ME02316B - Imidazopiridazini kao inhibitori akt kinaze - Google Patents
Imidazopiridazini kao inhibitori akt kinazeInfo
- Publication number
- ME02316B ME02316B MEP-2016-1A MEP20161A ME02316B ME 02316 B ME02316 B ME 02316B ME P20161 A MEP20161 A ME P20161A ME 02316 B ME02316 B ME 02316B
- Authority
- ME
- Montenegro
- Prior art keywords
- mthf
- phase
- methyltriphenylphosphonium
- nalmefene
- process according
- Prior art date
Links
- 150000005233 imidazopyridazines Chemical class 0.000 title 1
- 229940043355 kinase inhibitor Drugs 0.000 title 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 title 1
- 238000000034 method Methods 0.000 claims 17
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims 9
- 239000000203 mixture Substances 0.000 claims 8
- 239000012071 phase Substances 0.000 claims 8
- AZFQCTBZOPUVOW-UHFFFAOYSA-N methyl(triphenyl)phosphanium Chemical class C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 AZFQCTBZOPUVOW-UHFFFAOYSA-N 0.000 claims 5
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 claims 5
- 229960003086 naltrexone Drugs 0.000 claims 5
- 239000007787 solid Substances 0.000 claims 5
- 238000002156 mixing Methods 0.000 claims 4
- 239000012074 organic phase Substances 0.000 claims 4
- GYWMRGWFQPSQLK-OPHZJPRHSA-N (4r,4as,7as,12bs)-3-(cyclopropylmethyl)-7-methylidene-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,9-diol;hydron;chloride Chemical compound Cl.N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 GYWMRGWFQPSQLK-OPHZJPRHSA-N 0.000 claims 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 3
- WJBLNOPPDWQMCH-MBPVOVBZSA-N Nalmefene Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 WJBLNOPPDWQMCH-MBPVOVBZSA-N 0.000 claims 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 3
- 239000007864 aqueous solution Substances 0.000 claims 3
- 229960005297 nalmefene Drugs 0.000 claims 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 2
- 238000007865 diluting Methods 0.000 claims 2
- 150000002576 ketones Chemical class 0.000 claims 2
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical group [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 claims 2
- 239000003960 organic solvent Substances 0.000 claims 2
- 229910052698 phosphorus Inorganic materials 0.000 claims 2
- 239000011574 phosphorus Substances 0.000 claims 2
- 238000002360 preparation method Methods 0.000 claims 2
- 239000000243 solution Substances 0.000 claims 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 2
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims 1
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims 1
- 238000007239 Wittig reaction Methods 0.000 claims 1
- 150000001298 alcohols Chemical class 0.000 claims 1
- 235000019270 ammonium chloride Nutrition 0.000 claims 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 claims 1
- 238000001035 drying Methods 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 150000002170 ethers Chemical class 0.000 claims 1
- 239000007789 gas Substances 0.000 claims 1
- 150000008282 halocarbons Chemical class 0.000 claims 1
- QRPRIOOKPZSVFN-UHFFFAOYSA-M methyl(triphenyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 QRPRIOOKPZSVFN-UHFFFAOYSA-M 0.000 claims 1
- JNMIXMFEVJHFNY-UHFFFAOYSA-M methyl(triphenyl)phosphanium;iodide Chemical compound [I-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 JNMIXMFEVJHFNY-UHFFFAOYSA-M 0.000 claims 1
- 229960000677 nalmefene hydrochloride Drugs 0.000 claims 1
- 238000001953 recrystallisation Methods 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 238000003756 stirring Methods 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Reproductive Health (AREA)
- Endocrinology (AREA)
- Pregnancy & Childbirth (AREA)
- Gynecology & Obstetrics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Cosmetics (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Claims (15)
1. Postupak za pripremanje nalmefena od naltreksona Wittig-ovom reakcijom u kojem se 2-metiltetrahidrofuran (MTHF) koristi i u formiranju fosfornog ilida i u naknadnoj reakciji između pomenutog ilida i naltreksona, pri čemu je nalmefen izolovan kao hidrohloridna so nalmefena u jednofaznom postupku bez izolovanja osnove i pripremanja hidrohloridne soli u naknadnoj i odvojenoj fazi.
2. Postupak prema zahtevu 1, koji obuhvata faze a) dobijanje fosfornog ilida umešavanjem metiltrifenilfosfonijumove soli sa MTHF i pogodnom bazom, i b) dodavanje mešavine koja obuhvata naltrekson i MTHF mešavini dobijenoj u fazi a).
3. Postupak prema zahtevu 2, u kojem se faze a) i b) izvode simultano u istoj posudi ili se faze a) i b) izvode sekvencijalno.
4. Postupak prema bilo kom od prethodnih zahteva, u kojem je metiltrifenil fosfonijumova so izabrana između metiltrifenilfosfonijum bromida (MTPPB), metiltrifenilfosfonijum hlorida ili metiltrifenilfosfonijum jodida.
5. Postupak prema bilo kom od prethodnih zahteva, u kojem su pomenuti MTHF i pomenuta metiltrifenilfosfonijum so umešavani u količini (v/w) od 1:1 do 4:1, poželjno 2:1 MTHF u odnosu na pomenutu metiltrifenil fosfonijum so.
6. Postupak prema bilo kom od prethodnih zahteva, u kojem je pomenuta baza koja se dodaje u fazi a) kalijum terc-butoksid (KO-t-Bu).
7. Postupak prema zahtevu 6, gde se pomenuti KO-t-Bu dodaje u ekvimolarnoj količini u odnosu na metiltrifenil fosfonijum so.
8. Postupak prema bilo kom od zahteva 2-7, u kojem se pomenuta mešavina dobijena u fazi a) meša najmanje 1 sat, poželjnije dva sata, pre faze b).
9. Postupak prema bilo kom od zahteva 2-8, u kojem se pomenuti naltrekson koji se koristi u fazi b) dodaje kao anhidrovana čvrsta materija ili kao anhidrovani rastvor u MTHF.
10. Postupak prema zahtevu 9, u kojem je količina pomenutog MTHF u odnosu na naltrekson (v/w) od 2:1 do 6:1, kao što je 3:1 do 5:1 ili 4:1.
11. Postupak za pripremanje nalmefen hidrohlorida prema bilo kom od zahteva 2-10, dalje je okarakterisan izolovanjem proizvoda iz faze b) postupkom koji obuhvata sledeće faze c) (i) mešanje vodenog rastvora koji obuhvata amonijum hlorid (NH4CI) sa mešavinom dobijenom u fazi b), ili (ii) mešanje kiseline ili rastvor koji sadrži neku kiselinu sa mešavinom dobijenom u fazi b), ili (iii) mešanje ketona sa mešavinom dobijenom u fazi b), ili (iv) izvođenje kombinacije gornje faze fazama (i), (ii) i (iii), a zatim (v) opciono razblaživanje mešavine vodom, d) razdvajanje organske faze dobijene u fazi c), e) opciono ispiranje organske faze dobijene u c) vodom i razdvajanje organske faze, f) koncentrovanje organske faze dobijene u fazi d) ili e) pod vakuumom kako bi se uklonile isparljive materije, g) razblaživanje dobijenog ostatka iz faze f) u jednom ili više odgovarajućih organskih rastvarača, h) dodavanje vodonikhlorida (HCI) u mešavinu dobijenu u fazi g), i) izolovanje dobijenog čvrstog ostatka, j) opciono, ponovno suspendovanje čvrste materije iz faze i) jednim ili više odgovarajućih rastvarača i izololovanje čvrstog ostatka, i k) opciono sušenje konačne čvrste materije.
12. Postupak prema zahtevu 11, u kojem je pomenuti organski rastvarač koji se koristi fazi g), i) i/ili fazi j) izabran iz grupe koja obuhvata halogenovane ugljovodonike, alkohole, etre, ketone, estre i aromatične ugljovodonike ili njihove kombinacije kao što je aceton, etil acetat, MTHF, 2-propanol, toluen, dihlorometan ili njihova kombinacija.
13. Postupak prema bilo kom od zahteva 11-12, u kojem se vodonikhlorid (HCl) iz faze h) dodaje kao gas ili kao koncentrovani vodeni rastvor.
14. Postupak prema bilo kom od zahteva 11-13, u kojem se vodonikhlorid (HCl) dodaje u fazi h) pod energičnim mešanjem na temperaturi koja je u opsegu od 0 do 40°C, poželjno 20 do 30°C.
15. Postupak prema bilo kom od zahteva 11-14, u kojem se dobijeni nalmefen HCl transformiše u nalmefen HCl dihidrat rekristalizacijom u vodenom rastvoru.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201161472732P | 2011-04-07 | 2011-04-07 | |
| EP12713963.2A EP2694510B1 (en) | 2011-04-07 | 2012-04-05 | Imidazopyridazines as akt kinase inhibitors |
| PCT/EP2012/056300 WO2012136776A1 (en) | 2011-04-07 | 2012-04-05 | Imidazopyridazines as akt kinase inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ME02316B true ME02316B (me) | 2016-06-20 |
Family
ID=45953129
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MEP-2016-1A ME02316B (me) | 2011-04-07 | 2012-04-05 | Imidazopiridazini kao inhibitori akt kinaze |
Country Status (43)
Families Citing this family (16)
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| US9334242B2 (en) | 2008-06-16 | 2016-05-10 | Gtx, Inc. | Compounds for treatment of cancer |
| LT2303021T (lt) | 2008-06-16 | 2019-06-25 | University Of Tennessee Research Foundation | Junginiai, skirti vėžio gydymui |
| US9447049B2 (en) | 2010-03-01 | 2016-09-20 | University Of Tennessee Research Foundation | Compounds for treatment of cancer |
| US9029408B2 (en) | 2008-06-16 | 2015-05-12 | Gtx, Inc. | Compounds for treatment of cancer |
| US11084811B2 (en) | 2010-03-01 | 2021-08-10 | Oncternal Therapeutics, Inc. | Compounds for treatment of cancer |
| SI2694510T1 (sl) * | 2011-04-07 | 2016-02-29 | Bayer Intellectual Property Gmbh | Imidazopiridazini kot inhibitorji AKT kinaze |
| EP2802586B1 (en) * | 2012-01-10 | 2016-05-25 | Bayer Intellectual Property GmbH | Substituted imidazopyrazines as akt kinase inhibitors |
| JP6106694B2 (ja) * | 2012-01-10 | 2017-04-05 | バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツングＢａｙｅｒ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ ＧｍｂＨ | Ａｋｔキナーゼ阻害剤としての置換ピラゾロピリミジン類 |
| SG11201503688SA (en) * | 2012-11-30 | 2015-06-29 | Glaxosmithkline Llc | Novel pharmaceutical composition |
| CN109568312A (zh) | 2013-03-05 | 2019-04-05 | 田纳西大学研究基金会 | 用于治疗癌症的化合物 |
| US20150352121A1 (en) * | 2013-03-12 | 2015-12-10 | Glaxosmithkline Llc | Combination |
| WO2014153001A1 (en) * | 2013-03-14 | 2014-09-25 | Epizyme, Inc. | Combination therapy for treating cancer |
| CN105899512A (zh) * | 2014-01-09 | 2016-08-24 | 拜耳医药股份公司 | 可用于治疗过度增殖性和/或血管生成疾病的酰胺基团取代的咪唑并哒嗪 |
| US10774086B2 (en) | 2016-11-28 | 2020-09-15 | Bristol-Myers Squibb Company | GSK-3 inhibitors |
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| EP2413932A4 (en) * | 2009-04-01 | 2012-09-19 | Merck Sharp & Dohme | HAMMER OF ACT ACTIVITY |
| AR076936A1 (es) | 2009-06-02 | 2011-07-20 | Vitae Pharmaceuticals Inc | Inhibidores de carbamato y urea de la 11 beta hidroxiesteroide deshidrogenasa 1 |
| WO2011033265A1 (en) * | 2009-09-18 | 2011-03-24 | Almac Discovery Limited | Pharmaceutical compounds |
| JP5830094B2 (ja) * | 2010-07-12 | 2015-12-09 | バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツングＢａｙｅｒ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ ＧｍｂＨ | 置換イミダゾ［１，２−ａ］ピリミジンおよび−ピリジン |
| CA2806655A1 (en) | 2010-07-28 | 2012-02-02 | Bayer Intellectual Property Gmbh | Substituted imidazo[1,2-b]pyridazines |
| SI2694510T1 (sl) * | 2011-04-07 | 2016-02-29 | Bayer Intellectual Property Gmbh | Imidazopiridazini kot inhibitorji AKT kinaze |
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2012
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