JPH09221424A - Antitumor agent - Google Patents

Abstract

(57) Abstract: An antitumor agent useful as a medicine is provided. SOLUTION: The following general formula: (In the formula, ----- means the presence or absence of a single bond,
X represents N or C—Rx, wherein Rx represents a hydrogen atom or a halogen atom, R ₁ and R ₂ are the same or different and represent a hydrogen atom or a halogen atom, and R
₃ means a hydrogen atom or a carboxyl group, R ₄ means an oxo group or a hydroxyl group, R ₅ means a hydrogen atom or an amino group, and R ₆ means a substituent such as cyclic amino. ) An antitumor agent comprising a compound represented by the formula (1) as an active ingredient.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an antitumor agent useful as a medicine.

[0002]

It is known that a pyridonecarboxylic acid derivative having a 2-thiazolyl group has antibacterial activity.
For example, the following compound is described in Example 24 of JP-A No. 61-152682 (hereinafter referred to as Ref. 1).

[0003]

Embedded image

The following compounds are described in Example 5 of Ref.

[0005]

Embedded image

Further, in Example 12 of Ref. 1, the following compounds are described.

Embedded image

The compounds represented by [Chemical Formula 13] and [Chemical Formula 14] are also described in Table 1 of JP-A-62-33176 (hereinafter referred to as Ref. 2). JP-A-60-56959 (hereinafter
The following compounds are described in Example 24-4 of Ref. 3) and Example 15 of JP-A-61-251667 (hereinafter referred to as Rf. 4).

[0008]

Embedded image

The following compounds are described in Example 28-16 of JP-A-60-163866 (hereinafter referred to as Ref.5).

[0010]

Embedded image

Further, JP-A-2-85255 (hereinafter referred to as Ref.
6) describes the following compound.

[0012]

Embedded image

However, the above Refs. 1 to 6 only mention that these compounds have an antibacterial action, and do not teach antitumor activity or anticancer activity at all. Note that these compounds have in common that a fluorine atom is substituted at the 6-position.

It is also known that certain pyridonecarboxylic acid derivatives have antitumor activity and anticancer activity.
For example, Cancer Research 52 , 2818 (1992) examined the antitumor activity of 90 kinds of pyridonecarboxylic acid derivatives, and found that most of the pyridonecarboxylic acid derivatives had no antitumor activity. It was just that. In this paper, the cyclopropyl group substituted at the 1-position and the two halogen atoms substituted at the 6-position and the 8-position play an important role in the expression of antitumor action. It is taught that pyridonecarboxylic acid derivatives without substituents do not show antitumor activity.

[0015]

DISCLOSURE OF THE INVENTION The present inventors have intensively searched for a compound having an antitumor effect, and as a result, a pyridonecarboxylic acid having no cyclopropyl group at the 1-position and a related compound have a remarkable antitumor effect. The present invention has been completed by finding that it has an action.

[0016]

According to the present invention, a compound having the following general formula (I) containing a 2-thiazolyl group, its stereoisomer or optical isomer, or a physiologically acceptable salt thereof, or There is provided an antitumor agent comprising any of the above hydrates or solvates as an active ingredient.

[0017]

Embedded image

The numbers representing the respective positions of the basic skeleton in the general formula (I) are, as a general rule, sequentially given in the counterclockwise direction from the position where the 2-thiazolyl group is bonded. Therefore, the position where the 2-thiazolyl group is bonded is 1
And the position to which R ₆ binds is position 7 (this numbering may be different from the usual case, but in this specification, it may be treated as such for convenience of description). .

Each symbol (substituent) in the above general formula (I) will be defined and explained below.

--------- in the general formula (I) means the presence or absence of a single bond. That is, the bond between the 2-position carbon atom and the 3-position carbon atom and the bond between the 4-position carbon atom and the substituent R ₄ may be a single bond or a double bond.

X means N or C-Rx, where Rx means a hydrogen atom or a halogen atom. In the present specification, “halogen” or “halogen atom”
The term means fluorine, chlorine, bromine or iodine, with fluorine or chlorine being preferred.

R ₁ and R ₂ are the same or different and each represents a hydrogen atom, a halogen atom, a nitro group, a lower alkoxy group, a lower alkyl group (the lower alkyl group may be substituted with lower alkoxycarbonyl or carboxyl),
Phenyl group or thienyl group which may be substituted with halogen, or phenylsulfonyl group (wherein the phenyl moiety may be substituted with halogen or nitro)
Or R ₁ and R ₂ together form a benzene ring or naphthalene ring, which benzene ring or naphthalene ring may be substituted with halogen, nitro or lower alkyl.

As used herein, the term "lower" refers to
Unless otherwise stated, groups designated by this term are meant to contain 1 to 5 carbon atoms. Thus, for example, R ₁
The lower alkyl group included in the definition of is a straight chain or branched group, for example, a methyl group, an ethyl group,
n-propyl group, isopropyl group, n-butyl group, te
Examples thereof include rt-butyl group and pentyl group, with methyl group and ethyl group being preferred. Further, the "lower alkoxy group" is a combination of the lower alkyl group and an oxygen atom,
Examples thereof include a methoxy group and an ethoxy group.

R ₃ represents a hydrogen atom, a benzyl group, a hydroxyl group, a carboxyl group or a group capable of being converted into a carboxyl group.

The “group capable of being converted into a carboxyl group” included in the definition of the substituent R ₃ may be any group as long as it can be removed by a chemical means or an enzymatic means to be converted into a carboxyl group. It does not necessarily have to be converted to a carboxyl group in vivo.

As the group capable of being converted into such a carboxyl group, a hydroxymethyl group, a formyl group, an ester form, a carbamoyl group or an amide form is preferable.

Examples of the ester form include lower alkyl esters such as methyl ester and ethyl ester, acetoxymethyl ester and 1-acetoxyethyl ester,
Lower alkanoyloxy lower alkyl ester such as pivaloyloxymethyl ester, lower alkoxycarbonyloxy lower alkyl ester such as 1-ethoxycarbonyloxyethyl ester, dilower alkylamino lower alkyl ester such as 2-dimethylaminoethyl ester, 2 -(1-piperidinyl) ethyl ester, 3-butyrolactonyl ester, choline ester,
Phthalidyl ester, (5-methyl-2-oxo-1,
3-dioxol-4-yl) methyl ester and the like can be mentioned.

R ₄ represents an oxo group or a hydroxyl group.
When R ₄ is an oxo group and R ₃ is a carboxyl group, the compound represented by the general formula (I) is a pyridonecarboxylic acid derivative.

The substituent R _{5 at the} 5-position means a hydrogen atom, an amino group, a halogen atom or a lower alkyl group, and the lower alkyl group may be substituted with halogen. Examples of the lower alkyl group substituted with halogen here include a trifluoromethyl group.

R ₆ represents a substituent bonded to the mother nucleus by an N—C bond, a C—C bond, an S—C bond or an O—C bond, and more specifically, the following (a) Examples thereof include any group selected from to (e).

(A): R ₆ is represented by the following formula (a) 4
Is a 7-membered monocyclic amino group.

[0032]

Embedded image

(In the formula, --------- means the presence or absence of a single bond, R6a1, Ra2, R6a3 and R6a4 are the same or different, and are C, CH, CH ₂ , CH ₂ CH. ₂ ,
CH = CH, S (O) _0-2 , O, N or N-R6a, wherein R6a means a hydrogen atom, a lower alkyl group or a phenyl group, and the phenyl group is a lower alkoxy, a lower alkyl, It may be substituted with halogen or nitro. k and m are the same or different and mean an integer of 0 or 1. R6a5, R6a6 and R6a7 will be described later. )

The formula (a) includes, for example, the groups represented by the following [Chemical Formula 20], and these groups have an NC bond (m
Is 0) or a C—C bond (m is 1) to the 7-position of the nucleus.

[0035]

Embedded image

(In the formula, R6a, R6a5, R6a6, R6a7
And m have the same meanings as above. )

The substituent R6a5 in the formula (a) means a hydrogen atom, a methylene group or a group represented by the following formula (R6a-5):

[0038]

[Chemical 21]

[In the formula, R6a51 represents a hydrogen atom or a phenyl group (the phenyl group may be substituted with halogen), or a lower alkyl group which may be substituted with phenyl or halogenophenyl. R6a52 is a hydrogen atom, a lower alkyl group or a group convertible to a hydrogen atom, and n is an integer of 0-4. ]

The “group capable of being converted into a hydrogen atom” included in the definition of the substituent R6a52 may be any group capable of being converted into a hydrogen atom by a chemical means such as hydrolysis or an enzymatic means, and is not necessarily a radical. It need not be converted to hydrogen atoms in the body.

Examples of the "group capable of being converted into a hydrogen atom" include a group having an acyl group such as formyl or acetyl, an oxycarbonyl group such as ethoxycarbonyl, an amino acid residue or a peptide residue, and o- Examples thereof include nitrophenylsulfenyl, trimethylsilyl, tetrahydropyranyl, diphenylphosphinyl and the like, with amino acid residues and peptide residues being particularly preferred.

Amino acids are generally represented by the three-letter English letters, which will be used in the present specification. Also, L-
Body, D-body or mixtures of these may begin with the letter "L".
A distinction will be made by adding a symbol "-", "D-" or "DL-". When referring to these isomers without distinction, these symbols will not be attached.

Examples of amino acid residues include Gly (glycine), Ala (alanine), Arg (arginine), Asn (asparagine), Asp (aspartic acid), Cys (cysteine), Glu (glutamic acid), His (histidine). ), Ile (isoleucine), Leu (leucine), Lys (lysine), Met (methionine), Phe (phenylalanine), Pro (proline)
, Ser (serine), Thr (threonine), Trp (tryptophan), Tyr (tyrosine), Val (valine), Nva (norvaline), Hse (homoserine), 4-Hyp (4-hydroxyproline), 5-Hyl ( Examples thereof include amino acid residues such as 5-hydroxylysine) and Orn (ornithine).

The peptide residue is a peptide residue in which 2 to 5, preferably 2 to 3 of the above-mentioned amino acids are linked, and examples thereof include Ala-Ala, Gly-Phe, Nva-Nva and Ala-.
Phe, Gly-Gly, Gly-Gly-Gly, Ala-Met, Met-Met, L
Examples include residues of peptides such as eu-Met and Ala-Leu.

The stereochemical configuration of these amino acid or peptide residues may be D-form, L-form or a mixture thereof, but the L-form is preferred. Furthermore, when the “group capable of being converted into a hydrogen atom” is a residue of an amino acid or a peptide, the residue may have an asymmetric carbon atom. Examples of amino acid residues having an asymmetric carbon atom include Ala, Leu, Phe, Trp, Nva, Val, Met, Ser and Ly.
Examples include amino acid residues such as s, Thr and Tyr, and examples of peptide residues having an asymmetric carbon atom include those having these amino acid residues having an asymmetric carbon atom as a constituent component.

The substituent R6a6 contained in the formula (a) is a hydrogen atom, a halogen atom, a hydroxyl group, an azido group, a formyl group,
It means an oxo group, a lower alkoxy group, a lower alkylthio group or a lower alkyl group (the lower alkyl group may be substituted with halogen or hydroxy).

The substituent R6a7 included in the formula (a) is also included.
Means the same as R6a6 or a spiro cyclic amino group represented by the following formula (R6a-7):

[0048]

Embedded image

[In the formula, p means an integer of 3 or 4] The same or different R6a6 and R6a7 may be selected.

(B): Substituent R _{6 at the} 7-position is a bicyclic amino group represented by the following formula (b).

[0051]

Embedded image

(Wherein --------- means the presence or absence of a single bond, q, s and t are the same or different,
It is an integer of 0 to 2, and the sum of q and t is 2 or 3.
R6b1 means C, CH, a CH ₂ or N-R6b,
R6b wherein is a hydrogen atom or a lower alkyl group, R6b2 means C, CH, and CH _2, CH ₂ CH ₂ or CH = CH, R6b3 means C, CH, and CH ₂ or O, u , V and w are the same or different and are 0
Or an integer of 1, meaning that the sum of these is 1 to 3, R6b4 and R6b5 are the same or different,
It means a hydrogen atom, a hydroxyl group, a lower alkyl group, an amino group, a mono- or di-lower alkylamino group or a mono- or di-lower alkylamino lower alkyl group. )

The formula (b) includes, for example, groups represented by the following [Chemical formula 24], and these groups are bonded to the 7-position of the mother nucleus by an N—C bond.

[0054]

Embedded image

(Wherein ---, R6b, R6b4 and R6
6b5 means the same as above. )

(C): R ₆ is a 3- to 7-membered cyclic group represented by the following formula (c).

[0057]

Embedded image

(Wherein --------- means the presence or absence of a single bond, and R6c1, R6c2, R6c3 and R6c4
Are the same or different and are C, CH, CH ₂ , CH ₂ CH
₂ , CH = CH, S (O) _0-2 , O, N or NR
6c, where R6c represents a hydrogen atom or a lower alkyl group. R6c5 is O, refers to S or CH _2, it is R6c6 and R6c7 same or different, represents a hydrogen atom, an amino group or a lower alkyl group. f, g
And h are the same or different and mean an integer of 0 or 1. )

The formula (c) includes, for example, groups represented by the following [Chemical Formula 26], and these groups have a C—C bond (R6).
When c5 is CH ₂ or h is 0), an O—C bond (R
6c5 is O and h is 1) or S—C bond (R6
When c5 is S and h is 1), it is bonded to the 7-position of the nucleus.

[0060]

Embedded image

(In the formula, R6c, R6c5, R6c6, R6c7 and h have the same meanings as described above.)

(D): R ₆ is an amino group represented by the following formula (d).

[0063]

Embedded image

(In the formulae, R6d1 means S or NH,
R6d2 and Rd3 are the same or different and each represents a hydrogen atom or a lower alkyl group, i represents an integer of 0 or 1, and j represents an integer of 1 to 5. )

In formula (d), an amino group optionally substituted by lower alkyl (when i is 0), an aminoalkylamino optionally substituted by lower alkyl (wherein i is 1 and R 6d 1 is NH Case) and aminoalkylthio optionally substituted with lower alkyl (when i is 1 and R6d1 is S).

(E): R ₆ is a hydroxyl group, a lower alkyl group, a lower alkenyl group or a lower alkynyl group. Examples of the lower alkenyl group include a vinyl group, and examples of the lower alkynyl group include an ethynyl group.

In the compound represented by the general formula (I) according to the present invention, its stereoisomer or its optical isomer, or a physiologically acceptable salt thereof or a water thereof which may be present depending on the case. A solvate and a solvate are included.

Examples of the salt include a salt of a carboxyl group portion which may be present in the structure and an acid addition salt of a basic substituent portion such as an amino group or a cyclic amino group.

Examples of the salt at the carboxyl group include sodium, potassium, magnesium, zinc, silver,
Examples thereof include salts with metals such as aluminum and platinum, and salts with organic bases such as dimethylaminoethanol, methylaminoethanol, triethanolamine and guanidine.

Examples of the acid addition salt having a basic substituent include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,
Salts with inorganic acids such as phosphoric acid, or methanesulfonic acid,
Oxalic acid, maleic acid, fumaric acid, malonic acid, lactic acid, malic acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, ascorbic acid, glucuronic acid, 2-hydroxyethanesulfonic acid, lactobionic acid, glucoheptonic acid, Examples thereof include salts with organic acids such as gluconic acid.

The compounds according to the present invention, which have been described in detail above, are novel except for a very small part of the compounds described above which have a fluorine atom at the 6-position.

The compounds according to the present invention are all excellent as antitumor agents or anticancer agents. Among them, the compounds included in the following general formula (Ia), their stereoisomers or optical isomers, or these Physiologically acceptable salt thereof, or a hydrate or solvate of any of the above is preferable as the antitumor agent.

[0073]

Embedded image

(Wherein ---, R ₁ , R ₂ , R ₃ , R
_{4, R 5, X, R6a1} , R6a2, R6a3, R6a4, R6
a5, R6a6, R6a7 and k have the same meanings as above. )

Further, the compound according to the present invention suitable as an antitumor agent is a compound represented by the following general formula (Ib):
Stereoisomers or optical isomers thereof, physiologically acceptable salts thereof, or hydrates or solvates of any of the above.

[0076]

Embedded image

(In the formula, W is a hydrogen atom or a fluorine atom, and -------, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R 6a
5, R6a6 and R6a7 mean the same as above. )

The compound according to the present invention which is particularly suitable as an antitumor agent is a compound represented by the following formula (Ic):
Stereoisomers or optical isomers thereof, physiologically acceptable salts thereof, or hydrates or solvates of any of the above.

[0079]

Embedded image

(In the formula, R6a511 is a lower alkyl group, and R6a61 and R6a71 are the same or different and mean a hydrogen atom, a lower alkoxy group or a lower alkyl group.)

The structural characteristics of the compound represented by the general formula (Ic) are (1) 1,8-naphthyridine skeleton as a base, and (2) a 2-thiazolyl group is bonded to the 1-position. ,
(3) The 3-position is a carboxyl group, (4) the 4-position is an oxo group, (5) there is no substituent such as a fluorine atom at the 5-position and the 6-position, and (6) is specific to the 7-position. This is because a 1-pyrrolidinyl group having a substituent is bonded, and in particular, a combination of substituents at the 1-position and the 7-position and a fluorine atom at the 6-position are not included.

Specific compounds included in the general formula (Ic) include, for example, 1,4-dihydro-7- (3-methoxy-4-methylamino-1-pyrrolidinyl) -4-.
Examples thereof include oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid, its stereoisomer or optical isomer, or a physiologically acceptable salt thereof.

The compounds according to the present invention are specifically described in Examples below, but in addition to these compounds, the following compounds:
Examples thereof include stereoisomers or optical isomers or physiologically acceptable salts thereof, or hydrates or solvates of any of the above.

7- (3-amino-4-fluoro-1-pyrrolidinyl) -1,4-dihydro-4-oxo-1-
(2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid

7- (3-amino-4-methoxy-3-methyl-1-pyrrolidinyl) -1,4-dihydro-4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carvone acid

5,8-dihydro-2- (3-methoxy-
4-methylamino-1-pyrrolidinyl) -5-oxo-
8- (2-thiazolyl) pyrido [2,3-d] pyrimidine-6-carboxylic acid

8- (4-fluoro-2-thiazolyl)-
5,8-Dihydro-2- (3-methoxy-4-methylamino-1-pyrrolidinyl) -5-oxopyrido [2,3
-D] pyrimidine-6-carboxylic acid

5-amino-1- (4-fluoro-2-thiazolyl) -1,4-dihydro-7- (3-methoxy-
4-Methylamino-1-pyrrolidinyl) -4-oxo-
1,8-naphthyridine-3-carboxylic acid

5-amino-7- (1-amino-3-azabicyclo [3.1.0] hex-3-yl) -1,4-
Dihydro-4-oxo-1- (2-thiazolyl) -1,
8-naphthyridine-3-carboxylic acid

The three-dimensional structures that may be shown below are relative ones rather than absolute ones unless otherwise specified. And the column of "3D" in the table below is 7
The relative stereostructure of the position is shown, and an optically active compound is represented by (+) (−) or (R) (S).

The symbols sometimes used in the following have the following meanings. Me: methyl group, Et: ethyl group, Ac: acetyl group, Bz: benzyl group, Ph: phenyl group, Bu: butyl group, t-: tert-.

[0092]

[Test Example] Next, the antitumor activity of the compound according to the present invention will be described with reference to test examples. The commercial anti-cancer agents etoposide (EP) and the commercial anti-bacterial agents ciprofloxacin (CPFX) and enoxacin (ENX) were used as controls.

Test Example 1 : Antitumor activity against P388 lymphoid mouse leukemia cells

Using P388 lymphoid mouse leukemia cells, MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphe was used.
Nyltetrazolium bromide] method was used to test the antitumor activity of the test compounds.

0.1 m of culture medium containing 1000 to 2000 P388 lymphoid mouse leukemia cells and a test compound at a predetermined concentration
1 of each of them was added to each well of the 96-well plate and incubated at 37 ° C. under 5% carbon dioxide gas condition for 72 hours. After culturing, MTT (5
0.02 ml of the (mg / ml) solution was added to each well and the cells were further cultured for 4 hours. Centrifuge the culture (4 ℃, 2000rpm
X 20 minutes), and the supernatant was removed by suction. Then, 0.1 ml of dimethyl sulfoxide was added to each well to dissolve the formed formazan, and then 0.1 ml of dimethyl sulfoxide was added. The absorbance (OD) of this solution was measured by a multi-scan bichromatic (main wavelength 570 nm, sub wavelength 690 nm). The absorbance of untreated cells (control) was set to 100%, and the 50% growth inhibitory concentration (IC ₅₀ : μg / ml) was calculated by the least squares method.

The results are shown in Tables 1 to 9 below. The data of the control compound are shown in Table 9.

Table 1 Antitumor activity against P388 lymphoid murine leukemia cells

Embedded image

[0098]

[Table 1] *: 1 = HCl

[0099]

[Table 2] *: 1 = HCl, 2 = 1/2 HCl, 3 = 1/5 HCl

[0100]

[Table 3] *: 1 = HCl

[0101]

[Table 4] *: "-" = Free form, 1 = HCl

[0102]

Table 2 Antitumor activity against P388 lymphoid murine leukemia cells

[0104]

Embedded image

[0105]

[Table 5] *: 1 = HCl

[0106]

[Table 6] *: "-" = Free form, 1 = HCl

[0107]

[Table 7] *: "-" = Free form, 1 = HCl

[0108]

[Table 8] *: "-" = Free form, 1 = HCl

[0109]

[Table 9] *: “−” = Free form, 1 = HCl, 4 = 1/2 H ₂ SO ₄

[0110]

Embedded image

Table 3 Antitumor activity against P388 lymphoid murine leukemia cells

[0112]

Embedded image

[0113]

[Table 10] *: "-" = Free form, 1 = HCl

Table 4 Antitumor activity against P388 lymphoid murine leukemia cells

[0115]

Embedded image

[0116]

[Table 11] *: “−” = Free form, 1 = HCl, 4 = 1/2 H ₂ SO ₄

Table 5 Antitumor activity against P388 lymphoid murine leukemia cells

[0118]

[Table 12]

Table 6 Antitumor activity against P388 lymphoid murine leukemia cells

[0120]

[Table 13]

[0121]

[Table 14] Continuation of Table 6

Table 7 Antitumor activity against P388 lymphoid murine leukemia cells

[0123]

Embedded image

[0124]

[Table 15] *: “−” = Free form, 1 = HCl, 5 = 4/3 CF ₃ COOH, 6 = 3/2 HCl

[0125]

Embedded image

Table 8 Antitumor activity against P388 lymphoid murine leukemia cells

[0127]

Embedded image

[0128]

[Table 16] *: 1 = HCl, 7 = CF ₃ COOH

Table 9 Antitumor activity against P388 lymphoid murine leukemia cells

[0130]

[Table 17]

As shown in Tables 1 to 9, the in vitro antitumor activity (IC ₅₀ ) of the compounds of the present invention against P388 lymphoid mouse leukemia cells is excellent. On the other hand, as shown in Table 9, the commercially available antibacterial agents ciprofloxacin and enoxacin have substantially no antitumor activity.

Test Example 2 : In vitro on human cancer cells
Antitumor activity in

Of the culture medium containing 500 to 2000 human cancer cells
Add 0.1 ml each to each well of the 96-well plate,
The cells were cultured under 5% carbon dioxide gas condition for about 20 hours. After culturing, a solution of the test compound having a predetermined concentration was added, and the cells were further cultivated for 72 hours. After culturing, 0.01 ml of MTT (5 mg / ml) solution
Each of them was added to each well and further cultured for 4 hours. The supernatant of the culture solution was removed by suction, and then 0.1 ml of dimethylsulfoxide was added to each well to dissolve the formed formazan, and 0.1 ml of dimethylsulfoxide was further added. The 50% growth inhibitory concentration (IC ₅₀ : μg / ml) of this solution was calculated in the same manner as in Test Example 1, and the results shown in Table 10 below were obtained.

[0134]

[Table 18] The numbers in the table indicate IC ₅₀ (μg / ml).

[0135]

[Table 19] The numbers in the table indicate IC ₅₀ (μg / ml).

As shown in Table 10, the in vitro antitumor activity (IC ₅₀ ) of the compounds of the present invention on human cancer cells is excellent. In particular, the H-based compounds according to the present invention, that is, the compounds in which the 6-position is an unsubstituted compound, showed antitumor activity equivalent to or higher than that of etoposide (EP), which is a commercially available anticancer agent.

Test Example 3 : P388 lymphocytic mouse leukemia cell transplantation-prolonging effect in mice

1 × 10 ⁶ P388 lymphoid mouse leukemia cells were intraperitoneally transplanted into SLC: BDF ₁ mice (8 to 10 weeks old, female, 7 mice per group). Test compound (drug) 0.1
It was dissolved in N-NaOH or suspended in a 0.4% carboxymethylcellulose solution, and this was diluted with distilled water or a 0.4% carboxymethylcellulose solution to each concentration for administration. 0.2 ml of each solution was intraperitoneally (ip) administered twice the day after transplantation (the first day) and the fifth day. The live / dead state of the mice was observed over 30 days, the median number of survival days of each group was calculated, and the survival rate (ILS:%) was calculated by the following formula.

[0139]

[Equation 1]

Evaluation of drug efficacy was performed according to the standards of the National Cancer Institute of the United States. That is, the life extension rate was determined to be ≧ 75%, ++ (satisfactory effect); 20 to 74%, + (effective); ≦ 19%, − (ineffective). The results are shown in Table 11.

[0141]

[Table 20]

[0142]

[Table 21]

[0143]

[Table 22]

[0144]

[Table 23]

As shown in Table 11, the life prolonging effect of the compounds according to the present invention on mice transplanted with P388 lymphoid mouse leukemia cells is excellent.

Test Example 4 : Tumor growth inhibitory effect in mice transplanted with colon 26 mouse tumor cells

SLC: CDF ₁ female mice (7 to 9 weeks old, 7 mice per group) were intradermally implanted with 0.1 ml of 2% brei of colon 26 mouse tumor cells. Test compound (drug)
Was dissolved in 0.1 N-NaOH, and this was diluted with distilled water to each concentration for administration. 0.2 ml of each solution was intraperitoneally (ip) administered once a day from the day after transplantation (the first day) to the ninth day. The estimated tumor weight was calculated from the tumor diameter on day 21 to 22 after transplantation, and the tumor growth inhibition rate (IR:%) of the drug administration group to the control group was calculated from the following formula, and the results in Table 12 were obtained. .

[0148]

[Equation 2]

[0149]

[Table 24] Table 12 Tumor growth inhibitory effect in colon 26 mouse tumor cell transplanted mice ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ━ Compound dose (mg / kg) Tumor growth inhibition rate (%) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ H- 1-1-1 1.56 86 ──────────────────────────── H-1-2 1.10 69 ───────── ──────────────────── H-1-3 1.56 50 2.21 75 ────────────────────── ─────── H-1-4 3.13 61 ──────────────────────────── H-2 12.5 79 ─── ───────────────────────── H-3 3.13 77 ━━━━━━━━━━━━━━━━━━━━ ━━━━━━━━━━━━

[0150]

[Table 25] Continuation of Table 12 ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Compound dose (mg / kg) Tumor Growth inhibition rate (%) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ H-4 1.56 64 3.13 89 ────── ─────────────────────── H-5 1.56 78 ────────────────────── ────── H-6 1.56 71 ──────────────────────────── H-7 1.56 61 3.13 95 ──── ──────────────────────── 7H-1 0.78 50 1.56 58 ━━━━━━━━━━━━━━━━━━━━ ━━━━━━━━━ 2F-1 6.25 62 ──────────────────────────── 2F1-3 7.5 68 ─── ───────────────── ─────── 2F-2 6.25 59 ──────────────────────────── 2F-3 6.25 55 ━━━━━ ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Etoposide 12.5 57 ━━━━━━━━━━━━━━━━━━━━━━━━━ ━━━━━━━━

As shown in Table 12, the tumor growth inhibitory effect (IR) of the compound of the present invention on the mouse transplanted with colon 26 mouse tumor cells is excellent.

In Test Examples 5 to 9 below, human cancer cells were transplanted into nude mice, and a test compound dissolved in an aqueous solution containing NaOH was administered to the mice to observe the degree of suppression of cancer cell growth. Is.

The results of the following test examples 5 to 9 are shown in FIGS.
It is shown in the figure, and the daily change of the tumor growth inhibition rate (IR) described in Test Example 4 is shown therein. In addition, the dose of each compound (mg / kg / day) and the tumor growth inhibition rate on the last day of observation are also shown in each figure.

For convenience of explanation, the administration schedule of test compounds to nude mice will be described below. The test compound was administered for y days [intraperitoneal administration (ip)] x days after the transplantation of human cancer cells into nude mice, and then the drug was discontinued (discontinued) for z days, and then the test compound was administered again for y days. When dosed daily, the dosing (y days) and rest (z days) cycle was termed the "course." The dosing schedule in this case shall be represented by the following symbols.

[(X) (y) (z) (cool) (i
p)]

Next, this symbol will be described with reference to an example. However, the arrow indicates the dosing date.

Example: One dose (i) on the 25th day after transplantation
p), followed by a 6-day washout period, then 1 again
Dosing twice. Repeat this 5 times.

[0158]

[Table 26]

Test Example 5 : Antitumor effect on nude mice transplanted with human nasopharyngeal carcinoma cells

The experiment was conducted under the following conditions. Experimental conditions: Animals used: Female BALB / c nude mice (9 to 14 weeks old, 5 to 7 mice per group). Cancer cells used: Human nasopharyngeal carcinoma KB. Transplantation of cancer cells: 2 to 2.5 × 10 ⁶ cancer cells were transplanted into the abdominal skin of mice. Medication schedule: [(5) (1) (6) (6 courses) (ip)]. Results: Figure 1.

Test Example 6 : Antitumor effect on nude mice transplanted with human breast cancer cells

The experiment was conducted under the following conditions. Experimental conditions: Animals used: Female BALB / c nude mice (7-9 weeks old, 5-7 animals per group). Cancer cells used: Human breast cancer MX-1. Transplantation of cancer cells: 2 mm ³ pieces of cancer tissue were subcutaneously transplanted on the back of mice. Medication schedule: [(15-23) (1) (6) (6 courses) (ip)]. Results: Figure 2.

Test Example 7 : Antitumor effect on human colon cancer cell-transplanted nude mice

The experiment was conducted under the following conditions. Experimental conditions: Animals used: Female BALB / c nude mice (9 weeks old, 1
Group 6). Cancer cells used: Human colon cancer WiDr. Transplantation of cancer cells: 2.5 × 10 ⁶ cancer cells were transplanted into the abdominal skin of mice. Medication schedule: [(7) (1) (6) (6 courses) (ip)]. Result: Fig. 3.

Test Example 8 : Antitumor effect on human melanoma-transplanted nude mice

The experiment was conducted under the following conditions. Experimental conditions: Animals used: Female BALB / c nude mice (8 to 15 weeks of age, 6 to 7 mice per group). Cancer cells used: Melanoma HMV-2. Transplantation of cancer cells: 2.5 to 4.4 × 10 ⁶ cancer cells were transplanted into the abdominal skin of mice. Medication schedule: [(8-10) (1) (6) (9 cool) (ip)]. Results: Figure 4.

Test Example 9 : Antitumor effect on nude mice transplanted with human lung cancer

The experiment was conducted under the following conditions. Experimental conditions: Animals used: Female BALB / c nude mice (13 weeks old,
6 animals per group). Cancer cells used: Human lung cancer LX-1. Transplantation of cancer cells: 2 mm ³ pieces of cancer tissue were subcutaneously transplanted on the back of mice. Medication schedule: [(19-26) (1) (6) (5-6 cool) (i
p)]. Results: Figure 5.

As shown in FIGS. 1 to 5 above, the compounds according to the present invention markedly suppressed the growth of human cancer cells transplanted into nude mice.

Test Example 10 : Acute toxicity

Mice were administered a test solution of a predetermined concentration (0.1 ml /
The body weight was 10 g), and the LD ₅₀ value was calculated from the mortality rate of the mouse 14 days after the administration, and the results in the following table were obtained. In the following table, the toxicity of H-type compounds to female BALB / c CrSlc mice (5-10 mice per group, 10 weeks old), and the F-type compounds of female JCL: ICR mice (5-10 groups per group). Toxicity).

[0172]

[Table 27] Table 13 Acute toxicity (LD ₅₀ : mg / kg) ━━━━━━━━━━━━━━━━━━━━━━━━━━━ Compound intraperitoneal administration (ip ) Intravenous administration (iv) ━━━━━━━━━━━━━━━━━━━━━━━━━━ H-1-1-1 93.2 ─── H-2 135 ── ─ H-3 55.2 119 H-4 ─── 100 H-5 ─── 66.7 ━━━━━━━━━━━━━━━━━━━━━━━━━━━ 2F-1 123 71 2F1-3 123 81 2F-2 141 115 2F-3 141 123 ━━━━━━━━━━━━━━━━━━━━━━━━━━ EP 71 123 ━━━━━ ━━━━━━━━━━━━━━━━━━━━━━━

As shown in Table 13, the acute toxicity of the compounds according to the present invention is shown by the commercial anticancer drug etoposide (E
It is about the same as P).

As shown in the above test results, the compounds according to the present invention can be used for not only non-solid tumors such as lymphocytic leukemia tumors but also lung, milk, stomach, uterus, skin, intestines, bladder, nasopharynx, etc. It shows remarkable antitumor activity against various solid tumors occurring in each tissue. Moreover, the safety of the compounds according to the present invention is high. Therefore, the compound according to the present invention is useful as a therapeutic or prophylactic agent for human tumors.

The dose of the compound according to the present invention is a tumor suppressive action amount of the compound, and varies depending on its pharmacodynamic properties, administration method, symptoms / age, treatment mode (prevention or treatment) and the like. Usually about 0.4 mg / kg body weight per day
To about 20 mg, preferably about 1 mg to about 10 mg, particularly preferably 3 to 6 mg. For example, weight of about 50kg
In patients with the above, the total daily dose is about 20 mg to about 1 g, preferably 50 mg to 500 mg, and particularly preferably 150 mg.
~ 300 mg of active ingredient is administered. It may be divided into 2 to 4 divided doses a day. The route of administration may be oral or parenteral, but parenteral administration is recommended.

The compounds according to the invention are generally administered in the form of formulations. These preparations can be prepared by mixing the compound of the present invention and a preparation carrier. For example, a solvent is an essential component as a formulation carrier in a liquid formulation as a parenteral formulation, and other auxiliary components such as an isotonicity agent, a solubilizing agent, a soothing agent, a pH adjusting agent, a buffering agent and a preservative. , As appropriate.

As the solvent, water is generally used, and an organic solvent such as propylene glycol or a mixture of water and an organic solvent is also used.

Examples of the tonicity agent include sugars such as sorbit and mannitol, sodium chloride and the like, and sugars are preferable.

Examples of the pH adjusting agent include bases such as sodium hydroxide and acids such as hydrochloric acid and phosphoric acid.

Examples of the solubilizing agent include surfactants such as polysorbate 80 and Pluronic F68, and organic acids such as lactic acid and methanesulfonic acid capable of forming an acid addition salt with the compound according to the present invention.

Pain-reducing agents include lidocaine hydrochloride and procaine hydrochloride, preservatives such as benzyl alcohol, stabilizers such as ascorbic acid and antioxidants, and buffering agents such as phosphoric acid, citric acid and lactic acid. Examples thereof include acid salts and the like.

Liquids such as injections and infusions are prepared by dissolving or suspending the compound of the present invention in a solvent, preferably dissolving it, and optionally adding other auxiliary components before or after the dissolution or suspension. it can. Lyophilized formulations can be prepared by lyophilizing these solutions and reconstituted or resuspended in the solvent when administered.

Further, as a carrier in solid preparations such as tablets, capsules, granules, fine granules and powders, any carrier which does not react with the compound of the present invention and is used in the art may be used. For example, starch, mannite, crystalline cellulose, carboxymethyl cellulose, etc. are used.

In addition to these compounds of the present invention, these preparations may further contain other therapeutically effective pharmaceutical ingredients.

[0185]

[Production Method] Next, a method for producing the compound according to the present invention will be described. The compound according to the present invention can be basically produced by almost the same method as the method for producing an antibacterial pyridonecarboxylic acid. The production method by the 7-position substitution method, which is a typical production method, will be described below. Other manufacturing methods will be described in detail in a manufacturing example described later.

7-position is N-C bond, S-C bond or O-
The compound according to the present invention, which is bonded to the mother nucleus by C bond, has the following general formula (II):

[0187]

Embedded image

(In the formula, L is a removable group, and ----,
R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and X have the same meanings as above. ) Or a salt thereof and an amine, a thiol or an alcohol corresponding to the substituent R ₆ can be produced.

The eliminable group (L) of the formula (II) may be any group which can be eliminated by substituting with the amines and the like, and examples thereof include a halogen atom, a lower alkoxy group, a lower alkylthio group and a lower alkyl. Examples thereof include a sulfinyl group, a lower alkylsulfonyl group, an allylsulfonyl group, a lower alkylsulfonyloxy group and an allylsulfonyloxy group, and a halogen atom such as a fluorine atom or a chlorine atom is particularly preferable.

One of the starting materials, amines, is a monocyclic amino group of group (a) and a bicyclic amino group of group (b) in which m contained in the substituent R ₆ described above is 0. , I is 0
Examples thereof include those corresponding to the amino group of group (d). As thiols and alcohols, R 6c5 contained in the substituent R ₆ is S or O and h is 1 (c)
Examples thereof include groups and groups represented by group (d) in which R6d1 is S and i is 1.

The reaction of compound (II) with amines can be carried out without solvent or in a suitable solvent, preferably in the presence of a base, in the temperature range of 10 to 150 ° C. As the solvent, acetonitrile, water, ethanol,
Pyridine, dimethyl sulfoxide, 1-methyl-2-pyrrolidone and the like are used. The base functions as an acid acceptor, and for example, triethylamine, 1,8-
Diazabicyclo [5.4.0] -7-undecene, carbonates such as sodium carbonate and sodium hydrogen carbonate, sodium hydride and the like are used. When using amines,
It can also be used in excess to serve as an acid acceptor.

The compound (I
I) is also novel and can be produced, for example, by the production examples described below.

When the compound according to the present invention obtained by this method is an ester, it can be converted to a carboxylic acid by hydrolyzing the ester portion by a conventional method. On the contrary, the carboxylic acid moiety can be esterified by a conventional method or can be converted into a group which can be converted into a carboxyl group. Further, when a protected amino group is present, the protecting group can be removed by a conventional method.

The compound of the present invention thus produced is isolated and purified according to a conventional method. Isolation
Depending on the purification conditions, it can be obtained in the form of a salt, a free carboxylic acid or a free amine, which can be converted into each other depending on the purpose to produce the desired compound.

When the compound is a racemate, it can be separated into respective optical isomers, if necessary, by applying a known method. Compound stereoisomers (cis-trans, R-S) and optically active compounds (+
If necessary, the body and the body can be separated from each other by a conventional method, for example, a fractional crystallization method or a chromatography method.

[0196]

EXAMPLES Next, the production method of the compound according to the present invention will be explained in detail with reference to the examples. In the following, the method for producing the intermediate (II) will be described in Examples of series A, the method for producing the starting amines will be described in Examples of series B, and the target compound (I) will be described in Examples of series C. Manufacturing method,
The production method of the preparation is specifically described in Examples of series D, respectively.

Series A : Method for producing intermediate (II)

Example A-1 : Preparation of Intermediate (II)
-: 7-chloro-1,4-dihydro-4-oxo-1- (2
-Thiazolyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester

(1) 2,6-dichloropyridine (20
g) was dissolved in tetrahydrofuran (200 ml), and an n-hexane solution (84.5 ml) of n-butyllithium (1.6M) was added dropwise at -78 ° C over 30 minutes under an argon stream. After stirring at the same temperature for 1 hour, a large excess of carbon dioxide (solid) was added. After stirring for 1 hour, the temperature was raised to -10 ° C, water and hydrochloric acid were sequentially added to adjust the pH to 1-2, and the mixture was extracted with ethyl acetate.
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to dryness. Thionyl chloride (40 ml) was added to the obtained solid,
The mixture was heated under reflux for 3 hours. Excess thionyl chloride was distilled off under reduced pressure, and the crude product was distilled under reduced pressure to obtain 2,6-dichloronicotinic acid chloride (19.8 g).

Boiling point: 97-99 ° C./1 mmHg; IR (neat) cm ⁻¹ : 1784

(2) Ethoxymagnesium malonic acid diethyl ester derived from magnesium metal (5.36 g), malonic acid diethyl ester (35.4 g) and ethanol (27 ml), mixed with tetrahydrofuran (35 ml) and toluene (140 ml). Dissolve in solution. This solution was ice-cooled and, with stirring, tetrahydrofuran (19 ml) containing the acid chloride (44.9 g) obtained in the preceding paragraph in it.
And a mixture of toluene (32 ml) was added dropwise. After the addition, the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. After drying this over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain an oily substance.
Water (190 ml) and p-toluenesulfonic acid (0.1 g) were added thereto, and the mixture was refluxed for 2 hours. After cooling, the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain an oily substance. The crude product was distilled under reduced pressure2.
6-Dichloronicotinoyl acetic acid ethyl ester (45.2
g) was obtained. Boiling point: 135-140 ° C / 2 mmHg

(3) The compound (44.9) obtained in (2) above.
g), acetic anhydride (43.8 g) and ethyl orthoformate (3
The mixture consisting of 7.7 g) was refluxed for 1 hour. The mixture was dried under reduced pressure, diisopropyl ether (500 ml) and 2-aminothiazole (20 g) were added under ice cooling, and the mixture was stirred at room temperature for 5 hours. The precipitated crystals were collected by filtration to give 2- (2,6-dichloronicotinoyl) -3- (2-thiazolylamino) acrylic acid ethyl ester (52.8 g).

Melting point: 119-122 ° C. (recrystallized from diisopropyl ether); IR (KBr) cm ^-1 : 1700

(4) The compound (51.7
g) was dissolved in dioxane (310 ml), potassium carbonate (21.4 g) was added, and the mixture was stirred at 60 ° C for 1 hr. After adding ice water, the mixture was neutralized with 10% aqueous hydrochloric acid, and the precipitated crystals were collected by filtration. Recrystallized from a mixture of chloroform and diisopropyl ether to give 7-chloro-1,4-dihydro-4-
Oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester (44.6 g) was obtained.

Melting point: 176-177 ° C .; IR (KBr) cm ⁻¹ : 1724; NMR (CDCl ₃ ) δ: 1.43 (t, 3H, J = 6.5 H)
z), 4.45 (q, 2H, J = 6.5 Hz), 7.38
(D, 1H, J = 3.5 Hz), 7.52 (d, 1H, J = 8.
5 Hz), 7.75 (d, 1H, J = 3.5 Hz), 8.78
(D, 1H, J = 8.5 Hz), 10.00 (s, 1H)

Example A-2 : Preparation of Intermediate (II)
-: 7-chloro-1- (4-fluoro-2-thiazolyl)-
1,4-Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester

The ester obtained in Example 1 (4) (250 m
A mixture consisting of g), N-fluoro-2,6-dichloropyridinium tetrafluoroborate (240 mg) and 1,2-dichloroethane (10 ml) was heated under reflux for 2 days. Water was added to the reaction solution, and extracted with chloroform.
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent chloroform) and recrystallized from ethyl acetate to give the title compound (40 mg).

Melting point: 174-175 ° C .; IR (KBr) cm ⁻¹ : 1700; NMR (CDCl ₃ ) δ: 1.42 (t, 3H, J = 6.5 H)
z), 4.45 (q, 2H, J = 6.5 Hz), 7.33
(D, 1H, J = 3.5 Hz), 7.51 (d, 1H, J = 8.
5 Hz), 8.78 (d, 1H, J = 8.5 Hz), 9.85
(S, 1H)

Example A-3 : -Production of Intermediate (II)-
-: 5,7-dichloro-1,4-dihydro-4-oxo-1
-(2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid

(1) A mixture of 4-amino-2,6-dichloropyridine (5.5 g), cuprous chloride (4.4 g) and concentrated hydrochloric acid (50 ml) was added to sodium nitrite (3.5 g) under ice-salt cooling. g) was added in small portions. After stirring at the same temperature for 1 hour and at room temperature for 1.5 hours, water was added and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 2,4,6-trichloropyridine (5.5 g).

IR (neat) cm ⁻¹ : 1563, 1357, 11
55, 851, 823; NMR (CDCl ₃ ) δ: 7.31 (s, 2H)

(2) The compound (5.5
To a mixture of g) and tetrahydrofuran (55 ml) was added a solution of n-butyllithium (1.6 M) in n-hexane (20 ml) at -78 ° C. After stirring at the same temperature for 1 hour, a large excess of carbon dioxide (solid) was added. After stirring for 1 hour, the temperature was raised to 0 ° C., hydrochloric acid was added to acidify the mixture, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, diisopropyl ether was added to the residue, and the crystals were collected by filtration to give 2,4,6-trichloronicotinic acid (6.5 g).

Melting point: 138-141 ° C .; IR (KBr) cm ⁻¹ : 1715

(3) The compound (6.5) obtained in (2) above.
A mixture of g) and thionyl chloride (25 ml) was refluxed for 3 hours. Excess thionyl chloride was distilled off under reduced pressure, and the crude product was distilled under reduced pressure to obtain 2,4,6-trichloronicotinic acid chloride (6.6 g).

Boiling point: 93-95 ° C./1 mmHg; IR (neat) cm ⁻¹ : 1791

(4) Malonic acid monoethyl ester (3.
To a mixture of 6 g) and tetrahydrofuran (30 ml) was added dropwise a solution of methylmagnesium bromide (3M) in ether (19 ml) at 0 ° C. After stirring at room temperature for 1 hour, a mixture of the compound (6.6 g) obtained in (3) above and tetrahydrofuran (30 ml) was added dropwise, and the mixture was heated at 60 ° C. for 1.5 hours. The solvent was evaporated under reduced pressure, hydrochloric acid was added to the residue, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the crude product was distilled under reduced pressure to obtain 2,4,6-trichloronicotinoyl acetic acid ethyl ester (4.8 g).

Boiling point: 160-162 ° C./2 mmHg; IR (neat) cm ⁻¹ : 1746

(5) The compound (4.8) obtained in the above item (4)
g), acetic anhydride (4.2 g) and ethyl orthoformate (3.
The mixture consisting of 6 g) was refluxed for 1.5 hours. The mixture was dried under reduced pressure, diisopropyl ether (100 ml) and 2-aminothiazole (1.6 g) were added under ice cooling, and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent chloroform), and recrystallized from ethyl acetate to give 2- (2.
4,6-Trichloronicotinoyl) -3- (2-thiazolylamino) acrylic acid ethyl ester (4.0 g) was obtained.

Melting point: 126-127 ° C .; IR (KBr) cm ⁻¹ : 1691

(6) The compound (4.0
g), potassium carbonate (1.5 g) and ethyl acetate (40
ml) was heated at 60 ° C. for 1 hour. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure,
The obtained residue was purified by silica gel column chromatography (eluent chloroform), recrystallized from chloroform, and 5,7-dichloro-1,4-dihydro-4-.
Oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester (2.5 g) was obtained.

Melting point: 226-227 ° C .; IR (KBr) cm ⁻¹ : 1737,1692

(7) The ester form (1.
A mixture of 8 g) and 20% aqueous hydrochloric acid (60 ml) was heated under reflux for 5 hours, and after cooling, water was added and the precipitated crystals were collected by filtration and washed with water to give the title 5,7-dichloro-1,4-dihydro-4. -Oxo-1- (2-thiazolyl) -1,8-naphthyridine-3
-Carboxylic acid (1.4 g) was obtained.

Melting point: 264-266 ° C .; IR (KBr) cm ⁻¹ : 1729

Example A-4 : Preparation of Intermediate (II)
-: 5-amino-7-chloro-1,4-dihydro-4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-
3-carboxylic acid

(1) A mixture of the compound (500 mg) obtained in Example A-3 (6), benzylamine (140 mg), triethylamine (280 mg) and toluene (15 ml) was refluxed for 30 minutes. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethyl acetate to give 5-benzylamino-7-chloro-1,4-dihydro-4-oxo-1- (2- Thiazolyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester (510 mg) was obtained.

Melting point: 141-143 ° C .; IR (KBr) cm ⁻¹ : 1733; NMR (CDCl ₃ ) δ: 1.42 (t, 3H, J = 7H
z), 4.41 (q, 2H, J = 7Hz), 4.49 (d,
2H, J = 6.5 Hz), 6.47 (s, 1H), 7.31
(D, 1H, J = 3.5 Hz), 7.32-7.40 (m, 5
H), 7.70 (d, 1H, J = 3.5 Hz), 9.87
(S, 1H), 11.2-11.7 (m, 1H)

(2) The ester (1.0) obtained in the above item (1)
A mixture consisting of g), concentrated sulfuric acid (2 ml) and acetic acid (8 ml) was stirred at 110 ° C for 5 hours, cooled, 8 ml of water was added, and the mixture was stirred at 110 ° C for 1 hour. The precipitated crystals were collected by filtration and washed with water to obtain 740 mg of the title compound.

Melting point: 264-265 ° C .; IR (KBr) cm ⁻¹ : 1727

Example A-5 : Preparation of Intermediate (II)
-: 7-chloro-1,4-dihydro-4-oxo-1- (2
-Thiazolyl) -5-trifluoromethyl-1,8-naphthyridine-3-carboxylic acid ethyl ester

(1) 2,6-Dichloro-4-trifluoromethylpyridine (5 g) and tetrahydrofuran (5
0 ml) was cooled to −78 ° C. and n-butyllithium (1.6 M) in n-hexane (16 ml) was added.
Was added dropwise and stirred for 30 minutes. A large excess of carbon dioxide (solid) was added thereto and stirred for 1 hour. Raise the temperature to 0 ° C,
Ethyl acetate and diluted hydrochloric acid were added for extraction, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, thionyl chloride (20 ml) was added to the residue, and the mixture was heated under reflux for 6 hours. Excess thionyl chloride was distilled off under reduced pressure, and the residue was distilled under reduced pressure to obtain 2,6
-Dichloro-4-trifluoromethylnicotinic acid chloride (3.8 g) was obtained.

Boiling point: 77-78 ° C./2 mmHg; IR (neat) cm ⁻¹ : 1797

(2) To a mixture of magnesium (0.36 g) and ethanol (1.5 ml) was added 1 drop of carbon tetrachloride, and diethyl malonate (2.4 g) and ethanol (1.5 g) were added.
(ml) and toluene (10 ml), and the mixture was stirred for 2 hours. Further, under ice cooling, the compound (3.8 g) obtained in (1) above and tetrahydrofuran (10 ml)
The mixture was added dropwise and stirred at room temperature for 3 hours. The mixture was extracted with ethyl acetate and diluted hydrochloric acid, the organic layer was washed with water, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. Water (20 ml) and p-toluenesulfonic acid (50 mg) were added to the residue, and the mixture was heated under reflux for 3 hours. Chloroform and water were added thereto for extraction, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 2,6-dichloro-4-trifluoromethylnicotinoyl acetic acid ethyl ester (0.9 g). .

IR (neat) cm ^-1 : 1744,17
21; MS (m / z): 330 (MH ⁺ ).

(3) The compound obtained in the above (2) (0.9
g), ethyl orthoformate (0.6 g) and acetic anhydride (0.
The mixture consisting of 7 g) is heated at 140 ° C. for 1.5 hours under reflux,
The residue was dried under reduced pressure. Diisopropyl ether (20m
l) was added, and 2-aminothiazole (0.3 g) was added under ice cooling.
Was added and the mixture was stirred at room temperature for 3 hours, and the solvent was evaporated. Chloroform and water were added to this for extraction, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent chloroform) to give 2- (2,6-dichloro-4-trifluoromethylnicotinoyl) -3- (2-thiazolylamino) acrylic acid ethyl ester (0.37 g). It was

IR (neat) cm ^-1 : 1713; MS (m / z): 440 (MH ⁺ ).

(4) Compound (0.37) obtained in the above item (3)
g), potassium carbonate (0.13 g) and ethyl acetate (10
ml) was heated under reflux for 15 minutes, ethyl acetate and water were added for extraction, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was recrystallized from ethyl acetate to give the title compound, 7-chloro-1,4-dihydro-4-oxo-1- (2-thiazolyl) -5-trifluoromethyl-.
1,8-naphthyridine-3-carboxylic acid ethyl ester (0.27 g) was obtained.

Melting point: 184-185 ° C .; IR (KBr) cm ⁻¹ : 1736, 1703

Example A-6 : -Production of Intermediate (II)-
-: 7-chloro-6-fluoro-1,4-dihydro-4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester

(1) Japanese Patent Laid-Open No. 61-152682
According to the method described in (Ref.1), 2,6-dichloro-
5-Fluoronicotinoyl acetic acid ethyl ester (9.8 g) was treated with ethyl orthoformate and acetic anhydride to give 2- (2,6
-Dichloro-5-fluoronicotinoyl) -3-ethoxyacrylic acid ethyl ester, and this compound was then reacted with 2-aminothiazole and triethylamine in ethanol at room temperature to give 2- (2,2 12.3 g of ethyl 6-dichloro-5-fluoronicotinoyl) -3- (2-thiazolylamino) acrylic acid was obtained. Melting point: 125-126 ° C

(2) 12.3 g of the above compound was reacted with potassium t-butoxide in anhydrous dioxane to give 7-chloro-6-fluoro-1,4-dihydro-4-oxo-.
1- (2-thiazolyl) -1,8-naphthyridine-3-
7.1 g of carboxylic acid ethyl ester was obtained. Melting point: 182-184 ° C

Example A-7 : Preparation of Intermediate (II)
-: 5,8-Dihydro-2-methanesulfonyl-5-oxo-8- (2-thiazolyl) pyrido [2,3-d] pyrimidine-6-carboxylic acid ethyl ester

(1) Malonic acid monoethyl ester (1
A tetrahydrofuran solution (80 ml) of 2.3 g) was ice-cooled, an ether solution (64 ml) of methylmagnesium bromide (3M) was added dropwise, and the mixture was stirred for 20 minutes and then 4-chloro-
A tetrahydrofuran solution (100 ml) of 2-methylthiopyrimidine-5-carbonyl chloride (8.6 g) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water, adjusted to pH 5 to 6 with concentrated hydrochloric acid, and extracted with ethyl acetate. After drying over sodium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent chloroform) to give 3- (4-chloro-2-methylthiopyrimidine-5).
-Yl) -3-oxopropionic acid ethyl ester (8.
0 g) was obtained.

IR (neat) cm ^-1 : 1743; MS (m / z): 275 (MH ⁺ ).

(2) The compound (7.95) obtained in (1) above.
g), ethyl orthoformate (6.80 g) and acetic anhydride (7.
The mixture consisting of 76 g) was heated under reflux at 130 ° C. for 1 hour and concentrated under reduced pressure. Under ice cooling, diisopropyl ether (100 m
l) and 2-aminothiazole (3.28 g) were added, the mixture was stirred at room temperature overnight, and the precipitated crystals were collected by filtration and washed with diisopropyl ether. 1,4-dioxane (70m
It was dissolved in l), potassium carbonate (2.72 g) was added under ice cooling, and the mixture was stirred at room temperature for 5 hours. This is ice-cooled, and ice water (200
ml) was added and neutralized with 10% aqueous hydrochloric acid. The precipitated crystals were collected by filtration, washed successively with water, 1,4-dioxane and diisopropyl ether and washed with 5,8-dihydro-2-methylthio-5-oxo-8- (2-thiazolyl) pyrido [2,3- d] Pyrimidine-6-carboxylic acid ethyl ester (6.0 g) was obtained.

Melting point: 183-184 ° C .; IR (KBr) cm ⁻¹ : 1736

(3) Compound (5.99) obtained in the above item (2)
g) in methylene chloride solution (450 ml) was ice-cooled to 80%
M-Chloroperbenzoic acid (9.30 g) was added little by little, and the mixture was stirred at room temperature overnight. The extract was washed successively with aqueous sodium thiosulfate solution, aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, evaporated to remove the solvent under reduced pressure, and recrystallized from a mixed solution of ethyl acetate and diisopropyl ether to give the title 5,8-dihydro. 2-Methanesulfonyl-5-oxo-8- (2-thiazolyl) pyrido [2,3-d] pyrimidine-6-carboxylic acid ethyl ester (4.48 g) was obtained.

Melting point: 185-187 ° C .; IR (KBr) cm ⁻¹ : 1741

Example A-8 : Preparation of Intermediate (II)
-: The intermediate (II) shown in Table 14 was obtained by the method described in Examples A-1 to A-6 or a method analogous thereto.

Table 14 Intermediate (II)

Embedded image

[0250]

[Table 28]

[0251]

[Table 29]

[0252]

Embedded image

Series B : Method for producing starting amines

Example B-1 : Preparation of amines ---: trans-3- (Nt-butoxycarbonylmethylamino) -4-methylpyrrolidine

(1) Trans-3-amino-1-benzyl-4-methylpyrrolidine (19 g) was dissolved in methylene chloride (200 ml), and di-t-butyl dicarbonate (22.9 g) was added.
A solution of g) in methylene chloride (20 ml) was added under water cooling.
After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure to obtain trans-1-benzyl-3- (t-butoxycarbonylamino) -4-methylpyrrolidine (28.2 g).

Melting point: 138-140 ° C. (recrystallized from ethyl acetate-n-hexane); IR (KBr) cm ^-1 : 3198,1706; MS (m / z): 291 (MH ⁺ ).

(2) 70% toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride (40
(ml) was diluted with toluene (150 ml), and the compound (10 g) obtained in (1) above was added little by little under ice cooling. The reaction solution was heated under reflux for 1 hour, cooled with ice, and then excess reagent was decomposed with water. The insoluble material was filtered off, the filtrate was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in methylene chloride (100 ml), and a solution of di-t-butyl dicarbonate (7.5 g) in methylene chloride (10 ml) was added thereto under ice cooling. After stirring at room temperature for 3.5 hours, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent n-hexane: ethyl acetate = 5: 1) to give trans-1-benzyl-3- (Nt-butoxycarbonylmethylamino) -4-methylpyrrolidine. (9.9 g) was obtained.

IR (neat) cm ^-1 : 1694; MS (m / z): 305 (MH ⁺ ).

(3) The compound (1.52) obtained in the above item (2)
g) was dissolved in ethanol (50 ml), 10% palladium carbon (200 mg) was added, and a theoretical amount of hydrogen was absorbed at 50 ° C. After the catalyst was filtered off, the solvent was distilled off under reduced pressure to obtain the desired trans-3- (Nt-butoxycarbonylmethylamino) -4-methylpyrrolidine (950 mg).

IR (neat) cm ⁻¹ : 3337, 16
85; MS (m / z): 215 (MH ⁺ ).

Example B-2 : Preparation of amines-: (+)-trans-3- (Nt-butoxycarbonylmethylamino) -4-methoxypyrrolidine

(1) trans-3-Amino-1-benzyl-4-methoxypyrrolidine (racemic form, 22.4 g) described in JP-A-2-69474 and 19.6 g of L-tartaric acid were added to methanol (350 ml). And was left at room temperature for 7 hours. The precipitated L-tartrate salt was collected by filtration and recrystallized from methanol and water to give trans-3-amino-1-benzyl-4-methoxypyrrolidine L-tartrate salt (14.1
g) was obtained.

Then, all the mother liquors were combined, the solvent was distilled off under reduced pressure, saturated brine was added, the mixture was made basic with potassium carbonate and extracted with ethyl acetate. Washed with saturated saline,
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue and D-tartaric acid (6.73 g) were mixed with methanol (180
ml) and left at room temperature for 7 hours. Precipitated D-
The tartrate salt was collected by filtration and recrystallized from methanol and water to obtain trans-3-amino-1-benzyl-4-methoxypyrrolidine D-tartrate salt (9.9 g) having the following physical properties.

L-Tartrate salt; Melting point: 206-208 ° C. (decomposition); [α] _D ²⁹ + 33.0 ° (c = 1.003, water); Elemental analysis value (%): C ₁₂ H ₁₈ N ₂ O. As 3/2 C ₄ H ₆ O ₆ ; calculated value C, 50.11; H, 6.31; N, 6.49; measured value C, 49.85; H, 6.26; N, 6.27;

D-Tartrate salt; Melting point: 207-209 ° C. (decomposition); [α] _D ²⁹ -33.4 ° (c = 1.020, water); Elemental analysis value (%): C ₁₂ H ₁₈ N ₂ O.3 As / 2 C ₄ H ₆ O ₆ ; calculated value C, 50.11; H, 6.31; N, 6.49; measured value C, 50.35; H, 6.32; N, 6.47;

(2) To the L-tartrate salt (3.65 g) obtained in (1) above, saturated saline was added, neutralized with potassium carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure (+)-.
Trans-3-amino-1-benzyl-4-methoxypyrrolidine (1.23 g) was obtained. [Α] _D ²⁷ + 32.2 ° (c = 1.053, methanol)

(3) Compound (5.74) obtained in the above item (2)
g) was dissolved in methanol (65 ml), and di-t-butyl dicarbonate (7.29 g) was added under ice cooling. The mixture was stirred at the same temperature for 30 minutes and at room temperature for 4 hours. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (eluent chloroform: methanol = 50: 1), and (+)-
Trans-1-benzyl-3- (t-butoxycarbonylamino) -4-methoxypyrrolidine (8.55 g) was obtained.

Melting point: 44-45 ° C. [α] _D ²⁹ + 9.5 ° (c = 1.044, methanol)

(4) Lithium aluminum hydride (3.
43 g) was suspended in anhydrous tetrahydrofuran (150 ml), a solution of the compound (8.4 g) obtained in (3) above in anhydrous tetrahydrofuran (50 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After heating under reflux for a further 5 hours, the excess reagent was decomposed with water under ice cooling, and the insoluble material was filtered off. The filtrate was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in methylene chloride (180 ml), and dicarbonate di-t under ice cooling.
-Butyl (6.3 g) was added. After stirring at the same temperature for 30 minutes and at room temperature for 2 hours, the solvent was distilled off under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent chloroform: methanol = 50: 1) and (+)-trans-1-benzyl-3- (Nt-butoxycarbonylmethylamino) -4-methoxy. Pyrrolidine (8.26
g) was obtained. [Α] _D ²⁹ +9.9 ° (c = 1.002, methanol)

(5) In the same manner as in Example B-1 (3), the desired (+)-trans-3- (Nt-butoxy) was obtained from the compound (8.15 g) obtained in (4) above. Carbonylmethylamino) -4-methoxypyrrolidine (5.59 g) was obtained.

[Α] _D ²⁹ + 12.5 ° (c = 1.051, methanol); IR (neat) cm ⁻¹ : 3318, 1693; MS (m / z): 231 (MH ⁺ ).

Example B-3 : Preparation of amines-: (-)-trans-3- (Nt-butoxycarbonylmethylamino) -4-methoxypyrrolidine

(1) D-tartrate salt obtained in Example B-2 (1) (2.57 g) in the same manner as in Example B-2 (2).
To (-)-trans-3-amino-1-benzyl-4
-Methoxypyrrolidine (1.01 g) was obtained. [Α] ^{_{D 27 -32.7 ° (c = 1.016}} , methanol)

(2) From the compound (3.03 g) obtained in the previous section, (-)-trans-1-benzyl-3- (t-butoxycarbonylamino) -in the same manner as in the section (3) of Example B-2. 4-Methoxypyrrolidine (4.5 g) was obtained.

Melting point: 44-45 ° C .; [α] _D ²⁹ -9.5 ° (c = 1.080, methanol)

(3) Example B-2 In the same manner as in item (4), from the compound (4.25 g) obtained in the above item, (-)-trans-1-benzyl-3- (Nt-butoxycarbonylmethyl). Amino) -4-methoxypyrrolidine (4.25 g) was obtained. [Α] _D ²⁹ -10.1 ° (c = 1.054, methanol)

(4) In the same manner as in the item (5) of Example B-2, the compound (4.25 g) obtained in the above item was used as the target (-).
-Trans-3- (Nt-butoxycarbonylmethylamino) -4-methoxypyrrolidine (2.81g) was obtained.

[Α] _D ²⁹ -12.2 ° (c = 1.003, methanol); IR (neat) cm ^-1 : 3318,1693; MS (m / z): 231 (MH ⁺ ).

Example B-4 : Preparation of amines-: 3- (Nt-butoxycarbonylmethylamino) -3
-Methylpyrrolidine

(1) From 3-amino-1-benzyl-3-methylpyrrolidine (20 g) to 1-benzyl-3- (Nt-butoxycarbonylamino) in the same manner as in Example B-1 (1). -3-Methylpyrrolidine (28.3g)
I got

IR (neat) cm ⁻¹ : 3356, 17
16, 1697; MS (m / z): 291 (MH ⁺ ).

(2) In the same manner as in Example B-1 (2), 1-benzyl-3- (Nt-butoxycarbonylmethylamino) was prepared from the compound (11.4 g) obtained in the above (1).
-3-Methylpyrrolidine (7.5 g) was obtained.

IR (neat) cm ^-1 : 1697; MS (m / z): 305 (MH ⁺ ).

(3) In the same manner as in Example B-1 (3), the compound (7.5 g) obtained in the above (2) was used to obtain the desired 3-
(Nt-butoxycarbonylmethylamino) -3-methylpyrrolidine (5.5 g) was obtained.

IR (neat) cm ⁻¹ : 3337, 1
682; MS (m / z): 215 (MH ⁺ ).

Example B-5 : Preparation of amines
-: (1R ^* , 4R ^* , 5S ^* )-4-t-butoxycarbonylamino-2-azabicyclo [3.3.0] octane

(1) To 97 g of 2-ethoxycarbonylcyclopentanone, 71.2 ml of benzylamine and 5.9 g of p-toluenesulfonic acid, 500 ml of toluene was added, and Dean-St
The mixture was heated under reflux for 2 hours while dehydrating with an ark device. The reaction solution was evaporated to dryness under reduced pressure, the residue was purified by silica gel column chromatography (eluent: n-hexane), and ethyl 2-benzylamino-1-cyclopentene-1-carboxylate 1
19.6 g was obtained.

Melting point: 31-32 ° C .; IR (neat) cm ⁻¹ : 3328, 2951, 1656, 1606; MS (m / z): 246 (MH ⁺ ); NMR (CDCl ₃ ) δ: 1.25 (t, 3H, J = 7.5H
z), 1.80 (m, 2H), 2.55 (t, 4H, J = 7.5 H
z), 4.15 (q, 2H, J = 7.5 Hz), 4.40 (d, 2)
H, J = 6.5Hz), 7.20-7.40 (m, 5H), 7.75 (b
rs, 1H)

(2) 60 g of the compound obtained in the preceding paragraph was dissolved in 500 ml of ethanol, 1 g of platinum dioxide was added, and catalytic reduction was carried out at medium pressure. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: chloroform) to give ethyl cis-2-benzylamino-1-cyclopentanecarboxylate 3
Obtained 4.0 g.

IR (neat) cm ^-1 : 2955, 2871, 1727; MS (m / z): 248 (MH ⁺ ); NMR (CDCl ₃ ) δ: 1.25 (t, 3H, J = 7.5 H)
z), 1.40-2.10 (m, 7H), 2.95 (m, 1H), 3.3
0 (m, 1H), 3.80 (s, 2H), 4.15 (q, 2H,
J = 7.5 Hz), 7.15-7.35 (m, 5H)

(3) To the compound (85.6 g) obtained above, 46 ml of ethyl bromoacetate, 57.4 g of potassium carbonate and 2.9 g of potassium iodide, 1000 ml of dioxane was added, and the mixture was heated under reflux for 18 hours. The reaction solution was filtered off, the filtrate was concentrated under reduced pressure,
The obtained residue is purified by silica gel column chromatography (eluent: n-hexane) to give cis-2-
[(N-benzyl) ethoxycarbonylmethylamino]
92.5 g of ethyl 1-cyclopentanecarboxylate was obtained.

IR (neat) cm ^-1 : 2976, 2871, 1732; MS (m / z): 334 (MH ⁺ ); NMR (CDCl ₃ ) δ: 1.10-1.30 (m, 6H), 1.50
-2.10 (m, 6H), 3.10 (m, 1H), 3.35 (s, 2
H), 3.50-3.70 (m, 1H), 3.85-4.30 (m, 6)
H), 7.15-7.35 (m, 5H)

(4) In 1000 ml of tetrahydrofuran
12.2 g of 60% sodium hydride was suspended, and 400 ml of a tetrahydrofuran solution containing 92.5 g of the compound obtained in the preceding section was added. After heating under reflux for 1 hour, the reaction solution was concentrated under reduced pressure,
1000 ml of 20% hydrochloric acid water was added to the residue, and the mixture was heated under reflux for 6 hours. The reaction solution was neutralized and extracted with toluene. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 53.7 g of cis-2-benzyl-2-azabicyclo [3.3.0] octane-4-one.

IR (neat) cm ^-1 : 2952, 2866, 1751; MS (m / z): 216 (MH ⁺ ); NMR (CDCl ₃ ) δ: 1.50-2.05 (m, 6H), 2.75
(M, 1H), 2.80 (m, 1H), 3.15 (d, 1H, J
= 16Hz), 3.42 (d, 1H, J = 13Hz), 3.45-3.55
(M, 1H), 4.03 (d, 1H, J = 13Hz), 7.20-7.
40 (m, 5H)

(5) 26 g of hydroxylamine hydrochloride was dissolved in 500 ml of water, and 200 ml of an ethanol solution containing 53.7 g of the compound obtained in the preceding paragraph was added. Further, 80 ml of 20% aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 17 hours. Acetic acid water was added to the reaction solution to make it acetic acid acidic and washed with toluene.
The aqueous layer was made alkaline and extracted with toluene. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give cis-2-benzyl-2-azabicyclo [3.3.0] octane-4-one oxime (30.6 g).

Melting point: 90-91 ° C. IR (KBr) cm ⁻¹ : 3279, 2958, 1699; MS (m / z): 231 (MH ⁺ ); NMR (CDCl ₃ ) δ: 1.40-2.10 (m, 6H) ), 2.90
-4.00 (m, 6H), 7.15-7.35 (m, 5H), 7.80
(Br s, 1H)

(6) 12 g of the compound obtained in the preceding paragraph was dissolved in 120 ml of dioxane, 6 g of Raney nickel was added, and
The theoretical amount of hydrogen was added at ° C. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure, the obtained residue was dissolved in 100 ml of methylene chloride, and 13.6 g of di-t-butyl dicarbonate was added. At room temperature
After stirring for 11 hours, the reaction solution was concentrated under reduced pressure, ethyl acetate and diisopropyl ether were added to the obtained residue, and the precipitated crystals were collected by filtration (1R ^* , 4R ^* , 5R ^* )-2-benzyl-4-. 10.6 g of t-butoxycarbonylamino-2-azabicyclo [3.3.0] octane was obtained.

Melting point: 161-162 ° C .; IR (KBr) cm ⁻¹ : 3353, 2950, 1678; MS (m / z): 317 (MH ⁺ ); NMR (CDCl ₃ ) δ: 1.20-1.80 (m, 6H), 1.40
(S, 9H), 2.20 (m, 1H), 3.00-3.20 (m, 2)
H), 3.35 (d, 1H, J = 13Hz), 3.85 (d, 1H,
J = 13Hz), 3.60-3.80 (m, 1H), 4.55 (br
s, 1H), 7.15-7.35 (m, 5H)

The mother liquor obtained above was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform) to give (1R ^* , 4S ^* , 5).
R ^* )-2-benzyl-4-t-butoxycarbonylamino-2-azabicyclo [3.3.0] octane 3.0 g
I got

IR (neat) cm ^-1 : 3447, 2952, 1713; MS (m / z): 317 (MH ⁺ ); NMR (CDCl ₃ ) δ: 1.20-1.80 (m, 6H), 1.45
(S, 9H), 2.20-2.40 (m, 1H), 2.55-3.00
(M, 3H), 3.10-3.95 (m, 2H), 4.10 (m, 1)
H), 4.80 (brs, 1H), 7.15-7.35 (m, 5
H)

(7) (1R ^* , 4 obtained in the previous section)
R ^* , 5R ^* )-2-benzyl-4-t-butoxycarbonylamino-2-azabicyclo [3.3.0] octane (10.5 g) was dissolved in ethanol (150 ml), and 5% palladium-carbon (1.0 g) was added. Hydrogen was added. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain 7.1 g of the desired product.

Melting point: 102-103 ° C .; IR (KBr) cm ⁻¹ : 3305, 3184, 2926, 1709; MS (m / z): 227 (MH ⁺ ); NMR (CDCl ₃ ) δ: 1.40 to 1.90 ( m, 6H), 1.45
(S, 9H), 2.20 (m, 1H), 2.60-3.20 (m, 2
H), 3.65 (brs, 1H), 3.75 (m, 1H), 4.
70 (br s, 1H)

Example B-6 : Preparation of amines-: (1R ^* , 4S ^* , 5S ^* )-4-t-butoxycarbonylamino-2-azabicyclo [3.3.0] octane

(1R) obtained in item (6) of Example B-5 was used.
^* , 4S ^* , 5R ^* )-2-benzyl-4-t-butoxycarbonylamino-2-azabicyclo [3.3.0]
Octane (1.58 g), 5% palladium on carbon (200 mg) and ethanol (20 ml) were used and treated in the same manner as in Example B-5 (7) to give 940 mg of the desired product.

Melting point: 85-87 ° C .; IR (KBr) cm ⁻¹ : 3372, 3210, 2940, 1682; MS (m / z): 227 (MH ⁺ ); NMR (CDCl ₃ ) δ: 1.40 to 1.90 ( m, 6H), 1.45
(S, 9H), 2.05 (brs, 1H), 2.60-3.10
(M, 3H), 3.70 (br s, 1H), 4.05 (m, 1
H), 4.75 (br s, 1H)

Example B-7 : Preparation of amines ---: 1-amino-3-azabicyclo [3.1.1] heptane

(1) 60% sodium hydride 1.29 g
-Washed twice with hexane and then suspended in 60 ml of ether.
5.0g diethyl malonate dissolved in 5ml ether under ice cooling
Was added dropwise over 10 minutes. This mixture was stirred at room temperature for 30 minutes, cooled with ice, added with 5.38 g of benzyl chloromethyl ether dissolved in 10 ml of ether over 10 minutes, stirred at room temperature overnight, and further refluxed for 5 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 9.0 g of a crude product of diethyl benzyloxymethylmalonate.

This was dissolved in 50 ml of ether and added dropwise to a mixture of 2.85 g of lithium aluminum hydride and 300 ml of ether under ice cooling. The mixture was stirred at the same temperature for 1.5 hours and further at room temperature for 2 hours. Saturated aqueous sodium tartrate was added under ice cooling, and the mixture was stirred overnight. The insoluble material was filtered off, the filtrate was dried over sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent chloroform: ethanol = 4
Purification by 0: 1 to 20: 1) gave 1.96 g of 2-benzyloxymethyl-1,3-propanediol.

IR (neat) cm ^-1 : 3380; ¹ H-NMR (CDCl ₃ ) δ: 2.05 (m, 1H), 2.3
5 (br s, 2H), 3.63 (d, 2H, J = 5.5Hz
), 3.81 (dd, 4H, J = 5.5, 5.5Hz), 4.52
(S, 2H), 7.25-7.40 (m, 5H)

(2) 206.3 g of p-toluenesulfonyl chloride was added in 3 batches while cooling a mixture consisting of 84.8 g of the compound obtained in the previous section and 360 ml of pyridine with ice-salt, and kept at the same temperature for 2 hours at room temperature. It was stirred overnight. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (eluent chloroform: ethanol = 30: 1) to obtain 162.3 g of 2-benzyloxymethyl-1,3-bis (p-toluenesulfonyloxy) propane. It was

IR (neat) cm ⁻¹ : 1598, 1361; ¹ H-NMR (CDCl ₃ ) δ: 2.33 (m, 1H), 2.4
4 (s, 6H), 3.41 (d, 2H, J = 6Hz), 4.04
(M, 4H), 4.34 (s, 2H), 7.10-7.40 (m, 9
H), 7.74 (d, 4H, J = 8Hz)

(3) Add 22.8 g of 60% sodium hydride to n
-Washed twice with hexane and then suspended in 350 ml of toluene. Diethyl malonate dissolved in 150 ml of toluene under ice cooling
91.1 g was added dropwise over 25 minutes. This mixture was stirred at room temperature for 40 minutes, then added with 119.6 g of the compound obtained in the previous section dissolved in 300 ml of toluene and refluxed for 4.5 days. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. The solvent and unreacted diethyl malonate were distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent chloroform: ethanol = 50:
Purification in 1) gave 66.8 g of 3-benzyloxymethylcyclobutane-1,1-dicarboxylic acid diethyl ester.

IR (neat) cm ⁻¹ : 1726, 1263; ¹ H-NMR (CDCl ₃ ) δ: 1.23 (t, 3H, J =
7Hz), 1.25 (t, 3H, J = 7Hz), 2.25-2.50
(M, 2H), 2.55-2.80 (m, 3H), 3.44 (d, 2)
H, J = 6Hz), 4.17 (q, 2H, J = 7Hz), 4.21
(Q, 2H, J = 7Hz), 4.50 (s, 2H), 7.20-7.
40 (m, 5H)

(4) 66.8 g of the compound obtained in the preceding paragraph was dissolved in 500 ml of ethyl acetate, 6.68 g of 5% palladium carbon was added, and the theoretical amount of hydrogen was added at 30-40 ° C. After the catalyst was filtered off, the solvent was distilled off, and the residue was purified by silica gel chromatography (eluent: chloroform: ethanol = 20: 1) to give 3-hydroxymethylcyclobutane-1,1-dicarboxylic acid diethyl ester 45.0 g. It was

IR (neat) cm ⁻¹ : 3452, 1728, 1266; ¹ H-NMR (CDCl ₃ ) δ: 1.25 (t, 3H, J =
7Hz), 1.27 (t, 3H, J = 7Hz), 1.70 (br
s, 1H), 2.30-2.50 (m, 2H), 2.50-2.70
(M, 3H), 3.62 (d, 2H, J = 5.5 Hz), 4.20
(Q, 2H, J = 7Hz), 4.23 (q, 2H, J = 7Hz)

3-Hydroxymethylcyclobutane-1,1-dicarboxylic acid diethyl ester 45.0 obtained in the preceding paragraph
Under ice cooling, 48.5 g of p-toluenesulfonyl chloride was added to the mixture of g and pyridine (350 ml) in four portions. 5.5 at the same temperature
After stirring at room temperature for 13.5 hours and at 30-40 ° C for 8 hours, ice water was added and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate, water, dilute hydrochloric acid and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of 3-p-toluenesulfonyloxymethylcyclobutane-1,1-dicarboxylic acid diethyl ester.

A mixture of the above crude product, benzylamine (42.2 g), potassium carbonate (32.4 g) and dioxane (600 ml) was added.
Refluxed for 4.5 days. Ice water was added to the reaction solution, and the mixture was extracted with chloroform, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent chloroform: ethanol = 20: 1) to obtain 32.3 g of 3-benzylaminomethylcyclobutane-1,1-dicarboxylic acid diethyl ester. It was

IR (neat) cm ⁻¹ : 3324, 2813, 1727,
1263; ¹ H-NMR (CDCl ₃ ) δ: 1.23 (t, 3H, J =
7Hz), 1.25 (t, 3H, J = 7Hz), 2.15-2.30
(M, 2H), 2.40-2.70 (m, 3H), 2.67 (d, 2)
H, J = 6 Hz), 3.76 (s, 2H), 4.17 (q, 2H,
J = 7Hz), 4.21 (q, 2H, J = 7Hz), 7.20-7.40
(M, 5H)

(5) A mixture of 32.3 g of 3-benzylaminomethylcyclobutane-1,1-dicarboxylic acid diethyl ester obtained in the preceding section, 120 ml of 10% aqueous sodium hydroxide solution and 120 ml of tetrahydrofuran was added at room temperature for 13.5 hours and then The mixture was stirred at 50-60 ° C for 6 hours. The mixture was concentrated under reduced pressure, 100 ml of water and activated carbon were added, and the mixture was filtered. 54.5 ml of 20% hydrochloric acid water was added to the filtrate at room temperature with stirring. After cooling with ice, the crystals were collected by filtration and washed with water and ethanol to obtain 20 g of 3-benzylaminomethylcyclobutane-1,1-dicarboxylic acid.

Melting point: 224-226 ° C. (decomposition); IR (KBr) cm ⁻¹ : 3444, 1632; ¹ H-NMR (DMSO-d ₆ ) δ: 2.10-2.26
(M, 2H), 2.30-2.45 (m, 2H), 2.65-2.95
(M, 1H), 3.02 (d, 2H, J = 7Hz), 4.11
(S, 2H), 7.35-7.55 (m, 5H), 9.00 (br
s, 2H)

(6) 20 g of the compound obtained in the preceding paragraph and N,
To a mixture consisting of 200 ml of N-dimethylformamide, 37 g of carbonyldiimidazole was added, and the mixture was allowed to stand at room temperature for 13 hours at
The mixture was stirred at 40 ° C for 5.5 hours and at 60 to 70 ° C for 4 hours. The solvent was distilled off under reduced pressure, and diluted hydrochloric acid was added to the residue to adjust the pH to 2. It was extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, diisopropyl ether-n-hexane (2: 1) was added to the residue, and the precipitated crystals were collected by filtration to give 3-benzyl-2-oxo-3-azabicyclo [3.1.1] heptane- 15.5 g of 1-carboxylic acid was obtained.

Melting point: 127-128 ° C. (recrystallized from ethyl acetate); IR (KBr) cm ⁻¹ : 2531, 1750, 1732; ¹ H-NMR (CDCl ₃ ) δ: 1.85-2.00 (m, 2
H), 2.70-2.84 (m, 1H), 2.84-2.97 (m, 2
H), 3.44 (d, 2H, J = 2Hz), 4.65 (s, 2)
H), 7.20-7.45 (m, 5H)

(7) A mixture of 15.5 g of the compound obtained in the preceding paragraph, 9.6 g of triethylamine and 150 ml of t-butanol was heated to 70 ° C., and 26 g of diphenylphosphoryl azide was added dropwise. The reaction was refluxed for 15 hours. The mixture was concentrated under reduced pressure, ice water was added to the residue, and the mixture was extracted with ethyl acetate.
The extract was washed with a dilute aqueous solution of sodium hydroxide and then with saturated saline and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (eluent chloroform: ethanol = 50: 1), and the residue was purified by 3
-Benzyl-1-t-butoxycarbonylamino-3-
Azabicyclo [3.1.1] heptan-2-one 14.6g
I got

Melting point: 106-107 ° C. (recrystallized from methylene chloride-diisopropyl ether); IR (KBr) cm ⁻¹ : 3402, 1723, 1646; ¹ H-NMR (CDCl ₃ ) δ: 1.45 (s, 9H). ， 1.7
0-1.83 (m, 2H), 2.56 (tt, 1H, J = 2.5,
7Hz), 3.10-3.35 (m, 2H), 3.25 (d, 2H, J
= 2.5Hz), 4.60 (s, 2H), 6.22 (br s, 1)
H), 7.20-7.40 (m, 5H)

(8) Compound obtained in the previous section 6.07 g, 10
A mixture consisting of 12% aqueous hydrochloric acid (12 ml) and tetrahydrofuran (6 ml) was heated at 50-60 ° C for 3 hours. The mixture was concentrated under reduced pressure, a small amount of water was added to the residue, and the mixture was washed with n-hexane. The aqueous layer was made alkaline with aqueous sodium hydroxide solution and extracted with chloroform. The extract was washed with saturated saline and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and 1-amino-3-benzyl-3-azabicyclo [3.1.1] heptane-2-
Obtained 4.09 g of on.

IR (neat) cm ⁻¹ : 3381, 1659, 1495,
1250; ¹ H-NMR (CDCl ₃ ) δ: 1.85-2.00 (m, 2
H), 1.90 (s, 2H), 2.10-2.25 (m, 2H), 2.
54 (tt, 1H, J = 2.5, 7Hz), 3.26 (d, 2H,
J = 2.5Hz), 4.60 (s, 2H), 7.20-7.40 (m, 5)
H)

(9) A 1.0 M solution of borane-tetrahydrofuran complex in tetrahydrofuran was added to a mixture of 2.1 g of the compound obtained above and 25 ml of tetrahydrofuran.
30 ml was added. After refluxing for 7 hours, the mixture was concentrated under reduced pressure. 40 ml of ethanol was added to the residue and refluxed for 9 hours. The mixture was concentrated under reduced pressure, ice water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was distilled using a Kugelrohr microdistillation apparatus to obtain 1.86 g of 1-amino-3-benzyl-3-azabicyclo [3.1.1] heptane.

Boiling point: about 100 ° C. (3 mmHg); IR (neat) cm ⁻¹ : 3360, 2791, 1603; ¹ H-NMR (CDCl ₃ ) δ: 1.51 (br s, 2)
H), 1.60-1.90 (m, 4H), 2.18 (tt, 1H, J
= 3,6Hz), 2.65 (s, 2H), 2.69 (d, 2H, J
= 3Hz), 3.67 (s, 2H), 7.15-7.40 (m, 5H)

(10) 1.86 g of the compound obtained in the preceding paragraph was dissolved in 20 ml of ethanol, 190 mg of 5% palladium carbon was added, and a theoretical amount of hydrogen was added. The catalyst was filtered off and the solvent was distilled off under reduced pressure to obtain 1.0 g of the desired product.

Example B-8 : Preparation of amines-: 9-methylene-1,7-diazaspiro [4.4] nonane dihydrochloride

(1) 300 g of 2,3-dibromopropene,
A mixture of 245.3 g of 3,4-dimethoxybenzylamine, 503.7 g of triethylamine and 3000 ml of toluene was heated under reflux for 45 minutes, cooled, water and acetic acid water were added, and the mixture was extracted with ethyl acetate and washed with water. After drying over anhydrous sodium sulfate, the solvent was evaporated and the residue was purified by silica gel column chromatography (eluent chloroform) to obtain 120 g of 2-bromo-3- (3,4-dimethoxybenzylamino) propene. IR (neat) cm ⁻¹ : 2934, 2833, 1516

(2) N- (t-butoxycarbonyl)
-L-proline 73.8 g, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC)
A mixture of 108 g of the compound obtained in the preceding paragraph and 100 ml of dichloromethane was added dropwise to a mixture of 72.4 g and 1000 ml of dichloromethane under ice-cooling over 20 minutes, followed by stirring at room temperature for 20 hours, adding water thereto, and then adding dichloromethane. It was extracted by. After drying over anhydrous sodium sulfate, the solvent was evaporated, the residue was purified by silica gel column chromatography (eluent chloroform), and N- (2-bromopropenyl) -N- (3,4-dimethoxybenzyl).
-1- (t-butoxycarbonyl) prolinamide 14
9 g were obtained. IR (neat) cm ⁻¹ : 2974, 1697

(3) A mixture of 67.7 g of the compound obtained in the previous section and 800 ml of toluene was added with 0.5 N- under ice cooling.
Toluene solution of potassium hexamethyldisilazane 800
ml was added dropwise over 20 minutes, and the mixture was stirred at the same temperature for 90 minutes. Water and acetic acid water were added thereto, and the mixture was extracted with ethyl acetate.
After washing with a saturated saline solution, it was dried with anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: chloroform) to obtain 1- (t-butoxycarbonyl) -7- (3.4. 29.3 g of -dimethoxybenzyl) -9-methylene-6-oxo-1,7-diazaspiro [4.4] nonane was obtained.

IR (neat) cm ⁻¹ : 2971,169
2; MS (m / z): = 403 (MH ⁺ ).

(4) To a mixture of 20 g of the compound obtained in the preceding paragraph and 500 ml of dichloromethane, 100 ml of trifluoroacetic acid was added dropwise over 10 minutes under ice cooling, and the mixture was stirred at room temperature for 16 hours. Water and an aqueous sodium hydroxide solution were added to this, and the mixture was extracted with dichloromethane. After drying over anhydrous sodium sulfate, the solvent was evaporated and the residue was purified by silica gel column chromatography (eluent chloroform) to give 7- (3,4-dimethoxybenzyl)-.
10.6 g of 9-methylene-6-oxo-1,7-diazaspiro [4.4] nonane was obtained.

IR (neat) cm ^-1 : 2959,169
9; MS (m / z): 303 (MH ⁺ ).

(5) To a mixture consisting of 10.6 g of the compound obtained in the preceding paragraph and 200 ml of toluene, 20.5 ml of a 70% toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride in toluene was added dropwise over 5 minutes under ice cooling. ,
Stirred at room temperature for 5 hours. Brine and aqueous sodium hydroxide solution were added thereto, and the mixture was extracted with ethyl acetate. After washing with a saturated saline solution, it was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent chloroform) to give 7- (3,4-dimethoxybenzyl) -9-methylene-1,7-diazaspiro [4.4] nonane (7.8 g).

IR (neat) cm ⁻¹ : 2953, 151
6; MS (m / z): 289 (MH ⁺ ).

(6) A mixture consisting of 0.23 g of the compound obtained in the preceding paragraph, 0.57 g of 1-chloroethyl chloroformate and 10 ml of 1,2-dichloroethane was heated under reflux for 2 hours, and the solvent was distilled off. 10 ml of methanol was added to the residue, and the mixture was heated under reflux for 1 hour and the solvent was distilled off to give the desired 9-methylene-
0.17 g of 1,7-diazaspiro [4.4] nonane dihydrochloride
I got This compound was used as a starting material for producing compound 6F-6 described below.

IR (neat) cm ⁻¹ : 3400, 291
7,1631; MS (m / z) : 139 (MH +); 1 H-NMR (DMSO-d 6) δ: 1.8 -2.1
(M, 4H), 3.0-3.3 (m, 4H), 3.6.-3.9
(M, 2H) 5.26 (t, 1H, J = 2Hz), 5.43
(T, 1H, J = 2Hz)

Example B-9 : Preparation of amines-: 3-hydroxy-3-trifluoromethylpyrrolidine

(1) 1-benzyl-3-pyrrolidone 1
4.5 g of tetrahydrofuran 150 ml, tetra-n-
0.92 ml of a 1 M tetrahydrofuran solution of butylammonium fluoride was added. 16.5 g of trimethylsilyltrifluoromethane was added to the mixture under ice cooling, and the mixture was stirred for 30 minutes. The reaction solution was brought to room temperature and further stirred for 3 hours. 1M of tetra-n-butylammonium fluoride
-Add 30 ml of a tetrahydrofuran solution and add 4 at room temperature.
Stirred for hours. After completion of the reaction, water and ethyl acetate were added for extraction. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent chloroform) to obtain 13.3 g of 1-benzyl-3-hydroxy-3-trifluoromethylpyrrolidine. Melting point 60-61 ° C

(2) To 1.0 g of the compound obtained in the preceding paragraph, 15 ml of ethanol and 100 mg of 10% palladium carbon were added, and a theoretical amount of hydrogen was absorbed at 60 ° C. The catalyst was filtered off and the solvent was evaporated to dryness under reduced pressure to obtain 630 mg of the desired amine.

Example B-10 : Preparation of Amines-
-: (1R, 5S, 8R) -8- (tert-butoxycarbonylamino) -2-oxa-6-azabicyclo [3.3.
0] Octane

(1) J. Org. Che from D-tartaric acid as a raw material
m. 60 , 103-108 (1995).
S, 4R, 5S) -1-benzyl-3,4-bis (tert
-Butyldimethylsilyloxy) -5- (2-hydroxyethyl) -2-pyrrolidinone 125.5 g 60% acetic acid water 1200
ml was added and refluxed overnight. After concentration under reduced pressure, 300 ml of concentrated aqueous ammonia and 500 ml of methanol were added to the residue, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent chloroform: methanol = 10: 1) to give (3S, 4R, 5S) -1.
35 g of -benzyl-3,4-dihydroxy-5- (2-hydroxyethyl) -2-pyrrolidinone were obtained.

IR (neat) 3370, 1682 cm ^-1 ; MS (m / z): 252 (MH ⁺ ).

¹ H-NMR (CDCl ₃ ) δ: 7.10-7.32 (m, 5H), 5.
52 (br s, 2H), 4.90 (d, 1H, J = 15.0Hz), 4.50 (d, 1H, J
= 7.5Hz), 4.21 (br t, 1H, J = 7.5Hz), 3.94 (d, 1H, J = 1
5.0Hz), 3.55 (br s, 3H), 2.20-2.00 (br s, 1H), 1.86 (b
rs, 2H)

(2) 35 g of the compound obtained in the previous section was added to pyridine 40
In addition to 0 ml, 26.6 g of p-toluenesulfonyl chloride was added to the mixture after cooling with ice, and the mixture was stirred overnight. Water in the reaction solution,
After adding chloroform to extract the product into the organic layer, 10
% Aqueous hydrochloric acid, and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure to give an oily (1R, 5S, 8S) -6-
Benzyl-8-hydroxy-7-oxo-2-oxa-
24 g of 6-azabicyclo [3.3.0] octane was obtained.

IR (neat): 3390, 1692 cm ^-1 ; MS m / z: 234 (MH ⁺ ).

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.18 (m, 5H), 4.
84 (d, 1H, J = 15.0Hz), 4.49 (br, 1H), 4.42 (dd, 1H, J =
6.5, 1.7Hz), 4.32 (br, 1H), 4.16-4.06 (m, 2H), 3.92-
3.66 (m, 2H), 1.92-1.82 (m, 2H)

(3) 14 g of the compound obtained in the preceding paragraph was added to 250 ml of methylene chloride, and 14.6 ml of pyridine was added to the mixture when cooled with ice, and then slowly added to trifluoromethanesulfonic anhydride.
13.1 ml was added. After 2 hours, 550 ml of dimethylformamide and 58.9 g of potassium acetate were added to the reaction solution, and the mixture was stirred overnight. Insoluble matter was filtered, water and chloroform were added to the residue obtained by concentration under reduced pressure, and the product was extracted into an organic layer.
The solvent was removed under reduced pressure to give crude (1R, 5S, 8S) -8.
-Acetoxy-6-benzyl-7-oxo-2-oxa-6-azabicyclo [3.3.0] octane was obtained.

To this compound were added 500 ml of etal and 200 ml of concentrated aqueous ammonia, the mixture was stirred at room temperature overnight, and concentrated under reduced pressure.
Water and chloroform were added to the residue, the product was extracted into an organic layer, the solvent was evaporated under reduced pressure, and silica gel column chromatography (eluent chloroform: methanol = 30:
Purified in 1) and (1R, 5S, 8R) -6-benzyl-
9.2 g of 8-hydroxy-7-oxo-2-oxa-6-azabicyclo [3.3.0] octane was obtained.

IR (neat): 3381, 1694 cm ^-1 ; MS m / z: 234 (MH ⁺ ).

¹ H-NMR (CDCl ₃ ) δ: 7.40-7.20 (m, 5H), 4.
93 (d, 1H, J = 15.0Hz), 4.50 (dd, 1H, J = 6.0, 5.0Hz), 4.
28 (d, 1H, J = 6.0Hz), 4.09 (d, 1H, J = 15.0Hz), 4.08-3.
93 (m, 2H), 3.80-3.66 (m, 1H), 3.22 (br s, 1H), 2.24-
2.11 (m, 1H), 2.01-1.81 (m, 1H)

(4) 9.2 g of the compound obtained in the preceding paragraph was added to 100 ml of methylene chloride, and 9.5 ml of pyridine was added to the mixture when ice-cooled, and then trifluoromethanesulfonic anhydride was slowly added.
9.1 ml was added. After 2 hours, 300 ml of dimethylformamide and 24.4 g of sodium azide were added to the reaction solution, and the mixture was stirred overnight. Water and chloroform were added to the residue obtained by concentration under reduced pressure, and the product was extracted into the organic layer. After washing with dilute hydrochloric acid and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and (1R, 5S, 8S) -8-azido-6-benzyl-7-oxo-2-oxa-6-azabicyclo [3 ．
3.0] Octane (7.4 g) was obtained.

IR (neat): 2109, 1694 cm ^-1 ; ¹ H-NMR (CDCl ₃ ) δ: 7.40-7.20 (m, 5H), 4.93 (d, 1H, J =
15.0Hz), 4.23 (dd, 1H, J = 6.0, 1.5Hz), 4.16-4.02 (m, 3
H), 3.94-3.82 (m, 1H), 3.81-3.67 (m, 1H), 2.00-1.80
(m, 2H)

(5) 7.4 g of the compound obtained in the preceding paragraph was added to 300 ml of tetrahydrofuran, and when cooled with ice, 116 ml of a 1.0 mol solution of borane-tetrahydrofuran complex-tetrahydrofuran was added. Heated after 30 minutes and refluxed overnight. The reaction was cooled to room temperature and excess borane was treated with ethanol. After concentration under reduced pressure, 600 ml of ethanol was added to the residue, and the mixture was refluxed overnight. After concentration under reduced pressure, 10% aqueous hydrochloric acid was added to the residue, the product was extracted into the aqueous layer, and washed with chloroform. 20% NaOH
It was made alkaline with water and then extracted with chloroform. It was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure (1
5.5 g of S, 5S, 8R) -8-Amino-6-benzyl-2-oxa-6-azabicyclo [3.3.0] octane was obtained.

Subsequently, this compound was added to 100 ml of methanol and cooled with ice, 7.2 g of dicarbonic acid-di-tert-butyl was added thereto, and the mixture was stirred overnight. The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography (eluent n-hexane: ethyl acetate = 6: 1) to give (1S, 5S, 8R) -6-benzyl-8- (tert-butoxycarbonylamino). ) -2
-Oxa-6-azabicyclo [3.3.0] octane 7.
0 g was obtained.

Melting point 115-116 ° C. (recrystallized from ethyl acetate); [α] _D ²⁷ + 2.3 ° (c = 1.023, methanol)

(6) Using 5.4 g of the compound obtained in the preceding section with ethanol
Dissolve in 100 ml, add 5% palladium on carbon 350 mg, add 40
The theoretical amount of hydrogen was taken up at ° C. The catalyst was filtered off, the solvent was evaporated under reduced pressure, and the obtained crude crystals were recrystallized from ethyl ether-diisopropyl ether to give the final target product (1R, 5S, 8R) -8- (tert-butoxycarbonyl). Amino) -2-oxa-6-azabicyclo [3.3.
0] Octane 3.5 g was obtained.

Melting point 110-111 ° C; IR (KBr): 3377, 3228, 1680 cm ^-1 ; [α] _D ²⁹ -44.4 ° (c = 1.026, methanol)

Series C : Method for producing target product

Example C-1 : -Production of Target (I)-
-: 1,4-dihydro-7- (trans-3-methoxy-4
-Methylamino-1-pyrrolidinyl) -4-oxo-1
-(2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid (racemic form) and related compounds

(1) Ethyl 7-chloro-1,4-dihydro-4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylate obtained in Example A-1 (4). Ester (7.1 g) and trans-3-methoxy-4-
Triethylamine (18 ml) was added to a suspension consisting of methylaminopyrrolidine dihydrochloride (6.0 g) and acetonitrile (150 ml). The mixture was stirred at room temperature for 5 hours, the reaction mixture was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent chloroform: methanol = 6: 1) to give 1,4-dihydro-7- (. Trans-3-methoxy-4-methylamino-
1-Pyrrolidinyl) -4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester (6.1 g) was obtained. Melting point: 73-76 ° C

(2) The above ester (6.0 g) and 1
A solution consisting of 8% aqueous hydrochloric acid (100 ml) was stirred at 100 ° C. for 28 hours. The precipitated crystals were collected by filtration, washed with a mixed solution of ethanol and diisopropyl ether, and 4.45 g of 1,4-dihydro-7- (trans-3-methoxy-4).
-Methylamino-1-pyrrolidinyl) -4-oxo-1
There was obtained-(2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid hydrochloride (Compound H-1-1-1) (4.45 g). Melting point: 270-273 ° C

(3) Hydrochloride obtained in (2) above (51.5
g), water (500 ml) and aqueous ammonia (40 ml)
The solution consisting of was stirred at 50 ° C. overnight. Acetonitrile was added thereto, the mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The obtained crystals were washed with water and acetonitrile to give 32.6 g of 1,4-dihydro-7- (trans-3-methoxy-4.
-Methylamino-1-pyrrolidinyl) -4-oxo-1
There was obtained-(2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid (Compound H-1-1-0). Melting point: 290-292 ° C (decomposition)

(4) Compound (2.0) obtained in the above item (3)
A mixture consisting of g), lactic acid (3.1 g) and distilled water (4 ml) was dissolved by heating at 60 ° C. After cooling to room temperature, ethanol (70 ml) was added, and the precipitated crystals were collected by filtration and washed with ethanol to obtain 2 g of lactate salt (Compound H-1-1-2). Melting point: 288-291 ° C (decomposition)

(5) The ester (1.89) obtained in the above item (1)
g), Nt-butoxycarbonyl-L-alanine (1.
1.27 g of WSC was added to a mixture of 26 g) and methylene chloride (80 ml), and the mixture was stirred at room temperature for 3 hours. After washing with water, it was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purified by silica gel column chromatography (eluent chloroform: methanol = 50: 1) to give 7- {trans-3- [N- (Nt-butoxycarbonyl-L-
Alanyl)] methylamino-4-methoxy-1-pyrrolidinyl} -1,4-dihydro-4-oxo-1- (2-
Thiazolyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester (2.15 g) was obtained.

Melting point: 120-123 ° C .; [α] _D ²⁸ + 10.2 ° (c = 1.0, chloroform)

A mixture of this ethyl ester (1.71 g), 0.5 N aqueous hydrochloric acid (42 ml) and ethanol (22 ml) was heated with stirring at 80 ° C. for 17.5 hours. The solution was concentrated under reduced pressure, the precipitated crystals were collected by filtration, washed with 10% aqueous hydrochloric acid and ethanol, and then 7- [trans-3- (N-L-alanylmethylamino) -4-methoxy-1-pyrrolidinyl].
-1,4-Dihydro-4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid hydrochloride 1.
16 g were obtained.

Melting point: 230-233 ° C .; [α] _D ²⁹ + 8.4 ° (c = 1.0, water)

Example C-2 : -Production of Target (I)-
-: (+)-1,4-dihydro-7- (trans-3-methoxy-4-methylamino-1-pyrrolidinyl) -4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3 -Carboxylic acid (optically active substance) and related compounds

(1) Ethyl 7-chloro-1,4-dihydro-4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylate obtained in Example A-1 (4). The ester and the (+)-trans-3 obtained in Example B-2.
-(Nt-butoxycarbonylmethylamino) -4-
(-)-7- [trans-3- (Nt-butoxycarbonylmethylamino) -4-methoxy-1-pyrrolidinyl] -1, using methoxypyrrolidine in the same manner as in Example C-1 (1). 4-dihydro-4-oxo-1- (2
-Thiazolyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester (non-crystalline substance) was obtained. [Α] _D ²⁹ −9.1 ° (c = 1.006, chloroform)

(2) According to the method described in Example C-1 (2), the title hydrochloride (Compound H-1-2) was obtained from the ethyl ester derivative obtained in the above (1).

Melting point: 278-282 ° C. (decomposition); [α] _D ²⁹ + 24.8 ° (c = 0.500, water)

(3) The hydrochloride salt (28.1) obtained in (2) above.
g), water (300 ml) and aqueous ammonia (25 ml)
Was stirred overnight at 50 ° C. and then concentrated under reduced pressure. The precipitated crystals were collected by filtration, washed with water and ethanol, and the desired carboxylic acid compound (Compound H-1-2-1) (19.5
g) was obtained.

Melting point: 268-271 ° C .; [α] _D ³⁰ + 53.1 ° (c = 1.005, 1N NaOH)

(4) Carboxylic acid derivative obtained in the above item (3)
Dissolve 6.22 g in 150 ml of distilled water and add 1.00 under ice cooling.
14.8 ml of 2N-sodium hydroxide aqueous solution was added, and the mixture was immediately stirred for 10 minutes. The solvent was distilled off under reduced pressure, acetonitrile and diisopropyl ether were added to the residue, and the precipitated crystals were collected by filtration to obtain the desired sodium salt (compound H-1
-2-2) 6.28 g was obtained. Melting point: 189-190 ° C (decomposition)

(5) The compound (300) obtained in the above (3)
Methanesulfonic acid (140 mg) was added to a suspension consisting of (mg) and water (1.2 ml), and dissolved by heating at 60 ° C. It was filtered while hot and the filtrate was cooled at room temperature. Add acetone (1
0 ml) was added, and the precipitated crystals were collected by filtration and washed with acetone to give the methanesulfonate of the title compound (Compound H-1-2).
-3) was obtained.

Melting point: 283-285 ° C. (decomposition); [α] _D ²⁸ + 46.9 ° (c = 1.00, 1N NaOH)

(6) The lactate salt of the title compound (Compound H-1-2-4) was obtained from the compound obtained in (3) above according to the method described in Example C-1 (4).

Melting point: 273-275 ° C. (decomposition); [α] _D ²⁷ + 44.7 ° (c = 1.00, 1N NaOH)

(7) Compound (350) obtained in the above (3)
mg) and gluconic acid (about 50%, 1.1 g) in water (1
It melt | dissolved by heating (60 degreeC) in (ml). After allowing to cool, acetone (100 ml) was added, and the precipitated solid was recrystallized from water-methanol, and the precipitated crystal was collected by filtration and washed with methanol to give the gluconate salt of the title compound (Compound H-1-2-5. )
I got

Melting point: 129-132 ° C. [α] _D ²⁸ + 36.7 ° (c = 0.36, 1N NaOH)

(8) The compound obtained in (1) above was treated with hydrochloric acid-
Treated with ethanol (30%) to give (-)-1,4-dihydro-7- (trans-3-methoxy-4-methylamino-1-pyrrolidinyl) -4-oxo-1- (2-thiazolyl). -1,8-Naphthyridine-3-carboxylic acid ethyl ester (Compound H-1-2-6) was obtained.

Melting point: 184-185 ° C .; [α] _D ²⁸ -16.9 ° (c = 0.503, chloroform)

Example C-3 : -Production of Target (I)-
-: (-)-1,4-dihydro-7- (trans-3-methoxy-4-methylamino-1-pyrrolidinyl) -4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3 -Carboxylic acid (optically active substance) and its salt

(1) Ethyl 7-chloro-1,4-dihydro-4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylate obtained in Example A-1 (4). The ester and (-)-trans-3 obtained in Example B-3.
-(Nt-butoxycarbonylmethylamino) -4-
(+)-7- [trans-3- (Nt-butoxycarbonylmethylamino) -4-methoxy-1-pyrrolidinyl] -1, using methoxypyrrolidine in the same manner as in Example C-1 (1). 4-dihydro-4-oxo-1- (2
-Thiazolyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester (non-crystalline substance) was obtained. [Α] _D ²⁹ + 9.0 ° (c = 1.002, chloroform)

(2) According to the method described in Example C-1 (2), the hydrochloride of the title compound (Compound H-1-3) was obtained from the ethyl ester derivative obtained in the above (1).

Melting point: 278-282 ° C. (decomposition); [α] _D ²⁹ −25.2 ° (c = 0.504, water)

(3) According to the method described in Example C-2 (3), the desired carboxylic acid compound (Compound H-1-3-1) was obtained from the compound obtained in (2) above.

Melting point: 277-279 ° C. (decomposition); [α] _D ²⁹ -59.9 ° (c = 1.00, 1N NaOH)

(4) According to the method described in Example C-2 (5), the methanesulfonate of the title compound (Compound H-1-3-2) was obtained from the compound obtained in (3) above. It was

Melting point: 287-289 ° C. (decomposition); [α] _D ³⁰ −47.2 ° (c = 1.00, 1N NaOH)

Example C-4 : -Production of Target (I)-
-: 1,4-dihydro-7- (cis-3-methoxy-4-methylamino-1-pyrrolidinyl) -4-oxo-1-
(2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid and related compounds

(1) Ethyl 7-chloro-1,4-dihydro-4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylate obtained in Example A-1 (4). Using an ester and cis-3-methoxy-4-methylaminopyrrolidine, in the same manner as in Example C-1 (1)
4-dihydro-7- (cis-3-methoxy-4-methylamino-1-pyrrolidinyl) -4-oxo-1- (2-
Thiazolyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester was obtained. Melting point 253-259 ° C (decomposition)

(2) According to the method described in Example C-1 (2), the hydrochloride of the title compound (Compound H-1-4) was obtained from the ethyl ester derivative obtained in the above (1). Melting point: 263-269 ° C (decomposition)

Example C-5 : -Production of Target (I)-: 7- (3-Amino-1-pyrrolidinyl) -6-fluoro-1,4-dihydro-4-oxo-1- ( 2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid hydrochloride (Compound 2F-1)

(1) 7-Chloro-6-fluoro-1,4-dihydro-4-oxo-1-obtained in Example A (6)
A mixture of 6.5 g of ethyl (2-thiazolyl) -1,8-naphthyridine-3-carboxylate, 1.7 g of 3-aminopyrrolidine, 5.6 g of triethylamine and 65 ml of acetonitrile was heated under reflux for 30 minutes. After cooling, the crystals were collected by filtration and recrystallized from ethanol to give 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1,4-dihydro-4-oxo-1- (2-thiazolyl). ) -1,8-Naphthyridine-3-carboxylic acid ethyl ester (ester of compound 2F-1) (7.1 g) was obtained. Melting point: 218-220 ° C.

(2) A mixture of 7.1 g of the above ester and 200 ml of 10% aqueous hydrochloric acid was heated under reflux for 1 hour. After cooling, the crystals were collected by filtration and recrystallized from water-ethanol to give 6.9 g.
7- (3-amino-1-pyrrolidinyl) -6-fluoro-1,4-dihydro-4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid hydrochloride (compound 2F -1) was obtained. Melting point: 294-296 ° C (decomposition)

(3) The above hydrochloride was treated according to a conventional method to give 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1,4-dihydro-4-oxo-1- (2-thiazolyl)-. 1,8-naphthyridine-3-carboxylic acid (free form of compound 2F-1) was obtained. Melting point: 253-254 ° C (decomposition)

(4) Using (R) -3-aminopyrrolidine, the reaction and treatment were carried out in the same manner as described above to obtain the following compound.

7-[(R) -3-Amino-1-pyrrolidinyl] -6-fluoro-1,4-dihydro-4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3
-Carboxylic acid ethyl ester; Melting point: 254-257 ° C

7-[(R) -3-Amino-1-pyrrolidinyl] -6-fluoro-1,4-dihydro-4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3
-Carboxylic acid hydrochloride (Compound 2F-1-1)

Melting point: 297-300 ° C. (decomposition); [α] _D ²⁸ = -21.0 ^O (1N NaOH, c = 0.1)

(5) Using (S) -3-aminopyrrolidine, the same reaction and treatment as above were carried out to obtain the following compound.

7-[(S) -3-Amino-1-pyrrolidinyl] -6-fluoro-1,4-dihydro-4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3
-Carboxylic acid ethyl ester; Melting point: 256-259 ° C

7-[(S) -3-Amino-1-pyrrolidinyl] -6-fluoro-1,4-dihydro-4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3
-Carboxylic acid hydrochloride (Compound 2F-1-2)

Melting point:> 300 ° C .; [α] _D ²⁸ = + 20.0 ^O (1N NaOH, c = 0.1)

(6) 7- [3- (N-L-alanylamino) -1-pyrrolidinyl] -6-fluoro-1,4-dihydro-4- according to the description in Example C-1 (5). Oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid hydrochloride (Compound 2F-1-3) was obtained. Melting point: 236-239 ° C.

Example C-6 ; -Production of Target (I)-
-: By the method described in Examples C-1 to C-5 or a method analogous thereto, the compounds and their ethyl esters shown in Tables 15 to 21 below were obtained.

Table 15 Target compound (I)

[0413]

Embedded image

[0414]

[Table 30] *: 1 = HCl, 2 = 1/2 HCl, 3 = 1/5 HCl **: (min) indicates a decomposition point. The same applies hereinafter.

[0415]

[Table 31] *: 1 = HCl

[0416]

[Table 32] *: "-" = Free form, 1 = HCl

Table 16 Target compound (I)

Embedded image

[0418]

[Table 33] *: 1 = HCl

[0419]

[Table 34] *: "-" = Free form, 1 = HCl

[0420]

[Table 35] *: "-" = Free form, 1 = HCl

[0421]

[Table 36] *: "-" = Free form, 1 = HCl

[0422]

[Table 37] *: “−” = Free form, 1 = HCl, 4 = 1/2 H ₂ SO ₄

[0423]

[Table 38] *: "-" = Free form, 1 = HCl

[0424]

Embedded image

Table 17 Target compound (I)

[0426]

Embedded image

[0427]

[Table 39] *: "-" = Free form, 1 = HCl

Table 18 Target compound (I)

[0429]

Embedded image

[0430]

[Table 40] *: “−” = Free form, 1 = HCl, 4 = 1/2 H ₂ SO ₄

[0431]

[Table 41] *: "-" = Free form, 1 = HCl, **: 3-position ethyl ester form

Table 19 Target compound (I)

[0433]

[Table 42]

[0434]

[Table 43] Continuation of Table 19

Table 20 Target compound (I)

[0436]

[Table 44]

[0437]

[Table 45] Continuation of Table 20

[0438]

[Table 46] Continuation of Table 20

Table 21 Target compound (I)

[0440]

Embedded image

[0441]

[Table 47] *: Measured in water (c = 0.1). **: Measured in DMSO (c = 0.1).

[0442]

[Table 48] *: Measured in water (c = 0.1). **: dihydrochloride.

[0443]

[Table 49] *: Measured in water (c = 0.1). **: Measured in water (c = 0.5).

Example C-7 : -Production of Target (I)-
-: 2- (3-Amino-1-pyrrolidinyl) -5,8-dihydro-5-oxo-8- (2-thiazolyl) pyrido [2,3-d] pyrimidine-6-carboxylic acid

5,8-Dihydro-2 obtained in Example A-7
-Methanesulfonyl-5-oxo-8- (2-thiazolyl) pyrido [2,3-d] pyrimidine-6-carboxylic acid ethyl ester and 3-aminopyrrolidine were prepared according to Example C-.
The reaction was carried out by a method similar to that of 1, and the title compound (9N
-1) was obtained. Melting point: 288-291 ° C (decomposition)

Example C-8 : -Production of Target (I)-
-: 3-formyl-1,4-dihydro-7- (trans-3
-Methoxy-4-methylamino-1-pyrrolidinyl)-
4-oxo-1- (2-thiazolyl) -1,8-naphthyridine hydrochloride (Compound 7H-1)

(1) Ethyl 7-chloro-1,4-dihydro-4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylate obtained in Example A-1 (4). Ester (8.49g), trans-3-methoxy-4-
Triethylamine (13.4 ml) was added to a suspension consisting of methylaminopyrrolidine dihydrochloride (6.5 g) and acetonitrile (400 ml). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Methylene chloride (500 ml) was added to the obtained residue, and di-t-butyl dicarbonate (6.4 g) was added under ice cooling. After stirring overnight at room temperature,
The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent chloroform: methanol = 100: 1) to give 7- [trans-3- (N-
t-Butoxycarbonylmethylamino) -4-methoxy-1-pyrrolidinyl] -1,4-dihydro-4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3
-Carboxylic acid ethyl ester (9.1 g) was obtained.

IR (KBr) cm ^-1 : 1735,169
5; MS (m / z): 530 (MH ⁺ ).

(2) Compound (8.95) obtained in the above item (1)
g) and ethanol (150 ml) under ice cooling, 1N
Aqueous sodium hydroxide solution (150 ml) was added, and the mixture was stirred at the same temperature for 30 minutes and at room temperature overnight. Made acidic with acetic acid water,
Extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 7- [trans-3- (Nt-butoxycarbonylmethylamino) -4-methoxy-1-pyrrolidinyl] -1, 4-dihydro-4-oxo-1- (2-thiazolyl) -1,8
-Naphthyridine-3-carboxylic acid (7.19g) was obtained.

Melting point 185-188 ° C .; IR (KBr) cm ⁻¹ : 1715,1690; MS (m / z): 502 (MH ⁺ ).

(3) The compound (7.15) obtained in (2) above.
To a mixture of g) and methanol (400 ml) was added sodium borohydride (2.16 g) under ice cooling, and the mixture was stirred at the same temperature for 15 minutes and at room temperature overnight. The solvent was distilled off under reduced pressure,
Then, it was extracted with chloroform. Washed with saturated saline,
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent chloroform: methanol = 100: 1) to give 7- [trans-3- (Nt-butoxycarbonylmethylamino) -4-methoxy-1-pyrrolidinyl]. −
1,2,3,4-tetrahydro-4-oxo-1- (2
-Thiazolyl) -1,8-naphthyridine (3.9 g) was obtained.

IR (neat) cm ^-1 : 1690; MS (m / z): 460 (MH ⁺ ).

(4) The compound (3.8
g) was dissolved in tetrahydrofuran (500 ml), and -7
A n-hexane solution (6.1 ml) of n-butyllithium (1.6 M) was added dropwise at 8 ° C. After stirring at the same temperature for 30 minutes,
Ethyl formate (1.34 ml) was added, the temperature was raised slowly, and the mixture was stirred overnight. The solvent was evaporated under reduced pressure, acetic acid water was added to the residue, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 7- [trans-3- (Nt-butoxycarbonylmethylamino).
-4-Methoxy-1-pyrrolidinyl] -3-formyl-
1,2,3,4-tetrahydro-4-oxo-1- (2
-Thiazolyl) -1,8-naphthyridine (3.87g) was obtained.

IR (neat) cm ^-1 : 1690,16
15; MS (m / z): 488 (MH ⁺ ).

(5) The compound obtained in the above (4) (3.6
g) was dissolved in 1,4-dioxane (160 ml),
3-Dichloro-5,6-dicyano-1,4-benzoquinone (2.51 g) was added slowly. After stirring for 2 hours, the solvent was evaporated under reduced pressure, aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent chloroform: methanol = 100: 1) to give 7- [trans- 3- (Nt-butoxycarbonylmethylamino) -4-methoxy-1-pyrrolidinyl] -3-formyl-1,4-dihydro-4-oxo-1- (2-thiazolyl) -1,8-naphthyridine ( 1.73 g) was obtained.

Melting point 130-132 ° C .; IR (KBr) cm ⁻¹ : 1695, 1645, 161
5; MS (m / z): 486 (MH ⁺ ).

(6) The compound (1.65) obtained in the above (5)
g) 10% aqueous hydrochloric acid (10 ml) and ethanol (4
0 ml) was heated at 50-60 ° C. for 7 hours. The precipitated crystals were collected by filtration, washed with ethanol and diisopropyl ether, and washed with 3-formyl-1,4-dihydro-7- (trans-3-methoxy-4-methylamino-
1-pyrrolidinyl) -4-oxo-1- (2-thiazolyl) -1,8-naphthyridine hydrochloride (Compound 7H-1)
(1.05 g) was obtained.

Melting point 255-263 ° C. (decomposition); IR (KBr) cm ⁻¹ : 3460, 1695, 164
5; MS (m / z): 386 (MH ⁺ ).

Example C-9 : -Production of Target (I)-
-: 1,2,3,4-tetrahydro-4-hydroxy-3-
Hydroxymethyl-7- (trans-3-methoxy-4
-Methylamino-1-pyrrolidinyl) -1- (2-thiazolyl) -1,8-naphthyridine (Compound 7H-2)

Under ice cooling, 4.90 g of 1,4-dihydro-
7- (trans-3-methoxy-4-methylamino-1
-Pyrrolidinyl) -4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester was dissolved in 150 ml of anhydrous tetrahydrofuran,
Lithium aluminum hydride (3.00 g) was added, and the mixture was stirred for 30 minutes and further stirred at room temperature overnight. The reaction solution was slowly added to water, and an ammonium chloride aqueous solution and a sodium hydrogen carbonate aqueous solution were sequentially added. This was extracted with chloroform, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent chloroform: methanol =
The target compound 7H-2 (1.60
g) was obtained. Melting point: 69-70 ° C

Example C-10 : -Preparation of target compound (I)-: 1,4-dihydro-7- (trans-3-methoxy-4)
-Methylamino-1-pyrrolidinyl) -4-oxo-1
-(2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid 2-hydroxyethyl ester 4/3 trifluoroacetic acid salt (Compound 7H-3)

(1) Under ice cooling, 1.00 g of 7- [trans-3- (Nt-butoxycarbonylmethylamino) -4-methoxy-1-pyrrolidinyl] -1,4-dihydro-4- Oxo-1- (2-thiazolyl) -1,8
-Naphthyridine-3-carboxylic acid 90m methylene chloride
Dissolved in 1 l, ethylene glycol 1.24g, WSC420
mg, 4-dimethylaminopyridine 50 mg and added 3
The mixture was stirred for 0 minutes and then at room temperature overnight. Add water,
This is extracted with chloroform, washed with saturated saline,
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent chloroform: methanol = 50: 1), 1,4
-Dihydro-7- [trans-3- (Nt-butoxycarbonylmethylamino) -4-methoxy-1-pyrrolidinyl] -4-oxo-1- (2-thiazolyl) -1,
8-Naphthyridine-3-carboxylic acid 2-hydroxyethyl ester (590 mg) was obtained. Melting point: 101-105 ° C

(2) 250 mg of the above compound was dissolved in 3 ml of methylene chloride, and trifluoroacetic acid was added under ice cooling.
1.0 ml was added, and the mixture was stirred for 1 hour and further stirred at room temperature overnight. Diisopropyl ether was added and the precipitated crystals were collected by filtration to obtain the target compound 7H-3 (150 mg). Melting point: 125-127 ° C

Example C-11 : -Production of Target (I)-: 1- [1,4-dihydro-7- (trans-3-methoxy-4-methylamino-1-pyrrolidinyl) -4 -Oxo-1- (2-thiazolyl) -1,8-naphthyridine-
3-Carbonyl] -3-hydroxypyrrolidine 3/2
Hydrochloride (Compound 7H-4)

(1) Under ice cooling, 250 mg of 7-
[Trans-3- (Nt-butoxycarbonylmethylamino) -4-methoxy-1-pyrrolidinyl] -1,4
-Dihydro-4-oxo-1- (2-thiazolyl)-
1,8-naphthyridine-3-carboxylic acid was dissolved in 20 ml of methylene chloride, and 52 m of 3-pyrrolidinol was added to the solution.
g, benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent) 265 mg and triethylamine 0.17
After adding ml, the mixture was stirred for 30 minutes, and further stirred at room temperature overnight. Water was added, and this was extracted with chloroform, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent chloroform: methanol = 20: 1), 1- {7- [trans-3- (Nt-butoxycarbonylmethylamino) -4-methoxy-1-pyrrolidinyl]. -1,4-dihydro-4-oxo-1- (2
-Thiazolyl) -1,8-naphthyridine-3-carbonyl} -3-hydroxypyrrolidine (280 mg) was obtained. Melting point: 127-129 ° C

(2) 275 mg of the above compound was dissolved in 5 ml of ethanol, and the mixture was cooled with ice to give 10% ethanol.
3.0 ml of hydrochloric acid was added, and the mixture was stirred for 1 hour and further stirred at room temperature overnight. Diisopropyl ether was added and the precipitated crystals were collected by filtration to obtain the target compound 7H-4 (163 mg). Melting point: 189-193 ° C (decomposition)

Example C-12 : -Preparation of target compound (I)-: 3-hydroxymethyl-1,4-dihydro-7- (trans-3-methoxy-4-methylamino-1-pyrrolidinyl) -4-oxo-1- (2-thiazolyl) -1,8
-Naphthyridine hydrochloride (compound 7H-5)

110 m obtained in Example C-8 under ice cooling.
g of 3-formyl-1,4-dihydro-7- (trans-3-methoxy-4-methylamino-1-pyrrolidinyl) -4-oxo-1- (2-thiazolyl) -1,8-
Dissolve naphthyridine hydrochloride in 30 ml of methanol,
Cerium chloride heptahydrate (108 mg) and sodium borohydride (30 mg) were added thereto, and the mixture was stirred for 30 minutes, and chloroform and an acetic acid aqueous solution were added. The mixture was made alkaline with an aqueous sodium hydrogen carbonate solution and extracted with chloroform.
The extract was washed with saturated brine and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, an ethanol-hydrochloric acid solution was added, and the precipitated crystals were collected by filtration to give 69 mg of the target compound 7H-5. Melting point: 263-268 ° C (decomposition)

Example C-13 : -Preparation of target compound (I)-: 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1,4-dihydro-4-oxo-1- ( 2-thiazolyl) -1,8-naphthyridine-3-carboxamide trifluoroacetic acid salt (compound 8F-1)

(1) Methanol 150 m under ice cooling
9.00 g of 7- [3- (Nt-butoxycarbonylamino) -1-pyrrolidinyl] -6-fluoro-1,4 per liter
-Dihydro-4-oxo-1- (2-thiazolyl)-
1,8-naphthyridine-3-carboxylic acid ethyl ester, 150 ml of 1N-sodium hydroxide aqueous solution was added,
The mixture was stirred for 30 minutes and then at room temperature overnight. Aqueous acetic acid solution was added and extracted with chloroform. After washing with saturated brine, it was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give 7- [3- (Nt-butoxycarbonylamino).
-1-Pyrrolidinyl] -6-fluoro-1,4-dihydro-4-oxo-1- (2-thiazolyl) -1,8-
8.50 g of naphthyridine-3-carboxylic acid was obtained. Melting point: 220-224 ° C

(2) Dissolve 2.20 g of the above-mentioned compound in 20 ml of chloroform and, under cooling with ice, add triethylamine (0.2 ml).
97 ml and 604 mg of ethyl chloroformate were added, and the mixture was stirred for 1 hour, and further stirred at room temperature for 1 hour. Again, 20 ml of saturated ammonia-ethanol solution was added under ice cooling, and the mixture was stirred for 1 hour, and further stirred overnight at room temperature. The solvent was distilled off under reduced pressure,
Water was added to the residue and extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent chloroform: methanol = 100: 1) to give 7- [3-
(Nt-butoxycarbonylamino) -1-pyrrolidinyl] -6-fluoro-1,4-dihydro-4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3
-1.19 g of carxamide was obtained. Melting point: 240-243 ° C

(3) 700 mg of the compound of the preceding paragraph was dissolved in 40 ml of chloroform, 1.3 ml of trifluoroacetic acid was added under ice cooling, and the mixture was stirred for 1 hour and further stirred at room temperature overnight. The solvent was distilled off under reduced pressure, ethanol was added to the residue, and the precipitated crystals were collected by filtration to give 635 mg of the desired compound (8F
-1) was obtained. Melting point: 227-233 ° C (decomposition)

Example C-14 : -Production of Target (I)-: 7- (3-Amino-1-pyrrolidinyl) -6-fluoro-1,4-dihydro-4-oxo-1- ( 2-thiazolyl) -1,8-naphthyridine trifluoroacetic acid salt (Compound 8F-2)

(1) Under ice cooling, 7- [3- (N-t
-Butoxycarbonylamino) -1-pyrrolidinyl]-
6-Fluoro-1,4-dihydro-4-oxo-1-
11.2-g of (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid was dissolved in 400 ml of methanol, 4.5 g of sodium borohydride was added, and the mixture was stirred for 30 minutes and further stirred at room temperature overnight. The solvent was evaporated under reduced pressure, acetic acid water was added to the residue, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent chloroform: methanol = 100: 1), and 7- [3- (Nt-butoxycarbonylamino) was obtained.
-1-Pyrrolidinyl] -6-fluoro-1,2,3,4
-Tetrahydro-4-oxo-1- (2-thiazolyl)
5.41 g of -1,8-naphthyridine was obtained. Melting point: 234-236 ° C

(2) 700 mg of the above-mentioned compound was added to 1,4
-Dissolved in 70 ml dioxane, 2,3-dichloro-
440 mg of 5,6-dicyano-1,4-benzoquinone was added, and the mixture was heated under reflux overnight. The solvent was evaporated under reduced pressure, aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with chloroform. Dry over anhydrous sodium sulfate, remove the solvent under reduced pressure,
Silica gel column chromatography of the residue (eluent
Purified with chloroform: methanol = 100: 1), 7
-[3- (Nt-butoxycarbonylamino) -1-
Pyrrolidinyl] -6-fluoro-1,4-dihydro-4
270 mg of -oxo-1- (2-thiazolyl) -1,8-naphthyridine was obtained. Melting point: 234-236 ° C

(3) 160 mg of the compound of the preceding paragraph was dissolved in 12 ml of chloroform, 0.6 ml of trifluoroacetic acid was added under ice cooling, and the mixture was stirred for 1 hour and further stirred at room temperature overnight. The solvent was distilled off under reduced pressure, ethanol was added to the residue, and the precipitated crystals were collected by filtration to obtain 150 mg of the target compound (8F
-2) was obtained. Melting point: 237-240 ° C

Example C-15 : -Preparation of target compound (I)-: 7- (3-amino-1-pyrrolidinyl) -3-benzyl-6-fluoro-1,4-dihydro-4-oxo -1-
(2-thiazolyl) -1,8-naphthyridine (Compound 8
F-3)

(1) Example C-in 10 ml of ethanol
14- (7)-[3- (N-t-butoxycarbonylamino) -1-pyrrolidinyl] -6-fluoro-obtained
1,2,3,4-tetrahydro-4-oxo-1- (2
-Thiazolyl) -1,8-naphthyridine 400 mg, 2
5 ml of 0% sodium hydroxide aqueous solution was added, 350 mg of benzaldehyde was added there, and it stirred overnight. Acetic acid water was added, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent chloroform: methanol = 100: 1), 3-benzyl-7- [3- (Nt-butoxycarbonylamino) -1-pyrrolidinyl] -6-fluoro-.
325 mg of 1,4-dihydro-4-oxo-1- (2-thiazolyl) -1,8-naphthyridine was obtained. Melting point: 234-236 ° C

(2) 200 mg of the above-mentioned compound was dissolved in 15 ml of chloroform, 0.59 ml of trifluoroacetic acid was added under ice cooling, and the mixture was stirred for 1 hour and further stirred at room temperature overnight. The solvent was evaporated under reduced pressure, diisopropyl ether was added to the residue, and the precipitated crystals were collected by filtration to obtain 185 mg of the target compound (8F-3). Melting point: 237-240 ° C

Example C-16 : -Production of Target (I)-: 7- (3-Amino-1-pyrrolidinyl) -3-formyl-1,4-dihydro-6-fluoro-4-oxo -1-
(2-thiazolyl) -1,8-naphthyridine hydrochloride (Compound 8F-4)

The title compound (8F-4) was obtained according to the method described in Example C-8. Melting point: 242-250 ° C (decomposition)

Example C-17 : -Preparation of target compound (I)-: 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1,4-dihydro-3-hydroxy-4-oxo -1
-(2-thiazolyl) -1,8-naphthyridine trifluoroacetic acid salt (Compound 8F-5)

(1) 7- [3- (Nt-butoxycarbonylamino) -1-pyrrolidinyl] -6-fluoro-1,4-dihydro-4-oxo-1- (2-thiazolyl) -1, 8-naphthyridine-3-carboxylic acid 0.5 g,
A mixture of 0.75 g of potassium superoxide, 5 ml of ethanol and 5 ml of water was heated under reflux for 15 minutes, and the solvent was distilled off.
The mixture was neutralized with acetic acid water and extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from chloroform-ethanol to give 7- [3- (Nt
-Butoxycarbonylamino) -1-pyrrolidinyl]-
6-fluoro-1,4-dihydro-3-hydroxy-4
260 mg of -oxo-1- (2-thiazolyl) -1,8-naphthyridine was obtained. Melting point: 251-252 ° C

(2) A mixture consisting of 260 mg of the above compound, 6 ml of methylene chloride and 6 ml of trifluoroacetic acid was stirred at room temperature for 20 hours, and the solvent was evaporated under reduced pressure. Acetonitrile was added to the residue and the precipitated crystals were collected by filtration and washed with acetonitrile to obtain 170 mg of the target compound (8F-5). Melting point: 206-207 ° C

Example C-18 : Preparation of Target (I)-: 1,4-dihydro-4-oxo-1- (2-thiazolyl) -7-vinyl-1,8-naphthyridine-3 -Carboxylic acid (Compound 9H-1)

(1) 7-Chloro-1,4-dihydro-
A suspension of 3.6 g of 4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester, 3.8 g of vinyltributyltin, 1.0 g of bistriphenylphosphine palladium dichloride and 150 ml of toluene for 6.5 hours. Refluxed. After cooling with ice, the mixture was washed with water and the solvent was distilled off under reduced pressure. The obtained crystals were washed with toluene and ethanol to give 1,4-dihydro-4-oxo-1-
2.7 g of ethyl (2-thiazolyl) -7-vinyl-1,8-naphthyridine-3-carboxylic acid was obtained. Melting point: 163-164 ° C

(2) A suspension consisting of 0.32 g of the compound of the above-mentioned item, 15 ml of 10% hydrochloric acid water and 2 ml of ethanol was added.
After heating at 00 ° C. for 13 hours, the crystals were collected by filtration and washed with ethanol to obtain the target product 9H-1 (0.19 g). Melting point: 284-288 ° C (decomposition)

Example C-19 : Preparation of Target (I)-: 1,4-dihydro-7- (2,6-dimethyl-4-pyridinyl) -4-oxo-1- (2- Thiazolyl) -1,
8-naphthyridine-3-carboxylic acid (compound 9H-2)

(1) 7-chloro-1,4-dihydro-
4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester 1.1 g, 2,6
-Dimethyl-4- (trimethyltin) pyridine 0.98 g,
Bistriphenylphosphine palladium dichloride 0.25
g and 51 ml of toluene was refluxed for 6.5 hours. After cooling with ice, the mixture was washed with water and the solvent was distilled off under reduced pressure. Purified by silica gel column chromatography (eluent chloroform), washed with ethanol, and 1,4-dihydro-7- (2,6-dimethyl-4-pyridinyl) -4.
0.38 g of -oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester was obtained. Melting point: 232-235 ° C

(2) By treating in substantially the same manner as in Example C-18 (2), the target compound 9H-2 was obtained. Melting point: 272-275 ° C (decomposition)

Example C-20 : -Preparation of target compound (I)-: 7-ethynyl-1,4-dihydro-4-oxo-1-
(2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid (compound 9H-3)

(1) 7-Chloro-1,4-dihydro-
A suspension composed of 1.5 g of 4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester, 2.0 g of (trimethylsilyl) ethynyltributyltin, 0.45 g of bistriphenylphosphine palladium dichloride and 75 ml of toluene. Was heated at 100 ° C. under an argon atmosphere for 3 hours. After cooling with ice, the mixture was washed with water and the solvent was distilled off under reduced pressure. Purified by silica gel column chromatography (eluent: chloroform), 1,4
1.0 g of -dihydro-4-oxo-7- (trimethylsilyl) ethynyl-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester were obtained.

(2) A suspension consisting of 1.0 g of the compound obtained in the preceding paragraph, 0.45 g of potassium fluoride and 25 ml of ethanol was refluxed for 2 hours, and the solvent was distilled off under reduced pressure. Chloroform and water were added, the insoluble matter was separated by Celite filtration, washed with water, and the solvent was concentrated under reduced pressure. This was washed with a mixture of chloroform-ethanol to give 7-ethynyl-1,4
-Dihydro-4-oxo-1- (2-thiazolyl)-
1,8-Naphthyridine-3-carboxylic acid ethyl ester
0.34 g was obtained. Melting point: 228-231 ° C (decomposition)

(3) The compound obtained in the preceding paragraph was used as Example C.
The target compound 9H-3 was treated in substantially the same manner as in -18 (2).
I got Melting point:> 300 ° C

Example C-21 : -Production of Target (I) --- The following compounds were obtained by the method described in Examples C-18 to C-20 or a method analogous thereto.

1,4-Dihydro-4-oxo-7-phenyl-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid (Compound 9H-4); Melting point: 227-230 ° C. (decomposition) )

1,4-dihydro-7-methyl-1- (2
-Thiazolyl) -1,8-naphthyridine-3-carboxylic acid (compound 9H-5); melting point: 268-269 ° C.

1- (5-bromo-2-thiazolyl)-
1,4-dihydro-7- (1-pyrrolidinyl) methyl-
1,8-naphthyridine-3-carboxylic acid (compound 9H-
6); Melting point: 238-239 ° C

Example C-22 : -Production of Target (I) ---: 1,4-dihydro-4-oxo-7- (3-pyrazolyl) -1- (2-thiazolyl) -1,8 -Naphthyridine-3-carboxylic acid (compound 9H-7)

(1) Example C-20: 7 obtained in (2)
-Ethynyl-1,4-dihydro-4-oxo-1- (2
-Thiazolyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester 0.34 g, trimethylsilyldiazomethane (10% hexane solution) 1.3 g and chloroform 2
A suspension consisting of 0 ml was refluxed for 5.5 hours. The solvent was distilled off under reduced pressure, washed with ethanol, and 1,4-dihydro-4-
0.31 g of ethyl ester of oxo-7- (3-pyrazolyl) -1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid was obtained. Melting point: 285-287 ° C (decomposition)

(2) The compound obtained in the preceding paragraph was used as Example C.
Treated in substantially the same manner as in -18 (2), the target compound 9H
-7 was obtained. Melting point:> 300 ° C

Example C-23 : Preparation of Target (I)-: 6-Fluoro-1,4-dihydro-7-hydroxy-4
-Oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid (Compound 9F-1)

7-Chloro-6-fluoro-1,4-dihydro-4-oxo-1- (2-thiazolyl) -1,8-
To 1.0 g of naphthyridine-3-carboxylic acid ethyl ester was added 10 ml of a sodium hydroxide aqueous solution, and the mixture was stirred at 85 ° C for 6.5 hours. The reaction solution was made acidic with hydrochloric acid, and the precipitated crystals were collected by filtration. The crystals were dissolved in a 5% aqueous sodium hydroxide solution, treated with activated carbon, acidified with hydrochloric acid, and the precipitated crystals were collected by filtration. The crystals were washed with water and then with ethanol to obtain 690 mg of the target compound. Melting point: 261-264 ° C

Example C-24 : Production of Target (I)-: 7- (3-Amino-1-pyrrolidinyl) -6-chloro-
1,4-Dihydro-4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid 0.85 hydrochloride (Compound Cl-1)

(1) To a mixed solution of acetic anhydride (60 ml) and concentrated nitric acid (5 ml) was added 2,6-dimethoxynicotinic acid (8.71 g) under ice cooling. 3 hours at the same temperature,
After stirring at room temperature for 4 hours, the precipitated crystals were collected by filtration and washed with isopropanol and diisopropyl ether. The filtrate was extracted with ethyl acetate, the solvent was distilled off under reduced pressure, and the obtained crystal was washed with isopropanol and diisopropyl ether. The above crystals were combined to obtain 2,6-dimethoxy-5-nitronicotinic acid (6.95 g). It was

Melting point: 227-230 ° C. (decomposition); IR (KBr) cm ⁻¹ ; 1706, 1610; MS (m / z): 229 (MH ⁺ ); ¹ H-NMR (DMSO-d ₆ ) δ: 4.03 (s, 3H),
4.08 (s, 3H), 8.71 (s, 1H)

(2) Ethyl potassium malonate (18.6
g), magnesium chloride (11.3 g) in ethyl acetate (250
ml) was added, and triethylamine (28.0 g) was added dropwise to the obtained suspension under ice cooling, and the mixture was stirred at room temperature for 2.5 hours.

On the other hand, carbonyldiimidazole (14.8 g) was added to a solution of the compound (18.5 g) obtained in the previous section in tetrahydrofuran (150 ml), and the mixture was stirred at 70 ° C. for 1 hour. This solution was added to the above suspension under ice cooling, and the mixture was stirred at room temperature overnight and further at 70 ° C. for 30 minutes. Concentrated hydrochloric acid was added to the reaction solution to make it acidic, and the precipitated crystals were collected by filtration and washed with ethyl acetate. The filtrate was extracted with ethyl acetate, the solvent was distilled off under reduced pressure, and the obtained crystal was recrystallized from a mixture of ethyl acetate and diisopropyl ether. Combined with the above crystals, 2,6-dimethoxy-5-nitronicotinoyl acetic acid ethyl ester (19.9 g) was obtained.

MS (m / z): 299 (MH ⁺ ); ¹ H-NMR (DMSO-d ₆ ) δ: 1.19 (t, 3H, J
= 7 Hz), 4.00 (s, 2H), 4.10 (s, 3H), 4.
11 (q, 2H, J = 7Hz), 4.15 (s, 3H), 8.78
(S, 1H)

(3) A mixture of the compound (2.2 g) obtained in the previous section, ethyl orthoformate (1.7 g) and acetic anhydride (2.4 g) was heated under reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure, and diisopropyl ether (10 ml) and 1,2 were added to the residue.
4-dioxane (3 ml) was added. 2-Aminothiazole (0.84 g) was added to this solution under ice cooling, and the mixture was stirred overnight at room temperature. The precipitated crystals were collected by filtration and washed with diisopropyl ether to give 2- (2,6-dimethoxy-5-nitronicotinoyl) -3- (2-thiazolylamino) acrylic acid ethyl ester (2.3 g).

Melting point: 166-170 ° C .; IR (KBr) cm ⁻¹ ; 1729,1603

(4) Potassium carbonate (1.0 g) was added to a suspension composed of the compound (2.0 g) obtained in the previous section and 1,4-dioxane (90 ml), and the mixture was heated at 60 ° C. for 3 hours.
After cooling, water was added and neutralized with 20% hydrochloric acid water, and the precipitated crystals were collected by filtration. Wash sequentially with water, ethanol and diisopropyl ether to give 1,4-dihydro-7-methoxy-6-nitro-4-oxo-1- (2-thiazolyl)-
1,8-naphthyridine-3-carboxylic acid ethyl ester (1.7 g) was obtained.

Melting point: 208-210 ° C .; IR (KBr) cm ⁻¹ ; 1739; MS (m / z): 337 (MH ⁺ ); ¹ H-NMR (DMSO-d ₆ ) δ: 1.31 (t, 3H). , J
= 7Hz), 4.30 (s, 3H), 4.33 (q, 2H, J =
7Hz), 7.85 (d, 1H, J = 4Hz), 7.88 (d,
1H, J = 4Hz), 9.08 (s, 1H), 9.69 (s, 1
H)

(5) Compound (10.3 g) obtained in the previous section, 3
-(T-butoxycarbonylamino) pyrrolidine (5.9
g) and potassium carbonate (4.7 g) in dimethylformamide (150 ml) was heated at 60 ° C. for 2 hours. After cooling, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline and then dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was recrystallized from a mixed solution of ethyl acetate and ethanol to give 7- (3-t-butoxycarbonylamino-1-pyrrolidinyl) -1,4-dihydro-6-nitro-. 4-Oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester (11.4 g) was obtained. Melting point: 204-205 ° C

(6) The compound (1.0 g) obtained in the preceding section was treated with ethanol (100 ml) and 1,4-dioxane (5
(0 ml), Raney-nickel (about 1 g) was added, and hydrogen was absorbed at 50 ° C. for 2.5 hours. The precipitated crystals were collected by filtration, added with dimethylformamide and heated, and the insoluble matter was filtered. The filtrate was concentrated under reduced pressure, and the obtained crystals were washed with a mixed solution of dimethylformamide, 1,4-dioxane and ethanol to give 6-amino-7- (3-t-butoxycarbonylamino-1-pyrrolidinyl) -1, 4-
Dihydro-4-oxo-1- (2-thiazolyl) -1,
8-Naphthyridine-3-carboxylic acid ethyl ester (0.
81 g) was obtained. Melting point: 270-272 ° C (decomposition)

(7) To a mixture of the compound (250 mg) obtained in the previous section and concentrated hydrochloric acid (5 ml), a solution of sodium nitrite (60 mg) in water (2 ml) was added dropwise under ice cooling, and the mixture was kept at the same temperature for 10 minutes. It was stirred. This reaction liquid was added dropwise to a mixture of copper (I) chloride (70 mg) and concentrated hydrochloric acid (2 ml) under ice cooling. After stirring at the same temperature for 1 hour and at 60 ° C for 30 minutes, 20
It was made alkaline with a sodium hydroxide aqueous solution and then extracted with chloroform. The extract was dried over sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from a mixed solution of chloroform and diisopropyl ether to give 7- (3-amino-1-pyrrolidinyl) -6-chloro-1. , 4-Dihydro-4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester (30 mg) was obtained. Melting point: 208-210 ° C

(8) In accordance with the method described in Example C-1 (2), the desired ethyl 7- (3-amino-1-pyrrolidinyl) -6- is obtained by hydrolyzing the ethyl ester obtained in the preceding paragraph.
Chloro-1,4-dihydro-4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid
0.85 hydrochloride (Compound Cl-1) was obtained. Melting point: 288-291 ° C (decomposition)

Example C-25 : Production of Target (I) ---: C-series system The following compounds were obtained by a method described in any of Examples or a method analogous thereto.

[0519]

Embedded image

[0520]

[Table 50] Table 22

Example C-26 : -Production of the object compound (I)-: 3- [1,4-dihydro-7- (trans-3-methoxy-4-methylamino-1-pyrrolidinyl) -4 -Oxo-1- (2-thiazolyl) -1,8-naphthyridine-
3-yl] acrylic acid methyl ester 0.9 trifluoroacetic acid salt (Compound 9H-9)

3-Formyl-1,4 obtained in Example C-8
-Dihydro-7- (trans-3-methoxy-4-methylamino-1-pyrrolidinyl) -4-oxo-1- (2
-Thiazolyl) -1,8-naphthyridine hydrochloride (100
3 ml of aqueous ammonia was added to (mg) and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give an oil.

On the other hand, 60% sodium hydride (19 m
g) was washed with n-hexane and tetrahydrofuran 10
ml was added. Trimethylphosphonoacetate (65 mg) was added to the obtained suspension at room temperature, and the mixture was stirred for 10 minutes and then ice-cooled to obtain the oily substance obtained above as tetrahydrofuran (5 ml).
The solution was added dropwise. After stirring at room temperature for 3 hours, water was added and the mixture was extracted with chloroform. After washing with saturated saline, it was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent chloroform: methanol = 50: 1) to give an oil. This was dissolved in methylene chloride, 5 drops of trifluoroacetic acid was added under ice cooling, diisopropyl ether was further added, and the precipitated crystals were collected by filtration to obtain the title compound (22 mg).

Melting point: 230-233 ° C. (decomposition); IR (KBr) cm ⁻¹ ; 2950,1680,162
0; MS (m / z): 442 (MH ⁺ ).

Example C-27 : Preparation of Target (I) ---: 3-acetyl-1,4-dihydro-7- (trans-3
-Methoxy-4-methylamino-1-pyrrolidinyl)-
4-oxo-1- (2-thiazolyl) -1,8-naphthyridine (Compound 9H-10)

(1) Ethyl potassium malonate (572 m
Ethyl acetate (60 ml) was added to g), magnesium chloride (343 mg) and triethylamine (1.0 ml) were added to the obtained suspension at room temperature, and the mixture was stirred for 5 hours.

On the other hand, 7- [trans-3- (Nt-butoxycarbonylmethylamino) -4-methoxy-1-pyrrolidinyl] -1,4-dihydro-4 obtained in Example C-8 (2) was used. -Oxo-1- (2-thiazolyl) -1,8
To a solution of -naphthyridine-3-carboxylic acid (1.2 g) in chloroform (120 ml) was added BOP reagent (1.27 g) and triethylamine (0.8 ml) at room temperature, and the mixture was stirred for 20 minutes. This reaction solution was added to the previous reaction solution at room temperature and stirred for 1 day.

The reaction solution was poured into water and extracted with chloroform. After washing with saturated saline, it was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent chloroform: methanol = 200: 1) to give 3- {7- [trans-3- (Nt-butoxycarbonylmethyl). Amino)-
4-Methoxy-1-pyrrolidinyl] -1,4-dihydro-4-oxo-1- (2-thiazolyl) -1,8-naphthyridin-3-yl} -3-oxopropionic acid ethyl ester (397 mg) was added. Obtained. MS (m / z): 572 (MH ⁺ ).

(2) Compound (170 m) obtained in the above (1)
g) was dissolved in ethanol (2 ml), and 10% hydrochloric acid water (10 ml) was added. The mixture was stirred at room temperature for 30 minutes and at 95 ° C for 4 hours. After cooling, the mixture was made alkaline with aqueous sodium hydrogen carbonate and then extracted with chloroform. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from diisopropyl ether to give the title compound (76 mg).

Melting point: 112-114 ° C .; IR (KBr) cm ⁻¹ ; 3085, 1685, 162
0; MS (m / z): 400 (MH ⁺ ).

Example C-28 : Preparation of target compound (I) ---: N- [1,4-dihydro-7- (trans-3-methoxy-4-methylamino-1-pyrrolidinyl) -4 -Oxo-1- (2-thiazolyl) -1,8-naphthyridine-
3-Carbonyl] glycine ethyl ester trifluoroacetate (Compound 9H-11)

[0532] According to the method described in Example C-11 (1), 7- [trans-3- (Nt-butoxycarbonylmethylamino) -4-methoxy-1-pyrrolidinyl] was used.
-1,4-Dihydro-4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid (250
mg) and glycine ethyl ester hydrochloride (78 mg) to give N- {7- [trans-3- (Nt-butoxycarbonylmethylamino) -4-methoxy-1-pyrrolidinyl] -1,4-dihydro-4-oxo. -1- (2-Thiazolyl) -1,8-naphthyridine-3-carbonyl] glycine ethyl ester (290 mg) was obtained.

This was dissolved in methylene chloride (9 ml),
Trifluoroacetic acid (1.2 ml) was added under ice cooling. After stirring at room temperature for one day, diisopropyl ether was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain the desired compound 9H-11.
(260 mg) was obtained. Melting point: 233-236 ° C (decomposition)

Example C-29 : Preparation of target compound (I)-: N- [1,4-dihydro-7- (trans-3-methoxy-4-methylamino-1-pyrrolidinyl) -4 -Oxo-1- (2-thiazolyl) -1,8-naphthyridine-
3-Carbonyl] -L-alanine trifluoroacetate (Compound 9H-12)

The title compound was obtained in the same manner as in Example C-28. Melting point: 168-170 ° C (decomposition)

[0536] Next, production examples of the preparation will be described.

Example D-1 : --- Preparation of liquid preparation ---: Method: ---

[0538]

Table 51 Compound H-1-1-1 2 g Sorbitol 50 g Sodium hydroxide Appropriate amount Distilled water for injection Appropriate amount ──────────────────────── ── Total volume 1000 ml

Preparation method: Compound H-1-1-1 and sorbitol were dissolved in a part of distilled water for injection, sodium hydroxide and the remaining distilled water were added, and the pH of the solution was adjusted to 5.0.
Was prepared. Add this solution to a membrane filter (0.22 μ
m) was filtered to obtain an injectable solution.

Example D-2 : --- Preparation of lyophilized formulation-
-: Method: ---

[0541]

Table 52 Compound H-1-1-1 1 g Mannitol 5 g Sodium hydroxide Appropriate amount Distilled water for injection Appropriate amount ─────────────────────────── 100 ml

Preparation method: Compound H-1-1-1 and mannitol were dissolved in a portion of distilled water for injection, sodium hydroxide and the remaining distilled water were added, and the pH of the solution was adjusted to 5.0.
Was prepared. Add this solution to a membrane filter (0.22 μ
It was filtered through m) and freeze-dried to obtain a powder for injection.

[0543]

INDUSTRIAL APPLICABILITY The compounds according to the present invention can be used not only for non-solid tumors such as lymphocytic leukemia tumors but also for lungs,
It also shows a remarkable antitumor effect against various solid tumors occurring in tissues such as milk, stomach, uterus, skin, intestine, bladder, and nose and throat. In addition, the compound according to the present invention is highly safe for living bodies. Therefore, the compounds according to the present invention are useful as therapeutic agents or prophylactic agents for human tumors.

[Brief description of drawings]

FIG. 1 is a graph showing an antitumor effect on human nasopharyngeal carcinoma (KB).

FIG. 2 is a diagram showing an antitumor effect on human breast cancer (MX-1).

FIG. 3 is a graph showing an antitumor effect on human colon cancer (WiDr).

FIG. 4 is a diagram showing an antitumor effect on human melanoma (HMV-2).

FIG. 5 is a diagram showing an antitumor effect on human lung cancer (LX-1).

Front Page Continuation (72) Inventor Koichiro Shibamori 3-22-22-702 Kotoen, Nishinomiya-shi, Hyogo Prefecture (72) Inventor Yasushi Chikuki 3-chome 14-29 Mishima, Settsu-shi, Osaka (72) Inventor Tajima Masanori 2-11-17 Higashiizumioka, Toyonaka City, Osaka Prefecture 2nd Kumano Heights 202 (72) Inventor Tomio Oue 3-16-1 Higashikohama, Sumiyoshi-ku, Osaka City, Osaka Prefecture

Claims (7)

[Claims] 1. A compound represented by the following general formula (I), its stereoisomer or optical isomer, or a physiologically acceptable salt thereof, or a hydrate or solvate of any of the above. Antitumor agent as an active ingredient: (Wherein --------- means the presence or absence of a single bond. X means N or C-Rx, where R is
x means a hydrogen atom or a halogen atom. R ₁ and R ₂ are the same or different and each represents a hydrogen atom, a halogen atom,
A nitro group, a lower alkoxy group, a lower alkyl group (the lower alkyl group may be substituted with a lower alkoxycarbonyl or carboxyl), a phenyl group or a thienyl group optionally substituted with a halogen, or a phenylsulfonyl group (the above A phenyl moiety may be substituted with halogen or nitro), or R ₁ and R ₂ together form a benzene ring or a naphthalene ring, wherein the benzene ring or naphthalene ring is halogen, nitro or It may be substituted with lower alkyl. R ₃ means a hydrogen atom, a benzyl group, a hydroxyl group, a carboxyl group or a group capable of being converted into a carboxyl group. R ₄ means an oxo group or a hydroxyl group. R ₅ represents a hydrogen atom, an amino group, a halogen atom or a lower alkyl group, and the lower alkyl group may be substituted with halogen. R ₆ represents a substituent bonded to the mother nucleus by an N—C bond, a C—C bond, a S—C bond or an O—C bond. ) 2. The antitumor agent according to claim 1, wherein R ₆ in the general formula (I) is any group selected from the following (a) to (e). (A) 4- to 7-membered monocyclic amino group represented by the following formula (a): (Wherein --------- means the presence or absence of a single bond, R6a1, R6a2, R6a3 and R6a4 are identical or _{different, C, CH, CH 2,} CH 2 CH 2, CH = C
H, S (O) _0-2 , O, N or N-R6a,
Here, R6a means a hydrogen atom, a lower alkyl group or a phenyl group, and the phenyl group may be substituted with lower alkoxy, lower alkyl, halogen or nitro. k and m are the same or different and mean an integer of 0 or 1. R6a5 represents a hydrogen atom, a methylene group or a group represented by the following formula (R6a-5): [Wherein R6a51 represents a hydrogen atom or a phenyl group (the phenyl group may be substituted with halogen), or a lower alkyl group optionally substituted with phenyl or halogenophenyl, and R6a52 Is a hydrogen atom, a lower alkyl group or a group convertible to a hydrogen atom, and n is an integer of 0-4. R6a6 is a hydrogen atom, a halogen atom, a hydroxyl group, an azido group,
It means a formyl group, an oxo group, a lower alkoxy group, a lower alkylthio group or a lower alkyl group (the lower alkyl group may be substituted with halogen or hydroxy). R6a7 means the same as R6a6 or a spiro cyclic amino group represented by the following formula (R6a-7): [In formula, p means the integer of 3 or 4. (B) Bicyclic amino group represented by the following formula (b): (In the formula, --------- means the presence or absence of a single bond, q, s and t are the same or different and are integers of 0 to 2, and the sum of q and t is 2 Or 3. R6b1 is C,
CH, CH ₂ or N—R6b means R6b means a hydrogen atom or a lower alkyl group, and R6
b2 is _{C, CH, CH 2, CH} 2 CH 2 or CH = CH
Means, R6b3 means C, CH, and CH ₂ or O, u, v and w are the same or different, is 0 or the integer 1, meaning that the sum of these is 1 to 3 , R6b4 and R6b5 are the same or different and each represents a hydrogen atom, a hydroxyl group, a lower alkyl group, an amino group, a mono- or di-lower alkylamino group or a mono- or di-lower alkylamino lower alkyl group. ) (C) 3- to 7-membered cyclic group represented by the following formula (c): (Wherein --------- means the presence or absence of a single bond, R6c1, R6c2, R6c3 and R6c4 are identical or _{different, C, CH, CH 2,} CH 2 CH 2, CH = C
H, S (O) _0-2 , O, N or N-R6c,
Here, R6c means a hydrogen atom or a lower alkyl group. R6c5 is O, refers to S or CH _2, it is R6c6 and R6c7 same or different, represents a hydrogen atom, an amino group or a lower alkyl group. f, g and h are the same or different and mean an integer of 0 or 1. ) (D) An amino group represented by the following formula (d): (In the formula, R6d1 represents S or NH, R6d2 and R6d3 are the same or different and represent a hydrogen atom or a lower alkyl group, i represents an integer of 0 or 1, and j represents 1
Means an integer of ~ 5. ) (E) Hydroxyl group, lower alkyl group, lower alkenyl group or lower alkynyl group. 3. A compound represented by the following general formula (Ia), its stereoisomer or optical isomer, or a physiologically acceptable salt thereof, or a hydrate or solvate of any of the above. An antitumor agent according to claim 1 or 2, which comprises a substance as an active ingredient: (In the formula, ------, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , X,
R6a1, R6a2, R6a3, R6a4, R6a5, R6a6, R
6a7 and k have the same meaning as in claim 2. ) 4. A compound represented by the following general formula (Ib), its stereoisomer or optical isomer, or a physiologically acceptable salt thereof, or a hydrate or solvate of any of the above. The antitumor agent according to claim 3, wherein the substance is an active ingredient: (In the formula, W is a hydrogen atom or a fluorine atom,
_{-, R 1, R 2,} R 3, R 4, R 5, R6a5, R6a6 and Ra7 are the same meaning as described in the second claims. ) 5. A compound represented by the following general formula (Ic), a stereoisomer or an optical isomer thereof, or a physiologically acceptable salt thereof, or a hydrate or solvate of any of the above. The antitumor agent according to claim 3 or 4, which comprises a substance as an active ingredient: (In the formula, R6a511 is a lower alkyl group, and R6a61 and R6a71 are the same or different and mean a hydrogen atom, a lower alkoxy group or a lower alkyl group.) 6. A compound represented by the following general formula (Ic), its stereoisomer or optical isomer, or a physiologically acceptable salt thereof, or a hydrate or solvate of any of the above. Medicine consisting of: (In the formula, R6a511 is a lower alkyl group, and R6a61 and R6a71 are the same or different and mean a hydrogen atom, a lower alkoxy group or a lower alkyl group.) 7. 1,4-Dihydro-7- (3-methoxy-4-methylamino-1-pyrrolidinyl) -4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3.
7. The pharmaceutical according to claim 6, which comprises a carboxylic acid, its stereoisomer or optical isomer, or a physiologically acceptable salt thereof.