CN1329505A - Composition and method for treating allergic diseases - Google Patents
Composition and method for treating allergic diseases Download PDFInfo
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- CN1329505A CN1329505A CN99814057A CN99814057A CN1329505A CN 1329505 A CN1329505 A CN 1329505A CN 99814057 A CN99814057 A CN 99814057A CN 99814057 A CN99814057 A CN 99814057A CN 1329505 A CN1329505 A CN 1329505A
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- neurokinin
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- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
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- 235000010338 boric acid Nutrition 0.000 description 1
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- 239000000648 calcium alginate Substances 0.000 description 1
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- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- OKHHGHGGPDJQHR-YMOPUZKJSA-L calcium;(2s,3s,4s,5s,6r)-6-[(2r,3s,4r,5s,6r)-2-carboxy-6-[(2r,3s,4r,5s,6r)-2-carboxylato-4,5,6-trihydroxyoxan-3-yl]oxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylate Chemical compound [Ca+2].O[C@@H]1[C@H](O)[C@H](O)O[C@@H](C([O-])=O)[C@H]1O[C@H]1[C@@H](O)[C@@H](O)[C@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@H](O2)C([O-])=O)O)[C@H](C(O)=O)O1 OKHHGHGGPDJQHR-YMOPUZKJSA-L 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
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- 238000004132 cross linking Methods 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229960001985 dextromethorphan Drugs 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000014632 disordered eating Nutrition 0.000 description 1
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- 238000011010 flushing procedure Methods 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
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- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
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- 239000000499 gel Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 229960002146 guaifenesin Drugs 0.000 description 1
- 239000007887 hard shell capsule Substances 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
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- 206010022000 influenza Diseases 0.000 description 1
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- 235000010420 locust bean gum Nutrition 0.000 description 1
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- 206010027599 migraine Diseases 0.000 description 1
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- LBFBRXGCXUHRJY-HKHDRNBDSA-M montelukast sodium Chemical compound [Na+].CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC([O-])=O)CC1 LBFBRXGCXUHRJY-HKHDRNBDSA-M 0.000 description 1
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- 230000004770 neurodegeneration Effects 0.000 description 1
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- 125000004971 nitroalkyl group Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229940041672 oral gel Drugs 0.000 description 1
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- 229960005489 paracetamol Drugs 0.000 description 1
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- 230000002093 peripheral effect Effects 0.000 description 1
- 239000002985 plastic film Substances 0.000 description 1
- 229920006255 plastic film Polymers 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000307 polymer substrate Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229940114930 potassium stearate Drugs 0.000 description 1
- ANBFRLKBEIFNQU-UHFFFAOYSA-M potassium;octadecanoate Chemical compound [K+].CCCCCCCCCCCCCCCCCC([O-])=O ANBFRLKBEIFNQU-UHFFFAOYSA-M 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
- ICNCMCHAPLUNBG-UHFFFAOYSA-N propyl carbamodithioate Chemical compound CCCSC(N)=S ICNCMCHAPLUNBG-UHFFFAOYSA-N 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
- 229960003908 pseudoephedrine Drugs 0.000 description 1
- 239000012925 reference material Substances 0.000 description 1
- 210000001533 respiratory mucosa Anatomy 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
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- 239000003765 sweetening agent Substances 0.000 description 1
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- 230000001839 systemic circulation Effects 0.000 description 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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- MWLSOWXNZPKENC-UHFFFAOYSA-N zileuton Chemical compound C1=CC=C2SC(C(N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- 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
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/14—Decongestants or antiallergics
-
- 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
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- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Ophthalmology & Optometry (AREA)
- Otolaryngology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention is directed towards a pharmaceutical composition useful for the treatment of allergic rhinitis, asthma and related disorders. In one embodiment, the composition comprises, in combination, a therapeutically effective amount of at least one neurokinin antagonist, and a therapeutically effective amount of at least one 5-lipoxygenase inhibitor.
Description
Invention field
The present invention relates generally to be used for the treatment of the compositions and the method for allergic rhinitis and other respiratory disorder.It especially openly comprises the combination of (i) neurokinin receptor antagonists and LTRA, the (ii) compositions of the combination of neurokinin receptor antagonists and 5-lipoxidase inhibitor, and the method for using so above-mentioned disease of combination treatment.
Background of invention
Neurokinin (" NK ") receptor is NK for example
1And NK
2Receptor is found in mammiferous central nervous system, blood circulation and peripheral tissues, and is participated in regulate several biological processes.Therefore, the expectation neurokinin receptor antagonists is used for the treatment of or prevents multiple mammiferous disease, for example pulmonary disease such as asthma, cough, bronchospasm, chronic obstructive pulmonary disease and respiratory tract anaphylaxis; The dermatosis and the atopic dermatitis of for example scratching where it itches, skin wind is determined and flushing, neuron inflammatory diseases such as arthritis, migraine, nociperception; The CNS disease is anxiety, vomiting, parkinson, movement disorders and psychosis for example; Convulsions disease, nephropathy, urinary incontinence, ophthalmia, inflammatory pain and eating disorder such as food intake suppress; Allergic rhinitis, neurodegenerative disease, psoriasis, Huntington's disease, depression and multiple disease such as Ke Langshi disease.It is reported NK
1Receptor participates in microvascular leakage and mucous secretion, and NK
2Receptor is relevant with smooth muscle contraction, makes NK
1And NK
2Receptor antagonist is used in particular for treatment and prevention of asthma.For example in U.S. patent 5,798,359,5,795,894,5,789,422,5,783,579,5,719,156,5,696,267,5,691,362,5,688,960,5, in 654,316 (all the transferring Schering-Plough company, Madison, New Jersey) and by C.J.Ohnmacht Jr etc., Annual Reports in Medicinal Chemistry, A.M.Doherty edits, and 33, reported NK among the 71-80 (1998) " neurokinin receptor antagonists latest developments "
1And NK
2Receptor antagonist.
Product, the especially leukotriene of arachidonic 5-lipoxygenase metabolism (" 5-LO ") approach can mediate bronchoconstriction, mucosa secretion, respiratory mucosa edema, cell chemotaxis and move in the bronchus in the inflammatory process of asthma.Therefore, suppressing 5-LO should help to cure, alleviate or prevent such disease.Similarly, leukotriene (" LK ") antagonist is the treatment multiple symptom relevant with respiratory tract disease for example pollinosis, annual allergic rhinitis, flu, sinusitis and work in the relevant concomitant symptom with allergic asthma.The symptom of disease can comprise sneeze like this, the nose snotty of scratching where it itches, nasal congestion, one's eyes became bloodshot, shed tears, ear or palate are scratched where it itches and the cough relevant with the postnasal drip symptom.In R. Robertson, Prostaglandins, 31, can find the discussion of leukotriene receptor in 395 (1986), and at J.Musser etc., Agents and Actions, 18,332 (1986), J.Piwinski etc., Annual Reports in Medicinal Chemistry, 22,73-76 (1987), with R.Bell etc., Annual Reports in Medicinal Chemistry, 32, in 91 (1997), can find the discussion of leukotriene antagonist.
The effectiveness that strengthens neurokinin to be improving their whole effectiveness by the activity of disturbing 5-LO and leukotriene receptor, and alleviates or prevent above-mentioned disease to press for.
Summary of the invention
The present invention emphasizes the purpose and the requirement of above-mentioned purpose and other, and the present invention provides treatment and prevention of allergic rhinitis and other respiratory tract disease for example asthma, the compositions of coughing, stridulating etc. in one embodiment.Described inventive compositions comprises at least a neurokinin of the treatment effective dose that exists with combining form and at least a leukotriene antagonist of treatment effective dose.Can for example salt, ester etc. be replaced one or more antagonisies by pharmaceutically acceptable derivates.Described compositions can be chosen wantonly and comprise pharmaceutically acceptable carrier, Decongestant (for example pseudoephedrine), cough suppressant's (for example dextromethorphan), expectorant (for example guaifenesin), analgesic (for example aspirin, ibuprofen and acetaminophen) or their mixture in addition.
The content of the neurokinin in the present composition of per unit dosage form is generally about 1-1, and 000 milligram of amount with leukotriene antagonist is about 2-500 milligram.Amount separately is preferably about 10-500 milligram and about 5-500 milligram, and amount separately is typically about 50-200 milligram and about 10-50 milligram.
The respiratory disorder that the present invention provides treatment and prevention of allergic rhinitis and other in addition is asthma, the compositions of coughing, stridulating etc. for example, and described compositions comprises at least a neurokinin of the treatment effective dose that exists with combining form and treats at least a 5-LO inhibitor of effective dose.Can for example salt, ester etc. be replaced one or more chemical compounds by pharmaceutically acceptable derivates.In addition, compositions can comprise pharmaceutically acceptable carrier, Decongestant, cough suppressant, expectorant or their mixture.
The present invention also provide to needs like this mammals organism treatment asthma, chronic obstructive pulmonary disease (" COPD ") of treatment with allergic disease, sneeze, the nose snotty of scratching where it itches, nasal congestion, one's eyes became bloodshot, shed tears, ear or palate is scratched where it itches, the method for sinusitis and the cough relevant with the postnasal drip symptom, this method comprises and gives Pharmaceutical composition described above.Detailed Description Of The Invention
In one embodiment, the present invention openly is used for the treatment of the Pharmaceutical composition with prevention of allergic rhinitis, asthma and relevant disease.Described compositions comprises at least a neurokinin of the treatment effective dose that exists with combining form and at least a leukotriene antagonist of treatment effective dose.Can for example salt, ester etc. be replaced one or more antagonisies by pharmaceutically acceptable derivates.
Known several neurokinins are useful in the present invention's practice at present.The limiting examples of the neurokinin that these are useful comprises those types of compounds that for example belong to oximes, hydrazone class, piperidines, piperazine, aryl alkyl amine, hydrazone class, nitro alkanes, amide-type, isoxazoline, quinoline, isoquinolin, azepine norborneol alkanes (azanorbornane), naphthyridine, benzodiazepine etc.In the U.S. patent of in present patent application, before having quoted, manyly be disclosed.Preferred NK antagonist is those disclosed antagonist in above-mentioned U.S. patent 5,798,359,5,795,894,5,789,422,5,783,579,5,719,156,5,696,267,5,691,362,5,688,960,5,654,316.The general formula of some disclosed chemical compounds like this is:
Wherein Z is
Or
Wherein B is OR
2, NR
6COR
2, CONR
6R
7Or NR
2CONR
6R
7,
M=0 or 1,
P is R
5-aryl or R
5-heteroaryl; With
Y is H, CR
2R
3CO
2R
6, CR
2R
3CONR
6R
7Or CR
2R
3NR
6COR
2
A=b=0,1 or 2;
Q has the identical definition as above P, and condition is that P can be identical or different with Q;
A is=N-OR
1,=N-NR
2R
3Or=CR
1R
2
X is-O-,-NR
6-,-N (R
6) CO-or-CO-NR
6-;
T is R
4-aryl, R
4-heteroaryl, R
4-cycloalkyl or R
2-bridge ring alkyl;
R
1Be H, C
1-C
6Alkyl or the (CH of n=1-6 wherein
2)
n-G,
G is H, R
4-aryl, R
4-heteroaryl, COR
6, CO
2R
6, CONR
6R
7, CN, OCOR
6, SO
3R
2, C (=NOR
2) NR
6R
7, C (=NR
2) NR
6R
7, condition is that G can be OR in addition when n ≠ 1
6, NR
6R
7Or NR
6(CO) R
7
R
2And R
3Independent is H or C
1-C
6Alkyl;
R
4And R
5Independently be 1,2 or 3 and independently be selected from OR
2, OC (O) R
2, OC (O) NR
6R
7, C
1-C
6Alkyl, H, halogen, CF
3, C
2F
5Or OCF
3Substituent group; With
R
6And R
7Independently be selected from H or C
1-C
6Alkyl, condition are to work as R
6And R
7Be NR
6R
7A part of the time, so described NR
6R
7Can form C
5-C
6The part of ring, wherein 0-2 annular atoms be selected from-O-,-S-and-NR
2-, condition is described C in addition
5-C
6Ring can have described be selected from hydrogen, halogen ,-OR
6With-COOR
6Substituent described ring on contain substituent group.
Particularly preferred neurokinin is those disclosed antagonist in above-mentioned U.S. patent, and belongs to following general formula and their stereoisomer.
More particularly preferred for having the stereoisomer of following general formula:
Wherein R is H, CH
2CONH
2, CH
2CONHMe, CH
2CONMe
2Or
The limiting examples as illustration that is used for the leukotriene antagonist of the present invention's practice comprises that montelukast (from Merck ﹠ Co., Inc.), pranlukast are (from Ono pharmaceutical Co. Ltd; CAS registration number: 103177-37-3), zafirlukast is (from zeneca drugmaker; CAS registration number: 107753-78-6), CP-195494 (from Pfizer) etc.The technical name of montelukast is [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolyl) vinyl] phenyl]-3-[2-(1-hydroxyl-1-Methylethyl) phenyl] propyl dithiocarbamate] the methyl Cyclopropylacetic acid.The technical name of pranlukast is N-[4-oxo-2-(1H-tetrazolium-5-yl)-4H-1-.alpha.-5:6-benzopyran-8-yl]-4-(4-phenyl butoxy)-Benzoylamide.The technical name of disclosed zafirlukast is [3-[[2-methoxyl group-4-[[[2-aminomethyl phenyl) sulfonyl] amino in EP-00199543] carbonyl] phenyl] methyl]-1-Methyl-1H-indole-5-yl]-carbamic acid ring pentyl ester.Useful especially leukotriene antagonist is a montelukast.Montelukast is a leukotriene D
4Antagonist, the receptor of its energy antagonism cysteinyl-leukotriene.At EP480, this chemical compound is described in 717.Preferred pharmaceutically acceptable montelukast salt is single sodium salt, is also referred to as Menglusitena (CAS registration number: 151767-02-1).
In another embodiment, to be disclosed in treatment and prevention of allergic rhinitis, asthma and the relevant disease be the Pharmaceutical composition of useful other in the present invention.Described compositions comprises at least a neurokinin of the treatment effective dose that exists with combining form and at least a 5-lipoxidase inhibitor of treatment effective dose.Can for example salt, ester etc. be replaced one or more chemical compounds by pharmaceutically acceptable derivates.
The limiting examples of useful neurokinin is those disclosed antagonist in U.S. patent cited above, for example comprises, wherein R is H, CH
2CONH
2, CH
2CONHMe, CH
2CONMe
2Or the chemical compound of following formula.
Useful 5-LO inhibitor for example comprise zileuton (from Abbott Lab, the CAS registration number: 111406-87-2) and Atreluton (from Abbott Lab, CAS registration number: 154355-76-7).The technical name of zileuton is N-(1-benzo [b] thiophene-2-base ethyl)-N-hydroxyl-urea.The technical name of Atreluton is N-[(1R)-the 3-[5-[(4-fluorophenyl) methyl]-the 2-thienyl]-1-methyl-2-propynyl]-the N-hydroxyurea.
Also in another embodiment, the present invention is disclosed in the mammals organism that needs treatment like this treat asthma, allergic rhinitis and other allergic disease, sneeze, the nose snotty of scratching where it itches, nasal congestion, one's eyes became bloodshot, shed tears, ear or palate are scratched where it itches, stridulate, the method for sinusitis and the cough relevant with the postnasal drip symptom, and this method comprises the Pharmaceutical composition that contains neurokinin described above and leukotriene antagonist.
In another embodiment, the present invention lectures at needs and treats asthma, allergic rhinitis and other allergic disease, sneeze in the mammals organism of treatment like this, the nose snotty of scratching where it itches, nasal congestion, one's eyes became bloodshot, shed tears, ear or palate are scratched where it itches, stridulate, the method for sinusitis and the cough relevant with the postnasal drip symptom, and this method comprises the Pharmaceutical composition that contains neurokinin described above and 5-LO inhibitor.
In Pharmaceutical composition of the present invention and method, general to be suitable for the form of medication of selected plan, give active component with form of mixtures with suitable medicinal diluent, excipient or carrier (being generically and collectively referred to as carrier material) at this, be oral tablet, capsule (solid is filled, the semi-solid filling or liquid filling) but, the powder that is used to constitute, oral gel, elixir dispersible granule, syrup, suspensoid etc., and meet conventional medicinal practice.For example, to with tablet or Capsule form oral administration, active pharmaceutical ingredient can mix with any oral atoxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, Pulvis Talci, mannitol, ethanol (liquid form) etc.In addition, when requiring or need, suitable binding agent, lubricant, disintegrating agent and coloring agent also can be incorporated in the mixture.Powder and tablet can comprise about 5% to about 95% the present composition.Suitable binding agent comprises starch, gelatin, natural sugar, corn sweetener, natural and rubber polymer such as arabic gum, sodium alginate, carboxy methyl cellulose, Polyethylene Glycol and cured.What the lubricant that is used for these dosage forms also can be mentioned boric acid, sodium benzoate, sodium acetate, sodium chloride etc. are arranged.Disintegrating agent comprises starch, methylcellulose, guar gum etc.Also can comprise sweeting agent, correctives and antiseptic when suitable.Below more going through more above-mentioned terms is disintegrating agent, diluent, lubricant, binding agent etc.
In addition, the present composition can be mixed with the slow release form with any or multiple composition of the release that provides speed to be controlled or active component, with reach make that following treatment does use optimization, for example neurokinin antagonism, leukotriene antagonism mechanism, 5-LO inhibitory action etc.The suitable dosage form that is used for continue discharging comprise contain with active component blended, the multilayer tablet of the disintegration rate of variation or sustained release polymeric matrix, and make it to be configured as tablet form or the capsule that contains such mixing or capsule porous polymer substrate.
Liquid form preparation comprises solution, suspensoid and Emulsion.As an example can be referred be to be used for the injection of non-intestinal or to be used for pleasantly sweet dose of the adding of oral solution, suspensoid and Emulsion and the water or the water-propylene glycol solution of opacifier.Liquid form preparation also can comprise the solution of intranasal administration.
The aerosol preparations that is suitable for sucking can comprise solution and the solid that exists with powder form, and they can for example inertia Compressed Gas such as nitrogen be united with pharmaceutically acceptable carrier.
For preparation suppository, at first with cured for example fatty glyceride of low melting point such as cocoa butter fusion, and by stirring or similar mixing makes active component homodisperse therein.Then fused uniform mixture is poured in the mould of proper volume, makes it cooling and therefore curing.
The solid form preparation comprises that also its requirement faces with before being converted into the liquid form preparation that is used for oral or parenterai administration.Such liquid form comprises solution, suspensoid and Emulsion.
But also percutaneous transmission of The compounds of this invention.Described transdermal composition can adopt the form of cream, lotion, aerosol and/or Emulsion and can be included in the percutaneous patch with substrate or the storage storehouse type as this area routine that is used for this purpose.
Preferred oral gives chemical compound.
Pharmaceutical formulation preferably exists with unit dosage forms.In such form, preparation is further divided into the active component that contains appropriate amount and for example reaches requirement purpose, the unit dose of the suitable size of effective dose.
The amount of active compound of the present invention in the unit dose of preparation generally can be in about 0.01 microgram to about 1, between 000 microgram, preferably about 0.01 between about 750 micrograms, more preferably about 0.01 to changing between about 500 micrograms or adjusting, and according to concrete application, generally about 0.01 to changing between about 250 micrograms or adjusting.According to patient's age, sex, body weight with treated severity of disease, can change employed actual dose.Such technology is known those skilled in the art.Contain general administration every day 1 of human peroral dosage form of active component or 2 times.According to attending doctor's judgement, can adjust the amount and the number of times of administration.The general recommended scheme that is used for oral administration can be every day about 0.04 microgram to the scope of about 4,000 micrograms at single or the dosage that separates.
Capsule-refer to the special container or the encapsulation of methylcellulose, Polyethylene Glycol or metagelatin or starch preparation, they are used for keeping or contain comprising composition of active components.Generally prepare the hard-shell capsule agent by the skeleton of relative high-gel strength and the admixture of pigskin gelatin.Capsule itself can contain dyestuff, opacifier, plasticizer and antiseptic in a small amount.
Tablet-refer to contains compacting or the mold pressing solid dosage forms with the active component of suitable diluent.Through wet granulation, dry granulation or the mixture or the granule that obtain by the powder extruding, can prepare tablet by compacting.
Oral gel-the refer to active component that is dispersed in or is dissolved in the hydrophilic semisolid matrix.
The powder that is used for constituting-refer to contains the powder admixture of the suitable diluent that active component and its can suspend at water or juice.
Diluent-the refer to most material of common formation compositions or dosage form.Suitable diluent comprises saccharide such as lactose, sucrose, mannitol and sorbitol, from starch and cellulose such as the microcrystalline Cellulose of Semen Tritici aestivi, corn and Rhizoma Solani tuber osi.The amount of diluent in compositions can total composition about 10 to changing between about 90% (weight), be preferably about 25 to about 75%, more preferably about 30 to about 60% (weight), even more preferably about 12 to about 60%.
Disintegrating agent-refer to joins in the compositions to help it and breaks (disintegrate) and discharge the material of medicine.Suitable disintegrating agent comprises starch, " cold water soluble " modified starch such as carboxymethyl starch sodium, natural and rubber polymer such as locust bean gum, karaya, guar gum, Tragacanth and agar, cellulose derivative such as methylcellulose and sodium carboxymethyl cellulose, microcrystalline Cellulose and crosslinked microcrystalline Cellulose such as cross-linking sodium carboxymethyl cellulose, alginate such as alginic acid and sodium alginate, potter's clay such as bentonite and effervescent mixture.The amount of disintegrating agent in compositions can compositions about 2 to changing between about 15% (weight), more preferably about 4 to about 10% (weight).
Binding agent-refer to powder-stuck or " gummed " together and make them bonding by forming granule, therefore as " bur " in the preparation.Binding agent is increased in existing bonding strength in diluent or the filler.Suitable binding agent comprises saccharide such as sucrose, is derived from Semen Tritici aestivi, starch, natural gum such as arabic gum, gelatin and Tragacanth, zostera marina derivant such as alginic acid, sodium alginate and calcium alginate ammonium, cellulose derivative such as methylcellulose, sodium carboxymethyl cellulose and hydroxypropyl emthylcellulose, polyvinylpyrrolidone and the inorganic matter of corn and Rhizoma Solani tuber osi Magnesiumaluminumsilicate for example.The amount of binding agent in compositions can compositions about 2 to changing between about 20% (weight), more preferably about 3 to about 10% (weight), even more preferably about 3 to about 6% (weight).
Lubricant-refer to joins in the dosage form to make after them tablet, the granule etc. can be by the material of reducing friction or wearing and tearing and discharging from towards film or plastic film in compacting.Suitable lubricant comprises metallic stearate such as magnesium stearate, calcium stearate or potassium stearate, stearic acid, high-melting-point is cured and soluble oil such as sodium chloride, sodium benzoate, sodium acetate, enuatrol, Polyethylene Glycol and d ' l-leucine.Usually before compacting, add lubricant in the last step because they must be present in particulate surface and be in them and tablet stamping machine parts between the two.The amount of lubricant in compositions can compositions about 0.2 to changing between about 5% (weight), be preferably about 0.5 to about 2%, more preferably about 0.3 to about 1.5% (weight).
Fluidizer-refer to prevents to lump and improves the material of mobility of particle, so that it is level and smooth and evenly to flow.Suitable fluidizer comprises silicon dioxide and Pulvis Talci.The amount of fluidizer in compositions can total composition about 0.1% to changing between about 5% (weight), be preferably about 0.5 to about 2% (weight).
Coloring agent-color the is provided excipient that gives compositions or dosage form.Such excipient can comprise the dyestuff of food stage and absorb for example dyestuff of the food stage on potter's clay or the aluminium oxide of suitable absorbent.The amount of coloring agent can compositions about 0.1 to changing between about 5% (weight), be preferably about 0.1 to about 1%.
Bioavailability-refer to reference material or tester and compare, active pharmaceutical ingredient or treatment part absorb speed and the degree that enters in the systemic circulation from form of administration.
The conventional method that is used to prepare tablet is known.Such method comprises that dry method for example directly suppresses and suppress the granule that produces by powder extruding, perhaps wet method or other specific process.The form of medication that is used to prepare other for example conventional method such as capsule, suppository is also known.
It will be apparent for a person skilled in the art that and to implement many improvement of the present disclosure, variation and change, comprise material and method.Such improvement, variation and change are planned to be in the spirit and scope of the present invention.
Claims (31)
1. Pharmaceutical composition, it comprises at least a neurokinin or their pharmaceutically acceptable derivates and at least a leukotriene antagonist of treatment effective dose or their pharmaceutically acceptable derivates of the treatment effective dose that exists with combining form.
2. the Pharmaceutical composition of claim 1, wherein said neurokinin or its pharmaceutically acceptable derivates are with the described Pharmaceutical composition 1-1 of per unit dosage, and 000 milligram amount exists.
3. the Pharmaceutical composition of claim 1, wherein said neurokinin or its pharmaceutically acceptable derivates exist with the amount of the described Pharmaceutical composition 10-500 milligram of per unit dosage.
4. the Pharmaceutical composition of claim 1, wherein said neurokinin or its pharmaceutically acceptable derivates exist with the amount of the described Pharmaceutical composition 50-200 milligram of per unit dosage.
5. the Pharmaceutical composition of claim 1, wherein said leukotriene antagonist or its pharmaceutically acceptable derivates exist with the amount of the described Pharmaceutical composition 2-500 milligram of per unit dosage.
6. the Pharmaceutical composition of claim 1, wherein said leukotriene antagonist or its pharmaceutically acceptable derivates exist with the amount of the described Pharmaceutical composition 5-100 milligram of per unit dosage.
7. the Pharmaceutical composition of claim 1, wherein said leukotriene antagonist or its pharmaceutically acceptable derivates exist with the amount of the described Pharmaceutical composition 10-50 milligram of per unit dosage.
8. the Pharmaceutical composition of claim 1, wherein said neurokinin is piperidines, piperazine, oxime, hydrazone, alkene, quinoline, isoquinolin, nitroparaffin, amide, isoxazoline, azepine norbornane, naphthyridine, benzodiazepine or aromatic yl alkyl amine.
9. the Pharmaceutical composition of claim 1, wherein said neurokinin is the chemical compound with following general formula:
Wherein Z is
Or
Wherein B is OR
2, NR
6COR
2, CONR
6R
7Or NR
2CONR
6R
7,
M=0 or 1,
P is R
5-aryl or R
5-heteroaryl; With
Y is H, CR
2R
3CO
2R
6, CR
2R
3CONR
6R
7Or CR
2R
3NR
6COR
2
A=b=0,1 or 2;
Q has the definition identical as above P, and condition is that P can be identical or different with Q;
A is=N-OR
1,=N-NR
2R
3Or=CR
1R
2
X is-O-,-NR
6-,-N (R
6) CO-or-CO-NR
6
T is R
4-aryl, R
4-heteroaryl, R
4-cycloalkyl or R
2-bridge ring alkyl;
R
1Be H, C
1-C
6Alkyl or the (CH of n=1-6 wherein
2)
n-G,
G is H, R
4-aryl, R
4-heteroaryl, COR
6, CO
2R
6, CONR
6R
7, CN, OCOR
6, SO
3R
2, C (=NOR
2) NR
6R
7, C (=NR
2) NR
6R
7, condition is that G can be OR in addition when n ≠ 1
6, NR
6R
7Or NR
6(CO) R
7
R
2And R
3Independent is H or C
1-C
6Alkyl;
R
4And R
5Independently be 1,2 or 3 and independently be selected from OR
2, OC (O) R
2, OC (O) NR
6R
7, C
1-C
6Alkyl, H, halogen, CF
3, C
2F
5Or OCF
3Substituent group; With
R
6And R
7Independently be selected from H or C
1-C
6Alkyl, condition are to work as R
6And R
7Be NR
6R
7A part of the time, so described NR
6R
7Can form C
5-C
6The part of ring, wherein 0-2 annular atoms be selected from-O-,-S-and-NR
2-, condition is described C in addition
5-C
6Ring can have described be selected from hydrogen, halogen ,-OR
6With-COOR
6Substituent described ring on contain substituent group.
10. the Pharmaceutical composition of claim 1, wherein said neurokinin are to have the chemical compound of following general formula and their stereoisomer,
Wherein R=H, CH
2CONH
2, CH
2CONHMe, CH
2CONMe
2Or
11. the Pharmaceutical composition of claim 1, wherein said neurokinin inhibitor is the chemical compound with following general formula:
Wherein R is H, CH
2CONH
2, CH
2CONHMe, CH
2CONMe
2Or
12. the Pharmaceutical composition of claim 11, wherein said neurokinin are R is CH
2CONH
2Chemical compound.
13. the Pharmaceutical composition of claim 11, wherein said neurokinin are R is CH
2The chemical compound of CONHMe.
14. the Pharmaceutical composition of claim 1, wherein said leukotriene antagonist is selected from montelukast, Menglusitena, pranlukast, zafirlukast and CP-195494.
15. the Pharmaceutical composition of claim 14, wherein said leukotriene antagonist are Menglusitena.
16. the Pharmaceutical composition of claim 1, it also comprises one or more materials that is selected from pharmaceutically acceptable carrier, Decongestant, cough suppressant and expectorant.
17. in the mammals organism that needs are treated like this, treat asthma, allergic rhinitis, chronic obstructive pulmonary disease, sneeze, the nose snotty of scratching where it itches, nasal congestion, one's eyes became bloodshot, shed tears, ear or palate are scratched where it itches, stridulate, the cough relevant with the postnasal drip symptom and with anaphylaxis the method for relevant respiratory tract disease, described treatment comprises: give Pharmaceutical composition, it comprises at least a neurokinin or their pharmaceutically acceptable derivates and at least a leukotriene antagonist of treatment effective dose or their pharmaceutically acceptable derivates of the treatment effective dose that exists with combining form.
18. Pharmaceutical composition, it comprises at least a neurokinin of the treatment effective dose that exists with combining form or at least a 5-lipoxidase inhibitor or their pharmaceutically acceptable derivates of their pharmaceutically acceptable derivates and treatment effective dose.
19. the Pharmaceutical composition of claim 18, wherein said neurokinin is piperidines, piperazine, oxime, hydrazone, alkene, quinoline, isoquinolin, nitroparaffin, amide, isoxazoline, azepine norbornane, naphthyridine, benzodiazepine or aromatic yl alkyl amine.
20. the Pharmaceutical composition of claim 18, wherein said neurokinin are the chemical compound with following general formula:
Wherein Z is
Or
Wherein B is OR
2, NR
6COR
2, CONR
6R
7Or NR
2CONR
6R
7,
M=0 or 1,
P is R
5-aryl or R
5-heteroaryl; With
Y is H, CR
2R
3CO
2R
6, CR
2R
3CONR
6R
7Or CR
2R
3NR
6COR
2
A=b=0,1 or 2;
Q has the definition identical as above P, and condition is that P can be identical or different with Q;
A is=N-OR
1,=N-NR
2R
3Or=CR
1R
2
X is-O-,-NR
6-,-N (R
6) CO-or-CO-NR
6
T is R
4-aryl, R
4-heteroaryl, R
4-cycloalkyl or R
2-bridge ring alkyl;
R
1Be H, C
1-C
6Alkyl or the (CH of n=1-6 wherein
2)
n-G,
G is H, R
4-aryl, R
4-heteroaryl, COR
6, CO
2R
6, CONR
6R
7, CN, OCOR
6, SO
3R
2, C (=NOR
2) NR
6R
7, C (=NR
2) NR
6R
7, condition is that G can be OR in addition when n ≠ 1
6, NR
6R
7Or NR
6(CO) R
7
R
2And R
3Independent is H or C
1-C
6Alkyl;
R
4And R
5Independently be 1,2 or 3 and independently be selected from OR
2, OC (O) R
2, OC (O) NR
6R
7, C
1-C
6Alkyl, H, halogen, CF
3, C
2F
5Or OCF
3Substituent group; With
R
6And R
7Independently be selected from H or C
1-C
6Alkyl, condition are to work as R
6And R
7Be NR
6R
7A part of the time, so described NR
6R
7Can form C
5-C
6The part of ring, wherein 0-2 annular atoms be selected from-O-,-S-and-NR
2-, condition is described C in addition
5-C
6Ring can have described be selected from hydrogen, halogen ,-OR
6With-COOR
6Substituent described ring on contain substituent group.
21. the Pharmaceutical composition of claim 18, wherein said neurokinin are to have the chemical compound of following general formula and their stereoisomer,
Wherein R=H, CH
2CONH
2, CH
2CONHMe, CH
2CONMe
2Or
22. the Pharmaceutical composition of claim 18, wherein said neurokinin are the chemical compound with following general formula:
Wherein R is H, CH
2CONH
2, CH
2CONHMe, CH
2CONMe
2Or
23. the Pharmaceutical composition of claim 18, wherein said neurokinin are with the about 1-1 of described Pharmaceutical composition of per unit dosage, 000 milligram amount exists.
24. the Pharmaceutical composition of claim 18, wherein said 5-lipoxidase inhibitor exists with the amount of the about 2-500 milligram of described Pharmaceutical composition of per unit dosage.
25. the Pharmaceutical composition of claim 18, wherein said 5-lipoxidase inhibitor is zileuton or Atreluton.
26. the Pharmaceutical composition of claim 25, wherein said 5-lipoxidase inhibitor is a zileuton.
27. the compositions of claim 18, it also comprises one or more materials that is selected from pharmaceutically acceptable carrier, Decongestant, cough suppressant and expectorant.
28. in the mammals organism that needs are treated like this, treat asthma, allergic rhinitis, chronic obstructive pulmonary disease, sneeze, the nose snotty of scratching where it itches, nasal congestion, one's eyes became bloodshot, shed tears, ear or palate are scratched where it itches, stridulate, the cough relevant with the postnasal drip symptom and with anaphylaxis the method for relevant respiratory tract disease, described treatment comprises: give Pharmaceutical composition, it comprises at least a neurokinin of the treatment effective dose that exists with combining form or at least a 5-lipoxidase inhibitor or their pharmaceutically acceptable derivates of their pharmaceutically acceptable derivates and treatment effective dose.
29. the method for claim 17 or claim 28, wherein said neurokinin are the chemical compound with following general formula:
Wherein Z is
Or
Wherein B is OR
2, NR
6COR
2, CONR
6R
7Or NR
2CONR
6R
7,
M=0 or 1,
P is R
5-aryl or R
5-heteroaryl; With
Y is H, CR
2R
3CO
2R
6, CR
2R
3CONR
6R
7Or CR
2R
3NR
6COR
2
A=b=0,1 or 2;
Q has the definition identical as above P, and condition is that P can be identical or different with Q;
A is=N-OR
1,=N-NR
2R
3Or=CR
1R
2
X is-O-,-NR
6-,-N (R
6) CO-or-CO-NR
6
T is R
4-aryl, R
4-heteroaryl, R
4-cycloalkyl or R
2-bridge ring alkyl;
R
1Be H, C
1-C
6Alkyl or the (CH of n=1-6 wherein
2)
n-G,
G is H, R
4-aryl, R
4-heteroaryl, COR
6, CO
2R
6, CONR
6R
7, CN, OCOR
6, SO
3R
2, C (=NOR
2) NR
6R
7, C (=NR
2) NR
6R
7, condition is that G can be OR in addition when n ≠ 1
6, NR
6R
7Or NR
6(CO) R
7
R
2And R
3Independent is H or C
1-C
6Alkyl;
R
4And R
5Independently be 1,2 or 3 and independently be selected from OR
2, OC (O) R
2, OC (O) NR
6R
7, C
1-C
6Alkyl, H, halogen, CF
3, C
2F
5Or OCF
3Substituent group; With
R
6And R
7Independently be selected from H or C
1-C
6Alkyl, condition are to work as R
6And R
7Be NR
6R
7A part of the time, so described NR
6R
7Can form C
5-C
6The part of ring, wherein 0-2 annular atoms be selected from-O-,-S-and-NR
2-, other condition is described C
5-C
6Ring can have described be selected from hydrogen, halogen ,-OR
6With-COOR
6Substituent described ring on contain substituent group.
30. the method for claim 17 or claim 28, wherein said leukotriene antagonist is selected from montelukast, Menglusitena, pranlukast, zafirlukast and CP-195494.
31. the method for claim 17 or claim 28, wherein said 5-lipoxidase inhibitor is zileuton or Atreluton.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16960998A | 1998-10-09 | 1998-10-09 | |
| US09/169,609 | 1998-10-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1329505A true CN1329505A (en) | 2002-01-02 |
Family
ID=22616408
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99814057A Pending CN1329505A (en) | 1998-10-09 | 1999-10-06 | Composition and method for treating allergic diseases |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP1119372A1 (en) |
| JP (1) | JP2002527406A (en) |
| CN (1) | CN1329505A (en) |
| AR (1) | AR020741A1 (en) |
| AU (1) | AU6391199A (en) |
| CA (1) | CA2346228A1 (en) |
| CO (1) | CO5140080A1 (en) |
| PE (1) | PE20001095A1 (en) |
| WO (1) | WO2000021564A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102847155A (en) * | 2004-07-14 | 2013-01-02 | 炎症研究中心有限公司 | Method for inhibiting tumor metastasis |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1633357A4 (en) * | 2003-04-15 | 2010-02-10 | Merck & Co Inc | Polymorphic form of montelukast sodium |
| US8093268B2 (en) | 2007-01-24 | 2012-01-10 | Glaxo Group Limited | Pharmaceutical compositions comprising 2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl-benzyl)-(2S-phenylpiperidin-3S-yl-) |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9415997D0 (en) * | 1994-08-08 | 1994-09-28 | Merck Sharp & Dohme | Therapeutic agents |
| EP0799051B1 (en) * | 1994-12-12 | 2005-07-27 | Omeros Corporation | Irrigation solution and use thereof for perioperatively inhibiting pain, inflammation and spasm at a wound |
| US5696267A (en) * | 1995-05-02 | 1997-12-09 | Schering Corporation | Substituted oximes, hydrazones and olefins as neurokinin antagonists |
| US5688960A (en) * | 1995-05-02 | 1997-11-18 | Schering Corporation | Substituted oximes, hydrazones and olefins useful as neurokinin antagonists |
| GB9521781D0 (en) * | 1995-10-24 | 1996-01-03 | Merck Sharp & Dohme | Therapeutic agents |
-
1999
- 1999-10-06 CA CA002346228A patent/CA2346228A1/en not_active Abandoned
- 1999-10-06 PE PE1999001013A patent/PE20001095A1/en not_active Application Discontinuation
- 1999-10-06 CO CO99063418A patent/CO5140080A1/en unknown
- 1999-10-06 WO PCT/US1999/021438 patent/WO2000021564A1/en not_active Application Discontinuation
- 1999-10-06 AU AU63911/99A patent/AU6391199A/en not_active Abandoned
- 1999-10-06 CN CN99814057A patent/CN1329505A/en active Pending
- 1999-10-06 EP EP99951477A patent/EP1119372A1/en not_active Withdrawn
- 1999-10-06 JP JP2000575537A patent/JP2002527406A/en not_active Withdrawn
- 1999-10-07 AR ARP990105083A patent/AR020741A1/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102847155A (en) * | 2004-07-14 | 2013-01-02 | 炎症研究中心有限公司 | Method for inhibiting tumor metastasis |
Also Published As
| Publication number | Publication date |
|---|---|
| AR020741A1 (en) | 2002-05-29 |
| EP1119372A1 (en) | 2001-08-01 |
| CA2346228A1 (en) | 2000-04-20 |
| CO5140080A1 (en) | 2002-03-22 |
| PE20001095A1 (en) | 2000-10-31 |
| JP2002527406A (en) | 2002-08-27 |
| AU6391199A (en) | 2000-05-01 |
| WO2000021564A1 (en) | 2000-04-20 |
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