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WO1998002419A1 - Inhibiteurs de proliferation de cellules cancereuses - Google Patents

Inhibiteurs de proliferation de cellules cancereuses Download PDF

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Publication number
WO1998002419A1
WO1998002419A1 PCT/JP1997/002406 JP9702406W WO9802419A1 WO 1998002419 A1 WO1998002419 A1 WO 1998002419A1 JP 9702406 W JP9702406 W JP 9702406W WO 9802419 A1 WO9802419 A1 WO 9802419A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
substituent
lower alkyl
alkyl group
methylphenyl
Prior art date
Application number
PCT/JP1997/002406
Other languages
English (en)
Japanese (ja)
Inventor
Tsutomu Chiba
Original Assignee
Chugai Seiyaku Kabushiki Kaisha
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 Chugai Seiyaku Kabushiki Kaisha filed Critical Chugai Seiyaku Kabushiki Kaisha
Priority to AU34594/97A priority Critical patent/AU3459497A/en
Publication of WO1998002419A1 publication Critical patent/WO1998002419A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol

Definitions

  • the present invention relates to a cancer cell growth inhibitor, a cancer therapeutic agent, and an anti-neoplastic agent, comprising as an active ingredient an indolin-1-one derivative or a pharmaceutically acceptable salt thereof, which is useful as a medicament.
  • a halogen atom may have a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a nitro group, a trifluoromethyl group, a lower alkylthio group, an acyl group, a carboxyl group, a mercapto group, and a substituent.
  • R 2 represents a hydrogen atom, a lower alkyl group optionally having a substituent, a lower alkenyl group optionally having a substituent, a lower alkynyl group optionally having a substituent, An optionally substituted lower alkoxy group, an optionally substituted acyl group, an optionally substituted aryl group, and an optionally substituted heterocyclic ring
  • R 3 represents a lower alkyl group optionally having a substituent, a cycloalkyl group optionally having a substituent, an aryl group optionally having a substituent, or a substituent Represents an optionally substituted heterocyclic group
  • R 4 is a hydrogen atom, an optionally substituted lower alkyl group which may have a substituent Ariru group, optionally substituted heterocyclic group, - OR 5, one SR 5 , one NR 6 R 7 , R 5 , R e , R 7 may be the same or different A hydrogen atom, a lower alkyl
  • a salt thereof has an action of selectively antagonizing the gastrin receptor and the CCK-I B receptor, peptic ulcer, gastritis, reflux esophagitis, Zo11inger-E It has been suggested that the compound has an effect of treating and preventing gastrointestinal diseases such as 11 ison syndrome or treating neoplasms of gastrointestinal origin. It is also used for the treatment of CCK-related disorders in the appetite control system, to enhance and prolong the duration of analgesia via obiates and non-aged piates, and to prevent or treat anesthesia or psychiatric symptoms including anesthesia, anxiety and panic. It has been suggested to be useful (WO 94/19322, JP-A-7-46083, EP 685463). However, no specific experimental data are disclosed on the therapeutic effect of neoplasms of gastrointestinal origin.
  • Human cerebral CCK-B receptor and gastrin receptor were reported to be identical by gene cloning (J. Biol. Chem. 268, 18300, 19993; J. Biol. Chem. 268, 8164, 1993), expressed in many human cancer cell lines such as lung cancer, colorectal cancer, colorectal cancer, gastric cancer, and T-cell lymphoma. These human cell lines are known to grow in a concentration-dependent manner by ligands such as CCK and gastrin (Am. J. Physiol. 266.277, 1994; Cancer Res. 53, 5208, 1993; Cancer Res. 49, 2840, 1989; On cogene, 9, 861, 1994).
  • a selective CCK-B / gastrin receptor antagonist L-365,260 (the compound of Example 281 described in JP-A-63-238069) has a binding ability to a gastrin receptor. Is high, but its effect on gastric acid secretion It is not strong and has not yet been applied to cancer treatment in clinical practice. Disclosure of the invention
  • the present inventors have conducted intensive studies on a compound represented by the general formula (1) or a salt thereof having a selective gastrin receptor antagonism and a selective CCK-B receptor antagonism. Found that they inhibited the growth of carcinoid tumors, and completed the present invention.
  • the present invention provides a compound represented by the general formula (1) or a compound represented by the general formula (1), which exhibits a gastrin-responsive cancer cell growth inhibitory action based on a selective gastrin receptor antagonistic action or a selective CCK-B receptor antagonistic action.
  • the present invention relates to a cancer cell growth inhibitor comprising a salt as an active ingredient, and an antineoplastic agent.
  • the target cancer is preferably a cancer in which CCK-B receptor or gastrin receptor is expressed.
  • lung cancer cancer of the colon, colorectal cancer, gastric cancer, and T-cell lymphoma.
  • the lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, and a s.
  • a methyl group such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, and a s.
  • the lower alkenyl group refers to a linear or branched alkenyl group having 2 to 6 carbon atoms, such as a vinyl group, an aryl group, a butenyl group, a pentenyl group, and a hexenyl group.
  • the lower alkynyl group means a linear or branched alkynyl group having 2 to 6 carbon atoms, such as an ethynyl group, a propynyl group, and a butynyl group.
  • the lower alkoxy group means a linear or branched alkyloxy group having 1 to 6 carbon atoms, such as methyloxy, ethyloxy, n-propylpyroxy, i-propyloxy, n-butyloxy, s-butyloxy. And a t-butyloxy group, a pentyloxy group, a hexyloxy group and the like.
  • An acyl group is a carbonyl group substituted with an alkyl group, an aryl group, an alkoxy group, an amino group, etc., which may have a hydrogen atom or a substituent.
  • Examples include an alkylcarbonyl group such as a tyl group, a propionyl group, a bivaloyl group, and a cyclohexanecarbonyl group, and an arylcarbonyl group such as a benzoyl group, a naphthoyl group, and a toluoyl group.
  • An aryl group is a monovalent group obtained by removing one hydrogen atom from an aromatic hydrocarbon, and examples thereof include a phenyl group, a tolyl group, a xylyl group, a biphenyl group, a naphthyl group, an anthryl group, and a phenanthryl group.
  • the alkylene group refers to a linear or branched alkylene group having 1 to 6 carbon atoms, for example, a methylene group, an ethylene group, a propylene group, a butylene group, a pentylene group, a hexylene group and the like.
  • the cycloalkyl group refers to a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like. Examples of the group include a menthyl group and an adamantyl group.
  • the aralkyl group refers to a lower alkyl group substituted with an aryl group, and examples thereof include a benzyl group, a diphenylmethyl group, a trityl group, a phenethyl group, and a naphthylmethyl group.
  • a benzyl group and a phenethyl group are exemplified.
  • the lower alkoxy group means a linear or branched alkyloxy group having 1 to 6 carbon atoms, such as a methyloxy group, an ethyloxy group, an n-propyloxy group, an i-propyloxy group, an n-butyloxy group, and an s-butyloxy group.
  • the heterocyclic group refers to an aromatic heterocyclic group having one or more hetero atoms, and examples thereof include a pyridyl group, a furyl group, a chenyl group, an imidazolyl group, a virazinyl group, and a pyrimidyl group.
  • substituent include a halogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a hydroxyl group, an alkoxy group, an aryloxy group, an alkylthio group, a heterocyclic group, and a formyl group (which may be protected with acetal, etc.).
  • An alkylcarbonyl group, an arylcarbonyl group, a carboxyl group, an alkoxycarbonyl group, an amino group which may have a substituent, an imino group, a thioacetal group, a nitro group, a nitryl group, and a trifluoromethyl group. can give.
  • R t is preferably a lower alkyl group or an unsubstituted form in which n is 0, particularly preferably an unsubstituted form in which n is 0.
  • R 2 is preferably a lower alkyl group substituted with an alkoxy group, and more preferably two alkoxy groups or 10-Z-0-groups (Z may have a substituent) on the same carbon.
  • a lower alkyl group having a lower alkylene group) is suitable, and a 2,2-diethoxyshethyl group is particularly preferable.
  • R 3 is preferably an aryl group which may have a substituent, more preferably a phenyl group substituted by a lower alkyl group or a lower alkoxy group, particularly preferably a methyl group or a methoxy group. Preferred is a phenyl group.
  • R 4 is one NR 6 R 7 , one of R 6 and R 7 is a hydrogen atom and the other is an aryl group which may have a substituent or a heterocyclic group which may have a substituent More preferably, one is NR 6 R 7 , one of R 6 and R 7 is a hydrogen atom and the other is substituted with a lower alkyl group or a lower alkoxy group or a substituted or unsubstituted amino group. A phenyl group substituted with a methyl group or an N, N-dimethylamino group is particularly preferable.
  • X is preferably one NH—.
  • Y is preferably one CH 2 —.
  • the (10) form is preferable.
  • FIG. 1 is a graph showing the amount of [ 3 H] -thymidine incorporated into cells by gastrin I and CCK-8.
  • FIG. 2 is a graph showing the amount of [ 3 H] -thymidine taken up into cells by the compound of Example 174.
  • FIG. 3 is a diagram showing the results of a test for suppressing the growth of ECL carcinoid tumor cells that developed in the glandular stomach of mastomys.
  • the compound of the present invention can be used in the form of a salt by a conventional method.
  • the salt used include inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate, succinate, malonate, acetate, and maleate.
  • organic salts such as fumarate, citrate, benzoate and salicylate, and metal salts such as sodium, potassium and magnesium salts.
  • the compound of the present invention or a salt thereof is prepared into tablets, powders, fine granules, capsules, pills, solutions, injections, suppositories, ointments, patches and the like, and is orally (including sublingually) or non-lingually. It is administered orally.
  • a simple substance or excipient for a preparation includes solid or liquid substances. Examples thereof include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, ethylene glycol and the like, and other commonly used ones.
  • the clinical dose of the compound of the present invention or a salt thereof is appropriately determined in consideration of the type, symptom, body weight, age, etc. of the patient, and is usually from 0.01 to 100 mg per adult.
  • Example 80 (RS) -1- (2,2-Diethoxyquinethyl) 1-3-((4-methylphenyl) aminocarbonylmethyl) 1-3- ( ⁇ ′-Cyclohexyl perylene) indrin-1-one
  • Example 172 1- (2,2-diethoxyquinethyl) 13- (L-menthoxy) carbonylmethyl-3- ( ⁇ '-(4-methylphenyl) ureido) Indolin-12-one single diastereomer ( Component before HPLC)
  • (+) 1-formylmethyl-1-3-hydroquininecarboxymethyl-3- ( ⁇ ′ — (4-methylphenyl) peridode) indrin-1-one
  • CL carcinoid tumors were minced with scissors and treated with 0.4 mg of Zm1 collagenase (type I) and 4 mg of dispase to isolate cells.
  • Cells were spiked with various hormones and test drugs and incubated in RPMI 1640 for 6 hours in the presence of [ 3 H] -thymidine (lmCiZm1). After the reaction was stopped, the radioactive concentration of [ 3 H] -thymidine incorporated into the cells was measured. The results are shown in FIGS.
  • gastrin I and CCK-8 promoted the uptake of [ 3 —]-thymidine into cells in a concentration-dependent manner, and showed a growth effect of mastomys ECL carcinoid tumor cells.
  • Example 174 inhibited gastrin-induced ECL carcinoid tumor cell growth in a concentration-dependent manner.
  • the compound of the present invention has a selective antagonistic effect on gastrin receptor and CCK-I B receptor, exhibits a cancer cell growth inhibitory effect, and is used as a cancer cell growth inhibitor, a cancer therapeutic agent, and an antineoplastic agent. Useful.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical 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

L'invention concerne des composés représentés par la formule générale (1) ou des sels de ses composés, ces composés ou sels étant utiles comme inhibiteurs de la prolifération de cellules cancéreuses et en tant que remèdes contre le cancer en raison de leurs antagonismes sélectifs contre les récepteurs de gastrine et des récepteurs CCK-B, et ils présentent un effet inhibitoire sur la prolifération des cellules cancéreuses. Dans cette formule, R1 représente halogéno, alkyle inférieur, alkoxy inférieur, hydroxy, nitro, trifluorométhyle, alkylthio inférieur, acyle, carboxy, mercapto ou amino; R2 représente hydrogène, alkyle inférieur, alkényle inférieur, alkynyle inférieur, aryle ou hétérocycle; R3 représente alkyle inférieur, cycloalkyle, aryle ou hétérocycle; R4 représente hydrogène, alkyle inférieur, aryle ou hétérocycle; X et Y sont identiques ou différents et représentent chacun -CH2-, -NH- ou -O-; et n est un nombre entier compris entre 0 et 4.
PCT/JP1997/002406 1996-07-12 1997-07-11 Inhibiteurs de proliferation de cellules cancereuses WO1998002419A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU34594/97A AU3459497A (en) 1996-07-12 1997-07-11 Cancer cell proliferation inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP21588696 1996-07-12
JP8/215886 1996-07-12

Publications (1)

Publication Number Publication Date
WO1998002419A1 true WO1998002419A1 (fr) 1998-01-22

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AU (1) AU3459497A (fr)
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000044722A1 (fr) * 1999-01-29 2000-08-03 Chugai Seiyaku Kabushiki Kaisha Promoteurs de la chondrogenese et derives d'indolin-2-one
WO2001066142A1 (fr) * 2000-03-10 2001-09-13 Chugai Seiyaku Kabushiki Kaisha Preparations pour chondrogenese
WO2002092096A1 (fr) * 2001-05-11 2002-11-21 Yamanouchi Pharmaceutical Co., Ltd. Agents antitumoraux
CN1324009C (zh) * 2003-01-30 2007-07-04 普文英 化合物1－n－甲氧基－2－氧－吲哚－3－乙酰胺及其药物用途
AU785463B2 (en) * 2001-11-26 2007-07-26 Gsa Bloodstock Pty Ltd Soil based material and method for producing same

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06321917A (ja) * 1991-06-14 1994-11-22 Merck & Co Inc 新規なベンゾジアゼピン類似体
JPH06339380A (ja) * 1992-02-07 1994-12-13 New England Medical Center Hospitals Inc ガストリン及びＣＣＫ−Ｂ受容体をコードするｃＤＮＡ
WO1995003285A1 (fr) * 1993-07-20 1995-02-02 Glaxo Spa Derives de 1,5-benzodiazepine utiles comme antagonistes de ckk et de la gastrine
WO1995004720A2 (fr) * 1993-08-10 1995-02-16 Black James Foundation Ligands de recepteur de cck et de gastrine
JPH0748349A (ja) * 1993-02-17 1995-02-21 Chugai Pharmaceut Co Ltd インドリン−２−オン誘導体
WO1995005359A1 (fr) * 1993-08-12 1995-02-23 James Black Foundation Limited Derives de bicyclo{2.2.2}octanes utilises comme antagonistes de la cholecystokinine et/ou de la gastrine
JPH07258081A (ja) * 1994-03-25 1995-10-09 Shionogi & Co Ltd 抗ガン剤及びｇｒｐレセプター拮抗剤
JPH0840908A (ja) * 1994-07-28 1996-02-13 Yamanouchi Pharmaceut Co Ltd 癌細胞増殖抑制剤

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06321917A (ja) * 1991-06-14 1994-11-22 Merck & Co Inc 新規なベンゾジアゼピン類似体
JPH06339380A (ja) * 1992-02-07 1994-12-13 New England Medical Center Hospitals Inc ガストリン及びＣＣＫ−Ｂ受容体をコードするｃＤＮＡ
JPH0748349A (ja) * 1993-02-17 1995-02-21 Chugai Pharmaceut Co Ltd インドリン−２−オン誘導体
WO1995003285A1 (fr) * 1993-07-20 1995-02-02 Glaxo Spa Derives de 1,5-benzodiazepine utiles comme antagonistes de ckk et de la gastrine
WO1995004720A2 (fr) * 1993-08-10 1995-02-16 Black James Foundation Ligands de recepteur de cck et de gastrine
WO1995005359A1 (fr) * 1993-08-12 1995-02-23 James Black Foundation Limited Derives de bicyclo{2.2.2}octanes utilises comme antagonistes de la cholecystokinine et/ou de la gastrine
JPH07258081A (ja) * 1994-03-25 1995-10-09 Shionogi & Co Ltd 抗ガン剤及びｇｒｐレセプター拮抗剤
JPH0840908A (ja) * 1994-07-28 1996-02-13 Yamanouchi Pharmaceut Co Ltd 癌細胞増殖抑制剤

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000044722A1 (fr) * 1999-01-29 2000-08-03 Chugai Seiyaku Kabushiki Kaisha Promoteurs de la chondrogenese et derives d'indolin-2-one
US6500854B1 (en) * 1999-01-29 2002-12-31 Chugai Sei Yaku Kabushiki Kaisha Chondrongenesis promotors and indolin-2-one derivatives
US6716628B2 (en) 1999-01-29 2004-04-06 Chugai Seiyaku Kabushiki Kaisha Chondrogenesis promoters and indolin-2-one derivatives
WO2001066142A1 (fr) * 2000-03-10 2001-09-13 Chugai Seiyaku Kabushiki Kaisha Preparations pour chondrogenese
WO2002092096A1 (fr) * 2001-05-11 2002-11-21 Yamanouchi Pharmaceutical Co., Ltd. Agents antitumoraux
AU785463B2 (en) * 2001-11-26 2007-07-26 Gsa Bloodstock Pty Ltd Soil based material and method for producing same
CN1324009C (zh) * 2003-01-30 2007-07-04 普文英 化合物1－n－甲氧基－2－氧－吲哚－3－乙酰胺及其药物用途

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Publication number Publication date
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