CA2472954C - Aza-arylpiperazines - Google Patents

Info

Publication number

CA2472954C

CA2472954C CA002472954A CA2472954A CA2472954C CA 2472954 C CA2472954 C CA 2472954C CA 002472954 A CA002472954 A CA 002472954A CA 2472954 A CA2472954 A CA 2472954A CA 2472954 C CA2472954 C CA 2472954C

Authority

CA

Canada

Prior art keywords

methyl

triaza

diabetes

fluorene

compound

Prior art date

2002-01-29

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Expired - Fee Related

Links

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• 150000001875 compounds Chemical class 0.000 claims abstract description 313
• 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 95
• 238000011282 treatment Methods 0.000 claims abstract description 78
• 230000002265 prevention Effects 0.000 claims abstract description 29
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 28
• 150000003839 salts Chemical class 0.000 claims abstract description 26
• 208000008589 Obesity Diseases 0.000 claims abstract description 23
• 235000020824 obesity Nutrition 0.000 claims abstract description 23
• 208000035475 disorder Diseases 0.000 claims abstract description 22
• 150000002148 esters Chemical class 0.000 claims abstract description 19
• 210000003169 central nervous system Anatomy 0.000 claims abstract description 9
• 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 7
• 208000018522 Gastrointestinal disease Diseases 0.000 claims abstract description 6
• 239000012453 solvate Substances 0.000 claims abstract description 6
• 201000002859 sleep apnea Diseases 0.000 claims abstract description 5
• 238000000034 method Methods 0.000 claims description 107
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 79
• 125000000217 alkyl group Chemical group 0.000 claims description 66
• -1 hydroxyalkoxyalkyl Chemical group 0.000 claims description 64
• 229940086609 Lipase inhibitor Drugs 0.000 claims description 54
• 239000001257 hydrogen Substances 0.000 claims description 51
• 229910052739 hydrogen Inorganic materials 0.000 claims description 51
• 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 39
• 239000003814 drug Substances 0.000 claims description 39
• 238000006243 chemical reaction Methods 0.000 claims description 32
• AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical group CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 claims description 31
• 229960001243 orlistat Drugs 0.000 claims description 29
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 27
• 125000006239 protecting group Chemical group 0.000 claims description 25
• 230000008569 process Effects 0.000 claims description 22
• 238000004519 manufacturing process Methods 0.000 claims description 21
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
• 201000001421 hyperglycemia Diseases 0.000 claims description 18
• 230000009467 reduction Effects 0.000 claims description 18
• 208000002249 Diabetes Complications Diseases 0.000 claims description 17
• 206010012655 Diabetic complications Diseases 0.000 claims description 17
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
• 208000016222 Pancreatic disease Diseases 0.000 claims description 17
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
• 150000003431 steroids Chemical class 0.000 claims description 17
• 206010022489 Insulin Resistance Diseases 0.000 claims description 16
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 16
• 238000011321 prophylaxis Methods 0.000 claims description 16
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
• 125000003545 alkoxy group Chemical group 0.000 claims description 13
• 125000001188 haloalkyl group Chemical group 0.000 claims description 13
• 229910052736 halogen Inorganic materials 0.000 claims description 13
• 150000002367 halogens Chemical group 0.000 claims description 13
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 13
• 238000002360 preparation method Methods 0.000 claims description 13
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
• 229910052799 carbon Inorganic materials 0.000 claims description 11
• 125000003342 alkenyl group Chemical group 0.000 claims description 10
• 150000001721 carbon Chemical group 0.000 claims description 10
• 229940079593 drug Drugs 0.000 claims description 9
• 239000008194 pharmaceutical composition Substances 0.000 claims description 9
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
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• 125000005081 alkoxyalkoxyalkyl group Chemical group 0.000 claims description 8
• 125000005080 alkoxycarbonylalkenyl group Chemical group 0.000 claims description 8
• 201000010064 diabetes insipidus Diseases 0.000 claims description 8
• VFLUBEQSNNICTK-WCABBAIRSA-N (1s)-1-[(5ar,9r)-9-methyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazin-2-yl]ethanol Chemical compound C1NC[C@@H](C)N2C3=NC([C@@H](O)C)=CC=C3C[C@@H]21 VFLUBEQSNNICTK-WCABBAIRSA-N 0.000 claims description 6
• RWHZKUHKJJABFU-VXNVDRBHSA-N (5ar,9r)-2-bromo-9-methyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound C1=C(Br)N=C2N3[C@H](C)CNC[C@H]3CC2=C1 RWHZKUHKJJABFU-VXNVDRBHSA-N 0.000 claims description 6
• 125000005127 aryl alkoxy alkyl group Chemical group 0.000 claims description 6
• 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 6
• 125000003118 aryl group Chemical group 0.000 claims description 6
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
• 208000030814 Eating disease Diseases 0.000 claims description 5
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• 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
• 235000014632 disordered eating Nutrition 0.000 claims description 5
• 229910052757 nitrogen Inorganic materials 0.000 claims description 5
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• 238000002560 therapeutic procedure Methods 0.000 claims description 5
• YCGIBRPJFAKJEZ-MWLCHTKSSA-N (5ar,9r)-2,9-dimethyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound C1=C(C)N=C2N3[C@H](C)CNC[C@H]3CC2=C1 YCGIBRPJFAKJEZ-MWLCHTKSSA-N 0.000 claims description 4
• IACZCHZSSZAVGU-VXNVDRBHSA-N (5ar,9r)-2-(difluoromethyl)-9-methyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound C1=C(C(F)F)N=C2N3[C@H](C)CNC[C@H]3CC2=C1 IACZCHZSSZAVGU-VXNVDRBHSA-N 0.000 claims description 4
• PYJAIOOKUMKWAJ-LDYMZIIASA-N (5ar,9r)-2-(fluoromethyl)-9-methyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound C1=C(CF)N=C2N3[C@H](C)CNC[C@H]3CC2=C1 PYJAIOOKUMKWAJ-LDYMZIIASA-N 0.000 claims description 4
• AUVNCNYPOJVIRZ-BXKDBHETSA-N (5ar,9r)-2-(methoxymethyl)-9-methyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound C1NC[C@@H](C)N2C3=NC(COC)=CC=C3C[C@@H]21 AUVNCNYPOJVIRZ-BXKDBHETSA-N 0.000 claims description 4
• OZKJKXGCRKEWKL-NTZNESFSSA-N (5ar,9r)-2-[(1s)-1-ethoxyethyl]-9-methyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound C1NC[C@@H](C)N2C3=NC([C@H](C)OCC)=CC=C3C[C@@H]21 OZKJKXGCRKEWKL-NTZNESFSSA-N 0.000 claims description 4
• SAODIZUAXCAGTK-JFGNBEQYSA-N (5ar,9r)-2-[(1s)-1-methoxyethyl]-9-methyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound C1NC[C@@H](C)N2C3=NC([C@H](C)OC)=CC=C3C[C@@H]21 SAODIZUAXCAGTK-JFGNBEQYSA-N 0.000 claims description 4
• PKOPGQYFQBKBPB-VXNVDRBHSA-N (5ar,9r)-2-chloro-9-methyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound C1=C(Cl)N=C2N3[C@H](C)CNC[C@H]3CC2=C1 PKOPGQYFQBKBPB-VXNVDRBHSA-N 0.000 claims description 4
• ZRNVRGJQVCODRO-BXKDBHETSA-N (5ar,9r)-2-cyclopropyl-9-methyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound C([C@@H]1CNC[C@H](N1C1=N2)C)C1=CC=C2C1CC1 ZRNVRGJQVCODRO-BXKDBHETSA-N 0.000 claims description 4
• GVCOTWGEKWXLPZ-SECBINFHSA-N (9r)-2,9-dimethyl-6,7,8,9-tetrahydropyrido[3,4]pyrrolo[3,5-a]pyrazine Chemical compound C1=C(C)N=C2N3[C@H](C)CNCC3=CC2=C1 GVCOTWGEKWXLPZ-SECBINFHSA-N 0.000 claims description 4
• MMOQJRSPKZSHHF-SSDOTTSWSA-N (9r)-2-chloro-5,9-dimethyl-6,7,8,9-tetrahydropyrido[3,4]pyrrolo[3,5-a]pyrazine Chemical compound C1=C(Cl)N=C2N3[C@H](C)CNCC3=C(C)C2=C1 MMOQJRSPKZSHHF-SSDOTTSWSA-N 0.000 claims description 4
• 208000007848 Alcoholism Diseases 0.000 claims description 4
• 208000000103 Anorexia Nervosa Diseases 0.000 claims description 4
• 208000019901 Anxiety disease Diseases 0.000 claims description 4
• 208000020925 Bipolar disease Diseases 0.000 claims description 4
• 208000032841 Bulimia Diseases 0.000 claims description 4
• 206010006550 Bulimia nervosa Diseases 0.000 claims description 4
• 206010008874 Chronic Fatigue Syndrome Diseases 0.000 claims description 4
• 206010012289 Dementia Diseases 0.000 claims description 4
• 208000026139 Memory disease Diseases 0.000 claims description 4
• 201000009906 Meningitis Diseases 0.000 claims description 4
• 208000019695 Migraine disease Diseases 0.000 claims description 4
• 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims description 4
• 206010036618 Premenstrual syndrome Diseases 0.000 claims description 4
• 208000028017 Psychotic disease Diseases 0.000 claims description 4
• 201000001880 Sexual dysfunction Diseases 0.000 claims description 4
• 206010041250 Social phobia Diseases 0.000 claims description 4
• 208000006011 Stroke Diseases 0.000 claims description 4
• 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 4
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
• 208000025748 atypical depressive disease Diseases 0.000 claims description 4
• 238000003776 cleavage reaction Methods 0.000 claims description 4
• 206010013663 drug dependence Diseases 0.000 claims description 4
• 206010014599 encephalitis Diseases 0.000 claims description 4
• 206010015037 epilepsy Diseases 0.000 claims description 4
• 125000004692 haloalkylcarbonyl group Chemical group 0.000 claims description 4
• 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 4
• 208000014674 injury Diseases 0.000 claims description 4
• 201000009941 intracranial hypertension Diseases 0.000 claims description 4
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 4
• 206010027599 migraine Diseases 0.000 claims description 4
• 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 claims description 4
• 230000004770 neurodegeneration Effects 0.000 claims description 4
• 208000015122 neurodegenerative disease Diseases 0.000 claims description 4
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
• 208000022821 personality disease Diseases 0.000 claims description 4
• 201000000484 premenstrual tension Diseases 0.000 claims description 4
• 201000000980 schizophrenia Diseases 0.000 claims description 4
• 230000007017 scission Effects 0.000 claims description 4
• 231100000872 sexual dysfunction Toxicity 0.000 claims description 4
• 208000019116 sleep disease Diseases 0.000 claims description 4
• 208000011117 substance-related disease Diseases 0.000 claims description 4
• 230000008733 trauma Effects 0.000 claims description 4
• LJRLAJVWAFFRLV-IAQYHMDHSA-N (5ar,9r)-2-(cyclopropylmethoxymethyl)-9-methyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound C([C@@H]1CNC[C@H](N1C1=N2)C)C1=CC=C2COCC1CC1 LJRLAJVWAFFRLV-IAQYHMDHSA-N 0.000 claims description 3
• HBPFKRQLQBROKQ-TYNCELHUSA-N (5ar,9r)-2-[(1s)-1-(cyclopropylmethoxy)ethyl]-9-methyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound O([C@@H](C)C=1N=C2N3[C@H](C)CNC[C@H]3CC2=CC=1)CC1CC1 HBPFKRQLQBROKQ-TYNCELHUSA-N 0.000 claims description 3
• CTPWPURTEYFXDP-VXNVDRBHSA-N (5ar,9r)-9-methyl-2-(trifluoromethyl)-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound C1=C(C(F)(F)F)N=C2N3[C@H](C)CNC[C@H]3CC2=C1 CTPWPURTEYFXDP-VXNVDRBHSA-N 0.000 claims description 3
• 208000027626 Neurocognitive disease Diseases 0.000 claims description 3
• 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 3
• 208000010643 digestive system disease Diseases 0.000 claims description 3
• 208000018685 gastrointestinal system disease Diseases 0.000 claims description 3
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
• 125000000335 thiazolyl group Chemical group 0.000 claims description 3
• PSZVQDFUQAGMRZ-BXKDBHETSA-N (5ar,9r)-2-ethyl-9-methyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound C1NC[C@@H](C)N2C3=NC(CC)=CC=C3C[C@@H]21 PSZVQDFUQAGMRZ-BXKDBHETSA-N 0.000 claims description 2
• GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 2
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 2
• 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
• 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 2
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
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• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 259
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 174
• 239000000543 intermediate Substances 0.000 description 132
• 239000003921 oil Substances 0.000 description 121
• 235000019198 oils Nutrition 0.000 description 121
• 239000000243 solution Substances 0.000 description 115
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 99
• 235000019439 ethyl acetate Nutrition 0.000 description 87
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 80
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 76
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 65
• 239000000047 product Substances 0.000 description 58
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 56
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• 239000000203 mixture Substances 0.000 description 45
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 43
• 239000000741 silica gel Substances 0.000 description 42
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• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 41
• 239000012267 brine Substances 0.000 description 41
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 41
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 41
• 239000002904 solvent Substances 0.000 description 40
• 235000019341 magnesium sulphate Nutrition 0.000 description 38
• 239000011541 reaction mixture Substances 0.000 description 37
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• 239000007787 solid Substances 0.000 description 35
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 30
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
• 239000012044 organic layer Substances 0.000 description 27
• USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 23
• 239000005695 Ammonium acetate Substances 0.000 description 23
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• 239000000725 suspension Substances 0.000 description 23
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• GXZXZZARSCCAGF-ZYHUDNBSSA-N tert-butyl (5ar,9r)-2-bromo-9-methyl-5a,6,8,9-tetrahydro-5h-pyrido[1,2]pyrrolo[4,5-a]pyrazine-7-carboxylate Chemical compound C1=C(Br)N=C2N3[C@H](C)CN(C(=O)OC(C)(C)C)C[C@H]3CC2=C1 GXZXZZARSCCAGF-ZYHUDNBSSA-N 0.000 description 20
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• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
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• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
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• 239000000460 chlorine Substances 0.000 description 13
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
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• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 12
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• 150000003512 tertiary amines Chemical class 0.000 description 1
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• WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
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• 229940029284 trichlorofluoromethane Drugs 0.000 description 1
• 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
• 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
• MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
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• 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
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• HGBOYTHUEUWSSQ-UHFFFAOYSA-N valeric aldehyde Natural products CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 1
• 235000015112 vegetable and seed oil Nutrition 0.000 description 1
• 239000008158 vegetable oil Substances 0.000 description 1
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
• 238000010792 warming Methods 0.000 description 1
• 238000005406 washing Methods 0.000 description 1
• 239000008215 water for injection Substances 0.000 description 1
• 239000001993 wax Substances 0.000 description 1
• 230000004580 weight loss Effects 0.000 description 1
• 229940002552 xenical Drugs 0.000 description 1