WO2009069966A2 - Utilisation de composés pour contrôler la fonction de la sphingosylphosphorylcholine - Google Patents

Utilisation de composés pour contrôler la fonction de la sphingosylphosphorylcholine Download PDF

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Publication number
WO2009069966A2
WO2009069966A2 PCT/KR2008/007044 KR2008007044W WO2009069966A2 WO 2009069966 A2 WO2009069966 A2 WO 2009069966A2 KR 2008007044 W KR2008007044 W KR 2008007044W WO 2009069966 A2 WO2009069966 A2 WO 2009069966A2
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WO
WIPO (PCT)
Prior art keywords
naphthalen
spc
propyl
yloxy
function
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PCT/KR2008/007044
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English (en)
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WO2009069966A3 (fr
Inventor
Jaeyoung Ko
Eun Sil Han
Hyuk Kim
Jung Ju Kim
Minsoo Noh
Sanghee Kim
Chaemin Lim
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Amorepacific Corporation
Seoul National University Industry Foundation
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Publication of WO2009069966A2 publication Critical patent/WO2009069966A2/fr
Publication of WO2009069966A3 publication Critical patent/WO2009069966A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

  • the present invention relates to a use of a specific compound for the manufacture of a medicament for effectively controlling the function of sphingosylphosphorylcholine.
  • SPC Sphingosylphosphorylcholine
  • SPC Sphingosylphosphorylcholine
  • SM sphingomyelin
  • SPC is known to function as a mitogen for various types of cells and to stimulate the secretion of specific cytokines (Meyer et al., Biochim Biophys).
  • SPC is also known to be closely associated with the growth and proliferation of various cells (Desai et al., Biochem . Biophys.
  • SPC is responsible for wound healing by stimulating the proliferation of keratinocytes and fibroblasts (Wakita et al., J. Invest. Dermatol, 110: 253-258 (1998); and Berger et al., Proc. Natl. Acad. Sci. U. S. A., 92: 5885-5889 (1995)).
  • SPC is involved in Ca 2+ release from endoplasmic reticulum (Desai et al., J. Cell.
  • NPD Niemann- Pick disease
  • ASM acidic sphingomyelinase
  • SPC also causes atopic dermatitis induced by reduced antimicrobial activity, leading to the loss of barrier function due to a reduced amount of lipids in the stratum corneum, and the weakening of the defense against external stimuli.
  • Such inflammatory responses cause itching, which, in turn, tends to lead to secondary infections, such as hyperimmune responses.
  • rho kinase The key regulatory factor of such chemotactic migration is rho kinase (Verena Niggli, The International Journal of Biochemistry & Cell Biology., 35: 1619- 1638 (2003)).
  • the rho kinase is also known to play a significant role in the SPC-controlled intracellular Ca 2+ concentration (Zhu et al., Exp Dermatol., 14: 509-514 (2005); and Todoroki-Ikeda et al., FEBS Lett., 482: 85-90 (2000)). This suggests that the SPC-mediated cell response mechanism is very closely associated with the inflammatory response mechanism.
  • eosinophils which are inflammatory cells responsible for asthma, allergic rhinitis, eosinophilic pneumonia, eosinophilic enteritis, hypereosinophilic syndrome, and inflammation in the respiratory tract, the intestinal canal and other tissues, are known to induce the formation of pro- inflammatory cytokines during the process of pathology such as allergic diseases, asthma, etc.
  • eosinophils are found only in selected areas like the digestive tract.
  • eosinophils are found in the tissues of patients with acute and chronic atopic dermatitis, and skin hypertrophy of the epidermis and dermis of a mouse model with atopic dermatitis is found during the healing process after exposure to cytotoxic eosinophil major basic proteins or eosinophil cationic proteins.
  • SPC modulators are effective for the treatment or prevention of various eosinophil-mediated diseases such as atopic dermatitis.
  • lysophosphatic acid having structural similarity to SPC causes a patient suffering from atopic dermatitis pain and itching/scratching, resulting in the degradation of the patient's life quality (Hashimoto et al., Pharmacology, 72: 51-56(2004)). This suggests that SPC can also cause itching in vivo. Further, the present inventors have demonstrated that the intradermal administration of SPC causes itching (WO 2006/049451).
  • X is O or S
  • Y is CH 2 or carbonyl;
  • R 1 is hydrogen or C 1-1O alkyl;
  • R 2 is hydrogen or methyl;
  • R 3 is Ci -4 alkyl, with the proviso that when X is O, R 1 and R 2 are not hydrogen at the same time.
  • the compound of formula (I) may be selected from the group consisting of:
  • the controlling of the function of SPC may be to inhibit scar formation after a trauma.
  • the controlling of the function of SPC may be to inhibit chemotactic cell migration.
  • the controlling of the function of SPC may be to inhibit inflammatory response.
  • the controlling of the function of SPC may be to inhibit itching.
  • a method of controlling the function of SPC in a mammal comprising administering thereto a compound of formula (I) or a pharmaceutically acceptable salt thereof in an effective amount:
  • X, Y, R 1 , R 2 and R 3 are as defined above.
  • the present invention provides a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for controlling the function of SPC:
  • X is O or S
  • Y is CH 2 or carbonyl
  • R 1 is hydrogen or Ci -I0 alkyl
  • R 2 is hydrogen or methyl
  • R 3 is C 1-4 alkyl, with the proviso that when X is O, R 1 and R 2 are not hydrogen at the same time.
  • the pharmaceutically acceptable salt of the compound of formula (I) may be an addition salt of an inorganic acid or an organic acid, or an acid addition salt with a base.
  • the base may be alkaline (earth) metal such as sodium, potassium, magnesium or calcium
  • the inorganic acid may be hydrochloric acid or sulfuric acid
  • the organic acid may be acetic acid or maleic acid.
  • alkyl as used herein is a saturated straight or branched hydrocarbon, and may be methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, hexyl, etc.
  • Preferred examples of the compound of formula (I) include:
  • Z is Cl, Br or I
  • R 4 is methyl or ethyl.
  • step 1 a compound of formula (II) is subjected to a reaction with a compound of formula (III) in the presence of a base in a solvent to obtain a compound of formula (IV).
  • the solvent which may be used in step 1 includes polar aprotic solvents, among which acetone is preferred.
  • the base which may be used in step 1 includes amines such as pyridine, triethylamine, imidazole and N,N-dimethylaminopyridine, and inorganic compounds such as calcium carbonate and potassium carbonate, among which potassium carbonate is preferred.
  • amines such as pyridine, triethylamine, imidazole and N,N-dimethylaminopyridine
  • inorganic compounds such as calcium carbonate and potassium carbonate, among which potassium carbonate is preferred.
  • the reaction temperature of step 1 may vary depending on the solvent used, but may be generally in a range from -10 to 80 0 C , preferably from 0 to room temperature (25 " C).
  • the reaction time of step 1 may vary depending on the reaction temperature and the solvent used, but it is generally from one hour to one day, preferably four hours or less.
  • step 2 the compound of formula (IV) is stirred in a solvent in the presence of a base to obtain a compound of formula (V).
  • the base which may be used in step 2 includes sodium hydroxide, potassium hydroxide, lithium hydroxide, and others, among which sodium hydroxide is preferred.
  • the solvent which may be used in step 2 is an absolute alcohol such as 100% methanol, 100% ethanol, and 100% propanol; or a mixture of alcohol and water ( 1 : 1 , by volume), wherein absolute ethanol is preferred.
  • the reaction temperature of step 2 may vary depending on the solvent used, but may be generally in a range from -10 to 80 ° C , preferably from 0 to room temperature (25 " C).
  • the reaction time of step 2 may vary depending on the reaction temperature and the solvent used, but it is generally from one hour to one day, preferably six hours or less.
  • step 3 the compound of formula (V) is subjected to a reaction with a compound of formula (VI) in a solvent to form a peptide bond, thereby producing a compound of formula (Ia).
  • NMP N-methylpyrrolidone
  • DTMM 4-(5,6- dimethoxy-l,3,5-triazin-2-yl)-4-methyl-mo ⁇ holium chloride
  • the solvent which may be used in step 3 includes dichloromethane, chloroform, tetrahydrofuran, and others, among which tetrahydrofuran is preferred.
  • the reaction temperature of step 3 may vary depending on the solvent used, but may be generally in a range from -10 to 80 0 C 5 preferably from 0 to room temperature (25 ° C).
  • the reaction time of step 1 may vary depending on the reaction temperature and the solvent used, but it is generally from one hour to one day, preferably 12 hours or less.
  • R 1 , R 2 and R 3 are as defined above.
  • the reducing agent may be lithium aluminum hydride, borane (BH 3 ), and others, among which borane (BH 3 ) is preferred.
  • the solvent may be selected from ethers, among which tetrahydrofuran is preferred.
  • the reaction temperature may vary depending on the solvent used, but may be generally in a range from -50 to 50 ° C , preferably 25 ° C .
  • the reaction time may be generally from one to two days, preferably one day.
  • the present invention provides a pharmaceutical composition for controlling the function of SPC in vivo and in vitro, which comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the inventive pharmaceutical composition is responsible for improved wound healing and reduced scar formation after a trauma, reduced chemotactic cell migration, and alleviated inflammatory response and itching.
  • the pharmaceutical composition may further include a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition can be formulated into various pharmaceutical formulations in accordance with any of methods known in the art.
  • the active ingredient may be admixed or diluted with a carrier, or enclosed within a container-type carrier.
  • the carrier When used as a diluent, it may be a solid, semi-solid or liquid material acting as a carrier, excipient or medium for the active ingredient.
  • the formulation may be in the form of a tablet, pill, powder, sachet, elixir, suspension, emulsion, solution, syrup, aerosol, soft or hard gelatin capsule, sterile injectable solution, sterile powder or the like.
  • suitable carrier and excipient are lactose, dextrose, sucrose, sorbitol, mannitol, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • the pharmaceutical composition may additionally include fillers, anti-agglutinating agents, lubricants, wetting agents, flavoring agents, emulsifiers, presevatives and the like.
  • the pharmaceutical composition may also be formulated to provide quick, sustained or delayed release of the active ingredient after its administration to a mammal.
  • the pharmaceutical composition may be administered to mammals via various routes including oral, transdermal, subcutaneous, intravenous, and intramuscular routes.
  • the active ingredient can be administered in an effective amount ranging from about 0.001 to 1000 mg/kg (body weight)/dose, preferably 0.1 to 10 mg/kg/dose in a single dose or in divided doses.
  • the dosage of the active ingredient may be adjusted in light of various relevant factors such as the condition of the subject to be treated, an administration route, the age, sexuality and weight of a patient, severity of disease, which do not limit the scope of the present invention.
  • the present invention also provides a method of controlling the function of SPC in a mammal, comprising administering thereto the compound of formula (I) or a pharmaceutically acceptable salt thereof in an effective amount.
  • inventive compounds can effectively control adverse effects induced by in vitro and in vivo action of SPC, including cell proliferation, inflammatory response, and itching, and thus, are useful for the prevention and treatment of atopic dermatitis, or other diseases accompanying inflammation, itching or skin infection.
  • the 2-(naphthalen-2-yloxy)-propanoic acid (200 mg, 0.925 mmol) was dissolved in tetrahydrofuran, and N-methylpropylamine (189.8 ⁇ i, 1,850 mmol) and NMP (305 ⁇ i, 2.775 mmol) were added thereto. Then, DMTMM (307 mg, 1.11 mmol) was added and the reaction mixture was stirred for 10 hours. After the reaction was terminated, the resultant solution was extracted with chloroform and IN HCl.
  • Example 1 The procedure of Example 1 was repeated except for using 2-naphthol and ethyl 2-bromobutyrate as starting materials to give the title compound as represented by the following formula.
  • Example 1 The procedure of Example 1 was repeated except for using 2-naphthol and ethyl 2-bromovalonate as starting materials to give the title compound as represented by the following formula.
  • Example 1 The procedure of Example 1 was repeated except for using 2-naphthol and ethyl 2-bromohexanoate as starting materials to give the title compound as represented by the following formula.
  • Example 2 The procedure of Example 2 was repeated except for using 2-naphthol and ethyl 2-bromobutyrate as starting materials to give the title compound as represented by the following formula.
  • Example 2 The procedure of Example 2 was repeated except for using 2-naphthol and ethyl 2-bromovalonate as starting materials to give the title compound as represented by the following formula.
  • Example 2 The procedure of Example 2 was repeated except for using 2-naphthol and ethyl 2-bromohexanoate as starting materials to give the title compound as represented by the following formula.
  • SPC SPC induces excessive proliferation of cells, which may cause pathological symptoms such as atopic dermatitis (Desai et al., Biochem. Biophy. Res. Commun. 181 : 361-366 (1991)).
  • pathological symptoms such as atopic dermatitis (Desai et al., Biochem. Biophy. Res. Commun. 181 : 361-366 (1991)).
  • inventive compounds were analyzed.
  • NIH 3T3 cells American Type Culture Collection, Manassas, VA, USA
  • NIH 3T3 cells American Type Culture Collection, Manassas, VA, USA
  • a culture plate at a density of about 1 x 10 5 cells (generally, l * 10 4 to 10 6 cells), and cultured in an RPMI medium free from fetal bovine serum (FBS) for 24 hours for serum starvation.
  • FBS fetal bovine serum
  • the cells were treated with the compounds of Examples 1 to 13 and FTY 720 (Seoul National University, Lipidomics NRL) as a control compound which is an agonist of sphingosine-1 -phosphate ("SPl”) (0.001 uM, 0.01 uM, 0.1 uM and 1 uM for each compound), and cultured for 30 minutes.
  • SPl sphingosine-1 -phosphate
  • the inventive compounds of Examples 1-13 acted as an agonist or an antagonist on SPC-induced cell proliferation.
  • Excessive cell proliferation induced by inflammatory response occurring during the process of wound healing after a trauma results in scar formation.
  • a substance inhibiting such excessive cell proliferation can be used to prevent the formation of undesirable scars.
  • a substance promoting cell proliferation can be used to accelerate wound healing after a trauma.
  • inventive compounds of Examples 1-13 showed dose-dependent inhibition of SPC-induced cell proliferation even though the degree of inhibition was different.
  • FTY 720 a SlP agonist having a chemical structure similar to SPC, did not exhibit such suppression.
  • Such inhibition of cell proliferation is considered to be a consequence of intrinsic activity of the inventive compounds, and thus, it is expected that the inventive compounds can inhibit scar formation resulting from excessive cell proliferation due to inflammatory response occurring during a wound healing process after a trauma.
  • a polycarbonate membrane of 25 x 80 mm (Neuro Probe, Inc.) which has a pore size of 8 ⁇ m was immersed in a solution containing 0.01% gelatin and 0.1% acetic acid overnight and then dried at room temperature.
  • human umbilical vein endothelial cells cultured in complete EBM-2 medium (Cambrex, Catalog No. CC-3121) supplemented with 2% FBS were cultured in EBM-2 medium free from FBS for four hours for serum starvation, and then harvested with a trypsin/EDTA solution.
  • the HUVECs were suspended in a EBM-2 medium supplemented with 0.1% FBS albumin, seeded in silicone-coated Eppendorf tubes and treated with 0 to 10 ⁇ g/ml of the compound of Example 9 at 37 ° C for 30 minutes.
  • Equation II Inhibition (%) 100 x (cell number of SPC-treated group - cell number of test compound-treated group)/(cell number of SPC-treated group - cell number of SPC-untreated group)
  • the inventive compound of Example 9 effectively inhibited SPC-induced chemotactic cell migration. This result shows that the inventive compounds can inhibit the migration of endothelial or immune cells, thereby to control tumor angiogenesis or amplification of immune response against a foreign antigen.
  • TPA tetradecanoyl phorbol acetate
  • mice of 6 weeks old were subjected to TPA treatment.
  • their left ear skin was coated with 20 ⁇ i of TPA (125 ⁇ gl ml) (Sigma Aldrich Korea) dissolved in acetone.
  • TPA 125 ⁇ gl ml
  • hydrocortisone Sigma Aldrich Korea
  • each 20 ⁇ i of the above reagents was further applied to the same sites.
  • 24 hours after TPA coating the mice were sacrificed by cervical dislocation, and the left ear tissues were dissected. The tissue samples were weighed, and the inhibition (%) was calculated by the following Equation III. The results are shown in Table 4.
  • Equation III Inhibition (%) 100 x (weight of TPA only- treated group - weight of test compound-treated group)/(weight of TPA only-treated group - weight of TPA- untreated group)
  • the compounds of Examples 9, 12 and 13 significantly inhibited TPA-induced inflammatory response. Further, the inhibitory effect of each compound of Examples 9, 12 and 13 was comparable to about 50 to 60% of that of hydrocortisone commonly used as a strong anti- inflammatory agent. These results show that the anti-inflammatory effect of the inventive compounds is achieved by inhibiting the infiltration of neutrophils around ears.
  • mice male ICR mice (8 weeks old) were shaved on the back and rear-neck areas and left in a cage for two days. Then, D-SPC and the compound of Example 9 was each dissolved in PBS (phosphate buffered saline) or PEG (polyethyleneglycol) 400 to a concentration of 2 mM, and 50 ⁇ i of each solution was intradermally administered to the mice. Then, the mice were moved into a cage and videotaped for 30 minutes to count the number of the behaviors of scratching the back portions of the mice using the hind paws.
  • PBS phosphate buffered saline
  • PEG polyethyleneglycol
  • Equation IV Inhibition (%) 100 x (number of scratch events in test-treated group - number of scratch events in untreated group)/(number of scratch events in D- SPC only-treated group - number of scratch events in untreated group) ⁇ Table 5>
  • Example 9 As shown in Table 5, the compound of Example 9 exhibited a significant inhibitory effect on SPC-induced itch-scratch response.

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  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

L'invention porte sur l'utilisation d'un composé spécifique pour la fabrication d'un médicament pour contrôler la fonction de la sphingosylphosphorylcholine. Le composé de l'invention peut contrôler de manière efficace des effets défavorables induits par une action in vitro et in vivo de la SPC, comprenant la prolifération cellulaire, la réponse inflammatoire et le prurit, et est ainsi utile pour la prévention et le traitement de la dermatite atopique, ou autres maladies accompagnant l'inflammation, du prurit ou d'une infection cutanée.
PCT/KR2008/007044 2007-11-30 2008-11-28 Utilisation de composés pour contrôler la fonction de la sphingosylphosphorylcholine WO2009069966A2 (fr)

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KR10-2007-0123798 2007-11-30
KR1020070123798A KR20090056584A (ko) 2007-11-30 2007-11-30 스핑고실포스포릴콜린의 작용을 조절하는 약학 조성물

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014055941A2 (fr) * 2012-10-04 2014-04-10 Pappalardo Juan Sabastian Composés et procédés de délivrance ciblée au système immunitaire

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118121578B (zh) * 2024-05-06 2024-08-16 广州市朝利良生物科技有限公司 化合物eh-p008v及在制备促伤口愈合药物中的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4895840A (en) * 1987-06-10 1990-01-23 A. H. Robins Company, Incorporated N-(aryl-,aryloxy-,arylthio-arylsulfinyl-and arylsulfonyl-)alkyl-N,N'-(or n'n')alkylaminoalkyl ureas and cyanoguanidines
WO2006049451A1 (fr) * 2004-11-05 2006-05-11 Amorepacific Corporation Utilisation de sphingosylphosphorylcholine ou de son derive
WO2007136159A1 (fr) * 2006-05-18 2007-11-29 Amorepacific Corporation Utilisation d'antagoniste de sphingosylphosphorylcholine pour restaurer l'expression de peptides antimicrobiens

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4895840A (en) * 1987-06-10 1990-01-23 A. H. Robins Company, Incorporated N-(aryl-,aryloxy-,arylthio-arylsulfinyl-and arylsulfonyl-)alkyl-N,N'-(or n'n')alkylaminoalkyl ureas and cyanoguanidines
WO2006049451A1 (fr) * 2004-11-05 2006-05-11 Amorepacific Corporation Utilisation de sphingosylphosphorylcholine ou de son derive
WO2007136159A1 (fr) * 2006-05-18 2007-11-29 Amorepacific Corporation Utilisation d'antagoniste de sphingosylphosphorylcholine pour restaurer l'expression de peptides antimicrobiens

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HASHIMOTO ET AL.: 'Itch-Scratch Responses Induced by Lysophosphatidic Acid in Mice' PHARMACOLOGY vol. 72, no. 1, 2004, pages 51 - 56 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014055941A2 (fr) * 2012-10-04 2014-04-10 Pappalardo Juan Sabastian Composés et procédés de délivrance ciblée au système immunitaire
WO2014055941A3 (fr) * 2012-10-04 2014-07-03 Pappalardo Juan Sabastian Composés et procédés de délivrance ciblée au système immunitaire
US9962448B2 (en) 2012-10-04 2018-05-08 Northeastern University Compounds and methods for targeted immune system delivery

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