WO2015102418A2 - Composé peptidomimétique et composition pharmaceutique destinée au traitement des troubles allergiques, renfermant ledit composé - Google Patents

Composé peptidomimétique et composition pharmaceutique destinée au traitement des troubles allergiques, renfermant ledit composé Download PDF

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WO2015102418A2
WO2015102418A2 PCT/KR2014/013134 KR2014013134W WO2015102418A2 WO 2015102418 A2 WO2015102418 A2 WO 2015102418A2 KR 2014013134 W KR2014013134 W KR 2014013134W WO 2015102418 A2 WO2015102418 A2 WO 2015102418A2
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Prior art keywords
dpr
serine
tyrosine
tryptophan
valine
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PCT/KR2014/013134
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English (en)
Korean (ko)
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WO2015102418A3 (fr
Inventor
유재상
이경림
박윤정
김미영
김효영
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이화여자대학교 산학협력단
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Priority claimed from KR1020140000945A external-priority patent/KR101590949B1/ko
Priority claimed from KR1020140000942A external-priority patent/KR101576231B1/ko
Priority claimed from KR1020140000944A external-priority patent/KR101600049B1/ko
Priority claimed from KR1020140000946A external-priority patent/KR101590952B1/ko
Priority claimed from KR1020140000943A external-priority patent/KR101600048B1/ko
Application filed by 이화여자대학교 산학협력단 filed Critical 이화여자대학교 산학협력단
Publication of WO2015102418A2 publication Critical patent/WO2015102418A2/fr
Publication of WO2015102418A3 publication Critical patent/WO2015102418A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a novel peptidomimetic compound exhibiting a prophylactic or therapeutic activity against allergic diseases, and a pharmaceutical composition for the prevention or treatment of allergic diseases.
  • Mast cells and hypertensive basophils are body cells that cause various allergic diseases, including allergic rhinitis, allergic atopic dermatitis, allergic conjunctivitis, allergic asthma, food allergy and anaphyl act ic shock.
  • These cells have receptors for allergens on the cell surface, and when stimulated they secrete various allergens out of the cell.
  • peptides peptide ide
  • the biologically active peptide is easily by the enzyme or acid in vivo
  • it is hydrolyzed and its molecular weight is generally large, making it difficult to use as a drug.
  • methods for modifying the side chains or skeletal structures of peptides or for using them as templates for inducing specific structures have been proposed. All these materials are collectively called peptidomimetic compounds.
  • these compounds can be used for molecular diagnosis such as detection of harmful microorganisms and environmental hormones, and can be used for new drug designs, nanocomposites, and new drug carriers.
  • the present invention is to provide a novel peptidomimetic compound exhibiting a prophylactic or therapeutic activity against allergic diseases.
  • the present invention relates to a pharmaceutical composition for preventing or treating allergic diseases, including the compound.
  • the present invention relates to a method for treating an allergic disease, comprising administering to a subject a pharmaceutically effective amount of said compound.
  • the peptidomimetic compound of the present invention exhibits an excellent antiallergic effect in allergic animal models, such as inhibiting the secretion of cytokines and histamine, including IL-8, IL-5, and the like. By blocking the pathway that causes the various side effects can be eliminated can be used more usefully.
  • 1 shows a step-by-step schematic diagram for synthesizing peptidomimetic compounds.
  • 2 shows selective removal of Mtt protecting groups confirmed by HPLC.
  • Figure 3 shows a schematic diagram of dividing the compound prepared in Preparation Example 3 into two parts, tetramer of the NH2 terminal and tetramer of the COOH terminal around the Dpr site.
  • Figure 4 shows the selected compounds out of dTBP2 more effectively among the compounds prepared in Preparation Example 3.
  • Figure 5 shows the degree of inhibition of interleukin-8 secretion of the compound prepared in Preparation Example 2.
  • Figure 6 shows the degree of inhibition of interleukin-8 secretion of the compound prepared in Preparation Example 3.
  • Figure 7 compares the relative activity between the compound prepared in Preparation Example 4 and the compound prepared in Preparation Example 5.
  • Figure 8 shows the degree of inhibition of interleukin-8 secretion of the compound prepared in Preparation Example 6.
  • Figure 9 shows the results of in situ competition assay (competition assay) of the compound prepared in Preparation Example 2.
  • Figure 10A shows that the symptom score (symptom score) was reduced when dTBP2 treatment
  • Figure 10B shows the eosinophil changes when dTBP2 treatment
  • Figure 11 shows that the treatment of compounds 122, 123 and 129, the secretion of interleukin-5 is suppressed in the bronchoalveolar lavage fluid.
  • Figure 12 is treated with compounds 122, 123 and 129, stained with 1 drug per iodic Acid-Schi ff (PAS) ⁇ and observed the mucosa thickness of lung tissue.
  • PAS iodic Acid-Schi ff
  • FIG. 13 shows that treatment of compounds 97 and 121. inhibits the secretion of interleukin-5 in bronchoalveolar lavage fluid.
  • Figure 14 is treated with compounds Nos. 97 and 121 and staining mucosal membranes of lung tissue with Hematoxylin and eosin (H & E) reagents to show changes.
  • H & E Hematoxylin and eosin
  • the present invention relates to a novel peptidomimetic compound exhibiting a prophylactic or therapeutic activity against allergic diseases.
  • the present invention provides a peptide or fragment thereof consisting of the amino acid sequence of SEQ ID NO: 1 (Trp-Tyr ⁇ Val-Tyr-Pro— Ser-Met), the first amino acid of tryptophan or the fourth amino acid tyrosine of SEQ ID NO:
  • This modified and novel peptidomimetic compound exhibits prophylactic or therapeutic activity against allergic diseases.
  • the peptidomimetic compound of the present invention is an amino acid sequence of the amino acid sequence of SEQ ID NO: 1, or a fragment thereof, acyl group in the tryptophan site of the first amino acid of the SEQ ID NO.
  • a tyrosine the fourth amino acid of SEQ ID NO, is substituted with a diaminopropionic acid (Dpr) to which an acyl group is linked, or an acyl group is introduced at a tryptophan site, the first amino acid of SEQ ID NO:
  • Dpr diaminopropionic acid
  • the fourth amino acid of the present invention relates to a peptidomimetic compound exhibiting prophylactic or therapeutic activity against allergic diseases in which tyrosine is substituted with an acyl group-linked diaminopropionic acid.
  • the peptide consisting of the amino acid sequence of SEQ ID NO: 1 is a heptamer (heptatner) also known as dTBP2 [dTCTP (dimer i zed trans l at l ly control l ed tumor protein) binding pept ide 2].
  • the peptides are known to bind to dTCTP with a high affinity to inhibit the interaction between dTCTP and its receptors, thereby inhibiting the transmission of allergen related information due to their interaction. It is also known to be involved in alleviating various allergic diseases that can be induced by inhibiting the secretion of cytokines and histamine, including interleukin (IL) -8, IL-5 and the like.
  • IL interleukin
  • the present inventors have described peptidomimetic compounds which acylated NH 2 terminus with various acids and peptidomimetic compounds that have tried various changes to dTBP2 for the purpose of inhibiting the binding between dTCTP and its receptor. It was synthesized and the efficacy was confirmed by measuring the biological activity of these compounds.
  • an acyl group was introduced into tryptophan, which is an N-terminal amino acid, and a compound having a good effect was selected.
  • the compounds have increased binding to dTCTP.
  • the newly introduced functional group may provide an additional binding site, and it was confirmed that the binding force of dTCTP-dTBP2 was significantly increased by replacing loose binding residues such as internal tyrosine with hard bonds (Experimental Examples 1 to 4). ).
  • the peptide is a peptide or fragment thereof consisting of the amino acid sequence of SEQ ID NO: 1, the peptidomimetic compound having an acyl group introduced into tryptophan, the first amino acid of the SEQ ID NO: Can be.
  • it may be a peptidomimetic compound comprising the structure of Formula 1.
  • W tryptophan (W)
  • Y is Tyrosine
  • V is valine (V) and ⁇
  • P is Proline, P,
  • S is Serine
  • M Methionine (M).
  • the present invention provides a peptide in which an acyl group is introduced into a tryptophan site, the first amino acid of SEQ ID NO: 1, and a tyrosine acyl group (acyl group) is linked to the fourth amino acid of SEQ ID NO.
  • Peptidomimetics which are substituted with diaminopropionic acid (Dpr) and exhibit prophylactic or therapeutic activity against allergic diseases Compound.
  • an isonicotinyl group may be introduced at the tryptophan site, which is the first amino acid of SEQ ID NO.
  • the Dpr is a benzoyl group, cinnamil group, carboxyl group, acetyl group, nucleosinyl group, orotyl group, naphthoyl group, nicotinyl group, nucleodienyl group, glyoxyl group furoyl group, nucleosanyl group, quinadiyl group, tie And an acyl group-containing substituent including one or more selected from the group consisting of a glayl group, a troloxyl group, a heteroalkyl, and an arylheteroalkyl.
  • it may be a peptidomimetic compound including the structure of Formula 2 below.
  • Dpr is Diaminopropionic acid
  • R 2 is unsubstituted or substituted linear, branched or cyclic alkyl having 1 to 20 carbon atoms, unsubstituted or substituted alkoxy having 1 to 10 carbon atoms, unsubstituted or substituted aryl, N ⁇ 0 or S Unsubstituted or substituted heteroaryl containing, Unsubstituted or substituted heterocycle containing N, 0 or S,
  • W is tryptophan, O,
  • Y is Tyrosine (Y)
  • V is valine (V)
  • P is proline (P)
  • S is Serine
  • M Methionine (M).
  • Formula 2 may be specifically represented by the following chemical structure:
  • the compound is isonicotinyl-tryptophan-tyrosine-valine-Dpr (3, 5-dimethylbenzoyl) -proline-serine-methionine oxidation type, isicotinyl-tryptophan-tyrosine-valineb Dpr (3, 5-dimethylbenzoyl) -prine-serine-methionine, non-oxidized, isonicotinyl-tryptophan-tyrosine—valinec Dpr (alpha-cyano-4-hydroxycinnamil) chlorine-serine ⁇ methionine oxidized , Isonicotinyl-tryptophan-tyrosine-valine-Dpr (alpha-cyano—4′hydroxycinnamil) -proline-serine-methionine non-oxidized type, isicotinyl-tryptophan-tyrosine-valine-Dpr (4-pentyl Bicycl
  • Isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-pyrazincarboxylyl) —proline-cerine-methionine oxidized type
  • isicotinyl-tryptophan-tyrosine bovine valine-Dpr (2-pyrazincarboxylyl) -proline -Serine-Methionine non-oxidized
  • isonicotinyl-Tryptophan-Tyrosine-Valine-Dpr (2-chloronicotinyl)-Proline-Serine-Methionine Oxidized type
  • Isicotinyl- Tryptophan-Tyrosine-Valine-Dpr (2- Chloronicotinyl) -proline-serine-methionine non-oxidized isoninicotinyl-tryptophan-tyrosine ⁇ valine -Dpr (2,4-nuxadiene oil
  • Isonicotinyl-Tryptophan Tyrosine Chevvaline-Dpr (5-nitro-2-furoyl) -Pr-line-serine-Methionine Oxidized, Isicotinyl-Tryptophan—Tyrosine-Valine-Dpr (5-Nitrojan 2 -Furoyl) Keplin-serine-Methionine non-oxidized, isonicotinyl-tryptophan—TyrosineJetvaline -Dpr (beta-nahydroxyacetyl) -Pr-serine-methionine oxidized, isicotinyl- Tryptophan-Tyrosine-Valine-Dpr (Beta-naphthoxyacetyl) —Plin-serine-Methionine Non-oxidized, Isicotinyl-Tryptophan-Tyrosine-Valine-Dpr (3
  • Isonicotinyl-tryptophan-tyrosine valinex Dpr (Taigliyl) -plinxetrine-methionine oxidation type
  • Isonicotinyl-tryptophan-tyrosine valine-Dpr (Taigliyl) -prine-serine-methionine non-oxidizing type
  • the present invention provides a peptide fragment consisting of the amino acid sequence of SEQ ID NO: 1, wherein the fragment is a peptide fragment consisting of four amino acids and C-terminal is methionine, and not the tyrosine site corresponding to the fourth amino acid of SEQ ID NO. It may be a peptidomimetic compound substituted with di aminopropionic acid (Dpr) to which an acyl group is linked and showing prophylactic or therapeutic activity against allergic diseases.
  • Dpr di aminopropionic acid
  • the Dpr is a benzoyl group, cinnamil group, carboxyl group, acetyl group, oroyl group, quinyl group, tigylyl group, troloxyl group, heteroalkyl and arylheteroalkyl containing at least one selected from the group consisting of May be linked to a real group-containing substituent.
  • the present invention may be a peptidomimetic compound comprising a structure of formula (3).
  • Dpr is Di aminopropionic acid
  • R 3 is unsubstituted or substituted linear, branched or cyclic alkyl having 1 to 20 carbon atoms, unsubstituted or substituted alkoxy having 1 to 10 carbon atoms, unsubstituted or substituted aryl, N ⁇ 0 or Unsubstituted or substituted heteroaryl containing S, or unsubstituted or substituted heterocycle containing N, 0 or S,
  • P is proline (Prol ine, P),
  • S is Serin (S)
  • M Methionine (M).
  • the peptidomimetic compound comprising the structure of Chemical Formula 3 is preferably Dpr (4-pentylbicyclo [2.2.2] octane # 1—carboxyl) -proline-serine-methionine oxidized type, Dpr (4—pentylbicyclo [2.2.2] octane-1-carboxyl) -proline-serine-methionine non-oxidation type,
  • the present invention provides a peptide fragment composed of the amino acid sequence of SEQ ID NO: 1, wherein the fragment is a fragment consisting of four amino acids from the N-terminus of SEQ ID NO: 1, in place of the first amino acid tryptophan Di aminopropioni c acid, in which an acyl group is introduced and a tyrosine corresponding to the fourth amino acid of SEQ ID NO is linked to an acyl group.
  • Dpr may be a peptidomimetic compound that exhibits prophylactic or therapeutic activity against allergic diseases.
  • an isonicotinyl group may be introduced at the tryptophan site, which is the first amino acid of SEQ ID NO.
  • the Dpr is an acyl group-containing substituent containing at least one selected from the group consisting of a benzoyl group, a carboxyl group, an acetyl group, an orthyl group, a quinyl group, a tiegyl group, a troloxyl group, a heteroalkyl and an arylheteroalkyl. Can be connected.
  • the present invention may be a peptidomimetic compound comprising a structure of formula (4).
  • Dpr is Di aminopropionic acid
  • W tryptophan (W)
  • V is valine (Val ine, V).
  • Formula 4 may be specifically represented by the following chemical structure:
  • the peptidomimetic compound comprising the structure of Chemical Formula 4 is preferably isonicotinyl-tryptophan—tyrosine-valine-Dpr (orotyl),
  • Isicotinyl-Tryptophan-Tyrosine-Valine-Dpr (7-methoxy-l—benzofuran-2-carboxyl), Isicotinyl-Tryptophan-Tyrosine-Valine -Dpr (2- (2-cyanophenylthio) Benzoyl), isonicotinyl-tryptophan-tyrosine-valine -Dpr ((R) — (+)-troxyl),
  • Isonicotinyl-tryptophan-tyrosine-valine-Dpr (1-cyano-1-cyclopropanecarboxyl), isonicotinyl-tryptophan-tyrosine-valine-Dpr (rhodanine-3-acetyl),
  • Isicotinyl-tryptophan-tyrosine-valine-Dpr (4-pentylbicyclo [2.2.2] octane-1-car Fylyl), isonicotinyl-tryptophan-tyrosine bovine valine -Dpr (quinaldil), isonicotinyl ⁇ tryptophan ⁇ tyrosine-valine brine Dpr (Taigliyl),
  • the present invention is a peptide fragment consisting of the amino acid sequence of SEQ ID NO: 1, the fragment is a peptide fragment consisting of three or four amino acids, C-terminal serine, corresponding to the fourth amino acid of SEQ ID NO: Tyrosine is substituted with a diaminopropionic acid (D ami nopropionic acid, Dpr) to which an acyl group is linked, and may be a peptidomimetic compound that exhibits prophylactic or therapeutic activity against allergic diseases.
  • D ami nopropionic acid Dpr
  • the Dpr may be connected to an acyl group-containing substituent including at least one selected from the group consisting of a benzoyl group, a carboxyl group, an acetyl group, an orthyl group, a heteroalkyl, and an arylheteroalkyl.
  • it may be a peptidomimetic compound comprising the structure of Formula 5 or Formula 6.
  • -PS Dpr is di aminopropionic acid (Di aminopropi oni c ac id),
  • R 5 is unsubstituted or substituted linear, branched or cyclic alkyl having 1 to 20 carbon atoms, unsubstituted or substituted alkoxy having 1 to 10 carbon atoms, unsubstituted or substituted aryl, ⁇ , ⁇ or Unsubstituted or substituted heteroaryl containing S, or unsubstituted or substituted heterocycle containing ⁇ , 0 or S,
  • ⁇ is proline (Pl ine, P), S is Serine (S).
  • Formula 5 may be specifically represented by the following chemical structure
  • Dpr is Diaminopropionic acid
  • 3 ⁇ 4 comprises at least one selected from the group consisting of a benzoyl group, a carboxyl group, an acetyl group orothyl group, heteroalkyl and aryl heteroalkyl,
  • V is valine (V)
  • P is Proline, P,
  • S Serine (S).
  • Singe ⁇ ⁇ ⁇ including the structure of Formula 5 or Formula 6-3 ⁇ 4- thidomimetic compounds are preferably valine -Dpr (orthyl) -plin -serine valine -Dpr (gmethoxy-1- Benzofuran— 2-carboxyl) prine-serine Valine-Dpr (3,5-—dimethylbenzoyl) champlin-serine,
  • Valine-Dpr (2-fluorophenylacetyl) -plin-serine, Dpr (orotyl) -plin-serine,
  • Dpr (3,5—dimethylbenzoyl) —prolinexerine, Dpr (5-chloroindolone 2-carboxylyl) -proline-serine, or Dpr (2-fluorophenylacetyl) —proline-serineyl Can be.
  • alkyl means an aliphatic hydrocarbon group.
  • Alkyl may be "saturated alkyl” containing no alkene or alkyne moiety or "unsaturated alkyl” containing at least one alkene or alkyne moiety.
  • Alkene means a group containing at least one carbon-carbon double bond
  • alkyne means a group containing at least one carbon-carbon triple bond.
  • Alkyl may be branched or straight chain, respectively, when used alone or in combination, such as alkoxy.
  • Alkyl groups may have 1 to 20 carbon atoms unless otherwise defined.
  • the alkyl group may be a medium sized alkyl having 1 to 10 carbon atoms.
  • the alkyl group may be lower alkyl having i to 6 carbon atoms.
  • Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, nucleus, ethenyl propenyl, butenyl and the like.
  • d-alkyl has 1 to 4 carbon atoms in the alkyl chain and is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl do.
  • alkoxy means alkyloxy having 1 to 10 carbon atoms unless otherwise defined.
  • 'cycloalkyl means a saturated aliphatic 3-10 membered ring unless otherwise defined.
  • Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclonuclear chamber, and the like.
  • aryl' includes at least one ring having a shared pi electron system, for example a monocyclic or fused polycyclic (i.e. adjacent to carbon atoms Rings with pairs). That is, in the present specification, aryl means a 4-10 membered, preferably 6-10 membered aromatic monocyclic or multicyclic ring including phenyl, naphthyl and the like unless otherwise defined.
  • heteroaryl' comprises from 1 to 3 heteroatoms selected from the group consisting of N, 0 and S and is an aromatic 3-10 membered group which can be fused with benzo or C 3 -C 8 cycloalkyl It means a ring, preferably a 4-8 membered ring, more preferably a 5-6 membered ring.
  • monocyclic heteroaryl include thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, isothiazole pyrazole, triazole, triazine, thiadiazole, tetrazole and oxadia.
  • Sol pyridine, pyridazine, pyrimidine, pyrazine and similar groups, but is not limited to these.
  • bicyclic heteroaryls include indole, indolin, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisazole, benzthiazole, benzthiadiazole, benztriazole, quinoline, isoquinoline, purine Furopyridine and similar groups, but is not limited to these.
  • heterocycle' includes one to three heteroatoms selected from the group consisting of N, 0 and S, unless defined otherwise, and can be fused with benzo or C 3 -C 8 cycloalkyl, saturated or 1 Or it means a 3 to 10 membered ring, preferably a 4 to 8 membered ring, more preferably a 5 to 6 membered ring containing two double bonds.
  • heterocycles include, but are not limited to, pyrroline, pyrridine, imidazoline, imidazolidine, pyrazoline pyrazolidine, pyran, piperidine morpholine, thiomorpholine, piperazine, hydrofuran and the like. It is not limited only.
  • the present invention relates to a pharmaceutical composition for the prevention or treatment of allergic diseases comprising the novel peptidomimetic compound.
  • the present invention comprises administering to a subject a pharmaceutically effective amount of the novel peptidomimetic compound, allergic disease It relates to a treatment method.
  • the novel peptidoglycan bream matic compound provided by the present invention while exhibiting a biological activity of dTBP2, its activity and it is an enhanced feature capability bioavailable, relaxed by dTBP2, improved ", prevention, inhibition or treatment of all the possible allergic diseases It can be applied for medical use.
  • the peptidomimetic compound of the present invention can be applied to medicinal use for allergic diseases that can alleviate, improve, prevent, inhibit or treat by inhibiting the interaction between dTCTP and its receptor.
  • the peptidomimetic compound of the present invention is directed against allergic diseases capable of alleviating, improving, preventing, inhibiting or treating by inhibiting the secretion of cytokines and histamines including IL-8, IL-5, and the like. It can be used for therapeutic purposes.
  • the allergic disease may include, but is not limited to, asthma, rhinitis, gallbladder, anaphylaxis, allergic bronchiectasis, allergic conjunctivitis, urticaria or atopic dermatitis, but is not limited to, interaction between dTCTP and its receptor, or IL All allergic diseases which can be induced by the secretion of cytokines and histamine, including -8, IL-5 and the like, are included in the scope of the present invention.
  • compositions of the present invention can be administered to children, adolescents and adults, both oral and parenteral routes of administration. Preferably parenteral administration.
  • administration means the introduction of the pharmaceutical composition of the present invention to an individual in need of treatment of the disease in any suitable manner, and the route of administration of the composition of the present invention may reach the target tissue Administration can be via one oral or parenteral route.
  • the term “pharmaceutically effective amount” refers to the amount of the active ingredient from which the desired pharmaceutical effect can be obtained, and in some cases, the concentration of the active ingredient in the pharmaceutical composition for exerting the desired pharmaceutical effect or Dosage may mean.
  • the specific pharmaceutically effective amount for a particular patient is determined by the specific composition, including the type and extent of reaction to be achieved and whether other agents are used in some cases, the age, body weight, general state of health and sex of the patient. And diet, time of administration, It is desirable to apply differently depending on the route of administration and the rate of release of the composition, the duration of treatment, and the various factors and similar factors well known in the medical arts, including drugs used with or concurrent with the specific composition.
  • injectable formulations include isotonic aqueous solutions or suspensions, and can be prepared according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • each component may be formulated for injection by dissolving in saline or buffer.
  • oral dosage forms include, but are not limited to, powders, granules, tablets, pills, emulsion dogs, syrups, and capsules.
  • the composition for preventing or treating allergic diseases of the present invention may further comprise a pharmaceutically acceptable carrier.
  • the term "pharmaceutically acceptable carrier” refers to a carrier or diluent that does not significantly irritate an organism and does not inhibit the biological activity and properties of the administered compound.
  • Pharmaceutically acceptable carriers include, for example, oral carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and parenteral administration such as water, suitable oils, saline, aqueous glucose and glycols. Carriers and the like. Such pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethane, and one or more of these components.
  • other conventional additives such as stabilizers, preservatives, antioxidants, complete solutions and bacteriostatic agents can be added.
  • Fmoc (F 1 LIO r eny 1 me t hy 1 oxy c ar bony 1 chlor ide) -Met-0H (10.0 equiv, 483.0 mg, 1.3 mmol) was placed in a 50 mL pear flask and replaced with argon gas, followed by addition of anhydrous dichloromethane (CH 2 C1 2 ) (7 mL) and anhydrous dimethylformamide (DMF, about 20 drops). It was. DIC (5.0 equiv, O.lmL, 0.65 ⁇ L) was added to the mixture and stirred at 0 ° C. for 20 min.
  • Fmoc-Pr as OH, Fmoc-Tyr (tBu) -OH, Ser- et as dTBP2, Trp-Tyr-Val-Tyr-Pr was synthesized by coupling Fmoc-Val-OH, Fmoc-Tyr (tBu) -OH, and Finoc-Trp (Boc) —OH.
  • Fmoc group a proline protecting group
  • Peptide (30mg, 0.013 ⁇ ol) prepared in 1-2 was placed in a 1 mL Micro Bio—Spin chromatography column, 20% piper idine / anhydrous DMF (0.6 mL) was used to remove the Fmoc group, and 94% degassed.
  • TFA cocktail (TFA: H 2 0: EDT: TIS, 94%: 2.5%: 2.5%: 1, 0.6 mL) was added and reacted at room temperature for 1 hour, followed by filtration to obtain a filtrate. Resin was again washed with TFA solution (0.3 tnL ⁇ 2) to receive the filtrate. The filtrates were combined to remove TFA using an evaporator and then decanted three times using cold ether.
  • Trp-Tyr-Va 1 -Tyr-Pro-Ser-Met (dTBP2)
  • an acid library was created to identify the space around the NH 2 terminus and the central tyrosine.
  • the N3 ⁇ 4 terminus was acylated and screened in situ.
  • a solid phase protocol was used as a synthesis method. 1100 (: 6 3661 ⁇ 11 and dTBP2 were synthesized by the use of SS linker.
  • the remaining amino acids of dTBP2 were then sequentially pasted using HCTU and the Fmoc protecting group was removed using 30% piperidine in DMF before each coupling.
  • the elimination of the Fmoc protecting group and the reaction of the amino acid coupling reaction proceeded well and confirmed by the Kaiser test or the Chloranil test for each stprint.
  • Trp-Tyr-Val-Tyr-Pro-Ser-Met in solid phase in the same manner as in dTBP2 of Preparation Example 1, peptide-resin (50 mg, 0.022 ⁇ ol) to 30% piper idine / anhydrous DMF ( 1.0 mL) was used to remove the Fmoc group, PyBOP (10.0 equiv, 114.5 mg, 0.22 ⁇ l ol), H0Bt.H 2 0 (10.0 equiv, 33.7 mg, 0.22 ⁇ l ol), 2-Methylhexanoic acid (10.0 equiv, 28.6 mg, 0.22 ⁇ ol) and ⁇ (20 equivalents, 48.4 uL, 0.44 ⁇ ol) were dissolved in anhydrous DMF (0.6 mL), stirred for 3 minutes, and swelled in DMF for 30 minutes (500 mg, 0.22 ⁇ ol) After addition to the mixture was mixed for 2 hours using anhydrous
  • the tyrosine moiety with weak binding force was changed according to the result of alanine scanning mutagenesis.
  • a linker nker
  • the amine was changed to Diaminoprop ionic acid (Fmoc Dpr (Mtt) ⁇ OH) protected with 4-methyltrityl (Mtt) group.
  • 4-Methyltrityl (Mtt) groups can be easily removed under mild acid conditions such as 1% TFA in CH 2 C1 2 .
  • HBTU (8.0 equiv, 33.4 mg, 0.088 mmol), HOBt .3 ⁇ 40 (8.0 equiv, 13.5 mg) for coupling 3,5-dimethylbenzoic acid to the amine from which the Mtt group of diaminopropionic acid was removed , 0.088 ⁇ l), 3,5-dimethylbenzoic acid (8.0 equivalents, 13.2 mg, 0.088 ⁇ l), DIPEA (8.0 equivalents, 15.4yL, 0.088 ⁇ l) and anhydrous DMF (0.5 mL) Coupling was carried out according to the 1-2 method.
  • TFA cocktail (0.5 mL) was added to the prepared peptide (25 mg, 0.011 ⁇ ol), and the mixture was mixed at room temperature for 1 hour, filtered, and filtered. The filtrate was washed again with TFA (0.3 mL X 2). Received. The filtrates were combined to remove TFA using an evaporator and then decant at ion three times using cold ether.
  • Isicotinyl-tryptophan-tyrosine-valine-Dpr (alpha-cyano-4-hydroxycinnamil) -prine-serine-methionine oxidative type (Isonicotinyl-Trp-Tyr-Val-Dpr (a-cyano -4) hydroxy ci nnamy 1) -Pro-Ser-Met (0))
  • A was synthesized using the same method as 3-1, with an acid (acid) for coupling the alpha-cyano ⁇ 4 hydroxycinnamic acid (Q -cyano-4-hydr oxyc i nnam ic acid) was used .
  • Compounds produced by mass spectometry (MS) were identified and further confirmed using 3 ⁇ 4 MR.
  • Isicotinyl-tryptophan-tyrosine-valine-Dpr alpha-cyano-4-hydroxycinnamil
  • Isonicotinyl-Trp-Tyr-Val-Dpr a -cyano -4- hydr ox ci nnamy 1 — Pro—Ser— Met
  • Isonicotinyl-tryptophan-tyrosine-valine-Dpr phenoxyacetyl
  • prine-serine-methionine oxidation type I soni cot i ny 1 -Tr -Tyr-Va 1 -Dpr (phenoxyacety 1) -Pro-Ser -Met (0)
  • the compound was synthesized in the same manner as in the above 3-11, and the compound produced by mass spectrometry (MS) was confirmed.
  • Isonicotinyl-Tryptophan-Tyrosine-Valine-Dpr (orthyl) -Plin-serine-Methionine deoxidation (Isoni cot i ny 1 -Tr p-Ty r -Va 1 -Dpr (or oty 1) —Pro one Ser—Met)
  • Isonicotinyl-tryptophan-tyrosine-valine-Dpr (4—benzyloxybenzoyl) -prine-serine-methionine oxidation type (I son icotinyl -Trp-Tyr -Va 1 -Dpr (-benzy 1 oxybenzoy 1)- Pro-Ser-Met (0))
  • Isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-pyrazincarboxylyl) -prine-serine-methionine oxidized type (I son i cot i ny 1 -Tr p- "Tyr-Val -Dpr (2- pyr az i ne car boxy lyl)
  • Isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-pyrazincarboxyl) -prine-serine-methionine non-oxidized (I son i Co ti ny 1 -Tr p-Tyr --Va 1 -Dpr (2 -pyr az i ne carboxylyl) -Pro-S -Met)
  • Isicotinyl-tryptophan-tyrosine-valine-Dpr (biphenyl-4-carboxylyl) -plin-serine-methionine j: flame (Isonicotinyl -Trp-Tyr -Va 1—Dpr (bi pheny 1 -4 — Car boxy lyl)
  • Isicotinyl-tryptophan tyrosine-valine-Dpr (phenylglyoxylyl) -plin-serine-methionine oxidative type (Isonicotinyl-Trp— Tyr-Val-Dpr (phenylglyoxylyl) -Pro-Ser-Met (0 ))
  • the compound was synthesized in the same manner as in the 3-27 above, and the produced compound was confirmed by mass spectometry (MS).
  • Isonicotinyl-tryptophan-tyrosine valine-Dpr (2-fluorophenylacetyl) —plin-serine-methionine oxidation type (I soni cot i ny 1 -Tr -Tyr-Va 1 -Dpr (2-f 1 uor opheny 1 acetyl) -Pro-S -Met (O))
  • Isonicotinyl-tryptophan tyrosine-valine-Dpr (2-fluorophenylacetyl) -plin-serine-methionine non-oxidized type (I son i cot i ny 1 -Tr -Ty r-Va 1 -D r
  • the compound was synthesized in the same manner as in the above 3-33, and the compound produced by mass spectometry (MS) was confirmed.
  • Isonicotinyl-tryptophan-tyrosine-valine-Dpr (5-nitro-2-furoyl) -prine-serine-methionine non-oxidative type (I soni cot inyl-Trp-Tyr-Val-Dpr -nitro- ⁇ furoyl ) -Pro-Ser-Met)
  • the compound was synthesized in the same manner as in the above 3-37, and the compound produced by mass spectrometry (MS) was confirmed.
  • the compound was synthesized in the same manner as in the 3-39 method, and the produced compound was confirmed by mass spectometry (MS).
  • Isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-methoxynucleonoyl) -prine-serine-methionine non-oxidative (Isonicotinyl-Tn3-Tyr-Val-Dpr (2-tnethylhexanoyl) -Pro-Ser- Met)
  • Isonicotinyl-tryptophan-tyrosine-valine-Dpr (3-chlorobenzo [b] thiophene-2-carboxyl)-proline-serine-methionine oxidized type (Isonicotinyl-Trp-Tyr-Va 1 -Dpr
  • Isonicotinyl-tryptophan-tyrosine-valine-Dpr (3-chlorobenzo [b] thiophene-2-carboxylyl) -prine-serine-methionine non-oxidized type (I soni cot i nyl-Trp-Tyr-Va 1 — Dpr
  • Isonicotinyl-tryptophan-tyrosine-valine-Dpr quinalyl
  • -plin-serine-methionine oxidized type I soni cot i ny 1 -Tr -Tyr-Va 1 -Dpr (qu i na 1 dy 1)- Pro to Ser-Met (0)
  • Isicotinyl-tryptophan-tyrosine-valine-Dpr quinalyl;
  • -plin-serine-methionine non-oxidative type Isonicotinyl -Trp-Tyr -Va 1 -Dpr (quinaldyl) -Pr o— Ser—Me t
  • Isonicotinyl-Tryptophan-Tyrosine-Valine-Dpr (Taigliyl) —Pr-serine-Methionine Oxidation Type (Isonicot inyl-Trp-Tyr-Val-Di) r (t iglyl) -Pro to Ser-Met ( 0))
  • Isonicotinyl-Tryptophan-Tyrosine-Valine-Dpr (Taigliyl) -Plin-serine-Methionine Non-oxidative (Isonicot inyl-Trp-Tyr-Val-Dpr (tifilyl) -Pro to Ser-Met)
  • Isonicotinyl-tryptophan -tyrosine -valine -Dpr isonicotinyl :) -plin-serine-methionine oxidized (I sonicot inyl-Trp-Tyr-Val-Dpr (i soni cot inyl) -Pro-Ser- Met (0))
  • Isonicotinyl-Tryptophan-Tyrosine-Valine-Dpr (5-Chloroindole-2-carboxylyl) -Prinlin-Serine-Methionine Oxidation Type (Isonicot inyl-Trp-Tyr-Val-Dpr (5-chloroindole-2-carboxylyl) -Pro-Ser-Met (0))
  • the compound was synthesized in the same manner as in the above 3-53, and the produced compound was confirmed by mass spectometry (MS).
  • the compound was synthesized in the same manner as in the above 3-55, and the compound produced by mass spectrometry (MS) was confirmed.
  • the compound was synthesized in the same manner as in the 3-59 method, and the produced compound was confirmed by mass spectometry (MS).
  • Isonicotinyl-tryptophan-tyrosine-valine-Dpr (rhodanine-3-acetyl) -prine-serine-methionine non-oxidative type (I soni cot i ny 1 -Tr p-Tyr-Va 1 -Dpr (rhodani ne-3-acety 1) -Pro-Ser-Met)
  • Serine-Methionine Oxidation Type I soni cot inyl -Trp-Tyr-Va 1 -Dpr
  • Serine-methionine non-oxidizing type (I son icotinyl -Trp-Tyr-Va 1 -Dpr
  • the compound was synthesized in the same manner as in the 3-67 method, and the produced compound was confirmed by mass spectometry (MS).
  • Isonicotinyl-tryptophan-tyrosine-valine-Dpr (2- (4-methylphenylsulfonamido) acetyl) -proline-serine-methionine oxidic type (Isonicot iny 1 -Trp-Tyr-Va 1 -Dpr (2-
  • Serine-methionine non-oxidizing type (I son i cot i nyl-Trp-Tyr-Va 1 -Dpr
  • Isonicotinyl-tryptophan-tyrosine-valine-Dpr (benzotriazole-5-carboxylyl) -prine-serine-methionine oxidic type (Isoni cot i nyl -Trp-Tyr-Val -Dpr (benzot ri azo 1 e to 5-
  • the compound was synthesized in the same manner as in the 3-77, and the produced compound was confirmed by mass spectometry (MS).
  • Serine-methionine non-oxidizing type (Isonicotinyl -Trp-Tyr-Va 1 -Dpr (4—oxo—tetravalent chr omene-3-c ar boxy 1 y 1) —Pro—Ser— Met)
  • the compound was synthesized in the same manner as in the 3-79, and the compound produced by mass spectrometry (MS) was confirmed.
  • Isicotinyl-tryptophan-tyrosine-valine-Dpr (4-methyl-2-oxo-2 ⁇ chromen 7-yloxy) acetyl) -prine-serine-methionine non-oxidative type (Isonicotinyl-Trp— Tyr-Val -Dpr
  • Fmoc-based SPPSol was used for Wang resin to synthesize 15 acid-coupled C00H-terminated tetramers, but 14 compounds except rhodanine-3-acetic acid and 5 compounds oxidized sulfur of Methione residue. This was made. The production ratio of oxidized and non-oxidized forms varied from 1: 2.3 to 1: 5.6. As a result, a total of 19 compounds were synthesized (88-106).
  • Dpr (2-fluorophenylacetyl) -plinxetrine-methionine was synthesized in the solid phase, and then synthesized in the same manner as in Preparation Example 4-1, produced by mass spectometry (MS) It was confirmed, and further confirmed by using NMR and 13 C NMR.
  • Dpr (7-methoxyl-l-benzofuran-2-carboxylyl) -plin-serine-methionine was synthesized in the solid phase, and then synthesized in the same manner as in Herbicide Example 4-1, mass spectometry , MS) was confirmed, and further confirmed using 3 ⁇ 4 NMR and 13 C NMR.
  • Dpr (1-cyano-1-cyclopropanecarboxyl) -plin-serine-methionine was synthesized in the solid phase, and then synthesized in the same manner as in Preparation Example 4-1, by mass spectometry (MS). The produced compound was confirmed, and further confirmed by using 3 ⁇ 4 NMR and 13 C NMR.
  • Dpr (alpha-cyano-4—hydroxycinnamil) -proline-serine-methionine was synthesized in the solid phase, and synthesized in the same manner as in Preparation Example 4-1, and produced by mass spectometry (MS). The compound was confirmed, and further confirmed by using 3 ⁇ 4 ⁇ R and 13 C NMR.
  • Fmoc-based SPPS was used (Scheme 5), and among 15 acids Compounds with 14 acid couplings except a -cyano-4-hydroxy cinnami c acid were obtained (107-120).
  • the concentration of resin is assumed to be 0.4 ⁇ ol, and isonicotinyl-tryptophan-tyrosine-valine-Dpr (ortho) is synthesized in the same manner as in Preparation Example 3, and then Degassed 94% TFA cocktail (0.7 mL) was added to the resulting resin (35 mg, 0.0154 mmol), and the mixture was mixed at room temperature for 1 hour, and then filtered. The filtrate was collected and washed with TFA solution (0.4 mL X 2). Received. The filtrates were combined to remove TFA using an evaporator and then decantation three times using cold ether.
  • Isonicotinyl-tryptophan-tyrosine-valine-Dpr (7-methoxy-1-benzofuran-2-carboxylyl) was synthesized in the same manner as in Preparation Example 3, and was prepared in the same manner as in Preparation Example 5-1. Synthesis using the method. Compounds produced by mass spectrometry (MS) were identified and further confirmed using 3 ⁇ 4 NMR and 13 C NMR.
  • the resin 200 mg, 0.088 ⁇ l was swelled in anhydrous DMF for 30 minutes to deprotection the Fmoc group, followed by the addition of 20% piper idine / anhydrous DMF (4.0 mL) for 10 minutes in an orbital shaker (130 rpm). After mixing, draining the solvent and washing with DMF, iPrOH and CH 2 Cl 2 (10 mL x 1 min x 3). After 30 minutes vacuum dry using an aspirator, reaction was completed using Kaiser test. Confirmed.
  • Valine -Dpr (3,5-dimethylbenzoyl) -purene-serine was synthesized in the same manner as in Preparation Example 3, and synthesized using the same method as in Preparation Example 6-1.
  • Compounds produced by mass spectrometry (MS) were identified and further confirmed using 3 ⁇ 4 ⁇ R and 13 C NMR. 99.9% Purity. R t 26.9 min.
  • Valine -Dpr (5-chloroindole-2-carboxylyl) -plinxeline was synthesized in the same manner as in Preparation Example 3, and synthesized using the same method as in Preparation Example 6-1.
  • Compounds produced by mass spectrometry (MS) were identified and further confirmed using 3 ⁇ 4 MR and 13 C NMR.
  • Dpr (3,5-dimethylbenzoyl) -prine-serine was synthesized in the same manner as in Preparation Example 3, and synthesized using the same method as in Preparation Example 6-1.
  • Compounds produced by mass spectrometry (MS) were identified and further confirmed using 3 ⁇ 4 NMR and 13 C NMR.
  • Dpr (5-chloroindole-2-carboxylyl) -prine-serine was synthesized and synthesized using the same method as in Preparation Example 6-1. Compounds produced by mass spectrometry (MS) were identified and further confirmed using 3 ⁇ 4 NMR and 13 C NMR.
  • dTBP2 and compounds were 75 nM concentration processing the BEAS- 2B cells (human bronchial epithelium cell) for 15 minutes and, after inserting the dTCTP of 75 nM was taken and the supernatant after 18 hours. the supernatant was taken by centrifuge at 4 0 C 10, 000 X g to separate The IL-8 assay was performed on the supernatant, and the IL-8 assay was performed using IL-8 ELISA kit of PIERCE company to confirm the degree of inhibition of IL-8 secretion according to the manufacturer's protocol.
  • Biological activity of dTBP2 was measured in a mouse model (5 weeks old, Female Balb / c (orientbio), 5-6 animals in each group) that caused an allergic disease state with ovalbumin (OVA). Mice from each group (6 / group) were sensitized with egg albumin, treated with 2.5 mg / kg or 5 mg / kg of dTBP2 and challenged with egg albumin. When treated with dTBP2 symptom score (symptom score) was reduced, it was found that the concentration infiltrates eosinophils (eosinophi 1) (Fig. 10).
  • mice were sensitized with egg albumin and challenged with egg albumin after administration of 5 mg / kg of peptidomimetic compounds.
  • interleukin-5 was identified using mouse IL-5 EL ISA kit (PIERCE), and hyperplasia of pulmonary mucosa was confirmed by Periodic Acid-Schiff (PAS) reagent (Sigma— Aldrich) and confirmed.

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Abstract

La présente invention concerne un nouveau composé peptidomimétique ayant une activité de prévention ou de traitement des troubles allergiques, ainsi qu'une composition pharmaceutique destinée à la prévention ou au traitement des troubles allergiques, renfermant ledit composé.
PCT/KR2014/013134 2014-01-03 2014-12-31 Composé peptidomimétique et composition pharmaceutique destinée au traitement des troubles allergiques, renfermant ledit composé WO2015102418A2 (fr)

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KR10-2014-0000943 2014-01-03
KR1020140000945A KR101590949B1 (ko) 2014-01-03 2014-01-03 화학식 4의 구조를 포함하는 펩티도미메틱 화합물 및 이를 포함하는 알레르기성 질환 치료용 약학조성물
KR1020140000942A KR101576231B1 (ko) 2014-01-03 2014-01-03 화학식 1의 구조를 포함하는 펩티도미메틱 화합물 및 이를 포함하는 알레르기성 질환 치료용 약학조성물
KR1020140000944A KR101600049B1 (ko) 2014-01-03 2014-01-03 화학식 3의 구조를 포함하는 펩티도미메틱 화합물 및 이를 포함하는 알레르기성 질환 치료용 약학조성물
KR1020140000946A KR101590952B1 (ko) 2014-01-03 2014-01-03 화학식 5 또는 6의 구조를 포함하는 펩티도미메틱 화합물 및 이를 포함하는 알레르기성 질환 치료용 약학조성물
KR10-2014-0000946 2014-01-03
KR10-2014-0000942 2014-01-03
KR1020140000943A KR101600048B1 (ko) 2014-01-03 2014-01-03 화학식 2의 구조를 포함하는 펩티도미메틱 화합물 및 이를 포함하는 알레르기성 질환 치료용 약학조성물
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KR10-2014-0000945 2014-01-03

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