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

2002-02-05

Higel, Floyd D. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06344563

ABSTRACT:

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-triazotyl; 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-rected 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 pyrroyl; 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 in 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 chemotacbic 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 Repoits 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 X
1
is thio, and Q is a displaceable group in the presence of thiourea and a suitable catalyst, e.g., tetrakis(triphenylphosphine)-palladium. Reference is made to
Chem. Lett
., 1379-1380 (1986). 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.
As already noted above, it is known in the art that compounds of the type in Formula (1.0.0) may be prepared by a process which initially uses a palladium catalyzed nucleophilic substitution of aryl halides by thiolate anions or thiols themselves. As in the Williamson reaction, which is the best general method for preparing unsymmetrical as well as symmetrical ethers, yields are improved by phase transfer catalysis. For a detailed treatment of the use of phase transfer catalysis in the preparation of sulfur-containing compounds, see, e.g., Weber; Gokel
Phase Transfer Catalysis in Organic Synthesis
, Springer; New York, 221-233 (1977). Further details concerning the initial stage of the process of the present invention may be found in Migita et al.,
Bull. Chem. Soc
. Japan 53, 1385-1389 (1980). Said initial stage may be represented by the following reaction scheme:
where X is I or Br; and R is phenyl or (C
1
-C
4
) alkyl.
The technical literature contains a number of disclosures relating to palladium-catalyzed synthesis. See, e.g., Brocato et al.,
Tetrahedron Lett
. 33, 7433 (1992), which describes ring formation based on the palladium-, especially Pd(PPh
3
)
4
,-catalyzed reaction of bifunctional aromatic compounds with terminal alkynes and carbon monoxide, requiring both palladium(0) and palladium(II) catalysts.
Arcadi et al.,
Tetrahedron Lett
. 34, 2813 (1993) discloses synthesis of 2,3,5-trisubstituted furans from aryl halides and 2-propargyl-1,3-dicarbonyl compounds in the presence of tetrakis(triphenylphosphine)palladium(0) and K
2
CO
3
. The authors observe that the nature of the base strongly affects the reaction course.
McClure and Danishefsky,
J. Am. Chem. Soc
. 115, 6094-6100 (1993) discloses synthesis of 1,5-epoxybenzazocine congeners in 90% yield using catalytic tetrakis(triphenylphosphine)-palladium(0) in acetonitrile containing triethylamine.
Nuss et al,
J. Am. Chem. Soc
. 115, 6991-6992 (1993) discloses synthesis of neocarzinostatin chromophore analogs using catalytic tetrakis(triphenylphosphine)-palladium(0) in THF and alkynyl stannane reactants.
Paquette and Astles,
J. Org. Chem
. 58, 165-169 (1993) discloses synthesis of furanocembranolides with side chain extension mediated by palladium(0) catalyzed coupling to vinylstannane performed in refluxing benzene or dimethoxyethane. The authors note that the reaction is solvent-dependent, with a change to chloroform being particularly beneficial.
T

Affiliated with

Also associated with

Rating

Process for making 5-lipoxygenase inhibitors having varied... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for making 5-lipoxygenase inhibitors having varied..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for making 5-lipoxygenase inhibitors having varied... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2954922