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SI9720025A - Spojine in sestavki za prenos aktivne snovi - Google Patents

Spojine in sestavki za prenos aktivne snovi Download PDF

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Publication number
SI9720025A
SI9720025A SI9720025A SI9720025A SI9720025A SI 9720025 A SI9720025 A SI 9720025A SI 9720025 A SI9720025 A SI 9720025A SI 9720025 A SI9720025 A SI 9720025A SI 9720025 A SI9720025 A SI 9720025A
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SI
Slovenia
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compound
och3
group
carrier
composition according
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SI9720025A
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English (en)
Inventor
Andrea Leone-Bay
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Emishphere Technologies, Inc.
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Publication of SI9720025A publication Critical patent/SI9720025A/sl

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/23—Calcitonins
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/27—Growth hormone [GH], i.e. somatotropin
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    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
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    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
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    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/541—Organic ions forming an ion pair complex with the pharmacologically or therapeutically active agent
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
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    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
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Abstract

Izum zagotavlja modificirane spojine amino kislin, ki so uporabne pri prenosu aktivnih snovi, kot tudi metode administracije in priprave.ŕ

Description

SPOJINE IN SESTAVKI ZA PRENOS AKTIVNE SNOVI
PODROČJE IZUMA
Ta izum se nanaša na spojine za prenašanje aktivnih snovi in predvsem biološko ali kemijsko aktivnih snovi, kot so na primer bioaktivni peptidi in podobno. Te spojine uporabljamo kot nosilce za olajševanje prenosa tovora do cilja. Nosilci so modificirane aminokisline, prilagojene tako, da tvorijo nekovalentne zmesi, oziroma sestavke, z biološko aktivnimi snovmi, za oralno aplikacijo živalim. Prav tako so tu vključene metode za pripravo in aplikacijo takšnih zmesi.
OZADJE IZUMA
Običajne metode za prenos aktivnih snovi največkrat zelo omejujejo različne biološke, kemijske in fizikalne ovire. Te zapreke se ponavadi pojavijo zaradi okolja, v katerem se prenos pojavi, zaradi okolja cilja prenosa ali zaradi cilja samega.
Posebej občutljive za takšne vrste preprek so biološko in kemijsko aktivne snovi. Na primer pri prenosu farmakološko in terapevtsko aktivnih snovi v živalsko telo, prepreke postavlja oz. predstavlja telo. Primeri fizikalnih ovir, ki jih je treba preiti preden se doseže cilj, so koža ter membrane različnih organov. Kemijske prepreke vključujejo, vendar se nanje ne omejujejo, spremembe pH, lipidne dvoplasti in encime za razgradnjo.
Te ovire imajo še poseben pomen pri razvijanju oralnih sistemov za prenos aktivnih snovi. Za aplikacijo mnogih biološko ali kemijsko aktivnih snovi živalim, pogosto izberemo oralno pot, če ne, zaradi bioliških, kemijskih in fizikalnih ovir, kot so spremembe pH v gastrointestinalnem (Gl) traktu, močni razgradni encimi in za aktivne snovi neprepustne gastrointestinalne membrane. Med številnimi aktivnimi snovmi, ki niso posebej primerne za oralno aplikacijo, so biološko ali kemijsko učinkoviti peptidi, kot sta kalcitonin in insulin; polisaharidi in še posebej mukopolisaharidi, vključujoč heparin (vendar se ne omejujejo nanj); heparinoidi; antibiotiki in ostale organske substance. Te aktivne snovi se hitro spremenijo v neaktivno obliko ali se gastrointestinalnem traktu uničijo s kislinsko hidrolizo, encimi ali podobno.
Zgodnejše metode za oralno aplikacijo občutljivih farmakoloških snovi so temeljile na sočasni aplikaciji adjuvansev (npr. rezorcinolov in neionskih površinsko aktivnih snovi, kot je polioksietilen oleil eter in n-heksadecilpolietilen eter), ki umetno povečujejo prepustnost intestinalnih sten ter sočasni aplikaciji inhibitorjev encimov (npr. inhibitorji tripsina nadledvične žleze, diizopropilfluorofosfat (DFF) in trazilol), ki zavirajo encimsko razgradnjo.
Liposomi so bili že opisani kot sistemi za prenos aktivnih učinkovin za insulin in heparin. Glej na primer U.S.Patent št. 4,239,754; Patel in ostali (1976), FEBS Letters, Vol.62, str. 60; in Hashimoto in ostali (1979), Endocrinology Japan, Vol.26, str. 337.
Kakorkoli že, pa je širok spekter uporabe takšnih sistemov za prenos aktivne snovi izključen, zaradi sledečih vzrokov: (1) sistem potrebuje toksične količine adjuvansev ali inhibitorjev; (2) primerne nizko- molekularne aktivne snovi so nedosegljive; (3) sistem ima slabo stabilnost in neustrezno življenjsko dobo; (4) sistem je težko proizvesti;
(5) sistem ne zaščiti aktivne učinkovine (tovora); (6) sistem neugodno spreminja aktivno snov; (7) sistem ne dovoli ali ne pomaga pri absorpciji aktivne snovi.
V novejšem času se za prenos farmacevtskih učinkovin uporabljajo mikrosfere umetnih polimerov mešanih aminokislin (proteinoidi). Na primer, U.S.Patent št. 4,925,673 opisuje proteinoidne mikrosferne nosilce, ki vsebujejo zdravilne učinkovine ter tudi metode za njihovo pripravo in uporabo.
Te proteinoidne mikrosfere so uporabne za prenos številnih aktivnih učinkovin.
Vendar v stroki ostaja potreba po sistemih za prenos, ki so preprosti, poceni, se jih da lahko pripraviti in lahko prenašajo veliko različnih aktivnih učinkovin.
POVZETEK IZUMA
Izum zagotavlja zmesi, ki so uporabne pri prenosu aktivnih snovi. Te zmesi vključujejo vsaj eno aktivno snov, biološko ali kemijsko aktivno snov in vsaj eno izmed spojin I-CXXIII ali njeno sol.
II
III
ο
Cl
XII
XIII
XIV
XV
XVI
XVII
XVIII
XIX
XX
HO ο
H
N
XXI
XXII
XXIII
XXIV
XXV
XXVI
O
O
OH
O
XXVII
HO
I
XXVIII ο
ο
OH
HO
XXIX
XXX
XXXI
XXXII
XXXIII
XXXIV
N
H
XXXV
HO
NHSO2Ph
XXXVI
Spojina
XXXVII
XXXVIII
XXXIX
XL
XLI
XLII
XLIII
XLIV
XLV
XLVI
XLVII
XLVIII
XLIX
L
LI
Lil
LIH
LIV
LV
LVI
LVII
LVI II
LIX
LX
LXI
LXII
LXIII
LXIV
LXV n
m o
o o
o
X
4-C1
H
4-CH3
2-F
2- CH3
3- CF3
H
3-C1
3-F
3- CH3
2-CF3
H
2-F
3.4- OCH2O2-COOH 2-OH
2,6-dihidroksi
2- OH
2.4- difluoro
2.6- dihidroksi
4- CF3
3- NMe2
3- NMe2
2.6- dimetil 2-NO2 2-CF3
4- n-Pr 2-NH2 2-OCH3
LXVI 3 O 3-NO2
LXVII 3 O 3-NH2
LXVIII 2 O 2-NO2
LXIX 2 O 2-NH2
LXX 3 O 2-OCF3
LXXI 2 O 2-OCH3
LXXII 2 O 2~OCF3
Spojina n X
LXXIII 3 4-CF3
LXXIV 1 2-F
LXXV 1 4-CF3
LXXVI 3 3,4-dimetoksi
LXXVII 0 3-OCH3
LXXVIII 3 3-OCH3
LXXIX 3 2,6-difluoro
LXXX 3 4-CH3
LXXXI 1 4-OCH3
LXXXII 2 2-F
LXXXIII 0 2-F
LXXXIV 2 4-OCH3
LXXXV 0 2-OCH3
LXXXVI 2 2-OCH3
LXXXVII 0 4-CF3
LXXXVIII 3 3-F
LXXXIX 3 2-OCH3
ίο
o mX
Spojina n
XC 3
XCI 3
XCII 3
XCIII 3 m
X
2-karboksi-cikloheksil cikloheksil
2-adamantil
1-morfolino
Spojina m
XCIV o
XCV 3
Spojina X
XCVI OH
XCVII =0
Spojina n
XCVIII o
XCIX 2 c
E-513
Cl
E-516
CII
E-534
CIII
E-515
CIV
E-463
HO cv
E-592
CVI
E-595
CVII
E-555
CVIII
E-561
CIX
E-583
CX
Spojina n m X
CXI 6 0 2-OH
CXII 7 3 H
CXIII 7 0 2-1
CXIV 7 0 2-Br
cxv 7 0 3-NO2
CXVI 7 0 3-N(CH3)2
CXVII 7 0 2-NO2
CXVIII 7 0 4-NO2
CXIX 9 0 2-OH
ho 0 H 0
Spojina X
cxx 1-morfolino
CXXI O-t-butil
CXXII CH (CH2Ph) NC (0) O-t-Bu
CXXIII 2-hidroksifenil
Odkrili so, da so spojine organskih kislin ter njihove soli, ki imajo aromatsko amidno skupino, hidroksi skupino substituirano na orto mestu na aromatskem obroču in lipofilno verigo z 4 do 20 ogljikovimi atomi v verigi, uporabni nosilci za prenos aktivnih snovi. Najbolje je, če lipofilna veriga vsebuje od 5 do 20 ogljikovih atomov.
Zmesi, ki vsebujejo zgoraj omenjene nosilne spojine in aktivne snovi so pokazale kot učinkovite pri prenosu aktivnih snovi v izbrane biološke sisteme. Te spojine vključujejo vsaj eno aktivno snov, ki je biološko ali kemijsko aktivna snov in vsaj en nosilec s formulo
2-HO-Ar-CONR8-R7-COOH kjer je Ar substituiran ali nesubstituiran fenil ali naftil;
R7 je izbran iz skupine, ki jo sestavlja C4 do C20 alkil,
C4 do C2o alkenil, fenil, naftil, (Ci do Cio alkil) fenil, (Ci do Cio alkenil) fenil, (Ci do Cio alkil) naftil, (Ci do Cio alkenil) naftil, fenil (Ci do Cio alkil), fenil (Ci do Cio alkenil), naftil (Ci do Cio alkil) in naftil (Ci do CXo alkenil) ;
R8 je izbran iz skupine, ki jo sestavljajo vodik, Cx do C4 alkil, Ci do C4 alkenil, hidroksi in Cx do C4 alkoksi;
R7 je opcionalno substituiran z Cx do C4 alkil, Cx do C4 alkenil, Cx do C4 alkoksi, -OH, -SH in -CO2R9 ali njihovo kombinacijo;
R9 je vodik, Cx do C4 alkil ali Cx do C4 alkenil;
R7 je lahko prekinjen s kisikom, dušikom, žveplom ali njihovo kombinacijo;
s pogojem, da spojine niso substituirane z amino skupino na mestu alfa glede na kislinsko skupino, ali njihove soli.
Prednostne R7 skupine so C4 do C2o alkil in C4 do C2o alkenil. Najboljše R7 skupine pa so C5 do C2o alkil in C5 do C20 alkenil.
Prednostna nosilna spojina ima lahko naslednjo formulo
/COOH
R.
'7
OH 0 kjer je R7 definiran zgoraj.
Nadalje ta izum vključuje oblike dozirnih enot, ki vsebujejo te zmesi.
Prav tako vključuje tudi metode za pripravo teh zmesi, ki so sestavljene iz mešanja vsaj ene aktivne snovi z vsaj eno spojino, kot je opisano zgoraj ter neobvezno tudi dozirno sredstvo.
Alternativno lahko te netoksične spojine oralno apliciramo živalim, kot del sistema za prenašanje aktivne snovi, z mešanjem ali spajanjem snovi z aktivno učinkovino pred aplikacijo.
Nadalje je zagotovljena metoda za pripravo spojine s formulo
II
HO—C—Rl— N-Y-R3 I
CXXIV R2 kjer je Y C=0 ali S02;
R1 je C3-C24 alkil, C2-C2o alkenil, C2-C2o alkin, cikloalkil ali aromat;
R2 je vodik, Ci~C4 alkil ali C2-C4 alkenil; in
R3 je C1-C7 alkil, C3-C10 cikloalkil, aril, tienil, pirolo ali piridil, kjer je R3 opcionalno substituiran z eno ali več C1-C5 alkilnimi skupinami, C2-C4 alkenilnimi skupinami, F, CI, OH, S02, COOH ali SO3H;
omenjena metoda je sestavljena iz sledečih korakov:
(a) reagiranje v vodi v prisotnosti baze, spojine s formulo cxxv
N-R!
R2 s snovjo s formulo R3-Y-X, kjer so Y, R1, R2 in R3 opisani zgoraj, X pa je izstopajoča skupina.
KRATEK OPIS SLIK
Slika 1 prikazuje rezultate subkutanega injiciranja rhGH (op.p. rekombinanten človeški rastni hormon) spojin pri podganah.
Slika 2 je grafični prikaz rezultatov sublingualnega (SL,op.p. pod jezik), intranasalnega (IN, op.p. v nos) in intrakolonalnega (IC, op.p. v črevo) doziranja rhGH pri podganah.
Slika 3 je grafični prikaz rezultatov prenosa heparina s spojino XXXI kot nosilcem pri intrakolonalnem doziranju.
PODROBEN OPIS IZUMA
Specifične zmesi tega izuma vključujejo aktivno snov in modificirano aminokislino. Te spojine lahko uporabljamo za prenos različnih aktivnih snovi prek različnih bioloških, kemijskih in fizikalnih ovir. Posebej primerne so za prenos aktivnih snovi, ki so izpostavljene razgradnji v določenem okolju. Zmesi tega izuma so še posebno uporabne za prenos ali aplikacijo biološko ali kemijsko učinkovitih aktivnih snovi katerimkoli živalim, kot so ptice; sesalcem, kot so primati in še posebej ljudje; ter insektom.
Ostale prednosti tega izuma vključujejo tudi uporabo surovin, ki se lahko pripravijo in so poceni. Zmesi tega izuma in metode za njihovo pripravo so cenovno sprejemljive, nezapletene glede na izvedbo in primerne za industrijsko komercialno proizvodnjo.
Tu opisane subkutane, sublingualne in intranasalne sočasne aplikacije aktivne učinkovine, kot je rekombinanten človeški rastni hormon (rhGH) in snovi za prenos, še posebej proteini, povečujejo biološko dosegljivost aktivne snovi v primerjavi z aplikacijo same aktivne snovi. Podobne rezultate dobimo s sočasno aplikacijo lososovega kalcitonina z nosilci pri podganah. Podatki, ki podpirajo te trditve so predstavljeni v primerih.
AKTIVNE SNOVI
Aktivne snovi primerne za uporabo v tem izumu vključujejo biološko in kemijsko aktivne snovi, kamor spadajo tudi dišave, kot tudi ostale aktivne snovi, kot je na primer kozmetika, vendar se nanje ne omejuje.
Biološko in kemijsko aktivne snovi vključujejo pesticide, farmakološko aktivne snovi in terapevtske učinkovine, vendar se nanje ne omejujejo. Na primer, biološko in kemijsko aktivne snovi primerne za uporabo v tem izumu vključujejo, vendar se nanje ne omejujejo, peptide, še posebej majhne peptide; hormone, posebno hormone, ki sami po sebi ne prehajajo ali pa le del aplicirane doze prehaja skozi gastrointestinalno sluz in/ali so občutljive na kemijske cepitve s kislinami in encimi v gastrointestinalnem traktu; polisaharidi, posebno zmesi mukopolisaharidov; ogljikovi hidrati; lipidi; ali njihova kombinacija. Nadaljni primeri vključujejo, vendar se ne omejujejo nanje, človeški rastni hormon; volovski rastni hormon; sproščujoči rastni hormon; interferone; interleukin-1; insulin; heparin, posebno nizkomolekularni heparin; kalcitonin; eritro-poetin; atrialni naturetični faktor; antigene; monoklonalna protitelesa; somatostatin; adrenokortikotropin, gonadotropni sproščujoči hormon; oksitocin; vazopresin; kromolin natrij (natrijev ali dinatrijev kromoglikat); vankomicin;
desferioksamin (DFO); obščitnični hormon nemikrobne aktivne snovi, vključujoč negljivične aktivne snovi; ali kakršnakoli kombinacija zgoraj naštetih snovi.
MODIFICIRANE AMINOKISLINE
Izrazi modificirane aminokisline, modificirane poliaminokisline in modificirani peptidi vključujejo aminokisline, ki so bile modificirane, ali poliaminokisline in peptide pri katerih je bila vsaj ena aminokislina modificirana z aciliranjem ali sulfoniranjem vsaj ene proste amino skupine z acilirnim ali sulfonirnim sredstvom, ki reagira z vsaj eno izmed prisotnih prostih amino skupin.
Aminokisline, poliaminokisline in peptide lahko v modificirani obliki uporabimo za prenos aktivnih snovi, ki vključujejo, vendar se nanje ne omejujejo, biološko in kemijsko aktivne snovi, kot so na primer farmakološke in terapevtske učinkovine.
Aminokislina je katerakoli karboksilna kislina, ki ima vsaj eno prosto amino skupino in vključuje tako naravne kot sintetične aminokisline.
Poliaminokisline so lahko ali peptidi ali pa dve ali več aminokislin povezanih z vezjo, ki jih tvorijo druge skupine, ki se lahko povezujejo, npr. ester, anhidrid ali anhidridna vez.
Peptidi sta dve ali več aminokislin povezanih s peptidno vezjo. Peptidi varirajo po dolžini, od dipeptidov z dvema aminokislinama do polipeptidov z nekaj sto aminokislinami. Glej Chambers Biological Dictionary, editor Peter M.B.Walker, Cambridge, England: Chambers Cambridge, 1989, str. 215. Posebej omenjeni so dipeptidi, tripeptidi, tetrapeptidi in pentapeptidi.
Čeprav zgoraj naštete spojine I-CXXIII učinkujejo kot prenašalci pri oralni aplikaciji biološko in kemijsko aktivnih snovi, je potrebno posebej izpostaviti spojine IXXXI.
Modificirane aminokisline pripravimo z modificiranjem aminokisline ali njenega estra. Večino izmed teh spojin pripravimo z aciliranjem ali sulfoniranjem s snovmi, ki imajo sledečo formulo:
Χ-ϊ-R4 kjer je R4 primeren radikal za modifikacijo na končnem produktu, Y je C=0 ali S02, X je izstopajoča skupina.
Tipične izstopajoče skupine so halogeni, kot na primer klor, brom ali jod, vendar se nanje ne omejujejo. Snovi za modificiranje so lahko ustrezni anhidridi.
Veliko spojin tega izuma lahko brez težav pripravimo iz aminokislin, po metodah, ki so znane v stroki in v skladu z že prej opisanim. Na primer: spojine I-VII pripravimo iz aminobutanojske kisline; spojine VIII-X in XXXII-XXXV dobimo iz aminoheksanojske kisline; spojine XI-XXVI in XXXVI pridobimo iz aminokaprilne kisline. Zgoraj omenjene aminokislinske spojine lahko pripravimo na primer z reagiranjem ene aminokisline s primernim reagentom za modificiranje, ki reagira z prostim aminskim deležem v aminokislini ter tako tvori amide. Kot je v stroki poznano lahko uporabimo tudi zaščitne skupine, da se tako izognemo nezaželenim stranskim reakcijam.
Aminokislino lahko raztopimo v vodni alkalijski raztopini kovinskega hidroksida, npr. natrijevega ali kalijevega hidroksida, in segrevamo pri temperaturi med 5°C in 70°C, najbolje med 10 in 40°C, 1 do 4 ure, najbolje okrog dve uri in pol. Količina alkalije na ekvivalent NH2 skupine se giblje med 1.25 in 3 mmoli, najbolje med 1.5 in 2.25 mmoli na ekvivalent NH2. Običajen pH raztopine je med 8 in 13, najbolje je, če je med 10 in 12.
Med mešanjem aminokislinske raztopine dodamo primeren reagent za modificiranje amino skupine. Temperaturo zmesi običajno vzdržujemo 1 do 4 ure med 5°C in 70°C, najbolje med 10 in 40°C. Količina dodanega reagenta za modificiranje je povezana s količino aminokisline in sicer temiji na molih skupnih prostih NH2 skupin v aminokislini. Običajna količina reagenta za modificiranje je med 0.5 in 2.5 moli ekvivalenta, najbolje med 0.75 in 1.25 moli na ekvivalent skupnih NH2 skupin v aminokislini.
Reakcijo zadušimo s prilagajanjem pH zmesi s primerno kislino, npr. koncentrirano klorovodikovo kislino, dokler ne dosežemo pH med 2 in 3. Zmes ločimo tako, da jo pustimo stati na sobni temperaturi, da tvori transparentno zgornjo plast in belo ali umazano belo oborino. Zgornjo plast zavržemo, modificirane aminokisline pa zberemo s filtracijo ali dekantiranjem iz spodnje plasti. Surove modificirane aminokisline nato raztopimo v vodi pri pH med 9 in 13 ali bolje med 11 in 13. Netopne snovi odstranimo s filtriranjem in filtrat vakuumsko osušimo. Tako dobimo med 30 in 60% izkoristek modificiranih aminokislin, običajno okrog 45%.
Če želimo lahko za pripravo modificiranih aminokislin tega izuma uporabimo aminokislinske estre, kot so na primer benzil, metil ali etil ester aminokislinske spojine. Aminokislinski ester, raztopljen v primernem organskem topilu, kot je dimetilformamid, piridin ali tetrahidrofuran, reagiramo s primernim reagentom za modifikacijo, 7 do 24 ur, pri temperaturi med 5 in 70°C, najbolje okrog 25°C. Količina dodanega reagenta za modificiranje je povezana s količino aminokislinskega estra in je enaka, kot zgoraj za aminokisline. To reakcijo lahko izvedemo z ali brez baze, kot sta na primer trietilamin ali diizopropiletilamin.
Reakcijsko topilo odstranimo pod znižanim tlakom. Estre odstranimo s hidrolizo modificiranih aminokislinskih estrov s primerno alkalijsko raztopino, npr. 1 N natrijevim hidroksidom, pri temperaturi med 50 in 80°C , najbolje okrog 70°C, v času, ki je primeren za hidrolizo estrske skupine in tvorbo modificiranih aminokislin s prosto karboksilno skupino. Hidrolizno zmes nato ohladimo na sobno temperaturo in nakisamo, npr. z 25% vodno raztopino HCI, do pH med 2 in 2.5. Modificirane aminokisline nato oborimo ter filtriramo ali dekantiramo. Benzil estre lahko odstranimo s hidrogeniranjem v organskem topilu z uporabo kovinskega katalizatorj a.
Modificirane aminokisline lahko očistimo z rekristalizacijo ali frakcioniranjem na trdnih kolonskih nosilcih. Primerna topila za rekristalizacijo vključujejo acetonitril, metanol in tetrahidrofuran. Frakcioniranje lahko izvršimo na primernih kolonskih nosilcih, kot je aluminij, z uporabo zmesi metanol/n-propanol kot mobilne faze, pri kolonskih nosilcih z reverzno fazo kot mobilno fazo uporabimo zmes trifluoroocetno kislino/acetonitril; pri ionsko izmenjevalni kromatografiji pa je mobilna faza voda. Če izvajamo ionsko-izmenjevalno kromatografijo, je potreben 0.500 mM gradient natrijevega klorida.
Po alternativni metodi imajo modificirane aminokisline formulo
O
II
HO—C—RI—N-Y-R3 I
CXXIV R2 kjer je Y C=O ali SO2;
R1 je C3-C24 alkil, C2-C2o alkenil, C2-C20 alkin, cikloalkil ali aromat;
R2 je vodik, Ci~C4 alkil ali C2-C4 alkenil; in
R3 je C1-C7 alkil, C3-C10 cikloalkil, aril, tienil, pirolo ali piridil, kjer je R3 opcionalno substituiran z eno ali več C1-C5 alkilnimi skupinami, C2-C4 alkenilnimi skupinami,
F, Cl, OH, SO2, COOH ali SO3H;
lahko jih pripravimo po sledečih korakih:
(a) reagiranje v vodi v prisotnosti baze, spojine s formulo
Ο cxxv
N-Ri r2 s snovjo s formulo R3-Y-X, kjer so Y, R1, R2 in R3 opisani zgoraj, X pa je izstopajoča skupina.
Spojino CXXV lahko pripravimo na primer po metodi opisani v Olah in ostali, Synthesis, 537-538 (1979).
Spojino XXXI pripravimo kot je prikazano na shemi I, iz 10-undeken-l-ola, (1), v treh korakih in z 31% izkoristkom. Alkilaciji ftalimida z alkanolom, (1), pod Mitsunobu pogoji, sledi reakcija s hidrazinom in dobimo l-aminoundeka-10-en, (2), s 66% izkoristkom. Amin dobimo z O-acetilsaliciloil kloridom in dobljen alken, (3), oksidiramo do kisline z uporabo kalijevega permanganata. Odstranitvi acetata sledi obarjanje kisline in tako dobimo spojino XXXI s 47% izkoristkom glede na amin (2).
SHEMA 1 (1) PPh3, DEAD,
ΧΧΧΧΙ
SISTEMI ZA PRENOS
Zmesi tega izuma lahko vključujejo eno ali več aktivnih snovi.
Spojine I-CXXIII ali poliaminokisline ali peptide, ki vključujejo vsaj eno izmed teh spojin, lahko uporabimo direktno kot nosilec, tako da pred aplikacijo preprosto zmešamo eno ali več spojin, poliaminokisline ali peptide z aktivno snovjo.
Alternativno pa lahko te spojine, poliaminokisline ali peptide uporabimo za tvorbo mikrosfer, ki vsebujejo aktivno snov. Te spojine, poliaminokisline in peptidi so še posebej uporabni pri oralni aplikaciji določenih biološko aktivnih snovi, npr. majhnih peptidnih hormonov, ki sami po sebi ne prehajajo skozi gastrointestinalno sluz in/ali so dovzetni za kemijske cepitve s kislinami in encimi v gastrointestinalnem traktu.
Če modificirane aminokisline, poliaminokisline ali peptide uporabimo za tvorbo mikrosfer, zmes lahko segrejemo do 20 ali 50°C, najbolje okrog 40°C, dokler se modificirane aminokisline ne raztopijo. Končna raztopina vsebuje od 1 mg do 2000 mg spojine, poliaminokisline ali peptida na mL raztopine, najbolje med 1 in 500 mg/mL. Koncentracija aktivne snovi v končni raztopini se spreminja in je odvisna od doze, ki je potrebna za zdravljenje. Ko je potrebno lahko točne koncentracije določimo na primer s HPLC z reverznimi fazami.
Če uporabimo spojine, poliaminokisline ali peptide za pripravo mikrosfer lahko uporabimo še en postopek: spojine, poliaminokisline ali peptide raztopimo v deionizirani vodi, pri koncentraciji med 75 in 200 mg/mL, najbolje okrog 100 mg/mL in temperaturi med 25°C in 60°C, najbolje okrog 40°C. Drobce, ki ostanejo v raztopini odstranimo z običajnimi metodami, kot je na primer filtracija.
Nato raztopino spojin, poliaminokislin ali peptidov vzdržujemo pri temperaturi okrog 40°C, zmešamo v razmerju 1:1 (v/v) z vodno raztopino kisline (tudi okrog 40°C), katere koncentracija je med 0.05 in 2 N, najbolje okrog 1.7
N. Dobljeno zmes nadalje inkubiramo pri 40°C, toliko časa, kot je potrebnega za učinkovito tvorbo mikrosfer, kar opazujemo z mikroskopom. V praksi je najbolje, če najprej dodamo raztopino spojine, poliaminokisline ali peptida k razredčeni raztopini kisline.
Primerne kisline za tvorbo mikrosfer vključujejo katerekoli kisline, ki:
(a) ne vplivajo neugodno na modificirane aminokisline, poliaminokisline ali peptide; to je da ne pričnejo ali pospešujejo njihove razgradnje;
(b) se ne vmešavajo v tvorbo mikrosfer;
(c) se ne vmešavajo vključevanje aktivne snovi v mikrosfere; in (d) ne reagirajo z aktivno snovjo.
Prednostne kisline za uporabo s tega vidika so ocetna kislina, citronska kislina, klorovodikova kislina, fosforna kislina, butandiojska kislina in 2-hidroksi butandiojska kislina.
V razredčeno raztopino kisline, v spojino ali v raztopino aktivne snovi lahko pred procesom tvorbe mikrosfer vključimo tudi aditiv, ki stabilizira mikrosfere. Z nekaterimi aktivnimi snovmi, prisotnost takšnih aditivov izboljšuje stabilnost in/ali disperzibilnost mikrosfer v raztopini.
Aditive za stabilizacijo lahko dodamo v koncentaciji med
O. 1 in 5% (w/v) (weight/volume - teža/volumen; Op. prev.), najbolje okrog 0.5% (w/v). Primeri aditivov, ki stabilizirajo mikrosfere vključujejo akacijev gumij, želatino, metilcelulozo, polietilen glikol, polipropilen glikol, karboksilne kisline ter njihove soli in polilizin, vendar se nanje ne omejujejo. Najboljši aditivi za stabilizacijo so akacijeva guma, želatina in metil celuloza.
Pod zgornjimi pogoji molekule spojin, poliaminokislin ali peptidov tvorijo votle ali trdne matrične mikrosfere, kjer je tovor razporejen v nosilnih matričnih ali kapsulnih mikrosferah, ki vsebujejo tekočino ali trden tovor. Če mikrosfere tvorimo v prisotnosti topne snovi, npr. farmacevtska učinkovina, v zgoraj omenjeni raztopini kisline, bo ta snov zajeta v notranjosti mikrosfer. Na ta način lahko zajamemo farmakološko aktivne snovi, kot so peptidi, proteini in polisaharidi, kot tudi nabite organske molekule, npr. antimikrobne snovi, ki so običajno po oralni poti slabo biološko dosegljive. Količina farmakološke snovi, ki jo lahko vključimo v mikrosfere je odvisna od številnih faktorjev, ki vključujejo koncentracijo snovi v raztopini, kot tudi afiniteto tovora do nosilca. Mikrosfere spojin, poliaminokislin ali peptidov ne spreminjajo fizioloških in bioloških lastnosti aktivne snovi. Prav tako tudi proces zajemanja (enkapsulacije) ne spreminja farmakoloških lastnosti aktivne snovi. V mikrosfere lahko vgradimo katerokoli farmakološko snov. Sistem je še posebej primeren za prenos kemijsko in biološko aktivnih snovi, ki bi sicer, zaradi pogojev v telesu živali, kateri ga apliciramo, še preden dosežejo cilj (to je mesto na katerem naj bi se sprostila vsebina mikrosfer), razpadle ali bi bile manj učinkovite. Primeren je tudi za prenos farmakoloških učinkovin, ki se v gastro-intestinalnem traktu slabo absorbirajo. Ciljni predeli se lahko spreminjajo glede na to katero učinkovino uporabljamo.
Velikost delcev mikrosfer igra pomembno vlogo pri določevanju sproščanja aktivne snovi v ciljnem območju gastrointestinalnega trakta. Prednostno je premer delcev mikrosfer < 0.1 pm in okrog 10 pm, najbolje med 0.5 in 5 pm. Mikrosfere so dovolj majhne, da sproščajo aktivno snov v ciljni predel v gastro-intestinalnem traktu, kot je npr. predel med trebuhom in zgornjim delom tankega črevesa (jejunum). Majhne mikrosfere lahko prav tako apliciramo parenteralno, tako da jih suspendiramo v primerni nosilni tekočini (npr. izotonična sol) in injiciramo intramuskularno ali subkutano, direktno v cirkulatorni sistem. Način aplikacije se spreminja v odvisnosti od zahtev aktivne snovi, ki jo apliciramo. Velike aminokislinske mikrosfere (>50 pm) so manj aktivne, če jih apliciramo oralno.
Velikost mikrosfer, ki jih tvorimo s kontaktiranjem spojin, poliaminokislin ali peptidov z vodo ali vodno raztopino, ki vsebuje aktivno snov, lahko nadzorujemo s spreminjanjem različnih fizikalnih ali kemijskih parametrov, kot je pH, osmolarnost ali ionska moč zajete raztopine, velikost ionov v raztopini in tudi z izbiro kisline, ki jo bomo uporabili v procesu zajemanja.
Zmesi za aplikacijo pripravimo z mešanjem vodne raztopine nosilca z vodno raztopino aktivne spojine tik pred aplikacijo. Alternativno lahko nosilec in biološko ali kemijsko aktivno snov zmešamo med procesom tvorbe. Raztopine lahko vsebujejo tudi aditive, kot so soli fosfatnih pufrov, citronska kislina, ocetna kislina, želatina in akacijeva guma.
V raztopino nosilca lahko vključimo tudi aditive za stabilizacijo. Pri nekaterih učinkovinah, prisotnost takšnih snovi izboljšuje stabilnost in disperzibilnost učinkovine v raztopini.
Aditive za stabilizacijo lahko vključujemo v koncentracijah med 0.1 in 5% (w/v), prednostno okrog 0.5% (w/v). Primerni aditivi za stabilizacijo vključujejo akacijev gumij, želatino, metilcelulozo, polietilen glikol, karboksilne kisline ter njihove soli in polilizin, vendar se nanje ne omejujejo. Najboljši aditivi za stabilizacijo so akacijeva guma, želatina in metil celuloza.
Količina aktivne snovi, je količina, ki je dovolj visoka, da izpolni namen aplikacije določene aktivne snovi. Količina v zmesi je ponavadi biološko ali kemijsko učinkovita količina. Količina pa je lahko tudi manjša od farmakološko in biološko učinkovite količine, če zmes uporabimo v enotni dozirni obliki, kot je kapsula, tableta ali tekočina. To pa zato, ker lahko enotna doza vsebuje več zmesi nosilec/biološko ali kemijsko aktivna snov ali pa vsebuje porazdeljene farmakološko in biološko aktivne količine. Skupno učinkovite količine lahko tako apliciramo v kumulativnih enotah, ki skupno vsebujejo farmakološko ali biološko aktivne količine farmakološke ali biološke učinkovine.
Skupno količino aktivne snovi in še posebej biološke in kemijske učinkovine, ki jo uporabimo, lahko določijo strokovnjaki. Odkrili so, da prej opisani nosilci v kombinaciji z nekaterimi biološkimi in kemijskimi učinkovinami, zagotavljajo skrajno učinkovit prenos, posebej v oralnem, intranasalnem, sublingvalnem intraduodenalnem ali subkutanem sistemu. Zato lahko uporabljamo pri aplikaciji nižje količine biološke in kemijske učinkovine, kot pri prejšnjih dozirnih enotah in še vedno dosežemo enake krvne nivoje in terapevtske učinke.
Količina nosilca v prisotni zmesi je učinkovita količina po prenosu in jo lahko določimo za katerikoli določen nosilec ali biološko ali kemijsko učinkovito snov, z metodami, ki so znane v stroki.
Dozirne enote lahko prav tako vključujejo katerekoli ekscipiente; diluente; dezintegrante; lubrikante; plastifikatorje; barvila in nosilce doze, vključujoč vodo,
1,2-propan-diol, etanol, olivno olje ali kakršnokoli kombinacijo le teh, vendar se nanje ne omejujejo.
Aplikacija teh zmesi ali oblik dozirnih enot je prednostno oralna ali pa intraduodenalno injiciranje.
Zmesi za prenos tega izuma lahko prav tako vključujejo enega ali več encimskih inhibitorjev. Takšni inhibitorji vključujejo, spojine kot so aktinonin ali epiaktinonin ter njuni derivati, vendar pa z njimi niso omejeni. Te spojine imajo spodnje formule:
CXXVI
CXXVII
Derivati teh spojin so opisani v U.S.Patent št. 5,206,384. Derivati aktinonina imajo naslednjo formulo:
CXXVIII o
kjer je R5 sulfoksimetil ali karboksil ali substituirana karboksi skupina izbrana med karboksamidno, hidroksiaminokarbonilno in alkoksikarbonilno skupino; in R6 je hidroksil, alkoksi, hidroksiamino ali sulfoksiamino skupina. Ostali encimski inhibitorji vključujejo aprotinin (Trasilol) in Bowman-Birkov inhibitor.
Spojine in zmesi tega izuma so uporabne za apliciranje biološke in kemijske učinkovine katerikoli živali, kot so npr. ptice; sesalcem, kot so primati in še posebej ljudje; ter insektom. Sistem je še posebej primeren za prenos kemijsko ali biološko aktivne snovi, ki bi se sicer v telesu živali, kateri jo apliciramo, uničila ali bi bila manj učinkovita zaradi spremenjenih pogojev, še preden aktivna snov doseže ciljno območje (to je območje, kjer naj bi se aktivna snov sprostila iz zmesi za prenos). Spojine in zmesi tega izuma so še posebej učinkovite pri oralni aplikaciji aktivne učinkovine, še posebej tiste, ki običajno niso primerne za oralno aplikacijo.
OPIS PREDNOSTNIH UPODOBITEV
Sledeči primeri prikazujejo izum brez omejitev. Če ni drugače označeno, so vsi deli podani na glede na težo.
Primer 1
Spojino XIX pripravimo po sledečem postopku:
V 3 L trivratno bučko z okrogli dnom namestimo mehansko mešalo in termometer, ter jo ohladimo na ledeni kopeli. V bučko damo raztopino 8-aminokaprilne kisline (100.0 g, 0.65 molov) v 2 M vodni raztopini natrijevega hidroksida (1.4 L). Temperaturo raztopine vzdržujemo pri 5°C ter po deležih, v 7 urah, dodamo O-acetilsaliciloil klorid (198.6 g, 0.76 molov,
1.2 ekvivalenta). Zmes mešamo pri 5°C 12 ur, da dobimo rumeno homogeno raztopino. Raztopino nakisamo z 1 M klorovodikovo kislino do pH 6.8 in ekstrahiramo z etil acetatom (2 x 600 mL). pH vodne plasti ponovno nastavimo na
6.3 in naprej ekstrahiramo z etil acetatom (2 x 600 mL). Organske plasti združimo, osušimo nad natrijevim sulfatom, filtriramo in evaporiramo pod znižanim pritiskom. Ostanek ponovno raztopimo v minimalni količini 2 M vodne raztopine NaOH in pH raztopine bo med 9.5 in 10. Zmes med mešanjem nakisamo z 1 M HCI do pH 6.2. Tvori se trdna snov, ki jo odfiltriramo, speremo z vodo (3 x 300 mL) in rekristaliziramo iz 55% raztopine metanol/voda (v/v). Tako dobimo spojino XVIII v obliki umazano bele trdne snovi (99.7 g, 57%) .
Lastnosti so navedene spodaj.
Ttai 116-117°C. XH NMR (300 MHz, DMSO-d6) δ: 12.70 (lH,br s),
11.95 (lH,br s), 8.81 (lH,t), 7.82 (IH,m), 7.38 (IH, m),
6.84 (2H,m), 2.36 (2H,q), 2.18 (2H,t), 1.50 (4H,br m), 1.28 (6H,m) . Izračunani anal. podatki za C15H21NO4: C, 64.50; H, 7.58; N, 5.02. Dobljeni: C, 64.26; H, 7.81; N, 4.93.
Podobne postopke uporabimo za pripravo spojin I, II, III, IV, VI, IX, X, XI, XII, XIII, XIV, XX, XXI, XXIII, XXVII, XXVIII, XXXIII in XXXIV.
Lastnosti so navedene spodaj.
Spojina I: XH NMR (300 MHz, D2O) δ: 1.5 (2H,m), 2.0 (2H,t),
2.3 (2H,t), 7.5 (2H,t), 7.6 (IH,m), 7.3 (2H,m).
Spojina II: ΧΗ NMR (300 MHz, D20) δ: 1.4 (8H,m) , 1.7 (6H,m),
2.1 (2H,t), 1.25 (IH,m), 3.05 (2H,t).
Spojina III: XH NMR (300 MHz, DMSO-d6) δ: 0.7 (3H,m) , 0.9 (2H,m), 1.1 (3H,q), 1.6 (5H,m), 1.75 (2H,q), 2.1 (2H,t), 3.0 (2H,q), 7.9 (IH,m).
Spojina IV: izračunana anal. za C11H13NO4: C, 59.9, H, 5.87,
N,6.27; dobljeni podatki: C, 58.89, H, 5.85, N, 6.07. 1H NMR (300 MHz, DMSO-d6) δ: 1.8 (2H,m), 2.3 (2H,t), 3.1 (2H,q), 3.1 (2H,q), 6.9 (2H,t), 7.4 (lH,t), 7.8 (IH,d), 8.85 (lH,t), 12.0 (IH,s), 12.15 (IH,s).
Spojina VI: XH NMR (300 MHz, DMSO-ds) δ: 0.8 (2H,m) , 1.1 (4H,m), 1.4 (2H,q), 1.6 (7H,m), 2.15 (4H,m), 3.1 (2H,t).
Spojina IX: XH NMR (300 MHz, DMSO-d6) δ: 0.9 (3H,q), 1.2 (7H,m), 1.3 (2H,q), 1.5 (3H,q), 1.9 (2H,d), 2.0 (IH,d), 2.2 (lH,t), 3.0 (3H,q), 7.7 (IH,s).
Spojina X: XH NMR (300 MHz, DMSO-d6) δ: 0.7 (2H,d), 0.9 (lH,dd), 1.2-1.3 (7H,m), 1.5 (3H,q), 1.6-1.8 (5H,m), 2.15 (2H,t), 3.0 (3H,m), 7.5 (IH,s), 12.0 (IH,s).
Spojina XI: izračunana anal. za C15H20NO3CI: C, 60.48, H,6.78, N,4.70; dobljeni podatki: C, 60.4, H, 6.68, N, 4.53. 1H NMR (300 MHz, DMSO-de) δ: 1.28 (6H,m), 1.48 (4H,m), 2.19 (2H,t),
3.19 (2H,qt), 7.323-7.48 (4H,m), 8.39 (lH,t), 12.09 (IH,s).
Spojina XII: izračunana anal. za C17H22NO3: C, 66.42, H,7.32,
N,4.56; dobljeni podatki: C, 65.80, H, 7.17, N, 4.14. XH NMR
(300 MHz , DMSO-d6) δ: 1.25 (6H,m), 1.43-1.49 (4H,m), 2.18
(2H,t), 3.15 (2H,qt) , 6.72 (IH,d), 7.21-7.26 (2H,m), 7.39
(lH,t), 7.48 (IH,d), 7.65 (lH,t) , 8.21 (lH,t)
Spoj ina XIII: izračunana anal. za C15H19NO3: C ,60.18, H,6.41,
N,4.67; dobljeni podatki: C, 60.26, H, 6.53, N, 4.61. XH NMR (300 MHz, DMSO-de) δ: 1.28 (6H,m), 1.45-1.52 (4H,m), 2.19 (2H,t), 2.22 (2H,qt), 7.13 (2H,m), 7.43-7.53 (lH,m), 8.67 (lH,t), 12.03 (IH,s).
Spojina XIV: izračunana anal. za C14H20N2O3'0.66 H20: C, 63.04,
H, 7.91, N,10.34; dobljeni podatki: C, 63.21, H, 7.59,
N,10.53. XH NMR (300 MHz, DMSO-d6) δ: 1.22-1.28 (6H,m), 1.48I. 50 (4H,m), 2.18 (2H,t), 3.24 (2H,qt), 7.48 (IH,m), 8.15 (IH,d), 8.63-8.69 (2H,m), 8.97 (IH,d).
Spojina XX: izračunana anal. za Ci5H20NO3F: C, 60.09, H, 7.19,
N,4.98; dobljeni podatki: C, 63.82, H, 7.23, N, 4.94. XH NMR (300 MHz, DMSO-d6) δ: 1.28 (6H,m), 1.49 (4H,m), 2.19 (2H,t),
3.23 (2H,qt), 7.24-7.30 (2H,m), 7.49-7.60 (2H,m), 11.99 (IH,s) .
Spojina XXI: izračunana anal. za C17H23NO4: C, 66.85, H,7.61,
N,4.58; dobljeni podatki: C, 66.81, H, 7.69, N, 4.37. A NMR (300 MHz, DMSO-de) δ: 1.26 (6H,m) , 1.42-1.50 (4H,m) , 2.18 (2H,t), 3.13 (2H,qt),6.63 (IH,d), 6.80 (lH,t), 6.86 (IH,d), 7.15 (lH,t), 7.39 (lH,d), 7.60 (IH,d), 8.03 (lH,t), 9.95 (IH,s), 12.12 (IH,s).
Spojina XXIII: izračunana anal. za C15H27NO3: C, 66.86,
H,10.22, N,5.19; dobljeni podatki: C, 66.92, H,10.72, N, 5.14. XH NMR (300MHz, DMSO-d6) δ: 1.56-1.34 (13H,m), 1.46 (2H,t), 1.60-1.68 (5H,m), 2.04 (lH,t), 2.17 (2H,t), 2.97 (2H,qt), 7.62 (lH,t), 11.98 (IH,s).
Spojina XXVII: izračunana anal. za C18H27NO4: C, 67.25,
H, 8.48, N,4.36; dobljeni podatki: C, 67.23, H, 8.57, N,
4.20. ΧΗ NMR (300 MHz, DMSO-d6) δ: 1.22-1.26 (12H,m), 1.45I. 51 (4H,m), 2.16 (2H,t), 3.25 (2H,qt), 6.85 (2H,t), 7.37 (lH,t), 7.81 (IH,d), 8.79 (lH,t), 11.95 (IH,s), 12.72 (IH,s) .
Spojina XXVIII: A NMR (300 MHz, DMSO-dg) δ: 1.26 (8H,br m),
1.49 (4H,m), 2.17 (2H,t), 3.26 (2H,m), 6.86 (2H,m), 7.37 (IH,m), 7.83 (IH,m), 8.80 (lH,t), 11.95 (IH,s), 12.73 (IH,s) .
Spojina XXXIII: A NMR (300 MHz, DMSO-d6) δ: 1.2 (2H,a), 1.3 (2H,q), 1.3 (2H,q), 1.5 (2H,q), 2.2 (2H,t), 3.0 (2H,q), 3.5 (2H,s), 7.3 (5H,m), 8.0 (lH,s).
Spojina XXXIV: izračunana anal. za C12H17NO4: C, 62.23,
H,6.83, N,5.57; dobljeni podatki: C, 61.93, H, 6.80, N,
5.56. XH NMR (300 MHz, DMSO-d6) δ: 1.24-1.34 (2H,m), 1.491.57 (4H,m), 2.19 (2H,t), 3.26 (2H,qt), 6.68 (2H,t), 7.37 (IH,s), 7.83 (IH,d), 8.81 (lH,t), 12.08 (lH,s), 12.72 (IH,s) .
Primer IA
Alternativna sinteza spojine XIX je sledeča:
L trivratni bučki z okrogli dnom namestimo grelni plašč, mehansko mešalo in termometer. Reakcijo izvedemo v argonski atmosferi. V bučko damo raztopino hidroksilamin-O-sulfonske kisline (196.7 g, 1.74 molov, 1.10 ekv.) v 1 L mravljične kisline ter mešamo, da se tvori bela suspenzija. Prek lija dodamo po kapljicah raztopino ciklooktanona (200.0 g, 1.58 molov, 1.0 ekviv.) v mravljični kislini (600 mL). Do končanem dodajanju lij zamenjamo z refluksnim kondenzatorjem in reakcijsko zmes segrevamo 1 uro pri temperaturi refluksa (notranja temperatura 105°C) ter tako dobimo rjavo raztopino. Potem, ko raztopino ohladimo na sobno temperaturo, jo vlijemo v zmes nasičene vodne raztopine amonijevega klorida (1.5 L) in vode (1.5 L). Vodno zmes ekstrahiramo s kloroformom (3 x 1200 mL). Združene kloroformske plasti prenesemo v bučko ter počasi dodamo nasičen natrijev bikarbonat (2 L). Nato ločimo kloroformske plasti, jih osušimo nad brezvodnim natrijevim sulfatom in evaporiramo pod znižanim pritiskom, da dobimo rjavo olje. Olje damo v 500 mL bučko z okroglim dnom in magnetnim mešalom. Bučko damo nato v silicijevo oljno kopel in ji namestimo manjšo glavo za vakuumsko destilacijo, opremljeno s termometrom. Sprejemnik tipa Cow povežemo s tremi 250 mL bučkami. Z vakuumsko destilacijo (frakcija z glavnim temperaturnim območjem med 80 in 120°C in tlakom med 3.0 in
3.4 mmHg) dobimo 2-azaciklononanon (145 g, 65%, Ttai=6469°C).
L trivratni bučki z okrogli dnom namestimo grelni plašč, mehansko mešalo, refluksni kondenzator in termometer 29. V bučko damo suspenzijo 2-azaciklononanona (83 g, 0.59 molov, 1.0 ekv.) v 5M vodni raztopini NaOH (650 mL, 3.23 molov, 5.5 ekv.). Zmes segrevamo 4 ure pri temperaturi refluksa (notranja temperatura okoli 110°C) , da dobimo bistro rumeno raztopino. Grelni plašč in kondenzator odstranimo. Raztopino ohladimo na sobno temperaturo, razredčimo z vodo (650 mL) in nadalje ohladimo na ledeni kopeli. Nato med mešanjem, po delih dodajamo O-acetilsaliciloil klorid (114.7 g, 0.59 molov, 1.0 ekvivalenta) in hladimo še 1 uro. Po nadaljnih 30 minutah ledeno kopel odstranimo ter z mešanjem nadaljujemo pri sobni temperaturi 21 ur, da dobimo rjavo-rumeno raztopino. Mešano raztopino nakisamo z 2 M žvepleno kislino (okrog 850 mL) do pH 1. Tvori se rumena trdna snov. Trdno snov zberemo s filtracijo in raztopimo v toplem metanolu (1.7 L). Metanolu dodamo aktivno oglje (okrog 5 g) in raztopino mešamo 10 minut. Aktivno oglje odstranimo s filtracijo, ter spiramo z dodatnimi 300 mL metanola. K združenim filtratom (to je 2 L metanola) dodamo vodo (2 L) in pustimo stati čez noč pri 4°C. Pojavi se umazano bela oborina, ki jo filtriramo in rekristaliziramo iz 65% raztopine metanol/voda (v/v). Tako dobimo spojino XIX (69.1 g, 42%) v obliki umazano bele trdne snovi.
Lastnosti so navedene spodaj:
Ttai 116-117°C. HPLC, XH NMR in izračunani anal. podatki za
C15H21NO4: C, 64.50; H, 7.58; H, 7.81; N, 4.93. N, 5.02. Dobljeni: C, 64.26;
Primer 2
Spojino XXXI pripravimo po sledečem postopku:
l-aminoundeka-10-en:
Zmes 10-undekaen-l-ola (5.00 g. 29.36 mmolov, 1 ekv.),
trifenilfosfina (7.70 g, 29.36 mmolov, 1 ekv.) in ftalimida (4.32 g, 29.36 mmolov, 1 ekv.) v suhem tetrahidrofuranu (THF, 30 mL) močno mešamo pod atmosfero argona. Dietil azodikarboksilat (DEAD, 5.11 g, 29.36 mmolov, 1 ekv.) raztopimo v THF (12 mL) in z brizgalko dodajamo po kapljicah. Po končanem dodajanju reakcijsko zmes mešamo pri sobni temperaturi 4 ure. Topilo odparimo pod vakuumom in dodamo eter (30 mL), da oborimo trifenilfosfin oksid in hidrazin dikarboksilat ter ju odstranimo s filtriranjem. Oborino spiramo z etrom (2 x 30 mL) in združene filtrate evaporiramo, da dobimo rumeno trdno snov. To trituriramo s toplim heksanom (3 x 50 mL) in filtriramo. Nato evaporiramo in dobimo l-ftalimidil-undeka-10-en v obliki rumenega voska.
Vosek nato raztopimo v raztopini hidrazin hidrata (1.47 g, 1 ekv., 29.36 mmolov) v etanolu (38 mL). Zmes segrevamo pri refluksu 2 uri. Potem, ko zmes ohladimo na sobno temperaturo, dodamo koncentrirano HC1 (30 mL) in trdno snov filtriramo skozi sintriran steklen filter. Ostanek speremo z vodo (50 mL) in združene filtrate evaporiramo, da dobimo rumeno trdno snov. To ponovno raztopimo v IM NaOH (100 mL) in ekstrahiramo z etrom (2 x 50 mL). Eter osušimo in evaporiramo, da dobimo rumeno olje. Olje očistimo z Kugelrohrovo destilacijo (ca. 0.1 mmHg, 100°C) ter tako dobimo l-aminoundeka-10-en (2) v obliki rahlo rumenega olja (3.29 g, 66%).
Lastnosti so navedene spodaj.
XH NMR (300 MHz, DMSO-d6) δ: 1.23 (14H,br m), 1.99 (2H,m),
2.48 (2H,m), 4.94 (2H,m), 5.77 (IH,m).
1-(O-acetilsaliciloilamino)undeka-10-en:
O-acetilsaliciloil klorid (3.82 g, 19.25 mmolov, 1 ekv.) v THF (30 mL) ohladimo na ledeni kopeli. S kapalko dodamo trietilamin (1.95 g, 19.25 mmolov, 1 ekv.), raztopino 1aminoundeka-10-ena (3.26 g, 19.25 mmolov, 1 ekv.) v THF (10 mL). Ledeno kopel odstranimo in reakcijsko zmes mešamo 3.5 ure pri sobni temperaturi. Po odstranitvi topila ostanek raztopimo v EtOAc (50 mL) in speremo z vodo (2 x 30 mL). Organsko plast osušimo in evaporiramo, da dobimo 1-(Oacetilsaliciloilamino)undeka-10-en, v obliki brezbarvnega olja, s kvantitativnim izkoristkom, 6.59 g.
Lastnosti so navedene spodaj.
XH NMR (300 MHz, DMSO-d6) δ: 1.26 (12H,br s), 1.47 (2H,m),
1.99 (2H,m), 2.19 (3H,s), 3.15 (2H,q), 4.95 (2H,m), 5.78 (IH,m), 7.15 (IH,m), 7.30 (lH,m), 7.50 (2H,m), 8.24 (lH,t).
Spojina XXXI
K zmesi vode (108 mL), žveplove kisline (9M, 13 mL), glacialne ocetne kisline (2.16 mL) in metiltrialkil(CgCio) amonijevega klorida (0.32 g) (Aldogen® 464, dobavitelj Aldrich Chemical Co.) dodamo raztopino l-(O-acetilsaliciloilamino)undeka-10-ena (6.59 g, 19.25 mmolov, 1 ekv.) v diklorometanu (108 mL). Zmes močno mešamo v vodni kopeli in v 1.5 uri, dodamo po delih, kalijev permanganat (9.13 g, 57.75 mmolov, 3 ekv.). Po končanem dodajanju ledeno kopel odstranimo in dobljeno vijolično raztopino mešamo pri sobni temperaturi 20 ur. Raztopino ohladimo na ledeni kopeli in dodamo natrijev bisulfit (6.8 g) da nevtraliziramo presežek permanganata. Organske plasti ločimo in vodno plast ekstrahiramo z etilacetatom (2 x 50 mL). Združene organske plasti speremo s slanico (2M, 50 mL), osušimo in evaporiramo. Ostanku dodamo natrijev hidroksid (2M, 50 mL) in mešamo 30 minut. Raztopino razredčimo z vodo (50 mL), speremo z etrom (50 mL) in nakisamo do pH 1 z 2M HCI. Tvori se trdna snov, ki jo zberemo s filtracijo. Z rekristalizacijo trdne snovi iz 65% MeOH/H2O dobimo XXXI, v obliki rahlo obarvane trdne snovi (2.78 g, 47% glede na amin).
Lastnosti so navedene spodaj.
XH NMR (300 MHz, DMSO-d6) δ: 1.24 (10H,br m), 1.51 (4H,m), 2.17 (2H,t), 3.27 (2H,m), 6.86 (2H,m), 7.37 (lH,m), 7.82 (IH,m), 8.80 (lH,t), 11.95 (lH,s), 12.72 (IH,s).
Primer 3
Spojino LXXXVI pripravimo po sledečem postopku:
V litrsko trivratno bučko z okroglim dnom namestimo magnetno mešalo in kondenzator. V bučko damo raztopino 3-(4 aminofenil)propionske kisline (30 g, 0.182 mola) v metilen kloridu (300 mL) ter naenkrat dodamo trimetilsilil klorid (46.2 mL, 0.364 mole). Reakcijsko zmes refluktiramo 1.5 ure pustimo, da se ohladi na sobno temperaturo in nato potopimo v ledeno/vodno kopel. Dodamo trietilamin (76.2 mL, 0.546 mola) ter nato še 2-metoksi-cinamoil klorid (35.8 g, 0.182 mola). Reakcijsko zmes pustimo, da se segreje na sobno temperaturo in nato mešamo 48 ur. Topilo odstranimo z rotacijsko evaporacijo in k ostanku dodamo nasičeno raztopino natrijevega bikarbonata in etil acetata. Plasti ločimo in vodno plast nakisamo do pH 1.4 z 2N vodno raztopino žveplove kisline ter ekstrahiramo z etil acetatom (2 x 400 mL). Združene organske ekstrakte koncentriramo in vacuo in ostanek rekristaliziramo iz 50% (v/v) vodne raztopine metanola, da dobimo produkt v obliki rahlo obarvane trdne snovi (48.57 g, 82%).
Lastnosti so navedene spodaj.
XH NMR (300 MHz, DMSO-d6) δ: 12.1 (lH,br), 7.8 (lH,dd), 7.6 (3H,m), 7.4 (IH,m), 7.3 (2H,m), 7.1 (IH,d), 7.0 (lH,t), 6.9 (IH,d), 3.9 (3H,s), 2.8 (2H,t), 2.5 (4H,m).
izračunana anal. za C19H19NO4: C, 70.14, H, 5.88, N, 4.31; dobljeni podatki: C, 69.76, H, 5.91, N, 4.21.
Primer 4
Spojino CXVII pripravimo kot sledi:
V trilitrsko bučko z okroglim dnom namestimo mehansko mešalo in termometer. V bučko damo raztopino 8-aminokaprilne kisline (10.0 g, 0.054 mole) v 2 M vodni raztopini natrijevega hidroksida (1.4 L) ter po delih, v 7 urah dodamo še O-nitrobenzoil klorid (12.0 g, 0.065 mole, 1.2 ekv.).
Zmes mešamo pri 25°C 12 ur, da dobimo rumeno homogeno raztopino. Raztopino nato nakisamo z 1 M HC1 do pH 2, da se oljni ostanek loči in ga dekantiramo. Olje raztopimo v vodi (300 mL), ki jo mešamo in ohladimo na ledeno/vodni kopeli. Produkt se obori v obliki bele trdne snovi. Le-to filtriramo, speremo z vodo (3 x 300 mL) in rekristaliziramo iz 55% zmesi acetonitril/voda (v/v). Tako dobimo spojino CXVII v obliki umazano bele trdne snovi (7.4 g, 47%). Ttai= 89-92°C.
Lastnosti so navedene spodaj.
1H NMR (300 MHz, DMSO-d6) δ: 12.0 (IH,s), 8.65 (lH,t), 8.0 (lH,dd), 7.8 (IH,m), 7.65 (IH,m), 7.5 (IH,m), 3.2 (2H,q),
2.2 (2H,t), 1.5 (4H,br m), 1.3 (6H,br m).
izračunana anal. za C15H20N2O5: 0,58.41, H,6.54, N,9.09; dobljeni podatki: C, 58.50, H, 6.71, N, 9.14.
Tudi ostale spojine tega izuma lahko brez težav pripravimo po postopkih opisanih v primerih 1-4.
Primeri 5-15
In vivo vrednotenje rekombinantnega rastnega hormona pri podganah
Dozirne zmesi pripravimo z mešanjem modificiranih aminokislin in rekombinantnega človeškega rastnega hormona (rhGH), kot je navedeno v tabeli 1 spodaj, v raztopini fosfatnega pufra pri pH med 7 in 8.
Podganam apliciramo dozirne zmesi sublingualno (op.p., pod jezik), oralno, intraduodenalno (op.p., v dvanajsternik) ali kolonalno (op.p., v debelo črevo). Prenos ovrednotimo z ELISA testom za rhGH, Medix Biotech, Inc. Za intrakolonalno aplikacijo vzorec pripravimo in apliciramo podganam, ki smo jih postili, v količini 25 mg/kg v pufrski raztopini, ki vsebuje propilen glikol (0-50%) in 1 mg/kg rhGH.
Rezultati so podani v tabeli 1 spodaj.
Primerjalni primer 5A
Podganam oralno apliciramo rhGH (6 mg/mL) in prenos vrednotimo po postopku primera 5.
Rezultati so podani v tabeli 1 spodaj.
Tabela 1
In vivo prenos rhGH
Primer Nosilec Količina nosilca (mg/kg) Količina učinko- vine (mg/kg) Način aplika- cije Povprečni vrhnji serumski nivoji rhGH (ng/mL)
5 I 500 6 oralna 26.6+/-43.83
5A brez 0 6 oralna <10+/-10
6 V 500 6 oralna 3.22+/-7.2
7 VI 500 6 oralna 19.34+/-18.73
8 VIII 500 6 oralna 73.41+/-70.3
9 IX 500 6 oralna 28.70+/-41.7
10 XIII 25 1 v črevo 109.52+/-36.1
11 XIX 200 3 oralna 60.92+/-26.3
12 XIX 25 1 v črevo 111.52+/-16.4
13 XIX 100 3 pod 119.14+/-65.6
jezik
14 XIX 25 1 v nos 92.7+/-73.2
15 XXVII 25 1 v črevo 73.72+/-4.9
Primeri 16-27
In vivo vrednotenje rekombinantnega rastnega hormona pri podganah
Priprava dozirne raztopine
Snovi za prenos osnujemo v destilirani vodi in pH prilagodimo na 7.2-8.0 z vodno raztopino HCI ali vodno raztopino NaOH. Osnovno raztopino rhGH pripravimo z mešanjem rhGH, D-manitola in glicina in to zmes raztopimo v 2% raztopini glicerola v vodi. Osnovno raztopino nato dodamo k raztopini snovi za prenos. Opazovali so obnašanje nekaj različnih količinskih razmerij snovi za prenos in aktivne snovi.
In vivo eksperimenti
Sprague-Dawley podgane ženskega spola, s težo od 200 g do 250 g postimo 24 ur in jim nato 15 minut pred doziranjem apliciramo ketamin (44 mg/kg) in klorpromazin (1.5 mg/kg). Podganam apliciramo eno izmed dozirnih raztopin opisanih spodaj, subkutano, intranazalno ali sublingualno. Krvne vzorce zberemo serijsko iz repne arterije, za določevanje serumske koncentracije kalcija ali koncentracije rhGH v serumu. Doza apliciranega rhGH v teh poskusih je bila 0.1 mg/kg.
Serumske koncentracije rhGH kvantificiramo z RHgh encimsko imunskim testom. Rezultati so podani v tabeli 2 ter diagramih 1 in 2.
Na diagramu 2 krogi predstavljajo odziv sledečih SL (op.p., sublingvalih) doz v vodni raztopini spojine CXXIII in rhGH. Kvadrati predstavljajo odziv sledečih IN (op.p., intranazalnih) doz v vodni raztopini spojine CXXIII in rhGH. Količina spojine CXXIII je 25 mg/kg in količina rhGH je 1 mg/kg.
Primerjalni primer 16A
Podganam oralno apliciramo rhGH (lmg/kg) in prenos vrednotimo po postopku primera 16.
Rezultati so podani spodaj v tabeli 2.
Tabela 2
Izboljšava biološke dosegljivosti rekombinantnega človeškega rastnega hormona z nosilcem pri subkutani aplikaciji
Primer Nosilec Količina nosilca (mg/kg) Vrhnj a serumska količina (rhGH) (ng/mL)
16 CXXIII 1.0 22 ± 3
16A brez 0.0 4 + 2
17 CXXIII 2.5 25 ± 5
18 CXXIII 25 30 ± 6
19 CXI 2.5 16 ± 2
20 LVIII 1.0 29 ± 10
21 LXXXVI 1.0 22 ± 7
22 LXXXVI 2.5 23 ± 5
23 LXI 2.5 26 + 5
24 cx 1.0 15 ± 3
25 CXV 1.0 25 ± 3
26 LXVI 1.0 33 ± 5
27 CIX 1.0 16 ± 3
Primeri 28-33
In vivo vrednotenje interferona pri podganah
Dozirne zmesi pripravimo z mešanjem spojin modificirane aminokisline in interferona a2B, kot je navedeno spodaj v tabeli 3, v Trizma® klorovodikove pufrske raztopine (TrisHC1) pri pH okrog 7-8. Po potrebi dodamo kot snov za raztapljanje propilen glikol (0-25%).
Podganam apliciramo dozirne zmesi oralno, intraduodenalno ali intrakolonalno. Prenos vrednotimo z uporabo ELISA testa za človeški interferon a (Biosource, Inc.). Rezultati intrakolonalne aplikacije so podani v tabeli 3, spodaj.
Primerjalni primer 28A
Podganam apliciramo interferon a2b (250 mg/kg) intrakolonalno in prenos vrednotimo po postopku primera 14.
Rezultati so podani spodaj, v tabeli 3.
Tabela 3
In vivo prenos interferona z intrakolonalno aplikacijo
Primer Nosilec Količina nosilca (mg/kg) Količina interferona (gg/kg) Povprečni vrhnji serumski nivoji interferona (pg/mL)
28 VII 100 250 5241+/-2205
28A brez 0 250 0
29 XI 100 250 1189+/-1373
30 XII 100 250 6955+/-2163
31 XIX 100 250 11193+/-8559
32 XXI 100 250 4238+/-2789
33 XXXIV 100 250 4853+/-5231
Primeri 34-37
In vivo vrednotenje lososovega kalcitonina pri podganah
Dozirne zmesi pripravimo z mešanjem modificiranih aminokislin in lososovega kalcitonina, kot je prikazano v tabeli 4, spodaj. 400 mg nosilca dodamo k 2.9 mL 25% vodne raztopine propilen glikola. Dobljeno raztopino mešamo in pH prilagodimo na 7.2 z natrijevim hidroksidom (1.0 N). Do skupnega volumna 2.0 mL razredčimo z vodo. Vzorec ima končno koncentracijo nosilca 200 mg/mL. K raztopini dodamo kalcitonin (10 μg). Skupna koncentracija kalcitonina je 2.5 μg/mL.
Za vsako vzorčno skupino podgane, ki smo jih postili, anesteziramo.Podganam apliciramo dozirno zmes oralno, intrakolonalno ali intraduodenalno. Vzorce krvi zberemo iz repne arterije in serumski kalcij določimo s kalcijevim testom (Sigma Chemical Company, St.Louis, Missouri, USA). Rezultati so podani v tabeli 4, spodaj.
Tabela 4
In vivo prenos kalcitonina
Primer Nosilec Količina nosilca (mg/kg) Količina učinko- vine (mg/kg) Način aplika- cije Povprečni vrhnji serumski nivoji kalcija (% pod osnovno linijo)
34 I 400 10 oralna
35 V 400 10 oralna 18.35+/-2.87
36 XIX 10 3 v črevo 26.49+/-12.3
37 XIX 200 7.5 oralna 25.48+/-4.7
Primeri 38-43
In vivo vrednotenje lososovega kalcitonina pri podganah
Priprava dozirne raztopine
Snovi za prenos osnujemo v destilirani vodi in pH prilagodimo na 7.2-8.0 z vodno raztopino HCI ali vodno raztopino NaOH. Osnovno raztopino sCT pripravimo z raztapljanjem sCT v citronski kislini (0.085 N). Osnovno raztopino nato dodamo k raztopini snovi za prenos. Opazovali so obnašanje nekaj različnih količinskih razmerij snovi za prenos in aktivne snovi.
In vivo eksperimenti
Ženske Sprague-Dawley podgane, težke 200-250 g postimo 24 ur in jim nato 15 minut pred doziranjem apliciramo ketamin (44 mg/kg) in klorpromazin (1.5 mg/kg). Podganam subkutano apliciramo eno izmed dozirnih raztopin opisanih zgoraj.
Krvne vzorce zberemo serijsko iz repne arterije, za določevanje serumske koncentracije kalcija.
Serumske koncentracije kalcija kvantificiramo z okrezolftalein komplekson metodo (Sigma) z uporabo UV/VIS spektrofotometra (Perkin Elmer). Rezultati so podani v tabeli 5.
Primerjalni primer 38A
Podganam oralno apliciramo sCT in prenos vrednotimo po postopku primera 38.
Rezultati so podani spodaj v tabeli 5.
Tabela 5
Izboljšava biološke dosegljivosti lososovega kalcitonina (sCT, doza 0.2 gg/kg) z nosilcem pri subkutani aplikaciji
Primer Nosilec Količina nosilca (gg/kg) Upad serumskega kalcija v odstotkih
38 ΟΧΧΙΙΙ 2 17 ± 3
38A brez 0 17 ± 2
39 ΟΧΧΙΙΙ 20 25 ± 4
40 ΟΧΧΙΙΙ 200 25 ± 5
41 ΟΧΧΙΙΙ 2000 26 ± 5
42 ΟΧΙΙΙ 20 21 ± 4
43 CXIV 20 20 ± 3
Primeri 44-50
In vivo vrednotenje heparina pri podganah
Dozirne zmesi pripravimo z mešanjem modificiranih aminokislin in heparina, kot je prikazano v tabeli 4. V testni epruveti raztopimo 900 mg nosilca v 3 mL propilen glikola in 0.299 g natrijevega heparina v 3 mL vode. Raztopini zmešamo z vorteksom. K dobljeni zmesi dodajamo NaOH (10M), toliko časa, da dobimo raztopino. Nato prilagodimo pH na 7.4 ± 0.5 s koncentrirano HCI in dobljeno raztopino sonificiramo 30 minut pri 40°C.
Skupini podgan, ki jih postimo in so pri zavesti, oralno apliciramo dozirne zmesi. Krvne vzorce zberemo s srčno punkturo, sledi aplikacija ketamina (44 mg/kg). Aktivnost heparina določimo z uporabo aktiviranega delnega tromboplastinskega časa (APTT), po metodi Henry, J.B., Clinical Diagnosis and Management by Laboratory Methods; Philadelphia, PA; WB Saunders (1979).
Rezultati so podani v tabeli 6, spodaj.
Primerjalni primer 44A
Podganam oralno apliciramo heparin (100 mg/kg) in aktivnost heparina določimo po postopku Primera 44.
Rezultati so podani v tabeli 6, spodaj.
Tabela 6
In vivo prenos heparina z oralno aplikacijo
Primer Nosilec Količina nosilca (mg/kg) Količina učinkovine (mg/kg) Povprečni vrhnji nivoji APTT (sec)
44 II 300 100 25.45+/-2.8
4 4A brez brez 100 20.7+/-0.17
45 III 300 100 38.64+/-17
46 V 300 100 87.4+/-34.1
47 XII 300 100 49.53+/-17.1
48 XIX 300 100 119.99+/-56.3
49 XXXI 50 25 127.56+/-22.97
50 XXXI 50 10 50.85+/-9.1
Primer 51
Delamo po metodi primera 44, le da nizkomolekularen heparin zamenjamo za heparin in po potrebi spreminjamo količine propilen glikola in vode za raztapljanje.
Primeri 50-58
In vivo vrednotenje paratiroidnega hormona pri podganah
Priprava dozirne raztopine
Snovi za prenos osnujemo v destilirani vodi in pH prilagodimo na 7.2-8.0 z vodno raztopino HC1 ali vodno raztopino NaOH. Osnovno raztopino rparatiroidnega hormona pripravimo z raztapljanjem tega hormona v vodi. Osnovno raztopino nato dodamo k raztopini snovi za prenos. Opazovali so obnašanje nekaj različnih količinskih razmerij snovi za prenos in aktivne snovi.
In vivo eksperimenti
Ženske Sprague-Dawley podgane, težke 200-250 g postimo 24 ur in jim nato 15 minut pred doziranjem apliciramo ketamin (44 mg/kg) in klorpromazin (1.5 mg/kg). Podganam apliciramo oralno ali intrakolonalno, eno izmed dozirnih raztopin opisanih zgoraj. Krvne vzorce zberemo serijsko iz repne arterije, za določevanje serumske koncentracije paratiroidnega hormona. Serumske koncentracije paratiroidnega hormona kvantificiramo z radioimunotestom paratiroidnega hormona.
In vivo oralna aplikacija
Oralno aplikacijo raztopin, ki vsebujejo paratiroiden hormon (PTH) in ne-a-aminokislinske snovi za prenos, testiramo in vivo pri podganah. Rezultati kažejo pomembno povečanje biološke razpoložljivosti paratiroidnega hormona po oralni aplikaciji, v primerjavi s podobno aplikacijo aktivne snovi same. Rezultati so predstavljeni v tabeli 7.
Tabela 7
Izboljšava biološke dosegljivosti obščitničnega hormona (PTH) pri oralni aplikaciji
Primer Nosilec Količina nosilca (mg/kg) Količina učinko- vine (gg/kg) Način aplikacij e Vrhnji serumski nivoji (PTH) (pg/mL)
51 CXXIII 100 25 v črevo 130 ± 20
52 CXXIII 250 100 oralna 75 ± 25
53 CXXIII 250 25 oralna 20 ± 6
54 CVIII 100 25 v črevo 115 ± 20
55 LXXXVI 100 25 v črevo 40 ± 12
56 LVIII 100 25 v črevo 145 ± 25
57 CXIV 100 25 v črevo 65 ± 15
58 LXXXIX 100 25 v črevo 70 ± 15
Zgoraj omenjeni patenti, aplikacije, testne metode in objave so v predmetni izum v celoti vključene z referencami.
Po zgornjih podrobnejših opisih izuma, se bo v strokim izkušenim ponudilo veliko variacij tega izuma. Vse takšne očitne variacije so obsežene v celotnem obsegu patentnih zahtevkov.

Claims (19)

  1. PATENTNI ZAHTEVKI
    1. Farmacevtski sestavek, značilen po tem, da vsebuje:
    (A) vsaj en biološko aktivno snov; in (B) vsaj eno nosilno spojino s formulo
  2. 2-HO-Ar-CONR8-R7-COOH kjer je Ar substituiran ali nesubstituiran fenil ali naftil;
    R7 je izbran iz skupine, ki jo sestavlja C4 do C20 alkil, C4 do C2o alkenil, fenil, naftil, (Cx do Cio alkil) fenil, (Cx do Cio alkenil) fenil, (Cx do Cxo alkil) naftil, (Cx do Cxo alkenil) naftil, fenil (Cx do Cxo alkil), fenil (Cx do Cxo alkenil), naftil (Cx do C10 alkil) in naftil (Cx do CXo alkenil);
    R8 je izbran iz skupine, ki jo sestavljajo vodik, Cx do C4 alkil, Ci do C4 alkenil, hidroksi in Cx do C4 alkoksi;
    R7 je opcionalno substituiran z Cx do C4 alkil, Cx do C4 alkenil, Cx do C4 alkoksi, -OH, -SH in -CO2R9 ali njihovo kombinacijo;
    R9 je vodik, Cx do C4 alkil ali Cx do C4 alkenil;
    R7 je lahko prekinjen s kisikom, dušikom, žveplom ali njihovo kombinacijo;
    s pogojem, da spojine niso substituirane z amino skupino na mestu alfa glede na kislinsko skupino, ali njihove soli.
    2. Sestavek po zahtevku 1, značilen po tem, da omenjeno biloško aktivno sredstvo vsebuje vsaj en peptid, mukopolisaharid, karbohidrat ali lipid.
  3. 3. Sestavek po zahtevku 2, značilen po tem, da je omenjeno biološko aktivno sredstvo izbrano iz skupine, ki obsega človeški rastni hormon, volovski rastni hormon, sproščujoči rastni hormon, interferon, interleukin-II, insulin, heparin, kalcitonin, eritro-poetin, atrialni naturetični faktor, antigen, monoklonalno protitelo, somatostatin, adrenokortikotropin, gonadotropni sproščujoči hormon, oksitocin, vazopresin, natrijev kromolin, vankomicin, obščitnični hormon nemikrobne aktivne snovi, desferioksamin (DFO), ali kakršnekoli kombinacija naštetih snovi.
  4. 4. Sestavek po zahtevku 2, značilen po tem, da omenjeno biološko aktivno sredstvo obsega interferon, interleukin II, insulin, heparin, kalcitonin, oksitocin, vazopresin, vankomicin, DFSO ali njihovo kombinacijo.
  5. 5. Sestavek po zahtevku 4, značilen po tem, da omenjeno biološko aktivno sredstvo vsebuje kalcitonin.
  6. 6. Sestavek po zahtevku 1, značilen po tem, da je R7 izbran iz skupine, ki obsega C4-C20 alkil in C4-C20 alkenil.
  7. 7. Sestavek po iz skupine, zahtevku 1, značilen po tem, da je R7 izbran ki obsega C5-C2o alkil in C5-C2o alkenil.
    Sestavek po zahtevku 1, značilen po tem, da je omenjeni nosilec spojina s formulo:
    COOH ali njene soli.
  8. 9. Sestavek po zahtevku 1, značilen po tem, da je omenjeni nosilec izbran iz skupine, ki vsebuje naslednje spojine
    XIX
    XXII
    XXVII
    XXVIII
    XXIX
    XXX o
    OH
    XXXI
    XXXV
    CII
    E-534
    CIV
    E-463
    CV
    E-592
    CVI
    E-595
    CIX
    E-583
    HONH ali njihovih soli
  9. 10. Sestavek po zahtevku 1, značilen po tem, da je omenjeni nosilec izbran iz skupine, ki obsega naslednje spojine:
    Spojina n
    Lil 1
    LIH 3
    LIV 2
    LVI 2 m X
    0 2-OH
    0 2,6-dihidroksi
    0 2-OH
    0 2,6-dihidroksi ali njihovih soli.
  10. 11. Sestavek po zahtevku 1, značilen po tem, da je omenjeni nosilec izbran iz skupine, ki obsega naslednje spojine:
    Spoj ina n m X CXI 6 0 2-OH CXIX 9 0 2-OH
    ali njihovih soli.
  11. 12. Sestavek po zahtevku 1, značilen po tem, da je omenjeni nosilec izbran iz skupine, ki obsega naslednjo spojino:
    XIX ali njihovih soli.
  12. 13. Sestavek po zahtevku 1, značilen po tem, da je omenjeni nosilec izbran iz skupine, ki obsega naslednje spojine:
    XXXI
    0 ali njihovih soli. Dozirna enota, značilna po tem (A) farmacevtski sestavek po (B) (a) ekscipient, (b) topilo, (c) dezintegrant (d) lubrikant (e) plastifikator, (f) kolorant, (g) nosilec doze, ali (h) njihovo kombinacijo.
  13. 15. Dozirna enota po zahtevku 14, značilna po tem, da obsega tableto, kapsulo ali tekočino.
  14. 16. Dozirna enota po zahtevku 15, značilna po tem, da je omenjeni nosilec doze izbran iz skupine, ki obsega vodo,
    1,2-propan diol, etanol ali katerekoli njihove kombinacij e.
  15. 17. Način priprave farmakološkega sestavka, značilen po tem, da obsega mešanje:
    (A) vsaj enega biološko aktivnega sredstva;
    (B) vsaj ene nosilne spojine po zahtevku 1; in (C) neobveznega nosilca doze.
  16. 18. Spojina, značilna po tem, obsega:
    da je izbrana iz skupine, ki
    Ο
    Cl
    XII
    XIII
    XIV
    XV
    XVI
    XVII
    O COOH
    XVIII
    XIX
    XX
    XXI
    XXII
    XXIII
    XXIV
    XXV
    XXVI
    XXVII
    XXVIII
    XXIX
    XXX
    XXXI
    XXXIII
    XXXV
    XXXVI
    Spojina n
    XXXVII o
    XXXVIII 3
    X
    4-C1
    H
    XXXIX 3 1 4-CH3 XL 3 1 2-F XLI 3 1 2-CH3 XLII 3 0 3-CF3 XLIII 3 4 H XLIV 3 0 3-C1 XLV 3 0 3-F XLVI 3 0 3-CH3 XLVII 0 0 2-CF3 XLVIII 1 2 H XLIX 3 2 2-F L 3 0 3,4-OCH2O- LI 3 0 2-COOH LII 1 0 2-OH LIH 3 0 2,6-dihidroksi LIV 2 0 2-OH LV 0 0 2,4-difluoro LVI 2 0 2,6-dihidroksi LVII 0 0 4-CF3 LVI II 3 0 3-NMe2 LIX 2 0 3-NMe2 LX 3 0 2,6-dimetil LXI 3 0 2-NO2 LXII 3 0 2-CF3 LXIII 3 0 4-n-Pr LXIV 3 0 2-NH2 LXV 3 0 2-OCH3 LXVI 3 0 3-NO2 LXVII 3 0 3-NH2 LXVIII 2 0 2-NO2 LXIX 2 0 2-NH2 LXX 3 0 2-OCF3 LXXI 2 0 2-OCH3 LXXII 2 0 2-OCF3
    Spojina n X LXXIII 3 4-CF3 LXXIV 1 2-F LXXV 1 4-CF3 LXXVI 3 3,4-dimetoksi LXXVII 0 3-OCH3 LXXVIII 3 3-OCH3 LXXIX 3 2,6-difluoro LXXX 3 4-CH3 LXXXI 1 4-OCH3 LXXXII 2 2-F LXXXIII 0 2-F LXXXIV 2 4-OCH3 LXXXV 0 2-OCH3 LXXXVI 2 2-OCH3 LXXXVII 0 4-CF3 LXXXVIII 3 3-F LXXXIX 3 2-OCH3
    Spojina
    XC
    XCI
    X
    2-karboksi-cikloheksil cikloheksil
    XCII
    XCIII
    D
    2-adamantil
    1-morfolino
    Spojina
    XCIV xcv
    Spojina
    XCVI
    XCVII
    OH =0
    Spojina
    XCVIII
    XCIX
    Ε-513
    CI
    Ε-516
    CII
    Ε-534
    CIII
    Ε-515
    CIV
    Ε-463
    CV
    Ε-592 ο
    ΗΟΝΗ
    Ο
    ΟΗ
    CVI
    E-595
    CVII
    E-555
    CVIII
    E-561
    CIX
    E-583
    CX
    Spojina
    CXI n m X
    2-OH
    Η in
  17. 19.
    CXII 7 3 H CXIII 7 0 2-1 CXIV 7 0 2-Br CXV 7 0 3-NO2 CXVI 7 0 3-N(CH3)2 CXVII 7 0 2-NO2 CXVIII 7 0 4-NO2 CXIX 9 0 2-0H HO^ 0 H 0 Spojina X CXX 1-morfolino CXXI O-t-butil CXXII CH(CH2Ph) NC(0)0-t-Bu CXXIII 2-hidroksifenil nj ihove soli. Spoj ina po zahtevku 18, značilna po tem, da
    iz skupine, ki obsega:
    XIX
    XXXI
    Spojina
    Lil n
    m
    X
    2-OH in njihove soli
  18. 20. Sestavek značilen po tem, da obsega (a) aktivno učinkovino; in (b) spojino izbrano iz skupine, ki obsega
    VI
    VII
    VIII
    IX
    XI
    XII ο
    F
    XIII
    XIV
    XV
    XVI
    XVII
    XVIII
    XIX
    XX ο
    OH
    XXI
    XXII
    XXIII
    XXIV
    XXV
    XXVI
    XXVII
    XXVIII
    XXIX
    XXX
    HO ο
    ί!
    XXXI
    XXXII
    XXXIII
    XXXIV
    XXXV
    XXXVI
    X
    4-C1
    Η
    Spojina η
    XXXVII ο
    XXXVIII 3
    XXXIX 3 1 4-CH3 XL 3 1 2-F XLI 3 1 2-CH3 XLII 3 0 3-CF3 XLIII 3 4 H XLIV 3 0 3-C1 XLV 3 0 3-F XLVI 3 0 3-CHs XLVII 0 0 2-CF3 XLVIII 1 2 H XLIX 3 2 2-F L 3 0 3,4-OCHzO- LI 3 0 2-COOH Lil 1 0 2-OH LIH 3 0 2,6-dihidroksi LIV 2 0 2-OH LV 0 0 2,4-difluoro LVI 2 0 2,6-dihidroksi LVII 0 0 4-CF3 LVIII 3 0 3-NMe2 LIX 2 0 3-NMe2 LX 3 0 2,6-dimetil LXI 3 0 2-NO2 LXII 3 0 2-CF3 LXIII 3 0 4-n-Pr LXIV 3 0 2-NH2 LXV 3 0 2-OCH3 LXVI 3 0 3-NO2 LXVII 3 0 3-NH2 LXVIII 2 0 2-NO2 LXIX 2 0 2-NH2 LXX 3 0 2-OCF3 LXXI 2 0 2-OCH3 LXXII 2 0 2-OCF3
    Spojina n X LXXIII 3 4-CF3 LXXIV 1 2-F LXXV 1 4-CF3 LXXVI 3 3,4-dimetoksi LXXVII 0 3-OCH3 LXXVIII 3 3-OCH3 LXXIX 3 2,6-difluoro LXXX 3 4-CH3 LXXXI 1 4-OCH3 LXXXII 2 2-F LXXXIII 0 2-F LXXXIV 2 4-OCH3 LXXXV 0 2-OCH3 LXXXVI 2 2-OCH3 LXXXVII 0 4-CF3 LXXXVIII 3 3-F LXXXIX 3 2-OCH3
    H
    Spojina xc
    XCI m X
    0 2-karboksi-cikloheksil
    3 cikloheksil
    XCII
    XCIII
    D
    2-adamantil
    1-morfolino
    Spojina m
    XCIV o
    XCV 3
    Spojina X
    XCVI OH
    XCVII =0
    Spojina n
    XCVIII o
    XCIX
    CI
    E-516
    CII
    E-534
    CIII
    E-515
    OCH3
    HONH
    CVI
    E-595
    CVII
    E-555
    CVIII
    E-561
    CIX
    E-583
    CX
    Spojina
    CXI
    2-OH
    Η
    CXII 7 3 H CXIII 7 0 2-1 CXIV 7 0 2-Br cxv 7 0 3-NO2 CXVI 7 0 3-N(CH3)2 CXVII 7 0 2-NO2 CXVIII 7 0 4-NO2 CXIX 9 0 2-OH ho 0 H —νύ 0 Spojina X cxx 1-morfolino CXXI O-t-butil CXXII CH(CH2Ph) NC(0)O-t-Bu
    X
    CXXIII 2-hidroksifenil in njihove soli.
  19. 21. Sestavek po zahtevku 20, značilen po tem, da je spojina katero vsebuje izbrana iz skupine, ki se sestoji iz:
SI9720025A 1996-03-29 1997-03-18 Spojine in sestavki za prenos aktivne snovi SI9720025A (sl)

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US7417022B2 (en) 2008-08-26
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