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Isoindole Derivative
| Content Provider | The Lens |
|---|---|
| Abstract | Disclosed is a compound of formula (I) and a stereoisomer thereof:wherein R1, R2, R3 and R4 are as defined in the present disclosure. |
| Related Links | https://www.lens.org/images/patent/EP/3782983/A1/EP_3782983_A1.pdf |
| Language | English |
| Publisher Date | 2021-02-24 |
| Access Restriction | Open |
| Alternative Title | Isoindolderivate Dérivé D'isoindole |
| Content Type | Text |
| Resource Type | Patent |
| Date Applied | 2019-04-16 |
| Agent | Engelhard, Markus |
| Applicant | Tianjin Hemay Pharmaceutical Co Ltd |
| Application No. | 19788517 |
| Claim | A compound of formula (I) and a stereoisomer thereof: wherein R1 represents one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, C1-C8hydrocarbyl, amino, C1-C8hydrocarbylcarbonylamino, C1-C8hydrocarbyloxycarbonylamino, amino substituted with one or more C1-C4hydrocarbyl and substituted aminocarbonylC1-C8hydrocarbyl; R2 is selected from the group consisting of carboxyl and ester group; R3 is selected from the group consisting of hydrogen, hydroxy, halogen, C1-C8hydrocarbyloxy, C5-C12aryloxy and C5-C12cycloaryloxy; and R4 is selected from the group consisting of hydrogen, halogen, hydroxy, C1-C8hydrocarbyloxy and C5-C12aryloxy. The compound of formula (I) of claim 1, wherein R1 represents one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, C1-C8hydrocarbyl, amino, C1-C8hydrocarbylcarbonylamino, C1-C8hydrocarbyloxycarbonylamino, amino substituted with one or more C1-C4hydrocarbyl and substituted aminocarbonylC1-C8hydrocarbyl; R2 is selected from the group consisting of -COOH, -COOCH3, -COOCH2CH3, -COOCH2CH2CH3 and -COOCH(CH3)2; R3 is selected from the group consisting of hydrogen, hydroxy, halogen, benzyloxy, C1-C4alkyloxy, C5-C12aryloxy and C5-C12cycloaryloxy; and R4 is selected from the group consisting of hydrogen, halogen, hydroxy, C1-C4hydrocarbyloxy, benzyloxy and C5-C12aryloxy. The compound of formula (I) of claim 1, wherein R1 is selected from the group consisting of hydrogen, -OH, -F, -Cl, -CH3, -CH2CH3, -CH2CH2CH3, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -NHCOOCH3, -NHCOCH2OH, -NHCOCH2Cl, -NHCOCH2F and -NCH3COCH3; R2 is selected from the group consisting of -COOH, -COOCH3, -COOCH2CH3, -COOCH2CH2CH3 and -COOCH(CH3)2; R3 is selected from the group consisting of -H, -OH, -Cl, -F, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2 and benzyloxy; and R4 is selected from the group consisting of -H, -Cl, -F, -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2 and benzyloxy. The compound of formula (I) and the stereoisomer thereof of any one of claims 1 to 3, selected from the group consisting of: methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl 3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3,4-dimethoxyphenyl)propionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3,4-diethoxyphenyl)propionate; 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl) propanoic acid; ethyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl (R)-3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl (S)-3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl (R)-3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propiona te; methyl (S)-3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propiona te; propyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; isopropyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; butyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl 3-(4-(2-chloroacetamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)pr opionate; methyl 3-(4-(2-(dimethylamino)acetamido)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxy phenyl)propionate; methyl 3-(4-(dimethylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propio nate; methyl 3-(4-(2-hydroxyacetamido)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl) propionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-isopropoxyphenyl)propionat e; methyl 3-(4-fluoro-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-cyclopentyloxyphenyl)propi onate; methyl 3-(4-methyl-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl 3-(5-fluoro-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl 3-(4,7-dichloro-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl 3-(4-(N-methylacetamido)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)p ropionate; methyl 3-(5-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-(benzyloxy)-4-methoxyphenyl)propion ate; methyl 3-(4-(N-methyl-tert-butoxycarbonylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl 3-(4-(methylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propion ate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-propoxy-4-methoxyphenyl)propionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-cyclopentyloxy-4-methoxyphenyl)pro pionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-propoxyphenyl)propionate; methyl 3-(4-hydroxy-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl 3-(4-acetoxy-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl 3-(4-(tert-butyloxycarbonylamino)-7-hydroxy-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl 3-(4-amino-5-hydroxy-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propi onate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-hydroxy-4-methoxyphenyl)propionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-(benzyloxy)phenyl)propionat e; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-hydroxyphenyl)propionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-methoxy-4-(benzyloxy)phenyl)propion ate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-methoxy-4-hydroxyphenyl)propionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-phenylpropionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-chlorophenyl)propionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(4-ethoxypheny)propionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(4-chlorophenyl)propionate; and methyl 3-(4-(tert-butyloxycarbonylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxy phenyl)propionate. A pharmaceutical composition comprising the compound or the stereoisomer thereof of any one of claims 1 to 4 and a pharmaceutically acceptable carrier. The pharmaceutical composition of claim 5, formulated as tablet, solution, granule, patch, ointment, capsule, aerosol or suppository administered via parenteral, transdermal, mucosal, nasal, buccal, sublingual or oral route. Use of the compound, the stereoisomer thereof of any one of claims 1 to 4 or the pharmaceutical composition of claim 5 or 6 in the preparation of a medicament for treating dermatosis, psoriasis, eczema and atopic dermatitis. A process for preparing the compound of formula (I) or the stereoisomer thereof of claim 1: wherein R1 represents one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, C1-C4alkyl, amino, C1-C8hydrocarbylcarbonylamino, C1-C8hydrocarbyloxycarbonylamino, amino substituted with one or more C1-C4alkyl, aminocarbonylC1-C4alkyl substituted with halogen, and aminocarbonylC1-C4alkyl substituted with hydroxy; R2 is selected from the group consisting of -COOH, -COOCH3, -COOCH2CH3, -COOCH2CH2CH3 and -COOCH(CH3)2; R3 is selected from the group consisting of hydrogen, hydroxy, halogen, benzyloxy, C1-C4alkyloxy, C5-C12aryloxy and C5-C12cycloaryloxy; and R4 is selected from the group consisting of hydrogen, halogen, hydroxy, C1-C4hydrocarbyloxy, benzyloxy and C5-C12aryloxy; wherein the process comprises: (1) reacting a compound of formula (A-I) with malonic acid and ammonium acetate to obtain a compound of formula (A-II), wherein groups represented by R3' and R4' in formula (A-I) and formula (A-II) have the same definitions as R3 and R4 in formula (I), (2) esterifying the compound of formula (A-II) with alcohol to obtain a compound of formula (A-III), wherein groups represented by R3' and R4' in formula (A-II) and formula (A-III) have the same definitions as R3 and R4 in formula (I), and R2' is selected from the group consisting of hydrogen and C1-C4alkyl; and (3) reacting a compound of formula (A-IV) with the compound of formula (A-III) to obtain the compound of formula (I), wherein groups represented by R1', R3' and R4' in formula (A-III) and formula (A-IV) have the same definitions as R1, R3 and R4 in formula (I), and R2' is selected from the group consisting of hydrogen and C1-C4alky A compound of formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: wherein R1 represents one or more identical or different substituents selected from the group consisting of halogen, hydroxy, optionally substituted hydrocarbyl, optionally substituted amino, optionally substituted hydrocarbylcarbonylamino, optionally substituted hydrocarbylcarbonyloxy, optionally substituted hydrocarbyloxycarbonylamino and optionally substituted hydrocarbylcarbonylamino; R2 is selected from the group consisting of optionally substituted hydrocarbyloxycarbonyl and carboxyl; R3 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted arylhydrocarbyloxy and optionally substituted cyclohydrocarbyloxy; R4 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted hydrocarbyloxy, optionally substituted arylhydrocarbyloxy and optionally substituted cyclohydrocarbyloxy; and X is -CR5R6-, wherein if R5 is selected from the group consisting of hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cyclohydrocarbyl, optionally substituted aryl and optionally substituted heteroaryl; and R6 is selected from the group consisting of hydrogen, halogen, optionally substituted hydrocarbyl, optionally substituted cyclohydrocarbyl, optionally substituted aryl and optionally substituted heteroaryl, n is 0, 1, 2, 3 or 4; and if R5 and R6 together with a carbon atom to which they are attached form an optionally substituted cyclohydrocarbyl, n is 1. The compound of formula (II), the stereoisomer thereof or the pharmaceutically acceptable salt thereof of claim 9, wherein R2 is selected from the group consisting of optionally substituted C1-C6hydrocarbyloxycarbonyl or carboxyl; preferably selected from the group consisting of optionally substituted alkyloxycarbonyl and carboxyl; and more preferably selected from the group consisting of optionally substituted C1-C6alkyloxycarbonyl and carboxyl . The compound of formula (II), the stereoisomer thereof or the pharmaceutically acceptable salt thereof of claim 9 or 10, wherein R3 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C1-C6hydrocarbyloxy, optionally substituted C6-C18arylhydrocarbylloxy and optionally substituted C3-C10cyclohydrocarbyloxy; preferably selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted alkyloxy, optionally substituted arylalkyloxy and optionally substituted cycloalkyloxy; and more preferably selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C1-C6alkyloxy, optionally substituted C6-C18arylalkyloxy, and optionally substituted C3-C10cycloalkyloxy. The compound of formula (II), the stereoisomer thereof or the pharmaceutically acceptable salt thereof of any one of claims 9 to 11, wherein R4 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C1-C6hydrocarbyloxy, optionally substituted C6-C18arylhydrocarbyloxy and optionally substituted C3-C10cyclohydrocarbyloxy; preferably selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted alkyloxy, optionally substituted arylalkyloxy and optionally substituted cycloalkyloxy; and more preferably selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C1-C6alkyloxy, optionally substituted C6-C18arylalkyloxy and optionally substituted C3-C10cycloalkyloxy. The compound of formula (II), the stereoisomer thereof or the pharmaceutically acceptable salt thereof of any one of claims 9 to 12, wherein R1 represents one or more identical or different substituents selected from the group consisting of halogen, hydroxy, optionally substituted C1-C6hydrocarbyl, optionally substituted amino, optionally substituted C1-C6hydrocarbylcarbonylamino, optionally substituted C1-C6hydrocarbylcarbonyloxy, optionally substituted C1-C6hydrocarbyloxycarbonylamino, and optionally substituted C1-C6hydrocarbylcarbonylamino; preferably selected from the group consisting of halogen, hydroxy, optionally substituted alkyl, optionally substituted amino, optionally substituted alkylcarbonylamino, optionally substituted alkylcarbonyloxy, optionally substituted alkyloxycarbonylamino, optionally substituted alkylcarbonylamino; and more preferably selected from the group consisting of halogen, hydroxy, optionally substituted C1-C6alkyl, optionally substituted amino, optionally substituted C1-C6alkylcarbonylamino, optionally substituted C1-C6alkylcarbonyloxy, optionally substituted C1-C6alkyloxycarbonylamino, and optionally substituted C1-C6alkylcarbonylamino. The compound of formula (II), the stereoisomer thereof or the pharmaceutically acceptable salt thereof of any one of claims 9 to 13, wherein R2 is selected from the group consisting of optionally substituted methoxycarbonyl, optionally substituted ethoxycarbonyl, optionally substituted propoxycarbonyl, optionally substituted butoxycarbonyl, optionally substituted isopropoxycarbonyl and carboxyl; and preferably R5 is selected from the group consisting of hydrogen, halogen and C1-C4hydrocarbyl, R6 is selected from the group consisting of hydrogen, halogen and C1-C4hydrocarbyl and n is 1 or 2. The compound of formula (II), the stereoisomer thereof or the pharmaceutically acceptable salt thereof of any one of claims 9 to 14, wherein R3 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted methoxy, optionally substituted ethoxy, optionally substituted propoxy, optionally substituted isopropoxy, optionally substituted benzyloxy and optionally substituted cyclopentyloxy. The compound of formula (II), the stereoisomer thereof or the pharmaceutically acceptable salt thereof of any one of claims 9 to 15, wherein R4 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted methoxy, optionally substituted ethoxy, optionally substituted propoxy, optionally substituted isopropoxy, optionally substituted benzyloxy and optionally substituted cyclopentyloxy. The compound of formula (II), the stereoisomer thereof or the pharmaceutically acceptable salt thereof of any one of claims 9 to 16, wherein R1 represents one or more identical or different substituents selected from the group consisting of halogen, hydroxy, optionally substituted methyl, optionally substituted amino, optionally substituted acetamido, optionally substituted acetoxy and optionally substituted tert-butoxycarbonylamino. The compound of formula (II), the stereoisomer thereof or the pharmaceutically acceptable salt thereof of any one of claims 9 to 17, wherein R1 represents one or more substituents selected from the group consisting of halogen, hydroxy, C1-C6alkyl, amino, amino substituted with C1-C4alkyl, C1-C6alkylcarbonylamino, C1-C6alkylcarbonyloxy, C1-C6alkyloxycarbonylamino, C1-C6alkylcarbonylamino substituted with amino substituted with C1-C6alkyl and C1-C6alkylcarbonylamino substituted with N-C1-C6alky The compound of formula (II), the stereoisomer thereof or the pharmaceutically acceptable salt thereof of any one of claims 9 to 18, wherein R2 is selected from the group consisting of C1-C6alkyloxycarbonyl and carboxyl; and preferably R5 is hydrogen, R6 is hydrogen and n is 1. The compound of formula (II), the stereoisomer thereof or the pharmaceutically acceptable salt thereof of any one of claims 9 to 19, wherein R3 is selected from the group consisting of hydrogen, hydroxy, halogen, C1-C8alkyloxy, C5-C12aryloxy and C5-C12cyclohydrocarbyloxy. The compound of formula (II), the stereoisomer thereof or the pharmaceutically acceptable salt thereof of any one of claims 9 to 20, wherein R4 is selected from the group consisting of hydrogen, hydroxy, halogen, C1-C8alkyloxy, C5-C12aryloxy and C5-C12cyclohydrocarbyloxy. The compound of formula (II), the stereoisomer thereof or the pharmaceutically acceptable salt thereof of any one of claims 9 to 21, wherein R1 represents one or more identical or different substituents selected from the group consisting of fluoro, chloro, hydroxy, methyl, amino, methylamino, dimethylamino, acetamido, 2-chloroacetamido, 2-hydroxyacetamido, N-methylacetamido, 2-(dimethylamino)acetamido, acetoxy, tert-butoxycarbonylamino and N-methyl-tert-butoxycarbonylamino. The compound of formula (II), the stereoisomer thereof or the pharmaceutically acceptable salt thereof of any one of claims 9 to 22, wherein R3 is selected from the group consisting of hydrogen, chloro, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, propoxy, isopropoxy, benzyloxy and cyclopentyloxy. The compound of formula (II), the stereoisomer thereof or the pharmaceutically acceptable salt thereof of any one of claims 9 to 23, wherein R4 is selected from the group consisting of hydrogen, chloro, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, propoxy, isopropoxy, benzyloxy and cyclopentyloxy. The compound of formula (II), the stereoisomer thereof or the pharmaceutically acceptable salt thereof of any one of claims 9 to 24, wherein R2 is selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, propoxy carbonyl, isopropoxycarbonyl and butoxycarbonyl; and preferably R5 is hydrogen, R6 is hydrogen and n is 1. The compound of formula (II), the stereoisomer thereof or the pharmaceutically acceptable salt thereof of any one of claims 9 to 25, wherein: R1 is acetamido; R2 is selected from the group consisting of methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; R3 is selected from the group consisting of methoxy and ethoxy; R4 is selected from the group consisting of methoxy and ethoxy; R5 is hydrogen; R6 is hydrogen; and n is 1. A compound, a stereoisomer thereof or a pharmaceutically acceptable salts thereof selected from the group consisting of: methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl 3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3,4-dimethoxyphenyl)propionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3,4-diethoxyphenyl)propionate; 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl) propanoic acid; ethyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl (R)-3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl (S)-3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl (R)-3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propiona te; methyl (S)-3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propiona te; propyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; isopropyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; butyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl 3-(4-(2-chloroacetamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)pr opionate; methyl 3-(4-(2-(dimethylamino)acetamido)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxy phenyl)propionate; methyl 3-(4-(dimethylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propio nate; methyl 3-(4-(2-hydroxyacetamido)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl) propionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-isopropoxyphenyl)propionat e; methyl 3-(4-fluoro-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-cyclopentyloxyphenyl)propi onate; methyl 3-(4-methyl-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl 3-(5-fluoro-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl 3-(4,7-dichloro-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl 3-(4-(N-methylacetamido)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)p ropionate; methyl 3-(5-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-(benzyloxy)-4-methoxyphenyl)propion ate; methyl 3-(4-(N-methyl-tert-butoxycarbonylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl 3-(4-(methylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propion ate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-propoxy-4-methoxyphenyl)propionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-cyclopentyloxy-4-methoxyphenyl)pro pionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-propoxyphenyl)propionate; methyl 3-(4-hydroxy-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl 3-(4-acetoxy-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate; methyl 3-(4-amino-7-hydroxy-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propi onate; methyl 3-(4-amino-5-hydroxy-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propi onate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-hydroxy-4-methoxyphenyl)propionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-(benzyloxy)phenyl)propionat e; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-hydroxyphenyl)propionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-methoxy-4-(benzyloxy)phenyl)propion ate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-methoxy-4-hydroxyphenyl)propionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-phenylpropionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-chlorophenyl)propionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(4-ethoxypheny)propionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(4-chlorophenyl)propionate; methyl 3-(4-(tert-butyloxycarbonylamino)-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxy phenyl)propionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-isopropoxy-4-methoxyphenyl)propion ate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(4-(difluoromethoxy)-3-ethoxyphenyl)pr opionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-(trifluoromethoxy)phenyl)pr opionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-(difluoromethoxy)-4-methoxyphenyl)) propionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(4-methoxy-3-(trifluoromethoxy)phenyl) propionate; ethyl (R)-3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propiona te; ethyl (S)-3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propiona te; methyl (R)-3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-isopropoxy-4-methoxyphenyl)pro pionate; methyl (S)-3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(3-isopropoxy-4-methoxyphenyl)prop ionate; methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(benzo[d][1,3]dioxol-5-yl)propionate; and methyl 3-(4-acetamido-1,3-dioxoisoindolin-2-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pro pionate. A pharmaceutical composition comprising the compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof of any one of claims 9 to 27, and a pharmaceutically acceptable carrier, diluent or excipient. The pharmaceutical composition of claim 28, formulated as tablet, solution, granule, patch, ointment, gel, capsule, aerosol or suppository administered via parenteral, transdermal, mucosal, nasal, buccal, sublingual or oral route. A method for treating or preventing a disease associated with immunoglobulin E (IgE), preferably mediated by immunoglobulin E (IgE), comprising administering a therapeutically effective amount of the compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof of any one of claims 9 to 27 or a therapeutically effective amount of the pharmaceutical composition of claim 28 or 29 to a subject in need thereof. The method of claim 30, wherein the subject is a mammal, preferably a human. The method of claim 30 or 31, wherein the disease is selected from the group consisting of dermatosis, psoriasis, eczema, atopic dermatitis, urticaria, asthma, asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS), allergic rhinitis, seasonal allergic rhinitis, drug-induced interstitial lung disease, bronchopulmonary aspergillosis, leprosy, pemphigoid and parasitic infections. The compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof of any one of claims 9 to 27 for treating or preventing a disease associated with immunoglobulin E (IgE), preferably mediated by immunoglobulin E (IgE) . A pharmaceutical composition for treating or preventing a disease associated with immunoglobulin E (IgE), preferably mediated by immunoglobulin E (IgE) comprising a therapeutically effective amount of the compound, the stereoisomer thereof or the pharmaceutically acceptable salt thereof of any one of claims 9 to 27, and a pharmaceutically acceptable carrier, diluent or excipient. A process for preparing the compound , the stereoisomer thereof or the pharmaceutically acceptable salt thereof of any one of claims 9 to 27, comprising: (1) reacting a compound of formula (B-I) with malonic acid and ammonium acetate to obtain a compound of formula (B-II), wherein groups represented by R3'and R4' in formula (B-I) and formula (B-II) have the same definitions as R3 and R4 in formula (II), (2) esterifying the compound of formula (B-II) with alcohol to obtain a compound of formula (B-III), wherein groups represented by R3 and R4' in formula (B-II) and formula (B-III) have the same definitions as R3 and R4 in the formula (II), and R2' is selected from the group consisting of hydrogen and hydrocarbyl; and (3) reacting a compound of formula (B-IV) with the compound of formula (B-III) to obtain the compound of formula (II), wherein groups represented by R1', R3' and R 4' in formula (B-III) and formula (B-IV) have the same definitions as R1, R3 and R4 in formula (II), and R2' is selected from the group consisting of hydrogen and hydrocarbyl; wherein X is -CR5R6-, wherein R5 is hydrogen, R6 is hydrogen and n is 1. The process of claim 35, wherein the compound of formula (B-I), malonic acid and ammonium acetate react in a solvent, preferably in methanol, ethanol, isopropanol, water or a mixture thereof and more preferably at 50°C to 130°C to obtain the compound of formula (B-II). The process of claim 35 or 36, wherein the compound of formula (B-II) is esterified with alcohol in an organic solvent, preferably in alcohols, tetrahydrofuran, dichloromethane, ethyl acetate, methyl tert-butyl ether or a mixture thereof to obtain the compound of formula (B-III); and preferably the reaction is carried out at -20°C to 30°C, and the alcohol is preferably selected from the group consisting of methanol, ethanol, isopropanol and a mixture thereof. The process of any one of claims 35 to 37, wherein an esterifying agent is selected from the group consisting of sulfoxide chloride, oxalyl chloride, HCl gas, acetyl chloride and a mixture thereof. The process of any one of claims 35 to 38, wherein a catalyst is added during the reaction of the compound of formula (B-IV) with the compound of formula (B-III) to obtain the compound of formula (II), the catalyst is preferably selected from the group consisting of sodium acetate, potassium acetate, sodium carbonate, potassium carbonate and a mixture thereof; and more preferably the reaction is carried out at 50°C to 180°C, and more preferably the reaction is carried out in an organic solvent, and the organic solvent is preferably selected from the group consisting of acetic acid, formic acid, dimethylformamide, dimethylacetamide and a mixture thereof. |
| CPC Classification | HETEROCYCLIC COMPOUNDS Specific Therapeutic Activity Of Chemical Compounds Or Medicinal Preparations Preparations For Medical; Dental Or Toiletry Purposes |
| Extended Family | 005-588-296-262-618 076-841-253-817-179 100-407-570-132-989 147-077-264-602-408 012-290-019-137-351 010-799-835-844-897 184-064-453-913-757 072-813-144-311-618 127-696-865-376-079 098-664-944-622-403 031-738-958-419-236 077-809-346-109-848 049-445-187-542-926 110-157-208-310-141 036-448-673-176-855 057-195-282-943-032 016-780-211-374-194 |
| Patent ID | 3782983 |
| Inventor/Author | Zhang Hesheng |
| IPC | C07D209/44 A61K31/4015 A61P11/06 A61P11/14 A61P17/00 |
| Status | Pending |
| Simple Family | 005-588-296-262-618 076-841-253-817-179 100-407-570-132-989 147-077-264-602-408 012-290-019-137-351 010-799-835-844-897 184-064-453-913-757 072-813-144-311-618 127-696-865-376-079 098-664-944-622-403 031-738-958-419-236 077-809-346-109-848 049-445-187-542-926 110-157-208-310-141 036-448-673-176-855 057-195-282-943-032 016-780-211-374-194 |
| CPC (with Group) | C07D209/48 C07D405/06 A61P17/00 A61P17/06 A61P11/06 A61P11/02 A61P11/00 A61P29/00 A61P37/08 A61P33/00 A61P31/10 A61K31/4035 A61P11/14 C07D209/44 |
| Issuing Authority | European Patent Office (EPO) |
| Kind | Patent Application Publication |
