Fused pyrimidine compounds and their use as pharmaceuticals
First Claim
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1. A compound of the formula ##STR27## in which R1 is either R1a selected froma) hydrogen,b) C1-8 -alkyl, C3-8 -cycloalkyl, C4-8 -cycloalkylalkyl, or C4-8 -alkylcycloalkyl, which optionally may be substituted by one or more fluoro or chloro substituents, or by a single hydroxy, C1-4 -alkoxy, or C1-4 -alkylthio,c) phenyl or phenyl-C1-3 -alkyld) C2-8 -alkenyl, C3-8 -cycloalkenyl, or C2-8 -alkynyl, which optionally may be substituted by phenyl, orR1b selected froma) C1-6 -alkylthio, C3-6 -cycloalkylthio, C1-6 -alkoxy, C3-6 -cycloalkoxy, mono-C1-6 -alkylamino, or mono-C3-6 -cycloalkylamino, in which an alkyl group optionally may be substituted by phenyl or by one or more fluoro substituents,b) phenylthio or phenoxy,c) di-C1-4 -alkylamino, in which the alkyl groups may be the same or different or together form a polymethylene ring with three, four, five, or six carbon atoms, which optionally may be interrupted by an oxygen atom and optionally may be substituted by one or more fluoro substituents,d) mono-phenylamino or mono-C1-4 -alkyl-monophenylamino, in which the alkyl groups optionally may be substituted by one or more fluoro substituents, ore) halo,R2 isa) hydrogen,b) C1-8 -alkyl, which optionally may be substituted by one or more fluoro substituents,c) phenyl,R3 is hydrogen or C1-4 -alkyl, and n is 0 or 1,X is O, S, or NR4, andR4 isa) hydrogen,b) C1-8 -alkyl, C3-8 -cycloalkyl, C4-8 -cycloalkylalkyl, or C4-8 -alkylcycloalkyl, which optionally may be substituted by phenyl or by one or more fluoro substituents,c) phenyl,d) (CH2)m COOR22,e) (CH2)m CONR23 R24,f) (CH2)m COOP1, in which P1 is a carboxy-protecting group,g) (CH2)m CN,h) (CH2)m (5-tetrazolyl),and m is 1 or 2 in groups d), e), f), g) or h)═
- A--B-- together with the pyrimidine ring formsa) a pyrazolo[1,5-a]pyrimidine of formula (A), ##STR28## c) an imidazo[1,5-a]pyrimidine of formula (C), ##STR29## or d) an imidazo[1,2-a]pyrimidine of formula (D), ##STR30## in which R5 isa) hydrogen,b) C1-8 -alkyl, C3-8 -cycloalkyl, C4-8 -cycloalkylalkyl, or C4-8 -alkylcycloalkyl, which optionally may be substituted by one or more fluoro or chloro substituents,c) phenyl-C1-3 -alkyl,d) hydroxy, C1-6 -alkoxy, C3-6 -cycloalkoxy, C1-3 -phenylalkoxy, or phenoxy, in which the alkyl and cycloalkyl groups optionally are substituted by one or more fluorine atoms,e) halo,f) mercapto,g) C1-6 -alkylthio, C1-6 -alkylsulfinyl, C1-6 -alkylsulfonyl, C3-6 -cycloalkylthio, C3-6 -cycloalkylsulfinyl, or C3-6 -cycloalkylsulfonyl, which optionally may be substituted by one or more fluorine atoms,h) phenylthio, phenylsulfinyl, phenylsulfonyl, phenyl-C1-3 -alkylthio, phenyl-C1-3 -alkylsulfinyl, or phenyl-C1-3 -sulfonyl,i) optionally substituted phenyl,j) cyano,k) COOR22,l) CONR23 R24,m) 5-tetrazolyl,n) COOP1, in which P1 is a carboxy-protecting group,o) SO3 H,p) SO2 NR23 R24,q) nitro or nitroso, with the proviso that these groups are not connected to C-2 of the heterocycle,r) NR23 R24,s) C1-6 -alkanoyl or 1-hydroxy-C1-6 -alkyl, which optionally may be substituted by one or more fluorine atoms,t) benzoyl or phenylhydroxymethyl,u) NH(C1-6 -alkanoyl) or NH(C1-6 -alkylsulfonyl), in which the alkyl groups optionally may be substituted by one or more fluorine atoms,v) NH(benzoyl) or NH(benzenesulfonyl),R6 isa) hydrogen,b) C1-8 -alkyl, C3-8 -cycloalkyl, C4-8 -cycloalkylalkyl, or C4-8 -alkylcycloalkyl, which optionally may be substituted by one or more fluoro or chloro substituents,c) halo,d) optionally substituted phenyl,e) C1-6 -alkylthio, C1-6 -alkylsulfinyl, C1-6 -alkylsulfonyl, C3-6 -cycloalkylthio, C3-6 -cycloalkylsulfinyl, or C3-6 -cycloalkylsulfonyl, which optionally may be substituted by one or more fluorine atoms,R7 has the meaning as defined for R5 with the exception of nitro and nitroso,R8 isa) hydrogen,b) C1-8 -alkyl, C3-8 -cycloalkyl, C4-8 -cycloalkylalkyl, or C4-8 -alkylcycloalkyl, which optionally may be substituted by one or more fluoro or chloro substituents,c) halo,d) phenyl,e) nitro,f) cyano,g) 5-tetrazolyl,h) COOR22,i) CONR23 R24,j) COOP1, in which P1 is a carboxy-protecting group,k) NR23 R24,l) NH(C1-6 -alkanoyl) or NH(C1-6 -alkylsulfonyl), in which the alkyl groups optionally may be substituted by one or more fluorine atoms,m) NH(benzoyl) or NH(benzenesulfonyl),R9 isa) hydrogen,b) C1-8 -alkyl, C3-8 -cycloalkyl, C4-8 -cycloalkylalkyl, or C4-8 -alkylcycloalkyl, which optionally may be substituted by one or more fluoro or chloro substituents,c) phenyl group,d) cyano,e) COOR22,f) CONR23 R24,g) 5-tetrazolyl,h) COOP1, in which P1 is a carboxy-protecting group,i) formyl,j) hydroxymethyl,R10 has independently the same meaning as R5,R11 has independently the same meaning as R6,Ar1 is a group selected froma) 1,4-phenylene of formula (E), ##STR31## b) 1,4-substituted pyridine of formula (F) or formula (G), ##STR32## or c) benzofuran, benzothiophene, or indole of formula (H), ##STR33## in which the group Z is O, S, or NR12, and R12 is hydrogen or C1-4 -alkyl,and in each of the groups Ar1 the substituentR13 isa) hydrogen,b) halo,c) C1-4 -alkyl,d) C1-4 -alkoxy,e) trifluoromethyl,f) nitro,R14 isa) hydrogen,b) C1-6 -alkyl, C3-6 -cycloalkyl, C4-6 -cycloalkylalkyl, or C4-6 -alkylcycloalkyl, which optionally may be substituted by one or more fluoro or chloro substituents,c) C2-6 -alkenyl or C3-6 -cycloalkenyl,d) halo,e) cyano,f) nitro,g) C1-6 -alkanoyl, in which the alkyl group optionally may be substituted by one or more fluorine atoms,h) C1-6 -alkoxy,i) COOR22,j) CONR23 R24,Ar2 is a group selected froma) phenyl of formula (I), ##STR34## b) pyridine of formula (J), ##STR35## c) 1-pyrrolyl of formula (K), ##STR36## or d) a five-membered heterocycle of formula (L), ##STR37## in which the group V is O, S, SO, SO2, or NR15, the group W is CH or N, and R15 is hydrogen or C1,4 -alkyl,with the proviso that in groups Ar2 of formula (J) and (L) the substituent R16 and the group Y are in ortho positions, and in each of the groups Ar2 the substituentR16 is hydrogen, 5-tetrazolyl, carboxy, sulpho, phosphono,COOP1, in which P1 is a carboxy-protecting group, or a group selected froma) cyano,b) a protected 5-tetrazolyl of formula (M), ##STR38## in which the group P2 is a protecting group, d) nitro,e) amino,f) mercapto,g) SO2 Cl,h) SO2 (OC1-4 -alkyl),i) PO(OC1-4 -alkyl)2,R17 has independently the same meaning as R13,R18 and R19 are independently selected froma) hydrogen,b) C1-6 -alkyl, C3-6 -cycloalkyl, C4-6 -cycloalkylalkyl, or C4-6 -alkylcycloalkyl, which optionally may be substituted by one or more fluoro or chloro substituents,c) C2-6 -alkenyl or C3-6 -cycloalkenyl,d) halo,e) nitro,f) cyano,g) C1-4 -alkylthio,Y is a group selected froma) a direct bond, CHR20, CHR20 CH2, OCHR20, OCHR20 CH2, SCHR20, SCHR20 CH2, NR21 CHR20, NR21 CHR20 CH2, CH2 CHR20, CH2 CHR20 CH2,b) O, S, SO2, NR21, CO, CONH, NHCO, CH2 O, CH2 S, CH2 NR21, with the proviso that when Y is (b), Ar1 is 1,4-phenylene of formula (E) and Ar2 is phenyl of formula (I),R20 is hydrogen ora) COOH,b) COOP1, in which P1 is a carboxy-protecting group,d) 5-tetrazolyl,e) cyano,f) a protected 5-tetrazolyl of formula (M),with the proviso that one of the substituents R16 and R20 is hydrogen and the other is a substituent other than hydrogen,R21 and R22 are independently selected from hydrogen or C1-6 -alkyl, andR23 and R24 are independently selected from hydrogen or C1-4 -alkyl, or together may form a polymethylene chain containing three, four or five carbon atoms, which optionally may be interrupted by an oxygen atom;
the phenyl groups of R1 choice c, R1a choice c), R1b choice b), R1b choice c), R2 choice c), R4 choice c), R5 choice d), R5 choice h), R5 choice t), R5 choice v), R8 choice d), R8 choice m) and R9 choice c) being unsubstituted or substituted by at least one member selected from the group consisting of halo, C1-4 -alkyl, C1-4 -alkoxy, C1-4 -alkylthio, C1-4 -alkylsulfinyl, C1-4 -alkylsulfonyl, cyano, nitro, trifluoromethyl and hydroxy.
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Accused Products
Abstract
Pharmaceutical compounds which are azolo-fused pyrimidine compounds having the formula ##STR1## in which ═A--B-- together with the pyrimidine ring forms a) a pyrazolo[1,5-a]pyrimidine of formula (A), ##STR2## b) a [1,2,4]triazolo[1,5-a]pyrimidine of formula (B), ##STR3## c) an imidazo[1,5-a]pyrimidine of formula (C), ##STR4## or d) an imidazo[1,2-a]pyrimidine of formula (D), ##STR5##
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Citations
14 Claims
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1. A compound of the formula ##STR27## in which R1 is either R1a selected from
a) hydrogen, b) C1-8 -alkyl, C3-8 -cycloalkyl, C4-8 -cycloalkylalkyl, or C4-8 -alkylcycloalkyl, which optionally may be substituted by one or more fluoro or chloro substituents, or by a single hydroxy, C1-4 -alkoxy, or C1-4 -alkylthio, c) phenyl or phenyl-C1-3 -alkyl d) C2-8 -alkenyl, C3-8 -cycloalkenyl, or C2-8 -alkynyl, which optionally may be substituted by phenyl, or R1b selected from a) C1-6 -alkylthio, C3-6 -cycloalkylthio, C1-6 -alkoxy, C3-6 -cycloalkoxy, mono-C1-6 -alkylamino, or mono-C3-6 -cycloalkylamino, in which an alkyl group optionally may be substituted by phenyl or by one or more fluoro substituents, b) phenylthio or phenoxy, c) di-C1-4 -alkylamino, in which the alkyl groups may be the same or different or together form a polymethylene ring with three, four, five, or six carbon atoms, which optionally may be interrupted by an oxygen atom and optionally may be substituted by one or more fluoro substituents, d) mono-phenylamino or mono-C1-4 -alkyl-monophenylamino, in which the alkyl groups optionally may be substituted by one or more fluoro substituents, or e) halo, R2 is a) hydrogen, b) C1-8 -alkyl, which optionally may be substituted by one or more fluoro substituents, c) phenyl, R3 is hydrogen or C1-4 -alkyl, and n is 0 or 1, X is O, S, or NR4, and R4 is a) hydrogen, b) C1-8 -alkyl, C3-8 -cycloalkyl, C4-8 -cycloalkylalkyl, or C4-8 -alkylcycloalkyl, which optionally may be substituted by phenyl or by one or more fluoro substituents, c) phenyl, d) (CH2)m COOR22, e) (CH2)m CONR23 R24, f) (CH2)m COOP1, in which P1 is a carboxy-protecting group, g) (CH2)m CN, h) (CH2)m (5-tetrazolyl), and m is 1 or 2 in groups d), e), f), g) or h) ═ - A--B-- together with the pyrimidine ring forms
a) a pyrazolo[1,5-a]pyrimidine of formula (A), ##STR28## c) an imidazo[1,5-a]pyrimidine of formula (C), ##STR29## or d) an imidazo[1,2-a]pyrimidine of formula (D), ##STR30## in which R5 is a) hydrogen, b) C1-8 -alkyl, C3-8 -cycloalkyl, C4-8 -cycloalkylalkyl, or C4-8 -alkylcycloalkyl, which optionally may be substituted by one or more fluoro or chloro substituents, c) phenyl-C1-3 -alkyl, d) hydroxy, C1-6 -alkoxy, C3-6 -cycloalkoxy, C1-3 -phenylalkoxy, or phenoxy, in which the alkyl and cycloalkyl groups optionally are substituted by one or more fluorine atoms, e) halo, f) mercapto, g) C1-6 -alkylthio, C1-6 -alkylsulfinyl, C1-6 -alkylsulfonyl, C3-6 -cycloalkylthio, C3-6 -cycloalkylsulfinyl, or C3-6 -cycloalkylsulfonyl, which optionally may be substituted by one or more fluorine atoms, h) phenylthio, phenylsulfinyl, phenylsulfonyl, phenyl-C1-3 -alkylthio, phenyl-C1-3 -alkylsulfinyl, or phenyl-C1-3 -sulfonyl, i) optionally substituted phenyl, j) cyano, k) COOR22, l) CONR23 R24, m) 5-tetrazolyl, n) COOP1, in which P1 is a carboxy-protecting group, o) SO3 H, p) SO2 NR23 R24, q) nitro or nitroso, with the proviso that these groups are not connected to C-2 of the heterocycle, r) NR23 R24, s) C1-6 -alkanoyl or 1-hydroxy-C1-6 -alkyl, which optionally may be substituted by one or more fluorine atoms, t) benzoyl or phenylhydroxymethyl, u) NH(C1-6 -alkanoyl) or NH(C1-6 -alkylsulfonyl), in which the alkyl groups optionally may be substituted by one or more fluorine atoms, v) NH(benzoyl) or NH(benzenesulfonyl), R6 is a) hydrogen, b) C1-8 -alkyl, C3-8 -cycloalkyl, C4-8 -cycloalkylalkyl, or C4-8 -alkylcycloalkyl, which optionally may be substituted by one or more fluoro or chloro substituents, c) halo, d) optionally substituted phenyl, e) C1-6 -alkylthio, C1-6 -alkylsulfinyl, C1-6 -alkylsulfonyl, C3-6 -cycloalkylthio, C3-6 -cycloalkylsulfinyl, or C3-6 -cycloalkylsulfonyl, which optionally may be substituted by one or more fluorine atoms, R7 has the meaning as defined for R5 with the exception of nitro and nitroso, R8 is a) hydrogen, b) C1-8 -alkyl, C3-8 -cycloalkyl, C4-8 -cycloalkylalkyl, or C4-8 -alkylcycloalkyl, which optionally may be substituted by one or more fluoro or chloro substituents, c) halo, d) phenyl, e) nitro, f) cyano, g) 5-tetrazolyl, h) COOR22, i) CONR23 R24, j) COOP1, in which P1 is a carboxy-protecting group, k) NR23 R24, l) NH(C1-6 -alkanoyl) or NH(C1-6 -alkylsulfonyl), in which the alkyl groups optionally may be substituted by one or more fluorine atoms, m) NH(benzoyl) or NH(benzenesulfonyl), R9 is a) hydrogen, b) C1-8 -alkyl, C3-8 -cycloalkyl, C4-8 -cycloalkylalkyl, or C4-8 -alkylcycloalkyl, which optionally may be substituted by one or more fluoro or chloro substituents, c) phenyl group, d) cyano, e) COOR22, f) CONR23 R24, g) 5-tetrazolyl, h) COOP1, in which P1 is a carboxy-protecting group, i) formyl, j) hydroxymethyl, R10 has independently the same meaning as R5, R11 has independently the same meaning as R6, Ar1 is a group selected from a) 1,4-phenylene of formula (E), ##STR31## b) 1,4-substituted pyridine of formula (F) or formula (G), ##STR32## or c) benzofuran, benzothiophene, or indole of formula (H), ##STR33## in which the group Z is O, S, or NR12, and R12 is hydrogen or C1-4 -alkyl, and in each of the groups Ar1 the substituent R13 is a) hydrogen, b) halo, c) C1-4 -alkyl, d) C1-4 -alkoxy, e) trifluoromethyl, f) nitro, R14 is a) hydrogen, b) C1-6 -alkyl, C3-6 -cycloalkyl, C4-6 -cycloalkylalkyl, or C4-6 -alkylcycloalkyl, which optionally may be substituted by one or more fluoro or chloro substituents, c) C2-6 -alkenyl or C3-6 -cycloalkenyl, d) halo, e) cyano, f) nitro, g) C1-6 -alkanoyl, in which the alkyl group optionally may be substituted by one or more fluorine atoms, h) C1-6 -alkoxy, i) COOR22, j) CONR23 R24, Ar2 is a group selected from a) phenyl of formula (I), ##STR34## b) pyridine of formula (J), ##STR35## c) 1-pyrrolyl of formula (K), ##STR36## or d) a five-membered heterocycle of formula (L), ##STR37## in which the group V is O, S, SO, SO2, or NR15, the group W is CH or N, and R15 is hydrogen or C1,4 -alkyl, with the proviso that in groups Ar2 of formula (J) and (L) the substituent R16 and the group Y are in ortho positions, and in each of the groups Ar2 the substituent R16 is hydrogen, 5-tetrazolyl, carboxy, sulpho, phosphono, COOP1, in which P1 is a carboxy-protecting group, or a group selected from a) cyano, b) a protected 5-tetrazolyl of formula (M), ##STR38## in which the group P2 is a protecting group, d) nitro, e) amino, f) mercapto, g) SO2 Cl, h) SO2 (OC1-4 -alkyl), i) PO(OC1-4 -alkyl)2, R17 has independently the same meaning as R13, R18 and R19 are independently selected from a) hydrogen, b) C1-6 -alkyl, C3-6 -cycloalkyl, C4-6 -cycloalkylalkyl, or C4-6 -alkylcycloalkyl, which optionally may be substituted by one or more fluoro or chloro substituents, c) C2-6 -alkenyl or C3-6 -cycloalkenyl, d) halo, e) nitro, f) cyano, g) C1-4 -alkylthio, Y is a group selected from a) a direct bond, CHR20, CHR20 CH2, OCHR20, OCHR20 CH2, SCHR20, SCHR20 CH2, NR21 CHR20, NR21 CHR20 CH2, CH2 CHR20, CH2 CHR20 CH2, b) O, S, SO2, NR21, CO, CONH, NHCO, CH2 O, CH2 S, CH2 NR21, with the proviso that when Y is (b), Ar1 is 1,4-phenylene of formula (E) and Ar2 is phenyl of formula (I), R20 is hydrogen or a) COOH, b) COOP1, in which P1 is a carboxy-protecting group, d) 5-tetrazolyl, e) cyano, f) a protected 5-tetrazolyl of formula (M), with the proviso that one of the substituents R16 and R20 is hydrogen and the other is a substituent other than hydrogen, R21 and R22 are independently selected from hydrogen or C1-6 -alkyl, and R23 and R24 are independently selected from hydrogen or C1-4 -alkyl, or together may form a polymethylene chain containing three, four or five carbon atoms, which optionally may be interrupted by an oxygen atom; the phenyl groups of R1 choice c, R1a choice c), R1b choice b), R1b choice c), R2 choice c), R4 choice c), R5 choice d), R5 choice h), R5 choice t), R5 choice v), R8 choice d), R8 choice m) and R9 choice c) being unsubstituted or substituted by at least one member selected from the group consisting of halo, C1-4 -alkyl, C1-4 -alkoxy, C1-4 -alkylthio, C1-4 -alkylsulfinyl, C1-4 -alkylsulfonyl, cyano, nitro, trifluoromethyl and hydroxy. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)
- A--B-- together with the pyrimidine ring forms
Specification
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Current AssigneeBeiersdorf-Lilly GmbH (Eli Lilly and Company)
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Original AssigneeBeiersdorf-Lilly GmbH (Eli Lilly and Company)
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InventorsSchotten, Theo, Paal, Michael, Stenzel, Wolfgang, R uhter, Gerd
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Primary Examiner(s)Berch, Mark L.
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Application NumberUS08/254,803Time in Patent Office883 DaysField of Search514/257, 544/281US Class Current514/257CPC Class CodesA61P 13/02 of urine or of the urinary ...A61P 15/00 Drugs for genital or sexual...A61P 27/02 Ophthalmic agentsA61P 43/00 Drugs for specific purposes...A61P 9/00 Drugs for disorders of the ...A61P 9/12 AntihypertensivesC07D 487/04 Ortho-condensed systems
