Claims for Patent: 8,461,178

Summary for Patent: 8,461,178

Title:	Naphthyridine derivatives and the use thereof as kinase inhibitors
Abstract:	The present invention relates to kinase modulators of the naphthyridine type and to the preparation and use thereof as medicaments for the modulation of misdirected cellular signal transduction processes, in particular for influencing the function of tyrosine and serine/threonine kinases and for the treatment of malignant or benign tumors and other disorders based on pathological cell proliferation, such as, for example, restenosis, psoriasis, arteriosclerosis and cirrhosis of the liver.
Inventor(s):	Schuster; Tilmann (Grossostheim, DE), Gerlach; Matthias (Brachttal, DE), Seipelt; Irene (Offenbach, DE), Polymeropoulos; Emmanuel (Frankfurt am Main, DE), Mueller; Gilbert (Frankfurt am Main, DE), Guenther; Eckhard (Maintal, DE), Marchand; Pascal (Nort-sur-Erdre, FR), Defaux; Julien (Dijon, FR)
Assignee:	Aeterna Zentaris GmbH (Frankfurt, DE)
Application Number:	12/953,680
Patent Claims:	1. A naphthyridine derivative of the general formula I ##STR00074## wherein R1 and R3 are independently hydrogen or NR7R8, wherein at least one of R1 and R3 is NR7R8 wherein R7 is hydrogen, R8 is --C(Y)NR9R10, Y is O or S, R9 is hydrogen and R10 can independently be (i) unsubstituted or substituted alkyl, (ii) unsubstituted or substituted cycloalkyl, (iii) unsubstituted or substituted heterocyclyl, (iv) unsubstituted or substituted aryl, (v) unsubstituted or substituted heteroaryl, R2 is (vi) hydrogen, (vii) unsubstituted or substituted alkyl, (viii) unsubstituted or substituted heterocyclyl, (ix) unsubstituted or substituted aryl, (x) unsubstituted or substituted heteroaryl, (xi) halogen, (xii) cyano, (xiii) hydroxyl, (xiv) alkoxy, (xv) amino, (xvi) carboxyl, alkoxycarbonyl, carboxyalkyl or alkoxycarbonylalkyl, (xvii) alkoxycarbonylamino, alkoxycarbonylaminoalkyl, and (xviii) NR7R8, wherein in R2 or R3 R7 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl, and the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl may be optionally substituted, and R8 is --C(Y)NR9R10, where Y is O or S and R9 and R10 are independently of one another (i) hydrogen, (ii) unsubstituted or substituted alkyl, (iii) unsubstituted or substituted cycloalkyl, (iv) unsubstituted or substituted heterocyclyl, (v) unsubstituted or substituted aryl, (vi) unsubstituted or substituted heteroaryl, (vii) or R9 and R10 together may be heterocyclyl, --C(Y)NR11R12, where Y is NH and R11 and R12 are independently of one another (i) hydrogen, (ii) unsubstituted or substituted alkyl, (iii) unsubstituted or substituted cycloalkyl, (iv) unsubstituted or substituted heterocyclyl, (v) unsubstituted or substituted aryl, (vi) unsubstituted or substituted heteroaryl, (vii) or R11 and R12 together may be heterocyclyl, --C(NR13)R14 where R13 is H and R14 is (i) unsubstituted or substituted alkyl, (ii) unsubstituted or substituted cycloalkyl, (iii) unsubstituted or substituted heterocyclyl, (iv) unsubstituted or substituted aryl, (v) unsubstituted or substituted heteroaryl, R5 is a unsubstituted or substituted heteroaryl, R4 and R6 are independently of one another: (i) hydrogen, (ii) unsubstituted or substituted alkyl, (iii) unsubstituted or substituted cycloalkyl, (iv) unsubstituted or substituted heterocyclyl, (v) unsubstituted or substituted aryl, (vi) unsubstituted or substituted heteroaryl, (vii) halogen, (viii) cyano, (ix) hydroxyl, (x) alkoxy, (xi) NR15R16, where R15 and R16 are, independently of each other, hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcyclyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl, and the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl are optionally substituted, or R15 and R16 are together heterocyclyl, where heterocyclyl is optionally substituted, (xii) OR17, where R17 can be alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl, and the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl are optionally substituted, (xiii) SR18, where R18 can be alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl, and the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl are optionally substituted, their physiologically acceptable salts, hydrates, solvates, where the compounds of the general formula (I) and their salts, hydrates or solvates may be present in the form of their racemates, enantiomers and/or diastereomers, or in the form of mixtures of the enantiomers and/or diastereomers, in the form of the tautomers and their polymorphic forms. 2. The naphthyridine derivative of the general formula I according to claim 1 in which R2 is (i) hydrogen, (ii) unsubstituted or substituted alkyl, (iii) unsubstituted or substituted heterocyclyl, (iv) unsubstituted or substituted aryl, (v) unsubstituted or substituted heteroaryl, (vi) halogen, (vii) cyano, (viii) hydroxyl, (ix) alkoxy, (x) amino, (xi) carboxyl, alkoxycarbonyl, carboxyalkyl or alkoxycarbonylalkyl, (xii) alkoxycarbonylamino, alkoxycarbonylaminoalkyl, and R4 and R6 are independently of one another: (i) hydrogen, (ii) unsubstituted or substituted alkyl, (iii) unsubstituted or substituted cycloalkyl, (iv) unsubstituted or substituted heterocyclyl, (v) unsubstituted or substituted aryl, (vi) unsubstituted or substituted heteroaryl, (vii) halogen, (viii) cyano, (ix) hydroxyl, (x) alkoxy, (xi) NR15R16, where R15 and R16 are, independently of each other, hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcyclyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl, and the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl are optionally substituted, or R15 and R16 are together heterocyclyl, where heterocyclyl is optionally subtituted, (xii) OR17, where R17 can be alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl, and the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl are optionally susbtituted, (xiii) SR18, where R18 can be alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl, and the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl are optionally susbtituted. 3. The naphthyridine derivative of the general formula I according to claim 1 in which R2 is (i) hydrogen, (ii) unsubstituted or substituted alkyl, R4 and R6 are independently of one another: (i) hydrogen, (ii) unsubstituted or substituted alkyl. 4. The naphthyridine derivative of the general formula I according to claim 1, selected from the group consisting of: TABLE-US-00002 # Structure Name 5 ##STR00075## 1-[7-(1-Methyl-1H-pyrazol-4-yl)- [1,5]naphthyridin-2-yl]-3-phenethyl- urea 10 ##STR00076## 1-Ethyl-3-[7-(1-methyl-1H-pyrazol-4- yl)-[1,5]naphthyridin-4-yl]-urea 11 ##STR00077## 1-tert-Butyl-3-[7-(1-methyl-1H-pyrazol- 4-yl)-[1,5]naphthyridin-4-yl]-urea 17 ##STR00078## 1-Cyclobutyl-3-[7-(1-methyl-1H- pyrazol-4-yl)-[1,5]naphthyridin-4-yl]- urea 18 ##STR00079## 1-Cyclopropyl-3-[7-(1-methyl-1H- pyrazol-4-yl)-[1,5]naphthyridin-4-yl]- urea 19 ##STR00080## 1-[7-(1-Methyl-1H-pyrazol-4-yl)- [1,5]naphthyridin-4-yl]-3-propyl-urea 20 ##STR00081## 1-[7-(1-Methyl-1H-pyrazol-4-yl)- [1,5]naphthyridin-4-yl]-3-(2,2,2- trifluoro-ethyl)-urea 21 ##STR00082## 1-[7-(1-Methyl-1H-pyrazol-4-yl)- [1,5]naphthyridin-4-yl]-3-(4-phenyl- butyl)-urea 22 ##STR00083## 1-Cyclohexyl-3-[7-(1-methyl-1H- pyrazol-4-yl)-[1,5]naphthyridin-4-yl]- urea 23 ##STR00084## 1-[7-(1-Methyl-1H-pyrazol-4-yl)- [1,5]naphthyridin-4-yl]-3-phenyl-urea 24 ##STR00085## 1-(3,3-Difluoro-cyclobutyl)-3-[7-(1- methyl-1H-pyrazol-4-yl)- [1,5]naphthyridin-4-yl]-urea 25 ##STR00086## 1-Hexyl-3-[7-(1-methyl-1H-pyrazol-4- yl)-[1,5]naphthyridin-4-yl]-urea 26 ##STR00087## 1-tert-Butyl-3-[7-(1-methyl-1H-pyrazol- 4-yl)-[1,5]naphthyridin-2-yl]-urea 27 ##STR00088## 1-[7-(1-Methyl-1H-pyrazol-4-yl)- [1,5]naphthyridin-2-yl]-3-phenyl-urea 28 ##STR00089## 1-Benzyl-3-[7-(1-methyl-1H-pyrazol-4- yl)-[1,5]naphthyridin-2-yl]-urea 29 ##STR00090## 1-[7-(1-Methyl-1H-pyrazol-4-yl)- [1,5]naphthyridin-2-yl]-3-(4-phenyl- butyl)-urea 30 ##STR00091## 1-Isopropyl-3-[7-(1-methyl-1H-pyrazol- 4-yl)-[1,5]naphthyridin-4-yl]-urea 31 ##STR00092## 1-Benzyl-3-[7-(1-methyl-1H-pyrazol-4- yl)-[1,5]naphthyridin-4-yl]-urea 32 ##STR00093## 1-Butyl-3-[7-(1-methyl-1H-pyrazol-4- yl)-[1,5]naphthyridin-4-yl]-urea 33 ##STR00094## 1-[7-(1-Methyl-1H-pyrazol-4-yl)- [1,5]naphthyridin-4-yl]-3-phenethyl- urea 34 ##STR00095## 1-Cyclopentyl-3-[7-(1-methyl-1H- pyrazol-4-yl)-[1,5]naphthyridin-4-yl]- urea 35 ##STR00096## 1-Cyclopropyl-3-[7-(1H-pyrazol-4-yl)- [1,5]naphthyridin-4-yl]-urea 36 ##STR00097## 1-Cyclopropyl-3-(7-thiophen-3-yl- [1,5]naphthyridin-4-yl)-urea 37 ##STR00098## 1-Cyclopropyl-3-[7-(2-fluoro-pyridin-4- yl)-[1,5]naphthyridin-4-yl]-urea 38 ##STR00099## 1-Cyclopropyl-3-{7-[1-(2-morpholin-4- yl-ethyl)-1H-pyrazol-4-yl]- [1,5]naphthyridin-4-yl}-urea 40 ##STR00100## 1-Cyclopropyl-3-[7-(1H-indol-5-yl)- [1,5]naphthyridin-4-yl]-urea. 5. A pharmaceutical composition comprising a pharmacologically active amount of at least one compound according to claim 1. 6. The pharmaceutical composition according to claim 5 further comprising at least one further pharmacologically active substance. 7. The pharmaceutical composition according to claim 5 further comprising a pharmaceutically acceptable carrier and/or auxiliary. 8. The pharmaceutical composition according to claim 7 wherein the additional pharmacologically active substance is selected from the group consisting of: asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin adriamycin), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thalidomide, thioguanine, topotecan, vinblastine, vincristine, vindesine, aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulphan, diethylstilbestrol, 2',2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine, ethynylestradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, oxaliplatin, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, vinorelbine, epothilone, gemcitabine, taxotere, BCNU, CCNU, DTIC, herceptin, avastin, erbitux, sorafenib (nexavar), imatinib (gleevec, glivec), gefitinib (iressa), erlotinib (tarceva), rapamycin, actinomycin D, sunitinib (sutent), dasatinib (sprycel), nilotinib (tasigna), lapatinib (tykerb, tyverb), vatalanib. 9. A process for preparing a medicament, comprising processing one or more naphthyridine derivatives according to claim 1 to a pharmaceutical preparation or converting the naphthyridine derivatives into a therapeutically usable form with pharmaceutically acceptable carriers and/or auxiliaries.

Details for Patent 8,461,178

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2029-11-26
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2029-11-26
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2029-11-26
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2029-11-26
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	03/28/2007		2029-11-26
Genentech, Inc.	AVASTIN	bevacizumab	Injection	125085	02/26/2004		2029-11-26