IE54683B1 - Antiatherosclerotic substituted ureas - Google Patents
Antiatherosclerotic substituted ureasInfo
- Publication number
- IE54683B1 IE54683B1 IE146/83A IE14683A IE54683B1 IE 54683 B1 IE54683 B1 IE 54683B1 IE 146/83 A IE146/83 A IE 146/83A IE 14683 A IE14683 A IE 14683A IE 54683 B1 IE54683 B1 IE 54683B1
- Authority
- IE
- Ireland
- Prior art keywords
- urea
- benzyl
- butyl
- group
- compound
- Prior art date
Links
- 235000013877 carbamide Nutrition 0.000 title abstract description 177
- 150000003672 ureas Chemical class 0.000 title abstract description 17
- 230000000879 anti-atherosclerotic effect Effects 0.000 title abstract description 7
- -1 phenoxy, mercapto Chemical class 0.000 claims abstract description 60
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 23
- 125000001424 substituent group Chemical group 0.000 claims abstract description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 19
- 239000001257 hydrogen Substances 0.000 claims abstract description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 15
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 14
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 14
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 9
- 125000004953 trihalomethyl group Chemical group 0.000 claims abstract description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims abstract description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 5
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims abstract description 5
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims abstract description 5
- 125000003118 aryl group Chemical group 0.000 claims abstract description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 5
- 125000006277 halobenzyl group Chemical group 0.000 claims abstract description 5
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 5
- 239000001301 oxygen Substances 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims abstract description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract description 4
- 125000006178 methyl benzyl group Chemical group 0.000 claims abstract description 4
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 claims abstract description 4
- 125000003944 tolyl group Chemical group 0.000 claims abstract description 4
- 125000001475 halogen functional group Chemical group 0.000 claims abstract 9
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 323
- 239000004202 carbamide Substances 0.000 claims description 163
- 150000001875 compounds Chemical class 0.000 claims description 108
- 238000000034 method Methods 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 201000001320 Atherosclerosis Diseases 0.000 claims description 12
- 230000003902 lesion Effects 0.000 claims description 10
- 241000124008 Mammalia Species 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 150000004982 aromatic amines Chemical class 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 239000012948 isocyanate Substances 0.000 claims description 5
- 230000003143 atherosclerotic effect Effects 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims 5
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims 3
- 125000001589 carboacyl group Chemical group 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract description 4
- 150000003585 thioureas Chemical class 0.000 abstract description 4
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 abstract description 3
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 abstract 1
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 abstract 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract 1
- 125000002541 furyl group Chemical group 0.000 abstract 1
- 229910052717 sulfur Inorganic materials 0.000 abstract 1
- 239000011593 sulfur Substances 0.000 abstract 1
- 239000003921 oil Substances 0.000 description 96
- 235000019198 oils Nutrition 0.000 description 96
- 239000007787 solid Substances 0.000 description 65
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 51
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 45
- 239000000243 solution Substances 0.000 description 41
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- 238000002844 melting Methods 0.000 description 27
- 239000000203 mixture Substances 0.000 description 27
- 230000008018 melting Effects 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 21
- 235000012000 cholesterol Nutrition 0.000 description 19
- 239000000543 intermediate Substances 0.000 description 16
- GKEHHLJOYZDXMI-UHFFFAOYSA-N (2,4-dimethylphenyl)urea Chemical compound CC1=CC=C(NC(N)=O)C(C)=C1 GKEHHLJOYZDXMI-UHFFFAOYSA-N 0.000 description 14
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 14
- 230000005764 inhibitory process Effects 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 150000003335 secondary amines Chemical class 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 241000700159 Rattus Species 0.000 description 8
- 235000005911 diet Nutrition 0.000 description 8
- 230000037213 diet Effects 0.000 description 8
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 7
- 150000002632 lipids Chemical class 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- HIPXPABRMMYVQD-UHFFFAOYSA-N n-benzylbutan-1-amine Chemical compound CCCCNCC1=CC=CC=C1 HIPXPABRMMYVQD-UHFFFAOYSA-N 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 229930182558 Sterol Natural products 0.000 description 5
- 239000000010 aprotic solvent Substances 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 150000003432 sterols Chemical class 0.000 description 5
- 235000003702 sterols Nutrition 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 4
- ZSUBZLUMQRVHST-UHFFFAOYSA-N 1-benzyl-1-butyl-3,3-diphenylurea Chemical compound C=1C=CC=CC=1N(C=1C=CC=CC=1)C(=O)N(CCCC)CC1=CC=CC=C1 ZSUBZLUMQRVHST-UHFFFAOYSA-N 0.000 description 4
- QUOBVYPFBJUOAJ-UHFFFAOYSA-N 1-isocyanato-2,4-dimethylbenzene Chemical compound CC1=CC=C(N=C=O)C(C)=C1 QUOBVYPFBJUOAJ-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000004380 Cholic acid Substances 0.000 description 4
- 102000001494 Sterol O-Acyltransferase Human genes 0.000 description 4
- 108010054082 Sterol O-acyltransferase Proteins 0.000 description 4
- 230000035508 accumulation Effects 0.000 description 4
- 238000009825 accumulation Methods 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 4
- 235000019416 cholic acid Nutrition 0.000 description 4
- 229960002471 cholic acid Drugs 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 4
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 210000003608 fece Anatomy 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- DGWIPMVOWWLJMU-UHFFFAOYSA-N n-(2,4-dichlorophenyl)-1-(2,4-dimethylphenyl)methanimine Chemical compound CC1=CC(C)=CC=C1C=NC1=CC=C(Cl)C=C1Cl DGWIPMVOWWLJMU-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- KIOZZICXWLXDJG-UHFFFAOYSA-N 1-[(4-chlorophenyl)methyl]-3-(2,4-difluorophenyl)-1-(naphthalen-1-ylmethyl)urea Chemical compound FC1=CC(F)=CC=C1NC(=O)N(CC=1C2=CC=CC=C2C=CC=1)CC1=CC=C(Cl)C=C1 KIOZZICXWLXDJG-UHFFFAOYSA-N 0.000 description 3
- DMPLFFSQDMYJIH-UHFFFAOYSA-N 1-benzyl-1-[(4-butoxyphenyl)methyl]-3-(2,4,6-trichlorophenyl)urea Chemical compound C1=CC(OCCCC)=CC=C1CN(C(=O)NC=1C(=CC(Cl)=CC=1Cl)Cl)CC1=CC=CC=C1 DMPLFFSQDMYJIH-UHFFFAOYSA-N 0.000 description 3
- GJMDHHKQGWMBDD-UHFFFAOYSA-N 1-benzyl-1-[(4-butylphenyl)methyl]-3-(4-chloro-2-methylphenyl)urea Chemical compound C1=CC(CCCC)=CC=C1CN(C(=O)NC=1C(=CC(Cl)=CC=1)C)CC1=CC=CC=C1 GJMDHHKQGWMBDD-UHFFFAOYSA-N 0.000 description 3
- CQCRPHVZWXLSLZ-UHFFFAOYSA-N 1-benzyl-1-butyl-3-(2,4-dimethylphenyl)urea Chemical compound C=1C=C(C)C=C(C)C=1NC(=O)N(CCCC)CC1=CC=CC=C1 CQCRPHVZWXLSLZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 150000001448 anilines Chemical class 0.000 description 3
- 210000001367 artery Anatomy 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 230000001906 cholesterol absorption Effects 0.000 description 3
- 208000029078 coronary artery disease Diseases 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 150000002185 fatty acyl-CoAs Chemical class 0.000 description 3
- 208000031225 myocardial ischemia Diseases 0.000 description 3
- VLJJFRIHSLTXSI-UHFFFAOYSA-N n-[(2-chlorophenyl)methyl]-2-(3-methoxyphenyl)acetamide Chemical compound COC1=CC=CC(CC(=O)NCC=2C(=CC=CC=2)Cl)=C1 VLJJFRIHSLTXSI-UHFFFAOYSA-N 0.000 description 3
- IWFYZVFKBNNZHX-UHFFFAOYSA-N n-benzyl-n-butylcarbamoyl chloride Chemical compound CCCCN(C(Cl)=O)CC1=CC=CC=C1 IWFYZVFKBNNZHX-UHFFFAOYSA-N 0.000 description 3
- GTWJETSWSUWSEJ-UHFFFAOYSA-N n-benzylaniline Chemical class C=1C=CC=CC=1CNC1=CC=CC=C1 GTWJETSWSUWSEJ-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 150000003141 primary amines Chemical class 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- FHHAREUTFAQJPL-UHFFFAOYSA-N (2,4,5-trimethylphenyl)urea Chemical compound CC1=CC(C)=C(NC(N)=O)C=C1C FHHAREUTFAQJPL-UHFFFAOYSA-N 0.000 description 2
- KDDNKZCVYQDGKE-UHFFFAOYSA-N (2-chlorophenyl)methanamine Chemical compound NCC1=CC=CC=C1Cl KDDNKZCVYQDGKE-UHFFFAOYSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- ITJZEPDILNRMBR-UHFFFAOYSA-N 1,1-dibenzyl-3-(2,4-dichlorophenyl)urea Chemical compound ClC1=CC(Cl)=CC=C1NC(=O)N(CC=1C=CC=CC=1)CC1=CC=CC=C1 ITJZEPDILNRMBR-UHFFFAOYSA-N 0.000 description 2
- UQTSCLRTSKBRST-UHFFFAOYSA-N 1,1-dibenzyl-3-(4-methylphenyl)urea Chemical compound C1=CC(C)=CC=C1NC(=O)N(CC=1C=CC=CC=1)CC1=CC=CC=C1 UQTSCLRTSKBRST-UHFFFAOYSA-N 0.000 description 2
- QSYRUHADNYPGOI-UHFFFAOYSA-N 1,1-dibenzyl-3-(4-phenoxyphenyl)urea Chemical compound C=1C=CC=CC=1CN(CC=1C=CC=CC=1)C(=O)NC(C=C1)=CC=C1OC1=CC=CC=C1 QSYRUHADNYPGOI-UHFFFAOYSA-N 0.000 description 2
- GYTNGFIBMOBPOD-UHFFFAOYSA-N 1,1-dibutyl-3-(2,3,5-trichlorophenyl)urea Chemical compound CCCCN(CCCC)C(=O)NC1=CC(Cl)=CC(Cl)=C1Cl GYTNGFIBMOBPOD-UHFFFAOYSA-N 0.000 description 2
- ZKUUQLDOBKHWMO-UHFFFAOYSA-N 1,1-dibutyl-3-(2,4-dichlorophenyl)urea Chemical compound CCCCN(CCCC)C(=O)NC1=CC=C(Cl)C=C1Cl ZKUUQLDOBKHWMO-UHFFFAOYSA-N 0.000 description 2
- ZSQJFAFRRMBAPQ-UHFFFAOYSA-N 1,1-dibutyl-3-(4-butylphenyl)urea Chemical compound CCCCN(CCCC)C(=O)NC1=CC=C(CCCC)C=C1 ZSQJFAFRRMBAPQ-UHFFFAOYSA-N 0.000 description 2
- DEQVMPSQJBXWJG-UHFFFAOYSA-N 1-[(4-butoxyphenyl)methyl]-1-heptyl-3-(2,4,5-trimethylphenyl)urea Chemical compound C=1C(C)=C(C)C=C(C)C=1NC(=O)N(CCCCCCC)CC1=CC=C(OCCCC)C=C1 DEQVMPSQJBXWJG-UHFFFAOYSA-N 0.000 description 2
- BFOPLSIIQVFPGC-UHFFFAOYSA-N 1-[(4-butoxyphenyl)methyl]-3-(2,4-dichlorophenyl)-1-heptylurea Chemical compound C=1C=C(Cl)C=C(Cl)C=1NC(=O)N(CCCCCCC)CC1=CC=C(OCCCC)C=C1 BFOPLSIIQVFPGC-UHFFFAOYSA-N 0.000 description 2
- YWIWLPCTXRTJHW-UHFFFAOYSA-N 1-[(4-butoxyphenyl)methyl]-3-(2,4-dimethylphenyl)-1-heptylurea Chemical compound C=1C=C(C)C=C(C)C=1NC(=O)N(CCCCCCC)CC1=CC=C(OCCCC)C=C1 YWIWLPCTXRTJHW-UHFFFAOYSA-N 0.000 description 2
- VNZQNFWZDFXVRY-UHFFFAOYSA-N 1-[(4-butylphenyl)methyl]-1-heptyl-3-(2,4,5-trimethylphenyl)urea Chemical compound C=1C(C)=C(C)C=C(C)C=1NC(=O)N(CCCCCCC)CC1=CC=C(CCCC)C=C1 VNZQNFWZDFXVRY-UHFFFAOYSA-N 0.000 description 2
- YNYFIWZHVCWOQM-UHFFFAOYSA-N 1-[(4-butylphenyl)methyl]-1-heptyl-3-(2-methylphenyl)urea Chemical compound C=1C=CC=C(C)C=1NC(=O)N(CCCCCCC)CC1=CC=C(CCCC)C=C1 YNYFIWZHVCWOQM-UHFFFAOYSA-N 0.000 description 2
- YXCLZQGGADBQKE-UHFFFAOYSA-N 1-[(4-chlorophenyl)methyl]-1-(naphthalen-1-ylmethyl)-3-(2,4,5-trichlorophenyl)urea Chemical compound C1=CC(Cl)=CC=C1CN(C(=O)NC=1C(=CC(Cl)=C(Cl)C=1)Cl)CC1=CC=CC2=CC=CC=C12 YXCLZQGGADBQKE-UHFFFAOYSA-N 0.000 description 2
- BKOZZERQLGDVDM-UHFFFAOYSA-N 1-[(4-chlorophenyl)methyl]-3-(2,4-dichlorophenyl)-1-(naphthalen-1-ylmethyl)urea Chemical compound C1=CC(Cl)=CC=C1CN(C(=O)NC=1C(=CC(Cl)=CC=1)Cl)CC1=CC=CC2=CC=CC=C12 BKOZZERQLGDVDM-UHFFFAOYSA-N 0.000 description 2
- BJHWYBZFDHPWAV-UHFFFAOYSA-N 1-benzyl-1-[(4-butoxyphenyl)methyl]-3-(2,4,5-trimethylphenyl)urea Chemical compound C1=CC(OCCCC)=CC=C1CN(C(=O)NC=1C(=CC(C)=C(C)C=1)C)CC1=CC=CC=C1 BJHWYBZFDHPWAV-UHFFFAOYSA-N 0.000 description 2
- ARNLGZUMKMBXDL-UHFFFAOYSA-N 1-benzyl-1-[(4-butoxyphenyl)methyl]-3-(2,4-dimethylphenyl)urea Chemical compound C1=CC(OCCCC)=CC=C1CN(C(=O)NC=1C(=CC(C)=CC=1)C)CC1=CC=CC=C1 ARNLGZUMKMBXDL-UHFFFAOYSA-N 0.000 description 2
- LFKDKYFTIXHYDI-UHFFFAOYSA-N 1-benzyl-1-[(4-butylphenyl)methyl]-3-(2,4,6-trimethylphenyl)urea Chemical compound C1=CC(CCCC)=CC=C1CN(C(=O)NC=1C(=CC(C)=CC=1C)C)CC1=CC=CC=C1 LFKDKYFTIXHYDI-UHFFFAOYSA-N 0.000 description 2
- SXXGWNNIVJZDPD-UHFFFAOYSA-N 1-benzyl-1-butyl-3-(2-methylphenyl)urea Chemical compound C=1C=CC=C(C)C=1NC(=O)N(CCCC)CC1=CC=CC=C1 SXXGWNNIVJZDPD-UHFFFAOYSA-N 0.000 description 2
- RKVHAWULYXIBGC-UHFFFAOYSA-N 1-benzyl-1-butyl-3-(3-chloro-2-methoxyphenyl)urea Chemical compound C=1C=CC(Cl)=C(OC)C=1NC(=O)N(CCCC)CC1=CC=CC=C1 RKVHAWULYXIBGC-UHFFFAOYSA-N 0.000 description 2
- JKXLTTZJKQMKLA-UHFFFAOYSA-N 1-benzyl-1-butyl-3-(3-chlorophenyl)-3-phenylurea Chemical compound C=1C=CC=CC=1N(C=1C=C(Cl)C=CC=1)C(=O)N(CCCC)CC1=CC=CC=C1 JKXLTTZJKQMKLA-UHFFFAOYSA-N 0.000 description 2
- SAPLBENRNUWLDZ-UHFFFAOYSA-N 1-benzyl-1-butyl-3-(3-chlorophenyl)urea Chemical compound C=1C=CC(Cl)=CC=1NC(=O)N(CCCC)CC1=CC=CC=C1 SAPLBENRNUWLDZ-UHFFFAOYSA-N 0.000 description 2
- OPXRPBOSFMMZMA-UHFFFAOYSA-N 1-benzyl-1-butyl-3-(4-methylphenyl)urea Chemical compound C=1C=C(C)C=CC=1NC(=O)N(CCCC)CC1=CC=CC=C1 OPXRPBOSFMMZMA-UHFFFAOYSA-N 0.000 description 2
- JAWIZQPLEIGXQQ-UHFFFAOYSA-N 1-benzyl-1-butyl-3-naphthalen-2-yl-3-phenylurea Chemical compound C=1C=CC=CC=1N(C=1C=C2C=CC=CC2=CC=1)C(=O)N(CCCC)CC1=CC=CC=C1 JAWIZQPLEIGXQQ-UHFFFAOYSA-N 0.000 description 2
- XYSIADNGRMHABQ-UHFFFAOYSA-N 1-benzyl-1-butyl-3-phenylurea Chemical compound C=1C=CC=CC=1NC(=O)N(CCCC)CC1=CC=CC=C1 XYSIADNGRMHABQ-UHFFFAOYSA-N 0.000 description 2
- QPDUGXKFHNQTOI-UHFFFAOYSA-N 1-heptyl-1-(2-phenylethyl)-3-[3-(trifluoromethyl)phenyl]urea Chemical compound C=1C=CC(C(F)(F)F)=CC=1NC(=O)N(CCCCCCC)CCC1=CC=CC=C1 QPDUGXKFHNQTOI-UHFFFAOYSA-N 0.000 description 2
- JLKZDESEPHIECO-UHFFFAOYSA-N 2,4-dichloro-n-[(2,4-dimethylphenyl)methyl]aniline Chemical compound CC1=CC(C)=CC=C1CNC1=CC=C(Cl)C=C1Cl JLKZDESEPHIECO-UHFFFAOYSA-N 0.000 description 2
- KQCMTOWTPBNWDB-UHFFFAOYSA-N 2,4-dichloroaniline Chemical compound NC1=CC=C(Cl)C=C1Cl KQCMTOWTPBNWDB-UHFFFAOYSA-N 0.000 description 2
- CZZZABOKJQXEBO-UHFFFAOYSA-N 2,4-dimethylaniline Chemical compound CC1=CC=C(N)C(C)=C1 CZZZABOKJQXEBO-UHFFFAOYSA-N 0.000 description 2
- QZCSIEVETDPPGQ-UHFFFAOYSA-N 3-(2,4-dimethylphenyl)-1,1-bis(2-ethylhexyl)urea Chemical compound CCCCC(CC)CN(CC(CC)CCCC)C(=O)NC1=CC=C(C)C=C1C QZCSIEVETDPPGQ-UHFFFAOYSA-N 0.000 description 2
- ZXTVIGMUOUZQCR-UHFFFAOYSA-N 3-(2,4-dimethylphenyl)-1,1-diheptylurea Chemical compound CCCCCCCN(CCCCCCC)C(=O)NC1=CC=C(C)C=C1C ZXTVIGMUOUZQCR-UHFFFAOYSA-N 0.000 description 2
- CLNWLMJLAHUVOJ-UHFFFAOYSA-N 3-(3-bromophenyl)-1,1-dibutylurea Chemical compound CCCCN(CCCC)C(=O)NC1=CC=CC(Br)=C1 CLNWLMJLAHUVOJ-UHFFFAOYSA-N 0.000 description 2
- RHZRGNBQZOEJJF-UHFFFAOYSA-N 3-(4-acetylphenyl)-1,1-dibutylurea Chemical compound CCCCN(CCCC)C(=O)NC1=CC=C(C(C)=O)C=C1 RHZRGNBQZOEJJF-UHFFFAOYSA-N 0.000 description 2
- LEGPZHPSIPPYIO-UHFFFAOYSA-N 3-Methoxyphenylacetic acid Chemical compound COC1=CC=CC(CC(O)=O)=C1 LEGPZHPSIPPYIO-UHFFFAOYSA-N 0.000 description 2
- DHYHYLGCQVVLOQ-UHFFFAOYSA-N 3-bromoaniline Chemical compound NC1=CC=CC(Br)=C1 DHYHYLGCQVVLOQ-UHFFFAOYSA-N 0.000 description 2
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 2
- AESQUTRXAMDOSL-UHFFFAOYSA-N 4-(dibenzylcarbamoylamino)benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1NC(=O)N(CC=1C=CC=CC=1)CC1=CC=CC=C1 AESQUTRXAMDOSL-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 2
- 101100260565 Dictyostelium discoideum thyA gene Proteins 0.000 description 2
- 102000004895 Lipoproteins Human genes 0.000 description 2
- 108090001030 Lipoproteins Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000005484 gravity Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- PUEUFOKKVOOXEW-UHFFFAOYSA-N n-[(2-chlorophenyl)methyl]butan-1-amine Chemical compound CCCCNCC1=CC=CC=C1Cl PUEUFOKKVOOXEW-UHFFFAOYSA-N 0.000 description 2
- PERRBGDAOVSLIV-UHFFFAOYSA-N n-butyl-2-chlorobenzamide Chemical compound CCCCNC(=O)C1=CC=CC=C1Cl PERRBGDAOVSLIV-UHFFFAOYSA-N 0.000 description 2
- 230000004903 negative regulation of intestinal cholesterol absorption Effects 0.000 description 2
- IWQSGWGBBCDEPM-UHFFFAOYSA-N phenyl n-(3-bromophenyl)carbamate Chemical compound BrC1=CC=CC(NC(=O)OC=2C=CC=CC=2)=C1 IWQSGWGBBCDEPM-UHFFFAOYSA-N 0.000 description 2
- ODRCCNDEGWDDGA-UHFFFAOYSA-N phenyl n-(3-chlorophenyl)carbamate Chemical compound ClC1=CC=CC(NC(=O)OC=2C=CC=CC=2)=C1 ODRCCNDEGWDDGA-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 238000013222 sprague-dawley male rat Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 101150068774 thyX gene Proteins 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- PZFNDWHDAMZYEL-UHFFFAOYSA-N (2,4,5-trichlorophenyl)urea Chemical compound NC(=O)NC1=CC(Cl)=C(Cl)C=C1Cl PZFNDWHDAMZYEL-UHFFFAOYSA-N 0.000 description 1
- PODOAIWAYUVDEF-UHFFFAOYSA-N (2,4,6-trichlorophenyl)urea Chemical compound NC(=O)NC1=C(Cl)C=C(Cl)C=C1Cl PODOAIWAYUVDEF-UHFFFAOYSA-N 0.000 description 1
- CTXZGDFFAGQHGE-UHFFFAOYSA-N (2,4,6-trimethylphenyl)urea Chemical compound CC1=CC(C)=C(NC(N)=O)C(C)=C1 CTXZGDFFAGQHGE-UHFFFAOYSA-N 0.000 description 1
- SBBRRSKIPTXBCO-UHFFFAOYSA-N (2,4-difluorophenyl)urea Chemical compound NC(=O)NC1=CC=C(F)C=C1F SBBRRSKIPTXBCO-UHFFFAOYSA-N 0.000 description 1
- UVQVMNIYFXZXCI-UHFFFAOYSA-N (3-methylphenyl)urea Chemical compound CC1=CC=CC(NC(N)=O)=C1 UVQVMNIYFXZXCI-UHFFFAOYSA-N 0.000 description 1
- UKGJZDSUJSPAJL-YPUOHESYSA-N (e)-n-[(1r)-1-[3,5-difluoro-4-(methanesulfonamido)phenyl]ethyl]-3-[2-propyl-6-(trifluoromethyl)pyridin-3-yl]prop-2-enamide Chemical compound CCCC1=NC(C(F)(F)F)=CC=C1\C=C\C(=O)N[C@H](C)C1=CC(F)=C(NS(C)(=O)=O)C(F)=C1 UKGJZDSUJSPAJL-YPUOHESYSA-N 0.000 description 1
- RXHMMZUNGFNBMA-UHFFFAOYSA-N 1,1-di(butan-2-yl)-3-(2,4-dimethylphenyl)urea Chemical compound CCC(C)N(C(C)CC)C(=O)NC1=CC=C(C)C=C1C RXHMMZUNGFNBMA-UHFFFAOYSA-N 0.000 description 1
- CRIIESGQQIOAON-UHFFFAOYSA-N 1,1-dibenzyl-3-(2,4,5-trimethylphenyl)urea Chemical compound C1=C(C)C(C)=CC(C)=C1NC(=O)N(CC=1C=CC=CC=1)CC1=CC=CC=C1 CRIIESGQQIOAON-UHFFFAOYSA-N 0.000 description 1
- PUESRTPEYCCVDE-UHFFFAOYSA-N 1,1-dibenzyl-3-(2,4,6-trimethylphenyl)urea Chemical compound CC1=CC(C)=CC(C)=C1NC(=O)N(CC=1C=CC=CC=1)CC1=CC=CC=C1 PUESRTPEYCCVDE-UHFFFAOYSA-N 0.000 description 1
- XZZPSMCICXEUHZ-UHFFFAOYSA-N 1,1-dibenzyl-3-(2,4-dimethylphenyl)urea Chemical compound CC1=CC(C)=CC=C1NC(=O)N(CC=1C=CC=CC=1)CC1=CC=CC=C1 XZZPSMCICXEUHZ-UHFFFAOYSA-N 0.000 description 1
- HPLRGPMVWSLYNM-UHFFFAOYSA-N 1,1-dibenzyl-3-(2,5-dichlorophenyl)urea Chemical compound ClC1=CC=C(Cl)C(NC(=O)N(CC=2C=CC=CC=2)CC=2C=CC=CC=2)=C1 HPLRGPMVWSLYNM-UHFFFAOYSA-N 0.000 description 1
- IYXIKYXLEDBNMC-UHFFFAOYSA-N 1,1-dibenzyl-3-(2,5-dimethoxyphenyl)urea Chemical compound COC1=CC=C(OC)C(NC(=O)N(CC=2C=CC=CC=2)CC=2C=CC=CC=2)=C1 IYXIKYXLEDBNMC-UHFFFAOYSA-N 0.000 description 1
- FFZSSNUSZPLNPW-UHFFFAOYSA-N 1,1-dibenzyl-3-(2,6-diethylphenyl)urea Chemical compound CCC1=CC=CC(CC)=C1NC(=O)N(CC=1C=CC=CC=1)CC1=CC=CC=C1 FFZSSNUSZPLNPW-UHFFFAOYSA-N 0.000 description 1
- FHZYFORTTOYVEK-UHFFFAOYSA-N 1,1-dibenzyl-3-(2-bromophenyl)urea Chemical compound BrC1=CC=CC=C1NC(=O)N(CC=1C=CC=CC=1)CC1=CC=CC=C1 FHZYFORTTOYVEK-UHFFFAOYSA-N 0.000 description 1
- QENSTJKJSDMWLV-UHFFFAOYSA-N 1,1-dibenzyl-3-(2-methoxy-5-methylphenyl)urea Chemical compound COC1=CC=C(C)C=C1NC(=O)N(CC=1C=CC=CC=1)CC1=CC=CC=C1 QENSTJKJSDMWLV-UHFFFAOYSA-N 0.000 description 1
- BBCOEADOJWPHKO-UHFFFAOYSA-N 1,1-dibenzyl-3-(3,4-dimethylphenyl)urea Chemical compound C1=C(C)C(C)=CC=C1NC(=O)N(CC=1C=CC=CC=1)CC1=CC=CC=C1 BBCOEADOJWPHKO-UHFFFAOYSA-N 0.000 description 1
- RESBNNVJQNNILW-UHFFFAOYSA-N 1,1-dibenzyl-3-(3,5-dimethylphenyl)urea Chemical compound CC1=CC(C)=CC(NC(=O)N(CC=2C=CC=CC=2)CC=2C=CC=CC=2)=C1 RESBNNVJQNNILW-UHFFFAOYSA-N 0.000 description 1
- ZCXXQJWBFZKNCZ-UHFFFAOYSA-N 1,1-dibenzyl-3-(3-chloro-2-methylphenyl)urea Chemical compound CC1=C(Cl)C=CC=C1NC(=O)N(CC=1C=CC=CC=1)CC1=CC=CC=C1 ZCXXQJWBFZKNCZ-UHFFFAOYSA-N 0.000 description 1
- BDOVPEIAFDHKLW-UHFFFAOYSA-N 1,1-dibenzyl-3-(4-chloro-2-methylphenyl)urea Chemical compound CC1=CC(Cl)=CC=C1NC(=O)N(CC=1C=CC=CC=1)CC1=CC=CC=C1 BDOVPEIAFDHKLW-UHFFFAOYSA-N 0.000 description 1
- MIWUOXSDNYRMJC-UHFFFAOYSA-N 1,1-dibenzyl-3-(4-iodophenyl)urea Chemical compound C1=CC(I)=CC=C1NC(=O)N(CC=1C=CC=CC=1)CC1=CC=CC=C1 MIWUOXSDNYRMJC-UHFFFAOYSA-N 0.000 description 1
- QTJZUZAPBCEYJS-UHFFFAOYSA-N 1,1-dibenzyl-3-(5-chloro-2-methylphenyl)urea Chemical compound CC1=CC=C(Cl)C=C1NC(=O)N(CC=1C=CC=CC=1)CC1=CC=CC=C1 QTJZUZAPBCEYJS-UHFFFAOYSA-N 0.000 description 1
- BLMMMPXZBCZKPM-UHFFFAOYSA-N 1,1-dibenzyl-3-[2-(trifluoromethyl)phenyl]urea Chemical compound FC(F)(F)C1=CC=CC=C1NC(=O)N(CC=1C=CC=CC=1)CC1=CC=CC=C1 BLMMMPXZBCZKPM-UHFFFAOYSA-N 0.000 description 1
- KZEMDLLHTKCHRW-UHFFFAOYSA-N 1,1-dibutyl-3-(2,3-dichlorophenyl)urea Chemical compound CCCCN(CCCC)C(=O)NC1=CC=CC(Cl)=C1Cl KZEMDLLHTKCHRW-UHFFFAOYSA-N 0.000 description 1
- JDPKNNMXLNFCSQ-UHFFFAOYSA-N 1,1-dibutyl-3-(2-methylphenyl)urea Chemical compound CCCCN(CCCC)C(=O)NC1=CC=CC=C1C JDPKNNMXLNFCSQ-UHFFFAOYSA-N 0.000 description 1
- XYOUIZSNPKALSK-UHFFFAOYSA-N 1,1-dibutyl-3-(3,5-dichlorophenyl)urea Chemical compound CCCCN(CCCC)C(=O)NC1=CC(Cl)=CC(Cl)=C1 XYOUIZSNPKALSK-UHFFFAOYSA-N 0.000 description 1
- IOKBPHPZJHRVSD-UHFFFAOYSA-N 1,1-dibutyl-3-(3-chlorophenyl)urea Chemical compound CCCCN(CCCC)C(=O)NC1=CC=CC(Cl)=C1 IOKBPHPZJHRVSD-UHFFFAOYSA-N 0.000 description 1
- WAJNLXRVSDCMLN-UHFFFAOYSA-N 1,1-dibutyl-3-(3-methoxyphenyl)urea Chemical compound CCCCN(CCCC)C(=O)NC1=CC=CC(OC)=C1 WAJNLXRVSDCMLN-UHFFFAOYSA-N 0.000 description 1
- HKKNIVLOYNGPJM-UHFFFAOYSA-N 1,1-dibutyl-3-(3-methylphenyl)urea Chemical compound CCCCN(CCCC)C(=O)NC1=CC=CC(C)=C1 HKKNIVLOYNGPJM-UHFFFAOYSA-N 0.000 description 1
- MFMCRJKCTRKJJW-UHFFFAOYSA-N 1,1-dibutyl-3-(3-methylsulfanylphenyl)urea Chemical compound CCCCN(CCCC)C(=O)NC1=CC=CC(SC)=C1 MFMCRJKCTRKJJW-UHFFFAOYSA-N 0.000 description 1
- VWNILTMMJQSIIE-UHFFFAOYSA-N 1,1-dibutyl-3-(4-chloro-2-methylphenyl)urea Chemical compound CCCCN(CCCC)C(=O)NC1=CC=C(Cl)C=C1C VWNILTMMJQSIIE-UHFFFAOYSA-N 0.000 description 1
- DMQXKZRISBXSCF-UHFFFAOYSA-N 1,1-dibutyl-3-(4-fluorophenyl)urea Chemical compound CCCCN(CCCC)C(=O)NC1=CC=C(F)C=C1 DMQXKZRISBXSCF-UHFFFAOYSA-N 0.000 description 1
- VJEDPFYJNAODPX-UHFFFAOYSA-N 1,1-dibutyl-3-(4-iodophenyl)urea Chemical compound CCCCN(CCCC)C(=O)NC1=CC=C(I)C=C1 VJEDPFYJNAODPX-UHFFFAOYSA-N 0.000 description 1
- SRAWWSSZOMEQHP-UHFFFAOYSA-N 1,1-dibutyl-3-(4-methylphenyl)urea Chemical compound CCCCN(CCCC)C(=O)NC1=CC=C(C)C=C1 SRAWWSSZOMEQHP-UHFFFAOYSA-N 0.000 description 1
- ALSBFRUBAAFKOV-UHFFFAOYSA-N 1,1-dibutyl-3-(4-propan-2-ylphenyl)urea Chemical compound CCCCN(CCCC)C(=O)NC1=CC=C(C(C)C)C=C1 ALSBFRUBAAFKOV-UHFFFAOYSA-N 0.000 description 1
- XIAPXMNZZWNYJS-UHFFFAOYSA-N 1,1-dibutyl-3-(5-chloro-2-methylphenyl)urea Chemical compound CCCCN(CCCC)C(=O)NC1=CC(Cl)=CC=C1C XIAPXMNZZWNYJS-UHFFFAOYSA-N 0.000 description 1
- FITZPTZUGQEKMO-UHFFFAOYSA-N 1,1-dibutyl-3-[4-chloro-3-(trifluoromethyl)phenyl]urea Chemical compound CCCCN(CCCC)C(=O)NC1=CC=C(Cl)C(C(F)(F)F)=C1 FITZPTZUGQEKMO-UHFFFAOYSA-N 0.000 description 1
- LZWRJCKRKIAVRA-UHFFFAOYSA-N 1,1-dicyclopentyl-3-(2,4-dimethylphenyl)urea Chemical compound CC1=CC(C)=CC=C1NC(=O)N(C1CCCC1)C1CCCC1 LZWRJCKRKIAVRA-UHFFFAOYSA-N 0.000 description 1
- BSFGJAQNWOUCGU-UHFFFAOYSA-N 1,1-didecyl-3-(2,4-dimethylphenyl)urea Chemical compound CCCCCCCCCCN(CCCCCCCCCC)C(=O)NC1=CC=C(C)C=C1C BSFGJAQNWOUCGU-UHFFFAOYSA-N 0.000 description 1
- GINXIYJFLCPRAU-UHFFFAOYSA-N 1,3-dibenzyl-1-butyl-3-(2,4-dichlorophenyl)urea Chemical compound C=1C=CC=CC=1CN(C=1C(=CC(Cl)=CC=1)Cl)C(=O)N(CCCC)CC1=CC=CC=C1 GINXIYJFLCPRAU-UHFFFAOYSA-N 0.000 description 1
- NQYIWBNNPHOSSX-UHFFFAOYSA-N 1,3-dibenzyl-1-butyl-3-(2,4-dimethylphenyl)urea Chemical compound C=1C=CC=CC=1CN(C=1C(=CC(C)=CC=1)C)C(=O)N(CCCC)CC1=CC=CC=C1 NQYIWBNNPHOSSX-UHFFFAOYSA-N 0.000 description 1
- LUBJCRLGQSPQNN-UHFFFAOYSA-N 1-Phenylurea Chemical compound NC(=O)NC1=CC=CC=C1 LUBJCRLGQSPQNN-UHFFFAOYSA-N 0.000 description 1
- VYDPTHWCQYKHFR-UHFFFAOYSA-N 1-[(2,4-dichlorophenyl)methyl]-3-(2,4-dimethylphenyl)-1-[(4-methoxyphenyl)methyl]urea Chemical compound C1=CC(OC)=CC=C1CN(C(=O)NC=1C(=CC(C)=CC=1)C)CC1=CC=C(Cl)C=C1Cl VYDPTHWCQYKHFR-UHFFFAOYSA-N 0.000 description 1
- NJHHWPCFONNFFY-UHFFFAOYSA-N 1-[(3-chlorophenyl)methyl]-3-(2,4-dimethylphenyl)-1-[(4-methoxyphenyl)methyl]urea Chemical compound C1=CC(OC)=CC=C1CN(C(=O)NC=1C(=CC(C)=CC=1)C)CC1=CC=CC(Cl)=C1 NJHHWPCFONNFFY-UHFFFAOYSA-N 0.000 description 1
- OFDKKNMPXBLFMN-UHFFFAOYSA-N 1-[(4-butoxyphenyl)methyl]-1-heptyl-3-(2,4,6-trichlorophenyl)urea Chemical compound ClC=1C=C(Cl)C=C(Cl)C=1NC(=O)N(CCCCCCC)CC1=CC=C(OCCCC)C=C1 OFDKKNMPXBLFMN-UHFFFAOYSA-N 0.000 description 1
- YVEYRNZPUHVECU-UHFFFAOYSA-N 1-[(4-butoxyphenyl)methyl]-3-(4-chloro-2-methylphenyl)-1-heptylurea Chemical compound C=1C=C(Cl)C=C(C)C=1NC(=O)N(CCCCCCC)CC1=CC=C(OCCCC)C=C1 YVEYRNZPUHVECU-UHFFFAOYSA-N 0.000 description 1
- KBPGXZOKJALMHF-UHFFFAOYSA-N 1-[(4-butoxyphenyl)methyl]-3-[4-chloro-2-(trifluoromethyl)phenyl]-1-heptylurea Chemical compound C(CCCCCC)N(C(=O)NC1=C(C=C(C=C1)Cl)C(F)(F)F)CC1=CC=C(C=C1)OCCCC KBPGXZOKJALMHF-UHFFFAOYSA-N 0.000 description 1
- QDWYQFLKWCSOMI-UHFFFAOYSA-N 1-[(4-butylphenyl)methyl]-1-heptyl-3-(2,4,5-trichlorophenyl)urea Chemical compound C=1C(Cl)=C(Cl)C=C(Cl)C=1NC(=O)N(CCCCCCC)CC1=CC=C(CCCC)C=C1 QDWYQFLKWCSOMI-UHFFFAOYSA-N 0.000 description 1
- WXIZNHAOABRKPH-UHFFFAOYSA-N 1-[(4-butylphenyl)methyl]-1-heptyl-3-(2,4,6-trichlorophenyl)urea Chemical compound ClC=1C=C(Cl)C=C(Cl)C=1NC(=O)N(CCCCCCC)CC1=CC=C(CCCC)C=C1 WXIZNHAOABRKPH-UHFFFAOYSA-N 0.000 description 1
- PTGMAUVPFRYLJY-UHFFFAOYSA-N 1-[(4-butylphenyl)methyl]-1-heptyl-3-[3-(trifluoromethyl)phenyl]urea Chemical compound C=1C=CC(C(F)(F)F)=CC=1NC(=O)N(CCCCCCC)CC1=CC=C(CCCC)C=C1 PTGMAUVPFRYLJY-UHFFFAOYSA-N 0.000 description 1
- BQIRPLYKNRXSMI-UHFFFAOYSA-N 1-[(4-butylphenyl)methyl]-3-(2,4-dichlorophenyl)-1-heptylurea Chemical compound C=1C=C(Cl)C=C(Cl)C=1NC(=O)N(CCCCCCC)CC1=CC=C(CCCC)C=C1 BQIRPLYKNRXSMI-UHFFFAOYSA-N 0.000 description 1
- RHZPLSCNTZDZFL-UHFFFAOYSA-N 1-[(4-butylphenyl)methyl]-3-(2,4-difluorophenyl)-1-heptylurea Chemical compound C=1C=C(F)C=C(F)C=1NC(=O)N(CCCCCCC)CC1=CC=C(CCCC)C=C1 RHZPLSCNTZDZFL-UHFFFAOYSA-N 0.000 description 1
- VEIKVCBDZNZGPY-UHFFFAOYSA-N 1-[(4-butylphenyl)methyl]-3-(2,4-dimethylphenyl)-1-heptylurea Chemical compound C=1C=C(C)C=C(C)C=1NC(=O)N(CCCCCCC)CC1=CC=C(CCCC)C=C1 VEIKVCBDZNZGPY-UHFFFAOYSA-N 0.000 description 1
- LCVIPSFXSDQQON-UHFFFAOYSA-N 1-[(4-butylphenyl)methyl]-3-(2,4-dimethylphenyl)-1-octadec-9-enylurea Chemical compound C=1C=C(C)C=C(C)C=1NC(=O)N(CCCCCCCCC=CCCCCCCCC)CC1=CC=C(CCCC)C=C1 LCVIPSFXSDQQON-UHFFFAOYSA-N 0.000 description 1
- AZHKELKHBWQIMI-UHFFFAOYSA-N 1-[(4-butylphenyl)methyl]-3-(4-chloro-2-methylphenyl)-1-heptylurea Chemical compound C=1C=C(Cl)C=C(C)C=1NC(=O)N(CCCCCCC)CC1=CC=C(CCCC)C=C1 AZHKELKHBWQIMI-UHFFFAOYSA-N 0.000 description 1
- IJBHBTJBBNENLV-UHFFFAOYSA-N 1-[(4-butylphenyl)methyl]-3-[4-chloro-2-(trifluoromethyl)phenyl]-1-heptylurea Chemical compound C(CCCCCC)N(C(=O)NC1=C(C=C(C=C1)Cl)C(F)(F)F)CC1=CC=C(C=C1)CCCC IJBHBTJBBNENLV-UHFFFAOYSA-N 0.000 description 1
- BDWAJHSDXIBOEN-UHFFFAOYSA-N 1-[(4-chlorophenyl)methyl]-1-(naphthalen-1-ylmethyl)-3-(2,4,6-trichlorophenyl)urea Chemical compound C1=CC(Cl)=CC=C1CN(C(=O)NC=1C(=CC(Cl)=CC=1Cl)Cl)CC1=CC=CC2=CC=CC=C12 BDWAJHSDXIBOEN-UHFFFAOYSA-N 0.000 description 1
- AOVYPIGKUGUNGI-UHFFFAOYSA-N 1-[(4-chlorophenyl)methyl]-1-(naphthalen-1-ylmethyl)-3-[3-(trifluoromethyl)phenyl]urea Chemical compound ClC1=CC=C(CN(C(=O)NC2=CC(=CC=C2)C(F)(F)F)CC2=CC=CC3=CC=CC=C23)C=C1 AOVYPIGKUGUNGI-UHFFFAOYSA-N 0.000 description 1
- CTGNFOBBHRYUMV-UHFFFAOYSA-N 1-benzyl-1-[(4-butoxyphenyl)methyl]-3-(2,4,5-trichlorophenyl)urea Chemical compound C1=CC(OCCCC)=CC=C1CN(C(=O)NC=1C(=CC(Cl)=C(Cl)C=1)Cl)CC1=CC=CC=C1 CTGNFOBBHRYUMV-UHFFFAOYSA-N 0.000 description 1
- LPJWGEOWDOUIHJ-UHFFFAOYSA-N 1-benzyl-1-[(4-butoxyphenyl)methyl]-3-(2,4-dichlorophenyl)urea Chemical compound C1=CC(OCCCC)=CC=C1CN(C(=O)NC=1C(=CC(Cl)=CC=1)Cl)CC1=CC=CC=C1 LPJWGEOWDOUIHJ-UHFFFAOYSA-N 0.000 description 1
- JXJKOOUNIHTFDJ-UHFFFAOYSA-N 1-benzyl-1-[(4-butylphenyl)methyl]-3-(2,4,5-trimethylphenyl)urea Chemical compound C1=CC(CCCC)=CC=C1CN(C(=O)NC=1C(=CC(C)=C(C)C=1)C)CC1=CC=CC=C1 JXJKOOUNIHTFDJ-UHFFFAOYSA-N 0.000 description 1
- VTAYTGNKCUMKNA-UHFFFAOYSA-N 1-benzyl-1-[(4-butylphenyl)methyl]-3-(2,4-dimethylphenyl)urea Chemical compound C1=CC(CCCC)=CC=C1CN(C(=O)NC=1C(=CC(C)=CC=1)C)CC1=CC=CC=C1 VTAYTGNKCUMKNA-UHFFFAOYSA-N 0.000 description 1
- QIUSKIYBFZRTFM-UHFFFAOYSA-N 1-benzyl-1-[(4-butylphenyl)methyl]-3-(4-phenoxyphenyl)urea Chemical compound C1=CC(CCCC)=CC=C1CN(C(=O)NC=1C=CC(OC=2C=CC=CC=2)=CC=1)CC1=CC=CC=C1 QIUSKIYBFZRTFM-UHFFFAOYSA-N 0.000 description 1
- LTIWXYAHZVENNJ-UHFFFAOYSA-N 1-benzyl-1-[2-phenyl-1-(4-phenylmethoxyphenyl)ethyl]-3-(2,4,6-trimethylphenyl)urea Chemical compound C(C1=CC=CC=C1)N(C(=O)NC1=C(C=C(C=C1C)C)C)C(CC1=CC=CC=C1)C1=CC=C(C=C1)OCC1=CC=CC=C1 LTIWXYAHZVENNJ-UHFFFAOYSA-N 0.000 description 1
- JOUBLGWLPRKRPX-UHFFFAOYSA-N 1-benzyl-1-butyl-3-(2,3-dimethylphenyl)urea Chemical compound C=1C=CC(C)=C(C)C=1NC(=O)N(CCCC)CC1=CC=CC=C1 JOUBLGWLPRKRPX-UHFFFAOYSA-N 0.000 description 1
- UWKFDLFIDDDVAQ-UHFFFAOYSA-N 1-benzyl-1-butyl-3-(2,4-dichlorophenyl)-3-[(2,4-dichlorophenyl)methyl]urea Chemical compound C(C1=CC=CC=C1)N(C(=O)N(C1=C(C=C(C=C1)Cl)Cl)CC1=C(C=C(C=C1)Cl)Cl)CCCC UWKFDLFIDDDVAQ-UHFFFAOYSA-N 0.000 description 1
- CSNNSBCTKPLPAY-UHFFFAOYSA-N 1-benzyl-1-butyl-3-(2,4-dichlorophenyl)-3-[(2,4-dimethylphenyl)methyl]urea Chemical compound C(C1=CC=CC=C1)N(C(=O)N(C1=C(C=C(C=C1)Cl)Cl)CC1=C(C=C(C=C1)C)C)CCCC CSNNSBCTKPLPAY-UHFFFAOYSA-N 0.000 description 1
- UAMMZAIIPBUZOS-UHFFFAOYSA-N 1-benzyl-1-butyl-3-(2,6-dimethylphenyl)urea Chemical compound CC=1C=CC=C(C)C=1NC(=O)N(CCCC)CC1=CC=CC=C1 UAMMZAIIPBUZOS-UHFFFAOYSA-N 0.000 description 1
- WVVURDQILNRHLZ-UHFFFAOYSA-N 1-benzyl-1-butyl-3-(2-chlorophenyl)-3-[(2-chlorophenyl)methyl]urea Chemical compound C=1C=CC=C(Cl)C=1CN(C=1C(=CC=CC=1)Cl)C(=O)N(CCCC)CC1=CC=CC=C1 WVVURDQILNRHLZ-UHFFFAOYSA-N 0.000 description 1
- TXIYNYNMYANNEX-UHFFFAOYSA-N 1-benzyl-1-butyl-3-(3,4-dichlorophenyl)urea Chemical compound C=1C=C(Cl)C(Cl)=CC=1NC(=O)N(CCCC)CC1=CC=CC=C1 TXIYNYNMYANNEX-UHFFFAOYSA-N 0.000 description 1
- RTSCWIYJSUSUQX-UHFFFAOYSA-N 1-benzyl-1-butyl-3-(3,4-dimethylphenyl)urea Chemical compound C=1C=C(C)C(C)=CC=1NC(=O)N(CCCC)CC1=CC=CC=C1 RTSCWIYJSUSUQX-UHFFFAOYSA-N 0.000 description 1
- AGYWMLJGOQMPDZ-UHFFFAOYSA-N 1-benzyl-1-butyl-3-(3,5-dichlorophenyl)urea Chemical compound C=1C(Cl)=CC(Cl)=CC=1NC(=O)N(CCCC)CC1=CC=CC=C1 AGYWMLJGOQMPDZ-UHFFFAOYSA-N 0.000 description 1
- RBQXUXOVVFMJTC-UHFFFAOYSA-N 1-benzyl-1-butyl-3-(3,5-dimethylphenyl)urea Chemical compound C=1C(C)=CC(C)=CC=1NC(=O)N(CCCC)CC1=CC=CC=C1 RBQXUXOVVFMJTC-UHFFFAOYSA-N 0.000 description 1
- YBJJTIBZTOKFLF-UHFFFAOYSA-N 1-benzyl-1-butyl-3-(3-chloro-2-hydroxyphenyl)urea Chemical compound C=1C=CC(Cl)=C(O)C=1NC(=O)N(CCCC)CC1=CC=CC=C1 YBJJTIBZTOKFLF-UHFFFAOYSA-N 0.000 description 1
- COJMLDQLJWCYDJ-UHFFFAOYSA-N 1-benzyl-1-butyl-3-(3-chloro-4-methoxyphenyl)urea Chemical compound C=1C=C(OC)C(Cl)=CC=1NC(=O)N(CCCC)CC1=CC=CC=C1 COJMLDQLJWCYDJ-UHFFFAOYSA-N 0.000 description 1
- DQKVOIDAPGJUPB-UHFFFAOYSA-N 1-benzyl-1-butyl-3-(3-chloro-4-methylphenyl)urea Chemical compound C=1C=C(C)C(Cl)=CC=1NC(=O)N(CCCC)CC1=CC=CC=C1 DQKVOIDAPGJUPB-UHFFFAOYSA-N 0.000 description 1
- QUMQURXEFSSGLJ-UHFFFAOYSA-N 1-benzyl-1-butyl-3-(3-methylphenyl)urea Chemical compound C=1C=CC(C)=CC=1NC(=O)N(CCCC)CC1=CC=CC=C1 QUMQURXEFSSGLJ-UHFFFAOYSA-N 0.000 description 1
- GGMNLPSTOPHGQE-UHFFFAOYSA-N 1-benzyl-1-butyl-3-(4-methylphenyl)-3-[(4-methylphenyl)methyl]urea Chemical compound C=1C=C(C)C=CC=1CN(C=1C=CC(C)=CC=1)C(=O)N(CCCC)CC1=CC=CC=C1 GGMNLPSTOPHGQE-UHFFFAOYSA-N 0.000 description 1
- NOVOOSMKCVYNRU-UHFFFAOYSA-N 1-benzyl-1-butyl-3-[(2,4-dichlorophenyl)methyl]-3-(2,4-dimethylphenyl)urea Chemical compound C(C1=CC=CC=C1)N(C(=O)N(C1=C(C=C(C=C1)C)C)CC1=C(C=C(C=C1)Cl)Cl)CCCC NOVOOSMKCVYNRU-UHFFFAOYSA-N 0.000 description 1
- LMQNMOLYTJSOOY-UHFFFAOYSA-N 1-benzyl-1-butyl-3-[(2,4-dimethylphenyl)methyl]-3-phenylurea Chemical compound C(C1=CC=CC=C1)N(C(=O)N(C1=CC=CC=C1)CC1=C(C=C(C=C1)C)C)CCCC LMQNMOLYTJSOOY-UHFFFAOYSA-N 0.000 description 1
- RAQAPJYXYADDQC-UHFFFAOYSA-N 1-benzyl-1-butyl-3-[(3-chloro-4-methylphenyl)methyl]-3-(4-methylphenyl)urea Chemical compound C(C1=CC=CC=C1)N(C(=O)N(C1=CC=C(C=C1)C)CC1=CC(=C(C=C1)C)Cl)CCCC RAQAPJYXYADDQC-UHFFFAOYSA-N 0.000 description 1
- IFGCEVZHQPZOMQ-UHFFFAOYSA-N 1-benzyl-1-butyl-3-[3-(trifluoromethyl)phenyl]urea Chemical compound C=1C=CC(C(F)(F)F)=CC=1NC(=O)N(CCCC)CC1=CC=CC=C1 IFGCEVZHQPZOMQ-UHFFFAOYSA-N 0.000 description 1
- ZPZXGIWDJQEXKE-UHFFFAOYSA-N 1-benzyl-1-butyl-3-naphthalen-1-yl-3-phenylurea Chemical compound C=1C=CC=CC=1N(C=1C2=CC=CC=C2C=CC=1)C(=O)N(CCCC)CC1=CC=CC=C1 ZPZXGIWDJQEXKE-UHFFFAOYSA-N 0.000 description 1
- VDFUCSQUJYZLAZ-UHFFFAOYSA-N 1-benzyl-1-butyl-3-phenylthiourea Chemical compound C=1C=CC=CC=1NC(=S)N(CCCC)CC1=CC=CC=C1 VDFUCSQUJYZLAZ-UHFFFAOYSA-N 0.000 description 1
- HUVBFGMXRUTCKD-UHFFFAOYSA-N 1-benzyl-3-(2,4-dimethylphenyl)-1-(1,2-diphenylethyl)urea Chemical compound CC1=CC(C)=CC=C1NC(=O)N(C(CC=1C=CC=CC=1)C=1C=CC=CC=1)CC1=CC=CC=C1 HUVBFGMXRUTCKD-UHFFFAOYSA-N 0.000 description 1
- JVNRLCNTRINRBJ-UHFFFAOYSA-N 1-benzyl-3-(2,4-dimethylphenyl)-1-undecylurea Chemical compound C=1C=C(C)C=C(C)C=1NC(=O)N(CCCCCCCCCCC)CC1=CC=CC=C1 JVNRLCNTRINRBJ-UHFFFAOYSA-N 0.000 description 1
- FVWYAQOBBJQUGD-UHFFFAOYSA-N 1-benzyl-3-(4-butylphenyl)-1-[(4-butylphenyl)methyl]urea Chemical compound C1=CC(CCCC)=CC=C1CN(C(=O)NC=1C=CC(CCCC)=CC=1)CC1=CC=CC=C1 FVWYAQOBBJQUGD-UHFFFAOYSA-N 0.000 description 1
- YETBXLZFTBYAEP-UHFFFAOYSA-N 1-benzyl-3-[4-chloro-2-(trifluoromethyl)phenyl]-1-[2-phenyl-1-(4-phenylmethoxyphenyl)ethyl]urea Chemical compound C(C1=CC=CC=C1)N(C(=O)NC1=C(C=C(C=C1)Cl)C(F)(F)F)C(CC1=CC=CC=C1)C1=CC=C(C=C1)OCC1=CC=CC=C1 YETBXLZFTBYAEP-UHFFFAOYSA-N 0.000 description 1
- IFNCOAFUGZBNBC-UHFFFAOYSA-N 1-butyl-1-[(3-chlorophenyl)methyl]-3-(2,4-dimethylphenyl)urea Chemical compound C=1C=C(C)C=C(C)C=1NC(=O)N(CCCC)CC1=CC=CC(Cl)=C1 IFNCOAFUGZBNBC-UHFFFAOYSA-N 0.000 description 1
- RTNORZQKLFLYFM-UHFFFAOYSA-N 1-butyl-1-[(4-chlorophenyl)methyl]-3-(2,4-dimethylphenyl)urea Chemical compound C=1C=C(C)C=C(C)C=1NC(=O)N(CCCC)CC1=CC=C(Cl)C=C1 RTNORZQKLFLYFM-UHFFFAOYSA-N 0.000 description 1
- QJHRLBHCKZRXOO-UHFFFAOYSA-N 1-butyl-1-[2-(2-chlorophenyl)ethyl]-3-(2,4-dimethylphenyl)urea Chemical compound C=1C=C(C)C=C(C)C=1NC(=O)N(CCCC)CCC1=CC=CC=C1Cl QJHRLBHCKZRXOO-UHFFFAOYSA-N 0.000 description 1
- ZGBBSERQQNWUKG-UHFFFAOYSA-N 1-butyl-3-(2,4-dimethylphenyl)-1-[(4-methylphenyl)methyl]urea Chemical compound C=1C=C(C)C=C(C)C=1NC(=O)N(CCCC)CC1=CC=C(C)C=C1 ZGBBSERQQNWUKG-UHFFFAOYSA-N 0.000 description 1
- WLVVRNRBOFFHAN-UHFFFAOYSA-N 1-butyl-3-(2,4-dimethylphenyl)-1-[(4-methylsulfanylphenyl)methyl]urea Chemical compound C=1C=C(C)C=C(C)C=1NC(=O)N(CCCC)CC1=CC=C(SC)C=C1 WLVVRNRBOFFHAN-UHFFFAOYSA-N 0.000 description 1
- VDCGIDKFISXVDM-UHFFFAOYSA-N 1-butyl-3-(2,4-dimethylphenyl)-1-[(4-pentylphenyl)methyl]urea Chemical compound C1=CC(CCCCC)=CC=C1CN(CCCC)C(=O)NC1=CC=C(C)C=C1C VDCGIDKFISXVDM-UHFFFAOYSA-N 0.000 description 1
- VBHCHHNMWNQQRB-UHFFFAOYSA-N 1-phenyl-n-(2,4,6-trimethylphenyl)methanimine Chemical compound CC1=CC(C)=CC(C)=C1N=CC1=CC=CC=C1 VBHCHHNMWNQQRB-UHFFFAOYSA-N 0.000 description 1
- UIFVCPMLQXKEEU-UHFFFAOYSA-N 2,3-dimethylbenzaldehyde Chemical compound CC1=CC=CC(C=O)=C1C UIFVCPMLQXKEEU-UHFFFAOYSA-N 0.000 description 1
- GISVICWQYMUPJF-UHFFFAOYSA-N 2,4-Dimethylbenzaldehyde Chemical compound CC1=CC=C(C=O)C(C)=C1 GISVICWQYMUPJF-UHFFFAOYSA-N 0.000 description 1
- 125000000301 2-(3-chlorophenyl)ethyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- QJLOCCVVLZHSDX-UHFFFAOYSA-N 2-chloro-n-[(2-chlorophenyl)methyl]aniline Chemical compound ClC1=CC=CC=C1CNC1=CC=CC=C1Cl QJLOCCVVLZHSDX-UHFFFAOYSA-N 0.000 description 1
- YPWJMCVFKRDPCA-UHFFFAOYSA-N 3-(2,4-dichlorophenyl)-1-[(4-pentoxyphenyl)methyl]-1-[(4-pentylphenyl)methyl]urea Chemical compound C(CCCC)C1=CC=C(CN(C(=O)NC2=C(C=C(C=C2)Cl)Cl)CC2=CC=C(C=C2)OCCCCC)C=C1 YPWJMCVFKRDPCA-UHFFFAOYSA-N 0.000 description 1
- NNAQFLKCVHUNDF-UHFFFAOYSA-N 3-(2,4-dichlorophenyl)-1-heptyl-1-(2-phenylethyl)urea Chemical compound C=1C=C(Cl)C=C(Cl)C=1NC(=O)N(CCCCCCC)CCC1=CC=CC=C1 NNAQFLKCVHUNDF-UHFFFAOYSA-N 0.000 description 1
- IWFVKXFVJZKUCL-UHFFFAOYSA-N 3-(2,4-difluorophenyl)-1-[(4-pentoxyphenyl)methyl]-1-[(4-pentylphenyl)methyl]urea Chemical compound C(CCCC)C1=CC=C(CN(C(=O)NC2=C(C=C(C=C2)F)F)CC2=CC=C(C=C2)OCCCCC)C=C1 IWFVKXFVJZKUCL-UHFFFAOYSA-N 0.000 description 1
- ULJCCRYFVUPXEC-UHFFFAOYSA-N 3-(2,4-difluorophenyl)-1-heptyl-1-(2-phenylethyl)urea Chemical compound C=1C=C(F)C=C(F)C=1NC(=O)N(CCCCCCC)CCC1=CC=CC=C1 ULJCCRYFVUPXEC-UHFFFAOYSA-N 0.000 description 1
- NXJFRQPOEPJJDC-UHFFFAOYSA-N 3-(2,4-dimethylphenyl)-1,1-bis(3-methylbutyl)urea Chemical compound CC(C)CCN(CCC(C)C)C(=O)NC1=CC=C(C)C=C1C NXJFRQPOEPJJDC-UHFFFAOYSA-N 0.000 description 1
- MMNCLVOZLVBESW-UHFFFAOYSA-N 3-(2,4-dimethylphenyl)-1,1-di(undecyl)urea Chemical compound CCCCCCCCCCCN(CCCCCCCCCCC)C(=O)NC1=CC=C(C)C=C1C MMNCLVOZLVBESW-UHFFFAOYSA-N 0.000 description 1
- JLKFWGMUCHKIGD-UHFFFAOYSA-N 3-(2,4-dimethylphenyl)-1,1-dipentylurea Chemical compound CCCCCN(CCCCC)C(=O)NC1=CC=C(C)C=C1C JLKFWGMUCHKIGD-UHFFFAOYSA-N 0.000 description 1
- JVCQJHDEQCCTKR-UHFFFAOYSA-N 3-(2,5-dimethylphenyl)-1,1-bis(2-methylpropyl)urea Chemical compound CC(C)CN(CC(C)C)C(=O)NC1=CC(C)=CC=C1C JVCQJHDEQCCTKR-UHFFFAOYSA-N 0.000 description 1
- BBJKLEPTXSAVPQ-UHFFFAOYSA-N 3-(2,6-dimethylphenyl)-1,1-bis(2-methylpropyl)urea Chemical compound CC(C)CN(CC(C)C)C(=O)NC1=C(C)C=CC=C1C BBJKLEPTXSAVPQ-UHFFFAOYSA-N 0.000 description 1
- ZKWHIHJKUJWALJ-UHFFFAOYSA-N 3-(2-chlorophenyl)-1,1-bis(2-methylpropyl)urea Chemical compound CC(C)CN(CC(C)C)C(=O)NC1=CC=CC=C1Cl ZKWHIHJKUJWALJ-UHFFFAOYSA-N 0.000 description 1
- IWLQENQDBDKROZ-UHFFFAOYSA-N 3-(3-acetylphenyl)-1,1-dibenzylurea Chemical compound CC(=O)C1=CC=CC(NC(=O)N(CC=2C=CC=CC=2)CC=2C=CC=CC=2)=C1 IWLQENQDBDKROZ-UHFFFAOYSA-N 0.000 description 1
- ISSZSDVLXPEONC-UHFFFAOYSA-N 3-(3-acetylphenyl)-1,1-dibutylurea Chemical compound CCCCN(CCCC)C(=O)NC1=CC=CC(C(C)=O)=C1 ISSZSDVLXPEONC-UHFFFAOYSA-N 0.000 description 1
- YLFZMCLAZHQPFN-UHFFFAOYSA-N 3-(4-chloro-2-methylphenyl)-1-heptyl-1-(2-phenylethyl)urea Chemical compound C=1C=C(Cl)C=C(C)C=1NC(=O)N(CCCCCCC)CCC1=CC=CC=C1 YLFZMCLAZHQPFN-UHFFFAOYSA-N 0.000 description 1
- ODZRBTUVRQUISV-UHFFFAOYSA-N 3-chloro-4-methyl-n-[(4-methylphenyl)methyl]aniline Chemical compound C1=CC(C)=CC=C1CNC1=CC=C(C)C(Cl)=C1 ODZRBTUVRQUISV-UHFFFAOYSA-N 0.000 description 1
- OHHIBZKYXJDQEU-UHFFFAOYSA-N 3-chloro-n-phenylaniline Chemical compound ClC1=CC=CC(NC=2C=CC=CC=2)=C1 OHHIBZKYXJDQEU-UHFFFAOYSA-N 0.000 description 1
- HOVRQUHNZHBKKJ-UHFFFAOYSA-N 4-(carbamoylamino)benzoic acid Chemical compound NC(=O)NC1=CC=C(C(O)=O)C=C1 HOVRQUHNZHBKKJ-UHFFFAOYSA-N 0.000 description 1
- JEZWNFUVMREVTR-UHFFFAOYSA-N 4-methyl-n-[(4-methylphenyl)methyl]aniline Chemical compound C1=CC(C)=CC=C1CNC1=CC=C(C)C=C1 JEZWNFUVMREVTR-UHFFFAOYSA-N 0.000 description 1
- ZRPZPNYZFSJUPA-UHFFFAOYSA-N ARS-1620 Chemical compound Oc1cccc(F)c1-c1c(Cl)cc2c(ncnc2c1F)N1CCN(CC1)C(=O)C=C ZRPZPNYZFSJUPA-UHFFFAOYSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- BNPXJLKPHMGRTO-UHFFFAOYSA-N C1([N+](=O)[O-])=CC([N+](=O)[O-])=CC([N+](=O)[O-])=C1O.C(C1=CC=CC=C1)N(C(=O)N(C1=CC(=CC(=C1)OC)OC)CC1=CC(=CC=C1)N)CCCC Chemical compound C1([N+](=O)[O-])=CC([N+](=O)[O-])=CC([N+](=O)[O-])=C1O.C(C1=CC=CC=C1)N(C(=O)N(C1=CC(=CC(=C1)OC)OC)CC1=CC(=CC=C1)N)CCCC BNPXJLKPHMGRTO-UHFFFAOYSA-N 0.000 description 1
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical class NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- BDCFUHIWJODVNG-UHFFFAOYSA-N Desmosterol Natural products C1C=C2CC(O)C=CC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 BDCFUHIWJODVNG-UHFFFAOYSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical class [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 239000000219 Sympatholytic Substances 0.000 description 1
- 101150052863 THY1 gene Proteins 0.000 description 1
- BAECOWNUKCLBPZ-HIUWNOOHSA-N Triolein Natural products O([C@H](OCC(=O)CCCCCCC/C=C\CCCCCCCC)COC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CCCCCCC/C=C\CCCCCCCC BAECOWNUKCLBPZ-HIUWNOOHSA-N 0.000 description 1
- PHYFQTYBJUILEZ-UHFFFAOYSA-N Trioleoylglycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCCCCCCCC)COC(=O)CCCCCCCC=CCCCCCCCC PHYFQTYBJUILEZ-UHFFFAOYSA-N 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000000507 anthelmentic effect Effects 0.000 description 1
- 239000000921 anthelmintic agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 229940121357 antivirals Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- AVSXSVCZWQODGV-DPAQBDIFSA-N desmosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCC=C(C)C)C)[C@@]1(C)CC2 AVSXSVCZWQODGV-DPAQBDIFSA-N 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 125000004188 dichlorophenyl group Chemical group 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- HLVGAFHZUPLCML-UHFFFAOYSA-N ethyl 4-(carbamoylamino)benzoate Chemical compound CCOC(=O)C1=CC=C(NC(N)=O)C=C1 HLVGAFHZUPLCML-UHFFFAOYSA-N 0.000 description 1
- GOBYFGLUHUGHDQ-UHFFFAOYSA-N ethyl 4-[(4-phenylmethoxyphenyl)methylamino]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1NCC(C=C1)=CC=C1OCC1=CC=CC=C1 GOBYFGLUHUGHDQ-UHFFFAOYSA-N 0.000 description 1
- BWSMFVJXLIVYOM-UHFFFAOYSA-N ethyl 4-[(4-phenylmethoxyphenyl)methylideneamino]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1N=CC(C=C1)=CC=C1OCC1=CC=CC=C1 BWSMFVJXLIVYOM-UHFFFAOYSA-N 0.000 description 1
- JQPSQUTYMIGHAE-UHFFFAOYSA-N ethyl 4-[[(4-butylphenyl)methyl-heptylcarbamoyl]amino]benzoate Chemical compound C=1C=C(C(=O)OCC)C=CC=1NC(=O)N(CCCCCCC)CC1=CC=C(CCCC)C=C1 JQPSQUTYMIGHAE-UHFFFAOYSA-N 0.000 description 1
- 235000013861 fat-free Nutrition 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000002550 fecal effect Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000000055 hyoplipidemic effect Effects 0.000 description 1
- 208000020346 hyperlipoproteinemia Diseases 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 230000006372 lipid accumulation Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229940111688 monobasic potassium phosphate Drugs 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- RRFPPNUZXMNIBU-UHFFFAOYSA-N n,1-bis(2,4-dichlorophenyl)methanimine Chemical compound ClC1=CC(Cl)=CC=C1C=NC1=CC=C(Cl)C=C1Cl RRFPPNUZXMNIBU-UHFFFAOYSA-N 0.000 description 1
- AFAMOLWHCXGAKY-UHFFFAOYSA-N n,1-bis(2,4-dimethylphenyl)methanimine Chemical compound CC1=CC(C)=CC=C1C=NC1=CC=C(C)C=C1C AFAMOLWHCXGAKY-UHFFFAOYSA-N 0.000 description 1
- LKMIOABGTREIHR-UHFFFAOYSA-N n,1-bis(4-methylphenyl)methanimine Chemical compound C1=CC(C)=CC=C1C=NC1=CC=C(C)C=C1 LKMIOABGTREIHR-UHFFFAOYSA-N 0.000 description 1
- NGWDQWLRGODIPF-UHFFFAOYSA-N n-(2,4-dichlorophenyl)-1-phenylmethanimine Chemical compound ClC1=CC(Cl)=CC=C1N=CC1=CC=CC=C1 NGWDQWLRGODIPF-UHFFFAOYSA-N 0.000 description 1
- CCUWEZJBHOXLPA-UHFFFAOYSA-N n-(2,4-dimethylphenyl)-1-phenylmethanimine Chemical compound CC1=CC(C)=CC=C1N=CC1=CC=CC=C1 CCUWEZJBHOXLPA-UHFFFAOYSA-N 0.000 description 1
- BYMDTJKFACBBBD-UHFFFAOYSA-N n-(3-chloro-4-methylphenyl)-1-(4-methylphenyl)methanimine Chemical compound C1=CC(C)=CC=C1C=NC1=CC=C(C)C(Cl)=C1 BYMDTJKFACBBBD-UHFFFAOYSA-N 0.000 description 1
- VVUAADACTIQHDR-UHFFFAOYSA-N n-(3-chlorophenyl)-n-phenylcarbamoyl chloride Chemical compound C=1C=CC(Cl)=CC=1N(C(=O)Cl)C1=CC=CC=C1 VVUAADACTIQHDR-UHFFFAOYSA-N 0.000 description 1
- HFGFPUPROHHWFT-UHFFFAOYSA-N n-(3-nitrophenyl)-1-phenylmethanimine Chemical compound [O-][N+](=O)C1=CC=CC(N=CC=2C=CC=CC=2)=C1 HFGFPUPROHHWFT-UHFFFAOYSA-N 0.000 description 1
- NWCAQYVAHZWHIO-UHFFFAOYSA-N n-(4-chlorophenyl)-1-phenylmethanimine Chemical compound C1=CC(Cl)=CC=C1N=CC1=CC=CC=C1 NWCAQYVAHZWHIO-UHFFFAOYSA-N 0.000 description 1
- WWIIUZRDEYPOAR-UHFFFAOYSA-N n-[(2,4-dichlorophenyl)methyl]-2,4-dimethylaniline Chemical compound CC1=CC(C)=CC=C1NCC1=CC=C(Cl)C=C1Cl WWIIUZRDEYPOAR-UHFFFAOYSA-N 0.000 description 1
- YSEGFBXNCKAPKQ-UHFFFAOYSA-N n-[(2,4-dimethylphenyl)methyl]-2,4-dimethylaniline Chemical compound CC1=CC(C)=CC=C1CNC1=CC=C(C)C=C1C YSEGFBXNCKAPKQ-UHFFFAOYSA-N 0.000 description 1
- WFKMKLYNZWOGGA-UHFFFAOYSA-N n-[3,5-bis(trifluoromethyl)phenyl]-1-phenylmethanimine Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(N=CC=2C=CC=CC=2)=C1 WFKMKLYNZWOGGA-UHFFFAOYSA-N 0.000 description 1
- LRIYKLNPLHUXOO-UHFFFAOYSA-N n-[3-[benzyl-[benzyl(butyl)carbamoyl]amino]phenyl]acetamide Chemical compound C=1C=CC=CC=1CN(C=1C=C(NC(C)=O)C=CC=1)C(=O)N(CCCC)CC1=CC=CC=C1 LRIYKLNPLHUXOO-UHFFFAOYSA-N 0.000 description 1
- JMUDYTLZQVUDLG-UHFFFAOYSA-N n-benzyl-2,4,6-trimethylaniline Chemical compound CC1=CC(C)=CC(C)=C1NCC1=CC=CC=C1 JMUDYTLZQVUDLG-UHFFFAOYSA-N 0.000 description 1
- CIOZTNUIZOLRED-UHFFFAOYSA-N n-benzyl-2,4-dichloroaniline Chemical compound ClC1=CC(Cl)=CC=C1NCC1=CC=CC=C1 CIOZTNUIZOLRED-UHFFFAOYSA-N 0.000 description 1
- SIBVVRORCRNRLU-UHFFFAOYSA-N n-benzyl-2,4-dimethylaniline Chemical compound CC1=CC(C)=CC=C1NCC1=CC=CC=C1 SIBVVRORCRNRLU-UHFFFAOYSA-N 0.000 description 1
- OVZNWAWUJPSLHM-UHFFFAOYSA-N n-benzyl-3-nitroaniline Chemical compound [O-][N+](=O)C1=CC=CC(NCC=2C=CC=CC=2)=C1 OVZNWAWUJPSLHM-UHFFFAOYSA-N 0.000 description 1
- MMEIYVXPSXIGET-UHFFFAOYSA-N n-benzyl-4-chloroaniline Chemical compound C1=CC(Cl)=CC=C1NCC1=CC=CC=C1 MMEIYVXPSXIGET-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- XDUHQPOXLUAVEE-BPMMELMSSA-N oleoyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CCCCCCC\C=C/CCCCCCCC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 XDUHQPOXLUAVEE-BPMMELMSSA-N 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- 239000005648 plant growth regulator Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- LZMJNVRJMFMYQS-UHFFFAOYSA-N poseltinib Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC(OC=2C=C(NC(=O)C=C)C=CC=2)=C(OC=C2)C2=N1 LZMJNVRJMFMYQS-UHFFFAOYSA-N 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000003345 scintillation counting Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000000948 sympatholitic effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000021195 test diet Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- 229940117972 triolein Drugs 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
- C07C273/1809—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety
- C07C273/1818—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety from -N=C=O and XNR'R"
- C07C273/1827—X being H
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
Abstract
Substituted ureas and thioureas of the formula below are disclosed which are useful as antiatherosclerotic agents wherein X represents at least one substituent selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, hydroxy, C1-C4 alkoxy, phenoxy, mercapto, C1-C4 alkylthio, amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, halo, trihalomethyl, C1-C4 alkanoyl, benzoyl, C1-C4 alkanamido, C1-C4 alkanesulfonyl, C1-C4 alkanesulfinyl, benzenesulfonyl, toluenesulfonyl, nitro, cyano, carboxy, C1-C4 carboalkoxy, carbamoyl, sulfamyl, methylenedioxy, phenyl, ortho-phenylene, tolyl, benzyl, halobenzyl, methylbenzyl, and the group: wherein Y is selected from the group consisting of oxygen and sulfur; R1 and R2 are the same or different and are independently selected from the group consisting of C4-C12 alkyl, C4-C12 alkenyl, C4-C12 alkynyl, C4-C12 cycloalkyl, C4-C12 cycloalkylalkyl, C7-C14 aralkyl, furyl and C7-C14 aralkyl in which an aromatic ring bears at least one substituent selected from the group consisting of C1-C10 alkyl, C1-C10 alkoxy, phenoxy, benzyloxy, methylenedioxy, C1- C4 alkylthio, phenyl, halo, trihalomethyl, adamantyl, C1-C4 carboalkoxy, and nitro; and R3 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, benzyl, benzyl bearing at least one substituent Z, naphthyl, phenyl, and phenyl bearing at least one substituent Z, Z being selected independently of X from the group consisting of those from which X is selected.
Description
This invention relates to substituted urea and thiourea compounds useful as pharmaceutical agents, some of which are novel compounds. The compounds of the present invention are antiatherosclerotic agents capable of ame5 liorating atherosclerosis by counteracting the formation or development of atheromatous lesions in the arterial wall of mammals. The invention also relates to the chemical synthesis of the compounds disclosed herein. In addition, the invention pertains to pharmaceutical com10 positions for the utilization of these compounds in the treatment of disease in mammals. Further, the invention contemplates methods for treating atherosclerosis in a manner designed to prevent, arrest, or reverse the course of the disease.
A variety of urea and thiourea compounds can be found in the literature, for example, in J. Med. Chem. 18, 1024 (1975); Chem Absts. 95: 6758m (1981) and 91: 74631g (1979); U.S. Patent Nos. 2,688,039; 3,335,142; 3,856,952; 3,903,130; and in West German Offenlegungschrift 29 28 485. The compounds found in the literature are disclosed as being useful herbicides, plant growth regulators, bactericides, pesticides, fungicides, algacides, photographic sensitizers, antihelmintics, sympatholytics. and antivirals. Those urea compounds found in Offenlegung25 schrift 29 28 485 are disclosed as useful in inhibiting lipid absorption. There are, however, no literature references disclosing the tettasubstituted urea and thiourea compounds of the present invention or their use in the treatment of atherosclerosis or hyperlipidemia.
Atherosclerosis is a form of arteriosclerosis characterized by lipid accumulation in and thickening of the arterial walls of both medium- and large-sized arteries. Arterial walls are thereby weakened and the elasticity and effective internal size of the artery is decreased. Atherosclerosis is the most common cause of ischemic heart disease and is of great medical importance since the occlusion of medium- and large-sized arteries diminishes the supply of blood to vital organs such as the heart muscles and the brain. The sequelae to atherosclerosis include ischemic heart disease, heart failure, life-threatening arrythmias, senility, and stroke.
The fact that cholesterol is a major component of atherosclerotic lesions or plaques has been known for more than 100 years. Various researchers have studied the role of cholesterol in lesion formation and development and also, more importantly, whether lesion formation can be prevented or lesion development arrested or reversed. Atheromatous lesions have now been shown [Adams, et al., Atherosclerosis, 13, 429 (1974)] to contain a greater quantity of esterified as opposed to unesterified cholesterol than the surrounding undiseased arterial wall. The intracellular esterification of cholesterol with fatty acids is catalyzed by the enzyme Fatty acyl CoA:cholesterol acyl transferase or ACAT and the accumulation and storage of cholesteryl esters in the arterial wall is associated with increased activity of this enzyme [Hashimoto and Dayton, Atherosclerosis, 28, 447 (1977)]. In addition, cholesteryl esters are removed from cells at a slower rate than unesterified cholesterol [Bondjers and Bjorkerud, Atherosclerosis, 15, 273 (1972) and 22, 379 (1975)]. Thus, inhibition of the ACAT enzyme would diminish the rate of cholesterol esterification, decrease the accumulation and storage of cholesteryl esters in the arterial wall, and prevent or inhibit the formation and development of atheromatous lesions. The compounds of the present invention are very potent inhibitors of the ACAT enzyme. Thus, these compounds ate useful for controlling and reducing the cholesteryl ester content of mammalian arterial walls, and decreasing the accumulation and storage of cholesterol in the arterial walls of mammals. Further, the compounds of this invention inhibit the formation or development of artherosclerotic lesions in mammals.
The evidence that hyperlipidemia is one of the factors involved in coronary heart disease is very impressive. A most important study carried out in Framingham, Massachusetts (Gordon and Verter, 1969) in over 5,000 persons for more than 12 years established a correlation between high concentrations of blood cholesterol and increased risk of heart attack. Although the causes of coronary artery disease are multiple, one of the most constant factors has been the elevated concentration of lipids in the hlood plasma. A combined elevation of cholesterol and triglycerides has been shown (Carlson and Bottiger, 1972) to carry the highest risk of coronary heart disease. The majority of patients with ischemic heart disease or peripheral vascular disease were found to have hyperlipoproteinemia, involving very low-density and/or liw-density lipoproteins (lewis, et al., 1974).
We have now found that certain members of this class of compounds can safely and effectively lower both serum lipids in warm-blooded animals. Such action on serum lipids is considered to be very useful in the treatment of atherosclerosis. For some time, it has been considered desirable to lower serum-lipid levels and to correct lipoprotein imbalance in mammals as a preventive measure against atherosclerosis. The compounds of the present invention do not act by blocking late stages of cholesterol biosynthesis and thus do not produce accumulation of intermediates such as desmosterol, as equally undesirable as cholesterol itself, compounds with the combination of therapeutically favorable characteristics possessed by those of the present invention can be safely administered to warm-blooded mammals for the treatment of hyperlipidemic and atherosclerotic states found in patients with or prone to heart attacks, to peripheral or cerebral vascular disease and to stroke.
The compounds of this invention exhibit antiatherosclerotic activity and the invention should not be construed as limited to any particular mechanism of antiatherosclerotic action.
More specifically, this invention relates to certain novel compounds which may be represented by formula I: «3 Y Rl \ u z N-C-N \ «2 I wherein X represents at least one substituent selected from the group consisting of alkyl, Cj-C^ alkenyl, Cj-Cz, alkynyl, hydroxy, C4-C4 alkoxy, phenoxy, mercapto, C1-C4 alkylthio, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, halo, trihalomethyl, C1-C4 alkanoyl, benzoyl, C1-C4 alkanamido, C}-C4 alkanesulfonyl, Cj-C4 alkanesulfinyl, benzenesulfonyl, toluenesulfonyl, nitro, cyano, carboxy, C1-C4 carboalkoxy, carbamoyl, sulfamyl, methylenedioxy, phenyl, ortho-phenylene, tolyl, benzyl, halobenzyl, methylbenzyl and the group Ri y \ (I N-C-N z \ R? H wherein Y is oxygen; R-| and R2 are the same or different and are independently selected from the group consisting of C^-C-jg alkyl, C4-Cj2 C4_C12 C?-C14 aralkyl, and Cy-C^ aralkyl in which an aromatic ring bears at least one substituent selected from the group consisting of CpC-iQ alkyl, C^-C1Q alkoxy, phenoxy, benzyloxy, methylenedioxy, C-|-C4 alkylthio, phenyl, halo, trihalomethyl, adamantyl, C-|-C4 carboalkoxy, and nitro; R3 is selected from the group consisting of hydrogen, C^-C4 alkyl, C^-C^ alkenyl, C-j-C4 alkynyl, benzyl, benzyl bearing at least one substituent Z, naphthyl, phenyl and phenyl bearing at least one substituent Ζ, Z being selected independently of X from the group consisting of those from which X is selected; with the proviso that when Rj is hydrogen then R-j and Rj cannot be the same.
Preferred compounds of the invention are those in which X represents at least one C^-C^ alkyl or halo substituent and Rj and Rj are the same or different and are independently selected from the group consisting of C^-C^ alkyl, C?-C14 aralkyl and substituted C?-C14 aralkyl. The most preferred are those in which X represents at least one methyl or chloro substituent and Z is hydrogen, methyl, or chloro.
This invention further relates to a process for preparing compounds of formula I wherein Rj is hydrogen, which comprises reacting an 20 aryl isocyanate of formula III with a secondary amine of formula IV, IV wherein X, Y, R^ and Rz are as defined hereinabove.
A specific process for preparing the compounds of formula I comprises reacting a compound of formula V: Y II A-C-B V 6. wherein Y is as defined in formula I and A and B are independently selected from the group consisting of halo, C1-C4 alkoxy, C1-C4 alkylthio, phenoxy, 4-chlorophenoxy, and 4-nitrophenoxy, with a secondary amine of formula IV: /R1 HN \ *2 IV wherein R) and R2 are as defined in formula I to yield an intermediate of formula VI: Y I 0 A-C-N Rl R2 VI and then reacting the intermediate with an arylamine of formula VII: Ra VII wherein X and R3 are as defined in formula I.
A still further specific process for preparing the compounds of formula I comprises reacting a compound of formula V: Y ί A-C-B V wherein Y is as defined in formula I and A and B are independently selected from the group consisting of halo, C1-C4 alkoxy, Ci-C4 alkylthio, phenoxy, 4-chlorophenoxy, and 4-nitrophenoxy, with an arylamine of formula Vll: VII wherein X and R3 are as defined in formula I» to yield an 10 intermediate of formula VIII: and then reacting the intermediate with a secondary amine of formula IV: HN IV wherein Ri and R2. are as defined in formula I.
This invention relates to a pharmaceutical composition for treating of the arterial wall, inhibiting atherosclerotic lesion development, and/or treating hyperlipidemia in a mammal in need of such treatment, which comprises an effective amount of a compound of the formula: Y R. 437 Rs. wherein X represents at least one substituent selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, hydroxy, C1-C4 alkoxy, phenoxy, mercapto, C1-C4 alkylthio, amino, C1-C4 alkylamino, di5 (C-| -C4 alkyl)amino, halo, tr ihalomethyl, C1-C4 alkanoyl, benzoyl, C1-C4 alkanamido, C1-C4 alkanesulfonyl, C1-C4 alkanesulfinyl, benzenesulfonyl, toluenesulfony, nitro, cyano, carboxy,· C1-C4 carboalkoxy, carbamoyl, sulfamyl, methylenedioxy, phenyl, ortho-phenylene, tolyl, benzyl, halobenzyl, and the group Y is oxygen; and Rg are the same or different and are independently selected from the group consisting of C4C12 alkyl, C4-C12 alkenyl, C4-C12 alkynyl, C4-C12 cycloalkyl, C4-C12 cycloalkylalkyl, C7-C14 aralkyl, and C7-C14 aralkyl in which an aromatic ring bears at least one substituent selected from the group consisting of C^-C^q alkyl, C^-Cio alkoxy, phenoxy, benzyloxy, methylenedioxy, C1-C4 alkylthio, phenyl, halo, trihalomethyl, adamantyl, C1-C4 carboalkoxy, and nitro; and R3 is selected from the group consisting of hydrogen, C1-C4 alkyl, C4-C4 alkenyl, C1-C4 alkynyl, benzyl, benzyl bearing at least one substituent Z, naphthyl, phenyl, and phenyl bearing at least one substituent Ζ, Z being selected independently of X from the group consisting of those from which X is 3θ selected; and a non-toxic pharmaceutically acceptable carrier.
Certain of the ureas of this invention are prepared by reacting activated derivatives of carbonic acid such as phosgene, thiophosgene, or phenyl chloroformate with secondary amines to yield an. inter5 mediate, for instance, a disubstituted carbamyl chloride. This intermediate is in turn reacted with an arylamine to yield the urea. The preparation of the intermediate is conducted in an aprotic solvent such as tetrahydrofuran, toluene, xylene, or the like at temper10 atures from about room temperature up to the boiling point of the solvent. The intermediate may be isolated by evaporation and purified by distillation if necessary. The intermediate is then reacted with an arylamine in an aprotic solvent such as dimethylacetamide in the presence of a base such as sodium hydride at temperatures from about room temperature up to the boiling point of the solvent used. An example of this process is the reaction of phosgene with N-benzyl-n-butylamine in toluene to yield the intermediate N-benzyl-N-(n-butyl)carbamyl chloride, which is then reacted with diphenylamine in Ν,Ν-dimethylacetamide in the presence of sodium hydride to yield 1benzyl-1-(n-butyl)-3,3-diphenylurea.
Other of the ureas of this invention are prepared by' reacting arylamines with activated derivatives of carbonic acid such as phosgene or thiophosgene to yield an intermediate, for instance, an arylcarbamyl chloride. This intermediate is then reacted with a secondary amine to yield the urea. The preparation of this intermediate is conducted in an 30 aprotic solvent such as tetrahydrofuran, toluene, or xylene at temperatures from about room temperature up to the boiling point of the solvent in the presence of a base, for example, Ν,Ν-dimethylaniline. The intermediate is then reacted with a secondary amine in an aprotic solvent such as toluene at temperatures from room temperature or below up to the boiling point of the solvent. An example of this process is the reaction of phosgene with N-phenyl5 3-chloroaniline to yield the intermediate N-(3-chlorophenyl) -N-phenyl carbamyl chloride, which is then reacted with N-benzyl-n-butylamine to yield l-benzyl-l-(nbutyl)-3-(3-chlorophenyl)-3-phenylurea.
The ureas of this invention which 10 contain carboxy groups are prepared by alkaline hydrolysis of the corresponding carboalkoxy ureas, prepared by the synthetic methods described above. Likewise, those which contain hydroxy, mercapto, or amino groups are prepared by alkaline hydrolysis of the cor15 responding 0-acetyl, S-acetyl, and N-acetyl ureas, respectively, the latter also having been obtained by the urea syntheses described above. Alternatively, ureas containing hydroxy groups are prepared by cleavage of the corres20 ponding methoxy compounds using Lewis acids such as boron tribromide.
Certain substituted N-benzylanilines which are intermediates required for the synthesis of some of the novel tetrasubstituted ureas of this inven25 tion are not known in the art. The requisite N-benzylanilines are prepared by reactions of various benzaldehydes with anilines to yield anils. The anils are then reduced to yield the substituted N-benzylanilines. An example of such a synthesis involves the reaction of 2,430 dimethylbenzaldehyde with 2,4-dichloroaniline to yield N(2,4-dimethylbenzylidene)-2,4-dichloroaniline followed by reduction with sodium borohydride to yield N-(2,4dimethylbenzyl)-2,4-dichloroaniline.
Many of the ureas of this invention are prepared by reacting aryl isocyanates with secondary amines. These reactions may be performed in aprotic solvents such as hexane, diethyl ether, toluene, tetrahydrofuran, and the like at temperatures from room temperature or below up to the boiling point of the solvent used. The ureas are isolated by filtering or by evaporating the solvent, and they may be purified by recrystallization, absorption chromatography, or distillation under reduced pressure. An example of this process is the reaction of 2,4-dimethylphenylisocyanate with di-(n-butyl)amine to yield l,l-di-(n-butyl)-3-(2,4-dimethylphenyl) urea.
Many of the secondary amines required for the synthesis of the ureas of this invention are prepared by diborane reductions of the corresponding amides. An example of this reaction is the synthesis of N-(n-butyl)-2-chlorobenzylamine by diborane reduction of N-(n-butyl)-2-chlorobenzamide. Certain of the amides required by these reductions are prepared by acylation of primary amines with carboxylic acids by methods well known to those skilled in the art, for example, by conversion of the carboxylic acid to the corresponding carboxylic acid chloride using thionyl chloride and then reacting the acid chloride with the primary amine in the presence of a base. One method especially useful for this transformation is the boron trifluoride etherate catalized reaction of a carboxylic acid with a primary amine. An example of this transformation is the boron trifluoride etherate catalyzed acylation of 2-chlorobenzylamine with 3-methoxyphenylacetic acid to yield N-(2-chlorobenzyl)-3-methoxyphenylacetamide.
The ureas of the present invention are obtained as crystalline solids or distillable liquids. They are characterized by distinct melting or boiling points and unique spectra. They are appreciably soluble in organic solvents but generally less soluble in water. Those compounds which contain carboxylic acid groups may be converted to their alkali metal and alkaline earth salts by treatment with the appropriate metal hydroxides and those which contain amino groups may be converted to their ammonium salts by treatment with organic or mineral acids. Both these types of salts exhibit increased water solubility.
The properties and utility of the compounds of this invention will be illustrated in conjunction with the specific tables shown below.
The compounds of the present invention were assayed for two types of biological activity related to their potential use as antiatherosclerotic agents. Com10 pounds were tested in vitro for their ability to inhibit the enzyme fatty acyl CoA:cholesterol acyl transferase (ACAT) and in vitro for serum hypolipidemic activity as measured by their ability to inhibit lipid absorption in rats. The compounds were tested for their ability to inhibit ACAT according to the following procedure: Rat adrenals were homogenized in 0.2M monobasic potassium phosphate buffer, pH 7.4, and centrifuged at 1,000 times gravity for 15 minutes at 5°C. The supernatant, containing the nicrosomal fraction, served as the souce of the cholesterol-esterifying enzyme, fatty acyl CoA:cholesterol acyl transferase (ACAT). A mixture comprising 50 parts of adrenal supernatant, 10 parts of albumin (BSA) (50 mg./ml.), 3 parts of test compound (final concentration 5.2 g./ml.), and 500 parts of buffer was preincubated at 37°C. for 10 minutes. After treatment with 20 parts of oleoyl CoA(14c-0.4 Ci) the mixture was incubated at 37°C. for 10 minutes. A control mixture, omitting the test compound, was prepared and treated in the same manner. The lipids from the incubation mixture were extracted into an organic solvent and separated by thin-layer chromatography. The cholesteryl ester fraction was counted in a scintillation counter. This procedure is a modification of that described by Hashimoto, et al., Life Science, 12 (Part II), 1-12 (1973).
The results of this test on representative compounds to which this invention relates appear in Table. I.
TABLE I COMPOUNDF INHIBITION ς 1-Benzyl-l-(n-butyl)-3,3-diphenylurea 75.9 1-Benzyl-l-(n-butyl)-3-(3-chlorophenyl)3-phenylarea 72.3 1-Benzyl-l-(n-butyl)-3-(2-naphthyl)-3phenylurea 83.6 10 1-Benzyl-l-(n-butyl)-3-benzyl-3-pheny1urea 81.8 l-Benzyl-l-(n-butyl)-3-(3-methylphenyl)- 3-phenylurea 82.0 15 1-Benzyl-l-(n-butyl)-3-(3-methoxyphenyl) 3-phenylurea 1-Benzyl-l-(n-butyl)-3-(4-isopropoxyphenyl)-3-phenylurea 82.5 77.8 1-Benzy1-1-(n-butyl)-3-(1-naph thyl)-3phenylurea 76.3 20 1-Benzyl-1-(n-butyl)-3-(2-naphthyl)-3(3-chloropheny1)urea 82.7 1,3-Dibenzyl-l,3-di-(n-butyl)urea 95.4 1-Benzyl-1-(n-butyl)-3-(3-me thylpheny1)urea 92.3 25 1-Benzyl-1-(n-butyl)-3-(3-trifluoromethylphenylTurea - 85.7 1-Benzyl-l-(n-butyl)-3-(3,5-dichlorophenyl)urea 90.7 30 1-Benzyl-l-(n-butyl)-3-(3,4-dichlorophenyl) urea 95.9 1-Benzyl-l-(n-butyl)-3-(3-chlorophenyl) -urea 88.6 1-Benzyl-l-(n-butyl)-3-(2,4-dimethyl phenyl)urea 91.3 TABLE I 7, INHIBITION Compound 1-Benzyl-1-(n-butyl)-3-(2-methylphenyl)urea 78.8 1-Benzyl-l-(n-butyl)-3-(4-methylphenyl)urea 78.0 1-Benzyl-l-(n-butyl)-3-(2,3-dimethylphenyl)urea ~ 85.8 1-Benzyl-1-(n-butyl)-3-(2,5-dimethylphenyljurea 92.7 1-Benzyl-l-(n-butyl)-3-(2,6-dimethylphenyl)urea 83.1 1-Benzyl-1-(n-butyl)-3-(3,5-dimethylphenyl) urea 94.2 1-Benzyl-l-[l-(3-methoxyphenyl)-2-phenylethyl]-3-(2,4-dimethylphenyl)urea 86.4 1-Benzyl-l-[1-(4-benzyloxyphenyl)-2-phenylethyl)-3-(2,4-dimethylphenyl)urea 93.0 l-Benzyl-l-(l,2-diphenylethyl)-3-(2,4dimethylphenyl)urea 95.0 1-Benzyl-1-(n-butyl)-3-(3,4-dimethylphenyl)urea " 87.1 l-Benzyl-l-[l-(3-methoxyphenyl)-2-phenylethyl]-3-(3-tri fluoromethyl phenyl)urea 88.1 1-Benzyl-l-(n-buty1)-3-(3-chloro-2methoxyphenyT)urea 84.5 1-Benzyl-l-(n-butyl)-3-(5-chloro-2methoxyphenyT)urea 80.6 1-Benzyl-l-(n-butyl)-3-phenyl thiourea 82.4 l-(n-Butyl)-l-(2-fluorobenzyl)-3-(2,4- dimethylplhenyDurea 82.6 l-(n-Butyl)-1-(4-fluorobenzyl)-3-(2,4dimethylphenyl)urea 80.6 l-(n-Butyl)-l-(2-chlorobenzyl)-3-(2,4dimethylphenyl)urea 95.5 1 TABLE I COMPOUND 7 i INHIBITION 5 l-(n-Butyl)-l-(2,6-dichlorobenzyl)-3(2,4-dimethylphenyl)urea 74.5 l-(n-Butyl)-l-(4-bromobenzyl)-3-(2,4d ime thy1phenyl)ur ea 81.0 l-(n-Butyl)-1-(4-(n-butyl)benzyl)]-3(2,4-dimethylphenyl)urea 94.4 10 l-(n-Butyl)-l-(4-methylbenzy1)-3-(2,4dimethylphenyl)urea 96.7 l-(n-Butyl)-l-(4-tert-butylbenzyl)-3(2,4-dimethylphenyl)urea 96.4 15 1-(n-Butyl)-1-(4-chlorobenzyl)-3-(2,4dimethylphenyl)urea 94.6 l-(n-Butyl)-l-(4-methoxybenzyl)-3-(2,4dimethylphenyl)urea 94.2 1-(n-Butyl)-1-(3,4-methylened'oxybenzy1)- 3-(2,4-dimethylphenyl)urea 88.2 l-(n-Butyl)-l-(4-trifluoromethylbenzyl)3-(2,4-dimethylphenyl)urea 93.3 l-(n-Butyl)-l-(4-phenylbenzyl)-3-(2,4d ime thy1ph eny1)ur ea 97.1 25 l-(n-Decyl)-l-benzyl-3-(2,4-dimethylphenyl)urea 96.1 l-(n-Butyl)-l-(2-phenylethyl)-3-(2,4d ime thyIpheny1)ur ea 87.9 30 l-(n-Butyl)-l-[2-(4-fluorophenyl)ethyl]3-(2,4-dimethylplhenyl)urea 96.1 l-(n-Butyl/-1-(2-(4-chlorophenyl)ethyl]3-(2,4-d ime thylphenyl)urea 93.3 l-(n-Butyl)-l-(2-(3-methoxyphenyl)ethyl]3-(2,4-d ime thylphenyl)urea 89.3 35 l-(n-Butyl)-l-(3-phenylpropyl)-3-(2,4- dimethylphenyl)urea 97.4 l-(n-Buty1)-1-benzyl-3-(2,4,6-trimethylphenyl) urea 75.8 54G8 £ TABLE I COMPOUND % INHIBITION 1-(n-Butyl)-1-)4-(n-hexyl)benzyl] -3-(2,4dimethylphenyl )urea l-(n-Butyl)-l-[2-(3-bromophenyl)ethyl]3-(2,4-dimethylphenyl)urea 93.8 97.0 1,l-Dibenzyl-3-(2,4-dimethylphenyl)urea 89.9 1,l-Dibenzyl-3-(2-methylphenyl)urea 77.0 1,l-Dibenzyl-3-(3-methylphenyl)urea 88.9 1,l-Dibenzyl-3-(4-methylphenyl)urea 86.5 1,l-Dibenzyl-3-(4-n-butylphenyl)urea 91.3 1,l-Dibenzyl-3-(2,3-dimethylphenyl) urea 88.1 1,l-Dibenzyl-3-(2,5-dimethylphenyl)urea 89.1 1,l-Dibenzyl-3-(2,6-dimethylphenyl)urea 56.1 1,l-Dibenzyl-3-(3,4-dimethylphenyl)urea 71.8 1,1-Dibenzyl-3-(3,5-dimethylphenyl)urea 90.2 1,1-Dibenzyl-3-(2,4,6-trimethylphenyl) urea 36.9 1,l-Dibenzyl-3-(4-methoxyphenyl)urea 71.6 1,l-Dibenzyl-3-(4-n-butoxyphenyl)urea 90.2 1,l-Dibenzyl-3-(4-methylthiophenyl)urea 67.1 1,l-Dibenzyl-3-(2-chlorophenyl)urea 87.8 l,l-Dibenzyl-3-(3-chlorophenyl)urea 94.2 1.1- Dibenzyl-3-(4-chlorophenyl)urea 1.1- Dibenzyl-3-(2-bromophenyl)urea 77.5 93.9 54UU3 TABLE I COMPOUND % INHIBITION 1,1-Dibenzy1-3-(4-bromophenyl)urea 79.9 1,1-Dibenzyl-3-(4-iodophenyl)urea 85.2 l,l-Dibenzyl-3-(2,3-dichlorophenyl)urea 79.7 1,l-Dibenzyl-3-(2,4-dichlorophenyl) urea 83.3 1,1-Dibenzyl-3-(2,5-dichlorophenyl)urea 82.4 1,l-Dibenzyl-3-(3,5-dichlorophenyl)urea 86.1 1,l-Dibenzyl-3-(3-trifluoromethylphenyDurea 94.2 1,1-Dibenzyl-3-(3-acetylphenyl)urea 80.7 1,1-Dibenzyl-3-(4-phenoxyphenyl)urea 94.3 1,l-Dibenzyl-3-(3-chloro-2-methylphenyl) urea 83.8 1,l-Dibenzyl-3-(3-chloro-4-methylphenyl) urea 94.0 1,l-Dibenzyl-3-(4-chloro-3-trifluoromethy 1 phenyl)ur ea 92.0 1,l-Dibenzyl-3-(4-chloro-2-trifluoromethylphenyl)urea 81.8 1,l-Dibenzyl-3-(3-methylphenyl)thiourea 71.2 1,1-Dibenzyl-3-(bromophenyl)urea 91.9 1,1-Dibenzyl-3-(5-chloro-2-methylphenyl) urea 71.3 1,l-Dibenzyl-3-(3-methoxyphenyl)urea 87.0 1,1-D ibenzy1-3-(2-me thoxyphenyl) urea 91.0 l,l-Dibenzyl-3-(3-nitrophenyl)urea 81.3 1,1-Dibenzyl-3-(2,5-dimethoxyphenyl) urea 87.9 1,l-Diben2yl-3-(2,6-dxchlorophenyl)urea 88.6 1,l-Dibenzyl-3-(3,4-dichlorophenyl)urea 94.5 54687 TABLE I COMPOUND % INHIBITION 5 1,l-Dibenzyl-3-(4-chloro-2-methylphenyl)urea 62.7 1,l-Dibenzyl-3-(2-methoxy-5-metbylphenyl)urea 87.8 10 1,l-Dibenzyl-3-(6-chloro-2-methylphenyl)urea 83.9 1,l-Dibenzyl-3-(6-ethyl-2-methylphenyl)urea 73.6 1,1-Dibenzyl-3-(2,6-diethylphenyl)urea 72.0 1,1-Dibenzyl-3-(2,6-i sopropylpheny1) urea 59.1 15 1,l-Dibenzyl-3-(4-nitrophenyl)urea 52.2 l,l-Dibenzyl-3-(4-ethoxyphenyl)urea 95,8 1,l-Dibenzyl-3-(2,5-difluorophenyl)urea 72.0 1,l-Dibenzyl-3-(2,4-dibromophenyl)urea 81.9 1,1-Dibenzyl-3-(2,4,5-trimethylphenyl)urea 69.1 20 1,l-Dibenzy1-3-(2-trifluoromethylphenyl)urea 68.4 1,1-Dibenzyl-3-(4-methylphenyl)urea 89.8 1,1-Di benzyl-3-phenyl)urea 90.4 1,1-Di benzyl-3-(4-carboxyphenyl)urea 14.1 TABLE I COMPOUND ' 7,· INHIBITION 1.1- Dibenzyl-3-(4-carbethoxyphenyl)urea 94.9 1-Benzyl-l-(n-butyl)-3-(phenyl)urea 82.0 1.1- di-(n-butyl)-3-(2,4-dimethylphenyl) urea 81.1 1.1- di-(n-butyl)-3-(2-methylphenyl)urea 61.8 1.1- di-(n-butyl)-3-(3-methylphenyl)urea 78.4 1.1- di-(n-butyl)-3-(4-methylphenyl)urea 79.9 1.1- di-(n-butyl)-3-(4-N-butylphenyl)urea 93.5 1.1- di-(n-butyl)-3-(2,3-d imethylphenyl) urea 87.6 1.1- di-(n-butyl)-3-(2,5-dimethylphenyl) urea 96.1 1.1- di-(n-butyl)-3-(2,6-dimethylphenyl) urea . 85.3 1.1- di-(n-butyl)-3-(3,4-dimethylphenyl) urea 49.2 1.1- di-(n-butyl)-3-(3,5-dimethylphenyl) urea 83.5 1.1- di-(n-butyl)-3-(2,4,6-trimethylphenyDurea 73.4 1.1- di-(n-butyl)-3-(4-methoxyphenyl)urea 58.7 1.1- di-(n-butyl)-3-(4-ethoxyphenyl)urea 78.6 1.1- di-(n-butyl)-3-(3-methylthiophenyl) urea 84.7 1.1- di-(n-butyl)-3-(2-chlorophenyl)urea 71.0 1.1- di-(n-butyl)-3-(3-chlorophenyl)urea 88.3 1.1- di-(n-butyl)-3-(3-bromophenyl) urea 86.0 1.1- di-(n-butyl)-3-(4-fluorophenyl)urea 55.9 1.1- di-(n-butyl)-3-(4-iodophenyl)urea 83.1 1.1- di-(n-butyl)-3-(2,3-dichlorophenyl) urea 71.8 TABLE I X INHIBITION Compound 1, 1-di-(n-butyl)-3-(2,4-dichlorophenyl) urea 70.0 1,l-di-(n-butyl)-3-(3,5-dichlorophenyl) urea " 79.3 1,l-di-(n-butyl)-3-(3-trifluoromethylphenyl)urea 75.0 1,1-di-(n-butyl)-3-(3-acetylphenyl)urea 50.9 1,1-di-(n-butyl)-3-(4-acetylphenyl)urea 55.1 l,l-di-(n-butyl)-3-(3-chloro-2-methyl- pbenyl)urea 80.2 1,l-di-(n-butyl)-3-(3-chloro-4-methylphenyl)urea 91.2 1,l-di-(n-butyl)-3-(3-chloro-4-fluorophenyl)urea 90.9 1,l-di-(n-butyl)-3-(2-chloro-4-nitrophenyl)urea 86.7 1,l-di-(n-butyl)-3-(4-chloro-3-trifluorome thylpheny1) urea 87.3 1,1-d i-(sec-butyl)-3-(2,4-d imethy1phenyl)urea 78.1 l,l-di-(n-pentyl)-3-(2,4-dimethyl- phenyl)urea 90.3 1,1-di-(isopentyl)-3-(2,4-dimethylphenyl)urea 88.7 1,1-d i-(n-hexyl)-3-(2,4-dime thy1pheny1) urea 95.1 1,1-di-(n-heptyl)-3-(2,4-dimethylphenyl)urea 91.1 1,1-di-(n-decyl)-3-(2,4-dimethylphenyl) urea 64.0 1,1-di-(n-octy1)-3-(2,4-dimethylphenyl) urea ~ 88.6 TABLE I COMPOUND ΠΠ SHIBITION 1,1-di-(4-cyclohexyl-n-buty1)-3-(2,4dimethylphenyl)urea 86.3 5 1,1-di-(cyclopentyl)-3-(2,4-dimethyl- phenyl)urea 90.4 1,1-di-(n-butyl)-3-(4-chloro-2-methylphenyl) urea 88.0 10 1,l-dicyclohexyl-3-(2,4-dimethylphenyl) urea 94.3 1,1-di-(n-butyl)-3-(3-methoxyphenyl)urea 77.1 1,1-di-(n-butyl)-3-((3,3-dibutyl)urea-4methylphenyl]urea 94.5 15 1, 1-di-(n-butyl)-3-(2,3,5-trichlorophenyl)urea 61.6 1,1-di-(isabutyl)-3-(2-chlorophenyl)urea 35.4 1,1-di-(isobutyl)-3-((3,3-diisobutyl) urea-4-methylphenyl)(urea 94.7 20 1,1-di-(isobutyl) -3 - (2,5 -d imethylphenyl) urea 74.3 1,1-di-(isobutyl)-3-(2,6-dimethylphenyl) urea 41 .2 l,l-di-(n-butyl)-3-(5-chloro-2-methyl- phenyl)urea 75.3 25 1,1-di-(n-butyl)-3-(4-n-butylphenyl)urea 93.5 1,1-di-(n-butyl)-3-(4-isopropylphenyl)urea 76.4 l,l-di-(3,5,5-trimethylhexyl)-3-(2,4-di- methylphenyl)urea 90.4 30 1,1-di-(2-ethylhexyl)-3-(2,4-dimethylphenyl) urea 86.2 1,1-di-(n-nony1)-3-(2,4-dimethylphenyl) urea 90.0 TABLE I COMPOUND 7« , INHIBITION 1,1-di-(n-undecyl)-3-(2,4-dimethylphenyl) urea 48.9 1,1-di-(n-dodecyl)-3-(2,4-dimethylphenyl) urea 26.3 1-[2-(3,4-dimethoxyphenyl)ethyl )-1(3-chloro-4-methylbenzyl)-3-(2,4d imethyIphenyl) urea 53.3 1-[2-(2-methylphenyl)ethyl)-1-^-bromobenzyl)^ -(2, 4 -dime thylphenyl) urea 29.2 l-[2-(3-trifluoromethylphenyl)ethyl)-1(2-chlorobenzyl)-3-(2,4-dimethylphenyl) urea 7.8 1-(2-fluorobenzyl)-1-(2-methoxybenzyl)3-(2,4-dimethyIphenyl)urea 41.5 l-[2-(3,4-dimethoxyphenyl)ethyl )-1(4-fluorobenzyl)-3-(2,4-dimethylphenyl)urea 57.4 l-[2-(4-ethoxyphenyl)ethyl]-l-(2,4-dimethylbenzyl)-3-(2,4-d imethylphenyl) urea 34.9 l-[2-(3-methylphenyl)ethyl]-l-(3-nitrobenzyl)-3-(2,4-dimethyIphenyl)urea 95.7 1-[2-(2,5-dimethoxyphenyl)ethyl )-1-(3chlorobenzyl)-3-(2,4-dimethylphenyl)urea 97.1 1-(n-butyl)-1-(2-methyl-2,2-diphenyl) ethy1-3-(2,4-dimethyIphenyl)urea 97.4 1-(n-butyl)-l-(4-hexyloxybenzy1)-3(2,4,6-trimethylphenyl)urea 97.1 1-(n-butyl)-1-(4-heptyloxybenzy1)-3(2,4,6-trimethyIphenyl)urea 97.3 1-benzyl-1-(4-n-buty lbenzyl)-3-(2,4dimethylphenyl)urea 91.9 1-benzyl-l-(4-n-butylbenzyl)-3-(2,4,6tr ime thy Iphenyl) urea 92.8 TABLE I COMPOUND % INHIBITION 1-benzyl-l-(4-n-butylbenzyl)-3-(4-nbutylphenyl)urea 92.0 l-benzyl-l-(4-n-butylbenzyl)-3-(4phenoxyphenyl)urea 93.5 1-(n-heptyl)-1-(4-n-butylbenzyl)-3(2,4-dimethylphenyl)urea 94.8 1-(n-heptyl)-1-(4-n-butylbenzyl)-3(2,4,5-trimethylphenyl)urea 95.3 1-benzyl-l-[2-phenyl-l-(4-benzyloxypheny1)e thyl] -3 - (2,4,5 - tr imethy1phenyl) urea 93.7 1-(n-heptyl)-1-(4-butyloxybenzyl)-3(2,4-dimethylphenyl)urea 94.6 1-(n-heptyl)-1-(4-butyloxybenzyl)-3(2,4,5-trimethylphenyl)urea 95.6 l-benzyl-l-(4-butyloxybenzyl)-3-(2,4dimethylphenyDurea 91.7 1-benzyl-l-(4-butyloxybenzyl)-3-(2,4,5trimethylphenyl)urea 95.8 1-(9-octadecenyl)-1-(4-n-butylbenzyl)-3(2,4-dimethylphenyl)urea 42.2 1-benzyl-l-(4-n-butylbenzyl)-3-(2,4,5trimethylphenyl)urea 90.5 l-(9-octadecenyl)-1-(4-n-butylbenzyl)-3(2,4,5-trimethylphenyl)urea 9.4 I-benzyl-1(2-phenyl-l-(4-benzyloxyphenyl) ethyl1-3-(2,4,6-trimethylphenyl) urea 90.0 1-(n-heptyl)-1-(4-n-butoxybenzyl)-3(2,4,6-trichlorophenyl)urea 90.0 1-(n-heptyl)-(4-n-butoxybenzyl)-3-(2,4dichlorophenyl)urea 79.9 1-(n-heptyl)-(4-n-butoxybenzyl)-3-(2trifluoromethy1-4-chlorophenyl)urea 89.4 1-benzyl-l-(4-n-butoxybenzyl)-3-(2,4,6trichlorophenyl)urea 95.2 4 08 TABLE I COMPOUND ............... X INHIBITION l-benzyl-l-(4-n-butoxybenzyl)-3-(2,4dichlorophenyl)urea 80.0 l-benzyl-l-(4-n-butoxybenzyl)-3-(2trifluoromethyl-4-chlorophenyl)urea 85.0 1-(n-heptyl)-1-(4-n-butoxybenzy1)-3-(3trifluoromethylphenyl)urea 82.4 1-(n-benzyl-1-(4-n-butoxybenzy1)-3-(3trifluoromethylphenyl)urea 87.0 1-(n-heptyl)-1-(4-n-butylbenzyl)-3-(2,4dichlorophenyl)urea 80.0 1-(n-heptyl)-1-(4-n-butylbenzyl)-3-(2trifluoromethyl-4-chlorophenyl)urea 90.0 1-(n-heptyl)-1-(4-n-butylbenzyl)-3(2,4,6-trichlorophenyl)urea 90.0 1-(n-heptyl)-1-(4-n-butylbenzyl)-3(3-trifluoromethylphenyl)urea 85.0 1-(n-hepty1)-1-(4-n-butylbenzyl)-3(2,4,5-trichlorophenyl)urea 46.5 1-benzyl-1-(4-n-butylbenzyl)-3-(2methyl-4-chlorophenyl)urea 94.3 1-(n-heptyl)-1-(4-n-butoxybenzy1)-3(2,4-difluorophenyl)urea 82.7 1-(n-heptyl)-1-(4-n-butoxybenzy1)-3-(2methyl-4-chlorophenyl)urea 91.7 1-(n-hepty1)-1-(4-n-butylbenzy1)-3-(2-methy14-chlorophenyl)urea 92.5 1-(n-heptyl)-1-(4-n-butylbenzyl)-3-(2,4difluorophenyl)urea 90.0 1-(n-heptyl)-1-(4-n-butylbenzyl)-3-(4carboethoxyphenyl)urea 92.4 TABLE I COMPOUND ! F INHIBITION 1-(n-heptyl)-1-(4-n-butylbenzyl)-3-(2methylphenyl)urea 97.4 l-(n-heptyl)-l-(4-n-butylbenzyl)-3-(3- methylphenyl)urea 93.8 1-(n-heptyl)-1-(4-n-butylbenzy1)-3-(4carboxyphenyl)urea 61.8 1-(n-heptyl)-1-(2-phenylethyl)-3-(2methyl-4-chlorophenyl)urea 93.8 l-(n-heptyl)-l-(2-phenylethyl)-3-(2,4,5trichlorophenyl)urea 77.3 l-(n-heptyl)-l-(2-phenylethyl)-3-(2trifluoromethyl-4-chlorophenyl)urea 88.3 1-(n-heptyl)-1-(2-phenylethyl)-3-(2,4d ime thylphenyl) urea 95.7 1-(n-heptyl)-1-(2-phenylethyl)-3-(2,4dichlorophenyl)urea 91.8 1-(n-heptyl)-l-(2-phenylethyl)-3-(2,4difluorophenyl)urea 94.1 1-(n-heptyl)-1-(2-phenylethyl)-3-(3trifluoromethylphenyl)urea 88.4 l-benzyl-l-[2-phenyl-l-(4-benzyloxyphenyl)ethyl]-3-(2,4,6-trichlorophenyl)urea 95.0 l-(4-n-pentylbenzyl)-l-(4-n-pentyloxyhenzyl)-3-(2,4,6-trichlorophenyl)urea 95.5 1-(4-n-pentylbenzyl)-1-(4-n-pentyloxybenzyl)-3-(2,4-dichlorophenyl)urea 85.0 l-(4-n-pentylbenzyl)-I-(4-n-pentyloxybenzyl)-3-(2,4,5-trichlorophenyl)urea 80.0 1-(4-n-pentylbenzyl)-1-(4-n-pentvloxybenzyl)-3-(2-ttifluoromethyl-4-chlorophenyl) urea 81.0 I-(4-n-pentylbenzyl)-l-(4-n-pentyloxybenzyl)-3-(3-trifluoromethylphenyl)urea 85.0 1-(4-n-pentylbenzyl)-1-(4-n-pentyloxybenzyl)-3-(2,4-d i f1uoropheny1)ur ea 90.0 4 0 8 TABLE I COMPOUND T INHIBITION l-(4-n-pentylbenzyl)-l-(4-n-pentyloxy- benzyl)-3-(2-methyl-4-chlorophenyl)urea 91.0 1-(4-chlorobenzyl)-1-(1-naphthylmethyl)3-(2,4,6-trichlorophenyl)urea 77.0 l-(4-chlorobenzyl)-l-(l-naphthylmethyl)- 3-(2-methyl-4-chlorophenyl)urea 94.0 1-(4-chlorobenzyl)-l-(l-naphthylmethyl)3-(2,4-di fluorophenyl)urea 84.0 l-(4-chlorobenzyl)-l-(l-naphthylmethyl)- 3-(3-trifluoromethylphenyl)urea 80.0 1-(4-chlorobenzyl)-1-(1-naphthylmethyl)3-(2,4,5-trichlorophenyl)urea 86.0 l-benzyl-l-[2-phenyl-l-(4-benzyloxyphenyl)ethyl1-3-(2,4,5-trichlorophenyl)urea 95.0 1-benzyl-1-(4-n-butyloxybenzyl)-3-(2,4,5trichlorophenyl)urea 89.0 1-benzyl-l-[2-phenyl-l-(4-benzyloxyphenyl)ethyl]-3-(2,4-dif1uorophenyl)urea 70.0 l-benzyl-l-(4-n-butoxybenzyl)-3-(2,4d i fluorophenyl) urea 88.0 l-benzyl-l-[2-phenyl-l-(4-benzyloxyphenyl)ethyl]-3-(2,4-difluorophenyl)urea 91.0 1-benzyl-l-[2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(2-trifluoromethyl-4chlorophenyl) urea 92,0 l-benzyl-l-[2-phenyl-l-(4-benzyloxyphe- nyl)ethyl]-3-(3-trifluoromethylphenyl) urea 74.0 l-benzyl-l-[2-phenyl-l-(4-benzyloxyphenyl)ethyl 1-3-(2-methyl-4-chlorophenyl) urea 89.3 1-(4-chlorobenzyl)-l-(l-naphthylmethyl)3-(2,4-dichlorophenyl)urea 92.0 l-(4-chlorobenzyl)-l-(l-naphthylmethyl)3-(2-trifluoromethyl-4-chlorophenyl)urea 83.0 Inhibition of cholesterol absorption was determined by feeding male Sprague-Dawley rats, weighing 150-170 g., a 17« cholesterol : 0.5% cholic acid diet for 2 weeks. The diet also contained compounds being tested at a dose of 0.03% of the diet. Control rats were fed the same diet without any compound. At the end of the test, the rats were sacrificed by decapitation. Blood is collected, centrifuged at 1.5 kg times gravity for 10 minutes at 4°C., and the serum is then analyzed for cholesterol and triglycerides enzymatically by the method of Trinder, P., Analyst, 77, 321 (1952) on a *Centrifichem 400 Analyzer. Livers are removed, a 0.4 g. sample is taken from the center of the large lobe, and the sample is subjected to saponification using 25% saturated potassium hydroxide in ethanol. The resulting neutral sterols are extracted with petroleum ether, and the extract was analyzed for cholesterol. The effectiveness of the compound in inhibiting cholesterol absorption is measured by the lowering of either serum cholesterol or liver cholesterol relative to the values for control rats.
The results of this test on typical compounds of this invention appear in Table II.
TABLE II COMPOUND RESULT 1-Benzyl-l-(n-butyl)-3-(3-methyoxyphenyI)3-phenylurea Active 1.1- di-(n-butyl)-3-(2,4-dimethylphenyl)urea Active 1.1- di-(n-butyl)-3-(3,5-dimethylphenyl)urea Active 1.1- di-(n-butyl)-3-(2-methyl-3-chlorophenyl) urea Active 1.1- di-(n-butyl)-3-(3,5-dichlorophenyl)urea Active 1.1- di-(n-butyl)-3-(4-n-butylphenyl)urea Active 1.1- di-(n-hexyl)-3-(2,4-dimethylphenyl)urea Active 1.1- di-(n-octyl)-3-(2,4-dimethylphenyl)urea Active *Centrifichem is a Trade Hark 546G3 TABLE II COMPOUND RESULT 1,1-di-(n-butyl)-3-(2-methylpheynyl)urea Active 1, 1-di-(n-pentyl)-3-(2,4-dimethlyphenyl) urea Active 1,l-di-(n-decyl)-3-(2,4-dimethlyphenyl)urea Active 1,1-di-(isopentyl)-3-(2,4-dimethlyphenyl) urea Active 1,1-di- (3,5,5-trimethiyhexyl)-3-(2,4-dimethylphenyl ) urea Active 1,l-Dibenzyl-3-(2-methyl-5-chlorophenyl) urea Active 1,1-Dibenzyl-3-(2,4-dichlorophenyl)urea Active 1,1-Dibenzyl-3-(2-methyl-4-chlorophenyl) urea Active 1,1-Dibenzyl-3-(2,4-d imethylphenyl)urea Active 1,l-Dibenzyl-3-(3-chloro~4-methylphenyl) urea Active 1,1-Dibenzyl-3-(2-methoxy-5-methylphenyl) urea Active 1,l-Dibenzyl-3-(2,3-dimethylphenyl)urea Active 1,l-Dibenzyl-3-(3,4-dimethylphenyl)urea Active 1,l-Dibenzyl-3-(2,4,6-trimethylphenyl)urea Active 1,l-Dibenzyl-3-(4-n-butylphenyl)urea Active 1,1-Dibenzyl-3-(4-phenoxyphenyl)urea Acti ve 1,1-dibenzyl-3-(2,4-5-trimethylphenyl)urea Active 1,l-Dibenzyl-3-(2-tri fluoromethyl-4-chlorophenyl)urea Active TABLE II COMPOUND RESULT 1,l-Dibenzyl-3-(3-bromophenyl)urea Active 1,1-Dibenzyl-3-(2-trifluoromethylphenyl) urea Active 1,l-Dibenzyl-3-(4-carboethoxyphenyl) urea Active 1-Benzyl-l-(n-butyl)-3-(2,4-dimethylphenyl) urea Active 1-Benzyl-l-(n-butyl)-3-(2,6-dimethylphenyl) urea Active 1-Benzyl-l-(n-butyl)-3-(3,5-dimethylphenyl) urea Active 1-Benzyl-1-(1,2-diphenylethyl)-3-(2,4-dimethylphenyl ) urea Active l-(2-Fluorobenzyl)-1-(2-methoxybenzyl)-3(2,4-dimethylphenyl)urea Active 1-(n-Butyl)-1-(4-hexyloxybenzyl)-3-(2,4, 6-trimethy1pheny1)urea Active 1-(n-Butyl)-1-(4-heptyloxybenzy1)-3-(2, 4,6-tr ime thylphenyl) urea Active 1-Benzyl-l-(4-n-butylbenzyl)-3-(2,4dimethylphenyl)urea Active 1-Benzyl-1-(4-n-butylbenzyl)-3-(2,4,6trimethylphenyl)urea Active 1-Benzyl-l-(4-n-butylbenzyl)-3-(4-nbutylphenyl)urea · Active 1-(n-heptyl)-1-(4-n-butylbenzyl)-3-(2,4d ime thy1pheny1)ur ea Active 1-(n-heptyl)-1-(4-n-butylbenzyl)-3-(2,4, 5-trimethylphenyl)urea Active 1-(n-heptyl)-1-(4-butyloxybenzyl)-3-(2, 4-dimethylphenyl)urea Active 1-(n-heptyl)-1-(4-butyloxybenzyl)-3-(2,4, 5-trimethylphenyl)urea Active 1-Benzyl-1-(4-butyloxybenzyl)-3-(2,4-dimethylphenyl) urea Active TABLE II COMPOUND RESULT 1-Benzyl-l-(4-butyloxybenzyl)-3-(2,4,5tr imethylphenyl) urea Active l-Benzyl-l-(4-n-butylbenzyl)-3-(2,4,5trimethylphenyl)urea Active 1-Benzyl-l-(2-phenyl-l-(4-benzyloxyphenyl)ethyl )-3-(2,4,6-trimethylphenyl) urea Active l-(n-Heptyl)-1-(4-n-butoxybenzyl)-3(2,4,6-trichlorophenyl)urea Active 1-(n-Heptyl)-(4-n-butoxybenzyl)-3-(2,4d ichloropheny1) urea Active 1-(n-Heptyl)-(4-n-butoxybenzyl)-3-(2-trifluoromethyl-4-chlorophenyl)urea Active 1-Benzyl-l-(4-n-butoxybenzyl)-3-(2,4,6trichlorophenyl)urea Active l-Benzyl-l-(4-n-butoxybenzyl)-3-(2,4dichloropheny1)urea Active 1-Benzyl-1-(4-n-butoxybenzyl)-3-(2-trifluoromethy1-4-chlorophenyl)urea Active l-(n-Heptyl)-!-(4-n-butoxybenzy1)-3-(3tr i f1uorome thylphenyl) urea Active l-(n-Heptyl)-l-(4-n-butylbenzyl)-3-(2,4dichloropheny1)urea Active 1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2trifluoromethy1-4-chlorophenyl)urea Active l-(n-Heptyl)-l-(4-n-butylbenzyl)-3-(2, 4,6-trichlorophenyl)urea Active 1-Benzyl-l-(4-n-butylbenzyl)-3-(2-methyl -4-chlorophenyl) urea Active l-(n-Heptyl)-1-(4-n-butoxybenzyl)-3-(2,4difluorophenyl)urea Active l-(n-Heptyl)-l-(4-n-butoxybenzyl)-3-(2methyl-4-chlorophenyl)urea Active Ou ι-* TABLE II COMPOUND RESULT 1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2methyl-4-chlorophenyl)urea Active 5 l-(n-Hepty1)-1-(4-n-butylbenzyl)-3-(2,4- difluorophenyl)urea Active l-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(4carboe thoxyphenyl)urea Active 1-(n-Heptyl)-l-(4-n-butylbenzyl)-3-(210 methylphenyI)urea Active l-(n-Hepty1)-1-(4-n-butylbenzyl)-3-(3- methylphenyl)urea Active l-(n-Heptyl)-l-(2-phenylethyl)-3-(2methyl-4-chlorophenyl)urea Active 15 l-(n-Heptyl)-l-(2-phenylethyl)-3-(2- trifluoromethy1-4-chlorophenyl)urea Active l-(n-Heptyl)-1-(2-phenylethyl)-3-(2,4dimethylphenyl)urea Active 1-(n-Heptyl)-1-(2-phenylethyl)-3-(2,420 dichlorophenyl)urea Active l-(n-Heptyl)-l-(2-phenylethyl)-3-(2,4di fluorophenyl)urea Active 1-(n-Heptyl)-1-(2-phenylethyl)-3-(3trifluoromethylphenyl)urea Active 25 1-Benzyl-l-[2-phenyl-l-(4-benzyloxyphe- nyi)ethyl)-3-(2,4,6-trichlorophenyl)urea Active l-(4-n-Pentylbenzyl)-l-(4-n-pentyloxybenzyl)-3-(2,4., 6-trichlorophenyl) urea Active l-(4-n-pentylbenzyl)-l-(4-n-pentyloxyben30 zyl)-3-(2,4-dichlorophenyl)urea Active l-(4-n-Pentylbenzyl)-l-(4-n-pentyloxybenzyl)-3-(2,4,5-trichlorophenyl)urea Active l-(4-n-Pentylbenzyl)-l-(4-n-pentyloxyben- zyl)-3-(2,4-difluorophenyl)urea Active TABLE II COMPOUND RESULT l-(4-n-Pentylbenzyl)-l-(4-n-pentyloxyben- zyl)-3-(2-methyl-4-chlorophenyl)urea Active l-(4-Chlorobenzyl)~l-(l-naphthylmethyl)3-(2,4,6-trichlorophenyl)urea Active 1-(4-Chlorobenzyl)-1-(1-naphthyImethyl)3-(2-methyl-4-chlorophenyl)urea Active 1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)3-(2,4-difluorophenyl)urea Active 1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)3-(3-trifluoromethylphenyl)urea Active l-(4-Chlorobenzyl)-l-(l-naphthylmethyl)3-(2,4,5-trichlorophenyl) urea Active l-Benzyl-l-(4-n-butyloxybenzyl)-3-(2,4,5- trichlorophenyl)urea Active 1-Benzyl-1-(2-phenyl-l-(4-benzyloxyphenyl) ethyl]-3-(2,4-difluorophenyl)urea Active l-Benzyl-l-(4-n-butoxybenzyl)-3-(2,4-difluorophenyl)urea Active 1-Benzyl-1-(2-phenyl-l-(4-benzyloxyphenyl) ethyl]-3-(2-tri fluoromethyl-4-chlorophenyl) urea Active 1-Benzyl-1-(2-phenyl-l-(4-benzyloxyphenyl)ethyl1-3-(2-methyl-4-chlorophenyl) urea Active 1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)3-(2,4-dichlorophenyl)urea Active The tests repotted or shown in Tables I-II, inclusive, have been actually carried out and the results therein actually obtained or concluded therefrom.
Inhibition of cholesterol absorption was also determined by feeding male Sprague-dawley rats weighing 150-170 g. a 1% cholesterol:0.5% cholic acid diet for 2 weeks. The diet also contained compounds being tested at doses of between 0.01% and 0.1% of the diet. After the rats had been on the test diet for 9 days, each rat is given by gavage a sonicated mixture of [4-^C] cholesterol (6 Ci), 0.2 ml. triolein, 10 mg. cholic acid, 20 mg. cholesterol, and 2 mg. of test compound in 0.8 ml. of 10% nonfat dry milk. Feces were collected for each 24 hour period for the remaining 5 days during which the rats were maintained on the 1% cholesterol:0.5% cholic acid plus test compound diet. Fecal l^C-neutral sterols were extracted with petroleum ether from saponified feces by the method of grundy, S. M. et al., J. Lipid Res., 6, 397 (1965) and counted in a scintillation counter. Acidic sterols (bile acids) were extracted by acidifying the saponified feces and extracting in chloroform:methanol (2:1) and counting the chloroform phase in a scintillation counter. Total extraction of radioactivity (98-100%) from saponified feces is realized by this procedure.
Radioactivity in liver and adrenals were determined by saponification and extraction into petroleum ether and counting by scintillation techniques. Total cholesterol in liver and adrenals was determined by the cholorimetric method of Zlatkis, A., et al., J. Lab. Clin. Med., 41, 486 (1953) on saponified organic solvent extracted tissue prepared by the method of Trinder, P., Analyst, 77 , 321 (1952). Serum cholesterol and triglycerides were assayed enzymatically by the method of Allain, C. C., et al., Clin. Chem. 20, 470 (1974) on a centrifichem 400 Analyzer. l^C-cholesterol in serum was determined by direct scintillation counting.
The effect of a test compound on cholesterol absorption was determined by: 1. increase in excreted l^C-neutral sterol. 2. decrease in excreted l^C-acidic sterol. 3. decrease in I^C-cholesterol or l^C-cholesteryl ester in the liver. 4. decrease in l^C-cholesterol or I^C-cholesteryl ester in the serum.
A compound is considered active in inhibiting cholesterol absorption if it meets at least the first two criteria.
The results of this test on typical compounds of this invention appear in Table III.
TABLE III Compound result 1-Benzy1-1-(n-butyl)-3-(2,4-dimethylphenyl)urea Active 1,1-Dibenzyl-3-(2,4-dimethylphenyl)urea Active The tests reported or shown in Table III have been actually carried out, and the results therein actually obtained or concluded therefrom.
When the compounds are employed for the above utility, they may be combined with one or more pharmaceutically acceptable carriers, e.g., solvents, dilutents, and the like and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, suspensions containing, for example, from about 0.5% to 5% of suspending agent, syrups containing, for example, from about 10% to 50% of sugar, and elixirs containing, for example, from about 20% to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.5% to 5% suspending agent in an isotonic medium. These pharmaceutical preparations may contain, for example, from about 0.5% up to about 90% of the active ingredient in combination with the carrier, more usually between 5% and 60% by weight.
The antiatherosclerotic effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention ate administered at a daily dosage of from about 2 mg. to about 500 mg./kg. of animal body weight, preferably given in divided doses two to four times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 100 mg. to about 5,000 mg., preferably from about lOOmg. to 2,000 mg. Dosage forms suitable for internal use comprise from about 25 mg. to 500 mg. of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A decided practical advantage is that these active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes if necessary. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose, and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants, and edible oils such as corn, peanut, and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, e.g., vitamin E, ascorbic acid, BHT, and BHA.
The preferred pharmaceutical compositions from the stand-point of ease of preparation and administration are solid compositions, particularly tablets and hardfilled or liquid-filled capsules. Oral administration of the compounds is preferred.
These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propyleneglycol, and liquid polyethyleneglycol), suitable mixtures thereof, and vegetable oils.
The preparation of representative compounds to which this invention relates is illustrated by the following specific examples. There are no Examples 10, 11, 85, 124, 157, 169, 171, 189, 190, 265, 266, 284-288 or 337.
Example 1 1-Benzyl-l-(n-butyl)-3,3-diphenylurea A solution of 20.0 g. of phosgene in 100 ml. of toluene is stirred at 0°C. while a solution of 32.6 g. of N-benzyl-n-butylamine in 50 ml. of toluene is added during 15 minutes. The mixture is filtered, and the filtrate is evaporated. The residue is evaporatively distilled at 105°C. under reduced pressure (250-350 microns) to yield N-benzyl-N-(n-butyl)carbamyl chloride as a colorless liquid.
A solution of 3.89 g. of diphenylamine in 25 ml. of dimethylacetamide is added during one hour to a stirred mixture of 5.19 g. of N-benzyl-N-(n-butyl)carbamyl chloride, 0.685 g. of sodium hydride, and 65 ml. of dimethylacetamide under a nitrogen atmosphere at 45-50°C. The mixture is stirred for 2 hours at 50°C. and then poured into water. The mixture is extracted with methylene chloride, and the extract is evaporated. The residue is purified by chromatography using silica gel as the adsorbant and the acetone-hexane as the eluent. After evaporation of the eluent, the residue is evaporatively distilled at 165°C. under reduced pressure (150 microns) to yield 1-benzyl-l-(n-butyl)-3,3-diphenylurea as a viscous, clear, colorless liquid.
Example 2 1-Benzyl-l-(n-butyl)-3-(3-chlorophenyl)-3-phenylurea A solution of 5.09 g. of N-phenyl-3-chloraniline in 20 ml. of toluene is added to a solution of 4.70 g. of phosgene and 3.64 g. of Ν,Ν-dimethylaniline in 55 ml. of toluene and the mixture is warmed to 40°C. and then stirred while cooling to room temperature during 45 minutes. The mixture is extracted with water, and the organic layer is separated and evaporated to about one-half its volume. To this solution is added 100 ml. of toluene followed by 9.80 g. of N-benzyl-n-butylamine, The resulting mixture is stirred under reflux for 30 minutes and then washed with water, IN hydrochloric acid, and saturated 546S3 sodium bicarbonate solution. The organic layer is separated, dried over sodium sulfate, decolorized using activated charcoal, and evaporated. The residue is evaporatively distilled at 185-190°C. under reduced pressure (105 microns) to yield 1-benzyl-l -(n-butyl)-3-(3chlorophenyl)-3-phenylurea as a viscous, pale-yellow liquid.
The compounds in Table IV were prepared from the appropriate amines using phosgene or thiophosgene by the methods of Examples 1 and 2.
TABLE IV EX. COMPOUND MELTING POINT 3 1,3-Dibenzy1-1-(n-butyl)-3phenylurea Yellow Oil 4 1-Benzyl-1-(n-butyl)-3-(2naphthyl)-3-phenylurea Orange Oil 5 l-Benzyl-l-(n-butyl)-3-(3me thylpheny17-3-phenylurea Oil 6 1-Benzy1-1-(n-butyl)-3-(4isopropylphenyl)-3-phenylurea Amber Oil 7 1-Benzyl-l-(n-butyl)-3-(3methoxyphenyT)-3-phenylurea Amber Oil 8 1-Benzyl-1-(n-butyl)-3-(3cblorophenyl7-3-(2-naphthyl) urea Yellow Oil 9 10 11 12 1-Benzyl-1-(n-butyl)-3-(1naphthyl)-3-phenylurea Amber Oil 1-Benzy1-1-(n-butyl)-3-benzy13-(4-chlorophenyl) urea Oil 13 1-Benzyl-1-(n-butyl)-3-benzyl3-(2,4-dimethylphenyl)urea Oil TABLE IV EX. COMPOUND MELTING POINT 14 1-Benzyl-l-(n-butyl)-3-benzyl3-(2,4-dichlorophenyl)urea Oil 15 l-Benzyl-l-(n-butyl)-3-(3nitrobenzyl)-3-(3,5-dimethoxyphenyl) urea Oil 16 l-Benzyl-l-(n-butyl)-3-(2,4- dimethylbenzyl)-3-(2,4-di- phenyl)urea Oil 17 1-Benzyl-1-(n-butyl)-3-(2,4dichlorobenzyl)-3-(2,4-dichlorophenyl) urea Oil 18 1-Benzyl-1-(n-butyl)-3-(2chlorobenzyl)-3-(2-chlorophenyl)urea Oil 19 1-Benzyl-1-(n-butyl)-3-(4methylphenyl)-3-(4-methylbenzyl)urea Oil 20 1-Benzyl-1-(n-butyl)-3-(2,4dimethylbenzyl)-3-(2,4-dichlorophenyl) urea Oil 21 1-Benzyl-1-(n-butyl)-3-(2,4dichlorobenzyl)-3-(2,4-dimethylphenyl)urea Oil 22 1-Benzyl-1-(n-butyl)-3-(3chloro-4-methylbenzyl)-3(4-methylphenyl)urea Oil 23 1-Benzyl-1-(n-butyl)-3-(2,4dimethylbenzyl)-3-phenyl urea Oil 24 l-Benzyl-I-(n-butyl)-3-[3,5di(trifluoromethyl)benzyl]-3phenyl urea on 25 1-Benzyl-1-(n-butyl)-3-(3aminobenzyl)-3-(3,5-dimethoxyphenyl)urea picrate 156-158θ 26 1-Benzyl-1-(n-butyl)-3-benzyl3-(3-aminopheny1) urea 96-980 27 1-Benzy1-1-(n-butyl)-3-benzyl3-(2,4,6-trimethylphenyl)urea 63-690 54G83 TABLE IV ex. Compound melting point l-Benzyl-l-(n-butyl)-3-benzyl3-(3-nitrophenyl)urea Yellow Oil 1-Benzyl-1-(n-butyl)-3-benzyl3-(3-acetamidophenyl)urea Oil Example 30 N-(2,4-Dimethylbenzylidene)-2,4-dichloroaniline A mixture of 26.8 g. of 2,4-dimethylbenzaldehyde, 32.4 g. of 2,4-dichloroaniline, 0.20 g. of ptoluenesulfonic acid, and 150 ml. of toluene is stirred under reflux using a Dean-Stark moisture trap. Evaporation of the mixture affords a solid which is recrystallized from ethanol to yield N-(2,4-dimethylbenzylidene)-2,4-dichloroaniline, mp 102-106°.
Anilines prepared by the method of Example 30 are set forth in Table V.
TABLE V EXT'CUMPODND-MEETINff'TOfNT 31 N-benzylidene-2,4,6-trimethylaniline Yellow Oil 32 N-benzylidene-2,4-dichloroaniline 60-63° 33 N-(4-methylbenzylidene)-3chloro-4-methylaniline 86-89° 34 N-(2,4-dimethylbenzylidene)2,4-dimethylaniline 118-121° 35 N-(2,4-d ichlorobenzy1idene)2,4-dimethylaniline 105-107° 36 N-(3-ni trobenzylidene)-3,5d ime thoxyan i1ine 113-116° 37 N-benzylidene-4-chloroaniline 60-62° 38 N-benzylidene-2,4-dimethylaniline Oil 1 TABLE V Ex. Compound MELTING POINT 5 39 N-(2,4-dichlorobenzylidene)-2, 4-dichloroaniline 134-139° 40 N-(2-chlotobenzylidene)-2chloroaniline 111-117° 41 N-(4-methylbenzylidene)-4methylaniline 90-93° 10 42 N-benzylidene-3,5-di(tr i fluoromethyl)aniline Yellow Oil 43 N-(4-benzyloxybenzylidene)-4carboethoxy aniline 140-142° 44 N-benzylidene-3-nitroaniline 69-72° Example 45 Ν-(2,4-dimethylbenzyl)-2,4-dichloroaniline A mixture of 13.9 g. of N-(2,4-dimethylbenzylidene)-2,4-dichloroaniline, 1.89 g. of sodium borohydride, and 150 ml. of ethanol is stirred under reflux for one hour, allowed to cool, and poured into water. Recrystallization from ethanol yields N-(2,4-dimethylbenzyl)2,4-dichloroaniline, mp. 88-90°.
Anilines prepared by the method of example 45 are set forth in Table VI.
TABLE VI EX. COMPOUND MELTING POINT 46 N-benzyl-2,4,6-trimethylaniline Oil 47 N-benzyl-2,4-dichloroaniline Oil 48 N-(4-methylbenzyl)-3-chloro-4methylaniline Oil 49 N- (2,4-dimethylbenzyl)-2,4dimethylaniline 72-74° 50 N-(2,4-dichlorobenzyl)-2,4dimethylaniline 70-72° TABLE VI EX. COMPOUND MELTING POINT 51 N-(3-ni trobenzyl)-3, 5-dimethoxyaniline Amber Oil 52 N-benzyl-4-chloroaniline 48-49° 53 N-benzyl-2,4-dimethylaniline 28-33° 54 N-(2,4-dichlotobenzyl)-2,4- dichloroaniline 84-86° 55 N-(2-chlorobenzyl)-2-chloro- aniline 41-44° 56 N-(4-methylbenzyl)-4-methyl- aniline 50-54° 57 N-benzy1-3,5-di(trifluoromethyl) aniline Oil 58 N-(4-benzyloxybenzyl)-4-carboethoxyaniline 147-150° 59 N-benzyl-3-nitroaniline 106-108° Example 60 1-Benzyl-1-(n-butyl)-3-(2,4-dimethylphenyl)urea A solution of 4.89 g. of 2,4-dimethylphenylisocyanate in 100 ml. of hexane is added to a solution of 4.41 g. of N-benzyl-n-butylamine in 150 ml. of hexane and the solution is stirred at room temperature for 2 hours and then evaporated. The residual solid is recrystallized from pentane to yield l-benzyl-l-(n-butyl)-3-(2,4-dimethylphenyl)urea, m.p. 70-71°C.
Those compounds in Table VII were prepared from the appropriate arylisocyanates or arylisothiocyanates and secondary amines by the method of Example 60.
TABLE VII EX. COMPOUND MELTING POINT 61 1-Benzyl-1-(n-butyl)-3-(2-methylphenyl) urea ~ 48-53° 62 1-Benzyl-l-(n-butyl)-3-(3-methylphenyl) urea 91-92° 63 1-Benzyl-l-(n-butyl)-3-(4-methylphenyl)urea 102-103° 64 1-Benzyl-l-(n-butyl)-3-(2,3-dimethylphenyljurea 77-78° 65 l-Benzyl-l-(n-butyl)-3-(2,5-di- methylphenylTurea 87-89° 66 1-Benzyl-l-(n-butyl)-3-(2,6-dimethylphenylTurea 125-126° 67 1-Benzyl-l-(n-butyl)-3-(3,4-dimethylphenyljurea 94-95° 68 l-Benzyl-l-(n-butyl)-3-(3,5-di- methylphenylTurea 108-109° 69 l-Benzyl-l-(n-butyl)-3-(2,4,6- trimethylphenyl)urea 141-144° 70 l-Benzyl-l-(n-butyl)-3-(3,4,5trimethoxypher.yl) urea 144-145° 71 1-Benzyl-l-(n-butyl)-3-(3,4-dichlorophenyljurea 102-105° 72 1-Benzyl-l-(n-butyl)-3-(3,5-dichlorophenylTurea 100-103° 73 1-Benzyl-l-(n-butyl)-3-(3-trifluoromethylphenyl)urea 86-87° 74 1- Benzyl-l-(n-butyl)-3-(3-chloro- 2- methoxyphenyl)urea 52-54° 75 1-Benzyl-l-(n-butyl)-3-(5-chloro4-methoxyphenyl)urea 61-63° 76 1-Benzyl-l-(n-butyl)-3-(3-chloro4-methylphenyl)urea Yellow Oil 77 l-Benzyl-l-(l,2-diphenylethyl)-3- (2,4-dimethylphenyl)urea 157-158° 54G83 1 TABLE VII EX. COMPOUND MELTING POINT 5 78 1- Benzyl-l-[l-(3-methoxyphenyl)- 2- phenylethyl]-3-(2,4-dimethylphenyl) urea 124-126° 79 1- Benzyl-l-[l-(4-benzyloxyphenyl)- 2- phenyl]-3-(2,4-dimethyIphenyl) urea 140-141° 10 80 1-Benzyl-1-(1-(3-methoxyphenyl)-2phenylethyl]-3-(3-trifluoromethylphenyl) urea 125-126° 81 l-Benzyl-l-(n-pentyl)-3-(2,4-di- methylphenyljurea Oil 15 82 1-Benzyl-1-(n-hexyl)-3-(2,4-dime thy lphenylTurea Oil 83 1-Benzyl-l-(n-octai)-3-(2,4-dime thyl pheny ljurea Oil 84 85 1-Benzyl-l-(n-undecyl)-3-(2,4dimethylphenyl) urea Oil 20 86 1- Benzyl-l-(n-butyl)-3-(3-chloro- 2- methoxyphenyl)urea 52-54° 87 1- Benzyl-l-(n-butyl)-3-(5-chloro- 2- me thoxyphenyl) urea 161-163° 25 88 l-(n-Butyl)-l-(2-fluorobenzyl)-3(2,7-dimethylphenyl)urea 76-77° 89 1-(n-Buty1)-1-(4-fluorobenzyl)-3(2,?-dimethylphenyl)urea 78-79° 90 l-(n-Butyl)-l-(2-chlorobenzyl)-3(2,7J-d imethylphenyl) urea 101-102° 30 91 l-(n-Butyl)-l-(2,6-dichlorobenzy17-3-(2,4-dimethylphenyl)urea 145-146° 92 1-(4-Bromobenzyl)-1-(n-butyl)-3(2,4-d imethylphenyl) urea 61-63° 93 l-(n-Butyl)-1-(4-n-butylbenzyl)3-(7,4-dimethyIphenyl)urea 60-62° TABLE VII EX. COMPOUND MELTING POINT 1-(n-Butyl)-l-(4-methylbenzyl)-3(2,4-dimethylphenyl)urea Oil l-(n-Butyl)-l-(4-tert-butylbenzyl)-3-(2,4-dimethylphenyl)urea 28-31° l-(n-Butyl)-l-(4-chlorobenzyl)-3(2,4-dimethylphenyl)urea Oil l-(n-Butyl)-l-(4-methoxybenzyl)3-(2,4-dimethylphenyl)urea Oil 1-(n-Butyl)-l-(3,4-methylenedioxybenzy1)-3-(2,4-d imethylphenyl) urea Oil l-(n-Butyl)-l-(4-trivluocomethylbenzyl)-3-(2,4-dimethylphenyl) urea Oil 100 1-(n-Butyl)-l-(4-phenylbenzy1)-3(2,4-dimethylphenyl)urea 82-83° 101 I-(n-Butyl)-1-(2-phenylethyl)-3(2,4-dimethylphenyl)urea Oil 102 l-(n-Butyl)-l-[2-(4-fluorophenyl) ethyl]-3-(2,4-dimethylphenyl)urea Oil 103 l-(n-Butyl)-l-[2-(4-chlorophenyl) ethyl]-3-(2,4-dimethylphenyl)urea Oil 104 l-(n-Butyl)-l-[2-(3-methoxyphenyl) ethyl]-3-(2,4-dimethylphenyl)urea Oil 105 l-(n-Butyl)-l-(3-phenylpropyl)-392,4-dimethylphenyl)urea Oil 106 1-(n-Butyl)-l-[4-(n-pentyl)benzyl ]-3-(2,4-dimethylphenyl)urea 65-67° 107 1-(n-Butyl)-1-(4-(n-hexyl)benzyl]3-(2,4-dimethylphenyl)urea Oil 108 1-(n-Butyl)-1-(3-chlorobenzyl)-3(2,4-dimethylphenyl)urea Oil 109 l-(n-Butyl)-l-[4-(n-butoxy)benzyl]-3-(2,4-dimethylphenyl)urea Oil TABLE VII EX. COMPOUND MELTING POINT 5 110 l-(n-Butyl)-l-(4-(n-pentyloxy) benzyl]-3-(2,4-dimethylphenyl) urea Oil 111 1-(n-Butyl)-l-[4-(n-hexyloxy)benzyl (-3-(2,4-dimethylphenyl)urea Oil 10 112 1-(n-Butyl)-1-(4-(n-heptyloxy) benzyl]-3-(2,4-dimethylpheny) urea Oil 113 l-(n-Butyl)-1-(4-nitrobenzyl)-3(2,4-dimethylphenyl)urea Oil 15 114 1-(n-Butyl)-1-(2-(2-methylphenyl) ethyl 1-3-(2,4-dimethylphenyl)urea 102-103° 115 l-(n-Buty1)-1-(2-(3-methylphenyl) ethyl]-3-(2,4-dimethylphenyl)urea Oil 116 l-(n-Butyl)-1-(2-(4-methylphenyl) ethyl]-3-(2,4-dime thylphenyl)urea Oil ?n 117 l-(n-Butyl)-1-(2-(4-methoxyphenyl) ethyl 1-3-(2,4-dime thylphenyl)urea Oil 118 l-(n-Butyl)-1-(2-(3-fluorophenyl) ethyl(-3-(2,4-dimethylphenyl)urea Oil 119 1-(n-Butyl)-1-[2-(2-chlorophenyl) ethyl]-3-(2,4-dimethylphenyl)urea Oil 25 120 1-(n-Butyl)-1-[2-(3-chlorophenyl) ethyl 1-3-(2,4-dimethylphenyl)urea Oil 121 1-(n-Butyl)-1-[2-(3-bromophenyl) ethyl (-3-(2,4-dimethylphenyl)urea Oil 122 1-(n-Butyl)-1-(2-(3,4-methylene- dioxyphenyl)ethyl 1-3-(2,4-di- methylphenyl)urea Oil 123 l-(n-Butyl)-l-(2-adamantylethyl)- 3-(2,4-dimethylphenyl)urea 134-135° 124 —------------—_—-.-—-- 125 1-(n-Butyl)-1-(di-(4-chlorophenyl) me thy1)-3-(2,4-dime thylphenyl)urea 145-147° .TABLE VII 5468 3 EX. COMPOUND MELTING POINT 5 IG6 l-(n-Butyl)-l-(3,4-dichlorobenzyl )-3- (2, 4-dime thylphenyl) urea 120-121° 127 1-(n-Butyl)-1-(3-tri fluoromethylbenzyl)-1-(4-fluorobenzyl)-3(2,4-dimethylphenyl)urea 114-115° 10 128 1-(4-Chlorobenzy1)-1-(1-naphthylmethyl-3- (2 ,4-dimethylphenyl) urea 134-136° 129 1-(4-Methoxybenzyl)-1-(2,4-dichlorobenzyl)-3-(2,4-dimethylphenyl) urea 124-126° 15 130 1-(3-Chlorobenzyl)-1-(4-methoxybenzyl)-3-(2,4-dimethylphenyl)urea 108-109° 131 l-(4-Phenylbenzyl)-l-(3,4-dichlorobenzyl)-3-(2,4-dimethylphenyl)urea 103-105° 20 132 1-(4-Pluorobenzyl)-1-(4-methylbenzyl) -3-(2,4-dimethylphenyl) urea 128-130° 133 l-(4-Chlorobenzyl)-1-(3,4-dimethoxybenzyl)-3-(2,4-dimethylphenyl) urea 94-96° 25 134 (l-(4-Fluorobenzyl)-l-(3,4methylenedioxybenzy1)-3-(2,4dimethylphenyl) urea 122-124° 135 1-(n-Butyl)-1-(4-methylthiobenzyl)-3-(2,4-dimethylphenyl)urea Oil 30 136 1-(2,4-Dichlorobenzyl)-1-(4-methylthiobenzyl)-3-(2,4-dimethylphenyl) urea 124-125° 137 l-[2-(3,4-Dimethoxyphenyl)ethyl]1-(3,4-methylenedioxybenzyl)-3(2,4-dimethylphenyl)urea Oil 35 138 l-[2-(2-Methylphenyl)ethylJ-l(2,4-dichlorobenzyl)-3-(2,4dimethylphenyl) urea 120-122° 139 1-[2-(4-Me thylphenyl)e thy1]-1(4-chlorobenzyl)-3-(2,4-dimethylphenyl) urea Oil S4G83 1 TABLE VII EX. COMPOUND MELTING POINT 5 140 1-(2-(4-Ethoxypheny1)e thyl]-l(2-chlorobenzy1)-3-(2,4-d imethylphenyl)urea Oil 141 1-(2- (3-Fluorophenyl)ethyl J-ΙΟ-methoxybenzyl )-3 - (2,4-d imethylphenyl)urea 94-95° 10 142 l-[2-(3-Methoxyphenyl)ethyl]-l(2-chlorobenzyl)-3-(2,4-dimethylphenyl)urea 73-74° 143 l-(3,3-Diphenylpropyl)-l-(4fluorobenzyl)-3-(2,4-dimethylphenyl)urea 109-110° 15 144 l-(n-Butyl)-l-(3,3-diphenylpropy1)-3-(2,4-dimethylphenyl)urea 94-95° 145 l-(n-Butyl)-l-(4-cyclohexylbutyl)· 3-(2,4-dimethylphenyl)urea Oil 20 146 1-(2-(3,4-Dimethoxyphenyl)ethyl]1-(3-chloro-4-methylbenzy1)-3(2,4-dimethylphenyl)urea Gum 147 l-[2-(2-Methylphenyl)ethyl]-l(4-bromobenzyl)-3-(2,4-dimethylpheny 1) urea 126-127° 25 148 l-[2-(3-Trifluoromethylphenyl) ethyl]-l-(2-chlorobenzyl)-3(2,4-dimethylphenyl)urea 115-117° 149 l-(2-Fluorobenzyl)-l-(2-methoxybenzyl)-3-(2,4-dimethylphenyl) urea 96-98° 30 150 l-[2-(3,4-Dimethoxyphenyl)ethyl]l-(4-fluorobenzyl)-3-(2,4-dimethylphenyl)urea Gum 151 l-[2-(4-Ethoxyphenyl)ethyl]-l(2,4-dimethylbenzyl)-3-(2,4dimethylphenyl)urea Gum 35 152 l-[2-(3-Methylphenyl)ethyl(-ΙΟ -nitrobenzyl )-3 - (2, 4 -dime thyl phenyl)urea 99-1010 I TABLE VII EX. COMPOUND MELTING POINT 153 1-(2-(2,5-Dimethoxypheny1)e thyl]- 1-(3-chlorobenzyl)-3-(2,4-di- methylphenyl)urea 86-88° 154 1-(n-Butyl)-1-(2-methyl-2,2-di- phenyl)ethyl-3-(2,4-dimethyl- phenyl)urea 159-160° 155 l-(n-Butyl)-l-(4-hexyloxybenzyl)- 3-(2,4,6-trimethyIphenyl)urea 90-91° 156 l-(n-Butyl)-l-(4-heptyloxyben- zyl)-3-(2,4,6-trimethylphenyl) urea 86-87° 157 158 l-Benzyl-l-(4-n-butylbenzyl)-3- (2,4-dimethyIphenyl)urea Oil 159 1-Benzyl-l-(4-n-butylbenzyl)-3- (2,4,6-trimethylphenyl) urea Oil 160 1-Benzyl-l-(4-n-butylbenzyl)-3- (4-n-butylphenyl) urea Yellow Oil 161 1-Benzyl-l-(4-n-butylbenzyl)-3- (4-phenoxyphenyl)urea 79-80° 162 l-(n-Heptyl)-l-(4-n-butylbenzyl)- 3-(2,4-dimethylphenyl)urea Yellow Oil 163 1-(n-Heptyl)-l-(4-n-butylbenzyl)· 3-(2,4,5-trimethylphenyl)urea Yellow Oil 164 1-Benzyl-l-[2-pheny1-1-(4-benzyl- oxyphenyl)ethyl (-3-(2,4,5-tri- methylphenyl)urea 157-158° 165 l-(n-Heptyl)-l-(4-butyloxyben- zy1)-3-(2,4-dimethyIphenyl)urea Oil 166 l-(n-Heptyl)-l-(4-butyloxyben- zy1)-3-(2,4,5-trimethyIphenyl) urea Yellow Oil TABLE VII EX. COMPOUND MELTING POINT 5 167 1-Benzyl-l-(4-butyloxybenzyl)3-(2,4-dimethylphenyl)urea Solid 168 169 1-Benzyl-l-(4-butyloxybenzyl)3-(2,4,5-trimethylphenyl)urea Solid Ιϋ 170 171 1-Benzyl-l-(4-n-butylbenzyl)-3(2,4,5-Crimethylphenyl)urea Yellow Oil 172 l-Benzyl-l-[2-phenyl-l-(4-benzyloxyphenyl)ethyl 1-3-(2,4,6trimethylphenyl)urea 140-141° 15 173 1-(n-Heptyl)-1-(4-n-butoxybenzyl) -3- (2, 4, 6 -tr ichloropheny 1) urea 63-64° 174 1-(n-Heptyl)-(4-n-butoxybenzyl)3-(2,4-dichlorophenyl)urea Gum 20 175 1-(n-Heptyl)-(4-n-butoxybenzyl)- 3-(2-trifluoromethyl-4-cbloro- phenyl)urea Gum 176 1-Benzyl-l-(4-n-butoxybenzyl)3-(2,4,6-trichlorophenyl)urea 91-93° 25 177 1-Benzyl-l-(4-n-butoxybenzyl)3-(2,4-dichlorophenyl)urea Gum 178 1-Benzyl-1-(4-n-bu toxybenzyl)3-(2-trifluoromethyl-4-chlorophenyl ) urea Gum 30 179 1-(n-Heptyl)-1-(4-n-butoxybenzyl )-3- (3-tr if luorome thylpbenyl)urea Gum 180 1-(n-Benzy1)-1-(4-n-butoxybenzyl )-3-(3-trifluoromethylphenyl) urea Gum TABLE VII EX. COMPOUND MELTING POINT 5 181 l-(n-Heptyl)-l-(4-n-butylbenzyl)3-(2,4-dichlorophenyl)urea Cum 182 l-(n-Heptyl)-!-(4-n-butylbenzyl)- 3-(2-trifluoromethyl-4-chloro- phenyl)urea Gum 10 183 l-(n-Heptyl)-l-(4-n-butylbenzyl)3-(2,4,6-trichlorophenyl)urea Gum 184 l-(n-Heptyl)-l-(4-n-butylbenzyl)3-(3-trIfluorome thylphenyl) urea Gum 185 1-(n-Heptyl)-1-(4-n-butylbenzyl)3-(2,4,5-trichlorophenyl)urea Gum 15 186 1-Benzyl-l-(4-n-butylbenzyl)-3(2-methyl-4-chlorophenyl)urea 107-108° 187 l-(n-Heptyl)-l-(4-n-butoxybenzyl)-3-(2,4-difluorophenyl)urea Gum 20 188 189 190 1-(n-Heptyl)-1-(4-n-butoxybenzyl)-3-(2-methyl-4-chlorophenyl) urea Gum 25 191 l-(n-Heptyl)-1-(4-n-butylbenzyl) -3- (2-methyl -4-chlorophenyl) urea Oil 192 l-(n-Heptyl)-l-(4-n-butylbenzyl)-3-(2,4-di fluorophenyl) urea Oil 193 I-(n-Heptyl)-l-(4-n-butylbenzyl)· 3-(4-carboethoxyphenyl)urea 65-66° 30 194 1-(n-Heptyl)-1-(4-n-butylbenzyl) 3-(2-methylphenyl)urea Oil - 195 l-(n-Heptyl)-l-(4-n-butylbenzyl) 3-(3-methylphenyl)urea Oil 196 l-(n-Heptyl)-l-(4-n-butylbenzyl) 3-(4-carboxyphenyl)urea 147-149° TABLE VII EX. , COMPOUND MELTING POINT 197 l-(n-Heptyl)-l-(2-phenylethyl)3-(2-methyl-4-chlorophenyl)urea Gum 198 1-(n-Hepty1)-1-(2-phenylethyl)3-(2,4,5-trichlorophenyl)urea Gum 199 l-(n-Heptyl)-l-(2-phenylethyl)- 3-(2-trifluoromethyl-4-chloro- phenyl)urea Gum 200 l-(n-Heptyl)-l-(2-phenylethyl)3-(2,4-dimethylphenyl)urea Gum 201 l-(n-Heptyl)-l-(2-phenylethyl)3-(2,4-dichlorophenyl)urea Gum 202 l-(n-Heptyl)-1-(2-phenylethyl)3-(2,4-difluorophenyl)urea Gum 203 l-(n-Heptyl)-l-(2-phenylethyl)- 3-(3-trifluoromethylphenyl)urea Gum 204 1-Benzyl-l-[2-pheny1-1-(4-benzyloxyphenyl)ethyl]-3-(2,4,6-trichlorophenyl)urea 131-133° 205 l-(4-n-Pentylbenzyl)-l-(4-n-pen- tyloxybenzyl)-3-(2,4,6-tri- chlorophenyl)urea Oil 206 l-(4-n-Pentylbenzyl)-l-(4-n-pentyloxybenzyl)-3-(2,4-dichlorophenyl) urea Oil 207 l-(4-n-Pentylbenzyl)-l-(4-n-pen- tyloxybenzyl)-3-(2,4,5-tri- chlorophenyl)urea Oil 208 l-(4-n-Pentylbenzyl)-1-(4-n-pentyloxybenzyl)-3-(2-trifluoromethyl -4-chlorophenyl) urea Oil 209 l-(4-n-Pentylbenzyl)-l-(4-n-pentyloxybenzyl)-3-(3-tri fluoromethyl phenyl) urea Oil 210 1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxybenzyl)-3-(2,4-difluorophenyl) urea Oil TABLE VII EX. COMPOUND t IELTING POINT 211 l-(4-n-Pentylbenzyl)-l-(4-n-pen~ tyloxybenzy1)-3-(2-me thy1-4chlorophenyl)urea Oil 212 1-(4-Chlorobenzyl)-1-(1-naphthylme thyl) -3 -(2, 4, 6-tr ichlorophenyl) urea 157-159° 213 1-(4-Chlorobenzyl)-1-(1-naphthylmethyl )-3 -(2-me thyl-4-chlorophenyl) urea 168-169° 214 1-(4-Chlorobenzyl)-1-(1-naphthylmethyl )-3- (2, 4-di fluorophenyl) urea 122-124° 215 l-(4-Chlorobenzy1)-1-(1-naphthylmethyl) -3-(3-trifluoromethylphenyl) urea 127-129° 216 1-(4-Chlorobenzyl)-1-(1-naphthylmethyl) -3-(2,4,5-trichlorophenyl) urea 110-113° 217 1-Benzyl-1-[2-phenyl-1-(4-benzyloxypheny1) e thy 1 ] -3 - (2,4,5 -tr i chlorophenyl)urea 142-145° 218 1-Benzyl-l-(4-n-butyloxybenzy1)3-(2,4,5-trichlorophenyl)urea Oil 219 1-Benzyl-l-[2-phenyl-1-(4-benzyloxyphenyl) ethyl]-3-(2,4-d ifluorophenyl)urea 84-85° 220 1-Benzyl-1-(4-n-butoxybenzyl)-3(2,4-d i f1uoropheny1)urea Oil 221 l-BenzyI-l-[2-phenyl-l-(4-benzyloxyphenyl)ethylJ-3-(2,4-difluorophenyl)urea 126-128° 222 1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphenyl)ethylI-3-(2-trifluoromethyl-4-chlorophenyl)urea 99-101° 223 l-Benzyl-l-[2-phenyl-l-(4-benzyloxyphenyl)ethyl(-3-(3-trifluoromethylphenyl) urea 102-104° TABLE VII EX. COMPOUND MELTING POINT 224 l-Benzyl-l-[2-phenyl-l-(4-benzyloxypheny)ethyl]-3-(2-methyl-4chlorophenyl)urea 125-126° 225 l-(4-Chlorobenzyl)-l-(l-naphthylmethy1)-3-(2,4-dichlorophenyl) urea 96-98° 226 1-(4-Chlorobenzy1)-1-(1-naphthylmethyl)-3-(2-trifluoromethyl-4chlorophenyl)urea Yellow Glass Example 227 1-Benzyl-l-(n-butyl)-3-(3-chlorophenyl)urea A solution of 1.56 g. of phenyl chloroformate in 50 ml. of ether is added dropwise to a stirred solution of 2.55 g. of 3-chloroaniline in 35 ml. of ether. The mixture is stirred for one hour at room temperature and then filtered. The filtrate is evaporated and the residue is crystallized from hexane to yield phenyl N-(3-chlorphenyl)carbamate.
A solution of 1.46 g. of phenyl N-(3-chlorophenyl)carbamate in 15 ml. of tetrahydrofuran is added to a solution of 1.92 g. of N-benzyl-n-butylamine in 20 ml. of tetrahydrofuran and the mixture is stirred under reflux for 24 hours. The mixture is diluted with hexane and the precipitate collected by filtration. Recrystallization from pentane affords l-benzyl-l-(n-butyl)-3-(3-chlorophenyl)urea, m.p. 69-70°C.
Example 228 1-Benzyl-l-(n-buty1)-3-(4-carboxyphenyl)urea A solution of 5.30 g. of l-benzyl-l-(n-butyl)3-(4-carboethoxyphenyl)urea in 100 ml. of ethanol is treated with 25 ml. of IN aqueous sodium hydroxide, stirred under reflux for 16 hours, allowed to cool, acidified with IN hydrochloric acid, and filtered. The solid is recrystallized from ethanol to yield 1-benzyl-l(n-butyl)-3-(4-carboxyphenyl)urea as a white solid.
Example 229 1-Benzyl-l-(n-butyl)-3-(2-hydroxy-3-chlorophenyl)urea A solution of 1.73 g. of l-benzyl-l-(n-butyl)3-(2-methoxy-3-chlorophenyl)urea and 1.00 ml. of boron tribromide in 40 ml. of methylene chloride is stirred at ambient temperature for 3 days and diluted with water. The organic layer is separated, dried, and evaporated. The residue is crystallized from hexane to yield 1-benzyl-l(n-butyl)-3-(2-hydroxy3-chlorophenyl)urea, m.p. 59-62°.
Example 230 N-(2-Chlorobenzyl)-3-methoxyphenylacetamide A mixture of 12.5 g. of 3-methoxyphenylacetic acid, 21.2 g. of 2-chlorobenzylamine, 15.1 g. of triethylamine, 19.3 ml. of borontrifluoride etherate, and 500 ml. of toluene is stirred under reflux for 18 hours using a Dean-Stark moisture trap and allowed to cool. The mixture is extracted with aqueous sodium hydroxide, dilute hydrochloric acid, and water. The remaining organic solution is then evaporated and the residue crystallized from hexane to yield N-(2-chlorobenzyl)-3-methoxyphenylacetamide as a yellow solid, m.p. 89-91°.
Example 231 N-(n-Butyl)-2-chlorobenzylamine A solution of 21.2 g. of N-(n-butyl)-2-chlorobenzamide in 100 ml. of tetrahydrofuran is added with cooling to 200 ml. of IMborane in tetrahydrofuran, and the mixture is stirred under reflux for 18 hours, allowed to cool, and treated with 6N hydrochloric acid. The organic 4 0 8 3 solvent is evaporated, and the residue is partitioned between ether and aqueous sodium hydroxide solution. The ether layer is separated, dried, and evaporated. The residue is distilled to yield N-(n-hutyl)-2-chloroben5 zylamine as a colorless liquid, b.p. 65-75° at 60 .
Example 232 1,1-Dibenzy1-3-(2,4-dimethylphenyl) urea A solution of 4.89 g. of 2,4-dimethylphenylisocyanate in 100 ml. of hexane is added to a solution of .32 g. of dibenzylamine in 150 ml. of hexane, and the solution is stirred at room temperature for 2 hours and then evaporated. The residual solid is recrystallized from pentane to yield 1,l-dibenzyl-3-(2,4-dimethylphenyl)urea, m.p. 124-126°.
The ureas shown in Table VIII were prepared from the appropriate aryl isocyanates and secondary amines by the method of Example 60, or they were obtained commercially.
TABLE VIII EX. COMPOUND MELTING POINT 233 1,1-Dibenzy1-3-(2-methylpehnyl) urea White Solid 234 1,l-Dibenzyl-3-(3-methylphenyl) urea 126-128° 235 1,1-Dibenzyl-3-(4-methylphenyl) urea 170-172° 236 1,l-Dibenzyl-3-(4-n-butylphenyl) urea 104-106° 237 1,l-Dibenzyl-3-(2,3-dimethylphenyl)urea White Solid 238 1,l-Dibenzyl-3-(2,5-dimethylphenyl)urea White Solid 239 1,1-Dibenzy1-3-(2,6-dimethylphenyl) urea White Solid 240 1,1-Dibenzyl-3-(3,4-dimethylphenyl)urea White Solid TABLE VIII EX. COMPOUND MELTING POINT 241 1,l-Dibenzyl-3-(3,5-dimethylphenyl)urea Yellow Solid 242 1,l-Dibenzyl-3-(2,4,5-trimethylphenyl) urea 141-142° 243 1,l-Dibenzyl-3-(2,4,6-trimethylphenyl) urea 163-165° 244 1,1-Dibenzyl-3-(4-metboxyphenyl) urea Cream Solid 245 1,l-Dibenzyl-3-(4-n-butoxyphenyl)urea 119-120° 246 1,l-Dibenzyl-3-(4-methylthiophenyl) urea 196-198° 247 1,l-Dibenzyl-3-(2-cblorophenyl) urea White Solid 248 1,l-Dibenzyl-3-(3-chlorophenyl) urea White Solid 249 1,I-Dibenzyl-3-(4-chlorophenyl) urea White Solid 250 1,l-Dibenzyl-3-(2-bromophenyl) urea 118-119° 251 15l-Dibenzyl-3-(4-bromophenyl) urea White Solid 252 1,l-Dibenzyl-3-(4-iodophenyl)urea ι 233-235° 253 1,l-Dibenzyl-3-(2,3-dichlorophenyl)urea White Solid 254 1,1-Dibenzyl-3-(2,4-dichlorophenyl) urea White Solid 255 1,l-Dibenzyl-3-(2,5-dichlorophenyl)urea White Solid 256 1,l-Dibenzyl-3-(3,5-d ichlorophenyl)urea 144-145° 257 1,l-Dibenzyl-3-(3-trifluoromethy1pheny1) urea Cream Solid 4 0 8 3 TABLE VIII EX. COMPOUND MELTING POINT 5 258 1,l-Dibenzyl-3-(3-acetylphenyl) urea 124-127° 259 1,l-Dibenzyl-3-(4-carboethoxyphenyl)urea 91-93° 10 260 1,l-Dibenzyl-3-(4-phenoxyphenyl)urea 144-146° 261 1,1-Dibenzyl-3-(3-chloro-2methylphenyl) urea 138-139° 262 1,l-Dibenzyl-3-(3-chloro-4methylphenyl)urea White Solid 15 263 1,l-Dibenzyl-3-(4-chloro-3-trifluoromethylphenyl)urea 146-148° 264 1,l-Dibenzyl-3-(4-chloro-2-trifluoromethylphenyUurea 82-83° 265 266 267 1,l-Dibenzyl-3-(5-chloro-2methylphenyl)urea White Solid 268 1,l-Dibenzyl-3-(3-methoxyphenyl) urea White Solid 25 269 1,l-Dibenzyl-3-(2-methoxyphenyl) urea Cream Solid 270 1,l-Dibenzyl-3-(3-nitrophenyl) urea Yellow Solid 271 1,l-Dibenzyl-3-(2,5-dimethoxyphenyl)urea Cream Solid 30 272 1,l-Dibenzyl-3-(2,6-dichlorophenyl)urea White Solid 273 1,l-Dibenzyl-3-(3,4-dichlorophenyl)urea White Solid 274 1,l-Dibenzyl-3-(4-chloro-2methylphenyl)urea White Solid TABLE VIII EX. COMPOUND MELTING POINT 275 1,l-Dibenzyl-3-(2-methoxy-5me thylphenyl)urea White Solid 276 1,l-Dibenzyl-3-(6-chloro-2-methylphenyl)urea White Solid 277 1,l-Dibenzyl-3-(6-ethyl-2-methylphenyl)urea White Solid 278 1,l-Dibenzyl-3-(2,6-diethylphenyl)urea White Solid 279 l,l-Dibenzyl-3-(2,6-diisopropyl- phenyl)urea White Solid 280 1,l-Dibenzyl-3-(4-nitropheny1) urea Yellow Solid 281 1,1-Dibenzyl-3-(4-e thoxyphenyl) urea 129-130° 282 I,l-Dibenzyl-3-(2,5-difluorophenyl)urea 67-68° 283 284 285 1,l-Dibenzyl-3-(2,4-dibromophenyl)urea 107-108° 286 287 288 289 1,l-Dibenzyl-3-(2-trifluoromethylphenyl) urea 111-114° 4 6 8 3 TABLE VIII EX. COMPOUND_MELTING POINT 290 1,l-Dibenzyl-3-(4-methylphenyl) urea White Solid 291 1,l-Dibenzyl-3-phenyl urea White Solid Example 292 1,l-Dibenzyl-3-(3-bromophenyl)urea A solution of 1.56 g. of phenyl chloroformate in 50 ml. of ether is added dropwise to a stirred solution of 3.44 g. of 3-bromoaniline in 35 ml. of ether, the mixture is stirred for one hour at room temperature and then filtered. The filtrate is evaporated, and the residue is crystallized from hexane to yield phenyl N-(3-bromophenyl)carbamatel, m.p. 89-90°C.
A solution of 1.46 g. of phenyl N-(3-bromophenyl)carbamate in 15 ml. of tetrahyrofuran is added to a solution of 2.32 g. of dibenzylamine in 20 ml. of tetrahydrofuran and the mixture is diluted with hexane and the precipitate collected by filtration. Recrystallization from pentane affords 1,l-dibenzyl-3-(3-bromophenyl)urea, m.p. 102-103°.
Example 293 1, l-Dibenzyl-3-(4-carboxyphenyl)urea A solution of 5.61 g. of l,l-dibenzyl-3-(4carboethoxyphenyl)urea in 100 ml. of ethanol is treated with 25 ml. of IN aqueous sodium hydroxide solution, stirred under reflux for 16 hours, allowed to cool, acidified with IN hydrochloric acid, and filtered. The solid is crystallized from ethanol to yield 1,1-dibenzyl3-(4-carboxyphenyl)urea as a white solid, m.p. 210-214°.
Example 294 1-Benzyl-1-(n-butyl)-3-(phenyl)urea A solution of 4.89 g. of phenylisocyanate in 100 ml. of hexane was added to a solution of 4.41 g. of Nbenzyl-n-butylamine in 150 ml. of hexane, and the solution was stirred at room temperature for 2 hours and then evaporated. The residual solid was recrystallized from pentane to yield l-benzyl-l-(n-butyl)-3-(phenyl)urea.
Example 295 1,1-D1-(n-butyl)-3-(2,4-dimethylphenyl)urea A solution of 4.89 g. of 2,4-dimethylphenylisocyanate in 100 ml. of hexane is added to a solution of 3.48 g. of di (n-butyl) amine in 150 ml. of hexane, and the solution is stirred at room temperature for 2 hours and then evaporated. The residual solid is recrystallized from pentane to yield l,l-di-(n-butyl)-3-(2,4-dimethylphenyl)urea, m.p. 48-50°C.
The ureas shown in Table IX were prepared from the appropriate aryl isocyanates and secondary amines by. the method of Example 60, or they were obtained commercially.
TABLE IX EX. COMPOUND MELTING POINT 296 1,1-Di-(n-butyl)-3-(2-methylphenyl)urea Yellow Oil 297 1,1-Di-(n-butyl)-3-(3-methylphenyl) urea White Solid 298 1,1-Di-(n-butyl)-3-(4-methylphenyl)urea 90-91° 299 1,l-Di-(n-butyl)-3-(4-isoptopylphenyl)urea 60-61.5° 300 1,1-Di-(n-butyl)-3-(4-n-butylphenyl)urea 44-46° 301 1,l-Di-(n-butyl)-3-(2,3-dimethylphenylTurea White Solid 302 1,1-Di-(n-butyl)-3-(2,5-dimethyl pheny lTurea White Solid 303 1,1-Di-(n-butyl)-3-(2,6-dimethylphenylTurea 131-134° 304 1,l-Di-(n-butyl)-3-(3,4-dimethylphenylTurea 74-76° TABLE IX fix. COMPOUND MELTING POINT 305 1,1-Di-(n-butyl)-3-(3,5-dimethylphenyljurea White solid 306 1,1-Di-(n-butyl)-3-(2,4,6-trime thy1pheny1)ur e a 119-120° 307 1,1, -Di-(n-butyl)-3-(4-methoxypbenyl)urea White Solid 308 l,l-Di-(n-butyl)-3-(4-ethoxy- phenyl)urea 59-60° 309 1,1-Di-(n-butyl)-3-(3-methylthiophenyl)urea 64.5-65.5° 310 l,l-Di-(n-butyl)-3-(2-chloro- pbenyl)urea Oil 311 1,1-Di-(n-butyl)-3-(3-chlorophenyl) urea White Solid 312 1,1-Di-(n-butyl)-3-(4-fluorophenyl) urea White Solid 313 1,1-Di-(n-butyl)-3-(4-iodophenyl)urea 113-114° 314 1,1-Di-(n-butyl)-3-(2,3-dichlorophenyl)urea Oil 315 1,1-Di-(n-butyl)-3-(2,4-dichlorophenyl) urea Oil 316 1,1-Di-(n-butyl)-3-(3,5-dichlorophenyl) urea 80-81° 317 1,1-Di-(n-butyl)-3-(2,3,5-trichlorophenyl ) urea Yellow Solid 318 l,l-Di-(n-butyl)-3-(3-acetyl- phenyl)urea 80-81° 319 , 1,1-Di-(n-butyl)-3-(4-acetylphenyl)urea 94.5-95.5° 320 1,l-Di-(n-butyl)-3-(3-chloro2-methylphenyl)urea 73-75° 321 1,l-Di-(n-butyl)-3-(3-chloro4-methylphenyl)urea Yellow Solid TABLE IX EX. COMPOUND MELTING ! POINT 322 l,l-Di-(n-butyl)-3-(3-chloro- 4-fluorophenyl)urea 80-81° 323 1,1-Di-(n-butyl)-3-(2-chloro4-ni tropKenyl) urea Yellow Solid 324 1,1-Di-(n-butyl)-3-(4-chloro3-trifluoromethylphenyl)urea 84-85° 325 1,1-Di-(sec-butyl)-3-(2,4-dimethylphenyl)urea 97-99° 326 1,1-Di-(n-pentyl)-3-(2,4-dimethylphenyl)urea 45-46° 327 1,1-Di-(n-isopentyl)-3-(2,4dimethylphenyl) urea 66-68° 328 1,1-Di-(n-hexyl)-3-(2,4-dimethylphenylTurea Oil 329 1,1-Di-(n-heptyl)-3-(2,4-dimethylphenyl)urea Yellow Oil 330 1,1-Di-(n-octyl)-3-(2,4-dimethylphenyljurea Oil 331 1,1-Di-(n-undecyl)-3-(2,4-dimethylphenyl)urea Yellow Oil 332 1,1-Di-(n-decyl)-3-(2,4-dimethylphenyljurea Yellow Oil 333 1,1-Di-(n-dodecyl)-3-(2,4-dime thylphenyl)ur ea Yellow Oil 334 l,l-Di-(n-nonyl)-3-(2,4-dimeth- ylpbenyljurea Oil 335 1,l-Di-(4-cyclohexyl-n-butyl)-3(2,4-dimethylphenyl)urea 85-86° 336 1,1-Di-(cyclopentyl)-3-(2,4-dimethylphenyl ) urea 136-138° 337 338 1,1-di-(n-butyl)-3-(4-chloro2-methylphenyl) urea White Solid TABLE IX EX. COMPOUND MELTING POINT 339 1.1-dicyclohexyl-3-(2,4-d ime thylphenyl) urea White Solid 340 1,1-di-(n-butyl)-3-(3-methoxyphenyl) urea White Solid 341 1,1-di-(n-butyl)-3-((3,3-dibutylurea-4-methylphenyljurea White Solid 342 1,1-di-(isobutyl)-3-(2-chlorophenyl) urea White Solid 343 l,l-di-(isobutyl)-3-[(3,3-diisobutyl) urea-4-methylphenyl]urea Tan Solid 344 1,1-di-(isobutyl)-3-(2,5-dimethylphenyl)urea White Solid 345 1,1-di-(isobutyl)-3-(2,6-dimethy lphenyl) urea White Solid 346 1,1-di-(n-butyl)-3-(5-chloro-2methylphenyl)urea 55-56° 347 l,l-di-(3,5,5-trimethylhexyl)3-(2,4-d imethylphenyl) urea 69-70° 348 1,1-di-(2-ethylhexyl)-3-(2,4-dimethylphenyl ) urea 40° Example 349 1,1-Di(n-butyl)-3-(3-bromophenyl)urea A solution of 1.56 g. of phenyl ehloroformate in 50 ml. or ettier is added dropwise to a stirred solution of 3.44 g. of 3-bromoaniline in 35 ml. of ether and the mixture is stirred for one hour at room temperature and then filtered. The filtrate is evaporated, and the residue is crystallized from hexane to yield phenyl N-(3bromophenyl)carbamate, m.p. 88-90°C.
A solution of 1.46 g. of phenyl N-(3-bromophenylcarbamate in 15 ml. of tetrahydrofuran is added to a solution of 1.52 g. of di-n-butylamine in 20 ml. of tetrahydrofuran, and the mixture is stirred under reflux for 24 hours. The mixture is diluted with hexane and the precipitate collected by filtration. Recrystalli2ation from pentane affords 1,1-di-(n-butyl)-3-(3-bromophenyl)urea, m.p. 80-81°C. 546S3
Claims (14)
1. A compound of the formula wherein X represents at least one substituent selected from the group 5 consisting of Cj-C^ alkyl, C^-C^ alkenyl, alkynyl, hydroxy, C^-C^ alkoxy, phenoxy, mercapto, C^-C^ alkylthio, amino, C-j-C^ alkylamino, di-iC^-C^ alkyUamino, halo, trihalomethyl, C^-C^ alkanoyl, benzoyl, C^-C^ alkanamido, Cj-C^ alkanesulfonyl, C^-C^ alkanesulfinyl, benzenesulfonyl, 10 toluenesulfonyl, nitro, cyano, carboxy, C^-C 4 carboalkoxy, carbamoyl, sulfamyl, methylenedioxy, phenyl, ortho-phenylene, tolyl, benzyl, halobenzyl, methylbenzyl, and the group R. ί / N-C-N / \ , R, wherein Y is oxygen; R 1 and R g are the same or different and are 15 independently selected from the group consisting of C 4 -C^ 2 alkyl, C 4 -Cj 2 alkenyl, C 4 -C 12 alkynyl, Cy-C 12 aralkyl, and Cy-C^ aralkyl in which an aromatic ring bears at least one substituent selected from the group consisting of C^-C 1Q alkyl, 67. 54G83 C l” C 10 a1koxy > phenoxy, benzyloxy, methylenedioxy, C^-C^ alkylthio, phenyl, halo, trihalomethyl, adamantyl, Cj-C^ carboalkoxy, and nitro; and Rj is selected from the group consisting of hydrogen, C-j-C 4 alkyl, C^-C^ alkenyl, alkynyl, benzyl, 5 benzyl bearing at least one substituent Z, naphthyl, phenyl and phenyl bearing at least one substituent Ζ, Z being selected independently of X from the group consisting of those from which X is selected; with the proviso that when Rg is hydrogen, then R-j and R 2 cannot be the same.
2. A compound as recited in Claim 1, wherein X represents at least one 10 halo substituent.
3. A compound as recited in Claim 1, wherein X represents at least one substituent selected from the group consisting of C^-C^ alkyl, C-|-C 4 alkoxy, halo, Cj-C 4 carboalkoxy, and benzyl.
4. A compound as recited in Claim 1, wherein X represents at least one 15 C-j-C^ alkyl or halo substituent and R-| and R g are the same or different and are independently selected from C 4 ~C^ 2 alkyl, C 7 -C-| 4 aralkyl and substituted C ? -C 14 aralkyl.
5. The compound: l-(ir-heptyl)-l-(4-n-buty1benzyl)-3-(2,4-diphenylf1uorophenyl)urea. 20
6. A process for preparing a compound as defined in Claim 1 wherein Rg is hydrogen, which comprises reacting a compound of the formula: Y II A-C-B wherein Y is as defined in Claim 1 and A and B are independently selected from the group consisting of halo, Cj-C^ alkoxy, C^-C^ 25 alkylthio, phenoxy, 4-chlorophenoxy, and 4-nitrophenoxy; with an arylamine of the formula: 68. 54C83 wherein X and Rg are as defined in Claim 1 to yield an intermediate of the formula: Y II C-B /’ N \ and then reacting the intermediate with a secondary amine of the formula: R, / HN Ro wherein R·, and R 2 are as defined in Claim 1.
7. A process for preparing a compound as defined in Claim 1 wherein Rg is hydrogen, which comprises reacting a compound of the formula: A-C-B 69. 5 4 6 6-3 wherein Y is as defined in Claim 1 and A and B are independently selected from the group consisting of halo, Cj-C^ alkoxy, C^-C^ alkylthio, phenoxy, 4-chlorophenoxy, and 4-nitrophenoxy; with a secondary amine of the formula wherein Rj and R z are as defined in Claim 1 to yield an intermediate of the formula: A-C-N and then reacting the intermediate with an arylamine of the formula: wherein X and R 3 are as defined in Claim 1.
8. A process for preparing a compound as defined in Claim 1 wherein Rg is hydrogen, which comprises reacting an aryl isocyanate of the formula: with a secondary amine of the formula: /' HN \ »2 wherein X, Y and R-| and R? are as defined in Claim 1.
9. A pharmaceutical composition for treating atherosclerosis, reducing the chloesterol ester content of the arterial wall, inhibiting atherosclerotic lesion development and/or treating hyperlipidemia in a mammal in need of such treatment, which comprises a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of the formula: X Y R, H / 1 N-C-N \ R R 2 wherein X represents at least one substituent selected from the group consisting of hydrogen, C^-C^ alkyl, C^-C^ alkenyl, C^-C^ alkynyl, hydroxy, C^-C^ alkoxy, phenoxy, mercapto, C^-C^ alkylthio, amino, C,-C. alkylamino, di-(C -C alkyl)amino, halo, 14 14 71. trihalomethyl, C-j-C^ alkanoyl, benzoyl, C-j-C^ alkanamido, C-|-C 4 alkanesulfonyl, CpC^ alkanesulfinyl, benzenesulfonyl, toluenesulfonyl, nitro, cyano, carboxy, C^-C^ carboalkoxy, carbamoyl, sulfamyl, methylenedioxy, phenyl, ortho-phenylene tolyl, benzyl, 5 halobenzyl, methylbenzyl, and the group Y is oxygen; R-j and Rg are the same or different and are independently selected from the group consisting of C^-C·^ alkyl, C 4 C 12 a 1 ken Xl» C 4~ C 12 a lky n yl » C 4~ C 12 cycloalky 1 »
10. C 4 - Cj2 cycloalkylalkyl, Cy-C^ aralkyl, and Cy-C^ aralkyl in which an aromatic ring bears at least one substituent selected from the group consisting of C^-C^ alkyl, C-j-Ο^θ alkoxy, phenoxy, benzyloxy, methylenedioxy, C-j-C^ alkylthio, phenyl, halo, trihalomethyl, adamantyl, C^-C^ carboalkoxy, and nitro; and Rg is 15 selected from the group consisting of hydrogen, C^-C^ alkyl, C-pC^ alkenyl, C^-C^ alkynyl, benzyl, benzyl bearing at least one substituent Z, naphthyl, phenyl, and phenyl bearing at least one substituent Ζ, Z being selected independently of X from the group consisting of those from which X is selected. 20 10. A pharmaceutical composition according to Claim 9, wherein said compound is as defined in any one of Claims 2 to 5.
11. A compound according to Claim 1 and substantially as described herein.
12. A process for preparing a compound according to Claim 1, 25 substantially as described herein.
13. A pharmaceutical composition according to Claim 9 and substantially as hereinbefore described.
14. A compound as claimed in Claim 1, whenever prepared by a process as claimed in any of Claims 6 to 8 or 12. Dated this 25th day of January 1983,
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/342,693 US4473579A (en) | 1982-01-26 | 1982-01-26 | Antiatherosclerotic tetrasubstituted ureas and thioureas |
US06/342,698 US4387105A (en) | 1982-01-26 | 1982-01-26 | Methods of treating atherosclerosis with dialkylureas and dialkylthioureas |
Publications (2)
Publication Number | Publication Date |
---|---|
IE830146L IE830146L (en) | 1983-07-26 |
IE54683B1 true IE54683B1 (en) | 1990-01-03 |
Family
ID=26993144
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE146/83A IE54683B1 (en) | 1982-01-26 | 1983-01-25 | Antiatherosclerotic substituted ureas |
Country Status (20)
Country | Link |
---|---|
KR (1) | KR890001808B1 (en) |
AT (1) | AT391313B (en) |
AU (1) | AU562699B2 (en) |
CH (1) | CH654571A5 (en) |
DE (1) | DE3247581A1 (en) |
DK (1) | DK160869C (en) |
ES (2) | ES8406422A1 (en) |
FI (1) | FI85013C (en) |
FR (1) | FR2521134B1 (en) |
GB (1) | GB2113684B (en) |
GR (1) | GR77186B (en) |
HU (1) | HU200746B (en) |
IE (1) | IE54683B1 (en) |
IL (1) | IL67417A (en) |
IT (1) | IT1203647B (en) |
NL (1) | NL8300269A (en) |
NO (1) | NO158417C (en) |
PL (1) | PL143836B1 (en) |
PT (1) | PT76138A (en) |
SE (1) | SE462653B (en) |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2138804A (en) * | 1983-04-27 | 1984-10-31 | Sumitomo Chemical Co | Fungicidal N-phenylcarbamates |
GB2149394B (en) * | 1983-07-19 | 1986-09-24 | American Cyanamid Co | Ureas |
US4818899A (en) * | 1986-12-03 | 1989-04-04 | Minnesota Mining And Manufacturing Company | Second harmonic generation by carbamic acid derivatives |
US5116848A (en) * | 1988-03-30 | 1992-05-26 | Warner-Lambert Company | N-(((2,6-disubstituted)phenyl)-n-diarylalkyl)ureas as antihyperlipidemic and antiatherosclerotic agents |
EP0344425B1 (en) * | 1988-03-30 | 1993-12-08 | Warner-Lambert Company | N-[[(2,6-disubstituted)phenyl]-N'- arylalkyl] ureas as antihypercholesterolemic and antiatherosclerotic agents |
WO1991011994A1 (en) * | 1990-02-14 | 1991-08-22 | Chugai Seiyaku Kabushiki Kaisha | Inhibitor of denatured ldl formation |
US5668136A (en) * | 1990-09-25 | 1997-09-16 | Eisai Co., Ltd. | Trisubstituted benzene derivatives, composition and methods of treatment |
HUT62558A (en) * | 1991-07-01 | 1993-05-28 | Sandoz Ag | Process for producing n-phenylthiourea derivaties and pharmaceutical compositions comprising same |
HUT67475A (en) * | 1992-07-20 | 1995-04-28 | Eisai Co Ltd | Benzene derivatives and pharmaceutical compositions containing them as active components |
WO1999007672A1 (en) * | 1997-08-05 | 1999-02-18 | Novo Nordisk A/S | Derivatives of 2,5- and 3,5-disubstituted anilines, their preparation and use |
US6455566B1 (en) | 1997-09-03 | 2002-09-24 | Wyeth | Substituted 1-aryl-3-heteroaryl-thioureas (or isothioureas) as antiatherosclerotic agents |
TW415942B (en) * | 1997-09-03 | 2000-12-21 | American Home Prod | Novel substituted 1-aryl-3-heteroaryl-thioureas and substituted 1-aryl-3-heteroaryl-isothioureas as antiatherosclerotic agents |
CA2284864A1 (en) * | 1998-01-21 | 1999-07-29 | Zymogenetics, Inc. | Dialkyl ureas as calcitonin mimetics |
JP5504484B2 (en) * | 2007-07-10 | 2014-05-28 | アムジエン・インコーポレーテツド | Urea derivatives and related diamines, methods for their production and use |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL212631A (en) * | 1949-12-06 | |||
US2688039A (en) * | 1952-02-08 | 1954-08-31 | Ciba Pharm Prod Inc | Halogen-containing di-(substituted phenyl)-thioureas |
US3326663A (en) * | 1964-09-25 | 1967-06-20 | Shell Oil Co | Herbicidal phenylureas |
US3335142A (en) * | 1965-07-07 | 1967-08-08 | American Cyanamid Co | Process for the preparation of n, n'-disubstituted ureas |
US3659012A (en) * | 1969-05-26 | 1972-04-25 | Lilly Co Eli | Methods of treating helminth infections with thiourea derivatives |
US3728386A (en) * | 1970-07-27 | 1973-04-17 | Exxon Research Engineering Co | N-cycloalkylalkyl and n-cycloalkyl substituted phenyl ureas and halo acetamides |
US3928437A (en) * | 1970-09-02 | 1975-12-23 | Ciba Geigy Corp | Phenoxy-phenyl, phenylthiophenyl, phenylsulfonylphenyl and phenylaminophenyl diaminothioureas |
US3856952A (en) * | 1973-03-01 | 1974-12-24 | Pennwalt Corp | Synergistic antimicrobial compositions employing certain n-(phenyl-carbamyl)amino-benzene sulfonyl flourides |
US3903130A (en) * | 1974-05-03 | 1975-09-02 | Stauffer Chemical Co | 1-Trifluormethylphenyl-3-dicyanophenyl urea |
DE2928485A1 (en) * | 1979-07-14 | 1981-01-29 | Bayer Ag | USE OF UREA DERIVATIVES AS A MEDICINAL PRODUCT IN THE TREATMENT OF FATTY METABOLISM DISORDERS |
-
1982
- 1982-12-05 IL IL67417A patent/IL67417A/en not_active IP Right Cessation
- 1982-12-22 DE DE19823247581 patent/DE3247581A1/en not_active Withdrawn
- 1982-12-28 KR KR8205843A patent/KR890001808B1/en active
-
1983
- 1983-01-14 GR GR70261A patent/GR77186B/el unknown
- 1983-01-21 AU AU10681/83A patent/AU562699B2/en not_active Ceased
- 1983-01-24 GB GB08301863A patent/GB2113684B/en not_active Expired
- 1983-01-25 NL NL8300269A patent/NL8300269A/en not_active Application Discontinuation
- 1983-01-25 NO NO830238A patent/NO158417C/en unknown
- 1983-01-25 SE SE8300370A patent/SE462653B/en not_active IP Right Cessation
- 1983-01-25 PL PL1983240284A patent/PL143836B1/en unknown
- 1983-01-25 DK DK028683A patent/DK160869C/en not_active IP Right Cessation
- 1983-01-25 FR FR8301082A patent/FR2521134B1/en not_active Expired
- 1983-01-25 CH CH404/83A patent/CH654571A5/en not_active IP Right Cessation
- 1983-01-25 IT IT47605/83A patent/IT1203647B/en active
- 1983-01-25 PT PT76138A patent/PT76138A/en not_active IP Right Cessation
- 1983-01-25 AT AT0023983A patent/AT391313B/en not_active IP Right Cessation
- 1983-01-25 ES ES519246A patent/ES8406422A1/en not_active Expired
- 1983-01-25 HU HU83227A patent/HU200746B/en not_active IP Right Cessation
- 1983-01-25 IE IE146/83A patent/IE54683B1/en not_active IP Right Cessation
- 1983-01-25 FI FI830247A patent/FI85013C/en not_active IP Right Cessation
-
1984
- 1984-04-11 ES ES531508A patent/ES531508A0/en active Granted
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4473579A (en) | Antiatherosclerotic tetrasubstituted ureas and thioureas | |
US4387106A (en) | Method of treating atherosclerosis with di(aralkyl)ureas and di(aralkyl)thioureas | |
US4387105A (en) | Methods of treating atherosclerosis with dialkylureas and dialkylthioureas | |
US4623662A (en) | Antiatherosclerotic ureas and thioureas | |
IE54683B1 (en) | Antiatherosclerotic substituted ureas | |
US5612377A (en) | Method of inhibiting leukotriene biosynthesis | |
CS208663B2 (en) | Method of making the new r,s-n-/2-phenyl-2-hydroxyethyl0 -1-alkyl-3-/4-substituted phenyl/propylamines | |
US4397868A (en) | Method of treating atherosclerosis with trisubstituted ureas | |
CS655889A3 (en) | Anti-atherosclerotic active compounds, pharmaceuticals containing suchcompounds and process for preparing thereof | |
US5003106A (en) | Antiatherosclerotic ureas and thioureas | |
US4603145A (en) | Antiatherosclerotic diphenyl alkanamides | |
GB2149394A (en) | Ureas | |
US4198349A (en) | Benzylideneaniline derivatives | |
US5084457A (en) | Benzoylaminoquinazolinones | |
DE3415138A1 (en) | N- (AZOLYLCARBAMOYL) HYDROXYLAMINE AND FUNGICIDES CONTAINING THEM | |
US4450272A (en) | Antiatherosclerotic 1-piperazine-thicarboxamides | |
CA1291132C (en) | Anti-atherosclerotic trisubstituted ureas and thioureas | |
AU3985699A (en) | Amide therapeutics for the treatment of inflammatory bowel disease | |
US4547509A (en) | 5,6,7-Quinoline carbanilates and method of treating ischemic heart disease therewith | |
DE2021620A1 (en) | New phenylaminoalkanes and processes for their preparation | |
US5053426A (en) | Simplified thioester and isostere analogs of oleoyl coenzyme a as hypocholesterolemic agents | |
US4235929A (en) | Method of treatment | |
US5001157A (en) | Substituted N-[[2-(aminocarbonyl)phenylamino]thioxomethyl]benzamides | |
US4200648A (en) | Method of treatment | |
PL180668B1 (en) | Inhibition of biosynthesis |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM4A | Patent lapsed |