CN1370161A - 新的季铵化合物,其制备方法和其药物用途 - Google Patents
新的季铵化合物,其制备方法和其药物用途 Download PDFInfo
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- CN1370161A CN1370161A CN00809380A CN00809380A CN1370161A CN 1370161 A CN1370161 A CN 1370161A CN 00809380 A CN00809380 A CN 00809380A CN 00809380 A CN00809380 A CN 00809380A CN 1370161 A CN1370161 A CN 1370161A
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- 238000000034 method Methods 0.000 title claims description 7
- 150000003856 quaternary ammonium compounds Chemical class 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 101
- 125000005843 halogen group Chemical group 0.000 claims abstract description 22
- 210000000845 cartilage Anatomy 0.000 claims abstract description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 16
- -1 haloalkyl ammonium halide Chemical class 0.000 claims description 15
- 230000000694 effects Effects 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 10
- 206010007710 Cartilage injury Diseases 0.000 claims description 8
- 125000001118 alkylidene group Chemical group 0.000 claims description 6
- 150000002337 glycosamines Chemical class 0.000 claims description 5
- 229960001924 melphalan Drugs 0.000 claims description 5
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 claims description 5
- 229960002702 piroxicam Drugs 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 150000001263 acyl chlorides Chemical class 0.000 claims description 4
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims description 4
- 229960004630 chlorambucil Drugs 0.000 claims description 4
- 125000000524 functional group Chemical group 0.000 claims description 4
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims description 4
- 239000012026 peptide coupling reagents Substances 0.000 claims description 4
- 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 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 159000000000 sodium salts Chemical class 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000010306 acid treatment Methods 0.000 claims description 2
- 239000000730 antalgic agent Substances 0.000 claims description 2
- 230000002456 anti-arthritic effect Effects 0.000 claims description 2
- 229940041181 antineoplastic drug Drugs 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 2
- 206010061762 Chondropathy Diseases 0.000 claims 1
- 125000003277 amino group Chemical group 0.000 claims 1
- 208000015100 cartilage disease Diseases 0.000 claims 1
- 208000030159 metabolic disease Diseases 0.000 claims 1
- 229910052713 technetium Inorganic materials 0.000 claims 1
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 5
- 238000003745 diagnosis Methods 0.000 abstract 2
- 230000007170 pathology Effects 0.000 abstract 2
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 abstract 1
- 125000000623 heterocyclic group Chemical group 0.000 abstract 1
- 125000004430 oxygen atom Chemical group O* 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 239000000047 product Substances 0.000 description 21
- 238000005406 washing Methods 0.000 description 11
- 238000009834 vaporization Methods 0.000 description 10
- 238000001914 filtration Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000000354 decomposition reaction Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 238000001556 precipitation Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical class IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 125000002435 L-phenylalanyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- IUNMPGNGSSIWFP-UHFFFAOYSA-N dimethylaminopropylamine Chemical compound CN(C)CCCN IUNMPGNGSSIWFP-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000010415 tropism Effects 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical class CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QDEOUJHRROHPHD-UHFFFAOYSA-N [I-].[NH4+].C[NH+](C)C.[I-] Chemical compound [I-].[NH4+].C[NH+](C)C.[I-] QDEOUJHRROHPHD-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000011097 chromatography purification Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000007306 functionalization reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 229960003676 tenidap Drugs 0.000 description 2
- LXIKEPCNDFVJKC-QXMHVHEDSA-N tenidap Chemical compound C12=CC(Cl)=CC=C2N(C(=O)N)C(=O)\C1=C(/O)C1=CC=CS1 LXIKEPCNDFVJKC-QXMHVHEDSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- XZXYQEHISUMZAT-UHFFFAOYSA-N 2-[(2-hydroxy-5-methylphenyl)methyl]-4-methylphenol Chemical compound CC1=CC=C(O)C(CC=2C(=CC=C(C)C=2)O)=C1 XZXYQEHISUMZAT-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical class ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical class C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010039361 Sacroiliitis Diseases 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 229940107816 ammonium iodide Drugs 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000002975 chemoattractant Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000012502 diagnostic product Substances 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 231100000226 haematotoxicity Toxicity 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910000474 mercury oxide Inorganic materials 0.000 description 1
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012306 spectroscopic technique Methods 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical class CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- SZYJELPVAFJOGJ-UHFFFAOYSA-N trimethylamine hydrochloride Chemical compound Cl.CN(C)C SZYJELPVAFJOGJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D259/00—Heterocyclic compounds containing rings having more than four nitrogen atoms as the only ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
- C07F13/005—Compounds without a metal-carbon linkage
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
- C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
- C07H5/06—Aminosugars
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S436/00—Chemistry: analytical and immunological testing
- Y10S436/811—Test for named disease, body condition or organ function
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Saccharide Compounds (AREA)
- Cephalosporin Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明涉及通式(Ia)或(Ib)的化合物,其中:M代表可以用于治疗或诊断因软骨损伤而引起的病症的分子;R1,R2和R3代表烷基基团,或R1,R2和R3与携带它们的氮原子一起形成杂环;X代表(C1-C6)亚烷基链,其中一个或多个-CH2-基团任选地被硫原子,氧原子,或-NR-,-CO-,-CO-NH-,-CO2-,-SO-或-SO2基团替代;n代表0或1;Hal代表卤素原子,或通式(Ib);R4代表烷基基团;Hal代表卤素原子。通式(F1)代表可以用于治疗或诊断因软骨损伤而引起的病症的分子,其中氮原子可以任选地包括在饱和或不饱和的含氮杂环系统中,或包括在双键中。
Description
本发明涉及新的季铵化合物,它们的制备方法和含有它们的药物组合物。
新的季铵化合物使活性成分能够在软骨组织中向量化,所以能够治疗因软骨损伤而引起的病症,不管它们是关节性的或癌性的病症。这些新季铵化合物也可以用作诊断试剂,能够例如揭示软骨或代谢的病症(放射性标记,染色标记等)。
目前可购买得到的治疗关节病症如关节炎或骨关节炎的治疗剂通常对靶组织的亲和力低,并且需要高剂量给药才能达到所期望的治疗效果。
给予这样高剂量的活性成分会引起副作用出现率的增加。例如,已知给予非甾类抗炎剂会引起明显的消化毒性。
在骨癌学领域,已知目前用于治疗软膏肉瘤病的治疗剂同样会产生不良的副作用,特别是毒性,例如血液学或非血液学的毒性。
最后,在软骨病症的诊断产品领域中,目前所用产品的缺点是缺乏对目标靶的特异性。
所以,一直特别令人感兴趣的是使那些不同种类的化合物能够特异地靶向软骨组织,从而限制,或者甚至抑制直接给予这类化合物时所观察到的不良的副作用。
构成本发明主题的新化合物使通过提高向性和通过降低给药剂量明显减弱副作用和增强活性分子的治疗指数成为可能。
其中:
M代表可以用于治疗或诊断因软骨损伤而引起的病症的分子,
R1,R2和R3可以是相同或不同的,代表直链或支链的(C1-C6)烷基基团,
或R1,R2和R3与携带它们的氮原子一起形成饱和或不饱和含氮杂环,
X代表直链或支链(C1-C6)亚烷基链,其中一个或多个-CH2-基团任选地被硫原子,氧原子,-NR-基团(其中R代表直链或支链(C1-C6)烷基基团),-CO基团,-CO-NH-基团,-CO2-基团,-SO-基团或-SO2-基团替代,
n代表0或1,
Hal代表卤原子,或R4代表直链或支链(C1-C6)烷基基团,Hal代表卤素原子,代表可以用于治疗或诊断因软骨损伤而引起的病症的分子,其中氮原子可以任选地包括在饱和或不饱和含氮杂环系统中,或包括在双键中。
优选地,通式(Ia)的化合物是如下的化合物:其中n是1,X代表直链或支链(C1-C6)亚烷基链,基团-NR-(CH2)m-(其中R如上文中所定义),基团-CO-(CH2)m-,或基团-CO-NH-(CH2)m,其中m表示1到5的整数。
通式(Ia)的化合物中的R1,R2和R3优选地是相同或不同的,直链或支链(C1-C6)烷基基团或,与携带它们的氮原子一起,形成吡啶或哌啶环(其中那些基团之一是直链或支链(C1-C6)烷基基团)。可以用于治疗或诊断因软骨损伤而引起的病症的分子M或
更具体地是抗炎药,抗关节炎药,抗骨关节炎药,镇痛药,或特定的抗肿瘤药。
用作活性成分的优选的通式(Ia)的化合物是:×从通式(Ia1)的替尼达普衍生的分子:其中:X1代表直链或支链(C1-C6)亚烷基基团,R’1,R’2和R’3可以是相同或不同的,代表直链或支链(C1-C6)烷基基团,Hal代表卤素原子,×从通式(Ia2)的苯丙氨酸氮芥衍生的分子:其中:X2代表-NH-(CH2)m-,其中m如上文所定义,R’1,R’2,和R’3如上文所定义,Hal代表卤素原子,×从通式(Ia3)的苯丁酸氮芥衍生的分子:其中:X2,R’1,R’2和R’3如上文所定义,Hal代表卤素原子,×从通式(Ia4)的葡糖胺衍生的分子:其中:X4代表-CO-(CH2)m-,其中m如上文所定义,R1,R2和R3如上文所定义,Hal代表卤素原子。
本发明还涉及通式(Ia)或(Ib)的化合物的制备方法。
按照有机化学的常规方法,通过根据所需要的X基团的性质,以一步或多步反应使通式M-P的化合物(其中M如通式(Ia)中定义,P代表氢原子或羟基基团)或通式M-P的化合物的前体功能化形成最终的通式(Ia)的化合物所必需的反应,获得通式(Ia)的化合物。通过烷基卤与如上文所定义的通式
的化合物反应得到通式(Ib)的化合物。
衍生于上文所定义的通式(Ia1)的替尼达普的分子是通过如下步骤得到的:使5-氯-2,3-二氢-2-氧代-1H-吲哚-1-羧酸4-硝基苯基酯与通式(II)的胺反应:其中X1,R’1和R’2如上文所定义,得到通式(III)的化合物:其中X1,R’1和R’2如上文所定义,在惰性气氛下,在碱性介质中使通式(III)的化合物受到2-噻吩甲酰氯的作用,然后用酸处理,得到通式(IV)的化合物:将通式(IV)的化合物转化成相应的钠盐,然后使其受到直链或支链(C1-C6)烷基卤(R’3Hal)的作用得到通式(V)的化合物:通式(V)的化合物在盐酸介质中生成通式(Ia1)的化合物,如果必要,将其纯化。
从上文所定义的通式(Ia2)的苯丙氨酸氮芥衍生的分子是通过如下步骤得到的:从苯丙氨酸氮芥开始,其氨基官能团已经预先被叔丁氧羰基(Boc)保护起来,在肽偶联试剂的存在下使用通式(VI)的胺:其中R’1,R’2和m如上文所定义,得到通式(VII)的化合物:其中m,R’1和R’2如上文所定义,使通式(VII)的化合物受到直链或支链(C1-C6)烷基卤的作用,然后用HCl处理,得到通式(Ia2)的化合物,如果必要,将其纯化。
从上文所定义的通式(Ia3)的苯丁酸氮芥衍生的分子是通过如下步骤得到的:从苯丁酸氮芥开始,其酸官能团被转化成酰氯,在存在或缺乏肽偶联试剂的情况下使其与通式(VI)的胺反应:其中R’1,R’2和m如上文所定义,得到通式(VIII)的化合物:其中m,R’1和R’2如上文所定义,使通式(VIII)的化合物受到直链或支链(C1-C6)烷基卤的作用,得到通式(Ia2)的化合物,如果必要,将其纯化。
从上文所定义的通式(Ia4)的葡糖胺衍生的分子是通过下面的步骤得到的:将葡糖胺与通式(IX)的酰氯反应:
Cl-(CH2)m-CO-Cl (IX)得到通式(X)的化合物:其中m如上文所定义,使通式(X)的化合物与通式(XI)的胺缩合:其中R1,R2和R3如上文所定义,得到通式(Ia4)的化合物,如果必要,将其纯化,并且任选地根据常规分离技术将其分离成它的异构体。
上文所定义的通式(Ia5)的分子是通过下面的步骤得到的:从通式(XII)的化合物开始:使其与通式(XIII)的卤代烷基铵卤化物反应:其中X1,R1,R2和R3如上文所定义,Hal和Hal1可以相同或不同,代表卤素原子,得到通式(XIV)的化合物:其中X1,R1,R2,R3和Hal如上文所定义,在氯化锡存在下使通式(XIV)的化合物与高锝酸钠反应,得到通式(Ia5)的化合物,如果必要,将其纯化。
从上文所定义的通式(Ib1)的吡氧噻嗪衍生的分子是如下得到的:从吡氧噻嗪开始,使其与直链或支链(C1-C6)烷基卤反应,如果必要,将得到的化合物纯化。
上文所定义的通式(Ib2)的分子是如下得到的:从相应的胺开始,使其与直链或支链(C1-C6)烷基卤反应,如果必要,将得到的化合物纯化。
在生物学研究中,已经证明本发明的化合物对软骨组织的向性增加。通过季铵官能团功能化的那些分子因与非功能化分子非常不同的药物性能而进一步得到区别。
例如,直到给药后一小时,在软骨中观察到更高的浓度。
本发明还涉及含有至少一种通式(I)的化合物作为活性成分和一种或多种适当的惰性,非毒性赋形剂的药物组合物。在本发明的药物组合物中,可以更具体地提到的是适于口服,肠胃外(静脉内或皮下)或鼻内给药的片剂或糖衣片,舌下含片,明胶胶囊,锭剂,栓剂,乳膏,软膏,皮肤用凝胶,可注射制剂,可饮用悬浮液等等。
可以根据疾病的性质和严重性,给药途径和患者的年龄和体重采用可用的剂量,剂量也要根据所使用的化合物的性质而变化。
下面的实施例说明本发明,但不以任何方式限制本发明。
所用的起始物是已知的产物或根据已知方法制备的产物。
实施例中叙述的化合物的结构是根据常规光谱技术(红外NMR,质谱等等)确定的。实施例1:{3-{[(Z)-5-氯-2,3-二氢-3-(羟基-2-噻吩亚甲基)-2-氧代-1H-吲哚-1-基]碳酰氨基}丙基}三甲基氯化铵
步骤A:N-[3-(二甲氨基)丙基]5-氯-2,3-二氢-2-氧代-1H-吲哚-1-羧酰胺
在室温下,将12.08毫摩尔3-(二甲氨基)丙胺加入溶于70毫升二氯甲烷中的12.08毫摩尔5-氯-2,3-二氢-2-氧代-1H-吲哚-1-羧酸4-硝基苯基酯的溶液中。立即反应。在用0.05N氢氧化钠溶液萃取得到的溶液直到水相不再呈现黄色后,干燥有机相,过滤并在减压下蒸发。分离棕色固体形式的预期的化合物。熔点:84-85℃
步骤B:(Z)-N-[3-(二甲氨基)丙基]-5-氯-2,3-二氢-3-(羟基-2-噻吩亚甲基)-2-氧代-1H-吲哚-1-羧酰胺盐酸盐
在氩气环境下,将2.10毫升三乙胺和7.44毫摩尔2-噻吩甲酰氯加入溶于5毫升二甲基甲酰胺中的7.44毫摩尔在以上步骤中得到的化合物和186毫克4-N,N-二甲氨基吡啶的0℃的溶液中。在室温下搅拌反应混合物3小时。在加入4毫升甲醇,然后加入4毫升37%的盐酸后,在室温下再次搅拌混合物1小时,随后过滤。用冰冷却的水洗涤得到的黄色固体,干燥,得到预期的产物。熔点:197-198℃(分解)步骤C:(Z)-N-[3-(二甲氨基)丙基]-5-氯-2,3-二氢-3-(羟基-2-噻吩亚甲基)-2-氧代-1H-吲哚-羧酰胺钠盐
在室温下搅拌在70毫升甲醇中含有2.49毫摩尔在以上步骤中得到的产物和1.25毫摩尔Na2CO3的悬浮液5小时。然后,在减压下浓缩反应混合物并过滤。用冰冷却的水洗涤沉淀并干燥。再在室温下在甲醇介质中用Na2CO3处理得到的产物30分钟。在蒸发后,用甲醇洗涤残留物并干燥,得到预期的产物。熔点:211-212℃(分解)步骤D:(Z)-(5-氯-1,2-二氢-2-氧代-1-{[3-(三甲氨基)丙基]-氨基羰基}-3H-吲哚-3-亚基)2-噻吩甲醇化物
在氩气环境下,将3.33毫摩尔甲基碘加入溶于30毫升甲醇中的2.22毫摩尔在以上步骤中得到的化合物的溶液中。使混合物在室温下静置3小时。通过过滤分离随着反应的进行以黄色固体形式沉淀的预期的产物,用甲醇和乙醚洗涤,并干燥。熔点:260-261℃(分解)步骤E:{3-{[(Z)-5-氯-2,3-二氢-3-(羟基-2-噻吩亚甲基)-2-氧代-1H-吲哚-1-基]碳酰氨基}丙基}三甲基氯化铵
将2.5毫升2N乙醚氯化氢加入溶于7毫升二甲基甲酰胺中的0.95毫摩尔在以上步骤中得到的产物的溶液中。在室温下搅拌反应混合物10分钟。随后,将得到的溶液倒入100毫升乙醚中。立即过滤得到的黄色沉淀,用乙醚充分洗涤并干燥。熔点:209-211℃实施例2:{3-{[4-[双(2-氯乙基)氨基]-L-苯丙氨酰}氨基}丙基}三甲基铵盐酸盐步骤A:1-{{N-叔丁氧羰基-4-[双(2-氯乙基)氨基]-L-苯-丙氨酰}氨基}-3-(二甲氨基)丙烷
在室温下,向溶于7毫升甲醇中的1.32毫摩尔苯丙氨酸氮芥盐酸盐的溶液中,连续地加入2.7毫摩尔三乙胺和1.98毫摩尔二碳酸二叔丁酯。然后,使混合物达到30-40℃。一旦发生溶解,便在室温下搅拌溶液30分钟,然后在减压下蒸发。用冰冷却的释盐酸溶液(0.01N)处理得到的残留物直到pH达到2为止。然后,立即用乙酸乙酯萃取溶液。随后干燥有机相,过滤和在减压下浓缩。然后用10毫升二氯甲烷溶解得到的中间产物。向得到的溶液中连续地加入1.33毫摩尔1-羟基苯并三唑和1.33毫摩尔3-(二甲氨基)丙胺。然后,向得到的混合物中加入溶于10毫升二氯甲烷中的1.33毫摩尔二环己基碳化二亚胺的溶液。在室温下搅拌得到的反应混合物5小时。过滤分离形成的脲。用1N NaHCO3溶液萃取滤液,随后用水洗涤。干燥有机相,过滤和在减压下蒸发。然后,通过在硅胶上层析纯化得到的残留物(洗脱液:二氯甲烷/乙醇,1/1,然后,二氯甲烷/乙醇/氨,50/49/1)。分离油形式的预期的化合物,其形成结晶。熔点:80-82℃(分解)步骤B:{3-{{N-叔丁氧羰基-4-[双(2-氯乙基)氨基]-L-苯丙氨酰}氨基}丙基}三甲基碘化铵
在惰性气氛下,向溶于5毫升乙醇中的0.61毫摩尔在步骤A中所述的化合物的溶液中加入0.92毫摩尔甲基碘。使反应混合物在室温下静置3小时,然后在减压下浓缩。用最少量的甲醇溶解得到的残留物,然后倒入乙醚溶液中。通过过滤,用醚洗涤并干燥分离非常吸湿的固体形式的预期的产物。熔点:139-142℃步骤C:{3-{{4-[双(2-氯乙基)氨基]-L-苯丙氨酰}氨基}丙基}三甲基铵盐酸盐
在室温下,用10毫升2N盐酸乙醇处理0.148毫摩尔在步骤B中得到的产物2小时。然后,在减压下蒸发溶液。在50毫升甲醇中溶解得到的残留物,历时几分钟通过树脂。在减压下蒸发掉甲醇。用最少量的甲醇溶解得到的残留物,并倒入乙醚溶液中。通过过滤,用醚洗涤并干燥分离非常吸湿的米色固体形式的预期的产物。熔点:115-120℃旋光度:[α]D 25=+49.2°(c=1.04%,1N HCl)实施例3:{3-{[4-[4-[双(2-氯乙基)氨基]苯基]丁酰}氨基}-丙基}三甲基碘化铵步骤A:N-[3-(二甲基氨基)丙基]-4-{4-[双(2-氯乙基)氨基]苯基}-丁酰胺
在惰性气氛下,在0℃下,向溶于5毫升二氯甲烷中的1.61毫摩尔苯丁酸氮芥的溶液中加入1.25毫升亚硫酰氯。在4℃下,搅拌反应混合物16小时,在减压下蒸发掉过量的SOCl2。在10毫升二氯甲烷中溶解得到的残留物。在0℃下,在惰性气氛下,向得到的溶液中加入溶解于10毫升二氯甲烷中的1.61毫摩尔3-(二甲氨基)丙胺。然后,在室温下搅拌混合物1小时。在结束时,再次加入1.61毫摩尔二胺。搅拌4小时后,在减压下蒸发反应混合物。在用1N NaHCO3溶液中和后,用二氯甲烷萃取水相几次。合并不同的有机相,用水洗涤直到呈中性,干燥,过滤和在减压下蒸发。通过在硅胶上层析纯化得到的残留物(洗脱液:二氯甲烷中的乙醇梯度液:从0开始到50%,然后到结束,使用洗脱液:二氯甲烷/乙醇/氨:50/49/1)。得到油形式的预期的产物。步骤B:{3-{{4-[4-[双(2-氯乙基)氨基]苯基]丁酰}氨基}丙基-三甲基碘化铵
在惰性气氛下,向溶于7毫升乙醇中的1.34毫摩尔在以上步骤中得到的混合物的溶液中加入1.01毫摩尔甲基碘。在室温下搅拌混合物3小时,然后在减压下蒸发。用最少量的甲醇溶解得到的油。然后,将得到的溶液倒入150毫升乙醚中并在0℃下搅拌1小时。随后过滤形成的沉淀。在用乙醚洗涤并干燥后,得到非常吸湿的米色固体形式的预期的产物。熔点:118-120℃(分解)实施例4:2-(N,N,N-三甲基铵基乙酰氨基)-2-脱氧-α,β-D-吡喃葡糖氯化物步骤A:2-氯乙酰氨基-2-脱氧-α,β-D-吡喃葡糖
向冷却到0℃的溶于40毫升蒸馏水中的23.2毫摩尔盐酸葡糖胺和40毫摩尔K2CO3的溶液中逐滴加入46.4毫摩尔氯代乙酰氯。搅拌1小时。在减压下蒸发水溶液后,用乙醇洗涤得到的固体几次。然后,在减压下浓缩乙醇相直到出现白色固体沉淀为止。在充分冷却到0℃后,过滤溶液。用丙酮研制得到的白色固体,干燥,从乙醇中重结晶后得到预期的产物。熔点:183-185℃步骤B:2-(N,N,N-三甲基铵基乙酰氨基)-2-脱氧-α,β-D-吡喃葡糖氯化物
在惰性气氛下,在40℃下,将9.8毫摩尔在以上步骤中得到的化合物和10毫升三乙胺的4M乙醇溶液放置3天。过滤形成的沉淀,接着用乙醇和乙醚洗涤并干燥,得到预期的产物,。熔点:240-242℃实施例5:2-(吡啶鎓基乙酰氨基)-2-脱氧-α,β-D-吡喃葡糖氯化物
在惰性气氛下,在50毫升吡啶中,在40℃下,将9.8毫摩尔在实施例4的步骤A中得到的化合物放置3天。然后,在真空中蒸发掉吡啶,用乙醇和乙醚洗涤并干燥,得到预期的产物。熔点:223-225℃实施例6:{3-[(4-羟基-2-甲基-1,1-二氧代-2H-1,2-苯并噻嗪-3-基)-羧酰氨基]丙基}三甲基碘化铵
在氩气下,在80℃,在3毫升碘代甲烷的存在下加热3.39摩尔N-[3-(二甲氨基)丙基]-4-羟基-2-甲基-1,1-二氧代-2H-1,2-苯并噻嗪基-3-基]羧酰胺24小时。在冷却后,过滤得到的沉淀,用丙酮洗涤并干燥,得到预期的产物。熔点:220-222℃(分解)实施例7:2-[(4-羟基-2-甲基-1,1-二氧代-2H-1,2-苯并噻嗪-3-基)-羧酰氨基]-N-甲基吡啶鎓碘化物
向溶解于50毫升的去离子水中的10毫摩尔[15烷]-N5(*)的溶液中加入10毫摩尔(3-溴丙基)三乙基溴化铵。在90℃下,在惰性气氛下加热12小时,蒸发掉水分。用二氯甲烷洗涤油状残留物2次,然后溶解于100毫升乙醇中。逐滴加入4毫升10N HCl进行处理,同时使球状烧瓶冷却到0℃,产生片状白色沉淀,将其过滤,用乙醇,然后用乙醚洗涤并干燥,得到预期的产物。熔点:>200℃(分解)(*)[15烷]-N5:
步骤B:用锝标记的[15]烷-N5-(N-3-丙基)三乙基溴化铵盐酸盐
在真空中,在15毫升容量的无菌烧瓶中用锝标记在步骤A中得到的化合物,向烧瓶中加入:-溶于1毫升生理血清中的7.5毫摩尔在步骤A中得到的产物的溶液,-溶解于1毫升生理血清中的高锝酸钠(99mTcO4 -,25mCi;925MBq);在85℃加热烧瓶5分钟(金属浴),-临用前制备的SnCl2.2H2O的脱氧水溶液(9毫摩尔)。
在85℃加热30分钟进行标记。
本发明化合物的药理研究药动学研究:组织分布研究
这一研究是用14C标记的分子进行的。根据下面的方法通过直接测量全体切片的放射性进行组织分布研究:用一定剂量的标记分子经静脉内或口服途径对雄性Sprague-Dawley大鼠给药。然后,在给药后5分钟到24小时的时间内通过吸入乙醚处死动物并将其冷冻于液氮中。
然后用低温切片机制备切片,干燥后,用影像分析仪测量放射性的分布。
用本发明的化合物获得的结果证明这些化合物对软骨组织的向性提高。
对于实施例4和5的化合物,除了在注射后开始几分钟结合显著量的放射性的摘除器官肾之外,软骨和在较低程度上的皮肤是仅有的靶。当用非功能化的葡糖胺进行同样的研究时,肝是主要的靶器官。
对于实施例6的化合物,软骨比周围组织呈现出大得多的亲和性。在注射后5分钟达到了最大结合。当通过口服途径给予标记分子后进行这一研究时,同样观察到对软骨的亲和性非常高。
至于实施例8的化合物,在注射后10分钟,在软骨组织中化合物的浓度上升。
Claims (19)
M代表可以用于治疗或诊断因软骨损伤而引起的病症的分子,
R1,R2和R3可以是相同或不同的,代表直链或支链(C1-C6)烷基基团,
或R1,R2和R3与携带它们的氮原子一起形成饱和或不饱和含氮杂环,
3.根据权利要求1所述的通式(I)的化合物,如通式(Ia1)所示:其中:X1代表直链或支链(C1-C6)亚烷基基团,R’1,R’2和R’3可以是相同或不同的,代表直链或支链(C1-C6)烷基基团,Hal代表卤素原子。
6.根据权利要求1所述的通式(I)的化合物,如通式(Ia4)所示:其中:X4代表基团-CO-(CH2)m-,其中m代表1到5的整数,R1,R2和R3可以相同或不同,代表直链或支链(C1-C6)烷基基团,或R1,R2和R3与携带它们的氮原子一起形成饱和或不饱和的含氮杂环,Hal代表卤素原子。
7.根据权利要求1所述的通式(I)的化合物,如通式(Ib1)所示:其中:R4代表直链或支链(C1-C6)烷基基团,Hal代表卤素原子。
9.根据权利要求1所述的通式(I)的化合物,如通式(Ia5)所示:其中:X1代表直链或支链(C1-C6)亚烷基基团,R1,R2和R3可以相同或不同,代表直链或支链(C1-C6)烷基基团,或R1,R2和R3与携带它们的氮原子一起形成饱和或不饱和含氮杂环,Hal代表卤素原子。
10.根据权利要求3所述的通式(Ia1)的化合物的制备方法,其特征是如下获得该化合物:从5-氯-2,3-二氢-2-氧代-1H-吲哚-1-羧酸4-硝基苯基酯开始,使其与通式(II)的胺反应:其中X1,R’1和R’2如权利要求3所定义,生成通式(III)的化合物:其中X1,R’1和R’2如上文所定义,使通式(III)的化合物在惰性气氛下,在碱性介质中受到2-噻吩甲酰氯的作用,然后用酸处理,得到通式(IV)的化合物:其中X1,R’1和R’2如上文所定义,将通式(IV)的化合物转化成相应的钠盐,然后使其受到通式R’3Hal(其中R’3如上文定义,Hal代表卤素原子)的直链或支链(C1-C6)烷基卤的作用,得到通式(V)的化合物:其中X1,R’1,R’2和R’3如上文所定义,通式(V)的化合物在盐酸介质中生成通式(Ia1)的化合物,如果必要,将其纯化。
15.根据权利要求7所述的通式(Ib1)的化合物的制备方法,其特征是它们是如下得到的:从吡氧噻嗪开始,使其与直链或支链(C1-C6)烷基卤反应,如果必要将其纯化。
16.根据权利要求8所述的通式(Ib2)的化合物的制备方法,其特征是它们是如下得到的:从相应的胺开始,使其与直链或支链(C1-C6)烷基卤反应,如果必要将其纯化。
17.单独含有根据权利要求1到9的任一项所述的化合物作为活性成分,或与一种或多种药物上可接受的惰性非毒性赋形剂或载体组合的药物组合物。
18.根据权利要求17所述的药物组合物,含有根据权利要求1到9的任一项所述的化合物,用于治疗因软骨损伤而引起的病症。
19.根据权利要求17所述的药物组合物,含有权利要求1到9的任一项所述的化合物,用作能够揭示软骨或代谢病症的诊断试剂。
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CN101511774B (zh) * | 2006-10-03 | 2015-05-13 | 于崇曦 | 具有快速皮肤穿透速度的带正电荷的水溶性的芥子气类化合物及其相关化合物的前药 |
CN104987296A (zh) * | 2006-10-03 | 2015-10-21 | 于崇曦 | 具有快速皮肤穿透速度的带正电荷的水溶性的芥子类化合物及其相关化合物的前药 |
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DE19627523C1 (de) | 1996-07-09 | 1997-10-23 | Alpha Calcit Fuellstoff Gmbh | Verfahren zur Wiederverwertung von Füllstoffen und Streichpigmenten der Papier-, Pappe- und Kartonherstellung |
FR2818641B1 (fr) * | 2000-12-21 | 2004-03-05 | Servier Lab | Nouveaux derives de 1,1-dioxo-2h-1,2-benzothiazine 3-carboxamides, leur procede de preparation et les compositions pharmaceutiques que les contiennent |
FR2981849B1 (fr) * | 2011-10-28 | 2014-01-03 | Univ Claude Bernard Lyon | Nanoparticules fonctionnalisees pour le ciblage des proteoglycanes et leurs applications |
EP2639227A1 (en) * | 2012-03-14 | 2013-09-18 | Bracco Imaging S.p.A | A new class of diazepine derivative chelating agents and complexes with paramagnetic metals as MRI contrast agents |
FR2989280B1 (fr) | 2012-04-13 | 2017-02-24 | Univ Claude Bernard Lyon | Nanoparticules ultrafines comme agent de contraste multimodal |
EP3177598B1 (en) | 2014-07-28 | 2019-08-28 | Institut National de la Sante et de la Recherche Medicale (INSERM) | Macrocyclic complexes, their process of preparation and use as pet imaging agents |
FR3072281B1 (fr) | 2017-10-13 | 2020-12-04 | Nh Theraguix | Nanovecteurs et utilisations, en particulier pour le traitement de tumeurs |
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IL115113A (en) * | 1995-08-31 | 2002-11-10 | Israel State | 3-carbamoyloxy pyridinium derivatives and pharmaceutical compositions containing them |
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Cited By (5)
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CN101511774B (zh) * | 2006-10-03 | 2015-05-13 | 于崇曦 | 具有快速皮肤穿透速度的带正电荷的水溶性的芥子气类化合物及其相关化合物的前药 |
CN104987296A (zh) * | 2006-10-03 | 2015-10-21 | 于崇曦 | 具有快速皮肤穿透速度的带正电荷的水溶性的芥子类化合物及其相关化合物的前药 |
CN104987296B (zh) * | 2006-10-03 | 2018-11-23 | 于崇曦 | 具有快速皮肤穿透速度的带正电荷的水溶性的芥子类化合物及其相关化合物的前药 |
US10189774B2 (en) | 2006-10-03 | 2019-01-29 | Techfields Pharma Co., Ltd. | High penetration prodrug compositions of mustards and mustard-related compounds |
US11479527B2 (en) | 2006-10-03 | 2022-10-25 | Techfields Pharma Co., Ltd. | High penetration prodrug compositions of mustards and mustard-related compounds |
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