CZ296694A3 - Phosphonate compounds containing quaternary nitrogen atom and their use in a pharmaceutical preparation 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 present 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 present invention relates to a method of treating or preventing osteoporosis and arthritis, particularly rheumatoid arthritis and osteoarthritis using a compound or pharmaceutical composition. 'pea'l'e' * 'dhO'd' invented '-' --------------------------——------- --------------------—

Numerous pathological conditions that may affect warm-blooded animals include abnormal calcium and phosphate metabolism. These states can be divided into two broad categories.

Conditions characterized by anomalous mobilization of 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 anoral calcium and phosphate deposition in the body, such as rheumatoid arthritis and osteoarthritis. These conditions are sometimes referred to herein as pathological calcifications.

The first category includes most of the common disorders of bone metabolism, osteoporosis; osteoporosis is a condition in which hard bone tissue is lost disproportionately to the development of new hard tissue. Osteoporosis can usually be defined as a reduction in the amount of bone or as an atrophy of skeletal tissue. Bone marrow and bone holes are enlarged, fiber bonding decreases and compact bone becomes brittle. Osteoporosis can be subclassified as menopausal, senile, drug-induced (eg, adrenocorticoids that may occur with steroid therapy), caused by disease (arthritic and tumor), etc. However, the symptoms are essentially the same.

There are generally two types of osteoporosis: primary and secondary. Secondary osteoporosis is the result of a disease process or agent. However, approximately 90% of all osteoporosis cases are primary osteoporosis. Such primary osteoporosis includes postmenopausal osteoporosis, age-associated osteoporosis, disuse osteoporosis from (affecting a majority of _individuals, the age of 70-80 years), and idiopathic osteoporosis, which affects j'e '' men and ^- women ¹ ~ s tředním 'age —A-younger-man- and women —————

In some individuals with osteoporosis, bone loss is large enough to cause mechanical damage to the bone structure. Bone fractures often occur, for example, in the hip and spine of women suffering from postmenopausal osteoporosis. This can also lead to kyphosis (abnormally increased distortion of the thoracic spine).

The bone loss mechanism of osteoporosis is believed to be due to an imbalance in the process of bone remodeling. Bone remodeling occurs during life, when the skeleton is renewed and bone strength is maintained. This process erodes and replenishes discrete spots on the bone surface by an organized group of cells called base multicellular units or BMUs. BMUs primarily consist of osteoclasts and osteoblasts and their cellular precursors. During the remodeling cycle, the bone is resorbed at the site activated by the BMU by the osteoclast to form a resorptive cavity. This cavity is then replenished with osteoblast bone.

•. - ... i; n ^:

- · 3

The remodeling cycle in adults normally results in small deficits / bones due to incomplete refilling of the resorption cavity; Even .

Thus, ⁷ healthy healthy adults occur with age of bone loss.

. However, in .osteoporosý exists to increase the number of BMUs * které'jsou AK- ^one photoactivated. This increased activation accelerates bone remodeling, resulting in abnormally high bone loss. ·., · ''; _t '' i ';

· '' Ř ..? T -. 1: '' '71' t ... · 'And' 4. ',,. <'. ·· ..',,. '. . . )

'Etiology.not fully understood';'there are many ri- ¹ ? *'. . . -i '. '. . ..... .. the risk factors (whichever) are assumed. It is a sto-geosy. These include low body weight, low calcium intake, physical - no activity - and lack of estrogen. /.

- i -,. ·.-v ·. '' ·. · * £ ·, ·? Most of the time, treatment of osteoporosis is mostly / primarily based on the administration of calcium and estrogen. > - -. .-. Additional categories that include conditions for the appearance of anomalous calcium and phosphate deposition include progressive myositis ossifying, general calcinosis and such diseases as arthritis (including, for example, rheumatoid arthritis and osteoarthritis), neuritis, bursitis, tendonitis and other conditions for which they have tissue in which they store calcium.

osteoporosis may cause loss of bone in rheumatoid arthritis and osteoarthritis. Rheumatoid arthritis is a chronic, systemic and articular inflammatory disease characterized by weakened joint capsules and ligaments with subsequent destruction of cartilage, ligaments, tendons and bones, decreased viscosity of the synovial fluid and other changes in the fluid. Symptoms of rheumatoid arthritis include systemic, weakness, fatigue, localized pain, stiffness and weakness, and swelling and deformation of the body joints. Rheumatoid arthritis is most common in women in the fourth to. the sixth decade of life. ,,

The pathogenesis of rheumatoid arthritis, which leads to joint destruction, is characterized by an angular phase that includes microcirculation and synoyial cells that allow plasma proteins of α-cell elements to enter into the joint and 2) a chronic inflammatory phase occurring in the sub-synovium and subchondral bone, characterized by pannus formation (granular tissue) in the joint space, bone erosion, and cartilage destruction. Pannus can form adhesions and scar tissue that cause joint deformation characteristic of rheumatoid arthritis.

The etiology of rheumatoid arthritis remains shrouded. It is contemplating infectious agents such as bacteria and viruses. A common hypothesis is that the causative agent of rheumatoid arthritis is Epstein ^ Barr virus (EBV).

and

Conventional treatment of rheumatoid arthritis consists mainly in the elimination of symptoms by the administration of non-steroidal anti-inflammatory drugs. Anti-inflammatory non-steroidal treatment. the drug is particularly effective in the early stages of rheumatoid arthritis. Joint inflammation is unlikely to occur if the disease has existed for more than one year. With limited success were used: gold, methotrexate-immunosuppressin-i-in-idia- and cort-i-costero-i-d-y-.-

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

Treatment of common symptoms of osteoarthritis includes administration of analgesic agents, anti-inflammatory agents, steroids, and physical therapy.

Various phosphonic acid derivatives have been proposed for use in treating and preventing diseases involving abnormal calcium and phosphate metabolism. For example, numerous references, KTEI Ré ^are: incorporated by reference, describe compositions which comprise from polyphosphonates, _in particular diphosphonates such as ethane-1 ^{*.-Hydroxy-diphosphonic;} acid (EHDP), and their use in inhibiting anomalous deposition in the mobilization of calcium and phosphate. in animal tissue: 'U.S. Patent 3,683,080, issued Aug. 8, 1972, U.S. Patent 4,230,700, issued Oct. 28, 1980, (both Francis), and U.S. Patent 4,868T164, (Ebethinaj; issued .19 - September 1989?

. Numerous, .other .links. a description of her; difosf.onové acid .substituovanéV ^Ì \ 'the heterocyclic; li-ckou radical, which matches the "useful'Iéčéňí-osteo-s.

porosis and / or arthritis and which are incorporated herein by reference: U.S. Pat. U.S. Patent No. 4,868,144. Ebetina et al., Issued December 10, 1989, U.S. Pat. , issued; 19 / Sep. 1989, “USAT Patent5TO4 / 863Benedicta; et al. / issued l4. April 1992, U.S. Pat. No. 4,267 / 108 Bluma et al., Issued May 12, 1981, USA. U.S. Patent 4,746,654 to Brelier, et al., issued May 24, 19.8.8; U.S. Patent 4,876,247 Barbier et al., issued Oct. 24, 1989, European Patent Application No. 100,718 to Brelier et al., Pub. filed February 15, 1984, European Patent Application Publication (Boěhringer Mannhein GmbH) No. 170 228, published February 5, 1986, European Patent Application (Application No. 186'405 'to Benedict and Perkins, published Jul. 2, 1986, European Patent Application no. 298,553 Ebetino, published January 11, 1989, U.S. Patent 4,754,993 Bosieseua al., issued November 15, 1988, U.S. Patent 4,939,130-Jaeggiho et al., issued July 3 ^- 1990, U.S. Patent 4 971,958 Bosiése et al., Issued November 20, 1990, World Patent Patent WO 90/12017 Dunna et al., Published October 18, 1990, and WO 91/10646 Youssefyeha R. et al. on July 15, 1991, Australian Patent Application 26738/88 to Jaeggi, published June 15, 1989, and 45467/89 (Ciba-Geigy), published May 31, 1990.

Finally, U.S. Patent 4,208,401 Bauman, issued.17. June 1980, discloses non-heterocyclic ring substituted bisphosphonates with a quaternary ammonium group which are useful as anti-stone forming agents. - ·. · »· Γ.

i '·.

German Patent Jaeggi K., published October 18, 1990, discloses diphosphonate compounds substituted with a heterocyclic ring, wherein the 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 disclosures of these references are incorporated herein 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 simply relieving the symptoms of inflammation. The term osteoprotective activity as used herein means activity that modulates disease, bone, and surrounding soft tissue at the site of joint destruction.

* ·. ·

------- Surprisingly, it has been discovered that I have been trained under this term in a quaternary nitrogen atom. have stronger antiresorptive activity in bones and have therapeutic utility in the treatment of osteoporosis, rheumatoid arthritis and osteoarthritis than compounds; which contain a nitrogen atom but do not have a quaternary nitrogen.

In addition, the compounds of the invention have unusual solubility. Thus, the compounds of this invention can be readily absorbed orally, the more easily absorbed the compound, the more effective it is at lower dosages. Lower doses are usually preferred 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 antiarritic agents that are particularly useful in the treatment of osteoarthritis and rheumatoid arthritis. It is another object of the present invention to provide pharmaceutical compositions useful for the treatment and prophylaxis of osteoporosis and arthritis, particularly rheumatoid arthritis and osteoarthritis. It is also an object of the present invention to provide methods for treating or preventing osteoporosis and arthritis, particularly rheumatoid arthritis and osteoarthritis.

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

The essence of the invention

The present invention relates to phosphonate compounds _f containing a cyaternary nitrogen atom and "their pharmaceutically acceptable salts" and "est".

wherein m is up to 10, -n is li _; up to 10 and the sum of m + n is 1 to 10,

R ¹ represents nothing, -SR ⁶ or -R'SR ⁶ , hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, -OR ³ , -C00R ³ to -OOCR ³ , -NR ³ 2 , -N (R ³ ) C (O) R ³ , -C (O) N (R ³ ) ₂ , a halogen atom, a group. -C (O) R ³ , nitro, hydroxyl, substituted or unsubstituted saturated monocyclic or polycyclic heterocyclic group ^: substituted or unsubstituted monocyclic or polycyclic carbocyclic group,

R ⁵ is a group selected from the group consisting of -SR ⁶ or -R'SR ⁶ , hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, -QR ³ , -C00R ³ , -OOCR ³ , -NR ^3a , -N (R ³ ) C (O) R ³ , -C (O) N (R ³ ) _a , 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; ,

R ² represents a group selected from the group consisting of substituted or unsubstituted C 1 -C 35 alkyl, unsubstituted or substituted phenyl, benzyl or R ⁹ SR ⁶ '

R ^{3 is} 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 ') 2, -C (O) OR ⁷ , -C (S) N (R ⁷ ) 2, or -C (S) OR ⁷ , v wherein R ⁷ represents a hydrogen atom or an unsubstituted or substituted alkyl group having 1 to 8 carbon atoms,

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

R ^{9 represents a} substituted or unsubstituted C 1 -C 8 alkyl group;

R 6 is a group selected from the group consisting of hydrogen, atom, halogen, -SR ⁶ or -R ⁹ R ⁶ , an amine 7 '-hydroxyl-a-y-a-a group; unsubstituted alkyl groups having from 1 to 8 carbon atoms.

In this general formula, the quaternary nitrogen atom must be bound to the carbon atom containing the phosphonic acid by a bonding 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. 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, particularly rheumatoid arthritis and osteoarthritis, in humans or 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. ₉ .

can be used in this specification. · '. ·. ··' ·, · <· * '· s ^<, ·· r' After fine-znamená.atom heteroatom of nitrogen, oxygen sířy.nebó ... Groups · that "obsahujíujeden or more heteroatoms, the victim may include various heteroatoms. '··. '->

'·' * '; . ^R: * ·>. The term alkyl-represents unsubstituted or sub-

substituted or unsaturated hydrocarbon. ¹ ·, string .s. a straight or branched chain of this hydrocarbon group; may be saturated with 1 to 8 carbon atoms, and is preferably, unless otherwise stated, p. The aromatic hydrocarbon group may be; unsaturated, with 2 áž. 8. carbon-carbon, preferably when not otherwise specified. · · 2; áž '4 ^: carbon atoms? Thus, the term "alkyl" group as used herein 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 of 3 to 8, preferably 5 to 7 carbon atoms, or a polycyclic ring. group. Polycyclic carbocyclic groups consisting of two rings represent a group having from 6 to 1.6, preferably from 10 to 12, polycyclic carbocyclic groups consisting of three rings usually from 13 to 17, preferably from 14 to 15 atoms.

The term heteroalkyl means an unsubstituted or substituted saturated chain of 3 to 8 members 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 ¹ 'means an aromatic carbocyclic ring. Preferred aryl groups include, but are not limited to, phenyl, tolyl, xylyl, cumenyl, and naphthyl heteroaryl groups 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, wherein the hydrocarbon chain is alkyl. or an 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 (eg, -OH) and may have other substituents. Preferred hydroxyalkyl groups include, but are not limited to, hydroxyethyl and hydroxypropyl groups.

· * V

The term carboxyalkyl group means a substituted hydrocarbon chain that carries a carboxyl substituent (e.g.

-COOH 3 and may have other substituents. Preferred carboxyalkyl groups include the carboxymethyl and carboxyethyl group, and "their acids and esters".

<. * _F The term aminoalkyl refers to a hydrocarbon chain as · '·. * Λ (e.g. "-a'lkýlovou ·: Group) ysůbstitúov.aný /' amino, substituents 'j.'. (ŮapřT alkyl-NH-) y as is aminomethyl, 7; .

*, i. '' -_k i. . v. and·; . ** l- · 1ί, st · ·? '''A*''. «.U ·. ·? '* -. · her · . · · · · · · · · · · · · · ·. ..., · ··. .alkylamine; a group is -amino- is one or two-alkyl substituents ¹ (e.g., N-alkyl, i-);

A .1 .. ..... ¹ i- 'V · ¹ · ·. Is a dimethylamino group. '. · ^Γ '<·.

The term alkenylamino means an amino group. 3, with one or two alkenyl substituents (e.g. -N-alkenyl).

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

The term alkylimino means an imino 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 (eg, -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), for example O-C (= O) -alkyl.

The term acylamino means an amino group with an acyl substituent (eg, -N-acyl), for example -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 5 to 6 carbon atoms ^, preferably from 6 to 4 atoms. carbon. 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 (0) R ⁷ ], dithioesters [SC (S) R ⁷ when R ⁶ is C (S) R ⁷ ], thiocarbamates [-SC (O) N (R ⁷ ) and, when R ⁶ is C ( 0) (R ⁷ ) a], dithiocarbamates [SC (S) N (R ⁷ ) 2 if R ⁶ is C (S) N (R ⁷ ) 2], thiocarbonates [SC (0) 0R 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 is} usually hydrogen or C1 -C8 alkyl. Any SR ⁶ substituents may themselves be substituted with R ⁹ , ie R ⁹ SR ⁶ , wherein R ⁹ is substituted or unsubstituted C 1 -C 8 alkyl. Thus, other thio substituents of R ⁹ SR ⁶ are alkylthiols, alkylthioesters, alkyldithioesters, alkylthiocarbamates, alkyldithiocarbamates, 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 diphospho. , naphtha and diphosphonic acids. Using the formulas described herein, R is EO ₃ H _and . . '· -. ··' ... · / .. 'ýP.o jem.ý!, Átonv atoms ^{fosfoňóvé'-yl} ester as ~ as herein-O-

AND-. , ν.ι., · - ..... >>. >. .- ·. '''RT-f ** · - ^{1' J} '' J 'uses zňamgná ^ /; átpja5uhríjt. ₇ ýná '\ 3št.e.rý; Yippee; bonded to the acid group. ·. i ňý. phosphonic acid (PO 3 H 2), when attached to this carbon atom of the other, a further group of phosphonic acid, ^{and also a} sulfonic acid, is a phosphonic acid. When a sulfonate group is attached to this carbon atom, the resulting compound is a phosphonosulfonate. If the carbon atom is attached to this carbon atom, the carboxylate group is attached ^. group, the resulting compound is a phosphonocarboxylate. If this _hydrogen: carbon connected phosphinic acid, the resulting compound is a phosphonoalkylphosphinate.

The term pharmaceutically acceptable salt means a cationic salt formed on any acidic (eg carboxyl) group or an anionic salt formed on any basic (eg amine) group. Many such salts are known to those skilled in the art, as described in World Patent Application 87/05297 to Johnston. et al. _with published September 11, 1987 ,, which is incorporated herein; as a quote. Preferred cationic salts include alkali metal salts (such as sodium and potassium) and alkaline earth salts (such as magnesium / calcium). Preferred anionic salts include halides (such as chloride), acetates and phosphates.

The term biohydrolyzable ester means an ester of a heterocyclic phosphonate compound containing a quaternary nitrogen atom that does not interfere with the therapeutic activity of the compound or is readily metabolized by a human or other mammal. Many such esters are known to those skilled in the art, for example according to Jafc. described in _v? No. 87/05297 to Johnston et al., issued Sep. 11, 1987, which is incorporated herein by reference. These esters include lower alkyl esters, lower acyloxyalkyl esters (such as acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl, and pivoyloxyethyl ester), lactonyl esters (such as phthalidyl and thiophthalidyl ester), lower alkoxyacyloxyalkylmethyl esters (such as methoxyl) , ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl ester), alkoxyalkyl esters, choline esters and acylaminoalkyl esters (such as acetamidomethyl esters).

As mentioned above and as used herein, 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 substituted 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, amine, and -, - amine-no-alkyl-, and - (- to - methyl). cyano, halogen, carboxy, alkoxyacetyl (e.g., carboethoxy, etc.), thio, thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g. piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, etc.), imine, thioxo, hydroxyalkyl, aryloxy, arylalkyl and combinations thereof.

The compounds of this invention are phosphonate compounds containing a quaternary nitrogen atom, and pharmaceutically acceptable salts and esters thereof 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. A carbon atom with a phosphonic acid may contain two phosphonate groups, then a δ bisphosphonate compound, a phosphonate group and a carboxylate group, then a phosphono15 carboxylate compound, a phosphonate group and a sulfonate group, then a phosphonosulfonate compound and a phosphinate group and a phosphonate / group is a phosphonoalkylphosphinate compound. ' ¹ '<>''

The phosphonate compounds of the quaternary nitrogen atom of the present invention and their pharmaceutically acceptable salts and esters are compounds of the general formula. I ^; - - * · - · - - R ² ý R ^s ' ii-X f *

CD;

- w .., · _- · - tr ». · - «·· £ · T., ·· ·. #. * '·' Í ·. In this general. Formula ¹ & R · is selected from various noncyclic groups such as nothing group, -SR ⁶ or -R'SR ⁶ is hydrogen, an alkyl, group having 1 to 8 carbon atoms, -OR ^3, -COOR ³ group, -OOCR ³ , -NR 1, -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 polyeylic heterocyclic group and an unsubstituted saturated monocyclic carbocyclic group;

In this formula, the quaternary nitrogen atom is linked to the ^- phosphonic acid carbon atom linking chain / In this formula, n, which represents the numbers 1 to 10, znamená.uvedený linking chain.

The members of said binding chain are selected from a variety of R ⁵ groups. R ⁵ can be -SR ⁶ or -R ^{6 with} SR ⁶ , hydrogen, C 1 -C 8 alkyl, -OR ³ , -COOR ³ , -OOCR ³ , -NR 1, -N (R ³⁾ C (O) R ³ , -C (O) N (R ³ ) _S , halogen, -C (O) R ³ , nitro, hydroxyl, unsubstituted or substituted 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 phosphonate compounds containing the quaternary nitrogen atom of the present invention may be -COOH, -SO ₃ H, -PO ₃ H ₃ or -P (O) (OH) R ⁴ , wherein R ⁴ is an alkyl group of 1 to 8 carbon atoms. A preferred R group is -PO 2 H 1 or -P (O) (OH) R ^4. R ⁴ is a substituent on a carbon atom that carries a phosphonic acid and is selected from the group consisting of hydrogen, halogen, or a group. -SR ⁶ or -R ⁹ SR ⁶ , amino groups, hydroxyl groups and substituted or unsubstituted C 1 -C 8 alkyl groups. A preferred R group is a hydroxyl group, a halogen atom. gene and the amino group, R ² represents a substituted or unsubstituted alkyl group having 1 to 35 carbon atoms, substituted - or those nesubs-TUO tub - phenyl-l-esterification, cyclohexyloxycarbonylethyl esterification - - benz-yl-esterification, cyclohexyloxycarbonylethyl esterification or R ⁹ SR ⁶ . A preferred R ² group is a substituted or unsubstituted C 1 -C 8 alkyl group and R ⁹ SR ⁶ . and'

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

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

CHj

ΡΟ, Η,

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

CH.

CH _and ^ N + 'POjH, cr

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

- _{f T} .,. _r _-_ · '' Ι _ ' _t ··. - ^Λ . Γ. r. . ř · γ- ^; In this general group, R ¹ may be a monocyclic or polycyclic heterocycle. Between the preferred phosphate phosphate ... nitrogen quaternary atoin having a saturated monocyclic or polycyclic heterocycle.

.. «. · -.> .... -» ί · -. ·.

¹ group nuíf / out 2 quaternary ^! The nitrogen atom is attached to the carbon atom of the phosphonic acid with a linking chain, including:.

CH ₃ P (OHOH), cr [T] ⁺ P (O) (OH) _and CH 3

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

Other preferred compounds of this invention include those of the following formulas:

R ² —N

R ^z i ₁₊

Ø ² ΡΟ ₃ Η2

PO ₃ Hj

Preferred compounds of the present invention also include phosphonates with a thiosubstituted quaternary / nitrogen atom of the following formulas:

I TR ^e r2 POjHj

R ²

R ² POaHj

Specific examples of compounds of the invention include:

N- (4-hydroxy-4,4-diphosphonobutyl) -N, N, β-trimethylamino-iodide, N-β-3-hydroxy-3. _f -3 = diphosphonopropyl-1'-N-N-dimethyl-N-pentyl ammonium iodide,

N- (3-hydroxy-3,3-diphosphopropyl) -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-dimethylammonium bromide,

N- (2-acetylthioethyl) -N- (3-hydroxy-3,3-diphosphonopropyl) -N-methyl-N-pentylarnonium bromide,

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, _t

N- (4-hydroxy-2-acetylthio-4,4-diphosphonobutyl) -N, N, N-trimethylammonium chloride,

N- (3-hydroxy-2-mercapto-3,3-diphosphopropyl) -N, N-dimethyl-N-pentylammonium chloride,

·· $ '

N- (3-hydroxy-2-acetylthio-3,3-diphosphoryl) -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) ) 7-- -ammonium chloride a. 7. ·· 7 ¹ ; •• “* * -. \ Ý * ...... '/ -' t '·' ..

N, N-dimethyl-N- (4, 4, 4-diphosphonobutyl) -N- (2- (3-piperidinyl) ethyl) -4-ammonium chloride. 7C <. . <'''. . > -. · ♦ * ',,,,? ř v ^J ! .L · ·. · '' ·. · '. ^; · '· V < _r ', -i * '.i'. * '. '' - JH,. '·' ·. : · -'I '''. ^In '' · · ”· '' ··. '- -,

For the assessment and evaluation of pharmacological activity;

The screening of the compound of the invention is carried out by means of tests in a manner known to those skilled in the art. Thus, the in vivo antiresorptive activity of bones can be demonstrated in a conventional manner by means of an assay designed to test the ability of these compounds to inhibit bone resorption, which is characteristic of abnormal calcium and phosphate metabolism. Examples of such known assays include the Schenk model. Another useful test known to those skilled in the art is the adjuvant arthritic test. An in vitro inhibitory assay for hydroxyapatite crystal growth is also useful. These and other relevant pharmacological activity assays are described and / or discussed in the following.

·. * 'ΐ ^? ·,. . , Shirioda et al .: Calcified Tissue International 35, 87 (1983), Schenk et al .: Calcified Tissue 'Research 11, 196 (1973), RushelP' et al .: Calcified Tissue Research 6, 183 .. (19.70), Muhlbauer and Fleisch. Mineral Electrolytic Metab. 5, 296 (1981), Nahollas et al., Oral Biol. 15, 731 (1970), U.S. Patent 3,683,080 to Francis, issued August 8, 1972 / U.S. Patent No. 4,134,969 to Schmidt-Dunker, issued January 16, 1979, and European Patent Specification

1986; the descriptions in are given here logical activity examples.

No. 189,662, published August 6, all of these articles and patent publications as citations. Some of these pharmacological tests are also described in more detail below

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

Pharmaceutical compositions containing phosphonates containing a quaternary nitrogen atom according to the present invention can be prepared according to the following non-limiting examples.

The novel quaternary nitrogen-containing phosphonate compounds of the invention can be administered to humans or other mammals in a variety of ways including, but not limited to, oral dosage forms and injections (intravenous, intramuscular, intraperitoneal, and subcutaneous). One skilled in the art can readily prepare numerous other dosage forms that comprise the novel phosphonate compounds containing the quaternary nitrogen atom of the present invention using the appropriate pharmaceutical diluents listed below. Usually, oral dosage forms are preferred for reasons of patient compliance.

The term pharmaceutical composition as used herein 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).

The term safe and effective amount as used herein means that amount of a compound or composition that

Γ

2 «l

is high enough to have a significantly positive modifier. 4.

lo symptoms and / or conditions, by which to be treated, but which is low enough. 'to avoid, serious side-effects (š.pdůyodněným benefit / risk ratio), within the scope of ^sound-4 lékařské- his assessment. Safe and effective amount. Active ingredients for *. *; ? . ;

use in pharmaceutical compositions which have been used

The method of the present invention will vary depending upon the particular condition being treated will depend upon age and physical state; treated for the severity of the condition for the duration of the treatment on the nature of the concurrent treatment / treatment.

The bed that is used on the respective bed. '' 'i * ... .

of pharmaceutically acceptable diluents and similar factors used, depending on the skill and practical experience of the attending physician. '' ’·. - Even a doctor.

The term &quot; pharmaceutically acceptable diluents &quot; as used herein, includes any physiologically inert, pharmacologically inactive material known to those skilled in the art that is compatible with the physical and chemical properties of the respective phosphonate compound containing a quaternary nitrogen atom as the active ingredient selected for use. Pharmaceutically acceptable diluents include, but are not limited to, polymers, resins, plasticizers, and the like. fillers, lubricants, sliding agents. solvents, co-solvents, buffering 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 intended to be systemically administered into the gastrointestinal tract of an individual by the mouth of that individual. For the purposes of the present invention, the form administered may be a coated or uncoated tablet, solution, suspension or a coated or uncoated capsule.

The term injection, as used herein, means any pharmaceutical composition intended for systemic administration to a human or other mammal, which is administered as a solution or as an emulsion containing the active ingredient, by puncturing the skin of said individual to make the solution or the emulsion was delivered to an individual's circulation system by either intravenous, intramuscular, intraperitoneal or subcutaneous injection.

The rate of system delivery can be satisfactorily controlled by one skilled in the art by utilizing one or more of the following:

(b) pharmaceutically acceptable diluents (vehicles, excipients), unless such changes interfere with the activity of the particular active ingredient selected;

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

(d) time-related conditions, namely the diluent itself and / or inside the diluents; '

-------- ej — vel-i-bone-part-i-ce-granulated-active-s-1-o-k-y — 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, e.g. alkali metal salts, caustic earth metal salts, etc. may be a guide for the selection, and esters such as alkyl, aryl and aralkyl esters. A suitable pH can be formed within the oral dosage forms by adding a suitable buffer to the active ingredient according to the desired release method.

As mentioned hereinabove, pharmaceutically acceptable diluents include, but are not limited to, resins, fillers, binders, lubricants, solvents, glidants, disintegrants, co-solvents, surfactants, preservatives, sweeteners, flavoring agents. , buffer systems, dyes or pigments for pharmaceutical use, and viscosity adjusting agents.

'. 2 3

The preferred solvent is water. ...

·> .- ·; -. _f .

Preferred flavorings include those činidla.podle'vynálezu • - · - ·· · 1 / _r. . r - RN agent. which are described in Remington's Pharmaceutical Sciences, 18th Edition, "Mack Publ ishing--company, .11990 / 'side' ^r 1288; '';'-,<. * To 1300. This reference is incorporated herein by reference; Pharmaceutical compositions suitable for use in accordance with the present invention generally comprise up to about 100%. 2 ^%; % of flavoring agents. .: h '/ 7'1 ·' - V.

, -. Dyes and pigments useful in the present invention include. J · '., A _x λ. These are described in the Handbook of Pharmaceuticals -Expilients, pp. B1A-SP, 1986, American Pharmaceutical. Association.

& 'PharmaceuťicalUSociety UK. This quote is included as a reference. The pharmaceutical compositions of the present invention generally contain up to 2% by weight of dyes or pigments.

Preferred co-solvents include, but are not limited to, ethanol, glycerin, propylene glycol polyethylene glycols. The pharmaceutical compositions of the present invention 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. gluconate, glutarate and glutamate and their sodium, potassium and ammonium salts. Particularly preferred are phosphoric acid, tartaric acid. citric and acetic salts thereof. The pharmaceutical composition according to the invention usually contains up to 5% by weight of the composition. 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, alkylsulfate salts and sodium, potassium, and ammonium salts of fatty acids. The pharmaceutical compositions of the present invention contain up to 2% by weight; surfactants.

Preferred preservatives include, but are not limited to, phenol, 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, thimerosal, phenylmercuracetate and nitrate , nitromersol, benzalkonium chloride, cetylpyridinium chloride, methylparaben and propylparaben. Particularly preferred are the salts of benzoic acid, cetylpyridinium chloride, methylparaben-4-methylpiperidine. Means ,,, _ί of this invention typically comprise up to 2% by weight. preservatives.

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. _ή

Preferred viscosity adjusting agents include but are not limited to. .. <.

They are, but are not limited to, methyl-1-cellulose-1-sodium-1-carboxymethyl. --- celluloses, hydroxypropylmethylcellulose, hydroxypropylcellulose, al-. , sodium ginate, 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% by weight of the composition. 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 'reagents.' * '· I

Preferred disintegrants include, but are not limited to, starch, sodium glycolate, crospovidone, sodium croscarmellose, and microcrystalline cellulose. Pharmaceutical preparations _; according to this invention comprise: from 4 to 5. %: wt., disintegrating agents; ⁵ *? ^ · '-''-''? - · '>

F

row; ‘7,

H. i. In ¹ .Mgz 1 - Advantageous. A ^ szobně-činíčílcisic are not - ns. — nie-oms “'' · ·. * '- _' 7: _ **. . >> · women; (acacia -, -, tragacanth, hydroxypropylcellulose, předželatinóváhýfškrob, řžeíatina, ^'J povidone;? Hydroxypropylceíulosa, Hýdroxyprópýlmeťhylceluipsa, methylcellulose, (· sugar solutions, such as sucrose and sorbitol, and eťhylceíulósa. The compositions of this invention comprise 1 to 10% by weight of binding agents.

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

The compounds of the invention preferably comprise from 20 to 80% of the weight of the pharmaceutical compositions of the invention.

í · '. ,. ·

The pharmaceutical compositions according to the invention contain from 15 to 95% by weight of active ingredient. phosphonate compounds containing a quaternary nitrogen atom or mixtures thereof, up to 2% by weight; flavoring agents, up to 50 wt. % co-solvents, up to 5 wt. % 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. 0.5 to 2 wt. % lubricants, 1 to 5 wt. glidants, 4 to 15 wt. % disintegrants and 1 to 10 wt. of binding agents. ‘;

(i ........ '.

Suitable pharmaceutical compositions are described herein in the Example. * Breath 9 to ll. It is within the ability of the skilled artisan to vary the non-limiting examples described herein to obtain a wide variety of pharmaceutical compositions.

to

The choice of pharmaceutical diluent to be used in conjunction with phosphonate compounds containing a quaternary nitrogen atom in the compositions of the invention is essentially determined by the manner in which the phosphonate is administered. If the compound is injected _f., N, N-Ýhodným farmaceu.t.ickým ^ ^ ^ no.si.čem je_st.e.riln.Í_fysip_lo ^. The pH of the solution was adjusted to 7.4. A preferred route of administration of the phosphonates 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 of the phosphonic acid compounds described herein. Pharmaceutical carriers suitable for the preparation of unit dosage forms for oral administration are well known to those skilled in the art. Their choice will depend on secondary considerations, such as taste, cost 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 artisan. The term mg P as used herein means the mass of phosphorus atoms present in a given amount of a phosphonic acid compound. according to the invention. This unit is used to standardize the amount of the phosphonic acid compounds of the invention 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. For the preparation of a pharmaceutical composition containing 0.17 mg of P of the compound, the composition should contain 1 mg of the compound. At a dose of 0.17 mg P / kg of the compound, a 50 kg patient should be administered a dose of 50 mg of the compound.

The pharmaceutically acceptable diluent used together with the diphosphonates of this invention is used at such a concentration, i

which is sufficient to achieve a practical size-benefit relationship. Pharmaceutically acceptable carriers are generally many.

. from 0.1 to 99.9 wt. % of the total weight of the composition / more preferably of > up to 80 Ύ mass / - ·, ' ^r ·'. f ^J •: · ·. vr * (·. '.''·''

Another aspect of the invention are methods of treatment or. preventing the disease characterized by abnor- ^;

- has lni - metabolism -aphy-Ku »-a; These include administering a safe and effective efficacy of the phosphate compound of the invention to a human or other animal in need thereof. / -. , -; ·. '/ - r ^ ^ The preferred manner of administration hjeydrálníjpoááyániTriJ.sou ^ ^ vš.akjJ / Xjiné useful modes of administration, e.g. dermatomukózně (e.g., _A .. __ - * £ r_ j -i -dermálně, rectally, etc.) And parenterally (například.suPkutánnlinjekcí, intramuscular injection, intraarticular ,, injections, intravenous injections, etc.}. also included inhalatory _'of administration. The specific modes of administration include, without limitation, oral, transdermal, mucosal, sublingual., intramusku-. linear, intravenous, intraperitoneal, and subcutaneous administration, as well as topical applications.

The term ( "abnormal -metabolismus, calcium aifosfátu as used herein, means 1} states which are characterized by anomalous mobilization of calcium. _And; phosphate leading to general or specific bone loss or excessively high calcium and phosphate body fluids, and 2). Stays 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, heperthyroidism, hypercalcemia of malignancy, heterotopic ossification, and osteolytic bone metastasis. The second category includes, but is not limited to, progressive myositis and ossifying, general calcinosis and conditions such as arthritis, osteoarthritis, neuritis, bursitis, tendbnitis and other inflammatory conditions in which calcium and phosphate deposition in tissues .

The term rheumatoid arthritis as used herein means a chronic systemic and articular inflammatory disorder of unknown etiology. It is characterized by the destruction of articular cartilage, ligaments, tendons and bones.

The term osteoarthritis as used herein means a non-inflammatory disorder of the movable joints. It is characterized by the destruction and abrasion of the articular cartilage and the formation of a new bone on the surface of the joint.

.Ά

As used herein, a person at risk and a person in need of such treatment means any human or lower animal exposed to a significant risk of abnormal calcium and phosphate metabolism if not treated, and any human or lower animal. animal,

- which, according to diagnosis, is affected by abnormal calcium and phosphate metabolism. For example, postmenopausal women, people who are

- - treats-1-y-steroids -, - persons, - who use, anticonvulsants, and others., _________.

persons with Paget's disease, hyperparathyroidism, malignancy hypercalcemia or osteolytic bone metastasis, persons whose diagnosis is one or more different forms of osteoporosis, the persons they belong to. k. a population known to have a significantly higher than average chance of developing osteoporosis, such as post-menopausal women, men over 65 and those receiving medication known to cause osteoporosis as a side effect, persons diagnosed with progressive myositis ossifying or generalizing calcinosis; and those affected by arthritis, osteoarthritis, neuritis, bursitis, tendonitis, and other inflammatory conditions in which calcium and phosphate are deposited in the tissues.

The term safe and effective amount as used herein means that amount of a compound or composition of the invention that is high enough to significantly positively modify the condition to be treated, but which is low enough to be effective. avoid serious side effects (at an acceptable benefit / risk ratio) to the extent of reasonable judgment by the physician. Safe and efficient quantity.

\ ‘J V. The phosphonate compounds of the present invention will vary.

⁴ will depend upon the particular condition being treated _; phthalazin -.věku and 'physical condition of the patient being treated ^of, on těžkosti'stavu, the duration of treatment, our -povaze · concurrent therapy, on the specific phosphonate, .The. the pharmaceutically acceptable diluents used, and the like.

^: 'to the knowledge; however, the practitioner of the individual dose will move; in range. from '00'-mg- ^: P'-to- · 350''-mg- -P; or- ^; -from ..0.-0002; to 70 mg

P / kg body weight (based on 50'kg body weight). Advantageous. The unit doses are from 1 mg P to 600 mg P or 60 mg. from 0.02 to 12 mg-P / kg body weight (based on the weight of the weight of the body). 'kg} 2 "can ^J is podávatgaŽ four to one t one-before. doses per day. the daily dose vyššíTnež 500 mg P / kg are not required, and · it is and may produce undesirable side effects. In the case of oral dosage forms are, however, required higher doses within this range, since oral absorption results in limited absorption.

The following examples further describe and demonstrate preferred arrangements within the scope of this invention. The examples are given here for illustration only and are not to be construed as limiting the present invention, since many / variations thereof are possible. these would depart from the spirit and scope of the invention. · '

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Synthesis of N- (4-hydroxy-4,4-diphosphonobutyl) -N, N, N-trimethylammonium iodide

CHj

I. Synthesis of [4- (Ν, Ν-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) was stirred at room temperature for 30 minutes. It is then heated at 60 ° C for 24 hours. The reaction mixture was then cooled to room temperature and concentrated hydrochloric acid (50 mL) was added. The reaction mixture was heated for another 24 hours under reflux, cooled to room temperature and filtered if RCE-1em-WE-IL-TRA-t ^ se.zah.us.tí .in vacuo _w .- »^ Surpyý the product is triturated. with ethanol, filtered and dried under vacuum.

II. Synthesis of N- (4-hydroxy-4,4-diphosphonobutyl) -N, N, N-trimethylammonium iodide

The bisphosphonic acid (0.30 mmol) was dissolved in water (10 mL) and ethanol (15 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. The mixture is then cooled and thickened with a saturated lacquer. The solid residue is released in a minimum amount of water. Kvarternizovaný. the 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-pentyllammonium iodide

CH,

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

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

'? .

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

'''/', · Ý ·; , f ¹ _ '

Bisphosphonic acid (0.50 mmol) is dissolved in water (15 ml) and acetonitrile (20 ml), and the pH is adjusted to 7.0 by addition of 1N NaOH, and to this solution is added foamed iodide (2.50 ml). The reaction mixture was heated at reflux for 22 hours

4 * 1. · _F ^X

The solid was evaporated under reduced pressure / solid evaporation with acetone. The product is recrystallized. aqueous ethanol. '/

Example 3. '-í

Synthesis of N-N-hydroxy (1,3-diphosphonopropyl) -N, N, N-trimethylammonium iodides,. · ··· .. ·.

- CH ₃ ^CH '-i ⁺ -V ^ r _CH3 POaHj

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

Example 4 t

AND:

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

CH ₃ C (O) SCH ₂ CH ₂

Br * [4- (Ν, Ν-Diemethylamino) -1-hydroxybutylidene] bis [phosphonic acid] (0.75 mmol), prepared as above. Example 1, dissolved in water (50 ml) and acetonitrile (35 ml). To this solution was added S-acetyl-2-bromoethane 32 thiol (3.75 mmol) and the reaction mixture was heated under reflux for 12 hours. The mixture was concentrated under reduced pressure. Solid residue

Spread with acetone. The quaternized product is recrystallized from water and ethanol.

Example 5 ^r saturates for ^L ^ N ^ C ^ -acetamide y lthioeth Jc-yl-N ^ p ^ hy dr oxy-third "3-diřosfonopr a propyl) -N-methyl-N-pentylamoniumbromidu

CK,

CH 3 CH 3 CH 3 CH 2 CH 2 CH 3 O 2 -J

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

In essentially the same manner as described above in Part I of Example 1, 3- (N-methyl-N-pentylamino) propanoic acid was 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

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

Example 6

Schenk model

Compounds are evaluated for in vivo inhibition of bone resorption and inhibition of mineralization in an animal model system. . 33 in / '. · /.

known in the field of bone metabolism * as the Schenk model. The general principles of this model are described by Shinoda and spoi. ^; : Calcif. Tissue Int. 35, 87 (198.3) and Schenk et al., Calcif. Tissue · Ress. li, 196 (1973), which are. incorporated herein by reference.

Materials and methods:

-Animal; x ;;; x <: - ''-;·; ·. _: ,. · · _ · ···· _ - · · .-? · - ·· ý, .- ··; - _r · - ·. / '· -; *' · 17; days · old male Sprague Dawley ^ SO'g} rats (Charles RI, ver Breedirig Laboratories) before. by shutting down, they displace spies ^; g is _woven. "A" is placed .se _sQo.l.ečněi se..svými ¹ Jnatkainv do'plastických cages. At the age of 19 days, the chicks who receive the Ratt ChowT and the water hatcher are controlled. groups, experimental groups of 7 animals per group. On the first day and again on day 7, all animals received an intraperitoneal ( _t IP) injection of Calcein [1% (w / w) solution in 0.9% (w / w) saline; 0.2 ml / 100 g body weight was dosed]. On day 4, all animals are given an IP injection of tetracycline hydrochloride [1% (w / w) solution in 0.9% (w / w) saline; 0.2-ml / 100 g body weight] is dosed. These compounds refer to actively mineralizing bones and cartilage. .

Dosing solutions and dosing procedure ' ^: .

All solutions are prepared for subcutaneous injection

0.9% (w / w) of normal saline, pH is adjusted to 7.4 with NaOH and / or HCl. The weight of powder (based on molecular weight) is taken into account when calculating the dose of solution. hydration) of the active material in mg / kg (body weight) corresponding to mg. P / kg. 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. 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 made daily. ,.

Necropsy, tissue processing and histomorphometry

On day 8 after the start of dosing, all animals are sacrificed by IP overdose of pentabarbitol. The tibia was removed and placed in 70% (w / w) ethyl alcohol. One tibia is dehydrated in ethanol solution and fixed in methyl methacrylate as described by Schenk: Methodes of Calcified Tissue Preparation (G. R. Dickso.n, eds., Elsevier Science Publ., The Netherlands, 1984.); this description is incorporated herein by reference. The tibia is slit longitudinally through the metaphyseal surface. Samples are stained with silver nitrate on the surface and mounted on a microscope slide for evaluation by a Quantimet Image Analyzer (Cambridge Instruments, Inc) under both fluorescent and ultraviolet illumination. The content of metaphyseal trabecular bone is measured in the regime between the fluorescent label and the growth plate; it is expressed as a percentage of the total area (bone + bone marrow). The width of the epiphyseal growth plate is obtained as the mean of 10 equal spatial measurements of the sections. j Statistical evaluation of the data is performed by parameter and non-parameter variation analysis by Wilcoxon summation test. This results in a statistically significant effect 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 numerous 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 pelvic 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 Actions 7, 145 (1977).} Numerous prophylactic and therapeutic treatments: '''''''' · t '. *, 35 *. ·.' · studies demonstrate the potential use ^of anti-inflammatory drugs [Winter CA, Nuss, GW Arth. Rheum., 9, 394 (1966) - Winder 'J.,.', · «.

Lembke, LA, Stephens MD: Arth. Řehum -. / 12, '472' ^: (1969).]] A'disphosphoonate in arthritis [Franscis MD, Flora L. / King W-.R ;: Calcif. Tiss. Res. 9, 109 (1972); / Flora L .: Arth. Řheum. 22, 340 (1979)]. ^{: 1} · '-. ~ r ií.V 4.. jv ⁴ .-.- 4 * '' t * '·

- Ad jů cook Ni-jě- arthritis, strong "cellulitis' and ^{synpviťida--in-"}

male rat ducator (either currency; Sprague ^And Dawlin or Lewis) by a single subcutaneous (SC) injection of Mycobacterium butyricum. (8 rog / jnljj-mineral oil on day 0. ^{r r} ^ is slouSěnihv poďáv.ajl. Jed 'thereto either _daily, orally (PO) or enterally vapor' • (SCJ .-. ^, And may be TE- stovatbuď 'vprofylaktickém'7_(BDE;dne'O.') - něbp'-térápéilt-ical (' garments 'Done at 9, 10 or' 14) mode. Antiarthritic efficacy can be measured as a reduction in paw volume, body weight loss, bone loss or new bone formation when compared to an arthritic control treated with saline, treatment can be stopped and the flare response (rapid increase in inflammation) is investigated, indicating the compound's ability to retain efficacy.

Materials and methods

A. · -. .Animals \ - /

Lewis rats (LEW) were used as animals. Upon delivery, the rats are randomly distributed by computer-controlled random numbering and placed in individual wire cages. Food and water are administered ad libitum for the duration of the study. Routine care and maintenance of animals is performed according to state and federal regulations. Each rat is identified by a number located at the head of the cage and at the tail of the rat.

B. Experimental conditions

On the first day, body weight (BW) and hind paw volume (PV) (measured by mercury displacement by a pressure sensor connected to a computer) of all rats were recorded. o induced arthritis using MFA [Mycobacterium butyricum (Mb); 4.4 mg / kg. in oil] as follows: the rats were anesthetized and under aseptic conditions a single SC injection of MFA was administered to their tail.

Thereafter, puff volumes and body weights are measured on vigorous days (usually twice a week). For the prophylactic regimen, rats are randomly assigned to groups of 8 to 10 rats. Treatment begins on day 0 and continues daily until the end. For the therapeutic regimen, the rats are randomly divided into groups of 8 to 10 rats according to the value of PV at the beginning of the day at the beginning of the day. -Ow-and-cont-ačuj-e ^ _l .denně to end. In both regimens, animals are placed in deep-day cages either on day 10 or earlier.

and

Dosing solutions ‘

For compounds that are unlikely to undergo oxidation

The drugs are weighed on a calibrated balance and mixed with the distilled water in a graduated flask; The pH of the solution, 1N NaOH Prep ňá7'74'7 Γ ^- RDZ flow "with" then "1 zfi Tru j'e" 0 74'5'μιη "ster Inlm i f r i'lt ENR into a sterile storage container . Store the stock solution in the freezer when not in use.

For compounds that are likely to undergo oxidation Drugs are weighed on a calibrated balance and then mixed with deoxygenated water in a volumetric flask. The stock solution is filtered through a 0.45 µm sterile filter into a sterile reservoir.

Store the stock solution in the freezer when not in use.

Depending on the daily amount required, an appropriate amount of solution is taken from the stock solution, placed in a small dosing beaker and adjusted to pH 7.4 according to a predetermined calculation. If necessary, the treated solution can be further 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 vaginal fold, alternately on both wipes every day; or 1 ml / 200 g body weight administered by an orally bent stainless steel dosing tube, the body weight adjustment is performed weekly. ^z _v

-Radiography, necropsy and isolation of "tissues ... Λ <>; .

'. At the end . each rat was sacrificed intraperitoneally _f (IP) in ml of S.ocoirib ⁽ ? r). Immediately, it would make a radio-whole-body-Torrox-12-x-ray unit: / MA = 5., ISUP = 50 ' / 60.1 seconds and a Kodak medical non-screening film, each rat is eaten to remove the hind paw. - w * ·· '''''' r '''Ι*' ^J · * '*' * ^L * '· *' ·· ky_and in-bed - with - up to - 10% - -puf-rovanéhG form if-nu ^ is arranged together with -kouskem ja "ter, kidney, thymus sleziny.a. tibiotarsal joints dekalciγΐ f. ·. _(. - .. ·· · / · .. 1 ' .D .... ·· 's fikuj VE4'% '(wt.) EDTA, ^pH 7.4 and processed routinely in PA. ráfinoye blocks and H + E <-barvivém. - In the same manner elaborate parts of organs.

The light microscope evaluates histologically qualitatively the damage 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 ^: anterior paws on a 0 to 3 scale giving a total value of 0 to 60 for all four paws. For new bone formation (RNB), radiograms are scaled with a scale of 0-3 for the lateral and medical femur surfaces, and then 0-2 for all the other surfaces listed above, giving a total value of 0-44. Statistical-Analysis Paw volume data, bone resorption and new bone formation are analyzed by the 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 efficacy data for anti-arthritic compounds in terms of swollen paw reduction, bone loss, and new bone formation i.-ve; compared to animals with / arthritis receiving saline.

Example 8

The capsules are prepared as follows:

active ingredient:

N- (3-hydroxy-3,3-diphosphonopropyl) -Ν, Ν, Ν-trimethylammonium chloride _{: ιι} mg per capsule

350.0 thinner:

lactose 90.0 microcrystalline cellulose 60.0 magnesium stearate 1.0

Capsules having the above composition are prepared by a conventional method according to the following process: The active ingredient is mixed with microcrystalline cellulose in a mixer with rotating blades approximately 'ten minutes. The resulting mixture is passed through a hammer mill with a mesh screen of 0.177 mm. This mixture is transferred back to the two-blade mixer along with the lactose and mixed for approximately fifteen minutes. Magnesium stearate was added and the mixture was stirred for an additional five minutes. The resulting mixture is then compressed with a piston filler capsule. The active ingredient in the above capsules may be exchanged with any of the compounds prepared according to Examples 1-5.

Example 9 ε,

- .. .- ,. ¾. Tablets are prepared having the following composition:

.. i. '', * *.

active ingredient: · _; , mg on tablet

N- (4-hydroxy-4,4-diphosphonobutyl) -N, N-dimethyl- _; —N- (2-mercaptoethyl-1'-ampnium chloride- '.τ: -.-. -; · diluents: ^L

·. : 5 / .. - '. '!' Lactose - (spray-dried) starch ^: (T500) -? - ^: *? - u · -. · ^! · 4> δ _L '·. · Magnesium stearate '. . .....

at 700.00 ’

200.0. . ,. · Ττ / ιοο ', ογ ^?

25.0 ...

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

Example.10

Injectable solutions are prepared by conventional methods from 10.0 ml of physiological saline and N- (4-hydroxy-4,4-diphosphonobutyl) -1,4, Ν-trimethylammonium chloride, the pH is adjusted to 7/4.

One injection, one time daily for 4 days results in appreciable alleviation r.epnatické arthritis _patients: weight of approximately 70 kg. The active ingredient in the above injectable solution may be exchanged for any compound prepared according to Examples 1 to 5.

Example II

A Caucasian man weighing approximately 92 kilograms, 72 years old, suffers from mild to severe pain and occasional swelling of his right knee. After about one year of increasing adverse events, he visited a doctor who found a clinical diagnosis of right knee osteoarthritis, which was later confirmed by x-ray diagnosis.

After a period of improvement treatment with various NSAIDs, including aspirin, sputum and ketoprophea, the symptoms worsened and his condition seemed to degenerate. He returned to his doctor, who prescribed the tablets, prepared as described in Example 9 above, twice a day two hours before or after a meal for three months. Clinical signs of pain and swelling, especially during long-term walks, after seeding. treatment - significantly improved. At the end of the three-month treatment with a dose of two tablets per day, treatment is continued with half the originally prescribed dose (i.e., 1 capsule per day, prepared according to Example 8) for an indefinite period of time.

Example 12 A black woman weighing approximately 65 kg, aged 55, suffers from swelling and deformation of the toes joints on both hands with partial loss of power and / or dexterity of the toes and fingers. According to visual examination, X-ray examination and various relevant clinical trials approved by the American Rheumatology Society (ARA), her diagnosis was determined to be rheumatoid arthritis.

After an unsuccessful analgesic and anti-inflammatory treatment, her physician prescribed her tablets, which were prepared according to Example 9, twice daily two hours before or after a meal for 4 months. After one month of treatment, her joint swelling symptoms improved noticeably and her range of finger movement increased significantly. Treatment was continued for the remainder of four months. Then the doctor prescribed the same dose for the next two months. '·' '. · »

Example 13. ¹ '?

A.-Λ J- ‘. ·,, '' '.

•. ·! · · '! ».

A Spanish woman, twelve years old, weighing approximately 3.7 kg, came to her doctor with a -diopathic juvenile rheumatic-ar-. -g tritis. Symptoms included, 'considerable inflammation - multiple joints' - complicated by heat and pain in pressure, indicating rapid. apathological degeneration 'of the function of the joints. . * ^'L V' »her physician lódkázal nafrevmatológa which immediately aggressive therapy by IV administration of the solution, which matches the prescribed přiJejí law under. of Example 10, for three days, in a batch. i. daily injections: two. clock. At the conclusion _of the IV regimen, the physician prescribes · tablets prepared according to Example 9 for 2 months, during which she exhibits marked improvement with increased mobility and decreased pain. On. For the next two months, the doctor reduced the dose to 3/4 of the original oral dose by prescribing 3 tablets every two days, ie one day two tablets, the other day one tablet. Concentration of this regimen was reduced to 1/4 of the original dose by administering the tablets prepared according to Example 9 at a dose of 1 tablet daily for an additional 4 months.

Example 14

A 60-year-old Caucasian woman weighing 62 kg suffered from severe back pain. Her physician, with the help of a radiologist, found a diagnosis of a crushed LI vertebra fracture, probably due to osteoporotic bone loss. This patient was prescribed a 700 mg tablet, prepared as described in Example 9, administered once daily for 3 months. This 700 mg tablet is taken either two hours before or two hours after any meal. After three months, the dose is reduced to _L, 350mg capsule., Která.se _f prepared according to the procedure described in Example 8, which is administered once a day for 3 months. Her physician then transferred her to a maintenance dose of 42 for taking a 100 mg capsule, prepared according to the procedure of Example 8, daily for 6 months. After six months of this maintenance regimen, the patient experienced no back pain. Subsequent X-ray examination revealed no further fractures.

Example 15

A 75-year-old Oriental woman with a weight of 53 kg suffered a hip fracture when she fell. She was hospitalized and diagnosed as osteoporosis. She was prescribed treatment with calcitonin injections. Calcitonin injections are painful for the patient. The patient was unable to adapt to these injections. Her doctor then changed her treatment to oral administration of phosphonates. The patient received a 700 mg tablet twice daily for one month, which was prepared according to the procedure described in Example 9. At the end of this single month of treatment, she was administered. 700mg.table. Once, daily for two months. At the end of this two month period, she was prescribed a 100 mg capsule prepared according to the procedure of Example 8 for a period of 3 months. A subsequent visit to her doctor revealed no decrease in forearm mineral density (by absorption photometry). _t;

Example A 16-year-old American man, 65 kg, told his doctor that he was suffering from severe back pain. X-ray revealed minor vertebral collapse resulting from significant bone loss due to osteoporosis. This patient was prescribed a 700 mg tablet and a 350 mg capsule, which were administered the same day after eight hours in succession, prepared according to Example 9 and Example 8, respectively. After two months of administration, the dose was reduced to 350 mg capsule once daily for 2 months. Another soft fracture was detected by X-ray. The patient was then switched to a maintenance regimen with a 100 mg capsule, prepared according to the procedure of Example 8, administered once daily for 6 months. At the end of this time, no significant marked decrease in bone density was found.

Claims (9)

Compounds containing a quaternary nitrogen atom which are useful in the treatment or prevention of abnormal calcium and phosphate metabolism disorders, and their pharmaceutically acceptable salts and esters of formula I ΜΙΟινιξ Λ3Λ015, where m stands for 1O, n stands for 1 through 10 and the sum of m + n stands for 1 through 10, R ¹ represents a group selected from the group consisting of nothing, -SR ^{4 *} and -R ⁹ SR ⁶ , a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 2 8 carbon atoms, -OR ³⁸ , -CO * OR ³ , -00CR ³ , -NR ³ J groups; -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, substituted or unsubstituted saturated monocyclic or polycyclic carbocyclic group, preferably of substituted or unsubstituted saturated monocyclic or polycyclic heterocyclic groups, substituted or unsubstituted saturated monocyclic or polycyclic carbocyclic group, nothing, hydrogen, -SR ^6, and ^-R9 SR ⁶ , R ⁵ represents a group selected from the group consisting of -SR ⁶ and -R ⁹ SR ⁶ , a hydrogen atom, a substituted or unsubstituted alkyl group having from 1 to 8 carbon atoms, -OR ³ , -COOR ³ , -OOCR ³ groups , -NR ^3a , -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 cyclic or polycyclic mono45 carbocyclic groups, substituted or unsubstituted unsaturated monocyclic or polycyclic heterocyclic groups, substituted or unsubstituted unsaturated monocyclic or polycyclic carbocyclic group, and combinations thereof, preferably from the group -SR ^e, and -R ⁹ SR ^e , hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted saturated monocyclic or polycyclic heterocyclic groups and substituted or unsubstituted saturated monocyclic or polycyclic carbocyclic groups, R ² represents a group selected from the group consisting of substituted or unsubstituted C 1 -C 35 alkyl, unsubstituted or substituted phenyl, benzyl or R 5 SR ⁶ , preferably substituted or unsubstituted alkyl having 1 to 35 carbon atoms; 1 to 35 carbon atoms and R ⁶ SR ⁶ ' R ³ represents a group selected from the group consisting of hydrogen, unsubstituted or substituted C 1 -C 8 alkyl and R ⁹ SR ⁶ , preferably represents hydrogen, R ⁶ represents a group selected from the group consisting of hydrogen, -C (O) R ⁷ , -C (S) R ⁷ , -C (O) N (R ⁷ ) ² H -C (O) OR ⁷ , -C (S) N (R ⁷ ) 2, and -C (S) OR ⁷ , wherein R ⁷ represents a hydrogen atom and unsubstituted or substituted C 1 -C 8 alkyl groups, preferably from a hydrogen atom and a group -C (0) ^R7 and -C (S) R ^7, R is a group selected from the group consisting of -PO ₃ H ₂ and -P (O) (OH) R ⁴ wherein R ⁴ is C 1 -C 3 alkyl, preferably -PO ₃ H ₂ and -P (O) (OH) R ⁴ , R ⁹ represents a substituted or unsubstituted C 1 -C 8 alkyl group R ⁸ represents a group selected from the group consisting of hydrogen, halogen, -SR ^e and -R'SR ⁶ , amino, hydroxyl and substituted or unsubstituted C 1 -C 8 alkyl groups, preferably selected from: hydrogen atom and SR group ⁶ . A compound containing a quaternary nitrogen atom of the general 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 compound containing a quaternary nitrogen atom of the formula I according to claim 1, wherein R ^{3 4 5 6 7 8} is a group selected from the group consisting of hydrogen, -SR ⁶ and -R'SR ⁶ , substituted or unsubstituted C 1 -C 8 alkyl groups and substituted or unsubstituted saturated monocyclic or polycyclic heterogeneic cyclic groups. A compound containing a quaternary nitrogen atom of the general formula I according to claim 1, wherein R ¹ is a group selected from the group consisting of nothing, -SR ⁶ and -R ⁹ SR ⁶ and a hydrogen atom. A compound containing a quaternary nitrogen atom of formula (I) according to claim 1, wherein R ⁵ is a group selected from the group consisting of -SR ⁶ and -R'SR ⁶ , a hydrogen atom, and a substituted or unsubstituted alkyl group having 1 to ⁶ carbon atoms. 8 carbon atoms. A compound containing a quaternary nitrogen atom of the general formula I according to claim 1, wherein R ⁵ represents a substituted or unsubstituted C 1 -C 8 alkyl group. 7. A compound having a quaternary nitrogen atom of formula I according to claim 1, wherein ^R is the group -R ⁹ SR ^6th A compound containing a quaternary nitrogen atom of the general formula I according to claim 1, wherein R ⁵ represents a substituted or unsubstituted saturated or unsaturated heterocyclic group. A pharmaceutical composition useful for the treatment of a condition associated with abnormal calcium and phosphate metabolism, comprising: (a) a safe and effective amount of a phosphonate compound according to claim 1; and (b) a pharmaceutically acceptable diluent. The compound of claim 1 for use in treating or preventing pathological conditions associated with abnormal calcium and phosphate metabolism in a human or other animal in need thereof.