WO2005105808A1 - Thienopyridazines as ikk inhibitors - Google Patents
Thienopyridazines as ikk inhibitors Download PDFInfo
- Publication number
- WO2005105808A1 WO2005105808A1 PCT/EP2005/004478 EP2005004478W WO2005105808A1 WO 2005105808 A1 WO2005105808 A1 WO 2005105808A1 EP 2005004478 W EP2005004478 W EP 2005004478W WO 2005105808 A1 WO2005105808 A1 WO 2005105808A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- cycloalkyl
- phenyl
- hydrogen
- compound
- Prior art date
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- 239000003458 I kappa b kinase inhibitor Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 134
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- 229940002612 prodrug Drugs 0.000 claims abstract description 11
- 239000012453 solvate Substances 0.000 claims abstract description 11
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- -1 cyano, hydroxy Chemical group 0.000 claims description 111
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 41
- 201000010099 disease Diseases 0.000 claims description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 34
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- YNVOMSDITJMNET-UHFFFAOYSA-N thiophene-3-carboxylic acid Chemical compound OC(=O)C=1C=CSC=1 YNVOMSDITJMNET-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic 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
- 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
- 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
- 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
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
-
- 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
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
Definitions
- heteroaryl moieties include, but are not limited to, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyridinyl, pyridazyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl,
- the invention provides compounds of formula I:
- n 0, while in other embodiments m is 1 and R > 6 i • s halo, alkyl, alkoxy, haloalkyl, nitro, cyano, 2-cyanoethyl, or morpholmomethyl.
- the subject compounds are of the formula III:
- the present invention includes pharmaceutical compositions comprising at least one compound of the present invention, or an individual isomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients.
- the compounds of the present invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
- the pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
- the pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use.
- the compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
- the compounds of the present invention may be formulated for nasal administration.
- the solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray.
- the formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
- 5-(4-Fluorophenyl)-3-thiophenecarboxylic acid ethyl ester A mixture of 5 -bromo-thiophene-3 -carboxylic acid ethyl ester (l.Og, 4.5 mmol), 4-fluorophenylboronic acid (0.88 g. 6.4 mmol), potassium carbonate (1.75 g, 12 mmol) and tefra striphenylphosphinepalladium(O) (0.2 g, 4 mole%) in a 50:50 mixture of DME/ H 2 O (10ml) was heated at reflux temperature overnight under a nitrogen atmosphere.
- Step 5 4-Chloro-2-(4-fluorophenyl)-thienor2-3-dlpyridazine-7-carboxylic acid ethyl ester
- Example 3 This example describes an assay that is useful in evaluating and selecting a compound that modulates IKK.
- the assay measures the incorporation of radiolabeled 33 P gATP into the Biotin-peptide kinase substrate, derived from the IkB-alpha sequence.
- 26 ⁇ l of ADB diluted, purified recombinant human IKKb [25 nM] was mixed with 4 ⁇ l lOx concentration of test compounds, [usually lOO ⁇ M- 0.003 ⁇ M], [10%] DMSO and incubated for 10 minutes at room temperature.
- the kinase reaction was initiated by the addition of 10 ⁇ l 4x substrate cocktail containing the peptide substrate [0 or 30 ⁇ M] ATP [10 ⁇ M], and 33 PgATP [2 ⁇ Ci/rxn]. After 30 minutes of incubation at 30° C, the reaction was terminated by the transfer of 25 ⁇ l reaction sample to a phosphocellulose membrane/plate containing 150 ⁇ l 0.75% phosphoric acid. On the following day, the free radionucleotides in the phosphocellulose membrane were washed under vacuum with 3x200 ⁇ l of 0.15% phosphoric acid. After the last wash membrane/plates were transferred to an adoptor plate and 70 ⁇ l of scintillation cocktail was added to each well.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Rheumatology (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Emergency Medicine (AREA)
- Pain & Pain Management (AREA)
- Dermatology (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BRPI0510704-0A BRPI0510704A (en) | 2004-05-04 | 2005-04-27 | thienopyridazines as ikk inhibitors |
MXPA06012684A MXPA06012684A (en) | 2004-05-04 | 2005-04-27 | Thienopyridazines as ikk inhibitors. |
JP2007511951A JP2007536301A (en) | 2004-05-04 | 2005-04-27 | Thienopyridazine as an IKK inhibitor |
CA002563990A CA2563990A1 (en) | 2004-05-04 | 2005-04-27 | Thienopyridazines as ikk inhibitors |
EP05738162A EP1745051A1 (en) | 2004-05-04 | 2005-04-27 | Thienopyridazines as ikk inhibitors |
AU2005238178A AU2005238178A1 (en) | 2004-05-04 | 2005-04-27 | Thienopyridazines as IKK inhibitors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US56837204P | 2004-05-04 | 2004-05-04 | |
US60/568,372 | 2004-05-04 |
Publications (1)
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WO2005105808A1 true WO2005105808A1 (en) | 2005-11-10 |
Family
ID=34966237
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2005/004478 WO2005105808A1 (en) | 2004-05-04 | 2005-04-27 | Thienopyridazines as ikk inhibitors |
Country Status (11)
Country | Link |
---|---|
US (1) | US7135470B2 (en) |
EP (1) | EP1745051A1 (en) |
JP (1) | JP2007536301A (en) |
KR (1) | KR100822681B1 (en) |
CN (1) | CN1950378A (en) |
AU (1) | AU2005238178A1 (en) |
BR (1) | BRPI0510704A (en) |
CA (1) | CA2563990A1 (en) |
MX (1) | MXPA06012684A (en) |
RU (1) | RU2006142740A (en) |
WO (1) | WO2005105808A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009076454A2 (en) * | 2007-12-12 | 2009-06-18 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
WO2009092278A1 (en) * | 2008-01-08 | 2009-07-30 | Zhejiang Medicine Co., Ltd Xinchang Pharmaceutical Factory | Thienopyridazine compounds, their preparations, pharmaceutical compositions and uses |
EP2826780A1 (en) | 2009-09-18 | 2015-01-21 | Zhanggui Wu | Thieno[2,3-d]pyridazine derivatives and therapeutic use thereof for protein kinase inhibition |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20010020030A1 (en) * | 1998-06-04 | 2001-09-06 | Stewart Andrew O. | Cell adhesion-inhibiting antiinflammatory compounds |
WO2003103661A1 (en) * | 2002-06-06 | 2003-12-18 | Boehringer Ingelheim Pharmaceuticals, Inc. | SUBSTITUTED 3-AMINO-THIENO[2,3-b]PYRIDINE-2-CARBOXYLIC ACID AMIDE COMPOUNDS AND PROCESSES FOR PREPARING AND THEIR USES |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999062908A2 (en) * | 1998-06-04 | 1999-12-09 | Abbott Laboratories | Cell adhesion-inhibiting antinflammatory compounds |
EP1181296A1 (en) | 1999-06-03 | 2002-02-27 | Abbott Laboratories | Cell adhesion-inhibiting antiinflammatory compounds |
CA2390948A1 (en) * | 1999-06-03 | 2000-12-14 | Abbott Laboratories | Cell adhesion-inhibiting antiinflammatory compounds |
US6951848B2 (en) | 2001-03-12 | 2005-10-04 | Millennium Pharmaceuticals, Inc., | Functionalized heterocycles as modulators of chemokine receptor function and methods of use therefor |
ATE358673T1 (en) * | 2002-06-06 | 2007-04-15 | Smithkline Beecham Corp | NF-κB INHIBITORS |
JP2006512313A (en) | 2002-10-31 | 2006-04-13 | アムジェン インコーポレイテッド | Anti-inflammatory agent |
-
2005
- 2005-04-27 WO PCT/EP2005/004478 patent/WO2005105808A1/en active Application Filing
- 2005-04-27 KR KR1020067022757A patent/KR100822681B1/en not_active IP Right Cessation
- 2005-04-27 JP JP2007511951A patent/JP2007536301A/en active Pending
- 2005-04-27 AU AU2005238178A patent/AU2005238178A1/en not_active Abandoned
- 2005-04-27 MX MXPA06012684A patent/MXPA06012684A/en not_active Application Discontinuation
- 2005-04-27 BR BRPI0510704-0A patent/BRPI0510704A/en not_active IP Right Cessation
- 2005-04-27 EP EP05738162A patent/EP1745051A1/en not_active Withdrawn
- 2005-04-27 CA CA002563990A patent/CA2563990A1/en not_active Abandoned
- 2005-04-27 RU RU2006142740/04A patent/RU2006142740A/en not_active Application Discontinuation
- 2005-04-27 CN CNA2005800142092A patent/CN1950378A/en active Pending
- 2005-05-04 US US11/121,807 patent/US7135470B2/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20010020030A1 (en) * | 1998-06-04 | 2001-09-06 | Stewart Andrew O. | Cell adhesion-inhibiting antiinflammatory compounds |
WO2003103661A1 (en) * | 2002-06-06 | 2003-12-18 | Boehringer Ingelheim Pharmaceuticals, Inc. | SUBSTITUTED 3-AMINO-THIENO[2,3-b]PYRIDINE-2-CARBOXYLIC ACID AMIDE COMPOUNDS AND PROCESSES FOR PREPARING AND THEIR USES |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009076454A2 (en) * | 2007-12-12 | 2009-06-18 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
WO2009076454A3 (en) * | 2007-12-12 | 2009-09-24 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
US8389567B2 (en) | 2007-12-12 | 2013-03-05 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
WO2009092278A1 (en) * | 2008-01-08 | 2009-07-30 | Zhejiang Medicine Co., Ltd Xinchang Pharmaceutical Factory | Thienopyridazine compounds, their preparations, pharmaceutical compositions and uses |
RU2494103C2 (en) * | 2008-01-08 | 2013-09-27 | Чжэцзян Медисин Ко., Лтд, Синьчан Фармасеутикал Фэктори | Thienopyridazine compounds, preparing them, pharmaceutical compositions containing them, and using them |
KR101512530B1 (en) | 2008-01-08 | 2015-04-15 | 제 쟝 메더신 코.,엘티디 씬창 파마수티칼 팩토리 | Thienopyridazine Compounds, Their Preparations, Pharmaceutical Compositions and Uses |
EP2826780A1 (en) | 2009-09-18 | 2015-01-21 | Zhanggui Wu | Thieno[2,3-d]pyridazine derivatives and therapeutic use thereof for protein kinase inhibition |
Also Published As
Publication number | Publication date |
---|---|
US20050272730A1 (en) | 2005-12-08 |
CN1950378A (en) | 2007-04-18 |
RU2006142740A (en) | 2008-06-10 |
BRPI0510704A (en) | 2007-11-20 |
EP1745051A1 (en) | 2007-01-24 |
CA2563990A1 (en) | 2005-11-10 |
AU2005238178A1 (en) | 2005-11-10 |
JP2007536301A (en) | 2007-12-13 |
US7135470B2 (en) | 2006-11-14 |
KR20070015560A (en) | 2007-02-05 |
MXPA06012684A (en) | 2007-01-16 |
KR100822681B1 (en) | 2008-04-17 |
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