HRP20191181T1 - 7-benzil-10-(2-metilbenzil)-2,6,7,8,9,10-heksahidroimidazo[1,2-a]pirido[4,3-d]pirimidin-5(3h)-on za liječenje karcinoma - Google Patents

7-benzil-10-(2-metilbenzil)-2,6,7,8,9,10-heksahidroimidazo[1,2-a]pirido[4,3-d]pirimidin-5(3h)-on za liječenje karcinoma Download PDF

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HRP20191181T1
HRP20191181T1 HRP20191181TT HRP20191181T HRP20191181T1 HR P20191181 T1 HRP20191181 T1 HR P20191181T1 HR P20191181T T HRP20191181T T HR P20191181TT HR P20191181 T HRP20191181 T HR P20191181T HR P20191181 T1 HRP20191181 T1 HR P20191181T1
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compound
cancer agent
hydrochloride salt
butanol
hcl
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Martin Stogniew
Joshua E. Allen
Bhaskara Rao Nallaganchu
Richard S. Pottorf
Gary L. Olson
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Oncoceutics, Inc.
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
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    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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Claims (15)

1. Di-hidrokloridna sol protu-kancerogena sredstva, dobivena ili koja se može dobiti postupkom koji sadrži slijedeće korake: Korak 1: neutralizacija N-benzil-3-karbometoksi-4-piperidon hidroklorida (spoj (3)) s bazom, da bi se stvorila slobodna baza N-benzil-3-karbometoksi-4-piperidona (spoj(4)) Korak 2: reakcija spoja (4) sa spojem (5) da se stvorilo protu-kancerogeno sredstvo; i Korak 3: stvaranje di-hidrokloridne soli protu-kancerogeno sredstva stvoreno u Koraku 2, za uporabu u liječenju karcinoma.
2. Di-hidrokloridna sol protu-kancerogenog sredstva za uporabu sukladno patentnom zahtjevu 1, pri čemu u postupku Korak 1 sadrži neutralizaciju spoja (3) s anorganskom bazom ili organskom bazom; neutralizaciju spoja (3) s bazom uz prisutnost alkohola ili organskog otapala; ili neutralizaciju spoja (3) s bazom u prisutnost n-butanola i/ili etil acetata, u prisutnost NaHCO3 i n-butanola ili u prisustvu n-butanola i trietil amina (Et3N), i/ili Korak 2 sadrži zagrijavanje spoja (4) sa spojem (5), na primjer, refluksno zagrijavanje spoja (4) i spoja (5) zu prisutnost otapala, i/ili Korak 3 sadrži tretiranje protu-kancerogenog sredstva stvorenog u Koraku 2 sa HCl u dioksanu, na primjer, s 4N HCl u dioksanu.
3. Di-hidrokloridna sol protu-kancerogena sredstva za uporabu sukladno patentnom zahtjevu 1, pri čemu u postupku Korak 1 sadrži neutralizaciju spoja (3) zu prisutnost NaHCO3 i n-butanola ili etil acetata; Korak 2 sadrži refluksno zagrijavanje spoja (4) i spoja (5) uz prisutnost n-butanola; i Korak 3 sadrži tretiranje protu-kancerogenog sredstva stvorenog u Koraku 2 sa HCl.
4. Di-hidrokloridna sol sol protu-kancerogena sredstva za uporabu sukladno patentnom zahtjevu 1, pri čemu postupak nadalјe sadrži korak rekristalizacije di-hidrokloridne soli protu-kancerogenog sredstva stvorenog u Koraku 3.
5. Di-hidrokloridna sol protu-kancerogena sredstva za uporabu sukladno patentnom zahtjevu 1, pri čemu Koraci 1 i 2 sadrže slijedeće korake: dodavanje spoja (3) (239,7 g; 0,845 mol; 1,6 ekviv.), u porcijama, u 800 mL miješane zasićene otopine NaHCO3 u balonu s okruglim dnom od 2 L; dodavanje n-butanola (500 mL) u dobivenu mješavinu, miješanje smjese 30 min, a zatim prebacivanje u lijevak za razdvajanje; razdvajanje organske faze, koja sadrži spoj (4), i njeno prenošenje u trogrli balon s okruglim dnom od 2 L, opremlјen s mehaničkim miješanjem, N2 ulaznim ventilom, termoelementom, kondenzatorom i Dean-Stark-ovom aparaturom; dodavanje spoja (5) (100 g; 0,528 mol; 1 ekviv) i piridinij p-toluensulfonat (PPTS) (6,63 gm; 0,026 mol; 5 mol%) u sadržaj balona; zagrijavanje dobivene smjese do temperature refluksa tokom 6 sati; odvajanje vode iz reakcijske smjese u Dean-Stark-ovoj aparaturi po potrebi; povećanje temperature refluksa s 93 °C na 118 °C; i praćenje napretka reakcije HPLC analizom, kao i zaustavlјanje reakcije kada je površina pika protu-kancerogenog sredstva dobivenog HPLC analizom postala konstantna s reakcijskim vremenom, i pri čemu Korak 3 sadrži slijedeće korake: bez izolacije protu-kancerogenog sredstva, ispiranje reakcijske smjese s 500 mL vode i njeno otapanje s metil terc-butil eterom (MTBE) (800 mL); ispiranje organske faze vodom (500 mL x 2) i njeno prenošenje u trogrli balon s okruglim dnom od 3 L opremlјen s mehaničkim miješanjem, N2 ulaznim ventilom, termoelementom, kondenzatorom i Dean-Stark-ovom aparaturom; uz snažno miješanje reakcijske smjese, dodavanje 1 N HCl u otopinu dioksan-MTBE u kapima (4 N HCl u dioksanu: 300 mL; 1,2 mol; 2.27 ekviv. MTBE: 1200 mL) do prestanka taloženja čvrste supstance iz reakcijske smjese po dodavanju HCl-a; zagrijavanje reakcijske smjese do temperature refluksa na 60-65 °C tokom 2 sata; odvajanje vode u Dean-Stark-ovoj aparaturi po potrebi; nakon hlađenja do sobne temperature, filtriranje istaložene čvrste supstance kroz lijevak od sinteriranog stakla i njeno ispiranje s n-butanol-MTBE (1:2,600 mL) i MTBE (600 mL), tim redom; i sušenje čvrste supstance u vakuum peći na 65°C preko noći (16 sati) da bi se dobilo 200 g žute čvrste supstance.
6. Di-hidrokloridna sol protu-kancerogena sredstva za uporabu sukladno patentnom zahtjevu 5, pri čemu je di-hidrokloridna sol protu-kancerogenog sredstva stvorenog u Koraku 3 pročišćena na slijedeći način: dodavanjem žute čvrste supstance (200 g) u balon s okruglim dnom od 2 L opremlјen s mehaničkim miješanjem, N2 ulaznim ventilom, termoelementom i kondenzatorom, a zatim i dodavanjem etanola (1000 mL); zagrijavanje smjese do temperature refluksa na 78°C tijekom 2 sata; nakon hlađenja do sobne temperature, filtriranjem čvrste supstance kroz lijevak od sinteriranog stakla i njenim ispiranjem s etanolom (200 mL x 3); i sušenjem vlažne čvrste supstance u vakuum peći na 85°C tijekom 3 dana, dok rezidualno otapalo nije bio u skladu sa specifikacijom; čime se dobiva 120 g di-hidrokloridne soli protu-kancerogenog sredstva u obliku bijele čvrste supstance s prinosom od 49% i HPLC čistoćom od 99,7%.
7. Di-hidrokloridna sol protu-kancerogena sredstva za uporabu sukladno bilo kojem od patentnih zahtjeva 1-6, pri čemu tretman karcinoma dalјe sadrži primjenu dodatnog protu-kancerogenog.
8. Farmaceutsi pripravak koji sadrži di-hidrokloridnu sol protu-kancerogenog sredstva, dobivenog ili koja se može dobiti postupkom koji sadrži slijedeće korake: Korak 1: neutralizacija N-benzil-3-karbometoksi-4-piperidon hidroklorida (spoj(3)) s bazom, da bi se oblikovala slobodna baza N-benzil-3-karbometoksi-4-piperidona (spoj(4)) Korak 2: reakcija spoja (4) sa spojem (5) da bi se stvorilo protu-kancerogeno sredstvo; i Korak 3: stvaranje di-hidrokloridne soli protu-kancerogenog sredstva stvorenog u Koraku 2, dodatnog protu-kancerogenog sredstva, i farmaceutski prihvatlјivog nosača.
9. Farmaceutski pripravak sukladno patentnom zahtjevu 8, pri čemu u postupku Korak 1 sadrži neutralizaciju spoja (3) s anorganskom bazom ili organskom bazom; neutralizaciju spoja (3) s bazom u prisustvu alkohola ili organskog otapala; ili neutralizaciju spoja (3) s bazom u prisutnosti n-butanola i/ili etil acetata, u prisutnosti NaHCO3 i n-butanola ili uz prisutnost n-butanola i trietil amina (Et3N), i/ili Korak 2 sadrži zagrijavanje spoja (4) sa spojem (5), na primjer, refluksno zagrijavanje spoja (4) i spoja (5) u prisutnosti otapala, i/ili Korak 3 sadrži tretiranje protu-kancerogenog sredstva stvorenog u Koraku 2 sa HCl u dioksanu, na primjer, sa 4N HCl u dioksanu.
10. Farmaceutski pripravak sukladno patentnom zahtjevu 8, pri čemu u postupku Korak 1 sadrži neutralizaciju spoja (3) u prisutnosti NaHCO3 i n-butanola ili etil acetata; Korak 2 sadrži refluksno zagrijavanje spoja (4) i spoja (5) u prisutnosti n-butanola; i Korak 3 sadrži tretiranje protu-kancerogenog sredstva stvrorenog u Koraku 2 sa HCl.
11. Farmaceutski pripravak sukladno patentnom zahtjevu 8, pri čemu postupak dalјe sadrži korak rekristalizacije di-hidrokloridne soli protu-kancerogenog sredstva stvorenog u Koraku 3.
12. Farmaceutski pripravak sukladno patentnom zahtjevu 8, pri čemu Koraci 1 i 2 sadrže slijedeće korake: dodavanje spoja (3) (239,7 g; 0,845 mol; 1,6 ekviv.), u porcijama, u 800 mL miješanog zasićenog otapala NaHCO3 u balonu s okruglim dnom od 2 L; dodavanje n-butanola (500 mL) u dobivenu smjesu, miješanje smjese 30 min, a zatim prebacivanje u lijevak za razdvajanje; razdvajanje organske faze, koja sadrži spoj (4), i njeno prenošenje u trogrli balon s okruglim dnom od 2 L opremlјen s mehaničkim miješanjem, N2 ulaznim ventilom, termoelementom, kondenzatorom i Dean-Stark-ovom aparaturom; dodavanje spoja (5) (100 g; 0,528 mol; 1 ekviv) i piridinij p-toluensulfonata (PPTS) (6,63 gm; 0,026 mol; 5 mol%) u sadržaj balona; zagrijavanje dobivene smjese do temperature refluksa tijekom 6 sata; odvajanje vode iz reakcijske smjese u Dean-Stark-ovoj aparaturi po potrebi; povećanje temperature refluksa s 93 °C na 118 °C; i praćenje napretka reakcije HPLC analizom, kao i zaustavlјanje reakcije kada je površina pika protu-kancerogenog sredstva dobivenog HPLC analizom postala konstantna s vremenom reakcije. i pri čemu Korak 3 sadrži slijedeće korake: bez izolacije protu-kancerogenog sredstva, ispiranje reakcijske smjese s 500 mL vode i njeno otapanje s metil terc-butil eterom (MTBE) (800 mL); ispiranje organske faze vodom (500 mL x 2) i njeno prenošenje u trogrli balon s okruglim dnom od 3 L opremlјen s mehaničkim miješanjem, N2 ulaznim ventilom, termoelementom, kondenzatorom i Dean-Stark-ovom aparaturom; uz snažno miješanje reakcijske smjese, dodavanje 1 N HCl u otapalo dioksan-MTBE u kapima (4 N HCl u dioksanu: 300 mL; 1,2 mol; 2.27 ekviv. MTBE: 1200 mL) do prestanka taloženja čvrste supstance iz reakcijske smjese po dodavanju HCl-a; zagrijavanje reakcijske smjese do temperature refluksa na 60-65 °C tokom 2 sata; odvajanje vode u Dean-Stark-ovoj aparaturi po potrebi; nakon hlađenja do sobne temperature, filtriranje istaložene čvrste supstance kroz lijevak od sinteriziranog stakla i njeno ispiranje s n-butanol-MTBE (1:2,600 mL) i MTBE (600 mL), tim redom; i sušenje čvrste supstance u vakuum peći na 65 °C preko noći (16 časova) da bi se dobilo 200 g žute čvrste supstance.
13. Farmaceutski pripravak sukladno patentnom zahtjevu 12, pri čemu je di-hidrokloridna sol protu-kancerogenog sredstva stvorenog u Koraku 3 pročišćena na slijedeći način: dodavanjem žute čvrste supstance (200 g) u balon s okruglim dnom od 2 L opremlјen s mehaničkim miješanjem, N2 ulaznim ventilom, termoelementom i kondenzatorom, a zatim i dodavanjem etanola (1000 mL); zagrijevanjem smjee do temperature refluksa na 78°C tijekom 2 sata; nakon hlađenja do sobne temperature, filtriranjem čvrste supstance kroz lijevak od sinteriziranog stakla i njenim ispiranjem s etanolom (200 mL x 3); i sušenjem vlažne čvrste supstance u vakuum peći na 85°C tijekom 3 dana, dok rezidualno otapalo nije bio u skladu sa specifikacijom; čime se dobije 120 g di-hidrokloridne soli protu-kancerogenog sredstva u obliku bijele čvrste supstance s prinosom od 49% i HPLC čistoćom od 99,7%.
14. Farmaceutski pripravak sukladno bilo kojem od patentnih zahtjeva 8-13, za uporabu u obliku medikamenta.
15. Farmaceutski pripravak sukladno bilo kojem od patentnih zahtjeva 8-13, za liječenje karcinoma.
HRP20191181TT 2013-03-13 2019-07-01 7-benzil-10-(2-metilbenzil)-2,6,7,8,9,10-heksahidroimidazo[1,2-a]pirido[4,3-d]pirimidin-5(3h)-on za liječenje karcinoma HRP20191181T1 (hr)

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US201361779828P 2013-03-13 2013-03-13
US201361904718P 2013-11-15 2013-11-15
PCT/US2014/025885 WO2014160130A1 (en) 2013-03-13 2014-03-13 Combination therapy with 7-benzyl-10-(2-methylbenzyl)-2,6,7,8,9,10-hexahydroimidazo[1,2-a]pyrido[4,3-d]pyrimidin-5(3h)-one
EP14775569.8A EP2968294B1 (en) 2013-03-13 2014-03-13 7-benzyl-10-(2-methylbenzyl)-2,6,7,8,9,10-hexahydroimidazo[1,2-a]pyrido[4,3-d]pyrimidin-5(3h)-on for use in the treatment of cancer

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