WO2011022518A1 - Dérivés de la 1,2,3,4-tétrahydroisoquinoline efficaces en tant qu’agents anti-gliomes, procédés de fabrication, et leur utilisation - Google Patents

Dérivés de la 1,2,3,4-tétrahydroisoquinoline efficaces en tant qu’agents anti-gliomes, procédés de fabrication, et leur utilisation Download PDF

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Publication number
WO2011022518A1
WO2011022518A1 PCT/US2010/045948 US2010045948W WO2011022518A1 WO 2011022518 A1 WO2011022518 A1 WO 2011022518A1 US 2010045948 W US2010045948 W US 2010045948W WO 2011022518 A1 WO2011022518 A1 WO 2011022518A1
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WIPO (PCT)
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arh
och
compounds
cells
compound
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PCT/US2010/045948
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English (en)
Inventor
Renukadevi Patil
Charles Yates
Duane Miller
Eldon Geisert
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University Of Tennessee Research Foundation
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Publication of WO2011022518A1 publication Critical patent/WO2011022518A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines

Definitions

  • the present invention relates to compounds for use as
  • the invention relates to derivatives of 1 ,2,3,4-tetrahydroisoquinoline compounds for use as anti-tumor agents and in the treatment of cancer.
  • GBM glioblastoma multiforme
  • GBM glioblastoma multiforme
  • the average length of survival for people with GBM is 12 to 14 months, and common symptoms of GBM are seizures, nausea and vomiting, headaches that become progressively worse, a declining ability to move certain parts of the body, and weakness or numbness in the face or arm.
  • GBM rapidly affects the quality of the patient's life, and it may affect individuals of any age.
  • the present invention relates to compounds for the treatment of cancer, these compounds comprising 1 ,2,3,4-tetrahydroisoquinoline derivatives having structures as in Formula (I)
  • R 2 is— OCH 3 ,— CF 3 ,— NHSO 2 CH 3 — NHCOCH 3 ,— SO 2 CH 3 — N(CH 3 ) 2 , CN, -NO 2 ,— NH 2 , -CO 2 CH 3 , -OCF 3 , -CH 3 ,— F,—Br, or—I.
  • One aspect of the invention comprises compounds of Formula (I)
  • R 2 is— OCH 3 , these compounds being particularly effective for the selective destruction of tumor cells and the treatment of cancer.
  • the invention also provides methods for killing cancer cells, shrinking tumor size, and treating cancer, those methods comprising administering to a patient one or more compounds of Formula (I) as described above.
  • the cancer cells are glioblastoma cells.
  • the compound may be a compound of Formula I wherein R is
  • Figure I illustrates the synthesis of 6,8-dimethoxy- l -(2'- methoxybiphenyl-4-ylmethyl)- l ,2,3,4-tetrahydroisoquinoline hydrochloride 9a and 6,8-dimethoxy-l -[4-(4-methoxypyridin-3-yl)benzyl]-2-methyl- l ,2.3,4- tetrahydroisoquinoline dihydrochloridc 9b.
  • Figure 2 is a synthetic scheme illustrating the preparation of hydrochloride salts 12a and 13a.
  • Individual isomers were resolved by (R, R) WHELK-01 chiral HPLC column (Regis Technologies, Morton Grove, IL), enabling the inventors to obtain both enantiomers in nearly 100 % optical purity with an 85: 15 ratio of Hexane and isopropanol.
  • isomer-I&II (10a & Ha) were treated with trifluoroacetic acid in dichloromethane followed by reaction with 2M HCl in ether to afford corresponding hydrochloride salts 12a and 13a, respectively (Scheme-2).
  • Figure 3 is a synthetic scheme for the synthesis of compounds 17a, 17b, 18a, and 18b.
  • FIG 4 is a series of graphs illustrating the results of chiral separation of compound 7a using LC/DAD.
  • UV spectrum of isomer I (10a) is shown in panel A and isomer II (Ha) in panel B. Separation of racemic mixture (7a) is shown in panel C.
  • Figure 5 is a series of dose response curves testing the effects of
  • the first curve tests the effects of 7a/13a on primary cultures of normal rat astrocytes.
  • the calculated EC50 is 17.8 ⁇ M.
  • the second curve is for C6 rat glioma cells and the EC50 of 0.06 ⁇ M indicates that these cells are an order of magnitude more sensitive to the compound.
  • the third curve is from cultures of human U25 1 glioma.
  • the EC50 of 0.91 indicates that EDL-355 is killing glioma at a sub- ⁇ M concentration.
  • Figure 6 is a graph of the results of the use of a side pocket model to test the effects of 7a/13a on Human U251 glioma in the nude mouse.
  • Lines 1-5 are numbered starting from the top.
  • Line number 5 represents animals receiving EDL-355.
  • the inventors have synthesized 1 ,2,3,4-tetrahydroisoquinoline derivatives and have shown that these compounds are highly effective agents for the selective destruction of cancer cells.
  • compounds of the invention have demonstrated significant efficacy in selectively destroying glioma cells, while effective doses for destruction of tumor cells appear to have no noticeable detrimental effects on normal cells.
  • Compounds of the invention have been shown to destroy tumor cells and shrink or eradicate tumors in vivo, and are therefore effective agents for the treatment of cancer.
  • One class of cancers for which these compounds show efficacy is brain cancers, including glioblastoma.
  • Compounds of the invention may also be effective agents for other cancers, as well.
  • R 2 is -OCH 3 , -CF 3 , -NHSO 2 CH 3 -NHCOCH 3 ,— SO 2 CH 3 ,- N(CH 3 ) 2 , CN, -NO 2 , -NH 2 ,— CO 2 CH 3 , -OCF 3 , -CH 3 ,— F,—Br, or— I.
  • the inventors have also developed methods for the treatment of cancer and/or for decreasing tumor size, killing cancer cells, etc., comprising administering to a patient with cancer a therapeutically effective dose of one or more compounds disclosed herein.
  • One or more compounds of the invention may be provided in conjunction with other therapeutic agents for the treatment of cancer, if desired by the treating physician, and/or compounds of the invention may be administered in conjunction with one or more nutritional compositions containing, for example, vitamins, minerals, enzymes, co-factors, and/or nutritional compounds/compositions. Compounds of the invention may also be provided in conjunction with antiinflammatory agents, agents for the treatment of pain, etc.
  • one or more compounds of the present invention may be provided in a therapeutic regimen that includes the administration of an agent such as aspirin (acetylsalicylic acid), one or more compounds of the invention may be provided in a therapeutic regimen that includes administration of vitamin E (e.g., alpha-tocopherol, delta-tocopherol, gamma-tocopherol, alpha-tocotrienol, delta-tocotrienol, gamma-tocotrienol, or combinations thereof).
  • an agent such aspirin (acetylsalicylic acid)
  • vitamin E e.g., alpha-tocopherol, delta-tocopherol, gamma-tocopherol, alpha-tocotrienol, delta-tocotrienol, gamma-tocotrienol, or combinations thereof.
  • Compounds of the invention may be administered orally,
  • dihydrochloride 9b is shown in scheme-1.
  • the acid (2) was reacted with 2-(3,5- dimethoxyphenyl)ethylamine (1) in the presence of diethylcyanophosphonate and triethyl amine in anhydrous DMF to obtain the amide derivative (3).
  • the amide 3 was cyclized by Bischler-Napieralski reaction using POCl 3 in anhydrous acetonitrile followed by reduction with NaBH 4 to provide free amine, which was then treated with oxalic acid in methanol to form the more stable oxalyl salt (5).
  • the oxalyl salt 5 was converted to free amine using IN NaOH in dichloromethane prior to use.
  • Enantiomers of chiral compounds may demonstrate significant differences in their PK/PD profiles.
  • the inventors performed the enantioselective synthesis of (R)-and (S)- of 9a/9b by catalytic asymmetric transfer of hydrogenation of imines using 2-propanol and/or formic acid as a hydrogen source.
  • Ruthenium catalysts Noyori reagents 14SS and ⁇ 4RR may be used for the stereospecific synthesis of 9a/9b. These catalysts are prepared in situ in the reaction with conversion of imine to amine.
  • the amide 3 is subjected to Bischler-Napieralski cyclization using POCl 3 .
  • the crude iminium salt is subsequently converted to free imine 4 by means of neutralization using saturated sodium bicarbonate.
  • the catalytic system is prepared freshly every time by reacting the dimeric dichloro(p-cymene)ruthenium(II) with l ,2-(R, R)-N-tosyl- l ,2- diphenethylenediamine (for S-isomer) or 1, 2-(S,S)-N-tosy 1-1 ,2-diphenethylenediamine (for R-isomer) in presence of triethyl amine in DMF at 90 °C. The warm solution is added to dihydroisoquinoline derivative 4 in DMF and the reaction mixture is cooled to 0°C.
  • Compound 7b was prepared similarly to 7a using Pd 2 (dba) 3 as a catalyst, 2-(dicyclohexylphosphino)2',4',6'-tri-i-propyl-1,1'-biphenyl as a ligand, and K.3PO4 as a base.
  • the crude product was purified by flash column chromatography using acetone-hexane (40:60 to 50:50 v/v) to yield 7b (50 %).
  • the cells were trypsinized and transferred to 96-well plates at a cell density of 10 3 cells/mm 2 in the wells.
  • the cells were grown overnight in 100 ⁇ L of 10 % FCS BME in a 37°C incubator containing a humid, 5% CO 2 atmosphere.
  • EDL-355 was dissolved completely to make a 100 ⁇ M stock solution and diluted to produce a series of concentrations.
  • the screening data was collected as four wells for each dose per compound (screening) or concentration (dose response curve). Also, the average growth of 8 wells with no treatment was used as a negative control for each plate ( 100% growth). The cells for dose response curves were grown in the same media and were handled in a similar manner as in the screening assays.
  • Enantiomers of chiral drugs often show significant differences in their pharmacokinetics (PK), pharmacodynamics (PD), and adverse reactions. Therefore, with the aim of elucidating an enantiopharmacological profile of compound 9a, the inventors performed the chiral resolution of its precursor TV-substituted THI analog 7a by HPLC method. The inventors resolved the individual isomers by (R, R) WHELK- 01 chiral HPLC column (Regis technologies, Morton Grove, IL), which enabled them to directly and efficiently obtain both enantiomers in nearly 100 % optical purity with an 85: 15 ratio of Hexane and isopropanol ( Figure 2).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention a pour objet des composés dérivés de la tétrahydroisoquinoline efficaces pour tuer des cellules cancéreuses, réduire la taille de la tumeur, et traiter le cancer.
PCT/US2010/045948 2009-08-18 2010-08-18 Dérivés de la 1,2,3,4-tétrahydroisoquinoline efficaces en tant qu’agents anti-gliomes, procédés de fabrication, et leur utilisation WO2011022518A1 (fr)

Applications Claiming Priority (2)

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US23462909P 2009-08-18 2009-08-18
US61/234,629 2009-08-18

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WO2011022518A1 true WO2011022518A1 (fr) 2011-02-24

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108191758A (zh) * 2018-01-08 2018-06-22 连州市润邦生物科技有限公司 一种用于血管紧张素转换酶抑制剂合成的中间体及其制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080146597A1 (en) * 2006-11-21 2008-06-19 University Of Tennessee Research Foundation Therapeutic Tetrahydroisoquinoline-Based Compositions for Cancer Therapy

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080146597A1 (en) * 2006-11-21 2008-06-19 University Of Tennessee Research Foundation Therapeutic Tetrahydroisoquinoline-Based Compositions for Cancer Therapy

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108191758A (zh) * 2018-01-08 2018-06-22 连州市润邦生物科技有限公司 一种用于血管紧张素转换酶抑制剂合成的中间体及其制备方法

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