PL196194B1 - New tricyclic organic compound and method for its production - Google Patents
New tricyclic organic compound and method for its productionInfo
- Publication number
- PL196194B1 PL196194B1 PL363141A PL36314103A PL196194B1 PL 196194 B1 PL196194 B1 PL 196194B1 PL 363141 A PL363141 A PL 363141A PL 36314103 A PL36314103 A PL 36314103A PL 196194 B1 PL196194 B1 PL 196194B1
- Authority
- PL
- Poland
- Prior art keywords
- formula
- chlorophenyl
- organic compound
- new
- phenyl
- Prior art date
Links
- 150000002894 organic compounds Chemical class 0.000 title claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 title claims description 3
- 238000000034 method Methods 0.000 title description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims abstract description 13
- 239000000126 substance Substances 0.000 claims abstract description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 9
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- NUBJANMXAXISDQ-UHFFFAOYSA-N 3-[(2-aminopyridin-3-yl)amino]-1-phenylbut-2-en-1-one Chemical compound C=1C=CC=CC=1C(=O)C=C(C)NC1=CC=CN=C1N NUBJANMXAXISDQ-UHFFFAOYSA-N 0.000 claims description 2
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 claims description 2
- -1 [1,4] diazepine-5-carboxylic acid ethyl ester Chemical compound 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 230000001028 anti-proliverative effect Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- IDWPUWQDPFTXET-UHFFFAOYSA-N N1C=CN=C(C=C1)C(=O)O Chemical compound N1C=CN=C(C=C1)C(=O)O IDWPUWQDPFTXET-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- XRHGYUZYPHTUJZ-UHFFFAOYSA-N 4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-N 0.000 description 1
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 102220240796 rs553605556 Human genes 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
1. Nowy tricykliczny związek organiczny o nazwie chemicznej 16-(p-chlorofenylo)-13- -fenylo-2,7,9,11,12-pentaazatricyklo-[7.5.2.03.8]heksadeka-1(14),3,5,7,12-pentaen-10-on i o wzorze1. A new tricyclic organic compound with the chemical name 16- (p-chlorophenyl) -13-phenyl-2,7,9,11,12-pentaazatricyclo- [7.5.2.03.8] hexadeca-1 (14), 3, 5,7,12-pentaen-10-one and of the formula
Description
RZECZPOSPOLITAREPUBLIC
POLSKAPOLAND
(12) OPIS PATENTOWY (19) PL (11) (13) B1 (21) Numer zgłoszenia: 363141(12) PATENT DESCRIPTION (19) PL (11) (13) B1 (21) Application number: 363141
Urząd Patentowy Rzeczypospolitej Polskiej (22) Data zgłoszenia: 27.10.2003 (51) Int.Cl.Patent Office of the Republic of Poland (22) Date of filing: October 27, 2003 (51) Int.Cl.
C07D 471/18 (2006.01) C07D 487/02 (2006.01) C07D 487/22 (2006.01) A61K 31/4353 (2006.01) A61P 35/00 (2006.01) (54)C07D 471/18 (2006.01) C07D 487/02 (2006.01) C07D 487/22 (2006.01) A61K 31/4353 (2006.01) A61P 35/00 (2006.01) (54)
Nowy tncykNczny związekorganiczny i jegowytwarzaniaNew organic organic compound and its production
(57) 1. Nowy tricykliczny związek organiczny o nazwie chemicznej 16-(p-chlorofenylo)-13-fenylo-2,7,9,11,1 ^penteazaWc^o-p.^ZO38]heksadeka-1(14),3,5,7,12-pentaen-10-on i o wzorze 1.(57) 1. The new tricyclic organic compound with the chemical name 16- (p-chlorophenyl) -13-phen yl o- 2, 7.9, 11.1 penteazaWc ^ ^ op. ^ ZO 38] hexadeca-1 (14) , 3,5,7,12-pentaen-10-one and of formula 1.
PL 196 194 B1PL 196 194 B1
Opis wynalazkuDescription of the invention
Przedmiotem wynalazku jest nowy tricykliczny związek organiczny i sposób wytwarzania tego związku. Nowy związek wykazuje aktywność antyproliferacyjną i jest przeznaczony do leczenia chorób nowotworowych.The present invention relates to a novel tricyclic organic compound and a method for its preparation. The new compound exhibits antiproliferative activity and is intended for the treatment of neoplastic diseases.
Wynalazek dotyczy nowego tricyklicznego związku organicznego o nazwie chemicznej 16-(p-chlorofenylo)-13-fenylo-2,7,9,11,12-pentaazatricyklo[7.5.2.03'8]heksadeka-1(14)3,5,7,12-pentaen-10-on i o wzorze 1.The invention relates to new tricyclic organic compound with the chemical name 16- (pc hl oro en yl f o) f -13- en yl o-2,7,9,11,12- aaza p en t t r and c of YKL [7.5 .2.0 3 '8] h k sa d e e k-1 (14) 3,5,7,12- p t aen en-10-one and formula 1.
Wynalazek dotyczy także sposobu wytwarzania nowego tricyklicznego związku organicznego o nazwie chemicznej 16-(p-chlorofenylo)-13-fenylo-2,7,9,11,12-pentaazatricyklo[7.5.2.03-8]heksadeka-1(14),3,5,7,12-pentaen-10-on i o wzorze 1, charakteryzującego się tym, że najpierw ogrzewa się 3-(2-amiropirydyn-3-ylamino)-1-fenylo-2-buten-1-onu z aldehydem p-chlorobenzoesowym w metanolu wobec wodorotlenku potasu, w rezultacie czego powstaje nowy związek o nazwie chemicznej 1-fenylo-2-[4-(4'chlorofenylo)-1,3,4,5-tetrahydropirydo[2,3-b][1,4]diazepin-2-ylideno]-etanon i o wzorze 2, który z kolei w reakcji z chloromrówczanem etylu wobec trietyloaminy we wrzącym toluenie prowadzi do otrzymania nowego estru etylowego kwasu 4-(4'-chlorofenylo)-2-fenacylideno-1H-3,4-dihydropirydo[2,3-b][1,4]diazepino-5-karboksylowego o wzorze 3, który następnie ogrzewa się z wodzianem hydrazyny w toluenie.The invention also relates to a process for the preparation of a new tricyclic organic compound with the chemical name 16- (p-chlorophenyl) -13-phenyl-2,7,9,11,12-pentaazatricyclo [7.5.2.03- 8 ] hexadeca-1 (14), 3 , 5,7,12-pentaen-10-one and formula 1, characterized by first heating 3- (2-amyropyridin-3-ylamino) -1-phenyl-2-buten-1-one with p -chlorobenzoic acid in methanol in the presence of potassium hydroxide, resulting in a new compound with the chemical name 1-phenyl-2- [4- (4'chlorophenyl) -1,3,4,5-tetrahydropyrid [2,3-b] [1 , 4] diazepin-2-ylidene] -ethanone of the formula 2, which in turn by reaction with ethyl chloroformate in the presence of triethylamine in refluxing toluene gives a new ethyl ester of 4- (4'-chlorophenyl) -2-phenacylidene-1H- 3,4-dihydropyrid [2,3-b] [1,4] diazepine-5-carboxylic acid of formula 3 which is then heated with hydrazine hydrate in toluene.
Okazało się, że otrzymany wyżej wymieniony związek wykazuje aktywność antyproliferacyjną, czego nie można było z góry przewidzieć. Badania aktywności antyproliferacyjnej prowadzono przy użyciu testu SRB, mierzącego zahamowanie proliferacji komórek ludzkich linii nowotworowych HCV29T - rak pęcherza moczowego, MES/SA - rak macicy, SW707 - rak odbytnicy, HepG2 - rak wątroby, HL-60 - białaczka promielocytarna w hodowli in vitro. Stwierdzono, że ten sam efekt cytotoksyczny uzyskuje się przy stężeniach mniejszych niż stężenie cisplatyny. Nowy związek wykazuje aktywność cytotoksyczną (ID50) w stężeniach od 2,9 do 3,5 mg/ml.It turned out that the above-mentioned compound obtained shows an antiproliferative activity which could not be predicted in advance. Tests of antiproliferative activity were carried out using the SRB test measuring the inhibition of proliferation of human tumor lines HCV29T - bladder cancer, MES / SA - uterine cancer, SW707 - rectal cancer, HepG2 - liver cancer, HL-60 - promyelocytic leukemia in in vitro culture. It was found that the same cytotoxic effect is obtained at concentrations lower than the concentration of cisplatin. The new compound exhibits cytotoxic activity (ID50) at concentrations of 2.9 to 3.5 mg / ml.
Przedmiot wynalazku jest przedstawiony w przykładzie wykonania.The subject of the invention is presented in an exemplary embodiment.
Etap I. 2.53 g (0.01 mola) 3-(2-aminopirydyn-3-ylamino)-1-fenylo-2-buten-1-onu ogrzewa się we wrzeniu z 1.40 g (0.01 mola) aldehydu p-chlorobenzoesowego w 30 ml metanolu wobec 0.56 g (0.01 mola) wodorotlenku potasu przez 4 godziny. Powstały osad odsącza się i po wysuszeniu krystalizuje z toluenu wobec węgla aktywnego.Step I. 2.53 g (0.01 mol) of 3- (2-aminopyridin-3-ylamino) -1-phenyl-2-buten-1-one is refluxed with 1.40 g (0.01 mol) of p-chlorobenzaldehyde in 30 ml methanol versus 0.56 g (0.01 mol) of potassium hydroxide for 4 hours. The precipitate formed is filtered off and, after drying, crystallizes from toluene in the presence of active carbon.
Otrzymuje się 2.35 g nowego związku o temperaturze topnienia 194-195°C, z wydajnością 63%, o nazwie chemicznej 1-fenylo-2-[4-(4'chlorofenylo)-1,3,4,5-tetrahydropirydo(2,3-b][1,4]diazepin-2-ylideno]-etanon i o wzorze 2.2.35 g of a new compound with a melting point of 194-195 ° C and a yield of 63% with a chemical name of 1-phenyl-2- [4- (4'chlorophenyl) -1,3,4,5-tetrahydropyridine (2, 3-b] [1,4] diazepin-2-ylidene] -ethanone of the formula 2.
Etap II. 3.75 g (0.01 mola) 1-fenylo-2-[4-(4'chlorofenylo)-1,3,4,5-tetrahydropirydo[2,3-b]-[1,4]diazepin-2-ylideno]-etanonu rozpuszcza się w 50 ml wrzącego toluenu. Po ochłodzeniu do roztworu dodaje się 2.0 g (0.02 mola) trietyloaminy i 2.16 g (0.002 mola) chloromrówczanu etylu. Mieszaninę reakcyjną ogrzewa się we wrzeniu przez 9 godzin. Po oddestylowaniu toluenu pod zmniejszonym ciśnieniem, do suchej pozostałości dodaje się 50 ml wody destylowanej. Powstały osad odsącza się i po wysuszeniu krystalizuje, po oczyszczeniu węglem aktywnym, z etanolu.Stage II. 3.75 g (0.01 mol) 1-phenyl-2- [4- (4'-chlorophenyl) -1,3,4,5-tetrahydropyridine [2,3-b] - [1,4] diazepin-2-ylidene] - ethanone is dissolved in 50 ml of boiling toluene. After cooling, 2.0 g (0.02 mol) of triethylamine and 2.16 g (0.002 mol) of ethyl chloroformate are added to the solution. The reaction mixture is refluxed for 9 hours. After the toluene has been distilled off under reduced pressure, 50 ml of distilled water are added to the dry residue. The precipitate formed is filtered off and, after drying, crystallizes, after purification with active charcoal, from ethanol.
Otrzymuje się 3.66 g nowego związku o temperaturze topnienia 171-173°C, z wydajnością 82%, o nazwie chemicznej ester etylowy kwasu 4-(4'-chlorofenylo)-2-fenacylideno-1H-3,4-dihydropirydo[2,3-b][1,4]diazepino-5-karboksylowy i o wzorze 3.3.66 g of a new compound, m.p. 171-173 ° C, yield 82%, chemical name 4- (4'-chlorophenyl) -2-phenacylidene-1H-3,4-dihydropyridine [2,3 -b] [1,4] diazepine-5-carboxylic acid and of formula 3.
Etap III. 4.48 g (0.01 mola) estru etylowego kwasu 4-(4'-chlorofenylo)-2-fenacylideno-1H-3,4-dihydropirydo[2,3-b][1,4]diazepino-5-karboksylowego i 1.28 g (0.04 mola) 80% wodzianu hydrazyny ogrzewa się we wrzącym toluenie pod chłodnicą zwrotną przez 50 godzin, Mieszaninę reakcyjną zagęszcza się pod zmniejszonym ciśnieniem do sucha, a pozostałość po oczyszczeniu węglem aktywnym krystalizuje się z etanolu.Stage III. 4.48 g (0.01 mol) of 4- (4'-chlorophenyl) -2-phenacylidene-1H-3,4-dihydropyridine [2,3-b] [1,4] diazepine-5-carboxylic acid ethyl ester and 1.28 g ( 0.04 mol) 80% of hydrazine hydrate is heated in refluxing toluene for 50 hours, the reaction mixture is concentrated to dryness under reduced pressure, and the residue, after purification with active carbon, is crystallized from ethanol.
Otrzymuje się 2.68 g nowego związku o temperaturze topnienia 236-237°C, z wydajnością 64%, o nazwie chemicznej 16-(p-chlorofenylo)-13-fenylo-2,7,9,11,12-pentaaza-tricyklo-[7.5.2.03·8]heksadeka-1(14),3,5,7,12-pentaen-10-on i o wzorze 1.2.68 g of a new compound with a melting point of 236-237 ° C and a yield of 64% with the chemical name 16- (p-chlorophenyl) -13-phenyl-2,7,9,11,12-pentaaza-tricyclo [ 7.5.2.03 · 8 ] hexadeca-1 (14), 3,5,7,12-pentaen-10-one and of the formula 1.
PL 196 194 B1PL 196 194 B1
Charakterystykę nowego związku podaje poniższa tabelaThe characteristics of the new compound are given in the table below
Zastrzeżenia patentowePatent claims
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL363141A PL196194B1 (en) | 2003-10-27 | 2003-10-27 | New tricyclic organic compound and method for its production |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL363141A PL196194B1 (en) | 2003-10-27 | 2003-10-27 | New tricyclic organic compound and method for its production |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| PL363141A1 PL363141A1 (en) | 2005-05-02 |
| PL196194B1 true PL196194B1 (en) | 2007-12-31 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| PL363141A PL196194B1 (en) | 2003-10-27 | 2003-10-27 | New tricyclic organic compound and method for its production |
Country Status (1)
| Country | Link |
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| PL (1) | PL196194B1 (en) |
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2003
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Also Published As
| Publication number | Publication date |
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| PL363141A1 (en) | 2005-05-02 |
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