WO2010130224A1 - 噻吩衍生物 - Google Patents
噻吩衍生物 Download PDFInfo
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- WO2010130224A1 WO2010130224A1 PCT/CN2010/072767 CN2010072767W WO2010130224A1 WO 2010130224 A1 WO2010130224 A1 WO 2010130224A1 CN 2010072767 W CN2010072767 W CN 2010072767W WO 2010130224 A1 WO2010130224 A1 WO 2010130224A1
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- optionally substituted
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- ethyl
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- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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Definitions
- TNFa is a cytokine that is released primarily by mononuclear phage cells in response to immunostimulants. TNFa promotes most processes such as cell differentiation, recruitment, proliferation, and protein degradation. At low levels, TNFa has a protective effect against infectious agents, tumors and tissue damage. However, excessive release of TNFa can also cause disease, such as when administered to a mammal or human TNFa, causing or aggravating inflammation, fever, cardiovascular effects, bleeding, coagulation, and acute reactions similar to acute infections and shock states.
- TNFa production in animals or humans is often indicated by the following diseases: endotoxemia and / or toxic shock syndrome, cachexia, adult respiratory syndrome, cancer (such as solid tumors and hematological tumors) ), heart disease (such as congestive heart failure), viral infection, genetic disease, inflammatory disease, allergic disease or autoimmune disease.
- Cancer is a particularly devastating disease, and an increase in the level of TNFa in the blood is predictive of a risk of cancer or cancer spread.
- cancer cells cannot survive in the circulatory system of healthy subjects.
- One reason is that the inner wall of blood vessels is a barrier to extravasation of tumor cells.
- ELAM-1 on endothelial cells mediates the adhesion of colon cancer cells to the endothelium treated with cytokines.
- Cyclic adenosine monophosphate also plays a role in many diseases and conditions such as, but not limited to, asthma, inflammation, and other conditions. Increased cAMP concentration in leukocytes during inflammation inhibits activation of leukocytes, followed by release of inflammatory regulatory factors including TNFa and NF- ⁇ . Increased levels of cAMP also cause relaxation of the smooth muscles of the airways.
- PDEs cyclic nucleotide phosphodiesterases
- Inhibition of PDE4 enzyme leads to an increase in cAMP levels, thereby modulating TNFa levels, such as septic shock, sepsis, endotoxic shock, hemorrhagic shock, sepsis syndrome, post-ischemic reperfusion injury, malaria Mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic disease, cachexia, transplant rejection, cancer, autoimmune disorders, AIDS opportunistic infections, rheumatoid arthritis, rheumatic rotitis, osteoarthritis, Other inflammatory diseases, Crohn's disease, ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, leprosy Inflammation, infectious diseases, immune diseases or other malignant diseases such as nodular erythema, radiation damage, and hyperoxia-induced lung injury.
- TNFa levels such as septic shock, sepsis, endotoxic shock, hemorrhagic shock, seps
- PDE4 enzyme inhibitors are clinically effective against several inflammatory diseases, including asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, and allergic dermatitis. It is also effective in animal models for a variety of other diseases including arthritis and sepsis, but both have adverse reactions such as nausea and vomiting due to the inability to specifically inhibit PDE4 enzymes, which limits their clinical application. Therefore, specific PDE4 enzyme inhibitors have the potential to reduce adverse drug reactions and maintain the anti-inflammatory activity of the drug. Overview
- the present application relates to a compound of formula (I), a stereoisomer, enantiomer or tautomer thereof, or a mixture of stereoisomers, a pharmaceutically acceptable salt thereof, polymorph thereof
- R 1 and R 2 are each independently selected from the group consisting of hydrogen, a hydrazine, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, a hydroxyl group, a cyano group, a nitro group or an optionally substituted NR 6 R 7 ;
- R 3 is selected from a hydroxyl group, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally substituted hydrocarbon group (alkylene)oxy group, an optionally substituted aryl group, an optionally substituted aryl (alkylene)oxy group or an optionally substituted group.
- NR 6 R 7 is selected from a hydroxyl group, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally substituted hydrocarbon group (alkylene)oxy group, an optionally substituted aryl group, an optionally substituted aryl (alkylene)oxy group or an optionally substituted group.
- R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted hydrocarbyloxy, optionally substituted hydrocarbylthio, cyano, optionally substituted cycloalkyl, optionally substituted ((alkylene)cycloalkyl And optionally substituted cycloalkyl (alkylene)oxy, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted aryl(alkylene)oxy;
- R 6 and R 7 are each independently selected from hydrogen, an optionally substituted hydrocarbon group, an optionally substituted aryl group, an optionally substituted C(0)R 8 or an optionally substituted SO 2 R 8 , or R 6 and R 7 together represent an arbitrary substitution.
- R 8 is selected from hydrogen or an optionally substituted hydrocarbon group.
- the present application is directed to a process for the preparation of a compound of formula (I), the process comprising: , ',::
- R 1 and R 2 are each independently selected from the group consisting of hydrogen, a hydrazine, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, a hydroxyl group, a cyano group, a nitro group or an optionally substituted NR 6 R 7 ;
- R 3 is selected from a hydroxyl group, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally substituted hydrocarbon group (alkylene)oxy group, an optionally substituted aryl group, an optionally substituted aryl (alkylene)oxy group or an optionally substituted group.
- NR 6 R 7 is selected from a hydroxyl group, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally substituted hydrocarbon group (alkylene)oxy group, an optionally substituted aryl group, an optionally substituted aryl (alkylene)oxy group or an optionally substituted group.
- R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted hydrocarbyloxy, optionally substituted hydrocarbylthio, cyano, optionally substituted cycloalkyl, optionally substituted ((alkylene)cycloalkyl And optionally substituted cycloalkyl (alkylene)oxy, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted aryl(alkylene)oxy;
- R 6 and R 7 are each independently selected from hydrogen, an optionally substituted hydrocarbon group, an optionally substituted aryl group, an optionally substituted C(0)R 8 or an optionally substituted SO 2 R 8 , or R 6 and R 7 together represent an arbitrary substitution.
- R 8 is selected from hydrogen or an optionally substituted hydrocarbon group
- the present application relates to a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier And a therapeutically effective amount of a compound of the formula (I), a stereoisomer, an enantiomer or a tautomer thereof, or a mixture of stereoisomers, a pharmaceutically acceptable salt thereof, a polymorph thereof a solvate thereof, a prodrug thereof or a metabolite thereof,
- R 1 and R 2 are each independently selected from the group consisting of hydrogen, a hydrazine, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, a hydroxyl group, a cyano group, a nitro group or an optionally substituted NR 6 R 7 ;
- R 3 is selected from a hydroxyl group, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally substituted hydrocarbon group (alkylene)oxy group, an optionally substituted aryl group, an optionally substituted aryl (alkylene)oxy group or an optionally substituted group.
- NR 6 R 7 is selected from a hydroxyl group, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally substituted hydrocarbon group (alkylene)oxy group, an optionally substituted aryl group, an optionally substituted aryl (alkylene)oxy group or an optionally substituted group.
- R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted hydrocarbyloxy, optionally substituted hydrocarbylthio, cyano, optionally substituted cycloalkyl, optionally substituted ((alkylene)cycloalkyl And optionally substituted cycloalkyl (alkylene)oxy, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted aryl(alkylene)oxy;
- R 6 and R 7 are each independently selected from hydrogen, an optionally substituted hydrocarbon group, an optionally substituted aryl group, an optionally substituted C(0)R 8 or an optionally substituted SO 2 R 8 , or R 6 and R 7 together represent an arbitrary substitution.
- R 8 is selected from hydrogen or an optionally substituted hydrocarbon group.
- the application relates to a method of reducing the activity of a PDE4 enzyme, the method comprising administering a therapeutically effective amount of a compound of formula (I), a stereoisomer, an enantiomer or a tautomer thereof, or a stereo a mixture of isomers, a pharmaceutically acceptable salt thereof, a polymorph thereof, a solvate thereof, a prodrug thereof, or a metabolite thereof, is contacted with a PDE4 enzyme,
- R 1 and R 2 are each independently selected from the group consisting of hydrogen, a hydrazine, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, a hydroxyl group, a cyano group, a nitro group or an optionally substituted NR 6 R 7 ;
- R 3 is selected from a hydroxyl group, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally substituted hydrocarbon group (alkylene)oxy group, an optionally substituted aryl group, an optionally substituted aryl (alkylene)oxy group or an optionally substituted group.
- NR 6 R 7 is selected from a hydroxyl group, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally substituted hydrocarbon group (alkylene)oxy group, an optionally substituted aryl group, an optionally substituted aryl (alkylene)oxy group or an optionally substituted group.
- R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted hydrocarbyloxy, optionally substituted hydrocarbylthio, cyano, optionally substituted cycloalkyl, optionally substituted ((alkylene)cycloalkyl And optionally substituted cycloalkyl (alkylene)oxy, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted aryl(alkylene)oxy;
- R 6 and R 7 are each independently selected from hydrogen, an optionally substituted hydrocarbon group, an optionally substituted aryl group, an optionally substituted C(0)R 8 or an optionally substituted SO 2 R 8 , or R 6 and R 7 together represent an arbitrary substitution.
- R 8 is selected from hydrogen or an optionally substituted hydrocarbon group.
- the present application relates to a method of treating a PDE4 enzyme mediated disease or condition comprising administering to a subject in need of such a method a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, a pair Or a tautomer, or a mixture of stereoisomers, a pharmaceutically acceptable salt thereof, a polymorph thereof, a solvate thereof, a prodrug thereof or a metabolite thereof,
- R 1 and R 2 are each independently selected from the group consisting of hydrogen, a hydrazine, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, a hydroxyl group, a cyano group, a nitro group or an optionally substituted NR 6 R 7 ;
- R 3 is selected from a hydroxyl group, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally substituted hydrocarbon group (alkylene)oxy group, an optionally substituted aryl group, an optionally substituted aryl (alkylene)oxy group or an optionally substituted group.
- NR 6 R 7 is selected from a hydroxyl group, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally substituted hydrocarbon group (alkylene)oxy group, an optionally substituted aryl group, an optionally substituted aryl (alkylene)oxy group or an optionally substituted group.
- R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted hydrocarbyloxy, optionally substituted hydrocarbylthio, cyano, optionally substituted cycloalkyl, optionally substituted ((alkylene)cycloalkyl And optionally substituted cycloalkyl (alkylene)oxy, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted aryl(alkylene)oxy;
- R 6 and R 7 are each independently selected from hydrogen, an optionally substituted hydrocarbon group, an optionally substituted aryl group, an optionally substituted C(0)R 8 or an optionally substituted SO 2 R 8 , or R 6 and R 7 together represent an arbitrary substitution.
- R 8 is selected from hydrogen or an optionally substituted hydrocarbon group.
- C 7 -C 12 alkyl describes an alkyl group as defined below having a total of from 7 to 12 carbon atoms
- a C 4 -C 12 cycloalkylalkyl group is as defined below having a total of from 4 to 12 carbon atoms.
- Cycloalkylalkyl The total number of carbon atoms in the barrel symbol does not include carbon that may be present in the substituents of the group.
- Haldroxy means an -OH group.
- Cyano refers to the -CN group.
- Niro means a ⁇ 2 2 group.
- hydrocarbyl refers to an aliphatic hydrocarbon group.
- the hydrocarbyl moiety can be
- a “saturated alkyl” group means that it does not contain any alkene or alkyne moiety.
- the hydrocarbyl moiety may also be an "unsaturated alkyl” moiety, meaning that it contains at least one alkene or alkyne moiety.
- the "alkenyl” moiety refers to a group consisting of two to eight carbon atoms and at least one carbon-carbon double bond, and a straight or branched hydrocarbon chain group, such as a vinyl group, attached to the remainder of the molecule by a single bond.
- alkyne refers to two to eight carbon atoms and at least one a group consisting of a carbon-carbon triple bond, and a linear or branched hydrocarbon chain group bonded to the remainder of the molecule by a single bond.
- the hydrocarbyl moiety whether saturated or unsaturated, may be branched or linear.
- the hydrocarbyl group may have from 1 to 20 carbon atoms (in each occurrence in the present application, a numerical range such as “1 to 20” refers to each integer in a given range; such as “1 to 20”
- the hydrocarbyl group may be from 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms, although this definition also encompasses the occurrence of the term "hydrocarbyl group” in the unspecified range of values.
- the hydrocarbyl group may also be a medium-sized hydrocarbyl group having 1 to 10 carbon atoms.
- the hydrocarbyl group may also be a lower hydrocarbon group having 1 to 5 carbon atoms.
- the hydrocarbyl group of the compound of the present application can be designated as "d-hydrocarbyl” or the like.
- C hydrocarbyl indicates the presence of from 1 to 4 carbon atoms in the hydrocarbyl chain, ie the hydrocarbyl chain is selected from the group consisting of decyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl Base or tert-butyl.
- the hydrocarbyl group can be optionally substituted, that is, substituted or unsubstituted.
- the substituent group is one or more groups selected individually and independently from the group consisting of: cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, Sulfhydryl, hydrocarbylthio, arylthio, cyano, carbonyl, thiocarbonyl, 0-aminodecanoyl, N-aminodecanoyl, 0-thioaminodecanoyl, N-thioaminodecanoyl, C -Acylamino, N-acylamino, S-azidoamido, N-azidoamido, C-carboxy, 0-carboxyl, isocyanato, isocyanato, isothiocyanato , nitro, silane group, trihalodecanesulfonyl
- Group includes, but is not limited to, mercapto, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, vinyl, propenyl, butenyl, cyclopropyl, cyclobutane a group, a cyclopentyl group, a cyclohexyl group, etc.
- the substituent may be One of the substituents described below.
- d-hydrocarbyl means a hydrocarbyl group as defined above containing one to four carbon atoms.
- the c r c 4 hydrocarbyl group may be optionally substituted as defined for the hydrocarbyl group.
- C C6 hydrocarbyl means a hydrocarbyl group as defined above containing one to six carbon atoms.
- the cc 6 hydrocarbyl group can be optionally substituted as defined for the hydrocarbyl group.
- c r c 12 hydrocarbyl means a hydrocarbyl group as defined above containing one to twelve carbon atoms.
- the CC 12 hydrocarbyl group can be optionally substituted as defined for the hydrocarbyl group.
- C 2 -C 6 hydrocarbyl refers to a hydrocarbyl group as defined above containing two to six carbon atoms.
- the C 2 -C 6 hydrocarbyl group can be optionally substituted as defined for the hydrocarbyl group.
- the "c 3 -c 6 hydrocarbyl group” means a hydrocarbon group as defined above containing three to six carbon atoms.
- the c 3 -c 6 hydrocarbyl group may be optionally substituted as defined for the hydrocarbyl group.
- C 3 -C 12 hydrocarbon group means as defined above containing three to twelve carbon atoms.
- the c 3 -c 12 hydrocarbyl group may be optionally substituted as defined for the hydrocarbyl group.
- C 6 -c 12 hydrocarbyl means a hydrocarbyl group as defined above containing six to twelve carbon atoms.
- the c 6 -c 12 hydrocarbyl group may be optionally substituted as defined for the hydrocarbyl group.
- C 7 -c 12 hydrocarbyl means a hydrocarbyl group as defined above containing seven to twelve carbon atoms.
- the C 7 -C 12 hydrocarbyl group can be optionally substituted as defined for the hydrocarbyl group.
- hydrocarbyloxy refers to the formula -OR, wherein R is a hydrocarbyl group as defined above, such as decyloxy, ethoxy, n-propoxy, 1-decylethoxy (isopropyl) Oxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, tert-pentyloxy and the like.
- hydrocarbylthio refers to the formula -SR, wherein R is a hydrocarbyl group as defined above, such as sulfonylthio, ethylthio, n-propylthio, 1-decylethylthio (isopropyl) Sulfuryl), n-butylthio, isobutylthiol, sec-butylthio, tert-butylthio and the like.
- alkylene refers to a straight or branched divalent hydrocarbon chain consisting of only carbon and hydrogen and having from one to eight carbon atoms, linking the remainder of the molecule to the residue group, such as an anthracenylene group. , ethylene, propylene, n-butylene, vinylidene, propenylene, n-butenylene.
- the alkylene chain can be attached to the remainder of the molecule and to the residue group via one carbon in the chain or through any two carbons in the chain.
- aryl refers to a carbocyclic ring (all carbon) having a fully delocalized ⁇ -electron system or two or more fused rings (a ring sharing two adjacent carbon atoms).
- aryl groups include, but are not limited to, anthracenyl, phenyl, and naphthyl.
- the aryl group may have, for example, five to twelve carbon atoms.
- the aryl group of the present application may be substituted or unsubstituted.
- the hydrogen atom is substituted by one or more groups independently selected from the group consisting of: hydrocarbyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, protected hydroxy, alkoxy , aryloxy, fluorenyl, hydrocarbylthio, arylthio, cyano, carbonyl, thiocarbonyl, 0-aminodecanoyl, hydrazine-aminodecanoyl, 0-thioaminodecanoyl, hydrazine-sulfur Aminoguanidino, C-acylamino, oxime-amido, S-sulfonamido, oxime-sulfonamido, C-carboxy, protected C-carboxy, 0-carboxy, isocyanato, cyanide Sulfur, isothiocyanato, nitro, silyl, trioxosulfonyl, -NR'
- halogen as used herein, means bromo, chloro, fluoro or iodo.
- Cycloalkyl means a group consisting of only carbon and hydrogen atoms, having three to fifteen carbon atoms, preferably having three to twelve carbon atoms, and which are saturated or unsaturated, and which are bonded through a single bond The remainder of the linkage is a stable non-aromatic monocyclic or bicyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclodecyl and the like.
- cycloalkyl is intended to include a cyclic hydrocarbon group as defined above optionally substituted by one or more groups selected from the group consisting of cycloalkyl, aryl, heteroaryl, Heteroalicyclic, hydroxy, alkoxy, aryloxy, fluorenyl, thiol, arylthio, cyano, halo, carbonyl, thiocarbonyl, 0-aminodecanoyl, N-aminodecanoyl, 0 -thioaminodecanoyl, N-thioaminodecanoyl, C-acylamino, N-acylamino, S-lamidoamido, N-sulfonamido, C-carboxy, 0-carboxy, isocyanate Combination, thiocyano, isothiocyanate, nitro, silane group, tertiary decanesulfonyl,
- c 3 -c 6 cycloalkyl group means a cycloalkyl group as defined above having three to six carbon atoms.
- the C 3 -C 6 cycloalkyl group may be optionally substituted as defined for the above cyclic hydrocarbon group.
- C 3 -C 1 () cycloalkyl group means a cycloalkyl group as defined above having three to ten carbon atoms.
- the c 3 -c 1() cycloalkyl group may be optionally substituted as defined for the above cyclic hydrocarbon group.
- C 3 -C 12 cycloalkyl group means a cycloalkyl group as defined above having three to twelve carbon atoms.
- the c 3 -c 12 cycloalkyl group may be optionally substituted as defined for the above cyclic hydrocarbon group.
- heterocycloalkyl refers to a stable three to twelve membered non-aromatic ring group consisting of a carbon atom and one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
- heterocyclyl groups include, but are not limited to, dioxocyclopentyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, VIII Hydroquinone, octahydroisodecyl, 2-oxopiperrazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4 -piperidone, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuranyl, trithiaal
- heterocycloalkyl is intended to include the above-defined cycloalkyl groups optionally substituted by one or more groups selected from the group consisting of cycloalkyl, aryl, heteroaryl.
- heteroalicyclic hydroxy, alkoxy, aryloxy, fluorenyl, thiol, arylthio, cyano, carbonyl, thiocarbonyl, 0-aminodecanoyl, N-aminodecanoyl, 0 -thioaminodecanoyl, N-thioaminodecanoyl, C-amido, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, 0-carboxy, isocyanate , thiocyanato, isothiocyanate, nitro, silane group, trihalodecanesulfonyl, -NR'R" (R, and R" are the hydrocarbyl groups defined in the present application) or include An amino group, and a di-substituted amino group, and a protected derivative thereof.
- Prodrug is intended to mean a compound which can be converted to a biologically active compound for application under physiological conditions or by solvolysis.
- prodrug refers to a metabolically acceptable precursor of a compound of the present application.
- Prodrugs may be inactive when administered to an individual in need of a prodrug, but prodrugs in vivo may be converted to the active compound of the application.
- Prodrugs can generally be rapidly converted in vivo to obtain the parent compound of the present application, for example by hydrolysis in the blood.
- Prodrug compounds generally provide solubility, tissue compatibility or sustained release benefits in mammalian organisms (see Bundgard, ⁇ , Design of Prodrugs (1985), pp. 7-9, 21- 24 (Elsevier, Amsterdam)).
- prodrug is also intended to include any covalently bonded carrier that releases the active compound of the present invention in vivo when the prodrug is administered to a mammalian subject.
- the functional groups present in the compounds of the present invention can be modified in such a manner as to prepare prodrugs of the compounds of the present application such that the parent compound of the present application can be formed using conventional procedures or in vivo to modify the cleavage.
- a prodrug comprising a compound of the present application, wherein a hydroxy, amino or thiol group is bonded to any group, and when a prodrug of a compound of the present application is administered to a mammalian individual, the bonding group is cleaved to form a free Hydroxyl group, free amino group or free sulfhydryl group.
- prodrugs include, but are not limited to, acetates, citrates, and derivatives of benzoates, of the alcohol or amine functional groups in the compounds of the present application, and the like.
- “Arbitrary” or “arbitrarily” means that the condition of the subsequent description may or may not occur, and that the statement includes the occurrence or non-occurrence of the event or condition.
- “optionally substituted aryl” means that the aryl group may or may not be substituted, and the description includes substituted aryl groups and unsubstituted aryl groups.
- “Pharmaceutically acceptable carrier” includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, antiseptic that has been approved by the U.S. Food and Drug Administration for use in humans or animals. Agents, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers, etc., which have no side effects on the composition of the pharmaceutical composition. a.
- “Pharmaceutically acceptable salts” include “pharmaceutically acceptable acid addition salts” and “pharmaceutically acceptable base addition salts”.
- “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free base, which are biologically or otherwise suitable and which are formed using inorganic or organic acids.
- the inorganic acid is, for example but not limited to, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, etc.
- the organic acid is, for example but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, Ascorbic acid, aspartic acid, benzoic acid, benzoic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, citric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, Cyclohexane-amino acid, dodecyl sulfate, ethane-1,2-di-cross-acid,
- “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acid, which are biologically or otherwise suitable. These salts are prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, rhodium, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium and magnesium salts.
- Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, salts of cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, Tridecylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimercaptoethanol, 2-diaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, refined ammonia Acid, histidine, caffeine, procaine, seabamin, choline, betaine, benzylamine, phenethylenediamine, ethylenediamine, glucosamine, decyl glucosamine, theobromine, triethanolamine , tromethamine, hydrazine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, and
- solvate refers to an aggregate comprising one or more molecules of the present invention with one or more solvent molecules.
- the solvent may be water, and in this case, the solvate is a hydrate.
- the solvent may be an organic solvent.
- the compounds of the present invention may exist in the form of hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as in the corresponding solvated forms.
- the compound of the present application may be a true solvate, but in other cases, the compound of the present application may retain only a variable amount of water or the compound is a mixture of water and some indefinite solvent.
- Polymorph means a component having the same chemical formula but having a different structure.
- “Pharmaceutical composition” refers to a formulation of a compound of the present invention and a medium which is generally accepted in the art for delivery of a biologically activating compound to a mammal such as a human.
- Such media include all pharmaceutically acceptable carriers, diluents or excipients.
- “Therapeutically effective amount” means that when administered to a mammal, preferably to a human, the compounds of the present invention are sufficient to effectively treat (as defined below) the amount of a PDE4 enzyme mediated disease or condition in a mammal, preferably a human.
- the amount of the compound of the present application which constitutes a “therapeutically effective amount” will vary depending on the compound, the state of the disease and its severity, and the age of the mammal to be treated, but those skilled in the art will be able to rely on their own knowledge and the present disclosure.
- the formula determines the amount of the compound of the present application.
- treating encompasses a mammal having a related disease or condition, preferably a treatment-related disease or condition in a human, and includes: (i) preventing a disease or condition in a mammal, especially when the mammal is susceptible to the disease state, but has not been diagnosed with the disease state;
- disease and “disease state” may be used interchangeably or may be different, as a particular disease or condition may not have a known causative agent (and therefore cannot be explained by etiology). Therefore, it is not recognized as a disease, but is considered to be an undesired disease state or condition in which the clinician has identified more or less specific series of symptoms.
- the compound of the present application or a pharmaceutically acceptable salt thereof may contain one or more asymmetric centers, and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms, which may be based on absolute stereochemistry. It is defined as (R)- or (S)-, or (D)- or (L)- of the amino acid.
- This application is intended to include all such possible isomers, as well as the racemic and optically pure forms thereof.
- Optically active (+) and (; -), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, Or use conventional techniques for resolution, such as HPLC using a chiral column.
- a compound described herein contains an olefinic double bond or other geometrically asymmetric center, unless otherwise stated, it is meant that the compound includes both E and Z geometric isomers. Again, it is meant to include all tautomeric forms.
- Stepoisomer means a compound composed of the same atoms bonded by the same bond, but having different three-dimensional structures that are not interchangeable. This application covers various stereoisomers and mixtures thereof.
- Tautomer means that electrons move from one atom of a molecule to another atom of the same molecule. This application includes tautomers of any of the above mentioned compounds.
- the present application relates to a compound of the formula (I), a stereoisomer, an enantiomer or a tautomer thereof, or a mixture of stereoisomers, a pharmaceutically acceptable salt thereof, a polymorph thereof , its solvate, its prodrug or its metabolite:
- R 1 and R 2 are each independently selected from the group consisting of hydrogen, a hydrazine, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, a hydroxyl group, a cyano group, a nitro group or an optionally substituted NR 6 R 7 ;
- R 3 is selected from a hydroxyl group, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally substituted hydrocarbon group (alkylene)oxy group, an optionally substituted aryl group, an optionally substituted aryl (alkylene)oxy group or an optionally substituted group.
- NR 6 R 7 is selected from a hydroxyl group, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally substituted hydrocarbon group (alkylene)oxy group, an optionally substituted aryl group, an optionally substituted aryl (alkylene)oxy group or an optionally substituted group.
- R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted hydrocarbyloxy, optionally substituted hydrocarbylthio, cyano, optionally substituted cycloalkyl, optionally substituted ((alkylene)cycloalkyl And optionally substituted cycloalkyl (alkylene)oxy, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted aryl(alkylene)oxy;
- R 6 and R 7 are each independently selected from hydrogen, an optionally substituted hydrocarbon group, an optionally substituted aryl group, an optionally substituted C(0)R 8 or an optionally substituted SO 2 R 8 , or R 6 and R 7 together represent an arbitrary substitution.
- R 8 is selected from hydrogen or an optionally substituted hydrocarbon group.
- the dC 8 hydrocarbyl group is selected from a dC 4 hydrocarbyl group or a dC 6 hydrocarbyl group.
- the cc 8 alkoxy group is selected from the group consisting of cc 4 alkoxy or cc 6 alkoxy.
- C 3 -C 1 () cycloalkyl is selected from C 3 -C 6 cyclic hydrocarbon group.
- R 1 and R 2 are each independently selected from the group consisting of R 1 and R 2 are independently selected from the group consisting of hydrogen, decyl, ethyl, nitro, NH 2 , NHCH 3 , CH 3 C(0)NH or CH 3 CH 2 C(0)NH, CH 3 S0 2 NH or C1CH 2 C(0) Li.
- R 3 is selected from a CC 8 hydrocarbyl group or a CC 8 hydrocarbyloxy group.
- R 3 is selected from the group consisting of dC 8 hydrocarbyl, dC 8 hydrocarbyloxy, dC 8 hydrocarbon A (dC 8 alkylene)oxy group, a C 5 -C 12 aryl group, a C 5 -C 12 aryl (dC 8 alkylene)oxy group. In certain embodiments, R 3 is selected from the group consisting of decyl, ethyl or propyl.
- R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydroxy, C r C 8 hydrocarbyl, halo substituted ( ⁇ -( 8 hydrocarbyl, dC 8 hydrocarbyloxy, dC 8 hydrocarbylthio, cyano, C 3 -C 10 cycloalkyl, (dC 8 alkylene) C 3 -C 1Q cycloalkyl, C 3 -C 1Q cycloalkyl (dC 8 alkylene)oxy,
- R 4 and R 5 are each independently selected from the group consisting of CC 8 alkoxy, halogen substituted C r C 8 alkoxy, C 5 -C 12 aryloxy.
- R 4 and R 5 are each independently selected from the group consisting of a decyloxy group, a difluoromethoxy group, a trifluoromethoxy group, an ethoxy group, a propoxy group, or a benzyloxy group.
- R 8 is selected from the group consisting of hydrogen, C r C 8 hydrocarbyl, halogen substituted C r C 8 hydrocarbyl, (dC 8 hydrocarbyl substituted amino) substituted dC 8 hydrocarbyl or C 3 -C 12 heterocycloalkyl Substituted dC 8 hydrocarbyl group.
- R 8 is selected from the group consisting of hydrogen, decyl, ethyl, dinonylamino fluorenyl, diethylaminoguanidino, piperidinyl fluorenyl, or morphinolinyl fluorenyl.
- the compound of formula (I) is selected from the group consisting of
- the present application is directed to a process for the preparation of a compound of formula (I), the process comprising: , ',::
- R 1 and R 2 are each independently selected from the group consisting of hydrogen, a hydrazine, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, a hydroxyl group, a cyano group, a nitro group or an optionally substituted NR 6 R 7 ;
- R 3 is selected from a hydroxyl group, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally substituted hydrocarbon group (alkylene)oxy group, an optionally substituted aryl group, an optionally substituted aryl (alkylene)oxy group or an optionally substituted group.
- NR 6 R 7 is selected from a hydroxyl group, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally substituted hydrocarbon group (alkylene)oxy group, an optionally substituted aryl group, an optionally substituted aryl (alkylene)oxy group or an optionally substituted group.
- R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted hydrocarbyloxy, optionally substituted hydrocarbylthio, cyano, optionally substituted cycloalkyl, optionally substituted ((alkylene)cycloalkyl And optionally substituted cycloalkyl (alkylene)oxy, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted aryl(alkylene)oxy;
- R 6 and R 7 are each independently selected from hydrogen, an optionally substituted hydrocarbon group, an optionally substituted aryl group, an optionally substituted C(0)R 8 or an optionally substituted SO 2 R 8 , or R 6 and R 7 together represent an arbitrary substitution.
- R 8 is selected from hydrogen or an optionally substituted hydrocarbon group.
- a tertiary amine is added as a catalyst in the process of reacting a compound of the formula (A-IV) with a compound of the formula (A-VII) to give a compound of the formula (I).
- Suitable catalysts include, but are not limited to, pyridine, 4-diguanylidenepyridine, 4-pyrrolidinopyridine, and mixtures of one or more thereof.
- a dehydrating agent may also be added to the process of reacting a compound of the formula (A-IV) with a compound of the formula (A-VII) to give a compound of the formula (I).
- dehydrating agents examples include, but are not limited to, DCC,
- EDC HCL CDI EDC HCL CDI, DIC, diethyl azodicarboxylate, diisopropyl azodicarboxylate, dibenzyl azodicarboxylate and a mixture of one or more thereof.
- an activator may also be added to the method of reacting a compound of the formula (A-IV) with a compound of the formula (A-VII) to give a compound of the formula (I).
- activators include, but are not limited to, N-hydroxysuccinimide, HOBt, HOAt, BOP, Cl-HOBt, DEPBT, HATU, HBTU, HCTU, HOOBt, PyBOP, TATU, TBTU, and One or more mixtures thereof.
- organic solvent examples include, but are not limited to, chloroform, dichlorodecane, dichloroethane, tetrahydrofuran, diethyl ether, diisopropyl ether, ethyl acetate, ethylene glycol dioxime ether, ethylene glycol diethyl ether, benzene, toluene, Hexane, cyclohexane, DMF, DMSO, mercaptoethyl ether, mercaptopropyl ether, mercapto tert-butyl ether, acetone, butanone, decyl decanoate, ethyl decanoate, propyl citrate, Butyl phthalate, decyl acetate, propyl acetate, butyl acetate And a mixture of one or more thereof.
- the compound of the formula ( ⁇ - ⁇ ) is dehydrated to give a compound of the formula (A-IV),
- suitable organic solvents include, but are not limited to, chloroform, dichlorodecane, dichloroethane, tetrahydrofuran, diethyl ether, diisopropyl ether, cyclohexane, n-hexane, ethyl acetate, ethylene glycol.
- Dioxin ethylene glycol diethyl ether, benzene, toluene, DMF, DMSO, acetone, butanone, mercaptoethyl ether, mercapto tert-butyl ether, mercaptopropyl ether, decyl decanoate, citric acid Ethyl ester, propyl citrate, butyl phthalate, decyl acetate, propyl acetate, butyl acetate, acetic acid, trifluoroacetic acid, and a mixture of one or more thereof.
- the compound of formula (A-II) is subjected to an acid or base to give a compound of formula (A-III),
- acids examples include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, trace acid, ethionic acid or a mixture of one or more thereof.
- reaction of the compound of the formula (A-II) under the action of an acid or a base to give a compound of the formula (A-III) is carried out in a solvent.
- solvents examples include, but are not limited to, chloroform, dichlorodecane, dichloroethane, tetrahydrofuran, diethyl ether, diisopropyl ether, cyclohexane, n-hexane, ethyl acetate, ethylene glycol.
- Ether ether ethylene glycol diethyl ether, benzene, toluene, DMF, DMSO, acetone, butanone, mercaptoethyl ether, mercapto tert-butyl ether, mercaptopropyl ether, decyl decanoate, decanoic acid Ester, propyl citrate, butyl phthalate, decyl acetate, propyl acetate, butyl acetate, acetic acid, trifluoroacetic acid, water, and mixtures of one or more thereof.
- the compound of the formula (A-II) can be obtained as a compound of the formula ( ⁇ - ⁇ ) under the action of an acid or a base.
- the compound of the formula (A-II) is subjected to an acid or a base to obtain a compound of the formula ( ⁇ - ⁇ ) under C.
- the compound of the formula (A-II) is subjected to an acid or a base to obtain a compound of the formula ( ⁇ - ⁇ ) under C.
- a compound of formula (A-I) is reacted with cyanide to give a formula
- reaction of the compound of the formula (A-I) with cyanide to give a compound of the formula (A-II) is carried out in an organic solvent.
- suitable organic solvents include, but are not limited to, D MF, DMSO, acetamide, N-decylpyrrolidone, diethylene glycol dioxime ether, diethylene glycol diethyl ether, and a mixture of one or more thereof.
- the compound of formula (A-VI) provides a compound of formula (A-VII) under the action of a deprotecting agent
- deprotecting agents that can be used in the present application include, but are not limited to, tetrabutylammonium fluoride, tetraethylammonium fluoride, hydrochloric acid, sulfuric acid, phosphoric acid And nitric acid, acetic acid, trifluoroacetic acid, decanoic acid, decanoic acid, hexadecanoic acid, benzoic acid, p-toluic acid and a mixture thereof one or more.
- reaction of a compound of formula (A-VI) to a compound of formula (A-VII) under the action of a deprotecting agent is carried out in a solvent.
- solvents examples include, but are not limited to, chloroform, dichlorodecane, dichloroethane, tetrahydrofuran, diethyl ether, diisopropyl ether, ethyl acetate, ethanol, decyl alcohol, propanol, butanol, Ethylene glycol, ethylene glycol dioxime ether, ethylene glycol monoterpene ether, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, benzene, toluene, n-hexane, cyclohexane, DMF, DMSO, acetic acid, trifluoro Acetic acid, mercaptoethyl ether, mercaptopropyl ether, mercapto tert-butyl ether, acetone, butanone, decyl decanoate, ethyl decanoate, propyl
- the compound of the formula (A-VII) is obtained by a compound of the formula (A-VI) under a deprotecting agent.
- a compound of the formula (AV) is reacted with CH 3 S(0) 2 R 3 and (R 14 R 15 R 16 Si) 2 NM under the action of a strong base to give the formula (A-VII) Compound,
- suitable strong bases include, but are not limited to, alkyl lithium, sodium alkyl, potassium alkyl, sodium alkoxide, potassium alkoxide, lithium alkoxide, sodium alkylamine, lithium alkylamine and alkane Potassium amide.
- examples of suitable strong bases include, but are not limited to, n-butyllithium, tert-butyllithium, decyllithium, ethyllithium, sodium decylate, potassium decoxide, hydrazine Lithium alkoxide, lithium dimercaptoalkyl, lithium diethylamine, lithium dipropylamine, lithium diisopropylamide and one or more mixtures thereof
- Examples of suitable (R 14 R 15 R 16 Si) 2 NM that can be used in the present application include, but are not limited to, bistridecylsilylamine lithium, bistriethylsilylamide lithium, bistripropylsilyl Lithium amide, lithium bistriisopropylsilylamide, lithium bis(dimercaptoethylsilyl)amide, lithium bis(dimercaptopropylsilyl)amide, bis(didecyliso) Lithium propyl) amide lithium, bis(dimercaptophenylsilyl)amide lithium, bis(dimercaptobenzylsilyl)amide lithium, bis(diethylsilylsilyl)amide lithium , lithium bis(diethylpropylsilyl)amide, lithium bis(diethylisopropylsilyl)amide, lithium bis(diethylphenylsilyl)amide, bis(diethylbenzyl) Lithium-based lithium
- a compound of the formula (AV) is reacted with CH 3 S(0) 2 R 3 and (R 14 R 15 R 16 Si) 2 NM under the action of a strong base to give the formula (A-VII)
- the reaction of the compound is carried out under the action of a catalyst.
- Suitable catalysts that can be used in the present application include, but are not limited to, fluorinating agents.
- suitable fluorinating agents that can be used in the present application include, but are not limited to, boron trifluoride. In certain embodiments, at -100. -100. C
- the compound of the formula (AV) is reacted with CH 3 S(0) 2 R 3 and (R 14 R 15 R 16 Si) 2 NM under the action of a strong base to give a compound of the formula (A-VII).
- the present application is directed to a process for the preparation of a compound of the formula (B-II), which comprises reacting a compound of the formula (B-II) with the formula R u -Y, (R 12 ) 2 Y or YR 13 - The Z compound is reacted to obtain a compound of the formula ( ⁇ - ⁇ ),
- R 1 is selected from the group consisting of hydrogen, halogen, dC 8 hydrocarbon, dC 8 alkoxy, hydroxy, cyano, nitro Or NRV;
- R 3 is selected from hydroxy, CC 8 hydrocarbyl, CC 8 hydrocarbon group, CC 8 hydrocarbyl (CC 8 alkylene) oxy, C 5 -C 12 aryl group, C 5 -C 12 aryl group (C r C 8 alkylene Oxyl or NR 6 R 7 ;
- R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydroxy, dC 8 hydrocarbyl, dC 8 hydrocarbyloxy, dC 8 hydrocarbylthio, cyano, C 3 -C 10 cycloalkyl, (d-alkylene) C 3 -C 10 Cycloalkyl, C 3 -C 10 cycloalkyl (dC 8 alkylene)oxy, C 3 -C 10 cycloalkyloxy, C 5 -C 12 aryl, C 5 -C 12 aryloxy, C 5 - C 12 aryl (dC 8 alkylene)oxy;
- R 6 and R 7 are each independently selected from the group consisting of hydrogen, dC 8 hydrocarbyl, aryl, C(0)R 8 or S0 2 R 8 , or R 6 and R 7 together represent 1,4-butylene, 1,5-Asia Pentyl, 1,6-hexylene or CH 2 CH 2 XCH 2 CH 2 , wherein X is selected from 0, S or NR 8 ;
- R 8 is selected from hydrogen or C hydrocarbyl or a substituted diC 8 hydrocarbyl group
- R 11 is selected from dC 8 hydrocarbyl, C 5 -C 12 aryl, C(0)R 8 or S(0) 2 R 8 , and Y is selected from halogen, OMs or OTs;
- R 12 is selected from C(0)R 8 and Y is 0;
- R 13 is selected from 1,4-butylene, 1,5-pentylene, 1,6-hexylene or
- CH 2 CH 2 XCH 2 CH 2 , Y and Z are each selected from halogen, OMs or OTs, and X represents 0, S or NR 8 .
- reaction of a compound of the formula (B-II) with a compound of the formula R"-Y, (R 12 ) 2 Y or YR 13 -Z to give a compound of the formula (B-II) An alkaline reagent is added to it.
- alkaline agents examples include, but are not limited to, triethylamine, tridecylamine, tripropylamine, diisopropylethylamine, pyridine, N-mercaptomorpholine, N-ethylmorphine Porphyrin, N-mercaptopiperidine, N-ethylpiperidine, N-decylpyrrolidine, N-ethylpyrrolidine, 4-diguanylidenepyridine, 4-pyrrolidinopyridine, 2-mercaptopyridine , 3-mercaptopyridine, 4-mercaptopyridine, 2,6-dimercaptopyridine, 2,4,6-trimercaptopyridine, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate , lithium carbonate, cesium carbonate, sodium hydride, potassium hydride, lithium hydride, lithium aluminum hydride, sodium decoxide, potassium decoxide, lithium decoxide, sodium
- Examples of suitable (R 14 R 15 R 16 Si) 2 NM that can be used in the present application include, but are not limited to, bistridecylsilylamine lithium, bistriethylsilylamide lithium, bistripropylsilyl Lithium amide, lithium bistriisopropylsilylamide, lithium bis(dimercaptoethylsilyl)amide, lithium bis(dimercaptopropylsilyl)amide, bis(didecyliso) Lithium propyl) amide lithium, bis(dimercaptophenylsilyl)amide lithium, bis(dimercaptobenzylsilyl)amide lithium, bis(diethylsilylsilyl)amide lithium Double (two Ethylpropylsilyl)amide lithium, bis(diethylisopropylsilyl)amide lithium, bis(diethylphenylsilyl)amide lithium, bis(diethylbenzylsilyl) Amino lithium
- the compound of formula (B-II) is of the formula R u -Y, (R 12 ) 2 Y or
- reaction of the YR 13 -Z compound to give a compound of the formula (B-II) is carried out in a solvent.
- suitable solvents include, but are not limited to, chloroform, dichlorodecane, dichloroethane, tetrahydrofuran, acetone, butanone, decyl acetate, propyl acetate, butyl acetate, isopropyl acetate.
- a compound of formula (B-II) is prepared from a compound of formula (BI),
- R 1 is selected from the group consisting of hydrogen, halogen, dC 8 hydrocarbyl, dC 8 alkoxy, hydroxy, cyano, nitro or NR 6 R 7 ;
- R 3 is selected from the group consisting of hydroxyl, C r C 8 hydrocarbyl, C r C 8 alkoxy, C r C 8 hydrocarbyl (C r C 8 alkylene)oxy, C 5 -C 12 aryl, C 5 -C 12 aryl Base (dC 8 alkylene)oxy or NR 6 R 7 ;
- R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydroxy, dC 8 hydrocarbyl, dC 8 hydrocarbyloxy, dC 8 hydrocarbylthio, cyano, C 3 -C 10 cycloalkyl, (d-alkylene) C 3 -C 10 Cycloalkyl, C 3 -C 10 cycloalkyl (dc 8 alkylene)oxy, c 3 -c 10 cycloalkyloxy, c 5 -c 12 aryl, c 5 -c 12 aryloxy, C 5 - C 12 aryl (dC 8 alkylene)oxy;
- R 6 and R 7 are each independently selected from hydrogen, C r C 8 hydrocarbyl, aryl, C(0)R 8 or S0 2 R 8 , or R 6 and R 7 together represent 1,4-butylene, 1,5 - pentylene, 1,6-hexylene or CH 2 CH 2 XCH 2 CH 2 , wherein X is selected from 0, S or NR 8 ;
- R 8 is selected from hydrogen or C r C 8 hydrocarbyl or substituted prime C r C 8 hydrocarbon group.
- reaction of the compound of the formula (B-I) to prepare a compound of the formula (B-I) is carried out under the action of a reducing agent.
- Suitable reducing agents include, but are not limited to, iron powder, powdered powder, pollen, and hydrogen.
- reaction of the compound of the formula (B-I) to prepare a compound of the formula (B-I) is carried out under the action of a catalyst.
- Suitable catalysts include, but are not limited to, heavy metals such as palladium, platinum, rhodium, nickel, ruthenium or osmium and their oxides or acids, acid, acid, tannic acid, acetic acid, propionic acid, Sulfonic acid, ethanesulfonic acid, benzoic acid and p-toluene.
- heavy metals such as palladium, platinum, rhodium, nickel, ruthenium or osmium and their oxides or acids, acid, acid, tannic acid, acetic acid, propionic acid, Sulfonic acid, ethanesulfonic acid, benzoic acid and p-toluene.
- the reaction of the compound of the formula (BI) to prepare a compound of the formula ( ⁇ - ⁇ ) is carried out under the action of the following catalysts: hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, propionic acid, sulfonium Acid, ethanesulfonic acid, benzenesulfonic acid, p-toluene acid, palladium carbon, platinum carbon, dioxide Platinum, palladium chloride, platinum chloride, Raney nickel or a mixture of one or more thereof.
- the following catalysts hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, propionic acid, sulfonium Acid, ethanesulfonic acid, benzenesulfonic acid, p-toluene acid, palladium carbon, platinum carbon, dioxide Platinum, palladium chloride, platinum chloride, Raney nickel or a mixture of one or more thereof.
- reaction of the compound of the formula (B-I) to prepare a compound of the formula (B-I) is carried out in a solvent.
- solvents examples include, but are not limited to, decyl alcohol, ethanol, propanol, butanol, isopropanol, chloroform, dichlorodecane, carbon tetrachloride, 1,2-dichloroethane.
- ethylene glycol dioxime ether ethylene glycol diethyl ether, diethyl ether, mercaptoethyl ether, mercaptopropyl ether, mercaptobutyl ether, ethyl propyl ether, mercapto tert-butyl ether, tetrahydrofuran, acetic acid Ethyl ester, decyl acetate, propyl acetate, butyl acetate, decyl propionate, ethyl propionate, decyl decanoate, ethyl decanoate, propyl citrate, isopropyl acetate, acetone, butanone, Pyridine, DMF, DMSO, acetonitrile, propionitrile, benzene, toluene, water, and mixtures of one or more thereof.
- a compound of the formula (B-II) is prepared from a compound of the formula (B-I) under C.
- a compound of the formula (B-II) is prepared from a compound of the formula (B-I) under C.
- the compound of formula (B-II) is prepared from a compound of formula (B-I) at 1-100 atmospheres.
- the compound of formula (B-II) is prepared from a compound of formula (B-I) at 1-20 atmospheres.
- the present application relates to a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I), a stereoisomer, enantiomer or tautomer thereof, or a stereo a mixture of isomers, a pharmaceutically acceptable salt thereof, a polymorph thereof,
- R 1 and R 2 are each independently selected from the group consisting of hydrogen, a hydrazine, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, Hydroxyl, cyano, nitro or optionally substituted NR 6 R 7 ;
- R 3 is selected from a hydroxyl group, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally substituted hydrocarbon group (alkylene)oxy group, an optionally substituted aryl group, an optionally substituted aryl (alkylene)oxy group or an optionally substituted group.
- NR 6 R 7 is selected from a hydroxyl group, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally substituted hydrocarbon group (alkylene)oxy group, an optionally substituted aryl group, an optionally substituted aryl (alkylene)oxy group or an optionally substituted group.
- R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted hydrocarbyloxy, optionally substituted hydrocarbylthio, cyano, optionally substituted cycloalkyl, optionally substituted ((alkylene)cycloalkyl And optionally substituted cycloalkyl (alkylene)oxy, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted aryl(alkylene)oxy;
- R 6 and R 7 are each independently selected from hydrogen, an optionally substituted hydrocarbon group, an optionally substituted aryl group, an optionally substituted C(0)R 8 or an optionally substituted SO 2 R 8 , or R 6 and R 7 together represent an arbitrary substitution.
- R 8 is selected from hydrogen or an optionally substituted hydrocarbon group.
- Examples of pharmaceutically acceptable carriers, diluents or excipients that can be used in the pharmaceutical compositions of the present application include, but are not limited to, any adjuvants, carriers that have been approved by the U.S. Food and Drug Administration for use in humans or poultry. , excipients, glidants, sweeteners, thinners, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents , solvent or emulsifier.
- compositions of the present application further comprise at least one other active ingredient.
- suitable active ingredients include, but are not limited to, nitrogen mustard, aziridine, mercapto melamine, alkyl sulfonate, nitrosourea, triazene, folic acid analog, pyrimidine analog , guanidine analogues, vinca alkaloids, epipodophyllotoxin, antibiotics, topoisomerase inhibitors, anticancer vaccines, acevicin, arubicin, apodazole hydrochloride, acronin, ado Toxin, adiploid, ampomycin, ammine acetate, aminoglutethimide, ampicillin, anastrozole, aflatoxin, asparaginase, trilinomycin, azacitidine, a Zaltebide, azomycin, bamastat, benzozinidine, bicalutamide, chlorinated hydrochloride, bis-naphthyl sulfonate, bis, ble
- the pharmaceutical compositions of the present application are prepared as tablets, solutions, granules, patches, ointments for parenteral, transdermal, mucosal, nasal, buccal, sublingual or oral use. , capsules, aerosols or suppositories.
- the present application relates to a method of reducing PDE4 enzymatic activity, the method comprising administering a PDE4 enzyme to a therapeutically effective amount of a compound of formula (I), a stereoisomer, enantiomer or tautomer thereof , or a mixture of stereoisomers, pharmaceutically acceptable salts thereof, polymorphs thereof, solvates thereof, prodrugs thereof or metabolites thereof,
- R 1 and R 2 are each independently selected from the group consisting of hydrogen, a hydrazine, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, a hydroxyl group, a cyano group, a nitro group or an optionally substituted NR 6 R 7 ;
- R 3 is selected from a hydroxyl group, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally substituted hydrocarbon group (alkylene)oxy group, an optionally substituted aryl group, an optionally substituted aryl (alkylene)oxy group or an optionally substituted group.
- NR 6 R 7 is selected from a hydroxyl group, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally substituted hydrocarbon group (alkylene)oxy group, an optionally substituted aryl group, an optionally substituted aryl (alkylene)oxy group or an optionally substituted group.
- R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted hydrocarbyloxy, optionally substituted hydrocarbylthio, cyano, optionally substituted cycloalkyl, optionally substituted ((alkylene)cycloalkyl And optionally substituted cycloalkyl (alkylene)oxy, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted aryl(alkylene)oxy;
- R 6 and R 7 are each independently selected from hydrogen, an optionally substituted hydrocarbon group, an optionally substituted aryl group, optionally taken Substituting C(0)R 8 or optionally substituted S0 2 R 8 , or R 6 and R 7 together represent an optionally substituted 1,4-butylene, optionally substituted 1,5-pentylene group, optionally substituted 1,6-hexylene or optionally substituted CH 2 CH 2 XCH 2 CH 2 wherein X is selected from 0, S or NR 8 ;
- R 8 is selected from hydrogen or an optionally substituted hydrocarbon group.
- a PDE4 enzyme and a therapeutically effective amount of a compound of formula (I), a stereoisomer, an enantiomer or a tautomer thereof, or a mixture of stereoisomers, or a medicament thereof An acceptable salt, a polymorph thereof, a solvate thereof, a prodrug thereof, or a metabolite thereof is externally contacted.
- the present application is also directed to a method of treating a PDE4 enzyme mediated disease or condition, the method comprising administering to an individual in need of the method a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, Enantiomers or tautomers, or mixtures of stereoisomers, pharmaceutically acceptable salts thereof, polymorphs thereof, solvates thereof, prodrugs thereof or metabolites thereof,
- R 1 and R 2 are each independently selected from the group consisting of hydrogen, a hydrazine, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, a hydroxyl group, a cyano group, a nitro group or an optionally substituted NR 6 R 7 ;
- R 3 is selected from a hydroxyl group, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally substituted hydrocarbon group (alkylene)oxy group, an optionally substituted aryl group, an optionally substituted aryl (alkylene)oxy group or an optionally substituted group.
- NR 6 R 7 is selected from a hydroxyl group, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally substituted hydrocarbon group (alkylene)oxy group, an optionally substituted aryl group, an optionally substituted aryl (alkylene)oxy group or an optionally substituted group.
- R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted hydrocarbyloxy, optionally substituted hydrocarbylthio, cyano, optionally substituted cycloalkyl, optionally substituted ((alkylene)cycloalkyl And optionally substituted cycloalkyl (alkylene)oxy, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted aryl(alkylene)oxy;
- R 6 and R 7 are each independently selected from hydrogen, an optionally substituted hydrocarbon group, an optionally substituted aryl group, an optionally substituted C(0)R 8 or an optionally substituted SO 2 R 8 , or R 6 and R 7 together represent an arbitrary substitution.
- R 8 is selected from hydrogen or an optionally substituted hydrocarbon group.
- the disease or condition is selected from the group consisting of an inflammatory disease or condition, an infectious disease or disease state, an immune disease or disease state, and a cancer disease or disease state.
- Cancer squamous cell carcinoma, neck cancer, eye cancer, skin cancer, oral cancer, throat cancer, esophageal cancer, chest cancer, bone cancer, blood cancer, bone marrow cancer, lung cancer, colon cancer, sigmoid cancer, rectal cancer, stomach cancer, Prostate cancer, breast cancer, ovarian cancer, kidney cancer, liver cancer, pancreatic cancer, brain cancer, colon cancer, heart cancer, adrenal cancer, subcutaneous tissue cancer, lymph node cancer, pigmentoma, malignant glioma, HIV, hepatitis, adult Respiratory distress syndrome, bone resorption, chronic obstructive pulmonary disease, chronic pneumonia, dermatitis, inflammatory skin disease, specific dermatitis, spastic fibrosis, septic shock, sepsis, endotoxic shock, hemodynamic shock , sepsis syndrome,
- examples of the PDE4 enzyme mediated microbial infection and microbial infection syndrome described herein include, but are not limited to, bacterial infections, fungal infections, malaria, mycobacterial infections, and opportunistic infections caused by HIV.
- the unit dosage of the compound of formula (I) administered to a subject in need of treatment for a PDE4 enzyme mediated disease or condition is 0.1 mg to 1 00 mg.
- the unit dosage of the compound of formula (I) administered to a subject in need of treatment for a PDE4 enzyme mediated disease or condition is from 1 mg to 1 OOO mg.
- the method of treating a PDE4 enzyme mediated disease or condition further comprises administering to the individual in need of the method at least one additional active ingredient.
- Suitable active ingredients include, but are not limited to, nitrogen mustard, aziridine, mercapto melamine, alkyl sulfonate, nitrosourea, triazene, folic acid analog, pyrimidine analog , guanidine analogues, vinca alkaloids, epipodophyllotoxin, antibiotics, topoisomerase inhibitors, anticancer vaccines, acevicin, arubicin, apodazole hydrochloride, Cronin, adoline, adiploid, ampomycin, ammine acetate, aminoglutethimide, ampicillin, anastrozole, amphotericin, asparaginase, trilinine, Azacitidine, azatidine, azomycin, bamstat, benzozinidine, bicalutamide, chlorpyrifos hydrochloride, bis-naphthyl sulfonate, bismuth, sulphuric
- the compound of formula (I) and at least one other active ingredient are administered simultaneously, synergistically, separately or sequentially to the individual in need of treatment of a PDE4 enzyme mediated disease or condition.
- CDI 1, 1,-carbonyldiimidazole; DCM: dichlorodecane; THF: tetrahydrofuran; TFA: trifluoroacetic acid; DMAP: 4-(N,N-didecylamino)pyridine; TEA: triethylamine ; DMF: W, W-dimercaptoamide; DMSO: dimethyl sulfoxide; HOBt: 1-hydroxybenzotriazole; DCC: hydrazine, hydrazine-dicyclohexylcarbodiimide; TBFA: tetrabutyl Ammonium fluoride; EDC-HC1: 1-(3-diaminoaminopropyl)-3-ethylcarbodiimide hydrochloride; Fmoc: 9-oxime oxycarbonyl; MOM: oxime oxime; MEM : methoxy ethoxy fluorenyl; MTM: fluorenyl thi
- Example la The experimental procedure of Example la was repeated using iododecane instead of iodoethane to give a solid product. MS (m/z) 167 [M+l] + .
- Example la The experimental procedure of Example la was repeated with benzyl chloride instead of ethyl iodide to give a solid product. MS (m/z) 243 [M+l] + .
- the resulting reaction mixture was divided into 300 ml portions, extracted with DCM (300 ml ⁇ 2), and all DCM layers were combined.
- the extract is divided into 600 ml portions, and washed with 50 ml of x 2 6 N hydrochloric acid, water, a saturated aqueous solution of Na 2 CO 3 and a saturated aqueous solution of sodium chloride, dried over anhydrous MgSO 4 , filtered, and evaporated to dryness.
- the mixed solvent of ether 1:1 was washed, and filtered to give 21 g of white solid.
- Method 1 In a 50 ml round bottom flask equipped with an electromagnetic stirring, reflux condenser and drying tube, 0.1 g of 5-(1-(3-ethoxy-4-methoxyphenyl)-2-(indolyl sulfone) was added. Ethyl)ethyl)-1-amino-5H-thiophene[3,4-c]pyrrole-4,6-dione and 0.005 g of DMAP, 10 ml of acetic anhydride, heated to 60 ° C and stirred for 6 hours. The solvent was evaporated to dryness.
- Method 2 In a 50 ml round bottom flask equipped with an electromagnetic stirring, reflux condenser and drying tube, 0.1 g of 5-(1-(3-ethoxy-4-methoxyphenyl)-2-(sulfonate) was added. Ethyl)ethyl)-1-amino-5H-thiophene[3,4-c]pyrrole-4,6-dione and 5 ml of pyridine were added dropwise 0.2 ml of acetyl chloride under ice-cooling, and stirred at room temperature for 1 hour.
- Example 4 The experimental procedure of Example 4 was repeated using Compound 3b instead of Compound 3a to give a solid product. MS (m/z): 410 [M+l] + .
- Example 4 The experimental procedure of Example 4 was repeated using Compound 3d instead of Compound 3a to give a solid product. MS (m/z): 472 [M+l] + .
- Example 1 The experimental procedure of Example 1 was repeated using Compound 3d instead of Compound 3a to give a solid product. MS (m/z): 515 [Ml] + .
- Example 2 The experimental procedure of Example 2 was repeated using the target compound of Example 10 in place of the target compound of Example 1. A solid product was obtained. MS ( ): 487 [ ⁇ +1] + .
- Example 2 The experimental procedure of Example 1 was repeated using Compound 3c instead of Compound 3a to give a solid product. MS (m/z): 439 [Ml] + .
- Example 2 The experimental procedure of Example 2 was repeated using the title compound of Example 13 instead of the title compound of Example 1. A solid product was obtained. MS ( ⁇ ): 411 [ ⁇ +1] + .
- Example 2 The experimental procedure of Example 1 was repeated using Compound 3b instead of Compound 3a to give a solid product. MS (m/z): 453 [Ml] + .
- Example 2 The experimental procedure of Example 2 was repeated using the title compound instead of the title compound of Example 15. The solid product was obtained. MS ( ⁇ ): 425 [M+l] + .
- Example 1 The synthesis of Example 1 was repeated using Compound 4b and Compound 9.
- Example 2 The procedure of Example 2 was repeated using the title compound of Example 20. MS (m/z): 425 [M+l] + .
- Example 1 The procedure of Example 1 was repeated using Compound 4d and Compound 9.
- Example 2 The procedure of Example 2 was repeated using the title compound of Example 22. MS (m/z): 425 [M+l] + .
- Example 16 was repeated using the title compound.
- the title compound was obtained. m.j.
- Example 3 The experimental procedure of Example 3 was repeated using the title compound of Example 1 and propionyl chloride to give a solid product. MS ( ⁇ ): 541 [M-l]+.
- PBMCs LPS-stimulated monocytes
- cytokine TNFa The release of cytokine TNFa from PBMCs in human peripheral blood following lipopolysaccharide (LPS) stimulation can be performed in vitro.
- the medicinal active ingredients involved in the present application inhibit the release of cytokine TNFa by PBMCs stimulated by LPS as follows:
- PBMCs are obtained from heparinized blood of at least three volunteer donors. PBMCs were obtained from the heparin-treated blood of at least three volunteer donors by a known method, and the PBMCs were collected and used in 1640 medium (10% calf serum, 2 mM L-glutamylamine, 100 mM mercaptoethanol). 5 ( ⁇ g/ml streptomycin, 50 U/ml penicillin) was washed three times. The PBMCs were added to a 24-well plate and mixed with 1640 medium to a concentration of lx10 6 cells/ml.
- Dithizone prepared into the desired concentration of the test substance solution, added to the above cell culture medium, and incubated in a CO 2 incubator (5% C0 2 , 90% humidity) for 1 hour, and then added to LPS (Sigma) ) to 0.1 g/ml (excluding controls).
- PDE4 enzyme inhibitory activity The inhibitory effect of the compound on the hydrolysis of cAMP activity by PDE4 enzyme is as follows: Human PDE4A1A, PDE4B1, and PDE4D2 were purchased from BPS bioscience (catalog numbers: 60040, 60041, 60043, respectively). The enzymatic reaction was carried out in 10 mM Tris-HCl (pH 7.4), 1 mM MgCl 2 , and the cAMP concentration was 5 ⁇ M, 37. C reaction for 15-30 min, the substrate consumption was controlled within 20%, the reaction was stopped with an equal volume of acetonitrile, and the amount of substrate AMP was detected by HPLC-MS. The inhibitory activity of the compound on the PDE4 enzyme was obtained by comparing the amount of AMP produced by the experimental group plus the compound and the control group without the compound. The data are shown in Table 2.
- Human PDE2A was purchased from BPS bioscience (Catalog No.: 60020). The enzymatic reaction was carried out in 10 mM Tris-HCl (pH 7.4), 1 mM MgCl 2 , and the cAMP concentration was 5 ⁇ M, 37. C reaction for 30 min, the substrate consumption was controlled within 20%, the reaction was stopped with an equal volume of acetonitrile, and the amount of substrate AMP produced was determined by HPLC-MS. The inhibitory activity of the compound on PDE2 was obtained by comparing the amount of AMP produced by the experimental group plus the compound and the control group without the compound. The data are shown in Table 2. Table 2. Inhibition of PDE4 Enzyme Activity and PDE Enzyme Selective Activity Inhibition
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BRPI1012770A BRPI1012770B8 (pt) | 2009-05-14 | 2010-05-14 | derivados de tiofeno |
EP10774565.5A EP2431371B1 (en) | 2009-05-14 | 2010-05-14 | Thiophene derivatives |
MX2011012122A MX2011012122A (es) | 2009-05-14 | 2010-05-14 | Derivados de tiofeno. |
US13/320,533 US8952178B2 (en) | 2009-05-14 | 2010-05-14 | Thiophene derivatives |
KR1020117028599A KR101514866B1 (ko) | 2009-05-14 | 2010-05-14 | 티오펜 유도체 |
RU2011150786/04A RU2536865C2 (ru) | 2009-05-14 | 2010-05-14 | Производные тиофена |
ES10774565.5T ES2441740T3 (es) | 2009-05-14 | 2010-05-14 | Derivados de Tiofeno |
AU2010246749A AU2010246749B8 (en) | 2009-05-14 | 2010-05-14 | Thiophene derivatives |
JP2012510105A JP5752114B2 (ja) | 2009-05-14 | 2010-05-14 | チオフェン誘導体 |
CA2761845A CA2761845C (en) | 2009-05-14 | 2010-05-14 | Thiophene[3,4-c]pyrrole pde4 mediators |
ZA2011/08349A ZA201108349B (en) | 2009-05-14 | 2011-11-14 | Thiophene derivatives |
US14/281,289 US9630975B2 (en) | 2009-05-14 | 2014-05-19 | Thiophene derivatives |
US15/468,990 US10385062B2 (en) | 2009-05-14 | 2017-03-24 | Thiophene derivatives |
US16/460,710 US10611775B2 (en) | 2009-05-14 | 2019-07-02 | Thiophene derivatives |
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US13/320,533 A-371-Of-International US8952178B2 (en) | 2009-05-14 | 2010-05-14 | Thiophene derivatives |
US14/281,289 Continuation US9630975B2 (en) | 2009-05-14 | 2014-05-19 | Thiophene derivatives |
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US (4) | US8952178B2 (zh) |
EP (1) | EP2431371B1 (zh) |
JP (1) | JP5752114B2 (zh) |
KR (1) | KR101514866B1 (zh) |
CN (5) | CN107501290A (zh) |
AU (1) | AU2010246749B8 (zh) |
BR (1) | BRPI1012770B8 (zh) |
CA (1) | CA2761845C (zh) |
ES (1) | ES2441740T3 (zh) |
MX (1) | MX2011012122A (zh) |
RU (1) | RU2536865C2 (zh) |
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WO2017089347A1 (en) | 2015-11-25 | 2017-06-01 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods and pharmaceutical compositions for the treatment of braf inhibitor resistant melanomas |
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