TR201514635A2 - N-acetylpyrazole derivatives having anti-cancerogenic efficiency - Google Patents
N-acetylpyrazole derivatives having anti-cancerogenic efficiency Download PDFInfo
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- TR201514635A2 TR201514635A2 TR2015/14635A TR201514635A TR201514635A2 TR 201514635 A2 TR201514635 A2 TR 201514635A2 TR 2015/14635 A TR2015/14635 A TR 2015/14635A TR 201514635 A TR201514635 A TR 201514635A TR 201514635 A2 TR201514635 A2 TR 201514635A2
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- isoindole derivative
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Abstract
Description
TARIFNAME ANTIKANSEROJEN ETKINLIGE SAHIP N-ASETILPIRAZOL TÜREVLERI Mevcut bulus antikanserojen özellik gösteren kalkon-isoindol[(3aR,4R,7S,7aS)-2-(4- iliskindir. Mevcut bulusta kalkon-isoindol[(3aR,4R,7S,7aS)-2-(4-asetilfenil)- kanser hücreleri üzerinde etkinlige sahip oldugu kanitlanmis olup bu maddelerin kanser tedavisinde kullanilmaya aday moleküller olduklari gösterilmistir. DESCRIPTION N-ACETYPYRAZOL DERIVATIVES WITH ANTI-CANCEROGEN ACTIVITY The present invention contains anticarcinogenic chalcone-isoindole[(3aR,4R,7S,7aS)-2-(4- is related. In the present invention, chalcone-isoindole[(3aR,4R,7S,7aS)-2-(4-acetylphenyl)- It has been proven that these substances have activity on cancer cells. It has been shown that they are candidate molecules to be used in cancer treatment.
Bilinen Teknik Kanser, tipta genel olarak malin neoplazi olarak bilinen ve kontrolsüz hücre büyümesini içeren bir grup hastaliga verilen isimdir. Kanser hastaliginda hücreler kontrol edilemez sekilde bölünür ve büyüler ve bu da vücudun çesitli bölgelerini isgal eden tümörleri olusturur. Kanser ayni zamanda lenfatik sistem veya kan yoluyla vücudun diger bölgelerine yayilabilir. Known Technique Cancer is an uncontrolled cell type commonly known as malignant neoplasia. is the name given to a group of diseases involving the growth of cells in cancer disease it becomes uncontrollably divided and enchanted, which invades various parts of the body. form tumors. Cancer can also be transmitted through the lymphatic system or blood. It can spread to other parts of the body.
Kanser tedavisinde siklikla basvurulan yollardan bir tanesi kemoterapidir. Ancak kemoterapi için kullanilabilecek etken maddelerin sayisinin az olmasi ve bu etken maddelerin çok ciddi yan etkilere neden olmasi bu metodun kullanimini sinirlamaktadir. Chemotherapy is one of the most frequently used means of cancer treatment. However the low number of active substances that can be used for chemotherapy and The fact that the substances cause very serious side effects discourages the use of this method. it's annoying.
Bu bulustan önceki uygulamalarda, kanser tedavisinde sikça kullanilan ilaçlarin yapilarinda Kalkon-isoindol türevleri bulunmaktadir. Bu tür yapilari içeren moleküller çogunlukla bitkilerin bünyesinde yer alirlar ve bitkilerin çesitli kimyasal maddelerle özütlenerek sailastirilmasi ile elde edilirler. Ilgili maddelerin sentetik yoldan elde edilmesi oldukça zordur. Bu tür maddeleri elde etmek için oldukça fazla kimyasal harcanmakta ve sentezlenen bilesiklerin çogunda istenmeyen fonksiyonel gruplar yer almaktadir. In the applications prior to this invention, the drugs frequently used in the treatment of cancer were There are chalcone-isoindole derivatives in their structure. Molecules containing such structures they mostly take place within the body of plants and they are associated with various chemical substances of plants. They are obtained by extraction and purification. Synthetic production of related substances it is quite difficult to do. Quite a lot of chemicals to obtain such substances is consumed and most of the synthesized compounds contain undesirable functional groups. takes.
Teknigin bilinen durumu göz önüne alindiginda daha iyi antitümör etkisine sahip olan ve içerdigi gruplarla daha az yan etki gösteren yeni kemoterapi ajanlarina ihtiyaç duyuldugu görülmektedir. Considering the known state of the art, it has better antitumor effect. and there is a need for new chemotherapy agents that have less side effects with the groups they contain. appears to be heard.
Bulus sahipleri sasirtici bir sekilde mevcut bulusa uygun kalkon-isoindol türevi maddelerin düsük antikanserojen etki, yüksek toksisite problemlerinin üstesinden geldiklerin ve kanser hücrelerine karsi önemli biyolojik etkinlik gösterdiklerini bulmuslardir.Surprisingly, the present inventive chalcone-isoindole derivative overcome the problems of low anticarcinogenic effect, high toxicity of substances and showed significant biological activity against cancer cells. they have found.
Bulusun Amaci Buna göre bulusun öncelikli amaci teknigin bilinen durumunda var olan ajanlarin neden oldugu dezavantajlarin üstesinden gelinmesini saglayacak ve antikanserojen ve etkiye sahip yeni kalkon-isoindol türevi maddeler saglamaktir. Purpose of the Invention Accordingly, the primary aim of the invention is to reduce the agents existing in the state of the art. will enable to overcome the disadvantages caused by It is to provide new chalcone-isoindole derivative substances with an effective effect.
Bulusun bir diger amaci kalkon-isoindol türevi maddelerin elde edilmesinde kullanilacak bir yöntem saglamaktir. Another object of the invention is to obtain chalcone-isoindole derivatives. is to provide a method to use.
Bulusun bir baska amaci kalkon-isoindol türevi maddelerini içeren antikanserojen ve özellikte farmasötik bilesim saglamaktir. Another object of the invention is anticarcinogenic and is to provide pharmaceutical composition in particular.
Bulusun bir diger amaci kalkon-isoindol türevi maddelerin bilinen ajanlarla beraber kullanildiginda olumlu terapötik etki elde edilmesini saglayacak farmasötik kombinasyonlar hazirlanmasidir. Another object of the invention is to combine chalcone-isoindole derivatives with known agents. pharmaceuticals that will provide a positive therapeutic effect when used combinations are prepared.
Bu bulustan önceki uygulamalarda, kanser tedavisinde sikça kullanilan ilaçlarin yapilarinda bulunan kalkon-isoindol türevleri bulunmaktadir. Söz konusu ilaçlardin yapisinda istenmeyen fonksiyenel gruplarin bulunmasi nedeniyle hastalarda nefrotoksisite, hepatotoksisite, nörotoksisite ve reprodüktif toksisite gibi birçok yan etki ortaya çikmaktadir. Bu tür bilesiklerin kullanimindan dolayi hastalarda yasam kalitesi önemli ölçüde etkilenmektedir. Yan etki ortaya çikaracak gruplarin bulunmadigi bilesiklerin sentezi tedavinin basarisi ve hastanin tedaviye uyumu açisindan önem arz etmektedir. Bu nedenle hali hazirda kullanilan kanser ilaçlarina alternatif olabilecek yeni moleküllerin sentezlenmesi ile ilgili birçok çalisma yapilmaktadir. Bulus sahipleri sasirtici bir sekilde antikarsinojenik etkinligi bulunan ve yapisinda yan etkiye sebep olabilecek yapi bulundurmayan kalkon-isoindol 1,3(2H)-dion] türevlerinin mevcut kullanimda olan ilaçlardan daha az yan etkili ve daha düsük konsantrasyonlarda etkili olabilecegi görülmüstür.In the applications prior to this invention, the drugs frequently used in the treatment of cancer were There are chalcone-isoindole derivatives in their structure. The drugs in question were in patients due to the presence of undesirable functional groups in its structure. many side effects such as nephrotoxicity, hepatotoxicity, neurotoxicity and reproductive toxicity. effect occurs. Life expectancy of patients due to the use of such compounds quality is significantly affected. Groups that will cause side effects Synthesis of compounds that are not found in treatment success and patient compliance in terms of importance. Therefore, the currently used cancer drugs Many studies on synthesizing new molecules that can be alternative is being done. Surprisingly, the inventors were found to have anticarcinogenic activity. and chalcone-isoindol, which does not contain any structure that may cause side effects in its structure. 1,3(2H)-dione] derivatives have less side effects and It has been shown to be effective at lower concentrations.
Bulusun Detayli Açiklamasi Mevcut bulusa uygun kalkon-isoindol türevi maddelerin kimyasal yapisi formül 1”de gösterilmektedir. Detailed Description of the Invention The chemical structure of chalcone-isoindole derivatives according to the present invention is given in formula 1. is shown.
Formül 1: Bulusa uygun moleküllerin genel kimyasal yapisi Burada R = o-OCH3-Ph, o-Cl-Ph, m-Cl-Ph, o-Br-Ph, m-Br-Ph, furan, olarak gösterilmektedir. Formula 1: General chemical structure of the molecules according to the invention where R = o-OCH3-Ph, o-Cl-Ph, m-Cl-Ph, o-Br-Ph, m-Br-Ph, furan, is shown.
Formül 1 ile gösterilen bilesiklerin genel kimyasal ismi kalkon-isoindol 1,3(2H)-di0n] türevleridir. Mevcut bulus kapsaminda bu molekülleri genel olarak ifade etmek için “formül l”, ve/veya kalkon-isoindol [(3aR,4R,7S,7aS)-2-(4- Mevcut bulus kapsaminda kullanilan “etken madde” ifadesi vücutta fizyoloj ik ve/veya biyokimyasal süreçleri görev veya yapilari bakimindan farrnakolojik olarak etkileyen sentetik, yari sentetik veya natürel kimyasal bilesikleri ifade etmektedir. Bu dogrultuda bulus kapsaminda açiklanan formül 1, formül 3a, formül 3b, formül 3e, formül 3d, formül 3e, formül 3f, formül 3g, formül 3h, formül 3i, formül 3j ile gösterilen tüm moleküller ve bu moleküllerle kombine olarak kullanilabilecek diger ilaç etken maddeleri, bu basvuru kapsaminda etken madde olarak tanimlanmaktadir. The general chemical name of the compounds represented by formula 1 is chalcone-isoindole 1,3(2H)-diOn] derivatives. In the context of the present invention, these molecules are generally and/or chalcone-isoindole [(3aR,4R,7S,7aS)-2-(4- The expression "active substance" used in the present invention is related to physiological and/or physiological effects in the body. pharmacologically affecting biochemical processes in terms of their function or structure refers to synthetic, semi-synthetic or natural chemical compounds. This formula 1, formula 3a, formula 3b, formula 3e, explained within the scope of the invention in line with with formula 3d, formula 3e, formula 3f, formula 3g, formula 3h, formula 3i, formula 3j All the molecules shown and any other molecules that may be used in combination with these molecules. drug active ingredients are defined as active ingredient within the scope of this application.
Mevcut bulus kapsaminda kullanilan “yardimci madde” ifadesi etken maddelerin formüle edilmesi esnasinda onlara istenilen fiziksel özellikleri kazandirmak için kullanilan ve vücutta fizyolojik ve/veya biyokimyasal süreçleri görev veya yapilari bakimindan farmakoloj ik olarak etki göstermeyen sentetik, yari sentetik veya natürel kimyasal bilesikleri ifade etmektedir. The expression "auxiliary substance" used within the scope of the present invention to give them the desired physical properties during formulation. functions or structures of physiological and/or biochemical processes used in the body synthetic, semi-synthetic or natural refers to chemical compounds.
Mevcut bulusa uygun moleküllerden biri asagida formül 3a ile gösterilmektedir; Formül 3a bilesiginin kimyasal adi (3aR,4S,7R,7aS)-2-(4-((E)-3-(4- Mevcut bulus kapsaminda bu molekülü ifade etmek için “3a” metanoisoindol-l,3(2H)-dion” terimleri birbiri ile degisebilir sekilde kullanilmaktadir. One of the molecules according to the present invention is represented by formula 3a below; Chemical name of the compound of formula 3a (3aR,4S,7R,7aS)-2-(4-((E)-3-(4-) “3a” to denote this molecule in the context of the present invention. The terms "metanoisoindol-1,3(2H)-dione" are used interchangeably.
Mevcut bulusa uygun moleküllerden biri asagida formül 3b ile gösterilmektedir; Forinül 3b bilesiginin kimyasal adi 3aR,4S,7R,7aS)-2-(4-((E)-3-(o- Mevcut bulus kapsaminda bu molekülü ifade etmek için “Sb”, “formül 3b” ve/veya methanoisoindol-l,3(2H)-dion” terimleri birbiri ile degisebilir sekilde kullanilmaktadir. One of the molecules according to the present invention is represented by formula 3b below; Chemical name of forinule 3b compound 3aR,4S,7R,7aS)-2-(4-((E)-3-(o-) In the context of the present invention, "Sb", "formula 3b" and/or The terms “methanoisoindol-1,3(2H)-dione” are used interchangeably. is used.
Mevcut bulusa uygun moleküllerden biri asagida formül 30 ile gösterilmektedir; bulus kapsaminda bu molekülü ifade etmek için “3c”, “formül 3c” ve/veya methanoisoindol-l,3(2H)-dion” terimleri birbiri ile degisebilir sekilde kullanilmaktadir. One of the molecules according to the present invention is represented by formula 30 below; “3c”, “formula 3c” and/or “3c” to express this molecule within the scope of the invention The terms “methanoisoindol-1,3(2H)-dione” are used interchangeably. is used.
Mevcut bulusa uygun moleküllerden biri asagida forinül 3d ile gösterilmektedir; akriloil)fenil)- 3a,4,7,7a- tetrahidro- lH- metanisoindol- 1,3(2H)-dion,dur. Mevcut bulus kapsaminda bu molekülü ifade etmek için “3d”, “formül 3d” ve/veya (3a R, metanisoindol- 1,3(2H)-dion” terimleri birbiri ile degisebilir sekilde kullanilmaktadir. One of the molecules in accordance with the present invention is shown below by formula 3d; acryloyl)phenyl)-3a,4,7,7a-tetrahydro-1H-metanisoindole-1,3(2H)-dione. Available “3d”, “formula 3d” and/or (3a R, The terms “metanisoindole- 1,3(2H)-dione” are used interchangeably.
Mevcut bulusa uygun moleküllerden biri asagida formül 3e ile gösterilmektedir; Formül 3e bilesiginin kimyasal adi ((3aR,4S,7R,7aS)-2-(4-((E)-3-(4- Mevcut bulus kapsaminda bu molekülü ifade etmek için “3e”, “formül 3e” ve/veya metanoisoindol-1,3(2H)-di0n” terimleri birbiri ile degisebilir sekilde kullanilmaktadir. One of the molecules according to the present invention is represented by formula 3e below; Chemical name of the compound of formula 3e ((3aR,4S,7R,7aS)-2-(4-((E)-3-(4-) In the context of the present invention, "3e", "formula 3e" and/or methanoisoindole-1,3(2H)-di0n” terms are used interchangeably.
Mevcut bulusa uygun moleküllerden biri asagida formül 3f ile gösterilmektedir; Formül 3f bilesiginin kimyasal adi (3aR,4S,7R,7aS)-2-(4-((E)-3-(2-bromofenil) bulus kapsaminda bu molekülü ifade etmek için “3f”, “formül 3I” ve/veya 4,7-metan0isoindol-l,3(2H)-dion” terimleri birbiri ile degisebilir sekilde kullanilmaktadir. One of the molecules according to the present invention is represented by formula 3f below; Chemical name of the compound of formula 3f (3aR,4S,7R,7aS)-2-(4-((E)-3-(2-bromophenyl) “3f”, “formula 3I” and/or “3f” to refer to this molecule within the scope of the invention The terms “4,7-methane-isoindole-1,3(2H)-dione” are used interchangeably. is used.
Mevcut bulusa uygun moleküllerden biri asagida formül 3 g ile gösterilmektedir; Formül 3g bilesiginin kimyasal adi (3aR,4S,7R,7aS)-2-(4-((E)-3-(3- dionsdur. Mevcut bulus kapsaminda bu molekülü ifade etinek için “3 g”, “formül 3 g” tetrahidro-1H-4,7-metan0isoindol-1,3(2H)-di0n” terimleri birbiri ile degisebilir sekilde kullanilmaktadir. One of the molecules according to the present invention is shown below by the formula 3 g; Chemical name of the compound of formula 3g (3aR,4S,7R,7aS)-2-(4-((E)-3-(3-) is dions. To express this molecule in the context of the present invention, “3 g”, “formula 3 g” tetrahydro-1H-4,7-methaneoisoindole-1,3(2H)-di0n” terms are interchangeable is used in .
Mevcut bulusa uygun moleküllerden biri asagida formül 3h ile gösterilmektedir; Formül 3h bilesiginin kimyasal adi (3aR,4S,7R,7aS)-2-(4-((E)-3-(4- bromfenil)akriloil)fenil)-3a,4,7,7a-tetrahidr0- l H-metanoisoindol-l ,3 (2H)-di0n” dur.One of the molecules according to the present invention is shown below by formula 3h; Chemical name of the compound of formula 3h (3aR,4S,7R,7aS)-2-(4-((E)-3-(4-) bromophenyl)acryloyl)phenyl)-3a,4,7,7a-tetrahydro-1H-metanoisoindol-1,3 (2H)-di0n”.
Mevcut bulus kapsaminda bu molekülü ifade etmek için “3h”, “formül 3h” ve/veya metanoisoindol-l,3(2H)-di0n” terimleri birbiri ile degisebilir sekilde kullanilmaktadir. In the context of the present invention, "3h", "formula 3h" and/or methanoisoindol-1,3(2H)-di0n” terms are used interchangeably.
Mevcut bulusa uygun moleküllerden biri asagida formül 3i ile gösterilmektedir; Formül 3i bilesiginin kimyasal adi (E)-2-(4-(3-(furan-2-il)akriloil)fenil)-3a,4,7,7a- tetrahidro-1H-4,7-metanoisoindol-1,3(2H)-dion”dur. Mevcut bulus kapsaminda bu molekülü ifade etmek için “3i”, “formül 3i” ve/veya (E)-2-(4-(3-(furan-2- il)akriloil)fenil)-3a,4,7,7a-tetrahidro-lH-4,7-metanoisoindol-1,3(2H)-dion” terimleri birbiri ile degisebilir sekilde kullanilmaktadir. One of the molecules according to the present invention is represented by formula 3i below; Chemical name of the compound of formula 3i (E)-2-(4-(3-(furan-2-yl)acryloyl)phenyl)-3a,4,7,7a- tetrahydro-1H-4,7-metanoisoindole-1,3(2H)-dione. In the context of the present invention, this “3i”, “formula 3i” and/or (E)-2-(4-(3-(furan-2-) yl)acryloyl)phenyl)-3a,4,7,7a-tetrahydro-1H-4,7-metanoisoindole-1,3(2H)-dione are used interchangeably.
Mevcut bulusa uygun moleküllerden biri asagida formül 3j ile gösterilmektedir; Formül 3j bilesiginin kimyasal adi (E)-2-(4-(3-(piridin-4-il) akriloil)fenil)-3a,4,7,7a- tetrahidro-1H-4,7-etanoisoindol-l,3(2H)-di0n”dur. Mevcut bulus kapsaminda bu molekülü ifade etmek için “3j”, “formül 3j” ve/veya (E)-2-(4-(3-(piridin-4-il) birbiri ile degisebilir sekilde kullanilmaktadir. One of the molecules according to the present invention is represented by formula 3j below; Chemical name of the compound of formula 3j (E)-2-(4-(3-(pyridin-4-yl)acryloyl)phenyl)-3a,4,7,7a- tetrahydro-1H-4,7-ethanoisoindole-1,3(2H)-diOn”. In the context of the present invention, this “3j”, “formula 3j” and/or (E)-2-(4-(3-(pyridin-4-yl)) to denote the molecule are used interchangeably.
Dolayisiyla, mevcut bulus Formül 3a ile gösterilen moleküle, bu molekülün elde edilmesinde kullanilan yönteme, bu molekülün kanser tedavisinde kullanilmasina, bu molekülün kanser tedavisinde kullanilacak bir ilacin hazirlanmasinda kullanilmasina, bu ilacin bilinen terapötik ajanlarla beraber kullanilmasina iliskindir. Therefore, the present invention relates to the molecule represented by Formula 3a. the method used in the treatment of cancer, the use of this molecule in the treatment of cancer, to use the molecule in the preparation of a drug to be used in the treatment of cancer, relates to the use of this drug with known therapeutic agents.
Dolayisiyla, mevcut bulus Formül 3b ile gösterilen moleküle, bu molekülün elde edilmesinde kullanilan yönteme, bu molekülün kanser tedavisinde kullanilmasina, bu molekülün kanser tedavisinde kullanilacak bir ilacin hazirlanmasinda kullanilmasina, bu ilacin bilinen terapötik ajanlarla beraber kullanilmasina iliskindir. Therefore, the present invention relates to the molecule represented by Formula 3b. the method used in the treatment of cancer, the use of this molecule in the treatment of cancer, to use the molecule in the preparation of a drug to be used in the treatment of cancer, relates to the use of this drug with known therapeutic agents.
Dolayisiyla, mevcut bulus Formül 30 ile gösterilen moleküle, bu molekülün elde edilmesinde kullanilan yönteme, bu molekülün kanser tedavisinde kullanilmasina, bu molekülün kanser tedavisinde kullanilacak bir ilacin hazirlanmasinda kullanilmasina, bu ilacin bilinen terapötik ajanlarla beraber kullanilmasina iliskindir.Therefore, the present invention relates to the molecule represented by Formula 30, the method used in the treatment of cancer, the use of this molecule in the treatment of cancer, to use the molecule in the preparation of a drug to be used in the treatment of cancer, relates to the use of this drug with known therapeutic agents.
Dolayisiyla, mevcut bulus Formül 3d ile gösterilen moleküle, bu molekülün elde edilmesinde kullanilan yönteme, bu molekülün kanser tedavisinde kullanilmasina, bu molekülün kanser tedavisinde kullanilacak bir ilacin hazirlanmasinda kullanilmasina, bu ilacin bilinen terapötik aj anlarla beraber kullanilmasina iliskindir. Therefore, the present invention gives the molecule represented by Formula 3d, the method used in the treatment of cancer, the use of this molecule in the treatment of cancer, to use the molecule in the preparation of a drug to be used in the treatment of cancer, relates to the use of this drug with known therapeutic agents.
Dolayisiyla, mevcut bulus Formül 3e ile gösterilen moleküle, bu molekülün elde edilmesinde kullanilan yönteme, bu molekülün kanser tedavisinde kullanilmasina, bu molekülün kanser tedavisinde kullanilacak bir ilacin hazirlanmasinda kullanilmasina, bu ilacin bilinen terapötik ajanlarla beraber kullanilmasina iliskindir. Therefore, the present invention relates to the molecule represented by Formula 3e. the method used in the treatment of cancer, the use of this molecule in the treatment of cancer, to use the molecule in the preparation of a drug to be used in the treatment of cancer, relates to the use of this drug with known therapeutic agents.
Dolayisiyla, mevcut bulus Formül 3f ile gösterilen moleküle, bu molekülün elde edilmesinde kullanilan yönteme, bu molekülün kanser tedavisinde kullanilmasina, bu molekülün kanser tedavisinde kullanilacak bir ilacin hazirlanmasinda kullanilmasina, bu ilacin bilinen terapötik aj anlarla beraber kullanilmasina iliskindir. Therefore, the present invention gives the molecule represented by Formula 3f, the method used in the treatment of cancer, the use of this molecule in the treatment of cancer, to use the molecule in the preparation of a drug to be used in the treatment of cancer, relates to the use of this drug with known therapeutic agents.
Dolayisiyla, mevcut bulus Formül 3 g ile gösterilen moleküle, bu molekülün elde edilmesinde kullanilan yönteme, bu molekülün kanser tedavisinde kullanilmasina, bu molekülün kanser tedavisinde kullanilacak bir ilacin hazirlanmasinda kullanilmasina, bu ilacin bilinen terapötik ajanlarla beraber kullanilmasina iliskindir. Therefore, the present invention gives the molecule represented by Formula 3 g, that this molecule is obtained. the method used in the treatment of cancer, the use of this molecule in the treatment of cancer, to use the molecule in the preparation of a drug to be used in the treatment of cancer, relates to the use of this drug with known therapeutic agents.
Dolayisiyla, mevcut bulus Formül 3h ile gösterilen moleküle, bu molekülün elde edilmesinde kullanilan yönteme, bu molekülün kanser tedavisinde kullanilmasina, bu molekülün kanser tedavisinde kullanilacak bir ilacin hazirlanmasinda kullanilmasina, bu ilacin bilinen terapötik ajanlarla beraber kullanilmasina iliskindir. Therefore, the present invention gives the molecule represented by Formula 3h, the method used in the treatment of cancer, the use of this molecule in the treatment of cancer, to use the molecule in the preparation of a drug to be used in the treatment of cancer, relates to the use of this drug with known therapeutic agents.
Dolayisiyla, mevcut bulus Formül 3i ile gösterilen moleküle, bu molekülün elde edilmesinde kullanilan yönteme, bu molekülün kanser tedavisinde kullanilmasina, bu molekülün kanser tedavisinde kullanilacak bir ilacin hazirlanmasinda kullanilmasina, bu ilacin bilinen terapötik aj anlarla beraber kullanilmasina iliskindir. Therefore, the present invention relates to the molecule represented by Formula 3i. the method used in the treatment of cancer, the use of this molecule in the treatment of cancer, to use the molecule in the preparation of a drug to be used in the treatment of cancer, relates to the use of this drug with known therapeutic agents.
Dolayisiyla, mevcut bulus Formül 3)' ile gösterilen moleküle, bu molekülün elde edilmesinde kullanilan yönteme, bu molekülün kanser tedavisinde kullanilmasina, bu molekülün kanser tedavisinde kullanilacak bir ilacin hazirlanmasinda kullanilmasina, bu ilacin bilinen terapötik aj anlarla beraber kullanilmasina iliskindir. Therefore, the present invention refers to the molecule represented by Formula 3). the method used in the treatment of cancer, the use of this molecule in the treatment of cancer, to use the molecule in the preparation of a drug to be used in the treatment of cancer, relates to the use of this drug with known therapeutic agents.
Mevcut bulusa uygun kalkon-isoindol türevlerinin hayli etkin antikarsinojenik özellige sahip olduklari yapilan testlerde ortaya çikarilmistir. Bu bulusun diger kanser ilaçlarina göre avantaji; düsük dozda etki göstermesi ve saglikli hücrelere daha az toksik olmasidir.Highly effective anticarcinogenic compounds of chalcone-isoindole derivatives according to the present invention It has been revealed in the tests that they have this feature. This invention is other cancer advantage over drugs; low-dose effect and less damage to healthy cells it is toxic.
Asagidaki örneklerde de gösterildigi üzere kalkon-isoindol [(3aR,4R,7S,7aS)-2-(4- barindiran antikanser bilesikleri in-vitro ortamda HeLa (Insan Servical Kanser Hücresi), C6 (Siçan Beyin Tümörü) ve HT29 (Kolon kanser hücreleri) kanserli hücre hatlarinda, saglikli hücrelerle karsilastirmali olarak denenmistir. Bunun sonucunda bilesiklerin kullanilan ilaçlara göre düsük dozlarda daha etkin oldugu tespit edildiginden bu bilesiklerin ilaç gelistirme asamalarini geçtikten sonra kanser türlerinde de kullanilabilecegi düsünülmektedir. As shown in the examples below, chalcone-isoindole [(3aR,4R,7S,7aS)-2-(4- anticancer compounds containing HeLa (Human Cervical Cancer cell), C6 (Rat Brain Tumor) and HT29 (Colon cancer cells) cancerous cell lines, it has been tested in comparison with healthy cells. As a result of this It has been determined that the compounds are more effective at low doses than the drugs used. cancer after these compounds have passed the drug development stages. It is thought that it can be used in other types.
Bir baska açidan mevcut bulus formül 1 ile gösterilen moleküllerin hazirlanmasinda kullanilacak bir yönteme iliskindir.In another aspect, the present invention is used in the preparation of molecules represented by formula 1. It relates to a method to be used.
Mevcut bulusa uygun yöntem asagidaki adimlardan olusur; a) Formül 2 ile gösterilen madde; H2N`©MR Formül 2 ki burada R = o-OCHg-Ph, o-Cl-Ph, m-Cl-Ph, o-Br-Ph, m-Br-Ph, furan, olarak kullanilir, toluen-NEt3 karisiminda çözülür. furan-1,3-dion ilave edilir, ve 24 saat reIlüks islemine tabi tutulur, d) Tepkime sonunda toluen ortamdan uzaklastirilir, e) Ürün CH2C12 ile ekstrakte edilir, I) Elde edilen karisim NazSO4 ile kurutulur ve çözücü uzaklastirilir, g) Ürün CHzClz-Hekzan ile kristallendirilir. The method according to the present invention consists of the following steps; a) Substance represented by formula 2; H2N'©MR Formula 2 where R = o-OCHg-Ph, o-Cl-Ph, m-Cl-Ph, o-Br-Ph, m-Br-Ph, furan, used, dissolved in toluene-NEt3 mixture. furan-1,3-dione is added, and reIlux treated for 24 hours, d) At the end of the reaction, toluene is removed from the environment, e) The product is extracted with CH2Cl2, I) The resulting mixture is dried with NazSO4 and the solvent is removed, g) The product is crystallized from CH2Cl2-Hexane.
Mevcut bulusa uygun moleküllerin eldesinde kullanilabilecek bir diger yöntem asagidaki adimlardan olusur; 1,3(2H)-dion CH2C12 içerisinde çözülür, b) Karisima piperidin ilave edilir, c) Reaksiyon 1 saat reIlüks olduktan sonra üzerine etanolde çözünmüs aldehit türevi formül 5 ile gösterilen madde damla damla ilave edilir Formül 5 ki burada R = o-OCHs-Ph, o-Cl-Ph, m-Cl-Ph, o-Br-Ph, m-Br-Ph, furan, olarak kullanilir, (1) Reaksiyon 24 saat reflüks islemine tabi tutulur, e) Reaksiyon sonunda karisim su- CH2C12 ve %10”1uk HCl ilave edilerek ekstrakte I) Toplanan organik faz NazSO4 ile kurutulur ve çözücü uzaklastirilir, g) Elde edilen madde CHClg/n-Hekzan ile kristallendirilir. Another method that can be used to obtain molecules according to the present invention It consists of the following steps; 1,3(2H)-dione is dissolved in CH2Cl2, b) Piperidine is added to the mixture, c) After the reaction reIlux for 1 hour, aldehyde derivative dissolved in ethanol the substance indicated by formula 5 is added dropwise Formula 5 wherein R = o-OCHs-Ph, o-Cl-Ph, m-Cl-Ph, o-Br-Ph, m-Br-Ph, furan, used, (1) The reaction is refluxed for 24 hours, e) At the end of the reaction, the mixture is extracted by adding water- CH2Cl2 and 10% 1uk HCl. I) The collected organic phase is dried with NazSO4 and the solvent is removed, g) The obtained material is crystallized with CHClg/n-Hexane.
Mevut bulus bir baska açidan formül 1 ile gösterilen moleküllerin antikanserojen ajan olarak kullanimina iliskindir. Bulusun tercih edilen bir uygulamasinda formül 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j ile gösterilen moleküller antikanserojen ajan olarak kullanilir. The present invention is another aspect of the molecules represented by the formula 1 as an anticarcinogenic agent. related to its use. In a preferred embodiment of the invention, formulas 3a, 3b, Molecules designated 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j are considered anticarcinogenic agents. used.
Bir diger açidan mevcut bulus formül 1 ile gösterilen kalkon-isoindol türevi antikanserojen özellikte ilaçlarin hazirlanmasinda kullanimina iliskindir. Bulusun tercih edilen bir uygulamasinda forinül 1 ve/veya formül 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j ile gösterilen moleküller antikanserojen özellikte ilaçlarin hazirlanmasinda kullanilir. In another aspect, the chalcone-isoindole derivative represented by the present invention formula 1 It is related to its use in the preparation of anticarcinogenic drugs. find it in a preferred embodiment, formula 1 and/or formulas 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, Molecules shown as 3i, 3j are used in the preparation of anticarcinogenic drugs. used.
Bir diger açidan mevcut bulus formül 1 ile gösterilen moleküllerin kanser tedavisinde kullanilacak ilaçlarin hazirlanmasinda kullanimina iliskindir. Bulusun tercih edilen bir kanser tedavisinde kullanilacak ilaçlarin hazirlanmasinda kullanilir. In another aspect, the present invention uses the molecules represented by formula 1 in the treatment of cancer. It is related to its use in the preparation of drugs to be used. Invent a preferred It is used in the preparation of drugs to be used in cancer treatment.
Mevcut bulus kapsaminda kullanilan “kanser” ifadesi habis (malign) tümörlere veya kontrolsüz hücre büyümesi ile karakterize olan bir fizyolojik duruma isaret eder.The term “cancer” used in the present invention refers to malignant tumors or refers to a physiological state characterized by uncontrolled cell growth.
Kanser örnekleri karsinoma, lenfoma, blastoma sarkoma ve lösemiyi içermekte olup bunlarla sinirli degildir. Examples of cancer include carcinoma, lymphoma, blastoma sarcoma, and leukemia. not angry with them.
Karsinoma, burada kullanildigi sekliyle, epitel hücrelerden olusan bir kanser türünü ifade etmektedir. Carcinoma, as used herein, is a type of cancer composed of epithelial cells. means.
Lenfoma, burada kullanildigi sekliyle, lenfositlerden gelisen bir kanser türünü anlatmaktadir.Lymphoma, as used herein, is a type of cancer that develops from lymphocytes. it tells.
Blastoma, burada kullanildigi sekliyle, blast hücre adiyla da bilinen öncü hücrelerden gelisen bir kanser türünü anlatmaktadir. Blastoma, as used herein, is one of the progenitor cells, also known as blast cells. describes a developing type of cancer.
Sarkoma, burada kullanildigi sekliyle, mezenkimal kökenli degismis hücrelerden kaynaklanan kanser türünü anlatmaktadir. Sarcoma, as used herein, consists of altered cells of mesenchymal origin. describes the type of cancer caused.
Lösemi, burada kullanildigi sekliyle, kemik iliginde baslayan ve yüksek sayida anormal akyuvar hücresi olusumuna neden olan kanser türünü ifade etmektedir. Leukemia, as used herein, is bone marrow-onset and high-number refers to the type of cancer that causes abnormal white blood cell formation.
Kanser türlerine ait daha özel örnekler meme kanseri, prostat kanseri, kolorektal kanser, deri kanseri, küçük hücreli akciger kanseri, küçük hücreli olmayan akciger kanseri, mezotelyom, gastrointestinal kanser, pankreas kanseri, gliyoblastom, vulva kanseri, rahim agzi kanseri, endometriyal karsinom, yumurtalik kanseri, karaciger kanseri, hepatom, mesane kanseri, böbrek kanseri, tükürük bezi karsinomu, tiroid kanseri ve çesitli bas ve boyun kanserlerini içerir. More specific examples of cancer types are breast cancer, prostate cancer, colorectal cancer, skin cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, gastrointestinal cancer, pancreatic cancer, glioblastoma, vulva cancer, cervical cancer, endometrial carcinoma, ovarian cancer, liver cancer, hepatoma, bladder cancer, kidney cancer, salivary gland carcinoma, thyroid cancer and various head and neck cancers.
Mevcut bulus ayni zamanda formül 1 ile gösterilen molekülleri içeren farmasötik bilesimlere iliskindir. Bulusun tercih edilen bir uygulamasinda formül 3a, 3b, 3c, 3d, 3e, 3f, 3 g, 3h, 3i, 3j ile gösterilen moleküller farmasötik bilesim içerisinde kullanilir. The present invention also includes pharmaceutical formulations containing molecules of formula 1. relates to compositions. In a preferred embodiment of the invention, formulas 3a, 3b, 3c, 3d, Molecules designated 3e, 3f, 3g, 3h, 3i, 3j are used in the pharmaceutical composition.
Mevcut bulusa göre, formül 1 ile gösterilen molekülleri içeren farmasötik bilesimler bu etken maddeye ilave olarak bir veya daha fazla çesitli yardimci maddeler içerebilirler. Pharmaceutical compositions containing molecules of formula 1 according to the present invention In addition to this active ingredient, one or more various excipients they may contain.
Mevcut bulusa göre, formül 1 ile gösterilen molekülleri içeren farmasötik bilesimler bu etken maddeye ilave olarak en az bir diger etken madde içerebilir. Pharmaceutical compositions containing molecules of formula 1 according to the present invention In addition to this active ingredient, it may contain at least one other active ingredient.
Mevcut bulusa göre, formül 1 ile gösterilen molekülleri içeren farmasötik bilesimlerde bu etken maddeye ilave olarak en az bir diger etken madde antikanserojen ve/veya antimetastatik etki gösteren etken maddeler içerisinden seçilebilir. Ikinci etken madde formül 1 ile gösterilen moleküllerle beraber formüle edilebilecegi gibi formül 1 ile gösterilen moleküllerden ayri sekilde formüle edilip beraber kullanima uygun paketlerde satisa sunulabilir. According to the present invention, pharmaceuticals containing molecules of formula 1 In addition to this active ingredient in the compositions, at least one other active ingredient Among the active substances with anticarcinogenic and / or antimetastatic effects can be selected. The second active ingredient is formulated together with the molecules indicated by formula 1. can be formulated separately from the molecules indicated by formula 1 and It can be offered for sale in packages suitable for use together.
Formül 1 ile gösterilen molekülleri içeren farmasötik bilesimlerde bu etken maddeye ilave olarak en az bir diger etken madde kullanilmasi durumunda ikinci etken madde, cyclophosphamide, methotrexate, 5-Ilu0rouracil, doxorubicin, cyclophosphamide, mustine, vincristine, procarbazine, prednisolone, bleomycin, dacarbazine, bleomycin, etoposide, cisplatin, epirubicin, capecitabine, folinic acid, oxaliplatin, carboplatin, mechloramine, melphalan, chlorambucil, ifosfamide, busulfan, N-nitroso-N-methyl urea, carmustine, lomustine, semustine, fotemustine, streptozotocin, mitozolomide, temozolomide, thiotepa, mytomycin, procarbazine, cytarabine, gemcitabine, decitabine, Vidaza, Iludarabine, nelarabine, cladribine, clofarabine, pentostatin, etoposide, teniposide, novobiocin, merbarone, aclarubicinlden olusan bir grubun içerisinden seçilebilir. Mevcut bulusa uygun moleküller Yukarida sayilan ajanlardan en az biri ile veya 2 veya daha fazla aj anla kombine halde kullanilabilirler. In pharmaceutical compositions containing molecules represented by formula 1, this active ingredient In addition, if at least one other active substance is used, the second active substance, cyclophosphamide, methotrexate, 5-Ilu0rouracil, doxorubicin, cyclophosphamide, mustine, vincristine, procarbazine, prednisolone, bleomycin, dacarbazine, bleomycin, etoposide, cisplatin, epirubicin, capecitabine, folinic acid, oxaliplatin, carboplatin, mechloramine, melphalan, chlorambucil, ifosfamide, busulfan, N-nitroso-N-methyl urea, carmustine, lomustine, semustine, fotemustine, streptozotocin, mitozolomide, temozolomide, thiotepa, mytomycin, procarbazine, cytarabine, gemcitabine, decitabine, Vidaza, Iludarabine, nelarabine, cladribine, clofarabine, pentostatin, of a group consisting of etoposide, teniposide, novobiocin, merbarone, aclarubicin can be selected from. Molecules according to the present invention They can be used with at least one or in combination with 2 or more agents.
Mevcut bulusa göre, formül 1 ile gösterilen molekülleri içeren farmasötik bilesimlerde bu etken madde 1 mem/kg ile 1000 mg/kg araliginda bir dozda kullanilabilir. According to the present invention, pharmaceuticals containing molecules of formula 1 In the compositions, this active substance is administered at a dose between 1 mem/kg and 1000 mg/kg. can be used.
Mevcut bulusa göre, formül 1 ile gösterilen molekülleri içeren farmasötik bilesimler kombine halde, simültane olarak, sirali olarak veya ayri ayri bir veya daha fazla baska terapötik aktif madde, örnegin kanser tedavisinde kullanilan aktif maddelerle birlikte verilebilir. Pharmaceutical compositions containing molecules of formula 1 according to the present invention in combination, simultaneously, sequentially or separately, in one or more other therapeutically active substance, for example in combination with active substances used in the treatment of cancer can be given.
Mevcut bulusa göre, formül 1 ile gösterilen molekülleri içeren farmasötik bilesimler kati veya sivi dozaj formlarinda formüle edilebilirler. Pharmaceutical compositions containing molecules of formula 1 according to the present invention They can be formulated in solid or liquid dosage forms.
Mevcut bulusa göre, formül 1 ile gösterilen molekülleri içeren farmasötik bilesimler agiz yoluyla alima uygun dozaj formlarinda formüle edilebilirler. Pharmaceutical compositions containing molecules of formula 1 according to the present invention They may be formulated in dosage forms suitable for oral administration.
Mevcut bulusa göre, formül 1 ile gösterilen molekülleri içeren farmasötik bilesimler agiz yoluyla alima uygun dozaj formlarinda formüle edilmesi durumunda söz konusu dozaj formu tablet, kapsül, salinimi degistirilmis tablet, salinimi uzatilmis tablet, agizda dagilan tablet, dil alti tablet, efervesan tablet, sivi solüsyon, sivi süspansyon”dan olusan bir grubun içerisinden seçilebilir. Pharmaceutical compositions containing molecules of formula 1 according to the present invention If formulated in dosage forms suitable for oral administration, dosage form tablet, capsule, modified release tablet, extended release tablet, mouth dispersing tablet, sublingual tablet, effervescent tablet, liquid solution, liquid can be selected from a group consisting of "suspension".
Mevcut bulusa göre formül 1 ile gösterilen molekülleri içeren farmasötik bilesimler inhalasyon yoluyla alima uygun dozaj formlarinda formüle edilebilirler. Pharmaceutical compositions containing molecules of formula 1 according to the present invention They may be formulated in dosage forms suitable for inhalation.
Mevcut bulusa göre formül 1 ile gösterilen molekülleri içeren farmasötik bilesimlerin inhalasyon yoluyla alima uygun dozaj forinlarinda formüle edilmesi durumunda söz konusu dozaj formu aerosol, inhaler, nebulizer, vaporizöfden olusan bir grubun içerisinden seçilebilir. Pharmaceutical compositions containing molecules of formula 1 according to the present invention If formulated in dosage forms suitable for inhalation, The dosage form in question is a group consisting of aerosol, inhaler, nebulizer, vaporizer. can be selected from.
Mevcut bulusa göre formül 1 ile gösterilen molekülleri içeren farmasötik bilesimler enjeksiyon yoluyla alima uygun dozaj formlarinda formüle edilebilirler.Pharmaceutical compositions containing molecules of formula 1 according to the present invention They may be formulated in dosage forms suitable for administration by injection.
Mevcut bulusa göre formül 1 ile gösterilen molekülleri içeren farinasötik bilesimlerin enjeksiyon yoluyla alima uygun dozaj forinlarinda formüle edilmesi durumunda söz konusu dozaj formu deri içi, kas içi, damar içi, karin için uygulamaya uygun dozaj formlarindan birinde formüle edilebilirler. Pharmaceutical compositions containing molecules of formula 1 according to the present invention If formulated in dosage forms suitable for administration by injection, The dosage form in question is suitable for intradermal, intramuscular, intravenous, abdominal application. They can be formulated in one of the following forms.
Mevcut bulusa uygun formül 1 ile gösterilen molekülleri içeren farmasötik bilesimler deri yoluyla alima uygun dozaj formlarinda formüle edilebilirler. Pharmaceutical compositions containing molecules of formula 1 according to the present invention They may be formulated in dosage forms suitable for transdermal administration.
Mevcut bulusa uygun formül 1 ile gösterilen molekülleri içeren farmasötik bilesimlerin deri yoluyla alima uygun dozaj formlarinda formüle edilmesi durumunda krem, jel, losyon, merhem, kulak damlasi, göz damlasi, transdermal flaster”den olusan bir grubun içerisinden seçilebilir. Pharmaceutical containing molecules of formula 1 according to the present invention when the compositions are formulated in dosage forms suitable for transdermal administration cream, gel, lotion, ointment, ear drops, eye drops, transdermal patch can be selected from a group.
Bulus sahipleri bulusa uygun formül 1 ile gösterilen moleküllerin yapisini teyit eden verileri, molekülün üretim yöntemine iliskin örnekleri ve bulusa uygun molekülün antikanseroj en etkisini kanitlayan deneysel verileri bu basvuruda dikkatinize sunmaktadir. Sunulan tüm bu veriler ve teknigin bilinen durumu dikkate alindiginda bulusa uygun formül 1 ile gösterilen moleküllerin teknigin bilinen durumunda daha önce açiklanmamis olan yeni moleküller oldugu ve yapilan deneylerde de gösterildigi üzere bulus konusu moleküllerin teknigin bilinen durumunda var olan antikanserojen özellikteki moleküllerden hem daha etkili oldugu hem de daha düsük toksisiteye sahip oldugu görülmekte bu baglamda mevcut bulusa uygun moleküllerin yeni oldugu ve teknigin bilinen durumunu asarak bulus basamagina sahip oldugu gösterilmektedir. The inventors confirm the structure of the molecules indicated by the formula 1 according to the invention. data, examples of the method of manufacture of the molecule, and the molecule according to the invention. We bring to your attention the experimental data proving its anticancer effect in this application. offers. Considering all these data presented and the state of the art, The molecules represented by the formula 1 according to the invention are more in the state of the art. It has been shown that there are new molecules that have not been explained before and it has been shown in the experiments. Anticarcinogens existing in the state of the art of the molecules of the invention, such as It has both more effective and lower toxicity than molecules with In this context, it is seen that the molecules according to the present invention are new and It is shown that it has an invention step by exceeding the known state of the technique.
Asagida verilen örnekler bulusu açiklamak için verilmis olup bulus konusu burada verilen örneklerle sinirlandirilmamaktadir. ÖRNEKLER: tetrahidro-lH-metanoisoindol-1,3(2H)-dion (3a)molekülünün karakterizasyonu 1172. The following examples are given to illustrate the invention and the subject of the invention is here are not limited to the examples given. EXAMPLES: Characterization of tetrahydro-1H-metanoisoindole-1,3(2H)-dione (3a) molecule 1172.
Ayrica, bilesik yesil renkli kristal formunda, %80 verimle elde edilmistir ve erime noktasi 172-176 °C olarak belirlenmistir. 1H-4,7-methan0isoindol-1,3(2H)-dion(3b) molekülünün karakterizasyonu 1H-NMR (, 8.12-8.09 (dd, Ayrica, bilesik %76 verimle elde edilmistir ve erime noktasi 138-140 °C olarak belirlenmistir. 1218, 1170.In addition, the compound was obtained in the form of green crystals with a yield of 80% and melting. point is determined as 172-176 °C. Characterization of 1H-4,7-methanOisoindole-1,3(2H)-dione(3b) molecule 1H-NMR (, 8.12-8.09 (dd, In addition, the compound was obtained in 76% yield and its melting point was 138-140 °C. has not been determined. 1218, 1170.
Ayrica, bilesik %76 verimle elde edilmistir ve erime noktasi 169-172 °C olarak belirlenmistir. tetrahidro- 1H- metanisoindol- 1,3(2H)-dion (3d) molekülünün karakterizasyonu: Ayrica, bilesik %80 verimle elde edilmistir ve erime noktasi 147-150 °C olarak belirlenmistir. tetrahidro-1H-4,7-metanoisoindol-1,3(2H)-di0n (3e) molekülünün karakterizasyonu Ayrica, bilesik %73 verimle elde edilmistir ve erime noktasi 230-234 °C olarak belirlenmistir. 45.9 (2C); 45.6 (2C). 1168. In addition, the compound was obtained in 76% yield and its melting point was 169-172 °C. has not been determined. Characterization of the molecule tetrahydro-1H-metanisoindole-1,3(2H)-dione (3d): In addition, the compound was obtained in 80% yield and its melting point was 147-150 °C. has not been determined. Characterization of tetrahydro-1H-4,7-metanoisoindole-1,3(2H)-diOn(3e) molecule In addition, the compound was obtained in 73% yield and its melting point was 230-234 °C. has not been determined. 45.9 (2C); 45.6 (2C). 1168.
Ayrica, bilesik %77 verimle elde edilmistir ve erime noktasi 160-164 °C olarak belirlenmistir. 8.8 Hz, 1H). 45.9(2C); 45.6(2C). In addition, the compound was obtained in 77% yield and its melting point was 160-164 °C. has not been determined. 8.8 Hz, 1H). 45.9(2C); 45.6(2C).
Ayrica, bilesik %86 verimle elde edilmistir ve erime noktasi 166-169 °C olarak belirlenmistir. tetrahidro-1H-metan0is0indol-1 ,3(2H)-di0n (3h) molekülünün karakterizasyonu 1H-NMR (,' 7,76 (61, Ayrica, bilesik turuncu kristal formunda %75 verimle elde edilmistir ve erime noktasi 239-241 °C olarak belirlenmistir. metanoisoindol-l ,3(2H)-dion (3i) molekülünün karakterizasyonu Ayrica, bilesik kahverengi kristal formunda %77 verimle elde edilmistir ve erime noktasi 202-205 °C olarak belirlenmistir. etanoisoindol-l,3(2H)-dion (3j) molekülünün karakterizasyonu Ayrica, bilesik %80 verimle elde edilmistir ve erime noktasi 244-246 °C olarak belirlenmistir. In addition, the compound was obtained in 86% yield and its melting point was 166-169 °C. has not been determined. Characterization of tetrahydro-1H-methaneois0indole-1,3(2H)-di0n (3h) molecule 1H-NMR (,' 7.76 (61, In addition, the compound was obtained in the form of orange crystals in 75% yield and its melting point It is determined as 239-241 °C. Characterization of methanoisoindole-1,3(2H)-dione (3i) molecule In addition, the compound was obtained in the form of brown crystals in 77% yield and melting. point is determined as 202-205 °C. Characterization of ethanoisoindole-1,3(2H)-dione (3j) molecule In addition, the compound was obtained in 80% yield and its melting point was 244-246 °C. has not been determined.
Yukarida verilen NMR spektrumlari; Bruker 400 MHz 1H ve 13C NMRasinde Gaziosmanpasa Üniversitesinde alindi. Çözücü olarak CDC13, DMSO kullanildi. Elde edilen NMR spektrum verileri yapilar ile uyum içerisindedir. Erime noktalari elektrotermal erime noktasi tayin cihaziyla belirlendi. IR ölçümlerinde örnekler KBr ile hazirlanip Transform Infrared Spectrometer (JASCO FT/IR-430) cihazindan Gaziosmanpasa Üniversitesinde alindi. Örnek 14: Bulusa uygun moleküllerin (3a-3i) antikanser özelliklerini gösteren çalismalar Çalismada in vitro testler için HeLa (Insan Servical Kanser Hücresi), C6 (Siçan Beyin Tümörü) ve HT29 (Kolon kanser hücreleri) kanser hücre hatlari kullanildi. Tüm hücre hazirlama islemleri laminar kabinde steril ortamda gerçeklestirildi. Hücreler %10 PES (Fetal Bovine Serum) ve %2 PenStrep (Penisilin-Streptomisin) solusyonu içeren katkili DMEM (Sigma, Germany) besi yeri içeren steril T75 lik hücre kültür flasklarinda 37°C de %5 C02 ortaminda 4-5 gün inkübe edildi. Hücreler konIluent hale geldiginde, flasklardaki besi yeri 10 ml Tripsin-EDTA solusyonu ile degistirilerek, 5 dakika inkübe edildi. Inkübasyon sonrasinda flask hafifçe çalkalanarak hücrelerin yüzeyden ayrilmasi saglandi, olusan hücre süspansiyonu 50 ml steril falkon tüplere aktarildi, hücreler üzerine 10 ml taze besi yeri (DMEM) eklenerek Tripsin nötralize edildi ve hücreler 1500xg de 10 dakika santrifüj edildi.NMR spectra given above; Bruker 400 MHz in 1H and 13C NMR Taken at Gaziosmanpasa University. CDC13, DMSO was used as solvent. in hand The NMR spectrum data obtained are in good agreement with the structures. melting points The electrothermal melting point was determined with a device. Samples in IR measurements KBr prepared with Transform Infrared Spectrometer (JASCO FT/IR-430) Taken at Gaziosmanpasa University. Example 14: Molecules of the invention (3a-3i) demonstrating anticancer properties studies For in vitro tests in the study, HeLa (Human Cervical Cancer Cell), C6 (Rat Brain) Tumor) and HT29 (Colon cancer cells) cancer cell lines were used. whole cell Preparation processes were carried out in a sterile environment in a laminar cabinet. Cells 10% PES (Fetal Bovine Serum) and 2% PenStrep (Penicillin-Streptomycin) solution Sterile T75 cell culture medium containing DMEM (Sigma, Germany) supplemented They were incubated in flasks at 37°C in 5% CO2 environment for 4-5 days. Cells conIluent When it becomes solid, the medium in the flasks is mixed with 10 ml of Trypsin-EDTA solution. was changed and incubated for 5 minutes. After incubation, the flask is gently The cells were shaken to separate from the surface, the resulting cell suspension was 50 Transferred to ml sterile falcon tubes, 10 ml fresh medium (DMEM) on the cells Trypsin was neutralized and the cells were centrifuged at 1500xg for 10 minutes.
Süpematant kisim aspire edildikten sonra hücre pelleti 2ml taze besiyeri eklendi ve steril pastör pipetle süspansiyon haline getirildi. Hücre sayimi için hücre süspansiyonundan alinan 10 pl hücre 10 ul tripan mavisi solusyonu ile karistirildi, bu karisimin 10 ul si Thoma lamina pipetlenerek hücreler mikroskop altinda sayildi ve hücre konsantrasyonu belirlendi (Hücre sayisi = 5 kuyucuktan sayilan toplam hücre sayisi x seyreltme faktörü x 25.000). Sayim isleminden sonra yeni bir steril 15 ml lik hazirlandi. 100 ul hücre süspansiyonundan 96lik hücre kültür plaklarina pipetlendi.After the supernatant was aspirated, 2 ml of fresh medium was added to the cell pellet and was suspended with a sterile pasteur pipette. Cell for cell count 10 µl of cells from the suspension were mixed with 10 µl of trypan blue solution, which 10 μl of the mixture was pipetted into the Thoma lamina, and the cells were counted under the microscope and cell concentration was determined (Cell count = total cells counted from 5 wells number x dilution factor x 25,000). After counting, a new sterile 15 ml was prepared. 100 µl of cell suspension was pipetted into 96 cell culture plates.
Plakalardaki hücreler kontrol ve degisik konsantrasyonlardaki test maddelerinin eklenmesinden sonra 37 °C de 24 saat inkübe edildi. Cells in the plates contain control and test substances at different concentrations. After addition, it was incubated at 37 °C for 24 hours.
Inkübasyondan sonra hücreler üzerine göre BrDU isaretleme solüsyonundan 10 uL/kuyu olacak sekilde eklendi ve hücreler 37 derecede 2 saat yeniden inkübe edildi.10 of BrDU labeling solution relative to cells after incubation µL/well was added and cells were re-incubated at 37°C for 2 hours.
Daha sonra platelerdeki medyum aspire edilerek isaretleme solüsyonunu ortamdan uzaklastirildi, filtre kagidina blotlanarak sivi kalintisi alindi ve hücreler 60 derecede 1 saat bekletilerek kurutuldu. Kurutulan hücrelere, 200 uL/kuyu olacak sekilde FixDenat solüsyonu eklendi ve 15 ila 25 derecede 30 dakika inkübe edildi. F ixDenat hem hücreleri sabitleyip hem de DNA”yi denatüre ettigi için anti-BrdU-POD antikorlannin DNA”ya girmis BrdU°ya rahatça ulasmasi saglandi. Inkübasyondan sonra FixDenat solüsyonu aspirasyon ve blotlamayla uzaklastirildi. Hücreler üzerine Anti-BrdU-POD çalisma solüsyonu 100 uL/kuyu olacak sekilde eklendi ve 22 derecede yaklasik 90 dakika inkübe edildi. Daha sonra plateler blotlanarak antikor konjugesi uzaklastirildi ve kuyular 200 ila 300 uL/kuyu olacak sekilde yikama solüsyonuyla üç kez yikandi. Sonra yikama solüsyonu dökülerek ve blotlamayla uzaklastirildi ve 100 uL/kuyu olacak sekilde substrat solüsyonu eklendi. Renk olusuncaya kadar 22 derecede 30 dakika inkübe edildi. Son olarak her bir kuyucuga uL 1 M sülfürik asit (durdurma solüsyonu) eklendi ve bir çalkalayici üzerinde 300 rpm°de yaklasik 1 dakika boyunca mikroplate inkübe edildi. Daha sonra bir ELIZA okuyucusu (Ryto, China) kullanilarak plakalardaki hücrelerin proliferasyon miktari hücre kültür medyumunun 450 nm,deki absorbansi ölçülerek belirlendi. Sonuçlar % hücre inhibisyonu olarak rapor edilmekte olup, çözücü ile muamele edilmis hücrelerin optik densitesi % 100 olarak kabul edildi. Buna göre % inhibisyon [1-(A test maddesi /A çözücü kontrol) >< 100 formülüne göre hesaplandi. Deney sonuçlari 3 kanser hücre hatti kullanilarak yapilmis olup 3 ayri testin ortalamasi seklinde ifade edilmistir. Then, the media on the plates is aspirated and the marking solution is removed from the environment. were removed, the liquid residue was removed by blotting on filter paper and cells were hour and dried. Add dried cells to 200 µL/well. FixDenat solution was added and incubated at 15 to 25 degrees for 30 minutes. FixDenat anti-BrdU-POD as it both fixes cells and denatures DNA It was ensured that the antibodies could easily reach the BrdU that had entered the DNA. from incubation Then the FixDenat solution was removed by aspiration and blotting. on cells Anti-BrdU-POD working solution was added at 100 µL/well and was incubated for approximately 90 minutes. Plates were then blotted and antibodies were conjugate was removed and wells were washed with 200 to 300 µL/well. washed three times with the solution. Then by pouring the wash solution and blotting was removed and substrate solution was added at 100 µL/well. Colour It was incubated at 22 degrees for 30 minutes until it formed. Finally, each well µL of 1 M sulfuric acid (stop solution) was added and 300 The microplate was incubated at rpm for approximately 1 minute. Then an ELIZA Proliferation amount of cells in plates using reader (Ryto, China) The absorbance of the cell culture medium at 450 nm was determined by measuring. Results % It is reported as cell inhibition and results in solvent-treated cells. The optical density was accepted as 100%. Accordingly, % inhibition [1-(A test substance) /A solvent control) Calculated according to the formula <100. Experiment results 3 cancer cells line and expressed as the average of 3 separate tests.
Mevcut bulusa uygun 3a ~ 3j moleküllerinin kanser hücreleri üzerindeki antikanser etkisi Sekil 1-10”da gösterilmektedir. Bulusa uygun moleküllerin yukarida sayilan tüm hücre tipleri üzerinde olumlu antikanserojen etki gösterdigi belirlenmistir. Anticancer effects of 3a ~ 3j molecules in accordance with the present invention on cancer cells effect is shown in Figure 1-10. The above-mentioned molecules according to the invention It has been determined that it has a positive anticarcinogenic effect on all cell types.
Bulus kapsaminda verilen ve yukarida bahsedilen sekillerin kisa açiklamasi asagida verilmektedir; tetrahidro-lH-4,7-metanoisoindol-1,3(2H)-di0n molekülünün (3a) anti kanser grafigi 4,7-methanoisoindol-1,3(2H)-dion molekülünün (3b) anti kanser grafigi tetrahidro-lH-4,7-metanoisoindol-1,3(2H)-dion molekülünün (30) anti kanser grafigi tetrahidro-lH-4,7-metanoisoindol-1,3(2H)-dion molekülünün (3d) anti kanser grafigi tetrahidro-lH-4,7- metanoisoindol-l ,3(2H)-dion molekülünün (3e) anti kanser grafigi tetrahidro-1H-4,7-metan0isoindol-1,3(2H)-di0n molekülünün (3I) anti kanser grafigi tetrahidro-lH-4,7-methanoisoindol-1,3(2H)-di0n molekülünün (3 g) anti kanser grafigi tetrahidro-1H-4,7-metan0isoindol-1,3(2H)-dion molekülünün (3h) anti kanser grafigi 1H-4,7-metanoisoindol-1,3(2H)-di0n molekülünün (3i) anti kanser grafigi 120 « v» 0 o 100 ~ - ~ f - ~ A ° I 40 - ~ ~ ~ › 1 , « m »w i 60 ~ / “wiv- ,, w ~~~~~ m 40 › ~ ** > +5~FU » -~ 39 100 400 Konsatrasyon (mcg/ml) 96 'mhibisyon 100 400 ` Konsat__rssyon (mcglml) 96 inhibisyon 120 v ~ & Inhiblsvon 0 50 190 SG inhibîsvon Konsatrasyon (mcg/ml) 96 inhibisyon 1005- +5-FU Konsatrasyon (mcg/ml) 96 inhilikyon 5030.10 2%nsantrasva Below is a brief description of the above-mentioned figures given within the scope of the invention. are given; Anticancer graph of tetrahydro-1H-4,7-metanoisoindole-1,3(2H)-di0n molecule (3a) Anticancer graph of 4,7-methanoisoindole-1,3(2H)-dione molecule (3b) Anticancer graph of tetrahydro-1H-4,7-metanoisoindole-1,3(2H)-dione molecule (30) Anticancer graph of tetrahydro-1H-4,7-metanoisoindole-1,3(2H)-dione molecule (3d) Anticancer graph of tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione molecule (3e) Anticancer graph of tetrahydro-1H-4,7-methaneoisoindole-1,3(2H)-diOn molecule (3I) Anticancer graph of tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-di0n molecule (3 g) Anticancer graph of tetrahydro-1H-4,7-methaneoisoindole-1,3(2H)-dione molecule (3h) Anticancer graph of 1H-4,7-metanoisoindole-1,3(2H)-di0n molecule (3i) 120 « v » 0 o 100 ~ - ~ f - ~ A ° I 40 - ~ ~ ~ › 1 , « m » w i 60 ~ / “wiv- ,, w ~~~~~ m 40 › ~ ** > +5~FU » -~ 39 100 400 Concentration (mcg/ml) 96' inhibition 100 400 ` Concentration__rstion (mcglml) 96 inhibitions 120v~ & Inhibition 0 50 190 SG inhibition Concentration (mcg/ml) 96 inhibitions 1005- +5-FU Concentration (mcg/ml) 96 inhilicions 5030.10 2%nsantrasva
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