SK144594A3 - Quaternary nitrogen-containing phosphate compounds, for treating abnormal calcium and phosphate metabolism - Google Patents

Abstract

The present invention relates to quaternary nitrogen-containing phosphonate compounds, and the pharmaceutically-acceptable salts and esters thereof having general formula (I). The present invention further relates to pharmaceutical compositions containing a safe and effective amount of a compound of the present invention, and pharmaceutically-acceptable excipients. Finally, 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 need of such treatment a safe and effective amount of a compound or composition of the present invention.

Description

Phosphonate compounds containing a quaternary nitrogen atom and their use in a pharmaceutical composition for the treatment of abnormal calcium and phosphate metabolism

Technical field

The present invention relates to novel phosphonate compounds containing a quaternary nitrogen atom, including bisphosphonates, phosphonoalkylphosphinates, phosphonocarboxylates and phosphonosulfonates. The invention also relates to pharmaceutical compositions comprising these novel compounds and to a method of treating or preventing certain disorders of bone metabolism characterized by abnormal calcium and phosphate metabolism using a compound or pharmaceutical composition of the invention. In particular, the invention relates to a method of treating or preventing osteoporosis and arthritis, in particular rheumatoid arthritis and osteoarthritis using a compound or composition of the invention.

BACKGROUND OF THE INVENTION

Many pathological conditions of warm-blooded animals include abnormal calcium and phosphate metabolism. These states can be divided into two large groups.

1. Conditions characterized by anomalous mobilization of calcium, calcium and phosphate leading to total or specific bone loss, such as osteoporosis and Paget's disease, or excessively high levels of calcium and phosphate in body fluids, such as hypercalcemia of tumor origin . These conditions are sometimes referred to as pathological demineralization of hard tissues.

2. Conditions that cause or result from anomalous deposition of calcium and phosphate in the body, such as rheumatoid arthritis and osteoarthritis. These conditions are referred to as pathological calcification.

The first group includes the most common disorders of bone metabolism, osteoporosis. Osteoporosis is a condition in which hard bone tissue is disproportionately lost due to the development of new hard tissue. Osteoporosis can be defined as a reduction in the amount of bone or as an atrophy of bone tissue. Bone marrow and bone holes increase, fiber bonding decreases and compact bone becomes brittle. Osteoporosis can be subclassified as drug-induced menopausal, senile, (e.g., adrenocorticoids, which may occur in steroid therapy), caused by disease (arthritic and tumor), and so on. However, the symptoms are identical.

There are generally two types of osteoporosis: primary and secondary. Secondary osteoporosis is due to a disease process or agent. However, approximately 90% of all osteoporosis cases are primary osteoporosis, including postmenopausal osteoporosis, age-related osteoporosis, non-use osteoporosis (affecting most individuals over the age of 70-80) and idiopathic osteoporosis, which affects both middle-aged men and women, as well as younger men and women.

In some individuals with osteoporosis, the loss of bone tissue is large enough to cause mechanical damage to the bone structure. Bone fractures such as the loins and spines of women who suffer from postmenopausal osteoporosis often occur, but may also cause kyphosis (abnormally enlarged curvature of the thoracic spine).

The mechanism of bone loss in osteoporosis is believed to be due to an imbalance in the process of bone remodeling. Bone remodeling (bone remodeling) occurs during life, when the skeleton is renewed and bone strength is maintained. This process involves erosion and replenishment of discrete sites on the bone surface by an organized group of cells called basic multice2 lullar units or BMUs. BMUs primarily consist of osteoclasts and osteoblasts and their cell precursors. In the remodeling cycle, bone is resorbed at the site activated by BMU by the osteoclast to form a resorptive cavity, which is then supplemented with bone osteoblasts.

The adult remodeling cycle normally results in a small bone deficit due to incomplete replenishment of the resorption cavity. Thus, even in healthy adults, bone loss occurs, but there is an increase in the number of BMUs that are activated in osteoporosis. This increased activation accelerates bone remodeling, resulting in abnormally high bone loss.

Although origin is not fully understood, there are many risk factors that are thought to be related to osteoporosis. These include low body weight, low calcium intake, physical inactivity and estrogen deficiency.

The usual treatment of osteoporosis is primarily calcium and estrogen.

The second group, which includes conditions manifested by anomalous calcium and phosphate deposition, includes progressive ossifying myositis, general calcinosis, and such diseases as arthritis (including, for example, rheumatoid arthritis and osteoarthritis), neuritis, hurzitis, condition, tendonitis and others. they have tissues in which calcium is stored.

In addition to osteoporosis, bone loss may occur in rheumatoid arthritis and osteoarthritis. Rheumatoid arthritis is a chronic, systemic and articular inflammatory disease characterized by a weakening of the joint and ligament capsules with subsequent destruction of cartilage, ligaments, tendons and bones, a decrease in synovial fluid viscosity and other changes in the fluid. Symptoms of rheumatoid arthritis include systemic weakness, fatigue, localized pain, stiffness and weakness, and swelling with joint deformation. Reumajte <

tic arthritis is most common in women aged 40 to 60 years.

The pathogenesis of rheumatoid arthritis, which results in joint destruction, is characterized by two phases: 1) an exudative phase that includes microcirculation and synovial cells that allow plasma proteins and cellular elements to enter the joint, and 2) a chronic inflammatory phase that occurs in the sub -synovium and subchondral bone characterized by pannus formation (granulated tissue) in the joint space, bone erosion and cartilage destruction. Pannus can form adhesions and scar tissue, causing joint deformation characteristic of rheumatoid arthritis.

The origin of rheumatoid arthritis remains unclear. Infectious agents such as bacteria and viruses are contemplated. A common hypothesis is that the true cause of rheumatoid arthritis is the Epstein-Barr virus (EBV).

Conventional treatment of rheumatoid arthritis consists predominantly in the elimination of symptoms by the administration of non-steroidal anti-inflammatory drugs. Treatment against inflammatory NSAIDs is particularly effective in the early stages of rheumatoid arthritis. Suppression of joint inflammation is unlikely to occur if the disease has been present for more than one year. Gold, methotrexate, immunosuppressive agents and corticosteroids have been used with limited success.

Osteoarthritis, on the other hand, is a congenital non-inflammatory disease of the movable joints, characterized by the deterioration and abrasion of the articular cartilage, as well as the formation of new bone on the joint surface. If osteoarthritis continues, the articular cartilage surface is disrupted and the worn particles gain access to synovial fluid, which in turn stimulates phagocytosis by macrophage cells. Thus, an inflammatory response may be induced in osteoarthritis. Common clinical signs of osteoarthritis include enlargement of the cartilage and bones of the toes, stiffness upon awakening and pain on movement.

Treatment of the symptoms of osteoarthritis is accomplished by administering analgesic agents, anti-inflammatory agents, steroids, and physical therapy.

Various phosphonic acid derivatives have been proposed for the treatment and prevention of diseases of abnormal calcium and phosphate metabolism. For example, several references incorporated herein by reference disclose compositions comprising polyphosphonates, particularly diphosphonates, such as ethane-1-hydroxy-1,1-diphosphonic acid (EHDP), and their use to inhibit anomalous storage and mobilization of calcium, and phosphate in animal tissue, see U.S. Patent 3,683,080, issued August 8, 1972, U.S. Patent 4,230,700, issued October 28, 1980 (both Francis), and U.S. Patent 4,868,164 (Ebetina), issued September 19, 1989. Many further references disclose heterocyclic-substituted diphosphonic acids which are useful in the treatment of osteoporosis and / or arthritis and which are incorporated herein by reference, see US Patent 5,071,840 Ebetina and December 1991, US Patent 4 September 1989, US Patent April 1992, US Patent 4 267 108 Bluma et al., Issued May 12, 1981; U.S. Patent 4,746,654 to Brelier et al., Issued May 24, 1988; U.S. Patent 4,876,247 to Barbier, et al.

European Patent Application Ser. 100 718 Brešú col. , col. , col. , issued 10 issued 19th published 14.

868 164 Ebetino and 5,104,863 Benedict and Liera and February et al., Published 15 of this application (Boehringer Mannheim forged February 5, 1986, European 186 405 Benedict and Perkins, patent application No. 1989, US patent 4 754

1984, European patent publication no. 170,228, publ.

published 2 July 1986, European 298 553 Ebetina, published 11 January 993 Bosies et al., issued 15 November

1988, U.S. Pat. No. 4,939,130 to Jaeggi et al., Issued July 3, 1990; U.S. Pat. No. 4,971,958 to Bosies et al., Issued November 20, 1990; WO 90/12017 to Dunn et al., Published October 18, 1990; WO 91/10646 Youssefyeha R. et al., Published July 25, 1991, Australian Patent Application 26738/88 Jaeggi, published July 15, 1989 and 45467/89 (Ciba-Geigy), published May 31, 1990.

Finally, U.S. Pat. No. 4,208,401 Bauman, issued June 17, 1980, discloses non-heterocyclic ring substituted bisphosphonates with a quaternary ammonium group which are useful as anti-stone agents.

German Patent Jaeggi K., published October 18, 1990, describes diphosphonate compounds substituted with a heterocyclic ring, which heterocyclic ring may be substituted with a lower alkyl group. This heterocyclic ring is bridged to the phosphonic acid group by a quaternary non-ring nitrogen atom. This patent also discloses that these compounds show a significant inhibition of bone resorption and are therefore useful in the treatment of osteoporosis, inflammatory and degenerative joint diseases, peridentitis and hyperparathyroidism. The meanings of these references are herein incorporated by reference.

The compounds of the invention have osteoprotective activity at the site of joint destruction in arthritic conditions and are further active in the treatment of arthritis. This effect goes beyond just relieving the symptoms of inflammation. The term osteoprotective activity as used herein is an activity that treats the disease of bone and surrounding soft tissue at the site of joint destruction.

Surprisingly, it has been found that compounds of the present invention with a quaternary nitrogen atom have stronger anti-resorptive activity in bone and therapeutic utility in the treatment of osteoporosis, rheumatoid arthritis and osteoarthritis than compounds containing but not quaternary nitrogen. In addition, the compounds of the invention have unusual solubility and can therefore be readily absorbed orally. The easier the compound is absorbed, the more effective it is at smaller doses. Smaller doses are very advantageous as they reduce unwanted side effects.

It is therefore an object of the present invention to provide novel, more active compounds that are effective in the treatment of osteoporosis and anti-arthritic agents that are particularly useful in the treatment of osteoarthritis and rheumatoid arthritis. It is a further object of the present invention to provide pharmaceutical compositions suitable for the treatment and prevention of osteoporosis and arthritis, in particular rheumatoid arthritis and osteoarthritis. The present invention also provides a method of treating or preventing osteoporosis and arthritis, in particular rheumatoid arthritis and osteoarthritis.

These and other objects of the invention will be apparent from the following detailed description of the invention.

SUMMARY OF THE INVENTION

The present invention relates to phosphonate compounds containing a quaternary nitrogen atom and their pharmaceutically acceptable salts and esters of formula I

wherein m is up to 10, n is 1 to 10, and the sum of m + n is 12 to 10,

R ¹ represents nothing, -SR ⁸ or -R ⁹ SR ⁸ , hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, -OR ³ , -COOR ³ , -OOCR ³ , -NR ³ 2, - N (R ³ ) C (O) R ³ , -C (O) N (R ³ ) 2, halogen, -C (O) R ³ , nitro, hydroxyl, substituted or unsubstituted saturated, monocyclic or polycyclic heterocyclic a substituted or unsubstituted saturated monocyclic or polycyclic carbocyclic group,

R ⁵ represents a group selected from the group consisting of -SR ⁸ or -R ⁹ SR ⁸ , a hydrogen atom, a substituted or unsubstituted C 1 -C 8 alkyl group, -OR ³ , -COOR ³ , - OOCR ³ , -NR ³ 2, -N (R ³ ) C (O) R ³ , -C (O) N (R ³ ) ₂ , halogen, -C (O) R ³ , nitro, hydroxyl, substituted or unsubstituted saturated monocyclic or polycyclic heterocyclic groups, substituted or unsubstituted saturated monocyclic or polycyclic carbocyclic groups, substituted or unsubstituted unsaturated monocyclic or polycyclic heterocyclic groups, substituted or unsubstituted unsaturated monocyclic or polycyclic groups,

R ² is a group which is selected from the group consisting of substituted or unsubstituted alkyl group of 1 to 35 carbon atoms, unsubstituted or substituted phenyl, benzyl or R ⁹ SR ^6,

R ^{3 is} independently hydrogen, unsubstituted or substituted C 1 -C 8 alkyl or -R ⁹ SR ⁶ ,

R ⁶ is independently 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 or -C (S) OR ⁷ , wherein R ⁷ represents a hydrogen atom or an unsubstituted or substituted C 1 -C 8 alkyl group,

R is -COOH, -SO 3 H, -PO 3 H 2 or -P (O) (OH) R ⁴ , wherein R ⁴ is C 1 -C 3 alkyl,

R ⁹ represents a substituted or unsubstituted alkyl group having 1 to 8 carbon atoms and

R ⁸ represents a group selected from the group consisting of hydrogen, halogen, -SR ⁶ or -R ⁹ SR ⁶ , an amino group, a hydroxyl group and a substituted or unsubstituted C 1 -C 8 alkyl group.

In this general formula, the quaternary nitrogen atom must be attached to a carbon atom containing a phosphonic acid by a linking chain. It cannot be attached directly to a carbon atom containing phosphonic acid.

The invention further relates to pharmaceutical compositions comprising a safe and effective amount of a compound of the invention and pharmaceutically acceptable diluents. It also relates to a method of treating or preventing pathological conditions characterized by abnormal calcium and phosphate metabolism, such as osteoporosis and arthritis, in particular rheumatoid arthritis and osteoarthritis of humans and other mammals. According to this method, a safe and effective amount of a compound or composition of the invention is administered to a human or other mammal in need of such treatment.

The following is a list of definitions of terms used herein.

The term heteroatom means a nitrogen, sulfur or oxygen atom. Groups containing one or more heteroatoms may contain different heteroatoms.

The term alkyl means a straight or branched chain unsubstituted or substituted, saturated or unsaturated hydrocarbon chain. This hydrocarbon group may be saturated with 1 to 8 carbon atoms, and preferably, unless otherwise specified, 1 to 4 carbon atoms. This hydrocarbon group may also be unsaturated, having 2 to 8 carbon atoms, preferably, unless otherwise specified, having 2 to 4 carbon atoms. Thus, the term includes alkenyl hydrocarbon unsaturated chains with at least one olefinic double bond and alkynyl hydrocarbon unsaturated chains with at least one triple bond. Preferred alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and butyl.

The term carbocyclic ring as used herein means an unsubstituted or substituted, saturated, unsaturated or aromatic hydrocarbon ring. A carbocyclic group may be a monocyclic group having 3 to 8, preferably 5 to 7 carbon atoms, or a polycyclic group. Polycyclic carbocyclic groups consisting of two rings represent a group of 6 to 16, preferably 10 to 12 atoms, polycyclic carbocyclic groups of three rings usually represent a group of 13 to 17, preferably 14 to 15 atoms.

The term "heteroalkyl" means an unsubstituted or substituted 3 to 8 membered saturated chain containing carbon atoms and one or two heteroatoms.

The term "heterocyclic ring" or heterocycle, as used herein, means an unsubstituted or substituted, saturated, unsaturated or aromatic ring having carbon atoms and one or more ring heteroatoms. The term heterocyclic group includes monocyclic or polycyclic ring systems.

Monocyclic groups generally contain 3 to 8 atoms, preferably 5 to 7 atoms. Polycyclic groups consisting of two rings are usually 6 to 16, preferably 10 to 12, groups. Polycyclic groups consisting of three rings usually represent a group having 13 to 17, preferably 14 to 15 atoms. The heterocyclic group may consist of heterocycles or of heterocycles and carbocycles. Each heterocyclic group must contain at least one nitrogen atom. Other heteroatoms may be independently selected from the group consisting of oxygen, nitrogen and sulfur, unless otherwise specified.

The term aryl refers to an aromatic carbocyclic ring. Preferred aryl groups include, but are not limited to, phenyl, tolyl, xylyl, cumenyl, and naphthyl groups.

The term heteroaryl means an aromatic heterocyclic ring. Preferred heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiazolyl, quinolinyl, pyrimidinyl and tetrazolyl groups.

The term alkoxy means an oxygen atom with a substituent that is a hydrocarbon chain that represents an alkyl or alkenyl group (e.g., -O-alkyl or -O-alkenyl). Preferred alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and alkyloxy.

The term hydroxyalkyl means a substituted hydrocarbon chain having a hydroxyl substituent (e.g., -OH) and may have other substituents. Preferred hydroxyalkyl groups include, but are not limited to, hydroxyethyl and hydroxypropyl.

The term carboxyalkyl means a substituted hydrocarbon chain that carries a carboxyl substituent (e.g. -COOH) and may have other substituents. Preferred carboxyalkyl groups include carboxymethyl and carboxyethyl groups and their acids and esters.

The term aminoalkyl means a hydrocarbon chain (e.g., alkyl) substituted with an amino group (e.g., alkyl-NH-) such as an aminomethyl group.

The term alkylamino means an amino group with one or two alkyl substituents (e.g., -N-alkyl) such as dimethylamino.

The term alkenylamino means an amino group with one or two alkenyl substituents (e.g. -N-alkenyl).

The term alkynylamino means an amino group with one or two alkynyl substituents (e.g., -N-alkynyl)

The term alkylamino group means an imine group with one or two alkyl substituents (e.g. -N-alkyl).

The term arylalkyl means an alkyl group substituted with an aryl group. Preferred arylalkyl groups include benzyl and phenylethyl.

The term arylamino means an amino group substituted with an aryl group (e.g. -NH-aryl).

The term aryloxy means an oxygen atom with an aryl substituent (e.g. -O-aryl).

The term acyl or carbonyl means a carbon atom attached to an oxygen atom by a double bond (e.g. R-C (= O). Preferred acyl groups include, but are not limited to, acetyl, propionyl, butanoyl, and benzoyl groups).

The term acyloxy means an oxygen atom with an acyl substituent (e.g. -O-acyl), e.g. O-C (= O) -alkyl.

The term acylamino means an amino group with an acyl substituent (e.g. -N-acyl), e.g. -NH- (C = O) -alkyl.

The term halogen atom or halide means a group derived from a chlorine, bromine, fluorine or iodine atom. Preferred halogen atoms are chlorine, bromine and fluorine.

The term lower hydrocarbon group as used herein (e.g. lower alkyl) means a hydrocarbon chain of 1 to 6, preferably 1 to 4 carbon atoms, unless otherwise indicated.

The term thio-substituent as used herein (SR ⁶ or R ⁹ SR ⁶ ) includes thiols [-SH when R ⁶ is hydrogen], thioesters (-SC (O) R ⁷ when R ⁶ is C ( O) R ⁷ ], dithioesters [SC (S) R ⁷ if R ⁶ is C (S) R ⁷ ], thiocarbamates [-SC (O) N (R ⁷ ) 2 if R ⁶ is C (O) (R ⁷ ) 2], dithiocarbamates [SC (S) N (R ⁷ ) 2 if R ⁶ is C (S) N (R ⁷ ) 2, thiocarbonates [SC (O) OR ⁷ if R ⁶ is C (O) OR ⁷ ] and dithiocarbonates [SC (S) OR ⁷ when R ⁶ is C (S) OR ⁷ ]. The group R ⁷ usually represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms. SR ⁶ may themselves be substituted with R ⁹ , ie R ⁹ SR ⁶ , where R ⁹ represents a substituted or unsubstituted C 1 -C 8 alkyl group. Thus, other thio substituents of R ⁹ SR ⁶ are alkylthiols, alkylthioesters, alkyldithioesters, alkylthiocarbamates, alkylthithiocarbamates, alkylthiocarbonates and alkyldithiocarbonates.

The term bisphosphonate or bisphosphonic acid as used herein means those phosphonates or phosphonic acids having two phosphonate groups attached to the same carbon atom. These terms are used interchangeably with the terms diphosphonate and diphosphonic acid. Using the formulas described herein, R is PO 3 H 2.

As used herein, the term carbon atom of a phosphonic acid means a carbon atom to which a phosphonic acid group (PO 3 H 2) is attached. When another phosphonic acid group is attached to this carbon atom, the resulting compound is a bisphosphonate. When a sulfonate group is attached to this carbon atom, the resulting compound is a phosphonosulfonate. When a carboxylate group is attached to this carbon atom, the resulting compound is a phosphonocarboxylate. When phosphinic acid is attached to this carbon atom, the resulting compound is phosphonoalkylphosphinate.

The term pharmaceutically acceptable salt means a cationic salt formed on any acidic (e.g. carboxyl) group or an anionic salt formed on any basic (e.g. amine) group. Many such salts are known to those skilled in the art, as described in WO 87/05297 to Johnston et al., Published Sep. 11, 1987, which is incorporated herein by reference. Preferred cationic salts include alkali metal salts (such as sodium and potassium) and alkaline earth salts (such as magnesium and calcium). Preferred anionic salts include halides (such as chloride), acetates and phosphates.

The term hydrolyzable ester means an ester of heterocyclic phosphonate compounds containing a quaternary nitrogen atom that does not interfere with the therapeutic activity of these compounds or that is readily metabolised by a human or other mammal. Those skilled in the art will recognize many such esters, for example, as described in WO 87/05297 to Johnston et al. These esters include lower alkyl esters, lower acyloxyalkyl esters (such as acetoxymethyl-, acetoxyethyl-, aminocarbonyloxymethyl-, pivaloyloxymethyl- and pivaloyloxyethyl-), lactonyl esters (such as phthalidyl- and thiophthalidyl ester), lower alkoxyacyloxymethyl-oxyethyl- (such as and isopropoxycarbonyloxyethyl ester), alkoxyalkyl esters, choline esters and acylaminoalkyl esters (such as acetamidomethyl esters).

As mentioned above, substituent groups may themselves be substituted. Such substitutions may be made by one or more substituents. These substituents include, but are not limited to, those listed by C. Hansch and A. Leo in the Substituent Constants for Correlation Analysis in Chemistry and Biology (1979), which is incorporated herein by reference. Preferred substituents include, but are not limited to, alkyl, alkenyl, alkoxy, hydroxyl, oxo, amino, aminoalkyl (e.g., aminomethyl, etc.), cyano, halogen, carboxy, alkoxyacetyl (e.g. carboethoxy, etc.), thio, thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g., piperidinyl, morpholine, piperazinyl, pyrrolidine, etc.), imine, thioxo, hydroxyalkyl, aryloxyalkyl, and arylalkyl.

The compounds of the invention are phosphonate compounds containing a quaternary nitrogen atom and their pharmaceutically acceptable salts and esters with a quaternary nitrogen atom. The quaternary nitrogen atom is attached to the carbon atom containing the phosphonic acid by a linking chain.

The carbon atom to which the phosphonic acid group is attached may be unsubstituted (i.e., a hydrogen atom) or substituted. The phosphonic acid carbon atom may contain two phosphonate groups, then a bisphosphonate compound, a phosphonate group and a carboxylate group, then a phosphonocarboxylate compound, a phosphonate group and a sulfonate group, then a phosphonosulfonate compound and a phosphinate group and a phosphonate group, then a phosphonoalkylphosphinate compound.

The quaternary nitrogen-containing phosphonate compounds of the present invention and their pharmaceutically acceptable salts and esters are thus compounds of Formula I

In this general formula, R ¹ is selected from various non-cyclic groups such as nothing, -SR ⁸ or -R ⁹ SR ⁸ , hydrogen, C 1 -C 8 alkyl, -OR ³ , -COOR ³ , -OOCR ³ , -NR ³ z, -N (R ³ ) C (O) R ³ , -C (O) N (R ³ ) 2, halogen, -C (O) R ³ , nitro, hydroxyl a substituted or unsubstituted saturated monocyclic or polycyclic heterocyclic group and a substituted or unsubstituted saturated monocyclic or polycyclic carbocyclic group.

In this formula, the quaternary nitrogen atom is attached to the phosphonic acid carbon atom by a bonding chain and n, which is a number from 1 to 10, is said bonding chain.

The members of said bonding chain are selected from various R ⁵ groups, which may be -SR ⁸ or -R ⁹ SR ⁸ , a hydrogen atom, a C 1 -C 8 alkyl group, -OR ³ , -COOR ³ , -NR ³ 2, -N (R ³ ) C (O) R ³ , halogen, -C (O) R ³ , nitro, hydroxyl, unsubstituted or substituted saturated monocyclic or polycyclic heterocyclic, unsubstituted or substituted saturated monocyclic or polycyclic carbocyclic groups, unsubstituted or substituted unsaturated monocyclic or polycyclic heterocyclic groups, unsubstituted or substituted unsaturated monocyclic or polycyclic carbocyclic groups, and combinations thereof.

Finally, R in the quaternary nitrogen containing phosphonate compounds of the present invention may be -COOH, -SO 3 H, -PO 3 H 2, or -P (O) (OH) R ⁴ , wherein R ⁴ represents an alkyl group having 1 to 8 carbon atoms. A preferred R group is -PO 3 H 2 or -P (O) (OH) R ⁴ . R ⁸ represents a substituent on a carbon atom carrying a phosphonic acid and is selected from the group consisting of hydrogen, halogen, -SR ⁸ or -R ⁹ SR ⁸ , an amino group, a hydroxyl group and a substituted or unsubstituted alkyl group having 1 to 2 8 carbon atoms. Preferred R ⁸ groups are hydroxyl, halogen and amino. R ² represents a substituted or unsubstituted C 1 -C 35 alkyl, substituted or unsubstituted phenyl, benzyl or -R ⁹ SR ^{8 group} . A preferred R ² group is a substituted or unsubstituted C 3 -C 8 alkyl group and -R ⁹ SR ⁸ .

Preferred quaternary nitrogen containing phosphonates having an R ¹ group selected from the above R ¹ groups include

CH,

CH ₃ (CH ₂ ) ₃ CH ₂ - _r ch ₃ after ₃ h ₂

N- (3-hydroxy-3,3-diphosphonopropyl) -N, N-dimethyl-N-pentyl ammonium chloride οη, -ν "^^. Οη cr CH, ^IT and

N- (4-hydroxy-4,4-diphosphonobutyl) -N, N, N-trialkylammonium salt and

CH

I

CH

POaHj

Cl

N- (3-hydroxy-3,3-diphosphonopropyl) -N, N, N-trlalkylammonium salts.

In this formula, R ¹ may also be a saturated monocyclic or polycyclic heterocycle.

Preferred quaternary nitrogen containing phosphonates having a saturated monocyclic or polycyclic heterocycle such as the R ¹ group in which the quaternary nitrogen atom is attached to the phosphonic acid carbon atom by a linking chain include:

“CH ₃ P (O) (OH) _and “ ΑΓΆ ™ ^a '| ⁺ P (O) (OH) _and CH 3

N- (3-hydroxy-3,3-diphosphonopropyl) -N, N-dimethyl-N- (2-piperidinomethyl) ammonium chloride.

Other preferred compounds of the invention include those of the following formulas;

R ²

R ² PO ₃ H2

R ^{2 p} O ₃ Hj

R '

Preferred phosphonate compounds with thiosubstituted formulas of the general formulas:

R ²

R ^e SR ^e -

^R2 POjH _2; ^p 0 ₃ H ₂ according to the invention also include the quaternary nitrogen atoms followed by R ^{e s} R ® Λ * ^H *

R ² PO ^ Hj

R ²

R'SR ^e + - ^ JLy ^P ° 3 ^H J

R ²

PO, H

Specific examples of the compounds of the invention include:

N- (4-hydroxy-4,4-diphosphonobutyl) -N, N, N-trimetylamoniumjodid,

N- (3-hydroxy-3,3-diphosphonopropyl) -N, N-dimethyl-N- pentylammonium iodide,

N- (3-hydroxy-3,3-diphosphonopropyl) -N, N, N-trimethylammonium iodide, N-cycloheptyl-N, N-dimethyl-N- (diphosphonomethyl) ammonium iodide,

N- (2-acetylthioethyl) -N- (4-hydroxy-4,4-diphosphonobutyl) -N, N-dimethyl ammonium bromide,

N- (2-acetylthioethyl) -N- (3-hydroxy-3,3-diphosphopropyl) -N-methyl-N-pentylammonium bromide,

N- (4-hydroxy-4,4-diphosphonobutyl) -N- (3-mercaptopropyl) -N, N-dimethylammonium chloride,

N- (4-hydroxy-4,4-diphosphonobutyl) -N- (mercaptomethyl) -N, N-dimethylammonium chloride,

N- (4-hydroxy-4,4-diphosphonobutyl) -N- (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-pentyl-N- (2- (3-pyridyl) ethyl) ammonium chloride,

N-cycloheptyl-N- (2-mercaptoethyl) -N-methyl-N- (diphosphonomethyl) ammonium chloride,

N-cycloheptyl-N- (mercaptomethyl) -N-methyl-N- (diphosphonomethyl) ammonium chloride; and

N, N-dimethyl-N- (4,4-diphosphonobutyl) -N- (2- (3-piperidinyl) ethyl) ammonium chloride.

the pharmacological activity is carried out on animals

To determine and evaluate the testing of phosphonate compounds by various assays known. Thus, the in vivo anti-resorptive activity of bone can be demonstrated in a conventional manner using an assay designed to test the ability of these compounds to inhibit bone resorption that is characteristic of abnormal calcium and phosphate metabolism. An example of such a known test is the Schenk model. Another suitable test known to those skilled in the art is the adjuvant arthritis test. An in vitro hydroxyapatite crystal growth inhibition assay is also suitable. These and other relevant pharmacological activity assays are described and / or discussed in the following works: Shinoda et al .: Calcified Tissue International 35, 87 (1983), Schenk et al .: Calcified Tissue Research 11, 196 (1973), Russel et al .: Calcified Tissue Research 6, 183 (1970), Muhlhauer and Fleisch: Mineral Electrolyte

Metab. 5, 296 (1981), Nancollas et al., Oral Biol. 15, 731 (1970),

U.S. Patent 3,683,080 Francis, issued Aug. 8, 1972, U.S. Pat

134,969 Schmidt-Dunker, issued Jan. 16, 1979, and European Patent Application Ser. No. 189,662, published Aug. 6, 1986. Descriptions in all of these articles and patent publications are incorporated herein by reference. Some of these pharmacological activity assays are also described in more detail in the examples below.

In addition to use in the treatment or prevention of pathological conditions characterized by abnormal calcium and phosphate metabolism, the compounds of the invention have other uses. For example, the compounds of the present invention are believed to be useful as bone scanners after technetium (99) labeling. The compounds of this invention are also useful as agents for removing polyvalent metal ions, especially divalent (e.g. calcium and magnesium) and trivalent (e.g. indium) metal ions. Thus, the compounds of the present invention are useful as detergent, cleaning or water treatment components. They are also suitable as compound stabilizers, furthermore suitable for preventing the formation of tartar (i.e., stones) and / or plaque on the teeth. Finally, the compounds of the invention can also be used as herbicides that are not toxic to animals.

The quaternary nitrogen-containing phosphonate pharmaceutical compositions of the invention can be prepared according to the following non-limiting Examples 1 to 5.

The novel quaternary nitrogen-containing phosphonate compounds of the invention can be administered to humans or other mammals in a variety of ways, such as oral dosage forms and injections (intravenous, intramuscular, intraperitoneal, and subcutaneous). One of ordinary skill in the art can readily prepare many other dosage forms that comprise the novel quaternary nitrogen-containing phosphonate compounds of the invention using suitable pharmaceutical diluents listed below. For the sake of convenience, oral dosage forms are most preferred for the patient.

As used herein, the term pharmaceutical composition means a combination comprising a safe and effective amount of a phosphonate active ingredient containing a quaternary nitrogen atom or mixtures thereof, and pharmaceutically acceptable diluents (vehicles).

As used herein, the term safe and effective amount means an amount of a compound or composition that is sufficient to significantly and positively affect the symptoms and / or condition to be treated and not to cause serious side effects (s). justified benefit / risk ratio). The safe and effective amount of the active ingredient for use in the pharmaceutical compositions of this invention varies and depends on the condition being treated, the age and physical condition of the patient, the time of treatment, the nature of the concurrent treatment, the particular active ingredient used, and similar factors.

The term pharmaceutically acceptable diluents as used herein includes any physiologically inert, pharmacologically inactive material known to those skilled in the art that are compatible with the physical and chemical properties of the respective quaternary nitrogen-containing phosphonate compound as active ingredient selected for use. Pharmaceutically acceptable diluents include, but are not limited to, polymers, resins, plasticizers, fillers, lubricants, glidants, disintegrants, solvents, co-solvents, buffer systems, surfactants, preservatives, sweetening agents, flavoring agents, dyes or pigments for pharmaceutical use; and viscosity-adjusting agents.

The term oral dosage form as used herein means any pharmaceutical composition which is intended to be systemically administered into the gastrointestinal tract of an individual by the mouth of that individual. For the purposes of this invention, the form administered may be a coated or uncoated tablet, solution, suspension or capsule.

The term injection, as used herein, means any pharmaceutical composition intended to be systemically administered to a human or other mammal by administration as a solution or as an emulsion containing the active ingredient by puncturing the skin of said individual so as to provide such a solution or emulsion. into the circulatory system by intravenous, intramuscular, intraperitoneal or subcutaneous injection.

System delivery speed can be regulated by one of skill in the art by utilizing one or more of the following:

(a) the relevant active ingredient,

(b) pharmaceutically acceptable diluents (vehicles, excipients) insofar as such changes do not interfere with the activity of the particular active ingredient selected;

c) the type of diluent and the required thickness and permeability (swelling properties) of said diluents,

d) time-related conditions, namely the diluent itself and / or within the diluents,

(e) particle size of the granulated active ingredient; and

f) diluent according to pH.

In particular, the solubility, acidity, and sensitivity to hydrolysis of various phosphonate active ingredients containing a quaternary non-ring nitrogen atom, such as acid addition salts, salts formed with a carboxyl group, for example alkali metal salts, alkaline earth salts, etc. may be a guide of choice. and esters such as alkyl, aryl and aralkyl esters. A suitable pH may be formed within the oral dosage forms by adding a suitable buffer to the active ingredient according to the desired release method.

As mentioned above, pharmaceutically acceptable diluents include, but are not limited to, resins, polymers, fillers, binders, lubricants, solvents, glidants, disintegrants, co-solvents, surfactants, preservatives, sweeteners, flavoring agents. reagents, buffer systems,

J dyes or pigments for pharmaceutical use and viscosity adjusting agents. The preferred solvent is water.

Preferred flavoring agents of the invention include the following: agents described in Remington's Pharmaceutical ScienCes, 18th ed., Mack Publishing Company, 1990, p. 1288 až

1330. This reference is incorporated herein by reference. Pharmaceutical compositions suitable for use in the present invention generally contain up to 2% by weight. flavoring agents.

Dyes and pigments of the invention include those described in the Handbook of Pharmaceutical Excipients, p. 81-90, 1986, American Pharmaceutical Association & Pharmaceutical Society of England. This reference is incorporated herein by reference. The pharmaceutical compositions of the invention generally contain up to 2 wt.

dyes or pigments.

Preferred co-solvents include, but are not limited to, ethanol, glycerin, propylene glycol, and polyethylene glycols. The pharmaceutical compositions of the present invention contain up to 50 wt. co-solvents.

Preferred buffer systems include, but are not limited to, acetic, boric, carbonic, phosphoric, succinic, malic, 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 thereof. The pharmaceutical composition according to the invention contains up to 5 wt. 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 and sodium, potassium and ammonium salts of fatty acids. The pharmaceutical compositions of the present invention contain up to 2 wt. surfactants.

Preferred preservatives include, but are not limited to, alkyl esters of parahydroxybenzoic acid, o-phenylphenol, benzoic acid and its salts, boric acid and its salts, sorbic acid and its salts, chlorobutanol, benzyl alcohol, timerosal, phenylmercuracetate and nitrate, nitromersol, benzalkonium chloride, cetylpyridinium chloride, methylparaben and propylparaben. Particularly preferred are the salts of benzoic acid, cetylpyridinium chloride, methylparaben and propylparaben. The compositions of the present invention generally contain up to 2% by weight of the composition. protective means.

Preferred sweeteners include, but are not limited to, sucrose, glucose, saccharin, sorbitol, mannitol, and aspartame. Particularly preferred are sucrose and saccharin. The pharmaceutical compositions of the present invention contain up to 5 wt. sweeteners.

Preferred viscosity-adjusting agents include, but are not limited to, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, sodium alginate, carbomer, povidone, acacia, guar gum, xanthan gum, and tragacanth. Particularly preferred are methylcellulose, carbomer, xanthan gum, guar gum, povidone, sodium carboxymethylcellulose and magnesium aluminosilicate. The compositions according to the invention contain up to 5 wt. viscosity adjusting agents.

Preferred fillers include, but are not limited to, lactose, mannitol, sorbitol, calcium phosphate, dibasic calcium phosphate, milk sugar, starch, calcium sulfate, dextrin, and microcrystalline cellulose. The compositions of the present invention contain up to 75 wt. fillers.

Preferred lubricants include, but are not limited to, magnesium stearate, stearic acid, and talc. The pharmaceutical compositions of the present invention contain from 0.5 to 2 wt. lubricants.

Preferred glidants include, but are not limited to, talc and colloidal silica. The compositions of the present invention contain from 1 to 5 wt. of these agents.

Preferred disintegrants include, but are not limited to, starch, sodium glycolate, crospovidone, croscarmellose sodium and microcrystalline cellulose. The pharmaceutical compositions of the present invention contain from 4 to 15 wt. disintegrants.

Preferred binding agents include, but are not limited to, acacia, tragacanth, hydroxypropylcellulose, pregelatinized starch, gelatin, povidone, hydroxypropylmethylcellulose, methylcellulose, sugar solutions such as sucrose and sorbitol, and ethylcellulose. The compositions of the present invention contain from 1 to 10 wt. binding agents.

The compounds of the invention may comprise from 0.1 to 99.9% by weight. pharmaceutical compositions of the invention.

The compounds of the invention preferably contain from 20 to 80 wt. pharmaceutical compositions of the invention.

The pharmaceutical compositions of the present invention contain from 15 to 95% by weight of the active ingredient. % phosphonate compound containing a quaternary nitrogen atom or mixtures thereof; % of flavoring agents, up to 50 wt. % co-solvents, up to 5 wt. % of a buffer system, up to 2 wt. % surfactants, up to 2 wt. % preservatives, up to 5 wt. % sweeteners, up to 5 wt. % viscosity adjusting agents, up to 75 wt. % of fillers, 4 to 15 wt. % disintegrants and 1 to 10 wt. binding agents.

Suitable pharmaceutical formulations are described in Examples 9-11. A skilled artisan can vary non-limiting examples to obtain a wide variety of pharmaceutical formulations.

The choice of pharmaceutical diluent to be used together with the quaternary nitrogen-containing phosphonate compounds in the compositions of the invention is essentially determined by the manner in which the phosphonate is administered. When the compound is injected, the preferred pharmaceutical carrier is a sterile physiological saline solution, the pH of which is adjusted to 7.4. A preferred route of administration of the phosphonate of the invention is oral administration. Thus, a preferred unit dose is tablets, capsules and the like, containing from 0.1 mg P to 600 mg P in the phosphonic acid compounds described herein. Pharmaceutical carriers suitable for the preparation of individual dosage forms for oral administration are well known to those skilled in the art. Their selection depends on secondary considerations, such as taste, price and stability of the packaging, which are not critical for the purposes of the present invention and which can be determined without difficulty by a skilled person.

The term mg P as used herein means the weight of the phosphorus atoms present in a given amount of a phosphonic acid compound. This unit is used to standardize the amount of phosphonic acid compounds used in the pharmaceutical compositions and methods of the invention. For example, N- (4-hydroxy-4,4-diphosphonobutyl) -N, N-dimethyl-N- (2-mercaptoethyl) ammonium chloride has a molecular weight of 373.5 g / mol, of which 17% (62 g). (mol) is the two phosphorus atoms present in the molecule. Thus, one mg of this compound corresponds to 0.17 mg of P. In preparing a pharmaceutical composition containing 0.17 mg of P of the compound, the composition should therefore contain 1 mg of the compound. At a dose of 0.17 mg P / kg of this compound, a 50 kg patient should be administered a dose of 50 mg of this compound.

The pharmaceutically acceptable diluent used in conjunction with the diphosphonates of the present invention is used at a concentration sufficient to achieve a practical size-to-dose relationship. Pharmaceutically acceptable carriers may comprise in total from 0.1 to 99.9% by weight. % by weight of the composition, more preferably from 20 to 80 wt.

divided

Another object of the present invention are methods of treating or preventing diseases characterized by abnormal calcium and phosphate metabolism. Such methods include administering a safe and effective amount of a phosphonate compound to a human or lower mammal in need of such treatment.

Oral administration is the preferred route of administration. However, other modes of administration are also possible, for example, dermatomucous (e.g., dermal, rectal, etc.) and parenteral (e.g., subcutaneous injection, intramuscular injection, intra-articular injection, intravenous injection, and the like). This also includes an inhalation route of administration. Thus, specific routes of administration include, without limitation, oral, transdermal, mucosal, sublingual, intramuscular, intravenous, intraperitoneal and subcutaneous administration, as well as topical administration.

The term abnormal calcium and phosphate metabolism as used herein means 1) conditions characterized by anomalous mobilization of calcium and phosphate leading to total or specific bone loss or excessively high levels of calcium and phosphate in body fluids, and 2) conditions that cause or result from anomalous deposition of calcium and phosphate in the body. The first category includes, but is not limited to, osteoporosis, Paget's disease, hyperthyroidism, malignancy hypercalcemia, heterotopic ossification, and osteolytic bone metastasis. The second category includes, but is not limited to, progressive ossifying myositis, all types of calcinosis, and conditions such as arthritis, osteoarthritis, neuritis, bursitis, tendonitis and other inflammatory conditions in which calcium and phosphate deposition occurs in tissues.

The term rheumatoid arthritis, as used herein, means a chronic systemic and articular inflammatory disorder of unknown origin in which the articular cartilage, ligaments, tendons and bones are destroyed.

The term osteoarthritis, as used herein, means a non-inflammatory disorder of the movable joints in which articular cartilage disorder and abrasion occur and a new bone is formed on the surface of the joint.

As used herein, a person at risk and a person in need of such treatment means any human or lower animal who is at great risk of abnormal calcium and phosphate metabolism if not treated and who is diagnosed to be affected by this abnormal metabolism. calcium and phosphate. For example, postmenopausal women, people who have been treated with steroids, people who use anticonvulsant drugs, people with Paget's disease, hyperparathyroidism and grain, hypercalcaemia of malignancy or osteolytic bone metastases, people who are diagnosed with one or more different forms of osteoporosis, belong to a population known to have a significantly higher than average chance of developing osteoporosis, such as post-menopausal women, men over 55 and those receiving medications known to have osteoporosis as a side effect, persons diagnosed with progressive ossifying myositis, or all types of calcinosis, and those afflicted with arthritis, osteoarthritis, neuritis, bursitis, tendonitis, and other inflammatory conditions in which calcium and phosphate are deposited in the tissues.

As used herein, the term safe and effective amount means an amount of a compound or composition of the invention that is high enough to significantly positively control the condition to be treated, but which is low enough to allow for serious side effects (at an acceptable benefit / risk ratio) to the extent assessed by the physician. The safe and effective amount of the phosphonate compounds of the invention varies and depends on the condition to be treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of treatment, the nature of the concurrent treatment, the specific treatment employed. phosphonate, starting at 28

;! A variety of pharmaceutically acceptable diluents used and from about 1 to about 2% of the total amount of the drug used. good factors. However, the individual doses of 3a range from

0.01 mg P to 3500 mg P or from 0.0002 to 70 mg P / kg body weight (based on 50 kg). Preferred doses are

The doses are from 1 mg P to 600 mg P or from 0.02 to 12 mg P / kg body weight

Hmotnosti ij weight (based on 50 kg), and four single doses per day may be administered. Daily doses higher than 500 mg P / kg

I! they are not desirable because of side effects. However, in the case of oral dosing, higher dosages are required as they are limited in absorption by oral administration.

ii!

The following examples further describe and demonstrate preferred embodiments within the scope of the invention. The examples are given here for illustration only and are not to be construed as limiting the present invention, since multiple combinations thereof are possible without departing from the spirit and scope of the invention.

¹ '1 tíl. EXAMPLES i

Example 1 j Synthesis of N- (4-hydroxy-4,4-diphosphonobutyl) -N, N, N-trimethylammonium | Didu

CH, _CH3-n ^^ T Γ ^3-OH, for ₃ h ₂

I. Synthesis of 4- (N, N-dimethylamino) -1-hydroxybutylidene] bis [phosphonic acid]

The solution containing 4- (N, N-dimethylamino) butanoic acid (2.9 mmol), phosphorus trichloride (2.0 mmol) and diethyl phosphite (12 mmol) is stirred for 30 minutes at room temperature, then

I.

Ιι

I

The reaction mixture was then cooled to room temperature and concentrated hydrochloric acid was added. (50 ml). The reaction mixture was refluxed for an additional 24 hours, cooled to room temperature and filtered through celite. The filtrate is concentrated in vacuo, the crude product is triturated with ethanol, filtered and dried under vacuum.

l!

II. Synthesis of N- (4-Hydroxy-4,4-diphosphonobutyl) -N, N, N-trimethylaminium iodide 11 'Bisphosphonic acid (0.30 mmol) was dissolved in water (10 ml) and ethanol (15 ml). ml) and adjusted to pH 7.0 by addition of 1N NaOH. To this solution was added methyl iodide (1.50 mmol) and the mixture was heated under reflux for 24 hours, then cooled and concentrated under reduced pressure. The solid residue was dissolved in a minimum amount of water. The quaternized product is precipitated by the addition of isopropanol. The product was filtered off, washed with acetone and dried in vacuo.

Example 2

Synthesis of N- (3-hydroxy-3,3-diphosphonopropyl) -N, N-dimethyl-N-pentylammonium iodide

CH, (CH, CH, -

CH, PO, H,

I. Synthesis of [3- (N, N-dimethylamino) propylidene] bis (phosphonic acid)

In essentially the same manner as described in Part I of Example 1, 3- (N, N-dimethylamino) propanoic acid is converted to 13- (N, N-dimethylamino) propylidene] bis [phosphonic acid].

II. Synthesis of N- (3-hydroxy-3,3-diphosphonopropyl) -N, N-dimethyl-N-pentylammonium iodide

The bisphosphonic acid (0.50 mmol) was dissolved in water (15 mL) and acetonitrile (20 mL). The pH was adjusted to 7.0 by addition of 1N NaOH, pentyl iodide (2.50 mmol) was added and the reaction mixture was heated under reflux for 22 hours. The mixture was then concentrated under reduced pressure. The solid residue is triturated with acetone and the product is recrystallized from water and ethanol.

Example 3 * Synthesis of N- (3-hydroxy-3,3-diphosphonopropyl) -N, N, N-trimethylammonium iodide

CH ₃

In essentially the same manner as described in Part II of Example 1, [3- (N, N-dimethylamino) propylidene] 3bis [phosphonic acid], prepared according to Part I of Example 2, is converted to N- (3- hydroxy-3,3-diphosphonopropyl) -N, N, N-trimethylammonium iodide.

'Example 4

Synthesis of N- (2-acetylthioethyl) -N- (4-hydroxy-4,4-diphosphonobutyl) -N, N-dimethylammonium bromide

(4- (N, N-dimethylamino) -1-hydroxybutylidene] bis [phosphonic acid] (0.75 mmol), prepared according to Part I above

I!

Example 1 was dissolved in water (50 ml) and acetonitrile (35 ml).

j i! To this solution was added S-acetyl-2-bromomethanediol (3.75 mmol) and the reaction mixture was heated at reflux for 12 hours.

ii. under reduced pressure, the solid residue is triturated with acetone.

h

The quaternized product was recrystallized from water and ethanol.

Ii j; -.

h Example 5

I!

j

Synthesis of N- (2-acetylthioethyl) -N- (3-hydroxy-3,3-diphosphonopropyl) -N) N-methyl-pentylamóniumbromidu and CH, |, CH, C (O) p ^ ^Br

I. Synthesis of [3- (N-methyl-N-pentylamino) propylidene] bis [phosphonic acid].

In essentially the same manner as described in Part I, Example 1, 3- (N-methyl-N-pentylamino) propanoic acid is converted to [3- (N-methyl-N-pentylamino) propylidene] bis [phosphonic acid] .

• II. Synthesis of N- (2-acetylthioethyl) -N- (3-hydroxy-3,3-diphosphonopropyl) -N-methyl-N-pentylammonium bromide

Λ ·

In essentially the same manner as described in Example 4, [3- (N-methyl-N-pentylamino) propylidene] bis (phosphonic acid) is converted to Nr (2-acetylthioethyl) -N- (3-hydroxy-3,3) -difosfonopropy1) -N-methyl-N-pentylamóniumbromld.

Example 6

Schenkov model ίί | l

The compounds are evaluated for the in vivo inhibition of bone resorption and for the inhibition of mineralization in an animal model system known in the field of bone metabolism as the Schenk model. The general principles of this model are described by Shinod et al., Calcif. Tissue Int. 35, 87 (1983) and Schenkom et al., Calcif. Tissue Res. 11, 196 (1973), which are incorporated herein by reference.

Materials and methods:

ίι

The animal days old male Sprague Dawley rats (30 g) (Charles River Breeding Laboratories) before weaning are transferred to plastic cages with their mothers. At 19 days of age, rats receiving Rat Chow and water ad libitum are randomized into a control group and a test group of 7 animals per group. On day 1 and again on day 7, all animals receive an intraperitoneal (IP) injection of Calcein [1% (w / w) solution in 0.9% (w / w) saline, dosed 0.2 ml / 100 g body weight]. On day 4, all animals are given an IP injection of tetracycline hydrochloride [1% (w / w) solution in 0.9% (w / w) saline, dosed 0.2 ml / 100 g body weight]. These compounds denote active mineralizing bones and cartilage.

Dosing solutions and dosing procedure

All solutions are prepared for subcutaneous injection in 0.9% (w / w) normal saline, pH adjusted to 7.4 with NaOH and / or HCl. When calculating the dose of the solution, the weight of the powder (based on molecular weight, hydration) of the active material in mg / kg (body weight), which corresponds to mg P / kg, is taken into account. The concentrations are based on a dosage of 0.2 ml / 100 g body weight. Typically, all compounds are administered in amounts of 0.01, 0.1, 1.0 and 10.0 mg P / kg / day for 7 days. Compounds that exhibit activity at 0.1 mg P / kg / day are then tested with logarithmic losses of up to 0.001 mg P / kg / day. Dosage adjustment based on body weight change is performed daily.

I ί

T

I

I

I h

j!

íl h

! i

I

Necropsy, tissue processing and histomorphometry

On day 8 from the start of dosing, all animals are sacrificed by IP overdose with pentabarbitol. The tibia is removed and placed in 70% (w / w) ethyl alcohol. One tibia is dehydrated in ethanolic solution and fixed in methyl methacrylate as described by Schenk: Methods of Calcified Tissue Preparation (GR Dickson, eds., Elsevier Science Publ., The Netherlands, 1984), which is incorporated herein by reference. . The tibia is slit longitudinally through the metaphyseal surface. Samples are stained on the surface with silver nitrate and mounted on a microscope slide for evaluation by a Quantiment Image Analyzer (Camhridge Instruments, Inc.) under both fluorescent and ultraviolet illumination. The metaphyseal trabecular bone content is measured in the mode between the fluorescent label and the growth plate and expressed as a percentage of the total area (bone + bone marrow). The width of the epiphysial growth plate is obtained as the mean of 10 equal spatial measurements of the sections.

Statistical evaluation of the data is performed by parameter and non-parameter variation analysis by Wilcoxon summation test. This establishes a statistically significant effect when compared to control animals. The Schenk model provides data for in vivo inhibition of bone resorption by compounds.

Example 7

Adjuvant arthritis model

There are several animal models of arthritis, including adjuvant-induced arthritis using Mycobacterium butyricum. In many cases, this model mimics rheumatoid arthritis in humans (joint swelling associated with invasion of cells and pannus of the joint space, bone resorption and release of chemotaxic factors and lysosomal components into the joint space [Pearson C., Wood F .: Arth. Rheum. 2, 440 (1959), Blackman A., Burns JW, Framer JB, Radziwonik H., Westwick J.: Agents and

Action 7, 145 (1977)]. Numerous prophylactic and therapeutic studies have suggested the potential use of anti-inflammatory drugs [Winter C.A., Nuss G.W .: Arth. Rheum. 9, 394 (1966), Winder, C.V., Lembke, L.A., Stephens, M.D .: Arth. Rheum. 12, 472 (1969)] and arthritis diphosphonates [Francis M.D., Flora L., King W.R .: Calcif. Tissue Res. 9, 109 (1972), Flora L., Arth. Rheum. 22, 340 (1979)].

by subcutaneous (SC) injection in mineral oil on day 0

Adjuvant arthritis is severe cellulitis and synovitis induced in male rats (either Sprague Dawley or Lewis) of JediMycobacterium butyricum (8 mg / ml). Compounds are administered once daily either orally (PO) or parenterally (SC) and can be tested either prophylactic (from day 0) or therapeutic (from day 9, 10 or 14) regimen. Anti-arthritis efficacy can be measured as paw volume reduction, body weight loss, bone loss or new bone formation compared to an arthritic control treated with saline. Treatment can be stopped and the flare response (rapid increase in inflammation) is examined, indicating the compound's ability to maintain efficacy.

Materials and methods

A. Animals

Male Lewis rats (LEW) were used as animals. Upon delivery, rats are randomly distributed by computer-controlled random numbering and placed in individual wire suspension cages. Food and water are administered ad libitum throughout the experiment. Routine care and maintenance of animals is carried out according to state and federal regulations. Each rat is identified by a number located on the front wall of the cage and on the tail of the rat.

B. Experimental conditions

On the first day, the body weight (BW) and the volume of the hind paw (PV) (measured by mercury pressure printing connected to a computer) of all rats are recorded. On day 0, arthritis is induced using MFA [Mycobacterium butyricum (Mb), 4.4 mg / kg in oil].

j!

as follows: the rats are anesthetized and, under septic conditions, a single SC injection of MFA is given in the tail. Then, paw volumes and body weight are measured on various days (usually twice a week). For the prophylactic experiment, rats are randomized into groups of 8 to 10 rats and continued daily until the end of the experiment, rats are randomized into groups of 8 to 10 rats according to their PV on day 10. Dosing starts on day 10 and continues daily until the end of the experiment. In both experiments, animals are placed in deep-day cages either on day 10 or earlier.

Treatment begins at day 0 for the therapeutic trial

Dosing solutions

For compounds that are not likely to undergo oxidation

The drugs are weighed on a calibrated balance and mixed with distilled water in a graduated flask. The pH of the solution was adjusted to 7.4 with NaOH. The solution is then filtered through a 0.45 µm sterile filter into a sterile reservoir. When not in use, the stock solution is kept in the freezer.

For compounds that are likely to undergo oxidation

The drugs are weighed on a calibrated balance and then mixed with deoxygenated water in a graduated flask. The stock solution is filtered through a 0.45 µm sterile filter into a sterile reservoir. If the stock solution is not used, it is kept in the freezer.

Depending on the daily amount needed, the appropriate amount of solution is taken from the stock solution, placed in a small dosing beaker and the pH adjusted to 7.4 according to a predetermined calculation. If necessary, the treated solution may be diluted (deoxygenated water).

The calculation of the amount of drug is based on the molecular weight, the purity of the compound, the amount in mg / kg (body weight) and the desired final concentration in mg P / kg. A volume of 0.1 ml / 100 g of body weight of the rat is administered subcutaneously as an injection into the animal's guinea-pig fold, alternately on both sides each day,

Or 1 ml / 200 g of body weight by oral dosing

I! Stainless steel tube. Body weight adjustment is performed weekly.

! i

I, Radiography, necropsy and tissue isolation i

i i; At the end of the experiment, each rat is sacrificed intraperitoneally (IP)

ί. 1 ml SocombCU. Immediately a radiograph of the whole body is made by the unit

Ii, Torrox 120D x-rays at MA = 5, ISUP = 50, and 60 seconds per Kodak medical non-projecting film. The hind paws are removed from each rat

They are placed in 10% buffered formalin together with a piece of liver, kidney, spleen and thymus. The Tibiotarsal joints are decalcified in 4% (w / w) EDTA, pH 7.4, and routinely processed into H + E dye paraffin blocks. Parts of organs are processed in the same way.

A light microscope evaluates histologically qualitatively lesions of bone and soft tissue. Bone resorption (BR) radiograms are obtained at 6 anatomical sites of the trabecular bone in each hindpaw and at 4 sites in each ankle according to a scale of 0 to 3, giving a total value of 0 to 60 for all four paws. In the formation of a new bone (RNB), radiograms are scored 0 to 3 for the lateral and medical femur surfaces, and then 0 to 2 for all other areas listed above, giving a total value of 0 to 44.

C. Statistical analysis

Paw volume, bone resorption and new bone formation data are analyzed by student's t-test and one-way variation analysis (SAS). Differences are considered significant at p 0.05 or less.

This model provides in vivo data on the efficacy of anti-arthritic compounds in the values of paw edema reduction, bone loss and new bone formation as compared to saline treated arthritis animals.

Example 8

The capsules are prepared as follows:

active ingredient: mg per capsule N- (3-hydroxy-3,3-diphosphonopropyl) -N, N, N- trimethylammonium 350.0 Thinners: lactose 90.0 microcrystalline cellulose 60.0 magnesium stearate 1.0

Capsules having the above composition are prepared by known methods as follows. The active ingredient is mixed with microcrystalline cellulose in a rotating paddle mixer for approximately 10 minutes. The resulting mixture was passed through a hammer mill with a 0.177 mm mesh screen. This mixture is transferred back to the two-blade mixer along with the lactose and mixed for approximately 15 minutes. Magnesium stearate was added and the mixture was stirred for an additional 5 minutes. The resulting mixture is then compressed by a plunger capsule filler. The active ingredient in the above capsules may be exchanged for any compound prepared according to Examples 1-5.

Example 9

Tablets of the following composition are prepared:

active ingredient: mg per tablet N- (4-hydroxy-4,4-diphosphonobutyl) -N, N-dimethyl- N- (2-mercaptoethyl) ammonium chloride 700.0

Thinners:

lactose (spray-dried) 200.0 starch (1500) 100.0 magnesium stearate 25.0

Tablets are prepared in the above composition by known methods as follows. The active ingredient is ground in a ball mill for about 30 minutes. The milled active ingredient is then mixed for about 20 minutes in a two-blade mixer with spray-dried lactose. Starch is added to the mixture and the mixture is stirred for an additional 15 minutes. Tablets are compressed from this mixture on a standard tablet press. The active ingredient in these tablets can be exchanged with any of the compounds prepared according to Examples 1-5.

Example 10

Injectable solutions are prepared by known methods from 10.0 ml of physiological saline and N- (4-hydroxy-4,4-diphosphonobutyl) -N, N, N-trimethylammonium chloride, the pH is adjusted to 7.4.

One injection once daily for 4 days results in a marked improvement in the rheumatoid arthritis of patients weighing about 70 kg. The active ingredient in the above injectable solution may be exchanged for any compound prepared according to Examples 1 to 5.

Example 11

A Caucasian man weighing about 92 kg, 72 years old, suffers from mild to severe pain and occasional swelling of his right knee. around

Íl r

j after one year of ever-increasing unfavorable condition he also visited a doctor who found a clinical diagnosis of osteoarthritis of

J knee, which was later confirmed by X-ray diagnosis.

s

After treatment with various NSAIDs, including aspirin, hay and ketoprofen, symptoms worsened and seemed to be

i! degenerates. He returned to his doctor who prescribed him pulled i! squadrons, prepared according to Example 9, taken twice a day

I, í! two hours before or after a meal within three months.

Clinical signs of pain and swelling, especially during prolonged walk, i. significantly improved after 3 months of treatment. At the end of the three-day treatment at two tablets per day, treatment is continued at half the originally prescribed dose (i.e., one capsule per day, prepared according to Example 8) for an indefinite period of time.

Example 12

A black woman, weighing about 65 kg, 55 years old, suffers from swelling and deformation of the finger joints on both hands, with a partial loss of hand power and / or skill. According to visual examination, X-ray examination and various appropriate clinical trials, her diagnosis was established as rheumatoid arthritis.

After an unsuccessful analgesic and anti-inflammatory treatment, her doctor prescribed the tablets, which were prepared according to Example 9, taken twice a day two hours before or after a meal for 4 months. After one month of treatment, the symptoms of joint swelling * improved markedly, and her fingers' mobility was also greatly improved. Treatment was continued for another four months, after which her doctor prescribed the same dose for another two months.

Example 13

A 12-year-old Spanish woman, weighing about 37 kg, came to her doctor with idiopathic juvenile rheumatoid arthritis. Symptoms included inflammation of multiple joints, complicated by heat and bo40 lust at pressure, indicating rapid and pathological degeneration of joint function. Her physician referred her to a rheumatologist who immediately prescribed her aggressive IV treatment by administering the solution prepared according to Example 10 for three days with a dose of 1 injection a day for two hours. At the end of IV treatment, her doctor prescribed tablets prepared according to Example 9 for a period of 2 months, during which the patient improved mobility and reduced pain. For the next two months her doctor reduced her dose to 3/4 of the original oral dose, i. 3 tablets for two days, two tablets one day, one tablet the next day. In horses and in this treatment, the dose was again reduced to 1/4 of the original dose by administering the tablets prepared according to Example 9, 1 tablet per day for an additional 4 months.

Example 14

A 60-year-old Caucasian woman, weighing 62 kg, suffered from severe spinal pain. Her physician and radiologist found a crushed vertebral L1 fracture, probably due to osteoporotic bone loss. She was prescribed the use of 700 mg tablets prepared according to Example 9 once daily for 3 months. This 700 mg tablet is taken either two hours before or two hours after any meal. After 3 months, the dose was reduced to the 350 mg capsule prepared according to Example 8 and taken once daily for 3 months. Her doctor then prescribed only a maintenance dose of the 100 mg capsule prepared according to Example 8, which she took once daily for 6 months. After 6 months of this maintenance treatment, the patient did not experience any back pain. The following X-ray examination found no further fractures.

Example 15

A 75-year-old Oriental woman, weighing 53 kg, broke her hip in a fall. She was hospitalized and diagnosed as osteoporosis. She has been prescribed treatment with calcitonin injections, which are very painful. The patient was unable to adapt to these effects. Therefore, the doctor changed her treatment for oral administration of phosphonates. The patient took the 700 mg tablet prepared according to Example 9 twice a day for one month. Then, she took the 700 mg tablet once daily for two months, and for the next 3 months she took the 100 mg capsule prepared according to Example 8. photometry).

Example 16 * An 85-year-old American man, weighing 65 kg, told his doctor that he had severe back pain. Smaller vertebral collapse resulting from significant bone loss due to osteoporosis was detected by X-ray. This patient was prescribed a 700 mg tablet and a 350 mg capsule to be taken daily for eight consecutive hours. After two months, the dose was reduced to 350 mg capsule once daily for 2 months. Another fracture was detected by X-ray. The patient was then switched to a maintenance regimen with a 100 mg capsule prepared according to Example 8 and administered once daily for 6 months. At the end of treatment, there was no significant and marked decrease in bone density.

Claims (8)

PATENT CLAIMS 1. Quaternary nitrogen-containing phosphonate compounds suitable for the treatment or prevention of abnormal calcium and phosphate metabolism disorders and their pharmaceutically acceptable salts and esters of the general formula I in which m is up to 10, n is 1 to 10 and the sum of m + n is number 1 to 10 R ¹ represents a group selected from the group consisting of: -SR ⁸ and -R ⁹ SR ⁸ , a hydrogen atom, a substituted or unsubstituted C 1 -C 8 alkyl group, -OR ³ , -COOR ³ , - OOCR ³ , -NR ³ 2, -N (R ³ ) C (O) R ³ , -C (O) N (R ³ ) 2, halogen, -C (O) R ³ , nitro, hydroxyl groups a substituted or unsubstituted saturated monocyclic or polycyclic heterocyclic group, a substituted or unsubstituted saturated monocyclic or polycyclic carbocyclic group, preferably a substituted or unsubstituted saturated monocyclic or polycyclic heterocyclic group, a substituted or unsubstituted saturated monocyclic group. or a polycyclic carbocyclic group, nothing, a hydrogen atom, -SR ⁸ and -R ⁹ SR ⁸ , R ⁵ represents a group selected from the group consisting of -SR ⁸ and -R ⁹ SR ⁸ , a hydrogen atom, a substituted or unsubstituted C 1 -C 8 alkyl group, -OR ³ , -COOR ³ , -OOCR ³ -NR ³ 2, -N (R ³ ) C (O) R ³ ; -C (O) N (R ³ ) 2, halogen, -C (O) R ³ , nitro; a hydroxyl group substituted or unsubstituted saturated monocyclic or polycyclic heterocyclic groups, substituted or unsubstituted saturated mono-cyclic groups; cyclic or polycyclic carbocyclic group, substituted or unsubstituted unsaturated monocyclic or polycyclic heterocyclic group substituted or Unsubstituted unsaturated monocyclic or polycyclic I! i! carbocyclic groups and combinations thereof, preferably selected from the group consisting of -SR ⁶ and -R ⁹ SR ⁶ , a hydrogen atom, substituted or unsubstituted; an alkyl group having 1 to 8 carbon atoms; or a unsubstituted saturated monocyclic or polycyclic heterocyclic group and a substituted or unsubstituted saturated monocyclic or polycyclic carbocyclic group; R ² represents a group selected from the group consisting of substituted or unsubstituted monocyclic or polycyclic heterocyclic group; unsubstituted alkyl group; C 1 -C 35 pins, unsubstituted or substituted phenyl, benzyl or -R ⁹ SR ⁶ , preferably from substituted or unsubstituted α1; a (C 1 -C 35) -cyl group and -R ⁹ SR ⁶ , R ³ is a group selected from the group consisting of hydrogen, unsubstituted or substituted C 1 -C 8 alkyl and -R ⁹ SR ⁶ , i.e. preferably represents a hydrogen atom; R ⁶ represents a group selected from the group consisting of a hydrogen atom, a -C (O) R ⁷ , -C (S) R ⁷ group; -C (O) N (R ⁷ ) 2, -C (O) OR ⁷ , -C (S) N (R ⁷ ) 2, and -C (S) OR ⁷ , wherein R ⁷ is hydrogen, substituted or unsubstituted alkyl i j of 1 to 8 carbon atoms, preferably from H i -C (O) R ⁷ and -C (S) R ^7, R is a group which is selected from the group pozostávaj júcej from -PO3H2, and -P (O) (OH) ^R4, wherein ^R4 is or, alkyl group having 1 to 3 carbon atoms, preferably from ^s? -PO 3 H 2 and -P (O) (OH) R ⁴ ; R ⁹ represents a substituted or unsubstituted alkyl group having 1 to 8 carbon atoms and R ⁸ represents a group selected from the group consisting of hydrogen, halogen, -SR ⁸ and -R ⁹ SR ⁶ , an amino group, a hydroxyl group and a substituted or unsubstituted C 1 -C 8 alkyl group, preferably selected from: hydrogen atom and -SR ⁶ group. A quaternary nitrogen-containing phosphonate compound of formula I according to claim 1, wherein R ¹ represents a substituted or unsubstituted saturated monocyclic or polycyclic heterocyclic group or a substituted or unsubstituted saturated monocyclic or polycyclic carbocyclic group. A quaternary nitrogen-containing phosphonate compound of the formula I as claimed in claim 1, wherein R ⁵ is a group selected from the group consisting of hydrogen, -SR ⁶ and -R ⁹ SR ⁶ , substituted or unsubstituted alkyl with C 1 to C 8 and substituted or unsubstituted saturated monocyclic or polycyclic heterocyclic groups. A quaternary nitrogen-containing phosphonate compound of the formula I according to claim 1, wherein R ¹ is a group selected from the group consisting of nothing, t -SR ⁶ and -R ⁹ SR ⁶ and hydrogen. * A quaternary nitrogen-containing phosphonate compound of formula I according to claim 1, wherein R ⁵ is a group selected from the group consisting of -SR ⁶ and -R ⁹ SR ⁶ , a hydrogen atom and a substituted or unsubstituted C 1-6 alkyl group. up to 8 carbon atoms. A quaternary nitrogen-containing phosphonate compound of the formula I according to claim 1, wherein R ⁵ represents a substituted or unsubstituted C 1 -C 8 alkyl group. A phosphonate compound comprising the general formula I according to claim 1, -R ⁹ SR ⁶ . a quaternary nitrogen atom of all of which R ⁵ represents a group A quaternary nitrogen-containing phosphonate compound of the formula I according to claim 1, wherein R ⁵ represents a substituted or unsubstituted, saturated or unsaturated heterocyclic group. A pharmaceutical composition for the treatment of conditions associated with abnormal calcium and phosphate metabolism comprising a safe and effective amount of a phosphonate compound according to claim 1 and a pharmaceutically acceptable diluent. Use of a compound according to claim 1 for the manufacture of a medicament for use in treating or preventing pathological conditions associated with abnormal calcium and phosphate metabolism of humans or other animals in need of such treatment, characterized in that it is administered safely to such humans or other animals. and an effective amount of a compound of claim 1.