Pyrimidine compounds and their use as pharmaceuticals
First Claim
Patent Images
1. A compound of the formula ##STR23## 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 are 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 are 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 is substituted by phenyl or by one or more fluoro substituents,b) phenylthio or phenoxy,c) di-C1- -alkylamino in which the alkyl groups are the same or different or together form a polymethylene ring with three, four, five, or six carbon atoms, which optionally are interrupted by an oxygen atom and optionally is substituted by one or more fluoro substituents,d) mono-phenylamino or mono-C1-4 -alkyl-monophenylamino, in which the phenyl group optionally is substituted and the alkyl groups optionally are substituted by one or more fluoro substituents, ore) halo,R2 isa) hydrogen,b) C1-8 -alkyl, which optionally is substituted by one or more fluoro substituents,c) optionally substituted phenyl, orR1 and R2 together form a C3-5 polymethylene chain, which optionally is interrupted by an oxygen or sulfur atom,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 are substituted by phenyl or by one or more fluoro substituents,c) optionally substituted 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), ##STR24## c) an imidazo[1,5-a]pyrimidine of formula (C), ##STR25## or d) an imidazo[1,2-a]pyrimidine of formula (D), ##STR26## in which R5 isa) hydrogen,b) C1-8 -alkyl, C3-8 -cycloalkyl, C4-8 -cycloalkylalkyl, or C4-8 -alkylcycloalkyl, which optionally are 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 phenyl groups are optionally substituted and the alkyl and cycloalkyl groups optionally are substituted by one or more fluorine atoms,c) 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 are substituted by one or more fluorine atoms,h) phenylthio, phenylsulfinyl, phenylsulfonyl, phenyl-C1-3 -alkylthio, phenyl-C1-3 -alkyl sulfinyl, or phenyl-C1-3 -sulfonyl, in which the phenyl groups optionally are substituted,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 is substituted by one or more fluorine atoms,t) benzoyl or phenylhydroxymethyl, in which the phenyl group optionally is substituted,u) NH(C1-6 -alkanoyl) or NH(C1-6 -alkylsulfonyl), in which the alkyl groups optionally are substituted by one or more fluorine atoms,v) NH(benzoyl) or NH(benzenesulfonyl), in which the phenyl group optionally is substituted,R6 isa) hydrogen,b) C1-8 -alkyl, C3-8 -cycloalkyl, C4-8 -cycloalkylalkyl, or C4-8 -alkylcycloalkyl, which optionally are 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 are substituted by one or more fluorine atoms,R5 and R6 together may form a C3-5 polymethylene chain;
R8 isa) hydrogen,b) C1-8 -alkyl, C3-8 -cycloalkyl, C4-8 -cycloalkylalkyl, or C4-8 -alkylcycloalkyl, which optionally are substituted by one or more fluoro or chloro substituents,c) halo,d) optionally substituted phenyl,e) nitro,f) cyano,g) 5-tetrazolyl,h) COOR22,i) CONR23R24,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 are substituted by one or more fluorine atoms,m) NH(benzoyl) or NH(benzenesulfonyl), in which the phenyl group optionally is substituted,R9 isa) hydrogen,b) C1-8 -alkyl, C3-8 -cycloalkyl, C4-8 -cycloalkylalkyl, or C4-8 -alkylcycloalkyl which optionally are substituted by one or more fluoro or chloro substituents,c) an optionally substituted phenyl group,d) cyano,e) COOR22,f) CONR23 R24,g) 5-tetrazolyl,h) COOPl, 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), ##STR27## b) 1,4-substituted pyridine of formula (F) or formula (G), ##STR28## or c) benzofuran, benzothiophene, or indole of formula (H), ##STR29## 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 are substituted by one or more fluoro or chloro substituents.c) C2-4 -alkenyl or C3-6 -cycloalkenyl,d) halo,e) cyano,f) nitro,g) C1-6 -alkanoyl, in which the alkyl group optionally is 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), ##STR30## b) pyridine of formula (J), ##STR31## c) 1-pyrrolyl of formula (K), ##STR32## or d) a five-membered heterocycle of formula (L), ##STR33## in which the group V is O, S, SO, SO2, or NR15, the group W is CH or N, andR15 is hydrogen or C1-4 -alkyl, with the proviso that in groups Ar2 of formula (J) and (L) the substituentR16 and the group Y are in ortho positions, and in each of the groups Ar2 the substituentR16 is hydrogen, a bioisostere of a carboxylic acid which gives a compound of formula I having a pKa value between one and eleven,COOP1, in which P1 is a carboxy-protecting group, or a group selected froma) cyano,b) a protected 5-tetrazolyl of formula (M), ##STR34## 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 are substituted by one or more fluoro or chloro substituents,c) C2-6 -alkenyl or C3-6 -cycloalkenyld) halo,e) nitro,f) cyano,g) C1-4 -alkylthio,Y is a group selected froma) single 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 C3-5 polymethylene chain, which optionally is interrupted by an oxygen atom;
or a pharmaceutically acceptable salt thereof,with the proviso that R1 together with R2 forms a C3-5 polymethylene chain, which optionally is interrupted by an oxygen or sulfur atom, and/or R5 together with R6 forms a C3-5 polymethylene chain.
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Abstract
Compounds having the formula ##STR1## and the other variables are as defined herein, and are indicated for use in the treatment and prophylaxis of, for example, hypertension, congestive heart failure, ocular hypertension, renal failure, and CNS disorders, or are intermediates thereto.
58 Citations
14 Claims
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1. A compound of the formula ##STR23## 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 are 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 are 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 is substituted by phenyl or by one or more fluoro substituents, b) phenylthio or phenoxy, c) di-C1- -alkylamino in which the alkyl groups are the same or different or together form a polymethylene ring with three, four, five, or six carbon atoms, which optionally are interrupted by an oxygen atom and optionally is substituted by one or more fluoro substituents, d) mono-phenylamino or mono-C1-4 -alkyl-monophenylamino, in which the phenyl group optionally is substituted and the alkyl groups optionally are substituted by one or more fluoro substituents, or e) halo, R2 is a) hydrogen, b) C1-8 -alkyl, which optionally is substituted by one or more fluoro substituents, c) optionally substituted phenyl, or R1 and R2 together form a C3-5 polymethylene chain, which optionally is interrupted by an oxygen or sulfur atom, 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 are substituted by phenyl or by one or more fluoro substituents, c) optionally substituted 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), ##STR24## c) an imidazo[1,5-a]pyrimidine of formula (C), ##STR25## or d) an imidazo[1,2-a]pyrimidine of formula (D), ##STR26## in which R5 is a) hydrogen, b) C1-8 -alkyl, C3-8 -cycloalkyl, C4-8 -cycloalkylalkyl, or C4-8 -alkylcycloalkyl, which optionally are 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 phenyl groups are optionally substituted and the alkyl and cycloalkyl groups optionally are substituted by one or more fluorine atoms, c) 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 are substituted by one or more fluorine atoms, h) phenylthio, phenylsulfinyl, phenylsulfonyl, phenyl-C1-3 -alkylthio, phenyl-C1-3 -alkyl sulfinyl, or phenyl-C1-3 -sulfonyl, in which the phenyl groups optionally are substituted, 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 is substituted by one or more fluorine atoms, t) benzoyl or phenylhydroxymethyl, in which the phenyl group optionally is substituted, u) NH(C1-6 -alkanoyl) or NH(C1-6 -alkylsulfonyl), in which the alkyl groups optionally are substituted by one or more fluorine atoms, v) NH(benzoyl) or NH(benzenesulfonyl), in which the phenyl group optionally is substituted, R6 is a) hydrogen, b) C1-8 -alkyl, C3-8 -cycloalkyl, C4-8 -cycloalkylalkyl, or C4-8 -alkylcycloalkyl, which optionally are 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 are substituted by one or more fluorine atoms, R5 and R6 together may form a C3-5 polymethylene chain; R8 is a) hydrogen, b) C1-8 -alkyl, C3-8 -cycloalkyl, C4-8 -cycloalkylalkyl, or C4-8 -alkylcycloalkyl, which optionally are substituted by one or more fluoro or chloro substituents, c) halo, d) optionally substituted phenyl, e) nitro, f) cyano, g) 5-tetrazolyl, h) COOR22, i) CONR23R24, 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 are substituted by one or more fluorine atoms, m) NH(benzoyl) or NH(benzenesulfonyl), in which the phenyl group optionally is substituted, R9 is a) hydrogen, b) C1-8 -alkyl, C3-8 -cycloalkyl, C4-8 -cycloalkylalkyl, or C4-8 -alkylcycloalkyl which optionally are substituted by one or more fluoro or chloro substituents, c) an optionally substituted phenyl group, d) cyano, e) COOR22, f) CONR23 R24, g) 5-tetrazolyl, h) COOPl, 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), ##STR27## b) 1,4-substituted pyridine of formula (F) or formula (G), ##STR28## or c) benzofuran, benzothiophene, or indole of formula (H), ##STR29## 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 are substituted by one or more fluoro or chloro substituents. c) C2-4 -alkenyl or C3-6 -cycloalkenyl, d) halo, e) cyano, f) nitro, g) C1-6 -alkanoyl, in which the alkyl group optionally is 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), ##STR30## b) pyridine of formula (J), ##STR31## c) 1-pyrrolyl of formula (K), ##STR32## or d) a five-membered heterocycle of formula (L), ##STR33## 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, a bioisostere of a carboxylic acid which gives a compound of formula I having a pKa value between one and eleven, COOP1, in which P1 is a carboxy-protecting group, or a group selected from a) cyano, b) a protected 5-tetrazolyl of formula (M), ##STR34## 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 are 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) single 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 C3-5 polymethylene chain, which optionally is interrupted by an oxygen atom; or a pharmaceutically acceptable salt thereof, with the proviso that R1 together with R2 forms a C3-5 polymethylene chain, which optionally is interrupted by an oxygen or sulfur atom, and/or R5 together with R6 forms a C3-5 polymethylene chain. - 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
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Original AssigneeBeiersdorf-Lilly GmbH
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InventorsSchotten, Theo, Paal, Michael, Stenzel, Wolfgang, R uhter, Gerd
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Primary Examiner(s)McKane, Joseph
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Assistant Examiner(s)MYERS, RICHARD
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Application NumberUS08/451,586Time in Patent Office627 DaysField of Search544/244, 544/247, 544/250, 514/81, 514/257, 514/267US 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
