H); 3.22-3.03 (m, 3H); 2.97-2.90 (m, 1H); 1.67-1.57 (m, 1H); 1.51-1.38 (m, 1H); 1,341.25 (m, 1H), 0.93-0.84 (m, 6H); MS: 466 (M + H) < + >.
Izhodni material smo pripravili kot sledi:The starting material was prepared as follows:
(i) Raztopino 0.3 g 4-[2(R)-[l(R ali S)-(terc.butoksikarbonil)-2-ftalimidoetil]-4metilvaleril]tetrahidro-l,4-tiazina (diastereoizomer 1) v 20 ml diklorometana smo ohladili na 0 °C in obdelali z 0.3 g 85 % m-klorperoksibenzojske kisline. Zmes smo mešali preko noči pri sobni temperaturi in nato raztopino dvakrat izprali s 5 % vodne raztopine natrijevega hidrogen karbonata, sušili nad brezvodnim magnezijevim sulfatom in uparili, da smo dobili belo peno. Po čiščenju s flash kromatografijo na silikagelu ob uporabi etil acetata/heksana (2 : 3) za elucijo smo dobili 0.33 g 4-[2(R)[1(R ali S)-(terc.butoksikarbonil)-2-ftalimidoetil]-4-metilvaleril]-tetrahidro-l,4-tiazin(i) A solution of 0.3 g of 4- [2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2-phthalimidoethyl] -4methyl valeryl] tetrahydro-1,4-thiazine (diastereoisomer 1) in 20 ml of dichloromethane was cooled to 0 ° C and treated with 0.3 g of 85% m-chloroperoxybenzoic acid. The mixture was stirred overnight at room temperature and then the solution was washed twice with 5% aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and evaporated to give a white foam. Purification by flash chromatography on silica gel using ethyl acetate / hexane (2: 3) for elution gave 0.33 g of 4- [2 (R) [1 (R or S) - (tert-butoxycarbonyl) -2-phthalimidoethyl] - 4-methylvaleryl] -tetrahydro-1,4-thiazine
1,1-dioksida (diastereoizomer 1) v obliki bele pene, ki se je strdila v belo trdno snov; nmr (MeOD): 7.89-7.78 (m,4H); 4.36-4.23 (m,2H); 4.11 (dd, 1 H,J = 11,7); 4.07-3.98 (m,IH); 3.85-3.73 (m,2H); 3.44-3.18 (m,2H); 3.21-3.05 (m,4H); 1.73-1.64 (m,IH), 1.611.59 (m,IH); 1.40-1.32 (m,IH); 1.28 (s,9H); 0.95-0.88(m,4H).1,1-dioxide (diastereoisomer 1) in the form of a white foam which has solidified into a white solid; nmr (MeOD): 7.89-7.78 (m, 4H); 4.36-4.23 (m, 2H); 4.11 (dd, 1H, J = 11.7); 4.07-3.98 (m, 1H); 3.85-3.73 (m, 2H); 3.44-3.18 (m, 2H); 3.21-3.05 (m, 4H); 1.73-1.64 (m, 1H), 1.611.59 (m, 1H); 1.40-1.32 (m, 1H); 1.28 (s, 9H); 0.95-0.88 (m, 4H).
(ii) Na analogen način, kot smo opisali v Primeru l(ii), smo iz 0.33 g 4-[2(R)-[l(R ali S)-(terc.butoksikarbonil)-2-ftalimidoetil]-4-metilvaIeril]tetrahidro-l,4-tiazin 1,1dioksida (diastereoizomer 1) dobili 0.29 g 4-[2(R)-[ 1 (R ali S)-karboksi-2-ftalimidoetilj4-metilvaleril]tetrahidro-l,4-tiazin 1,1-dioksida (diastereoizomer 1) v obliki bele pene, ki smo jo uporabili brez nadaljnjega čiščenja.(ii) In an analogous manner as described in Example l (ii), 0.33 g of 4- [2 (R) - [l (R or S) - (tert-butoxycarbonyl) -2-phthalimidoethyl] -4- methylvaryl] tetrahydro-1,4-thiazine 1,1 dioxide (diastereoisomer 1) afforded 0.29 g of 4- [2 (R) - [1 (R or S) -carboxy-2-phthalimidoethyl 4-methylvaleryl] tetrahydro-1,4-thiazine 1,1-dioxide (diastereoisomer 1) in the form of white foam, which was used without further purification.
Primer 12Example 12
Na analogen način, kot smo opisali v prvem odstavku Primera 1, smo iz 0.3 g 8-[2(R)[1(R ali S)-karboksi-2-ftalimidoeti!]-4-metilvaleril]-l,4-dioksa-8-azaspiro[4.5]dekana (diastereoizomer 1), ki smo ga pripravili na analogen način, kot je opisano v Primeru I(i)-(ii), po čiščenju produkta s flash kromatografijo na silikagelu, ob uporabi etil acetata/metanola (200 : 5) za elucijo, dobili 0.105 g 8-[2(R)-[l(R ali S)(hidroksikarbamoil)-2-ftalimidoetilj-4-metilvaleril]-l,4-dioksa-8-azaspiro[4.5]dekana (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 7.87-7.75 (m,4H); 3.97 (m,4H); 3.91-3.81 (m,2H); 3.79-3.60 (m,3H); 3.45-3.26 (m,2H); 3.00-2.91 (m,IH); 1.891.80 (m,IH); 1.74-1.51 (m,4H), 1.45 -1.31 (m,IH); 1.23-1.13 (m,IH); 0.88 (d,3H,J=6); 0.85 (d,3H,J=5.5); MS: 474 (M + H)+.In an analogous manner as described in the first paragraph of Example 1, 0.3 g of 8- [2 (R) [1 (R or S) -carboxy-2-phthalimidoethyl] -4-methylvaleryl] -1,4-diox -8-azaspiro [4.5] decane (diastereoisomer 1) prepared in an analogous manner as described in Example I (i) - (ii) after purification of the product by flash chromatography on silica gel using ethyl acetate / methanol (200: 5) for elution to give 0.105 g of 8- [2 (R) - [1 (R or S) (hydroxycarbamoyl) -2-phthalimidoethyl-4-methylvaleryl] -1,4-dioxa-8-azaspiro [4.5 ] Dean (diastereoisomer 1) as a white solid; nmr (MeOD): 7.87-7.75 (m, 4H); 3.97 (m, 4H); 3.91-3.81 (m, 2H); 3.79-3.60 (m, 3H); 3.45-3.26 (m, 2H); 3.00-2.91 (m, 1H); 1.891.80 (m, 1H); 1.74-1.51 (m, 4H), 1.45 -1.31 (m, 1H); 1.23-1.13 (m, 1H); 0.88 (d, 3H, J = 6); 0.85 (d, 3H, J = 5.5); MS: 474 (M + H) < + >.
Primer 13Example 13
Raztopino 0.13 g 1-[2(R)-[1(R ali S)-(benziloksikarbamoil)-2-(l,2-dimetil-3,5-dioksol,2,4-triazolidin-4-il)etil]-4-metilvaleril]piperidina (diastereoizomer 1) v 7.0 ml metanola smo hidrogenirali v prisotnosti 40 mg 10 % paladija na oglju 30 minut. Katalizator smo odstranili s filtracijo in raztopino uparili, da smo dobili 0.076 g 1[2(R)-[1(R ali S)-(hidroksikarbamoil)-2-( 1,2-dimetil-3,5-diokso-l,2,4-triazolidin-4-il)etil]-4-metilvaleril]piperidina (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 3.81-3.72 (m,2H); 3.67 (dd,lH,J = 11.7); 3.64-3.55 (m,IH); 3.44 (dd,lH,J=11.5); 3.39-3.23 (m,2H); 3.11 (s,6H); 2.96-2.88 (m,IH); 1.77-1.33 (m,8H), 1.19 -1.11 (m,IH); 0.87 (d,3H,J=6); 0.85 (d,3H,J = 6); MS: 398 (M+H)+.Solution 0.13 g 1- [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (1,2-dimethyl-3,5-dioxol, 2,4-triazolidin-4-yl) ethyl] -4-Methyl valeryl] piperidine (diastereoisomer 1) in 7.0 ml of methanol was hydrogenated in the presence of 40 mg of 10% palladium on charcoal for 30 minutes. The catalyst was removed by filtration and the solution evaporated to give 0.076 g of 1 [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (1,2-dimethyl-3,5-dioxo-1. 2,4-triazolidin-4-yl) ethyl] -4-methylvaleryl] piperidine (diastereoisomer 1) as a white solid; nmr (MeOD): 3.81-3.72 (m, 2H); 3.67 (dd, 1H, J = 11.7); 3.64-3.55 (m, 1H); 3.44 (dd, 1H, J = 11.5); 3.39-3.23 (m, 2H); 3.11 (s, 6H); 2.96-2.88 (m, 1H); 1.77-1.33 (m, 8H), 1.19 -1.11 (m, 1H); 0.87 (d, 3H, J = 6); 0.85 (d, 3H, J = 6); MS: 398 (M + H) < + >.
Izhodni material smo pripravili kot sledi:The starting material was prepared as follows:
(i) 0.284 g 60 % natrijevega hidrida smo dodali k mešani ledeno mrzli raztopini 3.01 g(i) 0.284 g of 60% sodium hydride was added to a stirred ice-cold solution of 3.01 g
1.2- dibenzil 1-terc.butil 4-metil-l,l,2(R)-pentantrikarboksilata v 50 ml suhega dimetilformamida v atmosferi dušika. Zmes smo mešali 30 minut pri 0° C in nadaljnje 1.5 ure pri sobni temperaturi in ponovno ohladili na 0° C pred dodatkom 1.6 g 4-bromometil1.2- dimetilurazola. Zmes smo pustili, da se je vrnila na sobno temperaturo in jo mešali 3 ure. Hlapni material smo uparili v visokem vakuumu in ostanek raztopili v etil acetatu in izprali s 5 % vodno raztopino citronske kisline, vodo in nasičeno raztopino natrijevega klorida. Po sušenju nad brezvodnim magnezijevim sulfatom smo topilo uparili in ostanek očistili s flash kromatografijo na silikagelu ob uporabi heksana/etra (1:1), čemur sledi eter za elucijo. Tako smo dobili 2.464 g 1,2-dibenzil 1-terc.butil 4metil-l-[(l,2-dimetil-3,5-diokso- l,2,4-triazoIidin-4-il)metil]-l, l,2(R)-pentantrikarboksilata v obliki brezbarvnega olja.1,2-Dibenzyl 1-tert-butyl 4-methyl-1,2,2 (R) -pentantricarboxylate in 50 ml of dry dimethylformamide under nitrogen atmosphere. The mixture was stirred for 30 minutes at 0 ° C and for a further 1.5 hours at room temperature and cooled again to 0 ° C before the addition of 1.6 g of 4-bromomethyl 1,2,2-dimethylrazole. The mixture was allowed to return to room temperature and stirred for 3 hours. The volatile material was evaporated under high vacuum and the residue was dissolved in ethyl acetate and washed with 5% citric acid aqueous solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by flash chromatography on silica gel using hexane / ether (1: 1) followed by ether for elution. Thus, 2,464 g of 1,2-dibenzyl 1-tert-butyl 4-methyl-1 - [(1,2-dimethyl-3,5-dioxol-2,4-triazolidin-4-yl) methyl] -1 were obtained. 1,2 (R) -pentantricarboxylate in the form of a colorless oil.
(ii) 2.464 g 1,2-dibenzil 1-terc.butil 4-metil-l-[(l,2-dimetil-3,5-diokso-l,2,4-triazolidin4-il)metil]-l,l,2(R)-pentantrikarboksilata smo raztopili v 40 ml metanola, ki je vseboval 0.25 g 10 % katalizatorja paladija na oglju. Zmes smo hidrogenirali 2 uri, katalizator odstranili s filtacijo in topilo uparili, da smo dobili l-(terc.butoksikarbonil)4-metil-l-[(l ,2-dimetil-3,5-diokso-1,2,4-triazolidin-4-il)metil]-1,2(R)-pentan-dikarboksilno kislino v obliki brezbarvne gume. Le-to smo raztopili v 60 ml toluena, ki je vseboval 0.43 ml N-metilmorfolina, in zmes segrevali pod refluksom 1 uro. Raztopino smo izprali s 5 % vodno raztopino citronske kisline, vodo in nasičenim vodnim natrijevim kloridom, sušili nad brezvodnim magnezijevim sulfatom in uparili, da smo dobili 1.422 g 2(R)-[1(R ali S)-(terc.butoksikarbonil)-2-(l,2-dimetil-3,5-diokso-l,2,4triazolidin-4-il)etil]-4-metilvalerianske kisline v obliki voskaste trdne snovi kot približno 6:1 zmes diastereoizomera 1 in diastereoizomera 2.(ii) 2,464 g of 1,2-dibenzyl 1-tert-butyl 4-methyl-1 - [(1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin4-yl) methyl] -1. 1,2 (R) -pentantricarboxylate was dissolved in 40 ml of methanol containing 0.25 g of 10% palladium-on-carbon catalyst. The mixture was hydrogenated for 2 hours, the catalyst was removed by filtration and the solvent was evaporated to give 1- (tert-butoxycarbonyl) 4-methyl-1 - [(1,2-dimethyl-3,5-dioxo-1,2,4- triazolidin-4-yl) methyl] -1,2 (R) -pentane-dicarboxylic acid as a colorless gum. This was dissolved in 60 ml of toluene containing 0.43 ml of N-methylmorpholine and the mixture was refluxed for 1 hour. The solution was washed with 5% citric acid aqueous solution, water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated to give 1.422 g of 2 (R) - [1 (R or S) - (tert-butoxycarbonyl) - 2- (1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl) ethyl] -4-methylvaleric acid as a waxy solid as a mixture of diastereoisomer 1 and diastereoisomer 2, approximately 6: 1.
(iii) Na analogen način, kot smo opisali v Primeru (i), smo iz 0.831 g približno 6 : 1 zmesi diastereoizomera 1 in diastereoizomera 2 2(R)-[1(R ali S)-(terc.butoksikarbonil)-2-(l,2-dimetil-3,5-diokso-l,2,4-triazolidin-4-il)etil]-4-metilvalerianske kisline dobili 0.462 g 1-[2(R)-[1(R ali S)-(terc.butoksikarbonil)-2-(l,2-dimetil-3,5-dioksol,2,4-triazolidin-4-il)etil]-4-metilvaleril]-piperidina (diastereoizomer 1) v obliki brezbarvnega olja.(iii) In an analogous manner as described in Example (i), from 0.831 g, approximately 6: 1 is a mixture of diastereoisomer 1 and diastereoisomer 2 2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2 - (1,2-Dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl) ethyl] -4-methyl valeric acid gave 0.462 g of 1- [2 (R) - [1 (R or S ) - (tert-Butoxycarbonyl) -2- (1,2-dimethyl-3,5-dioxol, 2,4-triazolidin-4-yl) ethyl] -4-methylvaleryl] -piperidine (diastereoisomer 1) as a colorless oil .
(iv) Raztopino 0.462 g 1-[2(R)-[1(R ali S)-(terc.butoksikarbonil)-2-(l,2-dimetil-3,5diokso-l,2,4-triazolidin-4-il)etiI]-4-metilvaleril]-piperidina (diastereoizomer 1) v 7 ml diklorometana smo obdelali z 0.85 ml trifluorocetne kisline. Zmes smo mešali pri sobni temperaturi 1.5 ur in nato dodali toluen ter topila uparili. Po nadaljnjih treh uparjenjih iz toluena smo preostanek raztopili vil ml suhega dimetilformamida, ohladili na 0 °C in mešali pod dušikom med sledečimi dodajanji 0.13 g O-benzilhidroksilamina, 0.152 g(iv) 0.462 g solution of 1- [2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2- (1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4 -yl) ethyl] -4-methylvaleryl] -piperidine (diastereoisomer 1) in 7 ml of dichloromethane was treated with 0.85 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 1.5 hours and then toluene was added and the solvents were evaporated. After a further three evaporations from toluene, the residue was dissolved in a ml of dry dimethylformamide, cooled to 0 ° C and stirred under nitrogen during the subsequent additions of 0.13 g of O-benzylhydroxylamine, 0.152 g
1-hidroksibenzotriazola, 0.25 ml N-metilmorfolina in 0.20(8 g l-etil-3-(3-dimetilaminopropiljkarbodiimid hidroklorida. Zmes smo pustili ogreti na sobno temperaturo in jo mešali čez noč. Topilo smo uparili in preostanek obdelali s 5 % vodne raztopine natrijevega hidrogen karbonata. Produkt smo ekstrahirali z etil acetatom in etil acetatni ekstrakt izprali s 5 % raztopino citronske kisline in vodno raztopino natrijevega kolorida. Po sušenju nad brezvodnim magnezijevim sulfatom smo topilo uparili in preostanek očistili s flash kromatografijo na silikagelu ob uporabi etil acetata za elucijo. Poleg 0.14 g pridobljenega izhodnega materiala smo dobili 0.142 g 1[2(R)-[1(R ali S)-(benziloksi-karbamoil)-2-(l,2-dimetil-3,5-diokso-l,2,4-triazolidina-4il)etil]-4-metilvaleril]-piperidina (diastereoizomer 1) v obliki bele trdne snovi; nmr (CDC13): 9.77 (s,IH); 7.44-7.29 (m,5H); 4.90 (q,2H,J = 8); 3.78 (dd,lH,J= 11.5); 3.703.63 (m,2H); 3.62 -3.53 (m,IH); 3.49-3.42 (m,IH); 3.41-3.33 (m,IH), 3.28 -3.22 (m,IH); 3.10 (s,6H); 3.00-2.93 (m,IH); 1.81-1.38 (m,8H); 1.29-1.23 (m,IH); 0.88 (d,3H,J=6); 0.85 (d,3H,J=6).Of 1-hydroxybenzotriazole, 0.25 ml of N-methylmorpholine and 0.20 (8 g of l-ethyl-3- (3-dimethylaminopropylcarbodiimide hydrochloride) The mixture was allowed to warm to room temperature and stirred overnight The solvent was evaporated and the residue was treated with 5% aqueous solution. The product was extracted with ethyl acetate and the ethyl acetate extract was washed with a 5% citric acid solution and aqueous sodium chloride solution. In addition to 0.14 g of starting material obtained, 0.142 g of 1 [2 (R) - [1 (R or S) - (benzyloxy-carbamoyl) -2- (1,2-dimethyl-3,5-dioxo-1,2) was obtained , 4-triazolidin-4yl) ethyl] -4-methylvaleryl] -piperidine (diastereoisomer 1) as a white solid; nmr (CDCl 3 ): 9.77 (s, 1H); 7.44-7.29 (m, 5H); 4.90 ( q, 2H, J = 8) 3.78 (dd, 1H, J = 11.5); 3.703.63 (m, 2H); 3.62 -3.53 (m, 1H); 3.49-3.42 (m, 1H); 3.41-3.33 (m, 1H), 3.28 -3.22 (m, 1H); 3.10 (s, 6H); 3.00-2.93 (m, 1H); 1.81-1.38 (m, 8H); 1.29-1.23 (m, 1H); 0.88 (d, 3H, J = 6); 0.85 (d, 3H, J = 6).
Primer 14Example 14
Na analogen način, kot smo opisali v prvem odstavku Primera 13, smo iz 0.182 gIn an analogous manner to that described in the first paragraph of Example 13, 0.182 g is obtained
1-[2(R)-[1(R ali S)-(benziloksikarbamoil)-2-(2,6-dioksopiperidino)etil]-4-metilvaleril]22 piperidina (diastereoizomer 1) dobili 0.066 g 1-[2(R)-[1(R ali S)-(hidroksikarbamoil)2-(2,6-dioksopiperidino)etiI]-4-metilvaIeril]piperidina (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 4.06 (dd,lH,J = l 1,6.5); 3.80-3.57 (m,4H); 3.53-3.46 (m,IH); 3.34-3.24 (m, IH); 2.68-2.54 (m,5H); 1.92-1.82 (m,2H); 1.76-1.45 (m,7H); 1.44-1.32 (m,IH), 1.14-1.06 (m,IH); 0.87 (d,3H,J=6); 0.83 (d,3H,J=6); MS: 382 (M=H)+.1- [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (2,6-dioxopiperidino) ethyl] -4-methylvaleryl] 22 piperidine (diastereoisomer 1) gave 0.066 g of 1- [2 ( R) - [1 (R or S) - (hydroxycarbamoyl) 2- (2,6-dioxopiperidino) ethyl] -4-methylvaryl] piperidine (diastereoisomer 1) as a white solid; nmr (MeOD): 4.06 (dd, 1H, J = 1, 1.6.5); 3.80-3.57 (m, 4H); 3.53-3.46 (m, 1H); 3.34-3.24 (m, 1H); 2.68-2.54 (m, 5H); 1.92-1.82 (m, 2H); 1.76-1.45 (m, 7H); 1.44-1.32 (m, 1H), 1.14-1.06 (m, 1H); 0.87 (d, 3H, J = 6); 0.83 (d, 3H, J = 6); MS: 382 (M = H) < + >.
Izhodni material smo pripravili kot sledi:The starting material was prepared as follows:
(i) Na analogen način, kot smo opisali v Primeru 13(i)-(iii), smo iz 1,2-dibenzil 1-tercbutil 4-metil-l,l,2(R)-pentantrikarboksilata in N-bromometilglutarimida dobili 1[2(R)-[1(R ali S)-(terc.butoksikarbonil)-2-(2,6-dioksopiperidin)etil]-4-metilvaleril]piperidin (diastereoizomer 1) v obliki brezbarvne gume.(i) In an analogous manner to that described in Example 13 (i) - (iii), 1,2-dibenzyl 1-tertbutyl 4-methyl-1,1,2 (R) -pentantricarboxylate and N-bromomethylglutarimide were obtained 1 [2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2- (2,6-dioxopiperidine) ethyl] -4-methylvaleryl] piperidine (diastereoisomer 1) as a colorless gum.
(ii) Raztopino 0.324 g 1-[2(R)-[1-(R ali S)-(terc.butoksikarbonil)-2-(2,6-dioksopiperidino)etil]-4-metilvaleril]-piperidina (diastereoizomer 1) v 6.5 ml toluena smo obdelali z 0.065 g 3-metiI-3-pentanola in 0.65 ml trimetilsilil bromida. Zmes smo mešali v atmosferi suhega dušika 1 uro in nato topilo uparili. Po treh nadaljnjih uparjenjih iz toluena smo ostanek raztopili v 10 ml suhega dimetilformamida, ohladili na 0° C in mešali pod dušikom med zaporednimi dodajanji 0.095 g Obenzilhidroksilamina, 0.111 g 1-hidroksibenzotriazola, 0.18 ml N-metilmorfolina in 0.152 g l-etil-3-(3-dimetilaminopropil)karbodiimid hidroklorida. Zmes smo pustili ogreti na sobno temperaturo in jo mešali čez noč. Topilo smo uparili in ostanek obdelali s 5 % vodno raztopino natrijevega hidrogen karbonata. Produkt smo ekstrahirali z etil acetatom in etil acetatni ekstrakt izprali s 5 % raztopino citronske kisline in vodno raztopino natrijevega klorida. Po sušenju nad brezvodnim magnezijevim sulfatom smo topilo uparili in ostanek očistili s flash kromatografijo na silikagelu ob uporabi heksana/etil acetata (7 : 2) za elucijo. Tako smo dobili 0.182 g 1[2(R)-[1(R ali S)-(benziloksikarbamoil)-2-(2,6-dioksopiperidino)etil]-4-metilvaleril]piperidina (diastereoizomer 1) v obliki bele trdne snovi; nmr (CDCI3): 9.23 (s,IH); 7.46-7.31 (m,5H); 4.96-4.88 (m,2H); 3.98 (dd,lH,J=l 1,5); 3.89-3.76 (m,2H); 3.74-3.64 (m,IH); 3.52-3.42 (m,IH); 3.33-3.21 (m,2H), 2.76-2.67 (m,IH); 2.63-2,52 (m,4H); 1.941.37 (m,10H); 1.24-1.14 (m,IH); 0.88 (d,3H,J = 6); 0.84 (d,3H,J=6).(ii) A solution of 0.324 g of 1- [2 (R) - [1- (R or S) - (tert-butoxycarbonyl) -2- (2,6-dioxopiperidino) ethyl] -4-methylvaleryl] -piperidine (diastereoisomer 1 ) in 6.5 ml of toluene was treated with 0.065 g of 3-methyl-3-pentanol and 0.65 ml of trimethylsilyl bromide. The mixture was stirred under a dry nitrogen atmosphere for 1 hour and then the solvent was evaporated. After three further evaporations from toluene, the residue was dissolved in 10 ml of dry dimethylformamide, cooled to 0 ° C and stirred under nitrogen between successive additions of 0.095 g of obenzylhydroxylamine, 0.111 g of 1-hydroxybenzotriazole, 0.18 ml of N-methylmorpholine and 0.152 g of l-ethyl-ethyl and - (3-dimethylaminopropyl) carbodiimide hydrochloride. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was treated with 5% aqueous sodium hydrogen carbonate solution. The product was extracted with ethyl acetate and the ethyl acetate extract was washed with 5% citric acid solution and aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by flash chromatography on silica gel using hexane / ethyl acetate (7: 2) for elution. Thus, 0.182 g of 1 [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (2,6-dioxopiperidino) ethyl] -4-methylvaleryl] piperidine (diastereoisomer 1) was obtained as a white solid. ; nmr (CDCl3): 9.23 (s, 1H); 7.46-7.31 (m, 5H); 4.96-4.88 (m, 2H); 3.98 (dd, 1H, J = 1.5); 3.89-3.76 (m, 2H); 3.74-3.64 (m, 1H); 3.52-3.42 (m, 1H); 3.33-3.21 (m, 2H), 2.76-2.67 (m, 1H); 2.63-2.52 (m, 4H); 1,941.37 (m, 10H); 1.24-1.14 (m, 1H); 0.88 (d, 3H, J = 6); 0.84 (d, 3H, J = 6).
Primer 15Example 15
Na analogen način, kot smo opisali v prvem odstavku Primera 13, smo iz 0.39 gIn an analogous manner to that described in the first paragraph of Example 13, 0.39 g is obtained
1-[2(R)-[1(R ali S)-(benziloksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-l-imidazolidinil)etil]-4-metilvaleril]piperidina (diastereoizomer 1) dobili 0.255 g 1-[2(R)-[1(R ali S)(hidroksikarbamoil)-2-(3,4,4-trimetiI-2,5-diokso-1-imidazolidinil)etil]-4-metil-valeril]piperidina (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 3.84-3.63 (m,4H); 3.49-3.41 (m,IH); 3.38-3.25 (m,2H); 2.90-2.83 (m,4H); 1.80-1.28 (m,14H); 1.19-1.11 (m,IH); 0.89 (d,3H,J=5.5); 0.86 (d,3H,J=5.5); MS: 411 (M+H)+.1- [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -4-methylvaleryl] piperidine ( diastereoisomer 1) afforded 0.255 g of 1- [2 (R) - [1 (R or S) (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -4 -methyl-valeryl] piperidine (diastereoisomer 1) as a white solid; nmr (MeOD): 3.84-3.63 (m, 4H); 3.49-3.41 (m, 1H); 3.38-3.25 (m, 2H); 2.90-2.83 (m, 4H); 1.80-1.28 (m, 14H); 1.19-1.11 (m, 1H); 0.89 (d, 3H, J = 5.5); 0.86 (d, 3H, J = 5.5); MS: 411 (M + H) < + >.
Izhodni material smo pripravili kot sledi:The starting material was prepared as follows:
Na analogen način, kot smo opisali v Primeru 14(i)-(ii), smo iz 1,2-dibenzil 1-terc.butil 4-metil-l,l,2(R)-pentantrikarboksilata in 3-bromometil-l,5,5-trimetiIhidantoina dobili 1-[2(R)-[1-(R ali S)-(benziloksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-l-imidazolidinil)-etil]-4-metilvaleril]piperidina (diastereoizomer 1) v obliki bele pene; nmr (CDCI3); 9.50 (brs,IH); 7.45-7.39 (m,5H); 3.79-3.56 (m,4H); 3.52-3.42 (m,IH); 3.333.23 (m,2H); 2.94-2.80 (m,4H); 1.93-1.29 (m,14H); 1.26-1.16 (m,IH); 0.87 (d,3H,J=6); 0.84 (d,3H,J=6).In an analogous manner as described in Example 14 (i) - (ii), 1,2-dibenzyl 1-tert-butyl 4-methyl-1,2,2 (R) -pentantricarboxylate and 3-bromomethyl-1 , 5,5-trimethylhydantoin gave 1- [2 (R) - [1- (R or S) - (benzyloxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) - ethyl] -4-methylvaleryl] piperidine (diastereoisomer 1) as a white foam; nmr (CDCl3); 9.50 (brs, 1H); 7.45-7.39 (m, 5H); 3.79-3.56 (m, 4H); 3.52-3.42 (m, 1H); 3.333.23 (m, 2H); 2.94-2.80 (m, 4H); 1.93-1.29 (m, 14H); 1.26-1.16 (m, 1H); 0.87 (d, 3H, J = 6); 0.84 (d, 3H, J = 6).
Primer 16Example 16
Na analogen način, kot smo opisali v prvem odstavku Primera 13, smo iz 0.335 g 4-[2(R)-[l(R ali S)-(benziloksikarbamoil)-2-(3-metil-2,5-diokso-l-imidazolidinil)-etil]4-metilvaleril]morfolina (diastereoizomer 1) dobili 0.198 g 4-[2(R)-[l(R ali S)(hidroksikarbamoiI)-2-(3-metil-2,5-diokso-1 -imidazol idinil)etil]-4-metilvaleriI]morfolina (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 3.78 (s,2H); 3.73-3.45 (m,9H); 3.36 (dd,lH,J = l 1.5); 3.18-3.10 (m,IH); 2.85 (s,3H); 2.82-2.75 (m,IH); 1.57-1.47 (m,IH); 1.38-1.26 (m,IH); 1.14-1.05 (m,IH); 0.82-0.75 (m,6H);In an analogous manner as described in the first paragraph of Example 13, 0.335 g of 4- [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (3-methyl-2,5-dioxo) is obtained from 0.335 g. 1-imidazolidinyl) -ethyl] 4-methylvaleryl] morpholine (diastereoisomer 1) gave 0.198 g of 4- [2 (R) - [1 (R or S) (hydroxycarbamoyl) -2- (3-methyl-2,5-dioxo) -1-imidazole idinyl) ethyl] -4-methylvaleryl] morpholine (diastereoisomer 1) as a white solid; nmr (MeOD): 3.78 (s, 2H); 3.73-3.45 (m, 9H); 3.36 (dd, 1H, J = 1.5); 3.18-3.10 (m, 1H); 2.85 (s, 3H); 2.82-2.75 (m, 1H); 1.57-1.47 (m, 1H); 1.38-1.26 (m, 1H); 1.14-1.05 (m, 1H); 0.82-0.75 (m, 6H);
MS: 385 (M+H)+.MS: 385 (M + H) < + >.
Izhodni material smo pripravili kot sledi:The starting material was prepared as follows:
Na analogen način, kot smo opisali v Primeru 15(i)-(ii), smo iz 1,2-dibenzil 1-terc.butil 4-metil-l,l,2(R)-pentantrikarboksilata in 3-bromometil-l-metilhidantoina dobili 4[2(R)-[1-(R ali S)-(benziloksikarbamoil)-2-(3-metil-2,5-diokso-l-imidazolidinil)etil]-4metilvaleriljmorfolin (diastereoizomer 1) v obliki bele trdne snovi;In an analogous manner as described in Example 15 (i) - (ii), 1,2-dibenzyl 1-tert-butyl 4-methyl-1,2,2 (R) -pentantricarboxylate and 3-bromomethyl-1 -methylhydantoin gave 4 [2 (R) - [1- (R or S) - (benzyloxycarbamoyl) -2- (3-methyl-2,5-dioxo-1-imidazolidinyl) ethyl] -4methyl valerylmorpholine (diastereoisomer 1) in the form white solids;
MS: 475 (M + H) + .MS: 475 (M + H) < + >.
Primer 17Example 17
Na analogen način, kot smo opisali v prvem odstavku Primera 1, smo iz 0.273 gIn an analogous manner as described in the first paragraph of Example 1, 0.273 g was obtained
1- [2(R)-[1(R ali S)-karboksi-2-(3-metil-2,5-diokso-l-imidazolidinil)etil]-4-metilvaleril]piperidina (diastereoizomer 1) dobili 0.023 g 1-[2(R)-[1(R ali S)-(hidroksikarbamoil)2- (3-metil-2,5-diokso-l-imidazolidinil)etil]-4-metilvaleril]piperidina (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 3.78 (s,2H); 3.74-3.64 (m,2H); 3.63-3.48 (m,2H); 3.35-3.26 (m,2H); 3.25-3.15 (m,IH); 2.85 (s,3H); 2.82-2.73 (m,IH); 1.68-1.25 (m,8H); 1.10-1.03 (m,IH); 0.82 (d,3H,J=6); 0.75 (d,3H,J=6); MS: 383 (M+H)+.1- [2 (R) - [1 (R or S) -carboxy-2- (3-methyl-2,5-dioxo-1-imidazolidinyl) ethyl] -4-methylvaleryl] piperidine (diastereoisomer 1) gave 0.023 g 1- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) 2- (3-methyl-2,5-dioxo-1-imidazolidinyl) ethyl] -4-methylvaleryl] piperidine (diastereoisomer 1) in the form white solids; nmr (MeOD): 3.78 (s, 2H); 3.74-3.64 (m, 2H); 3.63-3.48 (m, 2H); 3.35-3.26 (m, 2H); 3.25-3.15 (m, 1H); 2.85 (s, 3H); 2.82-2.73 (m, 1H); 1.68-1.25 (m, 8H); 1.10-1.03 (m, 1H); 0.82 (d, 3H, J = 6); 0.75 (d, 3H, J = 6); MS: 383 (M + H) < + >.
Izhodni material smo pripravili kot sledi:The starting material was prepared as follows:
Na analogen način, kot smo opisali v Primeru 1 (ii), smo iz 0.325 g 1-[2(R)-[1(R ali S)(terc.butoksikarbonil)-2-(3-metil-2,5-diokso-1 -imidazolidiniI)etil]-4-metilvaleril]piperidina (diastereoizomer 1), pripravljenega na analogen način, kot je opisano v Primeru 13(i)-(iii), iz 1,2-dibenzil 1 -terc.butil 4-metil-l,l,2(R)-pentantrikarboksilata inIn an analogous manner as described in Example 1 (ii), 0.325 g of 1- [2 (R) - [1 (R or S) (tert-butoxycarbonyl) -2- (3-methyl-2,5- dioxo-1-imidazolidinyl) ethyl] -4-methylvaleryl] piperidine (diastereoisomer 1) prepared in an analogous manner as described in Example 13 (i) - (iii) from 1,2-dibenzyl 1-tert.butyl 4 -methyl-l, 1,2 (R) -pentantricarboxylate and
3- bromometil-l-metilhidantoina dobili 0.273 g 1-[2(R)-[1-(R ali S)-karboksi-2-(3-metil2,5-diokso-l-imidazolidinil)etil]-4-metilvaleril]piperidina (diastereoizomer 1) v obliki brezbarvne gume, ki smo jo uporabili brez nadaljnjega čiščenja.3-Bromomethyl-1-methylhydantoin gave 0.273 g of 1- [2 (R) - [1- (R or S) -carboxy-2- (3-methyl2,5-dioxo-1-imidazolidinyl) ethyl] -4-methylvaleryl ] piperidine (diastereoisomer 1) in the form of a colorless gum, which was used without further purification.
Primer 18Example 18
Na analogen način, kot smo opisali v prvem odstavku Primera 1, smo iz 0.45 g 4-[2(R)[1(R ali S)-karboksi-2-(3-metil-2,5-diokso-l-imidazolidinil)etil]-4-metilvaleril]tetrahidro-l,4-tiazina (diastereoizomer 1) dobili 0.155 mg 4-[2(R)-[l(R ali S)(hidroksikarbamoil)-2-(3-metil-2,5-diokso-1 -imidazolidinil )etil]-4-metilvaleril]tetrahidro-l,4-tiazina (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 4.09-3.88 (m,3H); 3.86 (s,2H); 3.78-3.70 (m,IH); 3.66 (dd,lH,J= 11.7); 3.42 (dd, 1H,J=11.5); 3.29-3.21 (m,IH); 2.92 (s,3H); 2.88-2.82 (m,IH); 2.78-2.71 (m,IH); 2.68-2.54 (m,3H); 1.65-1.57 (m,IH); 1.46-1.34 (m,IH); 1.22-1.15 (m,IH); 0.90-0.84 (m,6H);In an analogous manner as described in the first paragraph of Example 1, 0.45 g of 4- [2 (R) [1 (R or S) -carboxy-2- (3-methyl-2,5-dioxo-1-imidazolidinyl) is obtained ) ethyl] -4-methylvaleryl] tetrahydro-1,4-thiazine (diastereoisomer 1) afforded 0.155 mg of 4- [2 (R) - [1 (R or S) (hydroxycarbamoyl) -2- (3-methyl-2. 5-dioxo-1-imidazolidinyl) ethyl] -4-methylvaleryl] tetrahydro-1,4-thiazine (diastereoisomer 1) as a white solid; nmr (MeOD): 4.09-3.88 (m, 3H); 3.86 (s, 2H); 3.78-3.70 (m, 1H); 3.66 (dd, 1H, J = 11.7); 3.42 (dd, 1H, J = 11.5); 3.29-3.21 (m, 1H); 2.92 (s, 3H); 2.88-2.82 (m, 1H); 2.78-2.71 (m, 1H); 2.68-2.54 (m, 3H); 1.65-1.57 (m, 1H); 1.46-1.34 (m, 1H); 1.22-1.15 (m, 1H); 0.90-0.84 (m, 6H);
MS: 401 (M+H)+.MS: 401 (M + H) < + >.
Izhodni material smo pripravili kot sledi:The starting material was prepared as follows:
Na analogen način, kot smo opisali v Primeru 13(i)-(iii), smo iz 1,2-dibenzil 1-terc.butilIn an analogous manner as described in Example 13 (i) - (iii), 1,2-dibenzyl 1-tert.butyl
4-metil-l,l,2(R)-pentantrikarboksilata in 3-bromometil-l-metilhidantoina dobili 425 [2(R)-[1(R ali S)-(terc.butoksikarbonil)-2-(3-metil-2,5-diokso-l-imidazolidinil)etil]-4metilvaleril]tetrahidro-l,4-tiazin (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 3.98-3.84 (m,6H); 3.77 (dd,lH,J= 11.7); 3.47 (dd,lH,J= 11.5); 3.22-3.14 (m,IH); 3.09-3.03 (m,IH); 2.95 (s,3H); 2.81-2.73 (m,IH); 2.69-2.55 (m,3H); 1.77-1.68 (m,IH); 1.53-1.39 (m,10H); 1.26-1.18 (m,IH); 0.94-0.86 (m,6H);Of 4-methyl-1,1,2 (R) -pentantricarboxylate and 3-bromomethyl-1-methylhydantoin gave 425 [2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2- (3-methyl -2,5-dioxo-1-imidazolidinyl) ethyl] -4methylvaleryl] tetrahydro-1,4-thiazine (diastereoisomer 1) as a white solid; nmr (MeOD): 3.98-3.84 (m, 6H); 3.77 (dd, 1H, J = 11.7); 3.47 (dd, 1H, J = 11.5); 3.22-3.14 (m, 1H); 3.09-3.03 (m, 1H); 2.95 (s, 3H); 2.81-2.73 (m, 1H); 2.69-2.55 (m, 3H); 1.77-1.68 (m, 1H); 1.53-1.39 (m, 10H); 1.26-1.18 (m, 1H); 0.94-0.86 (m, 6H);
(ii) Raztopino 52 g 4-[2(R)-[l(R ali S)-(terc.butoksikarbonil)-2-(3-metil-2,5-diokso-limidazolidinil)etil]-4-metilvaIeril]tetrahidro-l,4-tiazina (diastereoizomer 1) v 15 ml diklorometana smo obdelali z 1.05 ml 4M hidrogen klorida v dioksanu. Raztopino smo mešali na sobni temperaturi 3.25 ur in nato dodali 25 ml toluena in topila uparili. Po treh dodatnih uparjenjih iz 25 ml toluena smo dobili 0.45 g 4-[2(R)-[l(R ali S)karboksi-2-(3-metil-2,5-diokso-l-imidazolidinil)etil]-4-metilvaleril]tetrahitro-l,4-tiazina (diastereoizomer 1) v obliki brezbarvne gume, ki smo jo uporabili direktno brez nadaljnjega čiščenja.(ii) A solution of 52 g of 4- [2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2- (3-methyl-2,5-dioxo-limidazolidinyl) ethyl] -4-methylvaryl] tetrahydro-1,4-thiazine (diastereoisomer 1) in 15 ml of dichloromethane was treated with 1.05 ml of 4M hydrogen chloride in dioxane. The solution was stirred at room temperature for 3.25 hours and then 25 ml of toluene was added and the solvents were evaporated. Three additional evaporations from 25 ml of toluene gave 0.45 g of 4- [2 (R) - [1 (R or S) carboxy-2- (3-methyl-2,5-dioxo-1-imidazolidinyl) ethyl] -4 -methylvaleryl] tetrahitro-1,4-thiazine (diastereoisomer 1) in the form of a colorless gum, which was used directly without further purification.
Primer 19Example 19
Na analogen način, kot smo opisali v prvem odstavku Primera 13, smo iz 0.278 g 4[2(R)-[1(R ali S)-(benziloksikarbamoil)-2-(2,5-diokso-1 -p i rol id i ni 1 )e til]-4-metilvaleril]morfolina (diastereoizomer 1) dobili 0.151 g 4-[2(R)-[ 1 (R ali S)-(hidroksikarbamoil)-2(2,5-diokso-l-pirolidinil)etil]-4-metilvaleril]morfolina (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 3.73-3.49 (m,9H); 3.34 (dd,lH,J= 11.5); 3.19-3.11 (m,IH); 2.74-2.66 (m,IH); 2.55 (s,4H); 1.57-1.49 (m,IH); 1.38-1.26 (m,IH); 1.12-1.03 (m,IH); 0.82-0.75 (m,6H); MS: 370 (M+H)+.In an analogous manner to that described in the first paragraph of Example 13, 0.278 g of 4 [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (2,5-dioxo-1-pyrid id) and neither 1) tyl] -4-methylvaleryl] morpholine (diastereoisomer 1) gave 0.151 g of 4- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2 (2,5-dioxo-1- pyrrolidinyl) ethyl] -4-methylvaleryl] morpholine (diastereoisomer 1) as a white solid; nmr (MeOD): 3.73-3.49 (m, 9H); 3.34 (dd, 1H, J = 11.5); 3.19-3.11 (m, 1H); 2.74-2.66 (m, 1H); 2.55 (s, 4H); 1.57-1.49 (m, 1H); 1.38-1.26 (m, 1H); 1.12-1.03 (m, 1H); 0.82-0.75 (m, 6H); MS: 370 (M + H) < + >.
Izhodni material smo pripravili kot sledi:The starting material was prepared as follows:
Na analogen način, kot smo opisali v Primeru 14(i)-(ii), smo iz 1,2-dibenzil 1-terc.butil 4-metil-l,l,2(R)-pentantrikarboksilata in N-bromometilsukcinimida dobili 4-[2(R)[1(R ali S)-(benziloksikarbamoil)-2-(2,5-diokso-1 -pirolidinil)etil]-4-metilvaleril]morfolin (diastereoizomer 1) v obliki bele trdne snovi; MS: 460 (M+H) + .In an analogous manner as described in Example 14 (i) - (ii), 4-methyl-1,2-dibenzyl 1-tert-butyl 4-methyl-1,2,2 (R) -pentantricarboxylate and N-bromomethylsuccinimide were obtained - [2 (R) [1 (R or S) - (benzyloxycarbamoyl) -2- (2,5-dioxo-1-pyrrolidinyl) ethyl] -4-methylvaleryl] morpholine (diastereoisomer 1) as a white solid; MS: 460 (M + H) < + >.
Primer 20Example 20
Na analogen način, kot smo opisali v prvem odstavku Primera 13, smo iz 0.19 gIn an analogous manner to that described in the first paragraph of Example 13, 0.19 g is obtained
4-[2(R)-[l(R ali S)-(benziloksikarbamoil)-2-(2-okso-1 -pirolidinil)etil]-4-metil-valeril]26 morfolina (diastereoizomer 1) dobili 0.104 g 4-[2(R)-[l(R ali S)-(hidroksikarbamoil)-2(2-okso-l-pirolidinil)etil]-4-metil-valeril]morfolina (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 3.70-3.39 (m,8H); 3.36-3.17 (m,4H); 3.14-3.05 (m,IH); 2.572.48 (m,IH); 2.28-2.17 (m,2H); 1.96-1.84 (m,2H); 1.62-1.52 (m,IH); 1.58-1.24 (m,IH); 1.13-1.03 (m,IH); 0.83-0.75 (m,6H); MS: 356 (M + H) + .4- [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (2-oxo-1-pyrrolidinyl) ethyl] -4-methyl-valeryl] 26 morpholine (diastereoisomer 1) gave 0.104 g 4 - [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2 (2-oxo-1-pyrrolidinyl) ethyl] -4-methyl-valeryl] morpholine (diastereoisomer 1) as a white solid; nmr (MeOD): 3.70-3.39 (m, 8H); 3.36-3.17 (m, 4H); 3.14-3.05 (m, 1H); 2,572.48 (m, 1H); 2.28-2.17 (m, 2H); 1.96-1.84 (m, 2H); 1.62-1.52 (m, 1H); 1.58-1.24 (m, 1H); 1.13-1.03 (m, 1H); 0.83-0.75 (m, 6H); MS: 356 (M + H) < + >.
Izhodni material smo pripravili kot sledi:The starting material was prepared as follows:
Na analogen način, kot smo opisali v Primeru 14(i)-(ii), smo iz 1,2-dibenzil 1-terc.butil 4-metil-l,l,2(R)-pentantrikarboksilata in N-bromometilpirolidina dobili 4-[2(R)-[l(R ali S)-(benziloksikarbamoil)-2-(2okso-l-pirolidinil)etil]-4-metilvaleril]morfolin (diastereoizomer 1) v obliki bele trdne snovi; MS: 446 (M + H) + .In an analogous manner to that described in Example 14 (i) - (ii), 4-methyl-1,2-tert-butanecarboxylate and N-bromomethylpyrrolidine were obtained from 1,2-dibenzyl 1-tert-butyl 4-methyl-1,2,2-R - [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (2-oxo-1-pyrrolidinyl) ethyl] -4-methylvaleryl] morpholine (diastereoisomer 1) as a white solid; MS: 446 (M + H) < + >.
Primer 21Example 21
Na analogen način, kot smo opisali v prvem odstavku Primera 13, smo iz 0.335 g 1-[2(R)-[1(R ali S)-(benziloksikarbamoil)-2-(2-okso-l-pirolidinil)etil]-4-metilvaleril]piperidina (diastereoizomer 1) dobili 0.19 g 1-[2(R)-[1(R ali S)-(hidroksikarbamoil)-2(2-okso-l-pirolidinil)etil]-4-metilvaleril]piperidina (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 3.78-3.58 (m,3H); 3.53-3.33 (m,4H); 3.27-3.17 (m,2H); 2.632.54 (m,IH); 2.34-2.26 (m,2H); 2.03-1.93 (m,2H); 1.77-1.45 (m,7H); 1.43-1.30 (m,IH); 1.20-1.08 (m,IH); 0.93-0.83 (m,6H); MS: 354 (M + H)+.In the analogous manner as described in the first paragraph of Example 13, 0.335 g of 1- [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (2-oxo-1-pyrrolidinyl) ethyl] -4-methylvaleryl] piperidine (diastereoisomer 1) afforded 0.19 g of 1- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2 (2-oxo-1-pyrrolidinyl) ethyl] -4-methylvaleryl] piperidine (diastereoisomer 1) as a white solid; nmr (MeOD): 3.78-3.58 (m, 3H); 3.53-3.33 (m, 4H); 3.27-3.17 (m, 2H); 2,632.54 (m, 1H); 2.34-2.26 (m, 2H); 2.03-1.93 (m, 2H); 1.77-1.45 (m, 7H); 1.43-1.30 (m, 1H); 1.20-1.08 (m, 1H); 0.93-0.83 (m, 6H); MS: 354 (M + H) < + >.
Izhodni material smo pripravili kot sledi:The starting material was prepared as follows:
Na analogen način, kot smo opisali v Primeru 14(i)-(ii), smo iz 1,2-benzil 1-terc.butil 4metil-l,l,2(R)-pentantrikarboksilata in N-bromometilpirolidina dobili 1-[2(R)-[1(R ali S)-(benziloksikarbamoil)-2-(2-okso-1 -pirolidinil)et il]-4-metilvaleril]piperidin (diastereoizomer 1) v obliki bele trdne snovi; MS: 444 (M + H) + .In an analogous manner to that described in Example 14 (i) - (ii), 1- [1- [b] methyl-l, 1,2,2 (R) -pentantricarboxylate and N-bromomethylpyrrolidine were obtained from 1,2-benzyl 1-tert-butyl 4-methyl-1,1 2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (2-oxo-1-pyrrolidinyl) ethyl] -4-methylvaleryl] piperidine (diastereoisomer 1) as a white solid; MS: 444 (M + H) < + >.
Primer 22Example 22
Na analogen način, kot smo opisali v prvem odstavku Primera 1, smo iz 0.226 g 4[2(R)-[1(R ali S)-karboksi-3-ftalimidopropil]-4-metilvaleril]-morfolina dobili 0.065 g 4[2(R)-[1(R ali S)-(hidroksikarbamoil)-3-ftalimidopropil]-4-metilvaleril]morfolina (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 7.88-7.76 (m,4H); 3.863.50 (m,8H); 3.24-3.15 (m,IH); 2.32-2.23 (m,IH); 1.99-1.89 (m,IH); 1.83-1.73 (m,IH); 1.66-1.57 (m,IH); 1.43-1.29 (m,IH); 1.17-1.09 (m,IH); 0.89-0.83 (m,6H); MS: 432 (M+H)+.In an analogous manner as described in the first paragraph of Example 1, 0.265 g of 4 [2 (R) - [1 (R or S) -carboxy-3-phthalimidopropyl] -4-methylvaleryl] -morpholine were obtained from 0.226 g 4 [ 2 (R) - [1 (R or S) - (hydroxycarbamoyl) -3-phthalimidopropyl] -4-methylvaleryl] morpholine (diastereoisomer 1) as a white solid; nmr (MeOD): 7.88-7.76 (m, 4H); 3.863.50 (m, 8H); 3.24-3.15 (m, 1H); 2.32-2.23 (m, 1H); 1.99-1.89 (m, 1H); 1.83-1.73 (m, 1H); 1.66-1.57 (m, 1H); 1.43-1.29 (m, 1H); 1.17-1.09 (m, 1H); 0.89-0.83 (m, 6H); MS: 432 (M + H) < + >.
Izhodni material smo pripravili kot sledi:The starting material was prepared as follows:
Na analogen način, kot smo opisali v Primeru l(i)-(ii), smo iz 0.65 g približno 5 : 1 zmesi diastereoizomerov 2(R)-[1(R ali S)-(terc.butoksikarbonil)-3-ftalimidopropil]4metil-valerianske kisline in 0.17 ml morfolina, dobili 0.462 g 4-[2(R)-[l(R ali S)karboksi-3-ftalimidopropil]-4-metilvaleril]morfolina v obliki brezbarvne gume, ki smo jo uporabili brez nadaljnjega čiščenja.In an analogous manner as described in Example l (i) - (ii), 0.65 g of about 5: 1 is a mixture of diastereoisomers of 2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -3-phthalimidopropyl ] 4methyl-valeric acid and 0.17 ml of morpholine, 0.462 g of 4- [2 (R) - [1 (R or S) carboxy-3-phthalimidopropyl] -4-methylvaleryl] morpholine were obtained in the form of a colorless gum, which was used without further purification.
Primer 23Example 23
Na analogen način, kot smo opisali pri Primeru 13, smo dobili iz 0.2 g N,N-dietil-2(R)[1(R ali S)-(beziloksikarbamoil)-2-ftalimidoetil]-4-metilvaleramida (diastereoizomer 1), pripravljenega na analogen način, kot je opisano v Primeru 13 (iii)-(iv), po očiščenju produkta s flash kromatografijo ob uporabi 3 % metanola v diklorometanu za elucijo, 0.085 g N,N-dietil-2(R)-[ 1 -(R ali S)-(hidroksikarabmoil)-2-ftalimidoetil]-4metil-valeramida (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 7.85-7.75 (m,4H); 3.97 (dd, J = 14.10,1 H); 3.68-3.6 (m,IH); 3.57-3.48 (m,2H); 3.38 (q,J=7,2H); 3.2 (dt,J=12.4, IH); 2.84 (dt,J= 14.5,IH); 1.67-1.59 (m,IH); 1.47-1.36 (m,IH); 1.26 (t,J=8,3H); 1.25-1.16 (m,IH); 1.13 (t,J=8,3H); 0.9 (d,J = 6,3H); 0.85 (d,J=6,3H);In an analogous manner as described in Example 13, 0.2 g of N, N-diethyl-2 (R) [1 (R or S) - (bezyloxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleramide (diastereoisomer 1) was obtained prepared in an analogous manner as described in Example 13 (iii) - (iv) after purification of the product by flash chromatography using 3% methanol in dichloromethane for elution, 0.085 g of N, N-diethyl-2 (R) - [ 1- (R or S) - (hydroxycarabmoyl) -2-phthalimidoethyl] -4methyl-valeramide (diastereoisomer 1) as a white solid; nmr (MeOD): 7.85-7.75 (m, 4H); 3.97 (dd, J = 14.10.1 H); 3.68-3.6 (m, 1H); 3.57-3.48 (m, 2H); 3.38 (q, J = 7.2H); 3.2 (dt, J = 12.4, 1H); 2.84 (dt, J = 14.5, 1H); 1.67-1.59 (m, 1H); 1.47-1.36 (m, 1H); 1.26 (t, J = 8.3H); 1.25-1.16 (m, 1H); 1.13 (t, J = 8.3H); 0.9 (d, J = 6.3H); 0.85 (d, J = 6.3H);
MS: 404 (M+H)+.MS: 404 (M + H) < + >.
Primer 24Example 24
Na analogen način, kot smo opisali pri Primeru 1, smo dobili iz 0.16 g 3-[2(R)-[l(R ali S)-karboksi-2-ftalimidoetil]-4-metilvaleril]-tiazolidina (diastereoizomer 1), pripravljenega na analogen način, kot je opisano v Primeru 1 (i)-(ii), po očiščenju produkta s flash kromatografijo ob uporabi 5 % metanola v diklorometanu za elucijo, 0.039 gIn an analogous manner as described in Example 1, 0.16 g of 3- [2 (R) - [1 (R or S) -carboxy-2-phthalimidoethyl] -4-methylvaleryl] -thiazolidine (diastereoisomer 1) was obtained. prepared in an analogous manner as described in Example 1 (i) to (ii) after purification of the product by flash chromatography using 5% methanol in dichloromethane for elution, 0.039 g
3-[-2(R)-[l-(R ali S)-(hidroksikarabmoil)-2-ftalimidoetil]-4-metilvaleril]-tiazolidina (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 7.86-7.75 (m,4H); 4.8 (d, J=10,0.5H); 4.63 (d,J=10,0.5H); 4.36 (d,J= 10,0.5H); 4.13-4.07 (m,0.5H); 4.03 (d,J=10,0.5H); 3.87-3.72 (m,2H); 3.63-3.55 (m,0.5H); 3.45-3.36 (m,0.5H); 3.24-2.95 (m,2.5H); 1.62-1.54 (m,IH); 1.46-1.37 (m,IH); 1.29-1.2 (m,IH); 0.9 (d,J=6,3H); 0.85 (d,J=6,3H); MS: 420 (M + H)+.3 - [- 2 (R) - [1- (R or S) - (hydroxycarabmoyl) -2-phthalimidoethyl] -4-methylvaleryl] -thiazolidine (diastereoisomer 1) as a white solid; nmr (MeOD): 7.86-7.75 (m, 4H); 4.8 (d, J = 10.0.5H); 4.63 (d, J = 10.0.5H); 4.36 (d, J = 10.0.5H); 4.13-4.07 (m, 0.5H); 4.03 (d, J = 10.0.5H); 3.87-3.72 (m, 2H); 3.63-3.55 (m, 0.5H); 3.45-3.36 (m, 0.5H); 3.24-2.95 (m, 2.5H); 1.62-1.54 (m, 1H); 1.46-1.37 (m, 1H); 1.29-1.2 (m, 1H); 0.9 (d, J = 6.3H); 0.85 (d, J = 6.3H); MS: 420 (M + H) < + >.
Primer 25Example 25
Na analogen način, kot smo opisali pri Primeru 13, smo iz 0.25 g N-etil-2(R)-[l(R S)(beziloksikarbamoil)-2-ftalimidoetil]-N,4-dimetilvaleramida (8 : 1 zmes diastereoizomerov), pripravljenega na analogen način, kot je opisano v Primeru 13 (iii)-(iv), dobili 0.083 g N,etil-2(R)-[l-(RS)-(hidroksikarabmoil)-2-ftalimidoetil]-N,4-dimetilvaleramida (8 : 1 zmes diastereoizomerov) v obliki bele trdne snovi; nmr (MeOD): 7.85-7.75 (m,4H); 3.95-3.83 (m,IH); 3.75-3.62 (m,IH); 3.4-3.08 (m,10H); 2.95-2.87 (m,IH); 2.83 (m,IH); 1.65-1.55 (m,IH); 1.43-1.33 (m,IH); 1.28-1.13 (m,2H); 1.03 (t,J=6,2H); 0.89 (d,J=6,3H); 0.85 (d,J=6,3H); MS: 390 (M+H)+.In an analogous manner to that described in Example 13, 0.25 g of N-ethyl-2 (R) - [1 (RS) (bezyloxycarbamoyl) -2-phthalimidoethyl] -N, 4-dimethylvaleramide (8: 1 mixture of diastereoisomers) were obtained prepared in an analogous manner as described in Example 13 (iii) - (iv) gave 0.083 g of N, ethyl-2 (R) - [1- (RS) - (hydroxycarabmoyl) -2-phthalimidoethyl] -N, 4-dimethylvaleramide (8: 1 mixture of diastereoisomers) as a white solid; nmr (MeOD): 7.85-7.75 (m, 4H); 3.95-3.83 (m, 1H); 3.75-3.62 (m, 1H); 3.4-3.08 (m, 10H); 2.95-2.87 (m, 1H); 2.83 (m, 1H); 1.65-1.55 (m, 1H); 1.43-1.33 (m, 1H); 1.28-1.13 (m, 2H); 1.03 (t, J = 6.2H); 0.89 (d, J = 6.3H); 0.85 (d, J = 6.3H); MS: 390 (M + H) < + >.
Primer 26Example 26
Na analogen način, kot smo opisali pri Primeru 13, smo iz 0.1 g 4-[2(R)-[l(RS)(beziloksikarbamoil)-5-ftalimidopentil]-4-metiIvaIerilmorfolina (5 : 1 zmes diastereoizomerov), pripravljenega na analogen način, kot je opisano v Primeru 1 (i)-(ii), dobili 0.045 g 4-[2(R)-[l-(RS)-(hidroksikarabmoil)-5-ftalimidopentil]-4-metilvaleril]morolina (3 : 1 zmes diastereoizomerov) kot krem obarvano trdno snov; nmr (MeOD): 7.85-7.75 (m,4H); 3.8-3.49 (m,12H); 3.15 (d,t,lH,J= 14.3); 2.18 (dt, 1 H,J = 12.3); 1.68-1.5 (m,4H); 1.38-1.05 (m,5H); 0.86-0.82 (m,6H); MS: 460 (M + H)+.In an analogous manner to that described in Example 13, 0.1 g of 4- [2 (R) - [1 (RS) (bezyloxycarbamoyl) -5-phthalimidopentyl] -4-methylarylaryl morpholine (5: 1 mixture of diastereoisomers) prepared from in an analogous manner as described in Example 1 (i) - (ii), 0.045 g of 4- [2 (R) - [1- (RS) - (hydroxycarabmoyl) -5-phthalimidopentyl] -4-methylvaleryl] morolin (0.045 g) was obtained 3: 1 mixture of diastereoisomers) as a cream colored solid; nmr (MeOD): 7.85-7.75 (m, 4H); 3.8-3.49 (m, 12H); 3.15 (d, t, 1H, J = 14.3); 2.18 (dt, 1H, J = 12.3); 1.68-1.5 (m, 4H); 1.38-1.05 (m, 5H); 0.86-0.82 (m, 6H); MS: 460 (M + H) < + >.
Primer 27Example 27
Na analogen način, kot smo opisali pri Primeru 13, smo dobili iz 1.06 g N-fenil-2(R)[1(R ali S)-(beziloksikarbamoil)-2-ftalimidoetil]-N,4-dimetilvaleramida po očiščenju produkta s flash kromatografijo ob uporabi 2 % metanola v diklorometanu za elucijo, 0.65 g N-fenil-2(R)-[ 1 -(R ali S)-(hidroksikarabmoil)-2-ftalimidoetil]-N,4-dimetilvaleramida kot belo peno; nmr (MeOD): 7.75-7.68 (m,4H); 7.28-7.17 (m,4H); 7.087.04 (m,IH); 3.77 (dd, 1 H,J = 14.8); 3.69 (dd, 1 H,J = 14.7), 3.14 (s,3H); 2.78-2.65 (m,2H); 1.62-1.55 (m,IH); 1.42-1.32 (m,IH); 1.25-1.18 (m,IH); 0.7 (d,3H,J=7); 0.54 (d,3H,J=7); MS: 438 (M+H) +In an analogous manner as described in Example 13, 1.06 g of N-phenyl-2 (R) [1 (R or S) - (bezyloxycarbamoyl) -2-phthalimidoethyl] -N, 4-dimethylvaleramide were obtained after purification of the product with flash chromatography using 2% methanol in dichloromethane for elution, 0.65 g of N-phenyl-2 (R) - [1- (R or S) - (hydroxycarabmoyl) -2-phthalimidoethyl] -N, 4-dimethylvaleramide as a white foam; nmr (MeOD): 7.75-7.68 (m, 4H); 7.28-7.17 (m, 4H); 7.087.04 (m, 1H); 3.77 (dd, 1H, J = 14.8); 3.69 (dd, 1H, J = 14.7), 3.14 (s, 3H); 2.78-2.65 (m, 2H); 1.62-1.55 (m, 1H); 1.42-1.32 (m, 1H); 1.25-1.18 (m, 1H); 0.7 (d, 3H, J = 7); 0.54 (d, 3H, J = 7); MS: 438 (M + H) < + >.
Izhodni material smo pripravili kot sledi:The starting material was prepared as follows:
(i) Raztopino 1,49 g 2(R)-[1(R ali S)-(terc.butoksikarbonil)-2-ftalimidoetil]-4metilvalerianske kisline (6 : 1 zmes diastereoizomera 1 in diastereoizomera 2) v 20 ml toluena smo ohladili na - 10 °C. Dodali smo nekaj kapljic N,N-dimetilformamida, zatem pa 0.34 ml oksalil klorida. Zmes smo mešali 1 uro pri - 10 °C in nato topilo uparili v visokem vakuumu pri 10 °C. Ostanek smo ponovno raztopili v 10 ml diklorometana in ohladili na 0 °C. Dodali smo 0.5 ml trietilamina, nato pa 0.4 ml Nmetilanilina. Zmes smo mešali 1 uro pri 0 °C in pustili ogreti na sobno temperaturo čez noč. Topilo smo uparili in ostanek ponovno raztopili v 50 ml etil acteata in zapored izprali s 5 % raztopino natrijevega hidrogen karbonata, 2N klorovodikovo kislino in nasičeno raztopino slanice. Organsko fazo smo sušili nad brezvodnim magnezijevim sulfatom in uparili, da smo dobili oranžno olje. Čiščenje s flash kromatografijo na silikagelu ob uporabi 3 : 1 heksana/etil acetata za elucijo je dalo 1.23 g N-fenil-2(R)[1(R ali S)-(terc.butoksi-karbonil)-2-ftalimidoetil]-N,4-dimetilvaleramida (diastereoizomer 1) kot bledorumeno olje; nmr (CDCI3) 7.83-7.78 (m,2H); 7.73-7.68 (m,2H); 7.32-7.05 (m,5H); 4.0 (dd, 1 H,J = 13.9); 3.74 (dd, 1 H,J = 14.6); 3.26 (s,3H); 3.03-2.96 (m,IH); 2.83-2.76 (m,IH); 1.78-1.68 (m,IH); 1.57-1.46 (m,IH); 1.1 (s,9H); 0.87 (d,3H,J=7); 0.65 (d,3H,J = 7); MS: 479 (M + H)+.(i) A solution of 1.49 g of 2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2-phthalimidoethyl] -4-methyl valeric acid (6: 1 mixture of diastereoisomer 1 and diastereoisomer 2) in 20 ml of toluene was obtained. cooled to - 10 ° C. A few drops of N, N-dimethylformamide were added followed by 0.34 ml of oxalyl chloride. The mixture was stirred for 1 hour at -10 ° C and then the solvent was evaporated under high vacuum at 10 ° C. The residue was redissolved in 10 ml of dichloromethane and cooled to 0 ° C. 0.5 ml of triethylamine was added followed by 0.4 ml of Nmethylaniline. The mixture was stirred for 1 hour at 0 ° C and allowed to warm to room temperature overnight. The solvent was evaporated and the residue was redissolved in 50 ml of ethyl acetate and washed successively with 5% sodium hydrogen carbonate solution, 2N hydrochloric acid and saturated brine. The organic phase was dried over anhydrous magnesium sulfate and evaporated to give an orange oil. Purification by flash chromatography on silica gel using 3: 1 hexane / ethyl acetate for elution gave 1.23 g of N-phenyl-2 (R) [1 (R or S) - (tert-butoxy-carbonyl) -2-phthalimidoethyl] - N, 4-dimethylvaleramide (diastereoisomer 1) as a pale yellow oil; nmr (CDCl3) 7.83-7.78 (m, 2H); 7.73-7.68 (m, 2H); 7.32-7.05 (m, 5H); 4.0 (dd, 1H, J = 13.9); 3.74 (dd, 1H, J = 14.6); 3.26 (s, 3H); 3.03-2.96 (m, 1H); 2.83-2.76 (m, 1H); 1.78-1.68 (m, 1H); 1.57-1.46 (m, 1H); 1.1 (s, 9H); 0.87 (d, 3H, J = 7); 0.65 (d, 3H, J = 7); MS: 479 (M + H) < + >.
(ii) Na analogen način, kot smo opisali pri Primeru 13(iv), smo dobili iz 1.23 g N-fenil2(R)-[1(R ali S)-(terc.butoksi-karbonil)-2-ftalimidoetil]-N,4-dimetilvaleramida po očiščenju produkta s flash kromatografijo ob uporabi 2 % metanola v diklorometanu za elucijo, 1.06 g N-fenil-2(R)-[ 1 -(R ali S)-(benziloksikarbamoil)-2-ftalimidoetil]-N,4dimetilvaleramida kot belo peno; nmr (CDCI3) 7.8-7.74 (m,4H); 7.45-7.28 (m,6H); 7.04-6.85 (m,4H); 4.96 (d,lH,J=10); 4.89 (d,lH,J=l 1); 3.95 (dd, 1H,J= 14.6); 3.72 (dd,lH,J = 14.9); 3.17 (s,3H); 3.05-2.98 (m,IH); 2.64-2.58 (m,IH); 1.68-1.6 (m,IH); 1.49-1.32 (m,2H); 0.79 (d,3H,J=6); 0.66 (d,3H,J=6); MS: 528 (M + H)+.(ii) In an analogous manner as described in Example 13 (iv), 1.23 g of N-phenyl2 (R) - [1 (R or S) - (tert-butoxy-carbonyl) -2-phthalimidoethyl] was obtained. N, 4-dimethylvaleramide after purification of the product by flash chromatography using 2% methanol in dichloromethane for elution, 1.06 g of N-phenyl-2 (R) - [1- (R or S) - (benzyloxycarbamoyl) -2-phthalimidoethyl] - N, 4dimethylvaleramide as white foam; nmr (CDCl3) 7.8-7.74 (m, 4H); 7.45-7.28 (m, 6H); 7.04-6.85 (m, 4H); 4.96 (d, 1H, J = 10); 4.89 (d, 1H, J = 11); 3.95 (dd, 1H, J = 14.6); 3.72 (dd, 1H, J = 14.9); 3.17 (s, 3H); 3.05-2.98 (m, 1H); 2.64-2.58 (m, 1H); 1.68-1.6 (m, 1H); 1.49-1.32 (m, 2H); 0.79 (d, 3H, J = 6); 0.66 (d, 3H, J = 6); MS: 528 (M + H) < + >.
Primer 28Example 28
Na analogen način, kot smo opisali v prvem odstavku Primera 13, smo dobili iz 0.31 g 1-[2(R)-[1(R ali S)-(beziloksikarbamoil)-2-ftalimidoetil]-4-metilvaleril]-2-(R)-pirolidin metanola (diastereoizomer 1) po očiščenju produkta s flash kromatografijo na silikagelu ob uporabi diklorometana/metanola (15 : 1) za elucijo in s kristalizacijo iz etil acetata, 0.07 g 1-[2(R)-[1(R ali S)-(hidroksikarbamoil)-2-ftalimidoetil]-4-metil30 valeril]-2-(R)-pirolidin metanola (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD); 7.86-7.74 (m,4H); 4.20-4.10 (m,IH); 4.05-3.97 (m,IH); 3.81-3.57 (n,5H); 3.10-3.02 (m,IH); 2.84-2.76 (m,IH,); 2.14-1.87 (m,4H); 1.73-1.63 (m,IH); 1.50-1.35 (m,IH); 1.24-1.14 (m,IH); 0.94-0.84 (m,6H); MS: 432 (M+H)+.In an analogous manner as described in the first paragraph of Example 13, 0.31 g of 1- [2 (R) - [1 (R or S) - (bezyloxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] -2- (R) -Pyrrolidine methanol (diastereoisomer 1) after purification of the product by flash chromatography on silica gel using dichloromethane / methanol (15: 1) for elution and by crystallization from ethyl acetate, 0.07 g 1- [2 (R) - [1 ( R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methyl30 valeryl] -2- (R) -pyrrolidine methanol (diastereoisomer 1) as a white solid; nmr (MeOD); 7.86-7.74 (m, 4H); 4.20-4.10 (m, 1H); 4.05-3.97 (m, 1H); 3.81-3.57 (n, 5H); 3.10-3.02 (m, 1H); 2.84-2.76 (m, 1H,); 2.14-1.87 (m, 4H); 1.73-1.63 (m, 1H); 1.50-1.35 (m, 1H); 1.24-1.14 (m, 1H); 0.94-0.84 (m, 6H); MS: 432 (M + H) < + >.
Izhodni material smo pripravili kot sledi:The starting material was prepared as follows:
(i) Na analogen način, kot smo opisali v drugem odstavku Primera 9, smo iz 0.41 g 1[2(R)-[1(R ali S)-(terc.butoksikarbonil)-2-ftalimidoetil]-4-metilvaleril]-2-(R)-pirolidin metanola (diastereoizomer 1), pripravljenega na analogen način, kot smo opisali v Primeru 1 (i), dobili 0.31 g 1-[2(R)-[1(R ali S)-karboksi-2-ftalimidoetil]-4-metilvaleril]2-(R)-pirolidin metanola (diastereoizomer 1) v obliki bledorjave pene, ki smo jo uporabili brez nadaljnjega čiščenja.(i) In an analogous manner to that described in the second paragraph of Example 9, 0.41 g of 1 [2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2-phthalimidoethyl] -4-methylvaleryl] -2- (R) -pyrrolidine methanol (diastereoisomer 1) prepared in an analogous manner as described in Example 1 (i) gave 0.31 g of 1- [2 (R) - [1 (R or S) -carboxy- 2-Phthalimidoethyl] -4-methylvaleryl] 2- (R) -pyrrolidine methanol (diastereoisomer 1) as a pale brown foam, which was used without further purification.
Primer 29Example 29
Na analogen način, kot smo opisali v prvem odstavku Primera 13, smo dobili iz 0.2 g benzil heksahidro-2-[2(R)-[l(R ali S)-(beziloksikarbamoil)-2-ftalimidoetil]-4-metilvaleril]-3(S)-(metilkarbamoil)-l-piridazinkarboksilata (diastereoizomer 1), po očiščenju produkta s flash kromatografijo na silikagelu ob uporabi diklorometana/metanola (20 : 1) za elucijo, 0.044 g heksahidro-2-[2(R)-[l(R ali S)-(hidroksikarbamoil)-2-ftalimidoetil]-4-metil-valeril]-N-metil-3(S)-piridazinkarboksamida (diastereoizomer 1), v obliki bele trdne snovi; nmr (MeOD): 7.83-7.69 (m,4H); 5.06 (m,IH); 3.99 (dd,lH,J = 14.9); 3.57 (dd,lH,J= 14.5); 3.04-2.95 (m,IH); 2.86-2.74 (m,2H); 2.70 (s,3H); 2.07-1.86 (m,2H); 1.68-1.35 (m,5H); 1.18-1.10 (m,IH); 0.88 (d,3H,J = 5.5); 0.80 (d,3H,J=6.0); MS: 474 (M + H) + .In an analogous manner as described in the first paragraph of Example 13, 0.2 g of benzyl hexahydro-2- [2 (R) - [1 (R or S) - (bezyloxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl was obtained -3 (S) - (methylcarbamoyl) -1-pyridazinecarboxylate (diastereoisomer 1), after purification of the product by flash chromatography on silica gel using dichloromethane / methanol (20: 1) for elution, 0.044 g hexahydro-2- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methyl-valeryl] -N-methyl-3 (S) -pyridazinecarboxamide (diastereoisomer 1), as a white solid; nmr (MeOD): 7.83-7.69 (m, 4H); 5.06 (m, 1H); 3.99 (dd, 1H, J = 14.9); 3.57 (dd, 1H, J = 14.5); 3.04-2.95 (m, 1H); 2.86-2.74 (m, 2H); 2.70 (s, 3H); 2.07-1.86 (m, 2H); 1.68-1.35 (m, 5H); 1.18-1.10 (m, 1H); 0.88 (d, 3H, J = 5.5); 0.80 (d, 3H, J = 6.0); MS: 474 (M + H) < + >.
Izhodni material smo pripravili kot sledi:The starting material was prepared as follows:
(i) Na analogen način, kot smo opisali v Primera 27(i), smo iz 1.02 g 2(R)-[1(R ali S)(terc.butoksikarbonil)-2-ftalimidoetil]-4-metilvalerianske kisline (6 : 1 zmes diastereoizomera 1 in diastereoizomera 2) in 0.7 g heksahidro-l-(benziloksikarbonil)-(3S)piridazinkarboksilne kisline, dobili po kromatografiji na silikagelu ob uporabi etra/heksana (1 : 4) zatem pa etil acetata za elucijo, 0.6 g heksa hidro-l-(benziloksikarbonil)-2-[2(R)-[l(R ali S)-(terc.butoksikarbonil)-2-ftalimidoetil]-4-metilvaleril]3(S)-piridazinkarboksilne kisline v obliki brezbarvne gume.(i) In an analogous manner to that described in Example 27 (i), from 1.02 g of 2 (R) - [1 (R or S) (tert-butoxycarbonyl) -2-phthalimidoethyl] -4-methylvaleric acid (6 : 1 mixture of diastereoisomer 1 and diastereoisomer 2) and 0.7 g of hexahydro-1- (benzyloxycarbonyl) - (3S) pyridazinecarboxylic acid, obtained by chromatography on silica gel using ether / hexane (1: 4) then ethyl acetate for elution, 0.6 g hexa hydro-1- (benzyloxycarbonyl) -2- [2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2-phthalimidoethyl] -4-methylvaleryl] 3 (S) -pyridazinecarboxylic acid as a colorless tires.
(ii) Raztopino 0.6 g heksahidro-1 -(benziloksikarbonil)-2-[2(R)-[ 1 (R ali S)(terc.butoksi-karbonil)-2-ftalimidoetil]-4-metilvaleril]-3(S)-piridazinkarboksilne kisline v 5ml dimetilformamida smo ohladili na 0 °C in dodali 0.27 g 1-hidroksibenzotriazola in 0.36 g l-etil-3-(3-dimetilaminopropil)karbodiimid hidroklorida. Po 40 minutah smo dodali 0.4 ml 40 % vodne raztopine metilamina in zmes mešali 2.5 ur. Topilo smo uparili in ostanek obdelali z 20 ml 5 % vodne raztopine natrijevega hidrogen karbonata. Produkt smo ekstrahirali z etil acetatom in ekstrakt izprali s 5 % citronsko kislino in vodno raztopino natrijevega klorida. Po sušenju nad brezvodnim magnezijevim sulfatom smo topilo uparili, da smo dobili 0.638 g brezbarvne gume, ki smo jo očistili s flash kromatografijo ob uporabi etra/heksana (3 : 1) za elucijo. Dobili smo 0.467 g benzil heksahidro-2-[2(R)-[l(R ali S)-(terc.butoksikarbonil)-2-ftalimidoetil]-4-metilvaleril]-3(S)-(metilkarbamoil)-1 -piridazinkarboksilata v obliki brezbarvne gume.(ii) Solution of 0.6 g hexahydro-1- (benzyloxycarbonyl) -2- [2 (R) - [1 (R or S) (tert-butoxycarbonyl) -2-phthalimidoethyl] -4-methylvaleryl] -3 (S ) -pyridazinecarboxylic acid in 5 ml of dimethylformamide was cooled to 0 ° C and 0.27 g of 1-hydroxybenzotriazole and 0.36 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride were added. After 40 minutes, 0.4 ml of 40% aqueous methylamine solution was added and the mixture was stirred for 2.5 hours. The solvent was evaporated and the residue was treated with 20 ml of 5% aqueous sodium hydrogen carbonate solution. The product was extracted with ethyl acetate and the extract was washed with 5% citric acid and aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated to give 0.638 g of a colorless gum which was purified by flash chromatography using ether / hexane (3: 1) for elution. 0.467 g of benzyl hexahydro-2- [2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2-phthalimidoethyl] -4-methylvaleryl] -3 (S) - (methylcarbamoyl) -1- pyridazinecarboxylate as a colorless gum.
(iii) Na analogen način kot pri Primeru 13 (iv), smo iz 0.23 g benzil heksahidro-2[2(R)-[1(R ali S)-(terc.butoksikarbonil)-2-ftalimidoetil]-4-metilvaleril]-3(S)-(metilkarbamoil)-l-piridazinkarboksilata dobili 0.2 g benzil heksahidro-2-[2(R)-[l(R ali S)(benziloksikarbamoil)-2-ftalimidoetil]-4-metilvaleril]-3(S)-(metilkarbamoil)-lpiridazin-karboksilata v obliki bele trdne snovi.(iii) In an analogous manner to Example 13 (iv), 0.23 g of benzyl hexahydro-2 [2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2-phthalimidoethyl] -4-methylvaleryl ] -3 (S) - (methylcarbamoyl) -1-pyridazinecarboxylate gave 0.2 g of benzyl hexahydro-2- [2 (R) - [1 (R or S) (benzyloxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] -3 (S) - (Methylcarbamoyl) -lpyridazine carboxylate as a white solid.
Primer 30Example 30
Na analogen način, kot smo opisali v prvem odstavku Primera 1 in delu (ii) Primera 1, smo iz 0.273 g benzil heksahidro-2-[2(R)-[l(R ali S)-(terc.butoksikarbonil)-2-ftalimidoetil]-4-metilvaleril]-3(S)-(metilkarbamoil)-l-piridazinkarboksilata dobili 0.12 g benzil heksahidro-2-[2(R)-[(R ali S)-(hidroksikarbamoil)-2-ftalimidoetil]-4-metilvaleril]-3(S)(metilkarbamoil)-l-piridazinkarboksilata v obliki bele trdne snovi; MS: 608 (M+H)+.In an analogous manner as described in the first paragraph of Example 1 and part (ii) of Example 1, 0.273 g of benzyl hexahydro-2- [2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2 -phthalimidoethyl] -4-methylvaleryl] -3 (S) - (methylcarbamoyl) -1-pyridazinecarboxylate gave 0.12 g benzyl hexahydro-2- [2 (R) - [(R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] -3 (S) (methylcarbamoyl) -1-pyridazinecarboxylate as a white solid; MS: 608 (M + H) < + >.
Primer 31Example 31
Na analogen način, kot smo opisali v prvem odstavku Primera 13, smo iz 0.185 g l-[2(R)-[ 1(R ali S)-(beziloksikarbamoil)-2-ftalimidoetil]-4-metilvaleril]-N-metil-2-(S)piperidin-karboksamida po očiščenju produkta s flash kromatografijo na silikagelu ob uporabi diklorometana/metanola (16 : 1) za elucijo, dobili 0.06 g 1-[2(R)-[1(R ali S)(hidroksikarbamoil)-2-ftalimidoetil]-4-metilvaleriI]-N-metil-2(S)-piperidinkarboksamida (diastereoizomer 1) v obliki bele trdne snovi; MS: 473 (M + H) + .In an analogous manner as described in the first paragraph of Example 13, 0.185 g of 1- [2 (R) - [1 (R or S) - (bezyloxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] -N-methyl -2- (S) piperidine-carboxamide after purification of the product by flash chromatography on silica gel using dichloromethane / methanol (16: 1) for elution to give 0.06 g of 1- [2 (R) - [1 (R or S) (hydroxycarbamoyl) ) -2-phthalimidoethyl] -4-methylvaleryl] -N-methyl-2 (S) -piperidinecarboxamide (diastereoisomer 1) as a white solid; MS: 473 (M + H) < + >.
Primer 32Example 32
Na analogen način, kot smo opisali v prvem odstavku Primera 1, smo iz 0.22 g 1-2(R)[1(R ali S)-karboksi-2-ftalimidoetil]-4-metilvaleril]-4-metoksipiperidina] (diastereoizomer 1), pripravljenega na analogen način, kot je opisano v Primeru 1 (i)-(ii), dobili 0.108 g 1-[2(R)-[1-(R ali S)-(hidroksikarbamoil)-2-ftalimidoetil]-4-metil-valeril 4metoksipiperidina (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 7.867.74 (m,4H); 4.05-3.83 (m,2.5H); 3.70-3.44 (m,3.5H); 3.41-3.27 (m,4.5H); 3.10-3.01 (m,0.5H); 2.97-2.90 (m,IH,); 2.10-2.00 (m,0.5H); 1.94-1.84 (m,IH); 1.80-1.68 (m,IH); 1.66-1.31 (m,3.5H); 1.21-1.13 (m,IH); 0.92-0.82 (m,6H);In an analogous manner as described in the first paragraph of Example 1, 0.22 g of 1-2 (R) [1 (R or S) -carboxy-2-phthalimidoethyl] -4-methylvaleryl] -4-methoxypiperidine] (diastereoisomer 1 ) prepared in an analogous manner as described in Example 1 (i) - (ii) gave 0.108 g of 1- [2 (R) - [1- (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] - 4-methyl-valeryl 4methoxypiperidine (diastereoisomer 1) as a white solid; nmr (MeOD): 7.867.74 (m, 4H); 4.05-3.83 (m, 2.5H); 3.70-3.44 (m, 3.5H); 3.41-3.27 (m, 4.5H); 3.10-3.01 (m, 0.5H); 2.97-2.90 (m, 1H,); 2.10-2.00 (m, 0.5H); 1.94-1.84 (m, 1H); 1.80-1.68 (m, 1H); 1.66-1.31 (m, 3.5H); 1.21-1.13 (m, 1H); 0.92-0.82 (m, 6H);
MS: 446 (M+H)+.MS: 446 (M + H) < + >.
Primer 33Example 33
Na analogen način, kot smo opisali v prvem odstavku pri Primeru 1, smo iz 0.44 g 12(R)-[1(R ali S)-karboksi-2-ftalimidoetil]-4-metilvaleril]-4-piperidinona, pripravljenega na analogen način, kot je opisano v Primeru 1 (ii)-(iii), dobili 0.157 g 1-[2(R)-[1-(R ali S)-(hidroksikarabmoil)-2-ftalimidoetil]-4-metilvaleril 4-piperidinon oksima (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 7.86-7.75 (m,4H); 3.923.76 (m,3H); 3.72-3.58 (m,2H); 3.38-2.82 (m,3H); 2.71-2.25 (m,4H); 1.66 -1.57 m,IH); 1.48-1.34 (m,IH); 1.26-1.17 (m,IH); 0.92-0.82 (m,6H); MS: 445 (M + H) + .In an analogous manner as described in the first paragraph of Example 1, 0.44 g of 12 (R) - [1 (R or S) -carboxy-2-phthalimidoethyl] -4-methylvaleryl] -4-piperidinone prepared for analog the procedure described in Example 1 (ii) - (iii) gave 0.157 g of 1- [2 (R) - [1- (R or S) - (hydroxycarabmoyl) -2-phthalimidoethyl] -4-methylvaleryl 4- oxime piperidinone (diastereoisomer 1) as a white solid; nmr (MeOD): 7.86-7.75 (m, 4H); 3,923.76 (m, 3H); 3.72-3.58 (m, 2H); 3.38-2.82 (m, 3H); 2.71-2.25 (m, 4H); 1.66 -1.57 m, 1H); 1.48-1.34 (m, 1H); 1.26-1.17 (m, 1H); 0.92-0.82 (m, 6H); MS: 445 (M + H) < + >.
Primer 34Example 34
Na analogen način, kot smo opisali v prvem odstavku pri Primeru 13, smo iz 0.32 g N[2(R)-[1(R ali S)-(benziloksikarbamoil)-2-ftalimidoetil]-4-metilvaleril]-L-prolin metil estra (diastereoizomer 1), pripravljenega na analogen način, kot je opisano v Primeru 13 (iii)-(iv), dobili 0.13 g N-[2(R)-[ 1 -(R ali S)-(hidroksikarbamoil)-2-ftalimidoetil]-4metilvaleril]-L-prolin metil estra (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 7.86-7.77 (m,4H); 3.95-3.84 (m,2H); 3.78 (d,2H,J=8); 3.69-3.61 (m,IH); 3.60 (s,3H); 3.11-3.04 (m,IH,); 3.00-2.92 (m,IH,); 2.21-2.12 (m,IH); 2.10-1.95 (m,2H); 1.90-1.82 (m,IH); 1.74-1.63 (m,IH); 1.60-1.52 (m,lH); 1.22-1.14 (m,IH); 0.94 (d,3H,J=6); 0.86 (d,3H,J = 6); MS: 460 (M + H) + .In the analogous manner as described in the first paragraph of Example 13, 0.32 g of N [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] -L-proline methyl ester (diastereoisomer 1) prepared in an analogous manner as described in Example 13 (iii) - (iv) gave 0.13 g of N- [2 (R) - [1- (R or S) - (hydroxycarbamoyl) - 2-phthalimidoethyl] -4methylvaleryl] -L-proline methyl ester (diastereoisomer 1) as a white solid; nmr (MeOD): 7.86-7.77 (m, 4H); 3.95-3.84 (m, 2H); 3.78 (d, 2H, J = 8); 3.69-3.61 (m, 1H); 3.60 (s, 3H); 3.11-3.04 (m, 1H,); 3.00-2.92 (m, 1H,); 2.21-2.12 (m, 1H); 2.10-1.95 (m, 2H); 1.90-1.82 (m, 1H); 1.74-1.63 (m, 1H); 1.60-1.52 (m, 1H); 1.22-1.14 (m, 1H); 0.94 (d, 3H, J = 6); 0.86 (d, 3H, J = 6); MS: 460 (M + H) < + >.
Primer 35Example 35
Na analogen način, kot smo opisali v prvem odstavku pri Primeru 13, smo iz 1.116 g 1-2(R)-[1(R ali S)-(benziloksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-l-imidazolidinil)etil]-4-metilvaleril]-4-piperidinola (diastereoizomer 1), pripravljenega na analogen način, kotje opisano v Primeru 14 (i)-(ii), dobili 0.785 g 1-[2(R)-[1-(R ali S)(hidroksikarbamoil)-2-(3,4,4-trimetil-4-2,5-diokso- l-imidazolidinil)etil]-4-metilvalerilj4-piperidinola (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 4.24-4.01 (m,2H); 3.93-3.81 (m,IH); 3.78-3.64 (m,IH); 3.52-3.22 (m,4H); 3.10-2.81 (m,4H); 2.021.77 (m,2H,); 1.67-1.26 (m,10H,); 1.19-1.09 (m,IH); 0.93-0.82 (m,6H);In an analogous manner as described in the first paragraph of Example 13, from 1,116 g of 1-2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (3,4,4-trimethyl-2, 5-dioxo-1-imidazolidinyl) ethyl] -4-methylvaleryl] -4-piperidinol (diastereoisomer 1) prepared in an analogous manner as described in Example 14 (i) - (ii) gave 0.785 g of 1- [2 ( R) - [1- (R or S) (hydroxycarbamoyl) -2- (3,4,4-trimethyl-4-2,5-dioxo-1-imidazolidinyl) ethyl] -4-methylvaleryl 4-piperidinol (diastereoisomer 1) in the form of a white solid; nmr (MeOD): 4.24-4.01 (m, 2H); 3.93-3.81 (m, 1H); 3.78-3.64 (m, 1H); 3.52-3.22 (m, 4H); 3.10-2.81 (m, 4H); 2,021.77 (m, 2H,); 1.67-1.26 (m, 10H,); 1.19-1.09 (m, 1H); 0.93-0.82 (m, 6H);
MS: 427 (M+H)+.MS: 427 (M + H) < + >.
Primer 36Example 36
Na analogen način, kot smo opisali v prvem odstavku pri Primeru 1, smo iz 1.55 g 1[2(R)-[1(R ali S)-karboksi-2-(tetrahidro-2-metil-3,5-diokso-l,2,4-oksadiazol-4-il)etil]-4metilvaleril]-4-piperidina (diastereoizomer 1), dobili 0.572 g 1-[2(R)-[1(R ali S)(hidroksikarbamoil)-2-(tetrahidro-2-metil-3,5-diokso-l,2,4-oksadiazol-4-il)etil]-4-metilvalerilj-4-piperidina (diastereoizomer 1) v obliki bele trdne snovi;In the analogous manner as described in the first paragraph of Example 1, 1.55 g of 1 [2 (R) - [1 (R or S) -carboxy-2- (tetrahydro-2-methyl-3,5-dioxo) 1,2,4-Oxadiazol-4-yl) ethyl] -4methylvaleryl] -4-piperidine (diastereoisomer 1), 0.572 g of 1- [2 (R) - [1 (R or S) (hydroxycarbamoyl) -2- (tetrahydro-2-methyl-3,5-dioxo-1,2,4-oxadiazol-4-yl) ethyl] -4-methylvaleryl-4-piperidine (diastereoisomer 1) as a white solid;
nmr (MeOD): 3.70-3.46 (m,4H); 3.42-3.29 (m,2H); 3.25-3.15 (m,4H); 2.89-2.76 (m,IH); 1.68-1.27 (m,8H); 1.27-1.04 (m,IH); 0.83-0.76 (m,6H); MS: 385 (M+H)+.nmr (MeOD): 3.70-3.46 (m, 4H); 3.42-3.29 (m, 2H); 3.25-3.15 (m, 4H); 2.89-2.76 (m, 1H); 1.68-1.27 (m, 8H); 1.27-1.04 (m, 1H); 0.83-0.76 (m, 6H); MS: 385 (M + H) < + >.
Izhodni material smo pripravili kot sledi:The starting material was prepared as follows:
(i) Na analogen način, kot smo opisali pri Primeru 18 (i)-(ii), smo iz 4.76 g 1,2-dibenzil(i) In an analogous manner to that described in Example 18 (i) - (ii), from 4.76 g of 1,2-dibenzyl
1- terc.butil 4-metil-1,1,2(R)-pentantrikarboksilata in 2.05 g 4-bromometil-2-tetrahidro2- metil-3,5-diokso-l,2,4-oksadiazola dobili 1,55 g 1-[2(R)-1(R ali S)-karboksi-2-(tetrahidro-2-metil-3,5-diokso-l,2,4-oksadiazol-4-il)etilj-4-metilvaleril]-4-piperidina (diastereoizomer 1) v obliki gume, ki smo jo uporabili brez nadaljnjega čiščenja.1-tert-Butyl 4-methyl-1,1,2 (R) -pentantricarboxylate and 2.05 g of 4-bromomethyl-2-tetrahydro2-methyl-3,5-dioxo-1,2,4-oxadiazole obtained 1.55 g 1- [2 (R) -1 (R or S) -carboxy-2- (tetrahydro-2-methyl-3,5-dioxo-1,2,4-oxadiazol-4-yl) ethyl-4-methylvalery] -4-piperidine (diastereoisomer 1) in the form of a gum which was used without further purification.
Primer 37Example 37
Na analogen način, kot smo opisali v prvem odstavku pri Primeru 13, smo iz 0.184 g 1[2(R)-[1(R ali S)-(benziloksikarbamoil)-2-(3-metil-2,4,5-triokso-l-imidazolidinil)etil]4-metilvaleril]-4-piperidinola (diastereoizomer 1), pripravljenega na analogen način, kotje opisano v Primeru 14 (i)-(ii), iz 1,2-dibenzil 1-terc.butil 4-metil-l,l,2(R)-pentan34 trikarboksilata in l-bromometil-3-metil-2,4,5-triokso-l-imidazola, dobili 0.08 g 1[2(R)-[1(R ali S)-(hidroksikarbamoil)-2-(3-metil-2,4,5-triokso-l-imidazolidinil)-etil]-4metilvaleril]-4-piperidinola (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 4.20-3.95 (m,2H); 3.93-3.75 (m,2H); 3.57-2.97 (m,7H); 2.90-2.81 (m,IH); 2.02-1.76 (m,2H); 1.66-1.29 (m,4H,); 1.20-1.12 (m,IH); 0.91-0.82 (m,6H,);In an analogous manner as described in the first paragraph of Example 13, 0.184 g of 1 [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (3-methyl-2,4,5- trioxo-1-imidazolidinyl) ethyl] 4-methylvaleryl] -4-piperidinol (diastereoisomer 1) prepared in an analogous manner as described in Example 14 (i) - (ii) from 1,2-dibenzyl 1-tert-butyl Of 4-methyl-1,2,2 (R) -pentane34 tricarboxylate and 1-bromomethyl-3-methyl-2,4,5-trioxo-1-imidazole, yielded 0.08 g of 1 [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3-methyl-2,4,5-trioxo-1-imidazolidinyl) -ethyl] -4methyl valeryl] -4-piperidinol (diastereoisomer 1) as a white solid; nmr (MeOD): 4.20-3.95 (m, 2H); 3.93-3. 75 (m, 2H); 3.57-2.97 (m, 7H); 2.90-2.81 (m, 1H); 2.02-1.76 (m, 2H); 1.66-1.29 (m, 4H,); 1.20-1.12 (m, 1H); 0.91-0.82 (m, 6H,);
MS: 413 (M+H)+.MS: 413 (M + H) < + >.
Primer 38Example 38
Na analogen način, kot smo opisali v prvem odstavku pri Primeru 13, smo iz 0.261 g 1[2(R)-[1(R ali S)-(benziloksikarbamoil)-2-(2,5-diokso-3-fenil-l-imidazolidinil)etil]-4metilvaleril]-4-piperidinola (diastereoizomer 1), pripravljenega na analogen način, kot je opisano v Primeru 14 (i)-(ii), dobili 0.169 g 1-[2(R)-[1 (R ali S)-(hidroksi-karbamoil)2-(2,5-diokso-3-fenil-1 -imidazolidinil)-etil]-4-metilva leril]-4-piperidinola (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 7.60-7.55 (m,2H); 7.35-7.29 (m,2H); 7.12-7.05 (m,IH); 4.37-4.24 (m,2H); 4.19-3.92 (m,2H); 3.89-3.66 (m,2H); 3.54-2.84 (m,5H,); 1.99-1.71 (m,2H,); 1.64-1.23 (m,4H); 1.17-1.08 (m,IH); 0.88-0.78 (m,6H);In an analogous manner to that described in the first paragraph of Example 13, 0.261 g of 1 [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (2,5-dioxo-3-phenyl- 1-imidazolidinyl) ethyl] -4methylvaleryl] -4-piperidinol (diastereoisomer 1) prepared in an analogous manner as described in Example 14 (i) - (ii) gave 0.169 g 1- [2 (R) - [1 (R or S) - (hydroxy-carbamoyl) 2- (2,5-dioxo-3-phenyl-1-imidazolidinyl) -ethyl] -4-methylva leryl] -4-piperidinol (diastereoisomer 1) as a white solid ; nmr (MeOD): 7.60-7.55 (m, 2H); 7.35-7.29 (m, 2H); 7.12-7.05 (m, 1H); 4.37-4.24 (m, 2H); 4.19-3.92 (m, 2H); 3.89-3.66 (m, 2H); 3.54-2.84 (m, 5H,); 1.99-1.71 (m, 2H,); 1.64-1.23 (m, 4H); 1.17-1.08 (m, 1H); 0.88-0.78 (m, 6H);
MS: 461 (M + H) + .MS: 461 (M + H) < + >.
Primer 39Example 39
Na analogen način, kot smo opisali v prvem odstavku pri Primeru 13, smo iz 0.146 g 4[2(R)-[1(R ali S)-(benziloksikarbamoil)-2-(3-metil-2,4,5-triokso-l-imidazolidinil)etil]4-metilvaleriljmorfolina (diastereoizomer 1), pripravljenega na analogen način, kot je opisano v Primeru 14 (i)-(ii), dobili 0.085 g 4-[2(R)-[l (R ali S)-(hidroksi-karbamoil)-2(3-metil-2,4,5-triokso-1 -imidazolidinil)-etil]-4-metilvaleril]morfolina (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 3.86-3.54 (m,l0H); 3.28-3.20 (m,IH); 3.08 (s,3H); 2.91-2.82 (m,IH); 1.66-1.57 (m,IH); 1.48-1.36 (m,1 H,); 1.23-1.15 (m,IH,); 0.890.84 (m,6H); MS: 399 (M + H)+.In an analogous manner as described in the first paragraph of Example 13, 0.146 g of 4 [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (3-methyl-2,4,5- trioxo-1-imidazolidinyl) ethyl] 4-methylvalerylmorpholine (diastereoisomer 1) prepared in an analogous manner as described in Example 14 (i) - (ii) gave 0.085 g of 4- [2 (R) - [1 (R) or S) - (hydroxy-carbamoyl) -2 (3-methyl-2,4,5-trioxo-1-imidazolidinyl) -ethyl] -4-methylvaleryl] morpholine (diastereoisomer 1) as a white solid; nmr (MeOD): 3.86-3.54 (m, 10H); 3.28-3.20 (m, 1H); 3.08 (s, 3H); 2.91-2.82 (m, 1H); 1.66-1.57 (m, 1H); 1.48-1.36 (m, 1H,); 1.23-1.15 (m, 1H,); 0.890.84 (m, 6H); MS: 399 (M + H) < + >.
Primer 40Example 40
Na analogen način, kot smo opisali v prvem odstavku pri Primeru 13, smo iz 0.363 gIn an analogous manner as described in the first paragraph of Example 13, 0.363 g is obtained
N2-[2(R)-[1(R ali S)-(benziloksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-l-imidazolidinil)-etil]-4-metilvaleril]N1 -metil-L-prolinamida (diastereoizomer 1), pripravljenega na analogen način, kot je opisano v Primeru 14 (i)-(ii), dobili 0.234 g N2-[2(R)-[1(R aliN 2 - [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) -ethyl] -4-methylvaleryl] N 1 -methyl-L-prolinamide (diastereoisomer 1) prepared in an analogous manner as described in Example 14 (i) - (ii) gave 0.234 g of N 2 - [2 (R) - [1 (R or
S)-(hidroksikarbamoil)-2-(3,4,4-trimetil-2,5-diokso-1 -imidazolidinil)etil]-4-metilvaleriljNkmetil-L-prolinamida (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 4.35-4.29 (m,IH); 3.92-3.83 (m,IH); 3.74-3.58 (m,2H); 3.47-3.41 (m,IH); 3.10-3.01 (m,IH); 2.88-2.75 (m,4H,); 2.59 (s,3H,); 2.26-1.84 (m,4H); 1.74-1.55 (m,2H); 1.34 (s,3H); 1.32(s,3H); 1.18-1.11 (m,IH); 0.92 (d,3H,J=5.5); 0.86 (d,3H,J=6); MS: 454 (M+H)+.S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -4-methylvalerylmethyl-L-prolinamide (diastereoisomer 1) as a white solid; nmr (MeOD): 4.35-4.29 (m, 1H); 3.92-3.83 (m, 1H); 3.74-3.58 (m, 2H); 3.47-3.41 (m, 1H); 3.10-3.01 (m, 1H); 2.88-2. 75 (m, 4H,); 2.59 (s, 3H,); 2.26-1.84 (m, 4H); 1.74-1.55 (m, 2H); 1.34 (s, 3H); 1.32 (s, 3H); 1.18-1.11 (m, 1H); 0.92 (d, 3H, J = 5.5); 0.86 (d, 3H, J = 6); MS: 454 (M + H) < + >.
Primer 41Example 41
Na analogen način, kot smo opisali v prvem odstavku pri Primeru 13, smo iz 0.3 g 1-[2(R)-[1(R ali S)-(benziloksikarbamoil)-2-(2-okso-1 -pirolidinil)etil]-4-metilvaleril]-4piperidinola (diastereoizomer 1), pripravljenega na analogen način, kot je opisano v Primeru 14 (i)-(ii), dobili 0.116 g 1-[2(R)-[1(R ali S)-(hidroksikarbamoil)-2-(2-okso-lpirolidinil)etil]-4-metilvaleril]4-piperidinola (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 4.16-3.91 (m,2H); 3.84-3.73 (m,IH); 3.43-2.97 (m,7H); 2.56-2.45 (m,IH); 2.27-2.18(m,2H); 1.96-1.70 (m,4H); 1.61-1.19 (m,4H); 1.11-1.01 (m,IH); 0.840.72 (m,6H); MS: 370 (M + H) + .In the analogous manner as described in the first paragraph of Example 13, 0.3 g of 1- [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (2-oxo-1-pyrrolidinyl) ethyl ] -4-methylvaleryl] -4piperidinol (diastereoisomer 1) prepared in an analogous manner as described in Example 14 (i) - (ii) gave 0.116 g of 1- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (2-oxo-pyrrolidinyl) ethyl] -4-methylvaleryl] 4-piperidinol (diastereoisomer 1) as a white solid; nmr (MeOD): 4.16-3.91 (m, 2H); 3.84-3.73 (m, 1H); 3.43-2.97 (m, 7H); 2.56-2.45 (m, 1H); 2.27-2.18 (m, 2H); 1.96-1.70 (m, 4H); 1.61-1.19 (m, 4H); 1.11-1.01 (m, 1H); 0.840.72 (m, 6H); MS: 370 (M + H) < + >.
Primer 42Example 42
Na analogen način, kot smo opisali v prvem odstavku pri Primeru 13, smo iz 0.16 g 1[2(R)-[1(R ali S)-(benziloksikarbamoil)-2-(2,5-diokso-1 -pirolidinil)etil]-4-metilvaleril]4-piperidinola (diastereoizomer 1), pripravljenega na analogen način, kot je opisano v Primeru 14 (i)-(ii), dobili 0.048 g 1 -[2(R)-[ 1 (R ali S)-(hidroksikarbamoil)-2-(2,5-dioksol-pirolidinil)etil]-4-metilvaleril]4-piperidinola (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 4.25-4.01 (m,2H); 3.94-3.80 (m,IH); 3.78-3.63 (m,IH); 3.52-3.02 (m,4H); 2.82-2.73 (m,IH); 2.63 (d,4H,J=6); 2.04-1.76 (m,2H); 1.64-1.27 (m,4H); 1.181.09 (m,IH); 0.92-0.80 (m,6H); MS: 384 (M + H) + .In the analogous manner as described in the first paragraph of Example 13, 0.16 g of 1 [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (2,5-dioxo-1-pyrrolidinyl) is obtained ethyl] -4-methylvaleryl] 4-piperidinol (diastereoisomer 1) prepared in an analogous manner as described in Example 14 (i) - (ii) gave 0.048 g of 1- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (2,5-dioxol-pyrrolidinyl) ethyl] -4-methylvaleryl] 4-piperidinol (diastereoisomer 1) as a white solid; nmr (MeOD): 4.25-4.01 (m, 2H); 3.94-3.80 (m, 1H); 3.78-3.63 (m, 1H); 3.52-3.02 (m, 4H); 2.82-2.73 (m, 1H); 2.63 (d, 4H, J = 6); 2.04-1.76 (m, 2H); 1.64-1.27 (m, 4H); 1.181.09 (m, 1H); 0.92-0.80 (m, 6H); MS: 384 (M + H) < + >.
Primer 43Example 43
Na analogen način, kot smo opisali v prvem odstavku pri Primeru 13, smo iz 0.43 g 1[2(R)-[ 1 (R ali S)-(benziloksikarbamoil)-2-(3-metil-2,5-diokso-l-imidazolidinil)etil]-4metilvaleril]4-piperidinola (diastereoizomer 1), pripravljenega na analogen način, kot je opisano v Primeru 14 (i)-(ii), dobili 0.158 g 1 -[2(R)-[ 1 (R ali S)-(hidroksi-karbamoil)36In an analogous manner as described in the first paragraph of Example 13, 0.43 g of 1 [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (3-methyl-2,5-dioxo) is obtained. 1-imidazolidinyl) ethyl] -4methylvaleryl] 4-piperidinol (diastereoisomer 1) prepared in an analogous manner as described in Example 14 (i) - (ii) gave 0.158 g of 1 - [2 (R) - [1 ( R or S) - (hydroxycarbamoyl) 36
2-(3-metil-2,5-dikso- l-imidazolidinil)etil]-4-metilvaleril]-4-piperidinola (diastereoizomer 1) v obliki bele trdne snovi; nmr (MeOD): 4.25-3.97(m,2H); 3.93-3.79 (m,2H); 3.74-3.61 (m,IH); 3.52-2.97 (m,4H); 2.93-2.80 (m,4H); 2.02-1.76 (m,2H); 1.67-1.27 (m,4H); 1.19-1.10 (m,IH); 0.91-0.80 (m,6H); MS: 399 (M + H)+.2- (3-methyl-2,5-dixo-1-imidazolidinyl) ethyl] -4-methylvaleryl] -4-piperidinol (diastereoisomer 1) as a white solid; nmr (MeOD): 4.25-3.97 (m, 2H); 3.93-3.79 (m, 2H); 3.74-3.61 (m, 1H); 3.52-2.97 (m, 4H); 2.93-2.80 (m, 4H); 2.02-1.76 (m, 2H); 1.67-1.27 (m, 4H); 1.19-1.10 (m, 1H); 0.91-0.80 (m, 6H); MS: 399 (M + H) < + >.
Naslednja Primera pojasnjujeta farmacevtske pripravke, ki vsebujejo derivate hidroksamske kisline, kijih nudi predloženi izum.The following Examples illustrate pharmaceutical compositions containing hydroxamic acid derivatives of the present invention.
Primer AExample A
Tablete, ki vsebujejo naslednje sestavine, lahko pripravimo na običajen način:Tablets containing the following ingredients can be prepared in the usual way:
Primer BExample B
Kapsule, ki vsebujejo naslednje sestavine, lahko pripravimo na običajen način:Capsules containing the following ingredients can be prepared in the usual way:
Sestavina Na kapsuloIngredient Per capsule
Derivat hidroksamske kisline 10.0 mgHydroxamic acid derivative 10.0 mg
Laktoza 165.0 mgLactose 165.0 mg
Koruzni škrob 20.0 mgCorn starch 20.0 mg
Smukec 5.0 mgTalc 5.0 mg
Masa polnitve kapsule 200.0 mgCapsule fill weight 200.0 mg
Za :For:
Claims (27)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB929212421A GB9212421D0 (en) | 1992-06-11 | 1992-06-11 | Hydroxamic acid derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
SI9300289A true SI9300289A (en) | 1993-12-31 |
Family
ID=10716942
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
SI9300289A SI9300289A (en) | 1992-06-11 | 1993-05-28 | Hydroxamic acid derivatives |
Country Status (11)
Country | Link |
---|---|
KR (1) | KR940005571A (en) |
GB (2) | GB9212421D0 (en) |
HR (1) | HRP930978A2 (en) |
MX (1) | MX9303391A (en) |
PL (1) | PL299261A1 (en) |
RO (1) | RO112613B1 (en) |
SI (1) | SI9300289A (en) |
TW (1) | TW237444B (en) |
UY (1) | UY23599A1 (en) |
YU (1) | YU39593A (en) |
ZA (1) | ZA933957B (en) |
-
1992
- 1992-06-11 GB GB929212421A patent/GB9212421D0/en active Pending
-
1993
- 1993-03-19 GB GB939305720A patent/GB9305720D0/en active Pending
- 1993-05-15 TW TW082103831A patent/TW237444B/zh active
- 1993-05-28 SI SI9300289A patent/SI9300289A/en unknown
- 1993-06-04 ZA ZA933957A patent/ZA933957B/en unknown
- 1993-06-04 RO RO93-00777A patent/RO112613B1/en unknown
- 1993-06-04 YU YU39593A patent/YU39593A/en unknown
- 1993-06-07 MX MX9303391A patent/MX9303391A/en unknown
- 1993-06-09 PL PL29926193A patent/PL299261A1/en unknown
- 1993-06-10 HR HR9212421.3A patent/HRP930978A2/en not_active Application Discontinuation
- 1993-06-10 UY UY23599A patent/UY23599A1/en unknown
- 1993-06-10 KR KR1019930010559A patent/KR940005571A/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
YU39593A (en) | 1997-08-22 |
HRP930978A2 (en) | 1997-04-30 |
RO112613B1 (en) | 1997-11-28 |
MX9303391A (en) | 1994-06-30 |
ZA933957B (en) | 1993-12-13 |
GB9212421D0 (en) | 1992-07-22 |
GB9305720D0 (en) | 1993-05-05 |
UY23599A1 (en) | 1993-12-01 |
TW237444B (en) | 1995-01-01 |
KR940005571A (en) | 1994-03-21 |
PL299261A1 (en) | 1994-01-10 |
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