U.S. patent application number 12/842655 was filed with the patent office on 2010-11-18 for compositions and methods for the treatment and prevention of disease.
This patent application is currently assigned to Centre National de la Recherche Scientifique (CNRS). Invention is credited to Gilles Guichard, Eliette Lallemand, Gersande Lena, Laurent Renia.
Application Number | 20100291199 12/842655 |
Document ID | / |
Family ID | 39030076 |
Filed Date | 2010-11-18 |
United States Patent
Application |
20100291199 |
Kind Code |
A1 |
Guichard; Gilles ; et
al. |
November 18, 2010 |
Compositions and Methods For The Treatment and Prevention of
Disease
Abstract
The present invention relates to various novel substituted
dipeptide derived nitrogen-containing heterocyclic compounds, their
pharmaceutically acceptable salt derivatives, and their methods of
use. In one aspect the present invention relates to compositions
and methods for the treatment and prevention of disease in a mammal
comprising administering the compounds of the invention in a
pharmaceutically acceptable form to a mammal. In particular, the
invention relates to medicaments comprising various novel
substituted dipeptide derived nitrogen-containing heterocyclic
compounds and pharmaceutically acceptable salt derivatives and
methods for administration to a mammal for the treatment and
prevention of malarial diseases. The compounds of the invention may
optionally be administered with at least one pharmaceutically
acceptable excipient, another biologically active agent or a
combination thereof.
Inventors: |
Guichard; Gilles;
(Wolfisheim, FR) ; Lena; Gersande; (Julienas,
FR) ; Lallemand; Eliette; (Argenteuil, FR) ;
Renia; Laurent; (Holland Rise, SG) |
Correspondence
Address: |
MCCARTER & ENGLISH, LLP STAMFORD
CANTERBURY GREEN, 201 BROAD STREET, 9TH FLOOR
STAMFORD
CT
06901
US
|
Assignee: |
Centre National de la Recherche
Scientifique (CNRS)
Paris Cedex
FR
ImmuPharma France SA
Mulhouse Cedex
FR
|
Family ID: |
39030076 |
Appl. No.: |
12/842655 |
Filed: |
July 23, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11644626 |
Dec 22, 2006 |
7777030 |
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12842655 |
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Current U.S.
Class: |
424/452 ;
424/465; 514/183; 514/211.03 |
Current CPC
Class: |
A61P 29/00 20180101;
A61K 31/395 20130101; C07D 513/04 20130101; Y02A 50/411 20180101;
A61P 33/06 20180101; Y02A 50/414 20180101; Y02A 50/415 20180101;
C07D 281/18 20130101; A61P 31/00 20180101; A61K 31/40 20130101;
C07D 273/02 20130101; C07D 273/06 20130101; C07D 255/02 20130101;
A61P 31/18 20180101; Y02A 50/30 20180101 |
Class at
Publication: |
424/452 ;
514/211.03; 514/183; 424/465 |
International
Class: |
A61K 31/553 20060101
A61K031/553; A61K 31/395 20060101 A61K031/395; A61K 9/28 20060101
A61K009/28; A61K 9/48 20060101 A61K009/48; A61P 31/18 20060101
A61P031/18; A61P 33/06 20060101 A61P033/06 |
Claims
1. A therapeutic composition for treating or preventing a disease
or condition in an individual comprising an effective amount of a
compound of formula I: ##STR00019## or a pharmaceutically
acceptable salt thereof, wherein, W is a member selected from the
group consisting of --C(R.sup.5)(R.sup.5a)--;
--C(R.sup.6)(R.sup.6a)--C(R.sup.7)(R.sup.7a)--;
--C(R.sup.8).dbd.C(R.sup.9)--; and --N(R.sup.10); X is a member
selected from the group consisting of
--N(R.sup.1a)C(.dbd.Y)N(R.sup.4)--; --OC(.dbd.Y)N(R.sup.4)--;
--N(R.sup.1a)C(.dbd.Y)O--; --N(R.sup.1a)S(.dbd.O)N(R.sup.4)--;
--N(R.sup.1a)S(.dbd.O).sub.2N(R.sup.4)--; and --C(R.sup.1
a)(R.sup.3a)C(.dbd.Y)N(R.sup.4)--; Y and Z represent, each
independent from the other, a member selected from the group
consisting of oxygen ("O") or sulfur ("S"); and R.sup.1, R.sup.1a,
R.sup.2, R.sup.3, R.sup.3a, R.sup.4, R.sup.5, R.sup.5a, R.sup.6,
R.sup.6a, R.sup.7, R.sup.7a, R.sub.8, R.sup.9, and R.sup.10
represent, each independent from the other, a member selected from
the group consisting of: a hydrogen atom; an amino acid side chain;
a (C1-C10) alkyl; (C1-C10) alkenyl; (C1-C10) alkynyl; (C5-C12)
monocyclic or bicyclic aryl; (C5-C14) monocyclic or bicyclic
aralkyl; monocyclic or bicyclic (C5-C14) heteroaralkyl; and
(C1-C10) monocyclic or bicyclic heteroaryl group having up to 5
heteroatoms selected from N, O, S, and P said groups being able to
be non-substituted or substituted by 1 to 6 substituents further
selected from the group consisting of: a halogen atom, an NO.sub.2,
OH, amidine, benzamidine, imidazole, 1,2,3-triazole, alkoxy,
(C1-C4), amino, piperazine, piperidine, dialkylamino, guanidine
group, bis alkylated or bis acylated guanido group, carboxylic
acid, carboxamide, ester, hydroxamic acid, phosphinic acid,
phosphonate, phosphonamidate, sulfhydryl and any combination
thereof.
2. The therapeutic composition of claim 1, wherein the disease or
condition comprises malaria.
3. The therapeutic composition of claim 1, wherein the composition
further comprises at least one of a pharmaceutically acceptable
carrier or vehicle, excipient, adjuvant, an additional biologically
active agent or combination thereof.
4. The therapeutic composition of claim 1, wherein the composition
comprises from about 1% to about 50% by weight of the compound of
formula I.
5. The therapeutic composition of claim 3, wherein the biologically
active agent comprises chloroquine, a chloroquine derivative, an
HIV protease inhibitor, an antiviral or a combination thereof.
6. The therapeutic composition of claim 3, wherein the composition
is present in a pharmaceutically acceptable form.
7. The therapeutic composition of claim 6, wherein the
pharmaceutically acceptable form comprises a tablet or capsule
having an enteric coating.
8. (canceled)
9. (canceled)
10. (canceled)
11. (canceled)
12. (canceled)
13. A kit for treating or preventing a physiological condition
associated with HIV infection, malaria or both, said kit comprising
a plurality of containers, wherein at least one of said containers
contains the compound of claim 1 or a pharmaceutically acceptable
salt thereof.
14. A method for the treatment or prevention of AIDS comprising;
administering to an individual in need thereof, a therapeutic
composition comprising an effective amount the compound of claim 1,
in a pharmaceutically acceptable form.
15. The method of claim 14, wherein the therapeutic composition is
administered as a single daily dose.
16. The method of claim 14, wherein the therapeutic composition is
administered in two or more unitary dosage units.
17. The method of claim 14, wherein the therapeutic composition
further comprises at least one of a pharmaceutically acceptable
carrier or vehicle, excipient, adjuvant, an additional biologically
active agent or combination thereof.
18. The method of claim 17, wherein the biologically active agent
comprises chloroquine, a chloroquine derivative, an HIV protease
inhibitor, an antiviral or a combination thereof.
19. The method of claim 14, wherein the composition comprises from
about 1% to about 50% by weight of the compound of formula I.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] Under 35 U.S.C. .sctn.119(e) this application claims the
benefit of U.S. Provisional Patent Ser. No. 60/755,631, filed Dec.
29, 2005, and titled "Compositions and Methods for Synthesizing
Novel Heterocyclic Therapeutics"; U.S. Provisional Patent Ser. No.
60/755,632, filed Dec. 29, 2005, and titled: "Compositions and
Methods for Treatment and Prevention of Disease"; and U.S.
Provisional Patent Application Ser. No. 60/755,626, filed Dec. 29,
2005, and titled "Compositions and Methods for the Inhibition of
Phospholipase A2"; all of which are incorporated herein by
reference in their entirety. This application also claims priority
to a commonly-assigned, co-pending non-provisional patent
application entitled "Compositions and Methods for the Treatment
and Prevention of Disease," which was filed on Dec. 22, 2006, and
assigned Ser. No. 11/644,626.
[0002] The present invention is related to U.S. nonprovisional
patent applications "Compositions and Methods for the Inhibition of
Phospholipase A2" filed Dec. 22, 2006, and assigned Ser. No.
11/644,625 and "Compositions and Methods for Synthesizing
Heterocyclic Therapeutic Compounds" filed Dec. 22, 2006, and
assigned Ser. No. 11/644,349, both of which are incorporated herein
by reference in their entirety.
FIELD OF THE INVENTION
[0003] The present invention relates to compositions and methods
for the treatment and prevention of disease in a mammal. In
particular, the invention relates to medicaments comprising various
novel substituted dipeptide derived nitrogen-containing
heterocyclic compounds and pharmaceutically acceptable salt
derivatives. The compounds of the invention may optionally be
administered with at least one pharmaceutically acceptable
excipient, another biologically active agent or a combination
thereof.
BACKGROUND
[0004] Approximately 40% of the world's population lives in areas
where a significant risk of contracting malaria exists. Each year,
300-500 million people suffer from acute malaria, and 0.5-2.5
million die from the disease. Although malaria has been widely
eradicated in many parts of the world, the global number of cases
continues to rise. The most important reason for this alarming
situation is the rapid spread of malaria parasites that are
resistant to antimalarial drugs, especially chloroquine, which is
by far the most frequently used.
[0005] The research and development of new antimalarial drugs has
been largely neglected since the 1970s owing to the end of
colonialism, changes in the areas of military engagement, and the
restricted market potential. Currently, few drugs against the
malaria liver stage parasites are available. Because of technical
difficulties, low yield and the complexity of the setting necessary
to produce liver stage parasites, no new drugs are assessed
systematically against these stages. Nevertheless, liver stages are
a strong potential for drug targeting because; a) they possess a
more complex and distinct metabolism than their blood stage
counterpart, and b) they precede the pathogenic blood stage and
thus offer prophylactic possibilities against malaria. Thus, the
evaluation of new drugs against the liver stage offers new
therapeutic horizons.
[0006] An additional observation is that some antimalarial
compounds, for example, chloroquine also exhibit anti-HIV-1
activity. (See, for example, Savarino A, Gennero L, Chen H C,
Serrano D, Malavasi F, Boelaert J R, Sperber K. Anti-HIV effects of
chloroquine: mechanisms of inhibition and spectrum of activity.
AIDS 2001 Nov. 23; 15 (17):2221-9; Savarino A, Gennero L, Sperber
K, Boelaert J R. The anti-HIV-1 activity of chloroquine. J Clin
Virol 2001 February; 20 (3):131-5.
[0007] Thus, the need in society exists for new therapeutics, which
demonstrate advantageous clinical efficacy for the treatment and/or
prevention of malaria, as well as for drugs that may be useful for
the treatment and/or prevention of HIV infection and/or AIDS.
SUMMARY OF THE INVENTION
[0008] The present invention relates to compounds and methods for
synthesizing compounds, and pharmaceutically acceptable salts
thereof, which are efficacious for the treatment and/or prevention
of disease in an individual. In one aspect, the invention relates
to dipeptide derived heterocyclic compounds synthesized using the
methods of the invention.
[0009] In additional aspects, the invention relates to
pharmaceutical compositions comprising effective amounts of said
compounds, and to therapeutic methods comprising their
administration to an individual in need thereof for the treatment
and/or prevention of a disease.
[0010] Additional objects and advantages of the present invention
will be apparent from the the drawings, detailed description,
examples of the preferred embodiments that follow, and are
expressly included within the scope of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1. Comparison of the 1,3,5-triazepan-2,6-dione
scaffold, B, and 2,5-diketopiperazines, A.
[0012] FIG. 2. a) EtOCOCl, NMM, THF, -20.degree. C., then NaN.sub.3
in H.sub.2O; b) Toluene, 65.degree. C., then HOSu and pyridine; c)
TFA, 30 min; d) DIEA, MeCN; e) PS-DIEA, CH.sub.2Cl.sub.2. g=gem,
refers to the 2-alkyl gem-diamino-derivative of the corresponding
amino-acid according to the nomenclature proposed by Chorev and
Goodman.
[0013] FIG. 3. X-ray crystal structures of representative
1,3,5-triazepan-2,6-diones 4, 7 and 9.
[0014] FIG. 4. a) NaH (4 equiv), RX (4 equiv); b)
KF/Al.sub.2O.sub.3 (10 equiv) or NaH (2 equiv), RX (1.5 equiv).
[0015] FIG. 5. Effect of selected 1,3,5-triazepan-2,6-diones on
malaria liver stage development. Compounds were added at the time
of sporozoite invasion and during liver stage development. Schizont
number was estimated by counting this mature parasite forms in 48
hours cultures. Results are expressed as the mean .+-.SD of 3
triplicate cultures. Data are representative of 2 to 6 experiments
per compounds tested. *, P<0.05, Mann-Whitney U test.
DETAILED DESCRIPTION OF THE INVENTION
[0016] When describing the compounds, compositions and methods of
the invention, the following terms have the following meanings,
unless otherwise indicated.
[0017] "Pharmaceutically acceptable salt" means those salts which
retain the biological effectiveness and properties of the parent
compounds and which are not biologically or otherwise harmful as
the dosage administered. The compounds of this invention are
capable of forming both acid and base salts by virtue of the
presence of amino and carboxy groups respectively. Pharmaceutically
acceptable base addition salts may be prepared from inorganic and
organic bases. Salts derived from inorganic bases include, but are
not limited to, the sodium, potassium, lithium, ammonium, calcium,
and magnesium salts. Salts derived from organic bases include, but
are not limited to, salts of primary, secondary and tertiary
amines, substituted amines including naturally-occurring
substituted amines, and cyclic amines, including isopropylamine,
trimethyl amine, diethylamine, triethylamine, tripropylamine,
ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine,
arginine, histidine, caffeine, procaine, hydrabamine, choline,
betaine, ethylenediamine, glucosamine, N-alkylglucamines,
theobromine, purines, piperazine, piperidine, and
N-ethylpiperidine. It should also be understood that other
carboxylic acid derivatives would be useful in the practice of this
invention, for example carboxylic acid amides, including
carboxamides, lower alkyl carboxamides, di(lower alkyl)
carboxamides, and the like.
[0018] Pharmaceutically acceptable acid addition salts may be
prepared from inorganic and organic acids. Salts derived from
inorganic acids include hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid and the like. Salts
derived from organic acids include acetic acid, propionic acid,
glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid,
succinic acid, maleic acid, fumaric acid, tartaric acid, citric
acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic
acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid
and the like.
[0019] The term "treatment" as used herein includes any treatment
of a condition or disease in an animal, particularly a mammal, more
particularly a human, and includes: [0020] (i) preventing the
disease or condition from occurring in a subject which has not yet
been diagnosed as having it; [0021] (ii) inhibiting the disease or
condition, i.e. arresting its development; relieving the disease or
condition, i.e. causing regression of the condition; or relieving
the conditions caused by the disease, i.e. symptoms of the
disease.
[0022] The term "therapeutically effective amount" refers to that
amount which is sufficient to effect treatment, as defined herein,
when administered to a mammal in need of such treatment. The
therapeutically effective amount will vary depending on the subject
and disease state being treated, the severity of the affliction and
the manner of administration, and may be determined routinely by
one of ordinary skill in the art.
[0023] "Heterocycle" refers to a heterocyclic group having from 4
to 9 carbon atoms and at least one heteroatom selected from the
group consisting of N, O or S.
[0024] "Alkyl" refers to a branched or unbranched alkyl group
having 1-6 carbon atoms, a branched or unbranched alkenyl group
having 1-6 carbon atoms, a branched or unbranched alkinyl group
having 1-6 carbon atoms.
[0025] "Hydroxyl" refers the functional group --OH when it is a
substituent in an organic compound.
[0026] "Heterocyclic groups" can be optionally substituted with 1
to 5, and preferably 1 to 3 substituents, selected from the group
consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted
cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,
acylamino, acyloxy, amino, substituted amino, aminoacyl,
aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto,
thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy,
thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy,
aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic,
heterocyclooxy, hydroxyamino, alkoxyamino, nitro, --SO-alkyl,
--SO-substituted alkyl, --SO-aryl, --SO-heteroaryl, --SO2-alkyl,
--SO2-substituted alkyl, --SO2-aryl, oxo (.dbd.O), and
--SO.sub.2-heteroaryl. Such heterocyclic groups can have a single
ring or multiple condensed rings. Preferred heterocyclics include
morpholino, piperidinyl, and the like.
[0027] Examples of nitrogen heterocycles and heteroaryls include,
but are not limited to, pyrrole, imidazole, pyrazole, pyridine,
pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole,
indazole, purine, quinolizine, isoquinoline, quinoline,
phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline,
pteridine, carbazole, carboline, phenanthridine, acridine,
phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine,
phenothiazine, imidazolidine, imidazoline, piperidine, piperazine,
indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like
as well as N-alkoxy-nitrogen containing heterocycles.
[0028] The term "thiol" refers to the group --SH.
[0029] The term "thioalkoxy" refers to the group --S-alkyl.
[0030] "Amino acid" refers to any molecule that contains both amino
and carboxylic acid functional groups, and includes any of the
naturally occurring amino acids (e.g. Ala, Arg, Asn, Asp, Cys, Glu,
Gln, Gly, His, Hyl, Hyp, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr,
Trp, Tyr, and Val) in D, L, or DL form. The side chains of
naturally occurring amino acids are well known in the art and
include, for example, hydrogen (e.g., as in glycine), alkyl (e.g.,
as in alanine, valine, leucine, isoleucine, proline), substituted
alkyl (e.g., as in threonine, serine, methionine, cysteine,
aspartic acid, asparagine, glutamic acid, glutamine, arginine, and
lysine), alkaryl (e.g., as in phenylalanine and tryptophan),
substituted arylalkyl (e.g., as in tyrosine), and heteroarylalkyl
(e.g., as in histidine).
[0031] "Amidine" refers to a functional group that has two amine
groups attached to the same carbon atom with one carbon-nitrogen
double bond: HN.dbd.CR'--NH''2.
[0032] "Alkoxyl" refers to an alkyl group linked to oxygen thus:
R--O--, where R is an alkyl.
[0033] "Substituted alkyl" refers to a branched or unbranched
alkyl, alkenyl or alkinyl group having 1-10 carbon atoms and having
substituted by one or more substituents selected from the group
consisting of hydroxyl, mercapto, carbylmercapto, halogen,
carbyloxy, amino, amido, carboxyl, cycloalkyl, sulfo or acyl. These
substituent generic groups having the meanings being identical with
the definitions of the corresponding groups as defined herein.
[0034] "Halogen" refers to fluorine, bromine, chlorine, and iodine
atoms.
[0035] "Acyl" denotes the group --C(O)R.sub.e, where R.sub.e is
hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, cycloalkyl, substituted
cycloalkyl whereas these generic groups have meanings which are
identical with definitions of the corresponding groups as defined
in this legend.
[0036] "Acloxy" denotes the group --OAc, where Ac is an acyl,
substituted acyl, heteroacyl or substituted heteroacyl whereas
these generic groups have meanings which are identical with
definitions of the corresponding groups as defined in this
legend.
[0037] "Alkylamino" denotes the group --NR.sub.f R.sub.g, where
R.sub.f and R.sub.g, that are independent of one another, represent
hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
heteroaryl or substituted heteroaryl, whereas these generic
substituents have meanings which are identical with definitions of
the corresponding groups defined herein.
[0038] "Aryl" refers to an aromatic carbocyclic group having from 1
to 18 carbon atoms and being composed of at least one aromatic or
multiple condensed rings in which at least one of which being
aromatic.
[0039] "Substituted aryl" refers to an aromatic carbocyclic group
having from 1 to 18 carbon atoms and being composed of at least one
aromatic ring or of multiple condensed rings at least one of which
being aromatic. The ring(s) are optionally substituted with one or
more substituents selected from the group consisting of halogen,
alkyl, hydroxyl, carbylmercapto, alkylamino, carbyloxy, amino,
amido, carboxyl, nitro, mercapto or sulfo, whereas these generic
substituent group have meanings which are identical with
definitions of the corresponding groups as defined in this
legend.
[0040] "Heteroaryl" refers to a heterocyclic group having from 4 to
9 carbon atoms and at least one heteroatom selected from the group
consisting of N, O or S with at least one ring of this group being
aromatic.
[0041] "Substituted heteroaryl" refers to a heterocyclic group
having from 4 to 9 carbon atoms and at least one heteroatom
selected from the group consisting of N, O or S with at least one
ring of this group being aromatic and this group being substituted
with one or more substituents selected from the group consisting of
halogen, alkyl, carbyloxy, carbylmercapto, alkylamino, amido,
carboxyl, hydroxyl, nitro, mercapto or sulfo, whereas these generic
substituent group have meanings which are identical with
definitions of the corresponding groups as defined in this
legend.
[0042] "Carboxyl" denotes the group --C(O)OR.sub.j, where R is
hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
heteroaryl or substituted heteroaryl, whereas these generic
substituents have meanings which are identical with definitions of
the corresponding groups defined herein.
[0043] "Cycloalkyl" refers to a monocyclic or polycyclic alkyl
group containing 3 to 15 carbon atoms.
[0044] "Substituted cycloalkyl" refers to a monocyclic or
polycyclic alkyl group containing 3 to 15 carbon atoms and being
substituted by one or more substituents selected from the group
consisting of halogen, alkyl, substituted alkyl, carbyloxy,
carbylmercapto, aryl, nitro, mercapto or sulfo, whereas these
generic substituent groups have meanings which are identical with
definitions of the corresponding groups as defined in this
legend.
[0045] "Heterocycloalkyl" refers to a monocyclic or polycyclic
alkyl group containing 3 to 15 carbon atoms which at least one ring
carbon atom of its cyclic structure being replaced with a
heteroatom selected from the group consisting of N, O, S or P.
[0046] "Substituted heterocycloalkyl" refers to a monocyclic or
polycyclic alkyl group containing 3 to 15 carbon atoms which at
least one ring carbon atom of its cyclic structure being replaced
with a heteroatom selected from the group consisting of N, O, S or
P and the group is containing one or more substituents selected
from the group consisting of halogen, alkyl, substituted alkyl,
carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulfo, whereas
these generic substituent group have meanings which are identical
with definitions of the corresponding groups as defined in this
legend.
[0047] The term "aryl" refers to an unsaturated aromatic
carbocyclic group of from 6 to 20 carbon atoms having a single ring
(e.g., phenyl) or multiple condensed (fused) rings, wherein at
least one ring is aromatic (e.g., naphthyl, dihydrophenanthrenyl,
fluorenyl, or anthryl). Preferred aryls include phenyl, naphthyl
and the like.
[0048] The term "alkenyl" refers to a monoradical of a branched or
unbranched unsaturated hydrocarbon group preferably having from 2
to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even
more preferably 2 to 6 carbon atoms. Preferred alkenyl groups
include ethenyl (--CH.dbd.CH2), n-propenyl (--CH2CH.dbd.CH2),
iso-propenyl (--C(CH3).dbd.CH2), and the like.
[0049] "Imidazole" refers to a heterocyclic base of the general
formula: C.sub.3H.sub.4N.sub.2.
[0050] "Aralkyl group" refers to, for example, a C1-C6 alkyl group
which is attached to 1 or 2 aromatic hydrocarbon rings having from
6 to 10 carbon atoms and which has a total of 7 to 14 carbon atoms,
such as the benzyl, alpha-naphthylmethyl, indenylmethyl,
diphenylmethyl, 2-phenethyl, 2-alpha-naphthylethyl, 3-phenylpropyl,
3-alpha-naphthylpropyl, phenylbutyl, 4-alpha-naphthylbutyl or
5-phenylpentyl groups.
[0051] "Guanidine" refers generally to the amidine of amidocarbonic
acid and has the general formula of: C(NH.sub.2).sub.3.
[0052] The terms "aralkyl" and "heteroarylalkyl" refer to groups
that comprise both aryl or, respectively, heteroaryl as well as
alkyl and/or heteroalkyl and/or carbocyclic and/or heterocycloalkyl
ring systems according to the above definitions.
[0053] In certain aspects the invention relates to
nitrogen-containing heterocyclic compounds represented by the
general formula I as follows:
##STR00001##
wherein, W is a member selected from the group consisting of
--C(R.sup.5)(R.sup.5a)--;
--C(R.sup.6)(R.sup.6a)--C(R.sup.7)(R.sup.7a)--;
--C(R.sup.8).dbd.C(R.sup.9)--; --N(R.sup.10), and combinations
thereof;
[0054] X is a member selected from the group consisting of
--N(R.sup.1a)C(.dbd.Y)N(R.sup.4)--; --OC(.dbd.Y)N(R.sup.4)--;
--N(R.sup.1a)C(.dbd.Y)O--; --N(R.sup.1a)S(.dbd.O)N(R.sup.4)--;
--N(R.sup.1a)S(.dbd.O).sub.2N(R.sup.4)--;
--C(R.sup.1a)(R.sup.3a)C(.dbd.Y)N(R.sup.4)--, and combinations
thereof;
[0055] Y and Z represent, each independent from the other, a member
selected from the group consisting of oxygen ("O") and sulfur
("S"); and
[0056] R.sup.1, R.sup.1a, R.sup.2, R.sup.3, R.sup.3a, R.sup.4,
R.sup.5, R.sup.5a, R.sup.6, R.sup.6a, R.sup.7, R.sup.7a, R.sup.8,
R.sup.9, and R.sup.10 represent, each independent from the other, a
member selected from the group consisting of: a hydrogen atom; an
amino acid side chain; a (C1-C10) alkyl; (C1-C10) alkenyl; (C1-C10)
alkynyl; (C5-C12) monocyclic or bicyclic aryl; (C5-C14) monocyclic
or bicyclic aralkyl; monocyclic or bicyclic (C5-C14) heteroaralkyl;
and (C1-C10) monocyclic or bicyclic heteroaryl group having up to 5
heteroatoms selected from N, O, S, and P said groups being able to
be non-substituted or substituted by 1 to 6 substituents further
selected from the group consisting of: a halogen atom, an NO.sub.2,
OH, amidine, benzamidine, imidazole, 1,2,3-triazole, alkoxy,
(C1-C4), amino, piperazine, piperidine, dialkylamino, guanidine
group, bis alkylated or bis acylated guanido group, carboxylic
acid, carboxamide, ester, hydroxamic acid, phosphinic acid,
phosphonate, phosphonamidate, sulfhydryl and any combination
thereof.
[0057] In any of the preferred embodiments, the compounds of the
invention include the free base or acid forms, as well as salts
thereof, of the dipeptide derivatived heterocyclics compounds
described by the above formula. The invention also includes the
optical isomers, analogs, and derivatives of the compounds
described by the above formula. In a further embodiment of the
invention, mixtures of enantiomers and/or diastereoisomers,
resulting from a single preparative step, combination, or
interconversion are encompassed. In yet a further embodiment of the
invention, the compounds described by the formula I are included in
a pharmaceutically acceptable form, and optionally include at least
one other ingredient, for example a suitable carrier, excipient,
another pharmaceutically active ingredient or a combination
thereof.
[0058] The invention also provides prodrug forms of the above
described analogs and derivatives, wherein the prodrug is
metabolized in vivo to produce an analog or derivative as set forth
above. Indeed, some of the above described analogs or derivatives
may be a prodrug for another analog or derivative.
[0059] The term "prodrug" is well understood in the art and
includes compounds that are converted to pharmaceutically active
compounds in a biological system. For example; see Remington's
Pharmaceutical Sciences, 1980, vol. 16, Mack Publishing Company,
Easton, Pa., 61 and 424.
[0060] In another aspect of the invention, compositions containing
the above described compounds are provided. Preferably, the
compositions are formulated to be suitable for pharmaceutical or
agricultural use by the inclusion of appropriate carriers or
excipients.
[0061] In certain aspects, the intermediates and the desired
compounds in the processes described can be isolated and purified
by purification methods conventionally used in organic synthetic
chemistry, for example, neutralization, filtration, extraction,
washing, drying, concentration, recrystallization, and various
kinds of chromatography. The intermediates may be subjected to the
subsequent reaction without purification.
[0062] The present invention covers all possible isomers including
tautomers and mixtures thereof. Where chiral carbons lend
themselves to two different enantiomers, both enantiomers are
contemplated as well as procedures for separating the two
enantiomers.
[0063] In the case where a salt of a compound is desired and the
compound is produced in the form of the desired salt, it can be
subjected to purification as such. In the case where a compound is
produced in the free state and its salt is desired, the compound is
dissolved or suspended in a suitable organic solvent, followed by
addition of an acid or a base to form a salt.
[0064] In other aspects, the present invention comprises
pharmaceutically acceptable salts, racemates, and optical isomers
thereof of formula I. The compounds of this invention typically
contain one or more chiral centers. Accordingly, this invention is
intended to include racemic mixtures, diasteromers, enantiomers and
mixture enriched in one or more steroisomer. The scope of the
invention as described and claimed encompasses the racemic forms of
the compounds as well as the individual enantiomers and non-racemic
mixtures thereof.
[0065] In a further aspect of the invention, methods for the use of
the above described analogs and derivatives, as well as
compositions, are provided. In certain embodiments, the method
comprises administration to an individual of an effective amount of
the compound of the invention for the treatment and/or prevention
of a disease or condition, for example, cancer, osteoporosis,
asthma, autoimmune diseases, HIV, AIDS, rheumatoid arthritis,
systemic lupus erythematosus, Type I insulin-dependent diabetes,
tissue transplantation, malaria, African sleeping sickness, Chagas
disease, toxoplasmosis, psoriasis, restenosis, inhibition of
unwanted hair growth as cosmetic suppression, hyperparathyroidism,
inflammation, treatment of peptic ulcer, glaucoma, Alzheimer's
disease, suppression of atrial tachycardias, stimulation or
inhibition of intestinal motility, Crohn's disease and other
inflammatory bowel diseases, high blood pressure (vasodilation),
stroke, epilepsy, anxiety, neurodegenerative diseases, hyperalgesic
states, protection against hearing loss (especially cancer
chemotherapy induced hearing loss), and pharmacological
manipulation of cocaine reinforcement and craving in treating
cocaine addiction and overdose and other fungal bacterial, viral,
and parasitic diseases.
[0066] The design and synthesis by combinatorial chemistry
techniques of cyclic/polycyclic molecular frameworks that can
efficiently distribute selected pharmacophores in the 3D space is
an important method to identify small-molecules capable of
modulating biological processes and for dissecting biological
pathways. Molecules incorporating small or medium rings derived
from peptides (e.g. 2,5-diketopiperazines) are of particular
interest owing to the facile access, the chemical and
stereochemical diversity of peptide derivatives, as well as
enhanced diversity resulting from appending operations.
Therapeutic Administration
[0067] In certain aspects, the present invention includes
therapeutic compositions comprising the compounds of the invention
in a pharmaceutically acceptable form. In still another of the
preferred embodiments, the present invention includes methods for
the treatment and/or prevention of disease in a mammal, for
example, a human, comprising administering of an effective amount
of a compound of the invention in a pharmaceutically acceptable
form. The compound of the invention may optionally be administered
together with at least one of a carrier, an excipient, another
biologically active agent or any combination thereof.
[0068] Suitable routes for administration include oral, rectal,
vassal, topical (including ocular, buccal and sublingual), vaginal
and parental (including subcutaneous, intramuscular, intravitreous,
intravenous, intradermal, intrathecal and epidural). The preferred
route of administration will depend upon the condition of the
patient, the toxicity of the compound and the site of infection,
among other considerations known to the clinician.
[0069] In certain aspects, the invention relates to therapeutic
compositions comprising from about 1% to about 100% by weight of
the compounds of the invention. In any of the embodiments of the
invention, the therapeutic compositions may be administered in a
single daily dosage form or divided into two or more unitary dosage
forms.
[0070] Unit dose forms are, for example, liquids, gels, coated
tablets, tablets, ampoules, vials, suppositories or capsules. Other
forms of administration are, for example, liquids, ointments,
creams, pastes, foams, tinctures, drops, sprays, emulsions,
suspensions, dispersions and the like. Examples are capsules
containing from about 0.05 mg to about 1.0 g of the active
ingredient. Unit dose forms can be administered by any
pharmaceutically acceptable route widely known to those in the art
including, for example, oral, enteral, parenteral, intravenous,
nasal, anal, sublingual, by inhalation, vaginal, rectal, and the
like.
[0071] The pharmaceutical compositions of the present invention are
prepared in a manner known per se, for example by means of
conventional mixing, granulating, coating, dissolving or
lyophilizing processes.
[0072] Preferably, solutions of the active ingredient, and in
addition also suspensions or dispersions, especially isotonic
aqueous solutions, dispersions or suspensions, are used, it being
possible for these to be prepared before use, for example in the
case of lyophilized compositions which comprise the active
substance by itself or together with a carrier, for example
mannitol. The pharmaceutical compositions can be sterilized and/or
comprise excipients, for example preservatives, stabilizers,
wetting agents and/or emulsifiers, solubilizing agents, salts for
regulating the osmotic pressure and/or buffers, and they are
prepared in a manner known per se, for example by means of
conventional dissolving or lyophilizing processes. The solutions or
suspensions mentioned can comprise viscosity-increasing substances,
such as sodium carboxymethylcellulose, carboxymethylcellulose,
dextran, polyvinylpyrrolidone or gelatin.
[0073] Pharmaceutically acceptable forms include, for example, a
gel, lotion, spray, powder, pill, tablet, controlled release
tablet, sustained release tablet, rate controlling release tablet,
enteric coating, emulsion, liquid, salts, pastes, jellies,
aerosols, ointments, capsules, gel caps, or any other suitable form
that will be obvious to one of ordinary skill in the art.
[0074] Suspensions in oil comprise, as the oily component, the
vegetable, synthetic or semi-synthetic oils customary for injection
purposes. Oils which may be mentioned are, in particular, liquid
fatty acid esters which contain, as the acid component, a
long-chain fatty acid having 8-22, in particular 12-22, carbon
atoms, for example lauric acid, tridecylic acid, myristic acid,
pentadecylic acid, palmitic acid, margaric acid, stearic acid,
arachidinic acid, behenic acid or corresponding unsaturated acids,
for example oleic acid, elaidic acid, euric acid, brasidic acid or
linoleic acid, if appropriate with the addition of antioxidants,
for example vitamin E, .beta.-carotene or
3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of these
fatty acid esters has not more than 6 carbon atoms and is mono- or
polyhydric, for example mono-, di- or trihydric alcohol, for
example methanol, ethanol, propanol, butanol, or pentanol, or
isomers thereof, but in particular glycol and glycerol. Fatty acid
esters are therefore, for example: ethyl oleate, isopropyl
myristate, isopropyl palmitate, "Labrafil M 2375" (polyoxyethylene
glycerol trioleate from Gattefosee, Paris), "Labrafil M 1944 CS"
(unsaturated polyglycolated glycerides prepared by an alcoholysis
of apricot kernel oil and made up of glycerides and polyethylene
glycol esters; from Gattefosee, Paris), "Labrasol" (saturated
polyglycolated glycerides prepared by an alcoholysis of TCM and
made up of glycerides and polyethylene glycol esters; from
Gattefosee, Paris) and/or "Miglyol 812" (triglyceride of saturated
fatty acids of chain length C.sub.8 to C.sub.12 from Huls AG,
Germany), and in particular vegetable oils, such as cottonseed oil,
almond oil, olive oil, castor oil, sesame oil, soybean oil and, in
particular, groundnut oil.
[0075] The preparation of the injection compositions is carried out
in the customary manner under sterile conditions, as are bottling,
for example in ampoules or vials, and closing of the
containers.
[0076] For example, pharmaceutical compositions for oral use can be
obtained by combining the active ingredient with one or more solid
carriers, if appropriate granulating the resulting mixture, and, if
desired, processing the mixture or granules to tablets or coated
tablet cores, if appropriate by addition of additional
excipients.
[0077] Suitable carriers are, in particular, fillers, such as
sugars, for example lactose, sucrose, mannitol or sorbitol
cellulose preparations and/or calcium phosphates, for example
tricalcium phosphate, or calcium hydrogen phosphate, and
furthermore binders, such as starches, for example maize, wheat,
rice or potato starch, methylcellulose,
hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or
polyvinyl-pyrrolidine, and/or, if desired, desintegrators, such as
the above mentioned starches, and furthermore carboxymethyl-starch,
cross-linked polyvinylpyrrolidone, alginic acid or a salt thereof,
such as sodium alginate. Additional excipients are, in particular,
flow regulators and lubricants, for example salicylic acid, talc,
stearic acid or salts thereof, such as magnesium stearate or
calcium stearate, and/or polyethylene glycol, or derivatives
thereof.
[0078] Coated tablet cores can be provided with suitable coatings
which, if appropriate, are resistant to gastric juice, the coatings
used being, inter alia, concentrated sugar solutions, which, if
appropriate, comprise gum arabic, talc, polyvinylpyrrolidine,
polyethylene glycol and/or titanium dioxide, coating solutions in
suitable organic solvents or solvent mixtures or, for the
preparation of coatings which are resistant to gastric juice,
solutions of suitable cellulose preparations, such as
acetylcellulose phthalate or hydroxypropylmethylcellulose
phthalate.
[0079] By "controlled release" it is meant for purposes of the
present invention that therapeutically active compound is released
from the preparation at a controlled rate or at a specific site,
for example, the intestine, or both such that therapeutically
beneficial blood levels (but below toxic levels) are maintained
over an extended period of time, e.g., providing a 12 hour or a 24
hour dosage form.
[0080] The term "rate controlling polymer" as used herein includes
hydrophilic polymers, hydrophobic polymers or mixtures of
hydrophilic and/or hydrophobic polymers that are capable of
retarding the release of the compounds in vivo. In addition, many
of the same polymers can be utilized to create an enteric coating
of a drug, drug suspension, or drug matrix. It is within the skill
of those in the art to modify the coating thickness, permeability,
and dissolution characteristics to provide the desired controlled
release profile (e.g., drug release rate and locus) without undue
experimentation.
[0081] Examples of suitable controlled release polymers to be used
in this invention include hydroxyalkylcellulose, such as
hydroxypropylcellulose and hydroxypropylmethylcellulose;
poly(ethylene)oxide; alkylcellulose such as ethycellulose and
methylcellulose; carboxymethylcellulose; hydrophilic cellulose
derivatives; polyethylene glycol; polyvinylpyrrolidone; cellulose
acetate; cellulose acetate butyrate; cellulose acetate phthalate;
cellulose acetate trimellitate; polyvinylacetate phthalate;
hydroxypropylmethylcellulose phthalate;
hydroxypropylmethylcellulose acetate succinate; poly(alkyl
methacrylate); and poly (vinyl acetate). Other suitable hydrophobic
polymers include polymers or copolymers derived from acrylic or
methacrylic acid esters, copolymers of acrylic and methacrylic acid
esters, zein, waxes, shellac and hydrogenated vegetable oils.
[0082] To ensure correct release kinetics, the controlled release
preparation of this invention contains about 5 and 75% by weight,
preferably about 20 and 50% by weight, more preferably about 30 to
45% by weight controlled release polymer(s) and about 1 to 40% by
weight, preferably about 3 to 25% by weight active compounds. The
controlled release preparation according to the invention can
preferably include auxiliary agents, such as diluents, lubricants
and/or melting binders. Preferably, the excipients are selected to
minimize the water content of the preparation. Preferably, the
preparation includes an antioxidant. Suitable diluents include
pharmaceutically acceptable inert fillers such as microcrystalline
cellulose, lactose, dibasic calcium phosphate, saccharides, and/or
mixtures of any of the foregoing. The diluent is suitably a water
soluble diluent. Examples of diluents include microcrystalline
cellulose such as Avicel ph112, Avicel pH101 and Avicel pH102;
lactose such as lactose monohydrate, lactose anhydrous, and
Pharmatose DCL 21; dibasic calcium phosphate such as Emcompress;
mannitol; starch; sorbitol; sucrose; and glucose. Diluents are
carefully selected to match the specific formulation with attention
paid to the compression properties. Suitable lubricants, including
agents that act on the flowability of the powder to be compressed
are, for example, colloidal silicon dioxide such as Aerosil 200;
talc; stearic acid, magnesium stearate, and calcium stearate.
Suitable low temperature melting binders include polyethylene
glycols such as PEG 6000; cetostearyl alcohol; cetyl alcohol;
polyoxyethylene alkyl ethers; polyoxyethylene castor oil
derivatives; polyoxyethylene sorbitan fatty acid esters;
polyoxyethylene stearates; poloxamers; and waxes.
[0083] To improve the stability in the controlled release
preparation, an antioxidant compound can be included. Suitable
antioxidants include sodium metabisulfite; tocopherols such as
alpha, beta, or delta-tocopherol tocopherol esters and
alpha-tocopherol acetate; ascorbic acid or a pharmaceutically
acceptable salt thereof; ascorbyl palmitate; alkyl gallates such as
propyl gallate, Tenox PG, Tenox s-1; sulphites or a
pharmaceutically acceptable salt thereof; BHA; BHT; and
monothioglycerol.
[0084] The controlled release preparation according to the
invention preferably can be manufactured by blending the compounds
with the controlled release polymer(s) and auxiliary excipients
followed by direct compression. Other methods for manufacturing the
preparation include melt granulation. Preferred melt granulation
techniques include melt granulation together with the rate
controlling polymer(s) and diluent(s) followed by compression of
the granules and melt granulation with subsequent blending with the
rate controlling polymer(s) and diluents followed by compression of
the blend. As desired prior to compression, the blend and/or
granulate can be screened and/or mixed with auxiliary agents until
an easily flowable homogeneous mixture is obtained.
[0085] Oral dosage forms of the controlled release preparation
according to the invention can be in the form of tablets, coated
tablets, enterically coated tablets or can be multiparticulate,
such as in the form of pellets or mini-tablets. If desired,
capsules such as hard or soft gelatin capsules, can contain the
multiparticulates. If desired, the multiparticulate oral dosage
forms can comprise a blend of at least two populations of pellets
or mini-tablets having different controlled-release in vitro and/or
in vivo release profiles. If desired, one of the pellet or
mini-tablet populations can comprise immediate release
multiparticulate, such as multiparticulates formed by conventional
means.
[0086] If desired, the controlled release matrix tablets or
multiparticulates of this invention can be coated with a controlled
release polymer layer so as to provide additional controlled
release properties. Suitable polymers that can be used to form this
controlled release layer include the rate controlling polymers
listed above.
[0087] As desired, the tablets, pellets or mini-tablets according
to the invention can be provided with a light-protective and/or
cosmetic film coating, for example, film-formers, pigments,
anti-adhesive agents and plasticizers. Such a film former may
consist of fast-dissolving constituents, such as low-viscosity
hydroxypropylmethylcelluose, for example Methocel E5 or D14 or
Pharmacoat 606 (Shin-Etsu). The film coating may also contain
excipients customary in film-coating procedures, such as
light-protective pigments, for example iron oxide, or titanium
dioxide, anti-adhesive agents, for example talc, and also suitable
plasticizers such as PEG 400, PEG 6000, and diethyl phthalate or
triethyl citrate.
[0088] The controlled release polymer of this invention may consist
of a hydrogel matrix. For instance, the compounds can be compressed
into a dosage form containing a rate controlling polymer, such as
HPMC, or mixture of polymers which when wet will swell to form a
hydrogel. The rate of release from this dosage form is controlled
both by diffusion from the swollen tablet mass and by erosion of
the tablet surface over time. The rate of release may be controlled
both by the amount of polymer per tablet and by the inherent
viscosities of the polymers used.
[0089] Dyes or pigments can be admixed to the tablets or coated
tablet coatings, for example for identification or characterization
of different doses of active ingredient.
[0090] Pharmaceutical compositions, which can be used orally, are
also hard capsules of gelatin and soft, closed capsules of gelatin
and a plasticizer, such as glycerol or sorbitol. The hard capsules
can contain the active ingredient in the form of granules, mixed
for example with fillers, such as maize starch, binders and/or
lubricants, such as talc or magnesium stearate, and stabilizers if
appropriate. In soft capsules, the active ingredient is preferably
dissolved or suspended in suitable liquid excipients, such as
greasy oils, paraffin oil or liquid polyethylene glycols or fatty
acid esters of ethylene glycol or propylene glycol, it being
likewise possible to add stabilizers and detergents, for example of
the polyethylene sorbitan fatty acid ester type.
[0091] Other oral forms of administration are, for example, syrups
prepared in the customary manner, which comprise the active
ingredient, for example, in suspended form and in a concentration
of about 5% to 60%, preferably about 20% or in a similar
concentration which results in a suitable individual dose, for
example, when 5 or 10 ml are measured out. Other forms are, for
example, also pulverulent or liquid concentrates for preparing of
shakes, for example in milk. Such concentrates can also be packed
in unit dose quantities.
[0092] Pharmaceutical compositions, which can be used rectally,
are, for example, suppositories that comprise a combination of the
active ingredient with a suppository base. Suitable suppository
bases are, for example, naturally occurring or synthetic
triglycerides, paraffin hydrocarbons, polyethylene glycols or
higher alkanols.
[0093] Compositions which are suitable for parenteral
administration are aqueous solutions of an active ingredient in
water-soluble form, for example of water-soluble salt, or aqueous
injection suspensions, which comprise viscosity-increasing
substances, for example sodium carboxymethylcellulose, sorbitol
and/or dextran, and if appropriate stabilizers. The active
ingredient can also be present here in the form of a lyophilisate,
if appropriate together with excipients, and be dissolved before
parenteral administration by addition of suitable solvents.
Solutions such as are used, for example, for parental
administration can also be used as infusion solutions. Preferred
preservatives are, for example. Antioxidants, such as ascorbic
acid, or microbicides, such as sorbic or benzoic acid.
[0094] Ointments are oil-in-water emulsions, which comprise not
more than 70%, but preferably 20-50% of water or aqueous phase. The
fatty phase consists, in particular, hydrocarbons, for example
vaseline, paraffin oil or hard paraffin's, which preferably
comprise suitable hydroxy compounds, such as fatty alcohol's or
esters thereof, for example cetyl alcohol or wool wax alcohols,
such as wool wax, to improve the water-binding capacity.
Emulsifiers are corresponding lipophilic substances, such as
sorbitan fatty acid esters (Spans), for example sorbitan oleate
and/or sorbitan isostearate. Additives to the aqueous phase are,
for example, humectants, such as polyalcohols, for example
glycerol, propylene glycol, sorbitol and/or polyethylene glycol, or
preservatives and odoriferous substances.
[0095] Fatty ointments are anhydrous and comprise, as the base, in
particular, hydrocarbons, for example paraffin, vaseline or
paraffin oil, and furthermore naturally occurring or semi-synthetic
fats, for example hydrogenated coconut-fatty acid triglycerides,
or, preferably, hydrogenated oils, for example hydrogenated
groundnut or castor oil, and furthermore fatty acid partial esters
of glycerol, for example glycerol mono- and/or distearate, and for
example, the fatty alcohols. They also contain emulsifiers and/or
additives mentioned in connection with the ointments which increase
uptake of water.
[0096] Creams are oil-in-water emulsions, which comprise more than
50% of water. Oily bases used are, in particular, fatty alcohols,
for example lauryl, cetyl or stearyl alcohols, fatty acids, for
example palmitic or stearic acid, liquid to solid waxes, for
example isopropyl myristate, wool wax or beeswax, and/or
hydrocarbons, for example vaseline (petrolatum) or paraffin oil.
Emulsifiers are surface-active substances with predominantly
hydrophilic properties, such as corresponding nonionic emulsifiers,
for example fatty acid esters of polyalcohols or ethyleneoxy
adducts thereof, such as polyglyceric acid fatty acid esters or
polyethylene sorbitan fatty esters (Tweens), and furthermore
polyoxyethylene fatty alcohol ethers or polyoxyethylene fatty acid
esters, or corresponding ionic emulsifiers, such as alkali metal
salts of fatty alcohol sulfates, for example sodium lauryl sulfate,
sodium cetyl sulfate or sodium stearyl sulfate, which are usually
used in the presence of fatty alcohols, for example cetyl stearyl
alcohol or stearyl alcohol. Additives to the aqueous phase are,
inter alia, agents which prevent the creams from drying out, for
example polyalcohols, such as glycerol, sorbitol, propylene glycol
and/or polyethylene glycols, and furthermore preservatives and
odoriferous substances.
[0097] Pastes are creams and ointments having secretion-absorbing
powder constituents, such as metal oxides, for example titanium
oxide or zinc oxide, and furthermore talc and/or aluminum
silicates, which have the task of binding the moisture or
secretions present.
[0098] Foams are administered from pressurized containers and they
are liquid oil-in-water emulsions present in aerosol for. As the
propellant gases, halogenated hydrocarbons, such as
chlorofluoro-lower alkanes, for example dichlorofluoromethane and
dichlorotetrafluoroethane, or, preferably, non-halogenated gaseous
hydrocarbons, air, N.sub.2O, or carbon dioxide are used. The oily
phases used are, inter alia, those mentioned above for ointments
and creams, and the additives mentioned there are likewise
used.
[0099] Tinctures and solutions usually comprise an
aqueous-ethanolic base to which, humectants for reducing
evaporation, such as polyalcohols, for example glycerol, glycols
and/or polyethylene glycol, and re-oiling substances, such as fatty
acid esters with lower polyethylene glycols, i.e. lipophilic
substances soluble in the aqueous mixture to substitute the fatty
substances removed from the skin with the ethanol, and, if
necessary, other excipients and additives, are admixed.
[0100] The invention also relates to a process or method for
treatment of the disease states mentioned above. The compounds can
be administered prophylactically or therapeutically as such or in
the form of pharmaceutical compositions, preferably in an amount,
which is effective against the diseases mentioned. With a
warm-blooded animal, for example a human, requiring such treatment,
the compounds are used, in particular, in the form of
pharmaceutical composition. A daily dose of about 0.1 to about 5 g,
preferably 0.5 g to about 2 g, of a compound of the present
invention is administered here for a body weight of about 70
kg.
[0101] It is understood that the examples and embodiments described
herein are for illustrative purposes only and that various
substitutions, modifications or changes in light thereof will be
suggested to persons skilled in the art and are included within the
spirit and purview of this application and are considered within
the scope of the appended claims. The following examples are given
by way of example of the preferred embodiments, and are in no way
considered to be limiting to the invention. For example, the
relative quantities of the ingredients may be varied to achieve
different desired effects, additional ingredients may be added,
and/or similar ingredients may be substituted for one or more of
the ingredients described. All publications, patents, and patent
applications cited herein are hereby incorporated by reference in
their entirety for all purposes.
EXAMPLES
[0102] To expand further the skeletal diversity attainable with
peptide substrates, a variety of compounds were synthesized and
densely functionalized from, for example, a dipeptide-derived
1,3,5-triazepan-2,6-dione scaffold. These compounds were found to
be active by screening a small "prospecting" library against the
malaria liver stage (LS).
[0103] Interest in designing and evaluating the dipeptide-derived
1,3,5-triazepan-2,6-dione scaffold stems from the remarkable
biological activities exhibited by molecules with diazepine and
triazepine skeletons. In particular seven-membered cyclic ureas
have attracted much attention in recent years with application in
the development of HIV-protease and reverse transcriptase
inhibitors, Factor Xa inhibitors, beta-lactamases inhibitors,
phospholipase C inhibitors, and chemokine receptor antagonists.
[0104] With reference to FIG. 2, 1,3,5-triazepan-2,6-diones 4 are
constructed in only four steps by cyclization of simple activated
dipeptide derivatives, and the approach benefits from the
considerable diversity of commercial alpha-amino acids. The
cyclization strategy parallels the previously reported approach to
the preparation of enantiopure macrocyclic oligoureas. Succinimidyl
carbamates 2 were prepared from Boc-dipeptides 1 as previously
described for N-protected alpha- and beta-amino acids. Selective
removal of the Boc group by treatment of crude 2 with
trifluoroacetic acid (TFA) afforded 3 which cyclized to 4 in the
presence of diisopropylethylamine (DIEA). The cyclization proceeded
rapidly with concomitant release of N-hydroxysuccinimide and
formation of the TFA salt of DIEA. These byproducts were removed by
either recrystallization of crude 4, liquid-liquid extraction or
polymer supported sequestration (PSS) with tris-(2-aminoethyl)amine
polystyrene (PS-triamine). Alternatively polymer-supported-DIEA
(PS-DIEA) was found to be very effective in promoting cyclization
and simultaneously removing byproducts.
[0105] A set of 18 monocyclic to tetracyclic
1,3,5-triazepin-2,6-diones 4 was synthesized by this approach in
moderate to high overall yield starting from a variety of dipeptide
sequences (Table 1).
TABLE-US-00001 TABLE 1 Solution phase synthesis of 1,3,5-triazepan-
2,6-diones (4) from dipeptides (1). 3 4 Entry 1 Xaa Xbb Yield
(%).sup.[a] Yield (%).sup.[b,c] 1 a Phe Sar 93 71.sup.[d] 2 b D-Phe
Sar 78 74.sup.[d] 3 c Val Sar 95 67.sup.[f] 4 d Leu Sar 86
34.sup.[f] 5 e Dap (Fmoc) Sar 72 43.sup.[f] 6 f Phg Sar 58
41.sup.[f] 7 g 2-Nal Sar 50 77.sup.[f] 8 h Tic Sar 59 68.sup.[d] 9
i Phe Pro 90 66.sup.[d] 10 j D-Phe Pro 80 66.sup.[g] 11 k 2-Nal Pro
82 78.sup.[d] 12 l Tic Pro 77 57.sup.[d] 13 m Phe NMe-Phe 34
97.sup.[d] 14 n Phe Hyp (Bn) 73 99.sup.[f,h] 15 p Ala Tic 54
97.sup.[i] 16 q Pro Val 66 11.sup.[g,j] 17 r Pro Leu 58 7.sup.[g,j]
(Bold numbers are in reference to FIG. 2). .sup.[a]overall yields
from 1; .sup.[b]yields from 3; .sup.[c]cyclization performed using
DIE A unless otherwise stated; .sup.[d]purification by
recrystallization; .sup.[e]PS-DIEA used for cyclization;
.sup.[f]purification by flash chromatography
(CH.sub.2Cl.sub.2/MeOH/AcOH, 97:3:1); .sup.[g]purification by
C.sub.18 RP-HPLC; .sup.[h]hydrogenation of the benzyl group
afforded triazepan-dione 4 with a hydroxyl side chain in 70% yield;
.sup.[i]purification using PS-triamine; .sup.[j]cyclization
performed with N-methyl morpholine at a concentration of 0.001 M.
The formation of 4 was accompanied by the formation of the
corresponding cyclodimer. Abbreviations: Dap = diaminopropanoic;
Phg = Phenylglycine; 2-Nal = 2-naphthylphenylalanine; Tic =
Tetrahydroisoquinoline-3-carboxylic acid; Hyp =
cis-4-Hydroxyproline.
[0106] Carbamates 2a-n and 2p bearing a tertiary amide N-terminal
to gXbb residue (R3.noteq.H) were expected to give an equilibrium
mixture between trans and cis isomers (a 1:1 ratio was observed for
2a by .sup.1H-NMR in CD.sub.3CN) and as a result readily cyclized
to 4 (entries 1-15). In contrast, cyclization of precursors 2 with
a secondary amide N-terminal to gXbb (R.sup.3.dbd.H, entries 16 and
17) gave 4 together with various proportion of the corresponding
14-membered ring cyclodimer.
[0107] X-ray diffraction and .sup.1H-NMR studies of representative
members of the library, revealed that the 1,3,5-triazepan-2,6-dione
ring system in compounds 4 generally adopts a rigid non planar
conformation (the values for the mean angle between the amide and
urea planes is close to 120.degree. with side chains R.sup.2 and
R.sup.4 in pseudo-equatorial position (FIG. 3).
[0108] Further functionalization and diversification of parent
scaffolds 4 was achieved by alkylation of urea nitrogens (FIG. 4).
Treatment of scaffold 4 with NaH (5 equiv) and various
electrophiles (3 equiv) afforded dialkylated cyclo-ureas (e.g. 6
and 7) in good yield and purities following liquid/liquid
extraction and PSS of excess electrophile with
N-(2-mercaptoethyl)aminomethyl-PS. Interestingly, in the presence
of KF/Al.sub.2O.sub.3 or NaH (2 equiv.) cyclo(Xaa-gSar-CO) 4a, 4c
and cyclo(Phe-gPro-CO) 4i were converted to 8 and 9 monoalkylated
at the gem-diamino urea nitrogen with good to excellent
selectivities (8:6 and 9:7 in the range 80:20 to 100:0). Crystal
structures of dialkylated and monoalkylated derivatives 7 and 9(I),
respectively, show a rearrangement of the ring geometry with
R.sup.1 side-chain now pointing in quasi axial orientation (FIG.
5).
[0109] Invasion of host hepatocytes by sporozoites represent an
early step in the life cycle of the malaria parasite. Malaria liver
stages hold great promise for drug targeting because i) they
possess a more complex and distinct metabolism than their blood
stage counterpart and ii) they precede the pathogenic blood stage,
thus offering prophylaxis possibilities against malaria. However,
very few drugs against LS parasites are available and most of them
like primaquine display severe side-effects or loose efficiency due
to the development of parasite resistance.
[0110] Seventeen different 1,3,5-triazepan-2,6-diones were randomly
selected and were first tested at different doses for toxicity on
primary mouse hepatocyte culture. From these, nine were shown to be
toxic at all doses tested (6, 25-100 .mu.g/ml) and two at high
doses(over 50 .mu.g/ml). The non toxic remaining six molecules were
thus tested to evaluate their effects on sporozoite invasion and
development in hepatocytes. Four of these 4j, 7a, 5q and 11 had no
significant effect on liver parasites (FIG. 5A, 5C and data not
shown). In contrast, two molecules, 4b and 8a, were shown to
inhibit significantly and repeatedly LS development (FIG. 5A and
5B), 4b being the most potent.
[0111] We have presented the design and the construction of a 32
members small library of dipeptide derived
1,3,5-triazepin-2,6-diones which led to the identification of two
molecules active against the malaria liver stages exempt of
toxicity on mouse hepatocytes. Studies aimed at increasing the
structural diversity of the library by integrating a more
comprehensive set of peptide precursors (including side-chain and
stereochemical diversity) and appending processes are undergoing
and should help for the rapid identification of more potent
molecules to the underexplored stage of malaria.
Examples of General Synthetic Schemes And Procedures
Example 1
Synthesis of [1,3,5]Oxadiazepane-2,6-diones (Formula Ia)
##STR00002##
##STR00003##
[0112] Example 2
Synthesis of 2-Thioxo[1,3,5]triazepan-6-ones (Formula Ib)
##STR00004##
##STR00005##
[0114] Step a) Dipeptide amide Ib-p1 was dissolved in THF/water
(3:1) and treated with iodobenzene bistrifluoroacetate (IBTFA),
THF/H.sub.2O (1.2 equiv.) for 3 h, time after which starting
material was consumed. Solvents were removed in vacuo and Et.sub.2O
was added. The solid which formed was collected and washed with
Et.sub.2O to yield the corresponding gem-diamino derivative which
was used in the next step without further purification.
Quantitative Yield.
[0115] Step b) bis(benzotriazol-1-yl)methanethione (1 equiv) was
dissolved in CH2C12 at rt. The previously synthesized gem-diamino
derivative was added dropwise and the reaction mixture was stirred
for 18 h. Solvent was removed under vacuum and the residue was
redissolved in EtOAc and washed with 5% aqueous sodium carbonate,
water and brine before drying over anhydrous sodium sulphate.
Solvent was removed under vacuum and 1b-p2 was recrystallized from
ethyl acetate.
[0116] Step c) The 1-thiocarbamoylbenzotriazole was treated with
TFA at 0.degree. C. After 30 min, TFA was removed by co-evaporation
with hexane and the TFA salt precipitated by addition of
diethylether. The resulting salt Ib-p3 was collected by filtration
and dried under high vacuum. It was used in the next step without
further purification.
[0117] Step d) The TFA salt Ib-p3 was dissolved in MeCN and
diisopropylethylamine (2.5 equiv) was then added and the reaction
mixture was stirred for 24 h. Solvent was removed in vacuum and the
residue was redissolved in EtOAc, washed with 5% aqueous sodium
carbonate, 1M HCl, water, and brine before drying over anhydrous
sodium sulphate. Solvent was removed in vacuum and cyclic Ib-1 was
purified by recrystallization from CH.sub.2Cl.sub.2/diisopropyl
ether.
Example 3
Synthesis of 4-Benzyl-6-methyl-[1,3,6]oxadiazocane-2,5-dione
(Formula Ib-1)
##STR00006##
##STR00007##
[0119] Step a) Dipeptide amide Ib-p 1 was dissolved in THF/water
(3:1) and treated with iodobenzene bistrifluoroacetate (IBTFA),
THF/H.sub.2O (1.2 equiv.) for 3 h, time after which starting
material was consumed. Solvents were removed in vacuo and Et.sub.2O
was added. The solid which formed was collected and washed with
Et.sub.2O to yield the corresponding gem-diamino derivative which
was used in the next step without further purification.
Quantitative Yield.
[0120] Step b) bis(benzotriazol-1-yl)methanethione (1 equiv) was
dissolved in CH2Cl2 at rt. The previously synthesized gem-diamino
derivative was added dropwise and the reaction mixture was stirred
for 18 h. Solvent was removed under vacuum and the residue was
redissolved in EtOAc and washed with 5% aqueous sodium carbonate,
water and brine before drying over anhydrous sodium sulphate.
Solvent was removed under vacuum and 1b-p2 was recrystallized from
ethyl acetate.
[0121] Step c) The 1-thiocarbamoylbenzotriazole was treated with
TFA at 0.degree. C. After 30 min, TFA was removed by co-evaporation
with hexane and the TFA salt precipitated by addition of
diethylether. The resulting salt Ib-p3 was collected by filtration
and dried under high vacuum. It was used in the next step without
further purification.
[0122] Step d) The TFA salt Ib-p3 was dissolved in MeCN and
diisopropylethylamine (2.5 equiv) was then added and the reaction
mixture was stirred for 24 h. Solvent was removed in vacuum and the
residue was redissolved in EtOAc, washed with 5% aqueous sodium
carbonate, 1M HCl, water, and brine before drying over anhydrous
sodium sulphate. Solvent was removed in vacuum and cyclic Ib-1 was
purified by recrystallization from CH.sub.2Cl.sub.2/diisopropyl
ether.
Example 4
Synthesis of 2-Thioxo-[1,3,5]oxadiazepan-6-ones (Formula Ic)
##STR00008##
##STR00009##
[0124] Step a) Dipeptide amide Ib-pl was dissolved in THF/water
(3:1) and treated with iodobenzene bistrifluoroacetate (IBTFA),
THF/H.sub.2O (1.2 equiv.) for 3 h, time after which starting
material was consumed. Solvents were removed in vacuo and Et.sub.2O
was added. The solid which formed was collected and washed with
Et.sub.2O to yield the corresponding gem-diamino derivative which
was used in the next step without further purification.
Quantitative Yield.
[0125] Step b) bis(benzotriazol-1-yl)methanethione (1 equiv) was
dissolved in CH2Cl2 at rt. The previously synthesized gem-diamino
derivative was added dropwise and the reaction mixture was stirred
for 18 h. Solvent was removed under vacuum and the residue was
redissolved in EtOAc and washed with 5% aqueous sodium carbonate,
water and brine before drying over anhydrous sodium sulphate.
Solvent was removed under vacuum and 1b-p2 was recrystallized from
ethyl acetate.
[0126] Step c) The 1-thiocarbamoylbenzotriazole was treated with
TFA at 0.degree. C. After 30 min, TFA was removed by co-evaporation
with hexane and the TFA salt precipitated by addition of
diethylether. The resulting salt Ib-p3 was collected by filtration
and dried under high vacuum. It was used in the next step without
further purification.
[0127] Step d) The TFA salt Ib-p3 was dissolved in MeCN and
diisopropylethylamine (2.5 equiv) was then added and the reaction
mixture was stirred for 24 h. Solvent was removed in vacuum and the
residue was redissolved in EtOAc, washed with 5% aqueous sodium
carbonate, 1M HCl, water, and brine before drying over anhydrous
sodium sulphate. Solvent was removed in vacuum and cyclic Ib-1 was
purified by recrystallization from CH.sub.2Cl.sub.2/diisopropyl
ether.
Example 5
Synthesis of [1,3,6]Oxadiaxocane-2,5-diones (Formula Id)
##STR00010##
##STR00011##
[0128] Example 6
Synthesis of 4-Benzyl-6-methyl-[1,3,6]oxadiazocane-2,5-dione
(Formula Id-1).
##STR00012##
##STR00013##
[0129] 1) Synthesis of P-Nitrophenyl Carbonate Precursor Id-p2
##STR00014##
[0131] The starting dipeptide alcohol Id-p1 (300 mg, 0.93 mmol, 1
eq) is dissolved in 5 mL CH.sub.2Cl.sub.2 and 82 .mu.L pyridine
(1.02 mmol, 1.1 eq). A solution of 4-nitrophenyl chloroformate
(0.37 g, 1.86 mmol, 2 eq) in 2 mL.
[0132] After stirring for 24 h, the reaction mixture is diluted
with 15 mL CH.sub.2Cl.sub.2, and washed with 1N NaHCO.sub.3 The
organic phase is dried on Na.sub.2SO.sub.4, concentrated and
purified by flash chromatography (eluant 1:2 AE/cyclohexane) to
yield pure carbonate Id-p2 with 59% yield. HPLC tR 14.1 (gradient
30-100% B, 20 min.)
[0133] .sup.1H NMR (300 MHz, CDCl3) .delta. 8.3 (m, 2H, arom-H
.alpha.-NO2), 7.39 (m, 2H, arom-H .beta.-NO2), 7.24 (m, 5H,
arom-H), 5.34 (m, J=10.55 Hz, 1H NH), 4.85 (q, J=14.9, 7.9 Hz, 1H
.alpha.-NH), 4.31 4.14 (dd, J=9.97, 5.1 Hz, 2H .alpha.-O), 3.77
3.54 (dd, J=14.5, 5.2 Hz, 2H .alpha.-NMe), 2.98 (m, 2H
.alpha.-Phe), 2.79 (s, 3H NMe), 1.43 (s, 9H Boc).
[0134] .sup.13C NMR (100 MHz, CDCl3) .delta. 171.8 (CO amide),
154.8 (CO carbamate), 154.5 (CO carbonate), 151.6 (C arom
.alpha.-NO2), 144.8 (C arom .delta.-NO2), 135.5 (C arom Phe), 128.8
(2CH Phe), 128.7 (2CH Phe), 127.8 (CH-Phe), 124.7 (CH arom), 121.1
(CH-arom), 79.3 (C Boc), 66.0 (CH2 .alpha.-O), 50.9 (CH
.alpha.-NH), 46.4 47.0 (CH2 .alpha.-N), 39.4 (CH2 Phe), 35.8 33.6
(CH3 NMe), 27.7 (3 CH3 Boc).
2) Cyclization To Id-p1
[0135] p-Nitrophenyl carbonate Id-p2 is treated with
trifluoroacetic acid for 30'. Addition of ether gave the
corresponding TFA salt which precipitated as a white solid. It was
filtered and used in the next step without further purification.
The TFA salt (220 mg, 0.44 mmol, 1 eq) dissolved in MeCN (10 mL)
was added slowly to a solution of Diisopropylethylamine (194 .mu.L,
1.14 mmol, 2.6 eq) and hydroxybenzotriazole (HOBt) (60 mg, 0.44
mmol, 1 eq) in 25 mL MeCN. The reaction mixture was stirred for 3
days and concentrated in vacuo. CH.sub.2Cl.sub.2 is then added and
the organic phase was washed with 1N NaHCO3, brine, dried over
Na2SO4 and concentrated in vacuo. The residue (110 mg) was then
purified by silica gel chromatography.
[0136] [CHCl.sub.3/MeOH/AcOH (20:0.5:0.1) then puis CHCl.sub.3/MeOH
[20:1]) to afford 42 mg of Id-1.
[0137] HPLC t.sub.R (Id-1) 5.88 (gradient 30-100% B, 20 min)
[0138] HRMS (ESI) calculated for C.sub.13H.sub.16N.sub.2O.sub.3
249.1234, found 249.1230.
[0139] .sup.1H NMR Id-1 (300 MHz, CDCl.sub.3) .delta. 7.25 (m, 5H,
arom-H), 6.10 (d, H.sup.4), 4.75 (dd, J=8.9, 7.4 Hz, H.sup.5), 4.20
(m, 2H.sup.3), 4.15 (m, H.sup.2), 3.28 (dd, J=14.0, 7.6 Hz,
1H.sup.6), 3.17 (m, H.sup.2'), 3.02 (dd, 1H.sup.6), 3.0 (s,
3H.sup.1).
[0140] .sup.13C NMR Id-1 (100 MHz, CDCl.sub.3) .delta. 172.3 (CO
amide), 157.7 (CO carbonate), 136.9 (C-arom), 129.3 (2CH arom),
128.6 (2CH arom), 126.8 (CH arom), 69.6 (CH.sub.2 .alpha.-O), 54.0
(CH .alpha.-N), 52.9 (CH.sub.2 .alpha.-N), 36.6 (CH.sub.3 Me), 35.7
(CH.sub.2 Phe).
Example 7
Synthesis of 1,1-Dioxo-1.lamda..sup.6-[1,2,5,8]thiatriazocan-4-ones
(Formula If)
##STR00015##
##STR00016##
[0141] Example 8
Synthesis of
10-methyl-6,6,11-trioxo-8,9,10,11,11a,12-hexahydro-5H-6.lamda..sup.6-thia-
-5a,7,10-triaza-cycloocta[b]naphthalene-7-carboxylic acid methyl
ester (Formula If-1)
##STR00017##
##STR00018##
[0143] i) The N-Boc protected dipeptide alcohol was treated with
TFA for 30 minutes at 0.degree. C. The TFA was removed under vacuum
and the residue was dissolved in AcOEt. Saturated NaHCO3 was added
under stirring and after 10 minutes the organic phase was dried
with Na2SO4 and concentrated under vacuum to give If-p1.
[0144] ii) Compound 1f-p1 (175 mg, 0.75 mmol, 1 eq), is dissolved
in 10 mL anhydrous THF and Burgess reagent (534 mg, 2.24 mmol, 2.5
eq) is added. The solution is then heated under reflux at from
about 70.degree. C. to about 90.degree. C. for 2 days. The reaction
mixture is then poured into a solution of saturated NH.sub.4Cl (40
mL). The mixture is extracted with CH2Cl2 and the organic phase is
washed with H.sub.2O, dried over Na.sub.2SO.sub.4 and concentrated
under vacuum. The crude mixture is then purified by silica gel
chromatography (CHCl.sub.3/MeOH/AcOH (18:1:0.2) to yield If-1.
[0145] The detailed examples are given by way of example of the
embodiments, and are in no way considered to be limiting to the
invention. For example, the relative quantities of the ingredients
may be varied to optimize the desired effects, additional
ingredients may be added, and/or similar ingredients may be
substituted for one or more of the ingredients described.
Additional advantageous features and functionalities associated
with the systems, methods, and processes of the present invention
will be apparent from the appended claims.
* * * * *