JP4132155B2 - Tricyclic amine derivatives - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an antibacterial compound useful as a medicine, veterinary drug, marine product drug, or antibacterial preservative, and further relates to an antibacterial drug and an antibacterial preparation containing this compound.
[0002]
[Prior art]
  Since the discovery of norfloxacin, quinolone synthetic antibacterial agents have improved antibacterial activity and pharmacokinetics, and many compounds have been put into clinical practice as effective chemotherapeutic agents for systemic infections.ServingHas been.
[0003]
[Problems to be solved by the invention]
In recent years, low-sensitivity bacteria to quinolone synthetic antibacterial agents are increasing in clinical settings. For example, bacteria that were resistant to drugs other than quinolone synthetic antibacterials, such as Staphylococcus aureus (MRSA), which are insensitive to β-lactam antibiotics, but those that became less sensitive to quinolone synthetic antibacterials Has increased. Therefore, it is desired to develop a drug having higher effectiveness in clinical settings.
[0004]
Furthermore, convulsions induced by taking with non-steroidal anti-inflammatory agents and side effects such as phototoxicity have been clarified, and development of safer quinolone synthetic antibacterial drugs is also required.
[0005]
[Means for Solving the Problems]
In view of such circumstances, the inventors of the present application have conducted intensive research to provide an excellent compound that satisfies the above requirements. As a result, the following tricyclic amine derivatives represented by the formula (I), salts thereof, and hydrates thereof have a wide range of excellent antibacterial activity against gram-negative and gram-positive bacteria. In particular, the present invention has been found by showing that it has a strong antibacterial activity against quinolone-resistant bacteria including MRSA, and also has good pharmacokinetics and safety.
[0006]
[Means for Solving the Problems]
  That is, the present invention relates to a compound represented by the following formula (I), a salt thereof,OrRegarding their hydrates:
[0007]
[Chemical 7]
{WhereR ¹ , R ² , R ^Three , R ^Four , R ^Five , R ⁶ and R ⁷ Represents a hydrogen atom,
X ¹ The substructure
[0008]
[Chemical 8]
(Where R⁸And R⁹IsRepresents a hydrogen atom, m Is an integer 1 Represents. )
[0009]
Represents
n Is an integer 1 Or 2 Represents
Q Is the formula
[0010]
[Chemical 9]
Or an expression
Embedded image
[Where R¹¹Is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, an optionally substituted cyclic alkyl group having 3 to 6 carbon atoms, An aryl group which may have a group, a heteroaryl group which may have a substituent, an alkoxyl group having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms;
R¹²Represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms,
  This R¹²And R above¹¹May be integrated so as to include a part of the mother nucleus to form a cyclic structure, but the ring formed in this way may contain a sulfur atom as a constituent atom of the ring. May have an alkyl group having 1 to 6 carbon atoms as a substituent.
R¹³Is a hydrogen atom, amino group, hydroxyl group, thiol group, halogenomethyl group, alkyl group having 1 to 6 carbon atoms, alkenyl group having 2 to 6 carbon atoms, alkynyl group having 2 to 6 carbon atoms, or 1 to 6 carbon atoms Represents an alkoxyl group of
  Of these, the amino group has 1 or 2 groups selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms, and an acyl group having 2 to 5 carbon atoms as a substituent. Also good.
X²Represents a halogen atom or a hydrogen atom,
A¹Is a nitrogen atom or formula (II)
[0011]
Embedded image
(Where X^ThreeIs a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, or Represents an alkoxyl group having 1 to 6 carbon atoms,
  Of these, the amino group has 1 or 2 groups selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms, and an acyl group having 2 to 5 carbon atoms as a substituent. Well,
  Furthermore this X^ThreeAnd R above¹¹May be integrated so as to include a part of the mother nucleus to form a cyclic structure, but the ring formed in this way has an oxygen atom, a nitrogen atom, or a sulfur atom as a constituent atom of the ring. Further, this ring may have an alkyl group having 1 to 6 carbon atoms as a substituent. )
It has the partial structure represented by these.
[0013]
Y Are a hydrogen atom, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyl group, choline group, dimethylaminoethyl group, Five- Indanyl group, phthalidinyl group, Five- Alkyl -2- Oxo -1,3- Dioxol -Four- Ylmethyl group, 3- Acetoxy -2- It represents a phenylalkyl group composed of an oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, or an alkylene group having 1 to 6 carbon atoms and a phenyl group. ]
Represents a partial structure represented by }.
[0014]
Furthermore, the present invention relates to each of the following. That is,
In formula (I), Q is the formula
[0015]
Embedded image
Or an expression
[0016]
Embedded image
The above-mentioned compound having a structure represented by:OrTheir hydrates;
In formula (I), Q is the formula
[0017]
Embedded image
The above-mentioned compound having a structure represented by:OrTheir hydrates;
In formula (I), Q is 9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1.2.3-de] [1.4] benzoxazine-6-carvone Acid-10-yl group [shown in the following formula]:
[0018]
Embedded image
The above compound, its salt,OrTheir hydrates;
In the formula (I), Q is 6-fluoro-1- [2- (S) -fluoro-1- (R) -cyclopropyl] -8-methoxy-1,4-dihydro-4-oxoquinoline-3 -Carboxylic acid-7-yl group [shown in the formula below]:
[0019]
Embedded image
The above compound, its salt,OrTheir hydrates;
In the formula (I), Q is 6-fluoro-1- [2- (S) -fluoro-1- (R) -cyclopropyl] -8-methyl-1,4-dihydro-4-oxoquinoline-3 -Carboxylic acid-7-yl group [shown in the formula below]:
[0020]
Embedded image
The above compound, its salt,OrTheir hydrates;
In the formula (I), Q is 5-amino-6-fluoro-1- [2- (S) -fluoro-1- (R) -cyclopropyl] -8-methyl-1,4-dihydro-4- Oxoquinolin-3-carboxylic acid-7-yl group [shown in the following formula]:
[0021]
Embedded image
The above compound, its salt,OrTheir hydrates;
[0022]
In formula (I): n Is an integer 1 Or a salt thereof, or a hydrate thereof:
[0023]
A compound of formula (I) wherein the compound is a stereochemically single compound, a salt thereof, or a hydrate thereof;
R ¹¹ Is a cyclopropyl group having a halogen atom as a substituent, a salt thereof, or a hydrate thereof;
A cyclopropyl group having a halogen atom as a substituent, 1,2- Cis - The above-mentioned compound which is a halogenocyclopropyl group, a salt thereof, or a hydrate thereof;
The above-mentioned compound, a salt thereof, or a hydrate thereof, wherein the cyclopropyl group having a halogen atom as a substituent is a stereochemically single substituent;
A cyclopropyl group having a halogen atom as a substituent, (1R, 2S) -2- The above-mentioned compound which is a halogenocyclopropyl group, a salt thereof, or a hydrate thereof;
The above compound, salt thereof, or hydrate thereof, wherein the halogen atom of the cyclopropyl group having a halogen atom as a substituent is a fluorine atom;
[0024]
A pharmaceutical comprising the above compound, a salt thereof, or a hydrate thereof as an active ingredient;
An antibacterial agent comprising the above compound, a salt thereof, or a hydrate thereof as an active ingredient;
A therapeutic agent for infectious diseases comprising the above-mentioned compound, a salt thereof, or a hydrate thereof as an active ingredient;
Compounds represented by the following formula, salts thereof, and hydrates thereof:
[0025]
Embedded image
[Where R¹¹¹IsRepresents a protecting group for a hydrogen atom or an amino group,
R ² , R ^Three , R ^Four , R ^Five , R ⁶ and R ⁷ Represents a hydrogen atom,
X ¹ The substructure
[0026]
Embedded image
(Where R⁸And R⁹IsRepresents a hydrogen atom, m Is an integer 1 Represents. )
[0027]
Represents
n represents an integer 1 or 2;
Q ' Means an amino-protecting group. ];
The protective group for the amino group may be an alkoxycarbonyl group which may have a substituent, an aralkyloxycarbonyl group which may have a substituent, an acyl group which may have a substituent, a substitution The above-mentioned compound, a salt thereof, or their Hydrates;
The protecting group of the amino group is a tertiary butoxycarbonyl group, 2,2,2- Trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, benzoyl group, Tertiary butyl group, benzyl group, paranitrobenzyl group, paramethoxybenzyl group, triphenylmethyl group, methoxymethyl group, tertiary butoxymethyl group, tetrahydropyranyl group, 2,2,2- The above compound, which is a protective group selected from the group consisting of trichloroethoxymethyl group, trimethylsilyl group, isopropyldimethylsilyl group, tert-butyldimethylsilyl group, tribenzylsilyl group, and tertiary butyldiphenylsilyl group, and salts thereof Or hydrates thereof;
R ¹¹¹ and Q ' Wherein the above are not the same protecting group, salts thereof, or hydrates thereof;
n Is an integer 1 Or a salt thereof, or a hydrate thereof;
[0028]
A compound represented by the following formula, a salt thereof, or a hydrate thereof:
[0029]
Embedded image
[Where R¹¹¹IsRepresents a hydrogen atom or an amino protecting group,
R ² , R ^Three , R ^Four , R ^Five , R ⁶ and R ⁷ Represents a hydrogen atom,
X ¹ The substructure
[0030]
Embedded image
(Where R⁸And R⁹IsRepresents a hydrogen atom, m Is an integer 1 Represents. )
[0031]
Represents
n Is an integer 1 Or 2 Represents. ];
The protective group for the amino group may be an alkoxycarbonyl group which may have a substituent, an aralkyloxycarbonyl group which may have a substituent, an acyl group which may have a substituent, a substitution The above-mentioned compound, a salt thereof, or their Hydrates;
The protecting group of the amino group is a tertiary butoxycarbonyl group, 2,2,2- Trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, benzoyl group, Tertiary butyl group, benzyl group, paranitrobenzyl group, paramethoxybenzyl group, triphenylmethyl group, methoxymethyl group, tertiary butoxymethyl group, tetrahydropyranyl group, 2,2,2- The above compound, which is a protective group selected from the group consisting of trichloroethoxymethyl group, trimethylsilyl group, isopropyldimethylsilyl group, tert-butyldimethylsilyl group, tribenzylsilyl group, and tertiary butyldiphenylsilyl group, and salts thereof Or hydrates thereof;
n Is an integer 1 Or a salt thereof, or a hydrate thereof;
[0032]
A compound represented by the following formula, a salt thereof, or a hydrate thereof:
[0033]
Embedded image
[Where R¹¹¹IsRepresents a protecting group for a hydrogen atom or an amino group,
R ² , R ^Three , R ^Four , R ^Five , R ⁶ and R ⁷ Represents a hydrogen atom,
X ¹ The substructure
[0034]
Embedded image
(Where R⁸And R⁹IsRepresents a hydrogen atom, m Is an integer 1 Represents. )
[0035]
Represents
n Is an integer 1 Or 2 Represents
Q ' Means an amino-protecting group. ]
of Q ' And, if desired, isolated and purified, the compound ( III ):
[0036]
Embedded image
[Where X²Represents a halogen atom or a hydrogen atom,
X^FourRepresents a fluorine atom, a chlorine atom, a bromine atom, a substituted or unsubstituted phenylsulfonyl group, or a substituted or unsubstituted alkylsulfonyl group having 1 to 3 carbon atoms;
Y¹Is a hydrogen atom, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyl group, choline group, dimethylaminoethyl group, 5-indanyl group, phthalidinyl group, 5-alkyl-2-oxo-1,3 -Dioxol-4-ylmethyl group, 3-acetoxy-2-oxobutyl group, alkyl group having 1 to 6 carbon atoms, alkoxymethyl group having 2 to 7 carbon atoms, or alkylene group having 1 to 6 carbon atoms and phenyl group A composed phenylalkyl group or of formula (IV)
[0037]
Embedded image
-B (Y¹¹) Y¹²                  (IV)
(Where Y¹¹And Y¹²Represents a fluorine atom or an alkylcarbonyloxy group having 2 to 4 carbon atoms. )
A boron-containing substituent represented by:
R¹¹Is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, an optionally substituted cyclic alkyl group having 3 to 6 carbon atoms, An aryl group which may have a group, a heteroaryl group which may have a substituent, an alkoxyl group having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms;
R¹²Represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms,
This R¹²And R above¹¹May be integrated so as to include a part of the mother nucleus to form a cyclic structure, but the ring formed in this way may contain a sulfur atom as a constituent atom of the ring. May have an alkyl group having 1 to 6 carbon atoms as a substituent.
R¹³Is a hydrogen atom, amino group, hydroxyl group, thiol group, halogenomethyl group, alkyl group having 1 to 6 carbon atoms, alkenyl group having 2 to 6 carbon atoms, alkynyl group having 2 to 6 carbon atoms, or 1 to 6 carbon atoms Represents an alkoxyl group of
Of these, the amino group has 1 or 2 groups selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms, and an acyl group having 2 to 5 carbon atoms as a substituent. Also good.
A¹Is a nitrogen atom or formula (II)
[0038]
Embedded image
(Where X^ThreeIs a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, or Represents an alkoxyl group having 1 to 6 carbon atoms,
Of these, the amino group has 1 or 2 groups selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms, and an acyl group having 2 to 5 carbon atoms as a substituent. Well,
Furthermore this X^ThreeAnd R above¹¹May be integrated so as to include a part of the mother nucleus to form a cyclic structure, but the ring formed in this way has an oxygen atom, a nitrogen atom, or a sulfur atom as a constituent atom of the ring. Further, this ring may have an alkyl group having 1 to 6 carbon atoms as a substituent. )
Represents a partial structure represented by ]
Or a compound represented by formula (V):
[0039]
Embedded image
(Where X², X^Four, R¹¹, R¹², R¹³, A¹, And Y are the same as defined above. )
In the presence of a base, and further, if desired, deprotection, a method for producing a quinolone compound;
A compound represented by the following formula, a salt thereof, or a hydrate thereof:
[0040]
Embedded image
[Where R¹¹¹IsRepresents a protecting group for a hydrogen atom or an amino group,
R ² , R ^Three , R ^Four , R ^Five , R ⁶ and R ⁷ Represents a hydrogen atom,
X ¹ The substructure
[0041]
Embedded image
(Where R⁸And R⁹IsRepresents a hydrogen atom, m Is an integer 1 Represents. )
[0042]
Represents
n Is an integer 1 Or 2 Represents. ]
And the expression ( III Compound represented by:
[0043]
Embedded image
[Where X²Represents a halogen atom or a hydrogen atom,
X^FourRepresents a fluorine atom, a chlorine atom, a bromine atom, a substituted or unsubstituted phenylsulfonyl group, or a substituted or unsubstituted alkylsulfonyl group having 1 to 3 carbon atoms;
Y¹Is a hydrogen atom, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyl group, choline group, dimethylaminoethyl group, 5-indanyl group, phthalidinyl group, 5-alkyl-2-oxo-1,3 -Dioxol-4-ylmethyl group, 3-acetoxy-2-oxobutyl group, alkyl group having 1 to 6 carbon atoms, alkoxymethyl group having 2 to 7 carbon atoms, or alkylene group having 1 to 6 carbon atoms and phenyl group A composed phenylalkyl group or of formula (IV)
[0044]
Embedded image
-B (Y¹¹) Y¹²                  (IV)
(Where Y¹¹And Y¹²Represents a fluorine atom or an alkylcarbonyloxy group having 2 to 4 carbon atoms. )
A boron-containing substituent represented by:
R¹¹Is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, an optionally substituted cyclic alkyl group having 3 to 6 carbon atoms, An aryl group which may have a group, a heteroaryl group which may have a substituent, an alkoxyl group having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms;
R¹²Represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms,
This R¹²And R above¹¹May be integrated so as to include a part of the mother nucleus to form a cyclic structure, but the ring formed in this way may contain a sulfur atom as a constituent atom of the ring. May have an alkyl group having 1 to 6 carbon atoms as a substituent.
R¹³Is a hydrogen atom, amino group, hydroxyl group, thiol group, halogenomethyl group, alkyl group having 1 to 6 carbon atoms, alkenyl group having 2 to 6 carbon atoms, alkynyl group having 2 to 6 carbon atoms, or 1 to 6 carbon atoms Represents an alkoxyl group of
Of these, the amino group has 1 or 2 groups selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms, and an acyl group having 2 to 5 carbon atoms as a substituent. Also good.
A¹Is a nitrogen atom or formula (II)
[0045]
Embedded image
(Where X^ThreeIs a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, or Represents an alkoxyl group having 1 to 6 carbon atoms,
Of these, the amino group has 1 or 2 groups selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms, and an acyl group having 2 to 5 carbon atoms as a substituent. Well,
Furthermore this X^ThreeAnd R above¹¹May be integrated so as to include a part of the mother nucleus to form a cyclic structure, but the ring formed in this way has an oxygen atom, a nitrogen atom, or a sulfur atom as a constituent atom of the ring. Further, this ring may have an alkyl group having 1 to 6 carbon atoms as a substituent. )
Represents a partial structure represented by ]
Or a compound represented by formula (V):
[0046]
Embedded image
(Where X², X^Four, R¹¹, R¹², R¹³, A¹, And Y are the same as defined above. )
In the presence of a base, and further, if desired, deprotection, a method for producing a quinolone compound;
Etc.
[0047]
BEST MODE FOR CARRYING OUT THE INVENTION
The substituents of the compound represented by the formula (I) of the present invention will be described.
Substituent R¹And R²Each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and this alkyl group is a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms, and an alkyloxy group having 1 to 6 carbon atoms. One or more groups selected from the group consisting of groups may be substituted.
Here, the alkyl group may be linear or branched having 1 to 6 carbon atoms, but is preferably a methyl group, an ethyl group, a normal propyl group or an isopropyl group.
When the alkyl group has a hydroxyl group as a substituent, the alkyl group may be linear or branched having 1 to 6 carbon atoms, and the hydroxyl group is substituted on the terminal carbon atom of the alkyl group. More preferred. The alkyl group having a hydroxyl group is preferably an alkyl group having up to 3 carbon atoms, and is preferably a hydroxymethyl group, a 2-hydroxyethyl group, a 2-hydroxypropyl group, a 3-hydroxypropyl group, or the like.
When the alkyl group has a halogen atom as a substituent, the alkyl group may be linear or branched having 1 to 6 carbon atoms, and the halogen atom is preferably a fluorine atom. Further, the number of fluorine atoms may be any from mono substitution to perfluoro substitution. A monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group and the like can be exemplified.
When the alkyl group has an alkylthio group as a substituent, the alkyl group may be linear or branched having 1 to 6 carbon atoms, and the alkylthio group may be linear or branched having 1 to 6 carbon atoms. Either of these may be used. As the alkyl group having an alkylthio group, an alkylthiomethyl group, an alkylthioethyl group, and an alkylthiopropyl group are preferable, and an alkylthio group having a carbon number of up to 3 is also preferable. More preferable examples include a methylthiomethyl group, an ethylthiomethyl group, and a methylthioethyl group.
When the alkyl group has an alkoxyl group as a substituent, the alkyl group may be linear or branched having 1 to 6 carbon atoms, and the alkoxyl group may be linear or branched having 1 to 6 carbon atoms. Either of these may be used. The alkyl group having an alkoxyl group is preferably an alkoxymethyl group, an alkoxyethyl group, or an alkoxypropyl group, and more preferably an alkoxyl group having up to 3 carbon atoms. More preferable examples include a methoxymethyl group, an ethoxymethyl group, and a methoxyethyl group.
[0048]
Substituent R^ThreeRepresents a hydrogen atom, a hydroxyl group, a halogen atom, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, or an alkylthio group having 1 to 6 carbon atoms. , One or more groups selected from the group consisting of a hydroxyl group, a halogen atom, and an alkoxyl group having 1 to 6 carbon atoms may be substituted.
The halogen atom is preferably a fluorine atom or a chlorine atom.
The alkyl group may be linear or branched having 1 to 6 carbon atoms, but is preferably a methyl group, an ethyl group, a normal propyl group or an isopropyl group.
The alkoxyl group may be linear or branched having 1 to 6 carbon atoms, but is preferably a methoxyl group or an ethoxyl group.
The alkylthio group may be linear or branched having 1 to 6 carbon atoms, but is preferably a methylthio group or an ethylthio group.
When the hydroxyl group is present as a substituent on the alkyl group having 1 to 6 carbon atoms, the alkyl group may be either linear or branched, and the substitution position of the hydroxyl group is the carbon atom at the terminal of the alkyl group. Those substituted above are more preferred. Preferred examples of the alkyl group having 1 to 6 carbon atoms substituted with a hydroxyl group include a hydroxymethyl group, a 2-hydroxyethyl group, and a 3-hydroxypropyl group.
As the halogen atom of the alkyl group having a halogen atom, a fluorine atom and a chlorine atom are preferable, and a fluorine atom is particularly preferable. The alkyl group may be linear or branched.
In the alkyl group having 1 to 6 carbon atoms having an alkoxyl group, any alkyl group portion may be linear or branched, and an alkoxymethyl group or an alkoxyethyl group is preferable. More preferred examples include a methoxymethyl group, an ethoxymethyl group, and a 2-methoxyethyl group.
[0049]
Substituent R^FourAnd R^FiveEach independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms. Among these, the alkyl group includes a hydroxyl group, a halogen atom, and 1 to 6 carbon atoms. One or more groups selected from the group consisting of the alkoxyl groups may be substituted.
As the halogen atom, a fluorine atom or a chlorine atom is preferable.
The alkyl group may be linear or branched having 1 to 6 carbon atoms, but is preferably a methyl group, an ethyl group, a normal propyl group or an isopropyl group.
The alkoxyl group may be linear or branched having 1 to 6 carbon atoms, but is preferably a methoxyl group or an ethoxyl group.
The alkyl group having 1 to 6 carbon atoms substituted with a hydroxyl group may be either linear or branched, and the substitution position of the hydroxyl group is more preferably substituted with the terminal carbon atom of the alkyl group. Preferred examples of the alkyl group having 1 to 6 carbon atoms substituted with a hydroxyl group include a hydroxymethyl group, a 2-hydroxyethyl group, and a 3-hydroxypropyl group.
As the halogen atom of the alkyl group having a halogen atom, a fluorine atom and a chlorine atom are preferable, and a fluorine atom is particularly preferable. The alkyl group may be linear or branched.
In the alkyl group having 1 to 6 carbon atoms having an alkoxyl group, any alkyl group may be linear or branched, and an alkoxymethyl group or an alkoxyethyl group is preferable. More preferred examples include a methoxymethyl group, an ethoxymethyl group, and a 2-methoxyethyl group.
[0050]
Substituent R⁶And R⁷Each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. The alkyl group may be linear or branched having 1 to 6 carbon atoms, but is preferably a methyl group, an ethyl group, a normal propyl group or an isopropyl group.
[0051]
  X ¹ The substructure
[0052]
Embedded image
(Where R⁸And R⁹IsRepresents a hydrogen atom, m Is an integer 1 Represents. )
[0053]
Represents.
[0055]
n Is an integer 1 Or 2 Represents an integer, especially 1 Is preferred.
[0060]
A preferred structure for Q is the formula
[0061]
Embedded image
Or an expression
[0062]
Embedded image
It is a structure of the condensed heterocyclic ring system represented by these.
[0063]
Substituent R¹¹Is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, an optionally substituted cyclic alkyl group having 3 to 6 carbon atoms, An aryl group which may have a group, a heteroaryl group which may have a substituent, an alkoxyl group having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms.
Here, the alkyl group having 1 to 6 carbon atoms is particularly preferably an ethyl group. The alkenyl group having 2 to 6 carbon atoms is preferably a vinyl group or a 1-isopropenyl group. The halogenoalkyl group having 1 to 6 carbon atoms is preferably a 2-fluoroethyl group. As the cyclic alkyl group, a cyclopropyl group is particularly preferable. As the substituent on the cyclic alkyl group, a halogen atom is preferable, and a fluorine atom is particularly preferable as the halogen atom.
Examples of the aryl group that may have a substituent include a halogen atom such as a fluorine atom, a chlorine atom, and a bromine atom, a hydroxyl group, an amino group, a nitro group, an alkyl group having 1 to 6 carbon atoms, and an alkyl group having 1 to 6 carbon atoms. A phenyl group optionally having 1 to 3 groups selected from the group consisting of alkoxyl groups as a substituent, such as a phenyl group, a 2-fluorophenyl group, a 4-fluorophenyl group, 2 1,4-difluorophenyl group and 2-fluoro-4-hydroxyphenyl group are preferred.
The heteroaryl group is a substituent derived from a 5-membered or 6-membered aromatic heterocyclic compound containing one or more hetero atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom. For example, a pyridyl group, a pyrimidyl group, etc. can be mentioned. As a substituent on these rings, an alkyl group, a halogen atom or the like is preferable.
The alkoxyl group having 1 to 6 carbon atoms is preferably a methoxyl group. The alkylamino group having 1 to 6 carbon atoms is preferably a methylamino group.
Substituent R¹¹Is preferably a cyclic alkyl group or a halogenocycloalkyl group. Among these, a cyclopropyl group or a 2-halogenocyclopropyl group is preferable. The halogen atom is preferably a fluorine atom.
[0064]
Substituent R¹²Represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms, or R¹¹And R¹²And include part of the mother nucleus (ie, R¹¹Nitrogen atom to which R is bonded, and R¹²May be integrated so as to form a hydrocarbon-based cyclic structure (so that it contains a carbon atom to which is bonded). The ring thus formed may contain a sulfur atom as a constituent atom, and this ring may have an alkyl group of carbon atoms 1 to 6 as a substituent. The ring formed here may have a size of a 4-membered ring to a 6-membered ring, and this ring may be saturated, partially saturated, or unsaturated. Examples of the condensed ring structure thus formed include the following.
[0065]
Embedded image
[0066]
Substituent X²Are each independently a halogen atom or a hydrogen atom, and in the case of a halogen atom, a fluorine atom is preferred. Among these, a fluorine atom or a hydrogen atom is preferable.
[0067]
Substituent R¹³Is a hydrogen atom, amino group, hydroxyl group, thiol group, halogenomethyl group, alkyl group having 1 to 6 carbon atoms, alkenyl group having 2 to 6 carbon atoms, alkynyl group having 2 to 6 carbon atoms, or 1 to 6 carbon atoms Wherein the amino group is a 1 or 2 group selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms, and an acyl group having 2 to 6 carbon atoms. You may have as a substituent.
The alkyl group may be a straight chain or branched chain group having 1 to 6 carbon atoms, and preferably a methyl group, an ethyl group, a normal propyl group, and an isopropyl group. The alkenyl group may be linear or branched having 2 to 6 carbon atoms, but is preferably a vinyl group. The alkynyl group may be linear or branched having 2 to 6 carbon atoms, but is preferably an ethynyl group. The halogen of the halogenomethyl group is particularly preferably a fluorine atom, and the number thereof may be 1 to 3. The alkoxyl group may have 1 to 6 carbon atoms, but is preferably a methoxyl group.
[0068]
Substituent R¹³Is preferably a hydrogen atom, an alkyl group, or an amino group, and among these, a methyl group or an unsubstituted amino group is preferable.
Substituent R¹³Are amino groups, hydroxyl groups or thiol groups, these may be protected by commonly used protecting groups.
Examples of such protecting groups include (substituted) alkoxycarbonyl groups such as tertiary butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group; benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group (Substituted) aralkyloxycarbonyl groups such as paranitrobenzyloxycarbonyl group; (substituted) acyl groups such as acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, benzoyl group ; (Substituted) alkyl groups such as tertiary butyl group, benzyl group, paranitrobenzyl group, paramethoxybenzyl group, triphenylmethyl group, or (substituted) aralkyl groups; methoxymethyl group, tertiary butoxymethyl Group, tetrahydropyranyl group, 2,2,2-trichloroethoxymethyl (Substituted) ethers such as trimethylsilyl group, isopropyldimethylsilyl group, tertiary butyldimethylsilyl group, tribenzylsilyl group, tertiary butyldiphenylsilyl group and the like (alkyl and / or aralkyl) substituted silyl groups (Here, “(substituted)” means that it may have a substituent. The same applies to the following). Compounds having substituents protected by these substituents are particularly preferred as production intermediates.
[0069]
A¹Is the formula (II)
[0070]
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X if it is a substructure of^ThreeIs a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, or An alkoxyl group having 1 to 6 carbon atoms, wherein the amino group is selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms, and an acyl group having 2 to 5 carbon atoms; You may have 2 groups as a substituent.
The alkyl group may be a straight chain or branched chain group having 1 to 6 carbon atoms, and preferably a methyl group, an ethyl group, a normal propyl group, and an isopropyl group. The alkenyl group may be linear or branched having 2 to 6 carbon atoms, but is preferably a vinyl group. The alkynyl group may be linear or branched having 2 to 6 carbon atoms, but is preferably an ethynyl group. The halogen of the halogenomethyl group is particularly preferably a fluorine atom, and the number thereof may be 1 to 3. The alkoxyl group may have 1 to 6 carbon atoms, but is preferably a methoxyl group. The halogen of the halogenomethoxyl group is particularly preferably a fluorine atom, and the number thereof may be 1 to 3.
Of these substituents, an alkyl group or an alkoxyl group is preferable. More preferred are a methyl group and an ethyl group. These are especially Q
[0071]
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Is a preferred substituent when the partial structure is as shown in FIG.
[0072]
Furthermore this X^ThreeAnd R mentioned above¹¹Includes part of the mother nucleus (ie, X^ThreeCarbon atom to which R is bonded, and R¹¹Hydrocarbon ring structure (ring size is from 4 to 7-membered ring, saturated, partially saturated or unsaturated) The ring thus formed may contain an oxygen atom, a nitrogen atom or a sulfur atom as a constituent atom of the ring, and the ring You may have a C1-C6 alkyl group as a substituent. Examples of the condensed ring structure thus formed include the following.
[0073]
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Among these fused ring systems, 2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid-10-yl groups, especially The 3 (S) -methyl form is preferred.
[0074]
Q is the formula
[0075]
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The partial structure is preferable. In this case A¹Is preferably a partial structure of formula (II).
Q is the above partial structure, and A¹R is a partial structure of formula (II)¹³And X^ThreePreferred as a combination of R¹³Is an amino group, a hydrogen atom, a hydroxyl group, or an alkyl group having 1 to 6 carbon atoms,^ThreeIs an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogenomethoxyl group, or a hydrogen atom.
A further preferred combination is R¹³Is an amino group, a hydrogen atom, a hydroxyl group, or a methyl group,^ThreeIs a methyl group, a methoxyl group, a difluoromethoxyl group, or a hydrogen atom.
A particularly preferred combination is R¹³Is an amino group, a hydrogen atom, a hydroxyl group, or a methyl group,^ThreeIs a methyl group or a methoxyl group.
These R¹³And X^ThreeX²Is preferably a fluorine atom.
Substituent X²And X^ThreeEach is a halogen atom, X²Is particularly preferably a fluorine atom, X²Is preferably a fluorine atom or a chlorine atom.
[0076]
Q is the formula
[0077]
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A partial structure represented by A¹R is a partial structure of formula (II)¹³And X^ThreePreferred as a combination of R¹³Is an amino group, a hydrogen atom, a hydroxyl group, or an alkyl group having 1 to 6 carbon atoms,^ThreeIs an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogenomethoxyl group, or a hydrogen atom.
A further preferred combination is R¹³Is an amino group, a hydrogen atom, a hydroxyl group, or a methyl group,^ThreeIs a methyl group, a methoxyl group, a fluorine atom, a chlorine atom, a difluoromethoxyl group, or a hydrogen atom.
A particularly preferred combination is R¹³Is an amino group, a hydrogen atom, a hydroxyl group, or a methyl group, and X^ThreeIs a methyl group or a methoxyl group.
Substituent X²And X^ThreeEach is a halogen atom, X^ThreeIs particularly preferably a fluorine atom, X^ThreeIs preferably a fluorine atom or a chlorine atom.
[0078]
Then R¹¹The halogenocyclopropyl group of is described.
Examples of the halogen atom to be substituted include a fluorine atom and a chlorine atom, and a fluorine atom is particularly preferable.
The steric environment at this part is particularly preferably a halogen atom and a pyridonecarboxylic acid part in a cis configuration with respect to the cyclopropane ring.
This R¹¹There are so-called enantiomer-related isomers only in the cis-2-halogenocyclopropyl moiety, and strong antibacterial activity and high safety were recognized in all of these.
[0079]
The compound of the present invention is characterized by having a substituent having the following structure. In this substituent, the substituent -N (R¹) R²And substituent R^ThreeAnd the substituent R^FourAnd substituent R^FiveAre usually in a cis configuration. Therefore, four kinds of isomers exist from the condensed part of the ring in which these substituents exist.
[0080]
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[0081]
When the compound of formula (I) which is a compound of the present invention has a structure in which a diastereomer exists, it is preferable to administer a compound consisting of a single diastereomer when the compound of the present invention is administered to humans or animals. . This “consisting of a single diastereomer” is understood to include not only the case where no other diastereomer is contained, but also the case of chemical purity. That is, it is interpreted that other diastereomers may be included as long as they do not affect physical constants and physiological activities. In addition, “stereochemically single” is composed of only one of them when there are a plurality of isomer-related species because an asymmetric carbon atom is contained in a compound or the like. It means to be a thing. In this case as well, this “unity” is considered in the same manner as described above.
[0082]
The pyridonecarboxylic acid derivative of the present invention may be in a free form, but may be an acid addition salt or a salt of a carboxyl group. Examples of acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate, acetate, methanesulfonate, benzene Examples thereof include organic acid salts such as sulfonate, toluenesulfonate, citrate, maleate, fumarate, and lactate.
Examples of the carboxyl group salt include alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, ammonium salt, triethylamine salt and N-methylglucamine salt, Tris- (hydroxylmethyl) aminomethane salt and the like may be any of inorganic salts and organic salts.
In addition, free forms, acid addition salts, and carboxyl group salts of these pyridonecarboxylic acid derivatives may exist as hydrates.
[0083]
On the other hand, quinolone derivatives in which the carboxylic acid moiety is an ester are useful as synthetic intermediates and prodrugs. For example, alkyl esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters and phenyl esters are useful as synthetic intermediates.
In addition, esters used as prodrugs are esters that are easily cleaved in vivo to produce a free form of carboxylic acid. For example, acetoxymethyl ester, pivaloyloxymethyl ester, ethoxycarbonyl ester, choline Oxos such as esters, dimethylaminoethyl esters, 5-indanyl esters and phthalidinyl esters, 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl esters, and 3-acetoxy-2-oxobutyl esters Mention may be made of alkyl esters.
[0084]
The compound of the present invention represented by the formula (I) is produced by various methods, and a preferred example thereof is, for example, the formula (III)
[0085]
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[Where X^FourRepresents a group that functions as a leaving group, such as a fluorine atom, a chlorine atom, a bromine atom, a substituted or unsubstituted phenylsulfonyl group, or a substituted or unsubstituted alkylsulfonyl group having 1 to 3 carbon atoms;
Y¹Is Y as defined in formula (I) or formula (IV)
[0086]
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-B (Y¹¹) Y¹²                  (IV)
(Where Y¹¹And Y¹²Represents a fluorine atom or an alkylcarbonyloxy group having 2 to 4 carbon atoms. )
A boron-containing substituent represented by:
R¹¹, R¹², R¹³, A¹, And X²Is the same as defined in formula (I). ]
Or a compound of formula (V)
[0087]
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[Where X^FourRepresents a substituent that functions as a leaving group such as a fluorine atom, a chlorine atom, a bromine atom, a substituted or unsubstituted phenylsulfonyl group, or a substituted or unsubstituted alkylsulfonyl group having 1 to 3 carbon atoms; R¹¹, R¹², R¹³, A¹, X², And Y are the same as defined in formula (I). ]
A compound represented by formula (VI)
[0088]
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[Where R¹¹¹Is R as defined in formula (I)¹Or represents an amino-protecting group, R², R^Three, R^Four, R^Five, R⁶, R⁷, X¹, And n are the same as defined in formula (I). ]
It can manufacture by making it react with the compound or its addition salt represented.
[0089]
The reaction can be carried out with or without a solvent. The solvent used in the reaction may be inert under the reaction conditions. For example, dimethyl sulfoxide, pyridine, acetonitrile, ethanol, chloroform, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, water, 3-methoxybutanol, Or a mixture thereof.
The reaction may be an acid acceptor such as an inorganic base or an organic base, for example, an alkali metal or alkaline earth metal carbonate or bicarbonate, or an organic basic compound such as triethylamine, pyridine, 1,8-diazabicycloundecene Is preferably carried out in the presence of.
The reaction temperature can usually be carried out in the temperature range of room temperature to 200 ° C, preferably in the range of 25 to 150 ° C. The reaction time may be in the range of 30 minutes to 48 hours, and is usually completed in about 30 minutes to 2 hours.
[0090]
The amino-protecting group may be any protecting group commonly used in this field. For example, a (substituted) alkoxycarbonyl group such as a tertiary butoxycarbonyl group or a 2,2,2-trichloroethoxycarbonyl group. (Substituted) aralkyloxycarbonyl groups such as benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group; acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, (Substituted) acyl groups such as formyl group and benzoyl group; (substituted) alkyl groups such as tertiary butyl group, benzyl group, paranitrobenzyl group, paramethoxybenzyl group and triphenylmethyl group, or (substituted) Aralkyl groups; methoxymethyl, tertiary butoxymethyl, tetra (Substituted) ethers such as lopyranyl group and 2,2,2-trichloroethoxymethyl group; trimethylsilyl group, isopropyldimethylsilyl group, tertiary butyldimethylsilyl group, tribenzylsilyl group, tertiary butyldiphenylsilyl group, etc. (Alkyl and / or aralkyl) substituted silyl groups.
[0091]
Y and Y¹In the case where is an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, or a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group, Can be converted to the corresponding carboxylic acid by treatment under acidic or basic conditions used in
Y¹In the case of the structure of formula (IV), after reacting compound (VI) with compound (III) or compound (V), it is converted to the corresponding carboxylic acid by treatment under acidic or basic conditions. be able to.
When deprotection is necessary, the protective compound can be removed under suitable conditions corresponding to the protective group to obtain the target compound represented by the formula (I).
[0092]
The compound of the formula (VI) is produced by various methods, but as a preferred example thereof, it is synthesized by the method shown in the reference example, but is not limited thereto.
[0093]
The compound of formula (VI) is
[0094]
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[Where R¹¹¹Is R as defined in formula (I)¹Or represents an amino-protecting group, R², R^Three, R^Four, R^Five, R⁶, R⁷, X¹, And n are the same as defined in formula (I).
Q ′ is an amino-protecting group.
Protecting groups for amino groups include (substituted) alkoxycarbonyl groups, (substituted) aralkyloxycarbonyl groups, (substituted) acyl groups, (substituted) alkyl groups, (substituted) aralkyl groups, and substituted silyl groups. It may be selected from the group consisting of ]
Q ′ can be removed from the compound represented by
The above compounds may also exist as salts, hydrates, or salt hydrates. Examples of acid addition salts include inorganic acid salts and organic acid salts. Specific examples of these include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate, or methanesulfonate, benzenesulfonate, toluenesulfonic acid. Organic acid salts such as salts (sulfonates), acetates, citrates, maleates, fumarate, lactates (carboxylates) and the like can be mentioned.
[0095]
R¹¹¹And Q ′ may be the same or different when both are amino-protecting groups, but in order to produce compound (I), each is cleaved under different reaction conditions. Is convenient.
R which is a protecting group for amino group¹¹¹Examples of Q ′ include the following. That is, (substituted) alkoxycarbonyl groups, (substituted) aralkyloxycarbonyl groups, (substituted) acyl groups, (substituted) alkyl groups, (substituted) aralkyl groups, substituted silyl groups.
Specifically, (substituted) alkoxycarbonyl groups such as tertiary butoxycarbonyl group and 2,2,2-trichloroethoxycarbonyl group; benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group (Substituted) aralkyloxycarbonyl groups such as: acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, benzoyl group and the like (substituted) acyl groups; tertiary butyl group, (Substituted) alkyl groups such as benzyl group, paranitrobenzyl group, paramethoxybenzyl group, triphenylmethyl group, or (substituted) aralkyl groups; methoxymethyl group, tertiary butoxymethyl group, tetrahydropyranyl group, Ethers such as 2,2,2-trichloroethoxymethyl group; Silyl group, an isopropyl dimethyl silyl group, tert-butyldimethylsilyl group, tribenzylsilyl group, a substituted silyl group such as tert-butyldiphenylsilyl group.
[0096]
When the compound (I) is produced using the above compound having a protecting group Q ′, it is necessary to remove the protecting group Q ′ for reaction. In this case, the reaction with the compound (III) or (V) may be carried out usually in one pot immediately after the removal of the protecting group, or the compound (VI) is once isolated after removing the protecting group. You may make it react.
[0097]
Cis-2-fluorocyclopropylamine consisting of a single isomer, which is preferable for the synthesis of a compound of formula (I) consisting of a single isomer, can be synthesized, for example, by the method described in JP-A-2-231475. The synthesis of the compound of formula (I) consisting of a single isomer from the optically active cis-2-fluorocyclopropylamine derivative thus obtained is described in, for example, JP-A-2-231475. It can implement by the method of.
[0098]
Examples of the compound of the present invention include the following.
10-{(1R, 2R, 6S) -1-Amino-4-azatricyclo [6.1.0.0^2,6] Nonan-4-yl} -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1.2.3-de] [1,4] benzoxazine-6- carboxylic acid;
8-amino-10-{(1R, 2R, 6S) -1-amino-4-azatricyclo [6.1.0.0^2,6] Nonan-4-yl} -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1.2.3-de] [1,4] benzoxazine-6- carboxylic acid;
5-Amino-7-{(1R, 2R, 6S) -1-amino-4-azatricyclo [6.1.0.0^2,6] Nonan-4-yl} -6-fluoro-1- [2- (S) -fluoro-1- (R) -cyclopropyl] -8-methyl-1,4-dihydro-4-oxoquinoline-3- carboxylic acid;
5-Amino-7-{(1R, 2R, 6S) -1-amino-4-azatricyclo [6.1.0.0^2,6] Nonan-4-yl} -6-fluoro-1- [2- (S) -fluoro-1- (R) -cyclopropyl] -8-methoxy-1,4-dihydro-4-oxoquinoline-3- carboxylic acid;
7-{(1R, 2R, 6S) -1-Amino-4-azatricyclo [6.1.0.0^2,6] Nonan-4-yl} -6-fluoro-1- [2- (S) -fluoro-1- (R) -cyclopropyl] -8-methoxy-1,4-dihydro-4-oxoquinoline-3- carboxylic acid;
7-{(1R, 2R, 6S) -1-Amino-4-azatricyclo [6.1.0.0^2,6] Nonan-4-yl} -6-fluoro-1- [2- (S) -fluoro-1- (R) -cyclopropyl] -8-methyl-1,4-dihydro-4-oxoquinoline-3- carboxylic acid;
7-{(1R, 2R, 6S) -1-Amino-4-azatricyclo [6.1.0.0^2,6] Nonan-4-yl} -6-fluoro-1- [2- (S) -fluoro-1- (R) -cyclopropyl] -1,4-dihydro-4-oxo-1,8-naphthyridine-3 -carboxylic acid;
8-{(1R, 2R, 6S) -1-Amino-4-azatricyclo [6.1.0.0^2,6] Nonan-4-yl} -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolidine-3-carboxylic acid;
10-{(1R, 2R, 6S) -1-Amino-4-azatricyclo [6.1.0.0^2,6] Nonan-4-yl} -9-fluoro-3- (S) -methyl-2H, 3H, 6H-6-oxopyrano [2,3,4-IJ] quinolizine-5-carboxylic acid
These have the following structure:
[0099]
Embedded image
[0100]
Since the compound of the present invention has a strong antibacterial action, it can be used as a medicine for human bodies, animals and fish, or as a preservative for agricultural chemicals and foods.
When the compound of the present invention is used as a pharmaceutical for the human body, the dosage is in the range of 50 mg to 1 g, preferably 100 mg to 300 mg per day for an adult.
The dose for animals varies depending on the purpose of administration (treatment or prevention), the type and size of the animal to be treated, the type and degree of the infectious pathogen, but the daily dose is generally animal. 1 mg to 200 mg per kg body weight, preferably 5 mg to 100 mg.
This daily dose is administered once a day or divided into 2 to 4 times. The daily dose may exceed the above amount if necessary.
[0101]
The compounds of the present invention are active against a wide range of microorganisms that cause various infectious diseases, and can treat, prevent, or alleviate diseases caused by these pathogens.
Bacteria or bacteria-like microorganisms in which the compound of the present invention is effective include staphylococci, Streptococcus pyogenes, hemolytic streptococci, enterococci, pneumococci, peptostreptococcus, gonococci, Escherichia coli, Citrobacter, Shigella, pneumonia Examples include Neisseria gonorrhoeae, Enterobacter, Serratia, Proteus, Pseudomonas aeruginosa, Haemophilus influenzae, Acinetobacter, Campylobacter, and Trachoma chlamydia.
Diseases caused by these pathogens include folliculitis, illness, erysipelas, cellulitis, lymphangiosis (nodal), hail cancer, subcutaneous abscess, sweat glanditis, congestive acne, infectious mass, anus Peripheral abscess, mastitis, superficial secondary infection such as trauma / burn / surgical wound, sore throat, acute bronchitis, tonsillitis, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, chronic respiratory disease Secondary infection, pneumonia, pyelonephritis, cystitis, prostatitis, accessory testicularitis, gonococcal urethritis, non-gonococcal urethritis, cholecystitis, cholangitis, bacterial dysentery, enteritis, uterine adnexitis, intrauterine Infection, bartholin adenitis, blepharitis, stye, lacrimal cystitis, pleurisy, corneal ulcer, otitis media, sinusitis, periodontitis, pericoronitis, jawitis, peritonitis, endocarditis, sepsis, Meningitis, skin infection, etc. can be illustrated.
Further, it is effective for various microorganisms that cause infectious diseases of animals, for example, Escherichia, Salmonella, Pasteurella, Haemophilus, Bordetella, Staphylococcus, Mycoplasma, and the like.
Specific examples of disease names include coliformosis, chick dysentery, chicken paratyphoid fever, poultry cholera, infectious coryza, staphylococci, and mycoplasma infections in birds, and colitis, salmonellosis, pasteurellosis, hemophilus in pigs. Infectious disease, atrophic rhinitis, exudative epidermitis, mycoplasma infection, etc. in cattle, colibacillosis, salmonellosis, hemorrhagic sepsis, mycoplasma infection, bovine lung disease, mastitis, etc., in dogs, colibacillary sepsis, salmonella Infectious diseases, hemorrhagic sepsis, uterine abscess, cystitis, etc. In cats, exudative pleurisy, cystitis, chronic rhinitis, hemophilus infection, kitten diarrhea, mycoplasma infection and the like can be mentioned.
[0102]
The antibacterial preparation containing the compound of the present invention can be prepared by selecting an appropriate preparation according to the administration method and preparing various preparations usually used. Examples of the dosage form of the antibacterial preparation comprising the compound of the present invention as the main ingredient include tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions and the like as oral preparations. It can be illustrated.
As injections, stabilizers, preservatives, and solubilizing agents may be used in the preparation. After storing a solution that may contain these adjuvants in a container, it is prepared as a solid preparation by freeze-drying etc. It is good also as a formulation. One dose may be stored in a container, and multiple doses may be stored in the same container.
Examples of external preparations include solutions, suspensions, emulsions, ointments, gels, creams, lotions, and sprays.
Solid preparations may contain pharmaceutically acceptable additives along with the active compound, for example, fillers, extenders, binders, disintegrants, dissolution promoters, wetting agents, lubricants Agents and the like can be selected and mixed as necessary to prepare a formulation.
Examples of liquid preparations include solutions, suspensions, emulsions, and the like, but additives may include suspending agents, emulsifiers, and the like.
[0103]
As a method of administering the compound of the present invention to animals, a method of administering orally directly or mixed with feed or the like, a method of administering orally after adding a solution or directly to drinking water or feed, A method of administering by injection can be exemplified.
[0104]
As a preparation for administering the compound of the present invention to an animal, a powder, a fine granule, a soluble powder, a syrup, a solution, or an injection is appropriately used according to a technique commonly used in this field. be able to.
Next, formulation formulation examples are shown.
[0105]
[Table 1]
[0106]
【Example】
EXAMPLES Next, although an Example and a reference example demonstrate this invention, this invention is not limited to this.
[0107]
[Reference Example 1]7- Benzyl -2- Oxo -7- Azabicyclo [3.3.0] Octane
At room temperature, trifluoroacetic acid (385 μl) was added to a solution of 2-cyclopenten-1-one (10.1 ml, 120 mmol) and benzylbutoxymethyltrimethylsilylmethylamine (41.9 g, 150 mmol) in dichloromethane (300 ml) and stirred for 16 hours. . After distilling off dichloromethane, a saturated aqueous sodium hydrogen carbonate solution was added. Extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent, the obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain 24.92 g (115.7 mmol, 96%) of the title compound as a yellow oil.
¹H-NMR (400MHz, CDCl_Three) δ: 1.75-1.83 (1H, m), 2.08-2.18 (1H, m), 2.24-2.32 (1H, m), 2.37-2.49 (2H, m), 2.59-2.64 (1H, m), 2.67 ( 1H, dd, J = 2.5,9.5Hz), 2.85-2.93 (1H, m), 3.04 (1H, dd, J = 1.5,9.5Hz), 3.48 (1H, d, J = 13.0Hz), 3.61 (1H , d, J = 13.0Hz), 7.21-7.31 (5H, m)
[0108]
[Reference Example 2]7- Benzyloxycarbonyl -2- Oxo -7- Azabicyclo [3.3.0] Octane
Benzyloxycarbonyl chloride (5.14 ml, 36.0 mmol) was added dropwise to a solution of 7-benzyl-2-oxo-7-azabicyclo [3.3.0] octane (5.20 g, 24.2 mmol) in dichloromethane (50 ml) under ice cooling. And stirred at room temperature for 24 hours. After ice cooling again, benzyloxycarbonyl chloride (5.14 ml, 36.0 mmol) was further added dropwise. After the solvent was distilled off, the residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain 4.52 g (17.4 mmol, 72%) of the title compound as a colorless oil.
¹H-NMR (400MHz, CDCl_Three) δ: 1.80-1.90 (1H, m), 2.12-2.22 (1H, m), 2.35-2.39 (2H, m), 2.76 (1H, dt, J = 3.5,8.5Hz), 3.01-3.11 (1H, m), 3.16-3.26 (1H, m), 3.61-3.66 (1H, m), 3.69-3.78 (1H, m), 5.11-5.12 (2H, m), 7.29-7.38 (5H, m)
[0109]
[Reference Example 3]2- (N- Benzyl -N- Benzyloxycarbonyl ) amino -7- Benzyloxycarbonyl -7- Azabicyclo [3.3.0] Octa -2- En
Under ice-cooling, 7-benzyloxycarbonyl-2-oxo-7-azabicyclo [3.3.0] octane (4.51 g, 17.4 mmol) and anhydrous magnesium sulfate (3.5 g) in tetrahydrofuran (50 ml) were mixed with benzylamine (2.08 ml). 19.0 mmol) was added dropwise. After stirring for 1 hour, insoluble matters were removed by filtration, and the filtrate was concentrated. The obtained residue was dissolved in benzene (60 ml), and triethylamine (4.88 ml, 35.0 mmol) was added. Further, triphosgene (2.67 g, 9.0 mmol) was added under ice cooling. After stirring at room temperature for 1 hour, insoluble matters were removed by Celite filtration, and the filtrate was concentrated. The obtained residue was dissolved in tetrahydrofuran (30 ml) and added dropwise to a tetrahydrofuran (50 ml) solution of benzyloxysodium (25.0 mmol) under ice cooling. Stir at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added under ice-cooling, followed by extraction with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain 2.22 g (10.3 mmol, 59%) of the title compound as a colorless oil.
[0110]
[Reference Example 4]1- (N- Benzyl -N- Benzyloxycarbonyl ) amino -Four- Benzyloxycarbonyl -Four- Azatricyclo [6.1.0.0 ^2,6 ] Nonane
2- (N-benzyl-N-benzyloxycarbonyl) amino-7-benzyloxycarbonyl-7-azabicyclo [3.3.0] oct-2-ene (920 mg, 1.91 mmol) in dichloromethane (50 ml) at room temperature After adding diethyl zinc (1 mol n-hexane solution; 20 ml, 20.0 mmol), diiodomethane (3.06 ml, 38.0 mmol) was added dropwise. After stirring for 16 hours, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium thiosulfate solution and saturated brine, and then dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 3: 1) to obtain 678 mg (1.36 mmol, 71%) of the title compound as a colorless oil.
[0111]
[Reference Example 5]1- amino -Four- Azatricyclo [6.1.0.0 ^2,6 ] Nonane
1- (N-benzyl-N-benzyloxycarbonyl) amino-4-benzyloxycarbonyl-4-azatricyclo [6.1.0.0^2,6] 20% palladium hydroxide-carbon (500 mg) was added to a methanol (50 ml) solution of nonane (675 mg, 1.36 mmol), and the mixture was vigorously stirred under a hydrogen atmosphere for 120 hours. The insoluble material was removed by Celite filtration, and the filtrate was concentrated to give a crude product of the title compound as a colorless oil.
[0112]
[Example 1]Five- amino -7- (1- amino -Four- Azatricyclo [6.1.0.0 ^2,6 ] Nonane -Four- Il ) -1- Cyclopropyl -6,8- Difluoro -1,4- Dihydro -Four- Oxoquinoline -3- carboxylic acid
At room temperature, 1-amino-4-azatricyclo [6.1.0.0^2,6] To a solution of nonane (206 mg, 1.36 mmol) and triethylamine (418 μl, 3.0 mmol) in acetonitrile (10 ml), 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4- After adding oxoquinoline-3-carboxylic acid (298 mg, 1.0 mmol), the mixture was heated to reflux for 16 hours. After cooling to room temperature, acetonitrile was distilled off. A hydrochloric acid aqueous solution was added to the residue, followed by washing with chloroform. The aqueous layer was made alkaline with an aqueous sodium hydroxide solution and then washed with chloroform. The aqueous layer was adjusted to pH 7.5 with an aqueous hydrochloric acid solution and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was recrystallized from ethanol. The obtained crystals were recrystallized from 2-propanol to obtain 21 mg of the title compound as yellow crystals.
¹H-NMR (400MHz, 0.1N-NaOD) δ: 0.06-0.08 (2H, m), 0.30-0.62 (4H, m), 0.73-0.75 (1H, m), 1.17-1.21 (1H, m), 1.27 -1.36 (1H, m), 1.72-1.77 (1H, m), 2.10-2.17 (1H, m), 2.73-2.77 (1H, m), 3.00-3.08 (1H, m), 3.23-3.31 (3H, m), 7.68 (1H, s)
Melting point: 197-202 ° C (decomposition)
Elemental analysis: C_{twenty one}H_{twenty two}F₂N_FourO_Three・ 0.5H₂As O
Theoretical value: C, 59.28; H, 5.44; N, 13.17
Measurements: C, 59.48; H, 5.40; N, 12.90
[0113]
[Reference Example 6](1R, 5S) -7- Benzyl -2- Oxo -7- Azabicyclo [3.3.0] Octa -3- En
(4R) -4-tert-butyldimethylsilyloxy-2-cyclopenten-1-one (5.79 g, 27.3 mmol) and benzylbutoxymethyltrimethylsilylmethylamine (15.4 g, 55.0 mmol) in dichloromethane (100 ml) at room temperature Trifluoroacetic acid (154 μl) was added to the solution and stirred for 20 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent, the obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain 4.21 g (19.7 mmol, 72%) of the title compound as a colorless oil. In addition, 3.10 g of (1R, 4R, 5S) -7-benzyl-4-tert-butyldimethylsilyloxy-2-oxo-7-azabicyclo [3.3.0] octane as a mixture with tert-butyldimethylsilanol was obtained. . 3.10 g of the resulting mixture of (1R, 4R, 5S) -7-benzyl-4-tert-butyldimethylsilyloxy-2-oxo-7-azabicyclo [3.3.0] octane and tert-butyldimethylsilanol was added to tetrahydrofuran ( 30 ml), 1M-tetrahydrofuran solution of tetrabutylammonium fluoride (15 ml) was added under ice cooling, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off, the obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain 1.57 g (7.34 mmol) of the title compound as a colorless oil.
¹H-NMR (400MHz, CDCl_Three) δ: 2.32 (1H, t, J = 9.0Hz), 2.37 (1H, t, J = 9.0Hz), 2.72-2.76 (1H, m), 2.78 (1H, d, J = 9.5Hz), 3.10 ( 1H, d, J = 9.5Hz), 3.36-3.41 (1H, m), 3.51 (1H, d, J = 13.0Hz), 3.60 (1H, d, J = 13.0Hz), 6.24 (1H, dd, J = 1.0,5.5Hz), 7.20-7.30 (5H, m), 7.56 (1H, dd, J = 2.5,5.5Hz)
(1R, 4R, 5S) -7- Benzyl -4-tert- Butyldimethylsilyloxy -2- Oxo -7- Azabicyclo [3.3.0] Octane
¹H-NMR (400MHz, CDCl_Three) δ: -0.01 (3H, s), 0.00 (3H, s), 0.81 (9H, s) 2.23 (1H, ddt, J = 1.5,3.0,17.0Hz), 2.33-2.38 (2H, m), 2.57 (1H, dd, J = 5.5,17.0Hz), 2.71-2.75 (3H, m), 3.04 (1H, d, J = 9.0Hz), 3.39 (1H, d, J = 13.0Hz), 3.60 (1H, d, J = 13.0Hz), 4.18-4.20 (1H, m), 7.18-7.27 (5H, m)
[0114]
[Reference Example 7](1R, 5S) -7- Benzyl -2- Oxo -7- Azabicyclo [3.3.0] Octane
5% rhodium alumina (700 mg) was added to a solution of (1R, 5S) -7-benzyl-2-oxo-7-azabicyclo [3.3.0] oct-3-ene (1.57 g, 7.34 mmol) in ethyl acetate (50 ml). In addition, the mixture was vigorously stirred under a hydrogen atmosphere for 3.5 hours. The insoluble material was removed by Celite filtration, and the filtrate was concentrated. The residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain 1.31 g (6.10 mmol, 83%) of the title compound as a colorless oil.
¹H-NMR (400MHz, CDCl_Three) δ: 1.75-1.83 (1H, m), 2.08-2.18 (1H, m), 2.24-2.32 (1H, m), 2.37-2.49 (2H, m), 2.59-2.64 (1H, m), 2.67 ( 1H, dd, J = 2.5,9.5Hz), 2.85-2.93 (1H, m), 3.04 (1H, dd, J = 1.5,9.5Hz), 3.48 (1H, d, J = 13.0Hz), 3.61 (1H , d, J = 13.0Hz), 7.21-7.31 (5H, m)
[0115]
[Reference Example 8](1R, 5S) -7- Benzyloxycarbonyl -2- Oxo -7- Azabicyclo [3.3.0] Octane
Under ice cooling, benzyloxycarbonyl chloride (4.28 ml, 30.0 mmol) was added to a solution of (1R, 5S) -7-benzyl-2-oxo-7-azabicyclo [3.3.0] octane (1.31 g, 6.10 mmol) in dichloromethane (20 ml). Of dichloromethane (15 ml) was added dropwise, followed by stirring at room temperature for 16 hours. After the solvent was distilled off, the residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain 1.36 g (5.24 mmol, 86%) of the title compound as a colorless oil.
¹H-NMR (400MHz, CDCl_Three) δ: 1.80-1.90 (1H, m), 2.12-2.22 (1H, m), 2.35-2.39 (2H, m), 2.76 (1H, dt, J = 3.5,8.5Hz), 3.01-3.11 (1H, m), 3.16-3.26 (1H, m), 3.61-3.66 (1H, m), 3.69-3.78 (1H, m), 5.11-5.12 (2H, m), 7.29-7.38 (5H, m)
[0116]
[Reference Example 9](1'R, 5'S)- Spyro [7'- Benzyloxycarbonyl -7'- Azabicyclo [3.3.0] Octane -1,2'-2,5- Dioxolane ]
(1R, 5S) -7-Benzyloxycarbonyl-2-oxo-7-azabicyclo [3.3.0] octane (8.27 g, 31.9 mmol) in a solution of benzene (100 ml) with ethylene glycol (4.46 ml, 80.0 mmol) and p -Toluenesulfonic acid monohydrate (190.2 mg, 1.0 mmol) was added. The mixture was refluxed for 3 hours while removing generated water using a Dean-Stark apparatus. After cooling to room temperature, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution. This was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 9.71 g (quantitative) of the title compound as a colorless oil.
¹H-NMR (400MHz, CDCl_Three) δ: 1.45-1.53 (1H, m), 1.75-1.83 (1H, m), 1.89-2.01 (2H, m), 2.61 (1H, dt, J = 5.5,9.0Hz), 2.74-2.84 (1H, m), 3.23-3.33 (1H, m), 3.44-3.62 (3H, m), 3.90-3.92 (4H, m), 5.11-5.14 (2H, m), 7.28-7.37 (5H, m)
[0117]
[Reference Example 10](1'R, 5'S)- Spyro [7'- Azabicyclo [3.3.0] Octane -1,2'-2,5- Dioxolane ]
The crude product (1′R, 5 ′S) -spiro [7′-benzyloxycarbonyl-7′-azabicyclo [3.3.0] octane-1,2′-2,5-dioxolane] (9.71 g, 31.9 mmol ) In methanol (200 ml) was added 10% palladium on carbon (2.0 g) and stirred vigorously under a hydrogen atmosphere for 2 hours. The insoluble material was removed by celite filtration, and the filtrate was concentrated to give a crude product of the title compound (5.17 g, 30.6 mmol, 95%) as a colorless oil.
¹H-NMR (400MHz, CDCl_Three) δ: 1.26-1.34 (1H, m), 1.63-1.69 (1H, m), 1.73-1.80 (1H, m), 1.93 (1H, dq, J = 7.5, 12.5Hz), 2.48-2.53 (1H, m), 2.62-2.71 (2H, m), 2.76 (1H, dd, J = 8.0,12.0Hz), 2.92 (1H, dd, J = 7.0,11.0Hz), 3.00 (1H, dd, J = 4.0, 12.0Hz), 3.88-3.95 (4H, m)
[0118]
[Reference Example 11](1'R, 5'S)- Spyro [7'-p- Anisoil -7'- Azabicyclo [3.3.0] Octane -1,2'-2,5- Dioxolane ]
Under ice cooling, (1′R, 5 ′S) -spiro [7′-azabicyclo [3.3.0] octane-1,2′-2,5-dioxolane] (5.17 g, 30.6 mmol) and triethylamine (6.97 ml, 50.0) mmol) in dichloromethane (100 ml) was added p-anisoyl chloride (6.82 g, 40.0 mmol). After stirring at room temperature for 1 hour, the reaction solution was poured into a 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel chromatography (chloroform: methanol = 50: 1) to obtain 9.02 g (29.7 mmol, 93%) of the title compound as a colorless oil.
[0119]
[Reference Example 12](1R, 5S) -7-p- Anisoil -2- Oxo -7- Azabicyclo [3.3.0] Octane
(1'R, 5'S) -spiro [7'-anisoyyl-7'-azabicyclo [3.3.0] octane-1,2'-2,5-dioxolane] (9.02g, 29.7mmol) was added to 80% acetic acid (150ml) ) And then refluxed for 2.5 hours. After cooling to room temperature, acetic acid was distilled off. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 7.91 g (quantitative) of a crude product of the title compound as a colorless oil.
[0120]
[Reference Example 13](1R, 5S) -2- (N- Benzyl -N- Benzyloxycarbonyl ) amino -7-p- Anisoil -7- Azabicyclo [3.3.0] Octa -2- En
Under ice cooling, tetrahydrofuran (1R, 5S) -7-p-anisoyl-2-oxo-7-azabicyclo [3.3.0] octane (7.91 g, 29.7 mmol) and anhydrous magnesium sulfate (10 g) in tetrahydrofuran ( Benzylamine (3.82 ml, 35.0 mmol) was added dropwise to the mixture. After stirring for 1 hour, insoluble matters were removed by filtration, and the filtrate was concentrated. The obtained residue was dissolved in benzene (100 ml), triethylamine (6.27 ml, 45.0 mmol) was added, and triphosgene (4.45 g, 15.0 mmol) was further added under ice cooling. After stirring at room temperature for 1 hour, insoluble matters were removed by Celite filtration, and the filtrate was concentrated. The obtained residue was dissolved in tetrahydrofuran (30 ml) and added dropwise to a solution of benzyloxysodium (36.0 mmol) in tetrahydrofuran (50 ml) under ice cooling. Stir at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added under ice-cooling, followed by extraction with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title compound (3.39 g, 7.02 mmol, 24%) as a colorless oil.
[0121]
[Reference Example 14](1R, 2R, 6S) -1- (N- Benzyl -N- Benzyloxycarbonyl ) amino -4-p- Anisoil -Four- Azatricyclo [6.1.0.0 ^2,6 ] Nonane
(1R, 5S) -2- (N-benzyl-N-benzyloxycarbonyl) amino-7-anisoyl-7-azabicyclo [3.3.0] oct-2-ene (3.39 g, 7.02 mmol) and diiodomethane ( To a solution of 3.06 ml, 38.0 mmol) in dichloromethane (50 ml), diethylzinc (1 mol n-hexane solution; 20.0 ml, 20.0 mmol) was added dropwise at room temperature and stirred for 16 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium thiosulfate solution and saturated brine, and then dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain 2.64 g (5.32 mmol, 76%) of the title compound as a colorless oil.
[0122]
[Reference Example 15](1R, 2R, 6S) -1-tert- Butoxycarbonylamino -4-p- Anisoil -Four- Azatricyclo [6.1.0.0 ^2,6 ] Nonane
(1R, 2R, 6S) -1- (N-Benzyl-N-benzyloxycarbonyl) amino-4-p-anisoyl-4-azatricyclo [6.1.0.0^2,6] 10% palladium on carbon (2.0 g) was added to a methanol (100 ml) solution of nonane (2.64 g, 5.32 mmol), and the mixture was vigorously stirred in a hydrogen atmosphere for 15 hours. The insoluble material was removed by Celite filtration, and the filtrate was concentrated. The obtained residue and triethylamine (1.39 ml, 10.0 mmol) were dissolved in dichloromethane (50 ml), di-tert-butyl dicarbonate (2.18 g, 10 mmol) was added at room temperature, and the mixture was stirred for 2 hours. After concentration, the residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 2) to obtain 970 mg (2.60 mmol, 49%) of the title compound as a colorless oil.
[0123]
[Reference Example 16](1R, 2R, 6S) -1-tert- Butoxycarbonylamino -4-p- Methoxybenzyl -Four- Azatricyclo [6.1.0.0 ^2,6 ] Nonane
Under ice cooling, (1R, 2R, 6S) -1-tert-butoxycarbonylamino-4-p-anisoyl-4-azatricyclo [6.1.0.0^2,6] To a tetrahydrofuran (20 ml) solution of nonane (970 mg, 2.60 mmol), a 1 mol-tetrahydrofuran solution (7.0 ml, 7.0 mmol) of borane-tetrahydrofuran complex was added dropwise and stirred at room temperature for 1 hour. Under ice-cooling, water was added to the reaction solution to decompose excess borane-tetrahydrofuran complex. Further, 1N aqueous sodium hydroxide solution (10 ml) was added, and the mixture was refluxed for 6 hours. After cooling to room temperature, the mixture was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel chromatography (chloroform: methanol = 20: 1) to give 453 mg (1.26 mmol, 48%) of the title compound as a colorless oil. Got as.
[0124]
[Reference Example 17](1R, 2R, 6S) -1-tert- Butoxycarbonylamino -Four- Azatricyclo [6.1.0.0 ^2,6 ] Nonane
(1R, 2R, 6S) -1-tert-butoxycarbonylamino-4-p-methoxybenzyl-4-azatricyclo [6.1.0.0^2,6] 10% palladium on carbon (400 mg) was added to a solution of nonane (453 mg, 1.26 mmol) in methanol (20 ml) and pressurized (5 kg / cm²) Vigorously stirred for 30 hours under hydrogen atmosphere. The insoluble material was removed by Celite filtration, and the filtrate was concentrated to give 286 mg (1.20 mmol, 95%) of the title compound as a colorless oil.
[0125]
[Reference Example 18](1R, 5S) -2- (N- Benzyl -N- Benzyloxycarbonyl ) amino -7- Benzyloxycarbonyl -7- Azabicyclo [3.3.0] Octa -2- En
A mixture of (1R, 5S) -7-benzyloxycarbonyl-2-oxo-7-azabicyclo [3.3.0] octane (1.0 g, 3.86 mmol) and anhydrous magnesium sulfate (1.5 g) in tetrahydrofuran (15 ml) under ice cooling. Benzylamine (546 μl, 5.0 mmol) was added dropwise. After stirring for 1 hour, insoluble matters were removed by filtration, and the filtrate was concentrated. The obtained residue was dissolved in benzene (15 ml), and triethylamine (753 μl, 35.0 mmol) was added. Further, triphosgene (534 mg, 1.8 mmol) was added under ice cooling. After stirring at room temperature for 1 hour, insoluble matters were removed by Celite filtration, and the filtrate was concentrated. The obtained residue was dissolved in tetrahydrofuran (10 ml) and added dropwise to a solution of benzyloxysodium (6.0 mmol) in tetrahydrofuran (5 ml) under ice cooling. Stir at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added under ice-cooling, followed by extraction with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the obtained residue was dissolved in dichloromethane (15 ml), triethylamine (1.25 ml, 9.0 mmol) and 4-dimethylaminopyridine (50 mg) were added, and acetic anhydride (660 μl, 7.0 mmol) was added dropwise. After stirring at room temperature for 30 minutes, the reaction mixture was poured into a 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain 1.07 g (2.22 mmol, 58%) of the title compound as a colorless oil.
[0126]
[Reference Example 19](1R, 2R, 6S) -1- (N -Benzyl -N- Benzyloxycarbonyl ) amino -Four- Benzyloxycarbonyl -Four- Azatricyclo [6.1.0.0 ^2,6 ] Nonane
(1R, 5S) -2- (N-benzyl-N-benzyloxycarbonyl) amino-7-benzyloxycarbonyl-7-azabicyclo [3.3.0] oct-2-ene (1.07 g, 2.22 mmol) and diiodomethane ( To a solution of 1.57 ml, 19.5 mmol) in dichloromethane (15 ml), diethylzinc (1 mol-n-hexane solution; 10.0 ml, 10.0 mmol) was added dropwise at room temperature and stirred for 16 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium thiosulfate solution and saturated brine, and then dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 3: 1) to obtain 785 mg (1.58 mmol, 71%) of the title compound as a colorless oil.
[0127]
[Reference Example 20](1R, 2R, 6S) -1- amino -Four- Azatricyclo [6.1.0.0 ^2,6 ] Nonane
(1R, 2R, 6S) -1- (N-benzyl-N-benzyloxycarbonyl) amino-4-benzyloxycarbonyl-4-azatricyclo [6.1.0.0^2,6] 10% palladium on carbon (800 mg) was added to a methanol (30 ml) solution of nonane (785 mg, 1.58 mmol), and the mixture was vigorously stirred in a hydrogen atmosphere for 9 hours. The insoluble material was removed by Celite filtration, and the filtrate was concentrated to obtain 283 mg of the title compound as a colorless oil.
[α]_D= -21.15 (c = 0.26, methanol, T = 24.5 ℃)
[0128]
[Reference Example 21]Spyro [7'- Benzyloxycarbonyl -7'- Azabicyclo [3.3.0] Octane -1,2'-2,5- Dioxolane ]
Ethylene glycol (44.6 ml, 800 mmol) and p-toluenesulfonic acid monohydrate in a solution of 7-benzyloxycarbonyl-2-oxo-7-azabicyclo [3.3.0] octane (90.69 g, 350 mmol) in benzene (800 ml) (951 mg, 5 mmol) was added. The mixture was heated to reflux for 3 hours while removing the water formed using a Dean-Stark apparatus. The reaction solution was cooled to room temperature and then poured into a saturated aqueous sodium hydrogen carbonate solution. The organic layer was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 104.15 g (343 mmol, 98%) of a crude product of the title compound as a colorless oil.
¹H-NMR (400MHz, CDCl_Three) δ: 1.45-1.53 (1H, m), 1.75-1.83 (1H, m), 1.89-2.01 (2H, m), 2.61 (1H, dt, J = 5.5,9.0Hz), 2.74-2.84 (1H, m), 3.23-3.33 (1H, m), 3.44-3.62 (3H, m), 3.90-3.92 (4H, m), 5.11-5.14 (2H, m), 7.28-7.37 (5H, m)
[0129]
[Reference Example 22]Spyro [7'- Azabicyclo [3.3.0] Octane -1,2'-2,5- Dioxolane ]
The crude product spiro [7'-benzyloxycarbonyl-7'-azabicyclo [3.3.0] octane-1,2'-2,5-dioxolane] (104.15 g, 343 mmol) in a methanol (1000 ml) solution of 10 % Palladium on carbon (15 g) was added, and the mixture was vigorously stirred under a hydrogen atmosphere for 2 hours. The insoluble material was removed by Celite filtration, and the filtrate was concentrated to quantitatively obtain the crude product of the title compound as a colorless oil.
¹H-NMR (400MHz, CDCl_Three) δ: 1.26-1.34 (1H, m), 1.63-1.69 (1H, m), 1.73-1.80 (1H, m), 1.93 (1H, dq, J = 7.5, 12.5Hz), 2.48-2.53 (1H, m), 2.62-2.71 (2H, m), 2.76 (1H, dd, J = 8.0,12.0Hz), 2.92 (1H, dd, J = 7.0,11.0Hz), 3.00 (1H, dd, J = 4.0, 12.0Hz), 3.88-3.95 (4H, m)
[0130]
[Reference Example 23]Spyro [7'- Azabicyclo [3.3.0] Octane -1,2'-2,5- Dioxolane ] L (+)- Tartrate ( F1 )
A solution of spiro [7'-azabicyclo [3.3.0] octane-1,2'-2,5-dioxolane] (39.46g, 233mmol) in methanol (200ml) was added to L (+)-tartaric acid (34.97g, 233mmol). Was added to a methanol (550 ml) solution and heated under reflux for 2 hours, and the precipitated crystals (37.70 g) were collected by filtration. The crystals were suspended in methanol (380 ml) and heated under reflux for 2 hours, and the precipitated crystals (29.73 g) were collected by filtration. The crystals were suspended in methanol (300 ml) and heated to reflux for 6 hours, and the precipitated crystals (26.49 g) were collected by filtration.
¹H-NMR (400MHz, D₂O) δ: 1.43-1.51 (1H, m), 1.73-1.81 (1H, m), 1.89-2.05 (2H, m), 2.84-2.91 (1H, m), 2.95-3.07 (2H, m), 3.26 -3.35 (2H, m), 3.42 (1H, dd, J = 8.0,11.5Hz), 3.97 (4H, s), 4.47 (2H, s)
[0131]
[Reference Example 24]Spyro [7'-p- Anisoil -7'- Azabicyclo [3.3.0] Octane -1,2'-2,5- Dioxolane] ( F1 )
Under ice-cooling, spiro [7'-azabicyclo [3.3.0] octane-1,2'-2,5-dioxolane] L (+)-tartrate (48.7g, 153mmol) was added to 2N aqueous sodium hydroxide (300ml). ) And tetrahydrofuran (400 ml). Further, a solution of p-anisoyl chloride (34.12 g, 200 mmol) in tetrahydrofuran (100 ml) was added dropwise, followed by stirring at room temperature for 1 hour. The organic layer was separated, washed with 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain 45.23 g (149 mmol, 97%) of the title compound as a colorless oil. TLC of this grade and¹The H-NMR data was consistent with that of the results of Reference Example 11 shown above. In addition, the optical purity of this product was found to be 98.4% ee by HPLC analysis under the following conditions.
・ HPLC conditions
Column; DAICEL CHIRALCEL AD; 0.46 × 25cm
Moving bed; hexane: ethanol = 1: 2
Flow rate: 0.5ml / min
Detection: UV (254nm)
[0132]
[Reference Example 25]
Spyro [7'-p- Anisoil -7'- Azabicyclo [3.3.0] Octane -1,2'-2,5- Dioxolane ]
A solution of spiro [7'-azabicyclo [3.3.0] octane-1,2'-2,5-dioxolane] (15.5 g, 91.8 mmol) and triethylamine (20.9 ml, 150 mmol) in dichloromethane (300 ml) under ice cooling p-Anisoyl chloride (17.1 g, 100 mmol) was added. After stirring at room temperature for 30 minutes, it was poured into a 10% aqueous citric acid solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel chromatography (chloroform: methanol = 50: 1) to obtain 27.6 g (90.9 mmol, 99%) of the title compound as a colorless oil.
[0133]
[Reference Example 26](+)-7-p- Anisoil -2- Oxo -7- Azabicyclo [3.3.0] Octane ( F1 )
Spiro [7'-anisoyyl-7'-azabicyclo [3.3.0] octane-1,2'-2,5-dioxolane] (27.6g, 90.9mmol) was dissolved in 80% acetic acid (450ml) for 2.5 hours. Heated to reflux. After cooling the reaction solution to room temperature, acetic acid was distilled off. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain 24.1 g (quantitative) of the racemic title compound as a colorless oil. TLC of this grade and¹The H-NMR data was consistent with that of the result (optically active substance) of Reference Example 12 shown above. Furthermore, the optically active form of this product was separated and purified by HPLC under the following conditions. 10.1 g (42%) of the highly polar optically active substance (F1) and 9.69 g of the optically active substance of low polarity (F2) (40%) obtained.
・ HPLC conditions
Column; DAICEL CHIRALCEL AD; 2 × 25cm
Moving bed; hexane: ethanol: methanol = 1: 1: 1
Flow rate: 5ml / min
Detection: UV (254nm)
F1;
[α]_D= 77.1 (c = 0.18, methanol, T = 23.7 ℃)
F2;
[α]_D= -69.2 (c = 0.29, methanol, T = 23.7 ℃)
The optically active substances (F1 and F2) were prepared according to Reference Examples 13, 14, 15, 16, and 17 shown above, and 1-tert-butoxycarbonylamino-4-azatricyclo [6.1.0.0].^2,6] Led to nonane (F1 and F2).
[0134]
[Example 2]10-{(1R, 2R, 6S) -1- amino -Four- Azatricyclo [6.1.0.0 ^2,6 ] Nonane -Four- Il } -9- Fluoro -2,3- Dihydro -3- (S)- Methyl -7- Oxo -7H- Pyrido [1.2.3-de] [1,4] Benzoxazine -6- carboxylic acid
At room temperature, (1R, 2R, 6S) -1-tert-butoxycarbonylamino-4-azatricyclo [6.1.0.0^2,6] To a solution of nonane (F1; 286 mg, 1.20 mmol) and triethylamine (348 μl, 2.5 mmol) in dimethyl sulfoxide (3 ml), 9,10-difluoro-2,3-dihydro-3- (S) -methyl-7-oxo- 7H-pyrido [1.2.3-de] [1,4] benzoxazine-6-carboxylic acid ・ BF₂Chelate (329 mg, 1.0 mmol) was added, and the mixture was stirred at room temperature for 15 hours. After triethylamine was distilled off, water was added and the precipitated crystals were collected by filtration. 90% methanol (30 ml) and triethylamine (5 ml) were added to the obtained crystals, and the mixture was heated to reflux for 5 hours. Methanol was distilled off, 10% aqueous citric acid solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was dissolved in dichloromethane (5 ml), and trifluoroacetic acid (10 ml) was added under ice cooling. The mixture was stirred at room temperature for 1 hour and concentrated. A hydrochloric acid aqueous solution was added to the obtained residue. After washing with chloroform, the pH was adjusted to 7.8 with an aqueous sodium hydroxide solution, followed by extraction with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off. The obtained residue was recrystallized from 2-propanol to obtain 124 mg (0.31 mmol, 31%) of the title compound as yellow crystals.
¹H-NMR (400MHz, 0.1N-NaOD) δ: 0.46-0.54 (1H, m), 0.55 (1H, dd, J = 5.0,8.5Hz), 1.23 (1H, dt, J = 4.0,8.5Hz)) , 1.41 (3H, d, J = 7.0Hz), 1.71-1.83 (2H, m), 2.22-2.32 (1H, m), 2.66 (1H, q, J = 8.5Hz), 3.13-3.17 (1H, m ), 3.46 (1H, t, J = 9.0Hz), 3.70-3.81 (2H, m), 4.19-4.25 (1H, m), 4.38-4.41 (1H, m), 4.47-4.54 (1H, m), 7.43 (1H, d, J = 13.5Hz), 8.22 (1H, s)
[α]_D= -93.00 (c = 0.30, 1N aqueous sodium hydroxide solution, T = 24.0 ° C)
Melting point: 216-221 ° C (decomposition)
Elemental analysis value: C_{twenty one}H_{twenty two}FN_ThreeO_FourAs
Theoretical value: C, 63.15; H, 5.55; N, 10.52
Measurement: C, 62.90; H, 5.63; N, 10.22
[0135]
[Example 3]10-{(1R, 2R, 6S) -1- amino -Four- Azatricyclo [6.1.0.0 ^2,6 ] Nonane -Four- Il } -9- Fluoro -2,3- Dihydro -3- (S)- Methyl -7- Oxo -7H- Pyrido [1.2.3-de] [1,4] Benzoxazine -6- carboxylic acid
At room temperature, (1R, 2R, 6S) -1-amino-4-azatricyclo [6.1.0.0^2,6] Nonane (73.6 mg, 0.533 mmol) and triethylamine (74.3 μl, 0.533 mmol) in dimethyl sulfoxide (3 ml) were added to 9,10-difluoro-2,3-dihydro-3- (S) -methyl-7-oxo- 7H-pyrido [1.2.3-de] [1,4] benzoxazine-6-carboxylic acid ・ BF₂Chelate (74 mg, 0.225 mmol) was added and stirred at room temperature for 5 hours. After distilling off the solvent, 90% ethanol (40 ml) and triethylamine (1 ml) were added to the residue, and the mixture was heated to reflux for 3 hours. After distilling off ethanol, an aqueous hydrochloric acid solution was added to the obtained residue. The mixture was washed with chloroform, adjusted to pH 7.4 with an aqueous sodium hydroxide solution, and extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off. The obtained residue was recrystallized from ethanol to obtain 69 mg (0.173 mmol, 77%) of the title compound as yellow crystals. This grade¹H-NMR and specific rotation data were consistent with the data of Example 1 shown above.
Elemental analysis value: C_{twenty one}H_{twenty two}FN_ThreeO_FourAs
Theoretical value: C, 63.15; H, 5.55; N, 10.52
Measurements: C, 62.98; H, 5.77; N, 10.43
[0136]
[Example 4]10- {1- amino -Four- Azatricyclo [6.1.0.0 ^2,6 ] Nonane -Four- Il } -9- Fluoro -2,3- Dihydro -3- (S)- Methyl -7- Oxo -7H- Pyrido [1.2.3-de] [1,4] Benzoxazine -6- carboxylic acid (F2)
At room temperature, (1S, 2S, 6R) -1-tert-butoxycarbonylamino-4-azatricyclo [6.1.0.0^2,6] Nonane (F2; 395 mg, 1.66 mmol) and triethylamine (557 μl, 4.0 mmol) in dimethyl sulfoxide (3 ml) in 9,10-difluoro-2,3-dihydro-3- (S) -methyl-7-oxo- 7H-pyrido [1.2.3-de] [1,4] benzoxazine-6-carboxylic acid ・ BF₂Chelate (526 mg, 1.6 mmol) was added and stirred at room temperature for 15 hours. After triethylamine was distilled off, water was added and the precipitated crystals were collected by filtration. 90% methanol (30 ml) and triethylamine (5 ml) were added to the obtained crystals, and the mixture was heated to reflux for 5 hours. Methanol was distilled off, 10% aqueous citric acid solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was dissolved in dichloromethane (5 ml), and trifluoroacetic acid (10 ml) was added under ice cooling. The mixture was stirred at room temperature for 1 hour and concentrated. A hydrochloric acid aqueous solution was added to the obtained residue. After washing with chloroform, the pH was adjusted to 7.8 with an aqueous sodium hydroxide solution, followed by extraction with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off. The obtained residue was recrystallized from 2-propanol to obtain 180 mg (0.45 mmol, 28%) of the title compound as yellow crystals.
¹H-NMR (400MHz, 0.1N-NaOD) δ: 0.46-0.54 (1H, m), 0.55 (1H, dd, J = 5.0,8.5Hz), 1.23 (1H, dt, J = 4.0,8.5Hz)) , 1.39 (3H, d, J = 7.0Hz), 1.71-1.83 (2H, m), 2.22-2.32 (1H, m), 2.66 (1H, q, J = 8.5Hz), 3.13-3.17 (1H, m ), 3.46 (1H, t, J = 9.0Hz), 3.70-3.81 (2H, m), 4.19-4.25 (1H, m), 4.38-4.41 (1H, m), 4.47-4.54 (1H, m), 7.41 (1H, d, J = 14.0Hz), 8.20 (1H, s)
[α]_D= -6.41 (c = 0.39, 1N sodium hydroxide aqueous solution, T = 24.2 ℃)
Melting point: 176-180 ° C (decomposition)
Elemental analysis value: C_{twenty one}H_{twenty two}FN_ThreeO_Four
Theoretical value: C, 63.15; H, 5.55; N, 10.52
Measurements: C, 63.01; H, 5.65; N, 10.29
[0137]
[Example 5]7- {1- amino -Four- Azatricyclo [6.1.0.0 ^2,6 ] Nonane -Four- Il } -6- Fluoro -1- [2- (S)- Fluoro -1- (R)- Cyclopropyl ] -1,4- Dihydro -8- Methoxy -Four- Oxoquinoline -3- carboxylic acid (F1)
At room temperature, 1-tert-butoxycarbonylamino-4-azatricyclo [6.1.0.0^2,6] Nonane (F1; 300 mg, 1.26 mmol) and triethylamine (697 μl, 5.0 mmol) in dimethyl sulfoxide (3 ml) were added to 6,7-difluoro-1- [2- (S) -fluoro-1- (R) -cyclo Propyl] -1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid / BF₂Chelate (433 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 15 hours. After triethylamine was distilled off, water was added and the precipitated crystals were collected by filtration. 90% methanol (30 ml) and triethylamine (5 ml) were added to the obtained crystals, and the mixture was heated to reflux for 5 hours. Methanol was distilled off, 10% aqueous citric acid solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off. The obtained residue was dissolved in dichloromethane (5 ml), and trifluoroacetic acid (10 ml) was added under ice cooling. The mixture was stirred at room temperature for 1 hour and concentrated. A hydrochloric acid aqueous solution was added to the obtained residue. After washing with chloroform, the pH was adjusted to 7.8 with an aqueous sodium hydroxide solution, followed by extraction with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off. The obtained residue was recrystallized from 2-propanol to obtain 180 mg (0.41 mmol, 34%) of the title compound as yellow crystals.
¹H-NMR (400 MHz, 0.1 N-NaOD) δ: 0.56-0.60 (2H, m), 1.25-1.35 (3H, m), 1.41-1.52 (1H, m), 1.72 (1H, ddd, J = 4.0, 9.0,13.0Hz), 1.81 (1H, dd, J = 8.5,12.5Hz), 2.26-2.34 (1H, m), 2.70 (1H, q, J = 8.0Hz), 3.23 (1H, d, J = 10.5 Hz), 3.45 (1H, t, J = 9.5Hz), 3.53 (3H, s), 3.79-3.84 (2H, m), 3.95 (1H, dt, J = 5.5, 9.0Hz), 4.96 (1H, ddd , J = 5.5, 8.5, 63.5Hz), 7.59 (1H, d, J = 14.5Hz), 8.32 (1H, d, J = 3.5Hz)
[α]_D= -69.39 (c = 0.49, sodium hydroxide aqueous solution, T = 24.4 ℃)
Melting point: 146-159 ° C (decomposition)
Elemental analysis value: C_{twenty two}H_{twenty three}F₂N_ThreeO_Four・ 0.5H₂0
Theoretical value: C, 59.99; H, 5.49; N, 9.54
Measurements: C, 59.79; H, 5.27; N, 9.49
[0138]
[Example 6]Five- amino -7- {1- amino -Four- Azatricyclo [6.1.0.0 ^2,6 ] Nonane -Four- Il } -6- Fluoro -1- [2- (S)- Fluoro -1- (R)- Cyclopropyl ] -1,4- Dihydro -8- Methyl -Four- Oxoquinoline -3- carboxylic acid( F1 )
At room temperature, 1-tert-butoxycarbonylamino-4-azatricyclo [6.1.0.0^2,6] Nonane (F1; 498 mg, 2.09 mmol) and triethylamine (5 ml) were added to dimethyl sulfoxide (10 ml), followed by 5-amino-6,7-difluoro-1- [2- (S) -fluoro-1- ( R) -Cyclopropyl] -1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (625 mg, 2.0 mmol) was added, and the mixture was stirred at an external temperature of 120 ° C. for 15 hours. Triethylamine and dimethyl sulfoxide were distilled off, 10% aqueous citric acid solution was added, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off. Concentrated hydrochloric acid was added to the obtained residue, washed with chloroform, adjusted to pH 7.8 with an aqueous sodium hydroxide solution, and extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off. The obtained residue was recrystallized from 2-propanol to obtain 74 mg (0.17 mmol, 9%) of the title compound as yellow crystals.
¹H-NMR (400MHz, 0.1N-NaOD) δ: 0.47 (1H, d, J = 4.5Hz), 0.56 (1H, dd, J = 4.5,8.0Hz), 0.92-1.03 (1H, m), 1.24- 1.26 (1H, m), 1.36-1.46 (1H, m), 1.62-1.1.67 (1H, m), 1.74 (1H, dd, J = 8.0,12.0Hz), 2.17-2.26 (1H, m), 2.61 (1H, q, J = 7.5Hz), 2.87 (1H, d, J = 9.5Hz), 3.11 (1H, t, J = 9.0Hz), 3.69-4.03 (3H, m), 4.60-4.99 (1H , m), 8.20 (1H, d, J = 3.5Hz)
Elemental analysis value: C_{twenty two}H_{twenty four}F₂N_FourO_Three
Theoretical value: C, 61.39; H, 5.62; N, 13.02
Measurements: C, 61.59; H, 5.64; N, 12.77
[0139]
[Reference Example 27](1R, 5S) -2- (N- Benzyl -N- Benzyloxycarbonyl ) amino -7-p- Anisoil -7- Azabicyclo [3.3.0] Octa -2- En; separate synthesis method of the method shown in Reference Example 13
A mixture of (1R, 5S) -7-p-anisoyl-2-oxo-7-azabicyclo [3.3.0] octane (20.72 g, 79.9 mmol) and anhydrous magnesium sulfate (20 g) in tetrahydrofuran (200 ml) under ice-cooling. A solution of benzylamine (10.9 ml, 100 mmol) in tetrahydrofuran (50 ml) was added dropwise. After stirring for 1 hour, insoluble matters were removed by filtration, and the filtrate was concentrated. The obtained residue was dissolved in dichloromethane (100 ml), and N, N-dimethylaniline (15.2 ml, 120 mmol) was added. Further, benzyl chloroformate (17.13 ml, 120 mmol) was added dropwise under ice cooling. After stirring at room temperature for 2 hours, the reaction mixture was added to 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain 31.64 g (65.5 mmol, 82%) of the title compound as a colorless oil.
[0140]
[Reference Example 28](1R, 2R, 6S) -1-tert- Butoxycarbonylamino -4-p- Methoxybenzyl -Four- Azatricyclo [6.1.0.0 ^2,6 ] Nonane: another synthetic method of the method shown in Reference Example 16
Under ice cooling, (1R, 2R, 6S) -1-tert-butoxycarbonylamino-4-p-anisoyl-4-azatricyclo [6.1.0.0^2,6] To a solution of nonane (13.40 g, 35.98 mmol) in tetrahydrofuran (200 ml) was added lithium aluminum hydride (1.37 g, 36 mmol). Stir at room temperature for 1 hour. Under ice-cooling, water (1.37 ml), 15% aqueous sodium hydroxide solution (1.37 ml) and water (4.11 ml) were successively added dropwise. After stirring at room temperature for 18 hours, insoluble matters were removed by Celite filtration. After the filtrate was concentrated, the residue was purified by silica gel chromatography (chloroform: methanol = 20: 1) to obtain 8.24 g (23.00 mmol, 64%) of the title compound as a colorless oil.
[Reference Example 29](1R, 5S) -2- (N- Benzyl -N- Benzyloxycarbonyl ) amino -7- Benzyloxycarbonyl-7-azabicyclo [3.3.0] Octa -2- En
Under ice cooling, (1R, 5S) -1-tert-butoxycarbonylamino-4-p-anisoyl-4-azatricyclo [6.1.0.0^2,6] To a solution of nonane (13.40 g, 35.98 mmol) in tetrahydrofuran (200 ml) was added lithium aluminum hydride (1.37 g, 36 mmol), and the mixture was stirred at room temperature for 1 hour. Under ice-cooling, water (1.37 ml), 15% aqueous sodium hydroxide solution (1.37 ml) and water (4.11 ml) were successively added dropwise. After stirring at room temperature for 18 hours, insoluble matters were removed by Celite filtration. After the filtrate was concentrated, the residue was purified by silica gel chromatography (chloroform: methanol = 20: 1) to obtain 8.24 g (23.00 mmol, 64%) of the title compound as a colorless oil.
[0141]
[Reference Example 30]11- Aza -11- Benzyl-tetracyclo [7.3.1 ^4,7 0 ^3,8 0] Torideka -Five- En -2- on
Tricyclo [5.2.1.0^2,6] A solution of deca-4,8-dien-3-one (Synthesis, 1994, 687) (2.00 g, 13.7 mmol) in dichloroethane (15 ml) was added with benzylbutoxymethyltrimethylsilylamine (4.59 g, 16.4 mmol) at room temperature. Trifluoroacetic acid (15 μl) was added, and the mixture was stirred at the same temperature for 2 hours and at 50 ° C. for 16 hours. A 10% aqueous citric acid solution was added, the organic layer was separated, and a saturated aqueous sodium hydrogen carbonate solution was added to the aqueous layer. After extraction with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, and after evaporation of the solvent, 3.40 g (89%) of the crude title compound was obtained. The product was used in the next reaction without further purification.
¹H-NMR (CDCl_Three) δ: 1.38 (1H, d, J = 8.3Hz), 2.18-2.22 (1H, m), 2.32-2.37 (3H, m), 2.44-2.48 (1H, m), 2.63-2.68 (2H, m) , 2.88 (1H, d, J = 7.8Hz), 3.00-3.06 (2H, m), 3.20-3.22 (1H, m), 3.47 (2H, AB-q, J = 13.2Hz), 6.06-6.08 (1H , m), 6.15-6.17 (1H, m), 7.22-7.31 (5H, m).
[0142]
[Reference Example 31]7- Benzyl -2- Oxo -7- Azabicyclo [3.3.0]- Octa -3- En
11-aza-11-benzyl-tetracyclo [7.3.1^4,70^3,8[0] A solution of tridec-5-en-2-one (3.40 g, 12.17 mmol) in diphenyl ether (70 ml) was stirred at 220 ° C. for 20 minutes. Diphenyl ether (130 ml) was then added, and the mixture was further stirred at 220 ° C. for 20 minutes. After cooling to room temperature, ether was added and extracted with a 10% aqueous citric acid solution. The aqueous layers were combined, washed with dichloromethane, sodium hydrogen carbonate was added, and a saturated aqueous sodium hydrogen carbonate solution was further added to make it alkaline, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to give 1.45 g (56%) of the title compound. Obtained.
¹H-NMR (CDCl_Three) δ: 2.31 (1H, t, J = 8.8Hz), 2.36 (1H, t, J = 8.8Hz), 2.71-2.75 (1H, m), 2.79 (1H, d, J = 9.3Hz), 3.10 ( 1H, d, J = 9.3Hz), 3.36-3.41 (1H, m), 3.55 (2H, AB-q, J = 13.2Hz), 6.24 (1H, d, J = 5.4Hz), 7.20-7.35 (5H , m), 7.55 (1H, dd, J = 3.0,5.8Hz)
[Reference Example 32]7- Benzyl -2- Oxo -7- Azabicyclo [3.3.0] Octane
To a solution of 7-benzyl-2-oxo-7-azabicyclo [3.3.0] octane-3-ene (1.45 g, 6.78 mmol) in ethyl acetate (50 ml) was added 5% rhodium alumina (700 mg). Stir vigorously for hours. The insoluble material was removed by Celite filtration, and the filtrate was concentrated. The residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1) to obtain 1.22 g (5.70 mmol, 84%) of the title compound as a colorless oil. TLC of this grade and¹The H-NMR data was consistent with that of the results of Reference Example 1 shown above.
[0143]
[Example 7]7- (1- amino -Four- Azabicyclo [6.1.0.0 ^2,6 ] Nonane -Four- Il ) -6- Fluoro -1- [2- (S)- Fluoro -1- (R)- Cyclopropyl ] -8- Methyl -1,4- Dihydro -Four- Oxoquinoline -3- carboxylic acid
(1R, 2R, 6S) -1-Tertiary butoxycarbonylamino-4-azatricyclo [6.1.0.0^2,6] Nonane (1.20 mmol) was dissolved in dimethyl sulfoxide (1.2 ml) and 6,7-difluoro-1- [2- (S) -fluoro-1- (R) -cyclopropyl] -1,4-dihydro- 8-Methyl-4-oxoquinoline-3-carboxylic acid, BF₂Chelate (345 mg; 1.00 mmol) and triethylamine (0.167 ml) were added, and the mixture was stirred for 132 hours under a nitrogen atmosphere. After the solvent was distilled off, water was added to the residue, and the precipitated yellow crystals were collected by filtration and washed with water. 90% methanol (50 ml) and triethylamine (2 ml) were added to the residue, and the mixture was heated to reflux for 3 hours. After methanol was distilled off, concentrated hydrochloric acid (10 ml) was added dropwise to the resulting residue under ice cooling, followed by stirring at room temperature for 1 hour. Water (20 ml) was added to the reaction mixture, washed with chloroform (30 ml × 3), adjusted to pH 12.0 with aqueous sodium hydroxide solution, then adjusted to pH 7.4 with 1N hydrochloric acid, and extracted with chloroform (150 ml × 3). . The combined organic layers were dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative TLC, and the crude product was recrystallized from ethanol and purified, and then dried under reduced pressure to obtain 51 mg (12%) of the title compound as a yellow powder.
¹H-NMR (400MHz, 0.1NNaOD) δ: 0.59-0.67 (2H, m), 1.37-1.40 (1H, m), 1.57-1.65 (1H, m), 1.80-1.89 (2H, m), 2.37-2.41 (1H, m), 2.53 (3H, s), 2.77-2.85 (1H, m), 3.04-3.09 (1H, m), 3.27-3.36 (1H, m), 3.83-3.93 (1H, m), 4.05 -4.11 (1H, m), 5.04 (1H, brd, J = 58.19Hz), 7.71 (1H, d, J = 14.16Hz), 8.44 (1H, d, J = 3.41Hz).
Elemental analysis value; C_{twenty two}H_{twenty three}F₂N_ThreeO_Three・ 0.5H₂As O:
Theoretical value; C, 62.25; H, 5.70; N, 9.90
Found: C, 62.05; H, 5.54; N, 9.61
[0144]
[Table 2]
[0145]
【The invention's effect】
The compound of the present invention has a wide range of excellent antibacterial activity against both gram-negative and gram-positive bacteria, particularly exhibits strong antibacterial activity against quinolone-resistant bacteria, as well as good pharmacokinetics and safety It is also useful as an antibacterial compound.

Claims (15)

A compound represented by the following formula (I), a salt thereof, or a hydrate thereof.
{Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ represent a hydrogen atom,
X ¹ is a partial structure:
(Wherein, R ^8, R ⁹ represents a hydrogen atom, m represents an integer 1.)
Represents
n represents an integer 1 or 2
Q is the formula
Or an expression
[Wherein, R ¹¹ represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, or an optionally substituted group having 3 to 6 carbon atoms. A cyclic alkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an alkoxyl group having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms Represent,
R ¹² represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms,
This R ¹² and R ¹¹ described above may be integrated so as to include a part of the mother nucleus so as to form a cyclic structure, but the ring thus formed has a sulfur atom as a constituent atom of the ring. Further, this ring may have an alkyl group having 1 to 6 carbon atoms as a substituent.
R ¹³ is a hydrogen atom, amino group, hydroxyl group, thiol group, halogenomethyl group, alkyl group having 1 to 6 carbon atoms, alkenyl group having 2 to 6 carbon atoms, alkynyl group having 2 to 6 carbon atoms, or 1 carbon atom. To 6 alkoxyl groups,
Of these, the amino group has 1 or 2 groups selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms, and an acyl group having 2 to 5 carbon atoms as a substituent. Also good.
X ² represents a halogen atom or a hydrogen atom,
A ¹ is a nitrogen atom or formula (II)
(In the formula, X ³ represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or 2 carbon atoms. Represents an alkynyl group of 6 or an alkoxyl group having 1 to 6 carbon atoms,
Of these, the amino group has 1 or 2 groups selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms, and an acyl group having 2 to 5 carbon atoms as a substituent. Well,
Further, X ³ and R ¹¹ may be integrated so as to include a part of the mother nucleus so as to form a cyclic structure, but the ring formed in this way includes an oxygen atom, a nitrogen atom, Alternatively, a sulfur atom may be included as a constituent atom of the ring, and this ring may have an alkyl group having 1 to 6 carbon atoms as a substituent. )
Y represents a hydrogen atom, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyl group, choline group, dimethylaminoethyl group, 5-indanyl group, phthalidinyl group, 5-alkyl-2-oxo-1, A 3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, or an alkylene group having 1 to 6 carbon atoms and a phenyl group; Represents a phenylalkyl group composed of ]
Represents a partial structure represented by } In formula (I), Q is the formula
The compound of Claim 1 which is a structure represented by these, its salt, or those hydrates. In formula (I), Q is 9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1.2.3-de] [1.4] benzoxazine-6-carvone The compound according to claim 1, which is an acid-10-yl group, a salt thereof, or a hydrate thereof. In the formula (I), Q is 6-fluoro-1- [2- (S) -fluoro-1- (R) -cyclopropyl] -8-methoxy-1,4-dihydro-4-oxoquinoline-3 The compound according to claim 1 or 2, or a salt or hydrate thereof, which is a -carboxylic acid-7-yl group. In the formula (I), Q is 6-fluoro-1- [2- (S) -fluoro-1- (R) -cyclopropyl] -8-methyl-1,4-dihydro-4-oxoquinoline-3 The compound according to claim 1 or 2, or a salt or hydrate thereof, which is a -carboxylic acid-7-yl group. In the formula (I), Q is 5-amino-6-fluoro-1- [2- (S) -fluoro-1- (R) -cyclopropyl] -8-methyl-1,4-dihydro-4- The compound according to claim 1, a salt thereof, or a hydrate thereof, which is an oxoquinoline-3-carboxylic acid-7-yl group. 7. The compound according to claim 1, a salt thereof, or a hydrate thereof, wherein the compound of formula (I) is a stereochemically single compound. The compound according to claim 1, a salt thereof, or a hydrate thereof, wherein R ¹¹ is a cyclopropyl group having a halogen atom as a substituent. Cyclopropyl group having a halogen atom as a substituent, 1,2-cis - halogenoalkyl compound of claim 8 wherein cyclopropyl group, a salt or hydrate thereof. The compound according to claim 9, a salt thereof, or a hydrate thereof, wherein the cyclopropyl group having a halogen atom as a substituent is a stereochemically single substituent. The compound according to claim 10, a salt thereof, or a hydrate thereof, wherein the cyclopropyl group having a halogen atom as a substituent is a (1R, 2S) -2-halogenocyclopropyl group. Halogen atom cyclopropyl group having a halogen atom as a substituent A compound according to claim 11 which is a fluorine atom, a salt or hydrate thereof.   A pharmaceutical comprising the compound according to any one of claims 1 to 12, a salt thereof, or a hydrate thereof as an active ingredient.   An antibacterial agent comprising the compound according to any one of claims 1 to 12, a salt thereof, or a hydrate thereof as an active ingredient.   A therapeutic agent for an infectious disease comprising the compound according to any one of claims 1 to 12, a salt thereof, or a hydrate thereof as an active ingredient.