WO1993000348A1

WO1993000348A1 - Dimethylamino-hydroxy-alkan diphosphonic acids and pharmaceutical compositions containing them

Info

Publication number: WO1993000348A1
Application number: PCT/IT1992/000058
Authority: WO
Inventors: Giuseppe Guainai-Ricci; Sergio Rosini; Murizio Mian
Original assignee: Istituto Gentili S.P.A.
Priority date: 1991-06-26
Filing date: 1992-05-27
Publication date: 1993-01-07
Also published as: ITFI910160A0; MX9203205A; PT100624A; JPH06508833A; AU2150792A; EP0592488A1; IT1247034B; PT100624B; CA2112250A1; ITFI910160A1

Abstract

Dimethylamino-1-hydroxy-alkan-1,1-diphosphonic acids of formula (I), wherein n = 4 or 5 and a process for their production, as well as use for the treatment of diseases associated with disturbances of bone metabolism.

Description

DIMETHYLAMINO-HYDROXY-ALKAN DIPHOSPHONIC ACIDS AND PHARMACEUTICAL COMPOSITION CONTAINING THEM

5 DESCRIPTION

Field of the Invention

The present invention relates to new dimethyl- amino-hydroxy-alkan diphosphonic acids and the salts 0 thereof.

Furthermore the invention relates to a method for their production, as well as the pharmaceutical compositions containing these products.

5 Description of the relevant art

It is known the high complexing activity shown with respect to divalent and polyvalent metallic ions by the diphosphonic acids and their water soluble 0 salts, in particular of the group comprising the amino- hydroxy-alkan-diphosphonic acids, even if used in substoichiometric quantities. .With respect to polyphosphates, which show like properties and can also be used in substoichiometric quantities, they have the 5 advantage, as it is well known, of being stable to the hydrolysis. Thanks to this property the above group of compounds has been used with advantage, inter alia, in the pharmaceutical field for the treatment of diseases associated with disturbances of the bone metabolism, 0 such as osteoporosis, Paget's disease, osteolysys caused by tumourand hyperparathyrodism, osteoarthrosis, arthritis and the like. The 4-amino-l-hydroxy-butan-l,1-diphosphonic acid and its derivatives (see Italian patent No.1201087 in the name of the same applicant) has proven particularly effective in this respect. The above compound is active and effective at concentrations much lower than other similar diphosphonic compounds with correspondingly lower unwanted side effects.

Dimethylamino-hydroxy-alkan diphosphonic acids and their derivatives are also known which show similar properties and activity when alkyl group is propyl or butyl. In particular, US patent No.4054598 discloses, inter alia, the 3-dimethylamino-hydroxy-propan-l,l- diphosphonic acid, its preparation and uses, while US patent No.4624947 discloses the 4-dimethylamino- hydroxy-butan-1,1-diphosphonic acid, its preparation and uses, under the form both of the acid and of its water soluble salts. The latter compounds are also described as possbile radionuclide carriers to particular biological tissues, such as for example the bone tissue, for the execution of scintigraphic analyses (see for instance Europeant patents No.96932 and 96933) .

The known processes for the preparation of phosphonic acids and in particular of amino-hydroxy- alkan-diphosphonic acids, comprise reacting the corresponding amino-carboxylic acid with a mixture of phosphorous acid and phosphorus halide, such as phosphorus trichloride, and hydrolyzing the polyemeric products thus obtained in order to give the wanted diphosphonic acid to be recovered under purified form, for example, by crystallization.

According to US patent No.4407761, the reaction is conducted in the presence of an organic inert substance, for example a chlorinated hydrocarbon such as chlorobenzene, while the hydrolysis is conducted with a not oxidizing strong acid. According to another process described in US patent No.4705651, the same reaction is conducted without either solvents or inert substances and with different reactants molar ratios, using water as hydrol zing agent and recovering the wanted amino diphosphonic acid by precipitation with an alcohol which is added to the hydrolized solution. According to US patents No.4054598 and No.4624947 the dimethylamino-l-hydroxy-alkan-1,1-diphosphonic acids can be prepared from the corresponding dimethylamino-l-amino-alkan-l-hydroxy-1,1-diphosphonic acids by reaction with nitrous acid, salts thereof and compounds forming nitrous acid under the reaction conditions,while the reactant acid can be obtained from the corresponding nitrile by reaction with phosphorous halide under anhydrous conditions in the presence of a solvent or an inert inorganic diluent followed by hydrolysis in water. As an alternative the reactant acid can be obtained by phosphonylation of the corresponding dimethylated aminoacid with phosphorous acid in the presence of PCI3 or by other phosphonylation reactions well known to the person skilled in the art.

It is an object of the present invention to provide new dimethylamino-l-hydroxy-alkan-1 ,1-diphosphonic acids, their derivatives and water soluble salts.

It is a further object of the present invention to provide a process for the industrial production of the above mentioned compounds.

Another object of the invention is to provide pharmaceutical compositions comprising the dimethylamino-l-hydroxy-alkan-1,1-diphosphonic acids, their derivatives and water soluble salts according to the present invention for the administration to patients suffering from diseases associated with disturbances of bone metabolism.

Summary of the Invention

The above objects are reached with the new dimethylamino-l-hydroxy-alkan-1,1-diphosphonic acids and salts thereof which are characterized by the formula

CH₃ P0₃H₂

N - (CHo - C-OH

CH₃ PO3H2 wherein n=4 or 5

More particularly, the compounds according to the present invention are the 5-dimethylamino-l-hydroxy- pentan-1,1-diphosphonic acid (DAPeDP) and the 6- dimethyla_ιino-l-hydroxy-hexan-l,1-diphosphonic acid (DAEDP) , as well as their non-toxic, pharmaceutically acceptable, water-soluble salts.

The compounds according to the present invention can be prepared in several ways. According to known methods already in use for compounds of the same class, both DAPeDP and DABDP can be obtained respectively from the 5-dimethylamino-l-amino-pentan-l,1-diphosphonic acid and from the 6-dimethyl-l-amino-esan-l,l-diphosphonic acid by reaction with nitrous acid or with reactants capable of forming nitrous acid under the reaction conditions. The dimethylated amino-alkyl diphosphonic acids used as reactants can be obtained by reaction of 5-dimethylamino-valeronitrile and, respectively, of 6- dimethylamino-capronitrile with an amount of PBr3 slightly higher than the stoichiometric under anhydrous conditions and in the presence of an inert solvent or diluent. The product obtained in this way is then treated with hot water to hydrolize the polymers thus formed. Both DAPeDP and DAEDP can also be produced by reacting the 5-dimethylamino valeric acid and, respectively, the 6-dimethylamino caproic acid with H3PO3 and PX3 (where X = halogen) either in the presence of or in the absence of solvents or diluting agents. The molar ratios among the reactants (aminoacid: H3PC>3:PX3) are quite variable, generally comprised between 1:1:1 and 1:20:5 according to whether a solvent is used or not. Preferred molar ratio of 1:5:2 in the absence of a solvent is used.

The product obtained in this way is subjected to hydrolysis which can be performed both with a non- oxidizing strong acid in aqueous solution and for a longer time with water only. The 5-dimethylamino valeric acid and the 6-dimethylamino caproic acid can be obtained by dialkylation according to methods known in the art.

Best made of carrying out the invention

Apart from the above described known processes for producing the compounds of the present invention, according to the same invention there is provided an origianl method particularly suitable, even on industrial scale, for the production of compounds of the formula:

wherein n is equal to 4 or 5. The method consists in reacting the 5-amino valeric acid, or respectively- the 6-amino caproic acid with formic acid and formaldehyde 40% solution with molar ratios generally comprised between 1:2:2 and 1:10:4 under reflux for a time variable from 0.5 and 3 hours. The mixture of reaction is then concentrated under vacuum and at a temperature of 100-120°C until distillation has gone to end and the residual product thus obtained is directly passed to the reaction with H3PO3 and PX3 in the previously indicated, known molar ratio without the need of isolating any intermediate product. The product resulting from the reaction can be easily recrystallized from water if necessary.

The above described method allows for the final product to be obtained from the corresponding aminoacids which are more easily available and less expensive than the corresponding dimethylamino substituted acids that are thus formed in situ and reacted with no need for their purification, this obviously resulting in a considerable overall saving of the process.

Practical examples of the method according to the invention are given herebelow. Example 1 131,2 g (1 mole) of 6-amino-caproic acid are dissolved in 190 ml (5 moles) of 99% formic acid and 170 ml (2,2 moles) of a 40% solution formic aldehyde; the solution is kept under reflux for 3 hours and then concentrated under vacuum up to about 110°C until the end of distillation. The reaction apparatus is placed under nitrogen and 246 g (3 moles) of H3PO3 are added; the temperature is raised to 90°C and 363 ml (4,14 moles) of PCI3 are gradually added. The mixture is kept under low reflux for 3 hours and then cooled. 500 ml of distilled water are then slowly added and heat is provided at low rate until an omogeneous solution is obtained; after 6 hours reflux, the solution is filtered with decolorizing coal, concentrated and treated with methanol until a white powder is obtained which is then filtered, washed with distilled water and dried at 40°C under vacuum.

164.8 g (0,54 moles) of 6-dimethylamino-hydroxy- hexan-l,l-diphosphonic acid are obtained whose identity and high purity are confirmed with the analyses. Example 2 206 g (1,5 moles) of PCI3 are dissolved in a mixture of 5-dimethylamino-valerianic acid (145,2 g, 1 mole) and H3PO3 (246 g, 3 moles) by a dropwise addition under anhydrous conditions, under vacuum and stirring; the solution is kept under slow PCI3 reflux for 3 hours and then caused to cool.

600 ml of distilled water are cautiously added while maintaining the reaction vessel in a ice bath; once the solution is become homogeneous, it is refluxed for 6 hours and then treated with decolorizing charcoal and filtered. An equal volume of methanol is then added and the solution is left under stirring for 24 hours. The obtained product is filtered washed with distilled water and dried at 60°C.

168.9 g (0,58 moles) of 5-dimethylamino-hydroxy- pentan-1,1-diphosphonic acid are obtained, the identity is confirmed by the elementary, alkalimetric and spectroscopic analyses. The yield is equal to 58%. Example 3

206 g (1,5 moles) of PCI3 are slowly added under stirring to a suspension obtained by mixing 159.2 g (1 mole) of 6-dimethylamino caproic acid with 164 g (2 moles) of H3PO3 in 500 ml of chlorobenzene brought to 90°C under a nitrogen stream; the mixture is moderately refluxed for 3 hours and then is caused to cool. 500 ml of distilled water are then added slowly and under stirring, once any solid matter possibly present is separated and the acqueous phase is refluxed for 6 hours. After cooling and filtering with decolorizing charcoal an equal volume of methanol is added and the mixture is left under stirring for 24 hours. The product obtained is filtered, washed with distilled water and dried at 60°C. 192.3 g (0.63 moles) of 6-dimethylamino-hydroxy-hexan-l,l-diphosphonic acid are obtained the identity of which is confirmed by the elementary alkalimetric and spectroscopic analyses.

The yield is equal to 63%. The water-soluble salts of the acids according to the present invention can be obtained by complete or partial neutralization with inorganic, organic bases or quaternary ammonium, such as NaOH, KOH, NH OH, alkaline carbonates, alkanolamines, and the like, and isolating the salt by a following concentration up to crystallization or, alternately and more simply, by precipitation with a C1-C3 alcohol or acetone. The diphosphonic acids according to the present invention and their saline derivatives are suitable for the preparation of pharmaceutical compositions useful in the therapeutic or preventive treatment of diseases associated with disturbances of bone metabolism, such as osteoporosis, Paget's disease, osteolysis caused by tumours and hyperparathyroidsm, osteoarthrosis, arthrytis and the like. The toxicological studies which have been carried out have shown a toxicity of the compounds of the invention much lower than that of the corresponding non-methylated products. The results of these studies are summarized herebelow. a) 6-dimethylamino-l-hydroxy-hexan-l ,1- diphosphonic acid (DAEDP) .

No case of death has been recorded for animals treated with doses of 60 mg/Kg of DAEDP, whereas with an equal dose of sodic aminohexandiphosphonate a death- rate of 85% has been recorded, analogous to that recorded in previous tests on the same product. Likewise, no case of death has been recorded when the animals are treated with a dose of 30 mg/Kg of DAEDP, whereas a death-rate of 25% is recorded when using an equal dose of sodic aminohexandiphosphonate. b) 5-dimethylamino-l-hydroxypentan-l ,1- diphosphonic acid (DAPeDP)

No case of death has been recorded for animals treated with doses of 90 mg/Kg of DAPeDP, whereas with an equal dose of sodic aminopentandiphosphonate a death-rate of 75% has been recorded, slightly lower than that recorded in previous tests on the same product. Likewise, no case of death has been recorded when the animals are treated with 45 mg/Kg of DAPeDP, whereas a death-rate of 25% has been recorded when an equal dose of sodic aminopentan-diphosphonate is used.

Tests of inhibition of bone reabsorption, induced by parathormone in the calve of newborn rats, show a dose-dependant inhibitory activity which has been found with all the concentrations used with a maximum of 55.9% for DAEDP and 64% for DAPeDP with the highest dose used in the relevant tests. Re inoid Test: the results show that the dimethylated derivatives (DAEDP and DAPeDP) according to the invention are able to inhibit the bone reabsorption in vivo induced by retinoid. The compounds have been proven more effective than the corresponding non-dimethylated compounds even if used at the same doses.

The pharmaceutical compositions according to the present invention can be prepared in the form of: - tablets, capsules, granules, pills, for oral administration;

- drops for oral administration;

- solutions for intra-articular or intravenous administration; - creams for local use.

The above compositions are advantageously prepared in combination with inert excipients, such as sugars (saccharose, glucose, lactose) , starch and derivatives, cellulose and derivatives, fatty acids and salts thereof, polyalcohols, talc, aromatic esters. Typical pharmaceutical formulations containing the 5- dimethylamino-hydroxypentan-1,1,-diphosphonic acid (DAPeDP) are given below.

OPERCULATE CAPSULES - One capsule contains DAPeDP 25 mg lactose 84 mg hydrolyzed starch 5 mg talc 5 mg magnesium stearate 1 mg

DROPS - 10 ml contain

DAPeDP 1 g buffer 1 ml stabilizing, aromatizing trace purified water balance

INJECTABLE SOLUTION - One phial contain

DAPeDP 20 mg sodium chloride 40 mg sodium bicarbonate IN soln. 0.15 mg methyl parahydroxybenzoate 5 mg purified water 5 ml

INJECTABLE SOLUTION FOR INTRA-ARTICULAR ADMINISTRATION -

One ampoule contains

DAPeDP 1 mg anhydrous sodium hydroxyde 0,325 mg lidocaine hydrochloride 1 mg glycine 20 mg water pH 6.45 1 mg

GRANULAR PRODUCT - One dose contains

DAPeDP 200 mg talc 10 mg magnesium stearate 2 mg silica gel 4 mg cornstarch 9 mg

EFFERVESCENT GRANULAR PRODUCT - One dose contains

DAPeDP 10 mg anydhrous sodium carbonate 12 mg sodium bicarbonate 63 mg anyhydrous citric acid 110 mg sodium saccharinate 5 mg saccharose 493 mg dehydrated lemmon juice 55 mg le mon natural juice 2 mg

3% CREAM DAPeDP 3 g cetyl alcohol 18 g propylene glycol 10 g

PEG monostearate 4 g cholesterin-stearate 1 g linol-linoleic acid 1.5 g preservative, stabilizers 0.5 g distilled water 100 g

Similar formulations can be adopted when 6- dimethylamino-hydroxyhexan-1,1-diphosphonic acid (DAEDP) is used.

The dosage range of the diphosphonic acids according to the present invention and of the relevant water-soluble saline derivative, according to the therapeutic use and referred to 1 Kg of body weight can be the following:

Capsules, tablets 5 - 400 mg drops 5 - 200 mg i.v. phial 1 - 100 mg subcutaneous phial 1 - 50 mg intramuscular phial 1 - 50 mg intra-articular phial 0.1 - 5 mg

Claims

1. Dimethylamino-l-hydroxyalkan-1,1-diphosphonic acids of the formula:

wheren n= 4 or 5

2. 5-dimethylamino-1-hydroxypentan-l,1-diphosphonic acid of the formula:

3. 6-dimethylamino-1-hydroxyhexan-l,1-diphosphonic acid of the formula:

4. A process for the preparation of dimethylamino- hydroxy-alkan-diphosphonic acids of the formula

wherein n= 4 or 5, characterized in that it comprises: reacting a corresponding aminoacid with formic acid and 40% solution formaldehyde according to a molar ratio comprised between 1:2:2 and 1:10:4; - concentrating under vacuum the reaction mixture at 100-120°C;

- reacting the concentrate with H3PO3 and with PX3 (X-halogen) according to a molar ratio known in the art; diluting with distilled water under reflux for about 6 hours and subjecting to crystallization;

- filtering, washing with distilled water and drying under vacuum the crystalline precipitate.

5. A process according to the claim 4, wherein said corresponding aminoacid is 5-amino valeric acid.

6. A process according to the claim 4, wherein said corresponding amino acid is 6-aminocaproic acid.

7. A process according to the claim 4, wherein the reaction between said corresponding aminoacid, formic acid and 40% solution formaldehyde is carried out under reflux for a time comprised between 0.5 and 3 hours.

8. A process according to the claim 4, wherein the concentration under vacuum of the reaction mixture between said corresponding aminoacid, formic acid and formaldehyde 40% solution is carried out until the distillation is complete.

9. A pharmaceutical composition comprising an effective amount of dimethylamino-l-hydroxy-alkan-1,1- diphosphonic acid according to the claim 1, or a pharmaceutically acceptable water-soluble salt thereof and suitable pharmaceutical excipients.

10. Use of dimethylamino-hydroxy-alkan-1,1- diphosphonic acids according to the claims 1,2 and 3 and pharmaceutically acceptable water-soluble salts thereof, for the preparation of drugs effective in the treatment of diseases associated with disturbances of bone metabolism such as osteoporosis, Paget's disease, osteolysis caused by tumours or hyperparathyroidism, osteoarthrosis, arthritis and the like.