U.S. patent application number 10/384979 was filed with the patent office on 2003-10-09 for indolo[2,1-b] quinazole-6,12-dione antimalarial compounds and methods of treating malaria therewith.
Invention is credited to Gerena, Lucia, Kyle, Dennis E., Pitzer, Kevin K., Scovill, John P..
Application Number | 20030191138 10/384979 |
Document ID | / |
Family ID | 22289636 |
Filed Date | 2003-10-09 |
United States Patent
Application |
20030191138 |
Kind Code |
A1 |
Pitzer, Kevin K. ; et
al. |
October 9, 2003 |
Indolo[2,1-b] quinazole-6,12-dione antimalarial compounds and
methods of treating malaria therewith
Abstract
Compounds, compositions and methods are provided for treating
malaria parasites in vitro and in vivo by administering
indolo[2,1-b]quinazoline-- 6,12-dione compounds of Formula I. 1
wherein A, B, C, D, E, F, G and H are independently selected from
carbon and nitrogen, or A and B or C and D can be taken together to
be nitrogen or sulfur, with the proviso that not more than three of
A, B, C, D, E, F, G and H are other than carbon; wherein R.sub.1
through R.sub.8 are independently selected from the group
consisting of, but not limited to, the halogens (F, Cl, Br, and I),
alkyl groups, trifluoromethyl groups, methoxyl groups, the carboxy
methyl or carboxy ethyl group (COOCH.sub.3 or COOCH.sub.2CH.sub.3),
nitro, aryl, heteroaryl, cyano, amino, dialkylaminoalkyl,
1-(4-alkylpiperazinyl), and the pharmaceutically acceptable salts
thereof; and wherein X is independently selected from the group
consisting of any atom especially oxygen, or any side chain
necessary to make the indolo[2,1-b]quinazoline-6,12-dione compound
a "prodrug" as the term is understood by one of ordinary skill in
the art of medicinal chemistry. In other words, a side chain having
a structure where a carbon-nitrogen double bond bears substituents
that make the prodrug more water soluble and bioavailable.
Inventors: |
Pitzer, Kevin K.; (Pasadena,
MD) ; Scovill, John P.; (Walkersville, MD) ;
Kyle, Dennis E.; (Gaithersburg, MD) ; Gerena,
Lucia; (Silver Spring, MD) |
Correspondence
Address: |
Caroline Nash
Nash & Titus, LLC
3415 Brookeville Road
Brookeville
MD
20833
US
|
Family ID: |
22289636 |
Appl. No.: |
10/384979 |
Filed: |
March 10, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10384979 |
Mar 10, 2003 |
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09850996 |
May 8, 2001 |
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6531487 |
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09850996 |
May 8, 2001 |
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09407196 |
Sep 28, 1999 |
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6284772 |
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60102399 |
Sep 30, 1998 |
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Current U.S.
Class: |
514/257 ;
514/252.16; 544/247 |
Current CPC
Class: |
C07D 487/04 20130101;
C07D 487/14 20130101; C07D 471/14 20130101; Y10S 514/895 20130101;
C07D 513/04 20130101; Y02A 50/30 20180101 |
Class at
Publication: |
514/257 ;
544/247; 514/252.16 |
International
Class: |
A61K 031/519; C07D
487/14 |
Claims
We claim:
1. An antimalarial compound comprising one or more
indolo[2,1-b]quinazolin- e-6,12-dione compounds of Formula I:
97wherein A, B, C, D, E, F, G and H are independently selected from
carbon and nitrogen, or A and B or C and D can be taken together to
be nitrogen or sulfur, with the proviso that not more than three of
A, B, C, D, E, F, G and H are other than carbon; wherein R.sub.1
through R.sub.8 are independently selected from the group
consisting of, but not limited to F, Cl, Br, I, alkyl groups,
trifluoromethyl groups, methoxyl groups, a carboxy methyl or a
carboxy ethyl group (COOCH.sub.3 or COOCH.sub.2CH.sub.3), nitro,
aryl, heteroaryl, cyano, amino, dialkylaminoalkyl,
1-(4-alkylpiperazinyl), and pharmaceutically acceptable salts
thereof; and wherein X is independently selected from the group
consisting of oxygen and a side chain rendering the
indolo[2,1-b]quinazoline-6,12-dione compound a prodrug.
2. The antimalarial compound of claim 1, wherein the
indolo[2,1-b]quinazoline-6,12-dione compound is a prodrug.
3. The antimalarial compound of claim 1, wherein said compound of
the Formula I comprises asymmetrically substituted carbon
atoms.
4. The antimalarial compound of claim 3, wherein said
asymmetrically substituted carbon atoms comprise mixtures of
steroisomers.
5. The antimalarial compound of claim 3, wherein said compound
comprises at least one member of the group consisting of racemic
mixtures, diastereomer mixtures, diastereomers and single
enantiomers.
6. The antimalarial compound of claim 1, wherein said
indolo[2,1-b]quinazoline-6,12-dione compound comprises Formula II:
98
7. The antimalarial compound of claim 1, wherein said
indolo[2,1-b]quinazoline-6,12-dione compound comprises Formula III
99
8. An antimalarial composition comprising a pharmaceutically
effective amount of one or more indolo[2,1-b]quinazoline-6,12-dione
compounds of Formula I: 100wherein A, B, C, D, E, F, G and H are
independently selected from carbon and nitrogen, or A and B or C
and D can be taken together to be nitrogen or sulfur, with the
proviso that not more than three of A, B, C, D, E, F, G and H are
other than carbon; wherein R.sub.1, through R.sub.8 are
independently selected from the group consisting of, but not
limited to F, Cl, Br, I, alkyl groups, trifluoromethyl groups,
methoxyl groups, a carboxy methyl or a carboxy ethyl group
(COOCH.sub.3 or COOCH.sub.2CH.sub.3), nitro, aryl, heteroaryl,
cyano, amino, dialkylaminoalkyl, 1-(4-alkylpiperazinyl), and
pharmaceutically acceptable salts thereof; and wherein X is
independently selected from the group consisting of oxygen and a
side chain rendering the indolo[2,1-b]quinazoline-6,12-dione
compound a prodrug.
9. The antimalarial composition of claim 8, wherein said
composition further comprises one or more adjuvants.
10. The antimalarial composition of claim 9, wherein said adjuvants
comprise one or more antiparasitic drug.
11. The antimalarial composition of claim 8, wherein said
composition further comprises one or more antimalarial drugs
selected from the group consisting of mefloquine, halofantrine,
artesunate, artemether, chloroquine, halofantrine, primaquine,
sulfadoxine, sulfalene, pyrimethamine, doxycycline, tetracycline,
azithromycine, proguanil, cycloguanil, dapsone, artemsinin and
atovoquone.
12. The antimalarial composition of claim 8, wherein said
composition further comprises a pharmaceutically acceptable
carrier.
13. The antimalarial composition of claim 8, wherein said
composition further comprises one or more pharmaceutically
acceptable additive selected from the group consisting of water,
Ringer's solution, isotonic sodium chloride solution, sterile fixed
oils, fatty acids, cocoa butter/polyethylene glycol, sucrose,
lactose, starch, lubricating agents, buffering agents or
liposomes.
14. The antimalarial composition of claim 8, wherein said salts are
selected from the group consisting of acetate, adipate, alginate,
citrate, aspartate, benzoate, benzenesulfonate, bisulfate,
butyrate, camphorate, camphorsulfonate, digluconate,
cyclopentanepropionate, dodecylsulfate, ethanesulfonate,
glucoheptanoate, glycerophosphate, hemisulfate, heptanoate,
hexanoate, fumarate, hydrochloride, bydrobromide, hydroiodide,
2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,
nicotinate, 2-napthalenesulfonate, oxalate, pamoate, pectinate,
persulfate, 3-phenylproionate, picrate, pivalate, propionate,
succinate, tartrate, thiocyanate, p-toluenesulfonate and
undecanoate.
15. The antimalarial composition of claim 8, wherein said
composition is water soluble, oil-soluble or dispersible.
16. The antimalarial composition of claim 8, wherein said
composition of the Formula I is in a form of a pharmaceutically
acceptable acid addition salt.
17. The antimalarial composition of claim 16, wherein said acid
addition salt is formed with hydrochloric acid, sulphuric acid,
phosphoric acid, oxalic acid, maleic acid succinic acid or citric
acid.
18. The antimalarial composition of claim 8, wherein said
composition is in the form of a tablet, inhalant, parenteral
injection, oral liquid, transdermal preparation, suppository or
spray.
19. A method of treating malaria in a host caused by malaria
parasites comprising: contacting said malaria parasites in said
host with a pharmaceutically effective, growth inhibiting amount of
an antimalaria compostion comprising one or more
indolo[2,1-b]quinazoline-6,12-dione compounds of Formula I: wherein
A, B, C, D, E, F, G and H are independently selected from carbon
and nitrogen, or A and B or C and D can be taken together to be
nitrogen or sulfur, with the proviso that not more than three of A,
B, C, D, E, F, G and H are other than carbon; wherein R.sub.1
through R.sub.8 are independently selected from the group
consisting of, but not limited to F, Cl, Br, I, alkyl groups,
trifluoromethyl groups, methoxyl groups, a carboxy methyl or a
carboxy ethyl group (COOCH.sub.3 or COOCH.sub.2CH.sub.3), nitro,
aryl, heteroaryl, cyano, amino, dialkylaminoalkyl,
1-(4-alkylpiperazinyl), and pharmaceutically acceptable salts
thereof; and wherein X is independently selected from the group
consisting of oxygen and a side chain rendering the
indolo[2,1-b]quinazoline-6,12-dione compound a prodrug; and
inhibiting the growth of said malaria parasites.
20. The method of claim 19, wherein said malaria parasites are one
or more of the strains of the group consisting of Plasmodium
falciparum, Plasmodium ovale, Plasmodium malariae and Plasmodium
vivax.
21. The method of claim 19, wherein said malaria parasites are a
sensitive-strain resistant origin or a multi-drug resistant strain
origin.
22. The method of claim 19, wherein said antimalarial composition
further comprises an adjuvant.
23. The method of claim 19, wherein the
indolo[2,1-b]quinazoline6,12-dione compound is a prodrug.
24. The method of claim 23, where said prodrug comprises the
Formula II 101
25. The method of claim 19, further comprises contacting said
malaria parasites with one or more additional antimalarial drugs
selected from the group consisting of mefloquine, halofantrine,
artesunate, artemether, chloroquine, halofantrine, primaquine,
sulfadoxine, sulfalene, pyrimethamine, doxycycline, tetracycline,
azithromycine, proguanil, cycloguanil, dapsone, artemsinin and
atovoquone.
26. The method of claim 25, wherein said compound of the Formula I
and said additional antimalarial drug contact said malaria
parasites together in a single dosage form or separately in
separate dosage forms given simultaneously or at different
times.
27. The method of claim 19, wherein said composition of the Formula
I is in the form of salts derived from inorganic or organic
acids.
28. The method of claim 27, wherein said salts are selected from
the group consisting of acetate, adipate, alginate, citrate,
aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,
camphorate, camphorsulfonate, digluconate, cyclopentanepropionate,
dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,
bydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate,
maleate, methanesulfonate, nicotinate, 2-napthalenesulfonate,
oxalate, pamoate, pectinate, persulfate, 3-phenylproionate,
picrate, pivalate, propionate, succinate, tartrate, thiocyanate,
p-toluenesulfonate and undecanoate.
29. The method of claim 19, wherein said composition is water
soluble, oil-soluble or dispersible.
30. The method of claim 19, wherein said composition of the Formula
I is in the form of pharmaceutically acceptable acid addition
salts.
31. The method of claim 30, wherein said acid addition salts are
formed with hydrochloric acid, sulphuric acid, phosphoric acid,
oxalic acid, maleic acid succinic acid or citric acid.
32. The method of claim 19, wherein said host is contacted with
said composition in a daily dose of 0.001 to 1000 mg/kg of body
weight.
33. The method of claim 32, wherein said host is contacted with
said composition in a daily dose of 1.0 to 50 mg/kg body
weight.
34. The method of claim 22, wherein said host is contacted with
said adjuvant in a daily dose of 0.001 to 1000 mg/kg of body
weight.
35. The method of claim 19, wherein said composition is in the form
of a tablet, inhalant, parenteral injection, oral liquid,
transdermal preparation, suppository or spray.
36. The method of claim 19, wherein said contacting is via an
administration given orally, parenterally, sublingually, rectally,
topically or with an inhalation spray.
37. A method of inhibiting the growth of malaria in vitro
comprising: contacting said malaria parasites with a growth
inhibiting amount of an antimalaria compostion comprising one or
more indolo[2,1-b]quinazoline-6,- 12-dione compounds of Formula I:
102wherein A, B, C, D, E, F, G and H are independently selected
from carbon and nitrogen, or A and B or C and D can be taken
together to be nitrogen or sulfur, with the proviso that not more
than three of A, B, C, D, E, F, G and H are other than carbon;
wherein R.sub.1 through R.sub.8 are independently selected from the
group consisting of F, Cl, Br, I, alkyl groups, trifluoromethyl
groups, methoxyl groups, a carboxy methyl or carboxy ethyl group
(COOCH.sub.3 or COOCH.sub.2CH.sub.3), nitro, aryl, heteroaryl,
cyano, amino, dialkylaminoalkyl, 1-(4-alkylpiperazinyl), and
pharmaceutically acceptable salts thereof; and wherein X is
independently selected from the group consisting of oxygen and a
side chain rendering the indolo[2,1-b]quinazoline-6,12-dione
compound a prodrug; and inhibiting the growth of said malaria
parasites.
38. The method of 37, wherein said malaria parasites are present in
Albuman I.RTM. serum or blood serum.
39. The method of claim 37, further comprising contacting said
malaria parasites with one or more adjuvants.
40. The method of claim 39, wherein said one ore more adjuvant is
selected from the group consisting of antiparasitic drugs.
41. An antimalarial prodrug composition comprising a
pharmaceutically effective amount of one or more
indolo[2,1-b]quinazoline-6,12-dione compounds of Formula I:
103wherein A, B, C, D, E, F, G and H are independently selected
from carbon and nitrogen, or A and B or C and D can be taken
together to be nitrogen or sulfur, with the proviso that not more
than three of A, B, C, D, E, F, G and H are other than carbon;
wherein R.sub.1 through R.sub.8 are independently selected from the
group consisting of, but not limited to F, Cl, Br, I, alkyl groups,
trifluoromethyl groups, methoxyl groups, a carboxy methyl or a
carboxy ethyl group (COOCH.sub.3 or COOCH.sub.2CH.sub.3), nitro,
aryl, heteroaryl, cyano, amino, dialkylaminoalkyl,
1-(4-alkylpiperazinyl), and pharmaceutically acceptable salts
thereof; and wherein X is a side chain rendering the
indolo[2,1-b]quinazoline-6,12-dione compound a prodrug.
42. The antimalarial prodrug of claim 41, comprising an
indolo[2,1-b]quinazoline-6,12-dione compounds of Formula II:
104
43. The antimalarial prodrug of claim 41, comprising an
indolo[2,1-b]quinazoline-6,12-dione compounds of Formula III: 105
Description
FIELD OF THE INVENTION
[0001] The present invention relates to new and existing
indolo[2,1-b]quinazoline-6,12-dione derivatives which are useful in
killing malaria parasites, antimalarial compositions containing the
compounds, and to methods of treating malaria with the compounds
and compositions, alone or in combination with other antimalarial
agents both in vitro and in vivo.
BACKGROUND OF THE INVENTION
[0002] The current global situation in respect to malaria has
recently been detailed by Peters [W. Peters, "Drug Resistance in
Malaria Parasites of Animals and Man", Advances in Parasitology,
vol. 41, pp 1-62 (1998)]. Currently, about two billion people are
exposed to malaria and 400 million are infected with the disease.
Between 100-200 million new cases occur each year. There are
approximately 1-2 million deaths annually due to malaria. The
global situation is worsening. The pertinent facts are these: very
few new antimalarial drugs have been introduced in the past quarter
century; there is massive pressure for the development of drug
resistance due to the presence of large numbers of non-immune
people in areas where malaria is efficiently transmitted; and
resistance by Plasmodium falciparum and Plasmodium vivax to
chloroquine is being documented in an increasingly wide geographic
area.
[0003] Other frontline drugs currently used for the treatment and
prevention of malaria such as mefloquine and halofantrine, are
becoming increasingly ineffective. Newly introduced artemsinin
analogs (artesunate and artemether), while effective for
the-treatment of malaria, may be too toxic for long term
administration required for prophylaxis. As a result, the idea of
malaria eradication has been abandoned and replaced with the more
realistic target of malaria control.
[0004] Indolo[2,1-b]quinazoline-6,12-dione is a compound with a
long history [see C. W. Bird, Tetrahedron, 19, 901 (1963), and
references therein]. The structure of the compound has been
verified by x-ray crystallography: M. Brufani, et al., Experientia,
27, 1249 (1971); W. Fedeli, et al., J. Chem. Soc. Perkin
Transactions 2, 621 (1974). Early developments were described by
Friedlander and Reschdestwensky [Ber., 48, 1843 (1915). Numerous
synthetic approaches to the parent compound have been described: H.
Karpf, et al., Tet. Let, 3007 (1978); L. A. Mitscher, et al.,
Heterocycles, 15, 1017 (1981); L. Capuano, et al., Chem. Ber., 116,
741 (1983); S. Euguchi, et al., 33, 153 (1992).
Indolo[2,1-b]quinazoline-6,12-dione is also a naturally occurring
compound, that is found in the higher plants such as Couroupita
guianensis Aubl [Bergman, et al., Tet. Let., 2625 (1977)];
Strobilanthes cusia [G. Honda, et al., Planta Medica, 37, 172,
(1979)]; Polygonum tinctorum and Isatis tinctorum [G. Honda, et
al., Planta Medica, 38, 275 (1980). It is produced by Candida
liplytica when grown in media containing an excess of tryptophan,
hence its name, tryptanthrin. Indolo[2,1-b]quinzoline-6,12-dione
has been shown to possess antibacterial activity against a variety
of pathogenic bacteria, particularly the causative agent of
tuberculosis, Mycobacterium tuberculosis. Antibacterial activity is
also claimed against Staphylococcus aureus, Klebsiella pneumoniae,
Mycobacterium smegmatis, and the fungi, Candida albicans [Mitscher,
et al., "Antimicrobial Agents from Higher Plants. New Synthesis and
Bioactivity of Tryptanthrin (Indolo[2,1-b]quinazoline-6,12-dione)
and its Analogues", Heterocycles 15, 1017-1021 (1981); Honda, G.
and Tabata., M., "Isolation of Antifungal Principal Tryptanthrin
from Strobilanthes Cusia O. Kuntze,", Planta Medica, J Med. Plant
Res., 36, 85-86 (1979); Mitscher, et al., "Part 1. Antitubercular
Agents from Higher Plants: Synthesis and In Vitro Activity of
Indolo[2,1-b]quinazoline-6,12-diones and Related Analogs",
Abstracts of Papers, 35 International Congress of Antimicrobial
Agents and Chemotherapy, Abstract F16, San Diego, Calif., 1995;
Baker, W. "Part II. Antitubercular Agents from Higher Plants:
Antimycobacterial Activity of Azaindoloquinazolines. Novel Agents
against Sensitive and Multi-drug Resistant Tuberculosis", Abstracts
of Papers, 35 International Congress of Antimicrobial Agents and
Chemotherapy, Abstract F17, San Diego, Calif., 1995. To date,
however, there has been no evidence or indication that
Indolo[2,1-b]quinazoline-6,12-dione and derivatives exhibit
anti-malarial activity against malaria parasites or would be useful
in treating malaria in vivo or in vitro.
[0005] Historically, the first antimalarial drugs stemmed from
natural remedies. The quinchona alkaloids were utilized for
centuries before their active principals, alkaloids such as quinine
and quinidine, were isolated and shown to be effective in
themselves against malaria. These compounds are devoid of useful
clinical antibacterial activity. The discovery of the first
synthetic antimalarial drugs was prompted by the selective staining
of plasmodium tissues by vital stains. This lead, based upon the
organic chemistry of synthetic dyes, led after a period of perhaps
twenty years, to the discovery of two classes of quinoline
antimalarial drugs, the 4-aminoquinolines (such as chloroquine) and
the 8-aminoquinolines (such as primaquine). The biochemical basis
of the antimalarial action of these agents, despite investigations
spanning the last 50 years, is still unknown. Notwithstanding their
extensive use as antimalarial agents, these compounds have found no
clinical utility against bacterial species.
[0006] Some antibacterial agents have found application in the
therapy and prevention of malaria. These include compounds whose
mechanisms of antibacterial action are well documented. Those
interfering with folate metabolism are the best known. These
include the drug combination pyrimethamine-sulfadoxine, and
dapsone. However, well known antimalarials which inhibit the
metabolism of folate within the plasmodium, such as proguanil and
cycloguanil, have not found application as antibacterial agents
despite their extensive clinical application as antimalarial drugs.
Doxycycline is used for malaria prophylaxis, and recently
azithromycin C has shown antimalarial activity. Many extremely
powerful antibacterial agents, such as the penicillins and
cephalosporins, are devoid of antimalarial activity.
[0007] U.S. Pat. No. 5,441,955, the disclosure of which is
expressly incorporated herein by reference, describes the general
Formula I described herein, with the exception that it does not
disclose that X can be a side chain necessary to make the compound
of Formula I a prodrug. However, the '955 patent focuses on
antibacterial compounds for treating bacterial infections, but
fails to contemplate treating malaria parasites with these
compounds or using them as antimalarial agents. Thus, the inventors
of this invention have discovered the unexpected result of these
particular compounds, and the compounds with side chains rendering
the compounds prodrugs, as antimalarial agents.
[0008] That there is little relationship between antibacterial
activity in a drug such as described in the '955 patent and
antimalarial activity in a drug is not surprising. The bacteria and
the plasmodia are very distant genetically: Bacteria are
prokaryotes and plasmodia are eukaryotes. Thus, the search for
acceptable antimalarial drugs is more difficult than the search for
antibacterials as the metabolic processes of the plasmodia more
closely resemble those of their eukaryotic hosts while the genetic
and metabolic gap between bacterial and mammals is large as they
belong to different kingdoms. Hence, an agent that is useful for
treating a bacterial infection is not necessarily useful for
treating a parasitic infection like malaria.
SUMMARY OF THE INVENTION
[0009] The inventors of the present invention have surprisingly
discovered that Indolo[2,1-b]quinazoline-6,12-dione, and
substituted derivatives, exhibit potent in vitro antimalarial
activity against Plasmodium falciparum. Highly active compounds
show IC.sub.50values (50% inhibitory concentration) in the 0.43 to
10 ng/mL concentration range, about one one-thousandth of the
concentrations necessary to inhibit bacteria. Furthermore, these
compounds are also highly active against strains of Plasmodium
falciparum which are up to 5000-fold resistant to atovoquone,
50-fold resistant to chloroquine, and 20-fold resistant to
mefloquine. Therefore, this invention provides methods for
inhibiting the growth of malaria parasites in vitro and provides
methods for the prevention and treatment of malaria in vivo using
indolo[2,1-b]quinazoline-6,12-dione compounds of formula I. 2
[0010] wherein A, B, C, D, E, F, G and H are independently selected
from carbon and nitrogen, or A and B or C and D can be taken
together to be nitrogen or sulfur, with the proviso that not more
than three of A, B, C, D, E, F, G and H are other than carbon;
wherein R.sub.1 through F.sub.8 are independently selected from the
group consisting of, but not limited to, the halogens (F, Cl, Br,
and I), alkyl groups, trifluoromethyl groups, methoxyl groups, the
carboxy methyl or carboxy ethyl group (COOCH.sub.3 or
COOCH.sub.2CH.sub.3), nitro, aryl, heteroaryl, cyano, amino,
dialkylaminoalkyl, 1-(4-alkylpiperazinyl), and the pharmaceutically
acceptable salts thereof; and wherein X is independently selected
from the group consisting of any atom especially oxygen, or any
side chain necessary to make the
indolo[2,1-b]quinazoline-6,12-dione compound a "prodrug" as the
term is understood by one of ordinary skill in the art of medicinal
chemistry. In other words, a side chain having a structure where a
carbon-nitrogen double bond bears substituents that make the
prodrug more water soluble and bioavailable. Improved
bioavailability results in a lower effective dosage. It also makes
more predictable and uniform absorbance which increases the
predictability of the response which in turn increases safety by
reducing drug side effects.
[0011] An example of a prodrug containing a labile carbon-nitrogen
double bond side chain exocyclic to the tryptanthin structure is
shown in Formula II. Such an example may be more water soluble, but
can be readily converted to the tryptantrin structure through
hydrolysis of the carbon-nitrogen bond to give tryptanthrin. 3
[0012] Another example of a labile structure attached to the keto
position which can increase the aqueous solubility of the
tryptanthrin nucleous, but will be hydrolysed back to tryptanthrin
in the blood stream is shown in Formula III. 4
[0013] These examples of prodrugs are not intended to limit the
invention in any way. Other side chains are contemplated that would
make the indolo[2,1-b]quinazoline-6,12-dione compound of the above
formula I a prodrug as the term is understood by one of ordinary
skill in the art of medicinal chemistry. Prodrugs are described in
Medicimal Chemestry Principles and Practice, Frank D. Cane, Royal
Society of Chemistry, Cambridge England, Chapter 14, pp 215-218
(1994), which is herein incorporated by reference.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0014] In accordance with the present invention, an antimalarial
compound, composition and methods are provided for treating or
control of strains of Plasmodium falciparum, Plasmodium ovale,
Plasmodium malariae and Plasmodium vivax, either in vitro or in
vivo by administering the compound or composition of the present
invention. Thus, one aspect the present invention provides a method
of inhibiting the growth of strains of P. falciparum, Plasmodium
ovale, Plasmodium malariae and P. vivax in vitro comprising
contacting the strains of P. falciparum, Plasmodium ovale,
Plasmodium malariae and P. vivax with a growth inhibitory amount of
a indolo[2,1-b]quinazoline-6,12-dione compound of the formula
I.
[0015] In a second aspect, the invention provides methods for
inhibiting the growth of malaria parasites in vitro and provides
methods for the prevention and treatment of malaria in vivo using
indolo[2,1-b]quinazolin- e-6,12-dione compounds of formula I. 5
[0016] wherein A, B, C, D, E, F, G and H are independently selected
from carbon and nitrogen, or A and B or C and D can be taken
together to be nitrogen or sulfur, with the proviso that not more
than three of A, B, C, D, E, F, G and H are other than carbon;
wherein R.sub.1 through R.sub.8 are independently selected from the
group consisting of the halogens (F, Cl, Br, and I), alkyl groups,
trifluoromethyl groups, methoxyl groups, the carboxy methyl or
carboxy ethyl group (COOCH.sub.3 or COOCH.sub.2CH.sub.3), nitro,
aryl, heteroaryl, cyano, amino, dialkylaminoalkyl,
1-(4-alkylpiperazinyl), and the pharmaceutically acceptable salts
thereof; further wherein X is independently selected from the group
consisting of any atom especially oxygen, or any side chain
necessary to make the indolo[2,1-b]quinazoline-6,12-dione compound
a "prodrug" as described above and as the term is understood by one
of ordinary skill in the art of medicinal chemistry.
[0017] In another aspect, the present invention proposes methods of
treating human or animal subjects suffering from a malarial
infection, e.g., whether of sensitive-strain or multi-drug
resistant strain (MDR-malaria) origin. Thus, the present invention
provides a method of treating a human or animal subject in need of
such treatment comprising administering to the subject a
therapeutically effective amount of a
indolo[2,1-b]quinazoline-6,12-dione compound of formula (I), above,
either alone or in combination with other antimalarial agents or
adjuvants.
[0018] Other antimalarial agents that can be used in combination
with the compounds of the present invention include mefloquine,
halofantrine, artesunate, artemether, chloroquine halofantrine,
primaquine, sulfadoxine, sulfalene, pyrimethamine, doxycycline,
tetracycline, azithromycin, proguanil, cycloguanil, dapsone,
artemsinin, atovoquone and the like to name a few. These compounds
can be combined with the compounds of the present invention in the
same dosage, in a tablet, injectable liquid, or any other known
form of administering drugs. These compounds can also be
administered to a patient in a separate dosage.
[0019] Other adjuvants that can be used in combination with the
compounds of the present invention are any other antiparasitic
drugs.
[0020] The term "acylamino" means an acyl (CO--) radical to which
an amino group is appended.
[0021] The term "loweralkyl" as used herein refers to branched or
straight chain alkyl groups comprising one to ten carbon atoms,
including, e.g., methyl, ethyl, propyl, isopropyl, n-butyl,
t-butyl, neopentyl and the like.
[0022] The term "alkoxy" as used herein refers to RO wherein R is
loweralkyl as defined above. Representative examples of lower
alkoxy groups include methoxy, ethoxy, t-butoxy and the like.
[0023] The term "alkenyl" as used herein refers to a branched or
straight chain groups comprising two to twenty carbon atoms which
also comprises one or more carbon-carbon double bonds.
Representative alkenyl groups include 2-propenyl (i.e., ally)),
3-methyl-2-butenyl, 3,7-dimethyl-2,6-octadienyl,
4,8-dimethyl-3,7-nonadienyl, 3,7,11-trimethyl-2,6,10-dodecatrienyl
and the like.
[0024] The term "alkynyl" as used herein refers to a branched or
straight chain comprising two to twenty carbon atoms which also
comprises one or more carbon-carbon triple bonds. Representative
alkynyl groups include ethynyl, 2-propynyl (propargyl), 1-propynyl
and the like.
[0025] The term "aryl" as used herein refers to a phenyl or a C9-
or C10-bicyclic carbocyclic ring system having one or more aromatic
rings, including naphthyl, tetrahydronaphthyl indanyi, indenyl and
the like. Aryl groups can be unsubstituted or substituted with one,
two or three substituents independently selected from loweralkyl,
haloalkyl, alkoxy and halo.
[0026] The term "arylalkyl" as used herein refers to a lower alkyl
radical to which is appended an aryl group. Representative
arylalkyl groups include benzyl, phenylethyl, hydroxybenzyl,
fluorobenzyl, fluorophenylethyl and the like.
[0027] The term "arylalkylaryl" as used herein refers to an
arylalkyl group-as previously defined appended to an aryl group.
Representative arylalkylaryl groups include 4-benzylphenyl,
3-benzylphenyl, 4-phenethylphenyl and the like.
[0028] The term "arylaryl" as used herein refers to an aryl group
as previously defined which is appended to an aryl group.
Representative arylaryl groups include biphenyl,
4-(1-naphthyl)phenyl, 4-(2-naphthyl)phenyl and the like.
[0029] The term "aryloxy" as used herein refers to RO wherein R is
an aryl group. Representative arylalkoxy groups include benzyloxy,
phenylethoxy and the like.
[0030] The term "arylalkoxy" as used herein refers to a lower
alkoxy radical to which is appended an aryl group. Representative
arylalkoxy group include benzyloxy, phenylethoxy and the like.
[0031] The term "aryloxyaryl" as used herein refers to an aryl
radical to which is appended an aryloxy group. Representative
aryloxyaryl groups include 4-phenoxypbenyl, 3-phenoxyphenyl,
4-phenoxy-1-naphthyl, 3-phenoxy-1-naphthyl and the like.
[0032] The term "aryloxyarylalkyl" as used herein refers to an
arylalkyl radical to which is appended an aryloxy group.
Representative aryloxyarylalkyl groups include
4-phenoxyphenylmethyl, 3-phenoxyphenylmethyl, 4phenoxyphenylethyl,
3-phenoxyphenylethyl and the like.
[0033] The term "arylalkoxyaryl" as used herein refers to an aryl
radical to which is appended an arylalkoxy group. Representative
arylalkoxyaryl groups include 4-benzyloxylphenyl, 3-benzyloxyphenyl
and the like.
[0034] The term "arylalkoxyarylalkyl" as used herein refers to an
arylalkyl radical to which is appended an arylalkoxy group.
Representative arylalkoxyarylalkyl groups include
4-benzyloxylbenzyl, 3-benzyloxybenzyl and the like.
[0035] The term "cycloalkyl" as used herein refers to an alicyclic
group comprising from 3 to 7 carbon atoms including, but not
limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
the like.
[0036] The term "cycloalkylalkyl" as used herein refers to a
loweralkyl radical to which is appended a cycloalkyl group.
Representative examples of cycloalkylalkyl include
cyclopropylmethyl, cyclohexylmethyl, 2-(cyclopropyl)ethyl and the
like.
[0037] The term "halogen" or "halo" as used herein refers to iodo,
bromo, chloro or fluoro and the like.
[0038] The term "haloalkyl" as used herein refers to a lower alkyl
radical, as defined above bearing at least one halogen substituent,
for example, chloromethyl, fluoroethyl or trifluoromethyl and the
like.
[0039] The term "heterocycle" as used herein refers to an aromatic
ring system composed of 5 or 6 atoms selected from the heteroatoms
nitrogen, oxygen, and sulfur. The heterocycle may be composed of
one or more heteroatoms that are either directly connected such as
pyrazole or connected through carbon such as pyrimidine.
Heterocycles can be substituted or unsubstituted with one, two or
three substituents independently selected from amino, alkylamino,
halogen, alkyl acylamino, lower alkylaryl, alkoxy.
[0040] The term "substituted heterocycle" or "heterocyclic group"
or heterocycle as used herein refers to any 3- or 2,5 4-membered
ring containing a heteroatom selected from nitrogen, oxygen, and
sulfur or a 5- or 6-membered ring containing from one to three
heteroatoms selected from the group consisting of nitrogen, oxygen,
or sulfur; wherein the 5-membered ring has 0-2 double bonds and the
6-membered ring has 0-3 double bonds; wherein the nitrogen and
sulfur atom maybe optionally oxidized; wherein the nitrogen and
sulfur heteroatoms maybe optionally quarternized; and including any
bicyclic group in which any of the above heterocyclic rings is
fused to a benzene ring or another 5- or 6-membered heterocyclic
ring independently defined above. Heterocyclics in which nitrogen
is the heteroatom are preferred. Fully saturated heterocyclics are
also preferred.
[0041] The compounds of the invention comprise asymmetrically
substituted carbon atoms. Such asymmetrically substituted carbon
atoms can result in the compounds of the invention comprising
mixtures of stereoisomers at a particular asymmetrically
substituted carbon atom or a single stereoisomer. As a result,
racemic mixtures, mixtures of diastereomers, as well as single
diastereomers or single enantiomers of the compounds of the
invention are included in the present invention. Examples thereof
are shown in Table 1, Example No. 34, 35, 71, 73 and 85. The terms
"S" and "R" configuration, as used herein, are as defined by the
IUPAC 1974 Recommendations for Section E, Fundamental
Stereochemistry, Pure Appl Chem. (1976) 45, 13-30. The terms
.alpha. and .beta. are employed for ring positions of cyclic
compounds. The .alpha.-side of the reference plane is that side on
which the preferred substituent lies at the lowered numbered
position. Those substituents lying on the opposite side of the
reference plane are assigned .beta. descriptor. It should be noted
that this usage differs from that for cyclic stereoparents, in
which ".alpha." means "below the plane" and denotes absolute
configuration. The terms .alpha. and .beta. configuration, as used
herein, are as defined by the Chemical Abstracts Index
Guide-Appendix IV (1987) paragraph 203.
[0042] In yet a further aspect of the present invention,
pharmaceutical compositions are provided which comprise a compound
of the present invention in combination with a pharmaceutically
acceptable carrier.
EXAMPLE 1
[0043] In Vitro Inhibition of Plasmodium falciparum
[0044] The in vitro assays were conducted by using a modification
of the semiautomated microdilution technique of Desjardins et
al..sup.11 and Chulay et al..sup.12 Two strains of Plasmodium
falciparum clones, from CDC Indochina III (W-2), CDC Sierra Leone I
(D-6). The W-2 clone is susceptible to mefloquine but resistant to
chloroquine, sulfadoxine, pyrimethamine, and quinine. The D-6 clone
is resistant to mefloquine but susceptible to chloroquine,
sulfadoxine, pyrimethamine, and quinine. They were derived by
direct visualization and micromanipulation from patient
isolates..sup.13 Test compounds were initially dissolved in DMSO
and diluted 400-fold in RPMI 1640 culture medium supplemented with
25 mM Hepes, 32 mM HaHCO.sub.3, and 10% Albumax I.RTM. (GIBCO BRL,
Grand Island, N.Y.). These solutions were subsequently serially
diluted 2-fold with a Biomek 1000.RTM. (Beckman, Fullerton, Calif.)
over 11 different concentrations. The parasites were exposed to
serial dilutions of each compound for 48 h and incubated at
37.degree. C. with 5% O.sub.2, 5% CO.sub.2, and 90% N.sub.2 prior
to the addition of [.sup.3H]hypoxanthine. After a further
incubation of 18 h, parasite DNA was harvested from each microtiter
well using Packard Filterrnate 196 Harvester.RTM. (Meriden, Conn.)
onto glass filters. Uptake of [.sup.3H]hypoxanthine was measured
with a Packard Topcount scintillation counter.
Concentration-response data were analyzed by a nonlinear regression
logistic dose-response model, and the IC50 values (50% inhibitory
concentrations) for each compound were calculated (see Table 1,
values within parentheses ( )). This procedure was repeated with
the test compounds initially dissolved in DMSO and diluted 400-fold
in RPMI 1640 culture medium supplemented with 25 mM Hepes, 32 mM
HaHCO.sub.3, and with blood serum replacing the 10% Albumax I.RTM.
(see Table 1, figures without parentheses). The values without
parentheses indicate culture in blood serum which more closely
resemble conditions in a living animal.
[0045] Four strains of Plasmodium falciparum clones, from CDC
Indochina III (W-2), CDC Sierra Leone I (D-6), Thai WR75-TM9, and
Thai TM90C2B were utilized in susceptibility testing and the
IC.sub.50 results appear in Table 1.
1TABLE 1 In Vitro Antimalarial Activity. Concentration of
Indolo[2,3-b]quinazoline-6,12-dione Inhibiting uptake of
[.sup.3H]Hypoxanthine by Parasitized Red Blood Cells by 50%
(IC.sub.50, ng/mL) Example IC.sub.50 IC.sub.50 IC.sub.50 IC.sub.50
No. Structure (W-2) (D-6) (TM90C2B) (WR75-TM9) 1. 6 (69)* (69) 2. 7
(15626) (12481) 3. 8 (>50000) (>50000) 4. 9 (2.33) 15.335*
(4.07) 18.888 29.846 27.319 7.165 5. 10 (263.86) (313.106) 6. 11
(502.79) (527) 7. 12 (512.7) (576.53) 8. 13 (62) (62) 9. 14 (403)
(471) 10. 15 (131) (138) 11. 16 (2.8) 14.678 (4.9) 22.068 16.383
35.991 1.587 12. 17 (1.6) 5.274 5.787 6.539 (4.9) 8.535 14.239
11.005 9.738 16.914 11.1113 11.951 16.249 19.374 13. 18 (5.1) 4.335
(14.3) 14.842 10.531 9.837 21.542 13. 19 (5.8) 10.091 (10.0) 23.258
20.119 10.499 14. 20 (5.76) (10.17) 15. 21 (81.99) (125.58) 16. 22
(1014) (2160) 17. 23 (0.84) 2.125 (1.53) 4.928 4.207 9.932 8.002
18. 24 (512.93) (812.73) 19. 25 (1.58) 8.138 (2.57) 13.523 9.784
18.937 .485 20. 26 (734.34) (1054.46) 21. 27 (0.43) 1.278 (0.93)
0.926 2.302 2.997 1.349 22. 28 (262.92) (277.72) 23. 29 (1.67)
(3.97) 24. 30 (0.91) 0.912 4.638 (2.01) 10.078 7.782 17.411 8.059
25. 31 (1990.37) (1842.69) 26. 32 (609.29) (589.01) 27. 33 (1.79)
35.649 (3.01) 95.331 41.090 139.605 5.86 28. 34 (126) (19.925)
(124) (38.541) 29. 35 (130.58) (149.32) 30. 36 (354.29) (499.81)
31. 37 (134.03) (160.67) 32. 38 (2588.82) (3848.62) 33. 39 (79.58)
(67.06) 34. 40 (601.05) (588.27) 35. 41 (133.86) (103.44) 36. 42
(4815.61) (4204.57) 37. 43 (3483.15) (3778.15) 38. 44 (203.16)
(241.86) 39. 45 (1.88) 1.870 (3.57) 3.570 46.039 4.203 40. No entry
41. 46 (7.66) (12.34) 42. 47 (63.17) (76.43) 43. 48 (23,000)
(38,236) 44. 49 (5859.64) (6924.46) 45. 50 (0.728) 4.741 (1.28)
6.767 8.759 1.147 14.152 46. 51 (6.32) 22.995 (7.61) 42.612 24.417
66.441 47. No Entry 48. 52 (7.74) 58.100 (13.9) 97.106 55.796
66.666 157.162 48. 53 (508.19) (584.37) 49. 54 (74.75) (73.93) 50.
55 (11.16) (44.22) 51. 56 (8760) (8693) 52. 57 (64.69) (73.33) 53.
58 (4872.21) (9006) 54. 59 (124.03) (74.58) 55. 60 (2.1) 2.303
(7.2) 11.238 5.483 14.216 56. 61 (117) (216) 57. 62 (10.58) 28.943
(20.33) 46.492 62.233 82.551 58. 63 (2.73) 4.272 (4.52) 10.461
8.095 17.291 59. 64 (2.47) 17.707 (4.37) 37.894 24.005 50.842 1.306
60. 65 (67.86) (78.08) 61. 66 (187) (247) 62. 67 (16) (31.27) 63.
68 (1.5) 1.228 (3.16) 0.946 1.162 1.965 64. 69 (9.25) 36.831
(15.86) 70.142 38.338 38.389 65. 70 (153.98) (258.88) 66. 71
(448.53) (516.51) 67. 72 (4423.91) (4435.40) 68. 73 (3.86) 2.455
(7.86) 4.121 3.731 5.469 69. 74 (2.13) 8.494 (4.04) 12.333 10.170
23.876 70. 75 (8.69) 6.098 (13.22) 5.736 77.808 10.999 24.37 71. 76
(120.06) (143.32) 72. 77 (7465) (7860) 73. 78 (3.75) 2.855 (5.40)
4.889 4.464 10.506 74. 79 (3.52) 59.846 (2.19) 79.578 42.505 127.39
75. 80 (572.94) (534.47) 76. 81 (159.65) (223.53) 77. 82 (165.32)
(220.3) 78. 83 (0.86) 0.935 (0.93) 1.966 1.764 3.297 79. 84 (68.76)
(69.96) 80. 85 (6902.53) (7965.51) 81. 86 (73.92) (110.16) 82. 87
(124) (62.82) 83. 88 (1.8) 7.186 (3.11) 15.141 12.864 25.717 84. 89
(937.57) (1710.33) 85. 90 (105.36) (135.96) 86. 91 (2.3) 1.908
(3.6) 3.63 2.079 35.678 4.506 87. 92 (3.51) 1.252 (4.92) 2.310
0.696 4.438 88. 93 (177.45) (490.16) 89. 94 (68.77) (111.69) 90. 95
(3.93) 15.601 (7.59) 16.320 6.145 30.045 91. 96 (1.8) 5.521 4.977
(0.24) 9.064 10.137 9.825 4.594 9.941 5.438 4.449 9.941 16.412
*Values in parenthesis represent assays conducted in Albumax.
**Values without parenthesis represent assays conducted in blood
plasma.
[0046] Regarding the foregoing compounds, MW refers to molecular
weight, W2 refers to a malaria parasite which is susceptible to
mefloquine but resistant to chloroquine, sulfadoxine, pyrimethamine
and quinine. D6 refers to a malaria parasite which is naturally
resistant to mefloquine but susceptible to chloroquine,
sulfadoxine, pyrimethamine and quinine. The numbers associated with
both W2 and D6 refer to IC.sub.50 values and the units are
ng/ml.
[0047] As is shown in Table 1, the compounds 1-91 of the present
are effective in treating/reducing malaria parasites. It can be
seen that the lower the IC.sub.50 concentration, the more effective
the compound. The most effective compounds tested were compounds
21, 63, and 78.
[0048] The compounds of the invention are useful in the study of
the treatment of malaria in vitro.
[0049] Lin, A. J.; Zikry, A. B.; Kyle, D. E. J. Med. Chem., 1997,
40 (9), 1399-1400, which disclosure is herein expressly
incorporated by reference, describes in detail the procedures
followed by the inventors for in vitro antimalarial studies. That
disclosure also describes the procedures for conducting in vivo
antimalarial studies.
EXAMPLE 2
[0050] In Vivo Inhibition of Plasmodium falciparum, Plasmodium
ovale, Plasmodium malariae and Plasmodium vivax.
[0051] The in vivo efficacy of the compounds of the present
invention alone or in combination with an adjuvant can be
determined in a modified Thompson test. This test measures the
survivability of mice and parasitemia clearance following
administration of the compound or composition of the invention on
days 3-5 post infection. In brief, 5.times.10.sup.5 malaria
parasites of one or more of the four described strains are
inoculated intraperitoneally to female mice that weight
approximately 24-30 g. Each compound is dissolved in 5% sodium
bicarbonate, and is administered p.o. twice daily from day 3 to day
5 postinfection. Total dosage of the compounds of the invention is
0.001 to 1000 mg/kg. The percent suppression of parasitemia in the
treated mice compared to untreated controls is determined for each
test compound. Survival of mice to day 60 postinfection is
considered a cure. Compounds are considered active when the
survival time of the treated mice is greater than twice the control
mice.
[0052] When the compounds of the present invention are administered
with an adjuvant, the amount of adjuvant given is 0.001 to 1000
mg/kg body weight.
[0053] The compounds of the present invention can be used in the
form of salts derived from inorganic or organic acids. These salts
include but are not limited to the following: acetate, adipate,
alginate, citrate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,
cyclopentanepropionate, dodecylsulfate, ethanesulfonate,
glucoheptanoate, glycerophosphate, hemisulfate, heptanoate,
hexanoate, fumarate, hydrochloride, bydrobromide, hydroiodide,
2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,
nicotinate, 2-napthalenesulfonate, oxalate, pamoate, pectinate,
persulfate, 3-phenylproionate, picrate, pivalate, propionate,
succinate, tartrate, thiocyanate, p-toluenesulfonate and
undecanoate. Also, the basic nitrogen-containing groups can be
quaternized with such agents as loweralkyl halides, such as methyl,
ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl
sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long
chain halides such as decyl, lauryl, myristyl and stearyl
chlorides, bromides and iodides, aralkyl halides like benzyl and
phenethyl bromides, and others. Water or oil-soluble or dispersible
products are thereby obtained.
[0054] Examples of acids which may be employed to form
pharmaceutically acceptable acid addition salts of the compounds of
Formula I include such inorganic acids as hydrochloric acid,
sulphuric acid and phosphoric acid and such organic acids as oxalic
acid, maleic acid, succinic acid and citric acid. Basic addition
salts can be prepared in situ during the final isolation and
purification of the compounds of Formula I, or separately by
reacting carboxylic acid moieties with a suitable base such as the
hydroxide, carbonate or bicarbonate of a pharmaceutical acceptable
metal cation or with ammonia, or an organic primary, secondary or
tertiary amine. Pharmaceutical acceptable salts include, but are
not limited to, cations based on the alkali and alkaline earth
metals, such as sodium, lithium, potassium, calcium, magnesium,
aluminum salts and the like, as well as nontoxic ammonium,
quaternary ammonium, and amine cations, including, but not limited
to ammonium, tetramethylammonium, tetraethylammonium, methylamine,
dimethylamine, trimethylamine, triethylamine, ethylamine, and the
like.
[0055] Other representative organic amines useful for the formation
of base addition salts include diethylamine, ethylenediamine,
ethanolamine, diethanolamine, piperazine and the like. The
compounds of the invention are useful in vitro in inhibiting the
growth of malaria parasite, and in vivo in human and animal hosts
for treating malarial parasitic infections. The compounds may be
used alone or in compositions together with a pharmaceutically
acceptable carrier.
[0056] Total daily dose administered to a host in single or divided
doses may be in amounts, for example, from 0.001 to 1000 mg/kg body
weight daily and more preferred from 1.0 to 50 mg/kg body weight
daily. Dosage unit compositions may contain such amounts of
submultiples thereof to make up the daily dose.
[0057] The amount of active ingredient that may be combined with
the carrier materials to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration. It will be understood, however, that the specific
dose level for any particular patient will depend upon a variety of
factors including the activity of the specific compound employed,
the age, body weight, general health, sex, diet, time of
administration, route of administration, rate of excretion, drug
combination, and the severity of the particular disease undergoing
therapy.
[0058] The compounds of the present invention may be administered
orally, parenterally, sublingually, by inhalation spray, rectally,
or topically in dosage unit formulations containing conventional
nontoxic pharmaceutically acceptable carriers, adjuvants, and
vehicles as desired. Topical administration may also involve the
use of transdermal administration such as transdermal patches or
ionophoresis devices. The term parenteral as used herein includes
subcutaneous injections, intravenous, intramuscular, intrasternal
injection, or infusion techniques.
[0059] Injectable preparations, for example, sterile injectable
aqueous or oleagenous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-propanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, and
isotonic sodium chloride solution. In addition, sterile, fixed oils
are conventionally employed as a solvent or suspending medium. For
this purpose any bland fixed oil may be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid find use in the preparation of injectables.
[0060] Suppositories for rectal administration of the drug can be
prepared by m g the drug with a suitable nonirritating excipient
such as cocoa butter and polyethylene glycols which are solid at
ordinary temperatures but liquid at the rectal temperature and will
therefore melt in the rectum and release the drug.
[0061] Solid dosage forms for oral administration may include
capsules, tablets, pills, powders, and granules. In such solid
dosage forms, the active compound may be admixed with at least one
inert diluent such as sucrose lactose or starch. Such dosage forms
may also comprise, as is normal practice, additional substances
other than inert diluents, e.g., lubricating agents such as
magnesium Stuart. In the case of capsules, tablets, and pills, the
dosage forms may also comprise buffering agents. Tablets and pills
can additionally be prepared with enteric coatings.
[0062] Liquid dosage forms for oral administration may include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs containing inert-diluents commonly used in the
art, such as water. Such compositions may also comprise adjuvants,
such as wetting agents, emulsifying and suspending agents, and
sweetening, flavoring, and perfuming agents.
[0063] The compounds of the present invention can also be
administered in the form of liposomes. As is known in the art,
liposomes are generally derived from phospholipids or other lipid
substances. Liposomes are formed by monoamellar or multiamellar
hydrated liquid crystals that are dispersed in an aqueous medium.
Any nontoxic, physiologically acceptable and metabolizable lipid
capable of forming liposomes can be used. The present compositions
in liposome form can contain, in addition to the compound of the
present invention, stabilizers, preservatives, excipients, and the
like which are well known in the art of formulation of drugs. The
preferred lipids are the phospholipids and phosphatidyl cholines
(lecithins), both natural and synthetic. Methods to form liposomes
are known in the art. See, for example, Prescott, Ed., Methods in
Cell Biology, Volume XIV, Academic Press, New York, N.W. (1976), p.
33 et seq.
[0064] While the compounds of the invention can be administered as
the sole active pharmaceutical agent, they can also be used in
combination with one or more other agents used in the treatment of
malarial parasitic infections. Representative agents useful in
combination with the compounds of the invention for the treatment
of malaria include, for example, quinine, mefloquine, chloroquine,
halofantrine, primaquine, sulfadoxine, sulfalene, pyrimethamine,
doxycycline, tetracycline, azithromycin, proguanil, cycloguanil,
dapsone, artemsinin, artesunate, artemether, atovoquone and the
like.
[0065] The above compounds to be employed in combination with the
indolo[2,1-b]quinazoline-6,12-dione compounds of the invention will
be used in therapeutic amounts as indicated in the Physicians' Desk
Reference (PDR) 51st Edition (1997), which is incorporated herein
by reference, or such therapeutically useful amounts as would be
known to one of ordinary skill in the art such as from 0.001 to
1000 mg/kg body weight daily. The compounds of the invention and
the other antiinfective agent can be administered together at the
recommended maximum clinical dosage or at lower doses. Dosage
levels of the active compounds in the compositions of the invention
may be varied so as to obtain a desired therapeutic response
depending on the route of administration, severity of the disease
and the response of the patient. The combination can be
administered as separate compositions or as a single dosage form
containing both agents. When administered as a combination, the
therapeutic agents can be formulated as separate compositions which
are given at the same time or different times, or the therapeutic
agents can be given as a single composition.
[0066] While the preferred embodiments of the invention have been
illustrated and described, it will be appreciated that various
changes can be made therein without departing from the spirit and
scope of the invention.
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