US20060004014A1 - 2-Benzylaminodihydropteridinones, process for their manufacture and use thereof as medicaments - Google Patents
2-Benzylaminodihydropteridinones, process for their manufacture and use thereof as medicaments Download PDFInfo
- Publication number
- US20060004014A1 US20060004014A1 US11/157,883 US15788305A US2006004014A1 US 20060004014 A1 US20060004014 A1 US 20060004014A1 US 15788305 A US15788305 A US 15788305A US 2006004014 A1 US2006004014 A1 US 2006004014A1
- Authority
- US
- United States
- Prior art keywords
- alkyl
- hydrogen
- optionally substituted
- group selected
- aryl
- Prior art date
- 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.)
- Abandoned
Links
- 0 [1*]C1([2*])C(=O)N([5*])C2=C(N=C(N([7*])C([4*])([10*])[11*])N=C2[6*])N1[3*] Chemical compound [1*]C1([2*])C(=O)N([5*])C2=C(N=C(N([7*])C([4*])([10*])[11*])N=C2[6*])N1[3*] 0.000 description 10
- GDOPTJXRTPNYNR-UHFFFAOYSA-N CC1CCCC1 Chemical compound CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 6
- UZJLYRRDVFWSGA-UHFFFAOYSA-N CC(=O)NCC1=CC=CC=C1 Chemical compound CC(=O)NCC1=CC=CC=C1 UZJLYRRDVFWSGA-UHFFFAOYSA-N 0.000 description 1
- ZELKSMDUSRIPPL-HNCPQSOCSA-N CC[C@@H]1C(=O)N(C)C2=CN=C(Cl)N=C2N1C1CCCC1.CN1CC(=O)N(C)C2=CN=C(Cl)N=C21 Chemical compound CC[C@@H]1C(=O)N(C)C2=CN=C(Cl)N=C2N1C1CCCC1.CN1CC(=O)N(C)C2=CN=C(Cl)N=C21 ZELKSMDUSRIPPL-HNCPQSOCSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
-
- 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
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
Definitions
- the present invention relates to new 2-benzylaminodihydropteridinones of general formula (I) wherein the groups R 1 to R 7 , R 10 and R 11 have the meanings given in the claims and specification, the isomers thereof, processes for preparing these dihydropteridinones and their use as medicaments.
- Pteridinone derivatives are known from the prior art as active substances with an antiproliferative activity.
- WO 01/019825 and WO 03/020722 describe the use of pteridinone derivatives for the treatment of tumoral diseases.
- Tumour cells wholly or partly elude regulation and control by the body and are characterised by uncontrolled growth. This is based on the one hand on the loss of control proteins, such as e.g. Rb, p16, p21 and p53 and also on the activation of so-called accelerators of the cell cycle, the cyclin-dependent kinases (CDK's).
- CDK's cyclin-dependent kinases
- Aurora B has been described as having an essential function during entry into mitosis.
- Aurora B phosphorylates histone H3 at Ser10 and thus initiates chromosome condensation (Hsu et al. 2000, Cell 102:279-91).
- a specific cell cycle arrest in the G2/M phase may however also be triggered e.g. by the inhibition of specific phosphatases such as e.g. Cdc25C (Russell and Nurse 1986. Cell 45:145-53).
- Cdc25C e.g. Cdc25C
- an arrest in the G2/M phase may also be triggered by the inhibition of certain motor proteins, the so-called kinesins such as e.g. Eg5 (Mayer et al. 1999, Science 286:971-4), or by agents which stabilise or destabilise microtubules (e.g. colchicin, taxol, etoposide, vinblastin, vincristine) (Schiff and Horwitz 1980, Proc Natl Acad Sci USA 77:1561-5).
- kinesins such as e.g. Eg5 (Mayer et al. 1999, Science 286:971-4)
- agents which stabilise or destabilise microtubules e.g. colchicin, taxol, etoposide, vinblastin, vincristine
- polo-like kinases In addition to the cyclin-dependent and Aurora kinases the so-called polo-like kinases, a small family of serine/threonine kinases, play an important part in the regulation of the eukaryotic cell cycle. Hitherto, the polo-like kinases PLK-1, PLK-2, PLK-3 and PLK-4 have been described in the literature. PLK-1 in particular has been shown to play a central part in the regulation of the mitosis phase. PLK-1 is responsible for the maturation of the centrosomes, for the activation of phosphatase Cdc25C, and for the activation of the Anaphase Promoting Complex (Glover et al. 1998, Genes Dev.
- tumours The resistance of many types of tumours calls for the development of new pharmaceutical compositions for combating tumours.
- the aim of the present invention is to provide new compounds having an antiproliferative activity.
- compounds of general formula (I) wherein the groups R 1 to R 7 , R 10 and R 11 have the meanings given hereinafter act as inhibitors of specific cell cycle kinases particularly the polo-like kinases.
- the compounds named have an antiproliferative activity, in that they arrest cells in the mitosis phase of the cell cycle before programmed cell death is initiated in the arrested cells.
- the compounds according to the invention may be used for example to treat diseases connected with the activity of specific cell cycle kinases and characterised by excessive or abnormal cell proliferation.
- the present invention therefore relates to compounds of general formula (I) wherein
- R 1 , R 2 which may be identical or different, denote a group selected from among optionally substituted C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl, aryl, heteroaryl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, —X-aryl, —X-heteroaryl, —X-cycloalkyl, —X-heterocycloalkyl, —NR 8 -aryl, —NR 8 -heteroaryl, —NR 8 -cycloalkyl, and —NR 8 -heterocycloalkyl, or
- R 1 and R 2 together denote a 2- to 5-membered alkyl bridge which may contain 1 to 2 heteroatoms
- R 3 denotes hydrogen or a group selected from among optionally substituted C 1 -C 12 -alkyl, C 2 -C 12 -alkenyl, C 2 -C 12 -alkynyl, aryl, heteroaryl, C 3 -C 12 -cycloalkyl, C 3 -C 12 -cycloalkenyl, C 7 -C 12 -polycycloalkyl, C 7 -C 12 -polycycloalkenyl and C 5 -C 12 -spirocycloalkyl or
- R 1 and R 3 or R 2 and R 3 together denote a saturated or unsaturated C 3 -C 4 -alkyl bridge which may contain 1 to 2 heteroatoms,
- R 4 denotes optionally substituted aryl or heteroaryl
- R 5 denotes a group selected from among hydrogen, CHO, XH, —X—C 1 -C 2 -alkyl and an optionally substituted C 1 -C 3 -alkyl group,
- R 6 denotes a group selected from among hydrogen, NH 2 , XH, halogen and a C 1 -C 3 -alkyl group optionally substituted by one or more halogen atoms,
- R 7 denotes hydrogen or —CO—C 1 -C 4 -alkyl, —CO—NH—C 1 -C 4 -alkyl, -CO-X-C 1 -C 4 -alkyl, and
- X in each case independently of one another denote O or S
- R 8 in each case independently of one another denote hydrogen or a group selected from among optionally substituted C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, benzyl and phenyl,
- R 10 and R 11 in each case independently of one another denote hydrogen or a group selected from among optionally substituted C 1 -C 4 -alkyl,
- R 10 and R 11 together denote a 2-5 membered alkyl bridge
- R 1 to R 4 have the meanings specified
- R 5 denotes methyl
- R 6 and R 7 denote hydrogen
- R 10 and R 11 in each case independently of one another denote hydrogen or methyl
- R 3 to R 7 , R 10 and R 11 have the meanings given above and R 1 , R 2 which may be identical or different denote hydrogen or a group selected from among optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, and C 2 -C 6 -alkynyl, or
- R 1 and R 2 together denote a 2- to 5-membered alkyl bridge.
- R 1 , R 3 , R 4 to R 7 , R 10 and R 11 have the meanings given above, and
- R 3 is hydrogen or contains a group, selected from among optionally substituted C 1 -C 12 -alkyl, C 2 -C 12 -alkenyl, C 2 -C 12 -alkynyl and C 6 -C 14 -aryl, or a group selected from among optionally substituted and/or bridged C 3 -C 12 -cycloalkyl, C 3 -C 12 -cycloalkenyl, C 7 -C 12 -polycycloalkyl, C 7 -C 12 -polycycloalkenyl and C 5 -C 12 -spirocycloalkyl.
- R 4 denotes a group of general formula
- R 9 which may be identical or different, denotes a group selected from among optionally substituted C 1 l-C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, —O—C 1 l-C 6 -alkyl, —O—C 2 -C 6 -alkenyl, —O—C 2 -C 6 -alkynyl, C 3 -C 6 -heterocycloalkyl, C 3 -C 6 -cycloalkyl, aryl, heteroaryl, —O-aryl, —O-heteroaryl, —O-cycloalkyl, and —O -heterocycloalkyl or a group selected from among hydrogen, —CONH 2 , —COOR 8 , —OCON(R 8 ) 2 , —N(R 8 ) 2 , —NHCOR 8 , —NHCON(R
- Q 1 denotes hydrogen, —NHCOR 8 , or a group selected from among an optionally substituted —NH-aryl, —NH-heteroaryl, aryl, heteroaryl, C 3 -C 8 -cycloalkyl and heterocycloalkyl group,
- Q 2 denotes hydrogen or a group selected from among an optionally substituted aryl, heteroaryl and C 3 -C 8 -cycloalkyl group, and
- n denotes 0, 1, 2, 3, 4 or 5.
- R 1 , R 2 which may be identical or different, denote hydrogen or a group selected from among methyl, ethyl, propyl, allyl and propargyl or
- R 1 and R 2 together denote cyclopropyl
- R 3 denotes hydrogen, or optionally substituted C 1 -C 6 -alkyl or optionally substituted and/or bridged C 3 -C 12 -cycloalkyl, and
- R 10 and R 11 represent hydrogen.
- R 9 which may be identical or different, denote hydrogen or a group selected from among halogen, (C 1 -C 6 -alkyl) 2 N, CF 3 , NH 2 SO 2 , —CONH—C 6 -C 14 -aryl, —CONH—C 1 -C 4 -alkyl-C 6 -C 14 -aryl and —O—C 1 -C 4 -alkyl.
- the invention further relates to compounds of formula (I) for use as pharmaceutical compositions.
- the invention also relates to the use of a compound of formula (I) for preparing a pharmaceutical composition for the treatment and/or prevention of diseases selected from among cancer, bacterial and viral infections, inflammatory and autoimmune diseases, chemotherapy-induced alopecia and mucositis, cardiovascular diseases, nephrological diseases, as well as chronic and acute neurodegenerative diseases, preferably for the treatment of cancer, inflammatory and autoimmune diseases, particularly preferably for the treatment of cancer and inflammatory diseases.
- diseases selected from among cancer, bacterial and viral infections, inflammatory and autoimmune diseases, chemotherapy-induced alopecia and mucositis, cardiovascular diseases, nephrological diseases, as well as chronic and acute neurodegenerative diseases, preferably for the treatment of cancer, inflammatory and autoimmune diseases, particularly preferably for the treatment of cancer and inflammatory diseases.
- the invention further relates to the use of a compound of formula (I) for preparing a pharmaceutical composition for inhibiting the polo-like kinases, particularly the polo-like kinase PLK-1.
- the invention further relates to the use of a compound of formula (I) for preparing a pharmaceutical composition for the treatment and/or prevention of tumour diseases based on the overexpression of the polo-like kinases, particularly the PLK-1 kinases.
- the invention further relates to a method for the treatment and/or prevention of diseases selected from among cancer, bacterial and viral infections, inflammatory and autoimmune diseases, chemotherapy-induced alopecia and mucositis, cardiovascular diseases, nephrological diseases, as well as chronic and acute neurodegenerative diseases, preferably for the treatment of cancer, inflammatory and autoimmune diseases, particularly preferably for the treatment of cancer and inflammatory diseases, in which an effective amount of a compound of formula (I) is administered to a patient.
- diseases selected from among cancer, bacterial and viral infections, inflammatory and autoimmune diseases, chemotherapy-induced alopecia and mucositis, cardiovascular diseases, nephrological diseases, as well as chronic and acute neurodegenerative diseases, preferably for the treatment of cancer, inflammatory and autoimmune diseases, particularly preferably for the treatment of cancer and inflammatory diseases, in which an effective amount of a compound of formula (I) is administered to a patient.
- the invention also relates to pharmaceutical preparations, containing as active substance one or more compounds of general formula (I) optionally combined with conventional excipients and/or carriers.
- alkyl groups including alkyl groups which are a part of other groups, denotes branched and unbranched alkyl groups with 1 to 12 carbon atoms, preferably 1-6, most preferably 1-4 carbon atoms, such as, for example: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl.
- propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl include all the possible isomeric forms.
- propyl includes the two isomeric groups n-propyl and iso-propyl
- butyl includes n-butyl, iso-butyl, sec. butyl and tert.-butyl
- pentyl includes iso-pentyl, neopentyl, etc.
- alkyl groups one or more hydrogen atoms may optionally be replaced by other groups.
- these alkyl groups may be substituted by methyl, chlorine or fluorine, preferably fluorine. All the hydrogen atoms of the alkyl group may optionally also be replaced.
- alkyl bridge denotes branched and unbranched alkyl groups with 2 to 5 carbon atoms, for example ethylene, propylene, isopropylene, n-butylene, iso-butyl, sec. butyl and tert.-butyl etc. bridges. Ethylene, propylene and butylene bridges are particularly preferred.
- 1 to 2 C-atoms may optionally be replaced by one or more heteroatoms selected from among oxygen, nitrogen or sulphur.
- alkenyl groups denotes branched and unbranched alkylene groups with 2 to 10 carbon atoms, preferably 2-6 carbon atoms, most preferably 2-3 carbon atoms, provided that they have at least one double bond. Examples include: ethenyl, propenyl, butenyl, pentenyl etc. Unless otherwise stated, the abovementioned terms propenyl, butenyl, etc also include all the possible isomeric forms.
- butenyl includes 1-butenyl, 2-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl and 1-ethyl-1-ethenyl.
- alkenyl groups unless otherwise stated, one or more hydrogen atoms may optionally be replaced by other groups.
- these alkenyl groups may be substituted by methyl, chlorine or fluorine, preferably fluorine. All the hydrogen atoms of the alkenyl group may optionally also be replaced.
- alkynyl groups denotes branched and unbranched alkynyl groups with 2 to 10 carbon atoms, provided that they have at least one triple bond, for example ethynyl, propargyl, butynyl, pentynyl, hexynyl etc., preferably ethynyl or propynyl.
- one or more hydrogen atoms may optionally be replaced by other groups.
- these alkynyl groups may be substituted by methyl, chlorine or fluorine, preferably fluorine. All the hydrogen atoms of the alkynyl group may optionally also be replaced.
- aryl denotes an aromatic ring system with 6 to 14 carbon atoms, preferably 6 or 10 carbon atoms, preferably phenyl, which, unless otherwise stated, may carry one or more of the following substituents, for example: OH, NO 2 , CN, OMe, —OCHF 2 , —OCF 3 , —NH 2 , halogen, preferably fluorine or chlorine, C 1 -C 10 -alkyl, preferably C 1 -C 5 -alkyl, preferably C 1 -C 3 -alkyl, particularly preferably methyl or ethyl, —O—C 1 -C 3 -alkyl, preferably —O-methyl or —O-ethyl, —COOH, —COO—C 1 -C 4 -alkyl, preferably —O-methyl or —O-ethyl, or —CONH 2 .
- heteroaryl groups wherein up to two C atoms are replaced by one or two nitrogen atoms are, for example, pyrrole, pyrazole, imidazole, triazole, pyridine, pyrimidine, while each of the above-mentioned heteroaryl rings may optionally also be anellated to a benzene ring, preferably benzimidazole, and these heterocycles, unless stated to the contrary, may for example carry one or more of the following substituents: F, Cl, Br, OH, OMe, methyl, ethyl, CN, CONH 2 , NH 2 , optionally substituted phenyl, optionally substituted heteroaryl, preferably optionally substituted pyridyl.
- cycloalkyl groups are cycloalkyl groups with 3-12 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, preferably cyclopropyl, cyclopentyl or cyclohexyl, while each of the above-mentioned cycloalkyl groups may optionally also carry one or more substituents, for example: OH, NO 2 , CN, OMe, —OCHF 2 , —OCF 3 , —NH 2 or halogen, preferably fluorine or chlorine, C 1 -C 10 -alkyl, preferably C 1 -C 5 -alkyl, preferably C 1 -C 3 -alkyl, particularly preferably methyl or ethyl, —O—C 1 -C 3 -alkyl, preferably —O-methyl or —O-e
- cycloalkenyl groups are cycloalkyl groups with 3-12 carbon atoms which have at least one double bond, for example cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, preferably cyclopropenyl, cyclopententyl or cyclohexenyl, while each of the above-mentioned cycloalkenyl groups may optionally also carry one or more substituents.
- ⁇ O denotes an oxygen atom linked by a double bond.
- heterocycloalkyl groups are 3 to 12 membered, preferably 5-, 6- or 7-membered, saturated or unsaturated heterocycles, which may contain as heteroatoms nitrogen, oxygen or sulphur, for example tetrahydrofuran, tetrahydrofuranone, ⁇ -butyrolactone, ⁇ -pyran, ⁇ -pyran, dioxolane, tetrahydropyran, dioxane, dihydrothiophene, thiolane, dithiolane, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetrazole, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine, thiomorpholine, diazepan, oxazine, tetrahydro-o
- polycycloalkyl groups are optionally substituted, bi-, tri-, tetra- or pentacyclic cycloalkyl groups, for example pinane, 2,2,2-octane, 2,2,1-heptane or adamantane.
- polycycloalkenyl groups are optionally bridged and/or substituted, 8- membered bi-, tri-, tetra- or pentacyclic cycloalkenyl groups, preferably bicycloalkenyl or tricycloalkenyl groups, if they contain at least one double bond, for example norbornene.
- spiroalkyl groups are optionally substituted spirocyclic C 5 -C 12 alkyl groups.
- halogen generally denotes fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, particularly preferably chlorine.
- the compounds according to the invention may be present in the form of the individual optical isomers, mixtures of the individual enantiomers, diastereomers or racemates, in the form of the tautomers, in the form of the solvates, preferably in the form of the hydrates thereof and also in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids—such as for example acid addition salts with hydrohalic acids, for example hydrochloric or hydrobromic acid, or organic acids, such as for example oxalic, fumaric, diglycolic or methanesulphonic acid.
- pharmacologically acceptable acids such as for example acid addition salts with hydrohalic acids, for example hydrochloric or hydrobromic acid, or organic acids, such as for example oxalic, fumaric, diglycolic or methanesulphonic acid.
- the substituent R 1 may be a group selected from among optionally substituted C 1 -C 10 -alkyl, preferably C 1 -C 4 -alkyl, particularly preferably methyl, ethyl or propyl, C 2 -C 10 -alkenyl, preferably allyl, C 2 -C 10 -alkynyl, preferably propargyl, aryl, heteroaryl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloal kyl, —X-aryl, —X-heteroaryl, —X-cycloalkyl, —X-heterocycloalkyl, —NR 8 -aryl, —NR 8 -heteroaryl, —NR 8 -cycloalkyl, and —NR 8 -heterocycloalkyl, or a group selected from among hydrogen, halogen, COXR 8 , CON(R 8 ) 2
- the substituent R 1 denotes ethyl or hydrogen, particularly preferably hydrogen.
- the substituent R 2 may represent a group selected from among optionally substituted C 1 -C 10 -alkyl, preferably C 1 -C 4 -alkyl, particularly preferably methyl, ethyl or propyl, C 2 -C 10 -alkenyl, preferably allyl, C 2 -C 10 -alkynyl, preferably propargyl, aryl, heteroaryl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, —X-aryl, —X-heteroaryl, —X-cycloalkyl, —X-heterocycloalkyl, —NR 8 -aryl, —NR 8 -heteroaryl, —NR 8 -cycloalkyl, and —NR 8 -heterocycloalkyl, or a group selected from among hydrogen, halogen, COXR 8 , CON(R 8 ) 2
- the substituent R 2 denotes ethyl or hydrogen, particularly preferably ethyl.
- the substituents R 1 and R 2 may together denote a 2- to 5-membered alkyl bridge, preferably a 2-membered alkyl bridge which may contain 1 to 2 heteroatoms, for example oxygen, sulphur or nitrogen, preferably oxygen or nitrogen.
- the substituent R 3 may denote hydrogen or a group selected from among optionally substituted C 1 -C 12 -alkyl, preferably C 1 -C 6 -alkyl, C 2 -C 12 -alkenyl, C 2 -C 12 -alkynyl, aryl, heteroaryl, —C 3 -C 12 -cycloalkyl, C 3 -C 12 -cycloalkenyl, C 7 -C 12 -polycycloalkyl, C 7 -C 12 -polycycloalkenyl and C 5 -C 12 -spirocycloalkyl or R 1 and R 3 or R 2 and R 3 together denote a saturated or unsaturated C 3 -C 4 -alkyl bridge which may contain 1 to 2 heteroatoms.
- the substituent R 3 denotes C 1 -C 6 -alkyl or —C 3 -C 12 -cycloalkyl, particularly preferably methyl or cyclopentyl.
- the substituent R 4 may represent optionally substituted aryl or heteroaryl, preferably a group of general formula
- the index n may represent 0, 1, 2, 3, 4 or 5, preferably 1 or 2, particularly preferably 1.
- the substituent R 5 may represent a group selected from among hydrogen, halogen, CHO, XH, —X—C 1 -C 2 -alkyl and an optionally substituted C 1 -C 3 -alkyl group, preferably methyl.
- the substituent R 5 denotes methyl
- the substituent R 6 may represent a group selected from among hydrogen, NH 2 , XH, halogen and a C 1 -C 3 -alkyl group optionally substituted by one or more halogen atoms.
- the substituent R 6 denotes hydrogen
- the substituent R 7 may represent hydrogen, —CO—X—C 1 -C 4 -alkyl, preferably —CO—O-methyl or —CO—O-ethyl, —CO—NH—C 1 -C 4 -alkyl, preferably —CO—NH-methyl or —CO—NH-ethyl, or —CO—C 1 -C 4 -alkyl, preferably —CO-methyl.
- the substituent R 7 denotes hydrogen.
- X may in each case independently of one another denote oxygen or sulphur, preferably oxygen.
- the substituent R 8 may in each case independently of one another denote hydrogen or a group selected from among optionally substituted C 1 -C 4 -alkyl, preferably methyl or ethyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, benzyl and phenyl.
- the substituent R 8 denotes methyl, phenyl or benzyl.
- the substituent R 9 which may be identical or different, may denote a group selected from among optionally substituted C 1 -C 6 -alkyl, preferably methyl, ethyl or isopropyl, C 2 -C 6 -alkenyl, preferably allyl or homoallyl, C 2 -C 6 -alkynyl, preferably propargyl —O—C 1 -C 6 -alkyl, preferably —O-methyl or —O-ethyl, —O—C 2 -C 6 -alkenyl, —O—C 2 -C 6 -alkynyl, C 3 -C 6 -heterocycloalkyl, preferably piperazinyl, morpholinyl, pyrrolidinyl or piperidinyl, C 3 -C 6 -cycloalkyl, preferably cyclopropyl, cyclopentyl or cyclohexyl, aryl, preferably
- the substituent R 9 denotes —CONR 8 -Q 2 or —CONR 8 OC 1 —C 10 -alkyl-Q 1 .
- R 10 and R 11 may in each case independently of one another denote hydrogen or optionally substituted C 1 -C 4 -alkyl, preferably hydrogen or methyl, or
- R 10 and R 11 may together denote a 2-5 membered alkyl bridge, preferably a 2-membered alkyl bridge.
- substituents R 10 and R 11 denote hydrogen.
- Q 1 may represent hydrogen, —NHCOR 8 or a group selected from among an optionally substituted —NH-aryl, —NH-heteroaryl, aryl, preferably phenyl, heteroaryl, C 3 -C 8 -cycloalkyl and heterocycloalkyl group.
- Q 2 may represent hydrogen or a group selected from among an optionally substituted aryl, preferably phenyl, heteroaryl and C 3 -C 8 -cycloalkyl group.
- R 1 to R 9 may optionally be branched and/or substituted.
- the compounds of general formula (I) may be prepared by the following method of synthesis, while the substituents of general formulae (A1), (A2) and (I) are as hereinbefore defined. This method is to be understood as illustrating the invention without restricting it to the object thereof.
- a compound of formula (A1) is reacted with an optionally substituted benzylamine (A2) to obtain general formula (I).
- the compounds of formula (A1) may be obtained as described on page 23 of WO 2003/020722.
- Enantiomerically pure compounds (A1) with respect to the stereochemistry at R1/R2 may also be obtained analogously to the process described therein.
- the 4-aminomethyl-N-benzylbenzamide used may be obtained e.g. according to the following reference: H. G. Kazmirowski, P. Neuland, H. Landmann, F. Markwardt Pharnazie 1967, 22(9), 465-70.
- the new compounds of general formula (I) may be prepared analogously to the following Examples.
- the compounds of general formula (I) are characterised by their wide range of applications in the therapeutic field. Particular mention should be made of those applications in which the inhibition of specific cell cycle kinases, particularly the inhibiting effect on the proliferation of cultivated human tumour cells but also the proliferation of other cells, such as endothelial cells, for example, plays a part.
- the inhibition of proliferation brought about by the compounds according to the invention is mediated by the arrest of the cells, particularly at the G2/M phase of the cell cycle.
- the cells arrest depending on the cells used, for a specific length of time in this phase of the cell cycle before programmed cell death is initiated.
- An arrest in the G2/M phase of the cell cycle is triggered, for example, by the inhibition of specific cell cycle kinases.
- the compounds of general formula I according to the invention their isomers and their physiologically acceptable salts are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation.
- Such diseases include, for example: viral infections (e.g. HIV and Kaposi's sarcoma); inflammatory and autoimmune diseases (e.g. colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and/or parasitic infections; leukaemias, lymphoma and solid tumours; skin diseases (e.g. psoriasis); bone diseases; cardiovascular diseases (e.g. restenosis and hypertrophy). They are also suitable for protecting proliferating cells (e.g. hair, intestinal, blood and progenitor cells) from damage to their DNA caused by radiation, UV treatment and/or cytostatic treatment (Davis et al., 2001).
- viral infections e.g. HIV and Kaposi's sarcoma
- inflammatory and autoimmune diseases e.g. colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing
- bacterial, fungal and/or parasitic infections e.g. colitis, arthritis,
- the new compounds may be used for the prevention, short-term or long-term treatment of the abovementioned diseases, also in combination with other active substances used for the same indications, e.g. cytostatics, hormones or antibodies.
- the activity of the compounds according to the invention was determined in the PLK1 inhibition assay, in the cytotoxicity test on cultivated human tumour cells and/or in a FACS analysis, for example on HeLaS3 cells.
- the compounds exhibited a good to very good activity, i.e. for example an EC 50 value in the HeLaS3 cytotoxicity test of less than 5 ⁇ mol/L, generally less than 1 ⁇ mol/L and an IC 50 value in the PLK1 inhibition assay of less than 1 ⁇ mol/L.
- Recombinant human PLK1 enzyme attached to GST at its N-terminal end is isolated from Baculovirus-infected insect cells (Sf21). Purification is carried out by affinity chromatography on glutathione sepharose columns.
- the cell number is determined, the cells are removed by centrifuging (5 minutes, 4° C., 800 rpm) and washed 1 ⁇ with PBS (8 g NaCl/I, 0.2 g KCl/I, 1.44 g Na 2 HPO 4 /I, 0.24 g KH 2 PO4/I). After centrifuging again the pellet is flash-frozen in liquid nitrogen.
- the pellet is quickly thawed and resuspended in ice-cold lysing buffer (50 mM HEPES pH 7.5, 10 mM MgCl 2 , 1 mM DTT, 5 ⁇ g/ml leupeptin, 5 ⁇ g/ml aprotinin, 100 ⁇ M NaF, 100 ⁇ M PMSF, 10 mM ⁇ -glycerolphosphate, 0.1 mM Na 3 VO 4 , 30 mM 4-nitrophenylphosphate) to give 1 ⁇ 8 cells/17.5 ml. The cells are lysed for 30 minutes on ice.
- ice-cold lysing buffer 50 mM HEPES pH 7.5, 10 mM MgCl 2 , 1 mM DTT, 5 ⁇ g/ml leupeptin, 5 ⁇ g/ml aprotinin, 100 ⁇ M NaF, 100 ⁇ M PMSF, 10 mM ⁇ -glycerolphosphate
- the clear supernatant is combined with glutathione sepharose beads (1 ml resuspended and washed beads per 50 ml of supernatant) and the mixture is incubated for 30 minutes at 4° C. on a rotating board.
- the protein concentration is determined by Bradford Assay.
- the reaction is started by adding the ATP solution and continued for 45 minutes at 30° C. with gentle shaking (650 rpm on an IKA Schüttler MTS2).
- the reaction is stopped by the addition of 125 ⁇ l of ice-cold 5% TCA per well and incubated on ice for at least 30 minutes.
- the precipitate is transferred by harvesting onto filter plates (96-well microtitre filter plate: UniFilter-96, GF/B; Packard; No. 6005177), then washed four times with 1% TCA and dried at 60° C. After the addition of 35 ⁇ l scintillation solution (Ready-Safe; Beckmann) per well the plate is sealed shut with sealing tape and the amount of P33 precipitated is measured with the Wallac Betacounter.
- the measured data are evaluated using the standard Graphpad software (Levenburg-Marquard Algorhythmus).
- cells of cervical carcinoma tumour cell line HeLa S3 obtained from American Type Culture Collection (ATCC) are cultivated in Ham's F12 Medium (Life Technologies) and 10% foetal calf serum (Life Technologies) and harvested in the log growth phase. Then the HeLa S3 cells are placed in 96-well plates (Costar) at a density of 1000 cells per well and incubated overnight in an incubator (at 37° C. and 5% CO2), while on each plate 6 wells are filled with medium alone (3 wells as the medium control, 3 wells for incubation with reduced AlamarBlue reagent).
- ATCC American Type Culture Collection
- the active substances are added to the cells in various concentrations (dissolved in DMSO; DMSO final concentration: 0.1%) (in each case as a triple measurement). After 72 hours incubation 20 ⁇ l AlamarBlue reagent (AccuMed International) are added to each well, and the cells are incubated for a further 7 hours. As a control, 20 ⁇ l reduced AlamarBlue reagent is added to each of 3 wells (AlamarBlue reagent, which is autoclaved for 30 min). After 7 h incubation the colour change of the AlamarBlue reagent in the individual wells is determined in a Perkin Elmer fluorescence spectrophotometer (excitation 530 nm, emission 590 nm, slits 15, integrate time 0.1).
- the amount of AlamarBlue reagent reacted represents the metabolic activity of the cells.
- the relative cell activity is calculated as a percentage of the control (HeLa S3 cells without inhibitor) and the active substance concentration which inhibits the cell activity by 50% (IC 50 ) is derived.
- the values are calculated from the average of three individual measurements—with correction of the dummy value (medium control).
- Propidium iodide binds stoichiometrically to double-stranded DNA, and is thus suitable for determining the proportion of cells in the G1, S, and G2/M phase of the cell cycle on the basis of the cellular DNA content.
- Cells in the G0 and G1 phase have a diploid DNA content (2N), whereas cells in the G2 or mitosis phase have a 4N DNA content.
- PI staining for example, 0.4 million HeLa S3 cells were seeded onto a 75 cm 2 cell culture flask, and after 24 h either 0.1% DMSO was added as control or the substance was added in various concentrations (in 0.1% DMSO). The cells were incubated for 24 h with the substance or with DMSO before the cells were washed 2 ⁇ with PBS and then detached with trypsin/EDTA. The cells were centrifuged (1000 rpm, 5 min, 4° C.), and the cell pellet was washed 2 ⁇ with PBS before the cells were resuspended in 0.1 ml PBS. Then the cells were fixed with 80% ethanol for 16 hours at 4° C.
- the fixed cells were centrifuged (1000 rpm, 5 min, 4° C.), washed with PBS and then centrifuged again.
- the cell pellet was resuspended in 2 ml 0.25% Triton X-100 in PBS, and incubated on ice for 5 min before 5 ml PBS are added and the mixture is centrifuged again.
- the cell pellet was resuspended in 350 ⁇ l PI staining solution (0.1 mg/ml RNase A (Sigma, No. R-4875), 10 ⁇ g/ml prodium iodide (Sigma, No. P-4864) in 1 ⁇ PBS).
- the cells were incubated for 20 min in the dark with the staining buffer before being transferred into sample measuring containers for the FACS scan.
- the DNA measurement was carried out in a Becton Dickinson FACS Analyzer, with an argon laser (500 mW, emission 488 nm), and the DNA Cell Quest Programme (BD).
- the logarithmic PI fluorescence was determined with a band-pass filter (BP 585/42).
- the cell populations in the individual cell cycle phases were quantified using the ModFit LT Programme made by Becton Dickinson.
- tumour cells were also tested accordingly on other tumour cells.
- these compounds are effective on carcinomas of all kinds of tissue (e.g. breast (MCF7); colon (HCT116), head and neck (FaDu), lung (NCI-H460), pancreas (B ⁇ PC-3), prostate (DU145)), sarcomas (e.g. SK-UT-1B, Saos-2), leukaemias and lymphomas (e.g. HL-60, Jurkat, THP-1) and other tumours (e.g. melanomas (BRO), gliomas (U-87MG)) and could be used for such indications.
- MCF7 breast
- HCT116 colon
- FaDu head and neck
- lung NCI-H460
- pancreas B ⁇ PC-3
- prostate DU145
- sarcomas e.g. SK-UT-1B, Saos-2
- leukaemias and lymphomas e.g. HL-60, Jurkat, THP-1
- the compounds of general formula (I) may be used on their own or in conjunction with other active substances according to the invention, optionally also in conjunction with other pharmacologically active substances.
- suitable preparations include for example tablets, capsules, suppositories, solutions,
- compositions particularly solutions for injection (s.c., i.v., i.m.) and infusion—elixirs, emulsions or dispersible powders.
- the content of the pharmaceutically active compound(s) should be in the range from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of the composition as a whole, i.e. in amounts which are sufficient to achieve the dosage range specified below.
- the doses specified may, if necessary, be given several times a day.
- Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
- excipients for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
- excipients for example inert dilu
- Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
- the core may also consist of a number of layers.
- the tablet coating may consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
- Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
- a sweetener such as saccharine, cyclamate, glycerol or sugar
- a flavour enhancer e.g. a flavouring such as vanillin or orange extract.
- suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
- Solutions for injection and infusion are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles.
- isotonic agents e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aid
- Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.
- Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.
- Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose) emulsifiers (e.g.
- pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly disper
- lignin e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone
- lubricants e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate.
- the preparations are administered by the usual methods, preferably by oral or transdermal route, most preferably by oral route.
- the tablets may, of course contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like.
- lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process.
- the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.
- solutions of the active substances with suitable liquid carriers may be used.
- the dosage for intravenous use is from 1-1000 mg per hour, preferably between 5 and 500 mg per hour.
- the finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened.
- the sodiumcarboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.
- the active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic.
- the solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion.
- the ampoules contain 5 mg, 25 mg and 50 mg of active substance.
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Oncology (AREA)
- Immunology (AREA)
- Communicable Diseases (AREA)
- Dermatology (AREA)
- Biomedical Technology (AREA)
- Virology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Physical Education & Sports Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Tropical Medicine & Parasitology (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Hematology (AREA)
- Transplantation (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Molecular Biology (AREA)
- Urology & Nephrology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- AIDS & HIV (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/357,731 US7759347B2 (en) | 2004-06-21 | 2009-01-22 | 2-benzylaminodihydropteridinones, process for their manufacture and use thereof as medicaments |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102004029784A DE102004029784A1 (de) | 2004-06-21 | 2004-06-21 | Neue 2-Benzylaminodihydropteridinone, Verfahren zur deren Herstellung und deren Verwendung als Arzneimittel |
DE102004029784 | 2004-06-21 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/357,731 Continuation US7759347B2 (en) | 2004-06-21 | 2009-01-22 | 2-benzylaminodihydropteridinones, process for their manufacture and use thereof as medicaments |
Publications (1)
Publication Number | Publication Date |
---|---|
US20060004014A1 true US20060004014A1 (en) | 2006-01-05 |
Family
ID=35149569
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/157,883 Abandoned US20060004014A1 (en) | 2004-06-21 | 2005-06-21 | 2-Benzylaminodihydropteridinones, process for their manufacture and use thereof as medicaments |
US12/357,731 Active US7759347B2 (en) | 2004-06-21 | 2009-01-22 | 2-benzylaminodihydropteridinones, process for their manufacture and use thereof as medicaments |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/357,731 Active US7759347B2 (en) | 2004-06-21 | 2009-01-22 | 2-benzylaminodihydropteridinones, process for their manufacture and use thereof as medicaments |
Country Status (8)
Country | Link |
---|---|
US (2) | US20060004014A1 (de) |
EP (1) | EP1761536B1 (de) |
JP (1) | JP5102021B2 (de) |
AT (1) | ATE382049T1 (de) |
CA (1) | CA2571293C (de) |
DE (2) | DE102004029784A1 (de) |
ES (1) | ES2297724T3 (de) |
WO (1) | WO2005123736A1 (de) |
Cited By (58)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060009457A1 (en) * | 2004-07-09 | 2006-01-12 | Boehringer Ingelheim International Gmbh | New pyridodihydropyrazinones, process for their manufacture and use thereof as medicaments |
US20060025411A1 (en) * | 2003-02-26 | 2006-02-02 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Methods for treating diseases or conditions using dihydropteridinone compounds |
US20060035902A1 (en) * | 2004-08-14 | 2006-02-16 | Boehringer Ingelheim International Gmbh | Hydrates and polymorphs of 4-[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)-benzamide, process for their manufacture and their use as medicament |
US20060046989A1 (en) * | 2004-08-25 | 2006-03-02 | Boehringer Ingelheim International Gmbh | New dihydropteridione derivatives, process for their manufacture and their use as medicament |
US20070117816A1 (en) * | 2005-10-07 | 2007-05-24 | Brown Jason W | Kinase inhibitors |
US20070208027A1 (en) * | 2004-12-02 | 2007-09-06 | Adil Duran | Intermediate compounds for the manufacture of fused piperazin-2-one derivatives |
US20080009482A1 (en) * | 2006-07-06 | 2008-01-10 | Astrazeneca Ab | Novel compounds |
US20080113992A1 (en) * | 2004-08-25 | 2008-05-15 | Matthias Grauert | Dihydropteridione Intermediate Compounds |
WO2008051493A3 (en) * | 2006-10-19 | 2008-07-03 | Signal Pharm Llc | Heteroaryl compounds, compositions thereof, and their use as protein kinase inhibitors |
US20080177066A1 (en) * | 2004-08-14 | 2008-07-24 | Boehringer Ingelheim International Gmbh | Process for the manufacture of dihydropteridinones |
US20080221099A1 (en) * | 2004-08-14 | 2008-09-11 | Gerd Munzert | Dihydropteridinones for the treatment of cancer diseases |
US20090030004A1 (en) * | 2006-02-08 | 2009-01-29 | Guenter Linz | Specific salt, anhydrous and crystalline form of a dihydropteridione derivative |
US20090124628A1 (en) * | 2004-06-21 | 2009-05-14 | Boehringer Ingelheim International Gmbh | 2-benzylaminodihydropteridinones, process for their manufacture and use thereof as medicaments |
US20090143379A1 (en) * | 2004-08-14 | 2009-06-04 | Boehringer Ingelheim International Gmbh | Storage stable perfusion solution for dihydropteridinones |
US20090238828A1 (en) * | 2004-08-14 | 2009-09-24 | Boehringer Ingelheim International Gmbh | Combinations for the Treatment of Diseases involving Cell Proliferation |
US20100120717A1 (en) * | 2006-10-09 | 2010-05-13 | Brown Jason W | Kinase inhibitors |
US20100160633A1 (en) * | 2007-04-18 | 2010-06-24 | Takeda Pharmaceutical Company Limited | Kinase inhibitors |
US20100216781A1 (en) * | 2008-10-27 | 2010-08-26 | Sophie Perrin-Ninkovic | mTOR KINASE INHIBITORS FOR ONCOLOGY INDICATIONS AND DISEASES ASSOCIATED WITH THE mTOR/PI3K/AKT PATHWAY |
US20100280037A1 (en) * | 2007-08-03 | 2010-11-04 | Boehringer Ingelheim International Gmbh | Crystalline form of a dihydropteridione derivative |
WO2011038185A2 (en) | 2009-09-25 | 2011-03-31 | Vertex Pharmaceuticals Incorporated | Methods for preparing pyrimidine derivatives useful as protein kinase inhibitors |
WO2011036566A1 (en) | 2009-09-25 | 2011-03-31 | Vertex Pharmaceuticals Incorporated | Methods for preparing pyrimidine derivatives useful as protein kinase inhibitors |
CN102076691A (zh) * | 2008-06-23 | 2011-05-25 | 维泰克斯制药公司 | 蛋白激酶抑制剂 |
CN102076690A (zh) * | 2008-06-23 | 2011-05-25 | 维泰克斯制药公司 | 蛋白激酶抑制剂 |
US20110137028A1 (en) * | 2009-10-26 | 2011-06-09 | Harris Roy L | Methods of synthesis and purification of heteroaryl compounds |
WO2011097333A1 (en) * | 2010-02-03 | 2011-08-11 | Signal Pharmaceuticals, Llc | Identification of lkb1 mutation as a predictive biomarker for sensitivity to tor kinase inhibitors |
US8461149B2 (en) | 2007-08-15 | 2013-06-11 | Vertex Pharmaceuticals Incorporated | Compounds useful as protein kinase inhibitors |
US8546566B2 (en) | 2010-10-12 | 2013-10-01 | Boehringer Ingelheim International Gmbh | Process for manufacturing dihydropteridinones and intermediates thereof |
US8829007B2 (en) | 2009-06-17 | 2014-09-09 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
US9051319B2 (en) | 2011-08-01 | 2015-06-09 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
US9155736B2 (en) | 2012-10-18 | 2015-10-13 | Signal Pharmaceuticals, Llc | Inhibition of phosphorylation of PRAS40, GSK3-beta or P70S6K1 as a marker for TOR kinase inhibitory activity |
US9346812B2 (en) | 2013-01-16 | 2016-05-24 | Signal Pharmaceuticals, Llc | Substituted pyrrolopyrimidine compounds, compositions thereof, and methods of treatment therewith |
US9358232B2 (en) | 2013-04-17 | 2016-06-07 | Signal Pharmaceuticals, Llc | Methods for treating cancer using TOR kinase inhibitor combination therapy |
US9359364B2 (en) | 2013-04-17 | 2016-06-07 | Signal Pharmaceuticals, Llc | Pharmaceutical formulations, processes, solid forms and methods of use relating to 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b] pyrazin-2(1H)-one |
US9358233B2 (en) | 2010-11-29 | 2016-06-07 | Boehringer Ingelheim International Gmbh | Method for treating acute myeloid leukemia |
US9370535B2 (en) | 2011-05-17 | 2016-06-21 | Boehringer Ingelheim International Gmbh | Method for treatment of advanced solid tumors |
US9375443B2 (en) | 2012-02-24 | 2016-06-28 | Signal Pharmaceuticals, Llc | Method for treating advanced non-small cell lung cancer (NSCLC) by administering a combination of a TOR kinase inhibitor and azacitidine or erlotinib |
US9403829B2 (en) | 2011-12-02 | 2016-08-02 | Signal Pharmaceuticals, Llc | Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-b]pyrazin-2(1H)-one, a solid form thereof and methods of their use |
US9416134B2 (en) | 2014-04-16 | 2016-08-16 | Signal Pharmaceuticals, Llc | Solid forms of 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, as TOR kinase inhibitors |
US9434735B2 (en) | 2014-07-14 | 2016-09-06 | Signal Pharmaceuticals, Llc | Amorphous form of 4-((4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7h-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-n-methylbenzamide, compositions thereof and methods of their use |
US9474757B2 (en) | 2013-04-17 | 2016-10-25 | Signal Pharmaceuticals, Llc | Methods for treating cancer using TOR kinase inhibitor combination therapy |
US9493466B2 (en) | 2011-10-19 | 2016-11-15 | Signal Pharmaceuticals, Llc | Treatment of cancer with TOR kinase inhibitors |
US9505764B2 (en) | 2013-04-17 | 2016-11-29 | Signal Pharmaceuticals, Llc | Treatment of cancer with dihydropyrazino-pyrazines |
US9512129B2 (en) | 2014-04-16 | 2016-12-06 | Signal Pharmaceuticals, Llc | Solid forms comprising 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one and a coformer |
US9604939B2 (en) | 2013-05-29 | 2017-03-28 | Signal Pharmaceuticals, Llc | Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-YL)pyridin-3-YL)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-B]pyrazin-2(1H)-one, a solid form thereof and methods of their use |
US9623028B2 (en) | 2014-07-14 | 2017-04-18 | Signal Pharmaceuticals, Llc | Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof |
US9630966B2 (en) | 2013-04-17 | 2017-04-25 | Signal Pharmaceuticals, Llc | Treatment of cancer with dihydropyrazino-pyrazines |
US9718824B2 (en) | 2014-04-16 | 2017-08-01 | Signal Pharmaceuticals, Llc | Solid forms comprising 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, and a coformer, compositions and methods of use thereof |
US9737535B2 (en) | 2014-04-16 | 2017-08-22 | Signal Pharmaceuticals, Llc | Methods for treating cancer using TOR kinase inhibitor combination therapy comprising administering substituted pyrazino[2,3-b]pyrazines |
US9771361B2 (en) | 2013-11-13 | 2017-09-26 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
US9782427B2 (en) | 2013-04-17 | 2017-10-10 | Signal Pharmaceuticals, Llc | Methods for treating cancer using TOR kinase inhibitor combination therapy |
US9867831B2 (en) | 2014-10-01 | 2018-01-16 | Boehringer Ingelheim International Gmbh | Combination treatment of acute myeloid leukemia and myelodysplastic syndrome |
US9937169B2 (en) | 2013-04-17 | 2018-04-10 | Signal Pharmaceuticals, Llc | Methods for treating cancer using dihydropyrazino-pyrazine compound combination therapy |
US9956225B2 (en) | 2013-07-26 | 2018-05-01 | Boehringer Ingelheim International Gmbh | Treatment of myelodysplastic syndrome |
US10023569B2 (en) | 2013-11-13 | 2018-07-17 | Vertex Pharmaceuticals Incorporated | Methods of preparing inhibitors of influenza viruses replication |
US10273233B2 (en) | 2015-05-13 | 2019-04-30 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
US10533004B2 (en) | 2015-05-13 | 2020-01-14 | Vertex Pharmaceuticals Incorporated | Methods of preparing inhibitors of influenza viruses replication |
CN112218865A (zh) * | 2018-04-24 | 2021-01-12 | 沃泰克斯药物股份有限公司 | 喋啶酮化合物及其用途 |
US11096940B2 (en) | 2017-06-22 | 2021-08-24 | Celgene Corporation | Treatment of hepatocellular carcinoma characterized by hepatitis B virus infection |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5243970B2 (ja) | 2006-02-14 | 2013-07-24 | バーテックス ファーマシューティカルズ インコーポレイテッド | タンパク質キナーゼの阻害剤として有用なジヒドロジアゼピン |
KR101432316B1 (ko) | 2006-04-12 | 2014-08-29 | 버텍스 파마슈티칼스 인코포레이티드 | 증식성 장애의 치료를 위한 단백질 키나제 plk1 억제제로서의 4,5-디히드로-[1,2,4]트리아졸로[4,3-f]프테리딘 |
CN101484457B (zh) * | 2006-04-12 | 2014-09-03 | 弗特克斯药品有限公司 | 作为用于治疗增殖病症的蛋白激酶PLK1抑制剂的4,5-二氢-[1,2,4]三唑并[4,3-f]蝶啶 |
EP2100894A1 (de) | 2008-03-12 | 2009-09-16 | 4Sc Ag | Pyridopyrimidinone verwendbar als Plk1 (polo-like kinase) Hemmen |
EP2112152A1 (de) * | 2008-04-22 | 2009-10-28 | GPC Biotech AG | Dihydropteridinones als Plk-Inhibitoren |
UY32306A (es) | 2008-12-09 | 2010-07-30 | Gilead Sciences Inc | Derivados de pteridinona y pirimidinodiazepinona y composiciones farmacéuticas que modulan en forma selectiva los receptores tipo toll, métodos y usos |
PL2477987T3 (pl) | 2009-09-14 | 2018-06-29 | Gilead Sciences, Inc. | Modulatory receptorów toll-podobnych |
EP2325185A1 (de) | 2009-10-28 | 2011-05-25 | GPC Biotech AG | Plk-Inhibitor |
CN103492381A (zh) | 2010-12-16 | 2014-01-01 | 沃泰克斯药物股份有限公司 | 流感病毒复制的抑制剂 |
JP2015501793A (ja) | 2011-11-10 | 2015-01-19 | オーエスアイ・ファーマシューティカルズ,エルエルシー | ジヒドロプテリジノン類 |
TWI806081B (zh) | 2014-07-11 | 2023-06-21 | 美商基利科學股份有限公司 | 用於治療HIV之toll樣受體調節劑 |
PT3194401T (pt) | 2014-09-16 | 2020-12-23 | Gilead Sciences Inc | Formas sólidas de modulador de recetor tipo toll |
AU2015318062B2 (en) | 2014-09-16 | 2018-07-05 | Gilead Sciences, Inc. | Methods of preparing toll-like receptor modulators |
Family Cites Families (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL8303657A (nl) | 1983-10-24 | 1985-05-17 | Pharmachemie Bv | Voor injectie geschikte, stabiele, waterige, zoutzuur bevattende oplossing van cisplatine, alsmede werkwijze ter bereiding daarvan. |
DE3537761A1 (de) * | 1985-10-24 | 1987-04-30 | Bayer Ag | Infusionsloesungen der 1-cyclopropyl-6-fluor-1,4-dihydro-4-oxo-7- (1-piperazinyl)-chinolin-3-carbonsaeure |
DE68908786T2 (de) | 1988-06-16 | 1994-03-17 | Smith Kline French Lab | Condensierte Pyrimidinderivate, Verfahren und Zwischenprodukte zu ihrer Herstellung und diese enthaltende pharmazeutische Zubereitungen. |
FR2645152B1 (fr) * | 1989-03-30 | 1991-05-31 | Lipha | 3h-pteridinones-4, procedes de preparation et medicaments les contenant |
CA2029651C (en) | 1989-11-17 | 2000-06-06 | David D. Davey | Tricyclic pteridinones and a process for their preparation |
TW274550B (de) | 1992-09-26 | 1996-04-21 | Hoechst Ag | |
CO4410190A1 (es) | 1994-09-19 | 1997-01-09 | Lilly Co Eli | 3-[4-(2-AMINOETOXI)-BENZOIL]-2-ARIL-6-HIDROXIBENZO [b] TIOFENO CRISTALINO |
IL117923A (en) | 1995-05-03 | 2000-06-01 | Warner Lambert Co | Anti-cancer pharmaceutical compositions containing polysubstituted pyrido¬2,3-d¾pyrimidine derivatives and certain such novel compounds |
ES2154825T3 (es) * | 1995-05-19 | 2001-04-16 | Novartis Ag | Procedimiento para la hidrogenacion catalitica de nitro compuestos aromaticos. |
US5698556A (en) * | 1995-06-07 | 1997-12-16 | Chan; Carcy L. | Methotrexate analogs and methods of using same |
EA001881B1 (ru) | 1996-09-23 | 2001-10-22 | Эли Лилли Энд Компани | Форма d дигидрата оланзапина |
EE200100085A (et) * | 1998-08-11 | 2002-08-15 | Pfizer Products Inc. | Asendatud 1,8-naftüridiin-4(1H)-oonid kui fosfodiesteraas 4 inhibiitorid |
JP2003509425A (ja) * | 1999-09-15 | 2003-03-11 | ワーナー−ランバート・カンパニー | キナーゼ阻害剤としてのプテリジノン |
AP2002002643A0 (en) | 2000-03-06 | 2002-12-31 | Warner Lambert Co | 5-alkylpyrido[2,3-d]pyrimidines tyrosine kinase inhibitors |
DE10018783A1 (de) | 2000-04-15 | 2001-10-25 | Fresenius Kabi De Gmbh | Lagerstabile Infusionslösung des Ciprofloxacins mit verringertem Säuregehalt |
US20020183292A1 (en) * | 2000-10-31 | 2002-12-05 | Michel Pairet | Pharmaceutical compositions based on anticholinergics and corticosteroids |
DE10058119A1 (de) * | 2000-11-22 | 2002-05-23 | Bayer Ag | Pepinotan-Kit |
US6756374B2 (en) | 2001-01-22 | 2004-06-29 | Hoffmann-La Roche Inc. | Diaminothiazoles having antiproliferative activity |
WO2002076985A1 (en) | 2001-03-23 | 2002-10-03 | Smithkline Beecham Corporation | Compounds useful as kinase inhibitors for the treatment of hyperproliferative diseases |
WO2002076954A1 (en) | 2001-03-23 | 2002-10-03 | Smithkline Beecham Corporation | Compounds useful as kinase inhibitors for the treatment of hyperproliferative diseases |
US20030055026A1 (en) * | 2001-04-17 | 2003-03-20 | Dey L.P. | Formoterol/steroid bronchodilating compositions and methods of use thereof |
US6806272B2 (en) * | 2001-09-04 | 2004-10-19 | Boehringer Ingelheim Pharma Kg | Dihydropteridinones, processes for preparing them and their use as pharmaceutical compositions |
EP1427730B1 (de) * | 2001-09-04 | 2006-07-12 | Boehringer Ingelheim Pharma GmbH & Co.KG | Neue dihydropteridinone, verfahren zu deren herstellung und deren verwendung als arzneimittel |
EP1312365A1 (de) * | 2001-11-20 | 2003-05-21 | Jenapharm GmbH & Co. KG | Pteridinone zur Behandlung der erektilen Dysfunktion |
WO2003051344A1 (en) * | 2001-12-14 | 2003-06-26 | Applied Research Systems Ars Holding N.V. | Methods of inducing ovulation_using a non-polypeptide camp level modulator |
CN1649853A (zh) * | 2002-05-03 | 2005-08-03 | 舍林股份公司 | 噻唑烷酮类化合物、其制备方法以及作为药物的应用 |
AU2003265348B2 (en) | 2002-08-08 | 2007-08-16 | Smithkline Beecham Corporation | Thiophene compounds |
CN100537570C (zh) * | 2003-02-26 | 2009-09-09 | 贝林格尔英格海姆法玛两合公司 | 二氢蝶啶酮、其制法及作为药物制剂的用途 |
US6861422B2 (en) * | 2003-02-26 | 2005-03-01 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Dihydropteridinones, processes for preparing them and their use as pharmaceutical compositions |
CA2517010C (en) | 2003-03-26 | 2013-09-24 | Wyeth | Plasmid dna in combination with recombinant vsv for use in prime-boost immunization regimens |
WO2004093848A2 (en) | 2003-04-14 | 2004-11-04 | Vectura Ltd | Dry power inhaler devices and dry power formulations for enhancing dosing efficiency |
WO2005067935A1 (de) | 2004-01-17 | 2005-07-28 | Boehringer Ingelheim International Gmbh | Verwendung von substituierten pteridinen zur behandlung von atemwegserkrankungen |
DE102004002557A1 (de) * | 2004-01-17 | 2005-08-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verwendung von substituierten Pyrimido(5,4-d)pyrimidinen zur Behandlung von Atemwegserkrankungen |
DE102004029784A1 (de) | 2004-06-21 | 2006-01-05 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue 2-Benzylaminodihydropteridinone, Verfahren zur deren Herstellung und deren Verwendung als Arzneimittel |
DE102004033670A1 (de) * | 2004-07-09 | 2006-02-02 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Pyridodihydropyrazinone, Verfahren zu Ihrer Herstellung und Ihre Verwendung als Arzneimittel |
DE102004034623A1 (de) * | 2004-07-16 | 2006-02-02 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue 6-Formyl-tetrahydropteridine, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
US20060058311A1 (en) * | 2004-08-14 | 2006-03-16 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation |
US7759485B2 (en) | 2004-08-14 | 2010-07-20 | Boehringer Ingelheim International Gmbh | Process for the manufacture of dihydropteridinones |
US20060035903A1 (en) * | 2004-08-14 | 2006-02-16 | Boehringer Ingelheim International Gmbh | Storage stable perfusion solution for dihydropteridinones |
US7728134B2 (en) * | 2004-08-14 | 2010-06-01 | Boehringer Ingelheim International Gmbh | Hydrates and polymorphs of 4[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)-benzamide, process for their manufacture and their use as medicament |
US20060074088A1 (en) * | 2004-08-14 | 2006-04-06 | Boehringer Ingelheim International Gmbh | Dihydropteridinones for the treatment of cancer diseases |
EP1632493A1 (de) * | 2004-08-25 | 2006-03-08 | Boehringer Ingelheim Pharma GmbH & Co.KG | Dihydropteridinonderivative, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel |
EP1630163A1 (de) * | 2004-08-25 | 2006-03-01 | Boehringer Ingelheim Pharma GmbH & Co.KG | Dihydropteridinonderivative, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel |
WO2006021547A1 (de) * | 2004-08-26 | 2006-03-02 | Boehringer Ingelheim International Gmbh | Pteridinone als plk (polo like kinase) inhibitoren |
EP1784406A1 (de) * | 2004-08-27 | 2007-05-16 | Boehringer Ingelheim International GmbH | Dihydropteridinone, verfahren zu deren herstellung und deren verwendung als arzneimittel |
DE102004058337A1 (de) * | 2004-12-02 | 2006-06-14 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verfahren zur Herstellung von annelierten Piperazin-2-on Derivaten |
EP1915155A1 (de) * | 2005-08-03 | 2008-04-30 | Boehringer Ingelheim International GmbH | Dihydropteridinone bei der behandlung von atemwegserkrankungen |
US7439358B2 (en) | 2006-02-08 | 2008-10-21 | Boehringer Ingelheim International Gmbh | Specific salt, anhydrous and crystalline form of a dihydropteridione derivative |
CA2695406A1 (en) | 2007-08-03 | 2009-02-12 | Boehringer Ingelheim International Gmbh | Crystalline form of a dihydropteridione derivative |
-
2004
- 2004-06-21 DE DE102004029784A patent/DE102004029784A1/de not_active Withdrawn
-
2005
- 2005-06-15 EP EP05751714A patent/EP1761536B1/de active Active
- 2005-06-15 CA CA2571293A patent/CA2571293C/en active Active
- 2005-06-15 AT AT05751714T patent/ATE382049T1/de active
- 2005-06-15 DE DE502005002356T patent/DE502005002356D1/de active Active
- 2005-06-15 WO PCT/EP2005/006404 patent/WO2005123736A1/de active IP Right Grant
- 2005-06-15 JP JP2007517147A patent/JP5102021B2/ja active Active
- 2005-06-15 ES ES05751714T patent/ES2297724T3/es active Active
- 2005-06-21 US US11/157,883 patent/US20060004014A1/en not_active Abandoned
-
2009
- 2009-01-22 US US12/357,731 patent/US7759347B2/en active Active
Cited By (149)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7750152B2 (en) | 2003-02-26 | 2010-07-06 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Intermediate compounds for making dihydropteridinones useful as pharmaceutical compositions and processes of making the same |
US7786299B2 (en) | 2003-02-26 | 2010-08-31 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Methods for treating diseases or conditions using dihydropteridinone compounds |
US8003786B2 (en) | 2003-02-26 | 2011-08-23 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Dihydropteridinone compounds |
US20080293944A1 (en) * | 2003-02-26 | 2008-11-27 | Matthias Hoffmann | Piperazinyl Compounds |
US20100324288A1 (en) * | 2003-02-26 | 2010-12-23 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Dihydropteridinone Compounds |
US7816530B2 (en) | 2003-02-26 | 2010-10-19 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Piperazinyl compounds |
US20060025411A1 (en) * | 2003-02-26 | 2006-02-02 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Methods for treating diseases or conditions using dihydropteridinone compounds |
US20080171747A1 (en) * | 2003-02-26 | 2008-07-17 | Matthias Hoffman | Intermediate Compounds for making Dihydropteridinones Useful as Pharmaceutical Compositions |
US7759347B2 (en) | 2004-06-21 | 2010-07-20 | Boehringer Ingelheim International Gmbh | 2-benzylaminodihydropteridinones, process for their manufacture and use thereof as medicaments |
US20090124628A1 (en) * | 2004-06-21 | 2009-05-14 | Boehringer Ingelheim International Gmbh | 2-benzylaminodihydropteridinones, process for their manufacture and use thereof as medicaments |
US20100029642A1 (en) * | 2004-07-09 | 2010-02-04 | Boehringer Ingelheim International Gmbh | Methods of Using Pyridodihydropyrazinones |
US20060009457A1 (en) * | 2004-07-09 | 2006-01-12 | Boehringer Ingelheim International Gmbh | New pyridodihydropyrazinones, process for their manufacture and use thereof as medicaments |
US7625899B2 (en) | 2004-07-09 | 2009-12-01 | Boehringer Ingelheim International Gmbh | Pyridodihydropyraziones, process for their manufacture and use thereof as medicaments |
US8193188B2 (en) | 2004-07-09 | 2012-06-05 | Boehringer Ingelheim International Gmbh | Methods of using pyridodihydropyrazinones |
US20080177066A1 (en) * | 2004-08-14 | 2008-07-24 | Boehringer Ingelheim International Gmbh | Process for the manufacture of dihydropteridinones |
US20090318457A1 (en) * | 2004-08-14 | 2009-12-24 | Boehringer Ingelheim International Gmbh | Methods of Using hydrates and polymorphs of 4-[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)-benzamide |
US8058270B2 (en) | 2004-08-14 | 2011-11-15 | Boehringer Ingelheim International Gmbh | Dihydropteridinones for the treatment of cancer diseases |
US8034816B2 (en) | 2004-08-14 | 2011-10-11 | Boehringer Ingelheim International Gmbh | Hydrates and polymorphs of 4-[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)-benzamide, process for their manufacture and their use as medicament |
US20080221099A1 (en) * | 2004-08-14 | 2008-09-11 | Gerd Munzert | Dihydropteridinones for the treatment of cancer diseases |
US20060035902A1 (en) * | 2004-08-14 | 2006-02-16 | Boehringer Ingelheim International Gmbh | Hydrates and polymorphs of 4-[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)-benzamide, process for their manufacture and their use as medicament |
US8138341B2 (en) | 2004-08-14 | 2012-03-20 | Boehringer Ingelheim International Gmbh | Intermediate compounds useful for the manufacture of dihydropteridinones |
US8138373B2 (en) | 2004-08-14 | 2012-03-20 | Boehringer Ingelheim International Gmbh | Process for the manufacture of dihydropteridinones |
US8143247B2 (en) | 2004-08-14 | 2012-03-27 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation |
US8591895B2 (en) | 2004-08-14 | 2013-11-26 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation |
US8202867B2 (en) | 2004-08-14 | 2012-06-19 | Boehringer Ingelheim International Gmbh | Methods of using hydrates and polymorphs of 4-[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)-benzamide |
US20100249412A1 (en) * | 2004-08-14 | 2010-09-30 | Boehringer Ingelheim International Gmbh | Process for the manufacture of dihydropteridinones |
US20090143379A1 (en) * | 2004-08-14 | 2009-06-04 | Boehringer Ingelheim International Gmbh | Storage stable perfusion solution for dihydropteridinones |
US20100249458A1 (en) * | 2004-08-14 | 2010-09-30 | Boehringer Ingelheim International Gmbh | Process for the manufacture of dihydropteridinones |
US20090238828A1 (en) * | 2004-08-14 | 2009-09-24 | Boehringer Ingelheim International Gmbh | Combinations for the Treatment of Diseases involving Cell Proliferation |
US7759485B2 (en) | 2004-08-14 | 2010-07-20 | Boehringer Ingelheim International Gmbh | Process for the manufacture of dihydropteridinones |
US8445675B2 (en) | 2004-08-14 | 2013-05-21 | Boehringer Ingelheim International Gmbh | Storage stable perfusion solution for dihydropteridinones |
US20090298840A1 (en) * | 2004-08-14 | 2009-12-03 | Boehringer Ingelheim International Gmbh | Hydrates and polymorphs of 4-[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)-benzamide, process for their manufacture and their use as medicament |
US7728134B2 (en) | 2004-08-14 | 2010-06-01 | Boehringer Ingelheim International Gmbh | Hydrates and polymorphs of 4[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)-benzamide, process for their manufacture and their use as medicament |
US7807831B2 (en) | 2004-08-25 | 2010-10-05 | Boehringer Ingelheim International Gmbh | Dihydropteridione derivatives, process for their manufacture and their use as medicament |
US20060046989A1 (en) * | 2004-08-25 | 2006-03-02 | Boehringer Ingelheim International Gmbh | New dihydropteridione derivatives, process for their manufacture and their use as medicament |
US7700769B2 (en) | 2004-08-25 | 2010-04-20 | Boehringer Ingelheim International Gmbh | Dihydropteridione derivatives, process for their manufacture and their use as medicament |
US7414053B2 (en) | 2004-08-25 | 2008-08-19 | Boehringer Ingelheim International Gmbh | Dihydropteridione derivatives, process for their manufacture and their use as medicament |
US20080113992A1 (en) * | 2004-08-25 | 2008-05-15 | Matthias Grauert | Dihydropteridione Intermediate Compounds |
US7723517B2 (en) | 2004-08-25 | 2010-05-25 | Boehringer Ingelheim International Gmbh | Dihydropteridione derivatives, process for their manufacture and their use as medicament |
US7629460B2 (en) | 2004-08-25 | 2009-12-08 | Boehringer Ingelheim International Gmbh | Dihydropteridione derivatives, process for their manufacture and their use as medicament |
US20080319193A1 (en) * | 2004-08-25 | 2008-12-25 | Boehringer Ingelheim International Gmbh | New dihydropteridione derivatives, process for their manufacture and their use as medicament |
US20080319190A1 (en) * | 2004-08-25 | 2008-12-25 | Boehringer Ingelheim International Gmbh | New dihydropteridione derivatives, process for their manufacture and their use as medicament |
US20090018333A1 (en) * | 2004-08-25 | 2009-01-15 | Boehringer Ingelheim International Gmbh | Dihydropteridione derivatives, process for their manufacture and their use as medicament |
US7547780B2 (en) | 2004-08-25 | 2009-06-16 | Boehringer Ingelheim International Gmbh | Dihydropteridione intermediate compounds |
US20070219369A1 (en) * | 2004-12-02 | 2007-09-20 | Adil Duran | Process for the Manufacture of fused piperazin-2-one derivatives |
US20070213530A1 (en) * | 2004-12-02 | 2007-09-13 | Adil Duran | Intermediate Compounds for the Manufacture of fused piperazin-2-one derivatives |
US20070213531A1 (en) * | 2004-12-02 | 2007-09-13 | Adil Duran | Process for the Manufacture of fused piperazin-2-one derivatives |
USRE43115E1 (en) | 2004-12-02 | 2012-01-17 | Boehringer Ingelheim International Gmbh | Process for the manufacture of fused piperazin-2-one derivatives |
US20070213529A1 (en) * | 2004-12-02 | 2007-09-13 | Adil Duran | Process for the Manufacture of fused piperazin-2-one derivatives |
US20070208027A1 (en) * | 2004-12-02 | 2007-09-06 | Adil Duran | Intermediate compounds for the manufacture of fused piperazin-2-one derivatives |
US20070213528A1 (en) * | 2004-12-02 | 2007-09-13 | Adil Duran | Process for the Manufacture of Fused piperazin-2-one derivatives |
US20070213534A1 (en) * | 2004-12-02 | 2007-09-13 | Adil Duran | Process for the Manufacture of fused piperazin-2-one derivatives |
US7626019B2 (en) | 2004-12-02 | 2009-12-01 | Boehringer Ingelheim International Gmbh | Intermediate compounds for the manufacture of fused piperazin-2-one derivatives |
US8119655B2 (en) | 2005-10-07 | 2012-02-21 | Takeda Pharmaceutical Company Limited | Kinase inhibitors |
US20070117816A1 (en) * | 2005-10-07 | 2007-05-24 | Brown Jason W | Kinase inhibitors |
US8664222B2 (en) | 2006-02-08 | 2014-03-04 | Boehringer Ingelheim International Gmbh | Specific salt, anhydrous and crystalline form of a dihydropteridione derivative |
US20090030004A1 (en) * | 2006-02-08 | 2009-01-29 | Guenter Linz | Specific salt, anhydrous and crystalline form of a dihydropteridione derivative |
US8188086B2 (en) | 2006-02-08 | 2012-05-29 | Boehringer Ingelheim International Gmbh | Specific salt, anhydrous and crystalline form of a dihydropteridione derivative |
US20080009482A1 (en) * | 2006-07-06 | 2008-01-10 | Astrazeneca Ab | Novel compounds |
US7709471B2 (en) | 2006-07-06 | 2010-05-04 | Astrazeneca Ab | Compounds |
US20100120717A1 (en) * | 2006-10-09 | 2010-05-13 | Brown Jason W | Kinase inhibitors |
US8372976B2 (en) | 2006-10-19 | 2013-02-12 | Signal Pharmaceuticals, Llc | Methods of treatment comprising the administration of heteroaryl compounds |
EP2457913A3 (de) * | 2006-10-19 | 2012-08-15 | Signal Pharmaceuticals LLC | Heteroarylverbindungen, Zusammensetzungen davon und Verfahren zur Behandlung damit |
WO2008051493A3 (en) * | 2006-10-19 | 2008-07-03 | Signal Pharm Llc | Heteroaryl compounds, compositions thereof, and their use as protein kinase inhibitors |
US7981893B2 (en) | 2006-10-19 | 2011-07-19 | Signal Pharmaceuticals, Llc | Heteroaryl compounds, compositions thereof, and methods of treatment therewith |
US20090023724A1 (en) * | 2006-10-19 | 2009-01-22 | Deborah Sue Mortensen | Heteroaryl compounds, compositions thereof, and methods of treatment therewith |
US20100160633A1 (en) * | 2007-04-18 | 2010-06-24 | Takeda Pharmaceutical Company Limited | Kinase inhibitors |
US8278450B2 (en) | 2007-04-18 | 2012-10-02 | Takeda Pharmaceutical Company Limited | Kinase inhibitors |
US8329695B2 (en) | 2007-08-03 | 2012-12-11 | Boehringer Ingelheim International Gmbh | Crystalline form of the free base N-[trans-4-[4-(cyclopropylmethyl)-1-piperazinyl]cyclohexyl]-4-[[(7r)-7-ethyl-5,6,7,8-tetrahydro-5-methyl-8-(1-methylethyl)-6-oxo-2-pteridinyl]amino]-3-methoxy-benzamide |
US20100280037A1 (en) * | 2007-08-03 | 2010-11-04 | Boehringer Ingelheim International Gmbh | Crystalline form of a dihydropteridione derivative |
US8461149B2 (en) | 2007-08-15 | 2013-06-11 | Vertex Pharmaceuticals Incorporated | Compounds useful as protein kinase inhibitors |
CN102076691A (zh) * | 2008-06-23 | 2011-05-25 | 维泰克斯制药公司 | 蛋白激酶抑制剂 |
CN102076690A (zh) * | 2008-06-23 | 2011-05-25 | 维泰克斯制药公司 | 蛋白激酶抑制剂 |
US8618106B2 (en) | 2008-06-23 | 2013-12-31 | Vertex Pharmaceuticals Incorporated | Protein kinase inhibitors |
US9771371B2 (en) | 2008-10-27 | 2017-09-26 | Signal Pharmaceuticals, Llc | Substituted pyrazino[2,3-b]pyrazines as mTOR kinase inhibitors |
US10683298B2 (en) | 2008-10-27 | 2020-06-16 | Signal Pharmaceuticals, Llc | Substituted pyrazino[2,3-b]pyrazines as mTOR kinase inhibitors |
US20100216781A1 (en) * | 2008-10-27 | 2010-08-26 | Sophie Perrin-Ninkovic | mTOR KINASE INHIBITORS FOR ONCOLOGY INDICATIONS AND DISEASES ASSOCIATED WITH THE mTOR/PI3K/AKT PATHWAY |
US8907087B2 (en) | 2008-10-27 | 2014-12-09 | Signal Pharmaceuticals, Llc | Substituted pyrazino[2,3-b]pyrazines as mTOR kinase inhibitors |
US8492381B2 (en) | 2008-10-27 | 2013-07-23 | Signal Pharmaceuticals, Llc | Pyrazino[2,3-b]pyrazine mTOR kinase inhibitor for oncology indications and diseases associated with the mTOR/PI3K/Akt pathway |
US8507492B2 (en) | 2008-10-27 | 2013-08-13 | Signal Pharmaceuticals, Llc | Pyrazino[2,3-b]pyrazine mTOR kinase inhibitor for oncology indications and diseases associated with the mTOR/PI3K/AKT pathway |
US11292796B2 (en) | 2008-10-27 | 2022-04-05 | Signal Pharmaceuticals, Llc | Substituted pyrazino[2,3-b]pyrazines as mTOR kinase inhibitors |
US9193692B2 (en) | 2008-10-27 | 2015-11-24 | Signal Pharmaceuticals, Llc | Halogen substituted pyrazines as intermediates of mTOR kinase inhibitors |
US10167290B2 (en) | 2008-10-27 | 2019-01-01 | Signal Pharmaceuticals, Llc | Substituted pyrazino[2,3-b]pyrazines as mTOR kinase inhibitors |
US8110578B2 (en) | 2008-10-27 | 2012-02-07 | Signal Pharmaceuticals, Llc | Pyrazino[2,3-b]pyrazine mTOR kinase inhibitors for oncology indications and diseases associated with the mTOR/PI3K/Akt pathway |
US10874673B2 (en) | 2009-06-17 | 2020-12-29 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
US10039762B2 (en) | 2009-06-17 | 2018-08-07 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
US9808459B2 (en) | 2009-06-17 | 2017-11-07 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
US9518056B2 (en) | 2009-06-17 | 2016-12-13 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
US8829007B2 (en) | 2009-06-17 | 2014-09-09 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
US9345708B2 (en) | 2009-06-17 | 2016-05-24 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
WO2011038185A2 (en) | 2009-09-25 | 2011-03-31 | Vertex Pharmaceuticals Incorporated | Methods for preparing pyrimidine derivatives useful as protein kinase inhibitors |
WO2011036566A1 (en) | 2009-09-25 | 2011-03-31 | Vertex Pharmaceuticals Incorporated | Methods for preparing pyrimidine derivatives useful as protein kinase inhibitors |
US8686135B2 (en) | 2009-10-26 | 2014-04-01 | Signal Pharmaceuticals, Llc | Methods of synthesis and purification of heteroaryl compounds |
US9079900B2 (en) | 2009-10-26 | 2015-07-14 | Signal Pharmaceuticals, Llc | Methods of synthesis and purification of heteroaryl compounds |
US8569494B2 (en) | 2009-10-26 | 2013-10-29 | Signal Pharmaceuticals, Llc | Methods of synthesis and purification of heteroaryl compounds |
US20110137028A1 (en) * | 2009-10-26 | 2011-06-09 | Harris Roy L | Methods of synthesis and purification of heteroaryl compounds |
US9555033B2 (en) | 2010-02-03 | 2017-01-31 | Signal Pharmaceuticals, Llc | Identification of LKB1 mutation as a predictive biomarker for sensitivity to TOR kinase inhibitors |
WO2011097333A1 (en) * | 2010-02-03 | 2011-08-11 | Signal Pharmaceuticals, Llc | Identification of lkb1 mutation as a predictive biomarker for sensitivity to tor kinase inhibitors |
US8546566B2 (en) | 2010-10-12 | 2013-10-01 | Boehringer Ingelheim International Gmbh | Process for manufacturing dihydropteridinones and intermediates thereof |
US9358233B2 (en) | 2010-11-29 | 2016-06-07 | Boehringer Ingelheim International Gmbh | Method for treating acute myeloid leukemia |
US9370535B2 (en) | 2011-05-17 | 2016-06-21 | Boehringer Ingelheim International Gmbh | Method for treatment of advanced solid tumors |
US10875855B2 (en) | 2011-08-01 | 2020-12-29 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
US9908878B2 (en) | 2011-08-01 | 2018-03-06 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
US9394302B2 (en) | 2011-08-01 | 2016-07-19 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
US9051319B2 (en) | 2011-08-01 | 2015-06-09 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
US9493466B2 (en) | 2011-10-19 | 2016-11-15 | Signal Pharmaceuticals, Llc | Treatment of cancer with TOR kinase inhibitors |
US9937170B2 (en) | 2011-10-19 | 2018-04-10 | Signal Pharmaceuticals, Llc | Treatment of cancer with TOR kinase inhibitors |
US9403829B2 (en) | 2011-12-02 | 2016-08-02 | Signal Pharmaceuticals, Llc | Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-b]pyrazin-2(1H)-one, a solid form thereof and methods of their use |
US9375443B2 (en) | 2012-02-24 | 2016-06-28 | Signal Pharmaceuticals, Llc | Method for treating advanced non-small cell lung cancer (NSCLC) by administering a combination of a TOR kinase inhibitor and azacitidine or erlotinib |
US9557338B2 (en) | 2012-10-18 | 2017-01-31 | Signal Pharmaceuticals, Llc | Inhibition of phosphorylation of PRAS40, GSK3-beta or P70S6K1 as a marker for tor kinase inhibitory activity |
US9155736B2 (en) | 2012-10-18 | 2015-10-13 | Signal Pharmaceuticals, Llc | Inhibition of phosphorylation of PRAS40, GSK3-beta or P70S6K1 as a marker for TOR kinase inhibitory activity |
US9428509B2 (en) | 2013-01-16 | 2016-08-30 | Signal Pharmaceuticals, Llc | Substituted pyrrolopyrimidine compounds, compositions thereof, and methods of treatment therewith |
US9346812B2 (en) | 2013-01-16 | 2016-05-24 | Signal Pharmaceuticals, Llc | Substituted pyrrolopyrimidine compounds, compositions thereof, and methods of treatment therewith |
US9795607B2 (en) | 2013-01-16 | 2017-10-24 | Signal Pharmaceuticals, Llc | Substituted pyrrolopyrimidine compounds, compositions thereof, and methods of treatment therewith |
US9474757B2 (en) | 2013-04-17 | 2016-10-25 | Signal Pharmaceuticals, Llc | Methods for treating cancer using TOR kinase inhibitor combination therapy |
US9937169B2 (en) | 2013-04-17 | 2018-04-10 | Signal Pharmaceuticals, Llc | Methods for treating cancer using dihydropyrazino-pyrazine compound combination therapy |
US10052322B2 (en) | 2013-04-17 | 2018-08-21 | Signal Pharmaceuticals, Llc | Pharmaceutical formulations, processes, solid forms and methods of use relating to 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one |
US9782427B2 (en) | 2013-04-17 | 2017-10-10 | Signal Pharmaceuticals, Llc | Methods for treating cancer using TOR kinase inhibitor combination therapy |
US9505764B2 (en) | 2013-04-17 | 2016-11-29 | Signal Pharmaceuticals, Llc | Treatment of cancer with dihydropyrazino-pyrazines |
US9358232B2 (en) | 2013-04-17 | 2016-06-07 | Signal Pharmaceuticals, Llc | Methods for treating cancer using TOR kinase inhibitor combination therapy |
US9630966B2 (en) | 2013-04-17 | 2017-04-25 | Signal Pharmaceuticals, Llc | Treatment of cancer with dihydropyrazino-pyrazines |
US9827243B2 (en) | 2013-04-17 | 2017-11-28 | Signal Pharmaceuticals, Llc | Pharmaceutical formulations, processes, solid forms and methods of use relating to 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one |
US9359364B2 (en) | 2013-04-17 | 2016-06-07 | Signal Pharmaceuticals, Llc | Pharmaceutical formulations, processes, solid forms and methods of use relating to 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b] pyrazin-2(1H)-one |
US9980963B2 (en) | 2013-04-17 | 2018-05-29 | Signal Pharmaceuticals, Llc | Treatment of cancer with dihydropyrazino-pyrazines |
US10183019B2 (en) | 2013-04-17 | 2019-01-22 | Signal Pharmaceuticals, Llc | Treatment of cancer with dihydropyrazino-pyrazines |
US10391092B2 (en) | 2013-04-17 | 2019-08-27 | Signal Pharmaceuticals, Llc | Methods for treating cancer using dihydropyrazino-pyrazine compound combination therapy |
US10052323B2 (en) | 2013-05-29 | 2018-08-21 | Signal Pharmaceuticals, Llc | Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-b]pyrazin-2(1H)-one, a solid form thereof and methods of their use |
US9974786B2 (en) | 2013-05-29 | 2018-05-22 | Signal Pharmaceuticals, Llc | Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3- B]pyrazin-2(1H)-one, a solid form there of and methods of their use |
US9604939B2 (en) | 2013-05-29 | 2017-03-28 | Signal Pharmaceuticals, Llc | Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-YL)pyridin-3-YL)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-B]pyrazin-2(1H)-one, a solid form thereof and methods of their use |
US9795603B2 (en) | 2013-05-29 | 2017-10-24 | Signal Pharmaceuticals, Llc | Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-B]pyrazin-2(1H)-one, a solid form thereof and methods of their use |
US9956225B2 (en) | 2013-07-26 | 2018-05-01 | Boehringer Ingelheim International Gmbh | Treatment of myelodysplastic syndrome |
US10640501B2 (en) | 2013-11-13 | 2020-05-05 | Vertex Pharmaceuticals Incorporated | Methods of preparing inhibitors of influenza viruses replication |
US9771361B2 (en) | 2013-11-13 | 2017-09-26 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
US10023569B2 (en) | 2013-11-13 | 2018-07-17 | Vertex Pharmaceuticals Incorporated | Methods of preparing inhibitors of influenza viruses replication |
US11345700B2 (en) | 2013-11-13 | 2022-05-31 | Vertex Pharmaceuticals Incorporated | Methods of preparing inhibitors of influenza viruses replication |
US10004735B2 (en) | 2014-04-16 | 2018-06-26 | Signal Pharmaceuticals, Llc | Methods for treating cancer using TOR kinase inhibitor combination therapy comprising administering substituted pyrazino[2,3-b]pyrazines |
US9512129B2 (en) | 2014-04-16 | 2016-12-06 | Signal Pharmaceuticals, Llc | Solid forms comprising 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one and a coformer |
US9981971B2 (en) | 2014-04-16 | 2018-05-29 | Signal Pharmaceuticals, Llc | Solid forms of 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one as TOR kinase inhibitors |
US9737535B2 (en) | 2014-04-16 | 2017-08-22 | Signal Pharmaceuticals, Llc | Methods for treating cancer using TOR kinase inhibitor combination therapy comprising administering substituted pyrazino[2,3-b]pyrazines |
US9975898B2 (en) | 2014-04-16 | 2018-05-22 | Signal Pharmaceuticals, Llc | Solid forms of 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-YL)-3,4-dihydropyrazino [2,3-b]pyrazin-2(1H)-one as tor kinase inhibitors |
US9718824B2 (en) | 2014-04-16 | 2017-08-01 | Signal Pharmaceuticals, Llc | Solid forms comprising 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, and a coformer, compositions and methods of use thereof |
US9416134B2 (en) | 2014-04-16 | 2016-08-16 | Signal Pharmaceuticals, Llc | Solid forms of 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, as TOR kinase inhibitors |
US9434735B2 (en) | 2014-07-14 | 2016-09-06 | Signal Pharmaceuticals, Llc | Amorphous form of 4-((4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7h-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-n-methylbenzamide, compositions thereof and methods of their use |
US9623028B2 (en) | 2014-07-14 | 2017-04-18 | Signal Pharmaceuticals, Llc | Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof |
US9867831B2 (en) | 2014-10-01 | 2018-01-16 | Boehringer Ingelheim International Gmbh | Combination treatment of acute myeloid leukemia and myelodysplastic syndrome |
US10533004B2 (en) | 2015-05-13 | 2020-01-14 | Vertex Pharmaceuticals Incorporated | Methods of preparing inhibitors of influenza viruses replication |
US10273233B2 (en) | 2015-05-13 | 2019-04-30 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
US11096940B2 (en) | 2017-06-22 | 2021-08-24 | Celgene Corporation | Treatment of hepatocellular carcinoma characterized by hepatitis B virus infection |
CN112218865A (zh) * | 2018-04-24 | 2021-01-12 | 沃泰克斯药物股份有限公司 | 喋啶酮化合物及其用途 |
Also Published As
Publication number | Publication date |
---|---|
ES2297724T3 (es) | 2008-05-01 |
DE102004029784A1 (de) | 2006-01-05 |
JP5102021B2 (ja) | 2012-12-19 |
CA2571293A1 (en) | 2005-12-29 |
DE502005002356D1 (de) | 2008-02-07 |
EP1761536B1 (de) | 2007-12-26 |
ATE382049T1 (de) | 2008-01-15 |
WO2005123736A8 (de) | 2006-03-30 |
US20090124628A1 (en) | 2009-05-14 |
US7759347B2 (en) | 2010-07-20 |
CA2571293C (en) | 2013-05-28 |
JP2008503515A (ja) | 2008-02-07 |
WO2005123736A1 (de) | 2005-12-29 |
EP1761536A1 (de) | 2007-03-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7759347B2 (en) | 2-benzylaminodihydropteridinones, process for their manufacture and use thereof as medicaments | |
US7241889B2 (en) | 6-formyl-tetrahydropteridines, process for their manufacture and use thereof as medicaments | |
US7625899B2 (en) | Pyridodihydropyraziones, process for their manufacture and use thereof as medicaments | |
US7332491B2 (en) | Dihydropteridione derivatives, process for their manufacture and their use as medicament | |
EP2536725B1 (de) | Dihydropteridinone, herstellungsverfahren dafür und verwendung davon | |
US7700769B2 (en) | Dihydropteridione derivatives, process for their manufacture and their use as medicament | |
US6806272B2 (en) | Dihydropteridinones, processes for preparing them and their use as pharmaceutical compositions |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: BOEHRINGER INGELHEIM INTERNATIONAL GMBH, GERMANY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HOFFMANN, MATTHIAS;GRAUERT, MATTHIAS;LEHMANN-LINTZ, THORSTEN;AND OTHERS;REEL/FRAME:016815/0454;SIGNING DATES FROM 20050726 TO 20050905 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |