JP2005060376A - Piperidine derivatives - Google Patents

Abstract

（式中、ｍは０〜４の整数を表し、Ｒ^１は、置換もしくは非置換の低級アルキルなどを表し、Ｒ^２は、水素原子、置換もしくは非置換の低級アルキルなどを表し、Ｒ^３およびＲ^４は、同一または異なって、水素原子または置換もしくは非置換の低級アルキルなどを表す）で表されるピペリジン誘導体またはその薬理学的に許容される塩を提供する。
【選択図】 なしPROBLEM TO BE SOLVED: To provide a novel piperidine derivative having a phosphodiesterase (PDE) -IV inhibitory action.
SOLUTION: General formula (I)
[Chemical Formula 10]

(In the formula, m represents an integer of 0 to 4, R ¹ represents a substituted or unsubstituted lower alkyl or the like, R ² represents a hydrogen atom, a substituted or unsubstituted lower alkyl, or the like, R ³ and R ⁴ is the same or different and represents a hydrogen atom or a substituted or unsubstituted lower alkyl, etc.), or a pharmaceutically acceptable salt thereof.
[Selection figure] None

Description

  The present invention has a phosphodiesterase (PDE) -IV inhibitory action, for example, inflammatory allergic diseases such as bronchial asthma, allergic rhinitis, atopic dermatitis, nephritis, chronic obstructive pulmonary disease, rheumatism, multiple sclerosis, Autoimmune diseases such as Crohn's disease, psoriasis and systemic lupus erythematosus, diseases of the central nervous system such as gonorrhea, amnesia, dementia, organ damage associated with ischemia-reperfusion caused by heart failure, shock, cerebrovascular disorder, The present invention relates to a piperidine derivative useful as a therapeutic agent for insulin-resistant diabetes, wounds, AIDS, osteoporosis, urinary calculus, urinary incontinence, etc., and an improving agent for fatigue, fatigue and the like.

Conventionally, many hormones and neurotransmitters have concentrations of adenosine 3 ′, 5′-cyclic monophosphate (cAMP) or guanosine 3 ′, 5′-cyclic monophosphate (cGMP), which are intracellular second messengers. It is known to exert its action by raising The intracellular concentrations of cAMP and cGMP are controlled by their production and degradation, and these degradations are performed by PDE. Thus, inhibiting PDE increases the concentration of these intracellular second messengers. It has been clarified that there are 8 types of isozymes in PDE so far, and isozyme-selective PDE inhibitors exhibit pharmacological effects based on the physiological significance and distribution in the body of the isozyme ["Trends in Pharmacological Science", 1990, Vol. 11, p. 150, 1991, Vol. 12, p. 19, “Biochemical & Biophysical Research Communications”, 1998, vol. 250, p. 751].
It is known that when the intracellular cAMP concentration of inflammatory white blood cells is increased, their activation can be suppressed. Activation of white blood cells leads to secretion of inflammatory cytokines such as tumor necrosis factor (TNF), expression of cell adhesion molecules such as intercellular adhesion molecule (ICAM) and subsequent cell invasion [“Journal of "Molecular and Cellular Cardiology", 1989, Volume 12 (Suppl. II), S61].
Increasing cAMP concentration in tracheal smooth muscle cells is known to be able to suppress the contraction ["TJ Tofy in Directions for New Anti-Azuma Drugs (TJ Torphy"). in Directions for New Anti-Asthma Drugs), SR O'Donell et al., 1988, p. 37, Birkhauser-Verlag]. Tracheal smooth muscle contraction is a major pathology of bronchial asthma. In ischemia-reperfusion organ disorders such as myocardial ischemia, infiltration of inflammatory leukocytes such as neutrophils is observed in the lesion. In these inflammatory cells and tracheal smooth muscle cells, it has been revealed that PDE-IV is mainly involved in cAMP degradation. Therefore, a PDE-IV selective inhibitor can be expected to have a therapeutic and / or preventive effect on inflammatory diseases, airway obstructive diseases, ischemic diseases and the like.
The PDE-IV inhibitor suppresses the secretion of inflammatory cytokines such as TNFα and interleukin (IL) -8 due to the increase in cAMP, and further prolongs the progress of inflammatory reactions and the like transmitted by these cytokines. It is expected that it can be prevented. For example, TNFα has been reported to reduce the mechanism of insulin receptor phosphorylation in muscle and adipocytes and contribute to insulin-resistant diabetes ["Journal of Clinical Investigation (Journal of Clinical (Clinical Investigation), 1994, 94, p. 1543] Similarly, TNFα is involved in the development of autoimmune diseases such as rheumatism, multiple sclerosis, Crohn's disease, and PDE- It has been suggested that IV inhibitors may be effective ["Nature Medicine", 1995, Vol. 1, p. 211, 1995, Vol. 1, p. 244].
In addition, it has been reported that THFα is involved in fatigue feeling after dialysis and cancer patients [“International Journal of Artificial Organs”, 1998, Vol. 21, p. 83, “Oncology Nursing Forum”, 1992, Vol. 19, p. 419]. Therefore, the PDE-IV inhibitor can be expected to be effective in improving fatigue, fatigue and the like.
It has been reported that drugs that increase cAMP promote wound healing [The 68th Annual Meeting of the Japanese Pharmacological Society (Nagoya), 1995, Title P3-116).
It has been suggested that PDE-IV inhibitors show therapeutic effects in cancer osteogenesis models, sciatic nerve resection models, and ovariectomy models, which are animal models of osteoporosis, and may be therapeutic drugs for osteoporosis [“Japanese”・ Journal of Pharmacology ”, 1999, vol. 79, p. 477].
Although relaxation of the ureter is known to promote stone excretion, PDE-IV inhibitors are effective in the treatment and / or prevention of urinary calculi because they suppress the peristaltic movement of the ureter. A possibility has been suggested ["Journal of Urology", 1998, vol. 160, p. 920].
However, PDE-IV inhibitors known so far have been reported to also exhibit side effects such as emetic action [Current Pharmaceutical Design, 2002, 8th. Volume, p. 1255].
On the other hand, piperidine derivatives having a PDE-IV inhibitory action are known (see Patent Documents 1 and 2).
International Publication No. 94/25437 Pamphlet International Publication No. 02/14280 Pamphlet

  An object of the present invention is to provide a novel piperidine derivative having a PDE-IV inhibitory action.

The present invention relates to the following (1) to (8).
(1) General formula (I)

［式中、ｍは０〜４の整数を表し、
Ｒ^１は、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換の低級アルカノイルまたは−ＮＲ^５Ｒ^６（式中、Ｒ^５およびＲ^６は同一または異なって、水素原子、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、ホルミルまたは置換もしくは非置換の低級アルカノイルを表すか、またはＲ^５とＲ^６が隣接する窒素原子と一緒になって置換もしくは非置換の複素環基を形成する）を表し、
Ｒ^２は、水素原子、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアリール、置換もしくは非置換のアラルキル、置換もしくは非置換のヘテロアラルキル、置換もしくは非置換の芳香族複素環基または置換もしくは非置換の脂環式複素環基を表し、
Ｒ^３およびＲ^４は、同一または異なって、水素原子または置換もしくは非置換の低級アルキルを表すか、またはＲ^３とＲ^４が隣接する炭素原子と一緒になって飽和炭素環を形成する］で表されるピペリジン誘導体またはその薬理学的に許容される塩。
（２） Ｒ^１が置換もしくは非置換の低級アルケニルである（１）記載のピペリジン誘導体またはその薬理学的に許容される塩。
（３） Ｒ^２が置換もしくは非置換のシクロアルキルである（１）または（２）記載のピペリジン誘導体またはその薬理学的に許容される塩。
（４） Ｒ^２が置換もしくは非置換の低級アルキルである（１）または（２）記載のピペリジン誘導体またはその薬理学的に許容される塩。
（５） Ｒ^３およびＲ^４が水素原子である（１）〜（４）のいずれかに記載のピペリジン誘導体またはその薬理学的に許容される塩。
（６） ｍが０である（１）〜（５）のいずれかに記載のピペリジン誘導体またはその薬理学的に許容される塩。
（７） （１）〜（６）のいずれかに記載のピペリジン誘導体またはその薬理学的に許容される塩を含有する医薬。
（８） （１）〜（６）のいずれかに記載のピペリジン誘導体またはその薬理学的に許容される塩を含有するホスホジエステラーゼ（ＰＤＥ）−ＩＶ阻害剤。
以下、一般式（Ｉ）で表される化合物を化合物（Ｉ）という。他の式番号の化合物についても同様である。

[Wherein m represents an integer of 0 to 4,
R ¹ represents substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkanoyl, or —NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ Are the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, formyl or substituted or unsubstituted lower alkanoyl, or R ⁵ and R ⁶ are adjacent nitrogen atoms Together form a substituted or unsubstituted heterocyclic group)
R ² represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted An aralkyl, a substituted or unsubstituted heteroaralkyl, a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted alicyclic heterocyclic group,
R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a substituted or unsubstituted lower alkyl, or R ³ and R ⁴ together with adjacent carbon atoms form a saturated carbocycle] Or a pharmacologically acceptable salt thereof.
(2) The piperidine derivative or a pharmaceutically acceptable salt thereof according to (1), wherein R ¹ is substituted or unsubstituted lower alkenyl.
(3) The piperidine derivative or a pharmaceutically acceptable salt thereof according to (1) or (2), wherein R ² is substituted or unsubstituted cycloalkyl.
(4) The piperidine derivative or a pharmaceutically acceptable salt thereof according to (1) or (2), wherein R ² is substituted or unsubstituted lower alkyl.
(5) The piperidine derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (4), wherein R ³ and R ⁴ are hydrogen atoms.
(6) The piperidine derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (5), wherein m is 0.
(7) A medicament containing the piperidine derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (6).
(8) A phosphodiesterase (PDE) -IV inhibitor comprising the piperidine derivative according to any one of (1) to (6) or a pharmacologically acceptable salt thereof.
Hereinafter, the compound represented by formula (I) is referred to as compound (I). The same applies to the compounds of other formula numbers.

  According to the present invention, it has a PDE-IV inhibitory action, such as bronchial asthma, allergic rhinitis, atopic dermatitis, nephritis and other inflammatory allergic diseases, chronic obstructive pulmonary disease, rheumatism, multiple sclerosis, Crohn's disease, Autoimmune diseases such as psoriasis, systemic lupus erythematosus, central nervous system diseases such as depression, amnesia, dementia, organ diseases associated with ischemia-reperfusion caused by heart failure, shock, cerebrovascular disorder, insulin resistance A piperidine derivative or a pharmacologically acceptable salt thereof useful as a therapeutic agent for diabetes, wound, AIDS, osteoporosis, urinary calculus, urinary incontinence, etc., an improving agent for fatigue, fatigue, etc. can be provided.

In the definition of each group of the general formula (I), examples of the lower alkyl part of lower alkyl and lower alkanoyl include linear or branched alkyl having 1 to 10 carbon atoms, more specifically methyl, Examples thereof include ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonanyl, decanyl and the like.
Examples of the lower alkenyl include linear or branched alkenyl having 2 to 10 carbon atoms, and more specifically vinyl, allyl, 1-propenyl, methacryl, crotyl, 1-butenyl, 3-butenyl, 2 -Pentenyl, 4-pentenyl, 2-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 1-decenyl, 2-decenyl and the like .
Examples of lower alkynyl include linear or branched alkynyl having 2 to 10 carbon atoms, and more specifically, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. It is done.
Examples of the cycloalkyl moiety in the saturated carbocycle formed together with cycloalkyl and adjacent carbon atoms include cycloalkyl having 3 to 8 carbon atoms, and more specifically, cyclopropyl, cyclobutyl, cyclopentyl, Examples include cyclohexyl, cycloheptyl, cyclooctyl and the like.
Examples of cycloalkenyl include cycloalkenyl having 4 to 10 carbon atoms, and more specifically, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl and the like.
Examples of aryl include aryl having 6 to 14 carbon atoms, and more specifically phenyl, naphthyl, anthryl and the like.
Examples of aralkyl include aralkyl having 7 to 15 carbon atoms, and more specifically, benzyl, phenethyl, benzhydryl, naphthylmethyl and the like.
The heteroaralkyl includes, for example, a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom in an alkylene chain having 1 to 4 carbon atoms, 3 A bicyclic or tricyclic condensed 8-membered ring and a condensed aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the like, More specifically, 4-pyridylmethyl, 3-pyridylmethyl, 2-pyridylmethyl, (2-pyrimidinyl) methyl, (4-pyrimidinyl) methyl, (5-pyrimidinyl) methyl, (2-pyrazinyl) methyl, (2 -Furyl) methyl, (3-furyl) methyl, (2-thienyl) methyl, (3-thienyl) methyl, (1-imidazolyl) methyl, (2-imidazolyl) methyl, (4- (Midazolyl) methyl, (2-oxazolyl) methyl, (3-isoxazolyl) methyl, (2-benzofuranyl) methyl, 2- (4-pyridyl) ethyl, 2- (3-pyridyl) ethyl, 2- (2-pyridyl) Ethyl, 2- (2-pyrimidinyl) ethyl, 2- (4-pyrimidinyl) ethyl, 2- (5-pyrimidinyl) ethyl, 2- (2-pyrazinyl) ethyl, 2- (2-furyl) ethyl, 2- ( 3-furyl) ethyl, 2- (2-thienyl) ethyl, 2- (3-thienyl) ethyl, 2- (1-imidazolyl) ethyl, 2- (2-imidazolyl) ethyl, 2- (4-imidazolyl) ethyl 2- (2-oxazolyl) ethyl, 2- (3-isoxazolyl) ethyl, 2- (2-benzofuranyl) ethyl, 3- (4-pyridyl) propyl, 3- (3 Pyridyl) propyl, 3- (2-pyridyl) propyl and the like.
As the aromatic heterocyclic group, for example, a 5- or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a 3- to 8-membered ring are condensed. A bicyclic or tricyclic condensed aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and more specifically, pyridyl, pyrazinyl, pyrimidinyl, Pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, oxazolyl, isoxazolyl, indazolyl, indazolyl, indazolyl, indazolyl, indazolyl, indazolyl Zoriru, benzoxazolyl, such as purinyl and the like.
Examples of the alicyclic heterocyclic group include a 5-membered or 6-membered monocyclic alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a 3- to 8-membered ring. And a condensed alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and more specifically, imidazolidinyl, pyrrolidinyl , Piperidino, piperidinyl, piperazinyl, morpholino, morpholinyl, thiomorpholino, thiomorpholinyl, homopiperidino, homopiperidinyl, homopiperazinyl, tetrahydropyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydrobenzofuranyl, etc. Can be given.
Examples of the heterocyclic group formed together with the adjacent nitrogen atom include a 5-membered or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic group includes other A nitrogen atom, an oxygen atom or a sulfur atom), a bicyclic or tricyclic condensed 3- to 8-membered ring and containing at least one nitrogen atom (the condensed group) The cyclic heterocyclic group may contain other nitrogen atom, oxygen atom or sulfur atom), and more specifically, 1-pyrrolyl, pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, homopiperidino , Homopiperazinyl, tetrahydropyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and the like.
Examples of the substituent (a) in the substituted lower alkyl and the substituted lower alkanoyl are the same or different and have, for example, 1 to 3 substituents, specifically halogen, hydroxy, oxo, carboxy, cyano, nitro, substituted or unsubstituted lower Alkoxy [substituent (b) in the substituted lower alkoxy includes halogen, hydroxy, oxo, carboxy, cyano, nitro, lower alkoxy, amino, lower alkylamino, di-lower alkylamino (two lower groups in the di-lower alkylamino) Alkyl may be the same or different)], amino, substituted or unsubstituted lower alkylamino [the substituent in the substituted lower alkylamino has the same meaning as the substituent (b) in the substituted lower alkoxy ], Substituted or unsubstituted di-lower alkyl Amino [two lower alkyls in the di-lower alkylamino may be the same or different, and the substituent in the substituted di-lower alkylamino has the same meaning as the substituent (b) in the substituted lower alkoxy], substituted or Unsubstituted cycloalkyl [substituent (c) in the substituted cycloalkyl includes halogen, hydroxy, oxo, carboxy, cyano, nitro, lower alkyl, lower alkoxy, amino, lower alkylamino, di-lower alkylamino (the di- The two lower alkyls in the lower alkylamino may be the same or different)], substituted or unsubstituted cycloalkenyl [the substituent in the substituted cycloalkenyl is the substituent (c) in the substituted cycloalkyl Synonymous with], substituted or unsubstituted Aryl [substituent (d) in the substituted aryl includes halogen, hydroxy, carboxy, cyano, nitro, lower alkyl, lower alkoxy, lower alkanoyl, amino, lower alkylamino, di-lower alkylamino (in the di-lower alkylamino] The two alkyls may be the same or different), etc.], a substituted or unsubstituted aromatic heterocyclic group [the substituent in the substituted aromatic heterocyclic group is the substituent (d) in the substituted aryl A substituted or unsubstituted alicyclic heterocyclic group [the substituent (e) in the substituted alicyclic heterocyclic group includes halogen, hydroxy, oxo, carboxy, cyano, nitro, lower alkyl, Lower alkoxy, lower alkanoyl, amino, lower alkylamino, di-lower alkylamino The two alkyls in the di-lower alkylamino may be the same or different.)] And the like.
The lower alkyl part of the lower alkyl, lower alkoxy, lower alkylamino, di-lower alkylamino and lower alkanoyl shown here has the same meaning as the aforementioned lower alkyl, cycloalkyl, cycloalkenyl, aryl, aromatic heterocyclic group and aliphatic The cyclic heterocyclic group has the same meaning as the aforementioned cycloalkyl, cycloalkenyl, aryl, aromatic heterocyclic group and alicyclic heterocyclic group. Halogen means each atom of fluorine, chlorine, bromine and iodine.
In the substituted lower alkenyl, substituted lower alkynyl, substituted cycloalkyl, and substituted cycloalkenyl, the substituent (f) includes, in addition to the groups described in the substituent (a) in the substituted lower alkyl, the lower alkyl as defined above, and the like. can give.
The substituent (g) in the substituted aryl, substituted aralkyl, substituted heteroaralkyl and substituted aromatic heterocyclic group may be the same or different and has, for example, 1 to 3 substituents, specifically halogen, hydroxy, carboxy, cyano, nitro. , Lower alkyl, substituted or unsubstituted lower alkoxy [the substituent in the lower alkoxy has the same meaning as the substituent (b) in the substituted lower alkoxy], amino, substituted or unsubstituted lower alkylamino [the substituted lower The substituent in the alkylamino has the same meaning as the substituent (b) in the substituted lower alkoxy], a substituted or unsubstituted di-lower alkylamino [the two lower alkyls in the di-lower alkylamino may be the same or different Well, the substituent in the substituted di-lower alkylamino is Substituted or unsubstituted lower alkoxycarbonyl (the substituent in the substituted lower alkoxycarbonyl has the same meaning as substituent (b) in the substituted lower alkoxy), substituted Or unsubstituted lower alkanoyl (the substituent in the substituted lower alkanoyl has the same meaning as the substituent (b) in the substituted lower alkoxy), carbamoyl, substituted or unsubstituted lower alkylcarbamoyl [substitution in the substituted lower alkylcarbamoyl; Group is as defined for the substituent (b) in the substituted lower alkoxy], substituted or unsubstituted di-lower alkylcarbamoyl [the two lower alkyls in the di-lower alkylcarbamoyl may be the same or different, Di-lower alkyl carbamoy Substituent in is the same meaning as substituent (b) in the substituted lower alkoxy], and the like.
The lower alkyl moiety in the lower alkyl, lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkoxycarbonyl, lower alkanoyl, lower alkylcarbamoyl and di-lower alkylcarbamoyl shown here has the same meaning as the above lower alkyl, and halogen is It is synonymous with the said halogen.
As the substituent (h) in the heterocyclic group formed together with the substituted alicyclic heterocyclic group and the adjacent nitrogen atom, in addition to the groups mentioned as the substituent (g) in the aryl etc., oxo and the like Is given.
The pharmacologically acceptable salt of compound (I) includes, for example, a pharmacologically acceptable acid addition salt, metal salt, ammonium salt, organic amine addition salt, amino acid addition salt and the like.
Examples of the pharmacologically acceptable acid addition salt of Compound (I) include inorganic acid salts such as hydrochloride, sulfate, nitrate, and phosphate, acetate, maleate, fumarate, citrate, and the like. Examples of the pharmacologically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt and zinc salt. Examples of the pharmacologically acceptable ammonium salt include salts such as ammonium and tetramethylammonium. Examples of the pharmacologically acceptable organic amine addition salt include addition salts such as morpholine and piperidine. Examples of pharmacologically acceptable amino acid addition salts include addition salts such as glycine, phenylalanine, lysine, aspartic acid, and glutamic acid. That.
Next, the manufacturing method of compound (I) is demonstrated.
In the production method shown below, when the defined group changes under the conditions of the production method or is inappropriate for carrying out the method, a method commonly used in organic synthetic chemistry, for example, protection of a functional group, Deprotection [e.g., Protective Groups in Organic Synthesis, third edition, by John Wiley and Sons, Inc., by TW Greene] (e.g., Protective Groups in Organic Synthesis, third edition). John Wiley & Sons Inc. (1999)] can be used to produce the target compound. Further, the order of reaction steps such as introduction of substituents can be changed as necessary.
Compound (I) can be produced, for example, according to the following steps.
Manufacturing method 1
Compounds (I) wherein R ¹ is substituted or unsubstituted lower alkyl as defined above, substituted or unsubstituted lower alkenyl as defined above, or substituted or unsubstituted lower alkynyl as defined above (Ia ) Can be produced according to the following steps.

（式中、ｍ、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４はそれぞれ前記と同義であり、Ｘは、塩素原子、臭素原子、ヨウ素原子、トリフルオロメタンスルホニルオキシ、メタンスルホニルオキシ、ベンゼンスルホニルオキシまたはｐ−トルエンスルホニルオキシを表し、Ｒ^１ａは、前記と同義の置換もしくは非置換の低級アルキル、前記と同義の置換もしくは非置換の低級アルケニルまたは前記と同義の置換もしくは非置換の低級アルキニルを表し、Ｒ^７は前記と同義の低級アルキルまたは前記と同義のアラルキルを表し、Ｒ^８は前記と同義の低級アルキルを表す）
工程１−１
化合物（ＩＶ）は、国際公開第０２／１４２８０号に記載の方法またはそれに準じて製造することができる。また、以下の方法によっても製造することができる。
すなわち、化合物（ＩＶ）は、化合物（ＩＩ）と１〜１０当量の化合物（ＩＩＩ）とを、溶媒中、１〜３０当量の適当な塩基の存在下、必要に応じ０．０１〜１当量のヘキサデシルトリブチルホスホニウムブロミドなどの添加剤の存在下、−３０℃〜用いる溶媒の沸点の間の温度で、５分間〜４８時間反応させることにより製造することができる。
塩基としては、例えば水酸化ナトリウム、水酸化カリウム、水素化ナトリウム、ｎ−ブチルリチウム、１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（ＤＢＵ）などがあげられる。溶媒としては、例えば水、メタノール、エタノール、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン、ヘキサン、トルエンなどがあげられ、これらを単独でまたは混合して用いることができる。
化合物（ＩＩ）は、国際公開第０２／１４２８０号、国際公開第９３／１９７５０号もしくはジャーナル・オブ・メディシナル・ケミストリー（Ｊｏｕｒｎａｌ ｏｆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ）、１９９８年、４１巻、ｐ．８２１に記載の方法で、またはそれらに準じて得ることができる。化合物（ＩＩＩ）は、ジャーナル・オブ・ヘテロサイクリック・ケミストリー（Ｊｏｕｒｎａｌ ｏｆ Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍｉｓｔｒｙ）、１９８６年、２３巻、ｐ．７３に記載の方法で、またはそれに準じて得ることができる。
工程１−２
化合物（Ｖ）は、化合物（ＩＶ）を、反応に不活性な溶媒中、１〜１００当量のチオール化合物、酸、ヨウ化トリメチルシリルまたは硫化ナトリウムの存在下、−３０℃〜用いる溶媒の沸点の間の温度で５分間〜８０時間処理することにより製造することができる。
チオール化合物としては、例えばチオフェノール、メタンチオール、エタンチオールなどがあげられ、これらのアルカリ金属塩、例えばナトリウムチオフェノキシド、ナトリウムチオメトキシド、ナトリウムチオエトキシドなどもまた用いることができる。酸としては、例えば臭化水素／酢酸、塩化ピリジニウム、三臭化ホウ素、三塩化ホウ素、臭化アルミニウム、塩化アルミニウムなどがあげられる。反応に不活性な溶媒としては、例えばジクロロメタン、クロロホルム、１，２−ジクロロエタン、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ−メチルピロリドン（ＮＭＰ）などがあげられ、これらを単独でまたは混合して用いることができる。
工程１−３
化合物（ＶＩ）は、化合物（Ｖ）を無溶媒でまたは適当な溶媒中、１〜３０当量のトリフルオロメタンスルホン酸無水物と、必要に応じ１〜３０当量の適当な塩基の存在下、−３０℃〜６０℃の間の温度で５分間〜４８時間反応させることにより製造することができる。反応は窒素、アルゴンなどの不活性気体雰囲気下で実施することが好ましい。
適当な塩基としては、例えばピリジン、２，６−ルチジン、２，４，６−コリジン、Ｎ，Ｎ−ジメチルアミノピリジン（ＤＭＡＰ）、トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、ＤＢＵ、１，５−ジアザビシクロ［４．３．０］ノン−５−エン（ＤＢＮ）などがあげられる。適当な溶媒としては、例えばピリジン、ＤＭＦ、ＮＭＰ、ＴＨＦ、ジクロロメタン、１，２−ジクロロエタン、１，４−ジオキサンなどがあげられ、これらを単独でまたは混合して用いることができる。
工程１−４
化合物（ＶＩＩ）は、化合物（ＶＩ）と化合物（Ｘ）とをスティルカップリング反応（Ｓｔｉｌｌｅ Ｃｏｕｐｌｉｎｇ）に付すことにより製造することができる。
すなわち、化合物（ＶＩＩ）は、反応に不活性な溶媒中、化合物（ＶＩ）と１〜２０当量の化合物（Ｘ）とを、０．０１ｍｏｌ％〜３０ｍｏｌ％のパラジウム触媒の存在下、必要に応じ０．０１〜２０当量の適当な添加剤の存在下、−３０℃〜用いる溶媒の沸点の間の温度で、５分間〜１００時間反応させることにより製造することができる。
パラジウム触媒としては、例えばテトラキス（トリフェニルホスフィン）パラジウム、トリス（ジベンジリデンアセトン）ジパラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム、ビス（アセトニトリル）ジクロロパラジウム、酢酸パラジウムなどがあげられる。適当な添加剤としては、例えばヨウ化銅、塩化亜鉛、塩化リチウム、フッ化セシウム、炭酸リチウム、炭酸ナトリウム、トリエチルアミン、２，６−ジ−ｔｅｒｔ−ブチル−４−メチルフェノール、４−ｔｅｒｔ−ブチルカテコール、トリフェニルホスフィンなどがあげられ、これらを単独でまたは混合して用いることができる。反応に不活性な溶媒としては、例えばＴＨＦ、ＤＭＦ、ＮＭＰ、１，２−ジメトキシエタン（ＤＭＥ）、１，４−ジオキサン、ベンゼン、トルエンなどがあげられ、これらを単独でまたは混合して用いることができる。
工程１−５
化合物（ＶＩＩＩ）は、化合物（ＶＩＩ）を適当な溶媒中、１〜３０当量のクロロギ酸１−クロロエチルと、０℃〜用いる溶媒の沸点の間の温度で、５分間〜４８時間反応させ、次いで無溶媒でまたは適当な溶媒中、１〜５００当量の低級アルコールの存在下、０℃〜１５０℃の間の温度で、５分間〜４８時間処理することにより製造することができる。
クロロギ酸１−クロロエチルとの反応、および低級アルコールでの処理に用いられる適当な溶媒としては、例えばジクロロメタン、１，２−ジクロロエタン、ＴＨＦ、トルエン、酢酸エチル、アセトニトリル、ピリジンなどがあげられ、これらを単独でまたは混合して用いることができる。低級アルコールとしては、例えばメタノール、エタノール、プロパノールなどがあげられる。
化合物（ＶＩＩＩ）はまた、化合物（ＶＩＩ）を接触還元反応に付すことによっても製造することができる。すなわち、化合物（ＶＩＩＩ）は、化合物（ＶＩＩ）を反応に不活性な溶媒中、０．０１〜３０当量の例えばパラジウム炭素、ラネーニッケルなどの存在下、水素気流中、常圧〜５０，０００ｋＰａの圧力下で、０℃〜溶媒の沸点の間の温度で５分間〜４８時間処理するか、または１〜２００当量の例えばギ酸、ギ酸アンモニウム、ヒドラジン、シクロヘキセン、シクロヘキサジエン、トリエチルシランなどの水素供与体の存在下、必要に応じ例えばアンモニア、酢酸、塩酸、硫酸などの存在下、−２０℃〜溶媒の沸点の間の温度で５分間〜１００時間処理することによっても製造することができる。
反応に不活性な溶媒としては、例えばメタノール、エタノール、酢酸エチル、ＴＨＦ、１，４−ジオキサン、水などがあげられ、これらを単独でまたは混合して用いることができる。
工程１−６
化合物（ＩＸ）は、化合物（ＶＩＩＩ）と１〜３０当量の化合物（ＸＩ）とを、適当な溶媒中、１〜３０当量の適当な塩基の存在下、−７８℃〜用いる溶媒の沸点の間の温度で５分間〜４８時間反応させることにより製造することができる。
適当な溶媒としては、例えばジエチルエーテル、ＴＨＦ、ＤＭＦ、ＮＭＰ、ジメチルスルホキシド（ＤＭＳＯ）、トルエン、酢酸エチル、アセトニトリル、エタノール、ピリジン、ジクロロメタンなどがあげられ、これらを単独でまたは混合して用いることができる。適当な塩基としては、例えば炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸リチウム、ピリジン、２，６−ルチジン、２，４，６−コリジン、ＤＭＡＰ、トリエチルアミン、ジイソプロピルエチルアミン、トリブチルアミン、ＤＢＵ、ＤＢＮ、水素化ナトリウム、ｔｅｒｔ−ブトキシカリウムなどがあげられる。
工程１−７
化合物（Ｉａ）は、化合物（ＩＸ）を無溶媒でまたは適当な溶媒中、アルカリ水溶液または触媒量から１００当量の酸の存在下、−３０℃〜１５０℃の間の温度で５分間〜４８時間処理することにより製造することができる。
アルカリ水溶液としては、例えば水酸化ナトリウム、水酸化カリウム、水酸化リチウムなどのアルカリを含有する水溶液があげられ、化合物（ＩＸ）に対して、１〜５００当量のアルカリを含有する水溶液が好ましい。酸としては、例えば塩酸、硫酸、酢酸、ギ酸、トリフルオロ酢酸、ｐ−トルエンスルホン酸、メタンスルホン酸、四塩化チタン、三フッ化ホウ素などがあげられる。適当な溶媒としては、例えばメタノール、エタノール、プロパノール、アセトニトリル、トルエン、ジエチルエーテル、ＴＨＦ、１，４−ジオキサン、ＤＭＦ、ジクロロメタン、１，２−ジクロロエタンなどがあげられ、これらを単独でまたは混合して用いることができる。
製造法２
化合物（Ｉ）のうち、Ｒ^１が−ＣＨＲ^９ＣＨＲ^１０Ｒ^１１（式中、Ｒ^９、Ｒ^１０およびＲ^１１は、同一または異なって、水素原子または前記と同義の置換もしくは非置換の低級アルキルを表す）である化合物（Ｉｃ）は、製造法１で得られる化合物（Ｉｂ）より以下の工程によっても製造することができる。

Wherein m, R ¹ , R ² , R ³ and R ⁴ are as defined above, and X is a chlorine atom, a bromine atom, an iodine atom, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy or represents p-toluenesulfonyloxy, R ^1a represents substituted or unsubstituted lower alkyl as defined above, substituted or unsubstituted lower alkenyl as defined above, or substituted or unsubstituted lower alkynyl as defined above, R ⁷ represents lower alkyl as defined above or aralkyl as defined above, and R ⁸ represents lower alkyl as defined above.
Step 1-1
Compound (IV) can be produced according to the method described in WO 02/14280 or a modification thereof. Moreover, it can manufacture also with the following method.
That is, the compound (IV) comprises compound (II) and 1 to 10 equivalents of compound (III) in the presence of 1 to 30 equivalents of a suitable base in a solvent, if necessary, 0.01 to 1 equivalents. In the presence of an additive such as hexadecyltributylphosphonium bromide, it can be produced by reacting at a temperature between −30 ° C. and the boiling point of the solvent used for 5 minutes to 48 hours.
Examples of the base include sodium hydroxide, potassium hydroxide, sodium hydride, n-butyllithium, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and the like. Examples of the solvent include water, methanol, ethanol, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, hexane, toluene and the like, and these can be used alone or in combination.
Compound (II) is disclosed in WO 02/14280, WO 93/19750, or Journal of Medicinal Chemistry, 1998, Vol. 41, p. 821 or according to them. Compound (III) can be prepared according to Journal of Heterocyclic Chemistry, 1986, Vol. 23, p. 73, or according thereto.
Step 1-2
Compound (V) is obtained by reacting Compound (IV) between −30 ° C. and the boiling point of the solvent used in the presence of 1 to 100 equivalents of a thiol compound, acid, trimethylsilyl iodide or sodium sulfide in a solvent inert to the reaction. It can manufacture by processing for 5 minutes-80 hours at the temperature of.
Examples of the thiol compound include thiophenol, methanethiol, ethanethiol and the like, and alkali metal salts thereof such as sodium thiophenoxide, sodium thiomethoxide, sodium thioethoxide and the like can also be used. Examples of the acid include hydrogen bromide / acetic acid, pyridinium chloride, boron tribromide, boron trichloride, aluminum bromide, aluminum chloride and the like. Examples of the solvent inert to the reaction include dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP) and the like. These may be used alone or in combination. Can be used.
Step 1-3
Compound (VI) is obtained by removing Compound (V) in the presence of 1 to 30 equivalents of trifluoromethanesulfonic anhydride and optionally 1 to 30 equivalents of a suitable base in the absence of a solvent or in a suitable solvent. It can manufacture by making it react for 5 minutes-48 hours at the temperature of between 60 degreeC and 60 degreeC. The reaction is preferably carried out in an inert gas atmosphere such as nitrogen or argon.
Suitable bases include, for example, pyridine, 2,6-lutidine, 2,4,6-collidine, N, N-dimethylaminopyridine (DMAP), triethylamine, tributylamine, diisopropylethylamine, DBU, 1,5-diazabicyclo [ 4.3.0] non-5-ene (DBN) and the like. Examples of suitable solvents include pyridine, DMF, NMP, THF, dichloromethane, 1,2-dichloroethane, 1,4-dioxane, and the like, and these can be used alone or in combination.
Step 1-4
Compound (VII) can be produced by subjecting compound (VI) and compound (X) to a Still coupling reaction (Still Coupling).
That is, the compound (VII) is obtained by subjecting the compound (VI) and 1 to 20 equivalents of the compound (X) in a solvent inert to the reaction in the presence of 0.01 mol% to 30 mol% of a palladium catalyst as necessary. In the presence of 0.01 to 20 equivalents of a suitable additive, the reaction can be carried out at a temperature between −30 ° C. and the boiling point of the solvent used for 5 minutes to 100 hours.
Examples of the palladium catalyst include tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, dichlorobis (triphenylphosphine) palladium, bis (acetonitrile) dichloropalladium, and palladium acetate. Suitable additives include, for example, copper iodide, zinc chloride, lithium chloride, cesium fluoride, lithium carbonate, sodium carbonate, triethylamine, 2,6-di-tert-butyl-4-methylphenol, 4-tert-butyl. Catechol, triphenylphosphine and the like can be mentioned, and these can be used alone or in combination. Examples of the solvent inert to the reaction include THF, DMF, NMP, 1,2-dimethoxyethane (DME), 1,4-dioxane, benzene, toluene and the like, and these may be used alone or in combination. Can do.
Step 1-5
Compound (VIII) is obtained by reacting Compound (VII) with 1 to 30 equivalents of 1-chloroethyl chloroformate in a suitable solvent at a temperature between 0 ° C. and the boiling point of the solvent used for 5 minutes to 48 hours. It can be produced by treating for 5 minutes to 48 hours without solvent or in a suitable solvent in the presence of 1 to 500 equivalents of a lower alcohol at a temperature between 0 ° C. and 150 ° C.
Suitable solvents used for the reaction with 1-chloroethyl chloroformate and the treatment with lower alcohols include, for example, dichloromethane, 1,2-dichloroethane, THF, toluene, ethyl acetate, acetonitrile, pyridine and the like. They can be used alone or in combination. Examples of the lower alcohol include methanol, ethanol, propanol and the like.
Compound (VIII) can also be produced by subjecting compound (VII) to a catalytic reduction reaction. That is, the compound (VIII) is obtained by reacting the compound (VII) in a solvent inert to the reaction in the presence of 0.01 to 30 equivalents of, for example, palladium carbon and Raney nickel, in a hydrogen stream, and at a pressure of normal pressure to 50,000 kPa. Treatment at a temperature between 0 ° C. and the boiling point of the solvent for 5 minutes to 48 hours, or 1 to 200 equivalents of a hydrogen donor such as formic acid, ammonium formate, hydrazine, cyclohexene, cyclohexadiene, triethylsilane, etc. In the presence, if necessary, for example, in the presence of ammonia, acetic acid, hydrochloric acid, sulfuric acid or the like, it can also be produced by treatment at a temperature between −20 ° C. and the boiling point of the solvent for 5 minutes to 100 hours.
Examples of the solvent inert to the reaction include methanol, ethanol, ethyl acetate, THF, 1,4-dioxane, water and the like, and these can be used alone or in combination.
Step 1-6
Compound (IX) is compound (VIII) and 1-30 equivalents of compound (XI) in a suitable solvent in the presence of 1-30 equivalents of a suitable base between -78 ° C and the boiling point of the solvent used. It can manufacture by making it react at the temperature of 5 minutes-48 hours.
Suitable solvents include, for example, diethyl ether, THF, DMF, NMP, dimethyl sulfoxide (DMSO), toluene, ethyl acetate, acetonitrile, ethanol, pyridine, dichloromethane, etc., and these may be used alone or in combination. it can. Suitable bases include, for example, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, pyridine, 2,6-lutidine, 2,4,6-collidine, DMAP, triethylamine, diisopropylethylamine, tributylamine, DBU, DBN, hydrogen And sodium tert-butoxypotassium.
Step 1-7
Compound (Ia) is obtained by reacting Compound (IX) without solvent or in a suitable solvent in the presence of an alkaline aqueous solution or a catalytic amount to 100 equivalents of acid at a temperature between −30 ° C. and 150 ° C. for 5 minutes to 48 hours. It can be manufactured by processing.
Examples of the aqueous alkali solution include aqueous solutions containing alkali such as sodium hydroxide, potassium hydroxide, and lithium hydroxide. An aqueous solution containing 1 to 500 equivalents of alkali is preferable with respect to compound (IX). Examples of the acid include hydrochloric acid, sulfuric acid, acetic acid, formic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, titanium tetrachloride, boron trifluoride and the like. Suitable solvents include, for example, methanol, ethanol, propanol, acetonitrile, toluene, diethyl ether, THF, 1,4-dioxane, DMF, dichloromethane, 1,2-dichloroethane, and these may be used alone or in combination. Can be used.
Manufacturing method 2
Among the compounds (I), R ¹ is —CHR ⁹ CHR ¹⁰ R ¹¹ (wherein R ⁹ , R ¹⁰ and R ¹¹ are the same or different and are a hydrogen atom or a substituted or unsubstituted lower alkyl as defined above) Compound (Ic), which represents a compound represented by

（式中、ｍ、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^９、Ｒ^１０およびＲ^１１は、それぞれ前記と同義である）
化合物（Ｉｃ）は、製造法１で得られる化合物（Ｉｂ）を反応に不活性な溶媒中、０．０１〜３０当量の例えばパラジウム炭素、ラネーニッケルなどの存在下、水素気流中、常圧〜５０，０００ｋＰａの圧力下で、０℃〜溶媒の沸点の間の温度で５分間〜４８時間処理するか、または１〜２００当量の例えば、ギ酸、ギ酸アンモニウム、ヒドラジン、シクロヘキセン、シクロヘキサジエン、トリエチルシランなどの水素供与体の存在下、必要に応じ例えばアンモニア、酢酸、塩酸、硫酸などの存在下、−２０℃〜溶媒の沸点の間の温度で５分間〜１００時間処理することによって製造することができる。
反応に不活性な溶媒としては、例えばメタノール、エタノール、酢酸エチル、ＴＨＦ、１，４−ジオキサン、水などがあげられ、これらを単独でまたは混合して用いることができる。
製造法３
化合物（Ｉ）のうち、Ｒ^１が−ＣＯＣＨＲ^１２Ｒ^１３（式中、Ｒ^１２およびＲ^１３は、同一または異なって、水素原子または前記と同義の置換もしくは非置換の低級アルキルを表す）である化合物（Ｉｄ）は、以下の工程に従い製造することができる。

(Wherein, m, R ² , R ³ , R ⁴ , R ⁹ , R ¹⁰ and R ¹¹ are as defined above)
Compound (Ic) is obtained by reacting Compound (Ib) obtained by Production Method 1 in a solvent inert to the reaction, in the presence of 0.01 to 30 equivalents of palladium carbon, Raney nickel, etc. Treated at a temperature between 0 ° C. and the boiling point of the solvent for 5 minutes to 48 hours under a pressure of 1,000 kPa, or 1 to 200 equivalents of formic acid, ammonium formate, hydrazine, cyclohexene, cyclohexadiene, triethylsilane, etc. In the presence of a hydrogen donor, if necessary, for example, in the presence of ammonia, acetic acid, hydrochloric acid, sulfuric acid, etc., by treatment at a temperature between −20 ° C. and the boiling point of the solvent for 5 minutes to 100 hours. .
Examples of the solvent inert to the reaction include methanol, ethanol, ethyl acetate, THF, 1,4-dioxane, water and the like, and these can be used alone or in combination.
Production method 3
Among the compounds (I), R ¹ is —COCHR ¹² R ¹³ (wherein R ¹² and R ¹³ are the same or different and each represents a hydrogen atom or a substituted or unsubstituted lower alkyl as defined above). Compound (Id) can be produced according to the following steps.

（式中、ｍ、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^１２およびＲ^１３は、それぞれ前記と同義である）
工程３−１
化合物（ＸＩＩ）は、製造法１の工程１−３で得られる化合物（ＶＩ）と化合物（ＸＩＩＩ）または（ＸＩＶ）とをパラジウム触媒の存在下で反応させた後、酸で処理することによって製造することができる。
すなわち、製造法１の工程１−３で得られる化合物（ＶＩ）を１〜１００当量の化合物（ＸＩＩＩ）または（ＸＩＶ）と、０．０１ｍｏｌ％〜３０ｍｏｌ％のパラジウム触媒の存在下、無溶媒でまたは反応に不活性な溶媒中、必要に応じ０．０１〜５０当量の適当な塩基および／または適当な添加剤の存在下、−３０℃から１５０℃の間の温度で、５分間〜１００時間反応させ、次いで、得られる反応混合物を０℃〜１５０℃の間の温度で、１〜３００当量の適当な酸で処理することにより、化合物（ＸＩＩ）を製造することができる。
パラジウム触媒としては、例えばテトラキス（トリフェニルホスフィン）パラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム、ビス（アセトニトリル）ジクロロパラジウム、酢酸パラジウムなどがあげられる。適当な塩基としては、例えばトリエチルアミン、炭酸カリウム、炭酸ナトリウムなどがあげられ、適当な添加剤としては、例えば塩化リチウム、１，３−ビス（ジフェニルホスフィノ）プロパン、トリ（ｏ−トリル）ホスフィン、トリフェニルホスフィン、２，６−ジ−ｔｅｒｔ−ブチル−４−メチルフェノール、４−ｔｅｒｔ−ブチルカテコールなどがあげられ、これらを単独でまたは混合して用いることができる。適当な酸としては、例えば塩酸、硫酸などがあげられる。反応に不活性な溶媒としては、例えばＤＭＦ、ＴＨＦ、ＮＭＰ、１，４−ジオキサン、ベンゼン、トルエン、アセトニトリルなどがあげられ、これらを単独でまたは混合して用いることができる。
工程３−２
化合物（Ｉｄ）は、化合物（ＸＩＩ）を用い、製造法１の工程１−５〜工程１−７に記載の方法と同様にして製造することができる。
製造法４
化合物（Ｉ）のうち、Ｒ^１が−Ｃ≡Ｃ−Ｒ^１４（式中、Ｒ^１４は水素原子または前記と同義の置換もしくは非置換の低級アルキルを表す）である化合物（Ｉｅ）は、以下の工程によっても製造することができる。

(Wherein, m, R ² , R ³ , R ⁴ , R ¹² and R ¹³ are as defined above)
Step 3-1
Compound (XII) is produced by reacting compound (VI) obtained in step 1-3 of production method 1 with compound (XIII) or (XIV) in the presence of a palladium catalyst and then treating with acid. can do.
That is, the compound (VI) obtained in Step 1-3 of Production Method 1 is used in the absence of a solvent in the presence of 1 to 100 equivalents of Compound (XIII) or (XIV) and 0.01 mol% to 30 mol% of a palladium catalyst. Or in a solvent inert to the reaction, optionally in the presence of 0.01 to 50 equivalents of a suitable base and / or a suitable additive, at a temperature between −30 ° C. and 150 ° C. for 5 minutes to 100 hours. Compound (XII) can be prepared by reacting and then treating the resulting reaction mixture at a temperature between 0 ° C. and 150 ° C. with 1 to 300 equivalents of a suitable acid.
Examples of the palladium catalyst include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, bis (acetonitrile) dichloropalladium, and palladium acetate. Suitable bases include, for example, triethylamine, potassium carbonate, sodium carbonate, etc. Suitable additives include, for example, lithium chloride, 1,3-bis (diphenylphosphino) propane, tri (o-tolyl) phosphine, Examples thereof include triphenylphosphine, 2,6-di-tert-butyl-4-methylphenol, 4-tert-butylcatechol, and these can be used alone or in combination. Examples of suitable acids include hydrochloric acid and sulfuric acid. Examples of the solvent inert to the reaction include DMF, THF, NMP, 1,4-dioxane, benzene, toluene, acetonitrile and the like, and these can be used alone or in combination.
Step 3-2
Compound (Id) can be produced in the same manner as in Step 1-5 to Step 1-7 of Production Method 1 using Compound (XII).
Manufacturing method 4
Among the compounds (I), the compound (Ie) in which R ¹ is —C≡C—R ¹⁴ (wherein R ¹⁴ represents a hydrogen atom or substituted or unsubstituted lower alkyl as defined above) It can also be manufactured by this process.

（式中、ｍ、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^１４はそれぞれ前記と同義である）
工程４−１
化合物（ＸＶＩ）は、製造法１の工程１−３で得られる化合物（ＶＩ）と１〜２０当量の化合物（ＸＶ）とを、反応に不活性な溶媒中、０．０１ｍｏｌ％〜３０ｍｏｌ％のパラジウム触媒および１〜２０当量の適当な塩基の存在下、−２０℃〜用いる溶媒の沸点の間の温度で５分間〜４８時間反応させることにより製造することができる。反応は窒素、アルゴンなどの不活性気体雰囲気下で実施することが好ましい。
パラジウム触媒としては、例えばテトラキス（トリフェニルホスフィン）パラジウム、トリス（ジベンジリデンアセトン）ジパラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム、ビス（アセトニトリル）ジクロロパラジウム、酢酸パラジウムなどがあげられる。適当な塩基としては、例えば炭酸リチウム、炭酸ナトリウム、トリエチルアミンなどがあげられる。反応に不活性な溶媒としては、例えばＤＭＦ、ＮＭＰ、ＴＨＦ、ＤＭＥ、１，４−ジオキサン、ベンゼン、トルエンなどがあげられ、これらを単独でまたは混合して用いることができる。
また、化合物（ＸＶ）としては、例えば市販品を用いることができる。
工程４−２
化合物（Ｉｅ）は、化合物（ＸＶＩ）を用い、製造法１の工程１−５〜工程１−７に記載の方法と同様にして製造することができる。
製造法５
化合物（Ｉ）のうち、Ｒ^１が−ＮＲ^５Ｒ^６（式中、Ｒ^５およびＲ^６はそれぞれ前記と同義である）である化合物（Ｉｆ）は、以下の工程に従い製造することができる。

(Wherein m, R ² , R ³ , R ⁴ and R ¹⁴ are as defined above)
Step 4-1
Compound (XVI) is obtained by reacting Compound (VI) obtained in Step 1-3 of Production Method 1 with 1 to 20 equivalents of Compound (XV) in an amount of 0.01 mol% to 30 mol% in a solvent inert to the reaction. It can be produced by reacting in the presence of a palladium catalyst and 1 to 20 equivalents of a suitable base at a temperature between −20 ° C. and the boiling point of the solvent used for 5 minutes to 48 hours. The reaction is preferably carried out in an inert gas atmosphere such as nitrogen or argon.
Examples of the palladium catalyst include tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, dichlorobis (triphenylphosphine) palladium, bis (acetonitrile) dichloropalladium, and palladium acetate. Suitable bases include, for example, lithium carbonate, sodium carbonate, triethylamine and the like. Examples of the solvent inert to the reaction include DMF, NMP, THF, DME, 1,4-dioxane, benzene, toluene and the like, and these can be used alone or in combination.
Moreover, as a compound (XV), a commercial item can be used, for example.
Step 4-2
Compound (Ie) can be produced in the same manner as in Step 1-5 to Step 1-7 of Production Method 1, using Compound (XVI).
Manufacturing method 5
Among compounds (I), compound (If) in which R ¹ is —NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ are as defined above) can be produced according to the following steps.

（式中、ｍ、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６はそれぞれ前記と同義であり、Ｐｈはフェニルを表す）
工程５−１
化合物（ＸＶＩＩ）は、製造法１の工程１−３で得られる化合物（ＶＩ）を用い、例えばジャーナル・オブ・オーガニック・ケミストリー（Ｊｏｕｒｎａｌ ｏｆ Ｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ）、１９９７年、第６２巻、ｐ．１２６８などに記載の方法で、またはそれらに準じて製造することができる。すなわち、化合物（ＶＩ）と１〜２０当量のＲ^５Ｒ^６ＮＨ（ＸＶＩＩＩ）とを、反応に不活性な溶媒中、０．０１ｍｏｌ％〜３０ｍｏｌ％のパラジウム触媒および１〜２０当量の適当な塩基の存在下、必要に応じ０．１〜２０当量の適当な添加剤の存在下、０℃〜用いる溶媒の沸点の間の温度で、５分間〜７２時間反応させることにより製造することができる。反応は窒素、アルゴンなどの不活性気体雰囲気下で実施することが好ましい。
パラジウム触媒としては、例えば酢酸パラジウム、ビス（ジベンジリデンアセトン）パラジウム、トリス（ジベンジリデンアセトン）ジパラジウムなどがあげられる。適当な塩基としては、リン酸カリウム、炭酸カリウム、炭酸セシウム、ｔｅｒｔ−ブトキシナトリウム、トリエチルアミンなどがあげられる。適当な添加剤としては、例えば２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル（ＢＩＮＡＰ）、１，１’−ビス（ジフェニルホスフィノ）フェロセン（ＤＰＰＦ）などがあげられる。反応に不活性な溶媒としては、例えばＴＨＦ、１，４−ジオキサン、ＤＭＥ、トルエン、アセトニトリル、グライムなどがあげられる。
工程５−２
化合物（Ｉｆ）は、化合物（ＸＶＩＩ）を用い、製造法１の工程１−５〜工程１−７に記載の方法と同様にして製造することができる。
化合物（Ｉｆ）のうち、Ｒ^５およびＲ^６が水素原子である化合物（Ｉｆａ）は以下の工程によっても製造することができる。
工程５−３
化合物（ＸＩＸ）は、製造法１の工程１−３で得られる化合物（ＶＩ）と化合物（ＸＸＩ）を用い、工程５−１に記載の方法と同様にして製造することができる。
工程５−４
化合物（ＸＸ）は、化合物（ＸＩＸ）を用い、製造法２に記載の方法と同様にして製造することができる。
工程５−５
化合物（Ｉｆａ）は、化合物（ＸＸ）を用い、製造法１の工程１−６〜工程１−７に記載の方法と同様にして製造することができる。
製造法６
化合物（Ｉ）のうち、Ｒ^１が−ＣＦ＝ＣＲ^１５Ｒ^１６（式中、Ｒ^１５およびＲ^１６は、同一または異なって、水素原子または置換もしくは非置換の低級アルキルを表す）または−ＣＨＦＣＨＲ^１５Ｒ^１６（式中、Ｒ^１５およびＲ^１６はそれぞれ前記と同義である）である化合物（Ｉｇ）または（Ｉｈ）は、以下の工程によっても製造することができる。

(Wherein, m, R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above, and Ph represents phenyl)
Step 5-1
Compound (XVII) uses Compound (VI) obtained in Step 1-3 of Production Method 1, and is described in, for example, Journal of Organic Chemistry, 1997, Vol. 62, p. 1268 or the like, or according to them. That is, compound (VI) and 1 to 20 equivalents of R ⁵ R ⁶ NH (XVIII) are combined with 0.01 to 30 mol% of a palladium catalyst and 1 to 20 equivalents of an appropriate base in a solvent inert to the reaction. In the presence of 0.1 to 20 equivalents of an appropriate additive, if necessary, at a temperature between 0 ° C. and the boiling point of the solvent used for 5 minutes to 72 hours. The reaction is preferably carried out in an inert gas atmosphere such as nitrogen or argon.
Examples of the palladium catalyst include palladium acetate, bis (dibenzylideneacetone) palladium, and tris (dibenzylideneacetone) dipalladium. Suitable bases include potassium phosphate, potassium carbonate, cesium carbonate, tert-butoxy sodium, triethylamine and the like. Suitable additives include, for example, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), 1,1′-bis (diphenylphosphino) ferrocene (DPPF), and the like. Examples of the solvent inert to the reaction include THF, 1,4-dioxane, DME, toluene, acetonitrile, glyme and the like.
Step 5-2
Compound (If) can be produced in the same manner as in Step 1-5 to Step 1-7 of Production Method 1, using Compound (XVII).
Among compounds (If), compound (Ifa) in which R ⁵ and R ⁶ are hydrogen atoms can also be produced by the following steps.
Step 5-3
Compound (XIX) can be produced in the same manner as in Step 5-1, using Compound (VI) and Compound (XXI) obtained in Step 1-3 of Production Method 1.
Step 5-4
Compound (XX) can be produced in the same manner as in Production Method 2 using Compound (XIX).
Step 5-5
Compound (Ifa) can be produced in the same manner as in Steps 1-6 to 1-7 of Production Method 1 using Compound (XX).
Manufacturing method 6
Among the compounds (I), R ¹ is —CF═CR ¹⁵ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are the same or different and each represents a hydrogen atom or a substituted or unsubstituted lower alkyl) or —CHFCHR ¹⁵ Compound (Ig) or (Ih) which is R ¹⁶ (wherein R ¹⁵ and R ¹⁶ are as defined above) can also be produced by the following steps.

（式中、ｍ、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^７、Ｒ^１５およびＲ^１６はそれぞれ前記と同義である）
工程６−１
化合物（ＸＸＩＩ）は、製造法１の工程１−４で得られる化合物（ＶＩＩａ）を用い、テトラへドロン（Ｔｅｔｒａｈｅｄｒｏｎ）、１９９０年、第４６巻、ｐ．４２５５などに記載の方法に準じて製造することができる。すなわち、化合物（ＶＩＩａ）を反応に不活性な溶媒中、１〜１０当量のＮ−ブロモスクシンイミドおよび１〜１０当量のトリエチルアミン・三フッ化水素の存在下、−７８℃〜６０℃の間の温度で、５分間〜４８時間処理することにより、化合物（ＸＸＩＩ）を製造することができる。
反応に不活性な溶媒としては、例えばジクロロメタン、１，２−ジクロロエタンなどがあげられ、これらを単独でまたは混合して用いることができる。
工程６−２
化合物（ＸＸＩＩＩ）は、化合物（ＸＸＩＩ）を無溶媒でまたは適当な溶媒中、１〜１００当量の適当な塩基の存在下、−３０℃〜用いる溶媒の沸点の間の温度で５分間〜４８時間処理することにより製造することができる。
適当な塩基としては、例えばＤＢＵ、ＤＢＮ、ｔｅｒｔ−ブトキシカリウム、リチウムジイソプロピルアミド（ＬＤＡ）、リチウムヘキサメチルジシラジド（ＬｉＨＭＤＳ）、ナトリウムヘキサメチルジシラジド（ＮａＨＭＤＳ）などがあげられる。適当な溶媒としては、例えばＴＨＦ、１，４−ジオキサン、ＤＭＦ、ＤＭＳＯなどがあげられ、これらを単独でまたは混合して用いることができる。
工程６−３
化合物（ＸＸＩＶ）は、化合物（ＸＸＩＩＩ）を用い、製造法１の工程１−５〜工程１−６に記載の方法と同様にして製造することができる。
工程６−４
化合物（Ｉｇ）は、化合物（ＸＸＩＶ）を用い、製造法１の工程１−７に記載の方法と同様にして製造することができる。
工程６−５
化合物（ＸＸＶ）は、化合物（ＸＸＩＶ）を用い、製造法２に記載の方法と同様にして製造することができる。
工程６−６
化合物（Ｉｈ）は、化合物（ＸＸＶ）を用い、製造法１の工程１−７に記載の方法と同様にして製造することができる。
製造法７
化合物（Ｉａ）のうち、Ｒ^２が置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアラルキル、置換もしくは非置換のヘテロアラルキルまたは置換もしくは非置換の脂環式複素環基である化合物（Ｉｉ）は、製造法１で得られる化合物（ＶＩＩａ）より以下の工程によっても製造することができる。

(Wherein, m, R ² , R ³ , R ⁴ , R ⁷ , R ¹⁵ and R ¹⁶ have the same meanings as described above)
Step 6-1
Compound (XXII) was obtained by using compound (VIIa) obtained in Step 1-4 of Production Method 1, using tetrahedron, 1990, 46, p. 4255 or the like. That is, the temperature between −78 ° C. and 60 ° C. in the presence of 1 to 10 equivalents of N-bromosuccinimide and 1 to 10 equivalents of triethylamine / hydrogen trifluoride in a solvent inert to the reaction of compound (VIIa). The compound (XXII) can be produced by treating for 5 minutes to 48 hours.
Examples of the solvent inert to the reaction include dichloromethane and 1,2-dichloroethane, and these can be used alone or in combination.
Step 6-2
Compound (XXIII) is obtained by reacting Compound (XXII) without solvent or in a suitable solvent in the presence of 1 to 100 equivalents of a suitable base at a temperature between −30 ° C. and the boiling point of the solvent used for 5 minutes to 48 hours. It can be manufactured by processing.
Suitable bases include DBU, DBN, tert-butoxy potassium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), and the like. Suitable solvents include, for example, THF, 1,4-dioxane, DMF, DMSO and the like, and these can be used alone or in combination.
Step 6-3
Compound (XXIV) can be produced in the same manner as in Step 1-5 to Step 1-6 of Production Method 1, using Compound (XXIII).
Step 6-4
Compound (Ig) can be produced using compound (XXIV) in the same manner as in the method described in Step 1-7 of Production Method 1.
Step 6-5
Compound (XXV) can be produced in the same manner as in Production Method 2 using compound (XXIV).
Step 6-6
Compound (Ih) can be produced using compound (XXV) in the same manner as in Step 1-7 of Production Method 1.
Manufacturing method 7
Among the compounds (Ia), R ² is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aralkyl, substituted Alternatively, compound (Ii) which is an unsubstituted heteroaralkyl or a substituted or unsubstituted alicyclic heterocyclic group can also be produced from compound (VIIa) obtained by Production Method 1 by the following steps.

（式中、ｍ、Ｘ、Ｒ^1a、Ｒ^３およびＲ^４はそれぞれ前記と同義であり、Ｒ^２ａは前記Ｒ^２の定義のうち、水素原子、置換もしくは非置換のアリールおよび置換もしくは非置換の芳香族複素環基を除いた基を表し、Ｒ^２ｂは前記Ｒ^２ａと同義である）
工程７−１
化合物（ＸＸＶＩ）は、化合物（ＶＩＩａ）を用い、製造法１の工程１−２に記載の方法と同様にして製造することができる。
工程７−２
化合物（ＸＸＶＩＩＩ）は、化合物（ＸＸＶＩ）と１〜３０当量の化合物（ＸＸＶＩＩ）とを、溶媒中、１〜３０当量の適当な塩基の存在下、必要に応じ０．０１〜３０当量のヨウ化カリウムなどの添加剤の存在下、０℃〜用いる溶媒の沸点の間の温度で、５分間〜７２時間反応させることにより製造することができる。
適当な塩基としては、例えばトリエチルアミン、炭酸カリウム、炭酸ナトリウム、炭酸水素ナトリウムなどがあげられる。溶媒としては、例えばピリジン、ＤＭＦ、ＮＭＰ、ＴＨＦ、ジクロロメタン、１，２−ジクロロエタン、１，４−ジオキサン、トルエンなどがあげられ、これらを単独でまたは混合して用いることができる。
工程７−３
化合物（Ｉｉ）は、化合物（ＸＸＶＩＩＩ）を用い、製造法１の工程１−５〜工程１−７に記載の方法と同様にして製造することができる。
化合物（Ｉ）におけるＲ^１、Ｒ^２、Ｒ^３またはＲ^４に含まれる官能基の変換は、上記工程以外にも公知の他の方法［例えば、コンプリヘンシブ・オーガニック・トランスフォーメーションズ（Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ）、Ｒ．Ｃ．ラロック（Ｌａｒｏｃｋ）著（１９８９年）などに記載の方法］でまたはそれらに準じて行うこともできる。
また、上記の方法を適宜組み合わせて実施することにより、所望の位置に所望の官能基を有する化合物（Ｉ）を得ることができる
上記各製造方法における中間体および目的化合物は、有機合成化学で常用される分離精製法、例えば、ろ過、抽出、洗浄、乾燥、濃縮、再結晶、各種クロマトグラフィーなどに付して単離精製することができる。また、中間体においては特に精製することなく次の反応に供することも可能である。
化合物（Ｉ）の中には、幾何異性体、光学異性体、互変異性体などの立体異性体が存在し得るものもあるが、本発明は、これらを含め、全ての可能な異性体およびそれらの混合物を包含する。
化合物（Ｉ）の塩を取得したいとき、化合物（Ｉ）が塩の形で得られるときはそのまま精製すればよく、また、遊離の形で得られるときは、化合物（Ｉ）を適当な溶媒に溶解または懸濁し、酸または塩基を加えて単離、精製すればよい。
また、化合物（Ｉ）およびその薬理学的に許容される塩は、水または各種溶媒との付加物の形で存在することもあるが、これらの付加物も本発明に包含される。
本発明によって得られる化合物（Ｉ）の具体例を第１表に示す。

Wherein m, X, R ^1a , R ³ and R ⁴ are as defined above, and R ^2a is a hydrogen atom, substituted or unsubstituted aryl and substituted or unsubstituted in the definition of R ² . Represents a group excluding an aromatic heterocyclic group, and R ^2b has the same meaning as R ^2a ).
Step 7-1
Compound (XXVI) can be produced using compound (VIIa) in the same manner as in Process 1-2, Process 1-2.
Step 7-2
Compound (XXVIII) is prepared by combining compound (XXVI) and 1-30 equivalents of compound (XXVII) in a solvent in the presence of 1-30 equivalents of a suitable base, optionally 0.01-30 equivalents of iodide. It can manufacture by making it react for 5 minutes-72 hours at the temperature between 0 degreeC-the boiling point of the solvent to be used in presence of additives, such as potassium.
Suitable bases include, for example, triethylamine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate and the like. Examples of the solvent include pyridine, DMF, NMP, THF, dichloromethane, 1,2-dichloroethane, 1,4-dioxane, toluene and the like, and these can be used alone or in combination.
Step 7-3
Compound (Ii) can be produced in the same manner as in Step 1-5 to Step 1-7 of Production Method 1, using Compound (XXVIII).
The conversion of the functional group contained in R ¹ , R ² , R ³ or R ⁴ in compound (I) may be carried out by other known methods other than the above steps [for example, Comprehensive Organic Transformations (for example, Comprehensive Organic Transformations). Transformations), R.A. C. The method described in Larock (1989) or the like] or in accordance with them.
In addition, by appropriately combining the above methods, a compound (I) having a desired functional group at a desired position can be obtained. Intermediates and target compounds in each of the above production methods are commonly used in organic synthetic chemistry. It can be isolated and purified by subjecting it to separation and purification methods such as filtration, extraction, washing, drying, concentration, recrystallization, various chromatography and the like. The intermediate can be subjected to the next reaction without any particular purification.
Some compounds (I) may have stereoisomers such as geometrical isomers, optical isomers, tautomers and the like, and the present invention includes all possible isomers including these, Including mixtures thereof.
When it is desired to obtain a salt of compound (I), it can be purified as it is when compound (I) is obtained in the form of a salt. When it is obtained in a free form, compound (I) can be obtained in an appropriate solvent. It may be dissolved or suspended and isolated and purified by adding acid or base.
Compound (I) and pharmacologically acceptable salts thereof may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention.
Specific examples of the compound (I) obtained by the present invention are shown in Table 1.

次に、代表的な化合物（Ｉ）の薬理作用について試験例により具体的に説明する。
試験例：組み換えヒトＰＤＥ−ＩＶ酵素阻害試験
ヒトＰＤＥｃＤＮＡ（ＨＳＰＤＥ４Ａ）を、ＨＬ−６０細胞より単離した。予想されるアミノ酸配列は、ボルガー（Ｂｏｌｇｅｒ，Ｇ．）ら［「モレキュラー・アンド・セルラー・バイオロジー（Ｍｏｌｅｃｕｌａｒ ａｎｄ Ｃｅｌｌｕｌａｒ Ｂｉｏｌｏｇｙ）」、１９９３年、１３巻、ｐ．６５５８］の報告した配列（ＨＳＰＤＥ４Ａ４）と同一である。この組み換えタンパク質を、Ｓｆ９昆虫細胞を用いて発現させた。ＰＤＥ活性は、Ｋｉｎｃａｉｄ Ｒ．Ｌ．およびＭａｎｇａｎｉｅｌｌｏ Ｖ．Ｃ．の方法［「メソッズ・イン・エンザイモロジー（Ｍｅｔｈｏｄｓ ｉｎ Ｅｎｚｙｍｏｌｏｇｙ）」、１９８８年、１５９巻、ｐ．４５７］に従い、次の二段階過程により測定した。基質には［^３Ｈ］ｃＡＭＰ（最終濃度１μｍｏｌ／Ｌ）を用い、反応は、Ｎ，Ｎ−ビス（２−ヒドロキシエチル）−２−アミノエタンスルホン酸（５０ｍｍｏｌ／Ｌ，ｐＨ ７．２）、ＭｇＣｌ_２（１ｍｍｏｌ／Ｌ）およびＳｏｙｂｅａｎ ｔｒｙｐｓｉｎ ｉｎｈｉｂｉｔｏｒ（０．１ｍｇ／ｍＬ）を含む標準混合液中で行った。反応は酵素の添加により開始し、３０℃で１０〜３０分間インキュベーションした。塩酸により反応を停止し、生成した５’−ＡＭＰを５’−ヌクレオチダーゼによって完全に分解した。ＤＥＡＥ−Ｓｅｐｈａｄｅｘ Ａ−２５でクロマトグラフィーによる処理を行い、溶出した［^３Ｈ］アデノシンをシンチレーションカウンターでカウントした。薬物はＤＭＳＯに溶解して（濃度１．７％）添加した。
本試験において、化合物１、２および４は、薬物濃度１μｍｏｌ／Ｌにおいて６０％以上の酵素阻害活性を示した。
化合物（Ｉ）またはその薬理学的に許容される塩は、そのまま単独で投与することも可能であるが、通常各種の医薬製剤として提供するのが望ましい。また、それら医薬製剤は、動物および人に使用されるものである。
本発明に係わる医薬製剤は、活性成分として化合物（Ｉ）またはその薬理学的に許容される塩を単独で、あるいは任意の他の治療のための有効成分との混合物として含有することができる。また、それら医薬製剤は、活性成分を薬理学的に許容される一種もしくはそれ以上の担体と一緒に混合し、製剤学の技術分野においてよく知られている任意の方法により製造される。
投与経路としては、治療に際し最も効果的なものを使用するのが望ましく、経口または、例えば静脈内、気管内、経皮などの非経口をあげることができる。
投与形態としては、例えば錠剤、注射剤、吸入剤、外用剤などがあげられる。徐放的な適応もまた利用できる。
経口投与に適当な、例えば錠剤などは、乳糖、マンニットなどの賦形剤、澱粉などの崩壊剤、ステアリン酸マグネシウムなどの滑沢剤、ヒドロキシプロピルセルロースなどの結合剤、脂肪酸エステルなどの界面活性剤、グリセリンなどの可塑剤、安息香酸、ｐ−ヒドロキシ安息香酸エステル類などの防腐剤などを用いて製造できる。
非経口投与に適当な、例えば注射剤は、好ましくは受容者の血液と等張である活性化合物を含む滅菌水性剤からなり、例えば、塩溶液、ブドウ糖溶液または塩水とブドウ糖溶液の混合物からなる担体などを用いて注射用の溶液を調製する。
吸入剤は、活性成分を粉末または液状にして、吸入噴霧剤または担体中に配合し、例えば、定量噴霧式吸入器、ドライパウダー吸入器などの吸入容器に充填することにより製造される。吸入噴射剤としては、従来公知のものを広く使用することができ、例えばフロン−１１、フロン−１２、フロン−２１、フロン−２２、フロン−１１３、フロン−１１４、フロン−１２３、フロン−１４２ｃ、フロン−１３４ａ、フロン−２２７、フロン−Ｃ３１８、１，１，１，２−テトラフルオロエタンなどのフロン系ガス、ＨＦＡ−２２７、ＨＦＡ−１３４ａなどの代替フロンガス、プロパン、イソブタン、ｎ−ブタンなどの炭化水素系ガス、ジエチルエーテル、窒素ガス、炭酸ガスなどがあげられる。担体としては、従来公知のものを広く使用でき、例えば糖類、糖アルコール類、アミノ酸類などがあげられ、乳糖、Ｄ−マンニトールなどが好ましい。
外用剤としては、特に限定されるものではないが、例えば基剤に活性成分を溶解または混合分散しクリーム状、ペースト状、ゼリー状、ゲル状、乳液状、液状などの形状になされたもの（軟膏剤、ローション剤など）、基剤に活性成分および経皮吸収促進剤を溶解または混合分散させたものを例えばポリエチレンなどの支持体上に展延したもの（パップ剤、テープ剤など）などがあげられる。上記基剤としては、薬理学的に許容しうるものであればいずれでもよく、軟膏剤、リニメント剤、ローションなどの基剤として従来公知のものを用いることができ、例えば、アルギン酸ナトリウム；ゼラチン、コーンスターチ、トラガントガム、メチルセルロース、キサンタンガム、デキストリン、ポリビニルアルコールなどのポリマー；オリーブ油、ラノリンなどの油脂類；白色ワセリン；パラフィン；ステアリン酸などの高級脂肪酸；セチルアルコールなどの高級アルコール；ポリエチレングリコール；水などがあげられる。上記経皮吸収促進剤としては、薬理学的に許容しうるものであればいずれでもよく、例えばエタノール、ジエチレングリコールなどのアルコール類；ドデシルピロリドンなどの極性溶剤；尿素；ラウリル酸エチル；エイゾン；オリーブ油などがあげられる。さらに必要に応じて、カオリン、ベントナイト、酸化亜鉛、酸化チタンなどの無機充填剤；粘度調節剤；老化防止剤；ｐＨ調節剤；グリセリン、プロピレングリコールなどの保湿剤などを添加してもよい。
また、これら非経口剤においても、経口剤で例示した賦形剤、崩壊剤、滑沢剤、結合剤、界面活性剤、可塑剤、防腐剤などから選択される１種もしくはそれ以上の補助成分を添加することもできる。
化合物（Ｉ）またはその薬理学的に許容される塩の投与量および投与回数は、投与形態、患者の年齢、体重、治療すべき症状の性質もしくは重篤度などにより異なるが、通常経口の場合、成人一人当り０．０１ｍｇ〜１ｇ、好ましくは０．０５〜５０ｍｇを一日１回ないし数回投与する。静脈内投与などの非経口投与の場合、成人一人当り０．００１〜１００ｍｇ 、好ましくは０．０１〜５０ｍｇを一日１回ないし数回投与する。気管内投与（吸入剤）の場合、成人一人当たり、０．００１ｍｇ〜１ｇ、好ましくは０．０１ｍｇ〜１００ｍｇ、より好ましくは０．５ｍｇ〜２０ｍｇを一日１回ないし数回投与する。しかしながら、これら投与量および投与回数に関しては、前述の種々の条件により変動する。
以下に、本発明の態様を実施例、参考例および製剤例で説明する。

Next, the pharmacological action of a typical compound (I) will be specifically described with reference to test examples.
Test Example: Recombinant human PDE-IV enzyme inhibition test Human PDE cDNA (HSPDE4A) was isolated from HL-60 cells. The predicted amino acid sequence is described in Bolger, G. et al. ["Molecular and Cellular Biology", 1993, vol. 13, p. 6558] is the same as the reported sequence (HSPDE4A4). This recombinant protein was expressed using Sf9 insect cells. PDE activity was determined by Kincaid R. L. And Manganello V. C. [“Methods in Enzymology”, 1988, 159, p. 457] according to the following two-step process. [ ³ H] cAMP (final concentration 1 μmol / L) was used as the substrate, and the reaction was performed using N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid (50 mmol / L, pH 7.2), It was carried out in a standard mixture containing MgCl ₂ (1 mmol / L) and Soybean trypsin inhibitor (0.1 mg / mL). The reaction was started by addition of enzyme and incubated at 30 ° C. for 10-30 minutes. The reaction was stopped with hydrochloric acid, and the produced 5′-AMP was completely decomposed with 5′-nucleotidase. Chromatographic treatment was performed with DEAE-Sephadex A-25, and the eluted [ ³ H] adenosine was counted with a scintillation counter. The drug was dissolved in DMSO (concentration 1.7%) and added.
In this test, compounds 1, 2 and 4 showed an enzyme inhibitory activity of 60% or more at a drug concentration of 1 μmol / L.
Compound (I) or a pharmacologically acceptable salt thereof can be administered alone as it is, but it is usually desirable to provide it as various pharmaceutical preparations. These pharmaceutical preparations are used for animals and humans.
The pharmaceutical preparation according to the present invention may contain Compound (I) or a pharmacologically acceptable salt thereof as an active ingredient alone or as a mixture with any other active ingredient for treatment. In addition, these pharmaceutical preparations are produced by any method well known in the technical field of pharmaceutics by mixing the active ingredient with one or more pharmacologically acceptable carriers.
As the administration route, it is desirable to use one that is most effective in the treatment, and examples thereof include oral administration and parenteral administration such as intravenous administration, intratracheal administration and transdermal administration.
Examples of the dosage form include tablets, injections, inhalants, and external preparations. Sustained release indications are also available.
Suitable for oral administration, such as tablets, excipients such as lactose and mannitol, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and surface activity such as fatty acid esters Agent, plasticizer such as glycerin, benzoic acid, and preservatives such as p-hydroxybenzoic acid esters.
Suitable for parenteral administration, for example injections, comprise a sterile aqueous agent containing an active compound, preferably isotonic with the blood of the recipient, for example a carrier consisting of a salt solution, a glucose solution or a mixture of saline and glucose solution A solution for injection is prepared using such as.
An inhalant is produced by making an active ingredient into a powder or liquid and blending it into an inhalation spray or carrier and filling the inhalation container such as a metered dose inhaler or a dry powder inhaler. As the inhalation propellant, conventionally known ones can be widely used. For example, chlorofluorocarbon-11, chlorofluorocarbon-12, chlorofluorocarbon-21, chlorofluorocarbon-22, chlorofluorocarbon-113, chlorofluorocarbon-114, chlorofluorocarbon-123, chlorofluorocarbon-142c. , Freon gases such as Freon-134a, Freon-227, Freon-C318, 1,1,1,2-tetrafluoroethane, alternative Freon gases such as HFA-227, HFA-134a, propane, isobutane, n-butane, etc. Hydrocarbon gas, diethyl ether, nitrogen gas, carbon dioxide gas and the like. As the carrier, conventionally known ones can be widely used, and examples thereof include sugars, sugar alcohols, amino acids and the like, and lactose, D-mannitol and the like are preferable.
Although it does not specifically limit as an external preparation, For example, the active ingredient is melt | dissolved or mixed-dispersed in the base, and it was made into shapes, such as cream form, paste form, jelly form, gel form, emulsion, and liquid ( Ointments, lotions, etc.) and active ingredients and percutaneous absorption accelerators dissolved or mixed and dispersed in a base, for example, spread on a support such as polyethylene (paps, tapes, etc.) can give. The base may be any pharmacologically acceptable, and conventionally known bases such as ointments, liniments, and lotions can be used, such as sodium alginate; gelatin, Polymers such as corn starch, tragacanth gum, methylcellulose, xanthan gum, dextrin, polyvinyl alcohol; fats and oils such as olive oil and lanolin; white petrolatum; paraffin; higher fatty acids such as stearic acid; higher alcohols such as cetyl alcohol; polyethylene glycol; It is done. As the transdermal absorption enhancer, any pharmacologically acceptable one may be used. For example, alcohols such as ethanol and diethylene glycol; polar solvents such as dodecylpyrrolidone; urea; ethyl laurate; Can be given. Furthermore, if necessary, inorganic fillers such as kaolin, bentonite, zinc oxide and titanium oxide; viscosity modifiers; anti-aging agents; pH regulators; humectants such as glycerin and propylene glycol may be added.
In these parenterals, one or more auxiliary components selected from excipients, disintegrants, lubricants, binders, surfactants, plasticizers, preservatives and the like exemplified in the oral preparations. Can also be added.
The dose and frequency of administration of Compound (I) or a pharmacologically acceptable salt thereof vary depending on the administration form, patient age, body weight, nature or severity of symptoms to be treated, etc. In addition, 0.01 mg to 1 g, preferably 0.05 to 50 mg per adult is administered once to several times a day. In the case of parenteral administration such as intravenous administration, 0.001 to 100 mg, preferably 0.01 to 50 mg per adult is administered once to several times a day. In the case of intratracheal administration (inhalation agent), 0.001 mg to 1 g, preferably 0.01 mg to 100 mg, more preferably 0.5 mg to 20 mg is administered once or several times a day per adult. However, the dose and the number of doses vary depending on the various conditions described above.
Below, the aspect of this invention is demonstrated with an Example, a reference example, and a formulation example.

[4-Cyano-4- (3-cyclopentyloxy-4-ethenylphenyl) piperidin-1-yl] acetic acid (Compound 1)
Step 1:
1-Benzyl-4- (3-cyclopentyloxy-4-trifluoromethanesulfonyloxyphenyl) piperidine-4-carbonitrile (13.25 g) obtained in Reference Example 1 was dissolved in DMF (123 mL) and dichlorobis (triphenyl Phosphine) palladium (340 mg, 0.48 mmol), tributylvinyltin (7.3 mL, 25 mmol) and anhydrous lithium chloride (7.39 g, 174 mmol) were added, and the mixture was stirred at 100 ° C. for 2 hours. Further, tributylvinyltin (0.73 mL, 2.50 mmol) was added, and the mixture was stirred at the same temperature for 50 minutes. The reaction mixture was allowed to cool to room temperature, an aqueous ammonium fluoride solution was added, and the mixture was stirred for 30 min. The mixture was filtered through celite. Water was added to the filtrate, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1-benzyl-4- (3-cyclopentyloxy-4-ethenylphenyl) piperidine-4-carbonitrile. Subsequently, the obtained 1-benzyl-4- (3-cyclopentyloxy-4-ethenylphenyl) piperidine-4-carbonitrile was cooled with ice under a 4 mol / L hydrogen chloride-ethyl acetate solution (26.4 mL, 105 mmol). ) Was added dropwise. The precipitated solid was collected by filtration to give 1-benzyl-4- (3-cyclopentyloxy-4-ethenylphenyl) piperidine-4-carbonitrile hydrochloride (7.94 g, 78% (from Step 3 of Reference Example 1). Two steps)) were obtained as a pale yellow solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 13.17 (br s, 1H), 7.73-7.69 (m, 2H), 7.49-7.45 (m, 4H), 7.12-7.10 (m, 2H), 6.95 (dd, J = 17.8, 11.2 Hz, 1H), 5.76 (dd, J = 17.8, 1.3 Hz, 1H), 5.27 (dd, J = 11.2, 1.3 Hz, 1H), 4.89-4.84 (m, 1H), 4.25 (d, J = 5.0 Hz, 2H), 3.62 (br d, J = 10.9 Hz, 2H), 3.32-3.07 (m, 4H), 2.17 (br d, J = 13.3 Hz, 2H), 2.08-1.95 (m, 2H), 1.87-1.61 (m, 6H).
Step 2:
The compound (4.16 g, 9.83 mmol) obtained in the above Step 1 was suspended in ethyl acetate (50 mL), and 1 mol / L aqueous sodium hydroxide solution (9.83 mL, 9.83 mmol) was added dropwise under ice cooling. Next, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 1,2-dichloroethane (50 mL), 1-chloroethyl chloroformate (1.27 mL, 11.8 mmol) was added, and the mixture was heated to reflux for 2 hours. Further, 1-chloroethyl chloroformate (0.210 mL, 1.95 mmol) was added and refluxed for 1 hour, and then the solvent was distilled off under reduced pressure. Methanol (70 mL) was added to the obtained residue and the mixture was heated to reflux for 1 hour, and then the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and crystallized to give 4- (3-cyclopentyloxy-4-ethenylphenyl) piperidine-4-carbonitrile hydrochloride (2.88 g, 88%) as a white solid.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 10.0 (br s, 2H), 7.49 (d, J = 8.5 Hz, 1H), 7.10-6.90 (m, 3H), 5.77 (dd, J = 18.0 , 1.1 Hz, 1H), 5.29 (dd, J = 11.4, 1.1 Hz, 1H), 4.91-4.80 (m, 1H), 3.77-3.62 (m, 2H), 3.50-3.30 (m, 2H), 2.83- 2.65 (m, 2H), 2.33-2.20 (m, 2H), 2.10-1.55 (m, 8H).
Step 3:
The compound (2.38 g, 7.15 mmol) obtained in Step 2 above was suspended in DMF (25 mL), ethyl bromoacetate (0.951 mL, 8.57 mmol) and potassium carbonate (1.98 g, 14.3 mmol) were added, and room temperature was added. For 2 hours. Furthermore, after adding ethyl bromoacetate (0.159 mL, 1.43 mmol) and stirring for 1 hour, saturated brine was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), 4 mol / L hydrogen chloride-ethyl acetate solution (3.57 mL, 14.3 mmol) was added, and the precipitated solid was collected by filtration to give [4-cyano-4- ( 3-Cyclopentyloxy-4-ethenylphenyl) piperidin-1-yl] acetic acid ethyl ester hydrochloride (2.20 g, 73.4%) was obtained as a white solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 13.7 (br s, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.20-7.05 (m, 2H), 6.96 (dd, J = 17.8 , 11.2 Hz, 1H), 5.77 (dd, J = 17.8, 1.3 Hz, 1H), 5.28 (dd, J = 11.2, 1.3 Hz, 1H), 4.92-4.82 (m, 1H), 4.34 (q, J = 7.0 Hz, 2H), 3.95 (s, 2H), 3.90-3.60 (m, 4H), 3.35-3.15 (m, 2H), 2.30-2.15 (m, 2H), 2.10-1.55 (m, 8H), 1.35 (t, J = 7.0 Hz, 3H).
Step 4:
The compound (2.21 g, 5.27 mmol) obtained in the above Step 3 was suspended in ethanol (30 mL), 1 mol / L aqueous sodium hydroxide solution (15.8 mL, 15.8 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Next, the reaction solution was concentrated under reduced pressure, and the resulting residue was washed with diethyl ether, neutralized with 1 mol / L hydrochloric acid, and the precipitated crystals were collected by filtration. Next, the obtained crystals were dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with isopropyl alcohol to give the title compound 1 (1.19 g, 63.7%) as a white solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 7.54 (d, J = 8.6 Hz, 1H), 7.10-7.02 (m, 2H), 6.89 (dd, J = 17.8, 11.2 Hz, 1H) , 5.81 (dd, J = 17.8, 1.3 Hz, 1H), 5.26 (dd, J = 11.2, 1.3 Hz, 1H), 5.00-4.92 (m, 1H), 3.23 (s, 2H), 3.08-2.96 (m , 2H), 2.66-2.54 (m, 2H), 2.12-2.02 (m, 4H), 1.95-1.85 (m, 2H), 1.80-1.55 (m, 6H).

[4-Cyano-4- (3-cyclopentyloxy-4-ethylphenyl) piperidin-1-yl] acetic acid (Compound 2)
Compound 1 (250 mg, 0.706 mmol) obtained in Example 1 was dissolved in a mixed solvent of ethyl acetate (10 mL) and methanol (10 mL), water-containing 10% palladium on carbon (0.90 g) was added, and under a hydrogen stream. And stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized from isopropyl alcohol and diisopropyl ether to give the title compound 2 (0.052 g, 20.7%) as a white solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.16 (d, J = 8.6 Hz, 1H), 7.02-6.94 (m, 2H), 4.88-4.80 (m, 1H), 3.57-3.40 (m, 4H), 3.05-2.90 (m, 2H), 2.70-2.40 (m, 4H), 2.03-1.60 (m, 8H), 1.16 (t, J = 7.6 Hz, 3H).

[4-Cyano-4- (3-cyclopentylmethyloxy-4-ethenylphenyl) piperidin-1-yl] acetic acid (Compound 3)
The title compound 3 was synthesized in the same manner as in Reference Example 1 in place of 1-benzyl-4- (3-cyclopentyloxy-4-trifluoromethanesulfonyloxyphenyl) piperidine-4-carbonitrile in the starting compound. Synthesis was performed in the same manner as in Example 1 except that 4- (3-cyclopentylmethyloxy-4-trifluoromethanesulfonyloxyphenyl) piperidine-4-carbonitrile was used.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.49 (d, J = 8.1 Hz, 1H), 7.01 (dd, J = 10.5, 17.9 Hz, 1H), 7.06-7.00 (m, 2H), 5.79 (dd, J = 1.4, 7.7 Hz, 1H), 5.30 (dd, J = 1.4, 11.1 Hz, 1H), 4.90 (d, J = 6.8 Hz, 2H), 3.37 (s, 2H), 3.25 (br d , J = 11.3 Hz, 2H), 2.95 (br t, J = 11.7 Hz, 2H), 2.44-2.27 (m, 3H), 2.21-2.17 (m, 2H), 1.95-1.79 (m, 2H), 1.71 -1.57 (m, 4H), 1.46-1.34 (m, 2H).

[4-Cyano-4- (3-cyclopropylmethyloxy-4-ethenylphenyl) piperidin-1-yl] acetic acid (Compound 4)
The title compound 4 was synthesized in the same manner as in Reference Example 1 except that 1-benzyl-4- (3-cyclopentyloxy-4-trifluoromethanesulfonyloxyphenyl) piperidine-4-carbonitrile was used as the starting compound. Synthesis was performed in the same manner as in Example 1 except that 4- (3-cyclopropylmethyloxy-4-trifluoromethanesulfonyloxyphenyl) piperidine-4-carbonitrile was used.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 7.55 (d, J = 7.9 Hz, 1H), 7.10-7.06 (m, 2H), 6.96 (dd, J = 11.4, 17.8 Hz, 1H) , 5.85 (dd, J = 1.7, 17.7 Hz, 1H), 5.30 (dd, J = 1.7, 11.4 Hz, 1H), 3.94 (s, 1H), 3.91 (s, 1H), 3.24 (s, 2H), 3.05-3.00 (m, 2H), 2.62-2.54 (m, 2H), 2.09-1.99 (m, 4H), 1.26-1.22 (m, 1H), 0.62-0.55 (m, 2H), 0.37-0.34 (m , 2H).

(±) -2- [4-Cyano-4- (3-cyclopentyloxy-4-ethenylphenyl) piperidin-1-yl] propionic acid (Compound 5)
Step 1:
To DMF (8 mL), 4- (3-cyclopentyloxy-4-ethenylphenyl) piperidine-4-carbonitrile hydrochloride (0.54 g, 1.6 mmol) obtained in Step 2 of Example 1, potassium carbonate (0.45 g, 3.2 mmol) and ethyl 2-bromopropionate (0.41 g, 2.3 mmol) were added, and the mixture was stirred at room temperature for 3 hours under an argon atmosphere. After completion of the reaction, the suspension diluted with ethyl acetate was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to give (±) -2- [4-cyano-4- (3-cyclopentyl). Oxy-4-ethenylphenyl) piperidin-1-yl] propionic acid ethyl ester (0.45 g, 70%) was obtained as a colorless oil.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.46 (d, J = 8.8 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 6.99 (s, 1H), 6.96 (dd, J = 17.7, 11.2 Hz, 1H), 5.75 (dd, J = 17.7, 1.5 Hz, 1H), 5.24 (dd, J = 11.2, 1.5 Hz, 1H), 4.82 (m, 1H), 4.27-4.19 (m, 2H), 3.37 (q, J = 7.0 Hz, 1H), 3.08-2.70 (m, 4H), 2.11-1.65 (m, 12H), 1.35 (d, J = 7.0 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H).
Step 2:
The title compound 5 (0.035 g, 32%) was obtained as a white solid by hydrolyzing the compound (0.12 g, 0.30 mmol) obtained in the above Step 1 according to the method described in Step 4 of Example 1. Obtained.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.47 (d, J = 8.4 Hz, 1H), 7.06 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 17.8, 11.2 Hz, 1H), 5.74 (dd, J = 17.8, 1.3 Hz, 1H), 5.26 (dd, J = 11.2, 1.3 Hz, 1H), 4.69 (m, 1H), 3.49 (t, J = 7.1 Hz, 1H), 3.37-2.90 (m, 4H), 2.50-1.64 (m, 12H), 1.46 (d, J = 7.1 Hz, 3H).

3- [4-Cyano-4- (3-cyclopentyloxy-4-ethenylphenyl) piperidin-1-yl] propionic acid (Compound 6)
Step 1:
To THF (20 mL) was added 4- (3-cyclopentyloxy-4-ethenylphenyl) piperidine-4-carbonitrile hydrochloride (0.50 g, 1.5 mmol), triethylamine (1.8 g) obtained in Step 2 of Example 1. , 18 mmol) and methyl acrylate (3.1 g, 36 mmol) were added, and the mixture was stirred at 45 ° C. for 48 hours under an argon atmosphere. After completion of the reaction, the suspension diluted with ethyl acetate was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to give 3- [4-cyano-4- (3-cyclopentyloxy-4- Ethenylphenyl) piperidin-1-yl] propionic acid methyl ester (0.36 g, 63%) was obtained as an orange oil.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.45 (d, J = 8.5 Hz, 1H), 7.00 (s, 1H), 6.98 (dd, J = 17.9, 11.2 Hz, 1H), 6.75 (d , J = 8.5 Hz, 1H), 5.74 (dd, J = 17.9, 1.5 Hz, 1H), 5.25 (dd, J = 11.2, 1.5 Hz, 1H), 4.82 (m, 1H), 3.70 (s, 3H) , 3.00 (m, 2H), 2.81 (t, J = 7.1 Hz, 2H), 2.55 (t, J = 7.1 Hz, 2H), 2.59-2.47 (m, 2H), 2.10-1.64 (m, 12H).
Step 2:
The title compound 6 (0.084 g, 73%) was obtained as a white solid by hydrolyzing the compound (0.12 g, 0.31 mmol) obtained in the above Step 1 according to the method described in Step 4 of Example 1. Obtained.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.48 (d, J = 8.1 Hz, 1H), 6.98 (s, 1H), 6.97 (d, J = 8.1 Hz, 1H), 6.97 (dd, J = 18.0, 11.2 Hz, 1H), 5.76 (d, J = 18.0 Hz, 1H), 5.28 (d, J = 11.2 Hz, 1H), 4.83 (m, 1H), 3.26 (m, 2H), 2.89 (m , 2H), 2.77 (m, 2H), 2.59 (m, 2H), 2.28-1.65 (m, 12H).

{4-Cyano-4- [3-cyclopentyloxy-4- (1-fluoroethenyl) phenyl] piperidin-1-yl} acetic acid (Compound 7)
Step 1:
1-Benzyl-4- (3-cyclopentyloxy-4-ethenylphenyl) piperidine-4-carbonitrile (770 mg, 2.0 mmol) obtained in Step 1 of Example 1 was dissolved in dichloromethane (15 mL). Under ice-cooling, a solution of triethylamine / hydrogen trifluoride (3.2 mL, 20 mmol) in dichloromethane (7.0 mL) and N-bromosuccinimide (430 mg, 2.4 mmol) were added, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was dissolved in THF (21 mL). To this was added 1 mol / L THF solution (7.9 mL, 7.9 mmol) of tert-butoxypotassium under ice-cooling, and the mixture was stirred at 0 ° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 1-benzyl-4- [3-cyclopentyloxy-4- (1-fluoroethenyl). Phenyl] piperidine-4-carbonitrile (650 mg, 81%) was obtained.
¹ H NMR (270MHz, CDCl ₃ ) δ (ppm) 7.56 (d, J = 8.1 Hz, 1H), 7.40-7.25 (m, 5H), 7.09 (s, 1H), 7.04 (d, J = 8.1 Hz, 1H), 5.45 (dd, J = 54, 2.3 Hz, 1H), 5.03 (dd, J = 22, 2.3 Hz, 1H), 4.95-4.85 (m, 1H), 3.61 (s, 2H), 3.05-2.95 (m, 2H), 2.60-2.45 (m, 2H), 2.20-1.60 (m, 12H).
Step 2:
The compound obtained in Step 1 (650 mg, 1.6 mmol) is dissolved in 1,2-dichloroethane (16 mL), 1-chloroethyl chloroformate (0.26 mL, 2.4 mmol) is added, and the mixture is heated under reflux for 1 hour. did. Next, the reaction solution was concentrated under reduced pressure, methanol (15 mL) was added to the residue, and the mixture was heated to reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in 2 mol / L hydrochloric acid. The resulting solution was washed with diethyl ether, then made basic with the addition of 2 mol / L aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 4- [3-cyclopentyloxy-4- (1-fluoroethenyl) phenyl] piperidine- 4-carbonitrile (450 mg, 89%) was obtained.
¹ H NMR (270MHz, CDCl ₃ ) δ (ppm) 7.58 (d, J = 8.1 Hz, 1H), 7.10 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 5.46 (dd, J = 54, 2.3 Hz, 1H), 5.04 (dd, J = 22, 2.3 Hz, 1H), 4.95-4.90 (m, 1H), 3.30-3.10 (m, 4H), 2.40-1.60 (m, 12H).
Step 3:
The compound (450 mg, 1.4 mmol) obtained in the above Step 2 was dissolved in DMF (14 mL), and potassium carbonate (400 mg, 2.9 mmol) and benzyl bromoacetate (0.27 mL, 1.7 mmol) were added. Stir at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 0 → 1: 1) to give {4-cyano-4- [3-cyclopentyloxy-4- (1-fluoroethenyl) Phenyl] piperidin-1-yl} acetic acid benzyl ester (400 mg, 60%) was obtained.
¹ H NMR (270MHz, CDCl ₃ ) δ (ppm) 7.57 (d, J = 8.1 Hz, 1H), 7.40-7.20 (m, 5H), 7.07 (s, 1H), 7.06 (d, J = 8.1 Hz, 1H), 5.45 (dd, J = 54, 2.2 Hz, 1H), 5.20 (s, 2H), 5.04 (dd, J = 21, 2.3 Hz, 1H), 4.95-4.85 (m, 1H), 3.36 (s , 2H), 3.20-3.00 (m, 2H), 2.75-2.60 (m, 2H), 2.30-1.60 (m, 12H).
Step 4:
The compound obtained in Step 3 above (100 mg, 0.22 mmol) is dissolved in ethanol (5.0 mL), 2 mol / L aqueous sodium hydroxide solution (0.32 mL, 0.65 mmol) is added, and the mixture is stirred at room temperature for 2 hours. did. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water, and 2 mol / L hydrochloric acid was added. The precipitated crystals were collected by filtration and triturated with ethyl acetate to give the title compound 7 (46 mg, 57%) as a white solid.
¹ H NMR (270MHz, DMSO-d ₆ ) δ (ppm) 7.57 (d, J = 8.1 Hz, 1H), 7.24 (s, 1H), 7.17 (d, J = 8.1 Hz, 1H), 5.45 (dd, J = 55, 2.3 Hz, 1H), 5.13 (dd, J = 21, 2.3 Hz, 1H), 5.10-5.05 (m, 1H), 4.20 (s, 2H), 3.75-3.55 (m, 2H), 3.40 -3.20 (m, 2H), 2.65-2.35 (m, 2H), 2.10-1.50 (m, 10H).

{4- [3- (1-Acetylpiperidin-4-ylmethoxy) -4-ethenylphenyl] -4-cyanopiperidin-1-yl} acetic acid (Compound 8)
Step 1: [4-Cyano-4- (4-ethenyl-3-hydroxyphenyl) piperidin-1-yl] acetic acid
1-Benzyl-4- (3-cyclopentyloxy-4-ethenylphenyl) piperidine-4-carbonitrile hydrochloride (0.60 g, 1.4 mmol) obtained in Step 1 of Example 1 was suspended in dichloromethane (46 mL). It became cloudy and cooled to 0 ° C. under an argon atmosphere. Boron tribromide (1 mol / L dichloromethane solution, 2.84 mL, 2.84 mmol) was added dropwise at an internal temperature of 4 ° C. or lower, and the mixture was stirred at 0 ° C. for 30 minutes. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.15 g, 33%).
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 8.00-7.30 (m, 6H), 6.99-6.87 (m, 3H), 5.78 (d, J = 17.8 Hz, 1H), 5.33 (d, J = 11.2 Hz, 1H), 3.61 (s, 2H), 3.03-2.90 (m, 2H), 2.53-2.45 (m, 2H), 2.05-1.87 (m, 4H).
Step 2: 4- [3- (1-Acetylpiperidin-4-ylmethoxy) -4-ethenylphenyl] -1-benzylpiperidine-4-carbonitrile [4-cyano-4- (4 -Ethenyl-3-hydroxyphenyl) piperidin-1-yl] acetic acid (0.55 g, 1.7 mmol) was dissolved in DMF (20 mL), and toluene-4-sulfonic acid 1-acetylpiperidine- obtained in Reference Example 2 was obtained. 4-ylmethyl ester (1.34 g, 4.32 mmol), potassium carbonate (0.95 g, 6.9 mmol) and sodium iodide (0.65 g, 4.3 mmoL) were added, and the mixture was stirred at 70 ° C. for 1 day. Further, toluene-4-sulfonic acid-1-acetylpiperidin-4-ylmethyl ester (0.43 g, 1.4 mmol), potassium carbonate (0.48 g, 3.4 mmol) and sodium iodide (0.26 g, 1.7 mmoL) were added, and 70 Stir at 4 ° C. for 4 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in toluene (50 mL), p-toluenesulfonic acid pyridine salt (1.41 g, 5.61 mmol) was added, and the mixture was heated to reflux for 8 hours. The reaction solution was returned to room temperature, water and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with a mixed solution of ethyl acetate and chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1 to 2: 1) to obtain the title compound (0.16 g, 20%).
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.48 (d, J = 8.3 Hz, 1H), 7.35-7.30 (m, 5H), 7.06-6.91 (m, 3H), 5.75 (d, J = 17.8 Hz, 1H), 5.28 (d, J = 12.5 Hz, 1H), 4.73-4.68 (m, 1H), 3.91-3.84 (m, 3H), 3.61 (s, 2H), 3.15-3.00 (m, 3H ), 2.63-2.47 (m, 3H), 2.18-1.86 (m, 7H), 2.12 (s, 3H), 1.38-1.28 (m, 2H).
Step 3: 4- [3- (1-Acetylpiperidin-4-ylmethoxy) -4-ethenylphenyl] piperidine-4-carbonitrile hydrochloride 4- [3- (1-Acetylpiperidine obtained in Step 2 above -4-ylmethoxy) -4-ethenylphenyl] -1-benzylpiperidine-4-carbonitrile (0.16 g, 0.35 mmol) was used in the same manner as described in Step 2 of Example 1, and the title compound ( 0.15 g, quantitative) was obtained.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.53-7.51 (m, 1H), 7.12-6.93 (m, 3H), 5.77 (d, J = 17.7 Hz, 1H), 5.33 (d, J = 11.4 Hz, 1H), 4.26-3.71 (m, 4H), 3.52-3.44 (m, 3H), 2.85-2.70 (m, 3H), 2.19-1.94 (m, 10H), 1.40-1.29 (m, 2H) .
Step 4: {4- [3- (1-Acetylpiperidin-4-ylmethoxy) -4-ethenylphenyl] -4-cyanopiperidin-1-yl} acetic acid ethyl ester 4- [3 obtained in Step 3 above Using-(1-acetylpiperidin-4-ylmethoxy) -4-ethenylphenyl] piperidine-4-carbonitrile hydrochloride (0.15 g, 0.37 mmol) and ethyl bromoacetate (0.053 mL, 0.48 mmol) The title compound (0.13 g, 77%) was obtained in the same manner as described in Step 1 of 1.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.48 (d, J = 8.4 Hz, 1H), 7.09-6.91 (m, 3H), 5.77 (d, J = 16.5 Hz, 1H), 5.29 (d , J = 12.5 Hz, 1H), 4.73-4.69 (m, 1H), 4.22 (t, J = 7.0 Hz, 2H), 3.87-3.77 (m, 3H), 3.31 (s, 2H), 3.16-3.08 ( m, 3H), 2.71-2.58 (m, 3H), 2.28-1.86 (m, 7H), 2.12 (s, 3H), 1.38-1.26 (m, 2H), 1.30 (t, J = 7.0 Hz, 3H) .
Step 5: {4- [3- (1-Acetylpiperidin-4-ylmethoxy) -4-ethenylphenyl] -4-cyanopiperidin-1-yl} acetic acid {4- [3- The method described in Step 4 of Example 1 using (1-acetylpiperidin-4-ylmethoxy) -4-ethenylphenyl] -4-cyanopiperidin-1-yl} acetic acid ethyl ester (0.12 g, 0.26 mmol) In the same manner as described above, the title compound 8 (0.034 g, 31%) was obtained.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 7.56 (d, J = 7.9 Hz, 1H), 7.11-7.09 (m, 2H), 6.94 (dd, J = 17.8, 11.2 Hz, 1H) , 5.85 (d, J = 17.8 Hz, 1H), 5.31 (d, J = 11.2 Hz, 1H), 4.44-4.39 (m, 1H), 4.04-3.83 (m, 3H), 3.24 (s, 2H), 3.11-3.01 (m, 3H), 2.61-2.57 (m, 3H), 2.11-1.91 (m, 5H), 2.00 (s, 3H), 1.81-1.76 (m, 2H), 1.29-1.12 (m, 2H ).

{4-Cyano-4- [4-ethenyl-3- (3-furylmethoxy) phenyl] piperidin-1-yl} acetic acid (Compound 9)
In the same manner as in Steps 3 to 5 of Example 8, 4- [3- (1-acetylpiperidin-4-ylmethoxy) -4-ethenylphenyl] -1-benzylpiperidine-obtained in Step 2 of Example 8 Using 1-benzyl-4- [4-ethenyl-3- (3-furylmethoxy) phenyl] piperidine-4-carbonitrile synthesized in the same manner as 4-carbonitrile, the title compound (0.045 g, 38%) was prepared. Obtained.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.54 (brd, J = 3.3 Hz, 1H), 7.50 (brs, 1H), 7.45-7.44 (m, 1H), 7.15-7.13 (m, 1H) , 7.09 (dd, J = 3.3, 7.9 Hz, 1H), 7.01 (dd, J = 11.2, 17.8 Hz, 1H), 6.50 (d, J = 1.3 Hz, 1H), 5.77 (dd, J = 1.3, 17.8 Hz, 1H), 5.30 (dd, J = 1.3, 11.2 Hz, 1H), 5.03 (s, 2H), 3.39 (s, 2H), 3.31-3.27 (m, 2H), 2.96 (brt, J = 11.3 Hz , 2H), 2.37 (brt, J = 14.8 Hz, 2H), 2.20-2.14 (m, 2H).

{4-Cyano-4- [3- (3,5-dimethylisoxazol-4-ylmethoxy) -4-ethenylphenyl] piperidin-1-yl} acetic acid (Compound 10)
4- [3- (1-Acetylpiperidin-4-ylmethoxy) -4-ethenylphenyl] -1-benzylpiperidine-obtained in Step 2 of Example 8 in the same manner as Steps 3 to 5 of Example 8. Using 1-benzyl-4- [3- (3,5-dimethylisoxazol-4-ylmethoxy) -4-ethenylphenyl] piperidine-4-carbonitrile synthesized in the same manner as 4-carbonitrile, the title compound (0.016 g, 24%) was obtained.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.92 (d, J = 8.2 Hz, 1H), 7.64 (s, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.31 (dd, J = 17.7, 11.1 Hz, 1H), 6.13 (dd, J = 17.7, 1.2 Hz, 1H), 5.68 (dd, J = 11.1, 1.2 Hz, 1H), 5.30 (s, 2H), 4.06-4.01 (m, 2H), 3.88 (s, 2H), 3.49-3.40 (m, 2H), 3.15-3.05 (m, 2H), 2.81 (s, 3H), 2.69 (s, 3H), 2.61-2.56 (m, 2H) .

{4-Cyano-4- [4-ethenyl-3- (1,2,3-thiadiazol-4-ylmethoxy) phenyl] piperidin-1-yl} acetic acid (Compound 11)
In the same manner as in Steps 3 to 5 of Example 8, 4- [3- (1-acetylpiperidin-4-ylmethoxy) -4-ethenylphenyl] -1-benzylpiperidine-obtained in Step 2 of Example 8 Using 1-benzyl-4- [4-ethenyl-3- (1,2,3-thiadiazol-4-ylmethoxy) phenyl] piperidine-4-carbonitrile synthesized in the same manner as 4-carbonitrile, the title compound ( 0.031 g, 50%).
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 8.69 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.33 (s, 1H), 7.21 (d, J = 8.6 Hz, 1H ), 7.02 (dd, J = 18.2, 11.2 Hz, 1H), 5.77 (d, J = 18.3 Hz, 1H), 5.74 (s, 2H), 5.30 (d, J = 11.2 Hz, 1H), 3.52 (s , 2H), 3.07 (m, 2H), 2.65 (m, 2H), 2.50-1.70 (m, 4H).

Reference Example 1: 1-Benzyl-4- (3-cyclopentyloxy-4-trifluoromethanesulfonyloxyphenyl) piperidine-4-carbonitrile Step 1:
(3-Cyclopentyloxy-4-methoxyphenyl) acetonitrile (7.25 g, 31.34 mmol) obtained according to the method described in WO 02/14280 was dissolved in aqueous sodium hydroxide (10 mol / L, 100 mL). In Journal of Heterocyclic Chemistry, 1986, 23, p. N-benzyl-N, N-bis (2-chloroethyl) amine hydrochloride (8.42 g, 31.34 mmol) and hexadecyltributylphosphonium bromide (1.59 g, 3.13 mmol) obtained according to the method described in 73 were added. And stirred at 100 ° C. for 90 minutes. Under ice-cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol / L hydrochloric acid, 2 mol / L sodium hydroxide aqueous solution, and then saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, and a 4 mol / L hydrogen chloride-ethyl acetate solution (31.8 mL, 127 mmol) was added dropwise. The precipitated solid was collected by filtration to give 1-benzyl-4- (3-cyclopentyloxy-4-methoxyphenyl) piperidine-4-carbonitrile hydrochloride (5.33 g, 40%) as a white solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 13.20 (br s, 1H), 7.73-7.70 (m, 2H), 7.50-7.45 (m, 3H), 7.12 (d, J = 2.1 Hz, 1H ), 7.09 (dd, J = 8.3, 2.1 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 4.86-4.80 (m, 1H), 4.23 (d, J = 5.3 Hz, 2H), 3.84 (s, 3H), 3.59 (br d, J = 10.9 Hz, 2H), 3.29-3.07 (m, 4H), 2.16 (br d, J = 12.6 Hz, 2H), 2.10-1.98 (m, 2H), 1.81-1.73 (m, 4H), 1.71-1.55 (m, 2H).
Step 2:
The compound obtained in the above Step 1 (20.0 g, 46.8 mmol) was suspended in DMF (225 mL), sodium thiomethoxide (content 95%, 21.43 g, 290.5 mmol) was added under nitrogen atmosphere, Stir for hours. The reaction solution was cooled to room temperature, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and a 4 mol / L hydrogen chloride-ethyl acetate solution (26.4 mL, 106 mmol) was added dropwise under ice cooling. The precipitated solid was collected by filtration to give 1-benzyl-4- (3-cyclopentyloxy-4-hydroxyphenyl) piperidine-4-carbonitrile hydrochloride (19.81 g, quantitative) as a white solid.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 13.20 (br s, 1H), 7.72-7.69 (m, 2H), 7.49-7.47 (m, 3H), 7.11 (d, J = 2.3 Hz, 1H ), 7.06 (dd, J = 8.3, 2.3 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 5.72 (s, 1H), 4.92-4.87 (m, 1H), 4.20 (br s, 2H ), 3.57 (br d, J = 11.6 Hz, 2H), 3.29-3.06 (m, 4H), 2.15 (br d, J = 13.9 Hz, 2H), 2.09-1.99 (m, 2H), 1.89-1.63 ( m, 6H).
Step 3:
The compound obtained in the above step 2 (10.00 g, 24.22 mmol) is suspended in dichloromethane (100 mL), triethylamine (10.1 mL, 109 mmol) is added dropwise under a nitrogen atmosphere, and the internal temperature is -8 ° C for 15 minutes. After stirring, trifluoromethanesulfonic anhydride (5.3 mL, 32 mmol) was added over 15 minutes, and the mixture was stirred at the same temperature for 70 minutes. Furthermore, triethylamine (1.7 mL, 18 mmol) and trifluoromethanesulfonic anhydride (0.82 mL, 4.9 mmol) were added, and the mixture was stirred at the same temperature for 40 minutes. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 1-benzyl-4- (3-cyclopentyloxy-4-trifluoromethanesulfonyloxyphenyl) piperidine. -4-carbonitrile (13.25 g) was obtained. The obtained compound was used in the next step without further purification.
Reference Example 2: Toluene-4-sulfonic acid 1-acetylpiperidin-4-ylmethyl ester Step 1: 1- (4-hydroxymethylpiperidin-1-yl) ethanone piperidin-4-ylmethanol (3.00 g, 26.0 mmol) ) Was dissolved in chloroform (30 mL), cooled to 0 ° C., triethylamine (2.08 mL, 39.1 mmol) and acetyl chloride (0.745 mL, 27.3 mmol) were added, and the mixture was stirred at 0 ° C. for 15 min. Ethyl acetate (1 mL) and acetone (1 mL) were added to the reaction solution to stop the reaction, and the resulting precipitate was removed by filtration. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 1: 0 to 9: 1) to give the title compound (1.41 g, 34%). .
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 4.67-4.61 (m, 1H), 3.87-3.80 (m, 1H), 3.57-3.46 (m, 2H), 3.05 (td, J = 12.6, 2.5 Hz, 1H), 2.55 (td, J = 12.9, 2.5 Hz, 1H), 2.09 (s, 3H), 1.93-1.66 (m, 3H), 1.29-1.07 (m, 2H).
Step 2: Toluene-4-sulfonic acid 1-acetylpiperidin-4-ylmethyl ester The compound obtained in Step 1 above (1.41 g, 8.97 mmol) was dissolved in dichloromethane (50 mL), and triethylamine (2.50 mL, 17.9 mmol), p-toluenesulfonyl chloride (2.56 g, 13.5 mmol) and 4- (dimethylamino) pyridine (0.55 g, 4.5 mmol) were added, and the mixture was stirred at room temperature for 3.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and then saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.74 g, 98%).
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 7.78 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 4.63-4.58 (m, 1H), 3.88-3.78 (m, 1H), 3.87 (d, J = 1.3 Hz, 1H), 3.85 (d, J = 1.3 Hz, 1H), 3.00 (td, J = 12.5, 3.0 Hz, 1H), 2.54-2.46 (m, 1H), 2.46 (s, 3H), 2.06 (s, 3H), 2.05-1.57 (m, 3H), 1.22-1.05 (m, 2H).

Formulation Example 1: Tablet (Compound 1)
A tablet having the following composition is prepared by a conventional method. 40 g of Compound 1, 286.8 g of lactose and 60 g of potato starch are mixed, and 120 g of a 10% aqueous solution of hydroxypropylcellulose is added thereto. This mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. To this was added 1.2 g of magnesium stearate, mixed, and tableted with a tableting machine (RT-15 model, manufactured by Kikusui Co., Ltd.) having a 8 mm diameter punch to contain tablets (containing 20 mg of active ingredient per tablet). To get).
Formulation Compound 1 20 mg
Lactose 143.4mg
Potato starch 30 mg
Hydroxypropylcellulose 6 mg
Magnesium stearate 0.6mg
200 mg
Formulation Example 2: Tablet (Compound 2)
Using 40 g of compound 2, the title tablet (containing 20 mg of active ingredient per tablet) is obtained in the same manner as in Example 1.
Formulation Compound 2 20 mg
Lactose 143.4mg
Potato starch 30 mg
Hydroxypropylcellulose 6 mg
Magnesium stearate 0.6mg
200 mg
Formulation Example 3: Injection (Compound 3)
An injection having the following composition is prepared by a conventional method. 1 g of Compound 3 and 5 g of D-mannitol are added to and mixed with distilled water for injection. Further, hydrochloric acid and aqueous sodium hydroxide solution are added to adjust the pH to 6, and then the total volume is made up to 1000 mL with distilled water for injection. The obtained mixed solution is aseptically filled into glass vials by 2 mL to obtain an injection (containing 2 mg of active ingredient per vial).
Formulation Compound 3 2 mg
D-mannitol 10 mg
Hydrochloric acid appropriate amount Sodium hydroxide aqueous solution appropriate amount
Distilled water for injection
2.00 mL

Claims (8)

Formula (I)

[Wherein m represents an integer of 0 to 4,
R ¹ represents substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkanoyl, or —NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ Are the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, formyl or substituted or unsubstituted lower alkanoyl, or R ⁵ and R ⁶ are adjacent nitrogen atoms Together form a substituted or unsubstituted heterocyclic group)
R ² represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted An aralkyl, a substituted or unsubstituted heteroaralkyl, a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted alicyclic heterocyclic group,
R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a substituted or unsubstituted lower alkyl, or R ³ and R ⁴ together with adjacent carbon atoms form a saturated carbocycle] Or a pharmacologically acceptable salt thereof. The piperidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ is substituted or unsubstituted lower alkenyl. The piperidine derivative or a pharmacologically acceptable salt thereof according to claim 1 or 2, wherein R ² is substituted or unsubstituted cycloalkyl. The piperidine derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R ² is substituted or unsubstituted lower alkyl. R ³ and piperidine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 4 R ⁴ is a hydrogen atom. m is 0, The piperidine derivative in any one of Claims 1-5, or its pharmacologically acceptable salt. The pharmaceutical containing the piperidine derivative in any one of Claims 1-6, or its pharmacologically acceptable salt. A phosphodiesterase (PDE) -IV inhibitor comprising the piperidine derivative according to any one of claims 1 to 6 or a pharmacologically acceptable salt thereof.