HK1091731B

HK1091731B - Pharmaceutical use of fused heterocyclic compounds as scce inhibitors for the treatment of skin conditions or cancer

Info

Publication number: HK1091731B
Application number: HK06112281.7A
Authority: HK
Inventors: M．林舍滕
Original assignee: 阿里克斯股份公司
Priority date: 2003-06-06
Filing date: 2004-06-07
Publication date: 2010-04-09

Description

Pharmaceutical use of heterocyclic compounds as SCCE inhibitors

Technical Field

The present invention relates to methods of inhibiting an increase in the activity of the serine protease Stratum Corneum Chymotrypsin (SCCE). The invention further relates to the use of SCCB inhibitors of formula (I) or (II) for the treatment of diseases, more particularly for the treatment of skin diseases and ovarian cancer.

Background

Protein degrading enzymes have broad spectrum of specificity and function. They are thus involved in a number of physiological as well as pathological reactions in cells and tissues. The possibility of designing specific inhibitors makes proteases interesting targets for new drugs for the treatment of diseases.

Serine protease stratum corneum chymotrypsin (SCCE; EC 3.4.21.); SwissProt P49862, also known as kallikrein 7; expression is preferentially obtained in keratinized epithelial tissue (WO 95/00651; Hansson L, et al T.cloning, expression and characterization of stratum cornum serotrophic enzyme. Ashin-specific human serum enzyme. J Biol Chem 1994, 269: 19420. 19426; Youef et al, The KLK7(PRSS6) gene, encoding for The stratum cornum serotrophic enzyme a new chamber of human kallikrein gene family-genetic characterization, mapping, tissue expression and pathological regulation. Gene 2000, 254: 128). Several studies have shown that SCCE can take part in the exfoliation of keratinocytes by degrading the intercellular components of desmosomes (Egelrud t. degelation in the stratum cornum. acta Derm Venereol 2000, 208: 44-45). In stratum corneum extracts, SCCE determines a major part of the overall proteolytic activity and is believed to have a potential role in skin pathophysiology, for example by acting as an activator of pro-inflammatory cytokine precursors (Nylon der-Lundqvist E, Egelrud. T. Formation of active IL-1beta from IL-1beta catalyzed by plasmid cornstarch kinase in vitro. acta Derm Venereol 1997: 77: 203-.

Furthermore, it has been observed that SCCE is upregulated in psoriatic lesions (Ekholm E, Egelrud T. Strateum communicating enzyme in psoriatic inflammation. Arch DermatolRes 1999, 291: 195-200) and chronic lesions of atopic dermatitis (Hansson L, et al, epidemic overexpression of Strateum communicating enzyme in micoe; a model for clinical diagnosis. J investeddermatum 2002, 118: 444-449). Taken together, these results indicate that there is dysregulation of SCCE keratinocyte expression in two diseases characterized by chronic inflammation, epidermal hyperproliferation, and scaling. Increasing the activity of SCCE present in the skin can actually play an important role in skin pathophysiology, and the use of inhibitors of SCCE activity provides a new therapeutic principle for the treatment of skin diseases.

Transgenic mice that overexpress human scce mRNA under viral promoter conditions have been bred (WO 02/062135). The only phenotypic changes observed were found in the skin, which showed some histological changes similar to those seen in human chronic inflammatory dermatoses. Transgenic mice express human SCCE in epidermal keratinocytes at the upper base and are found to develop pathological skin changes including increased epidermal thickness, hyperkeratosis, and skin exudate consisting of macrophages and granulocytes. There is also disturbed keratinocyte differentiation, hyperproliferation of the epidermis, increased transepithelial water loss, and MHCII expression by keratinocytes. Furthermore, most transgenic animals show severe itching symptoms with increasing age (Hansson L, et al, epidemic overexpression of stratum chrome in mice; a model for serum specificity evaluation. J invested Dermatols.2002, 118: 444-449; Ny A, Egelu T. transgenic microorganism overexpression a promoter in the mice: experience. Objections of Interferon gamma-indendedness MHC II expression by epidemic Keratino. Acerance vector. 2003, 83: 323-327; Ny A, Egelu T expression vector promoter. 2003, 83: 323-327; and 9A, Egelu T expression vector deletion promoter expression vector in mice: 18. with increasing age. These transgenic mice will provide a useful animal model for the development of new treatment regimens for human skin diseases and for the evaluation of therapeutically effective SCCE inhibitors.

SCCE has also been found to be very overexpressed in ovarian cancers (TanimotoH et al, The stratum cornum chlamydomone at media cultures expressed and desquamations of skin cells in cancer cells 1999, 86: 2074-82; Kyrokopouulolg et al, diagnostic value of qualitative assessment KLK7expression in ovarian cancer cells 2003, 36: 135-43). Inhibition of SCCE activity is therefore considered a novel therapeutic principle for the treatment of ovarian cancer.

Disclosure of Invention

It has now been found that the activity of SCCE can be inhibited by compounds of formula I or II. Moreover, such compounds have been found to be effective in alleviating skin disorders, such as inflammatory skin disorders, particularly when applied topically.

Accordingly, in a first aspect, the present invention relates to the use of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a dermatological condition:

wherein

X is O or S; y is independently O, S, NH or N if the nitrogen atom is bonded to an adjacent carbon atom by a double bond; z is independently O, NH or N if the nitrogen atom is bonded to an adjacent carbon atom by a double bond;

w, Q, V and T are independently CH, CH₂S, N or O;

ring a, ring B, ring C and ring D may be aromatic, saturated or partially saturated;

R₁and R₂And, if present, independently:

C_1-8-alkyl radical, C_2-8-alkenyl radical, C_2-8-alkynyl or C_3-6-cycloalkyl, each optionally substituted with: halogen, OH, NH₂、NHR₄、N(R₄)₂、NHCOR₄、C_1-6Alkoxy, trifluoromethoxy, carbamoyl、CONHR₄Or CON (R)₄)₂(ii) a H, halogen, CF₃，C_1-6-alkoxy radical, C_1-6Alkylthio, OCF₃，COOH，CN，CONH₂，CONHR₄，OH，NO₂，NH₂，NHR₄，N(R₄)₂，NHCOR₄，NHSO₂R₄，CON(R₄)₂，CONHSO₂R₄，SO₂NH₂，SO₂NHR₄，SO₂R₄，SOR₄，C_1-4-alkoxycarbonyl, aryl, aryloxy, heteroaryl, heteroaryloxy, alkylphenyl, or tetrazole;

or when R is₁And R₂When bonded to adjacent atoms in ring A or ring C, together form- (CH)₂)_n-a moiety, wherein n-1-5, and wherein 1, 2 or 3 CH in said moiety₂The unit may optionally be replaced by 1, 2 or 3 heteroatoms, if the nitrogen atom is bonded to an adjacent atom by a double bond, wherein each heteroatom is independently selected from O, S, NH and N, and wherein said moiety may optionally be substituted by 1, 2 or 3 heteroatoms independently selected from halogen, OH, NH₂、NHR₄、N(R₄)₂、NHCOR₄、C_1-6Alkoxy, trifluoromethoxy, carbamoyl, CONHR₄Or CON (R)₄)₂Substituted with the substituent(s);

R₃is aryl or heteroaryl, each optionally substituted with one or more of the following groups: halogen, CF₃，C_1-6-alkoxy radical, C_1-6Alkylthio, OCF₃，COOH，CN，CONH₂，CONHR₄，OH，NO₂，NH₂，NHR₄，N(R₄)₂，NHCOR₄，NHSO₂R₄，CON(R₄)₂，CONHSO₂R₄，SO₂NH₂，SO₂NHR₄，SO₂R₄，SOR₄，C_1-4Alkoxycarbonyl, aryl, aryloxy, heteroaryl, heteroaryloxy, alkylphenylTetrazole, C_1-8-alkyl radical, C_2-8-alkenyl radical, C_2-8-alkynyl or C_3-6-cycloalkyl radicals, each C_1-8Alkyl radical, C_2-8-alkenyl, C_2-8-alkynyl or C_3-6-cycloalkyl is optionally substituted by: halogen, CF₃，OCF₃，COOH，CN，CONH₂，CONHR₄，CON(R₄)₂，OH，NO₂，NH₂，NHR₄，N(R₄)₂，NHCOR₄，NHSO₂R₄，SO₂NH₂，SO₂NHR₄，SO₂R₄，SOR₄，C_1-4-alkoxy, or carbamoyl; and

R₄is C_1-4-alkyl radical, C_2-4-alkenyl radical, C_2-4-alkynyl, C_3-6-cycloalkyl radical, C_1-6-alkoxy radical, C_1-6Alkylthio, aryl, aryloxy, heteroaryl, or heteroaryloxy.

In another aspect, the invention relates to the use of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer.

In yet another aspect, the present invention relates to a method of modulating and/or normalizing damaged skin barriers in a mammal, comprising administering to a mammal in need thereof an effective amount of at least one compound of formula I or II, or a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention relates to a method of treating a skin disorder, the method comprising administering to a mammal in need thereof an effective amount of at least one compound of formula I or II, or a pharmaceutically acceptable salt thereof.

In a still further aspect, the present invention relates to a method of treating a mammal having cancer, the method comprising administering to a mammal in need thereof an effective amount of at least one compound of formula I or II, or a pharmaceutically acceptable salt thereof.

In a still further aspect, the present invention relates to a cosmetic or dermatological composition comprising at least one compound of formula I or II, or a pharmaceutically acceptable salt thereof, in a form suitable for topical administration and selected from the group consisting of creams, ointments, lotions, liniments, gels, pastes, sticks, sprays, shampoos, soaps, hair conditioners and powders.

In yet another aspect, the present invention relates to the use of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of a cosmetic skin condition.

Other aspects of the invention will be apparent from the following disclosure and appended claims.

Drawings

FIG. 1 shows: effect on transepithelial water loss (TEWL) in transgenic SCCE mice topically administered SCCE inhibitor-compound I-3(2- (2-iodo-phenyl) -6, 7-dimethoxy-benzo [ d ] [1, 3] oxazin-4-one).

30 μ M of an inhibitor in mouth,

an inhibitor of the activity of the enzyme,

o ═ control (excipient),

normal TEWL levels in wild type mice.

Detailed description of the invention

Definition of

In this text, the term“C_1-8Alkyl "means a straight or branched saturated hydrocarbon chain, wherein the chain has from one to eight carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl and octyl. Branched hydrocarbon chain means C substituted with a hydrocarbon chain at any carbon_1-8-an alkyl group.

Herein, the term "C_2-8-alkenyl "means a straight or branched hydrocarbon chain having from two to eight carbon atoms and containing one or more double bonds. C_2-8Illustrative examples of the alkenyl group include allyl, homoallyl, ethenyl, crotyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl. C with more than one double bond_2-8Illustrative examples of-alkenyl groups include succinalkenyl, pentadienyl, hexadienyl, heptadienyl, hexantrienyl, heptatrienyl and octatrienyl groups and branched versions of these groups. The position of the double bond may be anywhere along the carbon chain.

Herein, the term "C_2-8-alkynyl "means a straight or branched hydrocarbon chain having from two to eight carbon atoms and containing one or more triple bonds. C_2-8Illustrative examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl and octynyl as well as branched forms of these groups. More than one bond may be unsaturated, such that "C_2-8-alkynyl "is di-certain alkyne or alkenedi-certain alkyne, as known to the person skilled in the art. The triple bond may be located anywhere along the carbon chain.

Herein, the term "C_3-6Cycloalkyl "is a three, four, five and six membered ring which is intended to cover carbon atoms, wherein all carbon-carbon bonds are saturated. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "C" as used herein_1-6-alkoxy "means C_1-6Alkyl-oxy, such as methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, and hexyloxy.

The term "C" as used herein_1-6Alkylthio "means a straight or branched chain C in which the carbon atom is covalently linked to the sulfur atom_1-6-an alkyl group.

The term "halogen" as used herein refers to fluorine, chlorine, bromine, and iodine.

The term "aryl" herein refers to a carbocyclic aromatic ring or ring system. Furthermore, the term "aryl" includes fused ring systems wherein at least two aryl rings share a bond. As used herein, the term "heteroaryl" refers to an aryl group in which one or more carbon atoms in the aromatic ring have been replaced with one or more heteroatoms, such as nitrogen, sulfur, phosphorus, or oxygen. Also, as used herein, the term "heteroaryl" includes fused ring systems wherein at least one aryl ring and at least one heteroaryl ring or at least two heteroaryl groups share a bond.

Specific examples of "aryl" and "heteroaryl" include optionally substituted phenyl, biphenyl, indene, fluorene, naphthyl (1-naphthyl, 2-naphthyl), anthracene (1-anthryl, 2-anthryl, 3-anthryl), thiophene (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl, isoxazolyl, quinazoline, fluorenyl, xanthenyl, isoindolyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1, 2, 3-triazol-1-yl, 1, 2, 3-triazol-2-yl, 1, 2, 3-triazol-4-yl, 1, 2, 4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolinyl (2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 8-quinolinylYl), isoquinolinyl (1-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl, 8-isoquinolinyl), benzo [ b ]]Furyl (2-benzo [ b ]]Furyl, 3-benzo [ b ]]Furyl, 4-benzo [ b ]]Furyl, 5-benzo [ b ]]Furyl, 6-benzo [ b ]]Furyl, 7-benzo [ b ]]Furyl), 2, 3-dihydrobenzo [ b ]]Furyl (2- (2, 3-dihydro-benzo [ b ]]Furyl), 3- (2, 3-dihydro-benzo [ b)]Furyl), 4- (2, 3-dihydro-benzo [ b)]Furyl), 5- (2, 3-dihydro-benzo [ b)]Furyl), 6- (2, 3-dihydro-benzo [ b)]Furyl), 7- (2, 3-dihydro-benzo [ b)]Furyl)), benzo [ b ]]Phenylthio (2-benzo [ b ]]Phenylthio, 3-benzo [ b ]]Phenylthio, 4-benzo [ b ]]Phenylthio, 5-benzo [ b ]]Phenylthio, 6-benzo [ b ]]Phenylthio, 7-benzo [ b ]]Phenylthio), 2, 3-dihydro-benzo [ b ]]Phenylthio (2- (2, 3-dihydro-benzo [ b ]]Phenylthio), 3- (2, 3-dihydro-benzo [ b ]]Phenylthio), 4- (2, 3-dihydro-benzo [ b ]]Phenylthio), 5- (2, 3-dihydrobenzo [ b ]]Phenylthio), 6- (2, 3-dihydro-benzo [ b ]]Phenylthio), 7- (2, 3-dihydro-benzo [ b ]]Thiophenyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenzo [ b, f [ ]]Aza derivatives(5H-dibenzo [ b, f ]]Aza derivatives-1-yl, 5H-dibenzo [ b, f ]]Aza derivatives-2-yl, 5H-dibenzo [ b,f]aza derivatives-3-yl, 5H-dibenzo [ b, f ]]Aza derivatives-4-yl, 5H-dibenzo [ b, f ]]Aza derivatives-5-yl), 10, 11-dihydro-5H-dibenzo [ b, f)]Aza derivatives(10, 11-dihydro-5H-dibenzo [ b, f)]Aza derivatives-1-yl, 10, 11-dihydro-5H-dibenzo [ b, f]Aza derivatives-2-yl, 10, 11-dihydro-5H-dibenzo [ b, f]Aza derivatives-3-yl, 10, 11-dihydro-5H-dibenzo [ b, f]Aza derivatives-4-yl, and 10, 11-dihydro-5H-dibenzo [ b, f]Aza derivatives-5-yl).

The term "leaving group" includes, but is not limited to, halogen, sulfonate, or acyl. Other suitable leaving groups will be apparent to those skilled in the art.

The term "protecting group" (PG) refers to a chemical group that exhibits the following characteristics: 1) selectively reacting with the desired functional group in good yield to give a protected substrate which is stable to the intended reaction requiring protection; 2) can be selectively removed from the protective substrate to provide the desired functional group; and 3) reagents compatible with other functional groups generated in such protection reactions can be utilized in good yieldsAnd (4) removing. Protecting groups include, but are not limited to, CH₃Benzyl (Bn), Butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), 9-fluorenylmethoxy-carbonyl (Fmoc), or tosyl (Ts). Other nitrogen protecting groups are known to those skilled in the art. Examples of protecting groups can be found, for example, in the following documents: greene et al, (1991) Protective Groups in organic Chemistry, 2 nd edition (John Wiley& Sons，Inc.，New York)。

"coupling agent" means a suitable agent for forming acid derivatives from acids or activated acids and amines, phenols, alcohols or acids, including but not limited to hydroxybenzotriazole (HOBt) and its derivatives, and carbodiimides such as dicyclohexylcarbodiimide and ethyl dimethylaminopropyl carbodiimide (DCC, EIDAC). The skilled person is aware of suitable coupling agents. Activated acids include, but are not limited to, acid chlorides, anhydrides, esters, and similar derivatives.

"agent capable of causing ring closure" means an agent capable of causing the combined hydrolysis and ring closure under the action of absorbed water. Such agents include, but are not limited to, organic and inorganic anhydrides, such as acetic anhydride and P₂O₅Inorganic acids, e.g. concentrated sulfuric acid, phosphoric acid, etc., acid chlorides, e.g. SOCl₂、PCl₅And POCl₃。

"optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and that the description includes unsubstituted aryl groups and aryl groups in which substitution occurs.

"treating" means administering a therapeutically effective amount of a compound disclosed herein for the purpose of preventing the development of any symptom or disease state, or for the purpose of curing or alleviating such an already-developed symptom or disease state. The term "treatment" is therefore intended to include prophylactic treatment.

The abbreviation "SCCE" refers herein to stratum corneum chymotrypsin.

Certain of the above-defined terms may occur more than once in formulas I and II above, and each term should be defined independently of the other in such occurrences.

The compounds of the present invention may have one or more asymmetric centers, and means that stereoisomers (optical isomers) that exist as individual, pure or partially purified stereoisomers or as racemic mixtures thereof are included within the scope of the present invention.

As will be appreciated, the compounds of formula I or II described herein are potent SCCE inhibitors. However, since some variation in inhibitory efficacy may occur between the compounds of formula I or II alone, the inventors provide a suitable preliminary assay that can be used to assess the inhibitory efficacy of the compounds of formula I or II. For example, the "SCCE inhibitor test" described in example 1 herein is a simple test that can make an initial assessment of the efficacy of a compound. Accordingly, preferred compounds of formula I or II for use in the methods and uses disclosed herein are compounds having an IC of less than 5 μ M when determined in the "SCCE inhibitor assay" described herein₅₀Compounds of value (v). More preferably, having an IC of less than 4 μ M when determined in the "SCCE inhibitor test" described herein₅₀A compound of value; even more preferably, having an IC of less than 3. mu.M₅₀Compounds of value, more preferably, having an IC of less than 2. mu.M₅₀Compounds having a value of less than 1 μ M IC are most preferred₅₀Compounds of value, e.g. IC₅₀The value was less than 0.5. mu.M.

In addition, the compounds of formula I or II preferred for use in the methods and uses disclosed herein are the IC's of the compounds when determined in the "SCCE inhibitor test" described herein₅₀Value and 2-phenyl-benzo [ d][1，3]IC of oxazin-4-ones₅₀The ratio between the values is less than 2.5. More preferably, the ratio is less than 2.0, even more preferably the ratio is less than 1.5, when determined in the "SCCE inhibitor test" described hereinMore preferably the ratio is less than 1.0, most preferably the ratio is less than 0.5, for example less than 0.25.

Ring systems

Formulas I and II include, but are not limited to, the following types of ring systems (all having substituents R as shown in formulas I and II)₁、R₂And R₃As defined above and in claim 1):

benzo [ d ] [1, 3] oxazin-4-one,

benzo [ e ] [1, 3] oxazin-4-one,

benzo [ d ] [1, 3] oxazine-4-thione,

3H-quinazoline-4-one,

3H-quinazoline-4-thione,

benzo [ d ] [1, 3] thiazin-4-one,

thieno [3, 2-d ] [1, 3] oxazin-4-one,

thieno [2, 3-d ] [1, 3] oxazin-4-one,

thieno [3, 2-e ] [1, 3] oxazin-4-one,

thieno [2, 3-e ] [1, 3] oxazin-4-one,

thieno [3, 2-d ] [1, 3] oxazin-4-thione,

thieno [2, 3-d ] [1, 3] oxazine-4-thione,

3H-thieno [3, 2-d ] pyrimidine-4-thione,

3H-thieno [2, 3-d ] pyrimidine-4-thione,

3H-thieno [3, 2-d ] pyrimidin-4-one,

3H-thieno [2, 3-d ] pyrimidin-4-one,

1, 6-dithia-4-aza-inden-7-one,

thieno [2, 3-d ] [1, 3] thiazin-4-one,

pyrido [2, 3-d ] [1, 3] oxazin-4-one,

pyrazino [2, 3-d ] [1, 3] oxazin-4-one,

pyrimido [4, 5-d ] [1, 3] oxazin-4-one,

pyrazolo [1, 3] oxazin-4-one,

imidazo [1, 3] oxazin-4-one,

piperidino [1, 3] oxazin-4-one,

piperazino [1, 3] oxazin-4-ones,

morpholino [1, 3] oxazin-4-one,

pyrrolidinyl [1, 3] oxazin-4-ones,

pyrrolino [1, 3] oxazin-4-one,

imidazolino [1, 3] oxazin-4-ones,

pyrazolidino [1, 3] oxazin-4-ones,

pyrano [1, 3] oxazin-4-one,

pyrido [1, 3] oxazin-4-ones,

pyridazino [1, 3] oxazin-4-ones,

pyrimido [1, 3] oxazin-4-ones,

pyrazino [1, 3] oxazin-4-one,

furo [1, 3] oxazin-4-one,

pyrrolo [1, 3] oxazin-4-one,

isoxazolo [1, 3] oxazin-4-one,

isothiazolo [1, 3] oxazin-4-ones,

furazano [1, 3] oxazin-4-one,

tetrahydrofuran-o [1, 3] oxazin-4-one,

tetrahydrothieno [1, 3] oxazin-4-one,

imidazolidino [1, 3] oxazin-4-one,

pyrazolino [1, 3] oxazin-4-one,

oxathiacyclopenta [1, 3] oxazin-4-ones,

oxazolo [1, 3] oxazin-4-one,

isothiazolo [1, 3] oxazin-4-one,

thiazolidine [1, 3] oxazin-4-one,

thiazolo [1, 3] oxazin-4-one,

oxadiazolo [1, 3] oxazin-4-ones,

thiadiazolo [1, 3] oxazin-4-ones,

5, 6, 7, 8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one,

5, 6, 7, 8-tetrahydro-1-oxa-9-thia-3-aza-fluoren-4-one,

5, 6, 7, 8-tetrahydro-3-oxa-9-thia-1-aza-fluorene-4-thione,

5, 6, 7, 8-tetrahydro-3, 9-dioxa-1-aza-fluoren-4-one,

5, 6, 7, 8-tetrahydro-3-oxa-9-aza-1-aza-fluoren-4-one,

5, 6, 7, 8-tetrahydro-3H-benzo [4, 5] thieno [2, 3-d ] pyrimidine-4-thione,

5, 6, 7, 8-tetrahydro-3H-benzo [4, 5] thieno [2, 3-d ] pyrimidin-4-one,

5, 6, 7, 8-tetrahydro-3, 9-dithia-1-aza-fluoren-4-one,

2, 3-dihydro-1H-5-oxa-8-thia-7-aza-cyclopenta [ a ] inden-4-one,

2, 3-dihydro-1H-7-oxa-8-thia-5-aza-cyclopenta [ a ] inden-4-one,

2, 3-dihydro-1H-5-oxa-8-thia-7-aza-cyclopenta [ a ] indene-4-thione,

1, 2, 3, 5-tetrahydro-8-thia-5, 7-diaza-cyclopenta [ a ] indene-4-thione,

1, 2, 3, 5-tetrahydro-8-thia-5, 7-diaza-cyclopenta [ a ] inden-4-one,

2, 3-dihydro-1H-5, 8-dithia-7-aza-cyclopenta [ a ] inden-4-one,

2, 3-dihydro-1H-5, 8-dioxa-7-aza-cyclopenta [ a ] inden-4-one,

1, 2, 3, 8-tetrahydro-5-oxa-7, 8-diaza-cyclopenta [ a ] inden-4-one,

6, 7, 8, 9-tetrahydro-5H-3-oxa-10-thia-1-aza-benzo [ a ] azulen-4-one,

6, 7, 8, 9-tetrahydro-5H-1-oxa-10-thia-3-aza-benzo [ a ] azulen-4-one,

6, 7, 8, 9-tetrahydro-5H-3-oxa-10-thia-1-aza-benzo [ a ] azulene-4-thione,

3, 5, 6, 7, 8, 9-hexahydro-10-thia-1, 3-diaza-benzo [ a ] azulene-4-thione,

3, 5, 6, 7, 8, 9-hexahydro-10-thia-1, 3-diaza-benzo [ a ] azulen-4-one,

6, 7, 8, 9-tetrahydro-5H-3, 10-dithia-1-aza-benzo [ a ] azulen-4-one,

6, 7, 8, 9-tetrahydro-5H-3, 10-dioxa-1-aza-benzo [ a ] azulen-4-one or

5, 6, 7, 8, 9, 10-hexahydro-3-oxa-1, 10-dithia-benzo [ a ] azulen-4-one.

In a preferred embodiment of the invention, ring a does not contain any heteroatoms and ring C contains at least one sulfur atom. Thus, in a preferred embodiment of the invention, the compound is a compound having the general formula Ia or IIa:

wherein

X is O or S; y is independently O, S, NH or N if the nitrogen atom is bonded to an adjacent carbon atom by a double bond; z is independently O, NH or N if the nitrogen atom is bonded to an adjacent carbon atom by a double bond; t and W are CH, CH₂Or S, wherein one of T and W is S; ring a, ring B, ring C and ring D may be aromatic, saturated or partially saturated.

More preferably, neither X, Y nor Z is sulfur, i.e., for formulas Ia and IIa above, X is O; y is independently O, NH or N if the nitrogen atom is bonded to an adjacent carbon atom by a double bond; z is independently O, NH or N if the nitrogen atom is bonded to an adjacent carbon atom by a double bond; t and W are CH, CH₂Or S, wherein one of T and W is S. In a more preferred embodiment, rings B and D do not contain two nitrogen atoms. In a more preferred embodiment, rings a and C are aromatic and rings B and D are partially saturated.

Accordingly, preferred examples of compounds having formula Ia or IIa include (R)₁、R₂、R₃As defined above):

benzo [ d ] [1, 3] oxazin-4-ones having the formula

Benzo [ e ] [1, 3] oxazin-4-ones having the formula

Thieno [3, 2-d ] [1, 3] oxazin-4-ones having the formula

Thieno [2, 3-d ] [1, 3] oxazin-4-ones having the formula

Thieno [2, 3-e ] [1, 3] oxazin-4-ones having the formula

Thieno [3, 2-e ] [1, 3] oxazin-4-ones having the formula

Isothiazolo [5, 4-d ] [1, 3] oxazin-4-ones having the formula

Pyrido [3, 4-d ] [1, 3] oxazin-4-ones having the formula

Pyrido [2, 3-d ] [1, 3] oxazin-4-ones having the formula

Pyrazino [2, 3-d ] [1, 3] oxazin-4-ones having the formula

Pyrimido [4, 5-d ] [1, 3] oxazin-4-ones having the formula

Pyrrolo [3, 4-d ] [1, 3] oxazin-4-ones having the formula

Pyrazolo [3, 4-d ] [1, 3] oxazin-4-ones having the formula

Imidazo [4, 5-d ] [1, 3] oxazin-4-ones having the formula

Pyrazolo [4, 3-d ] [1, 3] oxazin-4-ones having the formula

Furo [2, 3-d ] [1, 3] oxazin-4-ones having the formula

Furo [3, 4-d ] [1, 3] oxazin-4-ones having the formula

Furo [3, 2-d ] [1, 3] oxazin-4-ones having the formula

Among the preferred examples of compounds of formula Ia or IIa described above, the following compounds (R) are particularly preferred₁，R₂，R₃As defined above):

benzo [ d ] [1, 3] oxazin-4-ones having the formula

Benzo [ e ] [1, 3] oxazin-4-ones having the formula

Thieno [3, 2-d ] [1, 3] oxazin-4-ones having the formula

Thieno [2, 3-d ] [1, 3] oxazin-4-ones having the formula

Thieno [2, 3-e ] [1, 3] oxazin-4-ones having the formula

Thieno [3, 2-e ] [1, 3] oxazin-4-ones having the formula

Isothiazolo [5, 4-d ] [1, 3] oxazin-4-ones having the formula

Pyrazolo [3, 4-d ] [1, 3] oxazin-4-ones having the formula

R₁And R₂Substituent group

As indicated above, if R is present₁And R₂Independently, it is:

C_1-8-alkyl radical, C_2-8-alkenyl radical, C_2-8-alkynyl or C_3-6Cycloalkyl, each optionally substituted by halogen, OH, NH₂、NHR₄、N(R₄)₂、NHCOR₄、C_1-6-alkoxy, trifluoromethoxy, carbamoyl, CONHR₄Or CON (R)₄)₂Substitution; h, halogen, CF₃，C_1-6-alkoxy radical, C_1-6Alkylthio, OCF₃，COOH，CN，CONH₂，CONHR₄，OH，NO₂，NH₂，NHR₄，N(R₄)₂，NHCOR₄，NHSO₂R₄，CON(R₄)₂，CONHSO₂R₄，SO₂NH₂，SO₂NHR₄，SO₂R₄，SOR₄，C_1-4-alkoxycarbonyl, aryl, aryloxy, heteroaryl, heteroaryloxy, alkylphenyl, or tetrazole;

or when R is₁And R₂When bonded to adjacent atoms in ring A or ring C, together form- (CH)₂)_n-a moiety, wherein n-1-5, and wherein 1, 2 or 3 CH in said moiety₂The unit may optionally be replaced by 1, 2 or 3 heteroatoms, if the nitrogen atom is bonded to an adjacent atom by a double bond, wherein each heteroatom is independently selected from O, S, NH and N, and wherein said moiety may optionally be substituted by 1, 2 or 3 heteroatoms independently selected from halogen, OH, NH₂、NHR₄、N(R₄)₂、NHCOR₄、C_1-6Alkoxy, trifluoromethoxy, carbamoyl, CONHR₄Or CON (R)₄)₂Is substituted with the substituent(s).

In a preferred embodiment of the invention, R, if present₁And R₂Independently, it is optionally substituted by halogen, OH, NH₂、NHR₄、N(R₄)₂、NHCOR₄、C_1-6-alkoxy, trifluoromethoxy, carbamoyl, CONHR₄Or CON (R)₄)₂Substituted C_1-8-an alkyl group; halogen, C_1-6-an alkoxy group;

or when R is₁And R₂When bonded to adjacent atoms, together form- (CH)₂)_n-partWherein n is 3, 4 or 5, and wherein said moiety may optionally be substituted with 1, 2 or 3 substituents independently selected from halogen, OH, NH₂、NHR₄、N(R₄)₂、NHCOR₄、C_1-6Alkoxy, trifluoromethoxy, carbamoyl, CONHR₄Or CON (R)₄)₂Is substituted with the substituent(s).

For compounds of formula I or Ia, if R is present₁And R₂Most preferably it is optionally substituted by halogen, OH, NH₂、NHR₄、N(R₄)₂、NHCOR₄、C_1-6-alkoxy, trifluoromethoxy, carbamoyl, CONHR₄Or CON (R)₄)₂Substituted C_1-8-an alkyl group; halogen or C_1-6Alkoxy, especially F, Cl, Br, I, O-CH₃Or O-CH₂-CH₃E.g. Cl or O-CH₃. In one embodiment of the invention, R₁And R₂Are absent. In another embodiment of the invention, R₁And R₂Only one of which is present. In another embodiment of the invention, R₁And R₂Both are present. R is generally preferred₁And R₂Is present.

For compounds of the formula II or IIa, if R is present₁And R₂Most preferably it is optionally substituted by halogen, OH, NH₂、NHR₄、N(R₄)₂、NHCOR₄、C_1-6-alkoxy, trifluoromethoxy, carbamoyl, CONHR₄Or CON (R)₄)₂Substituted C_1-8-an alkyl group; or when R is₁And R₂When bonded to adjacent atoms, together form- (CH)₂)_n-a moiety, wherein n ═ 3, 4 or 5, and wherein said moiety may optionally be substituted with 1, 2 or 3 moieties each independently selected from halogen, OH, NH₂、NHR₄、N(R₄)₂、NHCOR₄、C_1-6Alkoxy, trifluoromethoxy, carbamoyl, CONHR₄Or CON (R)₄)₂Is substituted with the substituent(s). Specific preferred examples include-CH₃、-CH₂-CH₃And

5, 6, 7, 8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one having the formula

5, 6, 7, 8-tetrahydro-1-oxa-9-thia-3-aza-fluoren-4-one having the formula

5, 6, 7, 8-tetrahydro-3, 9-dioxa-1-aza-fluoren-4-one having the formula

5, 6, 7, 8-tetrahydro-5H-3-oxa-1, 9-diaza-fluoren-4-one having the formula

2, 9-dioxa-4-aza-fluoren-1-one having the formula

2, 3-dihydro-1H-5-oxa-8-thia-7-aza-cyclopenta [ a ] inden-4-one having the formula

2, 3-dihydro-1H-7-oxa-8-thia-5-aza-cyclopenta [ a ] inden-4-one having the formula

2, 3-dihydro-1H-5, 8-dioxa-7-aza-cyclopenta [ a ] inden-4-one having the formula

1, 2, 3, 8-tetrahydro-5-oxa-7, 8-diaza-cyclopenta [ a ] inden-4-one having the formula

6, 7, 8, 9-tetrahydro-5H-3-oxa-10-thia-1-aza-benzo [ a ] azulen-4-one having the formula

6, 7, 8, 9-tetrahydro-5H-1-oxa-10-thia-3-aza-benzo [ a ] azulen-4-one having the formula

6, 7, 8, 9-tetrahydro-5H-3, 10-dioxa-1-aza-benzo [ a ] azulen-4-one having the formula

5, 6, 7, 8, 9, 10-hexahydro-3-oxa-1, 10-diaza-benzo [ a ] azulen-4-one having the formula

Another interesting embodiment of the present invention with respect to formulae II and IIa includes wherein R₁And R₂There are no examples.

R₄Preferred examples of (b) include methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclopentyl, cyclohexyl and phenyl.

R ₃ Substituent group

As indicated above, R₃Is aryl or heteroaryl, each optionally substituted with one or more of the following groups: halogen, CF₃，C_1-6-alkoxy radical, C_1-6Alkylthio, OCF₃，COOH，CN，CONH₂，CONHR₄，OH，NO₂，NH₂，NHR₄，N(R₄)₂，NHCOR₄，NHSO₂R₄，CON(R₄)₂，CONHSO₂R₄，SO₂NH₂，SO₂NHR₄，SO₂R₄，SOR₄，C_1-4Alkoxycarbonyl, aryl, aryloxy, heteroaryl, heteroaryloxy, alkylphenyl, tetrazole, C_1-8-alkyl radical, C_2-8-alkenyl radical, C_2-8-alkynyl or C_3-6-cycloalkyl radicals, each C_1-8Alkyl radical, C_2-8-alkenyl, C_2-8-alkynyl or C_3-6-cycloalkyl is optionally substituted by: halogen, CF₃，OCF₃，COOH，CN，CONH₂，CONHR₄，CON(R₄)₂，OH，NO₂，NH₂，NHR₄，N(R₄)₂，NHCOR₄，NHSO₂R₄，SO₂NH₂，SO₂NHR₄，SO₂R₄，SOR₄，C_1-4-alkoxy, or carbamoyl.

More preferably, R₃Is phenyl, 1-naphthyl, 4-pyridyl, 2-furyl or 2-thienyl, each optionally substituted by: halogen, CF₃，OCF₃，COOH，CN，CONH₂，CONHR₄，CON(R₄)₂，OH，NO₂，NH₂，NHR₄，N(R₄)₂，NHCOR₄，NHSO₂R₄，SO₂NH₂，SO₂NHR₄，SO₂R₄，SOR₄，C_1-4Alkoxy, or carbamoyl; halogen, CF₃，C_1-6-alkoxy radical, C_1-6Alkylthio, OCF₃，COOH，CN，CONH₂，CONHR₄，OH，NO₂，NH₂，NHR₄，N(R₄)₂，NHCOR₄，NHSO₂R₄，CON(R₄)₂，CONHSO₂R₄，SO₂NH₂，SO₂NHR₄，SO₂R₄，SOR₄，C_1-4-alkoxycarbonyl, aryl, aryloxy, heteroaryl, heteroaryloxy, alkylphenyl, or tetrazole; specific examples of the preferred substituted aryl or heteroaryl group include a phenyl group, a 2-fluorophenyl group, a 2-chlorophenyl group, a 2-iodophenyl group, a 2-methoxyphenyl group, a 3-methoxyphenyl group, a 2-hydroxyphenyl group, a 1-naphthyl group, a 2-tolyl group, a 2-chloro-4-nitrophenyl group, a 2-chloro-5-nitrophenyl group, a 4-fluorophenyl group, a 4-bromo-phenyl group, a 2-thienyl group, a 2-furyl group and a 4-pyridyl group.

Generally, it is preferred that the aryl or heteroaryl group is substituted with at least one electron withdrawing group, such as fluorine, chlorine; NO₂、CF₃And OCF₃. Most preferred are chlorine and fluorine, especially chlorine. Moreover, R is preferred₃Is ortho-substituted aryl (mono-or disubstituted) or heteroarylAnd (4) a ring. Preferred ortho substituents are: fluorine, chlorine, iodine, bromine, methyl, methoxy, hydroxy, acetoxy, or NHSO₂-an aryl group.

Examples of specific and preferred compounds

Specific examples of preferred compounds of formula I suitable for the purposes described herein include:

2-phenyl-benzo [ d ] [1, 3] oxazin-4-one (I-1)

7-chloro-2- (2-chloro-4-nitro-phenyl) -benzo [ d ] [1, 3] oxazin-4-one (I-2)

2- (2-iodophenyl) -6, 7-dimethoxy-benzo [ d ] [1, 3] oxazin-4-one (I-3)

7-chloro-2-thiophen-2-yl-benzo [ d ] [1, 3] oxazin-4-one (I-4)

2- (2-chloro-4-nitro-phenyl) -6, 7-dimethoxy-benzo [ d ] [1, 3] oxazin-4-one (I-5)

2- (2-chloro-5-nitro-phenyl) -benzo [ d ] [1, 3] oxazin-4-one (I-6)

5, 7-dichloro-2- (dimethylamino-benzo [ d ] [1, 3] oxazin-4-one (I-7)

2-pyridin-4-yl-benzo [ d ] [1, 3] oxazin-4-one (I-8)

2-thiophen-2-yl-benzo [ d ] [1, 3] oxazin-4-one (I-9)

2- (2-hydroxy-phenyl) -benzo [ d ] [1, 3] oxazin-4-one (I-10)

2- (2-fluoro-phenyl) -6, 7-dimethoxy-benzo [ d ] [1, 3] oxazin-4-one (I-11)

7-chloro-2- (4-ethyl-phenyl) benzo [ d ] [1, 3] oxazin-4-one (I-12)

7-chloro-2- (3-methyl-4-nitro-phenyl) -benzo [ d ] [1, 3] oxazin-4-one (I-13)

N- [4- (6, 7-dimethoxy-4-oxo-4H-benzo [ d ] [1, 3] oxazin-2-yl) -phenyl ] -acetamide (I-14)

Acetic acid 4- (4-oxo-4H-benzo [ d ] [1, 3] oxazin-2-yl) -phenyl ester (I-15)

2- (2-chlorophenyl) -6, 7-dimethoxy-benzo [ d ] [1, 3] oxazin-4-one (I-16)

6-chloro-2-thiophen-2-yl-benzo [ e ] [1, 3] oxazin-4-one (I-17)

6-chloro-2-furan-2-yl-benzo [ e ] [1, 3] oxazin-4-one (I-18)

2- (2-chlorophenyl) -benzo [ e ] [1, 3] oxazin-4-one (I-19)

2-thiophen-2-yl-benzo [ e ] [1, 3] oxazin-4-one (I-20)

2-furan-2-yl-benzo [ e ] [1, 3] oxazin-4-one (I-21)

Examples of particularly preferred compounds of formula I include:

7-chloro-2- (2-chloro-4-nitro-phenyl) -benzo [ d ] [1, 3] oxazin-4-one (I-2)

2- (2-iodophenyl) -6, 7-dimethoxy-benzo [ d ] [1, 3] oxazin-4-one (I-3)

7-chloro-2-thiophen-2-yl-benzo [ d ] [1, 3] oxazin-4-one (I-4)

2- (2-chloro-5-nitro-phenyl) -benzo [ d ] [1, 3] oxazin-4-one (I-6)

2- (2-fluoro-phenyl) -6, 7-dimethoxy-benzo [ d ] [1, 3] oxazin-4-one (I-11)

2- (2-chlorophenyl) -6, 7-dimethoxy-benzo [ d ] [1, 3] oxazin-4-one (I-16)

6-chloro-2-thiophen-2-yl-benzo [ e ] [1, 3] oxazin-4-one (I-17)

6-chloro-2-furan-2-yl-benzo [ e ] [1, 3] oxazin-4-one (I-18)

Preferred compounds of formula II are:

6-Ethyl-2- (2-fluoro-phenyl) -thieno [2, 3-d ] [1, 3] oxazin-4-one (II-1)

6-methyl-2-naphthalen-1-yl-thieno [2, 3-d ] [1, 3] oxazin-4-one (II-2)

6-Ethyl-2-o-tolyl-thieno [2, 3-d ] [1, 3] oxazin-4-one (II-3)

6-Ethyl-2- (4-fluoro-phenyl) -thieno [2, 3-d ] [1, 3] oxazin-4-one (II-4)

2- (2-chloro-phenyl) -4H-thieno [3, 2-d ] [1, 3] oxazin-4-one (II-5)

2-phenyl-4H-thieno [3, 2-d ] [1, 3] oxazin-4-one (II-6)

2-furan-2-yl-5, 6-dimethyl-thieno [2, 3-d ] [1, 3] oxazin-4-one (II-7)

2- (4-fluoro-phenyl) -4H-thieno [3, 2-d ] [1, 3] oxazin-4-one (II-8)

2- (4-bromo-phenyl) -6-ethyl-thieno [2, 3-d ] [1, 3] oxazin-4-one (II-9)

6- (2-chloro-phenyl) -2, 3-dihydro-1H-5-oxa-8-thia-7-aza-cyclopenta [ a ] inden-4-one (II-10)

6-Furan-2-yl-2, 3-dihydro-1H-5-oxa-8-thia-7-aza-cyclopenta [ a ] inden-4-one (II-11)

6-phenyl-2, 3-dihydro-1H-5-oxa-8-thia-7-aza-cyclopenta [ a ] inden-4-one (II-12)

6- (4-fluoro-phenyl) -2, 3-dihydro-1H-5-oxa-8-thia-7-aza-cyclopenta [ a ] inden-4-one (II-13)

6-thiophen-2-yl-2, 3-dihydro-1H-5-oxo-8-thia-7-aza-cyclopenta [ a ] inden-4-one (II-14)

2- (2-fluoro-phenyl) -5, 6, 7, 8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one (II-15)

2- (2-methoxy-phenyl) -5, 6, 7, 8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one (II-16)

2-phenyl-5, 6, 7, 8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one (II-17)

2-naphthalen-1-yl-5, 6, 7, 8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one (II-18)

2-thiophen-2-yl-5, 6, 7, 8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one (II-19)

2- (3-methoxy-phenyl) -5, 6, 7, 8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one (II-20)

2-pyridin-4-yl-6, 7, 8, 9-tetrahydro-5H-3-oxa-10-thia-1-aza-benzo [ a ] azulen-4-one (II-21)

Examples of particularly preferred compounds of formula II include:

6-Ethyl-2- (2-fluoro-phenyl) -thieno [2, 3-d ] [1, 3] oxazin-4-one (II-1)

6-methyl-2-naphthalen-1-yl-thieno [2, 3-d ] [1, 3] oxazin-4-one (II-2)

6-Ethyl-2-o-tolyl-thieno [2, 3-d ] [1, 3] oxazin-4-one (II-3)

6-Ethyl-2- (4-fluoro-phenyl) -thieno [2, 3-d ] [1, 3] oxazin-4-one (II-4)

2- (2-chloro-phenyl) -4H-thieno [3, 2-d ] [1, 3] oxazin-4-one (II-5)

6-thiophen-2-yl-2, 3-dihydro-1H-5-oxa-8-thia-7-aza-cyclopenta [ a ] inden-4-one (II-14)

2-phenyl-5, 6, 7, 8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one (II-17)

Preparation of

The compounds of the formulae I and II can be prepared from compounds of the formulae III or IV or V/VI or VII or VIII by the following process:

method a):

1) reacting a compound of formula III

And formula R₃Compound reaction of COL; r₁，R₂，R₃Z, X, Y, W, Q, V and T have the meanings described above, L is a leaving group such as halogen, sulfate or acyl, forming structure IV;

2) reacting a compound of formula IV

Wherein R is₁，R₂，R₃Z, X, Y, W, Q, V and T, as defined above, with a reagent capable of causing ring closure to form the structure of formula I. The reagent may be a carboxylic acid anhydride such as acetic anhydride, concentrated sulfuric acid, POCl₃、P₂O₅、CF₃COOH, or similar agents.

Method B):

1) reacting a compound of formula III

And formula R₃Reacting compounds of COOH; r₁，R₂，R₃Z, X, Y, W, Q, V and T have the meanings as described above; structure IV is formed using standard coupling reagents suitable for forming amide bonds from acids or activated acids and amines, such as HOBt or carbodiimides such as DCC or EDAC, or similar reagents;

2) reacting a compound of formula IV

Wherein R is₁，R₂，R₃Z, X, Y, W, Q, V and T are as defined above, with a reagent capable of causing ring closure to form the structure of formula I. The reagent may be a carboxylic acid anhydride such as acetic anhydride, concentrated sulfuric acid, POCl₃、P₂O₅、CF₃COOH, or similar agents.

Method C):

reacting a compound of formula IV

Method D):

reacting a compound of formula V

Wherein R is₁，R₂，R₃Z, X, Y, W, Q, V and T are as defined above, and R5 is C_1-8Alkyl, with agents capable of causing ring closure, e.g. concentrated H₂SO₄Or PPh₃/Et₃N/C₂Cl₄Br₂Or similar reagents which, under the action of water absorption, can cause a combined hydrolysis and ring closure to form the compound of structure I.

Method E):

1) reacting a compound of formula VI

And formula R₃Compound reaction of COL; r₁，R₂，R₃Z, X, Y, W, Q and T have the meanings described above, L is a leaving group such as halogen, sulfate or acyl, forming structure VII;

2) reacting a compound of formula VII

Wherein R is₁，R₂，R₃Z, X, Y, W, Q and T are as defined above, with a reagent capable of causing ring closure to form the structure of formula II. Such reagents may be carboxylic acid anhydrides such as acetic anhydride, concentrated sulfuric acid,POCl₃、P₂O₅、CF₃COOH, or similar agents.

Method F):

1) reacting a compound of formula VI

And formula R₃Reacting compounds of COOH; r₁，R₂，R₃Z, X, Y, W, Q and T have the meanings as described above; formation of structure VII using standard coupling reagents suitable for formation of amide bonds from acids or activated acids and amines, such as HOBt or carbodiimides such as DCC or EDAC, or similar reagents;

2) reacting a compound of formula VII

Wherein R is₁，R₂，R₃Z, X, Y, W, Q and T are as defined above, with a reagent capable of causing ring closure to form the structure of formula II. The reagent may be a carboxylic acid anhydride such as acetic anhydride, concentrated sulfuric acid, POCl₃、P₂O₅、CF₃COOH, or similar agents.

Method G):

reacting a compound of formula VII

Method H):

reacting a compound of formula VIII

Wherein R is₁，R₂，R₃Z, X, Y, W, Q and T are as defined above, and R₅Is C_1-8Alkyl, with agents capable of causing ring closure, e.g. concentrated H₂SO₄Or PPh₃/Et₃N/C₂Cl₄Br₂Or similar reagents which, under the action of water absorption, can cause a combined hydrolysis and ring closure to form the compound of structure II.

Examples of synthetic methods as described above are known to the person skilled in the art and are described many times in the literature; see, for example:

papadopoulos and c.d. torres: heterocycles 19 (6)1039-1042, 1982;

j.l.gilmore et al: bioorganic and medicinal chemical letters 6(6), 679-682, 1996;

M Davies，R.J.Hook，Wen Yang Wu：J Heterocyclic Chem 21369-373，1984；

G.Hamprecht，B.Wuerzer：US 4,315,766，1982；

H.Wamhoff；E.Kroth：Synthesis 405，1994。

examples of the synthesis of the following compounds of the general formula I are described in WO 99/48878. These compounds are examples of compounds of the general formula I which can be used according to the invention:

5, 8-dichloro-2- (2-fluoro-phenyl) -4H-3, 1-benzoxazin-4-one,

6-methyl-2-thiophen-2-yl-4H-3, 1-benzoxazine-4-one,

(2, 6-diamino-phenyl) -6-methyl-4H-3, 1-benzoxazin-4-one,

6-methyl-2- (2-trifluoromethoxy-phenyl) -4H-3, 1-benzoxazine-4-one,

(2, 6-difluoro-phenyl) -6-methyl-4H-3, 1-benzoxazin-4-one,

(2, 6-dimethoxy-phenyl) -6-methyl-4H-3, 1-benzoxazin-4-one,

(3-bromo-thiophen-2-yl) -6-methyl-4H-3, 1-benzoxazin-4-one,

(2, 3-dichloro-phenyl) -6-methyl-4H-3, 1-benzoxazin-4-one,

2- (2, 6-difluoro-phenyl) -6-nitro-benzo [ d ] [1, 3] oxazin-4-one,

6-acetylamino- (2, 6-difluoro-phenyl) -benzo [ d ] [1, 3] oxazin-4-one,

2- (2, 6-difluoro-phenyl) -5-methyl-benzo [ d ] [1, 3] oxazin-4-one,

2- (2, 6-difluoro-phenyl) -7-nitro-benzo [ d ] [1, 3] oxazin-4-one,

2- (2, 6-difluoro-phenyl) -5-nitro-benzo [ d ] [1, 3] oxazin-4-one,

5-chloro-2- (2, 6-difluoro-phenyl) -benzo [ d ] [1, 3] oxazin-4-one,

6-amino-2- (2, 6-difluoro-phenyl) -benzo [ d ] [1, 3] oxazin-4-one,

2- (2, 6-difluoro-phenyl) -8-hydroxy-benzo [ d ] [1, 3] oxazin-4-one,

5, 8-dichloro-2- (2, 6-difluoro-phenyl) -benzo [ d ] [1, 3] oxazin-4-one,

5-amino-2- (2, 6-difluoro-phenyl) -benzo [ d ] [1, 3] oxazin-4-one,

2- (2, 6-difluoro-phenyl) -6, 7-difluoro-benzo [ d ] [1, 3] oxazin-4-one,

7-amino-2- (2, 6-difluoro-phenyl) -benzo [ d ] [1, 3] oxazin-4-one,

2- (2, 6-difluoro-phenyl) -6-methoxy-benzo [ d ] [1, 3] oxazin-4-one,

2- (2-fluoro-phenyl) -6-methoxy-benzo [ d ] [1, 3] oxazin-4-one,

2- (2, 6-difluoro-phenyl) -7-trifluoromethyl-benzo [ d ] [1, 3] oxazin-4-one,

6, 7-difluoro-2- (2-fluoro-phenyl) -benzo [ d ] [1, 3] oxazin-4-one,

6, 7-difluoro-2-thiophen-2-yl-benzo [ d ] [1, 3] oxazin-4-one,

6, 7-difluoro-2-furan-2-yl-benzo [ d ] [1, 3] oxazin-4-one,

2- (2-methoxy-phenyl) -6-nitro-benzo [ d ] [1, 3] oxazin-4-one,

2- (2-methoxy-phenyl) -5-methyl-benzo [ d ] [1, 3] oxazin-4-one,

2- (2-methoxy-phenyl) -5-nitro-benzo [ d ] [1, 3] oxazin-4-one,

6-nitro-2- (2-nitro-phenyl) -benzo [ d ] [1, 3] oxazin-4-one,

6-nitro-2-o-tolyl-benzo [ d ] [1, 3] oxazin-4-one,

5-nitro-2- (2-nitro-phenyl) -benzo [ d ] [1, 3] oxazin-4-one,

2- (2-chloro-pyridin-3-yl) -6-nitro-benzo [ d ] [1, 3] oxazin-4-one,

2- (2-chloro-pyridin-3-yl) -5-methyl-benzo [ d ] [1, 3] oxazin-4-one,

2- (2-chloro-pyridin-3-yl) -5-nitro-benzo [ d ] [1, 3] oxazin-4-one,

2- (2, 3-difluorophenyl) -6-nitro-benzo [ d ] [1, 3] oxazin-4-one,

2- (2, 3-difluoro-phenyl) -5-methyl-benzo [ d ] [1, 3] oxazin-4-one,

2- (2, 3-difluoro-phenyl) -5-nitro-benzo [ d ] [1, 3] oxazin-4-one,

2- (2, 6-difluoro-phenyl) -6-trifluoromethyl-benzo [ d ] [1, 3] oxazin-4-one,

2- (2-fluoro-phenyl) -6-trifluoromethyl-benzo [ d ] [1, 3] oxazin-4-one,

2-thiophen-2-yl-6-trifluoromethyl-benzo [ d ] [1, 3] oxazin-4-one,

2- (2, 6-difluoro-phenyl) -5-trifluoromethyl-benzo [ d ] [1, 3] oxazin-4-one,

2- (2-fluoro-phenyl) -5-trifluoromethyl-benzo [ d ] [1, 3] oxazin-4-one,

2-thiophen-2-yl-5-trifluoromethyl-benzo [ d ] [1, 3] oxazin-4-one,

2- (2, 6-difluoro-phenyl) -8-trifluoromethyl-benzo [ d ] [1, 3] oxazin-4-one,

2- (2-fluoro-phenyl) -8-trifluoromethyl-benzo [ d ] [1, 3] oxazin-4-one,

2-furan-2-yl-8-trifluoromethyl-benzo [ d ] [1, 3] oxazin-4-one,

2- (2, 6-difluoro-phenyl) -7-fluoro-benzo [ d ] [1, 3] oxazin-4-one,

5-nitro-2- (5-nitro-furan-2-yl) -benzo [ d ] [1, 3] oxazin-4-one,

2- (2, 3-dichloro-phenyl) -6, 7-difluoro-benzo [ d ] [1, 3] oxazin-4-one,

6, 7-difluoro-2- (2-trifluoromethoxy-phenyl) -benzo [ d ] [1, 3] oxazin-4-one,

2- (2, 3-difluoro-phenyl) -6, 7-difluoro-benzo [ d ] [1, 3] oxazin-4-one,

6, 7-difluoro-2- (2-methoxy-phenyl) -benzo [ d ] [1, 3] oxazin-4-one,

2- (2-chloro-pyridin-3-yl) -6, 7-difluoro-benzo [ d ] [1, 3] oxazin-4-one,

2- (2, 6-difluoro-phenyl) -4-oxo-4H-benzo [ d ] [1, 3] oxazine-5-carboxylic acid methyl ester,

2- (2-fluoro-phenyl) -4-oxo-4H-benzo [ d ] [1, 3] oxazine-5-carboxylic acid methyl ester,

4-oxo-2-thiophen-2-yl-4H-benzo [ d ] [1, 3] oxazine-5-carboxylic acid methyl ester,

2-furan-2-yl-4-oxo-4H-benzo [ d ] [1, 3] oxazine-5-carboxylic acid methyl ester,

2- (2-fluoro-phenyl) -4-oxo-4H-benzo [ d ] [1, 3] oxazine-5-carboxylic acid ethyl ester,

acetic acid 2- (6-nitro-4-oxo-4H-benzo [ d ] [1, 3] oxazin-2-yl) -phenyl ester,

acetic acid 2- (5-methyl-4-oxo-4H-benzo [ d ] [1, 3] oxazin-2-yl) -phenyl ester,

acetic acid 2- (5-nitro-4-oxo-4H-benzo [ d ] [1, 3] oxazin-2-yl) -phenyl ester.

Examples of the synthesis of the following compounds of the general formula I are described in WO 00/30646. These compounds are examples of compounds of the general formula I which can be used according to the invention:

2- (2-fluorophenyl) -4H-pyrido [2, 3-d ] [1, 3] oxazin-4-one,

2- (2, 6-difluorophenyl) -4H-pyrido [2, 3-d ] [1, 3] oxazin-4-one,

7- (ethylsulfanyl) -2- (2-fluorophenyl) -4H-pyrimido [4, 5-d ] [1, 3] oxazin-4-one,

7- (ethylsulfanyl) -2- (2-methylphenyl) -4H-pyrimido [4, 5-d ] [1, 3] oxazin-4-one,

2- (2-chlorophenyl) -7- (ethylthio) -4H-pyrimido [4, 5-d ] [1, 3] oxazin-4-one.

Examples of the synthesis of compounds of the general formula II below are described in WO 00/30646. These compounds are examples of compounds of the general formula II which can be used according to the invention:

2- (2, 6-difluoro-phenyl) -7-methyl-thieno [3, 2-d ] [1, 3] oxazin-4-one,

5-methyl-2- (2-nitro-phenyl) -thieno [2, 3-d ] [1, 3] oxazin-4-one,

2-furan-2-yl-thieno [2, 3-d ] [1, 3] oxazin-4-one,

2-thiophen-2-yl-thieno [2, 3-d ] [1, 3] oxazin-4-one,

1-methyl-6- (2-nitrophenyl) -pyrazolo [3, 4-d ] [1, 3] oxazin-4 (1H) -one,

6- (2-fluorophenyl) -1-methyl-pyrazolo [3, 4-d ] [1, 3] oxazin-4 (1H) -one,

1-methyl-6- (2-methylphenyl) -pyrazolo [3, 4-d ] [1, 3] oxazin-4 (1H) -one.

Some of the structures described in this invention are commercially available from companies that sell specific chemicals. Examples of companies are e.g. Key Organics, Chemical university, Sigma-Aldrich, Maybridge, Specs, CSC and Merlin Chemicals.

The following are examples of compounds of formula I:

2- (2, 5-dimethyl-benzofuran-7-yl) -4H-3, 1-benzoxazine-4-one,

2- (3-bromo-phenyl) -4H-3, 1-benzoxazin-4-one,

2- (3-bromo-phenyl) -7-chloro-4H-3, 1-benzoxazin-4-one,

2- (2, 4-dichloro-phenyl) -4H-3, 1-benzoxazin-4-one,

2- (2-fluoro-phenyl) -6-methyl-3, 1-benzoxazin-4-one,

naphthalene-2-sulfinic acid [2- (4-oxo-4H-3, 1-benzoxazin-2-yl) -phenyl ] -amide,

2- (4-chloro-3-nitro-phenyl) -6, 7-dimethoxy-4H-3, 1-benzoxazine-4-one,

2- (5-chloro-2-methoxy-phenyl) -4H-3, 1-benzoxazine-4-one,

6-bromo (5-chloro-2-methoxy-phenyl) -4H-3, 1-benzoxazin-4-one,

2- (3, 4-dichloro-phenyl) -6, 7-dimethoxy-4H-3, 1-benzoxazin-4-one,

2- (3, 4-dimethyl-phenyl) -4H-3, 1-benzoxazin-4-one,

7-chloro-2- (4-methyl-3-nitro-phenyl) -4H-3, 1-benzoxazine-4-one,

6, 7-dimethoxy-2-p-tolyl-4H-3, 1-benzoxazine-4-one,

2-phenyl-4H-3, 1-benzoxazine-4-one,

6, 7, 8-trimethoxy-2- (3-trifluoromethyl-phenyl) -4H-3, 1-benzoxazin-4-one,

6, 7-dimethoxy-2- [2- (4-methoxy-phenoxy) -5-nitro-phenyl ] -4H-3, 1-benzoxazin-4-one,

5-chloro-2- [2- (4-methoxy-phenoxy) -5-nitro-phenyl ] -4H-3, 1-benzoxazin-4-one,

2- (4-tert-butyl-phenyl) -7-chloro-4H-3, 1-benzoxazin-4-one,

7-chloro-2-m-tolyl-4H-3, 1-benzoxazine-4-one,

6, 7-dimethoxy-2- (5-methyl-2-nitro-phenyl) -4H-3, 1-benzoxazine-4-one,

7-chloro-2- (4-chloro-3-nitro-phenyl) -4H-3, 1-benzoxazin-4-one,

2- (3, 4-dimethyl-phenyl) -6, 7-dimethoxy-4H-3, 1-benzoxazin-4-one,

7-chloro-2- [4- (5-ethyl-pyridin-2-yl) -phenyl ] -4H-3, 1-benzoxazin-4-one,

2- (4-chloro-3-nitrophenyl) -6, 7, 8-trimethoxy-4H-3, 1-benzoxazin-4-one,

2- (2, 6-difluorophenyl) -5-fluoro-4H-3, 1-benzoxazin-4-one,

2- (2-fluorophenyl) -4H-3, 1-benzoxazine-4-one,

5-chloro-2- (3-trifluoromethylphenyl) -4H-3, 1-benzoxazine-4-one,

2- (3, 4-dichloro-phenyl) -6-nitro-4H-3, 1-benzoxazin-4-one,

2- (2-chloro-6-fluorophenyl) -5-fluoro-3, 1-benzoxazine-4-one,

7-chloro-2- (2-fluorophenyl) -3, 1-benzoxazine-4-one,

2- (2-chloro-6-fluorophenyl) -6-methyl-4H-3, 1-benzoxazine-4-one,

2- (2- (4-fluorophenylsulfonyl) amidophenyl) -4H-3, 1-benzoxazin-4-one,

2- (2-bromo-5-methoxy-phenyl) -4H-3, 1-benzoxazin-4-one,

2- (2-chloromethyl-phenyl) -4H-3, 1-benzoxazine-4-one,

2- (4-tert-butyl-phenyl) -6, 8-dimethyl-4H-3, 1-benzoxazin-4-one,

2- (2-chloro-phenyl) -6-methyl-4H-3, 1-benzoxazin-4-one,

7-chloro-2- (3-chloromethyl-phenyl) -4H-3, 1-benzoxazine-4-one,

2- (2-chloro-phenyl) -6-iodo-4H-3, 1-benzoxazin-4-one,

7-chloro-2- (2-chloro-5-nitro-phenyl) -4H-3, 1-benzoxazin-4-one,

2- (2-bromo-phenyl) -6-chloro-4H-3, 1-benzoxazin-4-one,

6, 7-dimethoxy-2- (3-nitro-phenyl) -4H-3, 1-benzoxazine-4-one,

2- (3-nitro-phenyl) -4H-3, 1-benzoxazine-4-one,

7-chloro-2- (2, 4-dichlorophenyl) -4H-3, 1-benzoxazine-4-one,

2- (2, 4-dichloro-phenyl) -6-iodo-4H-3, 1-benzoxazin-4-one,

6-bromo-2- (3-chloro-5-trifluoromethyl-pyridin-2-yl) -4H-3, 1-benzoxazin-4-one,

6- (6, 7-dimethoxy-4-oxo-4H-3, 1-benzoxazin-2-yl) -pyridine-2-carboxylic acid methyl ester,

6, 7-dimethoxy-2-pyridin-4-yl-4H-3, 1-benzoxazin-4-one,

6-bromo-2-pyridin-4-yl-4H-3, 1-benzoxazin-4-one,

5-fluoro-2- (2-phenoxy-pyridin-3-yl) -4H-3, 1-benzoxazin-4-one,

6, 7, 8-trimethoxy-2- (2-phenoxy-pyridin-3-yl) -4H-3, 1-benzoxazin-4-one,

2- (3-chloro-5-trifluoromethyl-pyridin-2-yl) -6, 7-dimethoxy-4H-3, 1-benzoxazin-4-one,

2-thiophen-2-yl-4H-3, 1-benzoxazin-4-one,

6, 7, 8-trimethoxy-2- (5-nitro-furan-2-yl) -4H-3, 1-benzoxazine-4-one,

6-methyl-2- (5-nitro-furan-2-yl) -4H-3, 1-benzoxazine-4-one,

5, 8-dichloro-2- (2-fluoro-phenyl) -4H-3, 1-benzoxazin-4-one,

6-methyl-2-thiophen-2-yl-4H-3, 1-benzoxazine-4-one,

2- (2, 6-dichloro-phenyl) -6-methyl-4H-3, 1-benzoxazin-4-one,

6-methyl-2- (2-trifluoromethoxy-phenyl) -4H-3, 1-benzoxazine-4-one,

2- (2, 6-difluoro-phenyl) -6-methyl-4H-3, 1-benzoxazin-4-one,

2- (2, 6-dimethoxy-phenyl) -6-methyl-4H-3, 1-benzoxazine-4-one,

2- (3-bromo-thiophen-2-yl) -6-methyl-4H-3, 1-benzoxazin-4-one,

2- (2, 3-dichloro-phenyl) -6-methyl-4H-3, 1-benzoxazin-4-one,

2- (2, 4-dichloro-phenyl) -6-nitro-benzo [ d ] [1, 3] oxazin-4-one,

6, 8-dibromo-2- (2-fluoro-phenyl) -benzo [ d ] [1, 3] oxazin-4-one,

7-chloro-2- (2-chloromethyl-phenyl) -4H-3, 1-benzoxazine-4-one,

2- (4-chloro-phenyl) -6, 7-dimethoxy-4H-3, 1-benzoxazin-4-one,

2- (3-tolyl) -4H-3, 1-benzoxazine-4-one,

2- (4-fluoro-phenyl) -4H-3, 1-benzoxazin-4-one,

2- (4-chloro-phenyl) -4H-3, 1-benzoxazin-4-one,

6, 7-dibromo-2-phenyl-4H-3, 1-benzoxazine-4-one,

2- (2-iodo-phenyl) -4H-3, 1-benzoxazin-4-one,

2- (3, 4, 5-trimethoxy-phenyl) -4H-3, 1-benzoxazin-4-one,

7-chloro-2- (3-methoxy-phenyl) -4H-3, 1-benzoxazine-4-one,

7-chloro-2- (4-nitro-phenyl) -4H-3, 1-benzoxazine-4-one,

2- (4- (tert-butyl) -phenyl) -4H-3, 1-benzoxazin-4-one,

2- (3-chloro-phenyl) -4H-3, 1-benzoxazin-4-one,

2- (2-chloro-4-nitro-phenyl) -4H-3, 1-benzoxazine-4-one,

2- (4-chloro-2-nitro-phenyl) -4H-3, 1-benzoxazine-4-one,

2- (2-chloro-3, 5-dinitro-phenyl) -4H-3, 1-benzoxazine-4-one,

2- (3, 5-dinitro-2-methyl-phenyl) -4H-3, 1-benzoxazine-4-ketone,

2- (3, 4-dichloro-phenyl) -6-methyl-4H-3, 1-benzoxazin-4-one,

2- (2, 4-dinitro-phenyl) -4H-3, 1-benzoxazine-4-ketone,

2- (3-chloro-phenyl) -6-methyl-4H-3, 1-benzoxazin-4-one,

6-methyl-2- (4-nitro-phenyl) -4H-3, 1-benzoxazine-4-one,

6-methyl-2-phenyl-4H-3, 1-benzoxazine-4-one,

2- (3-methyl-4-nitro-phenyl) -4H-3, 1-benzoxazine-4-one,

2- (4-chloro-3-nitro-phenyl) -4H-3, 1-benzoxazine-4-one,

6-methyl-2- (3-tolyl) -4H-3, 1-benzoxazine-4-one,

2- (2-tolyl) -4H-3, 1-benzoxazin-4-one,

2- (3, 5-dinitro-phenyl) -4H-3, 1-benzoxazine-4-ketone,

2- (4-tolyl) -4H-3, 1-benzoxazine-4-one,

2- (4-chloro-phenyl) -6-methyl-4H-3, 1-benzoxazin-4-one,

2- (4-nitro-phenyl) -4H-3, 1-benzoxazine-4-one,

2- (4-ethoxy-phenyl) -4H-3, 1-benzoxazin-4-one,

2- (4-methyl-3-nitro-phenyl) -4H-3, 1-benzoxazine-4-one,

6, 8-dichloro-2-thiophen-2-yl-benzo [ d ] [1, 3] oxazin-4-one.

The following are examples of compounds of formula II:

2-tert-butyl-5, 6, 7, 8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one,

2- (4-bromo-phenyl) -5, 6, 7, 8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one,

2- (4-methoxy-phenyl) -5, 6, 7, 8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one,

2- (2-methoxy-phenyl) -5, 6, 7, 8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one,

2-methyl-5-thiophen-2-yl-thieno [2, 3-d ] [1, 3] oxazin-4-one,

2-furan-2-yl-5-thiophen-2-yl-thieno [2, 3-d ] [1, 3] oxazin-4-one,

2- (2-bromo-phenyl) -5, 6, 7, 8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one,

2-methyl-5, 6, 7, 8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one,

2- (4-chloro-phenyl) -5, 6-dimethyl-thieno [2, 3-d ] [1, 3] oxazin-4-one,

2-phenyl-5, 6, 7, 8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one,

2- (3-trifluoromethyl-phenyl) -thieno [3, 2-d ] [1, 3] oxazin-4-one,

2, 5-diphenyl-4H-thieno [2, 3-d ] [1, 3] oxazin-4-one,

8-chloro-2-phenyl-4H-benzofuro [3, 2-d ] [1, 3] oxazin-4-one,

2- [4- (trifluoromethyl) phenyl 1-4H-benzofuro [3, 2-d ] [1, 3] oxazin-4-one,

6- (2-methylphenyl) -1-phenyl-pyrazolo [3, 4-d ] [1, 3] oxazin-4 (1H) -one,

6- (2-fluorophenyl) -1-phenyl-pyrazolo [3, 4-d ] [1, 3] oxazin-4 (1H) -one,

6- (2-chlorophenyl) -1-phenyl-pyrazolo [3, 4-d ] [1, 3] oxazin-4 (1H) -one.

Salts and hydrates of compounds

Within the scope of the present invention, the compounds of the general formulae I and II can be prepared in the form of pharmaceutically acceptable salts, in particular acid addition salts, including salts of organic and inorganic acids. Examples of such salts include salts of organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, ascorbic acid, pamoic acid, methanesulfonic acid, malonic acid, and the like. Suitable inorganic acid addition salts include salts of hydrochloric, hydrobromic, sulfuric, and phosphoric acids, and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include pharmaceutically acceptable salts listed in Journal of pharmaceutical science, 66, 2(1977), which are known to the skilled person.

Also useful as pharmaceutically acceptable acid addition salts are the hydrates which the compounds currently available are able to form.

The acid addition salts may be obtained as the direct product of the synthesis of the compounds. In the alternative, the free base may be dissolved in a suitable solvent containing a suitable acid and the salt separated by evaporation of the solvent, or in other words, the salt and the solvent are separated.

The compounds of the invention may form solvates with standard low molecular weight solvents using methods known to the skilled person. The compounds of formula I and II may be administered in the form of pharmaceutically acceptable acid addition salts or in the form of suitable alkali or alkaline earth metal or lower alkyl ammonium salts. It is believed that such salt forms may exhibit approximately the same level of activity as the free base form.

Pharmaceutical composition and use

In another aspect, the present invention includes within its scope a pharmaceutical composition comprising as an active ingredient at least one compound having the general formulae I and II or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

The compounds having the general formulas I and II can be formulated into pharmaceutical compositions comprising the compounds and a pharmaceutically acceptable carrier or diluent.

Such carriers include water, physiological saline, ethanol, polyols, e.g., glycerol or propylene glycol, or vegetable oils. As used herein, "pharmaceutically acceptable carrier" also includes any carrier, along with all other solvents, dispersion media, coatings, antifungals, preservatives, isotonic agents and the like. Except insofar as any conventional media is incompatible with the active ingredient and its intended use, it is contemplated that any conventional media may be used in the compositions of the present invention.

Compositions containing compounds of formula I and II may be prepared by conventional techniques and presented in conventional forms, for example, capsules, tablets, solutions or suspensions. The pharmaceutical carrier employed may be a conventional solid or liquid carrier. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water. Similarly, the carrier or diluent may include any time delay material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or with a paraffin wax. The formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents. The formulations of the present invention may be formulated so as to provide rapid, sustained, or delayed release of the active ingredient after administration to the patient, using methods well known in the art.

The pharmaceutical compositions can be sterilized and, if desired, mixed with auxiliaries which do not react deleteriously with the active compounds, emulsifiers, salts for varying the osmotic pressure, buffers and/or colouring substances and the like.

The route of administration may be any route which is effective in delivering the active compound to the appropriate or desired site of action, for example topical, oral or parenteral routes, for example rectal, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solutions or ointments, preferably oral routes.

If a solid carrier for oral administration is used, the preparation may be in the form of a tablet, put into a hard capsule in the form of powder or pellets, or it may be in the form of a troche or lozenge.

The amount of solid carrier can vary widely, but is generally from about 25mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid, such as an aqueous or nonaqueous liquid suspension or solution.

For nasal administration, the formulations may contain the compound of formula I dissolved or suspended in a liquid carrier, especially an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizers, e.g., propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabens.

For parenteral applications, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions, with the active compound dissolved in polyhydroxylated castor oil.

Tablets, lozenges, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral administration. Preferred carriers for tablets, dragees or capsules include lactose, corn starch and/or potato starch. Syrups or elixirs may be presented for use in the container, where a sweetening excipient may be employed.

A typical tablet that can be prepared by conventional tableting techniques contains:

tablet core

Active Compound (in the form of the free Compound or a salt thereof) 100mg

Colloidal silicon dioxide (Areosil) 1.5mg

Cellulose, microcrystalline (Avicele) 70mg

Modified cellulose gum (Ac-Di-Sol) 7.5mg

Magnesium stearate

Coating film

HPMC is about 9mg

Mywacett 9-40T approximately 0.9mg

Acylated monoglyceride for use as a plasticizer for film coatings.

Pharmaceutical compositions of the invention suitable for topical administration may be creams, ointments, lotions, liniments, gels, solutions, suspensions, pastes, bars, sprays, shampoos, soaps, hair conditioners or powders.

Topical administration may be to or near the body part presenting the lesion, e.g. to the exterior of the body, e.g. to the skin surface. Such application may be a simple application of the composition, or it may comprise any device suitable for enhancing the establishment of contact between the composition and the pathological lesion, for example the use of an occlusive dressing such as an occlusive plaster containing the composition of the invention. The composition may be impregnated or distributed onto a pad, plaster, strip, gauze, sponge material, piece of lint, or the like. Optionally, the composition may be in the form of an injection into or near the lesion.

The topical composition according to the invention may comprise 1-80% by weight of the active compound, for example 0.001-25% w/w of the active compound, for example 0.1-10%, 0.5-5%, or 2-5%, based on the total weight of the formulation. More than one active compound may be incorporated into the composition; i.e. in combination with other pharmaceutical and/or cosmetic compounds, compositions comprising compounds of the general formulae I and II are also within the scope of the present invention. The composition is conveniently administered 1-10 times a day, depending on the type, severity and location of the lesion.

For topical administration, the formulations may be formulated in accordance with conventional pharmaceutical practice, with pharmaceutical excipients commonly used for topical administration. The nature of the excipients employed in the preparation of any particular composition will depend on the method designed to administer the composition. Excipients other than water that may be used in the composition may include solids or liquids such as lubricants, solvents, humectants, thickeners and powders. Examples of each such excipient that may be used alone or in a mixture with one or more excipients are as follows:

lubricants, for example stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane 2-diol, butane-1, 3-diol, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, stearyl alcohol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, castor oil, acetylated lanolin alcohol, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate;

solvents, such as water, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, tetrahydrofuran, vegetable and animal oils, glycerol, ethanol, propanol, propylene glycol, and other glycols or alcohols, non-volatile oils;

humectants or moisturizers, such as glycerol, sorbitol, sodium 2-pyrrolidone carboxylate, soluble collagen, dibutyl phthalate, gelatin;

powders, for example chalk, talc, kaolin, starch and their derivatives, gums, colloidal silicon dioxide, sodium polyacrylate, chemically modified magnesium aluminium silicate, hydrated aluminium silicate, carboxyvinyl polymer, sodium carboxymethylcellulose, ethylene glycol monostearate;

gelling or swelling agents, such as pectins, gelatins and their derivatives, cellulose derivatives such as methylcellulose, carboxymethylcellulose or oxidized cellulose, cellulose gums, guar gum, acacia gum, karaya gum, tragacanth gum, bentonite, agar, alginates, carbomers, gelatins, phyllanthus niveus, carob, dextrans and their derivatives, ghatti gum, hectorite, psyllium husk, xanthan gum;

polymers, such as polylactic acid or polyglycolic acid polymers or copolymers thereof, paraffin, polyethylene oxide, polyethylene glycol, polypropylene glycol, polyethylene alkenyl pyrrolidone;

surfactants, such as non-ionic surfactants, e.g., glycols and glycerides, polyglycol ethers and esters, sugar ethers and esters, e.g., sorbitan esters, ionic surfactants, e.g., amine soaps, metal soaps, sulfated fatty alcohols, alkyl ether sulfates, sulfated oils, and amphoteric surfactants and lecithins (lecithins);

buffers such as sodium, potassium, aluminium, magnesium or calcium salts (e.g. chloride, carbonate, bicarbonate, citrate, gluconate, lactate, acetate, glucoheptonate or tartrate).

For topical application, the pH of the composition can in principle be in a wide range, for example from 3 to 9. In a preferred embodiment of the invention, a pH of about 4 to 8 is preferred. Conventional buffers, as described above, may be used to obtain the desired pH.

The formulations of the present invention may also contain other additives such as stabilizers, preservatives, solubilizers, colorants, chelating agents, colloid-forming agents, ointment bases, pH adjusters, antioxidants, fragrances, and skin protectants, and the like. If the composition is in the form of a shampoo or soap, the composition may further include a foaming agent, a pearlizing agent and/or a conditioning agent.

Typical preservatives include parabens, formaldehyde, Kathon CG, Bronidox, Bronopol (Bronopol), p-chloro-m-cresol, chlorhexidine, benzalkonium chloride, and the like.

Conventional ingredients may be used wherein the compositions of the present invention are in the form of shampoos or soaps, and typical soaps and shampoo bases include such ingredients as betaines, sodium lauryl sulfate, nonylphenol, imidazoles, sulfosuccinates, refatting agents, humectants and conditioners.

Furthermore, it may be advantageous to provide modified release formulations in which the active compound is incorporated into a polymer matrix, or into nanoparticles, or liposomes or micelles, or adsorbed on an ion exchange resin, or carried by a polymer.

The compositions may be formulated according to conventional pharmaceutical practice and may be semi-solid formulations: gels, pastes, mixtures; liquid preparation: solution, suspension, drench and emulsion.

As indicated, the pharmaceutical compositions of the present invention may comprise the compounds of the present invention per se or functional derivatives thereof, or combinations of such compounds. Examples of suitable functional derivatives include pharmaceutically acceptable salts, particularly those suitable for use in the dermal environment. Examples include pharmaceutically acceptable salts of amino functions, such as salts with acids that produce pharmaceutically acceptable anions, particularly in the dermal environment. Examples include phosphates, sulfates, nitrates, iodides, bromides, chlorides, borates and anions derived from carboxylic acids including acetates, benzoates, stearates and the like.

Other amino-functional derivatives include amides, imides, ureas, carbamates, and the like.

Other suitable derivatives include carboxy derivatives of the compounds of the present invention, including salts, esters, and amides. Examples include salts with pharmaceutically acceptable cations such as lithium, sodium, potassium, magnesium, calcium, zinc, aluminum, iron, ferrous iron, ammonium and lower (C)_1-6) -an alkyl ammonium salt. Esters include lower alkyl esters.

The following examples of compositions illustrate examples of pharmaceutical, cosmetic and skin care formulations according to the invention, but should not in any way limit the scope of the compositions of the invention.

Cosmetic or dermatological compositions comprising a compound of formula I or II are preferably in a form suitable for topical administration, and preferably the compositions are in the form of creams, ointments, lotions, liniments, gels, pastes, sticks, sprays, shampoos, soaps, hair conditioners or powders. Such compositions may be prepared in the manner described hereinbefore.

The cosmetic or skin care compositions of the invention are suitable for the treatment of cosmetic skin disorders, such as acne, xeroderma or other keratotic disorders, such as scleroderma and keratosis pilaris.

Thus, in a further aspect, the invention relates to the use of a compound of formula I or II for the treatment or prevention of cosmetic skin disorders, such as acne, xeroderma or other keratotic disorders, such as scleroderma and keratosis pilaris.

In addition, the composition of the present invention is suitable for the treatment of skin diseases, in particular inflammatory skin diseases, such as atopic dermatitis, contact dermatitis, eczema, psoriasis, acne, hyperkeratosis of the epidermis, acanthosis, inflammation of the epidermis, inflammation of the dermis or pruritus. In particular, the skin disease may be pruritus.

Thus, in a still further aspect, the present invention relates to the use of a compound of formula I or II for the preparation of a medicament for the treatment of dermatological disorders, in particular inflammatory dermatological disorders, such as atopic dermatitis, contact dermatitis, eczema, psoriasis, acne, hyperkeratosis of the epidermis, acanthosis, inflammation of the epidermis, inflammation of the dermis or pruritus.

It is to be understood that in a preferred embodiment of the invention, the compounds and/or compositions are administered topically.

In addition, it is contemplated that the compositions of the present invention may also be used to treat microbial infections and wound healing.

Furthermore, it is expected that the compounds of formula I or II are suitable for the treatment of cancer, in particular ovarian cancer. In interesting embodiments of the invention, the cancer is a carcinoma, for example a carcinoma selected from the group consisting of: malignant melanoma, basal cell carcinoma, ovarian cancer, breast cancer, non-small cell lung cancer, renal cell carcinoma, bladder cancer, recurrent superficial bladder cancer, gastric cancer, prostate cancer, pancreatic cancer, lung cancer, cervical dysplasia, laryngeal warts, colon cancer, colorectal cancer, and carcinoid tumors, particularly ovarian cancer.

Accordingly, in a still further aspect, the present invention relates to the use of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer, in particular for the treatment of ovarian cancer.

The compounds of formula I or II are effective over a wide dosage range. For example, in the treatment of adults, dosages of from about 0.05 to about 100mg per day may be used, preferably from about 0.1 to about 100mg per day. Most preferably, the dosage is from about 0.1mg to about 70mg per day. In selecting a patient treatment regimen, it may often be necessary to start with a dose of from about 20 to about 70mg per day, and when the condition is being managed, to reduce the dose as much as possible to about 0.1 to about 10mg per day. The exact dosage will depend upon the mode of administration, the treatment desired, the form of administration, the patient being treated and the weight of the patient being treated, as well as the preferences and experience of the attending physician or veterinarian.

Typically, the compounds of the present invention are formulated in unit dosage forms, each unit dosage comprising from about 0.1 to about 100mg of the active ingredient, together with a pharmaceutically acceptable carrier.

In general, dosage forms suitable for oral, nasal, pulmonary, or transdermal administration include from about 0.001mg to about 100mg, preferably from about 0.01mg to about 50mg, of a compound of formula I or II in admixture with a pharmaceutically acceptable carrier or diluent.

The compounds may be administered concurrently, simultaneously or together with a pharmaceutically acceptable carrier or diluent, whether by oral, rectal or parenteral (including subcutaneous) route. The compounds are often and preferably in the form of their alkali metal or alkaline earth metal salts.

Suitable dosage ranges vary with the following conditions as described above: depending on the exact mode of administration, the form of administration, the indication for which the administration is intended, the patient involved and the weight of the patient involved, as well as the preferences and experience of the attending physician or veterinarian.

In addition to their therapeutic use, the compounds of formula I and II may be tools for the in vitro study of inhibition of SCCE activity.

The invention can be further illustrated by the following non-limiting examples.

Detailed Description

Example 1 method for identifying inhibitory Compounds

Preparation of active SCCE

Recombinant active human SCCE was prepared essentially as described in WO 95/00651. cDNA encoding human SCCE was introduced into BPV vectors under the control of the murine MT promoter and expressed in transfected C127 cells. The SCCE produced was purified and activated using immobilized bovine trypsin.

Identification of SCCE inhibitors ("SCCE inhibitor test")

SCCE activity was performed essentially as described in WO 95/00651 using chromogenic substrate S-2586(MeO-Suc-Arg-Pro-Tyr-pNA) (Chromogenix,sweden), by measuring the change in absorbance at 405 nm. The inhibitor was dissolved in DMSO and added to the reaction mixture (10mM sodium phosphate, pH 7.2, 0.5M NaCl, 2.5. mu.g/ml SCCE) at the appropriate concentration followed by 10 minutes of incubation before starting the enzymatic reaction by the subsequent addition of substrate S-2586 to a final concentration of 1 mM. The change in absorbance at 405nm after 60 minutes was recorded and used as a measure of SCCE activity. The measurement temperature was 37 ℃. Determination of IC of Compounds₅₀Values showing inhibitory effect on SCCE activity at concentrations of 10 μ M or less. IC (integrated circuit)₅₀The values were used to identify compounds that are SCCE inhibitors of the invention.

Results

TABLE 1A

	Compound (I)	ICμM
	Compound (I)	ICμM	I-1	2-phenyl-benzo [ d ]][1，3]Oxazin-4-ones	2
I-2	7-chloro-2- (2-chloro-4-nitro-phenyl) -benzo [ d][1，3]Oxazin-4-ones	0.1	I-1	2-phenyl-benzo [ d ]][1，3]Oxazin-4-ones	2
I-2		0.1	I-3	2- (2-iodo-phenyl) -6, 7-dimethoxy-benzo [ d][1，3]Oxazin-4-ones	0.1
I-4	7-chloro-2-thiophen-2-yl-benzo [ d][1，3]Oxazin-4-ones	0.25	I-3		0.1
I-4	7-chloro-2-thiophen-2-yl-benzo [ d][1，3]Oxazin-4-ones	0.25	I-5	2- (2-chloro-4-nitro-phenyl) -6, 7-dimethoxy-benzo [ d][1，3]Oxazin-4-ones	0.5
I-6	2- (2-chloro-5-nitro-phenyl) -benzo [ d][1，3]Oxazin-4-ones	0.5	I-5		0.5
I-6	2- (2-chloro-5-nitro-phenyl) -benzo [ d][1，3]Oxazin-4-ones	0.5	I-7	5, 7-dichloro-2- (dimethylamino-benzo [ d ]][1，3]Oxazin-4-ones	2
I-8	2-pyridin-4-yl-benzo [ d][1，3]Oxazin-4-ones	5	I-7		2
I-8	2-pyridin-4-yl-benzo [ d][1，3]Oxazin-4-ones	5	I-9	2-thiophen-2-yl-benzo [ d][1，3]Oxazin-4-ones	5
I-10	2- (2-hydroxy-phenyl) -benzo [ d][1，3]Oxazin-4-ones	5	I-9	2-thiophen-2-yl-benzo [ d][1，3]Oxazin-4-ones	5
I-10	2- (2-hydroxy-phenyl) -benzo [ d][1，3]Oxazin-4-ones	5	I-11	2- (2-fluoro-phenyl) -6, 7-dimethoxy-benzo [ d][1，3]Oxazin-4-ones	0.7
I-12	7-chloro-2- (4-ethyl-phenyl) benzo [ d][1，3]Oxazin-4-ones	2	I-11		0.7
I-12	7-chloro-2- (4-ethyl-phenyl) benzo [ d][1，3]Oxazin-4-ones	2	I-13	7-chloro-2- (3-methyl-4-nitro-phenyl) -benzo [ d][1，3]Oxazin-4-ones	2
I-14	N- [4- (6, 7-dimethoxy-4-oxo-4H-benzo [ d ]][1，3]Oxazines-2-yl) -phenyl]-acetamide	5	I-13		2
I-14		5	I-15	Acetic acid 4- (4-oxo-4H-benzo [ d ]][1，3]Oxazin-2-yl) -phenyl esters	5
I-16	2- (2-chloro-phenyl) -6, 7-dimethoxy-benzo [ d][1，3]Oxazin-4-ones	0.17	I-15		5
I-16		0.17	I-17	6-chloro-2-thiophen-2-yl-benzo [ e][1，3]Oxazin-4-ones	0.32
I-18	6-chloro-2-furan-2-yl-benzo [ e][1，3]Oxazin-4-ones	0.60	I-17	6-chloro-2-thiophen-2-yl-benzo [ e][1，3]Oxazin-4-ones	0.32
I-18	6-chloro-2-furan-2-yl-benzo [ e][1，3]Oxazin-4-ones	0.60	I-19	2- (2-chlorophenyl) -benzo [ e ]][1，3]Oxazin-4-ones	4
			I-19	2- (2-chlorophenyl) -benzo [ e ]][1，3]Oxazin-4-ones	4
			II-1	6-Ethyl-2- (2-fluoro-phenyl) -thieno [2, 3-d][1，3]Oxazin-4-ones	0.07
II-2	6-methyl-2-naphthalen-1-yl-thieno [2, 3-d][1，3]Oxazin-4-ones	0.05	II-1		0.07
II-2		0.05	II-3	6-Ethyl-2-o-tolyl-thieno [2, 3-d][1，3]Oxazin-4-ones	0.15
II-4	6-Ethyl-2- (4-fluoro-phenyl) -thieno [2, 3-d][1，3]Oxazin-4-ones	0.3	II-3	6-Ethyl-2-o-tolyl-thieno [2, 3-d][1，3]Oxazin-4-ones	0.15
II-4		0.3	II-5	2- (2-chloro-phenyl) -4H-thieno [3, 2-d][1，3]Oxazin-4-ones	0.5
II-6	2-phenyl-4H-thieno [3, 2-d][1，3]Oxazin-4-ones	1	II-5	2- (2-chloro-phenyl) -4H-thieno [3, 2-d][1，3]Oxazin-4-ones	0.5
II-6	2-phenyl-4H-thieno [3, 2-d][1，3]Oxazin-4-ones	1	II-7	2-furan-2-yl-5, 6-dimethyl-thieno [2, 3-d][1，3]Oxazin-4-ones	1.5
I1-8	2- (4-fluoro-phenyl) -4H-thieno [3, 2-d][1，3]Oxazin-4-ones	1	II-7		1.5
I1-8	2- (4-fluoro-phenyl) -4H-thieno [3, 2-d][1，3]Oxazin-4-ones	1	II-9	2- (4-bromo-phenyl) -6-ethyl-thieno [2, 3-d][1，3]Oxazin-4-ones	1
II-10	6- (2-chloro-phenyl) -2, 3-dihydro-1H-5-oxa-8-thia-7-aza-cyclopenta [ a]Indene-4-ones	0.02	II-9		1
II-10		0.02	II-11	6-furan-2-yl-2, 3-dihydro-1H-5-oxa-8-thia-7-aza-cyclopenta [ a]Indene-4-ones	0.2
II-12	6-phenyl-2, 3-dihydro-1H-5-oxa-8-thia-7-aza-cyclopenta [ a]Indene-4-ones	0.2	II-11		0.2
II-12		0.2	II-13	6- (4-fluoro-phenyl) -2, 3-dihydro-1H-5-oxa-8-thia-7-aza-cyclopenta [ a]Indene-4-ones	0.3
II-14	6-thiophen-2-yl-2, 3-dihydro-1H-5-oxo-8-thia-7-aza-cyclopenta [ a]Indene-4-ones	0.3	II-13		0.3
II-14		0.3	II-15	2- (2-fluoro-phenyl) -5, 6, 7, 8-tetrahydro-3-oxa-9-thia-1-aza-fluorene-4-	0.07

	Ketones
	Ketones		II-16	2- (2-methoxy-phenyl) -5, 6, 7, 8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one	0.07
II-17	2-phenyl-5, 6,7, 8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one	0.7	II-16		0.07
II-17		0.7	II-18	2-naphthalen-1-yl-5, 6, 7, 8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one	1
II-19	2-thiophen-2-yl-5, 6, 7, 8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one	1	II-18		1
II-19		1	I1-20	2- (3-methoxy-phenyl) -5, 6, 7, 8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one	2
II-21	2-pyridin-4-yl-6, 7, 8, 9-tetrahydro-5H-3-oxa-10-thia-1-aza-benzo [ a]Azulene-4-ketones	2	I1-20		2
II-21		2	II-22	2-methyl-6, 7, 8, 9-tetrahydro-5H-3-oxa-10-thia-1-aza-benzo [ a]Azulene-4-ketones	>10

TABLE 1B

EXAMPLE 2 in vivo evaluation of Compounds

Animal model

Transgenic mice overexpressing human SCCE were bred under the control of the SV40 early promoter according to the method described in WO 02/062135. Transgenic mice display SCCE expression patterns similar to those seen in psoriatic and chronic lesions in human atopic dermatitis, i.e. expression in the upper basal cells increases with distance from the basal lamina. Transgenic mice develop pathological skin changes with marked hyperkeratosis, increased epidermal thickness and dermal inflammation. From transgenic mice 8-10 weeks old, itching was observed, with an increasing frequency with age. The increased apparent changes in skin morphology, including increased epidermal thickness, also result in higher moisture loss through the epithelium.

In vivo effects of SCCE inhibitors

Transgenic mice 6-9 months of age were treated daily with compound I-3(2- (2-iodo-phenyl) -6, 7-dimethoxy-benzo [ d ] [1, 3] oxazin-4-one), identified above as an SCCE inhibitor, over an 8-day period. The material was initially dissolved in DMSO and formulated in vehicle containing 45% isopropanol, 6% propylene glycol to a final DMSO concentration of 1.2%. Two different concentrations of inhibitor were formulated, 300 μ M and 30 μ M.

The study included four different treatments for 3-4 mice in each group. Each mouse used in the study had phenotypic changes typical of SCCE transgenic animals.

Treatment:

high dose (300. mu.M) of Compound I-3

Low dose (30. mu.M) of Compound I-3

Positive control (Betnovat, GlaxoSmithKline AB) containing betamethasone

Negative control, excipient (pharmaceutical preparation without active substance)

The formulation (500 μ 1/mouse) was applied once daily (evening) to the area around the ears and back of the mice. Mice were treated for 8 days and transepithelial water loss (TEWL) measurements were performed during the treatment period.

Transepithelial water loss (TEWL)

TEWL was measured on the back of mice using an evaporator from dermlab (Cortex Technology ApS, Hadsund, Denmark) according to the preparation protocol. Prior to measurement, mice were injected intraperitoneally with a mixture of Dormicum, Hypnorm and sterile water (1: 2). The dose used was 2.5. mu.l/g body weight.

TEWL1 minutes were measured twice in the morning on days 0, 3, 5 and 8.

results-TEWL

Both concentrations of inhibitor increased TEWL by about half the efficacy of the positive control (betamethasone), see figure 1.

Histological changes

Histological studies of skin morphology were performed on sacrificed mice after the last day of treatment (day 8). Tissue samples were fixed in 4% phosphate buffered formaldehyde at Room Temperature (RT) for 24 hours and then embedded in paraffin using standard histological methods. For analysis of tissue morphology, embedded tissue sections (5 μm) were then stained with hematoxylin and eosin (H/E) using standard histological protocols.

Results-histological Change

Both concentrations of inhibitor had a higher degree of positive effect on skin morphology than vehicle group and no side effect (very thin epidermis) was found in the positive control group (betamethasone), see table 2.

TABLE 2 morphology of skin after treatment

Treatment of	Morphological changes	Very thin epidermis
Treatment of	Morphological changes	Very thin epidermis	Excipient	2/4	0/4
Betamethasone	0/3	3/3	Excipient	2/4	0/4
Betamethasone	0/3	3/3	Compound I-3, 30. mu.M	1/4	0/4
Compound I-3,300. mu.M	1/4	0/4	Compound I-3, 30. mu.M	1/4	0/4

Claims

1. Use of a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a dermatological condition selected from the group consisting of atopic dermatitis, contact dermatitis, eczema, psoriasis, acne, epidermal hyperkeratosis, acanthosis, epidermal inflammation, dermal inflammation and pruritus:

wherein

R₁And R₂Such asIf present, is independently C optionally substituted with_1-8-an alkyl group: halogen, OH, NH₂，NHR₄，N(R₄)₂，NHCOR₄，C_1-6Alkoxy, trifluoromethoxy, carbamoyl, CONHR₄Or CON (R)₄)₂(ii) a Halogen, C_1-6-an alkoxy group;

or R₁And R₂When bonded to adjacent atoms, together form- (CH)₂)_n-a moiety, wherein n ═ 3, 4 or 5, and wherein said moiety may be optionally substituted with 1, 2 or 3 substituents independently selected from: halogen, OH, NH₂，NHR₄，N(R₄)₂，NHCOR₄，C_1-6Alkoxy, trifluoromethoxy, carbamoyl, CONHR₄Or CON (R)₄)₂；

R₃Is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-iodophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-hydroxyphenyl, 1-naphthyl, 2-tolyl, 2-chloro-4-nitrophenyl, 2-chloro-5-nitrophenyl, 4-fluorophenyl, 4-bromophenyl, 2-thienyl, 2-furyl or 4-pyridyl; and

R₄is C_1-4-alkyl radical, C_2-4-alkenyl radical, C_2-4-alkynyl, C_3-6-cycloalkyl radical, C_1-6-alkoxy or C_1-6-alkylthio.

2. Use according to claim 1, wherein the skin disease is pruritus.

3. Use according to claim 1, wherein, if R is present₁And R₂Which is independently chlorine or O-CH₃。

4. Use according to claim 1, wherein the compound is selected from:

2-phenyl-benzo [ d ] [1, 3] oxazin-4-one,

7-chloro-2- (2-chloro-4-nitro-phenyl) -benzo [ d ] [1, 3] oxazin-4-one,

2- (2-iodophenyl) -6, 7-dimethoxy-benzo [ d ] [1, 3] oxazin-4-one,

7-chloro-2-thiophen-2-yl-benzo [ d ] [1, 3] oxazin-4-one,

2- (2-chloro-4-nitro-phenyl) -6, 7-dimethoxy-benzo [ d ] [1, 3] oxazin-4-one,

2- (2-chloro-5-nitro-phenyl) -benzo [ d ] [1, 3] oxazin-4-one,

2-pyridin-4-yl-benzo [ d ] [1, 3] oxazin-4-one,

2-thiophen-2-yl-benzo [ d ] [1, 3] oxazin-4-one,

2- (2-hydroxy-phenyl) -benzo [ d ] [1, 3] oxazin-4-one,

2- (2-fluoro-phenyl) -6, 7-dimethoxy-benzo [ d ] [1, 3] oxazin-4-one,

2- (2-chlorophenyl) -6, 7-dimethoxy-benzo [ d ] [1, 3] oxazin-4-one,

6-chloro-2-thiophen-2-yl-benzo [ e ] [1, 3] oxazin-4-one,

6-chloro-2-furan-2-yl-benzo [ e ] [1, 3] oxazin-4-one,

2- (2-chlorophenyl) -benzo [ e ] [1, 3] oxazin-4-one,

2-thiophen-2-yl-benzo [ e ] [1, 3] oxazin-4-one,

2-furan-2-yl-benzo [ e ] [1, 3] oxazin-4-one,

and pharmaceutically acceptable salts thereof.

5. Use according to claim 4, wherein said compound is selected from the group consisting of:

7-chloro-2- (2-chloro-4-nitro-phenyl) -benzo [ d ] [1, 3] oxazin-4-one,

2- (2-iodophenyl) -6, 7-dimethoxy-benzo [ d ] [1, 3] oxazin-4-one,

7-chloro-2-thiophen-2-yl-benzo [ d ] [1, 3] oxazin-4-one,

2- (2-chloro-4-nitro-phenyl) -6, 7-dimethoxy-benzo [ d ] [1, 3] oxazin-4-one,

2- (2-chloro-5-nitro-phenyl) -benzo [ d ] [1, 3] oxazin-4-one,

2- (2-fluoro-phenyl) -6, 7-dimethoxy-benzo [ d ] [1, 3] oxazin-4-one,

2- (2-chlorophenyl) -6, 7-dimethoxy-benzo [ d ] [1, 3] oxazin-4-one,

6-chloro-2-thiophen-2-yl-benzo [ e ] [1, 3] oxazin-4-one,

6-chloro-2-furan-2-yl-benzo [ e ] [1, 3] oxazin-4-one,

and pharmaceutically acceptable salts thereof.

6. Use according to claim 1, wherein the compound has an IC of less than 5 μ M when determined in the "SCCE inhibitor test" described herein₅₀The value is obtained.

7. Use according to claim 6, wherein the compound has an IC of less than 1 μ M when determined in the "SCCE inhibitor test" described herein₅₀The value is obtained.

8. Use according to claim 7, wherein the compound has an IC of less than 0.5 μ M when determined in the "SCCE inhibitor test" described herein₅₀The value is obtained.