WO2022003557A1 - Nouveaux inhibiteurs de l'autotaxine - Google Patents

Nouveaux inhibiteurs de l'autotaxine Download PDF

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Publication number
WO2022003557A1
WO2022003557A1 PCT/IB2021/055805 IB2021055805W WO2022003557A1 WO 2022003557 A1 WO2022003557 A1 WO 2022003557A1 IB 2021055805 W IB2021055805 W IB 2021055805W WO 2022003557 A1 WO2022003557 A1 WO 2022003557A1
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Prior art keywords
pyrrole
independently selected
carboxylate
oxoethyl
dichlorobenzyl
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PCT/IB2021/055805
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English (en)
Inventor
Rajiv Sharma
Rajesh Bahekar
Vijay PRAJAPATI
Pradip JADAV
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Cadila Healthcare Limited
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Publication of WO2022003557A1 publication Critical patent/WO2022003557A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • novel compounds of formula (I) as autotaxin (ATX) inhibitors for the treatment and prophylaxis of conditions or a disorder caused by autotaxin (ATX) activation or increased concentration of lysophosphatidic acid (LPA) and also a pharmaceutical composition containing the same.
  • Invention also describe pharmaceutically acceptable salts, enantiomers, tautomeric forms, their diastereomers.and pharmaceutical composition of novel autotaxin (ATX) inhibitors.
  • ATX enzyme is important for converting Lysophosphatidylcholine (LPC) into LPA, as a bioactive signaling molecule.
  • LPC Lysophosphatidylcholine
  • ATX is a secreted enzyme of the ectonucleotide phosphatase family, also known as Ectonucleotide Pyrophosphatase/ Phosphodiesterase 2 (ENPP-2 or NPP2).
  • ENPP-2 or NPP2 Ectonucleotide Pyrophosphatase/ Phosphodiesterase 2
  • LPA is a bioactive lipid that affects migration, proliferation and survival of various cell types. LPA mediates variety of cellular and biological actions through LPA receptors (LPAR).
  • the LPA shows broad tissue expression and it can couple to at least six distinct G proteins, known as LPAR1-6, which in turn, feed into multiple effector systems (Yung, Y.C. et al., J. Lipid Res. 2014, 55, 1192 and Kihara, Y. et al., Exp. Cell Res. 2015, 333, 171). Since the LPA level in plasma is highly related to the activity of ATX, it is believed that ATX is an important supply source of extracellular LPA.
  • LPA lymphocyte homing chronic inflammation
  • neuropathic pain fibrotic diseases
  • fibrotic diseases such as Idiopathic Pulmonary Fibrosis (IPF), thrombosis and cholestatic pruritus which caused and / or propagated by increased LPA levels and / or activation of ATX.
  • IPF Idiopathic Pulmonary Fibrosis
  • thrombosis thrombosis
  • IPF is characterized as a progressive scarring of lung tissue which leads to worsening lung function and is ultimately fatal within 3-5 years from the onset of symptoms.
  • FPAR1 has been identified to be the predominant FPA receptor (Tager, A. M. et al., Nat. Med. 2008, 14, 45 and Montesi, S. B. et al., BMC Pulm. Med. 2014). In the lung fibroblasts of an IPF patient, FPAR1 was found to be responsible for enhanced fibroblast cell migration and vascular leak.
  • FPAR1 antagonists will be a potential drug target for the treatment of IPF.
  • several FPAR1 antagonists have been reported, and some of these compounds are currently being evaluated for the treatment of IPF (Budd, D. C et al.., Future Med. Chem. 2013, 5, 1935; Qian, Y. et al., J. Med. Chem. 2012, 55, 7920 and Terakado, M. et al., ACS Med. Chem. Fett. 2016, 7, 913).
  • Fibrosis can develop in the liver, kidney, lung, dermis, vasculature, gut and other sites. Fibrosis develops due to action of pathways including growth factors, cytokines, integrin and lipids.
  • ATX, FPA and FPAR pathways have been implicated in fibrotic disease. Increased levels of ATX, FPA and FPARs observed in various rodent models of fibrosis and in patient fluids and biopsy tissues.
  • FPA can induce proliferative, survival and chemotactic responses in cells known to be critical in fibrotic disease, including: fibroblasts, smooth muscle cells, macrophages, epithelial and endothelial cells and leukocytes.
  • Inhibitors of FPARs indicate that antagonism of receptors within this pathway blocked or reversed fibrosis in the lung, liver, kidney and skin in rodents. Accordingly in fibrotic diseases, it is desirable to lower FPA levels. This can be accomplished through inhibition of enzymes involved in FPA biosynthesis, such as ATX.
  • ATX inhibitors for use in the treatment and / or prophylaxis of physiological and / or pathophysiological conditions such as cancer, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis which are caused, medicated and / or propagated by increased FPA levels and / or the activation of ATX.
  • the present invention describe novel compounds as autotaxin (ATX) inhibitors for treatment and prophylaxis of conditions or a disorder caused by ATX activation or increased concentration of LAP and also a pharmaceutical composition containing the same.
  • ATX autotaxin
  • the present invention includes certain substituted compounds described herein, their salts, preparations thereof, pharmaceutical compositions and formulations thereof and methods of treating diseases such as therewith.
  • the present invention includes novel compounds of formula (I) their pharmaceutically acceptable salts, tautomeric forms, enantiomers and their diastereomers.
  • compounds of the present invention are inhibitors of ATX.
  • Embodiments of the present invention include the compounds herein, pharmaceutically acceptable salts thereof, any physical forms thereof including solvates and hydrates, preparation of the compounds, intermediates and pharmaceutical compositions and formulations thereof.
  • An embodiment of the present invention provides novel compounds represented by the general formula (I), their pharmaceutically acceptable salts, tautomeric forms, enantiomers and their diastereomers.
  • compositions containing novel compounds of the general formula (I), their tautomeric forms, their enantiomers, their diastereomers, their stereoisomers, their pharmaceutically acceptable salts, or their mixtures in combination with suitable excipients are provided.
  • novel compounds of the present invention as ATX inhibitors, by administering a therapeutically effective and non-toxic amount of novel compounds of general formula (I) or their pharmaceutically acceptable compositions to the mammals.
  • the present invention relates to the novel compounds of the formula (I) represents below and their pharmaceutically acceptable salts, tautomeric forms, enantiomers and their diastereomers;
  • heterocycloalkenyl containing 1 double bond one or more heteroatom independently selected from O, N, and S;
  • heteroaryl containing one or more heteroatom independently selected from O, N, and S;
  • X is -C(0)0-, -NR a -C(0)-, -C(O)-, S(0) 2 -, -S(0) 2 NR a -;
  • Ri is selected from (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, haloalkyl, cycloalkyl, carbocycle, heterocyclyl, heteroaryl, aryl, arylalkyl, heterocycloalkyl, heteroarylalkyl, arylalkoxy, aryloxy, heteroaryloxy, heterocycloxy, arylalkenyl, arylalkynyl, arylcycloalkyl, wherein each of these groups, wherever applicableis further substituted with substituent(s) independently selected from halo, hydroxyl, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, (Ci-C 6 )acyloxy, haloalkyl, -N0 2 , -OCF 3 , -CN, -(CR b R c )) r NR d R
  • Y is absent, or is selected from -H, -(CR ab R ac ) r , -(CR ab R ac ) r C(0)-, -C(0)-(CR ab R ac ) r , - C(0)-C(0)-, -C(0)NR ad R ae -, -(CR ab R ac ) t C(0)NR ad R ae -, -(CR ab R ac ) t C(0)0R ad -, -C(O)- (CR ab R ac ) t -OR ad -, -(CR ab R ac ) t -OR ad -, -(CR ab R ac ) t -OR ad -, -(CR ab R ac ) t -OR ad -, -(CR ab R ac ) t -OR ad -, -S
  • heteroaryl containing one or more heteroatom independently selected from O, N, and S ;
  • R 3 , R 5 , and R 6 are independently selected from H, (CY jalkyl, halo, haloalkyl, - (CR af R ag ) v -COOR ah , -(CR af R ag ) v -CONR ah R ai , -(CR af R ag ) v -OR ah , -(CR af R ag ) v -NR ah R ai , -S(0) 2 - (CR af R ag ) v , -S(0) 2 -NR ah R ai , (C 3 -C 7 )cycloalkyl, heterocyclyl, aryl; R 4 & R 7 are independently selected from, H, (Ci-C 6 )alkyl, halo, haloalkyl, -ORA -CN, - NR ⁇ R ⁇ , (C
  • R a , R b , R c , R d , R e , R f , R s , R h , R ⁇ R ab , R ac , R ad , RA R af , R ag , R ah , and R ai are independently selected from H, (Ci-C 6 )alkyl, halo, haloalkyl, cycloalkyl, aryl or arylalkyl; r, s, t and v represents integers from 0-6.
  • A is selected from the following structures:
  • B is selected from the following structures:
  • present invention relates to novel compounds of the formula (I) is represented by (I-a) and (I-b) provided below their pharmaceutically acceptable salts, tautomeric forms, enantiomers and their diastereomers; (I-a) and (I-b)
  • A is selected from 4-10 membered mono, bi or spirocyclic heterocycloalkyl containing one or more hetereoatoms independently selected from O, N, and S.
  • A is selected from following structures: X is selected from -C(0)0-, -NR a -C(0)-, -C(O)-, S(0) 2 -, -S(0) 2 NR a -;
  • X is selected from -C(0)0- and -C(O)-.
  • Ri is selected from (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, haloalkyl, cycloalkyl, carbocycle, heterocyclyl, heteroaryl, aryl, arylalkyl, heterocycloalkyl, heteroarylalkyl, arylalkoxy, aryloxy, heteroaryloxy, heterocycloxy, arylalkenyl, arylalkynyl, arylcycloalkyl, wherein each of these groups, wherever applicable, is further substituted with substituent(s) independently selected from halo, hydroxyl, (C r C ( ) alkyl, (CY jalkoxy, (C 1 -C 6 )acyloxy, haloalkyl, -N0 2 , -OCF 3 , -CN, -(CR b R c )) r NR d R e
  • is selected from aryl or phenyl group, arylalkyl, arylalkoxy group optionally substituted with one or more halo, hydroxyl, (CYQjalkyl, (CYQjalkoxy, (C 1 -C 6 )acyloxy, haloalkyl, -N0 2 , -OCF 3 , -CN, -(CR b R c )) r NR d R e , -COOR d , -S(0) 2 NR d R e , - S(0) 2 (CR b R c ) r and -C(0)NR d R e substituents;
  • R 2 is selected from H, alkyl, halo and haloalkyl;
  • R 2 is H. is absent, or is selected from -H, -(CR ab R ac ) r , -(CR ab R ac ) r C(0)-, -C(0)-(CR ab R ac ) r , -C(O)- C(O)-, -C(0)NR ad R ae -, -(CR ab R ac ) t _C(0)NR ad R ae -, -(CR ab R ac ) t _C(0)0R ad -, -C(0)-(CR ab R ac ) t - OR ad -, -(CR ab R ac ) t -OR ad -, -S(0) 2 -, -S(0) 2 NR ad R ae -, -S(0) 2 _(CR ab R ac ) r ;
  • Y is selected from -(CR ab R ac ) t -C(0)-, -C(0)-(CR ab R ac ) t - and - (CR ab R ac ) t _C(0)0R ad -.
  • heteroaryl containing one or more heteroatom independently selected from O, N, and S;
  • B is absent or is selected from:
  • heteroaryl containing one or more heteroatom independently selected from O, N, and S.
  • B is absent or selected from the following structures:
  • R 3 , R 5 , and R 6 are independently selected from H, (Q-Q alkyl, halo, haloalkyl, - (CR af R ag ) v -COOR ah , -(CR af R ag ) v -CONR ah R ai , -(CR af R ag ) v -OR ah , -(CR af R ag ) v -NR ah R ai , -S(0) 2 - (CR af R ag ) v , -S(0) 2 -NR ah R ai , (C 3 -C 7 )cycloalkyl, heterocyclyl, aryl;
  • R 3 , R 5 , and R 6 are independently selected from H, (CVQjalkyl, haloalkyl.
  • R 4 & R 7 are independently selected from, H, (Q-C 6 )alkyl, halo, haloalkyl, -OR' 1 , -CN, - NR ⁇ R ⁇ , (C 3 -C 7 )cycloalkyl, aryl; In a preferred embodiment, R 4 & R 7 are independently selected from haloalkyl and -OR" 1 .
  • the groups, radicals described above may be selected from: “Alkyl”, as well as other groups having the prefix “alk”, such as alkoxy and alkanoyl, means carbon chain which may either be linear or branched, and combinations thereof, unless the carbon chain is defined otherwise.
  • alkyl group include but not limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert.-butyl, pentyl, hexyl etc.
  • alkyl also includes cycloalkyl groups, and combinations of linear or branched alkyl chains combined with cycloalkyl structures.
  • Cycloalkyl is the subset of alkyl and means saturated carbocyclic ring having a specified number of carbon atoms, preferably 3-6 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc. A cycloalkyl group generally is monocyclic unless otherwise stated. Cycloalkyl groups are saturated unless and otherwise stated.
  • Aryl means a mono- or polycyclic aromatic ring system containing carbon ring atoms.
  • the preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.
  • Heterocycloalkyl means, a mono or polycyclic non-aromatic/saturated ring system containing carbon atoms and one or more heteroatoms selected from nitrogen, sulfur and oxygen.
  • heterocycloalkyl include oxirane, oxetane, tetrahydrofuran, tetrahydro-2H-pyran, thietane, tetrahydrothiophene, tetrahydro-2H-thiopyran, azetidine, pyrrolidone, piperidine, azepane, diazetidine, imidazolidine, piperazine, diazepane, diazocane, triazinane, oxaziridine, oxazetidine, oxazolidine, morpholine, oxazepane, oxazocane, thiazetidine, thiazolidine, thiomorpholine, thiazepane, and
  • Heterocycloalkenyl means, a mono or polycyclic partially unsaturated ring system /containing double bond, containing carbon atoms and one or more heteroatoms selected from nitrogen, sulfur and oxygen.
  • heterocycloalkenyl include cyclobutenyl, cyclopentenyl, and cyclohexenyl,
  • Heteroaryl means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from nitrogen, sulfur and oxygen.
  • heteroaryl include furanyl, pyranyl, imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, benzofuranyl, indolyl, indazolyl, quinolinyl, benzothiazolyl, benzooxazolyl, benzoimidazolyl, and benzotriazolyl. Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • “Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of the basic residues.
  • Such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 1, 2-ethanedisulfonic, 2- acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, eidetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, is
  • cation includes H, Na, K, Mg, Ca, NH 4 + , (CH 3 CH 2 )3N + etc.
  • ‘optional’ or ‘optionally’ means that the subsequent described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occur and instances in which it does not.
  • ‘optionally substituted alkyl’ means either ‘alkyl’ or ‘substituted alkyl’.
  • an optionally substituted group means unsubstituted.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • molecules with a single chiral center unless otherwise noted, exist as a racemic mixture.
  • Those molecules with two or more chiral centers unless otherwise noted, exist as a racemic mixture of diastereomers.
  • Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.
  • Particularly useful compounds may be selected from but not limited to the following;
  • DIPE Diisopropyl ether
  • novel compounds of the present invention were prepared using the reactions and techniques described below, together with conventional techniques known to those skilled in the art of organic synthesis, or variations thereon as appreciated by those skilled in the art.
  • the reactions can be performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected.
  • Preferred methods include, but not limited to those described below, where all symbols are as defined earlier unless and otherwise defined below.
  • the compounds of the formula (I) can be prepared as described in general scheme-1 below along with suitable modifications/variations which are well within the scope of a person skilled in the art.
  • Substituted bicyclic acids (II) can be treated with diversified amines (III) in an appropriate solvent to give compound (IV) under the condition of coupling reaction to prepare amide linkage or can be prepared by the method reported in literature along with their suitable modifications as may be necessary.
  • Deprotection of Boc. group of compound (IV) can be accomplished by using appropriate acids like HC1, HBr, and TFA in a suitable solvent to give compound (V).
  • N-alkylation or N-acylation of compound (V) using alkyl halides or acyl halides of the type (VI) can be carried out preferably with base like K 2 C0 or Cs 2 C0 in a suitable solvents like ACN, acetone and DMF or can be prepared by the conventional methods reported in literature or conventional techniques known to those skilled in the art of organic synthesis to furnish compounds of formula (I).
  • General Scheme-1 :
  • Step-2 _ tot-butyl 5-(((R)-l-(((3,5-dichlorobenzyl)oxy)carbonyl)pyrrolidin-3- vDcarbamoyl) hexahydrocvclopentalclpyrrole-2(lH)-carboxylate (4)
  • Step-3 3.5-dichlorobenzyl (3R)-3-(octahvdrocvclopentalclpyrrole-5-carboxamido ' ) pyrrolidine- 1 -carboxylate (5)
  • Step-1 tot-butyl 5-hvdroxyhexahvdrocvclopentalclpyrrole-2(lH)-carboxylate (8)
  • Step-2 _ fert-butyl _ 5-((methylsulfonyl)oxy)hexahvdrocvclopentalclpyrrole-2(lH)- carboxylate (9)
  • Reaction mixture was washed sequentially with saturated NaHC0 3(aq) solution (150 ml), water and brine (150 ml each) organic layer was separated, dried and evaporated to dryness under reduced pressure to get teri-butyl 5- ((methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (9) as a thick oil (26.3 g, 97.8% yield) which gets solidify at RT over the time. Product was used as such in next reaction step without any purification.
  • reaction mixture cooled at room temperature, diluted with water (500 ml), extracted with ethyl acetate (200 ml X 3), and combined organic layer was washed with water (200 ml), brine (100 ml), dried over Na 2 S0 4 and evaporated to dryness under reduced pressure to get tert- butyl 5-cyanohexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (10) as a light yellow oil (7.58g, 97.9% yield). Product was used for next reaction step without any purification.
  • the present invention includes a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (I) or their pharmaceutically acceptable salts, tautomeric forms, enantiomers and their diastereomers, formulated with or without one or more pharmaceutical excipients.
  • the present invention includes a method for the treatment of at least one of cancer, chronic inflammation, neuropathic pain, fibrotic diseases mediated in part by ATX comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt of the novel compound of formula (I).
  • ATX Inhibitory activity was determined in a biochemical or whole blood assay as described previously (Bretschneider, T. et al., SLAS Discov 2017, 22, 425).
  • the biochemical reaction consisted of 50 mM Tris (pH 8.0), 3 mM KC1, 1 mM CaCl 2 , 1 mM Mg Cl 2 , 0.14 mM NaCl and 0.1% bovine serum albumin, which was supplemented with 5 nM recombinant rat ATX, 5 mM 18:1 LPC and the test compound (0.1 - 10 mM).
  • the reaction was stopped at 2 h by the addition of butanol, prior to the RapidFire -MS-based analysis.
  • the whole blood assay consisted of 45 pL heparinized mice/ rat whole blood and the test compound (0.12 - 100 mM). The reaction was stopped after 1 h at 37 °C by addition of 100 pL 40 mM disodium hydrogen phosphate buffer containing 30 mM citric acid (pH 4) and 1 pM 17:0 LPA (internal standard). Afterwards the samples were treated as described above and analysed by LC-MS/MS. The data was analyzed using graph pad prism (v 7.03) to arrive at the half-maximal inhibitory concentrations (IC50) of the test compounds.
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and optionally one or more pharmaceutically acceptable excipients.
  • the novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
  • One or more pharmaceutical excipients are selected from known to those skilled in the art such as diluents, carries, lubricants fillers and the like.
  • the pharmaceutical compositions further comprise an effective amount of compounds of formula (I) or pharmaceutically acceptable salts thereof.
  • the dosage of compounds of formula (I) may vary within wide limits and should be adjusted, in each particular case, to the individual conditions.
  • the compound of formula (I) may be used alone or in any combination with one or more therapeutic agents such as anti-inflammatory agents, antitumor agents, antifibrotic agents, autotaxin inhibitors, immunomodulators and cardiovascular agents and other therapeutic agents which are known to skilled medical practitioner.
  • the selection of such therapeutic agents may be depend upon the type of disease and its severity, condition of patient being treated, and other medications being taken by the patients, etc.
  • the compounds of formula (I), or pharmaceutical compositions containing them are useful as a medicament for the inhibition of ATX activity and suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration.
  • the present invention includes a method for the treatment of at least one of cancer, chronic inflammation, neuropathic pain, fibrotic diseases mediated in part by ATX comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt of the novel compound of formula (I).

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Abstract

La présente invention concerne de nouveaux composés hétérocycliques de formule générale (I) et leurs sels, énantiomères et diastéréomères pharmaceutiquement acceptables qui sont des inhibiteurs de l'autotaxine (ATX). Les composés de formule générale (I), leurs sels pharmaceutiquement acceptables et la composition pharmaceutique sont utiles pour le traitement et la prophylaxie d'états ou d'un trouble provoqué par l'activation de l'autotaxine (ATX) ou une concentration accrue d'acide lysophosphatidique (LPA).
PCT/IB2021/055805 2020-06-30 2021-06-29 Nouveaux inhibiteurs de l'autotaxine WO2022003557A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010130944A1 (fr) * 2009-05-12 2010-11-18 Sanofi-Aventis Dérivés de cyclopenta[c]pyrrole-2-carboxylates, leur préparation et leur application en thérapeutique
WO2014048865A1 (fr) * 2012-09-25 2014-04-03 F. Hoffmann-La Roche Ag Nouveaux dérivés bicycliques
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WO2014048865A1 (fr) * 2012-09-25 2014-04-03 F. Hoffmann-La Roche Ag Nouveaux dérivés bicycliques
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