EP0510066A1 - 1-azetidyl and 1-hexamethylenimine alkyl or aryl bisphosphonic acids and their use as pharmacological agents - Google Patents
1-azetidyl and 1-hexamethylenimine alkyl or aryl bisphosphonic acids and their use as pharmacological agentsInfo
- Publication number
- EP0510066A1 EP0510066A1 EP91902492A EP91902492A EP0510066A1 EP 0510066 A1 EP0510066 A1 EP 0510066A1 EP 91902492 A EP91902492 A EP 91902492A EP 91902492 A EP91902492 A EP 91902492A EP 0510066 A1 EP0510066 A1 EP 0510066A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- aryl
- compound
- pharmaceutical composition
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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- 125000003118 aryl group Chemical group 0.000 title claims description 19
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
-
- 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
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/5532—Seven-(or more) membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/568—Four-membered rings
Definitions
- This invention relates to novel bisphosphonic acids, to pharmaceutical compositions containing bisphosphonic acids, and to the use of such compositions in regulating calcium metabolism in mammals.
- a common and exemplary manifestation of abnormal calcium metabolism involves the mineral balance of bone tissue.
- bones are living tissues which constantly undergo calcium reso ⁇ tion (from the bone) and calcium deposition (to the bone), a dual process resulting in what is called "bone turnover".
- bone turnover a dual process resulting in what is called "bone turnover”.
- the rate of calcium deposition exceeds reso ⁇ tion, while in normal adults, the two processes are in equilibrium.
- Abnormal calcium metabolism results in a change in the rate of calcium reso ⁇ tion and/or deposition, leading to bone loss, calcium deposits or an excessive rate of bone turnover.
- Examples in humans of conditions with which abnormal calcium metabolism has been implicated include conditions associated with bone turnover, such as osteoporosis, osteodystrophia fibrosa, tumor-induced osteolytic processes, diseases of the collagen and the skeletal systems, Morbus Paget (Paget's disease), Morbus Bechterew (Bmürew's disease), periodontitis, bursitis fibrodysplasia, ankylosing spondylitis, ectopic calcifications, hype ⁇ arathyroidism, osteopenia and osteomalacia, and also conditions not generally associated with bone turnover, such as cardiovascular disorders (e.g., arteriosclerosis), tendinitis and neuritis.
- cardiovascular disorders e.g., arteriosclerosis
- calcium metabolism is regulated primarily by Vitamin D3, parathyroid hormone and other hormones such as calcitonin. Consequently, treatment of calcium metabolism disorders has been dominated by the use of these naturally-occurring compounds and analogs thereof, most commonly calcitonin.
- the therapeutic effect of calcitonin treatment is shortlived, as it is rapidly metabolized in the body, having a half-life of only about 10 minutes. Furthermore, calcitonin cannot be administered orally.
- Macrophages are immune cells which are ubiquitous throughout tissues, including bone. As immune cells, macrophages play an essential role in inflammatory joint disease, releasing a large number of destructive agents, such as lipid mediators, hydrolytic enzymes, proteases, and peroxides all of which cause injury to neighboring connective and soft tissues. IL-1 secretion by macrophages induces synovial cells and chondrocytes to produce large quantities of prostaglandins and proteases which further contribute to this degenerative process. Therefore, compounds inhibiting macrophage proliferation are thought to be of benefit in the treatment of this degenerative process. Compared with calcitonin, the use of bisphosphonic acids provides several advantages. For example, bisphosphonic acids are not metabolized at an appreciable rate in the body, leading to a longer duration of activity. In addition, they can be administered orally.
- Dialkylaminoalkyl bisphosphonic acids are disclosed in U.S. Patent Nos. 4,064,164; 4,134,969; and 4,624,947.
- Dialkylaminocycloalkyl bisphosphonic acids are disclosed in U.S. Patent No. 4,719,203.
- Azacycloalkyl-2,2-bisphos ⁇ honic acids are disclosed in U.S. Patent Nos. 3,941 ,772; 3,988,443; 4,034,086; 4,086,334; 4,108,961 ; and 4,117,090.
- Pyrrolidinyl-2-methyl bisphosphonic acid is disclosed in U.S. Patent No. 4,267,108.
- Heteroaromatic alkylbisphosphonic acids are disclosed in U.S. Patent Nos. 4,503,049; 4,687,767; and 4,777,163.
- a compound comprising: (A) a bisphosphonic acid endgroup; (B) an azetidine- or hexamethylenimine-derived azacyclic endgroup; and (C) an alkyl and/or aryl group linking the bisphosphonic acid azacyclic groups through the nitrogen atom of the azacyclic group. More specifically, there is included within the scope of the present invention 1 -azetidine or 1-hexamethylenimine alkyl or aryl bisphosphonic acids which are pharmaceutically active in regulating calcium metabolism and inhibiting macrophage proliferation in mammals, and to therapeutic compositions comprising said compounds.
- Preferred compounds within the scope of the present invention are azetidinyl alkylidene bisphosphonates and hexamethyleniminyl alkylidene bisphosphonates.
- Bisphosphonic acids within the scope of the present invention can be prepared by bisphosphorylation of their corresponding carboxylic acids using phosphorous acid and/or phosphorous trichloride.
- the present invention relates also to a pharmaceutical composition
- a pharmaceutical composition comprising, in admixture with a pharmaceutically acceptable carrier, a pharmaceutically-effective amount of a bisphosphonic acid compound(s) within the scope of the present invention.
- Still another aspect of the present invention relates to pharmacological methods comprising the administration of an effective amount of the above- mentioned pharmaceutical composition to human or other animal patients in need of therapy for disorders which are capable of being treated by regulation of calcium metabolism.
- Such therapy includes providing antiinflammatory . activity, inhibiting bone reso ⁇ tion and treating arthritic conditions.
- Some advantages which flow from the practice of the present invention include ease of manufacture, resulting in the availability of large quantities of pure compound, good activity in inhibiting bone reso ⁇ tion and a long duration of therapeutic activity.
- Alkyl means a saturated aliphatic hydrocarbon which may be either straight- or branched-chained containing from about 1 to about 8 carbon atoms.
- “Lower alkyl” means an alkyl group as above, having 1 to about 4 carbon atoms.
- Aryl means a 5 to 7 membered unsaturated cyclic organic group which can be homocyclic or heterocyclic.
- Alkoxy means an alkyl-oxy group in which "alkyl” is as previously described.
- the compounds of the present invention can be considered as having three essential groups, namely, two endgroups joined by a linking group.
- the bisphosphonic acid endgroup of the compounds of the present invention can be derived from -CH[PO(OH)2J2 in which each of the hydrogen atoms of the group is subject to substitution as defined herein.
- bisphosphonic acids all such compounds (unsubstituted and substituted) are referred to herein as "bisphosphonic acids”.
- the bisphosphonic acid endgroup is hydroxylated and is derived from -COH[PO(OH)2]2» again, with any of the hydrogen atoms of the group subject to substitution.
- the azacyclic endgroup of the compounds of the present invention can be a 4- or 7-membered ring containing one nitrogen atom, and can be fully or partially hydrogenated.
- 4-membered rings are 1-azetine (C3H5N) and azetidine (trimethylenimine, C 3 H 7 N).
- 7-membered rings are azepine (C6H7N), hexamethylenimine (C6H13N) and those related compounds having intermediate states of hydrogenation.
- the azacyclic group is fully hydrogenated.
- one or more of the carbon atoms of the ring can contain one or more substituent groups.
- the aforesaid bisphosphonic acid and azacyclic groups are bonded together by means of an alkyl or aryl bridge, provided that when the azacyclic ring contains an aryl substituent, the bridging group must be aryl.
- the atoms through which the two endgroups are connected are the nitrogen atom of the azacyclic ring and the carbon atom of the bisphosphonic acid group.
- the bridging group is alkyl, particularly straight chain lower alkyl.
- the most preferred bridging group is ethyl.
- the bridging group can contain a substituent group.
- Preferred substituent groups include hydroxy, amino or substituted amino, alkyl, cyclic alkyl, heterocyclic alkyl, aryl, heteroaryl, aralkyl, alkoxy, aryloxy, aralkoxy, halogen, CF3, carboxy carbonyl and alkali metal.
- vicinal substituent groups can form a cyclic ring.
- the most preferred substituent is hydroxy.
- a preferred class of bisphosphonic acids for use in the practice of the present invention has the structure:
- n 3 or 6;
- X is H, OH, amino, substituted amino, alkyl, aryl, aralkyl, halo or O-Y; each Y is independently alkyl, cyclic alkyl, aryl or aralkyl; each R is independently H, halogen, CF3, OH, alkoxy, amino, substituted amino, carboxy, carbonyl, alkyl, cyclic alkyl, heterocyclic alkyl, aryl or heteroaryl; vicinal R groups can optionally form a cyclic group or a double bond; and each R' is independently H, alkali metal, alkyl, aryl or aralkyl; with the proviso that Y is aryl when R is aryl or heteroaryl.
- a preferred class of bisphosphonic acids for use in the practice of the present invention are those having either of structures II or III below, or a salt or ester thereof, and wherein n is from 0 to about 3, each R is independently halogen, OH, alkoxy, amino, substituted amino or alkyl, and each R' is independently H, alkali metal or alkyl.
- Another preferred class of bisphosphonic acids for use in the practice of the present invention has either of structures II or III above, or a salt or ester thereof, wherein n is 0 and each R' is either H or alkali metal, most preferably sodium.
- Bisphosphonic acids included in the compositions of this invention may be useful in the form of free bases, and also in the form of salts, esters and as hydrates. All forms are within the scope of the invention.
- Acid addition salts may be formed and are simply a more convenient form for use; in practice, use of the salt form inherently amounts to use of the base form.
- the acids which can be used to prepare the addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose ions are non-toxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial pharmacological properties inherent in the free base are not vitiated by side effects ascribable to the ions.
- all addition salts are use as sources of the free base form even if the particular salt ⁇ £r ⁇ £ is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification and identification, or when it is used as an intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures.
- Pharmaceutically acceptable salts of the compounds useful in the practice of this invention include, for example, those derived from the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like.
- mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid
- organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulf
- the corresponding acid addition salts comprise the following: hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartarate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate, cyclohexylsulfamate and quinate, respectively.
- the acid addition salts of the bisphosphonic acids of the present invention are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
- bisphosphonic acids within the scope of the present invention can be prepared by the reaction of the corresponding carboxylic acid with phosphorous acid and phosphorous trichloride in chlorobenzene at about 80 to about 100°C.
- the compounds of the present invention can be administered to a mammalian host in a variety of forms adapted to the chosen route of administration, i.e., orally, or parenterally.
- Parenteral administration in this respect includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelially including transdermal, ophthalmic, sublingual and buccal; topically including ophthalmic, dermal, ocular, rectal and nasal inhalation via insufflation and aerosol and rectal systemic.
- the active compound may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
- the active compound may be inco ⁇ orated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
- Such compositions and preparations may, of course, be varied and, for example, may conveniently be between about 1 to about 10% of the weight of the unit.
- the amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.
- Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form for humans contains between about 2 and 100 mg of active compound.
- the tablets, troches, pills, capsules and the like may also contain the following: A binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring.
- a binder such as gum tragacanth, acacia, corn starch or gelatin
- excipients such as dicalcium phosphate
- a disintegrating agent such as corn starch, potato starch, alginic acid and the like
- a lubricant such as magnesium stearate
- a sweetening agent such as sucrose, lactose or saccharin
- a flavoring agent such as peppermint, oil of wintergreen,
- the dosage unit form When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier.
- tablets, pills, or capsules may be coated with shellac, sugar or both.
- a syrup or elixir may contain the active compound sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
- any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
- the active compound may be inco ⁇ orated into sustained-release preparations and formulations.
- the active compound may also be administered parenterally or intraperiotoneally.
- Solutions of the active compound as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
- Dispersion can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
- the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
- the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
- isotonic agents for example, sugars or sodium chloride.
- Prolonged abso ⁇ tion of the injectable compositions can be accomplished by the use of an agent effective in delaying abso ⁇ tion, for example, aluminum monostearate and gelatin.
- Sterile injectable solutions are prepared by inco ⁇ orating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by inco ⁇ orating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
- the preferred methods of preparation are vacuum drying and the freeze drying technique which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof.
- the therapeutic compounds of this invention may be administered to a mammal alone or in combination with pharmaceutically acceptable carriers, as noted above, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice.
- Pharmaceutical compositions containing the pharmacologically active bisphosphonic acids of the present invention are believed to function by binding with polyvalent ions, for example, calcium and iron. This affinity of the compounds of the resent invention for calcium allows them to be used in the treatment of diseases or disorders where abnormal calcium metabolism has been implicated. Furthermore, due to this affinity for calcium, and hence bone and other calcified tissues, the compounds of the present invention may be useful as vehicles for carrying other agents to such tissues.
- compositions containing the compounds of the present invention can be used for the general purpose of inhibiting bone resorption, and are believed to be particularly suitable for treating or preventing conditions such as arthritis (via inhibition of macrophage proliferation), osteoporosis, osteopenia, osteomalacia, Paget's disease, hypocalcemia- and hypercalcemia-related conditions.
- the dosage of the present therapeutic agents which will be most suitable for prophylaxis or treatment will vary with the form of administration, the particular compound chosen and the physiological characteristics of the particular patient under treatment. Generally, small dosages will be used initially and if necessary, will be increased by small increments until the optimum effect under the circumstances is reached.
- the therapeutic human dosage based on physiological studies using rats, will generally be from about 0.01 mg to about 10 mg/kg of body weight per day or from about 0.4 mg to about 1g or and higher although it may be administered in several different dosage units from once to several times a day. Oral administration requires higher dosages.
- Example 1 illustrates the preparation of bisphosphonic acids within the scope of the present invention.
- Example 1 is prepared from a 4- membered azacyclic ring, namely, azetidine
- Example 2 is prepared fro a 7-membered azacyclic ring, namely, hexamethylenimine.
- Acetone 500 ml was added to the aqueous phase, and the crude product came out of solution as a gum.
- Inorganic phosphorous impurities were removed by passing the crude product over Amberlite-120 cation exchange resin (115g) and eluting with water.
- a small amount of starting carboxylic acid was detected by 13 C and was removed by dissolving the mixture in water and adjusting the pH of the medium to 5.5 with 1 M sodium hydroxide solution.
- the sodium salt of the bisphosphonic acid was selectively precipitated by the addition of methanol and acetone (1 :1 , 500 ml) and isolated by filtration, yielding 2.1 g (40%) of product.
- the compound had a melting (decomposition) point of 250°C and the following elemental analysis: C, 18.01%; H, 5.56%; and N, 3.42%.
- the theoretical numbers (for the composition C 6 H ⁇ 4 N Na ⁇ 7P2 » 5.75 H 0) are C, 18.03%; H, 6.40%; and N, 3.50%.
- Example 2 1 -Hydroxy-3-(1 -hexamethyleniminyl)-propylidine- 1.1 -bisphosphonic acid, monosodium salt
- Ethyl 1-hexamethyleniminepropionate (6.8g, 0.034 mol) was treated with concentrated hydrochloric acid (500 ml) for 2 hours at 20°C and concentrated at 40°C on a rotary evaporator to yield 7.2g of 1- hexamethylenimmepropionic acid hydrochloride, a white crystalline product.
- the propionic acid (6g, 0.029 mol), phosphoric acid (4.3g, 0.052 mol) and anhydrous chlorobenzene (20 ml) were mechanically stirred for 15 minutes at 100°C under a nitrogen atmosphere.
- Phosphorous trichloride (7.12g, 0.052 mol) was added dropwise, and heating was continued for 5 hours.
- the assay chosen to test the new bisphosphonates for their inhibitory activity of bone resorption consists of measuring the preventive effect on the hypercalcemia induced by a retinoid in rats, according to the following method of Trechsel et al., J. Clin. Invest. 80:1679-1686 (1987).
- the results are calculated using the following method. Calcemia is measured at day 0 and at day 3, and the latter value is subtracted from the former to yield the change, ⁇ Ca. As a control, the retinoid alone is administered, and this value of ⁇ Ca is used as standard. The value for ⁇ Cas for the test compounds is calculated and expressed as a percentage of the value of ⁇ Ca for the control. This latter value is an index of the inhibitory activity. A value of 0% means no inhibition, 100% a complete inhibition and values over 100% indicate that besides complete inhibition of the retinoid induced hypercalcemia, the bisphosphonate decreased calcemia below the level present before the retinoid administration. Generally speaking, inhibitory values higher than about 50% are considered significant.
- the bisphosphonic acids of the present invention exhibit significant activity in inhibiting bone reso ⁇ tion when administered in concentrations at least as low as 0.01 mg/kg of animal body weight, and that at dosages at least as low as 0.1 mg/kg, the compounds can completely reverse the retinoid-induced hypercalcemia.
- Bisphosphonates were added as concentrated stock solutions in phosphate buffered saline (PBS) individually to each well (2.5% of the final volume) to reach the final desired concentration.
- PBS phosphate buffered saline
- the bisphosphonates (Sample 1 : 1 -hydroxy-3-(1 '-pyrrolidinyl)propylidene-1 ,1 - bisphosphonic acid disclosed in International Publication No.: WO89/09775; Sample 2: 1-hydroxy-3-(1-azetidinyl)propyfidine-1 ,1 -bisphosphonic acid of the present invention) were present throughout the entire test period.
- BMC (20 x 10 4 /ml) were suspended in Dulbecco's Modified Eagle's medium (DMEM) containing 30%(v/v) L-cell conditioned medium.
- DMEM Dulbecco's Modified Eagle's medium
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Abstract
L'invention se rapporte à des composés comprenant: (A) un groupe terminal d'acide bisphosphonique, (B) un groupe terminal azacyclique dérivé d'azétidine ou d'hexaméthylènimine; et (C) un groupe alkyle/ou aryle reliant le groupe d'acide bisphosphonique et le groupe azacyclique entre eux par l'intermédiaire de l'atome d'azote du groupe azacyclique. Ces composés sont utiles comme agents régulateurs du métabolisme d'ions polyvalents, en particulier du calcium. Cette invention se rapporte également à des préparations pharmaceutiques contenant ces composés, ainsi qu'à des procédés de traitement, au moyen de ces composés, d'états dans lesquels est impliqué un tel métabolisme.The invention relates to compounds comprising: (A) a bisphosphonic acid end group, (B) an azacyclic end group derived from azetidine or hexamethylenimine; and (C) an alkyl / aryl group linking the bisphosphonic acid group and the azacyclic group to each other via the nitrogen atom of the azacyclic group. These compounds are useful as regulating agents for the metabolism of polyvalent ions, in particular calcium. This invention also relates to pharmaceutical preparations containing these compounds, as well as methods of treating, with these compounds, conditions in which such metabolism is involved.
Description
Claims
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Application Number | Priority Date | Filing Date | Title |
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US46442390A | 1990-01-12 | 1990-01-12 | |
US464423 | 1990-01-12 |
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EP0510066A1 true EP0510066A1 (en) | 1992-10-28 |
EP0510066A4 EP0510066A4 (en) | 1992-12-02 |
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EP19910902492 Withdrawn EP0510066A4 (en) | 1990-01-12 | 1991-01-03 | 1-azetidyl and 1-hexamethylenimine alkyl or aryl bisphosphonic acids and their use as pharmacological agents |
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EP (1) | EP0510066A4 (en) |
JP (1) | JPH05507061A (en) |
AU (1) | AU7165791A (en) |
CA (1) | CA2073448A1 (en) |
WO (1) | WO1991010646A1 (en) |
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NZ253541A (en) * | 1992-05-29 | 1997-01-29 | Procter & Gamble Pharma | Cyclic quaternary-n-containing phosphonate derivatives and medicaments |
US5753634A (en) * | 1992-05-29 | 1998-05-19 | The Procter & Gamble Company | Quaternary nitrogen containing phosphonate compounds, pharmaceutical compostions, and methods for treating abnormal calcium and phosphate metabolism |
US5391743A (en) * | 1992-05-29 | 1995-02-21 | Procter & Gamble Pharmaceuticals, Inc. | Quaternary nitrogen-containing phosphonate compounds, pharmaceutical compositions, and methods of treating abnormal calcium and phosphate metabolism and methods of treating and preventing dental calculus and plaque |
CA2136818C (en) * | 1992-05-29 | 2000-01-18 | Susan M. Kaas | Sulfur-containing phosphonate compounds for treating abnormal calcium and phosphate metabolism |
US5763611A (en) * | 1992-05-29 | 1998-06-09 | The Procter & Gamble Company | Thio-substituted cyclic phosphonate compounds, pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism |
EP0642521A1 (en) * | 1992-05-29 | 1995-03-15 | Procter & Gamble Pharmaceuticals | Thio-substituted nitrogen-containing heterocyclic phosphonate compounds for treating abnormal calcium and phosphate metabolism |
ATE515265T1 (en) * | 1998-03-27 | 2011-07-15 | Univ Oregon Health & Science | VITAMIN D AND ITS ANALOGUES FOR THE TREATMENT OF TUMORS AND OTHER HYPERPROLIFERATIVE DISEASES |
US8586781B2 (en) | 1998-04-02 | 2013-11-19 | Mbc Pharma, Inc. | Bone targeted therapeutics and methods of making and using the same |
US7598246B2 (en) | 1998-04-02 | 2009-10-06 | Mbc Pharma, Inc. | Bisphosphonate conjugates and methods of making and using the same |
US6214812B1 (en) * | 1998-04-02 | 2001-04-10 | Mbc Research, Inc. | Bisphosphonate conjugates and methods of making and using the same |
US6896871B2 (en) | 1998-04-02 | 2005-05-24 | Mbc Research, Inc. | Biphosphonate conjugates and methods of making and using the same |
US6750340B2 (en) | 1998-04-02 | 2004-06-15 | Mbc Research, Inc. | Bisphosphonate conjugates and methods of making and using the same |
US9334300B2 (en) | 2011-08-01 | 2016-05-10 | Mbc Pharma, Inc. | Vitamin B6 derivatives of nucleotides, acyclonucleotides and acyclonucleoside phosphonates |
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DE3770787D1 (en) * | 1986-11-21 | 1991-07-18 | Ciba Geigy Ag | Aromatisch substituierte azacyclo-alkylalkandiphosphonsaeuren. |
EP0317505A1 (en) * | 1987-11-13 | 1989-05-24 | Ciba-Geigy Ag | Azacycloalkylalkandiphosphonic acids |
-
1991
- 1991-01-03 AU AU71657/91A patent/AU7165791A/en not_active Abandoned
- 1991-01-03 WO PCT/US1991/000055 patent/WO1991010646A1/en active Search and Examination
- 1991-01-03 CA CA002073448A patent/CA2073448A1/en not_active Abandoned
- 1991-01-03 JP JP91502976A patent/JPH05507061A/en active Pending
- 1991-01-03 EP EP19910902492 patent/EP0510066A4/en not_active Withdrawn
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JPH05507061A (en) | 1993-10-14 |
WO1991010646A1 (en) | 1991-07-25 |
CA2073448A1 (en) | 1991-07-13 |
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