Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
  • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
  • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
  • C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/20—Antivirals for DNA viruses

Definitions

• the present invention relates to organic compounds useful for therapy and/or prophylaxis in a mammal, and in particular to HBsAg (HBV Surface antigen) inhibitors useful for treating HBV infection.
• HBsAg HBV Surface antigen
• the present invention relates to novel dihydroquinolizinoncs having pharmaceutical activity, their manufacture, pharmaceutical compositions containing them and their potential use as medicaments.
• the present invention relates to compounds f formula I
• R 1 to R 6 are as described below, or to pharmaceutically acceptable salts, or to cnantiomcrs thereof.
• the hepatitis B virus is an enveloped, partially double-stranded DNA v irus.
• the compact 3.2 kb HBV genome consists of four ov erlapping open reading frames (ORF ), which encode for the core, polymerase (Pol), envelope and X-proteins.
• ORF open reading frames
• the P l ORF is the longest and the env elope ORF is located within it, while the X and core ORFs overlap with the P l ORF.
• the lifecycie f HBV has two main events: 1) generation f closed circular DNA (cccDNA) fr m relaxed circular (RC DNA), and 2) reverse transcription f pregenomic R A (pgRNA) to produce RC DNA.
• HBV genome Prior to the infection f host cells, the HBV genome exists within the virion as RC DNA. It has been determined that HBV virions are able to gain entry into host cells by Yingxian Zhu /March 24, 2015 non-specifically binding to the negatively charged proteoglycans present on the surface of human hepatocytes (Schulze, A., P. Gripon & S. Urban. Hepatology, 46. (2007), 1759-68) and via the specific binding of H BV surface antigens (HBsAg) to the hepatocyte sodiuni- taurocholate cotransporting polypeptide (NTCP) receptor (Yan, H . et al. ./ Virol, 87, (2013), 7977-91).
• H v irion Once the v irion has entered the cell, the v iral cores and the encapsidated RC DNA are transported by host factors, via a nuclear localization signal, into the nucleus through the
• cccDNA acts as the template for al l v iral mRNAs and as such, is responsible f r H BV persistence in infected indiv iduals.
• the transcripts produced from cccDNA are grouped into two categories; Pregenomic R NA ( pgRNA) and subgenomic RNA.
• Pregenomic R NA pgRNA
• Subgenomic transcripts encode for the three envelopes (L, M and S) and X proteins
• pgRNA encodes for Pre-Core, Core, and Pol proteins (Quasdorff, M. & U. Protzer.
• H BV viral replication and antigens production leads to the inhibition of H BV viral replication and antigens production (Mao, R . et al. PLoS Pathog, 9, (2013), el 003494; Mao, R. et al. ./ Virol, 85, (201 1), 1048-57).
• I FN -a was shown to inhibit H BV replication and v iral H BsAg production by decreasing the transcription f pgRNA and subgenomic RNA from the H BV covalently closed circular DNA (cccDNA) minichromosome.
• H BV viral mRNAs are capped and polyadenylated, and then exported to the cytoplasm for translation.
• the assembly f new virons is initiated and nascent pgRNA is packaged with viral Pol so that reverse transcription of pgRNA, v ia a single stranded DNA intermediate, into RC DNA can commence.
• the mature nucleocapsids containing RC DN A are enveloped with cellular lipids and v iral L, M, and S proteins and then the infectious H BV particles are then released by budding at the intracellular membrane ( L o a mini, S. Semin Liver Dis, (2005), 25 Suppl 1 , 9- 19).
• non-infectious particles are also produced that greatly outnumber the infectious v irions.
• These empty, enveloped particles (L, M and S) are referred to as subv iral particles.
• subviral particles share the same env elope proteins and as in fectious particles, it has been surmised that they act as decoys to the host immune system and have been used for HBV vaccines.
• the S, M, and L envelope proteins are expressed from a single ORF that contains three different start codons. All three proteins share a 226aa sequence, the S-domain, at their C- termini. M and L have additional pre-S domains, Pre-S2 and Pre-S2 and Pre-S l, respectiv ely. However, it is the S-domain that has the HBsAg epitope ( Lambert, C. & R. Prange. Virol J, (2007), 4, 45 ).
• HBV Hepatitis B v irus
• H BV empty subv iral particles SVPs, H BsAg
• H BV empty subv iral particles CU B
• the persistent exposure to HBsAg and other v iral antigens can lead to H BV-speeifie T-cell deletion or to progressive functional impairment (Kondo et al.
• HBsAg has been reported to suppress the function of immune cells such as monocytes, dendritic cells (DCs) and natural kil ler (NK) cells by direct interaction ( Op den Brouw et al . Immunology, (2009b), 1 26, 280-9; Woltman et al. PLoS One, (201 1), 6, el 5324; Shi et al. ./ Viral Hepat. (2012), 19, e26-33; Kondo et al. ISRN Gasteroenterology, (2013), Article I D 935295).
• HBsAg quant i fication is a significant biomarkcr for prognosis and treatment response in chronic hepatitis B. How ever the achievement of H BsAg loss and seroconversion is rarely observed in chronically infected patients but remains the ultimate goal of therapy.
• Current therapy such as Nucleos(t)ide analogues are molecules that inhibit H BV DNA synthesis but are not directed at reducing H BsAg level. Nucleos(t)ide analogs, even w ith prolonged therapy, have demonstrated rates of H BsAg clearance comparable to those observed natural ly (between - 1 %- 2%) (Janssen et al. Lancet, (2005), 365, 123-9; Marcellin et al. N. Engl.
• the present invention relates to novel compounds of formula (I)
• X is oxygen or N-R ;
• Y is CH 2 or C(O);
• R ! is hydrogen, halogen, C h alky!, or CV ,,alkoxy;
• R 2 is hydrogen: halogen; V. t ,alkyl, which is unsubstituted or once or more t imes subst ituted by tiuoro; or Ci_ 6 alkoxy;
• R 3 is hydrogen; halogen; Ci_ 6 alkyl, w hich is unsubstituted or once or more times substituted by tiuoro: cyano; morphol inyl; pyrrolidinyl; or R -O-, wherein R 8 is Ci ⁇ alkyi, which is unsubstituted or once or more times substituted by tiuoro, Ci ⁇ alkoxy, CYftalkylsiilfonyl, cyano, C3_ 7 cycloalkyl, Ci_ 6 alkylamino, diCY ⁇ alkylamino, hydroxy, phenyl, pyrrolidinyl or
• R 4 is hydrogen, halogen or Ci ⁇ alkyl
• R 5 is hydrogen; C h alky 1, w hich is unsubstituted or once or more times substituted by tiuoro; CY ⁇ alkoxy; CY 7 cycloalkyl or C vcycloalkyl-C x H. -;
• R 6 is hydrogen; (Yealkylsulfonyl: hydroxy!; lH-tetrazol-5-yl; Ci ⁇ alkyl, which is unsubstituted or once or more times substituted by tiuoro, CY ycloalkyl, earboxyl-( ⁇ ,H i -, phenyl, hyiiroxy, Ci ⁇ alkoxy, amino, Ci-ealkylamino or diC i ealky lamino;
• R is hydrogen or Ci-6alkyl
• Thc invention is also relates to their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula I as HBsAg inhibitors . Accordingly, the compounds of formula I are useful for the treatment or prophylaxis of H BV infection.
• al l technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this inv ention belongs. Furthermore, the following definitions are set forth to il lustrate and define the meaning and scope of the various terms used to describe the invention.
• the term alone or in combination signifies a saturated, linear- or branched chain alky i group containing I to 6, particularly 1 t 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, I -butyl, 2-butyl, teri-butyi and the like.
• Particular "Ci ⁇ alkyl” groups are methyl, ethyl, isopropyl and ferf-butyl.
• C X H2 X alone or in combination signifies a saturated, linear- or branched chain alky I group containing I to 6, particularly I to 4 carbon atoms.
• Cv T cycloalkyl refers to a saturated carbon ring containing from 3 to 7 carbon atoms, particularly from 3 to 6 carbon atoms, for example, cyclopropyl, cycl buty l, cyclopentyl, cyclohexyl, cyc!ohepty l and the like.
• Particular "C 3 ⁇ 4 _ cycloaikyl” groups are cyclopropyl, cyclopentyl and cyclohexyl.
• Ci_ 6 aikoxy alone or in combination signifies a group C ; f ,alkyl-0-, wherein the "Ci_ 6 alkyl” is as defined abov e; for example methoxy, ethoxy, propoxy, z ' o-propoxy, n-butoxy, wo-butoxy, 2-butoxy, fert-butoxy and the like.
• Particular "C ; ,,aikoxy " groups are methoxy and ethoxy and more particularly methoxy.
• amino alone r in combination, refers to primary (-Nl3 ⁇ 4), secondary ( -N H-) or
• cyano alone or in combination refers to the group -CN.
• halogen means fluorine, chlorine, bromine or iodine. Halogen is particularly fluorine, chlorine or bromine. Thc term "hydroxy" alone or in combination refers to the group -OH.
• C h alky! amino refers to amino group as defined above wherein at least one of the hydrogen atoms of the amino group is replaced by a Ci_ 6 alkyl group.
• G-ealkylsulfonyl refers to a group Ci-6alkyl-S(0)2-, wherein the "Ci-ealkyl” is as defined above.
• substituteducnt denotes an atom or a group of atoms replacing a hy drogen atom on the parent molecule.
• enantiomer denotes two stereoisomers of a compound which are non- superimposabie mirror images of one another.
• diastereomer denotes a stereoisomer with two or more centers f chirality and whose molecules are not mirror images of one another.
• the compounds according to the present inv ention may exist in the form of their pharmaceutical ly acceptable salts.
• pharmaceutical ly acceptable salt refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases.
• Acid-addition salts include for example those deriv ed from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those deriv ed from organic acids such as /j-toiuenesulfonic acid, salicylic acid, methanesulfonic ac id, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like.
• inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid
• organic acids such as /j-toiuenesulfonic acid, salicylic acid, methanesulfonic ac id, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fum
• Base-addition salts include those deriv ed from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as f r example, tetramethyl ammonium hydroxide.
• the chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stabil ity, hygroscopicity, flow ability and solubility of compounds.
• I t is for example described in Bastin R.J., et ah, Organic Process Research & Development 2000, 4, 427-435; r in A nsel, H., et al., I n: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed. (1995), pp. 196 and 1456- 1457.
• Racemates of the general formula I which contain one or several chiral centers can either be present as racematcs, diastereomcric mixtures, or optically active single isomers.
• the racemates can be separated according to known methods into the enantiomers.
• diastcreomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction w ith an optical ly active acid such as e.g. D- or L-tartaric acid, mandel ic acid, mal ic acid, lactic acid or camphorsulfonic acid.
• an optical ly active acid such as e.g. D- or L-tartaric acid, mandel ic acid, mal ic acid, lactic acid or camphorsulfonic acid.
• the present invention relates to (i) a compound of formula (I):
• X is oxygen or N-R ;
• Y is CH 2 or C(O);
• R 1 is hydrogen, halogen, Ci-6alkyl, or CY t ,alkoxy
• R ' is hydrogen; halogen; C h alky 1, which is unsubstituted or once or more times substituted by fluoro; or (Y ,>,alkoxy;
• R 4 is hydrogen, halogen or Ci ⁇ alkyl
• R 5 is hydrogen; Ci ⁇ alkyl, which is unsubstituted or once or more times subst ituted by fluoro; Ci- 6 alkoxy; C3_ 7 cycloalkyl or C •cycloalkyl-C 3 H ⁇ -;
• R 6 is hydrogen; C h alky lsulfonyl; hydroxy!; 1 1 l-tetrazol-5-yI; Ci ⁇ alkyl, w hich is unsubstituted or once or more times substituted by fluoro, C ycloalkyl, carboxyl-C N H.i -, phenyl, hydroxy, Ci ⁇ alkoxy, amino, Ci_ 6 alkylamino or diC ; ftalkylamino; R 7 is hydrogen or CYea!kyl;
• R 6 and R together with the nitrogen to which they arc attached, form pyrrolidinyl, piperidmyl, morpholinyl, which is unsubstituted or once or two times substituted by carboxyl; or pharmaceutical ly acceptable salts, enantiomers or diastereomers thereof.
• Another embodiment o present invention is (ii) a compound of formula (I), wherein
• X is oxygen or N -R ;
• Y is CH 2 or C(O);
• R 1 is hydrogen or halogen
• R ' is hydrogen, halogen or Ci-6alkoxy
• R 3 is R 8 -0-, wherein R 8 is Ci ⁇ alkyl, w hich is unsubstituted or once or two times substituted by Ci_ 6 alkoxy, C3_ 7 cycloalkyl or phenyl;
• R 3 is Ci-ealkyl, which is unsubstituted or once or two t imes substituted by trifluoromethyl; or C3- 7 cycloalkyl;
• R 6 is hydrogen; C h alky 1, which is unsubstituted or once or two times subst ituted by phenyl, hydroxy, Ci-ealkoxy, carboxy, diCi-eaikyi amino; hydroxy; 1 H-tctrazol-5-yl or Ci-ealkyisuifonyl; R is hydrogen or Ci- 6 alkyl;
• R 6 and R 7 together w ith the nitrogen to w hich they arc attached, form pyrrolidinyl, piperidinyl, morpholinyl, which is unsubstituted or once or two times substituted by carboxyl; or pharmaceut ical ly acceptable salts, enantiomers or diastereomers thereof.
• a further embodiment of present invention is (iii) a compound of formula (I), wherein
• X is oxygen or N -R ;
• Y is CH 2 or C(O);
• R ! is hydrogen or chloro
• R 2 is hydrogen, methoxy or chloro
• R 3 is R -0-, w herein R 8 is methyl, ethyl, propyl, isobutyl, w hich is unsubstituted or once or two times substituted by methoxy , cyclopropyl or phenyl;
• R 4 is hydrogen
• R 5 is ethy l, isopropyl, trifluoromethyl methyl, tert-butyl or cyclobutyl
• R 6 is hydrogen; methyl, ethyl, propyl, isopropy l or isobutyl, which is unsubstituted or once or two times substituted by phenyl, hydroxy, mcthoxy, carboxy, dimcthylamino; hydroxy; 1 H- tetrazol-5-y! or methylsulfonyi;
• R is hydrogen or methyl
• R 6 and R together with the nitrogen to which they arc attached, form pyrrolidinyl, pipcridinyl, morphol inyl, which is unsubstituted or once or two times substituted by carboxyl; or pharmaceutically acceptable salts, enantiomers or diastereomers thereof.
• Another embodiment of the present invention is (iv) a compound of formula (I) as defined above, or pharmaceutically acceptable salts, enantiomers or diastereomers thereof, wherein R ! is hydrogen, and all remaining substituents hav e the significances giv en herein before.
• FIG. 1 Another embodiment of present inv ention is (v) a compound of formula (I) as defined above, or pharmaceutically acceptable salts, enantiomers or diastereomers thereof, wherein R 2 is C ' ,alkoxy or halogen, and all remaining substituents hav e the signi ficances giv en herein before.
• a further embodiment of present inv ention is (vi) a compound of formula (I) wherein R 2 is mcthoxy or chloro.
• Another embodiment of present inv ention is (vii) a compound of formula (I) as defined abov e, or pharmaceutically acceptable salts, enantiomers or diastereomers thereof, wherein R 3 is R 8 -0-, wherein R 8 is Ci- 6 alkyl, which is unsubstituted or once or two times substituted by Ci_ ealkoxy or phenyl, and all remaining subst ituents hav e the significances given herein before.
• a further embodiment of present inv ention is (viii) a compound of formula (I), wherein ⁇ V is R 8 -0-, wherein R 8 is methyl or propyl, which is unsubstituted or once or two times substituted by mcthoxy or phenyl.
• Another embodiment of present inv ention is (ix) a compound of formula (I) as defined abov e, or pharmaceutically acceptable salts, enantiomers or diastereomers thereof, wherein R 5 is Ci- 6 alkyl, which is unsubstituted or once or two times substituted by fluoro; or C ⁇ Tcycloalkyl, and all remaining substituents hav e the significances giv en herein before.
• a further embodiment of present inv ention is (x) a compound of formula (I) as defined above, or pharmaceutical ly acceptable salts, enantiomers or diastereomers thereof, wherein R 5 is ethyl or isopropyl, and all remaining substituents hav e the significances giv en herein before.
• Another embodiment of present invention is (xi) a compound of formula (I) as defined above, or pharmaceutically acceptable salts, enantiomers or diastereomers thereof, wherein R 6 is hydrogen; methyl, ethyl, propyl, isopropyl or isobutyl, which is unsubstituted or once or two times substituted by phenyl, hydroxy, methoxy, carboxy, climcthylamino; hydroxy; 1 H-tetra/ol- 5-yl or methylsulfonyl, and all remaining substituents have the signi ficances given herein before.
• Another embodiment f present invention is (xii) a compound of formula (I) as defined above, or pharmaceutically acceptable salts, enantiomers or diastereomers thereof, wherein R 6 and R , together with the nitrogen to which they are attached, form pyrrolidinyl, piperidinyl, morpholinyl, which is unsubstituted or once or two times substituted by carboxyl, and all remaining substituents have the significances given herein before.
• Still another embodiment f present invention is (xiii) a compound f formula (I), wherein
• X is oxygen, NH or N(Ci- 6 alkyl);
• Y is CH 2 or C(O);
• R 1 is hydrogen
• R ' is Ci- 6 al.koxy r halogen
• R 3 is R 8 -0-
• R 8 is C halky I, which is unsubstituted or once substituted by phenyl or Ci ⁇ alkoxy; R 4 is hydrogen;
• R 5 is Ci-ealkyl or C 3 - 7 cycioalkyl
• R 6 is C ,alkylsulfonyl; lH-tetrazoi-5-yi; Ci ⁇ alkyl, which is unsubstituted or once substituted by Ci ⁇ alkoxy;
• a further embodiment f present invention is (xiv) a compound f formula (I), wherein
• X is oxygen, NH or N(CH 3 ) ;
• Y is CH > or C(O);
• R ! is hydrogen
• R ' is methoxy or chloro
• R 3 is R 8 -0-
• R 8 is methy l, ethyl, propyl or isobutyl, which is unsubstituted or once substituted by phenyl or methoxy;
• R 4 is hydrogen
• R 5 is ethyl, isopropyl, tert-butyl or cyclobutyl;
• R 6 is mcthylsulfonyl; lH-tetrazol-5-yl; methyl; or isopropyl, which is once substituted by methoxy;
• the invention relates to the following compounds of formula (I): 9-benzyioxy-6-ethyi- 10-methoxy-N-methylsuifonyi-2-oxo-6,7-dihydrobenzo[a]quinoiizine-3- carboxamide;
• the compounds of general formula (I) in this invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.
• Physiologically acceptable and mctabolical!y labile derivatives which are capable of producing the parent compounds of general formula (I) in vivo are also within the scope of this invention.
• the compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds as well as their starting materials are prov ided in the schemes below and in the examples. All substitucnts, in particular, R ! to R 7 , X and Y are as defined above unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbrev iations and symbols have the meanings well known to a person of ordinary skill in organic chemistry.
• Compound V is heated with ethyl formate or formic a id in a solvent such as ethanol or dioxane to afford Compound X I .
• Compound XI is treated with oxalyl chloride followed by FeCh at - 10 °C to room temperature, and then after separation, the intermediate is heated with a solution of concentrated H2SO4 in methanol to give Compound XI I .
• Compound XII reacts with Ci-eaikyl 2- (dimethylaminomethylene)-3-oxo-butanoate in a solvent such as DM SO, DMF or ethanol to give Compound XI I I . After dehydrogenation by p-chioranil, Compound XIV is obtained.
• Compound XV Hydrolyzation of X IV by lithium hydroxide or sodium hydroxide in a suitable solvent such as THF/H2O, EtOH H )0 or MeOH/H 2 0 affords Compound XV .
• Compound XV reacts with an amine in the presence o HATU, a base such as Di PEA, TEA or a iCO,, in a solvent such as DMF to give la.
• Compound XV can be reduced by DI BA L-H to give compound l b, which is converted to compound XVI by SOCI2.
• Compound XVI reacts w ith an amine or alcohol in the presence f a base such as TEA to give compound Ic.
• Chirai compound f formula I can be prepared by chiral 11 PLC separation of
• Til is invention also relates to a process for the preparation f a compound f formula (I) comprising one f the following steps:
• a base can be for example independently selected fr m Et-,N, DIPEA and K >C(X
• a compound f formula I when manufactured according to the above process is also an object of the invent ion.
• the invention also relates to a compound f formula I for use as therapeutically active substance.
• compounds f formula (I) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-tox ic to recipients at the dosages and concentrations employed into a galenical administration form.
• physiologically acceptable carriers i.e., carriers that are non-tox ic to recipients at the dosages and concentrations employed into a galenical administration form.
• the pH f the formulation depends mainly n the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8.
• a compound f formula (I) is formulated in an acetate buffer, at pH 5.
• the compounds of formula (I) are sterile.
• the compound may be stored, for example, as a solid or amorphous composition, as a lyophiiized formulation or as an aqueous solution.
• Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition f the indiv idual patient, the cause of the disorder, the site of delivery f the agent, the method of administration, the scheduling f administration, and other factors known to medical practitioners.
• the "effective amount " f the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit I I BsAg. For example, such amount may be below the amount that is toxic to normal cells, or the mammal as a whole.
• the pharmaceutically effective amount of the compound of the invention administered parentcrally per dose will be in the range of about 0.01 to 100 mg, kg, alternatively about 0.01 to 100 mg, kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 1 5 mg/kg/day.
• oral unit dosage forms, such as tablets and capsules preferably contain from about 0.1 to about 1000 mg of the compound of the invention.
• the compounds of the invent ion may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, i f desired for local treatment, intralesional administration.
• Parenteral infusions include intramuscular, intrav enous, intraarterial, intraperitoneal, or subcutaneous administration.
• the compounds of the present inv ention may be administered in any conv enient administrat iv e form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
• Such compositions may contain components conv entional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further activ e agents.
• a typical formulation is prepared by mi ing a compound of the present inv ention and a carrier or excipient.
• Suitable carriers and excipients are well known to those skilled in the art and are described in detai l in, e.g., A nsel, Howard C, et al., Ansel ' s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004;
• the formulations may also include one or more buffers, stabil izing agents, surfactants, wetting agents, lubricating agents, cmulsi fiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known addit iv es to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceut ical product (i.e., medicament ).
• An example of a suitable ral dosage form is a tablet containing about 0.
• anhydrous lactose about 0 to 2000 mg sodium croscarmeliose, about 0 to 2000 mg polyvinylpyrrolidone (PVP) K30, and about 0 to 2000 mg magnesium stearate.
• the powdered ingredients are first mixed together and then mixed with a solution f the PVP.
• the resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment.
• An example of an aerosol formulation can be prepared by dissolving the compound, for example 0. 1 to 1000 mg, f the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired.
• the solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants.
• An embodiment therefore, includes a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof.
• a pharmaceutical composition comprising a compound f Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
• a compound of formula I can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:
• Example B A compound of formula I can be used in a manner known per se as the active ingredient for the production of capsules f the following composition:
• the compounds of the invention can inhibit HBsAg production or secretion and inhibit HBV gene expression. Accordingly, the compounds of the invention are useful for the treatment or prophylaxis of H BV infection.
• the invention relates to the use of a compound of formula I for the inhibition of HBsAg production or secretion.
• the invention relates to the use of a compound of formula I for the inhibition of H BV gene expression.
• the invention relates to the use of a compound of formula I for the treatment or prophylaxis of H BV infection.
• the inv ention relates in particular to the use of a compound of formula I for the preparation of a medicament for the treatment or prophylaxis f H BV infection.
• Another embodiment includes a method for the treatment or prophylaxis f H BV infection, which method comprises administering an effectiv e amount of a compound of Formula I , a stereoisomer, tautomer, prodrug, conjugates or pharmaceutically acceptable salt thereof.
• COMBINATION THERAPY Tlic compounds of the invention can be combined with other anti HBV agents such as interferon alpha-2b, interferon alpha-2a, and interferon alphacon- 1 (pegylated and unpegylated), ribav irin, lamivudine (3TC), entecavir, tenofovir, teibivudinc (LdT), adefovir, or other emerging anti H BV agents such as HBV RNA replication inhibitor, HBsAg secretion inhibitors, HBV caps id inhibitors, antisense oligomer, siRNA, HBV therapeutic vaccine, H BV prophylactic vaccine, HBV antibody therapy (monoclonal or polyclonal) and TLR 2, 3, 7, 8 and 9 agonists for the treatment or prophylaxis of HBV.
• HBV RNA replication inhibitor HBsAg secretion inhibitors
• HBV caps id inhibitors antisense oligomer
• BSA bovine serum albumin
• DIPEA V..V-tliisopropylcthylaniinc
• HATU 0-(7-aza- 1 H-benzotriazole- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
• n M mil limoies per liter
• nM nanomoles per liter
• Pd(PPh 3 ) 4 tetrakis(triphenylphosphine)palladium(0)
• Pd(dppf)Cl 2 [ 1 , 1 '-bis(diphenyiphosphino)ferrocene]dichloropalladium(II) prep-HPLC: preparative high performance liquid chromatography
• Acidic condition A: 0.1% formic acid in 1LO; B: 0.1% formic acid in acctonitrile;
• Mass spectra generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (M+H) ! .
• the microwave assisted reactions were carried out in a Biotage Initiator Sixty or CEM Discover.
• a single crystal was mounted in a loop and cooled to 160 K in a nitrogen stream. Data were collected on a Gemini R Ultra diffractometer (Oxford Diffraction, UK) with Cu- alpha- radiation (1.54178 ⁇ ) and processed with the Crysalis-package. Structure solution and refinement was performed using the ShelXTL software (Broker AXS, Düsseldorf).
• Step 2 Preparation of 2-benzyloxy- l -methoxy-4-
• Step 3 Preparation of l -(3-benz loxy-4-methovy-phenyl)butan-2-amine
• Step 4 Preparation of N-
• Step 6 Preparation of ethyl 9-benzyIoxy-6-ethyl- 1 O-methoxy-2-oxo- 1 ,6,7, 1 1 b- tetrahydroben/o [a] quinoIizine-3-carboxylate
• Step 7 Preparation of ethyl 9-ben/yloxy-6-ethyl- 10-niethoxy-2-oxo-6,7- dihydrobenzo
• Step 8 Preparation of 9-benzy loxy-6-et hy i- 10-methoxy-2-oxo-6,7- dihydrobenzo [a] uinolizine-3-carboxylic acid
• Step 9 Preparation of N-benzyl-9-benzyloxy-6-ethyl-10-methoxy-2-oxo- 6,7-dihydrobenzo [a] quinolizine-3-carboxamide
• 3-carboxylic acid (81 mg, 0.2 mmoi, example 1 , step 8) in DMF (10 ml ., 0.2 mmol) was added HATU (1 14 mg, 0.3 mmol), triethylamine (100 ⁇ .) and 1 ,N I -dimethy propanc- 1 ,2-diamine (306 mg, Sigma Chemical).
• Example 13 4-
• Step 1 Preparation of ethyl 6-ethyl-9-hydroxy- 10-methoxy-2-oxo-6,7- dihydrobenzo [a] quinolizine-3-carboxylate
• Step 2 Preparation of ethyl 6-cthyl- l 0-methoxy-9-(3-nicthoxypropoxy)-2-oxo- 6,7-dihydrobenzo [a] quinolizine-3-carboxylate
• Step3 Preparation of 6-ethyl- 10-niethoxy-9-(3-methoxypropoxy)-2-oxo-6,7- dihydrobcnzo
• Step 4 Preparation of methyl 4-
• Step 1 Preparation of ethyl 9-ethoxy-6-ethyl- 10-inethoxy-2-oxo- 6,7-dihydroben/o [a] quinolizine-3-carboxylate
• Step 2 Preparation of 9-ethoxy-6-ethyl- 10-methoxy-2-oxo-6,7-dihydroben/o
• Step 3 Preparation of 9-ethoxy-6-cthy 1- 10-mct hoxy- -(2-niethoxy- 1 - methyl-ethyI)-2-oxo-6,7-dih drobenzo
• Step 1 Preparation of ethyl 6-ethyl-9-isobutoxy- 10-methoxy-2-oxo-6,7- dihydrobenzo [a] quinolizinc-3-carboxyIate
• Step 2 Preparation of 6-eth ⁇ 1-9-isobutoxy- 10-methoxy-2-oxo-6,7- dihydrobenzo
• Step 3 Preparation of 6-ethyl-9-isobutoxy- 10-methoxy- -(2-methoxy- l-niethyl- ethyl)-2-oxo-6,7-dihydroben/o a] quinolizine-3-carboxamide
• Example 19 9-(cyclopropylmethovy)-6-et yl- 10-niethoxy- -(2-methoxy-l-methyl- ethyl)-2-oxo-6,7-dihydrobenzo a] quinoli/ine-3-carboxaniide
• Step 1 Preparation of ethyl 9-(cyclopropyImethoxy)-6-ethyl-10-niethoxy
• Step 2 Preparation of 9-(cyclopropylmethoxy)-6-ethyl-10-methoxy-2-oxo-6,7- dihydroben/o [a] qiiinolizine-3-carboxylic acid
• Step 3 Preparation of 9-(cyclopropylniethoxy)-6-et yl-10-methoxy- -(2-niethovy-l- niethyl-ethyl)-2-oxo-6,7-dih droben/o [aj quinolizine-3-carboxamide
• Example 21 4-
• Step 1 Preparation of 3-(chloromethyl)-6-ethyl- 10-methoxy-9-(3-methoxypropoxy)- 6,7-dihydrobenzo [a] quinoli/in-2-one
• Step 2 Preparation of methyl 4-
• Step 3 Preparation of 4-
• Step 1 Preparation of methyl l-
• Step 2 Preparation of l -
• Step 1 Preparation of methyl l -
• Step 2 Preparation of l -
• Example 27 6-ethyl- 10-methoxy-9-(3-methoxypro
• Example 3D 2- [ 16-ethyl- 10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7- dihydrobenzo [a] uinolizin-3-yl
• Step 1 Preparation of methyl 2-
• Step 2 Preparation of 2-[[6-ethyl-10-methoxy-9-(3-methoxypropoxy)- 2-oxo-6,7-dihydrobenzo [a] uinolizin-3-yl
• Step 1 Preparation of l ,2-dimethoxy-4-
• Step 2 Preparation of 1 -(3,4-dimethox henyl)biitan-2-amine
• Step 3 Preparation of iV-[l-[(3,4-dimethoxyphenyl)methyl]propyl]formamide
• Step 6 Preparation of (6 )-6-ethyl-9,10-dimethoxy-2-oxo-6,7- dihydrobenzo
• Step 7 Preparation of (6Jf)-6-ethyl-9,10-dimethoxy-2-oxo-N-(lH-tetrazol-5-yl)-6,7- dihydrobenzo [a] quinolizine-3-carboxaniide
• Step 1 Preparation of l -
• Step 2 Preparation of l-[4-methoxy-3-(3-methoxypropoxy)phenyl]-3,3-dimethyl- butan-2-amine
• Step 5 Preparation of ethyl 6-tert-butyl- 10-niethoxy-9-(3-inethoxypropoxy)-2-oxo- 1 ,6,7,1 1 b-tctrahydrobcnzo [a
• Step 6 Preparation of ethyl 6-tert-butyl- 10-mcthoxy-9-(3-methoxypropoxy)-2-oxo- 6,7-dihydrobenzo [a] quinolizine-3-carboxylate
• Step 7 Preparation of 6-tert-butyl- 10-methoxy-9-(3-methoxypropoxy)-2-oxo-6,7- dihydrobenzo
• Step 8 Preparation of 6-tert-butyl- 10-met hoxy-9-(3-methoxypropoxy)-2-oxo-N-( 1 H- tetrazol-5-yl)-6,7-dihydrobenzo [a] quinolizine-3-carboxamide
• Step 1 Preparation of l -cycIobutyl-2-
• Step 2 Preparation of 1 -cyclobutyl-2-
• Step 3 Preparation of N-[l-cyclobutyl-2-[4-methoxy-3-(3- methoxypropoxy)phenyl] eth l] formamide
• Step 5 Preparation of ethyl 6-cyclobutyl-10-methoxy-9-(3-methoxypropoxy)-2-oxo- 1,6,7,1 1 b-tetrahydrobenzo [a] quinoli/ine-3-carboxylate
• Step 6 Preparation of ethyl 6-cyclobutyl-10-methoxy-9-(3-niethoxypro
• Step 7 Preparation of 6-cyclobutyI- 10-methoxy-9-(3-niethoxypropoxy)-2-oxo-6,7- dihydrobenzo [a] quinolizine-3-carboxylic acid
• Step 8 Preparation of 6-cyclobutyl- 10-niethoxy-9-(3-niethoxypro
• Example 34 1 1 -chloro-6-isopropy l-9-(2-mcthoxyet hoxy )-2-oxo- -( 1 H-tetrazol-5-y I)- 6,7-dihydroben/o [a] quinoli/ine-3-carboxamide
• Step 1 Preparation of 1 -bromo-3-ch!oro-5-(2-methoxyethoxy)b
• Step 2 Preparation of l -
• Step 3 Preparation of l -
• Step 4 Preparation of A r -[l-[[3-ch!oro-5-(2-methoxyethoxy)pheny!] methyl]-2-methy!- propylj formamide
• Step 6 Preparation of ethyl 1 1 -chIoro-6-isopropy l-9-(2-methoxyethoxy)-2-oxo-
• Step 7 Preparation of 1 l -chloro-6-isopropyl-9-(2-inethoxyethoxy)-2-oxo-6,7- dihydrobenzo [aj uinolizine-3-carboxylic acid
• Step 8 Preparation of ll-chloro-6-isopropyl-9-(2-methoxyethoxy)-2-oxo-N-(lH- tetrazol-5-yl)-6,7-dihydrobenzo a
• Step 1 Preparation of l -(3,4-dimethoxyphenyl)-4,4,4-trifluoro-butane- l ,3-dione
• Step 2 Preparation of 3-(3,4-dimethox henyl)-5-(trifluoromethyl)-4H-isoxazol-5-ol
• Step 4 Preparation of 2-(3,4-diniethox henyI)-3-(2,2,2-trifluoroethyI)azindine
• Step 5 Preparation of l -(3,4-diniethox enyl)-4,4,4-trifluoro-butan-2-amine
• Step 7 Preparation of 6,7-diniethox -3-(2,2,2-trifluoroethyl)-3,4-dihydroisoqiiinoline
• Step 8 Preparation of ethyl 9, 10-dimethoxy-2-oxo-6-(2,2,2-trifluoroethyl)- l ,6,7, l 1 b- tetrahydrobenzo [a] quinolizine-3-carboxylate
• Step 9 Preparation of ethyl 9, 10-diniethoxy-2-oxo-6-(2,2,2-trifluoroethyl)-6,7- dihydrobenzo [a] quinolizine-3-carboxylate
• Step 18 Preparation of 9,lD-dimethoxy-2-oxo-6-(2,2,2-triflnoroethyl)-6,7- dihydrobenzo [aj uinolizine-3-carbov lic acid
• Step 11 Preparation of 9,ie-dimethoxy-2-oxo-N-(lH-tetrazol-5-yl)-6-(2,2,2- trifluoroethyl)-6,7-dihydrobenzo [a] quinolizine-3-carboxamide
• Example 36 6-isopropyl- 10-methoxy-9-(3-methoxypropoxy)-2-oxo-N-( 1 H-tetrazol-5-yl)- 6,7-dihydrobenzo [aj quinolizine-3-carboxamide
• Step 2 Preparation of l-[4-methoxy-3-(3-methoxypropoxy)phenyl]-3-methyl-biitan-2- one
• Step 3 Preparation of l -
• Step 4 Preparation of A ⁇ -[l-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-2- methyl-propyl]formamide
• Step 6 Preparation of ethyl 10-methoxy-6-isopropyI-9-(3-methoxypropoxy)-2-oxo-
• Step 7 Preparation of ethyl 10-methoxy-6-isopropyl-9-(3-methoxypropoxy)-2-oxo- 6,7-dihyclroben/o [aj quinoli/ine-3-carboxyIate
• Step 8 Preparation of 10-methoxy-6-isopropyl-9-(3-methoxypropoxy)-2-oxo-6,7- dihydrobenzo
• Example 37 10-chloro-6-isopropyl-9-(3-niethovypro
• Step 2 Preparation of l -
• Step 3 Preparation of l -
• Step 4 Preparation of A r -[l-[[4-chloro-3-(3-methoxypropoxy)phenyl]methyl]-2- niethyl-propyl
• Step 6 Preparation of ethyl 10-chloro-6-isopropyl-9-(3-methoxypropovy)-2-oxo-
• Step 7 Preparation of ethyl 10-chloro-6-isopropyl-9-(3-metho ⁇ ypropoxy)-2-oxo-6,7- dihydrobenzo [a] quinolizine-3-carbovylale
• Step 8 Preparation of 10-chloro-6-isopropyl-9-(3-niethoxypropo ⁇ y)-2-oxo-6,7- dihydroben/o [a] quinolizine-3-carboxylic acid
• Step 9 Preparation of 10-c loro-6-isopropyl-9-(3-nietlioxypropoxy)-2-oxo-N-( l H- tetrazol-5-yl)-6,7-dihydrobcnzo [a] quinolizine-3-carboxarnide
• Step 1 (+)- 10-chloro-6-isopropyl-9-(3-niethoxypro[M)xy)-2-oxo-6,7- dihydrobenzo [a] uinoIizin -3-carboxylic acid
• Step 2 Preparation of (+)-10-chloro-6-isopropyl-9-(3-methoxypropoxy)-2-oxo-N-(lH- tetrazol-5-yI)-6,7-dihydrobenzo [a] quinolizine-3-carboxaniide
• (+)-10-chloro ⁇ 6-isopropyl-9-(3-niethoxypropoxy)-2-oxo-6,7- dihydrobenzo[a]quinolizine-3-carboxylic acid (30 nig, 0.074 mmol ) in DMF (2 n L) was added HATU (42. 1 mg, 0.1 1 mmol) and Et3 ⁇ 4N (20.7 ⁇ ,, 0.15 mmol). The reaction was stirred for 5 minutes at room temperature, then lH-tetrazol-5-amine (12.6 mg, 0.15 mm l ) was added.
• HepG2.2.15 cells (Acs et al. Proc Natl Acad Sci U S A, 84, (1987), 4641-4), a
• constitutively HBV-expressing cell line were cultured in DMEM+Glutamax-I medium
• HepG2.2 15 cells were seeded in duplicate into white, 96-well plates at 1.5 x 10 4 cells/well. The cells were treated with a three-fold serial dilution series of the compounds in DMSO. The final DMSO concentration in all wells was 1% and DMSO was used as no drug control.
• the HBsAg chemiluminescence immunoassay (CLIA) kit (Autobio Diagnostics Co., Zheng/hou, China, Catalog number: CL0310-2) was used to measure the lev els of secreted H BV antigens semi-quantitativcly.
• CLIA HBsAg chemiluminescence immunoassay
• 50 ⁇ culture supernatant was used and HBsAg was quantified using HBsAg chemiluminescence immunoassay (CLIA) kit (Autobio -S i - Diagnostics Co., Zhengzhou, China, Catalog number: CL0310-2), 50 ⁇ ⁇ of the supernatant was transferred to the CL IA assay plate and 50 ⁇ I . of enzyme conjugate reagent was added into each well.
• the plates were sealed and gently agitated for 1 hour at room temperature.
• the supematant-enzyme-mixture was discarded and wells were washed 6 times with 300 ⁇ L of PBS.
• the residual l iquid was removed by plating the CLIA plate right side down on absorbent tissue paper. 25 ⁇ L f substrates A and B were added to each well.
• Luminance was measured using a luminometer (Mithras LB 940 Multimode Microplate Reader) after 10 minutes incubation. Dose- response curves were generated and the IC50 v alue was extrapolated by using the E-WorkBook Suite ( I D Business Solutions Ltd., Guildford, UK).
• the IC 50 was defined as the compound concentration (or conditioned media log dilution ) at which HBsAg secretion was reduced by 50% compared to the no drug control.
• the compounds of the present inv ention were tested for their capacity to inhibit HBsAg as described herein.
• the Examples were tested in the abov e assay and found to have IC50 below 50.0 ⁇ .
• Particular compounds of formula I were found to hav e IC50 below 5.0 ⁇ .
• Results of H BsAg assay are giv en in Table 1 .
• Example IC50 Example IC50 Example IC50 Example IC50 Example IC50 No. ( ⁇ ) No. ( ⁇ ) No. ( ⁇ ) No. ( ⁇ )

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Virology (AREA)
• Epidemiology (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Oncology (AREA)
• Communicable Diseases (AREA)
• Molecular Biology (AREA)
• Biotechnology (AREA)
• Engineering & Computer Science (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

Priority Applications (8)

Applications Claiming Priority (4)

Related Child Applications (1)

Publications (1)

Family

ID=53055057

Family Applications (1)

Country Status (9)

Cited By (124)

Families Citing this family (5)

Citations (1)

Family Cites Families (3)

• 2015
  • 2015-05-11 KR KR1020167034686A patent/KR20160148715A/ko not_active Application Discontinuation
  • 2015-05-11 RU RU2016146365A patent/RU2016146365A/ru unknown
  • 2015-05-11 WO PCT/EP2015/060284 patent/WO2015173164A1/en active Application Filing
  • 2015-05-11 CN CN201580024679.0A patent/CN106459032B/zh active Active
  • 2015-05-11 MX MX2016014728A patent/MX2016014728A/es unknown
  • 2015-05-11 CA CA2948080A patent/CA2948080A1/en not_active Abandoned
  • 2015-05-11 EP EP15721009.7A patent/EP3143020B1/en active Active
  • 2015-05-11 JP JP2016567506A patent/JP6568106B2/ja active Active
• 2016
  • 2016-11-11 US US15/349,343 patent/US9920049B2/en active Active

Patent Citations (1)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events