| 摘要 |
#CMT# #/CMT# Substituted heterocyclic compounds (I) and their salts, are new. #CMT# : #/CMT# Substituted heterocyclic compounds of formula (I) and their salts, are new. A : (cyclo)alkyl, aryl(1-6C)alkyl, (hetero)aryl or heterocyclic (all optionally substituted by 1-5 halo, OH, hydroxy(1-6C)alkyl, 1-6C thioalkoxy, 1-6C alkylsulfonyl, CN, aryl, 1-6C (halo)alkyl, 1-6C (halo)alkoxy, NR3>R4>, NR3>COR4> or CONR3>R4>); either R3>, R4>1-6C alkyl or 1-6C alkoxy; or NR3>R4>heterocyclic radical; X : N or CR5>; R5>H, alkyl, N-(1-6C)alkylaminoalkyl, N,N-(1-6C)dialkylaminoalkyl, hydroxy(1-6C)alkyl, alkoxy(1-6C)alkyl or carbonylaminoalkyl; Y1>CH2, O, S, sulfoxide, sulfonyl, CO or NR6>; R6>H, alkyl or (1-6C) alkylcarbonyl; B1>2-6C alkylene; D : C or N; either R1>T (when D is N) or H, OH, 1-6C alkylcarbonyl or CN (when D is C); and R2>doublet electron (when D is N) or aryl, aryl(1-6C)alkyl, heterocycle, N-(1-6C)alkylamino or N,N-(1-6C)dialkylamino (all optionally substituted) (when D is C); or CR1>+R2>heterocyclic radical (when D is C); T : aryl(1-6C)alkyl, (hetero)aryl, heteroaryl(1-6C)alkyl, heterocycle, heterocyclo(1-6C)alkyl, N- (1-6C)alkylamino(1-6C)alkyl, N,N-(1-6C)dialkylamino(1-6C)alkyl or guanidino(1-6C)alkyl (all optionally substituted) or G; G : amine group of formula (-CH2-L-N(R7>)(R8>)); L : CO or (CH2)n; either R7>, R8>H, 1-6C alkyl, 1-6C alkenyl, 3-7C cycloalkyl, (3-7C)cycloalkyl(1-6C)alkyl, OH, (1-6C)alkoxy, amino, N-(1-6C)alkylamino, N,N-(1-6C)dialkylamino, heterocycle, heterocyclo(1-6C)alkyl, aryl(1-6C)alkyl, heteroaryl(1-6C)alkyl, N-(1-6C)alkylamino(1-6C)alkyl, N,N-(1-6C)dialkylamino(1-6C)alkyl, N-(1-6C)acylamino(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylsulfonyl(1-6C)alkyl, halo(1-6C)alkyl, (1-6C)alkylphosphono(1-6C)alkyl or aminocarbonyl(1-6C)alkyl (all optionally substituted); or NR7>+R8>optionally substituted heterocyclic radical; and n : 1-3. #CMT#[Image]#/CMT# #CMT#ACTIVITY : #/CMT# Cytostatic; Antipsoriatic; Antiarthritic; Antirheumatic; Nephrotropic; Antiarteriosclerotic; Immunosuppressive; Antiinflammatory. #CMT#MECHANISM OF ACTION : #/CMT# None given. #CMT#USE : #/CMT# (I) are useful in medicament to treat or prevent neoplastic disease, such as cancer, which is solid tumors, chronic and acute leukemia, metastases, cancer of prostate, lung, non small cell lung, breast, endometrium, colon, skin, pancreas, head and neck, uterus, ovaries, kidney, bone, rectum, anal region, stomach, esophagus, small intestine, endocrinal system, bladder, urethra, osteosarcoma, solid tumors of child, lymphocytic lymphomas, skin or intraocular melanoma, gynecologic tumor, Hodgkin disease, sarcoma of soft parts, pediatric malignant tumors and tumors of nervous central system, in particular cerebral tumor. (I) are useful in medicament to prevent or treat a disease associated with an abnormal cellular proliferation, such as psoriasis, rheumatoid arthritis, Kaposis sarcoma, acute and chronic nephropathies, atherosclerosis, autoimmune diseases and acute and chronic inflammatory diseases (all claimed). The ability of (I) to treat acute and chronic leukemia was tested in leukemia cells of type U937. The result showed that IC50 value of 2-(4-{5-[3-(4-chloro-phenyl)-benzofuran-6-yloxy]-pentyl}-piperazin-1-yl)-N-isopropyl-N-methyl-acetamide was 0.06 mu M. #CMT#ADVANTAGE : #/CMT# (I) are selective to kill the tumor cells, without reaching significantly healthy cells. #CMT#ORGANIC CHEMISTRY : #/CMT# Preparation (Disclosed): Preparation of (I) comprises: reaction of hydroxy compounds of formula (V) with heterocyclic compounds of formula (VI) in the presence of organic solvent to give (I). Z1>OH or nucleophile group such as Cl, Br, mesylate, tosylate or triflate. #CMT#[Image]#/CMT# #CMT#DEFINITIONS : #/CMT# Preferred Definitions: R5>H (preferred), acetylmethylaminomethyl, methylaminomethyl, hydroxymethyl or methylaminoethyl; Y1>N, O or NR6>; A : phenyl, naphthalene, pyridinyl, benzofuranyl, thiophenyl, benzothiophenyl, furanyl, dibenzofuranyl, 3-benzo[1,3]dioxolyl or dihydrobenzo[1,4]dioxinyl (all optionally substituted by 1-5 Cl, F, Br, CH3, OH, hydroxymethyl, OCH3, OC2H5, propoxy, methylsulfanyl, methanesulfonyl, ethanesulfonyl, CN, phenyl, CF3, trufluoromethoxy, NR3>R4>, NR3>COR4> or CONR3>R4>), preferably 4-chlorophenyl; R3>, R4>H, CH3 or isopropoxy; NR3>+R4>pyrrolidinyl; R6>H, CH3 (preferred) or acetyl; either R1>phenyl, piperidinyl, piperidinylmethyl, 2H-tetrazol-5-ylethyl, dimethylaminoethyl, dimethylaminopropyl or guanidinoethyl (all optionally substituted by CH3, -COOC(CH3)3 or OCH3), G, H, CN, OH or ethanone, preferably piperidinylmethyl or dimethylaminopropyl (both optionally substituted by CH3), G, H or OH; and R2>phenyl, benzyl, piperazidinyl, amino, methylamino or dimethylamino (all optionally substituted by CH3, Cl or N,N-dimethylacetamide), preferably piperazinyl or phenyl (both optionally substituted by CH3 or Cl); or CR1>+R2>indanyl, indenyl, 1,1-dioxo-1,2,3,4-tetrahydro-1-lambda 6>-tetrahydro-benzo[1,2,4]thiadiazin-3-yl, 1,3-dihydro-isobenzofuranyl, 3H-isobenzofuranone or 3,4-dihydro-1H-quinoxalin-2-one; L : CO; either R7>, R8>H, CH3, isopropyl, pyrrolidinylethyl, imidazolylpropyl, dimethylaminomethylethyl, dimethylaminoethyl, dimethylaminopropyl or butyldiethylester phosphonic acid (all preferred), C2H5, ethylpropyl, isobutyl, dimethylbutyl, n-secbutyl, allyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclohexylmethyl, cyclohexenylethyl, OH, OCH3, amino, dimethylamino, 1,1-dioxo-tetrahydro-1lambda 6>-thiophen-3-yl, indanyl, piperidinyl, azetidinyl, 2-oxopyrrolidinylethyl, pyrrolidinylmethyl, morpholinylethyl, 2,4-dioxo-thiazolidin-3-yl, piperidinylethyl, piperidinylpropyl, piperazinylpropyl, phenylethyl, thiophenylethyl, furanylmethyl, pyridinylethyl, pyrrolylethyl, pyrazolylpropyl, imidazolylethyl, 3-hydroxy-1H-pyrazol-4-ylpropyl, dimethylaminodimethylpropyl, dimethylaminomethylbutyl, diethylaminopropyl, diethylaminoethyl, diisopropylaminoethyl, dimethylaminoethyl, isopropylaminopropyl, acethylaminoethyl, methoxypropyl, methoxyethyl, methanesulfonylethyl, fluoroethyl or propionamide (all optionally substituted by CH3, C2H5, OH or sulfamoyl); or NR7>+R8>piperazinyl, oxopyrrolidinyl, piperidinyl or pyrrolidinyl (all optionally substituted by CH3 or dimethylamino); and B1>n-pentyl (-(CH2)5-) (preferred), -(CH2)4- or -(CH2)6-. #CMT#ADMINISTRATION : #/CMT# Administration of (I) is 1-1000 (preferably 0.1-500) mg, orally, intravenously, intraperitoneally, intranasally, transdermally, intramuscularly, intra-arterially, sublingually, topically, rectally or by subcutaneous implantation. #CMT#SPECIFIC COMPOUNDS : #/CMT# 83 Compounds (I) are specifically claimed e.g. 2-(4-{5-[3-(4-chloro-phenyl)-benzofuran-6-yloxy]-pentyl}-piperazin-1-yl)-N-isopropyl-acetamide of formula (Ia), 2-(4-{4-[3-(4-chloro-phenyl)-benzofuran-6-yloxy]-butyl}-piperazin-1-yl)-N-isopropyl-acetamide, 2-(4-{6-[3-(4-chloro-phenyl)-benzofuran-6-yloxy]-hexyl}-piperazin-1-yl)-N-isopropyl-acetamide, 2-(4-{5-[2-(acetylamino-methyl)-3-(4-chloro-phenyl)-benzofuran-6-yloxy]-pentyl}-piperazin-1-yl)-N,N-dimethyl-acetamide, and N'-[2-(4-{5-[3-(4-chloro-phenyl)-benzofuran-6-yloxy]-pentyl}-piperazin-1-yl)-ethyl]-N,N-dimethyl-ethane-1,2-diamine. #CMT#EXAMPLE : #/CMT# In a reactor, (3-(4-chlorophenyl)-benzofuran-6-ol) in the acetonitrile was added. Then 1.5-dibromopentane (2-5 equivalent) and potassium carbonate (2-3 equivalent) were added to the reaction mixture, refluxed for 3-5 hours and worked up to give (6-(5-bromopentyloxy)-3-(4-chlorophenyl) benzofuran). In a reactor, (6-(5-bromopentyloxy)-3-(4-chlorophenyl)benzofuran), N-isopropyl-2 -piperazin-1-yl-acetamide (1-3 equivalent) and potassium carbonate (2-5 equivalent) in acetonitrile were added. Then potassium iodide (0-1.3 equivalent) was added to the reaction mixture and refluxed for 5-20 hours. Then the reaction mixture was worked up to give 2-(4-{5-[3-(4-chloro-phenyl)-benzofuran-6-yloxy]-pentyl}-piperazin-1-yl)-N-isopropyl-acetamide (2.38 g, 70%). |
