CA2109318A1 - Medicaments containing azacyclodiphosphonic acid derivatives, new azacyclodiphosphonic acid derivatives, as well as processes for their preparation - Google Patents

Abstract

Summary Medicaments for the treatment of bone metabolism disturbances containing at least one compound of the formula I

Description

`^`` -2- 2~93~ 8 .
Boehringer Mannheim GmbH 3501/00/WO ~ -~
Medicaments containin~ azacyclodiphosphonic ao~d ---..... . .. . ... ... .
derivativest new azacyclodiphosphonic acid deriv~
atives~ as well as processes for their PrePar~tion The present invention concerns medicaments which contain azacyclodiphosphonic acid derivatives, new azacgclodipho~phonic acid derivatives~ 85 well ~ . ,, as processe~ for their preparation.
. , ,~
In D~-OS 2611768 and in D~-OS 2610678 are described azsc~cloalkane~dip~hGsphoric acids as components of photographic colour developer mixtures and pigment slurries as good calcium complex formers.
~here are specifioall~ mentioned azscycloheptsne~
(2,2)-diphosphonic ~cid, azac~clopentane (2,2)-dipho~phonic acid snd azacgclotridecane-(2,2)~
,: , . . .
diphosphonic acid and their salts.
- -: .
In D~-OS 2541981/D~-OS 2343196 are mentioned proces~es for the preparstion of these azacgclo~
- -, ....
alkane-diphosphonic acids.
It has now bcen found that azacgcloalkans-diphosphonic acid derivatives also show an excellent action on the calcium metsbeli~m and thus ;
are suitable for th~ broad treatment of calcium metabolism disturbancesO In particular, they can be uerg well used there where the bone build~up and breakdown is disturbed, i.e. the~ are suitable for the treatment of disesses of the skeletal sgstem, such a8 e.~ osteoporosis9 Paget!~ disesse, ~ 3_ 2~0~3~8 .;
Bechterew's dise~se and the like~
However, one the basis of these proper~ies, theg ~Iso find u~e in the therapg of urolithiasis ~nd for the prevention of heterotopic ossifications~ Further-5 more, due to thair influencing of the calcium :
metaboliDm, the~ ~orm a b~si~ for the treatment of ~ ~
rheumatoid arthriti~, of osteoarthritis and of -degenerative arthosis.
COnd~uentlg~ the sub~ect of the present invention are medicsments which contain diphosphonates of the general formuls I, ~5 well as their phsrmacologicall~
compatible sslt~
n ~OR.
P

(a ~ / \ ~OR (I) N~ Il~OR
O
in which R = hydrogen or Cl~C4-alkgl and n = 7 - 16, : :
and t heir use for the treatment o~ bone metaboliam disturbanc~
~ he rs~ical R prefersblg signifies hgdrogen or the methgl~ ethgl or isobutgl radical~
ni~ ~referablg 8, 9, 10, 11~ 12 ~he subject of the in~ention are also new compounds of the general formula I' , _ :
`` _4_ 2~0~31~ ~

~ OR ~;-~. ;
(CH2)n, ~ ~ OR (I), -N~ ~~ OR
', ~ ~ ~ ' ' - "' in which R ~ignifie~ h~drogen or CI-C4-slkyl and n' = 7 - 16, as well as their phsrmacologicslly ~ :compatible ~alts, whereby n' ma~ not aqual llo ~-;
;~ 5 ~he radical R prefersblg signi~ies hgdrogen or the ~; ~ me~h~l, ethgl or i~obutgl radicsl.
n' is pr~ferablg 8, 99 10 or 12.
a~ompQ~nds of the genersl formuls I are prepared sccording to per ~e known proce~ses.~ prefersbly takes place bg reaction of a lactam of the ~eneral formula II -(C~2)n / (II), i~ which n hae the above-given meaning~ with 8 mixture of phoeph~rous acid or phosphoric acid and a phosphoru~ ha~ide or phosphor~l hslide or also in that one brings the pho~phorus halide slone to :~
reaction in the.presence of water and sub~equentlg h~drol~ to the rree diphosphonic scid or~ if desired, convert~ the~i~olated compound~ Or the ~eneral formula I into their e~ters o~ pharmacol~
ogicallg compatible ~alt~

2~3~
~ he lactsms of the general formula II used in the preparstion process are mixed with i ~ 5, preferabl~ 2 ~ mol of phosphorous acid or phosphoric acid and 1 - 5, preferabl~ 2 - 3 mol phosphorgl halide, phosphorus trihalide or phosphorus pentahalide and brought to reaction at 80 - 100C, preferabl~ 100~, under inert ga~ atmosphere, ~ ~
preferabl~ nitroKen atmosphere. In the case of the - -phoEiphorus or phosph~rgl halides, it is preferablg quegtion of the chlorides or bromides. One can also carrg out the reaction in the pre~ence of dilution agents, such a~ halogenated h~drocarbons, especiallg chlorobenæene, tetrachloroethane,or also dioxane, po~sibl~ with the addition of water. ~he subsequent h~drolysis takes place b~ heating with water, expedientl~
however with semi-concent~ated hgdrochloric or h~d~o-bromic acid.
~ he free diphosphonic acids of the general formul~
I csn be converted into the corresponding tetraslkgl esters b~ heating with orthoformic acid alkgl esters.
As a rule, the saponification to diesters takes place in that one treats the tetraslkgl ester6 with an alkali metal halide, preferablg sodium iodide, in a suitable ~olvent, such as e.g~ acetone, at room temperature.
.. ~. .
There hereby results the sgmmetrical ~iester/ ~ ~
disDdium salt which c~n possibl~ be converted into ~;
the diester/diacid b~ means of an ion exchanger. ~ -.
,;' ' :

~he saponification of the esters ~o free diphosphonic acids takes pl~ce, 8S 8 rule, by boiling with hydro-chloric or hgdrobromic scid. However, one can also carr~ out 8 cleavage with trimethylsil~l halide, preferabl~ the bromide or iodide.
,: , . .
~ s pharmacologically compatible salts, there are, above all, used mono- or dislk~l metal or ammonium alts which one prepares in the usual wa~ e.g. bg titrfltion of the compounds with inorganic or organic ~ ~ -:~ - :
bases, such a9 e.g. sodium or potas~ium hydrogen carbonate, caustic soda solution, potash solution, , . .
a~ueous ammonia or amines, such as e.g. trimethgl-or trieth~lamine.
As a rule, the ~lts are purified b~ reprecipit-ation from water/methanol or Water/actone.
:. ~
The new ~ubstances of the formula I according to the invention and their salts can be administered enterelly or parenterallg in liquid or solid form.
~here hereb~ come into question all usual forms o~
administration, for example tablets, capsules, coated tablets, sgrups9 solutions, suspensions etc.
~ ~.
As injection medlum, water is preferablg used which contains the additive~ usual in the case of injection solutions, ~uch as stabilising a~ents, solubilising , . . . ~
agents snd buffers.
.
Such additives are e.g. tartrate and citrste ;~
buff2rs, ethanol,, complex ~ormers (such as eth~lene-diamine-tetraacetic acid and its non-toxic salts), ~ . .

`
93~
_7_ high molecular pol~mers (such as liquid poly-eth~lene oxide) for viscosity regulation. ~iquid carrier msterial~ for injection solutions mu~t be ~terile and are prefersbly filled into ampoules.
Soli~ carrier materials sre e.g. starch, lactose~
mannitol, methyl cellulose, talc, highl~ dispersed silicic acids, hi~h molecular fatty acids (such as stear~c acid), ~elatine, agar agsr, calcium phosphate, ma~nesium ~tearate, snimal and ve~etable fats, solid high molecular polgmers (such as polgethylene gl~cols);
compositio~s ~uitable for oral administration can, if desired, contain flavourin~ and sweetening materials.
The dosaging can depend ùpon various factors, such as mode of administration, species, age and/or individual state of health. ~he dose to be admin-istered dail~ lies at sbout 1 - 1000 mg/human, preferably 10 - 200 mg/humen snd can be taken divi~ed up one or more times.
Preferred in the meaning of the present inventio~
arel apart~from the compounds mentioned in the Examples and compounds derivable b~ combination of .. ....
all meanings of the qubstituents mentioned in the clsims, tha following diphosphonic acids, ~ well ss their ~odium salts, methgl and ethyl esters~
azscyclopentadecane-2,2-diphosphonic acid azac~clopentadecane-2,2-diphosphonic ~cid (mono~
~odium salt) -`~ 210~8 sz~cgclooctadecane 2,2-diphosphonic acid azac~clooctsdecane-2~2-diphosphonic acid (mono-~odium 6alt).
~he following ~xamples show some of the process 5 variants which can be used for the s~nthesis of the compound~ according to the invention. However, the~
are not to represent a limit~tion of the subJect matter of the invention~ A~ a rule, the compounds are obtained ~s high melting solid products (~ono or disodium ~alt), W~e structure of which was verified b~lH-9 3 ~ - snd possibly b~ 13C-NMR-spectro-scopy. The purity o~ the substances was determined bg means of C, ~, N, Ps S~ Na ansl~sis9 as well as b~ thin lager electrophoresis (cellulose, oxalata bu~fer of pH = 4.~)~
~ he lacta~s of the ~eneral formula II ~ed a~
starting compounds are prepared according to known : . , processes, ~g. in that one react~ the c~clic ketones with hgdrox~lamine 0-sulphonic acid.
lnsofar as theg were not commercizll~ obtainable~
the educts needed for the ~xamples were s~nthesised analogouslg to the followin~ literature reference~
S~nthesis 19Z~ 537-538.
Examl)le 1 Azac clonon~ne-2~2-dlphosphonic acid 2-~zac~clononanone (700 m~ 5 mmol) and phosphorou~
.
acid (800 m~ 10 mmol~ were heated under nitro~en for 1 hour at 100C. Phosphorus trichloride (1 ml, ~ ","~

21~3~.8 g 11 mmol) i~ then sdded dropwise, A~ter a further 12 hours ~t 100C, it is cooled, mixed with 50 ml o~ w~ter and heated to 100C for 12 hours. ~he resultin~ precipitate is filtered off with ~uction and the filtrate evaporated in a vacuum. The residue i recr~stallised from water.
~ield: 800 m~ (56% of theorg); m~p. 210-211C.
xample_ Azac~ onsne-2 2-diphosphonic acid (monosodium salt) DD Azacyclononsne-292 diphosphonic ~cid (200 mg, 0.7 mmol) i~ taken up in wster 20 ml and ~djusted with lN NsOH to pH 5. ~he solution is freeze driedO
~LC (cellulose; acetic acid ethyl ester, glaci~l acetic scid,. water 3:1~ Rf: 0.24 ~
Azac~clodecane-2~.2-diphosphonic scid 2-~zac~clodec~none (460 m~, 3 mmo~) and phosphorous acid (50Q mg,~ 6 mmol) ~re di~olved under nitro~en ~n 20 ml chlorobenzene ~nd stirred for 1 hour at 100C.
Phosphorus trichloride (0 6 ml, 6~6 mmol) is adde~
dropwi~e thereto with ~tirring.. After a fur~ther 10 ~ .
hours at 100C, it is cooled snd the chlorobenzene carefully decanted off, ~he residue is mixed with ::
~0 ml 6N hydrochloric acid snd boiled under reflux for 6 hours~ ~he mixture is cooled, the resultsnt precipitate is filtared off with suction s~d the .. - ~ ;
filtrate evaporated in a vacuum. ~he residue is brou~ht to cr~stallisation from water/acetona.

-lo_ 2~93~ 8 Yield 410 mg (45~ of thêor~), m.p. 286-288C.
:
Azacyclodecane-2~2-diPhosPhonic acid (mono~odium .
salt) Azacyclodecane-2,2-diphosphonic scid (200 mg9 0.66 mmol) is treated analo~ouslg to ExampI~ 2.
T~C (cellulose; acetic acid eth~l æ~ter/glacial acetic acid/wster 3~ R~ 0.42 _~am~le ~ ~
19 zac~cloundecsne-2~2~dipho~phonic acid 2-hzacycloundecanone (3.4g, 20 mmol) and phosphorus ~cid (3~2 g, 40 mmol) are st~rred under nitro~en st 80~ until a homogeneous melt ha~ formed.
Phosphor~l chloride (3.82 ml,;41 mmol) i~ then slowl~
~dded dropwi~e thereto ~nd heated to 100C for 7 hours. ~he resulting foam i~ mixed st room temper-ature with 100 ml of water and heated to 100C for 1 hour. The re~ultant precipitate is filtered off with suction and the filt~ate evaporated in ~ vacuum.
~he residue is recrystalli~ed`from water~
Yield: 4,75 ~ (76~ of theorg), m~p, 220_222C~
CloH23N06P2: calc.: C 38.01 H 7 35 N 4.44 P 19.65 (315.243) found: 38.08 7.33 4.46 19.90 xample 6 A~c~_l~undecane-2~2-diphosphonic acid 2-Azac~cloundecanone (1.7 g, 10 mmol) ~nd phosphorous acid (1 6 g, 20 mmol) are dissolved under nitro~en in 30 ml chlorobenzene and heated 21~93~

to 140C for 1 hour. The re~ction with phosphorus trichloride and the working up takes place ~nalo~-ously to ~xample 2 ~he residue i9 recrgstallised from water. Yield:
1,6 g (51% of theorg), m.pO 220-222C
Example_~ . ... .. .
Azacycloundecane-2.2-diPhosphonic acid (manDsodium , sslt) Azac~claundocane-2,2-diphosphonic acid (200 mg~
: 10 0.64 mmol) is treated analo~ously to ~ample 2~
~C (cellulo~e; acetic acid eth~l ester, glacial acetic acid,. water 3:1:1): Rf: 0.46.
Example 8 Azac~clododecane-2~2-diPho~phonic acid ~ :~
2-~zacgclododecanone (~.2 g, 12 mmol) and phosphorous acid (2.0 g,. 24 mmol) are heated at 100C under nitrogen until a homogeneous melt has formed. ~he re~ction with phosphor~l chloride (2.25 ml,. 24 mmol) and the workin~ up take place -. ;~
analogouRlg to ~ample 3..
Yield: 2.3 ~ (64~ of theory), m.p. 188-191C.
xamPle 9 Azac.~clododecane-2,2-diPhosphonic- acid (monosodium salt) Azacyclododecane-2,2-diphosphonic acid (200 mg, 0.61 mmol) is tre~ted analogouslg to Example 20 T~C ~cellulose; acetic acid eth~l ester, glacial scetic .
scid, water 2:1:1): Rf: 0~6~

-12- 2~0~3~
Example 10 Azac~clotetradecane-2~2-diphosphonic acid 2 Azacyclotetrsdecanone (1.1 g, 5 mmol) and pho~phorous scid (0~8 g5 10 mmol) are heated in 10 ml chlorobenzene under nitrogen for 1 hour at 80C.
Phosphor~l chloride (1 ml, 11 mmol) i9 added dropwise while stirring. After 10 hours at 100C, it i~
decanted off, the residue mixed with 40 ml of water a~d boiled under reflux for 1 hour. The,resulting precipitate is filtered off with suction; csrefullg after-washed with water and dried.
Yield: 1.1 g (62~ of theorg), m.p, 218-220C.
Example 11 , :
Azac~clotetradecane-2,2-diphosphonic acid 2-Azscyclotetradecanone (2.1 g, 10 mmol) and phosphorous scid (0,8 ~r 10 mmol) are rescted with phosphorgl chloride (1 ml, 11 mmol) analo~ously to Example 5. The working up takes place as in Example 6.
~ield: 2~78 ~ (78~ of theor~), m.p. 218-220C ~ ;
Example 12 Azacgclotetrsdecane-2`,2-diphosphonic scid (monosodium `~
3alti' Azac~clotetradecane-2,2-diphosphonic acid (200 m~
0.56 mmol~ is treated analo~ously to Example 2 TIC: (cellulose: scetic acid eth~ e~ter~ glacial scetic ccid, water 2:1:1): Rf: 0.62 ` ~-` 21~ 8 ., ,., l~i Exam~le 13 . . .
Azac~clohexadecane-2 2-diphosPhonic scid 2-Azac~clohexadecanone (2 g, 8.4 mmol) and phosphorous acid (1.4 g, 16.8 mmol) are reacted an~lo~ousl~ to Example 3 and worked up. ~he pre-cipitate res~ltin~ in the c~se of heatin~ with water i9 fiIter~d off with suction,. after-washed with water, suspended in metha~ol and again filtered off with ~ -: suction.
Xield: 2~4 ~ (74~ of theorg)9 m.pO 215-217C..
Example 14 Az3c~clohexadecane-2~2-diphosphonic acid 2-Azacgclohex~decanone (900 mg, 3.8 mmol) and phosphorous ~cid (600 m~, 7.6 mmol) are reacted 15 3nalo~0uslg to Exsmple 4. ~he precipitate resulting : ;
in the ca~e of coolin~ i9 filtered of~ with ~uction, after~wa~hed with water, 8uspended in methsnol and ugain filtered off with suction.
Yield: 880 m~ (~60~ of theorg), mOp. 215-217C
Azac~olohexadecane-2 2-diphosphonic acid ~ono~
90dium 981t) Azsc~clohexadecane-2,2-diphosphonic ~cid (200 mg, :~
0.52 mmol) i6 treated analo~ousl~ to Examplc 2.
TIC (cellulose, 8cetic acid ethyl ester~ gla~ial : ~ acetic acid~ wflter 3~ R~: 0.65.

',.~ ~,:

-; 2~a~8 .

Example 16 A~sc~cloheptadecane-2,2~di~ho~honic 3cid 2-~zac~clohept~deca~one (5 g9 20 mmol) and pho~ horous acid (3.2 g9 40 mmol) are dis~olved in 10 ml chlorobenzene under nitroge~. Pho~phorus trichloride (5~2 ml, 60 mmol) are ~lowlg added dropwise thereto at 5C over 1 hour.. 1,6 ml of ~ ~:
w~ter are then added dropwi~e thereto while cooling -~nd ~lo.wl~ heated to 90 - lQ0~ ter 10 hour~ it ;~
0 i5 cooled and 250 ml of watar sdded thereto~ ~he resultant precipitate i9 filtered off with suction, after-washed w.ith ~uch water, suspended in mekhanol snd again ~iltered of~ with ~uction.
Yield: 5,4 g (68~ o~ theor~), m.p, 210-212GC
15 Ex~mple 17 :~
Az~cgcloha~kadecane-?,2-diPhosPhonic acid (mono~
~odium salt~
~zacgcloheptadec~ne-2~.2-diphosphonic acid (200 mg, 0.50 mmol) is treated enalo~ouslg to :~
Example 2 ~LC. (cellulo~e; scetic scid ethgl ester, glaci~
acetic acid~ wster 3~ Rf: 0~67

Claims (5)

Patent Claims

1. Medicament containing at least one o the compounds of the formula I

(I) in which n is a whole number between 7 and 16 and R signifies hydrogen or C1-C4-alkyl, as well as their pharmacologically compatible salts, besides usual carrier and adjuvant materials.

2. Use of compounds of the formula I according to claim 1 for the preparation of medicaments for the treatment of bone metabolism disturbances.

3. New compounds of the formula I' (I') in which n' is a whole number between 7 and 16 and R
signifies hydrogen or C1-C4-alkyl, with the proviso that n' is not to represent the number II, as well as their pharmacologically compatible salts.

4. Compounds of the formula I' according to claim 3 selected from the group azacyclononone-2,2-diphosphonic acid azacyclodecane-2,2-diphosphonic acid azacycloundecane-2,2-diphosphonic acid azacyclododecane-2,2-diphosphonic acid azacyclotetradecane-2,2-diphosphonic acid azacyclopentadecane-2,2-diphosphonic acid azacyclohexadecane-2,2-diphosphonic acid azacycloheptadecane-2,2-diphosphonic acid azacyclooctadecane-2,2-diphosphonic acid as well as their pharmacologically compatible salts.

5. Process for the preparation of compound of the formula I' (I) in which n' is a whole number between 7 and 16 and R signifies hydrogen or C1-C4-alkyl, with the proviso that n' is not to represent the number 11, as well as of their pharmacologically compatible salts, characterised in that brings a lactam of the formula II
(II) in which n has the given meaning, to reaction with a mixture of phosphorous acid or phosphonic acid and a phosphorus halide or phosphoryl chloride or directly with a phosphorus halide in the presence of water and subsequently, if desired, converts the compounds obtained into their esters or pharmacol-ogically compatible salts.