Fused heterocyclic compounds Number:7,125,885 from the United States Patent and Trademark Office (PTO) owispatent The present invention provides compounds having the formula: ##STR00001## wherein R.sup.1, R.sup.2, R, R' and the subscript p are described herein. The compounds are useful in the treatment and/or prevention of a condition or disorder mediated by a G-protein coupled receptor. Pharmaceutical compositions and methods of using these compounds for the treatment and/or prevention of a condition or disorder mediated by a G-protein coupled receptor, such as eating disorder, obesity, anxiety disorders and mood disorders are also provided.<H heterocyclic, compounds, Fused, heterocyc, 7125885.html, Patent, pto, 7125885

Title: Fused heterocyclic compounds

Abstract: The present invention provides compounds having the formula: ##STR00001## wherein R.sup.1, R.sup.2, R, R' and the subscript p are described herein. The compounds are useful in the treatment and/or prevention of a condition or disorder mediated by a G-protein coupled receptor. Pharmaceutical compositions and methods of using these compounds for the treatment and/or prevention of a condition or disorder mediated by a G-protein coupled receptor, such as eating disorder, obesity, anxiety disorders and mood disorders are also provided.

Patent Number: 7,125,885 Issued on 10/24/2006 to Chen, et al.

Inventors: Chen; Xiaoqi (San Mateo, CA), Fan; Pingchen (Fremont, CA), Jaen; Juan (Burlingame, CA), Li; Leping (Burlingame, CA), Lizarzaburu; Mike (San Bruno, CA), Mihalic; Jeffrey Thomas (San Francisco, CA), Shuttleworth; Stephen Joseph (Foster City, CA)
Assignee: Amgen Inc. (Thousand Oaks, CA)

Appl. No.: 10/928,029

Filed: August 26, 2004

Related U.S. Patent Documents


Application Number	Filing Date	Patent Number	Issue Date
10289933	Nov., 2002	6809104
10138279	May., 2002	6858619

Current U.S. Class: 514/285 ; 546/70

Current International Class: C07D 471/04 (20060101); A61K 31/437 (20060101)

Field of Search: 546/70 514/285

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Primary Examiner: Habte; Kahsay
Attorney, Agent or Firm: Jones Day

Parent Case Text

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of, and claims the benefit under 35 U.S.C. .sctn. 120 of, U.S. application Ser. No. 10/289,933, filed Nov. 6, 2002 now U.S. Pat. No. 6,809,104, which is a continuation-in-part of U.S. patent application Ser. No. 10/138,279, filed May 3, 2002 now U.S. Pat. No. 6,858,619, and is related to International Application No. PCT/US02/13856, filed May 3, 2002, which claim the benefit of U.S. Application Ser. No. 60/288,665, filed May 4, 2001, the disclosures of which are incorporated herein by reference.

Claims

What is claimed is:

1. A compound or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein said compound is selected from the group consisting of: ##STR00039## ##STR00040##

2. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 1.

Description

FIELD OF THE INVENTION

The present invention relates to compounds, compositions and methods useful in the treatment or prevention of conditions and disorders associated with eating behavior, energy homeostasis and anxiety.

BACKGROUND OF THE INVENTION

G-protein coupled receptors play important roles in diverse signaling processes, including those involved with sensory and hormonal signal transduction. Eating disorders, which represent a major health concern throughout the world, have been linked to GPCR regulation. On the one hand, disorders such as obesity, the excess deposition of fat in the subcutaneous tissues, manifest themselves by an increase in body weight. Individuals who are obese often have, or are susceptible to, medical abnormalities including respiratory difficulties, cardiovascular disease, diabetes and hypertension. On the other hand, disorders like cachexia, the general lack of nutrition and wasting associated with chronic disease and/or emotional disturbance, are associated with a decrease in body weight.

The neuropeptide melanin-concentrating hormone (MCH), a cyclic hypothalamic peptide involved in the regulation of several functions in the brain, has previously been found to be a major regulator of eating behavior and energy homeostasis. It has previously been determined that MCH is the natural ligand for the 353-amino acid orphan G-protein-coupled-receptor (GPCR) termed SLC-1 (also known as GPR24). Subsequent to this determination, SLC-1, which is sequentially homologous to the somatostatin receptors, is frequently referred to as melanin-concentrating hormone receptor (MCH receptor, MCHR or MCHR1) (see Chambers et al., Nature 400:261 65 (1999); Saito et al., Nature 400:265 69 (1999); and Saito et al., TEM 11(8):299 303 (2000)).

Compelling evidence exists that MCH is involved in regulation of eating behavior. First, intracerebral administration of MCH in rats resulted in stimulation of feeding. Next, mRNA corresponding to the MCH precursor is up-regulated in the hypothalamus of genetically obese mice and of fasted animals. Finally, mice deficient in MCH are leaner and have a decreased food intake relative to normal mice. MCH is believed to exert its activity by binding to MCHR, resulting in the mobilization of intracellular calcium and a concomitant reduction in cAMP levels (see Chambers et al., Nature 400:261 65 (1999); Shimada et al. Nature 396:670 74 (1998)). MCH also activates inwardly rectifying potassium channels, and MCHR has been found to interact with both G.alpha.i protein and G.alpha.q protein (Saito et al., TEM 11(8):299 303 (2000)). Moreover, analysis of the tissue localization of MCHR indicates that it is expressed in those regions of the brain involved in olfactory learning and reinforcement. The cumulative data suggest that modulators of MCHR should have an effect on neuronal regulation of food intake (see Saito et al., Nature 400:265 69 (1999)).

MCH has been shown to modulate behaviors other than feeding, such as anxiety (Gonzales et al. (1996) Peptides 17:171 177; Monzon et al. (1999) Physiol. Behav. 67:813 817).

The identification of MCHR modulators is useful for the study of physiological processes mediated by MCHR and the development of therapeutic agents for the treatment or prevention of conditions and disorders associated with weight regulation, learning, anxiety and other neuronal-related functions.

SUMMARY OF THE INVENTION

The present invention provides fused heterocyclic compounds and compositions, and methods of use thereof to treat or prevent conditions and disorders mediated by MCHR. In particular, the present invention provides compounds, compositions and methods for treating or preventing conditions and disorders associated with eating behavior, energy homeostasis and anxiety.

The compounds provided herein have the formula (I):

##STR00002## wherein

L is a bond or (C.sub.1 C.sub.4)alkylene;

R and R' are independently selected from the group consisting of hydrogen, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)alkenyl, (C.sub.2 C.sub.8)alkynyl, CO.sub.2R.sup.13, SO.sub.2R.sup.13, C(O)NR.sup.13R.sup.14, SO.sub.2NR.sup.13R.sup.14and (C.sub.1 C.sub.4)alkylene-CO.sub.2R.sup.13;

optionally, R and R' may be combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing the nitrogen atom and from 0 to 2 additional heteroatoms selected from the group consisting of N, O and S;

R'' is hydrogen or (C.sub.1 C.sub.8)alkyl;

each R.sup.1 is independently selected from the group consisting of halogen, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)alkenyl, (C.sub.2 C.sub.8)alkynyl, fluoro(C.sub.1 C.sub.4)alkyl, --OR.sup.5, --SR.sup.5, fluoro(C.sub.1 C.sub.4)alkoxy, aryl, aryl(C.sub.1 C.sub.4)alkyl, --NO.sub.2, --NR.sup.5R.sup.6, --C(O)R.sup.5, --CO.sub.2R.sup.5, --C(O)NR.sup.5R.sup.6, --N(R.sup.6)C(O)R.sup.5, --N(R.sup.6)CO.sub.2R.sup.5, --N(.sup.7)C(O)NR.sup.5R.sup.6, --S(O).sub.mNR.sup.5R.sup.6, --S(O).sub.mR.sup.5, --CN and --N(R.sup.6)S(O).sub.mR.sup.5;

R.sup.2 is selected from the group consisting of halogen, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)alkenyl, (C.sub.2 C.sub.8)alkynyl, fluoro(C.sub.1 C.sub.4)alkyl, --OR.sup.8, --SR.sup.8, fluoro(C.sub.1 C.sub.4)alkoxy, aryl, aryl(C.sub.1 C.sub.4)alkyl, --NO.sub.2, --NR.sup.8R.sup.9, .dbd.O, --C(O)R.sup.8, --CO.sub.2R.sup.8, --C(O)NR.sup.8R.sup.9, --N(R.sup.9)C(O)R.sup.8, --N(R.sup.9)CO.sub.2R.sup.8, --N(R.sup.10)C(O)NR.sup.8R.sup.9, --S(O).sub.mNR.sup.8R.sup.9, --S(O).sub.mR.sup.8, --CN and --N(R.sup.9)S(O).sub.mR.sup.8;

R.sup.4 is selected from the group consisting of hydrogen --OR.sup.11, --C(O)R.sup.11, --CO.sub.2R.sup.11, --C(O)NR.sup.11R.sup.12, --CN, (C.sub.1 C.sub.4)alkyl and aryl;

R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.16 and R.sup.17 are independently selected from the group consisting of hydrogen, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)alkenyl, (C.sub.2 C.sub.8)alkynyl, fluoro(C.sub.1 C.sub.4)alkyl, hetero(C.sub.1 C.sub.4)alkyl, aryl and aryl(C.sub.1 C.sub.4)alkyl;

optionally, when two R groups selected from the group consisting of R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13 and R.sup.14 are attached to the same nitrogen atom, the R groups may be combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing the nitrogen atom and from 0 to 2 additional heteroatoms selected from the group consisting of N, O and S;

the subscript m is 1 or 2; and

the subscript n is 0, 1 or 2.

Also provided herein are compounds of formula (II):

##STR00003## wherein

R and R' are independently selected from the group consisting of hydrogen, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)alkenyl, (C.sub.2 C.sub.8)alkynyl, CO.sub.2R.sup.13, SO.sub.2R.sup.13, C(O)NR.sup.13R.sup.14, SO.sub.2NR.sup.13R.sup.14and (C.sub.1 C.sub.4)alkylene-CO.sub.2R.sup.13;

R'' is hydrogen or (C.sub.1 C.sub.8)alkyl;

each R.sup.1 is independently selected from the group consisting of halogen, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)alkenyl, (C.sub.2 C.sub.8)alkynyl, fluoro(C.sub.1 C.sub.4)alkyl, --OR.sup.5, --SR.sup.5, fluoro(C.sub.1 C.sub.4)alkoxy, aryl, aryl(C.sub.1 C.sub.4)alkyl, --NO.sub.2, --NR.sup.5R.sup.6, --C(O)R.sup.5, --CO.sub.2R.sup.5, --C(O)NR.sup.5R.sup.6, --N(R.sup.6)C(O)R.sup.5, --N(R.sup.6)CO.sub.2R.sup.5, --N(R.sup.7)C(O)NR.sup.5R.sup.6, --S(O).sub.mNR.sup.5R.sup.6, --S(O).sub.mR.sup.5, --CN and --N(R.sup.6)S(O).sub.mR.sup.5;

R.sup.2 is selected from the group consisting of halogen, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)alkenyl, (C.sub.2 C.sub.8)alkynyl, fluoro(C.sub.1 C.sub.4)alkyl, --OR.sup.8, --SR.sup.8, fluoro(C.sub.1 C.sub.4)alkoxy, aryl, aryl(C.sub.1 C.sub.4)alkyl, --NO.sub.2, --NR.sup.8R.sup.9, .dbd.O, --C(O)R.sup.8, --CO.sub.2R.sup.8, --C(O)NR.sup.8R.sup.9, --N(R.sup.9)C(O)R.sup.8, --N(R.sup.9)CO.sub.2R.sup.8, --N(R.sup.10)C(O)NR.sup.8R.sup.9, --S(O).sub.mNR.sup.8R.sup.9, --S(O).sub.mR.sup.8, --CN and --N(R.sup.9)S(O).sub.mR.sup.8;

R.sup.4 is selected from the group consisting of hydrogen --OR.sup.11, --C(O)R.sup.11, --CO.sub.2R.sup.11, --C(O)NR.sup.11R.sup.12, --CN, (C.sub.1 C.sub.4)alkyl and aryl;

R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13 and R.sup.14 are independently selected from the group consisting of hydrogen, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)alkenyl, (C.sub.2 C.sub.8)alkynyl, fluoro(C.sub.1 C.sub.4)alkyl, hetero(C.sub.1 C.sub.4)alkyl, aryl and aryl(C.sub.1 C.sub.4)alkyl;

optionally, when two R groups selected from the group consisting of R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13 and R.sup.14 are attached to the same nitrogen atom, the R groups may be combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing the nitrogen atom and from 0 to 2 additional heteroatoms selected from the group consisting of N, O and S;

the subscript m is 1 or 2; and

the subscript n is 0, 1 or 2; and

the subscript p is an integer of from 1 to 4.

Also provided herein are compounds of formula (III):

##STR00004## wherein

R and R' are independently selected from the group consisting of hydrogen, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)alkenyl, (C.sub.2 C.sub.8)alkynyl, CO.sub.2R.sup.13, SO.sub.2R.sup.13, C(O)NR.sup.13R.sup.14, SO.sub.2NR.sup.13R.sup.14and (C.sub.1 C.sub.4)alkylene-CO.sub.2R.sup.13;

optionally, R and R' may be combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing the nitrogen atom and from 0 to 2 additional heteroatoms selected from the group consisting of N, O and S;

R'' is hydrogen or (C.sub.1 C.sub.8)alkyl;

each R.sup.1 is independently selected from the group consisting of halogen, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)alkenyl, (C.sub.2 C.sub.8)alkynyl, fluoro(C.sub.1 C.sub.4)alkyl, --OR.sup.5, --SR.sup.5, fluoro(C.sub.1 C.sub.4)alkoxy, aryl, aryl(C.sub.1 C.sub.4)alkyl, --NO.sub.2, --NR.sup.5R.sup.6, --C(O)R.sup.5, --CO.sub.2R.sup.5, --C(O)NR.sup.5R.sup.6, --N(R.sup.6)C(O)R.sup.5, --N(R.sup.6)CO.sub.2 R.sup.5, --N(R.sup.7)C(O)NR.sup.5R.sup.6, --S(O).sub.mNR.sup.5R.sup.6, --S(O).sub.mR.sup.5, --CN and --N(R.sup.6)S(O).sub.mR.sup.5;

R.sup.2 is selected from the group consisting of halogen, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)alkenyl, (C.sub.2 C.sub.8)alkynyl, fluoro(C.sub.1 C.sub.4)alkyl, --OR.sup.8, --SR.sup.8, fluoro(C.sub.1 C.sub.4)alkoxy, aryl, aryl(C.sub.1 C.sub.4)alkyl, --NO.sub.2, --NR.sup.8R.sup.9, .dbd.O, --C(O)R.sup.8, --CO.sub.2R.sup.8, --C(O)NR.sup.8R.sup.9, --N(R.sup.9)C(O)R.sup.8, --N(R.sup.9)CO.sub.2R.sup.8, --N(R.sup.10)C(O)NR.sup.8R.sup.9, --S(O).sub.mNR.sup.8R.sup.9, --S(O).sub.mR.sup.8, --CN and --N(R.sup.9)S(O).sub.mR.sup.8;

R.sup.4 is selected from the group consisting of hydrogen --OR.sup.11, --C(O)R.sup.11, --CO.sub.2R.sup.11, --C(O)NR.sup.11R.sup.12, --CN, (C.sub.1 C.sub.4)alkyl and aryl;

R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.16 and R.sup.17 are independently selected from the group consisting of hydrogen, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)alkenyl, (C.sub.2 C.sub.8)alkynyl, fluoro(C.sub.1 C.sub.4)alkyl, hetero(C.sub.1 C.sub.4)alkyl, aryl and aryl(C.sub.1 C.sub.4)alkyl;

optionally, when two R groups selected from the group consisting of R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.16 and R.sup.17 are attached to the same nitrogen atom, the R groups may be combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing the nitrogen atom and from 0 to 2 additional heteroatoms selected from the group consisting of N, O and S;

the subscript m is 1 or 2;

the subscript n is 0, 1 or 2; and

the subscript p is an integer of from 1 to 4.

The compounds provided in the above formula are meant to include all pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof.

The pharmaceutical compositions provided herein comprise a pharmaceutically acceptable carrier or excipient in combination with a compound of formula I.

Methods for treating or preventing a condition or disorder selected from the group consisting of obesity, an eating disorder, an anxiety disorder and a mood disorder are provided herein. The methods comprise administering to a subject in need thereof a therapeutically effective amount of one of the foregoing compounds or pharmaceutical compositions.

Other objects, features and advantages of the present invention will become apparent to those skilled in the art from the following description and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides the structures of exemplary compounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Abbreviations and Definitions

The abbreviations used herein are conventional, unless otherwise defined.

The term "MCHR" refers to the melanin-concentrating hormone receptor protein 1 (MCHR1), unless otherwise stated.

The terms "treat", "treating" and "treatment" refer to a method of alleviating or abrogating a disease and/or its attendant symptoms.

The terms "prevent", "preventing" and "prevention" refer to a method of decreasing the probability or eliminating the possibility that a disease will be contracted.

As used herein, the term "MCHR-mediated condition or disorder" and the like refers to a condition or disorder characterized by inappropriate, e.g., less than or greater than normal, MCHR activity. An MCHR-mediated condition or disorder may be completely or partially mediated by inappropriate MCHR activity. However, an MCHR-mediated condition or disorder is one in which modulation of MCHR results in some effect on the underlying condition or disease (e.g., an MCHR antagonist results in some improvement in patient well-being in at least some patients). Exemplary MCHR-mediated conditions and disorders include obesity, eating disorders and other behavioral disorders, such as anxiety disorders and mood disorders.

The term "therapeutically effective amount" refers to that amount of the compound being administered sufficient to prevent development of or alleviate to some extent one or more of the symptoms of the condition or disorder being treated.

As used herein, the term "obesity" refers to the excessive accumulation of body fat. Obesity may have genetic, environmental (e.g., expending less energy than is consumed) and regulatory determinants. Cardiovascular disorders, lipid disorders and metabolic disorders, such as hypertension, hyperlidemia, coronary artery disease and diabetes, are commonly associated with obesity.

As used herein, the terms "eating disorder", "feeding disorder", and the like refer to an emotional and/or behavioral disturbance associated with an excessive decrease in body weight and/or inappropriate efforts to avoid weight gain, e.g., fasting, self-induced vomiting, laxative or diuretic abuse. Depression is commonly associated with eating disorders. Exemplary eating disorders include anorexia nervosa and bulimia.

As used herein, the term "anxiety disorder" refers to an emotional and/or behavioral disturbance characterized by persistent and pervasive worry or restlessness, tension or irritability about, e.g., health, work, money or family, for no clear reason. An anxiety disorder may be accompanied by tachycardia or dyspnea. Exemplary anxiety disorders include anxiety, generalized anxiety disorder, panic attacks, panic disorder and obsessive-compulsive disorder (OCD).

As used herein, the term "mood disorder" refers to an emotional and/or behavioral disturbance characterized by persistent and pervasive bouts of euphoria and/or depression. Exemplary mood disorders include depression and bipolar disorders. Anxiety is frequently associated with mood disorders, such as depression.

The term "modulate" refers to the ability of a compound to increase or decrease the function, or activity, of MCHR. Modulation, as described herein, includes the antagonism or agonism of MCHR, either directly or indirectly. Antagonist are compounds that, e.g., partially or totally block stimulation, decrease, prevent, delay activation, inactivate, inhibit, desensitize, or down-regulate signal transduction. Agonists are compounds that, e.g., stimulate, increase, activate, open, facilitate, enhance activation, sensitize or up-regulate signal transduction.

The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which is fully saturated, having the number of carbon atoms designated (i.e. C.sub.1 C.sub.8 means one to eight carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. As used herein, (C.sub.1 C.sub.8)alkyl refers to an alkyl group having from one to eight carbon atoms and includes, e.g., (C.sub.1 C.sub.4)alkyl.

The term "alkenyl", by itself or as part of another substituent, means a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e. C.sub.2 C.sub.8 means two to eight carbons) and one or more double bonds. Examples of alkenyl groups include vinyl, allyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl) and higher homologs and isomers thereof.

The term "alkynyl", by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e. C.sub.2 C.sub.8 means two to eight carbons) and one or more triple bonds. Examples of alkynyl groups include ethynyl, 1- and 3-propynyl, 3-butynyl and higher homologs and isomers thereof.

The term "alkylene" by itself or as part of another substituent means a divalent radical derived from alkyl, as exemplified by --CH.sub.2CH.sub.2CH.sub.2CH.sub.2--. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having seven or fewer carbon atoms.

The terms "alkoxy," "alkylamino" and "alkylthio" (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.

The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, Si and S, wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group. The heteroatom Si may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. Examples include --CH.sub.2--CH.sub.2--O--CH.sub.3, --CH.sub.2--CH.sub.2--NH--CH.sub.3, --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.3, --CH.sub.2--S--CH.sub.2--CH.sub.3, --CH.sub.2--CH.sub.2, --S(O)--CH.sub.3, --CH.sub.2--CH.sub.2--S(O).sub.2--CH.sub.3, --CH.dbd.CH--O--CH.sub.3, --Si(CH.sub.3).sub.3, --CH.sub.2--CH.dbd.N--OCH.sub.3, and --CH.dbd.CH--N(CH.sub.3)--CH.sub.3. Up to two heteroatoms may be consecutive, such as, for example, --CH.sub.2--NH--OCH.sub.3 and --CH.sub.2--O--Si(CH.sub.3).sub.3

Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by --CH.sub.2--CH.sub.2--S--CH.sub.2CH.sub.2-- and --CH.sub.2--S--CH.sub.2--CH.sub.2--NH--CH.sub.2--. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g. alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.

The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl", respectively. Accordingly, a cycloalkyl group has the number of carbon atoms designated (i.e., C.sub.3 C.sub.8 means three to eight carbons) and a heterocycloalkyl group consists of the number of atoms designated (i.e., C.sub.2 C.sub.8 means two to eight carbons) and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.

The terms "halo" and "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl," are meant to include alkyl substituted with halogen atoms, which can be the same or different, in a number ranging from one to (2m'+1), where m' is the total number of carbon atoms in the alkyl group. For example, the term "halo(C.sub.1 C.sub.4)alkyl" is mean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Thus, the term "haloalkyl" includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with halogen atoms in a number ranging from two to (2m'+1) halogen atoms, where m' is the total number of carbon atoms in the alkyl group). Accordingly, the term "fluoro(C.sub.1 C.sub.4)alkyl" includes fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 1,1-difluoroethyl, and the like. The term "perhaloalkyl" means, unless otherwise stated, alkyl substituted with (2m'+1) halogen atoms, where m' is the total number of carbon atoms in the alkyl group. For example the term "perhalo(C.sub.1 C.sub.4)alkyl" is meant to include trifluoromethyl, pentachloroethyl, 1,1,1-trifluoro-2-bromo-2-chloroethyl, and the like.

The term "aryl" means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. Non-limiting examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl and 4-biphenyl.

The term "heteroaryl" refers to aryl groups (or rings) that contain from zero to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of heteroaryl groups include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl.

For brevity, the term "aryl" when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term "arylalkyl" is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

Each of the above terms (e.g., "alkyl," "heteroalkyl," "aryl" and "heteroaryl") is meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

Substituents for the alkyl and heteroalkyl radicals (as well as those groups referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl) can be a variety of groups selected from: --OR', .dbd.O; .dbd.NR', .dbd.N--OR', --NR'R'', --SR', halogen, --Si'R''R''', --OC(O)R', --C(O)R', --CO.sub.2R', --CONR'R'', --OC(O)NR'R'', --NR''C(O)R', --NR'--C(O)NR''R''', --NR'--SO.sub.2NR''R''', --NR''CO.sub.2R', --NH--C(NH.sub.2).dbd.NH, --NR'C(NH.sub.2).dbd.NH, --NH--C(NH.sub.2).dbd.NR', --S(O)R', --SO.sub.2R', --SO.sub.2NR'R'', --NR''SO.sub.2R, --CN and --NO.sub.2, in a number ranging from zero to three, with those groups having zero, one or two substituents being particularly preferred. R', R'' and R''' each independently refer to hydrogen, unsubstituted (C.sub.1 C.sub.8)alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl(C.sub.1 C.sub.4)alkyl groups. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring. For example, --NR'R'' is meant to include 1-pyrrolidinyl and 4-morpholinyl. Typically, an alkyl or heteroalkyl group will have from zero to three substituents, with those groups having two or fewer substituents being preferred in the present invention. More preferably, an alkyl or heteroalkyl radical will be unsubstituted or monosubstituted. Most preferably, an alkyl or heteroalkyl radical will be unsubstituted. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups such as trihaloalkyl (e.g., --CF.sub.3 and --CH.sub.2CF.sub.3).

Preferred substituents for the alkyl and heteroalkyl radicals are selected from: --OR', .dbd.O, --NR'R'', --SR', halogen, --SiR'R''R''', --OC(O)R', --C(O)R', --CO.sub.2R', --CONR'R'', --OC(O)NR'R'', --NR''C(O)R', --NR''CO.sub.2R', --NR'--SO.sub.2NR''R''', --S(O)R', --SO.sub.2R', --SO.sub.2NR'R'', --NR''SO.sub.2R, --CN and --NO.sub.2, where R' and R'' are as defined above. Further preferred substituents are selected from: --OR', .dbd.O, --NR'R'', halogen, --OC(O)R', --CO.sub.2R', --CONR'R'', --OC(O)NR'R'', --NR''C(O)R', --NR''CO.sub.2R', --NR'--SO.sub.2NR''R''', --SO.sub.2R', --SO.sub.2NR'R'', --NR''SO.sub.2R, --CN and --NO.sub.2

Similarly, substituents for the aryl and heteroaryl groups are varied and selected from: halogen, --OR', --OC(O)R', --NR'R'', --SR', --R', --CN, --NO.sub.2, --CO.sub.2R', --CONR'R'', --C(O)R', --OC(O)NR'R'', --NR''C(O)R', --NR''CO.sub.2R', --NR'--C(O)NR''R''', --NR'--SO.sub.2NR''R''', --NH--C(NH.sub.2).dbd.NH, --NR'C(NH.sub.2).dbd.NH, --NH--C(NH.sub.2).dbd.NR', --S(O)R', --SO.sub.2R', --SO.sub.2NR'R'', --NR''SO.sub.2R, --N.sub.3, --CH(Ph).sub.2, perfluoro(C.sub.1 C.sub.4)alkoxy and perfluoro(C.sub.1 C.sub.4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R'' and R''' are independently selected from hydrogen, (C.sub.1 C.sub.8)alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-(C.sub.1 C.sub.4)alkyl and (unsubstituted aryl)oxy-(C.sub.1 C.sub.4)alkyl. Typically, an aryl or heteroaryl group will have from zero to three substituents, with those groups having two or fewer substituents being preferred in the present invention. More preferably, an aryl or heteroaryl group will be unsubstituted or monosubstituted. Most preferably, an aryl or heteroaryl group will be unsubstituted.

Preferred substituents for aryl and heteroaryl groups are selected from: halogen, --OR', --OC(O)R', --NR'R'', --SR', --R', --CN, --NO.sub.2, --CO.sub.2R', --CONR'R'', --C(O)R', --OC(O)NR'R'', --NR''C(O)R', --S(O)R', --SO.sub.2R', --SO.sub.2NR'R'', --NR''SO.sub.2R, --N.sub.3, --CH(Ph).sub.2, perfluoro(C.sub.1 C.sub.4)alkoxy and perfluoro(C.sub.1 C.sub.4)alkyl, where R' and R'' are as defined above. Further preferred substituents are selected from: halogen, --OR', --OC(O)R', --NR'R'', --R', --CN, --NO.sub.2, --CO.sub.2R', --CONR'R'', --NR''C(O)R', --SO.sub.2R', --SO.sub.2NR'R'', --NR''SO.sub.2R, perfluoro(C.sub.1 C.sub.4)alkoxy and perfluoro(C.sub.1 C.sub.4)alkyl

As used herein, the substituent CO.sub.2H, includes bioisosteric replacements therefor, such as:

##STR00005## and the like. See, e.g., The Practice of Medicinal Chemistry; Wermuth, C. G., Ed.; Academic Press: New York, 1996; p. 203.

Two of the substituents on adjacent atoms of the aryl ring may optionally be replaced with a substituent of the formula -T-C(O)--(CH.sub.2).sub.q--U-- wherein T and U are independently --NH--, --O--, --CH.sub.2-- or a single bond, and q is an integer of from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl ring may optionally be replaced with a substituent of the formula --A--(CH.sub.2).sub.r--B--, wherein A and B are independently --CH.sub.2--, --O--, --NH--, --S--, --S(O)--, --SO.sub.2--, --SO.sub.2NR'-- or a single bond, and r is an integer of from 1 to 3. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl ring may optionally be replaced with a substituent of the formula --(CH.sub.2).sub.s--X--(CH.sub.2).sub.t--, where s and t are independently integers of from 0 to 3, and X is --O--, --NR'--, --S--, --S(O)--, --SO.sub.2--, or --SO.sub.2NR'--. The substituent R' in --NR'-- and --SO.sub.2NR'-- is selected from the group consisting of hydrogen or unsubstituted (C.sub.1 C.sub.6)alkyl.

As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. M., et al. (1977) J. Pharm. Sci. 66:1 19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmacological compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound of the present invention which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound of the invention.

Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, enantiomers, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the present invention.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (.sup.3H), iodine-125 (.sup.125I) or carbon-14 (.sup.14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

EMBODIMENTS OF THE INVENTION

MCHR (GenBank Accession No. U71092) is expressed in brain, at moderate levels in the eye and skeletal muscle, and in low levels in tongue and the pituitary gland. Evidence suggests that MCHR is involved in, inter alia, olfactory learning, regulation of feeding behavior and energy metabolism, regulation of the hypothalmic-pituitary-adrenocortical axis following stress, arousal and the sensation of anxiety (Saito et al., TEM 11(8):299 303 (2000)). The compounds of the present invention inhibit MCHR activity, and thus, are useful in, for example, the treatment or prevention of disorders associated with these processes.

Compounds

In one aspect, the present invention provides compounds represented by the formula (I):

##STR00006## or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. In formula I, the symbol L represents a divalent linkage selected from a bond and (C.sub.1 C.sub.4)alkylene. Exemplary L groups are a single bond, methylene, ethylene, n-propylene and n-butylene.

R and R' are independently selected from hydrogen, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)alkenyl, (C.sub.2 C.sub.8)alkynyl, CO.sub.2R.sup.13, SO.sub.2R.sup.13, C(O)NR.sup.13R.sup.14, SO.sub.2NR.sup.13R.sup.14and (C.sub.1 C.sub.4)alkylene-CO.sub.2R.sup.13. Optionally, R and R' may be combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing the nitrogen atom and from 0 to 2 additional heteroatoms selected from N, O and S. Exemplary NRR'groups are:

##STR00007##

R'' is hydrogen or (C.sub.1 C.sub.8)alkyl.

Each R.sup.1 is independently halogen, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)alkenyl, (C.sub.2 C.sub.8)alkynyl, fluoro(C.sub.1 C.sub.4)alkyl, --OR.sup.5, --SR.sup.5, fluoro(C.sub.1 C.sub.4)alkoxy, aryl, aryl(C.sub.1 C.sub.4)alkyl, --NO.sub.2, --NR.sup.5R.sup.6, --C(O)R.sup.5, --CO.sub.2R.sup.5, --C(O)NR.sup.5R.sup.6, --N(R.sup.6)C(O)R.sup.5, --N(R.sup.6)CO.sub.2R.sup.5, --N(R.sup.7)C(O)NR.sup.5R.sup.6, --S(O).sub.mNR.sup.5R.sup.6, --S(O).sub.mR.sup.5, --CN or --N(R.sup.6)S(O).sub.mR.sup.5. Exemplary R.sup.1 groups are Cl and CF.sub.3.

R.sup.2 is selected from halogen, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)alkenyl, (C.sub.2 C.sub.8)alkynyl, fluoro(C.sub.1 C.sub.4)alkyl, --OR.sup.8, --SR.sup.8, fluoro(C.sub.1 C.sub.4)alkoxy, aryl, aryl(C.sub.1 C.sub.4)alkyl, --NO.sub.2, --NR.sup.8R.sup.9, .dbd.O, --C(O)R.sup.8, --CO.sub.2R.sup.8, --C(O)NR.sup.8R.sup.9, --N(R.sup.9)C(O)R.sup.8, --N(R.sup.9)CO.sub.2R.sup.8, --N(R.sup.10)C(O)NR.sup.8R.sup.9, --S(O).sub.mR.sup.8R.sup.9, --S(O).sub.mR.sup.8, --CN and --N(R.sup.9)S(O).sub.mR.sup.8. Exemplary R.sup.2 groups are methyl, isopropyl, trifluoromethyl, hydroxy, methoxy, hydroxymethyl, trifluoromethoxy, phenyl and .dbd.O.

R.sup.4 is hydrogen --OR.sup.11, --C(O)R.sup.11, --CO.sub.2R.sup.11, --C(O)NR.sup.11R.sup.12, --CN, (C.sub.1 C.sub.4)alkyl or aryl.

R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.16 and R.sup.17 are independently selected from hydrogen, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)alkenyl, (C.sub.2 C.sub.8)alkynyl, fluoro(C.sub.1 C.sub.4)alkyl, hetero(C.sub.1 C.sub.4)alkyl, aryl and aryl(C.sub.1 C.sub.4)alkyl. The subscript m is 1 or 2 and the subscript n is 0, 1 or 2. Optionally, when two R groups selected from the group consisting of R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13 and R.sup.14 are attached to the same nitrogen atom, the R groups may be combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing the nitrogen atom and from 0 to 2 additional heteroatoms selected from N, O and S.

The compounds of the invention feature a pyrido[4,3-b]carbazole-derived ring, minimally substituted at the 2- and 11-positions. The ring numbering system used herein is illustrated below.

##STR00008##

One of skill in the art will understand that formula I encompasses two enantiomers. The enantiomers have the structural orientations represented by the following formulae:

##STR00009##

Within formula I above, a number of groups of embodiments are preferred, described below.

In one group of preferred embodiments, L is (C.sub.1 C.sub.4)alkylene. In a preferred embodiment, L is unsubstituted (C.sub.1 C.sub.4)alkylene or (CH.sub.2).sub.p, wherein the subscript p is an integer of from 1 to 4. In a further preferred embodiment, p is 1, 2 or 3. In a still further preferred embodiment, p is 2 or 3.

One group of preferred embodiments is represented by the formula (II):

##STR00010## wherein L is (C.sub.1 C.sub.4)alkylene.

In a preferred embodiment, R and R' are combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing nitrogen and from 0 to 2 additional heteroatoms selected from O, N and S. In a further preferred embodiment, R and R' are combined to form a 5- or 6-membered ring containing nitrogen and from 0 to 2 additional heteroatoms selected from O, N and S.

In another group of preferred embodiments, R'' is hydrogen.

In another group of preferred embodiments, R'' is substituted (C.sub.1 C.sub.8)alkyl. In a preferred embodiment, R'' is (C.sub.1 C.sub.8)alkyl substituted with hydroxy, alkylamino (e.g., NHMe) or carboxy (CO.sub.2H). In a particularly preferred embodiment, R'' is (C.sub.3 C.sub.8)alkyl substituted with hydroxy, alkylamino or carboxy.

In another group of preferred embodiments, R.sup.1 is independently halogen, (C.sub.1 C.sub.4)alkyl, fluoro(C.sub.1 C.sub.4)alkyl, --OR.sup.5, fluoro(C.sub.1 C.sub.4)alkoxy, --CO.sub.2R.sup.5, --S(O).sub.mNR.sup.5R.sup.6, --S(O).sub.mR.sup.5 or --CN. In a further preferred embodiment, R.sup.1 is independently halogen or fluoro(C.sub.1 C.sub.4)alkyl. In a still further preferred embodiment, R.sup.1 is halogen or fluoro(C.sub.1 C.sub.4)alkyl and the subscript n is 0 or 1. In a particularly preferred embodiment, R.sup.1 is fluoro(C.sub.1 C.sub.4)alkyl and the subscript n is 0 or 1.

In another group of preferred embodiments, R.sup.2 is (C.sub.1 C.sub.4)alkyl or aryl.

In another group of preferred embodiments, R.sup.4 is hydrogen.

Also particularly preferred are those embodiments that combine two or more of these preferred groups. Accordingly, in one group of particularly preferred embodiments, R'' and R.sup.4 are hydrogen.

In another group of particularly preferred embodiments, R''