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WO2004054996A1 - Nouveaux derives de 1-phenyl-tetrahydronaphtalene substitues et leur utilisation en tant qu'inhibiteurs du recepteur de l'igf-1 - Google Patents

Nouveaux derives de 1-phenyl-tetrahydronaphtalene substitues et leur utilisation en tant qu'inhibiteurs du recepteur de l'igf-1 Download PDF

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Publication number
WO2004054996A1
WO2004054996A1 PCT/SE2003/002010 SE0302010W WO2004054996A1 WO 2004054996 A1 WO2004054996 A1 WO 2004054996A1 SE 0302010 W SE0302010 W SE 0302010W WO 2004054996 A1 WO2004054996 A1 WO 2004054996A1
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WIPO (PCT)
Prior art keywords
methylenedioxy
phenyl
igf
compound
receptor
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/SE2003/002010
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English (en)
Inventor
Magnus Axelson
Olle Larsson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Axelar AB
Swedish Orphan Biovitrum AB
Original Assignee
Biovitrum AB
Axelar AB
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 Biovitrum AB, Axelar AB filed Critical Biovitrum AB
Priority to AU2003288857A priority Critical patent/AU2003288857A1/en
Publication of WO2004054996A1 publication Critical patent/WO2004054996A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/70—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with ring systems containing two or more relevant rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics

Definitions

  • the present invention refers to new compounds as well as to the use of said new compounds as specific inhibitors of the insulin-like growth factor-1 receptor, the IGF-IR, for treatment of
  • IGF-IR dependent diseases such as cancer, psoriasis, and arteriosclerosis .
  • the insulin-like growth factor-1 receptor plays an important role in proliferation, protection against apoptosis and transformation of malignant cells.
  • the IGF-IR is also important for maintaining the malignant phenotype of tumour cells, and is involved in tumour cells developing resistance to the action of anti-cancer drugs. In contrast, the IGF-IR seems not to be an absolute requirement for normal cell growth.
  • the IGF-IR consists of two identical extracellular alpha- subunits that are responsible for ligand binding, and two identical beta-subunits with a transmembrane domain and an intracellular tyrosine kinase domain.
  • the ligand-receptor interaction results in phosphorylation of tyrosine residues in the tyrosine kinase domain, which spans from amino acid 973 to 1229 of the ⁇ -subunit.
  • the major sites for phosphorylation are the clustered tyrosines at position 1131, 1135 and 1136 (LeRoith, D. , et al., Endocr Rev 1995 April; 16(2), 143-63).
  • IGF-IR insulin receptor substrate-1 and She, which activate the phosphatidyl inositol-3 kinase and the mitogen-activated protein kinase signalling pathways, respectively.
  • IGF-IR is a target for cancer therapy (Baserga, R., et al., Endocrine vol. 7, no. 1, 99-102, August 1997) .
  • One strategy to block IGF-IR activity is to induce selective inhibition of the IGF-IR tyrosine kinase.
  • etoposide is a ethylidene glucoside derivative of 4 ' -demethyl-epipodophyllotoxin.
  • Etoposide which has no effect on microtubules (or the IGF-IR) , is a DNA topoisomerase II inhibitor, and is currently being used as such in cancer therapy.
  • the IGF-IR is a member of the tyrosine kinase receptor family, which also includes the receptors of insulin, epidermal growth factor (EGF) , nerve growth factor (NGF) , and platelet-derived growth factor (PDGF) .
  • EGF epidermal growth factor
  • NGF nerve growth factor
  • PDGF platelet-derived growth factor
  • a number of synthetic tyrosine kinase inhibitors, called tyrphostins have been studied by Parrizas, M., et al., Endocrinology 1997,. Vol. 138, No. 4, 1427-1433.
  • the major disadvantage with all tyrphostins active on IGF-IR is that . they cross-react with the insulin receptor, since these receptors are highly homologous.
  • PCT/SE02/01223 discloses new compounds, i.e. substituted 1- phenyl-tetrahydronaphtalenes, and the use thereof as well as the use of cyclolignans having a trans configuration in the lactone ring as specific inhibitors of the insulin-like growth factor-1 receptor. Said compounds can be used for treatment of IGF-IR dependent diseases, especially cancer. Before this, a connection between the IGF-IR and podophyllotoxin derivatives/cyclolignans had never been made.
  • the object of the present invention is to find new compounds and new methods for treatment of IGF-IR dependent diseases, such as cancer, psoriasis and arteriosclerosis, by means of a specific inhibition of the insulin-like growth factor-1 receptor.
  • Figure 1 shows a computer model of a 12 amino acid peptide comprising the tyrosines 1131, 1135 an 1136 of the IGF-1 receptor.
  • Figure 2 shows the structural formulas of the cyclolignan podophyllotoxin and the new compound 12-THN, which is the 2,3- carbonyldioxy (carbonate) derivative of 2, 3-dihydroxy-l- (3 , 4' , 5' - trimethoxy-phenyl) -6, 7-methylenedioxy-l, 2,3, 4-tetrahydronaphtalene .
  • FIG. 1 Another group of compounds, which may mimic the tyrosines 1135 and 1136, was found to be substituted 1-phenyl-tetrahydronaphtalenes . Advantages with these compounds are that they lack a lactone ring and may therefore not be as cytotoxic as podophyllotoxin and in that they may be easier to synthesize.
  • Figure 1 also shows the space structures of podophyllotoxin and the new compound 12-THN, which is the 2, 3-carbonyldioxy-l- (3' , 4' , 5' -trimethoxy-phenyl) -6, 7- methylenedioxy-1, 2,3, 4-tetrahydronaphtalene .
  • the inhibitor molecule also has to be relatively nonpolar, so that it can freely penetrate cell membranes and the IGF-1 receptor, but sufficiently polar to be reasonably soluble in water.
  • the polarity of the molecule is determined by the number and nature of the oxygen f nctions. The polarity seems to be optimal when the water solubility is between 0.01 mM and 0.1-0.2 inM. No charged or highly polar groups should be present in the molecule.
  • the invention refers to a compound of the formula I
  • R 2 is H, 0 or OH, and R 3 and R together are methylenedioxy, carbonyldioxy (carbonate) or dimethyl-methylenedioxy (acetonide) ; or R 2 and R 3 together are methylenedioxy, carbonyldioxy or dimethyl-methylenedioxy and R 4 is H, 0 or OH; or each is lower alkoxy; or R 2 is OH and R 3 and. R 4 are H; or R 2 is 0 and R 3 and R 4 are H; or R 3 is 0 and R 2 and R are H; or R 2 and R 3 are OH and R 4 is H; with the proviso that when R 3 and R 4 together are methylenedioxy, R 2 is not H.
  • Said compound can be used as a specific inhibitor of tyrosine phosphorylation of the insulin-like growth factor-1 receptor.
  • the invention especially refers to the following substances:
  • the compounds of the formula I especially can be used as specific inhibitors of the tyrosine autophosphorylation of the insulin-like growth factor-1 receptor, since the use of more cytotoxic and tissue irritating compounds, such as the cyclolignan podophyllotoxin should be avoided.
  • podophyllotoxin and some of its analogues are very potent inhibitors of tyrosine phosphorylation of the insulin-like growth factor-1 receptor, which plays a pivotal role as a survival factor in cancer cells. Their actions are also very specific for the IGF-IR in that sense that they do not cross- react with the insulin receptor, which is highly homologous to IGF- IR. Moreover, they do not inhibit other major growth factor receptor kinases either. Podophyllotoxin has been implicated in cancer therapy, but when it was administered to patients it produced severe and unacceptable side effects. The anti-cancer effect, as well as the side effects, was attributed to inhibition of microtubule assembly and mitotic block.
  • Substituted 1-phenyl- tetrahydronaphtalenes are structurally very similar to the cyclolignans such as podophyllotoxin, but have a 16-carbon skeleton instead of a 18-carbon skeleton. More important is that they lack the lactone ring which is essential for binding to microtubuli and therefore they can be much less cytotoxic than the cyclolignans. Relatively nontoxic compounds of the formula I can therefore be used for treatment of IGF-IR dependent diseases, such as cancer, arteriosclerosis, including prevention of restenosis of the coronary arteries after vascular surgery, psoriasis and acromegaly.
  • IGF-IR dependent diseases such as cancer, arteriosclerosis, including prevention of restenosis of the coronary arteries after vascular surgery, psoriasis and acromegaly.
  • the invention thus refers to the new compounds of the formula I for use as a medicament, and especially for the preparation of a medicament for treatment of cancer, arteriosclerosis, psoriasis and acromegaly.
  • cancer is used here in a broad sense including carcinomas, i.e. tumours of epithelial origin such as prostatic, breast, gastrointestinal and lung tumours; sarcomas, i.e.
  • mesenchymal tumours such as malignant fibrous histiocytoma and liposarcoma; neuroectodermal tumours such as malignant melanoma, Ewing sarcoma and neuroblastoma; gliomas such as glioblastoma multiforme, astrocytoma and medulloblastoma; myeloproliferative diseases such as myeloma and myeloid leukemia; and lympho- proliferative diseases such as Hodgkin and non-Hodgkin lymphoma and lymphatic leukemia.
  • the compounds of the invention can be useful to potentiate the effects of other anti-cancer drugs and treatments.
  • the invention therefore also refers to the use of a compound of the formula I in combination with another cytostaticum.
  • cytostatica which can be used together with the compounds of the
  • the compounds may be administered as injectable dosages or by continuous, intravenous infusion of a solution, suspension or emulsion of the compound in a physiologically acceptable diluent as the pharmaceutical carrier,
  • a sterile liquid such as water, alcohols, oils, emulsions, and other acceptable organic solvents, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants .
  • the compounds can also be administered in the form of a depot
  • injection or implant preparation which may be formulated in such a manner as to permit a sustained release of the active ingredient.
  • the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, powders, solutions, suspensions or emulsions.
  • the compounds can be administered in the form of an unguent, cream, ointment, lotion or a patch.
  • continuous infusion of the compound of the invention in connection with monitoring the plasma concentration, may be the strategy of treatment instead of giving one single or repetitive injections with relatively long time intervals, for instance once daily or weekly, which may lead to repeated reactivations of IGF-IR between the treatments.
  • the invention consequently also refers to a method of treatment of a cancer in a mammal, comprising the steps of administrating a pharmaceutical composition, containing a compound having the formula I in combination with a physiologically acceptable carrier, by constant infusion to a patient suffering from a tumour, monitoring the plasma level of the compound, and adjusting the rate of infusion to keep the plasma level between 0.05 and 5.0 ⁇ M depending on the potency and the general toxicity of the compound, for a period of time being required for the tumour to be retarded or to disappear.
  • Aqueous NaHS0 3 (8 g in 60 ml of water) was added and the mixture was stirred for 3 h, diluted with water and extracted with ethyl acetate. The organic layer was washed with 10 % HCl and brine, dried with Na 2 S0 4 , filtered and the solvents were evaporated to give a residue which was purified by chromatography, yielding 0.4 g of 3, 4-dihydroxy-l- (3' , 4' -dimethoxy-phenyl) -6, 7-dimethoxy-l, 2,3,4- tetrahydronaphthalene .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des nouveaux composés appartenant au groupe des 1-phényl-tétrahydronaphtalènes substitués et l'utilisation de ceux-ci en tant qu'inhibiteurs du récepteur du facteur de croissance insulinomimétique de type 1. Lesdits composés peuvent être utilisés pour le traitement de maladies dépendant du récepteur de l'IGF-1, notamment le cancer, le psoriasis, l'artériosclérose et l'acromégalie.
PCT/SE2003/002010 2002-12-18 2003-12-18 Nouveaux derives de 1-phenyl-tetrahydronaphtalene substitues et leur utilisation en tant qu'inhibiteurs du recepteur de l'igf-1 Ceased WO2004054996A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003288857A AU2003288857A1 (en) 2002-12-18 2003-12-18 New substituted 1-phenyl-tetrahydronaphtalene derivatives and their use as inhibitors of igf-1 receptor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0203746-3 2002-12-18
SE0203746A SE0203746D0 (sv) 2002-12-18 2002-12-18 New compounds

Publications (1)

Publication Number Publication Date
WO2004054996A1 true WO2004054996A1 (fr) 2004-07-01

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Family Applications (1)

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PCT/SE2003/002010 Ceased WO2004054996A1 (fr) 2002-12-18 2003-12-18 Nouveaux derives de 1-phenyl-tetrahydronaphtalene substitues et leur utilisation en tant qu'inhibiteurs du recepteur de l'igf-1

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AU (1) AU2003288857A1 (fr)
SE (1) SE0203746D0 (fr)
WO (1) WO2004054996A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007029107A1 (fr) * 2005-09-09 2007-03-15 Analytecon Sa Derives d'isoquinolines utilises en tant qu'inhibiteurs d'igf-1r
WO2007029106A1 (fr) * 2005-09-09 2007-03-15 Analytecon Sa Isoquinolines utilises en tant qu'inhibiteurs d'igf-1r
US7625859B1 (en) 2000-02-16 2009-12-01 Oregon Health & Science University HER-2 binding antagonists
WO2011083391A2 (fr) 2010-01-05 2011-07-14 Pfizer Inc. Biomarqueurs pour une thérapie du cancer par un anti-igf-1r
US8859614B2 (en) 2008-02-09 2014-10-14 University of Nebraska—Lincoln Analogues of (−)-picropodophyllin, synthesis and uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4788216A (en) * 1984-12-28 1988-11-29 Conpharm Ab Medicinal uses for podophyllotoxins
WO2002102805A1 (fr) * 2001-06-19 2002-12-27 Axelar Ab Nouvelle utilisation de cyclolignans et nouveaux cyclolignans

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4788216A (en) * 1984-12-28 1988-11-29 Conpharm Ab Medicinal uses for podophyllotoxins
WO2002102805A1 (fr) * 2001-06-19 2002-12-27 Axelar Ab Nouvelle utilisation de cyclolignans et nouveaux cyclolignans

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GORDALIZA MARINA ET AL.: "Preparation and cytotoxicity of podophyllotoxin derivatives lacking the lactone ring", TETRAHEDRON, vol. 53, no. 46, 1997, pages 15743 - 15760, XP004106423 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7625859B1 (en) 2000-02-16 2009-12-01 Oregon Health & Science University HER-2 binding antagonists
WO2007029107A1 (fr) * 2005-09-09 2007-03-15 Analytecon Sa Derives d'isoquinolines utilises en tant qu'inhibiteurs d'igf-1r
WO2007029106A1 (fr) * 2005-09-09 2007-03-15 Analytecon Sa Isoquinolines utilises en tant qu'inhibiteurs d'igf-1r
JP2009507819A (ja) * 2005-09-09 2009-02-26 アナリットコン エス アー Ｉｇｆ−１ｒ阻害剤としてのイソキノリン
AU2006288846B2 (en) * 2005-09-09 2011-08-18 Analytecon Sa Isoquinolines as IGF-1R inhibitors
US8044067B2 (en) 2005-09-09 2011-10-25 Analytecon S.A. Isoquinolines as IGF-1R inhibitors
CN101258130B (zh) * 2005-09-09 2012-11-28 阿纳里特康股份有限公司 作为胰岛素样生长因子-1受体抑制剂的异喹啉
US8859614B2 (en) 2008-02-09 2014-10-14 University of Nebraska—Lincoln Analogues of (−)-picropodophyllin, synthesis and uses thereof
WO2011083391A2 (fr) 2010-01-05 2011-07-14 Pfizer Inc. Biomarqueurs pour une thérapie du cancer par un anti-igf-1r

Also Published As

Publication number Publication date
SE0203746D0 (sv) 2002-12-18
AU2003288857A1 (en) 2004-07-09

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