5-(9-acridinylamino)-toluidine compounds

Details 5-(9-acridinylamino)-toluidine compounds 5-(9-acridinylamino)-toluidine compounds

2003-07-30

2004-11-23

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S106000, C546S105000, C546S103000

Reexamination Certificate

active

06821983

ABSTRACT:

TECHNICAL FIELD
This invention relates to 9-anilinoacridine compounds, and more particularly to their synthesis and their use in pharmaceutical compositions for treating diseases.
BACKGROUND
Inhibitors of topoisomerase II can exhibit antitumor activity. Among such inhibitors are 9-anilinoacridine compounds, e.g., 4′-(9-acridinylamino) methanesulfon-m-anisidine (m-AMSA) and CI-921 (5-methyl-4-methylcarboxamide derivative of m-AMSA), both of which were investigated for the treatment of leukemia and solid tumors. See e.g., Cain et al., Eur. J. Cancer 1974, 10:539 and Arlin Z.,
Cancer Treat. Rep.
1983, 967 and Baguley et al.,
Cancer Res.
1984, 44:3245 and Denny et al.,
J. Med. Chem.
1987, 30:658. A distinguishing chemical feature of these two 9-anilinoacridines is that they can readily undergo reversible oxidation, chemically or microsomally, to give quinonediimines. See e.g., Shoemaker et al,
Cancer Res.
1984, 44:1939 and Shoemaker et al.,
Drug Metab. Dispos.
1982, 10:35.
Su et al. reported a series of 9-anilinoacridines that exhibited antitumor activity, but were incapable of quinonediimine formation. See e.g., Su et al.
Am. Assoc. Cancer Res.
1994, 368, U.S. Pat. No. 5,939,428
, J. Med. Chem.
1995, 38, 3226-3235; and
J. Med. Chem.
1999, 42, 4147-4748. Examples include derivatives in which the 9-amino group was substituted by an oxygen or sulfur atom, and those in which the aniline substituents were located meta to the nitrogen attached to the 9-position of the acridine ring. Among the latter compounds, a series of 3-(acridin-9-yl)amino-5-hydroxymethylanilines and their ethylcarbamate derivatives were shown to have significant antitumor activity both in vitro and in vivo.
SUMMARY
In one aspect, this invention features compounds of Formula (I):
In the above formula, R
1
is hydrogen, COR
a
, or COOR
a
; each of R
2
, R
3
and R
4
is, independently, hydrogen, C
1
-C
10
alkyl, or OR
b
, with the proviso that R
2
, R
3
and R
4
cannot all be hydrogen. Each of R
5
and R
6
is, independently, hydrogen, C
1
-C
6
alkyl, OR
c
, nitro, halo, N(R
c
)
2
, NH(CH
2
)
p
N(R
c
)
2
, (CH
2
)
q
OH, (CH
2
)
q
X, CONHR
c
, CONH(CH
2
)
p
N(R
c
)
2
, SO
3
R
c
, or SO
2
R
c
with the proviso that when R
1
is hydrogen and R
4
is CH
3
, R
5
and R
6
cannot both be hydrogen. Each of m and n, is independently, 0-4. R
a
is aryl, or C
1
-C
10
alkyl, optionally substituted with oxo; R
b
is C
1
-C
10
alkyl; R
c
is hydrogen or C
1
-C
10
alkyl; p is 1-5; and q is 1-3.
Referring to formula (I) above, a subset of the compounds described above are those in which one of R
2
, R
3
and R
4
is C
1
-C
6
alkyl or OR
b
and one of R
2
, R
3
and R
4
is hydrogen. R
2
, R
3
, R
4
and R
b
can be C
1
-C
4
alkyl. R
2
, R
3
and R
4
and OR
b
can be e.g., CH
3
or OCH
3
.
Embodiments can include one or more of the following.
R
1
can be hydrogen, COR
a
or COOR
a
, and R
a
can be C
1
-C
4
alkyl, optionally substituted with oxo (e.g., R
1
can be COCH
2
CH
2
COCH
3
or COOCH
2
CH
3
).
Each of R
5
and R
6
can be independently, hydrogen, C
1
-C
6
alkyl, OR
c
or CONHR
c
, or CONH(CH
2
)
p
N(R
c
)
2
and each of m and n can be, independently, 1. R
c
can be C
1
-C
4
alkyl, and p can be 2. R
5
and R
6
can occupy the C-4 and C-5 positions of the acridine ring, respectively. For example, R
5
can be CONH(CH
2
)
2
N(CH
3
)
2
and R
6
can be CH
3
.
The compound can be {3-[4-(2-dimethylamino-ethylcarbamoyl)-5-methyl-acridin-9-ylamino]-5-methyl-phenyl}-carbamic acid ethyl ester.
The compound can be {3-[4-(2-dimethylamino-ethylcarbamoyl)-5-methyl-acridin-9-ylamino]-4-methyl-phenyl}-carbamic acid ethyl ester.
The compound can be [9-(3-amino-5-methyl-phenyl)amino]-5-methyl-acridine-4-carboxylic acid (2-dimethylamino-ethyl)-amide.
The compound can be [9-(5-amino-4-methyl-phenyl)amino]-5-methyl-acridine-4-carboxylic acid (2-dimethylamino-ethyl)-amide.
The term “halo” refers to any radical of fluorine, chlorine, bromine and iodine. The term “alkyl” refers to both cyclic and acyclic, saturated and unsaturated non-aromatic C
1
-C
10
hydrocarbon moieties, e.g., CH
3
, CH═C
2
H
4
, or C
6
H
11
(cyclic). The term “haloalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by halo, and includes alkyl moieties in which all hydrogens have been replaced by halo (e.g., perfluoroalkyl). The term “aryl” refers to both hydrocarbon aryl moieties and heteroaryl moieties. Examples of hydrocarbon aryl moieties include phenyl, naphthyl, pyrenyl, anthryl, and phenanthryl. Examples of heteroaryl moieties include furyl, fluorenyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, and indolyl.
The term “oxo” refers to an oxygen atom, which forms a carbonyl when attached to carbon.
Shown below are exemplary compounds, compounds 1-12, of this invention:
The 9-anilinoacridine compounds of this invention include the compounds themselves, as well as their salts and their prodrugs, if applicable. A salt, for example, can be formed between an anion and a positively charged substituent (e.g., amino) on a 9-anilinoacridine compound. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, a salt can also be formed between a cation and a negatively charged substituent (e.g., sulfate) on a 9-anilinoacridine compound of this invention. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylanunonium ion. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing active 9-anilinoacridine compounds.
In another aspect, the invention features a pharmaceutical composition that contains an effective amount of at least one of the 9-anilinoacridines described above and a pharmaceutically acceptable carrier. Also within the scope of this invention is a composition containing one or more of the 9-anilinoacridine compounds described above for use in treating cancer, and the use of such a composition for the manufacture of a medicament for the just-mentioned use.
In still another aspect, the invention is a method of treating a subject (e.g., human, mammal, dog, cat, horse) having cancer including administering to the subject an effective amount of a compound of Formula (I). The cancer can be a human leukemia, sarcoma, osteosarcoma, lymphoma, melanoma, ovarian, skin, testicular, gastric, pancreatic, renal, breast, prostate colorectal, head and neck, brain, esophageal, bladder, adrenal cortical, lung, bronchus, endometrial, cervical or hepatic cancer.
In one aspect, the invention features a method for synthesizing a compound of Formula (II):
The method includes contacting a compound of Formula (III):
with a compound of Formula (IV):
to form a compound of Formula (II). R
4
is C
1
-C
10
alkyl or OR
b
. Each of R
5
and R
6
is, independently, hydrogen, C
1
-C
6
alkyl, OR
c
, nitro, halo, N(R
c
)
2
, NH(CH
2
)
p
N(R
c
)
2
, (CH
2
)
q
OH, (CH
2
)
q
X, CONHR
c
, CONH(CH
2
)
p
N(R
c
)
2
, SO
3
R
c
, or SO
2
R
c
. Each of m and n, is independently, 0-4. R
a
is aryl, or C
1
-C
10
alkyl, optionally substituted with oxo; R
b
is C
1
-C
10
alkyl; R
c
is hydrogen or C
1
-C
10
alkyl; p is 1-5; q is 1-3; L is halo, OSO
2
R
7
, or OR
7
; and
R
7
is alkyl, haloalkyl, or aryl optionally substituted with halo or nitro.
The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.
DETAILED DESCRIPTION
The compounds of this invention can be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials. In general, the compounds of the formulae described herein are conveniently obtained via standard organic chemistry synthesis methods, including

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