WO2005123714A1 - Composes a base de quinazoline et leur utilisation dans le traitement de maladies induites par l'hormone concentrant la melanine (mch) - Google Patents

Composes a base de quinazoline et leur utilisation dans le traitement de maladies induites par l'hormone concentrant la melanine (mch) Download PDF

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Publication number
WO2005123714A1
WO2005123714A1 PCT/EP2004/006539 EP2004006539W WO2005123714A1 WO 2005123714 A1 WO2005123714 A1 WO 2005123714A1 EP 2004006539 W EP2004006539 W EP 2004006539W WO 2005123714 A1 WO2005123714 A1 WO 2005123714A1
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WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically
mch
methyl
solvate
Prior art date
Application number
PCT/EP2004/006539
Other languages
English (en)
Inventor
Thomas Michael Frimurer
Trond Ulven
Thomas Högberg
Pia Karina NØRREGAARD
Paul Brian Little
Jean Marie Receveur
Original Assignee
7Tm Pharma A/S
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 7Tm Pharma A/S filed Critical 7Tm Pharma A/S
Priority to PCT/EP2004/006539 priority Critical patent/WO2005123714A1/fr
Publication of WO2005123714A1 publication Critical patent/WO2005123714A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to novel quinazoline compounds and their use in the treatment, prophylaxis and/or diagnosis of conditions involving a melanin- concentrating hormone.
  • MCH Melanin-concentrating hormone
  • MCH receptors The biological effects of MCH are believed to be mediated by specific MCH receptors, and the MCH1 and MCH2 receptors have been described.
  • Antagonists of MCH receptor e.g. MCH1 receptor
  • MCH1 receptor are considered useful as obesity or weight reducing agents, and as antidepressant and/or anxiolytic agents.
  • the present invention provides a compound of formula (I), or a salt, hydrate or solvate thereof:
  • R-i is:
  • R 2 is CI-, CH 3 -, CF 3 -, or F 3 C-O-.
  • Compounds of the invention have a particularly useful combination of drug-like properties, including aqueous solubility and acceptable plasma protein binding.
  • compositions comprising a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt, hydrate or solvate thereof, together with a pharmaceutically or veterinarily acceptable carrier, are also included in the invention.
  • salt includes base addition, acid addition and quaternary salts.
  • Compounds of the invention which are acidic can form salts, including pharmaceutically or veterinarily acceptable salts, with bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. ⁇ /-ethyl pipehdine, dibenzylamine and the like.
  • bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. ⁇ /-ethyl pipehdine, dibenzylamine and the like.
  • Those compounds (I) which are basic can form salts, including pharmaceutically or veterinarily acceptable salts with inorganic acids, e.g.
  • hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like
  • organic acids e.g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic and p-toluene sulphonic acids and the like.
  • the compounds of the invention are highly potent antagonists of the MCH receptor, and are useful for the treatment of MHC -related disorders in mammals, including humans.
  • MHC-related disorders include overweight, adiposity, obesity and bulimia (e.g. malignant mastocytosis, exogeneous obesity, hyperinsulinar obesity, hyperplasmic obesity, hypophyseal adposity, hypoplasmic obesity, hypophysal adiposity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity, systemic mastocytosis, simple obesity, central obesity etc.), hyperfagia, emotional disorders, dementia, hormonal disorders, lifestyle diseases such as, e.g., diabetes, diabetic complications (e.g. retinopathy, neuropathy, nephropathy etc.), arteriosclerosis and gonitis..
  • bulimia e.g. malignant mastocytosis, exogeneous obesity, hyperinsulinar obesity, hyperplasmic obesity, hypophyseal adposity, hypoplasmic obesity, hypophysal adi
  • body mass index or BMI is defined as body weight (kg)/height 2 (m 2 ), and the term overweight is intended to indicate a BMI in a range from about 25 to about 29.9, whereas obesity is intended to indicate a BMI, which is at least about 30.
  • the invention includes (i) the use of a compound of formula (I) above, or a pharmaceutically or veterinarily acceptable salt, hydrate or solvate thereof, in the preparation of a composition for the treatment of an MHC-related disorder and (ii) a method of treating a mammal, including a human, suffering from a MHC- related disorder, comprising administering to the mammal an effective amount of a compound of formula (I) above, or a pharmaceutically or veterinarily acceptable salt, hydrate or solvate thereof.
  • the MHC-related disorder referred to in these aspects (i) and (ii) of the invention may be, for example, overweight; bulimia; bulimia nervosa; obesity; Syndrome X (metabolic syndrome); a combination of obesity, insulin resistance, dyslipidemia, impaired glucose tolerance and hypertension; Type II diabetes or Non Insulin Dependent Diabetes Mellitus (NIDDM), depression and/or anxiety.
  • NIDDM Non Insulin Dependent Diabetes Mellitus
  • MHC-related disorders include a steroid or pituitary hormone disorder, an epinephrine release disorder, a gastrointestinal disorder, a cardiovascular disorder, an electrolyte balance disorder, hypertension, diabetes, a respiratory disorder, asthma, a reproductive function disorder, a muscoskeletal disorder, a neuroendoc ne disorder, a cognitive disorder, a memory disorder such as, e.g., Alzheimer's disease, a sensory modulation and transmission disorder, a motor coordination disorder, a sensory integration disorder, a motor integration disorder, a dopaminergic function disorder such as, e.g.
  • Parkinson's disease a sensory transmission disorder, an olfaction disorder, a sympathetic innervation disorder, an affective disorder such as, e.g. depression, a stress-related disorder, a fluid-balance disorder, a urinary disorder such as, e.g., urinary incontinence, a seizure disorder, pain, psychotic behaviour such as, e.g., schizophrenia, morphine or opioid tolerance, opiate addiction or migraine.
  • the invention includes (iii) the use of a compound of formula (I) above, or a pharmaceutically or veterinarily acceptable salt, hydrate or solvate thereof, in the preparation of a composition for (a) modifying the feeding behaviour and/or reducing the body mass of a mammal, including a human and (iv) a method of modifying the feeding behaviour and/or reducing the body mass of a mammal, including a human, comprising administering to the mammal an effective amount of a compound of formula (I) above, or a pharmaceutically or veterinarily acceptable salt, hydrate or solvate thereof.
  • the compounds with which the invention is concerned are normally presented in the form of a pharmaceutical or a cosmetic composition comprising the specific compound or a physiologically acceptable salt thereof together with one or more physiologically acceptable excipients.
  • the compounds may be administered to the subject by any convenient administration route such as, e.g., the oral, buccal, nasal, ocular, pulmonary, topical, transdermal, vaginal, rectal, ocular, parenteral (including inter alia subcutaneous, r intramuscular, and intravenous), route in a dose that is effective for the individual purposes.
  • any convenient administration route such as, e.g., the oral, buccal, nasal, ocular, pulmonary, topical, transdermal, vaginal, rectal, ocular, parenteral (including inter alia subcutaneous, r intramuscular, and intravenous), route in a dose that is effective for the individual purposes.
  • a person skilled in the art will know how to chose a suitable administration route.
  • the pharmaceutical or cosmetic composition comprising a compound according to the invention may be in the form of a solid, semi-solid or fluid composition.
  • the solid composition may be in the form of tablets such as, e.g. conventional tablets, effervescent tablets, coated tablets, melt tablets or sublingual tablets, pellets, powders, granules, granulates, particulate material, solid dispersions or solid solutions.
  • a semi-solid form of the composition may be a chewing gum, an ointment, a cream, a liniment, a paste, a gel or a hydrogel.
  • the fluid form of the composition may be a solution, an emulsion including nano- emulsions, a suspension, a dispersion, a liposomal composition, a spray, a mixture, a syrup or a aerosol.
  • Fluid compositions which are sterile solutions or dispersions can be utilized by for example intraveneous, intramuscular, intrathecal, epidural, intraperitoneal or subcutaneous injection of infusion.
  • the compounds may also be prepared as a sterile solid composition, which may be dissolved or dispersed before or at the time of administration using e.g. sterile water, saline or other appropriate sterile injectable medium.
  • suitable dosages forms of the pharmaceutical compositions according to the invention may be vagitories, suppositories, plasters, patches, tablets, capsules, sachets, troches, devices etc.
  • the dosage form may be designed to release the compound freely or in a controlled manner e.g. with respect to tablets by suitable coatings.
  • the pharmaceutical composition may comprise a therapeutically effective amount of a compound according to the invention.
  • the content of a compound of the invention in a pharmaceutical composition of the invention is e.g. from about 0.1 to about 100% w/w of the pharmaceutical composition.
  • compositions may be prepared by any of the method well known to a person skilled in pharmaceutical or cosmetic formulation.
  • the compounds are normally combined with a pharmaceutical excipient, i.e. a therapeutically inert substance or carrier.
  • the carrier may take a wide variety of forms depending on the desired dosage form and administration route.
  • the pharmaceutically or cosmetically acceptable excipients may be e.g. fillers, binders, disintegrants, diluents, glidants, solvents, emulsifying agents, suspending agents, stabilizers, enhancers, flavours, colors, pH adjusting agents, retarding agents, wetting agents, surface active agents, preservatives, antioxidants etc. Details can be found in pharmaceutical handbooks such as, e.g., Remington's Pharmaceutical Science or Pharmaceutical Excipient Handbook.
  • Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the composition, the route of administration, the frequency of administration, the age, weight, gender, diet and condition of the subject to be treated and the condition being treated and the advancement of the disease condition etc.
  • Suitable dosages may be from about 0.001 mg to about 1 g such as, e.g. from about 0.005 to about 750 mg, from about 0.01 to about 500 mg, from about 0.05 to about 500 mg, from about 0.1 to about 250 mg, from about 0.1 to about 100 mg or from about 0.5 to about 50 mg.
  • the amounts can be divided into one or several doses for administration daily, every second day, weekly, every two weeks, monthly or with any other suitable frequency. Normally, the administration is daily.
  • a compound or a pharmaceutical composition according to the invention may be used in combination with other drug substances such as agents for treating disorders like e.g. diabetes, diabetes complications, obesity, hypertension, hyperlipidemia, arteriosclerosis, arthritis, anxiety, and/or depression etc.
  • agents for treating disorders like e.g. diabetes, diabetes complications, obesity, hypertension, hyperlipidemia, arteriosclerosis, arthritis, anxiety, and/or depression etc.
  • the cDNA encoding the human MCH-1 receptor was cloned from a human brain cDNA library and cloned into the eukaryotic expression vector pcDNA3.1 (Invitrogen). Assays were performed on transiently transfected COS-7 cells or stably transfected CHO (Chinese Hamster Ovary) cells, expressing the human MCH-1 receptor in pcDNA3.1.
  • Stable MCH-1 receptor transfectants of CHO cells were obtained using 5 ⁇ g plasmid cDNA and a standard calcium phosphate transfection method (Johansen er a/., 1990; Gether ef a/., 1992) with subsequent selection in 1 mg/ml G418 (Life Technology). Clones were screened by a MCH receptor radioligand binding assay (as described below). Stably transfected CHO cells were maintained in RPMI 1640 culture medium (Invitrogen), supplemented with 10 % fetal calf serum (Invitrogen), 100 U/ml penicillin, 100 ⁇ g/ml streptomycin (Life Technology), and 500 ⁇ g/ml G418 (Life Technology).
  • COS-7 cells were grown in Dulbecco ' s modified Eagle ' s medium (DMEM) 1885 (Invitrogen) supplemented with 10 % fetal calf serum, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, and were transiently transfected by a standard calcium phosphate transfection method (Johansen er a/., 1990; Gether er a/., 1992) two days before assay.
  • DMEM Dulbecco ' s modified Eagle ' s medium
  • Radioligand Binding Assay Transiently transfected COS-7 cells or stably transfected CHO cells, expressing human MCH-1 receptor were seeded in multi-well culture plates one day before the assay. The number of cells per well was determined by the apparent expression efficiency of the cell line aiming at 5 - 10 % binding of the added radioligand.
  • Cells were assayed by competition binding for 3 hours at room temperature using 15 pM [ 125 I]-MCH (Amersham Pharmacia Biotech) plus variable amounts of unlabeled ligand in 0.5 ml of a 25 mM Hepes buffer, pH 7.4, supplemented with 10 mM MgCI 2 , 5 mM MnCI 2 , 10 mM NaCI, 0.1 % (w/v) bovine serum albumin (BSA), 100 ⁇ g/ml bacitracin. The assay was performed in duplicate. Nonspecific binding was determined as the binding in the presence of 1 ⁇ M MCH (Bachem). Binding data were analyzed and IC 50 values determined by non-linear regression using the Prism software (GraphPad software, San Diego). The compounds of the examples had IC 50 s in the above assay of 25nM or less.

Abstract

L'invention concerne des composés représentés par la formule générale (I). Ces composés sont des ligands de l'hormone concentrant la mélanine (MCH), destinés à être utilisés dans le traitement de l'obésité et d'autres troubles induits par l'hormone concentrant la mélanine. Dans cette formule générale (I), R1 désigne (II), (III), (IV), (V), (VI) ou (VII) et R2 désigne CI-, CH3 CF3, ou F3C-O-.
PCT/EP2004/006539 2004-06-16 2004-06-16 Composes a base de quinazoline et leur utilisation dans le traitement de maladies induites par l'hormone concentrant la melanine (mch) WO2005123714A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/EP2004/006539 WO2005123714A1 (fr) 2004-06-16 2004-06-16 Composes a base de quinazoline et leur utilisation dans le traitement de maladies induites par l'hormone concentrant la melanine (mch)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2004/006539 WO2005123714A1 (fr) 2004-06-16 2004-06-16 Composes a base de quinazoline et leur utilisation dans le traitement de maladies induites par l'hormone concentrant la melanine (mch)

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WO2005123714A1 true WO2005123714A1 (fr) 2005-12-29

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1973905A1 (fr) * 2006-01-06 2008-10-01 AstraZeneca AB Composes
WO2013050527A1 (fr) 2011-10-05 2013-04-11 H. Lundbeck A/S Dérivés de quinazoline en tant qu'inhibiteurs de l'enzyme pde10a

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003015769A1 (fr) * 2001-08-17 2003-02-27 Aventis Pharma Deutschland Gmbh Composes bicycliques aromatiques a substitution aminoalkyle, procedes de production de ces composes et leur utilisation en tant que medicaments
WO2003045313A2 (fr) * 2001-11-27 2003-06-05 Merck & Co. Inc. Composés de 2-aminoquinoline
WO2004011440A1 (fr) * 2002-07-30 2004-02-05 Banyu Pharmaceutical Co., Ltd. Antagoniste de recepteur d'hormone concentrant de la melanine comprenant un derive de benzimidazole en tant qu'ingredient actif
WO2004052370A2 (fr) * 2002-12-11 2004-06-24 7Tm Pharma A/S Utilisation de composes de la quinoline pour traiter des troubles lies au recepteur mch

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003015769A1 (fr) * 2001-08-17 2003-02-27 Aventis Pharma Deutschland Gmbh Composes bicycliques aromatiques a substitution aminoalkyle, procedes de production de ces composes et leur utilisation en tant que medicaments
WO2003045313A2 (fr) * 2001-11-27 2003-06-05 Merck & Co. Inc. Composés de 2-aminoquinoline
WO2004011440A1 (fr) * 2002-07-30 2004-02-05 Banyu Pharmaceutical Co., Ltd. Antagoniste de recepteur d'hormone concentrant de la melanine comprenant un derive de benzimidazole en tant qu'ingredient actif
WO2004052370A2 (fr) * 2002-12-11 2004-06-24 7Tm Pharma A/S Utilisation de composes de la quinoline pour traiter des troubles lies au recepteur mch
WO2004052371A2 (fr) * 2002-12-11 2004-06-24 7Tm Pharma A/S Composes de quinoline cycliques utilises avec des troubles lies au recepteur mch

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1973905A1 (fr) * 2006-01-06 2008-10-01 AstraZeneca AB Composes
EP1973905A4 (fr) * 2006-01-06 2010-12-08 Astrazeneca Ab Composes
WO2013050527A1 (fr) 2011-10-05 2013-04-11 H. Lundbeck A/S Dérivés de quinazoline en tant qu'inhibiteurs de l'enzyme pde10a

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