WO2020085760A1 - 쇼그렌 증후군 예방 또는 치료용 조성물 - Google Patents
쇼그렌 증후군 예방 또는 치료용 조성물 Download PDFInfo
- Publication number
- WO2020085760A1 WO2020085760A1 PCT/KR2019/013885 KR2019013885W WO2020085760A1 WO 2020085760 A1 WO2020085760 A1 WO 2020085760A1 KR 2019013885 W KR2019013885 W KR 2019013885W WO 2020085760 A1 WO2020085760 A1 WO 2020085760A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acid
- alkyl
- oxo
- propionate
- chlorobenzoylamino
- Prior art date
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- 208000021386 Sjogren Syndrome Diseases 0.000 title claims abstract description 54
- 239000000203 mixture Substances 0.000 title claims abstract description 52
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 125000003118 aryl group Chemical group 0.000 claims description 47
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 35
- 210000003079 salivary gland Anatomy 0.000 claims description 33
- 125000001072 heteroaryl group Chemical group 0.000 claims description 29
- -1 C 2 -C 6 oxoalkyl Chemical group 0.000 claims description 23
- 210000004907 gland Anatomy 0.000 claims description 16
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 15
- 102000004127 Cytokines Human genes 0.000 claims description 15
- 108090000695 Cytokines Proteins 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 15
- 210000003296 saliva Anatomy 0.000 claims description 15
- 210000001519 tissue Anatomy 0.000 claims description 15
- 230000028327 secretion Effects 0.000 claims description 13
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 claims description 12
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 102000019034 Chemokines Human genes 0.000 claims description 12
- 108010012236 Chemokines Proteins 0.000 claims description 12
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 11
- 108020004999 messenger RNA Proteins 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 9
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 230000002757 inflammatory effect Effects 0.000 claims description 9
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims description 9
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 8
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 239000011593 sulfur Substances 0.000 claims description 7
- TXWREKCWZLGVFY-BTJKTKAUSA-N (Z)-but-2-enedioic acid 2-morpholin-4-ylethyl 2-[(4-chlorobenzoyl)amino]-3-(2-oxo-1H-quinolin-4-yl)propanoate Chemical compound OC(=O)\C=C/C(O)=O.c1cc(Cl)ccc1C(=O)NC(Cc1c2ccccc2[nH]c(=O)c1)C(=O)OCCN1CCOCC1 TXWREKCWZLGVFY-BTJKTKAUSA-N 0.000 claims description 6
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 claims description 6
- QCXJEYYXVJIFCE-UHFFFAOYSA-N 4-acetamidobenzoic acid Chemical compound CC(=O)NC1=CC=C(C(O)=O)C=C1 QCXJEYYXVJIFCE-UHFFFAOYSA-N 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 6
- 235000010323 ascorbic acid Nutrition 0.000 claims description 6
- 239000011668 ascorbic acid Substances 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
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- 230000010261 cell growth Effects 0.000 claims description 6
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 6
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 claims description 6
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims description 6
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 claims description 6
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 6
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 150000007522 mineralic acids Chemical class 0.000 claims description 6
- XTEGVFVZDVNBPF-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 claims description 6
- 235000001968 nicotinic acid Nutrition 0.000 claims description 6
- 239000011664 nicotinic acid Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 6
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 6
- 150000007524 organic acids Chemical class 0.000 claims description 6
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 6
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
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- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
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- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
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- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
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- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
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- 238000002360 preparation method Methods 0.000 claims description 4
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- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims description 3
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims description 3
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- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 3
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 3
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- LDMOEFOXLIZJOW-UHFFFAOYSA-N 1-dodecanesulfonic acid Chemical compound CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 claims description 3
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- DQIOXUGJBHYAMG-UHFFFAOYSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid 2-morpholin-4-ylethyl 2-[(4-chlorobenzoyl)amino]-3-(2-oxo-1H-quinolin-4-yl)propanoate Chemical compound OC(=O)CC(O)(CC(O)=O)C(O)=O.Clc1ccc(cc1)C(=O)NC(Cc1cc(=O)[nH]c2ccccc12)C(=O)OCCN1CCOCC1 DQIOXUGJBHYAMG-UHFFFAOYSA-N 0.000 claims description 3
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- 125000004658 aryl carbonyl amino group Chemical group 0.000 claims description 3
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4704—2-Quinolinones, e.g. carbostyril
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/04—Artificial tears; Irrigation solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
Definitions
- the present invention relates to a composition for preventing or treating Sjogren's syndrome.
- Sjogren's syndrome is a chronic inflammatory disease of the exocrine glands, particularly characterized by the destruction of the normal tissues of the salivary glands and lacrimal glands, thereby reducing the production of tears and saliva.
- the disease was first reported by Johann Mikulicz in 1888, and in 1933 the Swedish ophthalmologist Henrik Sjogren described this disease in patients with rheumatoid arthritis.
- the main symptoms of this disease are dry eyes and saliva, but in addition to the involvement of the salivary glands and lacrimal glands, the skin and bronchi, the mucous membranes of the woman's vagina, and the lungs and kidneys can also cause various symptoms.
- Sjogren's syndrome occurs 9 times higher in women than in men, well in middle-aged women, and the incidence is estimated to be about 8 per 10,000 women.
- the cause of the disease has not been fully understood, but several factors are believed to be related, and genetic factors such as family history and viruses, cytokines, and autoimmune antibodies have been reported as causes.
- Korean Patent Publication No. 10-2018-0084153 relates to a composition and a manufacturing method of a pyrimidine and a pyridine compound having BTK inhibitory activity, and for their therapeutic use, cancer, lupus, allergic disease, Sjogren's disease and Disclosed is a hyperproliferative disease comprising rheumatoid vasculitis.
- Korean Patent Publication No. 10-2018-0049144 discloses a non-steroidal anti-inflammatory drug (NSAIA) drug precursor having a very high skin and membrane penetration rate, and a new pharmaceutical use thereof.
- NSAIA non-steroidal anti-inflammatory drug
- Patent Document 1 Korean Patent Publication No. 10-2018-0084153
- Patent Document 2 Korean Patent Publication No. 10-2018-0049144
- An object of the present invention is to provide a composition for preventing or treating Sjogren's syndrome.
- the problems to be solved by the present invention are not limited to the problems described above, and other problems that are not described will be clearly understood by those skilled in the art from the following description.
- One embodiment of the present invention provides a composition for preventing or treating Sjogren's syndrome comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- X is any one of oxygen, nitrogen or sulfur
- Y is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, (C 1 -C 3 alkyloxy) C 1 -C 6 alkyl, (C 2 -C 6 alkenyloxy) C 1 -C 6 alkyl, (C 1 -C 6 alkylcarbonyloxy) C 1 -C 6 alkyl, (C 1 -C 6 alkylsulfanyl) C 1 -C 6 alkyl, (arylsulfanyl) C 1 -C 6 alkyl, (arylsulfuryl Fonyl) C 1 -C 6 alkyl, (C 1 -C 6 alkylamino) C 1 -C 6 alkyl, [(C 1 -C 6 alkyl) (C 1 -C 6 alkyl) amino] C 1 -C 6 alkyl , [(C 1 -C 3 alkyl) (aryl) amino] C 1 -C 6 alkyl, [(C
- the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 oxoalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cyclo Alkenyl, C 3 -C 8 heterocycloalkenyl, aryl or heteroaryl is one selected from the group consisting of C 1 -C 3 alkyl, fluoro, chloro, bromo, hydroxy groups, oxo, nitro groups and cyano groups. It may be substituted with the above substituents.
- the salt may be an acid addition salt formed by a pharmaceutically acceptable free acid.
- the free acid may be an organic acid or an inorganic acid.
- the organic acid is citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, dichloroacetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, benzoic acid, 4- Acetamidobenzoic acid, gluconic acid, sulfonic acid, methanesulfonic acid, capric acid, capronic acid, caprylic acid, carboxylic acid, cinnamic acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonic acid, ethane Sulfonic acid, 2-hydroxyethanesulfonic acid, galactaric acid, gentisic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, hippuric acid, oleic acid, orotic acid, palmitic acid, Pam
- the pharmaceutically acceptable salt of the compound of Formula 1 may be selected from the following.
- the composition may further include a carrier, excipient, diluent, filler, anti-coagulant, lubricant, wetting agent, fragrance, emulsifier or preservative.
- the composition may be formulated in the form of a powder, granule, tablet, emulsion, syrup, aerosol, soft or hard gelatin capsule, sterile injectable solution, or sterile powder.
- the composition may increase the amount of tears and salivation.
- the composition may reduce the mRNA expression level of inflammatory cytokines and chemotactic cytokines derived from immune cells in the tissues of the tear glands and salivary glands.
- the composition may activate survival and growth of cells constituting salivary gland and tear gland tissue.
- composition for preventing or treating Sjogren's syndrome may increase the amount of tears and saliva, and the mRNA expression level of inflammatory cytokines and chemotactic cytokines derived from immune cells in the tear glands and salivary glands tissue Can be reduced.
- composition for preventing or treating Sjogren's syndrome reduces tissue cytokine protein expression in salivary and tear gland tissues, relieves inflammation, and has tissue regeneration ability such as increased cell growth, resulting in Sjogren's syndrome. It can slow the onset and can be used for the purpose of preventing or treating Sjogren's syndrome.
- 1 is a graph showing the amount of tears in the Sjogren's syndrome disease model.
- 2 is a graph showing the amount of saliva secretion in the Sjogren's syndrome disease model.
- 3 is a result of protein expression and quantitation of IL-17A and p-AKT.
- 4A and 4B are results of quantifying mRNAs of inflammatory and chemotactic cytokines (pro-inflammatory cytokines and chemotactic cytokines).
- FIG. 5 is a result showing protein expression of IL-17A and autoantibodies (anti-SSA / Ro, anti-SSB / La) in plasma.
- FIG. 6 is a photograph showing a phenotypic change in inflammation of a diseased animal model.
- heterocycloalkyl or “heterocycloalkenyl” is substituted with any one of nitrogen, oxygen, or sulfur instead of saturated carbon, or the same atom or different atoms are single, two or three adjacent, or It means skipping and replacing.
- heterocycloalkyl or heterocycloalkenyl examples include aziridine, oxirane, azetidine, oxetane, pyrrolidine, pyrroline, pyrazolidine, pyrazoline, imidazolidine, imidazoline, triazolidine , Oxazolidine, tetrahydrofuran, tetrahydrothiophene, thiazolidine, dioxolane, dioxol, oxathiolane, morpholine. Thiomorpholine, dithiane, piperidine, piperazine, pyran, dioxane or azepanes, but is not limited thereto.
- aryl as used herein include, but are not limited to, benzene, naphthalene, anthracene, or phenanthrene.
- heteroaryl refers to aryl in which either nitrogen, oxygen, or sulfur is substituted, or the same atom or different atoms are single, two or three adjacent or skipped.
- heteroaryl examples include pyrrole, imidazole, pyrazole, triazole, furan, thiophene, oxazole, isooxazole, thiazole, isothiazole, oxadiazole, thiadiazole, pyridine, pyrimidine, Pyrazine, pyridazine, triazine, azepine, indole, benzimidazole, indazole, benzoxazole, benzoisoxazole, benzothiazole, benzotriazole, benzofuran, benzothiophene, quinoline, isoquinoline, quinox Examples include saline, quinazoline, synoline, naphthyridine, phthalazine, benzopyran, benzoxazine, benzotriazine, chroman, chroman, benzodioxate atridine, phenothiazine, phenooxazine,
- the present invention relates to a composition for preventing or treating Sjogren's syndrome
- the composition for preventing or treating Sjogren's syndrome according to the present invention may include a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof.
- Sjogren's syndrome is an autoimmune disease in which chronic inflammation of unknown cause occurs due to infiltrating inflammatory cells in the tear glands and salivary glands. This disease is known to occur due to loss of control of the body's body's defense system, the immune system. As a result, inflammatory cells infiltrate the tear glands, salivary glands, and the like, which maintain the body's humidity, and the normal cells are destroyed, so that they can no longer maintain their functions.
- the composition according to one embodiment of the present invention can be administered orally, thereby increasing the amount of tears and saliva, mRNA of inflammatory cytokines and chemotactic cytokines derived from immune cells in the tissues of the tear glands and salivary glands The expression level can be reduced.
- cytokine protein expression in the salivary and tear gland tissues, alleviate inflammation, and have tissue regeneration capabilities such as increased cell growth, which can slow the onset of Sjogren's syndrome, and thus can be used as a therapeutic agent for Sjogren's syndrome.
- composition for preventing or treating Sjogren's syndrome according to an embodiment of the present invention will be described in more detail.
- composition for preventing or treating Sjogren's syndrome may include a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof.
- X is any one of oxygen, nitrogen or sulfur
- Y is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, (C 1 -C 3 alkyloxy) C 1 -C 6 alkyl, (C 2 -C 6 alkenyloxy) C 1 -C 6 alkyl, (C 1 -C 6 alkylcarbonyloxy) C 1 -C 6 alkyl, (C 1 -C 6 alkylsulfanyl) C 1 -C 6 alkyl, (arylsulfanyl) C 1 -C 6 alkyl, (arylsulfuryl Fonyl) C 1 -C 6 alkyl, (C 1 -C 6 alkylamino) C 1 -C 6 alkyl, [(C 1 -C 6 alkyl) (C 1 -C 6 alkyl) amino] C 1 -C 6 alkyl , [(C 1 -C 3 alkyl) (aryl) amino] C 1 -C 6 alkyl, [(C
- C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 oxoalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, C 3 -C 8 heterocycloalkenyl, aryl or heteroaryl is one or more substituents selected from the group consisting of C 1 -C 3 alkyl, fluoro, chloro, bromo, hydroxy groups, oxo, nitro groups and cyano groups. Can be substituted.
- XY represents an amino acid or amino acid (C 1 -C 3 alkyl) ester.
- Amino acids include, but are not limited to, glycine, leucine, methionine, valine, alanine, isoleucine, proline, tryptophan, phenylalanine, serine, threonine, asparagine, glutamic acid, lysine, histidine, or tyrosine.
- composition for preventing or treating Sjogren's syndrome according to the present invention has been experimentally confirmed to be effective in preventing or treating Sjogren's syndrome by including the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- the compound represented by Chemical Formula 1 is a rebamipide prodrug, and has a structure excellent in absorption in the body compared to rebamipide.
- the pharmaceutically acceptable salt of the compound represented by Formula 1 may be an acid addition salt formed by a pharmaceutically acceptable free acid.
- Organic acids and inorganic acids can be used as the free acid.
- the organic acid is not limited thereto, citric acid, acetic acid, lactic acid, tartaric acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, Benzoic acid, 4-acetamidobenzoic acid, gluconic acid, sulfonic acid, methanesulfonic acid, capric acid, capric acid, caprylic acid, carboxylic acid, cinnamic acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-di Sulfonic acid, ethanesulfonic acid, 2-hydroxyethane
- the salt compound of the rebamipide precursor may include the following, but is not limited thereto.
- the compound represented by Chemical Formula 1 may be represented by any one of the following Chemical Formulas 1-1 to 1-6.
- a pharmaceutically acceptable salt of the compound of Formula 1 according to the present invention may be prepared from a compound of Formula 1 prepared by reacting a compound of Formula 2 with a compound of Formula 3 below.
- X and Y are as described above, and Z is a hydroxy, amino, amine, halogen or leaving group.
- Z is hydroxy, -NH 2 , Cl, Br, alkylsulfonyl or arylsulfonyl.
- the pharmaceutically acceptable salt of the compound of Formula 1 according to the present invention may be prepared from the compound of Formula 1 prepared by the method described in [Scheme 1], but is not limited thereto.
- X is any one of oxygen, nitrogen or sulfur
- the compound of [Formula 2] used as a starting material in [Scheme 1] may be prepared by the method described in US Patent No. 4,578,381.
- the inorganic salt indicated in [Scheme 1] may be an inorganic base such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or cesium carbonate, and the solvent is acetone, dimethylformamide, dimethyl sulfoxide, or It may be acetonitrile, and the reaction may be performed at 10 to 100 ° C for 1 to 24 hours.
- DCC is dicyclohexylcarbodiimide
- DMAP is 4-dimethylaminopyridine
- HOBT is 1-hydroxybenzotriazole
- EDCI means 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloric acid
- Y-OMs or Y-OTs are alkylsulfonyl groups such as methanesulfonyl groups as sulfonyl groups; Or arylsulfonyl groups such as paratoluenesulfonyl, benzenesulfonyl or 4-nitrobenzenesulfonyl groups.
- sodium hydrosulfide may be used in an amount of 1 to 10 equivalents, preferably 4 to 6 equivalents, and sodium sulfide may be used in an amount of 1 to 5 equivalents, preferably 2 to 3 equivalents .
- dimethylformamide, dimethylsulfoxide or acetonitrile may be used as a solvent, and the reaction may be performed at 10 to 100 ° C for 1 to 24 hours.
- NCS refers to N-chlorosuccinimide.
- the pharmaceutically effective amount of the compound represented by Formula 1 according to the present invention or a salt thereof may be 0.5 to 100 mg / day per 1 kg of a patient's body weight, specifically 1 to 30 mg / day. However, the pharmaceutically effective amount may be appropriately changed according to the degree of disease symptoms, the patient's age, weight, health status, sex, administration route, and treatment period.
- composition according to the present invention may further include a pharmaceutically acceptable additive.
- a pharmaceutically acceptable additive means physiologically acceptable, and when administered to humans, does not typically cause an allergic reaction such as gastrointestinal disorders, dizziness or similar reactions.
- the additives include carriers, excipients and diluents.
- carrier examples include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
- fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be further included.
- compositions of the present invention can be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.
- the formulation may be in the form of a powder, granule, tablet, emulsion, syrup, aerosol, soft or hard gelatin capsule, sterile injectable solution, sterile powder.
- the pharmaceutical composition according to the present invention can be administered through various routes including oral, transdermal, subcutaneous, intravenous or intramuscular, and the dosage of the active ingredient is the route of administration, the age of the patient, sex, weight, and the severity of the patient. It may be appropriately selected according to various factors, and may be administered in combination with a compound known to have a prophylactic or therapeutic use in the disease according to the type of disease to be treated.
- a 7-12-week-old Sjogren's syndrome autoimmune disease model ( Nfkbiz -/- or IkB- ⁇ -deficient male mice, C57BL / 6) was delivered from Seoul Asan Hospital.
- the environment of the animal laboratory was 25 ⁇ 5 °C in temperature, 55-70% in humidity, 12 hours light / 12 hours light dark.
- Sterilized litter, laboratory animal pellet type solid feed Teklad 2018S (Envigo, sterilizable), and sterile purified water were allowed to be freely consumed.
- the weight was measured immediately at the time of sale, and the group was separately screened in consideration of the age-old and Sjogren syndrome phenotype. All animal experiments in this study were conducted in accordance with the standard operation procedures under the approval of Samjin Pharmaceutical's own animal experiment ethics committee (approval number; SJ-2016-001).
- sterile cages sterile water, humidifier, dehumidifier, thermo-hygrostat, 1cc syringe, marker, balance, 20ml vial, sonde (feeding needle), surgical instruments, e-tube, dissecting microscope, clean bench, micro pipet
- phenol red thread Zone-Quick; Oasis Glendora, CA
- iQ SYBR Green Supermix Bio-rad
- cDNA conversion kit BR170-8891, Bio-rad
- alfaxane alfaxane
- phospho- Akt S473 antibody
- Cell signaling # 4060
- IL-17A antibody Santacruz, # sc-374218
- beta-actin antibody Sigma aldrich, # A5316
- pilocarpine hydrochloride sigma, P6503), heparin (Green Cross)
- -RIPA lysis buffer 50mM Tris-Cl pH7.4, 150mM NaCl, 1mM EDTA, 1% Triton X-100, 0.1% SDS, 1% Sodium deoxicolate, 0.5mM Phenylmethylsulfonyl fluoride, 2ug / ml leupeptin, 2ug / ml aprotinin, 10mM NaF, and 1mM sodium orthovanadate
- -ELISA kit IL-17A (Signosis, # EA-2516), anti-SSA (Signosis, # EA-5202), anti-SSB (Signosis, # EA-5204)
- Placebo Comparator N / C, Ctrl
- Drug Placebo (vehicle, 3% Tween80)
- Active Comparator SA001 80mg / kg b.i.d
- Drug SA001OPral administration 2 times per day for 5 weeks
- the SA001 is 2- (morpholin-4-yl) ethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate malonate. It was prepared in the same way.
- phenol red thread Zone-Quick; Oasis, Glendora, CA
- One end was placed on the lower eyelid of the external eye angle of the animal's eye and left for 60 seconds, and the length (mm) of the thread whose color had changed after wetting the tears with a capillary phenomenon was measured.
- the amount of tear secretion decreases, it is determined that the greater the amount of secretion, the greater the effect of the test substance, because the drying of the eyes due to Sjogren's syndrome symptoms is promoted.
- Pilocarpine hydrochloride (Sigma, P6503, made at 1mg / ml in PBS concentration, stored at 4 °C) intraperitoneally administered with 100ul / mari (IP injection) 2 minutes after anesthesia, saliva collected by micro pipet for 3 minutes to measure saliva secretion Did.
- the tear gland and salivary gland tissues of the test animals were separated and PBS was added to perform homogenizing (on ice). Crushed tissue was treated with RIPA lysis buffer (50mM Tris-Cl pH7.4, 150mM NaCl, 1mM EDTA, 1% Triton X-100, 0.1% SDS, 1% Sodium deoxicolate, 0.5mM Phenylmethylsulfonyl fluoride, 2ug / ml leupeptin, 2ug / ml aprotinin, 10 mM NaF, and 1 mM sodium orthovanadate) 1 ml each was added and reacted for 5 minutes (on ice).
- RIPA lysis buffer 50mM Tris-Cl pH7.4, 150mM NaCl, 1mM EDTA, 1% Triton X-100, 0.1% SDS, 1% Sodium deoxicolate, 0.5mM Phenylmethylsulfonyl fluoride, 2ug
- Akt-IP-samples are phospho-Akt (S473)
- IL-17A-IP-samples are IL-17A primary antibody blocking buffer (TBS + Tween20) + 0.1% Skim milk was reacted overnight at 4 °C at a ratio of 1: 100,000, and HRP-conjugated secondary antibody was reacted and finally irradiated with ECL solution in the dark to quantify it by exposing to X-ray film.
- Half of the tissue pulverized with PBS is separated from total RNA through a manufacturer's protocol using TRIzol and converted into cDNA using a reverse transcription system (iScript cDNA synthesis BR170-8891, Bio-Rad, US). This is quantified by using real-time PCR. Primers used for PCR were ordered and synthesized by Bionix (Seoul, Korea), a specialized manufacturing company.
- the primers ordered were mouse cytokines; IL-2 (forward 5'-TTG AGT GCC AAT TCG ATG AT-3 'and reverse 5'-TTG AGG GCT TGT TGA GAT GA-3'), IL-17A (forward 5'-TGT CTC TGA TGC TGT TGC TG -3 'and reverse 5'- AGT CCT TGG CCT CAG TGT TT-3'), IFN-g (forward 5'-AGC TCT TCC TCA TGG CTG TT-3 'and reverse 5'-TTT GCC AGT TCC TCC AGA TA -3 '), BAFF (forward 5'-GGT GAC CCT GTT CCG ATG TA-3' and reverse 5'- CTC CGT TGC GTG AAA TCT GT-3 '), FLT3L (forward 5'-TGG CAG GGT CTA AGA TGC AA-3 'and reverse 5'-AGG TGG GAG ATG TTG GTC TG-3'), IL-1 (forward 5'
- PCR (CFX connect, Bio-Rad, US) was used to react SsoAdvanced® Universal SYBR® Green Supermix (Bio-rad), primer (0.5pmole), and template cDNA using the following conditions. Initial denaturation at 95 °C for 3min, denaturation 95 °C 10sec, annealing 55 °C 30sec to 39cycles, and extension 65 °C 5sec.
- the degree of inflammation in the animal model was scored and analyzed.
- FIG. 2 is a graph showing the amount of saliva secretion in the Sjogren's syndrome disease model.
- 3 is a result of protein expression and quantitation of IL-17A and p-AKT.
- Autoimmune diseases are mainly caused by the differentiation and activation of helper 17 T cell (Th17) and quantifying the increase in the expression of pro-inflammatory cytokine interleukin-17A (IL-17A) produced by this T cell.
- Th17 helper 17 T cell
- IL-17A pro-inflammatory cytokine interleukin-17A
- 4A and 4B are results of quantifying mRNAs of inflammatory and chemotactic cytokines (pro-inflammatory cytokines and chemotactic cytokines).
- the results of quantifying the mRNA of inflammatory and chemotactic cytokines (T-cell and B lymphocytes) related to autoimmune diseases in the tear and salivary glands are compared with the control group as follows. .
- IL-2 (salivary glands; 1.3 fold, lacrimal glands; 4.5 fold), interferon-g (salivary glands; 1.3 fold, lacrimal glands; 1.3 fold), IL-17A (salivary glands; 3.3 fold, lacrimal glands; 2.8 fold) , BAFF (salivary glands; no significance, lacrimal glands; 1.6 fold), CXCL13 (salivary glands; 5 fold, lacrimal glands; 2.5 fold), CXCR5 (salivary glands; 2.5 fold, lacrimal glands; no significance), FLT3L (salivary glands ; 13 fold, lacrimal glands; 2.5 fold), IL-1 ⁇ (salivary glands; 10 fold, lacrimal glands; 2 fold), IL-6 (salivary glands; 2.5 fold, lacrimal glands; 2 fold), IL-12 (salivary glands; no significance, lacrimal glands; 10 fold), IL-18 (salivary
- FIG. 5 is a result showing protein expression of IL-17A and autoantibodies (anti-SSA / Ro, anti-SSB / La) in plasma.
- FIG. 6 is a photograph showing a phenotypic change in inflammation of a disease animal model
- FIG. 7 is a result of evaluating a phenotypic change as a disease score.
- tear production As described above, in this experiment, tear production, salivary scan, pro-inflammatory cytokines in various tissues (lacrimal glands, salivary glands), and autoantibodies (anti-antibodies in plasma) -SSA / Ro, anti-SSB / La) and IL-17A were compared.
- the amount of tears and saliva secretion showed a significant increase in the composition administration group of the present invention.
- the mRNA expression levels of inflammatory cytokines and chemotactic cytokines derived from immune cells in the tear glands and salivary glands were significantly decreased in the drug administration group.
- composition administration group of the present invention significantly decreased and IL-17A cytokine secretion was decreased.
- degree of inflammation through observation of the appearance phenotype, it was confirmed that the effect of slowing the onset of the composition of the present invention. That is, it was confirmed that the onset of the disease model was slowed by administration of the composition of the present invention, and the possibility of alleviating inflammation in the tissues of the tear glands and salivary glands directly related and increasing the growth of constituent cells was confirmed. Therefore, it is believed that the composition of the present invention has a prophylactic and therapeutic effect of Sjogren's syndrome.
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Abstract
Description
Arms | Assigned Interventions |
Placebo Comparator (N/C, Ctrl) | Drug: Placebo (vehicle, 3% Tween80) |
Active ComparatorSA001 (80mg/kg b.i.d) | Drug: SA001OPral administration 2 times per day for 5 weeks |
IkB- ξ-deficient male mice, | ||
No.(%) vehiclen=3 | No.(%) SA001(80mg/kg)n=3 | |
SSA/Ro | 100.0±2.0 | 61.0±8.7 |
SSB/La | 100.0±0.9 | 67.9±12.4 |
Claims (11)
- 하기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용 가능한 염을 포함하는 쇼그렌 증후군 예방 또는 치료용 조성물;[화학식 1](상기 식에서,X는 산소, 질소 또는 황 중 어느 하나이고;Y는 C 1-C 6알킬, C 1-C 6할로알킬, (C 1-C 3알킬옥시)C 1-C 6알킬, (C 2-C 6알켄일옥시)C 1-C 6알킬, (C 1-C 6알킬카르보닐옥시)C 1-C 6알킬, (C 1-C 6알킬설판일)C 1-C 6알킬, (아릴설판일)C 1-C 6 알킬, (아릴설폰일)C 1-C 6 알킬, (C 1-C 6알킬아미노)C 1-C 6알킬, [(C 1-C 6알킬)(C 1-C 6알킬)아미노]C 1-C 6알킬, [(C 1-C 3알킬)(아릴)아미노]C 1-C 6알킬, [(C 1-C 3알킬)(아릴)C 1-C 3알킬]아미노C 1-C 6알킬, [(C 1-C 3알킬)(헤테로아릴)아미노]C 1-C 6알킬, (아릴카르보닐아미노)C 1-C 6알킬,C 2-C 6알켄일, C 2-C 6알카인일, C 2-C 6옥소알킬, C 3-C 8사이클로알킬, (C 3-C 8사이클로알킬)C 1-C 6알킬, (C 3-C 8사이클로알켄일)C 1-C 6알킬, (C 3-C 8헤테로사이클로알킬)C 1-C 6알킬, [(C 1-C 3알킬)C 3-C 8헤테로사이클로알킬]C 1-C 6알킬, [(아릴)C 1-C 3알킬]C 3-C 8헤테로사이클로알킬C 1-C 6알킬, [(C 1-C 6알킬옥시카르보닐)C 3-C 8헤테로사이클로알킬]C 1-C 6알킬, [(C 1-C 3알킬옥시카르보닐)C 3-C 8헤테로사이클로알킬]C 1-C 6알킬, (C 3-C 8헤테로사이클로알킬)C 1-C 6알켄일, [(C 1-C 3알킬)C 3-C 8헤테로사이클로알켄일]C 1-C 6알킬, (아릴)C 1-C 6알킬, [(C 1-C 3알킬)아릴]C 1-C 6알킬, [(C 1-C 3알킬옥시)아릴]C 1-C 6알킬, [(아릴옥시)아릴]C 1-C 6알킬, [(C 1-C 3알킬설판일)아릴]C 1-C 6알킬, [(C 1-C 3알킬옥시카르보닐)아릴]C 1-C 6알킬, [(아릴옥시카르보닐)아릴]C 1-C 6알킬, (아릴)C 3-C 6알켄일, (헤테로아릴)C 1-C 6알킬, [(알킬옥시카르보닐)헤테로아릴]C 1-C 6알킬, [(C 1-C 3알킬)C 3-C 8헤테로아릴]C 1-C 6알킬, [(C 3-C 8사이클로알킬)헤테로아릴]C 1-C 6알킬, [(아릴)헤테로아릴]C 1-C 6알킬, [(C 1-C 3알킬)헤테로아릴]C 1-C 6알킬, [(아릴)C 1-C 3알킬]헤테로아릴C 1-C 6알킬, (C 1-C 6알킬옥시카르보닐)C 1-C 6알킬, [(C 3-C 8헤테로사이클로알킬)C 1-C 6알킬옥시카르보닐]C 1-C 6알킬, (C 3-C 8헤테로사이클로알킬카르보닐)C 1-C 6알킬, [(C 1-C 3알킬)C 3-C 8헤테로사이클로알킬카르보닐]C 1-C 6알킬, [(C 1-C 3알킬)C 3-C 8헤테로사이클로알킬카르보닐]C 1-C 6알킬, [(C 3-C 8사이클로알킬)옥시카르보닐옥시]C 1-C 6알킬, [(C 3-C 8헤테로사이클로알킬)옥시카르보닐옥시]C 1-C 6알킬, (유레이도)C 1-C 6알킬, (아릴유레이도)C 1-C 6알킬, [(아릴)(C 1-C 3알킬유레이도]C 1-C 6알킬, (C 1-C 6알킬아미노카르보닐)C 1-C 6알킬, [(C 3-C 8헤테로사이클로알킬)아미노카르보닐]C 1-C 6알킬, [(C 1-C 3알킬)C 3-C 8헤테로사이클로알킬]아미노카르보닐C 1-C 6알킬, [(C 1-C 3알킬)(C 1-C 3알킬옥시)아미노카르보닐]C 1-C 6알킬 또는 (옥소C 3-C 8헤테로사이클로알킬)C 1-C 6알킬이고,이 때, 상기 C 1-C 6알킬, C 2-C 6알켄일, C 2-C 6알카인일, C 2-C 6옥소알킬, C 3-C 8사이클로알킬, C 3-C 8사이클로알켄일, C 3-C 8헤테로사이클로알켄일, 아릴 또는 헤테로아릴은 C 1-C 3알킬, 플루오로, 클로로, 브로모, 하이드록시기, 옥소, 니트로기 및 시아노기로 이루어진 군으로서 선택된 하나 이상의 치환기로 치환될 수 있다.)
- 제1항에 있어서,상기 염은 약제학적으로 허용 가능한 유리산(free acid)에 의하여 형성된 산 부가염인 쇼그렌 증후군 예방 또는 치료용 조성물
- 제3항에 있어서,상기 유리산은 유기산 또는 무기산인 쇼그렌 증후군 예방 또는 치료용 조성물.
- 제4항에 있어서,상기 유기산은 구연산, 초산, 젖산, 주석산, 말레인산, 푸마르산, 포름산, 프로피온산, 옥살산, 다이클로로아세트산, 트리플로오로아세트산, 아디프산, 아스코브산, 벤조산, 4-아세트아미도벤조산, 글루콘산, 설폰산, 메탄설폰산, 카프르산, 카프론산, 카프릴산, 카르본산, 신남산, 사이클람산, 도데실설폰산, 에탄-1,2-다이설폰산, 에탄설폰산, 2-하이드록시에탄설폰산, 갈락타르산, 겐티스산, 글루타르산, 2-옥소글루타르산, 글리세로포스포르산, 히푸르산, 올레산, 오로트산, 팔미트산, 파모산, 파이로글루탐산, 세바스산, 스테아르산, 티오시안산, 운데실렌산, 아이소부티르산, 라우르산, 만델산, 나프탈렌-1,5-다이설폰산, 나프탈렌-2-설폰산, 나프토산, 니코틴산, 글리콜산, 석신산, 4-톨루엔설폰산, 캠퍼설폰산, 글루탐산, 아스파르트산, 살리실산, 4-아미노살리실산, 말론산, 말산 및 벤조설폰산으로 이루어진 군으로부터 선택되며, 상기 무기산은 염산, 브롬산, 황산, 질산 및 인산으로 이루어진 군으로부터 선택되는 쇼그렌 증후군 예방 또는 치료용 조성물.
- 제1항에 있어서,상기 화학식 1의 화합물의 약제학적으로 허용 가능한 염은 하기 중에서 선택되는 쇼그렌 증후군 예방 또는 치료용 조성물:1) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 글리콜레이트;2) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 락테이트;3) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 살리실레이트;4) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 옥살레이트;5) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 말로네이트;6) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 말레이트;7) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 타르타레이트;8) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 말레에이트;9) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 푸마레이트;10) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 시트레이트;11) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 벤젠설포네이트;12) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 토실레이트;13) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 하이드로클로레이트;14) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 설페이트;15) 2-(모폴린-4-일)에틸 2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 포스포레이트;16) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 아세테이트;17) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 다이클로로아세테이트;18) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 아디페이트;19) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 아스코베이트;20) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 벤조에이트;21) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 4-아세트아미도벤조에이트;22) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카프레이트;23) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카프로네이트;24) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카프릴레이트;25) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 카르보네이트;26) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 신나메이트;27) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 사이클라메이트;28) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 도데실설포네이트;29) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 에탄-1,2-다이설포네이트;30) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 에탄설포네이트;31) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 2-하이드록시에탄설포네이트;32) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 포르메이트;33) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 갈락타레이트;34) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 겐티세이트;35) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 글루타메이트;36) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 글루타레이트;37) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 2-옥소글루타레이트;38) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 글리세로포스포레이트;39) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 히푸레이트;40) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 올레에이트;41) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 오로테이트42) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 팔미테이트;43) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 파모에이트;44) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 프로피오네이트;45) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 파이로글루타메이트;46) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 4-아미노살리실레이트;47) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 세바세이트;48) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 스테아레이트;49) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 티오시아네이트;50) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 운데실레네이트;51) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 하이드로브로메이트;52) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 아이소부티레이트;53) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 라우레이트;54) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 DL-만델레이트;55) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 메탄설포네이트;56) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 나프탈렌-1,5-다이설포네이트;57) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 나프탈렌-2-설포네이트;58) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 2-나프토에이트;59) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 니코티네이트;60) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 니트레이트;61) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 석시네이트의 제조62) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 설퍼레이트; 및63) 2-모폴린-4-일-에틸2-(4-클로로벤조일아미노)-3-(2-옥소-1,2-다이하이드로퀴놀린-4-일)프로피오네이트 L-아스파르테이트.
- 제1항에 있어서,상기 조성물은 담체, 부형제, 희석제, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제 또는 방부제를 추가로 포함하는 쇼그렌 증후군 예방 또는 치료용 조성물.
- 제1항에 있어서,상기 조성물이 분말, 과립, 정제, 에멀젼, 시럽, 에어로졸, 연질 또는 경질 젤라틴 캅셀, 멸균 주사용액, 또는 멸균 분말의 형태로 제형화된 쇼그렌 증후군 예방 또는 치료용 조성물.
- 제1항에 있어서,상기 조성물은 눈물량 및 침 분비량을 증가시키는 쇼그렌 증후군 예방 또는 치료용 조성물.
- 제1항에 있어서,상기 조성물은 눈물샘 및 침샘 조직 내 면역세포 유래 염증성 사이토카인과 주화성 사이토카인들의 mRNA 발현량을 감소시키는 쇼그렌 증후군 예방 또는 치료용 조성물.
- 제1항에 있어서,상기 조성물은 침샘과 눈물샘 조직을 구성하는 세포의 생존 및 생장을 활성화하는 쇼그렌 증후군 예방 또는 치료용 조성물.
Priority Applications (8)
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BR112021007631-0A BR112021007631A2 (pt) | 2018-10-23 | 2019-10-22 | composição para a prevenção ou o tratamento da síndrome de sjogren |
EP19877003.4A EP3871675A4 (en) | 2018-10-23 | 2019-10-22 | COMPOSITION FOR THE PREVENTION OR TREATMENT OF SJÖGREN SYNDROME |
CA3117118A CA3117118A1 (en) | 2018-10-23 | 2019-10-22 | Composition for preventing or treating sjogren's syndrome |
US17/286,967 US20210393642A1 (en) | 2018-10-23 | 2019-10-22 | Composition for preventing or treating sjogren's syndrome |
CN201980069731.2A CN112969464A (zh) | 2018-10-23 | 2019-10-22 | 用于预防或治疗干燥综合征的组合物 |
JP2021521979A JP2022505588A (ja) | 2018-10-23 | 2019-10-22 | シェーグレン症候群の予防または治療用組成物 |
AU2019364114A AU2019364114A1 (en) | 2018-10-23 | 2019-10-22 | Composition for preventing or treating sjogren's syndrome |
IL282557A IL282557A (en) | 2018-10-23 | 2021-04-22 | Composition for preventing or treating sjogren's syndrome |
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KR1020180126875A KR102190019B1 (ko) | 2018-10-23 | 2018-10-23 | 쇼그렌 증후군 예방 또는 치료용 조성물 |
KR10-2018-0126875 | 2018-10-23 |
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WO2020085760A1 true WO2020085760A1 (ko) | 2020-04-30 |
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PCT/KR2019/013885 WO2020085760A1 (ko) | 2018-10-23 | 2019-10-22 | 쇼그렌 증후군 예방 또는 치료용 조성물 |
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US (1) | US20210393642A1 (ko) |
EP (1) | EP3871675A4 (ko) |
JP (1) | JP2022505588A (ko) |
KR (1) | KR102190019B1 (ko) |
CN (1) | CN112969464A (ko) |
AU (1) | AU2019364114A1 (ko) |
BR (1) | BR112021007631A2 (ko) |
CA (1) | CA3117118A1 (ko) |
IL (1) | IL282557A (ko) |
WO (1) | WO2020085760A1 (ko) |
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-
2018
- 2018-10-23 KR KR1020180126875A patent/KR102190019B1/ko active IP Right Grant
-
2019
- 2019-10-22 CA CA3117118A patent/CA3117118A1/en active Pending
- 2019-10-22 CN CN201980069731.2A patent/CN112969464A/zh active Pending
- 2019-10-22 US US17/286,967 patent/US20210393642A1/en active Pending
- 2019-10-22 JP JP2021521979A patent/JP2022505588A/ja active Pending
- 2019-10-22 WO PCT/KR2019/013885 patent/WO2020085760A1/ko active Application Filing
- 2019-10-22 EP EP19877003.4A patent/EP3871675A4/en active Pending
- 2019-10-22 BR BR112021007631-0A patent/BR112021007631A2/pt unknown
- 2019-10-22 AU AU2019364114A patent/AU2019364114A1/en not_active Abandoned
-
2021
- 2021-04-22 IL IL282557A patent/IL282557A/en unknown
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KR20150075443A (ko) * | 2013-12-25 | 2015-07-06 | 삼진제약주식회사 | 신규 레바미피드 전구체의 염 및 이의 용도 |
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Also Published As
Publication number | Publication date |
---|---|
CN112969464A (zh) | 2021-06-15 |
BR112021007631A2 (pt) | 2021-07-27 |
JP2022505588A (ja) | 2022-01-14 |
EP3871675A4 (en) | 2022-03-09 |
IL282557A (en) | 2021-06-30 |
KR102190019B1 (ko) | 2020-12-15 |
KR20200046226A (ko) | 2020-05-07 |
EP3871675A1 (en) | 2021-09-01 |
US20210393642A1 (en) | 2021-12-23 |
CA3117118A1 (en) | 2020-04-30 |
AU2019364114A1 (en) | 2021-06-03 |
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