Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-01-13
2001-03-27
Vollano, Jean F. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S102000, C560S040000, C562S013000
Reexamination Certificate
active
06207655
ABSTRACT:
The present invention relates to conjugates of 3-carboxy-4,4′-dihydroxyphosphorylbutenoic acids with alkylating agents. Such derivatives are endowed with marked antitumor activity, especially against multiple myeloma. The present invention relates as well to a process for the preparation thereof and to pharmaceutical compositions containing them.
The skeletal system is the third more common site of metastases and more than 80% of the total number of patients dead for cancer show bone tumors at the autopsy. Bone metastases account for a significant proportion of cancer-related morbidity, causing derangement in calcium metabolism and bone marrow involvement and are responsible for the consequences of most concern to patients with cancer, such as pain, pathologic fractures, compression of the spinal cord and hypercalcemia (Drew et al., Osseous complication of malignancy, Lokich, J. J. ed. Clinical cancer medicine: treatment tactics Boston: G. K. Hall Medical Publisher, 1980, 97-112).
One of the main problems to overcome in connection with the conjugates between osteotropic carriers and cytotoxic agents is the selective release of the cytotoxic agent to the bone. The molecules characterized by an amide bond may result too stable to the hydrolysis by the lysosomial enzymes. To obtain the selective release of the cytotoxin to the bone acid-labile bonds may be used. It is known that the osteoclasts generate an acidic microenvironment inside the bone resorption area. The low pH value is necessary in order to remove the mineral component (the solubility of calcium hydroxyapatite depends on the pH: the complex is almost totally insoluble at physiologic pH, while it dissolves at a 50 mM concentration of Ca
++
ions at about pH=3.5) and to remove the organic matrix by means of the lysosomial cathespins secreted by the same cells. The lower pH measured “in vivo” was 4.7, but the average pH was 6.01 (Silver A, et al., Experimental Cell Res., 175, 266-76 (1988)). The bis-phosphonates act at the osteoclast/bone interface and localize preferentially at the bone resorption sites. When the osteoclasts begin the resorption process, the bis-phosphonate, as a result of the acidification, is released from the bone surface toward the resorption area (Rodan G. A., Bone, 1, S1-S6, 1992). In this way an acid labile conjugate may be hydrolyzed and the cytotoxin may be selectively released inside the resorption area.
Moreover it is known that the tumor cells are able to stimulate the osteoclast's resorption activity, which causes a continuous acidification of the resorption area. Pro-drugs of daunomycin are known which contain the cis-aconitic acid as a spacer between the cytotoxin and the protein carrier (Shen W. C. et al., Biochem. and Biophysical Res. Comm., 102, 1048-54, 1981). It is reported that such molecules are stable in plasma at pH 7.4, while are hydrolized in the lysosomial compartment at pH<5.5. Such an effect is accomplished by means of the ability of the free carboxyl group of the aconitic acid to react on the amide bond formed by the other carboxyl group with the cytotoxin, by catalysing its hydrolysis.
Gem-diphosphonic acids and salts thereof are known and employed in the therapy of the osteoporosis and in the treatment of bone resorption (see EP 096 931, EP 252 504, BE 896.453, BE′903.519, DE 3.016.289, DE 3.540.150, DE 2.534.391, DE 3.512.536). However none of the above compounds is described to possess antitumor activity.
DE 3.425.812 (Blum et al.) describes derivatives of 1,1-diphosphonic acids, characterized by a bis[(haloalkyl)amino]phenyl residue, as agents useful in the treatment of bone tumors.
In WO 88/06158 are moreover described diphosphonic analogues of methotrexate as agents useful in the treatment of bone tumors.
In WO 92/18512 are described conjugates of melphalan with gem-diphosphonic acids, in which the two reactive groups are linked by amino acids.
WO91/05791 (Feb. 5, 1991) discloses gem-diphosphonic acid derivatives of melphalan wherein the alkylating moiety is attached to the carbon atom to which the phosphoric groups are bound through a spector comprising an amide bond.
Our research was addressed toward the modification of the structure of aconitic acid in order to confer affinity for the bone tissue and toward the coupling of the so obtained carriers with alkylating residues.
We have found that by coupling a diphospho-aconitic carrier with a cytotoxic agent, compounds exploiting a marked affinity for the bone tissue are obtained. Such compounds are endowed with a high antitumor activity, in particular against multiple myeloma.
Human multiple myeloma is a circulating tumor which hits the plasma cells. One of its target organs is bone marrow, from which the tumor invades the surrounding bone tissue and causes serious pathological consequences to the patient, such as pain and fractures. Although melphalan exploits activity against the multiple myeloma, it is not able to cure the secondary bone tumor. It is therefore evident that to have found compounds able to cure this latter too is a noteworthy clinical advantage. It should be noticed that any bis-phosphonate in the state of the art has been shown active against the multiple myeloma.
The present invention relates to compounds of the general formula (I):
wherein:
R, R
1
and R
2
are independently selected in the group consisting of hydrogen, methyl, ethyl, propyl, butyl, which can be linear or branched, with the proviso that R
1
cannot be tert-butyl;
X is chlorine, bromine or iodine;
enantiomers, racemates, diastereoisomers and mixtures thereof, as well as salts thereof with pharmaceutically acceptable bases.
The C═C double bond in the aconitic residue as shown in formula (I) has a purely indicative stereochemistry, being included in the present invention both cis and trans stereoisomers, wherein “cis” or “trans” relates to the relative position of the carboxyl and carboxamide groups.
Preferred compounds of formula (I) are those in which X is chlorine.
Other preferred compounds of formula (I) are those in which R, R
1
and R
2
are hydrogen.
Particularly preferred compounds of formula (I) are those in which the C═C double bond in the aconitic residue has a cis stereochemistry.
The compounds of formula (I) can be prepared by means of a process which comprises the following synthesis steps (where not expressly specified, the C═C double bonds stereochemistry is purely indicative):
(a) reaction of a compound of formula (II):
in which the R′ groups are linear (C
1
-C
4
)alkyl groups, with a compound of formula (III):
in which the R
1
′ groups are linear (C
1
-C
4
)alkyl groups, in the presence of a base, to give an intermediate of formula (IV):
The compounds of formula (IV) are known compounds [J. Org. Chem., 45(13), 2698-2703 (1980)].
(b) hydrolysis of the R
1
′ ester groups, preferably in alkaline conditions, to give the intermediates of formula (V):
optionally in the form of salts with the used base;
(c) cyclization reaction of intermediates of formula (V) in the presence of a dehydrating agent to give the anhydrides of formula (VI):
(d) condensation reaction of an anhydride of formula (VI) with a compound of formula (VII):
to give the compounds of formula (VIII):
(e) optional esterification of the free carboxyl group of a compound of formula (VIII) to give the compounds of formula (IX):
Compounds of formula (IX) in which R is hydrogen may be obtained by esterification of the free carboxyl group of a compound of formula (VIII) in which R is tert-butyl and subsequent hydrolysis of the tert-butyl group;
(f) hydrolysis of the phosphonic esters of a compound of formula (VIII) or (IX) to give the wanted compounds of formula (I).
The condensation reaction of step (a) is preferably performed in inert solvents such as for example benzene or toluene, and in the presence of a strong base, such as for example a hydride of an alkali or alkaline-earth metal, at temperatures ranging from −10° C. and the boiling point of the sol
Conti Marco
D'Alo' Simonetta
Livi Valeria
Menta Ernesto
Spinelli Silvano
Arent Fox Kintner & Plotkin & Kahn, PLLC
Novuspharma S.p.A.
Vollano Jean F.
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