JPH07507305A - Quaternary nitrogen-containing phosphonate compounds for treating abnormal calcium and phosphate metabolism - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Quaternary nitrogen-containing phosphonate compounds for treating abnormal calcium and phosphate metabolism Background of product invention The present invention relates to bisphosphonates, phosphonoalkylphosphinates, phosphonocarbons, Novel quaternary nitrogen-containing phosphorus containing ruboxylates and phosphonosulfonates nate compounds. The present invention further provides pharmaceutical compositions containing these novel compounds. By using the compound or pharmaceutical composition of the present invention, abnormal calcium and A method for treating or preventing certain metabolic bone disorders characterized by phosphate metabolism related. In particular, the present invention provides that, by utilizing the compounds or pharmaceutical compositions of the present invention, For the treatment or prevention of osteoporosis and arthritis, especially rheumatoid arthritis and osteoarthritis. Regarding the method of

Several pathologies affecting warm-blooded animals involve abnormal calcium and phosphate metabolism. this These symptoms can be divided into two broad categories.

1. Ca. Excessive body fluids such as abnormal metabolism of diphosphoric acid or hypercalcemia of tumor origin. A condition characterized by high calcium and phosphate levels. These symptoms sometimes is referred to herein as pathological hard tissue demineralization.

2. Abnormal calcium in the body, such as arthritis, especially rheumatoid arthritis and osteoarthritis. Symptoms that cause or are caused by the deposition of umum and phosphate. These symptoms are sometimes Referred to herein as pathological calcification.

The first category includes the most common metabolic bone disorder, osteoporosis; A condition in which prefecal tissue is lost out of proportion to the growth of new hard tissue. Osteoporosis is It can usually be defined as a loss of bone mass or atrophy of skeletal tissue. Bone marrow and bone spaces are large The fibrous connections decrease, and the compact bones become brittle. Osteoporosis is menopausal, senile, and drug related Inducible (e.g. occurs with adrenocorticoid, steroid therapy), disease-inducing (arthritis and tumors); however, expression is essentially similar It is.

Generally, there are two types of osteoporosis: primary and secondary. “Secondary osteoporosis” is It is the result of another disease process or factor. However, in all osteoporosis cases, approximately 90% of cases are "-stage osteoporosis". Postmenopausal osteoporosis is an example of this type of secondary osteoporosis. osteoporosis, age-related osteoporosis, disuse osteoporosis (most individuals in their 70s and 80s) ) and idiopathic osteoporosis, which affects middle-aged and young men and women.

In some individuals with osteoporosis, the loss of bone tissue is sufficient to cause mechanical failure of the bone structure. It's big. Fractures occur, for example, in the hip and vertebrae of women with postmenopausal osteoporosis. often occurs. Columnar kyphosis (abnormal increased curvature of the thoracic spine) may also occur.

The mechanism of bone loss in osteoporosis involves an imbalance in the process of “bone remodeling” it is conceivable that. Bone remodeling occurs throughout life, regenerating the skeleton and maintaining bone strength. do.

This remodeling involves organizing groups of cells called "basic multicellular units" or "BMUs." This involves erosion and filling of separate areas on the bone surface. BMU is mainly “osteoclasts” , consisting of "osteoblasts" and their cell precursors. During the remodeling cycle, bones Reabsorbed by osteoclasts at the site of “activated” BMU, forming resorption cavities . This cavity is then filled with bone by osteoblasts.

Usually in adults, the remodeling cycle consists of small defects in bone due to incomplete filling of resorptive cavities. cause a loss. This results in age-related anterior loss even in healthy adults. deer However, in osteoporosis there is an increase in the number of activated BMUs. This increase Activation promotes bone remodeling and results in abnormally high bone loss.

Although its etiology is not fully understood, there are numerous There are risk factors. These include low body weight, low calcium intake, and physical There is inactivity and estrogen deficiency.

Current osteoporosis treatments primarily consist of calcium and estrogen administration.

The second category, with symptoms manifested by abnormal calcium and phosphate deposits, includes progressive Myositis ossificans, generalized calcinosis, and arthritis (e.g. rheumatoid arthritis and osteoarthritis) ), nerve bundles, bursitis, visceritis, and related tissues are susceptible to calcium deposition. There is pain like a symptom.

In addition to osteoporosis, bone loss can result from rheumatoid arthritis and osteoarthritis. Ru. Rheumatoid arthritis causes weakening of the joint capsule and ligaments, followed by cartilage, ligaments, haze and bone. Chronic systemic disease characterized by destruction of synovial fluid and decreased viscosity and other changes in synovial fluid It is a joint inflammatory disorder. Symptoms of rheumatoid arthritis include general weakness, fatigue, local pain, and stiffness. and weakening, swelling, and deformation of the body's joints. Rheumatoid arthritis occurs between the ages of 40 and 60. It is most common in women.

The pathogenesis of rheumatoid arthritis, which leads to joint destruction, consists of two stages: 1) microcirculation and slippage. 2) the effusion phase, during which the cysts shed plasma proteins and cellular elements into the joint; and 2) the joint space. hyposchisis characterized by pannus (granular tissue) formation, bone erosion, and cartilage destruction; It is characterized by a chronic inflammatory phase that occurs in the costal subchondral bone. Vannus osteoarthritis They may also form adhesions and scar tissue that cause characteristic joint deformities.

The etiology of rheumatoid arthritis remains unclear. infections such as bacteria and viruses source was involved. The current hypothesis is that the Epstein-Barr (EBV) virus is the pathogen of rheumatoid arthritis.

Does the current treatment for rheumatoid arthritis reduce symptoms by administering non-steroidal anti-inflammatory drugs? become the lord. Non-steroidal anti-inflammatory drug treatment is mainly used in the early stages of rheumatoid arthritis. Effective; it is unlikely that it will suppress joint inflammation if the disease has been present for more than a year. Not likely. Also gold, methotrexate, immunosuppressants and corticosteroids. It has been attempted, but with limited success.

On the other hand, osteoarthritis is caused by deterioration and wear of articular cartilage and the formation of new bone on the joint surface. It is characterized by an essentially non-inflammatory disorder of movable joints. Osteoarthritis progresses , the surface of the articular cartilage breaks down and wear particles enter the synovial fluid, which then enters the macrophages. Stimulates cellular phagocytosis. Thus, an inflammatory response is ultimately induced in osteoarthritis. . Common clinical symptoms of osteoarthritis include cartilage and bone enlargement of the finger joints, stiffness upon waking, and There is an operating cloth.

Common symptom treatments for osteoarthritis include painkillers, anti-inflammatory drugs, steroids, and physical therapy. be.

Various polyphosphonic acid derivatives have been shown to treat diseases associated with abnormal calcium and phosphate metabolism. It has been proposed for therapeutic and prophylactic use. For example, all Numerous references are given to polyphosphonates, especially ethane-1-hydroxy-1, Compositions containing diphosphonates such as 1-diphosphonic acid (“EHDP”) and those that inhibit abnormal calcium and phosphate deposition and metabolism in animal tissues. Discloses the usage of: both dated August 8, 1972 in the order FIanc. No. 3,683,080 issued in and dated October 28, 1980. No. 4,230,700 issued and dated September 19, 1989. No. 4,868,164 to EbeNno. Numerous other references The present study describes heterocyclic-substituted diphosphonic acids useful in the treatment of osteoporosis and/or arthritis. and is incorporated herein by reference: December 10, 1991. No. 5,071,840 to Ebelino et al., issued on date; 198 U.S. Pat. No. 4,868,16 to Ebrlino et al., issued September 19, 2009. No. 4, issued April 14, 1992, U.S. Pat. No. 104,863, U.S. Patent to Blam et al., issued May 12, 1981. No. 4,267.108: B+elie issued on May 24, 1988 +e et al. U.S. Pat. No. 4,746,654; issued October 24, 1989; No. 4,876.247 to Bx+bi++ et al., February 15, 1984. B+elie+e European Patent Application No. 100.718, published on date 1 Boeh+inge+ Mannhein G published on February 5, 986 mbH European Patent Application No. 170゜228; Published on July 2, 1986 European Patent Application Publication No. 186.40 for Ben+dicl and P++kin+ No. 5; European patent application publication of Ebelino published on January 11, 1989 No. 298,553; Bo+ie+ et al. issued on November 15, 1988 No. 4,754,993, issued July 3, 1990. U.S. Pat. No. 4,939.130 to ggi et al., issued November 20, 1990. No. 4,971°958 to Bo+ie+ et al., October 1, 1990. WO 90/12017 of Dunn et al. published on July 8, 1991; Yoo++elyeh, R, et al. wo No. 91/10646 published on 5th. Issue, publication date June 15, 1989, iaeggi AU-A No. 26738/88 Issue, publication date May 31, 1990, Ciba-Geig7 AU-A No. 4546 7/89 specification.

Finally, B! issued on June 17, 1980! U.S. Patent No. 4, 2 of Mouth Man No. 08,401 discloses non-heterocyclic-substituted quaternary ammonia useful as anti-calculus agents. discloses umbisphosphonates.

DE No. 40 1 of iseggi, K, disclosed on October 18, 1990 1777 specification (DE=777) regarding heterocyclic-substituted diphosphonates and the heterocycle can be lower alkyl substituted. Hetero above The ring is bridged to the phosphonic acid group with a quaternary non-ring nitrogen atom. DE-777 is the The compound shows significant inhibition of bone resorption, thus preventing osteoporosis, inflammatory and degenerative joint It is also disclosed that it is useful in treating the diseases periodontitis and hyperparathyroidism.

The disclosures of these references are incorporated herein by reference.

The compounds of the present invention have osteoprotective activity at joint destruction sites with arthritic symptoms, and Its activity as an additional effect in the treatment of arthritis goes beyond the above-mentioned mere alleviation of the symptoms of arthritis. ing. As used herein, the term "bone protective activity" refers to the bone and It means disease-improving activity in surrounding soft tissues.

The compound of the present invention in which nitrogen is quaternized is a nitrogen-containing compound in which the nitrogen atom is not quaternized. More powerful than compounds in treating osteoporosis and rheumatoid arthritis and osteoarthritis It was unexpectedly discovered that it has bone anti-resorptive activity and therapeutic efficacy. Furthermore, the main The bright compounds exhibit unusual solubility properties. For this reason, the compounds of the present invention are even more capacious. It is a compound that is easily absorbed orally. The more easily the compound is absorbed, the lower the It becomes effective in doses. Lowering the dose is usually preferred as it reduces unwanted side effects. Delicious.

Therefore, it is an object of the present invention to provide a method useful for osteoporosis therapy and for osteoarthritis and osteoarthritis. A new, more potent anti-arthritic agent that is particularly useful in the treatment of rheumatoid arthritis It is to provide a compound. Another object of the invention is to treat osteoporosis and arthritis, especially rheumatoid arthritis. To provide a pharmaceutical composition useful for the treatment and prevention of gout-like arthritis and osteoarthritis. That is.

In addition, the object of the invention is to treat osteoporosis and arthritis, especially rheumatoid arthritis and osteoarthritis. An object of the present invention is to provide a method for treating and preventing inflammation.

These and other objects of the present invention will be apparent from the specific disclosure of the invention set forth below. It will be something like that.

Summary of the invention The present invention provides quaternary nitrogen-containing phosphonate compounds having the following general formula and their pharmaceutically acceptable compounds. Regarding acceptable salts and esters: In the above formula, m is an integer of 0 to 10; n is an integer of 1 to 10; m+n is 1 to It is 10; (1) R is nothing, -8RSRSR, hydrogen, substituted or unsubstituted c -c alkyl, - OR3, -N (R) C (0) R, -C (0) N (R3) 2ゝ halogen, -C(0)R3, nitro, hydroxy, substituted or unsubstituted saturated monocyclic or is from the group consisting of polycyclic heterocycles, substituted or unsubstituted saturated monocyclic or polycyclic carbocycles selected; (blR is -3R'', -R9SR6, hydrogen, I substituted or non-C(O)N(R3) Halogen, -C(0) Ra, S nitro, hydroxy, substituted or unsubstituted saturated monocyclic or polycyclic heterocycle, substituted or unsubstituted saturated monocyclic or polycyclic carbocycle, substituted or unsubstituted unsaturated monocyclic or polycyclic consisting of a terocycle, a substituted or unsubstituted unsaturated monocyclic or polycyclic carbocycle, and a combination thereof; selected from the group; (c) Each R is substituted or unsubstituted C-C3s alkyl, unsubstituted or substituted phenyl, selected from the group consisting of RSR6; (c) R6 is -H, -C(0)RS C(S)R7, --C(S)N (R7) 2. Group consisting of -C(S)OR7 (R7 is hydrogen or unsubstituted or substituted C-Cs alkyl) ; (+)Rli-COOH, -8o H, -PO3H2 and -P(O)(OH)R 4 (R4 is an alkyl group having 1 to 3 carbons) (h) R is hydrogen, halogen, SRSRSR, amino, hydroxy, substituted or selected from the group consisting of unsubstituted C-C alkyl;

In this -shell structure, the quaternary nitrogen atom is connected to the phosphonic acid-containing carbon atom through a bonding chain. must be connected to It is directly bonded to the phosphonic acid-containing carbon atom. must not be

The present invention provides pharmaceutical preparations containing safe and effective amounts of the compounds of the present invention and pharmaceutically acceptable excipients. Further related to pharmaceutical compositions. Finally, the present invention provides a method for treating osteoporosis in humans or other mammals. and arthritis, especially abnormal calcium and rheumatoid arthritis such as rheumatoid arthritis and osteoarthritis. The present invention relates to a method for treating or preventing a medical condition characterized by acid metabolism. This method is administration of the compounds or compositions of the present invention to humans or other mammals in need of such treatment. It consists of administering a safe and effective amount.

Definition and usage of terms Below is a list of definitions for terms used herein.

A "heteroatom" is a nitrogen, sulfur or oxygen atom.

Groups containing one or more heteroatoms may contain different heteroatoms.

“Alkyl” means an unsubstituted or substituted, straight or branched, saturated or unsaturated hydrocarbon chain. , the hydrocarbon chain is saturated and has from 1 to 8 carbon atoms, preferably as mentioned elsewhere may have 1 to 4 carbon atoms, unless otherwise specified, and the hydrocarbon chain is unsaturated. from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms unless otherwise stated It may contain atoms. Therefore, the term "alkyl" as used herein contains alkenyl hydrocarbon unsaturation with at least one olefinic double bond. chain and an alkynyl hydrocarbon unsaturated chain having at least one triple bond. good Preferred alkyl groups include methyl, ethyl, propyl, isopropyl and butyl. but not limited to.

As used herein, “carbocyclic ring” or “carbocycle” refers to unsubstituted or substituted, saturated unsaturated or aromatic hydrocarbon ring. Carbocycles may be monocyclic or polycyclic. It's okay. Monocyclic rings usually contain 3 to 8 atoms, preferably 5 to 7 atoms. Ru. Polycyclic rings containing two rings contain from 6 to 16 atoms, preferably from 10 to 12 atoms. Those containing three rings usually contain 13 to 17 atoms, preferably 14 to 15 atoms. I'm reading.

"Heteroalkyl" means having 3 to 8 member atoms, one or two carbon atoms and one or two carbon atoms. It is an unsubstituted or substituted, saturated chain containing a terroratom.

As used herein, "heterocyclic ring" or "heterocycle" means that the ring has carbon atoms. unsubstituted or substituted, saturated, unsaturated or aromatic ring composed of one or more heteroatoms It is. A heterocycle may be a monocyclic or polycyclic ring.

Monocyclic rings usually contain 3 to 8 atoms, preferably 5 to 7 atoms. two Polycyclic ring systems consisting of rings usually contain 6 to 16, preferably 10 to 12 atoms. 3 A polycyclic system consisting of two rings usually contains 13 to 17 atoms, preferably 14 to 15 atoms. nothing. The heterocyclic ring moiety consists of a heterocycle or a heterocycle and a carbocycle. each heterocycle The ring portion of the formula must have at least one nitrogen atom. mentioned elsewhere Unless otherwise specified, the other heteroatoms are independently selected from nitrogen, sulfur and oxygen. be done.

"Aryl" is an aromatic carbocycle. Preferred aryl groups include phenyl, tri- Examples include, but are not limited to, xylyl, cumenyl, cumenyl and naphthyl.

"Heteroaryl" is an aromatic heterocycle. Preferred heteroaryl groups include Chenyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, oxacylyl, thiazo including but not limited to lyl, quinolinyl, pyrimidinyl and tetrazolyl do not have.

“Alkoxy” means a hydrocarbon chain moiety in which the hydrocarbon chain is alkyl or alkenyl. An oxygen atom with a substituent (e.g. -〇-alkyl or -〇-alkenyl) . Preferred alkoxy groups include methoxy, ethoxy, propoxy and alkyloxy groups. There are but are not limited to these.

"Hydroxyalkyl" means having a hydroxy substituent (e.g., -0H); It is a substituted hydrocarbon chain that may also have other substituents. preferred hydroxy Alkyl groups include hydroxyethyl and hydroxypropyl, but are limited to these. Not done.

"Carboxyalkyl" means having a carboxy substituent (e.g., -COOH) It is a substituted hydrocarbon chain which may also have other substituents. preferred carbo The xyalkyl group includes carboxymethyl, carboxyethyl, and their acids and esters. There is a steal.

“Aminoalkyl” means a carbonized compound substituted with an amine moiety, such as aminomethyl. A hydrogen chain (eg, alkyl) (eg, NH-alkyl-).

"Alkylamino" means one or two alkyl substituents such as dimethylamino (e.g., -N-alkyl).

"Alkenylamino" means an amino moiety having one or two alkenyl substituents (eg -N-alkenyl).

"Alkynylamino" means an amino moiety having one or two alkynyl substituents (eg -N-alkynyl).

0 Alkylimino 1 refers to an imino moiety having one or two alkyl substituents (e.g. For example, -N-alkyl-).

"Arylalkyl" is an alkyl moiety substituted with an aryl group. preferred Examples of arylalkyl groups include benzyl and phenylethyl.

"Arylamino" means an amine moiety substituted with an aryl group (e.g., -N)I -aryl).

“Aryloxy” means an oxygen atom with an aryl substituent (e.g., -0-aryl) (rule).

"Acyl" or "carbonyl" means a carbon-oxygen double bond, e.g. R-C (=0) It is. Preferred acyl groups include acetyl, propionyl, butanoyl and benzoyl. There are but are not limited to these files.

“Acyloxy” means an oxygen atom with an acyl substituent (e.g. -〇-acyl) , for example -0-C(=C)alkyl.

"Acylamino" means an amino moiety having an acyl substituent (e.g., -N-acyl ), for example -NH-C(=C)-alkyl.

“Halo”, “halogen” or “/S ride” means chloro, bromo, fluoro or It is an iodine atom group. Chloro, bromo and fluoro are preferred halides. .

Additionally, "lower" hydrocarbon moieties as referred to herein (e.g., "lower" 1 to 6, preferably 1 to 4 carbon atoms, unless otherwise stated It is a hydrocarbon chain composed of

The term "thio substituent" (SR6 or R95R6) as used herein includes All [-3H] (R6=H); thioester [-3C(0)R7) (R6=C(○)R7); dithioester [-3C(S) R71 (R6=C(S)R7); thiocarbamate (-3C(0)N (R7) 2) (R6(R6=C(0)OR7); and dithiocarbonate C-3C(S )OR7)(R6=C(S)OR7). R is usually hydrogen or C-C alkyl It is. Any SR substituent is itself substituted with an R9 moiety, i.e. R95R6 where R9 is substituted or unsubstituted C-C alkyl. Therefore Therefore, the additional thio substituent represented by R9SR6 is alkylthiolalkylthiocal. Bamates, alkylthiol nocmates, alkylthiocarbonates and alkyl It is ludithiocarbonate.

As used herein, the term "bisphosphonate" or "bisphosphonic acid" refers to the same Phosphonates or phosphones with two phosphonic acid groups attached to one carbon atom With respect to acid compounds, the terms "diphosphonate" and "diphosphonic acid" are used interchangeably. It will be done. Using the structure described herein, moiety R is PO3H2.

As used herein, the term "carbon phosphonate" refers to a phosphonic acid group (PO3H2 ) is related to the carbon atom to which it is attached. Another phosphonic acid group is the above carbon atom When bound to , the resulting compound is a bisphosphonate. Sulfonic acid When a group is attached to the above carbon atom, the resulting compound is a phosphonosulfonate. It is.

When a carboxylic acid group is attached to the above carbon atom, the resulting compound is a phosphono It is carboxylate. When a phosphinic acid group is bonded to the above carbon atom, The resulting compound is a phosphonoalkylphosphinate.

A “pharmaceutically acceptable” salt is a salt formed with any acidic (e.g. carboxyl) group. or with any basic (e.g. amino) group It is an anionic salt. Many such salts are incorporated herein by reference. International Patent Publication No. 87 of Iohn+ton et al., published September 11, 1987 No. 15297, known in the art. preferable Cationic salts include alkali metal salts (e.g., sodium and potassium) and alkali metal salts (e.g., sodium and potassium) There are lithium metal salts such as magnesium and calcium. preferred anio Salts include halides (eg, chloride), acetic acid, and phosphate.

“Biohydrolyzable esters” are those that do not interfere with the therapeutic activity of the compound or quaternary nitrogen-containing heterocyclic phosphonates that are readily metabolized in humans or other mammals. It is an ester of a compound. Many such esters are incorporated herein by reference. International patent of Iohnston et al. published on September 11, 1987 As is known in the art, as described in Publication No. 8715297 . Such esters include lower alkyl esters and lower acyloxyalkyl esters. esters (e.g. acetoxymethyl, acetoxyethyl, aminocarbonyloxy dimethyl, pivaloyloxymethyl and pivaloyloxyethyl ester), ctonyl esters (e.g. phthalidyl and thiophthalidyl esters), lower Rukoxyacyloxyalkyl esters (e.g., methoxycarbonyloxymethane) ethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters and acylamides and noalkyl esters (eg, acetamidomethyl ester).

The substituents used herein as described above may themselves be substituted. child Substitutions such as may be one or more substituents. Such a substitution The groups include C, Hsch and ^, Leo, S, which are incorporated herein by reference. ub+1ilusnl Con+t+nls lot Co++elation ^n1lHi+ in Chemi+lB xnd BioloB (19791 There are some examples shown in , but it is not limited to these. Preferred substituents include alkino Pairkenyl, alkoxy, hydroxy, oxo, amino, aminoalkyl (e.g. (e.g., aminomethyl), cyano, halo, carboxy, alkoxyacetyl (e.g. (e.g., carboethoxy), thio, thiol, aryl, cycloalkyl, hetero loaryl, heterocycloalkyl (e.g. piperidinyl, morpholinyl, piperidinyl) perazinyl, pyrrolidinyl, etc.), imino, thioxo, hydroxyalkyl, ali aryloxy, arylalkyl and combinations thereof. do not have.

Detailed description of the invention Novel quaternary nitrogen-containing phosphonate compounds The compounds of the present invention are quaternary nitrogen-containing phosphonate compounds having a quaternary nitrogen atom and Pharmaceutically acceptable salts and esters of The quaternary nitrogen atom is phosphorized via a bonding chain. Bonded to the fonic acid-containing carbon.

The carbon atom to which the phosphonic acid group is attached may be unsubstituted (i.e., a hydrogen atom) or substituted. It may be When a phosphonate carbon has two phosphonic acid groups, it becomes a bisphosphonate. It becomes a phosphonocarboxylic compound when it has a phosphonic acid group and a carboxylic acid group. It becomes a sylate compound; when it has a phosphonic acid group and a sulfonic acid group, it becomes a sylate compound; It becomes a phonate compound; when it has a phosphinic acid group and a phosphonic acid group, it becomes a phosphono compound. It becomes a rukylphosphinate compound.

Thus, the quaternary nitrogen-containing phosphonate compounds of the present invention and their pharmaceutically acceptable Salts and esters have the following general structure: In this general structure, R is nothing, -8R6, -R9SR6, hydrogen, 1 to 8 carbon atoms Alkyl, halogen, -〇(0)R3, nitro, hydroxy, substituted or unsubstituted saturated monocyclic or polycyclic heterocycle, substituted or unsubstituted saturated monocyclic or polycyclic carbon Selected from a variety of acyclic moieties such as elementary rings.

Moreover, in this general structure, the quaternary nitrogen atom is connected to the phosphonate carbon by a bonding chain. combined. Furthermore, in this general structure, n is an integer from 1 to 10, Represents the above-mentioned connecting chain.

The linking chain component is selected from various R5 moieties.

nitro, hydroxy, unsubstituted or substituted saturated monocyclic or polycyclic heterocycle, unsubstituted or to substituted saturated monocyclic or polycyclic carbocycle, unsubstituted or substituted unsaturated monocyclic or polycyclic Terocycles, unsubstituted or substituted unsaturated monocyclic or polycyclic carbocycles, and combinations thereof .

Finally, in the quaternary nitrogen-containing phosphonate compounds of the present invention, R is -COOH, -3o H, -PO3H2 and -P(0)(OH)R4, where R4 is c a substituent on a phosphonic carbon alkyl selected from l-substituted C-C8 alkyl; Ru. Preferred R8 are hydroxy, halogen and amino. R2 is substituted or unsubstituted is substituted C1035 alkyl, substituted or unsubstituted phenyl, benzyl or RSR . Preferred R2 is substituted or unsubstituted C-C8 alkyl and R95R6.

Preferred quaternary nitrogen having an R1 moiety selected from the R moieties described herein above. For the phosphonate containing: N-(3-hydroxy-3,3-diphosphonopropyl )-N,N-dimethyl-N-pentylammonium chloride N-(4-hydroxy-4,4-diphosphonobutyl)N,N,N-trialkyl Ammonium salt N-(3-hydroxy-3,3-diphosphonobrovir)-N,N , N-trialkylammonium salts.

Furthermore, in this -shell structure, the R1 moiety is a saturated monocyclic or polycyclic heterocycle. You can.

As the R1 moiety, the quaternary nitrogen atom is bonded to the phosphonate carbon via a bonding chain. preferred quaternary nitrogen-containing phosphonates having saturated monocyclic or polycyclic heterocycles. is: N-(3-hydroxy-3,3-diphosphonobrovir)-N,N-dimethyl -N-(2-piperidinemethyl)ammonium chloride.

Additionally, preferred compounds of the invention include those having the structure: Preferred compounds of the invention also include thio-substituted quaternary nitrogen-containing phosphonates: Specific details of the compounds of the present invention: -pentylammonium bromide; N-(4-hydroxy-4,4-diphosphonobutyl)-N-(3-mercaptopyl) lopyl)-N,N-dimethylammonium chloride; N-(4-hydroxy-4,4-diphosphonobutyl)-N-(mercaptomethyl )-N,N-dimethylammonium chloride; N-(4-hydroxy-4,4-diphosphonobutyl)-N-(4-methoxybutyl) )-N,N-dimethylammonium chloride; N-(4-hydroxy-2-mercapto-4,4-diphosphonobutyl)-N,N , N-trimethylammonium chloride; N-(4-hydroxy-2-acetylthio-4,4-diphosphonobutyl)-N, N,N-trimethylammonium chloride; N-(3-hydroxy-2-mercapto-3,3-diphosphonopropyl)-N, N-dimethyl-N-pentylammonium chloride; N-(3-hydroxy-2-acetylthio-3,3-diphosphonopropyl)-N , N-dimethyl-N-pentylammonium chloride; N-(3-hydroxy-3,3-diphosphonopropyl)-N-methyl-N-pene thyl-N-(2-(3-pyridyl)ethyl]ammonium chloride; N-cyclohebutyl-N-(2-mercaptoethyl)-N-methyl-N-(dipho sulfonomethyl)ammonium chloride; N-cyclohebutyl-N-(mercaptomethyl)-N-methyl-N-(diphospho (methyl) ammonium chloride: N,N-dimethyl-N-(4,4-diphosphonobutyl)-N-(2-(3-pipe lysinyl)ethyl]ammonium chloride.

It is not appropriate to test phosphonate compounds in animals to determine and evaluate their pharmacological activity. This can be done using a variety of assays known to those skilled in the art. For this reason, in vivo bone antiresorption Activity is an approach designed to test the ability of these compounds to inhibit bone resorption. Although it is conveniently proven using assay, bone resorption is caused by abnormal calcium and phosphate metabolism. It is characteristic.

One such test known in the art is the Sienck It's a model. Another useful industry-known test is the adjuvant arthritis test. It is. In vitro hydroxyapatite crystal growth inhibition tests are also useful. pharmacology These and other suitable tests for activity are given by Hinods et al.

Cx1cilied Ti5sue Inter++1tion11,35゜p p, 87-99 (1983); 5chenk et al., ClIc1lied T i5sue Re5ei+ch, 11. Hl, 196-214 (1973); R++5sell et al., Ctleilied Ti5sue Re5ei+ch Lpp.

183-196 (197G); Mohlbxue+ and Ne1sch, M ins+xl.

El+ct+oly++ Mc+ab, 5. pp, 296-303 (19N); Nancolas et al.

0ral Biol, Is, 731197G); August 8, 1972 F+ancis U.S. Patent No. 3,683.080 issued in 1979 Scbmidt-Dunke+ U.S. Patent No. 4,13, issued January 16th. No. 4,969; EPO Patent Application Publication No. 189, published August 6, 1986 ．． No. 662; all these articles and patent specifications The disclosures of the documents are incorporated herein by reference in their entirety. Regarding pharmacological activity Some of these tests are also described in more detail in the examples below.

Useful in treating or preventing pathologies characterized by abnormal calcium or phosphate metabolism. In addition to being useful, the compounds of the invention also have other uses. For example, Ming's compound is thought to be useful as a bone scanning agent after labeling with 99m-technetium. It will be done. In addition, the compounds of the invention contain polyvalent metal ions, especially divalent (e.g. calcium) and trivalent (e.g. indium) and trivalent (e.g. indium) metal ions. It is useful. For this reason, the compounds of the present invention can be used as building blocks in detergents and cleansers. It is useful as a chemical or in treating water. They also serve as stabilizers for compounds. It is for use. In addition, they prevent tartar (i.e. tartar) and/or plaque formation. This will be useful in stopping the situation.

Finally, the compounds of the invention may be useful as herbicides that are non-toxic to animals.

The quaternary nitrogen-containing phosphonate contained in the pharmaceutical composition of the present invention can be used in the following non-limiting example 1. It can be manufactured according to 5.

Composition containing a novel quaternary nitrogen-containing phosphonate compound The novel quaternary nitrogen-containing phosphonate compound of the present invention Phosphonate compounds can be used in oral dosage forms and injectable (intravenous, intramuscular) formulations, including but not limited to administered to humans or other mammals by a variety of routes, including intraperitoneal and subcutaneous). Ru. Numerous other dosage forms containing the novel quaternary nitrogen-containing phosphonate compounds of this invention are available. can be readily formulated by those skilled in the art using suitable pharmaceutical excipients such as those described below.

Oral dosage forms and regular amounts are also preferred, given patient compliance.

As used herein, the term "Pharmaceutical Composition 1" refers to a safe and effective amount of a quaternary nitrogen-containing phosphatide. A fonate compound consists of an active ingredient or mixture thereof and a pharmaceutically acceptable excipient. means a combination of

As used herein, the term "safe and effective amount" refers to an amount within the scope of sound medical judgment. in an amount large enough to significantly improve the symptom and/or condition being treated, A sufficiently low amount of the compound to avoid serious side effects (with a reasonable benefit/risk ratio) or composition. Active ingredients for use in pharmaceutical compositions used in the methods of the invention The safe and effective amount of severity of symptoms, duration of treatment, nature of combination therapy, specific active ingredients used, specific pharmaceutically acceptable excipients and similar facilitators within the knowledge and skill of the attending physician. Varies depending on the actor.

As used herein, the term "pharmaceutically acceptable excipient" includes Physical and chemical characteristics of specific quaternary nitrogen-containing phosphonate compound active ingredients any physiologically inert and pharmacologically inert substances known to those skilled in the art that are compatible with include. Pharmaceutically acceptable excipients include polymers, resins, plasticizers, fillers, and binders. , lubricants, lubricants, disintegrants, solvents, co-solvents, buffer systems, surfactants, preservatives, sweeteners agents, flavoring agents, formulation dyes or pigments, and viscosity agents.

As used herein, the term "oral dosage form" refers to the administration of a composition into the gastrointestinal tract of an individual. any pharmaceutical composition that is administered systemically to an individual by delivery through the mouth Taste. For purposes of this invention, delivery forms include coated or uncoated tablets, solutions, suspensions. Alternatively, it is in the form of coated or uncoated capsules.

The term "injection" as used herein refers to intravenous, intramuscular, intraperitoneal or subcutaneous injection. puncturing the skin of an individual to deliver a solution or emulsion into the individual's circulatory system at delivery of solutions or emulsions containing the active ingredient to humans or other mammals. Refers to any pharmaceutical composition that is administered systemically to a mammal.

The rate of systemic delivery is determined by the following conditions: (1) Appropriate active ingredients (blPharmaceutically acceptable excipients (that do not interfere with the activity of the specific active ingredient selected) within range) (C) The type of excipient and the concomitant desired thickening and permeability (swelling) properties of that excipient. moisture properties) (d) time-dependent conditions within the excipient itself and/or within the excipient; (C) the particle size of the particulate active ingredient, and (1) pH-dependent conditions of excipients By operating any one or more of these, a person skilled in the art can control the Can roll.

In particular, acid addition salts, salts formed with carboxylic acid groups, such as alkali metal salts, alkali Lithium metal salts, etc. and esters, such as alkyl, aryl, aralkyl, etc. Solubility, acidity and hydrolytic susceptibility of quaternary acyclic nitrogen-containing phosphonate active ingredients Gender is used as a guideline for appropriate choices. In addition, appropriate pH conditions by adding appropriate buffering agents to the active ingredient according to the desired release pattern. , established within an oral dosage form.

As mentioned above, pharmaceutically acceptable excipients include resins, fillers, binders, lubricants, Solvents, lubricants, disintegrants, co-solvents, surfactants, preservatives, sweeteners, flavoring agents, buffer systems Examples include, but are not limited to, formulation dyes or pigments and viscosity agents.

The preferred solvent is water.

Flavoring agents useful in the present invention include Rsmingl, which is incorporated herein by reference. on’+ Pha+mxceoticzl 5science+, 18thEdi tion, Mxck Publishing CompaB, 1990. pp, There is one described in 1288-1300. Pharmaceutical compositions suitable for use in the invention usually contains 0-2% flavoring agent.

Dyes or pigments useful in the present invention include 1 (xn dbook of PhzrmxcrnticxlExcipienls, p p, 81-90.1986. The Ame+ic! nPha+mxceu licxl A++ocialion & the Pha+mxceulic There is something described in xlSocie17 oI Gte [Br1tain] .

The pharmaceutical composition of the present invention usually contains 0-2% of dye or pigment.

Preferred co-solvents include ethanol, glycerin, propylene glycol, polyethylene These include, but are not limited to, lene glycol. The pharmaceutical composition of the present invention comprises 0 to Contains 50% co-solvent.

Preferred buffer systems include acetic acid, boric acid, carbonic acid, phosphoric acid, succinic acid, malic acid, and tartaric acid. , citric acid, benzoic acid, lactic acid, glyceric acid, gluconic acid, glutaric acid and Tamic acid and its sodium, potassium and ammonium salts, It is not limited to these. Particularly preferred are salts with phosphoric acid, tartaric acid, citric acid and acetic acid. Book Pharmaceutical compositions of the invention typically contain 0-5% buffer system.

Preferred surfactants include polyoxyethylene sorbitan fatty acid esters and polyols. xyethylene monoalkyl ether, sucrose monoester, lanolin ester and ethers and alkyl sulfates of fatty acids, sodium, potassium and ammonia. including, but not limited to, nium salts. The pharmaceutical composition of the present invention has a range of 0 to 2%. Contains surfactant.

Preferred preservatives include phenol, alkyl esters of p-hydroxybenzoic acid, 0-phenylphenolbenzoic acid and its salts, boric acid and its salts, sorbic acid and Bison salt, chlorobutanol, benzyl alcohol, thimerosal, phenyl vinegar Acid and mercuric nitrate, nitromerzole, benzalkonium chloride, cetylpyridine chloride including, but not limited to, Nium, Methylparaben and Propylparaben . Salts of benzoic acid, cetylpyridinium chloride, methylparaben and propylparaben Particularly preferred are

The compositions of the present invention typically contain 0 to 2% preservative.

Preferred sweeteners include sucrose, glucose, saccharin, sorbitol, and manganese. These include, but are not limited to, nitol and aspartame. sucrose and Saccharin is particularly preferred. The pharmaceutical composition of the present invention contains 0-5% sweetener. There is.

Preferred viscosity agents include methylcellulose and sodium carboxymethylcellulose. , hydroxypropyl methyl cellulose, hydroxypropyl cellulose, alkaline Sodium Ginate, Carbomer, Povidone, Gum Arabic, Guar Gum, Xane These include, but are not limited to, tan gum and tragacanth. methylcellulose , carbomer, xanthan gum, guar gum, povidone, sodium carboxy Particularly preferred are methylcellulose and magnesium aluminum silicate. present invention The composition contains 0-5% viscosity agent.

Preferred fillers include lactose, mannitol, sorbitol, and tribasic phosphorus. calcium acid, dibasic calcium phosphate, compressed sugar, starch, calcium sulfate , dextro, and microcrystalline cellulose. of the present invention The composition contains 0-75% filler.

Preferred lubricants include magnesium stearate, stearic acid and talc. However, it is not limited to these.

The pharmaceutical composition of the invention contains 0.5-2% lubricant.

Preferred lubricants include, but are not limited to, talc and colloidal silicon dioxide. Not done. The compositions of the present invention contain 1-5% lubricant.

Preferred disintegrants include starch, sodium starch glycolate, and crospovid. croscarmellose sodium and microcrystalline cellulose, but are limited to these. Not determined. The pharmaceutical composition of the invention contains 4-15% disintegrant.

Preferred binders include gum arabic, gum tragacanth, and hydroxypropylcell. Loin, pre-gelatinized starch, gelatin, povidone, hydroxypropylcell loose, hydroxypropyl methylcellulose, methylcellulose, sucrose and sugar solutions such as sorbitol and ethylcellulose, but are not limited to these. Not possible. The compositions of the invention contain 1-10% binder.

The compounds of this invention represent from about 0.1% to about 99.9% by weight of the pharmaceutical compositions of this invention.

Preferably, the compound of the invention is about 20% to about 80% by weight of the pharmaceutical composition of the invention. Ru.

Therefore, the pharmaceutical compositions of the present invention contain quaternary nitrogen-containing phosphonate compounds as active ingredients or is the mixture 15-95%, flavoring agent 0-2%, co-solvent 0-50%, buffer system 0-5 %, surfactant 0-2%, preservative 0-2%, sweetener 0-5%, viscosity agent O-5%, Filler 0-75%, lubricant 0.5-2%, lubricant 1-5%, disintegrant 4-15% and 1 to 10% of a binder.

Suitable pharmaceutical compositions are described herein in Examples 9-11. wide range of medicine It will be apparent to those skilled in the art to modify the non-limiting examples described herein to obtain pharmaceutical compositions. belongs within the capabilities of

The selection of pharmaceutical excipients for use with the quaternary nitrogen-containing phosphonate compounds of the present compositions includes: This will essentially be determined by the manner in which the phosphonate compound is administered. The compound is injected If so, the preferred formulation carrier is sterile physiological saline, the pH of which is about 7. It is adjusted to 4. However, it is preferred to administer the phosphonates of the invention. The format is oral and therefore the preferred unit dosage form is a tablet, capsule etc. Contains from about 0.1 to about 60 On+gP of a phosphonic acid compound as described herein. oral Pharmaceutical carriers suitable for preparing dosage unit forms are well known in the art. Them The selection is based on secondary considerations such as taste, cost and shelf stability that are not important for the purposes of this invention. It depends on the particulars and can easily be done by a person skilled in the art.

The term "mgP" used herein refers to the phosphonic acid compound of the present invention. means the weight of phosphorus atoms present in This unit is used in pharmaceutical compositions and methods of the invention. used to standardize the amount of phosphonic acid compound of the invention used in the method.

For example, N-(4-hydroxy-4°4-diphosphonobutyl)-N,N-dimethyl Ru-N-(2-mercaptoethyl)ammonium chloride is 373, 5 g/ mol, of which 17% (62g/m01) is present in this molecule Due to two phosphorus atoms. Therefore, 1 mg of this compound has 0.17 mg P It is calculated as follows. Therefore, a pharmaceutical composition containing 0.17 mgP of this compound For manufacturing, the composition should contain the compound III+H: Compound 0. To administer 17 mgP/kg to a 50 kg patient, the patient must receive this compound It will be dosed at 50 mg.

Pharmaceutically acceptable excipients used in combination with the diphosphonates of the present invention may be dose-related. It is used in sufficient concentration to make it a practical size. preferably pharmaceutically acceptable The carrier in total comprises about 0.1% to about 9969% by weight of the total composition, more preferably The percentage is about 20% to about 80%.

Another aspect of the invention is a disease characterized by abnormal calcium and phosphate metabolism. It is a method of treatment or prevention.

Such methods are effective in treating humans or lower animals in need of such treatment. The method consists of administering a safe and effective amount of a specific phosphonate compound.

The preferred mode of administration is oral, although other known administration methods such as mucocutaneous (e.g. (e.g., dermal, rectal, etc.) and parenteral (e.g., subcutaneous, intramuscular, and intraarticular injections) , intravenous injection, etc.) are also contemplated. This includes inhalation. For this reason, specific dosing Modes include oral, transdermal, mucosal, sublingual, intramuscular, intravenous, intraperitoneal, subcutaneous, and topical administration. Applicable to, but not limited to.

The term “abnormal calcium and phosphate metabolism” as used herein refers to (1) total Abnormal metabolism of calcium and phosphate leading to body or specific bone loss, or excess in body fluids. (2) conditions characterized by high calcium and phosphate levels; and (2) symptoms that are abnormal in the body. Symptoms that cause or are caused by regular calcium and phosphate deposition.

The first category includes osteoporosis, Panett's disease, hyperparathyroidism, and elevated levels of malignant disease. including, but not limited to, calcemia, heterotopic ossification, and osteolytic bone metastases. stomach. The second category includes progressive myositis ossificans, generalized calcinosis, and arthritis and osteoarthritis. inflammation, neuritis, bursitis, visceritis and related tissues prone to calcium and phosphate deposition including, but not limited to, pain such as other inflammatory conditions that cause symptoms.

As used herein, the term "rheumatoid arthritis" refers to chronic systemic arthritis of unknown etiology. Refers to nodal inflammatory disorder. It is characterized by destruction of articular cartilage, ligaments, haze and bone. Ru.

The term "osteoarthritis" as used herein refers to a non-inflammatory disorder of a movable joint. . It is characterized by deterioration and wear of the articular cartilage and new bone formation on the joint surfaces.

As used herein, the term "person at risk" and "person in need of such treatment" “Humans” are at great risk for abnormal calcium and phosphate metabolism if left untreated. Humans or lower animals with abnormal calcium and phosphate metabolism means a human or lower animal that has been diagnosed with a disease. For example, postmenopausal women Humans receiving certain steroid therapy; Humans receiving certain antispasmodic drugs; Baguet disease, hyperparathyroidism, hypercalcemia of malignant disease, or osteolytic bone metastases. a person diagnosed with one or more of the various forms of osteoporosis; Belonging to a population group known to have a significantly higher than average chance of developing osteoporosis Causes osteoporosis as a side effect in humans, such as postmenopausal women and men over 65 years old. Humans treated with drugs known to cause myositis ossificans progressiva or generalized calcinosis. Humans diagnosed with: arthritis, osteoarthritis, neuritis, bursitis, visceritis and People with other inflammatory conditions that predispose associated tissues to calcium and phosphate deposition.

As used herein, the term "safe and effective amount" refers to the amount within the scope of sound medical judgment. (reasonable benefit/risk). means an amount of a compound or composition that is sufficiently low (in terms of risk) to avoid serious side effects. Ru. A safe and effective amount of the phosphonate compounds of the invention is determined based on the specific condition being treated, the treatment The age and physical condition of the patient being treated, the severity of symptoms, the duration of treatment, the nature of combined therapy, and its use. the specific phosphonate utilized, the specific pharmaceutically acceptable carrier utilized; It depends on similar factors related to the knowledge and proficiency of the attending physician. however, A single dose is 0.　01-3500mgP or 0.0002-70gP/kg Body weight (based on body weight of 50). Preferred single dose is 1-600mg P or 0, 02-12+ngP/kg body weight (based on 50 kg body weight) . A single dose is administered up to four times a day.

A daily dose of 500 mgP/kg or more is not required to show the desired effect and may be It causes unwanted side effects. Within this range, even higher doses can be inhaled. This is of course required in the case of oral administration due to storage limitations.

The following examples further describe and demonstrate preferred embodiments within the scope of the invention. The example is simply Presented for illustrative purposes and should not be construed as a limitation of the invention, its many variations tion is possible without departing from its spirit and scope.

4-(N,N-dimethylamino)butanoic acid (2.9 mmol), phosphorus trichloride ( 2, OIol) and diethyl phosphite (1.2 mmol) at room temperature. Stir for 30 minutes and then heat at 60° C. for 24 hours. The reaction mixture was then brought to room temperature. Cool to a temperature and add concentrated hydrochloric acid (50 ml). The reaction mixture was then heated under reflux for an additional 2 Heat for 4 hours, then cool to room temperature, filter through Celite, and concentrate the filtrate under vacuum. do.

The crude product is triturated with ethanol, filtered off and then dried under vacuum.

Bisphosphonic acid (0.30 mmol) was mixed with water (10 a+l) and ethanol (15 ml) and the pH is adjusted to 7.0 by addition of IN NaOH. This is good Methyl chloride (1.50 mmol) is added and the reaction is heated under reflux for 24 hours. Next Cool the mixture at and concentrate under reduced pressure. Dissolve the solid residue in a minimum amount of water and quaternary The reaction product is precipitated by the addition of isopropanol. The product was filtered and diluted with acetone. Wash and further dry under vacuum that night.

1, (3-(N,N-dimethylamino)propylide 2) as described above in Example 1, Part ■. Using essentially the same procedure as described above, 3-(N,N-dimethylamino)propyl phosphonic acid to [3-(N,N-dimethylamino)propylidene]bis[phosphonic acid] Convert.

Bisphosphonic acid (0,500 mol) was mixed with water (15 ml) and acetonitrile (2 0 ml) and the pH is adjusted to 7.0 by addition of 1N NaOH. This is good Pentyl chloride (2,50 ma+ol) was added and the reaction mixture was heated under reflux for 22 hours. do. The mixture is then concentrated under reduced pressure and the solid residue is triturated in acetone. next The product can be recrystallized from water and ethanol.

sail l N-(3-hydroxy-3,3-diphosphonopropyl)-N,N,N-)rimethyl Essentially as described above in Synthesis of Ammonium Iodide Example 1, Part 11 (3-(N, N-dimethylamino)propylidene]bis[phosphonic acid] -3,3-diphosphonopropyl)-N,N,N-trimethylammonium io Convert to Cito.

[4-(N,N-dimethylamino) prepared as described above in Example 1, Part ■ )-1-Hydroxybutylidene]bis[phosphonic acid] (0,75mII+ol ) in water (50 ml) and acetonitrile (35 ml). To this, S-A Cetyl-2-bromoethanethiol (3.75 mmol) was added and the reaction mixture was Heat under reflux for 12 hours. The mixture was then concentrated under reduced pressure and the solid residue was dissolved in acetate. Grind in a tank. The quaternized product can be recrystallized from water and ethanol. Ru.

Example 5 N-(2-acetylthioethyl)-N-(3-hydroxy-3,3-diphosphono Synthesis of propyl)-N-methyl-N-lidene]bis[phosphonic acid] Using essentially the same operations as described above in Example 1, Parte, the 3-(N-method) methyl-N-pentylamino)propanoic acid (3-(N-methyl-N-pentylamino) Converted to (mino)propylidene] bis[phosphonic acid].

+1. N-(2-acetylthioethyl)-N-(3-hydroxy-3,3-di Synthesis example of phosphonopropyl)-N-methyl-N-pentylammonium bromide Using essentially the same procedure as described above in 4, [3-(N-methyl-N-petrol N-(2-acetylthioethyl) methyl)-N-(3-hydroxy-3,3-diphosphonoprobyl)-N-methyl- Convert to N-pentylammonium bromide.

Example 6 The compound is used in animals known in the field of bone metabolism as the Schenk model. Model systems are evaluated for in vivo bone resorption inhibition and mineralization inhibition. This model The general principle of the system is described by Hinoda et al., Ca1ci1. Tizoe In1. ．． 3 5.87-99 (1983) and 5chenk et al., Ca1ci1. Ti5s ue Re3. If, 196-214 (1973), The disclosure of is incorporated herein by reference. ・Dolly (Sp+1gue D! vley) Rat [Charles River Bu Leading Laboratories (Cha+le+Riwt+B+e!din gLzbota+oBes)) with their mothers and They are placed in a plastic cage with their mother.

At 19 days of age, pups were given ad libitum access to rat chow and water, each group consisting of 7 animals. They were randomly assigned to treatment or control groups. On the first day and also on the seventh day, Intraperitoneal (“IP”) injection of calcein (1% solution in 0.9% saline solution) into all animals. ;0.2m! /100g body weight). On the fourth day, all animals were treated with hydrochloric acid. IP injection of tracycline (1% solution in 0.9% saline solution; 0.2 ml/100 (g weight). These compounds target actively mineralized bone and cartilage. Understand.

Dosing solutions and dosing operations All solutions were prepared for subcutaneous injection in 0.9% normal saline, containing N a, OH and/or Or adjust the pH to 7.4 using HCI. Calculation of dosing solutions is based on (minutes of active substance) Molecular weight, based on hydration () mg/kg (body weight), which corresponds to the mass of the powder in mgP/kg This is done by thinking. The concentration should be 0.211+I/100g body weight. based on. Typically all compounds 1;! 0. o:t, 0,1.1.0 and 10. OigP/kg/day is administered for 7 days. Then 0, 1 mgP/k 0.g/day of active compound. Logarithmic weight loss up to OO1mgP/kg/day test. Dosage adjustments based on changes in body weight will be made on a daily basis.

Autopsy, tissue processing and tissue morphology examination On day 8 after starting dosing, all animals are sacrificed with I filtration dose of bendoparbital. shin Cut out the bones and soak in 70% ethyl alcohol. Graded ethano for one tibia Dehydrated with 5 chenk, Melhod+ of C11cifitd Ti++aeP++px+1tion (G, R, Dick+on, Edilo +1El+5tit+5sciencePubl,,The Ntlh! +l+ embedded in methyl methacrylate as described in ndBI984); is incorporated herein by reference. The tibia is incised longitudinally from the metaphyseal region.

Quan dyeing the specimen with silver nitrate on one side and irradiating it with both incandescent light and ultraviolet light. Chimet Image Analyzer (Qu! QIimtt 1m1ge Anx lBe+) C Cambridge Instruments Co. (Cxmb+1d1e In +l+no+ents, I+c, )] on a microscope slide for evaluation. . Metaphyseal trabecular bone volume was measured in the area between the fluorescent label and the growth plate, and the total area (bone and expressed as a percentage of bone marrow). The width of the growth plate at the end of the growth plate is measured at 10 equally spaced intervals using intercepts. obtained as a constant average value.

Statistical evaluation of data examines statistically significant effects compared to control animals Therefore, parameter analysis of variance and non-parameter analysis and Wilcoxoos ) using rank summation tests. The Zienck model is compound-induced in vivo bone resorption. Gives inhibition data.

There are numerous animal models of arthritis, and some of these include Mycobacterium butyri. Adjuvant induction using CAM (M7cobgcje+iumbu17+1cI) I have arthritis. This model resembles human rheumatoid arthritis in several ways. (invasion of cells and vannus in the joint space, bone resorption, and chemotactic factors entering the joint space) joint swelling with release of lysosomal elements) (1, 2). Some prevention and treatment Studies have shown the use of anti-inflammatory drugs (3,4) and diphosphonates (5,6) in arthritis. It showed the possibility.

References 1, Ptazon, C., Wood F. (1959), 5ludie (o fPolB+lb+iti+ and (Nh++ LtI:ons Indo c4d b7Injection of M7cobacls+ixl Adj uyaot, 1. Gene+alClinicxl and Palholog ical Cha+acle+1stic+xnd SomeModilTi ng Facloz, (phycobacteria induced by injection of adjuvant) research on polyarthritis and other disorders.

1. General clinical and disease characteristics and some modifying factors), Arth.

Rheum, 2:440-459 2, Blackman, ^, Bu+n+, 1. W, Foams', 1. B.

Rzd+1vonik, Il,, We+tvick, 1. (1977) , An X-+xy Anii7+i+of Adjovanl Arth 1tis in the Ra1. The Effect ofP+edni+ olone and Indomethacin (adjuvant in rats) X-ray analysis of arthritis, effects of prednisolone and indomethacin), ^Hnl+ and Actions, 7:145-1513, Winter, C.A. Nots, G. W. (1966), T+extmEnt ofAdjnyxn l　^+th+iti+　in　Ra1s　with　Anti-inllam milo+7D+oH (Treatment of adjuvant arthritis in rats with anti-inflammatory drugs) , Arth, Rheum, 9:394-4044, Winded , C, V, , Le+nbke, L, ^, 5lephens, M, D. (1969).

COMPA+alive Bioassay Of Dr+Bs in Adi aya++t-1nducedA+lb+ili+ in R+1+:Ful enamic Ac1d, Mefenamic Ac1d.

1st Ph+n71bufx+onc (adjuvant-induced arthritis in rats) Comparative bioassay of drugs in: flufenamic acid, mefenamic acid and phenyl Butacin), Arth, Rbel, 12+5, F+inci3M, D, Nots, L., Niing, W. R. (1972), TheEIIect + of Disodium E+hxn-1-Hyd+ox7-1-Diph o+phonale 011 Adjutant 1nduced A+lh+ ili+ 1nR1ts (ethane- in adjuvant-induced arthritis in rats) Effect of disodium 1-hydroxy-1-diphosphonate), Ca1ci1.　 Ti1t, Red, , 9:109-1216, Flora, L, (1979), Compa+5tiye AnliinllzmmNoBan d Bone? otectiye Ellccls of two Diph o+phonatein Adjuvant Arthritis Comparative anti-inflammatory and osteoprotective effects of two diphosphonates in arthritis).

Arth, Rheum, 22:34G-346 What is adjuvant arthritis? On day 0, a single subcutaneous injection of Mycobacterium butyricum (8 mg/ml) in mineral oil ( SC) injection into male rats [Sprague-Dawley or Lewis (Levi+)]. Severe cellulitis and prolapse inflammation induced by any of these strains. The compound is administered orally (P ○) or parenterally (SC) once a day for prophylaxis (from day 0) or Treatment (from day 9, 10 or 14) can be tested with either protocol. Ru. Anti-arthritic efficacy was determined by constant dose reduction, body weight compared to saline-treated arthritic controls. It can be measured as decline, bone loss or reactive neoplasia. Stopping treatment and responding to “redness” (rapid increase in inflammation), which can be tested for compounds that can maintain efficacy. Show the ability of something.

The animals used are male Lewis rats (LEW).

Upon arrival, rats were randomized with a computer-generated random number and given individual Put it in a hanging cage. Food and water will be provided ad libitum throughout the study. motion Performs routine care and maintenance of property in accordance with state and federal regulations. Each rat is placed in front of the cage. On the first day, body weight (BW) and hind paw volume were determined by the number attached to the rat's tail. recorded by the mercury displacement method using a pressure transducer connected to a computer (P V)) Measurements are performed on all rats. On day 0, MFA [mycobacteria in oil] Um butyricum (Mb) 4. 4mg/kg) was used to induce arthritis. As described: Rats were anesthetized and treated with a single dose of MFA on the tail under sterile conditions. Receive SC injection.

Paw volume and body weight are then measured on various days, usually twice a week. Prevention protocol When Start and continue every day until you finish. For treatment protocols, rats were treated on day 100. Randomize into treatment groups of 8-10 rats according to their PV. The dosage is 100 Continue every day from the beginning of the day until the end. For both protocols, animals were born on day 100. is for a compound that is difficult to oxidize due to a shoe pox that has a deep bed in front of it. The drug is weighed on a graduated scale and then mixed with distilled water in a volumetric flask. O , IN Adjust the pH to 7.4 with NaOH. The solution was then passed through a 0.45 μm sterile filter. Filter into a sterile storage container. Store the solution in the refrigerator when not in use. Ru.

For compounds that are easily oxidized The drug is weighed on a graduated scale and then mixed with deoxygenated water in a volumetric flask. Stock Filter the solution through a 0.45 μm sterile filter into a sterile storage container. do not use When ready, keep the stock solution in the refrigerator.

On a daily basis, remove a specific amount of solution from the stock solution into a small dosing beaker. Then adjust the pH to 7.4 according to the prescribed calculation method. No more dilution of the adjusted solution Dissolution may also be performed (with deoxygenated water) if necessary.

Drug calculations are based on molecular weight, compound purity, mg/kg (body weight) and mgP/k. Based on the desired final concentration of g. The volume of horse dosing per rat is 0, 1 mg/dose administered subcutaneously as an injection in the inguinal fold on each side alternately every other day. 100 g body weight or oral administration using curved stainless steel dosing tube 1ml/200gBW. Adjustments based on weight changes are made weekly.

Radiography, autopsy and tissue collection At the end, kill each rat with 1 ml of Socomb intraperitoneally (IP). . Immediately, the whole radiograph was sent to the Trox (To++o) 12 OD X-ray unit. By knitting, MA = 5, 5UP = 50 and time = 60 seconds. k) Take to non-screen medical film. Remove the hind paws from each rat, remove the liver, and kidneys. , along with pancreas and thymus, are fixed in 10% buffered formalin. Tibiotarsal joint pH 7 , demineralized with 4% EDTA, paraffin block and H+E staining. Process it in a way. Organ parts are also processed with paraffin and stain H+E.

Tissue sections are qualitatively evaluated for bone and soft tissue lesions using light microscopy. release Radiographs showed six anatomical trabecular sites in each hindpaw and four sites in each forepaw. Graded for bone resorption (BR) on a scale of 0 to 3 and evaluated for all four feet. Give an arbitrary score from 0 to 60. For reactive neoplasia (RNB), radiation Pictures are 0-3 for the lateral and medial surfaces of the tibia, and all other areas listed above. is graded on a strict scale of 0 to 2 and given an arbitrary score of 0 to 44.

D. Statistical analysis Data analysis regarding foot volume, bone resorption and reactive neoplasia was performed using Student's t test and one-sided analysis of variance using T++ke7s (S A S ) (12). I will do it. Differences are considered significant at p=0.05 or less.

This model demonstrates the role of saline treatment in reducing paw swollen bone loss and reactive neoplasia. Provides in vivo data on the efficacy of anti-arthritic compounds compared to arthritic animals.

prefecture Produce capsules with the following composition: active ingredient mg/capsule N-(3-hydroxy-3,3-diphosphonopropyl)-N,N,Nl-rimethyl Ammonium chloride 350.0 Microcrystalline cellulose 60.0 Magnesium stearate 1.0 Capsules having the above composition are manufactured using conventional methods as follows: Mix the active ingredient with the microcrystalline cellulose in a turn shell blender for approximately 10 minutes. sum up

The resulting mixture is passed through a hammer mill equipped with an 80 mesh screen.

Return the mixture to the twin shell blender with the lactose, then blend for about 15 minutes. Mix.

Then add the magnesium stearate and blend for an additional 5 minutes. then obtained The blend is compressed in a piston-actuated capsule filling machine.

Any of the compounds prepared according to Examples 1 to 5 can be used in the capsules prepared above. May be used in place of the active ingredient.

Example 9 Prepare tablets with the following composition: Active ingredient mg/tablet N-(4-hydroxy-4,4-diphosphonobutyl)-N,N-dimethyl-N- (2-mercaptoethyl) ammonium chloride 700.0 ! shape roasting Lactose (spray dried) 200.0 Starch (+500) 100.0 Magnesium stearate 25.0 Tablets with the above composition are manufactured using the following conventional method. Grind the active ingredient in a ball mill for about 30 minutes.

The ground active ingredient is then spray-dried in a twin blade mixer. and blend for about 20 minutes.

Add the starch to the mixture and then mix for 15 minutes. Blend into a standard tablet Compress it into tablets using less.

Any of the compounds prepared according to Examples 1 to 5 was tested for its activity in the tablets prepared above. May be used in place of ingredients.

Example: Co-0 The injection solution was a physiological saline solution 10.01 and N-(4- Hydroxy-4,4-diphosphonobutyl)-N,N,N-trimethylammonium It is produced by a conventional method using muchloride.

One injection per day for 4 days cured rheumatoid arthritis in a 70 kg patient. It was reduced considerably.

Any of the compounds prepared according to Examples 1 to 5 can be used in the injection solutions prepared above. May be used in place of the active ingredient.

Example 11 A 72-year-old man weighing 92 kg had moderate to severe pain and occasional swelling in his right knee. Caucasian man. After about a year of steadily increasing discomfort, he consulted a doctor. During the visit, the doctor made a clinical diagnosis of osteoarthritis in the right knee, which was later confirmed by X-ray diagnosis. Approved.

Various NSAID modifications including aspirin, naprosen and ketoprofen. After a period of good therapy, his symptoms continued to worsen and his condition appeared to be regressing. . He went back to his doctor and the doctor told him that it was manufactured as described in Example 9. The tablets were prescribed twice a day for 3 months, 2 hours before or after meals. pain and His clinical symptoms of swelling improved significantly after 3 months of therapy, especially on long walks.

After 3 months of dosing with 2 tablets per day, the therapy was reduced to half the originally prescribed dose (immediately). (1 capsule per day prepared as described in Example 8) was continued indefinitely.

Example 12 A 55-year-old black woman weighing 65 kg suffered from swelling and deformity of the knuckles of both hands. There is a partial loss of strength and/or dexterity in the fingers. Vision and X-ray examination and US Liu Various appropriate clinical trials approved by the Rheumatoid Disease Association (ARA) have shown that she has rheumatoid arthritis. Diagnosed with arthritis.

After unsuccessful analgesic and anti-inflammatory therapy, her doctor, as described in Example 9, The manufactured tablets were prescribed twice a day for 4 months, 2 hours before or after meals. 1 After months of therapy, her finger joint swelling symptoms have significantly improved and her range of finger movement has improved significantly. She continued therapy for the remainder of the four months, after which her doctor The prescribed dose was continued for an additional two months.

Example 13 A Spanish female, 12 years old and weighing 37 kg, had idiopathic juvenile rheumatoid arthritis. Doctors diagnosed it as inflammation. Her symptoms include severe inflammation of multiple joints, fever and It is accompanied by ura, indicating rapid pathological deterioration of joint function.

Her doctor referred her to a rheumatologist, who was listed in Example 10. 3 days of IV administration over 2 hours at the rate of one daily injection of a solution prepared by sea bream. Aggressive therapy with administration was immediately prescribed. Based on the results of the IV method, the doctor wrote in Example 9. I prescribed the tablets manufactured as described above for two months, and during that time she showed marked improvement, with increased movement and decreased pain. For the next two months, the doctor will spend two days her dose by prescribing 3 tablets in between, alternating between 2 tablets per day and 1 tablet per day. was reduced to 3/4 of the original oral dose. From the results of this method, the dosage in Example 9 Give her one tablet every day for an additional 4 months, prepared as described. The dose was then reduced again to 1/4 of the original dose.

Example 14 A 60-year-old Caucasian woman weighing 62 kg develops severe back disease. her doctor is , with the aid of radiology, a compression fracture of the L1 vertebra was found, probably due to osteoporotic bone loss. diagnosed her. The patient received 700 mg tablets manufactured as described in Example 9. A once-daily dosing regimen for 3 months was prescribed. 700mg tablets are taken with prescribed meals. Take 2 hours before or 2 hours after. After 3 months, the dosage was as per the procedure described in Example 8. Reduced to manufactured 350mg capsules and taken every other day for 3 months . Her doctor then placed her on maintenance medication management, and she took the medication described in Example 8 daily for six months. 100 mg capsules manufactured according to the procedure described were taken.

After 6 months of maintenance medication management, the patient no longer had back pain. with tracking x-ray shows no fracture.

Example 15 My weight is 53! A 75-year-old woman of Asian descent suffered a hip fracture after a fall. she was hospitalized He was diagnosed with osteoporosis.

Prescribed treatment with calcitonin injections. Calcitonin injections are painful for patients; She was no longer able to comply with calcitonin treatment. So her doctor put her through therapy. Switched to oral phosphonate method. She was prepared according to the procedure described in Example 9. 700 mg tablets were administered twice daily for one month. After therapy for the past month, he The woman was given a 700 mg tablet once a day for two months. After these two months, she 1100I1 capsules prepared according to the procedure described in Example 8 every 3 months. I gave it a day. A follow-up visit to her doctor showed that the The mineral density of the forearm does not show any apparent decrease.

Example 16 An 85-year-old Native American man weighing 65 kg was diagnosed by a doctor with severe back pain.

X-rays show many small vertebral bodies collapsed due to significant bone loss due to osteoporosis.

The patient was given 8 hours' prior treatment on the same day, prepared according to the procedure described in cases 9 and 8, in each of the four cases. prescribed a two-month regimen of 700mg tablets and 350ωg capsules to be taken as . After 2 months on this method, his dosage was 350 mg tablets once a day for 2 months. decreased to An X-ray showed an additional compression fracture. So he said Example 8 100 mg capsules per day for 6 months manufactured according to the procedure described in The project was moved to maintenance management. After this 6-month period, there appears to be no significant decrease in bone mineral density. No small amount was observed.

Treasure Tomoki Kujira Cow international search report Continuation of front page (81) Designated countries EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), 0A (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN.

TD, TG), AU, BB, BG, BR, CA, CZ.

FI, HU, JP, KP, KR, KZ, LK, MG, MN, NiW, NO, NZ, PL, RO, RU, SD, SK, UA, VN (72) Inventor: Francis, Marion Dipid, Ohio, United States , Cincinnati, Winlake Drive, 10018

Claims (10)

[Claims] 1. The following are useful in treating or preventing disorders of abnormal calcium and phosphate metabolism: Quaternary nitrogen-containing compounds having the general structure and their pharmaceutically acceptable salts and esters: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [In the above formula, m is an integer of 0 to 10; n is an integer of 1 to 10; m+n is 1 ~10; (a) R1 is nothing, -SR6, -R9SR6, hydrogen, substituted or unsubstituted -C1-C8 alkyl, -OR3, -CO2R3, -O2CR3, -NR32, -N(R3)C(O)R3, -C(O)N(R3)2, halogen, -C(O)R 3. Nitro, hydroxy, substituted or unsubstituted saturated monocyclic or polycyclic heterocycle, substituted or unsubstituted saturated monocyclic or polycyclic carbocycle, preferably substituted or unsubstituted saturated monocyclic or polycyclic heterocycle, substituted or unsubstituted saturated monocyclic or polycyclic carbocycle, no, H, - selected from the group consisting of SR6, -R9SR6; (b) R5 is -SR6, -R9SR6, hydrogen, substituted or unsubstituted C1-C8 alkyl -OR3, -CO2R3, -O2CR3, -NR32, -N(R3)C(O )R3, -C(O)N(R3)2, halogen, -C(O)R3, nitro, hydro xy, substituted or unsubstituted saturated monocyclic or polycyclic heterocycle, substituted or unsubstituted saturated monocyclic ring formula or polycyclic carbocycle, substituted or unsubstituted unsaturated monocyclic or polycyclic heterocycle, substituted or is an unsubstituted unsaturated monocyclic or polycyclic carbocycle and combinations thereof, preferably -SR6 , -R9SR6, hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted saturated from a monocyclic or polycyclic heterocycle, a substituted or unsubstituted saturated monocyclic or polycyclic carbocycle (c) each R2 is substituted or unsubstituted C1-C35 alkyl; unsubstituted or substituted phenyl, benzyl and R9SR6, preferably substituted or unsubstituted selected from the group consisting of C1-C35 alkyl and R9SR6; (d) R3 is a group consisting of H, unsubstituted or substituted C1-C8 alkyl, R9SR6; preferably H; (e) R6 is -H, -C(O)R7, -C(S)R7, -C(O)N(R7)2 , -C(O)OR7, -C(S)N(R7)2, -C(S)OR7 (R7 is hydrogen or unsubstituted or substituted C1-C8 alkyl), preferably -H, -C( O) selected from the group consisting of R7 and -C(S)R7; (f) R is -PO3H2 and -P(O)(OH)R4 (R4 is an alkyl group having 1 to 3 carbons), preferably Preferably selected from the group consisting of -PO3H2 and -P(O)(OH)R4; (g) R9 is substituted or unsubstituted C1-C8 alkyl; (h) R8 is hydrogen, rogene, SR6, R9SR6, amino, hydroxy, substituted or unsubstituted C1-C8 alkyl, preferably selected from the group consisting of H and SR6]. 2. R1 is a substituted or unsubstituted saturated monocyclic or polycyclic heterocycle or a substituted or unsubstituted 2. A compound according to claim 1, which is a substituted saturated monocyclic or polycyclic carbocycle. 3. R5 is hydrogen, -SR6, -R9SR6, substituted or unsubstituted C1-C8 alkyl , substituted or unsubstituted saturated monocyclic or polycyclic heterocycles. Compounds listed. 4. Claim 1, wherein R1 is selected from nothing, -SR6, -R9SR6 and hydrogen. Compounds listed. 5. R5 is -SR6, -R9SR6, hydrogen, substituted or unsubstituted C1-C8 alkyl 2. A compound according to claim 1, selected from: 6. A compound according to claim 1, wherein R5 is substituted or unsubstituted C1-C8 alkyl. . 7. 2. A compound according to claim 1, wherein R5 is R9SR6. 8. According to claim 1, R5 is a substituted or unsubstituted, saturated or unsaturated heterocycle. Compound. 9. (a) a safe and effective amount of the phosphonate compound of claim 1; and (b) Pharmaceutically acceptable excipients A drug useful for the treatment of pathological conditions involving abnormal calcium and phosphate metabolism, consisting of Composition. 10. administering a safe and effective amount of a compound according to claim 1 to a human or other mammal; Conditions associated with abnormal calcium and phosphate metabolism, including For the manufacture of drugs used for the treatment or prophylaxis in humans or other mammals, 3. Use of a compound according to claim 1.