Detail of "409127-32-8"

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Preparation of novel phenylalanine derivatives as inhibitors of integrin a4

Preparation of novel phenylalanine derivatives as inhibitors of integrin a4. Suzuki, Nobuyasu; Yoshimura, Toshihiko; Izawa, Hiroyuki; Sagi, Kazuyuki; Makino, Shingo; Nakanishi, Eiji; Murata, Masahiro; Tsuji, Takashi (Ajinomoto Co., Inc., Japan). PCT Int. Appl. WO 2002028830 A1 11 Apr 2002, 95 pp. DESIGNATED STATES: W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PH, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW, AM, AZ, BY, KG, KZ, MD, RU, TJ, TM; RW: AT, BE, BF, BJ, CF, CG, CH, CI, CM, CY, DE, DK, ES, FI, FR, GA, GB, GR, IE, IT, LU, MC, ML, MR, NE, NL, PT, SE, SN, TD, TG, TR. (Japanese). (World Intellectual Property Organization). CODEN: PIXXD2. CLASS: ICM: C07D207-448. ICS: C07D209-48; C07D209-52; C07D209-76; C07D223-18; C07D217-24; C07D211-88; C07D221-14; C07D403-12; C07D209-46; C07D471-04; C07D487-04; C07D209-66; C07D207-38; C07D211-86; C07D223-10; C07D225-06; C07D227-087; C07D495-04; C07D221-20. APPLICATION: WO 2001-JP8489 28 Sep 2001. PRIORITY: JP 2000-299490 29 Sep 2000; JP 2001-41885 19 Feb 2001. DOCUMENT TYPE: Patent CA Section: 34 (Amino Acids, Peptides, and Proteins) Section cross-reference(s): 1 Specific phenylalanine derivs. (I) or pharmaceutically acceptable salts thereof [A = Q, Q1, Q2; X = CO, CR3R4; Y = bond, CR5R6, CR7:CR8, lower alkyl chain optionally contg. 1 or 2 of O, S, or arom. ring in the chain; Z = CR9R10, CR11R12CR13R14, lower alkyl or C2-3 alkylene chain optionally contg. 1 or 2 of O, S, or arom. ring in the chain; R1 - R14, R1', R2' = H, lower alkyl, alkenyl, alkynyl, or cycloalkyl optionally contg. a hetero atom in the ring, aryl, heteroaryl, cycloalkyl (optionally contg. a hetero atom)-lower alkyl or -lower alkoxy, aryl-lower alkyl, heteroaryl-lower alkyl, lower alkoxy, lower alkoxycarbonyl, lower alkylcarbonyl, cyano,NO2, lower alkylsulfonyl, lower alkylsulfonylamino, etc.; B = HO, lower alkoxy, hydroxyamino; E = H, lower alkyl, alkenyl, or alkynyl, cycloalkyl (optionally contg. a hetero atom in the ring)-lower alkyl, aryl-lower alkyl, heteroaryl-lower alkyl; D = lower alkyl, alkenyl, or alkynyl,lower alkoxy, hydroxyamino; E = H, lower alkyl, alkenyl, or alkynyl, cycloalkyl (optionally contg.In this study，409127-32-8 is also used. a hetero atom in the ring)-lower alkyl or -lower alkoxy, aryl-lower alkyl, heteroaryl-lower alkyl, lower alkoxy, aryl-lower alkoxy, heteroaryl-lower alkoxy, etc.; T = bond, COP, SO, SO2, NHCO, NHCS, CH2CO, CH:CHCO; J, J' = H, halo, lower alkyl, lower alkoxy, NO2] are prepd. These compds. have an effect of inhibiting a4 integrin and, therefore, are useful as remedies or preventives for inflammatory diseases wherein the a4 integrin-dependent adhesion process participates in the pathol. conditions, for example, rheumatoid arthritis, inflammatory intestinal diseases, systemic lupus erythematosus, multiple sclerosis, Sjogren's disease, asthma, psoriasis, allergy, diabetes, cardiovascular diseases, arteriosclerosis, restenosis, tumor proliferation, tumor metastasis, and rejection in transplantation. Thus, a mixt. of 2,6-dichloro-4-(5-tetrazolyl)benzoic acid 35, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 30, 1-hydroxybenzotriazole monohydrate 23, Et3N 15, and (2S)-2-amino-3-[4-(4-methyl-1,3-dioxo-1,3-dihydroisoindol-2-yl)phenyl]p ropionic acid Et ester hydrochloride 35 mg in 5 mL CH2Cl2 was stirred at room temp. for 3 days, followed by treatment with a mixt. of 4 N HCl/dioxane and H2O to (2S)-2-((2,6-dichloro-4-(5-tetrazolyl)benzoyl)amino)-3-[4-(4-methyl-1,3-d ioxo-1,3-dihydroisoindol-2-yl)phenyl]propionic acid (II). II in vitro inhibited the binding of VCAM-1 to human T-cell Jurkat expressing integrin a4b1 and that of VCAM-1 to human lymphoma B cell expressing integrin a4b7 with IC50 of 0.0059 and 0.00055 mM, resp. .