Process for making 5-lipoxygenase inhibitors having varied...

Details Process for making 5-lipoxygenase inhibitors having varied... Process for making 5-lipoxygenase inhibitors having varied...

2000-06-29

2001-05-29

McKane, Joseph K. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S311100, C548S362500, C548S365700

Reexamination Certificate

active

06239285

ABSTRACT:

Reference is also made to copending application Ser. No. 60/113,221 filed Dec. 22, 1998, which discloses a novel process for preparing 4-{3-[4-(2-methyl-imidazol-1-yl)-phenyl sulfanyl]-phenyl}-tetrahydro-pyran-4-carboxylic acid amide methyl sulfonate. However, said disclosed process is not the same as that of the present invention.
Reference is further made to copending applications filed of even date with the instant application, Attorney Docket Nos. PC10530 and PC10682, which also involve processes of making 5-lipoxygenase inhibitors having varied heterocyclic ring systems and which have some process elements in common with the process of the instant application.
BACKGROUND OF THE INVENTION
There is disclosed in WO 96/11911 a class of novel compounds active as inhibitors of the activity of the 5-lipoxygenase enzyme, characterized by the following structural Formula (1.1.0):
wherein:
Ar
1
is a heterocyclic moiety selected from the group consisting of imidazolyl; pyrrolyl; pyrazolyl; 1,2,3-triazolyl; 1,2,4-triazolyl; indolyl; indazolyl; and benzimidazolyl; bonded to X
1
through a ring nitrogen atom; and substituted with 0-2 substituents selected from the group consisting of halo; hydroxy; cyano; amino; (C
1
-C
4
)alkyl; (C
1
-C
4
)alkoxy; (C
1
-C
4
)alkylthio; (C
1
-C
4
)halo-substituted alkyl; (C
1
-C
4
)halo-substituted alkoxy; (C
1
-C
4
)alkylamino; and di(C
1
-C
4
)alkylamino;
X
1
is a direct bond or (C
1
-C
4
)alkylene;
Ar
2
is phenylene substituted with 0-2 substituents selected from the group consisting of halo; hydroxy; cyano; amino; (C
1-C
4
)alkyl; (C
1
-C
4
)alkoxy; (C
1
-C
4
)alkylthio; (C
1
-C
4
)halo-substituted alkyl; and (C
1
-C
4
)halo-substituted alkoxy;
X
2
is —A-X— or —X-A— wherein A is a direct bond or (C
1
-C
4
)alkylene and X is oxy; thio; sulfinyl; or sulfonyl;
Ar
3
is a member selected from the group consisting of phenylene; pyridylene; thienylene; furylene; oxazolylene; and thiazolylene; substituted with 0-2 substituents selected from halo; hydroxy; cyano; amino; (C
1
-C
4
)alkyl; (C
1
-C
4
)alkoxy; (C
1
-C
4
)alkylthio; (C
1
-C
4
)halo-substituted alkyl; (C
1
-C
4
)halo-substituted alkoxy; (C
1
-C
4
)alkylamino; and di(C
1
-C
4
)alkylamino;
R
1
and R
2
are each (C
1
-C
4
)alkyl; or together they form a group of formula: —D
1
-Z-D
2
— which together with the carbon atom to which it is attached defines a ring having 3 to 8 atoms, wherein D
1
and D
2
are (C
1
-C
4
)alkylene and Z is a direct bond or oxy; thio; sulfinyl; sulfonyl; or vinylene; and D
1
and D
2
may be substituted by (C
1
-C
3
)alkyl; and
Y is CONR
3
R
4
; CN; C(R
3
)═N-OR
4
; COOR
3
; COR
3
; or CSNR
3
R
4
; wherein
R
3
and R
4
are each H or (C
1
-C
4
)alkyl.
With respect to the above-recited compounds, the preferred meaning for (C
1
-C
4
)halo-substituted alkyl is trifluoromethyl; and the preferred meaning for (C
1
-C
4
)halo-substituted alkoxy is trifluoromethoxy. A preferred group of the above-recited compounds consists of those wherein Ar
2
is 1,4-phenylene and Ar
3
is 1,3-phenylene or 5-fluoro-1,3-phenylene. Within said preferred group, more preferred compounds are those in which Ar
1
is 2-alkylimidazolyl; X
1
is a direct bond; and Y is CONH
2
; and those in which Ar
1
is pyrrolyl; X
1
is CH
2
; and Y is CONH
2
.
A particularly preferred embodiment of the above-described class of inhibitory compounds is the following compound of Formula (1.0.0):
Compounds which inhibit the action of lipoxygenase enzyme are useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals including humans. Lipoxygenase enzyme activity occurs as part of the arachidonic acid cascade. Arachidonic acid is the biological precursor of several groups of biologically active endogenous metabolites. Arachidonic acid is first released from membrane phospholipids via the action of phospholipase A2. Arachidonic acid is then metabolized (i) by cyclooxygenase to give prostaglandins including prostacyclin, and thromboxanes; or (ii) by lipoxygenase to give hydroperoxy fatty acids, which may be further converted to leukotrienes.
Leukotrienes, in turn, are extremely potent and elicit a wide variety of biological effects, e.g., peptidoleukotrienes, LTC
4
, LTD
4
, and LTE
4
, are important bronchoconstrictors and vaso-constrictors, and cause plasma extravasation by increasing capillary permeability. LTB
4
is a potent chemotactic agent which intensifies leukocyte infiltration and degranulation at a site of inflammation. Leukotrienes have been implicated in a number of human disease states including asthma, chronic obstructive pulmonary disease, allergic rhinitis, rheumatoid arthritis, gout, psoriasis, atopic dermatitis, adult respiratory distress syndrome (ARDS), and inflammatory bowel diseases including. Crohn's disease. An agent which actively inhibits lipoxygenases, and as a consequence the production of leukotrienes, will be of significant therapeutic value in treating acute and chronic inflammatory conditions. See Masamune and Melvin,
Annual Reports in Medicinal Chemistry
24, 71-80 (1989). Particular lipoxygenase inhibitors have been disclosed in EP 0 462 830; EP 0 505 122; and EP 0 540 165.
Several preparation processes for the lipoxygenase inhibitors described in above-mentioned published application WO 96/39408 are set forth therein. An example of such a preparation process is the coupling of a compound of Formula (1.2.0) and a compound of Formula (1.2.1), which may be represented by the reaction scheme set out below:
where Ar
1
is 2-methyl-imidazol-1-yl; X
1
is a direct bond; Ar
2
and Ar
3
are both phenylene; Y is CN; and R
1
and R
2
are taken together to form 3,4,5,6-tetrahydro-2H-pyran. X
2
is S, resulting in a thioether, and is formed by the reaction of the two Q displaceable groups, in the presence of thiourea and a suitable catalyst, e.g., tetrakis(triphenylphosphine)-palladium, and a reducing agent, e.g., sodium cyanoborohydride. Reference is made to
Chem. Lett.,
1379-1380 (1986); and U.S. Pat. No. 5,883,106 mentioned further above. Suitable displaceable groups Q are said to include a halo or sulfonyloxy group.
DESCRIPTION OF THE STATE OF THE ART
The present invention is in the field of methods used for synthetic preparation of compounds of the type of Formula (1.0.0), some of which are known compounds, some of which are novel compounds, and some of which are not in the public domain because they cannot be obtained using methods of preparation heretofore known in the art. All of the compounds, however, possess biological activity as inhibitors of 5-lipoxygenase.
In order to facilitate a more ready and complete understanding of the preparation processes of the present invention and their relationship to the state of the art, there follows Sysnthesis Scheme (10.0.0) which depicts the flow of reaction steps in a simplified manner and demonstrates the process parameters by means of specific exemplification.
SYNTHESIS SCHEME (10.0.0)
It will be noted from the synthesis scheme which follows that the first step in the preparation processes of the present invention involves the formation of a thioether by use of an alkylthio-de-halogenation technique analogous to the Williamson Reaction for alkoxy-de-halogenation. This step is catalyzed by a palladium catalyst which is used together with a member from a particular class of bidentate auxiliary ligands, e.g., BINAP.
After this first step, the next two succeeding steps in the preparation processes of the present invention both involve alternate routes. The second step, in which, e.g., the 2-methyl-imidazol-1-yl group is attached by fluorine atom displacement, may be carried out in two ways, identified in the synthesis scheme as (ii-a) and (ii-b). The first involves the use of cesium carbonate, Cs
2
CO
3
while the second involves the use of solid sodium hydroxide, NaOH, and optionally a catalytic amount of cesium carbonate, Cs
2
CO
3
, or of a phase transfer catalyst such as TBAC.
The third step involves two different approaches to preparing the mesylate salt

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