Note: Descriptions are shown in the official language in which they were submitted.
CA 02212440 1997-08-06
Pharmaceutical Preparations for TNF Inhibition
The invention relates to the use of the compounds of formula
I for the production of pharmaceutical agents for treating
diseases that are mediated by activation of the tumor necrosis
factor (TNF).
The compounds of formula I are described in, for example,
USP-4,186,129 and WO 8602268. It is known from these patents
that the compounds of formula I have phosphodiesterase-inhibiting
action, exhibit central-depressive, anti-dopaminergic,
antinociceptive, and anticonvulsive action, and are suitable for
topical treatment of inflammations. It is further known from
USP-4,824,838 that compounds of formula I can be used as
antidepressants.
It has now been found that the compounds of formula I
inhibit TNF production and therefore can be used for treating
diseases that are mediated by the activation of TNF.
Suitable according to the invention are the racemic and
optically active compounds of formula I
OR2
R' O ~ Ra
0 N-R3 I
O
in which
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2
R~ means C~_4 alkyl,
RZ means C~_6 alkyl, C3_7 cycloalkyl, C3_7 cycloalkyl-C~_2
alkyl, CZ_6 alkenyl, C3_7 alkinyl, a heterocycle or C~_b alkyl,
which is substituted with one or more halogens, hydroxy, carboxy,
alkoxy, C~_4 alkoxycarbonyl, or an amino group that is
optionally substituted with C~_4 alkyl,
R3 means hydrogen, C~_6 alkyl, acyl, aryl, aralkyl, aryl
substituted with 1 or 2 methyl groups and
R4 means hydrogen or C~_6 alkyl.
The compounds of formula I can contain one or more chiral
centers and also comprise racemic diastereomer mixtures as well
as individual optical isomers.
In each case, alkyl means straight-chain or branched alkyl
groups, such as, for example, methyl, ethyl, n-propyl, isopropyl,
n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-methyl-butyl,
2,2-dimethylpropyl and hexyl. Alkyl radicals with 1-4 carbon
atoms can be viewed as preferred.
Alkenyl means, for example, 1-propenyl, 2-propenyl or 3-
methyl-2-propenyl and alkinyl, for example, propargyl.
Cycloalkyl is defined as, for example, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, especially
C3_5 cycloalkyls.
In each case, aryl or aralkyl means an aromatic ring or an
aromatic ring system with 6 to 10 carbon atoms, such as, for
example, phenyl, benzyl, phenethyl, or naphthyl. A monocyclic
form can be viewed as preferred.
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Acyl is defined as aliphatic and aromatic carboxylic acids,
such as, for example, C~-6 alkanoyl, benzoyl.
The term "heterocycle" comprises a 5- or 6-membered
saturated heterocycle with an oxygen, sulfur or nitrogen atom,
such as, for example, 2- or 3-tetrahydropyranyl, 2- or 3-
tetrahydrofuranyl, 2- or 3-tetrahydrothienyl, dihydropyranyl,
pyrrolidinyl, pyrrolinyl, piperidinyl as well as N-alkyl-
pyrrolidinyl and N-alkyl-piperidinyl, in which the alkyl radical
contains i-4 carbon atoms, preferably tetrahydrofuranyl.
Halogen is defined as chlorine, fluorine, bromine, and
iodine.
According to the invention, the compounds of formula I in
which R~ means methyl and R3 means hydrogen are preferred.
Especially suitable are compounds in which R4 means hydrogen or
methyl and RZ means alkyl or cycloalkyl, whereby R4 in the
meaning of CH3 is especially preferred.
The production of the compounds of formula I, their isomers
and their mixtures is carried out according to methods known in
the art, which are described in, for example, the prior art
mentioned above.
Diseases that are mediated by TNF are defined both as
diseases that are triggered by the production of TNF and diseases
in which other cytokines, such as, for example, I1-1 or I1-6, are
altered by TNF.
TNF is defined both as TNF-a and TNF-B, which are both
antagonized by the compounds of formula I. Preferably, TNF-a is
inhibited.
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The compounds of formula I are therefore suitable for the
production of a pharmaceutical preparation that is used for the
treatment and prophylaxis of diseases in living creatures, which
are triggered by stimulation of TNF. Diseases that are altered
by excessive or unregulated TNF stimulation include, for example,
allergic and inflammatory diseases, auto-immune diseases,
pulmonary diseases, infectious diseases and bone resorption
diseases, such as rheumatoid arthritis, rheumatoid spondylitis,
osteo-arthritis, gout, sepsis, septic shock, endotoxin shock,
gram-negative sepsis, toxic shock syndrome, ARDS (acute
respiratory distress syndrome), pulmonary sarcoidosis, asthma,
silicosis, cachexia, ulcerative colitis, Crohn's disease,
osteoporosis, organic lesions after reperfusion, inflammatory
diseases of the central nervous system such as cerebral malaria,
multiple sclerosis, panencephalitis, infectious diseases such as
AIDS, bovine insanity, inflammatory diseases of the skin such as
urticaria, psoriasis, atopic dermatitis, contact dermatitis,
lupus erythematosus as well as diabetes insipidus,
neuroprotection, e.g., in the case of Parkinson's disease,
dementia, for example, after multiple infarctions and stroke.
The effectiveness of the compounds of formula I in the
above-mentioned indications can be shown by appropriate, commonly
used pharmacological tests.
The agents are produced according to the usual processes, by
the active ingredient being put into the form of a pharmaceutical
preparation that is suitable for enteral or parenteral
administration, with suitable vehicles, adjuvants and/or
CA 02212440 1997-08-06
additives. The preparations thus obtained can be used as
pharmaceutical agents in human or veterinary medicine.
Administration can be done orally or sublingually as a solid in
the form of capsules or tablets or as a liquid in the form of
solutions, suspensions, elixirs, aerosols, or emulsions, or
rectally in the form of suppositories, or in the form of
injection solutions that can optionally also be administered
subcutaneously intramuscularly or intravenously, or topically, or
intrathecally. As adjuvants for the desired pharmaceutical agent
formulation, inert organic and inorganic media that are known to
one skilled in the art, such as, e.g., water, gelatin, gum
arabic, lactose, starch, magnesium stearate, talc, vegetable
oils, polyalkyleneglycols, etc., are suitable. Moreover,
preservatives, stabilizers, wetting agents, emulsifiers, or salts
can optionally be contained to alter the osmotic pressure or
buffers.
The pharmaceutical preparations can be present in solid
form, for example, as tablets, coated tablets, suppositories,
capsules or in liquid form, e.g., as solutions, suspensions or
emulsions.
As vehicle systems, near-interface adjuvants such as salts,
bile acids, or animal or plant phospholipids and mixtures of
them, as well as liposomes or their components can also be used.
For oral administration, especially tablets, coated tablets
or capsules with talc and/or hydrocarbon vehicles or binders,
such as, e.g., lactose, corn or potato starch, are especially
suitable. Application can also be done in liquid form, such as,
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6
e.g., in the form of juice, to which sweetener is optionally
added.
The compounds of formula I are used in dosages that are
sufficient to reduce TNF production to normal levels or below.
The dosage of the active ingredients can vary depending on
the method of administration, the age and weight of the patient,
the type and severity of the disease to be treated, and similar
factors. The daily dose is 0.5-50 mg, preferably 0.1-5 mg,
whereby the dose can be given as a single dose to be administered
one time or divided into 2 or more daily doses.
The effectiveness of the compounds according to the
invention can be shown in, for example, animals that suffer from
experimental allergic encephalomyelitis (EAE), a disease of the
central nervous system that is caused by T-lymphocytes. The
disease can be triggered in rodents and primates by immunization
and histopathologically and symptomatically resembles pathologic
conditions in humans. The course of the disease can be monitored
with the aid of nuclear spin tomography.
Macrophages and microglia cells, which perform macrophage
functions in the brain, mediate the release of TNF-a during
experimental allergic encephalomyelitis (EAE). If macrophages
are stimulated, for example, by lipopolysaccharide (LPS), a
secretion of TNF-a is carried out in vitro and in vivo within
hours.
A murine macrophage cell line (RAW 264) was preincubated for
30 minutes in the presence and in the absence of various
concentrations of PDE-IV inhibitors and then stimulated with LPS
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(10 ng/ml). 18 hours attar stipulation, the culture medium was
reaoved, and the TNF-a release was measured with a specific 8lisa
test.
The test can be obtained from various companies, i.a., from
the British Biotechnology company cenzyme, and it is carried out
as the aariulacturer describes.
5-(3-propoxy -4-methoxyphenyl)-5-methyl-Z-oxazolidinone
inhibited the LPS-induced TNF-a raleass by RAW cells with ICS
0. 50 (~t~I) .
5-(3-cyclopentyloxy-4-methoxyphenyl)-5-methyl-2-
oxazolidinone is another preferred compound used in the present
invention.
