EP1534700A1 - Neue thiophenderivate, verfahren zu deren herstellung und pharmazeutische zusammensetzungen, die diese enthalten - Google Patents

Neue thiophenderivate, verfahren zu deren herstellung und pharmazeutische zusammensetzungen, die diese enthalten

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Publication number
EP1534700A1
EP1534700A1 EP03792270A EP03792270A EP1534700A1 EP 1534700 A1 EP1534700 A1 EP 1534700A1 EP 03792270 A EP03792270 A EP 03792270A EP 03792270 A EP03792270 A EP 03792270A EP 1534700 A1 EP1534700 A1 EP 1534700A1
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Prior art keywords
phenyl
formula
methyl
group
compounds
Prior art date
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EP03792270A
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English (en)
French (fr)
Inventor
Anne-claude Pfizer PGRD DUBLANCHET
Delphine Pfizer PGRD COMPERE
Philippe Pfizer PGRD CLUZEAU
Stephane Pfizer PGRD BLAIS
Alexis Pfizer PGRD DENIS
Pierre Pfizer PGRD DUCROT
Karine Pfizer PGRD COURTE
Sophie Pfizer Global & Research Dev. DESCAMPS
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Warner Lambert Co LLC
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Warner Lambert Co LLC
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Priority to EP03792270A priority Critical patent/EP1534700A1/de
Publication of EP1534700A1 publication Critical patent/EP1534700A1/de
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/16—Central respiratory analeptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • the present invention relates to new thiophene derivatives, their preparation process and the pharmaceutical compositions containing them.
  • the compounds of the present invention are particularly advantageous from a pharmacological point of view for their specific interaction with metalloproteinases and more specifically with macrophagic metalloelastase (MMP-12), finding their application in the prevention and treatment of respiratory pathologies such as chronic obstructive pulmonary disease (COPD), emphysema, chronic bronchitis, chronic pulmonary inflammation, asthma, cystic fibrosis, acute respiratory distress (ARDS), respiratory allergies including allergic rhinitis, as well as diseases linked to the production of T F ⁇ including severe fibrotic pulmonary diseases, pulmonary sarcoidosis, and silicosis.
  • COPD chronic obstructive pulmonary disease
  • emphysema chronic bronchitis
  • chronic pulmonary inflammation chronic pulmonary inflammation
  • asthma cystic fibrosis
  • ARDS acute respiratory distress
  • respiratory allergies including allergic rhinitis
  • diseases linked to the production of T F ⁇ including severe fibrotic pulmonary diseases, pulmonary sarc
  • the compounds of the present invention also show, at a lesser level, an inhibitory activity of metalloproteinase-13 (MMP-13) making them potentially useful for the treatment of pathologies involving this enzyme, such as cancer, osteoporosis, osteoarthritis , arthritis, rheumatoid arthritis, atherosclerosis, multiple sclerosis, heart failure.
  • MMP-13 metalloproteinase-13
  • MMPs Metalloproteinases
  • MMPs Metalloproteinases
  • MMP-1, MMP-8 and MMP-13 collagenases
  • MMP-3 and MMP-10 stromelysins
  • MMP-2 and MMP-9 gelatinases
  • MMP-7 macrophagic metalloelastase 12
  • MMP-12 membrane-type MMPs
  • MMPs are zinc metalloproteinases capable of degrading almost all of the components of the extracellular matrix, that is to say the interstitium and the basement membranes. Increased synthesis of these enzymes is found in many destructive diseases (inflammatory arthritis, atherosclerosis, tumor invasion, angiogenesis).
  • the MMPs (in particular those with a powerful elastolytic activity) are involved in the pathophysiology of asthma and chronic obstructive pulmonary disease including tobacco-related pulmonary emphysema (COPD).
  • COPD tobacco-related pulmonary emphysema
  • HME Human macrophagic elastase
  • MMP-12 Human macrophagic elastase has all the characteristics of other MMPs. It degrades many macromolecules of the extracellular matrix (gelatin, fibronectin and laminin) and especially elastin.
  • MMP-12 is not synthesized by circulating monocytic cells, but only by macrophages or monocytes differentiated in vitro into macrophages.
  • the pathology of emphysema is characterized by the destruction of the elastin present in the walls of the pulmonary alveoli. The demonstration of the increase in the level of MMP-12 during the manifestation of this pathology, thus suggests a predominant role of this enzyme in the occurrence and development of this disease.
  • studies have demonstrated the absence of development of emphysema in mice deficient in MMP-12, these mice being exposed for a long time to cigarette smoke (Science 1997, 277, 2002-2004.).
  • MMP-12 human macrophagic elastase
  • COPD chronic obstructive pulmonary disease
  • emphysema bronchitis
  • chronic, chronic pulmonary inflammations but also respiratory pathologies due to an inflammation phenomenon such as asthma, cystic fibrosis, acute respiratory distress (ARDS), respiratory allergies including allergic rhinitis, as well as diseases related to TNF ⁇ production including severe fibrotic lung disease, pulmonary sarcoidosis, and silicosis.
  • ARDS acute respiratory distress
  • respiratory allergies including allergic rhinitis
  • diseases related to TNF ⁇ production including severe fibrotic lung disease, pulmonary sarcoidosis, and silicosis.
  • All metalloproteinases have a catalytic domain consisting of 162 to 173 amino acids containing the active site of the enzyme.
  • a Zn 2+ ion is present in the active site to which it is attached via histidine residues.
  • This site constitutes one of the preferred anchoring points for synthetic inhibitors of metalloproteinases because it allows in particular to create a stable, powerful and easily accessible chelation center for small molecules.
  • all the strong inhibitors described in the literature have a chemical function (such as a hydroxamic acid) allowing a chelation between the zinc atom of the catalytic site of metalloproteinase and said inhibitor. This chelation ensures blocking of the active site and results in the inhibition of said enzyme.
  • One of the objects of the invention is therefore to provide new compounds having inhibitory properties of metalloproteinase type 12 (MMP-12).
  • MMP-12 metalloproteinase type 12
  • WO 98/23605 which describes thien-2-yl-carboxamide derivatives substituted in position 4 by a cyclic system and in position 5 by a trifluoromethyl group. These compounds are claimed for their bactericidal and fungicidal activities.
  • Patent application WO 96/16954 also describes compounds optionally comprising a 4-arylthien-2-yl carboxamide system in which the amide function can be substituted by a phenyl group, useful for their anti-fungal property.
  • Patent application WO 01/06821 claims compounds useful for the treatment of psychotic pathologies. These compounds, which constitute nicotinic acetylcholine receptor agonists, may in particular have a central thien-2-ylcarboxamide motif in which the amide function is substituted by a 1- azabicyclo [2,2,2] oct-3- group. yl. There may also be cited patent application JP 63175853 or the article Chem. Common. 2001, 8, 759-760, which describe compounds comprising a substituted thiophene group, these compounds constituting fluorescence photo-regulators or photographic developers. None of these documents describes or suggests for these compounds an inhibitory activity of MMP-12 and a potential use of this type of product in the treatment of respiratory pathologies, original property of the compounds claimed by the applicant.
  • X represents an oxygen atom or a sulfur atom
  • Y represents an oxygen atom, an -NH group or an -N (C ⁇ -C 6 ) alkyl group
  • R a represents a group chosen from hydrogen, halogen, (C ⁇ -C 3 ) alkyl, hydroxy, and (C ⁇ -C 3 ) alkoxy,
  • R b represents a group chosen from hydrogen, halogen, and (C ⁇ -C 3 ) alkyl,
  • A represents a group chosen from phenyl, pyridyl, (C 5 -C 6 ) cycloalkyl and (C 5 -C 6 ) cycloalkenyl,
  • Ri and R 2 identical or different, independently of one another, each represent a group chosen from: hydrogen, halogen, cyano, nitro, halo (C ⁇ -C 6 ) alkyl, halo (C ⁇ -C 6 ) alkoxy, (C ⁇ -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, -OR4, -NR4R5, -S (O) n R4, -C (O) R4, -CO 2 R4, -OC (O) R, -C (O) NR4R 5 , -NR 5 -C (O) R4 , -NR 5 -SO 2 R4, -T-CN, -T-ORt, -T-OCF 3 , -T-NR4R5, -TS (O) n R 4 , -TC (O) R4, -T-CO 2 R, -TOC (O) R4,
  • R represents a hydrogen atom, a group (C ⁇ -C 6 ) alkyl, aryl, cycloalkyle, or a heterocycle, is R 5 represents a hydrogen atom or a group (C ⁇ -C 6 ) alkyl,
  • R 6 represents a group chosen from aryl, cycloalkyl and a heterocyl, each of these groups being optionally substituted by one to five groups, identical or different, independently of one another chosen from halogen, cyano, nitro, oxo, halo (C ⁇ -C 6 ) alkyl, halo (C ⁇ -
  • R 0 , R 50 , Ti and ni respectively have the same meanings as R 4 ,
  • O Gi represents a group chosen from aryl, cycloalkyl, and a heterocycle, each of these groups being optionally substituted by 1 to 5 groups, identical or different, independently of the other chosen from halogen, cyano, nitro, halo (C ⁇ -C 6 ) alkyl, halo (C ⁇ -C 6 ) alkoxy, (C ⁇ -C 6 ) alkyl, hydroxy, (C ⁇ -C 6 ) a ⁇ koxy, phenoxy, benzyloxy, amino, mono (C ⁇ - C 6 ) alkylamino, di (C ⁇ -C 6 ) alkylamino, mercapto, (C ⁇ -C 6 ) alkylthio, (C ⁇ -C 7 ) acyl, (C ⁇ -C 6 ) alkylsulfoxide, carboxy,
  • R 3 represents a group -R 7 or -U-R ⁇ , in which: SR represents a group chosen from hydrogen, (C ⁇ -C 6 ) alkyl, aryl, cycloalkyl and heterocycle, each ring system being optionally substituted by one to five groups , identical or different, independently of one another chosen from halogen, cyano, nitro, halo (C ⁇ -C 6 ) alkyl, halo (C ⁇ -C 6 ) alkoxy, (C ⁇ -C 6 ) alkyl, -OR_, -NR 8 R 9 , -S (O) m R 8 , -C (O) R_, -CO R 8 ,
  • SU represents a chain (C ⁇ -C 6 ) linear or branched alkylene optionally substituted by a hydroxy group, or (C 2 -C 6 ) linear or branched alkylene in which one of the carbon atoms is replaced by an oxygen atom, a sulfur atom, a group -NH-, or a group -N (C ⁇ -C 6 ) alkyl,
  • S Ru represents a group chosen from halogen, -OR ⁇ _, -NR 12 R 13 , -S (O) p R ⁇ 2 , -C (O) Ri2, -CO 2 R ⁇ 2 , -OC (O) R ⁇ 2 , - C (O) NR ⁇ 2 R ⁇ 3 , -NR ⁇ 3 -C (O) R ⁇ 2 , -NR ⁇ 3 -SO 2 R ⁇ 2 , and -R ⁇ 4 the latter group being optionally substituted by one to three groups, identical or different, independently of one another chosen from halogen, cyano, nitro, halo (C ⁇ -C 6 ) alkyl, halo (C ⁇ -C 6 ) alkoxy, (C ⁇ -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, -OR ⁇ 5 , -NR ⁇ 5 R ⁇ 6 , -S (O) q R ⁇ 5 ,
  • R ⁇ 2 represents a hydrogen atom, a group (C ⁇ -C 6 ) alkyl, aryl, cycloalkyle, or a heterocycle
  • R ⁇ 3 represents a hydrogen atom or a group (C ⁇ -C 6 ) alkyl
  • R ⁇ 4 represents an aryl, cycloalkyl or heterocycle group
  • -s R ⁇ 5 represents a hydrogen atom, a (C ⁇ -C 6 ) alkyl, aryl, cycloalkyl or a heterocycle group
  • __- R ⁇ 6 represents a hydrogen or an (C ⁇ -C 6 ) alkyl group
  • R ⁇ 7 represents an aryl, cycloalkyl or heterocycle group
  • __- p represents an integer between 0 and 2 inclusive
  • _ q represents an integer between 0 and 2 inclusive
  • W represents a group chosen from a chain (C ⁇ -C 6 ) linear or branched alkylene, a chain (C -C 6 ) linear or branched alkenylene, a cyclopropylene group, and a chain (C 2 -C 6 ) linear alkylene or branched in which one of the carbon atoms is replaced by an oxygen atom, a sulfur atom, an -NH- group, or a -N (C ⁇ -C 6 ) alkyl- group,
  • -if Wi represents a chain (C ⁇ -C 6 ) linear or branched alkylene
  • R a represents a hydrogen atom
  • A represents a cyclopenten-1-yl group substituted in position 2 by a group Ri taking the definition thienyl optionally substituted
  • R b represents a group chosen from hydrogen, halogen, and (C 2 - C 3 ) alkyl
  • R 3 represents a group R 7 taking the definition heterocycle then said heterocycle cannot represent a group 1-azabicyclo [2,2,2] oct-3-yl
  • R 3 represents a group R 7 taking the phenyl definition substituted in the para position by a Rio group, then said Rio group cannot represent a 5-methyl-4,5-dihydro-3-oxo-2H-pyridazin group 6-yl,
  • aryl group is understood a monocyclic or aromatic bicyclic system comprising from 4 to 10 carbon atoms, it being understood that in the case of a bicyclic system one of the rings has an aromatic character and the other ring is aromatic or unsaturated ; as an indication, the following groups may be cited: phenyl, naphthyl, indenyl, benzocyclobutenyl, 1,2,3,4-tetrahydronaphthyl, ...
  • cycloalkyl group is understood a monocyclic or bicyclic system, fused or bridged, saturated or partially unsaturated, comprising from 3 to 12 carbon atoms; as an indication, the following groups may be cited: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, decalyl, norbornyl, cyclopentenyl, cyclohexenyl, cyclohexenediyl, ...
  • a heterocycle is understood a monocyclic or bicyclic system, fused or bridged, from 3 to 12 links, saturated, unsaturated or aromatic, comprising from 1 to 4 heteroatoms, identical or different, independently of one another chosen from oxygen , sulfur and nitrogen, and optionally containing 1 or 2 oxo or thioxo groups, it being understood that in the case of a bicyclic system one of the rings can have an aromatic character and the other ring is aromatic or unsaturated, or both cycles are saturated, or one of the cycles is saturated and the other cycle is unsaturated, or both cycles are unsaturated; as an indication, the following groups may be cited: furyl, thienyl, pyrrolyl, pyrazolyle, pyridyle, pyrimidyle, pyrazinyle, benzofuryle, benzothiènyle, indolyle, quinolyle, isoquinolyle, imidazolyle, benzodioxolyle, benzo
  • C ⁇ -C 6 alkyl is understood a linear or branched carbon chain comprising from 1 to 6 carbon atoms; as an indication, the following groups may be cited: methyl, ethyl, propyl, isopropyl, tert-butyl, neopentyl, hexyl, etc.
  • (C 2 -C 6 ) alkenyl group is understood a linear or branched carbon chain comprising from 2 to 6 carbon atoms and one or more double bonds; as an indication, the following groups may be cited: vinyl, allyl, 3-buten-1-yl, 2-methyl-buten-1-yl, hexenyl, etc.
  • (C -C 6 ) alkynyl group is understood a linear or branched carbon chain comprising from 2 to 6 carbon atoms and one or more triple bonds; as an indication, the following groups may be cited: ethynyl, propynyl, 3-butyn-1-yl, 2-methyl-butyn-1-yl, hexynyl, ... - by group (C ⁇ -C 6 ) alkoxy, it is understood an alkyl group as defined above linked through an oxygen atom; as an indication, the following groups may be cited: methoxy, ethoxy, 7-propyloxy, tert-butyloxy, etc.
  • halo group (C ⁇ -C 6 ) alkyl is understood a linear or branched carbon chain comprising from 1 to 6 carbon atoms and substituted by 1 to 6 halogen atoms; as an indication, the following groups may be cited: trifluoromethyl,
  • halo group (C ⁇ -C 6 ) alkoxy is understood a linear or branched carbon chain comprising from 1 to 6 carbon atoms and substituted by 1 to 6 halogen atoms, said chain being linked to the compound of formula (I) by an oxygen atom; as an indication, the following groups may be cited: trifluoromethoxy, 2,2,2- trifluoroethoxy, etc.
  • halogen atom we mean an atom chosen from bromine, chlorine, fluorine and iodine,
  • acyl group is understood a hydrogen atom, an alkyl group as defined above, a cycloalkyl of 3 to 6 carbon atoms, or a phenyl group linked through an oxo group to the compounds of formula (I); for information only the following groups may be mentioned: formyl, acetyl, ethylcarbonyl, n-propylcarbonyl, tert-butylcarbonyl, cyclopropylcarbonyl, benzoyl, ... by cyclic system is understood aryl, cycloalkyl and heterocycles groups as defined above, - optical isomers refer to racemates, enantiomers and diastereoisomers.
  • the present invention relates to the compounds of formula (I) as defined above in which A represents a group chosen from phenyl, (C 5 -C 6 ) cycloalkyl and (C 5 -C 6 ) cycloalkenyl, Ri, R 2 , R 3 , R a , R b , X and Y being as defined above in formula (I).
  • the preferred compounds of the invention are the compounds of formula (LA):
  • A preferably represents a phenyl group in the compounds of formula (I) or of formula (LA).
  • the preferred compounds of the invention are the compounds of formula (I) as defined above in which A represents a phenyl group, R a represents a hydrogen atom, R b represents a atom of hydrogen, X represents an oxygen atom, Y represents a group -NH-, Ri is as defined in the general formula (I), R 2 represents a hydrogen atom, and R 3 represents a group -U-R ⁇ in which U and Ru are as defined in the general definition of formula (I).
  • said group A taking the phenyl definition is substituted by a group Ri as defined in formula (I) located in position ra.
  • the preferred Ri groups according to the invention are the groups chosen from trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy, (C ⁇ -C 6 ) alkyl, cyano, nitro,
  • ES) R represents a hydrogen atom, a group (C ⁇ -C 6 ) alkyl, aryl, cycloalkyl or a heterocycle
  • ESI R 5 represents a hydrogen atom or a group (C ⁇ -C 6 ) alkyl
  • R 6 represents a group chosen from aryl, cycloalkyl and a heterocyle, each of these groups being optionally substituted by one or two groups, identical or different, chosen from halogen, cyano, nitro, trifluoromethyl, halo (C ⁇ -C 6 ) alkoxy , (C ⁇ -C 6 ) alkyl, vinyl, -OR 0 , -N 4oR 5 o, -S (O) friendship ⁇ R4o, -C (O) R- ⁇ ), -CO.Rw, -OC (O) R4o , -C ⁇ N ⁇ oRso,
  • Ri represents a group chosen from (C 2 -C 4 ) alkyl
  • R 6 represents a group chosen from phenyl optionally substituted by one or two groups as defined in formula (I), cyclohexyl, and a 5 or 6-membered heterocycle comprising from 1 to 3 heteroatoms chosen from oxygen, nitrogen and sulfur.
  • Ri represents a group chosen from:
  • phenyl optionally substituted with a group chosen from halogen, hydroxy, (C ⁇ -C 4 ) alkoxy, phenoxy, trifluoromethoxy, acyl, (C ⁇ -C 4 ) alkylsulfone, -T-CO 2 R 40 and -T-CN in which T and R 0 are as defined in formula (I),
  • R 3 represents a group R 7 chosen from phenyl, cyclohexyl and pyridyl, each of these groups being optionally substituted by one or two groups, identical or different, independently of one another chosen from (C ⁇ -C 6 ) alkyl, -OR 8 , -NR 8 R 9 , -CO 2 R 8 , -V-OR 8 , -V-NR 8 R 9 and -N-CO 2 R 8 in which V represents a chain ( C ⁇ -C 4 ) linear or branched alkylene or chain
  • R 8 represents a hydrogen atom or a group (C ⁇ -C 6 ) alkyl
  • R 9 represents a hydrogen atom
  • R 3 represents a group -U-R ⁇ in which U represents a linear or branched alkylene chain (C ⁇ -C) and Ru represents a group chosen from -CO 2 R ⁇ 2 and -R ⁇ 4 in which :
  • R 12 represents a hydrogen atom or a group (C ⁇ -C 6 ) alkyl
  • R ⁇ 4 represents a group chosen from phenyl, cyclohexyl, morpholinyl, and pyridyl each of these groups being optionally substituted by one or two groups , identical or different, independently of one another chosen from halogen, (C ⁇ -C 6 ) alkyl,
  • R ⁇ 5 represents a hydrogen atom or a (C ⁇ -C 6 ) alkyl group
  • W represents a linear or branched (C ⁇ -C 6 ) alkylene chain , or a linear or branched (C 2 -C 6 ) alkenylene chain.
  • the invention also relates to the pharmaceutically acceptable salts of the compounds of formula (I).
  • Pharmaceutically acceptable acids mean non-toxic organic or mineral acids.
  • pharmaceutically acceptable acids non-limiting mention may be made of hydrochloric, hydrobromic, sulfirric, phosphonic, nitric, acetic, trifluoro acetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic acids. oxalic, methane sulfonic, camphoric, benzoic, toluenesulfonic, etc ...
  • Pharmaceutically acceptable bases mean non-toxic organic or mineral bases.
  • isomers of the compounds of the invention include optical isomers such as enantiomers and diastereoisomers. More particularly, the pure enantiomeric forms of the compounds of the invention can be separated from mixtures of enantiomers which are reacted with a releasable agent for resolution of the racemates, said agent existing in turn in the form of an enantiomer pure, allowing to obtain the corresponding diastereoisomers. These diastereoisomers are then separated according to separation techniques well known to those skilled in the art, such as crystallization or chromatography, then the resolving agent is eliminated using the conventional techniques of organic chemistry, to lead to obtaining a pure enantiomer. In another way, the pure enantiomeric forms of the compounds of the invention can be separated by chromatography on a chiral column.
  • the compounds of the invention which are present in the form of a mixture of diastereoisomers, are isolated in pure form by the use of conventional separation techniques such as chromatography.
  • the process for separating the compounds of the invention can lead to the predominant formation of one enantiomer or one diastereoisomer with respect to the other.
  • the invention also extends to the process for the preparation of the compounds of formula (I). More particularly, the compounds of formula (I) can be obtained from the compounds of formula (II):
  • R a and R b are as defined in formula (I) and Pi represents a halogen atom or a triflate group
  • R a , R and Pi are as defined above, or which are treated directly, under peptide coupling conditions in the presence for example of HATU (O- (7-azabenzotriazol-l-yl) -NNN ', N'-tetramethyluronium hexafluorophosphate) and in a basic medium, with a compound of formula (N):
  • Ri, R 2 and A have the same meanings as in formula (I) and Gio represent a halogen atom chosen from chlorine and bromine or a triflate group, either in the presence of triphenylphosphine arsenic and a palladium catalyst , in the case where Gio represents a triflate group, either in the presence of a halogen-copper compound such as CuBr 2 and of a palladium catalyst, under polar solvent conditions, in the case where Gio represents a halogen atom, to also lead to the compounds of formula (I / a):
  • R a , R b , Ri, R, R 3 , Y and A are as defined above,
  • A, Ri, and R 2 are as defined in formula (I),> either in the presence of triphenylphosphine arsenic and a palladium catalyst, in the case where Pi in the compounds of formula (NI) represents a triflate grouping, either in the presence of a halogen-copper compound such as CuBr 2 and a palladium catalyst, under polar solvent conditions, in the case where Pi in the compounds of formula (NI) represents a halogen atom, to also lead to the compounds of formula (I / a) as described above:
  • R 6 is as defined in formula (I), that is to say that it represents a group chosen from aryl, cycloalkyl, and a heterocycle, each being optionally substituted, to yield the compounds of formula (I / c), special case of the compounds of formula (I):
  • R a , R b , Y and R 3 are as defined above,
  • R 6 , R a , R b , Y and R 3 are as defined above,
  • R a , R b , Y and R 3 are as defined above, and R ⁇ represents an optionally substituted nitrogen heterocycle as defined in formula (I),
  • the compounds (I / a) to (I / f) forming all of the compounds of the invention which are purified, if necessary, according to a conventional purification technique, which can, if it is wishes to be separated into their different isomers according to a conventional separation technique, and which is converted, if necessary, into their addition salts with an acid or a pharmaceutically acceptable base.
  • the compounds of formula (II), (N), (Nile), (IX), (X) and (Xa) are either commercial compounds, or obtained according to known methods of organic synthesis, easily accessible and comprehensible to the skilled in the art.
  • the compounds of formula (I) can also be obtained by a second preparation process characterized in that a compound of formula (II) is used as starting material:
  • R a and R b are as defined in formula (I) and Pi represents a halogen atom or a triflate group
  • R a , R b , Ri, R 2 , A and P 4 are as defined above,
  • Ri, R 2 and A have the same meanings as in formula (I) and Gio represent a halogen atom chosen from chlorine and bromine or a triflate group,
  • R 6 is as defined in formula (I), that is to say that it represents a group chosen from aryl, cycloalkyl, and a heterocycle, each being optionally substituted, to yield the compounds of formula (I / i), special case of the compounds of formula (I):
  • the compounds (I / g) to (I / m) together forming the compounds of the invention which are purified, if necessary, according to a conventional purification technique, which can, if desired, be separated into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into their addition salts with a pharmaceutically acceptable acid or base.
  • the compounds of the present invention are useful in the prevention and treatment of respiratory pathologies such as chronic obstructive pulmonary disease (COPD), emphysema, bronchitis chronic, chronic pulmonary inflammation, asthma, cystic fibrosis, acute respiratory distress (ARDS), respiratory allergies including allergic rhinitis, as well as diseases linked to TNF ⁇ production including severe fibrotic pulmonary diseases, pulmonary sarcoidosis , and silicosis.
  • COPD chronic obstructive pulmonary disease
  • emphysema bronchitis chronic, chronic pulmonary inflammation, asthma, cystic fibrosis, acute respiratory distress (ARDS), respiratory allergies including allergic rhinitis, as well as diseases linked to TNF ⁇ production including severe fibrotic pulmonary diseases, pulmonary sarcoidosis , and silicosis.
  • COPD chronic obstructive pulmonary disease
  • emphysema bronchitis chronic, chronic pulmonary inflammation, asthma, cystic fibro
  • the compounds of the present invention also show, at a lesser level, an inhibitory activity of metalloproteinase-13 (MMP-13) making them potentially useful for the treatment of pathologies involving this enzyme, such as cancer, osteoporosis, osteoarthritis, arthritis, rheumatoid arthritis, atherosclerosis, multiple sclerosis, heart failure.
  • MMP-13 metalloproteinase-13
  • the compounds of the present invention are useful for the prevention and treatment of chronic obstructive pulmonary disease, emphysema and chronic bronchitis. More particularly, the compounds of the present invention are useful for the treatment of smoking-related emphysema.
  • the compounds of formula (I) are useful for the prevention and treatment of asthma.
  • the present invention also relates to pharmaceutical compositions containing as active principle at least one compound of formula (I), one of its isomers or one of its addition salts with a pharmaceutically acceptable acid or base, alone or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or vehicles.
  • compositions according to the invention particular mention will be made of those which are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per- or trans-cutaneous, intravaginal, rectal, nasal, perlingual or respiratory administration. .
  • compositions according to the invention for parenteral injections include in particular aqueous and non-aqueous sterile solutions, dispersions, suspensions or emulsions as well as sterile powders for the reconstitution of injectable solutions or dispersions.
  • compositions according to the invention for solid oral administration, include in particular simple or coated tablets, sublingual tablets, sachets, capsules, granules, and for oral, nasal or buccal administration, especially include emulsions , solutions, suspensions, drops, syrups and aerosols.
  • compositions according to the invention for administration by the respiratory route, comprise in particular compositions in the form of solutions for aerosols or powders for inhalers.
  • the compositions can be sterile stable solutions or solid compositions dissolved at the time of use in sterile pyrogen-free water, in physiological saline or any other pharmaceutically acceptable vehicle.
  • the active principle is possibly finely divided or micronized, and associated with a diluent or inert water-soluble solid vehicle.
  • compositions for rectal administration are preferably suppositories, and those for per- or trans-cutaneous administration include in particular powders, aerosols, creams, ointments, gels, and patches.
  • compositions cited above illustrate the invention but do not limit it in any way.
  • inert, non-toxic, pharmaceutically acceptable excipients or vehicles mention may be made, by way of indication and without limitation, of diluents, solvents, preservatives, wetting agents, emulsifiers, dispersing agents, binders, swelling agents, disintegrating agents, retardants, lubricants, absorbents, suspending agents, colorants, flavorings, etc.
  • the useful dosage varies according to the age and weight of the patient, the route of administration, the pharmaceutical composition used, the nature and severity of the condition, and the taking of any associated treatments.
  • the dosage ranges from 1 mg to 1000 mg in one or more doses per day.
  • the starting materials used are commercial products or products prepared according to known procedures from commercial compounds or known to those skilled in the art.
  • the various preparations lead to synthesis intermediates useful for the preparation of the compounds of the invention.
  • the structures of the compounds described in the examples and in the preparations were determined according to the usual spectrophotometric techniques (infrared (LR), nuclear magnetic resonance (NMR), mass spectrometry (SM) including electrospray (ES), ...) and purity was determined by high performance liquid chromatography (HPLC).
  • the product (0.367 g) is obtained according to the method of preparation 2, using the product obtained in the preceding stage 1 as a substrate. Yield: 74% 1 H NMR (CDCI 3 ) ⁇ (ppm): 0.325 (s, 9H), 1.05 (q, 2H), 1.25 (t, 3H), 1.42 (q, 2H), 1.57 (bs , 1H), 1.90 (d, 2H), 2.05 (d, 2H), 2.25 (t, 1H), 3.30 (t, 2H), 4.12 (q, 2H), 6 .00 (bs, 1H), 7.42 (s, 1H), 7.55 (s, 1H)
  • Stage 7 3- (6-Aminopyridin-3-yl) ethyl propanoate To a solution of 0.133 g of the compound obtained in Stage 6 in 3 ml of ethanol is added
  • Stage 2 4-Diethyl cyanophthalate To 0.95 g of the compound obtained in Stage 1 in 10 ml of 2-N-methyl-pyrrolidinone is added 0.508 g (1.8 equivalents) of copper cyanide. The reaction medium is stirred for 17 hours at 200 ° C. The solution is then hydrolyzed with an aqueous solution of ammonium hydroxide and extracted with ethyl acetate. The solution is washed with water, dried over sodium sulfate and then filtered to obtain 1.2 g of a brown oil after evaporation under reduced pressure. Chromatography of the residue on silica gel (cyclohexane / ethyl acetate: 8/2) allows 0.320 g of the expected product to be isolated. Yield: 41% DM: MH + 273
  • Stage 3 4- (Aminomethyl) diethyl phthalate To a solution of 0.15 g of product obtained in Stage 2 in 1 ml of ethanol are added, 0.5 ml of 36% hydrochloric acid and 15 mg (0 , 1 equivalent) of 10% palladium on carbon. The reaction medium is stirred under 15 bar of hydrogen at 60 ° C for 2 hours. The medium is filtered through celite and concentrated under reduced pressure to obtain 0.3 g of a beige powder. Yield: 24% SM: MH + 252
  • the product (0.503 g) is obtained according to the method of stage 7 of preparation 6, using as substrate 3- (4-aminophenyl) propionic acid.
  • the product (4.208 g) is obtained according to the process of stage 7 of preparation 6, using as substrate (4-bromophenyl) acetic acid. Efficiency: 93%
  • the product (0.213 g) is obtained according to the method of stage 3 of preparation 8, using as substrate 3-cyanobenzoic acid.
  • the product (0.15 g) is obtained according to the method of stage 7 of preparation 6, using as product the product obtained in preceding stage 1.
  • the product (0.164 g) is obtained according to the method of stage 7 of preparation 6, using as product the product obtained in preceding stage 1.
  • Stage 3 (3-Cyanophenyl) ethyl acetate
  • the product (0.065 g) is obtained according to the method of stage 2 of preparation 8, using as product the product obtained in the preceding stage 2. Yield: 61% MS: MH " 188
  • Stage 4 [3- (Aminomethyl) phenyl] ethyl acetate
  • the product (0.071 g) is obtained according to the method of stage 3 of preparation 8, using as product the product obtained in the preceding stage 3.
  • the product (0.708 g) is obtained according to the method of stage 1 of preparation 6, using 6-methyl nicotinic acid as the substrate.
  • the product (1.03 g) is obtained according to the process of stage 7 of preparation 6, using as substrate 4- (aminomethyl) benzoic acid.
  • the product (4.06 g) is obtained according to the method of stage 3 of preparation 5, using as substrate 4-bromothiophene-2-carboxylic acid.
  • Stage 2 4 - ⁇ ((4-Bromothien-2-yl) carboxamido] methyl ⁇ ethyl benzoate
  • the reaction medium is stirred for 17 hours at room temperature.
  • the solution is hydrolyzed with water, washed with a 1.0 M aqueous hydrochloric acid solution, then with a saturated sodium hydrogen carbonate solution.
  • the organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • Stage 1 (4-Aminophenyl) ethyl acetate
  • the product (1.686 g) is obtained according to the process of stage 7 of preparation 6 using as substrate 4-aminophenylacetic acid. Yield: 71% SM: MH + 179
  • Stage 2 ⁇ 4 - [(4-Bromothièn-2-yl) carboxamido] phenyl ⁇ ethyl acetate
  • the product (0.550 g) is obtained according to the process of stage 2 of preparation 17, using the product obtained as substrate in stage 1 of preparation 17, and as co-substrate the product described in preceding stage 1.
  • the product (1.046 g) is obtained according to the method of stage 7 of preparation 6, using 3- (4-chlorophenyl) propanoic acid as substrate.
  • the product (0.076 g) is obtained according to the method of stage 2 of preparation 8, using as product the product obtained in preceding stage 1.
  • the product (0.131 g) is obtained according to the method of stage 3 of preparation 8, using as product the product obtained in preceding stage 2.
  • Stage 1 ethyl 3- (3-Bromophenyl) propanoate
  • the product (1.778 g) is obtained according to the method of stage 7 of preparation 6, using as substrate 3- (3-bromophenyl) propanoic acid.
  • Efficiency 80%
  • Stage 2 methyl trans-3- [3- (tert-Butoxycarbonylamino) -cyclohexyl] -propanoate
  • the product (0.51 g) is obtained according to the process of stage 1 of preparation 6, using as substrate 0.5 g of the product obtained in previous stage 1. Yield: 97.4%
  • Stage 1 Trans-3- (tert-butoxycarbonylamino) -cyclohexyl acetic acid
  • the product (8.9 g) is obtained according to the process of stage 1 of preparation 23 using as substrate 13.2 g of 3-amino acid -phenyl acetic.
  • Stage 2 trans-3- (tert-Butoxycarbonylamino) -cyclohexyl methyl acetate
  • the product (0.54 g) is obtained according to the method of stage 1 of preparation 6, using as substrate 0.5 g of the product obtained at previous stage 1. Yield: 100%
  • Stage 3 trans-3-Aminocyclohexyl methyl acetate
  • the product (0.204g) is obtained according to the method of stage 3 of preparation 23, using as product the product obtained in preceding stage 2. Efficiency: 99%
  • the product (6.3 g) is obtained according to the method of stage 1 of preparation 23 using as substrate 20 g of 4-nitrocinnamic acid.
  • the product (0.52 g) is obtained according to the method of stage 1 of preparation 6, using as substrate 0.5 g of the product obtained in preceding stage 1. Efficiency: 99%
  • the product (1.9 g) is obtained according to the method of stage 1 of preparation 23 using as substrate 3.99 g of 4-aminomethyl-phenyl acetic acid. Yield: 40.7%
  • Stage 2 4 - [(tert-Butoxycarbonylamino) methyl] -cyclohexyl methyl acetate
  • the product (0.508 g) is obtained according to the process of stage 1 of preparation 6, using as substrate 0.5 g of the product obtained in stage 1 previous. Yield: 96.4%
  • the product (0.216 g) is obtained according to the method of stage 3 of preparation 23, using as product the product obtained in preceding stage 2.
  • the product (1.936 g) is obtained according to the method of stage 7 of preparation 6, using as substrate 5-iodo-2-hydroxybenzoic acid.
  • Stage 1 6-methyl cyanonicotinate To a solution of 70 g of methyl 6-aminonicotinic acid in a 1/1 diethyl ether / methanol mixture cooled to 0 ° C. are added over a period of one hour 803 ml (3.4 equivalents) of trimethylsilyldiazomethane 2.0 M in solution in diethyl ether. The reaction medium is stirred for 1 hour at room temperature and then concentrated under reduced pressure. The orange solid residue obtained is dissolved in 1.4 l of ethyl acetate and washed successively with water and an aqueous solution of sodium carbonate. After extraction of the aqueous phases with ethyl acetate, the organic phases are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 80.5 g of the expected product in the form of an orange solid. Yield: 100%
  • the product (642 mg) is obtained according to the method of stage 4 of Example 18 using as a substrate the compound obtained in preceding stage 1.
  • the product (54 mg) is obtained according to the method of stage 5 of Example 18 using as substrate 0.1 g of the compound obtained in preceding stage 2.
  • the product (0.9 g) is obtained according to the process of stage 7 of preparation 6 using as substrate 4-bromophenylacetic acid.
  • the product (193 mg) is obtained according to the method of stage 5 of Example 18 using as a substrate the compound obtained in preceding stage 2.
  • the product (57.7 mg) is obtained according to the method of Example 1 using as co-substrate (1,1'-biphenyl-4-yl) boronic acid.
  • the product (15.8 mg) is obtained according to the method of Example 1 using as co-substrate 4-ethylphenylboronic acid.
  • the product (64.4 mg) is obtained according to the method of Example 1, using 4- (methylthio) phenylboronic acid as co-substrate.
  • Example 5 4- [4- (Trifluoromethoxy) phenyl] -N- (2-morpholin-4-ylethyl) thiophene-2-carboxamide
  • the product (166.2 mg) is obtained according to the method of Example 1 using as co-substrate 4- (trifluoromethoxy) phenylboronic acid. Yield: 44% 1H NMR (CDC1 3 ) ⁇ (ppm): 2.50 (m, 4H), 2.60 (m, 2H), 3.55 (m, 2H), 3.75 (m, 4H) , 6.62
  • the product (199.8 mg) is obtained according to the method of stage 1 of preparation 9 using as substrate 4-bromothiophene-2-carbaldehyde and as co-substrate 4-tert-butylphenylboronic acid.
  • the product (2.73 g) is obtained according to the method of Example 1, using (4-hydroxyphenyl) boronic acid as co-substrate instead of (4-isopropylphenyl) boronic acid. Yield: 54% 1 H NMR (DMSO) ⁇ (ppm): 2.42 (m, 4H), 2.50 (m, 2H), 3.40 (m, 2H), 3.60 (m, 4H), 6.80 (d, 2H), 7.50 (d, 2H), 7.85 (s, IH), 8.10 (s, IH), 8.42 (bs, IH), 9.55 (s , IH)
  • Stage 1 4- (5 - ⁇ [(2-Morpholin-4-ylethyl) amino] carbonyl ⁇ thien-3-yl) phenyltrifluoro methane sulfonate
  • the product (23.7 mg) is obtained according to the method of Example 1, using as product the product obtained in Stage 1 above and as co-substrate (4-pyridyl) boronic acid instead of the acid (4-isopropylphenyl) boronic acid. Yield: 17% 1 H NMR (CDC1 3 ) ⁇ (ppm): 2.55 (m, 4H), 2.65 (m, 2H), 3.60 (m, 2H), 3.75 (m, 4H) , 6.65
  • the product (200.2 mg) is obtained according to the method of example 1, using as product the product of stage 1 of example 9 and as co-substrate the acid [3- (methoxycarbonyl)) phenyl] boronic instead of (4-isopropylphenyl) boronic acid. Yield: 68%
  • Example 11 4- [4- (Pyridin-3-yl) phenyl] -N- (2-morpholin-4-ylethyl) thiophene-2-carboxamide
  • the product (95.2 mg) is obtained according to the method of Example 1, using as product substrate the product obtained in Stage 1 of Example 9 and as co-substrate (3-pyridyl) boronic acid instead (4-isopropylphenyl) boronic acid. Yield: 45%
  • Example 12 4- [4- (Morpholin-4-yl) phenyl] -N- (2-morpholin-4-yethyl) thiophene-2-carboxamide
  • the product (40.3 mg) is obtained according to the method of Example 12, using piperidine as co-substrate in place of morpholine.
  • Example 15 4- [4- (1,4-Dioxa-8-azaspiro [4,5] dec-8-yl) phenyl] -N- (2-morpholin-4-ylethyl) thiophene-2-carboxamide
  • Example 16 4- [4- (1,2,3,6-Tetrahydropyridin-1-yl) phenyl] -N- (2-morpholin-4-ylethyl) thiophene-2-carboxamide
  • Example 17 4- [4- (3- (5R) -Hydroxy-pyrrolidin-1-yl) phenyl] -N- (2-.morpholin-4-ylethyl) thophene-2-carboxamide
  • the product (66.5 mg) is obtained according to the method of Example 12, using as co-substrate (5R) -pyrrolidin-3-ol in place of morpholine.
  • the product (1.43 g) is obtained according to the method of Example 1, using as product substrate the product obtained in the preceding stage 1 and as co-substrate (4-hydroxyphenyl) boronic acid in place of the (4-isopropylphenyl) boronic acid. Yield: 37%
  • Stage 3 Methyl 4- ⁇ 4 - [(Trifluoromethylsulfonyl) oxy] phenyl ⁇ thiophene-2-carboxylate
  • the product (1.74 g) is obtained according to the method of stage 1 of Example 9, using as product the product obtained in stage 2 above. Yield: 78%
  • reaction medium is stirred for 17 hours at 80 ° C, diluted with ethyl acetate (100 ml), washed with water (3x60 ml), dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel
  • Stage 8 4- [4- (1H-Imidazol-1-yl) phenyl] -N- (2-morpholin-4-ylethyl) thiophene-2-carboxamide
  • the product (22.1 mg) is obtained according to the method of stage 3 of Example 6, using as product the product obtained in preceding stage 7.
  • the product (99.1 mg) is obtained according to the process of stage 3 of Example 6, using as product the product obtained in the preceding stage 4.
  • Example 20 4- [4- (Isoxazol-5-yl) phenyl] -N- (2-morpholin-4-ylethyl) thiophene-2-carboxamide
  • Example 21 4- [4- (Cyclohexyl) phenyl] -N- (2-morpholin-4-ylethyl) thiophene-2-carboxamide
  • Example 22 4- [4- (1-Methyl-1H-pyrazol-3-yl) phenyl] -N- (2-morpholin-4-ylethyl) thiophene-2-carboxamide
  • Example 23 4- [4- (6-Oxo-1,4,5,6-tetrahydro-pyridazin-3-yl) phenyl] -N- (2- morpholin-4-ylethyl) thiophene-2-carboxamide
  • the product (8.1 mg) is obtained according to the method of Example 20, using as co-substrate 6- (4-bromophenyl) -4,5-dihydropyridazin-3 (2H) -one.
  • Example 25 Trans Acid 4- ⁇ [4- (4-phenyl-cyclohex-1-enyl) -thiophen-2-carboxamide] methyl ⁇ -cyclohexane carboxylic
  • the product (48.2 mg) is obtained according to the process of stage 7 of Example 18, using the product obtained in Example 24 as a substrate.
  • Example 27 3- (6 - ⁇ [4- (4-trifluoromethoxyphenyl) thien-2-yl] carboxamido acid ⁇ pyridin-3-yl) -propanoic acid
  • Example 28 Ethyl 3- (4 - ⁇ [4- (4-Trifluoromethoxyphenyl) thien-2-yl] carboxamido ⁇ phenyl) -propenate
  • the product (0.094 g) is obtained according to the method of Example 27, using the compound obtained in Example 28 as the substrate.
  • Example 30 4 - ( ⁇ [4- (Trifluoromethoxyphenyl) thien-2-yllcarboxamido ⁇ methyl) diethyl phthalate
  • the product (0.0729 g) is obtained according to the method of Example 27, using the compound obtained in Example 30 as a substrate.
  • the product (0.483 g) is obtained according to the method of Example 26, using the product obtained in Preparation 9 as co-substrate.
  • Example 33 3- (4 - ⁇ [4- (4-trifluoromethoxyphenyl) thien-2-yl] carboxamido ⁇ phenyl) -propanoic acid
  • the product (0.279 g) is obtained according to the method of Example 27, using the compound obtained in Example 32 as the substrate. Yield: 61%
  • Example 34 methyl trans 4 - ( ⁇ [4- (4-Trifluoromethoxyphenyl) -thien-2-yllcarboxamido ⁇ methyl) -cyclohexane carboxylate
  • the product (0.120 g) is obtained according to the method of Example 26, using the product obtained in preparation 10 as co-substrate. Yield: 41% 1H NMR (CDC1 3 ) ⁇ (ppm): 7.7 ( s, IH), 7.6 (m, 2H), 7.5 (s, IH), 6.0 (bs, IH), 4.1 (q, 2H),
  • Example 35 Trans acid 4 - ( ⁇ [4- (4-trifluoromethoxyphenyl) -thien-2-yI] carboxamido ⁇ methyl) -cyclohexane carboxylic
  • the product (0.112 g) is obtained according to the method of Example 27, using the compound obtained in Example 34 as the substrate. Yield: 100% 1 H NMR (DMSO) ⁇ (ppm): 12.1 (s, IH), 8.4 (bs, IH), 8.2 (s, 1H), 8.1 (s, IH), 7.85 (dd,
  • Example 36 2- [4 - ( ⁇ [4- (4-Trifluoromethoxyphenyl) thien-2-yl] carboxamido ⁇ methyl) phenyl] -ethyl acetate
  • the product (0.070 g) is obtained according to the method of Example 26, using the product obtained in preparation 12 as co-substrate. Yield: 20% 1 H NMR (CDCl3) ⁇ (ppm): 8.05 (bs , IH), 8.0 (d, IH), 7.7 (s, IH), 7.5 (m, 4H), 7.4 (t, IH),
  • Example 39 3 - ( ⁇ [4- (4-trifluoromethoxyphenyl) thien-2-yl] carboxamido ⁇ methyl) benzoic acid
  • the product (0.0076 g) is obtained according to the method of Example 27, using the compound obtained in Example 38 as the substrate. Yield: 11% 1 H NMR (DMSO) ⁇ (ppm): 12.1 ( s, IH), 9.1 (bs, IH), 8.05 (bs, IH), 8.0 (d, IH), 7.7 (s,
  • Example 40 2- [3 - ( ⁇ [4- (4-Trifluoromethoxyphenyl) thien-2-yl] carboxamido ⁇ methyl) phenyl] -ethyl acetate
  • the product (0.023 g) is obtained according to the method of Example 27, using the compound obtained in Example 40 as the substrate.
  • Example 42 4 - ( ⁇ [4- (4-Trfluoromethoxyphenyl) -thien-2-yllcarboxamido ⁇ methyl) - ethyl cyclohexane carboxylate
  • Example 43 4 - ( ⁇ [4- (4-trifluoromethoxyphenyl) -thien-2-yllcarboxamido ⁇ Methyl) -cyclohexane carboxylic acid
  • the product (0.082 g) is obtained according to the method of Example 27, using the compound obtained in Example 42 as the substrate. Yield: 78.5%
  • Example 45 6 - ( ⁇ [4- (4-trifluoromethoxyphenyl) thien-2-yl] carboxamido ⁇ methyl) -nicotinic acid
  • the product (0.051 g) is obtained according to the method of Example 1 using as substrate the compound obtained during preparation 17 and as co-substrate 4- (trifluoromethoxy) phenylboronic acid.
  • the product (0.008 g) is obtained according to the method of Example 27, using the compound obtained in Example 46 as the substrate.
  • the product (0.1 g) is obtained according to the method of Example 46, using 4- (methylthio) phenylboronic acid as co-substrate.
  • the product (0.152 g) is obtained according to the method of Example 27, using the compound obtained in Example 50 as the substrate.
  • the product (0.141 g) is obtained according to the method of Example 46, using the compound obtained in Preparation 18 and 4-tert-butylphenylboronic acid as substrate. Yield: 60% 1H NMR (CDC1 3 ) ⁇ (ppm): 7.9 (bs, IH), 7.6 (s, IH), 7.55 (m, 3H), 7.5 (m, 2H) , 7.4 (m,
  • Example 54 (4 - ⁇ [4- (4-Trifluoromethoxyphenyl) thien-2-yllcarboxamido ⁇ phenyl) ethyl acetate
  • the product (0.119 g) is obtained according to the method of Example 46, using the compound obtained in Preparation 18 as a substrate and 4- (methylthio) phenylboronic acid as co-substrate. Yield: 51%
  • the product (0.060 g) is obtained according to the method of Example 27, using the compound obtained in Example 58 as the substrate. Yield: 31% 1 H NMR (DMSO) ⁇ ppm: 12.9 (s, 1 H) , 9.1 (bs, IH), 8.2 (s, IH), 7.9 (s, IH), 7.85 (m, 2H),
  • Example 60 (4 - ⁇ [4- (4-Methoxyphenyl) thien-2-yllcarboxamido ⁇ phenyl) ethyl acetate
  • the product (0.0615 g) is obtained according to the method of Example 27, using the compound obtained from Example 60 as the substrate. Yield: 41% 1 H NMR (DMSO) ⁇ (ppm): 12.2 ( s, IH), 10.2 (s, IH), 8.5 (s, IH), 8.0 (s, IH), 7.75 (m,
  • Example 62 Ethyl 3- [4 - ( ⁇ [4- (4-Trifluoromethoxyphenyl) thien-2-yllcarboxamido ⁇ methyl) phenyl] propanoate
  • the product (0.084 g) is obtained according to the method of Example 26, using the product of preparation 5 and the product of preparation 20 as substrates.
  • the product (0.363 g) is obtained according to the method of Example 26, using the product of preparation 5 and the product of preparation 22 as substrates.
  • Example 68 Ethyl 4 - ( ⁇ [4- (4-Hydroxyphenyl) thien-2-yl] carboxamido ⁇ methyl) cyclohexane carboxylate
  • the product (0.974 g) is obtained according to the method of preparation 5 stage 1, using as substrate the compound obtained in preparation 3 stage 1 and (4-hydroxyphenyl) boronic acid. Yield: 40%
  • the product (0.133 g) is obtained according to the process of preparation 5 stage 1, using as substrate the compound obtained in preceding stage 1 and as co-substrate pyridine-4-boronic acid. Efficiency: 75%
  • Example 27 The product is obtained according to the method of Example 27, using as compound the compound obtained in Example 69.
  • the solid is stirred in 2.0 ml of diethyl ether and 1.8 ml of a 1.0 M solution HCl / Et 2 O are added dropwise.
  • the precipitate is filtered, washed with water and dried at 60 ° C under vacuum to obtain the expected product (0.0507 g).
  • the product (11.58 g) is obtained according to the method of stage 2 of preparation 1, using as compound the compound of the preceding stage 2.
  • the product (86.8 mg) is obtained according to the method of stage 1 of preparation 5, using the compound of Example 71 as a substrate and (4-acetylphenyl) boronic acid as co-substrate.
  • Example 74 4- [4- (3-Hydroxyphenyl) phenyl] -N- (2-morpholin-4-ylethyl) thiophene-2-carboxamide
  • Example 75 4- [4- (4-Methylsulfonylphenyl) phenyl ⁇ -N- (2-morpholin-4-ylethyl) thiophene-2-carboxamide
  • Example 76 4- [4- (3-Acetylphenyl) phenyl] -N- (2-morpholin-4-ylethyl) thiophene-2-carboxamide
  • Example 78 N- (2-Morpholin-4-ylethyl) -4- [4- (1,2,3-thiadiazol-4-yl) phenyl] thiophene- 2-carboxamide
  • the product (21.7 mg) is obtained according to the method of Example 20, using as co-substrate 4- (4-bromophenyl) -1,2,3-thiadiazole. Yield: 14.5% 1H NMR (DMSO) ⁇ (ppm): 2.42 (m, 4H), 2.50 (m, 2H), 3.40 (m, 2H), 3.60 (m, 4H ), 7.90
  • the reaction medium is stirred for 17 hours at room temperature and then concentrated under reduced pressure.
  • the residue obtained is dissolved in ethyl acetate (50 ml), washed with water (2x20 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. Chromatography on silica gel (cyclohexane / ethyl acetate: 70/30) of the residue allows 62.5 mg of the expected product to be isolated.
  • the product (62.0 mg) is obtained according to the method of Example 27, using the product obtained in Stage 1 as a substrate.
  • the product (164.0 mg) is obtained according to the method of Example 1, using the product obtained in Stage 1 and co-substrate (4-phenoxyphenyl) boronic acid as substrate.
  • Example 82 4- (4-Trifuoromethoxyphenyl) -N-methylthiophene-2-carboxamide
  • the product (112.9 mg) is obtained according to the process of stage 1 of Example 80, using as product the product obtained in stage 2 of preparation 5 and co-substrate methylamine. Yield: 43%
  • Stage 1 2- [4 - ( ⁇ [4- (4-Benzyloxyphenyl) thien-2-yl] carboxamido ⁇ methyl) phenyl] - ethyl acetate
  • the product (45.0 mg) is obtained according to the process of l 'Example 1, using as substrate the product obtained in stage 1 of Example 81 and co-substrate (4-benzyloxyphenyl) boronic acid. Yield: 47% HPLC: 100%
  • Stage 2 Acid2- [4 - ( ⁇ [4- (4-benzyloxyphenyl) thien-2-yl] carboxamido ⁇ methyl) phenyl] - acetic
  • the product (40.0 mg) is obtained according to the method of Example 27, using the product obtained in stage 2 as a substrate.
  • the product (409.0 mg) is obtained by applying the process described in stages 2 and 3 of Preparation 8, using 4-bromo-2,6-difluoro ⁇ henol as the substrate.
  • the product (49.0 mg) is obtained according to the method of stage 1 of example 80, using as product the product obtained in stage 1 and co-substrate the product obtained in stage 2 of preparation 5.
  • the product (66.2 mg) is obtained according to the method of Example 72, using (3-nitrophenyl) boronic acid as co-substrate.
  • the product (36.3 mg) is obtained according to the method of Example 72, using (2-chlorophenyl) boronic acid as co-substrate.
  • Example 87 4- [4- (3-Cyanophenyl) phenyll-N- (2-morpholin-4-yIethyl) thiophene-2-carboxamide
  • Example 90 4- ⁇ 4 - [(4-Hydroxymethyl) phenyl] phenyl ⁇ -N- (2-morpholin-4-ylethyl) thiophene-2-carboxamide
  • the product (146.0 mg) is obtained according to the method of Example 80 stage 1, using as co-substrate the product obtained in stage 2 of preparation 5 and cyclopropylmethylamine.
  • the product (171.0 mg) is obtained according to the method of Example 80 stage 1, using as co-substrate the product obtained in stage 2 of preparation 5 and tert-butylamine.
  • the product (281.0 mg) is obtained according to the method of Example 80 stage 1, using as co-substrate the product obtained in stage 2 of preparation 5 and cyclopentylamine.
  • the product (171.0 mg) is obtained according to the method of Example 80 stage 1, using as co-substrate the product obtained in stage 2 of preparation 5 and the
  • the product (95.6 mg) is obtained according to the method of Example 80 stage 1, using as co-substrate the product obtained in stage 2 of preparation 5 and 1-cyclopentylmethanamine.
  • Example 100 4- ⁇ 4 - [(3-Chloro-4-fluoro) phenyl] phenyl ⁇ -N- (2-morpholin-4-yIethyl) thiophene-2-carboxamide
  • Example 101 4- ⁇ 4 - [(3-Hydroxymethyl) phenyl] phenyl ⁇ -N- (2-morpholin-4-ylethyl) thiophene-2-carboxamide
  • the product (172.8 mg) is obtained according to the method of Example 1, using as substrates the compound of Example 71 and [(3-hydroxymethyl) phenyl] -boronic acid. Yield: 64%
  • Example 102 2- [4 - ( ⁇ [4- (4'-Propionyl-4-biphenyl) -thien-2-yl] carboxamido ⁇ methyl) phenyl ⁇ ethyl acetate
  • Stage 2 2- [4 - [( ⁇ 4- [4- (Pinacolboro) phenyl] -thien-2-yl ⁇ carboxamido) methyl] phenyl ⁇ -ethyl acetate
  • the product (19.5 g) is obtained according to the process of stage 4 of Example 18, replacing the methyl 4- (4 - ⁇ [((trifluoromethyl) sulfonyl] oxy ⁇ phenyl) thiophene-2-carboxylate with the product obtained in previous stage 1. Yield: 98%
  • the product (157.9 mg) is obtained according to the method of stage 1 of preparation 5, using as compounds the compound obtained in the preceding stage 3 and 1- (4-bromophenyl) -propanone.
  • the product (80 mg) is obtained according to the method of Example 27, using the compound obtained in Example 102 as the substrate.
  • the product (107.4 mg) is obtained according to the process of stage 4 of Example 102, using 1- (4-bromophenyl) cyclopropyl-methanone in place of 1- (4-bromophenyl) -propan-1 - one.
  • the product (77.5 mg) is obtained according to the method of Example 27, using the compound obtained in Example 104 as a substrate.
  • the product (167.0 mg) is obtained according to the method of stage 4 of Example 102, using 1- (4-bromophenyl) phenyl-methanone in place of 1- (4-bromophenyl) -propan-1 -one.
  • Example 108 2- [4 - ( ⁇ [4- (4'-Cyanomethyl-4-biphenyl) thien-2-yl] carboxamido ⁇ methyl) phenyl] ethyl acetate
  • the product (91.9 mg) is obtained according to the process of stage 4 of Example 102, using (4-bromophenyl) acetonitrile in place of 1 - (4-bromophenyl) -propan-1 -one.

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EP03792270A 2002-08-13 2003-08-07 Neue thiophenderivate, verfahren zu deren herstellung und pharmazeutische zusammensetzungen, die diese enthalten Withdrawn EP1534700A1 (de)

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EP03792270A EP1534700A1 (de) 2002-08-13 2003-08-07 Neue thiophenderivate, verfahren zu deren herstellung und pharmazeutische zusammensetzungen, die diese enthalten

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