Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-04
2003-06-17
Owens, Amelia A. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S689000, C549S401000, C568S331000, C424S195110
Reexamination Certificate
active
06579903
ABSTRACT:
The present invention relates to novel compounds of formula I
and/or of formula II
in which R
1
, R
2
, R
3
, R
4
, R
5
, X
1
, X
2
, X
3
, X
4
, X
5
and Y are defined as described below. The compounds of formulae I and II inhibit cyclin-dependent kinases (CDKs) and other kinases (e.g. KDR), have cytostatic actions, and are particularly suitable for treating tumors. The compounds of formulae I and II are obtainable by extracting the plant
Uvaria klaineri
, PLA 100484, by cell cultures of the plant
Uvaria klaineri
, or by chemical synthesis. Thus, the invention relates to a method for preparing the compounds of formulae I and II, to the use of the compounds for producing a pharmaceutical for the treatment of malignant disorders and of diseases which may be treated by inhibition of CDKs and KDR, and to pharmaceutical compositions comprising at least one compound of the formulae I or II.
Cancer is a disease of humans and animals which is in most cases fatal and which is caused by the uncontrolled growth of endogenous cells. The term “cancer” denotes the formation of malignant growths (malignancies) and neoplasms (tumors or carcinomas), or the malignant degeneration and dysmaturity of white blood cells (leukemia). Cancer or tumor cells are formed by transformation of endogenous cells. The malignancy of the cancer cell expresses itself in the autonomy of growth, i.e. in its capability of growing uninhibitedly, without integration into the organ system, and infiltrating, resulting in the destruction of tissue. A sure sign of malignancy is the formation of metastases far from the tumor after hematogenic or lymphogenic spreading of tumor cells. Cancer is one of the most frequent causes of death in humans, and there is therefore a great demand for methods and agents for curing or treating malignant degenerations. In addition to the—if possible radical—surgical removal of the tumor, the options for therapy of malignant tumors include radiotherapy with X-rays, &agr;-, &bgr;-, &ggr;-rays, immunotherapy and chemotherapy. As yet, the use of immunotherapy is limited. Chemotherapy of tumors is understood as meaning administration of cell toxins (cytostatics) for the treatment of tumors and remaining tumor cells after local surgical treatment or irradiation. These substances intervene specifically in certain processes of cell division, so that tissues having a high proportion of dividing cells, such as rapidly growing tumor tissue, react more sensitively. The agents used are alkylating compounds, such as cyclophosphamide (The Merck Index, 12th Ed. page 463), antimetabolites, such as methotrexate (The Merck Index, 12th Ed. page 1025), alkaloids, such as vincristine (The Merck Index, 12th Ed. page 1704), antibiotics, such as daunomycin (The Merck Index, 12th Ed. page 479), and adriamycin (The Merck Index, 12th Ed. pages 581-582). However, owing to massive side-effects, all these agents have great disadvantages, so that the death of the diseased individual is only delayed, but not prevented. Furthermore, degenerated (cancer) cells become resistant to the agents used. When this occurs, the conventional pharmaceuticals no longer have any cytostatic action, but they are toxic, owing to the side-effects. Furthermore, it has been found that a combined and/or sequential use of cytostatics exceeds the activity of an individual cytostatic (monotherapy), and it is therefore possible that the considerable side-effects in polychemotherapy are non-additive. For all these reasons, novel chemotherapeutics are urgently required and thus investigated worldwide.
Surprisingly, it has been found that the African plant
Uvaria klaineri
is capable of forming highly effective novel cytostatics which inhibit cell growth even at very low concentrations. The novel compounds are denoted klainetins below and are, together with klainetin derivatives, the subject of the invention. The klainetins are substituted phenols which inhibit cyclin-dependent kinases and therefore influence cell cycle regulation. Since in cancers cell proliferation is abnormally accelerated and regulation is out of control, CDK inhibitors are valuable agents for the treatment of malignant degenerations. The compounds of formula I belong to the substituted 2,3-dihydroflavone type and the ring structure corresponds to that of isochamanetin which has been described most recently by H. Achenbach et al. in Phytochemistry, vol. 44, pages 359-364 (1997). The compounds of the formula I according to the invention are novel substituted isochamanetins.
The compounds of formula II belong to the chalcone class of compounds; the ring structure and carbon skeleton correspond to that of uvaretin. Uvaretin has been found in many Uvaria species (M. H. H. Nkunya et al., Planta Med. 57:341-343 (1991); I. Muhammad & P. G. Waterman, J. Nat. Prod. 48:571-80 (1985)). The inventive compounds of the formula II are distinguished from uvaretin by substitution and dehydrogenation and have not yet been described in the literature. Owing to their different chemical structure, the compounds of the formulae I and II have novel and physicochemical, biological and pharmacological properties. In contrast, the substances known up until now often have disadvantages which are expressed in an unsatisfactory action level, high toxicity and/or undesired side-effects.
The present invention therefore relates to compounds of formula I
and/or of formula II
wherein
R
1
, R
2
, R
3
, R
4
and R
5
independently of one another are H, C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl or C
2
-C
6
-alkynyl, unsubstituted or substituted with one or more OH;
X
1
, X
2
, X
3
, X
4
and X
5
independently of one another are O, NH, N—C
1
-C
6
-alkyl, N—C
2
-C
6
-alkenyl, N—C
2
-C
6
-alkynyl, acyl, aryl or S;
Y is one or more H, halogen, OH, O—C
1
-C
6
-alkyl, O—C
2
-C
6
-alkenyl, O—C
2
-C
6
-alkynyl, NH
2
, NH—C
1
-C
6
-alkyl, NH—C
2
-C
6
-alkenyl, NH—C
2
-C
6
-alkynyl, NH-acyl, SH, S—C
1
-C
6
-alkyl, S—C
2
-C
6
-alkenyl, S—C
2
-C
6
-alkynyl, acyl or aryl;
wherein the compounds may be in any stereochemical form, mixtures of said forms in any ratio, physiologically tolerated salts, and/or chemical equivalents thereof.
In the formulae I and II
C
1
-C
6
-alkyl is a straight-chain or branched alkyl having 1 to 6 carbon atoms such as methyl, ethyl, isopropyl, tert-butyl and hexyl,
C
2
-C
6
-alkenyl is a straight-chain or branched alkenyl having 2 to 6 carbon atoms such as allyl, crotyl and pentenyl, and
C
2
-C
6
-alkynyl is a straight-chain or branched alkynyl having 2 to 6 carbon atoms such as propynyl, butynyl und pentynyl.
Aryl can be, for example, phenyl, benzyl or 1- or 2-naphthyl, which may also be unsubstituted or substituted, for example, by halogen such as chlorine, bromine and fluorine, by alkyl having 1-4 carbon atoms, preferably methyl, by hydroxyl, by alkoxy having 1-4 carbon atoms, in particular methoxy, and/or by trifluoromethoxy.
Acyl can be aliphatic or aromatic acyl radicals. Aliphatic acyl has 1-7, preferably 1-4, carbon atoms, such as formyl, acetyl, propionyl, butyryl, hexanoyl, acryloyl, crotonoyl, propioloyl, which may be further substituted, for example, by halogen such as chlorine, bromine and fluorine, by amino and/or by alkylamino having 1-4 carbon atoms, preferably methyl- or ethylamino groups. Aromatic acyl can be, for example, benzoyl or naphthoyl, which may also be further substituted, for example, by halogen such as chlorine, bromine and fluorine, by alkyl having 1-4 carbon atoms, preferably methyl, by hydroxyl, by amino groups such as ethylamino, or by alkoxy groups having 1-7, preferably 1-4, carbon atoms, in particular methoxy.
In formula I, X
1
R
1
, X
2
R
2
and X
3
R
3
preferably are OH, X
4
R
4
preferably is O—C
1
-C
4
-alkyl and Y is H. In the formula II, X
1
R
1
, X
2
R
2
, X
3
R
3
, and X
4
R
4
preferably are OH, X
5
R
5
preferably is O—C
1
-C
4
-alkyl and Y is H.
The invention thus relates to klainetin A of the formula IA
in all its stereochemical forms, to mixtures of said forms in any ratio, and to physiologically tolerated salts thereof.
The invention further relates
Haag Sabine
Kogler Herbert
Li Ziyu
Vértesy Laszló
Aventis Pharma Deutschland GmbH
Owens Amelia A.
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