WO2003101970A1 - Imidazolium cxcr3 inhibitors - Google Patents
Imidazolium cxcr3 inhibitors Download PDFInfo
- Publication number
- WO2003101970A1 WO2003101970A1 PCT/US2003/016782 US0316782W WO03101970A1 WO 2003101970 A1 WO2003101970 A1 WO 2003101970A1 US 0316782 W US0316782 W US 0316782W WO 03101970 A1 WO03101970 A1 WO 03101970A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- bromide
- oxoethyl
- aryl
- imidazol
- ium
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- 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
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- 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
- A61P17/04—Antipruritics
-
- 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
- A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- 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
- 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
- A61P35/00—Antineoplastic agents
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic 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
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
Definitions
- this invention relates to certain imidazoliums and their use as inhibitors of a chemokine receptor knows as CXCR3 and its equivalent chemokine receptors.
- chemokines In addition to stimulating chemotaxis other changes can be selectively induced by chemokines in responsive cells including changes in cell shape, transient rises in the concentration of intracellular free calcium ions, granule exocytosis, integrin upregulation, formation of bioactive lipids and respiratory bursts associated with leukocyte activation.
- chemokines are early triggers of the inflammatory response, causing inflammatory mediator release, chemotaxis and estravasation to the sites of infection or inflammation.
- CXC chemokines
- oc-chemokines such as interluken-8 (IL-8), melanoma growth stimulatory activity protein (MGSA), and stromal cell derived factor 1 (SDF-1) are chemotactic primarily for neutrophils and lymphocytes
- ⁇ -chemokines such as RANTES, MIP-loc, MlP-l ⁇ , monocyte chemotactic protein -1 (MCP-1), MCP-2, MCP-3 and eotaxin are chemotactic for macrophages, T-cells, eosinophils and basophils (Deng, et al, Nature, 381:661-666 (1996)).
- the C chemokine lymphotactin shows specificity for lymphocytes (Kelner, et al., Science, 266:1395-1399 (1994)) while-the CX 3 C chemokine fractalkine shows specificity for lymphocytes and monocytes (Bazan, et al., Nautre, 385:640-644 (1997)).
- chemokines bind specific cell-surface receptors belonging to the family of G- protein-coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends Pharm. Sci., 15,159-165 (1994)) which are termed "chemokine receptors.” On binding their cognate ligands, chemokine receptors transduce an intracellular signal though the associated trimeric G protein, resulting in a rapid increase in intracellular calcium concentration.
- chemokine receptors There are at least seven human chemokine receptors that bind or respond to .beta.-chemokines with the following characteristic pattern: CCR-1 (or "CKR-1" or "CC-CKR-1”) [MIP-1. alpha., MUM.
- CCR-4 or "CKR-4" or "CC-CKR-4" [MHM. alpha., RANTES, MCP-1] (Power, et al., J. Biol. Chem., 270, 19495-19500 (1995)); CCR-5 (or "CKR-5" or "CC-CKR-5") [MTP-1. alpha., RANTES, MDM.beta.] (Sanson, et al., Biochemistry, 35, 3362-3367 (1996)); and the Duffy blood-group antigen [RANTES, MCP-1] (Chaudhun, et al., J. Biol.
- the ⁇ - chemokines include eotaxin, MD? ("macrophage inflammatory protein”), MCP ("monocyte chemoattractant protein”) and RANTES ("regulation-upon-activation, normal T expressed and secreted").
- Chemokine receptors such as CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CX 3 CR1, and XCR1 have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
- Chemokine receptors such as CXCR-3 have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. For example it plays a pivotal role in attracting eosinophils to sites of allergic inflammation. Accordingly, agents, which modulate it, would be useful in such disorders and diseases.
- the compounds of this invention are inhibitors of this chemokine receptor and as such are useful in treating diseases which the CXCR3 chemokine receptor is involved
- this invention relates to a compound of formula (I)
- a " is an anion
- R , R2 and R3 are the same or different and are hydrogen, C -Cg alkyl, aryl, fused aryl, or heteroaryl; or are substituted aryl, fused aryl or heteroaryl;
- R4 and R5 are the same or different and are aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
- Rg is arykCj-Cg alkyl, OH, C ⁇ -Cg alkoxy, or aryloxy.
- this invention relates to pharmaceutically acceptable preparations containing one or more of the compounds of formula (I) or a hydrate thereof. Uses of these compositions for treating diseases in which the CXCR3 receptor is involved are within the scope of this invention. Methods for preparing the compounds of formula (I) are also within the scope of this invention. Description of the Invention
- alkyl means a straight or branched chain radical that may be fully saturated or mono- or polyunsaturated and can include di- and multivalent radicals.
- saturated hydrocarbon radicals include methyl, ethyl, rc-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, and n-hexyl and the like.
- An unsaturated alkyl group has one or more double bonds or triple bonds.
- unsaturated alkyl groups include vinyl, 2- propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
- aryl mean a polyunsaturated aromatic group which can be a single ring or multiple rings which are fused (“fused aryl”) together or linked covalently.
- heteroaryl refers to aryl groups that contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
- Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2- imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazoly, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3- isoxazolyi, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2- thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquion
- aryl groups are phenyl and substituted phenyl.
- Preferred fused aryl groups are naphthyl and phenanthrenyl.
- Preferred substituted aryls include phenyl and naphthyl.
- alkoxy and aryloxy refer to those groups attached to the remainder of the molecule via an oxygen atom.
- R', R" and R'" are independently selected from hydrogen, (C ⁇ -C 8 )alkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-(C ⁇ -C )alkyl, and (unsubstituted aryl)oxy-(C ⁇ -C 4 )alkyl.
- Anions may be any negatively charged, pharmaceutically acceptable group.
- the halides are preferred, particularly the bromide ion.
- Diseases or conditions of humans or other species which can be treated with inhibitors of chemokine receptor function include: inflammatory or allergic diseases and conditions, including respiratory allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilic pneumonia), delayed-type hypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporins), insect sting allergies; autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis,
- Other diseases or conditions in which undesirable inflammatory responses are to be inhibited can be treated, including, but not limited to, reperfusion injury, atherosclerosis, certain hematologic malignancies, cytokine-induced toxicity (e.g., septic shock, endotoxic shock), polymyositis, dermatomyositis.
- compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier that constitutes one or more accessory ingredients.
- the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
- the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
- composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
- compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
- compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
- Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets.
- excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
- the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- Inhibitors of CXCR3 can be administered by injection in solutions either intravenously, intramuscularly, intraperitoneally, or orally. These doses will contain the drug in the range of 1 to 140 mg/kg of body weight.
- the solution preferably contains a buffer (such as phosphate) to keep the pH in the range of about 3.5 to 7.
- DMSO or alcoholic solvents may also be present (at concentrations such as 0.01 to 10 mL/liter) to aid solubility.
- Exemplary bisphenacylimidazolium salts of this invention may be prepared by reacting an imidazole such as 1-Scheme 1 with an excess molar amount of a phenacyl halide such as 2-Scheme 1 in a polar organic solvent such as dimethylformamide or acetonitrile for example.
- a polar organic solvent such as dimethylformamide or acetonitrile for example.
- the major product obtained is the dialkylated imidazolium 3.
- Example 5 Preparation of l,3-Bis-[2-(3,4-difluorophenyl)-2-oxoethyl] ]-3H-imidazol-l-ium; bromide Following the procedure in Example 2 except substituting 2-bromo-l-(3-fluoro- phenyl)-ethanone with 2-bromo-l-(3,4-difluorophenyl)-2-imidazol-l-yl-ethanone. 97 mg of the caption product was obtained. LC MS (ES+) m/e 378[M+1]
- Example 11 Preparation of l-[2-(3,4-Dichlorophenyl)-2-oxoethyl]-3-[2-(3-fluoro-phenyl)-2-oxoethyl]-3H- imidazolium; bromide Following the procedure in Example 8 except replacing 3-fluorophenacyl bromide with
- Example 18 Preparation of 3-[2-(3-Chlorophenyl)-2-oxoethyl]-l-[2-(4-chloro-3-trifluoromethylphenyl)-2- oxoethyl]-3H-imidazol- 1-ium; bromide. Following the procedure in Example 18 except substituting 3,4-dichlorophenacyl bromide with 3-chlorophenacyl bromide. 55 mg of of the captioned product was obtained. LC/MS (ES+) m/e 443[M+1]
- Example 19 Preparation of l,3-Bis-[2-(3,4-dichlorophenyl)-2-oxoethyl]-3H-imidazol-l-ium; bromide 3,4-dichlorophenacyl bromide (1.34 g, 5 mmol) and 2-ethylimidazole were stirred in 3 ml of DMF at 0° C for 1 hour, then the reaction was warmed up to room temperature and stirred overnight. The mixture was poured into water, extracted with ethyl acetate.
- Example 23 General procedure of preparing: l-(3-fluorophenyl)-2-imidazol-l-yl-ethanone; 2-imidazol- 1-yl- l-(3-methoxy-phenyl)-ethanone; l-(3,4-dichlorophenyl)-2-(2-ethylimidazole-l-yl)-ethanone; and l-(3,4-difluorophenyl)-2-imidazol-l-yl-ethanone
- CXCR3 Ca ⁇ + mobilization studies were carried out using Fluo 3-loaded RBL 2H3 CXCR3 and a microtiter plate-based assay using FLIPR (Molecular Devices, Sunnyvale, CA). Briefly, cells (about 80% confluent) were harvested and plated in 96 well black wall/clear bottom plates (Packard view plate) at approximately 40,000 cells/well and grown in the incubator for 18-24 hr.
- the percent of maximal DMO-induced Ca ⁇ + mobilization was determined for each concentration of antagonist and the IC50 defined as the concentration of test compound that inhibits 50% of the maximal response induced by 3.3 nM IP-10.
- the EC50 is defined as the concentration that produces 50% of the maximal DMO-induced response.
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Neurology (AREA)
- Dermatology (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Endocrinology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Vascular Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Obesity (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Otolaryngology (AREA)
- Transplantation (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/516,970 US20050272936A1 (en) | 2002-06-03 | 2003-05-29 | Imidazolium cxcr3 inhibitors |
AU2003231872A AU2003231872A1 (en) | 2002-06-03 | 2003-05-29 | Imidazolium cxcr3 inhibitors |
JP2004509663A JP2005530813A (en) | 2002-06-03 | 2003-05-29 | Imidazolium CXCR3 inhibitor |
EP03756231A EP1554253A4 (en) | 2002-06-03 | 2003-05-29 | Imidazolium cxcr3 inhibitors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US38565802P | 2002-06-03 | 2002-06-03 | |
US60/385,658 | 2002-06-03 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2003101970A1 true WO2003101970A1 (en) | 2003-12-11 |
Family
ID=29712195
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2003/016782 WO2003101970A1 (en) | 2002-06-03 | 2003-05-29 | Imidazolium cxcr3 inhibitors |
Country Status (5)
Country | Link |
---|---|
US (1) | US20050272936A1 (en) |
EP (1) | EP1554253A4 (en) |
JP (1) | JP2005530813A (en) |
AU (1) | AU2003231872A1 (en) |
WO (1) | WO2003101970A1 (en) |
Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006129679A1 (en) | 2005-05-31 | 2006-12-07 | Ono Pharmaceutical Co., Ltd. | Spiropiperidine compound and medicinal use thereof |
US7230022B2 (en) | 2004-02-19 | 2007-06-12 | Bristol-Myers Squibb Company | Substituted fused bicyclic amines as modulators of chemokine receptor activity |
WO2007105637A1 (en) | 2006-03-10 | 2007-09-20 | Ono Pharmaceutical Co., Ltd. | Nitrogenated heterocyclic derivative, and pharmaceutical agent comprising the derivative as active ingredient |
US7288563B2 (en) | 2004-02-19 | 2007-10-30 | Bristol-Myers Squibb Company | Substituted bicycloalkylamine derivatives as modulators of chemokine receptor activity |
WO2008016006A1 (en) | 2006-07-31 | 2008-02-07 | Ono Pharmaceutical Co., Ltd. | Compound having cyclic group bound thereto through spiro binding and use thereof |
US7381738B2 (en) | 2004-02-19 | 2008-06-03 | Bristol-Myers Squibb Company | Substituted bicycloalkylamine derivatives as modulators of chemokine receptor activity |
US7479496B2 (en) | 2004-02-19 | 2009-01-20 | Bristol-Myers Squibb Company | Substituted spiro azabicyclics as modulators of chemokine receptor activity |
WO2009105435A1 (en) | 2008-02-19 | 2009-08-27 | Sanofi-Aventis | Inhibitors of the chemokine receptor cxcr3 |
US7763616B2 (en) | 2005-02-16 | 2010-07-27 | Schering Corporation | Piperazine-piperidines with CXCR3 antagonist activity |
US7776862B2 (en) | 2005-02-16 | 2010-08-17 | Schering Corporation | Pyridyl and phenyl substituted piperazine-piperidines with CXCR3 antagonist activity |
US7786124B2 (en) | 2006-03-21 | 2010-08-31 | Schering Corporation | Heterocyclic substituted pyridine compounds with CXCR3 antagonist activity |
US7799789B2 (en) | 2005-02-16 | 2010-09-21 | Schering Corporation | Heterocyclic substituted pyridine or phenyl compounds with CXCR3 antagonist activity |
US7868005B2 (en) | 2005-02-16 | 2011-01-11 | Schering Corporation | Pyrazinyl substituted piperazine-piperidines with CXCR3 antagonist activity |
US7868006B2 (en) | 2005-02-16 | 2011-01-11 | Schering Corporation | Heterocyclic substituted piperazines with CXCR3 antagonist activity |
US7879838B2 (en) | 2005-02-16 | 2011-02-01 | Schering Corporation | Heteroaryl substituted pyrazinyl-piperazine-piperidines with CXCR3 antagonist activity |
US7902199B2 (en) | 2006-07-14 | 2011-03-08 | Schering Corporation | Heterocyclic substituted piperazine compounds with CXCR3 antagonist activity |
WO2012000904A1 (en) | 2010-06-28 | 2012-01-05 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Pharmaceutical composition for use in the treatment of glaucoma |
EP2546234A1 (en) | 2004-09-13 | 2013-01-16 | Ono Pharmaceutical Co., Ltd. | Nitrogeneous heterocyclic derivative and medicine containing the same as an active ingredient |
EP2803356A1 (en) * | 2008-03-31 | 2014-11-19 | Agency for Science, Technology and Research | Method for treating neurological disorders with imidazolium and imidazolinium compounds |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101182308B (en) * | 2006-11-13 | 2010-06-09 | 浙江工业大学 | Imidazole chiral ionic liquids containing double function groups as well as preparation method and uses thereof |
CN101983057A (en) * | 2008-01-30 | 2011-03-02 | 新加坡科技研究局 | Method for treating fibrosis and cancer with imidazolium and imidazolinium compounds |
WO2010129351A1 (en) | 2009-04-28 | 2010-11-11 | Schepens Eye Research Institute | Method to identify and treat age-related macular degeneration |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4613609A (en) * | 1983-07-12 | 1986-09-23 | Schering A. G. | Antiarrhythmic imidazoliums |
JPS60184076A (en) * | 1984-02-29 | 1985-09-19 | Shikoku Chem Corp | Novel imidazolium compound, its synthesis, and synthesis of 2-vinyl-4,6-diamino-s-triazine therefrom |
EP0552292B1 (en) * | 1990-10-10 | 1995-06-21 | Schering Corporation | Substituted imidazobenzazepines and imidazopyridoazepines |
CA2435844A1 (en) * | 2001-02-07 | 2002-08-15 | Farrington Pharmaceuticals, Llc | Method and composition for rejuvinating cells, tissues, organs, hair and nails |
-
2003
- 2003-05-29 EP EP03756231A patent/EP1554253A4/en not_active Withdrawn
- 2003-05-29 US US10/516,970 patent/US20050272936A1/en not_active Abandoned
- 2003-05-29 JP JP2004509663A patent/JP2005530813A/en active Pending
- 2003-05-29 WO PCT/US2003/016782 patent/WO2003101970A1/en not_active Application Discontinuation
- 2003-05-29 AU AU2003231872A patent/AU2003231872A1/en not_active Abandoned
Non-Patent Citations (3)
Title |
---|
CHAPMAN ET AL.: "Synthesis and 13C NMR spectra of cis- and trans-(2-(haloaryl)-2-((1H-imidazol)-1-yl)methyl))-1,3-dioxolane-4-methanols(1)", JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 27, no. 7, November 1990 (1990-11-01) - December 1990 (1990-12-01), pages 2053 - 2061, XP002970888 * |
NARDI ET AL.: "Synthesis and anticonvulsant activity of N-(benzoylalkyl)imidazoles and N-(w-phenylhydroxyalkyl)imidazoles", J. MED. CHEM., vol. 24, 1981, pages 727 - 731, XP002970889 * |
See also references of EP1554253A4 * |
Cited By (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7479496B2 (en) | 2004-02-19 | 2009-01-20 | Bristol-Myers Squibb Company | Substituted spiro azabicyclics as modulators of chemokine receptor activity |
US7381738B2 (en) | 2004-02-19 | 2008-06-03 | Bristol-Myers Squibb Company | Substituted bicycloalkylamine derivatives as modulators of chemokine receptor activity |
US7230022B2 (en) | 2004-02-19 | 2007-06-12 | Bristol-Myers Squibb Company | Substituted fused bicyclic amines as modulators of chemokine receptor activity |
US7288563B2 (en) | 2004-02-19 | 2007-10-30 | Bristol-Myers Squibb Company | Substituted bicycloalkylamine derivatives as modulators of chemokine receptor activity |
EP2546234A1 (en) | 2004-09-13 | 2013-01-16 | Ono Pharmaceutical Co., Ltd. | Nitrogeneous heterocyclic derivative and medicine containing the same as an active ingredient |
US7879838B2 (en) | 2005-02-16 | 2011-02-01 | Schering Corporation | Heteroaryl substituted pyrazinyl-piperazine-piperidines with CXCR3 antagonist activity |
US8207170B2 (en) | 2005-02-16 | 2012-06-26 | Schering Corporation | Heterocyclic substituted piperazines with CXCR3 antagonist activity |
US7776862B2 (en) | 2005-02-16 | 2010-08-17 | Schering Corporation | Pyridyl and phenyl substituted piperazine-piperidines with CXCR3 antagonist activity |
US7763616B2 (en) | 2005-02-16 | 2010-07-27 | Schering Corporation | Piperazine-piperidines with CXCR3 antagonist activity |
US7799789B2 (en) | 2005-02-16 | 2010-09-21 | Schering Corporation | Heterocyclic substituted pyridine or phenyl compounds with CXCR3 antagonist activity |
US7868005B2 (en) | 2005-02-16 | 2011-01-11 | Schering Corporation | Pyrazinyl substituted piperazine-piperidines with CXCR3 antagonist activity |
US7868006B2 (en) | 2005-02-16 | 2011-01-11 | Schering Corporation | Heterocyclic substituted piperazines with CXCR3 antagonist activity |
WO2006129679A1 (en) | 2005-05-31 | 2006-12-07 | Ono Pharmaceutical Co., Ltd. | Spiropiperidine compound and medicinal use thereof |
WO2007105637A1 (en) | 2006-03-10 | 2007-09-20 | Ono Pharmaceutical Co., Ltd. | Nitrogenated heterocyclic derivative, and pharmaceutical agent comprising the derivative as active ingredient |
US7786124B2 (en) | 2006-03-21 | 2010-08-31 | Schering Corporation | Heterocyclic substituted pyridine compounds with CXCR3 antagonist activity |
US8017616B2 (en) | 2006-03-21 | 2011-09-13 | Schering Corporation | Heterocyclic substituted pyridine compounds with CXCR3 antagonist activity |
US7902199B2 (en) | 2006-07-14 | 2011-03-08 | Schering Corporation | Heterocyclic substituted piperazine compounds with CXCR3 antagonist activity |
WO2008016006A1 (en) | 2006-07-31 | 2008-02-07 | Ono Pharmaceutical Co., Ltd. | Compound having cyclic group bound thereto through spiro binding and use thereof |
WO2009105435A1 (en) | 2008-02-19 | 2009-08-27 | Sanofi-Aventis | Inhibitors of the chemokine receptor cxcr3 |
US8268828B2 (en) | 2008-02-19 | 2012-09-18 | Sanofi | Inhibitors of the chemokine receptor CxCR3 |
EP2803356A1 (en) * | 2008-03-31 | 2014-11-19 | Agency for Science, Technology and Research | Method for treating neurological disorders with imidazolium and imidazolinium compounds |
WO2012000904A1 (en) | 2010-06-28 | 2012-01-05 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Pharmaceutical composition for use in the treatment of glaucoma |
Also Published As
Publication number | Publication date |
---|---|
JP2005530813A (en) | 2005-10-13 |
AU2003231872A1 (en) | 2003-12-19 |
US20050272936A1 (en) | 2005-12-08 |
EP1554253A4 (en) | 2006-09-20 |
EP1554253A1 (en) | 2005-07-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2003101970A1 (en) | Imidazolium cxcr3 inhibitors | |
KR100883184B1 (en) | CXCR3 antagonists | |
DE60031285T2 (en) | HETEROCYCLIC COMPOUNDS AND METHOD FOR MODULATING CXCR3 FUNCTION | |
US7067662B2 (en) | CXCR3 antagonists | |
CA2114542C (en) | Benzimidazolone derivatives as 5-ht1a and 5-ht2 antagonists | |
EP1917250B1 (en) | Anti-inflammatory aryl nitrile compounds | |
JP2709225B2 (en) | Benzimidazoles and pharmaceutical compositions containing these compounds | |
JP5162236B2 (en) | Imidazole compounds | |
US7939538B2 (en) | Compounds, compositions and methods for prevention and treatment of inflammatory and immunoregulatory disorders and diseases | |
RU2285004C2 (en) | Tetrahydropyranyl-cyclopentyl-tetrahydropyridopyridine modulators of chemokine receptor activity | |
EP1100795B1 (en) | Disubstituted bicyclic heterocycles having, in particular, a thrombin inhibitive effect | |
WO1998037075A1 (en) | Disubstituted bicyclic heterocycles, their production and use as medicaments | |
JP2008504304A (en) | Tetrahydroquinazolin-4 (3H) -one related and tetrahydropyrido [2,3-D] pyrimidin-4 (3H) -one related compounds, compositions and methods of their use | |
EP2257552A1 (en) | Heterocyclic compounds as inhibitors of cxcr2 | |
DE60101372T2 (en) | PYRIMIDINE COMPOUNDS AND THEIR USE AS MODULATORS OF CHEMOKIN RECEPTOR ACTIVITY | |
JP2006508948A (en) | Heteroarylpiperidine modulators of chemokine receptor activity | |
CA2144374A1 (en) | Benzimidazoles, pharmaceutical compositions containing these compounds and processes for preparing them | |
CA2481532A1 (en) | Imidazole compounds as anti-inflammatory and analgesic agents | |
EP0358595B1 (en) | N-hetaryl imidazole derivatives | |
CA1340785C (en) | Platelet activating factor antagonists | |
US20040214864A1 (en) | Novel compounds | |
JP2003503488A (en) | Piperazine derivatives as modulators of chemokine receptor activity | |
WO2007076318A2 (en) | Camphor-derived cxcr3 antagonists | |
JPH01157982A (en) | Thiazole derivative and production thereof | |
WO2001047896A1 (en) | Benzimidazoles, production thereof and the use thereof as antithrombotic |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 10516970 Country of ref document: US Ref document number: 2004509663 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2003756231 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 2003756231 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 2003756231 Country of ref document: EP |