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US 5,843,999 AGranted
2-phenylazulene derivatives and a manufacturing method of these compounds
AssigneeKotobuki Seiyaku Co., Ltd.
InventorsTsuyoshi Tomiyama, Akira Tomiyama, Masayuki Yokota, Satoko Uchibori
Life of this patent
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Abstract
A series of new azulene derivatives are disclosed, which are represented by the following formula; ##STR1## wherein: R.sub.1 is hydrogen atom, lower alkoxycarbonyl group, carboxy group, halogen atom, lower alkyl group, phenyl group or lower alkanoyl group; R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom, lower alkyl group, lower alkoxy group or halogen atom; X is lower alkyl group or amino group. The compounds of the present invention are useful for treatment of inflammation.
Claims11
A compound of the general formula (I):
- ##STR13## wherein:
- R.sub.1 is hydrogen atom, lower alkoxycarbonyl group, carboxy group, halogen atom, lower alkyl group, phenyl group or lower alkanoyl group;
- R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom, lower alkyl group, lower alkoxy group or halogen atom;
- X is lower alkyl group or amino group.
1 more element
A compound of the general formula (II):
- ##STR14## wherein:
- R.sub.1 is hydrogen atom, methoxycarbonyl group, carboxy group, fluorine atom, chlorine atom, bromine atom, methyl group, phenyl group or acetyl group ;
- R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom, methyl group, methoxy group, fluorine atom or chlorine atom.
A compound of the general formula (III):
- ##STR15## wherein:
- R.sub.1 is hydrogen atom, methoxycarbonyl group, carboxy group, fluorine atom, chlorine atom, bromine atom, methyl group, phenyl group or acetyl group;
- R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom, methyl group, methoxy group, fluorine atom or chlorine atom.
A method of preparing a compound of general formula (XI):
- ##STR16## wherein:
- R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom, methyl group, methoxy group, fluorine atom or chlorine atom;
- comprising reacting a compound of general formula (IV):
- ##STR17## with a compound of general formula (V):
- ##STR18## wherein:
- OTMS represents trimethylsilyloxy group;
- to produce a compound of general formula (VI):
- ##STR19## and then a compound of formula (VI) is brominated to produce a compound of formula (VII):
- ##STR20## and then a compound of formula (VII) is reacted with a compound of formula (VIII):
- ##STR21## wherein:
- R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom, methyl group, methoxy group, fluorine atom or chlorine atom;
- Y is B(OH).sub.2 or SnMe.sub.3 ;
- to produce the general formula (IX):
- ##STR22## wherein:
- R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom, methyl group, methoxy group, fluorine atom or chlorine atom;
- and then a compound of formula (IX) is oxidized to produce a compound of formula (X):
- ##STR23## wherein:
- R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom, methyl group, methoxy group, fluorine atom or chlorine atom;
- further the compound (X) is demethoxycarbonylated to produce a compound of formula (XI):
- ##STR24## wherein:
- R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom, methyl group, methoxy group, fluorine atom or chlorine atom.
18 more elements
A method of preparing a compound of general formula (XVII):
- ##STR25## wherein:
- R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom, methyl group, methoxy group, fluorine atom or chlorine atom;
- comprising reacting a compound of general formula (XII):
- ##STR26## with a compound of the general formula (XIII):
- ##STR27## wherein:
- Y is B(OH).sub.2 or SnMe.sub.3 ;
- to produce a compound of general formula (XIV):
- ##STR28## and then a compound of formula (XIV) is brominated to produce a compound of formula (XV):
- ##STR29## and then a compound of formula (XV) is reacted with a compound of formula (VIII):
- ##STR30## wherein:
- R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom, methyl group, methoxy group, fluorine atom or chlorine atom;
- Y is B(OH).sub.2 or SnMe.sub.3 ;
- to produce a compound of general formula (XVI):
- ##STR31## wherein:
- R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom, methyl group, methoxy group, fluorine atom or chlorine atom;
- then the compound (XVI) is demethoxycarbonylated and de-t-butylated to produce the compound of formula (XVII):
- ##STR32## wherein:
- R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom, methyl group, methoxy group, fluorine atom or chlorine atom.
15 more elements
A method of preparing a compound of general formula (XIX):
- ##STR33## wherein:
- R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom, methyl group, methoxy group, fluorine atom or chlorine atom;
- X is lower alkyl group or amino group;
- comprising hydrolyzing a compound of general formula (XVIII):
- ##STR34## wherein:
- R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom, methyl group, methoxy group, fluorine atom or chlorine atom;
- X is lower alkyl group or amino group.
4 more elements
A method of preparing a compound of general formula (XX):
- ##STR35## wherein:
- R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom, methyl group, methoxy group, fluorine atom or chlorine atom ;
- R.sub.5 is fluorine atom, chlorine atom or bromine atom;
- X is lower alkyl group or amino group;
- comprising halogenating a compound of general formula (I):
- ##STR36## wherein:
- R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom, methyl group, methoxy group, fluorine atom or chlorine atom;
- X is lower alkyl or amino group.
5 more elements
A method of preparing a compound of general formula (XXIII):
- ##STR37## wherein:
- R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom, methyl group, methoxy group, fluorine atom or chlorine atom ;
- R.sub.6 is methyl group or phenyl group;
- X is lower alkyl group or amino group;
- comprising reacting a compound of general formula (XXI):
- ##STR38## wherein:
- R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom, methyl group, methoxy group, fluorine atom or chlorine atom;
- X is lower alkyl group or amino group;
- with a compound of general formula (XXII):
- R.sub.6 --B(OH).sub.2 (XXII)
- wherein:
- R.sub.6 is methyl group or phenyl group;
- to produce a compound of general formula (XXIII):
- ##STR39## wherein:
- R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom, methyl group, methoxy group, fluorine atom or chlorine atom ;
- R.sub.6 is methyl group or phenyl group;
- X is lower alkyl group or amino group.
14 more elements
A method of preparing a compound of general formula (XXIV):
- ##STR40## wherein:
- R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom, methyl group, methoxy group, fluorine atom or chlorine atom, R.sub.7 is methyl group ;
- X is lower alkyl group or amino group;
- comprising reacting a compound of general formula (I) by Friedel-Crafts reaction:
- ##STR41## wherein:
- R.sub.1 is hydrogen atom;
- R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom, methyl group, methoxy group, fluorine atom or chlorine atom;
- X is lower alkyl group or amino group.
5 more elements
A method of preparing a compound of general formula (XXV):
- ##STR42## wherein:
- R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom, methyl group, methoxy group, fluorine atom or chlorine atom;
- X is lower alkyl group or amino group;
- comprising transforming a compound of general formula (XXIV) to thiomorpholide by Willgerodt-Kindler reaction, then hydrolyzing said thiomorpholide:
- ##STR43## wherein:
- R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom, methyl group, methoxy group, fluorine atom or chlorine atom;
- R.sub.7 is methyl group;
- X is lower alkyl group or amino group.
5 more elements
Dependencies are inferred from the claim text.