CA2112250A1 - Dimethylamino-hydroxy-alkan diphosphonic acids and pharmaceutical compositions containing them - Google Patents

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

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Publication number
CA2112250A1
CA2112250A1 CA002112250A CA2112250A CA2112250A1 CA 2112250 A1 CA2112250 A1 CA 2112250A1 CA 002112250 A CA002112250 A CA 002112250A CA 2112250 A CA2112250 A CA 2112250A CA 2112250 A1 CA2112250 A1 CA 2112250A1
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CA
Canada
Prior art keywords
dimethylamino
acid
hydroxy
diphosphonic
alkan
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002112250A
Other languages
French (fr)
Inventor
Giuseppe Guainai-Ricci
Sergio Rosini
Maurizio Mian
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Istituto Gentili SpA
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Individual
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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

T-TL~
~ew ~im2 ~ ino~ croc~ l'.can cl~.os~honic ac cs zr.c ... . _ _ salts ~ e~~^ , tne~r Drocuction ~rocess and r~lz~Q-c ~:~_r~ace~-.ical com~csi iors.
.
~ ~E5~.~_?TI0~

~ r' Q 1 ~ O - ~_~n - T ,~ ~e n ' isr The ~QS~nt invention relates to new dimet:~yl-amino-h;icro~y--lkan diphosphonic ac ds anc the szl.s thereof.
Furthermore the invention relates to a method for their production, as well as the pharmaceutical compositions containing these product.s.

Description o~ the relevant art :: ` ~ :
It is known ~the~ h1gh comple~ing ac-ivity shown with res?ect to~divalent and poly~alent metallic ions :: .
~ by the diphosphonic~ acids and their water soluble i ~ 20 ~ salts, in particular~o~f the group comprising the ~mino-hydroxy-alkan-d1phos?honic acids, eS~en if used in substo1chiometric ~ quantities. With res?ect ~o ~ polyphosphates, which~show like prope~,ies an can also l~ be used in subs~oichiometric quantities, they ha~ the 25~ ~advantage, as it is well known, of being stable to tne hydrolysis. Thanks to this property the above group or compounds has been used with advantage, inter aliz, in the phar~aceu'ical field for the treatment OL diseases ; associat-d wit~ dis~ rbances ol the bone metabolism, ~ 30 s~ch as 0s,~3~0rosis, Paset's cise~se, osteol~ys~s~ ~ ~ caused by tumourand hyperparathyrodis~, osteoarthrosis, arthritis and tne like.

~ ~ ~ 211225;0 The l- t~7 .-o-l- h ~C-O:C ~ )utan-~ o s~r.or.i c ac G-`.d i _ ~ C ~ a t _ . 2s (s2G Ital_c.. ~c ~ o-1-0108/ _. t..2 na~e o~ t:-~ same ap?licar.t) h-s ~ ven par.icula~l~
2--~c_ ~ ~n -.is ~_s?ect. The a-c.-- c_~.-cunc is ~c= J-S ~ t c_~.c_..__~__~..s ...~ ._ t:;_.. _ ..__s;m~ ci~.os?~onic c~m?ou.cs .iith cor-2s?0-.d-nsl;
lowe~ u~wanted side ef ects.
3 .e_h c-.-nv-h~;c_,:;;-al.~an c~ O__^Gl-'C ac~__ cnC
their cerivz~ives are also knowr~ wnich snow similar pro?erties and ac~i.vity when al~l g.oup is prop~l or butyl. In particular, ~S patent ~0.40s459a discloses, inter alia, the 3-dime~hylamino-hydroxy-propan-1,1-. diphosphonic acid, its preparation a~d uses, while US
patent No.4624947 dlscloses the 4-dimethylamlno-lS hydrQxy-butan-l,l-diphosphonic acid, :its preparation ~: and uses t unaer the form both or the acid and of its ..
water soluble salts. .The latter compounds .are .also described as .possb1le ~ radionuclie caxriers to particular biological~tissues,: such as for example the bone~ t1ssue, for the eYecution ol- scintigraphic ana~Yses (see ~or ins~ance Eurooe~nt patents No.96932 and 96933).
The known ~Frocesses for the preoaration o~
phosphonic acids and in particular o,~ amino-hydroxy alkan-di~hos~honic . aci~s, :~com?r se re~c~ing the corr~espondin~ amino-carboxylic acid witn a mixture of phosphoxous acid and ~ phosphorus halide, such as phosphorus t~ichlor1de, and hydrol~zi nG the poly~ eric products thus obtained in orde- to give the wanted 3D ~dipnos?honic acid to be recover2G unce_ purifiec ~orm, : for e~am51e, b~I cr~stalliz~tion.
~: According to US patent No.~A07761 the reaction is :conducted in the presence or an organic inert :: ~
, ~

W~93/00348 PCT/~2/00~58 _ 3 _ 2il2250 - 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 ox inert substances and with different reactants molar ratios, using water as hydrolyzing agent and recovering the wanted amino diphosphonic ~cid 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~ diphosphonic acids can be prepared from the corresponding dimethylamino-l-amino-alkan-l-hydroxy-l,l-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 ~; sol~ent or an inert inorganlc diluent followed by hydroly5is in water. As an alternative the reactant acid can be obtalned by phosphonylation of the : corresponding dimethylated aminoacid with phosphorous ,, :
:~ ~ acid in the presence of PCl3 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-hydrcxy-alkan~ 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 .

W093/~0~8 PCTt~2/0~0~8 21122~0 dimethylamino-l-hydroxy-alkan-l,l-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 ob~ects are reached with the new dimethylamino-l~hydroxy-alkan-l,l-diphosphonic acids and salts ~hereof which are characterized by the formula N - ~CH2)n ~ f-OH

wher in n=4 or 5 More particularly, the compounds according to the ~; present invention are the 5-dimethylamino-1-hydroxy-: pentan-l,l-diphosphonic acid (DAPeDP) and the 6-dimethylamino-l-hydroxy-hexan-l,l-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. Accordiny to known methods already in: use for compounds of the same class, both DAPeDP and DABDP can be o~tained respectively from the 5;-dl~ethylamino-1-amino-pentan-1,1-diphosphonic acid and from the 6-dimethyl-1-amino-esan~ diphosphonic acid by react~lon with nitrous acid or with reactants capabIe 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-: ~ :

2~122~0 ci.~-~ ~.O~~?r^~t~ vlt~ Gn, 2mou;~.~ o- ?~r, si~c:^ ~ c:~e_ t~ e s.olchiome_~ic unce_ ann-,c~ous conc-_ic-s a..c in the ?res~nce o' an iner~ sollJe-.t or C' "~ ?rC'-C_ 05_' i -.eC ~ his va~ ls .:----or.._-. 30t'^. ~.-Pe~2 _-.d D.'~DP c~n ais~ ~e procuc^~
reac.ins the 5-~lmeth~lamino valeric acid and, _S___=' ';2 ',', .-e o-d'me_h~-l~mino ca~roic ac~c H3P03 and P.{3 (wrere ~ = halogen~ either in the presence o~ or in the absence of solvents or diluting agents. The molar ratios among the reactants ~aminoacia: H3P03:P~3) are quite variable, generally comprlsed between 1:1:1 and 1:20:5 acording to ~rhether 'a solvent is use~d or not. Preferred'molar ratio or '~ 15 1:5:2 in the absence of a solvent is used.
~' The product obtained in this way is subjected to hydrolysis wnich can be perrormed both with a non-oxidizing strong acid in aqueous solution and }or a : :
longer time with~ water only. The 5-dimethylamino 2a valeric acid and the 6-dimethylamino caproic acic can be obtained;by dialkylation according to methods ~nown ' in'the`art.
est ma'de or car-vLnq out the inventlon A~art rrom the above described known processes LOr pr'oducin~; t:-~e com~ou~ds of the ~res2nt inven~ion, accord~ng to the same invention there is provided an origl~nl method ~;p~rtlcularly suitable, even on industrial scale, for the production OL compounds OL
; the for~ula:

N - (CH2)n - C-OH
CH3 P3~2 wherein n is eaual to 4 or 5'.

W093/00~ ~ ;, PCT/~2/00058 i. ! , 211~ 6 - ! 'T~e 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 51:10:4 under reflux for a time variable irom 0.5 and 3 hours. The mixture of reaction is then concentrated under vacuum and at a temperature of 100-120C until distillation has gone to end and the residual product thus obtained is directl~ passed to the reaction with H3P03 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 correspon ing 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 ln a considerable overall saving of the process. ; ~
Practica1~ examples of the method according to the invention are given herebelow.
Example l 25~ ~131;,2 ~g (l~ mole~ of 6-amino-caproic acid are dissolved in 190 ml (5 moles) of 99% formic acid and 170 ml (2,2 molesjiof a 40% solution formic aldehyde;
` the solution is kept under reflux for 3 hours and then concentrated under vacuum up to about llO~C until the end of distillation. The reaction apparatus is placed nder nitrogen and 246 g (3 moles) of H3PO3 are added;
the temperature is raised to 90C and 363 ml (4,14 moles) of PCl3 are gradually added. The mixture is kept :~ :
,~ ~
j:

W093/~0~8 PCT/~2/0~058 - 7 - 21~ 22~
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, con~entrated and treated with methanol until a white powder is obtained which is then filtered, washed with distillëd water and dried at 40~C under vacuum.
164.8 g (O,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 PCl3 ar~ dissolved in a mixture of 5-dimethylamino-valerianic acid ~145,2 g, 1 mole) and H3PO3 (246 gr 3 moles3 by a dropwise addition under anh~drous condltions~ under ~acuum and stirring;
the solution is kept under slow PCl3 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 ~hen treated with decolorizing char~oal a~d filtered. An equal vol~me of methanol is then added and the solu~lon 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 mo~es~ of 5-dimethylamino-hydroxy-pentan-l,l-diphosphonic acid are obtained, the identity is confirmed by the elementary, alkalimetric and - ~ 30 spectroscopic analyses. The yield is equal to 58%.
: Examele 3 ~
~: ~ 206 g (1,5 moles) of PCl3 are slowly added under stirring to a suspension obtained by mixing 159.2 g tl .. . . . ...

WOg3/0~8 PCT/~2/00058 mole) of 6 ~ Q ino caproic acid with 164 g (2 moles) of H3PO3 in 500 ml of chlorobenzene brought to 90C under a nitrogen stream; the mixture is moderately refluxed for 3 hours and then is caused to cool.
5500 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 60C. 192.3 g (0.63 moles) of 6-dimethylamino-hydroxy-hexan-1,1-diphosphonic acid are obtained the identity of which is confirmed by the elementary alkalimetric and spectroscopic analyses.
~; ~ The yield i~s 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, NH40H, aIkaline 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 Cl-C3 alcohol~or acetone.
25The diphosphonic acids according to the present invention and their saline derivatives are suitable for ;~ ~ the preparation of pharmaceutical compositions useful ~ , :
in the therapeutic or pr ventive treatment of diseases associated~with ~dlsturbances of bone metabolism, such as osteoporosis, Paget's disease, osteolysis caused by tumours ~ and hyperparathyroidsm, osteoarthrosis, arthrytis and the like.

:"

- -~112250 - 8~ -Toxicoloqical studies Acute toxicity of DAEDP and DAPeDP has been tested on CD
rats "Charles River" of a weight equal to 2~0 g. 8 groups of rats each consistir.g of 8 female rats have been used.
The test compounds are in~culated in the caudal vein by 23G mirage microperfusor with 20 s administering time and an administered volume of 0.2 ml/100 g b.w. in a sterile, phisiological solution.
The tested doses have been the following:
- DAEDP : 60 and 30 mg/kg b.w.
- AEDP : 60 and 30 mg/kg b.w.
- DAPeDP : 90 and 45 mg/kg b.w.
APeDP : 90 and 45 ~g/kg b.w.

~15 The animals undergone the test were observed and controlled as to the death rate, the behaviour and the general conditions all over the first day o~ treatment and twice a day the next l4 days to evaluate possible clinical .
:behaviour modi~ications.
~ 2~0 '`',~:; ~: /

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-~ethylated products. The results of these studies are summarized herebelow.
a) 6-dimethYlamino-l-hYdroxy-hexan-l,l diphosohonic 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 amino-hydroxy-hexan-diphosphonate (AEDP) a death-rate of 85% has been recorded, analogous to that recorded in~previous tests on the same product.
Likewise, no c~se of death ~has- been recorded when the animals`are~ tre~ated~ with a dose of 30 mg/kg of DAEDP, is whereas a death-rate; of ~5% is recorded when using an ~ , ~
; equal dose of sodic ~amino-hydroxy-hexan-diphosphonate .(AEDP).~
b) 5-dimethYlamino-l-hydroxypentan-l,l-diphosphonic ;acid ~(DAPeDP) ~ ~
20~ No case~of~ death has been recorded~ for~ animals treated~with doses~af~90 mg/kg of DAPeDP, whereas with an equal~ ~dose ~of ~sodic~ amlno-hydroxy-pentan-diphosphonat~
`; (APeDP) a death-rate of 75%-has been recorded, slightly lower than that~ recorded in previous tests on the same 25~ produc~t. Llk.ewise,~no case of death has been recorded when the~animals~are treated wlth;45 mg/kg of DAPeDP, whereas a death-rate of 25%~has~ been recorded when an equal dose of sodic~ami~no-hydroxy-pentan-diphosphonate (APeDP~ is used.
Bone resorption inhibition Tests of inhlbition of bone reabsorption induced by SUB~TITUT~ S1 1-EET

2ll22sn - 9a 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~ Lor DAPeDP with the highest dose used in the relevant tests.
The experimental method was the following.
Two day old pups were injected subcutaneously (dorsal midline) with 50~ Qof sterile saline containing 5/~ Ci of Ca45. After four days the pups were sacrificed by decapitation and the calvaria recovered. Thereafter the hemicalvariae were positioned on top of stainless steel screens inside wells of a 24 microwell cluster pla~e each containing a total end-volume of 1.25 mls of culture .medium. The incubatio~n period was divided into two phases.
The fixst phase lasted 24 hr and involved preincubating ::
the calvariae at 37C in a 5% CO2 atmosphere in the presence of indvmethacin so as to inhibit osteoclast ; activation by ~prostaglandins. The second one involved changing the preincubation medium and replacing it with 20~ fresh indomethacin-free medium containing the various test substances plus~ PTH ~80~mg/ml) and incubating all for 72 hr at 37C in a 5%~ CO2 ~atmosphere. After the incubation tha calvarlae with their respective medium (1 ml) were recovered and place~d lnslde~ scintillation vials. Those 25~ vials containing the hemicalvaria were treated with 1 ml of 85% acetic acid and left standing overnight in order to dissolve the mineral con~ent of the neonatal bone. 9 ml of sc1ntillation cocktail was added to each vial and the radioactivity determined with a Bechman LS 6000~ ~ounter.
30~

C:l 11%~TITI IT~ ~s -- 21122~0 Retinoid Test The test was carried out using Sprague Dawley albino ~
rats (6 male animals each test group) from Ch"arles River , breedin~ having a body weight comprised between 250 and 300 g and an age of about 2 months at the beginning of the test. Feed consisted of rodent standard diet, i.e.
Altromin R (Rieper). The rat was selected ,~or the study t being the animal already used for like studies referred to in previous works (see, for instance, A.Stutzer, H.Fleish, U.Trechsel: Calc. Tissue int.- (1988) 43:294 299).
The compound of the invention , was administered intravenously in the penis dorsal vein in a single dose of ,,",~
,0.2 ml/10~ g'b.w. in~a st~erile phis~iological solution. '',~
~ The animals were tiroparatiroidectomized ~according 15 to test n25 of the "Manual for l~boratory work in '``
mammalian phisiologyj F.E.D'amour, F.R.Blood, D.A.Belden '~
Jr., Third edition, .revised) under total anaesthesia ';~', ~; induced by intravenously administering of Nembutal at the ,',"~' ~ concentrat~on of 50 mg/~g~'b.w~
2~0 ~ ~ ~Starting from the~operation day 2; ~ of Tiroxine was , `~
admlnlstered subcutaneous~ly to the animals four times each ,'' week. ';~-The fourth day from the operation the animals were ''-',, subjected to blood abstraction by cutting the end portion ,,"'~,' 25 of the ~tail. The plasma~was~separated from-the ~lood that ~"'' ha~ been added with eparine and total Ca dosage was ,,'', carried out on the plasma by EGTA complexo metric ,,-', titrat~on with a suitable apparatus ~Calcium analyzer '`~"' ~ Coxning 940). The animaIs with a total Ca lower than 2 mM '~
~(about~8; mg/dl) were redistributed in groups with total Ca average value as omogeneous as possible.

SUI~TlTUTE S7~EET

-, - lOa The sæ~e day the animals were treated both with retinoid ~lOO,~e/rat equal to 25 ~ ~ of retinoid administe~ec subcutaneously) and with the compounds u~der test. The treatment with retinoid is carried on for other t,wo days (5th and 6th day from the ope~ation). The 7th day from the operation the animals were subjected to blood abstraction from the abdominal aorta 'under CO2 anaesthesia and next killed by bleeding. The plasma was separated from the blood that had been added with eparine and total Ca dosage was carried out on it as above.
The results show that the dimethylated derivatives l'DAEDP and ~APeD,P3 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 lS corresponding non-dimethylated compounds even if used at the same doses4 The pharmaceutical compositions according to the present invention can be prepared in the form of:
- tabletsj capsules, granules, pills, for oral administration; ~ ~
- drops for oral administration;
- solutions for intra-articular or intravenous administration; ~ ' ' -'creams for local use.
The above compositlons are advantageously prepared in comb~nation with ~ inert e~cipients, such as sugars (saccharose;,~ glucose, lactose), starch and derivatives, cellulose and derlvatives, fatty acids and salts ~hereof, polyalcohols, talc, aromatic esters. Typical :

~ ~ I S~:2T1 T~ I TC Q~l 1:: ~T

~1122~0 - lo~ -pharmaceutical formulations contaning the 5-dimethylamino-hydroxypentan-l,l,-diphosphonic acid tDAPeDP) are given below.
OPERCUL~TE 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 mg buffer . 1 mg .
. ~. .~

"
,..
r' .
:~
: :
~ ~ ' , ', ,~

:
.

~:: ,.' : '- ' -2TlTI IT~ ~::FT

, W0~3/0~34~ PCT/~2/ ~ 58 11 21122~0 stabilizing, ar~matizing trace purified water balance INJECTABLE SOLUTION - One phial contain DAPeDP 20 mg sodium chloride 40 mg.
sodium bicarbonate lN soln. 0.15 mg methyl parahydroxybenzoate 5 mg purified water 5 ml INJECTABLE SOLUTION FOR INTR~-ARTICULAR
ADMINISTRATION -One ampoule contains DAPeDP 1 mg : 15 anhydrous sodlum hydroxyde 0,325 m~
lidocaine:hydrochloride 1 mg glycine ; 20 mg water pH 6.45 1 mg ~; 20 GRANULAR PROD~CT - One dose contains ~: DAPeDP ~ ~ 200 mg talc ~ - 10 mg magne~sium stearate 2 mg sillca gel 4 mg 25 ~ ~ ~ornstaxch 9 my : ~ :

"
EFFERVESCENT GRANULAR PRODUCT - One dose contains DAPeDP : 15 mg :: : : : :
: : anydhrous sodium car~onate 12 mg : 30 : sodium bicarbonate 63 mg anyhydrous citrIc acid 110 mg sodium saccharinate 5 mg ::
~ saccharose 493 mg : :

~: ~

W093/00~8 P~T/1T92/000~8 211~2~0 - 12 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.~ g preservative, stabilizers 0.5 g distilled water 100 g Similar formulations can be adopted when 6-1~ dimethylamino-hydroxyhexan-l,l-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 th~
therapeut:ic use and referred to 1 Kg of body weigh~ can be the~followlng:
Capsules~,~tablets 5 - 400 mg drops~ ~ 5 - 200 mg . phia~l~ 1 - 100 mg :~ subcutaneous~phial 1 - 50 mg : intramuscular phial 1 - 50 mg .intra-artlcular phial 0.1 - 5 mg :

~ 30 ~ ~
: :
:. ::: ~ : ::

~ ~ :
' ~

Claims (8)

1. Dimethylamino-1-hydroxyalkan-1,1-diphosphonic acids of the formula:
wherein n= 4 or 5
2. 5-dimethylamino-1-hydroxypentan-1,1-diphosphonic acid of the formula:
3. 6-dimethylamino-1-hydroxyhexan-1,1-diphosphonic acid of the formula:
4. A process for the preparation or dimethylamino-hydroxy-alkan-diphosphonic acids of the formula:
wherein n= 4 or 5, characterized in that it comprises:

- reacting 5 amino-valeric acid or 6 amino-caproic acid with formic acid and 40% solution formaldeyde 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 or about 6 hours and subjecting to crystallization;
5. A process according to the claim 4, wherein the reaction between said corresponding aminoacid, formic acid and 40% solution formaledeyde is carried out under reflux for a time comprised between 0.5 and 3 hours.
6. A process according to the claim 4, wherein the concentration under vacuum of the reaction mixture between said corresponding aminoacid, formic acid and formaldeyde 40% solution is carried out until the distillation is complete.
7. A pharmaceutical composition comprising an effective amount of dimethylamino-1-hydroxy-almkan-1,1-diphosphonic acid according to the claim 1, or a pharmaceutically acceptable water-soluble salt thereof and suitable pharmaceutical excipients.
8. 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, esteoarthrosis, arthritis.
CA002112250A 1991-06-26 1992-05-27 Dimethylamino-hydroxy-alkan diphosphonic acids and pharmaceutical compositions containing them Abandoned CA2112250A1 (en)

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ITFI/91/A/000160 1991-06-26
ITFI910160A IT1247034B (en) 1991-06-26 1991-06-26 DIMETHYLAMINE-HYDROXY ACIDS DIPHOSPHONICS AND THEIR SALTS, THEIR PRODUCTION PROCESS AND PHARMACEUTICAL COMPOSITIONS THAT INCLUDE THEM

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IT1303672B1 (en) 1998-07-28 2001-02-23 Nicox Sa NITRATED SALTS OF DRUGS ACTIVE IN BONE DISORDERS
DE60235085D1 (en) * 2001-07-16 2010-03-04 Univ Paris Xiii PREPARATION OF DERIVATIVES OF BISPHOSPHONATES
DE102014115154A1 (en) * 2014-10-17 2016-04-21 SCV-SpezialChemikalien-Vertrieb GmbH Conjugated bisphosphonates for the diagnosis and treatment of bone diseases

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IT1194748B (en) * 1981-02-12 1988-09-28 Gentili Ist Spa PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF OSTEOPATHIES
IT1201087B (en) * 1982-04-15 1989-01-27 Gentili Ist Spa PHARMACOLOGICALLY ACTIVE BIPPHOSPHONES, PROCEDURE FOR THEIR PREPARATION AND RELATED PHARMACEUTICAL COMPOSITIONS
DE3434667A1 (en) * 1984-09-21 1986-04-03 Henkel KGaA, 4000 Düsseldorf 4-DIMETHYLAMINO-1-HYDROXYBUTANE-1,1-DIPHOSPHONIC ACID, THEIR WATER-SOLUBLE SALTS, PROCESS FOR THEIR PRODUCTION AND THEIR USE
DE3623397A1 (en) * 1986-07-11 1988-01-14 Boehringer Mannheim Gmbh NEW DIPHOSPHONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS

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PT100624B (en) 1999-07-30
IT1247034B (en) 1994-12-12
AU2150792A (en) 1993-01-25
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MX9203205A (en) 1994-06-30
EP0592488A1 (en) 1994-04-20
ITFI910160A0 (en) 1991-06-26
JPH06508833A (en) 1994-10-06
PT100624A (en) 1993-10-29
WO1993000348A1 (en) 1993-01-07

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