Process for preparing...

Details Process for preparing... Process for preparing...

2000-03-01

2001-12-04

Dentz, Bernard (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S119000

Reexamination Certificate

active

06326495

ABSTRACT:

BACKGROUND OF THE INVENTION
The class of compounds prepared in accordance with the present invention have been named herein as 8-cyclopentyl-6-ethyl-3-[substituted]-5,8-dihydro-4H-1,2,3a,7,8-pentaaza-as-indacenes, although this class of compounds has been referred to in the art as being tricyclic 5,6-dihydro-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridines. In whatever preferred manner said class of compounds is named, however, the compounds prepared in accordance with the process of the present invention are represented by the following Formula (1.0.0):
where R
1
is a member selected from the group consisting of hydrogen; (C
1
-C
6
) alkyl; (C
1
-C
4
) alkoxy; (C
1
-C
4
) alkoxy(C
1
-C
4
) alkyl; (C
2
-C
8
) alkenyl; (C
3
-C
7
) cycloalkyl and 1′-methyl thereof, (C
3
-C
7
) cycloalkyl(C
1
-C
2
) alkyl; a saturated or unsaturated (C
4
-C
7
) heterocyclic-(CH
2
)
m
—group where m is 0, 1, or 2, comprising one or two heteroatoms selected from O, S, S(═O)
2
, N, NR
3
, O and N or NR
3
, S or S(═O)
2
and N or NR
3
, and N or N
3
and N or NR
3
, where R
3
is hydrogen or (C
1
-C
4
) alkyl; and a group of Formula (1.1.0):
where a is 1-5, and b and c are 0 or 1; R
5
is hydrogen, hydroxy, (C
1
-C
4
) alkyl, (C
2
-C
4
) alkenyl, (C
1
-C
4
) alkoxy, (C
3
-C
6
) cycloalkoxy, halogen, trifluoromethyl, CO
2
R
3a
, CONR
3a
R
3b
, NR
3a
R
3b
, NO
2
, or SO
2
NR
3a
R
3b
; where R
3a
and R
3b
are independently hydrogen or (C
1
-C
4
) alkyl; Z is O, S, S(═O)
2
, C(═O), or NR
3
; and Y is —(C
1
-C
4
) alkylene- or —(C
2
-C
4
) alkenylene-, either of which is optionally mono-substituted by hydroxy; wherein each above-recited alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic group is substituted by 0 to 3 substituents selected from (C
1
-C
2
) alkyl, trifluoromethyl, and halogen.
The above-described pentaaza-as-indacenes are known compounds having biological activity as inhibitors of phosphodiesterase type IV (PDE4) and the production of tumor necrosis factor (TNF). That biological activity makes said pentaaza-as-indacenes useful in the treatment of various inflammatory, allergic and immunological diseases and conditions, which include asthma, bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, psoriasis, dermatitis, and rheumatoid arthritis. The above-mentioned therapeutic utilities of said pentaaza-as-indacenes are well established and accepted in the art, as shown, e.g., by the published application WO 96/39408 already noted further above. The use of inhibitors of PDE4 and TNF in the treatment of inflammatory, allergic and immunological diseases and conditions is also well known in the art. See, e.g., WO 95101980 published on Jan. 19, 1995, and WO 96/12720 published on May 2, 1996.
A preparation process for 8-cyclopentyl-6-ethyl-3-[substituted]-5,8-dihydro-4H -1,2,3a,7,8-pentaaza-as-indacenes which is known in the art and described in above-mentioned published application WO 96/39408, uses a p-methoxyphenyl N-protecting group in the initial stages of the synthesis. The overall preparation process, depicted for the species where R
1
is 2-thienyl, is represented by reaction Scheme 1 set out further below.
In step a of the overall synthesis, 2-pyrrolidinone and 4-iodoanisole are heated in the presence of copper powder and potassium carbonate to give the N-(4-methoxyphenyl)pyrrolidin-2-one, which in step b is treated with ethylmagnesium bromide Grignard reagent to give an aliphatic ketone after ring opening of the pyrrolidinone. This ketone is isolated and then undergoes ring closure to form the 3-hydroxy-1,2,5,6-tetrahydropyridin-2-one intermediate in steps c and d using ethyl oxalyl chloride and sodium hydroxide in step c and sodium ethoxide and ethanol in step d. The corresponding 3-methoxy intermediate is obtained in step e by treatment with 3-methyl-p-tolyltriazine, after which in step f the 4,5,6,7-tetrahydro-7-oxo-1H-pyrazolo[3,4-c]pyridine intermediate is obtained by ring closure using cyclopentyl hydrazine hydrochloride. The 4-methoxyphenyl N-protecting group is removed in step g by treatment with cerium (IV) ammonium nitrate to give the lactam intermediate, after which in step h the lactam intermediate is converted to the corresponding thiolactam intermediate by treatment with phosphorus pentasulfide. The tricyclic final product is prepared in steps i′, j and k by treatment with anhydrous hydrazine in step i, followed by treatment with 2-thiophene carbonyl chloride in step j and refluxing in step k.
The above-described method of the prior art suffers from a number of disadvantages, however. Step a for example, is a neat reaction carried out in the presence of copper powder and potassium carbonate at a temperature of about 150° C. When carried out at a scale larger than that used for exploratory synthesis, the reaction of step a becomes exothermic and may form an intractable solid mass upon cooling unless the solvent, e.g., ethyl acetate, is added immediately to the crude melt comprising the reaction mixture. Further, in step e the cost of the triazine reactant, 3-methyl-p-tolyltriazine, is sufficiently high that it creates a problem with the overall economics of the process in Scheme 1, especially when considered in light of the fact that the yields in virtually all of the steps in the process of Scheme 1 are sub-optimal.
Moreover, in step b the aliphatic ketone prepared with the aid of the Grignard reagent, ethylmagnesium bromide, may be carried out in ethyl ether with substantially no problems, but in tetrahydrofuran, a much less problematic solvent, there is a tendency for side reactions to take place, leading to side products and potential stability problems. The p-methoxyphenyl protected amino ketone prepared in step b may be sufficiently unstable that it cannot be stored. Other problems may arise with regard to the synthesis and purification of the cyclopentyl hydrazine reactant; and the ceric ammonium nitrate deprotection of the p-methoxyphenyl amide.
Still further problems may be encountered with the procedures entailed in the use of thiolactam chemistry to introduce the triazole component of the tricyclic nucleus of the final products. These include the use of anhydrous hydrazine when introducing the triazole ring with thienoyl chloride. Anhydrous hydrazine is a hazardous chemical substance, fuming in air, and capable of exploding during distillation if traces of air are present. Accordingly, there is a currently unfilled need in the art for a process of preparing 8-cyclopentyl-6-ethyl-3-[substituted]-5,8-dihydro-4H-1,2,3a,7,8-pentaaza-as-indacenes which is less problematic, is more facile, and has greater economic feasibility. Responsive to that need, the process of preparation of the present invention is presented in detail herein.
DESCRIPTION OF THE STATE OF THE ART
The present invention is in the field of methods used for synthetic preparation of 8-cyclopentyl-6-ethyl-3-[substituted]-5,8-dihydro-4H-1,2,3a,7,8-pentaaza-as-indacenes, which are known compounds which possess biological activity as selective inhibitors of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF). Consequently, the process of the present invention have direct beneficial utility in providing the art with an improved method for obtaining compounds which are in turn known to be useful in the treatment of asthma, arthritis, bronchitis, chronic obstructive airway disease, psoriasis, allergic rhinitis, dermatitis, and other inflammatory diseases, AIDS, septic shock and other diseases in mammals, especially humans.
Since the recognition that cyclic adenosine phosphate (AMP) is an intracellular second messenger, e.g., in E. W. Sutherland, and T. W. Rall,
Pharmacol. Rev.,
12, 265, (1960), inhibition of the phosphodiesterases has been a target for modulation and, accordingly, therapeutic intervention in a range of disease processes. More recently, distinct classes of PDE have been recognized, e.g., in J. A. Beavo et al.,
TiPS,
11, 150, (1990), a

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