Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-04-11
2001-03-06
Ambrose, Michael G. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S120000, C558S170000, C558S179000, C558S182000
Reexamination Certificate
active
06197759
ABSTRACT:
The present invention relates to osteoblast-specific mitogenic compounds of formula (I), methods of preparing same, and drugs containing such compounds.
In healthy individuals, the formation and degradation processes in the bones are virtually at equilibrium, i.e., the activity of the osteoblasts and osteoclasts is balanced. However, if this equilibrium is disturbed in favor of the osteoclasts and/or to the disadvantage of the osteoblasts, a reduction in bone mass and a negative change in bone structure and function will be the result.
Up to now, bone resorption inhibitors such as estrogens, calcitonin and bisphosphonates are primarily used in the treatment of bone metabolic disorders. However, the use of these substances is limited and in addition, does not show the desired effect in all events. Compounds having a stimulating effect on bone formation and contributing to increase an already diminished bone mass are therefore of particular importance in the treatment of bone metabolic disorders. The European patent applications EP-A-625,522 and EP-A-524,023 describe substances having an osteoanabolic effect for osteoporosis therapy.
Lysophosphatidylic acid (LPA) is known to play a role as intracellular lipid messenger in various tissues and cell types (J. Biol. Chem. 270 (22), 12949-52, 1995; Curr. Opin. Cell. Biol. 7 (2), 203-10, 1995).
Surprisingly, it has now been found that the lysophosphatidylic acid derivatives of the present invention have a stimulating effect on bone formation and thus, are suitable for the general treatment of bone metabolic disorders. In particular, they can be used quite well in those cases where bone formation is disturbed, i.e., they are particularly suited for the treatment of osteopenic diseases of the skeletal system, such as osteoporosis, e.g., osteogenesis imperfecta, as well as for the local promotion of bone regeneration and osteoinduction, such as in orthopedic and orthodontic indications, in fracture curing, osteosyntheses, pseudarthroses and for bone implants to become incorporated.
Moreover, due to their influence on the bone metabolism, drugs containing the lysophosphatidylic acid derivatives of the present invention as active substances constitute a basis for the local and systemic treatment of rheumatoid arthritis, osteoarthritis and degenerative arthrosis.
The present invention is directed to new lysophosphatidylic acid derivatives of general formula (I)
wherein
R
1
=alkyl, alkenyl or alkynyl having from 6 to 24 carbon atoms;
n=0-12;
X=oxygen or NH;
the compounds (all-cis-5,8,11,14)-eicosatetraenoic acid 2-hydroxy-3-phosphonooxypropyl ester, cis-9,cis-12-octadecadienoic acid 2-hydroxy-3-phosphonooxypropyl ester, (all-cis-9,12,15)-octadecatrienoic acid 2-hydroxy-3-phosphonooxypropyl ester, or cis-9-octadecenoic acid 2-hydroxy-3-phosphonooxy-propyl ester being excluded, and with the proviso that if X represents oxygen, n in the —(CH
2
)
n
—CH
3
group does not represent the numbers 7, 9, 11, 13, or 15, and to the physiologically tolerable salts, esters, optically active forms, racemates, and derivatives thereof which can be metabolized in vivo to yield compounds of general formula (I), and to the use of said compounds in the production of drugs.
Methods of synthesizing the above compound wherein X=oxygen, and —(CH
2
)
n
—CH
3
with n=13, are well-known (e.g., Chem. Ber. 71, 1075 (1938), Hoppe-Seyler's Z. Physiol. Chem. 347, 94-101 (1966)). Methods of synthesizing said compound wherein X=oxygen, and —(CH
2
)
n
—CH
3
with n=15, are well-known (e.g., Chem. Phys. Lipids 1, 317 (1966/67)). Methods of synthesizing said compound wherein X=oxygen, and —(CH
2
)
n
—CH
3
with n=7, are well-known (e.g., Chem. Phys. Lipids 18, 316 (1977)).
The compounds (all-cis-5,8,11,14)-eicosatetraenoic acid 2-hydroxy-3-phosphonooxypropyl ester, cis-9,cis-12-octadecadienoic acid 2-hydroxy-3-phosphonooxypropyl ester and (all-cis-9,12,15)-octadecatrienoic acid 2-hydroxy-3-phosphonooxypropyl ester are described to have an effect on the contraction of an isolated rat colon (J. Pharm. Pharmacol. 43, 774-78 (1991). An effect on blood pressure has been described for compounds wherein X=oxygen, and —(CH
2
)
n
—CH
3
with n=9, 11, 13, 15, as well as for cis-9-octadecenoic acid 2-hydroxy-3-phosphonooxypropyl ester, cis-9,cis-12-octadecadienoic acid 2-hydroxy-3-phosphonooxypropyl ester, and (all-cis-9,12,15)-octadecatrienoic acid 2-hydroxy-3-phosphonooxypropyl ester (Arzneim. Forsch. 35, 587-92 (1985)).
Each alkyl is understood to represent a straight-chain or branched C
6
-C
18
alkyl group, such as hexyl, isohexyl, 2,2-dimethylhexyl, 5-methylhexyl, heptyl, isoheptyl, 6-methylheptyl, octyl, isooctyl, nonyl, isononyl, decyl, isodecyl, undecyl, isoundecyl, dodecyl, isododecyl, tridecyl, isotridecyl, tetradecyl, isotetradecyl, pentadecyl, isopentadecyl, hexadecyl, heptadecyl, isoheptadecyl, or octadecyl, particularly heptyl, decyl and dodecyl.
Each alkenyl represents an optionally substituted residue having 6-20 carbon atoms and one or more unsaturations, such as &Dgr;
1
-hexenyl, &Dgr;
1
-octenyl, &Dgr;
9
-nonenyl, &Dgr;
1
-decenyl, &Dgr;
10
-decenyl, &Dgr;
1,4
-decadienyl, &Dgr;
1,4,7
-decatrienyl, &Dgr;
1,4,7,10
-hexadecatetraenyl &Dgr;
1
-dodecenyl, &Dgr;
5
-dodecenyl, &Dgr;
1,4
-undecadienyl, &Dgr;
14
-tetradecenyl, particularly &Dgr;
1
-decenyl, &Dgr;
1,4
-decadienyl, &Dgr;
1,4,7
-decatrienyl, wherein the double bonds may be cis or trans, and all combinations are possible in compounds having multiple unsaturations.
Each alkynyl represents an optionally substituted residue having 6-20 carbon atoms and one or more unsaturations, such as &Dgr;
1
-decynyl, &Dgr;
1
-nonynyl, &Dgr;
1,3
-tetradecadiynyl, &Dgr;
1,3
-hexadecadiynyl, &Dgr;
1,3
-octadecadiynyl, particularly &Dgr;
1
-decynyl.
Compounds wherein X represents NH are particularly preferred.
Examples of physiologically usable salts of the compound of formula (I) are salts with physiologically tolerable mineral acids such as hydrochloric acid, sulfuric acid, sulfurous acid or phosphoric acid, or with organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid, or salicylic acid. Compounds of formula (I) having a free carboxyl group may also form salts with physiologically tolerable bases. Examples of these salts are alkali metal, alkaline earth metal, ammonium, and alkylammonium salts, such as sodium, potassium, calcium, or tetramethylammonium salts.
The compounds of general formula (I) contain at least one asymmetrical carbon atom and therefore, the present application is also directed to optically active compounds of general formula (I).
The pure enantiomers of the compounds of formula (I) wherein X=oxygen are obtained by using optically active alcohols which may be purchased or prepared according to well-known methods, e.g., by traditional racemate resolution via salt formation using optically active acids.
The pure enantiomers of the compounds of formula (I) wherein X=NH are obtained by using optically active aminoalcohols which may be purchased or prepared according to well-known methods, e.g., by traditional racemate resolution via salt formation using optically active acids, or by reduction of optically active amino acids.
The compounds of general formula (I) wherein X=oxygen are prepared according to per se known methods by removing the protective group R
2
from compounds of general formula (II)
wherein R
2
represents a protective group commonly used for hydroxyl groups.
The compounds of general formula (II) are prepared according to per se known methods, preferably by reacting alcohols of general formula (III)
wherein R
3
and R
4
represent protective groups commonly used for hydroxyl groups, with protective groups for 1,2-diols, such as cyclic acetals and ketals being preferred, with carboxylic acid derivatives of general formula (IV)
wherein R
1
and n have the above-mentioned meanings a
Esswein Angelika
Kling Lothar
Ambrose Michael G.
Epstein William H.
Johnston George W.
Parise John P.
Roche Diagnostics GmbH
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