Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-09-20
2002-05-21
Raymond, Richard L. (Department: 1609)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S253010, C514S254060, C514S257000, C514S403000, C540S575000, C544S251000, C544S363000, C544S371000, C548S361100, C548S362500
Reexamination Certificate
active
06391872
ABSTRACT:
Descriptive reference is made to catechol-containing protein tyrosine kinase receptor antagonists which are useful in treating hyperproliferative diseases in U.S. application Ser. No. 08/653,786 filed May 28, 1996, now U.S. Pat. No. 5,747,498 issued May 5, 1998; International application Ser. No. PCT/IB95/00436 filed Jun. 6, 1995, designating the United States, and published as WO 96/30347 on Oct. 3, 1996; and U.S. application Ser. No. 60/020,491 filed Jun. 24, 1996, now abandoned, filed as International application Ser. No.
PCT/IB97/675 filed Jun. 11, 1997, designating the United States, and published as WO 97/49688 on Dec. 31, 1997; the disclosures of all of which are incorporated herein by reference in their entireties.
Descriptive reference is also made to non-catechol-containing protein tyrosine kinase receptor antagonists useful in treating hyperproliferative diseases in U.S. application Ser. No. 08/682,565 filed Jan, 27, 1995, now U.S. Pat. No. 5,736,534 issued Apr. 7, 1998, corresponding to International application Serial No. PCT/IB95/00061 filed Jan. 27, 1995, and published as WO 95/23141 on Aug. 31, 1995; U.S. application Ser. No. 08/449,381 filed May 23, 1995, now U.S. Pat. No. 5,593,997 issued Jan. 14, 1997; and International application Seri. No. PCT/US95/07881 filed Jun. 7, 1995, designating the United States, and published as WO 96/40142 on Dec. 19, 1996; the disclosures of all of which are incorporated herein by reference in their entireties.
FIELD OF THE INVENTION
The present invention is in the field of compositions of matter, and pharmaceutical compositions and methods of treatment utilizing one or more of said compositions of matter as the active ingredient and the active agent with respect thereto, wherein said composition of matter comprises an indazole moiety as an essential feature of its overall chemical structure. Further, said indazole constitutes a bioisosteric replacement of a catechol moiety or functional derivative thereof in an original composition of matter in which said catechol moiety has been subject to bioisosteric replacement by said indazole moiety. The type and extent of biological activity found in said original composition of matter is retained and even increased and improved in said indazole bioisostere thereof.
BACKGROUND OF THE INVENTION
The term “catechol” as used herein refers to 1,2-benzenediol, sometimes referred to as “pyrocatechol”, which may be represented by Formula (1.0):
The name is derived from catechin or catechu which in turn refer to a slightly more complex composition derived from Acacia catechu. As a distinct chemical group or moiety, catechol is a key component of number of different molecules having pharmacological activity and consequently, usefulness as therapeutic agents.
The present invention is concerned with the discovery that the indazole nucleus is a moiety which is capable of being a bioisostere replacement for a catechol moiety comprising a functionally essential part of the makeup of compounds which are therapeutically active as a result of their fundamental operation as endogenous ligands, enzyme inhibitors, receptor antagonists, substrate mimics, regulating and signalling entities such as the chemokines, by means of which they carry out essential metabolic functions in the body.
Thus, in accordance with the present invention it has been discovered that the indazole nucleus is a bioisostere replacement for the catechol moiety which is an essential part of many classes and types of compounds, including numerous drugs which have been and will in the future be created and developed for therapeutic treatments as detailed further herein. This bioisostere replacement will be better understood from the following structural representation of the catechol moiety and the indazole moiety which replaces it, which may be represented respectively by Formulas (1.1) and (1.2):
It will be understood that the substituent “R
3
” in the above Formulas (1.1) and (1.2) is a generalized illustration, ie., it represents the possibility of more than one substituent as well as substitution at more than one position of the phenyl ring, and further, includes essentially all of the structural elements of all of the catechol-containing compounds for which the indazole-for-catechol bioisostere replacement of the present invention may be carried out.
Consequently, it will be understood that the terms “bioisostere”, “bioisosteric replacement”, “bioisosterism” and closely related terms as used herein have the same meanings as those generally recognized in the art. Bioisosteres are atoms, ions, or molecules in which the peripheral layers of electrons can be considered identical. The term bioisostere is usually used to mean a portion of an overall molecule, as opposed to the entire molecule itself. Bioisosteric replacement involves using one bioisostere to replace another with the expectation of maintaining or slightly modifying the biological activity of the first bioisostere. The bioisosteres in this case are thus atoms or groups of atoms having similar size, shape and electron density.
Included within the scope of the bioisostere indazole-for-catechol replacements of the present invention are a number of catechol-containing compounds which have a third hydroxy or derivative group, —OR
X
, on a third carbon of the phenyl ring, usually adjacent to one of the two carbons comprising the catechol moiety. Compounds of this type may be illustrated by Formula (1.3) and exemplified by cinepazet of Formula (6.8):
In this type of catechol moiety, which is described herein as having an “additional —OR
X
substituent”, the indazole-for-catechol bioisostere replacement of the present invention may “include” or “exclude” said additional —OR
X
substituent.
Where the additional —OR
X
substituent is included in the bioisostere replacement, all three of the —OR groups, including said additional substituent —OR
X
, are replaced by the indazole group, in effect as though the additional —OR
X
substituent were not present at all. On the other hand, where said additional —OR
X
substituent is excluded from the bioisostere replacement, it will remain as a substituent at the same position of the phenyl ring, but as part of the indazole ring. The case of indazole-for-catechol bioisostere replacement which includes said additional —OR
X
substituent may be illustrated by Formulas (1.3) and (1.4):
The case of indazole-for-catechol bioisostere replacement which excludes said additional —OR
X
substituent may be illustrated by Formulas (1.3) and (1.5):
Both the inclusionary and exclusionary indazole-for-catechol bioisostere replacements described above may be further illustrated in the case of cinepazet by Formulas (1.6) and (1.7), respectively, as follows:
Bioisosterism has often been viewed as arising from a reasonable expectation that a proposed bioisosteric replacement will result in maintenance of similar biological properties. Such a reasonable expectation may be based on structural similarity alone. This is especially true in those cases where a number of particulars are known regarding the characteristic domains of the receptor, etc. involved, to which the bioisosteres are bound or which works upon said bioisosteres in some manner. In the case of the present invention, however, there is a complete lack of such structural similarity, and the significant number of different therapeutic classes in which this indazole-for-catechol bioisostere replacement may be successfully employed belies any straightforward predictability. These various therapeutic classes will be reviewed briefly before being described in detail further below.
One class of catechol-containing compounds having significant pharmacological and therapeutic activity that is very well-known are the catecholamines. These catecholamines, typically epinephrine, norepinephrine and dopamine, are released by the sympathetic nervous system and by the adrenal medulla and perform an important function in the mammalian body by regulating innumerable aspects of its physiology, especially the myriad
Ginsburg Paul H.
Pfizer Inc
Raymond Richard L.
Richardson Peter C.
Speer Raymond M.
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