BRPI0610258A2 - compound or a pharmaceutically effective salt thereof, pharmaceutical composition, and use of a compound - Google Patents

Abstract

COMPOUND OR A PHARMACEUTICALLY EFFECTIVE SALT OF THE SAME, PHARMACEUTICAL COMPOSITION, AND USE OF A COMPOUND. The invention relates to benzisoxazole piperazine compositions and methods of using them to modulate sleep.

Description

1

"COMPOUND OR PHARMACEUTICALLY EFFICIENT SALT OF THE SAME, PHARMACEUTICAL COMPOSITION, AND USE OF A COMPOUND" FIELD OF THE INVENTION

The invention relates to methods for treating sleep disorders and compositions used in such methods.

BACKGROUND OF THE INVENTION

Difficulty falling asleep or continuing to sleep is a significant medical issue that arises for a variety of reasons. Sometimes these problems arise from endogenous conditions such as sleep apnea or insomnia. Other times these problems arise from exogenous stresses, such as shifting effect of work shift scale and "time zone fatigue". Whether caused by an endogenous or exogenous source, difficulty falling asleep or staying asleep can result in drowsiness problems, which impairs the health, quality of life and safety of those affected.

Existing sleep-inducing pharmaceutical treatments include sedatives or hypnotics, such as benzodiazepine and barbiturate derivatives. These treatments have numerous disadvantages including relapsing insomnia, delayed onset of desired sedative effects, persistence of desired sedative effects after the desired sleep period, and side effects due to nonspecific activity such as psychomotor and memory deficits, myorelaxation, and architecture. disturbed sleep, including REM sleep inhibition. Additionally, sedatives and hypnotics may be habit-forming, may lose their effectiveness after extended use, and may be metabolized more slowly by some people.

Consequently, doctors often recommend or prescribe antihistamines as a milder treatment for sleep disorders when hypnotics are less appropriate. However, many antihistamines suffer from numerous side effects. These side effects include QT interval prolongation on an electrocardiogram of a subject, as well as central nervous system (CNS) side effects such as decreased muscle tone and drooping eyelids. Finally, such compounds can bind to muscarinic receptors, which leads to anticholinergic side effects such as blurred vision, dry mouth, constipation, bladder weakness, dizziness and anxiety.

Consequently, there is a need for treatments that promote sleep with minor side effects. Additionally, although known sleep-inducing compounds are effective in treating sleep-onset insomnia, that is, a difficulty for the subject to fall asleep, there are currently no drugs to treat sleep-maintaining insomnia, that is, maintaining a person's sleep. subject throughout a normal sleep period after falling asleep. Thus, there is also a need for improved pharmaceutical treatments to maintain sleep in subjects in need of such treatment.

SUMMARY OF THE INVENTION The present invention relates to a sleep modulating benzisoxazole compounds. In one aspect, the invention relates to a compound of formula I:

<formula> formula see original document page 3 </formula> or a pharmaceutically acceptable salt, solvate, hydrate or prodrug

effective thereof, wherein m n, o, p, q are individually O, 1, 2, 3, 4, 5 or 6; X and Y are individually absent, O, Sj C (O), SO or SO2; R1, R2, R3 and R4 are independently selected from straight chain H, F, Cl, Br, I, CF3, C1 -C2 alkyl, C3, C4, C5 or C6, branched chain C3, C4, C5 or C6 alkyl C3, C4, C5, C6, C7, C8 or C8 cycloalkyl, C3, C4, C5, C6 or C7 heterocyclyl, OCF3, CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, C2, C3, C4, C5 or C6 hydroxyalkyl and C2, C3 hydroxyalkyl C4, C5 or C6; R 5, R 6, R 7 and R 8 are independently H, C 1 -C 2 alkyl, C 3, C 4, C 5 or C 6 straight chain, C 3, C 4, C 5 or C 6 branched chain alkyl; R5 and R6 Together with the carbon to which they are attached, are placed in contact to form a spiro ring of size 3, 4, 5, 6 or 7;

are placed in contact to form a spiro ring of size 3, 4, 5, 6 or

7; or substituents on two different atoms are contacted to form a ring of size 3, 4, 5, 6 or 7; and Z is selected from CO2H, CO2R9, where R9 is C1, C2, C3, C4, C5 or C6 alkyl, C0NHS (0) 2-alkyl, CONHS (0) 2-cycloalkyl, CONHS (O) rheter0alkyl, C0NHS (0 ) 2-aryl, CONHS (0) 2-heteroaryl, S (O) 2NHCO-alkyl, S (O) 2NHCO-cycloalkyl, S (O) 2NHCO-heteroalkyl, S (0) 2NHCO-aryl, S (0) 2NHCO -heteroaryl, C0NHS (0) 2N-alkyl, COS (0) 2N-cycloalkyl, CONHS (0) 2N-heteroalkyl, C0NHS (0) 2N-aryl, CONHS (O) 2N ^ heteroaryl, SO3H, SO2H, S (O ) NHCO-alkyl, S (0) NHCO-aryl, S (0) NHCO-heteroaryl, P (0) (OH) 2, P (O) OH,

another embodiment, Rb R3 and R4 are each H. In another embodiment, R1, R2 and R4 are each H. In another embodiment, at least one of R2 and R3

R7 and R8, along with the carbon to which they are attached,

provided that when m is zero, X is missing.

In one embodiment, Rh R2, R3 and R4 are each H. In a 4

It's not Η. In another embodiment, R1 is H. In another embodiment, R2 and R3 are not H. In one embodiment, at least one of R2 and R3 is selected from C1 -C6 alkyl or C1 -C6 alkoxy. In another embodiment, at least one of R2 and R3 is selected from CH3 or OCH3. In one embodiment, R2 is C1 -C6 alkyl. In another embodiment, R2 is CH3. In another embodiment, R3 is CH3. In one embodiment, R3 is C1 -C6 alkoxy. In another embodiment, R3 is OCH3.

In one embodiment, XeY are absent. In another embodiment, R5 and R6, together with the carbon to which they are attached, are absent. In one embodiment, R 5 and R 6 are each H. In one embodiment, R 5 and R 6 are each C 1 -C 6 alkyl. In another embodiment, R5 and R6 are each methyl. In another embodiment, R5 and R6 are each ethyl. In another embodiment, R5 and R6, together with the carbon to which they are attached, are placed in contact to form a spiro cyclopropyl ring.

In one embodiment, the sum of m, η, o, ρ eq is 1, 2, 3, 4, 5 or 6. In another embodiment, the sum of m, η, o, ρ eq is 1, 2, 3 or 4. In another embodiment, the sum of in, η, o, ρ eq is 1, 2 or 3. In another embodiment, the sum of m, η, o, ρ eq is 1. In another embodiment, the sum of m, η, o, ρ eq is 2. In another embodiment, the sum of m, η, o, ρ eq is 3. In one embodiment, q is 0.

In one embodiment, any hydrogen in the CH2 groups in the binder is substituted with a substituent selected from straight chain H, F, Cl, Br, I, CF3, CH3, C2, C3, C4 or C6 alkyl, C3, C4, C5 alkyl or branched chain C6, C3, C4, C5, C6, C7, C7 or heterocyclyl, C6, C5, C5, C7, C7 or C8 heterocyclyl C1 -C2 alkoxy, C3, C4, C5, C6, OCF3, CH2OCH3, CH2CH2OCH3 CH 2 OCH 2 CH 3 or C 2 C 2, C 3, C 4, C 5 or C 6 hydroxyalkyl.

In one embodiment, R 7 and R 8 are each H. In one embodiment, R 7 and R 8 are each C 1 -C 6 alkyl. In another embodiment, R 7 and R 8 are each methyl. In another embodiment, R 7 and R 8 are each ethyl. In another embodiment, R7 and Rs, together with the carbon to which they are attached, are placed in contact to form a spiro cyclopropyl ring. In one embodiment, Z is COOH. In another mode,

Z is selected from C0NHS (0) 2-alkyl, CONHS (O) 2-cycloalkyl, CONHS (0) 2-heteroalkyl, C0NHS (0) 2-aryl and CONHS (O) 2-Itereroaryl. In another embodiment, Z is selected from C0NHS02-alkyl and CONHSO2 -heteroalkyl. In one embodiment, Z is CONHSO2CH3. In another embodiment, Z is C0NHS02CH (CH3) 2. In another mode, Z is

C (O) NHSO2 ----

In one embodiment, the salt is an acid addition salt. In another embodiment, the salt is a hydrochloride salt.

In another aspect, the invention relates to a compound

of formula II:

(II)

or a salt, solvate, hydrate or prodrug thereof

pharmaceutically effective, wherein m, η and o are individually 0, 1, 2, 3, 4, 5 or 6; X is absent, O, S, C (O), SO or SO2; R 1, R 2, R 3 and R 4 are independently selected from H, F, Cl, Br, CF 3, CH 3, CH 2 CH 3, CH (CH 3) 2, cyclopropyl, OCH 3, OCF 3, CH 2 OCH 3 and CH 2 OCH 2 CH 3; R5 and R6 are independently H, straight chain C1 -C6 alkyl; C3-C6 alkyl of 6

branched chain or R5 and R6, together with the carbon to which they are attached, are contacted to form a spiro ring of size 3, 4, 5, 6 or 7; and Z is COOH, COOR9, where R9 is C1 -C6 alkyl, CONHS (O) 2-alkyl, CONHS (0) 2-cycloalkyl, CONHS (0) 2-heteroalkyl, CONHS (O) 2-aryl, CONHS (O) 2 -Ietheromeryl, S (O) 2NHCO-alkyl, S (O) 2NHCO-heteroalkyl, S (O) 2NHCO-aryl, S (O) 2NHCO-heteroaryl, CONHS (O) 2N-alkyl; CONHS (0) 2N-heteroalkyl; C0NHS (0) 2N-aryl; CONHS (O) 2N-heteroaryl; or tetrazole, provided that when m is zero, X is absent.

In one embodiment, R1, R2, R3 and R4 are each H. In another embodiment, Ri, R3 and R4 are each H. In another embodiment, Ri, R2 and R4 are each H. In another embodiment at least one of R2 and R3 is not H. In another embodiment, R2 and R3 are not H. In another embodiment, R1 is H. In one embodiment, at least one of R2 and R3 is selected from CH3 or OCH3 . In another embodiment, R2 is CH3. In another embodiment, R3 is CH3. In another embodiment, R3 is OCH3.

In one embodiment, X is absent. In one embodiment, the sum of m, η and o is 1. In another embodiment, the sum of m, η and o is 2. In one embodiment, o is zero.

In one embodiment, R5 and R6 are each H. In one embodiment, R5 and R6 are each C1 -C5 alkyl. In another embodiment, R5 and R6 are each methyl. In another embodiment, R5 and R6 are each ethyl. In another embodiment, R5 and R6, together with the carbon to which they are attached, are placed in contact to form a spiro cyclopropyl ring.

In one embodiment, Z is COOH. In another embodiment, Z is selected from C0NHS (0) ralkyl, CONHS (0) 2-cycloalkyl, CONHS (0) 2-heteroalkyl, C0NHS (0) 2-aryl and CONHS (0) 2-heteroaryl. In another embodiment, Z is selected from C0NHSO2-alkyl and CONHSO2-heteroalkyl. In one embodiment, Z is C0NHS02CH3. In another embodiment, Z is C0NHS02CH (CH3) 2. In another mode, Z is

<formula> formula see original document page 8 </formula>

In one embodiment, the salt is an acid addition salt. In another embodiment, the salt is a hydrochloride salt.

In another aspect, the invention relates to a compound

of formula III:

<formula> formula see original document page 8 </formula> or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein m and η are individually O, 1, 2, 3 or 4; X is missing, O, S, C (O) 5 SO or SO2; R 1, R 2, R 3 and R 4 are independently selected from H, F, Cl, Br, CF 3, CH 3, CH 2 CH 3, CH (CH 3) 2, cyclopropyl, OCH 3, OCF 3, CH 2 OCH 3 and CH 2 OCH 2 CH 3a R 5 and R 6 are independently H, C 1 alkyl, Straight chain C2, C3, C4, C5; C3, C4, C5, C6 branched chain alkyls or R5 and R6, together with the carbon to which they are attached, are contacted to form a spiro ring of size 3, 4, 5, 6 or 7; and Z is selected from CO2H, C0NHS (0) 2-alkyl, CONHS (0) 2-cycloalkyl, CONHS (0) 2-heteroalkyl, C0NHS (0) rare, CONHS (0) 2-heteroaryl and tetrazole; provided that when m is zero, X is missing.

In one embodiment, R1, R2, R3 and R4 are each H. In another embodiment, Ri, R3 and R4 are each H. In another embodiment, R1, R2 and R4 are each H. In one embodiment, at least one of R2 and R3 is not Η. In another embodiment, R2 and R3 are not H. In another embodiment, R1 is H. In another embodiment, at least one of R2 and P3 is selected from CH3 or OCH3. In another embodiment, R2 is CH3. In another embodiment, R3 is CH3. In another embodiment, R3 is OCH3.

In one embodiment, X is absent. In one embodiment, the

sum of m and η is 1. In another embodiment, the sum of m and η is 2.

In one embodiment, R5 and R6 are each H. In one embodiment, R5 and R6 are each CrC6 alkyl. In another embodiment, R5 and R6 are each methyl. In another embodiment, R5 and R6 are each ethyl. In another embodiment, R5 and R6, together with the carbon to which they are attached, are placed in contact to form a spiro cyclopropyl ring.

In one embodiment, Z is COOH. In another embodiment, Z is selected from C0NHS (0) 2-alkyl, CONHS (0) 2-cycloalkyl, C0NHS (0) 2-heteroalkyl, C0NHS (0) 2-aryl and CONHS (0) 2-heteroaryl. In another embodiment, Z is selected from C0NHS02-alkyl and CONHSO2 -heteroalkyl. In one embodiment, Z is C0NHS02CH3. In one embodiment, Z is C0NHS02CH (CH3) 2. In another mode Z is

In one embodiment, the salt is an acid addition salt. In another embodiment, the salt is a hydrochloride salt.

In another aspect, the invention relates to a compound

of formula IV: <image> image see original document page 10 </image>

or a pharmaceutically effective salt, solvate, hydrate or prodrug thereof wherein t is 1, 2, 3, 4, 5 or 6; R 1, R 2, R 3 and R 4 are independently H, F, Cl, Br, CF 3, CH 3, OH, OCH 3, CH 2 OCH 3 or CH 2 OCH 2 CH 3; R5-R6 are H, CH3, CH2CH3 or R5 and R6, together with the carbon to which they are attached, are brought into contact to form a spiro ring of size 3, 4, 5, 6 or 7; and Z is selected from CO2H, CONHS (0) 2-alkyl, CONHS (O) cycloalkyl, CONHS (0) 2-heteroalkyl and tetrazole.

In one embodiment, R1, R2, R3 and R4 are each H. In another embodiment, Ri, R3 and R4 are each H. In another embodiment, Rj, R2 and R4 are each H. In another embodiment at least one of R2 and R3 is not H. In another embodiment, R2 and R3 are not H. In another embodiment, R1 is H. In another embodiment, at least one of R2 and R3 is selected from CH3 or OCH3. In another embodiment, R2 is CH3. In another embodiment, R3 is CH3. In another embodiment, R3 is OCH3.

In one mode, t is 1. In another mode, t is 2. In one mode, R5 and R6 are each H. In another mode, R5 and R5 are each methyl. In another embodiment, R5 and R6 are each ethyl. In another embodiment, R5 and R6, together with the carbon to which they are attached, are placed in contact to form a spiro cyclopropyl ring.

In one embodiment, Z is COOH. In another embodiment, Z is selected from C0NHS02-alkyl and CONHS02-heteroalkyl. In another embodiment, Z is C0NHS02CH3. In another embodiment, Z is C0NHS02CH (CH3) 2. In another mode, Z is

<formula> formula see original document page 11 </formula> In one embodiment, the salt is an acid addition salt. In another embodiment, the salt is a hydrochloride salt.

In another aspect, the invention relates to a compound selected from:

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I: wherein mn, o, p, q are individually 0, 1,2, 3, 4, 5 or 6; X

and Y are individually absent, O, S, C (O), SO or SO2; R1, R2, R3 and R4 are independently selected from straight chain H, F, Cl, Br, I, CF3, C1 -C2 alkyl, C3, C4, C5 or C6, branched chain C3, C4, C5 or C6 alkyl C3, C4, C5, C6, C7, C8 or C8 cycloalkyl, C3, C4, C5, C6 or C7 heterocyclyl, OCF3, CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, C2, C3, C4, C5 or C6 alkoxy and C1, C2 hydroxyalkyl C3, C4, C5 or C6; R 5, R 6, R 7 and R 6 are independently H, C 1 -C 2 alkyl, C 3, C 4, C 5 or C 6 straight chain, C 3 C 4, C 5 or C 6 alkyl branched chain; R5 and R6, together with the carbon to which they are attached, are placed in contact to form a spiro ring of size 3, 4, 5, 6 or 7; R7 and R8, together with the carbon to which they are attached, are placed in contact to form a 3, 4, 5, 6 or 7 spiro ring; or substituents on two different atoms are contacted to form a ring of size 3, 4, 5, 6 or 7; and Z is selected from CO2H, CO2Rg, where R9 is C2, C3, C4, C5, or C6 alkyl, C0NHS (0) 2-alkyl, CONHS (0) 2-cycloalkyl, CONHS (0) 2-heteroalkyl, C0NHS ( 0) 2-aryl, CONHS (0) 2-heteroaryl, S (O) 2NHCO-alkyl, S (O) NNHCO-cycloalkyl, S (O) 2NHCO-heteroalkyl, S (0) NNHCO-aryl, S (O) 2NHCO-heteroaryl, C0NHS (0) 2N-alkyl, CONHS (O) 2N-cycloalkyl, CONHS (0) 2N-heteroalkyl, C0NHS (0) 2N-aryl, CONHS (0) 2N-heteroaryl, SO3 Η, SO2H, S (O) NHCO-alkyl, S (0) NHCO-aryl, S (O) NHCO-heteroaryl, P (0) (OH) 2, P (O) OH,

<image> image see original document page 13 </image>

provided that when m is zero X is absent ie a salt, solvate, hydrate or prodrug thereof and at least one pharmaceutically acceptable excipient.

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula II:

<image> image see original document page 13 </image>

wherein m, η and o are individually O, 1, 2, 3, 4, 5 or 6; X is absent, O, S, C (O), SO or SO2; R 1, R 2, R 3 and R 4 are independently selected from H, F, Cl, Br, CF 3, CH 3, CH 2 CH 3, CH (CH 3) 2, cyclopropyl, OCH 3, OCF 3, CH 2 OCH 3 and CH 2 OCH 2 CH 3; R5 and R6 are independently H, C1 -C2 alkyl, straight chain; C3, C4, C5 alkyl, branched chain C6 or R5 and R6, together with the carbon to which they are attached, are contacted to form a 3, 4, 5, 6 or 7 spiro ring; and Z is COOH, COOR9, where R9 is C1-C6 alkyl, C0NHS (0) 2-alkyl, CONHS (0) 2-cycloalkyl, CONHS (0) 2-heteroalkyl, C0NHS (0) 2-aryl, CONHS (0 ) 2-heteroaryl, S (O) 2NHCO-alkyl, S (O) 2NHCO-heteroalkyl, S (O) 2NHCO-aryl, S (O) 2NHCO -etheriylaryl C0NHS (0) 2N-alkyl; CONHS (O) 2N - heteroalkyl; CONHS (O) 2 N-aryl; CONHS (O) 2N- 13

heteroaryl; or tetrazole, provided that when m is zero X is absent ie a salt, solvate, hydrate or prodrug thereof and at least one pharmaceutically acceptable excipient.

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula III:

<formula> formula see original document page 14 </formula>

where m and η are individually O, 1, 2, 3 or 4, X is absent, O, S, C (O), SO or SO2; R 1, R 2, R 3 and R 4 are independently selected from H, F, Cl, Br, CF 3, CH 3, CH 2 CH 3, CH (CH 3) 2, cyclopropyl, OCH 3, OCF 3, CH 2 OCH 3 and CH 2 OCH 2 CH 3; R5 and R5 are independently H, straight chain C1 -C5 alkyl; C3 -C6 branched chain alkyl or R5 and R6, together with the carbon to which they are attached, are contacted to form a spiro ring of size 3, 4, 5, 6, or 7; and Z is selected from CO 2 H, C0NHS (0) 2-alkyl, CONHS (0) 2-cycloalkyl, CONHS (0) 2-heteroalkyl, C0NHS (0) 2-aryl, CONHS (O) 2-Iieteroaryl and tetrazole; provided that when m is zero X is absent ie a salt, solvate, hydrate or prodrug thereof and at least one pharmaceutically acceptable excipient.

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula IV: wherein t is 1, 2, 3, 4, 5 or 6; R 1, R 2, R 3 and R 4 are independently H, F, Cl, Br, CF 3, CH 3, OH, OCH 3, CH 2 OCH 3 or CH 2 OCH 2 CH 3; R5-R6 are H, CH3, CH2CH3 or R5 and R5, together with the carbon to which they are attached, are placed in contact to form a spiro ring of size 3, 4, 5, 6 or 7; and Z is selected from CO2H, CONHS (0) 2-alkyl, CONHS (0) 2-cycloalkyl, CONHS (0) 2-heteroalkyl and tetrazole.

In another aspect, the invention relates to a method of treating a subject of a sleep disorder, comprising administering to a subject in need of treatment of a sleep disorder a therapeutically effective amount of a compound represented by formula I:

(<formula> formula see original document page 15 </formula> or a pharmaceutically effective salt, solvate, hydrate or prodrug thereof, wherein mn, o, p, q are individually 0, 1, 2, 3, 4, 5 or 6; X and 15

Y are individually absent, O, S, C (O), SO or SO2;

R1, R2, R3 and R4 are independently selected from H, F,

Cl, Br, I, CF3, straight chain C2, C3, C4, C5 or C6 alkyl, branched chain C3, C4, C5 or C6 alkyl, C3, C4, C5, C6, C7 or C8 cycloalkyl, C3 heterocyclyl C4, C5, C6 or C7, OCF3, CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, C1 -C2 alkoxy C3, C4, C5 or C6 hydroxyalkyl C1, C2, C3, C4, C5 or C6; R 5, R 6, R 7 and R 8 are independently H, C 1 -C 2 alkyl, C 3, C 4, C 5 or C 6 straight chain, C 3, C 4, C 5 or C 6 branched chain alkyl;

are placed in contact to form a spiro ring of size 3, 4, 5, 6 or 7; R7 and R8, together with the carbon to which they are attached, are placed in contact to form a 3, 4, 5, 6 or 7 spiro ring; or substituents on two different atoms are contacted to form a ring of size 3, 4, 5, 6 or 7; and Z is selected from CO2H,

CO2 R9, where R9 is C1, C2, C3, C4, C5 or C6 alkyl, CONHS (O) 2 alkyl, CONHS (0) 2-cycloalkyl, CONHS (0) 2-heteroalkyl, C0NHS (0) 2-aryl, CONHS (O) 2-Itheroaryl, S (O) NNHCO-alkyl, S (O) 2NHCO-cycloalkyl, S (0) 2NHCO-heteroalkyl, S (0) 2NHCO-aryl, S (O) 2NHCO-heteroaryl, CONHS ( O) 2N-alkyl, CONHS (0) 2N-cycloalkyl, CONHS (O) 2N-heteroalkyl, CONHS (O) 2N-aryl, CONHS (0) 2N-heteroaryl, SO3H, SO2H, S (O) NHCO-alkyl, S (O) NHCO-aryl, S (0) NHCO-heteroaryl, P (0) (OH) 2, P (O) OH,

In one embodiment, the subject is a human. In one embodiment, sleep disorder is selected from the group consisting of insomnia, hypersomnia, narcolepsy, sleep apnea syndrome, parasomnia, restless leg syndrome, and circadian rhythm abnormality. In a

R5 and R6, along with the carbon to which they are attached,

provided that when m is zero, X is missing. Another mode, sleep disorder is abnormality of the circadian rhythm. In another embodiment, circadian rhythm abnormality is selected from the group consisting of time zone fatigue, shift work disorders, and delayed or advanced sleep phase syndrome. In one embodiment, the sleep disorder is insomnia. In another embodiment, insomnia is treated in the subject by performing at least one action selected from the group consisting of decreased sleep onset time, increased range of mean sleep activity, and increased range of maximum sleep activity. In one embodiment, the compound or pharmaceutically acceptable salt, solvate, hydrate or prodrug is administered as a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient. In another embodiment, the compound or pharmaceutically acceptable salt, solvate, hydrate or prodrug is co-administered with one or more additional therapies.

In another aspect, the invention relates to a method of treating a subject of a sleep disorder, comprising administering to a subject in need of treatment of a sleep disorder a therapeutically effective amount of a compound represented by formula II:

<image> image see original document page 17 </image> or a pharmaceutically effective salt, solvate, hydrate or prodrug thereof, wherein m, η and o are individually 0, 1, 2, 3, 4, 5 or 6 ; X is absent, O, S, C (O), SO or SO2; R 1, R 2, R 3 and R 4 are independently selected from H, F, Cl, Br, CF 3, CH 3, CH 2 CH 3, CH (CH 3) 2, cyclopropyl, OCH 3, OCF 3, CH 2 OCH 3 and CH 2 OCH 2 CH 3; R5 and R5 are independently H, straight chain C1 -C5 alkyl; C3 -C6 branched chain alkyl or R5 and R5, together with the carbon to which they are attached, are contacted to form a spiro ring of size 3, 4, 5, 6 or 7; and Z is COOH, COOR9, where R9 is C1-C5 alkyl, C0NHS (0) 2-alkyl, CONHS (O) 2-cycloalkyl, CONHS (0) 2-heteroalkyl, C0NHS (0) 2-aryl, CONHS (O ) 2-heteroaryl, S (0) 2NHCO-alkyl, S (0) 2NHCO-heteroalkyl, S (O) 2NHCO-aryl, S (O) 2NHCO-heteroaryl, CONHS (0) 2N-alkyl; CONHS (O) 2N-heteroalkyl; C0NHS (0) 2N-aryl; CONHS (0) 2N-heteroaryl; or tetrazole, provided that when m is zero, X is absent.

In one embodiment, the subject is a human. In another embodiment, sleep disorder is selected from the group consisting of insomnia, hypersomnia, narcolepsy, sleep apnea syndrome, parasomnia, restless leg syndrome, and circadian rhythm abnormality. In another embodiment, the sleep disorder is abnormal circadian rhythm. In another embodiment, circadian rhythm abnormality is selected from the group consisting of time zone fatigue, shift work disorders, and delayed or advanced sleep phase syndrome. In one embodiment, the sleep disorder is insomnia. In another embodiment, insomnia is treated in the subject by performing at least one action selected from the group consisting of decreased sleep onset time, increased range of mean sleep activity, and increased range of maximum sleep activity. In another embodiment, the pharmaceutically acceptable compound or salt, solvate, hydrate or prodrug is administered as a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient. In another embodiment, the compound or pharmaceutically acceptable salt, solvate, hydrate or prodrug is co-administered as one or more additional therapies.

In another aspect, the invention relates to a method of treating a subject of a sleep disorder, comprising administering to a subject in need of treatment of a sleep disorder a therapeutically effective amount of a compound represented by formula III:

<formula> formula see original document page 19 </formula>

or to a pharmaceutically effective salt, solvate, hydrate or prodrug thereof, wherein m and η are individually O, 1, 2, 3 or 4; X is absent, O, S, C (O), SO or SO2; R 1, R 2, R 3 and R 4 are independently selected from H, F, Cl, Br, CF 3, CH 3, CH 2 CH 3, CH (CH 3) 2, cyclopropyl, OCH 3, OCF 3, CH 2 OCH 3 and CH 2 OCH 2 CH 3a R 5 and R 6 are independently H, C 1 -C 5 alkyl of straight chain; C 3 -C 6 branched chain alkyl or R 5 and R 6 Together with the carbon to which they are attached, they are contacted to form a spiro ring of size 3, 4, 5, 6 or 7; and Z is selected from CO 2 H, C0NHS (0) 2-alkyl, CONHS (0) 2-cycloalkyl, CONHS (0) 2-heteroalkyl, C0NHS (0) 2-aryl, CONHS (0) 2-heteroaryl and tetrazole; provided that when m is zero, X is missing.

In one embodiment, the subject is a human. In another embodiment, sleep disorder is selected from the group consisting of insomnia, hypersomnia, narcolepsy, sleep apnea syndrome, parasomnia, restless leg syndrome, and circadian rhythm abnormality. In another embodiment, the sleep disorder is abnormality of the circadian rhythm. In another embodiment, circadian rhythm abnormality is selected from the group consisting of time zone fatigue, shift work disorders, and delayed or advanced sleep phase syndrome. In one embodiment, the sleep disorder is insomnia. In one embodiment, insomnia is treated in the subject by performing at least one action selected from the group consisting of decreased sleep onset time, increased range of mean sleep activity, and increased range of maximum sleep activity. In another embodiment, the pharmaceutically acceptable compound or salt, solvate, hydrate or prodrug is administered as a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient. In another embodiment, the compound or pharmaceutically acceptable salt, solvate, hydrate or prodrug is co-administered as one or more additional therapies.

In another aspect, the invention relates to a method of treating a sleep disorder subject comprising administering to a subject in need of treatment of a sleep disorder a therapeutically effective amount of a compound represented by formula IV:

<image> image see original document page 20 </image>

or a pharmaceutically effective salt, solvate, hydrate or prodrug thereof wherein is 1, 2, 3, 4, 5 or 6; R 1, R 2, R 3 and R 4 are independently H, F, Cl, Br, CF 3, CH 3, OH, OCH 3, CH 2 OCH 3 or CH 2 OCH 2 CH 3 and R 5 -R 6 are H, CH 3, CH 2 CH 3 or R 5 and R 6 together with the carbon to which they are attached, are placed in contact to form a spiro ring of size 3, 4, 5, 6 or 7; and Z is selected from CO2H, CONHS (O) 2-alkyl, CONHS (C)) 2-cycloalkyl, CONHS (C1) 2-heteroalkyl and tetrazole.

In one embodiment, the subject is a human. In another embodiment, sleep disorder is selected from the group consisting of insomnia, hypersomnia, narcolepsy, sleep apnea syndrome, parasomnia, restless leg syndrome, and circadian rhythm abnormality. In another embodiment, the sleep disorder is abnormality of the circadian rhythm. In another embodiment, circadian rhythm abnormality is selected from the group consisting of time zone fatigue, shift work disorders, and delayed or advanced sleep phase syndrome. In another embodiment, the sleep disorder is insomnia. In another embodiment, insomnia is treated in the subject by performing at least one action selected from the group consisting of decreased sleep onset time, increased range of mean sleep activity, and increased range of maximum sleep activity. In one embodiment, the compound or pharmaceutically acceptable salt, solvate, hydrate or prodrug is administered as a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient. In another embodiment, the compound or pharmaceutically acceptable salt, solvate, hydrate or prodrug is co-administered as one or more additional therapies. In another embodiment, the compound is selected from the group of compounds consisting of: DETAILED DESCRIPTION

Details of at least one embodiment of the invention

are given in the following description attached. While any of the methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present invention, the methods and materials of the present invention are now described. Other features and objects and advantages of the invention will become apparent from the description. In the specification, singular forms also include plural unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meanings commonly understood by one of ordinary skill in the art to which this invention relates. In case of conflict, this specification will control.

The invention relates to novel compositions of benzisoxazole piperazine. In one aspect, the invention provides a compound according to formula I:

<image> image see original document page 23 </image> or a pharmaceutically effective salt thereof, wherein m n, o, p, q are individually O, 1, 2, 3, 4, 5 or 6; X and Y are individually absent, O, S, C (O), SO or SO2; R1, R2, R3 and R4 are independently selected from H, F, Cl, Br, I, CF3, CH3, straight chain C2, C3, C4, C5 or C5 alkyl, branched chain C3, C4, C5 or C6 alkyl C3, C4, C5, C6, C7, C7, C8, C3, C4, C5, C6 or C7 heterocyclyl cycloalkyl, CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, C1, C2, C3, C4, C5 or C6 alkoxy and C1-6 hydroxyalkyl C 2, C 3, C 4, C 5 or C 6; any hydrogen in the CH2 groups in the binder is optionally substituted with H, F, Cl, Br, I, CF3, CH3, straight chain C2, C4, C5 or C6 alkyl, branched chain C3, C4, C5 or C6 alkyl, C 3, C 4, C 5, C 6, C 7 cycloalkyl or C 8, C 3, C 4, C 5, C 6, C 7 or C 8 heterocyclyl, C 1 -C 2 alkoxy, C 2, C 4, C 5, C 5, OCF 3, CH 2 OCH 3, CH 2 CH 2 OCH 3, CH 2 OCH 2 CH 3 or C 1 hydroxyalkyl C2, C3, C4, C5 or C6, provided such substitution does not result in the formation of unstable functionality; R 5, R 6, R 7 and R 8 are independently H, C 1, C 2, C 3, C 4, C 5 or C 5 straight chain alkyl, branched chain C 3, C 4, C 5 or C 6 alkyl; R5 and R6 Together with the carbon to which they are attached, are placed in contact to form a spiro ring of size 3, 4, 5, 6 or 7; R7 and Rs, together with the carbon to which they are attached, are placed in contact to form a 3, 4, 5, 6 or 7 spiro ring; or substituents on two different atoms are contacted to form a ring of size 3, 4, 5, 6 or 7; and Z is selected from CO2H, CO2R9, where R9 is C1, C2, C3, C4, C5 or C6 alkyl, C0NHS (0) 2-alkyl, CONHS (0) 2-cycloalkyl, C0NHS (0) 2-heteroalkyl, C0NHS (0) 2-aryl, CONHS (0) 2-heteroaryl, S (O) NNHCO-alkyl, S (0) NNHCO-cycloalkyl, S (0) 2NHCO-heteroalkyl, S (O) NNHCO-aryl, S (O ) NNHCO-heteroaryl, C0NHS (0) 2N-alkyl, 5 CONHS (O) 2N-cycloalkyl, CONHS (0) 2N-heteroalkyl, C0NHS (0) 2N-aryl,

CONHS (O) 2N-Iteriaryl, SO3H, SO2H, S (O) NHCO-alkyl, S (O) NHCO-aryl, S (O) NHCO-heteroaryl, P (0) (0H) 2, P (O) OH ,

<formula> formula see original document page 24 </formula> provided that when m is zero X is missing.

In one embodiment, Z is a sulfonamide. Sulfonamides include acyl sulfonamides. For example, Z may have the formula

<formula> formula see original document page 24 </formula> where W is a substituent for modulating the effects of the polar surface area of fraction Z. For example, such effects include the level of oral absorption, penetration, and / or rate of absorption. excretion in urine or bile. Examples of substituents W used for this purpose include an alkyl group (optionally containing a double or triple bond), a cycloalkyl group (optionally containing a double bond), a heterocyclyl group, an aryl group or a heteroaryl group, both optionally substituted, such as: as shown below <formula> formula see original document page 25 </formula> (where V is at least one of the side chains selected to modulate the pka of the acylsulfonamide moiety or to affect the physical or metabolic properties of the compound. V-side include halogens such as F, Cl or Br, C1 -C2, C3, C4, C5 or Ce alkoxy groups such as OCH3 or OCH2CH3, Q, C2, C3, C4, C5 or C6 alkyl groups or C3, C4 cycloalkyl C5, C6, C7 or C8, such as CH3 or CF3, cyclopropyl, C1-C2, C3, C4, C5 or C6 alkyl or heteroatom-substituted C3, C4, C6, C7 or C6 cycloalkyl such as CH2OCH3 or CH2OCH2CH3; groups that remove electr such as CN, a ketone, amide or a sulfone. <formula> formula see original document page 25 </formula> (and isomeres of In one embodiment, Z is a sulfamide. Sulfamides include acyl sulfamides. For example, Z may have the formula

(and isomers of <image> image see original document page 26 </image>

where Ra and Rb are independently, for example, an alkyl group, a

cycloalkyl group, a heterocyclyl group, an aryl group or a

optionally substituted heteroaryl. Examples include the following:

<image> image see original document page 26 </image> (where V is a halogen such as F, Cl or Br; alkoxy Cj, C2, C3, C4, C5 or

C6, such as OCH3 or OCH2CH3; C1 -C2, C3, C4, C5 or Ce alkyl or

C3, C4, C5, C6, C7 or C8 cycloalkyl, such as CH3 or CF3, cyclopropyl;

C1, C2, C3, C4, C5 or C6 alkyl or C3, C4, C5, C6, C7 or C8 cycloalkyl

substituted by heteroatom, such as CH2OCH3 or CH2OCH2CH3;

an electron withdrawing group such as CN, a ketone, an amide or a

<image> image see original document page 26 </image> sulfone), ch ^ (and pyridyl isomers), CH3

(and pyrimidine isomers). In one embodiment, Z is CO2H or tetrazole.

In one embodiment, Z is a sulfonamide or sulfamide. In another embodiment, Z is an acyl sulfonamide. Sulfonamide may be, for example, an acyl sulfonamide, such as -CONHS02-alkyl, where alkyl is straight chain C1 -C6 alkyl, branched chain C3 -C6 alkyl or C3 -C3 cycloalkyl.

In one embodiment, at least one of RpR4, R5-R6 and at least

least one of R7-Rg is not hydrogen.

In one embodiment at least one of R2 and R3 is not H. In another embodiment, Ri is not H.

In another mode, R2 is not H. In another mode, R3 is not H.

In another embodiment, R4 is not H.

In another embodiment R 1 is F, Cl, Br, I or C 1, C 2, C 3, C 4, C 5 or C 6 alkoxy.

In another embodiment R 2 is F, Cl, Br, I or C 1 -C 2 alkoxy, C 4, C 5 or C 6 alkoxy.

In another embodiment R3 is F, Cl, Br, I or Q, C2, C3, C4, C5 or C6 alkoxy.

In another embodiment R 5 is F, Cl, Br, I or C 1, C 2, C 3, C 4, C 5 or C 6 alkoxy.

In one embodiment, when Z is tetrazole, at least one of

R5-R4 and R7-R8 is not hydrogen.

In one embodiment, at least two of RrR4 are not

hydrogen.

In one embodiment, at least three of RpR4 are not

hydrogen.

In one embodiment, XeY are absent.

In one embodiment, R5 and R6 and the carbon to which they are attached are absent.

In one embodiment, q = 0. In one embodiment, m + n + o + p = 1,2 or 3.

In one embodiment, R9 is not C1 -C6 alkyl. In another embodiment, R 9 is not C 2 alkyl.

In another embodiment, RrR4 is each hydrogen. In one embodiment, R 5 and R 4 are each methyl. In another embodiment, R5 and R6 are each ethyl. In one embodiment, R 7 and R 8 are each methyl. In another embodiment, R 7 and R 8 are each ethyl. In one embodiment, R5 and R5 and the carbon to which they are attached are contacted to form a 3-7 size spiro ring. For example, in one embodiment, R 5 and R 6 and the carbon to which they are attached are contacted to form a three-membered spiro ring (cyclopropyl).

In one embodiment, the R5 and R6 and the carbon to which they are attached are absent. In one embodiment, R7 and R8, together with the carbon to which they are attached, are brought into contact to form a 3 to 7 spiro ring. For example, R7 and R8, together with the carbon to which they are attached, are placed in contact to form a 3-membered spiro cyclopropyl ring.

In one aspect, a composition of formula I also includes a pharmaceutically acceptable excipient. In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I.

In another aspect, the invention provides a compound of

formula II: <formula> formula see original document page 28 </formula> or a pharmaceutically effective salt thereof, wherein m, η and o are individually O, 1,2, 3, 4, 5 or 6; X is absent, O, S, C (O), SO or SO2; R 1, R 2, R 3 and R 4 are independently selected from H, F, Cl, Br, CF 3, CH 3, CH 2 CH 3, CH (CH 3) 2, cyclopropyl, OCH 3, OCF 3, CH 2 OCH 3 and CH 2 OCH 2 CH 3; R5 and R6 are independently H, C1 -C5 straight chain alkyl; C3 -C6 branched chain alkyl or R5 and R6, together with the carbon to which they are attached, are contacted to form a spiro ring of size 3 to 7; and Z is COOH, COOR9, where R9 is C1-C6 alkyl, C0NHS (0) 2-alkyl, CONHS (O) 2-cycloalkyl, C0NHS (0) 2-heteroalkyl, CONHS (O) 2-aryl, CONHS (O ) 2-Itereroaryl, S (0) 2NHCO-alkyl, S (0) 2NHCO-heteroalkyl, S (0) 2NHCO-aryl, S (O) 2NHCO-heteroaryl, C0NHS (0) 2N-alkyl; CONHS (0) 2N-heteroalkyl; C0NHS (0) 2N-aryl; CONHS (O) 2N-Iieroaryl; or tetrazole, provided that when m is zero, X is absent.

In one embodiment, R5 and R6 are each methyl. In another embodiment, R5 and R6 are each ethyl.

In one embodiment, R5 and R6, together with the carbon to which they are attached, are brought into contact to form a spiro ring of size 3 to 7. For example, in one embodiment, R5 and R6, together with the carbon to which they are attached. they are attached, are placed in contact to form a spiro cyclopropyl ring.

In one embodiment, Z is sulfonamide, for example an acyl sulfonamide. An example of an acyl sulfonamide is C (O) NHSO2 -alkyl; where alkyl is a straight chain C1 -C2, C3, C4, C5 or C6 alkyl or a branched chain C3, C4, C5 or C6 alkyl.

In one embodiment, Z is CO2H or tetrazole.

In one embodiment, the is zero.

In one embodiment, at least one of Ri-R4 and at least one of R5-R6 are not hydrogen. In one embodiment, at least two of RrR4 are not hydrogen. In one embodiment, at least three of R1-R4 are not hydrogen. In one embodiment, R1 is not hydrogen. In one embodiment, R2 is not hydrogen. In one embodiment, R3 is not hydrogen. In one embodiment, R4 is not hydrogen. In one embodiment, X is absent.

In one embodiment, m + η - 1,2 or 3. In one aspect, a composition of formula II also includes a pharmaceutically acceptable excipient. In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula II.

In another aspect, the invention provides a compound of

formula III:

<image> image see original document page 30 </image> or a pharmaceutically effective salt thereof, where m and i are individually 0, 1, 2, 3 or 4, X is missing, O, S, C (O), SO or SO2; R b R 2, R 3 and R 4 are independently selected from H, F, Cl, Br, CF 3, CH 3, CH 2 CH 3, CH (CH 3) 2, cyclopropyl, OCH 3, OCF 3, CH 2 OCH 3 and CH 2 OCH 2 CH 3; R5 and R1 are independently H, C1 -C5 straight chain alkyl; C3 -C6 branched chain alkyl or R5 and R6, together with the carbon to which they are attached, are contacted to form a 3-7 size spiro ring; and Z is selected from CO 2 H, C0NHS (0) 2-alkyl, CONHS (0) 2-cycloalkyl, CONHS (0) 2-heteroalkyl, C0NHS (0) 2-aryl, CONHS (O) 2-Iieteroaryl and tetrazole; provided that when m is zero, X is missing.

In one embodiment, R5 and R6, together with the carbon to which they are attached, are contacted to form a 3-7 size spiro ring. For example, in one embodiment, R5 and R6, together with the carbon to which they are attached, are contacted to form a spiro cyclopropyl ring.

In one embodiment, Z is CO2H or tetrazole. In one embodiment, at least one of RrR4 and at least one of R5-R6 are not hydrogen.

In another embodiment, Z is sulfonamide, for example an acyl sulfonamide. An example of an acyl sulfonamide is C (O) NHSO2 -alkyl, where alkyl is a straight chain C1-, C2, C3, C4, C5 or C6 alkyl or a branched chain C3, C4, C5 or C6 alkyl.

In one embodiment, at least one of R1-R4 is not

hydrogen.

In one embodiment, at least two of RrR4 are not hydrogen. In one embodiment, at least three of R1-R4 are not hydrogen.

In one embodiment, R5 and R6 are each methyl. In another embodiment, R5 and R6 are each ethyl.

In one embodiment, X is absent.

In one embodiment, m + η = 1, 2, 3 or 4.

In one aspect, a composition of formula III also includes a pharmaceutically acceptable excipient. In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula III.

In another aspect, the invention provides a compound of

formula IV: <image> image see original document page 32 </image>

or a pharmaceutically effective salt thereof wherein it is 1.2,

3, 4, 5 or 6; R 1, R 2, R 3 and R 4 are independently H, F, Cl, Br, CF 3, CH 3, OH, OCH 3, CH 2 OCH 3 or CH 2 OCH 2 CH 3; R5-R6 are H, CH3, CH2CH3 or R5 and R5, together with the carbon to which they are attached, are placed in contact to form a spiro ring of size 3 to 7; and Z is selected from CO2H, CONHS (0) 2-alkyl, CONHS (0) cycloalkyl, CONHS (O) 2-heteroalkyl and tetrazole. In one aspect, a composition of formula IV also includes a pharmaceutically acceptable excipient. In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula IV.

For example, when R5 and R4 are methyl, compounds have the general formula IVa:

In one embodiment, the formula IV is IVa, IVb, IVc or IVd. <image> image see original document page 32 </image>

when R5 and R6 are brought together to form a 3-membered spiro ring (cyclopropyl), compounds have the general formula IVb: <image> image see original document page 33 </image>

when R5 and R6 are ethyl, compounds have the general formula IVc: <image> image see original document page 33 </image>

when R5 and R6 are ethyl and C1 carbons are brought into contact to form a 3-membered spiro ring (cyclopropyl), compounds have the general formula IVd:

<image> image see original document page 33 </image>

In one embodiment, Z is CO2H or tetrazole. In another embodiment, Z is an acyl sulfonamide. For example, Z is CONHSOalkyl, where alkyl is straight chain C2, C3, C4, C5 or C6 alkyl, branched chain C3, C4, C5 or C6 alkyl or C2 -C3, C4, C5, C6, C7 cycloalkyl or C8. In one embodiment, t is 1.

In one embodiment, at least one of R1 - R4 and at least one of R5 - R6 are not hydrogen. In one aspect, the invention provides a compound of the structure of compound 1: The compounds of the invention show binding activity to a variety of targets, including the 5HT2a receptor. Accordingly, these compounds may be used in the treatment or prevention of diseases or disorders involving the 5HT2a receptor.

The compounds of the invention are used to treat a variety of subjects, including, for example, humans, companion animals, farm animals, laboratory animals and wild animals.

In one embodiment, the compounds of the invention may be used for sleep modulation in a subject. For example, the compound is used in decreasing sleep onset time, increasing the extent of average sleep activity, and / or increasing the extent of maximum sleep activity. In one embodiment, sleep modulation may treat a sleep disorder.

In one aspect, the benzisoxazole compounds of the invention may be used in the treatment of a sleep disorder, including, for example, circadian rhythm abnormality, insomnia, parasomnia, sleep apnea syndrome, narcolepsy and hypersomnia.

In one embodiment, the benzisoxazole compounds of the invention may be used in the treatment of a circadian rhythm abnormality, such as, for example, time zone tiredness, shift work disorders, delayed sleep phase syndrome, phase syndrome. advanced sleep disorder and 24-hour non-wakefulness disorder.

In another embodiment, benzisoxazole compounds may be used to treat insomnia, including, for example, extrinsic insomnia, psychophysiological insomnia, altitude insomnia, restless leg syndrome, periodic limb movement disorder, medication-dependent insomnia, insomnia. drug-dependent, alcohol-dependent insomnia, and insomnia associated with mental disorders such as anxiety. The compounds of the invention may also be used to treat sleep fragmentation associated with Parkinson's disease, Alzheimer's disease, Huntington's disease and other dystonias.

In one embodiment, the benzisoxazole compounds of the invention may be used to treat a parasomnia disorder, such as, for example, sleepwalking, dread nocturnus, REM sleep behavior disorder, sleep bruxism, and sleep urinary incontinence. In another embodiment, benzisoxazole compounds may be used to treat a sleep apnea disorder, such as, for example, central sleep apnea, obstructive sleep apnea, and mixed sleep apnea.

In another embodiment, the benzisoxazole compounds may be used to treat sleep disorder-related disorders, such as, for example, fibromyalgia. In another aspect, benzisoxazole compounds may be used to promote sleep. Definitions

For convenience, certain terms used in the specification, examples and appended claims are grouped herein.

"Treat" includes any effect, for example, decrease, reduction, modulation or elimination, which results in improvement of the condition, disease or disorder, etc.

"Alkyl" includes saturated aliphatic groups including straight chain alkyl groups (e.g. methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl), branched chain alkyl groups (e.g. isopropyl, tert-butyl, isobutyl), cycloalkyl (e.g. alicyclic) groups (e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloeptyl, cyclooctyl), cycloalkyl-substituted alkyl groups and alkyl-substituted cycloalkyl groups. In certain embodiments, a straight chain or branched chain alkyl has six or fewer carbon atoms in its backbone (e.g., C 1 -C 6 for straight chain, C 3 -C 6 for branched chain). In some examples, a straight chain or branched chain alkyl has four or less carbon atoms in its backbone. Additionally, cycloalkyls have from three to eight carbon atoms in their ring structure. For example, cycloalkyls have five or six carbons in the ring structure. "C1-C6" includes alkyl groups containing one to six carbon atoms.

The term "substituted alkyl" refers to alkyl moieties with substituents that replace a hydrogen on at least one of the hydrocarbon backbone carbons. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylamino carbonyl, dialkylamino, alkylamino carbonyl phosphate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureide), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfates, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or an aromatic or heteroaromatic moiety. Cycloalkyl may be further substituted, for example, with the substituents described above. An "alkylaryl" or an "aralkyl" moiety is an alkyl substituted with an aryl (e.g. phenylmethyl (benzyl)). "Substituted alkyl" further includes alkyl groups having oxygen, nitrogen, sulfur or phosphorus atoms that replace at least one of the hydrocarbon backbone carbon atoms.

"Aryl" includes aromatic groups, including "unconjugated" or single ring 6-membered aromatic groups which may include from zero to four heteroatoms, as well as "conjugated" or multicyclic systems with at least one aromatic ring. Examples of aryl groups include benzene, phenyl, pyrrol, fiirane, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine and pyrimidine and the like. In addition, the term "aryl" includes multicyclic aryl groups, for example tricyclic, bicyclic, for example naphthalene and, benzoxazole and benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine benzofuran, deazapurine or indolizine. Aryl groups with heteroatoms in the ring structure may also be referred to as "aryl heterocycles", "heterocycles", "heteroaryls" or "heteroaromatic". The aromatic ring may be substituted in at least one ring position with such substituents as described above, such as, for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylamino carbonyl, aralkylaminocarbonyl, alkylalaminaminyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthio carbonyl, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, diarylamino and alkylarylamino), acylamino (including alkylamino) arylaminocarbonylamino , imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfmyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or an aromatic or heteroaromatic moiety. Aryl groups may also be fused or bridged with alicyclic or heterocyclic rings, which are non-aromatic to form a multicyclic system (e.g., tetraline, methylenedioxyphenyl).

"Alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution in the alkyls described above but containing at least one double bond. For example, the term "alkenyl" includes straight chain alkenyl groups (e.g. ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), branched chain alkenyl groups, cycloalkenyl groups (e.g. alicyclic ) (e.g., cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloeptenyl, cyclooctenyl), cycloalkenyl substituted alkyl or alkenyl groups and alkenyl substituted cycloalkyl or cycloalkenyl groups. The term "alkenyl" further includes alkenyl groups, which include oxygen, nitrogen, sulfur or phosphorus atoms that replace at least one carbon of the hydrocarbon backbone. In certain embodiments, a straight or branched chain alkenyl group has six or fewer carbon atoms in its backbone (for example, straight chain C2-C6, branched chain C3-C6.) Similarly, cycloalkenyl groups may have three to eight carbon atoms in their ring structure and, for example, have five or six carbons in the ring structure. The term "C 2 -C 6" includes alkenyl groups containing two to six carbon atoms.

The term "alkenyl" also includes both "unsubstituted alkenyls" and "substituted alkenyls", the latter of which refers to alkenyl moieties with substituents that replace a hydrogen on at least one backbone of the hydrocarbon carbon atoms. Such substituents may include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl

alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, thioylaryl, alkylthio sulfates, alkylsulfmyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or an aromatic or heteroaromatic moiety.

"Alkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution for the alkyls described above, but which contain at least one triple bond. For example, "alkynyl" includes straight chain alkynyl groups (e.g., ethinyl, propynyl, butynyl, pentinyl, hexinyl, heptinyl, octinyl, noninyl, decynyl), branched chain alkynyl groups and alkynyl substituted cycloalkyl or cycloalkenyl groups. The term "alkynyl" additionally includes alkynyl groups substituted with oxygen, nitrogen, sulfur or phosphorus atoms that replace at least one carbon of the hydrocarbon backbone. In certain embodiments, a straight chain or branched chain alkynyl group has six or fewer carbon atoms in its backbone (for example, C2 -Cs for straight chain, C3-C6 for branched chain). The term "C 2 -C 6" includes alkynyl groups containing two to six carbon atoms.

The term "alkynyl" also includes both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl moieties with substituents that replace a hydrogen on at least one of the hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylamino carbonyl, dialkylaminocarbonyl, alkylamino phosphinate, cyano, amino (including alkylamino, diarylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureide), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylamino sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or an aromatic or heteroaromatic moiety.

Unless the number of carbons is otherwise specified, "lower alkyl" includes an alkyl group as defined above, but with from one to ten, for example from one to six, carbon atoms in its spine structure dorsal. "Lower alkenyl" and "lower alkynyl" have chain lengths of, for example, 2-5 carbon atoms.

"Acyl" includes compounds and fractions containing the acyl radical (CH3CO-) or a carbonyl group. "Substituted acyl" includes acyl groups where at least one of the hydrogen atoms are substituted by, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkoxycarbonyl groups alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoylaminoidylamino, iminoidyl, amino), arylthio, thiocarboxylate, sulfates, alkylsulfmyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or an aromatic or heteroaromatic moiety.

"Acylamino" includes fractions wherein an acyl moiety is attached to an amino group. For example, the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.

"Aroyl" includes compounds and fractions with an aryl or heteroaromatic moiety attached to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthylcarboxy, etc. "Alkoxyalkyl", "alkylaminoalkyl" and "thioalkoxyalkyl" include alkyl groups, as described above, which additionally include oxygen, nitrogen or sulfur atoms that replace at least one of the hydrocarbon backbone atoms, for example carbon atoms. oxygen, nitrogen or sulfur.

The term "alkoxy" or "alkoxy" includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently attached to an oxygen atom. Examples of alkoxy (or alkoxy) radicals include methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. Alkoxy groups may be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonylphosphonylcarbonyl, alkylamino carbonate, alkylamino , cyano, amino (including alkylamino, dialkylamino, arylamino, dialkylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureide), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonamide, alkylamino nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and chloromethoxy.

The terms "heterocyclyl" or "heterocyclic group" include closed ring structures, for example 3 to 10 or 4 to 7 membered rings, which include at least one heteroatom. The term "heteroalkyl" includes alkyl groups containing at least one heteroatom.

"Heteroatom" includes atoms of any element other than carbon or hydrogen. Examples of heteroatoms include nitrogen, oxygen, sulfur and phosphorus. The term "heteroalkyl" includes cycloalkyl groups, for example morpholine, piperidine, piperazine, etc.

Heterocyclyl groups may be saturated or unsaturated and include pyrrolidine, oxolane, thiolane, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams and sultones. Heterocyclic groups such as pyrrol and furan may be aromatic. They include fused ring structures such as quinoline and isoquinoline. Other examples of heterocyclic groups include pyridine and purine. The heterocyclic ring may be substituted at at least one of the positions with such substituents as described above, such as, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthio carbonyl, , phosphonate, phosphonate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureide), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl or an aromatic or heteroaromatic moiety. Heterocyclic groups may also be substituted on at least one of the constituent atoms with, for example, lower alkyl, lower alkenyl, lower alkoxy, lower alkylthio, lower alkylamino, lower alkylcarboxyl, nitro, hydroxyl, -CF3 or -CN or the like.

The term "thiocarbonyl" or "thiocarboxy" includes carbon-containing compounds and fractions in contact with a double bond to a sulfur atom.

The term "ether" includes compounds or fractions that contain oxygen attached to two different carbon atoms or heteroatoms. For example, the term includes "alkoxyalkyl" which refers to an alkyl, alkenyl or alkynyl group covalently bonded to an oxygen atom that is covalently bonded to another alkyl group.

The term "ester" includes compounds and fractions containing a carbon or heteroatom attached to an oxygen atom that is attached to the carbon of a carbonyl group. The term "ester" includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc. Alkyl, alkenyl or alkynyl groups are as defined above.

The term "thioether" includes compounds and fractions containing one sulfur atom attached to two different carbons or heteroatoms. Examples of thioethers include, but are not limited to, alkylthioalkyl, alkylthioalkenyls and alkylthioalkylyls. The term "alkylthioalkyl" includes compounds with an alkyl, alkenyl or alkynyl group attached to a sulfur atom that is attached to an alkyl group. Similarly, the terms "alkylthioalkenyls" and aquylthioalkynyls "refer to compounds or fractions wherein an alkyl, alkenyl or alkynyl group is attached to a sulfur atom that is covalently bonded to an alkynyl group.

The term "hydroxy" or "hydroxyl" includes groups with an -OH

or - O ".

The term "halogen" includes fluorine, bromine, chlorine, iodine, etc. The term "peralogenated" generally refers to a moiety in which all hydrogens are replaced by halogen atoms.

"Polycyclyl" or "polycyclic radical" refers to two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and / or heterocyclyls) wherein two or more carbons are common to two adjacent rings. Rings that are joined by nonadjacent atoms are called "bridged" rings. Each of the polycyclic rings may be substituted by such substituents as described above, for example halogen hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl,

alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, acylamino, diarylamino and alkylarylamino), acylaminocarbonylamino, alkylaminoamino , imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfonyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl or an aromatic or heteroaromatic moiety.

An "anionic group" as used herein refers to a group that is negatively charged at physiological pH. Anionic groups include carboxylate, sulfate, sulfonate, sulfate, sulfamate, tetrazolyl, phosphate, phosphonate, phosphinate or phosphorothioate or functional equivalents thereof. "Functional equivalents" of anionic groups are intended to include bioesters, for example bioesters of a carboxylate group. Bioesters encompass both classic bioisosteric equivalents and non-classic bioisosteric equivalents. Classic and non-classic bioesters are known in technology (see, for example, Silverman, R. B. The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc.: San Diego, Calif., 1992, pp. 19-23). Another anionic group is a carboxylate.

The term "unstable functionality" refers to a substitution pattern that contains an unstable binding, for example, a functionality or binding that is susceptible to hydrolysis or cleavage under physiological conditions (e.g. aqueous solutions in the neutral pH range). Examples of unstable features include acetals and ketals.

The terms "crystalline polymorphs" or "polymorphs" refer to the existence of more than one crystalline form for a compound, salt or solvate thereof. Crystalline polymorphs of benzisoxazole analog compounds are prepared by crystallization under different conditions.

Additionally, the compounds of the present invention, for example salts of the compounds, may exist in either hydrated or unhydrated (anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

"Tautomers" refers to compounds whose structures differ markedly in the arrangement of atoms, but which exist in quick and easy equilibrium. It is to be understood that compounds of formulas I-IVd may be described as different tautomers. It is also to be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the invention and the nomenclature of the compounds does not exclude any tautomeric form.

Some compounds of the present invention may exist in a tautomeric form which are also intended to be encompassed within the scope of the present invention.

The compounds, salts and prodrugs of the present invention may exist in various tautomeric forms, including the enol and imine form and the keto and enamine form and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the present invention. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually a tautomer predominates. Even though a tautomer can be described, the present invention includes all tautomers of the present compounds.

A tautomer is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to the other. This reaction results in the formal migration of a hydrogen atom accompanied by an exchange of adjacent conjugated double bonds. In solutions where tautomerization is possible, a chemical equilibrium of tautomers will be achieved. The exact ratio of tautomers depends on a number of factors including temperature, solvent and pH. The concept of tautomers that can be interconverted by tautomerizations is called tautomerism.

Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism there is a simultaneous exchange of electrons and a hydrogen atom. Ring-chain tautomerism is presented by glucose. It appears as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give a cyclic (ring shape) form.

Tautomerizations are catalyzed by: Base: 1. deprotonation;

2. formation of a dislocated anion (eg an enolate); 3. protonation in a different position from the anion; Acid: 1. protonation; 2. formation of a relocated cation; 3. deprotonation at a different position adjacent to the cation.

Common tautomeric pairs are: ketone - enol, amide - nitrile, lactam - lactima, amide - imidic acid tautomerism in heterocyclic rings (eg, guanine, thiamine and cytosine nucleobases), amine - enamine and enamine - enamine. Examples include:

<formula> formula see original document page 47 </formula>

"Solvates" means solvent addition forms containing both stoichiometric and non-stoichiometric amounts of solvent. Some compounds have a tendency to entrap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate.

If the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alkolate. Hydrates are formed by combining one or more water molecules with one of the substances in which water retains its molecular state as H2O, such combination being capable of forming one or more hydrates.

It should be noted that the structure of some of the compounds of the invention include asymmetric carbon atoms. Accordingly, it is to be understood that isomers appearing from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of the invention unless otherwise indicated. Such isomers may be obtained in substantially pure form by classical separation techniques and stereochemically controlled synthesis. In addition, the structures and other compounds and fractions discussed in this patent application also include all tautomers thereof. Alkenes may include both E- and Z geometry where appropriate.

Additionally, the structures and other compounds discussed in this patent application include all atropic isomers thereof. Atropic isomers are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers relate their existence to a restricted rotation caused by impediment of rotation of large groups over a central bond. Such atropic isomers typically exist as a mixture, however, due to recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in selection cases.

"Stable compound" and "stable structure" are understood to be a compound which is sufficiently robust to maintain isolation from a purity used from a reaction mixture and formulation into an effective therapeutic agent. The term benzisoxazole compounds or "benzisoxazole analogous compounds" "benzisoxazole type compounds" or "benzisoxazole derivative compounds" is intended to include benzisoxazole analogs or compounds that include an isozazole-linked benzene ring, (i.e. similar to that of benzisoxazole) attached at the 4-position of a piperazine ring.

As used herein, the term "analog" refers to a chemical compound that is structurally similar to one another, but which differs slightly in composition (as in the substitution of an atom with a different element atom or in the presence of a particular functional group, or the replacement of one functional group with another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound. For example, the reference compound may be a reference compound such as benzisoxazole, and an analog is a substance that has a chemical structure or chemical properties similar to those of the reference benzisoxazole.

As defined herein, the term "derivative", for example, in the term "benzisoxazole derivatives", refers to compounds that have a common core structure and are substituted by various groups as described herein. For example, all compounds represented by formulas I-IVd are benzisoxazole derivatives and have one of formulas I-IVd as a common nucleus.

The term "bioisoster" refers to a compound resulting from the exchange of one atom or group of atoms with another, generally similar atom or group of atoms. The goal of a bioisosteric substitution is to create a novel compound with biological properties similar to the parent compound. Bioisosteric substitution may be physiochemical or topologically based. Examples of carboxylic acid bioisesters include acyl sulfonimides, tetrazols, sulfonates and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176 (1996). In some embodiments, Z is a carboxylic acid or a carboxylic acid bioisester.

As used herein, the term "sleep disorder" includes conditions recognized by those skilled in the art as sleep disorders, for example, conditions known in the art or conditions that are suggested as sleep disorders or discovered as sleep disorders. A sleep disorder also appears in a subject who has other disorders, illness, or medical damage, or in a subject being treated with other medications or medical treatments, where the subject consequently has difficulty falling asleep and / or continues to sleep or has non invigorating sleep, for example, the subject goes through sleep deprivation.

The term "treating a sleep disorder" also includes treating a sleep disorder component of other disorders, such as CNS disorders (e.g., mental or neurological disorders, such as anxiety). Additionally, the term "treatment of a sleep disorder" includes the beneficial effect of alleviating other symptoms associated with the disorder.

The term "non-REM peak sleep time" is defined as an absolute peak amount of non-REM sleep per hour after treatment, with drug administration occurring in Circadian Time (TC) 18, which is 6 hours after erasure of lights in a nocturnal lab rat when housed in a light-dark LD 12:12 cycle (12 hours of light and 12 hours of darkness). The nominal criterion of 55% non-REM sleep per hour is equivalent to 33 minutes of non-REM sleep per hour.

As used herein, the term "cumulative non-REM sleep" is defined as the total net aggregate increase in the number of minutes of non-REM sleep, measured over the duration of a soporific drug effect that typically but not always occurs in first 6 hours post-treatment, adjusted for the total net aggregate number of non-REM sleep minutes that occurred during the corresponding non-treatment baseline hours recorded 24 hours earlier, for example with control vehicle treatment .

As defined herein, the term "sleep attack" refers to a discrete episode of continuous or near continuous sleep consisting of non-REM sleep, REM sleep, or both non-REM and REM sleep stages, delimited before and after sleep. episode for more than two continuous 10-second waking intervals.

As used herein, the term "sleep promotion" is defined as a decrease in sleep onset latency often, but not exclusively, as measured by the Multiple Sleep Latency Test or a decrease in later sleep latency. arousal reduces the tendency to arouse or remain aroused both spontaneously and as a response to the stimulus of the environment that promotes awakening (eg, noise, vibration, odor, pain, light). In general, a sleep-promoting drug reduces the onset of sleep to a desired bedtime or reduces the latency to return to sleep after waking at night or may increase the total sleep time at night. A compound exhibiting these properties is said to promote sleep. As used herein, the term "sleep consolidation" is defined as the ability to remain asleep or otherwise demonstrate persistent sleep after sleep onset and throughout the desired sleep period, with little or no waking intervening, objectively measured. by number of awakenings at night, sleep efficiency (number of awakenings per amount of time in bed) or number of transient awakenings. In general, a sleep consolidation medication improves the ability to continue sleeping by increasing the duration of continuous sleep between spontaneous waking episodes. A compound exhibiting these properties is said to consolidate sleep. Compared to NREM sleep or wakefulness, REM sleep causes ventilatory depression and episodic cardiovascular changes. During relapsing insomnia, the psychological effects of REM sleep are magnified and disrupt normal sleep cycles.

As defined herein, "disproportionate locomotor activity inhibition" is a reduction in locomotor activity that exceeds the normal and expected reduction in behavioral activity that can be attributed to sleep.

"Combination therapy" (or "co-therapy") includes the administration of a compound of the invention and at least one second agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. Administration of these therapeutic agents in combination is typically performed over a defined period of time (usually minutes, hours, days, or weeks depending on the combination selected). "Combination therapy" may encompass, but generally does not encompass, the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention. "Combination therapy" is intended to adopt the administration of these therapeutic agents in a sequential manner, that is, where each therapeutic agent is administered at a different time, as well as the administration of these therapeutic agents or at least two of the therapeutic agents in a substantially simultaneous manner. . Substantially simultaneous administration may be accompanied, for example, by administering to the subject a single capsule with a fixed ratio of each therapeutic agent or in multiple capsules unique to each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent may be by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. Therapeutic agents may be administered by the same or different routes. For example, a first therapeutic agent of the selected combination may be administered by intravenous injection whereas other combination therapeutic agents may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The sequence in which therapeutic agents are administered is not closely critical.

"Combination therapy" also encompasses the administration of therapeutic agents as described above and further combination with other biologically active ingredients and non-drug therapies (eg, surgery or mechanical treatments). Where combination therapy additionally comprises non-drug treatment, non-drug treatment may be conducted at any appropriate time provided that a beneficial effect of the co-action of the combination of therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when non-drug treatment is temporarily removed from the administration of therapeutic agents, perhaps for days or even weeks.

The terms "parenteral administration" and "parenterally administered" as used herein refer to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial injection and infusion, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal. The term "pulmonary" as used herein refers to any part, tissue or organ whose function preferably is gas exchange with the external environment, for example, O2 / CO2 exchange, in a patient. "Pulmonary" typically refers to respiratory tract tissues. Thus, the phrase "pulmonary administration" refers to the administration of formulations described herein to any part, tissue or organ whose preferential function is gas exchange with the external environment (e.g., mouth, nose, pharynx, oropharynx, laryngopharynx, larynx , trachea, carina, bronchus, bronchioles, alveoli). For purposes of the present invention, "pulmonary" also includes a tissue or cavity that is contingent upon the respiratory tract, in particular the bells.

An "effective amount" of a compound of the invention described is that which, when administered to a subject in need of treatment, alleviates the onset of symptoms of a sleep disorder, for example, results in the subject falling asleep faster, resulting in sleep. more invigorating, it reduces the duration or frequency of waking up during a sleep period or reduces the duration, frequency or intensity of other dyssonias, parasomnias. The amount of the described compound to be administered to a subject will depend upon the particular disorder, the mode of administration, co-administered compounds, if any, and the characteristics of the subject, such as general health, other diseases, age, gender, genotype, weight. body weight and drug tolerance. One skilled in the art will be able to determine appropriate dosages depending on these and other factors.

A "pharmaceutically acceptable salt" or "salt" of the described compound is a product of the described compound that contains an ionic bond and is typically produced by reacting the described compound with either an acid or a base suitable for administration to a subject.

A "pharmaceutical composition" is a formulation containing the compounds described in a form suitable for administration to a subject. In another embodiment, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump in an aerosol inhaler or a vial. The amount of active ingredient (e.g., a formulation of the compound described or salts thereof) in a unit dose of composition is an effective amount and varies with the particular treatment involved. One of skill in the art will appreciate that sometimes it is necessary to make variations in the dosage routine depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal and the like. Dosage forms for topical or transdermal administration of a compound of this invention include powders, jets, ointments, pastes, creams, lotions, gels, solutions, adhesives and inhalants. In another embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any of the preservatives, buffers or propellants that are required.

The term "light dose" refers to compound formulations that are rapidly dispersing dosage forms.

The term "immediate release" is defined as a release of the compound from a dosage form over a relatively short period of time, usually up to about 60 minutes. The term "modified release" is defined to include delayed release, extended release, and pulsed release. The term "pulsed release" is defined as a series of drug releases from a dosage form. The term "sustained release" or "extended release" is defined as continuous release of a compound from a dosage form over an extended period. A "subject" includes mammals, for example humans, companion animals (for example dogs, cats, birds and the like), farm animals (for example, cows, sheep, pigs, horses, chicken and the like) and pets. laboratory (for example, mice, mice,

r

guinea pigs, birds and the like). Typically, the subject is human.

The invention provides a method of modulating sleep by administering an effective amount of a benzisoxazole analog of the invention, which is a fraction which is a 5HT2a receptor antagonist or inverse agonist or a collection of 5HT2a receptors.

Effective sleep modulators have certain characteristics that correspond to greater effectiveness and minor side effects. These features include a desired half-life in a subject, controlled onset of desired sedative effects, and effect on psychomotor or other central nervous system (CNS) side effects (eg, memory deficits, decreased muscle tone, drooping eyelids, or numbness) minimal or undetectable.

One approach to developing an effective sleep modulator is to strategically derive a known family or compound with sleep modulating activity. Bypass can improve at least one of the biological properties to allow a compound to perform better. Examples of favorable biological properties include, but are not limited to, induction of discrete sleep or hypnotic state, activity of the therapeutic compound for a discrete period of time, penetration through the CNS blood brain barrier, for example resulting from lipophilicity of substituents or conformational lipophilicity (i.e. lipophilicity as a result of a particular conformation, such as internal salt formation between a carboxylate and anion and a protonated amine), modulation of the therapeutic compound half-life, a change in charge, a change in pharmacokinetics, a change in Pog by a value of at least one, greater receptor selectivity, shorter peripheral half-life, increased dosing capacity, lower peripheral elimination, lower antimuscarinic activity, lower anticholinergic activity and any combination thereof.

Derivation results in a variety of effects and alters different mechanisms of action. For example, in some circumstances, a compound containing a particular functional group, such as, for example, an ester group, carboxylic acid or alcohol, has better selectivity for a desired receptor over unwanted receptors when compared to a compound without it. group. In other circumstances, the compound containing the particular functional group is more active as a therapeutic agent for treating sleep disorders than the corresponding compound without this group. The effect of the derivative compound depends on the identity of the addition.

By deriving a compound in order to improve favorable biological properties and decrease undesirable side effects, it is possible to implement a strategy based on potential mechanistic effects or interactions. For example, in some compounds, the presence of a carboxylic acid results in the ability to form an intramolecular ionic bond that includes the corresponding carboxylate ion, for example, formation of zwitterionic species with a nitrogen atom in the compound or salt bridge formation. These interactions result in favorable biological effects, such as conformational lipophilicity, that is, higher lipophilicity as a result of a particular conformation, such as the formation of internal salt between a carboxylate anion and a protonated amine. Such conformational lipophilicity allows penetration through the brain's blood barrier into the CNS, although it is believed that the presence of two polar ions is generally to inhibit crossing of the supportive brain barrier. Another benefit of the presence of carboxylic acid is a better ability of the compound to selectively bind to the desired receptor. Compounds of the invention may also be derived to produce prodrugs. "Prodrugs" include a precursor form of the drug that is metabolically converted in vivo to produce the active drug. The invention further contemplates the use of prodrugs which are converted in vivo to the sleep modulating compounds used in the methods of the invention (see, for example, RB Silver man, 1992, "The Organic Chemistry of Drug Design and Drug Action", Academic Press, Chp. 8). Such prodrugs may be used to alter biodistribution (e.g., to allow compounds that would not typically cross the blood-brain barrier to cross the blood-brain barrier) or the pharmacokinetics of the sleep modulating compound. For example, an anionic group, for example a carboxylate, sulfate or sulfonate, may be esterified, for example, with an alkyl group (e.g. a methyl group) or a phenyl group to yield an ester. When the ester is administered to a subject, the ester is cleaved enzymatically or non-enzymatically, reductively or hydrolytically to present the anionic group. Such an ester may be cyclic, for example a cyclic sulfate or sulfone or two or more anionic moieties may be esterified by means of a linking group. An anionic group can be esterified with fractions (e.g., acyloxymethyl esters) that are cleaved to present a sleep-modulating intermediate which subsequently decomposes to yield the active sleep-modulating compound. In one embodiment, the prodrug is a reduced form of a carboxylate, sulfate or sulfonate, for example an alcohol or thiol, which is oxidized in vivo to the sleep modulating compound. In addition, an anionic fraction can be esterified into a group that is actively transported in vivo or that is selectively absorbed by target organs.

In general, in another aspect, the present invention relates to the use of the compounds of formula I-IVd to modulate sleep. In one embodiment, compounds of formula I-IVd modulate sleep with minor side effects: for example, compounds do not inhibit REM sleep (consequently, sleep induced by these compounds may more closely resemble a person's natural sleep cycles. ), compound use does not result in recurrent insomnia and / or the compounds do not inhibit locomotor activity or adversely affect body temperature.

In one embodiment, the compounds of formula I-IVd for use in the methods of the invention have one or more of the following characteristics: an inhibition constant (Ki) with respect to 5HT2a receptor binding of less than 1 μΜ; a Kj with respect to off-target binding to an off-target select from M1, M2, M3, D1, D2, A1 and a2 which is more than 5 times greater than Ki with respect to the 5HT2a receptor; a nonREM peak time value that is greater than 55% of nonREM sleep per hour for the third hour after the compound is administered to a subject; a cumulative total increase in non-REM sleep of not less than 20 minutes for compound doses that produce maximum sleep consolidation; a longer sleep attack that is more than 13 minutes long; posttreatment longer liquid sleep attack that is greater than or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep attack that is greater than 5 minutes at absolute peak; administration of the compound to a subject does not produce appreciable amounts of relapsing insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administering the compound to a subject does not disproportionately inhibit relative locomotor activity for normal sleep effects.

In another embodiment, the compound of formula I-IVd for use in the methods of the invention has one or more of the following characteristics: an inhibition constant (Kj) with respect to 5HT2a receptor binding of less than 300 nM; a Ki with respect to off target binding to an off target selected from M1, M2, M3, D1, D2, A1 and a2 which is more than 10 times greater than Ki with respect to 5HT2a; a nonREM peak time value that is greater than 55% of nonREM sleep per hour for the third hour after the compound is administered to a subject; a cumulative total increase in non-REM sleep of not less than 20 minutes for compound doses that produce maximum sleep consolidation; a larger sleep attack that is longer than 13 minutes in duration; major posttreatment liquid sleep attack that is greater than or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep attack that is greater than 5 minutes at absolute peak; administration of the compound to a subject does not produce appreciable amounts of relapsing insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administering the compound to a subject does not disproportionately inhibit locomotor activity with respect to normal sleep effects.

In another embodiment, the compound of formula I-IVd for use in the methods of the invention has one or more of the following characteristics: an inhibition constant (Kj) with respect to 5HT2a receptor binding of less than 150 nM; a Ki with respect to off-target binding to a selected off-target of D1, D2, M1, M2, M3, A1 and a2, which is more than 20 times greater than Ki with respect to 5HT2a; a nonREM peak time value that is greater than 55% of nonREM sleep per hour for the third hour after the compound is administered to a subject; a cumulative total increase in non-REM sleep of not less than 20 minutes for compound doses that produce maximum sleep consolidation; a larger sleep attack that is longer than 17 minutes in duration; major posttreatment liquid sleep attack that is greater than or equal to 5 minutes when adjusted using a baseline value obtained at least 24 hours prior to administration of the compound to a subject; an average sleep attack that is greater than 6 minutes at absolute peak; administration of the compound to a subject does not produce appreciable amounts of relapsing insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administering the compound to a subject does not disproportionately inhibit locomotor activity or motor tone with respect to normal sleep effects.

In vitro selection criteria for compounds of the invention are presented in table 1.

Table 1

<table> table see original document page 61 </column> </row> <table> In another embodiment, the off-target link Kj is 50 times the measured 5HT2a receiver Ki Ki. In some embodiments, the off-target binding Ki is 100 times the measured 5HT2a receptor Ki.

In vitro binding assays are used to determine 5HT2a binding (i.e. primary target binding) and M1, M2 and M3 binding (i.e. off-target binding). These binding assays measure the ability of benzisoxazole analogs to displace known 5HT2a, M1, M2, and M3 receptor patterns, where M1, M2, and M3 are cholinergic (muscarinic) receptors. Similar assays are performed with 5HT2a and dopamine receptors (D1 and D2) and with 5HT2a adrenergic receptors (A1 and a2).

Binding studies against the 5HT2a receptor indicate binding affinity, and thus the results of the binding assays are an indication of the activity of the benzisoxazole analog compound. Binding studies against muscarinic receptors indicate the extent to which compounds bind muscarinic receptors responsible for the anticholinergic activity of the compound. Binding to muscarinic receptors results in several unwanted side effects from many known antihistamines, for example dry mouth. A decrease in binding of compounds to M1-M3 receptors with respect to binding of the compound to the 5HT2a receptor is an indication of the greater specificity of the compound for the 5HT2a receptor over the muscarinic receptor. In addition, a drug with higher specificity for the 5HT2a receptor has fewer anticholinergic side effects.

5HT2a binding of benzisoxazole analogs of the invention (also referred to herein as "test compounds" or "compounds of the invention") is determined by measuring the specific binding of a given test compound or series of test compounds to the 5HT2a receptor and comparing it with known standard specific binding (i.e., reference compound).

In vitro selection criteria for benzisoxazole analogs of the invention are presented in Table 2.

Table 2

Connection to 5HT2a (Primary Target) Ki <300 nMolar_

Off target link

• cholinergic M1, M2, M3 · Ki> 10 times the 5HT2a receptor Ki measured Ki

• dopaminergic D1, D2 · Ki> 10 times the 5HT2a receptor Ki measured Ki

• adrenergic ai, a2_ · Ki> 10 times the 5HT2a receptor Ki measured Ki

Other in vitro benzisoxazole analogs of the invention are shown in table 3.

Table 3

Connection to 5HT2a (Primary Target) K, <150 nMolar_

Off target link

• cholinergic M1, M2, M3 · Ki> 20 times the 5HT2a receptor Ki measured Ki

• dopaminergic Dl, D2 · Ki> 20 times that of the 5HT2a receptor Ki measured

• adrenergic αϊ, a2 · Ki> 20 times the 5HT2a receptor Ki measured Ki

5HT2a binding (primary target binding) and M1, M2 and M3 binding (off-target binding) are determined using the described 5HT2a, M1, M2 and M3 binding assays.

The M1 binding assay determines the M1 binding of a test compound by measuring the specific binding of a given test compound to M1 and comparing it to the specific binding of a reference compound. (See, for example, Buckley, et al., Mol. Phannacol. 35: 469-76 (1989) (with modifications)). Reference compounds used in the M1 binding assay include, for example, scopolamine, MethylBr (Ki 0.09 nM); Metiodide 4-DAMP (Ki 0.27 nM); pyrenzepine (Ki 2.60 nM); HHSID (Ki 5.00 nM); and methoctramine (Ki 29.70 nM).

For example, in one embodiment of the M1 binding assay, the muscarinic receptor M1 is a recombinant human M1 expressed on cells.

CHO and a radioligand, [H] -scopolamine, N-methyl chloride (80-100 Ci / mmol) at a final binder concentration of 0.5 nM is used to detect specific binding for M1. Assay characteristics include a 0.05 nM KD (binding affinity) and a Bmax (receptor number) of .4.2 pmo / mg protein, (-) - scopolamine, methyl-, bromide (methylscopolamine bromide). ) (1.0 μΜ) is used as the nonspecific determinant, reference compound and positive control. Binding reactions are performed in PBS for 60 minutes at 25 ° C. The reaction is terminated by rapid vacuum filtration on fiberglass filters. The level of trapped radioactivity in the filters is measured and compared to control values to verify any interaction between a given test compound and the cloned muscarinic M1 binding site.

The M2 binding assay determines the M2 binding of a test compound by measuring the specific binding of a given test compound to M2 and comparing it with the specific binding of a reference compound. (See, for example, Buckley, et al., Mol. Pharmacol. 35: 469-76 (1989) (with modifications)). Reference compounds used in the M2 binding assay include, for example, scopolamine, MethylBr (0.3 nM Kj); Metiodide 4-DAMP (Ki 20.7 nM); methoctramine (Ki 20.460 nM); HHSID (Ki 212.7 nM); and pyrenzepine (Ki 832.9 nM).

For example, in one embodiment of the M2 binding assay, the muscarinic receptor M2 is a human muscarinic M2 expressed in CHO cells and a radioligand, [H] -scopolamine, N-methyl chloride (80-100 Ci / mmol) in a A final binder concentration of 0.5 nM is used to detect specific binding for M1. Assay characteristics include a 0.29 nM KD (binding affinity) and a Bmax (receptor number) of 2.1 pmol / mg protein, (-) - scopolamine, methyl-, bromide (methylscopolamine bromide) ( 1.0 μΜ) is used as the nonspecific determinant, reference compound and positive control. Binding reactions are performed in PBS for 60 minutes at 25 ° C. The reaction is terminated by rapid vacuum filtration on fiberglass filters. The level of trapped radioactivity in the filters is measured and compared to control values to verify any interaction between a given test compound and the cloned muscarinic M2 binding site.

The M3 binding assay determines the M3 binding of a test compound by measuring the specific binding of a given test compound after M3 and comparing it to the specific binding of a reference compound. (See, for example, Buckley, et al., Mol. Pharmacol. 35: 469-76 (1989) (with modifications)). Reference compounds used in the M3 binding assay include, for example, scopolamine, MethylBr (0.3 nM Ki); Metiodide 4-DAMP (Ki 0.8 nM); HHSID (Ki 14.5 nM); pyrenzepine (Ki 153.3 nM); and methoctramine (Ki 700.0 nM).

For example, in one embodiment of the M3 binding assay, the muscarinic receptor M3 is a recombinant human M3 expressed in CHO cells and a radioligand, [3H] scopolamine, N-methyl chloride (80-100 Ci / mmol) in a 0.2 nM final binder concentration is used to detect specific binding for M1. Assay characteristics include a 0.14 nM KD (binding affinity) and a Bmax (receptor number) of 4.0 pmol / mg protein, (-) - scopolamine, methyl-, bromide (methylscopolamine bromide) (1.0 μΜ) is used as the nonspecific determinant, reference compound and positive control. Binding reactions are performed in 50 mM TRIS-HCl (pH 7.4) containing 10 mM MgCl 2, 1 mM EDTA for 60 minutes at 25 ° C. The reaction is terminated by rapid vacuum filtration on fiberglass filters. The level of trapped radioactivity in the filters is measured and compared to control values to verify any interaction between a given test compound and the cloned muscarinic M3 binding site.

Binding to 5HT2a is determined as described, for example, in the British Journal of Pharmacology (1995) 115, 622-628.

Other in vitro selection criteria for benzisoxazole analogs of the invention include HERG binding. HERG binding is determined using hERG block comparative shading to evaluate the effect of a given test compound on cloned hERG channels expressed in mammalian cells. (See, for example, Brown and Rampe, Pharmaceutical News 7: 15-20 (2000); Rampe et al., FEBS Lett., 417: 28-32 (1997); Weirieh and Antoni, Basic Res. CardioL 93 Suppl. 1: 125-32 (1998); and Yap and Canon, Clin Exp Exp Allergy 5 Suppl, 3, 174-81 (1999)).

The binding of BERG, the cardiac potassium channel responsible for rapid delayed repair current (Ikt) in human ventricles, is evaluated because Ikx inhibition is the most common cause of prolongation of cardiac action potential by noncardiac drugs. (See Brown and Rampe (2000), Weirich and Antoni (1998); and Yap and Canon (1999)). Longer duration of action potential causes QT interval prolongation that has been associated with a dangerous ventricular arrhythmia, torsade de pointes. (Brown and Rampe (2000)).

In the hERG assay, BERG channels are expressed in a human embryonic kidney (HEK293) cell line lacking endogenous Irc. In some cases expression in a mammalian cell line may be preferable for transient expression in Xenopus oocytes, as the latter demonstrates a consistent 10-100-fold lower sensitivity to hERG channel blockers. (See, Rampe 1997).

In one embodiment of the hERG assay, the positive (i.e. reference compound) control is terfenadine (Sigma, St. Louis MO), which has been shown, at a concentration of 60 nM, to block the BERG current by approximately 75%. Test compounds are distributed in HEPES buffered physiological saline (HB-PS) + 0.1% dimethyl sulfoxide (DMSO). Each test compound is applied at a concentration of 10 μΜ on hERG-expressing HEK293 cells (n> 3, where η - the number of cells). Cells are exposed to the test compound for the time required to reach steady state block, but no more than 10 minutes. The positive control (60 mM terfenadine) is applied to two cells (n> 2).

The cells exposed to hERG are then transferred to the recording chamber and superimpressed with HB-PS solution. The pipette solution for whole cell recordings includes potassium aspartate (130 mM), MgCl2 (5 nM), EDTA (5 mM), ATP (4 mM) and HEPES (10 mM) at a pH adjusted to 7.2 with KOH. Action onset block and steady state of hERG current due to the test compound are measured using a fixed amplitude pulse pattern (depolarization: + 20 mV for 2 seconds; repolarization: -50 mV for 2 seconds), repeated at 10 seconds from a holding potential of -80 mV. Peak tail current is measured during the 2 second step to -50 mV. A steady state is maintained for at least 30 seconds before applying the test compound or positive control compound. Peak tail currents are measured until a new steady state is reached.

In addition to the in vitro selection criteria described above, the compounds of the invention may be selected using the following sleep-awakening and physiological estimates in vivo: Non-REM Sleep: Benzisoxazole analogs are selected if, in adult male Wistar rats, (i) amount non-REM peak exceeds 55% of non-REM per hour for not after the third hour after treatment; and (ii) the nature of this increase in non-REM sleep is such that the total cumulative net increase in non-REM sleep in the initial 6 hours posttreatment (adjusted for baseline in the corresponding circadian time 24 hours prior to and relative to control vehicle treatment) is not less than 20 minutes in total for compound doses that produce maximum sleep consolidation as measured by the extent of the sleep attack when the drug is orally distributed.

The term "non-REM peak sleep time" is defined as an absolute peak amount of non-REM sleep per hour after treatment, with drug delivery occurring in circadian time (TC) 18, which is 6 hours after erasure. of lights in a night laboratory mouse when housed in a light-dark cycle LD 12:12 (12 hours of light and 12 hours of darkness). The nominal criterion of 55% non-REM sleep per hour is equivalent to 33 minutes of non-REM sleep per hour.

As used herein, the term "cumulative non-REM sleep" is defined as the total net aggregate increase in the number of minutes of non-REM sleep, measured over the total duration of a soporific drug effect that typically, but not always, occurs. within the first 6 hours post-treatment, adjusted for the total net aggregate number of non-REM sleep minutes that occurred during the corresponding non-treatment baseline hours of the day recorded 24 hours earlier, with respect to similar control vehicle treatment. .

As defined herein, the term "sleep attack" refers to a discrete episode of continuous or near continuous sleep consisting of non-REM sleep, REM sleep, or both non-REM and REM sleep stages, delimited before and after sleep. episode for more than two continuous 10-second waking intervals. The following non-limiting description illustrates this concept: WWWWSSSSWSSSSSSSWWSSSSSSSWWWW, where each letter represents the predominant alert state (S = sleep, W = wake) observed every 10 seconds. The "episode" of measured sleep is 21 ten-second or 3.5-minute intervals.

Sleep Consolidation: Benzisoxazole analogs are selected if, in adult male Wilstar rats, (i) the absolute duration of the continuous continuous sleep attack (ie, "sleep attack") posttreatment is longer than 13 minutes; (ii) the major post-treatment net sleep attack is greater than or equal to 3 minutes when adjusted to baseline 24 hours earlier and calculated with respect to vehicle treatment; and (iii) the average absolute duration of each sleep attack when averaged over 15 hours in one hour per hour is greater than or equal to 5 minutes. The selection criteria mentioned above assume that sleep and wake stages are continuously determined every 10 seconds (eg, 10-second sleep score "intervals"), that sleep and wake are measured polygraphically using EEG and EMG criteria and Sleep attacks (non-REM and / or REM sleep compounds) are defined as continuous "episodes" until the episode is interrupted for more than two continuous 10-second waking intervals.

As used herein, the term "longer sleep attack length" is defined as the total number of minutes an animal remains asleep (non-REM and / or REM sleep stages) during the only major sleep attack that occurred at the beginning. given time after treatment. The "sleep attack extent" measurement criteria assumes that sleep is continuously measured at 10-second intervals and is classified based on the predominant state, computed or otherwise determined as a discrete sleep stage (where the stages of sleep sleep are defined as non-REM sleep, REM sleep, or waking) during the 10-second interval that defines the interval.

The term "average sleep attack duration" is defined as the average duration (in minutes) of each and every episode or attack that started in a given hour, regardless of the individual duration of each episode or attack.

Simultaneously Measured Side Effects: Benzisoxazole analogs are selected if, in adult male Wilstar rats, these compounds (i) do not produce appreciable amounts of relapsing insomnia; (ii) do not appreciably inhibit REM sleep; and (iii) do not disproportionately inhibit motor locomotor activity and / or motor tone in relation to the normal effects of sleep itself. The threshold definitions for these three variable side effects are as follows:

"Repeat insomnia" is defined as a recurrent, paradoxical or compensatory wakefulness that occurs after the sleep-promoting effects of a hypnotic or soporific agent.

Relapsing insomnia is typically observed during the common circadian resting phase 6-18 hours post-treatment in CT-18 (6 hours after lights out, given LD 12:12), but may occur anytime during the initial 30 hours. after treatment. Recurrence is considered unacceptable when, in adult male Wilstar rats, cumulative waking associated with recurrent insomnia is greater than a 10% reduction in average non-REM sleep times per hour during posttreatment circadian rest phase (lights on) .

In adult male Wilstar rats, recurrent insomnia manifests as an increase in wakefulness relative to corresponding baseline times (24 hours earlier) subsequent to the effect of drug-induced sleep and recurrent insomnia is cumulatively measured.

"REM sleep inhibition" is defined as the reduction of posttreatment REM sleep time in CT-18 (6 hours after lights out; LD 12: 12) or in CT-5 (5 hours after lights on; LD 12: 12). Compounds that reduce REM sleep time by more than 15 minutes (relative to baseline and adjusted for vehicle treatment) when administered on both CT-18 and CT-5 are considered unacceptable.

As defined herein, "disproportionate locomotor activity inhibition" is a reduction in locomotor activity that exceeds the normal and expected reduction in behavioral activity that can be attributed to sleep. Logic dictates that if an animal is sleeping, there will normally be a corresponding reduction in locomotor activity. If a hypnotic or soporific compound reduces locomotor activity levels in excess of 20% more than explained by sleep alone, the compound is considered unacceptable. Locomotor activity (LMA) or motor tone can be objectively quantified using any means of monitoring locomotor behavioral activity (non-specific movements, telemetry based activity monitoring, 3-dimensional motion detection devices, wheel racing activity, exploratory measurements, electromyographic recordings, etc.) provided that it is measured concurrently with objective sleep-wake measurements on the same animal.

In one embodiment, locomotor activity in an animal's cage is measured using a biotelemetric device surgically implanted in the animal's peritoneal cavity; The implantable device and associated telemetry receiver detect if and how many animals move in the cage. Sleep and wakefulness are measured at 10 second intervals simultaneously. The locomotor activity count per unit of time is divided by the concurrent amount of wakefulness by the same unit, yielding a "locomotor activity intensity" (LMAI) measured by the unit of time. Hypnotic or soporific compounds administered on CT-18 (6 hours after the lights go out; LD 12:12) that decrease locomotor activity per unit time awaken by more than 20% over what would be deemed unacceptable for the vehicle.

In another embodiment, the benzisoxazole analogs of the invention are selected using the in vivo sleep-awakening and physiological estimation criteria presented in table 4:

Table 4

<table> table see original document page 71 </column> </row> <table> Methods to evaluate these sleep estimation criteria

5 awakening and physiological are described earlier. The "absolute value" shown in the second column of table 4 refers to the value determined for each test compound, while the "change" value in the third column of table 4 reflects an adjusted value where the absolute value is the difference. when the vehicle values are adjusted to 10 baseline.

In some modalities, the major sleep attack is longer than 13 minutes. In others it is longer than 17 minutes. In some embodiments, the major posttreatment liquid sleep attack is greater than or equal to 3 minutes in duration. In others it is greater than or equal to 6 minutes 15 in length.

Other in vivo sleep-wake and physiological estimation criteria used to select benzisoxazole analogs of the invention include measurement of acute body temperature and latent body temperature as a change from baseline to vehicle. The change in acute body temperature should not exceed - 0.60 0C and the change in latent body temperature should not exceed + 0.60 0C in the time of 1-6 hours. The acute body temperature (TI-6) is adjusted to the corresponding baseline measured 24 hours earlier with respect to the vehicle (the vehicle decrease). The latent body temperature, measured 7-18 hours after drug treatment (T7-18), is adjusted to the corresponding baseline measured 24 hours earlier with respect to the vehicle (the vehicle decrease).

The pharmaceutically acceptable compounds or salts thereof are administered orally, nasal, transdermal, pulmonary, inhalational, buccal, sublingual, intraperintoneal, intravenous, rectal, intrapleural, intrathecally and parenterally. In another embodiment, the compound is administered orally. One of skill in the art will recognize the advantages of certain routes of administration.

In some embodiments, a compound of formula I-IVd is administered as a pharmaceutically acceptable salt. One of skill in the art will recognize the various methods for creating pharmaceutically acceptable salts and identifying the appropriate salt. In another embodiment, the pharmaceutically acceptable salt or compound thereof is included in a pharmaceutical composition.

The "subject" includes mammals, e.g. humans, companion animals (e.g. dogs, cats, birds and the like), farm animals (e.g. cows, sheep, pigs, horses, chicken and the like) and pets. laboratory (e.g., mice, mice, guinea pigs, birds, and the like). Typically, the subject is human.

A subject in need of treatment has a disease or disorder that may affect the health and / or well-being of the subject.

r

For example, the disorder may be a sleep disorder. Is well

It is known in the art that certain medical disorders, e.g. central nervous system (CNS) disorders, e.g. mental or neurological disorders, e.g. anxiety, may have a sleep disorder component, e.g. sleep deprivation. Thus, "treating a sleep disorder" also includes treating a sleep disorder component of other disorders, for example, CNS disorders. Additionally, treating the sleep disorder component of CNS disorders may also have the beneficial effect of alleviating other symptoms associated with the disorder. For example, in some subjects who experience sleep deprivation anxiety, treatment of the sleep deprivation component also treats the anxiety component. Thus, the present invention also includes a method of treating such medical disorders.

For example, sleep disorders associated with mental disorders include psychosis, mood disorders, anxiety disorders, panic disorder, addiction and the like. Specific mental disorders include, for example, depression, obsessive compulsive disorder, neurosis / affective disorder, neurosis / depressive disorder, anxiety neurosis; dysthymic disorder, behavioral disorder, mood disorder, schizophrenia, manic depression, delirium and alcoholism.

Sleep disorders associated with neurological disorders include, for example, degenerative brain disorders, dementia, parkinsonism, Huntington's disease, Alzheimer's disease, fatal familial insomnia, sleep-related epilepsy, sleep-related epilepsy, and sleep-related headaches. Sleep disorders associated with other medical disorders include, for example, soporific disease, nocturnal heart ischemia, chronic obstructive pulmonary disease, sleep-related asthma, sleep-related gastroesophageal reflux, peptic ulcer disease, and fibrositis syndrome.

In some circumstances, sleep disorders are also associated with pain, for example, neuropathic pain associated with restless leg syndrome; migraine; hyperalgesia, fibromyalgia, pain; increased or exaggerated pain sensitivity, such as hyperalgesia, causalgia, and allodynia; acute pain; buttock pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndromes I and II; arthritic pain; sports injury pain; infection-related pain, eg HIV, post polio syndrome, and postherpetic neuralgia; pain of the imaginary limb; work pain; cancer pain; post chemotherapy pain; pain after stroke; postoperative pain; neuralgia; conditions associated with visceral pain including irritable bowel syndrome, migraine and angina.

Other sleep disorders include, for example, short sleeper, long sleeper, subvigilia syndrome, fragmentary myoclonus, sleep hyperhidrosis, menstruation-associated sleep disorder, pregnancy-disturbing sleep, frightening hypnagogic hallucinations, sleep-related neurogenic tachypnea, laryngospasm related to sleep and sleep asphyxia syndrome.

Insomnia is typically classified as sleep-onset insomnia, where a subject takes more than 30 minutes to fall asleep; and sleep-maintaining insomnia, where the subject takes more than 30 minutes awake during an expected sleep period, or, for example, waking up before the desired lifting time with difficulty or an inability to go back to sleep. The compounds described are particularly effective in treating sleep onset and sleep maintenance insomnia, insomnia resulting from circadian rhythm adjustment disorders or insomnia resulting from CNS disorders. One embodiment is to treat a subject of a circadian rhythm adjustment disorder. Another embodiment is treating a subject of insomnia resulting from a mood disorder. In other embodiments, a subject is treated for sleep apnea, sleepwalking, night terrors, restless leg syndrome, sleep onset insomnia, and sleep maintenance insomnia. For example, a subject is treated for sleep onset insomnia or sleep maintenance insomnia. The compounds described are effective for treating sleep-onset insomnia. The described compounds are also effective for treating sleep-maintaining insomnia. In one embodiment, the disclosed compounds improve sleep quality, for example, the amount of slow sleep is greater.

The dosage regimen using the compounds is selected according to a variety of factors including the patient's type, species, age, weight, gender and medical condition; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt of this employee. A physician or veterinarian skilled in the art can readily determine and prescribe the effective amount of medication necessary to treat, prevent, contain or eliminate the progress of the condition.

Oral human dosages of the present invention, when used for the indicated purposes, will range from about 0.05 to 5,000 mg / day orally. Effective amounts of the described compound typically range from about 0.01 mg per day to about 100 mg per day and between about 0.1 mg per day and about 10 mg / day.

Techniques for administering the disclosed compounds of the invention can be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995).

For example, in some embodiments, an acid salt of an amine-containing compound or other basic group is obtained by reacting the compound with a suitable organic or inorganic acid, such as hydrogen chloride, hydrogen bromide, acetic acid, perchloric acid and the like. . Compounds with a quaternary ammonium group also contain a counter anion such as chloride, bromide, iodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (for example (+) 4 artrates, (-) - tartrates or mixtures thereof including racemic mixtures), succinates, benzoates and salts with amino acids, such as glutamic acid. Salts of compounds containing a carboxylic acid or other acid functional group are prepared by reacting with a suitable base. A pharmaceutically acceptable salt such as this is made with a base which provides a pharmaceutically acceptable cation which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts. as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N, N'-dibenzylethylenediamine, 2-hydroxyethylamine, bis (2-hydroxyethyl) amine, tri- ( 2-hydroxyethyl) amine, procaine, dibenzylpiperidine, N-benzyl-3-phenethylamine, dehydroabiethylamine, N, N'-bishydroabiethylamine, glucamine, N-methylaglucamine, collidine, quinine, quinoline and basic amino acid such as lysine and arginine.

In some embodiments, certain compounds and salts thereof also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.

The compounds and salts or solvates thereof described may exist in more than one crystalline form, for example as "crystalline polymorphs" or "polymorphs". Crystalline polymorphs of the described compounds are prepared by crystallization under different conditions. For example, using different solvents or different solvent mixtures for recrystallization; crystallization at different temperatures; various cooling modes, ranging from very fast to very slow cooling during crystallization and the like. Polymorphs are also obtained by heating or melting the described compounds followed by gradual or rapid cooling. The presence of polymorphs is determined by solid probe nuclear magnetic resonance spectroscopy, infrared spectroscopy, differential scanning calorimetry, X-ray diffraction, and other techniques known to those skilled in the art. In one embodiment, the compounds described herein and the pharmaceutically acceptable salts thereof are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in pharmaceutical compositions such as these in amounts sufficient to provide the desired dosage amount within the range described herein. Techniques for formulating and administering the disclosed compounds of the invention can be found in Remington: the Science and Practice of Pharmacy, above.

Typically, the compound is prepared for oral administration, wherein the described compounds or salts thereof are combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, pills, powders, syrups, solutions, suspensions and the like.

Tablets, pills, capsules and the like contain from about 1 to about 99 weight percent of the active ingredient and a binder such as gum tragacanth, acacia, cornstarch or gelatin; excipients, such as dicalcium phosphate; a disintegrating agent such as cornstarch, potato starch, alginic acid; a lubricant, such as magnesium stearate; and / or a sweetening agent such as sucrose, lactose, saccharin, xylitol and the like. When a dosage unit form is a capsule, it often contains, in addition to materials of the above type, a liquid carrier such as fatty oil.

In some embodiments, various other materials are present as coatings or to modify the physical form of the dosage unit. For example, in some embodiments, tablets are coated with shellac, sugar or both. In some embodiments, a syrup or elixir contains, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a pigment and a flavoring such as cherry or orange flavor and the like.

For some embodiments with respect to parent administration, the disclosed compounds or salts, solvates or polymorphs thereof may be combined with sterile aqueous or organic media to form injectable solutions or suspensions. Injectable compositions are, for example, aqueous isotonic solutions or suspensions. The compositions may be sterile and / or contain adjuvants such as preservative, stabilizing, wetting or emulsifying agents, solution promoters, osmotic pressure regulating salts and / or buffers. In addition, they may also contain other substances of therapeutic value. The compositions are prepared according to conventional mixing, granulating or coating methods, respectively and contain about 0.1 to 75%, for example about 1 to 50% of the active ingredient.

For example, injectable solutions are produced using solvents such as aqueous castor or peanut oil or propylene glycol, as well as aqueous solutions of salts of the water-soluble pharmaceutically acceptable compounds. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under common conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The terms "parenteral administration" and "parenterally administered" as used herein mean modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intrarterial, intrathecal, intracapsular, intraorbital injection and infusion. , intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intrarticular, subcapsular, subarachnoid, intraspinal and intrasternal.

For rectal administration, suitable pharmaceutical compositions are, for example, topical preparations, suppositories or enemas. Suppositories are advantageously prepared from serous emulsions or suspensions. The compositions may be sterile and / or contain adjuvants such as preservative, stabilizing, wetting or emulsifying agents, solution promoters, osmotic pressure regulating salts and / or buffers. In addition, they may also contain other substances of therapeutic value. The compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, for example about 1 to 50%, of the active ingredient.

In some embodiments, the compounds are formulated to deliver the active agent by pulmonary administration, for example, by administering an aerosol formulation containing the active agent from, for example, a hand pump jet, nebulizer or pressurized metered dose inhaler. . In some embodiments, suitable formulations of this type also include other agents, such as antistatic agents, for maintaining the compounds described as effective aerosols.

A medicament dispensing device for dispensing aerosols comprises a suitable aerosol pump with a metered valve containing a pharmaceutical aerosol formulation as described and an adapter housing an activator for holding the pump and allowing the medicament to be delivered. The pump in the drug delivery device has a larger void space that represents more than about 15% of the total pump volume. Frequently, the polymer intended for pulmonary administration is dissolved, suspended or emulsified in a mixture of a solvent, surfactant and propellant. The mixture is kept under pressure in a pump that has been sealed with a metering valve.

For nasal administration, either a solid carrier or a liquid carrier may be used. The solid carrier includes a particle size rough powder in the range of, for example, about 20 to about 500 microns and such formulation is administered by rapid inhalation through the nasal passages. In some embodiments where the liquid carrier is used, the formulation is administered as a jet or nasal drops and includes oily or aqueous solutions of the active ingredient.

Also contemplated are formulations which are in the form of rapidly dispersing dosages, also known as "flash dose" forms. In particular, some embodiments of the present invention are formulated as compositions that release their active ingredients in a short time, for example, typically less than about five minutes, for example less than about ninety seconds. Additionally, some embodiments of the present invention are formulated as compositions which release their active ingredients in less than about thirty seconds, for example, in less than about ten or fifteen seconds. Such formulations are suitable for administration to a subject by a variety of routes, for example by insertion into a body cavity or application to a moist body surface or open wound.

Typically, a "flash dosage" is an orally administered solid dosage form that readily disperses in the mouth and thus does not require much effort to swallow and allows the compound to be rapidly ingested or absorbed through the membranes of the oral mucosa. In some embodiments, suitable rapidly dispersing dosage forms are also used in other applications, including treatment of wounds and other body insults and disease states where release of the drug by externally supplied moisture is not possible.

"Lightning dose" forms are known in the art, see, for example, effervescent dosage forms and insoluble microparticle rapid release coatings in U.S. Patent Nos. 5,578,322 and 5,607,697; lyophilized foams and liquids in U.S. Patent 4,642,903 and 5,631,023; rotary hot extrusion dosage forms produced in U.S. Patent Nos. 4,855,326, 5,380,473 and 5,518,730; solid, freeform fabrication in U.S. Patent 6,471,992; saccharide-based carrier matrix and a liquid binder in U.S. Patent Nos. 5,587,172, 5,616,344, 6,277,406 and 5,622,719; and other forms known in technology.

Benzisoxazole analogs of the invention are also formulated as "pulsed release" formulations, wherein the analog is released from pharmaceutical compositions in a series of releases (i.e. pulses). Benzisoxazole analogs are also formulated as "sustained release" formulations wherein the analog is continuously released from the pharmaceutical composition over an extended period.

Also contemplated are formulations, for example, liquid formulations, including cyclic or acyclic encapsulating or solvating agents, for example, cyclodextrins, polyethers or polysaccharides (e.g. methylcellulose). For example, polyanionic β-cyclodextrin derivatives with a sodium sulfonate salt group separated from the lipophilic cavity by an alkyl ether or polysaccharide spacer group. In one embodiment, the agent is methylcellulose. In another embodiment, the agent is a polyanionic β-cyclodextrin derivative with a sodium sulfonate salt separated from the lipophilic cavity by a butyl ether spacer group, for example, CAPTISOL® (CyDex, Overland, KS). One of skill in the art can evaluate suitable described agent / compound formulation ratios by preparing a solution of the agent in water, for example a 40 wt% solution; prepare serial dilutions, for example to make solutions of 20%, 10, 5%, 2.5%, 0% (control) and the like; adding an excess (compared to the amount that may be solubilized by the agent) of the described compound; mixing under appropriate conditions, for example heating, stirring, sonication and the like; centrifuge or filter the resulting mixtures to obtain clear solutions; and analyzing solutions for the concentration of the described compound.

In addition to the therapeutic formulations described above, a therapy including the compounds of the present invention optionally includes co-administration with at least one additional therapy, for example drug or physical or behavioral treatments (e.g., light therapy, electrical stimulation, modification behavior, cognitive therapy, circadian rhythm modification and the like). A practice like this is referred to as "combination therapy." Other therapy or therapies in combination therapy include therapies recognized by one of skill in the art as desirable in combination with the compound of the invention, for example, therapies known in the art or therapies that are proposed or discovered in the art for treating sleep disorders or treating disorders. associated with sleep disorders, for example therapies for any of the sleep disorders or other conditions described herein. In some embodiments the compound is administered as a combination therapy although it is administered as a monotherapy in other embodiments.

Typically, the compound is administered as a

monotherapy.

One skilled in the art will appreciate that a therapy administered in combination with the compounds of the present invention is directed to the same or a different target targeted by the compounds of the present invention. Administration of the compound of the invention is first followed by another therapy; or alternatively, administration of the other therapy may be first. The other therapy is any known in the art to treat, prevent or reduce the symptoms of the targeted disorder, for example a sleep disorder or other disorders, for example other CNS disorders. Moreover, some embodiments of the present invention have compounds administered in combination with other known therapies for the target disorder. In addition, the other therapy includes any patient benefit agent when administered in combination with the described compound.

For example, in some embodiments where the other therapy is a medicament, it is administered in a separate formulation or in the same formulation as the compound of the invention. A compound of the invention is administered in combination therapy with any at least one of the commercially available over-the-counter or prescription medications including, but not limited to, antihistamines, antimicrobial agents, fungistatic agents, germicidal agents, hormones, antipyretic agents, antidiabetic agents. , bronchodilators, antidiarrheal agents, antiarrhythmic agents, coronary dilating agents, glycosides, spasmolytics, antihypertensive agents, antidepressants, antianxiety agents, antipsychotic agents, other psychotherapeutic agents, steroids, corticosteroids, analgesics, cold medications, vitamins, sedatives, sedatives , contraceptives, non-steroidal anti-inflammatory drugs, blood glucose lowering agents, cholesterol lowering agents, anticonvulsant agents, other antiepileptic agents, immunomodulators, anticholinergics, spasmolytics, sympathomimetics, agen vasodilators, anticoagulants, antiarrhythmic agents, prostaglandins with various pharmacological activities, diuretics, sleep aids, antihistamine agents, antineoplastic agents, oncolytic agents, antiandrogens, antimalarial agents, antileptic agents and various other types of medicines. For example, GABA agonists, alpha-2-delta modulators; other 5-HT 2a antagonists and inverse agonists are used in combination with the compounds of the invention to treat sleep disorders. See Goodman and Gilmant, The Basis of Therapeutics (Eighth Edition, Pergamon Press, Inc., USA, 1990) and The Merck Index (Eleventh Edition, Merck & Co., Inc., USA, 1989). Examples of medicaments in combination with the compounds of the invention include, but are not limited to, AMBIEN® STILNOX® (zolpidem tartrate), indiplon, ESTORRATM (eszopiclone), NEURONTIN® (gabapentin), LYRICA® (pregabalin), eplivanserin, SONATA® (zaleplon), LUNESTA ™ (eszopiclone), ZOPICLONE ™ (imovana), DESYREL ™ (Trazodone Hydrochloride), SEROQUEL® (Quetiapine fumarate), CLOZARIL © (Clozapine), ZYPREXA ™ (Olanzapine), RISPERDAL®, RISPERDAL®, Risis M00907 melatonin antagonists, for example, ROSEREM ™ (ramelteon).

In one embodiment, the compounds of the invention are used in combination with a mechanical therapy, such as CPAP. "CPAP" or "continuous positive airway pressure" is a mechanical treatment for sleep apnea and other sleep-related breathing disorders (including snoring) that is typically administered through the patient's nose or mouth.

Upon CPAP treatment, an individual wears a tightly fitting plastic mask over his nose when sleeping. The mask is attached to a compressor, which forces air into the nose creating positive pressure in the patient's airway. The principle of the method is that pressurizing the airways provides a mechanical "immobilizing" action that prevents or decreases airway collapse and thus obstructive sleep apnea. Although an effective therapeutic response is observed in most patients undergoing CPAP treatment, many patients cannot tolerate equipment or pressure and refuse treatment. In addition, recent secret monitoring studies have shown that long-term compliance with CPAP treatment is very low. Patients are known to remove their masks while sleeping.

In one aspect, the compound of the invention is administered in combination with a CPAP device for promoting sleep. In another aspect, the compound of the invention is administered in combination with a CPAP device for improving sleep. In another aspect, the compound of the invention is administered in combination with a CPAP device to improve adherence with respect to CPAP treatment. Without wishing to be bound by theory, it is believed that by administering an effective amount of a sleep promoting compound of the invention to a patient in combination with CPAP treatment, the patient will sleep better and more deeply and thus probably not remove the mask. .

In one embodiment, the compound of the present invention is administered prior to CPAP treatment. In another embodiment, the compound of the present invention is administered at substantially the same time as the CPAP treatment. In one embodiment, parallel delivery of an effective amount of the compound is accomplished by adding an additional aerosol channel to the air pressure treating portion of the CPAP device, thereby administering the compound of the present invention in a nebulized form by means of the mask. nasal or oral examination of the CPAP device. Alternatively, an effective amount of the compound may be added to the water or liquid reservoir that is typically part of the CPAP treatment device. Using CPAP mask treatment, the compound of the

The invention is administered at a low concentration throughout the night or at higher concentrations, such as a bolus, at different time points early and during the course of the night.

All publications and patent documents cited herein are incorporated by reference as if each such publication or document were specifically and individually incorporated herein by reference. Citation of publications and patent documents shall not be considered an admission of any relevance to the prior art, nor is it an admission with respect to their contents or dates. The invention having now been presented by way of written description, skilled in the art will realize that it may be practiced in a variety of embodiments and that the following description and examples are for illustration rather than limitation of the following claims. EXAMPLE 1: Synthesis of Benzisoxazole Compounds

A general synthesis of a benzisoxazole piperazine compound is given in scheme 1.

Scheme I

3-Chloro-1,2-benzisoxasol reacted with excess piperazine in the presence of pyridine to provide 3- (piperazin-1-yl) benzo [d] isoxazole (3A) in 76% yield. Reductive termination of compound (3A) with 2-carbomethoxy 2-methyl propionaldehyde gave alkylated piperazine (4A), which was purified on silica gel. Basic hydrolysis of methyl ester of (4A) in aqueous ethanol followed by acidification gave carboxylic acid (1) as the mono-HCl salt.

Sulfonamide compounds can be synthesized, for example, as shown in Scheme 2: <formula> formula see original document page 87 </formula>

EXAMPLE 2: Compound Evaluation

Mammalian sleep can be divided into sleep that occurs during periods of rapid eye movement (REM) associated with substantial brain activity and non-REM sleep periods (NREM) associated with decreased brain activity. Typically, a normal night's sleep period is occupied primarily by NREM sleep and thus NREM accumulation can serve as a measure of total sleep accumulation, for example, significantly lower NREM can be associated with insomnia and an accumulation of "NREM debt". sleep, "for example, an accumulated physiological need for sleep that tends to persist until a sufficient amount of additional sleep is accumulated. Thus, a treatment-associated increase in NREM may indicate the effectiveness of the treatment in treating insomnia.

Sleep quality may be associated with sleep continuity or sleep maintenance. For example, a subject with sleep apnea wakes up numerous times during a sleep period, for example, the subject has difficulty maintaining continuous sleep. Although such a subject may accumulate a typical length of sleep nights, for example, 8 hours, sleep is not invigorating due to awakening caused by sleep apnea. Thus, an increase in major uninterrupted sleep attack (LUSB, also known as a major sleep attack) associated with treatment may indicate the effectiveness of treatment in improving sleep continuity and thus in treating sleep-maintaining insomnia. .

Sleep-wake, locomotor activity and body temperature are monitored in male Wistar rats treated with a test compound (ie benzisoxazole analog) initially at a concentration of 10 mg / kg. Larger and smaller doses are tested to select compounds (for example, as high as 45 mg / kg and as low as necessary to establish a dose without effect). Treatments are administered on CT-18, the peak of the activity-dominated period (6 hours after lights-out) and produced soporific (sleep-inducing) effects characterized by longer non-REM sleep, longer sleep continuity, but no evidence of REM sleep inhibition or recurrent insomnia.

Sleep-wake, locomotor activity and body temperature were monitored in vivo with various compounds of the invention. Male adult Wistar rats (250 g at surgery time, Charles River Laboratories, Wilmington MA) were anesthetized (2% isofluorane in medical grade oxygen) and surgically prepared with a cranial implant to allow recording of chronic electroencephalogram (EEG) and electromyogram ( IN G). Body temperature and locomotor activity were monitored using a miniature transmitter (Mini-Mitter, Bend, OR) surgically placed on the abdomen. The cranial implant consisted of stainless steel screws (two frontal [+3.2 AP bregma, ± 2.0 ML] and two ocipitals [-6.9 AP, ± 5.5 ML]) for EEG recording. Two Teflon® coated stainless steel wires were placed on the trapezoid muscles to record EMG. All leads were soldered to a miniature connector prior to surgery and sterilized with ethylene oxide gas. The implant assembly was affixed to the skeleton with dental acrylic. A minimum of three weeks was left for recovery from surgery.

Each rat was permanently housed in its individual registration cage located in separate, ventilated compartments of custom designed stainless steel enclosures. Each cage has been enhanced with a filter top lift and low torque pivot switch. Food and water were available ad libitum. A 24-hour light-dark cycle (12 hours of light, 12 hours of darkness) was maintained throughout the study. Animals were not disturbed for at least 48 hours before and after treatments.

Sleep and wakefulness were determined using "SCORE-.2004TM" (Hypnion, Worcester, MA) - an Internet-based sleep-wake and psychological monitoring system. The system monitored amplified EEG (frequency range 1 -30 Hz), integrated EMG (frequency range 10-100 Hz), body temperature and non-specific locomotor activity (AML) through telemetry and drinking activity continuously and simultaneously. Alert states were classified online as non-REM sleep (NREM), REM sleep, wake up or wake up called theta every 10 seconds. Total drinking and locomotor activity counts and body temperature were quantified and recorded every minute using EEG feature extraction and algorithms that match the pattern. From these data, the major uninterrupted sleep attack (LUSB) was obtained. The classification algorithm used individually prescribes EEG alert state models, plus EMG criteria to differentiate REM sleep from theta wakefulness, plus behavior-dependent contextual rules (for example, if the animal drank, he is awake). The intensity of drinking and locomotor activity (AML) was recorded every .10 seconds, while body temperature was recorded every minute. Locomotor activity was detected by a telemetry receiver (Mini-Mitter) lower than the cage. Telemetry measurements (AML and body temperature) were not part of the classification algorithm; thus, sleep classification and telemetry data were independent measurements.

Compounds were administered on CT-18, the peak of the activity dominated period, sufficient time was left to see the time course of the treatment effect before the lights came on (6 hours posttreatment). Compounds were suspended in 0.25% or 0.5% sterile methylcellulose (1-2 mL / kg). Treatments were administered orally in the form of a bolus.

A parallel group study project was employed. Control vehicles were taken from a large set (N> 200): a subset of the grouped control vehicles was selected, based on computerized marriage with the 24-hour pretreatment baseline and the active treatment group.

The following pharmacokinetic parameters are computed from individual plasma concentrations of the modified benzisoxazole compound using a non-behavioral approach and appropriate validated pharmacokinetic software (eg WinNonlin Professional). Concentration values reported as BLQ are set to zero. If concentration data is available, interim calculations are made (non-QC.d data) between periods, if possible. Dose escalation does not depend on pharmacokinetic calculations.

Descriptive statistics including mean, standard deviation, geometric mean coefficient of variation, median, minimum and maximum are computed for each pharmacokinetic parameter by dosage group. Descriptive statistics for log-natural AUC (O-t), AUC (O-inf) and Cmax are provided for each dose level. In addition, mean and median concentration versus time graphs are provided.

Dosing proportionality after study medication is explored by analyzing pharmacokinetic variables AUC (O-t), AUC (O-inf) and Cmax transformed into natural yoghurt with a linear model including dosages transformed to natural yoghurt as covariates. Dosing proportionality is completed if the 95% confidence interval for the co-variant slope includes the value of 1. Dosing linearity for AUC (0 -t), AUC (0 -inf) and Cmax is also explored. by a linear model. See, for example, Gibaldi and Perrier, Pharmacokinetics, Second Ed., Mareei Dekker: New York, New York (1982). Nominal sample collection times were used in the calculations, except where actual sampling times fell were within the acceptable time ranges specified in the protocol. The following parameters are estimated:

Cmax: Maximum plasma concentration, Tmax: time to maximum concentration.

Cmax and Tmax: reported directly from concentration-time data.

Area under the plasma concentration-time curve from time 9 to the last time point with measurable concentrations, estimated by the linear trapezoidal rule.

Area under the plasma concentration-time extrapolated to infinity curve, calculated using the formula:

AUCo-Q0 = AUCo-i + Co / Xo Where Ct is the last measurable plasma concentration and X is the estimated terminal phase elimination rate constant using Iog-linear regression during the terminal elimination phase. The number of points used in the calculation of X was determined by visual inspection of the data describing the terminal phase. At least the last three time points with measurable values were used to calculate X0. The number of points used in calculating X is based on the best correlation (adjusted r2) obtained for the time points describing the terminal elimination phase. An adjusted value of r2 for the regression line is considered to define exactly the terminal deletion phase if the value is> 0.7. Elimination half-life, determined by In (2) λζ.

CL: systemic clearance; for bolus or intravenous infusion,

calculated using the formula: <formula> formula see original document page 92 </formula> Report CL / F, where F = absolute bioavailability, for all

other routes of administration. V2: Volume of distribution for all airways

administration, calculated using the formula:

<formula> formula see original document page 92 </formula> CL / F is used to calculate V2 / F for extravascular administration routes. Pharmacokinetic analysis is performed using WinNonlin Professional Edition (Pharsight Corporation, Version 3.3 or 4.1). Descriptive statistics such as mean and standard deviation are calculated in Microsoft Excel (Version 8.Oe).

Metabolism of test articles in monkey and human cryoconserved hepatocytes is assayed as follows:

MATERIALS

Materials Manufacturer, lot number and exp. Cellzdirect Hepatocytes Human Monkey Williams E Sigma Medium W1878, exp 11-2004 Fetal Bovine Fisher BW 14-501F, lot 01104637, exp 17 Feb. Trypan Blue 0.45 Biowhittaker 17-942E, lot 01104637, exp 17 Feb. Fisher DMSO Test Material Stock CB-I / 111/6 Solution BP231-100, lot 041215, exp 12 jul 09 10 mM ethoxycoumarin in methanol PSLB 22-A-15, exp 9-25-04 ACN Fisher A998-4, lot 041181, exp 6/07 Formic acid Fisher 032879, exp 03-14-06

Preincubation Preparation: Sample is diluted with DMSO to prepare 100 μΜ and 10 μΜ stocks. Formic acid 0.1% in acetonitrile is prepared by adding 1 mL of formic acid per 1 L of acetonitrile (RT storage for 3 months). 10-well, 60-minute, and 120-minute 96-well finishing plates are prepared with 150 μΐ acetonitrile + 0.1% formic acid in each well. Store on ice or refrigeration.

Next, hepatocytes are thawed and 100 μΐ of cell suspension are placed in a microfiigo tube with 100 μΕ of 0.4% Trypan Blue solution and gently mixed by inversion. A small amount of stained cell suspension (approximately 15 μΙ.) Is placed in a clean hepatocytometer with a glass cover. The hepatocytometer is placed at the microscope stage and focus and force are adjusted until a single count square fills the field. The number of cells in the four subdivided squares on the outside corner of the hematocytometer is counted. Viable cells are opalescent, round and pale with a darker outline. Unviable cells are dark, opaque blue.

% Viability is calculated as the number of viable cells divided by the total X 100 cells.

Viable cell density and total number of viable cells

are calculated:

Viable cell density (D) = Average 3 of viable cells counted (C) χ 10 4 x Ω; total number of viable cells (E) = D χ 26 (resuspension volume). The additional medium required to achieve a concentration of 1 x 106 cells / mL is calculated:

Additional media volume = total viable cells (E) -26 mL

T7T5

Cells are properly diluted and stored at room temperature. Hepatocyte incubations 198 µL are transferred to relevant wells in dosing plates. The remaining hepatocide suspension is combined and placed in a suitable boiling water container and left for 5 minutes to inactivate the cells (for preparation of inactive controls and standard curve).

198 \\ L of inactive hepatocytes are transferred to control wells and 198 μΐ of white medium are transferred to buffer control wells. Plates are preincubated for at least 15 minutes. Reactions are started 2 μΐ. of diluting appropriate test compound from the dosing plate. Plates are incubated in a 37 ° C set incubator for approximately 10 minutes, then 50 μΐ1 of incubated are removed to a 10-minute finisher containing 150 μϋ acetonitrile + 0.1% formic acid and stored refrigerated or on ice. . After 60 minutes, incubated 50 μί is removed to a 60 μm finisher containing 150 μΐ. acetonitrile + 0.1% formic acid and stored refrigerated or on ice. After 120 minutes, 50 μΐ incubated are removed to a 120-minute finishing plate containing 150 μΐ acetonitrile + 0.1% formic acid and stored refrigerated or on ice. The remaining 50 μΐ is frozen in incubation plates. Tubes are then centrifuged at -4 ° C at -1,400 g for 10 minutes. 100 μΐ of supernatant is diluted with 100 μΐ of water in assay loops, plates are stored frozen at -20 ° C prior to analysis. Preparation of Standard Curves 0.1 μ £ of standard is prepared by adding 2 μΐ of 10 μΜ to 198 μΐ dosing solutions. of inactive hepatocytes in standard preparation plate. 150 μι acetonitrile + 0.1% formic acid is added to the standard finishing plate. 150 μΐ. 0.1 μΜ of pattern are transferred into one column of a standard 75 μΐ of inactive hepatocyte is added to the remaining wells. 75 µL of 0.1 μΜ standard is transferred to adjacent well in column on plate and mixed well by titration. Serial dilution continued. 75 μΐ, are removed from the final standard (all wells contain 75 pL). Plates are incubated at approximately 37 ° C for 10 minutes. 50 µl is transferred to a standard finisher containing 150 µl acetonitrile + 0.1% formic acid.

Plates are centrifuged along with samples and 1: 1 diluted supernatant with water as above. Samples are stored frozen at -20 ° C.

Sleep parameters for representative compounds are

presented below.

<table> table see original document page 95 </column> </row> <table> <table> table see original document page 96 </column> </row> <table> Other Modalities

Although the invention has been described in combination with its detailed description, the preceding description is intended to illustrate and not to limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the following claims. Those skilled in the art will understand that various changes in shape and detail may be made without departing from the scope of the invention encompassed by the appended claims.

Claims (12)

1. A compound or a pharmaceutically effective salt thereof, characterized in that it is of formula IV: R1, R2, R3 and R4 are independently Hj F, Cl, Br, CF3, CH3, OH, OCH3, CH2OCH3 or CH2OCH2CH3; R5-R6 are H, CH3, CH2CH3, or R5 and R6, together with the carbon to which they are attached, are connected to form a spiro ring of size 3 to 7; and Z is CO2H. A compound according to claim 1, characterized in that Rb, R2, R3 and R4 are each H. A compound according to claim 1, characterized in that R1, R3 and R4 are each H. A compound according to claim 1, characterized in that R1, R2 and R4 are each H. A compound according to claim 1, characterized in that R 5 and R 6 are each methyl. A compound according to claim 1, characterized in that R 5 and R 6 together with the carbon to which they are attached are connected to form a spiro cyclopropyl ring. A compound according to any one of claims 1 to 6, characterized in that t is 1. Compound or salt according to claim 1, characterized in that the compound is <formula> formula see original document page 98 </formula> Salt according to Claim 8, characterized in that the salt is the hydrochloride salt. Pharmaceutical composition, characterized in that it comprises a compound as defined in any one of claims 1 to 9 or a salt, solvate, hydrate or prodrug thereof and at least one pharmaceutically acceptable excipient. Use of a compound as defined in any one of claims 1 to 9, characterized in that it is in the manufacture of a medicament for treating a sleep disorder. Use according to claim 11, characterized in that the sleep disorder is insomnia.