CN1524864A - Bis phosphate, preparation and uses of its pharmaceutical preparations - Google Patents
Bis phosphate, preparation and uses of its pharmaceutical preparations Download PDFInfo
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- CN1524864A CN1524864A CNA03146839XA CN03146839A CN1524864A CN 1524864 A CN1524864 A CN 1524864A CN A03146839X A CNA03146839X A CN A03146839XA CN 03146839 A CN03146839 A CN 03146839A CN 1524864 A CN1524864 A CN 1524864A
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- hydroxyl
- fluorine
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 239000000825 pharmaceutical preparation Substances 0.000 title description 2
- 125000005340 bisphosphate group Chemical group 0.000 title 1
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 15
- 201000011510 cancer Diseases 0.000 claims abstract description 7
- 201000008482 osteoarthritis Diseases 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 30
- -1 nitro, amino Chemical group 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 229910052731 fluorine Inorganic materials 0.000 claims description 19
- 239000011737 fluorine Substances 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 16
- 150000002431 hydrogen Chemical class 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 12
- XQRLCLUYWUNEEH-UHFFFAOYSA-L diphosphonate(2-) Chemical compound [O-]P(=O)OP([O-])=O XQRLCLUYWUNEEH-UHFFFAOYSA-L 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 150000003009 phosphonic acids Chemical class 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 8
- 208000020084 Bone disease Diseases 0.000 claims description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000005264 aryl amine group Chemical group 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 230000037396 body weight Effects 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 claims description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- 150000003863 ammonium salts Chemical class 0.000 claims description 2
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 claims description 2
- 230000003203 everyday effect Effects 0.000 claims description 2
- 229960002442 glucosamine Drugs 0.000 claims description 2
- 150000002301 glucosamine derivatives Chemical class 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 6
- 239000004480 active ingredient Substances 0.000 claims 1
- 238000006482 condensation reaction Methods 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 238000010255 intramuscular injection Methods 0.000 claims 1
- 239000007927 intramuscular injection Substances 0.000 claims 1
- 229940122361 Bisphosphonate Drugs 0.000 abstract description 6
- 150000004663 bisphosphonates Chemical class 0.000 abstract description 6
- 230000002265 prevention Effects 0.000 abstract description 2
- 206010028570 Myelopathy Diseases 0.000 abstract 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 12
- 239000003814 drug Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 235000011167 hydrochloric acid Nutrition 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- JJJOZVFVARQUJV-UHFFFAOYSA-N 2-ethylhexylphosphonic acid Chemical compound CCCCC(CC)CP(O)(O)=O JJJOZVFVARQUJV-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- JPAGYOZGZXCQCG-UHFFFAOYSA-N 1-butyl-2-propylhydrazine Chemical compound CCCCNNCCC JPAGYOZGZXCQCG-UHFFFAOYSA-N 0.000 description 1
- YYFZAOFDCWVRLQ-UHFFFAOYSA-N 1-naphthalen-1-yl-2-phenylhydrazine Chemical compound C=1C=CC2=CC=CC=C2C=1NNC1=CC=CC=C1 YYFZAOFDCWVRLQ-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 229940078581 Bone resorption inhibitor Drugs 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000030136 Marchiafava-Bignami Disease Diseases 0.000 description 1
- 208000029725 Metabolic bone disease Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 206010061363 Skeletal injury Diseases 0.000 description 1
- HEMHJVSKTPXQMS-DYCDLGHISA-M Sodium hydroxide-d Chemical compound [Na+].[2H][O-] HEMHJVSKTPXQMS-DYCDLGHISA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 125000005037 alkyl phenyl group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- KBWZTOAYWHAYJX-UHFFFAOYSA-N butylperoxycyclohexane Chemical compound CCCCOOC1CCCCC1 KBWZTOAYWHAYJX-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000008422 chlorobenzenes Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- HFXKQSZZZPGLKQ-UHFFFAOYSA-N cyclopentamine Chemical compound CNC(C)CC1CCCC1 HFXKQSZZZPGLKQ-UHFFFAOYSA-N 0.000 description 1
- 229960003263 cyclopentamine Drugs 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000006317 cyclopropyl amino group Chemical group 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000006298 dechlorination reaction Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical class ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Abstract
The invention discloses a bis-phosphonate medicinal preparation and uses thereof, wherein the reactive component of the preparation is bisphosphonate, and the medicinal preparation comprises reactive bisphosphonate and medicinal carrying agent or deflocculating agent, which can be used for the prevention and treatment for osteoporosis, osteoarthritis, malignant tumor, hypercalcinemia, myelopathy.
Description
Technical field
The present invention relates to a kind of preparation method of diphosphonate medicine and in the application aspect preventing and treating of treatment and preventing osteoporosis disease and the osteopathy for the treatment of malignant tumour, hypercalcinemia, multiple marrow disease, ostalgia and tumor promotion.
Background technology
At present, osteoporosis has become a kind of multiple disease of serious threat human health.According to World Health Organization's statistics, osteoporosis has reached popularity degree, and global patient surpasses 200,000,000.China classifies osteoporosis as three big geriatric diseases that emphasis is tackled key problems with diabetes, senile dementia.The morbidity of osteoporosis is relevant with multiple factor, and is the highest with the postmenopausal women sickness rate especially, this be a kind of relevant with bone forming be the endocrine regulation of feature with the bone resorption.At present, the method for Chang Yong treatment osteoporosis has controversies in hormone replacement in the elderly and diphosphonate therapy.Development in recent years bisphosphonates faster has the obvious treatment effect as a kind of optionally bone resorption inhibitor to postmenopausal women's osteoporosis.Such medicine begins to be applied to clinical from the eighties, so far be successfully used to the treatment of metabolic bone disease, clinical research confirmation, such medicine is all having significant curative effect aspect treatment osteoporosis, increase bone mass and the minimizing fracture, and, bisphosphonates has tangible prophylactic effect to osteoporosis, and this is that controversies in hormone replacement in the elderly is incomparable.
Diphosphonate also extensively applies to treat the hypercalcinemia that malignant tumour is brought out.Diphosphonate also is applied to treat osteopathy, bone injury and the ostalgia of tumor promotion in recent years, in particular for treating multiple marrow disease and mammary cancer (Samuel D. Vasikaran, " Bisphosphonates:an overview with special reference toalendronate ", Ann.Clin.Biochem., 2001,38,608-623).
Technology contents
One of the object of the invention is to disclose a class and is used for the treatment of diphosphonate medicine with the osteopathy of preventing osteoporosis disease and treatment malignant tumour, hypercalcinemia, multiple marrow disease, ostalgia and tumor promotion etc.;
Two of the object of the invention is to disclose the preparation method of the described medicine of a class;
Three of the object of the invention is to disclose the application of the described medicine of a class as the aspects such as osteopathy of treatment and preventing osteoporosis disease and treatment malignant tumour, hypercalcinemia, multiple marrow disease, ostalgia and tumor promotion.
Diphosphonate pharmaceutical preparation of the present invention, its dosage use range are diphosphonate 0.01～500mg/kg body weight.
Compound of the present invention, its chemical structure is shown in general formula (I):
Wherein, Z is nitrogenous five yuan, hexa-atomic single heterocycle or volution, the many heterocycles of condensed ring; Q is covalent linkage, O, S or NR
7R
8, R
9Be respectively a kind of in hydrogen, halogen, alkyl or the hydroxyl; R
10, R
11Be respectively a kind of in hydrogen, fluorine, alkyl or the hydroxyl, but R at least
10, R
11One of them is a fluorine; R
5Be single the replacement or multi-substituent on the Z ring, be respectively a kind of in hydrogen, halogen, alkyl, aryl, hydroxyl, alkoxyl group, arylalkyl, nitro, acyl group, amino, alkyl amine group or the arylamine group; R
6A kind of in hydrogen, halogen, alkyl, aryl, hydroxyl, alkoxyl group, arylalkyl, nitro, amino, alkyl amine group or the arylamine group; R
7A kind of in hydrogen, alkyl, aryl or the arylalkyl; A+b is 1 to 10 integer.
Two phosphonic preferred compounds shown in the general formula (I) are: Z is nitrogenous five yuan, hexa-atomic single heterocycle or volution, the many heterocycles of condensed ring; Q is a covalent linkage; R
8, R
9Be respectively hydrogen; R
10, R
11Be respectively hydrogen or fluorine, but R at least
10, R
11One of them is a fluorine; R
5Be single the replacement or multi-substituent on the Z ring, be respectively a kind of in hydrogen, halogen, alkyl, aryl, hydroxyl, alkoxyl group or the nitro; R
6A kind of in hydrogen, halogen, alkyl or the hydroxyl; R
7Be hydrogen; A+b is 1 to 4 integer.
Fluorine-containing pair of phosphonic most preferred compound shown in the general formula (I) is: Z is nitrogenous five yuan or hexa-atomic single heterocycle; Q is a covalent linkage; R
8, R
9Be respectively hydrogen; R
10, R
11Be respectively hydrogen or fluorine, but R at least
10, R
11One of them is a fluorine; R
5Be single the replacement or multi-substituent on the Z ring, be respectively a kind of in hydrogen, halogen, alkyl, hydroxyl, alkoxyl group or the nitro; R
6Be hydrogen or hydroxyl; R
7Be hydrogen; A+b is 2.
Diphosphonate shown in the general formula (I), because peculiar lipotropy of fluorine atom and penetrance, thereby compare with commercially available not fluorine-containing diphosphonate, have stronger fat-soluble and high bioavailability, have better therapeutic aspect the osteopathy such as prevention and treatment osteoporosis.
" heterocycle " of the present invention, comprise saturated or unsaturated five yuan of one or more heteroatomss (nitrogen, oxygen or sulphur), hexa-atomic single heterocycle or volution, the many heterocycles of condensed ring of containing, as Pyrrolidine, pyrrolin, pyrazoline, piperidines, morpholine, imidazoles, pyridine etc.
" halogen " of the present invention is fluorine, chlorine, bromine, iodine.
" alkyl " of the present invention comprises straight chain, side chain or cyclic alkyl, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.
" aryl " of the present invention comprises containing substituting group or not containing substituent aromatic ring, as phenyl, alkyl phenyl, alkoxyl phenyl, naphthyl etc.
" alkoxyl group " of the present invention is meant the alkyl formed group that links to each other with Sauerstoffatom, and wherein, Sauerstoffatom has free bonding power, as methoxyl group, oxyethyl group, propoxy-, butoxy, cyclohexyl oxygen base etc.
" arylalkyl " of the present invention is meant the straight chain, side chain or the cyclic alkyl that contain aromatic ring, as benzyl, styroyl, 3-phenyl propyl, 1-menaphthyl etc.
" alkyl amine group " of the present invention is meant the alkyl formed group that links to each other with the nitrogen-atoms of amino, and wherein, nitrogen-atoms has free bonding power, as methylamino, ethylamino-, Propylamino, butylamine base, cyclopropyl amino, cyclopentamine base, cyclohexylamino etc.
" arylamine group " of the present invention is meant the aryl formed group that links to each other with the nitrogen-atoms of amino, and wherein, nitrogen-atoms has free bonding power, as anilino, naphthylamine base etc.
" acyl group " of the present invention is meant the alkyl formed group that links to each other with carbonyl, as ethanoyl, propionyl, butyryl radicals, pentanoyl etc.
Two phosphonic acids shown in the general formula (I) can be prepared according to synthetic route shown in Figure 1:
The synthetic route of the two phosphonic of Fig. 1 general formula (I)
Concrete preparation method is: at KF/Al
2O
3Under the catalysis, nitrogen-containing heterocycle compound (1) and bromo carboxylicesters (2) are carried out the N-alkylated reaction, obtain heteroaromatic carboxylate (3) (yield 56～62%), then heteroaromatic carboxylate (3) is obtained heterocyclic carboxylic acid (4) (yield 80～85%) with 4 M hydrochloric acid hydrolysis, again with heterocyclic carboxylic acid (4) and H
3PO
3And PCl
3Carry out the phosphonic acids reaction and obtain fluorine-containing pair of phosphonic acids (5) (yield 40～45%).
Salts such as fluorine-containing pair of phosphonic sodium salt shown in the general formula (I), sylvite, ammonium salt, organic amine salt, glucosamine salt can be got by corresponding alkali such as fluorine-containing pair of phosphonic acids (I) and sodium hydroxide, potassium hydroxide, ammoniacal liquor, organic amine, glucosamine.
The present invention also comprises the medicinal preparations of described medicine, and said preparation is used to osteopathy of preventing and treating osteoporosis, osteoarthritis, malignant tumour, hypercalcinemia, multiple marrow disease, ostalgia and tumor promotion etc.
Medicinal preparations of the present invention is a medicine formulation commonly used, as tablet, capsule, pulvis, syrup, liquor, suspension agent, injection, can include spices, sweeting agent, liquid or solid filler or thinner.Usually contain 1～20% effective constituent (preferable content is 1～10%) in the said preparation, all the other components are carrier filler, thinner or solvent.
Medicine of the present invention can carry out medication to Mammals (comprising the people) by oral or injection system clinically, and dosage is 0.01～500mg/kg body weight every day, yet optimal dose is decided on individuality.
Further illustrate content of the present invention below in conjunction with example, but these examples do not limit protection scope of the present invention.
Specific implementation method
Embodiment 1
Catalyzer KF-Al
2O
3Preparation
60 gram KF are dissolved in 100 ml waters, add the neutral Al of 100 grams
2O
3(chromatography usefulness, 100～200 orders), in 65 ℃ of stirring reactions 1 hour, elevated temperature was the water evaporate to dryness then, and solids promptly gets KF-Al 120 ℃ of dryings 4 hours
2O
3Catalyzer.
Embodiment 2
The preparation of 2-fluoro-2-(1-imidazolyl) ethyl acetate
In reaction flask, add 6.80 gram (0.10 mole) imidazoles, 22.2 gram (0.12 mole) fluorine ethyl bromoacetate, 100 gram KF-Al
2O
3Catalyzer and 250 milliliters of acetonitriles, reflux is 3 hours under the vigorous stirring, filters.With KF-Al
2O
3Catalyzer washs (3 * 50 milliliters) with acetonitrile, and merging filtrate steams and removes acetonitrile.The residue underpressure distillation is got 10.3 gram (yield 60%) target products.
Embodiment 3
The preparation of 2-fluoro-2-(1-imidazolyl) acetate
In reaction flask, add 17.2 gram (0.10 mole) 2-fluoro-2-(1-imidazolyl) ethyl acetate and 200 milliliters of 4M hydrochloric acid, heating reflux reaction 4 hours, vacuum concentration gets 11.7 gram (yield 81%) target products with residue with ethyl alcohol recrystallization.
Embodiment 4
1-hydroxyl-2-fluoro-2-(1-imidazolyl) ethylidene-1, the preparation of 1-di 2 ethylhexyl phosphonic acid
Phosphorous acid and 100 milliliters of chlorobenzenes of in reaction flask, adding 14.4 gram (0.10 mole) 2-fluoro-2-(1-imidazolyl) acetate, 28.9 gram (0.30 moles) 85%, be warming up to 100～110 ℃, drip 27.5 gram (0.20 mole) phosphorus trichlorides, continue reaction 3～4 hours in 100～110 ℃.Hectare dechlorination benzene, residual sticky solid adds 100 milliliters of concentrated hydrochloric acids in bottle, and about 1 hour of reflux is filtered.The filtrate vacuum concentration is got the sticky solid crude product.Residual sticky solid adds 200 milliliters of ethanol in bottle, filter 12.2 gram (yield 42%) target products.
1HNMR(NaOD/D2O，300MHz)：δ7.82(s，1H)，7.32(s，1H)，6.95(s，1H)，4.40～4.60(m，1H)。
Ultimate analysis: theoretical value C (20.70%), H (3.13%), N (9.66%)
Measured value C (20.65%), H (3.14%), N (9.62%)
Embodiment 5
1-hydroxyl-2-fluoro-2-(1-imidazolyl) ethylidene-1, the composition of 1-di 2 ethylhexyl phosphonic acid tablet
Composition weight (milligram/sheet)
1-hydroxyl-2-fluoro-2-(1-imidazolyl) ethylidene-1,1-di 2 ethylhexyl phosphonic acid 0.25～10
Starch 45
Mierocrystalline cellulose 35
Polyvinylpyrrolidone (10% aqueous solution) 4
Xylo-Mucine 4.5
Magnesium Stearate 0.5
Talcum powder 1
Claims (11)
1, a kind of diphosphonate is characterized in that, described pair of phosphonic general structure is as follows:
Wherein, Z is nitrogenous five yuan, hexa-atomic single heterocycle or volution, the many heterocycles of condensed ring; Q is covalent linkage, O, S or NR
7R
8, R
9Be respectively a kind of in hydrogen, halogen, alkyl or the hydroxyl; R
10, R
11Be respectively a kind of in hydrogen, fluorine, alkyl or the hydroxyl, but R at least
10, R
11One of them is a fluorine; R
5Be single the replacement or multi-substituent on the Z ring, be respectively a kind of in hydrogen, halogen, alkyl, aryl, hydroxyl, alkoxyl group, arylalkyl, nitro, acyl group, amino, alkyl amine group or the arylamine group; R
6A kind of in hydrogen, halogen, alkyl, aryl, hydroxyl, alkoxyl group, arylalkyl, nitro, amino, alkyl amine group or the arylamine group; R
7A kind of in hydrogen, alkyl, aryl or the arylalkyl; A+b is 1 to 10 integer.
2. compound as claimed in claim 1 is characterized in that, one of described pair of phosphonic preferred method is:
Z is nitrogenous five yuan, hexa-atomic single heterocycle or volution, the many heterocycles of condensed ring; Q is a covalent linkage; R
8, R
9Be respectively hydrogen; R
10, R
11Be respectively hydrogen or fluorine, but R at least
10, R
11One of them is a fluorine; R
5Be single the replacement or multi-substituent on the Z ring, be respectively a kind of in hydrogen, halogen, alkyl, aryl, hydroxyl, alkoxyl group or the nitro; R
6A kind of in hydrogen, halogen, alkyl or the hydroxyl; R
7Be hydrogen; A+b is 1 to 4 integer.
3. compound as claimed in claim 1 is characterized in that, described pair of phosphonic most preferred compound is:
Z is nitrogenous five yuan or hexa-atomic single heterocycle; Q is a covalent linkage; R
8, R
9Be respectively hydrogen; R
10, R
11Be respectively hydrogen or fluorine, but R at least
10, R
11One of them is a fluorine; R
5Be single the replacement or multi-substituent on the Z ring, be respectively a kind of in hydrogen, halogen, alkyl, hydroxyl, alkoxyl group or the nitro; R
6Be hydrogen or hydroxyl; R
7Be hydrogen; A+b is 2.
4. compound as claimed in claim 1 is characterized in that, the steric isomer of described compound, enantiomer, diastereomer and hydrate can be prepared by following three-step reaction:
A) compound (1) and compound (2) are carried out condensation reaction and obtain compound (3):
B) compound (3) be hydrolyzed obtain compound (4):
C) compound (4) is carried out the phosphonic acids reaction and obtains compound (5):
5. pair phosphonic acids as claimed in claim 1, it is characterized in that, the described pair of phosphonic sodium salt, sylvite, ammonium salt, organic amine salt, glucosamine salt can be by described pair of phosphonic acids of claim 1 and sodium hydroxide, potassium hydroxide, ammoniacal liquor, organic amine, glucosamine corresponding alkali and get.
6. the preparation method of two phosphonic acids and medicinal preparations thereof is characterized in that, its preparation is made up of the two phosphonic salts of active ingredient and pharmaceutical carrier or thinner.
7. medicinal preparations as claimed in claim 6 is characterized in that the content of its contained active principle is between 0.01～500mg.
8. medicinal preparations as claimed in claim 6 is characterized in that the preferred content of its contained active principle is between 0.50～50mg.
9. medicinal preparations as claimed in claim 6 is characterized in that, its application method can be per os or intramuscular injection mode.
10. compound as claimed in claim 1 is characterized in that, can prevent and treat the osteopathy of osteoporosis, osteoarthritis, malignant tumour, hypercalcinemia, multiple marrow disease, ostalgia and tumor promotion.
11. methods of treatment as claimed in claim 9 is characterized in that, the dosage of active principle is between 0.03～50mg/kg body weight every day.
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| CN 03146839 CN1259325C (en) | 2003-09-12 | 2003-09-12 | Bis phosphate, preparation and uses of its pharmaceutical preparations |
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| CN 03146839 CN1259325C (en) | 2003-09-12 | 2003-09-12 | Bis phosphate, preparation and uses of its pharmaceutical preparations |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102190684A (en) * | 2010-03-15 | 2011-09-21 | 南通波锐生物医药有限公司 | Phosphorus-containing compound having drug actions, and preparation and application thereof |
| CN102659840A (en) * | 2012-05-10 | 2012-09-12 | 苏州普瑞诺药物技术有限公司 | Imidazole diphosphonie acid compound and pharmaceutically-acceptable salt and medicinal application thereof |
| US8882740B2 (en) | 2009-12-23 | 2014-11-11 | Stryker Trauma Gmbh | Method of delivering a biphosphonate and/or strontium ranelate below the surface of a bone |
| CN106172498A (en) * | 2016-07-07 | 2016-12-07 | 广州永创生物科技有限公司 | A kind of high price silver phosphate antibiosis agent and preparation method thereof |
-
2003
- 2003-09-12 CN CN 03146839 patent/CN1259325C/en not_active Expired - Lifetime
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8882740B2 (en) | 2009-12-23 | 2014-11-11 | Stryker Trauma Gmbh | Method of delivering a biphosphonate and/or strontium ranelate below the surface of a bone |
| CN102190684A (en) * | 2010-03-15 | 2011-09-21 | 南通波锐生物医药有限公司 | Phosphorus-containing compound having drug actions, and preparation and application thereof |
| CN102659840A (en) * | 2012-05-10 | 2012-09-12 | 苏州普瑞诺药物技术有限公司 | Imidazole diphosphonie acid compound and pharmaceutically-acceptable salt and medicinal application thereof |
| CN102659840B (en) * | 2012-05-10 | 2013-08-14 | 苏州普瑞诺药物技术有限公司 | Imidazole diphosphonie acid compound and pharmaceutically-acceptable salt and medicinal application thereof |
| CN106172498A (en) * | 2016-07-07 | 2016-12-07 | 广州永创生物科技有限公司 | A kind of high price silver phosphate antibiosis agent and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1259325C (en) | 2006-06-14 |
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