Method for preparing substituted...

Details Method for preparing substituted... Method for preparing substituted...

2001-11-08

2002-09-17

Killos, Paul J. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C560S059000, C558S409000, C564S163000, C514S417000, C514S475000, C514S520000

Reexamination Certificate

active

06452022

ABSTRACT:

SCOPE OF THE INVENTION
This invention covers intermediates and a synthetic route for making 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexanoic acid and its analogs. This acid and its named analogs are selective for inhibiting the catalytic site in the phosphodiesterase isoenzyme denominated IV (PDE IV hereafter) and as such the acids are useful in treating a number of diseases which can be moderated by affecting the PDE IV enzyme and its subtypes.
AREA OF THE INVENTION
Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airway and hyper-reactivity of the respiratory tract to external stimuli.
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 major 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.
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 Excerpta Medica, 17-29, 1973]. When the appropriate agonist binds to specific cell surface receptors, adenylate cyclase is activated, which converts Mg
+2
-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: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation. Hence, 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 IV, 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 IV 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 IV inhibitors would be effective in the asthmatic lung, where levels of prostaglandin E
2
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 process and intermediates of this invention provide a means for making certain 4-substituted-4-(3,4-disubstitutedphenyl)cyclohexanoic acids which are useful for treating asthma, and other diseases which can be moderated by affecting the PDE IV enzyme and its subtypes. The final products of particular interest are fully described in U.S. Pat. No. 5,552,483 issues Sep. 3, 1996. The information and representations disclosed therein, in so far as that information and those representations are necessary to the understanding of this invention and its practice, in total, are incorporated herein by reference.
SUMMARY OF THE INVENTION
This invention relates a method for making a compound of formula I
where
R
1
is —(CR
4
R
5
)
n
C(O)O(CR
4
R
5
)
m
R
6
, —CR
4
R
5
)
n
C(O)NR
4
(CR
4
R
5
)
m
R
6
, —(CR
4
R
5
)
n
O(CR
4
R
5
)
m
R
6
, or —(CR
4
R
5
)
r
R
6
wherein the alkyl moieties may be optionally substituted with one or more halogens;
m is 0 to 2;
n is 1 to 4;
r is 0 to 6;
R
4
and R
5
are independently selected from hydrogen or a C
1-2
alkyl;
R
6
is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC
1-3
alkyl, halo substituted aryloxyC
1-3
alkyl, indanyl, indenyl, C
7-11
polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C
3-6
cycloalkyl, or a C
4-6
cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl group;
provided that:
a) when R
6
is hydroxyl, then m is 2; or
b) when R
6
is hydroxyl, then r is 2 to 6; or
c) when R
6
is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or
d) when R
6
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 R
6
is other than H in —(CR
4
R
5
)
n
O(CR
4
R
5
)
m
R
6
;
X is YR
2
, halogen, nitro, NH
2
, or formyl amine;
X
2
is O or NR
8
;
Y is O or S(O)
m′
;
m′ is 0, 1, or 2;
R
2
is independently selected from —CH
3
or —CH
2
CH
3
optionally substituted by 1 or more halogens;
R
3
is hydrogen, halogen, C
1-4
alkyl, CH
2
NHC(O)C(O)NH
2
, halo-substituted C
1-4
alkyl, —CH═CR
8′
R
8′
, cyclopropyl optionally substituted by R
8′
, CN, OR
8
, CH
2
OR
8
, NR
8
R
10
, CH
2
NR
8
R
10
, C(Z′)H, C(O)OR
8
, C(O)NR
8
R
10
, or C≡CR
8′
;
R
8
is hydrogen or C
1-4
alkyl optionally substituted by one to three fluorines;
R
8′
is R
8
or fluorine;
R
10
is OR
8
or R
11
;
R
11
is hydrogen, or C
1-4
alkyl optionally substituted by one to three fluorines;
Z′ is O, NR
9
, NOR
8
, NCN, C(—CN)
2
, CR
8
CN, CR
8
NO
2
, CR
8
C(O)OR
8
, CR
8
C(O)NR
8
R
8
, C(—CN)NO
2
, C(—CN)C(O)OR
9
, or C(—CN)C(O)NR
8
R
8
;
R′ and R″ are independently hydrogen or —C(O)OX where X is hydrogen or metal or ammonium cation;
which method comprises:
a) combining a Group I(a) or Group II(a) metal halide, with an aprotic dipolar amide-based solvent and water and a compound of formula A or B,
 where R
1
, R
3
, X
2
and X are the same as for formula (I);
b) heating the combination to a temperature of at least about 60° for several hours, optionally under an inert atmosphere;
c) precipitating out a compound of formula (I) by adding a strong base to said combination;
d) removing the amide-based solvent and water from said precipitate, and optionally
1) purifying further the precipitate, or
2) acidifying the precipitate to obtain the free acid.
SPECIFIC EMBODIMENTS OF THE INVENTION
This process involves the synthesis of certain 4-substituted-4-(3,4-disubstitutedphenyl)cyclohexanoic acids. It allows for converting a cyanoepoxide to its corresponding homologated acid via the use of a Group I(a) or II(b) salt intermediate.
The compounds which are made by this process are PDE IV inhibitors. They are useful for treating a number of diseases as described in U.S. Pat. No. 5,552,438 issued Sept. 3, 1996.
The preferred compounds which can be made by this process are as follows:
Preferred R
1
substitutents for the compounds of all named formulas are CH
2
—cyclopropyl, CH
2
—C
5-6
cycloalkyl, C
4-6
cycloalkyl unsubstituted or substituted with OHC
7-11
polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C
1-2
alkyl unsubstituted or substituted by 1 or more fluorines, —(CH
2
)
1-3
C(O)

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