WO2004011005A2 - Antimicrobial 2, 4-diamino-pteridine derivatives - Google Patents

Antimicrobial 2, 4-diamino-pteridine derivatives Download PDF

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Publication number
WO2004011005A2
WO2004011005A2 PCT/GB2003/003287 GB0303287W WO2004011005A2 WO 2004011005 A2 WO2004011005 A2 WO 2004011005A2 GB 0303287 W GB0303287 W GB 0303287W WO 2004011005 A2 WO2004011005 A2 WO 2004011005A2
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Prior art keywords
compound
antimicrobial
formula
diamino
analogue
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PCT/GB2003/003287
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French (fr)
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WO2004011005A3 (en
Inventor
Charles Anthony Hart
Alexis Nzila Mouanda
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University of Liverpool
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University of Liverpool
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Publication of WO2004011005A3 publication Critical patent/WO2004011005A3/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
    • C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to pharmaceutical antimicrobial, for example
  • DHFS dihydrofolate synthase enzyme
  • MTX 2,4-diamino-pteridine compounds that compete with folate, because
  • APT and MTX comprise 2, 4-diamino
  • X is carbon or nitrogen R is selected from the group consisting of:
  • Another preferred group of antimicrobial compounds according to the invention have the general formula:
  • a pharmaceutical preparation for the treatment or prophylaxis of microbial or bacterial infections comprising, as an active ingredient, a compound as herein described.
  • the pharmaceutical preparation may be produced into a pharmaceutically active salt.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention relates to pharmaceutical antimicrobial compositions and in particular to such compositions comprising 2,4-diamino-6-(hydroxymethyl) pteridine (DAP), 2,4-diaminopteroic acid (DAPA) and 2,4-diamino-N10-methylpteroic acid (DAMPA) and their derivatives or analogues thereof.

Description

DESCRΓPTIQN PHARMACEUTICAL COMPOSITION
The present invention relates to pharmaceutical antimicrobial, for example
antibacterial, compositions and in particular to such compositions comprising
2,4-diamino-6-(hydroxymethyl) pteridine (DAP), 2,4-diaminopteroic acid
(DAPA) and 2,4-diamino-NlO-methylpteroic acid (DAMP A) and their derivatives
or analogues thereof.
Under normal conditions in the folate biochemical pathway,
dihydropteroate synthase (DHPS) condenses 2-amino-4-hydroxy-6-
hydroxymethyldihydro-pteridine pyrophosphate (HMDP-PP) with para amino
benzioc acid (pABA) to synthesise dihydropteroate (DHP). DHP is further
glutamated by dihydrofolate synthase enzyme (DHFS) to generate dihydrofolate.
Dihydrofolate (DHF) is then reduced to tetrahydrofolate by dihydrofolate
reductase enzyme (DHFR) before entering the tetrahydrofolate pool.
Aminopterin (APT) and methotrexate (amethopterin, MTX) were the first
antifolate drugs used against rapidly dividing (tumour) cells in human. Both APT
and MTX are 2,4-diamino-pteridine compounds that compete with folate, because
of their similar structure. Folate molecules comprise 2-amino-4-hydroxy-pteridine
coupled to pABA and a glutamate moiety, and both APT and MTX have the 4-
hydroxy replaced by 4-amino; thus, APT and MTX comprise 2, 4-diamino
pteridine coupled to pABA and glutamate. MTX has, in addition, a methyl group
on N (10). Folate analogues such as trimethoprim have been found to have a potent
antibacterial and antiprotozoal activity. It has also been found that trimethoprim
binds 105-fold less tightly to mammalian DHFR than to the DHFR of susceptible
microorganisms, with the small differences in the active-site clefts of these
enzymes resulting in the highly selective antimicrobial action. A widely used
method of treating these types of infections in humans is the combination of
trimethoprim and sulfamethoxazole.
Several biochemical inhibitors (namely 2,4-diaminopteridines and 2,4-
diaminoquinazolines) of the pteridine pathways of the parasite Leishmania have
been tested and their potency assessed against antifolate-resistant mutants (Hardy,
L. W. et al, Exp. Parasitology (1997) 87, 157-169). Although it was concluded
that potent inhibition of a novel alternative pteridine reductase which is relatively
insensitive to MTX was insufficient for growth inhibition of the parasite.
DAMPA has never been described as an antimicrobial or antibacterial
agent and has the structure identified below:
N
Figure imgf000003_0001
DAMPA is one of the metabolites of MTX in humans and its toxicity profile and
pharmacokinetic properties have been studied in non human primates within the
context of reducing the toxicity of MTX in patients with MTX-induced renal
failure by the rescue agent, carboxypeptidase-G2 (Widemann et a , J Pharmacol
Exp Ther. 2000, 294(3) :894-901). DAMPA was found to be safe at a dose of 200
mg/m2 in Rhesus monkeys and has a short half-life of less than 1 hour.
It has been reported that both MTX and APT have Ki to Escherisha coli
bacteria values similar to purified human dihydrofolate reductase (DHFR)
(Appleman et al. 1988, JBiol Chem, 263: 10304-13). However, the inability of
MTX and APT to cross bacteria cell walls and/or their efflux by multidrug
resistance proteins makes these compounds weak inhibitors of bacterial growth
(Kopytek et al. 2000, Antimicrobial Agents Chem, 44: 3210-2). A compound
which could be used by bacteria as a folate precursor and which could be
converted de novo to MTX or APT could be toxic to bacterial organisms. Such
compounds could have lower, or no, toxicity to humans because mammalian cells
lack the complete pathway leading to synthesis of folate derivatives.
According to the present invention there is provided a folate precursor, or
derivative or analogue thereof, for use as an antibacterial/antimicrobial compound.
In accordance with an aspect of the present invention, there is provided an
antimicrobial compound of the general formula:
N
Figure imgf000004_0001
where:
X is carbon or nitrogen R is selected from the group consisting of:
a) O - R'
Figure imgf000005_0001
Figure imgf000005_0002
Figure imgf000006_0001
wherein R' and R" are independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, alkaryl, cycloalkyl and alkenyl.
A preferred antimicrobial compound according to the invention is 2,4- diamino-6-(hydroxymethyl) pteridine (DAP) with the formula:
N
Figure imgf000006_0002
or derivative or analogue thereof.
Another preferred antimicrobial compound according to the invention is 2,4-diaminopteroic acid (DAPA) with the formula:
N
Figure imgf000006_0003
or derivative or analogue thereof.
A further preferred antimicrobial compound according to the invention is diamino-NlO-methylpteroic acid (DAMPA) with the formula:
H
Figure imgf000007_0001
or derivative or analogue thereof.
A further preferred antimicrobial compound according to the invention has the formula:
Figure imgf000007_0002
or is a derivative or analogue thereof.
Yet another preferred group of antimicrobial compounds have the general formula:
Figure imgf000008_0001
where:
X is selected from either carbon or nitrogen.
Another preferred group of antimicrobial compounds according to the invention have the general formula:
Figure imgf000008_0002
where:
R" is selected from hydrogen, alkyl, aryl and R' is selected from hydrogen or methyl.
Another preferred group of antimicrobial compounds according to the invention have the general formula:
H
Figure imgf000009_0001
where:
X is selected from either nitrogen or carbon.
The compounds of the invention are preferred as antibacterial pharmaceutical agents.
In accordance with yet another aspect of the present invention, there is provided a pharmaceutical antimicrobial or antibacterial preparation comprising, as an active ingredient, a compound as herein described.
DAP, DAPA and DAMPA are widely and cheaply available compounds which have relatively low toxicity towards humans. The use of these compounds as antimicrobial or antibacterial agents may have additional benefits of not only being effective against microbial or bacterial attack, but also provide additional compounds with which to use in combination therapies with established drugs to enable and enhance their efficacy. In an embodiment of the present invention, there is a compound as herein described, or a pharmaceutically active salt thereof, for use in the manufacture of a medicament for use as an antimicrobial or antibacterial agent.
The pharmaceutical preparation comprising, as an active ingredient, a compound as herein described may be prepared as a hydrogen chloride salt. Alternatively, the compound may be prepared as a phosphate salt.
In an embodiment of the present invention, there is provided a pharmaceutical preparation for the treatment or prophylaxis of microbial or bacterial infections comprising, as an active ingredient, a compound as herein described. The pharmaceutical preparation may be produced into a pharmaceutically active salt.
The pharmaceutical compositions according to the present invention, will now be more particularly described by way of example only.
The inventors have shown that HMDP-PP condenses with sulfa-drugs to generate HMDP-SD adducts, as is described in co-pending UK patent application no. 0211448.6 . Since the malaria parasite can metabolise sulfadoxine (SDX) and dapsone (DDS), analogs of HMDP can also serve as precursors in the folate biosynthesis pathway by the parasite. It was hypothesised that, 2, 4-diamino-4- hydroxy-6-hydroxymethyldihydro-pteridine (DAP), a HMDP analog that has the pterin ring of APT and MTX, will also be condensed with pABA to generate the DAP-pABA adduct, after its pyrophosphorylation. The glutamation of this DAP- pABA adduct by dihydrofolate synthase (DHFS) would then generate aminopterin (APT) de novo. This in situ synthesised APT should then inhibit DHFR, and other folate enzymes downstream in pathway. Similarly, diaminopetroic acid (DP A), an analog of dihydropterioc acid, the parasite will generate APT de novo,
glutamation by DHFS enzyme and the incubation of diamino-N-methyl-methyl
hydroxy-Pteroic acid (DAMPA) will lead to the synthesis of MTX after DAMPA
glutamation by DHFS. These compounds, as discussed previously, will inhibit
parasite folate enzymes. The biosynthetic generation of the toxic MTX and APT
should not affect the host, because the host lacks the enzymes for endogenous
folate biosynthesis.
This proposed mode of action of these antimetabolites in P. Falciparum
may also apply to other microorganisms that are reliant upon de novo folate
synthesis. Examples of such microorganisms include other apicomplexa parasites,
bacteria and fungi.
In order to establish whether DAP, DAPA and DAMPA would have
antibacterial activity, an in vitro experiment was carried out to assess their action
on reference isolates. Minimum inhibitory concentrations (MIC) of DAP, DAPA
and DAMPA were determined by a standard plate incorporation method according
to international standards (NCCLS, 1997, National Committee for Clinical
Laboratory Standards). Methods for dilution antimicrobial susceptibility for
bacteria that grow aerobically; Approved standards 4th edn. NCCS document
M7-A4, Wayne PA, USA).
Serial doubling dilutions or doubling increases starting at 1 mg/L of the
agents were incorporated into appropriate agar growth media. A wide selection of
microorganisms were individually suspended in broth to a concentration that when delivered by a mulitpoint innoculator would result in ca. 105 bacteria per spot.
After inoculation, the plates were incubated for 18 hours in air or air with 10%
CO2 as appropriate at 37° C. Presence or absence of growth was recorded. The
MIC was taken as the lowest concentration of the agent that restricted the bacterial
growth to five or fewer colonies.
The data showed that these compounds bear antibacterial activity at
concentrations well below those likely to be achievable in plasma against
Streptoccoccus pyogenes (group A strep), Group B streptococci, Streptococcus
viridans (all with MICs of 1 mg per litre or less), Moraxella catarrhalis (MIC 4
mg per litre). In addition, DAP, DAPA and DAMPA show promising activities
against Haemophilus influenzae, Neisseria meningitidis and Neisseria
gonorrhoeae. This indicates that one or more of the compounds may have useful
activity in treating for example, bacterial meningitis and exacerbation of infection
in chronic obstructive airway disease. In addition, these compounds could be used
as leads for the synthesis of analogs that can be potent against other bacteria
species.

Claims

1. An antimicrobial compound of the general formula:
N
Figure imgf000013_0001
where:
X is carbon or nitrogen
R is selected from the group consisting of: a) O - R' b)
Figure imgf000013_0002
c)
Figure imgf000013_0003
R'
Figure imgf000014_0001
Figure imgf000014_0002
H
Figure imgf000014_0003
wherein R' and R" are independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, alkaryl, cycloalkyl and alkenyl.
2. An antimicrobial compound as claimed in claim 1, wherein the compound is 2,4-diamino-6-(hydroxymethyl) pteridine (DAP) with the formula:
Figure imgf000014_0004
or derivative or analogue thereof.
3. An antimicrobial compound as claimed in claim 1, wherein the compound is 2,4-diaminopteroic acid (DAPA) with the formula:
H
Figure imgf000015_0001
or derivative or analogue thereof.
4. An antimicrobial compound as claimed in claim 1, wherein the compound is diamino-NlO-methylpteroic acid (DAMPA) with the formula:
Figure imgf000015_0002
or derivative or analogue thereof.
5. An antimicrobial compound as claimed in claim 1, wherein the compound has the formula:
Figure imgf000016_0001
or is a derivative or analogue thereof.
6. An antimicrobial compound as claimed in claim 1, wherein the compound has the formula:
Figure imgf000016_0002
where:
X is selected from either carbon or nitrogen.
7. An antimicrobial compound as claimed in claim 1, wherein the compound has the formula:
N
Figure imgf000017_0001
where:
R" is selected from hydrogen, alkyl, aryl and R' is selected from hydrogen or methyl.
8. An antimicrobial compound as claimed in claim 1, wherein the compound has the formula:
H
Figure imgf000017_0002
where:
X is selected from either nitrogen or carbon.
9. A compound as claimed in any one or claims 1 to 8, wherein the compound is used as an active ingredient in a pharmaceutical antimicrobial or antibacterial preparation.
10. A compound as claimed in any one of claims 1 to 9, wherein the compound or a pharmaceutically active salt thereof is used in the manufacture of a medicament for use as an antimicrobial or antibacterial agent.
11. A compound as claimed in any one of claims 1 to 10, wherein the compound is prepared as a hydrogen chloride salt.
12. A compound as claimed in any one of claims 1 to 10, wherein the compound is prepared as a phosphate salt.
13. A pharmaceutical preparation incorporating a compound as claimed in any one of claims 1 to 12, wherein the pharmaceutical preparation is for the treatment or prophylaxis of microbial or bacterial infections.
PCT/GB2003/003287 2002-07-31 2003-07-30 Antimicrobial 2, 4-diamino-pteridine derivatives Ceased WO2004011005A2 (en)

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Applications Claiming Priority (2)

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GBGB0217703.8A GB0217703D0 (en) 2002-07-31 2002-07-31 Pharmaceutical composition
GB0217703.8 2002-07-31

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010110907A1 (en) * 2009-03-25 2010-09-30 Biorelix, Inc. Diaminopteridine derivatives
US12421187B2 (en) 2022-04-08 2025-09-23 Washington Univeristy Dihydrofolate synthase (DHFS) inhibiting agents and methods of making and using same

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB981506A (en) * 1962-08-22 1965-01-27 Wellcome Found 2,4-diamino-6-hydroxymethyl-7,8-dihydropteridine
PL374259A1 (en) * 2001-06-28 2005-10-03 Pliva D.D. Novel heterocyclic compounds as selective bacterial dhfr inhibitors and their uses thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010110907A1 (en) * 2009-03-25 2010-09-30 Biorelix, Inc. Diaminopteridine derivatives
CN102438454A (en) * 2009-03-25 2012-05-02 佰欧莱利克斯公司 Diaminopteridine derivatives
US20120283219A1 (en) * 2009-03-25 2012-11-08 Coish Philip D G Diaminopteridine derivatives
US12421187B2 (en) 2022-04-08 2025-09-23 Washington Univeristy Dihydrofolate synthase (DHFS) inhibiting agents and methods of making and using same

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GB0217703D0 (en) 2002-09-11
AU2003255737A8 (en) 2004-02-16
AU2003255737A1 (en) 2004-02-16
WO2004011005A3 (en) 2004-06-03

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