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5-ht4 receptor antagonistsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai5-ht4 receptor antagonists description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060094702, 5-ht4 receptor antagonists. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This is a continuation of application Ser. No. 10/317,159 filed Dec. 11, 2002 (pending) which is a continuation of application Ser. No. 09/939,914 filed Aug. 27, 2001(abandoned), application Ser. No. 09/013,135 filed Jan. 26, 1998 (abandoned), which is a continued prosecution application of Application Ser. No. 09/013,135 filed Dec. 1, 2000, which is a continued prosecution application of application Ser. No. 09/013,135 filed Feb. 24, 2000, which is a divisional application of application Ser. No. 08/553,390 filed Nov. 22, 1995 U.S. Pat. No. 5,741,801, which is a 371 of International Application No. PCT/EP94/01583 filed May 16, 1994, which claims benefit from foreign application GB 9310582.3 filed May 22, 1993. [0002] This invention relates to novel compounds having pharmacological activity, to a process for their preparation and to their use as pharmaceuticals. [0003] European Journal of Pharmacology 146 (1988), 187-188, and Naunyn-Schmiedeberg's Arch. Pharmacol. (1989) 340:403-410, describe a non classical 5-hydroxytryptamine receptor, now designated the 5-HT.sub.4 receptor, and that ICS 205-930, which is also a 5-HT.sub.3 receptor antagonist, acts as an antagonist at this receptor. [0004] WO 91/16045 (SmithKline and French Laboratories Limited) describes the use of cardiac 5-HT.sub.4 receptor antagonists in the treatment of atrial arrhythmias and stroke. [0005] EP-A-501322 (Glaxo Group Limited), WO 93/02677, WO 93/03725, WO 93/05038, WO 93/05040, WO 93/18036, PCT/EP93/03054, PCT/GB93/01895, PCT/GB93/02028, PCT/EP93/02808, PCT/EP93/02775, PCT/EP93/02809, PCT/GB93/02130, PCT/EP93/003054, PCT/GB94/000172 (SmithKline Beecham plc) describe compounds having 5-HT.sub.4 receptor antagonist activity. [0006] It has now been discovered that certain novel compounds also have 5-HT.sub.4 receptor antagonist properties. [0007] Accordingly, the present invention provides a compounds of formula (I) and pharmaceutically acceptable salts thereof, and the use of a compound of formula (1) or a pharmaceutically acceptable salt thereof: X--CO--CH.sub.2-Z (I) [0008] X is a monocyclic or polycyclic aromatic group, such as a group of formula (a), (b), wherein [0009] L is N or CR.sub.S wherein R.sub.S is hydrogen, C.sub.1-6 alkoxy, halogen, C.sub.1-4 alkyl or cyano; [0010] Q is NR.sub.1.sup.a, CH.sub.2, O or S; [0011] W is CH or N; [0012] X.sub.1--(CH.sub.2).sub.x--X.sub.2 forms a 5-7 membered ring wherein X.sub.1 is O or S; X.sub.2 is O, S, --CH.sub.2--, NR or NRCO wherein R is hydrogen or C.sub.1-6 alkyl; and [0013] x is 1, 2 or 3; [0014] one of X.sub.3 and X.sub.4 is N and the other is C; and [0015] X.sub.5 is N or CR.sup.1 wherein R.sup.1 is hydrogen, C.sub.1-6 alkoxy, halo, C.sub.1-6 alkyl or cyano; [0016] R.sub.1.sup.a is hydrogen, C.sub.1-10 alkyl, C.sub.2-6 alkenyl, aralkyl, C.sub.2-6 alkanoyl or C.sub.2-6 alkanoyl C.sub.1-3 alkyl; [0017] R.sub.3.sup.a is hydrogen, halo, C.sub.1-6 alkyl, amino, nitro or C.sub.1-6 alkoxy; [0018] R.sub.4.sup.a is hydrogen, halo, C.sub.1-6 alkyl or C.sub.1-6 alkoxy; [0019] R.sub.1.sup.b is C.sub.1-6 alkoxy; and [0020] R.sub.2.sup.b is hydrogen, chloro or fluoro; [0021] R.sub.3.sup.b is hydrogen, C.sub.1-6 alkyl, amino optionally substituted by a C.sub.1-6 alkyl group, halo, hydroxy or C.sub.1-6 alkoxy; [0022] R.sub.4.sup.b is hydrogen, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, nitro, amino or C.sub.1-6 alkylthio; and [0023] R.sub.5.sup.b is hydrogen, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or amino; [0024] R.sub.c is hydrogen, C.sub.1-6 alkoxy, halo or C.sub.1-6 alkyl; [0025] R.sub.1.sup.d is hydrogen, amino, halo, C.sub.1-6 alkyl, hydroxy or C.sub.1-6 alkoxy; [0026] R.sub.2d is hydrogen, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, nitro, amino or C.sub.1-6 alkylthio; [0027] R.sub.3.sup.d is hydrogen, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or amino; [0028] R.sub.4.sup.d and R.sub.5.sup.d are independently hydrogen or C.sub.1-6 alkyl; [0029] R.sub.1.sup.e is hydrogen, halogen, CF.sub.3, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulphonyl, C.sub.1-6 alkylsulphinyl, C.sub.1-7 acyl, cyano, C.sub.1-6 alkoxycarbonyl, C.sub.1-7 acylamino, hydroxy, nitro or amino, aminocarbonyl, or aminosulphonyl, optionally N-substituted by one or two groups selected from C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, and C.sub.3-8 cycloalkyl C.sub.1-4 alkyl or disubstituted by C.sub.4 or C.sub.5 polymethylene; phenyl or phenyl C.sub.1-4 alkyl group optionally substituted in the phenyl ring by one or two of halogen, C.sub.1-6 alkoxy or C.sub.1-6 alkyl groups; [0030] R.sub.3.sup.e is hydrogen, halo, C.sub.1-6 alkyl, amino, nitro or C.sub.1-6 alkyl; [0031] R.sub.4.sup.e is hydrogen, halo, C.sub.1-6 alkyl or C.sub.1-6 alkoxy; [0032] X.sub.6-X.sub.7 is NR.sub.z--CO or CR.sub.1.sup.fR.sub.2.sup.f--CR.sub.3.sup.fR.sub.4.sup.f where [0033] R.sub.z and R.sub.1.sup.f to R.sub.4.sup.f are independently hydrogen or C.sub.1-6 alkyl; and/or [0034] R.sub.1.sup.f/R.sub.2.sup.f and R.sub.3.sup.f/R.sub.4.sup.f together are a bond and/or R.sub.1.sup.f/R.sub.2.sup.f/R.sub.3.sup.f/R.sub.4.sup.f are joined to form C.sub.3-6 polymethylene; [0035] R.sub.a.sup.f is hydrogen, halo, C.sub.1-6 alkyl, amino, nitro or C.sub.1-6 alkyl; [0036] R.sub.b.sup.f is hydrogen, halo, C.sub.1-6 alkyl or C.sub.1-6 alkoxy; [0037] X.sup.g is O, S, SO, SO.sub.2, CH.sub.2, CH, N or NR wherein R is hydrogen or C.sub.1-6 alkyl; [0038] A is a saturated or unsaturated polymethylene chain of 2-4 carbon atoms; [0039] R.sub.1.sup.g and R.sub.2.sup.g are hydrogen or C.sub.1-6 alkyl; [0040] R.sub.3.sup.g is hydrogen, halo, C.sub.1-6 alkyl, amino, nitro or C.sub.1-6 alkoxy; [0041] R.sub.4.sup.g is hydrogen, halo, C.sub.1-6 alkyl or C.sub.1-6 alkoxy; [0042] Z is of sub-formula (h), (j) or (k): wherein [0043] n.sup.1 is 1, 2, 3 or 4; n.sup.2 is 0, 1, 2, 3 or 4; n.sup.3 is 2, 3, 4 or 5; [0044] q is 0, 1, 2 or 3; p is 0, 1 or 2; m is 0, 1 or 2; [0045] R.sub.5 is hydrogen, C.sub.1-12 alkyl, aralkyl or R.sub.5 is (CH.sub.2).sub.z-R.sub.10 wherein z is 2 or 3 and R.sub.10 is selected from cyano, hydroxyl, C.sub.1-6 alkoxy, phenoxy, C(O)C.sub.1-6 alkyl, COC.sub.6H.sub.5, --CONR.sub.11R.sub.12, NR.sub.11COR.sub.12, SO.sub.2NR.sub.11R.sub.12 or NR.sub.11SO.sub.2R.sub.12 wherein R.sub.11 and R.sub.12 are hydrogen or C.sub.1-6 alkyl; or R.sub.5 is straight or branched chain alkylene of chain length 1-6 carbon atoms terminally substituted by aryl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 5 or 6 membered monocyclic heteroaryl or 9 or 10 membered fused bicyclic heteroaryl linked through carbon, C.sub.2-7 alkoxycarbonyl, or secondary or tertiary hydroxy substituted C.sub.1-6 alkyl; ; and [0046] R.sub.6, R.sub.7 and R.sub.8 are independently hydrogen or C.sub.1-6 alkyl; and [0047] R.sub.9 is hydrogen or C.sub.1-10 alkyl; having 5-HT.sub.4 receptor antagonist activity. [0048] Examples of alkyl or alkyl containing groups include C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, C.sub.8, C.sub.9, C.sub.10, C .sub.11 or C.sub.12 branched, straight chained or cyclic alkyl, as appropriate. C.sub.1-4 alkyl groups include methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl. Cyclic alkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl optionally substituted by one of more alkyl groups of up to 4 carbon atoms. [0049] Aryl includes phenyl and naphthyl optionally substituted by one or more substituents selected from halo, C.sub.1-6 alkyl and C.sub.1-6 alkoxy. [0050] Values for monocyclic heteroaryl include pyridyl, pyrimidyl, pyrazinyl, pyrryl, imidazolyl, thienyl, furanyl, oxazole or thiazole (all possible isomers). Bicyclic heteroaryl include benzofuranyl, benzothiophenyl, indolyl and indazolyl, quinolyl and isoquinolyl (all possible isomers). [0051] Values for 3 to 8 membered heterocyclyl, include cyclic polymethylene interrupted by one or two of N, O or S, linked through C or N, for example N-linked piperidinyl or pyrrolidinyl. [0052] Halo includes fluoro, chloro, bromo and iodo, preferably chloro. [0053] L in formula (a) is favourably C--H, C--CH.sub.3, C--Cl or C--OCH.sub.3. [0054] Q in formula (a) is favourably NR.sub.1.sup.a. [0055] R.sub.1.sup.a is preferably hydrogen or a methyl or ethyl group. [0056] R.sub.1.sup.b is preferably methoxy. [0057] R.sub.3.sup.b is preferably amino. [0058] R.sub.4.sup.b is preferably halo. [0059] R.sub.5.sup.b is preferably hydrogen. [0060] A substituent when halo is selected from fluoro, chloro, bromo and iodo. R.sub.4.sup.a when halo is preferably iodo [0061] Suitable examples of the X.sub.1--(CH.sub.2).sub.x--X.sub.2 moiety include O--(CH.sub.2).sub.2--O, O--(CH.sub.2).sub.3--O, O--CH.sub.2--O, O--(CH.sub.2).sub.2--NR, O--(CH.sub.2).sub.2--S or O--CH.sub.2--CONR, wherein any of the methylene linkages are optionally mono- or di- substituted by C.sub.1-6 alkyl groups, such as methyl. Preferably X.sub.1--(CH.sub.2).sub.2--X.sub.2 is O--(CH.sub.2).sub.2--O. [0062] Further suitable examples of X.sub.1--(CH.sub.2).sub.x--X.sub.2 include O--(CH.sub.2).sub.2--CH.sub.2, O--(CH.sub.2).sub.3--CH.sub.2, O--CH.sub.2--CH.sub.2, or corresponding values wherein X.sub.1.dbd.X.sub.2.dbd.CH.sub.2, wherein any of the methylene linkages are optionally mono- or di-substituted by C.sub.1-6 alkyl groups, such as methyl. Preferably such X.sub.1--(CH.sub.2).sub.2--X.sub.2 is O--(CH.sub.2).sub.2--CH.sub.2. [0063] R.sub.1.sup.d is preferably hydrogen or amino. [0064] R.sub.2.sup.d is preferably hydrogen or halo. [0065] R.sub.3.sup.d is preferably hydrogen or halo. [0066] R.sub.4.sup.d and R.sub.5.sup.d are often hydrogen. When R.sub.4.sup.d or R.sub.5.sup.d is C.sub.1-6 alkyl, it is often methyl. [0067] R.sub.1.sup.e is preferably CF.sub.3 or an ethyl group. [0068] X.sub.5 is preferably N, C--H or C--OCH.sub.3; [0069] R.sub.3.sup.e is preferably hydrogen. [0070] R.sub.4.sup.e is preferably hydrogen or halo, such as iodo. [0071] Suitable examples of X.sub.6-X.sub.7 when CR.sub.1.sup.fR.sub.2.sup.f--CR.sub.3.sup.fR.sub.4.sup.f include CH.sub.2--CH.sub.2 and CH.dbd.CH. X.sub.6--X.sub.7 is preferably NR.sub.z--CO, however, such as NH--CO or NEt-CO. [0072] R.sub.a.sup.f is preferably hydrogen. [0073] R.sub.b.sup.f is preferably hydrogen or halo, such as iodo. [0074] Values for A include --CH.sub.2--(CH.sub.2).sub.r--CH.sub.2-- wherein r is 0, 1 or 2; --CH.sub.2--CH.dbd.CH--; --C(CH.sub.3).dbd.CH-- or when Xg is CH or N, A may be --(CH.sub.2).sub.2--CH.dbd.or --CH.dbd.CH--CH.dbd.. Other examples of A are as described in the aforementioned patent publications. [0075] R.sub.1.sup.g and R.sub.2.sup.g are often hydrogen or R.sub.1.sup.g and R.sub.2.sup.9 are gem-dimethyl. r is often 1. [0076] R.sub.3.sup.g is preferably hydrogen. [0077] R.sub.4.sup.g is preferably hydrogen or halo, such as fluoro. [0078] Other suitable values of X are as described in PCT/GB93/020208, PCT/EP93/02808, PCT/EP93/02775, PCT/EP93/02809, PCT/GB93/02130, PCT/GB94/00172 (all in the name of SmithKline Beecham plc). [0079] When Z is of sub-formula (h), n.sup.1 is preferably 2, 3 or 4 when the azacycle is attached at the nitrogen atom and n1 is preferably 1 when the azacycle is attached at a carbon atom, such as the 4-position when q is 2. [0080] When Z is of sub-formula (j), n.sup.2 is preferably such that the number of carbon atoms between the ester or amide linkage is from 2 to 4 carbon atoms. [0081] Suitable values for p and m include p=m=1; p=0, m=1, p=1, m=2 p=2, m=1. [0082] When Z is of sub-formula (k), n.sup.3 is preferably 2, 3 or 4. Continue reading about 5-ht4 receptor antagonists... Full patent description for 5-ht4 receptor antagonists Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this 5-ht4 receptor antagonists patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. Start now! - Receive info on patent apps like 5-ht4 receptor antagonists or other areas of interest. ### Previous Patent Application: Heat sterilization of a steroid in the presence of phosphate Next Patent Application: Use of beta-2 bronchodilator drugs Industry Class: Drug, bio-affecting and body treating compositions ### FreshPatents.com Support Thank you for viewing the 5-ht4 receptor antagonists patent info. 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