WO1993024494A1 - Quaternary nitrogen-containing phosphonate compounds, for treating abnormal calcium and phosphate metabolism - Google Patents
Quaternary nitrogen-containing phosphonate compounds, for treating abnormal calcium and phosphate metabolism Download PDFInfo
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- WO1993024494A1 WO1993024494A1 PCT/US1993/004469 US9304469W WO9324494A1 WO 1993024494 A1 WO1993024494 A1 WO 1993024494A1 US 9304469 W US9304469 W US 9304469W WO 9324494 A1 WO9324494 A1 WO 9324494A1
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- 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 System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
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- 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 System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
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- 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
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- 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]
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- 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
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- 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 System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
- C07F9/3821—Acyclic saturated acids which can have further substituents on alkyl substituted by B, Si, P or a metal
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- 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 System
- 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
- C07F9/576—Six-membered rings
- C07F9/59—Hydrogenated pyridine rings
Definitions
- This invention relates to novel quaternary, nitrogen-containing phosphonate compounds, including bisphosphonates, phosphonoalkylphosphinates, phosphonocarboxylates, and phosphono-sulfonates.
- This invention also relates to pharmaceutical compositions containing these novel compounds as well as to a method of treating or preventing certain metabolic bone disorders characterized by abnormal calcium and phosphate metabolism by utilizing a compound or pharmaceutical composition of the present invention.
- this invention relates to a method of treating or preventing osteoporosis and arthritis, especially rheumatoid arthritis and osteoarthritis by utilizing a compound or pharmaceutical composition of the present invention.
- a number of pathological conditions which can afflict warm-blooded animals involves abnormal calcium and phosphate metabolism. Such conditions may be divided into two broad categories.
- the first category includes the most common metabolic bone disorder, osteoporosis; osteoporosis is a condition in which bone hard tissue is lost disproportionately to the development of new hard tissue. Osteoporosis can be generally defined as the reduction in the quantity of bone, or the atrophy of skeletal tissue. Marrow and bone spaces become larger, fibrous binding decreases, and compact bone becomes fragile. Osteoporosis can be subclassified as menopausal, senile, drug-Induced (e.g. adrenocorticoid, as can occur in steroid therapy); disease-induced (arthritic and tumor), etc.; however, the manifestations are essentially the same.
- drug-Induced e.g. adrenocorticoid, as can occur in steroid therapy
- disease-induced arthritic and tumor
- osteoporosis In general, there are two types of osteoporosis: primary and secondary. “Secondary osteoporosis” is the result of a separate disease process or agent. However, approximately 90% of all osteoporosis cases are “primary osteoporosis”. Such primary osteoporosis includes postmenopausal osteoporosis, age-associated osteoporosis, disuse osteoporosis (affecting a majority of individuals over the age of 70 to 80), and idiopathic osteoporosis affecting middle-aged and younger men and women.
- Bone fractures often occur, for example, In the hip and spine of women suffering from postmenopausal osteoporosis. Kyphosls (abnormally Increased curvature of the thoracic spine) may also result.
- osteoporosis Although its etiology is not fully understood, there are many risk factors thought to be associated with osteoporosis. These include low body weight, low calcium Intake, physical inactivity, and estrogen deficiency.
- the second category involving conditions manifested by anomalous calcium and phosphate deposition, includes myositis ossificans progressiva, calcinosis universalis, and such afflictions as arthritis (Including, for example, rheumatoid arthritis and osteoarthritis), neuritis, bursitis, tendonitis, and conditions which predispose Involved tissue to deposition of calcium.
- the pathogenesis of rheumatoid arthritis, leading to the destruction of the joints, is characterized by two phases: 1) an exudative phase involving the microcirculation and the synovial cells that allow an influx of plasma proteins and cellular elements into the joint and 2) a chronic inflammatory phase occurring in the sub-synovium and sub-chondral bone, characterized by pannus (granulation tissue) formation in the joint space, bone erosion, and cartilage destruction.
- pannus may form adhesions and scar tissue which causes the joint deformities characteristic of rheumatoid arthritis.
- Non-steroidal anti-inflammatory drug treatment is mainly effective in the early stages of rheumatoid arthritis; it is unlikely it will produce suppression of joint inflammation if the disease is present for more than one year.
- Gold, methotrexate, immunosuppressants and corticosteroids have been tried with limited success.
- osteoarthritis is an Inherently non-inflammatory disorder of the movable joints characterized by deterioration and abrasion of articular cartilage, as well as by formation of new bone at the joint surface.
- the surface of the articular cartilage is disrupted and wear particles gain access to the synovial fluid which in turn stimulates phagocytosis by macrophage cells.
- an inflammatory response is eventually induced in osteoarthritis.
- Common clinical symptoms of osteoarthritis include cartilaginous and bony enlargements of the finger joints and stiffness on awakening and painful movement.
- Patent 4,868,164 to Ebetino issued September 19, 1989.
- Numerous other references describe heterocyclic substituted diphosphonic acids useful for the treatment of osteoporosis and/or arthritis, and are hereby incorporated by reference herein: U.S. Patent 5,071,840, to Ebetino, et al., issued December 10, 1991; U.S. Patent 4,868,164, to Ebetino, et al., issued September 19, 1989; U.S. Patent 5,104,863, to Benedict, et al., issued April 14, 1992; U.S. Patent 4,267,108, to Blum et al., issued May 12, 1981; U.S. Patent 4,746,654 to Breliere et al., issued May 24, 1988; U.S.
- the compounds of the present invention have osteoprotective activity at the site of joint destruction in arthritis conditions and have that activity as an additional benefit in the treatment of arthritis over the above merely relieving the symptoms of inflammation.
- osteoprotedve activity as used herein means disease-modifying activity on bone and surrounding soft tissue at the site of joint destruction.
- the compounds of the present invention have more potent bone antiresorptive activity and therapeutic utility in treating osteoporosis and rheumatoid arthritis and osteoarthritis than nitrogen-containing compounds where the nitrogen atom is not quaternized.
- the compounds of the present Invention exhibit unusual solubility properties.
- the compounds of the present invention may be more readily orally absorbed compounds. The more readily absorbed a compound, the more effective it may be at lower doses. Lower doses are generally preferable because undesirable side effects are decreased.
- the present invention relates to quaternary nitrogen-containing phosphonate compounds, and the pharmaceutical ly-acceptable salts and esters thereof having the following general formula:
- n is an integer from 1-10;
- R 1 is selected from the group consisting of nil; -SR 6 -R 9 SR 6 ; hydrogen; substituted or unsubstltuted C 1 -C 8 alkyl -OR 3 ; -CO 2 R 3 ; -O 2 CR 3 ; -NR 3 2 ; -N(R 3 )C(O)R 3 ; -C(O)N(R 3 ) 2 halogen; -C(O)R 3 ; nitro; hydroxy; substituted or unsubstltuted saturated monocyclic or polycyclic heterocyclic rings; substituted or unsubstituted saturated monocyclic or polycyclic carbocyclic rings;
- R 5 is selected from the group consisting of -SR 6 ; -R 9 SR 6 ; hydrogen; substituted or unsubstltuted C 1 -C 8 alkyl; -OR 3 ; -CO 2 R 3 ; -O 2 CR 3 ; -NR 3 2 ; -N(R 3 )C(O)R 3 ; -C(O)N(R 3 ) 2 ; halogen; -C(O)R 3 ; nitro; hydroxy; substituted or unsubstituted saturated monocyclic or polycyclic heterocyclic rings; substituted or unsubstituted saturated monocyclic or polycyclic carbocyclic rings; substituted or unsubstituted unsaturated monocyclic or polycyclic heterocyclic rings; substituted or unsubstituted unsaturated monocyclic or polycyclic carbocyclic rings and combinations thereof;
- each R 2 is selected from the group consisting of substituted or unsubstituted C 1 -C 35 alkyl; unsubstituted or substituted phenyl; benzyl; or R 9 SR 6 ;
- R 3 is selected from the group consisting of H; unsubstltuted or substituted C 1 -C 8 alkyl; R 9 SR 6 ;
- R 6 is selected from the group consisting of -H; -C(O)R 7 ; -C(S)R 7 ; -C(O)N(R 7 ) 2 ; -C(O)OR 7 ; -C(S)N(R 7 ) 2 ; -C(S)OR 7 ; where R 7 is hydrogen or unsubstituted or substituted C 1 -C 8 alkyl;
- R is selected from the group consisting of -COOH; -SO 3 H; -PO3H2; and -P(O)(OH)R 4 , where R 4 is an alkyl group having 1-3 carbons.
- R 9 is substituted or unsubstltuted C 1 -C 8 alkyl
- R 8 is selected from the group consisting of hydrogen, halogen; SR 6 ; R 9 SR 6 ; amino; hydroxy; substituted and unsubstltuted C 1 -C 8 alkyl;
- the quaternary nitrogen atom must be linked to the phosphonic acid containing carbon atom via a linking chain. It cannot be bonded directly to the phosphonic add containing carbon atom.
- the present invention further relates to pharmaceutical compositions containing a safe and effective amount of a compound of the present invention, and pharmaceutically-acceptable exciplents.
- the present invention relates to methods for treating or preventing pathological conditions characterized by abnormal calcium and phosphate metabolism such as osteoporosis and arthritis, especially rheumatoid arthritis, and osteoarthritis, in humans or other mammals. This method comprises administering to a human or other mammal in heed of such treatment a safe and effective amount of a compound or composition of the present invention.
- Heteroatom is a nitrogen, sulfur, or oxygen atom. Groups containing one or more heteroatoms may contain different heteroatoms.
- Alkyl is an unsubstituted or substituted, straight-chain or branched, saturated or unsaturated hydrocarbon chain, said hydrocarbon chain may be saturated having 1 to 8 carbon atoms, and preferably, unless otherwise stated, from 1 to 4 carbon atoms; said hydrocarbon chain may be unsaturated, having 2 to 8 carbon atoms, and preferably, unless otherwise stated, 2 to 4 carbon atoms.
- alkyl encompasses alkenyl hydrocarbon unsaturated chains having at least one olefinic double bond and alkynyl hydrocarbon unsaturated chains having at least one triple bond.
- Preferred alkyl groups Include, but are not limited to, methyl, ethyl, propyl, isopropyl, and butyl.
- Carbocyclic ring or “Carbocycle” as used herein is an unsubstltuted or substituted, saturated, unsaturated or aromatic, hydrocarbon ring; Carbocyclic rings may be monocyclic or polycyclic: Monocyclic ring generally contain from 3 to 8 atoms, preferably 5 to 7 atoms. Polycyclic rings containing two rings contain 6 to 16, preferably 10 to 12, atoms and those with three rings generally contain 13 to 17, preferably 14 to 15, atoms.
- Heteroalkyl is an unsubstituted or substituted, saturated chain having from 3 to 8-members and comprising carbon atoms and one or two heteroatoms.
- Heterocyclic ring or “Heterocycle” as used herein is an unsubstituted or substituted, saturated, unsaturated or aromatic ring comprised of carbon atoms and one or more heteroatoms in the ring. Heterocyclic rings may be monocyclic or polycyclic rings.
- Monocyclic rings generally contain from 3 to 8 atoms, preferably 5 to 7 atoms.
- Polycyclic ring systems consisting of two rings generally contain 6 to 16, preferably from 10 to 12 atoms.
- Polycyclic ring systems consisting of three rings generally contain 13 to 17 atoms, preferably 14 to 15 atoms.
- a heterocyclic ring moiety may consist of heterocycles or heterocycles and carbocycles. Each heterocyclic ring moiety must have at least one nitrogen atom. Unless otherwise stated any additional heteroatoms may be independently chosen from nitrogen, sulfur, and oxygen.
- Aryl is an aromatic carbocyclic ring.
- Preferred aryl groups include, but are not limited to, phenyl, tolyl, xylyl, cumenyl, and naphthyl.
- Heteroaryl is an aromatic heterocyclic ring.
- Preferred heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiazolyl, quinolinyl, pyrimidinyl, and tetrazolyl.
- Alkoxy is an oxygen atom having a hydrocarbon chain substituent, where the hydrocarbon chain is an alkyl or alkenyl (e.g., -O-alkyl or -O-alkenyl).
- Preferred alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and alkyloxy.
- Hydroalkyl is a substituted hydrocarbon chain which has a hydroxy substituent (e.g., -OH), and may have other substituents.
- Preferred hydroxyal kyl groups include, but are not limited to, hydroxyethyl, hydroxypropyl.
- Carboxyalkyl is a substituted hydrocarbon chain which has a carboxy substituent (e.g. -COOH) and may have other substituents.
- Preferred carboxyalkyl groups include carboxymethyl, carboxyethyl, and their adds and esters.
- Aminoalkyl is a hydrocarbon chain (e.g. alkyl) substituted with an amine moiety (e.g., NH-alkyl-) such as aminomethyl.
- Alkylamino is an amino moiety having one or two alkyl substituents (e.g., -N-alkyl) such as dimethylamino.
- Alkenyl amino is an amino moiety having one or two alkenyl substituents (e.g., -N-alkenyl).
- Alkynalamino is an amino moiety having one or two alkynyl substituents (e.g., -N-alkynyl).
- Alkyl imino is an imino moiety having one or two alkyl substituents (e.g., -N-alkyl-).
- Arylalkyl is an alkyl moiety substituted with an aryl group.
- Preferred arylalkyl groups include benzyl and phenylethyl.
- Arylamino is an amine moiety substituted with an aryl group (e.g., -NH-aryl).
- Aryloxy is an oxygen atom having an aryl substituent (e.g., -O-aryl).
- Preferred acyl groups include, but are not limited to, acetyl, propionyl, butanoyl, and benzoyl.
- a “lower” hydrocarbon moiety is a hydrocarbon chain comprised of from, unless otherwise stated, 1 to 6, preferably from 1 to 4, carbon atoms.
- R 7 is generally a hydrogen or C 1 -C 8 alkyl. Any of the SR 6 substituents may themselves be substituted with an R 9 moiety, i.e. R 9 SR 6 , where R 9 is a substituted or unsubstituted C 1 -C 8 alkyl. Accordingly, additional thio-substituents denoted by R 9 SR 6 are alkylthiols, alkylthioesters, alkyldithioesters, alkylthiocarbamates, alkyldithiocarbmates, alkylthiocarbonates, and alkyldithio-carbonates.
- bisphosphonate or “bisphosphonic acid” as used herein relate to those phosphonate or phosphonic acid compounds that have two phosphonate groups attached to the same carbon atom and are used interchangeably with the terms “diphosphonate” and “diphosphonic acids.”
- the moiety R is PO 3 H 2 .
- the term "phosphonic acid carbon” refers to the carbon atom to which a phosphonic acid group (PO 3 H 2 ) is attached.
- the resulting compound is bisphosphonate.
- a sulfonate group is attached to said carbon atom, the resulting compound is a phosphonosulfonate.
- a carboxylate group is attached to said carbon atom, the resulting compound is a phosphonocarboxylate.
- a phosphinic acid group is attached to said carbon atom, the resulting compound is a phospho ⁇ oalkylphosphinate.
- a "pharmaceutically-acceptable" salt is a catonic salt formed at any acidic (e.g., carboxyl) group, or an anionic salt formed at any basic (e.g., amino) group.
- Preferred catonic salts include the alkali-metal salts (such as sodium and potassium), and alkaline earth metal salts (such as magnesium and calcium).
- Preferred anionic salts include the halide (such as chloride), acetate and phosphate salts.
- a “biohydrolyzable ester” is an ester of the quaternary nitrogen-containing heterocyclic phosphonate compounds that does not interfere with the therapeutic activity of the compounds, or that is readily metabolized by a human or other mammal. Many such esters are known in the art, as described in World Patent Publication 87/05297, Johnston et al., published September 11, 1987, and hereby incorporated by reference herein.
- esters include lower alkyl esters, lower acyloxyalkyl esters (such as acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxyethyl esters), lactonyl esters (such as phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such as methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters, and acyl amino alkyl esters (such as acetamidomethyl esters).
- lower alkyl esters such as acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxyethyl esters
- lactonyl esters such as phthalidy
- substituent groups may themselves be substituted. Such substitution may be with one or more substituents.
- substituents include, but are not limited to, those listed in C. Hansch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology (1979), hereby incorporated by reference herein.
- Preferred substituents include, but are not limited to, alkyl, alkenyl, alkoxy, hydroxy, oxo, amino, aminoalkyl (e.g. aminomethyl, etc.), cyano, halo, carboxy, alkoxyacetyl (e.g.
- thio, thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl e.g., piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, etc.
- the compounds of the present invention are quaternary nitrogen-containing phosphonate compounds, and the pharmaceutically-acceptable salts and esters thereof, having a quaternary nitrogen atom.
- the quaternary nitrogen atom is bonded to the phosphonic acid containing carbon via a linking chain to the phosphonic acid containing carbon.
- the carbon atom which has the phosphonic acid group attached to it may be unsubstituted (i.e., a hydrogen atom) or substituted.
- the phosphonic acid carbon may contain two phosphonate groups, rendering a bisphosphonate compound; a phosphonate group and an carboxylate group, rendering a phosphonocarboxylate compound; a phosphonate group and a sulfonate group, rendering a phosphonosulfonate compound, a phosphinate group and a phosphonate group, rendering a phosphonoalkylphosphinate compound.
- quaternary nitrogen-containing phosphonate compounds of the present invention and the pharmaceutically-acceptable salts and esters thereof, have the general structure:
- R 1 is selected from a variety of non-ring moieties such as nil, -SR 6 , -R 9 SR 6 , hydrogen, alkyl having 1-8 carbons, -OR 3 , -CO 2 R 3 , -O 2 CR 3 , -NR 3 2 , -N(R 3 )C(O)R 3 , -C(O)N(R 3 ) 2 ; halogen, -C(O)R 3 , nitro, hydroxy, substituted or unsubstltuted saturated monocyclic or polycyclic heterocyclic rings, substituted or unsubstituted saturated monocyclic or polycyclic carbocyclic rings.
- non-ring moieties such as nil, -SR 6 , -R 9 SR 6 , hydrogen, alkyl having 1-8 carbons, -OR 3 , -CO 2 R 3 , -O 2 CR 3 , -NR 3 2 , -N(R 3 )C
- n which is an integer from 1-10, represents said linking chain.
- R 5 can be -SR 6 , -R 9 SR 6 , hydrogen, C 1 -C 8 alkyl, -OR 3 , -CO 2 R 3 ; -O 2 CR 3 ; -NR 3 2 ; -N(R 3 )C(O)R 3 , -C(O)N(R 3 2 ); halogen, -C(O)R 3 ; nitro; hydrogen; unsubstituted or substituted saturated monocyclic or polycyclic heterocyclic ring, unsubstituted or substituted saturated monocyclic or polycyclic carbocyclic rings, unsubstituted or substituted unsaturated monocyclic or polycyclic heterocyclic rings, unsubstituted or substituted unsaturated monocyclic or polycyclic carbocyclic rings and combinations thereof.
- R can be -COOH, -SO 3 H, -PO 3 H 2 and -P(O)(OH)R 4 where R 4 is C 1 -C 8 alkyl.
- R is PO 3 H 2 and P(O)(OH)R 4 .
- R 8 is a substituent on the phosphonic acid containing carbon selected from hydrogen, halogen, SR 6 , R 9 ,SR 6 , amino, hydroxy, substituted and unsubstituted C 1 -C 8 alkyl.
- Preferred R 8 is hydroxy, halogen and amino.
- R 2 is substituted or unsubstituted C 1 -C 35 alkyl, substituted or unsubstituted phenyl, benzyl; or R 9 SR 6 .
- Preferred R 2 is substituted or unsubstituted C 1 -C 8 alkyl and R 9 SR 6 .
- Preferred quaternary nitrogen-containing phosphonates having an Rl moiety selected from the R 1 moieties described herein before include,
- the R 1 moiety can also be saturated monocyclic or polycyclic heterocycle.
- Preferred quaternary nitrogen-containing phosphonates having a saturated monocyclic or polycyclic heterocycle as an R 1 moiety wherein the quaternary nitrogen atom is linked via a linking chain to the phosphonic acid carbon include:
- Preferred compounds of the present invention also include the thio-substituted quaternary nitrogen containing phosphonates.
- N-cycloheptyl-N,N-dimethyl-N-(diphosphonomethyl) ammonium iodide N-(2-acetylthioethyl)-N-(4-hydroxy-4,4-diphosphonobutyl)-N,N-dimethyl ammonium bromide;
- testing of the phosphonate compounds in animals is carried out using various assays known to those skilled in the art.
- the In vivo bone antiresorptive activity may be conveniently demonstrated using an assay designed to test the ability of these compounds to Inhibit the resorption of bone, which bone resorption is characteristic of abnormal calcium and phosphate metabolism.
- One such test known to the art is the Schenk model.
- Another useful art-known test is the adjuvant arthritis test.
- Patent 4,134,969 to Schmidt-Dunker, Issued January 16, 1979; and EPO Patent Application Publication No. 189,662, published August 6, 1986; the disclosures of all these articles and patent specifications being incorporated herein by reference in their entirety. Certain of these tests for pharmacological activity are also described in more detail in the Examples provided hereinafter.
- the compounds of the present invention may have other uses.
- the compounds of the present invention are believed to be useful as bone scanning agents after labeling with 99m-technetium.
- the compounds of the present invention are useful as sequestering agents for polyvalent metal ions, particularly di-(e.g. calcium and magnesium) and trivalent (e.g. indium) metal ions.
- the compounds of the present invention are useful as builders in detergents and cleansers, or for treating water. They are also useful as stabilizers for compounds.
- they may be useful in preventing the formation of tartar (I.e., calculus) and/or plaque on teeth.
- the compounds of the present invention may be useful as herbicides which are non-toxic to animals.
- compositions Containing Novel Quaternary Nitrogen Containing Phosphonate Compounds
- novel quaternary nitrogen-containing phosphonate compounds of the present invention may be administered to humans or other mammals by a variety of routes, including, but not limited to, oral dosage forms and injections (intravenous, intramuscular, intraperitoneal and subcutaneous).
- oral dosage forms and injections intravenous, intramuscular, intraperitoneal and subcutaneous.
- Numerous other dosage forms containing the novel quaternary nitrogen-containing phosphonate compounds of the present invention can be readily formulated by one skilled in the art, utilizing the suitable pharmaceutical excipients as defined below.
- oral dosage forms are generally most preferred.
- composition means a combination comprised of a safe and effective amount of the quaternary nitrogen-containing phosphonate compound active ingredient, or mixtures thereof, and pharmaceutically-acceptable excipients.
- safe and effective amount means an amount of a compound or composition large enough to significantly positively modify the symptoms and/or condition to be treated, but small enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment.
- the safe and effective amount of active ingredient for use in the pharmaceutical compositions to be used in the method of the Invention herein will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient being employed, the particular pharmaceutically-acceptable excipients utilized, and like factors within the knowledge and expertise of the attending physician.
- pharmaceutically-acceptable excipients includes any physiologically inert, pharmacologically inactive material known to one skilled in the art, which is compatible with the physical and chemical characteristics of the particular quaternary nitrogen-containing phosphonate compound active ingredient selected for use.
- Pharmaceutically-acceptable excipients include, but are not limited to, polymers, resins, plasticizers, fillers, binders, lubricants, glidants, disintegrants, solvents, co-solvents, buffer systems, surfactants, preservatives, sweetening agents, flavoring agents, pharmaceutical grade dyes or pigments, and viscosity agents.
- oral dosage form means any pharmaceutical composition intended to be systemically administered to an individual by delivering said composition to the gastrointestinal tract of an individual, via the mouth of said individual.
- the delivered form can be in the form of a tablet, coated or non-coated; solution; suspension; or a capsule, coated or non-coated.
- injection means any pharmaceutical composition intended to be systemically administered to a human or other mammal, via delivery of a solution or emulsion containing the active ingredient, by puncturing the skin of said individual, in order to deliver said solution or emulsion to the circulatory system of the individual either by intravenous, intramuscular, intraperitoneal or subcutaneous injection.
- the rate of systemic delivery can be satisfactorily controlled by one skilled in the art, by manipulating any one or more of the following:
- solubility, acidity, and susceptibility to hydrolysis of the different quaternary non-ring nitrogen-containing phosphonate active ingredients such as acid addition salts, salts formed with the carboxylic group, e.g., alkali metal salts, alkaline earth metal salts, etc., and esters, e.g., alkyl, aryl, aralkyl, may be used as guidelines for the proper choice.
- suitable pH-conditions might be established within the oral dosage forms by adding a suitable buffer to the active ingredient in accordance with the desired release pattern.
- pharmaceutically-acceptable excipients include, but are not limited to, resins, fillers, binders, lubricants, solvents, glidants, disintegrants cosolvents, surfactants, preservatives, sweetener agents, flavoring agents, buffer systems, pharmaceutical -grade dyes or pigments, and viscosity agents.
- the preferred solvent is water.
- Flavoring agents among those useful herein include those described in Remington's Pharmaceutical Sciences. 18th Edition,
- compositions suitable for use herein generally contain from 0-2% flavoring agents.
- Dyes or pigments among those useful herein include those described in Handbook of Pharmaceutical Excipients. pp. 81-90, 1986 by the American Pharmaceutical Association & the Pharmaceutical Society of Great Britain, incorporated by reference herein.
- the pharmaceutical compositions herein generally contain from 0-2% dyes or pigments.
- Preferred co-solvents include, but are not limited to, ethanol, glycerin, propylene glycol, polyethylene glycols.
- the pharmaceutical compositions of the present invention include from 0-50% co-solvents.
- Preferred buffer systems include, but are not limited to, acetic, boric, carbonic, phosphoric, succinlc, malaic, tartaric, citric, acetic, benzoic, lactic, glyceric, gluconic, glutaric and glutamic acids and their sodium, potassium and ammonium salts. Particularly preferred are phosphoric, tartaric, citric, and acetic acids and salts.
- the pharmaceutical composition of the present invention generally contain from 0-5% buffer systems.
- Preferred surfactants include, but are not limited to, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene monoalkyl ethers, sucrose monoesters and lanolin esters and ethers, alkyl sulfate salts, sodium, potassium, and ammonium salts of fatty acids.
- the pharmaceutical compositions of the present invention include 0-2% surfactants.
- Preferred preservatives include, but are not limited to, phenol, alkyl esters of parahydroxybenzoic acid, o-phenylphenol benzoic acid and the salts thereof, boric acid and the salts thereof, sorbic acid and the salts thereof, chlorobutanol, benzyl alcohol, thimerosal, phenylmercuric acetate and nitrate, nitromersol, benzalkonium chloride, cetylpyridinium chloride, methyl paraben, and propyl paraben. Particularly preferred are the salts of benzoic acid, cetylpyridinium chloride, methyl paraben and propyl paraben.
- the compositions of the present invention generally include from 0-2% preservatives.
- Preferred sweeteners include, but are not limited to, sucrose, glucose, saccharin, sorbitol, mannitol, and aspartame. Particularly preferred are sucrose and saccharin.
- Pharmaceutical compositions of the present invention include 0-5% sweeteners.
- Preferred viscosity agents include, but are not limited to, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium alginate, carbomer, povidone, acada, guar gum, xanthan gum and tragacanth. Particularly preferred are methylcellulose, carbomer, xanthan gum, guar gum, povldone, sodium carboxymethylcellulose, and magnesium aluminum silicate.
- Compositions of the present invention include 0-5% viscosity agents.
- Preferred fillers include, but are not limited to, lactose, mannitol, sorbitol, tribasic calcium phosphate, dibasic calcium phosphate, compressible sugar, starch, calcium sulfate, dextro and microcrystalline cellulose.
- the compositions of the present invention contain from 0-75% fillers.
- Preferred lubricants include, but are not limited to, magnesium stearate, stearic acid, and talc.
- the pharmaceutical compositions of the present invention include 0.5-2% lubricants.
- Preferred glidants include, but are not limited to, talc and colloidal silicon dioxide.
- the compositions of the present invention include from 1-5% glidants.
- Preferred disintegrants include, but are not limited to, starch, sodium starch glycolate, crospovidone, croscarmelose sodium, and microcrystalline cellulose.
- the pharmaceutical compositions of the present invention include from 4-15% disintegrants.
- Preferred binders include, but are not limited to, acacia, tragacanth, hydroxypropylcellulose, pregelatinized starch, gelatin, povidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, sugar solutions, such as sucrose and sorbitol, and ethylcellulose.
- the compositions of the present invention include 1-10% binders.
- Compounds of the present invention may comprise from about 0.1% to about 99.9% by weight of the pharmaceutical compositions of the present invention.
- the compounds of the present Invention comprise from about 20% to about 80% by weight of the pharmaceutical compositions of the present invention.
- compositions of the present Invention include from 15-95% of a quaternary nitrogen- containing phosphonate compound active ingredient, or mixture, thereof; 0-2% flavoring agents; 0-50% co-solvents; 0-5% buffer system; 0-2% surfactants; 0-2% preservatives; 0-5% sweeteners; 0-5% viscosity agents; 0-75% fillers; 0.5-2% lubricants; 1-5% glidants; 4-15% disintegrants; and 1-10% binders.
- Suitable pharmaceutical compositions are described herein in Examples 9 to 11. It is well within the capabilities of one skilled in the art to vary the non-limiting examples described herein to achieve a broad range of pharmaceutical compositions.
- the choice of a pharmaceutical excipient to be used in conjunction with the quaternary nitrogen-containing phosphonate compounds of the present compositions is basically determined by the way the phosphonate is to be administered. If the compound is to be injected, the preferred pharmaceutical carrier is sterile, physiological saline, the pH of which has been adjusted to about 7.4. However, the preferred mode of administering the phosphonates of the present invention is orally, and the preferred unit dosage form is therefore tablets, capsules and the like, comprising from about 0.1 mg P to about 600 mg P of the phosphonic acid compounds described herein.
- compositions suitable for the preparation of unit dosage forms for oral administration are well known in the art. Their selection will depend on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of the present Invention, and can be made without difficulty by a person skilled in the art.
- the term "mg P", as used herein, means the weight of the phosphorus atoms present in an amount of a phosphonic acid compound of the present invention. This unit is used to standardize the amount of the phosphonic add compounds of the present invention to be used in the pharmaceutical compositions and methods of the present inventions.
- N-(4-hydroxy-4,4-diphosphonobutyl)-N,N-dimethyl-N-(2-mercaptoethyl)-ammonium chloride has a molecular weight of 373.5 g/mole, of which 17% ( 62 g/mole) is due to the two phosphorus atoms present In this molecule.
- One milligram of this compound is therefore calculated to have 0.17 mg P.
- the composition should contain 1 mg of the compound; and to dose 0.17 mg P/kg of this compound to a 50 kg patient, the patient would be dosed with 50 mg of this compound.
- the pharmaceutically-acceptable excipient employed in conjunction with the diphosphonates of the present invention is used at a concentration sufficient to provide a practical size to dosage relationship.
- the pharmaceutically-acceptable carriers in total, may comprise from about 0.1% to about 99.9% by weight of the total composition and more preferably from about 20% to about 80%.
- rheumatoid arthritis means a chronic systemic and articular inflammatory disorder of unknown etiology. It is characterized by destruction of articular cartilage, ligaments, tendons, and bone.
- osteoarthritis means a non-inflammatory disorder of the movable joints. It is characterized by deterioration and abrasion of the articular cartilage; and new bone formation at the joint surface.
- person at risk and "person in need of such treatment”, as used herein, mean any human or lower animal which suffers a significant risk of abnormal calcium and phosphate metabolism if left untreated, and any human or lower animal diagnosed as being afflicted with abnormal calcium and phosphate metabolism.
- postmenopausal women For example, postmenopausal women; persons undergoing certain steroid therapy; persons on certain anti-convulsant drugs; persons diagnosed as having Paget's disease, hyperparathyroidism, hypercalcemia of malignancy, or osteolytic bone metastases; persons diagnosed as suffering from one or more of the various forms of osteoporosis; persons belonging to a population group known to have a significantly higher than average chance of developing osteoporosis, e.g., postmenopausal women, men over age 65, and persons being treated with drugs known to cause osteoporosis as a side effect;
- safe and effective amount means an amount of a compound or composition of the present invention high enough to significantly positively modify the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment.
- the safe and effective amount of phosphonate compounds of the present invention will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the specific phosphonate employed, the particular pharmaceutically-acceptable carrier utilized, and like factors within the knowledge and expertise of the attending physician. However, single dosages can range from 0.01 mg P to 3500 mg P, or from 0.0002 to 70 mg P/kg of body weight (based on a body weight of 50 kg).
- Preferred single dosages are from 1 mg P to 600 mg P, or from 0.02 to 12 g P/kg of body weight (based on a body weight of 50 kg). Up to four single dosages per day may be administered. Daily dosages greater than 500 mg P/kg are not required to produce the desired effect and may produce undesirable side effects. The higher dosages within this range are, of course, required in the case of oral administration because of limited absorption.
- the blsphosphonic add (0.30 mmol) is dissolved in water (10 ml) and ethanol (15 ml) and the pH is adjusted to 7.0 by the addition of 1N NaOH. To this is added methyl iodide (1.50 mmol) and the reaction is heated at reflux for 24 hours. The mixture is then cooled and concentrated under reduced pressure. The solid residue is dissolved in a minimum amount of water and the quaternized product is precipitated by the addition of isopropanol. The product is collected by filtration, rinsed with acetone and then further dried under vacuum.
- Example 1 part II, hereinbefore, [3- (N,N-dimethylamino)propyl idene]bis[phosphonic add] , prepared as described in Example 2, part I, hereinbefore, is converted to N- (3-hydroxy-3,3-diphosphonopropyl ) -N,N,N-trimethyl ammonium iodide.
- the compounds are evaluated for in vivo bone resorption inhibition and mineralization inhibition in an animal model system known in the field of bone metabolism as the Schenk Model.
- the general principles of this model system are disclosed in Shinoda et al., Calcif. Tissue Int.. 35, 87-99 (1983); and in Schenk et al., Caldf, Tissue Res. 11 , 196-214 (1973), the disclosures of which are Incorporated herein by reference.
- All solutions are prepared for subcutaneous injection in 0.9% normal saline and adjusted to pH 7.4 using NaOH and/or HCl. Dose solution calculation is made by considering the mass of powder (based on molecular weight, hydration) of the active material in mg/kg (body weight) that corresponds to mgp/kg. Concentrations are based on dosing 0.2 ml/100 g body weight. Typically, all compounds are administered at 0.01, 0.1, 1.0 and 10.0 mg P/kg/day for 7 days. Compounds showing activity at 0.1 mg P/kg/day are then tested at logarithmic decrements down to 0.001 mg P/kg/day. Adjustments in dosage based on changes in body weight are made on a daily basis.
- tibia is dehydrated in graded ethanol solutions and embedded in methyl methacrylate as described in Schenk, Methods of Calcified Tissue Preparation (G.R. Dickson, Editor; Elsevier Science Publ., The Netherlands; 1984), the disclosures of which are incorporated herein by reference in their entirety.
- the tibia is sectioned longitudinally through the metaphyseal area.
- Specimens are stained on one surface with silver nitrate and mounted on microscope slides for evaluation with a Quantimet Image Analyzer (Cambridge Instruments, Inc.) using both incandescent and ultraviolet Illumination. Metaphyseal trabecular bone content is measured in the region between the fluorescent label and the growth plate: expressed as percent of total area (bone + marrow). Epiphyseal growth plate width is obtained as the mean value of 10 equally-spaced measurements across the section.
- Adjuvant arthritis is a severe cellulitis and synovitis induced in male rats (either Sprague Dawley or Lewis strain) by a single subcutaneous (SC) Injection of Mycobacterium butyric ⁇ m (8 mg/ml) in mineral oil on day 0.
- SC single subcutaneous
- the compounds are dosed once daily either orally (PO) or parenterally (SC) and can be tested in either prophylactic (from day 0) or therapeutic (from day 9 or 10 or 14) protocols.
- Antiarthritic efficacy can be measured as a reduction in paw volume, body weight loss, bone loss or reactive new bone formation compared to the saline-treated arthritic controls. Treatment can be stopped and the "flare" response (rapid increase in inflammation) examined, which indicates a compound's ability to maintain efficacy.
- Animals used are male Lewis rats (LEW). On arrival, the rats are randomized by computer generated random numbers and placed in Individual wire suspended cages. Food and water are administered ad libitum, throughout the entire study. Routine care and maintenance of the animals are performed according to State and Federal regulations. Each rat is identified with a number placed in front of the cage and on the tail of the rat.
- paw volumes and body weights are measured thereafter on various days, usually twice a week.
- rats are randomly allocated into groups of 8-10 rats and treatment begins on day 0 and continues daily until termination.
- the rats are randomized into treatment groups of 8-10 rats according to their PV on day 10. Dosing begins on day 10 and continues daily until termination.
- animals are placed in shoe box cages with deep bedding on or before day 10.
- Drugs are weighed out on a calibrated balance and then mixed with distilled water in a volumetric flask.
- the solution is adjusted to pH 7.4 with 0.1N NaOH.
- the solution is filtered through a 0.45 ⁇ m sterile filter Into a sterile storage container. When not in use, the solution is stored in the refrigerator.
- Drugs are weighed out on a calibrated balance and then mixed with deoxygenated water in a volumetric flask.
- the stock solution is filtered through a 0.45 ⁇ m sterile filter into a sterile storage container. When not in use, the stock solution is kept refrigerated.
- Drug calculations are made based on the molecular weight, the purity of the compound, the amount based on mg/kg (body weight) and the desired final concentration in mgP/kg.
- the volume dosed per rat Is 0.1 ml/100 gm of body weight subcutaneously, given as an Injection in the Inguinal fold of the animal, alternating sides each day or 1 ml/200 gm BW given orally using a curved stainless steel dosing tube. Adjustments based on changes in body weight are made weekly. Radiographs. Necropsy and Tissue Collection
- each rat is sacrificed with 1 ml Socomb ® intraperitoneally (IP).
- IP intraperitoneally
- time 60 second on Kodak non-screen medical film.
- Hind legs are removed from each rat and fixed in 10% buffered formalin along with a piece of liver, kidney, spleen, and thimus.
- the tibiotarsal joints are decalcified in 4% EDTA, pH 7.4 and processed routinely in paraffin blocks and H+E stain.
- the organ parts also processed in paraffin and stained H+E.
- Radiographs are graded for bone resorption (BR) in 6 anatomical trabecular bone sites in each hind leg and 4 sites in each front leg on a scale of 0-3 giving an arbitrary score of 0-60 for all 4 legs.
- BR bone resorption
- RTB reactive new bone formation
- This model provides in vivo data for the efficacy of antiarthritic compounds in terms of reducing paw swelling bone loss and reactive new bone formation compared to the saline treated arthritic animals.
- Capsules are prepared having the following composition:
- the capsules having the above composition are prepared using conventional methods as described below,
- the active ingredient is mixed with the microcrystalline cellulose in a turn shell blender for approximately ten (10) minutes.
- the resulting mixture is passed through a hammer mill with an 80 mesh screen.
- the mixture is put back into the twin shell blender along with the lactose and is then mixed for approximately fifteen (15) minutes.
- the magnesium stearate is next added and blended for an additional five (5) minutes.
- the resulting blend is then compressed on a piston-activated capsule filler.
- any of the compounds prepared according to Examples 1 to 5 may be substituted for the active Ingredient in the capsule prepared herelnabove.
- Tablets are prepared having the following composition:
- Tablets are prepared having the above composition using conventional methods as described below:
- the active ingredient is ground in a ball mill for approximately thirty (30) minutes.
- the milled active ingredient is then blended in a twinblade mixer with the spray-dried lactose for approximately twenty (20) minutes.
- the starch is added to the mixture and is then mixed for an additional fifteen (15) minutes.
- the blend is compressed into tablets on a standard tablet press.
- Injectable solutions are prepared by conventional methods using 10.0 ml of physiological saline solution and N-(4-hydroxy-4,4-diphosphonobutyl)-N, N, N-trimethyl ammonium chloride, adjusted to pH - 7.4.
- a Caucasian male weighing approximately 92 kilograms, seventy-two years of age, suffering from moderate to severe pain, and occasional swelling, of the right knee. After approximately out year of steadily increasing discomfort, he visits a physician who renders a clinical diagnosis of osteoarthritis of the right knee, which was subsequently verified by X-ray diagnosis.
- a black female weighing approximately 65 kilograms, fifty-five years of age, presents with swelling and deformation of the finger joints of both hands, with partial loss of strength and/or dexterity of her fingers and hands.
- ARA American Rheumatological Association
- her physician prescribes the tablets prepared as described In Example 9, two times dally two hours before or after meals for a period of four months. After a month of therapy, her symptoms of knuckle swelling noticeably improves and her range of finger motion Increases significantly; she continues therapy for the remainder of the four months, after which her physician continues the prescribed dose for an additional two months.
- Her symptoms Include marked Inflammatlon of multiple joints, complicated by heat and tenderness and Indicating rapid and pathological degeneration of joint function.
- Her physician with the aid of a radiologist, diagnoses her as having a crush fracture of the L1 vertebrae presumably due to osteoporotlc bone loss.
- the patient is prescribed a three month, once-daily dosage regimen of a 700 mg tablet prepared described In Example 9.
- the 700 mg tablet is taken either two hours before or two hours after any given meal. After three months, the dosage is reduced to a 350 mg capsule, prepared according to the procedure described in Example 8, taken every other day for a period of three months.
- Her physician puts her on a maintenance dosing regimen wherein she takes a 100 mg capsule, prepared according to the procedures described in Example 8, wry day for six months. After six months on the maintenance dosing regimen the patient is not experiencing any further back pain.
- follow-up x-rays reveal no additional fractures.
- the patient Is prescribed a two month regimen of a 700 mg tablet and a 350 mg capsule to be taken on the same day, eight hours apart, prepared according to the procedures described in Examples 9 and 8, respectively. After two months on this regimen, his dosage Is reduced to a 350 mg capsule once a day for two months. X-rays are then taken and an additional crush fracture is noted. He is then put on a maintenance regimen of a 100 mg capsule, prepared according to the procedure described In Example 8, once a day for six months. At the end of this six months, no significant apparent decrease In bone density Is observed.
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
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SK1445-94A SK144594A3 (en) | 1992-05-29 | 1993-05-11 | Quaternary nitrogen-containing phosphate compounds, for treating abnormal calcium and phosphate metabolism |
KR1019940704304A KR950701927A (en) | 1992-05-29 | 1993-05-11 | QUATERNARY NITROGEN-CONTAINING PHOSPHONATE COMPOUNDS, FOR TREATING ABNORMAL CALCIUM AND PHOSPHATE METABOLISM |
EP93911255A EP0642517A1 (en) | 1992-05-29 | 1993-05-11 | Quaternary nitrogen-containing phosphonate compounds, for treating abnormal calcium and phosphate metabolism |
AU42453/93A AU675224B2 (en) | 1992-05-29 | 1993-05-11 | Quaternary nitrogen-containing phosphonate compounds, for treating abnormal calcium and phosphate metabolism |
JP6500570A JPH07507305A (en) | 1992-05-29 | 1993-05-11 | Quaternary nitrogen-containing phosphonate compounds for treating abnormal calcium and phosphate metabolism |
NO944514A NO944514L (en) | 1992-05-29 | 1994-11-25 | Quaternary nitrogen-containing phosphonate compounds for the treatment of abnormal calcium and phosphate metabolism |
FI945598A FI945598A (en) | 1992-05-29 | 1994-11-28 | Quaternary nitrogen-containing phosphonate compounds for the treatment of abnormal calcium and phosphate metabolism |
Applications Claiming Priority (2)
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US89135592A | 1992-05-29 | 1992-05-29 | |
US07/891,355 | 1992-05-29 |
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PCT/US1993/004469 WO1993024494A1 (en) | 1992-05-29 | 1993-05-11 | Quaternary nitrogen-containing phosphonate compounds, for treating abnormal calcium and phosphate metabolism |
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EP (1) | EP0642517A1 (en) |
JP (1) | JPH07507305A (en) |
KR (1) | KR950701927A (en) |
CN (1) | CN1085906A (en) |
AU (1) | AU675224B2 (en) |
CA (1) | CA2136819A1 (en) |
CZ (1) | CZ296694A3 (en) |
FI (1) | FI945598A (en) |
HU (1) | HUT69732A (en) |
IL (1) | IL105831A0 (en) |
MX (1) | MX9303245A (en) |
NZ (1) | NZ252587A (en) |
RU (1) | RU94046139A (en) |
SK (1) | SK144594A3 (en) |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996031124A1 (en) * | 1995-04-07 | 1996-10-10 | Zeneca Limited | Herbicidal aza bisphosphonic acids and compositions containing the same |
WO1997008178A1 (en) * | 1995-08-23 | 1997-03-06 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Novel bisphosphonates, process for their preparation and pharmaceutical compositions containing them |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2319646A1 (en) * | 1975-08-01 | 1977-02-25 | 1-HYDROXY-3-AMINOALCANE-1,1-DIPHOSPHONIC ACIDS | |
DE4011777A1 (en) * | 1989-04-14 | 1990-10-18 | Ciba Geigy Ag | New tri:alkyl:ammonio 1-hydroxy-alkane-1,1-di:phosphonic acids - are calcium metabolism regulants e.g. for treating osteoporosis of calcium deposition in blood vessels |
-
1993
- 1993-05-11 RU RU94046139/04A patent/RU94046139A/en unknown
- 1993-05-11 AU AU42453/93A patent/AU675224B2/en not_active Ceased
- 1993-05-11 WO PCT/US1993/004469 patent/WO1993024494A1/en not_active Application Discontinuation
- 1993-05-11 KR KR1019940704304A patent/KR950701927A/en not_active Application Discontinuation
- 1993-05-11 NZ NZ252587A patent/NZ252587A/en unknown
- 1993-05-11 EP EP93911255A patent/EP0642517A1/en not_active Ceased
- 1993-05-11 SK SK1445-94A patent/SK144594A3/en unknown
- 1993-05-11 HU HU9403406A patent/HUT69732A/en unknown
- 1993-05-11 JP JP6500570A patent/JPH07507305A/en active Pending
- 1993-05-11 CA CA002136819A patent/CA2136819A1/en not_active Abandoned
- 1993-05-11 CZ CZ942966A patent/CZ296694A3/en unknown
- 1993-05-28 ZA ZA933758A patent/ZA933758B/en unknown
- 1993-05-28 IL IL105831A patent/IL105831A0/en unknown
- 1993-05-29 CN CN93108225A patent/CN1085906A/en active Pending
- 1993-05-31 MX MX9303245A patent/MX9303245A/en unknown
-
1994
- 1994-11-28 FI FI945598A patent/FI945598A/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2319646A1 (en) * | 1975-08-01 | 1977-02-25 | 1-HYDROXY-3-AMINOALCANE-1,1-DIPHOSPHONIC ACIDS | |
DE4011777A1 (en) * | 1989-04-14 | 1990-10-18 | Ciba Geigy Ag | New tri:alkyl:ammonio 1-hydroxy-alkane-1,1-di:phosphonic acids - are calcium metabolism regulants e.g. for treating osteoporosis of calcium deposition in blood vessels |
Non-Patent Citations (1)
Title |
---|
PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS vol. 54, nr.1-4, 1990 pa ges 197-202 K.A. JAEGGI ' A novel rearran gement in the series of gem-bisphosphonic acids' * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5728650A (en) * | 1993-10-07 | 1998-03-17 | Zeneca Limited | Herbicidal aza bisphosphonic acids and compositions containing the same |
WO1996031124A1 (en) * | 1995-04-07 | 1996-10-10 | Zeneca Limited | Herbicidal aza bisphosphonic acids and compositions containing the same |
WO1997008178A1 (en) * | 1995-08-23 | 1997-03-06 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Novel bisphosphonates, process for their preparation and pharmaceutical compositions containing them |
Also Published As
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CZ296694A3 (en) | 1995-12-13 |
NZ252587A (en) | 1997-02-24 |
FI945598A (en) | 1995-01-25 |
RU94046139A (en) | 1996-09-27 |
MX9303245A (en) | 1994-05-31 |
JPH07507305A (en) | 1995-08-10 |
CN1085906A (en) | 1994-04-27 |
IL105831A0 (en) | 1993-09-22 |
HUT69732A (en) | 1995-09-28 |
FI945598A0 (en) | 1994-11-28 |
KR950701927A (en) | 1995-05-17 |
CA2136819A1 (en) | 1993-12-09 |
SK144594A3 (en) | 1995-07-11 |
EP0642517A1 (en) | 1995-03-15 |
HU9403406D0 (en) | 1995-02-28 |
ZA933758B (en) | 1994-01-20 |
AU4245393A (en) | 1993-12-30 |
AU675224B2 (en) | 1997-01-30 |
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