Half-sandwich ruthenium (II) compounds comprising nitrogen...

Details Half-sandwich ruthenium (II) compounds comprising nitrogen... Half-sandwich ruthenium (II) compounds comprising nitrogen...

2002-04-26

2004-06-15

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heavy metal containing doai

C514S188000, C556S137000, C546S002000

Reexamination Certificate

active

06750251

ABSTRACT:

This invention relates to ruthenium (II) compounds, to their use in medicine, particularly for the treatment and/or prevention of cancer, and to a process for their preparation.
Certain ruthenium (II) complexes have been proposed for use in treating cancer. For example, U.S. Pat. No. 4,980,473 discloses 1,10-phenanthroline complexes of ruthenium (II) and cobalt (III) which are said to be useful for the treatment of tumour cells in a subject.
Some other ruthenium (II) and ruthenium (III) complexes which have been shown to exhibit antitumour activity are mentioned in Guo et al, Inorganica Chimica Acta, 273 (1998), 1-7, specifically trans-[RuCl
2
(DMSO)
4
], trans-[RuCl
2
(imidazole)
2
]- and trans-[RuCl
4
(indazole)
2
]. Guo et al discloses that the most interesting feature of these complexes is their anti-metastatic activity. Clarke et at have reviewed the anticancer and in particular the antimetastatic activity of ruthenium complexes: Chem. Rev. 1999, 99, 2511-2533. Also, Sava has reveiwed the antimetastatic activity in “Metal Compounds in Cancer Therapy” Ed by S P Fricker, Chapman and Hall, London 1994, p. 65-91.
Dale et al, Anti-Cancer Drug Design (1992), 7, 3-14, describes a metronidazole complex of ruthenium (II) ie, [(&eegr;
6
-C
6
H
6
)RuCl
2
(metronidazole)] and its effect on DNA and on
E. coli
growth rates. Metronidazole sensitises hypoxic tumour cells to radiation and appears to be an essential element of the complexes of Dale et al. There is no indication in Dale et al that the complexes would be at all effective in the absence of the metronidazole ligand.
Krämer et al,
Chem Eur J.,
1996, 2, No. 12, p. 1518-1526 discloses half sandwich complexes of ruthenium with amino esters.
There exists a need for novel anti-cancer compounds which can be used as alternatives to the compounds which are currently available.
The present invention provides a novel class of ruthenium (II) complexes having anti-tumour activity.
According to the present invention there is provided a ruthenium (II) compound of formula (I):
wherein:
R
1
, R
2
, R
3
, R
4
, R
5
and R
6
independently represent H, alkyl, —CO
2
R′, aryl or alkylaryl, which latter two groups are optionally substituted on the aromatic ring;
R′ represents alkyl, aryl or alkaryl;
X is halo, H
2
O, (R′)(R″)SO, R′CO
2
— or (R′)(R″)C═O, where R″ represents alkyl, aryl or alkaryl;
Y is a counterion;
m is 0 or 1;
q is 1, 2or 3;
C′ is C
1
to C
12
alkylene, optionally substituted in or on the alkylene chain, bound to two A groups;
p is 0 or 1 and r is 1 when p is 0 and r is 2 when p is 1; and
A and B are: each independently N-donor nitrile ligands; or B is halo and A is an N-donor pyridine ligand, optionally substituted at one or more of the carbon atoms of the pyridine ring; or p is 0, A is NR
7
R
8
and B is NR
9
R
10
, wherein R
7
, R
8
, R
9
and R
10
independently represent H or alkyl, and A and B are linked by an alkylene chain, optionally substituted in or on the alkylene chain; or p is 1, A is NR
7
and B is NR
9
R
10
, wherein R
7
, R
9
and R
10
are as previously defined, and A and B are linked by an alkylene chain, optionally substituted.
The compounds of the invention may be in the form of solvates and/or prodrugs. Prodrugs are variants of the compounds of the invention which can be converted to compounds of formula (I) in vivo.
The compounds of formula (I) may have one or more chiral centres. When the compounds of formula (I) have one or more chiral centres, they may be in the form of one enantiomer, may be enriched in one enantiomer or may be a racemic mixture.
The term “alkyl” as used herein includes C
1
to C
6
alkyl groups which may be branched or unbranched and may be open chain or, when they are C
3
to C
6
groups, cyclic. Unbranched open chain alkyl groups include, for example, methyl, ethyl, propyl, butyl, pentyl and hexyl. Branched open chain alkyl groups include, for example, 2-propyl, 2-butyl and 2-(2-methyl)propyl. Cyclic groups include cyclopropyl; cyclobutyl, cyclopentyl and cyclohexyl. The alkyl groups in the compounds of the invention may optionally be substituted. Substituents include one or more further alkyl groups and/or one or more further substituents, such as, for example, cyano, nitro, hydroxyl, haloalkyl, —CO
2
alkyl, halo, thiol (SH), thioether (eg, S-alkyl) and sulfonate. The term “alkylene” is defined similarly to the definition of the term “alkyl” but includes C
2
to C
12
groups and is a divalent species with radicals separated by two or more (eg, from two to twelve) carbon atoms linked in a chain. Preferably, the alkylene groups are straight chain groups. Alkylene groups are optionally substituted in the alkylene chain, preferably with one or more phenylene (eg, 1,4phenylene) and/or —CONR
1a
— groups and/or —NR
2a
— groups, where R
1a
and R
2a
independently represent H, alkyl, aryl or alkaryl. Preferably, R
1a
and R
2a
are H or C
1
to C
3
alkyl.
The term “aryl” as used herein includes aromatic carbocyclic rings such as phenyl and naphthyl and heterocyclic rings such as pyridyl, imidazolyl, pyrrolyl and furanyl. Aryl groups may optionally be substituted with one or more substituents including, for example, alkyl, cyano, nitro, hydroxyl, haloalkyl, —CO
2
alkyl, halo, thiol (SH), thioether (eg, S-alkyl) and sulfonate.
The term “alkaryl” means alkyl substituted with aryl eg, benzyl.
The term “halo” means a halogen radical selected from fluoro, chloro, bromo and iodo.
The term “haloalkyl” means alkyl substituted with one or more halo groups eg, trifluoromethyl.
In the compounds of formula (I), R
1
, R
2
, R
3
, R
4
, R
5
and R
6
may represent H. Alternatively, R
1
may be 2-propyl and R
4
may be methyl, with R
2
, R
3
, R
5
and R
6
all representing hydrogen. As a further alternative, R
1
may be phenyl, with R
2
, R
3
, R
4
, R
5
and R
6
all representing hydrogen. In a yet further alternative, R
1
may be —CO
2
R′, such as —CO
2
CH
3
for example, with R
2
, R
3
, R
4
, R
5
and R
6
all representing hydrogen.
In one aspect, A and B in the compounds of formula (I) both represent R
11
—CN. R
11
is alkyl, preferably C
1
to C
3
alkyl, more preferably methyl.
In another aspect, one of A and B in the compounds of formula (I) represents a 4-substituted pyridine and the other represents halo. The pyridine may be substituted at the 4-position by, for example, groups including nitro, cyano and C(O)NR
12
R
13
wherein R
12
and R
13
are independently selected from H and alkyl (eg, C
1
to C
6
alkyl). The group at the 4-position of the pyridine ring is preferably an electron withdrawing group.
In a further aspect, A and B may together represent NR
7
R
8
—(CR
12
R
13
)
n
—NR
9
R
10
, wherein R
12
and R
13
are independently H or allyl or R
12
and R
13
groups, on the same carbon atom or on neighbouring carbon atoms, are linked to form a carbocylic ring and n is an integer from 1 to 4. Preferably, R
12
and R
13
are both hydrogen and n is 2 or 3, more preferably 2. R
7
, R
8
, R
9
and R
10
are preferably H or methyl and, more preferably, all of R
7
, R
8
, R
9
and R
10
are H.
When R
8
is present in A, then p is 0. When R
8
is absent, then p is 1.
In a further aspect of the invention, R
8
is absent from A, p is 1 and C′ is C
4
to C
10
straight chain alkylene (eg, hexylene). Compounds according to this aspect of the invention are so-called dinuclear complexes comprising two ruthenium atoms per complex.
Other examples of dinuclear complexes of the invention are those in which is A and B together represent:
wherein each n′, n″, x′, x″ and y′ independently represents an integer from 1 to 12, preferably 1 to 6.
Y
q−
in compounds of formula (I) is a counterion and is only present in the compound when the complex containing the metal ion is charged. Y
q−
is preferably a non-nucleophilic anion such as PF
6
−
, for example.
R′ and R″ are preferably alkyl. Most preferably, both R′ and R″ are meth

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