EP1223969A2 - Kombinierte verwendung von plasminogenaktivator und interleukin-2-inhibitoren zur neuroprotektion - Google Patents
Kombinierte verwendung von plasminogenaktivator und interleukin-2-inhibitoren zur neuroprotektionInfo
- Publication number
- EP1223969A2 EP1223969A2 EP00963073A EP00963073A EP1223969A2 EP 1223969 A2 EP1223969 A2 EP 1223969A2 EP 00963073 A EP00963073 A EP 00963073A EP 00963073 A EP00963073 A EP 00963073A EP 1223969 A2 EP1223969 A2 EP 1223969A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- inhibitor
- plasminogen activator
- effect caused
- group
- increasing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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- KASDHRXLYQOAKZ-OLHLVPFQSA-N pimecrolimus Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C\C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@H](Cl)[C@H](OC)C1 KASDHRXLYQOAKZ-OLHLVPFQSA-N 0.000 description 1
- 230000010118 platelet activation Effects 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229940072288 prograf Drugs 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- AZJPTIGZZTZIDR-UHFFFAOYSA-L rose bengal Chemical compound [K+].[K+].[O-]C(=O)C1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1C1=C2C=C(I)C(=O)C(I)=C2OC2=C(I)C([O-])=C(I)C=C21 AZJPTIGZZTZIDR-UHFFFAOYSA-L 0.000 description 1
- 229930187593 rose bengal Natural products 0.000 description 1
- 229940081623 rose bengal Drugs 0.000 description 1
- STRXNPAVPKGJQR-UHFFFAOYSA-N rose bengal A Natural products O1C(=O)C(C(=CC=C2Cl)Cl)=C2C21C1=CC(I)=C(O)C(I)=C1OC1=C(I)C(O)=C(I)C=C21 STRXNPAVPKGJQR-UHFFFAOYSA-N 0.000 description 1
- 108010073863 saruplase Proteins 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000002306 tributylsilyl group Chemical group C(CCC)[Si](CCCC)(CCCC)* 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/49—Urokinase; Tissue plasminogen activator
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- plasminogen activators are well known.
- a certain macrolide compound i.e., tacrolimus, and its related compounds are known to have preventing or treating activity of cerebral infarction (USP 5,648,351).
- This invention relates to a new use of plasminogen activators, for increasing an effect caused by interleukin 2 inhibitor (hereinafter, referred to IL-2 inhibitor) .
- IL-2 inhibitor interleukin 2 inhibitor
- Another object of this invention is to provide a method for increasing an effect caused by IL-2 inhibitor by administering an effective amount of a plasminogen activator.
- a further object of this invention is to provide a use of a plasminogen activator for manufacturing a medicament for increasing an effect caused by IL-2 inhibitor.
- Still further object of this invention is to provide a composition comprising a plasminogen activator, for increasing an effect caused by IL-2 inhibitor.
- the "plasminogen activator” should not be limited and be considered to mean any compounds which can convert inactivate plasminogen to the protease plasmin.
- tissue-type plasminogen activator (tPA) tissue-type plasminogen activator (tPA) , urokinase (UK), pro-urokinase, streptokinase, acylated streptokinase/tPA conjugates, etc.
- IL-2 inhibitor used in the present invention should not be limited and be considered to mean any ones possessing IL-2 inhibitory activity.
- the particular example is the one possessing an inhibitory activity on the production of IL-2.
- the other is the one that inhibits the transmission of IL-2 signal.
- the preferable "effect caused by IL-2 inhibitor” is a neuroptotective activity.
- the effect caused by IL- 2 inhibitor may be the treatment and prevention of acute or chronic cerebral neurodegenerative diseases, such as cerebral ischemic diseases and/or brain damage caused by ischemia.
- IL-2 inhibitor is, for example, the tricyclic macrolide shown in EP-0184162, WO89/05303, WO93/05058, W096/31514, and so on, the disclosure of which is incorporated herein by reference. It is well known that those tricyclic macrolides have strong IL-2 inhibitory activity.
- the tricyclic compound of the following formula (I) can be exemplified.
- R 2 is two adjacent hydrogen atoms, but R 2 may also be an alkyl group or
- (b) may form another bond formed between the carbon atoms to which they are attached;
- R 7 is a hydrogen atom, a hydroxy group, a protected hydroxy group, or an alkoxy group, or an oxo group together with
- R 1 ; R 8 and R 9 are independently a hydrogen atom or a hydroxy group
- R 10 is a hydrogen atom, an alkyl group, an alkyl group substituted by one or more hydroxy groups, an alkenyl group, an alkenyl group substituted by one or more hydroxy groups, or an alkyl group substituted by an oxo group
- X is an oxo group, (a hydrogen atom and a hydroxy group) , (a hydrogen atom and a hydrogen atom) , or a group represented by the formula -CH 2 0-
- Y is an oxo group, (a hydrogen atom and a hydroxy group),
- lower means, unless otherwise indicated, a group having 1 to 6 carbon atoms .
- aryl groups include phenyl, tolyl, xylyl, cumenyl, mesityl and naphthyl .
- aliphatic acyl groups include a lower alkanoyl group optionally having one or more suitable substituents such as carboxy, e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, carboxyacetyl, carboxypropionyl, carboxybutyryl, carboxyhexanoyl, etc.; a cyclo (lower) alkoxy (lower) alkanoyl group optionally having one or more suitable substituents such as lower alkyl, e.g., cyclopropyloxyacetyl, cyclobutyloxypropionyl , cycloheptyloxybutyryl, menthyloxyacetyl, menthyloxypropionyl, menthyloxybutyryl, menthyloxypentanoyl, menthyloxyhexanoyl
- Examples of the aliphatic acyl groups substituted by an aromatic group include ar (lower) alkanoyl group optionally having one or more suitable substituents such as lower alkoxy or trihalo (lower) alkyl, e.g., phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifluoromethyl-2-methoxy-2-phenylacetyl, 2-ethyl-2-trifluoromethyl-2-phenylacetyl, 2-trifluoromethyl- 2-propoxy-2-phenylacetyl, etc.
- ar (lower) alkanoyl group optionally having one or more suitable substituents such as lower alkoxy or trihalo (lower) alkyl, e.g., phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifluoromethyl-2-methoxy-2-phenylacetyl, 2-ethyl-2-trifluoromethyl
- the most preferable ones are acetyl, carboxypropionyl, menthyloxyacetyl, camphorsulfonyl, benzoyl, nitrobenzoyl, dinitrobenzoyl, iodobenzenesulfonyl and 2- trifluoromethyl-2-methoxy-2-phenylacetyl .
- Preferable examples of the "5- or 6-membered nitrogen, sulfur and/or oxygen containing heterocyclic ring" include a pyrrolyl group and a tetrahydrofuryl group.
- R 24 is an optionally substituted ring system which may contain one or more heteroatoms .
- Preferable R 24 may be cyclo (C 5 . 7 ) alkyl group optionally having suitable substituents, and the following ones can be exemplified.
- a heteroaryl which may be substituted by suitable substituents moiety of the "heteroaryloxy which may be substituted by suitable substituents” may be the ones exemplified for R 1 of the compound of the formula of EP-A-532, 088, with preference given to 1-hydroxyethylindol -5-yl, the disclosure of which is incorporated herein by reference.
- ticyclic compounds (I) and its pharmaceutically acceptable salt for use in accordance with this invention are well known to have excellent i munosuppressive activity, antimicrobial activity and other pharmacological activities and, as such, be of value for the treatment or prevention of rejection reactions by transplantation of organs or tissues, graft-vs-host diseases, autoimmune diseases, and infectious diseases [EP-A-0184162, EP-A-0323042, EP-A-423714, EP-A-427680, EP-A-465426, EP-A-480623, EP-A-532088, EP-A-532089, EP-A-569337, EP-A-626385, WO89/05303, WO93/05058, W096/31514, W091/13889, W091/19495, WO93/04680, WO93/5059, etc. ] , the disclosures of which are incorporated herein by reference.
- the FK506 (general name: tacrolimus) of the following chemical formula, in particular, is a representative compound.
- the preferred examples of the tricyclic compounds (I) are the ones, wherein each of adjacent pairs of R 3 and R 4 or R 5 and R 6 independently form another bond formed between the carbon atoms to which they are attached; each of R 8 and R 23 is independently a hydrogen atom; R 9 is a hydroxy group; R 10 is a methyl group, an ethyl group, a propyl group or an allyl group; X is (a hydrogen atom and a hydrogen atom) or an oxo group; Y is an oxo group; each of R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 22 is a methyl group; R 24 is a 3-R 20 -4-R 21 -cyclohexyl group, in which R 20 is hydroxy, an alkoxy group, an oxo group, or a -OCH 2 OCH 2 CH 2 OCH 3 group, and R 21 is hydroxy, -OCN, an alkoxy group,
- O-substituted derivatives may be produced by reacting rapamycin (or dihydro or deoxo-rapamycin) with an organic radical attached to a leaving group (for example RX where R is the organic radical which is desired as the O-substituent, such as an alkyl, allyl, or benzyl moiety, and X is a leaving group such as CC1 3 C(NH)0 or CF 3 S0 3 ) under suitable reaction conditions.
- a leaving group for example RX where R is the organic radical which is desired as the O-substituent, such as an alkyl, allyl, or benzyl moiety, and X is a leaving group such as CC1 3 C(NH)0 or CF 3 S0 3
- the conditions may be acidic or neutral conditions, for example in the presence of an acid like trifluoromethanesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid or their respective pyridinium or substituted pyridinium salts when X is CC1 3 C(NH)0 or in the presence of a base like pyridine, a substituted pyridine, diisopropylethylamine or pentamethylpiperidine when X is CF 3 S0 3 .
- the most preferable one is 40-O- (2-hydroxy) ethyl rapamycin, which is disclosed in WO94/09010, the disclosure of which is incorporated herein by reference.
- IL-2 inhibitor is cyclosporin and its derivatives such as cyclosporin A, B, C, D, E, F, G, etc, which are shown in THE MERCK INDEX (12th edition) , No.2821, USP 4,117,118, 4,215,199, 4,288,431, 4,388,307, Helv. Chim. Acta. 60, 1568(1977) and 65, 1655(1982), Transplant. Proc. 17, 1362(1985), and so on.
- the most preferable one is cyclosporin A.
- the disclosures of the above references are incorporated herein.
- plasminogen activators in the present invention is used in the form of a conventional pharmaceutical preparation in admixture with a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration.
- a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration.
- the pharmaceutical preparation may be compounded in a solid form such as granule, capsule, tablet, dragee, suppository or ointment, or in a liquid form such as solution, suspension or emulsion for injection, intravenous drip, ingestion, eye drop, etc.
- auxiliary substance such as stabilizing agent, wetting or emulsifying agent, buffer or any other commonly used additives.
- this composition For applying this composition to a human, it is preferable to apply it by injection.
- Thrombotic occlusion of the MCA was induced by photochemical reaction as described by Umemura et al., (1993). Briefly, male Sprague-Dawley rats (SLC, Inc.) weighting about 300g were anesthetized with halothane (4% for induction, 1.5% for maintenance) . The animals were placed in the lateral position, and the left MCA was exposed by a microsurgical approach. A stable thrombotic occlusion of MCA was produced by photochemical reaction between intravenously administered photoreactive dye, rose bengal
- TTC triphenyltetrazolium chloride
- FK506 (1 mg/kg; Prograf (Trade Name: Fujisawa pharmaceutical Co., Ltd.) was administered intravenously by a single bolus injection through the femoral vein 2 hours after occlusion of the MCA.
- a tissue-type plasminogen activator (t-PA) (1 mg/kg) which is a recombinant t-PA, ⁇ reteplase' , was administered intravenously by a bolus injection (20 % of total volume) followed by infusion (80 % of total volume) for 30 min through the femoral vein 2 hours after occlusion of the MCA.
- t-PA tissue-type plasminogen activator
- the present invention provides useful neuroprotective agent for preventing or treating acute or chronic cerebral neurodegenerative diseases, such as cerebral ischemic diseases and/or brain damage caused by ischemia.
- cerebral infarction head injury, hemorrhage in brain such as subarachnoid hemorrhage or intracerebral hemorrhage, cerebral thrombosis, cerebral embolism, cardiac arrest, stroke (such as acute stroke) , transient ischemic attacks (TIA) , hypertensive encephalopathy, Alzheimer's disease, Huntington' s disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and so on.
- TIA transient ischemic attacks
- the present invention also provides the following inventions.
- a method for preventing and treating acute or chronic cerebral neurodegenerative diseases by administering an effective amount of a plasminogen activator and an effective amount of IL-2 inhibitor to a human being or an animal.
- a composition comprising a plasminogen activator and IL-2 inhibitor as a combined preparation for simultaneous, separate or sequential use for neuroprotective activity.
- An article of manufacture comprising packaging material and IL-2 inhibitor contained within said packaging material, wherein said IL-2 inhibitor is therapeutically effective for increasing or decreasing an effect caused by plasminogen activator, and wherein said packaging material comprises a label or a written material which indicates that said IL-2 inhibitor can be used for increasing or decreasing an effect caused by plasminogen activator.
- An article of manufacture comprising packaging material and a plasminogen activator contained within said packaging material, wherein said plasminogen activator is therapeutically effective for increasing an effect caused by IL-2 inhibitor, and wherein said packaging material comprises a label or a written material which indicates that said plasminogen activator can be used for increasing an effect caused by IL-2 inhibitor.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AUPQ3249A AUPQ324999A0 (en) | 1999-10-04 | 1999-10-04 | New use |
| AUPQ324999 | 1999-10-04 | ||
| AUPQ5643A AUPQ564300A0 (en) | 2000-02-15 | 2000-02-15 | New use |
| AUPQ564300 | 2000-02-15 | ||
| PCT/JP2000/006874 WO2001024784A2 (en) | 1999-10-04 | 2000-10-02 | New use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1223969A2 true EP1223969A2 (de) | 2002-07-24 |
Family
ID=25646165
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP00963073A Withdrawn EP1223969A2 (de) | 1999-10-04 | 2000-10-02 | Kombinierte verwendung von plasminogenaktivator und interleukin-2-inhibitoren zur neuroprotektion |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP1223969A2 (de) |
| JP (1) | JP2003510351A (de) |
| WO (1) | WO2001024784A2 (de) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016013938A1 (en) | 2014-07-24 | 2016-01-28 | Litevax B.V. | Adjuvants |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2003230777A1 (en) * | 2002-03-29 | 2003-10-13 | The Johns Hopkins University | Intraventricular hemorrhage thrombolysis |
| CN119909180A (zh) * | 2019-05-10 | 2025-05-02 | 深圳瑞健生命科学研究院有限公司 | 一种治疗肌萎缩侧索硬化的方法和药物 |
| EP3967322B1 (de) * | 2019-05-10 | 2025-03-05 | Talengen International Limited | Plasminogen zur behandlung von amyotropher lateralsklerose |
| CA3176941A1 (en) * | 2020-03-24 | 2021-09-30 | Talengen International Limited | Method and medicine for treating huntington's disease |
| WO2021190561A1 (zh) * | 2020-03-24 | 2021-09-30 | 泰伦基国际有限公司 | 一种治疗帕金森病的方法和药物 |
| CN115697385A (zh) | 2020-05-11 | 2023-02-03 | 泰伦基国际有限公司 | 一种治疗脊髓性肌萎缩症的方法和药物 |
| JP2025539229A (ja) * | 2022-11-04 | 2025-12-04 | 泰▲倫▼基国▲際▼有限公司 | 病理学的ｔｄｐ－４３タンパク質の分解を促進する方法及び薬剤 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9227055D0 (en) * | 1992-12-29 | 1993-02-24 | Fujisawa Pharmaceutical Co | New use |
| US5945432A (en) * | 1995-12-22 | 1999-08-31 | The University Of Vermont And State Agricultural College | Thrombolytic agents and thienopyridine derivatives in acute stroke |
-
2000
- 2000-10-02 EP EP00963073A patent/EP1223969A2/de not_active Withdrawn
- 2000-10-02 JP JP2001527783A patent/JP2003510351A/ja active Pending
- 2000-10-02 WO PCT/JP2000/006874 patent/WO2001024784A2/en not_active Ceased
Non-Patent Citations (1)
| Title |
|---|
| See references of WO0124784A2 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016013938A1 (en) | 2014-07-24 | 2016-01-28 | Litevax B.V. | Adjuvants |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2003510351A (ja) | 2003-03-18 |
| WO2001024784A3 (en) | 2002-05-10 |
| WO2001024784A2 (en) | 2001-04-12 |
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