AU609549B2

AU609549B2 - Araliphatylaminoalkanediphosphonic acids

Info

Publication number: AU609549B2
Application number: AU26738/88A
Authority: AU
Inventors: Knut A. Jaeggi
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1987-12-11
Filing date: 1988-12-09
Publication date: 1991-05-02
Anticipated expiration: 2008-12-09
Also published as: NO885489D0; DK688488A; PT89193A; NO885489L; MX14109A; ATE90353T1; DK688488D0; FI885710A0; HU202880B; FI92704C; NZ227273A; JPH01197495A; PH26416A; IE883680L; IE62738B1; FI885710A7; NO176663B; PT89193B; DE3881659D1; ES2054868T3

Abstract

Araliphatylaminoalkanediphosphonic acids of the formula <IMAGE> in which R1 represents an aromatically substituted aliphatic radical, R2 represents hydrogen or a monovalent aliphatic radical and alk denotes a divalent aliphatic radical, and their salts have a marked regulating action on calcium metabolism and can be used as medicaments for the treatment of diseases which can be traced back to disorders thereof. They are prepared, for example, by reacting a compound of the formula <IMAGE> in which X3 denotes carboxyl and R0 denotes a radical R2, with phosphorous acid and phosphorus trichloride and hydrolysing the primary product.

Description

signature of Applicant (s) r its Officers as prescribed by Its Articles of Association,.

(5) 09/ i2 Z/ee by t

A'

COMMONWEALTH OF 60O.9549 PATENTS ACT 1952-69 Form COMPLETE SPECIFICATION

(ORIGINAL)

Class Appiic: tion Number: Lodged: I t. Class Complete Specification Lodged: Accepted: Published: 'Priority ri rS Relpted Art:- Name of Applicant: CIBA-GEIGY AG .Address of Applicant; Klybeckstrasse 141, 4Q02 lasle, Switzerland Actual Inventor., Address for Service KNUT A, JAEGGI EPWD7~TR&OS- X n Ir TOM f~Lh0z~~. ~2\J CC,,

S-D>~

Comnlete Specificatioa for the invention entitled:.j ARALIPHATYT.AMINOALKANEDIPHOSPHONIC ACIDS Th e folIlo win g sta tement, Is a f ull descriptilon of th Is I nveantio n, inclu d ing the best method of perform Ing It k nown to U S 2< November 18, 199S CIBA-GEIGY AG Werner Waldegg Single Signature, by special power To: The Coimissioner of Patents 2.88 .521 WW 1 4-16803/+

AU

Araliphatylaminoalkanediphosphonic a ids The invention relates to araliphaty lair-inoalkanediphosphonic acids of formula Ri- 4a lk_-O0H MI, wherein RI, is a lower alkyl or lower alkenyl radical that is mono- or di-substituted by a 6-memberel monocyclic aryl radical -or by a lhicylic aryl radical composed of 5- or 6-membered rings or by a 5- or 6-membered 4 monocycli~ heeor 'rdcal or by a bicycliQ hetaroaryl radical conposed of 5- or 6-nembered rings, which heteroaryl radicals conta~in as hetero atom(s) 1 or 2 N-atom(s) 1 0-atom or 1 S-atom, 1 N-,Itom and 1 0-atom, or 1 N-atom and 1 S-atomt, amd which aryl and heteroaryl radicals are unsubstituted or substituted by lower alkyl, lower alkoxy, lower a:Lkylthio and/or by halogen, R 2 is hydrogen, lower alkyl or lower alkenyl, and al1k is lower alkylene, with the proviso that in compounds of formula I wherein Ri is mono-substituted by phenyl, R2 is hydrogen or, if RI contains 2 or 3 carbon atoms in the aliphatic moiety, is a lower alkyl or lower alkenyl radical containing at most 3 carbon atoms, and their salts, to processes for the preparation of the compounds of the invention, to pharmaceutical compositions containing them and to their use as fr active ingredients in medicanents.

5- or 6-Mlembered monocyclic aryl radicals, or bicyclic aryl radicals composed of 5- or. 6-membered rings, or 5- or 6-membered monocyclic heteroaryj. radicals, or bicyclic heteroaryl radicals. composed of 5- or 6-membered rings, which heteroaryl radicals contain as hetero atom(s) 1 or 2 N-atoms, 1 0-atom or S-atom, 1 N-atom and 1 O-A1tom, or 1 N-atom and 1 S-atom, are, for example, plhet, yl 4rj secondly, naphthyl or pyrroilylt thienylt, furyl, pyridy1, imidaz.,I pyieimidinyl or qUinoinyl* especial- OFFICE

C.T.A

V L4i 2 i ly phenyl, thienyl, pyridyl or imidazolyl, each of which is unsubstituted or, especially, is mono- or poly-substituted, preferably mono- or, secondly, di-substituted, by lower alkyl, lower alkoxy, lower alkylthio and/or by halogen. The radical RI may be substituted by one or more than one such substituent Ra, for example by one substituerkt R 3 or by two identical or different substituents R 3 These are preferably bonded by way of a carbon atom but may also be bonded by way of an additional nitrogen atom which may be present. If Ri has more than one such substituent, preferably two of these are bonded to the same carbon atom of the aliphatic radical. Preferred radicals Ri are those of formula (i 9 9C 99

E)

CH-alk'

R

4 (la), wherein R 3 is an aromatic radical RA, R4 is hydrogen or an aromatic radical R and alk' is lower alkylane, RA and R. each having one of the Smeanings given for R and the sum of the carbon atoms of alk' preferably not exceeding 6.

.fce- 9 i 9 6 4 9 99 *e 9 *9 9 Hereinafter there are to be understood by lower radicals and compounds those radicals and compounds having up to and including 7, especially up to and including 4, carbon atoms. The general terms also have, for example, the following meanings: Lower ilkyl is, for example, Ci-C4alkyl, such as methyl, ethyl, propyl, isopropyl or butyl, and also isohutyl, secondary butyl or tertiary butyl, but may also be a C 5

-C

7 alkyl g;oup, such as a pentyl, hexyl or heptyl group.

Lower alkoxy is, for example, Ci-Ctal'oxy, such as methoxy, ethoxy, propoxpropoxy ioropoxy or butoxy, and also isobutoxy, secondary butoxy or tertiary butoxy.

Lower alkylthio is, for example, Ci-C4alkylthio, such as methylthio, ethylthio. propylthio or butylthio, and also isobutylthio, secondary butylthio or tertiary butylthio.

K

-3- Halogen is, for example, halogen having an atomic number of up to and including 35, such as chlorine or fluorine, and also bromine.

Lower alkenyl is, for example, C2-Ci~alkenyl, such as, vinyl, allyl or buten-2-yl, but may also be a C5-C 7 alkenyl group, such as a pentenyl, hexenyl or heptenyl group.

Lower alkylene alk is, for example, C 2 -C4alkylene, especially straightchained C 2 -C4alkylene, such as a,uW-C2-C 4 -alkylene, for example ethylene, 1,3-propylene 8econdly, 1 ,4-butylene.

Lower alkylene alk' is, for example, C2-C~alkylene, especially straightchained C2-C~alkylene, such as c,W-C2-Csalkylene, for example ethylene, :1,3-prop,,rlene, 1,4-butylene, 1,5-pentylene or 1,6-hexylene, but may also be 1,2-pizopylene, 1,2- or 1,3-butylene or 1,4-pentylene.

SSalts of compounds of formula I are especially internal salts theroof and salts thereof with Pharmaceutically acceptable bases, such as mon-toxic Smetal sal~ts derived from metals of groups Ia, Ib, Na and Ilb, for Sexample alkali metal salts, especially sodium or potassium salts, alkaline earth metal salts, especially calcium or magnesium salts, copper salts, aluminium salts or zinc salts, or ammonium salts with ammonia or organic amines 6ir quaternary ammonium bases, such as optionally C-hydroxyiated a)liphat4.c amines, especially mono-, di- or tni-lower alkylamines, for example methyl-, ethyl-, dimethyl- or di~thyl-amine, mno- di- or t1ri-(hydroxy-lower alkyl)-amines, such as ethanol-, ethanol- or triethanol-amine, tris(hydroxymethyl)amino-methane or 2-hdroy-trt.butlcaneor N-(hydroxy-lower alkyl)-N,N-di-lower 2-(dimethylamino)-ethanol or D-glucamine, or quaternary aliphatic ammonium hydroxidas, for example tetrabutylammonium hydroxide. These salts include both complete salts and partial salts, i.e. salts with 1, 2, 3 or 4, preferably 2, equivilents of base per mole of the aqld of formula 1.

-4- The compounds of formula I and their salts have valuable pharmacological properties. In particular, they exhibit a pronounced regulatory action on the calcium metabolism of warm-blooded animals. In particular, in rats, they effect a marked inhibition of bone resorption, which can be demonstrated both in the test procedure according to Acta Endocrinol. 78, 613-24 (1975) by reference to the PTH-induced increase in the serum calcium level after subcutaneous administration in doses of from approximately 0.01 to approximately 1.0 mg/kg, and in the TPTX (thyroparathyroidectomised) rat model by reference to the experimental hypercalcaemia, induced by vitamin D 3 after the administration of doses of approximately from 0.001 to 1.0 mg The tumour hypercalcaemia induced by Walker-256-tumours is likewise inhibited after peroral administration of from approximately 1.0 to approximately 100 mg/kg.

Further, in adjuvant arthritis in rats in the test procedure according to o 9 S Newbould, Brit. J. Pharmacology 21, 127 (1963) and according to Kaibara S et al., J. Exp. Med. 159, 1388-96 (1984), they exhibit a marked 0 inhibition of the progression of chronic arthritic processes in doses of S approximately from 0.01 to 1.0 mg/kg They are therefore eminently suitable as active ingredients in medicaments for the treatment of diseases that may be associated with calcium metabolism disorders, for example inflammatory processes in joints and degenerative processes in the articular cartilage, of osteoporosis, periodontitis, hyperparathyroidism and of calcium deposits in blood vessels or on S prosthetic implants. A favourable effect is produced both in diseases in which an anomalous deposition of sparingly soluble calcium salts is to be observed, such as diseases from among the forms of arthritis, for example S Brechterew's disease, neuritis, bursitis, periodontitis and tendinitis, fibrodysplasia, osteoarthrosis and arteriosclerosis, and in diseases in which an anomalous degeneration of hard body tissue is the principal symptom, such as hereditary hypophosphatasia, degenerative processes in the articular cartilage, osteoporoses of various origins, Paget's disease and osteodystrophia fibrosa, and also in tumour-induced osteolytic processes.

'4 i I t

Q

5 The invention relates especially to compounds of formula I wherein Ri is a lower alkyl radical that is mono- or di-substituted by a 6-membered monocyclic aryl radical or by a bicyclic aryl radical composed of and/or 6-membered rings, which aryl radicals are unsubstituted or substituted by lower alkyl, lower alkoxy, lower alkylthio and/or by halogen, or is a lower alkyl radical that is mono-substituted by a 5- or 6-membered monocyclic heteroaryl radical that contains as hetero atom(s) 1 O-atom or S-atom or 1 or 2 N-atoms, R 2 is hydrogen or a lower alkyl radical, with the proviso that R, is hydrogen if Ri is an unsubstituted benzyl- or phenyl-C 3

-C

7 alkyl radical, or that Rz is hydrogen or lower alkyl containing 1 or 2 carbon atoms if RI is a phenethyl radical, and alk is lower alkylene, and their salts.

/r tThe invention relates especially to compounds of formula I wherein R 1 is a radical of formula (la) wherein R 3 is an aromatic radical RA, R4 is 44 4 hydrogen or an aroma:ic radical RB and alk' is lower alkylene, RA and R .4 9 a0fr 90 9 9 99 1# 4 4 4 Iq It 44 t It 1 ll 44 I Il 1 i t Q t 4 4 i:.E _i 6each being a 5- or 6-membered monocyclic aryl radical or a bicyclic aryl radical composed of 5- or 6-membered rings or a 5- or 6-membered monocyclic heteroaryl radical or a bicyclic heteroaryl radical composed of or 6-membered rings, which heteroaryl radicals contain as hetero atom(s) 1 or 2 N-atom(s), 1 O-atom or S-atom, 1 N-atom and 1 0-atom or 1 N-atom and 1 S-atom, and which aryl and heteroaryl radicals are unsubstituted or substituted by lower alkyl, lower alkoxy, lower alkylthio and/or by halogen, R 2 is hydrogen, lower alkyl or lower alkenyl, and alk is lower alkylene, for example those wherein alk' is C2-C 3 lower alkylene and R2 is hydrogen or Ci-C3alkyl if R 3 is unsubstituted phenyl and R4 is hydrogen, and their salts, especially their pharmaceutically acceptable salts.

o II *t The invention relates more especially, on the one hand, to compounds of formula I wherein R 1 is a radical of formula (Ia) wherein R 3 is a phenyl, thienyl, pyridyl, imidazolyl or naphthyl radical that is unsubstituted or S mono- or di-substituted by Cl-C4alkyl, such as methyl, C1-Calkoxy, such as methoxy, Ci-C 4 alkylthio, such as methylthio, and/or by halogen having an atomic number of up to and including 35, such as fluorine or chlorine, R4 is h/drogen or, if Ra is a pher.yl radical that is unsubstituted or mono- or di-substituted by Ci-C4alkyl, such as methyl, Ci-Calkoxy, such as methoxy, Ci-Cyalkylthio, such as methylthio, and/or by halogen having an atomic number of up to and including 35, such as fluorine or chlorine, R4 is likewise a phenyl radical that is unsubstituted or mono- or di-substituted by Cl-Cqalkyl, such as methyl, Ci-Cialkoxy, such as methoxy, Ci-Ctalkylthio, such as methylthio, and/or by halogen having an atomic number of up to and including 35, such as fluorine or chlorine, alk' is C1-Csalkylene, such as ethylene, 1,3-propylene or 1,4-butylene, R 2 is hydrogen, and alk is straight-chained C 2 -Cialkylene, such as ethylene or 1, 3 -propylene, and their salts, especially their pharmaceutically acceptable salts.

The inventicn relates more especially, on the other hand, to compounds of formula I wherein Ri is a radical of formula (la) wherein R 3 is a phenyl, naphthyl, thienyl, pyridyl or imidazolvy radical that is unsubstituted or mono- or di-substituted by Ci-C4alkyl, such as methyl, Ci-C4alkoxy, such l 1 t1 1

I

1 I 1 7as methoxy, Ci-C4alkylthio, such as methylthio, and/or by halogen having an atomic number of up to and including 35, such as fluorine or chlorine,

R

4 is hydrogen or, if R3 is a phenyl radical that is unsubstituted or mono-or di-substituted by C 1

-C

4 alkyl, such as methyl, Ci-C4alkoxy, such as methoxy, Ci-C4alkylthio, such as methylthio, and/or by halogen having an atomic number of up to and including 35, such as fluorine or chlorine,

R

4 is likewise a phenyl radical that is unsubstituted or mono- or di-substituted by Ci-C4alkyl, such as methyl, Ci-C4alkoxy, such as methoxy, C1-C4alkylthio, such as methylthio, and/or by halogen having an atomic number of up to and including 35, such as fluorine or chlorine, alk' is Ci-Csalkylene, such as 1,3-propylene, 1,4-butylene or 1,5-pentylene, R2 Pe", is Ci-C4alkyl, such as methyl, or C2-C4alkenyl, such as allyl, and alk is S straight-chained C 2 -C4alkylene, such as ethylene or 1,3-propylene, with the proviso that alk' is methylene and R 2 is hydrogen or Ci-C 2 alkyl if R 3 is unsubstituted phenyl and R 4 is hydrogen, and their salts, especially 'p i S their pharmaceutical. acceptable salts.

The invention relates preferably to compounds of formula I wherein Ri is Sa radical of formula (la) wherein Ra is phenyl that is unsubstituted or, i secondly, mono- or di-substituted by C 1 -C4alkyl, such as methyl, C 1 -C4alkoxy, such as methoxy, or by halogen having an atomic number of up to and including 35, such as chlorine or fluorine, R 4 is hydrogen, alk' is straight-chained, terminally bonded Cz-C4alkylene, such as ethylene or 1,3-propylene, Rz is hydrogen or Ci-C4alkyl, such as methyl, and alk is C2-Caalkylene, such as ethylene, for example those wherein alk' is Ci-C2alkylene and Rz is hydrogen or C1-Csalkyl if R3 is unsubstituted phenyl, and their salts, especially their pharmaceutically acceptable salts.

The invention relates most preferably to compounds of formula I wherein Ri is mono- or di-phenyl-C 2 -Csalkyl that is unsubstituted or mono- or di-substituted in the phenyl moiety by Ci-C4alkyl, such as methyl, Ci-C4alkoxy, such as methoxy, and/or by halogen having an atomic number of up to and including 35, such as chlorine, or is imidazolyl-, thienyl- or L ii Xnr 8 pyridyl-C2-C6alkyl, R 2 is hydrogen or Ci-C4-alkyl, such as methyl, and alk is C 2

-C

3 alkylene, such as ethylene, with the proviso that Rz is hydrogen if RI is unsubstituted phenyl-C 3 -Csalkyl, or R 2 hydrogen or C1-Czalkyl if RI is an unsubstituted phenethyl radical, and their salts, especially their pharmaceutically acceptable salts.

The invention relates most especially to compounds of formula I wherein Ri is a radical of formula (la) wherein R 3 is phenyl that is unsubstituted or, secondly, mono- or di-substituted by Ci-C4alkyl, such as methyl, Ci-C 4 -alkoxy, such as methoxy, and/or by halogen having an atomic number of up to and including 35, such as chlorine or fluorine, R4 is hydrogen, alk' is straight-chained, terminally bonded Cz-Calkylene, such as ethylene or 1,3-propylene, R 2 is hydrogen, and alk is C2-Caalkylene, such as ethylene, and their salts, especially their pharnmaceutically acceptable salts.

The invention relates specifically to the compounds of formula I mentioned in the Examples and their salts, especially their internal S salts and pharmaceutically acceptable salts with bases.

The invention also relates to a process for the preparation of compounds of formula I and their salts, which process is based on methods that are known per se. This process comprises a) in a compound of formula R alk -OH

(II),

wherein Ro is a radical R 2 or an amino-protecting group and X 1 is a functionally modified phosphono group and X2 is a free or functionally modified phosphono group, converting functionally modified phosphono Xi and, where appropriate, Xz into a free phosphono group, or i- -9b) reacting compounds of formulae ?0 3

H

2 R- Y 1 (III) and Y2- alk -OH (IV), wherein one of the radicals Y 1 and Y 2 is a reactive esterified hydroxy group and the other is a group of formula -N(Ro)-H wherein R 0 is a radical R2 or an amino-protecting group, or salts thereof, with each other, or c) reacting a compound of formula wherein Ro is a radical R 2 or an amino-protecting group and X3 is carbo3xy, carbamoyl or cyano, especially carboxy or cyano, with phosphorous acid and phosphorus trichloride, hydrolysing the primary product and$ in an intermediate of formula 002 P -N -alk- N 2

(VI)

obtained starting from compounds of formula V wherein X3 is cyano or carbamoyl, or in a salt thereof, replacing the amino group by hydroxy by treatment with nitrous acid, and in each case removing the aminoprotecting group if present and, if desired, converting a resulting compound into a different compound of formula I and/or convepting a resulting free compound into a salt or a resulting salt in the free compound or into a different salt, Suitable amino-protecting groups RO are, for excamplet ca-aryl-19wer alkyll such as benzyl or R -methoxybenzyl, (x,c,c-triaryl-lower alkyl, such as trityl, or tri-lower alkylsily., such as trimethylsilyl. c-Aryl- and cUcxc-tri-ayllower alkyl can readily be removed by hydrogenolysis, and tri-lower alkylsilyl and cct-b-ri-aryl-lower alkyl can readily be removed by hydrolysis. The removal of cv-aryl- and OtU;$Uc-tricoSY:L-lower alkyl RQ using bydrogenolysis is effected especially 1 by reaction vith hydrogen in the presence of a hydrogenation catalyst, such as a, nickel or noble metal catalyst, for example palladium-on-carbon, preferpbly in a lower alkanol under normal pressure an-d temperature conditions, for example at approximately from 2000 to 30'C and from approximately 0.95 bar xo approximately 1.3 bar.

Functionally modified phosphono groups that are to be converted into free phosphono in accordance with process variant a) are, for example, in the form of an ester, especially in the form of a diester of formula (lIe) wherein OR is ptherified hydroxy, for example lower alkoxy, lower alkapoyloxy-lower alloxy, such as C 2

-G

7 alkanoyloxy-CI-C4- Ai 4 d alkoxy, for example acetoxymethox~y or pivaloyloxymethoxy, or is a 0, 0 phenoxy, ca-phenyl-lower alkoxy or silyloxy group each unstuhstituted or substituted by lower alkyl, 2.ower aJlkoxy, halogen,, trifluornnethy. and/or by hydtroxyl such as tri-lower alkylsilyloxy.

The Conversion of functionally modified phosphono groups into fre phosphonQ grou~p5 s efetdi utmr anner, such as by hydrolysis, 0 4 for example I- ;he Presence of a mineral acid, such as hydrochloric or 0 0 sufurc ~tfro aproxmately $0'Q to approximately 1OQ'C,fo example at boiling temprature, or bv rtaotion with a tni-lower alkyl- 1# halos.Llane, for oxaiple trimethyJlchlorosilane or, especially, trimethyl- 0 4 0 iodosilane or tnimethyl1brol' oslano, preferably in metbylene Chloride, in a tomperoture range of from, approximately 0' to approximately 40'C, and 401. by subsequent treatment with water. cU-Phonyl-lower allyl esters can furthermore be Converted into compounds of formula I by hydrogonolysis, for example reaqtion with hydrogen in the presence of a hydrogenation catalyst, such as a nickel or noble metal Catalyst, for example palladium-on-carbon, preferably in a lower alkanol under normal pressure and temperature Conditions.

The starting materials of formula XX can be prepared, for example, by reacting a compound of formula R-L-alk coo" t~) or preferably the anhydride or acid chloridet 0, ;eof, with a corresponding phosphorous acid triester of formula P(OR) 3 (lIc), for example at from 000 to approximately 60*C, to give a compound of formula R- alk OR (lId), and further reacting the latter with a phosphorous acid diester of formula H-P(=O)(OR)2 (Ie) or P(OH)(OR)z (Ihf) in the presence of a dilower alkylamine, for excample diethylamine, or in the presence of an alk ili metal lower alkanolate, for example sodium methanolate, to give 4 I the corresponding compound of formula Ri -O (hg).

Ro R Starting materials of formula Ib can, if they are not known, be prepared* for example, by reacting a correspondi~ng compound of formula 4 ia R-X(Ro)-H (IIh), wt opudo Y alk COOR (Iii), _i Wherein Y is halogen, such as bromine, or, for the preparation of comnpounds Ilb wherein alk is 1,2-lower alky],ene, for example ethylene, with a compound of formula Alko -COOR (i) wherein alko is lower alk-l-enyl, hydrolysing the ester obtained in each case to the acid and onhydridising or cohloriodting the latter, for~ eXample using PhO$PhOtus pentathioride, and, if desired, removing the aimo-protecting group if present.

i ormula I wherein K 1 is nono-spustituted oy pneny X2 is nyarogen o, i

R

1 contai-,s 2 or 3 carbon atoms In the aliphatic moiety, is a lower alkyl or lower alkenyl radical containing at most 3 carbon atoms, and their salts.

/2 12 Reactive esters (III) and (IV) that are to be used in accordance with process variant b) contain as the reactive esterified hydroxy group, for example, a halogen atom, such as a chlorine, bromine or iodine atom, or a sulfonyloxy group, such as an alkanesulfonyloxy group or an unsubstituted or substituted benzeneulfonyloxy group, for example methanesulfonyloxy or p-toluenesulfony oxy.

The reaction with the reactive esters mentioned is effected, for example, in the presence of a base, such as an alkali metal hydroxide or an 4 t, alkaline earth metal hydroxide, for example sodium hydroxide, or a quaternary ammonium hydroxide, for example tetrabutylammonium hydroxide, advantageously in the presence of a solvent or diluent, for exomple a lower alkanol, a di-lower alkyl ketone or a cycloaliphatic ether, for example isopropanol, methyl ethyl ketone, dioxane or tetTahydrofuran.

i 4 The starting materials of formula IV can be prepared, for example, by reacting a compound of formula 'Y2 alk COOH (Iva) tn customary manner, for example in chloribenzene, with phosphorous acid 4 and phosphorus trichloride or with phosphoric acid and an excess of phosphorus tribromide, and subsequently working up by hydrolysi,.

The reaction of compounds of formula V with phosphorous acid and phosphorus trichloride in accordance with process v riant e) is effected in customary manner, the phosphorous aciL nent preferably being formed in situ by reaction of exce s phosphorus trichloride with watercontaining phosphoric acid, for example with commercially customary approximately 75 to approximately 95 preferably approximately 85 phosphoric acid. The reaction is advantageously carried out while heating, for example at from approximately 700 to approximately 120C, in i I -13a suitable solvent, such as tetrachloroethane, trichloroethane, chlorobenzene, chlorotoluene or paraffin oil, and with working up being effected by hydrolysis.

The treatment of intermdcciates of formula VI with nitrous acid is effected in customary manner with the latter being freed in aqueous solution from one of its salts, for example sodium nitrite, by acid treatment, for example by the action of hydrochloric acid, during which a corresponding, unstable diazonium salt, for example diazonium chloride, is formed as intermediate, which diazonium salt, with the introduction of the ?-hydroxy group, splits off nitrogen.

S The starting materials of formula V can, if they are not known, be prepared, for example, by reacting a corresponding compound of formula RI-N(Ro)-H (IIh), wherein Ro is a group R2 or an amino-protecting group, with a compound of formula Y alk COOR (Iii), wherein Y is halogen, such as bromine, or, for the preparation of compounds of formula V wherein alk is 1,2-lower alkylene, for example e thylene, with a compound of formula alko X3 J wherein alko is a lower alk-l-en 1 radical, and in each case removing the amino-protecting group if present and, if desired, in each case hydrolysing the resulting primary product to the acid, Compounds of formula I obtained by the process of the invention or by another method that is known per se can be converted it ao other compounds of formula I in a manner known per se.

The following statement is a full description of this invention, including the best method of performing it known to uS 14 n4 by reaction with a lower alkanal under reducing conditions, for example with formaldehyde and formic acid, or, secondly, with a reactive ester of a lower alkanol or lower alkenol in customary manner, preferably in the presence of a basic condensing agent, such as an alkali metal lower alkanolate, hydrogen can be replaced by a lower alkyl or lower alkenyl radical Rz, respectively.

Furthermore, non-aromatic double bonds present in Ri and/or R2 can be I reduced to single bonds in customary manner by hydrogenolysis, for o ot S example reaction with hydrogen in the presence of a hydrogenation catalyst, such as a nickel or noble metal catalyst, for example a tt palladium-on-carbon, preferably in a lower alkanol under normal pressure and temperature conditions.

q ea 4 0 The aromatic substituent(s) of Ri can also be substituted, For example, o, 0 halogen can be introduced by reaction with a customary nuclear 0 04 halogenating agent, for example with chlorine or bromine in the presence Q 04 es 0 of a Lewis acid, such as iron(III) chloride.

Depending on the starting materials and procedures chosen, the novel 0ses compounds may be obtained in the form of one of the possible isomers or S as a mixture thereof, for example depending on the number of asymmetric carbon atoms, they may be obtained in the form of pure optical isomers, such as antipodes, or in the form of isomeric mixtures, such as racemates, diastereoisomeric mixtures or mixtures of tacemates.

Resulting diastereoisomeric mixtures and mixtures of racemates can be separated on the basis of the physico-chfinical differences between the components into the pure isomers, diastereoisomers or racemates in known manner, for example by chromatography and/or fractional crystallisation.

C o u-dcIIum or 3-acom, I N-atom and 1 0-atom, or 1 N-atom and 1 S-atom, are, for example, pheryl or, secondly, naphthyl or pyrrolyl, thienyl, furyl, pyridyl, imidazolyl, pyrimidinyl or quinolinyl, especial- 15 Resulting racemates can furthermore be resolved into the optical antipodes by known methods, for example by recrystallisation fro an optically active solvent, vith the aid of microorganisms, or by reaction of an acid end product with an optically active base that forms salts with the racemic acid and by separation of the salts obtained in that manner, for example on the basis of their differing solubilities, into the diastereoisomers from which the antipodes can be freed by the action of suitable agents. Advantageously, the more active of the two antipodes is isolated.

Resulting free compounds of formula I, including their internal salts of formula I, can be converted into salts with bases by partial or complete i neutralisation with one of the bases mentioned at the beginning. Acid S addition salts also can be converted in an analogous manner into the corresponding free compounds or internal salts thereof.

4 Conversely, resulting free compounds of formula I can be converted into acid addition salts by treatment with a protonic acid.

Resulting salts can be converted in a manner known per se into other salts having a lower proportion of cations (partial salts) or into the free compounds, for example by treatment with an acid reagent, such as a S mineral acid. Resulting free compounds can bae conveted by treatment with a base, for example alkali hydroxide solution, into salts and/or resulting salts having a lower proportion of cations (partial salts) can be converted in the same manner into salts having a higher proportion of cations, for example complete salts.

The compounds, in luding their salts, may also be obtained in the form of their hydrates or may include the solvent used for crystallisation.

Owing to the close relationship between the novel compounds in free form and in the form of their salts, throughout this specification there is to be understood by thee compounds or their salts, where appopriate and expedient, also the corresponding salts or free compounds, respectively.

SResulting salts ca be converted in a manner known per se into other

I

16 The invention relates also to those embodiments of the process in which a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining steps are carrifd out, or a starting material is used in the form of a salt and/or racemate or antipode or, especially, is formed under the reaction conditions.

The starting materials used in the present invention are preferably those which result in the compounds described at the beginning as being especially valuable. The invention relates also to novel star:ing materials S and to processes for the preparation thereof.

The pharmaceutical preparations according to the invention, which contain compounds of formula I or pharmaceutically acceptable salts thereof, are for enteral, such as oral or rectal, and parenteral administration and S contain the pharmacologically active ingredient on its own or together with a pharmaceutically acceptable carrier.

The novel pharmaceutical preparations contain, for exanple, from approximately 10 to approximately 80 preferably from approximately 20 to approximately 60 active ingredient. Pharmaceutical preparations according to the invention for enteral and parenteral administration are, for example, those in dosage unit form, such as drag6es, tablets, capsules or suppositories, and also ampoules. Those are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes. For example, pharmaceutical preparations for oral administration can be obtained by ccmbnining the active ingredient with solid carriers, if desired granulating a resulting mixture and processing the mixture or granulate, if desired or necessary after the addition of suitable adjuncts, into tablets or drag6e cores.

Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, and cellulose preparations, and also binders, such as starch pastes using, for example, corn, wheat, formula I.

17 17 rice or potato starch, gelatine, tragacanth, methylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the abovementioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Adjuncts are especially flow-regulating and lubricating agents, foT example silica, talc, stearic acid andPor polyethylene glycol. Drag6e cores are provided with suitable coatings which may be resistant to gastric juices, there being used, inter alia, concentrated sugar solutions which may contain gum arabi-, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or lacquer solutions in suitable organic solvents or solvent mixtures, or, for the preparation of coatings I f that are resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Colourings or pigments may be added to the tablets or drag6e coatings, for example for identification purposes or to 4 4 0 indicate different doses of active ingredient.

Other orally administrable pharmaceutical preparations are dry-filled 0 0 capsules consisting of gelatine, and also soft sealed capsules consisting of gelatine and a plasticiser, such as glycerol or sorbitol. The dryfilled capsules may contain the active ingredient in the form of a granulate, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc, and, if desired, stabilisers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liq'uid polyethylene glycols, to which stabilisers 1iay also be added.

Suitable rectally administrable pharmaceutical preparations are, for -example, suppositories that consist of a combination of the active ingredient with a suppository base material. Suitable suppository base materials are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. It is also possible to use gelatine rectal capsules that contain a combination of 18 the active ingredient with a base material; suitable base materials are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

For parenteral administration there are suitable, especially, aqueous solutions of an active ingredient in water-soluble form, for exomple in the form of a water-soluble salt, or suspensions of the active ingredient, such as correponding oily injection suspensions, in which suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, are used, or aqueous injection suspensions that contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran and, if desired, also stabilisers.

The present invention relates also to the use of compounds of formula I S and their salts, preferably for the treatment of diseases that are attributable to calcium metabolism disorders, for example of the rheumatic type, and especially of osteoporoses.

9a 9 Dosages under 0.01 mg/kg body weight have only a negligible effect on pithologica' calcification or the degeneration of hard tissue. At dosages S *;above 100 mg/kg body weight, toxic side-effects may occur in long-term use. The compounds of formula I and their salts can be administered both orally and, in the form of a hypertonic solution, subcutaneously, intramuscularly or intravenously. The preferred daily doses are in the range of approximately from 0.1 to 5 mg/kg in the case of oral administration, in the range of approximately from 0.1 to 1 mg/kg in the case of subcutaneous and intramuscuiar administration, and in the range of approximately from 0.01 to 2 mg/kg, for example approximately from 0.013 to S0.67 mg/kg, in the case of intravenous administration.

The dosage of the compounds used is, however, variable and depends on the particular conditions, such as the nature and severity of the disease, the duration of treatment and on the particular compound. Single doses contain, for example, from 0,01 to 10 mg, dosage unit forms for 19 parenteral, such as intravenous, administration contain, for example, from 3.01 to 0.1 mg, preferably from 0.02 to 0.08 mg, and oral dosage unit forms contain, for example, from 0.2 to 2.5 mg, preferably from 0.3 to 1.5 mg, per kg of body weight. The preferred single dosage for oral administration is from 10 to 100 mg and for intravenous administration from 0.5 to 5 mg, and can be administered up to 4 times per day. The higher dosages in the case of oral administration are necessary owing to the limited resorption. In the case of long-term treatments, the initially higher dosage can normally be changed to lower dosages while still maintaining the desired effect.

The following Examples illustrate the invention described above; they are not intended, however, to limit the scope thereof in any way. Temperatt tures are given in degrees Celsius.

Example 1: (0.1 mol) of 3-[N-(3-phenylpropyl)-N-methyl- aminol-propionic acid hydrochloride is heated at 1,00 under reflux with 13.4 ml of 85 phosphoric acid and 50 ml of chlorobenzene while stirring. The,i, at 100°, 27 ml of phosphorus trichloride are added dropwise, gas evolution taking 4 place. A thick mass separates from the reaction mixture over the course of 30 minutes. The mixture is heated at 1000 for a further 3 hours and the supernatant chlorobenzene is then removed by decanting. The viscous *,det' mass which remains is refluxed with 100 ml of 9N hydrochloric acid for 3 hours while stirring. The mixture is filtered while hot, wich the addition of carbon, and the filtrate is diluted with acetone, whereupon 3-[N-(3-phenylpropyl)-N-methyl-amino]-l-hydroxy-propane-l,1-diphosphonic acid separates out in crystalline form; m.p. 2190 (decomposition).

The 3-[N-(3-phenylpropyl)-N-methyl-amino]-propionic acid hydrochloride used as starting material can be prepared as follows: (0.15 mol) of N-(3-phenylpropyl)-N-methyl-amine are introduced into 50 ml of diethyl ether, and 15.1 g of ethyl acrylate are gradually added thereto while stirring. With a slight increase in temperature, a clear naphthyl, thienyl, pyridyl or ixnidazolyl radical that is unsubstituted or mono- or di-substituted by Cl-CL~alkyl, 'such as,!methyl, Cl-C~alkoxy, such solution forms. After sta~nding overnight at room temperature, the ether is removed by distillation. The oil which remains is crude 3-[N--(3-phenj ylpropyl)-N-methyl-amino]-propionic acid ethyl ester.

The resulting ester is refluxed with 600 ml of 4N hydrochloric acid for 24 hours. The mixture is then completely concentrated by evaporation under reduced pressure and the crystalline residue is triturated with acetone. After the crystals have been filtered with suction, washed and dried, 3-[N-(3-phenylpropyl)-N-methyl-amino]-propionic acid hydrochloride is obtained.

Example 2: In a manner analogous to that described in Example 1, 3-(3-phenylpropylamino)-l-hydroxy-propane.K ,1-diphosphonic acid, M.P. 2190 (decomp.), 3 -(3-phenylprop-2-ylamino)-l-hydroxy-propane-1 ,1-diphosphonic acid, M.P. 208-210' (decomp.), 3-IN-(3-phenylpropyl)-N-ethyl-aniino]-1-hydroxy-propafle-l ,1-diphosphonic acid, M.P. 195-197' (decomp.), 3-(4-phenylbutylamino)-l-hydroxy-propane-1l,1-diphosphonic acid, 191-193' (decomp.) and 3-[l3-(pyrid-3-yl)propylamino]-1-hydroxy-propane-1 ,1-diphosphonic acid can be obtained starting from or via 3-(3-phenylpropylamino)-propionic acid hydrochloride 2190, decomp.), 3-(3-phenylprop-2--ylamino)-propionic acid hydrochloride 126-127')t 3-[N-(3-phenylpropyl)-N.-ethyl-amino]-propionic acid hydrochloride, oil, 3-(4-phenylbutylanino)-.propionic acid hydrochloride, M.P. 135-1370 and 3-[3-(pyrid-3-yl)propylamino]-propionic acid hydrochloride, respectively.

Example 3: 9.3 g (26.3 mmol) of 3-(3-phenylpropylamino)-lhydroxypropane-1,1-diphosphonic acid are refluxed for 36 hours with 6.1 ml of formic acid and 4.2 Ml. of a 38 formaldehyde solution in water. The, reaction solution is concentrated by evaporation under reduced pressure -21and the residue is diluted with acetrnne, yielding 3-[N-(3-phenylpropyl)- N-me thyl-amino-1 -hydroxy-propane- 1 ,1-dipho sphonic acid in the form of colourless crystals of m.p. 2190 (decomp.).

Example 4: In a manner analogous to that described in Example 1, 3-[4,4di(p-fluorophenyl)butylamino ]-l-hydroxy-propane-1 ,1 -dipho ,phonic acid, m.p. 220-222' (decomp.) is obtained starting from 3-14,4-di(p-fluorophenl)butylamino]-propionic acid ethyl ester via 3-14,4-di(p-fluorophenyl)butylaminol-propionic acid hydrochloride, m.p. 165-166'.

S The starting material can be prepared, for example, in the following manger: 26.1 g (0.1 mol) of 4,4-di(p-fluorophenyl)butylamine and 18.1 g of 3-broropropionic acid ethyl ester are refluxed with 21.0 g of potassium 4 carbonate in 200 ml of 2-butanone for 24 hours while stirring. The reaction mixture, is filtered and the filtrate is concentrated by evaporation under reduced pressure, yielding crude 3-[4,4-di(p_-fluorophenyl)butylamino]-propionic acid ethyl1 ester in the form of an oil.

In an analogous manner, 4 -[N-(2-phenethyl)-N-methyl-amino]-l-hydroxybutane-1,1-diphosphonic acid is obtained starting from N-(2-phenethyl)-Nmethyl-amine and 4-bromobutyric acid ethyl ester via 4-[N-(2-phenethyl)- N-methyl-amino]-butyric acid ethyl ester and 4-[N-(2-phenethyl)-N-methylaminolbutyric acid hydrochloride.

Example 5: in a manner analogous to that described in Example 1, 3-IN-[3imida o -4-yl) propyl I-N-me thyl -amino ~I -1-hydroxy-pro pane- 1 1-dipho sphoni c acid is obtained starting from N- imidazol-4-yl)propyl] -N-methyl-amine via 3-JN-[3-(imidazol-4-yl)propyl-N-methyl-amino)--propionic acid ethyl ester and 3-JN-[ 3 -(i'midazol- 4 -yl)propyl-N-methyl-aminol-propionic acid hydrochloride.

The starting material can be prepared, for example, in the following manner: -22- 16.8 g (0.12 mol) of 3-Ijimidazol-4(5)-yllpropionic acid are refluxed with 13.1 ml of thionyl chloride ,,or 2 hours. After removing excess thionyl chloride by distillation, 3-Iimidazol-4(5)-yllpropionic acid chloride hydrochloride remains as a semi-solid mass (yield 100%) 23.4 g (0.12 mol) of 3-Iimidazol-4(5)-yllpropionic acid chloride hydrochloride are dissolved in 80 ml of dime thylf ormamide an6 the solution is cooled to Methylamine gas is passed into the solution for 2 hours until there has been a weight increase of 15 g. After standing overnight at room temperature, the reaction mixture is concentrated to dryness by 4, evaporation under reduced pressure. The residue is chromatographed on 220 g of silica gel with the eluant chlorof orm/methanol/conc. ammonia q, (80:20:1). The fractions containing the product yield, from tetrahydrfuran, colourless crystals of 3-Iimidazol-4(5)-yl]propionic acid (N-methyl)amide, m.p. 168-170'. 10.9 g (0.0718 mol) of 3-[imidazol-4(5)yllpropionic acid (N-methyl)amide are added in portions, while stirring, to a suspension of 2. 8 g of lithium aluminium hydride in 200 ml of tetra- Shydrofuran and the reaction mixture is then refluxced for 30 hours. The 4V 0 reaction mixture is then cooled to and 3 ml of wqter, 2.2 ml of 1ON sodium hydroxide solution and 8.2 ml of water are add ed dropwise in 6 A succession, The inorganic precipitate Is filtered off at-. the filtrate is *444 concentrated by evaporation in vacue. The oil which rema~ins is crude N- [imidazol-4( 5)-yl-propyl )-N-methylamine.

Example 6: In a manner analogous to that described in Ex~ample 1, 3-[ 4 -(4-methoxyphenyl)butylamino-1-hydroxy-propane-1 ,1-dipholsphonic acid, m.p. 160-164* (decomp.); 4 -methoxyphenyl)propyl-N--methyl-amino )-1-hydroxy-propane-1 ,1-diphosphoniit acid, m.p. 154-1,~56' (decomp.); 3-1 3-( 4 -chloropheriyl)propyl-N-methyl-amino )-1-hydroxy-propane-1 ,1-diphosphonic acid, m.p. 162"166* (decomp.); 3-C 3-methytlphenyl)propyl-1N-methyl-amino]-1-Ydoy-Propane-l f -1 phosphonic acid, m.p. 193-195* (clecomp.); 4 removed by hydrolysis. The removal of ca-aryl- and ax, a,c-t ricosyl- lower L alkyl Ra using hydrogenolysis is effected especially by reaction with hydrogen in the presence of a hydrogenation catalyst, ,such as a nickel or -23- 3-f 3-(imidazol- 4 (5)-yl)propyl-N-methyl-amino]--hydroxy-propane-1 ,1-diphosphonic acid, m.p. 130-136' (decomp.); 3- 3- (pyrid-2 -yl) propyl-N-me thyl-amino-1 -hydroxy-pro pane- 1 ,1-diphosphonic acid, m.p. 142-147' (decoinp.); 3-[N-(2-phenethyl)-N-methyl-amino]-l-hydroxy.propane-1 ,1-diphosphonic acid, n.p. 187-183 (dacomp.); and 3-fN-(2-phenethyl)amino)Ihydroxy-propane-1 ,1-diphosphonic acid, m.p. 205-2O6* (deconip.) can be prepared starting from or via 3-E4-( 4 -methoxyphenyl)butylaminolpropionic acid hydrochloride, m.p. 150-1529; 3-f 3-( 4 -methoxyphenyl)prppyl-N-methyl-aminollpropionic acid hydrochloride, 3-f 3-(4-chlorophenyl)propyl-N-methyl-aminolpropionic acid hydrochloride, m~.128-130'; 3-f 3-(3-methytphwnyl)propyl-N-methyl-aminollpropionic acid hydrochloride, in~po 97-98'; 3-4 3-(imidazol-4(5)-yl)propyl-N-nethiyl-aminojpropionic acid aihydro- Schloride; 3-li3-(pyrid-2-y2,)proPyl-N-methyJ-amipolpropionic acid dihydrochloride, m.p. 157-160 (decomp.); S 3-f N-(2-phenethyl)-N-rnethyl--aminolpropionic acid hydrochloride, m. p. 144-1450 (decomp.);, and 3- (2 -phoeothyl) amino) propionic acid hydrochloride, m.p. 150-1520 (decomp.) respectively.

Example 7: Tablets, each containing 75 mig of active ingredient, for example 3-[N-(3-phenylpropyl.)-N-methyl-aninoI-1-hydroxy-propane- ,1diphosphonic acid or a salt thereof, for ex~ample the disodium salt, can be prepared in the following mannor: 24 Constituents (for 1000 tablets) active ingredient 75.0 g lactose 268.5 g corn starch 22,5 g polyethylene glycol 6000 5.0 g talcum 15.0 g magnesium stearate 4.0 g demineralised water q.s.

Preparation: The solid ingredients are first forced through a sieve of 0.6 mm mesh width. Then, the active ingredient, lactose, talcum, magnesium stearate and half of the starch are homogeneously mixed. The other half of the starch is suspended in 65 ml of water and this 4 t1 suspension is added to a boiling solution of the polyethylene glycol in 0 o 260 ml of water, The resulting paste is added to the pulverulent substances, and the whole is mixed and granulated, if necessary with the addition of water, The granulate is dried overnight at 35', forced through a sieve of 1.2 mm mesh width and compressed into tablets of S approximately 10 mm diameter which are concave on both sides and have a breaking notch on the upper side.

t Example 8: Tablets, each containing 10 mg of active ingredient, for example 3-[N-(3-phenylpropyl)-N-methyl-aminol-1 hydroxy-propane-1,i- S diphosphonic acid or a salt thereof, for example the disodium salt, can be prepated in the following manner: Constituents (for 1000 tablets) active ingredient 10.0 g lactose 328.5 g corn starch 17.5 g polvethylene glycol 6000 g talcum 25,0 g magnesium stearate 4.0 g demineralised water q.s.

example using phosphorus pentachloride, and, if desired, removing the amino-protecting group if present.

25 Preparation: The solid ingredients are first forced through a sieve of 0,6 mm mesh width. Then, the active ingredient, lactose, talcum, magnesium stearate and half of the starch are homogeneously mixed. The other half of the starch is suspended in 65 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 260 ml of water. The resulting paste is added to the pulverulent substances, and the whole is mixed and granulated, if necessary with the addition of water. The granulate is dried overnight at 35°, forced through a sieve of 1.2 mm mesh width and compressed into tablets of approximately 10 mm diameter which are concave on both sides and have a breaking notch on the upper side.

Example 9: Gelatine dry-filled capsules, each containing 100 mg of active ingredient, for example 3-[N-(3-phenylpropyl)-N-methyl-aminol-l-hydroxy- 1j propane-1,1-diphosphonic acid or a salt thereof, for example the disodium salt, can be prepared in the following manner: Constituents (for 1000 capsules) active ingredient 350.0 g microcrystalline cellulose 30.0 g sodium lauryl sulfate 2.0 g magnesium stearate 8,0 g The sodium lauryl sulfate is added to the active ingredient (lygphilised) through a sieve of mesh width 0.2 mm and the two components are intimatoly mixed for 10 minutes. The microcrystalline cellulose is then added through a sieve of mesh width 0.9 mm and the mixture is again intimately mixed for 10 minutes, Finally, the magnesium stearate is added through a sieve of mesh width 0.8 mm and, after mixing for a further 3 minute., the mixture is introduced into size 0 (elongated) gelatine dry-filled oapsules in portions of 390 mg.

1/ -7 t 1 i ill 26 Example 10: A 0.2 injection or infusion Qolution can be prepared, for example, in the following manner: active ingredient, f*r example 3-lN-(3-phenylpropyl)-N-methyl-amino]-1hydroxy-propane-1,1-diphosphonic acid or a salt thereof, for example the disodium salt 5.0 g sodium chloride 22.5 g phosphate buffer pH 7.4 30 0 g demineralised water ad 2500.0 ml The active ingredient is dissolved in 1000 ml of water and filtered through a mi:rofilter. The buffer solution is added and then water is added to give a volume of 2500 ml. For the preparation of dosage unit forms, portions of 1.0 or 2.5 al are introduced into glass ampoules (containing 2.0 or 5.0 mg of active ingredient, respectively).

r It st E II (C )f tr f

Y

6 i

E

r: L CU Example 11: 1,83 g of 3-( 4 -phenylbutylamino)-1-hydroxy-propae-1,1diphosphonic acid are dissolved in 10 ml of 1N sodium hydroxide solution.

The resulting solution is concentrated by evaporation tuiid' reduced S preassure. The product is precipitated by addition of methanol allowed to crystaliised and isolated by sU'ttion-filtration. Disodium-3-(4-penylbutylamino)-1-hydroxy-propare 1-diphosphonate of m.p, 313-316' (decomp.) is thus obtained.

In an analogous manner, disodium-3-[N-(3-phenylpropyl)-N-ethyl-amino 1-hydroxy-propane- 1,l-diphosphonate of mp. 321-25' is obtained.

i

Claims

1. Aromatically' substituted alkylaminoallanediphosphonic acids of formula 0 3 H2 R -alk- H0 12 0 3 i 2 wherein R 1 is a lower alkyl or lower alkenyl radical that is mono- or di-substituted by a 6-membered monocyclic 4ryl radical or by a bicylc aryl radical composed of 5- or 6-membered rings or by a 5- or 6-membered S monocyclic heteroaryl radical or by a bicyclic heteroaryl radical com- posed of 5- or 6-membered rings, which heteroaryl radicals contain as hetero atom(s) 1 or 2 N-atom(s), 1 0-atom or 1 S-atom, 1 N-atom and 4 9 1 0-atom, or 1 N-atom and 1 S-atom, amd which aryl and heteroaryl radi- cals are unsubstituted or subs' "ituted by lower alkyl, lower alkoxy, lower S alkylthio and/or by halogen, R2 is hydrogen, lower alkyl or lower alken- 0 yl, and alk is lower alkylene, with the proviso that in compounds Pf 0 0 4 formula I wherein Ri is mono-substituted by phenyl, R2 is hydrogew or, if Ri contains 2 or 3 carbon atoms in the aliphatic moiety, is a lower alkyl or lower alkenyl radical containing at most 3 carbon atoms, and their 4 4 44l4

2. Compounds act;nrding to claim 1 of formula I wherein R 1 is a lower 0' alkyl radical that is mono- or di-substituted by a 6-membered monocyclic aryl radical o- by a bicyclic aryl radical composed of 5- and/or S 6-membered rings, which aryl radicals are unsubstituted or substituted by SP lower alk3-yl, lo .er alktxy, lower alkylthio and/or by halogen, or is a a.0 lower alJkyl radical that is mono-substituted by a 5- or 6-membered monocyclic heteroaryl radical that contains as hetero atom(s) 1 0-atom or S-atom or 1I or 2 N-atoms, R2 is hydrogen or a lower alkyl radical and alk is lower alkylene, with the proviso that R2 is hydrogen if Ri is an unsubstituted benzyl- or phenyl-C 3 -Cialkyl radical, or that RZ is hydrogen or lower alkyl containing 1 or 2 carbon atoms if R 1 is a phenethyl radical, and their salts. L xpnleau, a±so une corresponding salts or free compounds, respectively. 28

3. Compounds according to claim I or 2 of formula I wherein R1 is a sidical of formula (Ia) RCH-alk'- (la), R. wherein R3 is an aromatic radjical R A' R4 is hydrogen or an aromatic radical RB and alk' is lower alkylene, R A and R B each being a 5- or

6-membered monocyclic aryl radical or a bicyclic aryl radical composed of or 6-membered rings radical or a bicyclic heteroaryl radical composed of 5- or 6-membered rings, which heteroaryl radicals contain as hetero atom(s) 1 or 2 N-atom(s), I O-atom or S-atom, 1 N-atom and 1 O-atom or 1 N-atom and which aryl radicals are unsubstituted or substituted by lower alkyl, lower alkoxy, lower alkylthio and/or by haloge, R2 is hydrogen, lower alkyl or lower alkenyl, and alk is lower alkylene, and their salts. 4. Compounds according to claim 1 or 2 of formula I wherein RI is a radical of formula (Ia) RCH-alk'- wherein R 3 is an aromatic radical R A R4 is hydrogen or an aromatic radical R and alk' is lower alkylene, RA and RB each being or a 5- or 6-membered monocyclic heteroaryl radical or a bicyclic heteroaryl radical composed of 5- or 6-membered rings, which heteroaryl radicals contain as hetero atom(s) I or 2 N-atom(s), 1 O-atom or S-atom, 1 N-atom and 1 0-atom or 1 N-atom and I S-atom, and which heueroaryl radicals are unsubstituted or substituted by lower alkyl, lower alkoxy, lower alkyl- thio andlor by halogen, R2 is hydrogen, lower alkyl or lower alkenyl, and alk is lower alkylene, and their salts. Compounds according to claim 1 of formula I wherein R is a radical of formulae CH-alk'- (Ia) -29 wherein R 3 is a phenyl, thienyl, pyridyl, imidazolyl or naphthyl radical that is unsubstituted or mono- or di-substituted by Ci-Calkyl, C1-C4- alkoxy, Cl-Cialkylthio and/or by halogen having an atomic number of up to and including 35, R 4 is hydrogen or, if R 3 is a phenyl radical that is unsubstituted or mono- or di-substituted by C1-Cialkyl, Ca-Cqalkoxy, C 1 -C4alkylthio and/or by halogen having an atomic number of up to and including 35, RA is likewise a phenyl radical that is unsubstituted or mono- or di-substituted by Cj-Cialkyl, C 1 -Cialkoxy, Cl-Calkylthio and/or by halogen having an atomic number of up to and including 35, alk' is Cl-Csalkylene, R 2 is hydrogen, and alk is straight-chained C:-C4alkylene, and their salts. 6. Compounds according to claim 1 of formula I wherein R 1 is a radical of formula 1R6 r rRCH-alk'- (la) 19* ,9 i wherein R 3 is a phenyl radical that is unsubstituted or mono- or di-sub- S stituted by Ci-C 4 alkyl, Ci-Ctalkoxy, Cl-C 4 alkylth1 and/or by halogen having an atomic number of up to and including 35, R4 is hydrogen or is likewise a phenyl radical that is unsubstituted or mono- or di-substitu- ted by Cl-C4alkyl, C-Cialkoxy, dCi-Calkylthio and/or by halogen having an atomic number of up to and including 35, alk' is straight-chained Ci-Csalkylene, R 2 is Ci-Cialkyl or C2-Cealkenyl, and alk is straight- chained Cz-C4al]ylene, with the proviso that alk' is methylene and R 2 is Cj-C 2 alky if R 3 is unsubstituted phenyl and R4 is hydrogen, and their salts.

7. Compounds according to claim 1 of formula I wherein R 1 is a radical of formula CH-alk'- (Ia) R4 wherein R 3 is a thienyl, pyridyl or imidazolyl radical that is unsubsti- tuted or mono- or di-substituted by C 1 -Cialkyl, Ci-C4alkoxy, C1-Calkyl- thio and/or by halogen having an atomic number of up to and including .t If R4 is hydrogen, R 2 is (Ca-Ci 4 alkyl Or CZ-Ci~alkenyl, and alk is straight- chained C 2 -Ct~alkylene, with the proviso that alk' is methylene and R 2 is CI-C 2 alkyl if R 3 is unsubstituted phenyl and R 4 is hydrogen, and their salts.

8. Compounds according to claim 1 or 2 of formula I wherein R, is a radical of formula C-l' (Ia) wherein R 3 is phenyl that is unsubstituted or mono- or di-substituted by C 1 -C~alkyl Ca-C4alkoxy and/or halogen having an atomic number of up to and including 35, Ri 4 is hydrogen, alk' is strzaight-chained', terminally bonded C 2 -Ci~alkylene, R2 is hydrogen or C2i-Ci~alkyl, and alk is C 2 -C 3 alk- ylene, and their salts.

9. Compounds according to claim 1 of formula I wherein Rj is mono- or ,tit di-phenyl-C 2 -Csalkyl that is unsubstituted or mono- or di-substituted in the phenyl moiety by Cl-C4alkyl, Ci-C4alkoxy and/or by halogen having an atomic number of up to and including 35, or is imidazolyl-, thiemyl- or pyridyl-CZ-Gsalkyl, R2 is hydrogen Or~ Ci.-C4alkyl, and alk is C 2 -C 3 alk- ylene, with the proviso that R 2 is hydrogen if RI is unsubstituted phenyl-C 3 -Csalkyl, or R 2 is hydrogen or Ca-Caalkyl if R1 is an unsub- stituted phenethyl radical,, and their salts. Compounds according to claim 1 of formula I wherein R, is a radical of formula /CH-alk' (Ia) wherein R3 is phenyl that is unsubstituted or mono- or di.- substituted by Cl-Ci~alkyl, Cl-Ci~alkoxy and/or by halogen having an atomic number of up to and including 35, R4. is hydvogen, alk' is straighti-chaimed, terminally bonded CkR-Cialkylene, R2 is hydrogen and alk is C2-C 3 alkylene, and their salts. 0 i contain, for example, from 0.01 to 10 mg, dosage unit forms for 31

11. 31 3-phenylpropyl) -N-methyl-amino] -1-hydroxy-propane-1 ,1-di- phosphonic acid or a salt thereof.

12. 3-(3-(Phenylpropylamino)-1-hydroxy-propane-1 ,l-diphosphonic acid or a salt thereof.

13. 3-IIN-( 3-phenyipropyl) -N-e 'iyl-amino I-1-hydroxy-propane-1 ,1-di- phosphonic acid or a salt thereof. 14, 3-(Pyrid-3-yl)-propylamino]-1-hydroxy-propane-1 ,1-diphosphonic acid or a salt thereof. 3-[4,4-di-T(p-fluorophenyl)butylamino]1lhydrixy-propale-1 ,1-di- phosphonic acid or a salt thereof.

16. 3-4N-[ 3-imidazol-4-yl)propyl]-N-methyl-amino )-l-hydroxy-propane-1 ,1- diphosphonic aci~d or a salt thereof.

17. 3-(4-PhenylbutylamiLno)-1-hydroxy-propane-1,1-diphosphonic acid or a salt thereof.

18. 31 4-Methoxyphenyl)butylamino]-1-hydroxy-propane-1 -diphosphonic acid or a salt thereof.

19. 31 4-Methoxyphenyl)propyl-{-methyl-amino I-1-hydroxy-propane-1 ,1 diphosphonic acid or a salt thereof. 3-1 4 -Chlorophenyl)propyl-N-methyl-amino I-1-hydroxy-propane-1 ,1- diphosphonic acid or a salt thereof.

21. 3 -Methylphenyl)propyl-N-methyl-amino ]-l-hydroxy-propane-1 diphosphonic acid or a salt thereof.

22. 3-13-(Imidazol-4(5)-yl)propyl-N-methyl-aminol-I-hydroxy-propane-l1,- 1-diphosphonic acid or a salt thereof. P 32

23. 3-[3-(Pyrid-2-yl)propyl-N-methyl-amino[-l-hydroxy-propane- 1,1-di-phosphonic acid or a salt thereof.

24. 3-[N-(2-phenethyl)amino]-l-hydroxy-propane-1,1-diphosphoni c acid or a salt thereof. 4-[N-(2-phenethyl)amino]-1-hydroxy-butane-1,1-diphosphonic acid or a salt thereof.

26. Pharmaceutical preparations containing a compound according to any one of claims 1, 3, 4, 8 and 10 to together with customary pharmaceutical carriers.

27. Pharmaceutical preparations containing a compound according to any one of claims 2, 5 to 7, 9 and 16 to together with customary pharmaceutical carriers.

28. A method of treating diseases that are associated with calcium metabolism disorders in a subject, which comprises administering to said subject an effective amount of a compound according to any one o- claims 1 to

29. A method according to claim 28 wherein said diseases are any one of osteoporeoses, Paget's disease, osteodystrophia, fibrosa, and tumour-induced osteolysis. A process for the preparation of aromatically substituted alkylaminoalkanediphosphonicacids according to claim 1 of formula I and of their salts, which comprises i 33 a) in a compound of formula R- alk OH (II), wherein Ro is a radical R2 or an amino-protecting group and Xi is a functionally modified phosphono group and X 2 is a free or functionally modified phosphono group, converting functionally modified phosphono Xi and, where appropriate, Xz into a free phosphono group, or b) reacting compounds of formulae 03H2 Ri Yi (1ii) und Y2 alk OH (IV), 03H2 wherein one of the radicals Ya and Y 2 is a reactive esterified hydroxy 400 group and the other is a group of formula -N(Ro)-H wherein Ro is a f, radical Rz or an amino-protecting group, or salts thereof, with each 9, other, or c) reacting a compound of formula Ri alk Xi 1 wherein Ro is a radical R2 or an amino-protecting group and X3 is carboxy, carbamoyl or cyano, especially carboxy or cyano, with phos- phorous acid or phosphorus trichloride, hydrolysing the primary product and, in an intermediate of formula Ri alk NH2I) H2 obtained starting from compounds of formula V wherein X3 is cyano or carbamoyl, or in a salt thereof, replacing the amino group by hydroxy by treatment with nitrous acid, and in each case removing the amino- protecting group if present and, if desired, converting a resulting compound into a different compound of formula I and/or converting a resulting free compound into a salt or a resulting salt into the free S, compound or into a different salt. manner: 34

31. Aromatically substituted alkylaminoalkanedyphosphonic acids substantially as herein described as the end-product with reference to any one of Examples 1 to 6 or 11.

32. A pharmaceutical preparation substantially as herein described with reference to any one of Examples 7 to DATED this 11th day of January, 1991. r Ir All pi I CIBA-GEIGY AG By Their Patent Attorneys ARTHUR S. CAVE CO.