JP2000191659A - Tumor necrosis factor production inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound consisting of a phthalazine derivative or its prodrug, and having a tumor necrosis factor(TNF) inhibition activity. SOLUTION: This tumor necrosis factor production inhibitor is a compound of formula I [R1 is H or a halogen; R2 to R5 are each H, OH, a halogen, a (substituted) alkyl, an alkoxy, a (substituted) aryl, a (substituted) acyl, a (substituted) acyloxy, nitro, a (substituted) amino or the like; R6 is a substituted alkyl, a (substituted) alkenyl, a (substituted) aryl or the like; R7 is H, a (substituted) alkyl or the like]. For example, 1-[4-(hydroxythienylmethyl) piperidino]phthalazine. The compound of the formula I is obtained as a compound of formula IV, e.g. in the case that R1 is a halogen, by reacting a compound of formula II (X is a halogen) with a piperidine derivative of formula III in an inert organic solvent at temeperatures of preferably 0-200 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel phthalazine derivative or a prodrug thereof or a pharmaceutically acceptable salt thereof. And a TNF production inhibitor or secretion inhibitor containing them.

[0002]

2. Description of the Related Art Tumor necrosis factor
r, hereinafter abbreviated as TNF. ) Is a peptide having a molecular weight of about 17,000 consisting of 157 amino acids and is one of cytokines produced from various cells including macrophages. TNF was initially found to be a cytokine with tumor-damaging effects, but subsequent studies have shown that its effects extend to many normal cells other than tumor cells and exhibit a wide variety of activities. . For example, inhibition of lipoprotein lipase activity of fat globules, expression of HLA antigen on vascular endothelial cells and fibroblasts, interleukin-1 production of fibroblasts or macrophages, activation of tumor-toxic macrophages, suppression of CFU, fibrosis Production of colony stimulating factor of blast cells, endothelial cells and certain tumor cells, inhibition of cartilage synthesis and absorption of proteoglycan, activation of neutrophils and generation of superoxide, production of procoagulant factor of vascular endothelial cells, fiber These include proliferation of blasts, changes in skeletal myofascial potential, production of interferon-β2 in fibroblasts, and damage to vascular endothelial cells. Recently, they have been widely understood as cytokines involved in host defense through inflammatory immune reactions. Have been. (Vass
alli, P., Ann. Rev. Immunol., 10 , 411 (1992)).

On the other hand, continuous or overproduction of TNF
Conversely, it has also been clarified that it acts on normal cells and causes various disease states. For example, it has been reported that TNF is the same substance as cachectin, which is an inducer of cachexia (catabolism of systemic metabolism and extreme exhaustion) in cancer and infectious diseases (B. Beutler, D. . Greenwa
ld, JD. Hulmes et al., Nature, 316 , 552 (1985), Masayoshi Kawakami, Biochemistry, 59 , 1244 (1987)). Regarding sepsis, TNF is one of the causes, and it has been reported that there is an inhibitory effect in an experiment using an anti-TNF antibody (Starnes, HF Jr., Pearce, MK, Tewari, A., Y
im, JH, Zou, JC., Abrams, JS, J. Immunol. 1
45 , 4185 (1990), Beutler, B., Milsark, IW, Ceram
i, AC, Science, 229 , 869 (1985), Hinshaw, L.
B., Tekamp-olson, P., Chang, ACK et al, Circ.
Shock, 30 , 279 (1990)).

[0004] In addition, rheumatoid arthritis
Increases in TNF have been reported in synovial fluid and blood (Te
tta, C., Camussi, G., Modena, V., Vittorio, C. D.,
 Baglioni, C., Ann. Rheum. Dis.,49, 665 (1990)),
Significant effect reported in clinical trials using anti-TNF antibody
(Elliott, M. J. Maini, R.N., Feldman,
M., Kalden, J.R., Antoni, C., Smolen, J.S., Lee
b, B., Breedveld, F.C., Macfarlane, J. D., Biji,
H., Woody, J.N., Lancet,344, 1105 (1994), Elliott,
 M. J. Maini, R.N., Feldman, M., Charles, P., Bi
ji, H., Woody, J.N., Lancet,344, 1125 (1994), E.C.
 C. Rankin, E. H.S.Choy, D. Kassimos, G. H. Pana
yi, British J. Rheum.,34334 (1995)). In addition,
About inflammatory bowel diseases such as ulcerative colitis and Crohn's disease
Also suggested a TNF relationship (Murch, S., Walke
r-Smith, J.A., Arch.Dis.Child, 66, 561 (1991), before
Tadahiro Hiroshi, Digestive system and immunity,twenty two, 111 (1989)), anti-TNF
The effect has been reported in clinical experiments using the body (Hend
rik, M. Van Dullemen, Sander, J. H. Van Deventer,
Daan, W. Hommes, Hannie, A. Bul, Jaap, Jansen, Gui
do, N.J.Tytgat, and James, Woody, GASTROENTEROLO
GY109, 129 (1995)).

[0005] In addition, osteoarthritis (Venn, G., Nietfe
ld, JJ, Duits, AJ, Brennan, FM, Arner,
E., Covington, M., Billingham, MEJ, Hardingha
m, TE, Arthritis Rheum., 36 (6), 819 (1993)), Kawasaki disease (Matsubara, T., Furukawa, S., Yubuta, K., Cli)
n. Immunol. Immunopathol., 56 , 29 (1990)), multiple sclerosis (Sharief, MK, Hentges, R., N. Engl. J. M.
ed., 325 (7), 467 (1991)), Behcet's disease (Akoglu,
T., Direskeneli, H., Yazici, H., Lawrence, R., J.
Rheumatol., 17 , 1107 (1990)), systemic lupus erythematosus (SL
E) (Maury, CPJ, Teppo, AM., Arthritis Rheu
m., 32 , 146 (1989)), rejection during bone marrow transplantation (GvHD)
(Nestel, FP, Price, KS, Seemeyer, TA, La
pp, WS, J. Exp. Med., 175 , 405 (1992)), multiple organ failure (Toshifumi Fujiwara, Masashu Kawakami, clinician, 17 (10), 2006 (199)
1)), malaria (Grau, GE, Fajardo, LF, Pigue
t, PF, et al, Science, 237 , 1210 (1987)), Acquired immunodeficiency syndrome (AIDS) (Masawa Kawakami, Kuniyasu Hayata, Medic
al Immunology, 20 , 615 (1990), Dezube, BJ, Pard
ee, AB, et al, J. Acquir. Immune Defic. Syndr.,
5 , 1099 (1992)), meningitis (Waage, A., Halstensen,
A., Espevik, T., Lancet I , 355 (1987)), hepatitis (Kozo Sugano, liver, 33 , 213 (1992)), type II diabetes (Hotamisligi)
l, GS, Shargill, NS, Spiegelman, BM, Scie
nce, 259 , 87 (1993)), and it has been suggested that excessive TNF production is involved in such diseases. As described above, it is clear that excessive TNF production has an adverse effect on the living body, and research and development of a TNF inhibitor (for example, a production inhibitor or / and secretion inhibitor) that can be a therapeutic agent for such a disease state is desired. .

[0006] Known compounds having a TNF inhibitory activity include, for example, pentoxifylline having a methylxanthine skeleton. This compound has a lethal protective activity even in an endotoxin shock model mouse, and is known to have severe pulmonary tuberculosis. In addition, it shows mood improvement and weight loss suppression in cancer patients, and also shows mood improvement and weight loss suppression effect in cancer patients, suppression effect in experimental allergic encephalitis model, or suppression effect of HIV-1 replication Have been reported (Zabel, P., Schade,
FU, Schlaak, M., Immunobiol., 187 , 447-463 (199
3), Dezube, BJ, Pardee, AB et al., Cancer Im
muno. Immunother., 36 , 57-60 (1993), Nataf, S., Lo
uboutin, JP, Chabannes, D., Feve, JR, Mulle
r, JY, Acta Neurol. Scand., 38 , 97-99 (1993), Fa
zely, F., Dezube, BJ, Allen-Ryan, J., Pardee,
AB, Ruprecht, RM, Blood, 77 , 1653-1656 (199
1)).

[0007] Other compounds or factors exhibiting TNF inhibitory activity include glucocorticoids, protease inhibitors, phospholipase A2 inhibitors, lipoxygenase inhibitors, PAF (platelet aggregation factor) antagonists, radical scavengers, and prostaglandins. Gin F ₂
Or, I ₂ , anti-TNF antibody and the like are known. However, these compounds may have side effects due to a wide variety of pharmacological actions (please give specific examples), and their use is problematic, and the development of highly safe drugs by a new mechanism is required. desired.

[0008]

DISCLOSURE OF THE INVENTION The present invention relates to diseases in which the continuous or excessive production of TNF is considered to be involved in the onset of TNF due to its inhibitory effect on TNF production or secretion, such as cachexia, septic shock, Multiple organ failure, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, osteoarthritis, Behcet's disease, systemic lupus erythematosus (SL
E), rejection during bone marrow transplantation (GvHD), malaria,
Acquired immunodeficiency syndrome (AIDS), meningitis, hepatitis, I
It is intended to provide a therapeutic drug for type I diabetes and the like.

[0009]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that a phthalazine derivative represented by the following general formula (1) or a prodrug thereof or a pharmaceutically acceptable salt thereof inhibits TNF inhibition. Find it works,
The present invention has been completed. That is, the present invention provides: [1] General formula (1)

Embedded image General formula (1) (Wherein, R ₁ represents a hydrogen atom or a halogen atom,
R ₂ , R ₃ , R ₄ and R ₅ each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group, a substituted alkyl group, an alkoxy group, a substituted alkoxy group, an aryl group, a substituted aryl group, an acyl group, a substituted acyl Group, acyloxy group, substituted acyloxy group, nitro group, amino group, substituted amino group,
Or represents a cyano group. R ₆ represents a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an aryl group, a substituted aryl group, a heterocyclic group, an acyl group, a substituted acyl group, and R ₇ represents a hydrogen atom, an alkyl group, a substituted alkyl group, an aryl group,
Phthalazine derivative represented by a substituted aryl group, an acyl group, a substituted acyl group or a heterocyclic group), a prodrug thereof, or a pharmaceutically acceptable salt thereof. [2] The phthalazine derivative or the prodrug thereof or the pharmaceutically acceptable thereof according to the above [1], wherein R ₆ is a substituted alkyl group, a substituted alkenyl group, an acyl group, or a substituted acyl group, and R ₇ is a hydrogen atom. Their salt. [3] The phthalazine derivative according to the above [1] or [2], a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R ₆ is a substituted methyl group, a substituted vinylidene group, a heterocyclic carbonyl group, or a substituted benzoyl group. salt. [4] The above-mentioned [1], wherein R ₆ is a benzyl group, a 2-thienylmethyl group, a hydroxy (2-thienyl) methyl group, a p-methoxybenzoyl group, a 2-thienylcarbonyl group, a 1-phenylethenyl group. The phthalazine derivative according to [2] or [3], a prodrug thereof, or a pharmaceutically acceptable salt thereof. [5] The phthalazine derivative according to the above-mentioned [1], wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₇ are a hydrogen atom, and R ₆ is a hydroxy (2-thienyl) methyl group. Prodrugs or pharmaceutically acceptable salts thereof. [6] A tumor necrosis factor comprising the phthalazine derivative according to the above [1], [2], [3], [4] or [5] or a prodrug thereof or a pharmaceutically acceptable salt thereof as an active ingredient. To production or secretion inhibitors.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The functional groups in the present invention will be described below. As the halogen atom, a fluorine atom, a chlorine atom,
Bromine atoms, and iodine atoms. Examples of the alkyl group include a linear or branched alkyl group having 1 to 6 carbon atoms, and specifically, methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, 2-methylpropyl, dimethylethyl , Pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl,
3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-
Dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethyl-1-methylpropyl, and 1-ethyl-2-
Methylpropyl and the like can be mentioned. Examples of the substituent in the substituted alkyl group include a hydroxyl group and a halogen atom such as methoxy, ethoxy, propoxy, butyloxy and the like.
To 6 lower alkoxy groups, carboxyl groups, amino groups,
For example, methylamino, ethylamino, dimethylamino,
A substituted amino group substituted with an alkyl group having 1 to 6 carbon atoms such as diethylamino, for example, an aryl group such as phenyl and naphthyl, for example, 4-hydroxyphenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-carboxyphenyl, 3, Substituted aryl groups substituted with one or more substituents such as 4-dihydroxyphenyl, 3,4-dichlorophenyl and the like, and heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl and indolyl, for example, 4-
Substituted heterocyclic groups such as methyl-2-thienyl and 4-methyl-2-imidazolyl, for example, aliphatic or aromatic acyl groups such as acetyl and benzoyl, and aliphatic or aromatic acyl groups such as acetyloxy and benzoyloxy; A substituted carbamoyl group substituted by an alkyl group having 1 to 6 carbon atoms such as an aromatic acyloxy group, a carbamoyl group such as monomethylcarbamoyl and dimethylcarbamoyl, and a carbamoyl group having 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl. And a lower alkoxycarbonyl group. Note that the substituent may be substituted with one or more substituents, and when a plurality of substituents are substituted, they may be substituted with the same or different substituents. Specific examples of the substituted alkyl group include hydroxymethyl, chloromethyl, bromomethyl, trichloromethyl, 2-hydroxyethyl, 2-aminoethyl, 3-hydroxypropyl, benzyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, 4-methoxy Examples include phenylmethyl, 4-hydroxyphenylmethyl, 2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl, 3-furylmethyl, and hydroxy-2-thienylmethyl.

Examples of the alkoxy group include methoxy, ethoxy, propoxy, methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, pentoxy,
1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,
2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethyl-1-methylpropoxy, and 1
And alkoxy groups having 1 to 6 carbon atoms such as -ethyl-2-methylpropoxy. Examples of the substituent of the substituted alkoxy group include the same substituents as those of the substituted alkyl group.
Specific examples of the substituted alkoxy group include, for example, pentyloxy, hexyloxy, allyloxy, isopentyloxy, benzyloxy, cyclopropylmethoxy, trifluoromethoxy, 2-pyrrolidinoethoxy, 2-pyridylmethoxy and the like.

Specific examples of the aryl group include a phenyl group and a naphthyl group. Examples of the substituent in the substituted aryl group include the same examples as in the case of the substituted alkyl group. Specific examples of the substituted aryl group include, for example,
4-hydroxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4- (dimethylethyl)
Examples include phenyl, 3-ethylphenyl, 2,3-dimethoxyphenyl, 3,5-dichlorophenyl, and 4-hydroxy-3,5-bis (dimethylethyl) phenyl.

Examples of the acyl group include those having 1 carbon atom such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl and pivaloyl.
-6 alkanoyl groups such as benzoyl, tenoyl,
An aroyl group such as floyl is exemplified. Examples of the substituent in the substituted acyl group include the same examples as in the case of the substituted alkyl group. Specific examples of the substituted alkanoyl group in the substituted acyl group include, for example, chloroacetyl, phenylacetyl, trifluoroacetyl, 3-hydroxypropionyl, isobutyryl, 4-methoxy-butyryl, isovaleryl, pivaloyl, and 12-hydroxylauroyl. No. Specific examples of the substituted aroyl group in the substituted acyl group include, for example, 4-methoxybenzoyl,
Examples include hydroxybenzoyl, 4-chlorobenzoyl, 2,4-dichlorobenzoyl, 3-nitrobenzoyl, 2,4,6-trimethoxybenzoyl and the like.

Examples of the substituent in the substituted amino group include the same examples as in the case of the substituted alkyl group. Specific examples of the substituted amino group include, for example, N-methylamino, N, N-dimethylamino, N-ethylamino, N, N-diethylamino, N-
(Dimethylethyl) amino, N-phenylamino and the like, and examples of the cyclic amino group include 5- to 8-membered heterocycles such as morpholino, piperazino and piperidino.

Examples of the acyloxy group include those having 1 carbon atom such as formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy and pivaloyloxy.
And alkanoyloxy groups having 10 or less carbon atoms, such as alkanoyloxy groups of 6 to 6, and benzoyloxy. Examples of the substituent in the substituted acyloxy group include the same substituents as those in the substituted alkyl group. Specific examples of the substituted alkanoyloxy group in the substituted acyloxy group include, for example, cyclopropylmethoxy, trifluoromethoxy, 2-pyrrolidinoethoxy, benzyloxy,
2-pyridylmethoxy and the like. Specific examples of the substituted aroyloxy group in the substituted acyloxy group include:
For example, 4-methoxybenzoyl, 4-hydroxybenzoyl, 4-chlorobenzoyl, 2,4-dichlorobenzoyl, 3-
Nitrobenzoyl, 2,4,6-trimethoxybenzoyl and the like can be mentioned. The alkenyl group includes an alkenyl group having 2 to 7 carbon atoms, and specifically, for example, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl,
2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2- Heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl and the like.

Examples of the substituent in the substituted alkenyl group include the same examples as in the case of the substituted alkyl group. Specific examples of the substituted alkenyl group include, for example, 2-chloro-1-propenyl and 2-methyl-1-propenyl , 3-hydroxy-1-propenyl, 2-chloro-1-butenyl, 4-methoxy-2-butenyl, 4-phenyl-3-butenyl, 3-bromo-1-pentenyl,
5-amino-3-pentenyl, 3-ethyl-2-pentenyl, 3-bromo-2-pentenyl, 3.4-dimethyl-1-hexenyl, 6-hydroxy-2-hexenyl, 2-methyl-1-heptenyl, 6- Chloro-6-heptenyl, 1-thienylethenyl, 2-thienylethenyl, 1-phenylethenyl, 2-phenylethenyl, 1,2-dithienylethenyl, 1,2-diphenylethenyl and the like.

The heterocyclic group may be a monocyclic or bicyclic heteroaromatic group containing 9 or less carbon atoms and 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur. Monocyclic saturated heterocycles containing the number 6 or less and 1 to 3 identical or different hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom are exemplified. Examples of heteroaromatic groups are 2-pyridyl, 3-pyridyl, 4-
Pyridyl, 2-pyrimidinyl, 4-pyridinyl, 5-
Pyrimidinyl, 2-thiazolyl, 4-thiazolyl, 5-
Thiazolyl, 2-oxazolyl, 4-oxazolyl, 5
-Oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-
Isothiazolyl, 5-isothiazolyl, 2-furyl, 3
-Furyl, 2-imidazolyl, 4-imidazolyl, 2-
Thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-pyrazinyl, 3-pyridazinyl, 4-pyridazinyl, 1H-1,2,4-triazole-1- Il, 1
H-1,2,4-triazol-3-yl, 1H-1,
2,4-triazol-5-yl, 3-oxadiazolyl, 5-oxadiazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 4-benzo [b] furan, 5
-Benzo [b] furan, 6-benzo [b] furan, 7-
Benzo [b] furan, 4-benzimidazole, 5-benzimidazole, 4-benzothiazole, 5-benzothiazole, 6-benzothiazole, 7-benzothiazole, 4-benzoxazole, 5-benzoxazole, 6-benzoxazole , 7-benzoxazole and the like.

The monocyclic saturated heterocyclic ring is preferably a 5- or 6-membered saturated heterocyclic ring. Examples of 5-membered saturated heterocycles include 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-oxolanyl,
Oxolanyl, 2-thiolanyl, 3-thiolanyl. Examples of the 6-membered saturated heterocyclic ring include piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl Morpholino, 2-morpholinyl, 3
-Morpholinyl and the like. The monocyclic saturated heterocycle may be substituted with an alkyl group.

The prodrug of the compound of the present invention refers to a prodrug in which a hydroxyl group and an amino group as substituents of the compound of the present invention are protected by an acyl group or the like. The compounds of the present invention may form salts with pharmaceutically acceptable acids or bases, such as salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid. Salts with organic carboxylic acids such as formic acid, acetic acid, fumaric acid, maleic acid, malic acid, tartaric acid, aspartic acid or glutamic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydroxybenzenesulfonic acid or dihydroxybenzene Salts with sulfonic acids such as sulfonic acid, salts with alkali metals such as sodium or potassium,
Salts with alkaline earth metals such as calcium or magnesium, salts with organic bases such as trimethylamine, triethylamine or pyridine, or ammonium salts and the like can be mentioned.

The compounds specifically included in the present compound (1) include, for example, 1- (4-benzylpiperidin-1-yl) phthalazine, 1- [4-benzoylpiperidino] phthalazine, 1- [ 4- (p-methoxybenzoyl) piperidino] phthalazine, 1- (4-thenoylpiperidino) phthalazine, 1- [4-
(Hydroxythienylmethyl) piperidino] phthalazine, 1- [4- (thienylmethyl) piperidino] phthalazine,
1- [4- (1-phenylvinyl) piperidino] phthalazine, 1-
Compounds such as [4- (1-phenylvinyl) piperidino] phthalazine are preferred, and preferably 1- (4-benzylpiperidine-
Examples thereof include 1-yl) phthalazine, 1- [4- (thienylmethyl) piperidino] phthalazine, 1- [4- (hydroxythienylmethyl) piperidino] phthalazine, and more preferably. 1
-[4- (hydroxythienylmethyl) piperidino] phthalazine.

The compound of the present invention can be synthesized, for example, by the following production method. In each reaction formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ have the same meaning as described above, and X represents a halogen atom.

Manufacturing method 1

[0023]

Embedded image

Each step in the above reaction formula will be described in detail step by step. Production method 1 is a general method for synthesizing compound (1) of the present invention. A phthalazine derivative (2) commercially available, obtained in the same manner as a known compound or a known compound, or obtained according to the method of Production Method 2 described below, in an inert organic solvent,
The compound of the present invention (1a) can be obtained by reacting with the piperidine derivative represented by (3) while controlling the reaction in the range of 0 ° C. to 200 ° C. In addition, this reaction may be performed by mixing a tertiary amine (for example, triethylamine, pyridine, N-methylmorpholine, N, N-dimethylaminopyridine, diisopropylethylamine, etc.). When X is a halogen atom, it may be further added to an inert organic solvent at room temperature to 100 ° C. and at atmospheric pressure to 1 ° C.
While controlling the reaction in the range of 00 atm, nickel, palladium, platinum, rhodium, ruthenium, cobalt, copper,
The target compound is obtained by hydrogenation using a metal catalyst such as a zinc compound or a catalyst obtained by adding a metal catalyst on activated carbon as a carrier, or reduction using ammonium formate under the same catalyst as above. The compound of the present invention represented by (1b) can be obtained.

Production method 2 is a method for synthesizing a dihalogenophthalazine derivative represented by the formula (2). Manufacturing method 2

[0026]

Embedded image

Commercially available or known 1,4-dihydroxyphthalazine derivatives (4) are commonly used halogenating agents, for example,
Phosphorus oxychloride, phosphorus oxybromide, thionyl chloride,
By reacting with thionyl bromide or the like, dihalogenophthalazine (2) can be produced.

Production methods 3 to 8 are methods for synthesizing compound (3). Manufacturing method 3

[0029]

Embedded image

Production method 3 is a method of synthesizing compound (3a) in which R ₇ is a hydrogen atom and R ₆ is an alkyl, substituted alkyl, aryl, substituted aryl, or heterocyclic ring in the piperidine derivative represented by (3). It is an example. Commercially available 4-benzylpiperidone represented by (5) was treated with -78 in an inert organic solvent.
Alkyl, substituted alkyl, aryl, substituted aryl lithium (eg, methyl lithium, ethyl lithium, propyl lithium, phenyl lithium,
Organic lithium compounds such as benzyllithium, thienyllithium, furyllithium, etc., and Grignard reagents such as alkyl, substituted alkyl, aryl, substituted arylmagnesium bromide or chloride (eg, methylmagnesium bromide, ethylmagnesium bromide,
Propyl magnesium bromide, phenyl magnesium bromide, benzyl magnesium chloride, thienyl magnesium bromide, furyl magnesium bromide, etc.)
To give an alcohol (6). Further, inorganic acids (for example, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, boric acid, etc.) and organic acids (for example, methanesulfonic acid, toluene, etc.) in an inert organic solvent at a temperature of 0 ° C. to 150 ° C. Sulfonic acid, naphthalene sulfonic acid, oxalic acid, acetic acid, trifluoroacetic acid, etc.) and a dehydrating reagent generally used for a dehydration reaction to lead to an alkenyl or substituted alkenyl derivative represented by (7). it can. Nickel, palladium, platinum, rhodium, and the like are formed by controlling the reaction between the double bond and the benzyl group of compound (7) in an inert organic solvent at room temperature to 100 ° C. and at atmospheric pressure to 100 atm. Ruthenium, cobalt,
The piperidine derivative represented by (3a) can be obtained by hydrogenation using a metal catalyst such as a copper or zinc compound or a catalyst obtained by adding a metal catalyst to activated carbon as a carrier.

Manufacturing method 4

[0032]

Embedded image

Production method 4 is a method for separately synthesizing compound (3a) in which R ₇ is a hydrogen atom and R ₆ is an alkyl, substituted alkyl, aryl, substituted aryl, or heterocyclic ring in the piperidine derivative represented by (3). It is. Commercially available 4-benzylpiperidone represented by (5) in an inert organic solvent at -78 ° C
While controlling the reaction in the range from to 100 ° C, a base (for example, an inorganic base such as sodium hydride, potassium hydride, potassium hydroxide, sodium hydroxide, or triethylamine, piperidine, morpholine, N-methylmorpholine,
Organic bases such as dimsyl anion, lithium diisopropylamide, sodium bistrimethylsilylamide and the like can be mentioned. ) To produce an enolate, and a sulfonyl chloride derivative (eg, p-toluenesulfonyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, etc.)
To give the enol ether derivative (8). This reaction is described in the literature (Synthesis, 283 (1980), Synthesis, 85
(1982)). The thus obtained (8) was placed in an aprotic organic solvent (for example, a hydrocarbon solvent such as toluene or xylene, ether, THF,
R ₆ Li, (R ₆ ) ₂ Cu, R ₆ CuLi, R ₆ MgX while controlling the reaction in the range of −78 ° C. to 100 ° C.
Is reacted to obtain a coupling body (9). This compound (9) is dissolved in an inert organic solvent (for example, a hydrocarbon solvent such as toluene and xylene, an ether solvent such as ether, THF, dioxane and dimethoxyethane, an alcohol solvent such as methanol and ethanol, and acetonitrile). , DMF, DMSO, etc.) and a base (eg, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium bicarbonate) while controlling the reaction in the range of -78 ° C to 100 ° C. In the presence of an inorganic base such as sodium carbonate, potassium carbonate, cesium carbonate and potassium phosphate, and an organic base such as triethylamine, diisopropylethylamine, diethylamine, morpholine, N-methylmorpholine and piperidine, a palladium catalyst (for example,
Dichlorobisdiphenylphosphonoferrocene palladium, tetrakistriphenylphosphonopalladium, palladium diacetate, dichlorobistriphenylphosphonopalladium, etc.) to form an organic boron compound, an organic aluminum compound, an organic zinc compound, an organic silicon compound. And an organic tin compound. Nickel, palladium and platinum were added to the double bond and benzyl group of the compound (9) in an inert organic solvent while controlling the reaction at room temperature to 100 ° C. and at atmospheric pressure to 100 atm. Hydrogenation using a metal catalyst such as rhodium, ruthenium, cobalt, copper, zinc compound, or a catalyst obtained by adding a metal catalyst on activated carbon as a carrier, to convert it into the piperidine derivative represented by (3a) can do.

Manufacturing method 5

[0035]

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In the production method 5, compound (3a) in which R ₇ is a hydrogen atom and R ₆ is an alkyl, substituted alkyl, aryl, substituted aryl, or heterocyclic ring in the piperidine derivative represented by (3). It is a separate synthesis method. While controlling the reaction of commercially available 4-benzylpiperidone represented by (5) in an inert organic solvent in the range of -78 ° C to 100 ° C, a reducing agent (for example, diisobutylaluminum hydride, lithium aluminum hydride, Lithium tri-t-butoxyaluminum hydride, sodium aluminum hydride, sodium triethoxyaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, sodium diethylaluminum hydride, sodium borohydride, lithium borohydride, etc. By using a metal hydride for reduction, an alcohol compound (10) can be obtained. While controlling the reaction of compound (10) in an inert solvent in the range of -78 ° C to 200 ° C, a commonly used halogenating agent (hydrogen chloride, hydrogen bromide,
Hydrogen iodide, phosphorus tribromide, phosphorus pentabromide, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, thionyl bromide, triphenylphosphine-carbon tetrachloride, triphenylphosphine-carbon tetrabromide, diphenyltribromo Compound (11) can be obtained by halogenation using phosphoran, diphenyltrichlorophosphoran and the like. Compound (11) in an aprotic organic solvent (for example, a hydrocarbon-based solvent such as toluene and xylene, and an ether-based solvent such as ether, THF, dioxane, and dimethoxyethane) at -78 ° C
While controlling the reaction in the range from to 100 ° C, R ₆ Li,
By reacting a carbon anion such as (R ₆ ) ₂ Cu, R ₆ CuLi, R ₆ MgX, or in an inert organic solvent (for example,
Hydrocarbon solvents such as toluene and xylene, ether, T
Ether solvents such as HF, dioxane and dimethoxyethane; alcohol solvents such as methanol and ethanol; aprotic polar solvents such as acetonitrile, DMF and DMSO; and heterocyclic compounds (for example, pyrrole, indole, pyrazole, (Indazole, imidazole, etc.) to give compound (12). This reaction is carried out using a tertiary amine (eg, triethylamine, pyridine, N-methylmorpholine, N, N-dimethylaminopyridine, diisopropylethylamine, etc.).
May be mixed to carry out the reaction. Further, the compound (1
(3a) can be obtained by deprotecting the benzyl group of 2) according to a conventional method.

Manufacturing method (6)

[0038]

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Production method (6) is another method for synthesizing compound (3). A Wittig reaction is carried out on a commercially available 4-benzylpiperidone represented by (5) in an inert organic solvent in a range of -78 ° C to 100 ° C to obtain a substituted alkenylpiperidine derivative represented by (13). Obtainable. As the phosphonium salt used at this time, for example, P ⁺ (R ₁₁ ) ₃ R ₆ X ⁻ (R ₆ has the same meaning as described above. R ₁₁ represents alkyl or phenyl, and X represents a halogen atom.) And more specifically, triphenylphosphonium methyl bromide, triphenylphosphonium ethyl bromide, triphenylphosphonium propyl bromide, triphenylphosphonium phenyl bromide, triphenylphosphonium benzyl bromide, triphenylphosphonium thenoyl bromide, triphenylphosphonium Examples include triphenylphosphonium alkyl or substituted alkyl bromide, such as furyl bromide, or triphenylphosphonium aryl or substituted aryl bromide. As the base to be used, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydroxide, an inorganic base such as sodium hydroxide, butyllithium, methyllithium, dimsyl anion, lithium diisopropylamide, Organic bases such as sodium bistrimethylsilylamide can be used. The double bond and the benzyl group of the compound (13) thus obtained are separated from the room temperature to 100 ° C. and from the atmospheric pressure to 100 ° C. in an inert organic solvent.
Hydrogenation using a metal catalyst such as nickel, palladium, platinum, rhodium, ruthenium, cobalt, copper, zinc compounds, or a catalyst obtained by adding a metal catalyst on activated carbon as a carrier while controlling the reaction within the atmospheric pressure range By doing so, it can be converted to the piperidine derivative represented by (3b).

Production method 7

[0041]

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The production method 7 includes the compounds (3b) and (3b) of the piperidine derivatives represented by (3) wherein R ₇ is a hydrogen atom.
c) and (3d). It is a known compound (1
1) -benzyl-4-formylpiperidine represented by 4) in an inert organic solvent in the range of -78 ° C to room temperature,
Organolithium compounds such as substituted alkyl, aryl, and substituted aryllithium (eg, methyllithium, ethyllithium, propyllithium, phenyllithium, benzyllithium, thienyllithium, furyllithium), and alkyl, substituted alkyl, aryl, and substituted arylmagnesium bromides Alternatively, it is reacted with a Grignard reagent such as chloride (for example, methyl magnesium bromide, ethyl magnesium bromide, propyl magnesium bromide, phenyl magnesium bromide, benzyl magnesium chloride, thienyl magnesium bromide, furyl magnesium bromide, etc.) to obtain an alcohol (15). . Further, in an inert organic solvent, an inorganic acid (eg, hydrochloric acid, sulfuric acid, nitric acid,
Hydrobromic acid, phosphoric acid, boric acid, etc.), organic acids (eg, methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, oxalic acid, acetic acid, trifluoroacetic acid, etc.), and generally used for dehydration reactions The alkenyl or substituted alkenyl derivative represented by the formula (13) can be obtained by a reaction using the resulting dehydration reagent. The double bond and the benzyl group of compound (13) are reacted with an inert organic solvent at room temperature for 1 hour.
While controlling the reaction in the range of 00 ° C and in the range of atmospheric pressure to 100 atm, a metal catalyst such as nickel, palladium, platinum, rhodium, ruthenium, cobalt, copper, or a zinc compound, or a metal on activated carbon as a carrier. By hydrogenation using a catalyst to which a catalyst has been added, (3b)
Can be obtained. In addition, a piperidine derivative having a hydroxy substituent at R _{6 ′} represented by (3c) can be obtained by reductively deprotecting the benzyl group of compound (15) in the same manner as described above. Further, compound (15) is converted to an acidic aqueous solution (eg, hydrochloric acid, sulfuric acid, nitric acid, acetic acid, etc.), an alkaline aqueous solution (eg, sodium hydroxide, potassium hydroxide, etc.), an organic solvent (dioxane, THF, acetone, pyridine, ether). , Dichloromethane, benzene, hexane, etc.)
In the range of -78 ° C to 100 ° C, an oxidizing agent (for example, permanganate such as potassium permanganate, sodium permanganate, barium permanganate, manganese dioxide, chromic acid, sodium bichromate, dichromic acid) Compound (16) is obtained by reacting with a dichromate such as potassium, pyridinium chlorochromate, pyridinium dichromate, etc., and reductive deprotection of the benzyl group in the same manner as described above to give (3d R _{6 ′ represented} by)
An acylpiperazine derivative having a carbonyl substituent can be obtained.

Production method 8

[0044]

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Production method 8 is a general method for synthesizing a group of compounds having a substituent at both R ₆ and R ₇ among the piperidine derivatives represented by (3). That is, the ketone of the compound (16), which is commercially available, known, or can be synthesized by the above-mentioned Production method 7, is converted into an enone compound (17) by a commonly used method. The conversion method includes the following example.

(1) Direct dehydrogenation method Compound (16) is dissolved in an inert organic solvent (for example, benzene, toluene, xylene, chlorobenzene, dioxane, acetone, methanol, ethanol, butanol,
Reacts with a dehydrogenating reagent (eg, quinones such as chloranil, DDQ, tetrachlorobenzoquinone, and oxidizing agents such as selenium, selenium dioxide, sulfur, manganese dioxide, and mercury acetate) in the range of room temperature to 200 ° C. By doing so, an enone compound (17) can be obtained.

(2) α-Halogenation-Dehalogenation Method Compound (16) is placed in an inert organic solvent (eg, chloroform, dichloromethane, carbon tetrachloride, ether, dioxane, acetic acid, formic acid, etc.) or in an aqueous solution ( Hydrochloric acid, sulfuric acid aqueous solution, etc.), hydrochloric acid gas, chlorine gas, bromine, bromate, thionyl chloride, -78 ° C to 100 ° C.
Reaction with a halogenating agent such as thionyl bromide, copper chloride, copper bromide, iron chloride, etc., and halogenation at the α-position of carbonyl, and then in an inert organic solvent (for example, hydrocarbons such as hexane, benzene, xylene, etc.) Solvent, ether, ether solvent such as dioxane, methanol, ethanol,
Alcoholic solvents such as butanol and ethylene glycol, aprotic hydrophilic solvents such as acetone, acetonitrile, DMSO, DMF, etc.) and bases (eg, sodium hydroxide, potassium hydroxide, etc.) in the range of -78 ° C to 200 ° C. Alkali alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide and potassium butoxide; amines such as triethylamine, pyridine, collidine, quinoline, DBN and DBU); or salts (for example, , Lithium chloride, lithium bromide, lithium perchlorate, etc.) to give compound (17)
Can be obtained. In this reaction, a base and a salt may be mixed.

(3) Enol ether-oxidation method Compound (16) was placed in an inert organic solvent (for example, a hydrocarbon solvent such as hexane, toluene, or xylene, or an ether solvent such as ether or THF) at -78 ° C. From 10
In the range of 0 ° C, a base (for example, an inorganic base such as sodium hydride, potassium hydride, potassium hydroxide, or sodium hydroxide, triethylamine, piperidine, morpholine, N-methylmorpholine, dimsyl anion, lithium diisopropylamide, An enolate is generated using an organic base such as sodium bistrimethylsilylamide), and reacted with silyl chloride (eg, trimethylsilyl chloride, triethylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, etc.), After the silyl enol ether is reacted in the solvent shown in 1) using the oxidizing agent shown in 1), the enone compound (17) can be obtained. In addition, this oxidation reaction is carried out in an inert organic solvent (for example, hydrocarbon solvents such as benzene, toluene, hexane, etc .; halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane, etc .; ethers such as tetrahydrofuran, diethyl ether, dioxane, etc.). System solvent, aprotic polar solvent such as dimethylformamide, dimethylsulfoxide, hexamethylphosphorotriamide), Pd catalyst (for example,
Palladium acetate, palladium chloride, etc.).

(4) α-Sulfinylation-oxidation-pyrolysis method Compound (16) is dissolved in an inert organic solvent (for example, a hydrocarbon solvent such as hexane, toluene, or xylene, or an ether solvent such as ether or THF). Etc.), from -78 ° C to 10
In the range of 0 ° C, a base (for example, an inorganic base such as sodium hydride, potassium hydride, potassium hydroxide, or sodium hydroxide, triethylamine, piperidine, morpholine, N-methylmorpholine, dimsyl anion, lithium diisopropylamide, An enolate is formed using an organic base such as sodium bistrimethylsilylamide, and a dialkyl or diaryl sulfide (eg, dimethyl sulfide, diphenyl sulfide, etc.), an alkyl sulfinyl halogenoid, or an aryl sulfinyl halogenoid (eg, , Methylsulfinyl chloride, phenylsulfinyl chloride, etc.) to synthesize an α-alkylthio or arylthio compound. As an oxidizing agent, an inorganic peroxide such as sodium periodate (representative solvent: methanol, water, etc.) or an organic peracid such as m-chloroperbenzoic acid (representative solvent: dichloromethane) is used. Then, thermal decomposition (using chloroform, carbon tetrachloride, benzene, toluene, xylene, etc., around the reflux temperature of the solvent) is performed to obtain the enone compound represented by (17).

(5) α-Selenylation-Oxidation-Thermal Decomposition Compound (16) is dissolved in an inert organic solvent (for example, a hydrocarbon solvent such as hexane, toluene and xylene, an ether solvent such as ether and THF, etc.). ), -78 ° C to 10
In the range of 0 ° C, a base (for example, an inorganic base such as sodium hydride, potassium hydride, potassium hydroxide, or sodium hydroxide, triethylamine, piperidine, morpholine, N-methylmorpholine, dimsyl anion, lithium diisopropylamide, Using an organic base such as sodium bistrimethylsilylamide) to form an enolate, a dialkyl or diaryl selenide (eg, dimethyl selenide, diphenyl selenide, etc.), an alkyl selenyl halogenoid, or an aryl selenide A nylhalogenoid (eg, methylselenyl chloride, phenylselenyl chloride, phenylselenyl bromide, etc.) is reacted to synthesize an α-alkylseleno or arylseleno compound. Using this as an oxidizing agent, sodium periodate, hydrogen peroxide (representative solvent:
Oxidation using an inorganic peroxide such as methanol, water, etc.) or an organic peracid such as m-chloroperbenzoic acid (typical solvent: dichloromethane), followed by thermal decomposition (dichloromethane, chloroform, carbon tetrachloride) , Benzene, toluene,
Using xylene or the like, from -78 ° C to around room temperature)
An enone compound represented by (17) can be obtained.

The enone compound (17) thus obtained
In an inert organic solvent (for example, hexane, toluene,
Hydrocarbon-based solvents such as xylene, ether-based solvents such as ether and THF), alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic,
A substituted heterocyclic organic copper compound R ₇ Cu (R ₇ has the same meaning as described above), cuprate R ₇ CuLi (R ₇ has the same meaning as described above), or Grignard reagent R ₇ MgX (R ₇ and X have the same meanings as described above) and copper (I) halide (for example, CuCl, CuBr, CuI, etc.) are combined and reacted to obtain the Michael adduct (18). Further, compound (18) is placed in an inert organic solvent (for example, a hydrocarbon-based solvent such as hexane, toluene, or xylene, or an ether-based solvent such as ether or THF).
While controlling the reaction in the range of -78 ° C to 100 ° C, a reducing agent (for example, diisobutylaluminum hydride, lithium aluminum hydride, lithium t-butoxyaluminum hydride, sodium aluminum hydride, sodium triethoxyaluminum hydride) By using a metal hydride such as sodium bis (2-methoxyethoxy) aluminum hydride, sodium diethylaluminum hydride, sodium borohydride, lithium borohydride, etc.
9) can be obtained. The obtained compound (19) is mixed with an inorganic acid (eg, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, boric acid, etc.) and an organic acid (eg, , Methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, oxalic acid, acetic acid, trifluoroacetic acid, etc.) and a dehydrating reagent generally used in a dehydration reaction to react with the alkenyl or substituted group represented by (20). It can lead to alkenyl derivatives.

The double bond and the benzyl group of the compound (20) were reacted with nickel, palladium, and the like in an inert organic solvent while controlling the reaction at room temperature to 100 ° C. and at atmospheric pressure to 100 atm. Hydrogenation using a metal catalyst such as a platinum, rhodium, ruthenium, cobalt, copper, zinc compound or a catalyst obtained by adding a metal catalyst on activated carbon as a carrier allows hydrogenation of the piperidine derivative represented by (3e). Obtainable. By deprotecting the protected benzyl compound represented by (18) or (19) by the same method, it is possible to synthesize the acyl derivative represented by (3f) or the hydroxy-substituted compound represented by (3g). it can. After completion of the reaction, the target compound is isolated and purified from the reaction mixture by a method generally known in the art, for example, by appropriately selecting and using a solvent extraction, column chromatography, recrystallization and the like. it can. The compound of the present invention includes stereoisomers and geometric isomers, and further includes all hydrates and crystal forms.

The inhibitor of tumor necrosis factor production or secretion of the present invention can be administered orally or parenterally.
That is, it can be orally administered in the form of commonly used dosage forms, for example, tablets, capsules, syrups, suspensions, etc., or injected in the form of solutions, such as solutions, emulsions, suspensions, etc. It can be administered as an agent. It can also be administered rectally in the form of suppositories. Such a dosage form can be produced according to a general method by blending the active ingredient with a usual carrier, excipient, binder, stabilizer and the like. When used in the form of an injection, a buffer, a solubilizing agent, an isotonic agent and the like can be added. The dosage and frequency of administration vary depending on symptoms, age, body weight, dosage form, etc.
In the case of oral administration, usually 1 dose per day for adults
0 to 500 mg, or 1 to 100 mg when parenterally administered, can be administered once or in several divided doses.

[0054]

The present invention will be described in detail below with reference to examples and reference examples, but the present invention is not limited to these examples. In all the examples, the free amino compound was made acidic by adding a hydrochloric acid / diethyl ether solution (about 7%) in a dichloromethane or chloroform solution, and the resulting salt was washed well with diethyl ether and used as the hydrochloride.

Reference Example 1 Phosphorus oxychloride (90.0 ml) was added dropwise to 1-chlorophthalazine phthalazone (30.0 g), and the mixture was heated to 100 ° C. After 1 hour, the reaction solution was allowed to cool,
It was poured into ice water (400 ml). The mixture was neutralized with a saturated aqueous solution of potassium carbonate, and the precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain 1-chlorophthalazine (31.1 g). ¹ H-NMR (CDCl ₃ ): δ 8.04 (3
H, m), 8.33 (1H, m), 9.45 (1H, s)

Example 1 1- (4-benzylpiperidin-1-yl) phthalazine 1-chlorophthalazine (1.00 g) obtained in Reference Example 1 was dissolved in xylene (50 ml), and triethylamine (4.2 ml) was dissolved.
And 4-benzylpiperidine (1.63 ml) were added, and the mixture was refluxed for about 5 hours. The reaction solution was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography,
1- (4-Benzylpiperidin-1-yl) phthalazine (1.46 g) was obtained. ¹ H-NMR (CDCl ₃ ): δ 1.57-1.66 (2H, m), 1.82-1.86 (3
H, m), 2.66 (2H, d, J = 6.6Hz), 3.03 (2H, m), 3.92 (2H,
d, J = 13.2Hz), 7.18-7.28 (3H, m), 7.29-7.34 (2H, m), 7.
73-7.85 (3H, m), 7.98-8.02 (1H, m), 9.11 (1H, d, J = 0.
7Hz).

Example 2 1- [4-Benzoylpiperidino] phthalazine 1-chlorophthalazine (1.00 g) obtained in Reference Example 1 was converted to DMF.
(25 ml), triethylamine (8.4 ml) and benzoylpiperidine hydrochloride (1.86 g) were added, and the same operation as in Example 1 was performed to obtain 1- [4-benzoylpiperidino] phthalazine (121 mg). . ¹ H-NMR (CDCl ₃ ): δ 2.11-2.19
(4H, m), 3.25 (2H, m), 3.59 (1H, m), 4.02 (2H, d, J = 1
3.2Hz), 7.56 (3H, m), 7.84 (2H, m), 8.00 (4H, m), 9.15
(1H, s).

Example 3 1- [4- (p-methoxybenzoyl)
Piperidino] phthalazine 1-chlorophthalazine (1.00 g) obtained in Reference Example 1 was added to DMF.
(25 ml), and triethylamine (8.4 ml) and p-methoxybenzoylpiperidine hydrochloride (1.86 g) were added.
The same operation as in Example 1 was performed to obtain 1- [4- (p-methoxybenzoyl) piperidino] phthalazine (121 mg). ¹ H-NMR (CDCl ₃ ): δ 2.08-2.24 (4H, m), 3.24 (2H, m),
3.55 (1H, m), 3.90 (3H, s), 4.03 (2H, d, J = 13.2Hz), 6.
90 (2H, m), 7.83 (2H, m), 8.05 (4H, m), 9.17 (1H, s).

Example 4 1- (4-Thenoylpiperidino) phthalazine 1-chlorophthalazine (2.52 g) obtained in Reference Example 1 was converted to DMF.
(150 ml), triethylamine (10.6 ml) and thenoyl piperidine hydrochloride (4.26 g) were added, and the same operation as in Example 1 was carried out to give 1- (4-thenoylpiperidino) phthalazine (3.00 g). Obtained. ¹ H-NMR (CDCl ₃ ): δ 2.09-2.31
(4H, m), 3.23 (2H, dt, J = 12.5, 2.6 Hz), 3.36-3.48
(1H, m), 4.00-4.06 (2H, m), 7.19 (1H, dd, J = 5.0,
3.6Hz), 7.69 (1H, dd, J = 5.0, 3.6Hz), 7.79-7.92 (4
H, m), 8.05-8.12 (1H, m), 9.18 (1H, s)

Example 5 1- [4- (Hydroxythienylmethyl) piperidino] phthalazine 1- (4-thenoylpiperidino) phthalazine (1.00 g) obtained in Example 4 was treated with ethanol (100 ml) and methylene chloride (100 ml). 20ml) and sodium borohydride (300mg)
Was added. After stirring at room temperature for one hour, the solvent was distilled off, chloroform and water were added, and the organic layer was separated. The organic layer was washed with water and brine, and dried (MgSO ₄ ). The solvent was distilled off under reduced pressure,
The residue was purified by silica gel column chromatography (elution solvent, chloroform: methanol = 97: 3),
1- [4- (Hydroxythienylmethyl) piperidino] phthalazine (0.97 g) was obtained. ¹ H-NMR (CDCl ₃ ): δ 1.60-1.82
(3H, m), 2.00 (1H, m), 2.25 (1H, m), 2.84 (1H, b
s), 3.06 (2H, m), 3.92 (2H, m), 4.82 (1H, d, J = 7.6
Hz), 7.00 (2H, m), 7.29 (1H, t, J = 1.7Hz), 7.81 (3
H, m), 8.01 (1H, t, J = 4.0Hz), 9.10 (1H, s)

Example 6 1- [4- (thienylmethyl) piperidino] phthalazine 1- (4-thenoylpiperidino) phthalazine (493 mg) obtained in Example 4 was dissolved in trifluoroacetic acid (20 ml).
After stirring overnight at room temperature to which sodium borohydride (150 mg) was carefully added, the solvent was distilled off under reduced pressure, ethyl acetate and aqueous sodium bicarbonate were added, and the organic layer was separated. The organic layer was washed with water and brine, and dried (MgSO4). The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent, ethyl acetate) to give 1- [4- (thienylmethyl) piperidino]
Phthalazine (38 mg) was obtained. ¹ H-NMR (CDCl ₃ ): δ1.58-1.68 (2H, m), 1.82-1.95 (3H,
m), 2.89 (2H, d, J = 6.6Hz), 3.02-3.12 (2H, m), 3.91-3.
97 (2H, m), 6.83 (1H, dd, J = 3.5, 1.2Hz), 6.95 (1H, d
d, J = 5.1, 3.5Hz), 7.15 (1H, dd, J = 5.1, 1.2Hz), 7.76
-7.88 (3H, m), 7.99-8.04 (1H, m), 9.13 (1H, s).

Example 7 1- [4- (1-Phenylvinyl) piperidino] phthalazine 7-1 1-benzyl-4-benzoylpiperidine 4-benzoylpiperidine (5.00 g) was treated with methylene chloride (50m2).
l), triethylamine (7.7 ml) and benzyl bromide (2.63 ml) were added, and the mixture was stirred at room temperature overnight. Water was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layers were combined, washed with water and saturated saline, and then dried (MgSO ₄ ). The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent, hexane: ethyl acetate = 3: 1) to obtain 1-benzyl-4-benzoylpiperidine (4.15 g). ¹ H-NMR (CDCl ₃ ): δ 1.86 (4H, m), 2.15 (2H, m), 2.96 (2
H, m), 3.18 (1H, m), 3.57 (2H, s), 7.32 (4H, m), 7.46
(2H, t, J = 7.6Hz), 7.54 (2H, d, J = 7.6Hz), 7.93 (2H,
d, J = 7.3Hz).

7-2 1-benzyl-4- (1-hydroxy-1-
Phenyl) ethylpiperidine 1-benzyl-4-benzoylpiperidine (2.60 g) obtained in 7-1 was dissolved in anhydrous THF (70 ml), and the mixture was dissolved under nitrogen atmosphere.
Cooled to -78 ° C. Hexane solution of n-methyllithium (1
2.1 ml, 1.15 M) was slowly added dropwise, and the mixture was stirred for 1 hour. Water was added and extracted with chloroform. The organic layers were combined, washed with water and saturated saline, and then dried (MgSO4). The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent, hexane: ethyl acetate = 3:
Purification in 1) gave 1-benzyl-4- (1-hydroxy-1-phenyl) ethylpiperidine (2.72 g). ¹ H-NMR (CDCl ₃ ): δ 1.50 (3H, m), 1.55 (2H, m), 1.84 (3
H, s), 2.06 (1H, s), 2.87 (2H, m), 3.43 (2H, s), 3.71
(2H, m), 7.19-7.39 (10H, m).

7-3 1-benzyl-4- (1-phenylvinyl) piperidine 1-benzyl-4- (1-hydroxy-1-phenyl) ethylpiperidine (3.17 g) obtained in 7-2 was added to toluene ( 60ml)
And p-toluenesulfonic acid (2.45 g) was added.
Reflux with heating for hours. After cooling, add saturated aqueous sodium bicarbonate,
Extracted with ethyl acetate. The organic layers were combined, washed with water and saturated saline, and then dried (MgSO ₄ ). The solvent was distilled off under reduced pressure,
The residue was purified by silica gel column chromatography (elution solvent, ethyl acetate) to obtain 1-benzyl-4- (1-phenylvinyl) piperidine (2.56 g). ¹ H-NMR (CDCl ₃ ): δ1.56 (2H, m), 1.75 (2H, d, J = 13.0H
z), 2.02 (2H, t, J = 10.8Hz), 2.41 (1H, m), 2.95 (2H,
d, J = 11.9Hz), 3.52 (2H, s), 5.03 (1H, s), 5.15 (1H,
s), 7.26 (10H, m).

7-4 4- (1-Phenylvinyl) piperidine 1-Benzyl-4- (1-phenylvinyl) piperidine (2.55 g) obtained in 7-3 was dissolved in methylene chloride (30 ml).
The mixture was ice-cooled under a nitrogen atmosphere. 2-Chloroethyl chloroformate (1.00 ml) was added, and the mixture was refluxed under heating for 3 hours. After allowing to cool, the solvent was distilled off under reduced pressure, methanol (10 ml) was added, and the mixture was refluxed under heating for 1 hour. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layers were combined, washed with water and saturated saline, and then dried (MgSO ₄ ). The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent, chloroform: methanol: triethylamine = 93: 5:
Purification in 2) gave 4- (1-phenylvinyl) piperidine (1.18 g). ¹ H-NMR (CDCl ₃ ): δ 1.92 (4H, m), 2.68 (1 H, m), 2.94 (2
H, m), 3.52 (2H, m), 5.09 (1H, s), 5.26 (1H, s), 7.31
(5H, m), 9.41 (1H, bs).

7-5 1- [4- (1-Phenylvinyl) piperidino] phthalazine 1-chlorophthalazine (575 mg) obtained in Reference Example 1 was converted to DMF.
(100 ml), triethylamine (1.50 ml) and 7-
4- (1-phenylvinyl) piperidine obtained in Step 4 (654 m
g) was added thereto, and the same operation as in Example 1 was performed to obtain 1- [4- (1-phenylvinyl) piperidino] phthalazine (378 mg). ¹ H-NMR (CDCl ₃ ): δ1.84 (2H, m), 2.00 (2H, d, J = 14.3H)
z), 2.76 (1H, m), 3.16 (2H, t, J = 12.4Hz), 4.01 (2H,
d, J = 14.3Hz), 5.15 (1H, s), 5.25 (1H, s), 7.32 (5H,
m), 7.85 (3H, m), 8.02 (1H, m), 9.15 (1H, s).

Example 9 TNF Production or Secretion Inhibition Test on Mouse Peritoneal Macrophages TNF Production or Secretion Inhibition Test on Mouse Peritoneal Macrophages The test compounds used here were prepared by converting the free amino compound of Example into a dichloromethane or chloroform solution.
A hydrochloric acid / diethyl ether solution (about 7%) was added to make the solution acidic, and the resulting salt was washed well with diethyl ether to form a hydrochloride. Preparation of mouse macrophages BALB / c mice (female, 5-7 weeks old, Charles River) were intraperitoneally administered with 1 ml of thioglycolate medium (2.4% w / v, Nissui, prepared in January 1994). After breeding for 4 days, the peritoneal cavity was washed with 4 ml of cold minimal nutrient medium (MEM) (Osaka Univ.
Intraperitoneal infiltrating cells were collected. After washing the cells three times with MEM, 10% fetal bovine serum (FBS) added MEM (FBS: Filtro
n, hereafter referred to as cMEM). Next, the number of cells was counted by trypan blue staining, adjusted to 2 × 10 ⁶ cells / ml, and then seeded on a 96-well plate (Corstar) at 100 μl / well. After culturing the cells at 37 ° C. for 1 hour, the cells were washed twice with warm MEM to remove floating cells, and cMEM added at 50 μl / well was used as a mouse intraperitoneal macrophage in the experiment.

Induction of TNFα production by LPS stimulation LPS (E. coli 111: B4 LPS, DIFCO, lot 767-427)
mg / ml prepared in cMEM and stored at -20 ° C
After dilution to 20 μg / ml with, the mixture was added to the above mouse intraperitoneal macrophages at 100 μl / well. After culturing at 37 ° C for 18 hours, collect 25 μl of supernatant from each well, and remove TNF from the supernatant.
α activity was measured. The test compound is dissolved in DMSO to a concentration of 10 mM or 5 mg / ml during random screening.
Use a 10-fold dilution series stored at
The cells were added to the cells at the same time as S at 50 μl / well.

Measurement of TNFα activity (ELISA method) Anti-TNF antibody (PharMingen, lot 8026-04) was added to a 96-well plate.
coating buffer (0.5M bicarbonate buffer (pH 8.
5)) to 2 μg / ml) was added at 50 μl / well, and allowed to stand overnight at 4 ° C. wash buffer
(20x, 200μl / well), then wash with block buffe
r (10% FBS-PBS (-) (FBS: GIBCO, lot 32P3237, PBS:
(Takara Shuzo Co., Ltd.)) (200 μl / well) was added and left at room temperature for 2 hours. The culture supernatant was diluted 4-fold in a plate (25 μl of the supernatant was added to 75 μl of diluent buffer **). At the same time, a recombinant mouse TNFα was used for the calibration curve.
(Genzyme) dilution series were also prepared and allowed to stand overnight at 4 ° C. After washing four times, a biotinylated anti-TNF antibody (Pha
rMingen, lot 7098-04, adjusted to 1 μg / ml with diluent buffer) at 100 μl / well, and add at room temperature.
Let stand for 45 minutes. After washing 6 times, peroxidase-strept
-avidin (KPL, prepared 1: 1000 with diluent buffer)
Was added at a concentration of 100 μl / well, and the mixture was allowed to stand at room temperature for 30 minutes. After washing 8 times, TMB microwell peroxida
se substrate (KPL) was added at a concentration of 100 μl / well, and the mixture was allowed to stand at room temperature for 10 minutes. Stop solution (1 M p
hosphoric acid) was added at a concentration of 100 μl / well, and the absorbance (A450 nm) of each well was measured with a microplate reader, followed by data processing using soft-max. TNFα activity was quantified by a calibration curve using rm-TNFα. The TNFα production inhibitory activity of the test compound was determined by the following formula. TNF production or secretion inhibitory activity (%) = (1−TNF activity in culture supernatant of compound-added group / TNF activity in culture supernatant of compound-free group) × 100 These results of Example 9 are shown in Table 1. As shown in FIG.

[0070]

[Table 1]

Formulation Example 1 Tablets can be produced, for example, by the following method. Ingredients 1-4
Are mixed, granulated using an aqueous solution of the component 5, added with the component 6, mixed, and tabletted to form a tablet of 120 mg. Each component is as shown in Table 2.

[0072]

[Table 2]Amount (mg / tablet)  Component 1 Hydrochloride salt of the compound of Example 5 10 Component 2 Lactose 72.5 Component 3 Corn starch 30 Component 4 Carboxymethylcellulose calcium 5 Component 5 Hydroxypropylcellulose (HPC-L) 2Ingredient 6 Magnesium stearate 0.5  120mg in total

Formulation Example 2 An injection can be produced, for example, as follows. The solution of components 1 and 2 can be sterilized by filtration, filled into a washed and sterilized vial, sealed with a washed and sterilized rubber stopper, and wrapped with a flip-off cap to produce an injection.
The components are as shown in Table 3.

[0074]

[Table 3]  Component 1 Hydrochloride of the compound of Example 5 10 mg / vialIngredient 2 physiological saline 10ml / vial

[0075]

The phthalazine derivative of the present invention or a prodrug thereof or a pharmaceutically acceptable salt thereof is
Excellent in TNF production or secretion inhibitory action,
Diseases that are thought to be involved in the development of persistent or overproduction of, for example, cachexia, septic shock, multiple organ failure, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis,
Osteoarthritis, Behcet's disease, systemic lupus erythematosus (S
LE), a remedy for bone marrow transplantation rejection (GvHD), malaria, acquired immunodeficiency syndrome (AIDS), meningitis, hepatitis, type II diabetes and the like.

Continued on the front page (51) Int.Cl. ⁷ Identification code FI Theme coat II (Reference) A61P 29/00 A61K 31/00 629A 31/04 631C 31/18 631M 33/06 633F 37/04 637C 43/00 643D A61K 31/502 643 C07D 409/14 211 31/50 602 C07D 409/14 211 (72) Inventor Norio Fujiwara 3-1-198, Kasuganaka, Konohana-ku, Osaka Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Kawakami Hajime 3-1-198 Kasuganaka, Konohana-ku, Osaka-shi F-term in Sumitomo Pharmaceutical Co., Ltd. ZB15 ZB35 ZB38 ZC35 ZC41 ZC54 ZC55

Claims (6)

[Claims] 1. A compound of the general formula (1) (Wherein, R ₁ represents a hydrogen atom or a halogen atom,
R ₂ , R ₃ , R ₄ and R ₅ each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group, a substituted alkyl group, an alkoxy group, an aryl group, a substituted aryl group, an acyl group, a substituted acyl group, an acyloxy group Represents a substituted acyloxy group, a nitro group, an amino group, a substituted amino group, or a cyano group, and R ₆ represents a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an aryl group, a substituted aryl group, a heterocyclic group, an acyl group, an acyl group, R ₇ is a hydrogen atom, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an acyl group, a substituted acyl group, phthalazine derivatives prodrug thereof or a pharmaceutical represented by a heterocyclic group) Their salts that are acceptable. 2. The phthalazine derivative according to claim 1, wherein R ₆ is a substituted alkyl group, a substituted alkenyl group, an acyl group, or a substituted acyl group, and R ₇ is a hydrogen atom, or a pharmaceutically acceptable prodrug thereof. Those salts. (3) R ₆ is a substituted methyl group, a substituted vinylidene group,
The phthalazine derivative according to claim 1 or 2, which is a heterocyclic carbonyl group or a substituted benzoyl group, a prodrug thereof, or a pharmaceutically acceptable salt thereof. 4. The method according to claim 1, wherein R ₆ is a benzyl group, a 2-thienylmethyl group, a hydroxy (2-thienyl) methyl group, a p-methoxybenzoyl group, a 2-thienylcarbonyl group, or a 1-phenylethenyl group. 4. The phthalazine derivative according to 2, 3 or 3, a prodrug thereof, or a pharmaceutically acceptable salt thereof. (5) R₁, R₂, R₃, R₄, R₅And R₇But
A hydrogen atom, and R ₆Is hydroxy (2-thienyl) meth
The phthalazine derivative or the phthalazine derivative according to claim 1, which is a tyl group.
Are their prodrugs or their pharmaceutically acceptable
salt. 6. An inhibitor of tumor necrosis factor production or secretion comprising the phthalazine derivative according to claim 1, 2, 3, 4 or 5 or a prodrug thereof or a pharmaceutically acceptable salt thereof as an active ingredient.