CN1293876C - 1，3－丙二醇衍生物的新用途 - Google Patents
1，3－丙二醇衍生物的新用途 Download PDFInfo
- Publication number
- CN1293876C CN1293876C CNB2004100059961A CN200410005996A CN1293876C CN 1293876 C CN1293876 C CN 1293876C CN B2004100059961 A CNB2004100059961 A CN B2004100059961A CN 200410005996 A CN200410005996 A CN 200410005996A CN 1293876 C CN1293876 C CN 1293876C
- Authority
- CN
- China
- Prior art keywords
- chemical compound
- formula
- rejection
- acceptable salt
- free form
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- YPFDHNVEDLHUCE-UHFFFAOYSA-N propane-1,3-diol Chemical class OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 title 1
- 150000003839 salts Chemical group 0.000 claims abstract description 26
- 230000002265 prevention Effects 0.000 claims abstract description 10
- UXFQFBNBSPQBJW-UHFFFAOYSA-N 2-amino-2-methylpropane-1,3-diol Chemical compound OCC(N)(C)CO UXFQFBNBSPQBJW-UHFFFAOYSA-N 0.000 claims description 10
- -1 4-octyl phenyl Chemical group 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 229960002930 sirolimus Drugs 0.000 claims description 5
- 206010052779 Transplant rejections Diseases 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 42
- 230000001684 chronic effect Effects 0.000 abstract description 13
- 210000000056 organ Anatomy 0.000 abstract description 11
- 125000000217 alkyl group Chemical group 0.000 abstract description 6
- 230000001154 acute effect Effects 0.000 abstract description 4
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 3
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 abstract description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 2
- 238000000034 method Methods 0.000 description 17
- 239000003018 immunosuppressive agent Substances 0.000 description 8
- 229960003444 immunosuppressant agent Drugs 0.000 description 7
- 230000001861 immunosuppressant effect Effects 0.000 description 7
- 206010059245 Angiopathy Diseases 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 238000002054 transplantation Methods 0.000 description 6
- 238000002689 xenotransplantation Methods 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000000890 drug combination Substances 0.000 description 5
- 210000002216 heart Anatomy 0.000 description 5
- 210000003734 kidney Anatomy 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 4
- 108010036949 Cyclosporine Proteins 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 229960001265 ciclosporin Drugs 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical group 0.000 description 4
- 230000036039 immunity Effects 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 210000001541 thymus gland Anatomy 0.000 description 4
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 241000699800 Cricetinae Species 0.000 description 3
- 229930105110 Cyclosporin A Natural products 0.000 description 3
- 206010020880 Hypertrophy Diseases 0.000 description 3
- 241001597008 Nomeidae Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 230000002612 cardiopulmonary effect Effects 0.000 description 3
- 210000001715 carotid artery Anatomy 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000002354 daily effect Effects 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 229960004866 mycophenolate mofetil Drugs 0.000 description 3
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 3
- 210000000496 pancreas Anatomy 0.000 description 3
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical class C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- 101150013553 CD40 gene Proteins 0.000 description 2
- 206010010356 Congenital anomaly Diseases 0.000 description 2
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 2
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 2
- 101001063392 Homo sapiens Lymphocyte function-associated antigen 3 Proteins 0.000 description 2
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 2
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 2
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 description 2
- 102100030984 Lymphocyte function-associated antigen 3 Human genes 0.000 description 2
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 2
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 2
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- PHEZJEYUWHETKO-UHFFFAOYSA-N brequinar Chemical compound N1=C2C=CC(F)=CC2=C(C(O)=O)C(C)=C1C(C=C1)=CC=C1C1=CC=CC=C1F PHEZJEYUWHETKO-UHFFFAOYSA-N 0.000 description 2
- 229950010231 brequinar Drugs 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 229930182912 cyclosporin Natural products 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000003038 endothelium Anatomy 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000008102 immune modulation Effects 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229960000951 mycophenolic acid Drugs 0.000 description 2
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 125000003884 phenylalkyl group Chemical group 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ZMKGDQSIRSGUDJ-VSROPUKISA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-30-propyl-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,1 Chemical compound CCC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O ZMKGDQSIRSGUDJ-VSROPUKISA-N 0.000 description 1
- IDINUJSAMVOPCM-UHFFFAOYSA-N 15-Deoxyspergualin Natural products NCCCNCCCCNC(=O)C(O)NC(=O)CCCCCCN=C(N)N IDINUJSAMVOPCM-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 101000729818 Bacillus licheniformis Glutamate racemase Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102000000989 Complement System Proteins Human genes 0.000 description 1
- 108010069112 Complement System Proteins Proteins 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 206010014144 Ectopia cordis Diseases 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- 241000699673 Mesocricetus auratus Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- HZQDCMWJEBCWBR-UUOKFMHZSA-N Mizoribine Chemical compound OC1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 HZQDCMWJEBCWBR-UUOKFMHZSA-N 0.000 description 1
- ZMKGDQSIRSGUDJ-UHFFFAOYSA-N NVa2 cyclosporine Natural products CCCC1NC(=O)C(C(O)C(C)CC=CC)N(C)C(=O)C(C(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(C)NC(=O)C(C)NC(=O)C(CC(C)C)N(C)C(=O)C(C(C)C)NC(=O)C(CC(C)C)N(C)C(=O)CN(C)C1=O ZMKGDQSIRSGUDJ-UHFFFAOYSA-N 0.000 description 1
- 208000034827 Neointima Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000013275 Somatomedins Human genes 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- HOBWAPHTEJGALG-JKCMADFCSA-N [(1r,5s)-8-methyl-8-azoniabicyclo[3.2.1]octan-3-yl] 3-hydroxy-2-phenylpropanoate;sulfate Chemical compound [O-]S([O-])(=O)=O.C([C@H]1CC[C@@H](C2)[NH+]1C)C2OC(=O)C(CO)C1=CC=CC=C1.C([C@H]1CC[C@@H](C2)[NH+]1C)C2OC(=O)C(CO)C1=CC=CC=C1 HOBWAPHTEJGALG-JKCMADFCSA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003872 anastomosis Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 229960002028 atropine sulfate Drugs 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000024203 complement activation Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 108010019249 cyclosporin G Proteins 0.000 description 1
- 230000001461 cytolytic effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 201000005577 familial hyperlipidemia Diseases 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 229940124589 immunosuppressive drug Drugs 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000009399 inbreeding Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000008069 intimal proliferation Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000007257 malfunction Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229950000844 mizoribine Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 238000007491 morphometric analysis Methods 0.000 description 1
- 210000000107 myocyte Anatomy 0.000 description 1
- BLUYEPLOXLPVCJ-INIZCTEOSA-N n-[(1s)-2-[4-(3-aminopropylamino)butylamino]-1-hydroxyethyl]-7-(diaminomethylideneamino)heptanamide Chemical compound NCCCNCCCCNC[C@H](O)NC(=O)CCCCCCNC(N)=N BLUYEPLOXLPVCJ-INIZCTEOSA-N 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000002560 nonimmunologic effect Effects 0.000 description 1
- 238000011889 obduction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 238000002559 palpation Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 210000001147 pulmonary artery Anatomy 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000008458 response to injury Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 210000001625 seminal vesicle Anatomy 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 231100000216 vascular lesion Toxicity 0.000 description 1
- 201000010653 vesiculitis Diseases 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005303 weighing Methods 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
- A61K31/13—Amines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/131—Amines acyclic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/133—Amines having hydroxy groups, e.g. sphingosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- 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
-
- 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
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Mycology (AREA)
- Emergency Medicine (AREA)
- Microbiology (AREA)
- Transplantation (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Polyurethanes Or Polyureas (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Peptides Or Proteins (AREA)
- Light Receiving Elements (AREA)
Abstract
本发明涉及式(I)化合物在预防或治疗器官或组织同种移植或异种移植接受者的慢性排斥反应，或异种移植接受者的急性排斥反应中的应用，其中R1是任选被取代的含有12至22个碳原子的直链或支链碳链，它可以任选被一个任选取代的亚苯基间断；和各R2、R3、R4和R5独立地为H或低级烷基，所述化合物为游离形式或可药用盐的形式。
Description
本发明申请是申请号为97199858.2、申请日为1997年11月17日、发明名称为“1，3-丙二醇衍生物的新用途”的专利申请的分案申请。
技术领域
本发明涉及一组包括2-氨基-1，3-丙二醇衍生物在内的化合物的新用途。
适用于本发明的化合物是式I所示化合物：
其中，
R1是任选被取代的含有12至22个碳原子的直链或支链碳链，它可以任选被一个任选取代的亚苯基间断；和各R2、R3、R4和R5独立地为H或低级烷基，所述化合物为游离形式或可药用盐的形式。
当作为R1的碳链被取代时，优选它被卤素、硝基、氨基、羟基或羧基取代。当该碳链被一个任选取代的亚苯基间断时，优选该碳链是未取代碳链。当亚苯基部分被取代时，优选它被卤素、硝基、氨基、甲氧基、羟基或羧基取代。
背景技术
这些化合物公开在EP-A1-627,406中，该文献的相关内容，尤其是与此类化合物有关的部分均在此引入作为参考。
发明内容
优选的式I化合物是那些其中R1为含有13至20个碳原子的直链或支链，优选直链的烷基并且该烷基可任选被硝基、卤素、氨基、羟基或羧基取代的化合物，更优选的化合物是那些其中R1为苯基烷基且该苯基烷基被任选由卤素取代的直链或支链C6-14烷基链所取代并且所述烷基部分是任选被羟基取代的C1-6烷基的化合物。更可取的是，R1是苯基-C1-6烷基并且该苯基上取代有直链或支链，优选直链的C6-14烷基链。所述C6-14烷基链可处于该苯基的邻位、间位或对位，优选位于对位。
各R2至R5优选是H。
式(I)化合物的可药用盐的例子包括与无机酸形成的盐，例如盐酸盐、氢溴酸盐和硫酸盐；与有机酸形成的盐，例如乙酸盐、富马酸盐、马来酸盐、苯甲酸盐、柠檬酸盐、苹果酸盐、甲磺酸盐和苯磺酸盐；当有羧基存在时，其与金属，例如钠、钾、钙和铝所形成的盐，与胺，例如三乙胺所成的盐，与二价氨基酸，例如赖氨酸所成的盐。本发明所述化合物及盐包括水合物和溶剂化物形式。
当式I化合物的分子内含有一个或多个不对称中心时，应将本发明理解为包括各种旋光异构体，也包括外消旋体、非对映异构体及其混合物。
更优选的式I化合物是2-氨基-2-十四烷基-1，3-丙二醇和特别优选的是2-氨基-2-[2-(4-辛基苯基)乙基]-1，3-丙二醇(此后称作化合物A)，它们可以是盐酸盐形式。
基于在例如EP-A1-627,406中所观测到的活性，发现式I化合物在例如急性同种移植物排斥反应的治疗中用作例如免疫抑制剂。
肝脏、肾脏、肺和心脏的器官移植现已正式成为晚期器官疾病的治疗方法。同种移植和异种移植均已被实现。然而，因为存在长期慢性排斥反应的问题，器官移植术仍未能成为不可逆性器官疾病的永久解决方案。在手术后第一年的一些病案中，慢性排斥反应是器官移植失败的主要原因，它表现为进行性和不可逆性的移植物机能障碍。慢性排斥反应的临床问题可以从移植存活时间明显看出；约半数的肾脏同种移植在移植术后5年内失败，在心脏同种移植的患者中可观察到类似结果。
慢性排斥反应被认为是一种多因性过程，其中不但对移植物的免疫反应，而且移植器官内的血管壁对损伤的反应(“损伤应答”(response-to-injury)反应)也发挥着作用。最坏预后时的慢性排斥反应是一种动脉硬化样变化，也称作移植血管病、移植物血管疾病、移植物动脉粥样硬化、移植物冠状疾病等。这种血管损害的特征是平滑肌细胞在生长因子的影响下发生迁移和增殖，其中这些因子由内皮合成。也可能通过其中的宿主抗体或抗原-抗体复合物所诱发的内皮反复损伤，通过内膜增殖和加厚，平滑肌细胞的肥大修复而发生，并且最终使腔体逐渐闭塞。所谓的非免疫因素如高血压、高脂血、血胆甾醇过多等也起作用。
因为没有已知有效的治疗或预防方法，慢性排斥反应看来既无情亦失控。因此，始终存在对有效预防、控制或逆转慢性移植物血管疾病指征的处理方法的需求。
根据本发明，现已令人惊奇地发现游离形式或可药用盐形式的式I化合物可以抑制移植物血管疾病，尤其是预防或治疗移植器官中的慢性排斥反应。
此外还发现，游离形式或可药用盐形式的式I化合物抑制异种移植排斥反应。
根据本发明的特殊发现，提供了：
1.1.一种预防或治疗器官或组织同种移植或异种移植接受者中的慢性排斥症状的方法，所述预防或治疗例如是避免、减轻或限制慢性排斥反应，所述同种-或异种-移植例如是心脏、肺、心肺联合、肝脏、肾脏或胰腺的移植，该方法包括给所述接受者施用治疗有效量的游离形式或可药用盐形式的式I化合物的步骤；
1.2.一种预防或治疗器官或组织同种-或异种-移植接受者中的移植物血管疾病的方法，所述移植物血管疾病例如是移植血管病、动脉硬化或动脉粥样硬化，所述同种-或异种-移植例如是心脏、肺、心肺联合、肝脏、肾脏或胰腺的移植，该方法包括给所述接受者施用治疗有效量的游离形式或可药用盐形式的式I化合物的步骤。
在其它一系列特定或变化的实施例中，本发明也提供了：
2.一种预防或控制异种移植接受者的急性排斥反应的方法，所述异种移植接受者例如是接受心脏、肺、合并性心肺、肾脏、肝脏、骨髓、胰腺肠(pancreatic bowel)、皮肤或角膜异种移植的患者，该方法包括给所述接受者施用治疗有效量的游离形式或可药用盐形式的式I化合物。
作为另外的变化，本发明还提供了：
3.游离形式或可药用盐形式的式I化合物在上述1或2所定义任一方法中的应用；或
4.游离形式或可药用盐形式的式I化合物在制备用于上述1或2所定义任一方法的药物组合物中的应用；或
5.一种用于上述1或2所定义任一方法的药物组合物，该药物组合物包含游离形式或可药用盐形式的式I化合物以及一种或多种可药用稀释剂或载体。
具体实施方式
游离形式或可药用盐形式的式I化合物在慢性排斥反应中的有效性以及在治疗前面具体指出的疾病和症状中的有效性可在动物试验(例如按照下列方法)中以及在临床科学(例如对移植的器官或组织进行定时活组织检查对照以及在心脏移植术的情况中进行超声扫描)中得到证实。
A.移植物血管疾病的预防
试验动物
试验采用重量在200至350g之间的近交大鼠品系DA(RT1a，供给体)和Lewis(RT11，同种移植物的接受者)。动物在手术前后均可自由地获取食物和水。
颈动脉移植术：
大鼠用异氟烷(Abbott)麻醉(4-5％诱导麻醉，1.5-2％维持麻醉)，并且在诱导后将300μg硫酸阿托品皮下注射。分割出左颈动脉。将该动脉在近侧和远侧夹住并且取出约7至10毫米的节段。开口用一个同种移植物桥接，并且该同种移植物接受了45分钟的冷缺血处理。采用Ethilon10/o缝合线。最后用4/o缝合线将皮肤缝合。若需要，随后可将Alzet渗透微泵(Alza Corp.Palo Alto，Calif.)皮下植入背部内(或者动物被口服处理)。
使大鼠接受下列处理中的一种：式I化合物以0.1至10mg/kg的剂量单独或与剂量为0.03、0.3或1mg/kg/天的环孢菌素A合并给药8周，这些给药既可利用皮下植入的Alzet渗透微泵也可口服给药。在8周时将大鼠处死，用0.1M的磷酸盐缓冲盐水溶液(PBS，pH7.4)将颈动脉灌注1分钟，随后用含2.5％戊二醛的磷酸盐缓冲液(pH7.4)灌注15分钟。随后切除颈动脉并用吉姆萨溶液染色以进行组织学评估。
形态测定分析法包括测定血管中层及内膜的厚度。形态学变化的定性分析包括以0-3的等级对单核细胞的外膜浸润和坏死(空泡变性、细胞肥大)、平滑肌细胞(SMC)核在血管中层中的数目(0-10、＜100、＞100和＞＞100个核分别是0、1、2和3的评分值)、SMC坏死(空泡变形和SMC肥大)和单核细胞的内膜浸润(13)进行评分。
在两个试验中，式I化合物，尤其是盐酸盐形式的化合物A极其显著地抑制了移植物浸润和新内膜形成。
B.体内心脏异种移植术(仓鼠-至-大鼠)
将仓鼠器官移植到大鼠体内的异种移植物结合是所谓的难于一致的结合。大鼠不具有足够量的先天性抗仓鼠抗体用于产生在一致性结合中所观察到的即发型超急性排斥反应。然而，未处理的接受者在3至4天内出现排斥反应，这是因为抗体与补体相结合。其在组织学方面表现为血管破坏、红细胞的渗出和外渗以及多形核粒细胞的流入；也经常出现出血和血栓形成的指征。一旦这种排斥反应通过有效抑制抗体合成或补体失活加以克服，细胞排斥的出现可被推迟。这在组织学方面表现为单核细胞(淋巴细胞、类淋巴母细胞和巨噬细胞)流入和肌细胞实质的破坏。对细胞排斥反应的抑制需要比抑制同种移植更强的免疫抑制作用。先天无胸腺(rnu/rnu)大鼠缺乏一种有效的(胸腺依赖型)细胞免疫系统，而且一般不能对同种移植物产生排斥。此类动物却在3至4天内对仓鼠异种移植产生与胸腺机能正常大鼠相似方式的排斥反应，这表明大鼠中(至少一部分)抗仓鼠抗体的合成在非胸腺依赖型B-细胞反应后出现。这些接受者可用于仓鼠异种移植，以由非胸腺依赖型抗体介导的排斥反应来评价排斥反应。
在供给者和接受者的主动脉之间以及供给者右肺动脉与接受者下腔静脉之间进行吻合术，从而将Syrian仓鼠的心脏异位移植到雄性Lewis(RT1’)大鼠的腹腔内。每天通过腹腔触诊对移植物进行监测。由心搏停止推断出发生的排斥反应。每周称量动物的体重。在本发明的一系列试验中，将试验终点设定为28天。将试验动物作尸体解剖；取出移植物，对胸腺、脾、肝、精囊和睾丸的重量和组织学进行评估。取血并处理血清，测定其溶细胞性抗仓鼠红细胞抗体和溶血补体活性。
将化合物溶解在水中并以2ml/kg体重的体积每日口服给药。式I化合物，例如盐酸盐形式的化合物A以5至30mg/kg/天的方式给药，结果是使移植物在无胸腺大鼠和胸腺机能正常大鼠中的存活期均被延长。
实施本发明方法所需的日剂量将取决于所用的式I化合物、宿主、给药方式、被治疗症状的严重程度以及任选联合施用的免疫抑制药物(例如CysA)。优选的日剂量范围是约0.03至2.5mg/kg/天，更优选0.1至2.5mg/kg/天，例如以0.5至2.5mg/kg/天作为单剂量或分用剂量。适合患者的日剂量例如口服约1至100mg。口服给药的适当单位剂型含有约1至50mg，通常是5至30mg的活性组分(例如化合物A，如其盐酸盐形式)以及一种或多种可药用稀释剂或载体。此外，游离形式或可药用盐形式的式I化合物也可以例如上述剂量一周给药两次或三次。
式I化合物可通过常规途径给药，优选肠内给药，例如口服，如以饮用溶液、片剂或胶囊的形式；或非肠道给药，例如以可注射溶液或悬浮液的形式。含有式I化合物的药物组合物可以以常规方式制备，例如EP-A1-627,406所述。
式I化合物既可作为单独的活性组分给药，也可与其他免疫调制方案所用药物或其他抗炎剂合用。例如，可与式I化合物合用的是：环孢菌素类、雷怕霉素类或子囊霉素类或其免疫抑制类似物(例如环孢菌素A、环孢菌素G、FK-506、雷怕霉素、40-O-(2-羟基)乙基-雷怕霉素)等；皮质类甾醇；环磷酰胺；硫唑嘌呤；甲氨蝶呤；布喹那(brequinar)；来氟米物；咪唑立宾；麦考酚酸；麦考酚酸莫非替克(mycophenolate mofetil)；15-脱氧精胍菌素；免疫抑制单克隆抗体，例如白细胞受体的单克隆抗体，例如对MHC、CD2、CD3、CD4、CD7、CD25、CD28、B7、CD40、CD45或CD58或其配体的单克隆抗体；或其他免疫调制化合物，例如CTLA4-Ig。
当式I化合物的给药与其他免疫抑制/免疫调制治疗相结合以用于预防或治疗上述慢性排斥反应时，合并给药的免疫抑制剂或免疫调制化合物的剂量当然应取决于合用药物的类型(例如是甾类还是环孢菌素)、所用的具体药物、被治疗的症状等。本发明还提供了下列方面的内容：
6.一种如上所述的方法，该方法包括将治疗有效量的式I化合物与一种第二药用物质联合给药，例如同时或顺序给药，所述第二药用物质是免疫抑制剂或免疫调制药物，例如上述药物。
7.一种在上述1或2所定义任一方法中所使用的试剂盒或药包，它包括游离形式或可药用盐形式的式I化合物以及至少一种药物组合物，该药物组合物含有免疫抑制剂或免疫调制药物。该试剂盒或药包可以含有用药说明书。
更具体地说，本发明还涉及
1.游离形式或其药学上可接受的盐形式的2-氨基-2-[2-(4-辛基苯基)乙基]-1，3-丙二醇与雷帕霉素或40-O-(2-羟基)乙基-雷帕霉素的联合用药的用途。
2.游离形式或其药学上可接受的盐形式的2-氨基-2-[2-(4-辛基苯基)乙基]-1，3-丙二醇与麦考酚酸或麦考酚酸莫非替克的联合用药的用途。
3.游离形式或其药学上可接受的盐形式的2-氨基-2-[2-(4-辛基苯基)乙基]-1，3-丙二醇与对MHC、CD2、CD3、CD4、CD7、CD25、CD28、B7、CD40、CD45或CD58的单克隆抗体或这样的抗体的配体的单克隆抗体的联合用药的用途。
4.游离形式或其药学上可接受的盐形式的2-氨基-2-[2-(4-辛基苯基)乙基]-1，3-丙二醇与CTLA4-Ig的联合用药的用途。
制剂实施例：软胶囊
式I化合物 30mg
例如化合物A
聚乙二醇300 300mg
多乙氧基醚
8020mg
总量 350mg
根据本发明应用所需要的游离形式或可药用盐形式的式I化合物剂量可被很好地耐受。例如，在大鼠和猴子中的急性LD50＞10mg/kg口服。
Claims (1)
1.游离形式或其药学上可接受的盐形式的2-氨基-2-[2-(4-辛基苯基)乙基]-1，3-丙二醇用于制备预防或治疗移植排斥的药物的用途，所述药物与40-O-(2-羟基)乙基-雷帕霉素相联合给药。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9624038.7A GB9624038D0 (en) | 1996-11-19 | 1996-11-19 | Organic compounds |
| GB9624038.7 | 1996-11-19 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB971998582A Division CN1146411C (zh) | 1996-11-19 | 1997-11-17 | 1,3-丙二醇衍生物的新用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1515253A CN1515253A (zh) | 2004-07-28 |
| CN1293876C true CN1293876C (zh) | 2007-01-10 |
Family
ID=10803173
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100059961A Expired - Fee Related CN1293876C (zh) | 1996-11-19 | 1997-11-17 | 1，3－丙二醇衍生物的新用途 |
| CNB971998582A Expired - Fee Related CN1146411C (zh) | 1996-11-19 | 1997-11-17 | 1,3-丙二醇衍生物的新用途 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB971998582A Expired - Fee Related CN1146411C (zh) | 1996-11-19 | 1997-11-17 | 1,3-丙二醇衍生物的新用途 |
Country Status (25)
| Country | Link |
|---|---|
| US (3) | US6274629B1 (zh) |
| EP (2) | EP1312359B1 (zh) |
| JP (2) | JP4004070B2 (zh) |
| CN (2) | CN1293876C (zh) |
| AT (2) | ATE369846T1 (zh) |
| AU (1) | AU728420B2 (zh) |
| BR (1) | BR9713105A (zh) |
| CA (1) | CA2270952C (zh) |
| CZ (1) | CZ174999A3 (zh) |
| DE (2) | DE69738033T2 (zh) |
| DK (1) | DK1312359T3 (zh) |
| ES (2) | ES2227726T3 (zh) |
| GB (1) | GB9624038D0 (zh) |
| HK (1) | HK1022639A1 (zh) |
| HU (1) | HUP0000343A3 (zh) |
| ID (1) | ID21568A (zh) |
| IL (1) | IL129824A (zh) |
| NO (1) | NO992259L (zh) |
| NZ (1) | NZ335629A (zh) |
| PL (1) | PL190348B1 (zh) |
| PT (2) | PT1312359E (zh) |
| RU (1) | RU2217136C2 (zh) |
| SI (1) | SI1312359T1 (zh) |
| SK (1) | SK284806B6 (zh) |
| WO (1) | WO1998022100A2 (zh) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1129066B1 (en) | 1998-11-11 | 2005-02-02 | Novartis AG | Production of 2-amino-2- 2-(4-c 2-20?-alkyl-phenyl)ethyl]propane-1,3-diols |
| IL149792A0 (en) * | 1999-12-16 | 2002-11-10 | Teva Pharma | Novel processes for making and a new crystalline form of leflunomide |
| AU8533101A (en) | 2000-08-31 | 2002-03-13 | Merck & Co Inc | Phosphate derivatives as immunoregulatory agents |
| EP1368015B1 (en) * | 2001-02-22 | 2006-08-09 | Novartis AG | Use of accelerated lymphocyte homing agents for the manufacture of a medicament for the treatment of delayed graft function |
| EP1379547B1 (fr) * | 2001-04-20 | 2005-12-21 | Debiopharm S.A. | Cyclosporine modifiee utilisable en tant que pro-drogue et son utilisation |
| BR0209319A (pt) * | 2001-06-08 | 2004-07-20 | Novartis Ag | Tratamento ou profilaxia de rejeição de enxerto de célula produtora de insulina |
| GB0117921D0 (en) * | 2001-07-23 | 2001-09-12 | Novartis Ag | Organic compounds |
| US7780993B2 (en) * | 2001-09-07 | 2010-08-24 | Yeda Research And Development Co. Ltd. | Therapeutic transplantation using developing, human or porcine, renal or hepatic, grafts |
| US20040136972A1 (en) * | 2001-09-07 | 2004-07-15 | Yeda Research And Development Co. Ltd. | Methods of treating disease by transplantation of developing allogeneic or xenogeneic organs or tissues |
| GB0125443D0 (en) | 2001-10-23 | 2001-12-12 | Novartis Ag | Organic Compounds |
| BR0306811A (pt) | 2002-01-11 | 2004-10-26 | Sankyo Co | Composto, éster farmacologicamente aceitável do mesmo, composição farmacêutica e métodos para prevenção ou tratamento de doenças autoimunes, da artrite reumatóide e da rejeição causada pelo transplante de vários órgãos em um mamìfero |
| GB0217777D0 (en) * | 2002-07-31 | 2002-09-11 | Novartis Ag | Organic compounds |
| IL165425A0 (en) * | 2004-11-28 | 2006-01-15 | Yeda Res & Dev | Methods of treating disease by transplantation of developing allogeneic or xenogeneic organs or tissues |
| EP2769713A1 (en) | 2003-04-08 | 2014-08-27 | Novartis AG | Solid oral composition comprising a S1P receptor agonist and a sugar alcohol |
| EP1484057A1 (en) * | 2003-06-06 | 2004-12-08 | Aventis Pharma Deutschland GmbH | Use of 2-amino-1-3-propanediol derivatives for the manufacture of a medicament for the treatment of various types of pain |
| US7524887B2 (en) | 2003-06-06 | 2009-04-28 | Sanofi-Aventis Deutschland Gmbh | 2-amino-1,3-propanediol compounds for the treatment of acute pain |
| JP2007523858A (ja) * | 2003-06-24 | 2007-08-23 | ユニバーシティ オブ コネチカット | 血管透過性およびアポトーシスの阻害方法 |
| US7074659B2 (en) * | 2003-11-13 | 2006-07-11 | Volterra Semiconductor Corporation | Method of fabricating a lateral double-diffused MOSFET (LDMOS) transistor |
| WO2005079788A1 (ja) | 2004-02-24 | 2005-09-01 | Sankyo Company, Limited | アミノアルコール化合物 |
| PL1773307T3 (pl) * | 2004-07-30 | 2015-03-31 | Novartis Ag | Preparaty 2-amino-1,3-propanodioli i ich analogów |
| US8809304B2 (en) | 2005-12-15 | 2014-08-19 | Mitsubishi Tanabe Pharma Corporation | Amine compound and use thereof for medical purposes |
| AR085749A1 (es) | 2011-04-01 | 2013-10-23 | Novartis Ag | Formulaciones |
| RU2496486C1 (ru) | 2012-07-11 | 2013-10-27 | Александр Васильевич Иващенко | Фармацевтическая композиция с улучшенной сыпучестью, лекарственное средство, способ получения и применение |
| ES2964891T3 (es) * | 2013-03-05 | 2024-04-10 | Biocon Ltd | Un proceso para la preparación de compuestos de 2-amino-1,3-propanodiol y sales de los mismos |
| EA201890477A1 (ru) | 2015-09-18 | 2018-08-31 | Сановел Иладж Санайи Ве Тиджарет А.С. | Инкапсулированная композиция финголимода |
| CN115477590B (zh) * | 2021-05-31 | 2023-12-12 | 上海云晟研新生物科技有限公司 | 芬戈莫德药用盐、制备方法、含其的药物组合物及应用 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0627406A1 (en) * | 1992-10-21 | 1994-12-07 | Yoshitomi Pharmaceutical Industries, Ltd. | 2-amino-1,3-propanediol compound and immunosuppressant |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3904679A (en) * | 1972-05-23 | 1975-09-09 | Upjohn Co | 15-Methyl and 15-ethyl prostaglandin F{HD 2{331 {0 {B analogs |
| US6136310A (en) * | 1991-07-25 | 2000-10-24 | Idec Pharmaceuticals Corporation | Recombinant anti-CD4 antibodies for human therapy |
| WO1993002108A1 (en) * | 1991-07-25 | 1993-02-04 | Idec Pharmaceuticals Corporation | Recombinant antibodies for human therapy |
| US5747034A (en) * | 1992-07-09 | 1998-05-05 | Chiron Corporation | Methods and materials for the induction of T cell anergy |
| GB9221220D0 (en) * | 1992-10-09 | 1992-11-25 | Sandoz Ag | Organic componds |
| CA2213989C (en) | 1995-12-28 | 2007-05-29 | Yoshitomi Pharmaceutical Industries Ltd. | External preparation for topical administration |
| JP2002241272A (ja) * | 1996-07-18 | 2002-08-28 | Mitsubishi Pharma Corp | 医薬処方組成物 |
| US6476004B1 (en) * | 1996-07-18 | 2002-11-05 | Mitsubishi Pharma Corporation | Pharmaceutical composition |
| EP0990440B1 (en) * | 1997-02-27 | 2008-10-29 | Novartis AG | Pharmaceutical composition comprising 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, a lecithin and a saccharide |
-
1996
- 1996-11-19 GB GBGB9624038.7A patent/GB9624038D0/en active Pending
-
1997
- 1997-11-17 PT PT02025422T patent/PT1312359E/pt unknown
- 1997-11-17 BR BR9713105-9A patent/BR9713105A/pt not_active Application Discontinuation
- 1997-11-17 RU RU99112577/14A patent/RU2217136C2/ru not_active IP Right Cessation
- 1997-11-17 PT PT97951219T patent/PT941082E/pt unknown
- 1997-11-17 JP JP52320098A patent/JP4004070B2/ja not_active Expired - Fee Related
- 1997-11-17 CN CNB2004100059961A patent/CN1293876C/zh not_active Expired - Fee Related
- 1997-11-17 CZ CZ991749A patent/CZ174999A3/cs unknown
- 1997-11-17 SK SK659-99A patent/SK284806B6/sk unknown
- 1997-11-17 EP EP02025422A patent/EP1312359B1/en not_active Expired - Lifetime
- 1997-11-17 CA CA002270952A patent/CA2270952C/en not_active Expired - Fee Related
- 1997-11-17 CN CNB971998582A patent/CN1146411C/zh not_active Expired - Fee Related
- 1997-11-17 NZ NZ335629A patent/NZ335629A/en unknown
- 1997-11-17 AU AU54831/98A patent/AU728420B2/en not_active Ceased
- 1997-11-17 AT AT02025422T patent/ATE369846T1/de not_active IP Right Cessation
- 1997-11-17 IL IL12982497A patent/IL129824A/xx not_active IP Right Cessation
- 1997-11-17 WO PCT/EP1997/006408 patent/WO1998022100A2/en not_active Application Discontinuation
- 1997-11-17 ES ES97951219T patent/ES2227726T3/es not_active Expired - Lifetime
- 1997-11-17 EP EP97951219A patent/EP0941082B1/en not_active Expired - Lifetime
- 1997-11-17 AT AT97951219T patent/ATE275947T1/de not_active IP Right Cessation
- 1997-11-17 ID IDW990370A patent/ID21568A/id unknown
- 1997-11-17 DE DE69738033T patent/DE69738033T2/de not_active Expired - Fee Related
- 1997-11-17 PL PL97333463A patent/PL190348B1/pl not_active IP Right Cessation
- 1997-11-17 SI SI9730772T patent/SI1312359T1/sl unknown
- 1997-11-17 DK DK02025422T patent/DK1312359T3/da active
- 1997-11-17 US US09/308,098 patent/US6274629B1/en not_active Expired - Lifetime
- 1997-11-17 HU HU0000343A patent/HUP0000343A3/hu unknown
- 1997-11-17 ES ES02025422T patent/ES2289041T3/es not_active Expired - Lifetime
- 1997-11-17 DE DE69730727T patent/DE69730727T2/de not_active Expired - Fee Related
-
1999
- 1999-05-10 NO NO992259A patent/NO992259L/no unknown
-
2000
- 2000-03-10 HK HK00101496A patent/HK1022639A1/xx not_active IP Right Cessation
-
2001
- 2001-07-03 US US09/898,143 patent/US6486209B2/en not_active Expired - Fee Related
-
2002
- 2002-09-30 US US10/261,536 patent/US20030069315A1/en not_active Abandoned
-
2004
- 2004-05-21 JP JP2004152002A patent/JP2004256554A/ja active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0627406A1 (en) * | 1992-10-21 | 1994-12-07 | Yoshitomi Pharmaceutical Industries, Ltd. | 2-amino-1,3-propanediol compound and immunosuppressant |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1293876C (zh) | 1，3－丙二醇衍生物的新用途 | |
| CN1124135C (zh) | 雷帕霉素衍生物在血管病和异种移植中的应用 | |
| CN1468111A (zh) | 治疗急性、慢性疼痛和/或神经病性疼痛和偏头痛的药物组合物 | |
| JPH10316567A (ja) | 過敏性腸症候群の症状の治療用のｎｋ−１受容体アンタゴニスト | |
| US20080015261A1 (en) | Use of accelerated lymphocyte homing agents for the manufacture of a medicament for the treatment of delayed graft function | |
| JP2019515926A (ja) | 長期寛容を誘導するためのおよびアテローム性動脈硬化症におけるマクロファージ蓄積を解決するための自然免疫システムの標的化 | |
| US20080286281A1 (en) | Cd25 binding molecules for the use in the treatment of manifestations of rejection in transplantation | |
| US20020193562A1 (en) | Hydroxamic acid containing compounds useful as ace inhibitors and / or nep inhibitors | |
| US20240197816A1 (en) | Composition and method for prolong survival of transplant and recipient | |
| Costanzo-Nordin et al. | Task Force 6: future developments | |
| US20030073737A1 (en) | Tolerance induction | |
| KR20070022241A (ko) | 자가 면역 질환 및 이식 거부반응의 치료를 위한 단백질키나제 ｃ 억제제 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20070110 Termination date: 20091217 |