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Description  |
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The present invention relates to thiosemicarbazone compounds having
valuable antimicrobial properties, particularly but not exclusively,
against protozoa.
Parasite protozoal diseases of man occur throughout the world, often in the
tropics, where they are a serious menace to health. Research into the
treatment of many of the diseases arising from infections by these
parasites has been relatively limited in the past, due to their geographic
distribution and incidence. This does not make them any less serious,
however.
In Africa, the disease known as trypanosomiasis (sleeping sickness), caused
by members of the genus Trypanosoma, exists in chronic (T. gambiense) and
acute (T. rhodesiense) forms. In the early stages of both diseases, the
parasite is principally free in the blood circulatory system; in late
stages, trypanosomes are present in the cerebro-spinal fluid. This causes
brain damage, coma and possible death (especially T. rhodesiense). In the
early stages of both diseases, treatment with drugs such as suramin and
pentamidine is possible; once the CNS is infected, only organic arsenicals
such as Mel B can be used. These are highly toxic drugs with low
chemotherapeutic indices and require hospitalization of the patient.
In Latin American, a related parasite, Trypanosoma cruzi, causes Chagas'
disease. The infection is transmitted by various species of triatomid bug
and in its early acute stage is often fatal, if untreted, in young
children. Where this is not the case, the disease enters a chronic phase
which may last 20 years or more. The protozoan replicates slowly in the
heart and/or alimentary tract causing various forms of heart disease and
disturbances of the gastro-intestinal tract (especially mega-oesophagus
and mega-colon). Acute cases can usually be successfully treated with
nifurtimax and benznidazole. Chronic cases respond less well; the drugs
are not well tolerated over the time scale (60-120 days) they have to be
administered, and there are geographic variations in success rates, these
being highest in the South and lowest in the North of Latin America.
In contrast to the trypanosomes, leishmaniasis is prevalent around the
world, household pets and wild rodents often acting as reservoirs of
infection. It too is caused by a parasite protozoan: Leishmania tropica
causes the cutaneous disease; L. donovani the visceral variety
(Kala-azar). The parasite replicates in macrophages, particularly those in
the skin and liver and spleen. The cutaneous variety can be cured with
antimonials such as pentostam; in the visceral disease, pentamidine is
often used instead.
Giardiasis (lambliasis) is a gastro-intestinal infection caused by the
protozoan Giardia lamblia. It is pandemic, affecting about 10% of the
world population, especially children. The condition tends to be chronic,
rather than fatal. Symptoms that may occur are usually diarrhoea, often
severe, and epigastric pains. Severe cases may result from gallbladder
infections, leading to jaundice, nausea and vomiting. Treatment is
currently usually with metronidazole; radical cure is not easily attained.
Another `protozoal` disease of increasing importance is Pneumocystis
carinii pneumonia (PCP). This disease commonly occurs in those suffering
from acquired immune deficiency syndrome (AIDS); previously it was usually
seen only as a highly contagious infantile pneumonia. It is becoming
increasingly common in the United States amongst male homosexual
communities. It responds to drugs such as pentamidine but cure is
difficult.
The filarial diseases of man amount to more than 200 million cases, world
wide and are caused by parasite helminths (worms) of the genera
Wuchereria, Brugia, Onchocerca and Loa. Such diseases can be controlled by
drugs such as diethylcarbamazine and suramin, but such drugs are not
always effective and side effects can be severe.
We have now found that certain thiosemicarbazones described below have
activity against the above-mentioned organisms. These compounds also have
the advantage that they are generally less toxic than many
chemotherapeutic agents hitherto used for the treatment of the disease
caused by these organisms.
The present invention therefore provide compounds of formula (I)
##STR1##
wherein R.sup.1 represents an unsubstituted phenyl, thienyl or pyridyl
group; a thienyl, pyridyl or phenyl group substituted by at least one
(e.g., 1, 2 or 3) substituent selected from C.sub.1-6 alkyl (e.g., methyl
or ethyl), C.sub.1-6 alkoxy (e.g., methoxy or ethoxy), amino, hydroxy,
halo (chloro, bromo, iodo or fluoro) and nitro radicals; or a 2-pyridyl
group further substituted in the 6-position by a group of formula
--C(R.sup.2).dbd.N--NH--CS--NR.sup.3 R.sup.4 (wherein R.sup.2, R.sup.3 and
R.sup.4 are hereinafter defined); R.sup.2 represents a hydrogen atom or a
C.sub.1-6 alkyl (e.g., methyl) group; R.sup.3 represents a hydrogen atom,
a C.sub.1-6 alkyl (e.g., methyl or ethyl) group, a group of formula Z-X
(wherein Z represents a C.sub.1-4 straight or branched alkylene group and
X represents a C.sub.1-6 alkoxy group, a phenyl group substituted by at
least one C.sub.1-6 alkoxy group, or a 5- or 6-membered heterocyclic ring
containing at least one heteroatom selected from oxygen, nitrogen and
sulphur, e.g., a 2-, 3- or 4-pyridyl, morpholino or 2-, 3- or 4-furanyl
group), or a group of formula
##STR2##
(wherein R.sup.5 and R.sup.6, which may be the same or different, each
representing a hydrogen atom or C.sub.1-6 alkyl group); and R.sup.4
represents a hydrogen atom or a C.sub.1-6 alkyl group; or R.sup.3 and
R.sup.4 together with the nitrogen atom to which they are attached form a
3- to 7-membered alkyleneimino ring (optionally containing a double bond)
or a homopiperazino, piperazino or morpholino group optionally containing
1, 2 or 3 substituents selected from C.sub.1-4 alkyl, hydroxy, phenyl and
benzyl.
It will be appreciated by those skilled in the art of organic chemistry
that some of the compounds of formula (I) can form salts or can form
complexes with metals. Such salts and complexes are encompassed in the
scope of this invention.
Preferred compounds of formula (I) include those wherein
R.sup.1 represents a pyridyl or thienyl group (preferably a 2-pyridyl or
2-thienyl group) or a phenyl group optionally substituted in the
2-position by a substituent selected from C.sub.1-6 alkoxy (e.g. methoxy),
hydroxy and amino radicals or in the 3-position by a nitro substituent and
if desired by one or more further substituents, e.g. C.sub.1-6 alkyl (e.g.
methyl) or hydroxy radicals, e.g. in the 3-, 4-, 5- and/or 6-positions, or
a 2-pyridyl group further substituted in the 6-position by a group of
formula
##STR3##
(wherein R.sup.2, R.sup.3 and R.sup.4 are as hereinafter defined);
R.sup.2 represents a hydrogen atom or a C.sub.1-6 alkyl (e.g. methyl)
group;
R.sup.3 represents a C.sub.1-6 alkyl (e.g. methyl or tert-butyl) group; a
group of formula --Z--X (wherein Z represents a C.sub.1-4 straight or
branched alkylene group, e.g. a methylene group) and X represents a phenyl
group substituted by at least one C.sub.1-6 alkoxy group (e.g. a methoxy
group) or a 5- or 6-membered heterocyclic ring containing at least one
heteroatom selected from oxygen, nitrogen and sulphur, e.g. a 2-, 3- or
4-pyridyl, morpholino or 2-, 3- or 4-furanyl group); a diphenyl methyl
group; or a group of formula
##STR4##
(wherein R.sup.5 and R.sup.6 which may be the same or different, each
represents a hydrogen atom or a C.sub.1-6 alkyl group e.g. methyl group);
and
R.sup.4 represents a hydrogen atom or a C.sub.1-6 alkyl group.
Particularly preferred compounds having generally high anti-microbial
activity particularly against one or more of the above-mentioned parasites
include:
(1) 2'-Aminoacetophenone 4,4-dimethylthiosemicarbazone
(2) 2-Acetylpyridine 4-tert-butylthiosemicarbazone
(3) 2-Acetylpyridine 4-furfurylmethylthiosemicarbazone
(4) 2-Acetylpyridine 4-(2-morpholinoethyl)thiosemicarbazone
(5) 2-Acetylpyridine 4-(3,4,5-trimethoxybenzyl)thiosemicarbazone
(6) 2'-Hydroxyacetophenone 4,4-dimethylthiosemicarbazone
(7) 2-Acetylpyridine 4-benzhydrylthiosemicarbazone
(8) 2,6-Diacetylpyridine bis(4,4-dimethylthiosemicarbazone)
(9) 2-Acetylthiophene 4,4-dimethylthiosemicarbazone
(10) 2-Acetylpyridine 5-[(dimethylamino)thiocarbonyl]thiocarbonohydrazone
(11) 3'-Nitroacetophenone 4,4-dimethylthiosemicarbazone
(12) 2-Acetylthiophene 5-(dimethylthiocarbamoyl)thiocarbonohydrazone
(13) 2',3'-Dihydroxybenzaldehyde 4,4-dimethylthiosemicarbazone
(14) 2'-Hydroxybenzaldehyde 4,4-dimethylthiosemicarbazone
(15) 2'-Hydroxy-5'-methylacetophenone 4,4-dimethylthiosemicarbazone
(16) Acetophenone 4,4-dimethylthiosemicarbazone
(17) 2'-Hydroxy-4',6'-dimethylacetophenone
5-(N,N-dimethylthiocarbamoyl)thiocarbonohydrazone
(18) 2'-Hydroxyacetophenone 4-tert-butylthiosemicarbazone
(19) 2'-Methoxyacetophenone 4,4-dimethylthiosemicarbazone
(20) 2'-Hydroxy-4',5'-dimethylacetophenone 4,4-dimethylthiosemicarbazone
(21) 2-Acetylpyridine 4-(3-morpholinopropyl)thiosemicarbazone
(22) 2-Acetylpyridine 4-[2-(2-pyridyl)ethyl]thiosemicarbazone
(23) 2-Acetylpyridine 4,4-(dimethylthosemicarbazonato)copper (II) bisulfate
(24) 2',3'-Dihydroxyacetophenone 4-(2-morpholinoethyl)thiosemicarbazone
(25) 2'-Hydroxy-5'-methylacetophenone
4-(2-morpholinoethyl)thiosemicarbazone
(26) 2',5'-Dihydroxyacetophenone 4-(2-morpholinoethyl)thiosemicarbazone
Compounds 4, 6 and 10 above have been found to be especially active in in
vitro tests against P. carinii, the activity of compound 6 being
especially high.
Compound 3, 4, 5, 6, 9, 10, 12, 21 and 22 have besen found to have activity
against the filarial organism Brugia pahangi, some compounds with the
advantage that they have a relatively low toxicity. Certain of the
compounds of formula (I) are also active sagainst Babesia, e.g. B.
rodhaini, especially compound 23. Also, compounds 24, 25 and 26 have been
found to be active against P. falciparum.
The present invention thus provides the novel compounds of formula (I)
identified above.
The compounds of formula (I) may be prepared in conventional manner by
techniques known in the art, for example by reacting a compound of formula
##STR5##
(wherein R.sup.1 and R.sup.2 are as defined above) with a compound of
formula
##STR6##
(wherein R.sup.3 and R.sup.4 are as defined above).
The reaction is advantageously effected in an appropriate solvent medium,
e.g. methanol, ethanol, 2-dichloroethane, if desired in the presence of
glacial acetic acid.
The present invention further provides the above compounds of formula (I)
for use in therapy, for example in the treatment or prophylaxis of
microbial infections in humans or animals, particularly infections caused
by protozoal organisms such as L. donovani, T. cruzi or T. gambiense, P.
falciparum and B. rodhaini, helminth organisms such as B. pahangi and
other organisms such as P. carinii.
The present invention also provides a method for the treatment or
prophylaxis of a microbial infection, e.g., as described above which
comprises administering to a human or non-human host an effective
anti-microbial amount of a compound of formula (I).
The compounds of formula (I) hereafter referred to as the active
ingredient(s) may be administered by any route appropriate to the
condition to be treated, suitable routes including oral, rectal, nasal,
topical (including subcutaneous, intramuscular, intravenous, intradermal,
intrathecal and epidural). It will be appreciated that the preferred route
may vary with, for example, the condition of the recipient.
For each of the above-indicated utilities and indications the amount
required of an active ingredient (as above defined) will depend upon a
number of factors including the severity of the conditions to be treated
and the identity of the recipient and will ultimately be at the discretion
of the attendant physician or veterinarian. In general, however, for each
of these utilities and indications, a suitable, effective dose will be in
the range 0.1 to 250 mg per kilogram bodyweight of recipient per day,
preferably in the range 1 to 100 mg/kg bodyweight per day and most
preferably in the range 5 to 20 mg/kg bodyweight per day. The desired dose
may be presented as two, three, four or more sub-doses administered at
appropriate intervals throughout the day. These sub-doses may be
administered in unit dosage forms, for example, containing 10 to 100 mg,
preferably 20 to 500 mg and most preferably 100 to 400 mg of active
ingredient per unit dosage form.
While it is possible for the active ingredients to be administered alone it
is preferable to present them as pharmaceutical formulations. The
formulations, both for veterinary and for human use, of the present
invention comprise at least one active ingredient, as above defined,
together with one or more acceptable carriers therefor and optionally
other therapeuti ingredients. The carrier(s) must be "acceptable" in the
sense of being compatible with the other ingredients of the formula and
not deleterious to the recipient thereof.
The formulations include those suitable for oral, rectal, nasal, topical
(including buccal and sublingual), vaginal or parenteral (including
subcutaneous, intramuscular, intravenous, intradermal, intrathecal andd
epidural) administration. The formulations can conveniently be presented
in unit dosage form and may be prepared by any of the methods will known
in the art of pharmacy. Such methods include the step of bringing into
association the active ingredient with the carrier which constitutes one
or more accessory ingredients. In general the formulations are prepared by
uniformly and intimately bringing into association the active ingredient
with liquid carriers or finely divided solid carriers or both, and then,
if necessary, shaping the product.
Formulations of the present invention suitable for oral administration may
be presented as discrete units such as capsules, cachets or tablets each
containing predetermined amounts of the active ingredients; as a powder or
granules; as solutions or suspensions in an aqueous liquid or a
non-aqueous liquid; or as oil-in-water emulsions or water-in-oil liquid
emulsions. The active ingredient may also be presented as a bolus
electuary or paste.
A tablet may be made by compression or moulding, optionally with one or
more accessory ingredients. Compressed tablets may be prepared by
compressing in a suitable machine the active ingredients in a free-flowing
form such as a powder or granules, optionally mixed with a binder,
lubricant, inert diluent, preservative, surface active or dispersing
agent. Moulded tablets may be made by moulding in a suitable machine a
mixture of the powdered compound moistened with an inert liquid diluent.
The tablets may optionally be coated or scored and may be formulated so as
to provide slow or controlled release of the active ingredient therein.
For infections of the eye or other external tissues, e.g., mouth and skin,
the formulations are preferably applied as a topical ointment or cream
containing the antiviral active ingredient in an amount of, for example,
0.075 to 20% w/w, preferably 0.2 to 15% w/w and most preferably 0.5 to 10%
w/w. When formulated in an ointment, the active ingedients may be employed
with either paraffinic or a water-miscible ointment base. Alternatively,
the active ingredients may be formulated in a cream with an oil-in-water
cream base.
Formulations suitable for topical administration to the eye also include
eye drops wherein the active ingredients are dissolved or suspended in
suitable carrier, especially an aqueous solvent for the active ingredient.
The antiviral active ingredient is preferably present in such formulations
in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly
about 1.5% w/w.
Formulations for rectal administration may be presented as a suppository
with a suitable base comprising for example cocoa butter or a salicylate.
Formulations suitable for nasal administration wherein the carrier is a
solid include a coarse powder having a particle size for example in the
range 20 to 500 microns which is administered in a manner in which snuff
is taken, i.e., by rapid inhalation through the nasal passage from a
container of the powder held close up to the nose. Suitable formulations
wherein the carrier is a liquid, for administration as for example a nasal
spray or as nasal drops, include aqueous or oil solutions of the active
ingredient.
Formulations suitable for vaginal administration may be presented as
pessaries, tampons, creams, gels, pastes, foams or spray formulations
containing in addition to the active ingredient such carriers as are known
in the art to be appropriate.
Formulations suitable for parenteral administration include aqueous and
non-aqueous sterile injection solutions which may contain anti-oxidants,
buffers, bacteriostats and solutes which render the formulation isotonic
with the blood of the intended recipient; and aqueous and non-aqueous
sterile suspensions which may include suspending agents and thickening
agents. The formulations may be presented in unit-dose or multi-dose
containers, for example sealed ampoules and vials, and may be stored in a
freeze-dried (lyophilized) condition requiring only the addition of the
sterile liquid carrier, for example water for injections, immediately
prior to use. Extemporaneous injection solution and suspensions may be
prepared from sterile powders, granules and tablets of the kind previously
described.
Preferred unit dosage formulations are those containing a daily dose or
unit daily sub-dose, as herein above recited, or an appropriate fraction
thereof, of the active ingredients.
It should be understood that in addition to the ingredients particularly
mentioned above the formulations of this invention may include other
agents conventional in the art having regard to the type of formulation in
question, for example those suitable for oral administration may include
flavouring agents.
The following Examples are for illustration only and are not intended to
limit the scope of the invention in any way.
EXAMPLES
(a) Preparation of Thiosemicarbazones
General procedure: The appropriate aldehyde or ketone (A) and 4-substituted
thiosemicarbazide (B) were refluxed in the specified reaction medium until
the reaction was complete. The solid product was collected by filtration
of the cooled reaction mixture and was then purified by recrystallization
from the specified solvent or by column chromatography on silica gel
followed by recrystallization from the specified solvent. Appropriate
modifications are indicated in the Table below.
A specific example is:
2-Acetylpyridine 4-(2-morpholinoethyl)thiosemicarbazone
A mixture of 6.00 g (0.0294 mole) of
4-(2-morpholinoethyl)thiosemicarbazide, 3.91 g (0.0323 mole) of
2-acetylpyridine, 20 mL of 95% ethanol, and 0.4 mL of glacial acetic acid
was heated under reflux for 1.25 hours. The mixture then stood overnight
at room temperature. Colourless crystals were collected and recrystallised
from 40 mL of 95% ethanol; yield 7.81 g (86%) of pale yellow crystals of
2-acetylpyridine 4-(2-morpholinoethyl)thioseicarbazone, mp
167.5.degree.-169.degree. C.
______________________________________
Analysis for C.sub.14 H.sub.21 N.sub.5 OS:
______________________________________
Calculated
C: 54.69 H: 6.89 N: 22.78
Found C: 54.66 H: 6.86 N: 22.88
______________________________________
Exceptions to the general procedure were the preparations of the
thiocarbonylthiocarbonohydrazones:
2-Acetylpyridine 5-[(dimethylamino)thiocarbonyl]thiocarbonohydrazone
A mixture of 24.2 g (0.203 mole) of 4,4-dimethylthiosemicarbazide, 26.6 g
(0.220 mole) of 2-acetylpyridine, 2.5 mL of glacial acetic acid, and 100
mL of 95% ethanol was refluxed for 1.5 hours. The mixture was incubated
overnight at room temperature. Thick orange needles contaminated with a
little light-coloured solid were collected, washed with 20 mL of ethanol,
and while still damp were added to 450 mL of boiling methanol. After the
orange needles dissolved (less than 10 minutes) the mixture was filtered,
and the undissolved solid was boiled again with methanol (50 mL) for three
minutes. The mixture stood for 0.25 hour at room temperture, then the
yellow crystals were collected by filtration; yield 1.47 g (5%) of
2-acetylpyridine 5-[(dimethylamino)thiocarbonyl]thiocarbonohydrazone, mp
152.5.degree. C., (evolved a gas, resolidified, and remelted at
175.degree.-181.5.degree.).
______________________________________
Analysis for C.sub.11 H.sub.16 N.sub.6 S.sub.2.
______________________________________
Calculated
C: 44.57 H: 5.44 N: 28.35
Found C: 44.75 H: 5.52 N: 28.45
______________________________________
2'-Hydroxy-4',6-dimethylacetophenone
5-(N,N-dimethylthiocarbamoyl)thiocarbonohydrazone
A mixture of 4,4-dimethyl-3-thiosemicarbazide (1.79 g, 0.015 mol),
2-hydroxy-4,6-dimethylacetophenone (2.71 g, 0.0165 mol), glacial acetic
acid (0.5 ml) and 95% EtOH (30 ml) was refluxed for 2 h. The resulting
solution was concentrated under vacuum to a dark golden oil determined by
TLC (silica/hexanes:EtOAc) to be a mixture. This mixture was subjected to
liquid chromatography on silica gel (Merck Kieselgel 60; 230-400 mesh
ASTM) with gradient elution (hexane-EtOAc). The product, eluted by 100%
EtOAc and twice recrystallized from EtOAc:hexane, was isolated as an
isomeric mixtue (based on NMR): yield 0.87 g (17%); mp 158.degree. C.
(dec).
______________________________________
Analysis for C.sub.14 H.sub.21 N.sub.5 OS.sub.2 :
______________________________________
Calculated C: 49.52 H: 6.23 N: 20.63
S: 18.89
Found C: 49.52 H: 6.34 N: 20.54
S: 18.84
______________________________________
2-Acetylthiophene 5-(N,N-dimethylthiocarbamoyl)thiocarbonohydrazone
A mixture of 2-acetylthiophene (5.04 g, 0.040 mol),
4,4-dimethylthiosemicarbazide (2.98 g, 0.025 mol), 95% EtOH (20 mL) and
glacial HOAc (0.4 mL) was refluxed for 1 h. The resulting solution was
allowed to stand overnight at ambient temperature. The crystals that had
separated were subsequently collected by filtration, washed with boiling
95% EtOH (30 mL), and recrystallized from 95% EtOH: yield, 0.48 g (13%) of
2-acetylthiophene 5-(N,N-dimethylthiocarbamoyl)thiocarbonohydrazone, mp
161.degree. C., then resolidified.
______________________________________
Analysis for C.sub.10 H.sub.15 N.sub.5 S.sub.3 :
______________________________________
Calculated C: 39.84 H: 5.02 N: 23.23
S: 31.91
Found C: 39.86 H: 5.04 N: 23.16
S: 31.86
______________________________________
2,6-Diacetylpyridine bis-(4,4-dimethylthiosemicarbazone)
A mixture of 4,4-dimethylthiosemicarbazide (2.70 g, 0.022 mol) and
2,6-diacetylpyridine (1.63 g, 0.10 mol) in 95% EtOH (45 ml) containing
glacial acetic acid (0.5 ml) was heated by a steam bath for 1 h and 10 min
and allowed to cool to ambient temperature. The yellow precipitate was
collected by filtration, washed with 95% EtOH, and subsequently
recrystallized from toluene: yield 2.72 g (73%); mp 215.degree. (dec).
______________________________________
Analysis for C.sub.15 H.sub.23 N.sub.7 S.sub.2.0.10 C.sub.7 H.sub.8
______________________________________
Calculated C: 50.31 H: 6.40 N: 26.17
S: 17.11
Found C: 50.26 H: 6.20 N: 26.12
S: 17.27
______________________________________
2-Acetylpyridine 4,4-(dimethylthosemicarbazonato)copper (II) 7/10 bisulfate
3/10 hydroxide hemihydrate
A solution of 2-acetylpyridine 4,4-dimethylthosemicarbazone (0.500 g,
0.00225 mol) in MeOH (100 ml) at ambient temperature was added to a
stirred solution of cupric sulfate pentahydrate (0.560 g, 0.00225 mol) in
MeOH (75 ml). After 0.5 h, the solution was concentrated by boiling to 75
ml and was subsequently chilled. The dark crystals that separated were
collected by filtration and washed with methanol: yield 0.42 g (51%), mp
242.degree.-244.degree. (dec).
______________________________________
Analysis for C.sub.10 H.sub.13 CuN.sub.4 S.7/10HSO.sub.4.3/10 OH.1/2
H.sub.2 O:
______________________________________
Calculated
C: 32.74 H: 4.12
N: 15.27
S: 14.85
Cu: 17.32
Found C: 32.81 H: 4.14
N: 15.02
S: 15.14
Cu: 17.23
______________________________________
THE FOLLOWING EQUATION APPLIES TO THE TABLE SHOWN BELOW:
##STR7##
__________________________________________________________________________
PREPARATION OF THIOSEMICARBAZONES
Mo-
lar
Ra- Reaction
Recrystal-
tio
Reaction Time lization
Yield
R.sup.1 R.sup.2
R.sup.3 R.sup.4
A/B
Medium.sup.a
(hr) Solvent
(%) mp
__________________________________________________________________________
(.degree.C.)
2-pyridyl
Me
H 1.9
ClCH.sub.2 CH.sub.2 Cl
3 i-PrOH
47 126.5-127
2-pyridyl
Me
##STR8## H 1.1
95% EtOH/ 5% glacial acetic
11/2 Toluene
71 125-127
2-pyridyl
Me CMe.sub.3 H 1.0
ClCH.sub.2 CH.sub.2 Cl
3/4 i-PrOH
42 118-120.5
2-pyridyl
Me
##STR9## H 1.05
ClCH.sub.2 CH.sub.2 Cl
11/4 i-PrOH
75 149
##STR10##
H Me Me 1.1
EtOH/2% HOAc
11/2 95% EtOH
71 206-207 (dec)
2-pyridyl
Me
##STR11## H 1.1
EtOH/5% HOAc
1.5 95% EtOH
80 163-164
##STR12##
H Me Me 1.1
EtOH/2% HOAc
2 95% EtOH
76 199-200 (dec)
##STR13##
Me Me Me 1.1
EtOH/2% HOAc
1.5 * 85 217-217.5
(dec)
##STR14##
Me Me Me 1.1
EtOH/2% 6 * 39 159-160
##STR15##
Me CMe.sub.3 H 1.1
EtOH/2% HOAc
17 EtOH/ hexanes.sup.b
24 166-167
##STR16##
Me Me Me 1.1
EtOH/2% HOAc
16.5 95% EtOH
19 107-108
##STR17##
Me Me Me 1.1
EtOH/1% HOAc
1.5 EtOAc.sup.c
18 164-165
##STR18##
Me Me Me 0.45
EtOH/2% HOAc
1.5 .sup.b
7 130-131.degree.
9
2-pyridyl
Me HCHPh.sub.2 H 1.1
EtOH/2.5% HOAc
1.5 Toluene
88 183-185
##STR19##
Me Me Me 1 EtOH/0.4% HOAc
3.5 95% EtOH
64 209-210
##STR20##
Me Me Me 1.1
MeOH 4 MeOH.sup.d
4 151-153 (dec)
##STR21##
Me Me Me 1.1
EtOH/2% 6 95% EtOH
26 234.5-235
__________________________________________________________________________
(dec)
*Crystallized analytically pure from the reaction medium
.sup.a EtOH refers to 95% ethyl alcohol and HOAc to glacial acetic acid.
The percent HOAc is based on weight.
.sup.b After Ic on silica gel with EtOAc/hexanes
.sup.c After fractional crystallisation from the reaction medium
.sup.d After Ic on silica gel with CH.sub.2 Cl.sub.2
(b) Pharmaceutical Formulations
In the following Examples, the active compound is a compound of formula
(I).
______________________________________
Tablet Amount (mg)
______________________________________
Active Compound 200
Lactose 105
Starch 50
Polyvinylpyrrolidinone
20
Magnesium Stearate
10
______________________________________
Mix the active compounds with the lactose and starch and wet granulate with
a solution of the polyvinylpyrrolidinone. Dry, sift, blend the granules
with magnesium stearate and compress.
______________________________________
Capsule Amount (mg)
______________________________________
Active Compound 200
Lactose 100
Sodium Starch Glycollate
10
Polyvinylpyrrolidinone
10
Magnesium Stearate 3
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Mix the active compounds with the lactose and sodium starch glycollate and
wet granulate with a solution of the polyvinylpyrrolidinone. Dry, sift,
blend the granules with the magnesium stearate and fill into hard gelatin
capsules.
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Intravenous Injections
Amount
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(1) Active Compound 200 mg
Glycerol 200 mg
Sodium Hydroxide solution qs
pH 7.0-7.5
Water for Injections to
10 mL
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Add the glycerol to some of the water for Injections. Dissolve the active
compound and adjust the pH with Sodium Hydroxide solution. Make up to
volume with additional Water for Injections. Under aseptic conditions,
sterilise the solution by filtration, fill into sterile ampoules and seal
the ampoules.
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(2) Active Compound 100 mg
Sodium Hydroxide solution qs to
pH 8.0-9.0
Mannitol 125 mg
Water for Injections to
2.5 ml
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Dissolve the active compounds and the mannitol in a part of the Water for
Injections. Adjust pH with the sodium hydroxide solution and make up to
volume with additional Water for Injections. Under aseptic conditions,
sterilise with solution by filtration, fill into sterile vials and remove
the water by freeze-drying. Seal the vials under an atmosphere of nitrogen
and close the vials with a sterile closure and a metal collar.
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