CN1367687A - Calcilytic compounds - Google Patents
Calcilytic compounds Download PDFInfo
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- CN1367687A CN1367687A CN00811177A CN00811177A CN1367687A CN 1367687 A CN1367687 A CN 1367687A CN 00811177 A CN00811177 A CN 00811177A CN 00811177 A CN00811177 A CN 00811177A CN 1367687 A CN1367687 A CN 1367687A
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- hydroxyl
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- methyl
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Images
Classifications
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Abstract
Novel methods of treating bone diseases or disorders are provided.
Description
Invention field
The present invention relates to treat and bone or the unusual relevant various diseases of mineral homoiostasis, include but not limited to hypoparathyroidism, osteosarcoma, periodontal disease, union of fracture, osteoarthritis, rheumatoid arthritis, Paget and osteoporosis.Method of the present invention relates to the Orally active antagonist of calcium receptor and the co-administered of anti-absorbent.
In mammal, extracellular Ca
2+Be under the tight homoiostasis control, regulate various processes, for example blood clotting, neural and muscle irritability and cell function.Extracellular Ca
2+Suppress parathyroid gland emiocytosis parathyroid hormone (PTH), suppress the bone resorption of osteoclast, and stimulate parafollicular cells of thyroid gland secretion calcitonin.Calcium receptor protein can make some specific cell rapidly in response to extracellular Ca
2+The variation of concentration.
PTH is the Ca that regulates in blood and the extracellular fluid
2+Homeostatic primary endocrine factor.By acting on bone and nephrocyte, PTH increases the Ca in the blood
2+Level.This extracellular Ca
2+Increase serve as a kind of negative-feedback signal, reduce the secretion of PTH.Extracellular Ca
2+Constitute maintenance body Ca with the excretory reciprocal relationship of PTH
2+Homeostatic important mechanism.
Extracellular Ca
2+Directly act on the parathyroid gland cell, regulate the secretion of PTH.Confirm that the existence of parathyroid gland cell surface protein can detect extracellular Ca
2+Variation.Referring to " nature " 366:574 such as Brown, 1993.In the parathyroid gland cell, this protein, be that the calcium receptor serves as extracellular Ca
2+Receptor, detect extracellular Ca
2+The variation of ion concentration causes functional cell and replys, is the PTH secretion.
Extracellular Ca
2+Influence various cell functions, referring to " cell and calcium " 11:319 such as Nemeth, 1990.For example, extracellular Ca
2+In parafollicular cell (C cell) and parathyroid gland cell, play a role.Referring to " cell and calcium " 11:323 such as Nemeth, 1990.Also studied extracellular Ca
2+Effect to osteoclast.Referring to Zaidi " bioscience report " 10:493,1990.
Known have an outer Ca of all cpds analog cell
2+Effect to the calcium receptor.Molten calcium preparation (calcilytics) be can the antagonism calcium receptor active chemical compound, cause one or more by extracellular Ca thus
2+Calling out the calcium receptor active that draws reduces.Molten calcium preparation is to Ca
2+Can be used as leading molecule in the exploration of the activated calcium receptor modulators of receptor, development, design, modification and/or the structure.It is the treatment of the morbid state of feature with one or more composition level unusually that the molten calcium preparation of this class can be used for various, and these components are polypeptide such as hormone, enzyme or somatomedin for example, and its expression and/or secretion are subjected to one or more Ca
2+The adjusting of receptor active or influence.The target disease of Calcilytic compounds or obstacle comprise that some relate to bone and the unusual disease of mineral metabolism.
The calcium homoiostasis is a feature with one or more following activity unusually: the unusual increase or the minimizing of serum calcium; The unusual increase or the minimizing of the homaluria of calcium; The unusual increase of bone calcium level or minimizing (what for example, measurement was assessed as bone mineral density); The unusual absorption of dietary calcium; Influence the generation of courier, for example PTH and calcitonin of serum calcium level and/or the unusual increase or the minimizing of release; With the abnormal change of replying that causes by the courier who influences serum calcium level.
Thereby, Calcilytic provides unique method for the Drug therapy with bone or the unusual diseases associated of mineral homoiostasis, and these diseases are hypoparathyroidism, osteosarcoma, periodontal disease, union of fracture, osteoarthritis, rheumatoid arthritis, Paget and osteoporosis for example.
Well-known be for example seen in hyperparathyroidism to the chronic rising of PTH cause that the bone loss and the osseous tissue of osteoclast mediation learn unusually.Dobnig and Tumer " endocrinology " Vol.138, pp.4607-4612 (1997) shows, heavy dose of PTH h inf (40 and 80 μ g/kg/ days) 2 hours or more than, cause body weight decline rapidly, hypercalcemia and skeletal tissue learn unusual, this with seen in hyperparathyroidism to variation be consistent.The document is pointed out, although the administration at intermittence of PTH is desirable in carrying out osteogenesis, if but PTH raises the long time, bone resorption has also raise so.The limitation of this PTH on the rising persistent period limited the selection of the chemical compound that may be used for antagonism calcium receptor.
Therefore, have the needs to the therapy that can utilize Calcilytic in industry, this antagonist may cause that moment PTH raises, and the absorption problem that occurs together that does not cause document and confirmed.
Further a kind of like this therapy being existed needs, and it causes raising than the PTH of low degree, has simultaneously and the identical beneficial effect of present available treatment.
Summary of the invention
The invention provides the method for the novelty of the unusual relevant various diseases of treatment and bone or mineral homoiostasis, include but not limited to hypoparathyroidism, osteosarcoma, periodontal disease, union of fracture, osteoarthritis, rheumatoid arthritis, Paget and osteoporosis.
Method of the present invention relates to molten calcium preparation and the anti-absorbent co-administered to the patient of needs treatment.The molten calcium preparation of the present invention comprises the reagent that can cause long-time PTH to raise.Preferably, reagent of the present invention causes the moment of PTH to raise.
The detailed description of accompanying drawing
Fig. 1 describes to handle back osteopenia rat according to research molten calcium preparation of 1 usefulness or PTH and closely saves tibia BMD.
Age in July, rat was OO (ovx), made it develop into osteopenia and reached two months.The rat of sham-operation is handled with carrier (zero), NPS 2,143 100 μ mol/kg p.o. () or P of Rats TH l-345 μ g/kg s.c. (△) with vehicle treated (◇), ovx rat.Shown in point in time measurement BMD.Significance,statistical is expressed as:
*P＜0.05;
*P＜0.01.
Fig. 2 describes the blood plasma PTH level according to the osteopenia rat of research molten calcium preparation of 1 usefulness or P of Rats TH processing.
After handling with molten calcium preparation (filled circles) or PTH (open circles), with respect to shown in reagent administration and gather plasma sample when deciding.
Fig. 3 describes according to research 1 the molten calcium preparation cyclical level after the molten calcium preparation administration.
With respect to shown in compound administration and gather plasma sample when deciding.
Fig. 4 describes to handle dynamic organization's somatometry of physique that back osteopenia rat is closely saved tibia according to research molten calcium preparation of 1 usefulness or PTH.
Fig. 4 a) describes the girth (%L.Pm) of % labelling;
Fig. 4 b) describes the erosive surface of % (%Er.P);
Fig. 4 c) describes the girth (%Os.Pm) of % bone sample;
Fig. 4 d) describes the osteogenesis rate: bone district indicant (BFR/B.Ar) %/year.Significance,statistical is expressed as:
*P＜0.05;
*P＜0.01.
Fig. 5 describe according to research 2 usefulness estrogen+/-molten calcium preparation handles back osteopenia ovx rat tibia with the painted zone of von kossa's stain.
Representative area is from the animal of handling 5 weeks of back, wherein:
Fig. 5 a) represents carrier;
Fig. 5 b) represents 17 beta estradiols (s.c. piller 0.01mg/90 days);
Fig. 5 c) represents NPS 2143 (100 μ mol/kg p.o. every day).
Fig. 6 describes to add/subtract 17 beta estradiols according to the molten calcium preparation of research 2 usefulness and handles the histomorphometricall that back osteopenia rat is closely saved tibia.
Fig. 6 a) describes % trabecular bone area (%Tb.Ar);
Fig. 6 b) describes skeletonization speed: organize area parameters (BFR/T.Ar) %/year.Significance,statistical is expressed as:
*P＜0.05;
*P＜0.01.
Detailed description of the invention
Calcilytic compounds of the present invention comprises all Calcilytic compounds." Calcilytic compounds " represents that this chemical compound can suppress calcium receptor active, causes one or more by extracellular Ca thus
2+The calcium receptor active that causes reduces.Such chemical compound includes but not limited to be selected from down the chemical compound of group:
N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1,1-dimethyl-2-(2-naphthyl) ethylamine hydrochloride;
N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1,1-dimethyl-2-(4-methoxyphenyl) ethylamine hydrochloride;
N-[(2R-hydroxyl-3-[(2, the 3-dichloro) phenoxy group-propyl group]-1,1-dimethyl-2-(4-methoxyphenyl) ethylamine hydrochloride;
N-[(R)-and 2-hydroxyl-3-[2-cyano group-4-[N-methyl-N-[3-carboxyl phenyl) sulphonyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(6-(1,2,3, the 4-tetralyl) ethamine;
N-[(R)-and 2-hydroxyl-3-[2-cyano group-4-[N-methyl-N-[3-carboxyl phenyl) sulphonyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(benzothiophene-3-yl) ethamine;
N-[(R)-and 2-hydroxyl-3-[2-cyano group-4-[N-methyl-N-[3-carboxyl phenyl) sulphonyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(benzothiophene-2-yl) ethamine;
N-[(R)-and 2-hydroxyl-3-[2-cyano group-4-[N-methyl-N-[3-carboxyl phenyl) sulphonyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(decahydronaphthalene-2-yl) ethamine;
N-[(R)-and 2-hydroxyl-3-[2-cyano group-4-[N-methyl-N-[3-carboxyl phenyl) sulphonyl] amino] phenoxy group] propyl group]-1,1-dimethyl-4-phenyl butyl amine;
N-[(R)-and 2-hydroxyl-3-[2-cyano group-4-[N-methyl-N-[3-carboxyl phenyl) sulphonyl] amino] phenoxy group] propyl group]-1,1-dimethyl-4-(2-methoxyphenyl) butylamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[N-methyl-N-[4-ethyl carboxyl phenyl] sulphonyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(2-naphthyl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[N-methyl-N-[3-methyl carboxyl methoxyphenyl] sulphonyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(2-naphthyl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[[N-sulfonyloxy methyl]-the N-[[[1-[2-[6-methyl] amino] pyridine radicals] ethyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(2-naphthyl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[[N-sulfonyloxy methyl]-the N-[[[1-[2-[6-methyl] amino] pyridine radicals] ethyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(1,2,3,4-four naphthalenes-6-yl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[[N-sulfonyloxy methyl]-the N-[[[1-[2-[6-methyl] amino] pyridine radicals] ethyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(benzothiophene-3-yl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[[N-sulfonyloxy methyl]-the N-[[[1-[2-[6-methyl] amino] pyridine radicals] ethyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(benzothiophene-2-yl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[[N-sulfonyloxy methyl]-the N-[[[1-[2-[6-methyl] amino] pyridine radicals] ethyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(decahydronaphthalene-2-yl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[[N-sulfonyloxy methyl]-the N-[[[1-[2-[6-methyl] amino] pyridine radicals] ethyl] amino] phenoxy group] propyl group]-1,1-dimethyl-4-(2-methoxyphenyl) butylamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[[N-sulfonyloxy methyl]-the N-[[[1-[2-[6-methyl] amino] pyridine radicals] ethyl] amino] phenoxy group] propyl group]-1,1-dimethyl-4-phenyl butyl amine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[N-benzyl-N-[4-aminomethyl phenyl] sulphonyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(4-methoxyphenyl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[N-[4-benzyl] sulphonyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(2-naphthyl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-5-[[4-carboxyl] phenyl] phenoxy group] propyl group]-1,1-dimethyl-2-(naphthyl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[[N-methyl-N-[3-carboxyl] phenyl] sulphonyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(2-naphthyl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[[N-methyl-N-[3-methyl carboxyl] phenyl] sulphonyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(2-naphthyl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-(2-phenyl-2-R, S-carboxyl) phenoxy group] propyl group]-1,1-dimethyl-2-(2-naphthyl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-(3-carboxyl propyl group) phenoxy group] propyl group]-1,1-dimethyl-2-naphthyl ethamine;
(N-[2R-hydroxyl-3-[[2-cyano group-5-(3-carboxyl propyl group) phenoxy group] propyl group]-1,1-dimethyl-2-naphthyl ethamine; With
(N-[2R-hydroxyl-3-[2-[2-[6-amino methyl] pyridine radicals] ethyoxyl]-1,1-dimethyl-2-naphthyl ethamine.
Bone is made up of albumen substrate, wherein is combined with spindle or plate shaped hydroxyapatite crystal.Type i collagen is represented the primary structure albumen of bone, comprises about 90% structural protein.All the other 10% substrate are made up of a large amount of non-collagenic structure proteins, comprise osteocalcin, Dan Baijutang, osteopontin, osteonectin, thrombospondin, fibronectin and bone sialoprotein.Skeleton experiences the remodeling of discrete focus in whole life process.These focuses or remodeling unit experience by bone resorption mutually with succeeded by cycle of bone displacement phase composition.
Bone resorption is undertaken by osteoclast, and they are apocytes of hemopoietic system.Osteoclast adheres to bone surface, forms the area of sealing, forms crumple film fluctuation widely on their surface, top (just absorbing) then.This produces the cell exocoel of sealing on bone surface, it is by the proton pump acidify in the crumple film, and osteoclast is to extracellular proteinase wherein.Hydroxyapatite on the low pH dissolving bone surface in chamber, and protease digestion albumen substrate.In this manner, form absorption lacuna or recessed.When this phase loop ends, osteoblast places on the new albumen substrate, subsequently by mineralising.In some morbid states, for example osteoporosis and Paget, bone resorption and generate between normal equilibrium destroyed, all there is the net loss of bone in each cycle.Finally, cause the reduction of bone, can increase the danger of fracturing because of microtrauma.
" the anti-absorption " used herein expression can prevent, delays or stop the reagent of bone resorption.Can be used for anti-absorbent of the present invention and include but not limited to estrogen, 1,25 (OH)
2Vitamin D
3, calcitonin, bisphosphonate and cathepsin K inhibitor.
The compounds of this invention can also be mixed with its pharmaceutically acceptable salt and coordination compound.Pharmaceutically acceptable salt is a nontoxic salt under the dosage of institute's administration and concentration.
Pharmaceutically acceptable salt comprises acid-addition salts, for example sulfate, hydrochlorate, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, mesylate, esilate, benzene sulfonate, right-toluene fulfonate, cyclohexylsulfamate and quinate.Pharmaceutically acceptable salt can be from obtaining such as following acid: hydrochloric acid, maleic acid, sulphuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid, right-toluenesulfonic acid, cyclohexyl sulfamic acid, fumaric acid and quinic acid.
If there is acidic functionality, for example carboxylic acid or phenol, then pharmaceutically acceptable salt also comprises those base addition salts, for example contains Benzathini Benzylpenicilinum, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine and zinc.
In order to use chemical compound of the present invention or its pharmaceutically acceptable salt to treat people and other mammals, under normal circumstances the pharmacy practice according to standard is mixed with pharmaceutical composition.
Calcilytic compounds can pass through the different approaches administration, comprises intravenous, intraperitoneal, subcutaneous, intramuscular, oral, local (transdermal) or saturating mucosal drug delivery.About the whole body administration, oral administration is preferred.About oral administration, for example, chemical compound can be mixed with conventional peroral dosage form, for example capsule, tablet and liquid preparation, for example syrup, elixir and concentrated drop.
Perhaps, can adopt injection (parenteral), for example intramuscular, intravenous, intraperitoneal and subcutaneous.About injection, The compounds of this invention is mixed with liquid solution, be preferably buffer compatible on the physiology or solution, for example saline solution, Han Keshi solution or Ringer's mixture.In addition, chemical compound can be mixed with solid dosage forms, face and use preceding dissolving or suspend it.Can also make freeze-dried formulation.
The whole body administration can also be by saturating mucosa or transdermal means.About saturating mucosa or transdermal administration, in preparation, use the penetrating agent be suitable for the barrier that will permeate.Such penetrating agent is known in the field, for example comprises bile salts and fusidic acid derivatives about saturating mucosal drug delivery.In addition, detergent can be used for promoting infiltration.Saturating mucosal drug delivery for example can be nasal spray, rectal suppository or vaginal suppository.
About topical, The compounds of this invention can be mixed with ointment, ointment, gel or cream, this is known in the field.
The dosage of various Calcilytic compounds can be determined by standard operation, and the IC of consideration such as chemical compound
50, EC
50, biological half-life, patient's age, size and the body weight of chemical compound, and factors such as patient's diseases associated or obstacle.The importance of these factors and other factors that will consider is that those of ordinary skills are known.
Dosage also depends on the degree of route of administration and oral administration biaavailability.For example, about the low chemical compound of oral administration biaavailability, will have to give high relatively dosage.
Preferably, compositions is a unit dosage forms.About oral medication, for example can give tablet or capsule, about the nose medication, can about the transdermal medication, can discharge about saturating mucosa with the aerosol of metering with topical formulations or patch, can use the buccal patch.In each case, the patient can accept single dose.
Per unit dosage about oral administration is fit to contain 0.01 to 500mg/kg, is preferably 0.1 to 50mg/kg formula (I) chemical compound or its pharmaceutically acceptable salt, in free alkali.About parenteral, nose, mouthful suction, saturating mucosa or transdermal route, suitable dosage every day contains formula (I) chemical compound of 0.01mg/kg to 100mg/kg.Topical formulations is fit to contain 0.01 to 5.0% formula (I) chemical compound.Active component every day can administration 1 to 6 time, is preferably once, promptly is enough to show required activity, and this is apparent to those skilled in the art.
" treatment " of disease used herein includes but not limited to preventing, suppress and preventing of disease.
Based on affected cell, the disease that may be treated or prevent and obstacle comprise and bone and mineral diseases associated or obstacle; Hypoparathyroidism; Central nervous system's disease or obstacle, for example neural cell injury (for example occurring in cardiac arrest or transient respiratory distress of the newborn), epilepsy, neurodegenerative disease (for example Alzheimer, Huntington's disease and parkinson), dementia, muscular tone, depression, anxiety, paranoid fears, obsessive idea and behavior disorder, post-traumatic stress disorder, schizophrenia, NM neuroleptic malignant syndrome and the Tourette's syndrome that bring out of epilepsy, apoplexy, a wound, spinal cord injury, hypoxgia; Relate to kidney and absorb the excessive disease of water again, for example syndrome of inappropriate ADH secretion (SIADH), liver cirrhosis, congestive heart failure and nephrosis; Hypertension; The nephrotoxicity of prevention and/or minimizing cation antibiotic (for example aminoglycosides antibiotic); Bowel movement sexual disorders, for example diarrhoea and spastic colon; The GI Peptic Ulcers; With the GI disease of excessive calcium absorption, for example sarcoidosis; Autoimmune disease and organ-graft refection; Squamous cell cancer; And pancreatitis.
In preferred implementation of the present invention, The compounds of this invention is used for increasing serum parathyroid hormone (PTH) level in the non-pulse mode.Increasing the serum PTH level can help treatment such as diseases such as hypoparathyroidism, osteosarcoma, periodontal disease, fracture, osteoarthritis, rheumatoid arthritis, Paget and osteoporosis.
Be about 10 to about 65pg/ml the normal range of int people PTH.Increase serum PTH and can also be used for preventative inhibition or prophylactic outbreak.For example can be to the low people of serum PTH or serum PTH are low but increasing the people that PTH has useful compensating action carries out prophylactic treatment.Preferably the patient has unusual low serum PTH." unusual low serum PTH " used herein expression serum PTH level is lower than mean level, and preferred amount is relevant with disease or seizure of disease.
Increase the serum PTH level and can be used for the treatment of various diseases, comprise and bone and mineral diseases associated.
The persistent period that the PTH level increases be preferably 12 hours or more than, more preferably 18 hours or more than, most preferably be 24 hours or more than.
PTH than preferably increase normal range of int people PTH 3 times or below.More preferably the PTH level increase than normal range 2 times or below.
The present invention also provides the compositions that comprises The compounds of this invention and pharmaceutically acceptable salt thereof, can be mixed with syrup, tablet, capsule and lozenge, has activity behind the oral administration.Syrup generally will be by chemical compound or salt and correctives or suspension or the solution composition of coloring agent in liquid-carrier, and this liquid-carrier is ethanol, Oleum Arachidis hypogaeae semen, olive oil, glycerol or water for example.If compositions is a tablet, then can use the pharmaceutical carrier that is usually used in preparing solid preparation.The example of this class carrier comprises magnesium stearate, hargil, Talcum, gelatin, arabic gum, stearic acid, starch, lactose and sucrose.If compositions is a capsule, then the encapsulating method of any conventional all is fit to, and for example uses above-mentioned carrier in the hard gelatin capsule shell.If compositions is soft gelatin shell capsule, then can consider to be usually used in arbitrarily preparing the pharmaceutical carrier that disperses or suspend, for example aqueous natural gum, cellulose, silicate or oil are added in them in the Perle shell.
Typical parenteral composition is made up of at aseptic aqueous or the solution in the non-aqueous carrier or suspension chemical compound or salt, can not contain or contain the acceptable oil of parenteral, for example Polyethylene Glycol, polyvinylpyrrolidone, lecithin, Oleum Arachidis hypogaeae semen or Oleum sesami.
Typical composition for inhalation is the form of solution, suspension or emulsion, and they can be mixed with dry powder, perhaps uses conventional propellant to be mixed with aerosol, for example dichlorodifluoromethane or Arcton 11.
After typical suppository comprises administration by this way is active The compounds of this invention or its pharmaceutically acceptable salt and binding agent and/or lubricant, for example Polyethylene Glycol, gelatin, cocoa butter or other low-melting wax classes or fat or their synthetic analogues.
Typical skin and preparation capable of permeating skin comprise conventional aqueous or non-aqueous excipient, for example cream, ointment, lotion or paste, or medicine plaster, patch or membrane.
Said composition is preferably with unit dosage forms, and the aerosol of tablet, capsule or metering for example is so that the patient can use single dose.
Require after taking chemical compound of the present invention, not have unacceptable toxicological effect according to the present invention.
Bioassay:
Carry out following evaluation.
Ovariectomized rat studies
The female place of Sprague Dawley in age in July Mus is carried out bilateral oophorectomy or sham-operation, and letting animals feed is three months then, makes it develop into osteopenia.At this moment, be divided into one group of sham operated rats (n=10) and three groups of spays (ovx) animals (n=10-14).The bone mineral density of selecting between the group of ovx group at lumbar vertebra, closely to save tibia or far to save femur (" BMD ") does not have significant difference.The ovx matched group that each group is respectively sham operated rats, handle with carrier (20% moisture coating (encapsin)) and with N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1, the ovx of PTH 1-34 (the 5 μ g/kg body weight s.c. every day) processing of 1-dimethyl-2-(2-naphthyl) ethylamine hydrochlorate (" with molten calcium preparation administration ") (100 μ mol/kg body weight p.o. every day) or rat organizes.
During studying, take a blood sample, be used to measure circulation PTH and Bone Gla protein.(QDR-4500 Hologic, Waltham Mass) measure BMD with DXA with the 4th, the 8th week before processing.The excision tibia that expires is used for histologic analysis.All animals begin to accept in preceding 10 days and 3 days tetracycline in administration, accept calcein (10mg/kg) in preceding 10 days and 3 days in execution.
Prepare animal and monitoring as mentioned above.Each is organized the ovx matched group and other 4 windings that are respectively sham operated rats, handle with oral carrier (20% moisture coating) and is subjected to N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1,1-dimethyl-2-(2-naphthyl) ethylamine hydrochlorate (100 μ mol/kd/d, p.o.), 17 beta estradiols (s.c. pilule 0.01mg/90 days) or N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1, the ovx group of 1-dimethyl-2-(2-naphthyl) ethylamine hydrochlorate+estradiol (separately as above).Administration continued for 5 weeks, put to death animal then, collected tibia, was used for histologic analysis.
The measurement of circulation chemical compound and PTH level
Timing acquiring relates to the plasma sample of chemical compound or PTH administration.(NicholsInstitute Diagnostics, San Juan Capistrano CA) measure PTH 1-34 with RIA.(detectability=10ng/ml) is the compound concentration in the blood plasma quantitatively with LC/MS/MS.
Histomorphometricall is estimated
Make the dehydration of bone sample by increasing concentration of ethanol, defat in acetone, be embedded in methylmethacrylate (Polysciences, Inc., Warrington, PA) in.On Leica microtome (SM2500S), cut the vertical undecalcified section (5 μ m) of nearly joint tibia; Piece of tissue is in advance with the dyeing of Villanueva stain.Do not knowing under the situation of set of dispense, utilizing Osteomeasure system (OsteoMetrics Incorpotated) to carry out histomorphometric.Measurement in the tibial metaphysis is limited to about 8mm that 1mm begins under the growth plate
2The average tissue area.Main measurement comprises the area (mm of bone and bone marrow
2), the long-pending (mm of surface of bone
2), the girth of bone girth (mm), single labelling and double labelling (sL.Pm, dL.Pm, mm), the girth of bone sample (O.Pm, mm) and erosive girth (Er.P, mm).The index that derives from comprises girder shape bone volume (%Tb.Ar), girder number (Tb.N, mm
-1), little cantilever thickness (Tb.Th, μ m), little case bay (Tb.Sp, μ m), skeletonization speed, surface parameter (BFR/Tb.Pm, μ m
3/ μ m
2/ year), BFR/Tb.Ar (surface of bone amasss parameter, %/year), BFR/B.Ar (organizational parameter, %/year), mineral add rate (MAR, μ m/ days) and labelling girth percentage ratio (%Lp).With sided t check assessment statistical analysis.
The bone resorption of human osteoclast mediation is measured
According to James " bone mineral research magazine " Vol.11, pp.1453-1460 separates the human osteoclast of depolymerization and carries out vitro human osteoclast Absorption mensuration from fresh osteoclast tumor tissue.In brief, under 37 ℃, human osteoclast is seeded on the Os Bovis seu Bubali compact substance particle that contains chemical compound or carrier reaches 24 hours.Remove culture medium then, (Denmark) quantitative people's type i collagen α 1 chain carboxyl terminal peptide level is as the biochemistry reading of Absorption for Osteometer A/S, Rodovre to utilize competitive desmoenzyme linked immunosorbent assay (ELISA) (19).Compare with cultivate osteoclast gained supernatant in the carrier that does not contain inhibitor, the result represents with the inhibition percentage ratio of Absorption.Measure IC from the gained dose-effect curve
50Value.
Tire Mus long bone Absorption is measured
This measures same basically Votta " bone " Vol.15, pp.533-538, (1994).In gestation the 18th day Sprague-Dawley rat (Taconic Farms, Germantown, NY) subcutaneous injection 200 micromicrocuries to timing gestation
45CaCl
2, raise in cages and spend the night, (IL) anesthesia is put to death by the neck dislocation for Pittman-Moore, Mundelein to use Innovar-Vet then.Aseptic excision fetus is removed surrounding soft tissue and cartilage sample end, dissects radius and ulna.Subsequently bone traces (n=4) contained the BGJb culture medium (Sigma of 1mg/ml BSA, St.Louis, MO) cultivated 18-24 hour in, be transferred to then in the fresh culture medium, be with or without PTH (human parathyroid hormone [1-34], Bachem, Torrence CA) and under the existence of required inhibitor cultivated 48 hours in addition.(at room temperature, in 5%TCA solubilising after 1 hour) quantitatively is discharged in the culture medium with liquid-scintillation spectrometry
45Ca and remaining in the bone
45Ca.With corresponding contrast bone photo ratio, data are to discharge from handled bone
45Ca percentage ratio is represented.With one way analysis of variance (ANOVA) assessment significant difference.IC
50Be based on twice independent experiment gained data.
Osteoblast cAMP produces and alkaline phosphatase activities
The cAMP that measures in people's TF274 osteoblast (immortalization by human bone marrow substrate cell gets) accumulates, and referring to James, ibid; Also measure from the cAMP among the former generation human osteoblast cell of trabecular bone explant and accumulate, as Beresford " biochemistry and biophysics's journal " Vol.801, pp.58-65 (1984) is described.Utilize the cAMP level in on-radiation scheme (Amersham test kit) the measurement cell sample.Utilize standard colorimetric method for determining alkaline phosphatase activities, as front Gowen " A﹠R " Vol.31, pp.1500-1507 (1988) is described.Test N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group under 0.1,1 and 10 μ M) phenoxy group-propyl group]-1,1-dimethyl-2-(2-naphthyl) ethylamine hydrochlorate.Use PTH 40ng/ml as positive control.
From studying 1 described mensuration gained presentation of results, the small and lasting rising of PTH level causes the rotten increase of bone, does not have os purum gain or loss.
Before handling, immediately and after eight weeks of administration, the in-vivo measurement lumbar vertebra, far save femur and closely save bone mineral density (BMD) in the tibia.The trimestral animal of spay is significantly lost bone mass at whole three skeletal sites in advance: lumbar vertebra and nearly joint tibia are 15%, and far saving femur is 24%.During processing procedure, with N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1, the bone mass that 1-dimethyl-2-(2-naphthyl) ethylamine is handled is unaffected, but the level (Fig. 1) the nearly joint tibia of handling with 5 μ g/kg PTH every day returns to ovx after eight weeks before.Blood plasma PTH horizontal survey when this experiment finishes shows, accept N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1, the animal of 1-dimethyl-2-(2-naphthyl) ethylamine raise the PTH level (＞100pg/ml), still kept higher PTH level (Fig. 2) behind the drug administration in four hours.It is unknown that this rising effect lasts long, but the PTH level falls after rise to baseline values at (just before the infra single administration) after 24 hours.Give 5 μ g/kgPTH animal the PTH level with accept N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1, in the identical scope of 1-dimethyl-2-(2-naphthyl) ethylamine, but after administration, returned to baseline values (Fig. 2) in 2-4 hour.Difference on the PTH duration of the reaction can be by continuing contact N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1,1-dimethyl-2-(2-naphthyl) ethylamine explains, finds that the latter raises to reach eight hours (Fig. 3).
Difference on gained PTH figure under these two kinds of administration conditions has made us can directly measure the time influence rotten to bone of contact PTH.Dynamic organization's somatometry of physique of nearly joint tibia shows, osteogenesis (%L.Pm, %Os.Pm) be increased to PTH and N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1, on 1-dimethyl-2-(2-naphthyl) ethylamine ovx control level (Fig. 4 a, b).The mineral of all processing rate that adds does not all have to change.But, the bone resorption of representing with the erosive girth of % is at N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1, be significantly higher than PTH or ovx matched group (Fig. 4 c) in 1-dimethyl-2-(2-naphthyl) ethylamine group.Compare N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group with other two groups) phenoxy group-propyl group]-1, increased further illustration this point (Fig. 4 d) by the rotten drama of the bone that BFR/B.Ar proved in 1-dimethyl-2-(2-naphthyl) ethylamine processed group.Thereby the PTH of the proper extension of being realized by the molten calcium preparation administration drama that causes osteogenesis and absorption that raises increases, and does not have os purum gain or forfeiture.The PTH of exogenous administration also increases absorption and generates, and surpasses absorption but generate, and causes sclerotin to increase.
Carry out second research, be with or without estrogenic in the presence of, use N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group every day) phenoxy group-propyl group]-1,1-dimethyl-2-(2-naphthyl) ethylamine hydrochlorate is to being reached for 4 weeks by ovx rat administration in trimestral age in July.Fig. 5 shows with the painted representative animal tibia section of von kossa's stain, animal does not have processed (5a) respectively, handles (5b) or add N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group with estrogen with independent estrogen behind ovx) phenoxy group-propyl group]-1,1-dimethyl-2-(2-naphthyl) ethylamine is handled (5c).Obviously, N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1,1-dimethyl-2-(2-naphthyl) ethylamine and estrogen co-administered (5c) cause sclerotin to increase and surpass independent estrogen.The static tissue somatometry of physique (table 1) of nearly joint tibia shows that the % girder area (%Tb.Ar) of ovx animal is than sham-operation animal low by 72% (P＜0.0001).This bone loss is not significantly recovered by estradiol.Independent N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1,1-dimethyl-2-(2-naphthyl) ethylamine is to the not effect of the inductive osteopenia of ovx.But, N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1,1-dimethyl-2-(2-naphthyl) ethylamine add estrogen cause %Tb.Ar to increase twice than the ovx group (Fig. 6 a).This is seemingly by N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1,1-dimethyl-2-(2-naphthyl) ethylamine add estrogen inductive girder thickness increase and cause (table 1).N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1,1-dimethyl-2-(2-naphthyl) ethylamine adds the skeletonization speed of estrogen group/organize area significantly raise (Fig. 6 b).Skeletonization speed/organize the rising of area to show, the bone mass in the measured zone is increasing, and not being reflected in is had new osteogenesis by the bone surface of remodeling (modeling), and this is the classical feature of PTH effect.The result of this Absorption reduction for the animal that NPS handles seemingly (general owing to handle with estrogen simultaneously) also is like this even osteogenesis keeps raising.
N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1,1-dimethyl-2-(2-naphthyl) ethylamine is to the direct effect of external osteoblast and osteoclast
Because we studies have shown that Ca
2+Therefore responsive receptor has just studied N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group to the effect of osteoblast and osteoclast) phenoxy group-propyl group]-1, the external direct effect of 1-dimethyl-2-(2-naphthyl) ethylamine to osteoblast and osteoclast.
The osteoblast activity
Although PTH causes the cAMP level of used two kinds of cell types to increase twice, N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1,1-dimethyl-2-(2-naphthyl) ethylamine is to basis or the not effect of the inductive cAMP level of PTH.With N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1,1-dimethyl-2-(2-naphthyl) ethylamine is handled the TF274 cell and is not caused alkaline phosphatase activities that any variation is arranged, the inductive alkali phosphatase of PTH is not subjected to N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group yet) phenoxy group-propyl group]-1, the influence of 1-dimethyl-2-(2-naphthyl) ethylamine.N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1,1-dimethyl-2-(2-naphthyl) ethylamine proves to have certain in vitro toxicity under 10 μ M concentration.
Osteoclast activity
N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1,1-dimethyl-2-(2-naphthyl) ethylamine under up to 3 μ M concentration to the not effect of bone resorption of human osteoclast mediation, and cathepsin K inhibitor 3, two (the 2-methyl-propyls)-4,7 of 11-, 10-trioxy--2,5,6,8,9, the IC of 12-six azepine tridecandioic acid esters
50Be 0.9 μ M.Therefore this mensuration is subjected to its restriction to the sensitivity of DMSO, can't experimental concentration surpasses N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group of 3 μ M) phenoxy group-propyl group]-1,1-dimethyl-2-(2-naphthyl) ethylamine.In tire Mus long bone is measured, N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1,1-dimethyl-2-(2-naphthyl) ethylamine suppresses the IC of Absorption
50Be 11.3+/-3 μ M.This inhibiting mechanism is still unknown, but is higher than Ca owing to it occurs in about 300 times
2+Receptor-mediated Ca
2+Mobilization IC
50Concentration under, therefore may be with any to Ca
2+The effect of receptor all has nothing to do.Can not get rid of the probability relevant with toxicity.
Above-mentioned experiment showed, can be designed a small amount of oral reactive compound, and inducing is enough to stimulate the rotten endogenous PTH of bone to secrete.The characteristics of pharmacokinetics of this molecule can obtain the long-term rising (＞4 hours) of PTH.There is any effect this persistent period that has made us can check that PTH raises under low-level cycle P TH.Surpass four hours if PTH raises, then bone is rotten further increases, but keeps balance, does not have net loss or gain.Carry out the co-therapy experiment with estrogen and antagonist, cause increasing as the measured osteogenesis of Histomorphometry.
As everyone knows, for example seen in hyperparathyroidism to chronic PTH raise and cause that bone loss and osseous tissue learn unusually.Ibid shows for Dobnig etc., heavy dose of PTH (40 and 80 μ g/kg/ days) h inf 2 hours or longer time cause that body weight decline rapidly, hypercalcemia and skeletal tissue learn unusually, this with seen in hyperparathyroidism to variation be consistent.In our research, much smaller although the increase of PTH continues, do not cause these detrimental effects.Yet the anabolic action of PTH is still lost because of the exposure that continues.This has pointed out gentle hyperparathyroidism no matter be abiogenous or pharmacology inductive, all may be asymptomatic.
These data also prove, about in response to N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1,1-dimethyl-2-(2-naphthyl) ethylamine and the amount of excretory PTH, the PTH level persistent period is short and increase that multiple is few to have influence to bone rotten.The dosage of 80 μ g/kg is used in the great majority open research that effect is carried out to P of Rats TH.This dosage causes that cyclical level reaches about 5,000-14, and 000pg/ml, and our research is 150-200pg/ml.This point proves, the effective modulating bone of PTH of very low dose rotten.This has also done elaboration in the clinical research of carrying out recently, more much lower dosage is used in these researchs, and wherein approximately the dosage of 0.4-0.8 μ g/kg body weight causes that bone mass increases (8,24).Reach about 90pmol/l (25) 0.4 caused the cyclical level of PTH 1-34 after the μ g/kg administration in 30 minutes.Cycle P TH level increases about three times.Thereby, if in response to Ca
2+As if receptor antagonist and discharging, the PTH that is stored in so in the parathyroid gland is enough to cause anabolic action.
Above-mentioned data prove for the first time, use parathyroid gland cell Ca
2+Receptor antagonist stimulation of endogenous parathyroid hormone secretion causes osteogenesis and absorbs increasing.At anti-absorbent N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1, under the existence of 1-dimethyl-2-(2-naphthyl) ethylamine, cause sclerotin to increase.This is that the exploitation that is used for the new class anabolic agent of osteoporosis treatment provides the foundation.
Whole publications that this description is quoted as proof, include but not limited to that patent and patent application all quote at this as a reference, each part publication all quotes in full at this as a reference respectively particularly.
Claims (8)
1, a kind of treatment is the disease of feature or the method for obstacle with bone or mineral homoiostasis unusually, and this method comprises curee's drug combination of the anti-absorbent of the Calcilytic compounds of effective dose and effective dose being given the needs treatment.
2, according to the process of claim 1 wherein that this Calcilytic compounds is selected from down group:
N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1,1-dimethyl-2-(2-naphthyl) ethylamine hydrochloride;
N-[(2R-hydroxyl-3-[(3-chloro-2-cyano group) phenoxy group-propyl group]-1,1-dimethyl-2-(4-methoxyphenyl) ethylamine hydrochloride;
N-[(2R-hydroxyl-3-[(2, the 3-dichloro) phenoxy group-propyl group]-1,1-dimethyl-2-(4-methoxyphenyl) ethylamine hydrochloride;
N-[(R)-and 2-hydroxyl-3-[2-cyano group-4-[N-methyl-N-[3-carboxyl phenyl) sulphonyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(6-(1,2,3, the 4-tetralyl) ethamine;
N-[(R)-and 2-hydroxyl-3-[2-cyano group-4-[N-methyl-N-[3-carboxyl phenyl) sulphonyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(benzothiophene-3-yl) ethamine;
N-[(R)-and 2-hydroxyl-3-[2-cyano group-4-[N-methyl-N-[3-carboxyl phenyl) sulphonyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(benzothiophene-2-yl) ethamine;
N-[(R)-and 2-hydroxyl-3-[2-cyano group-4-[N-methyl-N-[3-carboxyl phenyl) sulphonyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(decahydronaphthalene-2-yl) ethamine;
N-[(R)-and 2-hydroxyl-3-[2-cyano group-4-[N-methyl-N-[3-carboxyl phenyl) sulphonyl] amino] phenoxy group] propyl group]-1,1-dimethyl-4-phenyl butyl amine;
N-[(R)-and 2-hydroxyl-3-[2-cyano group-4-[N-methyl-N-[3-carboxyl phenyl) sulphonyl] amino] phenoxy group] propyl group]-1,1-dimethyl-4-(2-methoxyphenyl) butylamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[N-methyl-N-[4-ethyl carboxyl phenyl] sulphonyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(2-naphthyl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[N-methyl-N-[3-methyl carboxyl methoxyphenyl] sulphonyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(2-naphthyl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[[N-sulfonyloxy methyl]-the N-[[[1-[2-[6-methyl] amino] pyridine radicals] ethyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(2-naphthyl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[[N-sulfonyloxy methyl]-the N-[[[1-[2-[6-methyl] amino] pyridine radicals] ethyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(1,2,3,4-four naphthalenes-6-yl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[[N-sulfonyloxy methyl]-the N-[[[1-[2-[6-methyl] amino] pyridine radicals] ethyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(benzothiophene-3-yl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[[N-sulfonyloxy methyl]-the N-[[[1-[2-[6-methyl] amino] pyridine radicals] ethyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(benzothiophene-2-yl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[[N-sulfonyloxy methyl]-the N-[[[1-[2-[6-methyl] amino] pyridine radicals] ethyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(decahydronaphthalene-2-yl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[[N-sulfonyloxy methyl]-the N-[[[1-[2-[6-methyl] amino] pyridine radicals] ethyl] amino] phenoxy group] propyl group]-1,1-dimethyl-4-(2-methoxyphenyl) butylamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[[N-sulfonyloxy methyl]-the N-[[[1-[2-[6-methyl] amino] pyridine radicals] ethyl] amino] phenoxy group] propyl group]-1,1-dimethyl-4-phenyl butyl amine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[N-benzyl-N-[4-aminomethyl phenyl] sulphonyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(4-methoxyphenyl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[N-[4-benzyl] sulphonyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-[2-naphthyl] ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-5-[[4-carboxyl] phenyl] phenoxy group] propyl group]-1,1-dimethyl-2-(naphthyl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[[N-methyl-N-[3-carboxyl] phenyl] sulphonyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(2-naphthyl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-[[N-methyl-N-[3-methyl carboxyl] phenyl] sulphonyl] amino] phenoxy group] propyl group]-1,1-dimethyl-2-(2-naphthyl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-(2-phenyl-2-R, S-carboxyl) phenoxy group] propyl group]-1,1-dimethyl-2-(2-naphthyl) ethamine;
N-[2R-hydroxyl-3-[[2-cyano group-4-(3-carboxyl propyl group) phenoxy group] propyl group]-1,1-dimethyl-2-naphthyl ethamine;
(N-[2R-hydroxyl-3-[[2-cyano group-5-(3-carboxyl propyl group) phenoxy group] propyl group]-1,1-dimethyl-2-naphthyl ethamine; With
(N-[2R-hydroxyl-3-[2-[2-[6-amino methyl] pyridine radicals] ethyoxyl]-1,1-dimethyl-2-naphthyl ethamine.
3, according to the method for claim 2, wherein this anti-absorbent is selected from down group: estrogen, 1,25 (OH)
2Vitamin D
3, calcitonin, selective estrogen receptor modulator, Vitronectic receptor antagonist, V-H+-ATP enzyme inhibitor, src SH2 antagonist, bisphosphonate and cathepsin K inhibitor.
4, according to the process of claim 1 wherein that this bone or mineral disease or obstacle are selected from down group: periodontal disease, union of fracture, osteoarthritis, rheumatoid arthritis, Paget, pernicious humoral hypercalcemia, metastatic bone disease, joint replacement and osteoporosis.
5, according to the method for claim 3, wherein this bone or mineral disease or obstacle are osteoporosis.
6, according to the process of claim 1 wherein that this molten calcium preparation causes the serum PTH level to increase by 3 times or higher.
7, according to the process of claim 1 wherein that this molten calcium preparation causes the serum PTH level to increase by 2 times or higher.
8, a kind of treatment is the disease of feature or the method for obstacle with bone or mineral homoiostasis unusually, and this method comprises curee's drug combination of the anti-absorbent of the anabolism chemical compound of effective dose and effective dose being given the needs treatment.
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| US6756480B2 (en) | 2000-04-27 | 2004-06-29 | Amgen Inc. | Modulators of receptors for parathyroid hormone and parathyroid hormone-related protein |
| UY28089A1 (en) | 2002-11-26 | 2004-06-30 | Smithkline Beecham Corp | CALCILITICAL COMPOUNDS |
| US7205322B2 (en) | 2003-02-12 | 2007-04-17 | Bristol-Myers Squibb Company | Thiazolidine compounds as calcium sensing receptor modulators |
| US7265145B2 (en) | 2003-05-28 | 2007-09-04 | Bristol-Myers Squibb Company | Substituted piperidines and pyrrolidines as calcium sensing receptor modulators and method |
| UY30801A1 (en) * | 2006-12-18 | 2008-07-03 | Smithkline Beecham Corp | CALCILITICAL COMPOUNDS |
| EP2797591A1 (en) * | 2011-12-27 | 2014-11-05 | Ubaldo Armato | Use of calcilytic drugs as a pharmacological approach to the treatment and prevention of alzheimer's disease, alzheimer's disease-related disorders, and down's syndrome neuropathies |
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| AR014975A1 (en) * | 1998-04-08 | 2001-04-11 | Nps Pharma Inc | CALCILITICAL COMPOUNDS, A PHARMACEUTICAL COMPOSITION THAT UNDERSTANDS THEM, AND THE USE OF THEM FOR THE MANUFACTURE OF A MEDICINAL PRODUCT |
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