CA2091268A1 - 17-.beta.-oestradiol derivatives, processes for their preparation and medicaments containing these compounds - Google Patents

Abstract

Summary Compounds of the formula I

(I) in which Sp signifies a spacer, Z = valency bond, ,

Description

`8 Boehrin~er ~lannheim GmbH 3395/CA
New 17-~-oestradiol derivatives processes for their preparation and medicaments containin~ these compounds The present in~ention concerns new 17-~-oestradiol derivatives, processes for their preparation, as well as medicaments which contain these substances.
For the trestment of post-menopausal osteoporosis, todag, besides sodium fluoride or sodium fluorophosphate, there are 3bove all used 17-~-oestradiol or derivatives hereof. (Med. Klinik, 82, 238 (1987); Am J. Med., 85, 847 (1988). 17-~-Oestradiol or the deri~atives bere~f act, on the one hand, inhibitingly on the bone resorption but, on the other hand, also stimulatinglg on the osteoblasts building up bone. However, it is disadvantageous that one obtains not onlg the desired action on the bones but that these preparations also show a systemic action. In this connection, the danger of an increased risk of breast concer is also discu~sed.
Thus, the task exists to find a 17-~o~strsdiol deriY-ative which displays no systemic but only an action on t~e bones. One can schieve this object in that one couples t~e 17-oestradiol to a carrier which shows a high affinity bO tbe h~droxglapatite of the bone.
~imilar conjugates are published e.g. in EP 201.~57 wbere couplin~ products between carbonic anhydrase in~
witb tetracycline or diphospbonates are described.
In EP ~41.961 is described, inter aLia, a compound in whic~ 17-~-oestradiol is coupled with ~ tetra-carboxylic acid. ~ow the present invention describescompounds in which 17-~-oestradiol is coupled to a l,l-diphosphonate via an in vivo-hydrolysable spacer.
Because of the l,l-diphosphonate part, these substances~
adhere very well to the ~one and are then cleaved by esterases on the bone into 17-~-oestradiol and a diphosphonic acid-containing residue which acts on the basis of its special chemical structure but not bone resorption inbibitingly.
Conseguently, the subject of the present invention are compounds of the general formula I
P(O) (OR7)2 O-C-Y-SP-Z-alk-C-A
H C " ' ,~ P(o) (OR7)2 in which Sp signifies ,1 ,3 .5 - C - (C)m - (C)n ~ (CH2)r l - R6 = in each case independentlg of one a~other, hydrogen, phengl~ c~clohexyl, lo~er strai~ht-chained or brsnched alkyl, alkenyl or alkgngl with 1-5 or 2-5 carbon atoms, respectively, which is p~ssibly substituted bg phengl, whereby Rl and R2, to~ether with the csrbon ~tom to which they are attached, can form a -4~
saturated alicyclic 3 - 5 ring or ~1 and R5, together with the carbon atom(s) connecting them, can form a saturated, partly satursted or unsaturated 3 - 6 ring possibly interrupted by 1 or 2 nitrogen atoms, m, n and r, independently of one another, can assume values of O - 3, whereby m + n + r can assume the value of at most 7, and X = O or S, Y = valency bond or ~E
Z _ valency bond, -C-NH-, -NH-C_, NH or S, O O
A z hydrogen, hydroxyl or amino possibly substituted by lower alkyl, alk = a straight-chained or branched alkglene chain with 1 - 6 carbon atoms, R7 = hydrogen Gr lower alkyl, as well as their pharmacologically acceptable salts.
In the case of the radicals Rl ~ R7, lower alkyl ~eans alkyl ~roups with 1 - 5 carbon atoms, preferablg the methyl, ethyl, propyl, isopropyl, isobutgl, sec.-butyl and pentyl rsdical but especially the methgl, isopropyl, isobutyl or sec~-butyl radical.
In the case of the radical "A", lower alkyl pre-ferablg has the meaning methgl and ethgl, In the case of the radicals Rl - R6, ~l~eu~l preferably signifies radicals with preferably one one double bond, above all the allyl and.methallyl radical.

In the case of the radicals Rl - R6, alkyngl is to be especially tbe propargyl radical.
~ y the 31kyl group substituted by a phenyl ring, one understands especially the benzyl ~roup.
~ he alkglene chain in tbe case of the radical "alk"
is to represent radicals such as methglene, ethylene, propylene, isopropylene, butylene, isobutglene, pentylene and hexgLene but especially methylene, ethglene, propylene, butylene and isobutylene.
When Rl and R2, together with the carbon atom to which they are attached, form a ring, this is preferabl~
to be a five- or six-membered ring.
~ or the case bhat Rl and R5, together with the carbon atom(s) connecting them, form a ring, this i8 a cycloprop~lidene, cyclobutylidene, cyclopentylidene, cgclohexylidene, cyclohexenylidene and phenglene ring, pre~erably the cyclopropylidene, 1,2-cyclopent~ylidene~
1,2-cyclohexyLidene, 1,3-cyclohexylidene, 1,4-cgclo-hexg~idene, l,2-cgclohex-4-enylidene, 1,2-phenylid~e, 1,3-phenglidene and 1,4-phenylidene ring. If these rings are interrupted bg 1 or 2 nitrogen atoms, it is preferably a question of unsaturated ring systems, especially the pyridine rin~ substituted in the 2,3-or 3,4-poaition and the p~razine ring substituted in the 2,3-position, Asymmetric carbon atoms can possess the ~- or S-configuration and the compounds can be present in opticallg-active form or as racemic mixtures. ~hey are also the subject of the invention.

6 i`~ C~ ~ ~
Cis-trans isomers can be presenv as pure forms or as mixtures and are also the subject of the invention.
~he following groups are espccially preferred as "spacer" (Sp): unsubstituted methylene, methylene mono-substituted by methyl, n-pentyl, allyl, isobutyl, tert.-butyl, cyclohexyl, pbenyl or benzgl, methylene disubstituted by methyl, ethyl, n-pentyl or all~l, unsubstituted ethylene, ethylene monosubstituted by methyl, n-hexyl or l,l-cyclohexylidene, ethglene disubstituted by methyl, unsubstituted propylene, propylene monosubstituted by methyl, phenyl, l,l-cyclopentylidene or l,l-cyclohexylidene, propylene disubstituted by methyl, unsubstituted butylene, butylene tetrasubstituted by methyl, pentylene, hexylene, oct~lene, l,l-cyclopropylidene, l,2-cyclo-propglidene, l,l-cyclobutylidene, l,2-c~clobutylidene, l,l-cyclopentylidene, 1,2-c~clopentglidene, 1,3-cyclo-pentylidene, l,l-cyclohexylidene, l,2-cyclohexglidene, 1,3-cyclohexylidene, 1,4-cyclohexglidene, 1,2-cgclo-hex-4-en~lidene, 1,2-phen~lene, l,~-phenylene, 1,4-phenylene, 4-met~yleneC~clohexgl, 4-ethylidenephenyl, in 2,3-substituted pyridine, in 3,4-substituted pyridine and in 2,3-substituted pgrazine.
Compounds of the general formula I are prepared accordin~ to per se known processes, pre~erably in that one I for the case that Z si~nifies the group -C-~H-o -7~
reacts a carboxylic acid derivetive of t~e general formula II
X Rl ,3 5 O-C-Y-C ~ )n ~ CH2 )r C
~ ~ R2 R4 R6 H ~
in which X, Y, Rl - R6, m, n and r have the above-given ~eanings and ~ represents the hydroxyl group or an activating group, with a diphosphonic acid derivative of' the general formula III
P(O)(OR7)2 N-alk-C-A (III) P(O)(OR7)2 in which alk, R7 and A have the sbove-given mesnings, or II) for the case the Z signifies the group -~H-C_, reacts an amino compound of the general formula IV

" ,L ,3 ,5 O-C-Y-C ~ )n (CH2--t--r--N~2 (IV) ~0 -8~ ,s~
in '~J~iC~ ~, Y, Rl - R5, m, n and r have t~e 3bove-given meanin~s, ~lit'n a diphosphonic acid derivative of the general formula V

o P(O) (R7)2 T-C-alk-C-A (V), P(O) (CR7)2 in whic~ alk, A and R7 have the above-given meanings and T represents the hydroxyl or an activating group, or III for the case that Z signifies NH or S, reacts a compound of the general formula VI

X R R R
,. .~ .3 5 H3C C Y C--~-C ~ H2 ~ Z~

~ (VI~

HO
in which X, Y, Rl - R6, m, n and r hsve the above-given meanings and Z is NH or S, with a diphosphonic acid derivative of the general formula VII

P(o) (R7)2 U-alk-C-A (VII) P(o) (OR7)2 whereb~ alk, A and R7 have the above-given meanings and U represents a reactive residue, whereby, for the _9~
case that alk signifies a Cl group, U and A can together also represent a valency bond or an oxygen atom, or IV) for the case that X represents oxygen snd Y a valency bond, reacts a compound of the general formula VIII

" ~ 5 P(O)(OR7)2 Hal-C - C ( C )m (C )n (CH2 )r Z , (VIII) R2 R4 R5 P(O)(OR7)2 in which Rl - R7, Z, alk, A, m, n and r have the above-given meanings and Hal is chlorine or bromine, with a 17-~-oestradiol derivative of the ge~eral formuls IX
OH

~IX) V-O
in which V represents a protective group, or V) for the cs~e that Y is NH, a) reacts a compound of the general formula X

-10~ v~

Rl ,3 ,5 P(C)(OR7)7 X C ~ C ( C ) (C ) (CH2~Z-alk-C-A (X) R2 R4 R6 P()(R7)2 in which X, Rl - R7, Z, alk, m, n and r ~ave the above-given meanings, with a 17-~-oestradiol deriv-ative of the general formula IX
0~

m (IX) V-O
in wbich Y represents a protective group, or b) reacts an amino compound of the general formula XI

Rl R3 ,R5 P(O)(OR7)2 H2N C ( C )m (C )n (CH2 )r ~~alk~C~A (XI) R2 R4 R6 P()(R7)2 in which Rl - R7, Z, alk, A, m, n and r have the above-given meanings, with a 17-~-oestradiol de~iv-ati~e of the general formul~ XII

''1 h ~ ~

O-C -W

,~
V-O
in whic~ Y represents a protective group and W chlorine or is to be the group -X-M, whereby M represents lower slkyl, such as methgl or eth~l, or a possiblg substit-uted phenyl ring and X have the ~bove-given meaning, and subsequentlg, if desired, converts the C=O group into a C=S group, or VI) subseguently converts compounds of the genersl formuls I, in which X represents oxygen, into compounds of the general formula I with X = ~uL~hur, splits off the protective ~roups possibly present snd, if desired, saponifies the resulting tetraesters to diesters or acids of the general ~ormula I, O
~ he grouping -C-~ given in processes I and II can represent a reactive derivative of a carboxylic acid, There come into considerPtion herefor mixed anhgdride~, es~ecislly with csrbonicacid lower alkgl esters, such as ethyl or isobutyl esters, or sctive esters, especiallg p-nitrophenyl, 2,4,5-trichlorophenyl, N-hydroxysuccinimide or L-hgdroxgbenzotria~ole esters.
If ~ represents a hgdroxgl ~roup, the acti~ation o~

~ i3~6 of t~e carboxyl group can be carried out according to to the carbodiimide process. There are preferably used inert organic solvents, such as e.g. methglene chloride, acetone, acetonitrile, dimethylformamide, tetrahgdro-furan or dioxane or mixtures of these solvents at temperatures of -70 to +100C, preferably between -30 and +20C. If, in the case of the reaction, the phosphonic acid groups are protected by salt formation, then the reactions are preferably carried out in aqueous medium, possibly witb the addition of etherified diols, such as e.g. dimethoxyethane, or in a two-phase system, such as e.g. water/methglene chloride, when, as reactive derivative of the compound of the general formula II, a mixed anhydride or an active ester, preferably the N_hydroxysuccinimide ester, is used.
In the case of process III, the reactive residue U
in compounds of the general formula VII signifies a halogen residue, preferabl~ the corresponding iodide or bromide, or a sulphonate, such as e.g. the mes~late, benzenesuLphonate or p-toluenesulphonate.
If "U" with "A" together represent a valenc~ bond, in the case of the compounds of the general formula VII, it is a ~uestion of a methylenemethanedip~osphonic acid derivative, if "U" and "A'l together signifg a~ oxygen atom, it is a question of an oxirane-l,l-diphosphonic acid derivative. hs a rule, the reactions are carried out in inert solvents, such as methylene chloride, dimetilylformamide, dioxane or tetrahydrofuran, but also in alcohols, such as methanol or ethanol, at temperatures between O and 100C, preferably O and 30C, in the presence of bases, such as triethglamine, lutidine or diazabicycloundecene. Above all in the case of the reaction of thiols of the general formula VI, one can also very well first prepare the thiolate with the help of e.g. alkali metal alcoholates, such as sodium methglate or ethglate or potassium tert.-butylate, and subsequently brings these to resction with the compounds o~ the general formula VII.
One usually carries out the reaction of an acid halide in process IV in inert solvents, such as methglene chloride, acetonitrile, dioxane, tetrah~dro-furan or dimethylformamide, in the presence of bases, such as triethglamine, lutidine or also solid sodium hydrogen carbonate, at temperatures of -20 to ~30& .
The protective group V in the compound of the ~enersl formuls IX in the c~se of processes IV and V repres~nts either an acgl group, such as e.g. the formgl or scetgl ~roup, or the benzyl or tritgl group. ~he splitting off of the acyl ~roups preferably takes place bg reaction with dilute agueou~ smmouia or by treatment with alka~i metal alcoholates, such as sodium methglate or ethylate.
T~e benzgl and trityl group can be split off bg cata-lgtic bgdrogenation in the presence of noble metal catalysts, such as e.g palladium on carbon.

~ u ~ 8 In t~e case of process V, one carries out the resctions of the two compounds o~ the general formulae IX and X or XI and ~II in inert solvents, such as methylene chloride, acetonitrile, dimeth~lformamide, dioxane or tetrahydrofuran, at temperatures of O to +4GC, ss a rule at room temperature. If "W'~ in the compound of the general formula XII signifies chlorine, one also adds thereto bases, such as triethylamine or lutidine.
The subsequent conversion in the case of process VI of compounds of t~e general formula I with X =
ox~gen into compounds with X = sulphur takes place 8.g. bg reaction with P4Slo (Liebigs Ann, ~, 92 (1971)) or with ~awesson's reagent (Bull. Soc. Chim.
B~lg. 87, 223, 229, 525 (1978)).
One can prepared the compounds of the general formula II used in the case o~ process I, for the case thPt Y is a valency bond e.g. bg reaction of 17~B-oestradiol with a dicarboxylic ~cid anhydride (see e.g. J. Biol~ Chem. 25~, 8221).
For the case that Y in the compounds of the general formula II signifies ~, one obtains t~e desired compounds by reaction of 17-~-oestradiol ~rith an isocyanato- or isothiocyantocarboxylic acid. ~hese substances are described in the literature (e.g.
~iebigs Ann. 575, 217, Liebigs Ann. 6~6, 144 or J. Org.
Chem.28, 71) or can be prepared analogously to the there-described processes.

h ~ 6 3 Aminoalkyldiphosphonic acid derivatives of the general formula III can be well prepared bg reduction of the corres~ording nitrile compounds. As reduction process, one preferably choses the cat~l~tic hgdro-genation in the presence of noble metal catalysts, especially of palladium on carbon, whereby, in this case, the hydrogenation is preferably carried out in an alcohol, such as methanol or ethanol, in the presence of a hydrohalic acid, sucb as e.g. hydrochloric acid.
The nitriles used can be prepared e.g. by reaction of a corresponding nitrile alk~l halide, suc~ as e.g.
bromo- or chloroacetonitrile, with the alkali metal salt of a methanediphosphonic acid tetraalkyl ester in solvents, such as toluene or dimethylformamide.
However, one also obtains such compounds by addition of a possibly substituted acrglonitrile to an alkali metal salt of a methanediphosphonic acid tetraalkyl ester (s. EP 098 567). In these csses, one obtains compounds of the 3eneral formula III with A = hydrogen, The synthesis of aminoalkyldiphosphonic acid derivatives in which A signifies hgdroxyl is described in J. prakt.
Chemie 321, 361.
In the case of process II, one can prepare the amino compounds of the general formula IV for the case that Y represents a valency bond by reaction of a 17-~-oestradioL of the general formula IX protected on the phenoLic oxygen with an amino acid protected on the nitrogen atom, the carboxyl group of which is -~6- ~ J~ J '~
activated (in t~is rega.d, see description of process V a). The protective ~roup used on the p~enolic oxygen is preferably a benzyl or trityl group which can sub-sequently be split off by catalytic hydrogenation in the presence of noble metal catalysts, such as e.g.
palladium on carbon. However, as protective group, there can also be used an acyl group, such as e.g.
the acetyl group (Tetrabedron ~etters, 1979, 2431), which can subsequentlg be split off in weakly alkaline medium.
For the case that Y signifies the NH group, one can bring to reaction the corresponding a~inoisocyanato or aminoisothiocgansto compounds protected on the primar~ nitrogen stom with a 17-~-oestradiol protected on the phenolic oxygen atom (see above) under the conditions set out in the case of ProceSs V a. Tbe aminoisocyanato or aminoisothiocyanato compounds protected on the primary nitrogen atom needed herefor are partly known (J. Am. Chem. Soc. 72, 1620 or ~, 3469; J. Org. Chem. 43, 1544; J~ Ind. Chem. Soc. 47, 1143) or can be prepared according to the there-given methods. In this case, the protective group is preferably an acyl, e.g. an acetyl or benzoyl group, which, after the reaction has tsken place, can agsin be split off by acidic or alkaline hydrolysis.
One can prepare diphosphonic acid derivatives of the general formula V in the following wag. A methane-diphospbonic acid tetrsalkyl ester is reacted in the -~7-form of its alkali metal salt (prepared e.g. by reaction ~ith sodium bydride in toluene or dimethyl-formsmide) with 3 -haloalkanecarboxylic acid benzyl ester, e.g. bromoacetic acid benzyl ester. After the reaction bas taken place, the benzyl protective group is split off by catalytic hydrogenation in the presence of noble metaL catslysts, such as e.g. palladium on carbon. In this case, one obtains compounds of the general formula V in w~ic~ "A" is equal to hydrogen.
If ''Al' represents the hydroxyl group, one obtains the desired compound in the form of its benzyl ester analogouslg to the process described in Houben-Weyl 12/1, 453, 481 by reaction of an alkanedicarboxylic acid monobenzyl ester chloride, e.~. succinic acid benz~l ester chloride, with a trislkgl phosphite to give an acyl phospha'e which is subsequently brought to reaction with a dialk~l phosphite under weaklg basic catalysis. Subsequently, here too the resultant benzyl esters are reacted to the free carboxylic acid 88 described above.
In the case of process III, the compounds of the general formula VI for Z = NH correspond to the compounds of the general formuls IV and are prepared as there described. If Z represen~s sulphur, in the csse thPt Y = valency bond, it is a question of ~-mercaptocarboxylic acids (for the preparstion see e.g. J. Am. Chem. ~oc. 73, 4464 and 100. 7086; Org.
~nth. 34, 42) which, as a rule, one brings to reaction -18~
protected on the sulphur atom in the for~ of their acid h~lides, above all acid chlorides. As protective group, one preferably uses an acgl, especially the acetyl or benzoyl group (lit., for example: Chem.
Ber. 74, 1751, DOS 2.703,828). The reaction of the carboxylic into the acid chloride group takes place sccording to methods known from the literature, for example by reaction with phosphorus pentachloride.
If Z represents sulphur and Y signifies NH, one obtains the compounds of the general formula VI by reaction of a thioamine protected on the sulphur atom by e.g. scetyl or benzoyl with a compound of the general formula XII. The thioamines used can be purchased or sre described in the litersture.
Compounds of the general formula VII can be prepared e.g. by reaction of dihaloalkanes, such a~
e.g. chlorobromomethane, -propane or -butane, with the sodium salt of a methanediphosphonic acid tetra-alkyl ester. In this case, one obtains compounds of the general formula VII with A = hydrogen, However, in the case of process III, one preferably used a methylenemethanediphosphonic acid tetraalkyl ester (J Org. Chem. ~1, 3488) or an oxirane-l,l-diphos-phonic acld tetraalkyl ~ter (DOS 2,117,876).
One obtains the acid halides of the general formula VIII according to generally usual processes by reaction of the corresponding carboxylic acid with a halogen-ation agent, such as e.g. thionyl chloride or . 19~ ,3 phosphorus pe~t~chloride. The carb~x~ic acids used herefor can, for t~ case that Z ~ a(o)-NH, ~e pr~pared from thQ aminodiphosphonic acid derivatives of the general f ormula III by reaction with di-carbox~lic acid ~nhyd~ides. In~tead o~ these, one ~an alao uqe dicarboxylic acid e~ter chlorides and, a~tsr the ~eaction ha~ taken plsce, sapo~ he c~rboxylio acid ester accordin~ to usual ~ethod~ to the free car~oxylic acid or, in the oa~iof the benzy~
ester, bgdrogenate in the presence of nob~e metal catalysts to the free ¢~rboxyl~c acid. I~ Z ~ignifies the ~X-~(O) group, aminocarbozy~ic acid~ a~e react~d with a dipho~phonic acid deriva~ive of th~ gene~al _~ormula ~ As a ~ule, these aminocarbox~li¢ acids are to be obtained co~e~cially or are kno~n ~rom the literature, In the case in whi¢h Z si~nifies the NH
group or sulphur, the co~pou~ds are obt~ined by reaction o~ the above-me~tioned amlnocarbcxylic acids or thioalkanec~rbox~lic ~cids with a dipho~phonic acid dsrivative o~ th~ gsneral fo~muL~ YII~
~ he isocyanst~ or isothioc~an~to co~po~nd~ Or the ge~er~ for~ls X used in the case of proc~ss V a can be prcpared fro~ ~he correspondi~g aminas of the general formula XI anaLo~ou~1~ to the method4 ~3ve.n in ~e case of proces~ I. For the c~se that Z rep~e-sent~ t~e ~o~p -~(O)-N~, one o~tains these according to proc~sses ge~e~ally available in peptide chemistr~
by,reac~ion of ~n amino aci~ protected o~ the nitrogen, -2C~ 8 ~he carboxyl group of wbich is present in reactive form. The protective groups employed are described in detail e.g. in Houben-Wegl, Volume 15/1. ~ralkyloxy-carbonyl groups are preferred as protective group, especially the benzyloxycarbonyl but also the trityl group, the splitting off of which can be carried out by catalybic hgdrogenation in the presence of noble metal catalysts, suc~ as e.g. palladium on carbon.
As activated carboxyl group, there find use the radicals stated in the case of processes I and II.
If Z signifies t~e NH-~(O) group, one obtains the compounds of the general formula XI by reaction of a diamine wit~ 8 diphosphonic acid derivakive of the general formula V. As a rule, the diamines emploged are commercially available or known from the literature.
For the case that Z signifies the NH group or sulphur, one obtains the desired compounds by reaction of an aminothiol or of diamine protected on one nitrogen atom with a diphosphonic acid derivative of the general formula VII. As a rule, the aminothiols or diamines employed are commercially available or known from the Literature~ As protective group, there preferably finds use an aralkyloxycarbonyl group, especially the benzyl-oxycarbonyl or also t~e trit~l group, which can sub-sequently be hydrogenated off bg catslgtic hgdrogenation in the presence of noble metal catalysts, such as palLadium on carbon.

--21~ i h ~ ' ~
~ he 17-~- oe~radiol derivatives of the general formula XII used in the case of process V b are, for the case that ,J signifies chlorine, known (~P 341,961).
If W signifies the group X-M, it is prefersbly a question of carbonic acid esters which are obtainable from the compounds of the general formuls IX by reaCtiQn with chloroformic acid esters.
'rhe free diphosphonic acids of the generaL formula I can be converted into the corresponding tetraalk~l esters bg heating with orthoformic acid alkyl esters and saponified to diesters or again to the free tetra acids. As a rule, the saponification to diesters takes place in that one treats the tetraalkgl esters with an alksli metal halide, preferably sodium iodide, in a suitable so~vent, such as e.g. acetone, at room temperature.
~ here her~bgresults the sgmmetrical diester/disodium salt which can possibly be converted b~ an acidic ion ex¢hsnger into the diester/diacid. As a rule, the saponification of the esters to free diphosphonic acids takes place b~ treatment with trimethylsilyl halide, preferably the bromide or iodide.
As p~armacologically acceptable salts, there are, above all, used mono- or diaLkali metal or ammonium salts, whic~ are prepared in the usual wa~, e.g. by titration of the compounds with inorganic or organic bases, such as e~g. sodium or potassium hydrogen carbonate, aqueous sodium bydroxide solution, aqueous potassium hydroxide solution, aqueous ~mmonia or amines, such as e.g. trimethyl-, triethyl- or cyclo-hexylamine.
As a rule, the salts are purified by treatment witb water/methanol or water/acetone.
~ he new substances of formula I according to the invention and their salts can be administered enterally or parenterallg in liguid or solid form. ~here hereby come into question alL usual forms of administration, for example tablets, capsules, dragees, syrups, solutions, suspensions etc. As injection medium, water is preferably used which contains the additives usual in tbe case of injection solutions, such as stabilising agents, solubilising agents and buffers.
Such additives sre e.g. tsrtrste and citrste buffers, ethanol, complex formers (such as etbylenediamine-tetraacetic acid and its non-toxic salts), high molecular polgmers (such as liguid polgethglene oxide) for viscositg regulation. ~iquid carrier materisls for in~ection solutions must be sterile and are prefersblg filled into ampoules. ~olid carrier msterials are e.g.
~tarch, lactose, mannitol, methyl cellulose, talc, hi~hlg dispersed silicic acids, high molecular fattg acids (such as stearic acid), gelatine, agar-agar, calcium p~osphate, ma~nesium stearate, ani~al and vegetable fats, solid high molecular polymers (such ~s polyetbglene glgcols); compositions suitable for oral ~ U ~1 h ~ 3 administration can, if desired, contain flavouring and sweetening materials.
The dosaging can depend upon various factors, such as manner of administration, species, age and/or individual state of bealth. The doses to be ~dministered daily lie at about 0.1- lC0 mg/human, preferably at 1 - 10 ~g/human and can be taken once or divided up several times.
~ he followin~ Example shows one of the process variants which can be employed for the sgnthesis of the compounds according to the invention. However, it is not to represent a limitation of the subject of the invention, The structure of this compound i~ verified by lH- and 31P-NMR spectroscopg, the purity by means of 31P-N~.R spectroscopy, thin layer electrophoresis (cellulose, oxalate buffer ~f p~ = 4.0) and by means of C, H, N, P, Na analysis.
xample 1 3uccinic acid /I7-( oestra-1, 3,5(10)-triene-3,17-diol ~17~)~ ester N_succinimide (1) Succinic ~cid /I7-(oestra-1,3,5(10)-triene-~,17-diol (17~)~ ester (see J. Biol Chem. 253, 8221 (1978))(2.8 g, 7.5 mmol) dissolved in 20 ~1 tetrah~dro-furan is, after the addition of N_hydroxysuccinimide (950 mg, 8.25 mmol), N,N'-dicyclohexylcarbodiimide (1.7 ~, 8.25 mmol) and 4-dimethylaminopyridine (5~ mg, 0.4 mmol), stirred for 12 hours at room temperature.

'Lhe reaction mixture is filtered off, the fi~trate evaporated in a vacuum and the residue ~urified by chromatography over silica gel with toluene/acetone (5:1).
Yield 3 g (885/ of theory), m.p. 2C9 - 210C.
Succinic acid /I7-(oestra-1,3,5(10)-triene-3,17-diol (17~)17 ester N-/~3,3-dip~osphonic acid tetraethyl e3ter)-propy~ -amide (2) Succinic scid /l7-(oestra-l~3~5(lo)-triene-3~l7-diol-(17~)~ ester N-succinimide (500 mg, 1.1 mmol) is stirred for 18 hours at room temperature with 3-amino-propsne-l,l-diphosphonic acid tetr2ethyl ester (see EP 098 567)(320 mg, 1.2 mmol) in 20 ml methglene chloride. The reaction mixture is extracted with water (2 x 20 ml) and 2N HCl (2 x 10 ml), the org~nic phase dried over anhydrous magnesium sulphate, evaporated in a vacuum and, for purification, chromatographed over silica gel with toluene/acetone (5:1).
Yield 63C mg (86~ of theory).
Succinic acid /I7-(oestra-1,3,5(10)-triene-3,17-diol-(17~)~ ester N-/r3,3-diphosphono)-propy ~ -amide (3) To succinic acid /I7-(oestra-1,3,5(10)-triene-3,17-diol-(17~)~ ester N-/~,3-diphosphonic acid tetraethgl ester)-propy~ -amide (500 mg, 0.73 mmol) in 10 ml methylene chloride is added at 0C trimethylsilgl bromide (560 m~, 3.65 mmol). After 12 hours at room temperature, it is hydro~ysed with saturated sodium carbonate solution, extracted with ~ethylene chloride and t~e orgsnic phase evaporated in a vacuum.
Yield: 350 m~ (84~ of theor~); m.p. > 300~.

Example 2 Cyclohexene-4,5-dicarboxylic acid 4-/I7-(~estra-1,3-(10)-triene-3,17-diol(17~)7 ester (4) Oestradiol(1.08 g, 4 mmol), dissolved in 15 ml.
abs pyridine, is boiled under reflux for 4 hrs. at 140C with cis-4-cyclohexene-1,2-dicarboxylic acid anhydride (3 g, 20 mmol). After cooling, water (60 ml), methanol (40 ml) and potassium carbonate (4 g) are added thereto and the reaction mixture stirred,for

2 hrs. 2t R~. 6N HCl is then added and filtered off with suction. The residue is chromatograp~ed with toluene/acetone (3:1) over silica gel.
Yield: 1.2 g (72~ of theorg); Rf (toluene/acetone (3:1)):
0.25.
Cyclohexene-4,5-dicarboxylic scid 4-/I7-(oestra 1,3(10J-triene-3,17-diol (17~)~ ester N-succin-imide (5) 4 (850 mg, 20 mmol) is dissolved in abs. ~HF and stirred for 12 hrs. at R~ with N-hydroxysuccinimide (280 mg, 24 mmol), N,N'-dicyclohexglcarbodiimide (420 mg, 20 mmol) and 4-dimethglaminopyridine (100 mg, 10 mmol). The reaction mixture is filtered off, evaporated in a vacuum and the residue chromato-graphed with toluene/acetone (3:1) over silica gel, Yield: 920 mg (88% of theorg); Rf (toluene/acetone (3:1)): 0.48.

Cyclohexene-4,5-dicarboxylic acid 4-/I7-(oestra-1,3,5(1C)-triene-3,17-diol(17~) )7 ester 5-~ -(3,3-diphosp~onic acid tetrae~hyl ester)-propyl7-amide (6) 5 (700 mg, 13 mmol) is reacted with 3-aminopropane-l,1-dip~osp~onic acid tetraethyl ester (490 mg, 15 mmol) in abs. methylene chloride (20 ml) analog-ously to 2. $he residue is chromato~raphed with toluene/acetone (1:1) over silica gel.
Yield: 730 mg (76% of theorg); Rf (ethgl acetate/
acetone (1:3)): 0.56.
Cyclohexene-4,5-dicarboxglic acid 4-~ 7-(oestra-1,3,5(10)_triene-3,17-diol(17~)~ ester 5-~ -(3,3-diphosphono)-propg ~ -amide (7) To a solution of 6 (1 g, 1.5 mmol) in 10 ml abs.
acetonitrile is added dropwise at -20C trimethgl-5ilyl iodide (1.5 ml, 11 mmol). The mixture is warmed to 0O and stirred for 2 hrs. at RT. ~he solvent i8 stripped off, t~e residue mixed with water (20 ml) and met~ylene chloride (20 ml) and stirred for a furtller 30 min~ at 0C~ The aqueous phase is washed 3x wit~ methylen~ chloride and evaporated. The residue is recryst~llised from water/ethanol.
Yield: 610 mg (75~ of theory); m.p. >~00C~
Example 3 ~gclohexane-1,2-dicarboxglic acid 1-~ 7-(oestra-1,3,5(10)-triene-3,17-diol(L7~)~ ester (8) Oestradiol (1.35, 5 mmol) is reacted with cyclo-hexane-1,2-dicarboxylic acid an~ydride analogously ~ tJ

to 4 and worked up. ~he residue is chromatographed ~Jitb toluene/acetone (5:1) over silica gel.
Yield: 1.5 g (70~ of theory); Rf (toluene/acetone (5:1)): 0 30.
Cyclohexane-1,2-dicarboxglic acid-1-/17-oestra-1,~,5(10)-triene-3,17-diol(17~))7 ester 2-N-succinimide (~) 8 (800 mg, 20 mmol) is reacted analogouslg to 5.
The residue is chromatographed with toluene/acetone (5:1) over silica gel.
Yield: 890 mg (85~ of theorg); Rf (toluene/acetone (5:1)): 0.43.
Cgclohexsne-4,5-dicarboxglic acid 4-/17-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester 5-~ -(3,3-diphosphonic acid tetrsethgl ester)-propg~ -amide (10) 9 (2,6 g, 50 mmol) is reacted with 3-aminopropane-l,l-diphosphonic acid tetraethgl ester analogouslg to 2. The residue is chromatographed with toluene/scetone (2:3) over silica gel.
Yield: 2.8 g (76% of theorg); Rf (eth~l acetate/
acetone (2:1)): 0.50.
Cyclohexane-4,5-dicarbox~lic acid-4-/I7-(Oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester 5-~ -(3,3-diphosphono)-propg ~ -amide (11) 10 (l.O g, 1.5 mmol) is reacted analogouslg to 7.
~he a~ueous phase is washed 3x with meth~lene chloride and 3x with diethyL ether and evaporated. The residue is recr~stallised from water/ethanol.

~ L~

Yield: 61C mg (650, of theory); m.p. >~OC~.
Example 4 Phthalic acid 1-/l7-(oestra-l~3~5(lG)-triene-3~l7 diol(l7~)~ ester (12) Cestradiol (2.7 ~, 10 mmol) are reacte~ analogously to 4 with phtbalic acid anhydride (7 g, 50 mmol) and worked up.
Yield: 3.5 g (840/o of theory); m.p. 234 - 235C.
Phthalic acid-~I7-(oestra-1,3,5(10)-triene-3,17-diol-(17~))7 ester N-succinimide (13) 12 (1.7 g, 40 mmol) is reacted analogously to ~.
~he residue i9 chromatographed with toluene/acetone (7:1) over ~ilica gel.
Yield: 625 mg (65~ of theory); Rf (toluene/acetone (7:1): 0.61.
Phthalic acid-/I7-(oestra-1,3,5(10)-triene-3,17-diol-(17~)~ ester ~ -(3,3-diphosphonic acid tetraeth~l ester prop~ ~ -amide (14) 13 (700 mg, 13 mmol) is reacted analogously to 2 witb 3-aminopropsne-1,1-diphosphonic acid tetraethgl ester (500 mg, 15 mmol). ~he residue is chromabo-graphed witb toluene/acetone (1:2) over silica gel.
Yield: 670 mg (690~ of theory); R~ (toluene/acetone (1:2)) 0.49.
Phthalic acid-/17-(oestra-1,3,5(10)-triene-3,17-diol-(17~)~ ester ~ -(3,3-diphosphono)-propy~-amide (~) 1~ (220 mg, 3 mmol) are reacted analogousl~ to 7.
The residue is recrystallised,from water/ethanol.

-29~
Yield: 130 m~ (700,~ of theory); m.p ~30CC.
Example ~

3-0-Benzgl-oestra-1,3,5(10)-triene-3,17-diol(17b) (16) To a suspension of sodium hydride (0.5 g, 23.3 mmol) in abs~ ~ (10 ml) is added dropwise at -5C oestra-diol (4,3 g, 15.8 mmol), dissolved in abs. DMF (10 ml).
A~ter 1 hr. at -5C, benzyl bromide (2.8 ml, 23.3 mmol) is added dropwise thereto and subsequently stirred for 1 hr. at RT. The reaction mixture is filtered off over silica gel and evaporated in a hig~ vacuum, mixed wit~ 10% citric acid (150 ml) and extracted 3x with diethyl etber. The ether phase is washed neutral with ssturated sodium hydrogen carbonate solution, dried over magnesium sulphate and,evaporated. The residue is crgstallised with heptane.
Yield: 4.6 g (80% of tbeory); m.p, 98 - 100C;
Hf (heptane/ethyl acetate) (2:1)): 0.37.
Chloroformic acid 17-(3-0-benzyl-oestra-1,3~5(10)-triene-3,17-diol(17~)) ester (17) _ (3.6 ~, 10 mmol) 1~ dissolved in abs. dioxane (90 ml), mixed with active carbon (150 mg) and diphosgene (1.2 ml, 11 mmol) and boiled under reflux for 2 hrs. The reaction mixture is cooled, filtered and evaporated, Yield: 3 g (70% of theorg); Rf (heptane/ethgl acetate (2~ 0.80.

-30- ~y ~
3-C-~enzyl-oestra-1,3,5(10)-triene-3,17-diol(17~)-17-~-(4,4-diphosphono-4-hydroxy)-butyl7-carbon (mono-potassium salt)(l8)

4-Amino-l,l-diphosp~onobutanol (1.5 g, 6 mmol) is dissolved in water and adjusted to pH 10.5 with lN KOH.
17 (3 g, 7 mmol) dissolved in TE~F is then added drop-wise thereto. The pH vaLue is ~ept between 10 and 11 by addition of lN KOH. It is subsequently stirred for 12 hrs. and evaporated. ~he residue is taken up in water, filtered over a membrane (0.2 ~m) and evaporsted. ~he residue is recrgstal~ised from water/
et~anol.
Yield: 3.35 g (71~ of theory); m.p. ~ 300C.
3-Oestra-1,3,5(10)-triene-3,17-diol(17~)-17-~ -(4,4-dipbosphono-4-hydroxy)-buty~ carbamate (monopotassium salt)(19) 18 (1.5 g, 2.4 mmol) is dissolved in dioxane/water (60 ml) and hydrogenated under H2, with the addition of potassium carbonate (240 mg, 2.4 mmol) st 3.5 bar witb Pd/C 10% ss catPlyst. The mixture is fi~tered and evaporated. ~he residue is taken up in water and filtered over a membrane (0,1 ~ m) and extracted with methylene chloride. ~he aqueous phsse is evaporated and the residue recrystallised ~om water/ethanol, Yield: 940 mg (6~ of theorg); m.p. ~ 300C, ~mple ~
3-0-Benzyl-oestra-1,3,5(10)-triene-3,17-diol(17~)-17--(3,3-diphosphono)-propy~ carbamate ~monopotassium salt)(20) ~ J ~6~

3-Amino-l,l-dip~osp~onic acid (850 mg, 4 mmol) is dissolved in water and adjusted with lN KOH to pH 11 (1 9 g, 4.5 mmol) dissolved in TEF is then added dropwise thereto The furtber reaction and working up takes place analogously to 18.
Yield: 1.6 g (630~ of theorg); m p, >300C.
3-Oestra-1,3,5(10)-triene-3,17-diol(17~)-17-~ -(3,3-diphosphono)-propy~ carbamate (monopotassium salt)(21) 20 (650 mg, 1 m~ol) is hgdrogenated in dioxane/
water with the addition of potassium c~rbonate analog-ously to 19 and worked up.
Yield: 400 mg (72% of theory); m.p. ~300C
Preferred in the meanin~ of the present invention are, apsrt from the compounds mentioned in the Examples and compounds which can be derived by combination of all meanin~s of the substituents mentioned in the claims, the following diphosphonic acids, as well as their sodium sslts, methgl and ethyl esters:
methglmalonic acid /I7-(oestra-1,3,5(10)-triene-3,17-diol(l7~)~ ester N-(3,3-diphosphonopropyl)-amide pentylmalonic acid /I7-(oestra-1,3,5(10)-triene-3,17-diol(l7~)~ ester N-(3,3-diphosphonopropyl)-smide allgl~alonic acid /I7-(oestra-1,3,5(10)-triene-3,17-diol(l7~)~ ester N-(3,3-diphosp~onopropyl)-amide phenylm~lonic acid /I7-(oestra-1,3,5(10)-triene-3,17-diol(l7~)~ ester N-(3,3-diphosphonopropyl)-amide succinic acid /I7-(oestra-1,3,5(10)-triene-3,17-diol-(17~)~ ester N-(3,3-diphosphonoprop~l)-amide 2-methylsuccinic acid ~17-(oestra-1,3,5(10)-triene-3,17-diol(17~) )7 ester N-(3,3-diphosphonopropyl)-amide 2,2-dimethylsuccinic acid /I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(3,3-dipbosphon~propyl)_smide cgclohexane-1,2-dicarboxylic acid /I7-(oestra-1,3,5(10)-triene-3,17-diol)17~)~ ester N-(3,3-diphosphonopropyl)-amide cyclohexene-4,5-~icarboxglic acid 4-~I7-(oestra-1,3,5(10)-triene-3,17-diol(17~))7 ester N-(3,~-diphosphonopropyl)-amide phthalic acid l-/I7-(oestra-1,3,5(10)-triene-3,17-diol(l7~)~ ester N-(3,3-diphosphonopropyl)-amide pgrazine-2,3-dicarboxglic acid 2-/I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(3,3-diphosphonopropyl)-amide glutaric acid 1-~ 7-(oestra-1,3,5(1C)-triene-3,17-diol(l7~)~ ester N-(3,3-dipbosphonopropgl)-amide 3-meth~lglutaric acid 1-/I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(3,3-diphosphonopropyl)-amide 3-phen~lglutsric acid 1-/I7-(oestrs-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(3,3-diphosphonopropyl)-amide 3,3-dimeth~lglutaric acid 1-/I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(3,3-diphosphonopropyl)-amide 3,3-tetramethyleneglutaric acid 1-/I7-( oestra-1,3,5(10)-triene-3,17-diol(17~))7 ester N-(3,3-diphosphonopropyl)_amide cyclohexane-1,3-dicarboxylic acid 1-/I7-(oestra-1,3,5~10)-triene-3,17-diol(17~))7 ester N-(3,3-diphosp~onopropyl)-amide decanedioic acid l-~I7-(oestra-1,3,5(10)-triene-3,17-diol(l7~)~ ester M-(3,3-diphosphonopropyl)-amide mslonic acid ~I7-(oestra-1,3,5(10)-triene-3,17-diol-(17~)~ ester N-(3,3-diphosphonopropyl)-amide 2-tert.-butglmalonic acid ~I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(5,5-diphosphono-5-hydrox~-valer~l)-amide cyclohexylmalonic acid l-~I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(4,4-diphosphono-4-hydrox~-4-butyl)_amide benzylmalonic acid l-/I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(7,7-diphosphono-7-hydrox~-heptgl)_amide 2,2-dimethylmalonic acid 1-/I7-(oestr~-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(6,6-diphosphono-6-hydroxgbexyl)-amide 2,2-dipentylmalonic acid 1-~I7-(oestra-1,3,5(10)-triene-~,17-diol(17~)~ ester N-(3,3-diphosphono-3-hydroxypropyl)-amide 2,2-diethylmaIonic acid l-/I7-( oestra-1,3,5(10)-triene-3,17-diol(17~ ester N-(4,4-diphosphono-4-hydroxybutgl)-amide 2,2-diallglmalonic acid 1-/17-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(7,7-diphosphono-7-hydroxyheptyl)-amide cyclopropane~ dicarbox~lic acid l-/I7-(oestra-1,3,5(10)-triene-3,17-diol(17~ ester N-(4,4-diphosp~ono-4-hydroxybutyl)_amide cyclobutane-l,l-dicarboxylic acid l-/I7-(oestra-1,3,5(10)-triene-3~17-diol(17~)17_ester M-(3,3-diphosp~ono-3-hydroxgpropyl)-amide cyclopentane-l,l-dicarboxylic acid l-/I7-(oestra-1,3,5(10)-triene-3,17-diol(17~))7-ester N-(5,5-diphosp~ono-5-hydroxgpentgl)_amide cyclohexane-l,l-dicarboxylic acid l-~I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(2,2-diphosphono-2-hgdrox~eth~l)-amide 2-hexglsuccinic acid 1-~I7-(oestra-1,3,5(1G)-triene-3,17-diol(17~)17 ester ~-(2,2-diphosphono-2-hydroxy-ethyl)-amide 2,3-dimethylsuccinic acid /I7-(oestra-1,3,5(10)-triene-3,17-diol(I7~)~ ester N-(2,2-diphosphono-2-hgdrox~-ethylamide 3,3-dimethylsuccinic acid 1-~I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~' ester N-(7,7-diphosphono-7-hydroxyheptyl)-amide cyclopropsne-1,2-dicarboxylic acid 1-~I7-(~estra-1,3,5(10)-triene-3,17-diol(17~)~' ester N-(2,2-diphosphono-2-hydroxyethyl)_amide c~clobutane-1,2-dicarbox~lic acid 1-/I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(4,4-diphosph~no-4-hydroxybutyl)-amide ~r~ ~ J b~
pyridine-2,3-dicarboxylic acid 2-~I7-(oestra-1,3,5(10)-triene-3,17-diol(17~,)7 ester N-(3,3-dip~osphono-propyl)-amide pyridine-5,6-dicarboxylic acid 5-/17-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(3,3-diphosphono-propyl)-amide pyridine-3,4-dicarboxylic acid 3-/I7-(oestra-l~3~5(lo) triene-3,17-diol(17~)~ ester N-(3,3-diphosphono-3-hydroxypropyl)-amide pyridine-4,5-dicarboxylic acid 4-/I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(4,4-diphosphono-4-hgdroxybutyl)-amide 2-methylvaleric acid 1-/~^7-(oestrs-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(3,3-diphosphono-3-hydroxg-propyl)-amide 4-methylvaleric acid 1-~I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(3,3-diphosphono-3-hydroxg-propyl)-smide 2,4-dimethylvsleric acid 1-/I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(5,5-diphosphono-5-hydroxypentyl)-amide 2,2-di~ethylv~leric ~cid 1-~I7-(oestra-1,~,5(10)-triene-3,17-diol(17~)~ ester N-t7~7-diphospnono-7 hydroxyheptyl)-amide 4,4-dimethylvaleric acid 1-/I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(3,3-diphosphono-3-~ydroxgpropyl)-amide pen~ymethylene~lutaric acid l-/I7-(oestra-1,3,5(1C)-triene-3,17-diol(17~)17 ester N-(4,4-diphosphono-4-hydroxybutyl)-amide cyclopentsne-1,3-dicarboxylic acid 1-/l7-oestra 1,3,5(10)-triene-3,17-diol(17~) ~ ester N-(2,2-diphosphono-2-hydrox~ethgl)-amide h~xanedicarboxglic acid /17-(oestra-1,3~5(10)-triene-3,1~-diol(17~ ester N-(5,5-diphosphono-5-hgdroxg-pentgl)-amide heptanedicarboxglic scid ~I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(6,6-diphosphono-6-hydroxy-he~l)-amide N-(5J5-diphosphono-5-hydroxgvaleroyl)-glgcine ~I7-(oestrs-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(4,4-diphosphonobutgric acid)-L-alanine /I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N_(4,4-dip~osphonobutgric acid)-~_phenglalanine-/I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(5,5-diphosphono-5-hydrox~vslerogl)_2-methgl-L-alanine ~I7-(oestra-l~3~5(lo)-triene-3~l7-diol(l7b)~
ester N-(3,3-diphosphonopropiongl)-3-aminopropionic acid ~17-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(3,3-diphosphonopropionyl)-2-aminocyclohexane-carboxylic acid /I7-(oestra-1,3,5(10)-triene-3,17-di ol ( 17~)~ ester N-(3,3-diphosphonopropiongl)-4-aminocyclohexane-carboxylic acid /I7-(oestra-1,3,5(10)-triene-3,17-diol(l7~)~ ester 2 ~ 8 ;~T-(3,3-diphosphonopropionyl)-4-qminobenzoic acid ~17-(Oestra-1,3,5(10)-~riene-3,17-diol(17~))7 ester IM-(5,5-diphosphono-5-hgdroxyvaleroyl)-6-amino~exanoic acid ~I7-(oestra-l~3~5(lo)-triene-3~l7-diol-l7~)~ ester N-(3,3-diphosphonopropionyl)-9-aminononan~ic acid /I7-(oestrP-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(5,5-diphosphono-5-hydroxgvaleroyl)-L-leucine /I7-(oestra-1,3,5(10)-triene-3,17-diol(17~) ~ ester N-(5,5-diphosphono-5-hydroxy~aleroyl)-2-amino-2,2-tetramethgleneacetic acid /17-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(3,3-diphosphonopropionyl)-2-amino-2,2-pentamethylene-~cetic acid /17-(oestra-1,3,5(10)-triene-3,17-diol-(17~)~ ester N-(5,5-diphosphono-5-hydroxgvalero~1)-2-aminobenzoic acid ~I7-(oestra-1,~,5(10)-triene-3,17-diol(17~)~ ester N-(5,5-diphosphono-5-hydroxyvalerogl)_4-aminobutyric acid /17-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(3,3-diphosphonopropionyl)-4-amino-2,2-dimethgl-butyric acid /I7-(oestra-1,3,5(10)-triene-3,17-diol-(17~)~ ester N-(5,5-diphosphono-5-hydroxgvaleroyl)-3-ami~ocgclo-hexanecsrboxylic acid /I7-(oestrs-1,3,5(10)-triene-3,17-diol(17~)~ ester M-(5,5-diphosp~ono-5-hydroxgvalerogl)-3-aminobenzoic acid /I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~
ester ?~-(3,3-diphosphonopropionyl)-5-aminovaleric acid 7-(oestra-1,3,5(LC)-triene-3,L7-diol(17~))7 ester ~-(3,3-diphosphonopropionyl)-4-me~hylaminocyclohexane-carboxylic acid ~17-(oestra-1,3,5(10)-triene-3,17-duol(l7~)~ ester N-(oestra-1,3,5(10)-triene-3,17-diol(17~)-17-carbonyl)-2-aminoacetic acid N-(3,3-dipbosphonopropyl)-amide N-(oe~tra-1,3,5(10)-triene-3,17-diol(17~)-17-carbonyl)-3-aminopropionic acid N-(3,3-diphosphonoprop~l)_amide N-(oestra-1,3,5(10)-triene-3,17-diol(17~)-17-carbonyl)-L_alanine ~-(5,5-diphosphono-5-hydroxyvaleryl)-amide N-(oestra-1,3,5(10)-triene-3,17-diol(17~)-17-carbonyl)-4-aminobutyric acid N-(5,5-diphosphono-5-hydrox~-valeryl)-amide N-(oestra-1,3,5(10)-triene-3,17-diol(17~)-17-carbon~

5-aminovaleric acid N-(3,3-diphosphonopropyl)-amide N-(oestrs-1,3,5(10)-triene-3,17-diol(17~)-17-carbonyl)-4-aminocyclohexanecarboxglic acid N-(3,3-diphospbono-propyl)-amide N-(oestra-1,3,5(10)-triene-3,17-diol(17~)-17-carbon~l)-4-aminomethylcyclohexanec~rboxylic acid N-(5,5-diphosphono-5-hy~roxyvaleryl)-amide N-(oestrs-1,3,5(10)-triene-3,17-diol(17~)-17-carbonyl)-4-aminobenzoic acid N-(3,3-diphosphono-3-propyl)-amide N-(oe~tra-1,3,5(10)-triene-3,17-diol(17~)-17-thia)-4-aminopropionic acid N-(3,3-diphosphonopropyl)-amide N-(oestra-1,3,5(10)-triene-3,17-diol(17~)-17-thia)-3-aminocyclohexanoic acid N-(3,3-diphosphonopropyl)-amide -39~ 2 6 ~
~-(oestra-1,3,5(1C)-triene-3,17-diol(17~)-17-thia)-L-alanine N-(5,5-diphospbono-5-hydroxyvaleryl)-amide N-(oestra-1,3,5(10)-triene-3,17-diol(17~)-17-tbia)-2-aminoacetic acid N-(5,5-dipbospbono-5-hydroxyvaleryl)-amide N-(oestra-1,3,5(10)-triene-3,17-diol(17~)-17-thia)-4-aminobenzoic acid N-(3,3-diphosphonopropyl)-amide N-(oestra-1,3,5(10)-triene-3,17-diol(17~)_17-thia)-2-aminobenzoic acid N-(5,5-diphosphono-5-hydrox~-valeryl)-amide N-(oestra-1,3,5(10)-triene-3,17-diol(17~)-17-tbia)-4-aminobutyric acid N-(3,3-diphosphonopropyl)-amide N-(oestrs-1~3~5(10)-triene-3~17-diol(17~)-17-thia)-3-aminocrotonic acid N-(3,3-diphosphonopropyl)-amide N-(oestra-1,3,5(1C)-triene-3,17-diol(17,B)-17-carbongl)-N'-(3,3-diphosphonopropionyl)-ethylenediami~e N-(oestra-1,3,5(10)-triene-3,17-diol(17~)-17-carbonyl)-N'-(3,3-diphosphonopropionyl)-1,2-diaminocyclohexane N-(oestra-1,3,5(10)-triene-3,17-diol(17~)-17-carbon~l)-N'-(5,5-diphosphono-5-hydroxyvaleroyl)-1,1-dimethyl-ethylenediamine N-(oestra-1,3,5(1G)-triene-3,17-diol(17~)-17-carbonyl)-N'-(5,5-diphosphono-5-hydroxgvaleroyl)-1,3-diamino-propane N-(oestra-1,3,5(10)-triene-3,17-diol(17~)-17-carbongl)-N'-(3,3-diphosphonopropionyl)-1,3-diamino~2,2-dimethyl-propane .f-(oestra-1,3,5(1C)-triene-3,17-diol(17~)-17-carbonyl)-N'-(3,3-dip~osphonopropionyl)-1,4-diaminobutane N-(oestra-1,3,5(10)-triene-3,17-diol(17~)-l7-carbonyl)-N'-(3,3-diphosphonopropionyl)-1,4-diaminocyclohexane N-(oestra-1,3,5(10)-triene-3,17-diol(17~)-17-carbon;yl)-N'-(5,5-diphosphonovaleroyl)-1,4-diamino-1,1,4,4-tetramethylbut~ne N-(oestra-1,3,5(10)-triene-3,17-diol(17~)-17-carbonyl)-~'-(3,3-diphosphonopropionyl)-1,6-diaminohexane N_(oestra-1,3,5(10)-triene-3,17-diol(17~)-17-carbonyl)-N'-(5,5-diphosphono-5-hydroxyvaleroyl)-1,8-diamino-octahe N-(2',2'-diphosphonoethgl)_L_leucine /17-(oestra-1,3~5(10)-triene-3,17-diol(17~)~ ester N-(2',2'-diphosphonoethgl)-4-aminobutgric acid /17-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(2',2'-diphosphonoethgl)-glgcine ~ 7-(oestra-1,3,5(10)-triene-3,17-diol(17~))7 ester N-(2',2'-diphosphono-2-hgdroxyethgl)-L-alanine /17-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(2',2'-diphosphonoethyl)-~-phenglalanine /I7-(oestra-1,3,5(10)-triene-7,17-diol(17~)~ ester N-(2',2'-dipbosphono-2'-hgdroxyethyl)_2-methyla~anine ~I7-(oestra-1,3,5(10)-triene-7,17-diol(17~)~ ester N-(2',2'-diphosphono-2'-hydroxyethyl)-2,2-tetra-methgleneglgcine ~ l)oestra-1,7,5(10)-triene-3,17-diol(l7~)~ ester N-2',2'-dip~osp~onoethyl)-2,2-pentamethyleneglycine ~I7-(oestra-l~3~5(lo)-triene-3~l7-diol(l7~))7 ester ~;-(2',2'-dipbospbono-2'-hgdroxyetbyl)-3-aminopropionic acid ~I7-(oestra-1,3,5(1G)-triene-3,17-diol(17~)~
ester N-(2',2'-diphosphonoethyl)_2-aminocyclohexanecarboxglic scid /I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~
ester N-(2',2'-diphosphono-2'-hydroxgethyl)_2-aminobenzoic acid /I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(2',2'-diphosphono-2'_hydroxyethgl)-4-aminocgclo-hexanecarboxylic acid ~I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(2',2'-diphosp~onoethyl)-4-aminobenzoic acid /I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(2',2'-diphosphono-2'-hydroxgethyl)-4-methylamino-cyclohexanecarboxylic acid /I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(2',2'-diphosphonoethyl)-4-amino-2,2-dimethglbutyric acid /I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(2',2'-diphosphono-2'-hydroxyethyl)-3-amino-2,2-dimethglpropionic acid /I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(2',2'_diphosphonoethyl)_3-aminocyclohexanecarboxglic acid /I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester N-(2',2'-diphosphono-2'-~ydroxgethyl)-3-aminobenzoic acid ~I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester

6 8 ii-(2',2'-diphosphono-2'-~ydroxyethyl)-6-2minohexanoic acid ~I7-(oestra-1,3,5(10)-triene-3,17-dicl(17~))7 ester ~-(2',2'-diphosphonoethyl)-9-aminononanoic acid ~I7-(oe~tra-1,3,5(10)-triene-3,17-diol(17~)~ ester 3-(2',2'-diphosphono-2'-hydroxyethylmercapto)-propionic acid ~7-(oestra-1,3,5(10)-triene-3,17-diol(l7~)~ ester 2-(2',2'-diphosphono-2'-hydroxyethylmercapto)-benzoic acid /I7-(oestra-1,3,5(10)-triene-3,17-diol(17~))7 ester 4~(2',2'-diphosphonoethglmercapto)-butgric acid /I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester 5-(2',2'-diphosphono-2'-hyd~oxyethylmercapto)-~aleric acid ~I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester 9-(2',2'-diphosphono-2'-hydroxyethylmercapto)-nonanoic acid /I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester 3-(2',2(-diphosphonoethglmercapto)-3-methylpropionic acid ~17-(oestra-1,3,5(10)-triene-3,17-di~1(17~)~ ester 3-(2',2'-diphosphonoethylmercapto)-2-methylpropionic acid /I7-(oestr~-1,3,5(10)-triene-3,17-diol(17~)~ ester 2-(2',2'-diphosphonoethylmercapto)-acetic acid ~I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester 2-(2',2'-diphosphonoethglmercapto)-2-meth~lacetic acid /17-(oestra-1,395(10)-triene-3,17-diol(17~)~ ester 4-(2',2'-diphosphono-2'_hyd~oxyethylmercapto)-benzoic acid /I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester 4-/2'-(2",2"-diphosphonoetnglmercapto)-ethy~ -benzoic acid /I7-(oestra-1,3,5(10)-triene-3,17-diol(17~)~ ester -4~-i~.-(oestra-1,3,5(1G)-triene-3,17-diol(17~)-17-carbonyl)-I~'-(2,2-diphosphonoethyl)-1,3-diaminopropane N-(oestra-l~3~5(lc)-triene-3~l7-diol(l7b)-l7-carbomyl) N'-(2,2-diphosphonoet~yl)-1,3-diamino-2,2-dimethgl-propsne N-(oestra-l~3~5(lo)-triene-3~l7-diol(l7~B)-l7-carbonglJ
N'-(2,2-diphosphonoet~yl)_ethylenediamine N-(oest~8-1,3,5(10)-triene-3,17-diol(17R)-17-carbongl)-N'-(2,2-diphosphono-2-bydroxgethgl)-1,1-dimethglethglene-diamine N-(oestra-1,3,5(10)-triene-3,17-diol(17~ 17-carbonyl)-N'-(2,2-diphosphono-2-hydroxgethyl)-1,2-diamino¢gclo-hexane N-(~estra-1,3,5(10)-triene-3,17-diol(17~)-17-carbongl)-N'-(2,2-dip'.;osphono-2-hydroxgethyl)-1,4-diaminobutane N-(oestra-1,3,5(10)-triene-3,17-diol(17~)-17-carbonyl)-N'-(2,2-diphosphonoethgl)-1,4-diaminocyclohexane N-(oestra-1,3,5(10)-triene-3,17-diol(17~)-17-carbonyl)-N'-(2,2-diphosphonoethyl)-1,4-diamino-2,2,4,4-tetra-methylbutane N-(oestra-1,3,5(10)-triene-3,17-diol(17~)-17-carbonyl)-N'-(2,2-diphosphonoethyl)-1,6-diaminohexane N-(oestra-1,3,5(10)-triene-3,17-diol(17~)-17-carbonyl)-N'-(2,2-diphosphono-2-hydroxgethyl)-1,8-diaminooctane 2-(2',2'-diphosphonoethylmercapto)-N-(oestra-1,3,5(10)-triene-3,~7-diol(17~)-17-carbonyl)-ethglamine 2-(2',2'-diphosphonoéthylmercapto)-N-(oestra-1,3,5(10)-triene-3,17-diol(17~)-17-carbonyl)-cyclohexglamine h lJ ~

2-(2',2'-diphosphonoethylmercapto)-~l-(oestra-1,3,5(1C)-triene-3,17-diol(17~)-17-carbonyl)-butylamine oestra-1,3,5(1C)-triene-3,17-diol(17~)-17-~ -(3,3-diphosphonopropgl)7 csrbamate oestra-1,3,5(10)-triene-3,17-diol(17~)-17-~-(4,4-diphosphono-4-hydroxy)-butgl7 carbamate

Claims (4)

Patent Claims

1. Compounds of the general formula I

(I) in which Sp signifies R1 - R6 = in each case independently of one another hydrogen, phenyl, cyclohexyl, lower straight-chained or branched alkyl, alkenyl or alkynyl with 1 - 5 and 2 - 5 carbon atoms, respectively, which is possibly substituted by phenyl, whereby R1 and R2, together with the carbon atoms to which they are attached, can form a saturated alicyclic 3 - 6 ring or R1 and R5, together with the carbon atom(s) connecting them can form a saturated, partly saturated or unsaturated 3 - 6 ring possibly interrupted by 1 or 2 nitrogen atoms, m, n and r, independently of one another, can assume values of 0 - 3, whereby m + n + r may assume the value of at most 7, and X = C or S, Y = valency bond or NH
Z = valency bond, , , NH or S

A = hydrogen, hydroxyl or amino possibly substituted by lower alkyl, alk = a straight-chained or branched alkylene chain with 1 - 6 carbon atoms, R7 = hydrogen or lower alkyl, as well as their pharmacologically acceptable salts.

2. Process for the preparation of compounds of the general formula I
(I) in which Sp signifies R1-R6 = in each case independently of another, hydrogen, phenyl, cyclohexyl, lower straight-chained or branched alkyl, alkenyl or alkynyl with 1 - 5 and 2 - 5 carbon atoms, respectively, which is possibly substituted by phenyl, whereby R1 and R2, together with the carbon atom to which they are attached, can form a saturated alicyclic 3 - 6 ring or R1 and R5, together with the carbon atom(s) connecting them, can form a saturated, partly saturated or unsaturated 3-6 ring possibly interrupted by 1 or 2 nitrogen atoms, m, n and r, independently of one another, can assume values of C - 3, whereby m + n + r may assume the value of at most 7, and X = O or S, Y = valency bond or NH
Z = valency bond, , , NH or S, A = hydrogen, hydroxyl or amino possibly substituted by lower alkyl, alk = a straight-chained or branched alkylene chain with 1 - 6 carbon atoms, R7 = hydrogen or lower alkyl, as well as of their pharmacologically acceptable salts, characterised in that, in per se known manner, one I for the case that Z signifies the group, reacts a carboxylic acid derivative of the general formula II

in which X, Y, R1-R6, m, n and r have the above-given meanings and T represents the hydroxyl group or an activating group, with a diphosphonic acid derivative of the general formula III

(III) in which alk, R7 and A have the above-given meanings, or II) for the case that Z signifies the group , reacts an amino compound of the general formula IV

(IV) in which X, Y, R1-R6, m, n and r have the above-given meanings, with a diphosphonic acid derivative of the general formula V

(V) in which alk, A and R7 have the above-given meanings and T represents the hydroxyl or an activating group, or III for the case that Z = NH or S, reacts a compound of the general formula VI

(VI) in which X, Y, R1-R6, m, n and r have the above-given meanings and Z = NH or S, with a diphosphonic acid derivative of the general formula VII

(VII) whereby alk, A and R7 have the above-given meanings and U represents a reactive residue, whereby for the case that alk signifies a C1 group, U and A can together also represent a valency bond or an oxygen atom, or for the case that x = oxygen and Y = valency bond, reacts a compound of the general formula VIII

(VIII) in which R1-R7, Z, alk, A, m, n and r have the above-given meanings and Hal = chlorine or bromine, with a 17-.beta.-oestradiol derivative of the general formula IX

(IX) in which V represents a protective group, or V) for the case that Y , NH, a) reacts 8 compound of the general formula X

(X) in which X, R1-R7, Z, alk, A, m, n and r have the above-given meanings, with a 17-.beta.-oestradiol deriv-ative of the general formula IX

(IX) in which V represents a protective group, or b) reacts an amino compound of the general formula XI

(XI) in which R1-R7, Z, alk, A, m, n and r have the above-given meanings, with a 17-.beta.-oestradiol derivative of the general formula XII

(XII), in which V represents a protective group and W = is to be chlorine or the group -X-M, whereby M represents lower alkyl, such as methyl or ethyl, or a possibly substituted phenyl ring and X has the above-given meaning, and subsequently, is desired, converts the C=O group into a C=S group, or (VI) subsequently converts compounds of the general formula I, in which X = oxygen into compounds of the general formula I with X = sulphur, splits off the protective groups possibly present and, if desired, saponifies the resultant tetraseters to diesters or acids of the general formula I
and, if desired, converts the compounds obtained into pharmacologically acceptable salts.

3. Medicaments containing a compound of the formula I
according to claim 1, besides usual carrier and adjuvant materials.

4. Use of compounds of the formula I according to claim 1 for the treatment of osteoporosis.