| 摘要 |
#CMT# #/CMT# Benzene compounds (I) and their salts are new. #CMT# : #/CMT# Benzene compounds of formula (I) and their salts are new. Ar1(hetero)aryl (optionally substituted with 1-5 times of halo, 1-6C-alkyl, OH, hydroxy(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkyl, (1-6C)thioalkoxy, CN, (1-6C)haloalkyl, (1-6C) haloalkoxy, aryl, N-(1-6C)alkylamino or N,N-(1-6C)dialkylamino); X, Y1N or CH; D : C or N; R1G, aryl, aryl(1-6C)alkyl, heteroaryl, heteroaryl(1-6C)alkyl, heterocyclic or heterocycle(1-6C)alkyl (all optionally substituted) (when D is nitrogen atom) or H, OH, 1-6C alkylcarbonyl or CN (when D is carbon atom); R2electron doublets or (when D is nitrogen atom) or aryl (optionally substituted) (when D is carbon atom); G : amine group of formula (-CH2-L-N(R3)-R4) (1a); L : CO or (CH2)m; either R3, R4(1-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl(1-6C)alkyl, heterocyclic, heterocycle(1-6C)alkyl, aryl(1-6C)alkyl, heteroaryl(1-6C)alkyl, N(1-6C)alkylamino(1-6C)alkyl or N,N(1-6C)dialkylamino(1-6C)alkylene (all optionally substituted) or H; or NR3R4heterocyclic (optionally substituted); m : 1-3; and n : 4-6. #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 for treating/preventing: neoplastic diseases comprising cancer; solid tumor, chronic or acute leukemia and metastasis; abnormal cellular proliferation, psoriasis, rheumatoid arthritis, Kaposis sarcoma, acute or chronic nephropathy, atherosclerosis, autoimmune diseases and acute or chronic inflammatory, where the cancer is prostate, osteosarcoma, lung, non-small cell lung, breast, endometrium or colon, acute or chronic leukemia, solid tumors of the child, lymphocytic lymphoma, pancreas, skin, skin or intraocular melanoma, head and neck, uterus, ovary, gynecological tumor, Hodgkin, bones, rectum, anal region, stomach, oesophagus, small intestine, endocrine system, soft part sarcoma, penis, bladder, ureter, pediatric malignant tumor, kidney and central nervous system, preferably cerebral tumor (all claimed). The ability of (I) to treat neoplastic disease was tested in human leukemic monocyte lymphoma cell line (U937). The results showed that (I) (2-(4-{5-[1-(4-chloro-phenyl)-1H-indol-5-yloxy]-pentyl}-piperazin-1-yl)-N-isopropyl-N-methyl-acetamide) exhibited the IC50 value of 0.03 mu M. #CMT#ADVANTAGE : #/CMT# (I) have no side effects. #CMT#ORGANIC CHEMISTRY : #/CMT# Preparation (Disclosed): Preparation of (I) comprises: demethylating a 5-methoxy-1H-benzoimidazole compound of formula (D3) to give a 1H-benzoimidazol-5-ol compound of formula (E3); introducing alkyl chain in (E3) to give a 1H-benzoimidazole compound of formula (F3); and amino cylization of (F3) to give a benzoimidazole compound of formula (II) (representative of (I)). Z1OH or nucleophilic group comprising Cl, Br, mesylate radical, tosylate radical or triflate radical. #CMT#[Image]#/CMT# #CMT#[Image]#/CMT# #CMT#DEFINITIONS : #/CMT# Preferred Definitions: D : N; R1heterocyclic; R2electron doublets; X, Y1CH or N; Ar1phenyl (optionally substituted by at least an atom of halo, preferably Cl); and R3, R4H, 1-6C alkyl, N-(1-6C)alkylamino(1-6C)alkyl or N,N-(1-6C)dialkylamino(1-6C)alkyl. #CMT#ADMINISTRATION : #/CMT# Administration of (I) is 0.01-100 mg/kg, orally, intravenously, intraperitoneally, intranasally, transdermally, intramuscularly, intraarterially, rectally or topically. #CMT#SPECIFIC COMPOUNDS : #/CMT# 19 Compounds (I) are specifically claimed e.g. 2-(4-{5-[1-(4-chloro-phenyl)-1H-indol-5-yloxy]-pentyl}-piperazin-1-yl)-N-isopropyl-acetamide, 4-(4-chloro-phenyl)-1-{5-[1-(4-chloro-phenyl)-1H-indol-5-yloxy]-pentyl}-piperidin-4-ol, 1-(4-chloro-phenyl)-5-{5-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-pentyloxy}-1H-indole, 2-(4-{5-[1-(4-chloro-phenyl)-1H-indol-5-yloxy]-pentyl}-piperazin-1-yl)-N,N-dimethyl-acetamide and 2-(4-{5-[1-(4-chloro-phenyl)-1H-indol-5-yloxy]-pentyl} -piperazin-1-yl)-N-isopropyl-N-methyl-acetamide of formula (Ia). #CMT#EXAMPLE : #/CMT# A solution of dimethylformamide (DMF) (150 ml) (containing (isopropyl-carbamoyl-methyl)-piperazine-1-carboxylate (12 g) and tert-butyl(4-(isopropyl-carbamoyl-methyl)-piperazine-1-carboxylate) (42 mmol)) were added drop by drop to 0[deg] C on a suspension of sodium hydride (1.8 g) in DMF (60 ml), in a 500 ml of tricol. Methyl iodide (2.61 ml) was added and shaken to 0[deg] C during 16 hours. The mixture was agitated for 16 hours. The reaction mixture was concentrated. The obtained residue was worked up to give tert-butyl-(4-[(isopropyl-methyl-carbamoyl)-methyl]-piperazine-1-carboxylate) (A). Chlorohydride ether (60 ml) was added to a solution of DMF (200 ml) and (A) (10.4 g) and shaken to ambient temperature for 5 days, then concentrating to dry by distillation of the solvent under reduced pressure. The obtained residue was worked up to give (N-isopropyl-N-methyl-piperazin-1-yl-acetamide) (B1). In a tricol, (5-bromo-pentyloxy)-1-(4-chlorophenyl)-1H-indole (200 mg) and (B1) (208 mg), anhydride potassium carbonate (9.81 g), copper iodide (200 mg) and copper powder (1.27) were suspended in dimethylacetamide (20 ml) and shaken for 9 hours at 140[deg] C and worked up to give (2-(4-{5-[1-(4-chloro-phenyl)-1H-indol-5-yloxy]-pentyl}-piperazin-1-yl)-N-isopropyl-N-methyl-acetamide). |
