PL229106B1 - Bromides of butanamide 2-cyano-3-oxy-N-substituted derivatives and method for producing them - Google Patents
Bromides of butanamide 2-cyano-3-oxy-N-substituted derivatives and method for producing themInfo
- Publication number
- PL229106B1 PL229106B1 PL411238A PL41123815A PL229106B1 PL 229106 B1 PL229106 B1 PL 229106B1 PL 411238 A PL411238 A PL 411238A PL 41123815 A PL41123815 A PL 41123815A PL 229106 B1 PL229106 B1 PL 229106B1
- Authority
- PL
- Poland
- Prior art keywords
- bromides
- cyano
- oxy
- general formula
- butanamide
- Prior art date
Links
- 150000001649 bromium compounds Chemical class 0.000 title claims abstract description 8
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 title claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 title 1
- -1 benzylamine bromides Chemical class 0.000 claims abstract description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 7
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 7
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 7
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 6
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 6
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- 238000002425 crystallisation Methods 0.000 claims abstract description 5
- 230000008025 crystallization Effects 0.000 claims abstract description 5
- 239000002798 polar solvent Substances 0.000 claims abstract description 5
- 239000002244 precipitate Substances 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims abstract description 4
- 201000010099 disease Diseases 0.000 claims abstract 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract 2
- 230000001613 neoplastic effect Effects 0.000 claims abstract 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 8
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 8
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 6
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- 210000004072 lung Anatomy 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 3
- DJOJFYVMGCYKJV-UHFFFAOYSA-N ethyl 4-cyano-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CC#N DJOJFYVMGCYKJV-UHFFFAOYSA-N 0.000 claims 1
- QJFMCHRSDOLMHA-UHFFFAOYSA-N phenylmethanamine;hydrobromide Chemical class Br.NCC1=CC=CC=C1 QJFMCHRSDOLMHA-UHFFFAOYSA-N 0.000 claims 1
- 206010041823 squamous cell carcinoma Diseases 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 8
- WGQKYBSKWIADBV-UHFFFAOYSA-N aminomethyl benzene Natural products NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 abstract description 4
- FCVMPRQTRCSXKE-UHFFFAOYSA-N methanol propan-2-ol Chemical compound OC.CC(C)O.CC(C)O.CC(C)O FCVMPRQTRCSXKE-UHFFFAOYSA-N 0.000 abstract description 3
- 238000005917 acylation reaction Methods 0.000 abstract description 2
- PBLNBZIONSLZBU-UHFFFAOYSA-N 1-bromododecane Chemical compound CCCCCCCCCCCCBr PBLNBZIONSLZBU-UHFFFAOYSA-N 0.000 abstract 1
- NWOKVFOTWMZMHL-UHFFFAOYSA-N ethyl 2-cyanoacetoacetate Chemical compound CCOC(=O)C(C#N)C(C)=O NWOKVFOTWMZMHL-UHFFFAOYSA-N 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 25
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 12
- 231100000135 cytotoxicity Toxicity 0.000 description 9
- 230000003013 cytotoxicity Effects 0.000 description 9
- 231100000491 EC50 Toxicity 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 210000003494 hepatocyte Anatomy 0.000 description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical group C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 210000004413 cardiac myocyte Anatomy 0.000 description 4
- 150000001768 cations Chemical class 0.000 description 4
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 4
- 201000005243 lung squamous cell carcinoma Diseases 0.000 description 4
- 125000005447 octyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 206010017758 gastric cancer Diseases 0.000 description 3
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 3
- 201000011549 stomach cancer Diseases 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 210000003470 mitochondria Anatomy 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- YQYGGOPUTPQHAY-KIQLFZLRSA-N (4S)-4-[[(2S)-2-[[(2S)-2-[2-[6-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-5-amino-1-[[(4S,7R)-7-[[(2S)-1-[(2S)-6-amino-2-[[(2R)-2-[[(2S)-5-amino-2-[[(2S,3R)-2-[[(2S)-6-amino-2-[[(2S)-4-carboxy-2-hydrazinylbutanoyl]amino]hexanoyl]amino]-3-methylpentanoyl]amino]-5-oxopentanoyl]amino]propanoyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-2-methyl-5,6-dioxooctan-4-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-5-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-4-amino-2-[[(2S)-2-amino-3-hydroxypropanoyl]amino]-4-oxobutanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-4-carboxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-phenylpropanoyl]amino]-6-oxohexyl]hydrazinyl]-3-phenylpropanoyl]amino]-3-hydroxypropanoyl]amino]-5-[[(2S)-1-[[(2S,3S)-1-[[(2S)-4-amino-1-[[(2S)-1-hydroxy-3-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-5-oxopentanoic acid Chemical compound CC[C@@H](C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NN)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@H](C)C(=O)C(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](Cc1ccccc1)NC(=O)C(CCCCNN[C@@H](Cc1ccccc1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C=O)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO)[C@H](C)O)C(C)C)[C@H](C)O YQYGGOPUTPQHAY-KIQLFZLRSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- DEAGCAOJVRQUPK-UHFFFAOYSA-N 2-cyano-3-oxobutanoic acid Chemical compound CC(=O)C(C#N)C(O)=O DEAGCAOJVRQUPK-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 101150068326 bro1 gene Proteins 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 210000001700 mitochondrial membrane Anatomy 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Przedmiotem wynalazku są bromki 2-cyjano-3-oksy-N-podstawione pochodne butanamidu o wzorze ogólnym 1, gdzie X oznacza podstawnik alifatyczny odpowiednio etyl, butyl, heksyl, oktyl, dodecyl. Związki o wzorze ogólnym 1 otrzymuje się w reakcji acylowania odpowiednich bromków 4-[(2-trifenylofosfino)alkiloksy]benzyloaminy, 2-cyjanoacetylooctanem etylu reakcję prowadzi się w środowisku rozpuszczalnika polarnego, w temperaturze pokojowej przez 4 - 6 godzin, stosując proporcje molowe 1 : 1. Po zakończeniu reakcji, wytrącony osad odsącza się i oczyszcza przez krystalizację z mieszaniny metanol-propan-2-ol. Pochodne o wzorze ogólnym 1, gdzie X oznacza podstawnik alifatyczny odpowiednio etyl, butyl, heksyl, oktyl, dodecyl bromku do zastosowania w leczeniu chorób nowotworowych.The subject of the invention are bromides of 2-cyano-3-oxy-N-substituted butanamide derivatives of the general formula 1, where X is an aliphatic substituent, respectively ethyl, butyl, hexyl, octyl, dodecyl. Compounds of the general formula 1 are obtained in the acylation reaction of the appropriate 4-[(2-triphenylphosphino)alkyloxy]benzylamine bromides with ethyl 2-cyanoacetoacetate, the reaction is carried out in a polar solvent environment at room temperature for 4 - 6 hours, using the molar proportions 1: 1. After completion of the reaction, the precipitate is filtered off and purified by crystallization from a mixture of methanol-propan-2-ol. Derivatives of the general formula 1, where X is an aliphatic substituent, respectively ethyl, butyl, hexyl, octyl, dodecyl bromide for use in the treatment of neoplastic diseases.
Description
Przedmiotem wynalazku są bromki 2-cyjano-3-oksy-N-podstawionych pochodnych butanamidu o wzorze ogólnym 1, gdzie X oznacza podstawnik alifatyczny odpowiednio etyl, butyl, heksyl, oktyl, dodecyl oraz sposób ich otrzymywania i zastosowanie.The subject of the invention are bromides of 2-cyano-3-oxy-N-substituted butanamide derivatives of the general formula 1, where X is an aliphatic substituent, respectively ethyl, butyl, hexyl, octyl, dodecyl, and a method for their preparation and use.
W znanym stanie techniki opisany jest środek farmaceutyczny o nazwie Leflunomid, który należy do grupy prekursorów leków. Dopiero in vivo ulega przemianie do aktywnego terapeutycznie metabolitu Leflunomidu - Triflunomidu, który ma właściwości immunomodulujące, antyproliferacyjne względem limfocytów T i działanie przeciwzapalne. Triflunomid zawiera w swojej cząsteczce ugrupowanie 2-cyjano-3-oksybutanamidu. [patent EP 2004149 A1; Dieter Ruchatz 13.04.2007].The known art describes a pharmaceutical agent called Leflunomide, which belongs to the group of drug precursors. It is only in vivo that it is converted to the therapeutically active metabolite of Leflunomide - Triflunomide, which has immunomodulatory, anti-proliferative, T-lymphocyte and anti-inflammatory properties. Triflunomide contains a 2-cyano-3-oxybutanamide moiety in its molecule. [patent EP 2004149 A1; Dieter Ruchatz, April 13, 2007].
Otrzymane według wynalazku związki były poddane ocenie cytotoksyczności w stosunku do wybranych linii komórkowych raka: szpiczaka (RPMI8226), ostrej białaczki mieloblastycznej (Kasumi 1), raka płasko-nabłonkowego płuca (NCIH2170) i raka żołądka (MKN74) oraz komórkach prawidłowych: hepatocytach oraz kardiomiocytach (H2C9). Jedną ze strategii mającej na celu ułatwienie dotarcia leków do mitochondrium jest dołączenie ugrupowania trifenylofosfiny [Fulda S., Galluzzi L., Kroemer G.: Targeting mitochondrial for cancer therapy. Nat Rev Drug Discov. 2010; 9: 447-464]. Związki chemiczne, posiadające w swej strukturze trifenylofosfinę i tworzące lipofilowe kationy łatwo przenikają przez błonę mitochondrium, zbudowaną z podwójnej warstwy fosfolipidów. Kationy hydrofilowe ciężko przechodzą przez błony biologiczne, ponieważ zużywają w tym procesie duże ilości energii potrzebnej na przeniesienie jonów ze środowiska hydrofilowego do hydrofobowego wnętrza błony lipidowej. W przypadku kationów lipofilowych energia aktywacji jest mniejsza i proces ten zachodzi łatwiej [Murphy M.P.: Targeting lipohilic cations to mitochondria. Biochemica et Biophysica Acta 2008; 1777: 1028-1031].The compounds obtained according to the invention were subjected to cytotoxicity assessment against selected cancer cell lines: myeloma (RPMI8226), acute myeloblastic leukemia (Kasumi 1), lung squamous cell carcinoma (NCIH2170) and gastric cancer (MKN74) as well as normal cells: hepatocytes and cardiomyocytes (H2C9). One of the strategies aimed at facilitating the delivery of drugs to the mitochondrion is the addition of a triphenylphosphine moiety [Fulda S., Galluzzi L., Kroemer G.: Targeting mitochondrial for cancer therapy. Nat Rev Drug Discov. 2010; 9: 447-464]. Chemical compounds with triphenylphosphine in their structure and forming lipophilic cations easily penetrate the mitochondrial membrane, made of a double layer of phospholipids. Hydrophilic cations are difficult to pass through biological membranes because in this process they use large amounts of energy needed to transfer ions from the hydrophilic environment to the hydrophobic interior of the lipid membrane. In the case of lipophilic cations, the activation energy is lower and the process is easier [Murphy M.P.: Targeting lipophilic cations to mitochondria. Biochemica et Biophysica Acta 2008; 1777: 1028-1031].
Będące przedmiotem wynalazku nowe związki stanowią bromki 2-cyjano-3-oksy-N{4-[(trifenylofosfino)alkiloksy]benzylo}butanamidu, o wzorze ogólnym 1, gdzie X oznacza podstawnik alifatyczny odpowiednio etyl, butyl, heksyl, oktyl, dodecyl.The new compounds of the invention are 2-cyano-3-oxy-N{4-[(triphenylphosphino)alkyloxy]benzyl}butanamide bromides of the general formula I, where X is an aliphatic substituent, respectively ethyl, butyl, hexyl, octyl, dodecyl.
Związki o wzorze ogólnym 1, gdzie X oznacza podstawnik alifatyczny odpowiednio etyl, butyl, heksyl, oktyl, dodecyl, otrzymuje się w wyniku acylowania odpowiednich bromków 4-[(2-trifenylofosfino)alkiloksy]benzyloaminy o wzorze ogólnym 2, 2-cyjanoacetylooctanem etylu o wzorze 3, reakcję prowadzi się w środowisku rozpuszczalnika polarnego, korzystnie alkoholu etylowego, metylowego, propylowego, w temperaturze pokojowej przez 4-6 godzin, stosując proporcje molowe 1:1. Po zakończeniu reakcji, wytrącony osad odsącza się i oczyszcza korzystnie przez krystalizację z rozpuszczalnika polarnego propan-2-olu mieszaniny metanol-propan-2-ol, w stosunku 1:3.Compounds of general formula 1, where X is an aliphatic substituent, respectively ethyl, butyl, hexyl, octyl, dodecyl, are obtained by acylation of the corresponding 4-[(2-triphenylphosphino)alkyloxy]benzylamine bromides of general formula 2,2-cyanoacetoacetate with ethyl Formula 3, the reaction is carried out in a polar solvent environment, preferably ethyl, methyl, propyl alcohol, at room temperature for 4-6 hours, using a 1:1 molar ratio. After completion of the reaction, the precipitate is filtered off and purified preferably by crystallization from the polar solvent propan-2-ol of a mixture of methanol-propan-2-ol in a ratio of 1:3.
Istotą wynalazku jest także zastosowanie pochodnej metabolitu Leflunomidu - Triflunomid (A771726), zawierającej w swej strukturze trifenylofosfinę o wzorze 1 w leczeniu chorób nowotworowych, a w szczególności szpiczaka oraz raka płaskonabłonkowego płuc, ostrej białaczki mieloblastycznej.The essence of the invention is also the use of a derivative of Leflunomide's metabolite - Triflunomide (A771726), containing in its structure triphenylphosphine of the formula 1 in the treatment of cancer, in particular myeloma and lung squamous cell carcinoma, acute myeloblastic leukemia.
Wyniki przeprowadzonych testów farmakologicznych na przykładzie pochodnych: bromku 2-cyjano-3-oksy-N{4-[(trifenylofosfino)heksyloksy]benzylo}butanamidu, bromku 2-cyjano-3-oksy-N{4-[(trifenylofosfino)oktyloksy]benzylo}butanamidu, bromku 2-cyjano-3-oksy-N{4-[(trifenylofosfino)dodecyloksy]benzylo}butanamidu przedstawiono w Tabeli Nr 2.Results of pharmacological tests on the example of derivatives: 2-cyano-3-oxy-N{4-[(triphenylphosphino)hexyloxy]benzyl}butanamide bromide, 2-cyano-3-oxy-N{4-[(triphenylphosphino)octyloxy] bromide benzyl}butanamide, 2-cyano-3-oxy-N{4-[(triphenylphosphino)dodecyloxy]benzyl}butanamide bromide are presented in Table No. 2.
P r z y k ł a d 1: W kolbie stożkowej o pojemności 100 cm3 umieszczono 1.81 g (4 mmole) roztworu bromku 4-[(2-trifenylofosfino)etoksy]benzyloaminy w 30 cm3 alkoholu etylowego, do którego dodano porcjami etanolowy roztwór 2-cyjanoacetylooctanu etylu, w ilości 0.62 g (4 mmole) rozpuszczony w 30 cm3 alkoholu etylowego. Zawartość kolby mieszano przy użyciu mieszadła magnetycznego w temperaturze pokojowej przez 5-6 godzin. Po zakończeniu reakcji, wytrącony osad bromku 2-cyjano-3-oksy-N{4-[(trifenylofosfino)etoksy]benzylo}butanamidu wzór 1, odsączono i oczyszczono przez krystalizację z mieszaniny metanol-propan-2-ol (w stosunku 1:3).Example 1: In a 100 cm 3 conical flask, 1.81 g (4 mmol) of a solution of 4-[(2-triphenylphosphino)ethoxy]benzylamine bromide in 30 cm 3 of ethyl alcohol was placed, to which an ethanolic solution of 2-cyanoacetoacetate was added in portions ethyl alcohol, in the amount of 0.62 g (4 mmol) dissolved in 30 cm 3 of ethyl alcohol. The contents of the flask were stirred using a magnetic stirrer at room temperature for 5-6 hours. After completion of the reaction, the precipitate of 2-cyano-3-oxy-N{4-[(triphenylphosphino)ethoxy]benzyl}butanamide bromide formula 1 was filtered off and purified by crystallization from a methanol-propan-2-ol mixture (in the ratio of 1: 3).
Otrzymano 0.98 g (40% wydajności) osadu o t.t. 166-168°C0.98 g (40% yield) of solid with m.p. 166-168°C
Analiza elementarna dla wzoru C32H30BrN3O3P (m.cz. 601.48) obliczono:Elemental analysis for formula C32H30BrN3O3P (MW 601.48) calculated:
oznaczono:marked:
%C = 63.90 %C = 63.88 %H = 5.02 %H = 5.11 %N = 4.65 %N = 4.52 %Br = 13.28 %Br = 13.19%C = 63.90 %C = 63.88 %H = 5.02 %H = 5.11 %N = 4.65 %N = 4.52 %Br = 13.28 %Br = 13.19
Widmo 1H NMR ( DMSO-d6, δ, ppm) 1H NMR spectrum (DMSO-d6, δ, ppm)
9.31 (s, 1H, NH), 7.01-7.51 (m, 19H, H-Ar), 4.84 (s, 1H, CH), 3.63 (s, 2H, CH2benzyl), 1.96 (s, 3H, CHs), 1.48-1.70 (m, 4H, CH2),9.31 (s, 1H, NH), 7.01-7.51 (m, 19H, H-Ar), 4.84 (s, 1H, CH), 3.63 (s, 2H, CH2benzyl), 1.96 (s, 3H, CH3), 1.48 -1.70 (m, 4H, CH2),
PL 229 106 B1PL 229 106 B1
Dane fizykochemiczne pozostałych bromków 2-cyjano-3-oksy-N-podstawionych pochodnych butanamidu zamieszczono w Tabeli Nr 1.The physicochemical data of the other bromides of 2-cyano-3-oxy-N-substituted butanamide derivatives are presented in Table No. 1.
Związki: bromek 2-cyjano-3-oksy-N{4-[(trifenylofosfino)heksyloksy]benzylo}butanamidu, bromek 2-cyjano-3-oksy-N{4-[(trifenylofosfino)oktyloksy]benzylo}butanamidu, bromek 2-cyjano-3-oksy-N{4-[(trifenylofosfino)dodecyloksy]benzylo}butanamidu przebadano pod kątem cytotoksyczności na liniach komórek nowotworowych szpiczaka (RPMI 8226), ostrej białaczki mieloblastycznej (Kasumi 1), raka płasko-nabłonkowego płuca (NCIH2170) i raka żołądka (MKN74) oraz komórkach prawidłowych: hepatocytach oraz kardiomiocytach (H2C9) (wyniki przedstawiono w Tabeli Nr 2). Zbadano szereg stężeń: 25, 50, 100 i 200 pM badanych związków. Cytotoksyczność oceniono na podstawie liczby martwych komórek w obrazie mikroskopowym oraz testu MTT, na podstawie którego wyznaczono stężenia EC50 (half maximal effective concentration).Compounds: 2-cyano-3-oxy-N{4-[(triphenylphosphino)hexyloxy]benzyl}butanamide bromide, 2-cyano-3-oxy-N{4-[(triphenylphosphino)octyloxy]benzyl}butanamide bromide, bromide 2 -cyano-3-oxy-N{4-[(triphenylphosphino)dodecyloxy]benzyl}butanamide was tested for cytotoxicity on myeloma cancer cell lines (RPMI 8226), acute myeloblastic leukemia (Kasumi 1), lung squamous cell carcinoma (NCIH2170) and gastric cancer (MKN74) and normal cells: hepatocytes and cardiomyocytes (H2C9) (results are presented in Table No. 2). A series of concentrations were tested: 25, 50, 100 and 200 pM of the test compounds. Cytotoxicity was assessed on the basis of the number of dead cells in the microscopic image and the MTT test, on the basis of which EC50 (half maximal effective concentration) concentrations were determined.
Bromek 2-cyjano-3-oksy-N{4-[(trifenylofosfino)heksyloksy]benzylo}butanamidu wykazał toksyczne działanie w stosunku do komórek szpiczaka oraz raka płaskonabłonkowego płuc przy równoczesnym braku oddziaływania na komórki prawidłowe - kardiomiocyty.2-Cyano-3-oxy-N{4-[(triphenylphosphino)hexyloxy]benzyl}butanamide bromide showed toxic effects on myeloma and lung squamous cell carcinoma cells with no effect on normal cells - cardiomyocytes.
Bromek 2-cyjano-3-oksy-N{4-[(trifenylofosfino)oktyloksy]benzylo}butanamidu wykazał działanie cytotoksyczne na komórki szpiczaka oraz hepatocyty, a także ostrą białaczkę mieloblastyczną.2-Cyano-3-oxy-N{4-[(triphenylphosphino)octyloxy]benzyl}butanamide bromide has been shown to be cytotoxic to myeloma cells and hepatocytes, as well as to acute myeloblastic leukemia.
Bromek 2-cyjano-3-oksy-N{4-[(trifenylofosfino)dodecyloksy]benzylo}butanamidu wykazał silne działanie cytotoksyczne na komórki szpiczaka a także raka płuc oraz hepatocyty.2-Cyano-3-oxy-N{4-[(triphenylphosphino)dodecyloxy]benzyl}butanamide bromide has a strong cytotoxic effect on myeloma cells, lung cancer cells and hepatocytes.
PL229 106 Β1PL229 106 B1
Tabela Nr 1Table No. 1
Dane fizykochemiczne otrzymanych bromków 2-cyjano-3-oksy-N-podstawionych pochodnych butanamidu.Physicochemical data of the obtained bromides of 2-cyano-3-oxy-N-substituted butanamide derivatives.
PL229 106 Β1PL229 106 B1
Tabela Nr 2Table No. 2
Wyniki badań farmakologicznych pochodnych 2-cyjano-3-oksy-N{4-[(trifenylofosfino)alkiloksy]benzylo}butanamidu.Results of pharmacological studies of 2-cyano-3-oxy-N{4-[(triphenylphosphino)alkyloxy]benzyl}butanamide derivatives.
PL229 106 Β1PL229 106 B1
Legenda:Legend:
* powyżej 50% martwych komórek ** 25-50% martwych komórek *** 10-25% martwych komórek* more than 50% dead cells ** 25-50% dead cells *** 10-25% dead cells
Związek nr 6: bromek 2-cyjano-3-oksy-N{4-[(trifenylofosfino)heksyloksy]benzylo}butanamid, Związek nr 8: bromek 2-cyjano-3-oksy-N{4-[(trifenylofosfino)oktyloksy]benzylo}butanamid Związek nr 10: bromek 2-cyjano-3-oksy-N{4-[(trifenylofosfino)dodecyloksy]benzylo}butanamidCompound #6: 2-cyano-3-oxy-N{4-[(triphenylphosphino)hexyloxy]benzyl}butanamide bromide Compound #8: 2-cyano-3-oxy-N{4-[(triphenylphosphino)octyloxy] bromide benzyl}butanamide Compound #10: 2-cyano-3-oxy-N{4-[(triphenylphosphino)dodecyloxy]benzyl}butanamide bromide
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