AP910A

AP910A - Indazole bioisostere replacement of catechol in therapeutically active compounds.

Info

Publication number: AP910A
Application number: APAP/P/1998/001375A
Authority: AP
Inventors: Anthony Mafrat
Original assignee: Pfizer Prod Inc
Priority date: 1997-11-04
Filing date: 1998-10-29
Publication date: 2000-12-05
Also published as: CA2309150A1; JP2001521926A; DZ2640A1; TNSN98200A1; HUP0004150A2; NZ503918A; PL340753A1; TR200001234T2; BG104450A; EA200000488A1; IS5465A; US6391872B1; WO1999023077A1; BR9813926A; YU25000A; NO20002129D0; PE129199A1; CZ20001621A3; AU9455298A; EP1028946A1

Abstract

Therapeutically active compositions of matter and "member species thereof are described which comprise indazole-containing compounds, said compounds and their therapeutic activity resulting directly from an indazole-for-catechol bioisostere replacement of a catechol-containing compound having the same therapeutic activity, where non-catechol substituents are the same or homologous before and after said replacement, and wherein said compositions of matter comprise a compound of Formula (I1) or (I2): or a pharmaceutically acceptable salt thereof, wherein in a preferred embodiment R° is hydrogen; RA is cyclohexyl; and RB is ethyl. Ra and Rb are each individually and independently hydrogen or non-catechol substituents of said compounds resulting directly from an indazole-for-catechol bioisostere replacement of said catechol-containing compound having said therapeutic activity, where said non-catechol substituents are the same or homologous before and after said replacement, provided that both of Ra and Rb cannot be hydrogen at the same time. The therapeutic activity involved may comprise cholinesterase inhibitory activity, adrenergic cc,-antagonist and (3,-agonist activity, calcium channel inhibitory activity, antineoplastic activity, and phosphodiesterase type IV inhibitory activity.

Description

INDAZOLE BIOISOSTERE REPLACEMENT OF CATE-

CHOL IN THERAPEUTICALLY ACTIVE COMPOUNDS

REFERENCE TO CO-PENDING AND OTHER RELATED APPLICATIONS

Descriptive reference is made to catechol-containing protein tyrosine kinase receptor antagonists which are useful in treating hyperproliferative diseases in U.S. application Serial No. 08/653,786 filed May 28, 1996 (Attorney Docket No. PC8836B), now U.S. Pat. 5,747,498 issued May 5, 1998; International application Serial No. PCT/IB95/00436 filed June 6, 1995, designating the United States (Attorney Docket No. PC8836A), and published as WO 96/30347 on October 3, 1996; and U.S. application Serial No. 60/020491 filed June 24, 1996 (Attorney Docket No. 9365), now abandoned, filed as International application Serial No. PCT/IB97/675 filed June 11, 1997, designating the United States (Attorney Docket No. PC9365A), and published as WO 97/49688 on December 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 Serial No. 08/682565 filed January 27, 1995 (Attorney Docket No. PC8651A), now U.S. Pat. 5,736,534 issued April 7, 1998, corresponding to International application Serial No. PCT/IB95/00061 filed January 27, 1995 (Attorney Docket No. PC8651A), and published as WO 95/23141 on August 31, 1995; U.S. application Serial No. 08/449381 filed May 23, 1995 (Attorney Docket No. PC8865), now U.S. Pat. 5,593,997 issued January 14, 1997; and international application Serial No. PCT/US95/07881 filed June 7, 1995 (Attorney Docket No. PC8934), designating the United States, and published as WO 96/40142 on December 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):

CATECHOL

(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 .-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 iigands, 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):

(1-1) (1.2)

It will be understood that the substituent “R3” in the above Formulas (11) and (1.2) is a generalized illustration, i.e., 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, -ORX, 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): I

I

I (1.3) (6.8)

In this type of catechol moiety, which is described herein as having an “additional | -OR* substituent”, the indazole-for-catechol bioisostere replacement of the present invention j may “include” or “exclude” said additional -OR* substituent. «

Where the additional -OR* substituent is included in the bioisostere replacement, all three of the -OR groups, including said addtional substituent -OR*, are replaced by the indazole group, in effect as though the additional -OR* substituent were not present at all. On the other hand, where said addtional -OR* 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* substituent may be

illustrated by Formulas (1.3) and (1.4): (1-3) (1.4)

The case of indazole-for-catechol bioisostere replacement which excludes said additional -OR* substituent may be illustrated by Formulas (1.3) and (1.5):

(1.3) (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:

(1.6) (1.7)

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 b 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 responses of said body to multiple stresses which it encounters every day. The chemical structure of norepinephrine is representative and may be illustrated by Formula (2.0):

NOREPINEPHRINE

(2.0)

Numerous sympathomimetic drugs, which act as agonists and antagonists for the receptors of-said catecholamines utilize the catechol component as a key part of their overall chemical structure. The major classes of agonists and antagonists for said receptors of catecholamines, to which the indazole-for-catechol bioisostere replacement of the present invention is applicable, are described in the paragraphs which follow.

Cholinesterase inhibitors, i.e., anticholinesterase agents which have a catechol moiety as a central and characteristic portion of their overall chemical structure, are active in the inhibition of acetylcholinesterase, with the consequent accumulation of endogenous acetylcholine. As a result, such catechol-containing anticholinesterase agents have therapeutic utility in the treatment of glaucoma, the facilitation of gastrointestinal and bladder motility, and in combatting cognitive dysfunction and other aspects of Alzheimer’s disease.

Acetylcholinesterase is the enzyme responsible for the breakdown of the neurotransmitter acetylcholine and thus in terminating its action at the junctions of various cholinergic nerve endings with their effector organs or postsynaptic sites. Anticholinesterase agents inhibit acetylcholinesterase and thereby cause acetylcholine to accumulate at cholinergic receptor sites. Their actions are thus cholinomimetic and produce effects equivalent to excessive stimulation of cholinergic receptors throughout the central and peripheral nervous sytems. Cholinergic neurons are widely distributed in the body, and many anticholinesterase agents have been discovered to date, several of them being widely used as therapeutic agents.

Adrenergic ατ-antagonists and β-ι-agonists interact with certain of the four different catecholamine receptors in mammals, each of which has a distinctive response pattern. These receptors have been designated the a,-, a2-, Pr. ar|d P2-adrenergic receptors, and they occur in many different tissues and have various physiological effects. In particular, they play a very significant role in maintaining the activities of the sympathetic nervous system, which is responsible for mediating or regulating innumerable bodily functions. The areas controlled by the sympathetic nervous system are so essential and so diverse that it has long been the focus of medicinal chemists endeavoring to discover drugs which can antagonize, modify or even imitate its activity and thus become useful in the treatment of such important clinical conditions as hypertension, arrhythmias, cardiovascular shock, asthma, anaphylactic reactions, and migraine headaches.

For example, a.-,-adrenergic receptors may be found in the intestine where they are responsible for decreased motility, in the salivary glands where they regulate potassium and water secretion, in the iris of the eye where they play a role in contraction of the iris, in vascular smooth muscle where they mediate contraction, and in the tissue of the heart where they play a role in providing increased contractile force and in regulating the rhythm of heart muscle contractions.

The cx2-adrenergic receptors are located in the stomach where they result in decreased motility, in fat cells where they cause decreased lipolysis, in blood platelets where they are part of the process of aggregation, in pancreatic β cells where they have the effect of decreasing secretion, and in vascular smooth muscle where they regulate contraction. There are also tissues in which the particular α-adrenergic receptor subtype has not yet ber identified. These include the bladder sphincter where they effect contraction, and in arterioles found in the skin and mucosa, where they mediate constriction.

The β,-adrenergic receptors occur in heart tissue where they provide increased rate, force and depth of contraction. The β2^ΓβηβΓςΐο receptors occur in bronchial and lung tissue where they produce muscle relaxation, in liver tissue where they mediate increased glycogenolysis, and in the intestine where they are also responsible for decreased motility.

The mediatory contribution of the α,-, α2-, βτ, and β2-8άΓεηεφο receptors in the body can be modified or eliminated by the use of therapeutic agents which have antagonistic activity. Such antagonists tend to nullify the action of the active agents, e.g., neurotransmitters such as dopamine, by being bound to said receptors without, however, eliciting a biological response. The inhibitory potency of an antagonist is largely a measure of the ability of said antagonist to be bound preferentially and tightly to said receptor so as to competitively displace the natural ligand for said receptor. Accordingly, a compound whk has the essential structural features of a catecholamine or catechol that are required for it to be competitively bound to one or more of the α·,-. α2-, β,-, and β^,-θάΓεηβΓςϊο receptors, can function as a pharmaceutical active ingredient. Such an active ingredient would be suitable for the therapeutic treatment of any disease or condition whose treatment or prevention, or the amelioration of whose symptoms would tend to be accomplished by the antagonism, i.e., blockade of any one or more of the receptors for which a catecholamine or catechol type compound is the natural ligand in the body.

In the same manner, the mediatory contribution of the α,-. α2-, β,-, and β^ύΓβηεφιο receptors in the body can be modified or enhanced by the use of therapeutic agents which have agonist activity. Such agonists are structural analogs of catecholamines or catechols 1 which bind productively to a receptor and mimic its biological activity. Thus, an agonist is comparable to an alternative substrate for an enzyme. The binding of the agonist to the receptor is productive in that the metabolic response which is evoked is comparable to that which would result if the natural ligand were bound to said receptor. Accordingly, in the case of agonists a compound which has the essential structural features of a catecholamine or catechol that are required for it not only to be bound to one or more of the a·,-, α2-, β,-, and p2-adrenergic receptors, but also for it to be capable of producing a positive metabolic response, can function as a pharmaceutical active ingredient. Such an active ingredient would be suitable for the therapeutic treatment of any disease or condition whose treatment or prevention, or the amelioration of whose symptoms would tend to be accomplished by agonist activity, i.e., by being bound to any one or more of the receptors for which a catecholamine or catechol type compound is the natural ligand in the body, and further producing a positive metabolic response, usually of the type produced by said natural ligand.

An example of a β! -agonist is the active therapeutic agent isoproterenol, which may be represented by Formula (3.0):

ISOPROTERENOI (3.0)

Calcium channel antagonists comprise numerous endogenous ligands acting on important calcium channel receptors and thereby carrying out essential metabolic, especially cardiovascular functions in the body. Calcium channel antagonists, particularly those of the verapamil type, have a catechol moiety as a central and characteristic portion of their overall chemical structure, and they are therapeutically useful in the area of antihypertensive treatment, and in the cardiovascular field they are especially useful, often having activity as antianginal and antiarrhythmic agents in addtion to their antihypertensive utility. Calcium channel antagonists are especially useful in the treatment of variant agina; exertional angina, unstable angina, hypertension, myocardial ischemia, arrhythmia, and migraine prophylaxis.

Other calcium channel antagonists and related compounds having a catechol moiety as an essential part of their overall chemical structure, for which the indazole bioisosteres of the present invention possess equivalent or improved biological activity, comprise gallopamil; fantofarone, which possesses calcium transport inhibitory properties, as well as bradycardic, hypotensive and antiadrenergic properties, for which the indazole replacement bioisosteres are useful in the treatment of angina pectoris, hypertension, arrhythmia and cerebral circulatory insufficiency, as well as in the antitumor field, where it is a potentiator of anticancer chemotherapeutic agents; trimetazidine, which is a peripheral vasodilator whose action is exerted both on the peripheral circulation and on the coronary arteries, a mechanism involving the smooth muscle fibers of the vessel walls of the circulatory system and not the autonomous

nervous system, for which the indazole replacement bioisosteres are useful in treating various circulatory disorders such as arteritis or coronary insufficiency; lomerizine, for which the indazole replacement bioisosteres are useful as agents for improving cerebrovascular diseases of humans, and in particular are antimigraine agents; and zatebradine, for which the indazole replacement bioisosteres have iong-lasting bradycardiac activity and reduce the oxygen requirements of the heart, with only slight side effects such as antimuscarinic activity.

Cerebrovascular diseases, which are beneficially treated with the indazole replacement bioisosteres of the present invention, include intracranial hemorrhages such as intracerebral hemorrhage or subarachnoid hemorrhage, as well as cerebral infarctions such as cerebral thrombosis or cerebral embolus, transient ischemic attack, and hypertensive encephalopathy. A key mechanism in these diseases is infaction of brain parenchymal tissue resulting directly from hemorrhage, thrombus, or an embolus within the brain, which leads in turn to glucose and oxygen insufficiency, depriving the neurons of needed sources of energy. Functional and organic disturbances result in the ischemic area. Consequently, the indazole replacement bioisosteres of the present invention act as therapeutic agents which supply or enhance the supply of glucose and oxygen to the ischemic area by increasing cerebral blood flow, and are, therefore, effective for the treatment and prevention of such cerebrovascular diseases.

Antineoplastic and antiproliferative agents of the present invention include indazole bioisostere replacement compounds based on trimetrexate, which is an antifolate, i.e., an inhibitor of dihydrofolate reductase, and related to methotrexate, which has provided consistent cure of choriocarcinoma. The indazole replacement bioisosteres based on trimetrexate are lipid-soluble folate antagonists which facilitate penetration of the blood-brain barrier. These bioisosteres may also be used in the therapy of psoriasis, a non-neoplasti disease of the skin characterized by abnormally rapid proliferation of epidermal cells, as well as for the beneficial treatment of Pneumocystis carinii.

Therapeutic agents of the present invention useful in the treatment of neoplastic diseases also comprise indazole replacement bioisosteres which are protein tyrosine kinase inhibitors. Protein tyrosine kinase inhibitors play a fundamental role in signal transduction pathways, and deregulated protein tyrosine kinase activity has been observed in many proliferative diseases such restenosis in addition to cancer and psoriasis. A number of tumor types have disfunctional growth factor receptor protein tyrosine kinases which result in inappropriate mitogenic signalling; consequently, the indazole replacement bioisosteres are useful for the therapeutic treatment of cancer based on their inhibition of protein tyrosine kinases including particularly epidermal growth factor-receptor protein tyrosine kinase (EGF-R PTK). Especially potent and selective inhibitors of epidermal growth factor-receptor protein tyrosine kinases are indazole replacement bioisosteres which are 4-anilino-quinazolines, e.g., the compound PD-153,035.

Indazole replacement bioisosteres of the present invention also include those wherein the 4-position is occupied by bicyclic aminoheteroaromatic moieties or by heterocyclyl-substituted-6,7-dimethoxy-quinazolines, e.g., those which are the indazole replacement equivalent of the dihydro-indolyl compound CP-292,597. Also included are those where the anilino nitrogen is methylated or replaced by oxygen or sulfur; a phenoxyanilino moiety is used; or the analogous phenethylamino moiety is present. Further included are those bioisosteres which are selective EGF-R PTK inhibitors and are quinazoline derivatives which have various substituents in the anilino side chains, e.g., an ethynyi moiety as in the bioisostere equivalent of CP-358,774, or as in bioisosteres which are 4-indolyI compounds.

Modifications of the class of indazole replacement bioisostere comprising 4-anilino quinazoline moieties described above have not been limited to the 4-anilino group alone. Basic amino side chains have been used in the 6-position of the quinazoline ring and various substituents have been added to the 4-anilino moiety in order to improve solubility of the 4-anilino-quinazoline bioisosteres, as in the indazole replacement equivalent of ZD-1839.

Phosphodiesterase 4 (PDE4) inhibitors are another class of catechol-containing compounds having significant pharmacological activity Phosphodiesterase-4 is a cAMP-specific phosphodiesterase which plays an important role in the regulation of inflammatory and immune cell activation. A significant variety of different structural types of compounds active as PDE-4 inhibitors has been reported, and PDE isozymes have been characterized in cardiac muscle, and airway and arterial smooth muscles. Attention has also been focused on a high-affinity allosteric binding site which is abundant in brain PDE4 isozyme, whose differential modulation relative to the cAMP catalytic site has yielded drugs with greater therapeutic utility. Rolipram, which contains catechol as a key part of its overall chemical structure, is representative of this type of PDE4 inhibitor and may be depicted ir. accordance with Formula (4.0):

ROLIPRAN (4.0)

Thus, the present invention as it relates to PDE4 inhibitors includes compounds having therapeutic usefulness based on the activity thereof as phosphodiesterase-4 inhibitors comprising an indazole as one essential component of their overall chemical structure, wherein said indazole constitutes a bioisosteric replacement of a catechol component or functional derivative thereof in a known compound having the same said therapeutic

usefulness based on its activity as a phosphodiesterase-4 inhibitor and the same remaining said components of its overall chemical structure. In particular, this therapeutic usefulness includes treating asthma.

The present invention also inlcudes a method of treating asthma using a known compound having a catechol moiety or functional derivative thereof as one essential component of its overall chemical structure, the improvement consisting of using a compound having an indazole moiety as one essential component of its overall chemical structure and having the same remaining said components of its overall chemical structure, wherein said indazole moiety constitutes a bioisosteric replacement for said catechol moiety, and wherein said compound is useful for treating asthma.

The present invention as it relates to PDE4 inhibitors also includes compounds useful in treating or preventing one or members selected from the groups of diseases and conditions consisting essentially of (1) inflammatory diseases and conditions comprising: joint inflammation, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, inflammatory bowel disease, ulcerative colitis, chronic glomerulonephritis, dermatitis, and Crohn's disease; (2) respiratory diseases and conditions comprising: asthma, acute respiratory distress syndrome, chronic pulmonary inflammatory disease, bronchitis, chronic obstructive airway disease, and silicosis; (3) infectious diseases and conditions comprising: sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, fever and myalgias due to bacterial, viral or fungal infection, and influenza; (4) immune diseases and conditions comprising: autoimmune diabetes, systemic lupus erythematosis, graft vs. host reaction, allograft rejections, multiple sclerosis, psoriasis, and allergic rhinitis; and (5) other diseases and conditions comprising: bone resorption diseases; reperfusion injury; cachexia secondary to infection or malignancy; cachexia secondary to human acquired immune deficiency syndrome (AIDS), human immunodeficiency virus (HIV infectioin, or AIDS related complex (ARC); keloid formation; scar tissue formation; type 1 diabetes mellitus; .and leukemia; wherein said compound comprises an inhibitor of phosphodiesterase isozyme 4 (PDE4).

Especially important among the above-recited diseases and conditions which may be treated using the indazole bioisostere replacement compounds of the present invention are the inflammatory diseases and conditions and the respiratory diseases and conditions. Among the inflammatory diseases and conditions which are especially significant with regard to successful treatment using the compounds of the present invention comprise: joint inflammation, rheumatoid arthritis, osteoarthritis, and inflammatory bowel disease. Among the respiratory diseases and conditions which are especially significant with regard to successful treatment using the compounds of the present invention comprise: asthma, acute respiratory distress syndrome, and bronchitis.

The expression “treating or preventing", as used herein with regard to the administration of the compounds of the present invention for therapeutic purposes in the case of various members selected from the many groups of diseases and conditions specifically recited herein, is intended to denote both the therapeutic objective of said administration as well as the therapeutic results actually achieved by said administration. The extent of therapy accomplished by administration of the compounds of the present invention may range from an amelioration to a significant diminishing of the course of the disease involved, and beyond to active treatment of said disease, including a reversal of the disease process itself which is present. The higher or highest degrees of therapeutic effectiveness result in the prevention of any injury, damage, deterioration, or loss of body tissues or organs and basic body functions subsequent to the early stages of degeneration and decline in said body tissues or organs and basic body functions at the onset of the disease involved.

The expression “the early stages of degeneration and decline in body tissues or organs and basic body functions” is intended to mean the very beginning of the initial pathologic changes in said body tissues or organs and basic body functions which define and are the result of a disease process. Said pathologic changes with respect to tissues and organs include changes in the composition and cohesiveness; form and makeup; rigidity, strength, resilience, elasticity, conformational integrity and stability, density, tensile strength and other measures of physical quality; abundance and extent of its presence throughout the body; viability and regenerative capability on both a micro- and macro-level; and the ability to successfully resist various kinds of external stresses including mechanical force and invasion by microorganisms; of said tissues and organs from that present before the onset of said disease process, which result in a degradation and decline of the beneficial and necessary properties characterizing said tissues and organs.

Pathologic changes with respect to body functions are those which inherently arise from the changes above-described with respect to said tissues and organs, and which also, consequently, result in a degradation and decline in the beneficial and necessary performance which characterizes the normal and proper operation of said body functions. These pathologic changes, both with regard to tissues or organs and with respect to body functions, especially include improper repair of the above-discussed early stages of degeneration and decline.

SUMMARY OF THE INVENTION (I) Bioisostere Replacement Compounds Active As Cholinesterase Inhibitors

The present invention relates to the discovery that the indazole nucleus is a bioisostere replacement for the catechol moiety of numerous endogenous ligands acting on important cholinergic receptors and thereby carrying out essential metabolic functions in the body. The present invention relates in particular to indazole-for-catechol bioisostere replacements active as cholinergic antagonists and anticholinesterase agents, comprising a compound of Formulas (5.10) or (5.11): ill

(5.10) (5.11) wherein

Rc, is a member independently selected from the group consisting essentially of hydrogen; hydroxy; -O-^-CJalkyl; and phenyl substituted by 0 to 2 substituents Rs where Rs is a member independently selected from the group consisting essentially of Br, Cl, or F; (C,-CJalkoxy; and CF3 RA, is a member independently selected from the group consisting essentially of hydrogen; (Ο,-Cg) alkyl; -(CH2)n(C3-C10) cycloalkyi wherein n is 0 to 2; -(C,-C6) alkyI(C.,-Ce) alkoxy; (C2-Ce) alkenyl; -(CH2)n(C3-C9) heterocyclyl wherein n is 0 to 2; and -(Z’)b(Z")c(C6-C10) aryl wherein b and c are each independently 0 or 1, Z' is (Ο,-Ο6) alkylene or (C2-C6) alkenylene, and Z" is -0-, -S-, -SO2-, or -N(RS)-, and wherein said alkyl, alkenyl, alkoxyalkyl, heterocyclyl, and aryl moieties of said RA, groups are substituted by 0 to 3 substituents independently selected from halo; hydroxy; (Ο,-Cs) alkyl; (C2-C5) alkenyl; (0,-05) alkoxy; (C3-C6) cycloalkoxy; trifluoromethyl; nitro; -C(=O)ORS; -C(=O)NR9R10, -NR9R10, . and-S(=O)2NR9R10; where in preferred embodiments, said aryl moiety comprises a membere selected from the group consisting essentially of phenyl; naphthyl; indenyl (from 2,3-dihydro-1H-indene); indanyl; and fluorenyl (from 9-H-fluorene); where in more preferred embodiments said aryl moiety comprises a member independently selected from the group consisting essentially of phenyl and indanyl; where in preferred embodiments, said heterocyclyl moiety comprises a member independently selected from the group consisting essentially of acridinyl; benzimidazolyl; benzodioxolane; 1,3-benzodioxol-5-yl; benzo[b]furanyl; benzo[b]thiophenyl; benzoxazolyl; benzthiazolyl; carbazolyl; cinnolinyl; 2,3-dihydrobenzofuranyl; 1,3-dioxane; 1,3-dioxolane; 1,3-dithiane; 1,3-dithiolane; furanyl; imidazolidinyl; imidazolinyi; imidazolyl; 1 H-indazolyl; indolinyl; indolyl; 3H-indolyl; isoindolyl; isoquinolinyl; isothiazolyl; isoxazolyl; morpholinyl; 1,8-naphthyridinyl; oxadiazolyl; 1,3-oxathiolane; oxazolidinyl; oxazolyl; oxiranyl; parathiazinyl; phenazinyl; phenothiazinyl; phenoxazinyl; phthalazinyl; piperazinyl; piperidinyl; pteridinyl;

pyranyl; pyrazinyl; pyrazolidinyl; pyrazolinyl; pyrazolo[1,5-c]triazinyl; pyrazolyl; pyridazinyl; pyridyl; pyrimidinyl; pyrimidyl; pyrrolyl; pyrrolidinyl; purinyl; quinazolinyl; quinolinyl; 4H-quinolizinyl; quinoxalinyl; tetrazolidinyl; tetrazolyl; thiadiazolyl; thiazolidinyl; thiazolyl; thienyl; thiomorpholinyl; triazinyI; and triazolyl; and where in more preferred embodiments said heterocyclyi moiety comprises a member independently selected from the group consisting essentially of pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl; R9 and R10 are independently hydrogen or (C,-C4) alkyl substituted by 0 to 3 fluorine atoms;

Rb, is a member independently selected from the group consisting essentially of hydrogen; (C^Cg) alkyl; (C2-C3) alkenyl; phenyl; (C3-C7) cycloalkyl; and -(C^CJ alkyl(C3-C7) cycloalkyl; wherein said alkyl, alkenyl and phenyl RBn groups are substituted with 0 to 3 substituents independently selected from the group consisting essentially of methyl;ethyl; trifluoromethyl; and halo; and R1a and R1b are each individually and independently a member selected from the group consisting essentially of hydrogen and the substituents defined by partial Formulas (5.12); (5.14); (5.16); (5.18); (5.19); (5.21); (5.23); (5.25); (5.26); and (5.28) below, provided that both of R1a and R1b cannot be hydrogen at the same time; wherein preferred embodiments comprise compounds where one of R1a and R1b is independently selected as hydrogen; and wherein said substituents in addition to hydrogen which define each of R1a and R1b comprise a member independently selected from the group consisting essentially of the moieties of partial Formulas (5.12); (5.14); (5.16); (5.18); (5.19); (5.21); (5.23); (5.25); (5.26); and (5.28): ' (>-A)

(5.12) wherein R2, Rs, and R4 are independently selected from the group consisting essentially of hydrogen and (C,-C4) alkyl substituted by 0 to 3 substituents R5, where the substituent R5 is selected from the group consisting essentially of fluorine, chlorine, methyl, trifluoromethyl hydroxy, and methoxy;

(I-B) R1a is R5 and R1b is the group of partial Formula (5.14):

(5.14) wherein R6 is a member independently selected from the group consisting essentially of (CrC4) alkyl; (C4-C4) alkoxy; and hydroxy; (FC) (5.16) wherein R8, R9 and R10 are independently selected from the group consisting essentially of hydrogen and (C.,-C4) alkyl substituted by 0 to 3 substituents is a member independently selected R5, where the substituent R5 is as defined herein; (l-D) R1a and R’b are taken together to form the moiety of partial Formula (5.18):

(5.18) wherein p is 0 or p is 1 and W is -CH2- or -NH-; R12 is absent or is (CrC4)alkyl; R,A an R,0 are as defined herein; and R13 is -CH3 or is the remainder of the moiety of Formula (5.18) whereby a bis compound is formed as represented by partial Formula (5.19):

(5.19) wherein HX is an acid addtion salt,

O-Ε)

(5.21) wherein R14, R15, and R16 are each a member independently selected from the group consisting essentially of -NH2; -NH(C5-C4) alkyl; and -N[(C1-C4) alkyl]2, where the alkyl groups are selected independently of each other;

(5.23) wherein the moiety

represents the residue of a saturated secondary heterocyclic base having 4, 5, 6, or 7 atoms in the ring, where X is -CH2-, -O-, -S-, or -NH-; and preferably said secondary heterocyclic base is a member selected from the group consisting essentially of pyrrolidine, 1,3-thiazolidine, imidazolidine, 1,2-oxazolidine, 1,3-oxazolidine, piperidine, piperazine, tetrahydro-1,2-oxazine, tetrahydro-1,3-oxazine, tetrahydro- 1,4-oxazine, i.e., morpholine, tetrahydro-1,4-thiazine, and perhydroazepine; d-G) and (5.25) (5.26) wherein R14 is as defined herein; and R18 is (C,-C4) alkyl or (C2-C4) alkenyl where said alkyl and alkenyl groups are substituted by 0 to 3 substituents R5, where the substituent R5 is selected from the group consisting essentially of fluorine, chlorine, methyl, trifluoromethyl hydroxy, and methoxy;

(I-H) R1a and R1b are taken together to form the moiety:

(5.28) wherein the dashed line represents an optional double bond; YA is -C(=O)-; -C(=O)NH-; or -C(=O)N(CH3)-; YB is a member selected from the group consisting essentially of a direct single bond; a direct double bond; -CH2-; -CH2CH2-; -CH2CH2CH2-: =CH-; =CHCH2-; =CH CH2CH2CH2.: =CHCH2CH2CH2CH2-; and =CH-CH=CH-; and Yc is a member selected from the group consisting essentially of cyclohexyl; phenyl substituted by 0 to 3 R20 where R20 is a member selected from the group consisting essentially of methyl, methoxy, hydroxy, benzyloxy, and nitro; pyridyl; 1-naphthyl; 2-naphthyl. (II) Bioisostere Replacement Compounds Active As

Adrenergic ayAntagonists and PrAgonists

The subject matter of the present invention relates to all and every indazole-for-catechol bioisostere replacement involving adrenergic receptor agonists and antagonists, and particularly the α,-antagonist and β,-agonist classes of adrenergic agents which have a catechol moiety as a central and characteristic portion of their overall chemical structure. The present invention relates to both novel indazole compounds resulting from the indazole-for-catechol bioisostere replacement, as well as to the replacements as a general class or genus of chemical compounds. The present invention further relates to the corresponding therapeutic methods of treatment which utilize said novel indazole compounds as the active therapeutic agent, and to the corresponding pharmaceutical compositions which utilize said novel indazole compounds as the active ingredient therein.

The present invention relates in particular to indazole-for-catechol bioisostere replacements active as adrenergic α,-antagonists and β,-agonists, comprising a compound of Formulas (6.22) or (6.23): ill)

(6.22) (6.23) wherein

Rc2 and Ra2 and RB2 are defined the same as R0, and RA, and RB, herein under Formulas (5.10) and (5.11), but are selected on an independent basis therefrom; and

R2a and R2b are each individually and independently a member selected from the group consisting essentially of hydrogen and the substituents defined by partial Formulas (6.24), (6.26), (6.41), (6.43), (6.48), and (6.50) below, provided that both of R2a and R2b cannot be hydrogen at the same time; wherein preferred embodiments comprise compounds where one of R2a and R2b is independently selected as hydrogen; and wherein said substituents in addition to hydrogen which define each of R2a and R2b comprise a member independently selected from the group consisting essentially of the moieties of partial Formulas (6.24), (6.26), (6.41), (6.43), (6.48), and (6.50): (H-A)

(6.24) wherein the dashed line represents an optional double bond; R23 is a member selected from the group consisting essentially of hydrogen; (Cty-C^t) aikyl, (C2-C4) alkenyl, and phenyl(C,-C4) alkyl-, where said alkyl,alkenyl, and phenyl or alkyl group attached thereto are substituted by 0 to 3 substituents R5, where the substituent R5 is as defined herein, but independently selected therefrom; and R24 is a member selected from the group consisting essentially of hydrogen and (Cn-C4) alkoxy; (ll-B) R2a and R2b are taken together to form the moiety of partial Formula (6.26):

(6.26) wherein E represents N, resulting in a pyrimidinyl moiety and overall a quinazoline series of compounds; or represents CH, resulting in a pyridyl moiety and overall a quinoline series of compounds; R25 and R26 are each a member independently selected from the group consisting essentially of hydrogen; (C.,-Ce) alkyl; (C2-C6) alkenyl; (C3-C8) cycloalkyl; hydroxy(C.,-C6) alkyl; phenyl; benzyl; phenylethyl; and 2-furfuryl; and R27 is independently selected from the group consisting essentially of.

(Il-C) (6.41) wherein m is an integer independently selected from 2 and 3 in each instance of its occurrence; n is an integer selected from 2, 3, and 4; p is an integer selected from 2 and 3; and n and p together represent a total which is an integer selected from 5, 6, and 7; (H-D)

(6.43) wherein R47 is a member independently selected from the group consisting essentially of: (a) (C-|-C4) alkyl optionally substituted by 1 or 2 hydroxyl groups; phenyl(C,-C4) alkyl-optionally substituted on the phenyl portion thereof by 1 or 2 hydroxyl groups; and cinnamyl;

(b) -CH2C(=O)NHR48 where R48 is a member independently selected from the group consisting essentially of (C-,-C4) alkyl; and phenyl optionally substituted by (C,-C4) alkoxy, trifluoromethyl, fluoro, bromo, or chloro; (c) -CH2C(=O)NHR49Rso where R49 and R50 are each defined the same as R48; but are selected on an independent basis therefrom; (d) a radical of partial Formula (6.44):

(6.44) wherein the nitrogen atom forms part of a heterocyclic radical selected from the group consisting essentially of morphoiino; hexamethylene-imino; and pyrrolidino; and (e) -CH2C(=O)ORS1 where R51 is hydrogen or (C,-C4) alkyl; (H-E)

(6.48) wherein Rc2 is a member independently selected from the group consisting essentially of hydrogen; hydroxy; and -O-(C,-C4) alkyl, in accordance with whether an inclusionary or exclusionary bioisostere is intended; and RMa and R^t, are independently selected from the group consisting essentially of CnH^, where n is an integer selected from 1, 2, 3, and 4; and (IFF) (6.50) wherein R57 is a member independently selected from the group consisting essentially of hydrogen; (C,-C2) alkyl; and hydroxy; R58 is a member independently selected from the group consisting essentially of hydrogen; and (C,-C2) alkyl; W is -C(R64)(R55)-; -CH(R64)CH(R85)-; or -CHiR^O-KR^CHr; where R84 is a member independently selected from the group consisting essentially of hydrogen and methyl; and R65 is

Claims

Original document published without claims.