WO2016004035A1 - Dérivés 2-aryl-4-quinoléinecarboxamide pour le traitement de maladies de la thyroïde - Google Patents

Dérivés 2-aryl-4-quinoléinecarboxamide pour le traitement de maladies de la thyroïde Download PDF

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Publication number
WO2016004035A1
WO2016004035A1 PCT/US2015/038548 US2015038548W WO2016004035A1 WO 2016004035 A1 WO2016004035 A1 WO 2016004035A1 US 2015038548 W US2015038548 W US 2015038548W WO 2016004035 A1 WO2016004035 A1 WO 2016004035A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
halo
hydrogen
thyroid
alkoxy
Prior art date
Application number
PCT/US2015/038548
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English (en)
Inventor
Rauf LATIF
Terry Davies
Original Assignee
Icahn School Of Medicine At Mount Sinai
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Publication date
Application filed by Icahn School Of Medicine At Mount Sinai filed Critical Icahn School Of Medicine At Mount Sinai
Publication of WO2016004035A1 publication Critical patent/WO2016004035A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/18—Iodine; Compounds thereof
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G01N33/78—Thyroid gland hormones, e.g. T3, T4, TBH, TBG or their receptors

Definitions

  • the invention relates to 2-aryl-4-quinolinecarboxamides that are agonists at the TSH receptor (TSHR).
  • TSHR TSH receptor
  • R 4 is selected from O and S;
  • the invention in another aspect, relates to a method for activating a thyroid stimulating hormone receptor in a mammal comprising administering to the mammal an amount of a compound of formula I.
  • Cycloalkyl is a subset of hydrocarbon and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include cy-propyl, cy-butyl, cy-pentyl, norbornyl and the like.
  • carbocycle is intended to include ring systems in which the ring atoms are all carbon but of any oxidation state.
  • C3-C10 carbocycle refers to both non-aromatic and aromatic systems, including such systems as cyclopropane, benzene and cyclohexene;
  • Cs-Ci 2 ) carbopolycycle refers to such systems as norbornane, decalin, indane and naphthalene.
  • Carbocycle if not otherwise limited, refers to monocycles, bicycles and polycycles.
  • heterocycles include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and the like.
  • heterocyclyl residues include piperazinyl, piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl (also historically called thiophenyl), benzothienyl, thiamorpholinyl, oxadiazolyl, triazolyl and
  • Hydrocarbyloxy refers to groups of from 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms attached to the parent structure through an oxygen.
  • Alkoxy is a subset of hydrocarbyloxy and includes groups of a straight or branched configuration. Examples include methoxy, ethoxy, propoxy, isopropoxy and the like.
  • Lower-alkoxy refers to groups containing one to four carbons.
  • halogen means fluorine, chlorine, bromine or iodine atoms.
  • acyl refers to formyl and to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. Examples include acetyl, benzoyl, propionyl, isobutyryl and the like. Lower- acyl refers to groups containing one to four carbons.
  • the double bonded oxygen, when referred to as a substituent itself is called "oxo".
  • substituted refers to the replacement of one or more hydrogen atoms in a specified group with a specified radical.
  • the compounds described herein may contain an asymmetric center (depending on substitution) and may thus give rise to enantiomers, diastereomers, and other stereoisometric forms which may be defined in terms of absolute stereochemistry as (R)- or (5)-.
  • the present invention is meant to include all such possible diastereomers as well as their racemic and optically pure forms.
  • Optically active (R)- and (5)- isomers may be prepared using homo- chiral synthons or homo-chiral reagents, or optically resolved using conventional techniques. All tautomeric forms are intended to be included.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, adipic, alginic, ascorbic, aspartic, benzenesulfonic (besylate), benzoic, boric, butyric, camphoric, camphorsulfonic, carbonic, citric,
  • chloroprocaine choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium cations and carboxylate, sulfonate and phosphonate anions attached to alkyl having from 1 to 20 carbon atoms.
  • the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients.
  • the carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • Radioisotopes of hydrogen, carbon, phosphorous, fluorine, and chlorine include 2 H, 3 H, 13 C, 14 C, 15 N, 35 S, 18 F, and 36 C1, respectively.
  • Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention.
  • Tritiated, i.e. 3 H, and carbon-14, i.e., 14 C, radioisotopes are particularly preferred for their ease in preparation and detectability.
  • Compounds that contain isotopes n C, 13 N, 15 0 and 18 F are well suited for positron emission tomography.
  • TM4 primary Sertoli cells obtained from ATCC (CRL-1715) and cultured in DMEM: F12 medium (cat # 30-2006) with 2.5% FBS and 5% horse serum (ATCC; cat #30-2040).
  • the specificity against the LH/hCG receptor was tested using stable line of rat hCGR in HEK 293 cells that we obtained from Dr K.M.J Menon, University of Michigan, Ann Arbor, Michigan.
  • a high expressing stable line of CHO-HA TSHR cells carrying an amino terminus HA tagged TSHR was selected. These stable CHO cells were transfected with the construct pGL4.29 [CRE/minP/luc2P] carrying a minimal promoter driving a CREB response element (CRE) tagged to a modified form of luciferase reporter gene luc2P.
  • Luc2P is a synthetically derived luciferase sequence with humanized codon optimization that is designed for high expression and reduced anomalous transcription.
  • the luc2P gene contains hPEST, a protein destabilization sequence, which further reduces background, transcribed protein.
  • RNA isolation Total RNA was isolated from FRTL5 untreated with 1 ⁇ and 10 ⁇ of the compound of example 1 for 4hrs using TRIzol reagent (Invitrogen, Life Technologies, Carlsbad, CA, USA) and chromosomal DNA from this was removed in accordance with the manufacturer's instructions. The RNA concentration was determined on the basis of absorbance at 260 nm, and its purity was evaluated by the ratio of absorbance at 260/280 nm (>1.9). RNAs were kept frozen at -70°C until analyzed.
  • T4 was measured with Neonatal free T4 RIA kit (Coat-A-Count, Siemens Medical Solutions Diagnostics, CA) according to the manufacturer's protocol. All experiments involving animals were carried out according to the institutional animal care committee guidelines.
  • TSHR cell lines expressing various reporter vectors (CRE-, NFAT-RE, SRE-, SRF-RE-). These stable lines were characterized and optimized for responses using positive (TSH, inomycin, PMA) and negative controls.
  • 20,000 cells Prior to measurement of signaling, 20,000 cells were seeded in square bottom white plates (Nunc cat # 164610) in 20 ⁇ 1 of Ham's F12 complete medium and incubated overnight at 37°C. Following the complete medium was replaced with serum free medium for 2hrs and then treated with 10 ⁇ of compound and the appropriate controls for 4hrs. At the end of incubation period the cells were lysed using ⁇ , of Bright Glow reagent and incubated for 2 minutes at RT and the plates were read using BMG Pherastar microplate reader.
  • example 1 did not show any activity against the LH-receptor- nor the FSH- receptor-expressing cells, even at the highest concentration used (10 ⁇ ) and in contrast to the response of the cells against their respective ligands hCG and FSH incorporated as positive controls.
  • Example 1 In vivo potency of Example 1 : T4 levels were measured at different time points in Balb/c mice that received a single ip or iv injection of 20mg/kg body weight of example 1. T4 release was observed at 2hrs after the compounds reached peak levels in the blood but with no sustained action during the course of the study. T4 levels measured after 3 ip injections of 100 ⁇ g/mouse of example 1 dissolved in DMSO showed a sustained two-fold increase serum T4 levels. These in vivo studies clearly indicate the effectiveness of compounds of formula I as agonists to the TSHR.
  • Example 1 The compound of example 1 was also subjected to standard pharmacokinetic studies. A single injection of example 1 at 20mg/kg was given to Balb/c mice intravenously and intraperitoneally and their plasma was analyzed by mass spectrometry at different points after reaching Tmax. The half-life (Ti/ 2 ) was 3 hours by both routes of administration. Example 1 showed moderate plasma clearance of 24.13 mL/min/kg, high volume of distribution (9.6 fold higher than total body water) indicating extravascular distribution.
  • ALP Alkaline phosphatase
  • collagen may be used as osteoblast differentiation markers.
  • ALP measured after treating the cells with 10 ⁇ of test compound in the presence of osteogenic differentiation factor (ODF) for 10 days, would be expected to increase in a statistically significant manner.
  • ODF osteogenic differentiation factor
  • H89 N-[2- ((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide
  • gene expression for collagen, another osteoblast marker can be measured and a similar enhancement of osteoblast differentiation can be observed. Normally stimulation of cAMP can lead to proliferation of cells; colorimetric measurement at 72 hrs should show proliferation of osteoblast cells in a manner similar to TSH.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Urology & Nephrology (AREA)
  • Immunology (AREA)
  • Hematology (AREA)
  • Biomedical Technology (AREA)
  • Endocrinology (AREA)
  • Cell Biology (AREA)
  • Biochemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Inorganic Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Food Science & Technology (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'utilisation de 2-arylquinoléinecarboxamides de formule (I) est divulguée. Les composés sont des agonistes au niveau du récepteur TSH (TSHR) et sont par conséquent utiles dans le traitement de patients souffrant d'un dysfonctionnement de la thyroïde et dans la gestion du cancer différencié de la thyroïde.
PCT/US2015/038548 2014-07-01 2015-06-30 Dérivés 2-aryl-4-quinoléinecarboxamide pour le traitement de maladies de la thyroïde WO2016004035A1 (fr)

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US201462019491P 2014-07-01 2014-07-01
US62/019,491 2014-07-01

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017153234A1 (fr) 2016-03-09 2017-09-14 Bayer Pharma Aktiengesellschaft N-cyclo-2-arylchinolin-4-carboxamides substitués et leur utilisation
WO2017153231A1 (fr) 2016-03-09 2017-09-14 Bayer Pharma Aktiengesellschaft N-cyclo-2-arylisochinolinon-4-carboxamides substitués et leur utilisation
WO2017153235A1 (fr) 2016-03-09 2017-09-14 Bayer Pharma Aktiengesellschaft N-cyclo-3-aryl-1-naphthamides substitués et leur utilisation
WO2018189012A1 (fr) 2017-04-10 2018-10-18 Bayer Aktiengesellschaft N-aryléthyl-2-aminoquinoléine-4-carboxamides substitués et leur utilisation
WO2018189011A1 (fr) 2017-04-10 2018-10-18 Bayer Aktiengesellschaft N-aryléthyl-2-arylquinoléine-4-carboxamides substitués et leur utilisation
JP2019534865A (ja) * 2016-09-26 2019-12-05 デイナ ファーバー キャンサー インスティチュート，インコーポレイテッド クロモボックスタンパク質阻害剤およびその使用

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US20050096316A1 (en) * 1994-05-27 2005-05-05 Carlo Farina Quinoline derivatives(2)
US20110288081A1 (en) * 2004-11-19 2011-11-24 Synta Pharmaceuticals Corporation Pyrimidine compounds and uses thereof

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MA, C ET AL.: "rhTSH-aided low-activity versus high-activity regimens of radioiodine in residual ablation for differentiated thyroid cancer: a meta-analysis", NUCLEAR MEDICINE COMMUNICATIONS., vol. 34, no. 12, 2013, pages 1150 - 1156, XP055250824 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017153234A1 (fr) 2016-03-09 2017-09-14 Bayer Pharma Aktiengesellschaft N-cyclo-2-arylchinolin-4-carboxamides substitués et leur utilisation
WO2017153231A1 (fr) 2016-03-09 2017-09-14 Bayer Pharma Aktiengesellschaft N-cyclo-2-arylisochinolinon-4-carboxamides substitués et leur utilisation
WO2017153235A1 (fr) 2016-03-09 2017-09-14 Bayer Pharma Aktiengesellschaft N-cyclo-3-aryl-1-naphthamides substitués et leur utilisation
JP2019534865A (ja) * 2016-09-26 2019-12-05 デイナ ファーバー キャンサー インスティチュート，インコーポレイテッド クロモボックスタンパク質阻害剤およびその使用
JP7203018B2 (ja) 2016-09-26 2023-01-12 デイナ ファーバー キャンサー インスティチュート，インコーポレイテッド クロモボックスタンパク質阻害剤およびその使用
WO2018189012A1 (fr) 2017-04-10 2018-10-18 Bayer Aktiengesellschaft N-aryléthyl-2-aminoquinoléine-4-carboxamides substitués et leur utilisation
WO2018189011A1 (fr) 2017-04-10 2018-10-18 Bayer Aktiengesellschaft N-aryléthyl-2-arylquinoléine-4-carboxamides substitués et leur utilisation
US11136296B2 (en) 2017-04-10 2021-10-05 Bayer Aktiengesellschaft Substituted N-arylethyl-2-arylquinoline-4-carboxamides and use thereof
US11149018B2 (en) 2017-04-10 2021-10-19 Bayer Aktiengesellschaft Substituted N-arylethyl-2-aminoquinoline-4-carboxamides and use thereof

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