Note: Descriptions are shown in the official language in which they were submitted.
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PHOSPHODIESTERASE ISOENZYME DENOMINATED 4 (PDE 4) INHIBITING COMPOUNDS
Scope of the Invention
This invention covers certain ketones and amines represented by the likes of 3-
(3-
cyclopentyloxy-4-methoxyphenyl)-3-phenylethynylcyclobutan-I-one. These ketones
are
selective for inhibiting the catalytic site in the phosphodiesterase isoenzyme
denominated 4
(PDE 4 hereafter) while exhibiting little or no affinity for a second binding
site on the PDE 4
isoenzyme denominated the high affinity rolipram binding site. A method for
treating
diseases related to inhibiting the catalytic site in the PDE 4 isoenzyme,
e.g., asthma, COPD,
etc. is also disclosed.
1o Area of the Invention
Cyclic nulceotide phosphodiesterases (PDEs) represent a family of enzymes that
hydrolyze the ubiquitous intracellular second messengers, adenosine 3',5'-
monophosphate
(CAMP} and guanosine 3',5 =monophosphate (cGMP) to their corresponding
inactive 5 =
monophosphate metabolites. At least five distinct PDE isoenzymes are believed
to exist,
15 each possessing unique physical and kinetic charactersitics and each
representing a product of
a different gene family. Also the distribution of these isoenzymes appears to
differ markedly
among cell types.
Bronchial asthma is a complex, multifactorial disease characterized by
reversible
narrowing of the airway and hyperreactivity of the respiratory tract to
external stimuli.
20 Identification of novel therapeutic agents for asthma is made difficult by
the fact that
multiple mediators are responsible for the development of the disease. Thus,
it seems
unlikely that eliminating the effects of a single mediator will have a
substantial effect on all
three components of chronic asthma. An alternative to the "mediator approach"
is to regulate
the activity of the cells responsible for the pathophysiology of the disease.
25 One such way is by elevating levels of cAMP (adenosine cyclic 3',5'-
monophosphate).
Cyclic AMP has been shown to be a second messenger mediating the biologic
responses to a
wide range of hormones, neurotransmitters and drugs; [Krebs Endocrinology
Proceedings of
the 4th International Congress Excerpts Medics, 17-29, 1973]. When the
appropriate agonist
binds to specific cell surface receptors, adenylate cyclase is activated,
which converts Mg+2
30 ATP to cAMP at an accelerated rate.
Cyclic AMP modulates the activity of most, if not all, of the cells that
contribute to
the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of
cAMP would
produce beneficial effects including: I) airway smooth muscle relaxation, 2)
inhibition of
mast cell mediator release, 3) suppression of neutrophil degranulation, 4)
inhibition of
35 basophil degranulation, and 5) inhibition of monocyte and macrophage
activation. Hence,
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2
compounds that activate adenylate cyclase or inhibit phosphodiesterase should
be effective in
suppressing the inappropriate activation of airway smooth muscle and a wide
variety of
inflammatory cells. The principal cellular mechanism for the inactivation of
cAMP is
hydrolysis of the 3'-phosphodiester bond by one or more of a family of
isozymes referred to
as cyclic nucleotide phosphodiesterases (PDEs).
It has now been shown that a distinct cyclic nucleotide phosphodiesterase
(PDE)
isozyme, PDE 4, is responsible for cAMP breakdown in airway smooth muscle and
inflammatory cells. [Torphy, "Phosphodiesterase Isozymes: Potential Targets
for Novel Anti-
asthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBC Technical Services
Ltd.,
1989]. Research indicates that inhibition of this enzyme not only produces
airway smooth
muscle relaxation, but also suppresses degranulation of mast cells, basophils
and neutrophils
along with inhibiting the activation of monocytes and neutrophils. Moreover,
the beneficial
effects of PDE 4 inhibitors are markedly potentiated when adenylate cyclase
activity of target
cells is elevated by appropriate hormones or autocoids, as would be the case
in vivo. Thus
PDE 4 inhibitors would be effective in the asthmatic lung, where levels of
prostaglandin E2
and prostacyclin (activators of adenylate cyclase) are elevated. Such
compounds would offer
a unique approach toward the pharmacotherapy of bronchial asthma and possess
significant
therapeutic advantages over agents currently on the market.
The compounds of this invention also inhibit the production of Tumor Necrosis
Factor ('TNF), a serum glycoprotein. Excessive or unregulated TNF production
has been
implicated in mediating or exacerbating a number of diseases including
rheumatoid arthritis,
rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic
conditions; sepsis,
septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome,
adult respiratory
distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease,
silicosis,
pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft vs.
host reaction,
allograft rejections, fever and myalgias due to infection, such as influenza,
cachexia
secondary to infection or malignancy, cachexia secondary to human acquired
immune
deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid
formation, scar
tissue formation, Crohn's disease, ulcerative colitis, or pyresis, in addition
to a number of
autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and
systemic lupus
erythematosis.
AIDS results from the infection of T lymphocytes with Human Immunodeficiency
Virus (HIV). At least three types or strains of H1V have been identified,
i.e., HIV-1, HIV-2
and HIV-3. As a consequence of HIV infection, T-cell-mediated immunity is
impaired and
infected individuals manifest severe opportunistic infections and/or unusual
neoplasms. HIV
entry into the T lymphocyte requires T lymphocyte activation. Viruses such as
HIV-1 or
HIV-2 infect T lymphocytes after T cell activation and such virus protein
expression and/or
replication is mediated or maintained by such T cell activation. Once an
activated T
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3
lymphocyte is infected with HIV, the T lymphocyte must continue to be
maintained in an
activated state to permit HIV gene expression and/or HIV replication.
Cytokines, specifically TNF, are implicated in activated T-cell-mediated HIV
protein
expression and/or virus replication by playing a role in maintaining T
lymphocyte activation.
Therefore, interference with cytokine activity such as by inhibition of
cytokine production,
notably TNF, in an HIV-infected individual aids in limiting the maintenance of
T cell
activation, thereby reducing the progression of HIV infectivity to previously
uninfected cells
which results in a slowing or elimination of the progression of immune
dysfunction caused
by HIV infection. Monocytes, macrophages, and related cells, such as kupffer
and glial cells,
have also been implicated in maintenance of the HIV infection. These cells,
like T cells, are
targets for viral replication and the level of viral replication is dependent
upon the activation
state of the cells. [See Rosenberg et al., The Immunopathogenesis of HIV
Infection,
Advances in Immunology, Vol. 57, 1989]. Monokines, such as TNF, have been
shown to
activate HIV replication in monocytes and/or macrophages [See Poli et al.,
Proc. Natl. Acad.
Sci., 87:782-784, 1990], therefore, inhibition of monokine production or
activity aids in
limiting HIV progression as stated above for T cells.
TNF has also been implicated in various roles with other viral infections,
such as the
cytomegalovirus (CMV), influenza virus, adenovirus, and the herpes virus for
similar reasons
as those noted.
TNF is also associated with yeast and fungal infections. Specifically Candida
albicans has been shown to induce TNF production in vitro in human monocytes
and natural
killer cells. [See Riipi et al., Infection and Immunity, 58(9):2750-54, 1990;
and Jafari et al.,
Journal of Infectious Diseases, 164:389-95, 1991. See also Wasan et al.,
Antimicrobial
Agents and Chemotherapy, 35,(10}:2046-48, 1991; and Luke et al., Journal of
Infectious
Diseases, 162:211-214,1990].
The ability to control the adverse effects of TNF is furthered by the use of
the
compounds which inhibit TNF in mammals who are in need of such use. There
remains a
need for compounds which are useful in treating TNF-mediated disease states
which are
exacerbated or caused by the excessive and/or unregulated production of TNF.
3o Summary of the Invention
The novel compounds of this invention are represented by Formula (n:
Y
R,X2
R
(I}
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wherein:
R1 is -(C~5)nC(O)O(C~5)mR6~ -(C~5)nC(O)NR4(CR4R5)mR6, _
(CR4R5)n0(CR4R5)mR6~ or -(CR4R5)rR6 wherein the alkyl moieties may be
unsubstituted
or substituted with one or more fluorines;
misOto2;
n is 1 to 4;
risOto6;
R4 and RS are independently hydrogen or C 1 _2 alkyl;
R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCl_3
alkyl, halo
substituted aryloxyC l _3 alkyl, indanyl, indenyl, C7_ 11 polycycloalkyl,
tetrahydrofuranyl,
furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl,
tetrahydrothiopyranyl,
thiopyranyl, C3_6 cycloalkyl, or a C4_6 cycloalkyl containing one or two
unsaturated bonds,
wherein the cycloalkyl or heterocyclic moiety may be unsubstituted or
substituted by 1 to 3
methyl groups, one ethyl group or an hydroxyl group;
provided that:
a) when R6 is hydroxyl, then m is 2; or
b) when R6 is hydroxyl, then r is 2 to 6; or
c) when R( is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-
tetrahydrofuranyl, or
2-tetrahydrothienyl, then m is 1 or 2; or
d) when R( is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-
tetrahydrofuranyl, or
2-tetrahydrothienyl, then r is 1 to 6;
e) when n is 1 and m is 0, then R6 is other than H in -(CR4R5)n0(CR4R5)mR6;
X is VR2, halogen, nitro, NR4R5, or formyl amine;
V is O or S(O)m ;
m' is 0, 1, or 2;
X2 is O or NRg;
R2 is -CH3 or -CH2CH3 unsubstituted or substituted by 1 or more fluorines;
R3 is COOR 14, C(O)NR4R 14 or R~;
W is alkyl of 2 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl
of 2 to 6
carbon atoms;
Z is O, NR9, NORg, NCN, C(-CN)2, CRgCN, CRgN02, CRgC(O)ORg,
CRgC(O)NRgRg, C(-CN)N02, C(-CN)C(O)OR9, C(-CN)C(O)NRgRg;
Y is O, NR~, NCR4RSC2_( alkenyl, NOR14, NOR15, NOCR4RSC2_6 alkenyl,
NNR4R14. NNR4R15, NCN, NNRgC(O)NRgRl4, NNRgC(S)NRgRl4, or =Y is 2-(1,3-
dithiane), 2-(1,3-dithiolane), dimethylthio ketal, diethylthio ketal, 2-(1,3-
dioxolane), 2(1,3-
dioxane), 2-(1,3-oxathiolane), dimethyl ketal or diethyl ketal;
R~ is -(CR4R5)qR 12 or C 1 _6 alkyl wherein the R 12 or C 1 _6 alkyl group is
unsubstituted or substituted one or more times by methyl or ethyl
unsubstituted or substituted
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by 1-3 fluorines, -F, -Br, -Cl, -N02, -NR1pR11, -C(O)Rg, -C02Rg, -O(CH2)qRg, -
CN, -
C(O)NR1pR11. -O(CH2)qC(O)NR1pR11. -O(CH2)qC(O)Rg, -NRIpC(O)NR1pR11~ -
NR 1 OC(O)R 11 ~ -NR l OC(O)OR9, -NR l pC(O)R 13, -C(1'IR 10)NR l OR 11, -
C(NCN)NR 1 OR 11
-C(NCN)SR9, -NRIpC(NCN)SR9 , -NRIpC(NCN)NR1pR11, -NRIpS(O)2R9, -S(O)m'R9, -
5 NRIpC(O)C(O)NR1pR11. -NR10C(O)C(O)R10, or R13;
q is 0, l, or 2;
R12 is R13~ C3-C~ cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, ( 1-
or 2-
imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or
3-thienyl),
quinolinyl, naphthyl, or phenyl;
Rg is hydrogen or R9;
Rg~ is Rg or fluorine;
R9 is C 1 ~ alkyl unsubsdtuted or substituted by one to three fluorines;
R10 is ORg or R11;
R 11 is hydrogen, or C 1 ~ alkyl unsubstituted or substituted by one to three
fluorines;
1 S or when R 10 and R 11 are as NR 1 pR 11 they may together with the
nitrogen form a 5 to 7
membered ring comprised only of carbon atoms or carbon atoms and at least one
heteroatom
selected from O, N, or S;
R 13 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl,
imidazolyl,
imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and
each of these
heterocyclic rings is connected through a carbon atom and each may be
unsubstituted or
substituted by one or two C 1 _2 alkyl groups;
R 14 is hydrogen or R~; or when Rg and R 14 are as NRgR 14 they may together
with
the nitrogen form a 5 to 7 membered ring comprised only of carbon atoms or
carbon atoms
and at least ane heteroatom selected from O, N, or S; provided that:
R15 is C(O}R14, C(O)NR4R14, S(O)2R~, or S(O}2NR4R14;
or a pharmaceutically acceptable salt thereof.
A second set of compounds of this invention are represented by Formula (II)
Y
R~X2
W\ Ra
wherein the several groups are the same as those of formula (I) except:
Y is -(CR4R5)qZ';
Z'is OR14, ORIg, SR14, S(O)mR~, S(O)2NR1pR14~ NR1pR14~ NR14C(O)R9,
~lOC(I'~R14. NRIpC(O)OR~, NRIpC(Y~NR1pR14~ ~IOS(O)2~1OR14~
NRIpC(NCN)NR1pR14, NRIpS(O)2R~, NRIpC(CR4N02)NR1pR14, NRIpC(NCN)SR9,
NRIpC(CR4N02)SR9, NRIpC(NR10)NR1pR14, NRIpC(O)C(O)NR1pR14, or
NR1OC(O)C(O)OR14:
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6
Y'isOorS;
(g) When R12 is N-pyrazolyl" N-imidazolyl, N-triazolyl, N-pyrrolyl, N-
piperazinyl,
or N-morpholinyl, then q is not 1;
or a pharmaceutically acceptable salt thereof.
This invention also relates to the pharmaceutical compositions comprising a
compound of Formula {I) and (II) and a pharmaceutically acceptable carrier or
diluent.
The invention also relates to a method of mediation or inhibition of the
enzymatic
activity (or catalytic activity) of PDE 4 in mammals, including humans, which
comprises
administering to a mammal in need thereof an effective amount of a compound of
Formula
(I) and (II) as shown below.
The invention further provides a method for the treatment of allergic and
inflammatory disease which comprises administering to a mammal, including
humans, in
need thereof, an effective amount of a compound of Formula (I) and (II).
The invention also provides a method for the treatment of asthma which
comprises
administering to a mammal, including humans, in need thereof, an effective
amount of a
compound of Formula (I) and (II).
This invention also relates to a method of inhibiting TNF production in a
mammal,
including humans, which method comprises administering to a mammal in need of
such
treatment, an effective TNF inhibiting amount of a compound of Formula (I) and
(II). This
method may be used for the prophylactic treatment or prevention of certain TNF
mediated
disease states amenable thereto.
This invention also relates to a method of treating a human afflicted with a
human
immunodeficiency virus (HIV), which comprises administering to such human an
effective
TNF inhibiting amount of a compound of Formula (1) and {II).
Compounds of Formula (I) and (II) are also useful in the treatment of
additional viral
infections, where such viruses are sensitive to upregulation by TNF or will
elicit TNF
production in vivo.
In addition, compounds of Formula (I) and (II) are also useful in treating
yeast and
fungal infections, where such yeast and fungi are sensitive to upregulation by
TNF or will
elicit TNF production in vivo.
Detailed Description of the Invention
Phosphodiesterase 4 inhibitors are useful in the treatment of a variety of
allergic and
inflammatory diseases including: asthma, chronic bronchitis, atopic
dermatitis, urticaria,
allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis,
eosinophilic granuloma,
psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's
disease, reperfusion
injury of the myocardium and brain, chronic glomerulonephritis, endotoxic
shock and adult
respiratory distress syndrome. In addition, PDE 4 inhibitors are useful in the
treatment of
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diabetes insipidus and central nervous system disorders such as depression and
multi-infarct
dementia.
The viruses contemplated for treatment herein are those that produce TNF as a
result
of infection, or those which are sensitive to inhibition, such as by decreased
replication,
directly or indirectly, by the TNF inhibitors of Formula (I) and (II). Such
viruses include, but
are not limited to HIV-1, HIV-2 and HN-3, cytomegalovirus (CMV), influenza,
adenovirus
and the Herpes group of viruses, such as, but not limited to, Herpes zoster
and Herpes
simplex.
This invention more specifically relates to a method of treating a mammal,
afflicted
with a human immunodeficiency virus (HIV), which comprises administering to
such
mammal an effective TNF inhibiting amount of a compound of Formula (I) and
(II).
The compounds of this invention may also be used in association with the
veterinary
treatment of animals, other than in humans, in need of inhibition of TNF
production. TNF
mediated diseases for treatment, therapeutically or prophylactically, in
animals include
disease states such as those noted above, but in particular viral infections.
Examples of such
viruses include, but are not limited to feline immunodeficiency virus (FN) or
other retroviral
infection such as equine infectious anemia virus, caprine arthritis virus,
visna virus, maedi
virus and other lentiviruses.
The compounds of this invention are also useful in treating yeast and fungal
infections, where such yeast and fungi are sensitive to upregulation by TNF or
will elicit TNF
production in vivo. A preferred disease state for treatment is fungal
meningitis. Additionally,
the compounds of Formula (I) and (II) may be administered in conjunction with
other drugs
of choice for systemic yeast and fungal infections. Drugs of choice for fungal
infections,
include but are not limited to the class of compounds called the polymixins,
such as
Polymycin B, the class of compounds called the imidazoles, such as
clotrimazole, econazole,
miconazole, and ketoconazole; the class of compounds called the triazoles,
such as
fluconazole, and itranazole, and the class of compound called the
Amphotericins, in particular
Amphotericin B and liposomal Amphotericin B.
The compounds of Formula (I) and (II) may also be used for inhibiting and/or
reducing the toxicity of an anti-fungal, anti-bacterial or anti-viral agent by
administering an
effective amount of a compound of Formula (I) and (II) to a mammal in need of
such
treatment. Preferably, a compound of Formula (I) and (II) is administered for
inhibiting or
reducing the toxicity of the Amphotericin class of compounds, in particular
Amphotericin B.
The term "C 1 _3 alkyl", "C 1 ~ alkyl", "C 1 _6 alkyl" or "alkyl" groups as
used herein is
meant to include both straight or branched chain radicals of 1 to 10, unless
the chain length is
limited thereto, including, but not limited to methyl, ethyl, n-propyl,
isopropyl, n-butyl, sec
butyl, isobutyl, tert butyl, and the like.
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"Alkenyl" means both straight or branched chain radicals of 1 to 6 carbon
lengths,
unless the chain length is limited thereto, including but not limited to
vinyl, 1-propenyl, 2-
propenyl, or 3-methyl-2-propenyl.
The term "cycloalkyl" or "cycloalkyl alkyl" means groups of 3-7 carbon atoms,
such
as cyclopropyl, cyclopropylmethyl, cyclopentyl, or cyclohexyl.
"Aryl" or "aralkyl", unless specified otherwise, means an aromatic ring or
ring system
of 6-10 carbon atoms, such as phenyl, benzyl, phenethyl, or naphthyl.
Preferably the aryl is
monocyclic, i.e, phenyl. The alkyl chain is meant to include both straight or
branched chain
radicals of 1 to 4 carbon atoms. "Heteroaryl" means an aromatic ring system
containing one
or more heteroatoms.
"Halo" means all halogens, i.e., chloro, fluoro, bromo, or iodo.
"Inhibiting the production of IL-1" or "inhibiting the production of TNF"
means:
a) a decrease of excessive in vivo IL-1 or TNF levels, respectively, in a
human to
normal levels or below normal levels by inhibition of the in vivo release of
IL-1 by all cells,
including but not limited to monocytes or macrophages;
b) a down regulation, at the translational or transcriptional level, of
excessive in vivo
IL-1 or TNF levels, respectively, in a human to normal levels or below normal
levels; or
c) a down regulation, by inhibition of the direct synthesis of IL-1 or TNF
levels as a
postranslational event.
The phrase "TNF mediated disease or disease states" means any and all disease
states
in which TNF plays a role, either by production of TNF itself, or by TNF
causing another
cytokine to be released, such as but not limited to II,-1 or IL-6. A disease
state in which IL,-1,
for instance is a major component, and whose production or action, is
exacerbated or secreted
in response to TNF, would therefore be considered a disease state mediated by
TNF. As
TNF-B (also known as lymphotoxin) has close structural homology with TNF-a
(also known
as cachectin), and since each induces similar biologic responses and binds to
the same
cellular receptor, both TNF-a and TNF-Q are inhibited by the compounds of the
present
invention and thus are herein referred to collectively as "TNF" unless
specifically delineated
otherwise. Preferably TNF-a is inhibited.
"Cytokine" means any secreted polypeptide that affects the functions of cells,
and is a
molecule which modulates interactions between cells in immune, inflammatory,
or
hematopoietic responses. A cytokine includes, but is not limited to, monokines
and
lymphokines regardless of which cells produce them. The cytokine inhibited by
the present
invention for use in the treatment of a HIV-infected human must be a cytokine
which is
implicated in (a) the initiation and/or maintenance of T cell activation
and/or activated T cell-
mediated HIV gene expression and/or replication, and/or (b) any cytokine-
mediated disease
associated problem such as cachexia or muscle degeneration. Preferrably, his
cytokine is
TNF-a.
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All of the compounds of Formula (I) and (II) are useful in the method of
inhibiting the
production of TNF, preferably by macrophages, monocytes or macrophages and
monocytes,
in a mammal, including humans, in need thereof. All of the compounds of
Formula (n and
(II) are useful in the method of inhibiting or mediating the enzymatic or
catalytic activity of
PDE 4 and in treatment of disease states mediated thereby.
Preferred compounds are as follows:
When R1 for the compounds of Formula (IJ and (11) is an alkyl substituted by 1
or
more halogens, the halogens are preferably fluorine and chlorine, more
preferably a C1~
alkyl substituted by 1 or more fluorines. The preferred halo-substituted alkyl
chain length is
one or two carbons, and most preferred are the moieties -CF3, -CH2F, -CHF2, -
CF2CHF2, -
CH2CF3, and -CH2CHF2. Preferred R1 substitutents for the compounds of Formula
(I) and
(II) are CH2-cyclopropyl, CH2-CS-6 cycloalkyl, C4_6 cycloalkyl unsubstituted
or substituted
with OH, C7_ 11 polycycloalkyl, (3- or 4-cyclopentenyl), phenyl,
tetrahydrofuran-3-yl, benzyl
or C 1 _2 alkyl unsubstituted or substituted by 1 or more fluorines,
-(CH2)1-3C(O)O(CH2)0-2CH3. -(~2)1-30(CH2)0-2CH3. ~d -(CH2)2-40H.
When the R1 term is (CR4R5), the R4 and RS terms are independently hydrogen or
alkyl. This allows for branching of the individual methylene units as (CR4Rg)n
or
(CR4R5)m; each repeating methylene unit is independent of the other, e.g.,
(CR4R5}n
wherein n is 2 can be -CH2CH(-CH3)-, for instance. The individual hydrogen
atoms of the
repeating methylene unit or the branching hydrocarbon can be unsubsdtuted or
be substituted
by fluorine independent of each other to yield, for instance, the preferred R1
substitutions, as
noted above.
When R1 is a C7_11 polycycloalkyl, examples are bicyclo[2.2.1]-heptyl,
bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo[5.2.1.02.6]decyl, etc.
additional examples of
which are described in Saccamano et al., WO 87/06576, published 5 November
1987, whose
disclosure is incorporated herein by reference in its entirety.
Preferred Z terms are O, NCN, NR7, NOR14, NOR15. X14. NNR4R15, 2-(1,3-
dithiane), dimethylthio ketal, 2-(1,3-dioxolane), or dimethyl ketal. More
preferred are O,
NR7, NOR 14, NOR 15, and 2-( 1,3-dioxolane).
Preferred X groups for Formula (I) and (II) are those wherein X is YR2 and Y
is
oxygen. The preferred X2 group for Formula (I) and (II) is that wherein X2 is
oxygen. The
preferred X3 group for Formula (n and (11) is that wherein X3 is hydrogen.
Preferred R2
groups, where applicable, is a C 1-2 alkyl unsubstituted or substituted by 1
or more halogens.
The halogen atoms are preferably fluorine and chlorine, more preferably
fluorine. More
preferred R2 groups are those wherein R2 is methyl, or the fluoro-substituted
alkyls,
specifically a C 1-2 alkyl, such as a -CF3, -CHF2, or -CH2CHF2 moiety. Most
preferred are
the -CHF2 and -CH3 moieties.
Preferred R7 moieties include R 13, unsubstituted or substituted -(CH2)~2(2-,
3- or 4-
pyridyl), (CH2) 1-2(2-imidazolyl), (CH2)2(4-morpholinyl), (CH2)2(4-
piperazinyl),
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(CH2)1-2(2-thienyl), (CH2)1-2(4-~~lYl), unsubstituted or substituted
pyrimidinyl, and
substituted or uasubstituted (CH2)0-2Phenyl.
Preferred rings when RIO and RI 1 in the moiety -NRIORI1 together with the
nitrogen to which they are attached form a 5 to 7 membered ring comprised only
of carbon
5 atoms or carbon atoms and at least one heteroatom selected from O, N, or S
include, but are
not limited to I-imidazolyl, 2-(Rg}-1-imidazolyl, 1-pyrazolyl, 3-(Rg)-1-
pyrazolyl, 1-triazolyl,
2-triazolyl, 5-(Rg}-1-triazolyl, 5-(Rg)-2-triazolyl, 5-(Rg)-1-tetrazolyl, 5-
(Rg)-2-tetrazolyl, 1-
tetrazolyl, 2-tetrazloyl, morpholinyl, piperazinyl, 4-(Rg)-I-piperazinyl, or
pyrrolyl ring.
Preferred rings when Rg and R14 in the moiety -NRgRl4 together with the
nitrogen
10 to which they are attached may form a 5 to 7 membered ring comprised only
of carbon atoms
or carbon atoms and at least one heteroatom selected from O, N, or S include,
but are not
limited to I-imidazolyl, 1-pyrazolyl, I-triazolyl, 2-triazolyl, 1-tetrazolyl,
2-tetrazolyl,
morpholinyl, piperazinyl, and pyrrolyI. The respective rings may be
additionally substituted,
where applicable, on an available nitrogen or carbon by the moiety R~ as
described herein for
Formula (I) and (II). lllustrations of such carbon substitutions includes, but
is not limited to,
2-(R~)-1-imidazolyl, 4-(R~)-1-imidazolyl, 5-(R~)-I-imidazolyl, 3-(R~)-1-
pyrazolyl,
4-(R~)-1-pyrazolyl, 5-(R~)-1-pyrazolyl, 4-(R~)-2-triazolyl, 5-(R~)-2-
triazolyl,
4-(R~)-I-triazolyl, 5-(R~)-1-triazolyl, 5-(R~)-1-tetrazolyl, and 5-(R~)-2-
tetrazolyl.
Applicable nitrogen substitution by R~ includes, but is not limited to, I-(R~)-
2-tetrazolyl,
2-(R~)-1-tetrazolyl, 4-(R~)-1-piperazinyl. Where applicable, the ring may be
substituted one
or more times by R~.
Preferred groups for NRgRI4 which contain a heterocyclic ring are 5-(RI4}-1-
tetrazolyl, 2-(R14)-1-imidazolyl, 5-(R14)-2-tetrazolyl, 4-(R14)-1-piperazinyl,
or
4-(R15)-1-piperazinyl.
Preferred rings for RI3 include (2-, 4- or 5-imidazolyl), (3-, 4- or 5-
pyrazolyl), (4- or
5-triazolyl[1,2,3]), (3- or 5-triazolyl[1,2,4]), {5-tetrazolyl), (2-, 4- or 5-
oxazolyl}, (3-, 4- or 5-
isoxazolyl), (3- or 5-oxadiazolyl[1,2,4]), {2-oxadiazolyl[1,3,4]}, (2-
thiadiazolyl[1,3,4]), (2-,
4-, or 5-thiazolyl), (2-, 4-, 5-oxazolidinyl}, (2-, 4-, or 5-thiazolidinyl),
or (2-, 4-, or
5-imidazolidinyl).
When the R~ group is unsubstituted or substituted by a heterocyclic ring such
as
imidazolyl, pyrazolyl, pyrimidinyl, triazolyl, tetrazolyl, or thiazolyl, the
heterocyclic ring
itself may be unsubsdtuted or substituted by Rg either on an available
nitrogen or carbon
atom, such as 1-(Rg)-2-imidazolyl, 1-(Rg)-4-imidazolyl, 1-(Rg)-5-imidazolyl,
1-(Rg)-3-pyrazolyl, 1-(Rg)-4-pyrazolyl, 1-(Rg)-5-pyrazolyl, 1-(Rg)-4-
triazolyl, or
1-(Rg)-5-triazolyl. Where applicable, the ring may be substituted one or more
times by Rg.
W is preferably alkyl, alkenyl or alkynyl of 3 to 5 carbon atoms, and where it
is
alkenyl or alkynyl, that one or two double or triple bonds be present. It is
most preferred that
W is ethynyl or 1,3-butadiynyl.
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Preferred are those compounds of Formula (I) and (II) wherein R1 is -CH2-
cyclopropyl, -CH2-CS_6 cycloalkyl, -C~6 cycloalkyl unsubstituted or
substituted with OH,
tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or -C1_2 alkyl
unsubstituted or
substituted by 1 or more fluorines, and -(CH2)2..4 OH; R2 is methyl or fluoro-
substituted
alkyl, R, is R, where R, is an unsubstituted or substituted aryl or heteroaryl
ring, X is YR2,
and Z is O, NR~,
Most preferred are those compounds of Formula (I) are those wherein R 1 is
-CH2-cyclopropyl, cyclopentyl, 3-hydmxycyclopentyl, methyl or CFZH; X is VR2;
V is
oxygen; X2 is oxygen; R2 is CF2H or methyl, W is ethynyl or 1,3-butadiynyl, R3
is a
substituted or unsubstituted pyrimidinyl ring, and Z is O or NR~.
As regards preferred compounds of Formula (II) they are the same as for those
of
Formula (I) where Formula (II) shares a group in common with Formula (I). As
regards the
Y group in Formula (II), the preferred embodiment is where R4 and RS are
hydrogen, q is 0
or 1 and Z' is OR14, OR15, or NR1pR14, most particularly NR1pR14~
Pharmaceutically acceptable salts of the instant compounds, where they can be
prepared, are also intended to be covered by this invention. These salts will
be ones
which are acceptable in their application to a pharmaceutical use. By that it
is meant
that the salt will retain the biological activity of the parent compound and
the salt will
not have untoward or deleterious effects in its application and use in
treating diseases.
Pharmaceutically acceptable salts are prepared in a standard manner. If the
parent compound is a base it is treated with an excess of an organic or
inorganic acid.
If the parent compound is an acid, it is treated with an inorganic or organic
base
dissolved in a suitable solvent.
Pharmaceutical compositions of the present invention comprise a pharmaceutical
Garner or diluent and some amount of a compound of the Formula (I) and (II).
The
compound may be present in an amount to effect a physiological response, or it
may be
present in a lesser amount such that the user will need to take two or more
units of the
composition to effect the treatment intended. These compositions may be made
up as a solid,
liquid or in a gaseous form. Or one of these three forms may be transformed to
another at the
time of being administered such as when a solid is delivered by aerosol means,
or when a
liquid is delivered as a spray or aerosol.
The nature of the composition and the pharmaceutical carrier or diluent will,
of
course, depend upon the intended route of administration, for example
parenterally, topically,
orally or by inhalation.
For topical administration the pharmaceutical composition will be in the form
of a
cream, ointment, liniment, lotion, pastes, aerosols, and drops suitable for
administration to
the skin, eye, ear, or nose.
For parenteral administration the pharmaceutical composition will be in the
form of a
sterile injectable liquid such as an ampule or an aqueous or non-aqueous
liquid suspension.
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For oral administration the pharmaceutical composition will be in the form of
a tablet,
capsule, powder, pellet, atroche, lozenge, syrup, liquid, or emulsion.
When the pharmaceutical composition is employed in the form of a solution or
suspension, examples of appropriate pharmaceutical carriers or diluents
include: for aqueous
systems, water; for non-aqueous systems, ethanol, glycerin, propylene glycol,
corn oil,
cottonseed oil, peanut oil, sesame oil, liquid parafins and mixtures thereof
with water; for
solid systems, lactose, kaolin and mannitol; and for aerosol systems,
dichlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide.
Also, in
addition to the pharmaceutical carrier or diluent, the instant compositions
may include other
ingredients such as stabilizers, antioxidants, preservatives, lubricants,
suspending agents,
viscosity modifiers and the like, provided that the additional ingredients do
not have a
detrimental effect on the therapeutic action of the instant compositions.
The pharmaceutical preparations thus described are made following the
conventional
techniques of the pharmaceutical chemist as appropriate to the desired end
product.
In these compositions, the amount of carrier or diluent will vary but
preferably will be
the major proportion of a suspension or solution of the active ingredient.
When the diluent is
a solid it may be present in lesser, equal or greater amounts than the solid
active ingredient.
Usually a compound of formula I is administered to a subject in a composition
comprising a nontoxic amount sufficient to produce an inhibition of the
symptoms of a
disease in which leukotrienes are a factor. Topical formulations will contain
between about
0.01 to S.0% by weight of the active ingredient and will be applied as
required as a
preventative or curative agent to the affected area. When employed as an oral,
or other
ingested or injected regimen, the dosage of the composition is selected from
the range of
from 50 mg to 1000 mg of active ingredient for each administration. For
convenience, equal
doses will be administered 1 to 5 times daily with the daily dosage regimen
being selected
from about 50 mg to about 5000 mg.
It will be recognized that some of the compounds of Formula (I) and (II) may
exist in
both racemic and optically active forms; some may also exist in distinct
diastereomeric forms
possessing distinct physical and biological properties. All of these compounds
are considered
to be within the scope of the present invention.
The following examples are given to further illustrate the described
invention. These
examples are intented solely for illustrating the invention and should not be
read to limit the
invention in any manner. Reference is made to the claims for what is reserved
to the
inventors hereunder.
No unacceptable toxicological effects are expected when these compounds are
administered in accordance with the present invention.
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13
Methods Of Preparation
Synthetic Schemes) With Textual Description
Cyanocyclobutanone 1-Scheme 1. prepared as described in an accompanying patent
application filed on even date herewith may be protected, for example, as a
ketal, by
treatment with suitable reagents, such as bis(trimethylsilyloxy~thane and
catalytic
trimethylsilyl trifluoromethanesulfonate, in a suitable solvent, such as
dichloromethane. The
nitrile may then be reduced by a suitable reagent, such as diisobutylaluminum
hydride, in a
suitable solvent, such as toluene or an ether, such as tetrahydrofuran and
tetrabutyl methyl
ether. Aldehyde 2-Scheme 1 may be homologated to the alkyne by treatment with
an
appropriate reagent, such as dialkyl diazomethylphosphonate, [Seyferth et al,
J. Org. Chem.,
36: 1379, 1971 and a suitable base, such as potassium t-butoxide, in a
suitable solvent, such
as tetrahydrofuran. Deprotecdon of the ketal may be achieved by treatment with
an acidic
reagent, such as hydrogen chloride or p-toluenesulfonic acid, in an aqueous
solvent, such as
tetrahydrofuran, at temperatures from room temperature to reflux, preferably
at 60oC.
Terminal alkyne 3-Scheme 1 may be coupled with an aryl bromide or iodide, such
as
iodobenzene, using an appropriate catalyst system, such as
tetrakis(triphenylphosphine)palladium(0) and copper(I) iodide, in a suitable
solvent, such as
triethylamine, at elevated temperature, preferably at SSoC, to provide the
phenylethynylcyclobutanone 4 Scheme 1. [Brandsma et al, Syn. Comm., 20: 1889,
1990].
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WO 99/52847 PCT/US99/07995
14
Scheme t
O O
'O
O / ~ \\ ~ O / ~ ~ c-'
O \ N \O \ p
1
O ~ o
O / ~ ~ a O
~o \ ~ \o
Reagents: a) TMSOCH2CHZOTMS, TMSOTf, CHzCl2, -78°C to RT; b) DIBAL-H,
THF, TBME;
c) N2CHP(O)(OMe)2, KO~Bu, THF, -78~C to RT; d) HCI, H20, THF, eO~C; e) Phl,
(PPh~4Pd,
Cui, Et3N, 85~C.
Phenylethynylcyclobutanone 1 Scheme 2 may be treated with a suitable reagent,
such
as methoxymethyldiphenylphosphonium chloride, and a suitable base, such as
phenyllithium,
in a suitable solvent, such as ether or tetrahydrofuran. The resulting methyl
vinyl ether 2-
Scheme 2 may be hydrolyzed by treatment with an acidic reagent, such as p-
toluenesulfonic
acid, in a suitable aqueous solvent, such as isopropanol, at elevated
temperature, preferably at
reflux. [Demopoulos et al. J. Het. Chem., 25: 635, 1988] Separation of cis and
traps isomers
may conveniently be carned out at this stage. Aldehyde 3a- or 3b-Scheme 2 may
be
transformed into the amine by, for example, reductive amination by treatment
with suitable
reagents, such as ammonium acetate and sodium cyanoborohydride, followed by
hydrogen
chloride, in a suitable solvent, such as methanol, to provide the
aminomethylcyclobutane 4a-
or 4b-Scheme 2
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Scheme 2
O
O ~ O
\O \O
~O
O~/~~ ~ O_
\O~ y \
O
~, cis isomer
~ø, traps isomer 4~, cis isomer
4~t , traps isomer
Reagents: a) CH30CHzPPh3~ CI', PhU, EtzO, 0°C to RT; b) pTsOH, iPrOH,
H20, reflex; c) i. NH40Ac,
NaBH3CN, MeOH, 4 A sieves; ii. HCI, MeOH.
Terminal alkyne 1-Scheme 3 may be reduced to the alcohol by a variety of
reagents,
such as a borohydride, especially lithium borohydride, in a suitable solvent,
such as an
5 alcohol, such as ethanol, or an ether, such as dimethoxyethane or
tetrahydrofuran, at
temperatures from -78oC to room temperature. The mixture of cis and traps
alcohols may
then be subjected to Mitsunobu reaction conditions [Mitsunobu, Synth, I,
1981], for example
with diethyl azodicarboxylate, triphenylphosphine and phthalimide, in a
suitable solvent,
such as tetrahydrofuran, to give a mixture of phthalimidocyclobutanes, the cis
and traps
10 isomers of which may conveniently be separated.
Traps-phthalimidocyclobutane 2-Scheme 3 may be elaborated to the amine, for
example with hydrazine, in a suitable solvent, such as ethanol and
tetrahydrofuran, and
protected, for example as the t-butylcarboxylate, by treatment with a suitable
reagent, such as
di-t butyldicarboxylate, in a suitable solvent, such as dichloromethane.
Terminal alkyne 3-
15 Scheme 3 may be coupled to an aryl bromide or iodide, such as iodobenzene,
with an
appropriate catalyst system, such as tetrakis(triphenylphosphine)palladium(0)
and copper(I)
iodide, in a suitable solvent, such as triethylamine, at elevated
temperatures, preferably at
85oC. [Brandsma et al, Syn. Cotnm., .20: 1889, 1990] The intermediate may be
deprotected,
for example with trifluoracetic acid, in a suitable solvent, such as
dichloromethane, to give
the traps-phenylethynylcyclobutylamine 4-Scheme 3.
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Terminal alkyne 3-Scheme 3 may be reacted with even unreactive aryl iodides
and
bromides, such as 2-amino-5-iodopyrimidine, in the presence of a base, such as
diethylamine,
in a suitable solvent, such as dimethyl sulfoxide, using an appropriate
catalyst system, such as
tetrakis(triphenylphosphine)palladium(0) and copper(n iodide, at elevated
temperatures,
preferably at 65oC. The intermediate may be deprotected, for example with
trifluoracetic
acid, in a suitable solvent, such as dichloromethane, to provide the traps-(2-
aminopyrimidin-
S-ylethynyl)cyclobutylamine 5-Scheme 3.
Scheme 3
O
O . N
O a~ O
W \ ~ ~ ~ \
O O
1
,.rN~O~ N
O
O / ( ~ e~f O
\ ~~ ~ O
aN~O~ N
O
O / O
9,t
~O \ ( ~~ \O
N --'
N
Reagents: a) t.iBH,, THF, -30"C; b) DEAD, PPh3, phthalimide, THF; c) N2H; HzO,
THF, EtOH;
d) (t-BuOsC)20, CH2CI2; e) Phl, (PPH~4Pd, Cul, Et3N, 85°C;1) TFA,
CH2CI2; g) (PPh~,Pd, Cut,
2-amino-5-iodopyrimidine, DMSO, Et2NH, 65~C.
Terminal alkyne 1-Scheme 4 may be subjected to Mitsunobu [Pearson et al, J.
Org.
Chem., 54: 4235, 1989] reaction conditions, for example with
diphenylphosphoryl azide,
diethyl azodicarboxylate and triphenylphosphine, in a suitable solvent, such
as
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17
tetrahydrofuran, resulting in a mixture of cis and traps azides 2a- and 2b-
Scheme 4, which
may conveniently be separated. Traps-azide 2a-Scheme 4 may be coupled with an
aryl iodide
or bromide using a suitable catalyst system, such as
tetrakis(triphenylphosphine)palladium(0)
and copper(I) iodide, in a suitable solvent, such as triethylanune, at
elevated temperatures,
preferably at 85oC. [Brandsma et al, Syn. Comm., 20: 1889, 1990] Azide 3-
Scheme 4 may be
reduced with a suitable reducing system, such as triphenylphosphine, in the
presence of a
suitable base, such as pyridine, in a suitable solvent, such as ammoniacal
methanol. Salt
formation with, for example, ethereal hydrogen chloride, provides the amine
salts 4-Scheme
4. In those cases where the coupled aryl group is a benzoate ester 5-Scheme 4,
saponification
may be achieved by a variety of reaction conditions, for example with
potassium hydroxide
in tetrahydrofuran, methanol and water. Salt formation with, for example,
ethereal hydrogen
chloride provides the amine salts 6-Scheme 4
Scheme 4
O N,N~ _
N
O a~ O
\ \ ~ ~~ \ \
O v O
1_ ?,~, dens isomer
gø, cls isomer
~HCI
N.. + N
,,.. ~ [~ ~ N _ ,,a
O / ~ ~ d=e-1 O /
\O \ ~\ \O \
Ar Ar
4
N N ~HCI
,+~
O / f--e1 O /
\O \ ~ ~~ \O \O \ ( ~~ O
Ar-~ Ar-
$ O S O
Reagents: a) LiBH4, THF, -78°C; b) DEAD, PhzP(O)N3, PPh3, THF; c) Arl,
(PPh~4Pd, Cul,
Et3N, 85°C; d) PPh3, pyridine, NH3, MeOH; e) HCI, Et20; f) KOH, THF,
MeOH, H20.
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SYNTHETIC EXAMPLES
EXAMPLE 1
3-(3-Cyclopentyloxy-4-methoxyphenyl)-3-phen l~ynylcvclobutan-1-one
is 3-(3-Cyclopentvloxy-4-methoxyphenyl)-3-ethynvlcyclobutan-1-(13-
dioxolane ketal). To a suspension of potassium tert-butoxide ( 1.40 g, 12.5
mmol) in
tetrahydrofuran (50 mL) at -78oC under an argon atmosphere was added via
cannula a -78oC
solution of dimethyl diazomethylphosphonate ( 1.88 g, 12.5 mmol) (preparation
described in
PCT application PCT/US95/16711, published 4 July 1996 as W096/19988) in
tetrahydrofuran ( 15 mL), followed immediately by rapid syringe addition of a -
78oC solution
of 3-(1,3-dioxolane ketal)-I-(3-cyclopentyloxy-4-methoxyphenyl)cyclobutane-1-
carboxaldehyde (2.08 g, 6.25 mmol) (preparation described in patent ) in
tetrahydrofuran
( 15 mL). The reaction was stirred at room temperature for l .5h, was quenched
with
ammonium chloride and water and was extracted with three portions of
dichloromethane. The
organic extract was dried (magnesium sulfate) and evaporated. Purification by
flash
chromatography, eluting with 15:85 ethyl acetate : hexanes provided product as
an off white,
waxy solid ( 1.39 g, 68%), m.p. 55-56oC.
lb 3-(3-Cyclopentyloxy-4-methoxyphenyl)-3-ethynylcyclobutan-I-one. A
solution of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-ethynylcyclobutan-1-(1,3-
dioxolane
ketal) in tetrahydrofuran (65 mL) and 10% hydrochloric acid ( 15 mL) was
stirred at 50-60oC
under an argon atmosphere for 24h. The reaction was cooled, was poured into 5%
sodium
carbonate ( 100 mL) and was extracted with three portions of dichloromethane.
The organic
extract was dried (magnesium sulfate) and evaporated. Purification by flash
chromatography,
eluting with I:9 ethyl acetate : hexanes provided product as a white solid
(1.00 g, 83%),
m.p.58-59oC.
lc 3-(3-Cyclopentyloxy-4-methoxyphenyl)-3-phenyleth~nylcyclobutan-1-one. To
a solution,of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-ethynylcyclobutan-1-one
(0.15 g,
0.53 mmol) in triethylanune (3 mL) was added iodobenzene (0.06 mL, 0.53 mmol),
tetrakis(triphenylphosphine)palladium(0) (0.024g, 4%) and copper(I} iodide
(0.006 g, 6%).
The reaction was stirred at 80-85oC under an argon atmosphere for lh, was
cooled, was
diluted with water and was extracted with three portions of dichloromethane.
The organic
extract was dried (magnesium sulfate) and evaporated. Purification by flash
chromatography,
eluting with 1:9 ethyl acetate : hexanes provided product as a yellow oil
(0.12 g, 60%).
Analysis Calcd for C24H2403'~~125 H20: C 79.48, H 6.74; found: C 79.30, H
6.58.
EXAMPLE 2
trans-1-Aminomethyl-3-(3-cyclopentyloxy-4-metho~nhenyl)-3-
phenylethynylcyclobutane
2a Methoxv 3-(3-cyclopentyloxy-4-methoxyphenvl)-3-phenylethynylcyciobut-1-
li3r dene. To a suspension of methoxymethyl)triphenylphosphonium chloride
(0.94 g, 2.73
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19
mmol) in diethyl ether (20 mL) at OoC under an argon atmosphere was rapidly
added a
solution of 1.8 M phenyllithium in cyclohexane/diethyl ether (4.95 mL, 8.9
mmol), followed
immediately by a solution of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-
phenylethynylcyclobutan-1-one (0.82 g, 2.28 mmol) (prepared in example 12b) in
diethyl
ether (20 mL). The reaction was stirred at room temperature for 24h, was
quenched with
ammonium chloride, was diluted with water and was extracted with three
portions of
dichloromethane. The organic extract was dried (magnesium sulfate) and
evaporated.
Purification by flash chromatography, eluting with 1:9 ethyl acetate : hexanes
provided
product as a colorless oil (0.35 g, 40%). (Starting aldehyde was also
recovered (0.36 g,
44%)).
2b traps-3-(3-Cvclooentvloxy-4-methoxvphenyl)-3-phenyleth nvlcyclobutan-1-
carboxaldehvde and cis-3-l3-cvclopentyloxy-4-methoxyphenyl)-
3=phenylethynvlcyclobutan-
1-carboxaldehyde. A solution of methoxy 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-
phenylethynylcyclobut-1-ylidene (0.45 g, 1.16 mmol) in isopropanol (5 mL) and
water (5
mL) was deoxygenated, and then was treated with p-toluenesulfonic acid (0.02
g, 10%). The
reaction was stirred at reflux under an argon atmosphere for 20h, was cooled,
was diluted
with water and was extracted with three portions of dichloromethane. The
organic extract was
dried (magnesium sulfate) and evaporated. Purification by flash
chromatography, eluting with
5:95 ethyl acetate : hexanes provided both products: traps-3-(3-Cyclopentyloxy-
4-
methoxyphenyl)-3-phenylethynylcyclobutan-1-carboxaldehyde was obtained as a
colorless
oil (0.11 g, 26%), Rf--0.23 ( 1:9 ethyl acetate : hexanes), and cis-3-{3-
cyclopentyloxy-4.-
methoxyphenyl)-3-phenylethynylcyclobutan-1-carboxaldehyde was obtained as a
colorless
oil (0.15 g, 35%), Rf=0.16 ( 1:9 ethyl acetate : hexanes), contaminated with ~
10% traps
isomer. Additional product (0.044 g, 10%) was isolated as a mixture of
isomers.
2c traps-1-Aminomethyl-3-l3-cyclopentyloxy-4-methoxyphenyl)-3-
phenyleth,~ylcyclobutane. A mixture of traps-3-(3-cyclopentyloxy-4-
methoxyphenyl)-3-
phenylethynylcyclobutan-1-carboxaldehyde (0.11 g, 0.30 mmol), ammonium acetate
(0.23 g,
3.0 mmol), sodium cyanoborohydride (0.019 g, 0.30 mmol) and several 4A
molecular sieves
in methanol (3 mL) was stirred at mom temperature under an argon atmosphere
for 3d. The
reaction was treated with a crystal of methyl orange, then dropwise with
hydrogen chloride-
saturated methanol to attain a red color. The reaction was stirred for three
hours, maintaining
the acidity, was basified with 10% sodium hydroxide, was diluted with water
and was
extracted with three portions of 5/95 methanoUdichloromethane. The organic
extract was
dried (potassium carbonate) and evaporated. Purification by flash
chromatography, eluted
with 1:9 methanol : dichloromethane provided product as an amber oil (0.026 g,
23%). 1H-
NMR (CDCl3, 400mHz) 8 7.39 (m, 2H), 7.24 (m, 3H), 6.98 (d, J=2.3Hz, 1H), 6.91
(d, J=8.3
Hz, 1H), 6.79 (d, J=8.3 Hz, 1H), 4.78 (m, 1H), 3.80 (s, 3H), 3.13 (m, 1H),
3.05 (m, 2H), 2.82
(m, 2H), 2.36 (m, 2H), 1.8-2.0 (m, 6H), 1.65 (m, 2H) ppm. Mass spectrum (ES+):
376
(M+H).
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EXAMPLE 3
cis-1-Aminomethvl-3-(3-c~clopentyloxJr-4-methoxyphen 1~)-3-
phenylethpnylcvclobutane.
A mixture of cis-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-
phenylethynylcyclobutan-
5 1-carboxaldehyde (0.15 g, 0.41 mmol), ammonium acetate (0.31 g, 4.1 mmol),
sodium
cyanoboroliydride (0.026 g, 0.41 mmol) and several 4A molecular sieves in
methanol (3 mL)
was stirred at room temperature under an argon atmosphere for 3d. The reaction
was treated
with a crystal of methyl orange, then dropwise with hydrogen chloride-
saturated methanol to
attain a red color. The reaction was stirred for three hours, maintaining the
acidity, was
10 basified with 10°k sodium hydroxide, was diluted with water and was
extracted with three
portions of 5/95 methanol/dichloromethane. The organic extract was dried
(potassium
carbonate) and evaporated. Purification by flash chromatography, eluted with
5:95 methanol
dichloromethane provided product as an amber oil (0.029 g, 19%). 1H-NMR
(CDC13, 400
MHz) 8 7.39 (m, 2H), 7.25 (m, 3H), 7.09 (s, 1H), 7.04 {d, J=8.5 Hz, 1H), 6.81
(d, J=8.5Hz,
15 1H), 4.80 (m, 1H), 3.82 (s, 3H), 3.20 (m, 2H), 2.83 (m, 2H), 2.66 (m, 1H),
2.54 (m, 2H), 1.8-
2.0 (m, 6H), 1.65 (m, 2H) ppm. Mass spectrum (ES+) 376 (M+H), 359 (M+H-NH3),
291
(M+H-(O-cyclopentyl)). (The MS has numerous other peaks as well)
EXAMPLE 4
traps-1-Amino-3-(3-c~pent~oxy-4-methoxyphenyl)-3-phen~hy~lcyclobutane.
20 4a 3-(3-Cyclopentyloxy-4-methoxyphenyl)-3-ethvnylcyclobutan-1-ol. To a
solution of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-ethynylcyclobutan-1-one
(0.50 g, 1.76
mmol) (prepared in example ~ in tetrahydrofuran ( 10 mL) at -30--40oC under an
argon
atmosphere was added over 15 min a slurry of lithium borohydride (0.12 g, 5.28
mmol) in
tetrahydrofuran ( 16 mL). The reaction was stirred 0.5h and was poured into
OoC ammonium
chloride. 10% Hydrochloric acid was used to adjust to pH 3-4, the mixture was
warmed to
room temperature and was extracted with three portions of diethyl ether. The
organic extract
was dried (magnesium sulfate) and was evaporated. Purification by flash
chromatography,
eluting with 2:8 ethyl acetate : hexanes provided product as a colorless oil
(0.54 g, 100%).
1H-NMR indicated the cis : traps isomer ratio to be ~ 85:15.
4b traps-3-(3-Cyclopentyloxy-4-methoxyphenyl -3-ethvnvl-1-
phthalimidocyclobutane. A solution of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-
ethynylcyclobutan-1-oI (0.54 g, 1.76 mmol) in tetrahydrofuran (20 mL) was
treated with
phthalimide (0.39 g, 2.64 mmol), triphenylphosphine (0.69 g, 2.64 mmol) and
diethyl
azodicarboxylate (0.42 mL, 2.64 mmol). The reaction was stirred at room
temperature under
an argon atmosphere for 24h and was evporated. Purification by four flash
chromatographies,
eluting with 1:9 ethyl acetate : hexanes, with 5:48:48 ethyl acetate :
dichloromethane
hexanes, with 4:24:72 ethyl acetate : dichloromethane : hexanes and with
2:20:80 ethyl
acetate : dichloromethane : hexanes provided product as a white solid (0.57 g,
78%), m.p.
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WO 99/52847 PCT/US99/07995
21
130-131oC. Some cis-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-ethynyl-1-
phthalimidocyclobutane (0.08 g, 11 %) was also isolated.
4c traps-1-tertbutoxycarbonylamino-3-(3-cvclopent~v-4-methoxxphenyl)-3-
ethynylcyclobutane. A solution of traps-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-
ethynyl-1-
phthalimidocyclobutane (0.24 g, 0.58 mmol) in ethanol (4 mL) and
tetrahydrofuran (2 mL)
was treated with hydrazine monohydrate (0.26 mL, 5.8 mmol) and was stirred at
room
temperature under an argon atmosphere for 18h. The reaction was diluted with
water and
extracted with three portions of 5/95 methanoUdichloromethane. The organic
extract was
dried (magnesium sulfate) and evaporated to provide crude amine as a colorless
oil. The
crude intermediate was dissolved in dichloromethane (20 mL) and was treated
with
ditert.butyl dicarbonate (0.13 g, 0.61 mmol). The reaction was stirred at room
temperature
under an argon atmosphere for 24h, was partitioned between dichloromethane and
water, was
dried (magnesium sulfate) and was evaporated. Purification by flash
chromatography, eluting
with 1:9 ethyl acetate :hexanes provided product as a whitish solid (0.098 g,
44%), m.p.129-
130oC.
4d traps-1-tertbutoxvcarbonvlamino-3-(3-cyclopentyloxy-4-methoxynhen,~rll-3-
phen,Ylet~nvlcyclohutane. A solution of traps-1-tertbutoxycarbonylamino-3-(3-
cyclopentyloxy-4-methoxyphenyl)-3-ethynylcyclobutane (0.098 g, 0.25 mmol) in
triethylamine (3 mL) was treated with iodobenzene (0.03 mL, 0.25 mmol),
tetrakis(triphenylphosphine)palladium(0) (0.01 g, 4%) and copper(II) iodide
(0.003 g, 6%).
The reaction was stirred at 80-85oC under an argon atmosphere for lh, was
cooled, was
diluted with water and was extracted with three portions of dichloromethane.
The organic
extract was dried (magnesium sulfate) and evaporated. Purification by flash
chromatography,
eluting with 1:9 ethyl acetate : hexanes provided product as a yellow solid
(0.09g, 78%),
m.p.45-5loC.
4e traps-1-Amino-3-(3-cyclopen loxy-4-methoxyphenyl)-3-
phenylethynvlcyclobutane.A solution of traps-1-tertbutoxycarbonylamino-3-(3-
cyclopentyloxy-4-methoxyphenyl)-3-phenylethynylcyclobutane (0.09 g, 0.20 mmol)
in
dichloromethane (3 mL) was treated with trifluoroactic acid (0. I5 mL, 2 mmol)
and was
stirred at room temperature under argon for 24h. The reaction was again
treated with
trifluoroactic acid (0.15 mL, 2 mmol) and was stirred at mom temperature under
argon for
24h, was cooled to OoC, was quenched with sodium bicarbonate and water and was
extracted
with three portions of 5/95 methanol/dichloromethane. The organic extract was
dried
(potassium carbonate) and evaporated. Purification by two flash
chromatographies, eluting
first with 3:97 methanol : dichloromethane, then with 2:98 methanol :
dichloromethane
provided product as a yellow oil (0.039g, 55%).
Analysis Calcd for C24H27N02-0.75 H20 : C 76.87, H 7.66, N 3.74; found: C
77.13,
H 7.48, N 3.95.
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WO 99/52847 22 PCT'/US99/07995
EXAMPLE 5
traps-1-Amino-3-l2-aminopyrimidin-5-ylethynyl)-3-(3-cyclopen~loxy-4-
methoxyphenyl)cyclobutane.
~a traps-3-(2-aminopvrimidin-5-ylethynvl)-1-tertbutoxycarbon_ylamino-3-l3-
~clopentyloxy-4-methoxyphenyl)cyclobutane. A solution of traps-1-
tertbutoxycarbonylamino-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-
ethynylcyclobutane
(0.098 g, 0.25 mmol) (prepared in example 4c) in dimethyl sulfoxide ( 1.5 mL)
was added to a
mixture of 2-amino-5-iodopyrimidine (0.07 g, 0.30 mmol), diethylamine (0.06
mL, 0.60
mmol) and a spatula-tip each of tetrakis(triphenylphosphine)palladium(0) and
copper(II)
iodide in dimethyl sulfoxide ( 1.5 mL). The reaction was stirred at 65-70oC
under an argon
atmosphere for 4h, was cooled, was diluted with ammonium chloride and water
and was
extracted with two portions of ethyl acetate. The organic extract was washed
three times with
water, once with brine, was dried (magnesium sulfate) and was evaporated.
Purification by
flash chromatography, eluting with 35:65 ethyl acetate : hexanes provided
product as an off
white foam (O.IOg, 66%), m.p.63-67oC.
Sb traps-1-Amino-3-l2-aminopyrimidin-5-ylethynyl)-3-(3-cyclopentyloxy-4-
methoxyphenyl)cyclobutane.A solution of traps-3-(2-aminopyrimidin-5-ylethynyl)-
1-
tertbutoxycarbonylamino-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclobutane (0.10
g, 0.20
ramol) in dichloromethane (5 mL) was treated with trifluoroactic acid (0.16
mL, 2 mmol) and
was stirred at room temperature under argon for 9d. The reaction was quenched
with sodium
bicarbonate and water and was extracted with three portions of 5/95
methanoUdichloromethane. The organic extract was dried (magnesium sulfate) and
evaporated. Purification by flash chromatography, eluting with 0.5:5:95
ammonium
hydroxide : methanol : dichloromethane provided product as a pale tan solid
(0.037g, 48%),
m.p.126-128oC.
Analysis Calcd for C22H26N4~2' H2~ : C 66.64, H 7.12, N 14.13; found: C 66.43,
H 6.81, N 13.87.
EXAMPLE 6
traps-1-Amino-3-l3-cyclopentyloxy-4-methoxvphenyl)-3-!3-
nitrophenyl)eth~ylcyclobutane. hydrochloride salt
6a traps-1-azido-3-(3-Cvclopentyloxy-4.-methoxyphenyl)-3-ethynylcyclobutane
A solution of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-ethynylcyclobutan-1-of
(3.35 g, 11.7
mmol) (prepared in example 4a) in tetrahydrofuran ( 125 mL) at OoC under an
argon
atmosphere in a foil-wrapped flask was treated with triphenylphosphine (6.14
g, 23.4 mmol),
then dropwise first with diethyl azodicarboxylate (3.7 mL, 23.4 mmol), then
with diphenyl
phosphorylazide (5.05 mL, 23.4 mmol). The reaction was stirred at room
temperature under
an argon atmosphere for 20h and was evaporated. Purification by flash
chromatography,
eluting with 1:99 ethyl acetate : hexanes provided product as a colorless oil
( 1.62 g, 61 %).
Further chromatography allowed recovery of cis-1-azido-3-(3-cyclopentyloxy-4-
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23
methoxyphenyl)-3-ethynylcyclobutane (0.12 g, 3%), containing ~10% traps isomer
(by 1H-
NMR).
6b traps-1-Azido-3-l3-cyclopentvlox~ -methoxmhen 1)-y 3-(3
nitrophenyl)eth~nvlcyclobutane. A solution of traps-1-azido-3-(3-
cyclopentyloxy-4
methoxyphenyl)-3-ethynylcyclobutane (0.20 g, 0.64 mmol) in triethylamine (5
mL) was
treated with 3-nitro-iodobenzene (0.14 mL, 0.64 mmol},
tetralcis(triphenylphosphine)palladium(0) (0.03 g, 4%) and copper(II) iodide
(0.008 g, 6%).
The reaction was stirred at 80-85aC under an argon atmosphere for O.Sh, was
cooled, was
diluted with water and was extracted with three portions of dichloromethane.
The organic
extract was dried (magnesium sulfate) and evaporated. Purification by flash
chromatography,
eluting with 1:9 ethyl acetate : hexanes provided product as a yellow aiI
(0.19g, 69%).
6c traps-1-Amino-3-!3-cyclopentyloxy-4-methoxyphenyl)-3-!3-
nitrophenyl_)ethvnylc~clobutane, hydrochloride salt. A solution of traps-1-
azido-3-(3-
cyclopentyloxy-4-methoxyphenyl)-3-(3-nitrophenyl)ethynylcyclobutane (0.19 g,
0.44 mmol)
in SO% ammoniacal methanol (5 mL) and pyridine (5 mL) was treated with
triphenylphosphine (0.35 g, 1.32 mmol). The reaction was stirred for 24h at
room
temperature under an argon atmosphere, was diluted with water and was
extracted with 5/95
methanol/dichloromethane. The organic extract was dried (magnesium sulfate)
and
evaporated. Purification by flash chromatography, eluting with 2:98 methanol
dichloromethane, followed by treatment of the free amine with hydrogen
chloride-diethyl
ether provided product as a tan solid (0.11 g, 59%}, m.p.l 13-1 l7aC.
Analysis Calcd for C24H26N204'HCh 0.75 H20 : C 63.15, H 6.29, N 6.14; found: C
63.14, H 5.90, N 5.92
Proceeding in a similar manner, the following compounds were made:.
traps-1-Amino-3-!3-cyclapentyloxy-4-methox~phenyl)-3-l4-
nitrophenyl)ethynvlcyclobutane, hydrochloride salt. : m.p.162-163aC. Analysis
Calcd for
C24H26N204'HCh H20 : C 62.54, H 6.34, N 6.07; found: C 62.56, H 5.94, N 5.
traps-1-Amino-3-!3-cyclopent~y-4-methoxyphenyl)-3-(4-
trifluoromethoxyphenyl)ethynvlcyclobutane. hydrochloride. SB 259835 A salt:
m.p.170-
174aC. Analysis Calcd for C25H26F3N03'HC1~0.65 H20 : C 60.83, H 5.78, N 2.84;
found:
C60.87,H5.58,N2.86.
cis-1-Amino-3-l3-cyclopentyloxy-4-methoxyphenyl)-3-phenylethynjrlcyclobutane
hydrochloride salt. SB259717 A : m.p.131-132aC. Analysis Calcd for
C24H27N02'HCh
1.75 H20 : C 67.12, H 6.57, N 3.26; found: C 67.05, H 6.20, N 3.15.
EXAMPLE 7
traps-1-Amino-3-f!3-carboxyphenyl)eth~nxll 3-!3-cyclopentyloxy-4-
methoxyphenyl)cyclobutane, hydrochloride salt
7a traps-1-Amino-3-f!3-carboxymethylphenyl)ethynyl] 3-!3-cyclo"pent~rloxy-4-
methoxyphenyl)cyclobutane . This product was prepared as the free amine, but
otherwise in a
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WO 99/52847 PCT/US99/07995
24
manner similar to traps-1-arilino-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(3-
nitrophenyl)ethynylcyclobutane, hydrochloride salt. m.p.70-72oC.
7b traps-1-Amino-3-f (3-carboxyphen l~th~nyll 3-(3-cyclopentyloxy-4-
rnethoxyphenyl)cyclobutane. hydrochloride salt. A solution of traps-1-amino-3-
[(3-
carboxymethylphenyl)ethynyl] 3-(3-cyclopentyloxy-4-methoxyphenylkyclobutane
(0.28 g,
0.68 mmol) and potassium hydroxide (0.12 g, 2.03 mmol) in tetrahydrofuran (5
mL),
methanol (5 mL) and water (2 mL) was stinred at room temperature under an
argon
atmosphere for 24h. The reaction was acidified with ethereal hydrogen chloride
and
evaporated. Purification by reverse-phase flash chromatography, eluting with
6:4 methanol
water provided free amine as a white solid (0.19 g, 71%), m.p.I77-
18(?°C. The free amine
was suspended in dichloromethane, was treated with ethereal hydrogen chloride,
was filtered
and was died. Resuspension in methanol,filtration, evaporation and drying
provided product
as a white solid (0.09 g, 29%), m.p. greater than 225oC. Analysis Calcd for
C25H27N04~HC1~ 3 H20 : C 60.54, H 5.69, N 2.82; found: C 60.38, H 5.74, N
2.69.
Proceeding in a similar manner, the following compound was made:
traps-1-Amino-3-f(4-carboxyphenyl)ethvnyll 3-(3-cvclopen tyloxy-4-
methoxYphenyl)cyclobutane. hydrochloride salt. :m.p.greater than 225oC.
Analysis Calcd for
C25H27N04~HC1~ 1.5 H20 : C 64.03, H 6.66, N 2.99; found: C 64.22, H 6.26, N
2.78.
UTILITY EXAMPLES
EXAMPLE A
Inhibitory effect of compounds of Fownula (I) and (IIl on in vitro TNF
production by human
~nonocvtes
The inhibitory effect of compounds of Formula (I) and (II) on in vitro TNF
production
by human monocytes may be determined by the protocol as described in Badger et
al., EPO
published Application 0 411754 A2, February 6, 1991, and in Hanna, WO
90/15534,
December 27, 1990.
EXAMPLE B
Two models of endotoxic shock have been utilized to determine in vivo TNF
activity
for the compounds of Formula (I) and (II}. The protocol used in these models
is described in
Badger et al., EPO published Application 0 411754 A2, February 6, 1991, and in
Hanna,
WO 90/15534, December 27, 1990.
The compound of Example 1 herein demonstrated a positive in vivo response in
reducing serum levels of TNF induced by the injection of endotoxin.
EXAMPLE C
Isolation of PDE Isozymes
The phosphodiesterase inhibitory activity and selectivity of the compounds of
Formula (I} and (11) can be determined using a battery of five distinct PDE
isozymes. The
tissues used as sources of the different isozymes are as follows: 1) PDE Ib,
porcine aorta; 2)
CA 02328250 2000-10-12
WO 99/52847 PCT/US99/07995
PDE Ic, guinea-pig heart; 3) PDE III, guinea-pig heart; 4) PDE 4, human
monocyte; and 5)
PDE V (also called "Ia"), canine trachealis. PDEs Ia, Ib, Ic and III are
partially purified using
standard chromatographic techniques [Torphy and Cieslinski, Mol. Pharmacol.,
37:206-214,
1990]. PDE 4 is purified to kinetic homogeneity by the sequential use of anion-
exchange
5 followed by heparin-Sepharose chromatography [Torphy et al., J. Biol. Chem.,
267:1798-
1804, 1992].
Phosphodiesterase activity is assayed as described in the protocol of Torphy
and
Cieslinski, Mol. Pharmacol., 37:206-214, 1990. Positive IC50's in the
nanomolar to E.iM
range for compounds of the workings examples described herein for Formula (I)
and (II) have
10 been demonstrated.
