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WO2018150347A1 - Composés ayant un agoniste bêta-adrénergique et une activité antimuscarinique - Google Patents

Composés ayant un agoniste bêta-adrénergique et une activité antimuscarinique Download PDF

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Publication number
WO2018150347A1
WO2018150347A1 PCT/IB2018/050922 IB2018050922W WO2018150347A1 WO 2018150347 A1 WO2018150347 A1 WO 2018150347A1 IB 2018050922 W IB2018050922 W IB 2018050922W WO 2018150347 A1 WO2018150347 A1 WO 2018150347A1
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Prior art keywords
hydroxy
methyl
acetate
ethyl
hydroqui
Prior art date
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Ceased
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PCT/IB2018/050922
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English (en)
Inventor
Sanjay Srivastava
Pundlik SHINDE
Appaji Mandhare
Ramesh Chandra Gupta
Anita Chaudhary
Ram Gupta
Shailesh Deshpande
Kiran Chaudhari
Jaya Abraham
Deepa Joshi
Chaitanya Dutt
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Torrent Pharmaceuticals Ltd
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Torrent Pharmaceuticals Ltd
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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
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero 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
    • C07D417/14—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 novel compounds of formula (I), its pharmaceutically acceptable salts, and isomers, stereoisomers, atropisomers, conformers, tautomers, atropisomers, polymorphs, hydrates, solvates, N-oxide or S-oxide thereof.
  • the present invention also encompasses pharmaceutically acceptable compositions and process for preparing said compounds.
  • the i nvention further relates to the use of the above- mentioned compounds for the preparation of medicament for use as pharmaceuticals.
  • ai rway diseases have increased in recent decades despite therapeutic advances.
  • a mong the ai rway di seases are obstructive I ung di sorders whi ch i ncl ude A sthma, Bronchiectasis, Cystic Fibrosis and Chronic Obstructive Pulmonary Disease (COPD).
  • C 0 P D i s a term whi ch refers to a I arge group of I ung di seases character! zed by obstruct! on of air flow that interferes with normal breathing.
  • E mphysema and chronic bronchitis are the most important conditions that compose COPD. (Australian lung foundation, 2006).
  • COPD chronic obstructive pulmonary disease
  • Short acting b2-adrenoceptor agonists such as salbutamol and terbutaline
  • long acting b2-adrenoceptor agonists such as formoterol and salmeterol
  • Inhaled muscarinic antagonists which are currently used include the short-acti ng i pratropi um or oxitropi um and the I ong-acti ng ti otropi um.
  • the present invention provides novel compounds of formula (I), its pharmaceutically acceptable salts and isomers, stereoisomers, atropisomers, conformers, tautomers, polymorphs, hydrates, solvates, N -ox ides or S- ox ides thereof;
  • R ⁇ nd R 2 are independently selected from (C3-C 7 )cycloalkyl, aryl and heteroaryl, the said (C3-C 7 )cycloalkyl, aryl, and heteroaryl are optionally substituted by one or more (Ci- Ce)alkyl, aryl, (C 3 -C 7 )cycloalkyl, halogen, O-R 14 , SH, C N, (C H 2 ) p -aryl, (CH 2 ) p -heteroaryl, C H 2 OH, CH 2 -halogen, CH 2 0-(CrC 6 )alkyl, CH 2 0-aryl, COOR 12 , CONR 16 R 17 or NHCOR 12 ;
  • R 3 is selected from hydrogen, hydroxyl, (Ci-C 4 ) alkoxy, CH 2 OH, and (Ci-C6)alkyl;
  • R 4 is selected from hydrogen, (CrC6)alkyl, aryl, (C H 2 ) -aryl, (CH 2 ) p -heteroaryl and (C 3 - C 7 )cycloalkyl; m is 1 or 2;
  • R 5 and R 6 are independently selected from hydrogen, (CrC6)alkyl, halogen, (C 3 - C7)cycloalkyl, heterocycloalkyi, (C H 2 ) p -aryl and (CH 2 ) p -heteroaryl or R 5 and R 6 on same carbon form a 3-7 membered cycloalkyi or heterocycloalkyi ring in a spiro manner or is gem di methyl; n is selected from 0-4; R 7 and R 8 are independently selected from hydrogen, (Ci-Ce)alkyl and heterocycloalkyi or R 7 and R 8 on same carbon form a 3-7 membered cycloalkyi or heterocycloalkyi ring in a spi ro manner or is gem di methyl; p is 1 or 2;
  • R 9 and R 10 are independently selected from hydrogen, (Ci-Ce)alkyl, (C 3 -C7)cycloalkyl, heterocycloalkyi and oxo or R 9 and R 10 on same carbon form a 3-7 membered cycloalkyi or heterocycloalkyi ring in a spiro manner or is gem dimethyl;
  • R 11 is selected from hydrogen, (C i-Ce)alkyl, aryl, C H 2 OH, CH 2 -halogen, halogen, (C 3 - C7)cycloalkyl, heteroaryl, heterocycloalkyi, O-R 14 , SH, C N, (CH 2 ) p -aryl, (CH 2 ) P - heteroaryl, CH 2 0-(Ci-C 6 )alkyl, CH 2 0-aryl, COOR 12 , CONR 16 R 17 and NHCOR 12 ;
  • Q is N(A)R 12 or O-A
  • R 12 is selected from hydrogen, (C i-Ce)alkyl, aryl, (C H 2 ) -aryl, (C H 2 ) - heteroaryl, (C 3 - C7)cycloalkyl and heterocycloalkyi;
  • R 13 is selected from hydrogen, O-R 14 and
  • R 14 is independently selected from hydrogen, (CrC6)alkyl, aryl, heteroaryl, (C H 2 )p-aryl, (C H 2 ) -heteroaryl, (C3-C7)cycloalkyl, Si(Ci-C6)alkyl, and
  • R 15 is selected from (Ci-Ce)alkyl, (C3-C7)cycloalkyl, aryl, heteroaryl, (CH 2 )p-aryl and (C H 2 )p-heteroaryl;
  • R 16 and R 17 are independently selected from hydrogen, (Ci-Ce)alkyl, (C3-C7)cycloalkyl and heterocycloalkyl or R 16 and R 17 together with nitrogen atom form a 3-10 membered heterocycloalkyl ring;
  • A is selected from
  • the present invention pertains to a compound as above, however only incl udi ng pharmaceutical ly acceptable salts thereof.
  • the present invention includes synthetic intermediates that are useful in preparing the compounds of formula (I) and process for preparing such intermediates.
  • the present invention includes metabolites of the compounds of formula (I).
  • Another embodiment of the present invention is a method for preparation of a compound of formula (I) or i ntermediates as herei n descri bed i n Schemes 1 and 2.
  • Another embodiment of the present invention provides a pharmaceutical composition comprising a compound of formula (I), optionally in admixture with a pharmaceutically acceptable excipient(s).
  • Another embodiment of the present invention provides method for treating respiratory-tract disorders by administering a therapeutically effective amount of a compound of formula (I) to a mammal, including human being, in need thereof.
  • Another embodiment of the present invention provides method for treating respiratory-tract disorders such as asthma, chronic obstructive pulmonary disease, chronic bronchitis, acute respiratory distress syndrome (A RDS), chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema and allergic rhinitis, by administering a therapeutically effective amount of a compound of formula (I) to a mammal, including human being, in need thereof.
  • respiratory-tract disorders such as asthma, chronic obstructive pulmonary disease, chronic bronchitis, acute respiratory distress syndrome (A RDS), chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema and allergic rhinitis
  • Another embodiment of the present invention provides use of a compound of f ormul a (I) for the preparati on of a medi cament for treatment of respi ratory-tract di sorders.
  • Another embodiment of the present invention provides use of a compound of formula (I) for the preparation of a medi cament for treatment of respi ratory-tract disorders such as asthma, chronic obstructive pulmonary disease, chronic bronchitis, acute respiratory distress syndrome (A RDS), chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema and allergic rhinitis.
  • respi ratory-tract disorders such as asthma, chronic obstructive pulmonary disease, chronic bronchitis, acute respiratory distress syndrome (A RDS), chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema and allergic rhinitis.
  • FIGURES Another embodiment of the present invention provides the use of a compound of formula (I) for the preparation of a medicament for treatment of chronic obstructive pulmonary disease or asthma.
  • FIGURES Another embodiment of the present invention provides the use of a compound of formula (I) for the preparation of a medicament for treatment of chronic obstructive pulmonary disease or asthma.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , Q, m, n and p are as defined above; or pharmaceutically acceptable salts, isomers, stereoisomers, atropisomers, conformers, tautomers, polymorphs, hydrates, N-oxide, S-oxide and solvates thereof.
  • R 1 and R 2 are independently selected from (C3-C7)cycloalkyl, aryl and heteroaryl;
  • R 3 is selected from hydroxyl and (CrC6)alkyl;
  • R 4 is hydrogen
  • n 1 or 2;
  • R 5 and R 6 are independently hydrogen or R 5 and R 6 on same carbon is gem dimethyl
  • n is selected from 0-2;
  • R 7 and R 8 are independently hydrogen or R 7 and R 8 on same carbon is gem dimethyl
  • p 1 or 2;
  • R 9 and R 10 are hydrogen
  • R 11 is hydrogen or(Ci-C6)alkyl;
  • Q is N(A)R 12 ;
  • R 12 is hydrogen or (Ci-C6)alkyl
  • R 13 is hydrogen or O-R 14 ;
  • R 14 is selected from hydrogen and Si(Ci).
  • R 15 is (Ci-C 6 )alkyl
  • A is selected from
  • compound employed herein refers to any compound encompassed by the generic formula disclosed herein.
  • the compounds described herein may contain one or more double bonds and therefore, may exist as isomers, stereoisomers, such as geometric isomers, E and Z isomers, and may possess asymmetric carbon atoms (optical centers) and therefore may exist as enantiomers, diastereoisomers.
  • the chemical structures described herein encompasses all possible stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure) and stereoisomer! c mixtures (racemates).
  • the compound described herein may exist as conformational isomers such as chair or boat form
  • the compounds may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures described herein encompass all possible tautomeric forms of the illustrated compounds.
  • the compounds described also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that may be incorporated into the compounds of the invention include, but are not limited to 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, etc.
  • Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, compounds may be hydrated or solvated. Certain compounds may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present invention.
  • Such salts include: (1) acid addition salts, formed with i norganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, trifluoroaceticacid, propionic acid, isobutyric acid, hexanoic acid, cyclopentanepropionic acid, oxalic acid, glycol ic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, suberic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, triphenylacetic acid, 3-(4- hydroxy benzoyl) benzoic acid, phthalic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2- ethanedi sulfonic acid, 2-hydroxyethanesulf
  • salts of amino acids such as arginate and the like (see, for example, Berge, S.M., et al., " Pharmaceutical Salts_, J ournal of Pharmaceutical Science.1977; 66: 1-19).
  • Compounds of present invention may form hemi, mono, di or tri salt
  • polymorph pertains to compounds having the same chemical formula, the same salt type and having the same form of hydrate/solvate but havi ng di ff erent crystal I ographi c properti es.
  • hydrate pertains to a compound having a number of water molecules bonded to the compound.
  • solvate pertains to a compound having a number of solvent molecules bonded to the compound.
  • substituted includes mono- and poly-substitution by a named substituent to the extent such single and multiple substitution (includi ng multiple substitution at the same site) is chemical ly al lowed and which means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound, for example, when a substituent is keto, then the two hydrogens on the atom are replaced.
  • halogen substituent is a monovalent halogen radical chosen from chloro, bromo, iodo and fluoro.
  • al kyl _ used either al one or i n attachment with another group refers to an aliphatic hydrocarbon radical having the indicated number of carbon atoms and that is unsubstituted or substituted.
  • the subscri pt refers to the number of carbon atoms that group may contai n.
  • a " C i - C6_ would refer to any alkyl group containing one to six carbons in the structure.
  • alkyl _ may be linear (for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl) or branched chain (for example, isopropyl, isobutyl, sec-butyl, tert-butyl) and it may contain one or two double or triple bonds to form corresponding alkenes or alkynes.
  • the said " alkyl _ may also contain (C3-C 7 )cycloalkyl ring in a spiro manner.
  • al koxy _ refers to any al kyl group as def i ned herei n above attached to the parent mol ecular moi ety through an oxygen bri dge.
  • hydroxy I _ refers to -OH group.
  • cycl oal kyl _ used either al one or i n attachment with another group refers to a cyclic ring system havi ng the indicated number of carbon atoms and that is unsubstituted or substituted with groups or substituents attached at any available atom to produce a stable compound.
  • the subscript refers to the number of carbon atoms that group may contain.
  • (C3-C 7 )cycloalkyl _ would refer to a cyclic ring system having 3 to 7 carbon atoms and that is unsubstituted or substituted.
  • the said "(C3-C 7 )cycloalkyl _ means a cyclic ring system containing only carbon atom in the ring system backbone such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • Cycloalkyl may include bi cyclic rings. Cycloalkyl may have any degree of saturation provided that at least one ring in the ring system is not aromatic.
  • the term "aryl" used either alone or in attachment with another group refers to an aromatic group for example, which is a 6 to 10 membered monocyclic or bicyclic carbon- containing ring systern which may be unsubstituted or substituted.
  • the aryl groups include, but are not limited to, phenyl, naphthyl, bi phenyl, tetrahydronaphthyl and indane.
  • aryl is phenyl.
  • heteroaryl used either alone or in attachment with another group refers to an aromati c group for exampl e, whi ch is a 5 to 14 membered monocycl i c or bi cycl i c ri ng syster which has at least one heteroatom, which may be unsubstituted or substituted.
  • heteroatom as used herein includes oxygen, sulfur and nitrogen.
  • heteroaryl groups include, but are not limited to pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimdinyl, pyrazinyl, triazinyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazol, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazoli nyl, quinoxalinyl, phthalazi nyl
  • heterocycloalkyl refers to a fully or partially saturated cyclic group, for example, which is a 3 to 14 membered monocyclic or bicyclic ring systenri which has at least one heteroatom.
  • heteroatom as used herein includes O, N, S.
  • bicycl ic heterocyclic system at least one ring is not aromatic and the rings can also be attached to each other in a spiro manner.
  • heterocyclic or heterocycle groups include, but are not limited to, oxiranyl, aziridinyl, oxetanyl, azetidinyl, pyrrolidinyl, dihydropyrrolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, di y drothi opheny I , pyrazol idinyl, imidazolidinyl, oxazolidinyl, isoxazoliidinyl, thiazol idinyl, triazol idinyl, oxadiazolidinyl, piperidinyl, tetrahydropyridinyl, dihydropyridinyl, piperazinyl, tetrahydropyranyl, dioxanyl, morpholinyl, triazinanyl, azepanyl, diazepanyl, oxepanyl,
  • mammal _ means a human or an ani mal such as monkeys, primates, dogs, cats, horses, cows, etc.
  • a therapeutically effective amount means the amount of a compound that when administered to a patient for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, mode of administration, the disease and its severity and the age, weight, etc., of the pati ent to be treated.
  • metabolites of compounds of formula (I) that is, compounds formed in vivo upon administration of the drug.
  • Some examples of metabolites in accordance with the invention include following compounds.
  • the compounds of formula (I) of the present invention may be prepared as descri bed in the given schemes.
  • Compounds of formula II is synthesized from the treatment of compound of formula VII-A with compounds of either formula III or formula IV or formula V orformula VI in the presence of suitable base such as triethylamine and suitable solvent such as tetrahydrofuran at reflux temperature. Deprotection of compounds of formula VII in the presence of IPA-HCI yields compounds of f ormul a V II-A . C ompound of f ormul a V II i s obtai ned from the reacti on of compound of formula VIII and IX in the presence of suitable base such as sodium hydride and solvent such as tol uene.
  • suitable base such as sodium hydride and solvent such as tol uene.
  • Substituted chloro acetyl chloride of formula VIII and chloro propanoyl chloride of formula IX, N-acetyl indol ine compound of formula X II, N-acetyl tetrahydroquinoline compound of formula X III, hydroxyl pyrrolidine, hydroxyl pi perdine of formula VIII and appropriate ester compound of formula IX are either commercially available or synthesized using conventional methods known to one of skill in the art.
  • Schemes 1 and 2 provide general method of preparation of compounds and intermediates according to present invention.
  • One of ordinary skill wil l recognize to appropriately substitute various groups such as R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 in appropriately modified starting material to prepare desired compounds accordi ng to formula (I).
  • a lternative to the given schemes one of ordinary skill will readily synthesize the compounds according to the present invention using conventional synthetic organic techniques from suitable starting material which are either commercially available or may be readily prepared.
  • the compounds of the present invention may have chiral centers and occur as racemates, racemic mixtures and as individual diastereomers or enantiomers with all isomeric forms being included in the present invention. Therefore, where a compound is chiral, the separate enantiomers, substantially free of the other, are i ncluded within the scope of the invention; further included are all mixtures of the two enantiomers.
  • novel compounds of the present invention were prepared according to the procedure of the schemes as described herein above, using appropriate materials and are further exemplified by the following specific examples.
  • the examples are not to be consi dered or construed as I i mi ti ng the scope of the i nventi on set forth.
  • Mass of compounds prepared according to present invention is measured using Single quadrupole mass spectrometer (Water ZQ 2000 instrument) using APCI ionization technique (E lectro spray chemical ionization Probe) or Finnigan LX Q, thermo instrument Technique using either ESI or APCIJH NM R Spectra of all the compounds is recorded by using Bruker TopSpin400 M Hz NMR Spectrometer.
  • APCI ionization technique E lectro spray chemical ionization Probe
  • Finnigan LX Q thermo instrument Technique using either ESI or APCIJH NM R Spectra of all the compounds is recorded by using Bruker TopSpin400 M Hz NMR Spectrometer.
  • reaction mixture was cooled down to room temperature and sodium borohydride (3.62 gm, 0.097 mol) was added porti on-wi se for 30 to 45 mi nutes at 0-5°C and reacti on mixture was sti rred for 30 mi nutes.
  • reaction mixture was quenched with aqueous saturated sodium hydrogen carbonate (750 ml) at room temperature, extracted with MDC (1000 ml), the organic layer was separated, dried over sodium sulphate and filtered to get 1- ⁇ 2-[5-( ⁇ [(2R)-2- ⁇ [tert- butyl(dimethyl)silyl]oxy ⁇ -2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino ⁇ methyl)-2,3-dihydro-1 H-indol-1-yl]-2-oxoethyl ⁇ piperidin-4-yl hydroxy(dithiophen-2- yl)acetate in M DC layer.
  • T he obtai ned sol i d was f i Itered and washed with MDC.
  • the solid was suspended in water and neutralized with saturated sodium hydrogen carbonate and was sti rred at R T for 8 to 10 hours.
  • T he obtai ned sol i d was f i I tered, washed with plenty of water and dried under vacuum at 50 e5°C.
  • T he R M was cooled down to RT and sodium borohydride (43 mg, 0.00112 mol) was added portion wise for 5 minutes at 0- 5°C and R M was sti rred for 30 mi n.
  • T he R M was quenched with aqueous saturated sodi um hydrogen carbonate (20 ml) at RT and was extracted i n ethyl acetate (100 ml x 3).
  • T he sol i d was f i Itered and washed with M DC .
  • T he sol id was neutral i zed with aqueous saturated sodium hydrogen carbonate and stirred at RT for 6 to 8 hours.
  • the solid was filtered, washed with water and dried under vacuum at 50 e5°C.
  • the solid was suspended in ethyl acetate (15 ml) and sti rred f or 2 hours at RT, filtered and dried under vacuum at 50 e5°C to get 150 mg desi red compound as white sol i d.
  • C ompounds of the present i nventi on may be admi ni stered i n combi nati on wi th other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of Formula (I) are useful.
  • Such other drugs may be administered contemporaneously or sequentially with a compound of Formula (I).
  • a pharmaceutical composition containing such other drugs in addition to the compound of Formula (I) is preferred.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of Formula (I).
  • a pharmaceutical composition comprisi ng a therapeutical ly effective amount of one or more of a compound of formula (I). While it is possible to administer therapeutically effective quantity of compounds of formula (I) either individually or in combination, directly without any formulation, it is common practice to administer the compounds in the form of pharmaceutical dosage forms comprising pharmaceutically acceptable excipient(s) and at I east one active i ngredi ent T hese dosage forms may be admi ni stered by a vari ety of routes including intranasal, pulmonary, oral, topical, transdermal, subcutaneous, intramuscular, intravenous, intraperitoneal, etc.
  • 0 ral composi ti ons may be i n the form of sol i d or I i qui d dosage form
  • S ol i d dosage form may comprise pellets, pouches, sachets or discrete units such as tablets, multiparticulate units, capsules (soft & hard gelatin) etc.
  • L iquid dosage forms may be i n the form of elixirs, suspensions, emulsions, sol utions, syrups etc.
  • composition intended for oral use may be prepared according to any method known in the art for the manufacture of the composition and such pharmaceutical compositions may contain in addition to active ingredients, excipients such as diluents, disintegrating agents, binders, solubilizers, lubricants, glidants, surfactants, suspending agents, emulsifiers, chelating agents, stabilizers, flavours, sweeteners, colours etc.
  • excipients such as diluents, disintegrating agents, binders, solubilizers, lubricants, glidants, surfactants, suspending agents, emulsifiers, chelating agents, stabilizers, flavours, sweeteners, colours etc.
  • excipients include lactose, cellulose and its derivatives such as microcrystalline cel lulose, methyl cellulose, hydroxy propyl methyl cellulose & ethyl cellulose, di calcium phosphate, mannitol, starch, gelatin, polyvinyl pyrrolidone, various gums like acacia, tragacanth, xanthan, alginates & its derivatives, sorbitol, dextrose, xylitol, magnesium stearate, talc, colloidal silicon dioxide, mineral oi l, glyceryl mono stearate, glyceryl behenate, sodium starch glycolate, cross povidone, crossl inked carboxymethyl cellulose, various emulsifiers such as polyethylene glycol, sorbitol, fatty acid esters, polyethylene glycol alkyl ethers, sugar esters, polyoxyethylene polyoxypropyl block copolymers, poly ethoxy I
  • Intranasal or pulmonary compositions according to present invention can be in the form of liquid or solid or semisolid composition suitable for nasal administration.
  • L iquid composition can be aqueous, non-aqueous composition, suspension or emulsion
  • solid composition can be in the form of powder and the like
  • semi solid composition can be in form of gel and the like.
  • Nasal /pulmonary compositions may also form in-situ gel.
  • Said nasal or pulmonary composition comprises compounds of formula (I) optionally with one or more suitable excipients selected from in-situ gelling agent, mucoadhesive agent, polymer, humectant buff eri ng agent stabilizer, surfactant, preservative, thickening agent, solvents, co-solvents, permeation enhancer, chelating agent viscosity modifying agent, sweetener, taste masking agent, solubilizer, flavoring agent, and isotonicity agent.
  • suitable excipients selected from in-situ gelling agent, mucoadhesive agent, polymer, humectant buff eri ng agent stabilizer, surfactant, preservative, thickening agent, solvents, co-solvents, permeation enhancer, chelating agent viscosity modifying agent, sweetener, taste masking agent, solubilizer, flavoring agent, and isotonicity agent.
  • Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection, N - Methyl -2- Pyrrol i done, propylene glycol and other glycols, alcohols, a naturally occurring vegetable oil like sesame oi l, coconut oil, peanut oil, cotton seed oil or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, anti -oxidants, preservatives, complexing agents like cellulose derivatives, peptides, polypeptides and cycl odextri ns and the I i ke can be i ncorporated as requi red.
  • a vehicle such as water for injection, N - Methyl -2- Pyrrol i done, propylene glycol and other glycols, alcohols, a naturally occurring vegetable oil like sesame oi l, coconut oil, peanut oil, cotton seed oil or a synthetic fatty vehicle like e
  • the dosage form can have a slow, delayed or controlled release of active ingredients i n addi ti on to i mmedi ate rel ease dosage forms.
  • the amount of active ingredient which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment and the particular disorder or disease being treated.
  • the compounds of the invention may be administered by oral, inhalation or parenteral route at a dose of from 0.0005 to 100 mg/kg per day, preferably from 0.0005 to 50 mg/kg per day, more preferably from 0.001 to 20 mg/kg per day, most preferably from 0.001 to 10 mg/kg per day.
  • the dose range for adult humans is generally from 5 ⁇ g to 5 g per day and preferably 10 ⁇ g to 2 g per day.
  • Dosage forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for exampl e units contai ni ng 5 1 g to 1000 mg.
  • present invention provides method of treating respiratory- tract disorders such as asthma and chronic obstructive pulmonary disease, chronic bronchitis, adult/acute respiratory distress syndrome (A R DS), chronic respi ratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema and allergic rhinitis by administering a therapeutically effective amount of a compound of formula (I) to a mammal, including human being, in need thereof.
  • respiratory- tract disorders such as asthma and chronic obstructive pulmonary disease, chronic bronchitis, adult/acute respiratory distress syndrome (A R DS), chronic respi ratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema and allergic rhinitis
  • a preferred embodiment of the present invention is a method for treating chronic obstructive pulmonary disease or asthma by administering a therapeutically effective amount of a compound of formula (I) to a mammal, i ncl udi ng human bei ng, i n need thereof.
  • Beta 2 adrenergic receptor agonist activity showed increase in intracell ular cA MP levels.
  • the results were expressed as percentage i ncrease of cA M P as compared with vehicle treated control.
  • Intracellular calcium levels were monitored upto 90 seconds after agonist treatment on Multimode Plate Reader (E nV ision ⁇ ,PerkinEl mer ).
  • Compounds of present invention exhibiting muscarinic M3 receptor antagonistic activity showed inhibition of carbachol induced increase of intracellular calcium levels.
  • I n-vi tro data shows that compounds of present i nventi on have anti muscari ni c as well as beta adrenergic agonist activity.
  • bronchoprotection activity of compound no. 1 was evaluated in an anesthetized guinea pig model using ventilation pressure as a surrogate measure of airway resistance (J Pharmacol Toxicol Methods. 2011 J an- Feb; 63(1): 89-95). In this model, efficacy and duration of effect were assessed by determining the protective effect of Compound no. 1 against methacholine induced bronchoconstriction at 1.5 hours and 24 hours after inhalation dosing.
  • V ehicle or solution of compound no. 1 (300 ⁇ g/ml) was dosed by inhalation over a period of 15 minutes in a whole body exposure dosi ng chamber using 5 ml dosing solution.
  • Omron, N E- C29 nebulizer was used to generate aerosol used for dosing.
  • guinea pigs were anesthetized with an intraperitoneal injection of urethane (1 g/kg) and pentobarbital sodi um (20 mg/kg).
  • the jugular vein was isolated and cannulated using heparin saline filled polyethylene catheters to al I ow i ntravenous i nj ecti on of methachol i ne. T he trachea was then approached through a midline blunt incision, dissected free and cannulated.
  • the animals were venti lated at a stroke vol ume 1 ml/100 g body weight but not exceedi ng 2.5 ml vol ume and at rate of 100 strokes per mi nute usi ng smal I ani mal venti I ator (Columbus, U.S.A.).
  • Ventilation pressure was measured in the expiratory tubing of ventilator using a MT L844 physiological pressure transducer coupled to a Powerlab-quad bridge-computer assembly (A DInstruments, Australia). Throughout the experiment the animals were maintained at 37 eC using a heating pad. Prior to initiating data collection, pentobarbital (10 mg/kg) was administered intraperitoneal I y to suppress spontaneous breathi ng and obtai n a stabl e basel i ne.
  • guinea pigs were challenged intravenously with non- cumulatively incremental doses of the bronchoconstrictor methacholine. The changes in ventilation pressure were recorded using LabChart software (A DInstruments, Australia). After the completion of study, the animals were euthanized.
  • compound no. 1 produced potent and sustained bronchoprotective activity.
  • Single admi nistration of compound no. 1 completely abolished methacholine induced bronchoconstriction at 1.5 hr post dosing.
  • test compound elicited 87 % inhibition of methacholine- induced bronchoconstriction.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux composés de formule (I), leurs sels pharmaceutiquement acceptables, et leurs isomères, stéréoisomères, atropisomères, conformères, tautomères, atropisomères, polymorphes, hydrates, solvates, N-oxyde ou S-oxyde. La présente invention concerne également des compositions pharmaceutiquement acceptables et un procédé de préparation desdits composés. L'invention concerne en outre l'utilisation des composés susmentionnés pour la préparation de médicaments destinés à être utilisés comme produits pharmaceutiques.
PCT/IB2018/050922 2017-02-17 2018-02-15 Composés ayant un agoniste bêta-adrénergique et une activité antimuscarinique Ceased WO2018150347A1 (fr)

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WO2020244452A1 (fr) * 2019-06-06 2020-12-10 中国医药研究开发中心有限公司 DÉRIVÉ HÉTÉROCYCLIQUE AYANT UNE ACTIVITÉ D'ACTIVATION DU RÉCEPTEUR β2 ET UNE ACTIVITÉ ANTAGONISTE DU RÉCEPTEUR M ET UTILISATION MÉDICALE ASSOCIÉE
TWI814092B (zh) * 2020-09-28 2023-09-01 大陸商正大天晴藥業集團股份有限公司 稠合的三并環衍生物及其在藥學上的應用

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Publication number Priority date Publication date Assignee Title
WO2020244452A1 (fr) * 2019-06-06 2020-12-10 中国医药研究开发中心有限公司 DÉRIVÉ HÉTÉROCYCLIQUE AYANT UNE ACTIVITÉ D'ACTIVATION DU RÉCEPTEUR β2 ET UNE ACTIVITÉ ANTAGONISTE DU RÉCEPTEUR M ET UTILISATION MÉDICALE ASSOCIÉE
CN113544121A (zh) * 2019-06-06 2021-10-22 中国医药研究开发中心有限公司 具有β2受体激动及M受体拮抗活性的杂环衍生物及其医药用途
TWI814092B (zh) * 2020-09-28 2023-09-01 大陸商正大天晴藥業集團股份有限公司 稠合的三并環衍生物及其在藥學上的應用
JP2023542161A (ja) * 2020-09-28 2023-10-05 チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッド 縮合三環式誘導体及び薬学上のその使用
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