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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/20—Oxygen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • 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
  • C07D405/12—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 chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to novel compounds which are inhibitors of receptor tyrosine kinases of the AXL receptor family. These compounds are suitable for the treatment or prevention of disorders associated with, accompanied by or caused by hyperfunction of a receptor of the AXL family. The compounds are suitable for the treatment of hyperproliferative disorders, such as cancer, particularly cancer metastases.
• the receptor tyrosine kinase HER2/neu is overexpressed due to gene amplification in tumours of about 25% of breast cancer patients, and enhanced expression correlates with lack of response to adjuvant therapy and poor prognosis (6).
• Herceptin a monoclonal antibody against HER2/neu oncoprotein, has been developed and is in clinical use since 1998 both as a single agent and in combination with chemotherapies for HER2/neu overexpressing metastatic breast cancer, which has helped to significantly prolong survival of patients (7, 8).
• metastatic breast cancer patients showing no overexpression of HER2/neu do not benefit from this therapy. Therefore, novel therapeutic targets are still urgently needed for intervention in breast cancer metastatic progression.
• the mammalian AXL RTK subfamily includes three closely related members: AXL, SKY, and MER.
• the subfamily is characterised by an extracellular domain, consisting of two immunoglobulin-like domains followed by two fibronectin type 3-like domains.
• GAS6 originally isolated as a growth arrest- specific gene, is the common ligand for AXL subfamily receptors (9-11). GAS6 has the highest affinity for AXL 1 followed by SKY, and finally MER (11).
• GAS6-AXL signalling has been implicated in a host of discrete cellular responses including cell survival, proliferation, migration and adhesion (12).
• AXL was originally isolated from patients with chronic myelogenous leukaemia and was shown to have transforming potential when overexpressed (13, 14). Subsequently, AXL expression has been reported in a wide variety of human cancers(15-20). Especially, in breast cancer patients a significant correlation was found between AXL and tumour stage (15). Moreover, some reports indicated that AXL might be involved in cancer progression (21, 22).
• R 7 , R 8 , R 9 and R 10 which may be the same or different, represent a hydrogen atom, halogen, nitro, Ci -6 alkyl, Ci -6 alkoxy, wherein the Ci -6 alkyl or Ci -6 alkoxy groups are optionally mono- or polysubstituted by hydroxyl and/or halogen, Ci -4 alkyl and/or alkoxy, wherein the Ci-e alkyl, Ci -6 alkoxy, wherein the Ci -6 alkyl or Ci -6 alkoxy groups are optionally mono- or polysubstituted by hydroxyl and/or halogen, - R 11 represents
• R 15 represents a hydrogen atom or Ci -6 alkyl.
• the present invention relates to compounds as described above, preferably with the proviso that the compound is not N-[4- [(6,7-dimethoxy-4-quinolinyl)oxy]-3-fluorophenyl]- benzenemethanesulfonamide, N-[4-[(6,7-dimethoxy-4-quinolinyl)oxy]-3- fluorophenyl]-benzeneethanesulfonamide, or N-[4-[(6,7-dimethoxy-4- quinolinyl)oxy]-3-fluorophenyl]-benzenepropanesulfonamide.
• the present invention refers to compounds as described above, preferably with the proviso that compounds wherein R 7 is F and R 10 is H are excluded.
• the compounds of the present invention are efficient inhibitors of AXL receptor tyrosine kinase autophosphorylation and, thus, are suitable for the treatment of hyperproliferative disorders associated with, accompanied by and/or caused by AXL hyperf unction, particularly AXL receptor tyrosine kinase induced hyperproliferative disorders.
• the compounds of the present invention are quinoline-substituted sulfonamide derivatives which are inhibitors of autophosphorylation of receptors of the AXL family, particularly of the human AXL receptor.
• the compounds of the invention are capable of inhibiting cell proliferation and, thus, are suitable for the treatment and/or prevention of AXL receptor tyrosine kinase induced hyperproliferative disorders, particularly selected from the group consisting of cancer and primary tumor metastases.
• the AXL receptor tyrosine kinase induced disorders are associated with AXL receptor tyrosine kinase receptor overexpression and/or hyperactivity, e.g. an increased degree of autophosphorylation compared to normal tissues.
• the disorders may be selected from breast, colon, prostate, lung, gastric, ovarian, endometrial, renal, hepatocellular, thyroid, uterine, esophagus, squamous cell cancer, leukemia, osteosarcoma, melanoma, glioblastoma and neuroblastoma.
• the disorders are selected from breast cancer, glioblastoma, renal cancer, non-small cell lung cancer (NSCLC), and melanoma.
• NSCLC non-small cell lung cancer
• the disorder is breast cancer.
• the compounds of the present invention are also suitable for the prevention and/or treatment for other hyperproliferative disorders, particularly benign hyperproliferative disorders such as benign prostate hyperplasia.
• the compounds as described above are used for the treatment of cancer metastases, particularly primary metastases, optionally in combination with surgery, irradiation and/or administration of further antitumor agents, such as chemotherapeutic agents and/or antitumor antibodies.
• the compounds of the present invention are characterized by their ability to inhibit AXL receptor tyrosine kinase autophosphorylation in a cellular system, e.g. in NIH3T3 cells.
• the compounds have an IC 5 O value of 10 ⁇ M or less, more preferably of 5 ⁇ M or less, even more preferably of 2.5 ⁇ M or less, and most preferably of 1 ⁇ M or less.
• alkyl alkoxy
• alkenyl alkynyl
• alkynyl straight chain or branched chain alkyl, alkoxy, alkenyl, and alkynyl.
• d-6 alkyl is preferably alkyl.
• Ci-6 alkoxy is preferably Ci -4 alkoxy.
• C 2-6 alkenyl is preferably C 2 -* alkenyl.
• C 2 -6 alkynyl is preferably C 2 ⁇ alkynyl.
• Ci -6 alkyl examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, i- butyl, s-butyl, t-butyl, n-pentyl, and n-hexyl.
• Ci -6 alkoxy examples include methoxy, ethoxy, n-propoxy, i-propoxy, n- butoxy, i-butoxy, s-butoxy, and t-butoxy.
• C 2-6 alkenyl examples include allyl, butenyl, pentenyl, and hexenyl.
• C 2-6 alkynyl examples include 2-propynyl, butynyl, pentynyl, and hexynyl.
• alkyl optionally substituted by refers to alkyl, in which one or more hydrogen atoms on the alkyl group have been substituted by one or more substituents which may be the same or different, and unsubstituted alkyl. It will be apparent to a person having ordinary skill in the art that the maximum number of substituents may be determined depending upon the number of substitutable hydrogen atoms on the alkyl group. This is true of a group having a substituent other than the alkyl group.
• halogen means a fluorine, chlorine, bromine, or iodine atom.
• halogen means a fluorine or chlorine atom.
• the three- to twelve-membered ring system may comprise a saturated or unsaturated three- to eight-membered carbocyclic ring, preferably a four- to seven-membered, more preferably five- or six-membered, saturated or unsaturated carbocyclic ring.
• saturated or unsaturated three- to ten-membered carbocyclic rings include phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
• the three- to twelve-membered ring system may comprise a saturated or unsaturated three- to eight-membered heterocyclic group containing at least one hetero-atom selected from oxygen, nitrogen, and sulfur atoms.
• the heterocyclic group preferably contains one, two or three hetero-atoms with the remaining ring-constituting atoms being carbon atoms.
• the heterocyclic group preferably comprises a saturated or unsaturated four- to seven-membered heterocyclic ring, more preferably a saturated or unsaturated five- or six-membered heterocyclic ring.
• saturated or unsaturated three- to eight-membered heterocyclic groups include thienyl, pyridyl, 1 ,2,3-triazolyl, thiazolyl, imidazolyl, isoxazolyl, pyrazolyl, piperazinyl, quinolinyl, piperidyl, morpholinyl, homopiperazinyl, thiomorpholinyl, tetrahydropyrrole, and azepanyl.
• saturated or unsaturated carboxylic and heterocyclic ring systems include condensed ring systems wherein a cyclic group is condensed with another saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic ring to form a bicyclic group, preferably a saturated or unsaturated nine- to twelve-mem bered bicyclic carbocyclic or heterocyclic group.
• Such bicyclic groups include naphthyl, quinolyl, 1 ,2,3,4- tetrahydroquinolyl, 1 ,4-benzoxanyl, indanyl, indolyl, 1 ,2,3,4- tetrahydronaphthyl, and phthalimidyl.
• R 1 preferably represents a hydrogen atom or C1-4 alkyl, e.g. methyl. More preferably, R 1 represents a hydrogen atom.
• R 2 and R 3 may be the same or different.
• one of R 2 and R 3 represents a group other than a hydrogen atom. More preferably, R 2 and/or R 3 represent hydroxyl, optionally substituted C 1-6 alkoxy, halogen, or cyano.
• Ci -6 alkoxy is not substituted by amino.
• R 2 represents unsubstituted Ci -6 alkoxy, still more preferably methoxy or fluorine.
• R 2 represents unsubstituted Ci -6 alkoxy, still more preferably, methoxy
• R 3 represents hydroxyl or optionally substituted Ci -6 alkoxy, or alternatively R 2 represents hydroxy!
• Ci -6 alkoxy and R 3 represents unsubstituted Ci -6 alkoxy, still more preferably unsubstituted methoxy.
• R 2 and R 3 both represent methoxy.
• R 2 is halogen, e.g. fluorine and R 3 is hydrogen.
• R 3 is preferably selected from the group consisting of benzyloxy, 3-amino-propoxy, 2-morpholin-4-yl-ethoxy, 3-(4- methyl-piperidin-1 -yl), 3-(3-methyl-piperidin-1 -yl), 3-morpholin-4-yl-propoxy).
• R 2 is methoxy and R 3 is selected from said group.
• R 2 and/or R 3 may represent -O- (CH 2 )n-R 14 wherein n is an integer of 0 to 6, -(CH 2 ) n - is optionally substituted by Ci -6 alkyl, hydroxyl, or a halogen atom, and R 14 represents a hydrogen atom; hydroxyl; a halogen atom; Ci -6 alkoxy; d-e alkylcarbonyl; carboxyl; Ci.
• R 12 or R 13 which may be the same or different, represent a hydrogen atom or Ci -4 alkyl optionally substituted by hydroxyl, or alternatively R 12 and R 13 may combine with the nitrogen atom attached thereto to form a saturated or unsaturated five- or six-membered heterocyclic group, in which the heterocyclic group is optionally substituted by hydroxyl, an oxygen atom, Ci -6 alkyl, C 2-6 alkenyl, C2-6 alkynyl, Ci -6 alkoxy, Ci -6 alkoxycarbonyl, or a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system; wherein the C1- 6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl groups are optionally substituted by hydroxyl, Ci -6 alkoxy, or a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system; wherein the C1- 6 alkyl, C 2-6
• R 14 may represent a saturated heterocyclic ring attached through its nitrogen atom, wherein R 14 is selected from the following:
• R 14 may represent an unsaturated heterocyclic ring attached through its CH 2 group, wherein R 14 is selected from the following:
• R 4 is preferably hydrogen, Ci -6 alkyl or Ci -6 alkoxy, wherein the Ci -6 alkyl or Ci -6 alkoxy group is optionally substituted with one or more halogen atoms. More preferably, R 4 is hydrogen or trifluoromethyl.
• R 1 and R 4 are hydrogen and R 2 and R 3 are Ci -6 alkoxy, particularly methoxy.
• R 1 , R 2 and R 3 are hydrogen and R 4 is Ci -6 alkyl optionally substituted, particularly trifluoromethyl.
• R 1 , R 3 and R 4 are hydrogen and R 2 is halogen, e.g. fluorine.
• R 5 and R 6 are preferably selected from hydrogen, Ci -6 alkyl or Ci -6 alkoxy, optionally substituted, e.g. by halogen and/or NR 12 R 13 as described above. More preferably, R 5 and R 6 are hydrogen.
• R 7 , R 8 , R 9 and R 10 which may be the same or different, preferably represent a hydrogen atom, a halogen atom, nitro or C1-4 alkyl, or C M alkoxy, each optionally halogenated such as methoxy or trifluoromethyl. More preferably, R 7 and R 10 are hydrogen and at least one of R 8 and R 9 is different from hydrogen, e.g. halogen, such as fluorine.
• the carboxylic ring substituted by R 7 , R 8 , R 9 and R 10 is selected from the following:
• R 11 is Ci -6 alkyl substituted by a phenyl ring
• the phenyl ring is mono- or polysubstituted.
• R 11 preferably represents a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system which is optionally substituted, e.g.
• Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and Ci -6 alkoxy groups are optionally substituted by a halogen atom or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group.
• Examples of preferred substituents on the carbocyclic or heterocyclic group are halogen, e.g.
• the carbocyclic or heterocyclic group in R 11 comprises at least one halogen, e.g. fluorine or chlorine, trifluoromethyl or trifluoromethoxy substituent.
• R 11 represents an optionally substituted carbocyclic ring selected from the following (connecting atom attached to the sulfonyl group):
• R 11 may also represent an optionally substituted carbocylic or heterocyclic ring selected from the following (connecting atom attached to the sulfonyl group):
• R 11 represents an optionally substituted nitrogen atom selected from the following (connecting atom labeled by sulfonyl group):
• Examples of more preferred compounds according to the present invention include compounds represented by formula:
• the compounds of the present invention are suitable for use in medicine, particularly in human medicine, but also in veterinary medicine.
• the compounds of the present invention may be administered in a pharmaceutically effective amount by any suitable route to subjects in need thereof, e.g. parenterally, topically, rectally, nasally, bucally, vaginally, transdermal ⁇ , by inhalation, by injection or infusion, by spray or via implanted reservoirs.
• the compounds are administered orally or by injection or infusion, e.g. intravenously.
• the compounds are preferably formulated as a pharmaceutical composition, which comprises at least one compound as described above, and pharmaceutically acceptable carriers, diluents and/or adjuvants.
• the pharmaceutical composition may e.g. be a solid dosage form, e.g. a tablet, a capsule etc., or a liquid dosage form, e.g. an injectable or infundible solution.
• the dosage of the compounds may be determined by a skilled practitioner according to the type and severity of the disorder to be treated. In general, the dosage of the compound may vary from 0.0001 to 1000 or even more mg/day.
• the compounds of the present invention may be administered as a monotherapy or together with further active agents, particularly chemotherapeutic agents or antitumor antibodies.
• the compounds according to the present invention may be produced, for example, according to synthesis routes as depicted in schemes 1 to 3. Starting compounds necessary for the synthesis of the compounds according to the present invention are commercially available or alternatively can be easily produced by conventional methods.
• R 1 to R 10 are as defined in formula (I).
• the 4-chloroquinoline derivatives can be synthesized from substituted anilines by methods described in Org. Synth. CoI. Vol. 3, 272 (1955) or from substituted acetophenones by methods described in EP 1153920 (Scheme 1).
• a 4-(aminophenoxy)quinoline derivative may be produced by reacting a nitrophenol derivative with the 4-chloroquinoline derivative in a suitable solvent, for example, chlorobenzene, to synthesize a 4- (nitrophenoxy)quinoline derivative or a corresponding quinazoline derivative and then reacting the 4-(nitrophenoxy)quinoline derivative in a suitable solvent, for example, N,N-dimethyl formamide, in the presence of a catalyst, for example, palladium hydroxide-carbon or palladium-carbon, under a hydrogen atmosphere.
• a catalyst for example, palladium hydroxide-carbon or palladium-carbon
• the 4-(aminophenoxy)quinoline derivative can be produced by reacting an aminophenol derivative with the 4-chloroquinoline derivative in a suitable solvent, for example, dimethyl sulfoxide, in the presence of a base, for example, sodium hydride.
• a suitable solvent for example, dimethyl sulfoxide
• the 4-(aminophenoxy)quinazoline derivative can also be produced by dissolving an aminophenol derivative in an aqueous sodium hydroxide solution and subjecting the solution to a two- phase reaction with a solution of the 4-chloroquinazoline derivative in a suitable organic solvent, for example, ethyl methyl ketone, in the presence of a phase transfer catalyst, for example, tetra-n-butylammonium chloride, or in the absence of a catalyst (Scheme 2).
• a suitable organic solvent for example, ethyl methyl ketone
• a 4-(sulfamoylphenoxy)quinoline derivative may be produced by reacting a 4-(aminophenoxy)quinoline derivative with sulfonyl chloride derivative in a suitable solvent, for example, pyridine (Scheme 3).
• the reaction may be carried out in room temperature.
• the solvent can be diluted with hydrochloric acid, when the product precipitated.
• the crystals can be collected by filtration and the obtained solid material can be dissolved in e.g. 10% sodium acetate solution and extracted e.g. with ethyl acetate.
• the organic layer can be washed e.g. with sodium chloride solution, dried and the solvent can be evaporated.
• the resulted solid can be treated with diisopropyl ether.
• the product can be purified with column chromatography (if necessary).
• Analytical HPLC/MS was performed on an Waters HPLC/MS system using reverse phase Waters XTerra MS C18 (5cm x 4.6mm, 5um), gradient 0-95% B (0.00 min 5 % B, 0.50 min 5 % B, 5.50 min 95 % B, 6.00 min 95 %B, 6.50 min 5 % B, 7.00 min 5 % B) 1
• Solvent A Water/ 0.05% HCOOH
• UV spectra were recorded using a Waters 996 DAD UV detector. Mass spectra were obtained using Waters SQD MS detector (Ionization: ES7ES " , Source block temp: 120 C, Desolvation temp: 350 0 C 1 Desolvation Gas: 400 Uh 1 Cone Gas: 100 L/h, Capillary: 3000 V, Cone: 25 V, Extractor: 3 V, Rf Lens: 0.2 V, Scan: 120 to 1000 m/z in 1 sec, Inter-scan delay: 0.1 s). 1 H NMR spectra were recorded on a Bruker Avanve 300 MHz AV spectrometer in deuterated solvents (DMSO-d 6 ). Chemical shifts D are in parts per million (ppm).
• TLC Thin-layer chromatography
• Butane-1 -sulfonic acid [4-(6,7-dimethoxy-quinor ⁇ n-4-yloxy)-2-fluoro-phenyl]- amide

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