DK169677B1

DK169677B1 - New n-heterocyclic propylidene-1,1-bis:phosphonic acids - useful as drugs influencing calcium metabolism for treating arthritic disorders, atherosclerosis etc.

Info

Publication number: DK169677B1
Application number: DK197590A
Authority: DK
Inventors: Ernst Torndal Binderup; Sven Liisberg
Original assignee: Leo Pharm Prod Ltd
Priority date: 1988-04-07
Filing date: 1990-08-20
Publication date: 1995-01-09
Also published as: DK197590A; DK197590D0

Abstract

N-Heterocyclic propylidene-1,1-bisphoric acids of formula (I) and their salts are new. R1 to R8 = H, or 1-10C aliphatic hydrocarbon; opt. R3 when taken together with R1 or R5 forms a satd. aliphatic 5-7-membered ring opt. substd. with one or more 1-4C alkyl. R1 to R8 = H or 1-4C alkyl. The salt is selected from alkali metal salt, alkaline earth metal and salts with ammonia or non-toxic amines.

Description

i DK 169677 B1in DK 169677 B1

Den foreliggende opfindelse angår hidtil ukendte forbindelser, som er værdifulde i den humane og veterinære behandling, farmaceutisk acceptable salte af, fremgangsmåder til fremstilling af, samt farmaceutiske præparater indeholdende de nævnte nye forbindelser.The present invention relates to novel compounds which are valuable in the human and veterinary treatment, to pharmaceutically acceptable salts, to methods of preparing, and to pharmaceutical compositions containing said novel compounds.

5 Forbindelserne ifølge opfindelsen har formlen IThe compounds of the invention have the formula I

R3 T R1 rOl^C POÆ 10 R5^ V-ch2—ch2—c-oh i r^8 R' R8 1 o i hvilken R -R er ens eller forskellige og betyder hydrogen eller en lige eller 3 15 forgrenet alifatisk crcio hydrokarbongruppe, og i hvilken R sammen med enten R^ eller R^ eventuelt danner en mættet alifatisk 5-, 6- eller 7-leddet ring, som eventuelt er substitueret med en eller flere C j -C^-alkylgrupper.R 3 T R1 rOl ^ C PO 10 R5 ^ V-ch 2 —ch 2 —c-oh ir ^ 8 R 'R8 1 o in which R-R is the same or different and means hydrogen or a straight or branched aliphatic crcio hydrocarbon group, and in which R together with either R 1 or R 2 optionally forms a saturated 5-, 6- or 7-membered aliphatic ring optionally substituted by one or more C 1 -C 4 alkyl groups.

RJ-R^ betyder især hydrogen eller Cj-C^-alkyl.R 1 -R 3 especially means hydrogen or C 1 -C 4 alkyl.

Opfindelsen omfatter alle mulige stereoisomere former af forbindelser 20 med formlen I.The invention encompasses all possible stereoisomeric forms of compounds of formula I.

Som nævnt ovenfor, angår opfindelsen også salte af forbindelserne med formlen I, som er tetrabasiske syrer og således danner mono-, di-, tri- og tetra-basiske salte med baser. Som eksempler på salte som er dannet med farmaceutisk acceptable, ugiftige baser kan nævnes alkalimetalsalte og jordalkalimetal-25 salte, såsom lithium-, natrium-, kalium-, magnesium- og calciumsalte, såvel som salte med ammoniak og egnede ugiftige aminer, såsom lavere alkylaminer, fe triethylamin, lavere alkanolaminer, fe diethanolamin eller triefhanolamin, proca-in, cykloalkylaminer, fe dicyklohexylamin, benzylaminer, fe N-methylbenzyl-amin, N-ethylbenzylamin, N-benzyl^-phenethylamin, Ν,Ν’-dibenzylethylendi- DK 169677 B1 2 amin eller dibenzylamin, og heterocykliske aminer, fx morpholin, N-ethylpiperi-din og lignende.As mentioned above, the invention also relates to salts of the compounds of formula I which are tetrabasic acids and thus form mono-, di-, tri- and tetra-basic salts with bases. Examples of salts formed with pharmaceutically acceptable non-toxic bases include alkali metal salts and alkaline earth metal salts such as lithium, sodium, potassium, magnesium and calcium salts, as well as salts with ammonia and suitable non-toxic amines such as lower alkyl amines , fatty triethylamine, lower alkanolamines, fairy diethanolamine or triefhanolamine, proca-in, cycloalkylamines, fairy dicyclohexylamine, benzylamines, fairy N-methylbenzylamine, N-ethylbenzylamine, N-benzyl-phenylamine, Ν, Ν'-dibenzylethylenedi- B1 2 amine or dibenzylamine, and heterocyclic amines, for example morpholine, N-ethylpiperidine and the like.

Forbindelserne med formlen I kan også danne in vivo let hydrolyserbare estre. Da de er tetrabasiske syrer, kan de danne mono-, di-, tri- eller tetraestre.The compounds of formula I can also form readily hydrolyzable esters in vivo. Since they are tetrabasic acids, they can form mono-, di-, tri- or tetra-esters.

5 Eksempler på sådanne esterdannende remanenser er alkanoyloxymethyl med tre til seks karbonatomer, l-(alkanoyloxy)ethyl med fire til syv karbonato-mer, l-methyl-l-(alkanoyloxy)ethyl med fem til otte karbonatomer, alkoxykar-bonyloxy)ethyl med fire til seks karbonatomer, l-(alkoxykarbonyloxymethyl med fire til syv karbonatomer, 1 -methyl-1 -(alkoxykarbonyloxy)ethyl med fem 10 til otte karbonatomer, 3-phthalidyl, 4-crotonolactonyl, y-butyrolacton-4-yl, (2--oxo-1,3-dioxolen-4-yl)methyl, (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl og (5-phenyl-2-oxo-l,3-dioxolen-4-yl)methyl såvel som dialkylaminoalkyl, acetonyl og methoxymethyl.Examples of such ester-forming residues are alkanoyloxymethyl of three to six carbon atoms, 1- (alkanoyloxy) ethyl of four to seven carbon atoms, 1-methyl-1- (alkanoyloxy) ethyl of five to eight carbon atoms, alkoxycarbonylloxy) ethyl of four to six carbon atoms, 1- (alkoxycarbonyloxymethyl with four to seven carbon atoms, 1- methyl-1- (alkoxycarbonyloxy) ethyl with five to eight carbon atoms, 3-phthalidyl, 4-crotonolactonyl, γ-butyrolacton-4-yl, (2 - oxo-1,3-dioxolen-4-yl) methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl and (5-phenyl-2-oxo-1,3- dioxolen-4-yl) methyl as well as dialkylaminoalkyl, acetonyl and methoxymethyl.

En række bisphosphonsyrederivater er kendte til anvendelse indenfor det 15 aktuelle område. SU patentskrift nr. 1002300 beskriver fremstillingen af 1-hy-droxy-3-(4’-morpholinyl)-propyliden-l,l-bisphosphonsyre og l-hydroxy-3-(r-piperidyl)-propyliden-l,l-bisphosphonsyre og omtaler den mulige anvendelse af disse forbindelser som komplexdannende stoffer og til fremstillingen af medikamenter, som påvirker calciummetabolismen. Patentet beskriver ikke andre hete-20 rocyklisk substituerede forbindelser, og altså heller ikke de foreliggende pyr-rolidinylsubstituerede derivater med formlen I. Hvis man sammenligner aktiviteten af en forbindelse ifølge dette patent (der indeholder en piperidyl-substituent, nedenfor omtalt som SL 2333) med den tilsvarende forbindelse, der kun afviger ved i stedet for piperidyl at være substitueret med pyrrolidinyl (denne forbin-25 delse er betegnet som EB 1053), vil man konstatere, at EB 1053 og SL 2333 er nogenlunde lige stærke med hensyn til at hindre knogleresorptionen, men at EB 1053 har lavere generel toksicitet og en mindre evne til at hindre ny knogledannelse. I modsætning til SL 2333 viser EB 1053 ingen tegn på uheldig indflydelse på knoglemineraliseringsprocesserne.A number of bisphosphonic acid derivatives are known for use in the current field. SU Patent No. 1002300 discloses the preparation of 1-hydroxy-3- (4'-morpholinyl) propylidene-1,1-bisphosphonic acid and 1-hydroxy-3- (r-piperidyl) propylidene-1,1-bisphosphonic acid and discloses the possible use of these compounds as complexing agents and in the preparation of drugs which affect calcium metabolism. The patent does not disclose other heterocyclic substituted compounds, nor the present pyrrolidinyl substituted derivatives of formula I. Comparing the activity of a compound of this patent (containing a piperidyl substituent, hereinafter referred to as SL 2333) with the corresponding compound, which differs only by substituting for pyrrolidinyl instead of piperidyl (this compound is designated as EB 1053), it will be found that EB 1053 and SL 2333 are approximately as strong as to prevent bone resorption. , but that EB 1053 has a lower overall toxicity and a lower ability to prevent new bone formation. Unlike SL 2333, EB 1053 shows no evidence of undue influence on the bone mineralization processes.

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Normale knogler er levende væv, som konstant undergår resorption og genafsætning af calcium, idet nettoeffekten er, at der opretholdes en konstant mineralbalance. Den dobbelte proces omtales almindeligvis som "knogleomsætning". I normale, voksende knogler overstiger mineralafsætningen mineralre-5 sorptionen, medens knogleresoiptionen overstiger knogleafsætningen ved visse patologiske tilstande, resulterende i osteoporose eller i hypercalcæmi, fe som følge af ondartede lidelser eller primær hyperparathyroidisme. Under andre patologiske tilstande kan calciumafsætningen finde sted i uønskede mængder og på uønskede steder, hvilket fører til fe osteoarthritis, rheumatoid arthritis, nyre- og 10 blæresten, atherosclerosis og Paget’s sygdom, som er en kombination af en u-normal stor knogleresorption efterfulgt af en unormal calciumafsætning.Normal bones are living tissues that constantly undergo resorption and re-deposition of calcium, the net effect being that a constant mineral balance is maintained. The dual process is commonly referred to as "bone turnover". In normal, growing bones, mineral deposition exceeds mineral resorption, while bone resuscitation exceeds bone deposition in certain pathological conditions, resulting in osteoporosis or hypercalcaemia, fever due to malignant disorders or primary hyperparathyroidism. Under other pathological conditions, calcium deposition can occur in undesirable amounts and at undesirable sites, leading to fe osteoarthritis, rheumatoid arthritis, renal and bladder stones, atherosclerosis and Paget's disease, which is a combination of an abnormally large bone resorption followed by a abnormal calcium deposition.

.. Forbindelserne ifølge den foreliggende opfindelse kan forøge knoglemassen ved at reducere knogleresorptionen. Forøgelsen af knoglemassen måles ved forøgelsen af vægten af tibiametafysen.The compounds of the present invention can increase bone mass by reducing bone resorption. The increase in bone mass is measured by the increase in the weight of the tibia metaphysis.

15 Eksperimenter med rotter har vist, at forbindelserne ifølge den forelig gende opfindelse har en overraskende, udtalt forøgende effekt på vægten af tibiametafysen. Nedenstående tabel viser, at både vægten og calciumindholdet af tibiametafysen kan forøges betragteligt ved subkutan indgift af forbindelsen i Eksempel 2 (EB 1053, formel I, R*-R^ = H). EB 1053 sammenlignes med APD 20 (3-amino-l-hydroxy-propyliden-l,l-bisphosphonsyre), som for nylig er blevet tilgængelig som det andet og mest aktive bisphosphonat på markedet (Etidronat - 1-hydroxyethyliden-1,1-bisphosphonsyre har været på markedet en række år).Experiments with rats have shown that the compounds of the present invention have a surprisingly pronounced increasing effect on the weight of the tibiametaphysis. The following table shows that both the weight and calcium content of the tibiametaphysis can be significantly increased by subcutaneous administration of the compound of Example 2 (EB 1053, formula I, R * -R ^ = H). EB 1053 is compared to APD 20 (3-amino-1-hydroxy-propylidene-1,1-bisphosphonic acid), which has recently become available as the second and most active bisphosphonate on the market (Etidronate - 1-hydroxyethylidene-1,1- bisphosphonic acid has been on the market for a number of years).

DK 169677 B1 4DK 169677 B1 4

Calciumcalcium

Forbin- Dosis Tibia-metafysevægt mg/metafyse 5 delse /zmol/kg/dag % ændring sammen- % ændring s.c. lignet med kontrol sammenlignet (7 dage) med kontrol EB 1053 1,6 +50 pcO.OOl +62 pcO.OOl 10 0,16 +44 p<0.001 +64 p<0.005 0,016 +24 p<0.001 +25 p<0.001 15 0,0016 + 3 i.s. + 2 i.s.Combine-Dose Tibia metaphysis weight mg / metaphysis 5 distribution / zmol / kg / day% change together-% change s.c. compared to control compared (7 days) with control EB 1053 1.6 +50 pcO.OOl +62 pcO.OOl 10 0.16 +44 p <0.001 +64 p <0.005 0.016 +24 p <0.001 +25 p <0.001 Is 0.0016 + 3 + 2 i.s.

APD 1,6 +24 pcO.OOl +29 p<0.05 20 0,16 +12 i.s. +18 i.s.APD 1.6 +24 pcO.OOl +29 p <0.05 20 0.16 +12 i.s. +18 i.s.

statistisk analyse ved Students t-test, 25 i.s. = ikke signifikantstatistical analysis by Student's t-test, 25 i.s. = not significant

Det ses fra tabellen, at EB 1053 er betydeligt stærkere virkende end APD. Desuden har eksperimenter med rotter vist, at EB 1053 er mindre giftig end APD. EB 1053 har således et bedre terapeutisk index end APD.It can be seen from the table that EB 1053 is significantly stronger acting than APD. In addition, experiments with rats have shown that EB 1053 is less toxic than APD. Thus, EB 1053 has a better therapeutic index than APD.

30 En yderligere fordel ved den stærke virkning af de foreliggende forbin delser er, at de lave dosisniveauer, som kræves giver en mindre sandsynlighed for gastro-intestinale gener, som undertiden er forbundet med oral indgift af store doser af bisphosphonater.A further advantage of the strong effect of the present compounds is that the low dose levels required give a lesser likelihood of gastrointestinal genes, sometimes associated with oral administration of large doses of bisphosphonates.

Den udtalte virkning af forbindelserne gør dem også særligt egnede til 35 alternative indgivelsesveje, fe intranasal eller transdermal indgift.The pronounced effect of the compounds also makes them particularly suitable for alternative routes of administration, intranasal or transdermal administration.

Forbindelserne ifølge den foreliggende opfindelse kan fremstilles ved en fremgangsmåde, der er ejendommelig ved, at en forbindelse-med formlen IIThe compounds of the present invention can be prepared by a process characterized in that a compound of formula II

DK 169677 B1 5 R3 f R1DK 169677 B1 5 R3 f R1

. 4A. 4A

m π R7 R8 10 1 8 i hvilken R -R har de ovenfor anførte betydninger, omsættes med en forbindelse, med formlen ΠΙ 15 ch2=ch—coor9 m om π R7 R8 10 1 8 in which R-R has the above meanings, is reacted with a compound of formula ΠΙ 15 ch2 = ch-coor9 m o

i hvilken R er en lavere alkylgruppe, hvorved der dannes en forbindelse med den almene formel IVwherein R is a lower alkyl group to form a compound of general formula IV

20 R3 'f R120 R3 'to R1

R5 N—CH2—CH2—COOR9 IVR5 N-CH2-CH2-COOR9 IV

25 R R8 som efterfølgende hydrolyseres til den korresponderende frie syre (R^ = H), hvorefter den frie syre omsættes med fosforsyre og enten fosforoxychlorid eller fosfortrichlorid, efterfulgt af vandig hydrolyse, hvorved der fremstilles en for-30 bindelse med formlen Is som om ønsket omdannes til et salt deraf.R 8 is subsequently hydrolyzed to the corresponding free acid (R 2 = H), after which the free acid is reacted with phosphoric acid and either phosphorus oxychloride or phosphorus trichloride, followed by aqueous hydrolysis to give a compound of formula Is as desired. is converted into a salt thereof.

DK 169677 B1 6DK 169677 B1 6

Forbindelserne ifølge opfindelsen er som ovenfor nævnt beregnet til anvendelse i farmaceutiske præparater, som er anvendelige til behandling af osteo-porose, rheumatoid arthritis og andre arthritiske sygdomme, atherosclerose, hy-percalcemi som følge af ondartede lidelser og primær hyperparathyroidisme, 5 Paget’s sygdom og andre tilstande med en unormal calciumbalance.The compounds of the invention are, as mentioned above, intended for use in pharmaceutical compositions useful in the treatment of osteoporosis, rheumatoid arthritis and other arthritic diseases, atherosclerosis, hypercalcaemia due to malignant disorders and primary hyperparathyroidism, Paget's disease and others. conditions with an abnormal calcium balance.

De farmaceutiske præparater ifølge opfindelsen er ejendommelige ved, at de indeholder en effektiv mængde af en eller flere af forbindelserne med formlen I sammen med farmaceutisk acceptable, ugiftige bærere og/eller hjælpestoffer.The pharmaceutical compositions of the invention are characterized in that they contain an effective amount of one or more of the compounds of formula I together with pharmaceutically acceptable, non-toxic carriers and / or excipients.

10 Forbindelserne ifølge opfindelsen kan også anvendes i tandpasta til hin dring af calciumaflejring i form af tandsten eller beskyttelse mod calciumopløs-ning som følge af syreangreb.The compounds of the invention can also be used in toothpaste to prevent calcium deposits in the form of tartar or protection against calcium solution due to acid attack.

Den nødvendige mængde af en forbindelse med formlen I (i det efterfølgende betegnet som den aktive bestanddel) til opnåelse af terapeutisk virk-15 ning vil naturligvis afhænge af den givne forbindelse, indgivelsesvejen og den patient, som er under behandling. En hensigtsmæssig dosis af en forbindelse med formlen I er 0,001 til 15 mg pr. kilogram legemsvægt, idet den foretrukne dosis er 0,008 - 0,3 mg/kg legemsvægt/dag ved parenteral indgift og 0,1 - 10 mg/kg legemsvægt/dag ved oral indgift.Obviously, the amount of a compound of formula I (hereinafter referred to as the active ingredient) to achieve therapeutic effect will depend on the given compound, the route of administration, and the patient undergoing treatment. A suitable dose of a compound of formula I is 0.001 to 15 mg per day. The preferred dose is 0.008 - 0.3 mg / kg body weight / day by parenteral administration and 0.1 - 10 mg / kg body weight / day by oral administration.

20 Selv om det er muligt at indgive en aktiv bestanddel som sådan, er det undertiden foretrukket at give den som en farmaceutisk formulering. Den aktive bestanddel udgør hensigtsmæssigt fra 0,01 til 99,9 vægtprocent af formuleringen. Dosisenheder af en formulering indeholder hensigtsmæssigt 0,25 - 16 mg af den aktive bestanddel, når den gives parenteralt, og 3 - 600 mg, når det gives 25 oralt, idet de nævnte dosisenheder indgives én eller flere gange dagligt, eller med passende mellemrum (dage, uger eller måneder).While it is possible to administer an active ingredient as such, it is sometimes preferable to administer it as a pharmaceutical formulation. The active ingredient is conveniently from 0.01 to 99.9% by weight of the formulation. Dosage units of a formulation suitably contain 0.25 - 16 mg of the active ingredient when given parenterally and 3 - 600 mg when given orally, said dosage units being administered once or several times daily or at appropriate intervals ( days, weeks, or months).

Formuleringerne omfatter sådanne, som er i en form, der er egnet til oral, rektal, parenteral (herunder subkutan, intramuskulær og intravenøs), nasal, transdermal eller topisk indgift.The formulations include those which are in a form suitable for oral, rectal, parenteral (including subcutaneous, intramuscular and intravenous), nasal, transdermal or topical administration.

DK 169677 B1 7DK 169677 B1 7

Formuleringer ifølge den foreliggende opfindelse, som er egnede til oral indgift, kan være i form af adskilte enheder, såsom kapsler, breve, tabletter eller pastiller, som hver indeholder en forudbestemt mængde af den aktive bestanddel; i form af et pulver eller granuler, i form af en opløsning eller en suspension 5 i en vandig væske eller en ikke-vandig væske; eller i form af en olie-i-vand-e-mulsion eller en vand-i-olie-emulsion. Den aktive substans kan også være i form af en bolus, latværge eller pasta.Formulations of the present invention suitable for oral administration may be in the form of separate units, such as capsules, letters, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules, in the form of a solution or suspension 5 in an aqueous liquid or a non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. The active substance may also be in the form of a bolus, latewater or paste.

Formuleringer til rektal indgift kan være i form af et suppositorium indeholdende den aktive bestanddel og en bærer, såsom kokossmør, eller i form 10 af et lavementRectal administration formulations may be in the form of a suppository containing the active ingredient and a carrier, such as coconut butter, or in the form of a lavender

Formuleringer, som er egnede til parenteral indgift omfatter fortrinsvis en steril vandig præparation af den aktive bestanddel, som fortrinsvis er isoto-nisk med modtagerens blod.Formulations suitable for parenteral administration preferably comprise a sterile aqueous preparation of the active ingredient, which is preferably isotonic with the recipient's blood.

Formuleringer til nasal indgift kan være i fast, flydende eller tyktflyden-15 de form, efter valg sammen med en absorptionsforøger (e.g. natriumtauro-24,25--hydrofusidat).Nasal administration formulations may be in solid, liquid or viscous form, upon selection with an absorption enhancer (e.g., sodium tauro-24,25 hydrofusidate).

Præparaterne kan yderligere indeholde andre terapeutisk aktive forbindelser, som almindeligvis anvendes ved behandlingen af de ovenfor nævnte patologiske tilstande, fe vitamin D2 og Dg og hydroxylerede derivater, fe la-hy-20 droxy-vitamin Dg, Ια-hydroxy-vitamin D2, 1 a,25-dihydroxy-vitamin Dg, la,25-dihydroxy-vitamin D2, calcitonin (human, svine- eller lakse-), mitramy-cin, natriumfluorid, østrogener og ikke-steroide anti-inflammatoriske lægemidler, fe acetylsalicylsyre, indomethacin og naprosyn.The compositions may further contain other therapeutically active compounds which are commonly used in the treatment of the above pathological conditions, fairy vitamin D2 and Dg and hydroxylated derivatives, fairy-hydroxy vitamin Dg, α-hydroxy vitamin D2, 1a , 25-dihydroxy vitamin Dg, la, 25-dihydroxy vitamin D2, calcitonin (human, swine or salmon), mitramycin, sodium fluoride, estrogens and non-steroidal anti-inflammatory drugs, fatty acetylsalicylic acid, indomethacin and naprosyn .

Forbindelserne ifølge opfindelsen indgives til en patient, som lider af en 25 af de ovenfor nævnte patologiske tilstande i en daglig eller intermitterende dosis (til voksne) fra 250 pg - 600 mg.The compounds of the invention are administered to a patient suffering from 25 of the above-mentioned pathological conditions in a daily or intermittent dose (for adults) of 250 µg - 600 mg.

Opfindelsen beskrives nærmere i de følgende Eksempler: DK 169677 Bl 8The invention is further described in the following Examples: DK 169677 Bl 8

Eksempel 1 3-ί 1 ’-PvrrolidinvlVpropansvre. hvdrochloridExample 1 3-ί 1 '-PyrrolidinylVropanoic acid. hydrochloride

En blanding af 102,6 g ethyl 3-(r-pyrrolidinyl)-propanoat og 340 ml 6 N saltsyre kogtes under tilbagesvaling i 4 timer. Efter afkøling og inddampning 5 til tørhed i vakuum, opløstes remanensen i iseddikesyre, og opløsningen ind-dampedes i vakuum. Den krystallinske remanens omrørtes med iseddikesyre, filtreredes og vaskedes med iseddikesyre og ether. Tørring i vakuum gav den analytisk rene titelforbindelse. Smp. 175-177°C.A mixture of 102.6 g of ethyl 3- (r-pyrrolidinyl) propanoate and 340 ml of 6 N hydrochloric acid was refluxed for 4 hours. After cooling and evaporating to dryness in vacuo, the residue was dissolved in glacial acetic acid and the solution was evaporated in vacuo. The crystalline residue was stirred with glacial acetic acid, filtered and washed with glacial acetic acid and ether. Drying in vacuo gave the analytically pure title compound. Mp. 175-177 ° C.

10 Eksempel 2 1 -Hvdroxv-3-(T -nvrrolidinvlVproDvliden-1.1 -bisphosphon-svre (ΈΒ 1053) 27,5 g Fosforsyre opløstes i 30,7 ml fosforoxychlorid, og 30 g 3-(Γ--pyrrolidinyl)-propansyre - hydrochlorid tilsattes. Blandingen opvarmedes lang-15 somt under hydrogenchloridgas udstrømning til 100°C, hvor temperaturen holdtes i 2 timer. Reaktionsblandingen (et skum) behandledes med 178 ml vand og kogtes under tilbagesvaling i 3 timer. Efter afkøling og inddampning til tørhed i vakuum, blandedes remanensen i 35 ml vand, og 90 ml methanol tilsattes indtil krystallisation. Efter afkøling og filtrering vaskedes det farveløse krystallinske 20 produkt med ethanol og ether og tørredes i vakuum.Example 2 1 -Hydroxy-3- (T-pyrrolidinyl) -prodylidene-1,1-bisphosphonic acid (ΈΒ 1053) 27.5 g of phosphoric acid was dissolved in 30.7 ml of phosphorus oxychloride and 30 g of 3- (Γ-pyrrolidinyl) -propanoic acid - The mixture was slowly heated under hydrogen chloride gas effluent to 100 ° C where the temperature was maintained for 2 hours. The reaction mixture (a foam) was treated with 178 ml of water and refluxed for 3 hours. After cooling and evaporating to dryness in vacuo. , the residue was mixed in 35 ml of water and 90 ml of methanol were added until crystallization, After cooling and filtration, the colorless crystalline product was washed with ethanol and ether and dried in vacuo.

Smp. 235°C (sønderdeling).Mp. 235 ° C (dec.).

Mikroanalvse: Beregnet: C: 29,08, H: 5,99, N: 4,84, P: 21,42 Fundet: C: 28,93, H: 5,92, N: 4.91, P: 21.38 %-NMR (D2O, HDO = 4.66 ppm som reference): δ = 1,70-2,05 (m, 4H); 25 2,10-2,30 (m, 2H); 2,80-3,00 (m, 2H); 3,30-3,40 (t, 2H) og 3,45-3,65 (m, 2H) ppm.Microanalysis: Calculated: C: 29.08, H: 5.99, N: 4.84, P: 21.42 Found: C: 28.93, H: 5.92, N: 4.91, P: 21.38% - NMR (D 2 O, HDO = 4.66 ppm as reference): δ = 1.70-2.05 (m, 4H); 2.10-2.30 (m, 2H); 2.80-3.00 (m, 2H); 3.30-3.40 (t, 2H) and 3.45-3.65 (m, 2H) ppm.

13C-NMR (D20, absolut frekvens): δ = 25,56 (t, 2C), 32,33 (t, 1C), 54,11 (tt, 1C), 57,05 (t, 2C) og 74,79 (t, J = 140 Hz, 1C) ppm.13 C NMR (D 2 O, absolute frequency): δ = 25.56 (t, 2 C), 32.33 (t, 1 C), 54.11 (t, 1 C), 57.05 (t, 2 C), and 74, 79 (t, J = 140 Hz, 1C) ppm.

DK 169677 B1 9DK 169677 B1 9

Eksempel 3Example 3

Dinatrium-1 -hvdroxv-3-f 1 ’-pvrrolidinvlVpropvliden-1.1--bisphosphonat. trihvdrat 103,7 ml 2 N Natriumhydroxyd sattes til en omrørt suspension af 30 g 5 l-hydroxy-3-(l 5-pyrroIinyI)-propyliden-1,1-bisphosphonsyre i 120 ml vand. 225 ml Ethanol sattes under omrøring til den resulterende opløsning, hvorved man fik et krystallinsk bundfald. Krystallerne opsamledes ved filtrering, vaskedes med ethanol og lufttørredes.Disodium-1-hydroxy-3- [1'-pyrrolidinyl] -propylidene-1,1-bisphosphonate. Trihydrate 103.7 ml of 2 N Sodium hydroxide was added to a stirred suspension of 30 g of 5 l-hydroxy-3- (1,5-pyrrolinyl) propylidene-1,1-bisphosphonic acid in 120 ml of water. 225 ml of ethanol was added with stirring to the resulting solution to give a crystalline precipitate. The crystals were collected by filtration, washed with ethanol and air dried.

Mikroanalvse: 10 Beregnet: C: 21,71 H: 5,47 N: 3,62 P: 16,00, H20: 13,96 Fundet: C: 21,66 H: 5,47 N: 3,61 P: 15,91, H20: 14,08 *H-NMR (D20, HDO = 4,66 ppm som reference): δ = 1,90 (bm, 4H), 2,15 (m, 2H), 2,86 (bm, 2H), 3,29 (t, 2H), og 3,53 (bm, 2H) ppm.Microanalysis: Calculated: C: 21.71 H: 5.47 N: 3.62 P: 16.00, H 2 O: 13.96 Found: C: 21.66 H: 5.47 N: 3.61 P: 15.91, H 2 O: 14.08 * H-NMR (D 2 O, HDO = 4.66 ppm as reference): δ = 1.90 (bm, 4H), 2.15 (m, 2H), 2.86 ( bm, 2H), 3.29 (t, 2H), and 3.53 (bm, 2H) ppm.

13C-NMR (D20, absolut frekvens): δ = 20,72 (2C), 27,63 (1C), 49,62 (t, J = 7 15 Hz, 1C), 51,70 (2C) og 70,34 (t, J = 127 Hz, 1C) ppm.13 C NMR (D 2 O, absolute frequency): δ = 20.72 (2C), 27.63 (1C), 49.62 (t, J = 7 Hz, 1C), 51.70 (2C), and 70, 34 (t, J = 127 Hz, 1C) ppm.

Eksempel 4 3-Γ3 ’-Methvl-1 ’-pvrrolidinvlVoropansvre. hvdrochlorid 45 ml 3-Methylpyrrolidin sattes langsomt under omrøring til 50 ml 20 methylacrylat. Da den exotermiske reaktion var ophørt, destilleredes produktet i vakuum.Example 4 3-β3-Methyl-1 '-pyrrolidinylpyropanoic acid. Hydrochloride 45 ml of 3-methylpyrrolidine was slowly added with stirring to 50 ml of methyl acrylate. When the exothermic reaction had ceased, the product was distilled in vacuo.

Det rene methyl-3-(3’-methyl-r-pyrrolidinyl)-propanoat kogtes under tilbagesvaling i 3 timer med et overskud af 20% saltsyre. Inddampning til tørhed i vakuum og omrøring med acetone gave titelforbindelsen som farveløse kry-25 staller. Smp. 163-164°C.The pure methyl 3- (3'-methyl-r-pyrrolidinyl) propanoate was refluxed for 3 hours with an excess of 20% hydrochloric acid. Evaporation to dryness in vacuo and stirring with acetone gave the title compound as colorless crystals. Mp. 163-164 ° C.

^H-NMR (NaOD, HDO = 4,66 ppm som reference): δ = 0,91 (d, 3H), 1,35 (m, IH), 1,96 (m, IH), 2,20 (m, 1 H), 2,32 (m, 3H), 2,70-2,90 (m, 4H) og 3,00 (m, IH) ppm.1 H-NMR (NaOD, HDO = 4.66 ppm as reference): δ = 0.91 (d, 3H), 1.35 (m, 1H), 1.96 (m, 1H), 2.20 ( m, 1H), 2.32 (m, 3H), 2.70-2.90 (m, 4H) and 3.00 (m, 1H) ppm.

DK 169677 B1 10 13C-NMR (NaOD, absolut frekvens): δ = 21,13 (q, 1C), 34,13 (d, 1C), 34,29 (t, 1C), 37,68 (t, 1C), 55,11 (t, 1C), 56,25 (t, 1C), 63,18 (t, 1C) og 182,64 (s, 1C) ppm.DK 169677 B1 13 C-NMR (NaOD, absolute frequency): δ = 21.13 (q, 1C), 34.13 (d, 1C), 34.29 (t, 1C), 37.68 (t, 1C) ), 55.11 (t, 1C), 56.25 (t, 1C), 63.18 (t, 1C) and 182.64 (s, 1C) ppm.

5 Eksempel 5 l-Hvdroxv-3-(3 8 -methyl-1 5 -pvrrolidinvlVpropvliden-1.1--bisphosphonsvre 9,6 g 3-(3’-methyl-r-pyrrolidinyl)-propansyre, hydrochlorid og 8 g fosforsyre varmedes ved 140°C, indtil en klar opløsning dannedes. Efter af-10 køling til 80°C tilsattes dråbevis 15 ml fosfortrichlorid, og den resulterende blanding varmedes ved 85-90°C natten over. Overskydende fosfortrichlorid fjernedes i vakuum, og remanensen kogtes under tilbagesvaling med 60 ml vand i 4 timer. Efter fjernelse af opløsningsmidlet i vakuum krystalliseredes remanensen fra ethanol, hvorved man fik titelforbindelsen med smeltepunkt 225°C (sønder-15 deling).Example 5 1- Hydroxy-3- (3,8-methyl-1,5-pyrrolidinyl) -propylidene-1,1-bisphosphonic acid 9.6 g of 3- (3'-methyl-r-pyrrolidinyl) -propanoic acid, hydrochloride and 8 g of phosphoric acid are heated at After cooling to 80 ° C, 15 ml of phosphorus trichloride was added dropwise and the resulting mixture was heated at 85-90 ° C overnight. Excess phosphorus trichloride was removed in vacuo and the residue was boiled under reflux. with 60 ml of water for 4 h. After removal of the solvent in vacuo, the residue was crystallized from ethanol to give the title compound, mp 225 ° C (dec.).

1H-NMR (NaOD, HDO = 4,66 ppm som reference): δ = 0,88 (d, 3H), 1,42 (m, IH), 2,00 (m, 3H), 2,20 (m, 1 H), 2,45 (m, IH), 2,90-3,20 (m, 5H) ppm. 13C-NMR (NaOD, absolut frekvens): δ = 20,63 (1C), 34,17 (1C), 34,32 (1C), 34,69 (1C), 54,84 (1C), 55,82 (1C), 62,66 (1C) og 77,56 (t, J = 135 Hz, 1C) 20 ppm.1 H NMR (NaOD, HDO = 4.66 ppm as reference): δ = 0.88 (d, 3H), 1.42 (m, 1H), 2.00 (m, 3H), 2.20 (m , 1H), 2.45 (m, 1H), 2.90-3.20 (m, 5H) ppm. 13 C NMR (NaOD, absolute frequency): δ = 20.63 (1C), 34.17 (1C), 34.32 (1C), 34.69 (1C), 54.84 (1C), 55.82 (1C), 62.66 (1C) and 77.56 (t, J = 135 Hz, 1C) 20 ppm.

Eksempel 6 3-f2’-Methvl-l ’-PvrrolidinvD-propansvre. hvdrochloridExample 6 3- [2'-Methyl-1'-Pyrrolidinyl] D-propanoic acid. hydrochloride

En blanding af 110 g ethyl-3-(2’-methyl-r-pyrrolidinyl)propanoat og 25 350 ml 6 N saltsyre kogtes under tilbagesvaling i 4 timer. Efter afkøling og inddampning til tørhed i vakuum, omrørtes remanensen mecLacetone, hvorefter man fik titelforbindelsen i form af farveløse krystaller med smeltepunkt 144-145°C.A mixture of 110 g of ethyl 3- (2'-methyl-r-pyrrolidinyl) propanoate and 350 ml of 6 N hydrochloric acid was refluxed for 4 hours. After cooling and evaporating to dryness in vacuo, the residue was stirred with mecLacetone to give the title compound in the form of colorless crystals, mp 144-145 ° C.

DK 169677 B1 11 *H-NMR (D2O, HDO = 4,66 ppm som reference): δ = 1,31 (d, 3H), 1,60 (m, IH), 1,86-2,05 (m, 2H), 2,20 (m, 1 H), 2,73 (m, 2H), 2,95-3,15 (m, 2H), 3,32 (m, IH) og 3,55 (m, 2H) ppm.1 H-NMR (D 2 O, HDO = 4.66 ppm as reference): δ = 1.31 (d, 3H), 1.60 (m, 1H), 1.86-2.05 (m , 2H), 2.20 (m, 1H), 2.73 (m, 2H), 2.95-3.15 (m, 2H), 3.32 (m, 1H) and 3.55 (m , 2H) ppm.

5 Eksempel 7 l-Hvdroxv-3-(2 ’-methvl-1 ’ -pvrrolidinvlVnrop vliden-1.1 -bisphosphonsvreExample 7 1- Hydroxy-3- (2 '-methyl-1' -pyrrolidinyl) -propylidene-1,1-bisphosphonic acid

Denne forbindelse fremstilledes fra 3-(2’-methyl-r-pyrrolidinyl)-pro-pansyre, hydrochlorid ved at følge den i Eksempel 5 beskrevne fremgangsmåde. Krystallisation fra ethanol gav titelforbindelsen med smeltepunkt 230°C (sønder-10 deling).This compound was prepared from 3- (2'-methyl-r-pyrrolidinyl) -propanoic acid, hydrochloride following the procedure described in Example 5. Crystallization from ethanol gave the title compound, mp 230 ° C (dec.).

1H-NMR (D2O, HDO = 4,66 ppm som reference): δ = 1,26 (d, 3H), 1,55 (m, IH), 1,8-2,0 (m, 2H), 2,05-2,35 (m, 3H), 3,02 (m, 2H), 3,30 (m, IH), 3,55-3,70 (m, 2H) ppm.1 H NMR (D 2 O, HDO = 4.66 ppm as reference): δ = 1.26 (d, 3H), 1.55 (m, 1H), 1.8-2.0 (m, 2H), 2 , 05-2.35 (m, 3H), 3.02 (m, 2H), 3.30 (m, 1H), 3.55-3.70 (m, 2H) ppm.

13C-NMR (D20, absolut frekvens): δ = 18,21 (1C), 23,73 (1C) 31,79 (1C), 15 33,54 (1C), 51,80 (1C), 55,98 (1C), 67,60 (1C), og 74,27 (t, J = 141 Hz, 1C) ppm.13 C NMR (D 2 O, absolute frequency): δ = 18.21 (1 C), 23.73 (1 C) 31.79 (1 C), 33.54 (1 C), 51.80 (1 C), 55.98 (1C), 67.60 (1C), and 74.27 (t, J = 141 Hz, 1C) ppm.

Eksempel 8Example 8

De nedenfor nævnte forbindelser fremstilles ved at erstatte 3-methylp-20 yrrolidin i Eksempel 4 med den passende mono-, di- eller trialkylsubstituerede pyrrolidin og følge de deri beskrevne fremgangsmåder. For 2,5-disubstituerede pyrrolidiner er reaktionen med methylacrylat langsom og kan kræve adskillige timers opvarmning. De således fremstillede mellemprodukter omdannes derefter til følgende bisphophonsyrer under anvendelse af de i Eksempel 2 eller Eksem-25 pel 5 beskrevne fremgangsmåder: l-Hydroxy-3-(2’,3 ’-dimethyl-r-pyrrolidinyl)-propylidin--1,1 -bisphosphonsyre; 1 -Hydroxy-3-(2 ’,4 ’-dimethyl-1 ’-pyrrolidmyl)-propylidin-30 -1,1-bisphosphonsyre; DK 169677 B1 12 l-Hydroxy-3-(2’,5 ’-dimethyl-1 ’-pyrrolidinyl)-propylidin--1,1 -bisphosphonsyre; l-Hydroxy-3-(2’,2’-dimethyl-r-pyrrolidinyl)-propylidin--1,1 -bisphosphonsyre; 5 l-Hydroxy-3-(3 ’,3 ’-dimethyl-1 ’-pyrrolidinyl)-propylidin--1,1 -bisphosphonsyre; l-Hydroxy-3-(3 ’,4’-dimethyl-l’-pyrrolidmyl)-propylidin--1,1 -bisphosphonsyre; l-Hydroxy-3-(2’,2’,3 ’-trimethyl-1 ’-pyrrolidinyl)-propyl-10 idin-1,1 -bisphosphonsyre; 1 -Hydroxy-3-(2 ’,2 ’,4 ’-trimethyl-1 ’-pyrrolidinyl)-propyl-idin-1,1 -bisphosphonsyre; l-Hydroxy-3-(2’,2’,5’-trimethyl-r-pyrrolidinyl)-propyl-idin-1,1 -bisphosphonsyre; 15 l-Hydroxy-3-(2’,3’,5’-trimethyl-r-pyrrolidinyl)-propyl-idin-1,1 -bisphosphonsyre; l-Hydroxy-3-(2’,4’,4’-trimethyl-r-pyrrolidinyl)-propyl-idin-1,1 -bisphosphonsyre; 1 -Hydroxy-3 -(2 ’-ethyl-1 ’ -pyrrolidinyl)-propylidin-1,1-20 -bisphosphonsyre; l-Hydroxy-3-(3’-ethyl-l’-pyrrolidinyl)-propylidin-l,l- -bisphosphonsyre; l-Hydroxy-3-(3 ’,3 ’-diethyl-1 ’-pyrrolidinyl)-propylidin--1,1 -bisphosphonsyre; 25 l-Hydroxy-3-(3 ’,4’-diethyl-l ’-pyrrolidinyl)-propylidin- -1,1 -bisphosphonsyre; l-Hydroxy-3-(2’,3 ’,4’-triethyl-l ’-pyrrolidinyl)-propyl-idin-1,1 -bisphosphonsyre; 1 -Hydroxy-3 -(2 ’ -propyl-1 ’-pyrrolidinyl)-propylidin-1,1-30 -bisphosphonsyre; DK 169677 B1 13 1 -Hydroxy-3-(3 ’-propyl-1 ’-pyrrolidinyl)-propylidin-1,1--bisphosphonsyre; l-Hydroxy-3-(2’,2’-dipropyl-1 ’-pyrrolidinyl)-propylidin--1,1 -bisphosphonsyre; 5 1 -Hydroxy-3 -(2 ’ -butyl-1 ’ -pyrrolidinyl)-propylidin-1,1- -bisphosphonsyre; l-Hydroxy-3-(3 ’-butyl-1 ’-pyrrolidinyl)-propylidin-l, 1--bisphosphonsyre; 1 -Hydroxy-3-(2 ’-sec.butyl-1 ’-pyrrolidinyl)-propylidin-10 -1,1 -bisphosphonsyre; 1 -Hydroxy-3 -(2 ’ -isobutyl-1 ’ -pyrrolidinyl)-propy lidin-1,1--bisphosphonsyre; 1 -Hydroxy-3 -(2 ’ -hexyl-1 ’ -pyrrolidinyl)-propylidin-1,1--bisphosphonsyre; 15 l-Hydroxy-3-(l ’-cis-octahydroindolyl)-propylidin-l, 1-bisphosphonsyre; l-Hydroxy-3-(r-trans-octahydroindolyl)-propylidin-l,l-bisphosphonsyre; l-Hydroxy-3-(2’-cis-octahydroisoindolyl)-propylidin-l,l-bisphosphonsyre;The compounds listed below are prepared by replacing 3-methylp-20-yrrolidine in Example 4 with the appropriate mono-, di- or trialkyl-substituted pyrrolidine and following the procedures described therein. For 2,5-disubstituted pyrrolidines, the reaction with methyl acrylate is slow and may require several hours of heating. The intermediates thus prepared are then converted to the following bisphophonic acids using the procedures described in Example 2 or Example 5: 1-Hydroxy-3- (2 ', 3' -dimethyl-r-pyrrolidinyl) -propylidine-1, 1-bisphosphonic acid; 1-Hydroxy-3- (2 ', 4' -dimethyl-1 '-pyrrolidinyl) -propylidine-1,1-bisphosphonic acid; B1 12 1-Hydroxy-3- (2 ', 5' -dimethyl-1 '-pyrrolidinyl) -propylidine-1,1-bisphosphonic acid; 1-Hydroxy-3- (2 ', 2'-dimethyl-r-pyrrolidinyl) propylidine - 1,1-bisphosphonic acid; 5-Hydroxy-3- (3 ', 3' -dimethyl-1 '-pyrrolidinyl) -propylidine-1,1-bisphosphonic acid; 1-Hydroxy-3- (3 ', 4'-dimethyl-1'-pyrrolidinyl) propylidine - 1,1-bisphosphonic acid; 1-Hydroxy-3- (2 ', 2', 3 '-trimethyl-1' -pyrrolidinyl) -propyl-idin-1,1-bisphosphonic acid; 1-Hydroxy-3- (2 ', 2', 4 '-trimethyl-1' -pyrrolidinyl) -propylidine-1,1-bisphosphonic acid; 1-Hydroxy-3- (2 ', 2', 5'-trimethyl-r-pyrrolidinyl) propyl-idine-1,1-bisphosphonic acid; 1-Hydroxy-3- (2 ', 3', 5'-trimethyl-r-pyrrolidinyl) propylidine-1,1-bisphosphonic acid; 1-Hydroxy-3- (2 ', 4', 4'-trimethyl-r-pyrrolidinyl) propyl-idine-1,1-bisphosphonic acid; 1-Hydroxy-3- (2'-ethyl-1 '-pyrrolidinyl) -propylidine-1,1-20-bisphosphonic acid; 1-Hydroxy-3- (3'-ethyl-1'-pyrrolidinyl) -propylidine-1,1-bisphosphonic acid; 1-Hydroxy-3- (3 ', 3' -diethyl-1 '-pyrrolidinyl) -propylidine - 1,1-bisphosphonic acid; 1-Hydroxy-3- (3 ', 4'-diethyl-1' -pyrrolidinyl) propylidine-1,1,1-bisphosphonic acid; 1-Hydroxy-3- (2 ', 3', 4'-triethyl-1 '-pyrrolidinyl) -propyl-idine-1,1-bisphosphonic acid; 1-Hydroxy-3- (2'-propyl-1 '-pyrrolidinyl) -propylidine-1,1-30-bisphosphonic acid; 1-Hydroxy-3- (3 '-propyl-1'-pyrrolidinyl) -propylidine-1,1-bisphosphonic acid; 1-Hydroxy-3- (2 ', 2'-dipropyl-1' -pyrrolidinyl) -propylidine - 1,1-bisphosphonic acid; 5-Hydroxy-3- (2'-butyl-1 '-pyrrolidinyl) -propylidine-1,1-bisphosphonic acid; 1-Hydroxy-3- (3 '-butyl-1' -pyrrolidinyl) -propylidine-1,1-bisphosphonic acid; 1-Hydroxy-3- (2'-sec-butyl-1 '-pyrrolidinyl) -propylidine-10-1,1-bisphosphonic acid; 1-Hydroxy-3- (2'-isobutyl-1 '-pyrrolidinyl) -propylidine-1,1-bisphosphonic acid; 1-Hydroxy-3- (2 '-hexyl-1' -pyrrolidinyl) -propylidine-1,1-bisphosphonic acid; 1-Hydroxy-3- (1'-cis-octahydroindolyl) -propylidine-1,1-bisphosphonic acid; l-hydroxy-3- (s-trans-octahydroindolyl) -propylidin-l, l-bisphosphonic acid; l-hydroxy-3- (2'-cis-octahydroisoindolyl) -propylidin-l, l-bisphosphonic acid;

Claims

1. N-Heterocyclic Propylidene-1,1-Bisphosphonic Acids of the General Formula I 5 R1 2 R1 rOl ^ C poa r3 ^ Ofc-CH2-C-OH I

10 POsH2 R R 'V 1 5? in which R -R is the same or different and means hydrogen or a straight-chain or branched aliphatic C--Cjrok hydrocarbon group, and in which R together with either R eller or Ruelt optionally forms a saturated 5-, 6- or 7-membered aliphatic ring optionally substituted with one or more C 1 -C 4 alkyl groups, and salts thereof. 1 o

Compounds according to claim 1, characterized in that R -R is the same or different and means hydrogen or C1-C4 alkyl. Salt according to claim 1 or 2, characterized in that the salt is selected from the group consisting of alkali metal salts, alkaline earth metal salts, and salts with ammonia or suitable non-toxic amines. Compound according to claim 1 and salts thereof, characterized in that it is selected from the group consisting of 1-Hydroxy-3- (r-pyrrolidinyl) -propylidene-1,1-bisphosphonic acid, 3-1-Hydroxy-3- (3'-methyl-r-pyrrolidinyl) -propylidene-1,1-bisphosphonic acid, DK 169677 B1 1-Hydroxy-3- (2'-methyl-1'-pyrrolidinyl) -propylidene-1,1-bisphosphonic acid.

Salt according to claim 4, characterized in that it is the disodium salt of 1-hydroxy-3- (15-pyrrolidinyl) -propylidene-1,1-bisphosphonic acid. 5

Salt according to claim 5, characterized in that it is the trihydrate of the disodium salt of 1-hydroxy-3- (15pyrrolidinyl) propylidene-1,1-bisphosphonic acid.

Process for the preparation of a compound of formula I according to claim 1 or a salt thereof, characterized in that a compound of the general formula II R 3 R 1 R 8 R 8 R 8 R The above meanings are reacted with a compound of general formula III

CH 2 -CH-COOR 9 m wherein R 1 is a lower alkyl group to form a compound of general formula IV wherein R 1 -R 2 have the aforementioned meanings, which compound is subsequently hydrolyzed to the corresponding free acid (R 2 = H), after which the free acid is reacted with phosphoric acid and either phosphorus oxychloride or phosphorus trichloride, followed by aqueous hydrolysis to give the desired compound of formula I, as if desired, converted to a salt thereof.

Pharmaceutical composition, characterized in that it contains an effective amount of one or more of the compounds of claim 1 together with pharmaceutically acceptable non-toxic carriers and / or excipients.

Pharmaceutical composition according to claim 8 for parenteral or oral administration, characterized in that it contains for parenteral administration a unit dose of a total of 0.25 - 16 mg of one or more of the compounds according to claim 1, or that for oral administration. contains a unit dose of a total of 3 - 600 mg of one or more of the compounds of claim 1.

Use of one or more of the compounds of claims 1 to 6 for the preparation of a composition for use in treating a patient suffering from osteoporosis, rheumatoid arthritis or other arthritic diseases, atherosclerosis, hypercalcaemia due to malignant disorders or primary hyperparathyroidism, Paget's disease, or other abnormal calcium balance disorders. 30