TWI239246B - Compositions for promoting growth - Google Patents
Compositions for promoting growth Download PDFInfo
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- TWI239246B TWI239246B TW089105321A TW89105321A TWI239246B TW I239246 B TWI239246 B TW I239246B TW 089105321 A TW089105321 A TW 089105321A TW 89105321 A TW89105321 A TW 89105321A TW I239246 B TWI239246 B TW I239246B
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- 239000000203 mixture Substances 0.000 title claims description 13
- 230000012010 growth Effects 0.000 title claims description 4
- 230000001737 promoting effect Effects 0.000 title abstract description 4
- 239000003112 inhibitor Substances 0.000 claims abstract description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 102000018997 Growth Hormone Human genes 0.000 claims description 6
- 108010051696 Growth Hormone Proteins 0.000 claims description 6
- 239000000122 growth hormone Substances 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 4
- 108010016626 Dipeptides Proteins 0.000 claims description 3
- 206010013883 Dwarfism Diseases 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims 2
- ATHGHQPFGPMSJY-UHFFFAOYSA-N spermidine Chemical compound NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 claims 2
- 125000003277 amino group Chemical group 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims 1
- 229940063673 spermidine Drugs 0.000 claims 1
- 206010056438 Growth hormone deficiency Diseases 0.000 abstract description 2
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 abstract 1
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 abstract 1
- 208000020221 Short stature Diseases 0.000 abstract 1
- 230000001419 dependent effect Effects 0.000 abstract 1
- 230000008467 tissue growth Effects 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000011049 filling Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- -1 thiazolidine amine Chemical class 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 230000002079 cooperative effect Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 101150041968 CDC13 gene Proteins 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000017423 tissue regeneration Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- 101000886298 Pseudoxanthomonas mexicana Dipeptidyl aminopeptidase 4 Proteins 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 210000003016 hypothalamus Anatomy 0.000 description 2
- 229960000310 isoleucine Drugs 0.000 description 2
- 210000004731 jugular vein Anatomy 0.000 description 2
- 210000000867 larynx Anatomy 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 235000019833 protease Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 1
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 1
- 101150102363 Ghrh gene Proteins 0.000 description 1
- 101001075374 Homo sapiens Gamma-glutamyl hydrolase Proteins 0.000 description 1
- 101000664737 Homo sapiens Somatotropin Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- QGARCQDPKWXNMS-UHFFFAOYSA-N NC1(N(CCC1)C#N)C1=CC=CC=2C3=CC=CC=C3CC12 Chemical compound NC1(N(CCC1)C#N)C1=CC=CC=2C3=CC=CC=C3CC12 QGARCQDPKWXNMS-UHFFFAOYSA-N 0.000 description 1
- VEXUJZGGLHGXIY-UHFFFAOYSA-N NC1(N(CCC1)C=O)C1=CC=CC=2C3=CC=CC=C3CC12 Chemical compound NC1(N(CCC1)C=O)C1=CC=CC=2C3=CC=CC=C3CC12 VEXUJZGGLHGXIY-UHFFFAOYSA-N 0.000 description 1
- UWOJTZWEHJIHGG-UHFFFAOYSA-N OP(O)(O)=O.F.F.F Chemical compound OP(O)(O)=O.F.F.F UWOJTZWEHJIHGG-UHFFFAOYSA-N 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000009646 cyclic growth Effects 0.000 description 1
- ICODSBYUBBICCC-UHFFFAOYSA-D decasodium pentasulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O ICODSBYUBBICCC-UHFFFAOYSA-D 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000002143 fast-atom bombardment mass spectrum Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-L glutamate group Chemical group N[C@@H](CCC(=O)[O-])C(=O)[O-] WHUUTDBJXJRKMK-VKHMYHEASA-L 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 125000005597 hydrazone group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 150000002519 isoleucine derivatives Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000008481 normal tissue growth Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000012925 reference material Substances 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
- Pyrrole Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Description
1239246 Α7 r—_ Β7 五、發明說明（1 ) 本發明是有關於用以促進動物生長，如發育不全的人 類，和用以加速組織修復和再生的藥劑和組成物。 DP-IV和卩制劑 雙肽肽酶IV(DP-IV，也稱為雙肽胺基肽酶IV，DPP-IV ，DAP-IV，EC 3_4·14.5)是一個絲胺酸肽酶，可從肽和蛋 白質切斷胺端的雙肽。它會辨識其中Ν-終端序列為X-Pro 或X-Ala的受質。DP-IV抑制劑曾被建議用作為治療發炎 疾病和AIDS的治療藥劑。通常，已知的DP_IV抑制劑是受 質的同系物。DP-IV抑制劑的實施例如揭示於下面文獻者 ，DD 296 075 A5(Neubert等人，1991年 11月），W091/16339 (Bachovchin等人，1991 年 10月），WO93/08259 (Bachovchin 等人，1993 年4月），WO95/15309(Jenkins等人，1995 年六 月），W098/19998(Vilhauer，1998年五月），W099/46272 (Scharpe 等人，1999 年 9 月）和 W099/61431(Demuth 等人， 1999年12月）。一些抑制劑的前藥物被說明於W099/67278 和W099/67279(二者都屬於Demuth等人，1999年12月）。 下面的表中顯示DP-IV抑制劑化合物的通式，和一些 用於本發明較佳的特定實施例；這些形態和實施例是摘取 自顯示之專利公告文件較大範圍的揭示化合物。強調揭示 於引用的DD和WO說明書的所有DP-IV抑制劑都可用於本 發明，肯定的指出這些前面說明書内提到的一般和更特定 的化學式和個別的化合物的全部資訊作為參考資料。例如 ，在下面的表中顯示吼σ各淀和ϋ塞唾唆環可被大範圍的以其 他各種環大小的雜環化合物取代，及/或顯示的胺基-醯基 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) ▼裝-------1訂··--------線· 經濟部智慧財產局員工消費合作社印製 4 1239246 A7 B7
五、發明說明（2 部份可用廣大範圍的其他基團取代，如顯示公告的說明 得到用於本發明的其他DP-IV抑制劑。 胺基-醯基吡咯啶醯胺和噻唑啶醯胺（參考DD 296 075 A5)，如
H，N
胺基-醯基吡咯啶醛（參考DD 296 075 A5和WO95/35309)，如
CHO 胺基-醯基吡咯啶硼酸（參考W091/16339和WO93/08259)，如
々OH 胺基-醯基咣咯啶腈（參考WO95/15309和W098/19998)，如
生長荷爾蒙之作用 生長荷爾蒙（GH，生長激素）是腦下腺反應丘下腦部以 生長荷爾蒙釋放荷爾蒙（GHRH)形式的訊號而分泌的。人 類GH最多的異型是191-殘基的狀，GHRH是一個44 -殘基 的肽。GH是促進兒童正常發育的關鍵因子，GH不足可能 造成侏儒症。在成年人中GH的重要性較少被定義，雖然 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------—^----裝-------1 訂··--------線 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 1239246 A7
請 先 閱 讀 背 面 之 注 意 事 項 再 填 本 頁 >—/
訂 1239246 五、發明說明（4 :用合成的方法製備’但是這種合成是昂貴的，而且產物 :要小心地純化。相對的，DP_IV抑制劑是小的分子，容 易用標準的合成方法得到。它們是非抗原性的，容易純化 而且不貴的。 s DP IV#p制劑另外的優點是’它在許多情況下口服後 疋有生物活性的。這是與GH和ghrh相反的，它們必須 以注射投藥。因此使用购物制劑是對病人較少痛苦的 較少侵入性的方法。 在本务月的第一觀點，它提供一種治療常度下發育或 ，儒症的藥學組成物。該組成物特別有效於治療由於生長 荷爾豕不足造成的的常度下發育或侏儒症。本發明同樣的 也提供一種用於組織再生的組成物。 每些組成物的特徵是它們包含DP:IV抑制劑。該組成 物可另外包括藥學可接受的，如通常文獻已知的賦型劑， 例如稀釋劑，載劑，填充劑，黏著劑，分散劑，安定劑等 等。 在本發明本文中，如果一種化合物在i μΜ的濃度可抑 制酵素的作用，它就被認為是一種DP-IV抑制劑。較佳的 ，此化合物在低於1〇0ηΜ的濃度抑制Dp_IV的作用，而在 低於1 μΜ的濃度不抑制其他酵素的作用。下面的表中顯示 DP-IV抑制劑化合物的通式，和一些用於本發明較佳的特 定實施例；這些形態和實施例是摘取自顯示之專利公告文 件較大範圍的揭示化合物。強調揭示於引用的DD和w〇說 明書的所有DP-IV抑制劑都可用於本發明，肯定的指出這 7 (請先閱讀背面之注意事項再填寫本頁) ^-------Ί --------- 經濟部智慧財產局員工消費合作社印製
本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1239246 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（5 ) 些前面說明書内提到的一般和更特定的化學式和個別的化 合物的全部資訊作為參考資料。例如，在下面的表中顯示 口比洛唆和嗟唾唆環可被大範圍的以其他各種環大小的雜環 化合物取代，及/或顯示的胺基-醯基部份可用廣大範圍的 其他基團取代，如顯示公告的說明，得到用於本發明的其 他DP-IV抑制劑。
在一個本發明較佳的實例中，該DP-IV抑制劑是一個 胺基-醯基吡咯啶腈。特別佳的是那些揭示於WO95/15309 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --------J-----------1 訂----------線 (請先閱讀背面之注意事項再填寫本頁) 1239246 A7
1239246 A7 B7 五、發明說明（7 ) 的方法說明這些方法。 實施例1 A-(2S)-N-異白胺基咕咯°定-2-賸 木又
〇 〇 0
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經濟部智慧財產局員工消費合作社印製 (a)三級-丁氧基-異白胺基脯醯胺 攪拌的脯醯胺鹽酸鹽（225mg，1.50mmol)之無水二氣 甲烧（15mL)的懸浮液加入二異丙乙胺，得到澄清的驗性 (pH9)溶液。一次加入N-(三級-丁氧羰基-異白胺氧基）琥轴 醯亞胺（328mg，1 .Ommol)，混合物在氮蒙氣，室溫下擾 拌16小時。溶劑減壓蒸發，殘餘物以乙酸乙酯和〇.3N硫酸 氫鉀溶液分溶。有機層依序以飽和碳酸氫鈉溶液，水和食 鹽水洗，用硫酸納脫水，並減壓濃縮。殘餘物經過短填充 矽膠過濾純化，以己烷/乙酸乙酯（10 : 90)，然後乙酸乙 酉旨沖提。含產物之沖提物濃縮得到的標題化合物為無色泡 沫狀玻璃物質；301mg(92%)。 W NMR(CDC13) : δ 6·90(1Η，br· s) ; 5.51(1H，br. s) ;5.18(1H，d，J=9.6Hz) ; 4.62(1H，dd，J=2.6 & 7·〇Ηζ) ;4·29(1Η，dd，J=8.4 & 9.2Hz); 3.79_3.58(2H，m); 2.36(1H ，m);2.09-1.57(5H，m); 1.43(9H，s)，1.17(1H，m); 〇.95(3h 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 10 ------------ΦΜ,-------1 訂_---------線 Φ· (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印制衣 1239246 A7 B7 --------- 五、發明說明（8 ) ，d，J=6.6Hz) ; 0·90(3Η，t，J=7.3Hz) ppm。 (b) (2S)_N-(三級-丁乳幾基異白胺基比吸喷 攪拌的（a)部份醯胺（203mg，〇.62mmol)於無水啦唆 (1 OmL)的溶液，在氮蒙氣下加入哺嗤（84mg，1.24mmol^) 。混合物冷卻到-35QC，然後滴加入三氣化磷醯（〇25mL， 2.48mmol)。混合物攪拌1小時，這期間溫度上升到_2〇〇c ’>谷劑減壓洛發。殘餘物以砍膠層析法純化，得到的標題 化合物為無色油狀物質；收率180mg(94%)。 β NMR(CDC13) : (5 5.14(1H，d，J=9.2Hz) ; 4·80(1Η ，dd，J=2.6 & 7.1Hz);4.22(lH，dd，J=7.9 & 9.1Ηζ);3·81(1Η ，m) ; 3·71(1Η，m) ; 2·30_2·12(4Η，m) ; 1.75(1H，m); 1·60(1Η，m) ; 1.42(9H，s) ; 1.19(1H，m) ; 0.97(3H，d， J=6.9Hz) ; 0.91(3H，t，J=7.3Hz) ppm。 13C NMR(CDC13) : 5 171.7 ; 155.6 ; 118.0 ; 79.6 ; 56.0 ,46.5 , 46.0 ; 37·8 ; 29.6 ; 28.1 ; 25.0 ; 24.2 ; 15.2 ; i〇 9 ppm 〇 (c) (2S)-N-(異白胺基吡咯啶-2-賸三氟乙酸鹽 (b)部份腈溶解於三氟乙酸，溶液在室溫攪拌1小時。 溶劑減壓蒸發，殘餘物溶解於水。溶液透析得到的標題化 合物為白色絨毛狀固體；收率60mg。 FAB質譜：計算值m/e 209.3 ;實驗值210.2(M+H)+ 屮 NMR(D20):占 4·3(1Η，m) ; 3·64(1Η，d，J=5.6Hz) ;3·16(2Η，m) ; 1.86-1.48(5H，m) ; 0·98(1Η，m) ; 〇·68(1Η ，m) ; 0·51(3Η，d ’ J=6.9Hz) ; 0·38(3Η，t，J=7.3Hz) ppm。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 11 . -------- ---------^ (請先閱讀背面之注意事項再填寫本頁) 1239246 經濟部智慧財產局員工消費合作社印製 Α7 Β7 五、發明說明（9 ) 13C NMR(D20) ： (5 169.7 ； 119.7 ； 57.3 ； 48.6 ； 48.1 ； 36.9，30.2 ; 25.8 ; 24.5 ; 15.4 ; 11·5 ppm。 寬Uj 1B-(2SVN-((2’SV2’_ 脸篡 _3’，3’_二甲基丁醯基）賸之 合成 依照實施例1A的方法製備，以相關的三級-丁基甘胺 酸衍生物取代異白胺酸衍生物。 4 NMR(CD3OD) : (5 4.86-4.81(1H，m) ; 4·04(1Η，s) ;3·77-3.71(2Η，m); 3·34(2Η，s); 2·34-2·08(4Η，m); 1·14(9Η ，s) ppm 〇 13C NMR(CD3OD) : 5 167.40，117.99，58.78，46.53 ，34.21 ’ 29.54，25.22，25.03 ppm ο f施例2·循環生長荷爾蒙之影孿 實驗動物 以得自 Iffa Credo(L’Arbresle，France)的雄性 Sprague-
Dawley鼠（200-220g)進行實驗，用標準的實驗室任意食品 ，飼養於維持12小時亮-暗輪替之溫度和濕度控制的房間 〇 手術 將鼠秤重，以Narcorene麻醉。喉頭腹面去毛，從喉 頭中心向下切割。露出右頸靜脈，插入連接到醫用級石夕管 (OD 0.94mm)(矽膠面在頸靜脈内）聚乙烯管（〇d 1 〇mm)套 管。將套管固定，聚乙烯管經過頸背部切口面向外。導管 以含0.1%肝燐脂的林格氏溶液300μυ閏濕。受試鼠在個別 的籠子恢復至少24小時，給予現有的任意食物和水。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------— I.---ΦΜ-------1訂_---------線一 (請先閱讀背面之注意事項再填寫本頁) 12 !239246
五、 發明說明（10 ) 實驗方法 在一次注射GHRH(0·1吨/kg , i.v.)之前丨5分鐘注射實 施例1B化合物（3mg/kg’ iv)或其載劑。就在注射抑制劑 # GHRH别取出血液樣品（2〇〇 25〇此），然後在g服出主射 後的5 ’ H) ’ 15 ’ 2G ’ 3G和⑼分鐘取樣。各血液樣品以相 同體積含G.1%肝鱗脂的林格氏溶液取代。萃取血衆，貯 存於-20QC，直到以ria測定gh。 實驗結果 實施例1B化合物加強投藥GHRH引發的GH遽增（表υ 。載劑和抑制劑處理的族群累積的GH反應分別為60分鐘 720.2±217.0叩/1111和60分鐘5072.8±837.31^/1111〇)<0.05)。 (請先閱讀背面之注意事項再填寫本頁)
經濟部智慧財產局員工消費合作社印製 盘_1 ·實和惠⑺之對靜脈內注射GHRH引起GH 遽增的景多響。這些結果县6自n _LA m . 時間(分鐘） •15 0 5 10 15 20 30 60 AUC 42.1 40.1 155.7 91.0 61.0 53.6 34.1 26.7 720.2 〇 ±12.5 ±8.0 i25.1 ±15.6 ±12.9 ±12.5 ±8.2 43.0 d217.0 m 50.5 33.4 483.0 309.5 164.3 103.1 52.1 26.3 5072.8 g耸 ±16.4 ±6.9 m.o ±55.40 £28.3 ±18.1 ±7.7 43.3 +837.3 得到的結果顯示DP-IV抑制劑可以增加循環之生長荷 爾蒙的含量，因此可用於治療由於生長荷爾蒙不足造成的 常度下發育和其他促進組織生長是重要因素的病況。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） 13 ▲ 1239246 A7
154.5g 53.5g 13.5g 11.〇g 2.0g 165.5g 400.Og 實施例3.藥學 3 A-50mg 錠劍 用下面的方法製備含5〇mg當量實施例丨八化合物為活性藥 劑的錠劑： 實施例1Α化合物（三氟乙酸鹽） 玉米澱粉 羥丙基纖維素 羧曱基纖維素_ 硬脂酸鎂 乳糖____ 總共 將所有的材料混合，然後壓片得到2〇〇〇顆2〇〇rng的錠 劑’各含50mg當量的實施例丨八化合物游離鹼。 3B-100mg 陰道 以下面方法製備適用於陰道投藥，含lOOmg當量實施 例1A化合物為活性藥劑的塞劑： 實施例1A化合物（三氟乙酸鹽） 154.5g 玉米澱粉 210.Og 膠體碎 2.5g Povidone 30 49.〇g 硬脂酸鎂 23.Og 己二酸 57.〇g 碳酸氫納 43.Og 十*—基硫酸納 5.0g 乳糖 456.〇g 總共 1000.〇g 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ---------；-----------1 訂 *---------線 {：請先閱讀背面之注咅？事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 14 1239246 五、 A7 B7
發明說明（U 將所有的材料混合，然後壓片得到1〇〇〇顆1§的塞劑， 各含lOOmg當量的實施例以化合物游離鹼。 月1J述貫施例疋說明此處揭示的本發明，但是並非限制 11的。熱悉文獻者的擴大延伸同樣包括於本發明範圍和另 外定義範圍的申請專利範圍之内。 一個或更多個DP-N抑制劑可用作為用於本發明組成 物和方法特定目的有效的單一組成份。
.II ---------- (請先閱讀背面之注意事項再填寫本頁) 11訂.---------線 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公釐）
Claims (1)
1239246 申請專利範圍
弟〇8910532 1號專利再審查案申請專利範圍修正本 修正曰期：94年4月 •一種含胺基屬基対精之雙肽輯IV抑制劑於 用以治療常度下生長或侏儒症之藥學組成物的衣 2.如申請專利範圍第㈣之用途，其中該常度下、° 儒症是由於生長荷爾蒙不足造成的。 …朱 利乾圍第〗項之用途，其"亥藥學組成物是配 方為口服投樂之用。 其中該藥學組成物是配 其中該藥學組成物配方 其中该藥學組成物配方 4·如申請專利範圍第2項之用途 方為口服投藥之用。 5·如申請專利範圍第3項之用途 為鍵劑或膠囊。 •如申凊專利範圍第4項之用途 為錠劑或膠囊。 7·如申請專利範圍第丨至6 .θ 中任一項之用途，其中該藥學 、、且成物疋·以每天晚上一次投藥。 8·如申請專利範圍第丨至6 客 任一項之用途，其中一種或 種的又肽肽酶抑制劑為誃 勹。哀樂學組成物的單一組份，其 射於上述效用具有活性。
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| US5952301A (en) | 1996-12-10 | 1999-09-14 | 1149336 Ontario Inc. | Compositions and methods for enhancing intestinal function |
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1999
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- 2000-03-21 CZ CZ20013411A patent/CZ20013411A3/cs unknown
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|---|---|
| PL195529B1 (pl) | 2007-09-28 |
| DE60020825D1 (de) | 2005-07-21 |
| NO20014608D0 (no) | 2001-09-21 |
| US6521644B1 (en) | 2003-02-18 |
| WO2000056297A2 (en) | 2000-09-28 |
| CZ20013411A3 (cs) | 2002-04-17 |
| JP2002539244A (ja) | 2002-11-19 |
| EP1171121A2 (en) | 2002-01-16 |
| AU772421B2 (en) | 2004-04-29 |
| AR023130A1 (es) | 2002-09-04 |
| MXPA01009610A (es) | 2002-07-02 |
| RU2242228C2 (ru) | 2004-12-20 |
| CN1359293A (zh) | 2002-07-17 |
| CA2366926A1 (en) | 2000-09-28 |
| NO20014608L (no) | 2001-10-31 |
| ZA200108082B (en) | 2002-12-24 |
| NZ514450A (en) | 2002-11-26 |
| WO2000056297A3 (en) | 2001-01-25 |
| DE60020825T2 (de) | 2006-05-04 |
| TR200102648T2 (tr) | 2001-12-21 |
| HUP0200391A3 (en) | 2002-11-28 |
| HK1048589A1 (zh) | 2003-04-11 |
| MY124214A (en) | 2006-06-30 |
| GB9906715D0 (en) | 1999-05-19 |
| IL145568A (en) | 2007-09-20 |
| HUP0200391A2 (en) | 2002-06-29 |
| PL350796A1 (en) | 2003-02-10 |
| ATE297728T1 (de) | 2005-07-15 |
| AU3318600A (en) | 2000-10-09 |
| EP1171121B1 (en) | 2005-06-15 |
| UA73115C2 (en) | 2005-06-15 |
| KR100704348B1 (ko) | 2007-04-05 |
| KR20010108389A (ko) | 2001-12-07 |
| IL145568A0 (en) | 2002-06-30 |
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