HK1087114B - Substituted benzoxazinones and uses thereof - Google Patents

Description

Substituted benzo (58743)

The present invention relates to substituted benzo [ 58743, ].

5-hydroxytryptamine (5-HT), a major regulatory neurotransmitter in the brain, acts through a number of receptor families, known as 5-HT1, 5-HT2, 5-HT3, 5-HT4. 5-HT5, 5-HT6 and 5-HT 7. Based on the high levels of 5-HT6 receptor mRNA in the brain, the 5-HT6 receptor has been described as playing a role in the pathology and treatment of central nervous system disorders. In particular, 5-HT 2-selective ligands and 5-HT6 selective ligands have been identified as potentially useful in the treatment of certain CNS disorders, such as Parkinson's disease, Huntington's chorea, anxiety, depression, bipolar disorder, psychosis, epilepsy, obsessive-compulsive disorder, mood disorders, migraine, Alzheimer's disease (enhancing cognitive memory), sleep disorders, eating disorders such as anorexia, prandial and obesity, panic attacks, akathisia, Attention Deficit Hyperactivity Disorder (ADHD), Attention Deficit Disorder (ADD), drug abuse such as cocaine, ethanol, nicotine and benzodiazepinesWithdrawal, schizophrenia, and conditions associated with spinal trauma and/or head injury (head injury) such as hydrocephalus. These compounds are also expected to be useful in the treatment of certain Gastrointestinal (GI) disorders such as functional bowel disorders. See, e.g., b.l.roth et al, j.pharmacol. exp.ther., 1994, 268, 1403-14120; d.r.sibley et al, mol.pharmacol., 1993, 43, 320-; sleight et al, Neurotransmision, 1995, I1, 1-5 and A.J.Sleight et al, Serotonin ID Research Alert, 1997, 2(3), 115-8.

Although a number of 5-hydroxytryptamine modulators have been disclosed, there remains a need for compounds that are useful for modulating 5-HT2, 5-HT6, and other 5-HT receptors.

One object of the present invention is:

(i) a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof,

wherein:

y is C or S;

when Y is C, m is 1, and when Y is S, m is 2;

n is 1 or 2;

p is 0 to 3;

q is 1 to 3;

z is- (CR)^aR^b) r-or-SO₂-, wherein each R^aAnd R^bIndependently hydrogen or alkyl;

r is 0 to 2;

x is CH or N;

each R¹Independently is halo, alkyl, haloalkyl, heteroalkyl, alkoxy, cyano, -S (O)_s-R^c、-C(＝O)-NR^cR^d、-SO₂-NR^cR^d、-N(R^c)-C(＝O)-R^dor-C (═ O) -R^cWherein each R is^cAnd R^dIndependently hydrogen or alkyl;

s is 0 to 2;

R²is optionally substituted aryl or optionally substituted heteroaryl;

each R³And R⁴Independently hydrogen or alkyl, or R³And R⁴Together with the carbon they share may form a 3 to 6 membered cycloalkyl group; and is

Each R⁵、R⁶、R⁷、R⁸And R⁹Independently hydrogen or alkyl, or R⁵And R⁶One and R⁷、R⁸And R⁹One of which together with the atoms therebetween may form a 5 to 7 membered ring.

Other objects of the invention are:

(ii) (ii) a compound of (i), wherein

Y is C or S;

when Y is C, m is 1, and when Y is S, m is 2;

n is 1;

p is 0 or 1;

q is 2;

z is- (CR)^aR^b)_r-or-SO₂-, wherein each R^aAnd R^bIndependently hydrogen or alkyl;

r is 1;

x is N;

R²is optionally substituted aryl or optionally substituted heteroaryl;

each R³And R⁴Independently hydrogen or alkyl, or R³And R⁴Together with the carbon they share may form a 3 to 6 membered cycloalkyl group; and is

Each R⁵、R⁶、R⁷、R⁸And R⁹Independently hydrogen or alkyl.

(iii) (iii) the compound of (ii), wherein each R^aAnd R^bIndependently hydrogen or methyl; r²Is optionally substituted phenyl, naphthyl or optionally substituted pyridine; each R³And R⁴Independently is hydrogen or methyl, or R³And R⁴Together forming a cyclobutyl ring.

(iv) (iv) the compound of (iii), wherein R²Is 2-halophenyl, 3-halophenyl, 4-halophenyl, naphthalen-2-yl, 3-cyanophenyl, 4-cyanophenyl, 3-nitrophenyl, 3-aminophenyl, 3-methoxyphenyl, 3-urenophenyl, 3-methylsulfonylamino-phenyl or pyridin-4-yl.

(v) (ii) the compound of (i), wherein the compound is a compound of the formula or a pharmaceutically acceptable salt or prodrug thereof,

z, R therein¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹N and p are as defined in (i).

(vi) (ii) the compound of (i), wherein the compound is a compound of the formula or a pharmaceutically acceptable salt or prodrug thereof,

z, R therein¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹N and p are as defined in (i).

(vii) (ii) the compound of (i), wherein the compound is a compound of the formula or a pharmaceutically acceptable salt or prodrug thereof,

wherein R is¹、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R^a、R^bN, r and p are as defined in (i), and wherein t is 0 to 4; and each R¹⁰Independently hydrogen, halo, alkyl, alkoxy, cyano, nitro, amino, urea or ethanesulfonylamino.

(viii) (ii) the compound of (i), wherein the compound is a compound of the formula or a pharmaceutically acceptable salt or prodrug thereof,

wherein R is¹、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R^a、R^bN, r and p are as defined in (i), and wherein t is 0 to 4; and each R¹⁰Independently hydrogen, halo, alkyl, alkoxy, cyano, nitro, amino, urea or ethanesulfonylamino.

(ix) (viii) a compound of (i) to (viii), wherein said compound is selected from:

4-benzyl-6-methyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4-benzyl-6-methoxy-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (2-fluoro-somyl) -6-methoxy-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (2-chloro-benzyl) -6-methoxy-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (3-chloro-benzyl) -6-methoxy-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4-benzyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4-benzyl-6-fluoro-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (2-fluoro-benzyl) -8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (4-fluoro-benzyl) -8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (4-chloro-benzyl) -8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (4-fluoro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (2-fluoro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (2-chloro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (4-chloro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

6-fluoro-4-naphthalen-2-ylmethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (3-chloro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

3- (3-oxo-8-piperazin-1-yl-2, 3-dihydro-benzo [1, 4] * oxazin-4-ylmethyl) -benzonitrile;

4- (3-fluoro-benzyl) -8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4-benzyl-2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

(R) -4-benzyl-2-methyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4-benzyl-6-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (4-fluoro-benzyl) -6-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

(S) -4-benzyl-2-methyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

8-piperazin-1-yl-4-pyridin-4-ylmethyl-4H-benzo [1, 4] * oxazin-3-one;

4-benzyl-6-methyl-8- (4-methyl-piperazin-1-yl) -4H-benzo [1, 4] * oxazin-3-one;

4-benzyl-8- (4-methyl-piperazin-1-yl) -4H-benzo [1, 4] * oxazin-3-one;

4- (1-phenyl-ethyl) -8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (3-methoxy-benzyl) -8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (3-nitro-benzyl) -8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (3-amino-benzyl) -8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

3- (3-oxo-8-piperazin-1-yl-2, 3-dihydro-benzo [1, 4] * oxazin-4-ylmethyl) -benzonitrile;

n- [3- (3-oxo-8-piperazin-1-yl-2, 3-dihydro-benzo [1, 4] * oxazin-4-ylmethyl) -phenyl ] -methanesulfonamide;

4- (4-fluoro-benzyl) -2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (3-fluoro-benzyl) -2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

[3- (3-oxo-8-piperazin-1-yl-2, 3-dihydro-benzo [1, 4] * oxazin-4-ylmethyl) -phenyl ] -urea;

4- (3-chloro-benzyl) -2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4-benzyl-8- (3, 5-dimethyl-piperazin-1-yl) -4H-benzo [1, 4] * oxazin-3-one;

4- (4-chloro-benzyl) -2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4-benzyl-6-fluoro-2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (4-chloro-benzyl) -6-fluoro-2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

6-fluoro-4- (3-fluoro-benzyl) -2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

6-fluoro-4- (2-fluoro-benzyl) -2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

6-fluoro-4- (4-fluoro-benzyl) -2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (3-chloro-benzyl) -6-fluoro-2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4-benzyl-8- (3, 3-dimethyl-piperazin-1-yl) -4H-benzo [1, 4] * oxazin-3-one;

1-benzyl-5-piperazin-1-yl-1H-benzo [1, 3, 4] * thiazine 2, 2-dioxide; and

4-benzyl-2, 2-spiro-cyclobutane-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one.

(x) A pharmaceutical composition comprising an effective amount of a compound of (i) and a pharmaceutically acceptable carrier.

(xi) A method of making a substituted benzo\58743:

reacting an N-arylalkyl benzo [ 58743of formula i

Wherein:

A₁is a leaving group;

Z、Y、R¹、R³、R⁴m, n and p are as defined in (i);

R²is optionally substituted by (R)¹⁰)_tSubstituted aryl or heteroaryl, wherein t is 0 to 4; each R¹⁰Independently hydrogen, halo, alkyl, alkoxy, cyano, nitro, amino, urea, or ethanesulfonylamino;

with a heterocyclic compound of the formula g,

wherein:

q is 1 to 3; and is

Each R⁵、R⁶、R⁷、R⁸And R⁹Independently hydrogen or alkyl, or R⁵And R⁶One and R⁷、R⁸And R⁹One of which may together form a 5 to 7 membered ring;

to prepare a heterocyclyl-substituted N-arylalkyl benzo [ 58743 ] oxazinone compound of formula I:

(xii) (xi) a process comprising:

reacting an N-arylalkyl benzo \58743offormula j

With a heterocyclic compound of the formula h,

whereby the heterocyclyl-substituted N-arylalkyl benzo [ 58743,

and R is¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰N, p, r and t are as described in (xi).

(xiii) (xi) the process wherein the leaving group A¹Is halo.

(xiv) Use of one or more compounds of any of (i) to (ix) in the manufacture of a medicament for the treatment or prevention of a central nervous system disease state.

(xv) (xiv), wherein the disease state is selected from psychosis, schizophrenia, bipolar disorder, neurological disorder, memory disorder, attention deficit disorder, parkinson's disease, amyotrophic lateral sclerosis, alzheimer's disease, and huntington's disease.

(xvi) Use of one or more compounds of any of (i) to (ix) in the manufacture of a medicament for the treatment or prevention of a gastrointestinal disorder.

The invention also provides methods of making, compositions comprising, and methods of using the above compounds. In one embodiment, the method of the invention comprises:

(a) reacting an N-arylalkyl benzo \58743offormula f

Wherein:

A₁is a leaving group;

n is 1 or 2;

p is 0 to 3;

r is 0 to 2;

t is 0 to 4;

each R^aAnd R^bIndependently hydrogen or alkyl;

each R¹Independently is halo, alkyl, haloalkyl, heteroalkyl, alkoxy, cyano,

-S(O)_s-R^c、-C(＝O)-NR^cR^d、-SO₂-NR^cR^d、-N(R^c)-C(＝O)-R^dor-C (═ O) R^c，

Wherein each R^cAnd R^dIndependently hydrogen or alkyl and s is 0 to 2;

each R³And R⁴Independently hydrogen or alkyl; and is

Each R¹⁰Independently halo, alkyl, alkoxy, or cyano;

with a heterocyclic compound of the formula g,

wherein:

q is 1 to 3; and is

Each R⁵、R⁶、R⁷、R⁸And R⁹Independently hydrogen or alkyl, or R⁵And R⁶One and R⁷、R⁸And R⁹One of which may together form a 5 to 7 membered ring;

to produce a heterocyclyl-substituted N-arylalkyl benzo [ 58743 ] of formula Id:

the method may further comprise:

(b) reacting a benzo- (58743) -oxazinone of formula d

Wherein n, p, A₁、R¹、R³And R⁴As defined above, the above-mentioned,

with an alkylating agent of the formula e,

wherein:

A₂is a leaving group and may be reacted with A₁The same or different; and is

r、t、R^a、R^bAnd R¹⁰As described in (a);

to obtain N-arylalkyl benzo (58743) of formula f

The present invention provides substituted benzo (58743). In particular embodiments, the present invention provides piperazinyl substituted benzo [1, 4] * oxazin-3-one compounds and related pharmaceutical compositions and methods of using them to treat CNS disorders and gastrointestinal disorders.

Unless otherwise indicated, the following terms used in this application, including the specification and claims, have the definitions given below. It must be noted that: as used in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

An "agonist" refers to a compound that enhances the activity of another compound or receptor site.

"alkyl" means a monovalent straight or branched chain saturated hydrocarbon moiety consisting only of carbon and hydrogen atoms, having from 1 to 12 carbon atoms.

"lower alkyl" refers to alkyl of 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

"alkylene" means a straight chain saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon group of 3 to 6 carbon atoms, such as methylene, ethylene, 2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, and the like.

"alkoxy" means a moiety of the formula-OR, wherein R is an alkyl moiety as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

An "antagonist" refers to a compound that reduces or prevents the action of another compound or receptor site.

"aryl" means a monovalent cyclic aromatic hydrocarbon moiety consisting of a monocyclic, bicyclic, or tricyclic aromatic ring. The aryl group may be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to, optionally substituted phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylthio (diphenylsulfildyl), diphenylsulfonyl, diphenylisopropylidene, benzodioxanyl, benzofuranyl, benzodioxyyl, benzopyranyl, benzo \58743oxazinyl, benzo \, 58743oxazinonyl, benzopiperidinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like, including partially hydrogenated derivatives thereof.

"arylalkyl" and "aralkyl" are used interchangeably to mean the group-R^aR^bWherein R is^aIs alkylene as defined herein and R^bExamples of arylalkyl groups, which are aryl groups as defined herein, are, for instance, benzyl, phenylethyl, 3- (3-chlorophenyl) -2-methylpentyl and the like.

"cycloalkyl" means a monovalent saturated carbocyclic moiety consisting of a monocyclic or bicyclic ring. Cycloalkyl groups may be optionally substituted with one or more substituents, wherein each substituent is independently hydroxy, amino, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino, unless otherwise specifically indicated. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially unsaturated derivatives thereof.

"cycloalkylalkyl" means a moiety of the formula-R '-R', where R 'is alkylene as defined herein and R' is cycloalkyl as defined herein.

"Heteroalkyl" means a group in which one, two OR three hydrogen atoms have been independently selected from-OR^a、-NR^bR^cand-S (O)_nR^d(wherein n is an integer from 0 to 2) is substituted with an alkyl group as defined herein with the understanding that the point of attachment of the heteroalkyl group is through a carbon atom, wherein R is^aIs hydrogen, acyl, alkyl, cycloalkyl or cycloalkylalkyl; r^bAnd R^cIndependently of one another, hydrogen, acyl, alkyl, cycloalkyl or cycloalkylalkyl; and when n is 0, R^dIs hydrogen, alkyl, cycloalkyl or cycloalkylalkyl, R is hydrogen when n is 1 or 2^dIs alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino or dialkylamino.

Representative examples include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2, 3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2, 3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.

"heteroaryl" means a monocyclic or bicyclic group of 5 to 12 ring atoms having at least one aromatic ring containing one, two or three ring heteroatoms selected from N, O or S, the remaining ring atoms being C, it being understood that the attachment point of the heteroaryl group will be on the aromatic ring. The heteroaryl ring may be optionally substituted as defined herein. Examples of heteroaryl moieties include, but are not limited to, optionally substituted imidazolyl, * oxazolyl, iso * oxazolyl, thiazolyl, isothiazolyl, * oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, furyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiopyranyl, benzimidazolyl, benzo 58743oxazolyl, benzo * oxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, azazazolinylRadical diazaMesityl, acridinyl, and the like, including partially hydrogenated derivatives thereof.

The terms "halo" and "halogen" are used interchangeably to refer to the substituents fluoro, chloro, bromo, or iodo.

"haloalkyl" means an alkyl group, as defined herein, wherein one or more hydrogen atoms have been replaced by the same or different halogen. Exemplary haloalkyl groups include-CH₂Cl、-CH₂CF₃、-CH₂CCl₃Perfluoroalkyl (e.g., -CF)₃) And the like.

"Heterocyclylamino" means a saturated ring in which at least one ring atom is N, NH or N-alkyl and the remaining ring atoms form an alkylene group.

"heterocyclyl" means a monovalent saturated moiety consisting of 1 to 3 rings containing one, two or three or four heteroatoms (selected from nitrogen, oxygen or sulfur). The heterocyclyl ring may be optionally substituted as defined herein. Examples of heterocyclyl moieties include, but are not limited to, optionally substituted piperidinyl, piperazinyl, homopiperazinyl, azaExamples of the substituent include a substituent such as a phenyl group, a pyrrolidinyl group, a pyrazolidinyl group, an imidazolinyl group, an imidazolidinyl group, a pyridyl group, a pyridazinyl group, a pyrimidyl group, * oxazolidinyl group, an iso- * oxazolidinyl group, a morpholinyl group, a thiazolidinyl group, an isothiazolidinyl group, a quinuclidinyl group, a quinolyl group, an isoquinolyl group, a benzimidazolyl group, a thiadiazolidinyl group, a benzothiazolinyl group, a benzopyranyl group, a dihydrofuranyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a thiomorpholinyl sulfoxide, a thiomorpholinsulfone, a dihydroquinolyl group, a dihydroisoquinolyl group, a tetrahydroquinolyl group.

"optionally substituted" when used in combination with "aryl", "phenyl", "heteroaryl" or "heterocyclyl" means aryl, phenyl, heteroaryl or heterocyclyl optionally independently substituted with 1 to 4 substituents, preferably 1 or 2 substituents, selected from alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, monoalkylamino, dialkylamino, haloalkyl, haloalkoxy, -COR (wherein R is hydrogen, alkyl, phenyl or phenylalkyl), -CR 'R')_n-COOR (wherein n is an integer from 0 to 5, R 'and R' are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl) or- (CR 'R')_n-CONR^aR^b(wherein n is an integer from 0 to 5, R 'and R' are independently hydrogen or alkyl, and R^aAnd R^bIndependently of one another, hydrogen, alkylAlkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl).

By "leaving group" is meant a group having the meaning conventionally associated therewith in synthetic organic chemistry, i.e., an atom or group that is replaceable under the substitution reaction conditions. Examples of leaving groups include, but are not limited to, halogen, alkyl-or arylenesulfonyloxy groups such as methanesulfonyloxy, ethanesulfonyloxy, methylthio, benzenesulfonyloxy, toluenesulfonyloxy and thiophenyloxy, dihalophosphinyl (phosphinoyl) oxy, optionally substituted benzyloxy, isopropoxy, acyloxy and the like.

By "modulator" is meant a molecule that interacts with a target. Such interactions include, but are not limited to, agonists, antagonists, and the like, as defined herein.

"optional" means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

By "disease state" is meant any disease, disorder, symptom, or indication.

By "inert organic solvent" or "inert solvent" is meant a solvent that is inert under the reaction conditions associated therewith, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran, N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, di * alkane, pyridine, and the like. Unless indicated to the contrary, the solvents used in the reactions of the present invention are inert solvents.

"pharmaceutically acceptable" means that which can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes pharmaceutically acceptable for veterinary use as well as human.

By "pharmaceutically acceptable salt" of a compound is meant a salt, as defined herein, which is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Such salts include: acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or an acid addition salt with an organic acid: acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like; or salts formed when the acidic proton present in the parent compound is replaced by a metal ion, for example an alkali metal ion, an alkaline earth metal ion or an aluminium ion; or complexes with organic or inorganic bases. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.

Preferred pharmaceutically acceptable salts are those formed with acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc and magnesium.

It should be understood that: all references to pharmaceutically acceptable salts include the solvate addition forms (solvates) or crystal forms (polymorphs) as defined herein of the same acid addition salt.

The terms "prodrug" or "prodrug" are used interchangeably herein and refer to any compound that releases the active parent drug of formula I in vivo when the prodrug is administered to a mammalian subject. Prodrugs of compounds of formula I are prepared by modifying one or more functional groups present in the compounds of formula I in such a way that the modification is cleavable in vivo to release the parent compound. Prodrugs include compounds of formula I wherein a hydroxy, amino, or sulfhydryl group in a compound of formula I is bonded to any group that can be cleaved in vivo to regenerate the free hydroxy, amino, or sulfhydryl group. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of formula I; n-acyl derivatives of amino functions (e.g. N-acetyl), N-Mannich bases, Schiff bases and enaminones; oximes, acetals, ketals and enols of ketone or aldehyde functional groups in the compounds of formula I are described in Bundegaard, H. "design of prodrugs", pages 1-92, Elesevier, New York-Oxford (1985) and the like.

"protecting group" or "protecting group" means a group that selectively blocks one reactive site in a multifunctional compound in the sense conventionally associated therewith in synthetic chemistry such that a chemical reaction can be selectively carried out at another unprotected reactive site. Some methods of the invention rely on protecting groups to block reactive nitrogen and/or oxygen atoms present in the reactants. For example, the terms "amino protecting group" and "nitrogen protecting group" are used interchangeably herein to refer to those organic groups that are used to protect a nitrogen atom from undesirable reactions during synthesis. Examples of nitrogen protecting groups include, but are not limited to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl (carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, t-Butoxycarbonyl (BOC), and the like. One skilled in the art would know how to select groups that are easy to remove and able to undergo subsequent reactions.

"solvate" means a form of a solvent addition containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to trap a fixed molar proportion of solvent molecules in their crystalline solid state, thereby forming solvates. If the solvent is water, the solvate formed is a hydrate, and when the solvent is an alcohol, the solvate formed is an alcoholate. The hydrate is obtained by combining one or more water molecules with water molecules to maintain the molecular state H₂O, which combination is capable of forming one or more hydrates.

By "subject" is meant a mammal or a non-mammal. Mammal means any member of the class mammalia, including but not limited to humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds and the like. The term "subject" does not denote a particular age and gender.

By "therapeutically effective amount" is meant the amount of a compound that, when administered to a subject to treat a disease state, is sufficient to effect such treatment for that disease state. The "therapeutically effective amount" will vary with the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

The terms "defined above" and "defined herein" when referring to a variable include the broad definition of the variable as well as the definitions of preferred, more preferred, or most preferred, if any.

"treatment" of a disease state includes:

(i) prevention of a disease state, i.e., the prevention of clinical symptoms of the disease state in a subject who may be exposed to or predisposed to the disease state but does not yet experience or display symptoms of the disease state.

(ii) Inhibiting the disease state, i.e. arresting the development of the disease state or its clinical symptoms, or

(iii) Alleviation of the disease state, i.e., causing a temporary or permanent regression of the disease state or its clinical symptoms.

The terms "treating", "contacting", and "reacting", when referring to a chemical reaction, mean adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or desired product. It will be appreciated that the reaction to produce the indicated and/or desired product may not necessarily be produced directly from the combination of the two reagents initially charged, i.e., there may be one or more intermediates produced in the mixture which ultimately results in the formation of the indicated and/or desired product.

Generally, the nomenclature used in this application is based on AUTONOM^TMVersion 4.0, a Beilstein Institute computer for generating IUPAC systematic nomenclatureProvided is a system. For convenience, the IUPAC position number for representative benzo \58743:

the invention provides a compound of general formula I and a pharmaceutically acceptable salt or prodrug thereof,

wherein:

y is C or S; preferably Y is C;

when Y ═ C, m is 1, when Y ═ S, m is 2;

n is 1 or 2; preferably n is 1;

p is 0 to 3; preferably p is 1;

q is 1 to 3; preferably q is 2;

z is- (CR)^aR^b)_r-or-SO₂-, wherein each R^aAnd R^bIndependently hydrogen or alkyl; preferably Z is- (CR)^aR^b)_r-and preferably R^aAnd R^bIs hydrogen;

r is 0 to 2; preferably r is 2;

x is CH or N; preferably X is N;

each R¹Independently is halo, alkyl, haloalkyl, heteroalkyl, alkoxy, cyano, -S (O)_s-R^c、-C(＝O)-NR^cR^d、-SO₂-NR^cR^d、-N(R^c)-C(＝O)-R^dor-C (═ O) R^cWherein each R is^cAnd R^dIndependently of one another is hydrogenOr an alkyl group; preferably each R¹Independently is halo, alkyl or alkoxy;

s is 0 to 2;

R²is aryl or heteroaryl; preferably R²Is aryl, and more preferably optionally substituted phenyl or naphthyl such as 2-halophenyl, 3-halophenyl, 4-halophenyl, naphthalen-2-yl or 4-cyanophenyl;

each R³And R⁴Independently hydrogen or alkyl, or R³And R⁴Together with the carbon they share form a 3 to 6 membered cycloalkyl group; and is

Each R⁵、R⁶、R⁷、R⁸And R⁹Independently hydrogen or alkyl, or R⁵And R⁶One and R⁷、R⁸And R⁹One of which, together with the atoms therebetween, may form a 5 to 7 membered ring;

preferably R⁵、R⁶、R⁷、R⁸And R⁹Is hydrogen;

in which R is¹、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R^a、R^bIn embodiments where they are alkyl, they are preferably lower alkyl such as (C)₁-C₆) Alkyl, and more preferably (C)₁-C₄) An alkyl group.

It is to be understood that the scope of the present invention includes both the various isomers that may be present and also the mixtures of the various isomers that may be formed. Furthermore, solvates and salts of the compounds of formula I are also included within the scope of the present invention.

In certain embodiments, Z is- (CR)^aR^b)_r-, X is N and q is 2. R in this embodiment²May include, for example, 2-halophenyl, 3-halophenyl, 4-halophenyl, naphthalen-2-yl, 3-cyanophenyl, 4-cyanophenyl, 3-nitrophenyl, 3-aminophenyl, 3-methylOxyphenyl, 3-ureidophenyl or 3-methylsulfonylamino-phenyl. X may be located at the 8-position of the benzo 58743. In other embodiments, X may be located at the 6-position of the benzo 58743.

In some embodiments of the invention, the compound of formula I may be a compound of formula Ia:

y, Z, R therein¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹M, n and p are as defined herein.

In certain embodiments, the compound of formula I may be a compound of formula Ib:

z, R therein¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹N, r and p are as defined herein.

In certain preferred embodiments, the compound of formula I may be a compound of formula Ia 1:

wherein R is¹、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R^a、R^bN, r and p are as defined herein, and wherein:

t is 0 to 4; preferably t is 1; and is

Each R¹⁰Independently halo, alkyl, alkoxy, carbamoyl, alkylsulfonylamino or cyano; preferably R¹⁰Is halo or alkoxy.

In other embodiments, the subject compound may be a compound of formula Ib 1:

wherein R is¹、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R^a、R^bN, r, p and t are as defined herein.

In a particular embodiment of formula Ib1, R¹May be halo, methyl or methoxy, R³And R⁴May each independently be hydrogen or methyl or together with the carbon they share form a cyclobutyl radical, R⁶、R⁷、R⁸、R⁹May each independently be hydrogen or methyl, R^aAnd R^bMay each independently be hydrogen or methyl, and each R¹⁰May be hydrogen, halo, nitro, cyano, amino, urea, methoxy or methylsulfonylamino.

Representative compounds according to the invention are shown in table 1. Unless otherwise indicated, the melting point data in table 1 refer to the data for the hydrochloride salt of the indicated compound.

TABLE 1

Another aspect of the present invention provides a composition comprising a therapeutically effective amount of at least one compound of formula I and a pharmaceutically acceptable carrier.

Yet another aspect of the present invention provides a method of treating a Central Nervous System (CNS) disease state in a subject, comprising administering to said subject a therapeutically effective amount of a compound of formula I. The disease state may include, for example, psychosis, schizophrenia, manic depression, nervous system disorders, memory disorders, attention deficit disorder, parkinson's disease, amyotrophic lateral sclerosis, alzheimer's disease, or huntington's disease.

Yet another aspect of the present invention provides a method of treating a gastrointestinal disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula I.

In another aspect of the invention, there is provided a process for the preparation of a compound of formula I.

The compounds of the present invention can be prepared by various methods described in the illustrative synthetic reaction schemes shown and described below.

The starting materials and reagents used to prepare these compounds are generally available from suppliers such as aldrich chemical co, or prepared by methods well known to those skilled in the art, following procedures as shown in the following references: "Fieser and Fieser's organic synthesis reagents"; wiley & Sons: new york, 1991, volume 1-15; "Rodd's carbon Compound chemistry", Elsevier Science Publishers, 1989, Vol.1-5 and suppl.A.; and "organic reactions", Wiley & Sons: new york, 1991, volumes 1-40.

The following synthetic reaction schemes are merely illustrative of some of the methods by which the compounds of the present invention may be synthesized, and various modifications to these synthetic reaction schemes will be apparent to and can be made by those skilled in the art in light of the disclosure herein.

If desired, starting materials and intermediates of the synthetic reaction schemes can be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. The materials may be characterized using conventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein are preferably carried out under an inert atmosphere, at atmospheric pressure, at a reaction temperature in the range of from about-78 ℃ to about 150 ℃, more preferably from about 0 ℃ to about 125 ℃, and most preferably and conveniently at about room (ambient) temperature, e.g., about 20 ℃.

Scheme A below illustrates a synthetic procedure that may be used to prepare certain compounds of formula I, wherein each A is independently halo or other leaving group (e.g., triflate) and may be the same or different at each occurrence, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R^a、R^bN, p, q, r and t are as defined herein.

Scheme A

In step 1 of scheme A, o-nitrophenolaReduction to the corresponding aniline or aminophenolb. The reduction may be carried out under relatively mild aqueous conditions using sodium dithionite or a similar mild reducing agent.

Then, in step 2, cyclization is carried out to obtain the aminophenol from the reaction mixture produced in step 1bTo obtain a benzo 58743d. When n is 1, for example, benzo [ 58743 ]dIs 2H-1, 4-benzo \58743oxazin-3 (4H) -ketone, when n is 2, the compounddIs 2, 3-dihydro-1, 5-benzoxazepine-4(5H) -one. The cyclization can be effected by aminophenolsbAnd 2-haloacyl halidescSaid 2-haloacyl halidecSuch as chloroacetyl chloride (e.g. n ═ 1 and R)³、R⁴Is hydrogen), 2-chloropropaneAcyl chlorides (e.g. n ═ 1, R)³Is methyl and R⁴Is hydrogen), 3-chloropropionyl chloride (e.g. n ═ 2 and R)³、R⁴Hydrogen), 2-chloroisobutyryl chloride (e.g. n ═ 1, R)³Is isopropyl and R⁴Is hydrogen), 2-chloro-2-methylpropanoyl chloride (e.g. n ═ 1 and R)³And R⁴Methyl) and the like. Formation of benzo\58743; 33; 380-3861990. The cyclization can also be effected by reactingbWith 2-hydroxy esters under Mitsunobu reaction conditions, as described by Van Hes et al in WO 01/14330.

In step 3, a benzo 58743dThe N-alkylation of (A) is carried out in this way; treating the compound of step 2 with a strong base under dry, polar aprotic conditionsdAnd with alpha-haloalkyl aryl compoundseReacting to provide an N-arylalkyl-benzo [ 58743f. Halogenated alkyl aryl compoundeMay include, for example, benzyl halide (e.g., R ═ 1 and R^aAnd R^bIs hydrogen), 3-halo-3-phenylpropane (e.g. R ═ 2 and R)^a、R^bHydrogen), alpha-methylbenzyl halide (e.g. R ═ 1, R)^aIs hydrogen and R^bIs methyl) or otherwise according to the desired R^aAnd R^bAlpha-haloalkylphenyl halide in substituent configuration.

The alkylation of step 3 may also be carried out using an α -haloalkyl naphthyl compound, an α -haloalkyl biphenyl compound, or other α -haloalkyl aryl compound. In other embodiments, step 3 can be performed using α -haloalkyl heteroaryl compounds, such as α -haloalkyl pyridines, α -haloalkyl thiophenes, α -haloalkyl methylenedioxyphenyl compounds, α -haloalkyl ethylenedioxyphenyl compounds, and the like. For α -haloalkyl heteroaryl compounds, appropriate protecting group strategies may be employed to avoid undesired alkylation of the heteroatom during this step. In certain embodiments, the alkylation of step 3 may be replaced by aryl-or heteroaryl sulfonylation, wherein a suitable aryl or heteroaryl sulfonyl halide is reacted with a benzo [ 58743dThe ring nitrogen of (2).

Then, in step 4, an amination reaction is performed in which the N-arylalkyl-benzo \58743eWith nitrogen-containing heterocyclesfIn the presence of a palladium catalyst to replace the leaving group a "with a heterocyclyl group and provide a heterocyclyl-N-arylalkyl-benzo \58743oxazinonecompound Ie. In many embodiments, q is 1, such that the heterocyclyl compoundfIs a formulahThe piperazine compound of (a) is,

and the heterocyclyl-N-arylalkyl-benzo \58743oxazinonecompound of formula Id is a compound of formula Ie as discussed above:

several alkyl substituted piperazine compounds are commercially available or can be readily prepared according to known methods and can be used in this step. The amination of step 4 can be carried out under similar reaction conditions at both the 8-and 6-positions.

At R⁹In the case of hydrogen, BOC protection or other suitable protection strategies may be used to protect the ring nitrogen atom of the corresponding compound of formula f. Deprotection can be carried out in this step by treating the heterocyclyl-N-arylalkyl-benzo \58743witha weak acid solution when a BOC protecting group is present.

Many variations of the above-described steps may be contemplated by those skilled in the art upon review of the present disclosure. In some cases, the amination may be performed prior to the N-alkylation at position 1. Can select R¹The number, functionality, and/or position of substituents are such as to activate a particular position (i.e., any of positions 5 to 8) of the benzo \58743oxazinonering, thereby facilitating amination at a selected position, as described for particular embodiments of the subject compounds.

More specific details for the preparation of compounds of formula I are described in the examples section below.

The compounds of the present invention have selective affinity for 5-HT receptors, including 5-HT6, and are therefore expected to be useful in the treatment of certain CNS disorders such as Parkinson's disease, Huntington's chorea, anxiety, depression, manic depression, psychosis, epilepsy, obsessive-compulsive disorders, mood disorders, migraine, Alzheimer's disease (enhancing cognitive memory), sleep disorders, eating disorders such as anorexia, prandial and obesity, panic attacks, akathisia, Attention Deficit Hyperactivity Disorder (ADHD), Attention Deficit Disorder (ADD), drug abuse such as cocaine, ethanol, nicotine and benzodiazepinesWithdrawal, schizophrenia, and conditions associated with spinal trauma and/or craniocerebral injury such as hydrocephalus. These compounds are also expected to be useful in the treatment of certain GI (gastrointestinal) diseases such as functional bowel disease and irritable bowel syndrome.

The pharmacology of the compounds of the invention is determined by art-recognized methods. In vitro techniques for determining the affinity of test compounds for the 5-HT6 receptor using radioligand binding and functional assays are described in example 4.

The present invention includes pharmaceutical compositions comprising at least one compound of the present invention, or an individual isomer, racemic or non-racemic mixture of isomers, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients.

In general, the compounds of the present invention are administered in a therapeutically effective amount by any mode of administration acceptable for agents that exert similar effects. Suitable dosage ranges are generally from 1 to 500mg per day, preferably from 1 to 100mg per day and most preferably from 1 to 30mg per day, depending on various factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication for which the administration is intended, the preference and experience of the practitioner involved therein. Those skilled in the art of treating such diseases will be able to determine a therapeutically effective amount of a compound of the invention for a given disease without undue experimentation and with the knowledge of the individual and disclosure of this application.

In general, the compounds of the present invention may be administered as pharmaceutical formulations, including those suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration, or in a form suitable for administration by inhalation or insufflation. The preferred mode of administration is generally oral, using a convenient daily dosage regimen which can be adjusted to the degree of disease.

One or more compounds of the present invention, together with one or more conventional adjuvants, carriers or diluents, can be formulated into pharmaceutical compositions and unit dosage forms. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without other active compounds or ingredients, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage to be administered. The pharmaceutical composition may be used in the form of: solid such as tablets or filled capsules, semi-solid, powder, sustained release formulations, or liquid such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Formulations containing about one (1) milligram of active ingredient, or more broadly about 0.01 to about one hundred (100) milligrams per tablet, are accordingly suitable representative unit dosage forms.

The compounds of the present invention may be formulated in a wide variety of orally administrable dosage forms. Pharmaceutical compositions and dosage forms may contain one or more compounds of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutically acceptable carrier may be in solid or liquid form. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is usually a finely divided solid which is in admixture with the finely divided active component. In tablets, the active ingredient is usually mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. Powders and tablets preferably contain from about one (1) to about seventy (70) percent of the active compound. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "formulation" shall include a formulation of the active compound with encapsulating material as a carrier, providing a capsule in which the active ingredient is optionally surrounded by a carrier associated therewith. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be solid forms suitable for oral administration.

Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which should be converted to liquid form preparations shortly before use. Emulsions may be prepared in solution, for example, in aqueous propylene glycol, or may contain emulsifying agents, for example, lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickeners. Aqueous suspensions may be prepared by dispersing the finely divided active component in water containing viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. Solid form preparations include solutions, suspensions and emulsions and may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.

The compounds of the invention may be formulated for parenteral administration (e.g., by injection, e.g., bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled injections, small volume infusions, or in multi-dose containers with an added preservative. The composition may take the form of: suspensions, solutions or emulsions in oily or aqueous vehicles, for example, solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preservatives, wetting agents, emulsifying or suspending agents, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization of liquid for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

The compounds of the present invention may be formulated as ointments, creams or lotions or as a transdermal patch for topical application to the epidermis. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration to the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth, pastilles comprising the active ingredient in an inert base such as gelatin and glycerol or sucrose and acacia (pastilles) and mouthwashes comprising the active ingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated for administration as suppositories. A low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is dispersed homogeneously, for example by stirring. The molten homogeneous mixture is then poured into a suitably sized mold, allowed to cool, and solidified.

The compounds of the invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be suitable.

The compounds of the present invention may be formulated for nasal administration. The solution or suspension is applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in single or multiple dose forms. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate predetermined volume of solution or suspension. For an injector, this can be achieved by means of, for example, a metered atomizing injection pump.

The compounds of the invention may be formulated for aerosol administration, particularly to the respiratory tract and include intranasal administration. The compounds typically have a small particle size, for example on the order of 5 microns or less. Such a particle size may be obtained by methods known in the art, for example by micronization. The active ingredient is provided in pressurized packs containing a suitable propellant, such as a chlorofluorocarbon (CFC), e.g., dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may also conveniently contain a surfactant such as lecithin. The dosage of the medicament may be controlled by a metering valve. Alternatively, the active ingredient may be provided in dry powder form, for example as a powder mix of the compound with a suitable powder base such as lactose, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). The powder carrier can form a gel in the nasal cavity. The powder compositions may be in unit dosage form, for example in capsules or cartridges of e.g. gelatin or blister packs from which the powder may be administered by means of an inhaler.

If desired, formulations having enteric coatings suitable for sustained or controlled release administration of the active ingredient may be prepared. For example, the compounds of the present invention may be formulated in a transdermal or subcutaneous drug delivery device. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is critical. The compounds in transdermal delivery systems are often attached to a skin-adherent solid carrier. The compounds in question may also be combined with penetration enhancers such as Azone (1-dodecylazacycloheptan-2-one). The sustained release delivery system is inserted subcutaneously into the subcutaneous layer by surgery or injection. Subcutaneous implants encapsulate the compound in a lipid soluble membrane, such as silicone rubber, or a biodegradable polymer, such as polylactic acid.

The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form may be a packaged preparation, the package containing discrete quantities of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of them in packaged form.

Other suitable pharmaceutical carriers and their formulations are described in "Remington: pharmaceutical science and practice "1995, edited by e.w. martin, Mack Publishing Company, 19 th edition, Easton, Pennsylvania. Representative pharmaceutical formulations containing the compounds of the present invention are described in examples 6-12.

Examples

The following formulations and examples are provided so that those skilled in the art can more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being exemplary and representative thereof.

Example 1

4-benzyl-8-piperazin-1-yl-4H-benzo [1, 4]* oxazin-3-one hydrochloride

The synthetic procedure described in this example was carried out according to the method shown in scheme B, where R is¹And R¹⁰As defined herein.

Scheme B

Step 1: 2-amino-6-bromo-4-fluorophenol

Sodium dithionite (58g, 335mmol) was dissolved in warm water (300mL) and slowly added to a heated solution of 6-bromo-4-fluoro-2-nitrophenol (11.8g, 50mmol) in 250mL ethanol in a steam bath. The reaction mixture changed from dark orange to light yellow. The suspension was diluted with water until a clear yellow solution was obtained. Partial concentration was performed on a rotary evaporator to induce crystallization. The mixture was then cooled to room temperature and crystals formed. Filtration and drying gave the title compound as a white solid (5.04g, 49% yield). MS 207(M + H)⁺。

Step 2: 8-bromo-6-methoxy-4H-benzo [1, 4]]* oxazin-3-ones

The reaction in this example was carried out following analogous procedures reported in the literature, see, e.g., Combs, Donald w.; rampula, Marianne s.; bell, Stanley C.; klaubert, Dieter h.; tobia, Alfonso j. et al, j.med.chem.; 33; 1990; 380-386.

NaHCO is added₃A saturated solution in water (20mL) was added to a solution of 2-amino-6-bromo-4-methoxyphenol (9.8g, 45mmol) in 300mL 2-butanone. Chloroacetyl chloride (6.1g, 54mmol) was added dropwise at room temperature and the mixture was refluxed for 2 hours with stirring. After cooling to room temperature, water and ethyl acetate were added, the organic layer was separated and purified over Na₂SO₄After drying, filtration and concentration, a light brown solid was obtained. Recrystallization from EtOAc provided 2.2g of the title compound as a light red colorAnd (3) a solid. Chromatography of the mother liquor on silica gel using EtOAC/hexane (1: 4) gave an additional 2.6g of a pale red solid. MP is 236.1-237.5 ℃.

The following compounds were prepared in a similar manner:

8-bromo-4H-benzo [1, 4] * oxazin-3-one, MP 243.5-244.9 deg.C

8-bromo-6-fluoro-4H-benzo [1, 4]]* oxazin-3-one, MS 247(M + H)⁺。

And step 3: 4-benzyl-8-bromo-4H-benzo [1, 4]]* oxazin-3-ones

To 8-bromo-4H-benzo [1, 4] at 0 deg.C]* oxazin-3-one (343mg, 1.5mmol) in 10ml dry dimethylformamide was added sodium hydride (120mg of a 60% suspension in mineral oil, 3.0mmol) portionwise. The solution was stirred with a magnetic stirrer at 0 ℃ for 20 minutes, at which time the initial evolution of gas was stopped. Benzyl bromide (0.22ml, 1.8mmol) was added in one portion and the reaction mixture was stirred at 0 ℃ for 30 min. The solution was warmed to room temperature and the reaction mixture was partitioned between water (50ml) and ethyl acetate (50ml), the aqueous layer was extracted with ethyl acetate (2X 25ml) and the combined organic portions were washed with water (2X 25ml) and brine (2X 25 ml). Over MgSO₄After drying, the organic portion was concentrated in vacuo and the resulting brown residue was purified by flash chromatography (5% -15% ethyl acetate/hexanes over 30 min) to give 402mg of 4-benzyl-8-bromo-4H-benzo [1, 4%]* oxazin-3-one, as a yellow solid (84%). MS: 318(M + H)⁺。

Starting from the commercially available or known in the literature as appropriate bromobenzo [1, 4] * oxazinones and the various arylalkyl bromides and arylalkyl chlorides, the following compounds are prepared in an analogous manner:

4-benzyl-8-bromo-6-methyl-4H-benzo [1, 4]]* oxazin-3-one, MS (M + H)⁺：334.0。

4-benzyl-8-bromo-6-methoxy-4H-benzo [1, 4]]* oxazin-3-one, MS (M + H)⁺：350.0。

8-bromo-4- (2-fluoro-benzyl) -6-methoxy-4H-benzo [1, 4%]* oxazin-3-one, MS (M + H)⁺：367.9。

8-bromo-4- (2-chloro-benzyl) -6-methoxy-4H-benzo [1, 4%]* an oxazin-3-one,¹H NMR(CDC1₃，300MHz)δ：3.66(s，3H)，4.79(s，2H)，5.22(s，2H)，6.29(d，1H，J＝2.83Hz)，6.74(d，1H，J＝2.83Hz)，7.00(m，1H)，7.20(m，2H)，7.42(m，1H)。

8-bromo-4- (3-chloro-benzyl) -6-methoxy-4H-benzo [1, 4%]* oxazin-3-one; MS (M + H)⁺：382.9。

4-benzyl-8-bromo-6-fluoro-4H-benzo [1, 4%]* oxazin-3-one, MS (M + H)⁺：335.0。

8-bromo-4- (2-fluoro-benzyl) -4H-benzo [1, 4%]* oxazin-3-one, MS (M + H)⁺：338.1。

8-bromo-4- (4-fluoro-benzyl) -4H-benzo [1, 4]* oxazin-3-one, MS (M + H)⁺：334.9。

8-bromo-4- (4-chloro-benzyl) -4H-benzo [1, 4%]* oxazin-3-one, MS (M + H)⁺：354.0。

8-bromo-6-fluoro-4- (4-fluoro-benzyl) -4H-benzo [1, 4]* oxazin-3-one, MS (M + H)⁺：352.9。

8-bromo-6-fluoro-4- (2-fluoro-benzyl) -4H-benzo [1, 4]* an oxazin-3-one,¹H NMR(CDC 1₃，300MHz)δ：4.79(s，2H)，5.18(s，2H)，6.63(dd，1H，J＝2.64Hz，9.42Hz)，6.96(dd，1H，J＝2.83Hz，7.73Hz)，7.10(m，3H)，7.28(m，1H)。

8-bromo-6-fluoro-4- (2-chloro-benzyl) -4H-benzo [1, 4-]* oxazin-3-one, MS (M + H)⁺：371.0。

8-bromo-6-fluoro-4- (4-chloro-benzyl) -4H-benzo [1, 4]* oxazin-3-one, MS (M + H)⁺：370.9。

8-bromo-6-fluoro-4-naphthalen-2-ylmethyl-4H-benzo [1, 4]* oxazin-3-one, MS (M + H)⁺：384.9。

And 4, step 4: 4-benzyl-8-piperazin-1-yl-4H-benzo [1, 4]* oxazin-3-one hydrochloride

4-benzyl-8-bromo-4H-benzo [1, 4]]* solution of oxazin-3-one (402mg, 1.26mmol) and 1-Boc-piperazine (285mg, 1.53mmol) in 3mL of toluene was added to Pd₂(dba)₃(28mg, 0.03mmol), BINAP (2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl) (41mg, 0.066mmol), NaOt-Bu (175mg, 1.82mmol) in a mixture. The solution was heated to 95-100 ℃ for 1 hour with stirring and allowed to cool to room temperature. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was washed with water (2X 15ml) and brine (1X 15 ml). Over MgSO₄After drying, the organic portion was concentrated in vacuo and the resulting brown residue was purified by flash chromatography (10% -40% ethyl acetate/hexanes over 30 minutes) to give 168mg of boc-protected compound as a yellow solid (32%). 4- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [1, 4]]* oxazin-8-yl) -piperazine-1-carboxylic acid tert-butyl ester (0.168g, 0.4mmol) was dissolved in 4ml ethanol. To the solution was added 2M ethanol hydrochloride solution (3 ml). The mixture was heated at 100 ℃ (steam bath) for 20 minutes, at which time a crystalline solid formed. The solution was allowed to cool to room temperature and after filtration and drying in a vacuum oven, 0.115g of 4-benzyl-8-piperazin-1-yl-4H-benzo [1, 4]]* oxazin-3-one hydrochloride as a pale yellow powder. MS: 324(M + H)⁺，mp＝235.9-236.2℃。

The following compounds were prepared in an analogous manner from the appropriate substituted bromobenzo [1, 4] * ketazine:

4-benzyl-6-methyl-8-piperazin-1-yl-4H-benzo [1，4]* oxazin-3-one hydrochloride, MS: (M + H)⁺338，mp＝256.8-263.9℃。

4-benzyl-6-methoxy-8-piperazin-1-yl-4H-benzo [1, 4]* oxazin-3-one hydrochloride, MS: (M + H)⁺354。

4- (2-fluoro-benzyl) -6-methoxy-8-piperazin-1-yl-4H-benzo [1, 4]* oxazin-3-one hydrochloride, MS: (M + H)⁺372，mp＝268.1-271.0℃。

4- (2-chloro-benzyl) -6-methoxy-8-piperazin-1-yl-4H-benzo [1, 4]* oxazin-3-one hydrochloride, MS: (M + H)⁺388，mp＝286.9-288.9℃。

4- (3-chloro-benzyl) -6-methoxy-8-piperazin-1-yl-4H-benzo [1, 4]* oxazin-3-one hydrochloride, MS: (M + H)⁺388，mp＝55.2-58.8℃。

4-benzyl-6-fluoro-8-piperazin-1-yl-4H-benzo [1, 4-]* oxazin-3-one hydrochloride, MS: (M + H)⁺342，mp＝268.2-268.3℃。

4- (2-fluoro-benzyl) -8-piperazin-1-yl-4H-benzo [1, 4]* oxazin-3-one hydrochloride, MS: (M + H)⁺342，mp＝236.0-244.5℃。

4- (3-fluoro-benzyl) -8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one hydrochloride, mp ═ 231.7-236.5 ℃.

4- (4-fluoro-benzyl) -8-piperazin-1-yl-4H-benzo [1, 4-]* oxazin-3-one hydrochloride, MS: (M + H)⁺342，mp＝240.0-242.4℃。

4- (4-chloro-benzyl) -8-piperazin-1-yl-4H-benzo [1, 4]* oxazin-3-one hydrochloride, MS: (M + H)⁺358，mp＝250.9-253.8℃。

4- (4-fluoro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1, 4]* oxazin-3-one hydrochloride, MS: (M + H)⁺360，mp＝＞300℃。

4- (2-fluoro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1, 4]* oxazin-3-one hydrochloride, MS: (M + H)⁺360，mp＝282.0-282.9℃。

4- (2-chloro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1, 4]* oxazin-3-one hydrochloride, MS: (M + H)⁺376，mp＝＞300℃。

4- (4-chloro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1, 4]* oxazin-3-one hydrochloride, MS: (M + H)⁺376，mp＝271.7-272.4℃。

6-fluoro-4-naphthalen-2-ylmethyl-8-piperazin-1-yl-4H-benzo [1, 4]* oxazin-3-one hydrochloride, MS: (M + H)⁺392，mp＝255.8-256.1℃。

4- (3-methoxy-benzyl) -8-piperazin-1-yl-4H-benzo [1, 4]* oxazin-3-one hydrochloride, MS: (M + H)⁺354。

4- (3-nitro-benzyl) -8-piperazin-1-yl-4H-benzo [1, 4]* oxazin-3-one hydrochloride, MS: (M + H)⁺369。

4- (3-amino-benzyl) -8-piperazin-1-yl-4H-benzo [1, 4]* oxazin-3-one hydrochloride, MS: (M + H)⁺339。

3- (3-oxo-8-piperazin-1-yl-2, 3-dihydro-benzo [1, 4]]* oxazin-4-ylmethyl) -benzonitrile hydrochloride, MS: (M + H)⁺349。

4- (3-oxo-8-piperazin-1-yl-2, 3-dihydro-benzo [1, 4]]* oxazin-4-ylmethyl) -benzonitrile hydrochloride. MS: (M + H)⁺349。

N- [3- (3-oxo-8-piperazin-1-yl-2, 3-dihydro-benzo [1, 4]]* oxazin-4-ylmethyl) -phenyl]-methanesulfonamide hydrochloride, MS: (M + H)⁺417。

[3- (3-oxo-8-piperazin-1-yl-2, 3-dihydro-benzo [1, 4]]* oxazin-4-ylmethyl) -phenyl]Urea hydrochloride, MS: (M + H)⁺382。

4- (3-chloro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one hydrochloride, mp ═ 260.2-263.1 ℃.

The above procedure was followed, but in step 3 benzyl bromide was replaced with 4-bromomethylpyridine,preparation of 8-piperazin-1-yl-4-pyridin-4-ylmethyl-4H-benzo [1, 4]* oxazin-3-one hydrochloride. MS: (M + H)⁺325。

Preparation of 4- (1-phenyl-ethyl) -8-piperazin-1-yl-4H-benzo [1, 4] using the procedure described above, but replacing benzyl bromide with 1-bromoethylbenzene in step 3]* oxazin-3-one hydrochloride. MS: (M + H)⁺338。

Using the above procedure, but substituting boc-protected 3, 5-dimethyl-piperazine for boc-protected piperazine in step 4, 4-benzyl-8- (3, 5-dimethyl-piperazin-l-yl) -4H-benzo [1, 4-]* oxazin-3-one hydrochloride. MS: (M + H)⁺352. Similarly, boc-protected 3, 3-dimethyl-piperazine was used in step 4 to give 4-benzyl-8- (3, 3-dimethyl-piperazin-1-yl) -4H-benzo [1, 4-]* oxazin-3-one hydrochloride. MS: (M + H)⁺352。

Similarly, but using 2-amino-6-bromo-4-methoxyphenol in step 2, to give 6-bromo-4H-benzo [1, 4] * oxazin-3-one in step 3, the following compound was prepared:

4-benzyl-6-piperazin-1-yl-4H-benzo [1, 4]* oxazin-3-one hydrochloride. MS: (M + H)⁺324。

4- (4-fluoro-benzyl) -6-piperazin-1-yl-4H-benzo [1, 4]* oxazin-3-one hydrochloride, MS: (M + H)⁺342。

Example 2

4-benzyl-6-methyl-8- (4-methyl-piperazin-1-yl) -4H-benzo [1, 4]* oxazin-3-ones

To the 4-benzyl-6-methyl-8-piperazin-1-yl-4H-benzo [1, 4] obtained from example 1]* oxazin-3-one (140mg, 0.42mmol) in CH₂C1₂(5ml) to the solution was added formaldehyde (37 wt% aqueous, 50. mu.l, 0)67mmol) and NaBH (OAc)₃. The solution was stirred with a magnetic stirrer at room temperature for 2 hours and then in CH₂C1₂(20ml) and saturated NaHCO₃The solution (20ml) was partitioned between. CH for aqueous layer₂C1₂(2X 20ml) was extracted. Over MgSO₄After drying, the organic portion was concentrated in vacuo to give 4-benzyl-6-methyl-8- (4-methyl-piperazin-1-yl) -4H-benzo [1, 4-]* oxazin-3-one, as a yellow solid (140mg, 95%). MS: (M + H)⁺352。

Analogously to 4-benzyl-8-piperazin-1-yl-4H-benzo [1, 4]]* preparation of oxazin-3-one 4-benzyl-8- (4-methyl-piperazin-1-yl) -4H-benzo [1, 4]* oxazin-3-one: MS: (M + H)⁺338。

Example 3

4-benzyl-2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4]* oxazin-3-ones

The synthetic procedure described in this example was followed as shown in scheme C, where R¹And R¹⁰As defined herein.

Scheme C

Step 1: 2-bromo-N- (3-bromo-2-hydroxy-phenyl) -2-methyl-propionamide

Pyridine (1.8ml, 22.3mmol) was added to 2-amino-6-bromo-phenol (4.198g, 22.3mmol) in dry CH₂C1₂(200ml) in water. The mixture was cooled in ice and then 2-bromo-2-methyl-propionyl bromide solution (2.8ml, 22.6mmol) was added slowly. The mixture was stirred at room temperature for 1 hour and poured onto CH₂Cl₂And water. The organic layer was washed with water, dried and concentrated in vacuo to give crude 2-bromo-N- (3-bromo-2-hydroxy-phenyl) -2-methyl-propionamide, which was used directly in step 2.

Step 2: 8-bromo-2, 2-dimethyl-4H-benzo [1, 4]]* oxazin-3-ones

The 2-bromo-N- (3-bromo-2-hydroxy-phenyl) -2-methyl-propionamide of step 1 was dissolved in DMF (200ml) and the DMF solution was added to K₂CO₃(6.3g, 45.58 mmol). The mixture was heated at 150 ℃ overnight, then cooled and poured into a water/ethyl acetate mixture. The organic portion was washed with brine. After drying over MgSO4, the organic portion was concentrated in vacuo and the resulting brown residue was purified by flash chromatography to give 8-bromo-2, 2-dimethyl-4H-benzo [1, 4]]* oxazin-3-one, as a white solid (84.6%). MS: (M-H)^-256。

Analogously, 8-bromo-6-fluoro-2, 2-dimethyl-4H-benzo [1, 4] is prepared]* oxazin-3-one: MS: (M-H)^-272。

And step 3: 4-benzyl-8-bromo-2, 2-dimethyl-4H-benzo [1, 4]]* oxazin-3-ones

The N-benzylation of 8-bromo-2, 2-dimethyl-4H-benzo [1, 4] * oxazin-3-one in this step was carried out using the procedure described above in example 1, step 3 to give 4-benzyl-8-bromo-2, 2-dimethyl-4H-benzo [1, 4] * oxazin-3-one. MS: (M + H) 347.

And 4, step 4: 4-benzyl-2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4]]* oxazin-3-ones

Amination and subsequent deprotection of 4-benzyl-8-bromo-2, 2-dimethyl-4H-benzo [1, 4] * oxazin-3-one in this step was carried out using the procedure described above in example 1, step 4 to give 4-benzyl-2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one hydrochloride.

Using the procedure of example 3, using the appropriately substituted benzyl bromide, the following compounds were also prepared:

4- (4-fluoro-benzyl) -2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one hydrochloride, MS: (M + H) 370.

4- (3-fluoro-benzyl) -2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one hydrochloride, MS: (M + H) 370.

4- (3-chloro-benzyl) -2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one hydrochloride, MS: (M + H) 386.

4- (4-chloro-benzyl) -2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one hydrochloride, MS: (M + H) 386.

4-benzyl-6-fluoro-2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one hydrochloride, MS: (M + H) 370.

4- (4-chloro-benzyl) -6-fluoro-2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one hydrochloride, MS: (M + H) 405.

6-fluoro-4- (3-fluoro-benzyl) -2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one hydrochloride, MS: (M + H) 389.

6-fluoro-4- (2-fluoro-benzyl) -2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one hydrochloride, MS: (M + H) 389.

6-fluoro-4- (4-fluoro-benzyl) -2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one hydrochloride, MS: (M + H) 389.

4- (3-chloro-benzyl) -6-fluoro-2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one hydrochloride, MS: (M + H) 405.

Following the above procedure, but substituting (R) -and (S) -2-bromo-propionyl bromide for 2-bromo-2-methyl-propionyl bromide in step 1, the following compound was obtained:

(R) -4-benzyl-2-methyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one hydrochloride, MS: (M + H) 338; and

(S) -4-benzyl-2-methyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one hydrochloride, MS: (M + H) 338.

Similarly, but replacing 2-bromo-2-methyl-propionyl bromide in step 1 with (1-bromo-cyclobutyl) -acetyl bromide, was prepared 4-benzyl-2, 2-spiro-cyclobutane-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one hydrochloride, MS: (M + H) 363.

Example 4

1-benzyl-5-piperazin-1-yl-1H-benzo [1, 3, 4]* thia 2, 2-dioxidesThe synthetic procedure described in this example was performed according to the method shown in scheme D.

Scheme D

Step 1: 4- (2-benzyloxy-3-nitro-phenyl) -piperazine-1-carboxylic acid tert-butyl ester

To a dry round bottom flask was added 2-benzyloxy-1-bromo-3-nitro-benzene (9.24g, 30mmol), piperazine-1-carboxylic acid tert-butyl ester (6.15g, 33mmol), tris (dibenzylideneacetone) dipalladium (0) (1.09g, 1.2mmol), and rac-2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl (1.86g, 3 mmol). The flask was purged with nitrogen, charged with toluene (60mL) and warmed to 90 ℃ for 2.5 hours. The reaction mixture was filtered through celite and the celite was washed with 100mL ethyl acetate. The filtrate was concentrated in vacuo and the resulting residue was purified by flash chromatography (30% to 50% ethyl acetate in hexanes) to give 870mg of 4- (2-benzyloxy-3-nitro-phenyl) -piperazine-1-carboxylic acid tert-butyl ester as a red oil (9%). (M + H)⁺＝324。

Step 2: 4- (3-amino-2-hydroxy-phenyl) -piperazine-1-carboxylic acid tert-butyl ester

To a flask containing 10mg of platinum dispersed on charcoal (5%) were added 4- (2-benzyloxy-3-nitro-phenyl) -piperazine-1-carboxylic acid tert-butyl ester (680mg, 1.65mmol) and ethanol (5 mL). The system was purged with hydrogen by alternating application of vacuum and hydrogen. The resulting suspension was stirred at room temperature for 2 hours and then filtered through celite. The celite was rinsed with 45mL ethyl acetate, the organic solutions combined and concentrated in vacuo to give 280mg of 4- (3-amino-2-hydroxy-phenyl) -piperazine-1-carboxylic acid tert-butyl ester as a brown foam (58%). (M + H)⁺＝294。

And step 3: 4- (3-Chloromethylsulfonylamino-2-hydroxy-phenyl) -piperazine-1-carboxylic acid tert-butyl ester

In a dry round bottom flask, 4- (3-amino-2-hydroxy-phenyl) -piperazine-1-carboxylic acid tert-butyl ester (293mg, 1mmol) was dissolved in dry THF (3mL) under nitrogen. Chlorosulfonyl chloride (149mg, 1mmol) was added dropwise over 10 min while stirring and the solution was stirred for 30 min. Pyridine (0.121mL, 1.5mmol) was then added dropwise over 5 minutes and the solution was stirred for 18 hours. The reaction mixture was taken up in 40mL Et₂Diluted with O and washed with 40mL of 10% HC1 aqueous solution, 50mL water and 50mL brine. The organic fraction is over MgSO₄Dried and concentrated in vacuo. The residue was purified by flash chromatography (20% to 40% EtOAc in hexanes) to give 190mg of 4- (3-chloromethanesulfonylamino-2-hydroxy-phenyl) -piperazine-1-carboxylic acid tert-butyl ester as a amber oil (45%). (M-H)^-=404。

And 4, step 4: 4- (1-benzyl-2, 2-dioxo-2, 3-dihydro-1H-benzo [4, 2, 1 ]]* thiazin-5-yl) -piperazine-1- (iv) Carboxylic acid tert-butyl ester

To a flask containing 7mL of methanol was added 4- (3-chloromethanesulfonylamino-2-hydroxy-phenyl) -piperazine-1-carboxylic acid tert-butyl ester (190mg, 0.471mmol) and potassium carbonate (195mg, 1.4 mmol). The suspension was refluxed under nitrogen for 2 hours and allowed to cool to room temperature. To the reaction mixture was added benzyl bromide (0.083mL, 0.7mmol) and potassium carbonate (87mg, 0.7mmol), and the reaction was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and the resulting crude solid was dissolved in ethyl acetate. The solution was washed with 50mL of water and 50mL of brine, and the ethyl acetate was removed in vacuo. The resulting residue was purified by flash chromatography to give 57mg of 4- (1-benzyl-2, 2-dioxo-2, 3-dihydro-1H-benzo [4, 2, 1%]* Thiazin-5-yl) -piperazine-1-carboxylic acid tert-butyl ester as a light purple oil (26%). (M + H)⁺＝460。

And 5: 1-benzyl-5-piperazin-1-yl-1H-benzo [4, 2, 1]* thiazine 2, 2-dioxide hydrochloric acidSalt (salt)

4- (1-benzyl-2, 2-dioxo-2, 3-dihydro-1H-benzo [4, 2, 1 ]]* Thiazin-5-yl) -piperazine-1-carboxylic acid tert-butyl ester was dissolved in 1mL methanol and 1mL 2N HC1 ethanol solution was added. The solution was heated at 100 ℃ for 30 minutes, at which time about 2mL Et was added₂And O. On cooling to room temperature, 30mg 1-benzyl-5-piperazin-1-yl-1H-benzo [4, 2, 1]* thiazine 2, 2-dioxide hydrochloride as a white solid (61%). (M + H)⁺＝360。

Example 5: preparation

Pharmaceutical formulations delivered by various routes were formulated as shown in the following table. The "active ingredient" or "active ingredient" used in the tables means one or more compounds of formula I.

Orally administered composition

Composition (I)	％wt./wt.
		Active ingredient	20.0％
Lactose	79.5％
		Magnesium stearate	0.5％

The ingredients are mixed and sub-packaged in capsules, each containing 100mg, one capsule approximating the total daily dose.

Orally administered composition

Composition (I)	％wt./wt.
		Active ingredient	20.0％
Magnesium stearate	0.5％
		Croscarmellose sodium	2.0％
Lactose	76.5％
		PVP (polyvinylpyrrolidone)	1.0％

The ingredients are combined and granulated with a solvent such as methanol. The formulation is then dried and tableted with a suitable tablet press (containing about 20mg of active compound).

Orally administered composition

Composition (I)	Measurement of
		Active compound	1.0g
Fumaric acid	0.5g
		Sodium chloride	2.0g
P-hydroxybenzoic acid methyl ester	0.15g
		Propyl p-hydroxybenzoate	0.05g
Granular sugar	25.5g
		Sorbitol (70% solution)	12.85g

Veegum K(Vanderbilt Co.)	1.0g
		Flavoring agent	0.035ml
Coloring agent	0.5mg
		Distilled water	Proper amount to 100ml

Mixing the above components, and making into suspension for oral administration.

Parenteral formulation

Composition (I)	％wt./wt.
		Active ingredient	0.25g
Chlorination ofSodium salt	Proper amount to isotonic
		Water for injection	100ml

The active ingredient is dissolved in a portion of the water for injection. Sufficient sodium chloride is then added with stirring to make the solution isotonic, the solution is made up to weight with the remaining water for injection, filtered through a 0.2 micron membrane filter and packaged under sterile conditions.

Suppository

Composition (I)	％wt./wt.
		Active ingredient	1.0％
Polyethylene glycol 1000	74.5％
		Polyethylene glycol 4000	24.5％

The ingredients were melted together and mixed on a steam bath and poured into a mold containing a total weight of 2.5 g.

Topical formulations

Composition (I)	g
		Active compound	0.2-2
Span 60	2
		Soil temperature 60	2
Mineral oil	5
		Paraffin oil	10
P-hydroxybenzoic acid methyl ester	0.15
		Propyl p-hydroxybenzoate	0.05
BHA (butylated hydroxyanisole)	0.01
		Water (W)	Proper amount to 100

All ingredients except water were combined and heated to about 60 ℃ while stirring. Sufficient water at about 60 c was then added under vigorous stirring to emulsify the ingredients, and then an appropriate amount of water was added to about 100 g.

Nasal spray formulation

Several aqueous suspensions containing about 0.025-0.5% of the active compound were prepared as nasal spray formulations. The formulation optionally contains inactive ingredients such as microcrystalline cellulose, sodium carboxymethylcellulose, dextrose, and the like. Hydrochloric acid may be added to adjust the pH. The nasal spray formulations may be delivered via a nasal spray metering pump, typically delivering about 50-100 microliters of formulation per spray. A typical dosing regimen is to spray 2-4 times every 4-12 hours.

Example 6: radioligand binding studies

This example illustrates in vitro radioligand binding studies of compounds of formula I.

The in vitro binding activity of the compounds of the invention was determined as follows. By competing for binding to a cell membrane obtained from a HEK293 cell stably expressing a recombinant human 5-HT6 receptor³H]LSD, ligand affinity was determined in duplicate.

All assays were performed at 37 ℃ in test buffer containing 50mM Tris-HCl, 10mM MgSO₄0.5mM EDTA, 1mM ascorbic acid, pH 7.4, reaction volume 250 microliter. Will contain³H]LSD (5nM), competitor ligand and membrane test tubes were incubated in a shaking water bath at 37 ℃ for 60 min, filtered onto Packard GF-B plates (pre-soaked with 0.3% PEI) using a Packard 96-well cell harvester and washed 3 times with ice-cold 50mM Tris-HCl. The bound [ 2 ] is determined using a Packard TopCount in radioactive counts per minute³H]LSD。

The concentration-binding data was substituted into the 4-parameter logistic equation, pair³H]Displacement of LSD from the binding site was quantified:

wherein Hill is Hill slope, [ ligand ]]Concentration of competing radioligand, IC₅₀The concentration of radioligand that produces half-maximal specific binding of the radioligand. The specific binding window is the difference between Bmax and the baseline parameter.

Using the procedure of this example, compounds of formula I were tested and found to be selective 5-HT6 antagonists. Representative affinity data for the compounds of the invention are shown in table 2.

TABLE 2

Compound (I)	pKi
		4- (2-fluoro-benzyl) -8-piperazin-1-yl-4H-benzo [1, 4]* oxazin-3-ones	9.04
4- (2-fluoro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1, 4]* oxazin-3-ones	9.17
		4-benzyl-2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4]* oxazin-3-ones	9.13
(S) -4-benzyl-2-methyl-8-piperazin-1-yl-4H-benzo [1, 4]* oxazin-3-ones	9.12
		4- (3-chloro-benzyl) -2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4]* oxazin-3-ones	9.12

Example 7: recognition enhancement

The recognition enhancing property of the compound of the present invention can be verified in an animal recognition model, i.e., an object recognition task model (obj ect recognition task model). Male Wistar rats (Charles River, The Netherlands) of 4 months of age were used. The compounds were prepared daily, dissolved in physiological saline and tested at three doses. Intraperitoneal administration (injection volume 1ml/kg) 60 minutes before T1. Scopolamine hydrobromide was injected 30 minutes after compound injection. Two parallel experimental groups consisted of 24 rats and were tested by two experimenters. The order of the dose experiments was determined randomly. Experiments were performed using a double blind protocol. All rats were treated once with each dose condition. Such as Ennaceur, A., Delaour, J., 1988, A new one-tertiary test for neurological students of memory in rates.1: the pair identification experiments were performed as described in Behavioral data. behavv. brain res.31, 47-59.

While the invention has been described with reference to specific embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process step or steps, and the objective spirit and scope of the present invention. All such modifications are intended to be within the scope of the appended claims.

Claims (16)

1. A compound of formula I or a pharmaceutically acceptable salt thereof,

wherein:

y is C or S;

when Y is C, m is 1, and when Y is S, m is 2;

n is 1;

p is 0 or 1;

q is 2;

z is- (CR)^aR^b)_r-, wherein each R^aAnd R^bIndependently is hydrogen or C_1-12An alkyl group;

r is 1;

x is N;

each R¹Independently of one another is halo, C_1-12Alkyl or C_1-12An alkoxy group;

R²is an optionally substituted monocyclic or bicyclic aryl or monocyclic heteroaryl group;

each R³And R⁴Independently is hydrogen or C_1-12Alkyl, or R³And R⁴Together with the carbon they share may form a 3 to 6 membered cycloalkyl group; and is

Each R⁵、R⁶、R⁷、R⁸And R⁹Independently is hydrogen or C_1-12An alkyl group.

2. The compound of claim 1, wherein each R^aAnd R^bIndependently hydrogen or methyl; each R³And R⁴Independently is hydrogen or methyl, or R³And R⁴Together forming a cyclobutyl ring.

3. The compound of claim 1 or 2, wherein R²Is 2-halophenyl, 3-halophenyl, 4-halophenyl, naphthalen-2-yl, 3-cyanophenyl, 4-cyanophenyl, 3-nitrophenyl, 3-aminophenyl, 3-methoxyphenyl, 3-urenophenyl, 3-methylsulfonylamino-phenyl or pyridin-4-yl.

4. The compound of claim 1, wherein the compound is of the formula,

z, R therein¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹N and p are as defined in claim 1.

5. The compound of claim 1, wherein the compound is of the formula,

z, R therein¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹N and p are as defined in claim 1.

6. The compound of claim 1, wherein the compound is of the formula,

wherein R is¹、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R^a、R^bN, r and p are as defined in claim 1, and wherein t is 0 to 4; and each R¹⁰Independently of one another is hydrogen, halo, C_1-12Alkyl radical, C_1-12Alkoxy, cyano, nitro, amino, urea or ethanesulfonylamino.

7. The compound of claim 1, wherein the compound is of the formula,

wherein R is¹、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R^a、R^bN, r and p are as defined in claim 1, and wherein t is 0 to 4; and each R¹⁰Independently of one another is hydrogen, halo, C_1-12Alkyl radical, C_1-12Alkoxy, cyano, nitro, amino, urea or ethanesulfonylamino.

8. The compound of claim 1, wherein the compound is selected from the group consisting of:

4-benzyl-6-methyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4-benzyl-6-methoxy-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (2-fluoro-benzyl) -6-methoxy-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (2-chloro-benzyl) -6-methoxy-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (3-chloro-benzyl) -6-methoxy-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4-benzyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4-benzyl-6-fluoro-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (2-fluoro-benzyl) -8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (4-fluoro-benzyl) -8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (4-chloro-benzyl) -8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (4-fluoro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (2-fluoro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (2-chloro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (4-chloro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

6-fluoro-4-naphthalen-2-ylmethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (3-chloro-benzyl) -6-fluoro-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

3- (3-oxo-8-piperazin-1-yl-2, 3-dihydro-benzo [1, 4] * oxazin-4-ylmethyl) -benzonitrile;

4- (3-fluoro-benzyl) -8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4-benzyl-2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

(R) -4-benzyl-2-methyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4-benzyl-6-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (4-fluoro-benzyl) -6-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

(S) -4-benzyl-2-methyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

8-piperazin-1-yl-4-pyridin-4-ylmethyl-4H-benzo [1, 4] * oxazin-3-one;

4-benzyl-6-methyl-8- (4-methyl-piperazin-1-yl) -4H-benzo [1, 4] * oxazin-3-one;

4-benzyl-8- (4-methyl-piperazin-1-yl) -4H-benzo [1, 4] * oxazin-3-one;

4- (1-phenyl-ethyl) -8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (3-methoxy-benzyl) -8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (3-nitro-benzyl) -8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (3-amino-benzyl) -8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

3- (3-oxo-8-piperazin-1-yl-2, 3-dihydro-benzo [1, 4] * oxazin-4-ylmethyl) -benzonitrile;

n- [3- (3-oxo-8-piperazin-1-yl-2, 3-dihydro-benzo [1, 4] * oxazin-4-ylmethyl) -phenyl ] -methanesulfonamide;

4- (4-fluoro-benzyl) -2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (3-fluoro-benzyl) -2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

[3- (3-oxo-8-piperazin-1-yl-2, 3-dihydro-benzo [1, 4] * oxazin-4-ylmethyl) -phenyl ] -urea;

4- (3-chloro-benzyl) -2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4-benzyl-8- (3, 5-dimethyl-piperazin-1-yl) -4H-benzo [1, 4] * oxazin-3-one;

4- (4-chloro-benzyl) -2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4-benzyl-6-fluoro-2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (4-chloro-benzyl) -6-fluoro-2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

6-fluoro-4- (3-fluoro-benzyl) -2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

6-fluoro-4- (2-fluoro-benzyl) -2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

6-fluoro-4- (4-fluoro-benzyl) -2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4- (3-chloro-benzyl) -6-fluoro-2, 2-dimethyl-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one;

4-benzyl-8- (3, 3-dimethyl-piperazin-1-yl) -4H-benzo [1, 4] * oxazin-3-one;

1-benzyl-5-piperazin-1-yl-1H-benzo [1, 3, 4] * thiazine 2, 2-dioxide; and

4-benzyl-2, 2-spiro-cyclobutane-8-piperazin-1-yl-4H-benzo [1, 4] * oxazin-3-one.

9. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier.

10. A process for preparing a compound according to any one of claims 1 to 8, which process comprises: reacting an N-arylalkyl benzo [ 58743of formula i

Wherein:

A₁is a leaving group;

Z、Y、R¹、R²、R³、R⁴m, n and p are as defined in claim 1; with a heterocyclic compound of the formula g,

wherein:

q、R⁵、R⁶、R⁷、R⁸and R⁹As defined in claim 1;

to prepare a heterocyclyl-substituted N-arylalkyl benzo [ 58743 ] oxazinone compound of formula I:

11. the method of claim 10, comprising:

reacting an N-arylalkyl benzo \58743offormula j

With a heterocyclic compound of the formula h,

whereby the heterocyclyl-substituted N-arylalkyl benzo [ 58743a oxazinone compound is of formula Ic

And R is¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰N, p, r and t are as defined in claim 10.

12. The process of claim 10 or 11, wherein the leaving group a¹Is halo.

13. Use of one or more compounds according to any one of claims 1 to 8 for the preparation of a medicament for the treatment or prevention of a central nervous system disease state.

14. The use of claim 13, wherein the disease state is selected from psychosis, manic depression, neurological disorders, memory disorders, attention deficit disorder, parkinson's disease, amyotrophic lateral sclerosis, alzheimer's disease, and huntington's disease.

15. The use of claim 13, wherein the psychosis is schizophrenia.

16. Use of one or more compounds according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment or prevention of gastrointestinal disorders.