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WO2001068121A1 - Remedes contre des maladies allergiques - Google Patents

Remedes contre des maladies allergiques Download PDF

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Publication number
WO2001068121A1
WO2001068121A1 PCT/JP2001/002076 JP0102076W WO0168121A1 WO 2001068121 A1 WO2001068121 A1 WO 2001068121A1 JP 0102076 W JP0102076 W JP 0102076W WO 0168121 A1 WO0168121 A1 WO 0168121A1
Authority
WO
WIPO (PCT)
Prior art keywords
chain
straight
carbon atoms
allergic diseases
therapeutic agent
Prior art date
Application number
PCT/JP2001/002076
Other languages
English (en)
Japanese (ja)
Inventor
Takayuki Kajiura
Hideki Suzuki
Seiichi Sato
Sonoko Ishizaki
Junko Shinozaki
Makoto Shiozaki
Original Assignee
Ajinomoto Co., Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Ajinomoto Co., Inc. filed Critical Ajinomoto Co., Inc.
Priority to AU2001241162A priority Critical patent/AU2001241162A1/en
Publication of WO2001068121A1 publication Critical patent/WO2001068121A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • Th2 cells type 2 helper T cells
  • IgE production from B lymphocytes is induced by inulin-1 (hereinafter referred to as “IL-4”) produced from Th2 cells
  • IL-4 inulin-1
  • IL-15 Interleukin-5
  • Th2 cells works to maintain and activate eosinophils [Kinashi, T et al., Nature, Vol. 3 2 4 volumes, 70 pages ( See 1 9 8 6).
  • IL-4 also acts on the production and proliferation of Th2 cells themselves.
  • FK506 a drug that suppresses T lymphocytes, has been used as an external preparation for the treatment of atopic dermatitis and has been effective.
  • drugs have a problem because they have no selectivity for Th2 cells and thus suppress not only immune reactions related to allergy but also immune reactions related to infection protection.
  • the present inventors have investigated the production of compounds that have little effect on immune responses important for host defense, particularly the production of IgE and the production of IL-14 that induces the proliferation of Th2 cells themselves.
  • Compound becomes a drug that suppresses allergic reactions and can solve the above problems Therefore, we searched for a drug that selectively inhibits the production of IL-4 from various naturally occurring substances.
  • cyclic lipopeptide derivatives having the structure represented by the following general formula (I), in particular, two compounds of laxidine A and laxidine B exhibit selective IL-4 production inhibitory activity. And found that the present invention was completed.
  • the term "straight-chain or branched-chain acyl group” means that the acyl group contains a straight-chain or branched alkyl group.
  • the therapeutic agent of the present invention broadly means an agent aimed at preventing, ameliorating, treating, and the like of allergic diseases.
  • R is a hydrogen atom, and n is 11; raxidine A; R is a hydrogen atom, and laxidine B is 12 (raki cid in B) ) Is particularly useful as a therapeutic agent of the present invention, that is, a therapeutic agent for allergic diseases.
  • luxidine A and luxidine B have already been isolated as compounds having cytocidal activity against cultured cancer cells [McBrien, K et al. See The Journal of Antibiotics, vol. 48, p. 1446 (1995). Therefore, it is helpful when preparing those compounds.
  • the selective action on T lymphocytes, the therapeutic effect on allergic diseases, the anti-inflammatory action, and the like of these compounds have not been known at all, and no reports have been found.
  • the present invention provides, as another form, administering at least one selected from the cyclic lipopeptide derivative represented by the general formula (I) and a pharmaceutically acceptable salt thereof to a living body.
  • a method for treating, ameliorating and preventing or preventing an allergic disease having a characteristic and as still another form, selected from the cyclic ribopeptide rust conductor represented by the general formula (I) and a pharmaceutically acceptable salt thereof.
  • the subject to which the therapeutic agent of the present invention is administered is not particularly limited as long as it seeks prevention, amelioration, treatment, etc. of an allergic disease or a disease caused by allergy. Patient).
  • R is a hydrogen atom
  • n is 12
  • Laxidine B can be isolated from a culture solution of a microorganism using a known method (see the above-mentioned literature).
  • Microorganisms used for the production of the cyclic lipopeptide derivative used in the present invention as an effective component thereof can be any microorganisms that produce Rakicidins, for example, Yamanakako, Yamanashi Prefecture Microorganisms having the following mycological properties, ie, strain AJ9562, collected from the soil of the above can also be used.
  • the bacteriological properties of this strain are as follows.
  • ISP International Streptomyces Project
  • lactic acid-producing bacteria belonging to the genus Micromonospora can be irradiated with, for example, X-rays or ultraviolet rays, for example, nitrogen, nitrogen, azaserine, nitrite, or 2-amino acid.
  • a commonly used bacterial species conversion method such as treatment with a mutagenic agent such as Blin or N-methyl-N'-nitro-N-nitrosoguanidine (NTG), phage contact, transformation, transduction or conjugation Even such mutants or naturally obtained mutants are not substantially different from the taxonomic properties described above, and furthermore produce the compound. All those having the properties described above can be used for producing the compounds used as the active ingredients in the present invention.
  • the culturing is performed using a medium containing a nutrient source used by the microorganism.
  • a medium any of a synthetic, semi-synthetic or natural, solid or liquid medium may be used, but usually a liquid medium containing a natural nutrient is suitable.
  • the nutrient source added to the culture medium may be any carbon compound as long as it is an assimilable carbon compound.For example, arabinose, sucrose, starch, glucose, glucose, dextrin, coconut oil, soybean oil, etc., alone or in combination Used. Further, alcohols, organic acids, and the like may be used.
  • ammonium chloride ammonium nitrate, urea, etc.
  • organic nitrogen sources peptone, yeast extract, dried yeast, meat exercise, gluten meal, corn steep liquor, soy flour, fish meal, peanut Powder, cottonseed kashiwa, casamino acid and various amino acids are used alone or in combination.
  • the cultivation is preferably carried out under aerobic conditions, and any of stationary, shaking, and aeration and stirring cultures is possible. Shaking or aeration and stirring culture is advantageous.
  • the cultivation temperature is preferably in the range of about 25 to 35, and especially about 28 is advantageous. Further, it is preferable that the pH value of the medium is maintained at about neutral pH of about 5.5 to 8.5.
  • the cultivation period varies depending on the culture conditions such as the composition of the medium and the temperature, but it is usually about 3 to 10 days, and the cultivation should be performed at an appropriate time based on the timing at which the akicidins reach the maximum titer. finish.
  • a commonly used isolation and purification means may be applied.
  • the Micromonospora sp. AJ9562 strain is cultured under the cultivation conditions described in Examples described later, at least two types of luxidine-related substances are accumulated in the culture solution.
  • laxidine A or laxidine B can be produced.
  • other compounds have the structure represented by the above general formula by using these as raw materials and utilizing ordinary organic synthesis techniques.
  • a cyclic lipopeptide derivative wherein n is other than 11 or 12 can be produced.
  • the desired acyl group can be obtained by employing a method known as an acylation method for acylating a hydroxyl group.
  • An acylated derivative into which is introduced can be easily produced.
  • the acetyl group in this case, an acetyl group, a benzoyl group or the like can be employed as a particularly preferable one.
  • R represents a linear or branched alkyl group having 1 to 8 carbon atoms
  • a method known as an etherification method in which a hydrogen atom of a hydroxyl group is substituted with an alkyl group is employed.
  • an alkylated derivative having an intended alkyl group introduced therein can be easily produced.
  • the alkyl group in this case, a methyl group, an ethyl group, a benzyl group and the like can be mentioned as preferred alkyl groups.
  • the active ingredient used in the therapeutic agent of the present invention may be in a free form or in the form of a pharmaceutically acceptable salt.
  • the salt form in that case In order to produce the desired salt, the desired salt can be easily produced by subjecting it to a usual salt-forming step, for example, using a free form or another salt.
  • the salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include hydrochloride, sulfate, and nitrate.
  • the form of the preparation is not particularly limited.
  • Formulations suitable for various administrations such as inhalation administration, oral administration, intravenous administration, transdermal administration, ophthalmic administration, and the like can be produced.
  • the dosage in that case depends on the patient's condition, age, and administration method, but when using laxidine A or B, expressed as its net weight, preferably 1 to 300 mg by oral administration It is about ZkgZ days, more preferably about 5-100 mg / kg.
  • the amount of the active ingredient used is about ten to one-twentieth, which is sufficient, compared to the case of oral administration, and other techniques known as intravenous administration such as injections are used.
  • a pharmaceutical preparation can be manufactured.
  • Derivatives other than laxidine A and B can be manufactured by determining the amount of the target preparation to be used based on these contents and other known preparation techniques.
  • the active ingredient (compound) used in the therapeutic agent of the present invention can be formulated by a conventional method.
  • the form of the preparation is not particularly limited.
  • examples of the form of the preparation include inhalants, injections, tablets, granules, fine granules, powders, capsules, creams, ointments, suppositories, etc.
  • the carrier for the preparation include lactose, glucose, D-mannitol, starch, crystalline cellulose, calcium carbonate, kaolin, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, ethanol, carboxymethylcellulose, carboxymethylcellulose sodium salt, magnesium stearate, talc, acetyl Cellulose, sucrose, titanium oxide, benzoic acid, paraoxybenzoate, sodium dehydroacetate, gum arabic, tragacanth, methylcellulose, egg yolk, surfactant, simple syrup, citric acid, distilled water, Lyserine
  • the content of the active ingredient of the present invention in the preparation for the therapeutic agent of the present invention greatly varies depending on the form of the preparation, and is not particularly limited. Preferably it is about 0.01 to 100% by weight, more preferably about 1 to 100% by weight.
  • a medium (pH 7.0) containing 1.0% dextrose, 1.0% malt extract, 10% tomato juice, 0.1% yeast extract and 0.2% calcium carbonate was prepared, and this was 50 Om
  • Each 10 Om was poured into each Erlenmeyer flask (1) and sterilized at 120 for 20 minutes, and the seed culture was inoculated at a rate of 2.0%.
  • the culture was carried out at a temperature of 28 for 96 hours at 180 rotations.
  • the culture solution (7 L) thus obtained was separated into a supernatant and cells by centrifugation.
  • the supernatant was extracted with toluene (2.5 L), and the solvent was concentrated under reduced pressure to obtain about 300 ml of a water suspension.
  • methanol (200 ml) was added to the suspension, the mixture was extracted with black-mouthed form (350 ml ⁇ 2).
  • the black mouth form layer was concentrated to dryness under reduced pressure.
  • the obtained residue (1.2 g) was subjected to reverse phase column chromatography (COSMOSIL 140C
  • Example 1 Inhibition of IL-14 production in mouse spleen T cells
  • the spleen was excised from a mouse (Balb / c strain, female), and spleen cells were prepared by a conventional method. ⁇ Seed in RPMI-1640 medium containing 10% fetal serum, add anti-CD3 antibody to stimulate IL-4 production from helper T cells in spleen cells, and simultaneously add raki cidin A or rakicidin B. The cells were cultured for 20 hours at 37 ° C. in the presence of 5% C 2 . After completion of the culture, the culture supernatant was recovered, and the amount of IL-14 produced and secreted by the helper T cells in the culture supernatant was quantified by enzyme immunoassay. The amount of interferon (IFNr) produced and secreted by helper T cells in the same culture supernatant was also quantified by enzyme immunoassay. The results are shown in Table 1.
  • rakicidin A and rakicidin B suppressed IL_4 production.
  • rakicidin A and rakicidin B inhibited IL-4 production without suppressing IFNa production. It was shown to selectively suppress.
  • P388 cells derived from mouse
  • Jurkat cells human
  • ⁇ shea RPM 1 containing 10% calf serum - 1640 seeded in culture medium P388 cells 2 x 10 m 1 and Jurkat cells 5 say yes 10 4: 111
  • Rakicidin a or B, 72 h were cultured in the presence of 5% C_ ⁇ 2 at 37.
  • Example 2 Inhibition of allergic airway inflammation in a mouse asthma model
  • Corry et al. Corry, D et al., Journal of Experimental Medicine, Journal of Experimental Medicine, Vol. 183, p. 109 (1996). . ] was partially modified.
  • mice (Balb / c, female) were immunized with ovalbumin saline solution containing aluminum hydroxide, gel and adjuvant. The same immunization was performed again on the sixth day after the immunization, and a physiological saline solution containing ovalbumin was inhaled once a day from the 11th to the 14th day.
  • rakicidin A was administered by inhalation of a 200 ng / ml saline solution once daily through the nasal cavity from day 11 to day 14. Therefore, the total dose of rakicidin A is 40 ng per individual. Control animals that received the same immunization were treated with physiological saline solution without rakicidin A in the same manner.
  • the definition of the inflammation score is as follows.
  • rakicidin A is a saline solution of 1 or 10 igZm 1 in 0.1 ml each, 10 minutes before and 10 minutes after asthma induction by ovalbumin inhalation.
  • rakicidin A Administered by inhalation. Therefore, the dose of rakicidin A is 0.2 uL g MS 2 ti g per individual.
  • a control group of animals to which the same immunization was performed was administered a physiological saline solution containing no rakicid in A in the same manner.
  • Table 3 shows the results. As is clear from Table 3, it was shown that administration of rakicidin A suppressed an increase in airway resistance due to asthma.
  • an excellent therapeutic agent for allergic diseases that hardly inhibits immune reactions important for biological defense, that is, prevention of allergic diseases, Drugs suitable for improvement and / or treatment can be provided.
  • a method for preventing, ameliorating, and / or treating such a disease can also be provided.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Pulmonology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Selon l'invention, des dérivés de lypopeptide cyclique, tels que rakicidine A et rakicidine B, présentent une excellente action de suppression sélective des réactions immunitaires provoquant des maladies allergiques, sans inhiber les réactions immunitaires importantes pour la protection biologique. L'utilisation de ces dérivés en tant que principe actif permet de produire des médicaments, en particulier des remèdes contre des maladies allergiques (notamment des médicaments appropriés pour la prévention, l'amélioration, le traitement, etc.), ce qui donne des remèdes efficaces et très sûrs contre des maladies allergiques, ou des méthodes de traitement desdites maladies, etc.
PCT/JP2001/002076 2000-03-17 2001-03-16 Remedes contre des maladies allergiques WO2001068121A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001241162A AU2001241162A1 (en) 2000-03-17 2001-03-16 Remedies for allergic diseases

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JP2000076023 2000-03-17
JP2000-076023 2000-03-17

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105709205A (zh) * 2016-03-28 2016-06-29 福建省微生物研究所 Rakicidins类化合物用于抗临床致病厌氧菌的用途
CN105753936A (zh) * 2016-03-28 2016-07-13 福建省微生物研究所 一种Rakicidins类化合物Rakicidin B1及其制备方法
CN108130285A (zh) * 2017-11-24 2018-06-08 福建省微生物研究所 一种发酵产Rakicidin B的海洋小单孢菌株及其应用
CN110066745A (zh) * 2019-03-08 2019-07-30 福建省微生物研究所 一种发酵高产Rakicidin H的海洋小单孢菌株及其应用
CN110437313A (zh) * 2019-08-12 2019-11-12 福建省微生物研究所 一种Rakicidins酯化衍生物及其制备方法与应用
CN110437314A (zh) * 2019-08-12 2019-11-12 福建省微生物研究所 一种天然Rakicidins类化合物Rakicidin B1-1及其发酵提取方法
CN110698541A (zh) * 2019-08-12 2020-01-17 福建省微生物研究所 一种天然Rakicidins类化合物Rakicidin J及其发酵提取方法
CN110698537A (zh) * 2019-08-12 2020-01-17 福建省微生物研究所 一种天然Rakicidins类化合物Rakicidin B1-2及其发酵提取方法
CN111116707A (zh) * 2019-12-20 2020-05-08 福建省微生物研究所 一种Rakicidins氨基甲酸酯类衍生物及其制备方法与应用
CN117695374A (zh) * 2024-01-25 2024-03-15 超越健康科技(浙江)有限公司 一种用于治疗帕金森病的生物药物

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0496452A1 (fr) * 1991-01-24 1992-07-29 Merck & Co. Inc. Nouveaux antagonistes du récepteur d'endotheline isolés par microbispora
JPH04243894A (ja) * 1991-01-24 1992-08-31 Yamanouchi Pharmaceut Co Ltd 新規ｑ−６４０２化合物およびその製造法
JPH05246880A (ja) * 1992-03-04 1993-09-24 Hideji Itokawa 免疫抑制剤
JPH08291079A (ja) * 1995-04-24 1996-11-05 Sekisui Chem Co Ltd 抗炎症物質

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0496452A1 (fr) * 1991-01-24 1992-07-29 Merck & Co. Inc. Nouveaux antagonistes du récepteur d'endotheline isolés par microbispora
JPH04243894A (ja) * 1991-01-24 1992-08-31 Yamanouchi Pharmaceut Co Ltd 新規ｑ−６４０２化合物およびその製造法
JPH05246880A (ja) * 1992-03-04 1993-09-24 Hideji Itokawa 免疫抑制剤
JPH08291079A (ja) * 1995-04-24 1996-11-05 Sekisui Chem Co Ltd 抗炎症物質

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MCBRIEN K.D. ET AL: "Rakicidins, new cytotoxic lipopeptides from micromonospora sp. fermentation, isolation and characterization", J. ANTIBIOT., vol. 48, no. 12, December 1995 (1995-12-01), pages 1446 - 1452, XP002940684 *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105709205A (zh) * 2016-03-28 2016-06-29 福建省微生物研究所 Rakicidins类化合物用于抗临床致病厌氧菌的用途
CN105753936A (zh) * 2016-03-28 2016-07-13 福建省微生物研究所 一种Rakicidins类化合物Rakicidin B1及其制备方法
CN105753936B (zh) * 2016-03-28 2019-01-11 福建省微生物研究所 一种Rakicidins类化合物Rakicidin B1及其制备方法
CN105709205B (zh) * 2016-03-28 2019-02-19 福建省微生物研究所 Rakicidins类化合物用于抗临床致病厌氧菌的用途
CN108130285A (zh) * 2017-11-24 2018-06-08 福建省微生物研究所 一种发酵产Rakicidin B的海洋小单孢菌株及其应用
CN108130285B (zh) * 2017-11-24 2021-03-30 福建省微生物研究所 一种发酵产Rakicidin B的海洋小单孢菌株及其应用
CN110066745A (zh) * 2019-03-08 2019-07-30 福建省微生物研究所 一种发酵高产Rakicidin H的海洋小单孢菌株及其应用
CN110066745B (zh) * 2019-03-08 2021-03-30 福建省微生物研究所 一种发酵高产Rakicidin H的海洋小单孢菌株及其应用
CN110698541A (zh) * 2019-08-12 2020-01-17 福建省微生物研究所 一种天然Rakicidins类化合物Rakicidin J及其发酵提取方法
CN110698537A (zh) * 2019-08-12 2020-01-17 福建省微生物研究所 一种天然Rakicidins类化合物Rakicidin B1-2及其发酵提取方法
CN110698541B (zh) * 2019-08-12 2023-04-14 福建省微生物研究所 一种天然Rakicidins类化合物Rakicidin J及其发酵提取方法
CN110437314B (zh) * 2019-08-12 2021-03-26 福建省微生物研究所 一种天然Rakicidins类化合物Rakicidin B1-1及其发酵提取方法
CN110437313B (zh) * 2019-08-12 2021-03-26 福建省微生物研究所 一种Rakicidins酯化衍生物及其制备方法与应用
CN110437314A (zh) * 2019-08-12 2019-11-12 福建省微生物研究所 一种天然Rakicidins类化合物Rakicidin B1-1及其发酵提取方法
CN110437313A (zh) * 2019-08-12 2019-11-12 福建省微生物研究所 一种Rakicidins酯化衍生物及其制备方法与应用
CN110698537B (zh) * 2019-08-12 2023-05-12 福建省微生物研究所 一种天然Rakicidins类化合物Rakicidin B1-2及其发酵提取方法
CN111116707A (zh) * 2019-12-20 2020-05-08 福建省微生物研究所 一种Rakicidins氨基甲酸酯类衍生物及其制备方法与应用
CN111116707B (zh) * 2019-12-20 2021-10-22 福建省微生物研究所 一种Rakicidins氨基甲酸酯类衍生物及其制备方法与应用
CN117695374A (zh) * 2024-01-25 2024-03-15 超越健康科技(浙江)有限公司 一种用于治疗帕金森病的生物药物
CN117695374B (zh) * 2024-01-25 2024-09-06 超越健康科技(浙江)有限公司 一种用于治疗帕金森病的生物药物

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