Reference to Parent Applications This application is a continuation-in-part application of U.S. Ser. No. 574,482, filed

January 26, 1984. '

Field of the Invention

The present invention is concerned with the preparation of compounds, compositions and methods which are useful for treating diseases in human beings which are a result of a body tri-valent ion (i.e. Fe ⁺⁺⁺ , Al ⁺⁺⁺ ) overload state.

Background of the Invention Iron overload diseases include thalassemia major, sideroachrestic anemia, Blackfan-Diamond anemia, aplastic anemia, sickle cell anemia, other hemolytic anemias, and a number of other diseases and conditions in which hemosiderosis (a focal or general increase in tissue iron stores without associated tissue damage) occurs. One type of hemosiderosis occurs in most patients after multiple blood transfu¬ sions have occurred. Another type of hemosiderosis occurs as the result of the treatment of an anemia found in kidney damaged patients where dialysis is used to remove toxic wastes. Treatment of these conditions has generally involved the administration of a chelating agent having a selective affinity for tissue Fe ⁺⁺⁺ ion which can then be excreted as the iron chelate. The ideal chelating agent for the reduction of tissue metal ions, e.g. iron, aluminum, gallium,

ytterbium, indium and the like should have at least the following attributes:

1. Have high selectivity with respect to ion, e.g» iron, binding; 2. Be essentially metabolically inert;

3. Be essentially non-toxic;

4. Be inexpensive to produce; and

5. Be capable of oral administration.

Over the years a number of approaches have been investigated which have some of these attri¬ butes. The current drug of choice is deferoxamine, a compound obtained from the microorganism strepotomyces pilosus. Deferoxamine has the following structure:

0-H O-H OH

H-NH-(CH ₂ ) ₅ -N-C-CH ₂ C2i ₂ -C-NH-(CH ₂ ) ₅ -N-C-CH ₂ CH ₂ -C-NH-(OΪ ₂ ) ₅ -N-C-CH ₃

This material meets the aforementioned criteria except for oral availability. Deferoxamine (as the methanesulfonate salt) has been shown to be most effective when it is delivered parenterally via slow continuous (about an 8-12 hour period) subcutane- ous infusion using a portable infusion pump, i.e., a battery powered syringe pump.

This administration route for iron overload conditions is particularly difficult in view of the widespread occurrance of the disease, thalassemia major, found in the population in countries bordering on the Mediterranean Sea and extending eastward through the Middle East, India to Southeast Asia, and in sickle cell anemia which is prevalent in the populations in Africa.

The present invention concerns certain acyl derivatives of deferoxamine which are effective ion, e.g. iron, aluminum, etc. chelators when administered orally. Some compounds related to the compounds of the present invention are described in the literature by H. Biσkel, et al. in Helvitica Chimica Acta, Vol. 46, No. 153, pp 1385-1389, published in 1963 and their related U.S. Patent No. 3,247,197, both of which are incorporated herein by reference.

The focus of these references are the prepa¬ ration of N-acyl trihydroxy derivatives of deferoxa¬ mine which have the structure:

O-H O-H O-H R,-NH-(CH ₂ )ς-N-C-CH CH -C-NH-(C )ς-N-C-CHoCH -C-NH-(CH ₂ )ς-N-O-CHg

0 0 0 0 o

wherein R-^ may be an acyl group. These references mention tetra acyl materials, i.e., mater¬ ials of the formula:

O-R O-R 0-R

R-NH-(CH ₂ ) ₅ -N-C-αϊ ₂ CH ₂ -C-NH-(CH ₂ ) ₅ -N-C-CH ₂ CH ₂ -C-NH-(CH ₂ ) ₅ - -C-CH3 0 0 0 0 0

wherein the R groups are each acetyls, as intermedi- ates in the production of their focus compounds.

These references do not teach the use of tetra-acyl materials in body ion, e.g., iron, removal applications nor do they suggest that the tetra- or higher acyl materials either as pure isomers or as mixtures would be effective when orally administered in these applications.

U.S. Patents Nos. 3,118,823 and 3,153,621 are concerned with iron chelates of deferoxamine, which are used as growth factors. Additional refer¬ ences of interest in this art include Bickel, et al., Helvitica Chimica Acta, Vol. 43, pp. 2118 ff and 2129 ff, published in 1960; and V. Prelog and alser, Helvitica Chimica Acta, Vol. 45, pp 631 ff, published in 1962. Finally, D. E. Green and T. B. Okar a briefly reported on studies on the preparation of some tetra-acyl derivatives of deferoxamine and the bio¬ logical properties of these derivatives. (See Abstracts, 186th Annual American Chemical Society Meeting, August 28-September 2, 1983, Washington, D.C., Abstract No. MEDI 56.

Summary of the Invention

The present invention concerns a group of di-, tri-, tetra-, penta-, hexa- and hepta-acylated derivatives of deferoxamine, which are useful in the treatment of the diseases or conditions cited earlier. The invention is particularly useful in that its compounds are orally administered, absorbed from the digestive system into the body and cleaved to produce deferoxamine in the body.

In one aspect, this invention relates to compounds of the general formula:

I I I

R ₁ -N- ( CH ₂ ) ₅ - - -CH ₂ CH2-C-N- ( CH ₂ ) ₅ -N-C-CH ₂ CH ₂ -C-N- ( CH ₂ ) ₅ -N-C-CH3 j II II I II II I II

Rg 0 0 R ₇ 0 0 Rg 0

(I)

wherein :

R-i is an acyl of the formula R ₂ , R , R ₄ , Rg, R7 and Rg are each selected from the group consisting of hydrogen and acyls of the formula:

-C(=0)-R ₅ wherein R5 is independently selected for each from the group consisting of alkyls, substituted alkyls, alkenyls, substituted alkenyls, cycloalkyls, substitu¬ ted cycloalkyls., arylalkylenes, substituted aryl¬ alkylenes, alkylenecycloalkyls, alkylene substituted cycloalkyls, alkynyls, substituted alkynyls, aryls and substituted aryls. R ₂ R3 _* R4 Rg R7 and Rg are selected such that at least one of R ₂ , R , R ₄ , Rg, R ₇ and Rg is an acyl of the formula -C(=0)-R _c different than R-^ .

When R ₂ , R3, R4, Rg, R7 and R include one or more acyls of formula wherein Rg is not identical to the R ₅ of the acyl of R- _j _, these compounds of formula I are novel compounds and represent another aspect of this invention.

Compounds of formula I are prodrug forms of deferoxamine which liberate deferoxamine in the body to complex and/or chelate ions, such as iron and/or aluminum, for subsequent excretion when administered to a human being, and are therefore useful in therapy in the treatment of diseases in which ion, e.g. iron,

aluminum, levels in the body have elevated or toxic levels. These diseases for iron overload include, for example, thalassemia major, sideroachrestic anemia, Blackfan-Dia ond anemia, aplastic anemia, sickle cell anemia, hemolytic anemias and hemosiderosis brought about by multiple blood transfusions or such condition when brought about by treatment of an anemia found in kidney-damaged patients undergoing renal dialysis. Another aspect of the present invention relates to compounds of formula I as is described herein which liberate deferoxamine in the body to generally chelate any trivalent metal, such as iron, aluminum, chromium, gallium, ytterbium, indium and the like, for subsequent excretion, which is useful in the treatment of conditions (which is equivalent to diseases) in which the elevated levels of metal ion in the body cause or exacerbate disease conditions. The compounds of formula I are useful as oral pharmaceu¬ ticals in the treatment of Alzheimer's and related diseases in which elevated aluminum levels have been found in the body, particularly the brain. Diseases or conditions having elevated aluminum body levels also include senile dementia and dialysis encephalopathy. Thus other aspects of the invention concern pharmaceutical preparations incorporating the com¬ pounds of formula I, dosage forms thereof and methods of treatment of the aforementioned conditions employ¬ ing these preparations and/or dosage forms. Another aspect of this invention is a pro¬ cess for the preparation of the compounds of for¬ mula I, as is described in greater detail hereinafter.

Detailed Description of the Invention

Definitions

"Acyl" is defined to refer to a group having the structure, -(C=0)-Rg, wherein Rg is selected from the group consisting of alkyls, substituted alkyls, alkenyls, substituted alkenyls, cycloalkyls, substi¬ tuted cycloalkyls, arylalkylenes, substituted aryl¬ alkylenes, alkylenecycloalkyls, alkylene substituted cycloalkyls, alkynyls, substituted alkynyls, aryls and substituted aryls.

"Acylating agent" refers to a compound containing the group -(C=0)-Rc. which can react and insert an "acyl" into deferoxamine. Representative agents include, for example, acyl halides, acyl anhy- drides, mixed acyl anhydrides and mixtures thereof. When different acylating agents are employed herein they may include acylating agents which are in dif¬ ferent catagories, e.g., alkyl acyl (acetyl chloride) and alkenyl acyl (methacryloyl chloride) or may include different acylating agents within the same category (e.g., acetyl chloride and propionyl chlo¬ ride, etc.) or by substitution of one to three pro¬ tons, e.g., propionyl chloride and 2-chloropropionyl chloride. "Alkyl" refers to a branched or unbranched saturated hydrocarbon containing 1 to 25 carbon atoms, such as, for example, methyl, ethyl, n-propyl, i-pro- pyl, n-butyl, i-butyl, s-butyl, t-butyl, n-heptyl, i-heptyl, n-octyl, nonyl, decyl,. undecyl, tridecyl, pentadecyl, heptadecyl, pentacosanyl and the like.

"Substituted alkyl" refers to an "alkyl" group, wherein at positions on the linear or branched structure one to three protons have been replaced by a group such as alkoxyl or halogen.

"Alkenyl" refers to a linear or branched unsaturated hydrocarbon group containing from 2 to 25 carbon atoms, such as, for example, ethenyl, propenyl, butenyl (1- and 2-), isobutenyl, hexenyl, heptenyl, nonenyl, undecenyl, dodecenyl, nonadecenyl, cosenyl, pentacosenyl and the like.

"Substituted alkenyl" refers to an "alkenyl" where at positions on the linear or branched struc¬ ture, one to three protons have been replaced by a group such as alkoxyl or halogen.

"Cycloalkyl" refers to a cyclic alkyl struc¬ ture containing 3 to 25 carbon atoms. The cyclic structure may have alkyl substituents at any posi¬ tion. Representative groups include cyclopropyl, 4-methylcyclohexyl, cyclooctyl, cyclohexadecyl, cyclopentacosanyl and the like.

"Substituted cycloalkyl" refers to a "cyclo¬ alkyl" where at positions on the group, one to three protons have been replaced by a group, such as alkoxyl, alkyl or halogen.

"Arylalkylene" refers to a group containing an "aryl" attached through an "alkylene." Representa¬ tive groups include benzyl (phenyl ethylene) , phenyl- ethylene (phenethyl), phenyldecylene, naphthyl- methylene, naphthyl-2-methylethylene and the like.

"Substituted arylalkylene" refers to an "arylalkylene" containing a "substituted aryl" moiety. Representative groups include 2-methylphenyl- methylene, 4-chlorophenylethylene, 4-bromophenyl- propylene, 6-methoxynaphthylmethylene, 6-chloro- naphthyldecylene and the like.

"Alkylenecycloalkyl" refers to a group wherein the alkylene portion is a saturated hydro¬ carbon which contains 1 to 10 carbon atoms. One end

of which is attached to the -C(=0)- group and the other end of which is attached to a "cycloalkyl" group. Representative groups include ethylenecyclo- propyl, propylenecyclohexyl, 2-methylpropy- lenecyclodecyl, decylenecyσlopentacosanyl and the like.

"Alkylene substituted cycloalkyl" refers to an alkylenecycloalkyl having a "substituted cyclo¬ alkyl" moiety. Representative groups include methyl- ene-2-chlorocyclopropyl, ethylene-4-methylcyclohexyl, decylene-4-hydroxycyclodecyl, decylene-2-bromocyclo- pentacosanyl and the like.

"Alkynyl" refers to a branched or linear aliphatic hydrocarbon group having a -C ΞC- moiety which contains from 2 to 25 carbon atoms, such as for example, ethynyl, propynyl, isohexynyl, heptynyl, pentadecynyl, pentacosynyl and the like.

"Substituted alkynyl" refers to an "alkynyl" group, where at positions on the linear or branched structure, one to three protons have been replaced by a group such as alkoxy or halogen.

"Halo" or "halogen" refers to fluoro, c loro, bromo or iodo, usually as a substitutent replacing a hydrogen atom in an organic group. "Alkylene" refers to a saturated linear or branched hydrocarbon structure containing 1 to 10 carbon atoms which has two points of attachment to other functional groups. Representative "alkylenes" include methylene (-CH ₂ -), ethylene (-CH ₂ -CH ₂ ~), 2-methylpropylene [-CH ₂ -CH(CH ₃ )-CH ₂ ~], hexylene, decylene and the like.

"Aryl" refers to a carbon-containing aro¬ matic structure having 6 to 14 carbon atoms. Repre¬ sentative groups include phenyl, naphthyl, phenanthryl and the like.

"Substituted aryl" refers to an "aryl" ' wherein at 1 to 3 positions on the aromatic ring, one to three protons have been replaced by another group, such as alkyl, alkoxyl or halogen. The compounds of this present invention are generally named according to the IUPAC or Chemical Abstracts nomenclature. Thus, deferoxamine may be named N'-[5-t[4-[C-5-(acetylhydroxamino) pentyl]amino]-l,4-dioxobutyl]hydroxyamino]pentyl]-N- (5-aminopentyl)-N-hydroxybutanediamide; or N-[5-[3- C(5-aminopentyl)hydroxylcarbamoyl]propionamido]- pentyl]-3-[[5-(N-hydroxyacetamido)pentyl]-carbamoyl] propionohydroxamic acid; or l-amino-6,17-dihydroxy-7, 10,18,21-tetraoxo-27-(N-acetyIhydroxylamino)- 6,11,17,22-tetraazaheptaeicosane.

Because of the obvious complexity of the names for the substituted structures of deferoxamine, a shorthand form based upon the last written name above is used for the present invention. Therefore, the 1-amino group, when substituted by acyl (R-^-), is designated as N-acyl (-N-R- _j _). The hydroxamic acid hydrogen at the 6-position, when substituted by acyl (R ₂ -) is designated as O-acyl (-0-R ₂ ). The hydroxamic acid hydrogen at the 17-position, when substituted by acyl (R3-) is designated as O-acyl (-0-R3). And the hydroxamic acid hydrogen of the "27-(N-acetyIhydroxyl¬ amino) " when substituted by acyl (R4-) is designated as (-0-R4) . The second hydrogen on the 1-amino group and the hydrogens on the amide nitrogens at the 11 and 22 positions, when substituted by acyl, are also N- acyls designated by Rg(-N-Rg), R ₇ (-N-R ₇ ) and Rg(-N-Rg), respectively.

Thus in formula I, when R-^ is acetyl, and R ₂ , R3, and R ₄ are each n-octanoyl, the compound name

is N-acetyl-0,0,0-trioctanoyldeferoxamine. When R^ is isovaleryl, R ₂ is acetyl (i.e., Rg here is -CH3), R3 is butyryl (R ₅ here is -CH ₂ CH ₂ CH ₃ ) and R ₄ is n-octa- noyl [R ₅ here is -CH^CH^gC^], the compound name is N-isovaleryl-0,0,0-acetylbutyryl-n-octanoyldeferoxa- mine. If the a ino group or any combination of the hydroxamic acid groups are unsubstituted, the unsub- stituted position is designated as N-hydrogen (N-H) or -O-hydrogen (-O-H), respectively, reading R ₂ , R3, and R^, from left to right for the compound of formula I. In the compound when R-^ is acetyl, R ₂ » 3» R4, and Rg are each octanoyl and R7 and Rg are H, the compound is named N-acetyl-0,0,0,N,H,H-tetraoctanoyl- deferoxamine. In defining the size of organic groups, i.e., Rg- herein, "lower" groups (e.g., lower alkyl) contain 1 to 7 carbon atoms, "intermediate" groups (e.g., intermediate alkenyl) contain 8 to 15 carbon atoms, and "higher" groups (e.g., higher alkyl) contain from 16 to 25 carbon atoms.

Detailed Description and Presently Preferred Embodiments Although not understood with certainty, it appears that the best results are obtained when the total number of carbon atoms in the groups R-^, R ₂ , R3 Rg, R ₇ and R of formula I is between 10 and 60, preferably between 12 and 40, and especially between 14 and 30. Structures of formula I where the total of the carbon atoms in the groups R-^ , R ₂ # R3'/ ₄ » Rg 1 R7 and Rg are less than 9 have not yet achieved good results, perhaps because deferoxamine derivatives having these smaller acyls are not sufficiently absorbed through the membranes of the digestive tract.

Structures of formula I wherein the total of the carbon atoms of R^, R ₂ , R3, R ₄ , Rg, R and R is greater than 63 have not yet achieved good results, perhaps because the molecules are not sufficiently soluble in the fluids within the digestive tract to be absorbed into the body as the prodrug to be cleaved to produce deferoxamine.

The compounds of formula I, prepared according to the procedures described herein and which achieve good results in reducing the amount of tissue iron or aluminum in a human being, are found in Table I.

TABLE I

I I I

R _j _-»- ( CH ₂ ) ₅ -N-C-CH ₂ CH ₂ -C-N- ( CH ₂ ) ₅ -N-C-CH ₂ CH ₂ -C-N- ( CH ₂ ) 5-N-C-CH3

I II II I II il I ■■

*6 0 R ₇ 0 O Rg 0

DEFEROXAMINE DERIVATIVES

Compound Number of Carbon At Dins Group ^R l R ₂ R ₃ R ₄ ^R 6 ^R 7 ^R 8

1 2 3 3 3 0 0 0

1A 2 2 2 2 2 0 0

IB 2 2 2 2 2 0 2

1C 2 2 2 2 2 2 2

2 2 4 4 4 0 0 0 ■

3 2 5 5 5 - 0 0 0

4 2 6 6 6 0 0 0

5 2 7 7 7 0 0 0

6 2 8 8 8 0 0 0

6A 2 8 8 8 8 0 0

6B 2 8 8 8 0 0 8

6C 2 8 8 8 8 0 8

DEFEROXAMINE DERIVATIVES (Continued)

Compound Number of Carbon Atoms

Group ^R l R ₂ ^R 3 R ₄ ^R 6 ^R 7 ^R 8

6D 2 8 8 8 8 8 8

7 3 3 3 3 0 0 0

8 3 4 4 4 0 0 0

9 3 5 5 5 0 0 0

10 3 6 6 6 0 0 0

11 3 8 8 8 0 0 0

12 4 3 3 3 0 0 0

13 4 4 4 4 0 0 0

14 4 5 5 5 0 0 0

15 4 6 6 6 0 0 0

16 4 8 8 8 0 0 0

17 5 3 3 3 0 0 0

18 5 4 4 4 0 0 0

19 5 5 5 5 0 0 0

20 5 6 6 6 0 0 0

21 5 8 8 8 0 0 0

22 6 3 3 3 0 0 0

23 6 4 4 4 0 0 0

24 6 5 5 5 ^• 0 0 0

25A 6 5 5 5 5 0 0

20 6 6 6 6 0 .0 0

27 6 8 8 8 0 0 0

28 7 3 3 3 0 0 0

29 7 4 4 4 0 0 0

30 7 5 5 5 0 0 0

31 7 6 6 6 0 0 0

32 7 7 7 7 0 0 0

33 8 3 3 3 0 0 0

34 8 4 4 4 0 0 0

35 8 5 5 5 0 0 0

36 8 6 6 6 0 0 0

37 8 8 8 8 0 0 0

37A 8 8 8 8 8 0 0

37B 8 8 8 8 8 0 8

37C 8 8 8 8 8 8 8

Preferred compounds of formula I found in the "Compound Groups" in Table I are those compounds wherein in R , Rg is alkyl, and R ₂ , R3, R ₄ , Rg, R7 and RQ are independently selected from hydrogen or acyl of the formula -(C=0)-Rg, where Rg is independently

selected for each from alkyl groups. More preferred are the lower alkyl groups. Especially preferred are those compounds where Rg, R and Rg are hydrogen. Preferred compounds are those wherein R , Ry and Rg are hydrogen. Preferred groups include Compound

Groups 1A, 7, 13, 19, 26, 32, 37, 37A, 373 and 37C wherein R- _j _, R ₂ , R3, R , Rg, R7 and Rg each contain the same number of carbon atoms or hydrogen. More preferred are those groups wherein Rg is alkyl, particularly lower alkyl and especially where Rg is the same alkyl group. These compounds where Rg is alkyl are preferred to be orally administered to treat the iron and aluminum related diseases described herein. Preferred compounds of formula I also include those wherein up to five of R ₂ , R3, R ₄ -, Rg» R7 and Rg are hydrogen, more preferably the hydrogens are found on positions Rg, R7 and Rg. See, for example, Table II.

TABLE II

R _χ -N-(CH ₂ )g-N-C-CH ₂ CH ₂ -C-N-(CH ₂ )g-N-C-CH ₂ CH ₂ -C-N-(CH ₂ )5-N-C-CH3 Rg 0 O R7 O O Rg O

DEFEROXAMINE DERIVATIVES

Compound Number of Carbon Atoms ^a

Group R± R ₂ R ₃ R ₄ Rg R7 Rg

1 2 8 8

1A 2 8 8 0 8 0 0

IB 2 8 8 0 8 0 8

2 2 8 0 8 0 0 0 3 2 0 8 8 0 0 0

4 2 0 0 8 0 0 0

5 2 0 8 0 0 0 0

6 2 8 0 0 0 • 0 0

^' 7 4 4 4 0 0 0 0 8 4 6 0 6 0 0 0

9 4 0 8 8 0 0 0

10 5 5 5 0 0 0 0

11 5 0 6 6 0 0 0

12 6 6 6 0 0 0 0 13 6 5 5 . 0 0 0 0

14 6 8 8 0 0 0 0

15 8 8 8 0 0 0 0

16 8 8 0 8 0 0 0

17 8 0 8 8 0 0 0 17A 8 8 0 8 8 8 0

17B 8 8 8 0 8 0 8

17C 8 8 0 8 8 0 0

18 8 4 4 0 0 0 0

19 8 5 5 0 0 0 0 20 8 6 6 0 0 0 0

20A 8 6 6 0 6 0 0

20B 8 6 0 6 6 0 6

21 6 4 0 4 0 0 0

22 5 4 0 4 0 0 0 23 4 5 0 5 0 0 0

24 3 3 3 0 0 0 0

25 3 4 4 0 0 0 0

26 3 5 0 5 0 0 0

27 3 4 0 4 0 0 0

DEFEROXAMINE DERIVATIVES ( Continued)

Compound Number of Carbon Atoms ^a

Group ^R l R ₂ ^R 3 ^R 4 ^R 6 R ₇ ^R 8

28 2 4 0 4 0 0 0

29 2 5 5 0 0 0 0

30 2 6 0 6 0 0 0

a. When the carbon atom number is 0, the group Rn /

^R 3' ^R 4' Rg/ R7 and ^R 8 contains 0 carbon atoms, and is a hydrogen (-H). Because of the present difficulty of sepa¬ rating some of the isomers of the products described in Table I and Table II, this invention includes mix¬ tures of compounds which would normally be expected in the reaction products described in the examples below. For instance, if an excess of acylating agent is used as shown in Table I, then a mixture of compounds such as 6, 6A, 6B, 6C and 6D may be present. If in the Compound Group in Table II, • numbers 15, 16, 17, 17A, 17B and 17C are present as reaction products of the acylation of deferoxamine using a limited amount of R- _j _=8 [(i.e., Rg=7 carbon atoms) acylating agent], then the mixture of isomers may be used in therapy. These mixtures of isomers may be separated by, e.g. high pressure liquid chro a- tography or may be used in a pharmaceutical composition or method of treatment as a mixture of 2 or more isomers.

Presently preferred embodiments of the present invention as a oral pharmaceutical compositions and method of treatment, include those compounds of formula I wherein R^, R ₂ , R3, R ₄ , Rg, R7 and Rg are hydrogen or identical alkyl acyl groups, especially lower alkyl acyls. Especially preferred are those compounds where acyl is -C(=0)-Rg, and Rg is n-propyl, n-butyl, t-butyl, n-pentyl, n-hexyl or n- heptyl.

Another embodiment of the present invention includes those compounds of formula I as described herein, except that when R-^ is acyl of formula -C(=0)-Rg and Rg is alkyl, R ₂ , R3, R ₄ , Rg, and Rg as a group are hydrogen or are not each an acyl of formula -C(=0)-Rg wherein Rg is the identical alkyl of

^R l-

A preferred compound is where R-^ is acetyl,

R ₂ , R ₃ and R ₄ are each acyl where Rg is n-heptyl; and two of Rg, R7 and Rg are hydrogen and the other is acyl where Rg is n-heptyl.

Another embodiment of the present invention includes those compounds of formula I as described herein, except that when R- _j _ is acyl of formula -C(=0)-Rg and Rg is alkenyl, R ₂ / R3 R ₄ » Rg, R7 and R 8, as a group are not each acyl of formula -C(=0)-Rg wherein Rg is the identical alkenyl of R- _j _ _^

Especially preferred embodiments of the present invention also include those compounds of formula I wherein R-^ is acetyl and R ₂ , R , R ₄ , Rg, R7 and Rg are independently selected from hydrogen and acyl: -(C=0)-Rg, wherein each Rg is alkyl, particularly lower alkyl, especially propyl, i-butyl, t-butyl or n-heptyl. Additional preferred embodiments include those compounds of formula I wherein R- _j _ is -C(=θ)-Rg wherein Rg is intermediate alkyl, and R ₂ , R3, and ₄ are -C(=0)-Rg wherein Rg in each is lower alkyl. A particularly preferred embodiment is the compound where Rn is -(C=0)-Rg and Rg is undecyl, and R ₂ , R ₃ , and R ₄ are each -C(=0)-Rg wherein Rg is propyl.

Preferred compounds of the embodiments of formula I described above for a pharmaceutical composition and for a method of treatment of ion, e.g. iron or aluminum, overload diseases are those where _R6 , R7 and R8 ^{are each} hydrogen.

An additional embodiment of the present invention describes a pharmaceutical composition useful for treating one or more diseases or conditions in a human being, related to excess iron in the blood and/or tissue, which comprises using a therapeutically effective amount of a compound of formula I in admix¬ ture with a pharmaceutically acceptable excipient. Preferred embodiments include the pharmaceutical com¬ position containing the compound of formula I wherein R_, R ₂ , R3, R ₄ , Rg, R7 and Rg are identical acyl groups or hydrogen. Particularly preferred are those compounds containing 2 to 8 carbon atoms in each acyl, especially, acyls of the formula -C(=0)-Rg, where Rg is lower alkyl as is defined herein. Additional preferred embodiments include the pharmaceutical compositions including the compound of formula I wherein R-, is one acyl group- of the formula -C(=0)-Rg containing 2-8 carbon atoms, particularly lower alkyl; and ₂ =R ₃ =R ₄ and Rg=R ₇ =R are all hydrogen or a different acyl group of the formula -C(=0)-Rg wherein Rg contains 1 to 7 carbon atoms, particularly where Rg is lower alkyl. Preferred compounds include those where R-^ is acetyl and ^R 2 ^=R 3 ^=R 4 ^wnere 5 i ^s ethyl, n-propyl n-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, or n-heptyl and Rg, R and Rg are hydrogen. Especially preferred compounds are N-acetyl-0,O,O-tri-n-octanoyldeferoxamine and N-acetyl-0,0,O,N,H,H-tetra-n-octanoyldeferoxamine. An additional embodiment of the present invention describes a method of tre ^' ating a disease or condition in a human being, related to excess iron in the blood and/or tissue which method comprises admin¬ istering to a subject in need of such treatment a therapeutically effective amount of the compound of formula I. Preferred embodiments include the method involving the compound of formula I wherein Ri, R _2/

R ₃ , and R are identical acyl groups. Particularly preferred are those compounds containing 2 to 8 carbon atoms per acyl, especially, acyls of the formula -C(=0)-Rg, where Rg is lower alkyl as is defined herein. Additional preferred embodiments include the pharmaceutical composition including the compound of formula I wherein R-^ is one acyl group of the formula -C(=0)-Rg containing 2-8 carbon atoms; and

^R 2 ^=R 3 ^=R 4 ^=R 6 ^=R 7 ^=R 8 ^are ^ hy ^dr °9 ^{en or a} different acyl group from R-^ of the formula -C(=θ)-Rg wherein Rg contains 1 to 7 carbon atoms, particularly where Rg is lower alkyl. Preferred compounds include those where R- is acetyl and R ₂ =R ₃ =R ₄ =Rg=R ₇ =Rg where Rg is ethyl, n-propyl n-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl or n-heptyl. An especially preferred compound is N-acetyl-0,0,O-tri-n-octanoyldeferoxamine.

Still another embodiment of the present invention describes a process for the preparation of the compounds of formula I which process comprises contacting the unsubstituted deferoxamine wherein R- _j _, R , R3, R ₄ , Rg, R7 and Rg are each hydrogen with a suitable acylating agent in the presence of a strong base having a pK of about 9 to 11, treating the product with a weak base to form the N-acyl-0,0,0- trihydrogendeferoxamine; and treating this material with an excess of one or more different acylating agents to form the compound of formula I. In a preferred embodiment the first suitable acylating agent is R ₅ -C(«0)-X or Rg-(C=0)OC(C=0)-Rg where Rg contains 1 to 7 carbon atoms and X is halogen; the weak base has a pK _b value of about 4 to 6; and the second different acylating agent is Rg-C(=θ)-X or

R ₅ (C=O)OC(C=0)R ₅ wherein R5 contains 1 to 7 carbon atoms and X is halogen. A particularly preferred embodiment is the process wherein Rg of the first acylating agent contains one carbon atom; the weak

base is ammonia; and in the different acylating agent Rg contains 4 to 7 carbon atoms. An especially pre¬ ferred embodiment is the process wherein the first acylating agent is acetyl chloride or acetic anhy- dride; the base is anhydrous ammonia; and the different acylating agent is octanoyl chloride. The reaction products of formula I may be separated using HPLC or equivalent means.

Process for Preparation In Reaction Sequence 1, deferoxamine (la), as described by M. Windholz, _E<1. in The Merck Index, published by Merck Co., Inc. of Rahway, New Jersey in 1976 (p. 374), is used as a starting material.

REACTIQN SEQUENCE 1

O-H O-H O-H

H-NH-(CH ₂ ) ₅ -N-C-CH ₂ CH ₂ -C-NH-(CH ₂ ) ₅ -N-C-CH ₂ CH ₂ -C-NH-(CH ₂ ) _S -N-C-CH ₃

0-R2-, O ^U - ^_ R ^Λ 3, O ^u -R ^Λ .

R _L -NH-{CH ₂ ) ₅ -N-C-CH ₂ CH ₂ -C-NH-(CH ₂ ) ₅ -N-C-CH ₂ CH ₂ -C-NH-(CH _j ) ₅ -N-C-CH ₃

(lb)

Step 2 NH,

O-H O-H O-H

RJI-NH-(CH ₂ ) ₅ -N-C-CH ₂ CH ₂ -C-NH-(CH ₂ ) ₅ -N-C-CH ₂ CH ₂ -C-NH-(CH ₂ ) ₅ -N-C-CH ₃

St

R _χ -N-(CH ₂ ) ₅ -N-C-CH ₂ CH ₂ -C-N-(CH ₂ ) ₅ -N-C-CH ₂ CH ₂ -C-N-(CH ₂ )5-N-C-CH3

R ₆ 0 ^' 0 R ₇ 0 0 R8 °

⁽ I ⁾

In Step 1, deferoxamine (la) is treated with an excess of acyl anhydride, and 3 ₂ 0, in the presence of the alkaline salt of the anhydride in an alcoholic solvent. After about 12 to 24 hours, the solvent and acyl acid are removed under reduced pressure to yield lb. Rg, ^ _Q and R^ independently may be the same or different groups as is described herein for Rg. Thus anhydrides Rg-C(=0)- X, R ₁₀ -C(=0)-X and R ₁₁ -C(=0)-X as acyl halides may replace the corresponding anhydride and may be used alone or as a mixture to acylate deferoxamine. If these procedures are used, then it is possible to convert compound of formula la to the compound of formula I in one step. [See Example 4 (m) and 6 (m) below.] The reaction product is a mixture which may be used, as a mixture, as a pharmaceutical agent, as is described herein. On the other hand, the products may be separated by methods described herein below and used separately. Alternatively, deferoxamine (la) may be tetra- up to and including hepta-acylated using an acyl halide. Deferoxamine is suspended in a solution of water/solvent (i.e., water/dioxane, about 50/50) and the pH is adjusted to about 9 using a strongly basic solution, preferably 4 to 7N sodium hydroxide. In small portions, the acyl halide in a solvent, such as dioxane, is added dropwise keeping the pH at about 9. Water and a chlorinated solvent, such as chloro¬ form, may be needed to keep the reactants in solu- tion. Strong agitation of the reaction mixture is necessary. The dioxane (and chloroform) phase is removed, washed, dried and removed in vacuo to produce a mixture of compounds of formula lb and (I) . Step 1 and Step 3 below, using acyl halide are often referred

to as the Schotten-Baumann reaction, which is described in the art.

In Step 2, the compound of formula Ic is obtained by dissolving the N-acyl-θ,0,0-triacyl (to hepta-acyl) product of formula lb in an excess of an ethereal alcoholic solvent, such as methanol, and cooling to about -20°C to +20°C, preferably about 0°C, the reaction mixture is subsequently saturated wit a base, preferably gaseous ammonia. After maintaining the reaction mixture at about -20°C to +20°C, preferably at ambient temperature, and allowed to stir for about 24 to 48 hours, the solvent is decanted and the product, usually as a solid, is recovered, washed twice with boiling hexane, and the resulting solid is and dried under reduced pressure. After recrystal- lization from alcohol/water solution, the product is recovered and air dried.

In Step 3, compound Ic is suspended in a solution of water/solvent (i.e., water/chloroform about 50/50). The solution is adjusted to about pH of 9 using strong base, preferably 3-7N sodium hydroxide solution. To this mixture is added dropwise a solu¬ tion of the acyl halide, preferably the chloride, in a solvent such as chloroform. The pH of the solution is ^' continuously monitored and is maintained at pH of 9. The layer of chlorinated solvent is removed, washed, dried, filtered, and evaporated in vacuo to produce an oily or waxy product, the compound of formula I.

Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extrac¬ tion, crystallization, column chromatography, high pressure liquid chromatogrophy (HPLC) , thin-layer

chromatography or thick-layer chromatography, dry column chromatography or a combination of these procedures. Specific illustrations of suitable separation and isolation techniques can be had by reference to the examples herein below. Other equivalent separation or isolation procedures, however, could also be used.

In the preparation of the mixture of compounds of formula I, separation, purification, and identification of the fully acylated or 49 possible partially acylated derivatives of deferoxamine is difficult, uneconomic and sometimes impossible with present separation techniques. Therefore, this invention includes mixtures of compounds of formula I wherein the groups, _{l t} R ₂ , R3, R , Rg, R and Rg are hydrogen or acyl as. is defined and as limited above. -The mixture of isomers- is administered as part of a pharmaceutical composition to a person in the same manner that an essentially pure compound of formula I would be administered.

Although not known with certainty, it appears that of the N-acylated groups Rg, R7, and Rg, N-Rg is formed first because it is the least steri- cally hindered of the three available amides. However, it is to be understood that with present analytical techniques, it is not known with certainty which isomer(s) of the derivatives N-Rg, N-R7 and N-Rg is present.

The acyl halides and anhydrides, solvents, reagents and the like described herein are available according to Chemical Sources, published by Directories Publishing Company, Inc., Flemington, New Jersey in 1979. Those halides or anhydrides not available are prepared according to methods known or

adapted from the art, see for example, R. Morrison and R. Boyd, Organic Chemistry, 3rd ed., published by the Benjamin Co. in 1976.

Utility And Administration Administration of the compounds of this invention can be via any of the accepted modes of administration for therapeutic agents. These methods include oral, parenteral, transdermal, subcutaneous and other systemic modes. The preferred method of administration is oral.

Depending on the intended mode, the composi¬ tion may be in many forms, for example, solid, semi- solid, or liquid dosage forms, including tablets, time release agents, pills, capsules, suspensions, solu- tions and the like. The compositions will include a conventional pharmaceutical excipient and an active compound of formula I or the pharmaceutically accep¬ table salts thereof and may, in addition, include other medicinal agents, pharmaceutical agents, car- riers, adjuvants, diluents, etc.

The amount of the active compound of formula I administered will, of course, be dependent on the molecular weight of selected compound, the subject being treated, the subject's weight, the severity of the affliction, the manner of the administration and the judgment of the prescribing physician. However, an effective dose is in the range of about 25-200 mg/kg/day, preferably about 125 mg/kg/day. For an average 70 kg human, those dosages would amount to about 1.5 to 14 g/day, or preferably about 9 g/day.

For solid compositions, conventional non- toxic solids include for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stea-

rate, cellulose and the like may be used. Liquid pharmaceutically administratable compositions can be prepared by dissolving, dispersing, etc., a compound of formula I and optional pharmaceutical adjuvants in an excipient, such as, for example, water, glycerol, ethanol, vegetable oil and the like to form a suspension.

Actual methods of preparing such dosage forms are known, or will be apparent to those skilled in the art; see, for example. Remington' s

Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 15th Edition, 1975.

The following preparations and examples serve to illustrate the invention. They should not be construed as narrowing it, nor as limiting its scope.

EXAMPLE 1

Preparation of N-Acetyl 0,0,0-triacetyldeferoxamine

(a) Deferoxamine mesylate (13.1g) and 1.66g of anhydrous sodium acetate are dissolved in 200 ml of methanol. The methanol solution is boiled to complete the solution. The reaction mixture is then rapidly cooled to ambient temperature and treated immediately (before crystallization starts) with 180 ml of acetic anhydride. The mixture is maintained overnight (about 16 hrs) in the absence of moisture and then concentra¬ ted under vacuum to produce an oily residue. This residue is freed from acetic acid by evaporation under vacuum using two portions of 200 ml of butanol. The oily residue is air dried for several days to produce 14.lg of crude N-acetyl-0,0,O-triacetyldeferoxamine. The proton magnetic resonance spectrum of the recrystaliized product is consistent with this

structure; [structural unit, parts per million (ppm) downfield from tetramethysilane (TMS) reference]: (for C-H absorption): -N-C-C-CH ₂ -C-C-N-0-: 1.44 -N-C-C-C-CH ₂ -C-N-0-: 1.52;

-N-C-CH ₂ -C-C-C-N-0-: 1.58; CH ₃ -C(=0)-N-(0C0-C-); 1.95; CH ₃ -C(=0)-NH-C-C-C-; 1.99 -C-C(=0)-N-(0-CO-CH ₃ ); 2.17; -N-C(=0)-CH ₂ -CH ₂ -(C=0)-N-; 2.56;

-C-C-CH ₂ -N(-0)-(C=0)-; 3.22; -C-(C=0)-NH-CH ₂ -C-; 3.70; and (for the N-H absorption): -C-C(=0)-NH-C-C-; 6.28. (b) Similarily proceeding as in Subpart (a) above but substituting a stoichiometrically equivalent amount of propionyl anhydride; butyryl anhydride; valeryl anhydride; isovaleryl anhydride; octanoyl anhydride; dodecanoyl anhydride; palmitoyl anhydride; stearoyl anhydride; or hexacosanoyl anhydride instead of acetic anhydride, there is obtained the corresponding

N-propionyl-0,0,0-tripropionyldeferoxamine; N-butyryl-0,0,0-tributyryldeferoxamine;

N-valeryl-0,0,O-trivaleryldeferoxamine; N-isovaleryl-0,0,0-triisovaleryl- deferoxamine;

N-octanoyl-0,0,O-trioctanoyldeferoxamine;

N-dodecanoyl-0,O,O-tridodecanoyl- deferoxamine;

N-palmitoyl-0,O,O-tripalmitoyldeferoxamine;

N-stearoyl-0,0,0-tristearoyldeferoxamine; or N-hexacosanoyl-0,O,O-tri(hexacosanoyl)- deferoxamine.

It is often necessary to employ larger volumes of solvents to keep the substituted deferox¬ amine in solution and to obtain more complete acyla- tion of the three hydroxamic acids.

(c) Similarily, when proceeding as in Subpart (a) above but substituting less than a stoichiometrically equivalent amount of the acyl anhy¬ dride, there is obtained a compound wherein the N-acyl group is formed and a mixture containing less than complete acylation of the hydroxamic acid groups of deferoxamine. Such mixtures when acetic anhydride is used include the following compounds:

N-acetyl-O,0,O-hydrogendiacetyldeferoxamine and

N-acetyl-0,0,0- dihydrogenacetyldeferoxamine.

The exact positions of the acetyl and hydrogen groups on the hydroxamines is not yet established. (d) Similarily proceeding as in Subpart (a) above but substituting a stoichiometrically equivalent amount of a mixture of the following anhydrides: acetic anhydride, propionic anhydride, and butyric anhydride; or acryloyl .anhydride, acetic anhydride, propionic anhydride, and butyric anhydride instead of acetic anhydride, there is obtained a mixture of corresponding tetraacyl derivatives including:

N-acetyl-O,0,0- acetyIpropionylbutyryldeferoxamine;

N-butyryl-0,0,0- acetylpropionylbutyryldeferoxamine; and N-propionyl-0,0,0- butyrylpropionylacetyldeferoxamine; or

N-acryloyl-0,0,0- acetyIpropionylbutyryldeferoxamine;

N-acetyl-0,0,0- butyrylpropionylacryloyldeferoxamine; and

N-butyryl-0,0,0- acryloylpropionylacetyldeferoxamine The exact positions of the acyl groups on the hydroxamines is not yet established with certainty.

EXAMPLE 2

Preparation of N-Ac ^' etyl-0,0,0-trihydrogendeferoxamine

(a) N-Acetyl-0,0,0-triacetyldeferoxamine (prepared in Example 1) (10.0 g) is taken up in 200 ml of methanol and 500 ml of ether, cooled to 0°C, and the solution is saturated with anhydrous gaseous ammonia. The reaction mixture is kept at 0°C for 6 hr, and then at ambient temperature overnight (about 16 hr). The ammonia-containing methanol/ether is decanted and the resulting colorless crystalline solid is washed twice with boiling hexane and is dried in vacuum, crude yield 8.1 g. After two recrystalliza- tions using methanol/water (60/40), there are obtained about 7.0 grams of N-acetyl-0,0,0-trihydrogendeferox¬ amine, m.p. 179-181°. The infrared spectrum and pro- ton magnetic resonance spectrum are consistent with the structure.

(b) Similarily, proceeding as in Subpart (a) of this Example, but substituting a stoichiomet¬ rically equivalent amount of:

N-propionyl-0,0,0-tripropionyldeferoxamine; N-butyryl-0,0,0-tributyryldeferoxamine;

N-valeryl-0,0,O-trivaleryldeferoxamine;

N-octanoyl-0,0,O-trioctanoyldeferoxamine;

N-ρalmitoyl-0,0,0,-tripalmitoyldeferoxamine; or N-pentacosanoyl-0,O,0-tripentacosanoy1- deferoxamine instead of the N-acetyl-O,0,0- triacetyldeferoxamine, there is obtained the corresponding

N-propionyl-0,0,0-trihydrogendeferoxamine; N-butyryl-0,0,0-trihydrogendeferoxamine;

N-valeryl-0,0,0-trihydrogendeferoxamine;

N-octanoyl-0,0,0-trihydrogendeferoxamine;

N-palmitoy1-0,0,0-trihydrogendeferoxamine; or N-pentacosanoyl-0,0,0- trihydrogendeferoxamine.

EXAMPLE 3

Preparation of N-Acetyl-0,0,0- tripalmitoyldeferoxamine

(a) N-Acetyl-0,0,0-trihydrogendeferoxamine

(from Example 2) (6.0 g) is suspended in a solution of 40 ml of water and 50 ml of dioxane. The well-agita¬ ted suspension is adjusted to pH of 9 using 5N sodium hydroxide solution. To this mixture is added in 10 ml portions, a solution of 16.5 g of palmitoyl chloride in 60 ml of dioxane. The pH of 9 of the mixture is maintained by the addition of a 5N sodium hydroxide

solution after each 10 ml portion of the acyl chloride solution. After 40 ml of the palmitoyl chloride solu¬ tion are added, 50 ml of water and 200 ml of chloro¬ form are added to facilitate the mixing of the solu- tion. After the addition of the palmitoyl chloride solution is completed, the reaction mixture is stirred for 1 hr, with periodic monitoring to maintain a pH of 9. The reaction mixture is then diluted with 150 ml of water and 500 ml of chloroform, and centrifuged to separate the phases. The white material present at the liquid interface is discarded. [The aqueous phase is separated and extracted twice with 250 ml of chloroform. Essentially no product is obtained upon removal of the chloroform.] The chloroform phase contained a white solid which is removed using addi¬ tional centrifugation. The combined chloroform layers are washed twice with saturated so'dium bicarbonate solution, twice with saturated sodium chloride solu¬ tion, dried over anhydrous sodium sulfate, filtered and evaporated using reduced pressure. About 14 g of a crude, creamy white waxy solid is obtained which is highly soluble in chloroform. The waxy solid was triturated twice with 100 ml of ether to remove the palmitic acid formed. The insoluble residue, 11.8g, was recrystallized from methanol/ethanol (3/1). The solid is air dried to produce 6.1g of solid N-acety1- 0,0,0-tripalmitoyldeferoxamine. The nuclear magnetic resonance spectrum is consistent with the structure.

EXAMPLE 3A °

Preparation of N-Acetyl -0, 0, Q hl.l+ _f ti tetraoctanoyldeferoxamine - i≠

(a) N-Acetyl-0,O,O-trihydrogendeferoxamine (from Example 2) (3.0 g) is suspended in a mixture of 100 ml of water and 150 ml of chloroform. The suspension is adjusted to pH 9 using 5N sodium hydroxide. To the well-agitated mixture is added dropwise, over a period of 45 min, a solution of 7.3 g octanoyl chloride in 50 ml of chloroform. The mixture is continuously maintained at pH 9 by the addition of 5N sodium hydroxide as necessary. After the addition of the octanoyl chloride is completed, the reaction mixture is stirred for 1 hr, with periodic monitoring to maintain a pH of 9. The chloroform phase is removed and the aqueous phase is extracted two times - with 100 ml of chloroform, centrifuging to break the emulsion when necessary. The combined chloroform layers are washed twice with saturated sodium bicarbonate solution, twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The syrupy residue is triturated twice with 50 ml of ether to remove the octanoic acid formed. The insoluble residue (2.6 g) is dissolved in dichloromethane and fractionated by HPLC.

Four main fractions are obtained at the following retention times: 2.4 min (11% relative abundance), 3.4 min (29%), 4.7 min (15%) and 7.0 min (40%) using a 5 micron silica-CN column and a methanol gradient from 2% to 5% over 12 min in a mixture containing 25% chlorobutane and iso-octane at a flow rate of 2 ml/min.

Fr action number 3 (4.7 min) ( amounting to 313 mg) was determined by 300 MHz NMR to be N-acetyl- 0, 0 , O-tetraoctanoyl-N-octanoyldef eroxamine . Fraction number 4 ( 7.0 min) ( amounting to 799 mg ) was determined by 300 MHz NMR to be N-acetyl-0, 0, 0- trioctanoyldef eroxamine . The 300 MHz proton nuclear magnetic resonance (NMR) spectral results are shown below in Table III .

TABLE III

, Proton NMR Results

^■ Ab-aUl]5- Fract. 3 Fract. 4 _nι«a Assignment Actual Theory Actual Theory

0.9 CH3-(CH ₂ )5- 12. 12. 9. 9.

3.3 -N-CH^-C 4.6 6. 6.9 6.

3.7 (O^-N-CH^-C 9. 6. 7.7 6. (proton total) 108.6 106. 99.2 92. a - ppm from tetramethylsilane (TMS) as reference.

(b) Similarly, proceeding as is described in Subpart (a) above of this Example using HPLC separation there is obtained:

N-acety 1-0, 0,0,N,H,N-pentaoctanoyl deferoxamine; and N-acety l-0 , 0 , 0 , N , N , N-hexaoctanoyl deferoxamine .

EXAMPLE 4 Preparation of N-Octanoyl-O,O,O - trioctanoyldeferoxamine (Step 1, Schotten-Baumann conditions)

(a) Deferoxamine mesylate (6.0g) is sus¬ pended in 50 ml of water and 50 ml of dioxane. The suspension is adjusted to pH of 9 using 5N sodium hydroxide solution with strong agitation. In 10 ml portions, a solution of 13.0 g of octanoyl chloride in 60 ml of dioxane. The pH of the mixture is maintained at 9 by the dropwise addition of the 5N sodium hydrox¬ ide solution. After the addition of 40 ml of the octanoyl chloride/dioxane solution, the reaction mix¬ ture is treated with 50 ml of water and 200 ml of chloroform. The mixture separates into two phases which are agitated strongly. After the addition o.f all the acid chloride solution, the reaction mixture is agitated for 2 hr at pH of 9. The reaction mixture is diluted with 500 ml of water and 1000 ml of chloro- form and the aqueous phase is separated and extracted twice using 250 ml portions of chloroform. The com¬ bined chloroform phases are washed twice with satura¬ ted sodium bicarbonate solution, twice with saturated sodium chloride solution and dried using anhydrous sodium sulfate. The chloroform is removed under reduced pressure, and the waxy -residue is dissolved in 500 ml of diethyl ether and hexane was added almost to turbidity. A sticky, granular product weighing 3.8g is obtained. The infrared and proton magnetic reso- nance spectra are consistent with a structure of N-octanoyl-0,0,O-trioctanoyldeferoxamine.

(b) Similarily, proceeding as in Subpart (a) above, but substituting a stoichiometrically equivalent amount of

acetyl chloride; propionyl chloride; butyryl chloride; pi alyl chloride; valeryl chloride; isovaleryl chloride; dodecanoyl chloride; palmitoyl chloride; or hexacosanoyl chloride instead of octanoyl chloride, there is obtained the corresponding

N-acetyl-0,0,0-triacetyldeferoxamine; N-propionyl-0,O,O-tripropionyldeferoxamine; N-butyryl-O,0,0-tributyryldeferoxamine; N-pivalyl-0,O,O-tripivalyldeferoxamine; N-valeryl-0,O,O-trivaleryldeferoxamine;

N-isovaleryl-0,0,0-triisovaleryl- deferoxamine;

N-dodecanoyl-0,O,O-tridodecanoyl- deferoxamine; N-palmitoyl-0,0,0-tripalmitoyldeferoxamine; or

N-hexacosanoyl-O,O,O-trihexacosanoy1- deferoxamine.

(c) Similarily, proceeding as in Subpart (a) above, but substituting a stoichiometrically equivalent amount of

3-chlorobutanoyl chloride; 3-chloroisovaleryl chloride; 10-chlorooctadecanoyl chloride; 10-methoxyoctadecanoyl chloride;

9,10-dichlorooctadecanoy1 chloride; 9,10-dibromooctadecanoyl chloride; or 9, 10-dimethoxyoctadecanoyl chloride;

instead of octanoyl chloride, there is obtained the corresponding

N-(3-chlorobutanoyl)-O,0,O-tri- (3-chlorobutanoyl)deferoxamine; N-(3-chloroisovaleryl)-O,O,O-tri(3- chloroisovaleryl)deferoxamine;

N-(10-chlorooctadecanoyl)-O,0,O-tri(10- chlorooctadecanoyl)deferoxamine;

N-(1O-methoxyoctadecanoyl)-O,O,O-tri(10- methoxyoctadecanoyl)deferoxamine;

N-(9,10-dichlorooctadecanoyl)-O,O,O- tri(9,10-dichlorooctadecanoyl)deferoxamine;

N-(9,10-dibromooctadecanoyl)-O,O,O-tri( ,10- dibromooctadecanoyl)deferoxamine; or N-(9,10-dimethoxyoctadecanoyl)-O,O,O- tri(9,10-dimethoxyoctadecanoyl)deferoxamine.

(d) Similarily proceeding as in Subpart (a) above, but substituting a stoichiometrically equivalent amount of acryloyl chloride;

2-butenoyl chloride;

2-pentenoyl chloride;

2-octenoyl chloride; oleoyl chloride; or 2-pentacosenoyl chloride instead of octanoyl chloride, there is obtained the corresponding

N-acryloyl-0,O,O-triacryloyldeferoxamine;

N-2-butenoy1-0,O,O-tri(2-butenoyl)- deferoxamine;

N-2-pentenoyl-O,O,O-tri(2-pentenoyl)- deferoxamine;

N-2-octenoyl-O,O,O-tri(2-octenoyl)- deferoxamine;

N-2-oleoyl-O,O,O-trioleoyldeferoxamine; or N-2-pentacosenoyl-O,0,O-tri(2-pentacosenoyl)- deferoxamine.

(e) Similarily proceeding as in Subpart (a) above, but substituting a stoichiometrically equivalent amount of

2-chloroacryloyl chloride; 2-chloropropenoyl chloride; 4-methoxybutenoyl chloride; 2-chlorooctenoyl chloride;

2-chlorooleoyl chloride; or 2-chloropentacosenoyl chloride, instead of octanoyl chloride, there is obtained the corresponding N-2-chloroacryloyl-0,0,O-tri(2- chloroacryloyl)deferoxamine;

N-(2-chloropropenoyl)-O,0,O-tri(2- chloropropenoyl)deferoxamine;

N-(4-methoxybuteno 1)-O,0,0- ri(4- methoxybutenoyl)deferoxamine;

N-(2-σhlorooctenoyl)-O,O,O-tri(2- chlorooctenoyl)deferoxamine; or

N-(2-chloropentacosenoyl)-0,0,O-tri(2- chloropentacosenoyl)deferoxamine. (f) Similarily proceeding as in Subpart (a) above, but substituting a stoichiometrically equivalent amount of cyclopropylacetyl chloride; cyclobutylacetyl chloride; cyclohexylpropanoyl chloride; cyclodecyldecanoyl chloride; or cyclopentacosanylacetyl chloride instead of octanoyl chloride, there is obtained the corresponding

N-cyclopropylacetyl-0,0,O-tri(cyclopropyl- acetyl)deferoxamine;

N-cyclobutylacetyl-O,O,O-tri(cyclobutyl- acety1)defe oxamine; N-cyclohexylpropanoyl-0,O,O-tri(cyclohexyl- propanoyl)deferoxamine;

N-σyclodecyldecanoyl-0,O,O-tri(cyclodecyl- decanoyl) eferoxamine; or

N-cyclopentacosanylacetyl-0,0,O-tri(cyclo- pentacosanylacetyl)deferoxamine.

(g) Similarily proceeding as in Subpart (a) above, but substituting a stoichiometrically equiva¬ lent amount of

2—chlorocyclopropylacetyl chloride 4-chlorocyclohexylacetyl chloride

2-chlorocyclopentadecylacetyl chloride; or 10-(2-chloropentacosanyldecanoyl chloride instead of octanoyl chloride, there is obtained the corresponding N-(2-chlorocyclopropylacetyl)-O,O,O-tri(2- chlorocyclopropylacetyl)deferoxamine;

N-( -chlorocyclohexylacetyl)-0,O,O-tri(4- chlorocyclohexylacetyl)deferoxamine;

N-(2-chlorocyclopentadecylacetyl)-O,O,0- tri(2-chlorocyclopentadecylacetyl)deferoxamine; or

N-[10-(2-chloropentacosanyl)decanoyl]-0,0,O- tri[10-(2-chloropentacosanyl)decanoyl]deferoxamine.

(h) Similarily proceeding as in Subpart (a) above, but substituting a stoichiometrically equivalent amount of propynoyl chloride;

2-hexynoyl chloride;

2-decynoyl chloride; or

2-pentacosynoyl chloride

instead of octanoyl chloride, there is obtained the corresponding

N-(propynoyl)-O,0,O-tri(propynoy1) deferoxamine; N-(2-hexynoyl)-O,O,O-tri(2-hexynoyl- deferoxamine;

N-(2-decynoyl)-O,0,O-tri(2-decynoyl)- deferoxamine; or

N-(2-pentacosyno 1)-O,O,O-tri(2-penta- cosynoyl)deferoxamine.

(i) Similarily proceeding as in Subpart (a) above, but substituting a stoichiometrically equiva¬ lent amount of

4-chloro-2-butynoyl chloride; 10-chloro-2-decynoyl chloride;

15-chloro-3-pentadeσynoyl chloride; or 25-chloro-2-pentacosynoyl chloride instead of octanoyl chloride, there is obtained the corresponding N-(4-chloro-2-butynoyl)-O,0,O-tri(4-chloro-

2-butynoyl)deferoxamine;

N-(10-chloro-2-decynoyl)-O,0,O-tri(10- chloro-2-decynoyl)deferoxamine;

N-(15-chloro-3-pentadecynoyl)-0,O,O-tri(15- chloro-3-pentadecynoyl)deferoxamine; or

N-(25-chloro-2-pentacosynoyl)-O,O,O-tri(25- chloro-2-pentacosynoyl)deferoxamine.

(j) Similarily proceeding as in Subpart (a) above, but substituting a stoichiometrically equiva- lent amount of benzoyl chloride: 2-naphthoyl chloride; or 1-phenanthroyl chloride for octanoyl chloride, there is obtained the corresponding

N-benzoyl-0,0,O-tri(benzoyl)deferoxamine;

N-(2-naphthoyl)-O,O,O-tri(2-naphthoyl.)- deferoxamine; or

N-(1-phenanthroyl)-O,O,O-tri(1- phenanthroyl)deferoxamine.

(k) Similarly proceeding as in Subpart (a) above, but substituting a stoichiometrically equiva¬ lent amount of

4-chlorobenzoyl chloride; 6-methoxy-2-naphthoyl chloride; or

6-chloro-l-phenanthroyl chloride instead of octanoyl chloride, there is obtained the corresponding

N-( -chlorobenzoy1)-O,O,O-tri(4-chloro- benzoyl)deferoxamine;

N-(6-methoxy-2-naphthoyl)-O,O,O-tri(6- methoxy-2-naphthoyl) eferoxamine; or

N-(6-chloro-l-phenanthroyl)-O,0,O-tri(6- chloro-1-phenanthroyl)deferoxamine. (1) Similarly, proceeding as in Subpart (a) above but substituting a stoichiometrically equivalent amount of phenylacetyl chloride;

10-phenyldecanoyl chloride; or 2-naphthyldecanoyl chloride;instead of octanoyl chloride, there is obtained the corresponding

N-(phenylacetyl)-O,O,O-tri(phenylacetyl) deferoxamine;

N-(10-phenyldecanoyl)-O,O,O-tri(10- phenyldecanoyl)deferoxamine; or

N-(2-naphthyldecanoyl)-O,O,O-tri(2- naphthyldecanoyl)deferoxamine.

(m) Similarily, proceeding as is described in Subpart (a) of this Example, but substituting a

stoichiometrically equivalent amount of the following equimolar mixtures of acyl chlorides:

A. acryloyl chloride, butyryl chloride, benzoyl chloride, and cyclohexyl carbonyl chloride;

B. 2-naphthoyl chloride, 2-butynoyl chloride, phenylacetyl chloride, and 4- chlorophenylacetyl chloride; or

C. 3-chloropropionyl chloride, 4-chloro-2-butenoylchloride,

4-chlorocyclohexylcarbonyl chloride, and

4-chlorocyclohexylacetyl chloride for butyryl chloride. there is obtained the following mixtures of tetraacyldeferoxamines:

A. N-acryloyl-0,0,0- butyrylbenzoylcyclohexyldeferoxamine; N- yclohexyl-0,0,O- benzoylacryloylbutyryldeferoxamine; and

N-benzoyl-0,0,0- butyrylacryloylcyclohexylcarbonyl deferoxamine; B. N-(2-naphthoyl)-0,0,0- butynoylphenylacetyl-4- chlorophenylacetyldeferoxamine; N-phenylacetyl-0,0,0-butynoyl-4- chlorophenylacetyl-(2- naphthoyl)deferoxamine; and

N-butynoyl-0,0,0-(2-naphthoyl) 4-chlorophenylacetyldeferoxamine; and C. N-(3-chloropropionyl)-0,0,O-(4-chloro-2- butenoyl)-(4-chlorocyclohexyl-

carbonyl) (4-chlorocyclohexyl- acetyl)deferoxamine;

N-(4-chlorocyclohexylcarbonyl)-O,O,O-(4- chloro-2-butenoyl) (3-chloropropionyl) (4- chlorocyclohexylacetyl)deferoxamine; and

N-(4-chlorocyclohexylacetyl)-0,0,0-(4- chlorocyclohexylcarbonyl) (3- chloropropionyl) (4-chloro-2- butenoyl)deferoxamine.

Products A, B and C also include other possible isomers of the groups described therein. Also, the position of the acyl groups on the nitrogen and oxygen is not yet known with certainity.

EXAMPLE 5

Preparation of N-Octanoyl-0,0,0- trihydrogendeferoxamine

(Step 2)

(a) N-Octanoyl-0,0,0-trioctanoy1- deferoxamine (3.5 g, from Example 4) is dissolved in 250 ml of ether, 100 ml of methanol and saturated at ambient temperature with ammonia gas. After stirring for 3 days (about 72 hr) at ambient temperature, the reaction mixture is evaporated to dryness using reduced pressure, and the solid residue is boiled five times with hexane to remove the octanoic acid amide. The remaining colorless crystalline product is recrys- tallized from n-propanol/water (66/34) to give 1.5g of N-octanoyl-O,0,0-trihydrogendeferoxamine, m.p. 185- 187 ^θ _# ^r r^ _e infrared and nuclear magnetic resonance spectra are consistent with this structure. The

product is sparingly soluble in water and ordinary organic solvents.

(b) Similarly, proceeding as is described above in Subpart (a) of this Example, but substituting a stoichiometrically equivalent amount of the deferox- amines as prepared in Example 4, Subpart (b) above for N-octanoyl-O,O,0-trioctanoyldeferoxamine, there is obtained the corresponding

N-acetyl-0,0,0-trihydrogendeferoxamine; N-propionyl-0,O,O-trihydrogendeferoxamine;

N-butyryl-0,0,O-trihydrogendeferoxamine; N-pivaly1-0,0,O-trihydrogendeferoxamine; N-valeryl- ,0,0-trihydrogendeferoxamine; N-isovaleryl-0,0,0-trihydrogendeferoxamine; N-dodecanoy1-0,0,0-trihydrogendeferoxamine;

N-palmitoy1-0,0,0-trihydrogendeferoxamine; or

N-hexacosanoyl-0,0,0-trihydrogen¬ deferoxamine. (c) Similarly, proceeding as is described above in Subpart (a) of this Example, but substituting a stoichiometrically equivalent amount of the deferoxa ines as prepared in Example 4, Subpart (c) above for N-octanoyl-0,0,0-trioctanoyldeferoxamine, there is obtained the corresponding

N-(3-chlorobutanoyl)-0,0,0-trihydrogen¬ deferoxamine;

N-(3-chloroisovaleryl)-O,0,O-trihydrogen- deferoxamine; N-(10-chlorooctadecanoyl)-0,0,0-trihydrogen¬ deferoxamine;

N-(10-methoxyoctadecanoyl)-0,0,O-trihydro¬ gendeferoxamine;

N-(9,10-dichlorooctadecanoyl)-O,O,O-tri- hydrogendeferoxamine;

N-(9,10-dibromooctadecanoyl)-O,O,O-tri- hydrogendeferoxamine; or N-(9,10-dimethoxyoctadecanoyl)-0,0,0-tri- hydrogendeferoxamine.

(d) Similarly, proceeding as is described above in Subpart (a) of this Example, but substituting a stoichiometrically equivalent amount of the deferox- amines as prepared in Example 4, Subpart (d) above for N-octanoyl-O,0,0-trioctanoyldef roxamine, there is obtained the corresponding -acrylαyl-O,0,0-trihydrogendeferoxamine;

N-2-butenoyl-0,0,0-trihydrogendeferoxamine; N-2-pentenoyl-O,0,O-trihydrogendeferoxamine;

N-2-octenoyl-0,0,0-trihydrogendeferoxamine;

N-2-oleoy -0,0,0-trihydrogendeferoxamine; or

N-2-pentacosenoyl-O,0,O-trihydrogen- deferoxamine. (e) Similarly, proceeding as is described above in Subpart (a) of this Example, but substituting a stoichiometrically equivalent amount of the deferox- a ines as prepared in Example 4, Subpart (e) above for N-octanoyl-0,0,0-trioctanoyldeferoxamine, there is obtained the corresponding

N-(2-chloroacryloyl)-O,0,0-trihydrogen¬ deferoxamine;

N-(2-chloropropenoyl)-0,0,O-trihydrogen- deferoxamine; N-(4-methoxybutenoyl)-0,0,O-trihydrogen¬ deferoxamine;

N-(2-chlorooctenoyl)-0,0,0-trihydrogen¬ deferoxamine; or

N-(2-chloropentacosenoyl)-O,0,0-trihydrogen¬ deferoxamine.

(f) Similarily, proceeding as is described above in Subpart (a) of this Example, but substituting a stoichiometrically equivalent amount of the deferoxamines as prepared in Example 4, Subpart (e) above for N-octanoyl-0,0,0-trioctanoyldeferoxamine, there is obtained the corresponding

N-cyclopropylacetyl-0,O,O-trihydrogen- deferoxamine;

N-cyclobutylacety1-0,0,O-trihydrogen¬ deferoxamine;

N-cyclohexylpropanoy1-0,0,0-trihydrogen¬ deferoxamine; N-cyclodecyldecanoy1-0,0,O-trihydrogen¬ deferoxamine; or

N-(cyclopentacosanylacetyl)-0,0,0-tri- hydrogendeferoxamine.

(g) Similarly, proceeding as is described above in Subpart (a) of this Example, but substituting a stoichiometrically equivalent amount of the deferoxamines as prepared in Example 4, Subpart (g) above for N-octanoyl-0,0,0-trioctanoyldeferoxamine, there is obtained the corresponding N-(2-chlorocyclopropylacety1)-0,0,O- trihydrogendeferoxamine;

N-(4-chlorocyclohexylacetyl)-O,O,0- trihydrogendeferoxamine;

N-(2-chlorocyclopentadecylacety1)-0,0,0- trihydrogendeferoxamine; or

N-[10-(2-chloropentacosanyl)decanoyl]-0,0,0- trihydrogendeferoxamine.

(h) Similarly, proceeding as is described above in Subpart (a) of this Example, but substituting

a stoichiometrically equivalent amount of the deferox¬ amines as prepared in Example 4, Subpart (h) above for N-octanoyl-O,0,0,-trioctanoyldeferoxamine, there is obtained the corresponding N-( ropynoyl)-O,0,O-trihydrogende eroxamine;

N-(2-hexynoyl)-O,O,O-trihydrogen- deferoxamine;

N-(2-decynoyl)-O,O,O-trihydrogen- deferoxamine; or N-(2-pentacosynoyl)-O,0, -trihydrogen¬ deferoxamine.

(i) Similarly, proceeding as is described above in Subpart (a) of this Example, but substituting a stoichiometrically equivalent amount of the deferox- amines as prepared in Example 4, Subpart (i) above for N-octanoyl-O,0,0-trioctanoyldeferoxamine, there is obtained the corresponding -(4-chloro-2-butynoy1)-O,0,O-trihydrogen¬ deferoxamine; N-(10-chloro-2-decynoy1)-O,O,O-trihydrogen¬ deferoxamine;

N-(15-chloro-3-pentadecynoyl)trihydrogen- deferoxamine; or

N-(25-chloro-2-pentacosynoyl)-O,0,O- trihydrogendeferoxamine.

(j) Similarly, proceeding as is described above in Subpart (a) of this Example, but substituting a stoichiometrically equivalent amount of the defero¬ xamines as prepared in Example 4, Subpart (j) above for N-octanoyl-O,0,0-trioctanoyldeferoxamine, there is obtained the corresponding

N-benzoyl-0,O,O-trihydrogendeferoxamine;

N-(2-naphthoyl)-O,O,O-trihydrogen¬ deferoxamine; or

N-(1-phenanthroyl)-O,0,O-trihydrogen- deferoxamine.

(k) Similarly, proceeding as is described above in Subpart (a) of this Example, but substituting a stoichiometrically equivalent amount of the deferox¬ amines as prepared in Example 4, Subpart (k) above for N-octanoyl-O,0,0-trioctanoyldeferoxamine, there is obtained the corresponding

N-(4-chlorobenzoyl)-O,0,O-trihydrogen- deferoxamine;

N-(6-methoxy-2-naphthoyl)-O,O,O-trihydrogen¬ deferoxamine; or

N-(6-chloro-l-phenanthroyl)-O,0,O-tri- hydrogendeferoxamine. (1) Similarly, proceeding as is described above in Subpart (a) of this Example, but substituting a stoichiometrically equivalent amount of the deferoxamines as prepared in Example 4, Subpart (1) above for N-octanoyl-O,O,0-trioctanoyldeferoxamine, there is obtained the corresponding

N-(phenylacetyl)-O,O,O-trihydrogen¬ deferoxamine;

N-(10-phenyldecanoyl)-0,O,O-trihydrogen- deferoxamine; or N-[10-(2-naphthy1)decanoy1]-O,O,O-tri- hydrogendeferoxamine.

EXAMPLE 6

Preparation of N-Octanoyl-0,0,0- tributyryldeferoxamine

(Step 3)

(a) N-Octanoyl-0,0,0-trihydrogen deferox¬ amine [1.5g, from Example 5(a)] is suspended in a solution of 50 ml of water and 50 ml of chloroform. The well-agitated suspension is adjusted to pH of 9 using 5N sodium hydroxide solution. To this mixture is added dropwise, a solution of 1.4g of butyryl chloride in 30 ml of chloroform. The pH of 9 of the mixture is maintained by the addition of a 5N sodium hydroxide solution as needed. After 20 ml of the butyryl chloride solution are added, 25 ml of water and 100 ml of chloroform .are added to facilitate the mixing of the solution. After the butyryl chloride solution is all added, the reaction mixture is stirred for 2 hours, with periodic adjustment to maintain a pH of 9. The reaction mixture is then diluted with 50 ml of water and 200 ml of chloroform and centrifuged to separate the phases. Any white solid at the interface is removed and discarded. The chloroform phase is washed twice with 100 ml of saturated sodium bicar¬ bonate solution and twice with 100 ml of saturated sodium chloride solution, dried using anhydrous sodium sulfate, filtered and reduced to dryness using reduced pressure. About 2.Og of a crude waxy white solid is obtained, which is washed twice with ether and recrys- tallized from 60% ethanol. The solid is air dried to produce l.lg of N-octanoyl-0,0,0-tributyryl- deferoxamine. The infrared and nuclear magnetic resonance spectra are consistent with this structure.

(b) Similarly, proceeding as is described above in Subpart (a) of this Example, but substituting a stoichiometrically equivalent amount of the deferox¬ amines as prepared in Example 5, Subpart (b) above for N-octanoyl-O,O,0-trihydrogendeferoxamine, there is obtained the corresponding

N-acetyl-0,O,O-tributyryldeferoxamine;

N-propionyl-0,0,O-tributyryldeferoxamine; _.

N-butyryl-O,O,O-tributyryldeferoxamine; N-pivalyl-0,0,O-tributyryldeferoxamine;

N-valeryl-0,0,O-tributyryldeferoxamine;

N-isovalery1-0,0,0-tributyryldeferoxamine;

N-dodecanoy1-0,0,0-tributyryldeferoxamine;

N-palmitoyl-0,0,O-tributyryldeferoxamine; or N-hexacosanoyl-0,0,0-tributyryldeferoxamine.

(c) Similarly, proceeding as is described above in Subpart (a) of this Example, but substituting a stoichiometrically equivalent amount of the deferoxamines as prepared in Example 5, Subpart (c) above for N-octanoyl-O,0,0-trihydrogendeferoxamine, there is obtained the corresponding

N-(3-chlorobutanoyl)-0,0,0-tributyryl¬ deferoxamine;

N-(3-chloroisovaleryl)-O,O,O-tributyryl- deferoxamine;

N-(10-chlorooctadeσanoyl)-O,0,0-tributyryl- . deferoxamine;

N-(10-methoxyoctadecanoyl)-O,O,O-tributyryl¬ deferoxamine; N-(9,10-dichlorooctadecanoyl)-O,O,0- tributyryldeferoxamine;

N-(9,10-dibromooctadecanoyl)-O,O,O- tributyryldeferoxamine; or

N-(9,10-dimethoxyoctadecanoyl)-O,O,0- tributyryldeferoxamine.

(d) Similarly, proceeding as is described above in Subpart (a) of this Example, but substituting a stoichiometrically equivalent amount of the deferoxamines as prepared in Example 5, Subpart (d) above for N-octanoyl-0,0,O-trihydrogendeferoxamine, there is obtained the corresponding

N-acryloyl-0,0,0-tributyryldeferoxamine; N-2-butenoyl-0,0,0-tributyryldeferoxamine;

N-2-pentenoyl-O,0,0-tributyryldeferoxamine; N-2-octenoyl-O,0,0-tributyryldeferoxamine; N-2-oleoyl-O,0,O-tributyryldeferoxamine; or N-2-pentacosenoyl-O,O,O- tributyryldeferoxamine.

(e) Similarly, proceeding as is described above in Subpart (a) of this Example, but substituting a stoichiometrically equivalent amount of the deferoxamines as prepared in Example 5, Subpart (e) above for N-octanoyl-O,O,O-trihydrogendeferoxamine, there is obtained the corresponding

N-2-chloroacryloyl-O,0,O-tributyryl- deferoxamine;

N- 2-chloropropenoyl)-O,0,O-tributyryl- deferoxamine

N- 4-methoxybutenoyl)-O,O,0-tributyryl- deferoxamine

N- 2-chlorooctenoyl)-O,O,0-tributyryl- deferoxamine or N- 2-chloropentacosenoyl)-O,0,O-tributyryl- deferoxamine

(f Similarly, proceeding as is described above in Subpart (a) of this Example, but substituting a stoichiometrically equivalent amount of the

deferoxamines as prepared in Example 5, Subpart (f) above for N-octanoyl- ,O,O-trihydrogendeferoxamine, there is obtained the corresponding

N-cyclopropylacetyl-O,0,O-tributyryl- deferoxamine;

N-cyclobutylacetyl-0,O,O-tributyryl- deferoxamine;

N-cyclohexylpropanoy1-0,0,O-tributyryl¬ deferoxamine; N-[10-(cyclodecyl)decanoy1]-O,O,O- tributyryldeferoxamine; or

N-(cyclopentacosanylacetyl)-O,0,O- tributyryldeferoxamine.

(g) Similarly, proceeding as is described above in Subpart (a) of this Example, but substituting a stoichiometrically equivalent amount of the deferoxamines as prepared in Example 5, Subpart (g) . above for N-octanoyl-0,O,0-trihydrogendeferoxamine, there is obtained the corresponding N-(2-chlorocyclopropylacety1)-O,O,O- tributyryldeferoxamine;

N-(4-chlorocyclohexylacetyl)-O,O,O,- tributyryldeferoxamine;

N-(2-chloropentadecylacety1)-O,0,O,- tributyryldeferoxamine; or

N-[10-(2-chloropentacosanyl)decanoyl]- 0,0,0,-tributyryldeferoxamine.

(h) Similarly, proceeding as is described above in Subpart (a) of this Example, but substituting a stoichiometrically equivalent amount of the deferoxamines as prepared in Example 5, Subpart (h) above for N-octanoyl-0,0,0-trihydrogendeferoxamine, there is obtained the corresponding

N-(propynoyl)-O,0,0-tributyryldeferoxamine;

N-(2-hexynoyl)-O,O,O-tributyryldeferoxamine; N-(2-decynoyl)-0,O,O-tributyryldeferoxamine; or

N-(2-pentacosynoyl)-0,O,O-tributyryl- deferoxamine.

(i) Similarily, proceding as is described above in Subpart (a) of this Example, but substituting a stoichiometrically equivalent amount of the deferoxamines as prepared in Example 5, Subpart (i) above for N-octanoyl-O,0,O-trihydrogendeferoxamine, there is obtained the corresponding

N-(4-chloro-2-butynoy1)-0,O,0-tributyryl¬ deferoxamine;

N-(10-chloro-2-decynoyl)-0,O,O-tributyryl- deferoxamine;

N-(15-chloro-3-pentadecynoyl)-O,0,0- t ibutyryldeferoxamine; or

N-(25-chloro-2-pentacosynoyl)-0,O,0- tributyryldeferoxamine. (j) Similarly, proceeding as is described above in Subpart (a) of this Example, but substituting a stoichiometrically equivalent amount of the deferoxamines as prepared in Example 5, Subpart (j) above for N-octanoy1-0,0,O-trihydrogendeferoxamine, there is obtained the corresponding

N-benzoyl-0,0,O-tributyr ldeferoxamine;

N-(2-naphthoyl)-0,0,0-tributyryl¬ deferoxamine; or

N-(1-phenanthroy1)-0,0,0-tributyryl- deferoxamine.

(k) Similarly, proceeding as is described above in Subpart (a) of this Example, but substituting a stoichiometrically equivalent amount of the deferoxamines as prepared in Example 5, Subpart (k)

above for N-octanoyl-O,0,O-trihydrogendeferoxamine, there is obtained the corresponding

N-(4-chlorobenzoyl)-0,0,0-tributyryl- deferoxamine; N-(6-methoxy-2-naphthoyl)-0,0,0-tributyryl¬ deferoxamine; or

N-(6-chloro-l-phenanth ^" royl)-0,0,0- tributyryldeferoxamine.

(1) Similarly, proceeding as is described above in Subpart (a) of this Example, but substituting a stoichiometrically equivalent amount of the deferox¬ amines as prepared in Example 5, Subpart (1) above for N-octanoyl-0,0,O-trihydrogendeferoxamine, there is obtained the corresponding N-(phenylacetyl)-0,0,0-tributyryl- deferoxamine; .

N-(10-phenyldecanoyl)-0,0,0-tributyryl¬ deferoxamine; or

N-(2-naphthyldecanoyl)-O,0,0-tributyryl- deferoxamine.

(m) Similarily, proceeding as is described above in Subpart (a) of this example, but substituting one half of the stoichiometrically equivalent amount of the following equimolar mixtures of acyl chlorides: A. acetyl chloride, butyryl chloride, and acryloyl chloride;

B. octanoyl chloride and acryloylchloride; or

C. butyryl chloride and octanoyl chloride for butyryl chloride, there is obtained a corres¬ ponding mixture of products including:

A. N-octanoyl-0,O,0- acetylbutyrylacryloyldeferoxamine;

N-octanoyl-0,0,0- hydrogenacryloylacetyldeferoxamine; or N-octanoyl-0,0,0- butyrylacryloylhydrogendeferoxamine; B. N-octanoyl-0,0,0- octanoylhydrogenacryloyldeferoxamine; N-octanoyl-0,0,0- octanoylacryloyIhydrogendeferoxamine; or N-octanoyl-0,0,0- dioctanoylacryloyldeferoxamine; and C. N-octanoyl-0,0,0- butyryloctanoyIhydrogendeferoxamine; N-octanoyl-0,0,0- octanoylhydrogenbutyryldeferoxamine; or

N-octanoyl-0,0,0- hydrogenbutyryldeferoxamine. The exact positions of the acyl or hydrogen groups has not yet been established with certainity.

In Examples 7 and 8, the active ingredient is N-acetyl-0,0,O-trioctanoyldeferoxamine. Other compounds of formula I may be substituted therein. These include those compounds where R-^ is lower acyl, R ₂ , R ₃ and R ₄ are acyl (Rg is lower alkyl) and Rg, ₇ and Rg are hydrogen, and compounds where R-^ is acyl (Rg is lower alkyl), R ₂ , R3 and R ₄ are acyl (Rg is lower alkyl) and of Rg, R7 and Rg, two are hydrogen and the remaining one is acyl (Rg is lower alkyl) . Preferred is N-acetyl-0,0,0,N,H,H-tetraoctanoyl- deferoxamine.

EXAMPLE 7 Tablet Formation

Quantity per Ingredients Tablet, mgs.

Active Ingredient 350

Cornstarch 20 Lactose, spray dried 100

Magnesium stearate 2

The above ingredients are thoroughly mixed, granulated, and pressed into single scored tablets.

EXAMPLE 8 Capsule Formation

Quantity per Ingredients Capsule, mgs.

Active Ingredient 350

Lactose, spray dried 100 Magnesium stearate 2

The above ingredients are mixed and introduced into a hard-shell gelatin capsule.

While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in this art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the present invention. In addition, many modifications may be made to adapt a particular situation, material, or composition of matter, process, process step or steps, or the present objective to the spirit and scope of this invention, without departing from its essential teachings.