CN1398181A - Method and compsns. for treating inflammatory disease - Google Patents
Method and compsns. for treating inflammatory disease Download PDFInfo
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- CN1398181A CN1398181A CN01804708A CN01804708A CN1398181A CN 1398181 A CN1398181 A CN 1398181A CN 01804708 A CN01804708 A CN 01804708A CN 01804708 A CN01804708 A CN 01804708A CN 1398181 A CN1398181 A CN 1398181A
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- 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
- A61K31/60—Salicylic acid; Derivatives thereof
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
This invention relates to treating an inflammatory disease by administering a phosphodiesterase 4 inhibitor in combination with an inhibitor of prostaglandin synthesis, NSAIDs being exemplary.
Description
Invention field
The present invention relates to phosphodiesterase 4 inhibitors and the prostaglandin synthesis inhibitors for example compositions and the method for the prevention of NSAIDs co-administered or treatment inflammatory diseases.
Background of invention
Because multiple medium may all work to the development of pneumonopathy, institute is so that differentiate that new pneumotherapy agent is relatively more difficult.Like this, as if, can not eliminate the influence that single medium may have practical function to the component of all three kinds of chronic asthmas.Another method of " medium approach " is to regulate the physiopathologic cytoactive of this disease of decision.
One of this method is to improve the content of cAMP (3 ', 5 '-ring adenosine monophosphate).Ring-type AMP has been proved to be the second message,second messenger who regulates various hormones, neurotransmitter and medicine biological respinse; [Krebs, the 4th endocrinology made progress international conference medical science and taken passages 17-29,1973].When appropriate agonist was attached on the special cell surface receptor, adenyl cyclase just was activated, and it can be with Mg
+ 2-ATP quickens to be converted into cAMP.Ring-type AMP can regulate great majority, but is not the cytoactive that whole physiological and pathologicals to exogenous (allergy) asthma works.Like this, the rising of cAMP will bring about a wholesome effect, and comprise: 1) airway smooth muscle is lax, 2) suppress the release of labrocyte medium, 3) suppress the degeneration of neutrophilic leukocyte, 4) suppress the degeneration and 5 of basophil) suppress the activation of mononuclear cell and macrophage.So the chemical compound of activated adenyl cyclase or inhibition phosphodiesterase should effectively suppress abnormal activation of airway smooth muscle and various inflammatory cell.The main celelular mechanism of cAMP inactivation is 3 '-phosphodiester bond is referred to as cyclic nucleotide phosphodiesterase (PDEs) by gang or many families isozyme hydrolysis.
Shown that unique cyclic nucleotide phosphodiesterase (PDE) isozyme PDE IV has determined the destruction of the cAMP in airway smooth muscle and the inflammatory cell.[Torphy, " di-phosphate ester enzyme isoenzyme: the potential target of new anti-asthma agent ", the asthma new drug, Barnes edits, IBC Technology Service Co., Ltd, 1989].Studies show that suppressing this kind of enzyme not only can produce the lax of airway smooth muscle, but also can hinder the degeneration basophil and the neutrophilic leukocyte of mastocyte, and suppress the activation of mononuclear cell and neutrophilic leukocyte.And as situation in vivo, when the activity of the adenyl cyclase of target cell was raise by appropriate hormones or autacoid, the beneficial effect of PDE IV inhibitor was more remarkable.Like this, PDE IV inhibitor is that effectively prostaglandin E wherein can raise in lung
2And prostacyclin (activator of adenyl cyclase).This compounds provides unique approach of a Drug therapy bronchial allergy and has than in the market medicament significantly good treatment advantage.
In addition, comprise the fact of multiple medium, should use the combined treatment method according to the cause of disease of many pneumonopathy.The combined therapy and synthetic relevant inflammatory component medicable inflammatory diseases of associated PDE4-selective depressant or the symptom of prostacyclin that have PDE 4 inhibitor and non-steroidal anti-inflammatory agents in the present invention.
Summary of the invention
First aspect, the present invention relates to a kind of method for the treatment of the mammal inflammatory diseases, comprise the PDE 4-specific inhibitor of patient's effective dosage for the treatment of and the non-steroidal anti-inflammatory agents of effective dose to needs, its Chinese medicine is common or separately also administration in succession, and wherein administration time is close or far away in succession.
Detailed description of the present invention
Combination treatment involved in the present invention comprises that administration PDE4 inhibitor and non-steroidal anti-inflammatory agents treat inflammatory diseases.Chemical compound can the administration together of single dosage form.Perhaps they are with two kinds of different dosage form administrations.In order to describe in detail, two kinds of medicines can be respectively as peroral dosage form, and perhaps a kind of medicine is to provide with oral formulations or suppository or by injection or intravenous drip.Their administrations simultaneously.Perhaps they are at nearer time or time administration far away, administration and the second kind of medicine administration at night in the morning of a kind of like this medicine.
Be used for PDE4-specific inhibitor of the present invention and can be any known inhibition PDE4 chemical compound enzyme or that had been found that the effect of PDE4 inhibitor and be PDE4 inhibitor and do not suppress the chemical compound of other members of PDE family and PDE4.General preferred use IC
50Than being about 0.1 or bigger PDE4 antagonist, wherein IC
50Than being with the IC of high affinity in conjunction with the PDE IV catalysis form of Rolipram
50Divided by with the IC of low affinity in conjunction with the Rolipram form
50
The PDE inhibitor that resembles theophylline and pentoxifylline indistinguishably suppresses whole or most of PDE isozymes in a organized way.These chemical compounds have side effect, obviously because they non-selectively suppress the whole PDE isozyme classes in a organized way.Target disease can effectively be treated by this compounds, but may have undesirable side effect, if minimum is avoided or dropped in these side effect, will increase the overall therapeutical effect of some disease method of this treatment.For example, show that with the clinical research that is developed as the selectivity PDE4 inhibitor Rolipram of antidepressants it has the active of close spirit and produces gastrointestinal influence, for example heartburn, nausea and vomiting.
For purpose of the present invention, will be with low affinity in conjunction with cAMP catalytic site called after " low affinity " binding site (LPDE4) of the Rolipram of R and S and will be with high affinity this other form catalytic site called after " high affinity " binding sites (HPDE4) in conjunction with Rolipram.This term " HPDE4 " is not and be used to represent that the term " hPDE4 " of people's PDE4 obscures.
Carry out initial trial set up and confirm [
3H] the R-Rolipram in conjunction with measuring.To provide the details of these work among the following embodiment 1.
For determine the high affinity that is present on the homologous genes product in conjunction with active and low affinity in conjunction with activity, also follow in the recombinate expression of PDE4 of 6 hours yeast phases with the known method transformed yeast.Use western blot analysis method to show that the amount of expressed PDE4 increases in time, grow and reach maximum after 3 hours at anti-PDE4 antibody.In addition, the immune reaction product more than 90% is present in the high speed of yeast lysate (in 100,000 * g) the supernatant.Along with protein expression monitoring [
3H] combination and the PDE activity of R-Rolipram.With the active co expression PDE4 activity of the combination of Rolipram, show that two kinds of functions are present on the same gene outcome.Result with western blot analysis is similar, the Rolipram more than 85%-quenchable PDE active and [
3H] the R-Rolipram all finds to be present in yeast supernatant part in conjunction with activity.
In a word, expressed most of recombinant PDE4 exist with the LPDE4 form and have only small part to exist with the HPDE4 form in this system.So the inhibition of recombinant PDE4 catalytic activity mainly reflects the effect of chemical compound at LPDE4.Like this, the inhibition of PDE4 catalytic activity can be as the index of chemical compound in the LPDE4 effect.Chemical compound the effect of HPDE4 can by detect they with [
3H] competitiveness of R-Rolipram estimates.In order to develop the SARs of the Rolipram binding site that hangs down affinity and high affinity, the effect of selected compounds can be measured with two kinds of mensuration systems.Use the result of the test tabulation expression of n-compound.As desired, some chemical compound with [
3H] the R-Rolipram is that the competition at other positions of low affinity bonding agent has obviously stronger effect at the binding site that confirms to have high affinity than Rolipram.High affinity combination and low affinity in conjunction with between the SAR relation relatively poor, conclusion be high affinity [
3H] the R-Rolipram is different from the low bonded SAR of affinity Rolipram binding site in conjunction with the SAR that suppresses.
Now known can with the interactional person monocytic cell's recombinant of inhibitor PDE4 (hPDE4) at least two kinds of combining forms are arranged.A kind of explanation to these observations is that two kinds of hPDE4 existence are multi-form.A kind of can high affinity ground in conjunction with Rolipram and denbufylline analog and another can hang down affinity ground in conjunction with these chemical compounds.Being used for preferred PDE4 inhibitor of the present invention is those chemical compounds with useful treatment ratio, promptly, the preferred chemical compound that suppresses the cAMP catalytic activity, wherein this enzyme is the form of low affinity in conjunction with Rolipram, but reduce thus obviously with the inhibition high affinity in conjunction with the relevant side effect of Rolipram form.Another describing method is that preferred chemical compound has about 0.1 or higher IC
50Ratio, it is the IC of high affinity ground in conjunction with the PDE catalysis form of Rolipram
50Divided by hanging down the IC of affinity ground in conjunction with Rolipram
50
The expression that this standard is clearer and more definite is that wherein the PDE4 inhibitor has about 0.1 or bigger IC
50Ratio; But this ratio be high affinity ground in conjunction with the PDE4 form competition of Rolipram in conjunction with 1nM [
3H] IC of R-Rolipram
50Value and use 1mM[
3H]-cAMP makes substrate and suppresses the IC of low affinity ground in conjunction with the PDE IV catalytic activity of the form of Rolipram
50The ratio of value.This is tested further summary and finds in the description of the United States Patent (USP) 5,998,428 of pending trial at the same time, at this, is necessary to implementing the present invention as a reference with its content quotation in full.
Most preferably those have the IC greater than 0.5
50The PDE4 inhibitor of ratio, particularly those have the chemical compound of 1.0 above ratios.Preferred chemical compound is cis-4-cyano group-4-(3-cyclopentyloxy-4-methoxyphenyl) cyclohexane extraction-1-carboxylic acid (Ariflo
).In addition, following PDE4 inhibitor can be used for enforcement of the present invention: from AWD-12-281 (Hofgen, N. etc., pharmaceutical chemical the 15th the EFMC international symposium (JIUYUE 6-10 day, Edinburgh) 1998, summary, the 98th page) of Astra; The 9-benzyladenine derivant (INSERM) of called after NCS-613; D-4418 from Chiroscience and Schering-Plough; The benzodiazepine PDE4 inhibitor (PD-168787 of called after CI-1018; Parke-Davis/Warner-Lambert); Kyowa Hakko is disclosed benzo benzodioxole derivatives in WO 9916766; V-11294A (Landells, L.J. etc., Eur Resp J[Annu Cong Eur Resp Soc (JIUYUE 19-23 day, Geneva) 1998) 1998,12 (supplementary issue, 28) from Napp: summary, the 2393rd page); Roflumilast (CAS reference number 162401-32-3) and from the pthalazinone (WO 9947505) of Byk-Gulden; The perhaps chemical compound of called after T-440 (Tanabe Seiyaku; Fuji, K. etc., J Pharmacol Exp Ther, 1998,284 (1): 162).
Can be used for non-steroidal anti-inflammatory drugs of the present invention (NSAIDs) is that those can suppress the synthetic medicine of prostaglandin.Can think that NSAIDs is by suppressing cyclo-oxygenase-1 (COX-1) and cyclo-oxygenase-2 (COX-2) works.Many medicines belong to this class.For example, the present invention can use following one or more NSAIDs: aspirin, card network sweet smell, choline salicylate, ketone network phenol, magnesium salicylate, salicylamide, salsalate, sodium salicylate, thiosalicylic acid sodium, meclofenamate sodium, crovaril, Phenylbutazone, indomethacin, piroxicam, sulindac, tolmetin, tolmetin sodium, mefenamic acid, McN 2783-21-98, ibuprofen, fenoprofen, naproxen, naproxen sodium, diclofenac, flurbiprofen, ketoprofen, the ketone complex acid, tromethane, celecoxib, Diflunisal and nabumetone.All these medicines can all have clearly description from commercial source acquisition or they medical science and other scientific literatures.
The pain relieving and the antiinflammatory action of combination NSAIDs and PDE4-specific inhibitor can be so that this combination be particularly useful for the remission of pain and/or inflammation disease, these diseases comprise rheumatism such as rheumatic arthritis, osteoarthritis and spondyloarthropathy, also comprise periarticular disease and soft tissue rheumatism.This combination also can be used for the treatment of the pneumonopathy that has inflammation.
Can consider with two kinds of activating agents whiles or at very near time administration.Another method, the administration on daytime of then a kind of medicine of a kind of medicine administration in morning.Perhaps another scheme, a kind of medicine is administered twice every day, another or in twice administration every day once in or separate administration once.The administration simultaneously of preferred two kinds of medicines.
Have active The compounds of this invention and its pharmaceutically acceptable salt during oral administration and can be mixed with syrup, tablet, capsule, sustained release preparation or lozenge.Syrup generally by compound or its salt in for example suspension or the solution composition in ethanol, Oleum Arachidis hypogaeae semen, olive oil, glycerol or water and correctives or the coloring agent of liquid-carrier.When compositions was tablet, any common carrier that pharmaceutically prepares solid dosage forms can be used.The example of these carriers comprises magnesium stearate, Gypsum Fibrosum powder, Pulvis Talci, gelatin, arabic gum, stearic acid, starch, lactose and sucrose.When compositions was capsule, any encapsulation commonly used all was fit to, and for example uses aforementioned carriers in the hard gelatin capsule shell.When compositions is soft capsule, can consider the pharmaceutical carriers of using any preparation dispersion liquid or suspension to use always, for example moisture natural gum, cellulose, silicate or oils, and it can be incorporated in the soft gelatin softgel shell.
General parenteral compositions is made up of the solution or the suspension of compound or its salt in sterilized water or nonaqueous carrier, its optional acceptable oil of parenteral for example Polyethylene Glycol, polyvinylpyrrolidone, lecithin, Oleum Arachidis hypogaeae semen or Oleum sesami of containing.
General composition for inhalation is the form of solution, suspension or emulsion that can the dry powder administration, perhaps uses the aerosol form of conventional propellant such as fluorinated hydrocarbons such as Arcton 11.
The preferred composition of PDE4 inhibitor is the unit dosage forms as tablet or capsule or sustained release preparation.When NSAIDs generally passed through oral administration, some of them for example diclofenac, ketoprofen, ketorolac, piroxicam and tenoxicam can be by the intramuscular injection administration.Ketorolac and tenoxicam also can pass through intravenous administration.
These active component can administration every day 1 to 6 time, is enough to have required activity.Preferably, about 1 to 2 time of these active component administrations every day, more preferably twice of every day.
As for dosage, can think the PDE4 inhibitor can every day the amount administration of each adult's 1 to 200 microgram.NSIADs indicates administration according to approval.
Embodiment 1---and the combination of phosphodiesterase and Rolipram is measured
Embodiment 1A
Isolated person monocytic cell PDE4 and hrPDE (people's recombinant PDE4) are measured the low affinity form of main existence.So, use 1mM[
3H] cAMP do the standard test method of the PDE4 catalytic activity of substrate can the evaluation test chemical compound activity (Torphy etc., J.Of Biol.Chem., the 267th volume, the 3rd phase, 1798-1804 page or leaf, 1992) of PDE4 of anti-low affinity form.
With Mus brain high speed centrifugation supernatant do protein sources and with two kinds [
3H]-isomers of Rolipram is prepared into the specific activity of 25.6Ci/mmol.Improvement standard test condition makes it identical with the PDE condition determination, except last cAMP:50mM Tris HCl (pH7.5), 5mMMgCl from the method for announcing
2With 1nM [
3H]-Rolipram (torphy etc., J.Of Biol.Chem., the 267th volume, the 3rd phase, 1798-1804 page or leaf, 1992).30 ℃ of mensuration of carrying out 1 hour.Cessation reaction is also separated bonded part with the Brandel cell harvester with free ligand.Be used for measuring the competition of measuring the high affinity binding site under low active the same terms of affinity PDE with those, except [
3H]-cAMP and 5 ' AMP do not exist.
Embodiment 1B
The mensuration of phosphodiesterase activity
Use supplier (Amersham Life Science) described [
3H] cAMP SPA or [
3H] cGMP scintillation proximity analysis (SPA) enzyme assay mensuration PDE activity.At room temperature react in the 0.1ml reaction buffer in the plate of 96-hole, wherein reaction buffer contains (ultimate density): 50mM Tris-HCl, pH7.5,8.3mM MgCl
2, 1.7mM EGTA, [
3H] cAMP or [
3H] cGMP (approximately 2000dpm/pmol), the inhibitor of enzyme and various concentration.Make these mensuration carry out 1 hour and in the presence of zinc sulfate, add the SPA yttrium silicate pearl cessation reaction of 50 μ l.The vibration plate was also placed 20 minutes in room temperature.Measuring radiolabeled product with scintillation spectrometry forms.With 0.05 μ M[
3H] cAMP measures the activity of PDE3 and PDE7, and with 1 μ M[
3H] cAMP makes substrate and measures PDE4.With 1 μ M[
3H] cGMP makes the activity that substrate is measured PDE1B, PDE1C, PDE2 and PDE5.
[
3
H] the R-Rolipram in conjunction with measuring
With Schneider and colleague's modification method, referring to Nicholson etc., Trends Pharmacol.Sci., the 12nd volume 19-27 page or leaf (1991) and McHale etc., Mol.Pharmacol., the 39th rolls up, 109-113 page or leaf (1991), carry out [
3H] the R-Rolipram in conjunction with measuring.The R-Rolipram is attached to the catalytic site of PDE4, referring to Torphy etc., and Mol.Pharmacol., the 39th volume 376-384 page or leaf (1991).So, to [
3H] the bonded competition of R-Rolipram provides independently evidence for the effect of the PDE4 inhibitor of unlabelled competitor.This is determined at 30 ℃ and has carried out 1 hour, and 0.5 μ l buffer of use contains (ultimate density): 50mM Tris-HCl, pH7.5,5mM MgCl
2, 0.05% bovine serum albumin, 2nM[
3H] R-Rolipram (5.7 * 104dpm/pmol) and the nonradioactive labeling's of various concentration inhibitor.This reaction be by the ice-cold reaction buffer that adds 2.5ml (do not contain [
3H] the R-Rolipram) stop and the WhatmanGF/B filter fast vacuum filtration (Brandel cell harvester) by soaking in 0.3% polymine.With the ice-cold buffer washing and filtering device of other 7.5ml, dry also by the liquid-scintillation spectrum rolling counters forward.
The preparation of embodiment 2-sustained release sheet
Prepare sustained release agent with ingredients listed in the table 1.
Table 1
| Composition | ????％w/w |
| ?Ariflo | ????3.3 |
| Two alkali valency calcium phosphate (anhydrous) | ????88.5 |
| Carbomer934P | ????3.3 |
| Carbomer941P | ????1.6 |
| Magnesium stearate | ????1.0 |
| Opadry?White?OY-S-9603 | ????2.4 |
| Pure water | In right amount |
Mix and compact technique:
Mix
Be put in the mixer excipient and medicine and mixing.Added magnesium stearate and remix then 3 minutes.In hybrid technique, with excipient and medicament mixed, sieve, and then mix.
Compacting
With the about 350mg compacting of each mixture in flakes.Use the target patch of 10kp intensity.
Be suspended in Opadry White in the pure water and use suspension parcel tablet; In the coating process, remove moisture and do not form the part final products.
The preparation of embodiment 3-moderate releasing piece
Prepare the moderate releasing piece with standard method, it contains ingredients listed in the table 2.
Table 2
The moderate releasing piece
| Composition | Quantity (mg/ sheet) | Quantity (mg/ sheet) | Quantity (mg/ sheet) |
| Ariflo | ????5.0 | ????10.0 | ????15.0 |
| Single water and milk sugar | ????113.0 | ????108 | ????103 |
| Microcrystalline Cellulose | ????70.0 | ????70.0 | ????70.0 |
| The gluconic acid Starch Sodium | ????10.0 | ????10.0 | ????10.0 |
| Magnesium stearate | ????2.0 | ????2.0 | ????2.0 |
| Opadry?White?OY-S-9603 | ????5.0 | ????5.0 | ????5.0 |
| Total sheet weight (mg) | ????205.0 | ????205 | ????205 |
The arthritic treatment of embodiment 4-
Give be diagnosed as arthritis and since patient's every day that arthritis stands pain the prepared 30mg Ariflo that contains among twice administration embodiment 2
Sustained release sheet and 500mg Relafen (nabumetone) sheet.Continued treatment alleviates up to inflammation.
Claims (2)
1. method for the treatment of inflammatory diseases comprises to the patient of this treatment of needs with common form, divided mode or separately and in succession the PDE4 inhibitor and the nonsteroidal anti-inflammatory (NSAID) of form administration effective dose, in succession administration time near or far away.
2. the method for claim 1, wherein the PDE4 inhibitor is cis 4-cyano group-4-(3-cyclopentyloxy-4-methoxyphenyl) cyclohexane extraction-1-carboxylic acid, and NSAID is selected from the group of following medicine composition: aspirin, card network sweet smell, choline salicylate, ketone network phenol, magnesium salicylate, salicylamide, salsalate, sodium salicylate, thiosalicylic acid sodium, meclofenamate sodium, crovaril, Phenylbutazone, indomethacin, piroxicam, sulindac, tolmetin, tolmetin sodium, mefenamic acid, McN 2783-21-98, ibuprofen, fenoprofen, naproxen, naproxen sodium, diclofenac, flurbiprofen, ketoprofen, the ketone complex acid, tromethane, celecoxib, Diflunisal and nabumetone.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US18087900P | 2000-02-08 | 2000-02-08 | |
| US60/180,879 | 2000-02-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1398181A true CN1398181A (en) | 2003-02-19 |
Family
ID=22662062
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN01804708A Pending CN1398181A (en) | 2000-02-08 | 2001-02-08 | Method and compsns. for treating inflammatory disease |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP1253919A4 (en) |
| JP (1) | JP2003522142A (en) |
| KR (1) | KR20020073577A (en) |
| CN (1) | CN1398181A (en) |
| AU (1) | AU7205701A (en) |
| BR (1) | BR0108087A (en) |
| CA (1) | CA2398184A1 (en) |
| CZ (1) | CZ20022682A3 (en) |
| HK (1) | HK1051319A1 (en) |
| HU (1) | HUP0300689A3 (en) |
| IL (1) | IL150963A0 (en) |
| MX (1) | MXPA02007688A (en) |
| NO (1) | NO20023737L (en) |
| PL (1) | PL356447A1 (en) |
| WO (1) | WO2001058441A1 (en) |
| ZA (1) | ZA200206252B (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7338971B2 (en) * | 2001-08-30 | 2008-03-04 | El-Naggar Mawaheb M | Treatment of inflammatory, cancer, and thrombosis disorders |
| WO2003024489A2 (en) * | 2001-09-19 | 2003-03-27 | Altana Pharma Ag | Combination of a nsaid and a pde-4 inhibitor |
| EP1463509A1 (en) * | 2001-10-31 | 2004-10-06 | MERCK PATENT GmbH | Type 4 phosphodiesterase inhibitors and uses thereof |
| WO2004098605A1 (en) * | 2003-05-12 | 2004-11-18 | Altana Pharma Ag | Pharmaceutical composition comprising a pde4 inhibitor and il-1 trap |
| WO2005020926A2 (en) * | 2003-08-28 | 2005-03-10 | Pharmacia Corporation | Treatment or prevention of vascular disorders with cox-2 inhibitors in combination with cyclic amp-specific phosphodiesterase inhibitors |
| EP2400961B1 (en) * | 2009-02-27 | 2017-11-22 | Boehringer Ingelheim International GmbH | Medicine combinations containing pde4 inhibitors and nsaids |
| US9161927B2 (en) * | 2009-02-27 | 2015-10-20 | Boehringer Ingelheim International Gmbh | Drug combinations containing PDE4 inhibitors and NSAIDs |
| CA2804744C (en) | 2010-07-14 | 2019-05-28 | Novartis Ag | Ip receptor agonist 1,8-naphthyridinyl and 7,8-dihydropyrido[3,2-b]pyrazinyl heterocyclic compounds |
| ES2565826T3 (en) | 2012-01-13 | 2016-04-07 | Novartis Ag | Fused pyrroles as IP receptor agonists for the treatment of pulmonary arterial hypertension (PAH) and related disorders |
| EP2956455B1 (en) | 2013-02-13 | 2017-05-17 | Novartis AG | Ip receptor agonist heterocyclic compounds |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4061779A (en) * | 1973-09-11 | 1977-12-06 | Beecham Group Limited | Naphthalene derivatives having anti-inflammatory activity |
| GB9108128D0 (en) * | 1991-04-15 | 1991-06-05 | Zambeletti Spa L | Novel formulation |
| US5552438A (en) * | 1992-04-02 | 1996-09-03 | Smithkline Beecham Corporation | Compounds useful for treating allergic and inflammatory diseases |
| US6005118A (en) * | 1996-05-03 | 1999-12-21 | Caron; Stephane | Methods of preparing 4-cyano-4 (substituted indazole) cyclohexane-carboxylic acids useful as PDE4 inhibitors |
| FR2753706B1 (en) * | 1996-09-20 | 1998-10-30 | NOVEL N-SUBSTITUTED CYCLIC AMINES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
-
2001
- 2001-02-08 PL PL01356447A patent/PL356447A1/en not_active Application Discontinuation
- 2001-02-08 AU AU72057/01A patent/AU7205701A/en not_active Abandoned
- 2001-02-08 JP JP2001557552A patent/JP2003522142A/en not_active Withdrawn
- 2001-02-08 WO PCT/US2001/003972 patent/WO2001058441A1/en not_active Application Discontinuation
- 2001-02-08 KR KR1020027010037A patent/KR20020073577A/en not_active Application Discontinuation
- 2001-02-08 IL IL15096301A patent/IL150963A0/en unknown
- 2001-02-08 EP EP01951123A patent/EP1253919A4/en not_active Withdrawn
- 2001-02-08 CZ CZ20022682A patent/CZ20022682A3/en unknown
- 2001-02-08 CA CA002398184A patent/CA2398184A1/en not_active Abandoned
- 2001-02-08 HU HU0300689A patent/HUP0300689A3/en unknown
- 2001-02-08 BR BR0108087-3A patent/BR0108087A/en not_active Application Discontinuation
- 2001-02-08 CN CN01804708A patent/CN1398181A/en active Pending
- 2001-02-08 MX MXPA02007688A patent/MXPA02007688A/en not_active Application Discontinuation
-
2002
- 2002-08-06 ZA ZA200206252A patent/ZA200206252B/en unknown
- 2002-08-07 NO NO20023737A patent/NO20023737L/en not_active Application Discontinuation
-
2003
- 2003-03-25 HK HK03102154.5A patent/HK1051319A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CZ20022682A3 (en) | 2003-09-17 |
| NO20023737L (en) | 2002-09-27 |
| CA2398184A1 (en) | 2001-08-16 |
| HUP0300689A3 (en) | 2003-09-29 |
| NO20023737D0 (en) | 2002-08-07 |
| AU7205701A (en) | 2001-08-20 |
| EP1253919A1 (en) | 2002-11-06 |
| PL356447A1 (en) | 2004-06-28 |
| JP2003522142A (en) | 2003-07-22 |
| EP1253919A4 (en) | 2007-03-14 |
| BR0108087A (en) | 2002-10-29 |
| ZA200206252B (en) | 2003-08-26 |
| MXPA02007688A (en) | 2002-12-13 |
| KR20020073577A (en) | 2002-09-27 |
| WO2001058441A1 (en) | 2001-08-16 |
| HK1051319A1 (en) | 2003-08-01 |
| HUP0300689A2 (en) | 2003-07-28 |
| IL150963A0 (en) | 2003-02-12 |
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| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |