CN1157565A - Method for treatment of osteoporosis using bone active phosphonates and parathyroid hormone - Google Patents
Method for treatment of osteoporosis using bone active phosphonates and parathyroid hormone Download PDFInfo
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- CN1157565A CN1157565A CN95195007A CN95195007A CN1157565A CN 1157565 A CN1157565 A CN 1157565A CN 95195007 A CN95195007 A CN 95195007A CN 95195007 A CN95195007 A CN 95195007A CN 1157565 A CN1157565 A CN 1157565A
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- China
- Prior art keywords
- phosphonic acid
- ethylhexyl phosphonic
- hydroxyl
- acid
- bone
- Prior art date
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- 210000000988 bone and bone Anatomy 0.000 title claims abstract description 65
- 238000000034 method Methods 0.000 title claims abstract description 61
- 102000003982 Parathyroid hormone Human genes 0.000 title claims abstract description 40
- 108090000445 Parathyroid hormone Proteins 0.000 title claims abstract description 40
- 239000000199 parathyroid hormone Substances 0.000 title claims abstract description 40
- 229960001319 parathyroid hormone Drugs 0.000 title claims abstract description 40
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 title claims description 12
- 208000001132 Osteoporosis Diseases 0.000 title description 53
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims abstract description 39
- 241001465754 Metazoa Species 0.000 claims abstract description 14
- JJJOZVFVARQUJV-UHFFFAOYSA-N 2-ethylhexylphosphonic acid Chemical compound CCCCC(CC)CP(O)(O)=O JJJOZVFVARQUJV-UHFFFAOYSA-N 0.000 claims description 61
- 150000002148 esters Chemical class 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 20
- 239000001177 diphosphate Substances 0.000 claims description 17
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims description 16
- 235000011180 diphosphates Nutrition 0.000 claims description 16
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- HJZKOAYDRQLPME-UHFFFAOYSA-N oxidronic acid Chemical compound OP(=O)(O)C(O)P(O)(O)=O HJZKOAYDRQLPME-UHFFFAOYSA-N 0.000 claims description 7
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- ZVVVWZBHPWZJIA-UHFFFAOYSA-N diphosphonomethanesulfonic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)S(O)(=O)=O ZVVVWZBHPWZJIA-UHFFFAOYSA-N 0.000 claims description 4
- MBKDYNNUVRNNRF-UHFFFAOYSA-N medronic acid Chemical compound OP(O)(=O)CP(O)(O)=O MBKDYNNUVRNNRF-UHFFFAOYSA-N 0.000 claims description 4
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- 125000000217 alkyl group Chemical group 0.000 description 57
- -1 pyridine radicals Chemical class 0.000 description 55
- 150000001408 amides Chemical class 0.000 description 32
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 31
- 229910052739 hydrogen Inorganic materials 0.000 description 19
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Classifications
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- 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
-
- 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
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
-
- 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
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
- A61P5/12—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH for decreasing, blocking or antagonising the activity of the posterior pituitary hormones
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physical Education & Sports Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Zoology (AREA)
- Diabetes (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Nutrition Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides methods of treating a human or other animal subject having a bone metabolism disorder, comprising the steps of: (a) administering to said subject a safe and effective amount of a bone active phosphonate during a period of at least about 6 months; (b) administering to said subject a safe and effective amount of a parathyroid hormone, during a period of from about 3 to about 12 months.
Description
Background of invention
The present invention relates to increase the method for sclerotin in people and other animals, i.e. the treatment of osteoporosis and related bone metabolic disease.Particularly, the present invention relates to by using the method that bone active phosphonate and parathyroid hormone are treated.
The bone imbalance of modal metabolic type is an osteoporosis.Osteoporosis can be defined as the minimizing of bone quantity usually, or the atrophy of osseous tissue.2 types osteoporosis is generally arranged: constitutional and Secondary cases." secondary osteoporosis " is by appraisable lysis or material and cause.Yet about 90% is " primary osteoporosis " in all osteoporosis.This primary osteoporosis comprises the essential osteoporosis of osteoporosis after the amenorrhea, the osteoporosis relevant with the age (influencing most of individualities that the age surpasses 70-80 year) and influence middle age and younger Men's and Women's.
For some osteoporosis individualities, the forfeiture of osseous tissue is enough serious, thereby causes the mechanicalness of bone structure to lose efficacy.For example in the women who suffers from post menopausal osteoporosis disease, buttocks and spinal column are fractured through being everlasting.Also can cause kyphosis (curvature anomalies of breast spinal column increases).
The mechanism that it is believed that bone forfeiture in osteoporosis relates to the unbalance of " bone remodeling " process.Bone remodeling is all taking place in life, to upgrade skeleton and to keep bone strength.This reinventing relates to, and each site of bone surface is corroded and filled up by the one group of cell that is called " basic many cells unit " or " BMU ", and BMU mainly is made of " osteoclast ", " osteoblast " and precursor thereof.In remodeling process, bone is absorbed by osteoclast in " activated " BMU site, forms to absorb hole.This hole is filled up by osteoblast again then.
Generally, remodeling process can cause losing for a short time of bone in the adult, because do not fill up the bone resorption hole fully.Like this, even in the adult of health, the bone forfeiture relevant with the age takes place also.Yet, especially to suffer among the people of post menopausal osteoporosis disease many people, the number of the BMU that is activated can increase.Bone remodeling has been quickened in this more activation, thereby causes unusual high bone forfeiture.
Although its cause of disease is not also understood fully, there are many risk factors to be considered to relevant with osteoporosis.These factors comprise that body weight is low, the calcium absorption is low, do not get enough athletic exercise and oestrogen deficiencies.
The compositions and the method for " treatment " osteoporosis of many being used for have been described in medical literature.Many in these compositionss and the method are to attempt the net increase that slows down the bone forfeiture or produce sclerotin.Referring to for example R.C.Haynes, Jr. wait the people, " influence the material of calcification " (" Agents affectingCalcification "), treatment basic medical (The Pharmacological Basis of Therapeutics), the 7th edition (A.G.Gilman, people such as L.S.Goodman edit, and 1985); People such as G.D.Whedon, " analysis of present notion in osteoporosis and research interest " (＂ An Analysis of CurrentConcepts and Research Interest in Osteoporosis ＂), the present progress (Current Advances in Skeletogenesis) that skeleton forms people such as (edit 1985) A.Ornoy; With people such as W.A.Peck, the doctor is published by state-run osteoporosis foundation (National OsteoporosisFoundation) with osteoporosis Fact Book (Physician ＇ s Resource Manualon Osteoporosis) (1987).
In the Therapeutic Method of the osteoporosis of Ti Chuing, the method for using diphosphate or other bone active phosphonates is arranged in the literature.Referring to people such as for example Storm, " intermittent, periodically the treatment of vitamin D3 phosphonate in suffering from post menopausal osteoporosis disease women to the influence of bone mineralising and fracture rates " (＂ Effect ofIntermittent Cyclical Etidronate Therapy on Bone Mineralization and FractureRate in Women with Post-Menopausal Osteoporosis ＂) 322 new BMJs (New England Journal of Medicine) 1265 (1990); With people such as Watts, " intermittence of post menopausal osteoporosis disease, periodicity vitamin D3 phosphonate therapy " (＂ IntermittentCyclical Etidronate Treatment of Post-Menopausal Osteoporosis ＂), 323 new BMJs (New England Journal of Medicine) 73 (1990).This class uses the Therapeutic Method of various diphosphate to be described in United States Patent (USP) 4,761,406, people such as Flora, and on August 2nd, 1988 authorized; United States Patent (USP) 4,812,304, people such as Anderson, on March 14th, 1989 authorized; United States Patent (USP) 4,812,311, people such as Uchtman, on March 14th, 1989 authorized; With United States Patent (USP) 4,822,609, people such as Flora, on April 18th, 1989 authorized.This phosphonate is used for the treatment of osteoporosis and other relate to the purposes of abnormal calcium and the metabolic disease of phosphonate, also is disclosed in United States Patent (USP) 3,683,080, Francis, and on August 8th, 1972 authorized; United States Patent (USP) 4,330,537, Francis, on October 28th, 1980 authorized; United States Patent (USP) 4,267,108, people such as Blum, on May 12nd, 1981 authorized; European patent publication 298,553, Ebetino, on January 11st, 1989 published; With people's " chemistry of diphosphate, biochemistry and medicinal properties " (＂ Chemical such as Francis, Biochemical, and Medicinal Properties of Diphosphonates ＂), the effect (The Role of Phosphonates in Living System) of phosphonate in live body, the 4th chapter (1983).
Use estrogen and also be used as the means that prevent osteoporosis after the amenorrhea among the women.This Therapeutic Method is used other estrogen of about 0.625-1.25 milligram conjugated estrogen hormone or a great deal of typically every day.Estrogen also is used to treat osteoporosis (being the actual formation of bone in the osteoporosis), although do not establish fully as yet.Referring to for example Barzel, " estrogen in the prevention of post menopausal osteoporosis disease and treatment: summary " (＂ Estrogens in the Prevention and Treatment of Post-Menopausal Osteoporosis:a Review ＂), 85 JAMA (American Journalof Medicine) 847 (1988); Barzel, " estrin treatment of osteoporosis: effectively not? " (＂ Estrogen Therapy for Osteoporosis:It is Effective? ＂), hospital puts into practice (HospitalPractice) 95 (1990); People such as Ettinger, " treatment with low dose estrogen and calcium has prevented the forfeiture of post menopausal osteoporosis disease bone " (＂ Post-Menopausal Bone Loss is Prevented byTreatment with Low-Dosage Estrogen with Calcium ＂), 106 internal medicine annual reports (Annals in Internal Medicine) 40 (1987); People such as Lindsay, " be used to prevent the estrogen minimum effective dose of post menopausal osteoporosis disease bone forfeiture " (＂ The Minimum Effective Doseof Estrogen for Prevention of Post-Menopausal Bone Loss ＂), 63 obstetrics and gynecology (Obstetrics and Gynecology) 759 (1984); " estrogen " (＂ Estrogen ＂), drug information (Drug Information) 1765 (1990); With world patent publication 92 14474, McOsker, JIUYUE was published on the 3rd in 1992.In addition, estrogenic use is relevant with some side effect, for example metrorrhagia.Referring to Rudy, " hormone replacement therapy-how to select optimal formulation and scheme " (＂ Hormone Replacement Therapy-How to Select the Best Preparation andRegimen ＂), 88 postgraduate's medical science (Postgraduate Medicine) 157 (1990).
Parathyroid hormone also is suggested a kind of therapy as osteoporosis.Use the Therapeutic Method of parathyroid hormone to be disclosed in following document: people such as Hefti, " increase of whole body calcium and bone mass in the adult rat of normal and osteoporosis when handling " (＂ Increase of Whole--Body Calcium and Skeletal Mass in Normal and Osteoporotic Adult RatsTreated with Parathyroid Hormone ＂) with parathyroid hormone, 62 Clinical Sciences (Clin.Sci.) 389-396 (1982); People such as Hock, " the stimulation in rats osteogenesis is also nonessential in vivo for hPTH-(1-34) in absorption " (＂ Resorption Is Not Essential for the Stimulation of Bone Growth byhPTH-(1-34) in Rats In Vivo ＂), 4 (3). bone and mineralising research magazine (Jnl of Bone andMineral.Res.) 449-45 8 (1 989); German patent publication thing DE 39 35 738, Forssman, on May 8th, 1991 published; United States Patent (USP) 4,698,328, people such as Neer, on October 6th, 1987 authorized; United States Patent (USP) 4,833,125, people such as Neer, on May 23rd, 1989 authorized; United States Patent (USP) 5,118,667, people such as Adams, on June 2nd, 1992 authorized; World patent publication 93 11786, Geddes and Boyce published on June 24th, 1993; United States Patent (USP) 4,822,609, Flora, on April 18th, 1989 authorized; United States Patent (USP) 4,812,304, people such as Anderson, on March 14th, 1989 authorized; German patent publication thing DE 32 43 358, Hesch, on May 24th, 1984 published; People such as Hesch " with (1-38hPTH and diphosphate EHDP carry out the result of stimulation therapy to the low bone metabolism of osteoporosis " (" Results of a StimulatingTherapy of Low Bone Metabolism in Osteoporosis with (1-38hPTH andDiphosphonate EHDP ＂) 66 (19) Klin Wschr.976-984 (in October, 1988); German patent publication thing DE 32 43 358, Hesch, on May 24th, 1984 published; People such as Delling, " in the morphological research of carrying out ADFR treatment osteoporosis midpelvis ridge spongiosa with parathyroid hormone and diphosphate " (＂ Morphologic Study of Pelvic Crest Spongiosa in Patients withOsteoporosis During ADFR Therapy with Parathyroid Hormone andDiphosphonates ＂), 128 (1) Z.Orthop.1-5 (1990) (hereinafter referred to as people such as " " Delling); With people such as Delmas, " when bone resorption is blocked by diphosphate in the body of hPTH-(1-34) anabolism effect by bluntization ", (＂ The In Vivo Anabolic Effect of hPTH-(1-34) is Blunted when Bone Resorption Is Blocked by ABiphosphonate ＂) 6 (1) bones and mineralising research (J.Bone Mineral Res.) S136 (#214) (in August, 1991).
The applicant is surprisingly found out that administering parathyroid hormone can provide this area still unrecognized benefit after using the bone active phosphonate.Therefore, the inventive method provides the method for effective prevention and treatment osteoporosis, compares it with those methods as known in the art and renders a service higher and side effect is littler.
Summary of the invention
The invention provides a kind of method that the human body of suffering from bone metabolism imbalance or other animal target are treated, it consists essentially of the following step: in (a) during greater than about 6 months, give the bone active phosphonate of described object effective dose safe in utilization; (b) in during about 3-12 month, give the parathyroid hormone of described object effective dose safe in utilization.
The description of invention
The inventive method comprises to human body or other animal target uses bone active phosphonate and parathyroid hormone chemical compound.Therefore, particular compound or the compositions of using in the method must be pharmaceutically acceptable.In this article, this " pharmaceutically acceptable " component is applicable to the mankind and/or animal, does not have undue adverse side effect (as toxicity, stimulating and anaphylaxis), and rational interests/risk ratio is arranged again.
The bone active phosphonate
The inventive method comprises uses one or more bone active phosphonates.In this article, " bone active phosphonate " comprises the chemical compound of one or more following general formulas:
And pharmaceutically acceptable salt class and esters, A wherein, B and R are as following qualification.
In general formula (1), " R " is hydroxyl (for diphosphonates), or hydrogen, or alkyl (for the phosphine acyl-alkyl phosphonates).In the phosphine acyl-alkyl phosphonate, R is unsubstituted alkyl preferably, particularly low alkyl group.When R was substituted alkyl, substituent group comprised halogen preferably, the unsubstituted or phenyl that replaces, and the pyridine radicals that replaces or replace not, unsubstituted amino, by the amino that one or two low alkyl group replaces, hydroxyl or carboxyl.Best substituent group comprises fluorine, phenyl, unsubstituted amino and hydroxyl; Preferably fluorine (when particularly existing) and phenyl with the trifluoromethyl form.
Best R partly is unsubstituted low alkyl group in the phosphine acyl-alkyl phosphonate, the saturated low alkyl group of particularly unsubstituted straight chain.R partly is methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group and n-hexyl equally preferably.R is methyl preferably, ethyl, n-pro-pyl or normal-butyl.R is preferably methyl.
In general formula (1), " A " is hydrogen; Halogen; Nitro; Alkyl; Heterocyclic radical; Aryl; Heteroaryl; Unsubstituted amino or its amide derived from the substituent group carboxylic acid; With a substituent amino or its amide derived from the substituent group carboxylic acid; Respectively by an alkyl and the amino that substituent group replaces; Hydroxyl or its ester derived from the substituent group carboxylic acid; Has a substituent ether; Thiol or its mercaptan ester derived from the substituent group carboxylic acid; Have a substituent thioether or its sulfoxide and sulfone derivative;-SO
3H and pharmaceutically acceptable salt thereof, it is derived from the ester of substituent group alcohol, its unsubstituted amide, or its amide that is replaced by one or two alkyl;-CO
2H, its pharmaceutically acceptable salt, it is derived from the ester of substituent group alcohol, its unsubstituted amide or its amide that is replaced by one or two alkyl; Aldehyde; Has a substituent ketone; Carbamate unsubstituted or that replaced by one or two alkyl; Peptide class with about l-100 amino acid moiety; Or A and B part covalently is joined together to form and has 3-7 atom (wherein 0-3 is individual for being selected from nitrogen, sulfur, the hetero atom of phosphorus and oxygen) ring, this ring can be replaced by the substituent group of one or more above-mentioned A or not replace, perhaps two parts of A and B are connected to moieties unsubstituted together with on the carbon atom (geminal carbon, this carbon atom are presented in the top structure (1)) or that replace and are replaced with two keys.
A is preferably one of following part:
(1) hydrogen
(2) halogen (be preferably fluorine or chlorine, be preferably fluorine)
(3) have the replacement or the unsubstituted alkyl of following array structure:
Wherein:
(a) n is the integer of 1-10, is preferably 1-5, is preferably 1 or 2, is preferably 1;
(b) R
1Be respectively hydrogen, halogen, low alkyl group, unsubstituted amino or its amide derived from the carboxylic acid of low alkyl group, by amino or its amide of a low alkyl group replacement derived from the carboxylic acid of low alkyl group, respectively by the amino of two low alkyl groups replacements, hydroxyl or its carboxylate ,-CO derived from low alkyl group
2H, its pharmaceutically acceptable salt, its ester derived from lower alkyl alcohol, its unsubstituted amide or its are had the ether of two low alkyl groups ,-PO by the amide that one or two low alkyl group replaces
3H
3Or its pharmaceutically acceptable salt, and nitro, perhaps two R on same carbon atom
1Be=O or=NR
9(R wherein
9Be low alkyl group, or on same carbon atom, be connected with another nitrogen-atoms conduct=NR
9During part, it can be a hydrogen), perhaps two R on adjacent two carbon atoms
1Can be replaced by another key between two carbon atoms; The perhaps R on first carbon atom
1(right sides in said structure (2)) and B (referring to said structure (1)) can be replaced by an other key;
(c) Y is a halogen; Nitro; Cyano group; Heterocyclic radical; Aryl; Heteroaryl; Unsubstituted amino or its amide derived from alkyl, heterocyclic radical, aryl or heteroaryl carboxylic acid; By amino and its amide of an alkyl, heterocyclic radical, aryl or heteroaryl replacement derived from alkyl carboxylic acid; Respectively by an alkyl and the amino that alkyl, heterocyclic radical, aryl or heteroaryl replace; Hydroxyl and its ester derived from alkyl, heterocyclic radical, aryl or heteroaryl carboxylic acid; Ether with alkyl, heterocyclic radical, aryl or a heteroaryl; Thiol and its mercaptan ester derived from alkyl, heterocyclic radical, aryl or heteroaryl carboxylic acid; Thioether and its sulfoxide and sulfone derivative with alkyl, heterocyclic radical, aryl or a heteroaryl;-SO
3H, its pharmaceutically acceptable salt, it is derived from the ester of alkylol, its unsubstituted amide and its amide that is replaced by one or two alkyl;-CO
2H, its pharmaceutically acceptable salt, it is derived from the ester of alkylol, its unsubstituted amide and its amide that is replaced by one or two alkyl; PO
3H
2, its pharmaceutically acceptable salt, it is derived from the ester of alkylol, its unsubstituted amide and its amide that is replaced by one or two alkyl;-(R
8) PO
2H (R wherein
8Be hydrogen or unsubstituted low alkyl group), its pharmaceutically acceptable salt, it is derived from the ester of alkylol, its unsubstituted amide and its amide that is replaced by one or two alkyl; Aldehyde; Ketone with an alkyl; Carbamate unsubstituted or that replaced by one or two alkyl; Perhaps peptidyl.With regard to diphosphonates, Y is preferably heterocyclic radical (the 5-7 unit heterocyclic radical that preferably has one or two nitrogen-atoms); Amino; With the amino that replaces.Y partly is preferably pyridine radicals, amino and the amino that is replaced by one or two low alkyl group.With regard to the phosphine acyl-alkyl phosphonates, Y is preferably halogen (preferably fluorine); Trifluoromethyl; Ether with two low alkyl groups; Unsubstituted amino and derived from low-grade alkyl carboxylic acid's amide is by replace amino of a low alkyl group and derived from low-grade alkyl carboxylic acid's amide; Respectively by the amino of two low alkyl groups replacements; The peptidyl that perhaps has about 6 amino acid moieties of 1-.
(4) have 4-10 carbon atom, be preferably the cycloalkyl of 5 or 6 carbon atoms.
(5) have and be preferably 1 or 2 nitrogen-atoms in 5 or 6 annular atomses, the ring, preferably the heterocycle of 1 nitrogen-atoms arranged.Preferred heterocycle is that replace or unsubstituted piperidyl, pyrrolidinyl (pyrollidino), piperazinyl and morpholinyl.
(6) phenyl that does not replace and replace and naphthyl.
(7) 5-6 unit aromatic heterocyclic, the preferably pyridine radicals that has the not replacement of 1 or 2 hetero atom (preferably nitrogen heteroatom) or replace.
(8) have the amine moiety that contains of following general formula:
Wherein:
(a) m is 0-10, better is 0-5,0 or 1, preferred 0 integer preferably;
(b) R
1With Y as top definition;
(c) R
2Be hydrogen, low alkyl group or derived from low-grade alkyl carboxylic acid's acyl group.
What (9) have a following general formula contains the oxygen part:
Wherein:
(a) m is 0-10, better is 0-5,0 or 1, preferred 0 integer preferably;
(b) R
1With Y as top definition.
(10) have the sulfur-bearing part of following general formula:
Wherein:
(a) m is 0-10, better is 0-5,0 or 1, preferred 0 integer preferably;
(b) R1 and Y are as top definition.
In general formula (1), " B " is hydrogen; Halogen; The low alkyl group that does not replace or replace; The 3-7 unit cycloalkyl that does not replace or replace; Replace or unsubstituted 3-7 unit heterocyclic radical; Replace or unsubstituted phenyl; Hydroxyl or its ester derived from the low-grade alkyl carboxylic acid; Thiol; Unsubstituted amino or its amide derived from the low-grade alkyl carboxylic acid; By amino or its amide of a low alkyl group replacement derived from the low-grade alkyl carboxylic acid; Respectively by the amino of two low alkyl groups replacements; Or-CO
2H, its pharmaceutically acceptable salt, it is derived from the ester of lower alkyl alcohol, its unsubstituted amide or its amide that is replaced by one or two low alkyl group.
For making these chemical compounds keep chemically stable, A and B part preferably do not have two hetero atoms (nitrogen, oxygen or sulfur) or a hetero atom and halogen atom that is bonded on the phosphate radical part (promptly by the disubstituted carbon atom of phosphorus atoms) simultaneously.Therefore, when A partly had the oxygen that is bonded on the mesomethylene carbon atom that phosphorus replaces, sulfur, nitrogen or halogen atom, B was chosen as hydrogen; The low alkyl group that does not replace or replace, cycloalkyl, heterocyclic radical (a wherein heterocyclic carbon atom bonding is extremely together with on the carbon atom), or phenyl,-COOH, and pharmaceutically acceptable salt, derived from the ester of lower alkyl alcohol, its unsubstituted amide and the amide that is replaced by one or two low alkyl group thereof.
B is preferably hydrogen, halogen, the not low alkyl group that replaces or replace; The phenyl that does not replace or replace; The benzyl that does not replace or replace, hydroxyl or its ester derived from the low-grade alkyl carboxylic acid, thiol, unsubstituted amino or its amide derived from the low-grade alkyl carboxylic acid, by amino or its amide of a low alkyl group replacement derived from the low-grade alkyl carboxylic acid, the amino that is replaced by two low alkyl groups respectively, or-CO
2H, its pharmaceutically acceptable salt, it is derived from the ester of lower alkyl alcohol, and unsubstituted amide or its amide that is replaced by one or two low alkyl group.
B better is a hydrogen, chlorine, methyl, ethyl, hydroxyl, thiol, unsubstituted amino, (N-methyl) amino, (N, N-dimethyl) amino ,-COOH or its medically acceptable salt ,-COOCH
2, or-CONH
2B is preferably hydrogen, methyl, chlorine, amino or hydroxyl; Be preferably hydrogen, hydroxyl, amino or thiol; Be preferably hydroxyl.Preferred bone active phosphonates comprises that those A wherein are above-mentioned (3) or (8) group part, and B is the phosphonate of hydroxyl.
Be applicable to that preferred diphosphonates of the present invention has following general formula:
And pharmaceutically acceptable salt and ester.Wherein: n is the integer (be preferably 0-3, be preferably 1) of 0-7; R
1Be hydrogen, chlorine, amino or hydroxyl (being preferably hydrogen or hydroxyl); X is-NH-quaternary amine, oxygen, sulfur or singly-bound (being preferably-NH-or singly-bound); R
2Be that the first carbocylic radical of 5-7 that replace or unsubstituted (is preferably 6-7 unit carbocyclic ring, be preferably phenyl or suberyl), has 1-3 heteroatomic replacement or unsubstituted 5-7 unit heterocyclic radical (be preferably 6 yuan of heterocyclic radicals with 1 or 2 nitrogen-atoms, theheterocyclic nitrogen atom wherein can be quaternary ammoniated) ,-NH
2, by an alkyl or two alkyl (best C
1-C
5) replace the amino form secondary amine or tertiary amine respectively, season amino or hydrogen; If R wherein
2Be 5-7 unit's carbocyclic ring or the heterocyclic radical that replaces, then substituent group is one or more alkyl that are selected from replacement or about 6 carbon atoms of unsubstituted, the saturated or undersaturated 1-of having, replace or unsubstituted aryl, replacement or unsubstituted benzyl, hydroxyl, halogen, carbonyl, alkoxyl, nitro, acylamino-, amino, the amino of replacement, carboxylate group, and composition thereof, wherein hydrogen is best; R
3Be respectively hydrogen, have the replacement or a unsubstituted alkyl (saturated or undersaturated) of about 4 carbon atoms of 1-.
In this article, term " pharmaceutically acceptable salt or ester " is meant the hydrolyzable esters and the salt of bone active phosphonates, and they have overall identical pharmaceutical property with raw material acid and are pharmaceutically acceptable.Pharmaceutically acceptable salt comprises, alkali metal (as sodium and potassium) for example, alkaline-earth metal (as calcium and magnesium), the ammonium that avirulent heavy metal (as stannum and indium) and ammonium and low-molecular-weight replace (as one, two and triethanolamine) salt.Mixture is a sodium preferably, potassium and ammonium salt.Pharmaceutically acceptable ester comprises alkyl, aryl and the phosphorylic ester that does not replace or replace.The non-limitative example of pharmaceutically acceptable ester comprises, isopropyl for example, the tert-butyl group, 2-chloroethyl; 2,2,2-three chloroethyls; 2,2, the 2-trifluoroethyl; the p-toluenesulfonyl ethyl, glycyl, sarcosyl (sarcosyl); benzyl, phenyl, 1; 2-hexanoyl glyceryl, p-nitrophenyl, 2; 2-dimethyl-1,3-dioxolyl (dioxolene)-4-methyl, isopentene group; adjacent carbomethoxy phenyl, oxy acid methyl neopentyl salicyl, lignocaine phosphoryl; oxy acid methyl neopentyl, acyloxy methyl, propionyloxy methyl; isobutyl acyl-oxygen ylmethyl, dodecyl, octadecyl and isopropoxy methyl ester.
Be applicable in substituent object lesson of formula (1)-(6) chemical compound and the European patent publication 298,553 (list in this draw be with reference to) that definition is disclosed in disclosed Ebetino on January 11st, 1989.This application has also been described the phosphine acyl-alkyl phosphinates (wherein R is a hydrogen or alkyl) that is applicable to the inventive method, and the preparation method of this chemical compound.The preparation method of phosphine acyl-alkyl phosphinic acid salt also can be referring to the European patent publication 298,555 of disclosed Ebetio on January 11st, 1989 (list in this draw be with reference to).
The preparation method that is applicable to the diphosphonates (wherein R is a hydroxyl) of the inventive method and these chemical compounds can be referring to following patent literature, and all these documents are all listed in this and drawn and be reference: the United States Patent (USP) 3,553,314 of the Francis that on January 5th, 1971 announced; The United States Patent (USP) 3,683,080 of the Francis that on August 8th, 1972 announced; The United States Patent (USP) 3,846,420 of the Wollmann that on November 5th, 1974 announced etc.; The United States Patent (USP) 3,899,496 of the Schindler that on August 12nd, 1975 announced etc.; The United States Patent (USP) 3,941,772 of the Ploger that on March 2nd, 1976 announced etc.; The United States Patent (USP) 3,957,160 of the Ploger that on May 18th, 1976 announced etc.; The United States Patent (USP) 3,962,432 of the Schmidt-Dunker that on June 8th, 1976 announced; The United States Patent (USP) 3,979,385 of the Wollmann of JIUYUE in 1976 announcement on the 7th etc.; The United States Patent (USP) 3,988,443 of the Ploger that on October 26th, 1976 announced etc.; The United States Patent (USP) 4,054,598 of the Blum that on October 18th, 1977 announced etc.; The United States Patent (USP) 4,113,861 of the Fleisch of JIUYUE in 1978 announcement on the 12nd etc.; The United States Patent (USP) 4,117,090 of the Ploger of JIUYUE in 1978 announcement on the 26th; The United States Patent (USP) 4,134,969 of the Schmidt-Dunker that on January 16th, 1979 announced; The United States Patent (USP) 4,267,108 of the Blum that on May 12nd, 1981 announced etc.; The United States Patent (USP) 4,304,734 of the Jary of December in 1981 announcement on the 8th etc.; The United States Patent (USP) 4,330,537 of the Francis that announce May 18 nineteen eighty-two; The United States Patent (USP) 4,407,761 of the Blum that announce October 4 nineteen eighty-three; The United States Patent (USP) 4,469,686 of the Andrews of JIUYUE in 1984 announcement on the 4th; The United States Patent (USP) 4,578,376 of the Rosini that on March 25th, 1986 announced; The United States Patent (USP) 4,608,368 of the Blum that on August 26th, 1986 announced etc.; The United States Patent (USP) 4,621,077 of the Rosini that on November 4th, 1986 announced etc.; The United States Patent (USP) 4,687,767 of the Bosies that on August 18th, 1987 announced etc.; The United States Patent (USP) 4,687,768 of the Benedict that on October 18th, 1987 announced etc.; The United States Patent (USP) 4,711,880 of the Stahl of December in 1987 announcement on the 8th etc.; The United States Patent (USP) 4,719,203 of the Bosies that on January 12nd, 1988 announced etc.; The United States Patent (USP) 4,927,814 of the Gall that announce May 22 nineteen ninety etc.; The United States Patent (USP) 4,990,503 of the Isomura that on February 5th, 1991 announced etc.; August in 1972 disclosed Worms on the 17th German patent application 2,104,476; April in 1975 disclosed Ploeger on the 3rd etc. German patent application 2,343,147; June in 1975 disclosed Worms on the 26th etc. German patent application 2,360,798; October in 1976 disclosed Schmidt-Dunker on the 7th German patent application 2,513,966; March in 1977 disclosed Eimers on the 24th etc. German patent application 2,541,981; April in 1985 disclosed Blum on the 4th German patent application 3,334,211; The Japan Patent 78/59,674 of the Suzuki that on May 29th, 1978 announced etc.; The Japan Patent 79/135,724 of the Suzuki that on October 22nd, 1979 announced etc.; The Japan Patent 80/98193 of the Suzuki that on July 25th, 1980 announced etc.; The European patent 88,359 of the Blum of nineteen eighty-three JIUYUE announcement on the 14th etc.; The European patent 100,718 of the Breliere that on February 15th, 1984 announced; The European patent 186,405 of the Benedict that on July 2nd, 1986 announced etc.; The European patent 197,478 of the Bosies that on October 15th, 1986 announced etc.; The European patent 230,068 of the Benedict that on July 29th, 1987 announced etc.; The European patent 273,514 of the Ebetino that on July 6th, 1988 announced etc.; The European patent 274,158 of the Ebetino that on July 13rd, 1988 announced etc.; The European patent 282,309 of the Sakamoto of JIUYUE in 1988 announcement on the 14th etc.; The European patent 282,320 of the Isomura of JIUYUE in 1988 announcement on the 14th etc.; The PCT patent of the Binderup that announced on June 18th, 1987 etc. announces 87/03598, and the PCT patent of the Gall that announced on January 28th, 1988 etc. announces 88/00590.
The phosphonates of bone active preferably that is applicable to the inventive method comprises: N-(2 '-(3 '-methyl)-pyridine radicals) aminomethane (phosphonomethyl) phosphinic acid; N-(2 '-(5 '-methyl)-pyridine radicals) aminomethane (phosphonomethyl) phosphinic acid; N-(2 '-(3 '-methyl)-piperidylidene) aminomethane (phosphonomethyl) phosphinic acid; N-(2 '-(5 '-methyl)-piperidylidene) aminomethane (phosphonomethyl) phosphinic acid; 2-(2 '-pyridine radicals) ethane-1-phosphono-1-methyl phosphinic acid; 2-(2 '-piperidyl) ethane-1-phosphono-1-methyl phosphinic acid; 2-(p-aminophenyl)-1-hydroxyl ethane-1-phosphono-1-methyl phosphinic acid; 2-(m-aminophenyl base)-1-hydroxyl ethane-1-phosphono-1-methyl phosphinic acid; N-(1-(5-amino-2-methyl-1-oxo)-amyl group) aminomethyl (phosphonomethyl) phosphinic acid; N-(2 '-(3 '-methyl) piperidylidene aminomethane phosphono butyl phosphinic acid; S-(2 '-pyridine radicals) sulfo-methane (phosphonomethyl) phosphinic acid; 2-(2-pyridine radicals)-1-hydroxyl ethane-1-phosphono-1-methyl phosphinic acid; 2-(3-pyridine radicals)-1-hydroxyl ethane-1-phosphono-1-methyl phosphinic acid; 2-(TMSIM N imidazole base)-1-hydroxyl ethane-1-phosphono-1-methyl phosphinic acid; 3-(N-phenyl-N-methylamino)-1-hydroxy propane-1-phosphono-1-methyl phosphinic acid; 4-amino-1-hydroxyl butane-1 phosphono-1-methyl phosphinic acid; 3-(N-pyrrolidinyl)-1-hydroxy propane-1-phosphono-1-methyl phosphinic acid; N-suberyl aminomethane (phosphonomethyl) phosphinic acid; S-(rubigan) sulfo-methane (phosphonomethyl) phosphinic acid; (7-dihydro-1-benzazole) methane (phosphonomethyl) phosphinic acid; (7-dihydro-1-benzazole) hydroxyl methane (phosphonomethyl) phosphinic acid; (6-dihydro-2-benzazole) hydroxyl methane (phosphonomethyl) phosphinic acid; 2-(6-pyrrolo-benzazole)-1-hydroxyl ethane-1-phosphono-1-methyl phosphinic acid; 1-hydroxyl ethane-1, the 1-di 2 ethylhexyl phosphonic acid; 1-hydroxyl pentane-1, the 1-di 2 ethylhexyl phosphonic acid; Methanebisphosphonic acid; The dichloromethane di 2 ethylhexyl phosphonic acid; The hydroxyl methanebisphosphonic acid; 1-aminoethane-1, the 1-di 2 ethylhexyl phosphonic acid; 2-aminoethane-1, the 1-di 2 ethylhexyl phosphonic acid; 3-aminopropane-1, the 1-di 2 ethylhexyl phosphonic acid; 3-aminopropane-1-hydroxyl-1, the 1-di 2 ethylhexyl phosphonic acid; 3-(dimethylamino)-1-hydroxy propane-1, the 1-di 2 ethylhexyl phosphonic acid; 3,3-dimethyl-3-amino-1-hydroxy propane-1,1-di 2 ethylhexyl phosphonic acid; The phenyl amino methanebisphosphonic acid; N, N-dimethylamino methanebisphosphonic acid; N-(2-ethoxy) aminomethyl diphosphonic acid; 4-amino-1-hydroxyl butane-1,1, di 2 ethylhexyl phosphonic acid; 5-amino-1-hydroxyl pentane-1,1, di 2 ethylhexyl phosphonic acid; 6-amino-1-hydroxyl hexane-1, the 1-di 2 ethylhexyl phosphonic acid; 1,2-dihydroindene (indan)-2,2-di 2 ethylhexyl phosphonic acid; Hexahydro indenes-2, the 2-di 2 ethylhexyl phosphonic acid; 2-methyl cyclobutane-1, the 1-di 2 ethylhexyl phosphonic acid; 3-chlorine Pentamethylene .-1, the 1-di 2 ethylhexyl phosphonic acid; Cyclohexane extraction-1, the 1-di 2 ethylhexyl phosphonic acid; 2-(2-pyridine radicals)-1-hydroxyl ethane-1,1 di 2 ethylhexyl phosphonic acid; N-(2-(5-amino)-pyridine radicals) aminomethane di 2 ethylhexyl phosphonic acid; N-(2-(5-chlorine)-pyridine radicals)-aminomethane di 2 ethylhexyl phosphonic acid; N-(2-(3-picolyl))-aminomethane di 2 ethylhexyl phosphonic acid; N-(2-(4-picolyl))-aminomethane di 2 ethylhexyl phosphonic acid; N-(2-(5-picolyl))-aminomethane di 2 ethylhexyl phosphonic acid; N-(2-(6-picolyl))-aminomethane di 2 ethylhexyl phosphonic acid; N-(2-(3, the 4-lutidines))-aminomethane di 2 ethylhexyl phosphonic acid; N-(2-pyrimidine radicals)-aminomethane di 2 ethylhexyl phosphonic acid; N-(2-pyridine radicals)-2-aminoethane-1, the 1-di 2 ethylhexyl phosphonic acid; 2-(2-pyridine radicals)-ethane-1, the 1-di 2 ethylhexyl phosphonic acid; 2-(3-pyridine radicals)-ethane-1, the 1-di 2 ethylhexyl phosphonic acid; 2-(4-pyridine radicals)-ethane-1, the 1-di 2 ethylhexyl phosphonic acid; 2-(2-(3-picolyl))-hydroxyl ethane (oxaethane)-1, the 1-di 2 ethylhexyl phosphonic acid; 2-(3-pyridine radicals)-1-hydroxyl ethane-1, the 1-di 2 ethylhexyl phosphonic acid; 2-(TMSIM N imidazole base)-1-hydroxyl ethane-1, the 1-di 2 ethylhexyl phosphonic acid; 3-(N-amyl group-N-methylamino)-1-hydroxy propane-1, the 1-di 2 ethylhexyl phosphonic acid; 3-(N-pyrrolidinyl)-1-hydroxy propane-1, the 1-di 2 ethylhexyl phosphonic acid; N-suberyl aminomethane di 2 ethylhexyl phosphonic acid; S-(rubigan) sulfo-methanebisphosphonic acid; (7-dihydro-1-benzazole) methanebisphosphonic acid; (7-dihydro-1-benzazole) hydroxyl methanebisphosphonic acid; (6-dihydro-2-benzazole) hydroxyl methanebisphosphonic acid; 2-(6-pyrrolopyridine)-1-hydroxyl ethane-1, the 1-di 2 ethylhexyl phosphonic acid; And pharmaceutically acceptable salt and ester.
The best bone active phosphonates that is applicable to the inventive method comprises: 1-hydroxyl ethane-1,1-di 2 ethylhexyl phosphonic acid, dichloromethane di 2 ethylhexyl phosphonic acid; 3-amino-1-hydroxy propane-1, the 1-di 2 ethylhexyl phosphonic acid; 6-amino-1-hydroxyl hexane-1, the 1-di 2 ethylhexyl phosphonic acid; 4-amino-1-hydroxyl butane-1, the 1-di 2 ethylhexyl phosphonic acid; 2-(3-pyridine radicals)-1-hydroxyl ethane-1, the 1-di 2 ethylhexyl phosphonic acid; 2-(TMSIM N imidazole base)-1-hydroxyl ethane-1, the 1-di 2 ethylhexyl phosphonic acid; 3-(N-amyl group-N-methylamino)-1-hydroxy propane-1, the 1-di 2 ethylhexyl phosphonic acid; 3-(N-pyrrolidinyl)-1-hydroxy propane-1, the 1-di 2 ethylhexyl phosphonic acid; N-suberyl aminomethane di 2 ethylhexyl phosphonic acid; S-(rubigan) sulfo-methanebisphosphonic acid; (7-dihydro-1-benzazole) methanebisphosphonic acid; (7-dihydro-1-benzazole) hydroxyl methanebisphosphonic acid; (6-dihydro-2-benzazole) hydroxyl methanebisphosphonic acid; 2-(6-pyrrolopyridine)-1-hydroxyl ethane-1, the 1-di 2 ethylhexyl phosphonic acid; And pharmaceutically acceptable salt and ester.
Parathyroid hormone
The inventive method also comprises the use parathyroid hormone.In this article, " parathyroid hormone " refers to natural human body parathyroid hormone, and synthetic analog, by parathyroid hormone and parathyroid hormone segment and the parathyroid hormone and the pulsating analog of parathyroid hormone of DNA recombinant technique manufacturing.The parathyroid hormone that is applicable to the inventive method comprises, for example hPTH (1-38), hPTH (1-34), hPTH (1-37), hPTH (2-34) and hPTH (2-38).The type of obtainable parathyroid hormone and the manufacture method of parathyroid hormone are described in detail in the following list of references, and all these documents are all listed in this and drawn and be reference: the United States Patent (USP) 4,105,602 of the Colescott that on August 8th, 1978 announced etc.; The United States Patent (USP) 4,698,328 of the Neer that on October 6th, 1987 announced etc.; The United States Patent (USP) 4,833,125 of the Neer that on May 23rd, 1987 announced etc.; The Deutsche Bundespatent 3935738 of the Forssmann that the Deutsche Bundespatent 32 43 358 of the Hesch that on May 24th, 1984 announced and on May 8th, 1991 announce etc.
Therapeutic Method
The invention provides the method that the human body of suffering from bone metabolism imbalance or other animal target are treated, it consists essentially of the following step:
(a) give the bone active phosphonate of described object effective dose safe in utilization in during greater than about 6 months;
(b) give the parathyroid hormone of described object effective dose safe in utilization in during about 3-12 month.
Be preferably in step (a), the administration time of described bone active phosphonate was greater than about 8 months.Be preferably equally in step (b), the administration time of described parathyroid hormone better was about 6 months for about 4-8 month.Be preferably step (a) and (b) repetition 1 to 5 time (that is, entire method comprises in order to each step execution 2 to 6 times).In the method for optimizing of the present invention, the bone active phosphonate is administration during the treatment stage of step (b); Be that phosphonate is in parathyroid hormone administration simultaneously.
The dosage of bone active phosphonate and parathyroid hormone is " a safe and effective amount ", this is meant when using method of the present invention, the use amount of material should be enough to obtain required therapeutic response and not have disadvantageous side effect (as toxicity, zest or anaphylaxis), has reasonably to be benefited/risk-benefit risks.Concrete " safe and effective amount " is obviously along with the factor such as the character of the concrete state of an illness of being treated, patient's body constitution, the persistent period of treatment, common therapy (if existence) and used particular formulations changes and changes.In the methods of the invention, the consumption of concrete bone active phosphonate and dosage form are that chemical compound is renderd a service and function of other factors.Be preferably, give phosphonate to be used for treating consumption and the dosage form that osteoporosis approved according to the good experience of practising medicine in the prior art.
The effectiveness of bone active phosphonate can be expressed as " LED " or " minimum effective dose ", and this is that chemical compound itself produces the minimum dose that obviously suppresses bone resorption.Be preferably, in the methods of the invention, the anti-dosage of absorption compound again is at least about 0.8LED, is more preferably about 0.8 to 5LED, is preferably about 0.8-3LED.
The concrete LED of given bone active phosphonate is according to its chemical composition and different change of medication (being oral or parenteral administration).LED is low more, and the effectiveness of chemical compound is big more.In general, need be with than low dosage and the short phosphonate that uses higher effectiveness the course of treatment.Equally, LED is high more, and the effectiveness of chemical compound is poor more.Therefore, need be to use the higher dosage and the long course of treatment the low phosphonate compounds of rendeing a service.
Particularly, the LED of bone active phosphonate can be determined with any of the body inner model of approving in several this areas.A kind of such model is cut (thyroparathyroidectomized, TPTX) rat model of thyroid parathyroid gland.In this model, suppress the ability that calcium level increases in the serum (this increase is to cause by the rat administering parathyroid hormone of giving parathyroidectomize) by measuring chemical compound, assess their the interior bone resorption of body and suppress to render a service.This model description is in people such as Russell, and (Calcified Tissue Research) 183 (1970) studies in 6 calcified tissues; People such as Muhlbauer, 5 mineral Electrolyte metabolism (Mineral Electrolite Metabolism) 296 (1981); United States Patent (USP) 4,761,406, people such as Flora, on August 2nd, 1988 authorized; With European patent publication 298,553, Ebetino, on January 11st, 1989 published; All these documents all are incorporated herein by reference.
Alternate model is " a Schenk model ", and it measures the influence to osteogenesis in young rat of bone active phosphonate.This model description is in people such as Schenk, and (Calcif.TissueRes.) 196 (1973) studies in 11 calcified tissues; People such as Shinoda, research (the Calcif.Tissue Res.) 87 (1983) of 35 calcified tissues; United States Patent (USP) 4,761,406, people such as Flora, on August 2nd, 1988 authorized; With European patent publication 298,553, Ebetino, on January 11st, 1989 published; All these documents all are incorporated herein by reference.
Another kind of model is the ovariectomized OVX of being rat model, and its measures bone active phosphonate prevents the bone forfeiture brought out because of spay in female rats ability.This model description is in people such as Wronski, 125 endocrinologys (Endocrinology) 810 (1989), and the document is incorporated herein by reference.
The LED of bone active phosphonate can represent with ＂ mgP/kg ＂ easily, and so the place refers to, it is the quantity of the chemical compound represented with every kg body weight of the milligram number/object to be treated of phosphorus in the chemical compound.Because the molecular weight of bone active phosphonate is different, so represent that with mgP/kg dosage can make the comparison normalization that has between the different chemical compounds of rendeing a service.In order to determine to the mgP/kg number that patient uses, can to use following conversion formula according to the inventive method:
(for example, 2-(3-pyridine radicals)-1-hydroxyl ethane-1, the molecular weight of 1-diphosphate is 350.The molecular weight of two phosphorus atoms is 62.Therefore, if patient's dosage is the 0.01mg/kg chemical compound, used about 0.002mgP/kg so.
LED for the parenteral dosage of useful herein preferred bone active phosphonate is: to 1-hydroxyl ethane-1, and 1-di 2 ethylhexyl phosphonic acid, 1.0mgP/kg; To dichloromethane-di 2 ethylhexyl phosphonic acid, 0.5mgP/kg; To 3-amino-1-hydroxy propane-1,1-di 2 ethylhexyl phosphonic acid, 0.03mgP/kg; To 4-amino-1-hydroxyl butane-1,1-di 2 ethylhexyl phosphonic acid, 0.001mgP/kg; To 6-amino-1-hydroxyl hexane-1,1-di 2 ethylhexyl phosphonic acid, 0.1mgP/kg; To N-(2-pyridine radicals) aminomethane-1,1-di 2 ethylhexyl phosphonic acid, 0.01mgP/kg; To 2-(3-pyridine radicals)-1-hydroxyl ethane-1,1-di 2 ethylhexyl phosphonic acid, 0.0003mgP/kg; To N-suberyl-aminomethane di 2 ethylhexyl phosphonic acid, 0.0001mgP/kg; To 3-(N-amyl group-N-methylamino)-1-hydroxy propane-1,1-di 2 ethylhexyl phosphonic acid, 0.0001mgP/kg; To 3-(dimethylamino)-1-hydroxy propane-1,1-di 2 ethylhexyl phosphonic acid, 0.01mgP/kg; To 3-(N-pyrrolidinyl)-1-hydroxy propane-1,1-di 2 ethylhexyl phosphonic acid, 0.01mgP/kg; To N-suberyl aminomethane di 2 ethylhexyl phosphonic acid, 0.03mgP/kg; With to S-(rubigan) sulfo-methanebisphosphonic acid, 0.3mgP/kg.(LED of oral dose should be high, depends on that the whole body of phosphonate absorbs.Typically, oral administration is absorbed as about 1-10%.Therefore, oral LED is typically high about 10-100 times than the LED of parenteral.)
The unit of parathyroid hormone routine is iu (IU).In the methods of the invention, the about 100-700IU/ of the dosage of parathyroid hormone days, be preferably 200-600IU/ days, be more preferably about 400-500IU/ days.
During the treatment of step (a) and (choosing wantonly) step (b), but administration every day of bone active phosphonate or cycle administration.This cycle dosage regimen is summarized in United States Patent (USP) 4,761, people such as 406 Flora, and on August 2nd, 1988 authorized; United States Patent (USP) 4,812,304, people such as Anderson, on March 14th, 1989 authorized; United States Patent (USP) 4,822,609, people such as Flora, on April 18th, 1989 authorized; World patent publication 93 11786, Geddes and Boyce, on June 29th, 1993 published; With world patent publication 92 11474, McOsker, JIUYUE was published on the 3rd in 1992, and all these documents are incorporated herein by reference.For the method for using diphosphate, must use diphosphate at least one sky per 30 days of described data phase.Preferably, diphosphate can be in every day, per two days, per three days, per four days, per five days or the per six days administration during this treatment.
During step (b) treatment, gave 1 day at least in per 7 days that parathyroid hormone must be per 30 days.Be preferably, during at least 50% during the step (b), administering parathyroid hormone.
Method of the present invention is included in all stages of imbalance and treats osteoporosis.Because osteoporosis is the forfeiture of carrying out property of sclerotin, and do not have the imbalance of discrete beginning or terminal point, thus here " treatment " of indication by stop, slowing down or the osteoporosis of overturning in any method of process of the deossification that takes place constitute.
Better method of the present invention comprises to the object treatment osteoporosis that deossification (being called " set osteoporosis " here) is arranged.The method that the present invention treats set osteoporosis is included in the time that is enough to described object os purum matter is increased and uses active matter.The sclerotin that increases can be at cortical bone, trabecular bone or both places.Be preferably, os purum matter is annual to be increased at least about 5%, and being more preferably increases about 10% every year at least.
The time that is enough to described object os purum matter is increased decides according to various factors.This class factor comprises, for example, used specific active matter, the use amount of active matter, the age of object and sex, the concrete imbalance of being treated, used common therapy (if existence), the health condition (comprising the existence of other disease) that object is total, the degree of individual deossification and individual nourishment.
Therapeutic scheme with the inventive method continues preferably at least about 12 months.Certainly, therapeutic scheme can go down according to doctor's experience with not limiting continuously.Till being preferably object and being treated the doctor and think that having obtained danger that os purum matter fractures simultaneously also descends.
Also can use nutrient and other therapeutic agent with the auxiliary sclerotin that increases simultaneously to object.The optional preparation of this class comprises, as vitamin D and calcium.
In the method for the invention, " administration " refer to by veteran doctor to being used for active matter of the present invention to make up any method of bone effectively by the object of being treated.Active matter can be by various known medication administrations, as oral, mucosal (as transdermal administration, sublingual administration, intranasal administration and rectally), parenteral (as, subcutaneous injection, intramuscular injection, intra-arterial injection, intravenous injection) and inhalation.Like this, the AD HOC of administration includes, but not limited to for example oral, transdermal administration, mucosa delivery, sublingual administration, intramuscular injection, quiet notes, intraperitoneal administration, subcutaneous administration and topical.
The better method of treatment osteoporosis comprises that initial diagnosis algorithm is with existing that decision is lacked of proper care.Like this, the present invention's method preferably comprises human body is diagnosed detecting osteoporosis, and obtained male result from described diagnosis after, the method according to this invention is used active matter.Suffer from the female sex object of menopause for treatment before obvious deossification, described initial diagnosis algorithm comprises the diagnosis of checking menopause.These class methods are that this technical field is known, comprise, as measuring the reconstruction speed of sclerotin and bone.The reconstruction speed of bone can be measured by the measurement of biochemical markers.Referring to " deossification are to the effect of postmenopausal osteoporosis " such as Hui (" The Contribution of Bone Loss toPostmenopausal Osteoporosis ") 1 osteoporosis research (Osteoporosis Int) 30 (1990), classify reference as at this.
The proper diagnosis of measuring set osteoporosis also is that this technical field is known, and these class methods comprise the measurement of the radiodensity of skeleton radiation collection of illustrative plates, tomographic, monoergic photon absorption, dual energy photon absorption, dual energy X-radiation absorption method and the quantitative digital formula radiogram of quantitative calculation machine operation.These useful diagnostic techniquess are described in as W.A.Peck etc., with Fact Book (Physician ' s Resource Manual on Osteoporosis) (1987), national osteoporosis foundation (National Osteoporosis Foundation) is published about the doctor of osteoporosis.Classify reference as at this.
Dosage form:
Bone active phosphonate and parathyroid hormone can various pharmaceutically acceptable compositions administrations.This based composition can comprise active matter and pharmaceutically acceptable carrier.Pharmaceutically acceptable carrier comprises solid or liquid filler diluent or microencapsulation material and their mixture, and they are suitable for human body or rudimentary animals administer.Terminology used here " compatibility " expression, the composition energy of pharmaceutical composition and active matter and can mix each other, the result does not have obviously to reduce the reaction of pharmaceutical composition drug effect under normal operating position.Certainly, pharmaceutically acceptable carrier must be enough pure, and toxicity is enough low to be fit to human body or the rudimentary animals administer to being treated.
The example that can be used as pharmaceutical carrier has: sugar, as lactose, dextrose plus saccharose; Starch is as corn starch and potato starch; Cellulose and its derivant are as carboxymethyl cellulose, ethyl cellulose, cellulose ethanoate; The Tragacanth of powdered; Fructus Hordei Germinatus; Gelatin; Pulvis Talci; Stearic acid; Magnesium stearate; Vegetable oil is as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, Oleum sesami, olive oil, Semen Maydis oil and cupu oil; Polyhydric alcohol is as propylene glycol, glycerol, sorbitol, mannitol and Polyethylene Glycol; Agar; Alginic acid; Pyrogen-free water; Isotonic saline solution; Phosphonate buffer solution; Wetting agent and lubricant such as sodium lauryl sulphate; Coloring agent; Flavoring agent and antiseptic.The medicated premix of other compatibility and active matter also are included in the pharmaceutically acceptable carrier that is used for the present composition.
The selection that is used for the pharmaceutically acceptable carrier that matches with active matter can be by the administering mode decision of active matter.If drug administration by injection, pharmaceutical carrier is sterilized water, normal saline or their mixture preferably.The pH of this class parenteral compositions is adjusted to about 7.4 preferably.The pharmaceutically acceptable carrier that is fit to topical comprises that this technical field becomes known for the carrier in cream, gel, band agent, unguentum and the similar local delivery mode.
With the working concentration of the pharmaceutically acceptable carrier of active matter compatibility to be enough to the providing practical size of relevant dosage form to be as the criterion.The total amount of pharmaceutically acceptable carrier can account for about 0.1%-99.9% (weight) of pharmaceutical composition of the present invention, is preferably about 5-80%, is preferably about 10-50%.
Using the better method of diphosphate is oral (that is the dosage form that, contains the active matter that is suitable for single dose administration) of carrying out unit dosage forms.For diphosphate preferably unit dosage forms comprise tablet, capsule, suspending agent and solution, they comprise the active matter of safe and effective amount.The pharmaceutically acceptable carrier that is fit to the preparation oral unit dosage form is known in this technical field.Their selection basis is decided as second Considerations such as taste, cost, storage stabilities, and this is not the key of the object of the invention, can be made one's options without difficulty by this technical field skilled person.Be preferably, the oral unit dosage form of the phosphonate of bone active comprises the about 0.0005mgP/kg-1.0mgP/kg of oral phosphonate every day.
Parathyroid hormone form of medication preferably is subcutaneous injection, intranasal administration, transdermal administration, rectally, sublingual administration and oral.Peroral dosage form comprises preferably, for example, and liposome, lipoid Emulsion and protein box (cages).
Test kit
For convenience and implement method of the present invention effectively, the present invention also provides test kit.This class test kit comprises the bone active phosphonate of one or more unit dosage forms, the parathyroid hormone of one or more unit dosage forms and the device of enforcement the inventive method.This class test kit provides the means easily and effectively of guaranteeing to be absorbed in correct mode by treatment target the correct dose active matter.The enforcement means of this class test kit comprise any measure of the active matter of the method according to this invention use easily.The enforcement means of this class test kit comprise description, packing and the instrument of adjusting by prescription (dispensing means), and their combination.The example of the instrument of packing and adjusting by writing out a prescription is that this technical field is known, comprises as United States Patent (USP) 4,761 406 (Flora etc., promulgations on August 2nd, 1988); United States Patent (USP) 4,812,311 (Uchtman, promulgations on March 14th, 1989) and United States Patent (USP) 4,833,125 (Neer etc., promulgation on May 23rd, 1989) are classified reference as at this.
Following indefiniteness embodiment has disclosed compositions of the present invention, method and purposes.
Embodiment 1
Treat an about 65kg of body weight, diagnosed Asia patient male who suffers from primary osteoporosis with method of the present invention.Particularly, last in 8 months and use diphosphate, 2-(3-pyridine radicals)-1-hydroxyl ethane-1,1-di 2 ethylhexyl phosphonic acid to patient.Give patient's every day oral a slice, every diphosphate that contains 0.002mgP/kg.Interrupt the treatment of diphosphate.Then, parathyroid hormone (synthetic fragment 1-34, i.e. h PTH1-34) is used to patient in below 6 months.In 6 months with 13IU/kg dosage by insulin syringe subcutaneous injection hormone before thigh, injected weekly 5 days.
Hip ridge bone is carried out biopsy, find to compare with the biopsy of its benchmark, its mean wall thickness of rebuilding unit (BMU) increases.The absorption degree of depth again of activation frequency and the cavity on cancellus, cortex and cortex inner surface is not increased to more than the reference value significantly.Measure bone mineral density, showing has increased by 11%.
Embodiment 2
Treat an about 60kg of body weight, diagnosed the Caucasia women who suffers from postmenopausal osteoporosis with method of the present invention.Concrete is, uses diphosphate to patient, 4-amino-1-hydroxyl butane-1, and the 1-di 2 ethylhexyl phosphonic acid is for 1 year.After 1 year, continue to use di 2 ethylhexyl phosphonic acid.Use parathyroid hormone (synthetic fragment 1-34, i.e. hPTH1-34) to reach 6 months but return patient, every day intranasal spray delivery 5IU/kg.
Obtain blood sample, analyze bone special sign sclerotin element (osteocalcin) and come alkali metal phosphate autophya and total.With the treatment before compare, the sclerotin element has increased by 57%, alkali metal phosphate sclerotin and total has increase slightly.Fundamentals of Measurement inorganic matter density, showing has increased by 10%.
Claims (6)
1. the method that the human body of suffering from bone metabolism imbalance or other animal target are treated is characterized in that, consists essentially of the following step: (a) during greater than about 6 months, give the bone active phosphonate of described object effective dose safe in utilization;
(b) during about 3-12 month, give the parathyroid hormone of described object effective dose safe in utilization.
2. the method for treatment human body according to claim 1 or other animal target is characterized in that, in step (b), described parathyroid hormone uses and is about 6 months.
3. the method for treatment human body according to claim 1 or other animal target is characterized in that, described step (a) and (b) repeat 1-6 time.
4. the method for treatment human body according to claim 3 or other animal target is characterized in that, also is included in the step (b) and uses the bone active phosphonate.
5. the method for treatment human body according to claim 2 or other animal target is characterized in that, this phosphonate compounds is the diphosphate that is selected from down group: 1-oxo ethane (oxyethane)-1,1-di 2 ethylhexyl phosphonic acid, dichloromethane di 2 ethylhexyl phosphonic acid; 3-amino-1-hydroxy propane-1, the 1-di 2 ethylhexyl phosphonic acid; 6-amino-1-hydroxyl hexane-1, the 1-di 2 ethylhexyl phosphonic acid; 4-amino-1-hydroxyl butane-1, the 1-di 2 ethylhexyl phosphonic acid; 2-(3-pyridine radicals)-1-hydroxyl ethane-1, the 1-di 2 ethylhexyl phosphonic acid; 2-(TMSIM N imidazole base)-1-hydroxyl ethane-1, the 1-di 2 ethylhexyl phosphonic acid; 3-(N-amyl group-N-methylamino)-1-hydroxy propane-1, the 1-di 2 ethylhexyl phosphonic acid; 3-(N-pyrrolidinyl)-1-hydroxy propane-1, the 1-di 2 ethylhexyl phosphonic acid; N-suberyl aminomethane di 2 ethylhexyl phosphonic acid; S-(rubigan) sulfo-methanebisphosphonic acid; (7-dihydro-1-benzazole) methanebisphosphonic acid; (7-dihydro-1-benzazole) hydroxyl methanebisphosphonic acid; (6-dihydro-2-benzazole) hydroxyl methanebisphosphonic acid; 2-(6-pyrrolopyridine)-1-hydroxyl ethane-1, the 1-di 2 ethylhexyl phosphonic acid; And pharmaceutically acceptable salt and ester.
6. the method for treatment human body according to claim 5 or other animal target is characterized in that, this phosphonate compounds is 2-(3-pyridine radicals)-1-hydroxyl ethane-1, the 1-di 2 ethylhexyl phosphonic acid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US30392594A | 1994-09-09 | 1994-09-09 | |
| US08/303,925 | 1994-09-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1157565A true CN1157565A (en) | 1997-08-20 |
Family
ID=23174289
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95195007A Pending CN1157565A (en) | 1994-09-09 | 1995-09-06 | Method for treatment of osteoporosis using bone active phosphonates and parathyroid hormone |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0779812A4 (en) |
| JP (1) | JPH10505090A (en) |
| KR (1) | KR970705400A (en) |
| CN (1) | CN1157565A (en) |
| AU (1) | AU686458B2 (en) |
| CA (1) | CA2199252A1 (en) |
| IL (1) | IL115224A0 (en) |
| WO (1) | WO1996007417A1 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9702401D0 (en) * | 1997-06-19 | 1997-06-19 | Astra Ab | Pharmaceutical use |
| NZ523086A (en) | 2000-06-20 | 2007-07-27 | Novartis Ag | Method of administering bisphosphonates |
| CA2628945A1 (en) | 2005-11-10 | 2007-05-24 | Board Of Control Of Michigan Technological University | Black bear parathyroid hormone and methods of using black bear parathyroid hormone |
| US20160016982A1 (en) | 2009-07-31 | 2016-01-21 | Thar Pharmaceuticals, Inc. | Crystallization method and bioavailability |
| ES2650665T3 (en) | 2009-07-31 | 2018-01-19 | Grünenthal GmbH | Crystallization and bioavailability method |
| US9169279B2 (en) | 2009-07-31 | 2015-10-27 | Thar Pharmaceuticals, Inc. | Crystallization method and bioavailability |
| AU2009356227A1 (en) | 2009-12-07 | 2012-06-21 | Michigan Technological University | Black bear parathyroid hormone and methods of using black bear parathyroid hormone |
| WO2012071517A2 (en) | 2010-11-24 | 2012-05-31 | Thar Pharmaceuticals, Inc. | Novel crystalline forms |
| WO2017208070A1 (en) | 2016-05-31 | 2017-12-07 | Grünenthal GmbH | Bisphosphonic acid and coformers with lysin, glycin, nicotinamide for treating psoriatic arthritis |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE114473T1 (en) * | 1984-04-30 | 1994-12-15 | Procter & Gamble | EQUIPMENT FOR USE IN THE TREATMENT OF OSTEOPOROSIS. |
| US4812304A (en) * | 1984-12-21 | 1989-03-14 | The Procter & Gamble Company | Treatment of osteoporosis |
| US4833125A (en) * | 1986-12-05 | 1989-05-23 | The General Hospital Corporation | Method of increasing bone mass |
| US4868164A (en) * | 1986-12-19 | 1989-09-19 | Norwich Eaton Pharmaceuticals, Inc. | Octahydro-pyridine diphosphonate compounds, pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism |
| WO1993011786A1 (en) * | 1991-12-17 | 1993-06-24 | Procter & Gamble Pharmaceuticals, Inc. | Methods for the treatment of osteoporosis using bisphosphonates and parathyroid hormone |
| US5403824A (en) * | 1993-03-19 | 1995-04-04 | The Procter & Gamble Company | Methods for the treatment of osteoporosis |
-
1995
- 1995-09-06 AU AU35475/95A patent/AU686458B2/en not_active Ceased
- 1995-09-06 KR KR1019970701532A patent/KR970705400A/en active IP Right Grant
- 1995-09-06 CN CN95195007A patent/CN1157565A/en active Pending
- 1995-09-06 WO PCT/US1995/011335 patent/WO1996007417A1/en not_active Application Discontinuation
- 1995-09-06 EP EP95932426A patent/EP0779812A4/en not_active Ceased
- 1995-09-06 JP JP8509664A patent/JPH10505090A/en active Pending
- 1995-09-06 CA CA002199252A patent/CA2199252A1/en not_active Abandoned
- 1995-09-08 IL IL11522495A patent/IL115224A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0779812A4 (en) | 1997-09-10 |
| JPH10505090A (en) | 1998-05-19 |
| WO1996007417A1 (en) | 1996-03-14 |
| IL115224A0 (en) | 1995-12-31 |
| AU3547595A (en) | 1996-03-27 |
| EP0779812A1 (en) | 1997-06-25 |
| CA2199252A1 (en) | 1996-03-14 |
| KR970705400A (en) | 1997-10-09 |
| AU686458B2 (en) | 1998-02-05 |
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