U.S. patent application number 09/864943 was filed with the patent office on 2002-01-03 for fluoroalkoxy-substituted benzamide dichloropyridinyl n-oxide pde4 inhibitor.
Invention is credited to Ducharme, Yves, Friesen, Richard, Girard, Yves, Li, Chun, Robichaud, Annette.
Application Number | 20020002191 09/864943 |
Document ID | / |
Family ID | 22768891 |
Filed Date | 2002-01-03 |
United States Patent
Application |
20020002191 |
Kind Code |
A1 |
Friesen, Richard ; et
al. |
January 3, 2002 |
Fluoroalkoxy-substituted benzamide dichloropyridinyl N-oxide PDE4
inhibitor
Abstract
A PDE4 inhibiting compound is represented by 1
Inventors: |
Friesen, Richard; (Kirkland,
CA) ; Ducharme, Yves; (Montreal, CA) ; Girard,
Yves; (L'ille Bizard, CA) ; Li, Chun;
(Kirkland, CA) ; Robichaud, Annette; (Montreal,
CA) |
Correspondence
Address: |
MERCK AND CO INC
P O BOX 2000
RAHWAY
NJ
070650907
|
Family ID: |
22768891 |
Appl. No.: |
09/864943 |
Filed: |
May 24, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60207023 |
May 25, 2000 |
|
|
|
Current U.S.
Class: |
514/352 ;
546/309 |
Current CPC
Class: |
A61P 25/24 20180101;
A61P 35/00 20180101; A61P 11/06 20180101; A61P 29/02 20180101; A61P
27/02 20180101; A61P 7/00 20180101; A61P 9/10 20180101; A61P 17/06
20180101; A61P 19/10 20180101; A61P 43/00 20180101; A61P 21/00
20180101; A61P 37/08 20180101; A61P 17/00 20180101; C07D 213/89
20130101; A61P 19/02 20180101; A61P 27/16 20180101; A61P 25/28
20180101; A61P 11/14 20180101; A61P 29/00 20180101; A61P 11/00
20180101; A61P 1/00 20180101; A61P 15/00 20180101; A61P 9/08
20180101; A61P 13/12 20180101; A61P 19/08 20180101 |
Class at
Publication: |
514/352 ;
546/309 |
International
Class: |
A61K 031/44; C07D
213/75 |
Claims
What is claimed is:
1. A compound represented by Formula (I): 8
2. A pharmaceutical composition comprising a therapeutically
effective amount of the compound according to claim 1 or a
pharmaceutically acceptable salt thereof; and a pharmaceutically
acceptable carrier.
3. The pharmaceutical composition according to claim 2, further
comprising a Leukotriene receptor antagonist, a Leukotriene
biosynthesis inhibitor, or an M2/M3 antagonist.
4. A method of treatment of asthma, chronic bronchitis, chronic
obstructive pulmonary disease, eosinophilic granuloma, psoriasis
and other benign or malignant proliferative skin diseases,
endotoxic shock, laminitis in horses, colic in horses, septic
shock, ulcerative colitis, Crohn's disease, reperfusion injury of
the myocardium and brain, inflammatory arthritis, chronic
glomerulonephritis, atopic dermatitis, urticaria, adult respiratory
distress syndrome, infant respiratory distress syndrome, chronic
obstructive pulmonary disease in animals, diabetes insipidus,
allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis,
arterial restenosis, ortherosclerosis, atherosclerosis, neurogenic
inflammation, pain, cough, rheumatoid arthritis, osteoporosis,
ankylosing spondylitis, transplant rejection, graft versus host
disease, hypersecretion of gastric acid, bacterial, fungal induced
sepsis, viral induced sepsis, fungal induced septic shock, viral
induced septic shock, inflammation-mediated chronic tissue
degeneration, cytokine-mediated chronic tissue degeneration,
osteoarthritis, cancer, cachexia, muscle wasting, depression,
memory impairment, tumor growth, or cancerous invasion of normal
tissues comprising the step of administering a therapeutically
effective amount of the compound represented by Formula (I): 9
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention is directed to a
fluoroalkoxy-substituted benzamide dichloropyridinyl N-oxide
compound that is a phosphodiesterase-4 inhibitor. In particular,
this invention is directed to
N-(3,5-Dichloro-1-oxido-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylm-
ethoxybenzamide which is a phosphodiesterase-4 inhibitor.
[0003] 2. Related Background
[0004] Hormones are compounds that variously affect cellular
activity. In many respects, hormones act as messengers to trigger
specific cellular responses and activities. Many effects produced
by hormones, however, are not caused by the singular effect of just
the hormone. Instead, the hormone first binds to a receptor,
thereby triggering the release of a second compound that goes on to
affect the cellular activity. In this scenario, the hormone is
known as the first messenger while the second compound is called
the second messenger. Cyclic adenosine monophosphate (adenosine 3',
5'-cyclic monophosphate, "cAMP" or "cyclic AMP") is known as a
second messenger for hormones including epinephrine, glucagon,
calcitonin, corticotrophin, lipotropin, luteinizing hormone,
norepinephrine, parathyroid hormone, thyroid-stimulating hormone,
and vasopressin. Thus, cAMP mediates cellular responses to
hormones. Cyclic AMP also mediates cellular responses to various
neurotransmitters.
[0005] Phosphodiesterases ("PDE") are a family of enzymes that
metabolize 3', 5' cyclic nucleotides to 5' nucleoside
monophosphates, thereby terminating cAMP second messenger activity.
A particular phosphodiesterase, phosphodiesterase-4 ("PDE4", also
known as "PDE-IV"), which is a high affinity, cAMP specific, type
IV PDE, has generated interest as potential targets for the
development of novel anti-asthmatic and anti-inflammatory
compounds. PDE4 is known to exist as at lease four isoenzymes, each
of which is encoded by a distinct gene. Each of the four known PDE4
gene products is believed to play varying roles in allergic and/or
inflammatory responses. Thus, it is believed that inhibition of
PDE4, particularly the specific PDE4 isoforms that produce
detrimental responses, can beneficially affect allergy and
inflammation symptoms. It would be desirable to provide novel
compounds and compositions that inhibit PDE4 activity.
[0006] Inhibition of PDE4 activity is believed effective for the
treatment of osteoporosis by reducing bone loss. For example,
Ken-ici Miyamoto et al., Biochem. Pharmacology, 54:613-617(1997)
describes the effect of a PDE4 on bone loss. Therefore, it would be
desirable to provide novel compounds and compositions that inhibit
PDE4 activity.
[0007] A major concern with the use of PDE4 inhibitors is the side
effect of emesis which has been observed for several candidate
compounds as described in C.Burnouf et al., ("Burnouf"), Ann. Rep.
In Med. Chem., 33:91-109(1998). B.Hughes et al., Br. J.Pharmacol.,
118:1183-1191(1996); M. J. Perry et al., Cell Biochem. Biophys.,
29:113-132(1998); S. B. Christensen et al., J.Med. Chem.,
41:821-835(1998); and Burnouf describe the wide variation of the
severity of the undesirable side effects exhibited by various
compounds. As described in M. D. Houslay et al., Adv. In
Pharmacol., 44:225-342(1998) and D.Spina et al., Adv. In
Pharmacol., 44:33-89(1998), there is great interest and research of
therapeutic PDE4 inhibitors.
[0008] Fluoroalkoxy-substituted Benzamide PDE4 inhibitors are
described in U.S. Pat. No. 5,712,298 and International Publication
No. WO 98/35683.
[0009] International Patent Publication WO9422852 describes
quinolines as PDE4 inhibitors. A. H. Cook, et al., J.Chem. Soc.,
413-417(1943) describes gamma-pyridylquinolines. Other quinoline
compounds are described in Kei Manabe et al., J.Org. Chem.,
58(24):6692-6700(1993); Kei Manabe et al., J.Am. Chem. Soc.,
115(12):5324-5325(1993); and Kei Manabe et al., J.Am. Chem. Soc.,
114(17):6940-6941(1992).
[0010] Compounds that include ringed systems are described by
various investigators as effective for a variety of therapies and
utilities. For example, International Patent Publication No. WO
98/25883 describes ketobenzamides as calpain inhibitors, European
Patent Publication No. EP 811610 and U.S. Pat. Nos. 5,679,712,
5,693,672 and 5,747,541 describe substituted benzoylguanidine
sodium channel blockers, U.S. Pat. No. 5,736,297 describes ring
systems useful as a photosensitive composition.
[0011] U.S. Pat. Nos. 5,491,147, 5,608,070, 5,622,977, 5,739,144,
5,776,958, 5,780,477, 5,786,354, 5,798,373, 5,849,770, 5,859,034,
5,866,593, 5,891,896, and International Patent Publication WO
95/35283 describe PDE4 inhibitors that are tri-substituted aryl or
heteroaryl phenyl derivatives. U.S. Pat. No. 5,580,888 describes
PDE4 inhibitors that are styryl derivatives. U.S. Pat. No.
5,550,137 describes PDE4 inhibitors that are phenylaminocarbonyl
derivatives. U.S. Pat. No. 5,340,827 describes PDE4 inhibitors that
are phenylcarboxamide compounds. U.S. Pat. No. 5,780,478 describes
PDE4 inhibitors that are tetra-substituted phenyl derivatives.
International Patent Publication WO 96/00215 describes substituted
oxime derivatives useful as PDE4 inhibitors. U.S. Pat. No.
5,633,257 describes PDE4 inhibitors that are cyclo(alkyl and
alkenyl)phenyl-alkenyl (aryl and heteroaryl) compounds.
[0012] However, there remains a need for novel compounds and
compositions that therapeutically inhibit PDE4 with minimal side
effects.
SUMMARY OF THE INVENTION
[0013] A compound of this invention is represented by Formula (I):
2
[0014] A method of treatment of asthma, chronic bronchitis, chronic
obstructive pulmonary disease, eosinophilic granuloma, psoriasis
and other benign or malignant proliferative skin diseases,
endotoxic shock, laminitis in horses, colic in horses, septic
shock, ulcerative colitis, Crohn's disease, reperfusion injury of
the myocardium and brain, inflammatory arthritis, chronic
glomerulonephritis, atopic dermatitis, urticaria, adult respiratory
distress syndrome, infant respiratory distress syndrome, chronic
obstructive pulmonary disease in animals, diabetes insipidus,
allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis,
arterial restenosis, ortherosclerosis, atherosclerosis, neurogenic
inflammation, pain, cough, rheumatoid arthritis, osteoporosis,
ankylosing spondylitis, transplant rejection, graft versus host
disease, hypersecretion of gastric acid, bacterial, fungal induced
sepsis, viral induced sepsis, fungal induced septic shock, viral
induced septic shock, inflammation-mediated chronic tissue
degeneration, cytokine-mediated chronic tissue degeneration,
osteoarthritis, cancer, cachexia, muscle wasting, depression,
memory impairment, tumor growth, or cancerous invasion of normal
tissues comprises the step of administering a therapeutically
effective amount of a compound represented by Formula (I): 3
DETAILED DESCRIPTION OF THE INVENTION
[0015] A compound of this invention is represented by Formula (I):
4
[0016] The compound of Formula (I) ("Compound I") is made from
precursor compound II represented by Formula (II): 5
[0017] available from BYK Gulden Lomberg Chemische Fabrik GmbH,
Konstanz, Germany. Compound II is itself a PDE4 inhibitor. However,
Compound (I) has pharmacokinetics that are very different from
Compound (II). Further, the PDE4 inhibitory parameters and the
brain barrier interaction of Compound (I) differ substantially from
that of Compound (II). In particular, as shown below, the
properties of Compound (I) with regard the brain barrier are
unexpectedly superior to those properties demonstrated by Compound
(II).
[0018] Compounds having PDE 4 inhibitory activity can be
characterized using the following assay protocols.
Assays for Determining PDE 4 Inhibitory Activity
[0019] SPA Based PDE Activity Assay Protocol
[0020] Compounds which inhibit the hydrolysis of cAMP to AMP by the
type-IV cAMP-specific phosphodiesterases were screened in 96-well
plate format as follows:
[0021] In a 96 well-plate at 30.degree. C. was added the test PDE 4
inhibitory compound (dissolved in 2.mu.l DMSO), 188 ml of substrate
buffer containing [2,8-.sup.3H] adenosine 3',5'-cyclic phosphate
(cAMP, 100 nM to 50 .mu.M), 10 mM MgCl.sub.2, 1 mM EDTA, 50 mM
Tris, pH 7.5. The reaction was initiated by the addition of 10 ml
of human recombinant PDE-IV (the amount was controlled so that
.about.10% product was formed in 10 min. at 30.degree. C.). The
reaction was stopped after 10 min. by the addition of 1 mg of
PDE-SPA beads (Amersham). The product AMP generated was quantified
on a Microbeta 96-well plate counter. The signal in the absence of
enzyme was defined as the background. 100% activity was defined as
the signal detected in the presence of enzyme and DMSO with the
background subtracted. Percentage of inhibition was calculated
accordingly. IC.sub.50 value was approximated with a non-linear
regression fit of the standard 4-parameter/multiple binding sites
equation from a ten point titration.
[0022] LPS and fMLP-Induced TNF-.alpha. and LTB.sub.4 Assays in
Human Whole Blood
[0023] Whole blood provides a protein and cell-rich milieu
appropriate for the study of biochemical efficacy of
anti-inflammatory compounds such as PDE4-selective inhibitors.
Normal non-stimulated human blood does not contain detectable
levels of TNF-.alpha. and LTB.sub.4. Upon stimulation with LPS,
activated monocytes express and secrete TNF-.alpha. up to 8 hours
and plasma levels remain stable for 24 hours. Published studies
have shown that inhibition of TNF-.alpha. by increasing
intracellular cAMP via PDE4 inhibition and/or enhanced adenylyl
cyclase activity occurs at the transcriptional level. LTB.sub.4
synthesis is also sensitive to levels of intracellular cAMP and can
be completely inhibited by PDE4-selective inhibitors. As there is
little LTB.sub.4 produced during a 24 hour LPS stimulation of whole
blood, an additional LPS stimulation followed by fMLP challenge of
human whole blood is necessary for LTB.sub.4 synthesis by activated
neutrophils. Thus, by using the same blood sample, it is possible
to evaluate the potency of a compound on two surrogate markers of
PDE4 activity in the whole blood by the following procedure.
[0024] Fresh blood was collected in heparinized tubes by
venipuncture from healthy human volunteers (male and female). These
subjects had no apparent inflammatory conditions and had not taken
any NSAIDs for at least 4 days prior to blood collection. 500 .mu.L
aliquots of blood were pre-incubated with either 2 .mu.L of vehicle
(DMSO) or 2 .mu.L of test compound at varying concentrations for 15
minutes at 37.degree. C. This was followed by the addition of
either 10 .mu.L vehicle (PBS) as blanks or 10 .mu.L LPS (1 .mu.g/mL
final concentration, #L-2630 (Sigma Chemical Co., St. Louis, Mo.)
from E. coli, serotype 011:B4; diluted in 0.1% w/v BSA (in PBS)).
After 24 hours of incubation at 37.degree. C., another 10 .mu.L of
PBS (blank) or 10 .mu.L of LPS (1 .mu.g/mL final concentration) was
added to blood and incubated for 30 minutes at 37.degree. C. The
blood was then challenged with either 10 .mu.L of PBS (blank) or
10.mu.L of fMLP (1 .mu.M final concentration, #F-3506 (Sigma);
diluted in 1% w/v BSA (in PBS)) for 15 minutes at 37.degree. C. The
blood samples were centrifuged at 1500 xg for 10 minutes at
4.degree. C. to obtain plasma. A 50 .mu.L aliquot of plasma was
mixed with 200 .mu.L methanol for protein precipitation and
centrifuged as above. The supernatant was assayed for LTB.sub.4
using an enzyme immunoassay kit (#520111 from Cayman Chemical Co.,
Ann Arbor, Mich.) according to the manufacturer's procedure.
TNF-.alpha. was assayed in diluted plasma (in PBS) using an ELISA
kit (Cistron Biotechnology, Pine Brook, N.J.) according to
manufacturer's procedure. The IC.sub.50 values of Examples 1-42
generally ranged from 0.04 .mu.M to 8.71 .mu.M.
[0025] Effect on Duration of Anesthesia
[0026] Compound I of the present invention was compared to Compound
II by testing the for effects on the duration of anesthesia induced
by the combination of xylazine and ketamine in rats. Male
Sprague-Dawley rats were anaesthetised with a combination of
xylazine (10 mg/kg) and ketamine (10 mg/kg) administered in a
single intramuscular injection in the back hindlimb. Fifteen
minutes later, the drug to be tested or its vehicle was injected
intraperitoneally (dosing volume=1 ml/kg) and the animals were
placed in dorsal recumbence. The compounds were dissolved
immediately before use in polyethylene glycol (M.W. 200). The
return of the righting reflex (i.e. when the animal no longer
remained on its back and turned itself spontaneously to the prone
position) was used as an endpoint to determine the duration of
anaesthesia.
[0027] At the end of the experiment, at 60 minutes post-dosing,
plasma and brain samples were taken for drug concentration
determination. Referring to Table 1 below, administration of
Compound I (3 mg/kg i.p, n=5) did not significantly modify the
duration of anaesthesia. By contrast, the administration of
Compound II (3 mg/kg i.p., n=5) led to a significant reduction in
the duration of the anaesthesia induced by the combination of
xylazine/ketamine.
1TABLE 1 Effect of Compounds I and II on the duration of anesthesia
induced by the combination of xylazine and ketamine in rats.
Results are expressed as mean .+-. S.E.M. Duration of anesthesia
(min) Compound Treatment Vehicle treated treated Inhibition (3
mg/kg, i.p.) group (n = 8 - 9) group (n = 5) % Compound Formula I
44.33 .+-. 4.81 37.40 .+-. 7.83 15.6 Compound Formula II 42.38 .+-.
4.98 19.20 .+-. 4.68 54.7
[0028] Referring to Table 2 below, analysis of the plasma and brain
samples revealed that both compounds were absorbed. However, the
distribution to the brain was very different for each compound.
Consistent with the in vivo data on the duration of anaesthesia,
Compound Formula I was found to be less brain permeable than
compound of Formula II.
2TABLE 2 Plasma and brain concentrations of Compounds I and II
Plasma Brain Brain/plasma Compound (.mu.M) (.mu.M) % n Compound
Formula I 4.37 .+-. 1.65 0.41 .+-. 0.15 9.38 5 Compound Formula II
0.20 .+-. 0.08 0.15 .+-. 0.05 75 5
[0029] Accordingly, while disadvantageously Compound II readily
crosses the brain barrier, Compound (I) unexpected and
advantageously does not readily cross the brain barrier.
[0030] Compound (I) can be made according to the following
procedure shown in Scheme I: 6
[0031] The synthesis of Compound (II) is described in U.S. Pat. No.
5,712,298 and the compound is available from BYK Gulden (Konstanz,
Germany). Compound I was obtained from Compound II by the following
procedure:
EXAMPLE 1-COMPOUND I
[0032] 7
[0033] A mixture of
N-(3,5-Dichloropyridin-4-yl)-4-difluoromethoxy-3-cyclo-
propylmethoxybenzamide (3.0 g, 7.4 mmol) and magnesium
monoperoxyphthalate hexahydrate ("MMPP") (7.36 g, 14.9 mmol) in
CH.sub.2Cl.sub.2/MeOH (10 mL) was stirred under reflux for 48 h. An
additional amount of magnesium monoperoxyphthalate hexahydrate (7.4
g, 15 mmol) was added and the reaction mixture was stirred under
reflux for an additional 24 h. Ethyl acetate was then added and the
organic phase was washed by 25% aqueous NH.sub.4OAc, water and
brine, dried (MgSO.sub.4) and concentrated. The residue was
purified by column chromatography on silica (EtOAc) to yield
N-(3.5-Dichloro-1-oxido-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmeth-
oxybenzamide (Compound I) as a white solid (1.98 g, 63%). .sup.1H
NMR (500 MHz, acetone-d.sub.6): .delta. 0.40 (m, 2H), 0.60 (m, 2H),
1.30 (m, 1H), 4.0 (d, 2H), 7.05 (t, 1H), 7.35 (d, 1H), 7.7 (m, 1H),
7.75 (s, 1H), 8.40 (s, 2H), 9.6 (bs, 1H).
[0034] The pharmaceutical compositions of the present invention
comprise a compound represented by Formula I (or pharmaceutically
acceptable salts thereof) as an active ingredient, a
pharmaceutically acceptable carrier and optionally other
therapeutic ingredients or adjuvants. Such additional therapeutic
ingredients include, for example, i) Leukotriene receptor
antagonists, ii) Leukotriene biosynthesis inhibitors, and iii)
M2/M3 antagonists. The compositions include compositions suitable
for oral, rectal, topical, and parenteral (including subcutaneous,
intramuscular, and intravenous) administration, although the most
suitable route in any given case will depend on the particular
host, and nature and severity of the conditions for which the
active ingredient is being administered. The pharmaceutical
compositions may be conveniently presented in unit dosage form and
prepared by any of the methods well known in the art of
pharmacy.
[0035] Creams, ointments, jellies, solutions, or suspensions
containing the compound of Formula I can be employed for topical
use. Mouth washes and gargles are included within the scope of
topical use for the purposes of this invention.
[0036] Dosage levels from about 0.01 mg/kg to about 140 mg/kg of
body weight per day are useful in the treatment of conditions such
as asthma, chronic bronchitis, chronic obstructive pulmonary
disease, eosinophilic granuloma, psoriasis and other benign or
malignant proliferative skin diseases, endotoxic shock, laminitis
in horses, colic in horses, septic shock, ulcerative colitis,
Crohn's disease, reperfusion injury of the myocardium and brain,
inflammatory arthritis, chronic glomerulonephritis, atopic
dermatitis, urticaria, adult respiratory distress syndrome, infant
respiratory distress syndrome, chronic obstructive pulmonary
disease in animals, diabetes insipidus, allergic rhinitis, allergic
conjunctivitis, vernal conjunctivitis, arterial restenosis,
ortherosclerosis, atherosclerosis, neurogenic inflammation, pain,
cough, rheumatoid arthritis, osteoporosis, ankylosing spondylitis,
transplant rejection, graft versus host disease, hypersecretion of
gastric acid, bacterial, fungal induced sepsis, viral induced
sepsis, fungal induced septic shock, viral induced septic shock,
inflammation-mediated chronic tissue degeneration,
cytokine-mediated chronic tissue degeneration, osteoarthritis,
cancer, cachexia, muscle wasting, depression, memory impairment,
tumor growth, or cancerous invasion of normal tissues which are
responsive to PDE4 inhibition, or alternatively about 0.5 mg to
about 7 g per patient per day. For example, inflammation may be
effectively treated by the administration of from about 0.01 mg to
50 mg of the compound per kilogram of body weight per day, or
alternatively about 0.5 mg to about 3.5 g per patient per day.
Further, it is understood that the PDE4 inhibiting compounds of
this invention can be administered at prophylactically effective
dosage levels to prevent the above-recited conditions.
[0037] The amount of active ingredient that may be combined with
the carrier materials to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration. For example, a formulation intended for the oral
administration to humans may conveniently contain from about 0.5 mg
to about 5 g of active agent, compounded with an appropriate and
convenient amount of carrier material which may vary from about 5
to about 95 percent of the total composition. Unit dosage forms
will generally contain between from about 1 mg to about 500 mg of
the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300
mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
[0038] It is understood, however, that the specific dose level for
any particular patient will depend upon a variety of factors
including the age, body weight, general health, sex, diet, time of
administration, route of administration, rate of excretion, drug
combination and the severity of the particular disease undergoing
therapy.
[0039] In practice, the compound represented by Formula I, or
pharmaceutically acceptable salts thereof, of this invention can be
combined as the active ingredient in intimate admixture with a
pharmaceutical carrier according to conventional pharmaceutical
compounding techniques. The carrier may take a wide variety of
forms depending on the form of preparation desired for
administration, e.g., oral or parenteral (including intravenous).
Thus, the pharmaceutical compositions of the present invention can
be presented as discrete units suitable for oral administration
such as capsules, cachets or tablets each containing a
predetermined amount of the active ingredient. Further, the
compositions can be presented as a powder, as granules, as a
solution, as a suspension in an aqueous liquid, as a non-aqueous
liquid, as an oil-in-water emulsion or as a water-in-oil liquid
emulsion. In addition to the common dosage forms set out above, the
compound represented by Formula I, or pharmaceutically acceptable
salts thereof, may also be administered by controlled release means
and/or delivery devices. The compositions may be prepared by any of
the methods of pharmacy. In general, such methods include a step of
bringing into association the active ingredient with the carrier
that constitutes one or more necessary ingredients. In general, the
compositions are prepared by uniformly and intimately admixing the
active ingredient with liquid carriers or finely divided solid
carriers or both. The product can then be conveniently shaped into
the desired presentation.
[0040] Thus, the pharmaceutical compositions of this invention may
include a pharmaceutically acceptable carrier and a compound or a
pharmaceutically acceptable salt of Formula I. The compound of
Formula I, or pharmaceutically acceptable salts thereof, can also
be included in pharmaceutical compositions in combination with one
or more other therapeutically active compounds.
[0041] The pharmaceutical carrier employed can be, for example, a
solid, liquid, or gas. Examples of solid carriers include lactose,
terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium
stearate, and stearic acid. Examples of liquid carriers are sugar
syrup, peanut oil, olive oil, and water. Examples of gaseous
carriers include carbon dioxide and nitrogen.
[0042] In preparing the compositions for oral dosage form, any
convenient pharmaceutical media may be employed. For example,
water, glycols, oils, alcohols, flavoring agents, preservatives,
coloring agents and the like may be used to form oral liquid
preparations such as suspensions, elixirs and solutions; while
carriers such as starches, sugars, microcrystalline cellulose,
diluents, granulating agents, lubricants, binders, disintegrating
agents, and the like may be used to form oral solid preparations
such as powders, capsules and tablets. Because of their ease of
administration, tablets and capsules are the preferred oral dosage
units whereby solid pharmaceutical carriers are employed.
Optionally, tablets may be coated by standard aqueous or nonaqueous
techniques.
[0043] A tablet containing the composition of this invention may be
prepared by compression or molding, optionally with one or more
accessory ingredients or adjuvants. Compressed tablets may be
prepared by compressing, in a suitable machine, the active
ingredient in a free-flowing form such as powder or granules,
optionally mixed with a binder, lubricant, inert diluent, surface
active or dispersing agent. Molded tablets may be made by molding
in a suitable machine, a mixture of the powdered compound moistened
with an inert liquid diluent. Each tablet preferably contains from
about 0.1 mg to about 500 mg of the active ingredient and each
cachet or capsule preferably containing from about 0.1 mg to about
500 mg of the active ingredient.
[0044] Pharmaceutical compositions of the present invention
suitable for parenteral administration may be prepared as solutions
or suspensions of the active compounds in water. A suitable
surfactant can be included such as, for example,
hydroxypropylcellulose. Dispersions can also be prepared in
glycerol, liquid polyethylene glycols, and mixtures thereof in
oils. Further, a preservative can be included to prevent the
detrimental growth of microorganisms.
[0045] Pharmaceutical compositions of the present invention
suitable for injectable use include sterile aqueous solutions or
dispersions. Furthermore, the compositions can be in the form of
sterile powders for the extemporaneous preparation of such sterile
injectable solutions or dispersions. In all cases, the final
injectable form must be sterile and must be effectively fluid for
easy syringability. The pharmaceutical compositions must be stable
under the conditions of manufacture and storage; thus, preferably
should be preserved against the contaminating action of
microorganisms such as bacteria and fungi. The carrier can be a
solvent or dispersion medium containing, for example, water,
ethanol, polyol (e.g. glycerol, propylene glycol and liquid
polyethylene glycol), vegetable oils, and suitable mixtures
thereof.
[0046] Pharmaceutical compositions of the present invention can be
in a form suitable for topical use such as, for example, an
aerosol, cream, ointment, lotion, dusting powder, or the like.
Further, the compositions can be in a form suitable for use in
transdermal devices. These formulations may be prepared, utilizing
a compound represented by Formula I of this invention, or
pharmaceutically acceptable salts thereof, via conventional
processing methods. As an example, a cream or ointment is prepared
by mixing hydrophilic material and water, together with about 5 wt
% to about 10 wt % of the compound, to produce a cream or ointment
having a desired consistency.
[0047] Pharmaceutical compositions of this invention can be in a
form suitable for rectal administration wherein the carrier is a
solid. It is preferable that the mixture forms unit dose
suppositories. Suitable carriers include cocoa butter and other
materials commonly used in the art. The suppositories may be
conveniently formed by first admixing the composition with the
softened or melted carrier(s) followed by chilling and shaping in
moulds.
[0048] In addition to the aforementioned carrier ingredients, the
pharmaceutical formulations described above may include, as
appropriate, one or more additional carrier ingredients such as
diluents, buffers, flavoring agents, binders, surface-active
agents, thickeners, lubricants, preservatives (including
anti-oxidants) and the like. Furthermore, other adjuvants can be
included to render the formulation isotonic with the blood of the
intended recipient. Compositions containing a compound described by
Formula I, or pharmaceutically acceptable salts thereof, may also
be prepared in powder or liquid concentrate form.
[0049] The compounds and pharmaceutical compositions of this
invention have been found to exhibit biological activity as PDE4
inhibitors. Accordingly, another aspect of the invention is the
treatment in mammals of, for example, asthma, chronic bronchitis,
chronic obstructive pulmonary disease, eosinophilic granuloma,
psoriasis and other benign or malignant proliferative skin
diseases, endotoxic shock, laminitis in horses, colic in horses,
septic shock, ulcerative colitis, Crohn's disease, reperfusion
injury of the myocardium and brain, inflammatory arthritis, chronic
glomerulonephritis, atopic dermatitis, urticaria, adult respiratory
distress syndrome, infant respiratory distress syndrome, chronic
obstructive pulmonary disease in animals, diabetes insipidus,
allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis,
arterial restenosis, ortherosclerosis, atherosclerosis, neurogenic
inflammation, pain, cough, rheumatoid arthritis, osteoporosis,
ankylosing spondylitis, transplant rejection, graft versus host
disease, hypersecretion of gastric acid, bacterial, fungal induced
sepsis, viral induced sepsis, fungal induced septic shock, viral
induced septic shock, inflammation-mediated chronic tissue
degeneration, cytokine-mediated chronic tissue degeneration,
osteoarthritis, cancer, cachexia, muscle wasting, depression,
memory impairment, tumor growth, or cancerous invasion of normal
tissues--maladies that are amenable to amelioration through
inhibition of the PDE4 isoenzyme and the resulting elevated cCAMP
levels--by the administration of an effective amount of the
compounds of this invention. The term "mammals" includes humans, as
well as other animals such as, for example, dogs, cats, horses,
pigs, and cattle. Accordingly, it is understood that the treatment
of mammals other than humans is the treatment of clinical
correlating afflictions to those above recited examples that are
human afflictions.
[0050] Further, as described above, the compound of this invention
can be utilized in combination with other therapeutic compounds. In
particular, the combinations of the PDE4 inhibiting compound of
this invention can be advantageously used in combination with i)
Leukotriene receptor antagonists, ii) Leukotriene biosynthesis
inhibitors, or iii) M2/M3 antagonists.
[0051] Other variations or modifications, which will be obvious to
those skilled in the art, are within the scope and teachings of
this invention. This invention is not to be limited except as set
forth in the following claims.
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