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WO2009030224A2 - Nouveaux produits pharmaceutiques, procédés pour les produire et leur utilisation en thérapie médicale - Google Patents

Nouveaux produits pharmaceutiques, procédés pour les produire et leur utilisation en thérapie médicale Download PDF

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Publication number
WO2009030224A2
WO2009030224A2 PCT/DE2008/001528 DE2008001528W WO2009030224A2 WO 2009030224 A2 WO2009030224 A2 WO 2009030224A2 DE 2008001528 W DE2008001528 W DE 2008001528W WO 2009030224 A2 WO2009030224 A2 WO 2009030224A2
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WO
WIPO (PCT)
Prior art keywords
group
general formula
compounds
optionally
preparation
Prior art date
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PCT/DE2008/001528
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German (de)
English (en)
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WO2009030224A3 (fr
Inventor
Hans Scheefers
Original Assignee
Schebo Biotech Ag
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Filing date
Publication date
Priority claimed from DE200810012435 external-priority patent/DE102008012435A1/de
Application filed by Schebo Biotech Ag filed Critical Schebo Biotech Ag
Publication of WO2009030224A2 publication Critical patent/WO2009030224A2/fr
Publication of WO2009030224A3 publication Critical patent/WO2009030224A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen 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
    • C07D401/02—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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • the present patent application relates to novel pharmaceuticals, for example based on novel substituted quinazolines, processes for their preparation and their use in therapy, for example in the treatment of cancer.
  • Cancers are still a common cause of death for people in industrialized countries. In Germany alone, about 395,000 new cancers are diagnosed each year. The cure rate is 30-60%. Despite a number of known drugs for the treatment of cancer, there are a number of tumors that do not respond to therapeutics. In addition, the known therapies are characterized by a variety of side effects.
  • R 1 and R 2 independently of one another represent a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, a nitro group or an optionally C 1-3 -hydroxy, halogen or C 1 -C 6 -alkoxy-substituted (C 1 -C 4) -alkyl group, which may be interrupted one or more times by oxygen, nitrogen or sulfur atoms or by carbonyl or sulfonyl groups or by aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring systems, which may be unbranched or branched and optionally also a or may be polyunsaturated,
  • Sulfonyl groups or by aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring systems may be interrupted, which may be unbranched or branched and which may optionally also be mono- or polyunsaturated,
  • an optionally 1-3-fold hydroxy, halogen or C 1 -C 5 -alkoxy-substituted (C 1 -C 10) -alkylthio group which is mono- or polysubstituted by oxygen, nitrogen or sulfur atoms or by carbonyl or sulfonyl groups or by aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring systems may be interrupted, which may be unbranched or branched and which may optionally also be mono- or polyunsaturated,
  • a (C 1 -C 5 ) -perfluoroalkyl group which may be unbranched or branched and which may optionally also be mono- or polyunsaturated,
  • R 3 and R 4 independently of one another represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, a CF 3 group or a C 1 -C 4 -alkyl group, which may be unbranched or branched, or
  • R 5 is an aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring system, which may be fused with 1 or 2 further aliphatic or aromatic 5-7 ring atoms containing homo- or heterocyclic ring systems, and which one or more times with a halogen atom, a cyano group, a nitro group or a C- ⁇ -C 4 alkyl group, or a CiC 4 alkoxyl group, a C 2 -C 4 alkynyl group may be substituted 2 -C 4 alkenyl group of C, which is branched or unbranched and optionally also one or may be polyunsaturated with the C- ⁇ -C 4 alkyl group, the Cr
  • C 4 alkoxy group the C 2 -C 4 alkenyl group or the C 2 -C 4 alkynyl group is in turn substituted by phenyl groups or halogenated phenyl groups,
  • R 6 denotes hydrogen or a branched or unbranched C 1 -C 4 -alkyl group
  • This finding is based on the compounds described in this document.
  • the compounds of general formula I according to the invention are novel substituted linear quinazolines.
  • the radicals R 1 and R 2 are chains which may contain cyclic units.
  • the chains in R 1 and R 2 may in particular contain terminal N-containing aliphatic rings, such as piperidine or morpholine.
  • one of the two radicals R 1 and R 2 is a
  • the optional radicals R 3 and R 4 are preferably hydrogen, fluorine or CH 3 or CF 3 groups.
  • the radical R 5 is preferably a substituted aromatic, for example a phenyl group with halogen substituents, or a substituted heteroaromatic, for example a substituted indole group.
  • a substituent of the aromatic or heteroaromatic also another (in turn substituted) phenyl group comes into question, which is linked via a short alkyl or Oxyalkylkette.
  • the linker L represents an ether, ester, amine, amide, carbonyl or hydroxamate group.
  • the compounds of the invention may exist as stereoisomers due to the presence of asymmetric centers.
  • the present invention relates to all possible stereoisomers both as racemates, as well as in enantiomerically pure form.
  • stereoisomers also includes all possible ones Diastereomers and regioisomers and tautomers (eg keto-enol tautomers) in which the compounds according to the invention can be present, which are therefore also the subject of the invention.
  • radicals R 1 and R 2 are shown below and in FIGS. 1 and 2.
  • radicals R 5 are shown below and in FIG. 3:
  • the compounds of general formula I are suitable as medicaments. They are particularly suitable for the treatment of cancer. They are particularly useful for the treatment of hematological or solid tumors, e.g. non-Hodgkin's tumors, or of T-cell lymphnomata.
  • the effect of the compounds according to the invention as cancer therapeutics may possibly be due to their suitability for the inhibition of tyrosine kinase.
  • IC ⁇ o values in 25 different cell culture lines were generally between 4 and 40 ⁇ M.
  • Outstanding selectivity was found in small cell lung carcinoma (LXFS650), followed by renal carcinoma (RXF 1393).
  • the invention therefore teaches the use of a compound of the invention for the preparation of a pharmaceutical composition for the treatment of one or more diseases selected from the group consisting of cancer such as lung cancer, leukemia, ovarian cancer, sarcoma, meningioma, colorectal cancer, lymph node cancer, brain tumors, breast cancer, pancreatic cancer, prostate cancer , Skin cancer, gastric and esophageal cancer, T-cell lymphoma, CTLC, but also chronic inflammation, asthma, allergy, rhinitis, uveitis, urticaria, arthritis, osteoarthritis, chronic polyarthritis, rheumatoid arthritis, inflammatory bowel disease, degenerative joint disease, diseases of the Cartilage, sepsis, autoimmune diseases, type I diabetes, Hashimoto's thyroiditis, autoimmune thrombocytopenia, multiple sclerosis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, uveitis, psoriasis,
  • the present invention teaches a pharmaceutical composition containing at least one compound of the invention.
  • one or more physiologically acceptable excipients and / or carriers may be mixed with the compound and the mixture galenically prepared for local or systemic administration, especially orally, parenterally, for infusion, for injection.
  • the choice of additives and / or adjuvants will depend on the chosen dosage form.
  • the galenic preparation of the pharmaceutical composition according to the invention is carried out in the usual way.
  • Free carboxylic acid groups may also be present in the form of their salts with physiologically acceptable counterions such as Mg ++ , Ca ++ , Na + , K + , Li + or ammonium derivatives such as cyclohexylammonium.
  • Amino-containing compounds may also be present in the form of an ammonium salt, for example as chloride, bromide, mesylate, tosylate, oxalate, orotate, maleate, fumarate or tartrate.
  • Suitable solid or liquid pharmaceutical preparation forms are, for example, granules, powders, dragees, tablets, microcapsules, suppositories, syrups, juices, suspensions, emulsions, drops or solutions for injection (iV, ip, im, sc) or nebulization (aerosols), preparation forms for Dry powder inhalation, transdermal systems as well as preparations with sustained-release release, in the production of which conventional auxiliaries such as carriers, blasting agents, binders, coating substances, swelling or lubricants, flavorings, sweeteners and solubilizers are used.
  • excipients which may be mentioned are magnesium carbonate, titanium dioxide, lactose, manid and other sugars, tal
  • a pharmaceutical composition according to the invention can be prepared by virtue of the fact that at least one substance combination used according to the invention in a defined dose with a pharmaceutically suitable and physiologically tolerated carrier and optionally further suitable active ingredients, additives or Excipients mixed with a defined dose and prepared for the desired dosage form.
  • Suitable diluents are polyglycols, ethanol, water and buffer solutions.
  • Suitable buffer substances are, for example, N, N-dibenzylethylenediamine, diethanolamine, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, diethylamine, phosphate, sodium bicarbonate and sodium carbonate.
  • N, N-dibenzylethylenediamine, diethanolamine ethylenediamine, N-methylglucamine
  • N-benzylphenethylamine diethylamine
  • phosphate sodium bicarbonate and sodium carbonate.
  • the pharmaceutical composition is prepared and administered in dosage units, each unit containing as active ingredient a defined dose of the compound of formula I according to the invention.
  • this dose may be from 0.1 to 1000 mg, preferably from 10 to 50 mg, and in the case of injection solutions in the form of ampoules from 0.01 to 1000 mg, preferably from 10 to 40 mg.
  • the preparation of infusion solutions is another preferred embodiment.
  • daily doses for the treatment of an adult, patients weighing 50-100 kg, for example 70 kg, daily doses of 0.1-1,000 mg active ingredient, preferably 10 -50 mg, are indicated. However, higher or lower daily doses may be appropriate.
  • the administration of the daily dose can be achieved by single administration in the form of a single dose
  • Dosage unit or more smaller dosage units as well as by multiple subdivided doses can be done at specific intervals.
  • the preparations according to the invention can be prepared, for example, as follows:
  • 1 drag core contains:
  • the active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half of the stated amount of magnesium stearate.
  • a tableting machine compacts are produced with a diameter of about 13 mm, these are ground on a suitable machine through a sieve with 1, 5 mm mesh size and mixed with the remaining amount of magnesium stearate. This granulate is pressed on a tabletting machine into tablets of the desired shape.
  • Core weight 230 mg
  • the coated dragee cores are coated with a film consisting essentially of hydroxypropylmethylcellulose.
  • the finished film dragees are shined with beeswax. Dragee weight: 245 mg.
  • Composition 1 tablet contains: • Active substance 100.0 mg
  • Active ingredient, lactose and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After screening the wet mass (2.0 mm mesh size) and dried in a rack-type drier at 5O 0 C is sieved again (1, 5 mm mesh size) and the lubricant mixed. The ready-to-use mixture is processed into tablets.
  • 1 tablet contains:
  • the active substance mixed with milk sugar, corn starch and silica is moistened with a 20% strength aqueous solution of polyvinylpyrrolidone and beaten through a sieve of 1.5 mm mesh size.
  • Hard gelatine capsules (with 150 mg active substance)
  • 1 capsule contains:
  • the active ingredient is mixed with the excipients, passed through a sieve of 0.75 mm mesh size and mixed homogeneously in a suitable device.
  • the final mixture is filled into size 1 hard gelatin capsules. Capsule filling: approx. 320 mg
  • Suppositories (with 150 mg active substance) 1 suppository contains:
  • the active ingredient is distributed homogeneously therein and the melt is poured into pre-cooled molds.
  • Suspension (with 50 mg active substance) 100 ml suspension contain:
  • Dest. Water is heated to 70 0 C.
  • p-hydroxybenzoic acid methyl ester and propyl ester and also glycerol and carboxymethylcellulose sodium salt are dissolved with stirring. It is cooled to room temperature and added with stirring, the active ingredient and dispersed homogeneously. After adding and loosening the Sugar, the sorbitol solution and the aroma, the suspension is evacuated to vent with stirring.
  • 5 ml of suspension contain 50 mg of active ingredient.
  • the active substance is dissolved in the required amount of 0.01 N HCl, isotonic with saline, sterile filtered and filled into 2 ml ampoules.
  • compounds according to the invention can be combined with other active substances known per se.
  • active substances known per se.
  • the compound according to the invention can be mixed with the active substance in the context of a single galenic preparation.
  • the pharmaceutical composition consists of two (or more) different galenic preparations, wherein in a first preparation the compound according to the invention and in a second preparation of the active ingredient are included.
  • first preparation it is also possible to set up a substance which is different from the active ingredient of the second preparation.
  • the further compounds of the general formula I according to the invention are prepared by the methods of organic chemistry known to those skilled in the art, the introduction of the C-O-N-C group preferably (but not exclusively) by reaction with tert-butyl-dimethylsilylhydroxylamine (or its analogs).
  • Cultured human tumor cells for example, hormone-independent human mammary carcinoma cells, MCF7, human non-small cell lung carcinoma cells, e.g. DU145, hormone independent human prostate carcinoma cells, e.g. ATCC HTB-81 or MaTu-MDR can be prepared at a density of approximately 5,000 cells per measurement point in 96-well multi-well plates in 200 ⁇ l of the appropriate growth medium. After 24 hours, the cells of one plate can be stained with crystal violet while replacing the medium of the other plates with fresh culture medium to which the test substances are added at various concentrations (0 ⁇ mol and in the range 0.01-30 ⁇ mol). The cells can then be incubated for four days in the presence of the test substances. Cell proliferation can be determined by staining the cells with crystal violet.
  • the optimal starting cell count per well for each cell line was determined for an ideal measurement of the optical density.
  • correlation curves between the OD and the underlying cell number were generated for each cell line.
  • the optimal time of substance addition and culture time was determined for each cell line (see implementation).
  • the OD in the ELISA reader (620 nm reference wavelength) was measured at a wavelength of 450 nm.
  • MCF-7 human breast cancer cell line
  • MDA-MB-453 human breast cancer cell line
  • HT 29 human colon carcinoma cell line
  • BxPC-3 human pancreatic tumor cell line
  • KB-V1 multidrug-resistant derivative of HeLa cells
  • KBV600 internal name: KB-V1, cultured with 600 ng / ml vinblastine
  • KBVO internal name
  • KB-V1 without Virnblastin
  • Wl 38 human, fetal fibroblast-like cell line of the lung
  • NK Novikoff rat hepatoma cell line
  • R 6 is hydrogen or a branched or unbranched C 1 -C 4 - alkyl group
  • R 7 represents a halogen atom, a cyano group, a nitro group, a CF 3 or a -C 2 F 5 group
  • R 8 represents a halogen atom (preferably fluorine or chlorine), a cyano group, a hydroxy group, a C 1 -C 4 alkoxy group, a nitro group, a CF 3 or a C 1 -C 5 group,
  • Z is independently a direct bond or an oxygen atom, with the proviso that at least one Z for a
  • Oxygen atom is preferably, exactly Z is an oxygen atom
  • E is a nitrogen atom, which may also be present as N-oxide (N ⁇ -O ⁇ ),
  • E 2 is a carbon atom or a nitrogen atom, which may also be present as N-oxide (N ⁇ -O ⁇ ),
  • Z N independently represents a direct bond or a
  • R 6 has the abovementioned meaning
  • n is an integer from zero to four, e.g. for zero, one, two, three or four
  • n is an integer from zero to six, e.g. for zero, one, two, three, four, five or six
  • a p in the formula XLVIII has the same meaning as the group A in WO 03/011872 (PCT / US 02/23909)
  • D p in the formula XLVIII has the same meaning as the group D in WO 03/011872 (PCT / US 02/23909)
  • E p in the formula XLVIII has the same meaning as the group E in WO 03/011872 (PCT / US 02/23909)
  • W p in the formula XLVIII has the same meaning as the group W in WO 03/011872 (PCT / US 02/23909)
  • Y p in the formula XLVIII has the same meaning as the group Y in WO 03/011872 (PCT / US 02/23909) Quite surprisingly, the compounds of the alternative embodiments are effective in particular in the following indications:
  • Bipolar disorder especially schizophrenia, mania, XXIII depressive phases
  • HAE Hereditary Angioedema
  • the possible formulations, dosages, methods of preparation and proofs of action described for the compounds of the general formula I above correspond to those of the u.g. alternative embodiments.
  • the preparation of the compounds of the general formulas LI and LII is carried out by customary methods by solid-phase synthesis (fmoc strategy) on Merrifield resins using modified proteins (in particular modified arginine building blocks).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux produits pharmaceutiques, des procédés pour les produire et leur utilisation en thérapie médicale, notamment pour traiter le cancer.
PCT/DE2008/001528 2007-09-07 2008-09-08 Nouveaux produits pharmaceutiques, procédés pour les produire et leur utilisation en thérapie médicale WO2009030224A2 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
DE102007044564 2007-09-07
DE102007044564.6 2007-09-07
DE200810012435 DE102008012435A1 (de) 2008-02-29 2008-02-29 Neue Pharmazeutika, Verfahren zu ihrer Herstellung und ihre Verwendung in der Therapie
DE102008012435.4 2008-02-29
DE102008045244.0 2008-08-29
DE102008045244 2008-08-29

Publications (2)

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WO2009030224A2 true WO2009030224A2 (fr) 2009-03-12
WO2009030224A3 WO2009030224A3 (fr) 2009-08-13

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102009019852A1 (de) 2009-05-06 2010-11-11 Schebo Biotech Ag Polymere mit neuen Strukturelementen, Verfahren zu ihrer Herstellung und ihre Verwendung
WO2012028578A1 (fr) 2010-09-03 2012-03-08 Bayer Cropscience Ag Pyrimidinones et dihydropyrimidinones annelées substituées
JP2016510000A (ja) * 2013-02-20 2016-04-04 カラ ファーマシューティカルズ インコーポレイテッド 治療用化合物およびその使用
US9353122B2 (en) 2013-02-15 2016-05-31 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9688688B2 (en) 2013-02-20 2017-06-27 Kala Pharmaceuticals, Inc. Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof
US9790232B2 (en) 2013-11-01 2017-10-17 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US9890173B2 (en) 2013-11-01 2018-02-13 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
CN107840843A (zh) * 2017-10-17 2018-03-27 浙江工业大学义乌科学技术研究院有限公司 一种西地尼布中间体的合成方法
US10253036B2 (en) 2016-09-08 2019-04-09 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
WO2019071351A1 (fr) * 2017-10-12 2019-04-18 Trillium Therapeutics Inc. Nouveaux dérivés de 4-aryloxyquinazoline fluorés utilisés en tant qu'inhibiteurs d'egfr utiles pour le traitement de cancers
US10336767B2 (en) 2016-09-08 2019-07-02 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10766907B2 (en) 2016-09-08 2020-09-08 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof

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EP1553097A1 (fr) * 1999-02-10 2005-07-13 AstraZeneca AB Derives de quinazoline utilises comme inhibiteurs de l'angiogenese et produits intermediares
WO2001012604A1 (fr) * 1999-08-18 2001-02-22 Aventis Cropscience Gmbh Fongicides
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Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102009019852A1 (de) 2009-05-06 2010-11-11 Schebo Biotech Ag Polymere mit neuen Strukturelementen, Verfahren zu ihrer Herstellung und ihre Verwendung
WO2012028578A1 (fr) 2010-09-03 2012-03-08 Bayer Cropscience Ag Pyrimidinones et dihydropyrimidinones annelées substituées
US9006265B2 (en) 2010-09-03 2015-04-14 Bayer Intellectual Property Gmbh Substituted fused pyrimidinones and dihydropyrimidinones
US9827248B2 (en) 2013-02-15 2017-11-28 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9353122B2 (en) 2013-02-15 2016-05-31 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US10398703B2 (en) 2013-02-15 2019-09-03 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US10966987B2 (en) 2013-02-15 2021-04-06 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9877970B2 (en) 2013-02-15 2018-01-30 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9861634B2 (en) 2013-02-20 2018-01-09 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9833453B2 (en) 2013-02-20 2017-12-05 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US10285991B2 (en) 2013-02-20 2019-05-14 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US11369611B2 (en) 2013-02-20 2022-06-28 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9688688B2 (en) 2013-02-20 2017-06-27 Kala Pharmaceuticals, Inc. Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof
JP2021006574A (ja) * 2013-02-20 2021-01-21 カラ ファーマシューティカルズ インコーポレイテッド 治療用化合物およびその使用
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