PH26819A - Cycloalkylamino methylenebis (phosphonic acid) and medicines containing the same as an active ingredients - Google Patents

Cycloalkylamino methylenebis (phosphonic acid) and medicines containing the same as an active ingredients Download PDF

Info

Publication number: PH26819A
Authority: PH; Philippines
Prior art keywords: lower alkyl; acid; compound; phosphonic acid; methylenebis
Prior art date: 1988-01-20

Application number

PH38068A

Other languages

English (en)

Inventor

Yasuo Isomura

Makoto Takeuchi

Shuichi Sakamoto

Tetsushi Abe

Original Assignee

Yamanouchi Pharma Co Ltd

Priority date (The priority date 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 date listed.)

1988-01-20

Filing date

1989-01-19

Publication date

1992-11-05

1989-01-19 Application filed by Yamanouchi Pharma Co Ltd filed Critical Yamanouchi Pharma Co Ltd

1992-11-05 Publication of PH26819A publication Critical patent/PH26819A/en

Links

-1 Cycloalkylamino methylenebis (phosphonic acid) Chemical compound 0.000 title claims description 9
239000004480 active ingredient Substances 0.000 title claims description 7
239000003814 drug Substances 0.000 title description 8
229940079593 drug Drugs 0.000 title description 7
125000000217 alkyl group Chemical group 0.000 claims abstract description 17
150000003839 salts Chemical class 0.000 claims abstract description 17
125000006310 cycloalkyl amino group Chemical group 0.000 claims abstract description 8
229940078581 Bone resorption inhibitor Drugs 0.000 claims abstract description 5
150000001875 compounds Chemical class 0.000 claims description 56
239000000203 mixture Substances 0.000 claims description 15
125000005907 alkyl ester group Chemical group 0.000 claims description 12
239000002253 acid Substances 0.000 claims description 10
206010003246 arthritis Diseases 0.000 claims description 8
KGRVJHAUYBGFFP-UHFFFAOYSA-N 2,2'-Methylenebis(4-methyl-6-tert-butylphenol) Chemical compound CC(C)(C)C1=CC(C)=CC(CC=2C(=C(C=C(C)C=2)C(C)(C)C)O)=C1O KGRVJHAUYBGFFP-UHFFFAOYSA-N 0.000 claims description 5
ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims 4
235000002639 sodium chloride Nutrition 0.000 claims 3
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
235000010627 Phaseolus vulgaris Nutrition 0.000 claims 1
244000046052 Phaseolus vulgaris Species 0.000 claims 1
241000271569 Rhea Species 0.000 claims 1
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims 1
239000003112 inhibitor Substances 0.000 claims 1
HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims 1
239000011780 sodium chloride Substances 0.000 claims 1
150000002148 esters Chemical class 0.000 abstract description 3
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
229940124346 antiarthritic agent Drugs 0.000 abstract 1
239000003435 antirheumatic agent Substances 0.000 abstract 1
229910052739 hydrogen Inorganic materials 0.000 abstract 1
239000001257 hydrogen Substances 0.000 abstract 1
LWRDQHOZTAOILO-UHFFFAOYSA-N incadronic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)NC1CCCCCC1 LWRDQHOZTAOILO-UHFFFAOYSA-N 0.000 description 18
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
108090000445 Parathyroid hormone Proteins 0.000 description 15
241000700159 Rattus Species 0.000 description 14
102100036893 Parathyroid hormone Human genes 0.000 description 13
239000011575 calcium Substances 0.000 description 13
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
238000001819 mass spectrum Methods 0.000 description 12
210000002966 serum Anatomy 0.000 description 11
239000000243 solution Substances 0.000 description 11
208000006386 Bone Resorption Diseases 0.000 description 10
210000000988 bone and bone Anatomy 0.000 description 10
238000006243 chemical reaction Methods 0.000 description 10
OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 9
238000004458 analytical method Methods 0.000 description 9
230000024279 bone resorption Effects 0.000 description 9
239000007924 injection Substances 0.000 description 9
238000002347 injection Methods 0.000 description 9
239000000047 product Substances 0.000 description 9
229910052791 calcium Inorganic materials 0.000 description 8
MBKDYNNUVRNNRF-UHFFFAOYSA-N medronic acid Chemical compound OP(O)(=O)CP(O)(O)=O MBKDYNNUVRNNRF-UHFFFAOYSA-N 0.000 description 7
229940122361 Bisphosphonate Drugs 0.000 description 6
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
150000004663 bisphosphonates Chemical class 0.000 description 6
238000001816 cooling Methods 0.000 description 6
CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 6
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
238000000034 method Methods 0.000 description 6
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 6
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 6
239000000126 substance Substances 0.000 description 6
238000012360 testing method Methods 0.000 description 6
208000037147 Hypercalcaemia Diseases 0.000 description 5
FHZDYZJEMKMBKZ-UHFFFAOYSA-N [phosphono-[(1,2,2,3-tetraethylcyclooctyl)amino]methyl]phosphonic acid Chemical compound C(C)C1C(C(CCCCC1)(NC(P(O)(O)=O)P(O)(O)=O)CC)(CC)CC FHZDYZJEMKMBKZ-UHFFFAOYSA-N 0.000 description 5
230000000148 hypercalcaemia Effects 0.000 description 5
208000030915 hypercalcemia disease Diseases 0.000 description 5
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
MTUXIEQQZFYCDJ-UHFFFAOYSA-N [[(3-methylcyclohexyl)amino]-phosphonomethyl]phosphonic acid Chemical compound CC1CCCC(NC(P(O)(O)=O)P(O)(O)=O)C1 MTUXIEQQZFYCDJ-UHFFFAOYSA-N 0.000 description 4
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 4
230000000694 effects Effects 0.000 description 4
WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 4
230000002401 inhibitory effect Effects 0.000 description 4
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
238000001543 one-way ANOVA Methods 0.000 description 4
239000002504 physiological saline solution Substances 0.000 description 4
238000001953 recrystallisation Methods 0.000 description 4
238000007920 subcutaneous administration Methods 0.000 description 4
GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 4
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
108091003079 Bovine Serum Albumin Proteins 0.000 description 3
208000009386 Experimental Arthritis Diseases 0.000 description 3
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
210000004369 blood Anatomy 0.000 description 3
239000008280 blood Substances 0.000 description 3
229940098773 bovine serum albumin Drugs 0.000 description 3
239000002775 capsule Substances 0.000 description 3
LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 3
201000010099 disease Diseases 0.000 description 3
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
238000001914 filtration Methods 0.000 description 3
210000002758 humerus Anatomy 0.000 description 3
125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
230000007062 hydrolysis Effects 0.000 description 3
238000006460 hydrolysis reaction Methods 0.000 description 3
229960000905 indomethacin Drugs 0.000 description 3
239000008101 lactose Substances 0.000 description 3
235000019359 magnesium stearate Nutrition 0.000 description 3
239000008213 purified water Substances 0.000 description 3
238000010992 reflux Methods 0.000 description 3
239000007787 solid Substances 0.000 description 3
230000008961 swelling Effects 0.000 description 3
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
102000003982 Parathyroid hormone Human genes 0.000 description 2
UGPXWDIZFKGVEG-UHFFFAOYSA-N [(cyclopropylamino)-phosphonomethyl]phosphonic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)NC1CC1 UGPXWDIZFKGVEG-UHFFFAOYSA-N 0.000 description 2
239000002671 adjuvant Substances 0.000 description 2
208000020538 atrophic muscular disease Diseases 0.000 description 2
125000004432 carbon atom Chemical group C* 0.000 description 2
239000001768 carboxy methyl cellulose Substances 0.000 description 2
235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
239000008112 carboxymethyl-cellulose Substances 0.000 description 2
125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
239000008187 granular material Substances 0.000 description 2
238000010438 heat treatment Methods 0.000 description 2
239000001863 hydroxypropyl cellulose Substances 0.000 description 2
235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
230000005764 inhibitory process Effects 0.000 description 2
210000003141 lower extremity Anatomy 0.000 description 2
GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
OJWJPSDEEWTQIZ-UHFFFAOYSA-N n-[bis(diethoxyphosphoryl)methyl]cycloheptanamine Chemical compound CCOP(=O)(OCC)C(P(=O)(OCC)OCC)NC1CCCCCC1 OJWJPSDEEWTQIZ-UHFFFAOYSA-N 0.000 description 2
ICAPSXIAPPHHFN-UHFFFAOYSA-N n-[bis(diethoxyphosphoryl)methyl]cyclopentanamine Chemical compound CCOP(=O)(OCC)C(P(=O)(OCC)OCC)NC1CCCC1 ICAPSXIAPPHHFN-UHFFFAOYSA-N 0.000 description 2
239000000199 parathyroid hormone Substances 0.000 description 2
229960001319 parathyroid hormone Drugs 0.000 description 2
230000003389 potentiating effect Effects 0.000 description 2
238000002360 preparation method Methods 0.000 description 2
206010039073 rheumatoid arthritis Diseases 0.000 description 2
238000010898 silica gel chromatography Methods 0.000 description 2
239000002904 solvent Substances 0.000 description 2
238000003756 stirring Methods 0.000 description 2
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 2
238000010998 test method Methods 0.000 description 2
VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 2
206010065687 Bone loss Diseases 0.000 description 1
229920002261 Corn starch Polymers 0.000 description 1
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
101001135770 Homo sapiens Parathyroid hormone Proteins 0.000 description 1
101001135995 Homo sapiens Probable peptidyl-tRNA hydrolase Proteins 0.000 description 1
CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
208000010191 Osteitis Deformans Diseases 0.000 description 1
208000001132 Osteoporosis Diseases 0.000 description 1
229910018828 PO3H2 Inorganic materials 0.000 description 1
208000027868 Paget disease Diseases 0.000 description 1
241000700157 Rattus norvegicus Species 0.000 description 1
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
229920002472 Starch Polymers 0.000 description 1
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
UNLQCNUHOMXEEC-UHFFFAOYSA-N [(cyclobutylamino)-phosphonomethyl]phosphonic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)NC1CCC1 UNLQCNUHOMXEEC-UHFFFAOYSA-N 0.000 description 1
GBBBPWVJGMFZGX-UHFFFAOYSA-N [(cyclohexylamino)-phosphonomethyl]phosphonic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)NC1CCCCC1 GBBBPWVJGMFZGX-UHFFFAOYSA-N 0.000 description 1
PAJKVIAJYAPPGP-UHFFFAOYSA-N [[(2-methylcyclohexyl)amino]-phosphonomethyl]phosphonic acid Chemical compound CC1CCCCC1NC(P(O)(O)=O)P(O)(O)=O PAJKVIAJYAPPGP-UHFFFAOYSA-N 0.000 description 1
AOBGIGQTVRHCKF-UHFFFAOYSA-N [[(4-methylcyclohexyl)amino]-phosphonomethyl]phosphonic acid Chemical compound CC1CCC(NC(P(O)(O)=O)P(O)(O)=O)CC1 AOBGIGQTVRHCKF-UHFFFAOYSA-N 0.000 description 1
230000003187 abdominal effect Effects 0.000 description 1
MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 description 1
150000007513 acids Chemical class 0.000 description 1
239000003905 agrochemical Substances 0.000 description 1
150000001412 amines Chemical class 0.000 description 1
229910021529 ammonia Inorganic materials 0.000 description 1
150000003863 ammonium salts Chemical class 0.000 description 1
230000000202 analgesic effect Effects 0.000 description 1
230000003110 anti-inflammatory effect Effects 0.000 description 1
230000001754 anti-pyretic effect Effects 0.000 description 1
230000003356 anti-rheumatic effect Effects 0.000 description 1
239000002221 antipyretic Substances 0.000 description 1
239000007864 aqueous solution Substances 0.000 description 1
230000002917 arthritic effect Effects 0.000 description 1
244000052616 bacterial pathogen Species 0.000 description 1
BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
229960003773 calcitonin (salmon synthetic) Drugs 0.000 description 1
235000019994 cava Nutrition 0.000 description 1
239000001913 cellulose Substances 0.000 description 1
229920002678 cellulose Polymers 0.000 description 1
239000007795 chemical reaction product Substances 0.000 description 1
239000007810 chemical reaction solvent Substances 0.000 description 1
WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
230000001684 chronic effect Effects 0.000 description 1
239000008120 corn starch Substances 0.000 description 1
239000013078 crystal Substances 0.000 description 1
125000000753 cycloalkyl group Chemical group 0.000 description 1
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
VXVVUHQULXCUPF-UHFFFAOYSA-N cycloheptanamine Chemical compound NC1CCCCCC1 VXVVUHQULXCUPF-UHFFFAOYSA-N 0.000 description 1
125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
230000003247 decreasing effect Effects 0.000 description 1
238000011161 development Methods 0.000 description 1
239000012153 distilled water Substances 0.000 description 1
231100000673 dose–response relationship Toxicity 0.000 description 1
239000003937 drug carrier Substances 0.000 description 1
230000002894 effect on hypercalcemia Effects 0.000 description 1
238000002474 experimental method Methods 0.000 description 1
210000002683 foot Anatomy 0.000 description 1
239000007903 gelatin capsule Substances 0.000 description 1
230000002363 herbicidal effect Effects 0.000 description 1
239000004009 herbicide Substances 0.000 description 1
210000000548 hind-foot Anatomy 0.000 description 1
102000058004 human PTH Human genes 0.000 description 1
125000001183 hydrocarbyl group Chemical group 0.000 description 1
230000002757 inflammatory effect Effects 0.000 description 1
239000004615 ingredient Substances 0.000 description 1
230000002723 inhibitory effect on hypercalcemia Effects 0.000 description 1
229910052500 inorganic mineral Inorganic materials 0.000 description 1
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
208000027202 mammary Paget disease Diseases 0.000 description 1
238000004519 manufacturing process Methods 0.000 description 1
238000005259 measurement Methods 0.000 description 1
230000001394 metastastic effect Effects 0.000 description 1
206010061289 metastatic neoplasm Diseases 0.000 description 1
NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 1
239000011707 mineral Substances 0.000 description 1
239000012046 mixed solvent Substances 0.000 description 1
DNEHFYCUOVWICM-UHFFFAOYSA-N n-[bis(diethoxyphosphoryl)methyl]cyclohexanamine Chemical compound CCOP(=O)(OCC)C(P(=O)(OCC)OCC)NC1CCCCC1 DNEHFYCUOVWICM-UHFFFAOYSA-N 0.000 description 1
LHRXWTUDZWLZIH-UHFFFAOYSA-N n-[bis(diethoxyphosphoryl)methyl]cyclopropanamine Chemical compound CCOP(=O)(OCC)C(P(=O)(OCC)OCC)NC1CC1 LHRXWTUDZWLZIH-UHFFFAOYSA-N 0.000 description 1
239000002674 ointment Substances 0.000 description 1
150000007530 organic bases Chemical class 0.000 description 1
239000008194 pharmaceutical composition Substances 0.000 description 1
UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
239000006187 pill Substances 0.000 description 1
159000000001 potassium salts Chemical class 0.000 description 1
239000000843 powder Substances 0.000 description 1
238000001556 precipitation Methods 0.000 description 1
108090000765 processed proteins & peptides Proteins 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
239000011541 reaction mixture Substances 0.000 description 1
230000000246 remedial effect Effects 0.000 description 1
230000000630 rising effect Effects 0.000 description 1
108010068072 salmon calcitonin Proteins 0.000 description 1
239000000741 silica gel Substances 0.000 description 1
229910002027 silica gel Inorganic materials 0.000 description 1
159000000000 sodium salts Chemical class 0.000 description 1
210000004872 soft tissue Anatomy 0.000 description 1
239000008107 starch Substances 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
239000000725 suspension Substances 0.000 description 1
208000024891 symptom Diseases 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
239000003826 tablet Substances 0.000 description 1
OGBMKVWORPGQRR-UMXFMPSGSA-N teriparatide Chemical compound C([C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)[C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CNC=N1 OGBMKVWORPGQRR-UMXFMPSGSA-N 0.000 description 1
210000001364 upper extremity Anatomy 0.000 description 1
210000000689 upper leg Anatomy 0.000 description 1
239000003981 vehicle Substances 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
- A61K31/66—Phosphorus compounds
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
- 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4025—Esters of poly(thio)phosphonic acids
- C07F9/405—Esters of poly(thio)phosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
General Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Molecular Biology (AREA)
Biochemistry (AREA)
Veterinary Medicine (AREA)
Animal Behavior & Ethology (AREA)
Medicinal Chemistry (AREA)
Pharmacology & Pharmacy (AREA)
Public Health (AREA)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Physical Education & Sports Medicine (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
Epidemiology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Medicinal Preparation (AREA)
Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

PH38068A 1988-01-20 1989-01-19 Cycloalkylamino methylenebis (phosphonic acid) and medicines containing the same as an active ingredients PH26819A (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
JP1165688		1988-01-20

Publications (1)

Publication Number	Publication Date
PH26819A true PH26819A (en)	1992-11-05

Family

ID=11784011

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
PH38068A PH26819A (en)	1988-01-20	1989-01-19	Cycloalkylamino methylenebis (phosphonic acid) and medicines containing the same as an active ingredients

Country Status (14)

Country	Link
US (2)	US4970335A (es)
EP (1)	EP0325482B1 (es)
KR (1)	KR970005179B1 (es)
CN (1)	CN1022630C (es)
AT (1)	ATE74361T1 (es)
AU (1)	AU615711B2 (es)
CA (1)	CA1339805C (es)
DE (1)	DE68901097D1 (es)
DK (1)	DK174744B1 (es)
ES (1)	ES2032105T3 (es)
GR (1)	GR3004461T3 (es)
HU (1)	HU202243B (es)
IE (1)	IE60477B1 (es)
PH (1)	PH26819A (es)

Families Citing this family (48)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
CA1339805C (en) *	1988-01-20	1998-04-07	Yasuo Isomura	(cycloalkylamino)methylenebis(phosphonic acid) and medicines containing the same as an active
IE912115A1 (en) *	1990-06-25	1992-01-01	Takeda Chemical Industries Ltd	Bisphosphonic acid derivatives, their production and use
US5073339A (en) *	1990-08-23	1991-12-17	W. R. Grace & Co. - Conn	Method of inhibiting corrosion and scale formation in aqueous systems
EP0491374B1 (en) *	1990-12-19	1996-01-31	Takeda Chemical Industries, Ltd.	Bisphosphonic acid derivatives, their production and use
EP0498424A1 (en) *	1991-02-07	1992-08-12	Kaken Pharmaceutical Co., Ltd.	Bisphosphonic acid derivatives and bone resorption inhibitors containing them
CA2102303A1 (en) *	1991-06-19	1992-12-20	Roy Allen Johnson	Dialkyl (dialkoxyphosphinyl) methyl phosphates as anti-inflammatory agents
EP0522576A3 (en) *	1991-07-12	1993-07-14	Hoechst Aktiengesellschaft	Aminoethane-1,1-bisphosphonic acids and aminoethane-1,1-alkylphospinic/phosphonic acids, process of their preparation and their use
EP0541037A3 (en) *	1991-11-06	1997-02-26	Takeda Chemical Industries Ltd	Squalene synthetase inhibitory composition and use thereof
US5391743A (en) *	1992-05-29	1995-02-21	Procter & Gamble Pharmaceuticals, Inc.	Quaternary nitrogen-containing phosphonate compounds, pharmaceutical compositions, and methods of treating abnormal calcium and phosphate metabolism and methods of treating and preventing dental calculus and plaque
US6406714B1 (en)	1992-12-02	2002-06-18	Merck & Co., Inc.	Dry mix formulation for bisphosphonic acids
US5358941A (en) *	1992-12-02	1994-10-25	Merck & Co., Inc.	Dry mix formulation for bisphosphonic acids with lactose
US6399592B1 (en)	1992-12-23	2002-06-04	Merck & Co., Inc.	Bishphosphonate/estrogen synergistic therapy for treating and preventing bone loss
FR2703590B1 (fr) *	1993-04-05	1995-06-30	Sanofi Elf	Utilisation de derives d'acide bisphosphonique pour la preparation de medicaments destines a favoriser la reparation osseuse .
US5854227A (en) *	1994-03-04	1998-12-29	Hartmann; John F.	Therapeutic derivatives of diphosphonates
US20010007863A1 (en)	1998-06-18	2001-07-12	Merck & Co., Inc.	Wet granulation formulation for bisphosphonic acids
AU5973496A (en)	1995-06-06	1996-12-24	Merck & Co., Inc.	Bisphosphonate cement composition to prevent aseptic loosening of orthopedic implant devices
US20030096760A1 (en) *	1997-03-10	2003-05-22	Smithklinebeecham Corporation	Method of antagonizing the human SRC SH2 domain
IT1303672B1 (it)	1998-07-28	2001-02-23	Nicox Sa	Sali nitrati di farmaci attivi nei disordini ossei
AR024462A1 (es)	1999-07-01	2002-10-02	Merck & Co Inc	Tabletas farmaceuticas
US6682718B1 (en) *	1999-11-25	2004-01-27	Yamanouchi Pharmaceutical Co., Ltd.	Remedies for periodontosis
US6677320B2 (en)	2000-01-20	2004-01-13	Hoffmann-La Roches Inc.	Parenteral bisphosphonate composition with improved local tolerance
US20050070504A1 (en) *	2001-12-21	2005-03-31	The Procter & Gamble Co.	Risedronate compositions and their methods of use
HUP0402267A3 (en) *	2001-12-21	2007-05-29	Procter & Gamble	Method for treatment of bone disorders
WO2003061566A2 (en) *	2002-01-24	2003-07-31	Yissum Research Development Company Of The Hebrew University Of Jerusalem	Anti-cancer combination and use thereof
BR0308901A (pt)	2002-05-10	2005-01-04	Hoffmann La Roche	ácidos bisfosfÈnicos para tratamento e prevenção de osteoporose
CA2487977A1 (en) *	2002-06-06	2003-12-18	Merck Frosst Canada & Co./Merck Frosst Canada & Cie	1,5-disubstituted imidazolidin-2-one derivatives for use as ep4 receptor agonists in the treatment of eye and bone diseases
JP2006504679A (ja) *	2002-08-28	2006-02-09	メルクフロストカナダアンドカンパニー	緑内障の治療においてｅｐ４受容体作動薬として使用するためのオキサゾリジン−２−オンおよびチアゾリジン−２−オン誘導体
ES2530791T3 (es)	2002-12-20	2015-03-05	Hoffmann La Roche	Formulación de ibandronato de altas dosis
CN1839114A (zh)	2003-08-21	2006-09-27	默克弗罗斯特加拿大有限公司	组织蛋白酶半胱氨酸蛋白酶抑制剂
AU2004273672A1 (en) *	2003-09-19	2005-03-31	Wisconsin Alumni Research Foundation	Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin D derivatives and a bisphosphonate
US20050261250A1 (en) *	2004-05-19	2005-11-24	Merck & Co., Inc.,	Compositions and methods for inhibiting bone resorption
KR20080083068A (ko)	2004-05-24	2008-09-12	더 프록터 앤드 갬블 캄파니	킬레이팅제를 함유하는 비스포스포네이트의 고형의 장용 경구 투여 형태
UA87854C2 (en)	2004-06-07	2009-08-25	Мерк Энд Ко., Инк.	N-(2-benzyl)-2-phenylbutanamides as androgen receptor modulators
AU2006302797B2 (en)	2005-03-02	2012-02-02	Merck Canada Inc.	Composition for inhibition of cathepsin K
WO2006102117A1 (en) *	2005-03-17	2006-09-28	Elan Pharma International Limited	Nanoparticulate biphosphonate compositions
EP2234608A2 (en)	2007-12-11	2010-10-06	Viamet Pharmaceuticals, Inc.	Metalloenzyme inhibitors using metal binding moieties in combination with targeting moieties
CN101945853B (zh)	2007-12-21	2014-08-20	配体药物公司	选择性雄激素受体调节剂(sarm)及其应用
US20090181138A1 (en)	2008-01-11	2009-07-16	David Howard	Process for producing precooked bacon slices
FR2954320B1 (fr)	2009-12-17	2012-06-15	Cll Pharma	Composition pharmaceutique orale suprabiodisponible contenant un acide biphosphonique ou un de ses sels
EP2675440B1 (en)	2011-02-14	2020-03-25	Merck Sharp & Dohme Corp.	Cathepsin cysteine protease inhibitors
GB201200868D0 (en)	2012-01-19	2012-02-29	Depuy Int Ltd	Bone filler composition
WO2015051479A1 (en)	2013-10-08	2015-04-16	Merck Sharp & Dohme Corp.	Cathepsin cysteine protease inhibitors
RU2692799C2 (ru)	2013-10-08	2019-06-27	Мерк Шарп И Доум Корп.	Ингибиторы цистеинпротеаз катепсинов
WO2015120580A1 (en)	2014-02-11	2015-08-20	Merck Sharp & Dohme Corp.	Cathepsin cysteine protease inhibitors
PL407922A1 (pl)	2014-04-16	2015-10-26	Wrocławskie Centrum Badań Eit + Spółka Z Ograniczoną Odpowiedzialnością	Nowe bisfosfoniany i ich zastosowanie
ES2864079T3 (es)	2014-05-30	2021-10-13	Pfizer	Derivados de carbonitrilo como moduladores selectivos del receptor de andrógenos
AU2020257397B2 (en)	2019-04-19	2026-02-26	Ligand Pharmaceuticals Inc.	Crystalline forms and methods of producing crystalline forms of a compound
WO2023275715A1 (en)	2021-06-30	2023-01-05	Pfizer Inc.	Metabolites of selective androgen receptor modulators

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
DE1958123C3 (de) *	1969-11-19	1978-09-28	Henkel Kgaa, 4000 Duesseldorf	Verfahren zur Herstellung von 1 -Aminoalkan-1,1 -diphosphonsäuren oder deren Salzen
DE2037586C3 (de) *	1970-07-29	1980-05-22	Henkel Kgaa, 4000 Duesseldorf	Gipsmassen
DE2104476C2 (de) *	1971-02-01	1983-12-01	Henkel KGaA, 4000 Düsseldorf	Verfahren zur Verhinderung von Ausfällungen in Wasser oder wäßrigen Lösungen
DE3540150A1 (de) *	1985-11-13	1987-05-14	Boehringer Mannheim Gmbh	Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel
CA1339805C (en) *	1988-01-20	1998-04-07	Yasuo Isomura	(cycloalkylamino)methylenebis(phosphonic acid) and medicines containing the same as an active
JPH01231980A (ja) *	1988-03-10	1989-09-18	Ishikawajima Harima Heavy Ind Co Ltd	管内作業用ピグ

1989
- 1989-01-16 CA CA000588341A patent/CA1339805C/en not_active Expired - Fee Related
- 1989-01-19 PH PH38068A patent/PH26819A/en unknown
- 1989-01-20 DK DK198900243A patent/DK174744B1/da not_active IP Right Cessation
- 1989-01-20 AT AT89300560T patent/ATE74361T1/de not_active IP Right Cessation
- 1989-01-20 AU AU28670/89A patent/AU615711B2/en not_active Ceased
- 1989-01-20 EP EP89300560A patent/EP0325482B1/en not_active Expired - Lifetime
- 1989-01-20 CN CN89101539A patent/CN1022630C/zh not_active Expired - Lifetime
- 1989-01-20 DE DE8989300560T patent/DE68901097D1/de not_active Expired - Lifetime
- 1989-01-20 HU HU89230A patent/HU202243B/hu not_active IP Right Cessation
- 1989-01-20 ES ES198989300560T patent/ES2032105T3/es not_active Expired - Lifetime
- 1989-01-20 KR KR1019890000568A patent/KR970005179B1/ko not_active Expired - Lifetime
- 1989-01-20 IE IE18389A patent/IE60477B1/en not_active IP Right Cessation
- 1989-01-23 US US07/300,350 patent/US4970335A/en not_active Expired - Lifetime
1990
- 1990-07-10 US US07/551,434 patent/US5041428A/en not_active Expired - Lifetime
1992
- 1992-04-29 GR GR920400827T patent/GR3004461T3/el unknown

Also Published As

Publication number	Publication date
US5041428A (en)	1991-08-20
US4970335A (en)	1990-11-13
CN1035829A (zh)	1989-09-27
EP0325482B1 (en)	1992-04-01
DK24389A (da)	1989-07-21
DE68901097D1 (de)	1992-05-07
HU202243B (en)	1991-02-28
DK24389D0 (da)	1989-01-20
KR970005179B1 (ko)	1997-04-14
GR3004461T3 (es)	1993-03-31
KR890011601A (ko)	1989-08-21
IE60477B1 (en)	1994-07-13
HUT50841A (en)	1990-03-28
EP0325482A1 (en)	1989-07-26
ATE74361T1 (de)	1992-04-15
DK174744B1 (da)	2003-10-13
IE890183L (en)	1989-07-20
ES2032105T3 (es)	1993-01-01
CN1022630C (zh)	1993-11-03
CA1339805C (en)	1998-04-07
AU2867089A (en)	1989-07-20
AU615711B2 (en)	1991-10-10

Publication	Publication Date	Title
CA1339805C (en)	1998-04-07	(cycloalkylamino)methylenebis(phosphonic acid) and medicines containing the same as an active
EP0252505B1 (de)	1992-09-16	1-Hydroxy-3-(N-methyl-N-propylamino)propan-1,1-diphosphonsäure; Verfahren zu dessen Herstellung und diese Verbindung enthaltende Arzneimittel
EP0354806B1 (en)	1995-11-02	Heterocyclic bisphosphonic acid derivatives
US5013725A (en)	1991-05-07	Pharmaceutical compositions substituted aminomethylenebis(phosphonic acid) derivatives
GB2118042A (en)	1983-10-26	Pharmaceutical compositions containing biphosphonic acids
RU2079504C1 (ru)	1997-05-20	Новые производные бисфосфоновой кислоты и способ их получения
EP0282320B1 (en)	1991-12-11	Bisphosphonic acid derivatives and medicines containing the same
CA1321198C (en)	1993-08-10	Heterocycle-substituted diphosphonate compounds, pharmaceutical compositions, and methods of treating abnormal calcium and phosphate
AU615886B2 (en)	1991-10-17	Novel bicyclic diphosphonate compounds, pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism
CN1040110C (zh)	1998-10-07	新的含无环脒基团的二膦酸衍生物及基制备方法以及含该物的药用组合物
EP0282309A2 (en)	1988-09-14	Azole-aminomethylene bisphosphonic acid derivatives
JPH0248587A (ja)	1990-02-19	複素環置換ビスフォスフォン酸誘導体及びその医薬
JPH07629B2 (ja)	1995-01-11	（シクロアルキルアミノ）メチレンビス（フォスフォン酸）および該化合物を有効成分とする医薬
JPH02288886A (ja)	1990-11-28	置換アミノメチレンビスフォスフォン酸誘導体