Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-07-12
2001-12-04
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S104000, C558S153000
Reexamination Certificate
active
06326363
ABSTRACT:
The object of the present invention are novel methylenebisphosphonic acid derivatives, especially novel halogen substituted methylenebisphosphonic acid anhydrides, ester anhydrides, amide anhydrides and ester amide anhydrides, processes for the preparation of these novel compounds, as well as pharmaceutical preparations comprising these novel compounds.
According to the invention it has been found that the novel methylenebisphosphonic acid anhydrides, ester anhydrides, amide anhydrides, ester amide anhydrides and partial anhydrides as well as their salts in several cases exhibit clearly better properties than the corresponding bisphosphonic acids, their partial ester, partial amide and partial ester amide derivatives, due to the better kinetics and usability of anhydride derivatives, wherefore they have a more controlled effect on the metabolism and functions of the body.
The basic problem with all known methylenebisphosphonates, which are used only as salts of the tetra acid forms, is their poor absorption during oral administration. Thus the dose needed has to be larger.
Absorption and effectiveness may be influenced either by treating the substituents of the intermediate carbon or by changing the groups attached on the phosphorous. Several examples of the improvement of the properties of bisphosphonates by changing the substituents on the intermediate carbon are found in literature (Bisfosfonate on Bones, ed. Bijvoet, Fleisch and Russel, Elsevier, Amsterdam 1995). The absorption of bisphosphonates in tetra acid or salt form or patient compliance have also been tried to improve by formulatory means (CA 2120538, EP 407345, EP 550385, EP 566535, U.S. Pat. No. 5,462,932, WO 9321907, WO 9412200, WO 9426310, WO 9508331, WO 9528145, WO 9529679, WO 9531203), but the improvement on effectiveness has been only marginal in proportion to the dose. However, the phosphorous part has been used for regulation only in few cases. Typically such regulators in the phosphorous part have been partial esters, ester amides, and amides. The anhydride derivatives, which are the subject of the invention, are characterized by a desired selective and controlled effect, which means a better therapeutical index.
Methylenebisphosphonic acids, their salts, tetraesters, amide esters, partial esters and partial ester amides have been disclosed in several publications, but the anhydride derivatives which are the subject of the invention, have not been mentioned in literature nor have their properties been known.
The preparation of methylenebisphosphonic acid tetraesters has been disclosed in the publications U.S. Pat. No. 4,447,256; DE 28 31 578; EP 337 706; EP 282 320; EP 356 866; J. Am. Chem. Soc. 78 (1956) 4450; J. Chem. Soc. 1959, 2272; J. Am. Chem. Soc. 84 (1962) 1876; J. Org. Chem. 35 (1970) 3149; J. Org. Chem. 36 (1971) 3843, Phosphorus, Sulfur and Silicon 42 (1989) 73, J. Chem. Soc. Perkin Trans. 2, (1992) 835 and Phosphorus, Sulfur and Silicon 70 (1992) 182 (mixed tetraesters). The preparation of tetra amide esters has been disclosed in publications J. Organomet. Chem. 304 (1986) 283; Tetrahedron Lett. 26 (1985) 4435 and Acta Chem. Scand. 51 (1997) 932.
The preparation of partial esters has been disclosed in publications WO 9015806, WO 9211267, WO 9221169, Tetrahedron Lett., 34 (1993) 4551, Tetrahedron 51 (1995) 6805 and Tetrahedron Lett. 37 (1996) 3533, and the preparation of partial amides and partial amide esters has been disclosed in the patent publication WO 9211268.
Mono or bisphosphonate parts can be added to a known medicinal substance inseparably or as a pro-part, and thus increase targeting to the bone of the latter, when the same is used for the treatment of bone diseases or for increasing the solubility of a poorly water-soluble drug into water phase. Also some mixed anhydrides of mainly phosphoric acid and carboxylic acid are known for this purpose.
The novel molecules according to the present invention, which contain an acid anhydride group as a pro-part or are active as such, are very suitable for the treatment of disorders relating to the metabolism of calcium and other, especially bivalent metals. They can be used in the treatment of both bone diseases, especially bone formation and resorption disorders, such as osteoporosis and Paget's disease, and also diseases in the soft tissues, such as deposition, mineralisation conditions and ossification disorders.
On the other hand, being pyrophosphate analogs, the novel anhydride derivatives of methylenebisphosphonic acids are suitable for the treatment of disorders in the pyrophosphate functions of the organism, including those functions, wherein an active, but disturbance-prone or incorrectly functioning organic part is coupled to (pyro) phosphate or acts as a metal complex or as a combination of the latter.
The novel bisphosphonates regulate either directly or via an indirect mechanism the quality and level of both cations and/or pyrophosphate compounds, which are freely present in the body fluids or bind to tissues, are active in tissues and are liberated therefrom, i.e. formations, dissolutions, couplings and eliminations. Thus they are able to regulate cellular metabolism, growth and destruction.
Based on the above, they can be used for example in the treatment of bone cancer and its metastases, ectopic calcifications, urolithiasis, rheumatoid arthritis, osteitides and bone degenerations.
The invention concerns novel methylenebisphosphonic acid derivatives of the general formula I
wherein
Y
1
, Y
2
, Y
3
and Y
4
are a group OR
1
, NR
2
R
3
1
, OCOR
1
, OCNR
2
R
3
, O(CO)OR
1
, O(SO
2
)R
1
, O(SO
2
)OR
1
or OP(O)R
2
(OR
3
), wherein R
1
, R
2
ja R
3
are independently of each other hydrogen, straight or branched, optionally substituted, optionally unsaturated C
1
-C
22
alkyl, optionally substituted, optionally unsaturated C
3
-C
10
cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or silyl SiR
3
, wherein R means a C
1
-C
4
alkyl, phenyl, a substituted phenyl or combinations of C
1
-C
4
alkyls and/or phenyls, or the groups R
2
and R
3
together with the adjacent nitrogen atom form a 3 to 10-membered saturated, partly saturated or aromatic ring, wherein in addition to the nitrogen atom there may be one or two heteroatoms selected from the group N, O and S, or the groups R
2
and R
3
together with the adjacent O-PO-O group form a 5 or 6-membered ring,
with the proviso that in the formula I at least one of the groups Y
1
, Y
2
, Y
3
and Y
4
is other than a group OR
1
or NR
2
R
3
;
Q
1
and Q
2
are independently of each other hydrogen, fluorine, chlorine, bromine or iodine, including the stereoisomers, such as geometrical isomers and optically active isomers, of the compounds, as well as the pharmacologically acceptable salts of these compounds.
Optionally unsaturated C
1
-C
22
alkyl as a group R
1
, R
2
and R
3
means alkyl, alkenyl or alkynyl, which contain independently of each other 1 to 22, respectively 2 to 22 carbon atoms, preferably 1 to 8, respectively 2 to 8 carbon atoms, and most preferably 1 to 5, respectively 2 to 5 carbon atoms.
Optionally unsaturated C
3
-C
10
cycloalkyl as a group R
1
, R
2
and R
3
means cycloalkyl or -alkenyl, which contain 3 to 10 carbon atoms, preferably 5 or 6 carbon atoms, and may be unsubstituted or substituted for example with a lower alkyl (1-4 C). Preferably it is cyclopropyl, -butyl, -pentyl or -heptyl or the corresponding cycloalkenyl group. A heterocyclyl contains in its ring one or several heteroatoms from the group N, O and S.
Aryl or aralkyl as a group R
1
, R
2
and R
3
means an optionally C
1
-C
4
-alkyl, -alkoxy or halogen substituted monocyclic aryl or aralkyl, such as phenyl or benzyl, most preferably, however, an unsubstituted phenyl or benzyl.
When in the silyl group SiR
3
the group R is a lower alkyl containing 1 to 4 C-atoms, it is especially methyl, ethyl, isopropyl, butyl or t-butyl. When the group R in the silyl group means combinations of C
1
-C
4
-alkyls or phenyls, it is for example dimethyl t-butyl, methyldiisopropyl, dimethylphenyl, diethylphenyl
Ahlmark Marko
Hannuniemi Ritva
Jarvinen Tomi
Kähkönen Jouni
Lauren Leena
Birch & Stewart Kolasch & Birch, LLP
D'Souza Andrea M.
Lambkin Deborah C.
Leiras Oy
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