Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2000-03-01
2001-10-16
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C546S144000, C546S145000, C546S215000, C546S330000, C548S202000, C548S257000, C548S309700, C548S336100, C548S376100, C548S505000, C548S561000, C549S049000, C549S074000, C549S426000, C549S467000, C549S491000, C558S375000
Reexamination Certificate
active
06303782
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a novel process for preparing an aromatic compound substituted by a tertiary nitrile which is applicable to the preparation of a wide variety of compounds of this type. Such tertiary-nitrile-substituted aromatic compound final products comprise compounds of Formula (1.0.0):
wherein: the constituent parts W
1
, W
2
, W
3
, W
4
, and W
5
, and the substituent moieties R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and R
7
all have the meanings set out in detail further below. The process of the present invention may be illustrated by the follow reaction scheme:
The process of the present invention is one which is both facile and which affords acceptable yields of final product. The process of the present invention is distinguished from those heretofore available by the broad scope of its applicability, and by the criticality which has been discovered relating to the chemical makeup and reaction conditions of the base used to promote the reaction, as well as of the tertiary structure of the nitrile in the final product, both of which are described in detail further below.
The character of the base which is used in carrying out the process of the present invention is critical to obtaining the acceptable yields of tertiary-nitrile-substituted aromatic compound final product which serves to distinguish the process of the present invention from the processes of the prior art. The conjugate acid of the base which is used must have a pK
a
in the range of from about 17 to about 30. An example of a base which meets these critical requirements is the potassium, sodium or lithium salt of bis(trimethylsilyl)amide (KHMDS).
It has also been discovered in accordance with the present invention that the type of solvent which is used to carry out the reaction between a secondary nitrile and a substituted aromatic compound represents a choice which is critical to obtaining acceptable yields of final product. The solvent selected should be aprotic and have a dielectric constant (∈) of less than about 20. Toluene and tetrahydrofuran (THF) are examples of suitable solvents for use in the process of the present invention. The dielectric constant of THF is 7.6 and the dielectric constant of toluene is 2.4 (
Handbook of Chemistry and Physics
).
It will be appreciated that the nitrile reactant in the method of preparation of the present invention is “secondary”, referring to the degree of substitution of the carbon atom to which the nitrile moiety is attached. In the final products prepared by the method of the present invention, it will be further understood that the carbon atom to which the nitrile moiety is attached is “tertiary”, since it is not attached to any hydrogen atom.
The choice of the temperature at which the reaction mixture containing the secondary nitrile and aromatic compound is to be maintained is of less critical importance than the choice of the above-mentioned base or solvent. However, the proper reaction temperature is essential to obtaining acceptable yields of final product in accordance with the present invention, and should fall within the range of from about 0° C. to about 120° C.
The tertiary-nitrile-substituted aromatic compound final products prepared in accordance with the process of the present invention are characterized by a wide range of chemical structures and by a significant number of different practical utilities, which include both therapeutic and non-therapeutic applications of the said final products.
Preferred tertiary-nitrile-substituted aromatic compound final products prepared in accordance with the process of the present invention are those which are useful as therapeutic agents, especially inhibitors of phosphodiesterase type IV (PDE4). PDE4 inhibitors have applicability in therapeutic methods of treatment in humans and animals of many diseases, illnesses and conditions which are allergic or inflammatory in origin, especially including asthma, chronic obstructive pulmonary disease, bronchitis, rheumatoid arthritis and osteoarthritis, dermatitis, psoriasis, and allergic rhinitis.
Among such PDE4 inhibitors comprising tertiary-nitrile-substituted aromatic compound final products is a preferred class of selective PDE4 inhibitors disclosed in U.S. application Ser. No. 09/406,220, filed Sep. 27, 1999, now U.S. Pat. No. 6,127,398, issued Oct. 3, 2000; which is a division of U.S. application Ser. No. 08/963,904, filed Apr. 1, 1997, which is a continuation-in-part of U.S. provisional application Ser. No. 60/016861, filed May 3, 1996, now abandoned; and disclosed in International Application Ser. No. PCT/IB97/00323 based on said provisional application, filed Apr. 1, 1997, designating the United States, and published as WO 97/42174 on Nov. 13, 1997.
The above-mentioned preferred class of selective PDE4 inhibitors may be illustrated by the following generic Formula (4.0.0):
wherein R
a
is hydrogen, (C
1
-C
6
) alkyl phenyl or (C
1
-C
3
) alkyl-phenyl wherein said phenyl groups are optionally substituted by one or two —(C
1
-C
4
) alkyl, —O(C
1
-C
3
) alkyl, Br, or Cl; R is hydrogen, (C
1
-C
6
) alkyl, —(CH
2
)
n
(C
3
-C
7
) cycloalkyl where n is 0 to 2, or —(Z′)
b
(C
6
-C
10
) aryl where b is 0 or 1 and Z′ is (C
1
-C
6
) alkylene or (C
2
-C
6
) alkenylene, where said alkyl and aryl moieties of said R groups are optionally substituted by one or more halo, preferably F or Cl, hydroxy, (C
1
-C
5
) alkyl, (C
1
-C
5
) alkoxy, or trifluoromethyl; and R
1
is hydrogen, (C
1
-C
6
) alkyl phenyl, or (C
3
-C
7
) cycloalkyl, where said alkyl and phenyl R
1
groups are optionally substituted with up to 3 methyl, ethyl, trifluoromethyl, or halo. Said preferred class of selective PDE4 inhibitors may be further illustrated by more preferred specific compounds of Formulas (4.0.1) and (4.0.2):
A method for preparing the above-described class of selective PDE4 inhibitors is described in U.S. application Ser. No. 09/153,762, filed Sep. 15, 1998, now U.S. Pat. No. 6,005,118 issued Dec. 21, 1999; which is a continuation-in-part of U.S. provisional application Ser. No. 60/064211, filed Nov. 4, 1997 and now abandoned; and in the corresponding European application based on said continuation-in-part application, filed Nov. 2, 1998 and published as EP-A-0 915 089 on May 12, 1999. In particular, there is disclosed in the above-mentioned applications the following synthesis procedure for treating an indazole of Formula (2.1.0) with cyclohexane 1,4-dicarbonitrile of Formula (3.1.0) to yield a tertiary-nitrile-substituted aromatic compound final product of Formula (4.0.3):
The above-illustrated synthesis procedure is described as being carried out in the presence of a base such as lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide, or lithium 2,2,6,6-tetramethylpiperidine. The above-mentioned bases are described as being selective and as permitting desirably high levels of addition of cyclohexane-1,4-dicarbonitrile, Formula (2.0.1), to the R- and R
1
-substituted indazole, Formula (2.0.0), by displacement of the fluorine atom on the latter, while retaining both carbonitrile functionalities in place. It is further taught that it is preferred to use potassium bis(trimethylsilyl)amide (KHMDS) as the base promotant, in a solvent such as tetrahydrofuran, toluene, or xylene(s), preferably toluene, at a temperature between about 25° C. and about 125° C., preferably about 100° C., for a period of from 1 hour to 15 hours, preferably about 5 hours, in order to obtain acceptable yields of a tertiary-nitrile-substituted aromatic compound final product of Formula (1.0.0).
DESCRIPTION OF THE STATE OF THE ART
Loupy et al.,
Synth. Comm.,
1990, 20, 2855-2864, is concerned with the use of solid-liquid phase transfer catalysts without solvents to carry out S
N
Ar reactions on di- or mono-nitro halogeno compounds and unactivated aryl halides. The reaction is carried out with a nucleophile, e.g., Ph
2
CHCN, in the presence of a base, e.g., a stoichiometric a
Ginsburg Paul H.
McKenzie Thomas
Pfizer Inc
Richardson Peter C.
Shah Mukund J.
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