WO2015102418A2 - Peptidomimetic compound and pharmaceutical composition for treating allergic disorders including same - Google Patents

Peptidomimetic compound and pharmaceutical composition for treating allergic disorders including same Download PDF

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

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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

The present invention relates to a novel peptidomimetic compound that shows preventing or treating activity for allergic disorders, and to a pharmaceutical composition for preventing or treating allergic disorders including same.

Description

【명세서】  【Specification】
【발명의 명칭】  [Name of invention]
펩티도미메틱 화합물 및 이를 포함하는 알레르기성 질환 치료용 약학조성물  Peptidomimetic Compounds and Pharmaceutical Compositions for the Treatment of Allergic Diseases Comprising the Same
【기술분야】  Technical Field
본 발명은 알레르기성 질환에 대하여 예방 또는 치료 활성을 나타내는 신규 펩티도미메틱 화합물， 및 이를 포함하는 알레르기성 질환의 예방 또는 치료용 약학 조성물에 관한 것이다.  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.
【배경기술】  Background Art
비만세포 및 혈증 호염구는 여러가지 알레르기 질환， 즉， 알레르기성 비염, 알레르기성 아토피성 피부염， 알레르기성 결막염， 알레르기성 천식，음식 알레르기 및 아나필락틱 쇼크 ( anaphyl act i c shock) 등을 유발하는 체내세포로 알려져 있다. 이들 세포는 세포 표면에 알레르기를 유발하는 항체에 대한 수용체를 가지고 있으며， 자극을 받으면 자신이 가지고 있는 다양한 알레르기를 유발하는 물질을 세포 바깥으로 .분비한다.  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. Known. These cells have receptors for allergens on the cell surface, and when stimulated they secrete various allergens out of the cell.
알레르기 질환올 치료하기 위한 다양한 시도가 이루어지고 있으나， 현재 대부분의 알레르기 치료는 그 원인을 없애기보다는 증상을 완화시키는 방향으로 진행되고 있다. 대표적으로 알레르겐에 의해 비만세포 등에서 분비된 히스타민이나 류코트리엔 등 수용체에 대한 길항약들이 주를 이루고 있다.그러나, 이러한 약물은 환자에게 투여 후 단기간 내에 내성을 보이기 때문에 일정기간 지난 후 혹은 반복 투여 시 환자들의 증상을 호전시키지 못하는 경우가 많다. 따라서ᅳ 항히스타민제 등의 부작용이 없는 알레르기 치료제의 개발이 요구되고 있는 실정이다.  Various attempts have been made to treat allergic diseases, but most allergic treatments are currently progressing toward alleviating symptoms rather than eliminating the cause. Representative antagonists of histamine and leukotriene, which are secreted by allergens, are mainly dominant.However, since these drugs are resistant to patients within a short period of time after administration to patients, they may be treated after Many symptoms do not improve. Therefore, the development of an allergy treatment without side effects such as antihistamines is required.
또한， 다른 치료 방법으로 IgE가 비만 세포의 수용체에 결합하는 것을 차단하는 방법， 알레르기를 유발하는 사이토카인인 인터루킨 -4( IL-4)에 대한 항체 치료법 등의 치료적 접근법 등이 있으나， 이러한 접근법들은 비용이 많이 들거나 아직 그 치료효과가 완전히 규명되지 않은 문제가 있다.  In addition, there are other therapeutic methods such as blocking IgE from binding to mast cell receptors, and therapeutic approaches such as antibody therapy against allergic cytokine interleukin-4 (IL-4). They are expensive or have not yet been fully elucidated.
한편， 생체에는 생리활성에 관여하는 펩타이드 (pept ide)가 많이 존재하고 있으며 대부분의 생리활성 펩타이드는 생체 내 효소나 산에 의해 쉽게 가수분해되고 분자량이 일반적으로 커서 약으로 사용하기 어렵다는 문제점이 있다. 이를 극복하기 위해서 펩타이드의 곁가지 사슬이나 골격구조를 변형시키거나 특정 구조를 유도하는 주형으로 사용하는 방법들이 제시되고 있으며， 이러한 모든 물질을 총칭하여 펩티도미메틱 화합물 (pept idomimet i c compound)이라고 명명한다. 이러한 화합물은 질병유발 바이오마커 외에도 유해미생물 검출, 환경 호르몬 등 분자진단용으로 사용될 수 있으며, 신약설계， 나노복합체 및 새로운 약물 전달체 등으로 이용될 수 있다. On the other hand, there are a lot of peptides (pept ide) involved in the biological activity in the living body, most of the biologically active peptide is easily by the enzyme or acid in vivo There is a problem in that it is hydrolyzed and its molecular weight is generally large, making it difficult to use as a drug. In order to overcome this, 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. In addition to disease-causing biomarkers, 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.
【발명의 상세한 설명】  [Detailed Description of the Invention]
【기술적 과제】  [Technical problem]
그러나, 알레르기성 질환을 치료하기 위한 펩티도미메틱 화합물에 대한 연구는 아직 이루어지지 않았으며, 부작용 없이 알레르기를 치료할 수 있는 치료제의 개발에 대한 요구가 절실한 실정이다.  However, studies on peptidomimetic compounds for treating allergic diseases have not yet been made, and there is an urgent need for the development of therapeutic agents capable of treating allergies without side effects.
【기술적 해결방법】  Technical Solution
상기 목적을 달성하기 위한 하나의 일구현예로서， 본 발명은 알레르기성 질환에 대하여 예방 또는 치료 활성을 나타내는 신규한 펩티도미메틱 화합물을 제공하는 것이다.  As one embodiment for achieving the above object, the present invention is to provide a novel peptidomimetic compound exhibiting a prophylactic or therapeutic activity against allergic diseases.
또 다른 구현예로서， 본 발명은 상기 화합물을 포함하는， 알레르기성 질환의 예방 또는 치료용 약학 조성물에 관한 것이다.  In another embodiment, the present invention relates to a pharmaceutical composition for preventing or treating allergic diseases, including the compound.
또 다른 구현예로서， 본 발명은 상기 화합물의 약학적 유효량을 개체에 투여하는 단계를 포함하는, 알레르기성 질환의 치료방법에 관한 것이다.  In another embodiment, the present invention relates to a method for treating an allergic disease, comprising administering to a subject a pharmaceutically effective amount of said compound.
【유리한 효과】  Advantageous Effects
본 발명의 펩티도미메틱 화합물은 IL-8 , IL-5등을 포함하는 사이토카인 및 히스타민의 분비를 억제하는 등 알레르기 동물 모델에서 우수한 항알레르기 효과를 나타내며， 종래의 증상회복 위주의 치료와 달리 알레르기를 유발하는 경로를 차단함으로써 다양한 부작용을 제거할 수 있어 보다 유용하게 사용될 수 있다.  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.
【도면의 간단한 설명】  [Brief Description of Drawings]
도 1은 펩티도미메틱 화합물올 합성하기 위한 단계적 모식도를 나타낸 것이다. 도 2는 HPLC로 확인한 Mtt 보호기의 선택적 제거를 나타낸 것이다. 1 shows a step-by-step schematic diagram for synthesizing peptidomimetic compounds. 2 shows selective removal of Mtt protecting groups confirmed by HPLC.
도 3은 제조예 3을 통해 제조된 화합물을 Dpr site를 중심으로 NH2 말단의 테트라머 (tetramer) 와 COOH 말단의 테트라머 (tetramer )， 2개의 부분으로 나누는 모식도를 나타낸 것이다.  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.
도 4는 제조예 3을 통해 제조된 화합물 중, dTBP2 보다 효과적으로 나온 화합물들 선정하여 나타낸 것이다.  Figure 4 shows the selected compounds out of dTBP2 more effectively among the compounds prepared in Preparation Example 3.
도 5는 제조예 2에서 제조한 화합물의 인터루킨 -8분비 억제 정도를 나타낸 것이다.  Figure 5 shows the degree of inhibition of interleukin-8 secretion of the compound prepared in Preparation Example 2.
도 6은 제조예 3에서 제조한 화합물의 인터루킨 -8분비 억제 정도를 나타낸 것이다.  Figure 6 shows the degree of inhibition of interleukin-8 secretion of the compound prepared in Preparation Example 3.
도 7은 제조예 4에서 제조한 화합물과 제조예 5에서 제조한 화합물 사이의 상대적인 활성을 비교한 것이다.  Figure 7 compares the relative activity between the compound prepared in Preparation Example 4 and the compound prepared in Preparation Example 5.
도 8은 제조예 6에서 제조한 화합물의 인터루킨 -8분비 억제 정도를 나타낸 것이다.  Figure 8 shows the degree of inhibition of interleukin-8 secretion of the compound prepared in Preparation Example 6.
도 9는 제조예 2를 통하여 제조된 화합물의 in situ 경합측정 (competition assay) 결과를 나타낸 것이다.  Figure 9 shows the results of in situ competition assay (competition assay) of the compound prepared in Preparation Example 2.
도 10A는 dTBP2를 처리한 경우 증상점수 (symptom score)가 감소한 것을 나타낸 것이며, 도 10B는 dTBP2를 처리한 경우의 호산구 변화를 나타낸 것이다. 도 11은 122， 123 및 129번 화합물을 처리하고， 기관지 폐포세척액 검사 (bronchoalveolar lavage fluid) 에서 인터루킨 -5의 분비가 억제되는 것을 나타낸 것이다.  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.
도 12는 122， 123및 129번 화합물을 처리하고， Per iodic Acid-Schi ff (PAS) 入 1약으로 염색하여 폐 조직의 점막두께를 관찰한 것이다.  Figure 12 is treated with compounds 122, 123 and 129, stained with 1 drug per iodic Acid-Schi ff (PAS) 入 and observed the mucosa thickness of lung tissue.
도 13은 97 및 121.번 화합물을 처리하고， 기관지 폐포세척액 검사 (bronchoalveolar lavage fluid) 에서 인터루킨 -5의 분비가 억제되는 것올 나타낸 것이다.  FIG. 13 shows that treatment of compounds 97 and 121. inhibits the secretion of interleukin-5 in bronchoalveolar lavage fluid.
도 14는 97및 121번 화합물을 처리하고,폐 조직의 점막을 Hematoxylin and eosin (H&E) 시약으로 염색하여 변화를 나타낸 것이다.  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.
【발명의 실시를 위한 최선의 형태】 상기 목적을 달성하기 위한 하나의 일구현예로서, 본 발명은 알레르기성 질환에 대하여 예방 또는 치료 활성을 나타내는 신규한 펩티도미메틱 화합물에 관한 것이다. [Best form for implementation of the invention] As one embodiment for achieving the above object, the present invention relates to a novel peptidomimetic compound exhibiting a prophylactic or therapeutic activity against allergic diseases.
보다 상세하게， 본 발명은 서열번호 1의 아미노산 서열 (Trp-Tyrᅳ Val-Tyr-Pro— Ser-Met ) 로 이루어잔 펩타이드 또는 이의 단편에서， 상기 서열번호의 첫번째 아미노산인 트립토판 또는 네번째 아미노산인 타이로신이 변형되며， 알레르기성 질환에 대하여 예방 또는 치료 활성을 나타내는 신규한 펩티도미메틱 화합물에 관한 것이다.  More specifically, the present invention provides a peptide or fragment thereof consisting of the amino acid sequence of SEQ ID NO: 1 (Trp-Tyr ᅳ 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.
일예로， 본 발명의 펩티도미메틱 화합물은 서열번호 1의 아미노산 서열로 이루어진 펩타이드 또는 이의 단편에서, 상기 서열번호의 첫번째 아미노산인 트립토판 자리에 아실기가. 도입되거나， 상기 서열번호의 네번째 아미노산인 타이로신이 아실기가 연결된 다아미노프로피오닉 산 (Di aminopropioni c acid, Dpr )으로 치환되거나， 또는 상기 서열번호의 첫번째 아미노산인 트립토판 자리에 아실기가 도입되고 상기 서열번호의 네번째 아미노산인 타이로신이 아실기가 연결된 디아미노프로피오닉 산으로 치환된, 알레르기성 질환에 대하여 예방 또는 치료 활성을 나타내는 펩티도미메틱 화합물에 관한 것이다.  In one embodiment, 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. Or 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: 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.
상기 서열번호 1 의 아미노산 서열로 이루어진 펩타이드는， dTBP2 [dTCTP(dimer i zed trans l at i onal ly control l ed tumor protein) binding pept ide 2] 라는 명칭으로도 알려져 있는 헵타머 (heptatner)이다. 상기 펩타이드는 dTCTP 에 높은 친화력으로 결합하여 dTCTP와 그의 수용체 간의 상호작용을 억제함으로써 이들의 상호작용으로 인한 알러지 관련 정보의 전달을 억제하는 것으로 알려져 있다. 또한， 인터루킨 ( IL)-8 , IL-5 등을 포함하는 사이토카인 및 히스타민의 분비를 억제함으로써 이들에 의해 유도될 수 있는 다양한 알레르기성 질환들을 완화시키는 데 관여하는 것으로 알려져 있다.  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.
[dTBP2 의 화학구조] [Chemical structure of dTBP2]
Figure imgf000007_0001
Figure imgf000007_0001
이에， 본 발명자들은 dTCTP와 그의 수용체 간의 결합을 억제하는 것을 목적으로 하여 NH2 말단을 다양한 산 (acids)으로 아실화 (acylation)한 펩티도미메틱 화합물 및 dTBP2에 다양한 변화를 시도한 펩티도미메틱 화합물을 합성하였으며， 이들 화합물들에 대해서 생물학적 활성을 측정하여 효능을 확인하였다. Accordingly, 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.
상기 펩티도미메틱 화합물을 합성하기에 앞서， 우선 dTBP2 의 아미노산 잔기들을 하나씩 알라닌으로 치환한 변이체들을 제조하여 그 활성을 평가함으로써 (alanine scanning mutagenesis), dTCTP-dTBP2결합에 있어서 dTBP2의 필수적 잔기가 무엇인지 확인하였다ᅳ  Prior to synthesizing the peptidomimetic compound, first by preparing a variant in which amino acid residues of dTBP2 are substituted with alanine one by one and evaluating its activity (alanine scanning mutagenesis), what is an essential residue of dTBP2 in dTCTP-dTBP2 binding? I confirmed it
[표 1]  TABLE 1
Residue IL-8 reieasibility block Residue IL-8 reieasibility block
AA substitution comment number activity dTBP2 WYVYPS ++ Original one dTBP- 1 AYVYPSM ++ insignificant, deletion of W： j. activity dTBP- 2 WAVYPSM - dTBP- 3 WYAYPSM - dTBP- 4 WYVAPS dTBP-M5-1 WYVYKSM - Ala substitution: jsolubility dTBP- 6 WYVYPA - dTBP- 7 WYVYPSA - 상기 표 1에 나타난 결과에서 알 수 있는 바와 같이， 첫번째 아미노산인 트립토판과 네번째 아미노산인 타이로신의 경우 알라닌으로 치환하더라도 dTBP2 의 활성이 동등하게 유지되었다. 따라서, 본 발명에서는 위 트립토판 또는 타이로신을 변형시켜， 그 활성 및 생체이용능이 보다 증진된 dTBP2의 펩티도미메틱 화합물을 설계하였다. AA substitution comment number activity dTBP2 WYVYPS ++ Original one dTBP-1 AYVYPSM ++ insignificant, deletion of W ： j. activity dTBP-2 WAVYPSM-dTBP-3 WYAYPSM-dTBP-4 WYVAPS dTBP-M5-1 WYVYKSM-Ala substitution: jsolubility dTBP-6 WYVYPA-dTBP-7 WYVYPSA Amino acid Tryptophan and the fourth amino acid tyrosine maintained the same activity of dTBP2 even when substituted with alanine. Accordingly, the present invention designed a peptidomimetic compound of dTBP2 by modifying gastric tryptophan or tyrosine, and further enhancing its activity and bioavailability.
우선， N말단의 아미노산인 트립토판에 아실기를 도입하고，이 중 효과가 잘 나타나는 화합물을 선택하였다. 상기 화합물들은 dTCTP에 대한 결합력이 증가하였다. 또한， 본 발명자들은 alanine scanning mutagenesis로부터 가장 필수적이지 않은 것으로 밝혀진 네번째 아미노산 자리에 위치한 타이로신을 디아미노산 잔기 [diamino-acid, 예컨대， Diaminopropionic acid (Dpr)]로 변경 후 산 (acid)과 커플링 시켰다 (도 1).  First, 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. In addition, we changed tyrosine located at the fourth amino acid position, which was found to be the least essential from alanine scanning mutagenesis, to a diamino acid residue [diamino-acid such as Diaminopropionic acid (Dpr)] and then coupled with an acid ( 1).
이와 같이 새로 도입된 기능성 그룹은 추가적인 결합 부위를 제공할 수 있고, 내부의 타이로신과 같은 느슨한 결합 잔기를 단단한 결합으로 바꿈으로써 dTCTP-dTBP2의 결합력을 현저히 증가시킨 것을 확인할 수 있었다 (실험예 1 내지 4).  As such, 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). ).
따라서, 본 발명에서 제공하는 신규 펩티도미메틱 화합물의 일예는， 본 발명은 서열번호 1의 아미노산 서열로 이루어진 펩타이드 또는 이의 단편에서， 상기 서열번호의 첫번째 아미노산인 트립토판에 아실기가 도입된 펩티도미메틱 화합물일 수 있다.  Thus, one example of the novel peptidomimetic compound provided by the present invention, 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.
보다 바람직하게， 하기 화학식 1의 구조를 포함하는 펩티도미메틱 화합물일 수 있다.  More preferably, it may be a peptidomimetic compound comprising the structure of Formula 1.
[화학식 1]  [Formula 1]
Figure imgf000008_0001
또는
Figure imgf000009_0001
이고,
Figure imgf000008_0001
or
Figure imgf000009_0001
ego,
W는 트립토판 (Tryptophan, W)이고，  W is tryptophan (W),
Y는 타이로신 (Tyrosine, Y)이고，  Y is Tyrosine, Y
V는 발린 (Valine, V)이며ᅳ  V is valine (V) and ᅳ
P는 프를린 (Proline, P)이며，  P is Proline, P,
S는 세린 (Serine, S)이고，  S is Serine, S
M은 메티오닌 (Methionine, M)이다.  M is Methionine (M).
Figure imgf000009_0002
Figure imgf000009_0002
더욱 구체적으로， 상기 화합물은 More specifically, the compound
2ᅳ메틸핵사노일-트립토판 -타이로신-발린-타이로신-프를린-세린—메티오닌 2'methylnucleonoyl-tryptophan-tyrosine-valine-tyrosine-plin-serine-methionine
이소니코티닐-트립토판 -타이로신-발린-타이로신-프롤린-세린—메티오닌， 알파-시아노 -4-하이드록시신나밀-트립토판ᅳ타이로신 -발린 -타이로신—프를린-세린- 메티오닌, 또는 5-니트로 -3-피라졸카복실일-트립토판 -타이로신 -발린 -타이로신ᅳ프를린-세린-메티 오닌일 수 있다. Isonicotinyl-tryptophan-tyrosine-valine-tyrosine-proline-serine—methionine, alpha-cyano-4-hydroxycinnamil-tryptophanza tyrosine-valine-tyrosine—prine-serine-methionine, or 5-nitro 3-pyrazolcarboxylyl-tryptophan-tyrosine-valine-tyrosine champlin-serine-methionine.
다른 일예로, 본 발명은 서열번호 1의 아미노산 서열로 이루어진 펩타이드에서， 상기 서열번호의 첫번째 아미노산인 트립토판 자리에 아실기가 도입되고 상기 서열번호의 네번째 아미노산인 타이로신이 아실기 (acyl 그룹)가 연결된 디아미노프로피오닉 산 (Diaminopropionic acid, Dpr)으로 치환되며， 알레르기성 질환에 대하여 예방 또는 치료 활성을 나타내는 펩티도미메틱 화합물일 수 있다. In another embodiment, 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.
보다 바람직하게， 서열번호의 첫번째 아미노산인 트립토판 자리에는 이소니코티닐기가 도입된 것일 수 있다.  More preferably, an isonicotinyl group may be introduced at the tryptophan site, which is the first amino acid of SEQ ID NO.
또한， 상기 Dpr은 벤조일기， 신나밀기， 카르복실기， 아세틸기 , 핵시노일기， 오로틸기， 나프토일기， 니코티닐기， 핵사디엔오일기， 글리옥실기 푸로일기， 핵사노일기， 퀴나딜기， 타이글라일기， 트를록실기, 헤테로알킬 및 아릴헤테로알킬로 이루어진 군에서 선택되는 하나 이상을 포함하는 아실기—함유 치환기와 연결될 수 있다.  In addition, 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.
보다 바람직하게， 하기 화학식 2의 구조를 포함하는 펩티도미메틱 화합물일 수 있다.  More preferably, it may be a peptidomimetic compound including the structure of Formula 2 below.
Figure imgf000010_0001
Figure imgf000010_0001
Dpr 은 디아미노프로피오닉 산 (Diaminopropionic acid)이고, Dpr is Diaminopropionic acid,
R2는 탄소수 1 내지 20의 비치환된 또는 치환된 선형, 가지형 또는 고리형 알킬이거나，탄소수 1내지 10의 비치환된 또는 치환된 알콕시이거나， 비치환 또는 치환된 아릴이거나， Nᅳ 0또는 S를 포함하는 비치환 또는 치환된 헤테로아릴이거나， N, 0또는 S를 포함하는 비치환 또는 치환된 헤테로사이클이고，  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 ᅳ 0 or S Unsubstituted or substituted heteroaryl containing, Unsubstituted or substituted heterocycle containing N, 0 or S,
W는 트립토판 (Tryptophan, O이고，  W is tryptophan, O,
Y는 타이로신 (Tyrosine, Y)이고,  Y is Tyrosine (Y),
V는 발린 (Valine, V)이며，  V is valine (V),
P는 프롤린 (Proline, P)이며，  P is proline (P),
S는 세린 (Serine, S)이고，  S is Serine, S
M은 메티오닌 (Methionine, M)이다.  M is Methionine (M).
상기 화학식 2는 구체적으로 다음의 화학구조로 나타낼 수 있다:
Figure imgf000011_0001
Formula 2 may be specifically represented by the following chemical structure:
Figure imgf000011_0001
더욱 구체적으로， 상기 화합물은 이소니코티닐—트립토판 -타이로신—발린 -Dpr (3， 5—디메틸벤조일) -프롤린 -세린 -메티 오닌 산화형， 이소니코티닐-트립토판 -타이로신-발린ᅳ Dpr (3，5-디메틸벤조일) -프를린 -세린 -메티 오닌 , 비산화형， 이소니코티닐-트립토판 -타이로신—발린ᅳ Dpr (알파-시아노 -4-하이드록시신나밀 )ᅳ프 를린-세린ᅳ메티오닌 산화형, 이소니코티닐―트립토판 -타이로신 -발린 -Dpr (알파-시아노— 4ᅳ하이드록시신나밀 ) -프 롤린-세린-메티오닌 비산화형， 이소니코티닐—트립토판-타이로신 -발린 -Dpr (4-펜틸바이사이클로 [2.2.2]옥테인ᅳ1- 카복실일) -프를린-세린-메티오닌 산화형， 이소니코티닐 -트립토판—타이로신 -발린 -Dpr (4-펜틸바이사이클로 [2.2.2]옥테인ᅳ1- 카복실일 ) -프를린ᅳ세린-메티오닌 비산화형 , 이소니코티닐-트립토판 -타이로신-발린— Dpr (2-(2-시아노페닐티오)벤조일) -프롤린- 세린-메티오닌 산화형, 이소니코티닐-트립토판-타이로신 -발린 -Dpr (2-(2—시아노페닐티오)벤조일) -프를린- 세린—메티오닌 비산화형， 이소니코티닐-트립토판 -타이로신 -발린 -Dpr (페녹시아세틸) -프롤린-세린-메티오닌 산화형 ,  More specifically, 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 ᅳ methionine oxidized , Isonicotinyl-tryptophan-tyrosine-valine-Dpr (alpha-cyano—4′hydroxycinnamil) -proline-serine-methionine non-oxidized type, isicotinyl-tryptophan-tyrosine-valine-Dpr (4-pentyl Bicyclo [2.2.2] octane ᅳ 1-carboxyl) -prine-serine-methionine oxidized, isicotinyl-tryptophan—tyrosine-valine-Dpr (4-pentylbicyclo [2.2.2] octane ᅳ 1-carboxyl) -Plinxetrine-methionine non-oxidizing type, isonicoti -Tryptophan -Tyrosine-Valine— Dpr (2- (2-cyanophenylthio) benzoyl) -Proline- Serine-Methionine Oxidized, Isnicotinyl-Tryptophan-Tyrosine-Valine -Dpr (2- (2-Cyanophenyl) Thio) benzoyl) -prine-serine-methionine non-oxidized type, isicotinyl-tryptophan-tyrosine-valine-Dpr (phenoxyacetyl) -proline-serine-methionine oxidized type,
이소니코티닐-트립토판—타이로신 -발린 -Dpr (페녹시아세틸) -프롤린-세린ᅳ메티오닌 비산화형， Isonicotinyl-tryptophan—tyrosine-valine-Dpr (phenoxyacetyl) -proline-serine ᅳ methionine non-oxidized type ，
이소니코티닐-트립토판-타이로신 -발린 -Dpr (2-핵시노일) -프를린-세린-메티오닌 산화형， Isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-nucinonoyl) -prine-serine-methionine oxidation type,
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (2-핵시노일；) -프를린-세린―메티오닌 비산화형， Isicotinyl-Tryptophan-Tyrosine-Valine-Dpr (2-Nucinoyl; ) -Pr-serine-Methionine Non-oxidation type ，
이소나코티닐ᅳ트립토판 -타이로신-발린ᅳ Dpr (오로틸) -프를린―세린-메티오닌 산화형， 이소니코티닐 -트립토판—타이로신-발린ᅳ Dpr (오로틸)—프롤린—세린—메티오닌 Isonacortinyl-Tryptophan -Tyrosine-Valline ᅳ Dpr (Orotyl) -Plinine-serine-Methionine Oxidation Type, Isonicotinyl-Tryptophan-Tyrosine-Valline ᅳ Dpr (Orotyl) —Proline—Serine—Methionine
비산화형 , Non-oxidation
이소니코티닐—트립토판 -타이로신-발린ᅳ Dpr (4-벤질옥시벤조일) -프롤린 -세린 -메티 오닌 산화형， 이소니코티닐—트립토판 -타이로신-발린ᅳ Dpr (4-벤질옥시벤조일) -프를린 -세린 -메티 오닌 비산화형， 이소니코티닐-트립토판 -타이로신—발린 -Dpr (2-나프토일) -프롤린-세린-메티오닌 산화형, Isonicotinyl—Tryptophan-Tyrosine-Valine ᅳ Dpr (4-benzyloxybenzoyl) -Proline-Serine-Methionine Oxidized, Isonicotinyl-Tryptophan-Tyrosine-Valine ᅳ Dpr (4-Benzyloxybenzoyl) -Prline -Serine-methionine non-oxidized, isicotinyl-tryptophan-tyrosine-valine-Dr (2-naphthoyl)-proline-serine-methionine oxidized,
이소니코티닐ᅳ트립토판—타이로신ᅳ발린 -Dpr (2-나프토일 ) -프를린-세린ᅳ메티오닌 비산화형, Isonicotinyl 토 tryptophan—tyrosine ᅳ valine -Dpr (2-naphthoyl) -prine-serine ᅳ methionine non-oxidizing type,
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (2-피라진카복실일 )—프롤린 -세.린 -메티 오닌 산화형， 이소니코티닐-트립토판-타이로신ᅳ발린 -Dpr(2-피라진카복실일) -프롤린 -세린 -메티 오닌 비산화형， 이소니코티닐 -트립토판—타이로신 -발린 -Dpr (2-클로로니코티닐) -프롤린 -세린 -메티 오닌 산화형 , 이소니코티닐-트립토판-타이로신 -발린 -Dpr (2-클로로니코티닐) -프롤린 -세린 -메티 오닌 비산화형 이소니코티닐—트립토판—타이로신ᅳ발린 -Dpr (2 , 4-핵사디엔오일) -프를린—세린 -메티 오닌 산화형 , 이소니코티닐-트립토판-타이로신 -발린 -Dpr (2 , 4-핵사디엔오일) -프를린 -세린 -메티 오닌 비산화형, 이소니코티닐-트립토판 -타이로신 -발린 -Dpr (바이페닐 -4—카복실일 )-프를린—세린-메 티오닌 산화형， 이소니코티닐-트립토판 -타이로신—발린ᅳ Dpr (바이페닐 -4-카복실일) -프롤린-세린-메 티오닌 비산화형, 이소니코티닐 -트립토판—타이로신—발린 -Dpr (페닐글리옥실일) -프를린-세린-메티오 닌 산화형， 이소니코티닐ᅳ트립토판—타이로신-발린ᅳ Dpr (페닐글리옥실일) -프를린-세린—메티오 닌 비산화형， 이소니코티닐-트립토판 -타이로신 -발린 -Dpr (2-플루오로페닐아세틸) -프를린ᅳ세린- 메티오닌 산화형， 이소니코티닐ᅳ트립토판 -타이로신-발린ᅳ Dpr (2-플루오로페닐아세틸) -프를린-세린- 메티오닌 비산화형， 이소니코티닐ᅳ트립토판 -타이로신ᅳ발린ᅳ Dpr (트랜스-신나밀) -프를린-세린-메티오닌 산화형， 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 ᅳ valine -Dpr (2,4-nuxadiene oil) -prine-serine-methionine oxidized, isicotinyl-tryptophan -Tyrosine -Valine -Dpr (2, 4-nucleodiene oil) -Plinine -serine -Methionine non-oxidized, isonicotinyl-tryptophan -Tyrosine-valine -Dpr (biphenyl-4—carboxyl) Lean—Serine-Methionine Oxidized, Isicotinyl-Tryptophan-Tyrosine—Valline Dpr (biphenyl-4-carboxyl) -proline-serine-methionine non-oxidized, isicotinyl-tryptophan—tyrosine—valine -Dpr (phenylglyoxyyl) -plin-serine-methio Oxidized, isonicotinyl ᅳ tryptophan—tyrosine-valined Dpr (phenylglyoxylyl) -plin-serine—methionine non-oxidized type, isicotinyl-tryptophan-tyrosine-valine-Dpr (2-fluoro Phenylacetyl) -Prineurine Serine-Methionine Oxidized, Isonicotinyl ᅳ Tryptophan -Tyrosine-Valline (R) Dpr (2-Fluorophenylacetyl) -Prine-Serine-Methionine Non-oxidized, Isonicotinyl ᅳ Tryptophan- Tyrosine ᅳ valine ᅳ Dpr (trans-cinnamil)-p-serine-methionine oxidized type ，
이소니코티닐ᅳ트립토판—타이로신-발린ᅳ Dpr (트랜스-신나밀) -프롤린-세린―메티오닌 비산화형, Isonicotinyl ᅳ tryptophan—tyrosine-valinec Dpr (trans-cinnamil) -proline-serine-methionine non-oxidation type,
이소니코티닐ᅳ트립토판 -타이로신ᅳ발린ᅳ Dpr ( 1-나프토일 )—프롤린ᅳ세린—메티오닌 산화형， Isonicotinyl ᅳ tryptophan-tyrosine ᅳ valine ᅳ Dpr (1-naphthoyl) —proline ᅳ serine—methionine oxidized,
이소니코티닐-트립토판ᅳ타이로신ᅳ발린 -Dpr ( 1-나프토일) -프롤린-세린-메티오닌 비산화형, Isonicotinyl-tryptophan ᅳ tyrosine ᅳ valine -Dpr (1-naphthoyl) -proline-serine-methionine non-oxidizing type,
이소니코티닐 -트립토판—타이로신ᅳ발린 -Dpr (5-니트로 -2-푸로일) -프를린 -세린 -메티 오닌 산화형， 이소니코티닐 -트립토판—타이로신 -발린 -Dpr (5-니트로ᅳ 2-푸로일)ᅳ프를린 -세린 -메티 오닌 비산화형, 이소니코티닐-트립토판—타이로신ᅳ발린 -Dpr (베타-나프록시아세틸 ) -프를린-세린-메 티오닌 산화형, 이소니코티닐-트립토판 -타이로신 -발린 -Dpr (베타-나프특시아세틸)—프를린-세린-메 티오닌 비산화형， 이소니코티닐—트립토판-타이로신 -발린 -Dpr (3—페녹시벤조일) -프롤린-세린-메티오 닌 산화형 , 이소니코티닐-트립토판-타이로신 -발린 -Dpr (3-페녹시벤조일) -프롤린-세린-메티오 닌 비산화형, 이소니코티닐—트립토판-타이로신 -발린 -Dpr (그메특시 -1—벤조퓨란 -2—카복실일) -프 롤린—세린—메티오닌 산화형 이소니코티닐ᅳ트립토판ᅳ타이로신 발린 -Dpr (7-메톡시 1—벤조퓨란 -2—카복실일) -프 를린—세린-메티오닌 비산화형， 이소니코티닐ᅳ트립토판-타이로신 발린 -Dpr (2-메특시핵사노일) -프를린 -세린 -메티 오닌 산화형, 이소니코티닐ᅳ트립토판-타이로신 발린 -Dpr (2-메특시핵사노일) -프를린 -세린 -메티 오닌 비산화형， 이소니코티닐ᅳ트립토판 -타이로신 발린 -Dpr (3-클로로벤조 [b]티오펜 -2-카복실일) - 프를린—세린ᅳ메티오닌 산화형， 이소니코티닐-트립토판 -타이로신 발린 -Dpr (3-클로로벤조 [b]티오펜 -2-카복실일 ) - 프를린-세린-메티오닌 비산화형， 이소니코티닐-트립토판 -타이로신 발린ᅳ Dpr (퀴날딜) -프롤린-세린-메티오닌 산화형， 이소니코티닐ᅳ트립토판-타이로신 발린ᅳ Dpr (퀴날딜 ) -프롤린-세린-메티오닌 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—phenoxybenzoyl) -Proline-serine -Methionine Oxidized, Isonicotinyl-Tryptophan-Tyrosine-Valine-Dpr (3-phenoxybenzoyl) -Proline-serine-Methionine Non-oxidized, Isnicotinyl-Tryptophan-Tyrosine-Valine -Dpr -1—benzofuran-2—carboxyl) -proline-serine-methionine oxidized Isonicotinyl ᅳ tryptophan ᅳ tyrosine valine -Dpr (7-methoxy 1-benzofuran-2-carboxyl) -prine-serine-methionine non-oxidized type, isicotinyl ᅳ tryptophan-tyrosine valine -Dpr (2-method) Hexanoyl) -Prlin -serine -Methionine oxidized, isonicotinyl ᅳ tryptophan-Tyrosine valine -Dpr (2-methocyanosanoyl) -Plin -serine -methionine non-oxidized, isicotinyl ᅳ tryptophan -Tyrosine valine -Dpr (3-chlorobenzo [b] thiophene-2-carboxyl)-prine-serine-methionine oxidized type, isicotinyl-tryptophan-tyrosine valine -Dpr (3-chlorobenzo [b] Thiophene-2-carboxyl)-prine-serine-methionine non-oxidized type, isonicotinyl-tryptophan-tyrosine valine ᅳ Dpr (quinalyl)-proline-serine-methionine oxidized type, isonicotinyl ᅳ tryptophan-tyrosine valine ᅳ Dpr (quinaldyl) -proline-serine-methionine
비산화형, , Non-oxidation type,,
이소니코티닐-트립토판-타이로신 발린ᅳ Dpr (타이글라일) -프를린ᅳ세린-메티오닌 산화형， Isonicotinyl-tryptophan-tyrosine valinex Dpr (Taigliyl) -plinxetrine-methionine oxidation type,
이소니코티닐-트립토판-타이로신 발린 -Dpr (타이글라일) -프를린-세린-메티오닌 비산화형, Isonicotinyl-tryptophan-tyrosine valine-Dpr (Taigliyl) -prine-serine-methionine non-oxidizing type,
이소니코티닐-트립토판 -타이로신 발린ᅳ Dpr (이소니코티닐)ᅳ프롤린―세린-메티오닌 산화형， Isonicotinyl-tryptophan-tyrosine valine ᅳ Dpr (isonicotinyl) 롤 proline-serine-methionine oxidized
이소니코티닐-트립토판-타이로신 발린 -Dpr (이소니코티닐 ) -프를린-세린-메티오닌 비산화형， Isonicotinyl-tryptophan-tyrosine valine-Dpr (isonicotinyl) -prine-serine-methionine non-oxidation type,
이소니코티닐-트립토판-타이로신 발린— Dpr (5-클로로인돌 -2-카복실일) -프를린ᅳ세 린-메티오닌 산화형， 이소니코티닐 -트립토판—타이로신 발린 -Dpr (5-클로로인돌 -2-카복실일) -프를린ᅳ세 린-메티오닌 비산화형， 이소니코티닐-트립토판-타이로신 발린 -Dpr (5-페닐 -2-푸로일) -프를린-세린-메티오 닌 산화형， 이소니코티닐―트립토판 -타이로신 발린 -Dpr (5-페닐 -2-푸로일) -프를린-세린-메티오 닌 비산화형， 이소니코티닐-트립토판—타이로신 -발린 -Dpr (5-니트로ᅳ 3-피라졸카복실일 )ᅳ프롤린- 세린-메티오닌 산화형， 이소니코티닐ᅳ트립토판 -타이로신ᅳ발린ᅳ Dpr (5-니트로 -3-피라졸카복실일 ) -프를린- 세린—메티오닌 비산화형， 이소니코티닐-트립토판-타이로신 -발린 -Dpr ( (R)-(+)_트를록실) -프를린 -세린ᅳ메티 오닌 산화형， 이소니코티닐ᅳ트립토판ᅳ타이로신 -발린 -Dpr ( (R)-(+)-트롤록실) -프롤린 -세린 -메티 오닌 비산화형， 이소니코티닐-트립토판ᅳ타이로신-발린ᅳ Dpr ( (R)-(+)-2-피를리돈ᅳ 5ᅳ카복실일) -프를 린-세린-메티오닌 산화형， 이소니코티닐ᅳ트립토판ᅳ타이로신—발린ᅳ Dpr ( (R)-(+)— 2-피롤리돈 -5-카복실일 ) -프롤 린-세린―메티오닌 비산화형， 이소니코티닐-트립토판ᅳ타이로신-발린ᅳ Dpr ( 1ᅳ시아노 -1-사이클로프로페인카복실일 )ᅳ프를린-세린-메티오닌 산화형， 이소니코티닐-트립토판 -타이로신-발린ᅳ Dpr ( 1ᅳ시아노 -1-사이클로프로페인카복실일 )ᅳ프를린—세린-메티오닌 ' 비산화형， 이소니코티닐―트립토판ᅳ타이로신 -발린 -Dpr (로다닌 -3-아세틸) -프를린-세린-메티오 닌 산화형， 이소니코티닐-트립토판ᅳ타이로신—발린 -Dpr (로다닌— 3-아세틸) -프를린-세린-메티오 닌 비산화형, 이소니코티닐-트립토판 -타이로신—발린 -Dpr (그하이드록시쿠마린 -4-아세틸) -프를린 -세린-메티오닌 , 산화형, 이소니코티닐—트립토판ᅳ타이로신-발린— Dpr (7-하이드록시쿠마린 -4-아세틸)—프를린 -세린—메티오닌 비산화형, 이소니코티닐-트립토판-타이로신 -발린 -Dpr (2-(4ᅳ메틸페닐설폰아미도)아세틸) -프 를린-세린-메티오닌 산화형， 이소니코티닐-트립토판-타이로신ᅳ발린 -Dpr (2-(4-메틸페닐설폰아미도)아세틸) -프 를린ᅳ세린-메티오닌 비산화형， 이소니코티닐-트립토판—타이로신ᅳ발린 -Dpr ( 1-아세틸피페리딘 -4—카복실일 )-프를린 -세린-메티오닌 산화형， 이소니코티닐ᅳ트립토판 -타이로신-발린ᅳ Dpr ( 1-아세틸피페리딘 -4ᅳ카복실일) -프를린 -세린—메티오닌 비산화형, 이소니코티닐-트립토판-타이로신 -발린 -Dpr ( 1-페닐 -5- (트리플루오로메틸 )-1Η-피라 졸 -4-카복실일)—프를린-세린-메티오닌 산화형， 이소니코티닐ᅳ트립토판-타이로신 -발린 -Dpr ( 1—페닐—5ᅳ (트리플루오로메틸 )-1Η-피라 졸 -4—카복실일) -프를린-세린―메티오닌 비산화형， 이소니코티닐ᅳ트립토판—타이로신-발린ᅳ Dpr (2-티오펜아세틸 ) -프롤린-세린—메티오 닌 산화형 , 이소니코티닐-트립토판-타이로신 -발린 -Dpr (2-티오펜아세틸)ᅳ프를린-세린-메티오 닌 비산화형, 이소니코티닐-트립토판 -타이로신 -발린 -Dpr (벤조트리아졸 -5-카복실일 ) -프를린-세 린-메티오닌 산화형， 이소니코티닐-트립토판-타이로신 -발린 -Dpr (벤조트리아졸 -5-카복실일) -프롤린-세 린-메티오닌 비산화형， 이소니코티닐-트립토판-타이로신 -발린 -Dpr (4-옥소 -4H-크로멘 -3ᅳ카복실일)ᅳ프를린 -세린-메티오닌 산화형， 이소니코티닐-트립토판 -타이로신 -발린 -Dpr (4-옥소 -4H-크로멘 -3-카복실일 )ᅳ프롤린 -세린-메티오닌 비산화형， 이소니코티닐 -트립토판—타이로신 -발린 -Dpr (4-메틸 -2—옥소 -2H-크로멘 -그일옥시)아 세틸) -프를린-세린-메티오닌 산화형 및 이소니코티닐-트립토판-타이로신 -발린 -Dpr (4-메틸 -2-옥소 -2H-크로멘—그일옥시)아 세틸) -프를린-세린-메티오닌 비산화형인 것인， 화합물일 수 있다. Isicotinyl-Tryptophan-Tyrosine Valine— Dpr (5-Chloroindole-2-carboxyl) -Plinxetrine-Methionine Oxidized, Isicotinyl-Tryptophan—Tyrosine Valine -Dpr (5-Chloroindole-2 -Carboxyl) -Princexerine-Methionine Non-oxidized, Isonicotinyl-Tryptophan-Tyrosine Valine -Dpr (5-phenyl-2-furoyl) -Pr-serine-Methionine Oxide, Iso Nicotinyl-tryptophan-tyrosine valine-Dpr (5-phenyl-2-furoyl) -prine-serine-methionine non-oxidizing type, Isonicotinyl-tryptophan—tyrosine-valine-Dpr (5-nitrosip 3-pyrazolcarboxyl) ᅳ proline-serine-methionine oxidized type, isicotinyl ᅳ tryptophan-tyrosine ᅳ valinec Dpr (5-nitro-3- Pyrazolcarboxylyl) -prine-serine-methionine non-oxidizing type, isonicotinyl-tryptophan-tyrosine-valine-Dpr ((R)-(+) _ tropoxyl) -prine-serine ᅳ methionine oxidation Type, isonicotinyl ᅳ tryptophan ᅳ tyrosine-valine-Dpr ((R)-(+)-troloxyl) -proline-serine-methionine non-oxidized type, isicotinyl-tryptophantotyrosine-valinebine Dpr ((R) -(+)-2-pyridone ᅳ 5 ᅳ carboxyl) -Prine-serine-methionine oxidized, isicotinyl ᅳ tryptophan ᅳ tyrosine-valined Dpr ((R)-(+) — 2-pi Ralidone-5-carboxyl) -proline-serine-methionine non-oxidizing type, isicotinyl-tryptophan ᅳ tyrosine-valine ᅳ Dpr (1 ᅳ cyano -1-cyclopropane carboxyl) Prine-serine-methionine oxidized, isicotinyl-tryptophan-tyrosine-valinec Dpr (1-cyano-1-cyclopropanecarboxylyl) prine-serine-methionine non-oxidized, isicotinyl- Tryptophanpy tyrosine -valine -Dpr (rhodanin-3-acetyl) -plin-serine-methionine oxidized type, isonicotinyl-tryptophanputyrosine-valine -Dpr (rhodanine- 3-acetyl)- Lin-serine-methionine non-oxidized, isonicotinyl-tryptophan-tyrosine—valine-Dpr (glyhydroxycoumarin-4-acetyl) -prine-serine-methionine, oxidized, isicotinyl-tryptophanet-tyrosine -Valine- Dpr (7-hydroxycoumarin-4-acetyl) -plin-serine-methionine non-oxidizing type, isonicotinyl-tryptophan-tyrosine-valine -Dpr (2- (4 ᅳ methylphenylsulfonamido) acetyl) -Prine-serine-methionine oxidized type, isicotinyl-tryptophan-tyrosine ᅳ valine -Dpr (2- (4- Butyl phenyl sulfonamido) acetyl) program reulrin eu-serine-methionine non-photosetting, iso-nicotinyl-tryptophan-tyrosine eu Val -Dpr (1- acetyl-piperidin-4-yl carboxylate) - the profile Lin -Serine-Methionine Oxidized, Isonicotinyl ᅳ tryptophan -Tyrosine-valinec Dpr (1-acetylpiperidine-4 ᅳ carboxylyl) -Prine -serine-Methionine non-oxidized type, isicotinyl-tryptophan-tyrosine- Valine-Dpr (1-phenyl-5- (trifluoromethyl) -1Η-pyrazole-4-carboxylyl) —prine-serine-methionine oxidized, isicotinyl 코 tryptophan-tyrosine-valine-Dpr ( 1—Phenyl—5 ′ (trifluoromethyl) -1Η-pyrazole-4—carboxyl) -Plin-serine-methionine non-oxidized, isnicotinyl ᅳ tryptophan—tyrosine-valineb Dpr (2-thiophene Acetyl) -Proline-serine-Methionine Oxidized, Isonicotinyl-Tryptophan-Tyrosine-Valine-Dpr (2-thiophenacetyl) Keplin-serine-Methionine Non-oxidized, Isnicotinyl-Tryptophan-Tyrosine -Valine -Dpr (Benzotriazole-5-carboxylyl) -Plinine-serine-methionine oxidized type, isicotinyl-tryptophan-tie Cin-valine-Dpr (benzotriazole-5-carboxylyl) -proline-serine-methionine non-oxidizing type, isicotinyl-tryptophan-tyrosine-valine -Dpr (4-oxo-4H-chromen-3 ᅳ carboxylyl ) Kurplin-serine-methionine oxidized type, isicotinyl-tryptophan-tyrosine-valine-Dpr (4-oxo-4H-chromen-3-carboxyl) ᅳ proline-serine-methionine non-oxidized type, isicotinyl- Tryptophan—Tyrosine-valine-Dpr (4-Methyl-2—oxo-2H-chromen-gyloxy) acetyl) -prine-serine-methionine oxidative and isnicotinyl-tryptophan-tyrosine-valine -Dpr (4-methyl-2-oxo-2H-chromen-gyloxy) acetyl) -prine-serine-methionine non-oxidized, which may be a compound.
다른 일예로， 본 발명은 서열번호 1의 아미노산 서열로 이루어진 펩타이드 단편에서， 상기 단편은 네 개의 아미노산으로 이루어지며 C—말단이 메티오닌인 펩타이드 단편이고, 상기 서열번호의 네번째 아미노산에 해당하는 타이로신 자리이 아실기 (acyl group)가 연결된 디아미노프로피오닉 산 (Di aminopropioni c acid , Dpr )으로 치환되며, 알레르기성 질환에 대하여 예방 또는 치료 활성을 나타내는 펩티도미메틱 화합물일 수 있다. 보다 바람직하게， 상기 Dpr 은 벤조일기, 신나밀기, 카르복실기， 아세틸기， 오로틸기， 퀴나딜기， 타이글라일기， 트롤록실기, 헤테로알킬 및 아릴헤테로알킬로 이루어진 군에서 선택되는 하나 이상을 포함하는 아실기 -함유 치환기와 연결될 수 있다. In another embodiment, 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. More preferably, 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.
보다 바람직하게. , 본 발명은 하기 화학식 3의 구조를 포함하는 펩티도미메틱 화합물일 수 있다. More preferably . , The present invention may be a peptidomimetic compound comprising a structure of formula (3).
[화학식 3]  [Formula 3]
Figure imgf000017_0001
Figure imgf000017_0001
Dpr 은 디아미노프로피오닉 산 (Di aminopropioni c acid)이고，  Dpr is Di aminopropionic acid,
R3는 탄소수 1 내지 20의 비치환된 또는 치환된 선형， 가지형 또는 고리형 알킬이거나，탄소수 1내지 10의 비치환된 또는 치환된 알콕시이거나,비치환 또는 치환된 아릴이거나, Nᅳ 0또는 S를 포함하는 비치환 또는 치환된 헤테로아릴이거나， N , 0 또는 S를 포함하는 비치환 또는 치환된 헤테로사이클이고， 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 ᅳ 0 or Unsubstituted or substituted heteroaryl containing S, or unsubstituted or substituted heterocycle containing N, 0 or S,
P는 프롤린 (Prol ine , P)이며,  P is proline (Prol ine, P),
S는 세린 (Ser ine , S)이고，  S is Serin (S)
M은 메티오닌 (Methionine , M)이다.  M is Methionine (M).
화학구조로 나타낼 수 있다:  It can be represented by chemical structure:
Figure imgf000017_0002
Figure imgf000017_0002
상기 화학식 3의 구조를 포함하는 펩티도미메틱 화합물은 바람직하게 Dpr (4-펜틸바이사이클로 [2.2.2]옥탄ᅳ1—카복실일) -프롤린-세린―메티오닌 산화형， Dpr (4—펜틸바이사이클로 [2.2.2]옥탄 -1-카복실일) -프롤린-세린―메티오닌 비산화형 , 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,
Dpr (타이글라일 ) -프를린-세린-메티오닌 산화형 Dpr (타이글라일) -프롤린-세린-메티오닌 Dpr (Taigliyl) -Plin-serine-Methionine Oxidized Dpr (Taigliyl) -proline-serine-methionine
Dpr (5-클로로인돌 -2—카복실일 ) -프를린-세린―메티오닌 Dpr (5-Chloroindole-2—carboxyl) -Pr-serine-methionine
Dpr (5ᅳ클로로인돌—2-카복실일)ᅳ프를린-세린-메티오닌 Dpr (5 ᅳ Chloroindole—2-carboxyl) Keplin-serine-Methionine
Dpr (2ᅳ(2ᅳ시아노페닐티오)벤조일) -프를린-세린―메티오닌 Dpr (2 ′ (2′cyanophenylthio) benzoyl) -prine-serine-methionine
Dpr (2— (2-시아노페닐티오)벤조일 )—프를린ᅳ세린ᅳ메티오닌 Dpr (2— (2-cyanophenylthio) benzoyl) —Princelanserine ᅳ Methionine
Dpr (퀴날딜) -프를린―세린-메티오닌 산화형， Dpr (퀴날딜) -프롤린-세린-메티오닌 비산화형， Dpr(2-플루오로페닐아세틸) -프롤린 -세린 -메티오닌， Dpr (quinalyl) -proline-serine-methionine oxidized type, Dpr (quinalyl) -proline-serine-methionine non-oxidized type, Dpr (2-fluorophenylacetyl) -proline-serine-methionine,
Dpr (7-메록시ᅳ1-벤조퓨란 -2—카복실일) -프를린 -세린 -메티오닌， Dpr (7-Methoxy-l-benzofuran-2—carboxylyl) -prine-serine-methionine,
Dpr (오로틸) -프를린 -세린 -메티오닌， Dpr (orotyl) -plin-serine-methionine,
Dpr ( 1-시아노ᅳ1-사이클로프로판카복실일) -프롤린 -세린 -메티오닌, Dpr (1-cyano ᅳ 1-cyclopropanecarboxyl) -proline-serine-methionine,
Dpr (알파-시아노 -4-하이드록시신나밀 )ᅳ프를린ᅳ세린-메티오닌 , Dpr (alpha-cyano-4-hydroxycinnammyl) phrine ᅳ serine-methionine,
Dpr (3， 5-디메틸벤조일) -프를린 -세린 -메티오닌， Dpr (3, 5-dimethylbenzoyl) -prine-serine-methionine,
Dpr ( (R)—(+)-트를록실) -프를린 -세린ᅳ메티오닌, -Dpr ((R) — (+)-Troxyl) -Pr-lin-serine ᅳ methionine,-
Dpr (2ᅳ (4-메틸페닐설폰아미도)아세틸) -프를린-세린-메티오닌 및 Dpr (5—니트로ᅳ3—피라졸카복실일)ᅳ프롤린 -세린 -메티오닌일 수 있다. Dpr (2 ′ (4-methylphenylsulfonamido) acetyl) -proline-serine-methionine and Dpr (5—nitrojan3—pyrazolcarboxylyl) ᅳ proline-serine-methionine.
다른 일예로， 본 발명은 서열번호 1의 아미노산 서열로 이투어진 펩타이드 단편에서， 상기 단편은 상기 서열번호 1의 N-말단부터 네 개의 아미노산으로 이루어지는 단편이고， 상기 서열번호의 첫번째 아미노산인 트립토판 자리에 아실기가 도입되고 상기 서열번호의 네번째 아미노산에 해당하는 타이로신이 아실기 (acyl group)가 연결된 디아미노프로피오닉 산 (Di aminopropioni c acid , In another embodiment, 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 )으로 치환되며， 알레르기성 질환에 대하여 예방 또는 치료 활성을 나타내는 펩티도미메틱 화합물일 수 있다. Dpr), and may be a peptidomimetic compound that exhibits prophylactic or therapeutic activity against allergic diseases.
보다 바람직하게, 서열번호의 첫번째 아미노산인 트립토판 자리에는 이소니코티닐기가 도입된 것일 수 있다.  More preferably, an isonicotinyl group may be introduced at the tryptophan site, which is the first amino acid of SEQ ID NO.
또한， 상기 Dpr 은 벤조일기， 카르복실기， 아세틸기， 오로틸기， 퀴나딜기， 타이글라일기， 트롤록실기， 헤테로알킬 및 아릴헤테로알킬로 이루어진 군에서 선택되는 하나 이상을 포함하는 아실기 -함유 치환기와 연결될 수 있다.  In addition, 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.
보다 바람직하게， 본 발명은 하기 화학식 4의 구조를 포함하는 펩티도미메틱 화합물일 수 있다.
Figure imgf000019_0001
More preferably, the present invention may be a peptidomimetic compound comprising a structure of formula (4).
Figure imgf000019_0001
Dpr 은 디아미노프로피오닉 산 (Di aminopropioni c acid)이고,  Dpr is Di aminopropionic acid,
는 탄소수 1 내지 20의 비치환된 또는 치환된 선형， 가지형 또는 고리형 알킬이거나, 탄소수 1내지 10의 비치환된 또는 치환된 알콕시이거나，비치환 또는 치환된 아릴이거나， Ν , Ο또는 S를 포함하는 비치환 또는 치환된 헤테로아릴이거나， Ν, 0 또는 S를 포함하는 비치환 또는 치환된 헤테로사이클이고，  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 N, O or S Unsubstituted or substituted heteroaryl, or unsubstituted or substituted heterocycle, including Ν, 0 or S,
W는 트립토판 (Tryptophan , W)이고，  W is tryptophan (W),
Y는 타이로신 (Tyros ine , Y)이고，  Y is Tyrosine (Y)
V는 발린 (Val ine , V)이다.  V is valine (Val ine, V).
화학식 4 는 구체적으로 다음의 화학구조로 나타낼 수 있다:  Formula 4 may be specifically represented by the following chemical structure:
Figure imgf000019_0002
Figure imgf000019_0002
상기 화학식 4의 구조를 포함하는 펩티도미메틱 화합물은 바람직하게 이소니코티닐 -트립토판—타이로신 -발린 -Dpr (오로틸) ,  The peptidomimetic compound comprising the structure of Chemical Formula 4 is preferably isonicotinyl-tryptophan—tyrosine-valine-Dpr (orotyl),
이소니코티닐-트립토판 -타이로신—발린 -Dpr (3 , 5-디메틸벤조일)， Isicotinyl-tryptophan-tyrosine—valine-Dpr (3, 5-dimethylbenzoyl),
이소니코티닐—트립토판-타이로신 -발린 -Dpr (7-메톡시 -1—벤조퓨란 -2-카복실일) , 이소니코티닐-트립토판 -타이로신—발린 -Dpr (2-(2-시아노페닐티오)벤조일)， 이소니코티닐-트립토판-타이로신 -발린 -Dpr ( (R)— (+)-트를록실)， 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),
이소니코티닐-트립토판 -타이로신 -발린 -Dpr ( 1-시아노 -1-사이클로프로판카복실일 )， 이소니코티닐-트립토판 -타이로신 -발린 -Dpr (로다닌 -3-아세틸 ) , Isonicotinyl-tryptophan-tyrosine-valine-Dpr (1-cyano-1-cyclopropanecarboxyl), isonicotinyl-tryptophan-tyrosine-valine-Dpr (rhodanine-3-acetyl),
이소니코티닐―트립토판 -타이로신ᅳ발린 -Dpr (2—플루오로페닐아세틸 )， Isonicotinyl-tryptophan-tyrosine ᅳ valine -Dpr (2—fluorophenylacetyl),
이소니코티닐-트립토판-타이로신 -발린 -Dpr(4-펜틸바이사이클로 [2.2.2]옥탄 -1-카 복실일)， 이소니코티닐-트립토판-타이로신ᅳ발린 -Dpr (퀴날딜)， 이소니코티닐ᅳ트립토판ᅳ타이로신-발린ᅳ Dpr (타이글라일) , Isicotinyl-tryptophan-tyrosine-valine-Dpr (4-pentylbicyclo [2.2.2] octane-1-car Fylyl), isonicotinyl-tryptophan-tyrosine bovine valine -Dpr (quinaldil), isonicotinyl ᅳ tryptophan ᅳ tyrosine-valine brine Dpr (Taigliyl),
이소니코티닐―트립토판ᅳ타이로신-발린ᅳ Dpr (5-클로로인돌 -2-카복실일 ) Isicotinyl-tryptophan ᅳ tyrosine-valineb Dpr (5-chloroindole-2-carboxylyl)
이소니코티닐ᅳ트립토판ᅳ타이로신-발린— Dpr (5—니트로 -3-피라졸카복실일 ) 및 이소니코티닐ᅳ트립토판ᅳ타이로신ᅳ발린ᅳ Dpr (2-(4ᅳ메틸페닐설폰아미도)아세틸)일 수 있다. Isonicotinyl ᅳ tryptophan ᅳ tyrosine-valine— Dpr (5—nitro-3-pyrazolcarboxyl) and isonicotinyl ᅳ tryptophan ᅳ tyrosine ᅳ valine ᅳ Dpr (2- (4 ᅳ methylphenylsulfonamido) acetyl) have.
다른 일예로， 본 발명은 서열번호 1의 아미노산 서열로 이루어진 펩타이드 단편에서， 상기 단편은 세 개 또는 네 개의 아미노산으로 이루어지며 C—말단이 세린인 펩타이드 단편이고， 상기 서열번호의 네번째 아미노산에 해당하는 타이로신이 아실기 (acyl group)가 연결된 디아미노프로피오닉 산 (Di ami nopropi oni c aci d , Dpr )으로 치환되며， 알레르기성 질환에 대하여 예방 또는 치료 활성을 나타내는 펩티도미메틱 화합물일 수 있다.  In another embodiment, 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.
보다 바람직하게， 상기 Dpr 은 벤조일기 , 카르복실기 , 아세틸기， 오로틸기， 헤테로알킬 및 아릴해테로알킬로 이루어진 군에서 선택되는 하나 이상을 포함하는 아실기 -함유 치환기와 연결될 수 있다.  More preferably, 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.
보다 바람직하게, 하기 화학식 5 또는 화학식 6와 구조를 포함하는 펩티도미메틱 화합물일 수 있다.  More preferably, it may be a peptidomimetic compound comprising the structure of Formula 5 or Formula 6.
[화학식 5] [Formula 5]
-PS
Figure imgf000020_0001
Dpr 은 디아미노프로피오닉 산 (Di aminopropi oni c ac i d)이고， -PS
Figure imgf000020_0001
Dpr is di aminopropionic acid (Di aminopropi oni c ac id),
R5는 탄소수 1 내지 20의 비치환된 또는 치환된 선형， 가지형 또는 고리형 알킬이거나，탄소수 1내지 10의 비치환된 또는 치환된 알콕시이거나，비치환 또는 치환된 아릴이거나， Ν , Ο또는 S를 포함하는 비치환 또는 치환된 헤테로아릴이거나， Ν, 0 또는 S를 포함하는 비치환 또는 치환된 헤테로사이클이고， 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, Ν, Ο or Unsubstituted or substituted heteroaryl containing S, or unsubstituted or substituted heterocycle containing Ν, 0 or S,
Ρ는 프롤린 (Prol ine , P)이며, S는 세린 (Serine, S)이다. Ρ is proline (Pl ine, P), S is Serine (S).
상기 화학식 5 는 구체적으로 다음의 화학구조로 나타낼 수 있다  Formula 5 may be specifically represented by the following chemical structure
Figure imgf000021_0001
Figure imgf000021_0001
[화학식 6] PS
Figure imgf000021_0002
[Formula 6] PS
Figure imgf000021_0002
Dpr 은 디아미노프로피오닉 산 (Diaminopropionic acid)이고, Dpr is Diaminopropionic acid,
¾는 벤조일기， 카르복실기， 아세틸기 오로틸기， 헤테로알킬 및 아릴헤테로알킬로 이루어진 군에서 선택되는 하나 이상을 포함하고,  ¾ 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 는 발린 (Valine, V)이고,  V is valine (V),
P는 프를린 (Proline, P)이며,  P is Proline, P,
S는 세린 (Serine, S)이다. S is Serine (S).
의 화학구조로 나타낼 수 있다:  It can be represented by the chemical structure of:
Figure imgf000021_0003
Figure imgf000021_0003
싱끼 ≤ ί·학식 5 또는 화학식 6의 구조를― 포함―하.는— ¾―티도미메틱 화합물은 바람직하게 발린 -Dpr (오로틸) -프를린 -세린 발린 -Dpr (그메톡시 -1-벤조퓨란— 2-카복실일) 프를린 -세린 발린 -Dpr (3 , 5—디메틸벤조일)ᅳ프를린-세린， Singe ≤ ί · including the structure of Formula 5 or Formula 6-¾- 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,
발린— Dpr (5—클로로인돌 -2-카복실일) -프를린-세린， Valine— Dpr (5—chloroindole-2-carboxyl) -prine-serine,
발린 -Dpr (2-플루오로페닐아세틸) -프를린-세린， Dpr (오로틸) -프를린-세린，Valine-Dpr (2-fluorophenylacetyl) -plin-serine, Dpr (orotyl) -plin-serine,
Dpr (7-메를시 -1—벤조퓨란 -2-카복실일) -프롤린-세린， Dpr (7-Mercy-l—benzofuran-2-carboxylyl) -proline-serine,
Dpr (3，5—디메틸벤조일)—프를린ᅳ세린, Dpr (5-클로로인돌ᅳ 2-카복실일) -프롤린-세린， 또는 Dpr (2-플루오로페닐아세틸)—프를린-세린일 수 있다. Dpr (3,5—dimethylbenzoyl) —prolinexerine, Dpr (5-chloroindolone 2-carboxylyl) -proline-serine, or Dpr (2-fluorophenylacetyl) —proline-serineyl Can be.
본 발명에 따른 화합물의 치환기에 대한 정의에서, 용어 '알킬' 은 지방족 탄화수소 그룹을 의미한다. 알킬은 알켄이나 알킨 부위를 포함하지 않는 "포화 알킬 ( saturated alkyl ) " 이거나， 적어도 하나의 알켄이나 알킨 부위를 포함하는 "블포화 알킬 (unsaturated alkyl ) " 일 수 있다. "알켄" 은 적어도 하나의 탄소 -탄소 이중결합을 포함하는 그룹을 의미하며， "알킨" 은 적어도 하나의 탄소 -탄소 삼중 결합을 포함하는 그룹을 의미한다 . 알킬은 단독으로 또는 알콕시와 같이 조합하여 사용되는 경우에 각각 분지형 또는 직쇄형일 수 있다. 알킬 그룹은 달리 정의하지 않는 한 1 내지 20 개의 탄소원자를 가질 수 있다. 알킬 그룹은 1 내지 10 개의 탄소원자들을 가지는 중간 크기의 알킬일 수도 있다ᅳ 알킬 그룹은 i 내지 6 개의 탄소원자들을 가지는 저급 알킬일 수도 있다. 전형적인 알킬 그룹에는 메틸， 에틸,프로필， 이소프로필，부틸， 이소부틸, t-부틸, 펜틸, 핵실， 에테닐 프로페닐， 부테닐 등이 포함되지만， 이들 만으로 한정되는 것은 아니다. 예를 들어， d- -알킬은 알킬쇄에 1내지 4개의 탄소원자를 가지며， 메틸， 에틸， 프로필, 이소-프로필, n-부틸， 이소-부틸, sec-부틸 및 t-부틸로 이루어진 그룹에서 선택된다.  In the definition of the substituents of the compounds according to the invention, the term '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, and "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. For example, 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.
용어 '알콕시 '는 달리 정의하지 않는 한 1내지 10개의 탄소원자를 가지는 알킬옥시를 의미한다.  The term "alkoxy" means alkyloxy having 1 to 10 carbon atoms unless otherwise defined.
용어 '사이클로알킬'은 달리 정의하지 않는 한 포화 지방족 3~10원 환을 의미한다 . 전형적인 사이클로알킬 그룹에는 사이클로프로필 , 사이클로부틸， 사이클로펜틸, 사이클로핵실 등이 포함되지만， 이들 만으로 한정되는 것은 아니다.  The term '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.
용어 '아릴 '은 공유 파이 전자계를 가지는 적어도 하나의 링을 포함하며， 예를 돌어 모노사이클릭 또는 융합환 폴리사이클릭 (즉, 탄소원자들의 인접한 쌍들을 나 ¥] 가지는 링들) 그룹을 포함한다. 즉， 본 명세서에서 아릴은 달리 정의하지 않는 한 페닐， 나프틸 등을 포함하는 4~10원， 바람직하게는 6~10원 방향족 모노사이클릭 또는 멀티사이클릭환을 의미한다. The term '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.
용어 '헤테로아릴 '은 달리 정의하지 않는 한 N , 0 및 S로 이루어진 그룹에서 선택된 1 내지 3 개의 헤테로 원자를 포함하고， 벤조 또는 C3-C8 사이클로알킬과 융합될 수 있는 방향족 3~10원 환, 바람직하게는 4~8원 환, 더욱 바람직하게는 5~6원 환을 의미한다. 모노사이클릭 해테로아릴의 예로는 티아졸， 옥사졸, 티오펜,퓨란，피롤, 이미다졸, 이소옥사졸， 이소티아졸 피라졸,트리아졸， 트리아진， 티아디아졸， 테트라졸， 옥사디아졸， 피리딘， 피리다진， 피리미딘， 피라진 및 이와 유사한 그룹을 들 수 있으나 이들로 제한되는 것은 아니다. 비사이클릭 헤테로아릴의 예로는 인돌, 인돌린， 벤조티오펜， 벤조퓨란, 벤즈이미다졸，벤족사졸， 벤즈이속사졸， 벤즈티아졸， 벤즈티아디아졸, 벤즈트리아졸， 퀴놀린, 이소퀴놀린， 퓨린， 퓨로피리딘 및 이와 유사한 그룹을 들 수 있으나 이들로 제한되는 것은 아니다. The term 'heteroaryl', unless defined otherwise, 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. Examples of 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. Examples of 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.
용어 '헤테로사이클'은 달리 정의하지 않는 한 N , 0 및 S로 이투어진 그룹에서 선택된 1 내지 3개의 헤테로 원자를 포함하며, 벤조 또는 C3-C8 사이클로알킬과 융합될 수 있고， 포화되거나 1 또는 2 개의 이중결합을 포함하는 3~10원 환， 바람직하게는 4~8원 환， 더욱 바람직하게는 5~6원 환을 의미한다. 헤테로사이클의 예로는 피롤린， 피를리딘， 이미다졸린， 이미다졸리딘， 피라졸린 피라졸리딘,피란， 피페리딘 모폴린, 티오모폴린,피페라진,하이드로퓨란 등을 들 수 있지만 이들만으로 한정되는 것은 아니다. The term '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. Examples of 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.
기타 본 명세서에서 사용된 용어와 약어들은 달리 정의되지 않는 한 본 발명이 속하는 기술분야의 당업자에게 통상적으로 이해되는 의미로서 해석될 수 있다.  Other terms and abbreviations used herein may be interpreted as meanings commonly understood by those skilled in the art to which the present invention belongs unless otherwise defined.
또 다른 본 발명의 일구현예로서， 본 발명은 상기 신규한 펩티도미메틱 화합물을 포함하는 알레르기성 질환의 예방 또는 치료용 약학 조성물에 관한 것이다.  As another embodiment of the present invention, the present invention relates to a pharmaceutical composition for the prevention or treatment of allergic diseases comprising the novel peptidomimetic compound.
또 다른 본 발명의 일구현예로서, 본 발명은 상기 신규한 펩티도미메틱 화합물의 약학적 유효량을 개체에 투여하는 단계를 포함하는， 알레르기성 질환의 치료방법에 관한 것이다. As another embodiment of the present invention, 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.
본 발명에서 제공하는 신규한 펩티도미메틱 화합물은 dTBP2 의 생물학적 활성을 나타내면서， 그 활성 및 생체이용능이 증진된 특징이 있으므로, dTBP2 에 의하여 완화， 개선'， 예방, 억제 또는 치료가 가능한 모든 알레르기성 질환에 대한 의약 용도로 적용될 수 있다. 일예로， 본 발명의 펩티도미메틱 화합물은 dTCTP와 그의 수용체 간의 상호작용을 억제함으로써 완화, 개선ᅳ 예방， 억제 또는 치료가 가능한 모든 알레르기성 질환들 에 대한 의약 용도로 적용될 수 있다. 다른 일예로， 본 발명의 펩티도미메틱 화합물은 IL-8 , IL-5 등을 포함하는 사이토카인 및 히스타민의 분비를 억제함으로써 완화， 개선, 예방， 억제 또는 치료가 가능한 모든 알레르기성 질환들에 대하여 치료적 목적으로 사용될 수 있다. 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. For example, 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. In another embodiment, 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.
구체적으로, 상기 알레르기성 질환은 천식， 비염， 담마진， 아나필락시스, 알레르기성 기관지 확장증， 알레르기성 결막염, 두드러기 또는 아토피성 피부염일 수 있으나， 이에 제한되는 것은 아니며， dTCTP와 그의 수용체 간의 상호작용，또는 IL-8 , IL-5등을 포함하는 사이토카인 및 히스타민의 분비에 의해 유도될 수 있는 모든 알레르기성 질환이 본 발명의 범위에 포함된다.  Specifically, 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.
또한， 본 발명의 약학 조성물은 아동, 청소년 및 성인에게 투여될 수 있으며， 경구 및 비경구 투여 경로 모두 가능하다. 바람직하게는 비경구 투여될 수 있다.  In addition, the pharmaceutical compositions of the present invention can be administered to children, adolescents and adults, both oral and parenteral routes of administration. Preferably parenteral administration.
본 발명에서 용어, "투여' '는 어떠한 적절한 방법으로 질환의 치료를 필요로하는 개체에게 본 발명의 약학 조성물을 도입하는 것을 의미하며， 본 발명의 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 경구 또는 비경구의 다양한 경로를 통하여 투여될 수 있다.  As used herein, the term "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.
본 명세서에서 사용된 용어 "약학적 유효량 "은 목적하는 약학적 효과가 얻어질 수 있는 유효성분의 양을 의미하며， 경우에 따라서는 목적하는 약학적 효과 발휘를 위한 약학 조성물 내의 유효성분의 농도 또는 투여량을 의미할 수 있다.  As used herein, 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.
본 발명의 목적상，특정 환자에 대한 구체적인 약학적 유효량은 달성하고자 하는 반웅의 종류와 정도， 경우에 따라 다른 제제가 사용되는지의 여부를 비롯한 구체적 조성물， 환자의 연령， 체중， 일반 건강 상태， 성별 및 식이， 투여 시간， 투여 경로 및 조성물의 분비율， 치료 기간, 구체적 조성물과 함께 사용되거나 동시 사용되는 약물을 비롯한 다양한 인자와 의약 분야에 잘 알려진 유사 인자에 따라 다르게 적용하는 것이 바람직하다 . For the purposes of the present invention, 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.
또한， 비경구 투여로서， 주사용 제형으로는 등장성 수용액 또는 현탁액 등이 있으며， 적합한 분산제 또는 습윤제 및 현탁화제를 사용하여 당업계에 공지된 기술에 따라 제조할 수 있다. 예를 들면, 각 성분을 식염수 또는 완충액에 용해시켜 주사용으로 제형화 할 수 있다. 또한， 경구 투여용 제형으로는 이에 한정되지는 않으나, 분말, 과립， 정제， 환약, 에멀견， 시럽 및 캡술 등이 있다. 또한， 본 발명의 알레르기 질환의 예방 또는 치료용 조성물은 약학적으로 허용 가능한 담체를 더 포함할 수 있다.  In addition, for parenteral administration, 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. For example, each component may be formulated for injection by dissolving in saline or buffer. In addition, oral dosage forms include, but are not limited to, powders, granules, tablets, pills, emulsion dogs, syrups, and capsules. In addition, the composition for preventing or treating allergic diseases of the present invention may further comprise a pharmaceutically acceptable carrier.
본 발명에서 용어， "약학적으로 허용가능한 담체"란 생물체를 상당히 자극하지 않고 투여 화합물의 생물학적 활성 및 특성을 저해하지 않는 담체 또는 희석제를 말한다 . 약학적으로 허용되는 담체로는 예를 들면 , 락토스， 전분， 셀를로스 유도체， 마그네슘 스테아레이트， 스테아르산 등과 같은 경구 투여용 담체， 및 물， 적합한 오일， 식염수， 수성 글루코스 및 글리콜 등과 같은 비경구 투여용 담체 등이 있다. 이러한 약학적으로 허용 가능한 담체는 식염수， 멸균수， 링거액， 완충 식염수， 덱스트로즈 용액， 말토 덱스트린 용액, 글리세롤, 에탄을 및 이들 성분 중 1성분 또는 1성분 이상올 흔합하여 사용할 수 있으며， 필요에 따라 부형제로서 안정화제， 보존제，' 항산화제, 완층액 및 정균제 등 다른 통상의 첨가제를 첨가할 수 있다.  As used herein, 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. As excipients, other conventional additives such as stabilizers, preservatives, antioxidants, complete solutions and bacteriostatic agents can be added.
【발명의 실시를 위한 형태】  [Form for implementation of invention]
이하, 본 발명을 실시예에 의해 상세히 설명한다. 단， 하기 실시예는 본 발명을 예시하는 것일 뿐， 본 발명이 하기 실시예에 의해 한정되는 것은 아니다. 제조예 1. Trp-Tyr-Val-Tyr— Pn)-Ser-Met서열로 이루어진 펩타이드 (dTBP2)의 합성
Figure imgf000026_0001
Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are merely to illustrate the invention, the present invention is not limited by the following examples. Preparation Example 1 Synthesis of Peptide (dTBP2) Consisting of Trp-Tyr-Val-Tyr—Pn) -Ser-Met Sequences
Figure imgf000026_0001
1. i) 20% piperidine,  I) 20% piperidine,
ii) Fmoc-Ser(tBu)-OH, HBTU, HOBt, DIPEA, DMF  ii) Fmoc-Ser (tBu) -OH, HBTU, HOBt, DIPEA, DMF
2. i) 20% piperidine,  2. i) 20% piperidine,
ii) Fmoc-Pro-OH, HBTU, HOBt, DIPEA, DMF  ii) Fmoc-Pro-OH, HBTU, HOBt, DIPEA, DMF
3. i) 20% piperidine,  I) 20% piperidine,
ii) Fmoc-Tyr(tBu)-OH, HBTU, HOBt, DIPEA, DMF  ii) Fmoc-Tyr (tBu) -OH, HBTU, HOBt, DIPEA, DMF
4. i) 20% piperidine,  I) 20% piperidine,
ii) Fmoc-Val-OH, HBTU, HOBt, DIPEA, DMF  ii) Fmoc-Val-OH, HBTU, HOBt, DIPEA, DMF
5. i) 20% piperidine,  5.i) 20% piperidine,
ii) Fmoc-Tyr(tBu)-OH, HBTU, HOBt, DIPEA, DMF  ii) Fmoc-Tyr (tBu) -OH, HBTU, HOBt, DIPEA, DMF
6. i) 20% piperidine,  6.i) 20% piperidine,
ii) Fmoc-Trp(Boc)-OH, HBTU, HOBt, DIPEA, DMF  ii) Fmoc-Trp (Boc) -OH, HBTU, HOBt, DIPEA, DMF
Figure imgf000026_0002
Figure imgf000026_0002
1-1. 왕 레진 (Wang Resin)LL 에서의 Fmoc-Met^OH로딩 (loading) 1-1. Fmoc-Met ^ OH loading at Wang Resin LL
필터가 설치된 20 mL T0RVIQ PP시린지 (syr inge)에 왕 레진 (Wang res in) LL ( 100-200 mesh , 300 mg, 0.44 mmol /g , 0. 13 議 ol )을 넣고 무수 다이메틸포름아마이드 (dimethyl formamide , DMF)를 넣어 30분간 팽윤시킨 후 배수하였다.  In a 20 mL T0RVIQ PP syringe with filter, Wang res in LL (100-200 mesh, 300 mg, 0.44 mmol / g, 0.13 μl ol) was added and anhydrous dimethylformamide (dimethyl) was added. formamide and DMF) were added and swelled for 30 minutes and then drained.
Fmoc ( F 1 LIO r eny 1 me t hy 1 oxy c ar bony 1 chlor ide)-Met-0H ( 10.0 당량， 483.0 mg, 1.3mmol)을 50 mL pear형 플라스크 (flask)에 넣고 아르곤 가스로 치환한 후,무수 다이클로로메탄 (CH2C12) (7 mL)와 무수 다이메틸포름아마이드 (DMF, 약 20방울)를 첨가하였다. DIC(5.0당량， O.lmL, 0.65誦 ol)를 상기 흔합물에 첨가한 후 0°C에서 20분간 교반하였다. 상온에서 감압 증류한 후 남은 suspension을 최소량의 무수 DMF (7.0mL)에 녹이고， DMAP (0.1당량， 1.6 mg, 0.013隱 ol)을 무수 DMF (0.1 mL)에 녹여서 두 용액을 순서대로 팽윤 시킨 레진에 첨가하여 상온에서 1시간 동안 회전형 진탕기 (orbital shaker , 130 r.p.m.)를 사용하여 흔합하고 용매를 배수한 후 DMF, iPrOH와 CH2C12로 세척하였다 (각각 10 mL x 1 min x 3). UV 분광측정 (Spectrometry)을 이용하여 standard Fmoc 정량 (quantification)을 실시하여 loading level을 확인하였다 (99.9%). 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 μL) was added to the mixture and stirred at 0 ° C. for 20 min. After distillation under reduced pressure at room temperature, the remaining suspension is dissolved in a minimum amount of anhydrous DMF (7.0 mL), DMAP (0.1 equivalent, 1.6 mg, 0.013 μl) is dissolved in anhydrous DMF (0.1 mL), and the two solutions are sequentially poured into a resin. The mixture was mixed with a rotary shaker (orbital shaker, 130 rpm) for 1 hour at room temperature, and the solvent was drained and washed with DMF, iPrOH, and CH 2 C1 2 (10 mL × 1 min × 3, respectively). The loading level was confirmed by performing standard Fmoc quantification using UV spectrometry (99.9%).
1-2. Fmoc-base SPPS 1-2. Fmoc-base SPPS
Fmoc (Fluorenylmethyloxycar bony 1 chloride) 그룹을 제거하기 위해 상기 레진 (300 mg, 0.13画 ol)을 무수 DMF에 30분간 팽윤시킨 후, 20% piper idine/무수 DMF (6.0 mL, resin 100 mg당 2 mL)를 첨가하여 10분간 상온에서 orbital shaker (130 r.p.m.)를 사용하여 흔합하고 용매를 배수한 후 DMF, 1^01{와 (: (：12으로 세척하였다 (10 mL X 1 min 3). 30분간 aspirator를 사용하여 건조시킨 후 Kaiser test를 이용하여 반웅이 완결되었음을 확인하였다. Serine을 Methionine과 커플링 시키기 위해， HBTU(o-(benzotriazol-l-yl )-Ν,Ν,Ν' ,Ν' -tetramethyluronium After swelling the resin (300 mg, 0.13 μl) in anhydrous DMF for 30 minutes to remove the Fmoc (Fluorenylmethyloxycar bony 1 chloride) group, 20% piper idine / anhydrous DMF (6.0 mL, 2 mL per 100 mg resin) The mixture was mixed with an orbital shaker (130 rpm) at room temperature for 10 minutes, drained, and then washed with DMF, 1 ^ 01 {and (: (: 1 2 (10 mL X 1 min 3). after drying using aspirator it was confirmed that banung was completed using the Kaiser test to couple the ring and Methionine Serine, HBTU (o- (benzotriazol- l-yl) -Ν, Ν, Ν ', Ν' - tetramethyluronium
hexaf luorophosphate) (8.0 당량， 394.5 mg, 1.04 隱 ol), HOBt (Hydr oxybenzot r i azo 1 e ) . H20 (8.0 당량， 159.3 mg, 1.04 瞧 ol), Fmoc-Ser(tBu)-0H (8.0 당량， 398.8 mg, 1.04讓 ol)와 DIPEA (8.0 당량, 0.18 mL, 1.04 mmol)를 무수 DMF (6.0 mL)에 녹인 후 3분간 교반하여, DMF에 30분간 팽윤시킨 resin (300 mg, 0.13 mmol)에 첨가한 후 orbital shaker (130 r.p.m.)를 사용하여 2시간 동안 흔합시켰다. 2 시간 경과 후， 용매를 배수하고 DMF, iPrOH와 C C12으로 세척하였다 (각각 10 mL lmin x 3). 30분간 aspirator를 이용하여 건조시킨 후 Kaiser test를 이용하여 반웅이 완결되었음을 확인하였다. hexaf luorophosphate) (8.0 equivalents, 394.5 mg, 1.04 μl ol), HOBt (Hydr oxybenzot ri azo 1 e). H 2 0 (8.0 equiv, 159.3 mg, 1.04 μl ol), Fmoc-Ser (tBu) -0H (8.0 equiv, 398.8 mg, 1.04 μl ol) and DIPEA (8.0 equiv, 0.18 mL, 1.04 mmol) were dissolved in anhydrous DMF ( 6.0 mL), stirred for 3 minutes, added to resin (300 mg, 0.13 mmol) swollen for 30 minutes in DMF, and then mixed for 2 hours using an orbital shaker (130 rpm). After 2 hours, the solvent was drained and washed with DMF, iPrOH and C C1 2 (10 mL lmin × 3 each). After drying for 30 minutes using an aspirator, it was confirmed that reaction was completed using Kaiser test.
상기 보호기 제거 및 커플링 방법으로， Fmoc-Pr으 OH, Fmoc-Tyr (tBu)-OH, Fmoc-Val-OH, Fmoc-Tyr (tBu)-OH, 그리고 Finoc-Trp(Boc)— OH을 순서대로 커플링 하여 dTBP2, Trp-Tyr-Val-Tyr-Pr으 Ser— et을 합성하였다. Proline의 보호기인 Fmoc 그룹을 제거했을 때 와 proline 에 tyrosine을 커플링 하였을 때에는 Chloranil test 로 반웅이 완결되었음을 확인하였다. As the protecting group removal and coupling method, 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. When the Fmoc group, a proline protecting group, was removed and tyrosine was coupled to the proline, the reaction was confirmed by the Chloranil test.
1-3. 절단 (Cleavage) 1-3. Cleavage
상기 1-2에서 만들어진 펩타이드 (30mg, 0.013麵 ol)를 1 mL Micro Bio— Spin chromatography column에 넣은 후 , 20% piper idine/무수 DMF (0.6 mL)를 사용하여 Fmoc 그룹을 제거하고， degassed 94% TFA cocktail (TFA:H20:EDT:TIS, 94%：2.5%：2.5%：1 , 0.6 mL)를 첨가하여 상온에서 1시간 동안 반응시킨 후 여과하여 여액을 받았다. Resin을 다시 TFA 용액으로 세척하여 (0.3 tnL x 2) 그 여액을 받았다. 위 여액들을 합하여 증발기 (evaporator)를 이용하여 TFA를 제거한 후， 차가운 에테르 (ether)를 사용하여 3회 디캔테이션 (decantation)하였다. 이때 생성된 화합물의 손실을 막기 위해 원심 분리기를 이용하였으몌 건조시킨 후 semi-preparat ive HPLC (binary solvent system, solvent A: 0.1% TFA/H2O , solvent B: 0.1% TFA/CH3CN, 5- 73% B over 30 min)를 이용하여 분리하고 동결 건조한 후 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. Peptide (30mg, 0.013 麵 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. In this case, to prevent the loss of the produced compound using a centrifugal separator and dried, semi-preparative HPLC (binary solvent system, solvent A: 0.1% TFA / H 2 O, solvent B: 0.1% TFA / CH 3 CN, 5- 73% B over 30 min) was isolated and lyophilized to determine the compound produced by mass spectrometry (MS).
Trp-Tyr-Va 1 -Tyr-Pro-Ser-Met (dTBP2 ) Trp-Tyr-Va 1 -Tyr-Pro-Ser-Met (dTBP2)
Figure imgf000028_0001
Figure imgf000028_0001
99.9% purity. Rt 19.9 min. MALDI m/z calculated for C47H61N80iiS+ [M+H]' 945.42, found 945.58. 제조예 2. Acyl-Trp-Tyr-Val-Tyr-Pro— Ser-Met의 합성 99.9% purity. R t 19.9 min. MALDI m / z calculated for C 47 H 61 N 8 0iiS + [M + H] '945.42, found 945.58. Preparation Example 2 Synthesis of Acyl-Trp-Tyr-Val-Tyr-Pro— Ser-Met
결합 부위에 있어， NH2 말단과 중앙에 위치한 tyrosine 주변의 공간을 확인하기 위해 acid library를 만들어서， N¾ 말단을 아실화한 후 in situ로 스크리닝 하였고， 합성 방법으로는 solid phase protocol을 사용하였다. 1100(： 6 3661 ^ 11과 dTBP2는 S-S linker로 연결하여 합성하였고, 이러한 방법은 S-S 1 inker 가 DTT—Tris (Di thiothreitol-Tris(2-carboxyethyl )phosphine · HC1 ) buffer로 쉽게 끊어지고 또한 정제 과정 없이 바로 screening할 수 있기 때문에 유용하고 효과적인 실험 방법이다. 상기 방법을 이용하여 88 개의 NH2 말단이 아실화된 펩티도미메틱 화합물들을 96웰—필터플레이트 (filter plate)에서 아래와 같이 합성하였다. At the binding site, an acid library was created to identify the space around the NH 2 terminus and the central tyrosine. The N¾ 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. This method showed that SS 1 inker was easily broken by DTT—Tris (Di thiothreitol-Tris (2-carboxyethyl) phosphine · HC1) buffer It is a useful and effective experimental method because it can be screened immediately without using the above method, and 88 NH 2 terminal acylated peptidomimetic compounds were synthesized in 96-well-filter plate as follows.
Figure imgf000030_0001
Figure imgf000030_0001
경합측정 (competition assay)의 결과를 토대로, 화합물 4개를 선정하여 NHCH2CH2SH 가 붙어있지 않게 하는 방법으로， 즉 Fmoc-based solid phase peptide synthesisBased on the results of the competition assay, four compounds were selected to prevent the attachment of NHCH 2 CH 2 SH, ie Fmoc-based solid phase peptide synthesis
(SPPS) protocol 에 따라 개별적으로 재합성하여 정제하였다 (Scheme 2). Purification was performed separately by resynthesis according to the (SPPS) protocol (Scheme 2).
Sol id support 로서， Wang resin LL on polystyrene 을 선택하였고, DCC 를 사용하여 i½oc-Met-0H을 Fomc-methi on ine anhydride로 만든 후， DMAP을 촉매로 한 esterif ication으로 Fmoc-methionine 을 Wang resin 에 loading 하였다.  Wang Sol LL on polystyrene was selected for Sol id support, i½oc-Met-0H was converted to Fomc-methionine ine anhydride using DCC, and then Fmoc-methionine was loaded onto Wang resin by esterification with DMAP. It was.
HO '···'"¾¾-
Figure imgf000031_0001
HO '··· '" ¾¾-
Figure imgf000031_0001
1. f:l' 3-0¼ piperidine. 1.f: l ' 3-0¼ piperidine.
ii) Fmoc-Ser{'jBy>-OH, HCTU, HOBi, DIPEA, DMF ii) Fmoc-Ser { ' jBy> -OH, HCTU, HOBi, DIPEA, DMF
2. F) 30% pipertdine.  2. F) 30% pipertdine.
ii) Fmoc-Pro-OH. HCTU, HOBt. DIPEA, DMF  ii) Fmoc-Pro-OH. HCTU, HOBt. DIPEA, DMF
3. i'i 30% piperidifie. 3. i 'i 30% piperidifie.
ii) Fmoc-T r(tBu)-OH; HCTU, HOBL DIPEA DMF ii) Fmoc-T r (tBu) -OH ; HCTU, HOBL DIPEA DMF
) 30% piperidine,,  A) 30% piperidine ,,
i) Fmoc-Val-OH, HCTU, HOBt, DIPEA. DMF  i) Fmoc-Val-OH, HCTU, HOBt, DIPEA. DMF
j 30% piperidine.  j 30% piperidine.
i) Fmoc-TyritBui-OH,, HCTU, HOBt; DIPEA, DMF i) Fmoc-TyritBui-OH, HCTU, HOBt ; DIPEA, DMF
) 30% piperidins.  A) 30% piperidins.
i) Fmoc-Trpi.Boc^OH, HCTU. HOBt, DIPEA. DMF  i) Fmoc-Trpi. Boc ^ OH, HCTU. HOBt, DIPEA. DMF
Figure imgf000031_0002
이어서, HCTU 를 이용하여 dTBP2의 나머지 아미노산들을 순차적으로 붙여나갔으며, 각각의 커플링 전에 30% piperidine in DMF 를 사용하여 Fmoc 보호기를 제거하였다. Fmoc보호기의 제거와 아미노산 커플링 반웅이 잘 진행되었는지를， 매 st印 마다 Kaiser test 또는 Chloranil test 로 확인하였다. 4：개의 hit acids (isonicotinic acid, 2-methylhexanoic acid, a -cyano-4-hydroxy cinnamic acid, and 5-nitro-3-pyrazolecarboxyl ic acid) 커플링 반웅에는 PyBOP 을 이용하였으며， 1,2-ethanedi thiol and tr i isopropylsi lane (TIS) 을 함유하는 94% TFA를 사용하여 아미노산 잔기들의 보호기 (side— chain protecting그룹)들과 Wang resin 을 제거하였다. 마지막으로 HPLC 를 사용하여 분석하고 (analysis) 분리한 (purification) 후， 동결 건조하여 MALDI-T0F 로 물질을 확인하였다.
Figure imgf000031_0002
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. 4: PyBOP was used for coupling reactions of dog acids (isonicotinic acid, 2-methylhexanoic acid, a -cyano-4-hydroxy cinnamic acid, and 5-nitro-3-pyrazolecarboxyl ic acid), and 1,2-ethanedi thiol 94% TFA containing and tr i isopropylsi lane (TIS) was used to remove Wang resin and side-chain protecting groups of amino acid residues. Finally, the resultant was analyzed using HPLC, purified, purified and lyophilized to confirm the material by MALDI-T0F.
2-1. 2-메틸핵사노일- 트립토판-타이로신-발린-타이로신 -프를린-세린-메티오닌 (2-Methylhexanoyl-Trp-Ty r-Val-Tyr-Pro-Ser-Met)의 합성
Figure imgf000032_0001
2-1. Synthesis of 2-methylnucleosanyl-tryptophan-tyrosine-valine-tyrosine-prine-serine-methionine (2-Methylhexanoyl-Trp-Ty-Val-Tyr-Pro-Ser-Met)
Figure imgf000032_0001
상기 제조예 1의 dTBP2와 동일한 방법으로 Trp-Tyr-Val-Tyr-Pro-Ser-Met을 고체상으로 합성한 후, 펩타이드 -레진 (50 mg, 0.022讓 ol)를 30% piper idine/무수 DMF (1.0 mL)를 사용하여 Fmoc그룹을 제거하고, PyBOP (10.0당량, 114.5 mg, 0.22 隱 ol), H0Bt.H20 (10.0 당량， 33.7 mg, 0.22讓 ol), 2-Methylhexanoic acid (10.0 당량， 28.6 mg, 0.22瞧 ol)와醒 (20당량, 48.4 uL, 0.44讓 ol )를 무수 DMF (0.6 mL)에 녹인 후 3분간 교반하여， DMF에 30분간 팽윤시킨 resin (500 mg, 0.22 醒 ol)에 첨가한 후 orbital shaker (130 r.p.m.)를 사용하여 2시간 동안 흔합시켰다. 2 시간 경과 후, 2-Methylhexanoic acid 를 커플링 하였다. 이렇게 만들어진 레진 (50mg, 0.022隱 ol)을 필터가 설치된 3 mL T0RVIQ PP syr inge에 넣은 후, degassed 94% TFA cocktail (TFA:H20:EDT:TIS, 94%：2.5%：2.5%： 1%, 1.0 mL)를 첨가하여 상온에서 1시간 동안 반응시킨 후 여과하여 여액을 받았다. Resin을 다시 TFA 용액으로 세척하여 (0.5 mL X 2) 그 여액을 받았다. 위 여액들을 합하여 evaporator를 이용하여 TFA를 제거한 후, cold ether를 사용하여 3회 decan tion하였다. 이때 생성된 화합물의 손실을 막기 위해 원심 분리기를 이용하였으며， 건조시킨 早 semi -preparative HPLC (binary solvent system, solvent A: 0.1% TFA/H20, solvent B: 0.1% TFA/CH3CN, 5- 100% B over 30 min )를 이용하여 분리하고 동결 건조한 후 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다 (84.1% Purity. Rt 20.5min. MALDI m/z calcd for C54H72N8Na0i2S+ [M+Na]+ 1079.49, found 1079.50.). Synthesis of 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 讓 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 μl ol), H0Bt.H 2 0 (10.0 equiv, 33.7 mg, 0.22 μl ol), 2-Methylhexanoic acid (10.0 equiv, 28.6 mg, 0.22 瞧 ol) and 醒 (20 equivalents, 48.4 uL, 0.44 讓 ol) were dissolved in anhydrous DMF (0.6 mL), stirred for 3 minutes, and swelled in DMF for 30 minutes (500 mg, 0.22 醒 ol) After addition to the mixture was mixed for 2 hours using an orbital shaker (130 rpm). After 2 hours, 2-Methylhexanoic acid was coupled. The resin (50 mg, 0.022 μl) thus prepared was added to a 3 mL T0RVIQ PP syr inge equipped with a filter, followed by degassed 94% TFA cocktail (TFA: H 2 0: EDT: TIS, 94% ： 2.5% ： 2.5% ： 1 %, 1.0 mL) After addition, the mixture was reacted at room temperature for 1 hour and filtered to obtain a filtrate. R es i n was again washed with TFA solution (0.5 mL X 2) to receive the filtrate. The filtrates were combined to remove TFA using an evaporator and then decanted three times using cold ether. In this case, centrifuge was used to prevent the loss of the compound, and dried 早 semi-preparative HPLC (binary solvent system, solvent A: 0.1% TFA / H 2 0, solvent B: 0.1% TFA / CH 3 CN, 5 100% B over 30 min) was isolated and freeze-dried to identify the produced compound by mass spectometry (MS) (84.1% Purity.R t 20.5min.MALDI m / z calcd for C 54 H 72 N 8 Na0i 2 S + [M + Na] + 1079.49, found 1079.50.).
2-2. 2-2.
이소니코티닐―트립토판 -타이로신 -발린 -타이로신 -프를린-세린-메티오닌 (Isonicot i nyl-Tr - Tyr-Val-Tyr-Pro-Ser-Met ) 의 합성 Synthesis of Isonicotinyl-Tryptophan-Tyrosine-Valine-Tyrosine-Princeline-serine-Methionine
WYVYPSMWYVYPSM
Figure imgf000033_0001
Figure imgf000033_0001
상기 2-1과 동일한 방법을 이용하여 합성하였으며, 산 (acid)으로 isonicotinic acid를 사용하여 커플링 하였으며, 합성 후 질량분석계 (mass spectometry, MS)로 생성된 화합물올 확인하였다 (94.3% Purity. Rt 15.9 min. MALDI m/z calculated for C53H63N9Na0i2S+ [M+Na]+ 1072.42, found 1072.41.). 2-3. 알파-시아노 -4-하이드록시신나밀- 트립토판-타이로신-발린-타이로신 -프를린-세린-메티오닌 ( a-CyaiK)-4-hydroxycinna myl-Trp-Tyr-Val-Tyr-Pro-Ser-Met) 의 합성 WYVYPSM Synthesis was carried out using the same method as in the above 2-1, the acid was coupled using isonicotinic acid, and the compound was confirmed by mass spectometry (MS) after synthesis (94.3% Purity.R t 15.9 min.MALDI m / z calculated for C 53 H 63 N 9 Na0i 2 S + [M + Na] + 1072.42, found 1072.41.). 2-3. Alpha-cyano-4-hydroxycinnamil-tryptophan-tyrosine-valine-tyrosine-plin-serine-methionine (a-CyaiK) -4-hydroxycinna myl-Trp-Tyr-Val-Tyr-Pro-Ser- Synthesis of Met) WYVYPSM
상기 2-1과 동일한 방법을 이용하여 합성하였으며， 산 (acid)으로 a -Cy ano-4-hydr oxy c i nnam i c acid를 사용하여 커플링 하였으며, 합성 후 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다 (99.2 % Pur ity. Rt 19.3 min. MALDI m/z calculated for C57H65N9Na0i3S+ [M+Na]+ 1138.43, found 1138.37.). Synthesis was carried out using the same method as described above in 2-1, and a coupling was performed using a -Cy ano-4-hydroxy oxy ci nnam ic acid as an acid, followed by mass spectrometry (MS). The obtained compound was identified (99.2% Purity. R t 19.3 min. MALDI m / z calculated for C 57 H 65 N 9 Na0i 3 S + [M + Na] + 1138.43, found 1138.37.).
2-4. 5-니트로 -3-피라졸카복실일— 트립토판-타이로신 -발린 -타이로신—프를린-세린-메티오닌 (5-Nitro-3-pyrazolecarbo xylyl-T 합성 2-4. 5-nitro-3-pyrazolcarboxylyl-tryptophan-tyrosine-valine-tyrosine-prine-serine-methionine (5-Nitro-3-pyrazolecarbo xylyl-T synthesis
Figure imgf000034_0001
Figure imgf000034_0001
5  5
상기 2-1과 동일한 방법을 이용하여 합성하였으며, 산 (acid)으로 5-nitro-3-pyrazolecarboxylic acid를 사용하여 커플링 하였으며， 합성 후 질량분석계 (mass spectometry, MS)로 화합불을 확인하였다 (85.3% Purity. Rt 19.0 min. MALDI m/z calculated for C51H6iNuNa0i4S+ [M+Na]+ 1106.41, found 1106.40.). 제조예 3. Isonicotinyl-Trp— Tyr-Val-Dpr(acyl)-Pro— Ser— Met의 합성 Synthesis was carried out using the same method as in the above 2-1, and coupling was performed using 5-nitro-3-pyrazolecarboxylic acid as an acid. After synthesis, the compound was confirmed by mass spectometry (MS) ( 85.3% Purity.R t 19.0 min.MALDI m / z calculated for C 51 H 6 iN u Na0i 4 S + [M + Na] + 1106.41, found 1106.40.). Preparation Example 3 Synthesis of Isonicotinyl-Trp—Tyr-Val-Dpr (acyl) -Pro— Ser— Met
NH2 말단의 추가 binder를 확인한 후, 알라닌 스캐닝 돌연변이유발 (alanine scanning mutagenesis) 의 결과에 따라 약한 결합력을 갖는 타이로신 (tyrosine) 부분에 변화를 주었다. 결합력을 높이기 위해 타이로신 (tyrosine) 위치에 링커 ( nker)를 도입하기로 결정하고， 이를 디아민 (Diamine) 중 하나의 아민 (amine)이 4—메틸트리틸 (4-Methyltrityl， Mtt) 그룹으로 보호되어 있는 디아미노프로피오닉 산 (Diaminoprop ionic acid) (Fmocᅳ Dpr(Mtt )ᅳ OH)으로 바꾸었다. 4-메틸트리틸 (4-Methyltrityl, Mtt) 그룹은 1% TFA in CH2C12 와 같은 온화한 산 조건에서 쉽게 제거될 수 있다. 제거 조건을 확립하기 위해， 동일 조건의 탈보호 과정을 5회 반복하면서 각각의 여과액에 남아있는 MU-0H 의 양을 HP1X 로 확인하였다 (Figure 8). 이때 내부 표준 물질 (internal standard)로서 디부틸에테르 (Butylated hydroxytoluene, BHT,After checking the additional binder at the NH 2 end, the tyrosine moiety with weak binding force was changed according to the result of alanine scanning mutagenesis. In order to increase the binding force, it is decided to introduce a linker (nker) at the tyrosine position, which is one of the diamines. The amine was changed to Diaminoprop ionic acid (Fmoc Dpr (Mtt) ᅳ 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 . To establish the removal condition, the same amount of MU-0H remaining in each filtrate was confirmed by HP1X while repeating the same deprotection process five times (Figure 8). At this time, dibutyl ether (Butylated hydroxytoluene, BHT,
2，6-^-^기—13^ 1-4ᅳ111^1^11)11∞01)를 첨가하였다. 5회 절단하였을 때， Mtt-OH는 각각 61.7%, 28.6%, 8.5%, 1.1%, 0.1%가 제거되었음을 확인할 수 있었으며, 제거율은 내부표준 (internal standard), BHT의 면적에 대한 비율로서 측정하였다 (표 2). 그 결과 로 3번 처리하면 아미노산 잔기들의 보호기 (protecting 그룹)들은 유지하면서 98.8%의 Mtt그룹이 선택적으로 제거됨을 확인할 수 있었다. 이때 떨어져 나온 Mtt 그룹 의 양이온 (cation)을 안정화하기 위해 1% TFA 용액에 TIS (triisopropylsilane)( Sigma-Aldr ich) 를 넣어주었다. 2,6-^-^ group—13 ^ 1-4 ᅳ 111 ^ 1 ^ 11) 11 ∞ 01) were added. When cut 5 times, Mtt-OH was confirmed that 61.7%, 28.6%, 8.5%, 1.1%, 0.1% were removed, respectively, the removal rate was measured as the ratio of the area of the internal standard (BHT), BHT. (Table 2). As a result, it was confirmed that three treatments selectively remove 98.8% of the Mtt group while maintaining the protecting groups of the amino acid residues. At this time, TIS (triisopropylsilane) (Sigma-Aldr ich) was added to the 1% TFA solution to stabilize the cation of the separated Mtt group.
[표 2]  TABLE 2
내부 표준 물질과 비교한 MU 보호기의 제거율.  Removal rate of MU protector compared to internal standard.
Figure imgf000035_0001
Figure imgf000035_0001
[a] Intergration was calculated based on internal standard (BHT)  [a] Intergration was calculated based on internal standard (BHT)
Mtt 보호기의 선택적 제거 방법을 확립한 후， 왕 레진 (Wang resin) 을 이용한 Fmoc-based SPPS 방법으로 합성하였다. 생산성을 높이기 위해 일부 실험 조건, 즉 커플링 reagents및 이들의 당량， 반웅 시간 등을 조정하였다. 특히 HCTU 또는 PyBOP 대신에 HBTU 사용하였는데， HBTU 를 사용하였을 때 부산물이 적게 생기는 것을 HPLC 시스템 상에서 확인할 수 있었기 때문이다. After establishing the selective removal method of the Mtt protecting group, it was synthesized by Fmoc-based SPPS method using Wang resin. Some experimental conditions, such as coupling reagents and their equivalents and reaction times, were adjusted to increase productivity. In particular, HBTU was used instead of HCTU or PyBOP. This was because it was confirmed on the HPLC system.
Met , Ser, Pro, Fmoc-Dpr (Mtt )-0H, Val, Tyr, Trp, 및 이소니코티닉산 (isonicotinic acid), 8개의 잔기들을 순차적으로 왕 레진 (Wang resin)에 로딩 ( loading)한 후, Dpr 잔기의 Mtt 그룹을 1% TFA & 5"¾ TIS in CH2C12 로 처리하여 제거하고， 보호기가 제거된.아민을 44개의 acids로 아실화하였다. 이어서 펩타이드의 모든 보호기와 resin 을 94% TFA 로 처리하여 제거한 후, 합성된 화합물들을 HPLC 로 분석하였다. HPLC 상에서 두 개의 peak 가 관찰되었고， MALDI— TOF 로 확인한 결과， 앞의 peak는 Met의 황이 산화된 화합물의 것이고， 뒤의 peak는 산화되지 않은， 화합물 이었다. Met, Ser, Pro, Fmoc-Dpr (Mtt) -0H, Val, Tyr, Trp, and isonicicotinic acid, eight residues sequentially loaded into Wang resin The Mtt group of the Dpr residue was removed by treatment with 1% TFA & 5 "¾ TIS in CH 2 C1 2 , and the deprotected.amine was acylated with 44 acids. After removal by treatment with% TFA, the synthesized compounds were analyzed by HPLC.Two peaks were observed on HPLC, and MALDI—TOF confirmed that the previous peak was from a sulfur-oxidized compound of Met, and the latter peak was It was a compound that was not oxidized.
Figure imgf000037_0001
Figure imgf000037_0001
상기와 같은 방법으로 모두 82개의 화합물을 합성하였으며 (6 내지 87)， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고， 일부 화합물에 대해서는 ¾ NMR를 이용하여 추가로 확인하였다. All 82 compounds were synthesized by the same method as described above (6 to 87), and the compounds produced by mass spectrometry (MS) were identified, and some compounds were further confirmed by using ¾ NMR.
3- 이소니코티닐-트립토판 -타이로신-발린- (3 , 5-디메틸벤조일：) -프롤린-세린-메티 오닌 산화형 (Isonicotinyl-Trp-Tyr-Val-Dpr(3,5-dimethylbenzoyl)-3-isonicotinyl-tryptophan-tyrosine-valine- (3,5-dimethylbenzoyl:)-proline-serine-methionine oxidative type (Isonicotinyl-Trp-Tyr-Val-Dpr (3,5-dimethylbenzoyl)-
Pro-Ser-Met(O)) Pro-Ser-Met (O))
Figure imgf000038_0001
Figure imgf000038_0001
제조예 1의 dTBP2 합성과 동일한 방법으로 이소니코티닐-트립토판 -타이로신 -발린 -Dpr (3 , 5-디메틸벤조일 ) -프를린-세린-메티 오닌을 고체상으로 합성한 후， Diaminopropionic acid의 보호기를 제거하기 위해 필터가 설치된 1 mL Micro Bio-Spin chromatography column에 resin (25mg, 0.011 mmol)을 넣고 CH2C12 에 30분간 팽윤시킨 후, 아르곤 가스 압력을 이용하여 CH2C12 을 제거하고， 여기에 degassed 1% TFA (TFA:TIS:DCM, 1:5:94， 0.66 mL)를 첨가한 후 2분간 orbital shaker (130 r.p.m.)를 사용하여 흔합하고， 아르곤 가스 압력을 이용하여 1% TFA 용액을 제거하였으며, 이 과정을 3회 반복하였다. 반웅이 끝난 resin을 C C12으로 3회, 무수 DMF로 1회 세척한 후, 무수 DMF로 30분간 팽윤시켰다. Synthesis of isonicotinyl-tryptophan-tyrosine-valine-Dpr (3,5-dimethylbenzoyl) -prine-serine-methionine in the solid phase in the same manner as in the synthesis of dTBP2 of Preparation Example 1, followed by protecting groups of diaminopropionic acid in 1 mL Micro Bio-Spin chromatography column filter is installed in order to remove resin (25mg, 0.011 mmol) were dissolved after 30 minutes swollen in CH 2 C1 2, by using the argon gas pressure to remove the CH 2 C1 2, and here 1% TFA (TFA: TIS: DCM, 1: 5: 94, 0.66 mL) was added to the mixture, followed by mixing using an orbital shaker (130 rpm) for 2 minutes and argon gas pressure to prepare a 1% TFA solution. The procedure was repeated three times. After the reaction was completed, the resin was washed three times with C C1 2 and once with anhydrous DMF, and then swelled with anhydrous DMF for 30 minutes.
디아미노프로피오닉 산 (Diaminopropionic acid) 의 Mtt 그룹이 제거된 아민에 3,5-dimethylbenzoic acid를 커플링 시키기 위해, HBTU (8.0당량, 33.4 mg, 0.088 mmol), HOBt .¾0 (8.0당량， 13.5 mg, 0.088瞧 ol), 3,5-dimethylbenzoic acid (8.0 당량， 13.2 mg, 0.088匪 ol), DIPEA (8.0 당량， 15.4yL, 0.088 睡 ol )와 무수 DMF (0.5 mL)흔합액을 사용하여 제조예 1-2 방법에 따라 커폴링 하였다. 이렇게 만들어진 펩타이드 (25 mg, 0.011瞧 ol)에 degassed 94% TFA cocktail (0.5 mL)를 첨가하여 상온에서 1시간 동안 흔합한 후 여과하여 여액을 받고，다시 TFA(0.3mL X 2)로 세척하여 그 여액을 받았다. 위 여액들을 합하여 evaporator를 이용하여 TFA를 제거한 후 cold ether를 사용하여 3회 decant at ion하였다. 이 때 생성된 화합물의 손실을 막기 위해 원심 분리기를 이용하였으며， high vacciim dry 후 semi -preparative HPLC (binary solvent system, solvent A: 0.1% TFA/H20 , solvent B: 0.1% TFA/CH3CN, 5- 100% B over 42 min)를 이용하여 분리 및 정제하고 동결 건조한 후 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고, ¾ NMR를 이용하여 추가로 확인하였다. HBTU (8.0 equiv, 33.4 mg, 0.088 mmol), HOBt .¾0 (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 μl), 3,5-dimethylbenzoic acid (8.0 equivalents, 13.2 mg, 0.088 μl), DIPEA (8.0 equivalents, 15.4yL, 0.088 μl) and anhydrous DMF (0.5 mL) Coupling was carried out according to the 1-2 method. like this Degassed 94% TFA cocktail (0.5 mL) was added to the prepared peptide (25 mg, 0.011 瞧 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. In this case, centrifuge was used to prevent the loss of compound, semi-preparative HPLC (binary solvent system, solvent A: 0.1% TFA / H 2 0, solvent B: 0.1% TFA / CH 3 CN) after high vacciim dry , 5-100% B over 42 min) was isolated, purified and freeze-dried to confirm the compound produced by mass spectrometry (MS), it was further confirmed using ¾ NMR.
97.0% Purity. Rt 22.6 min. ¾ NMR (400 MHz, DMS0-i6) : δ 10.73 (d, 1H, J97.0% Purity. R t 22.6 min. ¾ NMR (400 MHz, DMS0-i 6 ): δ 10.73 (d, 1H, J
= 2.0), 9.10 (s, 1H), 8.78 (d, 1H, J = 8.4)， 8.67 (dd, 2H, J = 4.4， J = 1.6)， 8.33 (t, 1H, J = 6.0), 8.21 (d, 2H, J= 8.0)， 8.06 (dd, 1H, J= 7.6， J= 3.6)， 8.00 (dd, 1H, J = 7.6， J 3.2), 7.80 (d, 1Hᅳ J = 8.4), 7.65 (d, 1H, J= 8.0), 7.63 (dd, 2H, J 4.4, J= 1.6), 7.45 (s, 2H), 7.29 (d, 1H, J 8.0), 7.14 (d, 1H, J 2.0)， 7.13 (s, 1H), 7.03 (t, 1H, J= 8.0), 7.01 (d, 2H, /= 8.4), 6.95 (t, 1H, / = 8.0), 6.57 (d, 2H, J = 8.4)， 4.75- 4.67 (m, 2H), 4.52 (td, 1H, J = 8.4, J = 4.0), 4.42 (m, 1H) , 4.31- 4.25 (m, 2H)， 4.21 (dd, 1H, J = 8.4， J = 7.2 )' 3.68- 3.54 Cm, 4H), 3.47 (m, 1H) , 3.38- 3.23 Cm, 2H) , 3.15 (dd, 1H, J = 14.4, J = 4.0), 3.05 (dd, 1H, J = 14.4, J 10.4), 2.91 (dd, 1H, J = 13.6, /= 4.0)， 2.80- 2.57 (m, 3H) , 2.51 (s, 3H), 2.27 (s, 6H) , 2.13- 1.86 (m, 5H), 1.84- 1.79 (m, 2H) , 0.84 (d, 3H, / = 6.8), 0.81 (d, 3H, J = 6.8). MALDI m/z calculated for C56H68N10Na0i3S+ [M+Na]+ 1143.46, found 1143.43. = 2.0), 9.10 (s, 1H), 8.78 (d, 1H, J = 8.4), 8.67 (dd, 2H, J = 4.4, J = 1.6), 8.33 (t, 1H, J = 6.0), 8.21 ( d, 2H, J = 8.0), 8.06 (dd, 1H, J = 7.6, J = 3.6), 8.00 (dd, 1H, J = 7.6, J 3.2), 7.80 (d, 1H ᅳ J = 8.4), 7.65 (d, 1H, J = 8.0), 7.63 (dd, 2H, J 4.4, J = 1.6), 7.45 (s, 2H), 7.29 (d, 1H, J 8.0), 7.14 (d, 1H, J 2.0) ， 7.13 (s, 1H), 7.03 (t, 1H, J = 8.0), 7.01 (d, 2H, / = 8.4), 6.95 (t, 1H, / = 8.0), 6.57 (d, 2H, J = 8.4 ), 4.75- 4.67 (m, 2H), 4.52 (td, 1H, J = 8.4, J = 4.0), 4.42 (m, 1H), 4.31- 4.25 (m, 2H), 4.21 (dd, 1H, J = 8.4, J = 7.2) '3.68- 3.54 Cm, 4H), 3.47 (m, 1H), 3.38- 3.23 Cm, 2H), 3.15 (dd, 1H, J = 14.4, J = 4.0), 3.05 (dd, 1H , J = 14.4, J 10.4), 2.91 (dd, 1H, J = 13.6, / = 4.0), 2.80-2.57 (m, 3H), 2.51 (s, 3H), 2.27 (s, 6H), 2.13- 1.86 (m, 5H), 1.84- 1.79 (m, 2H), 0.84 (d, 3H, / = 6.8), 0.81 (d, 3H, J = 6.8). MALDI m / z calculated for C 56 H 68 N 10 Na0i 3 S + [M + Na] + 1143.46, found 1143.43.
3-2. 3-2.
이소니코티닐-트립토판-타이로신 -발린 -Dpr(3, 5-디메틸벤조일) -프를린 -세린 -메티 오닌 비산화형 (Isonicotinyl-Trp-Tyr-Val-Dpr(3,5-dimethylbenzoyl)-Isicotinyl-tryptophan-tyrosine-valine-Dpr (3,5-dimethylbenzoyl) -prine-serine-methionine non-oxidation type (Isonicotinyl-Trp-Tyr-Val-Dpr (3,5-dimethylbenzoyl)-
Pro-Ser-Met )
Figure imgf000040_0001
Pro-Ser-Met)
Figure imgf000040_0001
상기 3-1과 동일한 방법으로 합성하였으며, 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고， NMR를 이용하여 추가로 확인하였다.  Synthesis was carried out in the same manner as in 3-1, the compound produced by mass spectrometry (MS) was confirmed, and further confirmed by NMR.
98.0% Purity. Rt 24.8 min. ¾ NMR (400 MHz, DMS0_/6) : δ 12.70 (brs, 1H) , 10.73 (d, 1H, /= 2.0), 9.10 (brs, 1H), 8.82 (d, 1H, J= 8.8)， 8.70 (d, 2H, J = 5.6), 8.32 (t, 1H, /= 6.4), 8.22 (d, 1H, /= 8.0), 8.20 (d, 1H, J= 6.8), 8.08 (d, 1H, /= 8.0), 7.93 (d, 1H, J = 8.0)， 7.79 (d, 1H, J = 8.4), 7.68 (dd, 2H, J = 5.6, J = 1.6), 7.66 (d, 1H, J = 8.0), 7.45 (s, 2H)， 7.29 (d, 1H, J = 8.0), 7.14 (d, 1H, J 2.0), 7.13 (s, 1H), 7.03 (t, 1H, J= 8.0), 7.01 (d, 2H, J= 8.4), 6.95 (t, 1H, J 8.0), 6.57 (d, 2H, J= 8.4)， 4.73 (m, 1H), 4.66 (q, 1H, J= 6.8), 4.52 (td, 1H, J= 8.8, J = 4.0), 4.43 (dd, 1H, J= 8.0， J = 4.0), 4.34- 4.28 (m, 2H) , 4.20 (dd, 1H, J= 8.4， J= 7.2)， 3.63— 3.43 (m, 7H) , 3.16 (dd, 1H, J = 14.8， J 4.0), 3.05 (dd, 1H, J= 1.4.8, J = 10.8)， 2.91 (dd, 1H, J= 14.0, /= 4.0), 2.72 (dd, 1H, /= 14.0, J= 9.6)， 2.52- 2.38 (m, 2H), 2.27 (s, 6H), 2.07- 1.75 (m, 7H), 2.00 (s, 3H), 0.84 (d, 3H, 6.8), 0.82 (d, 3H, J= 6.8). MALDI m/z calculated for C56H68N10NaO12S+ [M+Na]+ 1127.46, found 1127.43. 98.0% Purity. R t 24.8 min. ¾ NMR (400 MHz, DMS0_ / 6 ): δ 12.70 (brs, 1H), 10.73 (d, 1H, / = 2.0), 9.10 (brs, 1H), 8.82 (d, 1H, J = 8.8), 8.70 ( d, 2H, J = 5.6), 8.32 (t, 1H, / = 6.4), 8.22 (d, 1H, / = 8.0), 8.20 (d, 1H, J = 6.8), 8.08 (d, 1H, / = 8.0), 7.93 (d, 1H, J = 8.0), 7.79 (d, 1H, J = 8.4), 7.68 (dd, 2H, J = 5.6, J = 1.6), 7.66 (d, 1H, J = 8.0) , 7.45 (s, 2H), 7.29 (d, 1H, J = 8.0), 7.14 (d, 1H, J 2.0), 7.13 (s, 1H), 7.03 (t, 1H, J = 8.0), 7.01 (d , 2H, J = 8.4), 6.95 (t, 1H, J 8.0), 6.57 (d, 2H, J = 8.4), 4.73 (m, 1H), 4.66 (q, 1H, J = 6.8), 4.52 (td , 1H, J = 8.8, J = 4.0), 4.43 (dd, 1H, J = 8.0, J = 4.0), 4.34- 4.28 (m, 2H), 4.20 (dd, 1H, J = 8.4, J = 7.2) , 3.63— 3.43 (m, 7H), 3.16 (dd, 1H, J = 14.8, J 4.0), 3.05 (dd, 1H, J = 1.4.8, J = 10.8) ， 2.91 (dd, 1H, J = 14.0 , / = 4.0), 2.72 (dd, 1H, / = 14.0, J = 9.6), 2.52- 2.38 (m, 2H), 2.27 (s, 6H), 2.07-1.75 (m, 7H), 2.00 (s, 3H), 0.84 (d, 3H, 6.8), 0.82 (d, 3H, J = 6.8). MALDI m / z calculated for C 56 H 68 N 10 NaO 12 S + [M + Na] + 1127.46, found 1127.43.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (알파-시아노 -4-하이드록시신나밀 ) -프 를린-세린-메티오닌 산화형 (Isonicotinyl-Trp-Tyr-Val-Dpr ( a- cyano -4ᅳ hydroxy ci nnamy 1 )-Pro-Ser-Met (0) )
Figure imgf000041_0001
상기 3—1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 알파一시아노一 4一하이드록시신남산 ( Q -cyano-4-hydr oxyc i nnam i c acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고， ¾ MR를 이용하여 추가로 확인하였다. 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))
Figure imgf000041_0001
A was synthesized using the same method as 3-1, with an acid (acid) for coupling the alpha-cyano一一一4 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 ¾ MR.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (알파-시아노 -4-하이드록시신나밀 ) -프 를린-세린-메티오닌 비산화형 (Isonicotinyl-Trp-Tyr-Val-Dpr ( a -cyano -4-hydr ox c i nnamy 1 )— Pro—Ser— Met ) Isicotinyl-tryptophan-tyrosine-valine-Dpr (alpha-cyano-4-hydroxycinnamil) -prine-serine-methionine non-oxidized (Isonicotinyl-Trp-Tyr-Val-Dpr (a -cyano -4- hydr ox ci nnamy 1) — Pro—Ser— Met)
Figure imgf000041_0002
Figure imgf000041_0002
상기 3-3과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고, ¾ NMR를 이용하여 추가로 확인하였다.  Synthesis was carried out in the same manner as in the above 3-3, the compound produced by mass spectrometry (MS) was confirmed, and further confirmed by ¾ NMR.
99.9% Purity. Rt 19.3 min. ¾ NMR (400 MHz, DMSOi/6): δ 12.73 (brs, 1H), 10.73 (s, 1H), 10.59 (brs, 1H), 9.10 (brs, 1H), 8.80 (d, 1H, 7= 8.0), 8.69 (d, 2H, J 4.4), 8.28- 8.22 (m, 2H) , 8.18 (d, 1H, J = 6.8)， 8.10 (s, 1H), 8.04 (d, 1H, / = 7.6)， 7.91 (d, 1H, J = 7.6), 7.86 (d, 2H, / = 8.8), 7.81 (d, 1H, / = 8.8), 7.67- 7.65 (m, 3H) , 7.29 (d, 1H, J = 8.0)， 7.14 (d, 1H, J = 2.0)， 7.04 (t, 1H, J 8.0)， 7.01 (d, 2H, J = 8.4)， 6.95 (t, 1H, J = 8.0)， 6.91 (d, 2H, J = 8.8)， 6.57 (d, 2H, J 8.4), 4.75- 4.67 (m, 2H), 4.52 (m, 1H)， 4.40 (dd, 1H, J 8.0, J = 3.6), 4.34 (m, 1H), 4.27 (m, 1H), 4.20 (dd, 1H, J = 8.8， J = 6.8), 3.64- 3.35 (m, 7H), 3.15 (dd, 1H, J= 15.2, J= 3.6), 3.05 (dd, 1H, J 15.2, J 10.4)， 2.92 (dd, 1H, J = 14.0， J = 4.4)， 2.73 (dd, 1H, J = 14.0, J = 10.4), 2.52- 2.38 (m, 2H), 2.03 (s, 3H), 2.02- 1.93 (m, 3H), 1.91-1.75 (m, 4H), 0.85 (d, 3H, J = 6.8), 0.82 (d, 3H, J = 6.8). MALDI m/z calculated for C57H65N11Na013S+ [M+Na]+ 1166.44， found 1166.38. 99.9% Purity. R t 19.3 min. ¾ NMR (400 MHz, DMSOi / 6 ): δ 12.73 (brs, 1H), 10.73 (s, 1H), 10.59 (brs, 1H), 9.10 (brs, 1H), 8.80 (d, 1H, 7 = 8.0) , 8.69 (d, 2H, J 4.4), 8.28- 8.22 (m, 2H), 8.18 (d, 1H, J = 6.8), 8.10 (s, 1H), 8.04 (d, 1H, / = 7.6), 7.91 (d, 1H, J = 7.6), 7.86 (d, 2H, / = 8.8), 7.81 (d, 1H, / = 8.8), 7.67-7.65 (m, 3H), 7.29 (d, 1H, J = 8.0 ), 7.14 (d, 1H, J = 2.0), 7.04 (t, 1H, J 8.0), 7.01 (d, 2H, J = 8.4), 6.95 (t, 1H, J = 8.0), 6.91 (d, 2H , J = 8.8), 6.57 (d, 2H, J 8.4), 4.75- 4.67 (m, 2H), 4.52 (m, 1H), 4.40 (dd, 1H, J 8.0, J = 3.6), 4.34 (m, 1H), 4.27 (m, 1H), 4.20 (dd, 1H, J = 8.8, J = 6.8), 3.64- 3.35 (m, 7H), 3.15 (dd, 1H, J = 15.2, J = 3.6), 3.05 (dd, 1H, J 15.2, J 10.4), 2.92 (dd, 1H, J = 14.0, J = 4.4), 2.73 (dd, 1H, J = 14.0, J = 10.4), 2.52- 2.38 (m, 2H), 2.03 (s, 3H), 2.02- 1.93 (m, 3H), 1.91-1.75 (m , 4H), 0.85 (d, 3H, J = 6.8), 0.82 (d, 3H, J = 6.8). MALDI m / z calculated for C 57 H 65 N 11 Na 0 13 S + [M + Na] + 1166.44, found 1166.38.
3-5. 3-5.
이소니코티닐-트립토판-타이로신 -발린 -Dpr(4-펜틸바이사이클로 [2.2.2]옥테인 -1- 카복실일 )-프를린—세린-메티오닌 산화형 (Isonicotinyl-Trp-Tyr-Val-Isicotinyl-tryptophan-tyrosine-valine-Dpr (4-pentylbicyclo [2.2.2] octane-1-carboxyl) -prine-serine-methionine oxidic type (Isonicotinyl-Trp-Tyr-Val-
Dpr (4-penty 1 bi eye 1 o [2.2.2] octane— l—carboxylyl )—Pr o— Ser— Met (0)) Dpr (4-penty 1 bi eye 1 o [2.2.2] octane— l—carboxylyl) —Pr o— Ser— Met (0))
Figure imgf000042_0001
Figure imgf000042_0001
상기 3-1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 4-펜틸바이사이클로 [2.2.2]옥테인-1-카복실산셰6 11) 010 [2.2.2] octane-l-carboxylic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고， NMR를 이용하여 추가로 확인하였다. Synthesis was carried out using the same method as described in 3-1, and 4-pentylbicyclo [2.2.2] octane-1-carboxylic acid 6 6 ) 010 [2.2.2] octane- as an acid for coupling. l-carboxylic acid) was used. Compounds produced by mass spectometry (MS) were identified, and further confirmed using NMR.
99.9% Purity. Rt 27.2 min. ¾ NMR (400 MHz, DMS0-i/6): δ 12.86 (brs, 1H), 10.73 (s, 1H), 9.09 (brs, 1H) , 8.82 (d, 1H, J = 8.4), 8.70 (dd, 2H, J = 4.4， J = 1.6), 8.23 (d, 1H, J= 8.0), 8.08 (d, 1H, J= 6.4), 8.03 (d, 1H, J= 6.4), 7.92 (dd, 1H, J 8.0， J = 4.0), 7.79 (d, 1H, J = 8.8), 7.68 (dd, 2H, J= 4.4, J= 1.6), 7.66 (d, 1H, J= 8.0), 7.29 (d, 1H, J = 8.0), 7.27 (t, 1H. J= 6.0). 7.14 (d, 1H, J = 2.4)， 7.04 (t, 1H, /= 8.0), 7.03 (d, 2H, J = 8.4), 6.96 (t, 1H, J= 8.0)， 6.57 (d, 2H, /= 8.4), 4.73 (m, 1H), 4.60— 4.51 (m, 2H), 4.38- 4.30 (m, 2H), 4.25 (m, 1H) , 4.19 (dd, 1H, J= 8.8， J= 6.4), 3.62- 3.37 (m, 7H), 3.16 (dd, 1H, J = 14.4, / = 7.6), 3.05 (dd, 1H, J= 14.4, J = 10.4), 2.93 (dd, 1H, J= 13.6, /= 4.0)， 2.83- 2.60 (m, 3H) , 2.52 (s, 3H) , 2.12 (m, 1H), 2.02— 1.80 On, 6H), 1.60- 1.56 (m, 6H), 1.29- 1.20 (m, 8H)， 1.18- 1.06 (m, 4H)， 1.00- 0.96 (m, 2H), 0.84 (d, 3H, /= 6.8), 0.83 (t, 3H, J= 6.8), 0.82 (d, 3H, J= 6.8). MALDI m/z calculated for C6iH82N10Na0i3S+ [M+Na]+ 1217.57, found 1217.38. 99.9% Purity. R t 27.2 min. ¾ NMR (400 MHz, DMS0-i / 6 ): δ 12.86 (brs, 1H), 10.73 (s, 1H), 9.09 (brs, 1H), 8.82 (d, 1H, J = 8.4), 8.70 (dd, 2H, J = 4.4, J = 1.6), 8.23 (d, 1H, J = 8.0), 8.08 (d, 1H, J = 6.4), 8.03 (d, 1H, J = 6.4), 7.92 (dd, 1H, J 8.0 ， J = 4.0), 7.79 (d, 1H, J = 8.8), 7.68 (dd, 2H, J = 4.4, J = 1.6), 7.66 (d, 1H, J = 8.0), 7.29 (d, 1H , J = 8.0), 7.27 (t, 1 H. J = 6.0). 7.14 (d, 1H, J = 2.4), 7.04 (t, 1H, / = 8.0), 7.03 (d, 2H, J = 8.4), 6.96 (t, 1H, J = 8.0), 6.57 (d, 2H, / = 8.4), 4.73 (m, 1H), 4.60— 4.51 (m, 2H), 4.38-4.30 (m, 2H), 4.25 (m, 1H), 4.19 (dd, 1H, J = 8.8, J = 6.4 ), 3.62- 3.37 (m, 7H), 3.16 (dd, 1H, J = 14.4, / = 7.6), 3.05 (dd, 1H, J = 14.4, J = 10.4), 2.93 (dd, 1H, J = 13.6 , / = 4.0), 2.83-2.60 (m, 3H), 2.52 (s, 3H), 2.12 (m, 1H), 2.02— 1.80 On, 6H), 1.60- 1.56 (m, 6H), 1.29-1.20 (m, 8H), 1.18-1.06 (m, 4H), 1.00- 0.96 (m, 2H), 0.84 (d, 3H, / = 6.8 ), 0.83 (t, 3H, J = 6.8), 0.82 (d, 3H, J = 6.8). MALDI m / z calculated for C 6 iH 82 N 10 Na0i 3 S + [M + Na] + 1217.57, found 1217.38.
이소니코티닐 -트립토판 -타이로신 -발린 -Dpr (4-펜틸바이사이클로 [2.2.2]옥테인 -1- 카복실일) -프를린―세린-메티오닌 비산화형 (Isonicotinyl— Trp— Tyr-Val- Isicotinyl-tryptophan-tyrosine-valine-Dpr (4-pentylbicyclo [2.2.2] octane-1-carboxyl) -prine-serine-methionine non-oxidative type (Isonicotinyl— Trp— Tyr-Val-
Figure imgf000043_0001
Figure imgf000043_0001
상기 3 5와 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, Synthesis was carried out in the same manner as in the above 35, mass spectometry,
MS)로 생성된 화합물올 확인하였고， ¾ NMR를 이용하여 추가로 확인하였다. MS) produced the compound was confirmed, and further confirmed by using ¾ NMR.
99.9% Purity. t 29.9 min. ¾ NMR (400 MHz, DMS으 ): δ 12.76 (brs, 1H) , 10.73 (d, 1H, J = 2.0)， 9.10 (brs, 1H), 8.81 (d, 1H, J = 8.0)， 8.70 (dd, 2H, J = 4.4, J = 1.6), 8.23 (d, 1H, J - 8.0), 8.08 (d, 1H, / - 6.4)， 7.94 (d, 2H, J= 8.0), 7.79 (d, 1H, J = 8.8), 7.68 (dd, 2H, J= 4.4， J= 1.6), 7.66 (d, 1H, J = 7.6), 7.29 (d, 1H, J= 7.6)， 7.26 (t, 1H, 6.4)， 7.14 (d, 1H, J= 2.0)， 7.04 (t, 1H, J - 7.6)， 7.03 (d, 2H, J = 8.8)， 6.95 (t, 1H, /= 7.6)， 6.58 (d, 2H, J 8.8), 4.73 (m, 1H), 4.58— 4.51 (m, 2H), 4.38- 4.31 (m, 2H), 4.26 (m, 1H), 4.19 (dd, 1H, J= 8.4, /= 6.4), 3.64- 3.35 (m, 7H) , 3.16 (dd, 1H, J = 14.8， /= 3.2), 3.05 (dd, 1H, J = 14.8, J= 10.4)， 2.93 (dd, 1H, J 14.4, J = 3.6), 2.74 (dd, 1H, J- 14.4, J= 10.4)， 2.52- 2.40 (m, 2H), 2.02 (s, 3H), 2.00— 1.78 (m, 7H), 1.61- 1.57 (m, 6H), 1.29- 1.22 (m, 8H), 1.19— 1.05 (m, 4H), 1.01- 0.97 (m, 2H), 0.84 (d, 3H, J = 6.8), 0.83 (t, 3H, J= 7.2)， 0.82 (d, 3H, J = 6.8). MALDI m/z calculated for C61H82N10Na0i2S+ [M+Na]+ 1201.57, found 1201.43. 3-7. 99.9% Purity. t 29.9 min. ¾ NMR (400 MHz, DMS): δ 12.76 (brs, 1H), 10.73 (d, 1H, J = 2.0), 9.10 (brs, 1H), 8.81 (d, 1H, J = 8.0), 8.70 (dd , 2H, J = 4.4, J = 1.6), 8.23 (d, 1H, J-8.0), 8.08 (d, 1H, /-6.4), 7.94 (d, 2H, J = 8.0), 7.79 (d, 1H , J = 8.8), 7.68 (dd, 2H, J = 4.4, J = 1.6), 7.66 (d, 1H, J = 7.6), 7.29 (d, 1H, J = 7.6), 7.26 (t, 1H, 6.4 ), 7.14 (d, 1H, J = 2.0), 7.04 (t, 1H, J-7.6), 7.03 (d, 2H, J = 8.8), 6.95 (t, 1H, / = 7.6), 6.58 (d, 2H, J 8.8), 4.73 (m, 1H), 4.58— 4.51 (m, 2H), 4.38-4.31 (m, 2H), 4.26 (m, 1H), 4.19 (dd, 1H, J = 8.4, / = 6.4), 3.64- 3.35 (m, 7H), 3.16 (dd, 1H, J = 14.8, / = 3.2), 3.05 (dd, 1H, J = 14.8, J = 10.4), 2.93 (dd, 1H, J 14.4 , J = 3.6), 2.74 (dd, 1H, J-14.4, J = 10.4), 2.52- 2.40 (m, 2H), 2.02 (s, 3H), 2.00— 1.78 (m, 7H), 1.61- 1.57 ( m, 6H), 1.29-1.22 (m, 8H), 1.19— 1.05 (m, 4H), 1.01- 0.97 (m, 2H), 0.84 (d, 3H, J = 6.8), 0.83 (t, 3H, J = 7.2), 0.82 (d, 3H, J = 6.8). MALDI m / z calculated for C 61 H 82 N 10 Na0i 2 S + [M + Na] + 1201.57, found 1201.43. 3-7.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (2-(2-시아노페닐티오)벤조일) -프를린- 세린-메티오닌 산화형 (Isonicot i ny 1 -Tr -Ty r -Va 1 -Isonicotinyl-tryptophan-tyrosine-valine-Dpr (2- (2-cyanophenylthio) benzoyl) -prine-serine-methionine oxidic type (Isonicot i ny 1 -Tr -Ty r -Va 1-
Dpr(2-(2-cyanophenylthio)benzoyl)-Pro-Ser-Met(0)) O) Dpr (2- (2-cyanophenylthio) benzoyl) -Pro-Ser-Met (0)) O)
Figure imgf000044_0001
Figure imgf000044_0001
상기 3-1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 2-(2-시아노페닐티오)벤조산 (2-(2-cyanophenylthio)benzoic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고, ¾ NMR를 이용하여 추가로 확인하였다.  Synthesis was carried out using the same method as in 3-1, and 2- (2-cyanophenylthio) benzoic acid (2- (2-cyanophenylthio) benzoic acid) was used as an acid for coupling. Compounds produced by mass spectometry (MS) were identified and further confirmed using ¾ NMR.
99.9% Purity. Rt 23.4 min. ¾ NMR (400 MHz, DMSO-ofe)： δ 12.89 (brs, 1H),99.9% Purity. R t 23.4 min. ¾ NMR (400 MHz, DMSO-ofe): δ 12.89 (brs, 1H),
10.73 (d, 1H, /= 2.0), 9.10 (brs, 1H)， 8.83 (d, 1H, J= 8.0), 8.70 (d, 2H, J = 6.0), 8.45 (t, 1H, J = 6.0), 8.25 (d, 2H, J = 8.0), 8.05 (d, 1H, / = 8.4). 7.98 (dd, 1H, J = 8.0, /= 2.0), 7.93 (dd, 1H, J= 8.0, J = 0.8), 7.81 (d, 1H, J = 8.8)， 7.68 (dd, 2H, J = 6.0， J = 2.0), 7.66- 7.64 (m, 2H), 7.63 (d, 1H, J = 7.2), 7.53 (t, 1H, J = 8.0), 7.45 (dd, 1H, /= 8.0， J= 0.8), 7.39- 7.32 (m, 2H), 7.29 (d, 1H, 8.0), 7.14 (d, 1H, J = 2.0)， 7.03 (t, 1H, J 8.0), 7.02 (d, 2H, /= 8.4), 6.97- 6.93 (m, 2H), 6.58 (d, 2H, J 8.4), 4.81- 4.71 (m, 2H), 4.53 (td, 1H, J= 8.8, J= 4.0), 4.40 (m, 1H), 4.34 (m, 1H), 4.29- 4.23 (m, 2H), 3.69- 3.30 (m, 7H) , 3.17 (dd, 1H, J = 14.8， /= 4.0), 3.06 (dd, 1H, J= 14.8， J 10.4), 2.93 (dd, 1H, J= 14.4, J= 4.0)， 2.82- 2.59 (m, 3H), 2.51 (s, 3H), 2.11 (m, 1H), 2.03- 1.93 (m, 3H) , 1.91- 1.77 (m, 3H), 0.85 (d, 3H, J = 6.8), 0.83 (d, 3H, J= 6.8). MALDI m/z calculated for C61H67NuNa0i3S2+ [M+Na]+ 1248.43， found 1248.44. 3-8. 10.73 (d, 1H, / = 2.0), 9.10 (brs, 1H), 8.83 (d, 1H, J = 8.0), 8.70 (d, 2H, J = 6.0), 8.45 (t, 1H, J = 6.0) , 8.25 (d, 2H, J = 8.0), 8.05 (d, 1H, / = 8.4). 7.98 (dd, 1H, J = 8.0, / = 2.0), 7.93 (dd, 1H, J = 8.0, J = 0.8), 7.81 (d, 1H, J = 8.8), 7.68 (dd, 2H, J = 6.0 , J = 2.0), 7.66-7.64 (m, 2H), 7.63 (d, 1H, J = 7.2), 7.53 (t, 1H, J = 8.0), 7.45 (dd, 1H, / = 8.0, J = 0.8 ), 7.39-7.32 (m, 2H), 7.29 (d, 1H, 8.0), 7.14 (d, 1H, J = 2.0), 7.03 (t, 1H, J 8.0), 7.02 (d, 2H, / = 8.4 ), 6.97-6.93 (m, 2H), 6.58 (d, 2H, J 8.4), 4.81-4.71 (m, 2H), 4.53 (td, 1H, J = 8.8, J = 4.0), 4.40 (m, 1H ), 4.34 (m, 1H), 4.29-4.23 (m, 2H), 3.69-3.30 (m, 7H), 3.17 (dd, 1H, J = 14.8, / = 4.0), 3.06 (dd, 1H, J = 14.8, J 10.4), 2.93 (dd, 1H, J = 14.4, J = 4.0), 2.82-2.59 (m, 3H), 2.51 (s, 3H), 2.11 (m, 1H), 2.03- 1.93 (m, 3H), 1.91-1.77 (m, 3H), 0.85 (d, 3H, J = 6.8), 0.83 (d, 3H, J = 6.8). MALDI m / z calculated for C 61 H 67 N u Na0i 3 S 2+ [M + Na] + 1248.43, found 1248.44. 3-8.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (2— (2-시아노페닐티오)벤조일 ) -프를린- 세린-메티오닌 비산화형 (Isonicotinyl-Trp-Tyr-Val- Dpr(2-( 2-cyanopheny lthio )benzoy 1 ) -Pr o—Ser -Met ) Isicotinyl-tryptophan-tyrosine-valine-Dpr (2— (2-cyanophenylthio) benzoyl) -prine-serine-methionine non-oxidized (Isonicotinyl-Trp-Tyr-Val-Dpr (2- (2- cyanopheny lthio) benzoy 1) -Pr o—Ser -Met)
Figure imgf000045_0001
Figure imgf000045_0001
상기 3— 7과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고， ¾赚를 이용하여 추가로 확인하였다.  Synthesis was carried out in the same manner as in the above 3-7, the compound produced by mass spectrometry (MS) was confirmed, and further confirmed by using ¾ 赚.
99.9% Purity. Rt 25.4 min. ¾ NMR (400 MHz, DMS0-/6) : δ 12.73 (brs, 1H) , 10.73 (d, 1H, J= 2.0)， 9.09 (brs, 1H), 8.82 (d, 1H, J = 8.4)， 8.70 (d, 2H, J = 6.0), 8.44 (t, 1H, /= 6.0), 8.30— 8.22 (m, 2H), 8.00 (d, 1H, J = 8.0), 7.95 (d, 1H, / = 8.0), 7.93 (d, 1H, J = 8.0), 7.81 (d, 1H, J= 8.8)， 7.67 (dd, 2H, J = 6.0, / = 1.6), 7.66- 7.64 (m, 2H), 7.63 (td, VA,' J = 7.6, J = 1.6), 7.53 (td, 1H, /= 8.0， J= 1.2)， 7.44 (d, 1H, J= 8.0), 7.37 (td, 1H, J = 7.6, J = 1.6), 7.33 (dd, 1H, J = 8.0, J = 1.2), 7.29 (d, 1H, / = 8.0), 7.14 (d, 1H, J = 2.0)， 7.04 (t, 1H, J = 8.0), 7.03 (d, 2H, J= 8.0)， 6.99- 6.93 (m, 2H), 6.58 (d, 2H, J= 8.0), 4.80- 4.71 (m, 2H), 4.53 (td, 1H, 8.8， J= 4.0)， 4.40 (dd, 1H, / = 8.4, J = 3.6)， 4.33 (m, 1H), 4.29- 4.23 (m, 2H) , 3.68- 3.63 (m, 2H) , 3.62- 3.45 (m, 5H), 3.17 (dd, 1H, J = 14.8, J= 3.6)， 3.06 (dd, 1H, J = 14.8， J= 10.4), 2.93 (dd, 1H, /= 14.4， J= 3.6), 2.73 (dd, 1H, J = 14.4, J= 10.0)， 2.52- 2.39 (m, 2H) , 2.36- 1.94 (m, 3H) , 2.01 (s, 3H) , 1.88— 1.76 (m, 4H) , 0.85 (d, 3H, /= 6.8), 0.83 (d, 3H, /= 6.8). MALDI m/z calculated for C61H67NuNa0i2S2+ [M+Na]+ 1232.43， found 1232.53. 3-9. 99.9% Purity. R t 25.4 min. ¾ NMR (400 MHz, DMS0- / 6 ): δ 12.73 (brs, 1H), 10.73 (d, 1H, J = 2.0), 9.09 (brs, 1H), 8.82 (d, 1H, J = 8.4), 8.70 (d, 2H, J = 6.0), 8.44 (t, 1H, / = 6.0), 8.30— 8.22 (m, 2H), 8.00 (d, 1H, J = 8.0), 7.95 (d, 1H, / = 8.0 ), 7.93 (d, 1H, J = 8.0), 7.81 (d, 1H, J = 8.8), 7.67 (dd, 2H, J = 6.0, / = 1.6), 7.66-7.64 (m, 2H), 7.63 ( td, VA, ' J = 7.6, J = 1.6), 7.53 (td, 1H, / = 8.0, J = 1.2), 7.44 (d, 1H, J = 8.0), 7.37 (td, 1H, J = 7.6, J = 1.6), 7.33 (dd, 1H, J = 8.0, J = 1.2), 7.29 (d, 1H, / = 8.0), 7.14 (d, 1H, J = 2.0), 7.04 (t, 1H, J = 8.0), 7.03 (d, 2H, J = 8.0), 6.99-6.93 (m, 2H), 6.58 (d, 2H, J = 8.0), 4.80-4.71 (m, 2H), 4.53 (td, 1H, 8.8 , J = 4.0), 4.40 (dd, 1H, / = 8.4, J = 3.6), 4.33 (m, 1H), 4.29-4.23 (m, 2H), 3.68-3.63 (m, 2H), 3.62- 3.45 ( m, 5H), 3.17 (dd, 1H, J = 14.8, J = 3.6), 3.06 (dd, 1H, J = 14.8, J = 10.4), 2.93 (dd, 1H, / = 14.4, J = 3.6), 2.73 (dd, 1H, J = 14.4, J = 10.0), 2.52- 2.39 (m, 2H), 2.36- 1.94 (m, 3H), 2.01 (s, 3H), 1.88— 1.76 ( m, 4H), 0.85 (d, 3H, / = 6.8), 0.83 (d, 3H, / = 6.8). MALDI m / z calculated for C 61 H 67 N u Na0i 2 S2 + [M + Na] + 1232.43, found 1232.53. 3-9.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (페녹시아세틸 ) -프를린-세린-메티오닌 산화형 ( I soni cot i ny 1 -Tr -Tyr-Va 1 -Dpr ( phenoxyacety 1 )-Pro-Ser-Met (0) ) 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))
Figure imgf000046_0001
Figure imgf000046_0001
상기 3-1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 페녹시아세트산 (phenoxyacetic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물올 확인하였다.  Synthesis was carried out using the same method as in the above 3-1, and phenoxyacetic acid was used as an acid for coupling. Mass produced by mass spectometry (MS) was confirmed.
99.9% Purity. t 15.8 min (5- 100% B over 36 min). MALE) I m/z calculated for C55H66N10Na0i4S+ [M+Na]+ 1145.44， found 1145.03. 99.9% Purity. t 15.8 min (5- 100% B over 36 min). MALE ) I m / z calculated for C 55 H 66 N 10 Na0i 4 S + [M + Na] + 1145.44, found 1145.03.
3-10. 3-10.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (페녹시아세틸 ) -프를린-세린-메티오닌 비산화형 (Isonicot inyl-Trp-Tyr-Val-Dpr(phenoxyacetyl ) 一 Pro-Ser一 Met) Isonicotinyl-tryptophan-tyrosine-valine-Dpr (phenoxyacetyl) -prine-serine-methionine non-oxidative type (Isonicot inyl-Trp-Tyr-Val-Dpr (phenoxyacetyl) Ⅰ Pro-Ser 一 Met)
Figure imgf000046_0002
Figure imgf000046_0002
상기 3-9와 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out in the same manner as in the above 3-9, and the produced compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 17.7 min (5- 100% B over 36 min). MALDI m/z calculated for C55H66N10Na0i3S+ [M+Na]+ 1129.44, found 1129.08. 이소니코티닐-트립토판-타이로신ᅳ발린 -DDr(2—핵시노일) -프를린-세린-메티오닌 산화형 ( I son i cot i nyl -Trp-Tyr-Va 1 -Dpr ( 2-hexynoy 1 )-Pro-Ser-Met (0) )
Figure imgf000047_0001
99.9% Purity. R t 17.7 min (5- 100% B over 36 min). MALDI m / z calculated for C 55 H 66 N 10 Na0i 3 S + [M + Na] + 1129.44, found 1129.08. Isonicotinyl-Tryptophan-TyrosineCatvaline -DDr (2—nucinonoyl) -Plin-serine-Methionine Oxidation Type (I son i cot i nyl -Trp-Tyr-Va 1 -Dpr (2-hexynoy 1) -Pro-Ser-Met (0))
Figure imgf000047_0001
상기 3-1과 동일한 방법을 이용하여 합성하였으며, 커플링을 위한 산 (acid)으로 2-핵신산 (2-hexynoic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. Synthesis was carried out by the same method as in the above 3-1, and 2-hexynoic acid was used as an acid for coupling. The produced compound was confirmed by mass spectometry (MS).
97.4% Purity. Rt 15.5 min (5- 100% B over 36 min). MALDI m/z calculated for C53H66N10Na0i3S+ [M+Na]+ 1105.44, found 1105.15. 97.4% Purity. R t 15.5 min (5- 100% B over 36 min). MALDI m / z calculated for C 53 H 66 N 10 Na0i 3 S + [M + Na] + 1105.44, found 1105.15.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (2-핵시노일：) -프를린-세린-메티오닌 비산화 ( I son i cot i ny 1 -Tr -Tyr-Va 1 -Dpr (2-hexynoy 1 )—Pro一 Ser—Met) Isonicotinyl-Tryptophan -Tyrosine -Valine -Dpr (2-nucleonoyl ：) -Plin-serine-Methionine deoxidation (I son i cot i ny 1 -Tr -Tyr-Va 1 -Dpr (2-hexynoy 1) —Pro 一 Ser—Met)
Figure imgf000047_0002
Figure imgf000047_0002
상기 3-11과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. The compound was synthesized in the same manner as in the above 3-11, and the compound produced by mass spectrometry (MS) was confirmed.
99.9% Purity. Rt 17.4 min (5— 100% B over 36 min). MALDI m/z calculated for C53H66N10Na012S+ [M+Na]+ 1089.45, found 1089.51. 3-13. 99.9% Purity. R t 17.4 min (5— 100% B over 36 min). MALDI m / z calculated for C 53 H 66 N 10 Na0 12 S + [M + Na] + 1089.45, found 1089.51. 3-13.
이소니코티닐-트립토판-타이로신 -발린 -Dpr (오로틸) -프를린-세린-메티오닌 산화형 Isonicotinyl-Tryptophan-Tyrosine-Valine-Dpr (Orotyl) -Pr-serine-Methionine Oxidized
Figure imgf000048_0001
Figure imgf000048_0001
상기 3-1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 오로트산 (orotic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out using the same method as in the above 3-1, and orotic acid was used as an acid for coupling. The produced compound was confirmed by mass spectometry (MS).
88.0% Purity. Rt 12.9 min (5- 100% B over 36 min). MALDI m/z calculated for C52H62N12Na015S+ [M+Na]+ 1149.41， found 1149.37. 88.0% Purity. R t 12.9 min (5- 100% B over 36 min). MALDI m / z calculated for C 52 H 6 2N 12 Na0 15 S + [M + Na] + 1149.41, found 1149.37.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (오로틸 ) -프를린-세린-메티오닌 비산화 (Isoni cot i ny 1 -Tr p-Ty r -Va 1 -Dpr ( or o t y 1 )—Pro一 Ser—Met ) 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)
Figure imgf000048_0002
Figure imgf000048_0002
상기 3-13과 동일한 방법으로 합성하였으며 , 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out in the same manner as in the above 3-13, and the compound produced by the mass spectrometry (MS) was confirmed.
93.6% Purity. Rt 14.8 min (5— 100% B over 36 min). MALDI m/z calculated for C52 2N12Na0i4S+ [M+Na]+ 1133.41, found 1133.39. 3-15. 93.6% Purity. R t 14.8 min (5— 100% B over 36 min). MALDI m / z calculated for C 52 2N 12 Na0i 4 S + [M + Na] + 1133.41, found 1133.39. 3-15.
이소니코티닐 -트립토판 -타이로신 -발린 -Dpr (4—벤질옥시벤조일) -프를린-세린-메티 오닌 산화형 ( I son icotinyl -Trp-Tyr -Va 1 -Dpr ( -benzy 1 oxybenzoy 1 ) -Pro-Ser-Met (0)) 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))
Figure imgf000049_0001
Figure imgf000049_0001
상기 3-1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 4-벤질옥시벤조산 (4-benzyloxybenzoic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out using the same method as in 3-1, and 4-benzyloxybenzoic acid was used as an acid for coupling. The produced compound was confirmed by mass spectometry (MS).
99.9% Purity. t 17.9 min (5- 100% B over 36 min). MALDI m/z calculated for C6iH70Ni0Na0i4S+ [M+Na]+ 1221.47, found 1221.41. 99.9% Purity. t 17.9 min (5- 100% B over 36 min). MALDI m / z calculated for C 6 iH 70 Ni 0 Na0i 4 S + [M + Na] + 1221.47, found 1221.41.
3-16. 3-16.
이소니코티닐-트립토판-타이로신 -발린 -Dpr(4-벤질옥시벤조일) -프를린 -세린 -메티 오닌 zyloxybenzoyl ) -Pro-Ser-Met ) Isonicotinyl-tryptophan-tyrosine-valine-Dpr (4-benzyloxybenzoyl) -prine-serine-methionine zyloxybenzoyl) -Pro-Ser-Met)
Figure imgf000049_0002
Figure imgf000049_0002
상기 3— 15와 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out in the same manner as in the above 3-15, and the compound produced by mass spectrometry (MS) was confirmed.
99.9% Purity. Rt 19.7 min (5- 100% B over 36 min). MALDI m/z calculated for C6iH7oNioNaOi3S+ [M+Na]+ 1205.47, found 1205.42. 99.9% Purity. R t 19.7 min (5- 100% B over 36 min). MALDI m / z calculated for C6iH 7 oNioNaOi 3 S + [M + Na] + 1205.47, found 1205.42.
3-17. 3-17.
이소니코티닐-트립토판 -타이로신-발린ᅳ Dpr(2-나프토일) -프롤린-세린-메티오닌 산화형 ( Isoni cot inyl-Trp-Tyr-Val-Dpr (2-naphthoy 1 )-Pro~Ser-Met (0) )
Figure imgf000050_0001
Isonicotinyl-tryptophan-tyrosine-valinec Dpr (2-naphthoyl) -proline-serine-methionine oxidized type (Isoni cot inyl-Trp-Tyr-Val-Dpr (2-naphthoy 1) -Pro ~ Ser-Met ( 0) )
Figure imgf000050_0001
상기 3-1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 2-나프토에산 (2- naphthoic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out using the same method as in 3-1, and 2-naphthoic acid was used as an acid for coupling. The produced compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 16.5 min (5— 100% B over 36 min). MALDI m/z calculated for C58H66N10Na0i3S+ [M+Na]+ 1165.44, found 1165.42. 99.9% Purity. R t 16.5 min (5— 100% B over 36 min). MALDI m / z calculated for C 58 H 66 N 10 Na0i 3 S + [M + Na] + 1165.44, found 1165.42.
3-18. 3-18.
이소니코티닐-트립토판—타이로신 -발린 -Dpr (2-나프토일) -프를린-세린-메티오닌 비산화형 (Isoni cot inyl -Trp-Tyr-Val-Dpr (2-naphthoy 1 )-Pro-Ser-Met )
Figure imgf000050_0002
Isicotinyl-Tryptophan—Tyrosine-Valine-Dpr (2-naphthoyl) -Princeline-serine-Methionine Nonoxidative Type (Isoni cot inyl -Trp-Tyr-Val-Dpr (2-naphthoy 1) -Pro-Ser- Met)
Figure imgf000050_0002
23  23
상기 3-17과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out in the same manner as in 3-17, and the compound produced by mass spectrometry (MS) was confirmed.
99.9% Purity. Rt 18.3 min (5- 100% B over 36 min). MALDI m/z calculated for C58H66 5+ [M+Na]+ 1149.45, found 1149.40. 99.9% Purity. R t 18.3 min (5- 100% B over 36 min). MALDI m / z calculated for C 58 H 66 5 + [M + Na] + 1149.45, found 1149.40.
3-19. 3-19.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (2-피라진카복실일 ) -프를린-세린-메티 오닌 산화형 ( 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-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)
-Pro-Ser-Met(O)) O) -Pro-Ser-Met (O)) O)
Figure imgf000051_0001
Figure imgf000051_0001
상기 3-1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 2-피라진카복실산 (2-pyrazine carboxylic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out using the same method as in 3-1, and 2-pyrazine carboxylic acid was used as an acid for coupling. The produced compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 13.7 min (5- 100% B over 36 min). MALDI m/z calculated for C52H62N12Na013S+ [M+Na]+ 1117.42, found 1117.39. 99.9% Purity. R t 13.7 min (5- 100% B over 36 min). MALDI m / z calculated for C 52 H 62 N 12 Na0 13 S + [M + Na] + 1117.42, found 1117.39.
3-20. 3-20.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (2-피라진카복실일 ) -프를린―세린-메티 오닌 비산화형 ( I son i Co t i ny 1 -Tr p-Tyr --Va 1 -Dpr ( 2-pyr az i ne carboxylyl ) -Pro-S -Met ) 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)
Figure imgf000051_0002
Figure imgf000051_0002
상기 3-19와 동일한 방법으로 합성하였으며, 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. Synthesis was carried out in the same manner as in the 3-19 method, and mass spectometry, MS) to confirm the resulting compound.
99.9% Purity. Rt 15.5 tnin (5— 100% B over 36 min). MALDI m/z calculated for C52H62N12Na0i2S+ [M+Na]+ 1101.42, found 1101.39. 99.9% Purity. R t 15.5 tnin (5— 100% B over 36 min). MALDI m / z calculated for C 52 H 62 N 12 Na0i 2 S + [M + Na] + 1101.42, found 1101.39.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr(2-클로로니코티닐 )—프를린―세린-메티 오닌 r(2-chloronicotinyl) -Pro-Ser-Met(O))
Figure imgf000052_0001
Isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-chloronicotinyl) —proline-serine-methionine r (2-chloronicotinyl) -Pro-Ser-Met (O))
Figure imgf000052_0001
상기 3-1과 동일한 방법을 이용하여 합성하였으며, 커플링을 위한 산 (acid)으로 2ᅳ클로로니코틴산 (2- chloronicot inic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물올 확인하였다.  Synthesis was performed using the same method as in 3-1, and 2- ᅳ chloronicotinic acid was used as an acid for coupling. Mass produced by mass spectometry (MS) was confirmed.
99.9% Purity. Rt 16.1 niin. MALDI m/z calculated for C53H62ClNuNa0i3S+ [M+Na] + 1150.38, found 1150.24. 3-22. 99.9% Purity. R t 16.1 niin. MALDI m / z calculated for C 53 H 62 ClN u Na0i3S + [M + Na] + 1150.38, found 1150.24. 3-22.
이소니코티닐-트립토판-타이로신 -발린 -Dpr(2-클로로니코티닐) -프를린 -세린 -메티 오닌 비 oUnyl-Trp-Tyr-Val-Dpr(2-chloronicotinyl) -Pro-Ser-Met ) Isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-chloronicotinyl) -plin-serine-methionine ratio oUnyl-Trp-Tyr-Val-Dpr (2-chloronicotinyl) -Pro-Ser-Met)
Figure imgf000052_0002
Figure imgf000052_0002
상기 3-21과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. Synthesis was carried out in the same manner as in the above 3-21, and mass spectometry, MS) to confirm the resulting compound.
99.9% Purity. Rt 18.2 min. MALDI m/z calculated for C53H62ClNi1Na012S+ [M+Na 1134.39, found 1134.28. 99.9% Purity. R t 18.2 min. MALDI m / z calculated for C 53 H 6 2 ClNi 1 Na 0 12 S + [M + Na 1134.39, found 1134.28.
이소니코티닐—트립토판-타이로신 -발린 -Dpr (2 ,4-핵사디엔오일) -프를린 -세린 -메티 오닌 산화형 (Isonicotinyl-Trp-Tyr-Val-D)r(2,4-hexadierioyl) -Pr으 Ser-Met(O))
Figure imgf000053_0001
Isicotinyl-tryptophan-tyrosine-valine-Dpr (2,4-nucleodiene oil) -prine-serine-methionine oxidative type (Isonicotinyl-Trp-Tyr-Val-D) r (2,4-hexadierioyl) -Pr Ser-Met (O))
Figure imgf000053_0001
상기 3-1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 2,4—소르브산 (sorbic acid, 2,4-hexadienoic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. Synthesis was carried out using the same method as in 3-1, and 2,4—sorbic acid (2,4-hexadienoic acid) was used as an acid for coupling. The produced compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 17.5 min. MALDI m/z calculated for C53H66N10NaO13S+ [M+Na] + 1105.44, found 1105.40. 3-24. 99.9% Purity. R t 17.5 min. MALDI m / z calculated for C 53 H 66 N 10 NaO 13 S + [M + Na] + 1105.44, found 1105.40. 3-24.
이소니코티닐-트립토판-타이로신 -발린 -Dpr(2, 4-헥사디엔오일) -프를린 -세린 -메티 오닌 비산화형 (Isonicotinyl-Trp-Tyr-Val-Dpr(2,4-hexadienoyl) -Pro-Ser-Met )
Figure imgf000053_0002
Isonicotinyl-tryptophan-tyrosine-valine-Dpr (2,4-hexadienoyl) -plin-serine-methionine non-oxidized (Isonicotinyl-Trp-Tyr-Val-Dpr (2,4-hexadienoyl) -Pro Ser-Met)
Figure imgf000053_0002
29  29
상기 3-23과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. 99.9% Purity. Rt 19.6 min. MALDI m/z calculated for CssHeeNwNaO^S' [M+Na] 1089.45, found 1089.43. Synthesis was carried out in the same manner as in the 3-23 above, and the compound produced by the mass spectrometry (MS) was confirmed. 99.9% Purity. R t 19.6 min. MALDI m / z calculated for Css Hee N w NaO ^ S '[M + Na] 1089.45, found 1089.43.
3-25. 3-25.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (바이페닐 -4-카복실일 ) -프를린-세린-메 티오닌 j:화형 (Isonicotinyl -Trp-Tyr -Va 1—Dpr ( b i pheny 1 -4— car boxy lyl)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)
■Pro-Ser-Met(O)) ■ Pro-Ser-Met (O))
Figure imgf000054_0001
Figure imgf000054_0001
상기 3-1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 바이페닐 -4—카복실산 (biphenyl-4-carboxylic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out using the same method as in the above 3-1, and biphenyl-4-carboxylic acid was used as an acid for coupling. The produced compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 24.8 min. MALDI m/z calculated for C60H68N10Na0i3S+ [M+Na] + 1191.46, found 1191.46. 3-26. 99.9% Purity. R t 24.8 min. MALDI m / z calculated for C 60 H 68 N 10 Na0i 3 S + [M + Na] + 1191.46, found 1191.46. 3-26.
이소니코티닐-트립토판 -타이로신—발린 -Dpr (바이페닐 -4-카복실일 ) -프를린-세린-메 티오닌 비산화형 (Isoni cot inyl-Trp-Tyr-Va 1 -Dpr (bi phenylIsicotinyl-tryptophan-tyrosine—valine-Dpr (biphenyl-4-carboxylyl) -plin-serine-methionine non-oxidized (Isoni cot inyl-Trp-Tyr-Va 1 -Dpr (bi phenyl
-4-carboxylyl )-Pro~Ser-Met ) -4-carboxylyl) -Pro ~ Ser-Met)
Figure imgf000054_0002
Figure imgf000054_0002
상기 3-25와 동일한 방법으로 합성하였으며, 질량분석계 (mass spectometry MS)로 생성된 화합물을 확인하였다. Synthesis was carried out in the same manner as in the above 3-25, mass spectometry MS) to confirm the resulting compound.
99.9% Purity. Rt 27.0 min. MALDI m/z calculated for C60H68N10Na0i2S+ [M+Na] 1175.46, found 1175.46. 99.9% Purity. R t 27.0 min. MALDI m / z calculated for C 60 H 68 N 10 Na0i 2 S + [M + Na] 1175.46, found 1175.46.
3-27. 3-27.
이소니코티닐 -트립토판—타이로신 -발린 -Dpr (페닐글리옥실일) -프를린-세린-메티오 닌 산화형 (Isonicotinyl-Trp— Tyr-Val-Dpr(phenylglyoxylyl) -Pro-Ser-Met (0) ) Isicotinyl-tryptophan—tyrosine-valine-Dpr (phenylglyoxylyl) -plin-serine-methionine oxidative type (Isonicotinyl-Trp— Tyr-Val-Dpr (phenylglyoxylyl) -Pro-Ser-Met (0 ))
Figure imgf000055_0001
Figure imgf000055_0001
상기 3-1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 페닐글리옥실산 (phenylglyoxylic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out using the same method as in 3-1 above, and phenylglyoxylic acid was used as an acid for coupling. The produced compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 21.5 min. MALDI m/z calculated for C55H64Ni0Na0i4S+ [M+Na] + 1143.42, found 1143.44. 3-28. 99.9% Purity. R t 21.5 min. MALDI m / z calculated for C 55 H 64 Ni 0 Na0i 4 S + [M + Na] + 1143.42, found 1143.44. 3-28.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (페닐글리옥실일；) -프를린-세린-메티오 닌 비산화형 (Isonicotinyl— Trp-Tyr-Val-Dpr henylglyoxylyl) -Pro-Ser-Met) Isicotinyl-Tryptophan-Tyrosine-Valine-Dpr (Phenylglyoxylyl) -Plin-serine-Methionine Non-oxidized (Isonicotinyl— Trp-Tyr-Val-Dpr henylglyoxylyl) -Pro-Ser-Met
Figure imgf000056_0001
Figure imgf000056_0001
상기 3-27과 동일한 방법으로 합성하였으며, 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  The compound was synthesized in the same manner as in the 3-27 above, and the produced compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 23.8 min. MALDI m/z calculated for C55H64N10Na0i3S+ [M+Na]" 1127.43, found 1127.51. 99.9% Purity. R t 23.8 min. MALDI m / z calculated for C 55 H 64 N 10 Na0i 3 S + [M + Na] " 1127.43, found 1127.51.
3-29. 3-29.
이소니코티닐-트립토판 -타이로신—발린 -Dpr (2-플루오로페닐아세틸 )—프를린-세린- 메티오닌 산화형 ( 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 oxidation type (I soni cot i ny 1 -Tr -Tyr-Va 1 -Dpr (2-f 1 uor opheny 1 acetyl) -Pro-S -Met (O))
Figure imgf000056_0002
Figure imgf000056_0002
상기 3-1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 2-플루오로페닐아세트산 (2-fluorophenylacetic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out using the same method as in the above 3-1, and 2-fluorophenylacetic acid was used as an acid for coupling. The produced compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 21.5 min. MALDI m/z calculated for C55H65FN10Na0i3S+ [M+Na] + 1147.43, found 1147.51. 3-30. 99.9% Purity. R t 21.5 min. MALDI m / z calculated for C 55 H 65 FN 10 Na0 3 S + [M + Na] + 1147.43, found 1147.51. 3-30.
이소니코티닐 -트립토판—타이로신 -발린 -Dpr (2-플루오로페닐아세틸 ) -프를린-세린- 메티오닌 비산화형 ( I son i cot i ny 1 -Tr -Ty r - Va 1 -D r
Figure imgf000057_0001
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
Figure imgf000057_0001
상기 3— 29와 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out in the same manner as in 3 to 29, and the compound produced by mass spectrometry (MS) was confirmed.
99.9% Purity. Rt 23.5min. MALDI m/z calculated for C55H65FN10Na0i2S+ [M+Na]' 1131.44, found 1131.53. 99.9% Purity. R t 23.5 min. MALDI m / z calculated for C 55 H 65 FN 10 Na0i2S + [M + Na] '1131.44, found 1131.53.
3-31. 3-31.
이소니코티닐-트립토판—타이로신 -발린 -Dpr (트랜스-신나밀 ) -프를린-세린-메티오닌 산화형 ( I son i cot i ny 1 -Tr -Tyr-Va 1 -Dpr ( trans-c i nnamy 1 ) 一 Pro—Ser— Met (0))Isonicotinyl-tryptophan—tyrosine-valine-Dpr (trans-cinnamil) -plin-serine-methionine oxidized type (I son i cot i ny 1 -Tr -Tyr-Va 1 -Dpr (trans-c i nnamy 1) 一 Pro—Ser— Met (0))
Figure imgf000057_0002
Figure imgf000057_0002
상기 3ᅳ1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 트랜스-신남산이 ^(：^113111 acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out using the same method as 3′1, and trans-cinnamic acid was ^ (: ^ 113111 acid) as an acid for coupling. The produced compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 22.2 min. MALDI m/z calculated for C56H66N10Na0i3S+ [M+Na] + 1141.44， found 1141.51. 99.9% Purity. R t 22.2 min. MALDI m / z calculated for C 56 H 66 N 10 Na0i 3 S + [M + Na] + 1141.44, found 1141.51.
3-32. 3-32.
이소니코티닐―트립토판 -타이로신 -발린 -Dpr (트랜스-신나밀 ) -프를린-세린-메티오닌 비산화형 (Isonicot inyl-Trp-Tyr-Val-Dpr ( rafls-cinnamyl ) 一 Pro一 Ser一 Met ) Isonicotinyl-Tryptophan-Tyrosine-Valine-Dpr (Trans-cinnamil) -Plin-serine-Methionine Non-oxidized (Isonicot inyl-Trp-Tyr-Val-Dpr (rafls-cinnamyl)
Figure imgf000058_0001
Figure imgf000058_0001
상기 3-31과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out in the same manner as in the above 3-31, and the compound produced by mass spectrometry (MS) was confirmed.
99.9% Purity. Rt 24.3 min. MALDI m/z calculated for C56H66N10Na012S+ [M+Na]" 1125.45, found 1125.57. 99.9% Purity. R t 24.3 min. MALDI m / z calculated for C 56 H 66 N 10 Na0 1 2S + [M + Na] " 1125.45, found 1125.57.
3-33. 3-33.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr ( 1—나프토일 ) -프를린-세린-메티오닌 산화형 ( I sonicot i nyl-Trp-Tyr-Va 1 -Dpr ( 1-naphthoyl )-Pro~Ser-Met (0) ) Isonicotinyl-tryptophan-tyrosine-valine-Dpr (1—naphthoyl) -plin-serine-methionine oxidized (I sonicot i nyl-Trp-Tyr-Va 1 -Dpr (1-naphthoyl) -Pro to Ser -Met (0))
Figure imgf000058_0002
Figure imgf000058_0002
상기 3ᅳ1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 1-나프토에산 (1-naphtoic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. 99.9% Purity. Rt 21.9 min. MALDI m/z calculated for C58H66N10Na013S+ [M+Na 1165.44, found 1165.53. Synthesis was carried out using the same method as 3 ′ 1, and 1-naphtoic acid was used as an acid for coupling. The produced compound was confirmed by mass spectometry (MS). 99.9% Purity. R t 21.9 min. MALDI m / z calculated for C 58 H 66 N 10 Na0 13 S + [M + Na 1165.44, found 1165.53.
3-34. 3-34.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (1-나프토일 ) -프를린-세린-메티오닌 비산화형 ( I son i cot inyl -Trp-Tyr-Val-Dpr ( 1-naphthoyl )-Pro~Ser-Met ) Isonicotinyl-tryptophan -tyrosine -valine -Dpr (1-naphthoyl) -plin-serine-methionine non-oxidized type (I son i cot inyl -Trp-Tyr-Val-Dpr (1-naphthoyl) -Pro to Ser -Met)
Figure imgf000059_0001
Figure imgf000059_0001
상기 3-33과 동일한 방법으로 합성하였으며, 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  The compound was synthesized in the same manner as in the above 3-33, and the compound produced by mass spectometry (MS) was confirmed.
99.9% Purity. Rt 24.4 min. MALDI m/z calculated for CssHeeNioNaOiS' [M+Na]J 1149.45, found 1149.64. 99.9% Purity. R t 24.4 min. MALDI m / z calculated for CssHeeNioNaOiS '[M + Na] J 1149.45, found 1149.64.
3-35. 3-35.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (5-니트로 -2-푸로일) -프를린-세린―메티 오닌 (Isonicotinyl— Trp-Tyr-Val— Dpr(5-nit:ro-2-furoyl) -Pro-Ser-Met (0))
Figure imgf000059_0002
Isicotinyl-tryptophan-tyrosine-valine-Dpr (5-nitro-2-furoyl) -plin-serine-methionine (Isonicotinyl— Trp-Tyr-Val— Dpr (5-nit: ro-2-furoyl ) -Pro-Ser-Met (0))
Figure imgf000059_0002
40  40
상기 3ᅳ 1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 5-니트로ᅳ 2-푸로산 (5-nitro-2-furoic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. Synthesis was carried out using the same method as 3 ′ 1, for coupling 5-nitro-2-furoic acid was used as an acid. The produced compound was confirmed by mass spectometry (MS).
93.1% Purity. Rt 20.9 min. MALDI m/z calculated for C52H61N11Na016S+ [M+Na]' 1150.39, found 1150.17. 93.1% Purity. R t 20.9 min. MALDI m / z calculated for C 52 H 61 N 11 Na0 16 S + [M + Na] '1150.39, found 1150.17.
3-36. 3-36.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (5-니트로 -2-푸로일) -프를린-세린-메티 오닌 비산화형 (I soni cot inyl-Trp-Tyr-Val-Dpr -nitro-^furoyl) -Pro-Ser-Met ) 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)
Figure imgf000060_0001
Figure imgf000060_0001
41  41
상기 3-35와 동일한 방법으로 합성하였으며, 질량분석계 (mass spectometry, MS)로 생성된 화합물올 확인하였다.  Synthesis was carried out in the same manner as in the above 3-35, and the compound produced by mass spectrometry (MS) was confirmed.
99.9% Purity. Rt 22.9 min. MALDI m/z calculated for C52H6iNi1Na0i5S+ [M+Na] + 1134.40, found 1134.23. 99.9% Purity. R t 22.9 min. MALDI m / z calculated for C 52 H 6 iNi 1 Na0i 5 S + [M + Na] + 1134.40, found 1134.23.
3-37. 3-37.
이소니코티닐-트립토판 -타이로신-발린— Dpr (베타-나프특시아세틸 ) -프를린-세린-메 티오닌 산화형 ( I soni cot i nyl-Trp-Tyr-Va 1 -Dpr ( β -naphthoxyacetyl )Isonicotinyl-tryptophan-tyrosine-valine— Dpr (beta-naphthoxyacetyl) -plin-serine-methionine oxidative type (I soni cot i nyl-Trp-Tyr-Va 1 -Dpr (β -naphthoxyacetyl )
-Pro-Ser-Met (0))
Figure imgf000061_0001
-Pro-Ser-Met (0))
Figure imgf000061_0001
상기 3ᅳ 1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 베타 -나프특시아세트산 (β-naphthoxyacetic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out using the same method as 3 ′ 1, and β-naphthoxyacetic acid was used as an acid for coupling. The produced compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 23.7 min. MALDI m/z calculated for C59H68N10Na014S+ [M+Na] + 1195.45, found 1195.18. 99.9% Purity. R t 23.7 min. MALDI m / z calculated for C 59 H 68 N 10 Na0 14 S + [M + Na] + 1195.45, found 1195.18.
3-38. 3-38.
이소니코티닐―트립토판 -타이로신 -발린 -Dpr (베타-나프톡시아세틸 ) -프를린―세린-메 티오닌 비산화형 (Isonicot inyl-Trp-Tyr-Val-Dpr( β -naphthoxyacetyl )Isonicotinyl-tryptophan-tyrosine-valine-Dpr (beta-naphthoxyacetyl) -prine-serine-methionine non-oxidized (Isonicot inyl-Trp-Tyr-Val-Dpr (β-naphthoxyacetyl)
-Pro-S -Met ) -Pro-S -Met)
Figure imgf000061_0002
Figure imgf000061_0002
상기 3-37과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  The compound was synthesized in the same manner as in the above 3-37, and the compound produced by mass spectrometry (MS) was confirmed.
99:9% Purity. Rt 25.7 min. MALDI m/z calculated for C59H68N10Na0i3S+ [M+Na] + 1179.46, found 1179.32. 99: 9% Purity. R t 25.7 min. MALDI m / z calculated for C 59 H 68 N 10 Na0i 3 S + [M + Na] + 1179.46, found 1179.32.
3-39. 3-39.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (3-페녹시벤조일 ) -프를린-세린-메티오 닌 산 Isonicotinyl-Trp-Tyr-Val-Dpr(3-phenoxybenzoyl) -Pro-Ser— Met (0)) Isicotinyl-tryptophan-tyrosine-valine-Dpr (3-phenoxybenzoyl) -prine-serine-methio Nitric Acid Isonicotinyl-Trp-Tyr-Val-Dpr (3-phenoxybenzoyl) -Pro-Ser— Met (0))
Figure imgf000062_0001
Figure imgf000062_0001
상기 3ᅳ 1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 3—페녹시벤조산 (3-phenoxybenzoic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성돤화합물을 확인하였다.  Synthesis was carried out using the same method as 3 ′ 1, and 3-phenoxybenzoic acid was used as an acid for coupling. Mass spectometry (MS) confirmed the produced compound.
97.3% Purity. Rt 24.3 min. MALDI m/z calculated for C60¾8N10Na014S+ [M+Na] + 1207.45, found 1207.24. 97.3% Purity. R t 24.3 min. MALDI m / z calculated for C 60 ¾ 8 N 10 Na0 14 S + [M + Na] + 1207.45, found 1207.24.
3-40. 3-40.
이소니코티닐-트립토판-타이로신 -발린 -Dpr(3-페녹시벤조일) -프를린-세린-메티오 닌 비 -Tr p-Ty r-Va 1 -Dpr ( 3-phenoxybenzoy 1 ) -Pro-Ser-Met ) Isonicotinyl-tryptophan-tyrosine-valine-Dpr (3-phenoxybenzoyl) -prine-serine-methionine ratio -Tr p-Ty r-Va 1 -Dpr (3-phenoxybenzoy 1) -Pro-Ser -Met)
Figure imgf000062_0002
Figure imgf000062_0002
상기 3-39와 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다ᅳ  The compound was synthesized in the same manner as in the 3-39 method, and the produced compound was confirmed by mass spectometry (MS).
98.2% Purity. Rt 26.3 min. MALDI m/z calculated for C6oH68N10Na013S+ [M+Na]98.2% Purity. R t 26.3 min. MALDI m / z calculated for C 6 oH 68 N 10 Na0 13 S + [M + Na]
1191.46, found 1191.30. 1191.46, found 1191.30.
3-41. 이소니코티닐-트립토판-타이로신 -발린 -Dpr(7-메톡시 -1-벤조퓨란 -2-카복실일) -프 를린-세린-메티오닌 산화형 (Isonicot inyl-Trp-Tvr-Val-Dpr3-41. Isonicotinyl-tryptophan-tyrosine-valine-Dpr (7-methoxy-1-benzofuran-2-carboxylyl) -prine-serine-methionine oxidized type (Isonicot inyl-Trp-Tvr-Val-Dpr
( 7-met hoxy-l-benzo f ur an-2-car boxy 1 y 1 )-Pro~Ser-Met (0) ) (7-met hoxy-l-benzo f ur an-2-car boxy 1 y 1) -Pro ~ Ser-Met (0))
Figure imgf000063_0001
Figure imgf000063_0001
상기 3-1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (ac i d)으로  Synthesis was carried out in the same manner as in the above 3-1, and as an acid (ac i d) for coupling
그메특시 -1ᅳ벤조퓨란ᅳ 2-카복실산 (그 tnethoxy-l-benzofuran-2-carboxyH c ac id)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. Chemome-l-benzofuran- 2-carboxylic acid (tnethoxy-l-benzofuran-2-carboxyHc ac id) was used. The produced compound was confirmed by mass spectometry (MS).
97.6% Pur i ty . Rt 22.3 min . MALDI m/z cal cul ated for C57¾6N10Na0i5S+ [M+Na] + 1185.43 , found 1185.34. 97.6% Pur i ty. R t 22.3 min. MALDI m / z calculed for C 57 ¾ 6 N 10 Na0i 5 S + [M + Na] + 1185.43, found 1185.34.
3-42. 3-42.
이소니코티닐—트립토판—타이로신 -발린 -Dpr (7-메톡시 -1-벤조퓨란 -2-카복실일 ) -프 를린-세린-메티오닌 비산화형 ( I sonicot i ny 1 -Trp-Tyr-Va 1 -Dpr (7-methoxy-l-benzofuran-2-carboxylyl )— Pro一 Ser—Met ) Isonicotinyl—tryptophan—tyrosine-valine-Dpr (7-methoxy-1-benzofuran-2-carboxyl) -prine-serine-methionine non-oxidized (I sonicot i ny 1 -Trp-Tyr-Va 1- Dpr (7-methoxy-l-benzofuran-2-carboxylyl) — Pro 一 Ser—Met)
Figure imgf000063_0002
Figure imgf000063_0002
상기 3-41과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. Synthesis was carried out in the same manner as in the above 3-41, and mass spectometry, MS) to confirm the resulting compound.
99.9% Purity. Rt 24.4 niin. MALDI m/z calculated for C57H66N10Na014S+ [M+Na] 1169.44, found 1169.40. . 99.9% Purity. R t 24.4 niin. MALDI m / z calculated for C 57 H 66 N 10 Na0 14 S + [M + Na] 1169.44, found 1169.40. .
이소니코티닐 -트립토판—타이로신 -발린 -Dpr(2-메특시핵사노일) -프를린—세린 -메티 오닌 -Trp-Tyr-Val-Dpr(2-niet:hylhexanoyl) -Pro-Ser-Met (0) )
Figure imgf000064_0001
Isonicotinyl-tryptophan—tyrosine-valine-Dpr (2-methocyanosanoyl) -plin-serine-methionine-Trp-Tyr-Val-Dpr (2-niet: hylhexanoyl) -Pro-Ser-Met ( 0) )
Figure imgf000064_0001
상기 3-1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 2—메특시 핵사노익산 (2-methylhexanoic acid)을 사용하였다ᅳ 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. Synthesis was carried out using the same method as 3-1, and 2-methylhexanoic acid was used as an acid for coupling. 생성 Mass spectometry (MS) generated The compound was identified.
95.7% Purity. Rt 22.4 min. MALDI m/z calculated for C54H72N10Na013S+ [M+Na] + 1123.49, found 1123.53. 3-44. 95.7% Purity. R t 22.4 min. MALDI m / z calculated for C 54 H 7 2N 10 Na0 13 S + [M + Na] + 1123.49, found 1123.53. 3-44.
이소니코티닐-트립토판-타이로신 -발린 -Dpr(2-메톡시핵사노일) -프를린 -세린 -메티 오닌 비산화형 (Isonicotinyl-Tn3-Tyr-Val-Dpr(2-tnethylhexanoyl) -Pro-Ser-Met)
Figure imgf000065_0001
Isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-methoxynucleonoyl) -prine-serine-methionine non-oxidative (Isonicotinyl-Tn3-Tyr-Val-Dpr (2-tnethylhexanoyl) -Pro-Ser- Met)
Figure imgf000065_0001
49  49
상기 3— 43과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out in the same manner as in 3 to 43, and the compound produced by mass spectrometry (MS) was confirmed.
99.9% Purity. Rt 24.8 min. MALDI m/z calculated for C54H72N10Na0i2S+ [M+Na] + 1107.49, found 1107.53. 99.9% Purity. R t 24.8 min. MALDI m / z calculated for C 54 H 72 N 10 Na0i 2 S + [M + Na] + 1107.49, found 1107.53.
3-45. 3-45.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (3-클로로벤조 [b]티오펜 -2-카복실일 ) - 프롤린-세린-메티오닌 산화형 (Isonicotinyl -Trp-Tyr-Va 1 -Dpr Isonicotinyl-tryptophan-tyrosine-valine-Dpr (3-chlorobenzo [b] thiophene-2-carboxyl)-proline-serine-methionine oxidized type (Isonicotinyl-Trp-Tyr-Va 1 -Dpr
Figure imgf000065_0002
상기 3ᅳ 1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로
Figure imgf000065_0002
Synthesis was carried out using the same method as 3 ′ 1, and as an acid for coupling.
3-클로로벤조 [b]티오펜 -2-카복실산 (3-chlorobenzo[b]thiophene-2-carboxylic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  3-chlorobenzo [b] thiophene-2-carboxylic acid was used. The produced compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 23.1 min. MALDI m/z calculated for C56H63ClN10Na0i3S2+ [M+Na]+ 1205.36, found 1205.36. 3-46. 99.9% Purity. R t 23.1 min. MALDI m / z calculated for C 56 H 63 ClN 10 Na0 3 S2 + [M + Na] + 1205.36, found 1205.36. 3-46.
이소니코티닐-트립토판-타이로신 -발린 -Dpr (3-클로로벤조 [b]티오펜 -2-카복실일) - 프를린-세린-메티오닌 비산화형 ( I soni cot i nyl-Trp-Tyr-Va 1— DprIsonicotinyl-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
( 3-ch 1 or obenzo [ b ] t h i ophene-2-c ar boxy 1 y 1 )-Pro-Ser-Met ) (3-ch 1 or obenzo [b] t h i ophene-2-c ar boxy 1 y 1) -Pro-Ser-Met)
Figure imgf000066_0001
Figure imgf000066_0001
51  51
상기 3-45와 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry , MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out in the same manner as in the 3-45 method, and the compound produced by the mass spectrometry (MS) was confirmed.
99.9% Pur i ty . Rt 25. 1 min . MALDI m/z calculated for C56H63ClN10Na0i2S2 + [M+Na]+ 1189.36 , found 1189.47. 99.9% Pur i ty. R t 25. 1 min. MALDI m / z calculated for C 56 H 63 ClN 10 Na0i2S 2 + [M + Na] + 1189.36, found 1189.47.
3-47. 3-47.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (퀴날딜 ) -프를린-세린-메티오닌 산화형 (I soni cot i ny 1 -Tr -Tyr-Va 1 -Dpr ( qu i na 1 dy 1 )-Pro~Ser-Met (0)) 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))
Figure imgf000066_0002
상기 3-1과 동일한 방법을 이용하여 합성하였으며 커플링을 위한 산 (acid)으로 퀴나딜산 (quina ii c aci d)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.
Figure imgf000066_0002
Synthesis was carried out using the same method as in 3-1, and quinadilic acid (quina ii c aci d) was used as an acid for coupling. Mass spectrometer The produced compound was confirmed by spectometry (MS).
99.9 Purity. Rt 22.3 min. MALDI m/z calculated for C57H65N11Na0i3S+ [M+Na] 1166.44, found 1166.47. 99.9 Purity. R t 22.3 min. MALDI m / z calculated for C 57 H 65 N 11 Na0i 3 S + [M + Na] 1166.44, found 1166.47.
3-48. 3-48.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (퀴날딜；) -프를린-세린-메티오닌 비산화형 (Isonicotinyl -Trp-Tyr -Va 1 -Dpr (quinaldyl) -Pr o— Ser—Me t ) Isicotinyl-tryptophan-tyrosine-valine-Dpr (quinalyl;)-plin-serine-methionine non-oxidative type (Isonicotinyl -Trp-Tyr -Va 1 -Dpr (quinaldyl) -Pr o— Ser—Me t)
Figure imgf000067_0001
Figure imgf000067_0001
상기 3ᅳ47과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out in the same manner as in the 3 ᅳ 47, and the compound produced by mass spectrometry (MS) was confirmed.
99.9% Purity. Rt 24.0 min. MALDI m/z calculated for C57H65NuNa0i2S+ [M+Na] 1150.44, found 1150.47. 99.9% Purity. R t 24.0 min. MALDI m / z calculated for C 57 H 65 N u Na0i 2 S + [M + Na] 1150.44, found 1150.47.
3-49. 3-49.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (타이글라일 )—프를린-세린-메티오닌 산화형 ( Isonicot inyl-Trp-Tyr-Val-Di)r(t iglyl )-Pro~Ser-Met (0)) 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))
Figure imgf000067_0002
상기 3-1과 동일한 방법을 이용하여 합성하였으며, 커플링을 위한 산 (acid)으로 티글린산 (tiglic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.
Figure imgf000067_0002
Synthesis was carried out using the same method as in 3-1, and tiglic acid was used as an acid for coupling. The produced compound was confirmed by mass spectometry (MS).
99.2% Purity. Rt 20.4 min. MALDI m/z calculated for C52¾7N10013S+ [M+H] + 1071.46, found 1071.56. 99.2% Purity. R t 20.4 min. MALDI m / z calculated for C 52 ¾ 7 N 10 0 13 S + [M + H] + 1071.46, found 1071.56.
3-50. 3-50.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (타이글라일) -프를린-세린-메티오닌 비산화 ( Isonicot inyl-Trp-Tyr-Val-Dpr(tifilyl )-Pro~Ser-Met ) Isonicotinyl-Tryptophan-Tyrosine-Valine-Dpr (Taigliyl) -Plin-serine-Methionine Non-oxidative (Isonicot inyl-Trp-Tyr-Val-Dpr (tifilyl) -Pro to Ser-Met)
Figure imgf000068_0001
Figure imgf000068_0001
상기 3-49와 동일한 방법으로 합성하였으며, 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out in the same manner as in the 3-49 method, and the resulting compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 22.3 min. MALDI m/z calculated for C52H66N10Na0i2S+ [M+Na] + 1077.45, found 1077.51. 99.9% Purity. R t 22.3 min. MALDI m / z calculated for C 52 H 66 N 10 Na0i2S + [M + Na] + 1077.45, found 1077.51.
3-51. 3-51.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (이소니코티닐：) -프를린-세린-메티오닌 산화형 ( I sonicot inyl-Trp-Tyr-Val-Dpr ( i soni cot inyl )-Pro-Ser-Met (0) )
Figure imgf000069_0001
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))
Figure imgf000069_0001
56  56
상기 3-1과 동일한 방법을 이용하여 합성하였으며, 커플링을 위한 산 (acid)으로 이소니코틴산 (isonicotinic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out using the same method as in the above 3-1, and isicotinic acid was used as an acid for coupling. The produced compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 18.0 min. MALDI m/z calculated for CssHesNnNaOisS' [M+Na99.9% Purity. R t 18.0 min. MALDI m / z calculated for CssHesNnNaOisS '[M + Na
1116.42, found 1116.49. 3-52. 1116.42, found 1116.49. 3-52.
이소니코티닐 -트립토판 -타이로신 -발린 -Dpr (이소니코티닐 ) -프를린-세린-메티오닌 비산화 (Isonicotinyl-Trp-Tyr— Val— Dpr(isonicotitiyl)— Pro— Ser— Met) Isicotinyl-tryptophan-tyrosine-valine-Dpr (isnicotinyl) -plin-serine-methionine non-oxidation (Isonicotinyl-Trp-Tyr— Val—isonpritiyl— Pro— Ser— Met)
Figure imgf000069_0002
Figure imgf000069_0002
상기 3— 51과 동일한 방법으로 합성하였으며, 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out in the same manner as in 3 to 51, and the compound produced by mass spectrometry (MS) was confirmed.
99.9% Purity. Rt 19.9 m in. MALDI m/z calculated for C53H63N11Na0i2S+ [M+Na] + 1100.43, found 1100.48. 99.9% Purity. R t 19.9 m in. MALDI m / z calculated for C 53 H 63 N 11 Na 0 i 2 S + [M + Na] + 1100.43, found 1100.48.
3-53. 3-53.
이소니코티닐-트립토판-타이로신 -발린 -Dpr(5-클로로인돌 -2-카복실일) -프를린-세 린-메티오닌 산화형 (Isonicot inyl-Trp-Tyr-Val-Dpr (5-chloroindole-2-carboxylyl)-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))
Figure imgf000070_0001
Figure imgf000070_0001
상기 3-1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 5-클로로인돌 -2-카복실산 (5-chloroindole-2-carboxylic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out using the same method as in the above 3-1, and 5-chloroindole-2-carboxylic acid was used as an acid for coupling. The produced compound was confirmed by mass spectometry (MS).
89.3% Purity. Rt 23.3 min. MALDI m/z calculated for C56H64ClNuNa013S+ [M+Na] + 1188.40， fomid 1188.44. 89.3% Purity. R t 23.3 min. MALDI m / z calculated for C 5 6H 64 ClN u Na0 13 S + [M + Na] + 1188.40, fomid 1188.44.
3-54. 3-54.
이소니코티닐-트립토판 -타이로신—발린 -Dpr (5-클로로인돌 -2-카복실일 ) -프를린-세 린-메티오닌 비산화형 (Isonicotinyl -Trp-Tyr -Va 1一 DprIsicotinyl-tryptophan-tyrosine—valine-Dpr (5-chloroindole-2-carboxyl) -plin-serine-methionine non-oxidized (Isonicotinyl-Trp-Tyr-Va 1 一 Dpr
(5-chl roindole-2-carboxylyl )—Pro—Ser一 Met ) (5-chl roindole-2-carboxylyl) —Pro—Ser 一 Met)
Figure imgf000070_0002
Figure imgf000070_0002
상기 3-53과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  The compound was synthesized in the same manner as in the above 3-53, and the produced compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 25.6 min. MALDI m/z calculated for C56H64ClNuNa0i2S+ [M+Na]' 1172.40, found 1172.47. 99.9% Purity. R t 25.6 min. MALDI m / z calculated for C 56 H 64 ClN u Na0i 2 S + [M + Na] ' 1172.40, found 1172.47.
3-55. 이소니코티닐-트립토판 -타이로신 -발린 -D " (5-페닐 -2-푸로일)—프를린-세린-메티오 닌 산화형 (Isonicot inyl-Trp-Tyr-Val-Dpr -phenyl—^furoyl) -Pro-Ser-Met(O))
Figure imgf000071_0001
3-55. Isonicotinyl-tryptophan-tyrosine-valine -D "(5-phenyl-2-furoyl) —prine-serine-methionine oxidation type (Isonicot inyl-Trp-Tyr-Val-Dpr -phenyl— ^ furoyl ) -Pro-Ser-Met (O))
Figure imgf000071_0001
60  60
상기 3-1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 5-페닐— 2ᅳ푸로산 (5— pheny卜 2-furoic acid)을 사용하였다. 질량분석계 (mass spectoraetry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out using the same method as in the above 3-1, and 5-phenyl-2 ᅳ furoic acid was used as an acid for coupling. Mass produced by mass spectoraetry (MS) was confirmed.
99.9% Purity. Rt 23.0 min. MALDI m/z calculated for C58H66N10Na0i4S+ [M+Na] + 1181.44, found 1181.44. 99.9% Purity. R t 23.0 min. MALDI m / z calculated for C 58 H 66 N 10 Na0i 4 S + [M + Na] + 1181.44, found 1181.44.
3-56. 3-56.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (5-페닐 -2-푸로일 )ᅳ프를린-세린-메티오 닌 비산화형 (Isonicot inyl-Trp-Tyr-Val-Dpr (5-pheny卜 2-furoyl) -Pro-Ser-Met )
Figure imgf000071_0002
Isonicotyl-Tryptophan-Tyrosine-Valine-Dpr (5-phenyl-2-furoyl) Veplin-serine-Methionine Non-oxidized (Isonicot inyl-Trp-Tyr-Val-Dpr (5-pheny 卜 2- furoyl) -Pro-Ser-Met)
Figure imgf000071_0002
61  61
상기 3-55와 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  The compound was synthesized in the same manner as in the above 3-55, and the compound produced by mass spectrometry (MS) was confirmed.
99.9% Purity. t 25.2 min. MALDI m/z calculated for C58H66N10Na013S+ [M+Na] + 1165.44, found 1165.48. 3-57. 99.9% Purity. t 25.2 min. MALDI m / z calculated for C 58 H 66 N 10 Na0 13 S + [M + Na] + 1165.44, found 1165.48. 3-57.
이소니코티닐 -트립토판 -타이로신 -발린 -ppr (5-니트로 -3—피라졸카복실일 ) -프롤린- 세린-메티오닌 산화형 ( I sonicot inyl-Trp-Tyr-Va 1 -Dpr (5-nit ro-3- pyrazolecarboxylyl)-Pro-Ser-Met(O)) Isonicotinyl-tryptophan-tyrosine-valine-ppr ( 5 -nitro-3-pyrazolcarboxylyl) -proline-serine-methionine oxidized (I sonicot inyl-Trp-Tyr-Va 1 -Dpr (5-nit ro- 3-pyrazolecarboxylyl) -Pro-Ser-Met (O))
Figure imgf000072_0001
상기 3-1과 동일한 방법을 이용하여 합성하였으며, 커플링을 위한 산 (acid)으로 5-니트로 -3-피라졸카복실산 (5— nitro-3- pyrazolecarboxylic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.
Figure imgf000072_0001
Synthesis was carried out using the same method as in the above 3-1, and 5-nitro-3-pyrazolecarboxylic acid was used as an acid for coupling. The produced compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 20.4 min. MALDI m/z calculated for C5iH6iN13Na0i5S+ [M+Na]+ 1150.40, found 1150.54. 99.9% Purity. R t 20.4 min. MALDI m / z calculated for C 5 iH 6 iN 13 Na 0i 5 S + [M + Na] + 1150.40, found 1150.54.
3-58. 3-58.
이소니코티닐-트립토판 -타이로신 -발린—Dpr (5-니트로 -3-피라졸카복실일) -프를린- 세린-메티오닌 비산화형 (Isonicotinyl -Trp-Tyr-Va 1 -Dpr (5-nit ro~3- pyrazolecarboxylyl)-Pro-Ser-Met) Isicotinyl-tryptophan-tyrosine-valine—Dpr (5-nitro-3-pyrazolcarboxylyl) -prine-serine-methionine non-oxidized (Isonicotinyl -Trp-Tyr-Va 1 -Dpr (5-nit ro to 3-pyrazolecarboxylyl) -Pro-Ser-Met)
Figure imgf000072_0002
Figure imgf000072_0002
상기 3-57과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. 99.9% Purity. Rt 22.3 min. MALDI m/z calculated for C5iH6iN13Na0i4S+ [M+Na] 1134.41, found 1134.51. The compound was synthesized in the same manner as in the 3-57 method, and the produced compound was confirmed by mass spectometry (MS). 99.9% Purity. R t 22.3 min. MALDI m / z calculated for C 5 iH 6 iN 13 Na0i 4 S + [M + Na] 1134.41, found 1134.51.
3-59. 3-59.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr ( (R)-(+)-트를록실) -프를린-세린―메티 오닌 ?)-(+)-troloxyl) -Pro-Ser-Met (0) ) Isonicotinyl-tryptophan-tyrosine-valine-Dpr ((R)-(+)-troroxyl) -prine-serine-methionine?)-(+)-Troloxyl) -Pro-Ser-Met (0 ))
Figure imgf000073_0001
Figure imgf000073_0001
상기 3-1과 동일한 방법을 이용하여 합성하였으며, 커플링을 위한 산 (acid)으로 6-히드록시ᅳ 2, 5，7，8-테트라메칠크로만 -2-카복실산 (trolox)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out using the same method as in 3-1, and 6-hydroxy- 2, 5, 7, 8-tetramethylchroman 2-carboxylic acid (trolox) was used as an acid for coupling. The produced compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 22.6 min. MALDI m/z calculated for
Figure imgf000073_0002
[M+Na] + 1243.51, found 1243.49. 99.9% Purity. R t 22.6 min. MALDI m / z calculated for
Figure imgf000073_0002
[M + Na] + 1243.51, found 1243.49.
3-60. 3-60.
이소니코티닐 -트립토판—타이로신 -발린 -Dpr ( (R)-(+)-트를록실 ) -프를린-세린-메티 오닌 비산화형 (Isonicotinyl-Trp-Tyr-Val-Dpr ^1)— (+)-troloxyl) -Pro-Ser-Met) Isicotinyl-Tryptophan—Tyrosine-Valine-Dpr ((R)-(+)-Troxyl) -Prinlin-serine-Methionine Non-oxidized (Isonicotinyl-Trp-Tyr-Val-Dpr ^ 1 ) — ( +)-troloxyl) -Pro-Ser-Met)
Figure imgf000073_0003
상기 3-59와 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.
Figure imgf000073_0003
The compound was synthesized in the same manner as in the 3-59 method, and the produced compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 24.7 min. MALDI m/z calculated for C61H76N10Na014S+ [M+Na] + 1227.52, found 1227.51. 99.9% Purity. R t 24.7 min. MALDI m / z calculated for C 61 H 76 N 10 Na0 14 S + [M + Na] + 1227.52, found 1227.51.
3-61. 3-61.
이소니코티닐—트립토판-타이로신 -발린 - ΪΗ·( ?)-(+)-2-피를리돈 -5-카복실일) -프를 린-세린-메티오닌 산화형 (Isonicotinyl -Trp-Tyr-Va 1 -Dpr ( - ( + ) -2- pyrrol idone-5-carboxylyl )— Pro—Ser— Met (0) ) Isicotinyl-Tryptophan-Tyrosine-Valine-ΪΗ · (?)-(+)-2-Pyridone-5-carboxyl) -Prine-serine-Methionine Oxidized (Isonicotinyl -Trp-Tyr-Va 1 -Dpr (-(+) -2-pyrrol idone-5-carboxylyl) — Pro—Ser— Met (0))
Figure imgf000074_0001
Figure imgf000074_0001
상기 3-1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 ?)-(+)-2-피를리돈 -5-카복실산Synthesis was carried out using the same method as in the above 3-1, and as an acid for coupling,?)-(+)-2-pyridone-5-carboxylic acid
((/?)- (+) -2-pyr roli done-5-car boxy 1 i c acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물올 확인하였다. ((/?)-(+)-2-pyr roli done-5-car boxy 1 i c acid) was used. Mass produced by mass spectometry (MS) was confirmed.
99.9% Purity. Rt 18.4 min. MALDI m/z calculated for C52H65NuNa0i4S+ [M+Na] + 1122.43, found 1122.34. 99.9% Purity. R t 18.4 min. MALDI m / z calculated for C 5 2H 65 NuNa0i 4 S + [M + Na] + 1122.43, found 1122.34.
3-62. 3-62.
이소니코티닐 -트립토판 -타이로신 -발린 -Dpr ( 0?)-(+)-2-피를리돈— 5-카복실일 ) -프를
Figure imgf000074_0002
Isonicotinyl-tryptophan-tyrosine-valine -Dpr (0?)-(+)-2-pyridone— 5-carboxyl)-
Figure imgf000074_0002
pyrrol idone—5—carboxylyl )-Pro-Ser-Met )
Figure imgf000075_0001
pyrrol idone—5—carboxylyl) -Pro-Ser-Met)
Figure imgf000075_0001
67  67
상기 3-61과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out in the same manner as in the above 3-61, and the compound produced by the mass spectrometry MS was confirmed.
99.9% Purity. Rt 20.5 min. MALDI m/z calculated for C52H65N11Na0i3S+ [M+Na] 1106.44, found 1106.45. 99.9% Purity. R t 20.5 min. MALDI m / z calculated for C 5 2H 65 N 11 Na0i 3 S + [M + Na] 1106.44, found 1106.45.
3-63. 3-63.
이소니코티닐 -트립토판—타이로신 -발린 -Dpr(l-시아노 -1-사이클로프로페인카복실일Isicotinyl-tryptophan—tyrosine-valine-Dpr (l-cyano-1-cyclopropanecarboxylyl
) -프를린-세린-메티오닌 산화형 (Isonicot inyl-Trp-Tyr-Val-Dpr) -Prine-serine-methionine oxidized (Isonicot inyl-Trp-Tyr-Val-Dpr
( 1-cyano- 1— eye 1 opropanecarboxy lyl) -Pro-Ser -Met (0 ) ) (1-cyano- 1— eye 1 opropanecarboxy lyl) -Pro-Ser -Met (0))
Figure imgf000075_0002
Figure imgf000075_0002
68  68
상기 3ᅳ1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 1-시아노—1-사이클로프로페인카복실산 Synthesis was carried out using the same method as 3′1, and 1-cyano—1-cyclopropanecarboxylic acid was used as an acid for coupling.
( l-cyano-1-cyc 1 opropanecarboxy 1 i c acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. (l-cyano-1-cyc 1 opropanecarboxy 1 i acid) was used. The produced compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 19.9 min. MALDI m/z calculated for C52H63N11Na0i3S+ [M+Na] + 1104.42, found 1104.43. 3-64. 99.9% Purity. R t 19.9 min. MALDI m / z calculated for C 52 H 63 N 11 Na0i 3 S + [M + Na] + 1104.42, found 1104.43. 3-64.
이소니코티닐 -트립토판 -타이로신 -발린 -Dpr ( 1-시아노 -1-사이클로프로페인카복실일Isicotinyl-tryptophan-tyrosine-valine-Dpr (1-cyano-1-cyclopropanecarboxylyl
) -프를린-세린-메티오닌 비산화형 (Isoni cot inyl-Trp-Tyr-Va 1 -Dpr) -Prine-serine-methionine non-oxidative type (Isoni cot inyl-Trp-Tyr-Va 1 -Dpr
( 1-cyano-l-cyc 1 opropanecarboxy lyl) -Pro-Ser -Met (1-cyano-l-cyc 1 opropanecarboxy lyl) -Pro-Ser -Met
Figure imgf000076_0001
Figure imgf000076_0001
상기 3-63과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. Synthesis was carried out in the same manner as in the above 3-63, and the compound produced by the mass spectrometry (MS) was confirmed.
99.9% Purity. Rt 22.3 min. MALDI m/z calculated for C52H63NuNa0i2S+ [M+Na] + 1088.43, found 1088.47. 99.9% Purity. R t 22.3 min. MALDI m / z calculated for C 52 H 63 N u Na0i2S + [M + Na] + 1088.43, found 1088.47.
3-65. 3-65.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (로다닌 -3-아세틸；) -프를린-세린-메티오 닌 산화형 (Isonicotinyl-Trp-Tyr-Val-Dpr(rhodanine-3-acetyl) -Pro-Ser-Met(O)) Isicotinyl-tryptophan-tyrosine-valine-Dpr (rhodanine-3-acetyl;)-prine-serine-methionine oxidative type (Isonicotinyl-Trp-Tyr-Val-Dpr (rhodanine-3-acetyl)- Pro-Ser-Met (O))
Figure imgf000076_0002
Figure imgf000076_0002
상기 3ᅳ 1과 동일한 방법을 이용하여 합성하였으며, 커플링을 위한 산 (acid)으로 로다닌 -3-아세트산 (rhodanine-3-acetic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out using the same method as 3 ′ 1, and rhodanine-3-acetic acid was used as an acid for coupling. The produced compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 20.6 min. MALDI m/z calculated for C52H63NuNa0i4S3 + [M+Na] + 1184.36 , found 1184.36. 99.9% Purity. R t 20.6 min. MALDI m / z calculated for C 5 2H 63 N u Na0i4S 3 + [M + Na] + 1184.36, found 1184.36.
3-66. 3-66.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (로다닌 -3-아세틸 ) -프를린-세린-메티오 닌 비산화형 ( I soni cot i ny 1 -Tr p-Tyr-Va 1 -Dpr ( rhodani ne-3-acety 1 ) -Pro-Ser-Met ) 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)
Figure imgf000077_0001
Figure imgf000077_0001
상기 3-65와 동일한 방법으로 합성하였으며， 질량분석계 (mass spectomet ry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out in the same manner as in 3-65, and the compound produced by a mass spectrometer (MS) was confirmed.
99.9% Pur i ty . t 23. 1 min . MALDI m/z cal cul ated for
Figure imgf000077_0002
[M+Na]' 1168.37 , found 1168.43. 99.9% Pur i ty. t 23. 1 min. MALDI m / z cal cul ated for
Figure imgf000077_0002
[M + Na] '1168.37, found 1168.43.
3-67. 3-67.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (7-하이드톡시쿠마린 -4-아세틸 )-프를린Isicotinyl-tryptophan-tyrosine-valine-Dpr (7-hydroxycoumarin-4-acetyl) -plin
-세린-메티오닌 산화형 (I soni cot inyl -Trp-Tyr-Va 1 -DprSerine-Methionine Oxidation Type (I soni cot inyl -Trp-Tyr-Va 1 -Dpr
(7-hydroxycoumar ine-4-acety 1 )—Pr으 Ser— Met (0) ) (7-hydroxycoumar ine-4-acety 1) —Pr Ser— Met (0))
Figure imgf000077_0003
상기 3ᅳ1과 동일한 방법을 이용하여 합성하였으몌 커플링을 위한 산 (aci d)으로 그하이드록시쿠마린 -4—아세트산 ( 7-hydroxycoumar i ne-4-ace t i c acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.
Figure imgf000077_0003
Synthesis was carried out using the same method as 3′1, and hydroxycoumarin-4—acetic acid (7-hydroxycoumar i ne-4-acetic) was used as an acid (aci d) for coupling. acid) was used. The produced compound was confirmed by mass spectometry (MS).
98.0% Purity. Rt 20.0 min. MALDI m/z calculated for C58H66Ni0NaOi6S+ [M+Na] + 1213.43, found 1213.35. 98.0% Purity. R t 20.0 min. MALDI m / z calculated for C 58 H 66 Ni 0 NaOi 6 S + [M + Na] + 1213.43, found 1213.35.
3-68. 3-68.
이소니코티닐 -트립토판—타이로신 -발린 -Dpr (7-하이드록시쿠마린 -4-아세틸 )-프를린Isicotinyl-tryptophan—tyrosine-valine-Dpr (7-hydroxycoumarin-4-acetyl) -plin
-세린-메티오닌 비산화형 ( I son icotinyl -Trp-Tyr-Va 1 -DprSerine-methionine non-oxidizing type (I son icotinyl -Trp-Tyr-Va 1 -Dpr
( 7-hydr oxycoumar i ne-4-acet y 1 )-Pro-Ser-Met ) (7-hydr oxycoumar i ne-4-acet y 1) -Pro-Ser-Met)
Figure imgf000078_0001
상기 3-67과 동일한 방법으로 합성하였으며, 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.
Figure imgf000078_0001
The compound was synthesized in the same manner as in the 3-67 method, and the produced compound was confirmed by mass spectometry (MS).
96.3% Purity. Rt 22.0 min. MALDI m/z calculated for C58H66Ni0Na0i5S+ [M+Na] 1197.43, found 1197.43. 96.3% Purity. R t 22.0 min. MALDI m / z calculated for C 58 H 66 Ni 0 Na0 5 S + [M + Na] 1197.43, found 1197.43.
3-69. 3-69.
이소니코티닐-트립토판-타이로신 -발린 -Dpr(2-(4-메틸페닐설폰아미도)아세틸) -프 롤린-세린-메티오닌 산화형 (Isonicot iny 1 -Trp-Tyr-Va 1 -Dpr (2-Isonicotinyl-tryptophan-tyrosine-valine-Dpr (2- (4-methylphenylsulfonamido) acetyl) -proline-serine-methionine oxidic type (Isonicot iny 1 -Trp-Tyr-Va 1 -Dpr (2-
(4-methylphenylsulfonamido)acetyl)-Pro-Ser-Met(0)
Figure imgf000079_0001
(4-methylphenylsulfonamido) acetyl) -Pro-Ser-Met (0)
Figure imgf000079_0001
상기 3-1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 2-(4-메틸페닐설폰아미도)아세트산 It was synthesized using the same method as in the above 3-1, 2- (4-methylphenylsulfonamido) acetic acid as an acid for coupling
(2-(4-methylphenylsLilfonamido)acetic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. (2- (4-methylphenylsLilfonamido) acetic acid) was used. The produced compound was confirmed by mass spectometry (MS).
96.7% Purity. Rt 21.9 min. MALDI m/z calculated for CseHggNnNaOisSa' [M+Na] + 1222.43, found 1222.45. 96.7% Purity. R t 21.9 min. MALDI m / z calculated for CseHggNnNaOisSa '[M + Na] + 1222.43, found 1222.45.
3-70. 3-70.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (2-(4-메틸페닐설폰아미도)아세틸 ) -프 를린-세린-메티오닌 비산화형 ( I soni cot inyl-Trp-Tyr-Val-Dpr(2-Isonicotinyl-tryptophan-tyrosine-valine-Dpr (2- (4-methylphenylsulfonamido) acetyl) -prine-serine-methionine non-oxidized (I soni cot inyl-Trp-Tyr-Val-Dpr (2-
(4-methylphenylsulfonamido)acetyl)-Pro-Ser-Met) (4-methylphenylsulfonamido) acetyl) -Pro-Ser-Met)
Figure imgf000079_0002
Figure imgf000079_0002
상기 3— 69와 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out in the same manner as in 3 to 69, and the compound produced by mass spectrometry (MS) was confirmed.
97.5% Purity. Rt 24.3 min. MALDI m/z calculated for C56H69NuNa0i4S2+ [M+Na] + 1206.44, found 1206.49. 3-71. 97.5% Purity. R t 24.3 min. MALDI m / z calculated for C 56 H 69 N u Na0i 4 S2 + [M + Na] + 1206.44, found 1206.49. 3-71.
이소니코티닐 -트립토판 -타이로신 -발린 -Dpr ( 1-아세틸피페리딘 -4-카복실일 )-프를린Isicotinyl-tryptophan-tyrosine-valine-Dpr (1-acetylpiperidine-4-carboxylyl) -plin
-세린-메티오닌 산화형 (Isonicot inyl-Trp-Tyr-Val-DprSeronic-Methionine Oxidation Type (Isonicot inyl-Trp-Tyr-Val-Dpr
(l-acetylpiperidine-4-carboxylyl)-Pro-Ser-Met(0)) (l-acetylpiperidine-4-carboxylyl) -Pro-Ser-Met (0))
Figure imgf000080_0001
상기 3-1과 동일한 방법을 이용하여 합성하였으며, 커폴링을 위한 산 (add)으로 1-아세틸피페리딘 -4-카복실산 (1-acetylpiper idine-4-carboxylic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.
Figure imgf000080_0001
Synthesis was carried out using the same method as 3-1, and 1-acetylpiperidine-4-carboxylic acid (1-acetylpiper idine-4-carboxylic acid) was used as an acid for adding. The produced compound was confirmed by mass spectometry (MS).
98.1% Purity. Rt 18.7 min. MALDI m/z calculated for CssHyiNnN OwS" [M+Na] + 1164.48, found 1164.57. 98.1% Purity. R t 18.7 min. MALDI m / z calculated for Cs s Yi N N N O w S "[M + Na] + 1164.48, found 1164.57.
3-72. -세린-메티오닌 비산화형 ( I son i cot i nyl-Trp-Tyr-Va 1 -Dpr3-72. Serine-methionine non-oxidizing type (I son i cot i nyl-Trp-Tyr-Va 1 -Dpr
( 1-acetylpiper idine-4-carboxylyl )-Pro~Ser-Met) (1-acetylpiper idine-4- carboxylyl) -Pro ~ Ser-Met)
Figure imgf000080_0002
Figure imgf000080_0002
상기 3-기과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. Synthesis was carried out in the same manner as in the 3-group, and mass spectometry, MS) to confirm the resulting compound.
99.9% Purity. Rt 20.7 min. MALDI m/z calculated for CssHyiNnNaOiaS" [M+Na] + 1148.48, found 1148.57. 3-73. 99.9% Purity. R t 20.7 min. MALDI m / z calculated for Cs s Yi N n Na Oia S "[M + Na] + 1148.48, found 1148.57. 3-73.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (1-페닐 -5- (트리플루오로메틸 피라 졸 -4-카복실일) -프를린-세린-메티오닌 산화형 (Isonicotinyl-Trp-TyrIsicotinyl-tryptophan-tyrosine-valine-Dpr (1-phenyl-5- (trifluoromethylpyrazole-4-carboxyl))-prine-serine-methionine oxidic type (Isonicotinyl-Trp-Tyr
-Va 1 -Dpr ( 1-pheny 1 -5- ( t r i f 1 uor ome t hy 1 ) - IH-y/yr azo 1 e-4-car boxy 1 y 1 )—Pro一 Ser— Met ( l -Va 1 -Dpr (1-pheny 1 -5- (t r i f 1 uorome t hy 1)-IH-y / yr azo 1 e-4-car boxy 1 y 1) —Pro 一 Ser— Met (l
Figure imgf000081_0001
Figure imgf000081_0001
상기 3-1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 1-페닐 -5- (트리플루오로메틸 )-1^피라졸 -4-카복실산 Synthesis was carried out using the same method as in the above 3-1, and 1-phenyl-5- (trifluoromethyl) -1 ^ pyrazole-4-carboxylic acid was used as an acid for coupling.
(l-phenyl-5-(tr i f luoromethyl )-l¾L-pyrazole-4-carboxyl ic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. (l-phenyl-5- (tr if luoromethyl) -l¾ L -pyrazole-4-carboxyl ic acid) was used. The produced compound was confirmed by mass spectometry (MS).
94.9% Purity. Rt 23.0 min. MALDI m/z calculated for C58H65F3Ni2Na013S+ [M+Na] + 94.9% Purity. R t 23.0 min. MALDI m / z calculated for C 58 H 65 F 3 Ni 2 Na0 13 S + [M + Na] +
1249.44, found 1249.50. 1249.44, found 1249.50.
3-74. 3-74.
이소니코티닐-트립토판-타이로신 -발린 -Dpr(l-페닐 -5- (트리플루오로메틸 )-L 피라 졸 -4-카복실일 )-프를린—세린-메티오닌 산화형 (Isonicotinyl-Trp-TyrIsicotinyl-tryptophan-tyrosine-valine-Dpr (l-phenyl-5- (trifluoromethyl) -L pyrazole-4-carboxyyl) -prine-serine-methionine oxidized (Isonicotinyl-Trp-Tyr
-Va 1 -Dpr ( 1-pheny 1 ~5-( t r i f 1 uoromethy 1 )—L¥~pyrazole一 4—carboxylyl )-Pro~Ser-Met ( 0))
Figure imgf000082_0001
-Va 1 -Dpr (1-pheny 1 ~ 5- (trif 1 uoromethy 1) —L ¥ ~ pyrazole 一 4—carboxylyl) -Pro ~ Ser-Met (0))
Figure imgf000082_0001
상기 3— 73과 동일한 방법으로 합성하였으며, 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out in the same manner as in 3 to 73 above, and the produced compound was confirmed by mass spectrometry (MS).
99.9% Purity. Rt 25.3min. MALDI m/z calculated for C58¾5F3N12Na0i2S+ [M+Na]' 1233.44, found 1233.52. 99.9% Purity. R t 25.3 min. MALDI m / z calculated for C 5 8¾ 5 F 3 N 12 Na0i 2 S + [M + Na] '1233.44, found 1233.52.
이소니코티닐―트립토판 -타이로신 -발린 -Dpr (2-티오펜아세틸 ) -프를린-세린-메티오 닌 산 -Tyr-Val-Dpr(2-thiopheneacetyl) -Pro-Ser-Met(O)) Isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-thiophenacetyl) -prine-serine-methionine acid-Tyr-Val-Dpr (2-thiopheneacetyl) -Pro-Ser-Met (O))
Figure imgf000082_0002
Figure imgf000082_0002
상기 3-1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 2-티오펜아세트산 (2ᅳ thiopheneacetic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  2-1 thiopheneacetic acid was used as an acid for coupling. The produced compound was confirmed by mass spectometry (MS).
95.6% Purity. Rt 20.9 min. MALDI m/z calculated for C53H64N10Na0i3S2+ [M+Na] + 1135.40, found 1135.40. 3-76. 95.6% Purity. R t 20.9 min. MALDI m / z calculated for C 53 H 64 N 10 Na0i 3 S2 + [M + Na] + 1135.40, found 1135.40. 3-76.
이소니코티닐ᅳ트립토판 -타이로신 -발린 -Dpr (2-티오펜아세틸) -프롤린-세린-메티오 닌 비산화형 (Isonicotinyl-Tn)-Tyr-Val-Dpr(2-t:hiopheneacetyl) -Pro-Ser-Met ) Isonicotinyl ᅳ tryptophan -Tyrosine -Valine -Dpr (2-thiophenacetyl) -Proline-serine-methionine non-oxidation type (Isonicotinyl-Tn) -Tyr-Val-Dpr (2-t: hiopheneacetyl) -Pro-Ser -Met)
Figure imgf000083_0001
Figure imgf000083_0001
상기 3-75와 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out in the same manner as in 3-75, and the compound produced by mass spectrometry (MS) was confirmed.
97.0% Purity. Rt 23.1 min. MALDI m/z calculated for C53H64Ni0NaOi2S2 + [M+Na] + 1119.40， found 1119.41. 97.0% Purity. R t 23.1 min. MALDI m / z calculated for C 53 H 64 Ni 0 NaOi 2 S 2 + [M + Na] + 1119.40, found 1119.41.
3-77. 3-77.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (벤조트리아졸 -5-카복실일 ) -프를린-세 린-메티오닌 산화형 (Isoni cot i nyl -Trp-Tyr-Val -Dpr (benzot r i azo 1 e~5- 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-
Figure imgf000083_0002
상기 3-1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 벤조트리아졸 -5-카복실산 (benzotriazole-5-carboxylic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.
Figure imgf000083_0002
Synthesis was carried out using the same method as in the above 3-1, and benzotriazole-5-carboxylic acid was used as an acid for coupling. Used. The produced compound was confirmed by mass spectometry (MS).
97.4% Purity. Rt 19.0 min. MALDI m/z calculated for C54H63N13Na013S+ [M+Na] + 1156.43, found 1156.55. 97.4% Purity. R t 19.0 min. MALDI m / z calculated for C 54 H 63 N 13 Na 0 13 S + [M + Na] + 1156.43, found 1156.55.
3-78. 3-78.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (벤조트리아졸 -5-카복실일 ) -프를린-세 린-메티오닌 비산화형 (Isonicotinyl-Trp-Tyr-Val-Dpr(beiizotriazole-5- carboxylyl )-Pro- -Met ) Isicotinyl-tryptophan-tyrosine-valine-Dpr (benzotriazole-5-carboxylyl) -prine-serine-methionine non-oxidized (Isonicotinyl-Trp-Tyr-Val-Dpr Pro- -Met)
Figure imgf000084_0001
Figure imgf000084_0001
83  83
상기 3-77과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  The compound was synthesized in the same manner as in the 3-77, and the produced compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 21.2 min. MALDI m/z calculated for C54H63N13Na0i2S+ [M+Na] +1140.43, found 1140.50. 99.9% Purity. R t 21.2 min. MALDI m / z calculated for C 54 H 63 N 13 Na0i 2 S + [M + Na] + 1140.43, found 1140.50.
3-79. 3-79.
이소니코티닐 -트립토판—타이로신 -발린 -Dpr (4-옥소— 4^크로멘 -3-카복실일 )-프를린Isicotinyl-tryptophan—tyrosine-valine-Dpr (4-oxo— 4 ^ chromen-3-carboxyl) -plin
-세린-메티오닌 산화형 (Isonicotinyl-Trp-Tyr-Val-Dpr (4-0X0-4/^ chr omene-3-c ar boxy 1 y 1 )—Pro— Ser—Met (0) )
Figure imgf000085_0001
-Seroline-Methionine Oxidized Type (Isonicotinyl-Trp-Tyr-Val-Dpr (4-0X0-4 / ^ chr omene-3-c ar boxy 1 y 1) —Pro— Ser—Met (0))
Figure imgf000085_0001
상기 3-1과 동일한 방법을 이용하여 합성하였으며， 커플.링을 위한 산 (acid)으로 4—옥소 -4^크로멘 -3—카복실산 (4-ox으 4^chromene-3— carboxyl ic acid)을 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out using the same method as described in 3-1, and 4—oxo-4 ^ chromen-3—carboxylic acid (4-ox 4 ^ chromene-3—carboxyl ic acid) as an acid for coupling. Was used. The produced compound was confirmed by mass spectometry (MS).
98.4% Purity. Rt 21.4 min. MALDI m/z calculated for C57H64N10Na0i5S+ [M+Na] + 1183.42， found 1183.48. 98.4% Purity. R t 21.4 min. MALDI m / z calculated for C 57 H 64 N 10 Na0i 5 S + [M + Na] + 1183.42, found 1183.48.
3-80. 3-80.
이소니코티닐-트립토판 -타이로신—발린— Dpr (4-옥소 -4^크로멘 -3-카복실일 )-프를린Isnicotinyl-tryptophan-tyrosine—valine— Dpr (4-oxo-4 ^ chromen-3-carboxyl) -plin
-세린-메티오닌 비산화형 (Isonicotinyl -Trp-Tyr-Va 1 -Dpr ( 4—oxo—4가 chr omene-3-c ar boxy 1 y 1 )—Pro—Ser— Met ) 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)
Figure imgf000085_0002
Figure imgf000085_0002
상기 3-79와 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물올 확인하였다.  The compound was synthesized in the same manner as in the 3-79, and the compound produced by mass spectrometry (MS) was confirmed.
99.9% Purity. Rt 23.5 min. MALDI m/z calculated for C57H64N10Na0i4S+ [M+Na]' 1167.42, found 1167.57. 3-81. 99.9% Purity. R t 23.5 min. MALDI m / z calculated for C 57 H 64 N 10 Na0i 4 S + [M + Na] '1167.42, found 1167.57. 3-81.
이소니코티닐 -트립토판 -타이로신—발린 -Dpr (4-메틸— 2-옥소 크로멘 -그일옥시 )아 세틸 ) -프를린-세린-메티오닌 산화형 (Isonicotinyl -Trp-Tyr-Va 1 -DprIsicotinyl-tryptophan-tyrosine—valine-Dpr (4-methyl—2-oxochromen-gyloxy) acetyl) -prine-serine-methionine oxidized (Isonicotinyl-Trp-Tyr-Va 1 -Dpr
((4-methyl-2-oxo-2ff-chromen-7-yloxy)acetyl)-Pro-Ser-Met(0)) ((4-methyl-2-oxo-2ff-chromen-7-yloxy) acetyl) -Pro-Ser-Met (0))
Figure imgf000086_0001
Figure imgf000086_0001
상기 3-1과 동일한 방법을 이용하여 합성하였으며， 커플링을 위한 산 (acid)으로 4ᅳ메틸 -2-옥소— 2 -크로멘 -7-일옥시)아세트산 Synthesis was carried out using the same method as in the above 3-1, and 4 ᅳ methyl-2-oxo- 2-chromen-7-yloxy) acetic acid was used as an acid for coupling.
( 4-me t hy 1 -2-oxo-2^chr omen-7-y 1 oxy ) ace t i c acid)을' 사용하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. A (4-me t hy 1 -2 -oxo-2 ^ chr omen-7-y 1 oxy) ace tic acid) ' was used. The produced compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 21.0 min. MALDI m/z calculated for C59H68N10Na016S+ [M+Na]+ 1227.44, found 1227.51. 99.9% Purity. R t 21.0 min. MALDI m / z calculated for C 59 H 68 N 10 Na0 16 S + [M + Na] + 1227.44, found 1227.51.
3-82. 3-82.
이소니코티닐―트립토판 -타이로신 -발린 -Dpr (4-메틸 -2-옥소 -2^크로멘 7-일옥시 )아 세틸) -프를린-세린-메티오닌 비산화형 (Isonicotinyl-Trp— Tyr-Val-DprIsicotinyl-tryptophan-tyrosine-valine-Dpr (4-methyl-2-oxo-2 ^ chromen 7-yloxy) acetyl) -prine-serine-methionine non-oxidative type (Isonicotinyl-Trp— Tyr-Val -Dpr
( (4-methy 1 -2-Qxo-2/it-chromen-7-y 1 oxy ) acetyl )~Pro一 Ser一 Met )
Figure imgf000087_0001
((4-methy 1-2-Qxo-2 / i t -chromen-7-y 1 oxy) acetyl) ~ Pro 一 Ser 一 Met)
Figure imgf000087_0001
상기 3-81과 동일한 방법으로 합성하였으며, 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Synthesis was carried out in the same manner as in the above 3-81, and the compound produced by the mass spectrometry (MS) was confirmed.
96.4% Purity. Rt 23.0 min. MALDI m/z calculated for C59H68N10Na0i5S+ [M+Na] 1211.45, found 1211.54. 제조예 4. Dpr(acyl)-Pro-Ser-Met의 합성 96.4% Purity. R t 23.0 min. MALDI m / z calculated for C 59 H 68 N 10 Na0i 5 S + [M + Na] 1211.45, found 1211.54. Preparation Example 4 Synthesis of Dpr (acyl) -Pro-Ser-Met
상기 제조예 3을 통해 제조된 화합물들의 7개 아미노산 잔기들이 모두 동일한 결합강도로 또는 필수적으로 peptide-dTCTP binding 에 기여하는 것은 아니므로, tight binding residues는 남겨두고 loose binding residues 는 잘라낸다면, 활성에 큰 영향 없이 화합물의 크기를 최소화 할 수 있을 것이라는 판단아래 , 이를 위해 Dpr site를 중심으로 N¾말단의 테트라머 (tetramer )와 C00H 말단의 테트라머 (tetramer), 2개의 부분으로 나누었다 (도 3).  Since the seven amino acid residues of the compounds prepared in Preparation Example 3 do not all contribute to the same binding strength or essentially peptide-dTCTP binding, if tight binding residues are left but loose binding residues are cut off, In order to minimize the size of the compound without affecting, for this purpose, it was divided into two parts, a tetramer at the N¾ terminal and a tetramer at the C00H terminal, centering on the Dpr site (FIG. 3).
제조예 3을 통해 제조된 화합물 중, dTBP2 보다 효과적으로 나온 화합물들을 살펴보면, 4개의 acid 구조는 공통적이었고, 나머지 11개의 구조는 어느 한쪽에서 효과적인 것으로 나타났다 (도 4). 따라서 15개의 acids 를 선정하여 제조예 4 및 5의 화합물을 합성하였다. 1. i Of the compounds prepared in Preparation Example 3, when looking at the compounds that came out more effectively than dTBP2, four acid structures were common, and the remaining 11 structures appeared to be effective on either side (FIG. 4). Thus, 15 acids were selected to synthesize the compounds of Preparation Examples 4 and 5. I
ii  ii
2. i  2. i
ii  ii
3. i  3. i
ii
Figure imgf000088_0001
ii
Figure imgf000088_0001
Figure imgf000088_0002
Figure imgf000088_0002
Wang resin에 Fmoc-based SPPS올 이용하여 15개의 산 (acid)이 커플링된 C00H말단의 tetramer를 합성하였으나, rhodanine-3-acetic acid를 제외한 14개의 화합물과 Methione잔기의 sulfur가 산화된 5개의 화합물이 만들어졌다. 산화형과 비산화형의 생성 비율은 1:2.3 에서부터 1:5.6까지 다양하게 나타났다. 결과적으로 총 19개의 화합물이 합성되었다 (88- 106). 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).
4-1. - Dpr (4-펜틸바이사이클로 [2.2.2]옥탄 -1-카복실일) -프를린-세린―메티오닌 산화형 (Dpr(4-pentylbicyclo[2.2.2]octane-l-carboxylyl)-Pro-Ser-Met(0))
Figure imgf000089_0001
4-1. Dpr (4-pentylbicyclo [2.2.2] octane-1-carboxylyl) -prine-serine-methionine oxidic type (Dpr (4-pentylbicyclo [2.2.2] octane-l-carboxylyl) -Pro- Ser-Met (0))
Figure imgf000089_0001
88 상기 제조예 3과 동일한 방법으로88 In the same manner as in Preparation Example 3
Dpr (4-펜틸바이사'이클로 [2.2.2]옥탄— 1-카복실일)ᅳ프롤린 -세린 -메티오닌을 Dpr (4-pentylbaisa ' iclo [2.2.2] octane—1-carboxylyl) proline-serine-methionine
고체상으로 합성한 후， resin (25 mg, 0.011 mmol)를 필터가 설치된 1 mL Micro Bio-Spin chromatography column에 넣고, 20% piper idine/무수 DMF (0.5 mL)를 사용하여 Fmoc 그룹을 제거하고, degassed 94% TFA cocktail (0.5 mL)을 첨가하여 상온에서 1시간 동안 흔합한 후 여과하여 여액을 받고， 다시 TFA용액 (0.3 mL X 2)으로 세척하여 그 여액을 받았다. 위 여액들을 합하여 evaporator를 이용하여 TFA를 제거한 후， cold ether를 사용하여 3회 decant at ion하였다. 이때 생성된 화합물의 손실을 막기 위해 원심 분리기를 이용하였으며, 건조시킨 후 semi-preparat ive HPLC (binary solvent system, solvent A: 0.1% TFA/H2O , solvent B: 0.1% TFA/CH3CN, 5- 100% B over 42 min)를 이용하여 분리 및 정제하고 동결 건조한 후 질량분석계 (mass spectometry, MS)로 확인하였다. After synthesis in solid phase, resin (25 mg, 0.011 mmol) was placed in a 1 mL Micro Bio-Spin chromatography column equipped with a filter, 20% piper idine / anhydrous DMF (0.5 mL) was used to remove the Fmoc group and degassed. 94% TFA cocktail (0.5 mL) was added thereto, and the mixture was mixed at room temperature for 1 hour, filtered to obtain a filtrate, and washed again with TFA solution (0.3 mL X 2) to receive the filtrate. The filtrates were combined to remove TFA using an evaporator and then decant at ion three times using cold ether. At this time, centrifuge was used to prevent the loss of the compound, and after drying, semi-preparative HPLC (binary solvent system, solvent A: 0.1% TFA / H2O, solvent B: 0.1% TFA / CH3CN, 5- 100%) B over 42 min) was isolated and purified, and lyophilized, and confirmed by mass spectometry (MS).
99.9% Purity. Rt 24.8 min. MALDI m/z calculated for C30H52N508S+ [M+H] + 642.35, found 642.38 99.9% Purity. R t 24.8 min. MALDI m / z calculated for C 30 H 52 N 5 0 8 S + [M + H] + 642.35, found 642.38
4-2. 4-2.
Dpr (4-펜틸바이사이클로 [2.2.2]옥탄 -1-카복실일 ) -프를린ᅳ세린-메티오닌 비산화형 (Dpr (4-pentylbicyc 1 o[2.2.2] oct ane—l— car boxy lyl )— Pro—Ser—Met )
Figure imgf000090_0001
상기 4—1과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고， NMR과 13C NMR을 이용하여 추가로 확인하였다. Dpr (4-pentylbicyclo [2.2.2] octane-1-carboxylyl) -plinxetrine-methionine non-oxidative type (Dpr (4-pentylbicyc 1 o [2.2.2] oct ane—l— car boxy lyl ) — Pro—Ser—Met)
Figure imgf000090_0001
Synthesis was carried out in the same manner as in the above 4-1, the compound produced by mass spectrometry (MS) was confirmed, and further confirmed by NMR and 13 C NMR.
99.9% Purity. Rt 27.4 min. ¾ NMR (400 MHz, D20) : δ 4.62- 4.56 (m, 2H),99.9% Purity. R t 27.4 min. ¾ NMR (400 MHz, D 2 0): δ 4.62-4.56 (m, 2H),
4.52- 4.47 (m, 2H), 3.97- 3.89 (m, 2H), 3.80- 3.73 (m, 2H), 3.67- 3.59 (m, 2H), 2.66-2.52 (m, 2H) , 2.40 (m, 1H), 2.21 (m, 1H), 2.10 (s, 3H), 2.07- 1.92 (m, 4H), 1.79- 1.70 (m, 6H), 1.46- 1.39 (m, 6H), 1.32- 1.08 (m, 8H), 0.85 (t, 3H, / = 6.8). 13C匪 R (100 MHz, D20): δ 182.2， 175.2, 173.2, 171.5， 167.0, 61.3, 60.8, 56.0， 52.1， 51.1, 48.3, 41.4, 40.0, 39,4, 33.0, 30.8, 30.6, 30.3, 29.9, 29.7, 28.6, 24.8, 23.5, 22.7, 14.8， 14,0. MALDI m/z calculated for C30H52N507S+ [M+H] + 626.36, found 626.38. 4.52- 4.47 (m, 2H), 3.97-3.89 (m, 2H), 3.80-3.73 (m, 2H), 3.67-3.59 (m, 2H), 2.66-2.52 (m, 2H), 2.40 (m, 1H ), 2.21 (m, 1H), 2.10 (s, 3H), 2.07-1.92 (m, 4H), 1.79-1.70 (m, 6H), 1.46- 1.39 (m, 6H), 1.32- 1.08 (m, 8H) ), 0.85 (t, 3H, / = 6.8). 13 C 匪 R (100 MHz, D 2 0): δ 182.2, 175.2, 173.2, 171.5, 167.0, 61.3, 60.8, 56.0, 52.1, 51.1, 48.3, 41.4, 40.0, 39,4, 33.0, 30.8, 30.6, 30.3, 29.9, 29.7, 28.6, 24.8, 23.5, 22.7, 14.8, 14,0. MALDI m / z calculated for C 30 H 5 2N 5 0 7 S + [M + H] + 626.36, found 626.38.
4-3. Dpr (타이글라일)—프롤린-세린-메티오닌 산화형 (Dpr(tiglyl)-Pn>-Ser -Met(0)) SM(O) 4-3. Dpr (Taigliyl) —proline-serine-methionine oxidized type (Dpr (tiglyl) -Pn> -Ser-Met (0)) SM (O)
Figure imgf000090_0002
상기 제조예 3과 동일한 방식으로 Dpr (타이글라일)ᅳ프롤린-세린-메티오닌 을 고체상으로 합성한 후， 상기 제조예 4-1과 동일한 방법으로 합성하였으며, 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.
Figure imgf000090_0002
In the same manner as in Preparation Example 3, Dpr (Tiglyyl) ᅳ proline-serine-methionine was synthesized in the solid phase, and then synthesized in the same manner as in Preparation Example 4-1, and produced by mass spectometry (MS). Identified compounds were identified.
99.9% Purity. Rt 12.2min. MALDI m/z calculated for C2i¾6N508S+ [M+H]+518.23 found 518.27. 99.9% Purity. R t 12.2 min. MALDI m / z calculated for C 2 i¾ 6 N 5 0 8 S + [M + H] + 518.23 found 518.27.
4-4. Dpr (타이글라일 ) -프를린-세린-메티오닌 비산화형4-4. Dpr (Taigliyl) -Plin-serine-Methionine Non-oxidized Type
(Dpr(tiglyl)-Pro-Ser -Met) (Dpr (tiglyl) -Pro-Ser -Met)
Figure imgf000091_0001
Figure imgf000091_0001
91 상기 4-3과 동일한 방법으로 합성하였으며, 질량분석계 (mass spectometry, 91 was synthesized in the same manner as in the above 4-3, mass spectometry,
MS)로 생성된 화합물을 확인하였고， ¾ NMR과 13C 匪 R을 이용하여 추가로 확인하였다. MS) was confirmed, and further confirmed by using ¾ NMR and 13 C 匪 R.
99.9% Purity. Rt 16.8 min. ¾ NMR (400 MHz, D20): δ 6.57 (q, 1H, /= 7.2)， 4.63- 4.55 (m, 3H), 4.46 (t, 1H, J = 5.6)， 3.97- 3.88 (m, 3H), 3.81 (m, 1H), 3.75- 3.68 (m, 2H), 2.74- 2.53 (m, 2H), 2.40 (m, 1H) , 2.22 (m, 1H), 2.13 (s, 3H), 2.12- 1.98 (m, 4H), 1.86 (s, 3H), 1.81 (d, 3H, J= 7.2). 13C NMR (125 MHz, D20): δ 175.7, 173.8, 173.7， 171.6, 166.6, 135.2, 130.0, 61.1, 60.8， 56.0, 52.3， 52.2， 48.2, 39.5, 30.4, 29.7, 29.5, 24.9， 14.3， 13.7， 11.6. MALDI m/z calculated for C21H36N507S+ [M+H]+ 502.23， found 502.30. 99.9% Purity. R t 16.8 min. ¾ NMR (400 MHz, D 2 0): δ 6.57 (q, 1H, / = 7.2), 4.63-4.55 (m, 3H), 4.46 (t, 1H, J = 5.6), 3.97-3.88 (m, 3H ), 3.81 (m, 1H), 3.75-3.68 (m, 2H), 2.74-2.53 (m, 2H), 2.40 (m, 1H), 2.22 (m, 1H), 2.13 (s, 3H), 2.12- 1.98 (m, 4H), 1.86 (s, 3H), 1.81 (d, 3H, J = 7.2). 13 C NMR (125 MHz, D 2 0): δ 175.7, 173.8, 173.7, 171.6, 166.6, 135.2, 130.0, 61.1, 60.8, 56.0, 52.3, 52.2, 48.2, 39.5, 30.4, 29.7, 29.5, 24.9, 14.3 , 13.7, 11.6. MALDI m / z calculated for C 21 H 36 N 5 0 7 S + [M + H] + 502.23, found 502.30.
4-5. Dpr(5-클로로인돌 -2-카복실일) -프를린-세린-메티오닌 산화형4-5. Dpr (5-chloroindole-2-carboxylyl) -prine-serine-methionine oxidation type
(Dpr ( 5-ch loroi ndo 1 e-2-carboxylyl ) -Pro-Ser-Met (0 ) )
Figure imgf000092_0001
(Dpr (5-ch loroi ndo 1 e-2-carboxylyl) -Pro-Ser-Met (0))
Figure imgf000092_0001
92 상기 제조예 3과 동일한 방식으로 92 In the same manner as in Preparation Example 3
Dpr(5ᅳ클로로인돌 -2-카복실일)ᅳ프롤린 -세린 -메티오닌을 고체상으로 합성한 후， 상기 제조예 4-1과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. Dpr (5 ᅳ chloroindole-2-carboxylyl) ᅳ proline-serine-methionine was synthesized in the solid phase, and then synthesized in the same manner as in Preparation Example 4-1, and produced by mass spectometry (MS). It was confirmed.
99.9% Purity. Rt 19.4 min. MALDI m/z calculated for C25H34C1N608S+ [M+H] + 613.18, found 613.22. 99.9% Purity. R t 19.4 min. MALDI m / z calculated for C 25 H 34 C 1 N 6 0 8 S + [M + H] + 613.18, found 613.22.
4-6. Dpr (5-클로로인돌 -2-카복실일) -프를린-세린-메티오닌 비산화형 (Dpr(5-chloroindole-2-carboxylyl)-Pro-Ser-Met) 4-6. Dpr (5-chloroindole-2-carboxylyl) -prine-serine-methionine nonoxidative type (Dpr (5-chloroindole-2-carboxylyl) -Pro-Ser-Met)
Figure imgf000092_0002
Figure imgf000092_0002
93 상기 4-5와 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물올 확인하였고, 匪 R과 13C NMR을 이용하여 추가로 확인하였다. 93 Synthesis was carried out in the same manner as in the above 4-5, the compound produced by mass spectrometry (MS) was confirmed, and further confirmed by 하여 R and 13 C NMR.
97.3% Purity. Rt 22.5 min. 證 (400 MHz, D20): δ 7.74 (d, 1H, J= 2.0), 7.50 (del, 1H, J- 8.8, J= 0.4)， 7.33 (dd, 1H, /= 8.8, /= 2.0), 7.07 (s, 1H), 4.70- 4.63 (m, 2H), 4.48- 4.42 (m, 2H) , 4.00 (td, 1H, J = 14.8, J= 5.6), 3.96 (td, 1H, J= 14.8, J = 5.6)， 3.91 (d, 2H, /= 5.6)， 3.83 (m, 1H)， 3.72 (m, 1H) , 2.51-.2.37 (m, 3H), 2.12- 2.01 (m, 4H), 1.99 (s, 3H), 1.94 (m, 1H). 13C NMR (125 MHz, D20): δ 175.7, 173.8， 171.5, 166.8, 164.3， 135.4, 130.8, 128.1， 125.8, 125.3, 121.4, 113.8, 104.6, 61.0, 60.9, 56.0, 52.4, 52.0, 48.4, 39.2, 30.3, 29.7, 29.5, 24.9, 14.2. MALDI m/z calculated for C25H34C1N607S+ [M+H]+ 597.19, found 597.26. 4-7. Dpr(2-(2-시아노페닐티오)벤조일) -프를린-세린-메티오닌 산화형97.3% Purity. R t 22.5 min. 400 (400 MHz, D 2 0): δ 7.74 (d, 1H, J = 2.0), 7.50 (del, 1H, J-8.8, J = 0.4), 7.33 (dd, 1H, / = 8.8, / = 2.0), 7.07 (s, 1H), 4.70- 4.63 (m, 2H), 4.48-4.42 ( m, 2H), 4.00 (td, 1H, J = 14.8, J = 5.6), 3.96 (td, 1H, J = 14.8, J = 5.6), 3.91 (d, 2H, / = 5.6), 3.83 (m, 1H), 3.72 (m, 1H), 2.51-.2.37 (m, 3H), 2.12- 2.01 (m, 4H), 1.99 (s, 3H), 1.94 (m, 1H). 13 C NMR (125 MHz, D 2 0): δ 175.7, 173.8, 171.5, 166.8, 164.3, 135.4, 130.8, 128.1, 125.8, 125.3, 121.4, 113.8, 104.6, 61.0, 60.9, 56.0, 52.4, 52.0, 48.4 , 39.2, 30.3, 29.7, 29.5, 24.9, 14.2. MALDI m / z calculated for C 2 5H 3 4 C1N 6 0 7 S + [M + H] + 597.19, found 597.26. 4-7. Dpr (2- (2-cyanophenylthio) benzoyl) -prine-serine-methionine oxidation type
(Dpr(2-(2-cyanophenylthio)benzoyl)-Pro-Ser-Met(0)) (Dpr (2- (2-cyanophenylthio) benzoyl) -Pro-Ser-Met (0))
Figure imgf000093_0001
상기 제조예 3과 동일한 방식으로
Figure imgf000093_0001
In the same manner as in Preparation Example 3
Dpr(2-(2-시아노페닐티오)벤조일) -프를린 -세린 -메티오닌을 고체상으로 합성한 후， 상기 제조예 4-1과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. Dpr (2- (2-cyanophenylthio) benzoyl) -prine-serine-methionine was synthesized in the solid phase, and then synthesized in the same manner as in Preparation Example 4-1, mass spectometry (MS) The produced compound was confirmed.
99.9% Purity. Rt 19.0 min. MALDI m/z calculated for C30H37N608S2 + [M+H]+ 673.21, found 673.31. 99.9% Purity. R t 19.0 min. MALDI m / z calculated for C 30 H 37 N 6 0 8 S 2 + [M + H] + 673.21, found 673.31.
4-8. Dpr(2-(2-시아노페닐티오)벤조일) -프롤린-세린-메티오닌 비산화형4-8. Dpr (2- (2-cyanophenylthio) benzoyl) -proline-serine-methionine non-oxidized
(Dpr (2~(2~cyanophenyI thi o)benzoyI )~Pr으 Ser一 Met ) (Dpr (2 ~ (2 ~ cyanophenyI thi o) benzoyI) ~ Pr SerI Met)
Figure imgf000094_0001
Figure imgf000094_0001
95 상기 4— 7와 동일한 방법으로 합성하였으며, 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고， 蘭 R과 13C NMR을 이용하여 추가로 확인하였다. 95 Synthesis was carried out in the same manner as 4-7, the compound produced by mass spectrometry (MS) was confirmed, and it was further confirmed using 蘭 R and 13 C NMR.
99.9% Purity. Rt 22.1 min. ¾ NMR (400 MHz, D20): δ 7.85 (d, 1H, J= 8.0),99.9% Purity. R t 22.1 min. ¾ NMR (400 MHz, D 2 0): δ 7.85 (d, 1H, J = 8.0),
7.67- 7.35 m, 7H), 4.66 (t, 1H, 5.2), 4.60 (t, 1H, J- 7.2)， 4.47 (dd, 1H, J = 8.8, / = 4.8), 4.38 (t, 1H, J - 5.6), 3.92- 3.71 (m, 6H)， 2.59- 2.34 (m, 4H), 2.20- 1.93 (m, 5H) , 2.07 (s, 3H) . 13C MR (125 MHz, D20)： δ 175.4, 173.6, 172.1, 171.5， 166.5, 13.8.7, 136.1， 134.7, 134.4， 133.8, 133.2, 132.5, 132.1, 128.9, 128.8, 128.5, 117.9, 114.5, 61.1， 60.9, 55.9， 52.1， 52.0, 48.4, 39.6, 30.3, 29.6， 29.5, 24.9， 14.3. MALDI m/z calculated for C30H37N607S2+ [M+H]+ 657.22, found 657.33. 7.67-7.35 m, 7H), 4.66 (t, 1H, 5.2), 4.60 (t, 1H, J-7.2), 4.47 (dd, 1H, J = 8.8, / = 4.8), 4.38 (t, 1H, J 5.6), 3.92-3.71 (m, 6H), 2.59-2.34 (m, 4H), 2.20- 1.93 (m, 5H), 2.07 (s, 3H). 13 C MR (125 MHz, D 2 0): δ 175.4, 173.6, 172.1, 171.5, 166.5, 13 . 8.7, 136.1, 134.7, 134.4, 133.8, 133.2, 132.5, 132.1, 128.9, 128.8, 128.5, 117.9, 114.5, 61.1, 60.9, 55.9, 52.1, 52.0, 48.4, 39.6, 30.3, 29.6, 29.5, 24.9, 14.3. MALDI m / z calculated for C 30 H 37 N 6 0 7 S 2+ [M + H] + 657.22, found 657.33.
4-9. Dpr (퀴날딜) -프를린-세린―메티오닌 산화형 (Dpr(quinaldyl) -Pro-Ser-Met(O)) 4-9. Dpr (quinalyl) -prine-serine-methionine oxidized type (Dpr (quinaldyl) -Pro-Ser-Met (O))
Figure imgf000095_0001
Figure imgf000095_0001
96 상기 제조예 3과 동일한 방식으로 Dpr (퀴나딜)—프를린 -세린 -메티오닌을 고체상으로 합성한 후， 상기 제조예 4-1과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  96 In the same manner as in Preparation Example 3, Dpr (quinadyl) -prine-serine-methionine was synthesized in the solid phase, and then synthesized in the same manner as in Preparation Example 4-1, mass spectometry (MS). The produced compound was confirmed.
99.9% Purity. Rt 16.2 min. MALDI m/z calculated for C26H35N608S+ [M+H]+ 591.22, found 591.25. 99.9% Purity. R t 16.2 min. MALDI m / z calculated for C 26 H 35 N 6 0 8 S + [M + H] + 591.22, found 591.25.
54-10. Dpr (퀴날딜) -프를린―세린-메티오닌 비산화형 (Dpr(quinaldyl)54-10. Dpr (quinalyl) -prine-serine-methionine non-oxidative type (Dpr (quinaldyl)
-Pro-Ser-Met ) -Pro-Ser-Met)
Figure imgf000095_0002
Figure imgf000095_0002
97 상기 4-9와 동일한 방법으로 합성하였으며, 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  97 The compound was synthesized in the same manner as in the method 4-9, and the resulting compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 19.8 min. ¾匪 R (400 MHz, D20)： δ 8.61 (d, 1H, = 8.8)， 8.15 (d, 1H, J = 8.4)， 8.12 (d, 1H, J - 8.8), 8.09 (d, 1H, J = 8.4), 7.95 (t, 1H, J=8.4), 7.79 (t, 1H, J=8.4), 4.74 (t, 1H, J=5.6), 4.63 (m, 1H), 4.44- 4.39 (m, 2H), 4.08- 4.06 (m, 2H), 3.87- 3.83 (m, 4H)， 2.49- 2.33 (m, 3H) , 2.12- 2.00 (m, 4H), 1.98 (s, 3H), 1.90 (m, 1H). 1C NMR (125 MHz, D20)： δ 175.1, 173.6, 171.5, 167.8, 166.7, 148.3, 145.6， 140.0， 131.8, 129.7, 129.3, 128.5, 128.3, 118.8, 61.0, 55.9, 52.1, 51.8, 51.7, 48.4, 39.4, 30.1, 29.7, 29.4, 24.9, 14.2. MALDI m/z calculated for C26H35N607S+ [M+H]+ 575.23， found 575.28.
Figure imgf000096_0001
99.9% Purity. R t 19.8 min. ¾ 匪 R (400 MHz, D 2 0): δ 8.61 (d, 1H, = 8.8), 8.15 (d, 1H, J = 8.4), 8.12 (d, 1H, J-8.8), 8.09 (d, 1H, J = 8.4), 7.95 (t, 1H, J = 8.4), 7.79 (t, 1H, J = 8.4), 4.74 (t, 1H, J = 5.6), 4.63 (m, 1H), 4.44- 4.39 (m, 2H), 4.08-4.06 (m, 2H), 3.87-3.83 (m, 4H), 2.49-2.33 (m, 3H), 2.12- 2.00 (m, 4H), 1.98 (s, 3H), 1.90 (m, 1H). 1 C NMR (125 MHz, D 2 0): δ 175.1, 173.6, 171.5, 167.8, 166.7, 148.3, 145.6, 140.0, 131.8, 129.7, 129.3, 128.5, 128.3, 118.8, 61.0, 55.9, 52.1, 51.8, 51.7 , 48.4, 39.4, 30.1, 29.7, 29.4, 24.9, 14.2. MALDI m / z calculated for C 26 H 35 N 6 0 7 S + [M + H] + 575.23, found 575.28.
Figure imgf000096_0001
(2-f luorophenylacetyl)-Pro-Ser-Met)  (2-f luorophenylacetyl) -Pro-Ser-Met)
Figure imgf000096_0002
Figure imgf000096_0002
98 상기 제조예 3과 동일한 방식으로98 In the same manner as in Preparation Example 3
Dpr (2-플루오로페닐아세틸) -프를린ᅳ세린 -메티오닌을 고체상으로 합성한 후， 상기 제조예.4-1과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고， NMR과 13C NMR을 이용하여 추가로 확인하였다. 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.
99.9% Purity. Rt 19.1 min. ¾ NMR (400 MHz, D20)： δ 7.43- 7.33 (m, 2H) ' 7.24- 7.17 (m, 2H) , 4.61— 4.54 (m, 3H) , 4.46 (t, 1H, J = 5.6)， 3.94— 3.61 (m, 8H), 2.66- 2.51 (m, 2H)， 2.38 (m, 1H) , 2.21 (m, 1H) , 2.09 (s, 3H) , 2.07- 1.94 (tn, 4H). 13C NMR (100 MHz, D20): δ 175.4， 175.1, 173.4, 171.3， 166.3, 160.9 (d, JC-F = 242.2), 131.9 (d, JC-F = 3.8), 129.6 (d, JC-F ^ 7.7), 124.5 (d, JC-F = 3.9), 121.2 (d, JC-F= 16.2), 115.3 (d, JC-F= 2Q.9) , 60.9, 60.6, 55.6, 51.7, 48.0, 39.2, 35.5, 35.4, 30.0， 29.4, 29.3, 24.6， 13.9. MALDI m/z calculated for C24¾5FN507S+ [M+H]+ 556.22, found 556.29. 99.9% Purity. R t 19.1 min. ¾ NMR (400 MHz, D 2 0): δ 7.43-7.33 (m, 2H) '7.24- 7.17 (m, 2H), 4.61-4.54 (m, 3H), 4.46 (t, 1H, J = 5.6) ， 3.94— 3.61 (m, 8H), 2.66- 2.51 (m, 2H), 2.38 (m, 1H), 2.21 (m, 1H), 2.09 (s, 3H), 2.07-1.94 (tn, 4H). 13 C NMR (100 MHz, D 2 0): δ 175.4, 175.1, 173.4, 171.3, 166.3, 160.9 (d, J C -F = 242.2), 131.9 (d, J C -F = 3.8), 129.6 (d , JC-F ^ 7.7), 124.5 (d, J C -F = 3.9), 121.2 (d, JC-F = 16.2), 115.3 (d, J C - F = 2Q.9), 60.9, 60.6, 55.6 , 51.7, 48.0, 39.2, 35.5, 35.4, 30.0, 29.4, 29.3, 24.6, 13.9. MALDI m / z calculated for C24¾ 5 FN 5 0 7 S + [M + H] + 556.22, found 556.29.
4-12. Dpr (7-메톡시 -1—벤조퓨란 -2-카복실일) -프를린-세린-메티오닌 (Dpr ( 7-me t hoxy- 1-benzo f ur an-2-c ar boxy 1 y 1 )-Pro-Ser-Met ) 4-12. Dpr (7-methoxy-1-benzofuran-2-carboxylyl) -prine-serine-methionine (Dpr (7-me t hoxy-1-benzo f ur an-2-c ar boxy 1 y 1) -Pro-Ser-Met)
Figure imgf000097_0001
Figure imgf000097_0001
99 상기 제조예 3과 동일한 방식으로 99 In the same manner as in Preparation Example 3
Dpr ( 7-메록시ᅳ 1-벤조퓨란 -2-카복실일) -프를린 -세린 -메티오닌을 고체상으로 합성한 후, 상기 제초예 4-1과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고， ¾ NMR과 13C NMR을 이용하여 추가로 확인하였다. 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 ¾ NMR and 13 C NMR.
99.9% Purity. Rt 20.5 min. ¾匪 R (400 MHz, D20)： δ 7.57 (s, 1H)， 7.39 (dd, 1H, /= 8.0, J = 0.8), 7.34 (t, 1H, J= 8.0), 7.14 (dd, 1H, J = 8.0, J = 0.8), 4.70 (dd, 1H, J = 6.0, J = 4.8), 4.62 (dd, 1H, J = 8.8， J 5.6)， 4.45 (d, 1H, J = 6.0)， 4.44 (dd, 1H, J = 5.2， J= 2.0), 4.05 (s, 3H) , 4.02- 3.95 (m, 2H), 3.89 (d, 2H, J = 5.6), 3.86— 3.77 (m, 2H), 2.52- 2.37 (m, 3H), 2.15- 2.05 (m, 4H), 2.02 (s, 3H) , 1.91 (m, 1H). 13C丽 R (100 MHz, D20) : δ 174.9, 173.4, 171.2， 166.3， 161.8, 146.8, 144.9， 144.3, 128.5， 124.9, 115.2， 112.2, 109.6， 60.8, 60.7, 56.1, 55.6, 51.8， 51.6, 48.1, 38.8, 29.9, 29.3, 29.1, 24.6, 13.9. MALDI m/z calculated for C26H36N509S+ [M+H]+ 594.22, found 594.35. 4-13, Dpr (오로틸) -프를린-세린-메티오닌 (Dpr orotyD-PrO-Ser-Met) 99.9% Purity. R t 20.5 min. ¾ 匪 R (400 MHz, D 2 0): δ 7.57 (s, 1H), 7.39 (dd, 1H, / = 8.0, J = 0.8), 7.34 (t, 1H, J = 8.0), 7.14 (dd, 1H, J = 8.0, J = 0.8), 4.70 (dd, 1H, J = 6.0, J = 4.8), 4.62 (dd, 1H, J = 8.8, J 5.6), 4.45 (d, 1H, J = 6.0) , 4.44 (dd, 1H, J = 5.2, J = 2.0), 4.05 (s, 3H), 4.02- 3.95 (m, 2H), 3.89 (d, 2H, J = 5.6), 3.86— 3.77 (m, 2H ), 2.52- 2.37 (m, 3H), 2.15- 2.05 (m, 4H), 2.02 (s, 3H), 1.91 (m, 1H). 13 Clli R (100 MHz, D 2 0): δ 174.9, 173.4, 171.2, 166.3, 161.8, 146.8, 144.9, 144.3, 128.5, 124.9, 115.2, 112.2, 109.6, 60.8, 60.7, 56.1, 55.6, 51.8, 51.6, 48.1, 38.8, 29.9, 29.3, 29.1, 24.6, 13.9. MALDI m / z calculated for C 26 H 36 N 5 0 9 S + [M + H] + 594.22, found 594.35. 4-13, Dpr (orotyl) -prine-serine-methionine (Dpr orotyD-PrO-Ser-Met)
Dpr-PSDpr-PS
Figure imgf000098_0001
Figure imgf000098_0001
100  100
상기 제조예 3과 동일한 방식으로 Dpr (오로틸)—프를린 -세린ᅳ메티오닌을 고체상으로 합성한 후， 상기 제조예 4-1과 동일한 방법으로 합성하였으며, 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고， ¾ NMR과 13C NMR을 이용하여 추가로 확인하였다. In the same manner as in Preparation Example 3, Dpr (orotyl) -prine -serine ᅳ 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 ¾ NMR and 13 C NMR.
99.9% Purity. Rt 13.8 min. ¾ NMR (400 MHz, D20)： δ 6.37 (s, 1H) , 4.69 (dd, 1H, 6.0, J= 3.2), 4.62 (dd, 1H, J = 8.4, J 6.4), 4.59 (dd, 1H, J = 9.2, / = 4.4), 4.48 (dd, 1H, 6.4， J = 5.2)， 4.11(dd, 1H, J = 15.2, J = 4.4), 3.96- 3.81 (m, 4H), 3.74 (m, 1H), 2.65- 2.50 (m, 2H), 2.41 (m, 1H) , 2.26- 2.13 (m, 2H), 2.11 (s, 3H), 2.10- 1.95 (m, 3H). 13C NMR (125 MHz, D20)： δ 175.5, 173.9， 171.6, 166.9, 166.0， 162.6, 152.3, 144.8, 101.6， 61.0， 60.8, 56.2, 52.2， 52.1， 48.2， 39.1， 30.4, 29.6, 29.5， 25.0, 14.2. MALDI m/z calculated for C21H32N7Na09S+ [M+Na]+ 580.18, found 580.22. 99.9% Purity. R t 13.8 min. ¾ NMR (400 MHz, D 2 0): δ 6.37 (s, 1H), 4.69 (dd, 1H, 6.0, J = 3.2), 4.62 (dd, 1H, J = 8.4, J 6.4), 4.59 (dd, 1H, J = 9.2, / = 4.4), 4.48 (dd, 1H, 6.4, J = 5.2), 4.11 (dd, 1H, J = 15.2, J = 4.4), 3.96-3.81 (m, 4H), 3.74 ( m, 1H), 2.65- 2.50 (m, 2H), 2.41 (m, 1H), 2.26- 2.13 (m, 2H), 2.11 (s, 3H), 2.10-1.95 (m, 3H). 13 C NMR (125 MHz, D 2 0): δ 175.5, 173.9, 171.6, 166.9, 166.0, 162.6, 152.3, 144.8, 101.6, 61.0, 60.8, 56.2, 52.2, 52.1, 48.2, 39.1, 30.4, 29.6, 29.5 , 25.0, 14.2. MALDI m / z calculated for C 21 H 3 2N 7 Na0 9 S + [M + Na] + 580.18, found 580.22.
4-14. Dpr ( 1-시아노 -1-사이클로프로판카복실일 ) -프를린-세린-메티오닌 (Dpr(l-cyano-l-cyclopropanecarboxylyl)-Pro-Ser-Met) -PSM 4-14. Dpr (l-cyano-l-cyclopropanecarboxylyl) -Pro-Ser-Met (D- (cyano-1-cyclopropanecarboxylyl)) -PSM
Figure imgf000099_0001
Figure imgf000099_0001
101 상기 제조예 3과 동일한 방식으로101 In the same manner as in Preparation Example 3
Dpr ( 1-시아노 -1-사이클로프로판카복실일 ) -프를린-세린-메티오닌을 고체상으로 합성한 후， 상기 제조예 4-1과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고, ¾ NMR과 13C NMR을 이용하여 추가로 확인하였다. 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 ¾ NMR and 13 C NMR.
99.9% Purity. Rt 15.8 min. ¾證 (400 MHz, D20)： δ 4.63- 4.56 (m, 3Η) ' 4.51 (t, , J= 6.0), 3.97 (dd, 1H, 14.8, 3.6), 3.93 (m, 1H) , 3.90 (dd, 1H, J = 11.6, J = 6.0), 3.83- 3.72 (m, 2H), 3.67 (dd, 1H, J = 14.8, J = 7.2), 2.69- 2.54 (m, 2H), 2.40 (ddd, 1H, J 11.6, J = 8.0, J = 6.0), 2.23 (m, 1H), 2.13 (s, 3H), 2.12- 1.95 (m, 4H) , 1.79- 1.69 (m, 4H) . 13C NMR (100 MHz, D20)： δ 177.9， 176.0, 174.0, 172.2， 168.5, 122.5， 63.4, 63.0, 58.2, 54.5, 54.4, 50.5, 42.2, 32.6, 31.9, 31.8， 27.2, 20.9， 20.8, 16.5, 16.4. MALDI m/z calculated for C21H33N607S+ [M+H]+ 513.21, found 513.23. 99.9% Purity. R t 15.8 min. ¾ (400 MHz, D 2 0): δ 4.63-4.56 (m, 3Η) '4.51 (t,, J = 6.0), 3.97 (dd, 1H, 14.8, 3.6), 3.93 (m, 1H), 3.90 (dd, 1H, J = 11.6, J = 6.0), 3.83-3.72 (m, 2H), 3.67 (dd, 1H, J = 14.8, J = 7.2), 2.69-2.54 (m, 2H), 2.40 (ddd , 1H, J 11.6, J = 8.0, J = 6.0), 2.23 (m, 1H), 2.13 (s, 3H), 2.12- 1.95 (m, 4H), 1.79-1.69 (m, 4H). 13 C NMR (100 MHz, D 2 0): δ 177.9, 176.0, 174.0, 172.2, 168.5, 122.5, 63.4, 63.0, 58.2, 54.5, 54.4, 50.5, 42.2, 32.6, 31.9, 31.8, 27.2, 20.9, 20.8 , 16.5, 16.4. MALDI m / z calculated for C 21 H 33 N 6 0 7 S + [M + H] + 513.21, found 513.23.
4-15. Dpr (알파-시아노 -4-하이드톡시신나밀 ) -프를린-세린-메티오닌4-15. Dpr (alpha-cyano-4-hydroxycinnamil) -prine-serine-methionine
(Dpr ( α -cyano-4-hydr oxyc i nnamy 1 )-Pro-Ser-Met )
Figure imgf000100_0001
(Dpr (α -cyano-4-hydr oxyc i nnamy 1) -Pro-Ser-Met)
Figure imgf000100_0001
102 상기 제조예 3과 동일한 방식으로102 In the same manner as in Preparation Example 3
Dpr (알파-시아노 -4—하이드록시신나밀 ) -프롤린-세린-메티오닌을 고체상으로 합성한 후， 상기 제조예 4-1과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고， ¾ 画 R과 13C NMR을 이용하여 추가로 확인하였다. 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 ¾ 画 R and 13 C NMR.
83.7% Purity. Rt 18.4 min. ¾ NMR (400 MHz, D20) : δ 8.12 (s, 1H), 7.94 (d, 2H, J= 8.8)， 7.03 (d, 2H, /= 8.8)， 4.80- 4.60 (m, 2H), 4.53— 4.46 (m, 2H)， 3.99 (dd, 1H, J = 15.2, J = 4.4), 3.91- 3.87 (m, 2H), 3.86— 3.75 (m, 3H), 2.55- 2.39 (m, 3H)， 2.14— 2.07 (m, 2H), 2.06 (s, 3H) , 2.04- 1.96 (m, 3H). 13C NMR (100 MHz, D20)： δ 173.6， 171.6, 166.5, 165.6, 161.1, 153.9, 134.0, 123.9, 117.1, 116.5, 116.1, 99.6, 61.0, 60.9, 55.9, 51.9, 51.8, 48.3, 39.8, 30.2， 29.6, 29.4, 24.9, 14.2. MALDI m/z calculated for C26H35N608S+ [M+H] + 591.22, found 591.22. 83.7% Purity. R t 18.4 min. ¾ NMR (400 MHz, D 2 0): δ 8.12 (s, 1H), 7.94 (d, 2H, J = 8.8), 7.03 (d, 2H, / = 8.8), 4.80-4.60 (m, 2H), 4.53— 4.46 (m, 2H), 3.99 (dd, 1H, J = 15.2, J = 4.4), 3.91-3.87 (m, 2H), 3.86— 3.75 (m, 3H), 2.55- 2.39 (m, 3H) , 2.14— 2.07 (m, 2H), 2.06 (s, 3H), 2.04- 1.96 (m, 3H). 13 C NMR (100 MHz, D 2 0): δ 173.6, 171.6, 166.5, 165.6, 161.1, 153.9, 134.0, 123.9, 117.1, 116.5, 116.1, 99.6, 61.0, 60.9, 55.9, 51.9, 51.8, 48.3, 39.8 , 30.2, 29.6, 29.4, 24.9, 14.2. MALDI m / z calculated for C 26 H 35 N 6 0 8 S + [M + H] + 591.22, found 591.22.
4-16. Dpr (3, 5-디메틸벤조일)—프를린-세린-메티오닌 (Dpr (3,5-dimethyl benzoyl )-Pro-Ser-Met )
Figure imgf000101_0001
4-16. Dpr (3, 5-dimethylbenzoyl) —prine-serine-methionine (Dpr (3,5-dimethyl benzoyl) -Pro-Ser-Met)
Figure imgf000101_0001
103 상기 제조예 3과 동일한 방식으로 103 in the same manner as in Preparation Example 3
Dpr(3, 5-디메틸벤조일)ᅳ프롤린 -세린 -메티오닌을 고체상으로 합성한 후， 상기 제조예 4-1과 동일한 방법으로 합성하였으몌 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다ᅳ After synthesizing Dpr (3,5-dimethylbenzoyl) proline-serine-methionine in the solid phase, the compound was synthesized in the same manner as in Preparation Example 4-1, and the resulting compound was confirmed by mass spectometry (MS). ᅳ
99.9% Purity. Rt 21.1min. MALDI m/z calculated for C25H38N507S+ [M+H]+ 552.25, found 552.28. 99.9% Purity. R t 21.1 min. MALDI m / z calculated for C 25 H 38 N 5 0 7 S + [M + H] + 552.25, found 552.28.
4-17. Dpr((R)-(+)-트를록실) -프를린-세린-메티오닌 (Dpr4-17. Dpr ((R)-(+)-Troxyl) -Pr-serine-Methionine (Dpr
((R)-(+)-troloxyl) -Pro-Ser-Met ) ((R)-(+)-troloxyl) -Pro-Ser-Met)
Figure imgf000101_0002
Figure imgf000101_0002
104 상기 제조예 3과 동일한 방식으로 104 In the same manner as in Preparation Example 3
Dpr((R)— (+)-트를록실) -프를린ᅳ세린 -메티오닌을 고체상으로 합성한 후, 상기 제조예 4—1과 동일한 방법으로 합성하였으며 , 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. Dpr ((R) — (+)-Troxyl) -Purlincexerine-Methionine was synthesized in the solid phase and synthesized in the same manner as in Preparation Example 4-1, mass spectometry (MS) in The resulting compound was identified.
99.9% Purity. Rt 21.3 min. MALDI m/z calculated for C30H46N509S+ [M+H] + 652.30 found 652.40. 99.9% Purity. R t 21.3 min. MALDI m / z calculated for C 3 0 H 46 N 5 0 9 S + [M + H] + 652.30 found 652.40.
4-18. Dpr(2-(4-메틸페닐설폰아미도)아세틸) -프를린-세린-메티오닌 (Dpr(2- (4-methylphenylsulfonamido)acetyl)-Pro-Ser-Met) 4-18. Dpr (2- (4-methylphenylsulfonamido) acetyl) -prine-serine-methionine (Dpr (2- (4-methylphenylsulfonamido) acetyl) -Pro-Ser-Met)
Figure imgf000102_0001
Figure imgf000102_0001
105 상기 제조예 3과 동일한 방식으로 105 In the same manner as in Preparation Example 3
Dpr ( 2- ( 4-메틸페닐설폰아미도)아세틸) -프를린 -세린 -메티오닌을 고체상으로 합성한 후， 상기 제조예 4-1과 동일한 방법으로 합성하였으며， 질량분석계 (mass spectometry, MS)로 생성된 화합물올.확인하였다. Dpr (2- (4-methylphenylsulfonamido) acetyl) -prine-serine-methionine was synthesized in the solid phase and synthesized in the same manner as in Preparation Example 4-1, mass spectometry (MS) The resulting compound was identified.
99.9% Purity. Rt 20.0 min. MALDI m/z calculated for C25H39N609S2 + [M+H] + 631.22, found 631.34. 99.9% Purity. R t 20.0 min. MALDI m / z calculated for C 2 5 H 39 N 6 0 9 S 2 + [M + H] + 631.22, found 631.34.
4-19. Dpr (5-니트로 -3-피라졸카복실일 ) -프를린-세린-메티오닌4-19. Dpr (5-nitro-3-pyrazolcarboxyl) -pr-serine-methionine
(Dpr( 5-n i t r ο-3-pyr azolecar boxy Iyl)-Pr o-Ser-Met ) (Dpr (5-nitr ο-3-pyr azolecar boxy Iyl) -Pr o-Ser-Met)
Figure imgf000103_0001
Figure imgf000103_0001
106 상기 제조예 3과 동일한 방식으로106 In the same manner as in Preparation Example 3
Dpr(5-니트로—3-피라졸카복실일)—프롤린 -세린 -메티오닌을 고체상으로 합성한 후， 상기 제조예 4-1과 동일한 방법으로 합성하였으며, 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고， ¾ NMR과 13C NMR을 이용하여 추가로 확인하였다. Dpr (5-nitro—3-pyrazolcarboxylyl) —proline-serine-methionine was synthesized in the solid phase, and then synthesized in the same manner as in Preparation Example 4-1, and produced by mass spectometry (MS). Compounds were identified and further confirmed using ¾ NMR and 13 C NMR.
99.9% Purity. Rt 17.2 min. ¾ NMR (400 MHz, D20): δ 7.56 (s, 1H), 4.71 (dd, 1H, /= 6.4, J = 4.0)， 4.65 (dd, 1H, J = 8.8, J = 6.0), 4.53 (dd, 1H, J = 8.8, J=AA), 4.49 (t, 1H, J= 5.6), 4.09 (dd, 1H, J= 14.8， J=4.0), 3.96- 3.82 (m, 4H), 3.75 (m, 1H), 2.63- 2.48 (m, 2H)， 2.35 (m, 1H), 2.18 (m, 1H) , 2.09 (s, 3H), 2.07- 1.97 (m, 4H). 13C NMR (125 MHz, D20)： δ 175.9, 173.9, 171.4, 166.3, 160.5， 155.8, 138.6, 102.6， 61.1， 60.8, 56.1, 52.6, 52.1, 48.3, 38.9, 30.5, 29.7， 29.5, 25.0， 14.2. MALDI m/z calculated for C20¾iN809S+ [M+H]+ 559.19, found 559.18. 제조예 5. Isonicotinic— Trp-Tyr-Val-Dpr(acyl)의 합성 99.9% Purity. R t 17.2 min. ¾ NMR (400 MHz, D 2 0): δ 7.56 (s, 1H), 4.71 (dd, 1H, / = 6.4, J = 4.0), 4.65 (dd, 1H, J = 8.8, J = 6.0), 4.53 (dd, 1H, J = 8.8, J = AA), 4.49 (t, 1H, J = 5.6), 4.09 (dd, 1H, J = 14.8, J = 4.0), 3.96-3.82 (m, 4H), 3.75 (m, 1H), 2.63- 2.48 (m, 2H), 2.35 (m, 1H), 2.18 (m, 1H), 2.09 (s, 3H), 2.07-1.97 (m, 4H). 13 C NMR (125 MHz, D 2 0): δ 175.9, 173.9, 171.4, 166.3, 160.5, 155.8, 138.6, 102.6, 61.1, 60.8, 56.1, 52.6, 52.1, 48.3, 38.9, 30.5, 29.7, 29.5, 25.0 , 14.2. MALDI m / z calculated for C 20 ¾iN 8 0 9 S + [M + H] + 559.19, found 559.18. Preparation Example 5 Synthesis of Isonicotinic—Trp-Tyr-Val-Dpr (acyl)
전반적으로 Isonicot inic-Trp-Tyr-Val-Dpr(acyl)의 합성은 상기 제조예 4의 조건을 따랐으나， Mtt 보호기의 size가 크기 때문에, DMAP/DIC를 이용하여 Fmoc-Dpr(Mtt) anhydride를 만들어서 resin에 loading 하는 것 (79.2%) 보다는 HBTU를 커플링 reagent로 사용하여 2번에 걸쳐 loading 하는 것 (85.8%) 이 더욱 효과적이어서 후자의 방법으로 loading 하였다.  Overall, the synthesis of Isonicot inic-Trp-Tyr-Val-Dpr (acyl) follows the conditions of Preparation Example 4, but the size of the Mtt protecting group is large, so that Fmoc-Dpr (Mtt) anhydride is prepared using DMAP / DIC. It was more effective to load HBTU twice as a coupling reagent (85.8%) than to make it and load it into resin (79.2%).
Isonicotinic-Trp-Tyrᅳ Val-Dpr(acyl)의 합성 역시 왕 레진 (Wang resin)에 Synthesis of Isonicotinic-Trp-Tyr® Val-Dpr (acyl) was also applied to Wang resin.
Fmoc-based SPPS를 이용하였고 (Scheme 5)， 15개의 acid 중에서 a -cyano-4-hydroxy cinnami c acid 를 제외한 14개의 산 (acid)이 커플링 된 화합물을 얻었다 ( 107- 120) . 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).
1 . Fmoc-Dpr(Mtt)-OH, HBTU, HOBt, DIPEA, DMF  One . Fmoc-Dpr (Mtt) -OH, HBTU, HOBt, DIPEA, DMF
2. i) 20% piperidine,  2. i) 20% piperidine,
ii) Fmoc-Val-OH, HBTU, HOBt, DIPEA, DMF  ii) Fmoc-Val-OH, HBTU, HOBt, DIPEA, DMF
3. i) 20% piperidine, I) 20% piperidine,
Figure imgf000104_0001
ii) Fmoc-Tyr(tBu)-OH, HBTU, HOBt, DIPEA, DMF
Figure imgf000104_0001
ii) Fmoc-Tyr (tBu) -OH, HBTU, HOBt, DIPEA, DMF
4. i) 20% piperidine,  I) 20% piperidine,
ii) Fmoc-Trp(Boc)-OH, HBTU, HOBt, DIPEA, DMF  ii) Fmoc-Trp (Boc) -OH, HBTU, HOBt, DIPEA, DMF
Figure imgf000104_0002
Figure imgf000104_0002
5-1.이소니코티닐-트립토판-타이로신 -발린 -Dpr (오로틸) (Isonicot inyl-Trp-5-1.Isonicotinyl-tryptophan-tyrosine-valine -Dpr (orotyl) (Isonicot inyl-Trp-
Tyr-Val-Dpr(orotyl ) Tyr-Val-Dpr (orotyl)
Figure imgf000105_0001
Figure imgf000105_0001
107 필터가 설치된 20 mL TORVIQ PP syringe에 Wang resin LLC 100-200 mesh, 500 mg, 0.44 mmol/g, 0.22 mmol)을 넣고 무수 DMF를 넣어 30분간 팽윤 시킨 후 배수시켰다. Fmoc-Dpr(Mtt)-0H(5.0당량， 614.0 mg, 1.1隱 ol), HBTU(5.0당량， 417 mg, 1.1 mmol), H0Bt.H20 (5.0 당량， 169 mg, 1.1 mmol), DIPEA (10.0 당량， 0.38 mL, 2.2 mmol) 를 무수 DMF(10.0 mL)에 녹인 후 3분간 교반하여 팽윤한 resin에 첨가한 후 3시간 동안 orbital shaker (130 r.p.m.)를 사용하여 흔합하고 용매를 배수한 후 DMF, iPrOH와 CH2C12으로 세척하였다 (각각 15 mL x lm x 3). UV Spectr optometry!- 이용하여 Fmoc quant i f icat ion ¾· 결과， loading level은 71.7%로 나타났다. Loading level을 높이기 위해 상기 반웅을 2회 반복하였다 (85.8%). Wang resin LLC 100-200 mesh, 500 mg, 0.44 mmol / g, 0.22 mmol) was added to a 20 mL TORVIQ PP syringe equipped with a 107 filter and swelled for 30 minutes with anhydrous DMF. Fmoc-Dpr (Mtt) -0H (5.0 equiv, 614.0 mg, 1.1 μl), HBTU (5.0 equiv, 417 mg, 1.1 mmol), H0Bt.H 2 0 (5.0 equiv, 169 mg, 1.1 mmol), DIPEA ( 10.0 equivalents, 0.38 mL, 2.2 mmol) was dissolved in anhydrous DMF (10.0 mL), stirred for 3 minutes, added to the swollen resin, mixed for 3 hours using an orbital shaker (130 rpm), and the solvent was drained. washed with iPrOH and CH 2 C1 2 (15 mL × lm × 3 each). Fmoc quant if icat ion ¾ · using UV Spectr optometry!-Showed loading level of 71.7%. The reaction was repeated twice to increase the loading level (85.8%).
Loading level을 90%로 계산하여 resin의 농도를 0.4 誦 ol이라 가정하고， 상기 제조예 3과 동일한 방법으로 이소니코티닐 -트립토판—타이로신 -발린 -Dpr (오로틸)을 고체상으로 합성한 후， 이렇게 만들어진 resin (35 mg, 0.0154 mmol)에 degassed 94% TFA cocktail (0.7 mL)를 첨가하여 상온에서 1시간 동안 흔합한 후 여과하여 여액을 받고， 다시 TFA 용액으로 세척하여 (0.4 mL X 2) 그 여액을 받았다. 위 여액들을 합하여 evaporator를 이용하여 TFA를 제거한 후， cold ether를 사용하여 3회 decantation하였다. 이때 생성된 화합물의 손실을 막기 위해 원심 분리기를 이용하였으며， high vacuum dry早 semi-preparat ive HPLC (binary solvent system, solvent A: 0.1% TFA/H20, solvent B: 0.1% TFA/CH3CN, 5- 100% B over 42 min)를 이용하여 분리 및 정제하고 동결 건조한 후 mass spectrometry 로 확인하였고 ¾ NMR과 13C NMR를 이용하여 추가로 확인하였다. Assuming the loading level is 90%, the concentration of resin is assumed to be 0.4 誦 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. At this time, centrifuge was used to prevent the loss of compound, and high vacuum dry 早 semi-preparative HPLC (binary solvent system, solvent A: 0.1% TFA / H 2 0, solvent B: 0.1% TFA / CH 3 CN) , 5- 100% B over 42 min) was isolated and purified, and lyophilized and confirmed by mass spectrometry. It was further confirmed using NMR and 13 C NMR.
99.9% Purity. Rt 19.2 min. ¾ NMR (400 MHz, DMSO-o : δ 11.34 (brs, IH), 10.75 (brs, IH), 10.74 (brs, IH), 8.81 (d, IH, J= 8.4)， 8.77 (t, IH, J= 5.6), 8.71 (brs, 2H), 8.27 (d, IH, J = 7.6)， 8.24 (d, IH, J = 8.4), 7.92 (d, IH, J = 8.0)， 7.69 (d, 2H, / - 5.2)， 7.65 (d, IH, J = 7.6), 7.29 (d, IH, J = 7.6), 7.15 (d, IH, J = 2.0), 7.05 (m, IH), 7.03 (d, 2H, J = 8.4), 6.95 (t, IH, J = 7.6)， 6.57 (d, 2H, /= 8.4), 6.04 (s, IH), 4.74 (m, IH), 4.57 (m, IH), 4.46 (td, IH, /= 7.6， J= 6.8), 4.18 (t, IH, J= 8.0), 3.65- 3.55 (m, 2H, identified from HSQC) , 3.17 (dd, IH, J= 14.4， J= 3.6)， 3.06 (dd, IH, J = 14.4, J= 10.4)， 2.94 (dd, IH, /= 14.0， / = 3.6)， 2.73 (dd, IH, J = 14.0, J = 8.4)， 2.00 (m, IH) , 0.89 (d, 3H, J= 6.4), 0.86 (d, 3H, /= 6.4). 13C NMR (100 MHz, DMS0-i/6): δ 171.4， 171.3， 171.2， 170.9, 164.4， 164.3， 160.5， 155.7, 150.8， 149.5， 145.0， 141.6， 136.0, 130.2， 127.8， 127.2, 123.6, 121.7， 120.9, 118.5, 118.2, 114.8， 111.3, 110.3, 100.1, 57.8, 54.2, 54.1, 51.3, 40.3, 36.3, 30.6, 27.3, 19.1, 18.1. MALDI m/z calculated for C39H4iN9Na0i0 + [M+Na]+ 818.29, found 818.58. 99.9% Purity. R t 19.2 min. ¾ NMR (400 MHz, DMSO-o: δ 11.34 (brs, IH), 10.75 (brs, IH), 10.74 (brs, IH), 8.81 (d, IH, J = 8.4), 8.77 (t, IH, J = 5.6), 8.71 (brs, 2H), 8.27 (d, IH, J = 7.6), 8.24 (d, IH, J = 8.4), 7.92 (d, IH, J = 8.0), 7.69 (d, 2H, /-5.2), 7.65 (d, IH, J = 7.6), 7.29 (d, IH, J = 7.6), 7.15 (d, IH, J = 2.0), 7.05 (m, IH), 7.03 (d, 2H , J = 8.4), 6.95 (t, IH, J = 7.6), 6.57 (d, 2H, / = 8.4), 6.04 (s, IH), 4.74 (m, IH), 4.57 (m, IH), 4.46 (td, IH, / = 7.6, J = 6.8), 4.18 (t, IH, J = 8.0), 3.65- 3.55 (m, 2H, identified from HSQC), 3.17 (dd, IH, J = 14.4, J = 3.6), 3.06 (dd, IH, J = 14.4, J = 10.4), 2.94 (dd, IH, / = 14.0, / = 3.6), 2.73 (dd, IH, J = 14.0, J = 8.4), 2.00 ( m, IH), 0.89 (d , 3H, J = 6.4), 0.86 (d, 3H, / = 6.4) 13 C NMR (100 MHz, DMS0-i / 6):. δ 171.4, 171.3, 171.2, 170.9, 164.4, 164.3, 160.5, 155.7, 150.8, 149.5, 145.0, 141.6, 136.0, 130.2, 127.8, 127.2, 123.6, 121.7, 120.9, 118.5, 118.2, 114.8, 111.3, 110.3, 100.1, 57.8, 54.2, 54.1, 51.3, 4 0.3, 36.3, 30.6, 27.3, 19.1, 18.1.MALDI m / z calculated for C 39 H 4 iN 9 Na0i 0 + [M + Na] + 818.29, found 818.58.
5-2. 이소니코티닐-트립토판-타이로신 -발린 -Dpr(3, 5-디메틸벤조일)5-2. Isicotinyl-tryptophan-tyrosine-valine-Dpr (3, 5-dimethylbenzoyl)
(Isoni cot i ny 1 -Trp-Tyr-Va 1 -Dpr (3 , 5— dimethyl benzoyl ) ) Isoni cot i ny 1 -Trp-Tyr-Va 1 -Dpr (3, 5— dimethyl benzoyl)
Figure imgf000106_0001
Figure imgf000106_0001
108 제조예 3과 동일한 방식으로 이소니코티닐ᅳ트립토판ᅳ타이로신ᅳ발린 -Dpr(3, 5-디메틸벤조일)을 고체상으로 합성하였으며, 상기 제조예 5-1과 동일한 방법을 이용하여 합성하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고， ¾ NMR과 13C NMR을 이용하여 추가로 확인하였다. 108 In the same manner as in Preparation Example 3 Isonicotinyl ᅳ tryptophan ᅳ tyrosine ᅳ valine -Dpr (3, 5-dimethylbenzoyl) was synthesized in the solid phase and synthesized using the same method as in Preparation Example 5-1. Compounds produced by mass spectrometry (MS) were identified and further confirmed using ¾ NMR and 13 C NMR.
99.9% Purity. Rt 24.7 min. ¾ NMR (400 MHz, DMSO-o : δ 10.74 (d, 1H, J99.9% Purity. R t 24.7 min. ¾ NMR (400 MHz, DMSO-o: δ 10.74 (d, 1H, J
= 2.0), 8.87 (d, 1H, J= 8.0), 8.74 (brs, 2H), 8.40 (tᅳ 1H, J 5.6)， 8.29 (d, 1H, J = 6.8), 8.21 (d, 1H, J = 8.0), 7.86 (d, 1H, J = 8.8), 7.72 (d, 2H, J = 5.6)， 7.66 (d, 1H, 7.6)， 7.41 Cs, 2H) , 7.29 (d, 1H, /= 7.6), 7.15 (d, 1H, / = 2.0), 7.13 (s, 1H), 7.04 (t, 1H, J = 7.6), 7.01 (d, 2H, /= 8.4)， 7.00 (t, 1H, J = 7.6) , 6.57 (d, 2H, J 8.4), 4.75 (m, 1H), 4.55 (m, 1H) , 4.43 (q, 1H, J = 6.8), 4.23 (dd, 1H, J = 8.8， / = 6.8)， 3.64- 3.57 (m, 2H), 3.17 (dd, 1H, /= 14.8, J= 4.0)， 3.06 (dd, 1H, J = 14.8， /= 10.4), 2.93 (dd, 1H, J 14.0, J = 4.0), 2.73 (dd, 1H, J = 14.0, J = 9.6)， 2.29 (s, 6H) , 2.00 (m, 1H) , 0.88 (d, 3H, J = 6.4), 0.85 (d, 3H, J - 6.4). 13C NMR (100 MHz, DMS0-G¾)： δ 171.7, 171.2, 171.0， 170.8， 167.1， 164.3, 155.7, 149.1， 141.9， 137.4, 136.0, 134.3， 132.6, 130.1, 127.8, 127.2, 125.0, 123.6, 121.9, 120.9， 118.5, 118.2, 114.8, 111.3, 110.4, 57.4, 54.2 (2C, identified from HSQC), 52.2, 40.3 (identified from HSQC) , 36.2, 30.9, 27.2, 20.8, 19.1, 18.0. MALDI m/z calculated for C43H47 7 a08 + [M+Na]+ 812.34, found 812.67. = 2.0), 8.87 (d, 1H, J = 8.0), 8.74 (brs, 2H), 8.40 (t ᅳ 1H, J 5.6), 8.29 (d, 1H, J = 6.8), 8.21 (d, 1H, J = 8.0), 7.86 (d, 1H, J = 8.8), 7.72 (d, 2H, J = 5.6), 7.66 (d, 1H, 7.6), 7.41 Cs, 2H), 7.29 (d, 1H, / = 7.6 ), 7.15 (d, 1H, / = 2.0), 7.13 (s, 1H), 7.04 (t, 1H, J = 7.6), 7.01 (d, 2H, / = 8.4), 7.00 (t, 1H, J = 7.6), 6.57 (d, 2H, J 8.4), 4.75 (m, 1H), 4.55 (m, 1H), 4.43 (q, 1H, J = 6.8), 4.23 (dd, 1H, J = 8.8, / = 6.8), 3.64- 3.57 (m, 2H), 3.17 (dd, 1H, / = 14.8, J = 4.0), 3.06 (dd, 1H, J = 14.8, / = 10.4), 2.93 (dd, 1H, J 14.0 , J = 4.0), 2.73 (dd, 1H, J = 14.0, J = 9.6), 2.29 (s, 6H), 2.00 (m, 1H), 0.88 (d, 3H, J = 6.4), 0.85 (d, 3H, J-6.4). 13 C NMR (100 MHz, DMS0-G¾): δ 171.7, 171.2, 171.0, 170.8, 167.1, 164.3, 155.7, 149.1, 141.9, 137.4, 136.0, 134.3, 132.6, 130.1, 127.8, 127.2, 125.0, 123.6, 121.9 , 120.9, 118.5, 118.2, 114.8, 111.3, 110.4, 57.4, 54.2 (2C, identified from HSQC), 52.2, 40.3 (identified from HSQC), 36.2, 30.9, 27.2, 20.8, 19.1, 18.0. MALDI m / z calculated for C 4 3 H 47 7 a0 8 + [M + Na] + 812.34, found 812.67.
5-3. 5-3.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (7-메톡시 -1-벤조퓨란 -2-카복실일 ) Isicotinyl-tryptophan-tyrosine-valine-Dpr (7-methoxy-1-benzofuran-2-carboxylyl)
(Isonicot i ny 1 -Tr -Tyr -Va 1 -Dpr ( 7-me t hoxy- 1-benzo f ur an-2-car boxy 1 y 1 ) ) (Isonicot i ny 1 -Tr -Tyr -Va 1 -Dpr (7-me t hoxy-1 -benzo f ur an-2-car boxy 1 y 1))
Figure imgf000108_0001
Figure imgf000108_0001
109 상기 제조예 3과 동일한 방식으로 이소니코티닐-트립토판 -타이로신 -발린 -Dpr (7-메톡시 -1-벤조퓨란 -2-카복실일 )을 고체상으로 합성하였으며， 상기 제조예 5-1과 동일한 방법을 이용하여 합성하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고, ¾ NMR과 13C NMR을 이용하여 추가로 확인하였다. 109 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 ¾ NMR and 13 C NMR.
99.9% Purity. t 24.3 min. :H NMR (400 MHz, DMS0-c/6)： δ 10.73 (s, IH) , 8.85 (d, IH, J = 8.0)， 8.73 (brsᅳ 2H), 8.66 (t, IH, J = 5.6), 8.35 (d, IH, J = 7.2), 8.21 (d, IH, / = 8.0)， 7,86 (d, IH, J = 8.4), 7.71 (d, 2H, J = 4.0)， 7.66 (d, IH, J = 7.6), 7.50 (s, IH), 7.29 (d, 2H, J = 7.6), 7.23 (t, IH, / = 7.6)， 7.14 (d,lH, J= 1.6)， 7.06- 7.01 (m, 2H) , 6.99 (d, 2H, /= 8.8)， 6.95 (t, IH, J = 7.6), 6.56 (d, 2H, /= 8.8), 4.74 (m, IH), 4.54 (m, IH), 4.45 (q, IH, J = 7.2), 4.23 (dd, IH, J = 8.4, J = 6.8), 3.94 (s, 3H)， 3.70- 3.60 (m, 2H, identified from HSQC) , 3.16 (dd, IH, /= 14.8, /= 3.6)， 3.06 (dd, IH, J= 14.8, 9.8)， 2.93 (dd, IH, J 13.6, J= 4.0), 2.72 (dd, IH, J = 13.6, J = 9.2)，99.9% Purity. t 24.3 min. : H NMR (400 MHz, DMS0-c / 6 ): δ 10.73 (s, IH), 8.85 (d, IH, J = 8.0), 8.73 (brs ᅳ 2H), 8.66 (t, IH, J = 5.6) , 8.35 (d, IH, J = 7.2), 8.21 (d, IH, / = 8.0), 7,86 (d, IH, J = 8.4), 7.71 (d, 2H, J = 4.0), 7.66 (d , IH, J = 7.6), 7.50 (s, IH), 7.29 (d, 2H, J = 7.6), 7.23 (t, IH, / = 7.6), 7.14 (d, lH, J = 1.6), 7.06- 7.01 (m, 2H), 6.99 (d, 2H, / = 8.8), 6.95 (t, IH, J = 7.6), 6.56 (d, 2H, / = 8.8), 4.74 (m, IH), 4.54 (m , IH), 4.45 (q, IH, J = 7.2), 4.23 (dd, IH, J = 8.4, J = 6.8), 3.94 (s, 3H), 3.70-3.60 (m, 2H, identified from HSQC), 3.16 (dd, IH, / = 14.8, / = 3.6), 3.06 (dd, IH, J = 14.8, 9.8), 2.93 (dd, IH, J 13.6, J = 4.0), 2.72 (dd, IH, J = 13.6, J = 9.2)
2.00 (m, IH), 0.87 (d, 3H, /= 6.8)， 0.84 (d, 3H, J = 6.8). 13C NMR (100 MHz, DMSO— f/6): δ 171.6, 171.2, 170.9, 170.8, 164.3, 158.3, 155.7, 149.2, 148.9, 145.2， 143.6, 141.8, 136.0, 130.1, 128.6， 127.8, 127.2, 124.6， 123.6, 121.8， 120.9， 118.5, 118.2， 114.8, 114.5, 111.3, 110.4， 110.2, 108.8, 57.4, 55.7, 54.2 (2C, identified from HSQC), 52.0, 35.9 (identified from HSQC), 36.3, 30.9, 27.2， 19.1， 18.0. MALDI m/z calculated for C44H45N7Na010 + [M+Na]+ 854.31, found 854.67. 5-4. 2.00 (m, IH), 0.87 (d, 3H, / = 6.8), 0.84 (d, 3H, J = 6.8). 13 C NMR (100 MHz, DMSO— f / 6 ): δ 171.6, 171.2, 170.9, 170.8, 164.3, 158.3, 155.7, 149.2, 148.9, 145.2, 143.6, 141.8, 136.0, 130.1, 128.6, 127.8, 127.2, 124.6 , 123.6, 121.8, 120.9, 118.5, 118.2, 114.8, 114.5, 111.3, 110.4, 110.2, 108.8, 57.4, 55.7, 54.2 (2C, identified from HSQC), 52.0, 35.9 (identified from HSQC), 36.3, 30.9, 27.2 , 19.1, 18.0. MALDI m / z calculated for C 44 H 45 N 7 Na0 10 + [M + Na] + 854.31, found 854.67. 5-4.
이소니코티닐ᅳ트립토판-타이로신 -발린 -Dpr(2-(2-사아노페닐티오)벤조일) Isnicotinyl ᅳ tryptophan-tyrosine-valine -Dpr (2- (2-sanophenylthio) benzoyl)
(Isonicotinyl -Trp-Tyr-Va 1一 Dpr ( 2- ( 2-Cyanopheny lthi o)benzoy 1 ) )  (Isonicotinyl -Trp-Tyr-Va 1 一 Dpr (2- (2-Cyanopheny lthi o) benzoy 1))
Figure imgf000109_0001
Figure imgf000109_0001
110 상기 제조예 3과 동일한 방식으로 이소니코티닐ᅳ트립토판 -타이로신 -발린 -Dpr (2-(2-시아노페닐티오)벤조일 )을 고체상으로 합성하였으며, 상기 제조예 5-1과 동일한 방법을 이용하여 합성하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고， NMR과 13C NMR을 이용하여 추가로 확인하였다. 110 In the same manner as in Preparation Example 3, isonicotinyl ᅳ tryptophan-tyrosine-valine-Dpr (2- (2-cyanophenylthio) benzoyl) was synthesized in a solid phase, using the same method as in Preparation Example 5-1. Synthesized. Compounds produced by mass spectometry (MS) were identified and further confirmed using NMR and 13 C NMR.
99.9% Purity. Rt 25.5 min. ¾ NMR (400 MHz, DMS0-(/6): δ 12.70 (brs, 1H), 10.73 (d, 1H, J= 2.0), 9.10 (brs, 1H), 8.83 (d, 1H, J= 8.4), 8.70 (brs, 2H), 8.53 (t, 1H, /= 5.6), 8.28 (d, 1H, J= 7.6)， 8.22 (d, 1H, J= 7.6)， 7.92 (dd, 1H, J = 8.0, / = 1.2)， 7.85 (d, 1H, J = 8.8), 7.68- 7.64 (m, 4H), 7.56- 7.51 (m, 2H), 7.44 (d, 1H, J= 8.0)， 7.40- 7.33 (m, 2H), 7.29 (d, 1H, J= 7.6), 7.15 (d, 1H, J = 2.0)， 7.05- 6.99 (m, 2H), 7.02 (d, 2H, J = 8.0), 6.96 (t, 1H, J = 7.6)， 6.57 (d, 2H, J = 8.0)， 4.74 (m, 1H)， 4.55 (m, 1H)， 4.46 (q, 1H, J= 7,2), 4.25 (dd, 1H, / = 8.8, / = 6.8)， 3.62- 3.56 (m, 2H)， 3.17 (dd, 1H, J = 14.8， /= 4.0)， 3.07 (dd, 1H, J = 14.8, J= 10.4)， 2.94 (dd, 1H, /= 14.4, J= 4.0)， 2.74 (dd, 1H, J= 14.4， J= 9.6), 2.02 (m, 1H), 0.89 (d, 3H, J 6.8)， 0.86 (d, 3H, J= 6.8). 13C NMR (100 MHz, DMS0-/6): δ 171.6, 171.3, 171.0, 170.8, 167.4, 164.5, 155.7, 149.7， 141.3, 138.7, 136.8， 136.0, 134.4, 134.1, 133.8, 133.5, 131.0, 130.5, 130.1, 128.8, 128.5， 127.9, 127.2, 127.1, 123.6， 121.6, 120.9, 118.5， 118.2, 117.0， 115.0, 114.8, 111.3, 110.4, 57.4, 54.2 (2C, identified from HSQC) , 51.9, 40.0 (identified from HSQC), 36.3, 30.9, 27.2, 19.2, 18.0. MALDI m/z calculated for C48H46N8Na08S + [M+Na]+ 917.31, found 917.72. 99.9% Purity. R t 25.5 min. ¾ NMR (400 MHz, DMS0-(/ 6 ): δ 12.70 (brs, 1H), 10.73 (d, 1H, J = 2.0), 9.10 (brs, 1H), 8.83 (d, 1H, J = 8.4), 8.70 (brs, 2H), 8.53 (t, 1H, / = 5.6), 8.28 (d, 1H, J = 7.6), 8.22 (d, 1H, J = 7.6), 7.92 (dd, 1H, J = 8.0, / = 1.2), 7.85 (d, 1H, J = 8.8), 7.68-7.64 (m, 4H), 7.56- 7.51 (m, 2H), 7.44 (d, 1H, J = 8.0), 7.40-7.33 (m , 2H), 7.29 (d, 1H, J = 7.6), 7.15 (d, 1H, J = 2.0), 7.05- 6.99 (m, 2H), 7.02 (d, 2H, J = 8.0), 6.96 (t, 1H, J = 7.6), 6.57 (d, 2H, J = 8.0), 4.74 (m, 1H), 4.55 (m, 1H), 4.46 (q, 1H, J = 7,2), 4.25 (dd, 1H , / = 8.8, / = 6.8), 3.62- 3.56 (m, 2H), 3.17 (dd, 1H, J = 14.8, / = 4.0), 3.07 (dd, 1H, J = 14.8, J = 10.4), 2.94 (dd, 1H, / = 14.4, J = 4.0), 2.74 (dd, 1H, J = 14.4, J = 9.6), 2.02 (m, 1H), 0.89 (d, 3H, J 6.8), 0.86 (d, 3H, J = 6.8) 13 C NMR (100 MHz, DMS0- / 6):. δ 171.6, 171.3, 171.0, 170.8, 167.4, 164.5, 155.7, 149.7, 141.3, 138.7, 136.8, 136.0, 134.4, 134.1, 133.8, 133.5, 131.0, 130.5, 130.1, 128.8, 128.5, 127.9, 127.2, 127.1, 123.6, 121.6, 120.9, 118.5, 118.2, 117.0, 115.0, 114.8, 111.3, 110.4, 57.4, 54.2 (2C, identified from HSQC), 51.9, 40.0 (identified from HSQC), 36.3, 30.9, 27.2, 19.2, 18.0. MALDI m / z calculated for C48H46N 8 Na0 8 S + [M + Na] + 917.31, found 917.72.
5-5. 이소니코티닐-트립토판-타이로신 -발린 -Dpr((R)-(+)-트를록실)5-5. Isicotinyl-tryptophan-tyrosine-valine -Dpr ((R)-(+)-troroxyl)
(Isonicotinyl-Trp-Tyr-Val-Dpr((R)-(+)-troloxyl)) (Isonicotinyl-Trp-Tyr-Val-Dpr ((R)-(+)-troloxyl))
Figure imgf000110_0001
Figure imgf000110_0001
111 상기 제조예 3과 동일한 방식으로 이소니코티닐-트립토판-타이로신 -발린 -Dpr((R)-(+)-트를록실)을 고체상으로 합성하였으며， 상기 제조예 5-1과 동일한 방법을 이용하여 합성하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고, NMR과 13C 匪 R을 이용하여 추가로 확인하였다. 111 In the same manner as in Preparation Example 3, isonicotinyl-tryptophan-tyrosine-valine -Dpr ((R)-(+)-troxyl) was synthesized in the solid phase, using the same method as in Preparation Example 5-1. Synthesized. Compounds produced by mass spectrometry (MS) were identified, and further confirmed using NMR and 13 C 匪 R.
91.3% Purity. Rt 25.0 min. ¾ NMR (400 MHz, DMSO— ί6): δ 10.73 (d, 1H, J91.3% Purity. R t 25.0 min. ¾ NMR (400 MHz, DMSO— ί 6 ): δ 10.73 (d, 1H, J
= 2.4)， 8.87 (d, 1H, 8.0)， 8.74 (brs, 2H), 8.31 (d, 1H, J = 7.2)， 8.25 (d, 1H, J = 8.0)， 7.83 (d, 1Hᅳ J = 8.8)， 7.73 (d, 2H, J = 6.0)， 7.66 (d, 1H, J = 8.0), 7.53 (dd, 1H, J = 6.8， J = 5.6)， 7.29 (d, 1H, J = 8.0), 7.15 (d, 1H, J = 2.4), 7.03 (m, 1H), 7.02 (d, 2H, / = 8.4), 6.96 (t, 1H, J = 8.0), 6.57 (d, 2H, J = 8.4)， 4.75 (m, 1H), 4.55 (m, 1H), 4.27 (q, 1H, J = 7.2), 4.20 (dd, 1H, J 8.8， J= 6.4)， 3.55 (m, 1H), 3.34 (m, 1H), 3.17 (dd, 1H, J = 14.4, /= 4.0)， 3.06 (dd, 1H, J.= 14.4 9.6), 2.94 (dd, 1H, /= 14.4, /= 4.0), 2.73 (dd, 1H, / = 14.4 J = 9.6), 2.54- 2.41 (m, 2H), 2.08 (s, 3H), 2.07 (m, 1H), 2.06= 2.4), 8.87 (d, 1H, 8.0), 8.74 (brs, 2H), 8.31 (d, 1H, J = 7.2), 8.25 (d, 1H, J = 8.0), 7.83 (d, 1H ᅳ J = 8.8), 7.73 (d, 2H, J = 6.0), 7.66 (d, 1H, J = 8.0), 7.53 (dd, 1H, J = 6.8, J = 5.6), 7.29 (d, 1H, J = 8.0) , 7.15 (d, 1H, J = 2.4), 7.03 (m, 1H), 7.02 (d, 2H, / = 8.4), 6.96 (t, 1H, J = 8.0), 6.57 (d, 2H, J = 8.4 ), 4.75 (m, 1H), 4.55 (m, 1H), 4.27 (q, 1H, J = 7.2), 4.20 (dd, 1H, J 8.8, J = 6.4), 3.55 (m, 1H), 3.34 ( m, 1H), 3.17 (dd, 1H, J = 14.4, / = 4.0) 3.06 (dd, 1H, J. = 14.4 9.6), 2.94 (dd, 1H, / = 14.4, / = 4.0), 2.73 (dd, 1H, / = 14.4 J = 9.6), 2.54- 2.41 (m, 2H) , 2.08 (s, 3H), 2.07 (m, 1H), 2.06
(s, 3H), 2.02 (s, 3H), 1. 96 (m, 1H), 1.75 (m, 1H) , 1.31 (s, 3H) , o. 88 (d, 3H,(s, 3H), 2.02 (s, 3H), 1. 96 (m, 1H), 1.75 (m, 1H), 1.31 (s, 3H), o. 88 (d, 3 H,
J = 6.8), 0.84 (d ' 3H, J = 6.8) . 13C NMR (100 MHz ' DMSO- δ 173 .9 J = 6.8), 0.84 (d '3H, J = 6.8). 13 C NMR (100 MHz 'DMSO- δ 173 .9
171 .2 170.9, 170 .8, 164. ,2 155 .7 149.0 145.9, 142.1, 136 .0, 171 .2 170.9, 170 .8, 164., 2 155 .7 149.0 145.9, 142.1, 136 .0,
127 .8 127.2 123 .6, 122. ■ 7, 121 .9 121.3, 120.9, 120.2, 118.5, 118 .2,127 .8 127.2 123 .6, 122. ■ 7, 121 .9 121.3, 120.9, 120.2, 118.5, 118 .2,
114.8, 111.3, 110.3, 77.1, 57.3, 54.2 (2C, identified from HSQC) , 52.0, 39.5 (identified from HSQC) , 36.3, 31.1 29.3, 27.2, 23.3, 19.9, 19.0 18.0, 12.8 12.0, 11.8. MALDI m/z calculated for C48H55N7Na010 + [M+Na]+ 912.39, found 912.74. 114.8, 111.3, 110.3, 77.1, 57.3, 54.2 (2C, identified from HSQC), 52.0, 39.5 (identified from HSQC), 36.3, 31.1 29.3, 27.2, 23.3, 19.9, 19.0 18.0, 12.8 12.0, 11.8. MALDI m / z calculated for C 4 8H 55 N 7 Na0 10 + [M + Na] + 912.39, found 912.74.
5-6. 5-6.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr ( 1-시아노 -1-사이클로프로판카복실일 ) (Isonicotinyl -Tr -Tyr-Va 1 -Dpr ( 1— cyano— 1一 eye 1 opropanecarboxylyl ) ) Isicotinyl-tryptophan-tyrosine-valine-Dpr (1-cyano-1-cyclopropanecarboxyl) (Isonicotinyl -Tr -Tyr-Va 1 -Dpr (1— cyano— 1 eye 1 opropanecarboxylyl))
i
Figure imgf000111_0001
O C i
Figure imgf000111_0001
OC
o o  o o
112 상기 제조예 3과 동일한 방식으로 이소니코티닐-트립토판-타이로신 -발린 -Dpr (1-시아노 -1-사이클로프로판카복실일) 을 고체상으로 합성하였으며， 상기 제조예 5-1과 동일한 방법을 이용하여 합성하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고， ¾ NMR과 13C NMR을 이용하여 추가로 확인하였다. 112 In the same manner as in Preparation Example 3, isonicotinyl-tryptophan-tyrosine-valine -Dpr (1-cyano-1-cyclopropanecarboxylyl) was synthesized in a solid phase, using the same method as in Preparation Example 5-1. Synthesized. Compounds produced by mass spectrometry (MS) were identified and further confirmed using ¾ NMR and 13 C NMR.
99.9% Purity. Rt 21.4 min. ¾丽 R (400 MHz, DMS0-i/6) : δ 10.74 (d, 1H, J = 1.2), 8.87 (d, 1H, 8.4), 8.74 (brs, 2H), 8.24 (d, 2H, J = 7.2), 8.13 (t, 1H, 6.0), 7.85 (d, 1H, / = 8.8)， 7.73 (d, 2H, / = 4.4), 7.67 (d, 1H, J = 7.6)， 7.29 (d, 1H, J = 7.6)， 7.15 (d, lH, J= 1.2), 7.04 (m, 1H), 7.03 (d, 2H, /= 8.0)， 6.96 (t, 1H, J = 7.6), 6.57 (d, 2H, J = 8.0), 4.75 (m, 1H), 4.56 (m, 1H), 4.34 (q, 1H, J 7.2), 4.20 (dd, 1H, J= 8.8， 6.8), 3.51- 3.40 (m, 2H) , 3.17 (dd, 1H, J 14.8, /= 4.0), 3.07 (dd, 1H, J 14.8， J= 10.4), 2.96 (dd, 1H, J= 14.0, 4.4)， 2.76 (dd, 1H, 14.0, J= 9.6), 2.00 (m, 1H) , 1.57- 1.51 (m, 2H), 1.50- 1.44 (m, 2H), 0.89 (d, 3H, J 6.4)， 0.85 (d, 3H, J= 6.4). 13C NMR (100 MHz, DMSO_f ): δ 171.5, 171.2， 170.9, 170.8, 165.6， 164.3, 155.7, 149.1 142.0, 136.0, 130.1, 127.8, 127.2， 123.6, 121.9, 120.9, 119.9, 118.5， 118.2, 114.8， 111.3, 110.4, 57.4， 54.2 (2C, identified from HSQC), 51.7, 40.5， 36.3, 30.9, 27.2, 19.1， 18.0, 16.8， 16.7, 13.6. MALDI m/z calculated for C39H42N8Na08 + [M+Na]+ 773.30, found 773.57. 99.9% Purity. R t 21.4 min. ¾ 丽 R (400 MHz, DMS0-i / 6 ) : δ 10.74 (d, 1H, J = 1.2), 8.87 (d, 1H, 8.4), 8.74 (brs, 2H), 8.24 (d, 2H, J = 7.2), 8.13 (t, 1H, 6.0), 7.85 (d, 1H, / = 8.8), 7.73 (d, 2H, / = 4.4), 7.67 (d, 1H, J = 7.6), 7.29 (d, 1H, J = 7.6), 7.15 (d, lH, J = 1.2), 7.04 (m, 1H), 7.03 (d, 2H, / = 8.0), 6.96 (t, 1H, J = 7.6), 6.57 (d, 2H, J = 8.0), 4.75 (m, 1H), 4.56 (m, 1H), 4.34 (q, 1H, J 7.2), 4.20 (dd, 1H, J = 8.8, 6.8 ), 3.51- 3.40 (m, 2H), 3.17 (dd, 1H, J 14.8, / = 4.0), 3.07 (dd, 1H, J 14.8, J = 10.4), 2.96 (dd, 1H, J = 14.0, 4.4 ), 2.76 (dd, 1H, 14.0, J = 9.6), 2.00 (m, 1H), 1.57- 1.51 (m, 2H), 1.50- 1.44 (m, 2H), 0.89 (d, 3H, J 6.4) ， 0.85 (d, 3H, J = 6.4). 13 C NMR (100 MHz, DMSO_f): δ 171.5, 171.2, 170.9, 170.8, 165.6, 164.3, 155.7, 149.1 142.0, 136.0, 130.1, 127.8, 127.2, 123.6, 121.9, 120.9, 119.9, 118.5, 118.2, 114.8, 111.3, 110.4, 57.4, 54.2 (2C, identified from HSQC), 51.7, 40.5, 36.3, 30.9, 27.2, 19.1, 18.0, 16.8, 16.7, 13.6. MALDI m / z calculated for C 39 H42N 8 Na0 8 + [M + Na] + 773.30, found 773.57.
5-7. 이소니코티닐-트립토판 -타이로신 -발린 -Dpr (로다닌 -3ᅳ아세틸 ) 5-7. Isonicotinyl-tryptophan-tyrosine-valine-Dpr (rhodanine-3 닌 acetyl)
Figure imgf000112_0001
Figure imgf000112_0001
113 상기 제조예 3과 동일한 방식으로 이소니코티닐-트립토판 -타이로신—발린 -Dpr (로다닌 -3-아세틸)을 고체상으로 합성하였으며， 상기 제조예 5—1과 동일한 방법을 이용하여 합성하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물올 확인하였고， NMR과 13C NMR을 이용하여 추가로 확인하였다. 113 In the same manner as in Preparation Example 3, isonicotinyl-tryptophan-tyrosine-valine-Dpr (rhodanine-3-acetyl) was synthesized in the solid phase, and synthesized in the same manner as in Preparation Example 5-1. Compounds produced by mass spectometry (MS) were identified and further identified using NMR and 13 C NMR.
99.9% Purity. Rt 22.3 min. ¾ NMR (400 MHz, DMS0-c6): δ 10.73 (d, 1H, J = 1.6), 8.84 (d, 1H, J= 8.4), 8.72 (brs, 2H), 8.28 (t, 1H, J = 6.0)， 8.24 (d, 1H, J - 8.0)， 8.20 (d, 1H, J = 7.6), 7.83 (d, 1H, J = 8.0), 7.69 (d, 2H, J = 4.0), 7.66 (d, 1H, J= 7.6), 7.29 (d, 1H, J= 7.6)， 7.14 (d, 1H, J= 1.6), 7.04 (m, 1H), 7.03 (d, 2H, J = 8.4)， 6.96 (t, 1H, /= 7.6), 6.57 (d' 2H, /= 8.4)， 4.74 (m, 1H), 4.55 (m, 1H), 4.49 (s, 2H), 4.31 (s, 2H), 4.29 (m, 1H), 4.20 (dd, 1H, J= 8.0, J = 6.8)， 3.44- 3.33 (m, 2H, identified from HSQC) , 3.16 (dd, 1H, J= 14.8, J= 3.6), 3.06 (dd, 1H, J = 14.8， J= 10.4), 2.97 (dd, 1H, J = 14.0, /= 3.6), 2.76 (dd, 1H, J= 14.0， J= 9.6)， 2.00 (m, 1H), 0.88 (d, 3H, J= 6.8)， 0.85 (d, 3H, J= 6.8). 13C NMR (100 MHz, DMSO-i¾) ·' δ 202.8, 173.9, 171.5， 171.3, 171.1, 170.8, 165.2, 164.5, 155.7, 149.5, 141.6， 136.1， 130.1, 127.9, 127.2, 123.6, 121.7, 120.9， 118.5， 118.2， 114.9, 111.3， 110.4, 57.5, 54.2, 54.1, 51.9, 45.9, 39.5, 36.2, 36.0, 30.9, 27.3, 19.2, 18.0. MALDI m/z calculated for C39H42N8Na09S2 + [M+Na]+ 853.24, found 853.52. 99.9% Purity. R t 22.3 min. ¾ NMR (400 MHz, DMS0-c 6 ): δ 10.73 (d, 1H, J = 1.6), 8.84 (d, 1H, J = 8.4), 8.72 (brs, 2H), 8.28 (t, 1H, J = 6.0), 8.24 (d, 1H, J-8.0), 8.20 (d, 1H, J = 7.6), 7.83 (d, 1H, J = 8.0), 7.69 (d, 2H, J = 4.0), 7.66 (d, 1H, J = 7.6), 7.29 (d, 1H, J = 7.6), 7.14 (d, 1H, J = 1.6), 7.04 (m, 1H), 7.03 (d, 2H, J = 8.4), 6.96 (t, 1H, / = 7.6), 6.57 (d '2H, / = 8.4), 4.74 (m, 1H), 4.55 (m, 1H), 4.49 (s, 2H), 4.31 (s, 2H), 4.29 (m, 1H), 4.20 (dd, 1H, J = 8.0, J = 6.8), 3.44- 3.33 (m, 2H, identified from HSQC), 3.16 (dd, 1H, J = 14.8, J = 3.6), 3.06 (dd, 1H, J = 14.8, J = 10.4), 2.97 (dd, 1H, J = 14.0, / = 3.6), 2.76 (dd, 1H, J = 14.0, J = 9.6), 2.00 (m, 1H), 0.88 (d, 3H, J = 6.8), 0.85 (d, 3H, J = 6.8 ). 13 C NMR (100 MHz, DMSO-i¾) ''' δ 202.8, 173.9, 171.5, 171.3, 171.1, 170.8, 165.2, 164.5, 155.7, 149.5, 141.6, 136.1, 130.1, 127.9, 127.2, 123.6, 121.7, 120.9, 118.5, 118.2, 114.9, 111.3, 110.4, 57.5, 54.2, 54.1, 51.9, 45.9, 39.5, 36.2, 36.0, 30.9, 27.3, 19.2, 18.0. MALDI m / z calculated for C 39 H 42 N 8 Na0 9 S 2 + [M + Na] + 853.24, found 853.52.
5-8. 이소니코티닐 -트립토판 -타이로신 -발린 -Dpr (2-플루오로페닐아세틸 )5-8. Isicotinyl-tryptophan-tyrosine-valine-Dpr (2-fluorophenylacetyl)
( I son i cot i ny 1 -Tr -Tyr - Va 1 -Dpr ( 2- f 1 uor opheny 1 ace t y 1 ) ) (I son i cot i ny 1 -Tr -Tyr-Va 1 -Dpr (2-f 1 uor opheny 1 ace t y 1))
Figure imgf000113_0001
Figure imgf000113_0001
114 상기 제조예 3과 동일한 방식으로 이소니코티닐-트립토판-타이로신 -발린 -Dpr(2-플루오로페닐아세틸)을 고체상으로 합성하였으며， 상기 제조예 5—1과 동일한 방법을 이용하여 합성하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  114 In the same manner as in Preparation Example 3, isonicotinyl-tryptophan-tyrosine-valine -Dpr (2-fluorophenylacetyl) was synthesized in the solid phase, and synthesized in the same manner as in Preparation Example 5-1. The produced compound was confirmed by mass spectometry (MS).
99.9% Purity. t 23.3 min. MALDI m/z calculated for C42H44FN7Na(V [M+Na] + 816.31, found 816.63. 99.9% Purity. t 23.3 min. MALDI m / z calculated for C 42 H 44 FN 7 Na (V [M + Na] + 816.31, found 816.63.
5-10. 5-10.
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (4-펜틸바이사이클로 [2.2.2]옥탄 -1-카 복실일) (Isoni cot i ny 1 -Trp-Tyr~Va 1 -Dpr (4-penty lbicyclo[2.2.2]octaneIsonicotinyl-tryptophan-tyrosine-valine-Dpr (4-pentylbicyclo [2.2.2] octane-1-carboxylyl) (Isoni cot i ny 1 -Trp-Tyr to Va 1 -Dpr (4-penty lbicyclo [2.2.2] octane
-1-carboxylyl)) -1-carboxylyl))
Figure imgf000114_0001
Figure imgf000114_0001
115 상기 제조예 3과 동일한 방식으로 이소니코티닐-트립토판 -타이로신-발린ᅳ Dpr (4-펜틸바이사이클로 [2.2.2]옥탄 -1-카 복실일)을 고체상으로 합성하였으며， 상기 제조예 5-1과 동일한 방법을 이용하여 합성하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  115 In the same manner as in Preparation Example 3, isonicotinyl-tryptophan-tyrosine-valinec Dpr (4-pentylbicyclo [2.2.2] octane-1-carboxylyl) was synthesized in a solid phase. It synthesize | combined using the same method as 1. The produced compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 31.1 min. MALDI m/z calculated for C48H6iN7Na( [M+Na] + 886.45, found 886.80. 5-11. 이소니코티닐-트립토판 -타이로신-발린— Dpr (퀴날딜) (Isonicotinyl-99.9% Purity. R t 31.1 min. MALDI m / z calculated for C 4 8H 6 iN 7 Na ([M + Na] + 886.45, found 886.80. 5-11.isonicotinyl-tryptophan-tyrosine-valine—Dpr (quinalyl) (Isonicotinyl-
Tr p-Tyr一 Va 1 -D r(quinaldyl)) Tr p-Tyr 一 Va 1 -D r (quinaldyl))
Figure imgf000114_0002
Figure imgf000114_0002
116 상기 제조예 3과 동일한 방식으로 이소니코티닐—트립토판-타이로신 -발린 -Dpr (퀴나딜)을 고체상으로 합성하였으며， 상기 제조예 5-1과 동일한 방법을 이용하여 합성하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. 116 In the same manner as in Preparation Example 3, isonicotinyl-tryptophan-tyrosine-valine-Dpr (quinadyl) was synthesized in a solid phase and synthesized using the same method as in Preparation Example 5-1. The produced compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 24.4 min. MALDI m/z calculated for C44H44N8Na08 + [M+Na] + 835.32, found 835.66 99.9% Purity. R t 24.4 min. MALDI m / z calculated for C4 4 H 44 N 8 Na0 8 + [M + Na] + 835.32, found 835.66
5-12. 이소니코티닐-트립토판—타이로신 -발린 -Dpr (타이글라일 )5-12. Isicotinyl-Tryptophan—Tyrosine-Valine-Dpr (Taigliil)
( I soni cot inyl -Trp-Tyr-Va 1 -Dpr (tiglyl)) (I soni cot inyl -Trp-Tyr-Va 1 -Dpr (tiglyl))
Figure imgf000115_0001
Figure imgf000115_0001
117 상기 제조예 3과 동일한 방식으로 이소니코티닐-트립토판-타이로신 -발린 -Dp 타이글라일)을 고체상으로 합성하였으며， 상기 제조예 5-1과 동일한 방법을 이용하여 합성하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  117 In the same manner as in Preparation Example 3, isonicotinyl-tryptophan-tyrosine-valine-Dp tiglayl) was synthesized in a solid phase, and synthesized using the same method as in Preparation Example 5-1. The produced compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 22.1 min. MALDI m/z calculated for C39H45N7Na08 + [M+Na] 762.32, found 762.72. 99.9% Purity. R t 22.1 min. MALDI m / z calculated for C 39 H 45 N 7 Na0 8 + [M + Na] 762.32, found 762.72.
5-13. 이소니코티닐-트립토판 -타이로신 -발린 -Dpr (5—클로로인돌 -2-카복실일 ) (Isonicotinyl -Trp-Tyr-Va 1 -Dpr (5-chloroi ndo 1 e一 2— car boxy lyl))
Figure imgf000116_0001
5-13. Isicotinyl-tryptophan-tyrosine-valine-Dpr (Isonicotinyl-Trp-Tyr-Va 1 -Dpr (5-chloroi ndo 1 e 一 2— car boxy lyl))
Figure imgf000116_0001
118 상기 제조예 3과 동일한 방식으로 이소니코티닐-트립토판 -타이로신-발린ᅳ Dpr (5ᅳ클로로인돌—2-카복실일)을 118 Isonicotinyl-tryptophan-tyrosine-valine ᅳ Dpr ( 5 ᅳ chloroindole— 2 -carboxylyl) was prepared in the same manner as in Preparation Example 3.
고체상으로 합성하였으며， 상기 제조예 5-1과 동일한 방법을 이용하여 합성하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. It synthesize | combined to the solid phase, and synthesize | combined using the same method as the preparation example 5-1. The produced compound was confirmed by mass spectometry (MS).
96.2% Purity. Rt 25.7 min. MALDI m/z calculated for C43H43ClN8Na08 + [M+Na] + 857.28， found 857.62. 96.2% Purity. R t 25.7 min. MALDI m / z calculated for C 43 H 43 ClN 8 Na0 8 + [M + Na] + 857.28, found 857.62.
5-14. 5-14.
이소니코티닐 -트립토판 -타이로신-발린— Dpr (5-니트로 -3—피라졸카복실일 ) Isicotinyl-tryptophan-tyrosine-valine— Dpr (5-nitro-3—pyrazolcarboxylyl)
(Isonicotinyl -Trp-Tyr -Va 1 -Dpr ( 5-ni r ο-3-pyr azo 1 ecarboxy 1 y 1 ) ) (Isonicotinyl -Trp-Tyr -Va 1 -Dpr (5-ni r ο-3-pyr azo 1 ecarboxy 1 y 1))
Figure imgf000116_0002
Figure imgf000116_0002
119 상기 제조예 3과 동일한 방식으로 이소니코티닐 -트립토판—타이로신 -발린 -Dpr (5-니트로 -3-피라졸카복실일)올 119 isonicotinyl-tryptophan—tyrosine-valine-Dpr (5-nitro-3-pyrazolcarboxylyl) ol in the same manner as in Preparation Example 3
고체상으로 합성하였으며，상기 제^예 5—1과 동일한 방법올 이용하여 합성하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. 87.7% Purity. Rt 21.5 min., MALDI m/z calculated for C38H40N10Na0i0 + [M+Na 819.28， found 819.68 It synthesize | combined to the solid phase and synthesize | combined using the same method as the said Example 5-1. The produced compound was confirmed by mass spectometry (MS). 87.7% Purity. R t 21.5 min., MALDI m / z calculated for C 38 H 40 N 10 Na0i 0 + [M + Na 819.28, found 819.68
5-15. 5-15.
이소니코티닐-트립토판-타이로신 -발린 -Dpr(2-(4-메틸페닐설폰아미도)아세틸) Isicotinyl-tryptophan-tyrosine-valine -Dpr (2- (4-methylphenylsulfonamido) acetyl)
Figure imgf000117_0001
Figure imgf000117_0001
120 상기 제조예 3과 동일한 방식으로 이소니코티닐-트립토판-타이로신 -발린 -Dpr(2-(4-메틸페닐설폰아미도)아세틸)을 고체상으로 합성하였으며，상기 제조예 5-1과 동일한 방법을 이용하여 합성하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  120 isonicotinyl-tryptophan-tyrosine-valine -Dpr (2- (4-methylphenylsulfonamido) acetyl) was synthesized in the same manner as in Preparation Example 3, using the same method as in Preparation Example 5-1. Synthesized. The produced compound was confirmed by mass spectometry (MS).
99.9% Purity. Rt 23.7 min. MALDI m/z calculated for C43H48N8Na0i0S+ [M+Na] + 891.31, found 891.59. 제조예 6. Val-Dpr(acyl)-Pro-Ser / Dpr(acyl)-Pro-Ser의 합성 99.9% Purity. R t 23.7 min. MALDI m / z calculated for C 43 H 48 N 8 Na0i 0 S + [M + Na] + 891.31, found 891.59. Preparation Example 6 Synthesis of Val-Dpr (acyl) -Pro-Ser / Dpr (acyl) -Pro-Ser
잘려진 (truncated)펩티도미메틱 화합물들의 생물학적 활성이 좋은 것으로 나타났으므로， 또 다른 잘려진 펩티도미메틱 화합물， 즉 C00H 말단이 Serine 인 trimer 와 tetramer 로 이루어진 화합물의 합성을 설계하였다.  Since the biological activity of truncated peptidomimetic compounds has been shown to be good, we have designed a synthesis of another truncated peptidomimetic compound, a compound consisting of a trimer and tetramer with Serine at the C00H terminus.
도 7에서 보는바와 같이， 제조예 4 및 5에서 합성된 대부분의 화합물들이 dTBP2 보다 효과적이었으므로， 5개의 산 (acids, As shown in Figure 7, since most of the compounds synthesized in Preparation Examples 4 and 5 were more effective than dTBP2, five acids (acids,
( 2， 6-di 0X0-1 ,2,3, 6— t e t r ahy dr opy r imidine-4-carboxyl ic acid,(2 ， 6-di 0X0-1, 2,3, 6— t e t r ahy dr opy r imidine-4-carboxyl ic acid,
7-methoxy-l-benzofuran-2-carboxyl ic acid, 3， 5_di methyl benzoic acid,7-methoxy-l-benzofuran-2-carboxyl ic acid, 3 ， 5_di methyl benzoic acid,
5-chloroindol-2-carboxyl ic acid and 2-f luoropheny 1 acet i c acid) 을 선정하여, 5-chloroindol-2-carboxyl ic acid and 2-f luoropheny 1 acet ic acid)
Figure imgf000118_0001
Figure imgf000118_0001
Figure imgf000119_0001
-1. 발린 -Dpr (오로틸) -프를린 -세린 (Val-Dpr(orotyl )-Pro-Ser)
Figure imgf000119_0001
-One. Valine-Dpr (orotyl) -Prlin-serine (Val-Dpr (orotyl) -Pro-Ser)
Figure imgf000120_0001
Figure imgf000120_0001
121 121
필터가 설치된 20 mL TORVIQ PP syringe에 Wang resin LL( 100-200 mesh, 320 mg, 0.44 mmol/g, 0.141 瞧 ol)을 넣고 무수 DMF를 넣어 30분간 팽윤 시킨 후 배수시켰다. Fmoc-Ser(tBu)-0H(10.0 equiv. , 541 mg, 1.41瞧 ol)을 50 mL pear shape flask에 넣고 아르곤 가스로 치환한 후, 무수 C¾C12 (4 mL) 에 녹였다. DIC (5.0 당량， 0.11 mL, 0.705 隱 ol)를 상기 흔합물에 첨가한 후 0°C에서 20분간 교반하였다 (white solid 생성). 상온에서 감압 증류한 후 남은 suspension을 최소량의 무수 DMF (4.5mL)에 녹이고， DMAP (0.1당량， 1.7 mg, 0.014隱 ol )올 무수 DMF (0.1 mL)에 녹여서 두 용액을 순서대로 팽윤 시킨 resin에 첨가하여 상온에서 1시간 동안 orbital shaker (130 r. p.m.)를 사용하여 흔합하고 용매를 배수한 후 DMF, iPrOH와 CH2C12으로 세척하였다 (각각 10 mL x 1 min X 3). UV Spectrometry를 이용하여 Fmoc quantification한 결과， loading level은 97.0%로 나타났다. Wang resin LL (100-200 mesh, 320 mg, 0.44 mmol / g, 0.141 瞧 ol) was added to a 20 mL TORVIQ PP syringe equipped with a filter and swelled for 30 minutes with anhydrous DMF. Fmoc-Ser (tBu) -0H (10.0 equiv., 541 mg, 1.41 μl) was placed in a 50 mL pear shape flask, replaced with argon gas, and dissolved in anhydrous C¾C1 2 (4 mL). DIC (5.0 equiv, 0.11 mL, 0.705 μl) was added to the mixture and stirred at 0 ° C. for 20 min (generating white solid). After distillation under reduced pressure at room temperature, the remaining suspension was dissolved in a minimum amount of anhydrous DMF (4.5 mL), dissolved in DMAP (0.1 equivalent, 1.7 mg, 0.014 隱 ol) ol anhydrous DMF (0.1 mL), and the solution was swollen in order. The mixture was mixed with an orbital shaker (130 rpm) for 1 hour at room temperature, drained, and washed with DMF, iPrOH, and CH 2 C1 2 (10 mL × 1 min × 3, respectively). Fmoc quantification using UV spectrometry showed that the loading level was 97.0%.
Fmoc 그룹을 deprotection 하기 위해 상기 resin (200 mg, 0.088 瞧 ol)을 무수 DMF에 30분간 팽윤시킨 후， 20% piper idine/무수 DMF (4.0 mL)을 첨가하여 10분간 상은에서 orbital shaker (130 r.p.m.)를 사용하여 흔합하고 용매를 배수한 후 DMF, iPrOH와 CH2Cl2으로 세척하였다 (10 mL x 1 min x 3).30분간 aspirator를 사용하여 vacuum dry 한 후 Kaiser test를 이용하여 반웅이 완결되었음을 확인하였다. The resin (200 mg, 0.088 μl) 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.
상기 제조예 3과 동일한 방식으로 발린 -Dpr (오로틸) -프롤린-세린을 고체상으로 합성한 후， resin (40 mg, 0.018 mmol) 을 필터가 설치된 3 mL TORVIQ PP syringe에 넣고， 20% piper idine/무수 DMF (0.8 mL)를 사용하여 Fmoc 그룹을 deprotection하고， degassed 94% TFA cocktail (0.8 mL)을 첨가하여 상은에서 1시간 동안 흔합한 후 여과하여 여액을 받고， 다시 TFA (0.4 mL x 2)로 세척하여 그 여액을 받았다. 위 여액들을 합하여 evaporator를 이용하여 TFA를 제거한 후, cold ether를 사용하여 3회 decant at ion하였다. 이때 생성된 화합물의 손실을 막기 위해 원심 분리기를 이용하였으며， highvaccumdry후 semi-preparat ive HPLC (binary solvent system, solvent A: 0.1% TFA/H20, solvent B: 0.1% TFA/MeOH , 10- 90% B over 31 min)를 이용하여 분리 및 정제한 후 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고， ¾ NMR과 13C NMR을 이용하여 추가로 확인하였다. Synthesis of valine -Dpr (orotyl) -proline-serine in the solid phase in the same manner as in Preparation Example 3, the resin (40 mg, 0.018 mmol) was put in a 3 mL TORVIQ PP syringe with a filter, 20% piper idine Fmoc group using anhydrous DMF (0.8 mL) After deprotection, degassed 94% TFA cocktail (0.8 mL) was added, and the mixture was mixed with silver for 1 hour, filtered, and the filtrate was obtained, and again washed with TFA (0.4 mL x 2) to obtain the filtrate. The filtrates were combined to remove TFA using an evaporator and then decant at ion three times using cold ether. In this case, centrifuge was used to prevent the loss of the produced compound. After highvaccumdry, semi-preparative HPLC (binary solvent system, solvent A: 0.1% TFA / H 2 0, solvent B: 0.1% TFA / MeOH, 10- 90 % B over 31 min) was isolated and purified, and the mass produced by mass spectrometry (MS) was identified, and further confirmed by using ¾ NMR and 13 C NMR.
99.9% Purity. Rt 13.7 min. ¾ NMR (400 MHz, D20)： δ 6.23 (s, 1H), 5.0899.9% Purity. R t 13.7 min. ¾ NMR (400 MHz, D 2 0): δ 6.23 (s, 1H), 5.08
(dd, 1H, /= 7.2, /= 5.2)， 4.59- 4.54 (m, 2H), 4.02 (dd, 1H, /= 12.0, J= 4.4), 3.94- 3.84 (m, 4H), 3.78 (m, 1H), 3.68 (dd, 1H, J = 14.0， J = 7.6), 2.36 (m, 1H), 2.24 (m, 1H)， 2.11— 1.98 (m, 3H)， 1.03 (d, 3H, J = 6.8), 1.02 (d, 3H, J = 6.8). 13C MR (100 MHz, D20)： δ 174.0, 173.4, 169.4, 169.0， 166.9, 162.2, 152.3, 145.2， 101.3, 61.2, 60.7, 58.5, 55.0， 51.2, 48.4, 40.5, 30.1, 29.6, 24.8, 17.7, 16.9. MALDI m/z calculated for C2iH32N709 + [M+H]+ 526.23, found 526.34. (dd, 1H, / = 7.2, / = 5.2), 4.59-4.54 (m, 2H), 4.02 (dd, 1H, / = 12.0, J = 4.4), 3.94-3.84 (m, 4H), 3.78 (m , 1H), 3.68 (dd, 1H, J = 14.0, J = 7.6), 2.36 (m, 1H), 2.24 (m, 1H), 2.11— 1.98 (m, 3H), 1.03 (d, 3H, J = 6.8), 1.02 (d, 3H, J = 6.8). 13 C MR (100 MHz, D 2 0): δ 174.0, 173.4, 169.4, 169.0, 166.9, 162.2, 152.3, 145.2, 101.3, 61.2, 60.7, 58.5, 55.0, 51.2, 48.4, 40.5, 30.1, 29.6, 24.8 , 17.7, 16.9. MALDI m / z calculated for C 2 i H 32 N 7 0 9 + [M + H] + 526.23, found 526.34.
6-2. 발린 -Dpr^-메록시 -1-벤조퓨란 -2-카복실일) -프를린 -세린 (Va卜 Dpr ( 7-me t hoxy-l-benzo fur an~2-c arboxy lyl) -Pr o— Ser ) 6-2. Valine -Dpr ^ -Methoxy-1-benzofuran-2-carboxylyl) -Plin -serine (Vapr Dpr (7-me t hoxy-l-benzo fur an ~ 2-c arboxy lyl) -Pr o — Ser)
Figure imgf000121_0001
Figure imgf000121_0001
122 상기 제조예 3과 동일한 방식으로 발린 -Dpr(7-메특시 -1-벤조퓨란 -2-카복실일) -프를린-세린을 합성하였으며， 상기 제조예 6-1과 동일한 방법을 이용하여 합성하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고， ¾ NMR과 13C MR을 이용하여 추가로 확인하였다. 122 Valine -Dpr (7-methoxy-1-benzofuran-2-carboxylyl) -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. It was. Compounds produced by mass spectrometry (MS) were identified and further confirmed using ¾ NMR and 13 C MR.
99.9% Purity. Rt 25.8 min. ¾ NMR (400 MHz, D20)： δ 7.56 (s, 1H), 7.38 (dd, 1H, /= 8.0, J = 1.2)， 7.33 (t, 1H, J= 8.0), 7.13 (dd, 1H, J = 8.0， / = 1.2), 5.09 (dd, 1H, J 7.2, J = 5.6), 4.57 (dd, 1H, J 8.8, J = 6.4)， 4.55 (t, 1H, J 4.4), 4.03 (s, 3H), 4.10- 3.77 (m, 7H), 2.37 (m, 1H) , 2.23 (m, 1H)， 2.11- 1.99 (m, 3H), 1.03 (d, 6H, J=7.2). 13C NMR (100 MHz, D20)： δ 173.8, 173.5, 169.4, 169.3, 161.5, 147.2, 145.1， 144.4， 128.7， 125.0, 115.2， 112.0, 109.5, 61.3, 60.8， 58.6, 56.2， 55.1, 51.6, 48.4, 39.9, 30.1, 29.5, 24.8， 17.7, 17.0. MALDI m/z calcul ted for C26H36N509 + [M+H]+ 562.25, found 562.32. 6z3, 발린 -Dpr(3, 5-디메틸벤조일) -프를린 -세린 (Val-Dpr(3,5- dimethylbenzoyl )-Pro~Ser) 99.9% Purity. R t 25.8 min. ¾ NMR (400 MHz, D 2 0): δ 7.56 (s, 1H), 7.38 (dd, 1H, / = 8.0, J = 1.2), 7.33 (t, 1H, J = 8.0), 7.13 (dd, 1H , J = 8.0, / = 1.2), 5.09 (dd, 1H, J 7.2, J = 5.6), 4.57 (dd, 1H, J 8.8, J = 6.4), 4.55 (t, 1H, J 4.4), 4.03 ( s, 3H), 4.10-3.77 (m, 7H), 2.37 (m, 1H), 2.23 (m, 1H), 2.11- 1.99 (m, 3H), 1.03 (d, 6H, J = 7.2). 13 C NMR (100 MHz, D 2 0): δ 173.8, 173.5, 169.4, 169.3, 161.5, 147.2, 145.1, 144.4, 128.7, 125.0, 115.2, 112.0, 109.5, 61.3, 60.8, 58.6, 56.2, 55.1, 51.6 , 48.4, 39.9, 30.1, 29.5, 24.8, 17.7, 17.0. MALDI m / z calculted for C2 6 H 36 N 5 0 9 + [M + H] + 562.25, found 562.32. 6z3, valine-Dpr (3, 5-dimethylbenzoyl) -plin-serine (Val-Dpr (3,5-dimethylbenzoyl) -Pro to Ser)
Figure imgf000122_0001
Figure imgf000122_0001
123  123
상기 제조예 3과 동일한 방식으로 발린 -Dpr(3, 5—디메틸벤조일) -프를린 -세린 을 합성하였으며， 상기 제조예 6ᅳ1과 동일한 방법을 이용하여 합성하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고， ¾画 R과 13C NMR을 이용하여 추가로 확인하였다. 99.9% Purity. Rt 26.9 min. ¾匪 R (400 MHz, D20): δ 7.44 (s, 2H) , 7.34 (s, 1H), 5.05 (t, 1H, J = 6.4)， 4.57 (dd, 1H, J = 8.4, J = 5.6)， 4.49 (t, 1H, /= 4.4), 3.96 (dd, 1H, J= 11.6， J = 4.8), 3.90- 3.80 Cm, 5H) , 3.72 (m, 1H), 2.37 (m, 1H), 2.36 (s, 6H), 2.24 (m, 1H), 2.06- 1.95 (m, 3H), 1.04 (d, 3H, J = 6.8)， 1.03 (d, 3H, J = 6.8). 13C NMR (100 MHz, D20)： δ 173.9, 173.3， 171.7， 169.6， 169.3, 139.3, 134.1, 133.0, 124.9, 61.2， 60.7, 58.5, 55.1, 51.7， 48.4, 40.3, 30.1, 29.5, 24.8, 20.4, 17.6, 17.0. MALDI m/z calculated for C25H38N507 + [M+H]+ 520.28, found 520.38. 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 ¾ 画 R and 13 C NMR. 99.9% Purity. R t 26.9 min. ¾ 匪 R (400 MHz, D 2 0): δ 7.44 (s, 2H), 7.34 (s, 1H), 5.05 (t, 1H, J = 6.4), 4.57 (dd, 1H, J = 8.4, J = 5.6), 4.49 (t, 1H, / = 4.4), 3.96 (dd, 1H, J = 11.6, J = 4.8), 3.90-3.80 Cm, 5H), 3.72 (m, 1H), 2.37 (m, 1H) , 2.36 (s, 6H), 2.24 (m, 1H), 2.06- 1.95 (m, 3H), 1.04 (d, 3H, J = 6.8), 1.03 (d, 3H, J = 6.8). 13 C NMR (100 MHz, D 2 0): δ 173.9, 173.3, 171.7, 169.6, 169.3, 139.3, 134.1, 133.0, 124.9, 61.2, 60.7, 58.5, 55.1, 51.7, 48.4, 40.3, 30.1, 29.5, 24.8 , 20.4, 17.6, 17.0. MALDI m / z calculated for C 25 H 38 N 5 0 7 + [M + H] + 520.28, found 520.38.
6-4. 발린 -Dpr (5-클로로인돌 -2-카복실일) -프를린 -세린 (Val-Dpr6-4. Valine-Dpr (5-chloroindole-2-carboxylyl) -prine-serine (Val-Dpr
(5-chloroi ndo 1 e—2— car boxy lyl) -Pr o-Ser ) (5-chloroi ndo 1 e—2— car boxy lyl) -Pr o-Ser)
Figure imgf000123_0001
Figure imgf000123_0001
124  124
상기 제조예 3과 동일한 방식으로 발린 -Dpr(5-클로로인돌 -2-카복실일) -프를린ᅳ세린을 합성하였으며， 상기 제조예 6-1과 동일한 방법을 이용하여 합성하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고， ¾ MR과 13C NMR을 이용하여 추가로 확인하였다. 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 ¾ MR and 13 C NMR.
99.9% Purity. Rt 28.8 min. ¾ NMR (400 MHz, D20): δ 7.61 (d, 1H, 2.0)， 7.42 (d, 1H, J= 8.8)， 7.26 (dd, 1H, J= 8.8, J= 2.0)， 6.97 (s, 1H), 5.00 (t, 1H, J = 6.8), 4.60- 4.56 (m, 2H), 4.01 (ddᅳ 1H, J = 11.6, J-.4.8), 3.93— 3.73 (m, 5H), 3.67 (m, 1H), 2.36 (dd, 1H, J= 15.2， /= 6.8), 2.24 (td, 1H, J= 13.6， J = 6.8)， 2.02— 1.94 (m, 3H) , 1.03 (d, 6H, /= 7.2). 13C醒 (100 MHz, D20)： δ 173.7， 173.3, 169.3, 169.1， 163.6， 134.9, 130.7, 127.7, 125.4, 124.8, 120.9, 113.4， 104.0, 61.0, 60.5， 58.3, 55.0, 51.4, 48.2, 39.7, 29.9, 29.3, 24.6, 17.4， 16.7. MALDI m/z calculated for C25H33ClN6Na07 + [M+Na] + 587.20, found 587.31. 99.9% Purity. R t 28.8 min. ¾ NMR (400 MHz, D 2 0): δ 7.61 (d, 1H, 2.0), 7.42 (d, 1H, J = 8.8), 7.26 (dd, 1H, J = 8.8, J = 2.0), 6.97 (s , 1H), 5.00 (t, 1H, J = 6.8), 4.60-4.56 (m, 2H), 4.01 (dd ᅳ 1H, J = 11.6, J-.4.8), 3.93— 3.73 (m, 5H), 3.67 (m, 1H), 2.36 (dd, 1H, J = 15.2, / = 6.8), 2.24 (td, 1H, J = 13.6, J = 6.8), 2.02— 1.94 (m, 3H), 1.03 (d, 6H , / = 7.2). 13 C 醒 (100 MHz, D 2 0): δ 173.7, 173.3, 169.3, 169.1, 163.6, 134.9, 130.7, 127.7, 125.4, 124.8, 120.9, 113.4, 104.0, 61.0, 60.5, 58.3, 55.0, 51.4, 48.2 , 39.7, 29.9, 29.3, 24.6, 17.4, 16.7. MALDI m / z calculated for C 25 H 33 ClN 6 Na0 7 + [M + Na] + 587.20, found 587.31.
6-5. 발린 -Dpr(2-플루오로페닐아세틸) -프를린 -세린 (Val-Dpr(2- f luorophenyl acetyl)一 Pro— Ser) 6-5. Valine-Dpr (2-fluorophenylacetyl) -prine-serine (Val-Dpr (2-f luorophenyl acetyl) 一 Pro— Ser)
Figure imgf000124_0001
Figure imgf000124_0001
125  125
상기 제조예 3과 동일한 방식으로 발린 -Dpr(2-플루오로페닐아세틸) -프를린-세린을 합성하였으며，상기 제조예 6-1과 동일한 방법올 이용하여 합성하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Valine -Dpr (2-fluorophenylacetyl) -prine-serine was synthesized in the same manner as in Preparation Example 3, and synthesized using the same method as Preparation Example 6-1. The produced compound was confirmed by mass spectometry (MS).
96.3% Purity. Rt 22.2 min. MALDI m/z calculated for C24H34FN5Na07 + [M+Na] + 546.23, found 546.32. 96.3% Purity. R t 22.2 min. MALDI m / z calculated for C 24 H 34 FN 5 Na0 7 + [M + Na] + 546.23, found 546.32.
6-6. Dpr (오로틸) -프를린 -세린 (Dpr(orotyl)-Pro-Ser) 6-6. Dpr (orotyl) -Pro-Ser
Figure imgf000124_0002
Figure imgf000124_0002
126 상기 제조예 3과 동일한 방식으로 Dpr (오로틸) -프를린-세린을 합성하였으며， 상기 제조예 6-1과 동일한 방법을 이용하여 합성하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고, ¾ 匪 R과 13C NMR을 이용하여 추가로 확인하였다ᅳ 126 In the same manner as in Preparation Example 3, Dpr (orotyl) -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 ¾ 匪 R and 13 C NMRMR.
93.9% Purity. Rt 10.8 min. ¾匪 R (400 MHz, D20): δ 6.29 (s, 1H), 4.69 (dd, 1H, J = 6.4, J= 3.2), 4.63 (dd, 1H, J = 8.0, J = 5.6), 4.57 (t, 1H, J = 4.4), 4.08- 4.00 (m, 2H), 3.94- 3.75 (m, 4H), 2.41 (m, 1H), 2.16- 2.00 (m, 3H). 13CNMR (100 MHz, D20): δ 173.6, 173.5, 166.6, 165.8, 162.5, 152.1, 144.5, 101.4，— 61.1， 60.7， 55.3， 51.9， 48.0, 39.0, 29.2, 24.7. MALDI m/z calculated for Ci6H23N608 + [M+H]+ 427.16, found 427.27. 93.9% Purity. R t 10.8 min. ¾ 匪 R (400 MHz, D 2 0): δ 6.29 (s, 1H), 4.69 (dd, 1H, J = 6.4, J = 3.2), 4.63 (dd, 1H, J = 8.0, J = 5.6), 4.57 (t, 1H, J = 4.4), 4.08-4.00 (m, 2H), 3.94-3.75 (m, 4H), 2.41 (m, 1H), 2.16- 2.00 (m, 3H). 13 CNMR (100 MHz, D 2 0): δ 173.6, 173.5, 166.6, 165.8, 162.5, 152.1, 144.5, 101.4, — 61.1, 60.7, 55.3, 51.9, 48.0, 39.0, 29.2, 24.7. MALDI m / z calculated for Ci 6 H 23 N 6 0 8 + [M + H] + 427.16, found 427.27.
6-7. Dpr(7_메를시 -1-벤조퓨란 -2-카복실일)—프를린-세린' (Dpr (그 methoxy -l-benzofuran-2-carboxylyl )-Pro~Ser ) 6-7. Dpr (7_Mercy-1-benzofuran-2-carboxylyl) —plin-serine ' (Dpr (its methoxy-l-benzofuran-2-carboxylyl) -Pro ~ Ser)
Figure imgf000125_0001
Figure imgf000125_0001
127  127
상기 제조예 3과 동일한 방식으로 In the same manner as in Preparation Example 3
Dpr(7-메를시 -1-벤조퓨란 -2-카복실일) -프를린ᅳ세린을 합성하였으몌 상기 제조예 6-1과 동일한 방법을 이용하여 합성하였다ᅳ 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다. Dpr (7-Mercy-1-benzofuran-2-carboxylyl) -plinxerine was synthesized and synthesized using the same method as Preparation Example 6-1. Mass spectometry (MS) ) Produced the compound.
99.9% Purity. Rt 24.7 min. MALDI m/z calculated for C2iH27N408 + [M+H]+463.18, found 463.28. 99.9% Purity. R t 24.7 min. MALDI m / z calculated for C 2 i H 27 N 4 0 8 + [M + H] + 463.18, found 463.28.
6-8. Dpr (3 ,5-디메틸벤조일) -프를린 -세린 (Dpr(3,5-dimethylbenzoyl)
Figure imgf000126_0001
6-8. Dpr (3,5-dimethylbenzoyl) -prine-serine (Dpr (3,5-dimethylbenzoyl)
Figure imgf000126_0001
128 128
상기 제조예 3과 동일한 방식으로 Dpr(3,5-디메틸벤조일) -프를린—세린을 합성하였으며， 상기 제조예 6-1과 동일한 방법을 이용하여 합성하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고, ¾ NMR과 13C NMR을 이용하여 추가로 확인하였다. 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 ¾ NMR and 13 C NMR.
99.9% Purity. Rt 25.9 min. ¾ NMR (400 MHz, D20) : δ 7.46 (s, 2H)， 7.36 (s, 1H), 4.70 (dd, 1H, J = 6.0, J= 4.0)， 4.63 (m, 1H), 4.40 (t, 1H, J = 4.0)， 4.04 (dd, 1H, /= 15.2, J= 4.0)， 3.93 (dd, 1H, J = 15.2, J = 4.8), 3.90 (dd, 1H, / = 15.2, / = 6.0)， 3.84 (m, 1H), 3.77- 3.70 (m, 2H), 2.41 (m, 1H), 2.38 (s, 6H), 2.09- 1.99 (m, 3H).13C NMR (125 MHz, D20)： δ 173.5, 173.2, 172.0, 166.2, 139.1, 134.0, 132.4, 124.8, 60.9, 60.6, 54.9, 52.1, 48.0, 39.3, 29.2, 24.7, 20.2. MALDI m/z calculated for C20H29N406 + [M+H]+ 421.21, found 421.30. 6-9. Dpr(5—클로로인돌 -2-카복실일) -프를린—세린 (Dpr(5-chloroindole-2- carboxy lyl) -Pr o-Ser ) 99.9% Purity. R t 25.9 min. ¾ NMR (400 MHz, D 2 0): δ 7.46 (s, 2H), 7.36 (s, 1H), 4.70 (dd, 1H, J = 6.0, J = 4.0), 4.63 (m, 1H), 4.40 ( t, 1H, J = 4.0), 4.04 (dd, 1H, / = 15.2, J = 4.0), 3.93 (dd, 1H, J = 15.2, J = 4.8), 3.90 (dd, 1H, / = 15.2, / = 6.0), 3.84 (m, 1H), 3.77-3.70 (m, 2H), 2.41 (m, 1H), 2.38 (s, 6H), 2.09-1.99 (m, 3H). 13 C NMR (125 MHz, D 2 0): δ 173.5, 173.2, 172.0, 166.2, 139.1, 134.0, 132.4, 124.8, 60.9, 60.6, 54.9, 52.1, 48.0, 39.3, 29.2, 24.7, 20.2. MALDI m / z calculated for C 20 H 29 N 4 0 6 + [M + H] + 421.21, found 421.30. 6-9. Dpr (5-chloroindole-2-carboxylyl) -prine-serine (Dpr (5-chloroindole-2-carboxylyl) -Pr o-Ser)
Figure imgf000127_0001
Figure imgf000127_0001
129 129
상기 제조예 3과 동일한 방식으로 In the same manner as in Preparation Example 3
Dpr(5-클로로인돌 -2-카복실일) -프를린-세린을 합성하였으며， 상기 제조예 6—1과 동일한 방법을 이용하여 합성하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였고, ¾ NMR과 13C NMR을 이용하여 추가로 확인하였다. 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 ¾ NMR and 13 C NMR.
99.9% Purity. t 28.3 min. ¾ NMR (400 MHz, D20)： δ 7.73 (d, 1H, /= 2.0), 7.50 (d, 1H, J=8.8), 7.33 (dd, 1H, J= 8.8, / =2.0), 7.09 (s, 1H), 4.68 (dd, 1H, J = 6.0, J = 4.0), 4.64 (dd, 1H, J= 8.4, J- 6.0), 4.46 (dd, 1H, J= 4.8, J= 4.0), 4.04 (dd, 1H, / = 15.2， / = 4.0), 3.93 (dd, 1H, J = 15.2， J - 4.8), 3.92- 3.71 (m, 4H), 2.42 (dd, 1H, J= 8.4, J= 6.0)， 2.12- 1.99 (m, 3H) . 13C NMR (100 MHz, D20): δ 173.7, 173.6, 166.4, 164.3, 135.3, 130.7, 128.0, 125.7, 125.2, 121.2, 113.8, 104.6, 61.2, 60.9， 55.5, 52.3, 48.3, 39.1， 29.5， 24.9. MALDI m/z calculated for C20H25C1N506 + [M+H]+ 466.15, found 466.23. 99.9% Purity. t 28.3 min. ¾ NMR (400 MHz, D 2 0): δ 7.73 (d, 1H, / = 2.0), 7.50 (d, 1H, J = 8.8), 7.33 (dd, 1H, J = 8.8, / = 2.0), 7.09 (s, 1H), 4.68 (dd, 1H, J = 6.0, J = 4.0), 4.64 (dd, 1H, J = 8.4, J-6.0), 4.46 (dd, 1H, J = 4.8, J = 4.0) , 4.04 (dd, 1H, / = 15.2, / = 4.0), 3.93 (dd, 1H, J = 15.2, J-4.8), 3.92-3.71 (m, 4H), 2.42 (dd, 1H, J = 8.4, J = 6.0), 2.12- 1.99 (m, 3H). 13 C NMR (100 MHz, D 2 0): δ 173.7, 173.6, 166.4, 164.3, 135.3, 130.7, 128.0, 125.7, 125.2, 121.2, 113.8, 104.6, 61.2, 60.9, 55.5, 52.3, 48.3, 39.1, 29.5 , 24.9. MALDI m / z calculated for C 20 H 25 C1N 5 0 6 + [M + H] + 466.15, found 466.23.
6-10. Dpr(2-플루오로페닐아세틸) -프를린-세린 (Dpr(2-fluorophenyl acetyl) -Pro-Ser) Dpr-PS 6-10. Dpr (2-fluorophenyl acetyl) -Pro-Ser) Dpr-PS
130 130
상기 제조예 3과 동일한 방식으로 Dpr (2-플루오로페닐아세틸) -프를린 -세린 을 합성하였으며, 상기 제조예 6-1과 동일한 방법을 이용하여 합성하였다. 질량분석계 (mass spectometry, MS)로 생성된 화합물을 확인하였다.  Dpr (2-fluorophenylacetyl) -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. The produced compound was confirmed by mass spectometry (MS).
91.0% Pur i ty . Rt 21.4 min . MALDI m/z cal culated for Ci9H26FN406 + [M+H] + 425. 18 , found 425.24. 실험예 L 인터루킨 -8분비 억제 측정 (IL-8 release inhibit ion assay) 1-1. 제조예 2에서 제조한 화합물의 인터루킨 -8 분비 억제 정도 확인 제조예 1의 (1TBP2 및 제조예 2에서 제조한 화합물들의 인터루킨 -8 분비 억제정도를 측정하였다. 구체적으로， dTBP2및 화합물들을 75 nM농도로 15분 동안 BEAS— 2B세포 (인간기관지상피세포)에 처리하고， 75 nM의 dTCTP를 넣은 후 18시간 후에 상등액을 취하였다. 취한 상등액은 4 0C에서 10 , 000 X g 으로 원심분리하고 분리된 상층액으로 IL-8 분석을 수행하였다. IL-8 분석에서는, PIERCE 사의 IL-8 ELISA ki t 를 이용하여 제조자의 프로토콜에 따라 IL-8 분비 억제 정도를 확인하였다. 91.0% Pur i ty. R t 21.4 min. MALDI m / z cal culated for Ci 9 H 26 FN 4 0 6 + [M + H] + 425. 18, found 425.24. Experimental Example L Interleukin-8 Secretion Inhibition Assay (IL-8 release inhibit ion assay) 1-1. Confirmation of the degree of inhibition of interleukin-8 secretion of the compound prepared in Preparation Example 2 The degree of inhibition of interleukin-8 secretion of the compounds prepared in Preparation Example 1 (1TBP2 and Preparation Example 2 was measured. Specifically, 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.
그 결과， 이소니코티닐 -트립토판-타이로신-발린-타이로신 -프롤린-세린-메티오닌 (3) 뿐만 아니라 2-메틸핵사노일ᅳ 트립토판—타이로신-발린-타이로신 -프를린-세린―메티오닌 (2)，  As a result, not only isonicotinyl-tryptophan-tyrosine-valine-tyrosine-proline-serine-methionine (3) but also 2-methylnusanoyl ᅳ tryptophan—tyrosine-valine-tyrosine-pr-lin-serine-methionine
알파—시아노 -4-하이드톡시신나밀— Alpha—cyano-4-hydroxycinnamil—
트립토판-타이로신-발린-타이로신 -프롤린-세린-메티오닌 (4)， . 및 5-니트로— 3-피라졸카복실일ᅳ Tryptophan-tyrosine-valine-tyrosine-proline-serine-methionine (4),. And 5-nitro— 3-pyrazolecarboxylyl
트립토판—타이로신—발린—타이로신 -프를린ᅳ세린-메티오닌 (5) 3 개의 화합물 모두 dTBP2 보다 효과적으로 나타나는 것을 확인할 수 있었다 (도 5). 1-2. 제조예 3에서 제조한 화합물의 인터루킨 -8분비 억제 정도 확인 제조예 1의 dTBP2 및 제조예 3에서 제조한 화합물들의 인터루킨 -8 분비 억제정도를 측정하였으며, 측정은 상기 실험예 1-1과 동일한 방법을 사용하였다. 측정결과， 41개의 비산화형 화합물 중 9개와 산화형 화합물 41 개 중 10개， 총 29개의 화합물이 dTBP2보다 강한 활성을 갖는 것으로 나타났다 (도 6). 이는， 이소니코티닐 그룹 (isonicotinyl 그룹)을 잔여 결합 잔기 (extra binding residue)로서 도입하고， 느슨한 결합 잔기 (loose binding residue)인 타이로신을 단단한 결합 잔기 (tight binding residue)로 바꿈으로써, dTBP2-dTCTP 결합 및 인터루킨— 8 분비 억제 활성올 높인 것으로 생각되었다. 1-3. 제조예 4에서 제조한 화합물의 인터루킨 -8분비 억제 정도 확인 제조예 4를 통해서 제조된 19개의 화합물 중 비산화형을 제외한 14개의 화합물에 대해서 인터루킨 -8 분비 억쎄정도를 측정한 결과， 14개 화합물 모두 dTBP2 보다 효과적인 것으로 나타났다. 측정 결과는 하기 표 3와 같다. Tryptophan-Tyrosine-Valine-Tyrosine-Plincexerine-Methionine (5) It was confirmed that all three compounds appeared more effectively than dTBP2 (FIG. 5). 1-2. Confirmation of the degree of inhibition of interleukin-8 secretion of the compound prepared in Preparation Example 3 The degree of inhibition of interleukin-8 secretion of the compounds prepared in dTBP2 and Preparation Example 3 of Preparation Example 1 was measured, and the measurement was performed in the same manner as in Experimental Example 1-1. Was used. As a result, 9 out of 41 non-oxidizing compounds, 10 out of 41 oxidizing compounds, and 29 compounds were found to have stronger activity than dTBP2 (FIG. 6). This allows dTBP2-dTCTP binding by introducing an isonicotinyl group as an extra binding residue and replacing tyrosine, a loose binding residue, with a tight binding residue. And interleukin-8 secretion inhibitory activity. 1-3. Confirmation of the degree of inhibition of interleukin-8 secretion of the compound prepared in Preparation Example 4 As a result of measuring the degree of interleukin-8 secretion inhibition of 14 compounds except the non-oxidized type among the 19 compounds prepared in Preparation Example 4, all 14 compounds It has been shown to be more effective than dTBP2. The measurement results are shown in Table 3 below.
[표 3] TABLE 3
Figure imgf000130_0001
Figure imgf000130_0001
[a] nd = not determined  [a] nd = not determined
1-4. 제조예 5에서 제조한 화합물의 인터루킨 -8 분비 억제 정도 확인 제조예 5를 통해서 제조된 14개의 화합물에 대해 인터루킨ᅳ 8 분비 억제정도를 측정한 결과, 4개 중 10개의 화합물들이 dTBP2 보다 효과적인 것으로 나타났다 (표 4) . 1-4. Confirmation of the degree of inhibition of interleukin-8 secretion of the compound prepared in Preparation Example 5 As a result of measuring the level of interleukin ᅳ 8 secretion inhibition for 14 compounds prepared through Preparation Example 5, it was found that 10 of 4 compounds were more effective than dTBP2 (Table 4).
[표 4]  TABLE 4
Figure imgf000131_0001
또한， 잘려진 (truncated) 펩티도미메틱 화합물들로 이루어진 제조예 4에서제조한 화합물과 제조예 5에서 제조한 화합물 사이의 상대적인 활성을 비교하기 위해서 같은 배지에서 생물학적 검정 (bioassay)을 실시하였다 (도 7). 이로부터 제조예 4에서 제조한 화합물과 제조예 5에서 제조한 화합물 중 24개가 dTBP2 보다 강한 활성을 보임을 알 수 있었다. 또한 제조예 4 및 5에서 제조된 상위 4개 화합물들을 살펴보면， 제조예 4의 93ᅳ 99， 103, 100 그리고 제조예 5 의 107， 109， 108, 114 의 산 (acid) 들 중 3개 화합물의 산 (acid) (7-methoxy-l-benzofuran-2-carboxyl ic acid, 3 , 5-d i me t hy 1 benzo i c acid, and 2 , 6-di oxo-1 ,2,3, 6-t et rahydropyr imi dine-4-car boxy 1 i c acid) 은 상기 제조예 4 및 5 모두에서 효과적인 것으로 나타났다 (99/109, 103/108， 100/107).
Figure imgf000131_0001
In addition, a bioassay was performed in the same medium to compare the relative activity between the compound prepared in Preparation Example 4 consisting of truncated peptidomimetic compounds and the compound prepared in Preparation Example 5 (FIG. 7). ). From this, it could be seen that 24 of the compound prepared in Preparation Example 4 and the compound prepared in Preparation Example 5 showed stronger activity than dTBP2. In addition, looking at the top four compounds prepared in Preparation Examples 4 and 5, 93 ᅳ 99, 103, 100 of Preparation Example 4 and three of the acid (acid) of 107, 109, 108, 114 of Preparation Example 5 Acids (7-methoxy-l-benzofuran-2-carboxyl ic acid, 3, 5-dimethy 1 benzoic acid, and 2, 6-di oxo-1, 2,3, 6-t et rahydropyr imi dine-4-car boxy 1 ic acid) was shown to be effective in both Preparation Examples 4 and 5 (99/109, 103/108, 100/107).
1-5. 제조예 6에서 제조한 화합물의 인터루킨 -8 분비 억제 정도 확인 1-5. Confirmation of the degree of inhibition of interleukin-8 secretion of the compound prepared in Preparation Example 6
이들에 대한 생물학적 활성 검사 (IL-8 Release Inhibition Assay)를 실시한 결과 10개 중 8개의 화합물들이 dTBP2 보다 효과적인 것으로 확인되었다 (표 5， 도 8).  As a result of the biological activity test (IL-8 Release Inhibition Assay), 8 of 10 compounds were found to be more effective than dTBP2 (Table 5, Figure 8).
[표 5]  TABLE 5
Rank Compound IL-8 Rank Compound IL-8 Rank Compound 3 oo Rank Compound IL-8 Rank Compound IL-8 Rank Compound 3 o o
No. (pg/ml) No. (pg/mi) No. dTCTP 630.0  No. (pg / ml) No. (pg / mi) No. dTCTP 630.0
1 127 145.5 5 124 161.0 9 dTBP2 179.5  1 127 145.5 5 124 161.0 9 dTBP2 179.5
2 128 149.5 5 126 161.0 10 129 181.5 2 128 149.5 5 126 161.0 10 129 181.5
3 130 153.0 7 122 167.5 11 123 197.0 3 130 153.0 7 122 167.5 11 123 197.0
4 121 155.5 8 125 171.0 실험예 2. 경합측정법 (competition assay)을 이용한 생물학적 활성 검사 dTBP2 를 근간으로 하여 제조예 2 내지 6을 통해 펩티도미메틱 화합물을 설계하고 합성하였다. 이들 화합물이 실험예 1에서 인터루킨— 8 분비 억제 활성이 뛰어난 것은 dTCTP 와의 결합에 기인한 것으로 판단하였다. 따라서 상기와 같은 사항을 확인하기 위하여 제조예 2 내지 6을 통해 합성된 모든 펩티도미메틱 화합물에 대하여 경합측정 (competition assay)를 실시하였으며， 하기 표 6에는 ΙΟμΜ 농도에서 실시한 경합측정의 상위 32개의 화합물들을 나타내었다. 또한， 도 9는 제조예 2를 통하여 제조된 화합물의 in situ 경합측정 (compet i t ion assay) 결과를 나타낸 것이다. 상기 도 9에 나타난 결과로부터 이소니코티닉 산 (isonicotinic acid)로 아실화된 화합물 하나를 찾아내었다. 4 121 155.5 8 125 171.0 Experimental Example 2 Biological Activity Test Using Competition Assay Based on dTBP2, peptidomimetic compounds were designed and synthesized through Preparation Examples 2 to 6. It was judged that these compounds were excellent in interleukin-8 secretion inhibitory activity in Experimental Example 1 due to binding to dTCTP. So as above In order to confirm the matter, all the peptidomimetic compounds synthesized through Preparation Examples 2 to 6 were subjected to a competition assay (competition assay), and Table 6 below shows the top 32 compounds of the contention measurement performed at ΙΟμΜ concentration. In addition, Figure 9 shows the results of in situ competition (compet it ion assay) of the compound prepared in Preparation Example 2. From the results shown in FIG. 9, one compound acylated with isisonicotinic acid was found.
[표 6]  TABLE 6
Figure imgf000133_0001
실험예 3. 인터루킨ᅳ8분비 억제 활성에 대한 IC 값측정
Figure imgf000133_0001
Experimental Example 3. Measurement of IC value for interleukin ᅳ 8 secretion inhibitory activity
상기 실험예 1 및 2의 결과를 토대로하여 보다 활성이 강한 화합물이 어느 것인지를 확인하기 위해 , 상위 66개의 화합물들을 선정하여 IC50값을 측정하였다. 이들 중 22개의 화합물들의 IC50 값이 dTBP2 (IC50 = 960 nM) 보다 낮은 것으로 나타났으며, 특히 110 은 가장 낮은 IC50값을 가지는 것을 확인하였다 (표 7). Based on the results of Experimental Examples 1 and 2, in order to identify which compounds are more active, the top 66 compounds were selected to measure IC 50 values. The IC 50 value of 22 of these compounds was found to be lower than dTBP2 (IC 50 = 960 nM), especially 110 was confirmed to have the lowest IC 50 value (Table 7).
[표 7]  TABLE 7
Figure imgf000134_0001
실험예 4. 알레르기 동물 모델에서의 펩티도미메틱 화합물의 생물학적 활성 검사
Figure imgf000134_0001
Experimental Example 4 Biological Activity Test of Peptidomimetic Compounds in Allergic Animal Models
4-1, dTBP2의 생물학적 활성 검사  4-1, Biological Activity Test of dTBP2
난알부민 (ovalbumin, OVA) 으로 알레르기성 질환 상태를 유발한 마우스 모델 (5주령, Female Balb/c (orientbio), 각 군당 5-6마리) 에서의 dTBP2 의 생물학적 활성을 측정하였다. 각 그룹 (6마리 /그룹)의 마우스들을 난알부민으로 민감화 (sensitization) 시키고， 2.5mg/kg 또는 5 mg/kg 의 dTBP2를 처리하고 난알부민으로 유발반웅 (challenge)을 일으켰다. dTBP2를 처리한 경우 증상점수 (symptom score)가 감소하였으며， 농도 의존적으로 호산구 (eosinophi 1 )에 침윤하는 것을 알 수 있었다 (도 10).  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).
4-2. 본 발명의 신규한 펩티도미메틱 화합물의 생물학적 활성 검사 난알부민 (ovalbumin, OVA) 으로 알레르기성 기도 염증을 유발한 마우스 모델 (5주령 , Female Balb/c (orientbio), 각 군당 5— 6마리) 에 상기 실험예 1내지 3의 결과를 토대로， 3개의 화합물 (122， 123 및 129)올 선정하여 처리한 후 생물학적 활성을 검사하였다. 하기 3개의 구조는 동물 실험에 사용한 화합물들의 구조를 나타낸 것이다. 4-2. Biological Activity Test of Novel Peptidomimetic Compounds of the Invention In the mouse model (5 weeks old, Female Balb / c (orientbio), 5-6 animals per group) inducing allergic airway inflammation with ovalbumin (OVA), Compounds (122, 123 and 129) were selected and treated for biological activity. The following three structures show the structures of the compounds used in animal experiments.
Figure imgf000135_0001
Figure imgf000135_0001
Mol. Wt.: 562.5916 Mol. Wt.: 520.598 Mol. Wt.: 466.8949 CLogP: 0.83 CLogP: 1.14 CLogP: 0.72 구체적으로， 마우스들을 난알부민으로 민감화 (sensitization) 시키고， 5mg/kg 의 펩티도미메틱 화합물들을 투여한 후， 난알부민으로 유발반응 (challenge)을 일으켰다. 기관지 폐포세척액 검사 (bronchoalveolar lavage fluid) 에서 인터루킨 -5는 mouse IL-5 EL ISA kit (PIERCE)를 이용하여 확인하였으며， 폐 점막의 비후현상 (hyperplasia)은 Periodic Acid-Schiff (PAS) 시약 (Sigma— Aldrich) 으로 염색하여 확인하였다.  Mol. Wt .: 562.5916 Mol. Wt .: 520.598 Mol. Wt .: 466.8949 CLogP: 0.83 CLogP: 1.14 CLogP: 0.72 Specifically, mice were sensitized with egg albumin and challenged with egg albumin after administration of 5 mg / kg of peptidomimetic compounds. . In bronchoalveolar lavage fluid, 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.
상기 화합물들은 기관지 폐포세척액 검사 (bronchoalveolar lavage fluid) 에서 인터루킨— 5 의 분비를 현저하게 감소시켰고 (도 11)， 폐 조직의 점막의 두께를 현저하게 감소시켰으며 (도 12)， 특히 122번 화합물의 효과가 가장 좋은 것으로 나타났다.  These compounds significantly reduced the secretion of interleukin-5 in the bronchoalveolar lavage fluid (FIG. 11) and significantly reduced the thickness of the mucous membranes of lung tissue (FIG. 12). The effect was found to be the best.
또한， 추가적으로 2개의 화합물 (97 및 121)을 선정하여, 상기 알레르기 마우스 모델을 대상으로하여 동일한 실험방법으로 추가 동물 실험을 하였다.하기 2개의 구조는 추가적으로 사용한 2개 화합물들의 구조를 나타낸 것이다. In addition, two compounds (97 and 121) were additionally selected and further animal experiments were performed in the same experimental method on the allergic mouse model. The following two structures show the structures of two additional compounds.
Figure imgf000136_0001
Figure imgf000136_0001
C' H35N607'S+ C2iH32 0g+ C ' H 35 N 6 0 7'S + C 2 iH32 0g +
Mol. Wt: 575.6566 Mol. Wt: 526.5197 CLogP: 0.40 CLogP: -231 상기 2개의 화합물 역시 기관지 폐포세척액 검사 (bronchoalveolar lavage fluid) 에서 인터루킨 -5의 분비를 효과적으로 억제하는 것을 알 수 있었다 (도 13).또한, 폐 조직의 점막을 Hematoxylin and eosin (H&E) 시약으로 염색하여 변화를 관찰하였으며， 점막 비대 현상이 감소하는 것을 확인할 수 있었다 (도 14) ·  Mol. Wt: 575.6566 Mol. Wt: 526.5197 CLogP: 0.40 CLogP: -231 The two compounds were also found to effectively inhibit the secretion of interleukin-5 in bronchoalveolar lavage fluid (FIG. 13). The change was observed by staining with Hematoxylin and eosin (H & E) reagent, and it was confirmed that mucosal hypertrophy was reduced (FIG. 14).

Claims

【청구의 범위】 【Scope of Claim】
【청구항 1】 【Claim 1】
서열번호 1의 아미노산 서열로 이루어진 펩타이드 또는 이의 단편에서， 상기 서열번호의 첫번째 아미노산인 트립토판 자리에 아실기가 도입되거나， 상기 서열번호의 네번째 아미노산인 타이로신이 아실기 (acyl group)가 연결된 디아미노프로피오닉 산 (Diaminopropionic acid, Dpr)으로 치환되거나，또는 상기 서열번호의 첫번째 아미노산인 트립토판 자리에 아실기가 도입되고 상기 서열번호의 네번째 아미노산인 타이로신이 아실기 (acyl group)가 연결된 디아미노프로피오닉 산 (Diaminopropionic acid, Dpr)으로 치환된， 알레르기성 질환에 대하여 예방 또는 치료 활성을 나타내는 펩티도미메틱 화합물. In a peptide consisting of the amino acid sequence of SEQ ID NO: 1 or a fragment thereof, an acyl group is introduced into the tryptophan position, which is the first amino acid of the SEQ ID NO, or tyrosine, the fourth amino acid of the SEQ ID NO, is a diaminopropionic acid to which an acyl group is connected. Diaminopropionic acid (Diaminopropionic acid) is substituted with an acid (Diaminopropionic acid, Dpr), or an acyl group is introduced into the tryptophan position, which is the first amino acid of the SEQ ID NO, and tyrosine, the fourth amino acid of the SEQ ID NO, is linked to an acyl group. A peptidomimetic compound substituted with acid, Dpr) and showing preventive or therapeutic activity against allergic diseases.
【청구항 2】 【Claim 2】
제 1항에 있어서， In clause 1,
서열번호 1의 아미노산 서열로 이루어진 펩타이드 또는 이의 단편에서， 상기 서열번호의 첫번째 아미노산인 트립토판 자리에 아실기가 도입된 펩티도미메틱 화합물; In the peptide or fragment thereof consisting of the amino acid sequence of SEQ ID NO: 1, a peptidomimetic compound in which an acyl group is introduced into the tryptophan position, which is the first amino acid of SEQ ID NO:
서열번호 1의 아미노산 서열로 이루어진 펩타이드에서， 상기 서열번호의 첫번째 아미노산인 트립토판 자리에 아실기가 도입되고 상기 서열번호의 네번째 아미노산인 타이로신이 아실기 (acyl group)가 연결된 디아미노프로피오닉 산 (Diaminopropionic acid, Dpr)으로 치환된 펩티도미메틱 화합물; In a peptide consisting of the amino acid sequence of SEQ ID NO: 1, an acyl group is introduced into the tryptophan position, which is the first amino acid of the SEQ ID NO, and tyrosine, the fourth amino acid of the SEQ ID NO, is diaminopropionic acid to which an acyl group is connected. , Dpr), a peptidomimetic compound substituted;
서열번호 1의 아미노산 서열로 이루어진 펩타이드의 단편에서， 상기 단편은 네 개의 아미노산으로 이루어지며 C-말단이 메티오닌인 펩타이드 단편이고, 상기 서열번호의 네번째 아미노산에 해당하는 타이로신이 아실기 (acyl group)가 연결된 디아미노프로피오닉 산 (Diaminopropionic acid, Dpr)으로 치환된 펩티도미메틱 화합물; In the peptide fragment consisting of the amino acid sequence of SEQ ID NO: 1, the fragment is a peptide fragment consisting of four amino acids and the C-terminus is methionine, and the tyrosine corresponding to the fourth amino acid of SEQ ID NO is an acyl group. peptidomimetic compounds substituted with linked diaminopropionic acid (Dpr);
서열번호 1의 아미노산 서열로 이루어진 펩타이드의 단편에서， 상기 단편은 상기 서열번호 1의 N-말단부터 네 개의 아미노산으로 이루어지는 단편이고， 상기 서열번호의 첫번째 아미노산인 트립토판 자리에 아실기가 도입되고 상기 서열번호의 네번째 아미노산에 해당하는 타이로신이 아실기 (acyl group)가 연결된 디아미노프로피오닉 산 (Diaminopropionic acid, Dpr)으로 치환된 펩티도미메틱 화합물;. 및 In the fragment of the peptide consisting of the amino acid sequence of SEQ ID NO: 1, the fragment is a fragment consisting of four amino acids from the N-terminus of SEQ ID NO: 1, and an acyl group is introduced into the tryptophan position, which is the first amino acid of SEQ ID NO: The tyrosine corresponding to the fourth amino acid of is connected to an acyl group. Peptidomimetic compounds substituted with diaminopropionic acid (Dpr); and
서열번호 1의 아미노산 서열로 이루어진 펩타이드의 단편에서 상기 단편은 세 개 또는 네 개의 아미노산으로 이루어지며 C-말단이 세린인 펩타이드 단편이고, 상기 서열번호의 네번째 아미노산에 해당하는 타이로신이 아실기 (acyl group)가 연결된 디아미노프로피오닉 산 (Diaminopropionic acid, Dpr)으로 치환된 펩티도미메틱 화합물로 이루어진 군에서 선택되는 1이상의 펩티도미메틱 화합물. In the 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 and the C-terminus is serine, and the tyrosine corresponding to the fourth amino acid of SEQ ID NO is an acyl group. ) One or more peptidomimetic compounds selected from the group consisting of peptidomimetic compounds substituted with diaminopropionic acid (Dpr) linked.
[청구항 3】 [Claim 3]
게 1항에 있어서， 하기 화학식 1의 구조를 포함하는 펩티도미메틱 화합물. [화학식 1] The peptidomimetic compound according to item 1, comprising the structure of Formula 1 below. [Formula 1]
또는or
Figure imgf000138_0001
Figure imgf000138_0001
W는 트립토판 (Tryptophan, W)이고， W is tryptophan (W),
Y는 타이로신 (Tyrosine, Y)이고， Y is tyrosine (Y),
V는 발린 (Valine, V)이며， V is valine (V),
P는 프롤린 (Proline, P)이며， P is proline (P),
S는 세린 (Serine, S)이고, S is Serine (S),
M은 메티오닌 (Methionine, M)이다. M is Methionine (M).
【청구항 4】 【Claim 4】
제 1항에 있어서, 서열번호의 첫번째 아미노산인 트립토판 자리에 이소니코티닐기가 도입된 것인 펩티도미메틱 화합물. The method of claim 1, wherein tryptophan is the first amino acid in SEQ ID NO. A peptidomimetic compound in which an isonicotinyl group is introduced.
【청구항 5】 【Claim 5】
' 게 1항에 있어서, 하기 화학식 2의 구조를 포함하는 펩티도미메틱 화합물. [화학식 21 ' The peptidomimetic compound according to item 1, comprising the structure of Formula 2 below. [Formula 21
Figure imgf000139_0001
Figure imgf000139_0001
D r 은 디아미노프로피오닉 산 (Diaminopropionic acid)이고， D r is diaminopropionic acid,
R2는 탄소수 1 내지 20의 비치환된 또는 치환된 선형， 가지형 또는 고리형 알킬이거나, 탄소수 1내지 10의 비치환된 또는 치환된 알콕시이거나，비치환 또는 치환된 아릴이거나 , N, 0또는 S를 포함하는 비치환 또는 치환된 헤테로아릴이거나, N, 0 또는 S를 포함하는 비치환 또는 치환된 헤테로사이클로이고， R2 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 It is unsubstituted or substituted heteroaryl containing, or unsubstituted or substituted heterocyclo containing N, 0 or S,
W는 트립토판 (Tryptophan, W)이고， W is tryptophan (W),
Y는 타이로신 (Tyrosine, Y)이고， Y is tyrosine (Y),
V는 발린 (Valine, V)이며， V is valine (V),
P는 프를린 (Proline, P)이며， P is Proline (P),
S는 세린 (Serine, S)이고， S is Serine (S),
M은 메티오닌 (Methionine, M)이다. M is Methionine (M).
【청구항 6】 【Claim 6】
제 5항에 있어서， 상기 펩티도미메틱 화합물은 The method of claim 5, wherein the peptidomimetic compound is
이소니코티닐-트립토판 -타이로신-발린— Dpr (3， 5—디메틸벤조일 ) -프를린ᅳ세린 ᅳ메티오닌 산화형 이소니코티닐—트립토판-타이로신 -발린 -Dpr(3, 5-디메틸벤조일) -프를린—세린 -메티 오닌 비산화형, 이소니코티닐-트립토판 -타이로신-발린ᅳ Dpr (알파-시아노 -4-하이드록시신나밀 ) -프 롤린-세린-메티오닌 산화형 , 이소니코티닐ᅳ트립토판—타이로신-발린ᅳ Dpr (알파-시아노 -4-하이드록시신나밀 ) -프 를린—세린-메티오닌 비산화형, 이소니코티닐ᅳ트립토판-타이로신 -발린 -Dpr (4-펜틸바이사이클로 [2.2.2]옥테인 -1- 카복실일 ) -프롤린ᅳ세린-메티오닌 산화형， 이소니코티닐-트립토판 -타이로신 -발린 -Dpr (4—펜틸바이사이클로 [2.2.2]옥테인 -1- 카복실일) -프를린ᅳ세린-메티오닌 비산화형， 이소니코티닐-트립토판 -타이로신—발린ᅳ Dpr (2-(2-시아노페닐티오)벤조일) -프를린- 세린-메티오닌 산화형， 이소니코티닐-트립토판 -타이로신-발린ᅳ Dpr (2-(2-시아노페닐티오)벤조일) -프를린- 세린—메티오닌 비산화형, 이소니코티닐-트립토판 -타이로신-발린ᅳ Dpr (페녹시아세틸) -프를린-세린-메티오닌 산화형， Isonicotinyl-tryptophan -tyrosine-valine— Dpr (3, 5—dimethylbenzoyl) -proline - serine - methionine oxidized form isonicotinyl—tryptophan-tyrosine -valine -Dpr (3, 5-dimethylbenzoyl) -pr Rlin—serine -methionine non-oxidized form, isonicotinyl-tryptophan -tyrosine-valine ᅳ Dpr (alpha-cyano-4-hydroxycinnamyl) -proline-serine-methionine oxidized form, Isonicotinyl-tryptophan—tyrosine-valine-Dpr (alpha-cyano-4-hydroxycinnamyl) -proline—serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (4-pentylbi) Cyclo [2.2.2] Octane -1- Carboxyl) -Proline - Serine - Methionine oxidized form, Isonicotinyl - Tryptophan - Tyrosine - Valine -Dpr (4—Pentylbicyclo [2.2.2] Octane -1- Carboxylyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan -tyrosine-valine-methionine Dpr (2-(2-cyanophenylthio)benzoyl) -proline-serine-methionine oxidized form, iso Nicotinyl-tryptophan -tyrosine-valine - Dpr (2-(2-cyanophenylthio)benzoyl) -proline- serine - methionine non-oxidized form, isonicotinyl-tryptophan -tyrosine-valine - Dpr (phenoxyacetyl) -Proline-serine-methionine oxidized form,
이소니코티닐-트립토판 -타이로신-발린ᅳ Dpr (페녹시아세틸) -프를린-세린-메티오닌 비산화형.， Isonicotinyl-tryptophan -tyrosine-valine ᅳ Dpr (phenoxyacetyl) -proline-serine-methionine non-oxidized form.，
이소니코티닐―트립토판 -타이로신 -발린 -Dpr (2-핵시노일 ) -프를린-세린-메티오닌 산화형 , Isonicotinyl - Tryptophan - Tyrosine - Valine - Dpr (2-hexinoyl) - Proline - Serine - Methionine oxidized form,
이소니코티닐-트립토판-타이로신 -발린 -Dpr (2-핵시노일) -프롤린ᅳ세린-메티오닌 비산화형， Isonicotinyl-tryptophan-tyrosine -valine -Dpr (2-hexinoyl) -proline ᅳserine-methionine non-oxidized form,
이소니코티닐—트립토판 -타이로신-발린ᅳ Dpr (오로틸) -프를린-세린-메티오닌 산화형, 이소니코티닐-트립토판-타이로신 -발린 -Dpr (오로틸) -프를린-세린-메티오닌 Isonicotinyl—Tryptophan -Tyrosine-Valine - Dpr (Olotyl) -Proline-Serine-Methionine Oxidized form, Isonicotinyl-Tryptophan-Tyrosine -Valine -Dpr (Olotyl) -Proline-Serine-Methionine
비산화형 Non-oxidizing type
이소니코티닐—트립토판—타이로신 -발린 -Dpr (4-벤질옥시벤조일) -프롤린 -세린 -메티 오닌 산화형， 이소니코티닐—트립토판—타이로신 -발린 -Dpr (4-벤질옥시벤조일) -프를린 -세린 -메티 오닌 비산화형， 이소니코티닐 -트립토판—타이로신—발린 -Dpr (2-나프토일) -프를린-세린-메티오닌 산화형， Isonicotinyl—tryptophan—tyrosine -valine -Dpr (4-benzyloxybenzoyl) -proline -serine -methionine oxidized form, isonicotinyl—tryptophan—tyrosine -valine -Dpr (4-benzyloxybenzoyl) -proline -Serine -methionine non-oxidized form, isonicotinyl -tryptophan—tyrosine—valine -Dpr (2-naphthoyl) -proline-serine-methionine oxidized form,
이소니코티닐-트립토판-타이로신 -발린 -Dpr (2-나프토일) -프를린-세린-메티오닌 비산화형， 이소니코티닐-트립토판—타이로신 -발린 -Dpr (2-피라진카복실일 ) -프롤린-세린-메티 오닌 산화형， 이소니코티닐 -트립토판—타이로신 -발린 -Dpr (2-피라진카복실일) -프를린 -세린 -메티 오닌 비산화형， 이소니코티닐-트립토판-타이로신 -발린 -Dpr (2-클로로니코티닐) -프를린—세린 -메티 오닌 산화형 , 이소니코티닐-트립토판-타이로신 -발린 -Dpr (2-클로로니코티닐) -프를린 -세린 -메티 오닌 비산화형， 이소니코티닐—트립토판—타이로신-발린— Dpr (2 , 4-핵사디엔오일 ) -프를린-세린-메티 오닌 산화형， 이소니코티닐—트립토판—타이로신 -발린 -Dpr (2 , 4—핵사디엔오일) -프롤린 -세린 -메티 오닌 비산화형, 이소니코티닐-트립토판 -타이로신 -발린 -Dpr (바이페닐 -4—카복실일 )—프롤린-세린-메 티오닌 산화형， 이소니코티닐-트립토판 -타이로신 -발린 -Dpr (바이페닐 -4—카복실일 ) -프롤린-세린-메 티오닌 비산화형, 이소니코티닐-트립토판 -타이로신 -발린 -Dpr (페닐글리옥실일 ) -프를린ᅳ세린-메티오 닌 산화형 , 이소니코티닐-트립토판 -타이로신-발린— Dpr (페닐글리옥실일) -프를린ᅳ세린-메티오 닌 비산화형, 이소니코티닐-트립토판 -타이로신 -발린 -Dpr (2-플루오로페닐아세틸 )—프를린-세린- 메티오닌 산화형， 이소니코티닐-트립토판 -타이로신-발린— Dpr (2-폴루오로페닐아세틸) -프를린―세린- 메티오닌 비산화형， 이소니코티닐-트립토판-타이로신 -발린 -Dpr (트랜스-신나밀) -프를린-세린-메티오닌 산화형， Isonicotinyl-tryptophan-tyrosine -valine -Dpr (2-naphthoyl) -proline-serine-methionine non-oxidized form, Isonicotinyl-tryptophan—tyrosine -valine - Dpr (2-pyrazinecarboxyl) -proline-serine-methionine oxidized form, isonicotinyl -tryptophan—tyrosine -valine -Dpr (2-pyrazinecarboxyl) -proline -Serine -methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine -valine -Dpr (2-chloronicotinyl) -Proline—Serine -methionine oxidized form, isonicotinyl-tryptophan-tyrosine -valine -Dpr ( 2-chloronicotinyl) -proline -serine -methionine non-oxidized form, isonicotinyl—tryptophan—tyrosine-valine—Dpr (2, 4-hexadienoyl) -proline-serine-methionine oxidized form, Isonicotinyl—Tryptophan—Tyrosine -Valine -Dpr (2, 4—Hexadienoyl) -Proline -Serine -Methionine non-oxidized form, Isonicotinyl-Tryptophan -Tyrosine -Valine -Dpr (Biphenyl -4—Carboxylyl) —Proline-serine-methionine oxidized form, isonicotinyl-tryptophan -tyrosine -valine -Dpr (biphenyl-4—carboxylyl) -Proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan -tyrosine - Valine -Dpr (phenylglyoxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan -tyrosine-valine— Dpr (phenylglyoxylyl)-proline-serine-methionine arsenic acid Oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-fluorophenylacetyl)—proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine—Dpr (2-fluorophenyl) Acetyl) -Proline-Serine-Methionine non-oxidized form, Isonicotinyl-Tryptophan-Tyrosine -Valine -Dpr (trans-cinnamyl) -Proline-serine-methionine oxidized form,
이소니코티닐-트립토판-타이로신 -발린 -Dpr (트랜스-신나밀) -프롤린-세린-메티오닌 비산화형 , Isonicotinyl-tryptophan-tyrosine -valine -Dpr (trans-cinnamyl) -proline-serine-methionine non-oxidized form,
이소니코티닐 -트립토판—타이로신 -발린 -Dpr ( 1—나프토일) -프를린-세린-메티오닌 산화형， Isonicotinyl -Tryptophan—Tyrosine -Valine -Dpr ( 1—Naphthoyl) -Proline-Serine-Methionine Oxidized type,
이소니코티닐-트립토판-타이로신 -발린 -Dpr ( l-나프토일) -프를린ᅳ세린-메티오닌 비산화형， Isonicotinyl-Tryptophan-Tyrosine -Valine -Dpr (l-naphthoyl) -Proline - Serine - Methionine non-oxidized form,
이소니코티닐—트립토판 -타이로신-발린— Dpr (5-니트로 -2-푸로일 ) -프를린-세린-메티 오닌 산화형， 이소니코티닐-트립토판 -타이로신-발린— Dpr (5-니트로 -2-푸로일) -프를린 -세린 -메티 오닌 비산화형， 이소니코티닐 -트립토판—타이로신—발린 -Dpr (베타 -나프록시아세틸) -프를린-세린-메 ' 티오닌 산화형， 이소니코티닐-트립토판 -타이로신—발린 -Dpr (베타ᅭ나프록시아세틸) -프롤린―세린-메 티오닌 비산화형， 이소니코티닐-트립토판-타이로신 -발린 -Dpr (3-페녹시벤조일) -프를린-세린—메티오 닌 산화형 , 이소니코티닐-트립토판 -타이로신 -발린 -Dpr (3-페녹시벤조일 )ᅳ프롤린ᅳ세린-메티오 닌 비산화형， 이소니코티닐-트립토관-타이로신 -발린 -Dpr (7-메톡시 -1-벤조퓨란 -2-카복실일) -프 롤린-세린ᅳ메티오닌 산화형， 이소니코티닐-트립토판-타이로신 -발린 -Dpr (7-메특시 -1-벤조퓨란 -2-카복실일) -프 를린ᅳ세린-메티오닌 비산화형ᅳ 이소니코티닐-트립토판 -타이로신-발린ᅳ Dpr (2-메특시핵사노일)—프를린 -세린 -메티 오닌 산화형 , 이소니코티닐-트립토판-타이로신 -발린 -Dpr (2-메특시핵사노일) -프롤린-세린—메티 오닌 비산화형， 이소니코티닐-트립토판 -타이로신—발린 -Dpr (3-클로로벤조 [b]티오펜 -2-카복실일) - 프를린-세린-메티오닌 산화형， 이소니코티닐-트립토판 -타이로신-발린— Dpr (3-클로로벤조 [b]티오펜 -2-카복실일) - 프롤린-세린-메티오닌 비산화형, 이소니코티닐-트립토판-타이로신 -발린 -Dpr (퀴나딜) -프를린—세린—메티오닌 산화형， 이소니코티닐—트립토판 -타이로신—발린 -Dpr (퀴나딜) -프롤린-세린-메티오닌 비산화형， Isonicotinyl—tryptophan -tyrosine-valine— Dpr (5-nitro -2-furoyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan -tyrosine-valine— Dpr (5-nitro -2 -Furoyl) -Proline -Serine -Methionine non-oxidized form, Isonicotinyl -Tryptophan—Tyrosine—Valine -Dpr (beta-naproxyacetyl) -Proline-serine- methionine oxidized form, Isonico Thinyl-tryptophan -tyrosine—valine -Dpr (beta ᅭ naproxyacetyl) -proline—serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine -valine -Dpr (3-phenoxybenzoyl) -proline- Serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (3-phenoxybenzoyl)-Proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr ( 7-methoxy -1-benzofuran -2-carboxyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine -valine -Dpr (7-methoxy -1-benzofuran -2-carboxyl 1) -Proline - serine-methionine non-oxidized form - isonicotinyl-tryptophan -tyrosine-valine - Dpr (2-methoxyhexanoyl)—proline -serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine -Valine -Dpr (2-methoxyhexanoyl) -Proline-serine—methionine non-oxidized form, isonicotinyl-tryptophan -Tyrosine—Valine -Dpr (3-chlorobenzo [b]thiophene -2-carboxylyl) - Proline-serine-methionine oxidized form, isonicotinyl-tryptophan -tyrosine-valine— Dpr (3-chlorobenzo [b]thiophene -2-carboxylyl) - Proline-serine-methionine non-oxidized form, isonicotinyl- Tryptophan-tyrosine -valine -Dpr (quinadyl) -proline—serine—methionine oxidized form, isonicotinyl—tryptophan -tyrosine—valine -Dpr (quinadyl) -proline-serine-methionine Non-oxidizing type,
이소니코티닐-트립토판-타이로신 -발린 -Dpr (타이글라일) -프를린―세린ᅳ메티오닌 산화형, Isonicotinyl-tryptophan-tyrosine -valine -Dpr (tyglyl) -proline -serine-methionine oxidized form,
이소니코티닐 -트립토판—타이로신—발린 -Dpr (타이글라일) -프롤린-세린-메티오닌 비산화형， Isonicotinyl - Tryptophan - Tyrosine - Valine - Dpr (tyglyl) - Proline - Serine - Methionine non-oxidized form,
이소니코티닐—트립토판-타이로신 -발린 -Dpr (이소니코티닐) -프를린-세린-메티오닌 산화형 , Isonicotinyl—tryptophan-tyrosine -valine -Dpr (isonicotinyl) -proline-serine-methionine oxidized form,
이소니코티닐 -트립토판—타이로신—발린 -Dpr (이소니코티닐) -프를린-세린-메티오닌 비산화형， Isonicotinyl - Tryptophan - Tyrosine - Valine - Dpr (Isonicotinyl) - Proline - Serine - Methionine non-oxidized form,
이소니코티닐―트립토판 -타이로신 -발린 -Dpr (5-클로로인돌 -2-카복실일)—프를린-세 린-메티오닌 산화형， 이소니코티닐-트립토판 -타이로신 -발린 -Dpr (5-클로로인돌 -2-카복실일 ) -프를린-세 린-메티오닌 비산화형， 이소니코티닐-트립토판 -타이로신 -발린 -Dpr (5-페닐 -2-푸로일；卜프를린—세린-메티오 닌 산화형， 이소니코티닐—트립토판—타이로신 -발린 -Dpr (5-페닐 -2-푸로일) -프를린-세린-메티오 닌 비산화형， 이소니코티닐-트립토판 -타이로신 -발린 -Dpr (5—니트로 -3-피라졸카복실일 ) -프를린- 세린-메티오닌 산화형， 이소니코티닐―트립토판 -타이로신 -발린 -Dpr (5-니트로 -3-피라졸카복실일 ) -프롤린- 세린-메티오닌 비산화형， 이소니코티닐—트립토판-타이로신 -발린 -Dpr ( (R)-(+)-트를록실) -프를린 -세린 -메티 오닌 산화형 , 이소니코티닐―트립토판 -타이로신 -발린 -Dpr ( (R)_(+)-트를록실 ) -프를린-세린-메티 오닌 비산화형， 이소니코티닐-트립토판 -타이로신—발린 -Dpr ( (R)-(+)-2-피롤리돈 -5-카복실일) -프롤 린-세린-메티오닌 산화형， 이소니코티닐-트립토판ᅳ타이로신-발린— Dpr ( (R)— (+)-2—피를리돈 -5-카복실일)ᅳ프를 린-세린-메티오닌 비산화형， 이소니코티닐-트립토판-타이로신 발린 -Dpr ( 1—시아노 -1-사이클로프로페인카복실일 )-프롤린—세린-메티오닌 산화형， 이소니코티닐-트립토판—타이로신 -발린—Dpr ( 1-시아노-：[ -사이클로프로페인카복실일 ) -프를린-세린-메티오닌 비산화형， 이소니코티닐-트립토판—타이로신 -발린 -Dpr (로다닌ᅳ 3-아세틸 ) -프롤린-세린-메티오 닌 산화형， 이소니코티닐-트립토판 -타이로신-발린ᅳ Dpr (로다닌 -3-아세틸 ) -프를린-세린-메티오 닌 비산화형, 이소니코티닐-트립토판 -타이로신 -발린 -Dpr (7-하이드록시쿠마린 -4—아세틸) -프롤린 ᅳ세린-메티오닌 산화형 , 이소니코티닐-트립토판 -타이로신 -발린 -Dpr (그하이드록시쿠마린 -4-아세틸) -프를린 ᅳ세린-메티오닌 비산화형， 이소니코티닐―트립토판—타이로신ᅳ발린 -Dpr (2-(4-메틸페닐설폰아미도)아세틸 ) -프 롤린-세린-메티오닌 산화형, 이소니코티닐-트립토판 -타이로신—발린 -Dpr (2-(4-메틸페닐설폰아미도)아세틸) -프 롤린-세린-메티오닌 비산화형， 이소니코티닐-트립토판 -타이로신 -발린 -Dpr ( 1-아세틸피페리딘 -4-카복실일 )-프를린 -세린—메티오닌 산화형, 이소니코티닐-트립토판 -타이로신—발린 -Dpr ( l-아세틸피페리딘 -4-카복실일) -프를린 ᅳ세린—메티오닌 비산화형， 이소니코티닐—트립토판-타이로신 -발린 -Dpr ( l-페닐 -5- (트리플루오로메틸) -1Hᅳ피라 졸 -4-카복실일) -프롤린―세린-메티오닌 산화형， 이소니코티닐-트립토판-타이로신 -발린 -Dpr ( 1—페닐 -5- (트리플루오로메틸 )—1Ηᅳ피라 졸 -4-카복실일) -프를린-세린-메티오닌 비산화형ᅳ 이소니코티닐-트립토판-타이로신 -발린 -Dpr (2-티오펜아세틸) -프롤린ᅳ세린-메티오 닌 . 산화형， 이소니코티닐-트립토판 -타이로신 -발린 -Dpr (2-티오펜아세틸 ) -프를린-세린-메티오 닌 비산화형， 이소니코티닐-트립토판-타이로신 -발린 -Dpr (벤조트리아졸 -5-카복실일) -프를린-세 린-메티오닌 산화형， 이소니코티닐―트립토판 -타이로신—발린 -Dpr (벤조트리아졸 -5-카복실일 ) -프를린-세 린ᅳ메티오닌 . 비산화형， 이소니코티닐―트립토판 -타이로신ᅳ발린 -Dpr (4-옥소— 4H-크로멘 -3-카복실일 )-프를린 ᅳ세린-메티오닌 산화형， 이소니코티닐-트립토판—타이로신 -발린 -Dpr (4-옥소— 4H-크로멘 -3-카복실일 )-프를린 ᅳ세린-메티오닌 비산화형， 이소니코티닐-트립토판 -타이로신 -발린 _Dpr (4_메틸 _2_옥소— 2H_크로멘 _7_일옥시 )아 세틸)—프를린―세린-메티오닌 산화형 및 이소니코티닐-트립토판 -타이로신—발린 -Dpr (4-메틸 -2-옥소 -2H-크로멘 -7-일옥시 )아 세틸) -프를린―세린-메티오닌 비산화형인 것인， 화합물. Isonicotinyl-tryptophan-tyrosine-valine-Dpr (5-chloroindole-2-carboxylyl)—proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (5-chloroindole -2-carboxyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan -tyrosine -valine -Dpr (5-phenyl -2-furoyl；卜proline—serine-methionine oxidized Type, Isonicotinyl—Tryptophan—Tyrosine -Valine -Dpr (5-phenyl-2-furoyl) -Proline-Serine-Methionine Non-oxidized type, Isonicotinyl-Tryptophan -Tyrosine -Valine -Dpr (5— Nitro-3-pyrazolecarboxylyl) -Proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine -Dpr (5-nitro-3-pyrazolecarboxylyl)-proline-serine-methionine arsenic acid Oxidized form, Isonicotinyl—Tryptophan-Tyrosine-Valine-Dpr ((R)-(+)-Trroxyl)-Proline-Serine-Methionine Oxidized form, Isonicotinyl—Tryptophan-Tyrosine-Valine-Dpr ( (R)_(+)-Trroxyl) -Proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan -Tyrosine—Valine -Dpr ( (R)-(+)-2-pyrrolidone - 5-carboxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine— Dpr ( (R)— (+)-2—pyrlidone -5-carboxylyl)-pryl- Serine-methionine non-oxidized form, Isonicotinyl-tryptophan-tyrosine valine -Dpr ( 1—cyano -1-cyclopropanecarboxylyl ) -proline—serine-methionine oxidized form, isonicotinyl-tryptophan—tyrosine -valine—Dpr ( 1-cyano- ：[ -cyclopropanecarboxyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan—tyrosine -valine -Dpr (rhodanine 3-acetyl) -proline-serine-methionine oxidized form, Isonicotinyl-tryptophan -tyrosine-valine - Dpr (rhodanine -3-acetyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan -tyrosine -valine -Dpr (7-hydroxycoumarin - 4—acetyl) -proline - serine-methionine oxidized form, isonicotinyl-tryptophan -tyrosine - valine -Dpr (hydroxycoumarin -4-acetyl) -proline - serine-methionine non-oxidized form, isonicotinyl-tryptophan —Tyrosine-Valine -Dpr (2-(4-methylphenylsulfonamido)acetyl) -Proline-serine-methionine oxidized form, isonicotinyl-tryptophan -Tyrosine—Valine -Dpr (2-(4-methylphenylsulfonamido) ) Acetyl) -Proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan -tyrosine -valine -Dpr (1-acetylpiperidine -4-carboxylyl)-proline -serine—methionine oxidized form, isonicotinyl Thinyl-Tryptophan -Tyrosine—Valine -Dpr ( l-Acetylpiperidine -4-carboxylyl) -Proline -Serine—Methionine non-oxidized form, Isonicotinyl—Tryptophan-Tyrosine -Valine -Dpr ( l-phenyl -5 - (trifluoromethyl) -1H-pyrazole -4-carboxylyl) -proline - serine - methionine oxidized form, isonicotinyl - tryptophan - tyrosine - valine -Dpr ( 1—phenyl -5- (trifluoromethyl )—1Ηᅳpyrazole -4-carboxylyl) -proline-serine-methionine non-oxidized formᅳ isonicotinyl-tryptophan-tyrosine -valine -Dpr (2-thiophenacetyl) -proline-serine-methionine . Oxidized form, isonicotinyl-tryptophan -tyrosine -valine -Dpr (2-thiophenacetyl) -proline-serine-methionine Non-oxidized form, isonicotinyl-tryptophan-tyrosine -valine -Dpr (benzotriazole - 5-carboxylyl)-prline-se Lin-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (benzotriazole-5-carboxylyl)-prline-serine-methionine. Non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine -Dpr (4-oxo— 4H-chromen-3-carboxylyl)-prline -serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine - Dpr (4-oxo— 4H-chromen -3-carboxylyl) -proline -serine-methionine non-oxidized form, isonicotinyl-tryptophan -tyrosine -valine _ Dpr ( 4 _methyl _ 2 _oxo— 2H _chloro Men_7_yloxy )Acetyl)—Proline—Serine-Methionine Oxidized and Isonicotinyl-Tryptophan-Tyrosine—Valine-Dpr (4-methyl-2-oxo-2H-chromen-7-yloxy ) Acetyl) -Proline - Serine - Methionine, a non-oxidized compound.
【청구항 7] [Claim 7]
거 U항에 있어서， 하기 화학식 3의 구조를 포함하는， 펩티도미메틱 화합물. According to item U, a peptidomimetic compound comprising the structure of the following formula (3).
[화학식 3] SM
Figure imgf000145_0001
[Formula 3] SM
Figure imgf000145_0001
Dpr 은 디아미노프로피오닉 산 (Di aminopropi oni c acid)이고， Dpr is diaminopropionic acid,
R3는 탄소수 1 내지 20의 비치환된 또는 치환된 선형， 가지형 또는 고리형 알킬이거나,탄소수 1내지 10의 비치환된 또는 치환된 알콕시이거나,비치환 또는 치환된 아¾이거나， N , 0또는 S를 포함하는 비치환 또는 치환된 헤테로아릴이거나 N , 0 또는 S를 포함하는 비치환 또는 치환된 해테로사이클로이고, R3 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 a¾, N, 0, or It is unsubstituted or substituted heteroaryl containing S or unsubstituted or substituted heterocyclo containing N, 0 or S,
P는 프롤린 (Prol ine , P)이며， P is proline (P),
S는 세린 (Ser ine , S)이고, S is serine (Serine, S),
M은 메티오닌 (Methionine , M)이다. M is methionine (M).
【청구항 8】 제 7항에 있어서， 상기 화학식 3의 펩티도미메틱 화합물은， 【Claim 8】 The method of claim 7, wherein the peptidomimetic compound of Formula 3 is:
Dpr (4-펜틸바이사이클로 [2.2.2]옥탄 -1-카복실일) -프를린-세린-메티오닌 형， Dpr (4-펜틸바이사이클로 [2.2.2]옥탄 -1—카복실일) -프를린-세린-메티오닌 비산화형, Dpr (타이글라일) -프를린-세린-메티오닌 산화형 Dpr (타이글라일) -프를린-세린-메티오닌 비산화형 Dpr (4-pentylbicyclo [2.2.2] octane -1-carboxylyl) -proline-serine-methionine type, Dpr (4-pentylbicyclo [2.2.2] octane -1—carboxylyl) -pr Proline-serine-methionine non-oxidized form, Dpr (tiglyl) -proline-serine-methionine oxidized form Dpr (tiglyl) -proline-serine-methionine non-oxidized form
Dpr (5—클로로인돌 -2-카복실일 ) -프를린-세린-메티오닌 산화형Dpr (5—chloroindole -2-carboxylyl) -proline-serine-methionine oxidized form
Dpr (5-클로로인돌ᅳ 2-카복실일) -프를린-세린-메티오닌 비산화형Dpr (5-chloroindole-2-carboxylyl) -proline-serine-methionine non-oxidized form
Dpr (2ᅳ (2-시아노페닐티오)벤조일 ) -프를린-세린-메티오닌 산화형Dpr (2ᅳ (2-cyanophenylthio)benzoyl) -proline-serine-methionine oxidized form
Dpr (2-(2-시아노페닐티오)벤조일) -프를린-세린-메티오닌 비산화형 Dpr (퀴나딜) -프를린-세린-메티오닌 산화형， Dpr (퀴나딜) -프롤린ᅳ세린-메티오닌 비산화형， Dpr (2-플루오로페닐아세틸) -프롤린 -세린 -메티오닌,Dpr (2-(2-cyanophenylthio)benzoyl) -proline-serine-methionine non-oxidized form Dpr (quinadyl) -proline-serine-methionine oxidized form, Dpr (quinadyl) -proline ᅳserine- Methionine non-oxidized form, Dpr (2-fluorophenylacetyl) -proline -serine -methionine,
Dpr (7—메록시 -1ᅳ벤조퓨란ᅳ 2—카복실일) -프롤린 -세린 -메티오닌, Dpr (7—meroxy -1ᅳbenzofuranᅳ 2—carboxylyl) -proline -serine -methionine,
Dpr (오로틸) -프를린 -세린ᅳ메티오닌， Dpr (orotyl) -proline -serine ᅳmethionine,
Dpr ( 1-시아노 -1—사이클로프로판카복실일 ) -프를린-세린 -메티오닌， Dpr (1-cyano -1—cyclopropanecarboxylyl) -proline-serine -methionine,
Dpr (알파-시아노 -4-하이드특시신나밀 )—프롤린-세린-메티오닌， Dpr (alpha-cyano-4-hydroxycinnamyl)—proline-serine-methionine,
Dpr (3ᅳ 5-디메틸벤조일 ) -프를린 -세린 -메티오닌 , Dpr (3ᅳ 5-dimethylbenzoyl) -Proline -Serine -Methionine,
Dpr ( (R)-(+)_트를록실) -프를린 -세린 -메티오닌， Dpr ((R)-(+)_Trloxyl) -Proline -Serine -Methionine,
Dpr (2-(4-메틸페닐설폰아미도)아세틸) -프를린-세린-메티오닌 및 Dpr (5-니트로 -3—피라졸카복실일 ) -프를린-세린-메티오닌인， 화합물 . Dpr (2-(4-methylphenylsulfonamido) acetyl) -proline-serine-methionine and Dpr (5-nitro -3—pyrazolecarboxylyl) -proline-serine-methionine, compounds.
【청구항 9】 【Claim 9】
저 항에 있어서, 하기 화학식 4의 구조를 포함하는， 펩티도미메틱 화합물. [화학식 4] In resistance, a peptidomimetic compound comprising the structure of Formula 4 below. [Formula 4]
Figure imgf000146_0001
Figure imgf000146_0001
Dpr 은 디아미노프로피오닉 산 (Di aminopropioni c ac i d)이고， Dpr is diaminopropionic acid (Di aminopropioni c a i d),
R4는 탄소수 1 내지 20의 비치환된 또는 치환된 선형， 가지형 또는 고리형 알킬이거나，탄소수 1내지 10의 비치환된 또는 치환된 알콕시이거나，비치환 또는 치환된 아릴이거나， N, 0또는 S를 포함하는 비치환 또는 치환된 헤테로아릴이거나， N, 0 또는 S를 포함하는 비치환 또는 치환된 헤테로사이클로이고, R4 is unsubstituted or substituted linear, branched or cyclic having 1 to 20 carbon atoms. It is alkyl, unsubstituted or substituted alkoxy of 1 to 10 carbon atoms, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl containing N, 0 or S, or containing N, 0 or S It is unsubstituted or substituted heterocyclo,
W는 트립토판 (Tryptophan, W)이고， W is tryptophan (W),
Y는 타이로신 (Tyrosine, Y)이고， Y is tyrosine (Y),
V는 발린 (Valine, V)이다. V is valine (V).
【청구항 10] [Claim 10]
제 9항에 있어서， 상기 화학식 4의 펩티도미메틱 화합물은 The method of claim 9, wherein the peptidomimetic compound of Formula 4 is
이소니코티닐-트립토판-타이로신 -발린 -Dpr (오로틸)， Isonicotinyl-tryptophan-tyrosine-valine-Dpr (orotyl),
이소니코티닐 -트립토판—타이로신 -발린 -Dpr(3, 5ᅳ디메틸벤조일)， Isonicotinyl -Tryptophan—Tyrosine -Valine -Dpr (3, 5 ᅳdimethylbenzoyl),
이소니코티닐-트립토판-타이로신 -발린 -Dpr(7-메특시ᅭ1-벤조퓨란 -2-카복실일)， 이소니코티닐ᅳ트립토판-타아로신 -발린 -Dpr (2-(2-시아노페닐티오)벤조일)， 이소니코티닐-트립토판 -타이로신—발린 -Dpr((R)-(+)-트롤록실)， Isonicotinyl-tryptophan-tyrosine -valine -Dpr (7-methoxy ᅭ 1-benzofuran -2-carboxylyl), isonicotinyl ᅳtryptophan-tyrosine -valine -Dpr (2-(2-cyanophenyl) Thio) benzoyl), isonicotinyl-tryptophan -tyrosine—valine -Dpr ((R)-(+)-troloxyl),
이소니코티닐-트립토판-타이로신 -발린 -Dpr (1—시아노 -1-사이클로프로판카복실일), 이소니코티닐-트립토판-타이로신 -발린 -Dpr (로다닌 -3-아세틸)， Isonicotinyl-tryptophan-tyrosine-valine-Dpr (1—cyano-1-cyclopropanecarboxylyl), isonicotinyl-tryptophan-tyrosine-valine-Dpr (rhodanine-3-acetyl),
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (2-플루오로페닐아세틸 ) , Isonicotinyl-tryptophan -tyrosine -valine -Dpr (2-fluorophenylacetyl),
이소니코티닐-트립토판-타이로신 -발린 -Dpr (4-펜틸바이사이클로 [2.2.2]옥탄 -1-카 복실일)， 이소니코티닐-트립토판-타이로신 -발린 -Dpr (퀴나딜), 이소니코티닐-트립토판 -타이로신—발린 -Dpr (타이글라일), Isonicotinyl-tryptophan-tyrosine-valine-Dpr (4-pentylbicyclo [2.2.2]octane-1-carboxylyl), isonicotinyl-tryptophan-tyrosine-valine-Dpr (quinadyl), isonicotinyl -Tryptophan -Tyrosine—Valine -Dpr (tyglyle),
이소니코티닐-트립토판 -타이로신 -발린 -Dpr (5-클로로인돌 -2-카복실일 )， Isonicotinyl-tryptophan -tyrosine -valine -Dpr (5-chloroindole -2-carboxylyl),
이소니코티닐-트립토판-타이로신 -발린 -Dpr (5—니트로 -3—피라졸카복실일) 및 이소니코티닐-트립토판 -타이로신—발린 -Dpr (2-(4-메틸페닐설폰아미도)아세틸)인， 화합물. Isonicotinyl-tryptophan-tyrosine-valine-Dpr (5—nitro-3—pyrazolecarboxylyl) and isonicotinyl-tryptophan-tyrosine—valine-Dpr (2-(4-methylphenylsulfonamido)acetyl), compound.
【청구항 11】 【Claim 11】
게 1항에 있어서， 하기 화학식 5의 구조를 포함하는， 펩티도미메틱 화합물. [화학식 5]
Figure imgf000148_0001
상기에서， The peptidomimetic compound according to claim 1, comprising the structure of Chemical Formula 5 below. [Formula 5]
Figure imgf000148_0001
From above,
Dpr 은 디아미노프로피오닉 산 (Diaminopropionic acid)이고， Dpr is diaminopropionic acid,
R5는 탄소수 1 내지 20의 비치환된 또는 치환된 선형， 가지형 또는 고리형 알킬이거나， 탄소수 1내지 10의 비치환된 또는 치환된 알콕시이거나，비치환 또는 치환된 아릴이거나， Ν, Ο또는 S를 포함하는 비치환 또는 치환된 헤테로아릴이거나, Ν, 0 또는 S를 포함하는 비치환 또는 치환된 헤테로사이클로이고， R5 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, Ν, Ο or S It is unsubstituted or substituted heteroaryl containing, or unsubstituted or substituted heterocyclo containing Ν, 0 or S,
Ρ는 프롤린 (Proline, P)이며, Ρ is Proline (P),
S는 세린 (Serine, S)이다. S is Serine (S).
【청구항 12】 【Claim 12】
제 11항에 있어서, 상기 화학식 5의 펩티도미메틱 화합물은， The method of claim 11, wherein the peptidomimetic compound of Formula 5,
Dpr (오로틸)ᅳ프를린-세린， Dpr (orotyl)-prline-serine,
Dpr (7-메를시 -1-벤조퓨란 -2—카복실일 ) -프를린-세린， Dpr (7-Mercy -1-Benzofuran -2—Carboxylyl) -Proline-Serine,
Dpr(3,5-디메틸벤조일)—프를린-세린, 또는 Dp 5-클로로인돌 -2-카복실일) -프를린 -세린 및 Dpr (2-플루오로페닐아세틸 ) -프롤린-세린인， 화합물 . Dpr (3,5-dimethylbenzoyl)—proline-serine, or Dp 5-chloroindole-2-carboxylyl)-proline-serine and Dpr (2-fluorophenylacetyl)-proline-serine, Compound .
【청구항 13】 【Claim 13】
제 1항에 있어서， 하기 화학식 6의 구조를 포함하는， 펩티도미메틱 화합물. [화학식 6] PS The peptidomimetic compound according to claim 1, comprising the structure of Formula 6 below. [Formula 6] P.S.
Figure imgf000149_0001
Figure imgf000149_0001
Dpr 은 디아미노프로피오닉 산 (Diaminopropionic acid)이고， Dpr is diaminopropionic acid,
R6는 탄소수 1 내지 20의 비치환된 또는 치환된 선형 가지형 또는 고리형 알킬이거나，탄소수 1내지 10의 비치환된 또는 치환된 알콕시이거나， 비치환 또는 치환된 아릴이거나, N, 0또는 S를 포함하는 비치환 또는 치환된 헤테로아릴이거나 N, 0 또는 S를 포함하는 비치환 또는 치환된 헤테로사이클로이고， R6 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 N, 0 or S It is an unsubstituted or substituted heteroaryl containing N, 0, or S, and is an unsubstituted or substituted heterocyclo,
V 는 발린 (Valine, V)이고， V is valine (V),
P는. 프롤린 (Proline, P)이며， P is. It is Proline (P),
S는 세린 (Serine, S)이다. S is Serine (S).
【청구항 14】 【Claim 14】
제 13항에 있어서， 상기 화학식 6의 펩티도미메틱 화합물은， The method of claim 13, wherein the peptidomimetic compound of Formula 6 is:
발린 -Dpr (오로틸) -프롤린-세린， Valine -Dpr (orotyl) -proline-serine,
발린 -Dpr (7-메록시 -1-벤조퓨란 -2-카복실일)—프를린-세린， Valine-Dpr (7-meroxy-1-benzofuran-2-carboxylyl)—proline-serine,
발린 -Dpr (3 ,5-디메틸벤조일) -프를린-세린， Valine -Dpr (3,5-dimethylbenzoyl) -Proline-Serine,
발린 -Dpr(5-클로로인돌 -2ᅳ카복실일) -프를린-세린, 또는 발린 -Dpr (2-플루오로페닐아세틸) -프롤린-세린， Dpr (오로틸) -프를린-세린인 화합물. Valine -Dpr (5-chloroindole -2-carboxylyl) -proline-serine, or valine -Dpr (2-fluorophenylacetyl) -proline-serine, Dpr (orotyl) -proline-serine compound.
【청구항 15】 【Claim 15】
제 1항에 있어서， 상기 알레르기성 질환은 천식 비염， 담마진， 아나필락시스， 알레르기성 기관지 확장증， 알레르기성 결막염 두드러기 또는 아토피성 피부염인 것인， 펩티도미메틱 화합물. 【청구항 16】 The peptidomimetic compound according to claim 1, wherein the allergic disease is asthma rhinitis, urticaria, anaphylaxis, allergic bronchiectasis, allergic conjunctivitis, urticaria, or atopic dermatitis. 【Claim 16】
제 1항 내지 제 15항 중 어느 한 항의 화합물을 포함하는， 알레르기성 질환의 예방 또는 치료용 약학 조성물. 【청구항 17】 A pharmaceutical composition for preventing or treating allergic diseases, comprising the compound of any one of claims 1 to 15. 【Claim 17】
제 16항에 있어서 , 상기 알레르기성 .질환은 천식， 비염， 담마진， 아나필락시스， 알레르기성 기관지 확장증， 알레르기성 결막염, 두드러기 또는 아토피성 피부염인 것인 조성물. 17. The allergic reaction according to claim 16 . A composition wherein the disease is asthma, rhinitis, urticaria, anaphylaxis, allergic bronchiectasis, allergic conjunctivitis, urticaria, or atopic dermatitis.
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