Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-22
2004-06-29
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S351000, C558S083000, C558S085000, C558S086000
Reexamination Certificate
active
06756402
ABSTRACT:
The invention relates to novel compounds, called cyclipostins, obtainable by culturing Streptomyces species HAG 004107 (DSM 13381), and their physiologically tolerable salts and chemical equivalents. The invention furthermore relates to a process for the preparation of the cyclipostins, the microorganism HAG 004107 (DSM 13381), the use of the cyclipostins and their physiologically tolerable salts and chemical equivalents as pharmaceuticals, in particular as inhibitors of lipases, and pharmaceutical preparations which contain cyclipostin or a physiologically tolerable salt or equivalent thereof.
A disease which can be treated particularly advantageously with lipase inhibitors is the sugar disease diabetes mellitus. Diabetes mellitus is a condition which is characterized by increased blood sugar concentrations on account of chronic metabolic disorders. The metabolic disorders are based on an insulin deficiency or reduced insulin action. Reduced insulin action leads to defective utilization by the body cells of the glucose absorbed in the blood. On account of this and because of neogenesis of glucose from proteins (gluconeogenesis), there is a rise in the blood glucose level. Moreover, in the case of decreased insulin action in the fatty tissue, the insulin-antagonistic hormones, such as glucagon, lead to increased lipolysis and thus to raised fatty acid concentrations in the blood. Ketoacidosis occurs, i.e., the increased formation of ketone bodies (acetic acid, &bgr;-hydroxybutyric acid, acetone). Under acute conditions, the extent of the biochemical dysregulation is life-threatening and, if untreated, leads to diabetic coma and finally to rapid death. Diabetes is one of the most frequent chronic metabolic disorders of man and it is estimated that up to more than 3% of the population have a diabetic or prediabetic disposition and are thus may be acutely threatened. There is therefore a great need for agents for the treatment or cure of diabetes mellitus.
Diabetes is treated by insulin administration. In adult-onset diabetes, the so-called noninsulin-dependent (NIDDM) or type II diabetes, sulfonylureas are first administered. The principle of action of the sulfonylureas is via proliferation of the secretion of insulin of the &bgr;-cells in the pancreas, thus compensating for the hormone deficiency or the insulin resistance. Upon progression of the condition, however, insulin also has to be employed. The action of insulin can be summarized in the following way. This peptide hormone lowers the concentration of the glucose in the blood and leads to an increase in anabolic processes and simultaneously to an inhibition of catabolic processes:
it increases the glucose transport into the body cells;
it increases the glycogen formation in the liver and in the muscles;
it inhibits lipolysis;
it increases the absorption of fatty acids into the fatty tissue; and
it increases the absorption of amino acids into the body cells and protein synthesis.
One of the strongest effects of insulin is the inhibition of lipolysis. In the case of type II diabetics, this regulation of lipolysis is no longer effective and an increased level of free fatty acids in the blood occurs. Free fatty acids in the blood stimulate gluconeogenesis in the liver and decrease utilization of glucose in the skeletal muscles. Lipolysis (the release of fatty acids by the so-called hormone-sensitive lipase (HSL), which is found in the fat cells and is inhibited by insulin by a phosphorylation cascade) is controlled. Inhibitors of HSL would therefore be desirable which stimulate the action of insulin and are able to lower the blood lipid level. Such agents are suitable for the treatment of type II diabetics to control the lipid metabolism, but applications would also be possible in other storage disorders. For these reasons, novel inhibitors of HSL and other lipases are urgently needed and therefore sought.
Surprisingly the microorganism strain Streptomyces species HAG 004107, DSM 13381, is able to form highly active novel lipase inhibitors which inhibit the hormone-sensitive lipase even at very low concentrations. The novel natural compounds are organophosphates which consist of a double ring system (bicycle) and a substituted carbon chain. The compounds specifically inhibit the lipases. The ring structure was described for the first time, with a methyl group instead of a carbon chain, as an acetylcholine esterase inhibitor, CGA 134 736, by R. Neumann & H. H. Peter in
Experientia,
43:1235-1237 (1987). The same compound was designated as “cyclophostin,” by T. Kurokawa et al. in
J. Antibiotics,
46:1315-1318 (1993). This structurally related compound has no selective lipase-inhibiting properties. The previously known substances have disadvantages which are manifested in an unsatisfactory level of action, high toxicity and/or undesirable side effects.
The present invention therefore relates to compounds of formula I
wherein
R
1
is
(a) a carbon chain having 2 to 30 carbon atoms, which can be straight-chain, branched, saturated or unsaturated, carbo- or heterocyclic, and wherein the carbon chain is optionally mono- or disubstituted by a radical selected from:
(a)(1) —OH,
(a)(2) ═O,
(a)(3) —O—C
1
-C
6
-alkyl, in which alkyl is linear or branched,
(a)(4) —O—C
2
-C
6
-alkenyl, in which alkenyl is linear or branched,
(a)(5) —C
1
-C
6
-alkyl, in which alkyl is linear or branched,
(a)(6) —aryl,
(a)(7) —C
1
-C
6
-alkylbenzene,
(a)(8) —diphenyl,
(a)(9) —NH—C
1
-C
6
-alkyl, in which alkyl is linear or branched,
(a)(10) —NH—C
2
-C
6
-alkenyl, in which alkenyl is linear or branched,
(a)(11) —NH
2
,
(a)(12) ═S,
(a)(13) —S—C
1
-C
6
-alkyl, in which alkyl is linear or branched,
(a)(14) —S—C
2
-C
6
-alkenyl, in which alkenyl is linear or branched, and
(a)(15) halogen, wherein the substituents (a)(1) to (a)(15) can also be additionally substituted, or
(b)-[-aryl-(CH
2
)
n
]
m
, wherein [-aryl-(CH
2
)
n
]
m
is unsubstituted, or mono- or disubstituted by a radical as described in (a)(1) to (a)(15), and n and m independently of one another are integers zero, 1, 2, or 3;
R
2
is
C
1
-C
6
-alkyl, in which alkyl is unsubstituted or mono- or disubstituted by a radical as described in (a)(1) to (a)(15),
C
2
-C
6
-alkenyl, in which alkenyl is unsubstituted or mono- or disubstituted by a radical as described in (a)(1) to (a)(15), or
C
2
-C
6
-alkynyl, in which alkynyl is unsubstituted or mono- or disubstituted by a radical as described in (a)(1) to (a)(15),
E is a phosphorus (P) or sulfur (S) atom; and
X
1
, X
2
and X
3
, independently of one another, are selected from
—O—,
—NH—,
—N═,
—S—,
—CH
2
—, and
—CHR
2
—.
in all their stereochemical forms and mixtures of these forms in any ratio, and their physiologically tolerable salts and chemical equivalents.
R
1
preferably has a chain length of 6 to 24 carbon atoms, very preferably of 10 to 18 carbon atoms. The chain can be saturated, e.g., -alkyl, in which alkyl can be linear or branched, or unsaturated, e.g., -alkenyl or -alkynyl, in which alkenyl or alkynyl is linear or branched. R
1
can be unsubstituted, or identically or differently mono- or disubstituted by groups (a)(1) to (a)(15), as described above. Substitution on the carbon atoms 8′ to 16′ is preferred and on the positions 10′ to 14′ is particularly preferred. The substituents (a)(1) to (a)(15) can also be additionally substituted by one or more groups selected from: alcohol, aldehyde, acetal, ketal, ether, carboxyl, ester, amino, nitrile, nitro, oxime, oxime ether, and halogen.
A carbocyclic carbon chain having 2 to 30 carbon atoms is a chain consisting of 2 to 30 carbon atoms with one or more, preferably with one, with two, or with three ring systems, which preferably in each case consists of 4, 5, 6 or 7 carbon atoms. The rings can be mono-, di- or tricyclic, preferably monocyclic, and may be positioned at the beginning, in the center, and/or at the end of the carbon chain. The carbocycles can be aliphatic or aromatic in nature. Some examples are substituted diphenyls or alkylben
Ehrlich Klaus
Kurz Michael
Vertesy Laszlo
Wink Joachim
Aventis Pharma Deutschland GmbH
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Lambkin Deborah C.
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