Pluraflavins and derivatives thereof, process for their...

Details Pluraflavins and derivatives thereof, process for their... Pluraflavins and derivatives thereof, process for their...

2001-02-16

2002-12-31

Barts, Samuel (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S004100, C536S017200, C536S014000, C536S016800, C536S018500, C514S027000, C514S034000, C514S062000, C514S453000, C549S384000, C435S125000

Reexamination Certificate

active

06500936

ABSTRACT:

The present invention relates to novel compounds of formula I
wherein R
1
, R
2
, R
3
, R
4
, R
5
,R
6
,R
8
, R
10
and n are as defined below. The compounds of formula I inhibit transcriptase, have a cytostatic action and are particularly suitable for treating tumors. The compounds of formula I can be obtained by growing Actinomycetales species HAG 003959, DSM 12931, in a culture medium. Accordingly, the invention relates to a process for preparing the compounds of formula I the use of the compounds for preparing a pharmaceutical for the treatment of malignant disorders and of diseases which can be treated by inhibiting transcriptase, and to pharmaceutical preparations comprising at least one compound of formula I.
Cancer is a disease of humans and animals which is in most cases fatal and which is generally caused by the uncontrolled growth of endogenous cells. Cancer is the term used for the formation of malignant tumors (malignancy), of neoplasms (tumors or carcinomas) or for the malignant degeneration and dysmaturity of white blood cells (leukemia). Cancer or tumor cells are generally formed by transformation of endogenous cells. The malignancy of the cancer cell expresses itself in the autonomy of growth, i.e. its capability of growing uninhibitedly and without integration into the organ system and infiltrating, with 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 radical approach of 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 generally 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 the rapidly growing tumor tissue, react sensitively. The agents used are alkylating compounds, such as, for example, 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) and 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 significant disadvantages, so that the death of the diseased person can, in many cases, only be delayed, but not prevented. Furthermore, degenerated (cancer) cells become resistant to the agents used; in this case, 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 world-wide.
Surprisingly, it has been found that the microorganism strain Actinomycetales species HAG 003959, DSM 12931, is capable of producing highly effective novel cytostatics which inhibit cell growth even at very low concentrations. Hereinbelow, the novel compounds are referred to as pluraflavins, and they form, together with pluraflavin derivatives, part of the subject matter of the invention. The pluraflavins are antibiotics which comprise a p-quinoid ring skeleton and various sugar building blocks. They inhibit transcription by intercalation of nucleic acid double strands and, if appropriate, additional alkylation. The ring skeleton was described for the first time by S. Kondo et al. in Journal of Antibiotics, volume 30, pages 1143-1145, 1977, as a part of pluramycin. Later, this ring skeleton was found in a plurality of antibiotics; in addition to pluramycin and neopluramycin, the compounds saptomycines (N. Abe et al. J. Antibiotics, 46, 1536-1549, 1993), ankinomycin (Y. Sato et al. J. Antibiotics 42, 149, 1989), kidamycin (N. Kanda et al. J. Antibiotics, 24, 599, 1971), hedamycin (U. Sequin et al. Tetrahedron, 34, 761, 1978) and the altromycines (G. M. Brill et al. J. Antibiotics, 43, 229-237, 1990) have been described as structurally related compounds. The prior art substances often have disadvantages which manifest themselves in an unsatisfactory efficacy, high toxicity and/or undesirable side-effects.
Accordingly, the present invention relates to compounds of formula (l)
wherein
R
1
is a sugar,
R
2
is —COOH or —CH
2
—O—(R
7
)m, wherein R
7
is a sugar group,
R
3
is chosen from epoxide-comprising groups,
C
1
-C
6
-alkyl groups, and C
2
-C
6
-alkenyl groups, wherein said alkyl and alkenyl groups are optionally substituted with at least one OH group,
R
5
is chosen from H, C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl and C
2
-C
6
-alkynyl,
R
4
, R
6
, R
8
and R
10
, are each independently chosen from H, C
1
-C
6
-alkyl, C
2
-C
6
—alkenyl, C
2
-C
6
—alkynyl, —X
2
H, and -X
2
R
12,
or
R
4
and R
6
together and/or R
8
and R
10
together are =X
2
,
X
2
is O, NH, N-C
1
-C
6
—alkyl, N-C
2
-C
6
—alkenyl, N-C
2
-C
6
-alkynyl or S,
R
12
is C
1
-C
6
—alkyl, C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl, aryl or acyl, and
m and n, independently of one another, are 1 or 2,
in all their stereochemical forms and mixtures of these forms in any ratio, and their physiologically acceptable salts and derivatives.
In formula (I)
C
1
-C
6
-alkyl is a straight-chain or branched alkyl having from 1 to 6 carbon atoms, for example, methyl, ethyl, isopropyl, tert-butyl and hexyl,
C
2
-C
6
-alkenyl is a straight-chain or branched alkenyl having from 2 to 6 carbon atoms, for example, allyl, crotyl and pentenyl, and
C
2
-C
6
-alkynyl is a straight-chain or branched alkynyl having from 2 to 6 carbon atoms, for example, propynyl, butynyl and pentynyl.
Aryl is an aromatic ring structure, for example, phenyl, benzyl or 1- or 2-naphthyl. Aryl may be optionally substituted, for example by halogen, such as chlorine, bromine, fluorine, by alkyl having 1-4 carbon atoms, for example, methyl, by hydroxyl, by alkoxy having 1-4 carbon atoms, for example methoxy, and/or by trifluoromethyl.
Acyl can be aliphatic or aromatic acyl groups. The aliphatic acyl has 1-7 carbon atoms, for example 1-4 carbon atoms, such as, formyl, acetyl, propionyl, butyryl, hexanoyl, acryloyl, crotonoyl, propioloyl, which can be substituted further, for example by halogen, such as chlorine, bromine, fluorine, by amino, and/or by alkylamino having 1-4 carbon atoms, such as methyl- or ethylamino groups. Aromatic acyl can, for example, be benzoyl or naphthoyl, which can also be substituted further, for example by halogen, such as chlorine, bromine, fluorine, by alkyl having 1-4 carbon atoms, for example methyl, by hydroxyl, by amino groups, such as, example ethylamino, or by alkoxy groups having 1-7 carbon atoms, such as 1-4 carbon atoms, for example methoxy.
The sugar (R
1
R
7
) is a monosaccharide (n=1) or a disaccharide (n=2), where two monosaccharides are linked glycosidically. The monosaccharide can be a hexose (C
6
H
12
O
6
), for example an aldohexose, such as, D-(+)-glucose, D-(+)-mannose or D-(+)-galactose. The monosaccharide can be mono-, di- or tri-substituted, independently of one another, by H, OH, NH
2
, NH(alkyl), N(alkyl)
2
, alkyl and alkoxy, where the H and/or OH of the monosaccharide can be optionally replaced by substituents. The term “sugar”, as used herein, includes amino sugars. An amino sugar is a monosaccharide or disaccharide optionally substituted as described wherein at least one OH- o

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