WO2008095852A1 - Arylamides bronchorelaxantes - Google Patents

Arylamides bronchorelaxantes Download PDF

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Publication number
WO2008095852A1
WO2008095852A1 PCT/EP2008/051189 EP2008051189W WO2008095852A1 WO 2008095852 A1 WO2008095852 A1 WO 2008095852A1 EP 2008051189 W EP2008051189 W EP 2008051189W WO 2008095852 A1 WO2008095852 A1 WO 2008095852A1
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compound according
mmol
disease
group
tetrahydroisoquinoline
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PCT/EP2008/051189
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English (en)
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Martin Johansson
Jörgen TOFTERED
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Respiratorius Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • 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
    • A61P11/08—Bronchodilators
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D417/06—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 only aliphatic carbon atoms
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • the present invention relates to a new class of bronchorelaxing arylamides, a composition comprising said new class of bronchorelaxing arylamides and use of said new class of bronchorelaxing arylamides.
  • Asthma and chronic obstructive pulmonary disease are diseases affecting the respiratory system, which millions of people suffer from.
  • the diseases are today regarded as inflammatory diseases and the symptoms comprise constriction of the airways.
  • Common treatment of the bronchoconstriction involves use of beta- agonists, such as terbutalin and formeterol, and anticholinergics, such as ipratropium bromide and thiotropium bromide. These treatments are in many ways insufficient and there is need for alternative treatments.
  • Corticosteroids have been used to treat the inflammation, such as the O inflammation seen in the airways of patients suffering from asthma. Such treatment is fairly effective in the case of asthma, although the inflammation may persist, at least to some extent. Further, corticosteroids are also used to treat the inflammation seen in the airways of patients suffering from COPD. The effect on the inflammation, in the case of COPD, is much less pronounced, if any effect at all is seen. Accordingly, an effective 5 treatment of the inflammation seen in the airways of patients suffering from COPD would be highly desirably.
  • Hypertension i.e. high blood pressure
  • Medications presently used for the treatment of hypertension include the administration of beta-blockers, calcium channel blockers, O diuretics, angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists.
  • Vasoconstriction results in an increase in the blood pressure.
  • WO 05/070887 discloses a new class of bronchorelaxing compounds, comprising a benzene ring fused with a saturated 5-, 6- or 7-membered ring, which comprises a nitrogen atom. This nitrogen is connected to a carbonyl or a thiocarbonyl.
  • the carbonyl does also carry a sp 3 -hybridized nitrogen or carbon atom linking the bicycle and the carbonyl to the last flexible part of the molecule.
  • a molecule such as pharmaceutical, will have one or several conformers, of which the active one or ones are the one or ones, which bind to the target of interest to affect to treat, alleviate or mitigate a disease or disorder.
  • a flexible molecule may have several structurally different low-energy conformers. This flexibility may imply, that although one low- energy conformer has affinity for the target, other low-energy conformers may have affinity for other targets.
  • a rigid molecule may not be able to bind to a target, although parts of said molecule may show affinity for the target, as steric repulsion will prevent the molecule from binding to the
  • a too lipophilic or too hydrophilic molecule may be less useful as a pharmaceutical, as it may never reach its designated target, despite having an intrinsically high affinity to the target.
  • the present invention seeks to mitigate, alleviate, circumvent or eliminate at least one, such as one or more of the above-identified deficiencies. According to one aspect of the inventions there is provided a compound, which may be represented with the general formula (I),
  • Rl and R4 represent, independent of each other, hydrogen or halogen;
  • R2 and R3 represent, independent of each other, hydrogen or a short alkyl, and at least one of R2 and R3 is hydrogen;
  • n is 1;
  • CYl represents a substituted or unsubstituted aryl or heteroaryl;
  • A is a direct bond or a group selected from -CH2-, -NH-, -NCH3-, -O-, -S-, - SO-, S02-, -C(O)-, -O(O)C-, -C(O)O-, -N(O)C- and -C(O)N-;
  • CY2 represents a substituted or unsubstituted aryl or a heteroaryl;
  • Such a compound or a composition comprising such a compound may be used in medicine. Such compounds or compositions may also be used to manufacture a medicament.
  • a medicament comprising a compound according to formula I may be used to treat or prevent a disease or disorder of the respiratory apparatus characterized by bronchoconstriction. Diseases and disorders characterized by bronchoconstriction comprise asthma, chronic obstructive pulmonary disease, which comprises chronic bronchitis and emphysema, bronchiectasis, cystic fibrosis, bronchiolitis or bronchopulmonary dysplasia.
  • a compound according to formula I may also be used in a method to treat or prevent pulmonary disease characterized by bronchoconstriction. Such a method comprises the administration to a person in need of a bronchoconstriction relaxing dose of a compound according to formula I. Definitions
  • short alkyl is intended to mean a saturated or unsaturated hydrocarbon with less than 6 carbons.
  • Such short alkyls may be, but are not limited to, methyl, ethyl, propyl, iso-propyl, butyl, .sec-butyl, tert-butyl, pentyl, neo-pentyl, ethylenyl and propyl enyl.
  • aryl is intended to mean a carbocyclic aromatic ringsystem, such as, but not limited to, benzene.
  • heteroaryl is intended to mean a cyclic aromatic ring system comprising at least one heteroatom.
  • heteroaryl is also intended to include charged ringsystems such as, but not limited to, quaternary pyridinium salts, quaternary pyrylium salts, quaternary azinium salts.
  • aromatic cyclic ring systems comprising at least one heteroatom, which ring system further comprises a carbonyl, which carbonyl have two tautomers, one keto form and on enol form, which enol form contribute to the aromaticity of said ringsystem.
  • heteroatom is intended to mean oxygen, nitrogen and sulphur.
  • addition salt is intended to mean salts formed by the addition of a acid, such as organic or inorganic acids
  • the organic acid may be, but is not limited to, acetic, propanoic, methanesulfonic, benzenesulfonic, lactic, malic, citric, tartaric, succinic or maleic acid
  • the inorganic acid may be, but is not limited to, hydrochloric, hydrobromic, sulfuric, nitric acid or phosphoric acid, or by addition of a base, the base may be, but is not limited to, ammonia and hydroxides of alkali or alkaline earth metals.
  • addition salt also comprises the hydrates and solvent addition forms, such as hydrates and alcoholates.
  • Rl and R4 represent, independent of each other, hydrogen or halogen
  • R2 and R3 represent, independent of each other, hydrogen or a short alkyl, and at least one of R2 and R3 is hydrogen; n is 1 ;
  • CYl represents a substituted or unsubstituted aryl or heteroaryl;
  • A is a direct bond or a group selected from -CH2-, -NH-, -NCH3-, -O-, -S-, -
  • CY2 represents a substituted or unsubstituted aryl or a heteroaryl
  • the invention relates to a compound according to formula (I) as described above.
  • the invention relates to a compound according to formula (I), wherein Rl and R4 independent of each other represent hydrogen or chlorine.
  • the invention relates to a compound according to formula (I), wherein Rl and R4 represent hydrogen.
  • the invention relates to a compound according to formula (1), wherein Rl and R4 represent chlorine.
  • the invention relates to a compound according to formula (I), wherein R2 and R3 represent, independent of each other, hydrogen or methyl and at least one of R2 and R3 is hydrogen.
  • the invention relates to a compound according to formula (I), wherein R2 is methyl and R3 is hydrogen.
  • the invention relates to a compound according to formula (I), wherein R2 is hydrogen and R3 is methyl. In another embodiment the invention relates to a compound according to formula (I), wherein both R2 and R3 are hydrogen. In an embodiment, wherein n is 1 a compound according to formula (I) could be described as comprising a 1,2,3,4-tetrahydroisoquinoline moiety.
  • the invention relates to a compound according to formula (I), wherein Rl and R4 represent chlorine or hydrogen, R2 and R4 represent hydrogen and n is 1.
  • the invention relates to a compound according to formula (I), wherein Rl and R4 represent chlorine, R2 and R3 represent hydrogen and n is l .
  • the invention relates to a compound according to formula (I), wherein CYl and/or CY2 is substituted with one or several substituents independently selected from short alkyl, halogen, OR6, SR6, NR6R7, CN, CF3, C(O)OR6 and C(O)NR6R7, wherein R6 and R7 represent, independent of each other, hydrogen, short alkyl, short acyl, phenyl or benzyl. Only one or both of CYl and CY2 may be substituted.
  • the invention relates to a compound according to formula (I), wherein at least one of CYl and CY2 is a heteroaryl.
  • a heteroaryl may provide the molecule with increased hydrophilicity, which may be beneficial in terms of increased solubility in aqueous media.
  • the invention relates to a compound according to formula (I), wherein CYl is benzene, optionally substituted in accordance with the embodiments disclosed above.
  • the invention in another embodiment relates to a compound according to formula (I), wherein CYl represents a 6-membered ring comprising 1 or 2 nitrogen atoms and the residual made up of carbon atoms, and wherein A is bound to a carbon atom in said 6-membered ring and the carbonyl in formula (I) is also bound to a carbon in said 6-membered ring.
  • Said 6-membered ring is optionally substituted in accordance with the embodiments disclosed above.
  • the invention in another embodiment relates to a compound according to formula (I), wherein CYl represents a 6-membered ring comprising 1 or 2 nitrogen atoms and the residual made up of carbon atoms and wherein A is bound to a carbon atom in said 6-membered ring and the carbonyl in formula (I) is bound to a carbon in said 6-membered ring.
  • Said carbonyl and A are meta with respect to each other.
  • Said 6- membered ring is optionally substituted in accordance with the embodiments disclosed above.
  • the invention in another embodiment relates to a compound according to formula (I), wherein CYl represents a 6-membered ring comprising 1 or 2 nitrogen atoms and the residual made up of carbon atoms and wherein A is bound to a carbon atom in said 6-membered ring and the carbonyl in fo ⁇ nula (I) is bound to a carbon in said 6-membered ring.
  • Said carbonyl and A are para with respect to each other.
  • Said 6- membered ring is optionally substituted in accordance with the embodiments disclosed above.
  • the invention relates to a compound according to formula (I), wherein CYl is a 6-membered ring selected from the group consisting of: benzene, pyridine, pyrazine or pyrimidine.
  • CYl varies in of the number of nitrogen atoms and in respect of meta and para position of A and the carbonyl carbon.
  • Rl to R4, n, A, and CY2 may be varied in accordance with the embodiments disclosed above.
  • the invention relates to a compound according to formula (I), wherein CYl is an aryl or heteroaryl substituted with one or several groups independently selected from short alkyl, halogen, CF3, 0R6, CN.
  • the invention relates to a compound according to formula (I), wherein CYl represents a 5-membered ring comprising at least 1 heteroatom. Said 5-membered ring is optionally substituted in accordance with the embodiments disclosed above.
  • the invention in another embodiment relates to a compound according to formula (I), wherein CYl represents a 5-membered ring comprising 1 heteroatom and the residual made up of carbon atoms and wherein A is bound to a carbon atom in said 5-membered ring and the carbonyl in formula (I) is bound to a carbon in said 5- membered ring.
  • Said 5-membered ring is optionally substituted in accordance with the embodiments disclosed above.
  • the invention relates to a compound according to formula (I), wherein CYl represents a 5-membered ring comprising at least 2 heteroatoms. Said 5-membered ring is optionally substituted in accordance with the embodiments disclosed above.
  • the invention in another embodiment relates to a compound according to formula (I), wherein CYl is a 5-membered ring selected from the group consisting of: furan, pyrrole, thiophene, imidazole, oxazole, thiazole, pyrazole, isoxazole and isothiazole. Said 5-membered ring is optionally substituted in accordance with the embodiments disclosed above.
  • the invention relates to a compound according to formula (I), wherein CYl is a 5-membered ring selected from the group consisting of: furan, thiophene, thiazole and pyrazole. Said 5-membered ring is optionally substituted in accordance with the embodiments disclosed above.
  • the invention relates to a compound according to formula (I), wherein A is a direct bond, -CH2 ⁇ , -O-, -S-, -NH- or -C(O)-.
  • the invention relates to a compound according to formula (I), wherein A is a direct bond.
  • the invention relates to a compound according to formula (I), wherein A is a direct bond or -O.
  • the invention relates to a compound according to formula (I), wherein CY2 is benzene, optionally substituted in accordance with the embodiments disclosed above.
  • the invention relates to a compound according to formula (I), wherein CY2 represents a 6-membered ring comprising 1 or 2 nitrogen atoms and the residual being carbon atoms and wherein A is bound to a carbon atom in said 6-membered ring. Said 6-membered ring is optionally substituted in accordance with the embodiments disclosed above.
  • the invention relates to a compound according to formula (I), wherein CY2 is an aryl or heteroaryl substituted with one or several groups independently selected from the group consisting of short alkyl, halogen, CF3, CN and OR6.
  • the invention relates to a compound according to formula (I), wherein CY2 represents a 5-membered ring comprising at least 1 heteroatom. Said 5-membered ring is optionally substituted in accordance with the embodiments disclosed above.
  • the invention in another embodiment relates to a compound according to formula (I), wherein CY2 represents a 5-membered ring comprising 1 heteroatom and 4 carbon atoms and wherein A is bound to a carbon atom next to said heteroatatom in said 5-membered ring.
  • Said 5-membered ring is optionally substituted in accordance with the embodiments disclosed above.
  • CY2 varies in :ct of the number of nitrogen atoms present and in respect of the position of A with regard to R5 and the nitrogen, optionally present in CY2.
  • Rl to R4, n, A, and CYl may be varied in accordance with the embodiments disclosed above.
  • R5 represents hydrogen, short alkyl, halogen, CF3, CN and 0R6.
  • the invention in another embodiment relates to a compound according to formula (I), wherein Rl and R4 represent chlorine or hydrogen, R2 and R3 represent hydrogen, n is 1, CYl is benzene, optionally substituted with short alkyl, halogen, CF3, CN or OR6, A is a direct bond or -O- and CY2 is a benzene, pyridine, pyrimidine or thiazole, optionally substituted in accordance with the embodiments disclosed above.
  • the invention in another embodiment relates to a compound according to formula (I), wherein Rl and R4 represent chlorine or hydrogen, R2 and R3 represent hydrogen, n is 1, CYl is a pyridine, pyrimidine, furan, pyrazine, thiazole, optionally substituted with short alkyl, halogen, CF3, CN or OR6, A is a direct bond or -O- and CY2 is benzene, optionally substituted in accordance with the embodiments disclosed above.
  • the invention in another embodiment relates to a compound according to formula (I), wherein Rl and R4 represent chlorine or hydrogen, R2 and R3 represent hydrogen, n is 1, CYl is a pyridine, pyrimidine, furan, pyrazine, thiazole, optionally substituted with short alkyl, halogen, CF3, CN or OR6, A is a direct bond or -O- and CY2 is pyridine, pyrimidine or thiazole, optionally substituted with short alkyl, halogen, CF3, CN or OR6.
  • the invention relates to a compound according to formula (I), wherein Rl and R4 represent chlorine or hydrogen, R2 and R3 represent hydrogen, n is 1, CYl is benzene, optionally substituted with short alkyl, halogen, CF3, CN or OR6, A is a direct bond or -O- and CY2 is benzene, optionally substituted with short alkyl, halogen, CF3, CN or 0R6.
  • the invention relates to a compound according to formula XXXII,
  • B is a radical selected from the group consisting of:
  • the invention relates to a compound, as defined in the preceding embodiments, in the form of an addition salt.
  • a molecule as defined in the preceding embodiments, may be used in medicine and/or therapy. It may be used to treat, revoke, mitigate, alleviate or prevent bronchoconstriction in a mammal, such as a human being. A method to treat, revoke, mitigate, alleviate or prevent bronchoconstriction in a mammal, such as a human being, in need thereof is also disclosed. Further, such a molecule as defined in the preceding embodiments may be used to treat, revoke, mitigate, alleviate or prevent a disease or condition characterized by inflammatory conditions of the respiratory apparatus.
  • Such diseases or conditions characterized by inflammatory conditions or bronchoconstriction of the respiratory apparatus may be asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiectasis, cystic fibrosis, bronchiolitis and bronchopulmonary dysplasia. It may also be used in the prevention and/or treatment of a disease or condition characterized by systemic or respiratory vasoconstriction.
  • Such a molecule may be used to manufacture a medicament.
  • a medicament may be useful to treat, revoke, mitigate, alleviate or prevent a condition of the respiratory apparatus characterized by bronchoconstriction.
  • diseases and/or disorders which may cause bronchoconstriction, are, but not limited to, asthma, chronic obstructive pulmonary disease (which comprises chronic bronchitis and emphysema), bronchiectasis, cystic fibrosis, bronchiolitis or bronchopulmonary dysplasia.
  • a medicament may also be useful to treat or prevent a disease or condition characterized by inflammatory conditions of the respiratory apparatus.
  • such a medicament may also be useful to treat or prevent a disease or condition characterized by systemic or respiratory vasoconstriction.
  • the usefulness of the compounds, as defined in the preceding embodiments, in treating, revoking, mitigating, alleviating and/or preventing a condition of the respiratory apparatus characterized by bronchoconstriction, were evaluated in a complex and relevant in vitro model.
  • the in vitro model was in accordance with the in vitro model disclosed in US 2006-0040254 Al and Skogvall, S., Berglund, M., Dalence- Guzman, M. F., Svensson, K., J ⁇ nsson, P., Persson, C. G. A and Sterner, Q., Pulmonary Pharmacology and Therapeutics., vol: 21, 2008, p.: 125-133
  • lung tissue was obtained from patients undergoing lobectomia or pulmectomia due to lung carcinoma. From the bronchus of this tissue were rectangular oblong preparations obtained. The contraction induced by inflammatory mediators, such as Leukotriene D4, histamine, prostaglandin D2 or acetylcholine, in the presence and absence of the compound to be evaluated, were compared.
  • inflammatory mediators such as Leukotriene D4, histamine, prostaglandin D2 or acetylcholine
  • Capsazepine one of the first reported TRPVl -antagonists, has been shown to have an effect of human airways Skogvall, S., Berglund, M., Dalence-Guzman, M. F., Svensson, K., J ⁇ nsson, P., Persson, C. G. A and Sterner, O., Pulmonary Pharmacology and Therapeutics., vol: 21, 2008, p.: 125-133, available online (doi:10.1016/j.pupt.2006.03.002), but is also known to posses a range of other biological effects. Consequently capsazepine is not selective towards one target and accordingly its usefulness as a molecular tool has been questioned (Gunthorpe, M. J., Neurpharmacology, 2004, 46, 133).
  • the compounds synthesized as described below were all tested and shown to be at least comparably active to Capsazepine in the In Vitro model referred to above, although structurally and even more important conformational distinct from capsezepine.
  • the compounds according to formula (I) are much less flexible than capsazepine. Still they are as active as capsazepine. As the compounds are much less flexible they are presumed to be much more selective for the target affected to relax contracted airways.
  • Such a medicament as has been described above may further comprise pharmaceutically acceptable carriers, diluents, stabilisers or excipients.
  • “Pharmaceutically acceptable” means a carrier, stabiliser, diluent or excipient that, at the dosage and concentrations employed, does not cause any unwanted effects in the patients to whom it is administered.
  • Such pharmaceutically acceptable carriers, stabilisers, dilutenls or excipients are well-known in the art (see Remington's Pharmaceutical Sciences, 18th edition, A. R Gennaro, Ed., Mack Publishing Company (1990) and handbook of Pharmaceutical Excipients, 3rd edition, A. Kibbe, Ed.,
  • the medicament will be administered to a patient in a pharmaceutically effective dose.
  • pharmaceutically effective dose is meant a dose that is sufficient to produce the desired effects in relation to the condition for which it is administered.
  • the exact dose is dependent on the activity of the compound, manner of administration, nature and severity of the disorder and/or disease and the general conditions, such as age and body weight of the patient.
  • the medicament of the invention may be administered alone or in combination with other therapeutic agents. These agents may be incorporated as part of the same medicament or may be administered separately.
  • the pharmaceutically effective dose of a compound according to the embodiments disclosed above and/or the above mentioned other therapeutic agent when administered in combination may be lower than the respective established therapeutically effective dose than when administered alone for prevention or treatment of the same disease or condition.
  • such other therapeutic agents to be administered in combination with the medicament of the invention are selected from therapeutic agents known to the one skilled in the art to prevent bronchoconstriction or revoke, fully or partly, any present bronchoconstriction, e.g. anti-asthmatics. Examples of such agents are, but not limited to, ⁇ 2-agonist, anticholinergic, corticosteroid, calcium antagonist, and other agents suitable for the treatment of asthma and/or COPD and related diseases and/or disorders.
  • a method to treat, revoke, mitigate, alleviate or prevent bronchoconstriction and/or an inflammatory condition in a mammal, such as a human being, in need thereof, by the administration of a compound or medicament, such as a pharmaceutical composition, according to the present invention may also include the simultaneous or consecutive administration a therapeutic agent, such as an anti-asthmatic.
  • a therapeutic agent such as an anti-asthmatic.
  • the therapeutically effective dose of said compound, medicament or pharmaceutical composition and said therapeutic agent may comprise 1 to 10 times less than the respective established therapeutically effective dose when administered alone for prevention or treatment of the same disease or condition.
  • Consecutive administration of a therapeutic agent may take place before of after the administration of a compound according to formula (I).
  • consecutive administration relates to consecutive administration of a therapeutic agent, such as an anti-asthmatic, and compound according to formula (I), wherein it less than 30 minutes, such as less than 15 minutes or even less than 5 minutes between the administrations.
  • a therapeutic agent such as an anti-asthmatic
  • compound according to formula (I) wherein it less than 30 minutes, such as less than 15 minutes or even less than 5 minutes between the administrations.
  • the therapeutic agent or the compound according to formula (I) may be administered first.
  • the medicament of the invention may be administered through different routes such as, but not limited to, intravenously, intraperitonealy, intramuscularly, intranasaleously, subcutaneously, sublingually, rectally, orally or through inhalation or insufflation.
  • compositions suitable for administration by the inhalation or insufflation route are known in the art.
  • the compound is dissolved in a suitable vehicle or employed as a fine powder, such as a micronized powder of a particle size from about 2 ⁇ m to about 20 ⁇ m.
  • An indicated daily dose for administration by inhalation may be 10 times and more lower than corresponding the oral dose. Satisfactory doses, preferably metered by using a device capable of metering, or by single doses of predetermined size, can easily be determined by experimentation. Oral administration could be advantageous for patient suffering from airways diseases or disorders such as asthma or especially COPD, as such patients may have a decreased ability to inhale pharmaceuticals. On the other hand this does not mean that inhalation is less preferred as administration route for this group of patients.
  • the present invention also relates to processes for preparing the compound of formula I as a free base, acid, or salts thereof. Further, it relates to synthetic intermediates, which are useful in the synthesis of a compound of formula I as a free base, acid, or salts thereof. Such intermediates may include compounds according to formula I, which may be used to produce another compound according to formula I.
  • transformations are given below, and it is to be understood that the described transformations are not limited only to the generic groups or substiluents for which the transformations are exemplified.
  • room temperature and “ambient temperature” shall mean, unless otherwise specified, a temperature between 16 and 25°C.
  • flash chromatography or flash column chromatography shall mean preparative chromatography on silica using an organic solvent, or mixtures thereof, as mobile phase.
  • the tetracyclic amide I may be dismantled into smaller building blocks by following one of the three pathways presented in scheme 1. Disconnection of the amide bond in I results in two fragments, namely bicyclic amine II and bicyclic carboxylic acid III. This acid may be further disconnected at the two bonds connecting linker A with the cycles CYl and CY2. Disconnecting the bond between A and CYl results in carboxylic acid IV and monocyclic fragment V, consequently carboxylic acid VI and monocyclic fragment VII are formed by disconnecting the bond between A and CY2. The latter two disconnections also differ in whether a hypothetical leaving group LG is introduced on the carboxylic acid IV or on the monocyclic fragment VII. HO
  • An alternative approach is to disconnect one of the bonds connecting A with CYl and CY2 before disconnection of the amide bond.
  • disconnection of the bond between A and CY2 gives monocyclic fragment VII and tricyclic amide IX which may be disconnected into bicyclic amine II and monocyclic fragment VI.
  • the pathway chosen for each individual I is largely dependant on the nature of linker A, cycles CYl and CY2, the substitution pattern of R1-R4 as well as the commercial availability of fragments HI-VII.
  • a more convergent synthesis may be performed which is advantageous when bicyclic amine II is obtained by a prolonged synthesis.
  • the drawback of this route is that the presence of a carboxylic acid in IV and VI may hamper or disrupt the coupling reaction necessary to produce III. This may be circumvented by introducing a protective group, such as an ester, into acid IV and VI.
  • the other two pathways may result in a more linear synthesis but are still advantageous in that the coupling reactions with monocyclic fragments V and VII may be performed in the absence of a potentially reactive carboxylic acid.
  • Regioselectivity issues may be expected in those cases when LG is prone to displacement by secondary amines or phenols. This may partially be alleviated by introducing protective groups, such as alkyls, at substituent R2 and R3.
  • Bicyclic amine II may be further disconnected into more readily obtained compounds (Scheme 2).
  • bonds are of particular interest, namely the two carbon-nitrogen bonds and the two bonds connecting the aliphatic ring with the aromatic ring.
  • the size of the aliphatic ring is an important factor as completely different fragments are formed upon disconnection of the different sizes mentioned in this patent. These fragments may differ considerably in their reactivity and availability. It may be beneficial to disconnect more than one bond simultaneously.
  • the five- membered amines X are a good example of this disconnection as it corresponds to a reaction involving a readily available xylylene dibromide XI and ammonia or an equivalent thereof (Di ederich, F., Jonas, U., Gramlich, V., Hermann, A., Ringsdorf, H. and Thilgen, C, HeIv Chim Acta., 1993, 76, 2445-2453; Bottino, F., Di Grazia, M.,
  • the second pathway consists of disconnection of a carbon-carbon bond followed by disconnection of the nearest carbon-nitrogen bond so that an equivalent of ethylamine is removed.
  • These disconnections would correspond to a reductive amination between a readily available benzaldehyde XIV and an ethylamine-derivative XV.
  • the amination is then followed by a cyclisation under reductive conditions to give the desired bicyclic amine XIl. (Bobbit, J. M., McNew Kiely, J., Khanna, K.L. and Ebermann, R., J Org Chem, 1965, 30, 2247-2250; Bobbit, J.M. and Sih, J.C., J Org Chem, 1968, 33, 856-858)
  • the aliphatic ring may also undergo a functional group conversion into a more readily available substance (Scheme 4). Seven-membered rings XVI are an obvious example of this procedure. Conversion into a lactam followed by disconnection of both carbon-nitrogen bonds gives a cyclic ketone XVII as starting material. The synthesis would then correspond to a Schmidt reaction followed by a reduction of a lactam into cyclic amine XVI (Shtacher, G., Erez, M., and Cohen, S., J Med Ghent, 1973, 16, 516- 519).
  • Substitutents R2 and R3 may also be manipulated at several different stages of the synthesis. Depending on the chemistry necessary to obtain the tetracyclic amide I, it may be favourable to modify these substituents at the very last of the synthesis.
  • Bronstedt or Lewis acids such as hydrogen bromide or boron tribromide (Hall, J. D., Duncan-Gould, N.W., Siddiqi, N.A., Kelly, J.N., Hoeferlin, L.A., Morrison, SJ. and Wyatt, J.K., BioorgMed Chem, 2005, 13, 1409-1413).
  • Substituents Rl and R4 are usually manipulated (Yu, G., Mason, H. J., Wu, X., Endo, M., Douglas, J.
  • the condensation of a carboxylic acid and a secondary amine may be performed with several different methods.
  • One approach is to convert the acid into an acid chloride which is then reacted with a secondary amine to give the desired amide.
  • Traditional reagents such as thionyl chloride (Ansell, M.F. in Patai "The chemistry of acyl halides", Wiley, New York, 1972, 35-64) have proven useful for converting carboxylic acids to acid chlorides.
  • a rapid synthesis of the desired amide may occur from the acid chloride and the secondary amine in the presence of a tertiary amine in a polar aprotic solvent such as dimethylformamide (Scheme 5).
  • An alternative approach is to perform the condensation by applying coupling agents frequently used in the synthesis of peptides (Han, S-Y. and Kim, Y-A., Tetrahedron, 2004, 60, 2447-2467).
  • the condensation should preferentially be performed with reagents which are easily separated from the desired amide.
  • the condensation is generally performed with a hydrophilic carbodiimide together with a benzotriazole catalyst in the presence of both an organic and an inorganic base (Toftered, J. and Nilsson, UJ. , SYNLETT, 2004, 2517TM 2520).
  • a polar aprotic solvent such as dimethylformamide
  • Scheme 8 Synthesis of halogenated compounds This protocol may also be applied to produce halogenated compounds such as Io (Scheme 8). Substance 2 was then chlorinated into 4 prior to generation of the tetracyclic intermediate 7 which was demethylated to give the halogenated product lo.
  • linker A consists of a direct bond between CYi and CY 2 this linkage may be obtained with traditional methods for preparing biaryl, biheteroaryl and arylheteroaryl moieties such as the Ullman reaction (Fanta, P. E., SYNTHESIS, 1974, 9-21) or with newer palladium-catalysed methods such as the Kumada, Negishi or Suzuki reactions (Amatore, C, Jutand, A., Negri, S. and Fauvarque, J-F., J Organomet Chem, 1990, 390, 389-398)( Gong, Y.
  • Ullman reaction Fanta, P. E., SYNTHESIS, 1974, 9-21
  • newer palladium-catalysed methods such as the Kumada, Negishi or Suzuki reactions (Amatore, C, Jutand, A., Negri, S. and Fauvarque, J-F., J Organomet Chem, 1990, 390, 3
  • linker A consists of atom C, N, O or S
  • the linkage may be obtained with traditional nucleophilic aromatic substitution (Miller, J. F, "Aromatic Nucleophilic Substitution", Elsevier, Amsterdam, 1968), including newer microwave-assisted methods (Cherng, Y-J., Tetrahedron, 2002, 58, 4931-4935) (Luo, G., Chen, L. and Poindexter, G.S., Tetrahedron Lett, 2002, 43, 5739-5742) (Yeh, V.S.C. and Wiedeman, P.E., Tetrahedron Lett, 2006, 47, 6011-6016).
  • Chart 1 Representative tetracyclic amides prepared
  • 3-Pyrid-3-ylbenzoic acid (100 mg, 0.502 mmol) was suspended in 3 triL thionyl chloride together with a catalytical amount of DMF and refluxed for 17 hours before evaporation. The remaining residue was dissolved in 5 mL DMF and 6,7- dihydroxy-l,2,3,4-tetrahydroisoquinoline hydrobromide (124 mg, 0.502 mmol) followed by Et 3 N (141 ⁇ L, 1.00 mmol) were added. The resulting mixture was stirred at room temperature for 3 hours and then diluted with 25 ml water followed by extraction with ethyl acetate (3*30mL). The combined organic phase was dried over MgSO 4 and evaporated into a pale mass.
  • N-(4-Phenoxybenzoyl)-6,7-dihydroxy-l,2,3,4-tetrahydroisoquinoline (Ig) 4-Phenoxybenzoic acid (131 mg, 0.609 mmol) was suspended in 5 mL thionyl chloride together with a catalytical amount of DMF and refluxed for 7 hours before evaporation. The remaining residue was dissolved in 5 mL DMF and 6,7-dihydroxy- 1,2,3,4-tetrahydroisoquinoline hydrobromide (150 mg, 0.609 mmol) followed by Et 3 N (171 ⁇ L, 1.22 mmol) were added.
  • 3-Phenoxybenzoic acid (136 mg, 0.635 mmol) was suspended in 5 mL thionyl chloride together with a catalytical amount of DMF and refluxed for 7 hours before evaporation. The remaining residue was dissolved in 5 mL DMF and 5,8-dichloro-6,7- dihydroxy-l,2,3,4-tetrahydroisoquinoline hydrobromide (200 mg, 0.635 mmol) followed by Et 3 N (178 ⁇ L, 1.27 mmol) were added. The resulting mixture was stirred at room temperature for 8 hours and then diluted with 30 ml water followed by extraction with ethyl acetate (3*25mL). The combined organic phase was dried over MgSO 4 and evaporated.
  • N-(2-(3-Pyridyl)-4-methyl-l,3-thiazol-5-oyl)-6,7-dimethoxy-l,2,3,4- tetrahydroisoquinoline (221 mg, 0.559 mmol) was dissolved in 20 mL CH 2 Cl 2 and cooled to 0 0 C.
  • Boron tribromide IM in CH 2 Cl 2
  • the reaction was quenched with 3 mL methanol and evaporated into a brownish residue.
  • N-(4-Phenyl-5-(trifluoromethyl)-lH-pyrazol-4-oyl-6,7-dimethoxy-l, 2,3,4- tetrahydroisoquinoline (243 mg, 0.563 mmol) was dissolved in 20 niL CH 2 Cl 2 and cooled to O 0 C.
  • Boron tribromide (IM in CH 2 Cl 2 )(1.52 mL, 1.52 mmol) was added slowly and the reaction was stirred at 0°C for 30 minutes, then at room temperature for 21 hours. The reaction was quenched with 4 mL methanol and evaporated into a brown syrup.
  • N-(6-Phenyl-4-pyrimidinoyl)-5,6-dicbloro-6,7-dimethoxy-l, 2,3,4- tetrahydroisoquinoline (285 mg, 0.641 mmol) was dissolved in 30 mL CH 2 Cl 2 and cooled to 0°C.
  • Boron tribromide (IM in CH 2 Cl 2 )(1.73 mL, 1.73 mmol) was added slowly and the reaction was stirred at 0°C for 60 minutes, then at room temperature for 4.5 hours. The reaction was quenched with 5 mL methanol and evaporated into a red residue.
  • N-(5-Phenylnicotinoyl)-6,7-dihydroxy-l,2,3j4-tetrahydroisoquinoline (Ip) N-(5-Phenylnicotinoyl)-6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline (115 mg, 0.306 mmol) was dissolved in 20 niL CH 2 Cl 2 and cooled to 0 0 C. Boron tribromide (IM in CH 2 CI 2 X827 ⁇ L, 0.827 mmol) was added slowly and the reaction was stirred at 0 c C for 60 minutes, then at room temperature for 5.5 hours.
  • IM in CH 2 CI 2 X827 ⁇ L, 0.827 mmol was added slowly and the reaction was stirred at 0 c C for 60 minutes, then at room temperature for 5.5 hours.
  • N-(5-BiOmonicotinoyl)-6,7-dimethoxy-l ,2,3,4-tetrahydroisoquinoline (214 mg, 0.567 mmol) was suspended with phenylboronic acid (97 mg, 0.794 mmol) in 2 mL toluene and 0.5 mL ethanol.
  • Aqueous sodium carbonate (2M, 1.13 mL, 2.27 mmol) was added and the resulting mixture was degassed with nitrogen before addition of tetrakis- triphenylphosphine palladium(O) (26 mg, 0.023 mmol).
  • the reaction was heated for 20 minutes at 140 C in a microwave oven then cooled and diluted with 30 mL dichloromethane.
  • lung tissue was obtained from patients undergoing lobectomia or pulmectomia due to lung carcinoma. From the bronchus of this tissue were rectangular oblong preparations obtained. The contraction induced by inflammatory mediators, such as Leukotriene D4, histamine, prostaglandin D2 or acetylcholine, in the presence and absence of the compound to be evaluated, were compared.
  • inflammatory mediators such as Leukotriene D4, histamine, prostaglandin D2 or acetylcholine
  • a tested compound is a general dilator or a specific antagonist for a given inflammatory mediator.

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Abstract

L'invention porte sur de nouvelles molécules ayant la formule générale (I), lesquelles molécules sont utiles pour fabriquer un médicament pour traiter un trouble ou une maladie caractérisée par une bronchoconstriction.
PCT/EP2008/051189 2007-02-08 2008-01-31 Arylamides bronchorelaxantes WO2008095852A1 (fr)

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EP2331095A1 (fr) * 2008-08-04 2011-06-15 CHDI, Inc. Certains inhibiteurs de kynurénine-3-monooxygénase, compositions pharmaceutiques, et procédés d'utilisation de ceux-ci
US8883785B2 (en) 2010-01-25 2014-11-11 Chdi Foundation, Inc. Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
EP2751086A4 (fr) * 2011-08-30 2015-09-16 Chdi Foundation Inc Inhibiteurs de kynurénine-3-monooxygénase, compositions pharmaceutiques et procédés d'utilisation de ces compositions
CN106467537A (zh) * 2015-08-14 2017-03-01 沈阳中化农药化工研发有限公司 一种取代的酰胺类化合物与用途
US9981918B2 (en) 2011-08-30 2018-05-29 Chdi Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US10258621B2 (en) 2014-07-17 2019-04-16 Chdi Foundation, Inc. Methods and compositions for treating HIV-related disorders
WO2020009653A1 (fr) * 2018-07-06 2020-01-09 Respiratorius Ab (Publ) Nouveaux amides hétéro-liés bronchodilatants

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EP0613879A1 (fr) * 1991-05-20 1994-09-07 TSUMURA & CO. Analogues de phellodendrine et suppresseur d'allergie de type iv les contenant en tant qu'ingredients actifs
WO2002034760A2 (fr) * 2000-10-23 2002-05-02 Smithkline Beecham Corporation Composes et procedes
EP1577291A1 (fr) * 2004-03-17 2005-09-21 Pfizer Limited Dérivés béta-2 agonistes de la phényléthanolamine

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Publication number Priority date Publication date Assignee Title
EP0613879A1 (fr) * 1991-05-20 1994-09-07 TSUMURA & CO. Analogues de phellodendrine et suppresseur d'allergie de type iv les contenant en tant qu'ingredients actifs
WO2002034760A2 (fr) * 2000-10-23 2002-05-02 Smithkline Beecham Corporation Composes et procedes
EP1577291A1 (fr) * 2004-03-17 2005-09-21 Pfizer Limited Dérivés béta-2 agonistes de la phényléthanolamine

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2331095A4 (fr) * 2008-08-04 2012-03-21 Chdi Foundation Inc Certains inhibiteurs de kynurénine-3-monooxygénase, compositions pharmaceutiques, et procédés d'utilisation de ceux-ci
US8536186B2 (en) 2008-08-04 2013-09-17 Chdi Foundation, Inc. Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
AU2009279787B2 (en) * 2008-08-04 2014-05-29 Chdi Foundation, Inc. Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US9145373B2 (en) 2008-08-04 2015-09-29 Chdi Foundation, Inc. Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
EP2331095A1 (fr) * 2008-08-04 2011-06-15 CHDI, Inc. Certains inhibiteurs de kynurénine-3-monooxygénase, compositions pharmaceutiques, et procédés d'utilisation de ceux-ci
US8883785B2 (en) 2010-01-25 2014-11-11 Chdi Foundation, Inc. Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
EP2751086A4 (fr) * 2011-08-30 2015-09-16 Chdi Foundation Inc Inhibiteurs de kynurénine-3-monooxygénase, compositions pharmaceutiques et procédés d'utilisation de ces compositions
US9428464B2 (en) 2011-08-30 2016-08-30 Chdi Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US9981918B2 (en) 2011-08-30 2018-05-29 Chdi Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US10258621B2 (en) 2014-07-17 2019-04-16 Chdi Foundation, Inc. Methods and compositions for treating HIV-related disorders
CN106467537A (zh) * 2015-08-14 2017-03-01 沈阳中化农药化工研发有限公司 一种取代的酰胺类化合物与用途
CN106467537B (zh) * 2015-08-14 2019-03-19 沈阳中化农药化工研发有限公司 一种取代的酰胺类化合物与用途
WO2020009653A1 (fr) * 2018-07-06 2020-01-09 Respiratorius Ab (Publ) Nouveaux amides hétéro-liés bronchodilatants
CN112437771A (zh) * 2018-07-06 2021-03-02 瑞思拜尔锐特略斯股份公司 新型支气管扩张杂原子连接的酰胺
JP2021532069A (ja) * 2018-07-06 2021-11-25 レスピラトリウス アーベー （パブル） 新規な気管支拡張性ヘテロ結合アミド
JP7193557B2 (ja) 2018-07-06 2022-12-20 アーケード ファーマ アーベー 新規な気管支拡張性ヘテロ結合アミド
US11680054B2 (en) 2018-07-06 2023-06-20 Arcede Pharma Ab Bronchodilating hetero-linked amides
CN112437771B (zh) * 2018-07-06 2024-06-18 阿凯德制药公司 支气管扩张杂原子连接的酰胺

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