Claims for Patent: 7,015,328

Summary for Patent: 7,015,328

Title:	Substituted coumarins and quinolines and analogs as activators of caspases and inducers of apoptosis and the use thereof
Abstract:	The present invention is directed to substituted coumarins and quinolines and analogs thereof, represented by the general Formula I: ##STR00001## wherein A, B, X, Y, and Z are defined herein. The present invention also relates to the discovery that compounds having Formula I are activators of caspases and inducers of apoptosis. Therefore, the activators of caspases and inducers of apoptosis of this invention can be used to induce cell death in a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.
Inventor(s):	Cai; Sui Xiong (San Diego, CA), Zhang; Hong (San Diego, CA), Kemnitzer; William E. (San Diego, CA), Jiang; Songchun (San Diego, CA), Drewe; John (Carlsbad, CA), Storer; Richard (Pinner, GB)
Assignee:	Cytovia, Inc. (San Diego, CA) Shire BioChem Inc. (Laval, CA)
Application Number:	10/146,136
Patent Claims:	1. A compound of Formula IIB: ##STR00029## or a pharmaceutically acceptable salt or prodrug thereof, wherein: X is O; Y is CN, COR.sub.7, CO.sub.2R.sub.7 or CONR.sub.xR.sub.y, wherein R.sub.7, R.sub.x and R.sub.y are independently hydrogen, C.sub.1-10 alkyl, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl or aminoalkyl; or R.sub.x and R.sub.y are taken together with the nitrogen to which they are attached to form a heterocycle; Z is O, S, NR.sub.8, or NCOR.sub.8, wherein R.sub.8 is independently H, C.sub.1-4 alkyl or aryl; A is optionally substituted and is aryl, heteroaryl, saturated carbocyclic, partially saturated carbocylic, partially saturated heterocyclic, arylalkyl or heteroarylalkyl, wherein said heteroaryl is thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, dihydrobenzofuranyl, benzofuranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, .beta.-carbolinyl, phenanthridinyl, acrindinyl, perimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, 1,4-dihydroquinoxaline-2,3-dione, 7-aminoisocoumarin, pyrido[1,2-a]pyrimidin-4-one, 1,2-benzoisoxazol-3-yl, benzimidazolyl, 2-thio-4-oxo-2,4H-pyrimidyl, 2-oxindolyl and 2-oxobenzimidazolyl; and R.sub.1-R.sub.4 are independently hydrogen, halo, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, C.sub.1-10 alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, methylenedioxy, carbonylamido or alkylthiol; wherein one of R.sub.1 and R.sub.2, or R.sub.2 and R.sub.3, or R.sub.3 and R.sub.4, taken together with the atoms to which they are attached form an aryl, heteroaryl or partially saturated heterocyclic group, wherein said group is optionally substituted; optional substituents on the aryl, heteroaryl, saturated carbocyclic, partially saturated carbocyclic, saturated heterocyclic, and partially saturated heterocyclic groups are halo, C.sub.1-C.sub.6 haloalkyl, C.sub.6-C.sub.10 aryl, C.sub.4-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10 aryl(C.sub.1-C.sub.6)alkyl, C.sub.6-C.sub.10 aryl(C.sub.2-C.sub.6)alkenyl, C.sub.6-C.sub.10 aryl(C.sub.2-C.sub.6)alkynyl, C.sub.1-C.sub.6 hydroxyalkyl, nitro, amino, ureido, cyano, C.sub.1-C.sub.6 acylamino, hydroxy, thiol, C.sub.1-C.sub.6 acyloxy, azido, C.sub.1-C.sub.6 alkoxy or carboxy; and with the proviso that when A is phenyl, Y is cyano, and Z is oxo then R.sub.3-R.sub.4 cannot be taken together to form pyrido; and when A is phenyl, Y is cyano, Z is oxo and R.sub.3-R.sub.4 are taken together to form benzo, then optional substituents on benzo cannot be hydroxy. 2. The compound of claim 1, wherein A is optionally substituted and selected from the group consisting of phenyl, naphthyl, quinolyl, isoquinolyl, pyridyl, thienyl, furyl, pyrrolyl, 2-phenylethyl and cyclohexyl. 3. A compound of claim 1, wherein said compound has one of the Formulae III-IV: ##STR00030## or a pharmaceutically acceptable salt or prodrug thereof. 4. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and a compound of claim 1. 5. The pharmaceutical composition of claim 4, further comprising at least one known cancer chemotherapeutic agent, or a pharmaceutically acceptable salt of said agent. 6. The pharmaceutical composition of claim 5, wherein said known cancer chemotherapeutic agent is selected from the group consisting of busulfan, cis-platin, mitomycin C, carboplatin, colchicine, vinblastine, paclitaxel, docetaxel, camptothecin, topotecan, doxorubicin, etoposide, 5-azacytidine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxy-uridine, ara-C, hydroxyurea, thioguanine, melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen, trastuzumab, rituximab and alanosine. 7. The pharmaceutical composition of claim 4, wherein said excipient or carrier is selected from the group consisting of saccharides, starch pastes, gelatin, tragacanth, cellulose preparations, calcium phosphates and polyvinyl pyrrolidone. 8. The pharmaceutical composition of claim 4, wherein said excipient or carrier is a saccharide selected from the group consisting of lactose, sucrose, mannitol and sorbitol. 9. The pharmaceutical composition of claim 4, wherein said excipient or carrier is a lipophilic solvent. 10. The pharmaceutical composition of claim 9, wherein said lipophilic solvent is selected from the group consisting of fatty oils, fatty acid esters, polyethylene glycols and paraffin hydrocarbons. 11. The pharmaceutical composition of claim 9, wherein said lipophilic solvent is selected from the group consisting of sesame oil, ethyl oleate, triglycerides, polyethylene glycol-400, cremophor and cyclodextrins. 12. The pharmaceutical composition of claim 4, wherein said excipient or carrier is selected from the group consisting of vegetable oils, mineral oils, white petrolatum, branched chain fats, branched chain oils, animal fats and high molecular weight alcohol (greater than C.sub.12). 13. The pharmaceutical composition of claim 4, wherein said excipient or carrier is a saline solution. 14. A compound selected from the group consisting of: 3-Cyano-4-(3-methoxyphenyl)-2-oxo-2H-pyrrolo[2,3-h]chromene; 3-Cyano-2-imino-4-(5-methyl-pyridin-3-yl)-2H-pyrrolo[2,3-h]chromene; 3-Cyano-2-imino-7-methly-4-(5-methyl-pyridin-3-yl)-2H-pyrrolo[2,3-h]chrom- ene; 4-(3-Bromo-4,5-dimethoxy-phenyl)-3-cyano-2-imino-7-methyl-2H-pyrrolo- [2,3-h]chromene; 3-Cyano-4-(5-methyl-pyridin-3-yl)-2-oxo-2H-pyrrolo[2,3-h]chromene; 3-Cyano-4-(5-methyl-pyridin-3-yl)-7-methly-2-oxo-2H-pyrrolo[2,3-h]chromen- e; 4-(3-Bromo-4,5-dimethoxy-phenyl)-3-cyano-7-methyl-2-oxo-2H-pyrrolo[2,3- -h]chromene; 4-(3,5-Dimethoxyphenyl)-3-cyano-2-oxo-2H-pyrrolo[2,3-h]chromene; 4-(3-Bromo-4,5-dimethoxyphenyl)-3-cyano-7,8-dihydro-8,8-dimethyl-2-oxo-2H- -furo[3,2-h]chromene; 3-Cyano-4-(2,5-dimethoxyphenyl)-2-oxo-2H-pyrrolo[2,3-h]chromene; 3-Cyano-2-imino-7-methyl-4-(3-nitro-phenyl)-2H-pyrrolo[2,3-h]chromene; 3-Cyano-2-imino-7-methyl-4-(3,4,5-trimethoxy-phenyl)-2H-pyrrolo[2,3-h]chr- omene; 3-Cyano-4-(3,5-dimethoxy-phenyl)-2-imino-7-methyl-2H-pyrrolo[2,3-h- ]chromene; 3-Cyano-2-imino-4-(3-methoxy-4,5-methylenedioxyphenyl)-7-methyl-2H-pyrrol- o[2,3-h]chromene; 3-Cyano-2-imino-4-(3-methoxy-phenyl)-7-methyl-2H-pyrrolo[2,3-h]chromene; 3-Cyano-2-imino-4-(3-bromophenyl)-7-methyl-2H-pyrrolo[2,3-h]chromene; 3-Cyano-7-methyl-4-(3-nitro-phenyl)-2-oxo-2H-pyrrolo[2,3-h]chromene; 3-Cyano-4-(3,5-dimethoxy-phenyl)-7-methyl-2-oxo-2H-pyrrolo[2,3-h]chromene- ; 3-Cyano-4-(3-methoxy-4,5-methylenedioxyphenyl)-7-methyl-2-oxo-2H-pyrrol- o[2,3-h]chromene; 3-Cyano-4-(3-methoxy-phenyl)-7-methyl-2-oxo-2H-pyrrolo[2,3-h]chromene; 3-Cyano-4-(3-bromo-phenyl)-7-methyl-2-oxo-2H-pyrrolo[2,3-h]chromene; and 3-Cyano-7-methyl-4-(3,4,5-trimethoxy-phenyl)-2-oxo-2H-pyrrolo[2,3-h]chrom- ene. 15. A pharmaceutical composition comprising a compound of claim 14 and a pharmaceutically acceptable excipient or carrier. 16. A process for the preparation of a compound having Formula III: ##STR00031## wherein Y is CN, COR.sub.7, CO.sub.2R.sub.7 or CONR.sub.xR.sub.y, wherein R.sub.7, R.sub.x and R.sub.y are independently hydrogen, C.sub.1-10 alkyl, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl or aminoalkyl; or R.sub.x and R.sub.y are taken together with the nitrogen to which they are attached to form a heterocycle; A is optionally substituted and is aryl, heteroaryl, saturated carbocyclic, partially saturated carbocylic, saturated heterocyclic, partially saturated heterocyclic, arylalkyl or heteroarylalkyl; and R.sub.1-R.sub.4 are independently hydrogen, halo, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, C.sub.1-10 alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, methylenedioxy, carbonylamido or alkylthiol; wherein one of R.sub.1 and R.sub.2, or R.sub.2 and R.sub.3, or R.sub.3 and R.sub.4, taken together with the atoms to which they are attached, form an aryl, heteroaryl, partially saturated carbocyclic or partially saturated heterocyclic group, wherein said group is optionally substituted; the process comprising reacting a 2-aminobenzopyran having the formula: ##STR00032## with an oxidant in an organic solvent to produce a 2-imino-2H-chromene of Formula IV: ##STR00033## contacting said 2-imino-2H-chromene with an aqueous acid, and isolating the product of Formula III. 17. The process of claim 16, wherein said organic solvent is dichloromethane, chloroform, toluene or xylene. 18. The process of claim 16, wherein said aqueous acid is aqueous sulfuric, hydrochloric, nitric or hydrobromic acid. 19. The process of claim 16, wherein said oxidant is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), 2,3,5,6-tetrachloro-1,4-benzoquinone (chlorinal), bromine, palladium dichloride or ferric chloride.

Details for Patent 7,015,328

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2021-05-16
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2021-05-16
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2021-05-16
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2021-05-16
Genentech, Inc.	RITUXAN HYCELA	rituximab and hyaluronidase human	Injection	761064	06/22/2017		2021-05-16
Genentech, Inc.	HERCEPTIN HYLECTA	trastuzumab and hyaluronidase-oysk	Injection	761106	02/28/2019		2021-05-16