CA2179203A1 - N,n'-bis(2-hydroxybenzyl)ethylenediamine-n,n'-diacetic acid derivatives as chelating agents - Google Patents
N,n'-bis(2-hydroxybenzyl)ethylenediamine-n,n'-diacetic acid derivatives as chelating agentsInfo
- Publication number
- CA2179203A1 CA2179203A1 CA002179203A CA2179203A CA2179203A1 CA 2179203 A1 CA2179203 A1 CA 2179203A1 CA 002179203 A CA002179203 A CA 002179203A CA 2179203 A CA2179203 A CA 2179203A CA 2179203 A1 CA2179203 A1 CA 2179203A1
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- bis
- formula
- hydroxybenzyl
- ethylenediamine
- diacetate
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- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
- C07C229/16—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D317/34—Oxygen atoms
- C07D317/40—Vinylene carbonate; Substituted vinylene carbonates
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Abstract
¢N,N'-bis(2-hydroxybenzyl)ethylenediamine N,N'-diacetic acid! derivatives of formula (I) in which R represents -(CO)-R1, -O-(CO)-R2, -O-(CO)-O-R3 or (a) wherein R1 is -NR4R5 or (III); whereby R4 and R5 are independent of each other C1-C3 alkyl or C3-C7 cycloalkyl or form together the group -(CH2)n-, n is an integer from 3 to 6; R2 is C1-C6 alkyl, unsubstituted phenyl or phenyl substituted by one to four substituents selected from the group consisting of halogen and hydroxy; R3 is C1-C6 alkyl or C3-C7 cycloalkyl; R4 is C1-C3 alkyl; and salts thereof form chelate-type metal complexes with trivalent metal ions, especially iron (III), and can be used, for example, for the treatment of pathological conditions in warm-blooded animals that are associated with an excess of trivalent metal ions in the body.
Description
-~ WO 95116663 2 1 7 '~ 2 0 3 r~ 1 l N,N'-BIS (2-HYDROXYBENZYL) ETHYLENEDIAMINE-N,N'-DIACETIC
ACID DERIVATIVES AS CHELATING AGENTS
Thc inventiOn rehtes to novd and ~ / effective chelaing agents embracing the derivatives of rN,N'-bis(2-~ ...~I)ethylene diamine N,N'-diaoeic acid] of the formula (I) as shown bdow, processes for their ' , I ~ -containing such I , ', and the use of these derivaives. 'rhe invenion is also directed to all~ali and alkaline earth metal salts of [N,N'-bis(2 ~L~,~J V~l~l)ethY1ene diamine N,N'-diaoetic acid] derivatives which represent valuable staning mate~ial and cxhibit valuable tl r '' ~ properties.
'rhe invenion rehtes especially to [N,N'-bis(2 hJ~ )etnylenG diamine N,N'-diaceic acid] derivatives of the formuh (I) HO
R-CH2-0-~CO) ~ N ~ N ~, (CO)-O-CH2-R
~J (I) OH
~ r in which R represents -(CO)-RI, -O-(CO)-R2, -O-(CO)-O-R3 or J~o~' wherein Rl is -NR4Rs or--N~JO whereby R4 and Rs are ' ' r ~ ' of each othcr Cl-C3 aLIcyl or C3-C7 cyc~oa~yl or form togetner the group -(CH2)n-, n is an imeger from 3 to 6;
R2 is CI-C6 alkyl, 1 ' ' ' phenyl or phenyl substitutGd by one to four selected from the group consisting of halogen and hydroxy;
R3 is Cl-C6 allcyl or C3-C7 cycloaDcyl;
R4 is Cl-C3 aLlcyl; and salts thereof, processes for the ' of these containing su~h ~ J~ and the use f these r-wogs/l6663 p_" 1.1
ACID DERIVATIVES AS CHELATING AGENTS
Thc inventiOn rehtes to novd and ~ / effective chelaing agents embracing the derivatives of rN,N'-bis(2-~ ...~I)ethylene diamine N,N'-diaoeic acid] of the formula (I) as shown bdow, processes for their ' , I ~ -containing such I , ', and the use of these derivaives. 'rhe invenion is also directed to all~ali and alkaline earth metal salts of [N,N'-bis(2 ~L~,~J V~l~l)ethY1ene diamine N,N'-diaoetic acid] derivatives which represent valuable staning mate~ial and cxhibit valuable tl r '' ~ properties.
'rhe invenion rehtes especially to [N,N'-bis(2 hJ~ )etnylenG diamine N,N'-diaceic acid] derivatives of the formuh (I) HO
R-CH2-0-~CO) ~ N ~ N ~, (CO)-O-CH2-R
~J (I) OH
~ r in which R represents -(CO)-RI, -O-(CO)-R2, -O-(CO)-O-R3 or J~o~' wherein Rl is -NR4Rs or--N~JO whereby R4 and Rs are ' ' r ~ ' of each othcr Cl-C3 aLIcyl or C3-C7 cyc~oa~yl or form togetner the group -(CH2)n-, n is an imeger from 3 to 6;
R2 is CI-C6 alkyl, 1 ' ' ' phenyl or phenyl substitutGd by one to four selected from the group consisting of halogen and hydroxy;
R3 is Cl-C6 allcyl or C3-C7 cycloaDcyl;
R4 is Cl-C3 aLlcyl; and salts thereof, processes for the ' of these containing su~h ~ J~ and the use f these r-wogs/l6663 p_" 1.1
2 1 7~2~3 The , ' of the formula (I) represent derivatives of HBED which is rN,N'-bis-(2 h.~vaylb~ )ethylene diamine N,N diacetic acid] a product of the formula (II) HO
HO ~CO~ ~N~N~ (CO) OH
~J (Il) OH
BED is described as a chelating agent for the treatment of iron overload m U.S. patent US-4'528' 19o. As tests in monkeys and human beings show, the major advantage of the U~ of the formula (1) over HBED is that the free molecules do not bind to heavy metal ions at all. Thus, they pass the intestinal tract without any loss. As free molecules they do not take up heavy metal ions but develop this met 1 binding properties ~ ;ly after their resorption when they circulate in the blood stream so that they can successfully be: ' ' systemically to warm-blooded animals, most preferred orally or parenterally. ~ ; t~ orally they even exhibit a si~ --;ric~ultly higher activity than BED. Thus the present invention provide agents that are even effective chelators when ~,1..".. .~,1 systemically. Although the free molecules of the formula (I) do not bind to heavy metal ions they develop strong chelating properties in the animal's blood A ~ 11y preferred subgroup within the formula (1) consists of those l~iy~ ,S wherein R is defined as under Formula (I) and Rl is -NR4R5 whereby R4 and R5 are i ~ of each otber Cl-C3 alkyl;
R2 is Cl-C3 aLlcyl;
R3 is Cl-C3 aLIcyl or C3-C7 cycloalkyl;
halogen is fluorine, chlorine or bromine;
cycloalkyl is .,~.loll~".yl, R4 is methyl; and salts thereof.
Most preferred are however I ' of the formula (I) wherein R represents -O-(CO)-R2 and R2 Cl-C6 alkyl and preferably Cl-C3 alkyl.
~ W095116663 2 l 79?03 Within the scope of the present ~f cf lirhf~n, the definitions used I ' f( and hereinafter have preferably the following meanings: Cl-C6 allcyl stands for an Ior branched allcyl group ~ t~ by the given number of carbon atoms. Typical aLi~-.f. are methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, tert-pentyl, neo-pentyl, n-hexyl, I-methyl-pentyl, I,l-dimethyl-butyl,
HO ~CO~ ~N~N~ (CO) OH
~J (Il) OH
BED is described as a chelating agent for the treatment of iron overload m U.S. patent US-4'528' 19o. As tests in monkeys and human beings show, the major advantage of the U~ of the formula (1) over HBED is that the free molecules do not bind to heavy metal ions at all. Thus, they pass the intestinal tract without any loss. As free molecules they do not take up heavy metal ions but develop this met 1 binding properties ~ ;ly after their resorption when they circulate in the blood stream so that they can successfully be: ' ' systemically to warm-blooded animals, most preferred orally or parenterally. ~ ; t~ orally they even exhibit a si~ --;ric~ultly higher activity than BED. Thus the present invention provide agents that are even effective chelators when ~,1..".. .~,1 systemically. Although the free molecules of the formula (I) do not bind to heavy metal ions they develop strong chelating properties in the animal's blood A ~ 11y preferred subgroup within the formula (1) consists of those l~iy~ ,S wherein R is defined as under Formula (I) and Rl is -NR4R5 whereby R4 and R5 are i ~ of each otber Cl-C3 alkyl;
R2 is Cl-C3 aLlcyl;
R3 is Cl-C3 aLIcyl or C3-C7 cycloalkyl;
halogen is fluorine, chlorine or bromine;
cycloalkyl is .,~.loll~".yl, R4 is methyl; and salts thereof.
Most preferred are however I ' of the formula (I) wherein R represents -O-(CO)-R2 and R2 Cl-C6 alkyl and preferably Cl-C3 alkyl.
~ W095116663 2 l 79?03 Within the scope of the present ~f cf lirhf~n, the definitions used I ' f( and hereinafter have preferably the following meanings: Cl-C6 allcyl stands for an Ior branched allcyl group ~ t~ by the given number of carbon atoms. Typical aLi~-.f. are methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, tert-pentyl, neo-pentyl, n-hexyl, I-methyl-pentyl, I,l-dimethyl-butyl,
3,3-dimethyl-butyl, 2,2-dimethyl-butyl, 2-methyl-pentyl, 3-methyl-pentyl, and
4-methyl-pentyl. Halogen is, for example, fluorine, bromine or chlorine, prefcrably fluorine or chlorine. C3-c7 cycloaLcyl represents a cauLu~ lic saturated ring with three to seven carbon atoms, for example, ~ .l~uu~yl, cyclobutyl, ~,y~ Lyl, cyclohexyl oro ~,luh~ l, preferably uy~ 1 or cyclohexyl.
Most preferred IL.~/Iu~ lLaLi~,S within the scope of formula (I) are the following ones:
Bis N,N-L~ ' ' y;~ lyl~[N~N'~bis(2~1ly~w~L~ll~l)]u N,N'-discetate;
Bis a~,tu~y.. ~ : [N,N'-bis(2-l.~Lu~l,~,~,~l)].,L;.~ f N,N'-diacetate;
Bis n~ ul~w~ ' yl [N,N'-bis(2 h~d~u~fl/ I.~yl)]~,Ll~' ' N,N'-diacetate;
Bis iso-~.ul!u,.yl.-~Lllyl [N.N'-bis(2-l-~Lw-Jb~ yl)]uLllyl~ f'l '''~"'' N N'-diacetate;
Bis au~w~ylll~ [N,N'-bis(2-l~yd-w-~b-,--~l)]~.Ll-yl~ I ~"';.'f N.N'-diacetate;
Bis tert-l,uLw.yl..~,Ll.yl-[N,N'-bis(2-ll~Lu~y~ l)]~,.ll~l -1; ;1~ N,N'-diacetate;
Bisn-lJ"..Lu,.y~ ,tl.~l-[N,N'-bis(2-llyLu~-y~.,.lL~l)]u.llrl 1 I;llf N,N'-diacetate;
Bis ~ IU~JIII~LIIJ [N,N'-bis(2-lly.Lu~.yl,~.. ~l)]~ N,N'-diacetate;
Bis c,llw~y~,aulJul.~lu~...~ l-[N~N~-bis(2-lly~Lu~ I)]~.LI,~
N,N'-diacetate;
Bis ~,y ' ' ~'u~y~ ful~ull~luA~llll,Lll~l-[N,N'-bis(2-L.~ u~yl~ll~yl)]~
N,N'-diacetate;
Bis (4-methyl-1,3-dioxolan-2-on-4-yl)methoxy-[N,N'-bis(2-l.y.Lu,~L,... yl)]-oLll~ f l:- ~:~ N,N'-diacetate; and Bis N I ' ' ' J~ LI~.r [N~N~-bis(2-~ L
N,N'-diacetate.
., The , ' of the formula (I) are capable of forming salts. The salts of the ~'f~ ' "I` according to the invention are, especially, ~ lly acceptable, non-toxic salts. Such salts are especially metal salts and salts, such as al6alimetal or aLcaline eafth metal salts, for example sodium, potassium, ~" or calcium salts as well as related 2+ salts such as zinc salts, and r ~~ salts with ammonia or suitable organic amines, there coming into ~.. :.1. .,.1;r~l~ for the salt formation especially -Wo95/16663 2 1 7 ~2 03 P~l/ L~C
aliphatic, ~ ;" ~ -aliphatic or araliphatic primary, secondary or tertiary mono-, di- or poly-amines, and also ll.,~l~l,li~, bases. Such amines are, for example, lower aLlcylamines, for example ui~ , hydroxy-lower alk~' for example 2 h~ 1a---;-le, bis-(2 h~L~ ,th~ amine or tris-(2-l.yLu~,tl-~l)-amine, basic aliphatic esters of carboxylic acids, for example acid 2~i~,dlyl~l-i--~11-yl ester, lower aLk;l~ for exarnple 1-e~ ,cycloalk~` forexarnple li"~,lol..,,.~' orb~ ~Lulli~ for example N,N'-dibenzyl~Lllyl ~ also bases of the pyridine type, for example pyridine, collidine or quinoline. The ~,..,1.~, l~ of the formula (I) can also for~n (as opposed LO -' ' , i.e. ~ iUIII~,) acid addition salts, for example with inorganic acids, such as h.~L~IIl~,l;c acid, sulphuric acid or phosphoric acid, or with suitable organic carboxylic or suiphonic acids, for exarnple ' If nnir acid, or with amino acids, such as arginine and Iysine.
For isolation and l~ 11y ~ J~ salts also can be used Only the 1~ ly acceptable, non-toxic salts are used for therapGutic application and, for that reason, they are preferred Taken up by the a warm-blooded animal, the ~ of the formula I are ~ " r"1 "
into a form that allows them to form suble complexes with meul ions, especially heavy metal ions. Of the heavy meul ions, there may be mentioned especially those in the 3+
oxidation state, such as Al3+ or, most especially, Fe3+.
Thus, the subsunces of the formula (I) exhibit valuable 1 1 -, ~ n~ lly properties when ~ t~,..-;~,dll~, especially after oral or 1~ arplirsl~inn Owing to their ability to form in the animal's body suble complexes with heavy meul ions, especially with those in the 3+ oxidation sute, such as Al3+ or, most especially, with Fe3+, the c~ u~ of the formula (I) prevent, for example, the deposition of iron-conuining pigments in the tissues and, in cases where iron has been deposited in the organism, bring about 1; ; -~ of the iron, for example in ll~ lu.,l,l~ and I~ and also in cirrhosis of the liver. They can also be used for the ~limir ~inn from the organism of other heavy metals, for example aluminium and also chromium and copper. Thus, the ' of the formula I can also be used in the case of dialysis rnr~rh ~lnp~hy, n~ and Alzheimer's disease.
~ Wo 9Y16663 ~ l 7 ~ 2 ~ 3 P~
,s-The . of the formula (~ according to the invention and salts thereof can be by chemical synthesis accordmg to processes known Per se. They are 1~ for example, by adding under cooling sodium hydride or potassium hydrogene carbonate to the compound of thc formula aI) HO
X-O-(Co) ~N~N~(CO)-O-X
~J (n OH
wherin X stands for hydrogen or the group -CHr~J and adding to the resultant solution either (a) in those cases where X stands for hydrogen a compound of the formula alI) Y-CH2-R (m), or (b) in those cases where X stands for the group -CH2J a compound of the formula (IV) HO-C(O)-R (rV)~
whereby R in the formulae (m) and (IV) is defined as under formula (I) and Y represents halogen. prcferably chlorine, bromine or iodine, most preferably bromine or iodine.
The compound of the formula (~) wherin X is hydrogen is BED which is as mentiondabove desdbed in the U.S. patent US4'528' 196. The compound of the formula (II) wherin X is -CH2J can be preparcd by reacting BED with CH2CIJ under suitable conditions. This type of reaction is desc~ibed in the literature and well known to the skilled chemist.
The reaction is performed in a inert dipolar aprotic solvent such as acetone. ar~r~ni~
(DMSO), _t~ u~ -I,1-dioxide (sulfolane) or diether of at rclatively low ~,~ preferably at h ~ arround 0C, for wo 95/16663 r~
example at about -10 to 30C, and preferably under an inert gas . ' Salts Of ~ Of the formula (I) can be ' ~ in a manner Icnown per se.
Thus, acid addition salts Of ~ A ~ of the formula a) are obtairled in customary manner, for example by treating with an acid or a suitable arlion-exchange reageM.
Internal salts of ~ ""l"J" lc of the formula (I) (~ ;ulul~ forms) can be formed, for example, by rlf'lltTAliCi A~ tbe ~ or salts, such as acid addtion salts, to the isoelectric point, for example with weak bases, or by treating with liquid ion ~alts can be converted in customary manner into the free ~ ~ , ' metal and salts can be converied into the free r ~, for example, by treating with suitab~e acids, and acid addition salts. for example, by treating with a suitable basic agent.
he starting materials, especia~ly those of formula ~II) and ~llI) are available ly andlor known or can be ' ' by known processes.
The ~ rnlf~ ly acceptable ~ of the present invention can be used, for example, for the ' c, f l ' c~ n- ~ which contain an effective amount of the active substance together or in admixture with inorganic or organic, solid or liquid, ~ y acceptable carriers.
The ~ IJ~ `''` according to the invention are those which are suitable for enteral, such as oral" - and for parenteral, such as ~
;.... to warm-blooded animals, especially humans, and which contain the ;f Al active substance on its own or together with a ~ AllY
acceptable carlier. The dosage of the active substance depends on the species ofwA-~r bl~d~d animal and on the age and individual condition, the illness to be treated and also on the mode of A.l .;,: ~I "-~
The novel l~l--- . - -; Al IJlUI~al_LiV.I~ contain from a~ ly 10 % toa~ 95 %, preferably from:, . 'y 20 % to f~ llf~ ly 90 %~ of the active substance. pl --, ~ '- according to the invenrion can, for example, be in unit dose form, such as dragées, tablets, capsules, ~ or ampoules, and contain from Ak~ .y 0.1 g to a~ 'y 3.0 g, preferably from y 0.3 g to Al.~ ly 1.0 g, of the active ingredient.
~ wo 95/16663 2 ~ 7 9 2 0 3 P~
The I ' ' C~ of the present invention are . - r, I ~ rd in a manne}
known per se, for example by means of ~,u.... ' mixing", ~ r dissolvingorly~ processes r~ ; fororalusecanbe obtained by combining the active substance with one or more solid catriers, if desired ~ a resulting mixture and processing the mixtute or gtanulate, if desired or necessaty after the addition ûf suitable adjuncts, to form tablets or dragée cores. In so doing, they can also be illcul~ ' into plastics carriers which release the active substances or allow them to diffuse in contrûlled amounts.
Suitable carriers are especially fillers, such as sugars, for example lactose, cq~rhq~nsC~
mannitol or sorbitol, cellulose 1" ~ and!or calcium rhnCphqt~ for example tricalcium phosphate or calcium hydrogen phosphate, also binders such as stqrches, for example corn, wheat, rice or potato sturch, gelatine, tragacanth, methylcellulose, I.yLu~ .ul,~h...,.l.JL,.,llulose. sodium ~bu~l~ yk,~,llulose andlorpolyvinyl-and/or, if desired. ~ O such as the abo /c-- ~ ;~ A starches, also "~u~ l stqrch, crosslinked puly~ yl~yllulidG~Ir" agar, alginic acid or a salt thereof, such as sodium alginate. Adjuncts are especially flow-regulating and lubricating agents. fûr example silica, talc, stearic acid or salts thereof. such as ~ or calcium steqrate, and/or ~u4,LI-~ , glycol. Dragée cores are provided with suitable coatings that are, if desired, resistant to gastric juice, there being used, ints aia, ~ .I sugar solutions which optionally contain gum arabic. talc, pol~ v .~ IUI;dU~ POI~ I.YL~
glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the ' of coatings that are resistant to gastric juice, solutions of suitable cellulose I .. I p - - ,. I in- ', such as ...,~i~ " ' phthalate or l. y Jl u..~l -ul,.~l-methylcdlulose phthalate. Colouring substances or pigments can be added to the tablets or dragée coatings, for example for the purpose of i-~ l ;- or for indicating different doses of active substance.
Other orally ~ . are dry-filled capsules made of gelatin, and also soft, sealed capsules made of gelatin and a plasticiser, such as glycerol or sorbitol. The dry-filled capsules may contain the active ingredient in the form of a grqnulate, for example in admixture with hllers, such as corn starch, binders and/or glidants, such as taic or 1" stearate, and optionally stabilisers. In soft capsules the active ingredient is preferably dissolved or suspended in suitable liquids or wax-like cllhctqn~ 5 such as fatty oils, parqffin oil or pol~ , glycols, it being possible also for stabilisers to be added.
WO95/16663 r .,~
? ~ 79~;~3 Other forms of oral: are, for example, syrups prepared in customary manner that conuin the active ingredient in, for example, suspended fotm and in a of 3~, 'S, from 5 % to 20 ~o, pteferably ~ y 10 %, or in a similar - that provides a suitable single dose when A~ i, for example, in measures of 5 or 10 ml~ Also suiuble are, for example, powdered or liquid .
for preparing shakes, for example in miL~ Such, can also be packed in single-dose quantities~
r~;- ulall~ suiuble dosage forms for parenteral A~ - are sterile aqueous solutions of an active ingredient in water-soluble form, for example a water-soluble salt, or sterile aqueous injection . which conuin subsunces increasing the viscosity, for example sodium C,J 1,~ 1 cellulose, sorbitol andlor dextran, and optionally subilisers. In addition, the active ingredient, with or without adjuvants, can also be in Iyophilised form and brought into solution prior to parenteral ~ ll by addition of suiuble solvents.
The invention relates also to ~ for diagnostic purposes that contain a suitable meul complex of a compound of the formula (I), preferably in the form of an aqueous solution or in the f rm of a dry rrf-r-~fm The invention relates also to a method of treatment of ~, -~1.,.1,,~;. Al conditions irl a mammal, especially human, which, as has been described l-- ~ l - f ~ are associated v~ith an excess of a trivalent meul cation such as aluminium or, especially, iron~m), in the body, which method comprises A~l ;' ' `~' ` ;"~ preferably orally, a l,lulJI-JI~, Lh,~ or Ih ~ ~1'` --';- Ally effective amount of a compound of formula (I) or of a I ' 'ly acceptable salt thereof. There are used for this purpose especially the above .
-c a daily dose of from f~ 'y 25 mg/kg to f~ / 200 mg/kg, preferably from ~rpr- ~.S~ 20 mg/kg to f~ 'S, 150 mglkg, of a compound of the present invention being ~ 1 to a w~r~- bl-~d animal. The dosage can be A~ d orally in several, for example three, individual doses. For systemic, e.g. ~ - - u ~ _ ' the more water soluble salt forms of the ~ .,..l.u - ..l- of the formula (I), e.g. the sodium salt, are preferred. Most preferred mode of ' is orally. An alternatively mode of A~l. . ~ `1~ ' 1 ;' ~. . is WO 95/16663 P~
2l 792a3 The invention concerns especially the r ~ of the formula a), the methods for their as outlined above, ~ containing as active ingredient a compound of the formula a)- Preferred are l ~ for sysoemic ' ' ' as described generally and in the examples, and especially the oral dosage forms. The invention further concerns a method of treatment Of 1~ ol ~,~i conditions in a mammal that are associated with an excess of trivalent metal ions in the body, .,t,~ g a~ c. systemically, most preferred orally, to said mammal a 111 .r ' '1~/ effective amount of a compound of formula a) or a l.h ""_ . ..~ lly acceptable salt thereo The following examples serve to illustrate the invention but should not be constmed as a limitation thereo T~ . are given in degrees Centigrade.
Examt)le 1: Bis a.,.,tuAy,l..,lllYl-rN,N'-bis(2-llyltuAy~ yl) N,N'-diacetaoe HO
,~
CH3(CO)-O-CH2-o-(co) ~N~N~ (CO)-O-CH2-O-(CO)CH3 OH
HBED (lg, 2.57 mMol) was dissolved in 15 ml of t~ tllylrl.. :Af, the resulting solution cooled to 0-4 C and kept under innert r- . ' Sodiurn hydride (280 mg, 6.43 mMol, 55-60% suspension in oil) was added and the resulting suspension stirred 30 min. at 0-4 C
R,l~, . .. ,...II.yla~clat~, (656 ml, 6.7 mMol) was added and the reaction mixture stirred for S
h at room Lt . The mixture was poured in 111ly' (100 ml) and washed with waoer (3 X 50 ml), brine (IX50ml) dried with Na2SO4, afoer filtration of the drying agent the solvent was evaporated under reduced pressure.
The residue was purified on a ' " . ' column containing 70g of silicagel and ~,illy' ~.Aatle 1:1 v/v as el~ting solvent. The fractions containing the pure WO95116663 r 21 79~t33-1O-compoumd were combimed and ' in vacuo. The residue is .~ from cll..y' /I..,A~I~ o yield the desired compound as a white crystals, mp 10~101C.
% calc. for C26H32N2Olo: C Sg.64 H 6.06 N5.26 O 30.04 % found: C 58.52 H 6.12 N 5.18 0 29.gl lH NMR (CDC13. 200 MH~): 2.13 (Sl 6H, 2 X H3CO-); 2.75 (s, 4H, N-CH2-CH2-N);
3.12 (s, 4H, 2 X N-CH2-CO-); 3.78 (s, 4H, 2 X -N-CH2-PH); 5.79 (s, 4H, 2 X O-CH2-O);
6.7-7.22 (m, 8H, 2 X Ph).
Example 2: Bis vlu~ urluA~ Lilrl iN.N'-bis(~ Y~LuAY~ yl)lethylene-diamine N,N'~iacetate ~
HO
C2Hs(CO)-O-CH2-O-(cOl ~N~N , (CO)-O-CH2-O-(CO)C2Hs ~OH
HBED (5.7g, 14.6 mMol) was dissolved in 100 ml DMF (N, N-~' ' jl r.., .., ;,i~) and KHCO3 (5.9g, 58.7 mMol) was added The mixture was stirred for ~0 min After that period I ' Jl~l~, (6.9ml, 61.67 mMûl) was added and the mixiure stirred for 18 h.
WO 95116663 r~
~ 21 79203 The reaction mixture was then poured in cthJ'a (lOQml) and washed with water (7~7~1), brine (lX20rhnl) and dricd over Na2S04. After filtration the solution was ' in Yacuo. The residue was recrystallized frorn cll."l~.,~t~ ~.., yielding the desired compound with a melting pomt of 91-92 C.
% calc. for C2sH36N2olo: C 59.99 H 6.47 N5.0 0 28.54 % found: C 60.1 H6.6 N5.0 0 28.2 ExamPle 3: Bis pivaluylu~ I r.N'-bis(2-llyLu~ ,.. ,.yl)l- - -' ' N,N'-diacetate HO
(CH3)3C(CO)-O-CH2-O-(CO) ~N~N~(CO)-O-CH2-0-(CO)C(CH3)3 OH
HBED (lOOmg, Q255 mMol) was dissolved in S ml of DMF. cooled at 0-4 C and kept under Ar. Sodium hydride (23mg, 0.52 mMol, 55-60% in oil) was added and the resulting mixture stirred for 18 h at 6-8 C.
After that time the reaction was diluted with ~,11.,,' (30ml) and washed with water (2XlQml), brine (lXlOml) and dried over Na2SO4. After filtration of the drying agent the solvent was evaporated in vacuo.
wo 95/16663 ~ ~ 7 5~ i P~ 5 I.t r The residue was purified on a .' ~ . ' column and the fractions containing the pure compound were combined and evaporated in vacuo to give the desired product as a colorless oil.
lH-NMR (CDC13, 200 MHz): 1.2 (s, 9H, -(CH3)3); 2.75 (s, 4H, N-CH2-CHrN); 3.32 (s, 4H, 2 X N-CH2-CO); 3.77 (s, 4H, N-CH2-Ph); 5.8(s, 4H, 2 X -CH2-Ph); 6.7-7.25(m, 8H, 2 X-Ph).
Example 4: Bis N~N~L~.Ihr~ Y il rN,N'-bis(2 ~.r~u~h~ ,rl)l~
r~ - N,N'-diacetate HO~
C2Hs)2N(CO)-CH2-O-(cO) ~ N ~ N ~ (CO)-O-CH2-(CO)N(c2H5)2 ~OH
HBED (200mg, 0.51 mMol) was dissolved in anhydrous DMF and cooled to 0-4 C underAr. Sodium hydride (52mg, 1.2 mMol, 55-60 9Q in oil) was added and the resultingsuspension was stiIred for 30 min. Then 2-chloro-N,N~L~,d.yl~.ku,,hL (168ml, 1.23 mMol) and sodium iodide (18mg, 0.12 mMol) were added and the resulting suspension stilred for 24 h at Toom i After that peTiod the Teaction mixture was diluted with c~ (SOml) and washed with sat. NH4CI (2X20ml), water (lX25ml), brine (lX20ml), dlied with Na2SO4 and filtratcd. The solvent was evaporated in vacuo amd the reidue purif~ed on a column. The fractions containing the pure compound were combined and ' in vacuo to give the desired compound as a colorless oil.
lH-NMR (CDCI~, 200 MHz): 1-1.2 (m, 12H, 4X -CH3); 2.8 (s, 4H, N-CH2-CH2-N); 3.2 (q, 4H, 2X -CH2-C 113), ~.3 (q, 4H, 2X -CH~-CH3); 3.45 s, 4H, N-CHrCO); 3.8 (s, 4H, N-CH2-Ph); 4.75 (s, 4H, -O-CH2-CO); 6.65-7.2 (m, 8H, 2X -Ph).
wo 95116663 2 1 7 q 2 0 3 p~ "
l~xamDle 5: Bis-N~ I rN.N'-bis(2 h~ ethylene-diamine N,N'~iaceute HO
O N--(CO~ ~N~N~ (CO)--N O
~OH
HBED (200 mg, 0.51 mmol) was dissolved in anhydrous DM!F (5ml) and cooled to 0-4 C.
NaH (50 mg, 1.12 mmol) was added and vhe suspension s~red for one hour. Then 2-bromo N " ,",~ ;-1; was added and the reaction st~rvd for seven hours at room i' '"1" '"1"'~
After that period ~he reaction mixture was diluted with v~yLI~,vLLtv (30ml) washed with water (2 X 10 ml), brine (1 X 10 ml) dried over Na2SO4. After filtration of the drying agent, the solvent was evaporated and the residue ' v 1l on column- The fractions containing the pure compound were combined and the solvent evaporated im vacuo to yield the desired product as an oil.
lH NMR (CDC13. 200 ~z): 2.81 (s, 4H, N-CH2-CH2-N); 3-42 (s, 4H, N-CH2-CO);
3.3-3.7 (m, 16H, 2 X N-CH2-CH2-O); 3.78 (s, 4H, 2 X N-CH~-Ph); 4.76 (s, 4H, 2 X
O-CH2-CO); 6.7-7.2 (m, 8H, 2 X -Ph).
WO 9S/16663 . P~
~xamPIe 6: Bis(5-methYI-1.3-dioxolan-2-one-4-Yl)methoxY-rN.N'-bis~2-llYLu;-Y~ Yl) ~,;I.y' - -N.N'-diacetate.
HO
O r cH20(co) ~N~N_ (cO)ocH2~ ~
¢~JOH H3C
HBED 4H2O ~1.31 g, 2.84 mmol) was dissolved in 40ml DMF (~,.~lh~lr.. ~ r), KHCO3 (potassium l,;~ ) tO.85 g, 8.5 mmol) was added and the reaction mixture was warmed to 65 C for one hour. The solution was then cooled to 15 C and 4-blu~-u-l-~.~llyl-
Most preferred IL.~/Iu~ lLaLi~,S within the scope of formula (I) are the following ones:
Bis N,N-L~ ' ' y;~ lyl~[N~N'~bis(2~1ly~w~L~ll~l)]u N,N'-discetate;
Bis a~,tu~y.. ~ : [N,N'-bis(2-l.~Lu~l,~,~,~l)].,L;.~ f N,N'-diacetate;
Bis n~ ul~w~ ' yl [N,N'-bis(2 h~d~u~fl/ I.~yl)]~,Ll~' ' N,N'-diacetate;
Bis iso-~.ul!u,.yl.-~Lllyl [N.N'-bis(2-l-~Lw-Jb~ yl)]uLllyl~ f'l '''~"'' N N'-diacetate;
Bis au~w~ylll~ [N,N'-bis(2-l~yd-w-~b-,--~l)]~.Ll-yl~ I ~"';.'f N.N'-diacetate;
Bis tert-l,uLw.yl..~,Ll.yl-[N,N'-bis(2-ll~Lu~y~ l)]~,.ll~l -1; ;1~ N,N'-diacetate;
Bisn-lJ"..Lu,.y~ ,tl.~l-[N,N'-bis(2-llyLu~-y~.,.lL~l)]u.llrl 1 I;llf N,N'-diacetate;
Bis ~ IU~JIII~LIIJ [N,N'-bis(2-lly.Lu~.yl,~.. ~l)]~ N,N'-diacetate;
Bis c,llw~y~,aulJul.~lu~...~ l-[N~N~-bis(2-lly~Lu~ I)]~.LI,~
N,N'-diacetate;
Bis ~,y ' ' ~'u~y~ ful~ull~luA~llll,Lll~l-[N,N'-bis(2-L.~ u~yl~ll~yl)]~
N,N'-diacetate;
Bis (4-methyl-1,3-dioxolan-2-on-4-yl)methoxy-[N,N'-bis(2-l.y.Lu,~L,... yl)]-oLll~ f l:- ~:~ N,N'-diacetate; and Bis N I ' ' ' J~ LI~.r [N~N~-bis(2-~ L
N,N'-diacetate.
., The , ' of the formula (I) are capable of forming salts. The salts of the ~'f~ ' "I` according to the invention are, especially, ~ lly acceptable, non-toxic salts. Such salts are especially metal salts and salts, such as al6alimetal or aLcaline eafth metal salts, for example sodium, potassium, ~" or calcium salts as well as related 2+ salts such as zinc salts, and r ~~ salts with ammonia or suitable organic amines, there coming into ~.. :.1. .,.1;r~l~ for the salt formation especially -Wo95/16663 2 1 7 ~2 03 P~l/ L~C
aliphatic, ~ ;" ~ -aliphatic or araliphatic primary, secondary or tertiary mono-, di- or poly-amines, and also ll.,~l~l,li~, bases. Such amines are, for example, lower aLlcylamines, for example ui~ , hydroxy-lower alk~' for example 2 h~ 1a---;-le, bis-(2 h~L~ ,th~ amine or tris-(2-l.yLu~,tl-~l)-amine, basic aliphatic esters of carboxylic acids, for example acid 2~i~,dlyl~l-i--~11-yl ester, lower aLk;l~ for exarnple 1-e~ ,cycloalk~` forexarnple li"~,lol..,,.~' orb~ ~Lulli~ for example N,N'-dibenzyl~Lllyl ~ also bases of the pyridine type, for example pyridine, collidine or quinoline. The ~,..,1.~, l~ of the formula (I) can also for~n (as opposed LO -' ' , i.e. ~ iUIII~,) acid addition salts, for example with inorganic acids, such as h.~L~IIl~,l;c acid, sulphuric acid or phosphoric acid, or with suitable organic carboxylic or suiphonic acids, for exarnple ' If nnir acid, or with amino acids, such as arginine and Iysine.
For isolation and l~ 11y ~ J~ salts also can be used Only the 1~ ly acceptable, non-toxic salts are used for therapGutic application and, for that reason, they are preferred Taken up by the a warm-blooded animal, the ~ of the formula I are ~ " r"1 "
into a form that allows them to form suble complexes with meul ions, especially heavy metal ions. Of the heavy meul ions, there may be mentioned especially those in the 3+
oxidation state, such as Al3+ or, most especially, Fe3+.
Thus, the subsunces of the formula (I) exhibit valuable 1 1 -, ~ n~ lly properties when ~ t~,..-;~,dll~, especially after oral or 1~ arplirsl~inn Owing to their ability to form in the animal's body suble complexes with heavy meul ions, especially with those in the 3+ oxidation sute, such as Al3+ or, most especially, with Fe3+, the c~ u~ of the formula (I) prevent, for example, the deposition of iron-conuining pigments in the tissues and, in cases where iron has been deposited in the organism, bring about 1; ; -~ of the iron, for example in ll~ lu.,l,l~ and I~ and also in cirrhosis of the liver. They can also be used for the ~limir ~inn from the organism of other heavy metals, for example aluminium and also chromium and copper. Thus, the ' of the formula I can also be used in the case of dialysis rnr~rh ~lnp~hy, n~ and Alzheimer's disease.
~ Wo 9Y16663 ~ l 7 ~ 2 ~ 3 P~
,s-The . of the formula (~ according to the invention and salts thereof can be by chemical synthesis accordmg to processes known Per se. They are 1~ for example, by adding under cooling sodium hydride or potassium hydrogene carbonate to the compound of thc formula aI) HO
X-O-(Co) ~N~N~(CO)-O-X
~J (n OH
wherin X stands for hydrogen or the group -CHr~J and adding to the resultant solution either (a) in those cases where X stands for hydrogen a compound of the formula alI) Y-CH2-R (m), or (b) in those cases where X stands for the group -CH2J a compound of the formula (IV) HO-C(O)-R (rV)~
whereby R in the formulae (m) and (IV) is defined as under formula (I) and Y represents halogen. prcferably chlorine, bromine or iodine, most preferably bromine or iodine.
The compound of the formula (~) wherin X is hydrogen is BED which is as mentiondabove desdbed in the U.S. patent US4'528' 196. The compound of the formula (II) wherin X is -CH2J can be preparcd by reacting BED with CH2CIJ under suitable conditions. This type of reaction is desc~ibed in the literature and well known to the skilled chemist.
The reaction is performed in a inert dipolar aprotic solvent such as acetone. ar~r~ni~
(DMSO), _t~ u~ -I,1-dioxide (sulfolane) or diether of at rclatively low ~,~ preferably at h ~ arround 0C, for wo 95/16663 r~
example at about -10 to 30C, and preferably under an inert gas . ' Salts Of ~ Of the formula (I) can be ' ~ in a manner Icnown per se.
Thus, acid addition salts Of ~ A ~ of the formula a) are obtairled in customary manner, for example by treating with an acid or a suitable arlion-exchange reageM.
Internal salts of ~ ""l"J" lc of the formula (I) (~ ;ulul~ forms) can be formed, for example, by rlf'lltTAliCi A~ tbe ~ or salts, such as acid addtion salts, to the isoelectric point, for example with weak bases, or by treating with liquid ion ~alts can be converted in customary manner into the free ~ ~ , ' metal and salts can be converied into the free r ~, for example, by treating with suitab~e acids, and acid addition salts. for example, by treating with a suitable basic agent.
he starting materials, especia~ly those of formula ~II) and ~llI) are available ly andlor known or can be ' ' by known processes.
The ~ rnlf~ ly acceptable ~ of the present invention can be used, for example, for the ' c, f l ' c~ n- ~ which contain an effective amount of the active substance together or in admixture with inorganic or organic, solid or liquid, ~ y acceptable carriers.
The ~ IJ~ `''` according to the invention are those which are suitable for enteral, such as oral" - and for parenteral, such as ~
;.... to warm-blooded animals, especially humans, and which contain the ;f Al active substance on its own or together with a ~ AllY
acceptable carlier. The dosage of the active substance depends on the species ofwA-~r bl~d~d animal and on the age and individual condition, the illness to be treated and also on the mode of A.l .;,: ~I "-~
The novel l~l--- . - -; Al IJlUI~al_LiV.I~ contain from a~ ly 10 % toa~ 95 %, preferably from:, . 'y 20 % to f~ llf~ ly 90 %~ of the active substance. pl --, ~ '- according to the invenrion can, for example, be in unit dose form, such as dragées, tablets, capsules, ~ or ampoules, and contain from Ak~ .y 0.1 g to a~ 'y 3.0 g, preferably from y 0.3 g to Al.~ ly 1.0 g, of the active ingredient.
~ wo 95/16663 2 ~ 7 9 2 0 3 P~
The I ' ' C~ of the present invention are . - r, I ~ rd in a manne}
known per se, for example by means of ~,u.... ' mixing", ~ r dissolvingorly~ processes r~ ; fororalusecanbe obtained by combining the active substance with one or more solid catriers, if desired ~ a resulting mixture and processing the mixtute or gtanulate, if desired or necessaty after the addition ûf suitable adjuncts, to form tablets or dragée cores. In so doing, they can also be illcul~ ' into plastics carriers which release the active substances or allow them to diffuse in contrûlled amounts.
Suitable carriers are especially fillers, such as sugars, for example lactose, cq~rhq~nsC~
mannitol or sorbitol, cellulose 1" ~ and!or calcium rhnCphqt~ for example tricalcium phosphate or calcium hydrogen phosphate, also binders such as stqrches, for example corn, wheat, rice or potato sturch, gelatine, tragacanth, methylcellulose, I.yLu~ .ul,~h...,.l.JL,.,llulose. sodium ~bu~l~ yk,~,llulose andlorpolyvinyl-and/or, if desired. ~ O such as the abo /c-- ~ ;~ A starches, also "~u~ l stqrch, crosslinked puly~ yl~yllulidG~Ir" agar, alginic acid or a salt thereof, such as sodium alginate. Adjuncts are especially flow-regulating and lubricating agents. fûr example silica, talc, stearic acid or salts thereof. such as ~ or calcium steqrate, and/or ~u4,LI-~ , glycol. Dragée cores are provided with suitable coatings that are, if desired, resistant to gastric juice, there being used, ints aia, ~ .I sugar solutions which optionally contain gum arabic. talc, pol~ v .~ IUI;dU~ POI~ I.YL~
glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the ' of coatings that are resistant to gastric juice, solutions of suitable cellulose I .. I p - - ,. I in- ', such as ...,~i~ " ' phthalate or l. y Jl u..~l -ul,.~l-methylcdlulose phthalate. Colouring substances or pigments can be added to the tablets or dragée coatings, for example for the purpose of i-~ l ;- or for indicating different doses of active substance.
Other orally ~ . are dry-filled capsules made of gelatin, and also soft, sealed capsules made of gelatin and a plasticiser, such as glycerol or sorbitol. The dry-filled capsules may contain the active ingredient in the form of a grqnulate, for example in admixture with hllers, such as corn starch, binders and/or glidants, such as taic or 1" stearate, and optionally stabilisers. In soft capsules the active ingredient is preferably dissolved or suspended in suitable liquids or wax-like cllhctqn~ 5 such as fatty oils, parqffin oil or pol~ , glycols, it being possible also for stabilisers to be added.
WO95/16663 r .,~
? ~ 79~;~3 Other forms of oral: are, for example, syrups prepared in customary manner that conuin the active ingredient in, for example, suspended fotm and in a of 3~, 'S, from 5 % to 20 ~o, pteferably ~ y 10 %, or in a similar - that provides a suitable single dose when A~ i, for example, in measures of 5 or 10 ml~ Also suiuble are, for example, powdered or liquid .
for preparing shakes, for example in miL~ Such, can also be packed in single-dose quantities~
r~;- ulall~ suiuble dosage forms for parenteral A~ - are sterile aqueous solutions of an active ingredient in water-soluble form, for example a water-soluble salt, or sterile aqueous injection . which conuin subsunces increasing the viscosity, for example sodium C,J 1,~ 1 cellulose, sorbitol andlor dextran, and optionally subilisers. In addition, the active ingredient, with or without adjuvants, can also be in Iyophilised form and brought into solution prior to parenteral ~ ll by addition of suiuble solvents.
The invention relates also to ~ for diagnostic purposes that contain a suitable meul complex of a compound of the formula (I), preferably in the form of an aqueous solution or in the f rm of a dry rrf-r-~fm The invention relates also to a method of treatment of ~, -~1.,.1,,~;. Al conditions irl a mammal, especially human, which, as has been described l-- ~ l - f ~ are associated v~ith an excess of a trivalent meul cation such as aluminium or, especially, iron~m), in the body, which method comprises A~l ;' ' `~' ` ;"~ preferably orally, a l,lulJI-JI~, Lh,~ or Ih ~ ~1'` --';- Ally effective amount of a compound of formula (I) or of a I ' 'ly acceptable salt thereof. There are used for this purpose especially the above .
-c a daily dose of from f~ 'y 25 mg/kg to f~ / 200 mg/kg, preferably from ~rpr- ~.S~ 20 mg/kg to f~ 'S, 150 mglkg, of a compound of the present invention being ~ 1 to a w~r~- bl-~d animal. The dosage can be A~ d orally in several, for example three, individual doses. For systemic, e.g. ~ - - u ~ _ ' the more water soluble salt forms of the ~ .,..l.u - ..l- of the formula (I), e.g. the sodium salt, are preferred. Most preferred mode of ' is orally. An alternatively mode of A~l. . ~ `1~ ' 1 ;' ~. . is WO 95/16663 P~
2l 792a3 The invention concerns especially the r ~ of the formula a), the methods for their as outlined above, ~ containing as active ingredient a compound of the formula a)- Preferred are l ~ for sysoemic ' ' ' as described generally and in the examples, and especially the oral dosage forms. The invention further concerns a method of treatment Of 1~ ol ~,~i conditions in a mammal that are associated with an excess of trivalent metal ions in the body, .,t,~ g a~ c. systemically, most preferred orally, to said mammal a 111 .r ' '1~/ effective amount of a compound of formula a) or a l.h ""_ . ..~ lly acceptable salt thereo The following examples serve to illustrate the invention but should not be constmed as a limitation thereo T~ . are given in degrees Centigrade.
Examt)le 1: Bis a.,.,tuAy,l..,lllYl-rN,N'-bis(2-llyltuAy~ yl) N,N'-diacetaoe HO
,~
CH3(CO)-O-CH2-o-(co) ~N~N~ (CO)-O-CH2-O-(CO)CH3 OH
HBED (lg, 2.57 mMol) was dissolved in 15 ml of t~ tllylrl.. :Af, the resulting solution cooled to 0-4 C and kept under innert r- . ' Sodiurn hydride (280 mg, 6.43 mMol, 55-60% suspension in oil) was added and the resulting suspension stirred 30 min. at 0-4 C
R,l~, . .. ,...II.yla~clat~, (656 ml, 6.7 mMol) was added and the reaction mixture stirred for S
h at room Lt . The mixture was poured in 111ly' (100 ml) and washed with waoer (3 X 50 ml), brine (IX50ml) dried with Na2SO4, afoer filtration of the drying agent the solvent was evaporated under reduced pressure.
The residue was purified on a ' " . ' column containing 70g of silicagel and ~,illy' ~.Aatle 1:1 v/v as el~ting solvent. The fractions containing the pure WO95116663 r 21 79~t33-1O-compoumd were combimed and ' in vacuo. The residue is .~ from cll..y' /I..,A~I~ o yield the desired compound as a white crystals, mp 10~101C.
% calc. for C26H32N2Olo: C Sg.64 H 6.06 N5.26 O 30.04 % found: C 58.52 H 6.12 N 5.18 0 29.gl lH NMR (CDC13. 200 MH~): 2.13 (Sl 6H, 2 X H3CO-); 2.75 (s, 4H, N-CH2-CH2-N);
3.12 (s, 4H, 2 X N-CH2-CO-); 3.78 (s, 4H, 2 X -N-CH2-PH); 5.79 (s, 4H, 2 X O-CH2-O);
6.7-7.22 (m, 8H, 2 X Ph).
Example 2: Bis vlu~ urluA~ Lilrl iN.N'-bis(~ Y~LuAY~ yl)lethylene-diamine N,N'~iacetate ~
HO
C2Hs(CO)-O-CH2-O-(cOl ~N~N , (CO)-O-CH2-O-(CO)C2Hs ~OH
HBED (5.7g, 14.6 mMol) was dissolved in 100 ml DMF (N, N-~' ' jl r.., .., ;,i~) and KHCO3 (5.9g, 58.7 mMol) was added The mixture was stirred for ~0 min After that period I ' Jl~l~, (6.9ml, 61.67 mMûl) was added and the mixiure stirred for 18 h.
WO 95116663 r~
~ 21 79203 The reaction mixture was then poured in cthJ'a (lOQml) and washed with water (7~7~1), brine (lX20rhnl) and dricd over Na2S04. After filtration the solution was ' in Yacuo. The residue was recrystallized frorn cll."l~.,~t~ ~.., yielding the desired compound with a melting pomt of 91-92 C.
% calc. for C2sH36N2olo: C 59.99 H 6.47 N5.0 0 28.54 % found: C 60.1 H6.6 N5.0 0 28.2 ExamPle 3: Bis pivaluylu~ I r.N'-bis(2-llyLu~ ,.. ,.yl)l- - -' ' N,N'-diacetate HO
(CH3)3C(CO)-O-CH2-O-(CO) ~N~N~(CO)-O-CH2-0-(CO)C(CH3)3 OH
HBED (lOOmg, Q255 mMol) was dissolved in S ml of DMF. cooled at 0-4 C and kept under Ar. Sodium hydride (23mg, 0.52 mMol, 55-60% in oil) was added and the resulting mixture stirred for 18 h at 6-8 C.
After that time the reaction was diluted with ~,11.,,' (30ml) and washed with water (2XlQml), brine (lXlOml) and dried over Na2SO4. After filtration of the drying agent the solvent was evaporated in vacuo.
wo 95/16663 ~ ~ 7 5~ i P~ 5 I.t r The residue was purified on a .' ~ . ' column and the fractions containing the pure compound were combined and evaporated in vacuo to give the desired product as a colorless oil.
lH-NMR (CDC13, 200 MHz): 1.2 (s, 9H, -(CH3)3); 2.75 (s, 4H, N-CH2-CHrN); 3.32 (s, 4H, 2 X N-CH2-CO); 3.77 (s, 4H, N-CH2-Ph); 5.8(s, 4H, 2 X -CH2-Ph); 6.7-7.25(m, 8H, 2 X-Ph).
Example 4: Bis N~N~L~.Ihr~ Y il rN,N'-bis(2 ~.r~u~h~ ,rl)l~
r~ - N,N'-diacetate HO~
C2Hs)2N(CO)-CH2-O-(cO) ~ N ~ N ~ (CO)-O-CH2-(CO)N(c2H5)2 ~OH
HBED (200mg, 0.51 mMol) was dissolved in anhydrous DMF and cooled to 0-4 C underAr. Sodium hydride (52mg, 1.2 mMol, 55-60 9Q in oil) was added and the resultingsuspension was stiIred for 30 min. Then 2-chloro-N,N~L~,d.yl~.ku,,hL (168ml, 1.23 mMol) and sodium iodide (18mg, 0.12 mMol) were added and the resulting suspension stilred for 24 h at Toom i After that peTiod the Teaction mixture was diluted with c~ (SOml) and washed with sat. NH4CI (2X20ml), water (lX25ml), brine (lX20ml), dlied with Na2SO4 and filtratcd. The solvent was evaporated in vacuo amd the reidue purif~ed on a column. The fractions containing the pure compound were combined and ' in vacuo to give the desired compound as a colorless oil.
lH-NMR (CDCI~, 200 MHz): 1-1.2 (m, 12H, 4X -CH3); 2.8 (s, 4H, N-CH2-CH2-N); 3.2 (q, 4H, 2X -CH2-C 113), ~.3 (q, 4H, 2X -CH~-CH3); 3.45 s, 4H, N-CHrCO); 3.8 (s, 4H, N-CH2-Ph); 4.75 (s, 4H, -O-CH2-CO); 6.65-7.2 (m, 8H, 2X -Ph).
wo 95116663 2 1 7 q 2 0 3 p~ "
l~xamDle 5: Bis-N~ I rN.N'-bis(2 h~ ethylene-diamine N,N'~iaceute HO
O N--(CO~ ~N~N~ (CO)--N O
~OH
HBED (200 mg, 0.51 mmol) was dissolved in anhydrous DM!F (5ml) and cooled to 0-4 C.
NaH (50 mg, 1.12 mmol) was added and vhe suspension s~red for one hour. Then 2-bromo N " ,",~ ;-1; was added and the reaction st~rvd for seven hours at room i' '"1" '"1"'~
After that period ~he reaction mixture was diluted with v~yLI~,vLLtv (30ml) washed with water (2 X 10 ml), brine (1 X 10 ml) dried over Na2SO4. After filtration of the drying agent, the solvent was evaporated and the residue ' v 1l on column- The fractions containing the pure compound were combined and the solvent evaporated im vacuo to yield the desired product as an oil.
lH NMR (CDC13. 200 ~z): 2.81 (s, 4H, N-CH2-CH2-N); 3-42 (s, 4H, N-CH2-CO);
3.3-3.7 (m, 16H, 2 X N-CH2-CH2-O); 3.78 (s, 4H, 2 X N-CH~-Ph); 4.76 (s, 4H, 2 X
O-CH2-CO); 6.7-7.2 (m, 8H, 2 X -Ph).
WO 9S/16663 . P~
~xamPIe 6: Bis(5-methYI-1.3-dioxolan-2-one-4-Yl)methoxY-rN.N'-bis~2-llYLu;-Y~ Yl) ~,;I.y' - -N.N'-diacetate.
HO
O r cH20(co) ~N~N_ (cO)ocH2~ ~
¢~JOH H3C
HBED 4H2O ~1.31 g, 2.84 mmol) was dissolved in 40ml DMF (~,.~lh~lr.. ~ r), KHCO3 (potassium l,;~ ) tO.85 g, 8.5 mmol) was added and the reaction mixture was warmed to 65 C for one hour. The solution was then cooled to 15 C and 4-blu~-u-l-~.~llyl-
-5-methyl- 1 .3-dioxolan-2-on 1.92 g. 9.94 mmol) in 1û ml DMF was added and the resulting solution stirred for two and a half homs at room ~ . ,1. ..1, r After that period the solution was diluted in 150 ml of i Llly' and washed with water (4 X 80 ml). The water phases were extracted with e Ll-Jl~..,.,~.ltl ( 100 ml). The organic phases were combined, dried with Na2SO4 and evaporated in vacuo. The residue was purified on a ~,1-1~ ,. , ' column and the fractions containing the pure compound were evaporated in vacuo. The residue was recrystallized from elll~l~t~ ,.a-~, to yield the desiredcompound with a melting point of 111-113 C
% calc. for C30H32N2ol2 C 58.82 H 5.27 N 4.57 O 3 1.34 % found: C 58.7 H5.2 N4.6 031.4 ~ Wo 95/16663 2 1 7 q 2 ~ 3 P~
:.
Example 7: r ~ "u~ for oral ~ ' 1000 gelatine capsules each containing 150 mg of active ingredient are ~ ' as follows:
C-,...1 ...~:~;....
150 g Bis ~,.u~y~ }lyl-[N,N'-bis(2 h~Lu~b~ yl)]-.,llly~ ; N,N' diacetate 36 g talc 24 g wheat starch 16 g .--~ stearate 4 g lactose The ~ substances are forced tbrough a sieve having a mesh width of 0.6 mm and mixed thoroughly to yield a total of 230 g. 1000 gelatine capsules are each filled with 330 mg of this mixture using a capsule filling machine.
% calc. for C30H32N2ol2 C 58.82 H 5.27 N 4.57 O 3 1.34 % found: C 58.7 H5.2 N4.6 031.4 ~ Wo 95/16663 2 1 7 q 2 ~ 3 P~
:.
Example 7: r ~ "u~ for oral ~ ' 1000 gelatine capsules each containing 150 mg of active ingredient are ~ ' as follows:
C-,...1 ...~:~;....
150 g Bis ~,.u~y~ }lyl-[N,N'-bis(2 h~Lu~b~ yl)]-.,llly~ ; N,N' diacetate 36 g talc 24 g wheat starch 16 g .--~ stearate 4 g lactose The ~ substances are forced tbrough a sieve having a mesh width of 0.6 mm and mixed thoroughly to yield a total of 230 g. 1000 gelatine capsules are each filled with 330 mg of this mixture using a capsule filling machine.
Claims (9)
1. A compound of the formula (I) (I) in which R represents -(CO)-R1, -O-(CO)-R2, -O-(CO)-O-R3 or wherein R1 is -NR4R5 or ; whereby R4 and R5 are independent of each other C1-C3 alkyl or C3-C7 cycloalkyl or form together the group -(CH2)n-, n is an integer from 3 to 6;
R2 is C1-C6 alkyl, unsubstituted phenyl or phenyl substituted by one to four substitutents selected from the group consisting of halogen and hydroxy;
R3 is C1-C6 alkyl or C3-C7 cycloalkyl;
R4 is C1-C3 alkyl; and salts thereof.
R2 is C1-C6 alkyl, unsubstituted phenyl or phenyl substituted by one to four substitutents selected from the group consisting of halogen and hydroxy;
R3 is C1-C6 alkyl or C3-C7 cycloalkyl;
R4 is C1-C3 alkyl; and salts thereof.
2. A compound of the formula (I) according to claim 1 in which R1 is -NR4R5 whereby R4 and R5 are independent of each other C1-C3 alkyl;
R2 is C1-C3 alkyl;
R3 is C1-C3 alkyl or C3-C7 cycloalkyl; halogen is fluorine, chlorine or bromine; cycloalkyl is cyclohexyl; and R4 is methyl; and salts thereof.
R2 is C1-C3 alkyl;
R3 is C1-C3 alkyl or C3-C7 cycloalkyl; halogen is fluorine, chlorine or bromine; cycloalkyl is cyclohexyl; and R4 is methyl; and salts thereof.
3. A compound of the formula (I) according to claim 1 in which R represents -O-(CO)-R2 and R2is C1-C6 alkyl, preferably C1-C3 alkyl: and salts thereo
4. A compound according to claim 1 selected from the group consisting of Bis N,N'-diethylaminocarbonylmethyl-[N,N-bis(2-hydroxybenzyl)ethylenediamine N,N' -diacetate;
Bis acetoxymethyl[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis n-propoxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis iso-propoxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N N'-diacetate;Bis acetoxymethyl-[N,N'-bis(2 hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis tert-butoxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;Bis n-pentoxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis phenoxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis ethoxycarbonyloxymethyl[N,N -bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis cyclohexyloxycarbonyloxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis (4-methyl-1,3-dioxolan-2-on-4-yl)methoxy-[N,N'-bis(2-hydroxybenzyl)]-ethylenediamine N,N'-diacetate. and Bis N-morpholinocarbamoylmethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate.
Bis acetoxymethyl[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis n-propoxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis iso-propoxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N N'-diacetate;Bis acetoxymethyl-[N,N'-bis(2 hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis tert-butoxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;Bis n-pentoxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis phenoxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis ethoxycarbonyloxymethyl[N,N -bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis cyclohexyloxycarbonyloxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis (4-methyl-1,3-dioxolan-2-on-4-yl)methoxy-[N,N'-bis(2-hydroxybenzyl)]-ethylenediamine N,N'-diacetate. and Bis N-morpholinocarbamoylmethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate.
5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1.
6. A pharmaceutical composition according to claim 5 for systemic, preferably oral administration comprising a therapeutically effecive amount of a compound of theformula (I) or a pharmaceutically acceptable salt thereof according to claim 1 together with a carrier suitable for oral uptake.
7. A method of treatment of pathological conditions in a mammal that are associated with an excess of trivalent metal ions in the body, comprising administering systemically to said mammal a therapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof according to claim 1.
8. A method according to claim 7 comprising the oral administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 together with a carrier suitable for oral uptake.
9. Process for the production of a compound of the formula (I) according to claim 1 comprising adding under cooling sodium hydride or potassium hydrogene carbonat to the compound of the formula (II) (II) wherin X stands for hydrogen or the group -CH2J and adding to the resultant solution either (a) in those cases where X sfands for hydrogen a compound of the formula (m) Y-CH2-R (III), or (b) in those cases where X stands for the group -CH2J a compound of the formula (IV) HO-C(O)-R (IV), whereby R in the formulae (III) and (IV) is defined as under formula (I) and Y represents halogen.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP93810886 | 1993-12-16 | ||
| EP93810886.7 | 1993-12-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2179203A1 true CA2179203A1 (en) | 1995-06-22 |
Family
ID=8215091
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002179203A Abandoned CA2179203A1 (en) | 1993-12-16 | 1994-12-05 | N,n'-bis(2-hydroxybenzyl)ethylenediamine-n,n'-diacetic acid derivatives as chelating agents |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0734374A1 (en) |
| JP (1) | JPH09507473A (en) |
| CN (1) | CN1137267A (en) |
| AU (1) | AU1033495A (en) |
| CA (1) | CA2179203A1 (en) |
| FI (1) | FI962435A0 (en) |
| HU (1) | HUT74457A (en) |
| NO (1) | NO962307D0 (en) |
| WO (1) | WO1995016663A1 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6140305A (en) | 1996-04-04 | 2000-10-31 | Bio-Rad Laboratories, Inc. | Hereditary hemochromatosis gene products |
| US7026116B1 (en) | 1996-04-04 | 2006-04-11 | Bio-Rad Laboratories, Inc. | Polymorphisms in the region of the human hemochromatosis gene |
| WO1997044313A1 (en) * | 1996-05-21 | 1997-11-27 | Novartis Ag | N,N'-Di(2-HYDROXYBENZYL)ETHYLENEDIAMINE-N,N'-DIACETIC ACID DERIVATIVES |
| US6849399B1 (en) | 1996-05-23 | 2005-02-01 | Bio-Rad Laboratories, Inc. | Methods and compositions for diagnosis and treatment of iron misregulation diseases |
| DE69835519T2 (en) | 1997-06-13 | 2007-04-05 | Bio-Rad Laboratories, Inc., Hercules | METHOD AND COMPOSITIONS FOR THE DIAGNOSIS AND THE TREATMENT OF DISEASES ASSOCIATED WITH IRON OXIDE OR IRON DEFICIENCY. |
| FR2768145B1 (en) * | 1997-09-09 | 1999-10-08 | Oreal | NOVEL COMPOUNDS DERIVED FROM DI- OR TRI-ACETIC ALKYLENE DIAMINE ACID, PROCESS FOR THEIR PREPARATION, THEIR USE IN COSMETIC AND PHARMACEUTICAL COMPOSITIONS, AND COMPOSITIONS COMPRISING THE SAME |
| PT1052985E (en) * | 1998-02-04 | 2005-04-29 | Univ Florida | N, N'-DIACEIC ACID N, N'-BIS (2-HYDROXYBENZYL) ETHYLENODIAMINO AND ITS SODIUM SALTS FOR IRON THICKNESS THERAPY |
| CA2394524A1 (en) * | 1999-12-21 | 2001-06-28 | Raymond J. Bergeron | N,n'-bis(2-hydroxybenzyl)ethylenediamine-n,n'-diacetic acid in iron chelating therapy |
| CN109438517B (en) * | 2018-12-27 | 2021-01-08 | 北京久杰净化工程技术有限公司 | Complex of bifunctional linking agent coordinated with carbonyl metal core and preparation method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4528196A (en) * | 1981-02-23 | 1985-07-09 | The United States Of America As Represented By The Department Of Health And Human Services | Chelating agents for the treatment of iron overload |
| DE69023394T2 (en) * | 1989-06-16 | 1996-07-04 | Merck Frosst Canada Inc | Chelate derivatives of atrial-natriurethic factor (ANF). |
-
1994
- 1994-12-05 CA CA002179203A patent/CA2179203A1/en not_active Abandoned
- 1994-12-05 HU HU9601658A patent/HUT74457A/en unknown
- 1994-12-05 WO PCT/IB1994/000388 patent/WO1995016663A1/en not_active Application Discontinuation
- 1994-12-05 JP JP7516635A patent/JPH09507473A/en active Pending
- 1994-12-05 AU AU10334/95A patent/AU1033495A/en not_active Abandoned
- 1994-12-05 CN CN94194494A patent/CN1137267A/en active Pending
- 1994-12-05 EP EP95900893A patent/EP0734374A1/en not_active Withdrawn
-
1996
- 1996-06-04 NO NO962307A patent/NO962307D0/en unknown
- 1996-06-12 FI FI962435A patent/FI962435A0/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| HUT74457A (en) | 1996-12-30 |
| JPH09507473A (en) | 1997-07-29 |
| WO1995016663A1 (en) | 1995-06-22 |
| CN1137267A (en) | 1996-12-04 |
| FI962435A (en) | 1996-06-12 |
| AU1033495A (en) | 1995-07-03 |
| NO962307L (en) | 1996-06-04 |
| HU9601658D0 (en) | 1996-08-28 |
| EP0734374A1 (en) | 1996-10-02 |
| NO962307D0 (en) | 1996-06-04 |
| FI962435A0 (en) | 1996-06-12 |
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