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WO1991005770A1 - Agents anti-cancereux potentiels derives de l'acridine - Google Patents

Agents anti-cancereux potentiels derives de l'acridine Download PDF

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Publication number
WO1991005770A1
WO1991005770A1 PCT/US1990/005958 US9005958W WO9105770A1 WO 1991005770 A1 WO1991005770 A1 WO 1991005770A1 US 9005958 W US9005958 W US 9005958W WO 9105770 A1 WO9105770 A1 WO 9105770A1
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WO
WIPO (PCT)
Prior art keywords
anilino
methylacridine
methoxy
dimethylacridine
dimethoxy
Prior art date
Application number
PCT/US1990/005958
Other languages
English (en)
Inventor
Kyoichi A. Watanabe
Kiyobumi Takahashi
Original Assignee
Sloan-Kettering Institute For Cancer Research
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sloan-Kettering Institute For Cancer Research filed Critical Sloan-Kettering Institute For Cancer Research
Publication of WO1991005770A1 publication Critical patent/WO1991005770A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/56—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position
    • C07C229/58—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position having the nitrogen atom of at least one of the amino groups further bound to a carbon atom of a six-membered aromatic ring, e.g. N-phenyl-anthranilic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C07D219/06—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C07D219/08—Nitrogen atoms
    • C07D219/10—Nitrogen atoms attached in position 9

Definitions

  • the natural products, 1A and 1B may have the intercalating capability but lack the alkylating function, whereas 2A and 2B may have the alkylating capability but are incapable of intercalating into DNA due to the presence of two bulky methoxy groups. These compounds are practically inactive against mouse leukemic cells L1210 in tissue culture. However, 3A and 3B which contain both intercalating and alkylating capabilities exhibited potent inhibitory activity against L1210 cells in tissue culture.
  • R 1 , R 2 , R 3 , R 4 are the same or different and are hydrogen (H), or a lower alkyl group of from about 1-4 carbon atoms, or a lower alkoxy group of from about 1-4 carbon atoms
  • R is a substituted aniline
  • Figure 1 Structures of compounds with properties related to the compound of the subject invention.
  • 1A is chrysophanol; 1B is emodin; 2A is a 1,8 dimethoxy derivative of 1B; 3A is 3-[N,N-bis (2- chloroethyl)-amino]methyl-1,8-dihydroxy- 9,10-anthraquinone; and 3B is the 6- methoxy analog of 3A.
  • Figure 2 Synthesis of 9-chloroacridine derivatives from o-chlorobenzoic acid and substituted aniline.
  • the subject invention provides a compound having the structure:
  • R is a substituted
  • R 5 , R 6 , R 7 is an alkanol
  • R' and R" are the same or different
  • R' and R" may be hydrogen (H), and the remaining groups are hydrogen.
  • Compounds having the above-identified structure may be selected from the group consisting of:
  • the subject invention also provides a method of synthesizing a compound having the structure:
  • each of R 1 , R 2 , R 3 , R 4 are the same or different and are hydrogen (H), or a lower alkyl group of from 1-4 carbon atoms, or a lower alkoxy group of from about 1-4 carbon atoms.
  • R 1 and R 2 are the same or different and are hydrogen, or a lower alkyl group of from about 1-4 carbon atoms or a lower alkoxy group of from about 1-4 carbon atoms, R 1 and R 2 are as herein defined throughout this synthesis; with a compound having the structure:
  • each of R 3 and R 4 are the same or different and are hydrogen, or a lower alkyl group of from about 1-4 carbon atoms or a lower alkoxy group of from about 1-4 carbon atoms; R 3 and R 4 are as herein defined throughout this synthesis; under such conditions so as to form a compound having the structure:
  • step (b) treating the compound formed in step (a) under such conditions so as to form a compound having the structure:
  • step (b) if the compound formed in step (b) is a compound having the structure:
  • step (b) condensing the compound formed in either step (b) or step (c) having the structure:
  • step (a) the contacting comprises condensing in the presence of copper, cuprous oxide, and base, and preferably the base is potassium carbonate or sodium carbonate. It is also preferred that in step (a) the contacting is effected in a solvent.
  • Preferred solvents include, but are not limited to, 2- ethoxyethanol, glyme, N,N-dimethylformamide, or acetamide.
  • the contacting of step (a) is preferably perfomed at a temperature range of from about 60oC to 200oC, and must preferably at about 140oC.
  • the treating comprises contacting the compound formed in step (a) with triphenylphosphine and bromotrichloromethane, and preferably the treating is effected in a solvent.
  • Preferred solvents include, but are not limited to tetrahydrofuran or dioxan.
  • the treating of step (b) is best perfomed at a temperature range of from about 36oC to 145oC, with the most preferred conditions being at about 66oC, for about 1 to 8 hours.
  • step (b) the treating comprises contacting the compound formed in step (a) with phosphorus oxychloride. It is also preferred that in step (c) the treating comprises contacting the compound formed in step (b) with phosphorus oxychloride.
  • step (d) the condensing comprises contacting the compound having the structure:
  • R 1 , R 2 , R 3 , R 4 are the same or different and are hydrogen (H), or a lower alkyl group of from about 1-4 carbon atoms, or a lower alkoxy group of from about 1-4 carbon atoms; with a substituted aniline having the structure:
  • step (d) the condensing is effected in the presence of an acid catalyst.
  • Preferred acid catalysts includes, but are not limited to, methylsufonic acid, toluenesulfonic acid, benzene sulfonic acid, or camphorsulfonic acid.
  • the acid catalyst can be a Lewis acid, with the preferred Lewis acid being boron trihalide.
  • step (d) the condensing is effected in an inert solvent such as a chlorohydrocarbon, and more preferrably the chlorohydrocarbon is methylene chloride, chloroform, ethylene dichloride, or ethylene tetrachloride.
  • an inert solvent such as a chlorohydrocarbon
  • the chlorohydrocarbon is methylene chloride, chloroform, ethylene dichloride, or ethylene tetrachloride.
  • Another preferred inert solvent is an ether, preferrably tetrahydrofuran, dioxan, or diethyl ether.
  • the treating comprises contacting the compound formed in step (d) with an alkylisocyanate in the presence of an organic amine.
  • organic amines include, but are not limited to, trimethylamine, triethylamine, N,N- dimethylaniline, 4-dimethylamino pyridine, 1,5- diazabicyclo[4.3.0] non-5-ene, or 1,8-diaza bicyclo [5.4.0] undec-7-ene.
  • the treating is effected in a solvent, preferrably a halogenated hydrocarbon.
  • a halogenated hydrocarbon include, but are not limited to, methylene chloride, chloroform, or dichloroethane.
  • the treating is performed at a temperature range of form about 0oC to 120oC, and most preferrably at about 25oC, wherein the treating is performed for about 1 hour to 5 days.
  • the subject invention also provides a compound having the structure:
  • R 1 , R 2 , R 3 , R 4 are the same or different and are hydrogen, or lower alkyl groups of from about 1-4 carbon atoms, or lower alkoxy groups of from about 1-4 carbon atoms.
  • the subject invention further provides a compound having the structure:
  • lower alkyl group of from about 1-4 carbon atoms, or a lower alkoxy group of from
  • This compound may be selected from the group consisting of, but not limited to:
  • the subject invention also provides a pharmaceutical composition comprising an amount of the compound of formula I or a salt thereof, effective to inhibit the growth of tumor cells and a physiologically acceptable carrier.
  • the pharmaceutical composition kills the tumor cells.
  • physiologically acceptable carriers are to include any carrier compatible with life.
  • the choice of carrier is readily determinable to one skilled in art.
  • the physiologically acceptable carrier encompasses any of the standard carriers such as sterile solutions, tablets, coated tablets and capsules.
  • Such carriers contain excipients such as starch, milk, sugar, certain types of clay, gelatin, stearic acid, talc, vegetable fats or oils, gums glycols, or other known excipients.
  • Such carriers may also include flavor and color additives or other ingredients.
  • Compositions comprising such carriers are formulated by well known conventional methods. However a composition comprising a compound of the subject invention effective to inhibit growth of tumor cells is previously unknown.
  • the subject invention also provides a method of treating a subject having a tumor which comprises administering to the subject an amount of a composition described above effective to inhibit the growth of tumor cells.
  • the method of treatment may be either in response to a diagnosed tumor or as a prophylactic measure designed to prevent the growth of tumor cells. It is preferred that the inhibition of tumor cell growth results ultimately in the death of the tumor cells.
  • composition may be effected by any of the well known methods, including but limited to, oral, intravenous, intramuscular, and subcutaneous administration.
  • the amount of the compound of formula I incorporated in the composition may vary widely. Methods for determining the precise amount are well known to those skilled in the art and depend inter alia upon the subject being treated, the specific pharmaceutical carrier and route of administration being employed, and the frequency with which the composition is to be administered.
  • the subject invention provides, a method of inhibiting the growth of tumor cells which comprises contacting the cells with an amount of a compound of formula I effective to inhibit the growth of tumor cells. Once again, it is preferred that the inhibition of tumor cell growth results in the killing of the tumor cells.
  • the present invention relates to the novel class of acridines which contain a covalent bond forming capability. Such compounds may intercalate into DNA and then bind covalently to DNA thereby exerting cytotoxic activity.
  • the mechanism(s) of biological action of the compounds incorporated into this invention are different than that of the known acridine anticancer agents, such as amsacrin, which appears to induce DNA cleavage mediated by topoisomerse II [E.M. Nelson et al., Proc. Nat. Acad. Sci., U.S.A., 81:1361 (1984); Y. Pommier et al..
  • Compounds 1 aad 2 are condensed to diphenylamine derivatives (3) in the presence of copper, cuprous oxide and base, such as potassium carbonate or sodium carbonate, in a solvent, such as 2-ethoxyethanol, glyme, N,N-dimethylformamide, acetamide, at a temperature range of about 60oC to 200oC, preferably at 140oC for a period of from 1 to 5 hours.
  • a solvent such as 2-ethoxyethanol, glyme, N,N-dimethylformamide, acetamide
  • Compounds 3 are then converted into the correspondng piperides 4 in the present of triphenylphosphine and bromotrichloromethane in a solvent such as tetrahydrofuran, dioxan, or the like, at a temperature range of from 36oC to 145oC, preferably at 66oC for a period of from 1 to 8 hours.
  • a solvent such as tetrahydrofuran, dioxan, or the like
  • Treatment of piperides 4 with phosphorus oxychloride affords the corresponding 9-chloroacridines having formula II.
  • the latter can also be prepared directly from 3 by phosphorous oxychloride treatment.
  • Compounds of formula II are condensed with substituted anilines in the presence of an acid catalyst such as methylsulfonic acid, toluenesulfonic acid, benzene- sulfonic acid, camphorsulfonic acid, and boron trihalide or other Lewis acid, in an inert solvent such as a chlorohydrocarbon, including methylene chloride, chloroform, ethylene dichloride, and ethylene tetra- chloride, or an ether, including tetrahydrofuran, dioxan,and diethylether under reflux for about 1 to 5 hours.
  • an acid catalyst such as methylsulfonic acid, toluenesulfonic acid, benzene- sulfonic acid, camphorsulfonic acid, and boron trihalide or other Lewis acid
  • an inert solvent such as a chlorohydrocarbon, including methylene chloride, chloroform, ethylene dichloride, and ethylene tetra- chlor
  • each of R 1 , R 2 , R 3 , R 4 are the same or different and are hydrogen (H), lower alkyl groups of 1-4 carbon atoms, such as methyl (Me), ethyl (Et) or propyl (Pr) groups, or lower alkoxy groups of 1-4 carbon atoms, such as methoxy (MeO), ethoxy (EtO) or propoxy (PrO) groups.
  • R 5 , R 6 , R 7 is an hydroxyalkyl group
  • Example 1 is illustrative of the process and products of the present invention, but are not to be construed as limiting.
  • the filtrate is acidified with concentrated hydrochloric acid to about pH 2, and the mixture is extracted with ethyl ether (5 x 100 ml).
  • the combined extracts are washed with 1 N hydrochloric acid (200 ml) and water (2 x 200 ml), dried over sodium sulfate, concentrated in vacuo, and the solid residue is recrystallized from ethanol-water to give N-(p-tolyl)- 5-methoxyanthranilic acid (13.9 g, 68% yield), mp 160- 161oC.
  • N-(m-Tolyl) anthranilopiperide 32 g, 0.11 mol is dissolved in phophorus oxychloride (150 ml), and the solution is heated at 150oC for 4 hours, and then excess phosphorus oxychloride is removed in vacuo. To the residue is added water (500 ml) followed by aqueous ammonia (200 ml) . The mixture is extracted with chloroform (3 x 500 ml).
  • Basic and planar molecules such as derivatives of acridine, readily intercalate into DNA. If such molecules can bind to DNA after intercalation, the DNA function should be permanently damaged and result in improved anticancer activity.
  • This invention is made on the basis of the above new concept.
  • Table 6 lists typical results of in vitro studies on 9- (substituted) anilinoacridines of formula III.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heat Sensitive Colour Forming Recording (AREA)
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Abstract

Les composés décrits peuvent être représentés par la formule (I), où: R?1, R2, R3, R4¿ sont chacun identiques ou différents et représentent l'hydrogène (H) ou un groupe alkyle inférieur d'environ 1 à 4 atomes de carbone ou un groupe alkoxy inférieur d'environ 1 à 4 atomes de carbone; R représente une aniline substituée représentée par la formule (α), où l'un des éléments R?5, R6, R7¿ représente un alkanol de formule -(CH¿2?)nOH, et n est égal à un nombre compris entre 1 et 4, ou son ester de carbamate de formule -(CH2)nOCONR'R'', et n est égal à un nombre compris entre 1 et 4, et où R'et R'' représentent des groupes alkyle inférieurs identiques ou différents d'environ 1 à 4 atomes de carbone, l'un des éléments R' et R'' pouvant représentés l'hydrogène (H) et les groupes restants représentant l'hydrogène. L'invention se rapporte en outre à des procédés de synthèse de ces composés, à des compositions physiologiquement acceptables contenant ces composés et à des procédés d'utilisation de ces composés en vue d'inhiber la croissance de cellules tumorales.
PCT/US1990/005958 1989-10-17 1990-10-17 Agents anti-cancereux potentiels derives de l'acridine WO1991005770A1 (fr)

Applications Claiming Priority (2)

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US42262989A 1989-10-17 1989-10-17
US422,629 1989-10-17

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5229395A (en) * 1989-10-17 1993-07-20 Sloan-Kettering Institute For Cancer Research Potential anticancer agents derived from acridine
WO2000037447A1 (fr) * 1998-12-18 2000-06-29 Samjin Pharmaceutical Co., Ltd. Derives 9-aminoacridine et leur processus de preparation
WO2003074490A1 (fr) * 2002-03-07 2003-09-12 Samjin Pharmaceutical Co., Ltd. Derives de 9-aminoacridine et procede de preparation

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4631286A (en) * 1984-10-25 1986-12-23 Hoechst-Roussel Pharmaceuticals Inc. 9-amino-1,2,3,4-tetrahydroacridin-1-ol and related compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4631286A (en) * 1984-10-25 1986-12-23 Hoechst-Roussel Pharmaceuticals Inc. 9-amino-1,2,3,4-tetrahydroacridin-1-ol and related compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF MEDIANAL CHEMISTRY, Volume 22, No. 3, pages 251-255, (March 1979), FERGUSON et al., Potential Antitumor Agents. *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5229395A (en) * 1989-10-17 1993-07-20 Sloan-Kettering Institute For Cancer Research Potential anticancer agents derived from acridine
WO2000037447A1 (fr) * 1998-12-18 2000-06-29 Samjin Pharmaceutical Co., Ltd. Derives 9-aminoacridine et leur processus de preparation
EP1380574A1 (fr) * 1998-12-18 2004-01-14 Samjin Pharmaceutical Co., Ltd. Derivés de la 9-aminoacridine et processus pur leur preparation
WO2003074490A1 (fr) * 2002-03-07 2003-09-12 Samjin Pharmaceutical Co., Ltd. Derives de 9-aminoacridine et procede de preparation
US7230105B2 (en) * 2002-03-07 2007-06-12 Samjin Pharmaceutical Co., Ltd. 9-aminoacridine derivatives and process for the preparation thereof

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