Patent EA-000363-B1 (EA)
Title: Method for preparing n-monosubstituted and n,n'-disubstituted unsymmetrical cyclic ureas
Inventor: RODGERS JAMES DAVID
IPC: A61K31/55
Filed: 1996-06-06
Abstract: thyl, ethyl, propyi, cyclopropyi, cyclopropylmethyl, cyclobutylmethyl. n-butyl, i-butyl, CH2 CH = C (CH3)2. pyridylmethyl, pyridyl, methallyl, n-pentyl, i-pentyl, hexyl, phenyl, benzyl, isoprenyl, propargylmethyl, picolinylmethyl, methoxymethyl, cyclohexylmethyl, dimethylbutyl, ethoxymethyl, napthyl<11>; C2-C8 alkenyl substituted with 0-3 R<11>; and C2-C8 alkynyl substituted with 0-3 R<11>; R<11> is independently selected at each occurrence from the group consisting of; H, keto, halogen, cyano, amantylmethyl, cyclopropylmethoxybenzyl, methoxybenzyl, methylbenzyl, ethoxybenzyl, hydroxybenzyl, h=NH)NHR<13>, -C (=O) NR<13>R<14>,-NR<14> C ( =O) Rnobenzyl, cinnarnyl, allyloxybenzyl, fluorobenzyl,13>R<14>, -NR<13>C(=O) NR<13>R<14>,-NR<:L4>SO2 NR<:13>R<:L4>, -NR <14>SO2 R<13>, -SO2 NR<13>R<14>,-Oobutyl, fonnaldoximebenzyl, cyclopentyl, cyclopentylmethyl, nitrobenzyl, (H2NC (=O)-benzyl, carbomethoxybenzyl, carboethoxybenzyl, tetrazolylbenzyl, dimethylallyl, aininomethylbenzyl, (O-benzyl-fonnal, C3-C6 cycloalkoxy, C1-C4 alkyl substituted with 3O3CO)-benzyl, (HOCH2CH2N = CH)-benzyl, N-benzylaminocarbonylbenzyl, N-methylaminobenzyl, N-ethylamiC1-C4 alkoxycarbonyl, pyridylcarbonyloxy, C1-C4 al acetoxybenzyl, N-l-ydroxylaminobenzyl, phenylmeth, 2-(1-morpholino)ethoxy, azido,-C(R<14>)=N(OR<14>roxyl)ethylbenzyl, (CH3 C (=NOH))-benzyl, (H2NNHC(=O))-benzyl, (H2NC(=O) NHN = CH)-benzyl, (CH3ONHC (=O))-benzyl, (HONHC(=O))-benzyl, (CH3NHC(=O))-benyl-, substituted with 0-2 R<12>; C1-C4 alkylcarbonyloxy substituted with 0-2 R<12>; C6-C10 arylcarbonyloxy substituted with 0-2 R<12> C5-C14 carbocycll. (hydroxy)butyl, (carboxy)butyl, (carbomethoxy)butyl, (methylthio)benzyl, (methylsulfonyl)benzyl, N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl, glycylaminobenzyl, N, N-dimethylglycylaminobenzyl, alanylaminobenzyl, (N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl, (N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (C (R<13A>) (R<14A>), -OR<13A>, -N (R<13A>) (R<14A>)l, N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl, N, N-diisopropylaminocarbonylbenzyl, N,-N- di-n-propylaminocarbonylbenzyl, (hydroxypropynyC3-C6 cycloalkylmethyl, benzyl, phenethyl, phenoxy=O))-benzyl, (pyridylmethylaminocarbonyl)benzyl, (cid, hydrazide, boronic acid, C3-C6 cycloalkoxy, C1-C4 alkyl substituted with -NH2 C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarnobenzyl, propionylbenzyl. butyrylbenzyl, (CH3CH2C (=NOH))-benzyl, (trifluorohydroxyethyl)benzyl, (Ced with 0-2 R<12A> C1-C4 alkyi substituted with 0-(4-morpholino)ethyl)aminocarbonylbenzyl, (N,N-dlmethylaminoethyl)aminocarbonylbenzyl, (N, N-diethylaminoethyl) aminocarbonylbenzyl, (4-methylpipsrazin-l-ylethyl) aminocarbonylbenzyl, (benzyl-NHC (=O)Oyclic ring system substituted with 0-3 R<12A>; SOmzyl, (NH2C(=NH) )benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl, (imidazolylmethyl)benzyl. ((Ctionally substituted with Cl, F, Br, CN, NO2, CF3, aminocarbonylbenzyl, (pyrrolidinylethyl) aminocarbonylbenzyl, (piperidinylethyl)aminocarbonylbenzyle taken together with the carbon atoms to which thbenzimidazolylmethyl, benzotriazolylmethyl, indazo or heterocyclic ring system, said carbocyclic or hyl, thienylmethyl, furylmethyl, N-butylaminobenzyted with Cl, F, Br, CN, NO2, CF3, C1-C4 alkyl, C1--methylaminomethylbenzyl, carbomethoxybenzyl, N-methyl aminocarbonylbenzyl, glycyi aminobenzyl, N,N-nce from the group consisting of: phenyl, benzyl, l, alanylaminobenzyl, phenylalanylaminobenzyl, (N-methylglycyl) aminobenzyl, (H2NC (=NOH) )benzyl, (cycloalkylmethyl, C7-C10 arylalkyi, C1-C4 alkoxy, -CO2H, hydroxamic acid, hydrazide, boronic acid, sdazolylmethyl, 3 -methylamino-5-indazolylmethyl, 3R<13>R<14>, C1-C4 alkyl substituted with -NR<13>R<14>, C2-C6 alkoxyalkyl optionally substituted with -Si (CH3)3, C1-C4 hydroxyalkyl, methylenedioxy, e, 3-chloro-5-indazolylmethyl, 3,4-methylenedioxybe1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4enzyl, 3-(4 -itiethyl-2-thiazolylaminocarbonyl) be13> -SO2 NR<13>R<14>, -NHSO2R<14>, -OCH2 CO2R<13>,l, 3-(5-methyl-1,3,4-thiadiazol-2-ylaminocarbonyl)benzyl, 3-(5-t-butyl-1,3,4-thiadlazol-2-ylaminocarrom 1 to 4 heteroatoms independently selected from)benzyl, 3-(4,5-diroethyl-2-thiazolylaminocarbonylor 4- carbon chain attached to adjacent carbons on the ring to form a fused 5-or 6-membered ring, sazolylaminocarbonyl)benzyl, 3 -(2 -benzimidazolylaminocarbonyl)benzyl, 3 -(2 -thiazolyloxy)benzyl, analkyl, C1-C4 alkoxy, hydroxy, or -NR<13>R<14>; and when R<12> is attached to a saturated carbon atom, it may be =0 or =S; or when R<12> is attached to sulfur it may be =0. R<12>, when a substituent on nitrogen, is independently selected at each occurrence from the group consisting of: phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2 NR<13>Rl<4>, -NR<13>R<14>, C2-C6 alkoxyalkyl, C1-C4 haloalky, C1-C4 alkoxycarbonyl, -CO2 H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbony, and -C(R<14>) = N (OR<14>); R<12A> when a substituent on carbon, is independently selected at each occurrence from the group consisting of: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, C1-C10 alkoxy, -CO2H, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, -OR<13A>, C1-C4 alkyl substituted with -NH2, -NH2, -NHMe, C2-C6 alkoxyalkyl optionally substituted with -Si(CH3)3, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkyicarbonylamino, -S(O)mMe, -SO2 NH2, -NHS02Me, -OCH2C)O2R<13A>, 2-(1-morpholino)ethoxy; a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur; R<12A> may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5-or 6-membered ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or -NH2; and when R<12A>- is attached to a saturated carbon atom, it may be =0 or =S; or when R<12A> is attached to sulfur it may be =0. R<12A>, when a substituent on nitrogen, is independently selected at each occurrence from the group consisting of: phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C2-C6 alkoxyalkyl C1-C4 haloalkyl, C1-C4 alkoxycarbonyl, -CO2H, C1-C4 alkylcarbonyloxy, and C1-C4 alkylcarbonyl; R<13> is independently selected at each occurrence from the group consisting of: H; heterocycle substituted with 0-3 R<11A> and 0-1 R<16>; phenyl substituted with 0-3 R<11A>; benzyl substituted with 0-3 R<11A>; C1-C6 alkyl substituted with 0-3 R<11A>; C2-C4 alkenyl substituted with 0-3 R<11A>; C1-C6 alkylcarbonyl substituted with 0-3 R<11A>; C1-C6 alkoxycarbonyl substituted with 0-3 R<11A>; C1-C6 alkylaminocarbonyl substituted with 0-3 R<11A>; C3-C6 alkoxyalkyl substituted with 0-3 R<11A>; an amine protecting group when R<13> is bonded to N; and a hydroxyl protecting group when R<13> is bonded to 0; R<14> is independently selected at each occurrence from the group consisting of/hydrogen, C1-C6 alkoxy, C3-C6 alkenyl, phenyl, benzyl, an amine protecting group when R<14> is bonded to N, a hydroxyl or carboxyl protecting group when R<14> is bonded to 0; and C1-C6 alkyl substituted with 0-3 groups selected from OH, C1-C4 alkoxy, halogen, R<13> and R<14> can alternatively join to form -(CH2)4-,-(CH2)5-, -CH2 CH2 N (R<15>) CH2CH2-, or-CH2CH2OH2CH2-; R<13A> and R<14A> are independently selected at each occurrence from the group consisting of: H and C1-C6 alkyl; R<13A> and R<14A> can alternatively join to form -(CH2)4-,-(CH2)5-, -CH2 CH2 N (R<15>) CH2CH2-, or-CH2CH2OCH2CH2-; R<15> is H or CH3; R<16> is independently selected from: halogen, -CN, -NO2, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C4 alkynyl, phenethyl, phenoxy. C3-C10 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, C2-C6 alkoxyalkyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, benzyloxy, C3-C6 cycloalkoxy, or phenyl, said phenyl being optionally substituted with Cl, F, Br, CN, NO2, CF3, C1-C4 alkyl, C1-C4 alkoxy or OH; or R<11A> and R<16>, when substituents on adjacent carbons, can be taken together with the carbon atoms to which they are attached to form a 5-6 membered carbocyclic or heterocyclic ring system, said carbocyclic or heterocyclic ring system being optionally substituted with Cl, F, Br, CN, NO2, CF3, C1-C4 alkyl, C1-C4 alkoxy or OH; m is 0, 1 or 2; R<22> and R<23> are independently selected at each occurrence from the group consisting of: C1-C8 alkyl substituted with 0-3 R<31>; C2-C8 alkenyl substituted with 0-3 R<31>; C2-C8 alkynyl substituted with 0-3 R<31>; C3-C14 carbocyclic ring system substituted with 0-5 R<31> and 0-5 R<32>; and a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R<32>; R<31> is independently selected at each occurrence from the group consisting of: -OH, C1-C4 alkoxy, -CO2 R<15>, -COR<15>, keto, halogen, cyano, -CH2NR<13>R<14>, -NR<13>R<14>, -CO2 R<13>, -C(=O)R<11>, -OC(=O)R<13>, -OR<13>, C2-C6 alkoxyalkyl, -S(O)mR<13>, -NHC (=NH) NHR<13>, -C (=NH) NHR<13> -C ( =O) NR<13>R<14>, -NR <14> C (=O) R<13>, =NOR<14>, -NR<14> C (=O) OR<14>, -OC (=O) NR<13>R<14>, -NR<13> C (=O) NR<13>R<14>, -NR<:L3>C(=S)NR<:L3>R<14>, -NR<14>SO2 NR<:13>R<14>, -NR<14> SO2R<13>, -SO2 NR<13>R<:L4>, C1-C4 alkyl, C2-C4 alkenyl, C3-C10 cycloalkyl, C3-C6 cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C7-C10 arylalkyl, hydroxamic acid, hydrazide, oxime, boronic a