Aryl sulfonamides and sulfamide derivatives and uses thereof

Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citation for these references may be found at the end of this application, preceding the sequence listing and the claims.

BACKGROUND OF THE INVENTION

The peptide neurotransmitter neuropeptide Y (NPY) is a 36 amino acid member of the pancreatic polypeptide family with widespread distribution throughout the mammalian nervous system (Dumont et al., 1992). The family includes the namesake pancreatic polypeptide (PP), synthesized primarily by endocrine cells in the pancreas; peptide YY (PYY), synthesized primarily by endocrine cells in the gut; and NPY, synthesized primarily in neurons (Michel, 1991; Dumont et al., 1992; Wahlestedt and Reis, 1993). All pancreatic polypeptide family members share a compact structure involving a “PP-fold” and a conserved C-terminal hexapeptide ending in Tyr

36

(or Y

36

in the single letter code). The striking conservation of Y

36

has prompted the reference to the pancreatic polypeptides' receptors as “Y-type” receptors (Wahlestedt et al., 1987), all of which are proposed to function as seven transmembrane-spanning G protein-coupled receptors (Dumont et al., 1992).

NPY and its relatives elicit a broad range of physiological effects through activation of at least five G protein-coupled receptor subtypes known as Y1, Y2, Y3, Y4 (or PP), and the “atypical Y1”. While the Y1, Y2, Y3, and Y4 (or PP) receptors were each described previously in both radioligand binding and functional assays, the “atypical Y1” receptor is unique in that its classification is based solely on feeding behavior induced by various peptides including NPY.

The role of NPY in normal and abnormal eating behavior, and the ability to interfere with NPY-dependent pathways as a means to appetite and weight control, are areas of great interest in pharmacological and pharmaceutical research (Sahu and Kalra, 1993; Dryden et al., 1994). NPY is considered to be the most powerful stimulant of feeding behavior yet described (Clark et al., 1984; Levine and Morley, 1984; Stanley and Leibowitz, 1984). The stimulation of feeding behavior by NPY is thought to occur primarily through activation of the hypothalamic “atypical Y1” receptor. For example, direct injection of NPY into the hypothalamus of satiated rats can increase food intake up to 10-fold over a 4-hour period (Stanley et al., 1992). Similar studies using other peptides has resulted in a pharmacologic profile for the “atypical Y1” receptor according to the rank order of potencies of peptides in stimulating feeding behavior as follows: NPY

2-36

≧NPY˜PYY˜[Leu

31

,Pro

34

]NPY>NPY

13-36

(Kalra et al., 1991; Stanley et al., 1992). The profile is similar to that of a Y1-like receptor except for the anomalous ability of NPY

2-36

to stimulate food intake with potency equivalent or better than that of NPY. A subsequent report in

J. Med. Chem.

by Balasubramaniam and co-workers (1994) showed that feeding can be regulated by [D-Trp

32

]NPY. While this peptide was presented as an NPY antagonist, the published data at least in part support a stimulatory effect of [D-Trp

32

]NPY on feeding. In contrast to other NPY receptor subtypes, the “feeding” receptor has never been characterized for peptide binding affinity in radioligand binding assays. The fact that a single receptor could be responsible for the feeding response has been impossible to validate in the absence of an isolated receptor protein; the possibility exists, for example, that the feeding response could be a composite profile of Y1 and Y2 subtypes.

This problem has been addressed by cloning rat and human cDNAs which encode a single receptor protein, referred to herein as Y5, whose pharmacologic profile links it to the “atypical Y1” receptor. The identification and characterization by applicants of a single molecular entity which explains the “atypical Y1” receptor allows the design of selective drugs which modulate feeding behavior. It is important to note, though, that any credible means of studying or modifying NPY-dependent feeding behavior must necessarily be highly selective, as NPY interacts with multiple receptor subtypes, as noted above (Dumont et al., 1992).

As used in this invention, the term “antagonist” refers to a compound which decreases the activity of a receptor. In the case of a G-protein coupled receptor, activation may be measured using any appropriate second messenger system which is coupled to the receptor in a cell or tissue in which the receptor is expressed. Some specific but by no means limiting examples of well-known second messenger systems are adenylate cyclase, intracellular calcium mobilization, ion channel activation, guanylate cyclase, and inositol phospholipid hydrolysis. Conversely, the term “agonist” refers to a compound which increases the activity of a receptor.

In order to test compounds for selective binding to the human Y5 receptor the cloned cDNAs encoding both the human and rat Y2 and Y4 (or PP) receptors have been used. The human and rat Y5 receptors were disclosed in PCT International Application No. PCT/US95/15646, published Jun. 6, 1996, and filed as a continuation in part of U.S. Ser. No. 08/349,025, filed Dec. 2, 1994, the contents of which are hereby incorporated by reference into this application. The human and rat Y2 receptors were disclosed in PCT International Application US95/01469, published Aug. 10, 1995, as WO 95/21245, and filed as a continuation-in-part of U.S. Ser. No. 08/192,288, filed Feb. 3, 1994, the contents of which are hereby incorporated by reference into this application. The human and rat Y4 receptors were disclosed in PCT International Application PCT/US94/14436, published Jul. 6, 1995, as WO 95/17906, and filed as a continuation-in-part of U.S. Ser. No. 08/176,412, filed Dec. 28, 1993, the contents of which are hereby incorporated by reference into this application. The Y1 receptor has been cloned from a variety of species including human, rat and mouse (Larhammar et al, 1992; Herzog et al, 1992; Eva et al, 1990; Eva et al, 1992).

The synthesis of novel aryl sulfonamide and sulfamide compounds are disclosed which bind selectively to the cloned human Y5 receptor compared to the other cloned human NPY receptors, and inhibit the activation of the cloned human Y5 receptor as measured in in vitro assays. The in vitro receptor binding and activation assays described hereinafter were performed using various cultured cell lines, each transfected with and expressing only a single Y-type receptor. In addition, the compounds of the present invention were shown to inhibit in animals either NPY-induced feeding behavior or feeding behavior exhibited by food-deprived animals.

This invention is also directed to the treatment of feeding disorders such as obesity and bulimia nervosa using the compounds described herein. In addition, the compounds of the present invention may also be used to treat abnormal conditions such as sexual/reproductive disorders, depression, epileptic seizure, hypertension, cerebral hemorrhage, congestive heart failure or sleep disturbances, or any condition in which antagonism of a Y5 receptor may be useful.

SUMMARY OF THE INVENTION

This invention is directed to novel aryl sulfonamide and sulfamide compounds which bind selectively to and inhibit the activity of the human Y5 receptor. This invention is also related to uses of these compounds for the treatment of feeding disorders such as obesity, anorexia nervosa, bulimia nervosa, and abnormal conditions such as sexual/reproductive disorders, depression, epileptic seizure, hypertension, cerebral hemorrhage, congestive heart failure or sleep disturbances and for the treatment of any disease in which antagonism of a Y5 receptor may be useful.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds having the structures:

wherein Ar is

wherein each Z is independently N or C;

wherein each Y is independently N or C;

wherein p is an integer from 0 to 2;

wherein o is an integer from 0 to 1 and a is an integer from 0 to 3;

wherein V is S, O, N, or NR

5

;

wherein X is a single bond or —NH—;

wherein each R

2

is independently H; F; Cl; Br; I; NO

2

; OH; C

1

-C

4

alkyl; C

2

-C

4

alkenyl; C

1

-C

4

alkoxy; C

1

-C

4

hydroxyalkyl; C

1

-C

4

methoxyalkyl; C

1

-C

4

monohaloalkyl; C

1

-C

4

polyhaloalkyl; N(R

5

)

2

; NHCOR

5

; N(COR

5

)

2

; NHCO

2

R

5

; NHCONHR

5

; NHSO

2

R

5

; N(SO

2

R

5

)

2

; CO

2

R

5

; CON(R

5

)

2

; SO

2

N(R

5

)

2

; phenoxy; phenyl; pyridyl; thiophenyl; naphthyl; phthalimide; C

5

-C

7

lactam, C

5

-C

7

cyclic imide, C

5

-C

7

cyclic amino; wherein the phthalimide, lactam, cyclic imide, or cyclic amine is linked by nitrogen; and wherein the phenoxy, phenyl, pyridyl, thiophenyl, naphthyl, phthalimide, lactam, cyclic imide, or cyclic amine is substituted with H, F, Cl, Br, I, CF

3

, C

1

-C

4

alkyl, C

1

-C

4

alkoxy, C

1

-C

4

alkylthio, or NO

2

;

wherein each R

3

is independently H; F; Cl; Br; I; NO

2

; OH; C

1

-C

4

alkyl; C

2

-C

4

alkenyl; C

1

-C

4

alkoxy; C

1

-C

4

hydroxyalkyl; C

1

-C

4

methoxyalkyl; C

1

-C

4

monohaloalkyl; C

1

-C

4

polyhaloalkyl; N(R

5

)

2

; NHCOR

5

; N(COR

5

)

2

; NHCO

2

R

5

; NHCONHR

5

; NHSO

2

R

5

; N(SO

2

R

5

)

2

; CO

2

R

5

; CON(R

5

)

2

; SO

2

N(R

5

)

2

; or R

2

and R

3

present on adjacent carbon atoms can constitute C

5

-C

7

cycloalkyl, C

5

-C

7

heterocycloalkyl or C

5

-C

7

heteroaryl;

wherein each R

4

is independently H; F; Cl; Br; I; NO

2

; OH; C

1

-C

4

alkyl; C

1

-C

4

alkoxy; C

1

-C

4

hydroxyalkyl; C

1

-C

4

methoxyalkyl; C

1

-C

4

monohaloalkyl; C

1

-C

4

polyhaloalkyl; N(R

5

)

2

; NHCOR

5

; N(COR

5

)

2

; NHCO

2

R

5

; NHCONHR

5

; NHSO

2

R

5

; N(SO

2

R

5

)

2

; CO

2

R

5

; CON(R

5

)

2

; or SO

2

N(R

5

)

2

;

wherein each R

5

is independently H; C

1

-C

3

alkyl; C

1

-C

3

monohaloalkyl; or C

1

-C

3

polyhaloalkyl;

wherein L′ is —NR

1

—L— or

wherein L is C

3

-C

9

alkyl; C

3

-C

9

alkenyl; C

3

-C

9

alkynyl;

wherein R

1

is H; or C

1

-C

3

straight chained alkyl;

wherein the alkyl, alkenyl or alkynyl is substituted with H, OR

5

, CN, C

1

-C

6

alkyl, CH

2

OR

5

, CON(R

5

)

2

, CO

2

R

5

, phenyl, pyridyl, thiophenyl or naphthyl;

wherein one dashed line is a double bond and the other dashed line is a single bond;

wherein each R

6

is independently H; CN; OR

5

; C

1

-C

5

alkyl; CH

2

OR

5

; CON(R

5

)

2

; CO

2

R

5

; phenyl; pyridyl; thiophenyl or naphthyl; wherein the phenyl, pyridyl, thiophenyl or naphthyl is substituted with H, F, Cl, Br, I, CF

3

, C

1

-C

4

alkyl, C

1

-C

4

alkoxy, C

1

-C

4

alkylthio, or NO

2

;

wherein i is an integer from 1 to 4; wherein n is an integer from 0 to 3; wherein m is an integer from 0 to 3;

wherein K is —CH

2

—NR

10

—CHR

7

—(CH

2

)

j

—; —CH

2

—NR

10

—CO—(CH

2

)

j

—; —CH

2

—NH—CO—NH—(CH

2

)

j

—; —CO—NH—CHR

7

—(CH

2

)

j

—; —CH

2

—NR

10

—CO—CHR

7

—(CH

2

)

j

; —CH

2

—NR

10

—CS—(CH

2

)

j

—; —CH

2

—NH—CS—NH—(CH

2

)

i

—; —CS—NH—CHR

7

—(CH

2

)

j

—; —CH

2

—NR

10

—CS—CHR

7

—(CH

2

)

j

; or —CH

2

—N═CSR

1

—NH—(CH

2

)

j

;

wherein j is an integer from 0 to 3;

wherein R

7

is H; C

1

-C

6

alkyl; CH

2

OR

5

; —(CH

2

)

p

NHCO

2

R

5

; (CH

2

)

p

NHSO

2

R

5

; CH

2

N(R

11

)

2

; phenyl; pyridyl; thiophenyl; or naphthyl;

wherein W is

wherein Q is O; S; N; NR

9

; or C(R

5

)

2

;

wherein b is an integer from 1 to 2;

wherein R

8

is independently H; F; Cl; Br; I; NO

2

; OH; ═O; C

1

-C

4

alkyl; C

1

-C

4

alkoxy; C

1

-C

4

hydroxyalkyl; C

1

-C

4

methoxyalkyl; C

1

-C

4

monohaloalkyl; C

1

-C

4

polyhaloalkyl; N(R

5

)

2

; NHCOR

5

; N(COR

5

)

2

; NHCO

2

R

5

; NHCONHR

5

; NHSO

2

R

5

; N(SO

2

R

5

)

2

; CO

2

R

5

; CON(R

5

)

2

; or SO

2

N(R

5

)

2

;

wherein R

9

is H; C

1

-C

3

alkyl; COR

5

; CO

2

R

5

; CON(R

5

)

2

;

wherein R

10

is H; or C

1

-C

6

alkyl;

wherein R

11

is H; COR

5

; COR

12

; SO

2

R

5

; SO

2

R

12

; and

wherein R

12

is phenoxy; phenyl, pyridyl; thiophenyl; or naphthyl; wherein the phenoxy, phenyl, pyridyl, thiophenyl or naphthyl is substituted with H, F, Cl, Br, I, CF

3

, C

1

-C

4

alkyl, C

1

-C

4

alkoxy, C

1

-C

4

alkylthio, NO

2

, phenyl, pyridyl or thiophenyl; or a pharmaceutically acceptable salt thereof.

The invention also provides for the (+) and (−) enantiomers of the compounds described herein.

In one embodiment the invention provides for a compound as described above, where R

1

is H;

where L is selected from C

3

-C

9

alkyl or

where the alkyl is substituted with H, OR

5

, CN, C

1

-C

6

alkyl, CH

2

OR

5

, CON(R

5

)

2

, CO

2

R

5

, phenyl, pyridyl, thiophenyl or naphthyl; and

where W is

In other embodiments of the present invention, the compounds may have the structures where Ar is selected from:

where each of R

2

, R

3

and R

4

is independently H; F, Cl, Br or I; NO

2

; OH; C

1

-C

4

alkoxy; C

1

-C

4

hydroxyalkyl; C

1

-C

4

monohaloalkyl; C

1

-C

4

polyhaloalkyl; or N(R

5

)

2

; where X is a single bond; where each R

5

is independently C

1

-C

3

alkyl;

where L is selected from C

5

-alkyl or C

7

-alkyl;

where R

7

is H; CH

2

OH; or CH

2

OR

5

;

where W is

and where R

9

is H; or C

1

-C

3

alkyl.

In other embodiments of the present invention Ar is selected from:

and K is —CH

2

—NR

10

—CHR

7

—(CH

2

)

j

—.

Additional embodiments of the present invention include the compounds selected from the group consisting of:

Additional embodiments of the present invention include those in which L is C

5

-alkyl or C

7

-alkyl.

In an embodiment of the invention the compounds have the structure:

In one embodiment of the invention K is —CH

2

—NR

10

—CO—(CH

2

)

j

—.

In another embodiment of the invention the compound has the structure:

In yet another embodiment of the present invention K is —CH

2

—NH—CO—NH—(CH

2

)

j

—.

In a further embodiment of the invention the compound has the structure:

The invention also provides for a method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound effective to decrease the consumption of food by the subject so as to thereby modify feeding behavior of the subject, where the compound has the structure:

wherein Ar is

wherein L is C

3

-C

9

alkyl; C

3

-C

9

alkenyl; C

3

-C

9

alkynyl;

wherein R

1

is H; or C

1

-C

3

straight chained alkyl;

wherein the alkyl, alkenyl or alkynyl is substituted with H, OR

5

, CN, C

1

-C

6

alkyl, CH

2

OR

5

, CON(R

5

)

2

, CO

2

R

5

, phenyl, pyridyl, thiophenyl or naphthyl;

wherein one dashed line is a double bond and the other dashed line is a single bond;

wherein each R

6

is independently H; CN; OR

5

; C

1

-C

5

alkyl; CH

2

OR

5

; CON(R

5

)

2

; CO

2

R

5

; phenyl; pyridyl; thiophenyl or naphthyl; wherein the phenyl, pyridyl, thiophenyl or naphthyl is substituted with H, F, Cl, Br, I, CF

3

, C

1

-C

4

alkyl, C

1

-C

4

alkoxy, C

1

-C

4

alkylthio, or NO

2

;

wherein i is an integer from 1 to 4; wherein n is an integer from 0 to 3; wherein m is an integer from 0 to 3;

wherein K is —CH

2

—NR

10

—CHR

7

—(CH

2

)

j

—; —CH

2

—NR

10

—CO—(CH

2

)

j

—; —CH

2

—NH—CO—NH—(CH

2

)

j

—; —CO—NH—CHR

7

—(CH

2

)

j

—; —CH

2

—NR

10

—CO—CHR

7

—(CH

2

)

j

; —CH

2

—NR

10

—CS—(CH

2

)

j

—; —CH

2

—NH—CS—NH—(CH

2

)

i

—; —CS—NH—CHR

7

—(CH

2

)

j

—; —CH

2

—NR

10

—CS—CHR

7

—(CH

2

)

j

; or —CH

2

—N═CSR

1

—NH—(CH

2

)

j

;

wherein j is an integer from 0 to 3;

wherein R

7

is H; C

1

-C

6

alkyl; CH

2

OR

5

; (CH

2

)

p

NHCO

2

R

5

; (CH

2

)

p

NHSO

2

R

5

; CH

2

N(R

11

)

2

; phenyl; pyridyl; thiophenyl; or naphthyl;

wherein W is

wherein Q is O; S; N; NR

9

; or C(R

5

)

2

;

wherein b is an integer from 1 to 2;

wherein R

8

is independently H; F; Cl; Br; I; NO

2

; OH; ═O; C

1

-C

4

alkyl; C

1

-C

4

alkoxy; C

1

-C

4

hydroxyalkyl; C

1

-C

4

methoxyalkyl; C

1

-C

4

monohaloalkyl; C

1

-C

4

polyhaloalkyl; N(R

5

)

2

; NHCOR

5

; N(COR

5

)

2

; NHCO

2

R

5

; NHCONHR

5

; NHSO

2

R

5

; N(SO

2

R

5

)

2

; CO

2

R

5

; CON(R

5

)

2

; or SO

2

N(R

5

)

2

;

wherein R

9

is H; C

1

-C

3

alkyl; COR

5

; CO

2

R

5

; CON(R

5

)

2

;

wherein R

10

is H; or C

1

-C

6

alkyl;

wherein R

11

is H; COR

5

; COR

12

; SO

2

R

5

; SO

2

R

12

; and

wherein R

12

is phenoxy; phenyl, pyridyl; thiophenyl; or naphthyl; wherein the phenoxy, phenyl, pyridyl, thiophenyl or naphthyl is substituted with H, F, Cl, Br, I, CF

3

, C

1

-C

4

alkyl, C

1

-C

4

alkoxy, C

1

-C

4

alkylthio, NO

2

, phenyl, pyridyl or thiophenyl; or a pharmaceutically acceptable salt thereof.

In one embodiment of the method described above the subject is a vertebrate, a mammal, a human or a canine. In another embodiment the compound is administered in combination with food.

The invention also provides for a method of modifying feeding behavior where the compound has the structure:

The invention further provides a method of treating a feeding disorder in a subject which comprises administering to the subject an amount of a compound effective to decrease consumption of food by the subject, where the compound has the structure:

wherein Ar is

wherein L is C

3

-C

9

alkyl; C

3

-C

9

alkenyl; C

3

-C

9

alkynyl;

wherein R

1

is H; or C

1

-C

3

straight chained alkyl;

wherein the alkyl, alkenyl or alkynyl is substituted with H, OR

5

, CN, C

1

-C

6

alkyl, CH

2

OR

5

, CON(R

5

)

2

, CO

2

R

5

, phenyl, pyridyl, thiophenyl or naphthyl;

wherein one dashed line is a double bond and the other dashed line is a single bond;

wherein each R

6

is independently H; CN; OR

5

; C

1

-C

5

alkyl; CH

2

OR

5

; CON(R

5

)

2

; CO

2

R

5

; phenyl; pyridyl; thiophenyl or naphthyl; wherein the phenyl, pyridyl, thiophenyl or naphthyl is substituted with H, F, Cl, Br, I, CF

3

, C

1

-C

4

alkyl, C

1

-C

4

alkoxy, C

1

-C

4

alkylthio, or NO

2

;

wherein i is an integer from 1 to 4; wherein n is an integer from 0 to 3; wherein m is an integer from 0 to 3;

wherein K is —CH

2

—NR

10

—CHR

7

—(CH

2

)

j

—; —CH

2

—NR

10

—CO—(CH

2

)

j

—; —CH

2

—NH—CO—NH—(CH

2

)

j

—; —CO—NH—CHR

7

—(CH

2

)

j

—; —CH

2

—NR

10

—CO—CHR

7

—(CH

2

)

j

; —CH

2

—NR

10

—CS—(CH

2

)

j

—; —CH

2

—NH—CS—NH—(CH

2

)

i

—; —CS—NH—CHR

7

—(CH

2

)

j

—; or —CH

2

—NR

10

—CS—CHR

7

—(CH

2

)

j

; or —CH

2

—N═CSR

1

—NH—(CH

2

)

j

;

wherein j is an integer from 0 to 3;

wherein R

7

is H; C

1

-C

6

alkyl; CH

2

OR

5

; (CH

2

)

p

NHCO

2

R

5

; (CH

2

)

p

NHSO

2

R

5

; CH

2

N(R

11

)

2

; phenyl; pyridyl; thiophenyl; or naphthyl;

wherein W is

wherein Q is O; S; N; NR

9

; or C(R

5

)

2

;

wherein b is an integer from 1 to 2;

wherein R

8

is independently H; F; Cl; Br; I; NO

2

; OH; ═O; C

1

-C

4

alkyl; C

1

-C

4

alkoxy; C

1

-C

4

hydroxyalkyl; C

1

-C

4

methoxyalkyl; C

1

-C

4

monohaloalkyl; C

1

-C

4

polyhaloalkyl; N(R

5

)

2

; NHCOR

5

; N(COR

5

)

2

; NHCO

2

R

5

; NHCONHR

5

; NHSO

2

R

5

; N(SO

2

R

5

)

2

; CO

2

R

5

; CON(R

5

)

2

; or SO

2

N(R

5

)

2

;

wherein R

9

is H; C

1

-C

3

alkyl; COR

5

; CO

2

R

5

; CON(R

5

)

2

;

wherein R

10

is H; or C

1

-C

6

alkyl;

wherein R

11

is H; COR

5

; COR

12

; SO

2

R

5

; SO

2

R

12

; and

wherein R

12

is phenoxy; phenyl, pyridyl; thiophenyl; or naphthyl; wherein the phenoxy, phenyl, pyridyl, thiophenyl or naphthyl is substituted with H, F, Cl, Br, I, CF

3

, C

1

-C

4

alkyl, C

1

-C

4

alkoxy, C

1

-C

4

alkylthio, NO

2

, phenyl, pyridyl or thiophenyl; or a pharmaceutically acceptable salt thereof.

In an embodiment of the present invention the feeding disorder may be obesity or bulimia. In another embodiment of the present invention the subject is a vertebrate, a mammal, a human or a canine. The invention also provides for the decrease in the consumption of food by the subject by the compound inhibiting the activity of the subject's Y5 receptor.

The invention further provides a method of treating a feeding disorder in a subject which comprises administering to the subject an amount of one of the following compounds:

This invention also provides a method for treating a disorder in a subject which is alleviated by administering to the subject an amount of a compound described herein which is a Y5 receptor antagonist.

This invention additionally provides a method of treating obesity in a subject which comprises administering to the subject an amount of a Y5 receptor antagonist compound described herein.

This invention additionally provides a method of treating non-feeding disorders in a subject which comprises administering to the subject an amount of a compound described herein which is a Y5 receptor antagonist.

This invention further provides that any of the methods for treating may comprise administering to the subject a plurality of compounds described herein.

The invention also provides for the (−) and (+) enantiomers of the compounds of the subject application described herein. Included in this invention are pharmaceutically acceptable salts and complexes of all of the compounds described herein. The salts include but are not limited to the acids and bases listed herein. The following inorganic acids; hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid. The organic acids; acetic acid, trifluoroacetic acid, formic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzoic acid, glycolic acid, lactic acid and mandelic acid. The following inorganic bases; ammonia, hydroxyethylamine and hydrazine. The following organic bases; methylamine, ethylamine, propylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, ethylenediamine, hydroxyethylamine, morpholine, piperazine and guanidine. This invention further provides for the hydrates and polymorphs of all of the compounds described herein.

This invention further provides for the metabolites and precursors of the compounds of the present invention. The in vivo actions of numerous enzymes responsible for the generation of metabolites of pharmaceutical compounds are well-known in the art. For example, ethers may be modified to alcohols, or esters may be modified by esterases to yield acids as products. Knowledge of the activities of endogenous enzymes also allows the design of precursors or prodrugs of the compounds of the present invention, which when administered to a subject, such as a vertebrate or a human, are expected to yield metabolites which include the compounds of the present invention. For example, secondary amines may be modified by various substituents, such as methyl, alkanoyl, aroyl, or alkyl or aryl carbamates may be formed, which are expected to yield the compounds of the present invention when acted upon in vivo by endogenous enzymes. Such modifications are intended only as illustrative examples, and are not intended to limit the scope of the present invention, as such modifications and techniques therefor are well-known in the art.

The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compounds described above and a pharmaceutically acceptable carrier. In the subject invention a “therapeutically effective amount” is any amount of a compound which, when administered to a subject suffering from a disease against which the compounds are effective, causes reduction, remission, or regression of the disease. In one embodiment the therapeutically effective amount is an amount from about 0.01 mg per subject per day to about 500 mg per subject per day, preferably from about 0.1 mg per subject per day to about 60 mg per subject per day and most preferably from about 1 mg per subject per day to about 20 mg per subject per day. In the practice of this invention the “pharmaceutically acceptable carrier” is any physiological carrier known to those of ordinary skill in the art useful in formulating pharmaceutical compositions.

In another embodiment the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in the form of a solution. In yet another embodiment, the pharmaceutically acceptable carrier is a solid and the composition is in the form of a powder or tablet. In a further embodiment, the pharmaceutical carrier is a gel and the composition is in the form of a suppository or cream. In a further embodiment the compound may be formulated as a part of a pharmaceutically acceptable transdermal patch.

A solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. Sterile liquid carriers can also be utilized for intranasal administration, for example with the use of a pressurized composition, or for inhalatory administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by for example, intramuscular, intrathecal, epidural, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compounds may be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium. Carriers are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.

The compound can be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents, for example, enough saline or glucose to make the solution isotonic, bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.

The compound can also be administered orally either in liquid or solid composition form. Compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.

Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.

One skilled in the art will readily appreciate that appropriate biological assays will be used to determine the therapeutic potential of the claimed compounds for treating the above noted disorders.

This invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter.

EXPERIMENTAL DETAILS

Synthetic Methods

The compounds of the present invention may be synthesized according to the methods described in Schemes 1-4, as described herein. It is generally preferred that the respective product of each process step, as described hereinbelow, is separated and/or isolated prior to its use as starting material for subsequent steps. Separation and isolation can be effect by any suitable purification procedure such as, for example, evaporation, crystallization, column chromatography, thin layer chromatography, distillation, etc. While preferred reactants have been identified herein, it is further contemplated that the present invention would include chemical equivalents to each reactant specifically enumerated in this disclosure.

Temperatures are given in degrees Centigrade (° C.). The structure of final products, intermediates and starting materials is confirmed by standard anlytical methods, e.g., microanalysis and spectroscopic characteristics (e.g. MS, IR, NMR). Unless otherwise specified, chromatography is carried out using silica gel. Flash chromatography refers to medium pressure column chromatography according to Still et al., J. Org. Chem. 43, 2921 (1978).

Synthesis of Compounds According to Scheme 1

Preparation of the compounds of the present invention having the structure shown in Formula 1-2, Scheme 1, was carried out using well-known methodology for the preparation of a sulfonamide or sulfamide from an amine. Preferably the appropriate arylsulfonyl or arylsulfamoyl halide, preferably the chloride (i.e., Ar—X—SO

2

Cl), is reacted with a monoprotected linear or cyclic alkylamine (Krapcho and Kuell,

Synth. Comm.

20(16):2559-2564, 1990) comprising H

2

N-L-K″, where K″ comprises methylene, in the presence of a base such as a tertiary amine, e.g., triethylamine, dimethylaminopyridine, pyridine or the like, in an appropriate solvent (e.g. CHCl

3

, CH

2

Cl

2

) as shown in Scheme 1, step A, followed by deprotection of the resulting amine as shown in Scheme 1, Step B, all under mild conditions (typically room temperature), to yield the deprotected amine of Formula 1-1. Alternatively, the primary amine H

2

N-L may be replaced with a secondary amine wherein L comprises a piperidine. The arylsulfonyl or arylsulfamoyl halides are either known in the art or can be prepared according to methods well known in the art.

The deprotected amine may be converted to the product amine of Formula 1-2 by either a single step or two step reductive amination with an aryl substituted aldehyde WCHO as shown in Scheme 1, Step C, in the presence of a solvent such as toluene or dioxane, at elevated temperature, followed by reduction using sodium borohydride in a solvent such as ethanol. The K″ amine and the aldehyde carbon attached to W together form K in the product.

Compounds of Formula 1-3 in Scheme 1, wherein R

1

is H and j=0 and K comprises an amide, may be synthesized from the compound of Formula 1-1 by amidation using suitable methods such as those taught in “The Peptides,” Vol. 1 (Gross and Meinehofer, Eds. Acaemic Press, N.Y., 1979). For example, the compound of Formula 1-1 may be treated with a carboxylic acid derivative of W in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and dimethylaminopyridine (DMAP) in a suitable solvent such as CH

2

Cl

2

as shown in Scheme 1, Step D, at room temperature in an inert atmosphere of argon or nitrogen, to yield the amide compound of Formula 1-3. As in the previous method, the K″ amine and the carboxylic acid carbon attached to W together form K in the product.

Alternatively, the compound of Formula 1-3 may be synthesized by acylation of the amine of Formula 1-1 using the acid chloride of W, i.e., WCOCl or W(CH

2

)

j

COCl where j is an integer from 1 to 3, in a solvent such as CH

2

Cl

2

and a suitable tertiary amine such as triethylamine, at room temperature. Again, the K″ amine and the acid chloride carbon attached to W together form K in the product.

This method also provides an alternative path to the compounds of Formula 1-2 by reduction of the amide of Formula 1-3 using borane-tetrahydorfuran (THF) complex, in THF as shown in Scheme 1, Step E, at elevated temperature in an inert atmosphere.

Compounds of Formula 1-4 in Scheme 1 where K comprises a ureido moiety may be synthesized by urea formation between the the compound of Formula 1-1 and a substituted aryl isocyanate or aryl carbamate, as shown in Scheme 1, Step F, in a suitable solvent and a suitable tertiary amine such as triethylamine and N-methylmorpholine, at room temperature in an inert atmosphere. The ureido moiety comprising K is formed between the K″ amine and the isocyanate (or isothiocyanate) attached to W, or between K″ and the carbamate derivative of W. Alternatively, compounds containing a thiourea moiety instead of a urea moiety may be synthesized similarly by simply replacing the aryl isocyanate described above with an aryl isothiocyanate.

Suitable aryl carbamates may be of the form WCO

2

Ar′ where W is for example

and Ar′ may be for example 4-nitrophenyl.

Synthesis of the compounds of Table 1

As an illustrative example of the synthesis of the compounds shown in Table 1, the synthesis of Example 1 from Table 1, is provided below:

N-[6{(Naphthalen-2-ylmethyl)-amino}-hexyl]-2-nitrobenzenesulfonamide

Step A, Scheme 1

[6-(2-Nitrobenzenesulfonylamino)-hexyl]-carbamic acid t-butyl ester:

To a stirred solution of N-Boc 1, 6-diaminohexane hydrochloride (1.51 g, 6 mmol) and triethyl amine (1.31 g, 13 mmol) in 50 mL methylene chloride was added 2-Nitrobenzenesulfonyl chloride (1.326 g, 6 mmol). The reaction mixture was stirred for 6 h at room temperature, quenched with brine, and extracted with methylene chloride (2×50 mL). The organic layer was washed with brine (a saturated solution of sodium chloride in water, unless otherwise specified), dried over anhydrous sodium sulfate, and concentrated in vacuo to yield the titled compound as yellow oil (2.1 g, 87%).

Step B, Scheme 1

N-(6-Aminohexyl)-2-nitrobenzenesulfonamideHydrochloride:

To a stirred solution of [6-(2-Nitrobenzenesulfonylamino)-hexyl]-carbamic acid t-butyl ester (2.0 g, 4.9 mmol) in 25 mL of methylene chloride at room temperature was added 3 mL of saturated HCl solution in ethyl acetate and stirred for 4 h. The precipitated solid was filtered to yield the titled compound as white solid (1.58 g, 95%); mp 161-162° C.

Step C, Scheme 1

N -[6{(Naphthalen-2-ylmethyl)-amino}-hexyl]-2-nitrobenzenesulfonamide:

A mixture of N-(6-Aminohexyl)-2-nitrobenzenesulfonamide hydrochloride (0.67 g, 2.0 mmol) and 2-naphthaldehyde (0.32 g, 2.1 mmol) in 75 mL of toluene was refluxed using a Dean Stark trap for 20 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethanol (40 mL) and sodium borohyride (0.020 g,6.0 mmol) was added. After the reaction was complete (6 h), the solvent was evaporated and residue taken up in 30 mL of saturated sodium chloride solution and extracted with ethyl acetate(3×40mL), washed with saturated sodium chloride solution, dried over sodium sulfate and concetrated to afford an oil. The oil was flash chromatographed over silica gel to afford the titled compound (0.16 g, 37%) which was converted into hydrochloride salt (mp 169° C.).

An example of the use of the alternative path to the compounds of Formula 1-2 by reduction of the amide of Formula 1-3 using borane-THF complex as previously described for Scheme 1, Step E, is provided for Example 15 of Table 1, as follows:

N-[6{(1, 2, 3, 4-tetrahydronaphthalen-2-ylmethyl)-amino}-hexyl]-2-aminobenzenesulfonamide

To a solution of 1, 2, 3, 4-tetrahydro-2-naphthalencarboxylic acid[6-(2-nitrobenzenesulfonylamino)-hexyl]-amide (0.090 g, 0.19 mmol) in tetrahydrofuran (5 mL) cooled to 0° C. was added 2 mL 1M solution of borane:THF complex and the reaction mixture was refluxed for 12 h. The reaction mixture was cooled in an ice bath and quenched with 2 mL of 1N HCl. The reaction mixture was neutralized with 10% aqueous sodium hydroxide solution and extracted with ethyl acetate (3×25 mL). The organic phase was washed with brine, dried over sodium sulfate, and evaporated in vacuo to afford an oil which was purified by preparative TLC to afford the titled compound (0.06 g,70%); hydrochloride salt mp (162-163° C.).

Using appropriately substituted starting materials, the other Examples shown in Table 1 were synthesized as described above, with the exception of Example 52. The compound of Example 52 in Table 1 was synthesized similarly, except that before deprotection of the amine of Formula 1-1 in Scheme 1 Step B, the sulfonyl nitrogen was alkylated with methyl iodide in dimethylformamide at room temperature to afford the N-methylated sulfonamide product (Sato et al., 1995), which was subsequently deprotected as in Scheme 1, Step B, for use in the remainder of Scheme 1. Other n-alkyl derivatives may be prepared similarly, using an n-alkyl halide in an inert solvent such as dimethylformamide as described above.

TABLE 1

No.

Ar

X

R

1

L

K

W

mp

Analysis

1