ZA200201156B - NSAID and EFGR kinase inhibitor containing composition for the treatment or inhibition of colonic polyps and colorectal cancer. - Google Patents
NSAID and EFGR kinase inhibitor containing composition for the treatment or inhibition of colonic polyps and colorectal cancer. Download PDFInfo
- Publication number
- ZA200201156B ZA200201156B ZA200201156A ZA200201156A ZA200201156B ZA 200201156 B ZA200201156 B ZA 200201156B ZA 200201156 A ZA200201156 A ZA 200201156A ZA 200201156 A ZA200201156 A ZA 200201156A ZA 200201156 B ZA200201156 B ZA 200201156B
- Authority
- ZA
- South Africa
- Prior art keywords
- carbon atoms
- alkyl
- phenyl
- carbon
- kinase inhibitor
- Prior art date
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- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 title claims description 60
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 title claims description 60
- 239000000203 mixture Substances 0.000 title claims description 35
- 230000005764 inhibitory process Effects 0.000 title claims description 13
- 206010009944 Colon cancer Diseases 0.000 title claims description 12
- 208000035984 Colonic Polyps Diseases 0.000 title claims description 11
- 208000001333 Colorectal Neoplasms Diseases 0.000 title claims description 11
- 229940043355 kinase inhibitor Drugs 0.000 title description 9
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 1222
- -1 ketoporfen Chemical compound 0.000 claims description 279
- 125000000217 alkyl group Chemical group 0.000 claims description 146
- 229940121647 egfr inhibitor Drugs 0.000 claims description 82
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 78
- 229910052739 hydrogen Inorganic materials 0.000 claims description 75
- 239000001257 hydrogen Substances 0.000 claims description 74
- 125000003342 alkenyl group Chemical group 0.000 claims description 72
- 125000000304 alkynyl group Chemical group 0.000 claims description 70
- 125000003545 alkoxy group Chemical group 0.000 claims description 62
- 150000002431 hydrogen Chemical class 0.000 claims description 61
- 238000000034 method Methods 0.000 claims description 60
- 229910052799 carbon Inorganic materials 0.000 claims description 57
- 229910052736 halogen Inorganic materials 0.000 claims description 55
- 150000002367 halogens Chemical group 0.000 claims description 55
- 125000003282 alkyl amino group Chemical group 0.000 claims description 51
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 51
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 51
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 50
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 50
- 125000004970 halomethyl group Chemical group 0.000 claims description 49
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 49
- 125000005042 acyloxymethyl group Chemical group 0.000 claims description 48
- 125000004414 alkyl thio group Chemical group 0.000 claims description 48
- 125000004849 alkoxymethyl group Chemical group 0.000 claims description 47
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 46
- 229910052757 nitrogen Inorganic materials 0.000 claims description 45
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 39
- 150000003254 radicals Chemical class 0.000 claims description 39
- 125000001424 substituent group Chemical group 0.000 claims description 39
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 37
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 35
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 35
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 34
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 32
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 31
- 239000000126 substance Substances 0.000 claims description 31
- 125000004076 pyridyl group Chemical group 0.000 claims description 30
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 27
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 26
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 25
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 21
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 20
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 20
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 19
- 125000004423 acyloxy group Chemical group 0.000 claims description 19
- 125000004429 atom Chemical group 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
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- 125000005422 alkyl sulfonamido group Chemical group 0.000 claims description 17
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 17
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- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 claims description 17
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 15
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 15
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 125000005118 N-alkylcarbamoyl group Chemical group 0.000 claims description 13
- 125000000033 alkoxyamino group Chemical group 0.000 claims description 13
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 13
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
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- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 7
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- MITFXPHMIHQXPI-UHFFFAOYSA-N Oraflex Chemical compound N=1C2=CC(C(C(O)=O)C)=CC=C2OC=1C1=CC=C(Cl)C=C1 MITFXPHMIHQXPI-UHFFFAOYSA-N 0.000 claims description 6
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (1)
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| US37326199A | 1999-08-12 | 1999-08-12 |
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| AT (1) | ATE341341T1 (enExample) |
| AU (1) | AU783116B2 (enExample) |
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| DE (1) | DE60031127T2 (enExample) |
| DK (1) | DK1202746T3 (enExample) |
| EA (1) | EA006876B1 (enExample) |
| ES (1) | ES2272305T3 (enExample) |
| HK (1) | HK1042244A1 (enExample) |
| HU (1) | HUP0203162A3 (enExample) |
| IL (1) | IL147913A0 (enExample) |
| MX (1) | MXPA02001448A (enExample) |
| NO (1) | NO20020663L (enExample) |
| NZ (1) | NZ517120A (enExample) |
| PL (1) | PL353267A1 (enExample) |
| PT (1) | PT1202746E (enExample) |
| WO (1) | WO2001012227A1 (enExample) |
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| US20040127470A1 (en) * | 1998-12-23 | 2004-07-01 | Pharmacia Corporation | Methods and compositions for the prevention or treatment of neoplasia comprising a Cox-2 inhibitor in combination with an epidermal growth factor receptor antagonist |
| WO2001068186A2 (en) * | 2000-03-13 | 2001-09-20 | American Cyanamid Company | Use of cyanoquinolines for treating or inhibiting colonic polyps |
| US6384051B1 (en) | 2000-03-13 | 2002-05-07 | American Cyanamid Company | Method of treating or inhibiting colonic polyps |
| EP1412367A4 (en) | 2001-06-21 | 2006-05-03 | Ariad Pharma Inc | NEW CHINOLINE AND ITS USE |
| ATE341545T1 (de) | 2001-07-16 | 2006-10-15 | Astrazeneca Ab | Quinolin-derivate und ihre verwendung als inhibitoren der tyrosine kinase |
| MXPA04003878A (es) * | 2001-10-25 | 2004-07-08 | Novartis Ag | Combinaciones que comprenden un inhibidor selectivo de cicloxigenasa-2. |
| US6924285B2 (en) | 2002-03-30 | 2005-08-02 | Boehringer Ingelheim Pharma Gmbh & Co. | Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them |
| AU2003250701A1 (en) | 2002-07-31 | 2004-02-16 | Wayne R. Danter | Protein tyrosine kinase inhibitors |
| ATE380810T1 (de) | 2002-10-09 | 2007-12-15 | Critical Outcome Technologies | Protein-tyrosine-kinase-inhibitoren |
| JP4606879B2 (ja) * | 2002-11-15 | 2011-01-05 | ジェノミック ヘルス， インコーポレイテッド | Ｅｇｆｒ陽性癌の遺伝子発現プロファイリング |
| WO2006074147A2 (en) | 2005-01-03 | 2006-07-13 | Myriad Genetics, Inc. | Nitrogen containing bicyclic compounds and therapeutical use thereof |
| US8309562B2 (en) | 2003-07-03 | 2012-11-13 | Myrexis, Inc. | Compounds and therapeutical use thereof |
| JP5129957B2 (ja) | 2003-07-03 | 2013-01-30 | ミリアド ジェネティクス， インコーポレイテッド | カスパーゼの活性化因子およびアポトーシスの誘発因子としての４−アリールアミノ−キナゾリン |
| GB0326459D0 (en) | 2003-11-13 | 2003-12-17 | Astrazeneca Ab | Quinazoline derivatives |
| TW200529846A (en) | 2004-02-20 | 2005-09-16 | Wyeth Corp | 3-quinolinecarbonitrile protein kinase inhibitors |
| MY143225A (en) | 2004-04-02 | 2011-03-31 | Osi Pharm Inc | 6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitors |
| AU2005231507B2 (en) | 2004-04-08 | 2012-03-01 | Targegen, Inc. | Benzotriazine inhibitors of kinases |
| RS52119B (sr) | 2004-05-06 | 2012-08-31 | Warner-Lambert Company Llc | 4-fenilamino-hinazolin-6-il-amidi |
| WO2005117916A1 (en) | 2004-06-03 | 2005-12-15 | F. Hoffmann-La Roche Ag | Treatment with cisplatin and an egfr-inhibitor |
| US8258145B2 (en) | 2005-01-03 | 2012-09-04 | Myrexis, Inc. | Method of treating brain cancer |
| JP5191391B2 (ja) | 2005-11-01 | 2013-05-08 | ターゲジェン インコーポレーティッド | キナーゼのビ−アリールメタ−ピリミジン阻害剤 |
| US8575164B2 (en) | 2005-12-19 | 2013-11-05 | OSI Pharmaceuticals, LLC | Combination cancer therapy |
| EP1921070A1 (de) | 2006-11-10 | 2008-05-14 | Boehringer Ingelheim Pharma GmbH & Co. KG | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstelllung |
| BRPI0807234A2 (pt) | 2007-02-06 | 2014-06-03 | Boehringer Ingelheim Int | Heterociclos bicíclicos, composições farmacêuticas que contêm estes compostos, o uso dos mesmos e processos para a preparação dos mesmos |
| EP2225226B1 (en) | 2007-12-26 | 2016-08-17 | Critical Outcome Technologies, Inc. | Compounds and their use in a method for treatment of cancer |
| KR20100111291A (ko) | 2008-02-07 | 2010-10-14 | 베링거 인겔하임 인터내셔날 게엠베하 | 스피로사이클릭 헤테로사이클, 상기 화합물을 함유하는 약제, 이의 용도 및 이의 제조 방법 |
| MY183041A (en) | 2008-05-13 | 2021-02-08 | Astrazeneca Ab | Fumarate salt of 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- {[1- (n-methylcarbamoylmethyl) piperidin- 4-yl] oxy}quinazoline |
| EP2283020B8 (en) | 2008-05-19 | 2012-12-12 | OSI Pharmaceuticals, LLC | Substituted imidazopyr-and imidazotri-azines |
| WO2010006438A1 (en) | 2008-07-17 | 2010-01-21 | Critical Outcome Technologies Inc. | Thiosemicarbazone inhibitor compounds and cancer treatment methods |
| CA2733153C (en) | 2008-08-08 | 2016-11-08 | Boehringer Ingelheim International Gmbh | Cyclohexyloxy substituted heterocycles, pharmaceutical compositions containing these compounds and processes for preparing them |
| PL387312A1 (pl) | 2009-02-19 | 2010-08-30 | Farma-Projekt Spółka Z Ograniczoną Odpowiedzialnością | Zastosowanie sulindaku i/lub jego metabolitu we wspomagającym leczeniu raka jelita grubego u ludzi |
| WO2010107968A1 (en) | 2009-03-18 | 2010-09-23 | Osi Pharmaceuticals, Inc. | Combination cancer therapy comprising administration of an egfr inhibitor and an igf-1r inhibitor |
| KR20120020099A (ko) | 2009-04-20 | 2012-03-07 | 오에스아이 파마슈티컬스, 엘엘씨 | Ｃ-피라진-메틸아민의 제조 |
| CA2794952C (en) | 2010-04-01 | 2018-05-15 | Critical Outcome Technologies Inc. | Compounds and method for treatment of hiv |
| AU2010363329A1 (en) | 2010-11-07 | 2013-05-09 | Targegen, Inc. | Compositions and methods for treating myelofibrosis |
| WO2012129145A1 (en) | 2011-03-18 | 2012-09-27 | OSI Pharmaceuticals, LLC | Nscle combination therapy |
| JP6093759B2 (ja) * | 2011-06-01 | 2017-03-08 | ジャナス バイオセラピューティクス，インク． | 新規の免疫系調節剤 |
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| YU25000A (sh) * | 1997-11-04 | 2003-12-31 | Pfizer Products Inc. | Indazol bioizoster zamena katehola u terapeutski aktivnim jedinjenjima |
| CN1278176A (zh) * | 1997-11-06 | 2000-12-27 | 美国氰胺公司 | 喹唑啉衍生物作为用于治疗结肠息肉的酪氨酸激酶抑制剂的应用 |
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2000
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- 2000-08-02 EP EP00950930A patent/EP1202746B1/en not_active Expired - Lifetime
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- 2000-08-02 MX MXPA02001448A patent/MXPA02001448A/es active IP Right Grant
- 2000-08-02 CN CNB008117977A patent/CN1229142C/zh not_active Expired - Fee Related
- 2000-08-02 JP JP2001516570A patent/JP2003507342A/ja active Pending
- 2000-08-02 PT PT00950930T patent/PT1202746E/pt unknown
- 2000-08-02 HK HK02104004.4A patent/HK1042244A1/zh unknown
- 2000-08-02 HU HU0203162A patent/HUP0203162A3/hu unknown
- 2000-08-02 AU AU63959/00A patent/AU783116B2/en not_active Ceased
- 2000-08-02 KR KR1020027001817A patent/KR20020018201A/ko not_active Ceased
- 2000-08-02 NZ NZ517120A patent/NZ517120A/en unknown
- 2000-08-02 DK DK00950930T patent/DK1202746T3/da active
- 2000-08-02 BR BR0013219-5A patent/BR0013219A/pt not_active IP Right Cessation
- 2000-08-02 ES ES00950930T patent/ES2272305T3/es not_active Expired - Lifetime
- 2000-08-02 PL PL00353267A patent/PL353267A1/xx not_active Application Discontinuation
- 2000-08-02 IL IL14791300A patent/IL147913A0/xx unknown
- 2000-08-02 EA EA200200246A patent/EA006876B1/ru not_active IP Right Cessation
- 2000-08-11 AR ARP000104159A patent/AR029763A1/es not_active Application Discontinuation
-
2002
- 2002-02-11 NO NO20020663A patent/NO20020663L/no not_active Application Discontinuation
- 2002-02-11 ZA ZA200201156A patent/ZA200201156B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO20020663L (no) | 2002-04-09 |
| WO2001012227A1 (en) | 2001-02-22 |
| PL353267A1 (en) | 2003-11-03 |
| DE60031127D1 (de) | 2006-11-16 |
| AU783116B2 (en) | 2005-09-29 |
| CA2380904A1 (en) | 2001-02-22 |
| EP1202746B1 (en) | 2006-10-04 |
| KR20020018201A (ko) | 2002-03-07 |
| EA200200246A1 (ru) | 2002-08-29 |
| AU6395900A (en) | 2001-03-13 |
| NO20020663D0 (no) | 2002-02-11 |
| ES2272305T3 (es) | 2007-05-01 |
| NZ517120A (en) | 2004-10-29 |
| HUP0203162A2 (hu) | 2003-01-28 |
| ATE341341T1 (de) | 2006-10-15 |
| CZ2002474A3 (cs) | 2003-02-12 |
| DE60031127T2 (de) | 2007-02-01 |
| PT1202746E (pt) | 2007-01-31 |
| DK1202746T3 (da) | 2007-01-02 |
| IL147913A0 (en) | 2002-08-14 |
| MXPA02001448A (es) | 2002-07-02 |
| CA2380904C (en) | 2009-02-10 |
| EA006876B1 (ru) | 2006-04-28 |
| EP1202746A1 (en) | 2002-05-08 |
| CN1370080A (zh) | 2002-09-18 |
| HUP0203162A3 (en) | 2006-07-28 |
| BR0013219A (pt) | 2002-04-23 |
| CN1229142C (zh) | 2005-11-30 |
| JP2003507342A (ja) | 2003-02-25 |
| HK1042244A1 (zh) | 2002-08-09 |
| AR029763A1 (es) | 2003-07-16 |
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