HK1058931A - Non-steroidal inflammation inhibitors - Google Patents
Non-steroidal inflammation inhibitors Download PDFInfo
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- HK1058931A HK1058931A HK04101712.1A HK04101712A HK1058931A HK 1058931 A HK1058931 A HK 1058931A HK 04101712 A HK04101712 A HK 04101712A HK 1058931 A HK1058931 A HK 1058931A
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- methyl
- hydroxy
- benzoxazin
- amino
- trifluoromethylvalerylamino
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Description
Technical Field
The present invention relates to the use of non-steroidal compounds in the manufacture of a medicament for the treatment of inflammation, selected compounds and a process for their preparation.
Background
In contrast to numerous steroids (glucocorticoids) which bind well to glucocorticoids and have an inflammation-inhibiting effect, the known nonsteroidal compounds, although binding to the glucocorticoid receptor, do not exhibit an inflammation-inhibiting effect (see: Nature Medicin 4(1998)92, mol. Pharmacol.52(1997) 571). In addition, non-steroidal compounds derived from steroids are known to have affinity for glucocorticoid receptors and are highly likely to be receptor-mediated anti-inflammatory effects (j.med. chem.36, (1993), 3278-. However, these compounds show no advantage in animal experiments over glucocorticoids, i.e. it has not been possible to separate the anti-inflammatory effect from the metabolic effect (e.g. inhibition of adrenal function).
WO 98/54159 discloses non-steroidal compounds with very high progestogenic activity. The document states that the claimed compounds have in part an effect on the glucocorticoid and/or mineralocorticoid receptors. In this regard, neither compounds nor experimental results are specifically disclosed. That is, no more specific compounds are disclosed in the scope of the compounds generally claimed by WO 98/54159, which have both high progestogenic activity and an effect on the glucocorticoid receptor. However, compounds that are selective for known effects are advantageous in terms of commercial applicability.
WO 00/32584 discloses phenol derivatives as non-steroidal inflammation inhibitors, which have a functional irrelevance between the anti-inflammatory effect and undesired metabolic side effects.
The compounds disclosed in the prior art have not been associated with a more satisfactory functional separation between the anti-inflammatory effect and the undesired side effects.
It is therefore an object of the present invention to provide a novel non-steroidal inflammation inhibitor which has at least comparable or better action irrelevance to the compounds of the prior art.
It has now been found that a non-steroidal compound binds well to the glucocorticoid receptor and through this binding produces an inflammation inhibitory effect. The compounds show in experiments a clearly better or at least equally good effect irrelevance between the anti-inflammatory effect and the undesired effect and are superior to or have at least equally good effects of currently known non-steroidal glucocorticoids.
Disclosure of Invention
According to the present invention, there are provided compounds of the general formula I below, as well as racemates or isolated stereoisomers, and optionally physiologically compatible salts, which compounds are useful for the preparation of a medicament having an inflammation inhibiting effect:wherein R is1And R2Identical or different and represent a hydrogen atom, C1-C5Alkyl radicals, or with carbon atoms in the chain
And the radicals together represent a ring having a total of 3 to 7 ring atoms, R3Represents a straight or branched chain C1-C5Alkyl, or linear or branched, partially or fully fluorinated
C of (A)1-C5Alkyl, A represents the following group
The dotted line represents the attachment site, wherein R4-R8Identical or different and represent a hydrogen atom, a halogen atom, a cyano group, a nitro group,
COOR9a group in which R9Represents a hydrogen atom, a linear or branched C1-C5Alkyl or benzyl
The base group is a group of a compound,
CONR10a group in which R10Represents a hydrogen atom, a linear or branched C1-C5An alkyl group, a carboxyl group,
NHR11a group in which R11Represents a hydrogen atom, a linear or branched C1-C5Alkyl radical, moiety
Linear or branched C, which is partially or fully fluorinated1-C5Alkyl radical, C1-C5Acyl, -SO2
-(C1-C5) Alkyl or optionally halogen or C1-C5Alkyl substituted-SO2-
A phenyl group,
straight or branched C1-C5Alkyl, straight or branched C2-C5Alkenyl, straight-chain or branched C2
-C5Alkynyl, straight-chain or branched, C partially or fully substituted by fluorine atoms1-C5
Alkyl radical, C1-C5Acyl, aryl or heteroaryl, R4And R5Together with the two carbon atoms of ring A to form a saturated ring having a total of 5 to 7 ring atoms
And or an unsaturated carbocyclic ring, Ar represents a ring system selected from the group consisting of the following partial formulae 1 or 2:wherein the group X3a、X3b、X4、X6、X7(partial formula 1) and Y4、Y5、Y7、Y8(section (C)
In the sub-formula 2) may be the same or different and represent a hydrogen atom, a straight chain or a branched chain C1-C5Alkane (I) and its preparation method
Or C being linear or branched, partially or fully fluorinated1-C5Alkyl, radical X4、X6、X7(partial formula 1) or Y5、Y7、Y8(partial formula 2) may be further combined
Are the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, C1-C5Alkoxy or C1
-C5An alkanoyloxy group.
The compounds of the general formula I according to the invention can exist in the form of various stereoisomers owing to the presence of asymmetric centers. In addition, racemates as well as isolated stereoisomers are also subject matter of the present invention.
It is also a particular subject of the present invention that the plane rotation of polarized light is expressed as an isomer of the (+) -compound.
In the compounds of the formula I, the radicals defined in the substituents have the following meanings.
R1、R2、R3、R4、R5、R12、Xn、YoC in (1)1-C5The alkyl group may be linear or branched and may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or n-pentyl, 2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl. Preferably methyl or ethyl.
When R is1And R2When taken together with the carbon atoms in the chain to form a 3-7 membered ring, the ring atoms may optionally be replaced by 1-2 oxygen atoms and may be, for example, cyclopropyl, cycloButyl, cyclopentyl, cyclohexyl, or cycloheptyl.
Partially or fully fluorinated C1-C5Alkyl groups can be considered as partially or fully fluorinated alkyl groups as described above. Preferred among them are trifluoromethyl or pentafluoroethyl, and partially fluorinated alkyl groups such as 5, 5, 5, 4, 4-pentafluoropentyl or 5, 5, 5, 4, 4, 3, 3-heptafluoropentyl. Preferably trifluoromethyl or pentafluoroethyl.
The substituents in the phenyl ring A may, independently of one another, be as defined in the claims, such as hydrogen, halogen, cyano, nitro, NHR11-a group (wherein R11Can represent a hydrogen atom, a linear or branched C1-C5Alkyl, straight or branched partially or fully fluorinated C1-C5Alkyl radical, C1-C5Acyl, -SO2-(C1-C5) Alkyl, or optionally substituted by halogen or C1-C5Alkyl substituted-SO2-phenyl), straight or branched chain C1-C5Alkyl, straight or branched C2-C5Alkenyl, straight-chain or branched C2-C5Alkynyl, straight-chain or branched, partially or fully fluorinated C1-C5Alkyl radical, C1-C5Acyl, aryl or heteroaryl. The phenyl ring A preferably carries 1 to 3 hydrogen atoms with different substituents.
In addition, R4And R5And may form, together with two carbon atoms in ring a, a saturated or unsaturated 5-7 membered carbocyclic ring, such as indane, naphthalene, tetrahydronaphthalene, benzocycloheptane.
The invention relates to the use of compounds of the general formula I, in which R4-R8May be the same or different and represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, a COOR group9-a group (wherein R9Represents a hydrogen atom, a linear or branched chain C1-C5Alkyl or benzyl), CONR10-a group (wherein R10Represents a hydrogen atom or a linear or branched C1-C5Alkyl), NHR11-a group (wherein R11RepresentsHydrogen atom, straight or branched C1-C5Alkyl, straight or branched partially or fully fluorinated C1-C5Alkyl radical, C1-C5Acyl, -SO2-(C1-C5) Alkyl, or optionally substituted by halogen or C1-C5Alkyl substituted-SO2-phenyl), straight or branched chain C1-C5Alkyl, straight or branched C2-C5Alkenyl, straight-chain or branched C2-C5Alkynyl, straight-chain or branched, partially or fully fluorinated C1-C5Alkyl radical, C1-C5Acyl, aryl or heteroaryl.
Halogen or halogen means a fluorine, chlorine, bromine or iodine atom. Preferably a fluorine, chlorine or bromine atom.
C2-C5The alkenyl group may be, for example, an ethenyl group, a 2-substituted ethenyl group, a 1-propenyl group, a 2-or 3-substituted 2-propenyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a 1-methyl-2-propenyl group, a 2-methyl-2-propenyl group, a 1-pentenyl group, a 1-methyl-1-butenyl group, a 2-methyl-1-butenyl group, a 3-methyl-1-butenyl group. Preferred alkenyl groups are those having a double bond in the 1-or 2-position. Methyl or ethyl may in particular be used as a substituent for the vinyl or propenyl group.
C2-C5Alkynyl is, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-methyl-1-butynyl, 4-methyl-1-butynyl or 1-pentynyl. Preferred alkynyl groups are those having a triple bond in the 1-or 2-position.
C1-C5Acyl is, for example, formyl, acetyl, propionyl, n-butyryl, 2-methylpropionyl, n-pentanoyl, 2-methylbutanoyl, 3-methylbutanoyl or pivaloyl.
R11Sulfonyl group of (C)1-C5) Alkyl is, for example, methanesulfonyl or ethanesulfonyl. R11Optionally substituted by halogen or C1-C5The alkyl-substituted sulfonylphenyl group may be 2-chloro (phenylsulfonyl), 3-chloro(phenylsulfonyl), 4-chloro (phenylsulfonyl), 2-methyl (phenylsulfonyl), 3-methyl (phenylsulfonyl), 4-methyl (phenylsulfonyl). The sulfonyl group is bonded to the NHR through its free valence bond11-on the nitrogen atom of the radical.
Aryl represents phenyl or substituted phenyl.
Substituents on the aryl radicals being considered to be halogen atoms, cyano groups, nitro groups, C1-C5Alkoxy, amino, hydroxy, carboxyl and C1-C5Alkanoyl, straight or branched C1-C5Alkyl, straight or branched and partially or fully fluorinated C1-C5An alkyl group.
Heteroaryl groups include aromatic heterocyclic 5-and 6-membered rings which may contain from 1 to 3 further heteroatoms selected from oxygen, nitrogen or sulfur atoms in the ring. Preferably a 5-membered heterocyclic ring. In particular, furyl, thienyl, pyridyl, thiazolyl, oxazolyl, oxadiazolyl and imidazolyl are preferable.
Heteroaryl groups may be optionally substituted with: straight or branched C1-C5Alkyl, straight-chain or branched and optionally fluorinated C1-C5Alkyl groups and/or halogen atoms.
For the group Xn、YoThe possible hydroxyl groups may optionally be present in the form of ethers or esters, which are defined as follows:
c for etherification of hydroxy groups1-C5The alkyl group may be an alkyl group as described above, in particular a methyl or ethyl group.
C for the esterification of hydroxy groups1-C5Alkanoyl may be formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl or pivaloyl, preferably acetyl.
C for the esterification of hydroxy groups1-C5The acyl group may be, for example, the alkanoyl groups mentioned above, preferably still the acetyl group, or benzoyl, toluoyl, phenylacetyl, acryloyl, cinnamoyl or cyclicA hexyl carbonyl group.
X4、X6、X7、Y4、Y5、Y7Or Y8C in (1)1-C5Alkanoyloxy is, for example, formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy or isovaleryloxy, preferably acetyloxy.
Preferred compounds are those in which Ar represents part of formula 2 and Y4Represents a methyl group.
Particularly preferred compounds are those in which Ar represents part of formula 2, Y4Represents methyl, and the remaining substituents Y5、Y7And Y8Represents a hydrogen atom.
Non-steroidal compounds with a mixed action of progestogenic and androgenic activity in different forms are the subject of WO 98/54159. The compounds of the general formula I according to claim 1, which are used according to the present patent application for the preparation of medicaments with inflammation-inhibiting action, although falling within the scope of the general formula covered by WO 98/54159, are not preferred in this document or are not specifically disclosed directly as compounds. Therefore, it is novel and has no relevance to undesired metabolism or other effects based on the inflammation inhibitory effect, and has the creativity required by the patent.
Undesired effects/influences in the context of the present invention refer to metabolic effects or binding to other steroid receptors.
The following specific compounds of formula I, while falling within the scope of the formula of WO 98/54159, are not specifically set forth in this patent. Therefore, they are also novel and meet the creativity needed for patents based on inflammation inhibitory effects not associated with undesired metabolic or other effects. These compounds are also subject of the present invention and are listed below. The nomenclature of the compounds of the invention will be more apparent with reference to the following examples:6- [4- (2-chloro-3-R)5-4-R6-5-R7-6-R8-phenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino]-4-methyl-2, 3-benzoxazine-1-one.
The subject of the invention is the following compounds: 5- [4- (5-fluoro-2-methylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -2-benzo [ c ] furanone 6- [4- (2-chloro-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 5- [4- (5-fluoro-2-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -2-benzo [ c ] furanone 6- [4- (5-fluoro-2-nitrophenyl) -2-hydroxy-4-methano i Yl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 5- [4- (3-fluoro-4-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -2-benzo [ c ] furanone 6- [4- (3-fluoro-4-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-bromo-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl- 2, 3-benzoxazin-1-one 6- [4- (indan-4 '-yl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (indan-4 c-yl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (indan-4' -yl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (5-fluoro-2-vinylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (5-fluoro-2-vinylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (5-fluoro-2-vinylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [ 2-hydroxy-4-methyl-2-trifluoromethyl-4- (4-trifluoromethylphenyl) -pentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [ 2-hydroxy-4-methyl-2-trifluoromethyl-4- (4-trifluoromethylphenyl) -pentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [ 2-hydroxy-4-methyl-2-trifluoromethyl-4- (4-trifluoromethylphenyl) -pentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-bromo-3, 5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-bromo-3, 5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-bromo-3, 5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino ] -4-methyl-2 3-benzoxazin-1-one 6- [4- (3, 5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (3, 5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (3, 5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-cyano-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-vinyl-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-ethyl-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (5-fluoro-2-phenylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- { 5-fluoro-2- (furan-2' -yl) phenyl } -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-bromo-3, 5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [ 2-hydroxy-4-methyl-2-trifluoromethyl-4- (1-naphthyl) -pentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [ 2-hydroxy-4-methyl-2-trifluoromethyl-4- (1-naphthyl) -pentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [ 2-hydroxy-4-methyl-2-trifluoromethyl-4- (1-naphthyl) -pentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-chlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-chlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-chlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-chloro-3-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-chloro-3-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-chloro-3-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2 3-benzoxazin-1-one 6- [4- (2-chloro-4-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-chloro-4-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-chloro-4-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl- 2, 3-benzoxazin-1-one 6- [4- (2-chloro-6-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-chloro-6-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-chloro-6-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl- 2, 3-benzoxazin-1-one 6- [4- (2, 3-dichlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2, 3-dichlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2, 3-dichlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [4- (2, 4-dichlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2, 4-dichlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2, 4-dichlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [4- (2, 5-dichlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2, 5-dichlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2, 5-dichlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [4- (4-bromo-2-chlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (4-bromo-2-chlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (4-bromo-2-chlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2 3-benzoxazin-1-one 6- [4- (2-chloro-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-chloro-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-chloro-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4- Methyl-2, 3-benzoxazin-1-one 6- [4- (2-chloro-3-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-chloro-3-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-chloro-3-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino- 4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2, 3-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2, 3-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2, 3-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2, 4-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2, 4-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2, 4-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2, 5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2, 5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2, 5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2, 6-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2, 6-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2, 6-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2, 3, 5-trifluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2, 3, 5-trifluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2, 3, 5-trifluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2, 3, 4-trifluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2, 3, 4-trifluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2, 3, 4-trifluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (3-chloro-2-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (3-chloro-2-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (3-chloro-2-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (4-chloro-2-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (4-chloro-2-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (4-chloro-2-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-fluoro-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-fluoro-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-fluoro-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [4- (4-fluoro-2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (4-fluoro-2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (4-fluoro-2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one -methyl-2, 3-benzoxazin-1-one 6- [4- (5-fluoro-2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (5-fluoro-2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (5-fluoro-2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [4- (5-chloro-2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (5-chloro-2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (5-chloro-2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one -trifluoromethylvaleryl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-chlorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-chlorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-chlorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] - Amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-chlorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-chlorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-chlorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl- 2, 3-benzoxazin-1-one 6- [3- {1- (2-chlorophenyl) -cyclopentyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-chlorophenyl) -cyclopentyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-chlorophenyl) -cyclopentyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-chloro-4-fluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-chloro-4-fluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-chloro-4-fluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one -methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-chloro-4-fluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-chloro-4-fluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-chloro-4-fluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-chloro-5-fluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-chloro-5-fluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-chloro-5-fluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one -trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-chloro-5-fluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-chloro-5-fluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-chloro-5-fluorophenyl) -cyclobutyl } - 2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2, 4-dichlorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2, 4-dichlorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2, 4-dichlorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2, 4-dichlorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2, 4-dichlorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2, 4-dichlorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-trifluoromethyl-phenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-trifluoromethyl-phenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-trifluoromethyl-phenyl) -cyclopropyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+) -trifluoromethyl-phenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-trifluoromethyl-phenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-trifluoromethyl-phenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-trifluoromethyl-phenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-trifluoromethyl-phenyl) -cyclohexyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-trifluoromethyl-phenyl) -cyclohexyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one -2, 3-benzoxazin-1-one (+)6- [3- {1- (2-trifluoromethyl-phenyl) -cyclohexyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (5-fluoro-2-trifluoromethyl-phenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (5-fluoro-2-trifluoromethyl-phenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethyl-propionic acid Propionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (5-fluoro-2-trifluoromethyl-phenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (5-fluoro-2-trifluoromethyl-phenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (5-fluoro-2-trifluoromethyl-benzene -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (5-fluoro-2-trifluoromethyl-phenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-fluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-fluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-fluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-fluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-fluorophenyl) -cyclobutyl } -2-hydroxy-2-tris (methyl) propanoylamino ] Fluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-fluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-fluorophenyl) -cyclopentyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-fluorophenyl) -cyclopentyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-fluorophenyl) -cyclopentyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-fluorophenyl) -cyclohexyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-fluorophenyl) -cyclohexyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-fluorophenyl) -cyclohexyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2, 3-difluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2, 3-difluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2, 3-difluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2, 3-difluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2, 3-difluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2, 3-difluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2, 5-difluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2, 5-difluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2, 5-difluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2, 3, 5-trifluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2, 3, 5-trifluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2, 3, 5-trifluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2, 3, 5-trifluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2, 3, 5-trifluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2, 3, 5-trifluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-bromophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-bromophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-bromophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [ 2-hydroxy-4-methyl-4- (3-methyl-2-nitrophenyl) -2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [ 2-hydroxy-4-methyl-4- (3-methyl-2-nitrophenyl) -2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [ 2-hydroxy-4-methyl-4- (3-methyl-2-nitrophenyl) -2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 5- [4- (2-amino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -2-benzo [ c ] furanone (-)5- [4- (2-amino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -2-benzo [ c ] furanone (+)5- [4- (2-amino-5-yl) Yl-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -2-benzo [ c ] furanone 6- [4- (2-amino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-amino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-amino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one Yl-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-acetylamino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-acetylamino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-acetylamino-5-fluorophenyl) -2 -hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 5- [4- (2-acetylamino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -2-benzo [ c ] furanone (-)5- [4- (2-acetylamino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -2-benzo [ c ] furanone (+)5- [4- (2-acetylamino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -2-benzo [ c ] furanone Acylamino ] -2-benzo [ c ] furanone 5- [4- (5-fluoro-2-methanesulfonylamino-phenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino ] -2-benzo [ c ] furanone (-)5- [4- (5-fluoro-2-methanesulfonylamino-phenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino ] -2-benzo [ c ] furanone (+)5- [4- (5-fluoro-2-methanesulfonylamino-phenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino ] -2-benzo [ c ] furanone 6- [4- (2-bromo-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-bromo-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-bromo-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-bromo-3-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-bromo-3-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-bromo-3-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-bromo-3-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-bromo-3-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-bromo-3-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2, 3-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylhexanoylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2, 3-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylhexanoylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2, 3-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylhexanoylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2, 6-difluorophenyl) -2-hydroxy-4-methyl-4-trifluoromethylhexanoylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2, 6-difluorophenyl) -2-hydroxy-4-methyl-4-trifluoromethylhexanoylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2, 6-difluorophenyl) -2-hydroxy-4-methyl-4-trifluoromethylhexanoylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- {3- [4- (2-chloro-5-fluorophenyl) -tetrahydropyran-4-yl ] -2-hydroxy-2-trifluoromethylpropionylamino } -4-methyl-2, 3-benzoxazin-1-one (-)6- {3- [4- (2-chloro-5-fluorophenyl) -tetrahydropyran-4-yl ] -2-hydroxy-2-trifluoromethylpropionylamino } -4-methyl-2, 3-benzoxazin-1-one (+)6- {3- [4- (2-chloro-5-fluorophenyl) -tetrahydropyran-4-yl ] -2-hydroxy- 2-trifluoromethylpropionylamino } -4-methyl-2, 3-benzoxazin-1-one
A particular aspect of the invention is a 2, 3-benzoxazine-1-one as described above.
A further aspect of the invention is a compound as described above, wherein the 2, 3-benzoxazine-1-one carries a methyl group in position 3.
If the compound of the formula I is present in the form of a salt, it may, for example, be in the form of the hydrochloride, sulfate, nitrate, phosphate, pivalate, maleate, fumarate, tartrate, benzoate, methanesulfonate, citrate or succinate salt.
When the compounds of the present invention are present as racemic mixtures, they can be separated into pure optically active forms by racemate separation methods known to those skilled in the art. For example, the racemic mixture can be separated into the pure isomers by chromatography on a support material (CHIRALPAK AD ) which is itself optically active. Alternatively, the separation can be carried out as follows: the free hydroxyl groups in the racemic compounds of formula I are esterified with an optically active acid, the resulting esters in the form of diastereoisomers are separated by fractional crystallization or chromatography, and the separated esters are then saponified to the optically pure isomers. Examples of the optically active acid include mandelic acid, camphorsulfonic acid, and tartaric acid. Process for preparing the Compounds of the invention
The compounds according to the invention can be prepared as follows: construction of C (R) from a commercially available or known phenyl Compound1)(R2)-CH2-C(OH)(R3) -B-NH-Ar chain, wherein the group R is introduced in the last step3Or a ring system (═ Ar) of formula (1) or (2) is introduced by formation of an amide bond B — NH — Ar.
If desired, the compounds may be prepared by the methods described below, and wherein A is a substituted aromatic ring, optionally substituted on the aromatic group according to known methods. These are, for example, catalytic hydrogenation of multiple bonds, nitration and halogenation. In addition, halogen and nitro substitution offer the possibility of further modifications. Thus, aryl bromides may be obtained using boron, tin or zinc reagents in the presence of palladium catalysts according to methods known to those skilled in the art. The nitro compound may be reduced to an aniline derivative, for example by hydrogenolysis, or with a metal such as iron or zinc. The aniline compound can be subjected to diazotization according to known methods, for example according to the Sandmeyer reaction. (A)
Alpha-carbonyl carboxylic acids of the general formula IIFormula (III) A, R1And R2As defined in formula I, or optionally with the formula (R) in the presence of a catalyst12)3SiR3(III) esterification of a compound of formula (III) wherein R3As defined in formula I, R12Is C1-C5Alkyl, or with an alkylmetal compound, such as a grignard reagent or an alkyllithium, to form a compound of formula IV:the catalyst may be a fluoride-salt or a basic compound such as an alkali metal carbonate (j.am. chem. soc.111, 393 (1989)).
The above esters may optionally be cleaved and then reacted with a compound of the formula Ar-NH-R13(V) compound of the formula (V) wherein R13Represents a hydrogen atom or C1-C5Acyl, and Ar is as defined for formula I, wherein the group R can be subsequently cleaved13Forming a compound of formula I or optionally activating the acid function by conversion to an acid chloride and then reacting directly with a compound of formula Ar-NH-R13(V) compound of the formula (V) wherein R13Represents a hydrogen atom or C1-C5Acyl, and Ar is as defined for formula I, wherein the group R is subsequently cleaved in any order13Then with formula (R)12)3SiR3(III) compound of the formula wherein R3And R12The same as defined above, to form the compounds of formula I. (B)
A compound of the general formula VIFormula (III) A, B, R1、R2And R3As defined in formula I, and LG represents a leaving group, with formula Ar-NH-R13(V) compound of the formula (V) wherein R13Represents a hydrogen atom or C1-C5Acyl, and Ar is as defined for formula I, wherein the group R can be subsequently cleaved13Form aA compound of the general formula I.
The compounds of formula VI may be formed as intermediates only, isolated when desired, or may be generated in situ. For example, it may be an acid chloride intermediate formed from the corresponding carboxylic acid. As the leaving group, for example, a fluorine, chlorine or bromine atom, or when an acid chloride intermediate is not formed, a methanesulfonic acid group or a toluenesulfonic acid group may be mentioned.
Binding of substances to the Glucocorticoid Receptor (GR) was examined by means of recombinant receptors. Cytosol (cytosol) preparations of Sf9 cells infected with recombinant baculovirus encoding GR were used in binding studies. And [2 ] as a reference substance3H]The substances of the invention show a high-very high affinity for GR compared to dexamethasone.
In addition, a cytosol preparation of Sf9 cells infected with a recombinant baculovirus encoding GR was used to perform a Mineralocorticoid Receptor (MR) binding assay with [2 ] as a reference substance3H]Aldosterone compared exhibits affinity for MR.
The basic molecular mechanism of anti-inflammatory action of glucocorticoids is their inhibition of transcription of cytokines, adhesion molecules, enzymes, and other inflammatory factors mediated by GR. This inhibition can be achieved by interaction of GR with other transcription factors such as AP-1 and NF-kappa-B (see: Cato, ACB and Wade E, BioEssays 18, 371-.
In the human monocyte line THP-1, the compounds of formula I of the present invention inhibit secretion of the cytokine IL-8 induced by Lipopolysaccharide (LPS). The concentration of the cytokine can be measured by a commercially available ELISA kit.
The anti-inflammatory effect of the compounds of general formula I according to the invention was tested in animal experiments by croton oil induced inflammation in rats and mice (j.exp.med. (1995), 182, 99-108). Here, an ethanol solution of croton oil was topically applied to the ears of the animals. The test substance is administered topically or systemically at the same time or 2 hours prior to the administration of croton oil. After 16-24 hours, ear weight was measured as a measure of inflammatory edema, peroxidase activity as a measure of granulocyte engraftment, and elastase activity as a measure of neutrophil engraftment. In this experiment, the compounds of general formula I according to the invention inhibit the three inflammatory parameters mentioned above both after local as well as after systemic administration.
The most common side effect in glucocorticoid therapy is the so-called "steroid diabetes" (see: Hatz, HJ, Glucocorticoide: Immunologische Grundling, Pharmakologie und Timenti, Wissenschafliche Verlagsgesellschaft mbH, Stuttgart, 1998). The reason for this is that gluconeogenesis is stimulated in the liver by the induction of the enzymes responsible for this and the free amino acids produced by protein breakdown (the catabolic action of glucocorticoids). The catabolic metabolic coding enzyme in the liver (Schluesselenzym) is Tyrosine Aminotransferase (TAT). The activity of this enzyme can be determined by photometric measurements of liver homogenates and can be a good measure of the undesired metabolic effects of glucocorticoids. To measure TAT induction, animals were sacrificed 8 hours after administration of the test substance, livers were removed, and TAT activity in the homogenate was measured. The compounds of the general formula I induce no or only very little tyrosine aminotransferase in this experiment at doses having an anti-inflammatory effect.
In summary, the novel compounds of general formula I have the following properties compared to the currently used steroidal glucocorticoids:
non-steroidal structures (that is to say that the substances according to the invention remain active in patients who are no longer suitable for treatment with conventional glucocorticoids due to their allergic response to their steroidal basic structure (cf. Lutz, ME, el-Azhary RA, Mayo Clin. Proc.72, 1141-1144, 1997))
Similarly good anti-inflammatory action, but small metabolic action
Due to their anti-inflammatory and additionally antiallergic, immunosuppressive and antiproliferative action, the compounds of general formula I according to the invention are useful as medicaments for the treatment or prevention of the following conditions in mammals and humans (the term "condition" herein refers to the following indications):
(i) pulmonary diseases accompanied by inflammatory, allergic and/or proliferative processes
Chronic obstructive pulmonary disease of various causes, in particular bronchial asthma
Bronchitis of various causes
All forms of restrictive lung disease, in particular allergic alveolitis
All forms of pulmonary edema, in particular toxic pulmonary edema
Sarcoidosis and granulomatosis, in particular Burkholderia
(ii) Rheumatism/autoimmune disease/arthropathy with inflammatory, allergic and/or proliferative processes
All forms of rheumatism, in particular rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica
Reactive arthritis
Inflammatory soft tissue diseases of other causes
Arthritic symptoms in degenerative arthritic diseases (arthralgia)
Traumatic arthropathy
Collagen diseases of various causes, such as systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, sjogren's syndrome, Still's syndrome, fischer's syndrome
(iii) Allergy accompanying inflammatory, allergic and/or proliferative processes
All forms of allergic reactions, such as Quincke's (Quincke) edema, hay fever (Heuschnupen), insect bites, allergic reactions by drugs, blood derivatives, contrast agents, etc., anaphylactic shock, urticaria, contact dermatitis
(iv) Vasculitis (vascular disease)
Nodose arteritis, temporal arteritis, erythema nodosum
(v) Skin diseases accompanied by inflammatory, allergic and/or proliferative processes
Atopic dermatitis (especially in childhood)
-psoriasis
Pityriasis rubra pilaris
Erythema induced by different etiologies such as radiation, chemicals, burns, etc
-bullous skin disease
Licheniform-like ring formation
Pruritus (e.g. allergic)
-seborrheic eczema
-rosacea
Common bullous sore
Erythema multiforme exudativum
Balanitis (balanitis)
-inflammation of the female pudendum
Alopecia such as alopecia areata
Cutaneous T cell lymphoma
(vi) Renal disease with inflammatory, allergic and/or proliferative processes
-nephrotic syndrome
All nephritis
(vii) Liver diseases accompanied by inflammatory, allergic and/or proliferative processes
Acute hepatocyte decay
Acute hepatitis of different etiologies, such as virus, toxin, drug induction
Chronic aggressive and/or chronic interstitial hepatitis
(viii) Gastrointestinal disorders accompanied by inflammatory, allergic and/or proliferative processes
Crohn's disease
Ulcerative colitis
-gastritis
Reflux esophagitis
Gastrointestinal diseases of other etiology, such as sprue
(ix) Rectal diseases accompanied by inflammatory, allergic and/or proliferative processes
-eczema of the anus
Anal fissure
Piles-hemorrhoids
-idiopathic proctitis
(x) Ocular diseases accompanied by inflammatory, allergic and/or proliferative processes
Allergic keratitis, uveitis, iritis
Conjunctivitis
Blepharitis
Optic neuritis
Choroiditis (choroiditis)
Sympathetic ophthalmia
(xi) Diseases of the cervical-nasal-ear region accompanied by inflammatory, allergic and/or proliferative processes
Allergic rhinitis, hay fever
Otitis externa, e.g. caused by contact, infection, etc
Otitis media
(xii) Neurological disorders accompanied by inflammatory, allergic and/or proliferative processes
Cerebral edema, in particular tumour-induced cerebral edema
Multiple sclerosis
-acute encephalomyelitis
Meningitis
Different forms of seizure attacks, such as NBS seizure
(xiii) Hematological disorders accompanied by inflammatory, allergic and/or proliferative processes
Acquired hemolytic anemia
Idiopathic thrombocytopenia
(xiv) Neoplastic diseases accompanied by inflammatory, allergic and/or proliferative processes
Acute lymphatic leukemia
-malignant lymphoma
Lymphogranuloma
-lymphosarcoma
Enlarged metastasis, in particular of breast, bronchial and prostate cancer
(xv) Endocrine diseases accompanied by inflammatory, allergic and/or proliferative processes
-endocrine orbital disorders
-thyroid toxicity crisis
-Quervain's (de Quervain) thyroiditis
Hashimoto's thyroiditis
Basedow disease
(xvi) Organ and tissue transplantation, graft versus host disease
(xvii) Severe states of shock, e.g. allergic shock, Systemic Inflammatory Response Syndrome (SIRS)
(xviii) Replacement therapy in the following cases:
congenital primary adrenal insufficiency, e.g. congenital adrenal genital syndrome
Acquired primary adrenal insufficiency, such as Addison's disease, autoimmune adrenalitis, post-infections (postinfections), tumors, metastases, etc
Congenital complications of adrenal insufficiency, such as pituitary insufficiency
Acquired concurrent adrenal insufficiency, such as postinfection, tumors, etc
(xix) Emesis associated with inflammatory, allergic and/or proliferative processes
E.g. in conjunction with 5-HT3Combination of antagonists in cytotoxic toxin (cytostatic) induced emesis
(xx) Pain in inflammation, e.g. lumbago
Furthermore, the compounds of the general formula I according to the invention can also be used for the treatment and prophylaxis of other diseases in which synthetic glucocorticoids are currently used (cf. Hatz, HJ, Glucocorticoide: Immunologische Grundling, Pharmakologie und Therapirichtien, Wissenschafliche Verlagsgesellschaft mbH, Stuttgart, 1998).
All of the above indications (i) - (xx) are described in detail in the following documents: hatz, HJ, glucoorticoide: immunologische Grundling, Pharmakologie und Timeririchtien, Wissenschafiiche Verlagsgesellschaft mbH, Stuttgart, 1998.
In the treatment of the above-mentioned conditions, suitable dosages will vary and depend, for example, on the strength of action of the compound of formula I, the host, the type of administration, and the type and severity of the condition to be treated, and also whether it is for therapeutic or prophylactic purposes.
The invention also relates to the following aspects:
(i) the use of a compound of the general formula I according to the invention or of mixtures thereof for the preparation of a medicament for the treatment of the abovementioned diseases;
(ii) a method of treating the above-mentioned disorders, which method comprises administering an amount of a compound according to the present invention, wherein said amount inhibits said disorder, and administering said amount of the compound to a patient in need thereof;
(iii) pharmaceutical compositions for the treatment of the above-mentioned diseases, which comprise a compound according to the invention or a mixture thereof and at least one pharmaceutical auxiliary and/or carrier substance.
In general, satisfactory results are expected in animals when the daily dose is from 1. mu.g to 100000. mu.g of a compound of the invention per kg of body weight. In larger mammals, such as humans, a recommended daily dose is from 1. mu.g to 100000. mu.g per kg of body weight. The preferred dose is 10-30000. mu.g/kg body weight, and the more preferred dose is 10-10000. mu.g/kg body weight. For example, the dose may suitably be administered multiple times per day. In the treatment of acute shock (e.g. anaphylactic shock) a single dose may be administered, which may significantly exceed the above doses.
The novel compounds according to the invention can be formulated in a known manner into various preparations in which the active substances are processed with the carrier substances, fillers, disintegrants, binders, humectants, lubricants, adsorbents, diluents, flavoring agents, pigments, etc., customary for preparations and are then converted into the desired dosage form. The following documents can be referred to for this purpose: remington's Pharmaceutical Science, 15th ed.MackPublishing Company，East Pennsylvania(1980)。
For oral administration, tablets, troches, capsules, pills, powders, granules, pastes, suspensions, emulsions or solutions are particularly contemplated.
For parenteral administration, injections and infusion solutions may be used.
For intra-articular injection, a correspondingly formulated crystal suspension may be used.
For intramuscular injection, aqueous and oily solutions or suspensions and corresponding depot preparations can be used.
In rectal administration, the novel compounds of the invention may be in the form of suppositories, capsules, solutions (e.g. enema) and ointments for systemic administration, but also for topical treatment.
For pulmonary administration, the novel compounds of the invention may be in the form of aerosols and inhalants.
The novel compounds of the invention can be used in corresponding pharmaceutical preparations such as drops, ointments and elixirs for topical administration to the eye, external auditory meatus, middle ear, nasal cavity and paranasal sinuses.
For topical administration, gels, ointments, lipoointments, creams, pastes, powders, emulsions, and elixirs may be used. The dosage of the compounds of formula I in these preparations should be in the range of 0.001-20% in order to achieve sufficient pharmacological effect.
The invention may comprise as therapeutically active substance a compound of general formula I according to the invention. In addition, the present invention may also comprise compounds of the general formula I according to the invention as therapeutically active substances, together with pharmaceutically acceptable auxiliary and carrier substances. The invention may also include pharmaceutical compositions comprising one of the compounds of the invention, or a mixture thereof, in pharmaceutically active form, together with pharmaceutically acceptable salts or pharmaceutically acceptable adjuvants and carrier materials.
Detailed Description
The compounds according to the invention will be illustrated in more detail by the following examples, which are in no way intended to limit the scope of the invention. The synthesis of the important preliminary steps, if not disclosed in the experimental part, is prior art and can be obtained, for example, from WO 98/54159. Experimental part
Example 16- [4- (5-fluoro-2-methylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one
EXAMPLE 25- [4- (5-fluoro-2-methylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino ] -2-benzo [ c ] furanone preparation: 2- (5-fluoro-2-methylphenyl) -2-methyl-propionitrile
5.25g of (5-fluoro-2-methylphenyl) acetonitrile and 5.25ml of methyl iodide were dissolved in 70ml of dimethylformamide, and then mixed with 2.7g of sodium hydride (80%) under ice-cooling for 2.5 hours. After 3 hours at 0 ℃ and 16 hours at room temperature, ice water and ethyl acetate were mixed, acidified with 1M hydrochloric acid, the ethyl acetate phase was washed with water, dried (sodium sulfate) and concentrated by evaporation. 6.1g of 2- (5-fluoro-2-methylphenyl) -2-methylpropanenitrile are obtained as an oil. 2- (5-fluoro-2-methylphenyl) -2-methylpropionaldehyde
6.1g of 2- (5-fluoro-2-methylphenyl) -2-methylpropanenitrile are dissolved in 60ml of toluene and then mixed at-70 ℃ with 44ml of a 1.2M toluene solution of diisobutylaluminium hydride for 45 minutes. After 4 hours at-78 ℃ 120ml of ethyl acetate were added dropwise. Warm to room temperature and then wash three times with 2N sulfuric acid and once with water. The ethyl acetate phase was dried (sodium sulfate) and concentrated by evaporation. After distillation 5.3g of 2- (5-fluoro-2-methylphenyl) -2-methylpropionaldehyde are obtained, boiling point: 120 ℃/0.031 hPa. 4- (5-fluoro-2-methylphenyl) -4-methyl-2-oxopentanoic acid
A solution of 8.04ml of ethyl 2-ethylphosphonyl-2-ethoxyacetate in 40ml of tetrahydrofuran was mixed under ice-cooling with 16.5ml of a 2M lithium isopropylamide tetrahydrofuran solution over a period of 20 minutes, and then stirred at 0 ℃ for 30 minutes. A solution of 5.2g of 2- (5-fluoro-2-methylphenyl) -2-methylpropionaldehyde in 30ml of tetrahydrofuran is added dropwise thereto at 0 ℃ over 30 minutes. After 20 hours at room temperature, 2N sulfuric acid was added, extracted with ethyl acetate, dried (sodium sulfate) and concentrated by evaporation. The crude product is saponified with 100ml of 2M sodium hydroxide solution. 5g of acid are obtained, which is heated under reflux with 450ml of 2N sulfuric acid under vigorous stirring. After extraction with ethyl acetate and washing with water, 4g of 4- (5-fluoro-2-methylphenyl) -4-methyl-2-oxopentanoic acid are obtained as a pale yellow oil. 5- [4- (5-fluoro-2-methylphenyl) -4-methyl-2-oxovalerylamino ] -2-benzo [ c ] furanone
A solution of 950mg of 4- (5-fluoro-2-methylphenyl) -4-methyl-2-oxopentanoic acid in 15ml of dimethylacetamide was mixed with 0.322ml of thionyl chloride at-10 ℃ and stirred for 30 minutes at-10 ℃ and then for 1 hour at 0 ℃ and subsequently mixed with 750mg of 5-amino 2-benzo [ c ] furanone. After 16 hours at room temperature, it is mixed with 2M hydrochloric acid and ethyl acetate, the organic phase is washed to neutrality with water, dried (sodium sulfate) and concentrated by evaporation. After chromatography on silica gel (hexane: ethyl acetate 3: 2) and recrystallization from diisopropyl ether, 486mg of 5- [4- (5-fluoro-2-methylphenyl) -4-methyl-2-oxovalerylamino ] -2-benzo [ c ] furanone are obtained, m.p.: 153 ℃. 6- [4- (5-fluoro-2-methylphenyl) -4-methyl-2-oxovalerylamino ] -4-methyl-2, 3-benzoxazin-1-one
According to the method, the compound is analogous to 5- [4- (5-fluoro-2-methylphenyl) -4-methyl-2-oxovalerylamino]-2-benzo [ c]Method for furanones from 4- (5-fluoro-2-methylphenyl) -4-methyl-2-oxopentanoic acid and 6-amino-2, 3-benzoxazin-1-one to give the title compound, m.p.: 186 ℃.6- [4- (5-fluoro-2-methylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentane Acylamino group]-4-methyl-2, 3-benzoxazin-1-one
514mg of 6- [4- (5-fluoro-2-methylphenyl) -4-methyl-2-oxovalerylamino]-4-methyl-2, 3-benzoxazin-1-one was dissolved in 10ml of dimethylformamide and mixed with 192mg of cesium carbonate and 0.44ml of trifluoromethyl (trimethyl) silane at 0 ℃. After 1 hour at 0 ℃ and 16 hours at room temperature, it was cooled again to 0 ℃ and then mixed with 1.3ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. After 30 minutes at 0 ℃ 2N sulfuric acid and ethyl acetate are added and the ethyl acetate phase is washed with water, dried (sodium sulfate) and concentrated by evaporation. Chromatography on silica gel with hexane-ethyl acetate (3: 2) gave 220mg of 6- [4- (5-fluoro-2-methylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino]4-methyl-2, 3-benzoxazine-1-one, melting point: 175 ℃ and 176 ℃. 5- [4- (5-fluoro-2-methylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino]-2-benzeneAnd [ c ]]Furanones
In analogy to the procedure of example 1, from 5- [4- (5-fluoro-2-methylphenyl) -4-methyl-2-oxovalerylamino ] -2-benzo [ c ] furanone was obtained the title compound, melting point: 165 ℃ and 168 ℃. The enantiomer was isolated from example 1:
the mixture of enantiomers obtained in example 1 was chromatographed on a chiral support material (CHIRALPAKAD , DAICEL Co.) using hexane/ethanol (9: 1, vv). Obtained from 140mg of racemate: (-)6- [4- (5-fluoro-2-methylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one, first fraction: 57mg, melting point: 203 ═ D ═ 92.7 ° (c ═ 0.5 in tetrahydrofuran), and (+)6- [4- (5-fluoro-2-methylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one, second fraction: 56mg, melting point: 202 ℃ and 203 ℃.
Example 36- [4- (2-chloro-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one preparative procedure: 2- (2-chloro-5-fluorophenyl) -2-methylpropanenitrile
In analogy to the preparation of 2- (5-fluoro-2-methylphenyl) -2-methylpropanenitrile, 2- (2-chloro-5-fluorophenyl) -2-methylpropanenitrile was synthesized with the boiling point: 100 ℃/0.04 hPa. 2- (2-chloro-5-fluorophenyl) -2-methylpropionaldehyde
In analogy to the preparation of 2- (5-fluoro-2-methylphenyl) -2-methylpropanal, 2- (2-chloro-5-fluorophenyl) -2-methylpropanal is obtained with the boiling point: 120 ℃/0.04 hPa. 4- (2-chloro-5-fluorophenyl) -4-methyl-2-oxopentanoic acid
In analogy to the procedure for 4- (5-fluoro-2-methylphenyl) -4-methyl-2-oxopentanoic acid, 4- (2-chloro-5-fluorophenyl) -4-methyl-2-oxopentanoic acid was obtained as oil. 6- [4- (2-chloro-5-fluorophenyl) -4-methyl-2-oxovalerylamino ] -4-methyl-2, 3-benzoxazin-1-one
According to the method, the compound is analogous to 5- [4- (5-fluoro-2-methylphenyl) -4-methyl-2-oxovalerylamino]-2-benzo [ c]Method for furanones from 4- (2-chloro-5-fluorophenyl) -4-methyl-2-oxopentanoic acid and 6-amino-2, 3-benzoxazin-1-one to give the title compound, m.p.: 198 ℃ and 199 ℃.6- [4- (2-chloro-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleryl Radical amino]-4-methyl-2, 3-benzoxazin-1-one
The title compound is obtained in analogy to example 1 from 6- [4- (2-chloro-5-fluorophenyl) -4-methyl-2-oxovalerylamino ] -4-methyl-2, 3-benzoxazin-1-one with the following melting points: 201 ℃ and 203 ℃. The enantiomer was isolated from example 3:
the mixture of enantiomers obtained in example 3 was chromatographed on a chiral support material (CHIRALPAKAD , DAICEL Co.) using hexane/ethanol (19: 1, vv). Obtained from 190mg of racemate: (-)6- [4- (2-chloro-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one, first fraction: 61mg, melting point: 247 ═ 249 ℃, α D ═ 74.2 ° (c ═ 0.5 in tetrahydrofuran), and (+)6- [4- (2-chloro-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one, second fraction: 74mg, melting point: 247 ℃ and 249 ℃.
The compounds shown in tables 1 to 3 below were prepared analogously to example 3. Chlorine compounds
TABLE 1
Fluorine compound (b):
| Compound (I) | R5 | R6 | R7 | R8 | R1/R2 | Melting Point (. degree.C.) | Isomer or [ alpha ]]D |
| 1 | H | H | H | H | CH3 | 169-171 | Racemic modification |
| 2 | H | H | H | H | CH3 | 198 | -173.3 |
| 3 | H | H | H | H | CH3 | 199 | (+) -form |
| 4 | F | H | H | H | CH3 | 189-192 | Racemic modification |
| 5 | F | H | H | H | CH3 | 189-192 | -89.1 |
| 6 | F | H | H | H | CH3 | 220-223 | +78.2 |
| 7 | H | F | H | H | CH3 | 208-209 | Racemic modification |
| 8 | H | F | H | H | CH3 | 179 | -77.1 |
| 9 | H | F | H | H | CH3 | 181-182 | +74.6 |
| 10 | H | H | H | F | CH3 | 222-224 | Racemic modification |
| 11 | H | H | H | F | CH3 | 232-235 | -110.0 |
| 12 | H | H | H | F | CH3 | 230-233 | +106.0 |
| 13 | Cl | H | H | H | CH3 | 228-230 | Racemic modification |
| 14 | Cl | H | H | H | CH3 | 252-254 | -32.8 |
| 15 | Cl | H | H | H | CH3 | 255-256 | +29.3 |
| 16 | H | Cl | H | H | CH3 | 249-253 | Racemic modification |
| 17 | H | Cl | H | H | CH3 | 253-255 | -126.2 |
| 18 | H | Cl | H | H | CH3 | 252-256 | (+) -form |
| 19 | H | H | Cl | H | CH3 | 210-211 | -96.7 |
| 20 | H | H | Cl | H | CH3 | 208-209 | 100.8 |
| 21 | H | Br | H | H | CH3 | 155-157 | Racemic modification |
| 22 | H | Br | H | H | CH3 | 151-152 | -16.6 |
| 23 | H | Br | H | H | CH3 | 150-155 | (+) -form |
| 24 | OH | H | H | H | CH3 | 235-241 | -75.3 |
| 25 | OH | H | H | H | CH3 | 236-240 | +76.0 |
TABLE 2
Bromine compound
| Compound (I) | R5 | R6 | R7 | R8 | R1/R2 | Melting Point (. degree.C.) | Isomer or [ alpha ]]D |
| 26 | H | H | H | H | CH3 | 220 | -85.5 |
| 27 | H | H | H | H | CH3 | 227 | (+) -form |
| 28 | F | H | H | H | CH3 | 204 | Racemic modification |
| 29 | F | H | H | H | CH3 | 204-205 | -90.3 |
| 30 | F | H | H | H | CH3 | 204-205 | +83.0 |
| 31 | H | F | H | H | CH3 | 175-176 | -83.8 |
| 32 | H | F | H | H | CH3 | 176-177 | (+) -form |
| 33 | H | H | F | H | CH3 | 174 | -81.5 |
| 34 | H | H | F | H | CH3 | 174-176 | (+) -form |
| 35 | H | H | H | F | CH3 | 205-210 | Outer coverRacemic modification |
| 36 | H | H | H | F | CH3 | 230-240 | -71.3 |
| 37 | H | H | H | F | CH3 | 240-245 | (+) -form |
| 38 | F | H | F | H | CH3 | 209 | Racemic modification |
| 39 | Cl | H | H | H | CH3 | 189-192 | -64.0 |
| 40 | Cl | H | H | H | CH3 | 184-187 | (+) -form |
| 41 | H | Cl | H | H | CH3 | 239-141 | Racemic modification |
| 42 | H | Cl | H | H | CH3 | 210-215 | -67.7 |
| 43 | H | Cl | H | H | CH3 | 198-199 | (+) -form |
| 44 | OCH3 | H | H | H | CH3 | 197-200 | Racemic modification |
TABLE 3
EXAMPLE 45- [4- (5-fluoro-2-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino]-2-benzo [ c]A furanone preparation step: 2- (3-fluorophenyl) -2-methylpropanenitrile
| Compound (I) | R5 | R6 | R7 | R8 | R1/R2 | Melting Point (. degree.C.) | Isomer or [ alpha ]]D |
| 45 | H | H | H | H | CH3 | 186-191 | Racemic modification |
| 46 | H | H | H | H | CH3 | 209-211 | -65.0 |
| 47 | H | H | H | H | CH3 | 205-207 | +66.0 |
In analogy to the preparation of 2- (5-fluoro-2-methylphenyl) -2-methylpropanenitrile, 2- (3-fluorophenyl) -2-methylpropanenitrile was synthesized with the boiling point: 102-103 ℃/0.029 hPa. 2- (3-fluorophenyl) -2-methylpropionaldehyde
In analogy to the preparation of 2- (5-fluoro-2-methylphenyl) -2-methylpropanal, 2- (3-fluorophenyl) -2-methylpropanal is obtained with a boiling point: 120 ℃/0.04 hPa. 4- (3-fluorophenyl) -4-methyl-2-oxopentanoic acid
In analogy to the procedure for 4- (5-fluoro-2-methylphenyl) -4-methyl-2-oxopentanoic acid, 4- (3-fluorophenyl) -4-methyl-2-oxopentanoic acid was obtained as oil. 4- (3-fluorophenyl) -4-methyl-2-oxopentanoic acid ethyl ester
5.6g of 4- (3-fluorophenyl) -4-methyl-2-oxopentanoic acid and 0.197ml of sulfuric acid are heated under reflux in 150ml of ethanol for 3 hours. The solvent was distilled off. The residue was taken up in ethyl acetate, washed with saturated sodium bicarbonate solution, dried (sodium sulfate) and concentrated by evaporation. After rotary distillation, 5.6g of ethyl 4- (3-fluorophenyl) -4-methyl-2-oxopentanoate are obtained with a boiling point of 130 ℃/0.04 hPa. 4- (3-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester
5.3g of ethyl 4- (3-fluorophenyl) -4-methyl-2-oxopentanoate are mixed in 60ml of dimethylformamide at 0 ℃ with 3.25g of cesium carbonate and 4.63ml of trifluoromethyl (trimethyl) silane. After 1 hour at 0 ℃ and 16 hours at room temperature, it was cooled again to 0 ℃ and mixed with 20ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. After 30 minutes at 0 ℃, 2N sulfuric acid and ethyl acetate are added, the ethyl acetate phase being washed with water, dried (sodium sulfate) and concentrated by evaporation. After chromatography on silica gel with hexane-ethyl acetate (20: 1) and rotary distillation, 4.45g of ethyl 4- (3-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoate (bp: 100 ℃ C./0.04 hPa) are obtained. 4- (5-fluoro-2-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester 4- (3-fluoro-4-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester
3.3g of ethyl 4- (3-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoate are dissolved in 20ml of trifluoroacetic acid and then mixed with 0.84ml of 100% nitric acid at 0 ℃. After 3 hours at 0 ℃ and 16 hours at room temperature, a precipitate was precipitated on ice, the crystals were extracted, washed with water and dried. Recrystallization from hexane gave 2.5g of ethyl 4- (5-fluoro-2-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoate, m.p. 66-67 ℃. Chromatography on silica gel with hexane-ethyl acetate (8: 1) gave, as a first effluent, a further 500mg of ethyl 4- (5-fluoro-2-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoate and, as a second effluent, 800mg of ethyl 4- (3-fluoro-4-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoate as an oil from the mother liquor. 4- (5-fluoro-2-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid
2.4g of ethyl 4- (5-fluoro-2-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoate are dissolved in 30ml of ethanol and then mixed with 60ml of 1M sodium hydroxide solution. After 2 days at room temperature, concentration is carried out by evaporation, the residue is dissolved in water, acidified at 0 ℃ and then extracted with ethyl acetate. The ethyl acetate phase is washed with water to neutrality, dried (sodium sulfate) and then concentrated by evaporation. After crystallization from isopropyl ether, 4- (5-fluoro-2-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid is obtained with a melting point of 130-.5- [4- (5-fluoro-2-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentane Acylamino group]2-benzo [ c ]]Furanones
255mg of 4- (5-fluoro-2-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid are mixed in 3ml of dimethylformamide at 0 ℃ with 0.105ml of thionyl chloride, stirred at 0 ℃ for 30 minutes and then at room temperature for 45 minutes, and then with 300mg of 5-amino-2-benzo [ c ] c]Mixing furanone. After 16 hours at room temperature, it is mixed with 2M hydrochloric acid and ethyl acetate, the organic phase is washed to neutrality with water, dried (sodium sulfate) and concentrated by evaporation. After chromatography on silica gel with hexane-ethyl acetate (3: 2) and recrystallization from diisopropyl ether, 80mg of 5- [4- (5-fluoro-2-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino]2-benzo [ c ]]Furanone, melting point 200-201C.5- [4- (5-fluoro-2-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoropentyl ] -amide Acyloxy radical]-4-methyl-2, 3-benzoxazin-1-one
In analogy to example 4, from 4- (5-fluoro-2-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid and 6-amino-2, 3-benzoxazin-1-one was obtained the title compound, melting point: 208-210 ℃.
EXAMPLE 65- [4- (3-fluoro-4-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino ] 2-benzo [ c ] furanone 4- (3-fluoro-4-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid
The title compound was obtained as an oil from ethyl 4- (3-fluoro-4-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoate in analogy to the preparation of 4- (5-fluoro-2-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoate in example 4.5- [4- (3-fluoro-4-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoropentyl ] -amide Acylamino group]2-benzo [ c ]]Furanones
The title compound was obtained in analogy to example 4 from 4- (3-fluoro-4-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid and 5-amino 2-benzo [ c ] furanone, mp 188-.
EXAMPLE 76- [4- (3-fluoro-4-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino]-4-methyl-2, 3-benzoxazin-1-one
In analogy to example 4, from 4- (3-fluoro-4-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid and 6-amino-2, 3-benzoxazin-1-one was obtained the title compound, melting point: 236 ℃ and 237 ℃.
EXAMPLE 86- [4- (2-bromo-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one preparation step 3-methyl-2-butenoic acid- (4-fluorophenyl) amide
A solution of 10.0g (0.1mol) of 3-methyl-2-butenoic acid in 200ml of THF is mixed at 0 ℃ with 9.4ml (0.1mol) of ethyl chloroformate and 14.1ml (0.1mol) of triethylamine. After 10 minutes at room temperature, 10.6ml (0.11mol) of 4-fluoroaniline were added thereto. The reaction was stirred at room temperature for 1 hour, diluted with water, and then extracted with ethyl acetate (1L). The organic phase is washed with saturated sodium chloride solution, dried (sodium sulfate) and concentrated by evaporation in vacuo. The residue was purified by column chromatography on silica gel with hexane-ethyl acetate. The yield was 18.8 g.
1H-NMR(CDCl3) δ (ppm) ═ 1.92(d, 3H), 2.25(d, 3H), 5.71(sept, 1H), 7.02(t, 2H), 7.13(br., 1H), 7.50(br., 2H)3, 4-dihydro-4, 4-dimethyl-6-fluoro-2-quinolone
9.4g (48.7mmol) of 3-methyl-2-butenoic acid- (4-fluorophenyl) amide were heated to 130 ℃ and 140 ℃ and mixed with 9.6g (73.5mmol) of aluminum trichloride in portions. After the addition was complete, the temperature was held at 80 ℃ for 30 minutes. Cooled to room temperature and then treated carefully with 60ml of ice water. After addition of 150ml of chloroform, the reaction was stirred for 15 minutes, acidified with dilute hydrochloric acid and extracted with chloroform (3X 150 ml). The combined organic extracts were washed with saturated sodium chloride solution, dried (sodium sulfate), and concentrated by evaporation in vacuo. Column chromatography on silica gel with hexane-ethyl acetate gave 6.0 g.
1H-NMR(CDCl3) δ (ppm) ═ 1.34(s, 6H), 2.48(s, 2H), 6.80(dd, 1H), 6.88(td, 1H), 7.02(dd, 1H), 9.02(br., 1H) 1-tert-butoxycarbonyl-3, 4-dihydro-4, 4-dimethyl-6-fluoro-2-quinolinone
A solution of 6.0g (30.9mmol) of 3, 4-dihydro-4, 4-dimethyl-6-fluoro-2-quinolone in 200ml of THF is mixed with 8.8g (40.2mmol) of di-tert-butyl carbonate and 4.9g (40.2mmol) of DMAP. After 24 hours at room temperature, concentration is carried out by evaporation and the residue is purified by column chromatography on silica gel with hexane-ethyl acetate. Yield: 9.0 g.
1H-NMR(CDCl3) δ (ppm) ═ 1.34(s, 6H), 1.61(s, 9H), 2.50(s, 2H), 6.91(m, 2H), 7.03(dd, 1H)3- (2-tert-butoxycarbonylamino-5-fluorophenyl) -3-methyl-1-butanol
To a solution of 44g (0.15mol) of 1-tert-butoxycarbonyl-3, 4-dihydro-4, 4-dimethyl-6-fluoro-2-quinolone in 1L of THF were added 375ml (0.75mol) of a 2M aqueous lithium hydroxide solution. After 24 hours at room temperature, the reaction was concentrated by evaporation, brought to pH 4 with 10% citric acid and extracted with diethyl ether. The combined organic extracts were washed with saturated sodium chloride solution, dried (sodium sulfate) and concentrated by evaporation in vacuo. The residue was subjected to column chromatography on silica gel with hexane-ethyl acetate to give 34.0g of 3- (2-tert-butoxycarbonylamino-5-fluorophenyl) -3-methylbutyric acid [2 ], [2- (tert-butoxycarbonylamino) -5-fluorophenyl ] -methyl-butyric acid1H-NMR(CDCl3)，δ(ppm)＝1.62(br s，15H)，2.77(s，2H)，6.41(br.1H)，6.93(td，1H)，7.07(dd，1H)，7.20(br.1H)]The acid was dissolved in 1L of THF and then mixed with 17ml (121mmol) of triethylamine and 11.5ml (121mmol) of ethyl chloroformate at 0 ℃. After 10 minutes at 0 ℃ 20.7g (546mmol) of sodium borohydride are added thereto and 1L of methanol is then slowly added dropwise. After stirring the reaction at 0 ℃ for 30 minutes, it was concentrated by evaporation and then diluted with ethyl acetate. Washing with saturated sodium chloride solution over sodium sulfateDried and purified by column chromatography on silica gel using hexane-ethyl acetate. Yield: 6.7 g.
1H-NMR(CDCl3) δ (ppm) ═ 1.40(s, 6H), 1.51(s, 9H), 2.06(t, 2H), 3.49(q, 2H), 6.32(br s, 1H), 6.91(ddd, 1H), 7.05(dd, 1H), 7.28(br, 1H)2, 2-dimethylpropionic acid- [3- (2-amino-5-fluorophenyl) -3-methylpropyl acid]Butyl ester
A solution of 6.7g (22.7mmol) of 3- (2-tert-butoxycarbonylamino-5-fluorophenyl) -3-methyl-1-butanol in 200ml of pyridine is mixed at 0 ℃ with 5.6ml of valeryl chloride. After 24 hours at room temperature, water was added thereto, followed by stirring at room temperature for 2 hours. The reaction was diluted with ethyl acetate, washed with 10% citric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried (sodium sulfate) and concentrated by evaporation in vacuo. Purification by column chromatography on silica gel with hexane-ethyl acetate gave 9.0g of 3- (2-tert-butoxycarbonylamino-5-fluorophenyl) -3-methyl ] butyl 2, 2-dimethylpropionate. 6.1g (16mmol) of the above-mentioned substance are dissolved in 100ml of dichloromethane and then mixed with 30ml of trifluoroacetic acid. After 30 minutes at room temperature, the reaction was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried (sodium sulfate) and concentrated by evaporation in vacuo. Column chromatography on silica gel with hexane-ethyl acetate afforded 4.0g of product.
1H-NMR(CDCl3) δ (ppm) ═ 1.15(s, 9H), 1.46(s, 6H), 2.15(t, 2H), 3.67(br, 2H), 3.92(t, 2H), 6.57(dd, 1H), 6.75(ddd, 1H), 6.92(dd, 1H)2, 2-dimethylpropionic acid- [3- (2-bromo-5-fluorophenyl) -3-methylpropyl acid]Butyl ester
A solution of 1.9g (8.5mmol) of copper (II) bromide and 1.4ml (7.0mmol) of tert-butylnitrite in 10ml of acetonitrile is heated to 65 ℃ and then mixed within 10 minutes with a solution of 2.0g (7.1mmol) of 3- (2-amino-5-fluorophenyl) -3-methyl-butyl-2, 2-dimethylpropionate in 10ml of acetonitrile. After 5 minutes at 65 ℃, cool to room temperature, concentrate by evaporation and purify the residue by column chromatography on silica gel with hexane-ethyl acetate: yield 1.6 g.
1H-NMR(CDCl3) δ (ppm) ═ 1.12(s, 9H), 1.52(s, 6H), 2.41(t, 2H), 3.88(t, 2H), 6.79(ddd, 1H), 7.12(dd, 1H), 7.53(dd, 1H)3- (2-bromo-5-fluorophenyl) -3-methylbutanol
A solution of 1.97g (5.7mmol) of 3- (2-bromo-5-fluorophenyl) -3-methyl ] butyl 2, 2-dimethylpropionate in 20ml of toluene is mixed with 11.9ml (14.3mmol) of a 1.2M solution of diisobutylaluminum hydride in toluene at-20 ℃. After 30 minutes at-20 ℃, the reaction was cooled to-70 ℃ and then mixed with 4ml isopropanol and 6ml water. After 2 hours at room temperature, the reaction was filtered and the filtrate was concentrated by evaporation in vacuo. Purification by column chromatography using hexane-ethyl acetate gave 1.25g of product.
1H-NMR(CDCl3) δ (ppm) ═ 1.52(s, 6H), 2.37(t, 2H), 3.45(q, 2H), 6.80(ddd, 1H), 7.12(dd, 1H), 7.54(dd, 1H)2- [ 1-benzoyl-3- (2-bromo-5-fluorophenyl) -3-methylbutyl]Furan compounds
A solution of 1.0g (3.8mmol) of 3- (2-bromo-5-fluorophenyl) -3-methylbutanol in 24ml of dichloromethane was treated with 8.5ml of DMSO, 2.66ml (19.2mmol) of triethylamine and 1.23g (7.7mmol) of pyridine-sulfur trioxide complex. After 1 hour at room temperature, the reaction was mixed with 30ml of saturated ammonium chloride solution and extracted with 400ml of diethyl ether after 15 minutes. The extract was washed with saturated sodium chloride, dried (sodium sulfate) and concentrated by evaporation in vacuo. The residue (1.1g) was dissolved in 8ml of THF and added at-70 ℃ over 30 minutes to a solution of 2-furyllithium in 38ml of THF, prepared from 0.85ml of furan (11.5mmol) and 7.7ml (123mmol) of a 1.6M solution of n-butyllithium in hexane according to the method of A.Dondononi et al, J.org.Chem.1997, 62, 5484. After 1.5 h at-70 ℃ the reaction was added to 50ml of saturated ammonium chloride solution and extracted with 400ml of MTBE. The organic phase is dried (sodium sulfate) and concentrated by evaporation in vacuo. The residue (1.1g) was dissolved in 40ml of pyridine and then reacted with 0.9ml (7.7mmol) of benzoyl chloride at 0 ℃. After 2 hours at 0 ℃ and 2 hours at room temperature, 30mg of DMAP were added thereto, and after a further 2 hours at room temperature, 0.9ml (7.7mmol) of benzoyl chloride were added. After 18 hours at room temperature, the reaction was mixed with 3ml of water and then concentrated by evaporation in vacuo. The residue is taken up in 400ml of MTBE and the solution obtained is washed with 10% citric acid and saturated sodium chloride solution, dried (sodium sulfate) and then concentrated by evaporation in vacuo. Further column chromatography over silica gel with hexane-ethyl acetate gave 1.46g of product.
1H-NMR(CDCl3) δ (ppm) ═ 1.52(s, 3H), 1.58(s, 3H), 2.53(dd, 1H), 3.33(dd, 1H), 6.10(dd, 1H), 6.26(m, 2H), 6.49(ddd, 1H), 6.97(dd, 1H), 7.34(m, 4H), 7.48(m, 1H), 7.81(m, 2H) methyl 2-benzoyl-4- (2-bromo-5-fluorophenyl) -4-methylpentanoate
A suspension of 10.9g (50.8mmol) sodium periodate in 140ml water-acetonitrile-tetrachloromethane (4: 2: 1) was mixed with 45mg (0.34mmol) of hydrated ruthenium (IV) oxide. After 10 minutes, a solution of 2- [ 1-benzoyl-3- (2-bromo-5-fluorophenyl) -3-methylbutyl ] furan in 40ml of acetonitrile was added thereto, stirred for a further 10 minutes, and the reaction was added to 400ml of a saturated sodium sulfite solution. The pH was adjusted to 5 with 10% citric acid and the reaction was extracted with ethyl acetate. The combined extracts were dried (sodium sulfate) and then concentrated by evaporation in vacuo. The residue was treated in 8ml of DMF and then with 0.42ml (6.8mmol) of methyl iodide and 2.21g (6.8mmol) of cesium carbonate. After 5 hours at room temperature, the reaction was diluted with 600ml of MTBE, washed with 10% sulfuric acid and saturated sodium chloride solution, dried (sodium sulfate) and concentrated by evaporation in vacuo. Column chromatography on silica gel with hexane-ethyl acetate afforded 0.9g of product.
1H-NMR(CDCl3) δ (ppm) ═ 1.58(s, 3H), 1.62(s, 3H), 2.55(dd, 1H), 3.10(dd, 1H), 3.72(s, 3H), 5.21(dd, 1H), 6.58(ddd, 1H), 7.03(dd, 1H), 7.35-7.47(m, 3H), 7.55(m, 1H), 7.83(m, 2H)4- (2-bromo-5-fluorophenyl) -2-hydroxy-4-methylpentanoic acid methyl ester
A solution of 0.9g (2.13mmol) of methyl 2-benzoyl-4- (2-bromo-5-fluorophenyl) -4-methylpentanoate in 50ml of methanol was mixed with 1.47g (10.6mmol) of potassium carbonate, followed by stirring at room temperature for 3 hours. The reaction was acidified with 10% sulfuric acid (pH3) and extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution, dried (sodium sulfate) and concentrated by evaporation in vacuo. The residue was taken up in 8ml of DMF and stirred with 1.92g (5.9mmol) of cesium carbonate and 0.38ml (5.9mmol) of iodomethane at room temperature for 3 hours. The reaction was mixed with 10% citric acid and extracted with MTBE. The organic phase is washed with saturated sodium chloride solution, dried (sodium sulfate) and concentrated by evaporation in vacuo. Column chromatography on silica gel with hexane-ethyl acetate afforded 250mg of product.
1H-NMR(CDCl3) δ (ppm) ═ 1.57(s, 3H), 1.61(s, 3H), 2.10(dd, 1H), 2.51(d, 1H), 2.82(dd, 1H), 3.74(s, 3H), 3.96(ddd, 1H), 6.81(ddd, 1H), 7.22(dd, 1H), 7.55(dd, 2H)6- [4- (2-bromo-5-fluorophenyl) -4-methyl-2-oxopentanoylamino]-4-methyl-2, 3-benzoxazin-1-one
To a solution of 250mg (0.78mmol) of methyl 4- (2-bromo-5-fluorophenyl) -2-hydroxy-4-methylpentanoate in 10ml of dichloromethane were added 663mg (1.56mmol) of 1, 1, 1-triacetoxy-1, 1-dihydro-1, 2-benzidoxol-3 (1H) -one (Dess-Martin-Periodinan, see D.B.dess, J.C.Martin, J.am.chem.Soc.1991, 113, 7277). After 1.5 h at room temperature, the reaction was diluted with 150ml of MTBE, washed with a solution of 1.2g of sodium bicarbonate and 4.0g of sodium sulfite in 50ml of water, a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried (sodium sulfate) and concentrated by evaporation in vacuo. The residue (250mg) was treated with 16ml of THF-ethanol (1: 1) and then mixed with 3.9ml (3.9mmol) of 1M sodium hydroxide solution. After 30 minutes, the reaction was concentrated in vacuo, diluted with 20ml of water and washed with MTBE. The aqueous phase is acidified with 10% sulfuric acid (pH2) and then extracted with 100ml of ethyl acetate and 100ml of dichloromethane. The combined extracts were dried (sodium sulfate) and concentrated by evaporation in vacuo. The residue (230mg) was dissolved in 5ml of dimethylacetamide, and then 0.06ml (0.92mmol) of thionyl chloride was added dropwise to the solution at-6 ℃. After 20 minutes at-60 ℃ 201mg (1.14mmol) of 6-amino-4-methyl-2, 3-benzoxazin-1-one are added. The reaction was stirred at room temperature for 15 hours, acidified with 50ml of 10% citric acid and extracted with 150ml of TMBE with shaking. The organic phase is washed with saturated sodium chloride solution, dried (sodium sulfate) and concentrated by evaporation in vacuo. Column chromatography on silica gel with hexane-ethyl acetate afforded 290mg of product.
1H-NMR([D]6-DMSO), δ (ppm) 1.57(s, 6H), 2.5(s, 3H; DMSO signal), 3.89(s, 2H), 7.03(ddd, 1H), 7.34(dd, 1H), 7.62(dd, 1H), 8.25(d, 1H), 8.33(m, 2H), 11.03(br., 1H)
MS(CI)m/z＝461，463(M+)6- [4- (2-bromo-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleryl Radical amino]-4-methyl-2, 3-benzoxazin-1-one
To a solution of 290mg (0.63mmol)6- [4- (2-bromo-5-fluorophenyl) -4-methyl-2-oxopentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one in 7ml DMF at 0 ℃ are added 0.23ml (1.25mmol) trifluoromethyl (trimethyl) silane and 256mg (0.79mmol) cesium carbonate. After 24 hours, the same amount of silane and base was added and stirring was continued at room temperature for 24 hours. The reaction was diluted with 150ml of ethyl acetate, washed with water and saturated sodium chloride solution, dried (sodium sulfate) and concentrated by evaporation in vacuo. Purification by column chromatography on silica gel gave 230mg of product.
1H-NMR(CDCl3)，δ(ppm)＝1.55(s，3H)，1.63(s，3H)，2.58(s，3H)，3.10(br.s，1H)，6.63(ddd，1H)，7.11(dd，1H)，7.40(dd，1H)，7.62(dd，1H)，8.14(d，1H)，8.33(d，1H)，8.52(br s，1H)
MS(CI)m/z＝531，533(M+)
Example 96- [4- (indan-4' -yl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one preparation: 4- (1-hydroxy-1-methylethyl) indane
To a solution of 1.6g (10mmol) of 4-acetylindane (F. Dallacker, J. Van Wersch, chem. Ber.1972, 105, 2565) in 40ml of THF is added dropwise a solution of 10ml (14mmol) of 1.4M methylmagnesium bromide in toluene-THF (3: 1) at 0 ℃. After 30 minutes at 0 ℃ and 1.5 hours at room temperature, the reaction is diluted with 200ml of ethyl acetate, washed with 1M hydrochloric acid and saturated sodium chloride solution, dried (sodium sulfate) and concentrated by evaporation in vacuo. The residue was purified by column chromatography on silica gel with hexane-ethyl acetate to give 0.64g of a product.
1H-NMR(CDCl3) δ (ppm) ═ 1.64(s, 6H), 1.74(s, 1H), 2.07(pent, 2H), 2.90(t, 2H), 3.16(t, 2H), 7.11-7.19(m, 2H), 7.29(m, 1H)4- (indan-4' -yl) -4-methyl-2-oxopentanoic acid
0.63g (3.4mmol) of 4- (1-hydroxy-1-methylethyl) indane is mixed with 0.96g (5.1mmol) of ethyl 2-trimethylsiloxyacrylate (H.Sugimura, K.yoshida, Bull.chem.Soc.Jpn.1992, 65, 3209) in 20ml of dichloromethane and then treated with 0.31ml (2.6mmol) of tin (IV) chloride at-70 ℃. After 20 minutes at-70 ℃, the reaction was added to a semi-concentrated potassium carbonate solution and then extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution, dried (sodium sulfate) and concentrated by evaporation in vacuo. 0.89g of an oil is obtained, which is dissolved in 30ml of ethanol-THF (2: 1) and reacted with 12.8ml (12.8mmol) of 1M sodium hydroxide solution. After 2 hours at room temperature, the reaction was concentrated by evaporation in vacuo and the residue was taken up in 30ml of water. The aqueous phase is washed with diethyl ether and then acidified with 50ml of 1M hydrochloric acid. Extraction with ethyl acetate, drying (sodium sulphate) and concentration by evaporation gave 0.64g of acid.
1H-NMR(CDCl3) δ (ppm) ═ 1.52(s, 6H), 2.07(pen, 2H), 2.85(t, 2H), 3.08(t, 2H), 3.42(s, 2H), 5.02(br.), 7.04-7.17(m, 3H)6- [4- (indan-4' -yl) -4-methyl-2-oxovalerylamino]-4-methyl-2, 3-benzoxazin-1-one
The title compound was prepared according to the method of example 1 from 0.63g (2.6mmol) of 4- (indan-4' -yl) -4-methyl-2-oxopentanoic acid and 0.69g (3.9mmol) of 6-amino-4-methyl-2, 3-benzoxazin-1-one to give 0.31g of product.
1H-NMR(CDCl3)，δ(ppm)＝1.56(s，6H)，2.08(pent，2H)，2.59(s，3H)，2.83(t，2H)，3.12(t，2H)，3.52(s，2H)，7.07-7.17(m，3H)，7.72(dd，1H)，8.20(d，1H)，8.36(d，1H)，8.87(br s，1H)6- [4- (indan-4' -yl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino] Di 4-methyl-2, 3-benzoxazine-1-one
Following the preliminary steps in example 1, 0.31g (0.77mmol) of 6- [4- (indan-4' -yl) -4-methyl-2-oxovalerylamino ] -4-methyl-2, 3-benzoxazin-1-one was reacted with 0.56ml (3.1mmol) of trifluoromethyl (trimethyl) silane and 626mg (1.9mmol) of cesium carbonate in 9ml of DMF. Column chromatography on silica gel with hexane-ethyl acetate afforded 90mg of product.
1H-NMR(CDCl3)，δ(ppm)＝1.47(s，3H)，1.49(s，3H)，2.11(m，2H)，2.62(s，3H)，2.76-2.92(m，4H)，2.96(s，1H)，3.17(t，2H)，7.14(m，4H)，7.63(dd，1H)，8.28(d，1H)，8.35(d，1H)，8.88(br s，1H)
MS(CI)m/z＝475(M+) The enantiomer was isolated from example 9:
the mixture of enantiomers obtained in example 9 was chromatographed on a chiral support material (CHIRALPAKAD , DAICEL Co.) using hexane/ethanol (95: 5, vv). Obtained from 830mg of racemate: (-)6- [4- (indan-4' -yl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino]-4-methyl-2, 3-benzoxazine-1-one, fraction: 310mg, MS (CI) m/z 475 (MH)+) α D ═ 55.7 ° (c ═ 0.5 in tetrahydrofuran), and (+)6- [4- (indan-4' -yl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino]-4-methyl-2, 3-benzoxazine-1-ketone, second fraction: 280mg, melting point: 196 ℃ 197 ℃, α D +55.7 ° (c 0.5 in tetrahydrofuran).
Example 106- [4- (5-fluoro-2-vinylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one 2-benzoyl-4- (5-fluoro-2-vinylphenyl) -4-methylpentanoic acid methyl ester
A solution of 0.53g (1.25mmol) of methyl 2-benzoyl-4- (2-bromo-5-fluorophenyl) -4-methylpentanoate and 77mg (0.07mmol) of tetrakis (triphenylphosphine) palladium in 40ml of toluene is heated at reflux with vinyl (tributyl) tin for 8 h. Evaporated and purified by column chromatography on silica gel with hexane-ethyl acetate: 320mg of product.
1H-NMR(CDC13) δ (ppm) ═ 1.51(s, 3H), 1.55(s, 3H), 2.44(dd, 1H), 2.66(dd, 1H), 3.70(s, 3H), 5.14(dd, 1H), 5.33(dd, 1H), 5.43(dd, 1H), 6.77(td, 1H), 6.97(dd, 1H), 7.22-7.33(m, 2H), 7.48(m, 2H), 7.55(m, 1H), 7.80(d, 2H) methyl 4- (5-fluoro-2-vinylphenyl) -2-hydroxy-4-methylpentanoate
The preparation is carried out analogously to example 8.
1H-NMR(CDCl3) δ (ppm) ═ 1.48(s, 3H), 1.53(s, 3H), 1.98(dd, 1H), 2.46(dd, 1H), 2.50(d, 1H), 3.70(s, 3H), 3.96(ddd, 1H), 5.28(dd, 1H), 5.41(dd, 1H), 6.90(td, 1H), 7.12(dd, 1H), 7.25(dd, 1H), 7.33(dd, 1H)6- [4- (5-fluoro-2-vinylphenyl) -4-methyl-2-oxopentanoylamino group]-4-methyl-2, 3-benzoxazin-1-one
The preparation is carried out analogously to example 8.
1H-NMR(CDCl3)，δ(ppm)＝1.56(s，6H)，2.58(s，3H)，3.65(s，2H)，5.28(dd，1H)，5.34(dd，1H)，6.91(td，1H)，7.13(dd，1H)，7.20-7.30(m，2H)，7.78(dd，1H)，8.22(d，1H)，8.35(d，1H)，8.98(br，1H)6- [4- (5-fluoro-2-vinylphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl Pentanoylamino group]-4-ARadical-2, 3-benzoxazin-1-ones
The preparation is carried out analogously to example 8.
1H-NMR(CDCl3)，δ(ppm)＝1.47(s，3H)，1.54(s，3H)，2.60(s，3H)，2.87(m，3H)，5.45(dd，1H)，5.50(dd，1H)，6.85(td，1H)，7.06(dd，1H)，7.25-7.37(m，2H)，7.67(dd，1H)，8.18(d，1H)，8.34(d，1H)，8.73(br s，1H)
MS(ES+)m/z＝479(MH+)
Example 116- [ 2-hydroxy-4-methyl-2-trifluoromethyl-4- (4-trifluoromethylphenyl) -pentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one 2-methyl-2- (4-trifluoromethylphenyl) propionitrile
A solution of 6.80g (41.4mmol) of 4-fluorotrifluorotoluene in 250ml of toluene was mixed at 0 ℃ with 124ml (62mmol) of a 0.5M solution of potassium hexamethyldisilazide-THF and 9.44g (137mmol) of isobutyronitrile. The reaction was stirred at 60 ℃ for 4 hours, cooled and diluted with water and ethyl acetate. The organic phase is separated, washed with 10% sulfuric acid and saturated sodium chloride solution, dried (sodium sulfate) and then concentrated by evaporation in vacuo. Column chromatography on silica gel with hexane-ethyl acetate gave 7.68g of product.
1H-NMR(CDCl3) δ (ppm) ═ 1.76(s, 6H), 7.62(d, 2H), 7.68(d, 2H) ethyl 4-methyl-4- (4-trifluoromethylphenyl) -2-pentenoate
A solution of 7.6g (36mmol) of 2-methyl-2- (4-trifluoromethylphenyl) propionitrile in 250ml of toluene is mixed at-70 ℃ with 57ml (68mmol) of a 1.2M solution of diisobutylaluminum hydride in toluene. After 1 hour at-70 ℃, 10% tartaric acid was added dropwise thereto and stirred at room temperature for 15 minutes. The reaction was diluted with ether, the organic phase was separated and washed with saturated aqueous sodium chloride solution, dried (sodium sulfate), concentrated by evaporation in vacuo: 7.96g of crude 2-methyl-2- (4-trifluoromethylphenyl) propanal. 2.05g (9.25mmol) of this material were dissolved in 6ml of DME and then added dropwise to a solution prepared from 3.10g (13.9mmol) of triethyl phosphonoacetate and 0.55g (13.9mmol) of 60% sodium hydride in 12ml of DME. After 1 hour at room temperature, the reaction was mixed with a saturated ammonium chloride solution and then diluted with ethyl acetate and water. The phases were separated, the aqueous phase being extracted with ethyl acetate and the combined organic extracts washed with saturated sodium chloride solution, dried (sodium sulphate) and concentrated by evaporation in vacuo. The residue was purified on silica gel with hexane-ethyl acetate: 1.72g of product.
1H-NMR(CDCl3) δ (ppm) ═ 1.30(t, 3H), 1.49(s, 6H), 4.21(q, 2H), 5.82(d, 1H), 7.10(d, 1H), 7.43(d, 2H), 7.59(d, 2H) ethyl 2-hydroxy-4-methyl-4- (4-trifluoromethylphenyl) pentanoate
1.72g (6.0mmol) of ethyl 4-methyl-4- (4-trifluoromethylphenyl) -2-pentenoate were stirred in the presence of 0.17g of a 10% palladium on activated carbon catalyst under a hydrogen atmosphere (1 atm). The reaction was filtered over Celite and then concentrated by evaporation in vacuo: 1.72g of ethyl 4-methyl-4- (4-trifluoromethylphenyl) pentanoate. 0.57g (2.0mmol) of this material was dissolved in 7ml of THF and then treated with 5.6ml (2.8mmol) of potassium hexamethyldisilazide-toluene solution at-78 ℃. After 25 minutes, a solution of 0.73g (2.8mmol) of 3-phenyl-2-phenylsulfonyloxaziridine (F.A. Davis, S.Chattopadhyay, J.C. Towson, S.Lai, T.Reddy J.org.chem.1988, 53, 2087) in 7ml of THF is added dropwise and stirred at-78 ℃ for 30 minutes. The reaction was mixed with a saturated ammonium chloride solution and then warmed to room temperature over 1 hour. The THF is removed in vacuo, the residue is treated with diethyl ether, the solid material is removed by filtration, the phases are separated and the aqueous phase is extracted with diethyl ether. The combined organic extracts were washed with saturated sodium chloride solution, dried (sodium sulfate), and concentrated by evaporation in vacuo. Column chromatography on silica gel with hexane-ethyl acetate afforded 0.14g of product.
1H-NMR(CDCl3)，δ(ppm)＝1.26(t，3H)，1.42(s，3H)，1.50(s，3H)，1.90(dd，1H)，2.10(br，1H)，2.24(dd，1H)，3.94(dd，1H)，4.15(m，2H) 7.53(d, 2H), 7.60(d, 2H)6- [ 4-methyl-2-oxo-4- (4-trifluoromethylphenyl) -pentanoylamino]-4-methyl-2, 3-benzoxazin-1-one
The preparation is carried out analogously to example 8.
1H-NMR(CDCl3)，δ(ppm)＝1.53(s，6H)，2.58(s，3H)，3.47(s，2H)，7.50(d，2H)，7.58(d，2H)，7.78(dd，1H)，8.21(d，1H)，8.35(d，1H)，8.98(br，1H)
MS(CI)m/z＝433(MH+)6- [ 2-hydroxy-4-methyl-2-trifluoromethyl-4- (4-trifluoromethylphenyl) -pentanoylamino]-4-methyl-2, 3-benzoxazin-1-one
The preparation is carried out analogously to example 8.
1H-NMR(CDCl3)，δ(ppm)＝1.47(s，3H)，1.50(s，3H)，2.53(d，1H)，2.58(s，3H)，2.91(s，1H)，2.95(d，1H)，7.55(s，4H)，7.62(dd，1H)，8.18(d，1H)，8.33(d，1H)，8.73(br s，1H)
MS(ES+)m/z＝503(MH+)
Example 126- [4- (2-bromo-3, 5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentanoylamino]-4-methyl-2, 3-benzoxazin-1-one
The preparation is carried out analogously to example 8.
1H-NMR(CDCl3)，δ(ppm)＝1.56(s，3H)，1.64(s，3H)，2.58(s，3H)，3.00(d，1H)，3.22(d，1H)，3.3 1(br s，1H)，6.58(td，1H)，6.97(dt，1H)，7.64(dd，1H)，8.11(d，1H)，8.34(d，1H)，8.43(br s，1H)
Example 136- [4- (3, 5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl-pentanoylamino]-4-methyl-2, 3-benzoxazin-1-one
Example 13 is a by-product of the synthesis of example 12.
1H-NMR(CDCl3)，δ(ppm)＝1.41(s，3H)，1.44(s，3H)，2.44(d，1H)，2.60(s，3H)，2.80(br s，1H)，2.89(d，1H)，6.53(tt，1H)，6.92(m，2H)，7.66(dd，1H)，8.24(d，1H)，8.35(d，1H)，8.70(br s，1H)
EXAMPLE 146- [4- (5-fluoro-2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one 2- (5-fluoro-2-trifluoromethylphenyl) -acetonitrile
1.95g (30mmol) of potassium cyanide were added to a solution of 5.14g (20mmol) of 5-fluoro-2-trifluoromethylbenzyl bromide in 45ml of ethanol/8 ml of water, followed by stirring at room temperature for 64 hours. The reaction solution was diluted with ethyl acetate and then extracted with saturated aqueous sodium bicarbonate. The organic phase is washed with water, dried and concentrated by evaporation. The residue was purified by rotary evaporation and then recrystallized. Yield: 3.6g (89%).
Melting point: 2- (5-fluoro-2-trifluoromethylphenyl) -2-methylpropanenitrile at 41-42 DEG C
In analogy to the preparation of 2- (5-fluoro-2-methylphenyl) -2-methylpropanenitrile, 2- (5-fluoro-2-trifluoromethylphenyl) -2-methylpropanenitrile was obtained as an oil with the boiling point: 90 ℃/0.04 hPa. 2- (5-fluoro-2-trifluoromethylphenyl) -2-methylpropionaldehyde
In analogy to the preparation of 2- (5-fluoro-2-methylphenyl) -2-methylpropanal, 2- (5-fluoro-2-trifluoromethylphenyl) -2-methylpropanal is obtained as an oil with a boiling point: 80C/0.04 hPa. 4- (5-fluoro-2-trifluoromethylphenyl) -4-methyl-2-oxopentanoic acid
In analogy to the procedure for 4- (5-fluoro-2-methylphenyl) -4-methyl-2-oxopentanoic acid, 4- (5-fluoro-2-trifluoromethylphenyl) -4-methyl-2-oxopentanoic acid was obtained as a viscous oil. 6- [4- (5-fluoro-2-trifluoromethylphenyl) -4-methyl-2-oxovalerylamino ] -4-methyl-2, 3-benzoxazin-1-one
6- [4- (5-fluoro-2-trifluoromethylphenyl) -4-methyl-2-oxopentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one was synthesized analogously to 6- [4- (5-fluoro-2-methylphenyl) -4-methyl-2-oxopentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one.
1H-NMR(CDCl3+DMSO)，δ(ppm)＝1.47(s，6H)，2.44(s，3H)，3.59(s，2H)，6.92(dt，1H)，7.33(dd，1H)，7.61(dd，1H)，8.03(dd，1H)，8.16(d，1H)，8.30(d，1H)，10.34(bs，1H)6- [4- (5-fluoro-2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethyl Pivaloylamino group]-4-methyl-2, 3-benzoxazin-1-one
6- [4- (5-fluoro-2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one was synthesized in analogy to the synthesis of 6- [4- (5-fluoro-2-methylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one.
1H-NMR(CDCl3)，δ(ppm)＝1.42(s，3H)，1.55(s，3H)，2.56(d，1H)，2.57(s，3H)，2.91(d，1H)，3.28(bs，1H)，6.85(dt，1H)，7.32(dd，1H)，7.56-7.66(m，2H)，8.13(d，1H)，8.34(d，1H)，8.51(bs，1H)
MS(EI)m/z＝520(M+) The enantiomer was isolated from example 14:
the mixture of enantiomers obtained in example 14 was chromatographed on a chiral support material (CHIRALPAKAD , DAICEL Co.) using hexane/ethanol (19: 1, vv). Obtained from 100mg of racemate: (-)6- [4- (5-fluoro-2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one, first fraction: 40mg, melting point: 162-: 38mg, melting point: 160 ℃ and 165 ℃.
The compounds shown in table 4 were prepared analogously to example 14. Trifluoromethyl compound
TABLE 4
Example 156- [ 2-hydroxy-4-methyl-2-trifluoromethyl-4- (1-naphthyl) -pentanoylamino]-4-methyl-2, 3-benzoxazin-1-one 2-methyl-2- (1-naphthyl) -propionitrile
| Compound (I) | R5 | R6 | R7 | R8 | R1/R2 | Melting Point (. degree.C.) | Isomer or [ alpha ]]D |
| 1 | H | H | H | H | CH3 | 154-156 | Racemic modification |
| 2 | H | H | H | H | CH3 | 164-170 | -72.8 |
| 3 | H | H | H | H | CH3 | 188-190 | +69.0 |
| 4 | H | F | H | H | CH3 | 170-172 | Racemic modification |
| 5 | H | F | H | H | CH3 | 173-175 | -67.5 |
| 6 | H | F | H | H | CH3 | 174-177 | (+) -form |
| 7 | H | H | F | H | CH3 | 170 | Racemic modification |
| 8 | H | H | F | H | CH3 | 162-166 | -45.5 |
| 9 | H | H | F | H | CH3 | 160-165 | (+) -form |
| 10 | H | H | Cl | H | CH3 | 172 | Racemic modification |
| 11 | H | H | Cl | H | CH3 | 178-181 | -143.1 |
| 12 | H | H | Cl | H | CH3 | 180-182 | (+) -form |
A solution of 16.7g (100mmol) of 1-naphthylacetonitrile in 200ml of DMF and 15ml (240mmol) of iodomethane is mixed at 0 ℃ with 10.4g (260mmol) of sodium hydride (added over 2.5 h). The reaction was stirred at 0 ℃ for 3 hours and then at 25 ℃ for 18 hours. Mixed with ice and ethyl acetate. The organic phase is acidified with 10% sulfuric acid, washed three times with water, dried (sodium sulfate) and then concentrated by evaporation in vacuo. Crude purification was carried out by rotary distillation (boiling range 60-130 ℃) in oil pump vacuum, yield: 18.8 g.
1H-NMR(CDCl3) δ (ppm) ═ 2.00(s, 6H), 7.41 to 7.60(m, 3H), 7.64(ddd, 1H), 7.87(d br, 1H), 7.93(dd, 1H), 8.55(d, 1H) ethyl 4-methyl-4- (1-naphthyl) -2-pentenoate
In analogy to the preparation of ethyl 4-methyl-4- (4-trifluoromethylphenyl) -2-pentenoate in example 11, 7.62g of product were obtained from 8.81g (45.1mmol) of 2-methyl-2- (1-naphthyl) -propionitrile.
1H-NMR(CDCl3)，δ(ppm)＝1.25(t，3H)，1.70(s，6H)，4.16(q，2H) 5.73(d, 1H), 7.38-7.50(m, 4H), 7.53(dd, 1H), 7.78(d, 1H), 7.81-7.89(m, 1H), 8.00-8.08(m, 1H) 2-hydroxy-4-methyl-4- (1-naphthyl) -pentanoic acid ethyl ester
In analogy to the preparation of ethyl 2-hydroxy-4-methyl-4- (4-trifluoromethylphenyl) pentanoate in example 11, 0.52g of product was obtained from 7.62g (28.4mmol) of ethyl 4-methyl-4- (1-naphthyl) -2-pentenoate.
1H-NMR(CDCl3) δ (ppm) ═ 1.14(t, 3H), 1.72(s, 3H), 1.74(s, 3H), 2.27(dd, 1H), 2.52(dd, 1H), 2.76(dd, 1H), 3.95-4.08(m, 3H), 7.38-7.51(m, 3H), 7.57(d, 1H), 7.75(d, 1H), 7.88(dd, 1H), 8.40(d, 1H)6- [ 4-methyl-2-oxo-4- (1-naphthyl) -pentanoylamino]-4-methyl-2, 3-benzoxazin-1-one
Prepared in analogy to example 11. 861mg of product are obtained.
1H-NMR(CDCl3)，δ(ppm)＝1.59(s，3H)，1.78(s，6H)，2.57(s，3H)，3.88(s，2H)，7.44(m，2H)，7.54(m，2H)，7.69(dd，1H)，7.75(d br，1H)，7.87(dd，1H)，8.15(d，1H)，8.32(d，1H)，8.46(d br，1H)6- [ 2-hydroxy-4-methyl-2-trifluoromethyl-4- (1-naphthyl) -pentanoylamino] -4-methyl-2, 3-benzoxazin-1-one
Prepared in analogy to example 11. 77.1mg of product are obtained
1H-NMR(CDCl3) δ (ppm) ═ 1.57(s, 3H), 1.67(s, 3H), 1.78(s, 3H), 2.45(s, 2H), 3.10(d, 1H), 3.23(d, 1H), 5.30(s, 2H), 7.25-7.38(m, 2H), 7.46(dd, 1H), 7.51(d, 1H), 7.60(m, 2H), 7.76(d, 1H), 7.97(d br, 1H), 8.24(d, 1H), 8.42(d, 1H) example 166- [3- {1- (2-chlorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl group]-amino-4-methyl-2, 3-benzoxazine-1-one preparation step: 1- (2-chlorophenyl) -cyclopropane-carbonitrile
A solution of 13.1g of 2-chlorophenylacetonitrile and 20.3g of 1, 2-dibromopropane in 142ml of DMF is mixed with 9g of sodium hydride (55-65% in oil) at room temperature. Stirred for several hours and then carefully added to water. After extraction with ethyl acetate and filtration over celite, the desired product is obtained: 13.1 g.
MS(ei)：M(+)1771- (2-chlorophenyl) -1-cyclopropanecarboxaldehyde
A solution of 13.1g of 1- (2-chlorophenyl) -cyclopropane-carbonitrile in 116ml of toluene was mixed dropwise with 64.5ml of diisobutylaluminum hydride at-70 ℃. After 4 hours at-70 ℃ it was mixed with 343ml of ethyl acetate. Left overnight at room temperature. Water and ethyl acetate were added, filtered over celite, and the ethyl acetate solution was washed with water, dried (sodium sulfate), and then concentrated by evaporation. Flash chromatography on silica gel with hexane-ethyl acetate (8: 2) gave the product: 9.7 g.
MS(ei)：M(+)1802-ethoxy-3- [1- (2-chlorophenyl) -1-cyclopropyl]-acrylic acid ethyl ester
14.3g of phosphonate are mixed with 29ml of lithium diisopropylamide in 40ml of tetrahydrofuran at 0 ℃. Stirring was carried out at 0 ℃ for 20 minutes. A solution of 9.7g of 1- (2-chlorophenyl) -1-cyclopropanecarboxaldehyde in 40ml of tetrahydrofuran is added dropwise thereto. After 24 hours at room temperature, it was mixed with water, extracted with ethyl acetate, and the ethyl acetate solution was washed with water and then dried (sodium sulfate). Evaporation concentration gave the product: 15.5 g.
MS(ei)：M(+)2942-ethoxy-3- [1- (2-chlorophenyl) -1-cyclopropyl]-acrylic acid
15.4g of 2-ethoxy-3- [1- (2-chlorophenyl) -1-cyclopropyl ] -acrylic acid ethyl ester are stirred in 350ml of 1M sodium hydroxide solution (ethanol-water 2: 1) at room temperature for 24 hours. The solvent was distilled off, the residue was partitioned between water and diethyl ether, the aqueous solution was acidified with 2N hydrochloric acid and extracted with diethyl ether. The organic phase is washed with water, dried (sodium sulfate) and then concentrated by evaporation to give the product: 11.2 g.
MS(ei)：M(+)2663- [1- (2-chlorophenyl) -1-cyclopropyl ═]-2-oxo-propionic acid
11.2g of 2-ethoxy-3- [1- (2-chlorophenyl) -1-cyclopropyl ] -acrylic acid are stirred in 230ml of 1M sulfuric acid and 42ml of concentrated acetic acid at 110 ℃ for 24 hours. Water was added, extraction was performed with ethyl acetate, and the ethyl acetate solution was washed with water. After drying (sodium sulfate) and concentration by evaporation the product is obtained: 10.7 g.
MS(ei)：M(+)＝238
1H-NMR(CDCl3) δ (ppm) ═ 0.98(m, 4H), 3.28(s, 3H), 7.13 to 7.22(m, 2H), 7.29 to 7.35(m, 1H), 7.43 to 7.49(m, 1H)6- {3- [1- (2-chlorophenyl) -cyclopropyl]-2-oxopropanoylamino } -4-methyl-2, 3-benzoxazin-1-one
10.7g of 3- [1- (2-chlorophenyl) -1-cyclopropyl ] -2-oxo-propionic acid are mixed in 175ml of dimethylacetamide at-5 ℃ with 4.1ml of thionyl chloride and then stirred for 20 minutes. 5.0g of MBO solid was added. After 20 hours at room temperature, water and ethyl acetate were added, the ethyl acetate solution was washed with water, dried (sodium sulfate) and then concentrated by evaporation. After chromatography on silica gel with hexane-ethyl acetate (0% -30%), the product is obtained: 9.6 g.
MS(ei)：M(+)3976- [3- {1- (2-chlorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino-l-4-methyl-2, 3-benzoxazin-1-one
9.5g of 6- {3- [1- (2-chlorophenyl) -cyclopropyl ] -2-oxopropanoylamino } -4-methyl-2, 3-benzoxazin-1-one were mixed in 140ml of dimethylformamide at 0 ℃ with 16.9ml of trifluoromethyl-trimethylsilane and 9.65g of cesium carbonate. After 24 hours at room temperature, a spatula of tetrabutylammonium fluoride hydrate was added and then stirred for 30 minutes. Mixed with water and ethyl acetate, the ethyl acetate solution washed with water, dried (sodium sulfate) and concentrated by evaporation. After chromatography on silica gel with hexane-ethyl acetate (0% -30%), the product is obtained: 2.98 g.
Melting point: the enantiomer was separated at 195-196 ℃ from example 16:
the mixture of enantiomers obtained in example 16 was chromatographed on a chiral support material (CHIRALPAKAD , DAICEL Co.) using hexane/ethanol (19: 1, vv). Obtained from 2.68g of racemate: (-)6- [3- {1- (2-chlorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one, first fraction: 1.3g, melting point: 233-: 1.25g, melting point: 238 and 240C.
The compounds shown in tables 5 to 8 were prepared analogously to example 16. Chlorine compounds
TABLE 5
Trifluoromethyl compound
| Compound (I) | R5 | R6 | R7 | R8 | n | Melting Point (. degree.C.) | Isomer or [ alpha ]]D |
| 1 | H | H | H | H | 2 | 231-233 | -47.1 |
| 2 | H | H | H | H | 2 | 230-232 | (+) -form |
| 3 | H | H | H | H | 3 | 195-197 | -70.5 |
| 4 | H | H | H | H | 3 | 202-203 | (+) -form |
| 5 | H | F | H | H | 1 | 228-230 | Racemic modification |
| 6 | H | F | H | H | 1 | 218-219 | -88.6 |
| 7 | H | F | H | H | 1 | 217-219 | (+) -form |
| 8 | H | F | H | H | 2 | 212-214 | Racemic modification |
| 9 | H | F | H | H | 2 | 236-238 | +74.2 |
| 10 | H | F | H | H | 2 | 235-237 | -75.0 |
| 11 | H | H | F | H | 1 | 196 | Racemic modification |
| 12 | H | H | F | H | 1 | 239-240 | -95.4 |
| 13 | H | H | F | H | 1 | 239-240 | (+) -form |
| 14 | H | H | F | H | 2 | 222-223 | Racemic modification |
| 15 | H | H | F | H | 2 | 247-249 | 77.6 |
| 16 | H | H | F | H | 2 | 247-249 | +79.6 |
| 17 | H | Cl | H | H | 1 | 235-239 | -81.6 |
| 18 | H | Cl | H | H | 1 | 199-201 | (+) -form |
| 19 | H | Cl | H | H | 2 | 232 | -46.7 |
| 20 | H | Cl | H | H | 2 | 232-234 | (+) -form |
TABLE 6
Fluorine compounds
| Compound (I) | R5 | R6 | R7 | R8 | n | Melting Point (. degree.C.) | Isomer or [ alpha ]]D |
| 21 | H | H | H | H | 1 | 205 | Racemic modification |
| 22 | H | H | H | H | 1 | 222-223 | -96.5 |
| 23 | H | H | H | H | 1 | 219-221 | (+) -form |
| 24 | H | H | H | H | 2 | 218-222 | Outer coverRacemic modification |
| 25 | H | H | H | H | 2 | 220-221 | -16.4 |
| 26 | H | H | H | H | 2 | 220-222 | (+) -form |
| 27 | H | H | H | H | 4 | 150-153 | Racemic modification |
| 28 | H | H | F | H | 1 | 242-245 | Racemic modification |
| 29 | H | H | F | H | 1 | 235-246 | -40.1 |
| 30 | H | H | F | H | 1 | 244-246 | (+) -form |
| 31 | H | H | F | H | 2 | 241-244 | Racemic modification |
| 32 | H | H | F | H | 2 | 242-244 | -82.7 |
| 33 | H | H | F | H | 2 | 242-244 | (+) -form |
TABLE 7
Bromine compound
| Compound (I) | R5 | R6 | R7 | R8 | n | Melting Point (. degree.C.) | Isomer or [ alpha ]]D |
| 34 | H | H | H | H | 1 | 215-216 | Racemic modification |
| 35 | H | H | H | H | 1 | 260-262 | -113.3 |
| 36 | H | H | H | H | 1 | 260-263 | (+) -form |
| 37 | H | H | H | H | 2 | 190-191 | Racemic modification |
| 38 | H | H | H | H | 2 | 198-201 | -103.4 |
| 39 | H | H | H | H | 2 | 207-209 | +103 |
| 40 | H | H | H | H | 3 | 168-171 | -117.6 |
| 41 | H | H | H | H | 3 | 167-170 | +112.3 |
| 42 | H | H | H | H | 4 | 90-93 | Racemic modification |
| 43 | H | H | H | H | 4 | 178-184 | -105 |
| 44 | H | H | F | H | 4 | 185-187 | +102.6 |
| 45 | F | H | F | H | 1 | 230-232 | Racemic modification |
| 46 | F | H | H | H | 1 | 238-250 | -106.3 |
| 47 | F | H | H | H | 1 | 254-256 | (+) -form |
| 48 | F | H | H | H | 2 | 182-185 | Racemic modification |
| 49 | H | H | F | H | 1 | 198-199 | Racemic modification |
| 50 | H | H | F | H | 1 | 240 | -130.2 |
| 51 | H | H | F | H | 1 | 241 | (+) -form |
| 52 | F | H | F | H | 1 | 215 | Racemic modification |
| 53 | F | H | F | H | 2 | 205 | Racemic modification |
TABLE 8
Example 176- [ 2-hydroxy-4-methyl-4- (3-methyl-2-nitrophenyl) -2-trifluoromethylpentanoylamino]-4-methyl-2, 3-benzoxazine-1-one preparation step: 2-methyl-2- (3-methyl-2-nitrophenyl) -propionitrile
| Compound (I) | R5 | R6 | R7 | R8 | n | Melting Point (. degree.C.) | Isomer or [ alpha ]]D |
| 54 | H | H | H | H | 1 | 196-200 | Racemic modification |
| 55 | H | H | H | H | 1 | 239-241 | -56.6 |
| 56 | H | H | H | H | 1 | 240-241 | +56.0 |
In analogy to the preparation of 2- (5-fluoro-2-methylphenyl) -2-methylpropanenitrile, 2-methyl-2- (3-methyl-2-nitrophenyl) -propionitrile was synthesized with a boiling point: 140 ℃/0.05 hPa. 2-methyl-2- (3-methyl-2-nitrophenyl) -propanal
Analogously to the preparation of 2- (5-fluoro-2-methylphenyl) -2-methylpropanal, 2-methyl-2- (3-methyl-2-nitrophenyl) -propanal is obtained with a boiling point: 140 ℃/0.05 hPa. 4-methyl-4- (3-methyl-2-nitrophenyl) -2-oxopentanoic acid
In analogy to the procedure for 4- (5-fluoro-2-methylphenyl) -4-methyl-2-oxopentanoic acid, 4-methyl-4- (3-methyl-2-nitrophenyl) -2-oxopentanoic acid was obtained as oil. 6- [4- (3-methyl-2-nitrophenyl) -4-methyl-2-oxovalerylamino ] -4-methyl-2, 3-benzoxazin-1-one
According to the method, the compound is analogous to 5- [4- (5-fluoro-2-methylphenyl) -4-methyl-2-oxovalerylamino]-2-benzo [ c]Method for furanones from 4-methyl-4- (3-methyl-2-nitrophenyl) -2-oxopentanoic acid and 6-amino-2, 3-benzoxazin-1-one to give the title compound, m.p.: 184 and 187 ℃.6- [4- (3-methyl-2-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl Pentanoylamino group]-4-methyl-2, 3-benzoxazin-1-one
In analogy to example 1, from 6- [4- (3-methyl-2-nitrophenyl) -4-methyl-2-oxopentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one was obtained the title compound, melting point: 201 ℃ and 203 ℃.
Example 185- [4- (2-amino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino]-2-benzo [ c]Furanones
65.8mg of (5-fluoro-2-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino (5-fluoro-2-nitrophenyl) in the presence of 20mg of palladium on carbon (10%)]-2-benzo [ c]The furanones were reduced with hydrogen in 15ml of methanol at normal pressure for 3 hours, filtered off with suction over kieselguhr and then concentrated by evaporation. After recrystallization from ethyl acetate/diisopropyl ether, 51mg of 5- [4- (2-amino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino]-2-benzo [ c]Furanone, melting point: 174 ℃ is carried out. Example 196- [4- (2-amino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino]-4-methyl-2, 3-benzoxazin-1-one
42mg of 6- [4- (5-fluoro-2-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one was dissolved in 1ml of acetic acid and 1ml of tetrahydrofuran, mixed with 22.5mg of iron powder, and then stirred at room temperature for 16 hours. Suction filtration over celite, concentration by evaporation and treatment of the residue with ethyl acetate and washing with saturated aqueous sodium bicarbonate. After chromatographic purification on silica gel with hexane/ethyl acetate (1.5+1) and recrystallization from diisopropyl ether, 10mg of 6- [4- (2-amino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one are obtained, melting point: 208 deg.C.
Example 206- [4- (2-acetylamino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino]-4-methyl-2, 3-benzoxazin-1-one
9.4mg of 6- [4- (2-amino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one and 0.04m of 1mg of acetic anhydride are stirred in 0.5ml of tetrahydrofuran at room temperature for 2 days and mixed with ethyl acetate and sodium bicarbonate solution. The ethyl acetate solution was dried and concentrated by evaporation. After purification by chromatography on silica gel, 8mg of 6- [4- (2-acetylamino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one are obtained. Ms (ei): m (+) ═ 510.
Example 215- [4- (2-acetylamino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino]-2-benzo [ c]Furanones
In analogy to example 20 from 5- [4- (2-amino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino]-2-benzo [ c]Furanone gives the title compound, melting point: 125 ℃. Example 225- [4- (5-fluoro-2-methanesulfonylaminophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino]-2-benzo [ c]Furanones
17.7mg of 5- [4- (2-amino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -2-benzo [ c ] furanone, 0.4ml of pyridine and 0.078ml of methanesulfonyl chloride were stirred at room temperature for 17 hours, mixed with ethyl acetate and washed 3 times with 1N hydrochloric acid. The ethyl acetate solution was dried and concentrated by evaporation. After chromatographic purification on silica gel with ethyl acetate/hexane (1: 1), 11mg of 5- [4- (5-fluoro-2-methanesulfonylaminophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -2-benzo [ c ] furanone are obtained, mp: 218 deg.C.
EXAMPLE 236- [4- (2-bromo-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one
Similar to realityThe method of example 3, from 6- [4- (2-bromo-3-methoxyphenyl) -4-methyl-2-oxopentanoylamino]-4-methyl-2, 3-benzoxazin-1-one to give the title compound, ms (esi): m(+)+1＝543(79Br) and 545(81Br). The enantiomer was isolated from example 23:
the enantiomeric mixture obtained in example 23 was chromatographed on a chiral support material (CHIRALPAKAD , DAICEL Co.) using hexane/ethanol (93: 7, vv). Obtained from 200mg of racemate:
(-)6- [4- (2-bromo-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one, first fraction: 86mg, melting point: 233-
(+)6- [4- (2-bromo-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one, second fraction: 82 mg.
Example 24(+)6- [4- (2-bromo-3-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino]-4-methyl-2, 3-benzoxazin-1-one
78mg of (+)6- [4- (2-bromo-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino]-4-methyl-2, 3-benzoxazin-1-one is mixed in 1.4ml of dichloromethane at 0 ℃ with 0.71ml of a 1M solution of boron tribromide in dichloromethane. After stirring for 2 hours at 0 ℃, the mixture is poured into water, extracted with ethyl acetate, the organic phase is dried (sodium sulfate) and concentrated by evaporation. After treatment of the residue with hexane, the title compound is obtained in crystalline form, melting point: 226 ° 231 ℃, α D +91.1 ° (c 0.5 in chloroform). Example 25(-)6- [4- (2-bromo-3-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino]-4-methyl-2, 3-benzoxazin-1-one
The title compound of example 25 was prepared in analogy to example 24 from the corresponding (-)6- [4- (2-bromo-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one, melting point: 227-.
Example 266- [4- (2, 3-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylhexanoylamino group]-4-methyl-2, 3-benzoxazine-1-one preparation step: 2-methyl-2- (2, 3-difluorophenyl) butyronitrile and 2-methyl-2- (2, 6-difluorophenyl) butyronitrile
A solution of 5.0g (37.85mmol) of 1, 2, 3-trifluorobenzene, 3.30g (39.74mmol) of 2-methylbutyronitrile and 75.5ml (0.5M in toluene) of potassium bistrimethylsilylamide in 182ml of toluene is heated at 60 ℃ for 3 hours. Mixing with ice water and diethyl ether. The organic phase is acidified with 10% sulfuric acid and then washed three times with water, dried (sodium sulfate) and concentrated by evaporation in vacuo. After chromatographic purification on silica gel with 0-4% diethyl ether-hexane, 3.8g of 2-methyl-2- (2, 3-difluorophenyl) butyronitrile and 1.6g of 2-methyl-2- (2, 6-difluorophenyl) butyronitrile were obtained.
2-methyl-2- (2, 3-difluorophenyl) butanenitrile:
1H-NMR(CDCl3)，δ(ppm)＝0.88(t，3H)，1.81(s，3H)，1.95-2.1(m，1H)，2.1-2.25(m，1H)，7.05-7.2(m，2H)，7.3-7.4(m，1H)
2-methyl-2- (2, 6-difluorophenyl) butanenitrile:
1H-NMR(CDCl3) δ (ppm) ═ 1.06(t, 3H), 1.89(t, 3H), 1.95-2.1(m, 1H), 2.15-2.3(m, 1H), 6.85-6.95(m, 2H), 7.2-7.3(m, 1H)2- (2, 3-difluorophenyl) -2-methylbutyraldehyde
In analogy to the preparation of 2- (5-fluoro-2-methylphenyl) -2-methylpropanal, 2- (2, 3-difluorophenyl) -2-methylbutanal is obtained as a colorless oil.
1H-NMR(CDCl3) δ (ppm) ═ 0.79(t, 3H), 1.41(s, 3H), 1.85-2.0(m, 1H), 2.0-2.15(m, 1H), 7.0-7.3(m, 3H), 9.68(d, 1H)4- (2, 3-difluorophenyl) -4-methyl-2-oxohexanoic acid
In analogy to the preparation of 4- (5-fluoro-2-methylphenyl) -4-methyl-2-oxopentanoic acid, 4- (2, 3-difluorophenyl) -4-methyl-2-oxohexanoic acid was prepared.
1H-NMR(CDCl3)，δ(ppm)＝0.71(t，3H)，1.47(s，3H)，1.7(m，1H)，2.0(m，1H)，3.26(d，1H)，3.74(d，1H)，6.9-7.1(m，3H)6- [4- (2, 3-difluorophenyl) -4-methyl-2-oxohexanoylamino]-4-methyl group -2, 3-benzoxazin-1-ones
In analogy to the procedure for the preparation of 6- [4- (5-fluoro-2-methylphenyl) -4-methyl-2-oxovalerylamino ] -4-methyl-2, 3-benzoxazin-1-one, 6- [4- (2, 3-difluorophenyl) -4-methyl-2-oxohexanoylamino ] -4-methyl-2, 3-benzoxazin-1-one was prepared.
1H-NMR(CDCl3)，δ(ppm)＝0.73(t，3H)，1.5(s，3H)，1.7(m，1H)，2.05(m，1H)，2.58(s，3H)，3.37(d，1H)，3.84(d，1H)，7.0(m，3H)，7.72(dd，1H)，8.24(d，1H)，8.33(d，1H)，9.0(bs，1H)6- [4- (2, 3-difluorophenyl) -2-hydroxy-4-methyl-2-tricyanomethylhexanoyl Amino group]-4-methyl-2, 3-benzoxazin-1-one
In analogy to the preparation of 6- [4- (5-fluoro-2-methylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one, 6- [4- (2, 3-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylhexanoylamino ] -4-methyl-2, 3-benzoxazin-1-one is obtained. Chromatography on silica gel with 20-100% ethyl acetate/hexane afforded a mixture of diastereomers.
Diastereomer 1:1H-NMR(CDCl3)，δ(ppm)＝0.66(t，3H)，1.39(s，3H)，1.7(m，1H)，2.1(m，1H)，2.61(s，3H)，2.7(m，2H)，6.9-7.2(m，3H)，7.67(dd，1H)，8.31(d，1H)，8.37(d，1H)，8.8(s，1H)
diastereomer 2:1H-NMR(CDCl3) δ (ppm) ═ 0.62(t, 3H), 1.59(s, 3H), 1.6(m, 1H), 2.15(m, 1H), 2.23(d, 1H), 2.55(s, 3H), 3.07(d, 1H), 6.58(m, 1H), 6.71(m, 1H), 6.92(m, 1H), 7.46(dd, 1H), 8.01(d, 1H), 8.27(d, 1H), 8.3(s, 1H) example 276- [4- (2, 6-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylhexanoylamino-1-4-methyl-2, 3-benzoxazin-1-one preparation step: 2- (2, 6-difluorophenyl) -2-methylbutyraldehyde
In analogy to the preparation of 2- (5-fluoro-2-methylphenyl) -2-methylpropanal, 2- (2, 6-difluorophenyl) -2-methylbutanal is obtained as a colorless oil.
1H-NMR(CDCl3) δ (ppm) ═ 0.83(t, 3H), 1.49(t, 3H), 1.9-2.1(m, 2H), 6.85-6.95(m, 2H), 7.2-7.3(m, 1H), 9.69(t, 1H)4- (2, 6-difluorophenyl) -4-methyl-2-oxohexanoic acid
In analogy to the preparation of 4- (5-fluoro-2-methylphenyl) -4-methyl-2-oxopentanoic acid, 4- (2, 6-difluorophenyl) -4-methyl-2-oxohexanoic acid was prepared.
1H-NMR(CDCl3) δ (ppm) ═ 0.76(t, 3H), 1.62(t, 3H), 1.7(m, 1H), 1.9(m, 1H), 3.0(dt, 1H), 4.0(d, 1H), 6.8(m, 2H), 7.13(m, 1H)6- [4- (2, 6-difluorophenyl) -4-methyl-2-oxohexanoylamino]-4-methyl-2, 3-benzoxazin-1-one
In analogy to the procedure for the preparation of 6- [4- (5-fluoro-2-methylphenyl) -4-methyl-2-oxovalerylamino ] -4-methyl-2, 3-benzoxazin-1-one, 6- [4- (2, 6-difluorophenyl) -4-methyl-2-oxohexanoylamino ] -4-methyl-2, 3-benzoxazin-1-one was prepared.
1H-NMR(CDCl3)，δ(ppm)＝0.81(t，3H)，1.64(t，3H)，1.77(m，1H)，1.96(m，1H)，2.5(s，3H)，3.12(dt，1H)，4.09(d，1H)，6.8(m，2H)，7.15(m，1H)，7.77(dd，1H)，8.30(d，1H)，8.34(d，1H)，9.1(bs，1H)6- [4- (2, 6-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylhexanoyl Amino group]-4-methyl-2, 3-benzoxazin-1-one
In analogy to the procedure for the preparation of 6- [4- (5-fluoro-2-methylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one, 6- [4- (2, 6-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylhexanoylamino ] -4-methyl-2, 3-benzoxazin-1-one was obtained as a mixture of diastereomers.
1H-NMR(CDCl3)，δ(ppm)＝0.7(m，3H)，1.4(m，1H)，1.5，1.7，(2t，3H)，2.0-3.2(m，6H)，6.4-7.3(m，3H)，7.4-8.4(m，3H)，8.5，8.9(2bs，1H)
Example 286- {3- [4- (2-chloro-5-fluorophenyl) -tetrahydropyran-4-yl ] -2-hydroxy-2-trifluoromethylpropionylamino } -4-methyl-2, 3-benzoxazin-1-one preparation step: 4- (2-chloro-5-fluorophenyl) -tetrahydropyran-4-carbonitrile
6.76g of (2-chloro-5-fluorophenyl) -acetonitrile and 5.7ml of 2, 2' -dichlorodiethyl ether were dissolved in 100ml of dimethylformamide, followed by mixing with 3.7g of sodium hydride (60%) under ice cooling for 2.5 hours. After 3 hours at 0 ℃ and 16 hours at room temperature, ice water and ethyl acetate were mixed, acidified with 1M hydrochloric acid, the ethyl acetate phase was washed with water, dried (sodium sulfate) and concentrated by evaporation. Chromatography on silica gel gives 6.2g of 4- (2-chloro-5-fluorophenyl) -tetrahydropyran-4-carbonitrile, melting point: 91-93 ℃. 4- (2-chloro-5-fluorophenyl) -tetrahydropyran-4-carbaldehyde
In analogy to the preparation of 2- (5-fluoro-2-methylphenyl) -2-methylpropanal, 4- (2-chloro-5-fluorophenyl) -tetrahydropyran-4-carbaldehyde was obtained as a colorless oil with boiling point: 145 ℃/0.04 hPa. 3- [4- (2-chloro-5-fluorophenyl) -tetrahydropyran-4-yl ] -2-oxopropanoic acid
In analogy to the procedure for the preparation of 4- (5-fluoro-2-methylphenyl) -4-methyl-oxopentanoic acid, 3- [4- (2-chloro-5-fluorophenyl) -tetrahydropyran-4-yl ] -2-oxopropanoic acid was obtained, melting point: 158 ℃. 6- {3- [4- (2-chloro-5-fluorophenyl) -tetrahydropyran-4-yl ] -2-oxopropanoylamino } -4-methyl-2, 3-benzoxazin-1-one
Analogous to 6- [4- (5-fluoro-2-methylphenyl) -4-methyl-2-oxovalerylamino]A preparation method of (E) -4-methyl-2, 3-benzoxazine-1-one to obtain 6- {3- [4- (2-chloro-5-fluorophenyl) -tetrahydropyran-4-yl]-2-oxopropanoylamino } -4-methyl-2, 3-benzoxazine-1-one, melting point: 206 and 208 ℃.6- {3- [4- (2-chloro-5-fluorophenyl) -tetrahydropyran-4-yl]-2-hydroxy-2- Trifluoromethylpropionyloxy } -4-methyl-2, 3-benzoxazin-1-one
In analogy to the preparation of 6- [4- (5-fluoro-2-methylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one, 6- {3- [4- (2-chloro-5-fluorophenyl) -tetrahydropyran-4-yl ] -2-hydroxy-2-trifluoromethylpropionylamino } -4-methyl-2, 3-benzoxazin-1-one was obtained, melting point: 224 ℃ and 226 ℃. The enantiomer was isolated from example 28:
the enantiomeric mixture obtained in example 28 was chromatographed on a chiral support material (CHIRALPAKAD , DAICEL Co.) using hexane/ethanol (9: 1, vv). Obtained from 300mg of racemate:
(-)6- {3- [4- (2-chloro-5-fluorophenyl) -tetrahydropyran-4-yl ] -2-hydroxy-2-trifluoromethylpropionylamino } -4-methyl-2, 3-benzoxazin-1-one, first fraction: 129mg, melting point: 181-
(+)6- {3- [4- (2-chloro-5-fluorophenyl) -tetrahydropyran-4-yl ] -2-hydroxy-2-trifluoromethylpropionylamino } -4-methyl-2, 3-benzoxazin-1-one, second fraction: 129mg, melting point: 181 ℃ and 183 ℃.
Example 29
The cytosol of Sf9 cells infected with a recombinant baculovirus encoding GR and then with 10nM of the recombinant baculovirus, were used in a Glucocorticoid Receptor (GR) binding assay3H]Dexamethasone as reference substance (Lefebvre et al, J. Steroid. biochem., 33, 557-563, 1989), indicating that the compounds of formula I have a high-very high affinity for GR (see Table 9)
Table 9: GR binding test
Example 30
| Compound (I) | IC50[mol/l] |
| Example 38 | ＜3.0×10-10 |
| Example 16, Compound 26 | 1.6×10-8 |
| Example 16, Compound 33 | 1.1×10-9 |
| Example 3, Compound 9 | ＜3.0×10-10 |
| Fruit of Chinese wolfberryExample 16, Compound 16 | 6.2×10-10 |
| Example 16, Compound 13 | ＜3.0×10-10 |
| Dexamethasone | 2.8×10-8 |
| Prednisolone | 4.0×10-8 |
The inflammation inhibitory potency is determined by inhibition of cytokine IL-8 secretion in a cellular assay. The compounds of general formula I according to the invention inhibit the secretion of the cytokine IL-8 induced by Lipopolysaccharide (LPS) in the human monocyte cell line THP-1. The concentration of this cytokine was determined in the later stage (Ueberstand) by means of a commercially available ELISA kit. Here, the compounds of the general formula I show a high-very high inhibitory potency and action (see table 10).
Table 10: IL-8 value
Example 31
| Compound (I) | Inhibition of IL-8 secretion IC50[mol/l] | Inhibitory potency (%) |
| Example 38 | 8.6×10-9 | 56 |
| Example 16, Compound 26 | 4.3×10-9 | 77 |
| Example 16, Compound 33 | 3.0×10-8 | 45 |
| Example 3, Compound 9 | 6.5×10-8 | 51 |
| Example 16, Compound 16 | 1.0×10-8 | 80 |
| Example 16, Compound 13 | 9.6×10-9 | 58 |
| Prednisolone | 2.4×10-8 | 95 |
The anti-inflammatory effects of the compounds of formula I were tested in animal models of croton oil-induced inflammation in rats and mice (j.exp.med. (1995), 182, 99-108). Topically applying croton oil in ethanol to the ear of the animal. The test substance was administered systemically 2 hours before croton oil. After 16-24 hours, ear weight was measured as a measure of inflammatory edema. Here, the compound of formula I is comparable to the standard (prednisolone) and also shows, in part, a higher inhibitory effect against croton oil-induced inflammation (see table 11).
Table 11: inhibition of edema formation
Example 32
| Compound (I) | Edema inhibitory action at 3mg/kg (%) | Edema inhibitory action at 30mg/kg (%) |
| Example 38 | 58 | 101 |
| Example 16, Compound 26 | 11 | 81 |
| Example 16, Compound 33 | 77 | 86 |
| Example 3, Compound 9 | 50 | 92 |
| Example 16, Compound 16 | 54 | 78 |
| Example 16, Compound 13 | 47 | 106 |
| Prednisolone | 35 | 84 |
The enzymatic activity of Tyrosine Aminotransferase (TAT) in liver homogenates was measured photometrically as a parameter for the side effects of catabolic metabolism induced by steroid drugs. This activity is a good measure of the undesirable metabolic effects of glucocorticoids. To measure TAT induction, animals were sacrificed 8 hours after administration of the test substance, livers were removed, and TAT activity in the homogenate was measured. In contrast to steroid drugs, the compounds of general formula I induced no or only very little tyrosine aminotransferase in this experiment at doses with an anti-inflammatory effect (table 12).
Table 12: induction of tyrosine aminotransferase Activity
*The induction factor is defined as the corresponding fold n increase in the enzymatic activity of tyrosine aminotransferase in treated animals compared to that in untreated animals.
| Compound (I) | Induction factor for TAT at 3mg/kg | Induction factor for TAT at 30mg/kg |
| Example 38 | 1.2 | 6.0 |
| Example 16, Compound 26 | 1.4 | 3.7 |
| Example 16, Compound 16 | 1.3 | 2.0 |
| Prednisolone | 2.6 | 8.0 |
Claims (8)
1. Use of a compound of general formula I, as well as racemates or isolated stereoisomers, and optionally physiologically compatible salts, for the preparation of a medicament for the treatment of inflammation:wherein R is1And R2Identical or different and represent a hydrogen atom, C1-C5Alkyl radicals, or with carbon atoms in the chain
And the radicals together represent a ring having a total of 3 to 7 ring atoms, R3Represents a straight or branched chain C1-C5Alkyl, or straight orBranched, partially or fully fluorinated
C of (A)1-C5Alkyl, A represents the following group
The dotted line represents the attachment site, wherein R4-R8Identical or different and represent a hydrogen atom, a halogen atom, a cyano group, a nitro group,
COOR9a group in which R9Represents a hydrogen atom, a linear or branched C1-C5Alkyl or benzyl
The base group is a group of a compound,
CONR10a group in which R10Represents a hydrogen atom, a linear or branched C1-C5An alkyl group, a carboxyl group,
NHR11a group in which R11Represents a hydrogen atom, a linear or branched C1-C5Alkyl radical, moiety
Linear or branched C, which is partially or fully fluorinated1-C5Alkyl radical, C1-C5Acyl, -SO2
-(C1-C5) Alkyl or optionally halogen or C1-C5Alkyl substituted-SO2-
A phenyl group,
straight or branched C1-C5Alkyl, straight or branched C2-C5Alkenyl, straight-chain or branched C2
-C5Alkynyl, straight-chain or branched, C partially or fully substituted by fluorine atoms1-C5
Alkyl radical, C1-C5Acyl, aryl or heteroaryl, or R4And R5Together with the two carbon atoms of ring A to form a saturated ring having a total of 5 to 7 ring atoms
And or an unsaturated carbocyclic ring, Ar represents a ring system selected from the group consisting of the following partial formulae 1 or 2:wherein the group X3a、X3b、X4、X6、X7(partial formula 1) and Y4、Y5、Y7、Y8(section (C)
In the sub-formula 2) may be the same or different and represent a hydrogen atom, a straight chain or a branched chain C1-C5Alkane (I) and its preparation method
Or C being linear or branched, partially or fully fluorinated1-C5Alkyl, radical X4、X6、X7(partial formula 1) or Y5、Y7、Y8(partial formula 2) may be further combined
Are the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, C1-C5Alkoxy or C1
-C5An alkanoyloxy group.
2. A compound of formula I according to claim 1, which is: 6- [4- (5-fluoro-2-methylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 5- [4- (5-fluoro-2-methylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -2-benzo [ c ] furanone 6- [4- (2-chloro-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 5- [4- (5-fluoro-2-nitrophenyl) - 2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -2-benzo [ c ] furanone 6- [4- (5-fluoro-2-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 5- [4- (3-fluoro-4-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -2-benzo [ c ] furanone 6- [4- (3-fluoro-4-nitrophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methylvalerylamino ] -4-methyl -2, 3-benzoxazin-1-one 6- [4- (2-bromo-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (indan-4 '-yl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (indan-4' -yl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (indan-4' -yl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (5-fluoro-2-vinylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (5-fluoro-2-vinylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (5-fluoro-2-vinylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [ 2-hydroxy-4-methyl-2-trifluoromethyl-4- (4-trifluoromethylphenyl) -pentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [ 2-hydroxy-4-methyl-2-trifluoromethyl-4- (4-trifluoromethylphenyl) -pentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [ 2-hydroxy-4-methyl-2-trifluoromethyl-4- (4-trifluoromethylphenyl) -pentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-bromo-3, 5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-bromo-3, 5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-bromo-3, 5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (3, 5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (3, 5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (3, 5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-cyano-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-vinyl-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-ethyl-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (5-fluoro-2-phenylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- { 5-fluoro-2- (furan-2' -yl) phenyl } -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-bromo-3, 5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [ 2-hydroxy-4-methyl-2-trifluoromethyl-4- (1-naphthyl) -pentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [ 2-hydroxy-4-methyl-2-trifluoromethyl-4- (1-naphthyl) -pentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [ 2-hydroxy-4-methyl-2-trifluoromethyl-4- (1-naphthyl) -pentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-chlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-chlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-chlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-chloro-3-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-chloro-3-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-chloro-3-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-chloro-4-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-chloro-4-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2 3-benzoxazin-1-one (+)6- [4- (2-chloro-4-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-chloro-6-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-chloro-6-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl- 2, 3-benzoxazin-1-one (+)6- [4- (2-chloro-6-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [4- (2, 3-dichlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2, 3-dichlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2, 3-dichlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [4- (2, 4-dichlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2, 4-dichlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2, 4-dichlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [4- (2, 5-dichlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2, 5-dichlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2, 5-dichlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [4- (4-bromo-2-chlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (4-bromo-2-chlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (4-bromo-2-chlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-chloro-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-chloro-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl -2, 3-benzoxazin-1-one (+)6- [4- (2-chloro-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-chloro-3-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-chloro-3-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one -methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-chloro-3-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleryl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2, 3-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2, 3-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2, 3-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2, 4-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2, 4-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2, 4-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2, 5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2, 5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2, 5-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2, 6-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2, 6-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2, 6-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2, 3, 5-trifluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2, 3, 5-trifluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2, 3, 5-trifluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2, 3, 4-trifluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2, 3, 4-trifluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2, 3, 4-trifluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (3-chloro-2-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (3-chloro-2-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (3-chloro-2-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (4-chloro-2-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (4-chloro-2-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (4-chloro-2-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-fluoro-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-fluoro-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-fluoro-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-bromophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleryl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleryl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [4- (4-fluoro-2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (4-fluoro-2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl- 2, 3-benzoxazin-1-one (+)6- [4- (4-fluoro-2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [4- (5-fluoro-2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (5-fluoro-2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino- 4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (5-fluoro-2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [4- (5-chloro-2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (5-chloro-2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoyl- Acyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (5-chloro-2-trifluoromethylphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvaleryl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-chlorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-chlorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] - Amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-chlorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-chlorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-chlorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl- 2, 3-benzoxazin-1-one (+)6- [3- {1- (2-chlorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-chlorophenyl) -cyclopentyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-chlorophenyl) -cyclopentyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-chlorophenyl) -cyclopentyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-chloro-4-fluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-chloro-4-fluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl- 2, 3-benzoxazin-1-one (+)6- [3- {1- (2-chloro-4-fluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-chloro-4-fluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-chloro-4-fluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino- 4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-chloro-4-fluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-chloro-5-fluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-chloro-5-fluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropyl Acyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-chloro-5-fluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-chloro-5-fluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-chloro-5-fluorophenyl) -cyclobutyl } -2-hydroxy- 2-Trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-chloro-5-fluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2, 4-dichlorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2, 4-dichlorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2, 4-dichlorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2, 4-dichlorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2, 4-dichlorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2, 4-dichlorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-trifluoromethyl-phenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2- Trifluoromethyl-phenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-trifluoromethyl-phenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-trifluoromethyl-phenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-trifluoromethyl-phenyl) -cyclobutylj 2-trifluoromethyl-phenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-trifluoromethyl-phenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-trifluoromethyl-phenyl) -cyclohexyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-trifluoromethyl-phenyl) -cyclohexyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-trifluoromethyl-phenyl) -cyclohexyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (5-fluoro-2-trifluoromethyl-phenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino- 4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (5-fluoro-2-trifluoromethyl-phenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (5-fluoro-2-trifluoromethyl-phenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (5-fluoro-2-trifluoromethyl-phenyl) -cyclobutyl } - 2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (5-fluoro-2-trifluoromethyl-phenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (5-fluoro-2-trifluoromethyl-phenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionyl ] -amino-4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2- Fluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-fluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-fluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-fluorophenyl) -cyclobutyl } -2-hydroxy- 2-Trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-fluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-fluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-fluorophenyl) -cyclopentyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methylpropionylamino ] -4-methyl -2, 3-benzoxazin-1-one (-)6- [3- {1- (2-fluorophenyl) -cyclopentyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-fluorophenyl) -cyclopentyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-fluorophenyl) -cyclohexyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-fluorophenyl) -cyclohexyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-fluorophenyl) -cyclohexyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2, 3-difluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2, 3-difluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2, 3-difluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2, 3-difluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2, 3-difluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2, 3-difluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2, 5-difluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2, 5-difluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2, 5-difluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2, 3, 5-trifluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2, 3, 5-trifluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2, 3, 5-trifluorophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2, 3, 5-trifluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2, 3, 5-trifluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2, 3, 5-trifluorophenyl) -cyclobutyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [3- {1- (2-bromophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [3- {1- (2-bromophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [3- {1- (2-bromophenyl) -cyclopropyl } -2-hydroxy-2-trifluoromethylpropionylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [ 2-hydroxy-4-methyl-4- (3-methyl-2-nitrophenyl) -2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [ 2-hydroxy-4-methyl-4- (3-methyl-2-nitrophenyl) -2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [ 2-hydroxy-4-methyl-4- (3-methyl-2-nitrophenyl) -2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 5- [4- (2-amino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -2-benzo [ c ] furanone ((2-hydroxy-4-methyl-2-trifluoromethylvalerylamino) -2-benzo [ c ] furanone [ ((C) -)5- [4- (2-amino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -2-benzo [ c ] furanone (+)5- [4- (2-amino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -2-benzo [ c ] furanone 6- [4- (2-amino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-amino-5-fluorophenyl) -2 -hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-amino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-acetylamino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-acetylamino-5-fluorophenyl) -2, 3-benzoxazin-1-one -hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-acetylamino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 5- [4- (2-acetylamino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -2-benzo [ c ] furanone (-)5- [4- (2-acetylamino-5-fluorophenyl) -2-hydroxy-4- Methyl-2-trifluoromethylvalerylamino ] -2-benzo [ c ] furanone (+)5- [4- (2-acetylamino-5-fluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -2-benzo [ c ] furanone 5- [4- (5-fluoro-2-methanesulfonylamino-phenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -2-benzo [ c ] furanone (-)5- [4- (5-fluoro-2-methanesulfonylamino-phenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -2-benzo [ c ] furo Furanone (+)5- [4- (5-fluoro-2-methanesulfonylamino-phenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -2-benzo [ c ] furanone 6- [4- (2-bromo-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-bromo-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-bromo-3-methoxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2-bromo-3-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-bromo-3-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-bromo-3-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2-bromo-3-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylvalerylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2-bromo-3-hydroxyphenyl) -2-hydroxy-4-methyl-2-trifluoromethylpentanoylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2, 3-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylhexanoylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2, 3-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylhexanoylamino ] -4-methyl-2, 3-benzoxazin-1-one (+)6- [4- (2, 3-difluorophenyl) -2-hydroxy-4-methyl-2-trifluoromethylhexanoylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- [4- (2, 6-difluorophenyl) -2-hydroxy-4-methyl-4-trifluoromethylhexanoylamino ] -4-methyl-2, 3-benzoxazin-1-one (-)6- [4- (2, 6-difluorophenyl) -2-hydroxy-4-methyl-4-trifluoromethylhexanoylamino ] -4-methyl-2, 3-Benzoxazin-1-one (+)6- [4- (2, 6-difluorophenyl) -2-hydroxy-4-methyl-4-trifluoromethylhexanoylamino ] -4-methyl-2, 3-benzoxazin-1-one 6- {3- [4- (2-chloro-5-fluorophenyl) -tetrahydropyran-4-yl ] -2-hydroxy-2-trifluoromethylpropionylamino } -4-methyl-2, 3-benzoxazin-1-one (-)6- {3- [4- (2-chloro-5-fluorophenyl) -tetrahydropyran-4-yl ] -2-hydroxy-2-trifluoromethylpropionylamino } - 4-methyl-2, 3-benzoxazin-1-one (+)6- {3- [4- (2-chloro-5-fluorophenyl) -tetrahydropyran-4-yl ] -2-hydroxy-2-trifluoromethylpropionylamino } -4-methyl-2, 3-benzoxazin-1-one.
3.2, 3-benzoxazin-1-one according to claim 2.
4. The use of a compound of formula I according to claim 2 for the preparation of a medicament.
5. Use of a compound according to claim 2 in the manufacture of a medicament for the treatment of inflammation.
6. A pharmaceutical composition comprising at least one compound of claim 2 and a pharmaceutically acceptable carrier.
7. Use of at least one compound of the general formula I according to claim 1 for the preparation of a medicament for the treatment of at least one of the following diseases which accompany inflammatory, allergic and/or proliferative processes:
(i) pulmonary diseases
(ii) Rheumatism/autoimmune disease/arthropathy
(iii) Allergy (S)
(iv) Vasculitis (vascular disease)
(v) Skin diseases
(vi) Renal disease
(vii) Liver disease
(viii) Gastrointestinal diseases
(ix) Rectal diseases
(x) Eye diseases
(xi) Diseases of the cervical-nasal-ear region
(xii) Neurological disorders
(xiii) Blood diseases
(xiv) Tumor diseases
(xv) Endocrine disorders
(xvi) Transplantation
(xvii) Severe state of shock
(xviii) Alternative therapy for adrenal insufficiency
(xix) Vomiting
(xx) Pain in inflammation (e.g. lumbago)
8. A process for the preparation of compounds of the general formula I as claimed in claim 1 or 2,
alpha-carbonyl carboxylic acids of the general formula IIFormula (III) A, R1And R2As defined in formula I, optionally with a compound of formula (R) in the presence of a catalyst such as a fluoride-salt or a basic compound such as an alkali metal carbonate12)3SiR3(III) esterification of a compound of formula (III) wherein R3As defined in formula I, R12Is C1-C5Alkyl, or with an alkylmetal compound, such as a grignard reagent or an alkyllithium, to form a compound of formula IV:the ester may optionally also be cleaved and then reacted with a compound of the formula Ar-NH-R13(V) compound of the formula (V) wherein R13Represents a hydrogen atom or C1-C5Acyl, and Ar is as defined for formula I, wherein the group R can be subsequently cleaved13，
Or
Optionally activated directly after conversion to the acid chloride with the general formula Ar-NH-R13(V) compound of the formula (V) wherein R13Represents a hydrogen atom or C1-C5Acyl, and Ar is as defined for formula I, wherein the group R is subsequently cleaved in any order13And then with a compound of formula (R) in the presence of a catalyst such as a fluoride-salt or a basic compound such as an alkali metal carbonate12)3SiR3(III) compound of the formula wherein R3And R12As defined above, or with an alkyl metal compound,such as grignard reagents or alkyl lithium.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10038639.3 | 2000-07-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK1058931A true HK1058931A (en) | 2004-06-11 |
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