Selective .beta..sub.3 adrenergic agonists Number:7,041,684 from the United States Patent and Trademark Office (PTO) owispatent The present invention is in the field of medicine, particularly in the treatment of Type II diabetes and obesity. More specifically, the present invention relates to selective .beta..sub.3 receptor agonists useful in the treatment of Type II diabetes and obesity. The invention provides compounds and methods of treating Type II diabetes and obesity, comprising administering to a mammal in need thereof compounds of formula (I). ##STR00001##<H adrenergic, Selective, Selective, beta, , 7041684.html, Patent, pto, 7041684

Title: Selective .beta..sub.3 adrenergic agonists

Abstract: The present invention is in the field of medicine, particularly in the treatment of Type II diabetes and obesity. More specifically, the present invention relates to selective .beta..sub.3 receptor agonists useful in the treatment of Type II diabetes and obesity. The invention provides compounds and methods of treating Type II diabetes and obesity, comprising administering to a mammal in need thereof compounds of formula (I). ##STR00001##

Patent Number: 7,041,684 Issued on 05/09/2006 to Rito, et al.

Inventors: Rito; Christopher J. (Mooresville, IN); Shuker; Anthony J. (Indianapolis, IN)
Assignee: Eli Lilly and Company (Indianapolis, IN)

Appl. No.: 694467

Filed: October 27, 2003

Related U.S. Patent Documents


Application Number	Filing Date	Patent Number	Issue Date
10120302	Apr., 2002	6686372
09610096	Jun., 2000	6413991
09068192		6140352
PCT/US97/15230	Aug., 1997
60029228	Oct., 1996
60025818	Sep., 1996

Current U.S. Class: 514/339 ; 546/276.7

Current International Class: A61K 31/4439 (20060101); C07D 401/12 (20060101)

Field of Search: 546/276.7 514/339

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Primary Examiner: Morris; Patricia L.
Attorney, Agent or Firm: Voy; Gilbert T.

Parent Case Text

This application is a continuation claiming the benefit under 35 U.S.C. .sctn.120 of U.S. Pat. No. 6,686,372, application Ser. No. 10/120,302, filed Apr. 10, 2002 which is a continuation claiming the benefit under 35 U.S.C. .sctn.120 of U.S. Pat. No. 6,413,991, application Ser. No. 09/610,096, filed Jun. 30, 2000, which is a division claiming the benefit under 35 U.S.C. .sctn.121 of U.S. Pat. No. 6,140,352, application Ser. No. 09/068,192, filed May 4, 1998, which claims the benefit under 35 U.S.C. .sctn.365(c) of PCT application No. US97/15230, filed Aug. 28, 1997, which claims the benefit under 35 U.S.C. .sctn.119(c) of U.S. Provisional Application No. 60/025,818, filed Sep. 5, 1996 and U.S. Provisional Application No. 60/029,228, filed Oct. 30, 1996.

Claims

We claim:

1. A compound represented by the following structural formula: ##STR00241##

2. A 2-butyne-1,4 dioate, 3-hexyne-2,5-dioate, acetate, acrylate, beazoate, beta-hydroxybutyrate, bisulfate, bisulfite, bromide, caprylate, carbonate, chlorobenzoate, citrate, decanoate, dihydrogenphosphate, formate, fumarate, glycollate, heptanoate, hippurate, hydroxybenzoate, iodide, isobutyrate, lactate, maleate, maleate, malonate, mandelatemetaphosphate, methanesulfonate, methoxybenzoate, mono-hydrogenphosphate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, oxalate, para-toluenesulfonate, para-bromophenylsulfonate, phenylacetate, phenylbutyrate, phenylpropionate, phosphate, phthalate, propanesulfonate, propiolate, propionate, pyrophosphate, pyrosulfate, sebacate, suberate, succinate, sulfate, sulfite, tartrate or xylenesulfonate salt of a compound represented by the following structural formula: ##STR00242##

3. A pharmaceutical formulation comprising the compound of claim 1 and one or more pharmaceutically acceptable carriers, excipients or diluents.

4. A pharmaceutical formulation comprising a salt of claim 2 and one or more pharmaceutically acceptable carriers, excipients or diluents.

5. A method for treating obesity which comprises administering a pharmaceutically effective amount of a salt of claim 2 to a patient in need thereof.

6. A method for treating Type II diabetes which comprises administering a pharmaceutically effective amount of a salt of claim 2 to a patient in need thereof.

7. The salt of claim 2 which is the succinate wherein said succinate salt is the hemi-succinate.

8. A method for treating obesity which comprises administering a pharmaceutically effective amount of the salt of claim 7 to a patient in need thereof.

9. A method for treating Type II diabetes which comprises administering a pharmaceutically effective amount of the salt of claim 7 to a patient in need thereof.

Description

FIELD OF INVENTION

The present invention is in the field of medicine, particularly in the treatment of Type II diabetes and obesity. More specifically, the present invention relates to selective .beta..sub.3 adrenergic receptor agonists useful in the treatment of Type II diabetes and obesity.

BACKGROUND OF THE INVENTION

The current preferred treatment for Type II, non-insulin dependent diabetes as well as obesity is diet and exercise, with a view toward weight reduction and improved insulin sensitivity. Patient compliance, however, is usually poor. There are no currently approved medications that adequately treat either Type II diabetes or obesity. The invention described herein is directed toward an effective and timely treatment for these serious diseases.

One therapeutic opportunity that has been recently recognized involves the relationship between adrenergic receptor stimulation, anti-hyperglycemic effects, and metabolic events such as increased basil metabolic rate. Compounds that act as .beta..sub.3 adrenergic receptor agonists have been shown to exhibit a marked effect on lipolysis, thermogenesis, and serum glucose levels in animal models of Type II (non-insulin dependent) diabetes.

The .beta..sub.3 receptor, which is found in several types of human tissue including human fat tissue, has roughly 50% homology to the .beta..sub.1 and .beta..sub.2 receptor subtypes yet is considerably less abundant. The importance of the .beta..sub.3 receptor is a relatively recent discovery since the amino-acid sequence of the human receptor was only elucidated in the late 1980's. A large number of publications have appeared in recent years reporting success in discovery of agents that stimulate the .beta..sub.3 receptor. Despite these recent developments there remains a need to develop a selective .beta..sub.3 receptor agonist which has minimal agonist activity against the .beta..sub.1 and .beta..sub.2 receptors.

The present invention provides methods of treating Type II diabetes, treating obesity, and stimulating the .beta..sub.3 receptor. In addition, the present invention also provides novel compounds that are selective .beta..sub.3 receptor agonists and as such are useful for treating Type II diabetes, obesity, and stimulating the .beta..sub.3 receptor. U.S. Pat. No. 4,503,067 discloses carbazolyl-(4)-oxypropanolamine compounds, some of which are within the scope of formula I, as .beta.-adrenoceptor antagonists and vasodilators.

SUMMARY OF THE INVENTION

The present invention provides methods of treating Type II diabetes, treating obesity, and stimulating the .beta..sub.3 receptor which comprise administering to a patient in need thereof a compound described in Formula I below.

##STR00002## wherein:

X.sub.1 is --OCH.sub.2--, --SCH.sub.2--, or a bond;

X.sub.2 is a bond, or a 1 to 5 carbon straight or branched alkylene;

X.sub.3 is O, S, or a bond;

R.sub.1 is a fused heterocycle of the formula:

##STR00003##

the A.sub.1 groups are independently carbon or nitrogen, provided that no more than 2 nitrogens may be contained in either fused 6 membered ring and those 2 nitrogens may not be adjacent;

R.sub.2 is independently hydrogen, C.sub.1 C.sub.4 alkyl, or aryl;

R.sub.3 is hydrogen or C.sub.1 C.sub.4 alkyl;

R.sub.4 is an optionally substituted heterocycle or a moiety selected from the group consisting of:

##STR00004##

R.sub.5 is hydrogen or C.sub.1 C.sub.4 alkyl;

R.sub.6 is hydrogen, C.sub.1 C.sub.4 alkyl, or CO.sub.2(C.sub.1 C.sub.4 alkyl);

or R.sub.5 and R.sub.6 combine with the carbon to which each is attached to form a C.sub.3 C.sub.6 cycloalkyl;

or R.sub.6 combines with X.sub.2 and the carbon to which each is attached to form a C.sub.3 C.sub.8 cycloalkyl;

or R.sub.6 combines with X.sub.2, R.sub.4, and the carbon to which each is attached to form:

##STR00005## provided that R.sub.5 is hydrogen;

R.sub.7 is independently hydrogen, halo, hydroxy, OR.sub.2, C.sub.1 C.sub.4 alkyl, C.sub.1 C.sub.4 haloalkyl, aryl, COOR.sub.2, CONR.sub.2R.sub.2, NHCOR.sub.2, C.sub.1 C.sub.4 alkoxy, NHR.sub.2, SR.sub.2, CN, SO.sub.2R.sub.2, SO.sub.2NHR.sub.2, or SOR.sub.2;

R.sub.8 is independently hydrogen, halo, or C.sub.1 C.sub.4 alkyl;

R.sub.9 is hydrogen, halo, hydroxy, CN, OR.sub.10, C.sub.1 C.sub.4 alkyl, C.sub.1 C.sub.4 haloalkyl, CO.sub.2R.sub.2, CONR.sub.11R.sub.12, CONH(C.sub.1 C.sub.4 alkyl or C.sub.1 C.sub.4 alkoxy), SR.sub.2, CSNR.sub.2, CSNR.sub.11R.sub.12, NR.sub.2SO.sub.2R.sub.2, SO.sub.2R.sub.2, SO.sub.2NR.sub.11R.sub.12, SOR.sub.2, NR.sub.11R.sub.12, optionally substituted aryl, optionally substituted heterocycle, or C.sub.2 C.sub.4 alkenyl substituted with CN, CO.sub.2R.sub.2 or CONR.sub.11R.sub.12;

R.sub.10 is C.sub.1 C.sub.4 alkyl, C.sub.1 C.sub.4 haloalkyl, (CH.sub.2).sub.nC.sub.3 C.sub.8 cycloalkyl, (CH.sub.2).sub.naryl, (CH.sub.2).sub.nheterocycle, (CH.sub.2).sub.nC.sub.3 C.sub.8 optionally substituted cycloalkyl, (CH.sub.2).sub.n optionally substituted aryl, (CH.sub.2).sub.n optionally substituted heterocycle, or (CH.sub.2).sub.nCO.sub.2R.sub.2;

R.sub.11 and R.sub.12 are independently hydrogen, C.sub.1 C.sub.4 alkyl, aryl, (CH.sub.2).sub.naryl, or combine with the nitrogen to which each is bound to form morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl;

m is 0 or 1; and

n is independently 0, 1, 2, or 3;

or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is the genus of novel compounds defined by Formula II below.

##STR00006## wherein:

X.sub.1 is --OCH.sub.2--, --SCH.sub.2--, or a bond;

X.sub.3 is O, S, or a bond;

R.sub.1 is a fused heterocycle of the formula:

##STR00007##

the A.sub.1 groups of said heterocycle are independently carbon or nitrogen, provided that no more than 2 nitrogens may be contained in either fused 6 membered ring and those 2 nitrogens may not be adjacent;

R.sub.2 is independently hydrogen, C.sub.1 C.sub.4 alkyl, or aryl;

R.sub.3 is hydrogen or C.sub.1 C.sub.4 alkyl;

R.sub.4 is an optionally substituted heterocycle or a moiety selected from the group consisting of:

##STR00008##

X.sub.2 is a bond, or a 1 to 5 carbon straight or branched alkylene;

R.sub.5 is hydrogen or C.sub.1 C.sub.4 alkyl;

R.sub.6 is hydrogen, C.sub.1 C.sub.4 alkyl, or CO.sub.2(C.sub.1 C.sub.4 alkyl);

or R.sub.5 and R.sub.6 combine with the carbon to which each is attached to form a C.sub.3 C.sub.6 cycloalkyl;

or R.sub.6 combines with X.sub.2 and the carbon to which each is attached to form a C.sub.3 C.sub.8 cycloalkyl;

or R.sub.6 combines with X.sub.2, R.sub.4, and the carbon to which each is attached to form:

##STR00009## provided that R.sub.5 is hydrogen;

R.sub.7 is independently hydrogen, halo, hydroxy, OR.sub.2, C.sub.1 C.sub.4 alkyl, C.sub.1 C.sub.4 haloalkyl, aryl, COOR.sub.2, CONHR.sub.2, NHCOR.sub.2, C.sub.1 C.sub.4 alkoxy, NHR.sub.2, SR.sub.2, CN, SO.sub.2R.sub.2, SO.sub.2NHR.sub.2, or SOR.sub.2;

R.sub.8 is independently hydrogen, halo or C.sub.1 C.sub.4 alkyl;

R.sub.9 is halo, CN, OR.sub.10, C.sub.1 C.sub.4 alkyl, C.sub.1 C.sub.4 haloalkyl, CO.sub.2R.sub.2, CONR.sub.11R.sub.12, CONH(C.sub.1 C.sub.4 alkyl or C.sub.1 C.sub.4 alkoxy), SR.sub.2, CSNR.sub.2, CSNR.sub.11R.sub.12, NR.sub.2SO.sub.2R.sub.2, SO.sub.2R.sub.2, SO.sub.2NR.sub.11R.sub.12, SOR.sub.2, NR.sub.11R.sub.12, optionally substituted aryl, optionally substituted heterocycle, or C.sub.2 C.sub.4 alkenyl substituted with CN, CO.sub.2R.sub.2 or CONR.sub.11R.sub.12;

R.sub.10 is C.sub.1 C.sub.4 alkyl, C.sub.1 C.sub.4 haloalkyl, (CH.sub.2).sub.nC.sub.3 C.sub.8 cycloalkyl, (CH.sub.2).sub.naryl, (CH.sub.2).sub.nheterocycle, (CH.sub.2).sub.nC.sub.3 C.sub.8 optionally substituted cycloalkyl, (CH.sub.2).sub.n optionally substituted aryl, (CH.sub.2).sub.n optionally substituted heterocycle, or (CH.sub.2).sub.nCO.sub.2R.sub.2;

R.sub.11 and R.sub.12 are independently hydrogen, C.sub.1 C.sub.4 alkyl, aryl, (CH.sub.2).sub.naryl, or combine with the nitrogen to which each is bound to form morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl;

m is 0 or 1;

n is independently 0, 1, 2, or 3;

provided:

when R.sub.5 or R.sub.6 is hydrogen; either

1) one or more A.sub.1 must be nitrogen, or

2) R.sub.9 is CN, OR.sub.10, CO.sub.2R.sub.2, CSNR.sub.2, CSNR.sub.11R.sub.12, NR.sub.2SO.sub.2R.sub.2, SO.sub.2NR.sub.11R.sub.12, optionally substituted aryl, optionally substituted heterocycle, or C.sub.2 C.sub.4 alkenyl substituted with CN, CO.sub.2R.sub.2 or CONR.sub.11R.sub.12; and

R.sub.10 is C.sub.1 C.sub.4 haloalkyl, (CH.sub.2).sub.nC.sub.3 C.sub.8 cycloalkyl, (CH.sub.2).sub.nheterocycle, (CH.sub.2).sub.nC.sub.3 C.sub.8 optionally substituted cycloalkyl, (CH.sub.2).sub.n optionally substituted aryl, or (CH.sub.2).sub.n optionally substituted heterocycle;

or a pharmaceutically acceptable salt thereof.

The present invention also provides novel processes for making, as well as novel pharmaceutical formulations of the compounds of Formula II.

The compounds of Formula I are selective .beta..sub.3 receptor agonists and as such are useful for treating Type II diabetes and obesity, as well as useful for stimulating or activating the .beta..sub.3 receptor. Therefore, the present invention also provides for methods of treating Type II diabetes and obesity, as well as a method of stimulating or activating the .beta..sub.3 receptor.

In addition, the present invention provides the use of compounds of Formulas I for treating Type II diabetes and obesity as well the use of compounds of Formulas I for stimulating or activating the .beta..sub.3 receptor.

In addition, compounds of Formula I can be used to prepare a medicament useful for the treatment of Type II diabetes, the treatment of obesity, and the stimulation or activation of the .beta..sub.3 receptor.

DETAILED DESCRIPTION

For the purposes of the present invention, as disclosed and claimed herein, the following terms are defined below. As they relate to the present invention, the terms below may not be interpreted, individually or collectively, to describe chemical structures that are unstable or impossible to construct.

The term "halo" represents fluorine, chlorine, bromine, or iodine.

The term "C.sub.1 C.sub.4 alkyl" represents a cyclo, straight or branched chain alkyl group having from one to four carbon atoms such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and the like. A "haloalkyl" is one such alkyl substituted with one or more halo atoms, preferably one to three halo atoms. An example of a haloalkyl is trifluoromethyl. An "alkoxy" is a alkyl group covalently bonded by an --O-- linkage.

The term "1 to 5 carbon straight or branched alkylene" represents a one to five carbon, straight or branched, alkylene moiety. A branched alkylene may have one or more points of branching. A 1 to 5 carbon straight or branched alkylene may optionally be unsaturated at one or more carbons. Thus, a 1 to 5 carbon straight or branched alkylene includes 1 to 5 carbon alkylene, alkenylene and alkylidene moieties. Examples include methylene, ethylene, propylene, butylene, --CH(CH.sub.3)CH.sub.2--CH(C.sub.2H.sub.5)CH.sub.2--, --CH(CH.sub.3)CH(CH.sub.3)--, --CH.sub.2C(CH.sub.3).sub.2--, --CH.sub.2CH(CH.sub.3)CH.sub.2--, --C(CH.sub.3).sub.2CH.dbd., --CH.dbd.CHCH.sub.2--, --CH.dbd.CH--, and the like.

The "acyl" moiety, alone or in combination, is derived from an alkanoic acid containing from one to seven carbon atoms. The term "acyl" also includes moieties derived from an aryl carboxylic acid.

The term "aryl" represents an optionally substituted or unsubstituted phenyl or naphthyl. The term (CH.sub.2).sub.naryl is preferably benzyl or phenyl.

The term "optionally substituted" or "substituted" as used herein means an optional substitution of one to three, preferably one or two groups independently selected from halo, C.sub.1 C.sub.4 haloalkyl, hydroxy, carboxy, tetrazolyl, acyl, COOR.sub.2, CONR.sub.11R.sub.12, CONH(C.sub.1 C.sub.4 alkoxy), cyano, C.sub.1 C.sub.4 alkoxy, C.sub.1 C.sub.4 alkyl, phenyl, benzyl, nitro, NR.sub.11R.sub.12, NHCO(C.sub.1 C.sub.4 alkyl), NHCO(benzyl), NHCO(phenyl), SR.sub.2, S(C.sub.1 C.sub.4 alkyl), OCO(C.sub.1 C.sub.4 alkyl), SO.sub.2(NR.sub.11R.sub.12), SO.sub.2(C.sub.1 C.sub.4 alkyl), or SO.sub.2(phenyl).

R.sub.2 is independently hydrogen, C.sub.1 C.sub.4 alkyl, or aryl.

R.sub.11 and R.sub.12 are independently H, C.sub.1 C.sub.4 alkyl, or combine with the nitrogen to which each is bound to form morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl.

The term "heterocycle" represents a stable, optionally substituted or unsubstituted, saturated or unsaturated 5 or 6 membered ring, said ring having from one to four heteroatoms that are the same or different and that are selected from the group consisting of sulfur, oxygen, and nitrogen; and when heterocycle contains two adjacent carbon atoms, the adjacent carbon atoms may be structured to form a group of the formula --CH.dbd.CH--; provided that (1) when the heterocyclic ring contains 5 members, the heteroatoms comprise not more than two sulfur or two oxygen atoms but not both; and (2) when the heterocyclic ring contains 6 members and is aromatic, sulfur and oxygen are not present. The heterocycle may be attached at any carbon or nitrogen which affords a stable structure. The heterocycle may be optionally substituted. Examples of a heterocycle include but are not limited to pyrazole, pyrazoline, imidazole, isoxazole, triazole, tetrazole, oxazole, 1,3-dioxolone, thiazole, oxadiazole, thiadiazole, pyridine, pyrimidine, piperazine, morpholine, pyrazine, pyrrolidine, piperidine, oxazolidone, oxazolidinedione, imidazolidinone, and the like.

The term "leaving group" as used in the specification is understood by those skilled in the art. Generally, a leaving group is any group or atom that enhances the electrophilicity of the atom to which it is attached for displacement. Preferred leaving groups are p-nitrobenzene sulfonate, triflate, mesylate, tosylate, imidate, chloride, bromide, and iodide.

The term "pharmaceutically effective amount", as used herein, represents an amount of a compound of the invention that is capable of stimulating the .beta..sub.3 receptor in mammals. The particular dose of the compound administered according to this invention will, of course, be determined by the particular circumstances surrounding the patient, including the compound administered, the route of administration, the particular condition being treated, and similar considerations.

The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.

The term "treating," as used herein, describes the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of a compound of present invention to prevent the onset of the symptoms or complications, to alleviate the symptoms or complications, or to eliminate the disease, condition, or disorder.

The term "selective" means preferential agonism or stimulation of the .beta..sub.3 receptor over agonism of the .beta..sub.1 or .beta..sub.2 receptor. In general, the compounds demonstrate a minimum of a twenty fold differential (preferably over a 50.times. differential) in the dosage required to behave as an agonist to the .beta..sub.3 receptor and the dosage required for equal agonism of the .beta..sub.1 and .beta..sub.2 receptors as measured in the Functional Agonist Assay. The compounds demonstrate this differential across the range of doses. Thus, .beta..sub.3 selective compounds behave as agonists for the .beta..sub.3 receptor at much lower concentrations with lower toxicity by virtue of their minimal agonism of the other receptors.

The term "stimulating", as used herein, means affecting, activating, or agonizing the .beta..sub.3 receptor to elicit a pharmacological response. The stimulation or activation of the receptor may be either complete or partial relative to a known stimulating agent such as isoproterenol.

As previously noted, the present invention provides a method of treating type II diabetes and obesity, comprising administering to a mammal in need thereof compounds of the Formula I.

Preferred embodiments of the present invention are set out in paragraphs below.

##STR00010## ##STR00011##

(m) X.sub.1 is --OCH.sub.2--, the oxygen of which is attached to R.sub.1.

(n) X.sub.1 is a bond.

(o) R.sub.3 is methyl.

(p) R.sub.3 is hydrogen.

(q) R.sub.5 is methyl or ethyl.

(r) R.sub.6 is methyl or ethyl.

(s) R.sub.5 and R.sub.6 are both methyl.

(t) R.sub.5 and R.sub.6 are both hydrogen.

(u) X.sub.2 is isopropylene, methylene, or ethylene.

(v) X.sub.2 is isopropylene

(w) X.sub.2 is methylene.

(x) X.sub.2 is ethylene.

(y) R.sub.4 is

##STR00012##

(ab) R.sub.4 is

##STR00013##

(ad) R.sub.8 is halo.

(ae) R.sub.8 is hydrogen.

(af) R.sub.9 is halo, CN, OR.sub.10, C.sub.1 C.sub.4 alkyl, CO.sub.2R.sub.2, CONR.sub.11R.sub.12, CONH(C.sub.1 C.sub.4 alkyl or C.sub.1 C.sub.4 alkoxy), NR.sub.2SO.sub.2R.sub.2, SO.sub.2R.sub.2, SO.sub.2NR.sub.11R.sub.12, SOR.sub.2, optionally substituted aryl, optionally substituted heterocycle.

(ag) R.sub.9 is CO.sub.2R.sub.2, CONR.sub.11R.sub.12, CONH(C.sub.1 C.sub.4 alkyl or C.sub.1 C.sub.4 alkoxy), NR.sub.2SO.sub.2R.sub.2, SO.sub.2R.sub.2, SO.sub.2NR.sub.11R.sub.12, optionally substituted aryl, optionally substituted heterocycle, or C.sub.2 C.sub.4 alkenyl substituted with CN, CO.sub.2R.sub.2 or CONR.sub.11R.sub.12.

(ah) R.sub.9 is halo, CN, C.sub.1 C.sub.4 haloalkyl, SR.sub.2, CSNR.sub.2, CSNR.sub.11R.sub.12, SO.sub.2R.sub.2, SO.sub.2NR.sub.11R.sub.12, SOR.sub.2, optionally substituted aryl, optionally substituted heterocycle, or C.sub.2 C.sub.4 alkenyl substituted with CN, CO.sub.2R.sub.2 or CONR.sub.11R.sub.12.

(ai) R.sub.9 is OR.sub.10, optionally substituted aryl, optionally substituted heterocycle, or C.sub.2 C.sub.4 alkenyl substituted with CN, CO.sub.2R.sub.2 or CONR.sub.11R.sub.12.

(aj) R.sub.9 is NR.sub.2SO.sub.2R.sub.2.

(ak) R.sub.9 is CN.

(al) R.sub.9 is CONR.sub.11R.sub.12.

(am) R.sub.9 is OR.sub.10.

(an) R.sub.10 is (CH.sub.2).sub.nC.sub.3 C.sub.8 cycloalkyl, (CH.sub.2).sub.naryl, (CH.sub.2).sub.nheterocycle, said aryl, C.sub.3 C.sub.8 cycloalkyl, or heterocycle being optionally substituted.

(ao) R.sub.10 is (CH.sub.2).sub.nC.sub.3 C.sub.8 cycloalkyl, (CH.sub.2).sub.nheterocycle, said C.sub.3 C.sub.8 cycloalkyl, or heterocycle being optionally substituted.

(ap) R.sub.10 is (CH.sub.2).sub.nheterocycle said heterocycle being unsubstituted or optionally substituted.

(aq) R.sub.10 is aryl.

(ar) R.sub.10 is pyridyl.

(as) R.sub.10 is aryl substituted with CONR.sub.11R.sub.12, CN, CO.sub.2R.sub.2, or NR.sub.2SO.sub.2R.sub.2.

(at) R.sub.10 is pyridyl substituted with CONR.sub.11R.sub.12, CN, CO.sub.2R.sub.2, or NR.sub.2SO.sub.2R.sub.2.

(au) R.sub.10 is aryl substituted with CONR.sub.11R.sub.12.

(av) R.sub.10 is aryl substituted with CN.

(ax) R.sub.10 is aryl substituted with CO.sub.2R.sub.2. (ay) R.sub.10 is aryl substituted with NR.sub.2SO.sub.2R.sub.2.

(az) R.sub.10 is pyridyl substituted with CONR.sub.11R.sub.12.

(ba) R.sub.10 is pyridyl substituted with CN.

(bb) R.sub.10 is pyridyl substituted with CO.sub.2R.sub.2. (bc) R.sub.10 is pyridyl substituted with NR.sub.2SO.sub.2R.sub.2.

(bd) Preferred optional substitution is halo, C.sub.1 C.sub.4 haloalkyl, hydroxy, carboxy, tetrazolyl, acyl, COOR.sub.2, CONR.sub.11R.sub.12, cyano, C.sub.1 C.sub.4 alkoxy, C.sub.1 C.sub.4 alkyl, phenyl, benzyl, nitro, NR.sub.11R.sub.12, NHCO(benzyl), SO.sub.2(C.sub.1 C.sub.4 alkyl), or SO.sub.2(phenyl).

(be) Other preferred optional substitution is halo, C.sub.1 C.sub.4 haloalkyl, hydroxy, carboxy, tetrazolyl, acyl, COOR.sub.2, CONR.sub.11R.sub.12, cyano, C.sub.1 C.sub.4 alkoxy, C.sub.1 C.sub.4 alkyl, phenyl, nitro, or NR.sub.11R.sub.12.

(bf) Other preferred optional substitution is halo, hydroxy, carboxy, acyl, COOR.sub.2, CONR.sub.11R.sub.12, cyano, C.sub.1 C.sub.4 alkoxy, C.sub.1 C.sub.4 alkyl, phenyl, or NR.sub.11R.sub.12.

(bg) Other preferred optional substitution is halo, hydroxy, acyl, C.sub.1 C.sub.4 alkoxy, C.sub.1 C.sub.4 alkyl, or phenyl.

(bh) Preferred halo groups include bromine, chlorine, or fluorine.

(bi) Other preferred halo groups include chlorine or fluorine.

(bj) Most preferred halo groups include fluorine.

(bk) R.sub.7 is hydrogen

(bl) R.sub.7 is halo, hydroxy, OR.sub.2, C.sub.1 C.sub.4 alkyl, C.sub.1 C.sub.4 haloalkyl, aryl, COOR.sub.2, CONR.sub.2R.sub.2, NHCOR.sub.2, C.sub.1 C.sub.4 alkoxy, NHR.sub.2, SR.sub.2, CN, SO.sub.2R.sub.2, SO.sub.2NHR.sub.2, or SOR.sub.2.

(bm) R.sub.7 is halo, hydroxy, OR.sub.2, C.sub.1 C.sub.4 alkyl, or C.sub.1 C.sub.4 alkoxy.

Especially preferred compounds include the following:

##STR00014##

By virtue of their acidic moieties, some of the compounds of Formula I include the pharmaceutically acceptable base addition salts thereof. Such salts include those derived from inorganic bases such as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, as well as salts derived from basic organic amines such as aliphatic and aromatic amines, aliphatic diamines, hydroxy alkamines, and the like. Such bases useful in preparing the salts of this invention thus include ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, methylamine, diethylamine, ethylenediamine, cyclohexylamine, ethanolamine and the like.

Because of a basic moiety, some of the compounds of Formula I can also exist as pharmaceutically acceptable acid addition salts. Acids commonly employed to form such salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic, acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, mono-hydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, 2-butyne-1,4 dioate, 3-hexyne-2,5-dioate, benzoate, chlorobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hippurate, .beta.-hydroxybutyrate, glycollate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like salts.

In addition, it is recognized that compounds of the present invention may for a variety of solvates with a number of different solvents. Representative solvates can be useful as final embodiments of the present invention or as intermediates in the isolation or preparation of the final embodiments of this invention. For example solvates can be prepared with lower alcohols such as ethanol and with alkyl esters such ethylacetate.

It is recognized that various stereoisomeric forms of the compounds of Formula I may exist. The compounds may be prepared as racemates and can be conveniently used as such. Therefore, the racemates, individual enantiomers, diastereomers, or mixtures thereof form part of the present invention. Unless otherwise specified, whenever a compound is described or referenced in this specification all the racemates, individual enantiomers, diastereomers, or mixtures thereof are included in said reference or description.

The compounds of Formula I can be prepared as described in the following Schemes and Examples. Schemes I and II describe methodology for the preparation of final embodiments of the present invention. Schemes III VII represent methodology for the preparation of intermediates required for the construction of the final embodiments of the invention.

##STR00015##

In Scheme I, X.sub.1, X.sub.2, R.sub.1, R.sub.2, R.sub.4, R.sub.5, and R.sub.6 have the same meaning as previously described; and X.sub.3 is a bond. The reaction of Scheme I is carried out under conditions appreciated in the art for the amination of epoxides. For example, the epoxide (A) may be combined with the amine (B) in an alcohol, such as ethanol, at room temperature to the reflux temperature of the reaction mixture. Preferably, the reaction is carried out under conditions generally described in Atkins et al., Tetrahedron Lett. 27:2451 (1986). These conditions include mixing the reagents in the presence of trimethylsilyl acetamide in a polar aprotic solvent such as acetonitrile, dimethylformamide (DMF), acetone, dimethylsulfoxide (DMSO), dioxane, diethylene glycol dimethyl ether (diglyme), tetrahydrofuran (THF), or other polar aprotic solvents in which the reagents are soluble. Preferably, the solvent is DMSO. The reaction is carried out at temperatures ranging from about 0.degree. C. to reflux.

Expoxides utilized in scheme I can be prepared by methods well known in the art, or according to Scheme III from starting material known in the art.

Certain compounds of the present invention are prepared by a novel combinatorial/parallel synthesis. This synthesis is described in Scheme II.

##STR00016##

In Scheme II, X.sub.1, X.sub.2, R.sub.1, R.sub.4, and R.sub.5 have the same meaning as previously described and R.sub.6 is hydrogen. The reaction of Scheme II is preferably carried out by adding to a glass vial: a non-reactive solvent such as methanol, DMF, methylene chloride or acetonitrile, amine (IV), and ketone (V). The solution is shaken to allow for imine formation and treated with Amberlite IRA400 borohydride resin (Aldrich Chemicals). The slurry is then shaken an additional 24 hours to effect reduction to the secondary amine. Methylene chloride and polystyrene-linked benzaldehyde resin (Frechet, J. M. et al., J. Am Chem. Soc. 93:492 (1971)) is added to the vial, in order to scavenge excess primary amine starting material. The slurry is shaken, preferably overnight. The slurry is then filtered through a cotton plug, and the residual solids are rinsed with methanol. Evaporation under a flow of air, followed by drying for several hours at room temperature in a vacuum oven yields the desired product of sufficient purity.

Alternatively, compounds of formula (V) can be prepared by dissolving, in a vial, the amine and ketone in a non-reactive solvent or solvent mixture such as methanol, DMF, or the like. Acetic acid and sodium cyanoborohydride are then added. After being shaken for approximately 72 hours the reaction mixture is applied to an ionexchange column such as SCX. The column is flushed with solvent and the product was then eluted using a solution such as ammonia, in methanol. The solvent was evaporated, followed by drying in a vacuum oven to yield the secondary amine product.

A modification of Scheme II is necessary when the amine hydrochloride salt is used. Addition of resin-bound base to the initial reaction mixture prior to reduction or scavenging allows the desired reaction to proceed. Imine formation using amine hydrochloride salts, an aldehyde or ketone, and a resin bound amine base may be carried out using two different resins: poly(4-vinylpyridine), commercially available from Aldrich, and resin (VIII), synthesized by the reaction of Merrifield resin with piperidine (Scheme IIa):

##STR00017## In Scheme IIa, PS is polysytrene. Both the poly(4-vinylpyridine) and resin (VIII) promote imine formation.

Scheme II can also be carried out by utilization of traditional techniques. Reductive aminations described in scheme II are well known in the art. They are typically performed by mixing the amine and ketone starting materials in a solvent and adding a reducing agent. Solvents typically include lower alcohols, DMF, and the like. A wide variety of reducing agents can be utilized, most commonly utilized are sodium borohydride and sodium cyanoborohydride. The reaction is typically performed at room temperature to the reflux temperature of the solvent. Products are isolated by techniques well known in the art.

The ketone and amino starting materials of Scheme II can be prepared by techniques recognized and appreciated by one skilled in the art. The synthesis of the starting materials is generally described in Schemes III and VII.

##STR00018##

In Scheme III, R.sub.1 is the same as previously defined. R.sub.13 is OH or SH. Equimolar amounts of the aromatic compound (Compound IX) and (2S)-(+)-glycidyl 3-nitrobenzenesulfonate (Compound X) are dissolved in an inert solvent such as acetone or DMF and treated with about 1.1 equivalents of a non-reactive acid scavenger, such as K.sub.2CO.sub.3. The suspension is then heated at reflux for 16 20 hours with stirring. The solvent is removed in vacuo. The residue is partitioned between chloroform or other organic solvent and water. The organic layer is dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give the compound (XI) in sufficient purity (>95%) and yield (85 100%).

The epoxide (XI) is dissolved in an alcohol, preferably methanol, and treated with one equivalent of dibenzylamine. The solution is preferably stirred at reflux for three to four hours and then cooled to ambient temperature. Approximately 10 equivalents of ammonium formate are added to the flask, followed by 10% palladium on carbon, and the suspension stirred vigorously at reflux for 30 45 minutes. The reaction mixture is then filtered through Celite, concentrated in vacuo to a minimum volume and treated with 1.1 equivalents of a 1.0 M anhydrous solution of HCl in ether. The solution is concentrated to dryness. The solid residue is triturated with pentane to yield products of sufficient purity (>97%) and yield (60 100%). If desired, further purification may be carried out by passing over a short plug of silica, eluting with CHCl.sub.3, then 95:5 CHCl.sub.3/MeOH, then 25:5:1 CHCl.sub.3/MeOH/NH.sub.4OH.

Alternatively, the epoxide (XI) is treated with a solution of methanol saturated with ammonia gas and stirred at room temperature in a sealed tube for 16 hours. This solution is then evaporated, and the residue subjected to standard purifications such as column chromatography or recrystallization. The HCl salt is then optionally produced by the addition of HCl gas in ether.

The ketone moieties of Scheme II, that are either unknown in the art or not commercially available, can be prepared in accordance with Scheme IV.

##STR00019##

In Scheme IV, R.sub.4 and R.sub.5 are the same as previously defined. The notation - - - indicates optional branching. Preferably, R.sub.4 is a substituted phenyl. The reaction described in Scheme IV is referred to as a Heck reaction and is described in A. J. Chalk et al., J. Org. Chem. 41: 1206 (1976). The reaction is achieved by treating compound (XIII) with an arylpalladium reagent. The arylpalladium reagent is generated in situ by treating Compound (XIV) with a palladium-triarylphosphine complex. The reaction is generally carried out under conditions appreciated in the art.

Additional amines, of the type where X.sub.2 is methylene, R.sub.4 is aryl, and R.sub.10 is aryl, heterocycle, optionally substituted aryl, or optionally substituted heterocycle, that are reacted in a manner analogous to Scheme I can be prepared in accordance with Scheme V.

##STR00020##

R.sub.5, R.sub.6, and R.sub.10 are as previously defined and X.sub.2 is methylene. Compounds of the formula (XVII) can be prepared by reacting 4-hydroxybenzyl alcohol with excess (5 mol/equiv) of a compound of formula (XVIA) by methods well known in the art. (see Sh. Prikl. Kin., Vol 45, 1573 77 (1972); Russ.) The reaction can also be carried out by mixing the reagents in an aprotic solvent, preferably diglyme, and adding potassium t-butoxide (0.5 mol/equiv.). The reaction is then heated to reflux and water removed. After removal of water is complete, generally 2 8 hours depending upon the scale of the reaction, the resulting solution is subjected to aqueous workup including acidic washes and the product is isolated by crystallization. Compound (XVII) can be reduced by methods well known in the art. Compound (XVIII) is preferably prepared by hydrogenation of the corresponding compound (XVII) over a precious metal catalyst. The hydrogenation can be affected at between 20 and 60 psi of hydrogen, and with a variety of solvents, temperatures, and catalysts well known in the art. The reaction is preferably carried out at 50 psi of hydrogen over 5% palladium on carbon wetted with 2B3 ethanol. Compound (XVII) is charged to the reactor along with one equivalent of acetic acid, diluted with methanol, heated to 50.degree. C., and subjected to hydrogen for 5 24 hours depending on the scale of the reaction. The product is isolated as the acetic acid salt upon work up by methods well known in the art.

A skilled artisan would appreciate that compound (XVIII) could be coupled with a wide variety of aromatic halides to yield the claimed ethers. The coupling can be carried out according to procedures well known in the art and is preferably performed by mixing the starting materials in N,N-dimethylacetamide and toluene in the presence of potassium carbonate. The reaction is then heated to reflux for 5 to 24 hours and water removed. The product is typically isolated by aqueous work up after rotory evaporation of the reaction solvent. The crude product can be purified by methods well know in the art. A skilled artisan would appreciate that the amines prepared by Scheme V can be utilized in Scheme I to prepare compounds of the present invention.

Other amines used to construct final embodiments of the present invention can be prepared according to scheme VI.

##STR00021##

Compounds of formula (XXI) can be prepared by the addition of a nucleophile, of the formula R.sub.6-M, wherein M is a metal or metal salt, to the compounds of formula (XX) according to procedures well known in the art. The skilled artisan would appreciate a wide variety of conditions amenable to performing the additions. Preferred nucleophiles include, but are not intended to be limited to, alkyl grignard reagents, alkyl lithium reagents, and the like.

Compounds of formula (XXII) can be prepared from the compounds of formula (XXI) by the Ritter reaction. (See Organic Reactions, Vol. 17, pp. 213 325, (1979)).

Compounds of formula (XXIII) can be prepared by reduction of the compounds of formula (XXII) according to procedures well known in the art. Preferred reducing agents include, but are not intended to be limited to, borane complexes and the like.

Compounds of formula (XXIV) can be prepared by reduction of the compounds of formula (XXIII) according to procedures well known in the art. (See Greene T. W., Protective Groups in Organic Synthesis, John Wiley and Sons, (1981)).

Other amines used to construct final embodiments of the present invention can be prepared according to scheme VII, wherein J is a protecting group.

##STR00022##

The compounds of formula (XXVI) can be prepared from the amino esters of formula (XXV) by methods well known in the art. (see, Greene supra).

The amides of formula (XXVII) can be prepared from the N-protected amino acids of formula (XXVI) by methods well known in the art. For example, any number of peptide coupling procedures will affect the desired reaction. (see March, Advanced Organic Chemistry, 3 ed.)

The deprotection of the compounds of formula (XXVII) can be accomplished by methods well known in the art. (see, Greene supra).

##STR00023##

Compound (IXXX) can be prepared by the addition of phenyl hydrazine to 1,3-cyclohexanedione by methods known in the art. For example, phenylhydrazine or it salt can be dissolved in water and cyclohexanedione added. The addition is preferably ca