CA2236851C - Substituted vinylpyridine derivatives and drugs containing the same - Google Patents

Abstract

The present invention relates to a substituted vinylpyridine derivative represented by the following formula (1): See Formula I (wherein R1 represents a hydrogen atom, an alkyl group, etc., R2 represents an alkyl group; one of R3 and R4, which are different from each other, represents a hydrogen atom and the other represents a nitrile group, R5 represents an aryl group or a heteroaryl group, X represents an oxygen atom, etc., and one of Q1, Q2, and Q3 represents a nitrogen atom and the other two represent CH); a salt of the derivative; and a drug containing the derivative or salt as the active ingredient. Due to strong PDE inhibitory action and TNF-.alpha. production inhibitory action, the derivative, salt, and drug are useful for the prevention and treatment of a wide variety of inflammatory diseases and autoimmune diseases.

Description

DESCRIPTION
Substituted Vinyl Pyridine Derivative and Drugs Containing the Same TECHNICAL FIELD
The present invention relates to a novel substituted vinylpyridine derivative and salts thereof, which are endowed with strong and selective phosphodiesterase (PDE) IV
inhibitory action and strong .inhibitory action against production of the tumor necrotizing factor (TNF-a,), as well as with high safety. The invention also relates to drugs containing the derivative or salts and useful for the prevention and treatment of a broad range of inflammatory diseases and autoimmune diseases.
BACKGROUND ART
PDE is an enzyme which acts as a catalyst in hydrolysis of cyclic adenosine 3',5'-phosphate (CAMP) or cyclic guanosine 3',5'-phosphate (cGMP) into 5'-monophosphate. cAMP and cGMP are produced from ATP and GTP,, respectively, following activation of adenylate cyclase or guanylate cyclase in re:>ponse to a hormone or chemical transmission substance, and work as intracellular second messengers. PDE inhibitory agents block the activity of PDE
to increase the amounts of intracellular cAMP and cGMP, to thereby suppress cellular response. At present, PDE is known to have type I to type VIII isozymes. These are found in the central nervous system, circulatory system, respiratory system, digesi~ive system, reproductive system, and blood cell system. Tree distribution of these isozymes differs according to the tissue. This suggests that a PDE-isozyme-specific inhibitor may increase the amount of CAMP
in certain specific tissue.
In recent years, considerable efforts have been devoted to research and development of highly specific PDE
isozyme inhibitors. For example, attempts have been made to develop drugs that exhibit organ specificity attributable to localization of respective isozymes. As a result of such attempts, PDE IV is considered to be a potential agent effective for both asthmatic attack and chronic respiratory tract inflammation, due t:o the facts that PDE IV is present predominantly in the airway tissue or inflammatory cells, such as eosinocytes and neutrophilic leukocytes, which are intimately related to asthmatic symptoms and that drugs that inhibit the action of PDE IV exhibit bronchodilatation action as well as inhibitory action against activation of inflammatory leukocytes. Thus, active studies have been performed worldwide focusing on development of a selective inhibitor against PDE IV as a new remedy for bronchial asthma.
PDE IV, which also exists in the central nervous system, is expected to improve memory and mitigate anxiety, based on the considerat~_on that a rolipram, a selective PDE
IV inhibitor, specifica=Lly localizes in the brain tissue to increase noradrenergic nervous transmission on a synapse or post-synapse level in response to an increased amount of cAMP, which is a second messenger of noradrenalin.
TNF-a is a cytokine produced by an activated macrophage. Although TNF-a was first discovered to be a factor which induces hemorrhagic necrosis in a tumor site, it is now recognized as a mediator which widely participates in inflammatory reactions and the immune mechanism.
Excessive production of TNF-a, however, induces disorders in tissue to cause a variety of pathological conditions.
Rapid release of TNF-a induced by intracellular toxins is responsible for the lethality.
TNF-a promotes production of platelet-activating factor (PAF), a variety of inflammatory arachidonic metabolites, and activated oxygen. Moreover, it induces production of interleukin(IL)--l, IL-6, and IL-8. As is understood from this, excessive production of TNF-a aggravates inflammatory react_Lons and, in the case of chronic inflammatory diseases such as rheumatism, osteoporosis, and terminal cancers, results in a persistence~
of complication of diseases, in which the concentrations of these cytokines are maintained consistently so as exacerbate the symptoms. Accordingly, ir_ pathological conditions in which TNF-a is produced excessively, control of its release is strongly sought by clinicians.
So far, molecular design of a selective PDE IV
inhibitor has not yielded. satisfactory results, and therefore limitation is imposed on use of the selective PDE

IV inhibitor. Theophylline, which is a xanthine-based drug widely used by clinician~~ as a therapeutic agent for the treatment of bronchial asthma, exhibits bronchodilating action stemming from the adenosine antagonizing action and PDE inhibitory action. However, theophylline sometimes causes adverse side effects in the circulatory system and central nervous system, as it inhibits PDE rion-selectively.
Thus, the safety range of theophylline is rather narrow.
Rolipram and Ro20-1724 selectively inhibit PDE IV at a potency 100 times that at: which they inhibit other PDE
isozymes. However, the inhibitory power itself is not significant, imposing limitations on applicable diseases.
TNF-a production inhibitors include antiphlogistic steroids, antihistaminic agents, PAF antagonists, and active-oxygen quencher. However, these are nonspecific inhibitors with either weak power or, when their power is strong, with low tissue specificity, thus limiting their methods of use. Moreover, protease inhibitors have recently been reported to be specific 'rNF-a production inhibitors.
The protease inhibitors a.re peptide derivatives and have not yet been extensively studied with regard to administration methods, etc.
Accordingly, the present invention i~ directed to the provision of therapeutics for a variety of diseases based on the selective PDE IV inhibitory action; the provision of therapeutics for a variety of diseases based on the TNF-a production inhibitory action; and the provision of drugs for the prevention and treatment of a wide variety of inflammatory diseases and autoimmune diseases, which drugs are designed based on concurrent actions of these two actions and are endowed with enhanced effects, higher specificity, and higher safety.
DISCLOSURE OF THE INVENTION
Under the above circumstances, the present inventors synthesized numerous compounds, and studied their PDE
inhibitory action and inhibitory action against production of a variety types of cytokines, and as a result found that the new substituted vinylpyridine derivatives represented by formula (1) or salts thereof potently and selectively inhibit PDE IV only, while not acting on other PDE isozymes, and that production of TNF-a is potently inhibited. As a result, the below-described substituted vinylpyridine derivatives have been shown to be effective for the prevention and treatment of the aforementioned wide ranges of inflammatory diseases, autoimmune diseases, and other diseases associated with disturbed matabolism of the - .-cerebrum. The present invention has been completed based on these findings.
Accordingly, the present invention provides a substituted vinylpyridine derivative represented by the following formula (1):
XR' Rz0 w Q2 ~l) ~J
\ 1~ ' 3 _ d S
Q (,CR )-C(R )R

wherein R1 represents a hydrogen atom, an alkyl group, an alkenyl group, a hydroxya.lkyl group which may have a substituent, an alkoxyalk:yl group, an alkoxycarbonyl alkyl group, an alkoxyalkoxyalkyl group, an aminoalkyl group which may have a substituent, a saturated heterocyclic group which may have a substituent, an aralkyl group which may have a substituent, a benzocycloalkyl group which may have a substituent, or an alkyl group having a heterocyclic group which may have a substituent; R' represents an alkyl group;
one o.f R3 and R4, which are different from each other, represents a hydrogen atom and the other represents a nitrile group, a carboxyl group, or an alkoxycarbonyl group;
R5 represents a monocyclic or ring-condensed aryl group which may have a substituent or a monocyclic or ring-condensed heteroaryl group wh-wch may have a substituent; X
represents an oxygen atom or a sulfur atom; and one of Q1, Q2, and Q3 represents a nitrogen atom and the other two represent CH; as well as a salt of the derivative, a hydrate of the derivative, or an N-oxide of the derivative. _ _ The present invention also provides a drug containing as the active ingredient a substituted vinylpyridine derivative represented by the above-described formula (1), a salt thereof, a hydrate thereof, or an N-oxide thereof.
The present invention also provides a pharmaceutical composition containing a substituted vinylpyridine derivative represented by the above-described formula (1), a salt thereof, a hydrate thereof, or an N-oxide thereof; and a pharmacologically acceptable carrier.
The present invention further provides use, as a drug, of a substituted vinylpyridine derivative represented by the above-described formula (1), a salt thereof, a hydrate thereof, or an N-oxide thereof:.
The present invention still further provides a preventive or therapeutic method for a disease caused by the production of PDE IV or Tt~F-a., which method comprises the step of administering to a manunal including a human an effective amount of a substituted vinylpyridine derivative represented by the above-described formula (1), a salt thereof, a hydrate thereof, or an N-oxide thereof.
BEST MODE FOR CARRYING OUT THE; INVENTION
In the substituted vinylpyridine derivative of formula (1) of the present invention, examples of alkyl groups represented by R1 include Cl-12 linear, branched, cyclic, cyclic-linear, or cyclic-:branc:hed alkyl groups: Of these, linear or branched alkyl groups are preferably Cl-8 alkyl groups, and examples include methyl, ethyl, n-propyl, i- _ _ propyl, n-butyl, i-butyl, n-pentyl, i-pentyl, n-hexyl, n-heptyl, and n-octyl. Cyc=_ic alkyl groups are preferably C3-8 cycloalkyl groups, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and norbornyl. Cyclic-linear or cyclic-branched alkyl groups are preferably C4-12 alkyl groups, and examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl, cyclobutylethyl, and cyclopentylethyl.

Examples of alkenyl groups include C2-12 linear, branched, or cyclic alker,.yl groups. Of these, C5-8 cyclic alkenyl groups are preferred, and examples include 3-cyclopentenyl, 2-cyclohexenyl, 3-cyclohexenyl, 4-cycloheptenyl, and norborneny:L.
Hydroxyalkyl groups may be linear, branched, or cyclic, and may be substituted with one or more hydroxy groups.
Hydroxyalkyl groups have preferably 2-12 carbon atoms, more preferably 2-8 carbon atoms. Examples of liner or branched hydroxyalkyl groups include 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, and 6-hydroxyhexyl. Cyclic hydroxyalkyl groups are preferably C4-8 hydroxycycloalkyl groups, and examples include 3-hydroxycyclobutyl, 3-hydroxycyclopentyl, 3-hydroxycyclohexyl, and 4-hydroxycyclohexyl. Dihyd:roxyalkyl groups are preferably C3-7 dihydroxyalkyl groups, and examples include 1,3-dihydroxy-2-propyl, 1,5-dihydroxypentyl, and 1,7-dihydroxyheptyl. A
hydroxy group of these hydroxyalkyl groups may be substituted with an alkoxycarbonyl group, an acyl group, or a TBS (t-butyldimethylsilyl) group.
Alkoxyalkyl groups are preferably those whose total carbon number is 2-12, and examples include methoxymethyl, methoxyethyl, and ethoxyethyl.
Alkoxyalkoxyalkyl groups are preferably those whose total carbon number is 3-12, and examples include methoxyethoxymethyl.
Alkoxycarbonylalkyl groups are preferably those whose total carbon number is 3--13, and examples include methoxycarbonylmethyl and ethoxycarbonylethyl.
Examples of aminoalkyl groups which may be substituted include C2-12 linear or branched aminoalkyl or diaminealkyl groups. Of these, C2-8 linear or branched aminoalkyl groups are preferred, and examples include 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, and 6-aminohexyl.
Diaminoalkyl groups are preferably those having 3-7 carbon atoms, and examples include 1,3-diamino-2-propyl, 1,5-diaminopentyl, and 1,7-diaminoheptyl. An amino group of these aminoalkyl groups m.ay be substituted with an alkoxycarbonyl group, an acyl group, etc.
Saturated heterocyclic groups include a 5-6-membered heterocycle having an oxygen atom, a sulfur atom, or a nitrogen atom as a hetero atom. Examples of these include 2-tetrahydropyranyl, 3-tetrahydropyranyl, 2-tetrahydrofuranyl, and 3-tetrahydrofuranyl.
Examples of aralkyl groups which may be substituted include benzyl, phenethyl, phenylpropyl, and phenylbutyl; _ w benzyl, phenethyl, and phenylpropyl having one or plurality o f methoxy group ( s ) , al koxycarbonyl group ( s ) , or alkylenedioxy groups) at o-, m-, and/or p-position. The alkoxy groups preferably have 1-6 carbon atom(s), and examples include methoxy, ethoxy, n-propoxy, and i-propoxy.
Benzocycloalkyl groups which may be substituted have 9-11 carbon atoms, and examples include 1-.indanyl, 2-indanyl, 1,2,3,4-tetrahydro-1-naphthyl and 1,2,3,4-tetrahydro-2-a naphthyl.
Examples of alkyl groups which may have a (optionally substituted) heterocyclic: group include C1-5 linear alkyl groups substituted with an aromatic heterocycle, a saturated heterocycle, or an unsaturated heterocycle. Of these, aromatic heterocycles may be 5- or 6-membered heteroaryl groups having 1-3 nitrogen atom(s), oxygen atom(s), or sulfur atom(s), and exam~~les include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 2-pyrazyl, 2-thiazolyl, 5-thiazolyl, 4-methyl-5-thiazolyl, 1-imidazolyl, 2-imidazolyl, 3-imidazolyl, 2-oxazolyl, 2-thienyl, 3-thienyl, and 2-furanyl.
Saturated or unsaturated heterocycles may be 5-7-member groups having 1-3 nitrogen atom(s), oxygen atom(s), or sulfur atom(s), and examples include 1-pyrrolidyl, 1-piperidyl, 1-azepanyl, 1-morpholino, pyrrolidin-2-on-1-yl, and pyridin-2-on-1-yl.
Substituents in benzocyc_Loalkyl groups or a heterocyclic group of heterocycle-substituted alkyl groups may be 1-3 groups) selected from hydroxy, halogeno, C1-6 alkyl, C1-6 alkoxy, C1-6 halogenoalkyl, cyano, and nitro.
Alkyl groups represented by Rz preferably have 1-6 carbon atom(s), and examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and tert-butyl.
Alkoxy groups of alkoxycarbonyl groups represented by R3 and R~ preferably have 1-6 carbon atom(s), and examples include methoxy, ethoxy, n-propoxy, and i-propoxy.
Examples of monocyclic (optionally substituted) aryl 1. 0 groups represented by RS include a phenyl group which may be substituted with 1-3 groL.p(s) selected from halogeno, Cl-6 alkyl, Cl-6 alkoxy, C1-6 halogenoalkyl, C1-6 alkoxycarbonyl, carboxyl, cyano, and nitro. Examples of these include phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-ethylphenyl, 2-i-propylphenyl, 2-t-butylphenyl, 2-methoxyphenyl, 2-trifluoromethylphenyl, 2-cyanophenyl, 2-nitrophenyl, 2-carboxyphenyl, 2-methoxycarbonylphenyl, 2-ethoxycarbonylphenyl, 3-carboxyphenyl, 3-methoxycarbonylphenyl, 3-ethoxycarbonylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethy,-phenyl, 4-cyanophenyl, 4-nitrophenyl, 4-carboxyphenyl, 4-methoxycarbonylphenyl, 4-ethoxycarbonylphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 2,6-dibromophenyl, 2,6-dimethylphenyl, 2,6-dimethoxyphenyl, and 2,6-ditrifluoromethylphenyl.
Examples of condensed-ring (optionally substituted) aryl groups include a naphthyl group which may be substituted with 1-3 groups) selected from halogeno, Cl-6_ alkyl, Cl-6 alkoxy, Cl-6 halogenoalkyl, Cl-6 alkoxycarbonyl, carboxyl, cyano, and nitro. Examples of these include 1-naphthyl, 2-naphthyl, 2-c:hloro-1-naphthyl, and 2-methoxy-1-naphthyl.
Examples of monocyclic (optionally substituted) heteroaryl groups include a 5-6-membered heteroaryl group (having 1-3 atoms) of nitrogen, oxygen, o~ sulfur) which may be substituted with 1-3 groups) selected from halogeno, C1-6 alkyl, C1-6 alkoxy, Cl-6 halogenoalkyl, C1-6 alkoxycarbonyl, carboxyl, cyano, and nitro. Examples of these include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-carboxy-4-pyridyl, 2-methoxycarbonyl-4-pyridyl, 2-ethoxycarbonyl-4-pyridyl, 3-chloro-4-pyriclyl, 3-bromo-4-pyridyl, 3-methoxy-4-pyridyl, 3,5-dichloro-4-pyridyl, 3,5-dibromo-4-pyridyl, 3,5-dimethoxy-4-pyridyl, 3-ch.loro-5-methoxy-4-pyridyl, 2-pyrimidyl, 2-pyrazyl, 2-thienyl, 3-thienyl, and 2-furanyl.
Examples of condensed-ring (optionally substituted) heteroaryl groups include a condensed-ring heteroaryl group (containing a nitrogen atom) which may be substituted with 1-3 groups) selected from halogeno, Cl-6 alkyl, C1-6 alkoxy, Cl-6 halogenoalkyl, C1-6 alkoxycarbonyl, carboxyl, cyano, and vitro. Examples of these include 2-quinolyl, 4-quinolyl, and 1-isoquinolyl.
Examples of salts or hydrates of the substituted vinylpyridine derivative of formula (1) of the present invention include hydrochlorides, nitrates, hydrobromides, p-toluenesulfonates, methanesulfonates, fumarates, maleates,_ malonates, succinates, citrates, tartarates, and hydrates thereof. Examples of N-oxides of the substituted vinylpyridine derivative incul.de pyridine-N-oxides and N-oxides of a monocyclic or condensed-ring heteroaryl group represented by R5.
The substituted vinylpyridine derivative of the present invention is prepared by, for example, the following reaction scheme. Briefly, a known compound (2) is easily i i derived from kojic acid (which is inexpensive and available in large quantities) through two or three reactions (Step 1~; the known compound (2) is processed to yield a key intermediate (3) or (4) of the synthesis of the present invention (Step 2 or 3); and the intermediate is condensed through reaction with commercially available (or separately synthesized) arylaldehydes (R5-CHO), arylacetonitriles or arylacetate esters (RS-CFiZR') to thereby obtain a compound (la) of the present invention. , Kojic acid Step 1 OH
Rz0 \
N~ CHZOY
(2) Step 3 ~ Step 2 OR'° OR~n R 0 \ R20 \
N CHO N ~CH2R6 C4) fig) R5-CH2R' -H20 Step 5 \, Step 4 R20 \ _ _ ~N~ CCRs)=CCR')R5 1 a) wherein one of R6 and R', which are different from each other, represents a hydrogen atom and the other represents a nitrile group or an alkoxycarbonyl group; Y represents a hydrogen atom or a proteci~ive group (preferably benzyl or tetrahydro-2-pyranyl); R2 and R' have the same meanings as described above; R'a is identical to R1 except when R' is a hydrogen atom, with the ~~resence of a protective group being preferred when Rla is a hvdroxyalkyl group.
In other words, the key intermediate (3) is reacted with RS-CHO (Step 4) or t:he key intermediate (4) is reacted with R'-CHAR' (Step 5) to thereby obtain a compound (la) .
These reactions easily proceed in the presence of a base such as sodium alkoxide, sodium amide, alkali hydroxide, alkyllithium, or a tertiary alkylamine. These reactions are preferably conducted in methanol with sodium methoxide or ir~
ethanol with sodium ethoxide in the temperature range from 0°C to room temperature.
The above-described key intermediate (3) may be easily obtained from the known compound (2) through the following reaction scheme.
OR'a ~a 2 ) R--~ -~ R ---Step 2a Step 2b N CHzOY -(5) OR'°

----~ c 3 N~ CH2C.C Step 2c C6) wherein R1a and R', and Y have the same meanings as described above and Z represents a Leaving group (typically a halogen atom) .
The compound (2) is reacted with halide reagents (Rla_ Z) to obtain a compound (5). If the compound (5) is having a protective group in Y, then it is de-protected and a compound (5: Y = a hydrogen atom) is derived therefrom (Step 2a).
Alternatively, the compound (2: Y = a protective group) is converted to the compound (5: Y = protective group) by Mitsunobu reaction with primary or secondary alcohols and the protective group is removed to thereby obtain the compound (5: Y = a hydrogen atom). Next, the compound (5: Y
- a hydrogen atom) is converted to a chloro compound (6) (Step 2b). The compound (6) is further~reacted with M-CN to obtain the key intermediate (3: R6 = a nitrile group), whose nitrile group undergoes an alcoholysis to obtain the other key intermediate (3: R6 = an alkoxycarbonyl group) (Step 2c).
Reactions of Step 2a are preferably carried out in a solvent such as an alcohol, tetrahydrofuran, dimethylformamide, or dimethyl sulfoxide in the presence of a base such as potassium carbonate, sodium carbonate, or, in_ some cases, potassium iodide, or sodium iodide in the temperature range from room temperature to 80°C; or in a water-alcohol mixed solvent in the presence of sodium hydroxide or potassium hydroxide as a base in the temperature range from 0°C to the reflux temperature. Also, the reaction between the compound (2: Y = a protective group) and R'°-Z proceeds easily, under conditions other than the above-described reaction conditions, i.e., in a solvent such as terahydrofuran, 1,2-dimethoxyethane, dioxane, dimethylformamide, or dirnethyl sulfoxide in the presence of sodium hydride or potass_Lum hydride as a base in the temperature range from 0"C to room temperature. The reaction between the compound (2: Y = a protective group) and primary or secondary alcohols easily proceeds to yield the compound (5: Y = a protective group) by the typical conditions of Mitsunobu reaction, i.e., in the presence of diethyl azodicarboxylate and triphenylphosphine.
In Step 2a, preferred examples of substituents of Rla in~~lude alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, anc~ (optionally substituted) aralkyl. By Mitsunobu reaction to obtain the compound (5: Y = a protective group), a substituent such as cycloalkyl, cycloalkenyl, helrerocycloalkyl, or benzocycloalkyl is preferred.
When the compound (5: Y = a protective group) is de-protected, there are employed conditions such as hydrogenation by use of a catalyst such as palladium or Raney nickel; reductive removal by use of a compound such as ammonium formate, cyclopentene, or 1,4-cyclohexadiene (for benzyl-substituted compound); or hydrolysis in a water-organic solvent with a mineral acid or an organic acid (for tetrahydro-2-pyranyl comp~~und).
The reaction between thionyl chloride and the compound (5) proceeds easily without or within a solvent inert to thionyl chloride at room temperature to obtain the chloro compound (6) from the cornpound (5: Y = a hydrogen atom) (Step 2b).
Step 2c, in which the key intermediate (3: R° - a nitrite group) is obtained from the chloro compound (6), is preferably carried out in a polar and aprotic solvent such as dimethyl sulfoxide or dimethylformamide in the presence of sodium cyanide in the temperature range from room temperature to 100°C. The also reaction is easily performed through the cyano-anion-activation method using a phase transfer catalyst or crown ether.
The key intermediate (3: Rb - an alkoxycarbonyl group) is obtained from the key intermediate (3: R~ - a nitrite group) through conversion. of the nitrite group in hydrogen -ch:Loride-gas-saturated methanol or a lower alcohol in the temperature range from room temperature to the reflux temperature.
The above-described key intermediate (4) may be easily obtained from the known compound (2) through the following reaction scheme .
(5) Step 2a Step 3b C2) C4) Step 3a OH
RZ() Step 3c N ~ CHO
(7) wherein R2 has the same meaning as described above.
The formyl compound (4) is obtained through conversion of the compound (5) obtained in the above-described Step 2a by use of an oxidant (StE:p 3b); or through oxidation of the compound (2) to obtain a compound (7) (Step 3a), followed by reaction with the halide reagent (Rla-Z) (Step 3c).
Step 3a, in which the compound (7) is obtained from thE: compound (2), is preferably carried out in a solvent such as tetrahydrofuran, 1,4-dioxane, or dimethylformamide with an excessive amount of active manganese dioxide or barium manganate(VI) as an oxidant in the temperature range from room temperature to 100°C.
Step 3b, in which the formyl compound (4) is obtained from the compound (5), is easily carried out in a solvent such as chloroform, dichl~oromethane, or acetone with an excessive amount of active manganese dioxide or barium manganate(VI) as an oxidant in the temperature range from room temperature to the reflux temperature; or through oxidation by a dimethyl sulfoxide/sulfur trioxide-pyridine- -complex (Parikh-Doering method) or oxidation by a dimethyl sulfoxide/oxalyl chloride (Swern method). Also, the formyl compound (4) may be obtained through oxidation by pyridinium chlorochromate (PCC) or pyridinium dichromate (PDC).
Step 3c, in which thE: formyl compound (4) is obatined from the compound (7), is carried out through reaction with Rla-Z in a solvent such as tetrahydrofuran, 1,2- ' dimE:thoxyethane, dimethylformamide, or dimethyl sulfoxide with a base such as sodium hydride or potassium hydride in the temperature range from 0°C to room temperature; or in a solvent such as an alcohol, tetrahydrofuran, dimethylformamide, or dinethyl sulfoxide with a base such as potassium carbonate or sodium carbonate, or in some cases, potassium iodide or sodium iodide in the temperature range from 0°C to 80°C.
The compound (1b') or (lb") of the present invention is obtained through removal of an oxyalkyi group from the compound (1a) of the present invention having a me~~hoxymethyl or methoxyethoxymethyl group as R1 and a hydrogen atom as R' (1a') or as R6 (la").
OH
R2~~ \
(la' N ~ C(Rs)=CHRS
(lb' OH
R20 \
Cla" ) -~
N CH=CCR')R5 Clb"
wherein R', R5, R6, and R~ have the same meanings as described above.
De-protection of the compound (la') or (la") of the present invention is carried out by use of trifluoroacetic acid or diluted acetic ac=Ld (for R1 - a methoxymethyl group) or trifluoroacetic acid (for R1 - a methoxyethoxymethyl group ) .
The compound (lc') o r (lc") of the present invention is obtained through hydrolysis of the compound (la) of the present invention having an alkoxycarbonyl group as Rb and a hydrogen atom as R' (la'''), or a hydrogen atom as R'' and an alkoxycarbonyl group as F;~ (la"").
OR' HO- R~0 \
(1a"' ) N ~ CCC02H)=CHRS
(lc' ) OR' R20 \
Cla~",) H~
N ~ CH=C(COzH)RS
Clc" ) wherein R1, R', and RS have the same meanings as described above.
The above hydrolysis reaction is carried out under al~;aline conditions through a widely employed method in which hydrolysis is allowed to proceed in a lower alcohol, by use of diluted NaOH aqueous solution or diluted KOH
aqL.eous solution in a temperature range from room ten.perature to reflux tem~~erature.
Compound (la) may also be obtained by reacting compound (lb') or (lb ") of the present invention with a halide reagent (Rla-Z) in the presence of a base, or alternatively, by Mitsunobu reaction between compound (lb') or (lb" ) and a primary or secondary alcohol (R'a-OH) .
Ills-z ~r R1~
(1 b' ) or (1 b" ) (1 a) The substituent-introduction reaction by use of a halide reagent (R1~-Z) is carried out in a solvent such as alcohol, tetrahydrofuran, dimethylformamide, or dimethyl su:Lfoxide, in the presence of a base such as potassium ca..bonate or sodium carbonate, or in some cases potassium iodide or sodium iodide, in a temperature range from room temperature to 80°C. Alternatively, this reaction is carried out in a solvent such as tetrahydrofuran, 1,2-dirlethoxyethane, dioxane, dimethylformamide, or dimethyl su7.foxide, by use of sodium hydride or potassium hydride as a base, in a temperature range from 0°C tc room temperature.
The substituent-introduction reaction through use of a primary or secondary alcohol (R'3-OH) proceeds easily by the ty~~ical conditions of Mitsunobu reaction; i.e., in the presence of diethyl azodicarboxylate and triphenylphosphine.y Among the formula (1) compounds of the present invention, those compounds (ld) in which X is a sulfur atom, are derived using the below-described scheme from the compound (2').

OH
R20 \ R20 POC .~ 3 I \ ~~1-CN
N~ CH20H N~ CH2C.~
c2' ) cs) C.~ sR~ a R20 \ R'°SH,K2C0~ R20 \ RS-CHO
---HZO
N CHZCN N ~ CHZCN
) (10) SR'°
RZO \
- N~ CCCM=CHRS
(ld) wherein Rla, Rz, and R'' hazre the same meanings as described above, and M represents an alkali metal.
The compound (2') is first transformed to a dichloro compound (8), then to an acetonitrile compound (9) through_ reaction with M-CN, and after being introduced with an RlaS
group to a key intermediate (10). The thus-obtained compound (10) is easily derived to compound (ld) of the present invention through a condensation reaction with RS-CHC~ .
The reactions for obtaining the compound (9) from the compound (8) and obtaining the compound (ld) of the present invention from the key intermediate (10) proceed under conditions same as those described above. The reaction for obtaining a dichloro compound (8) from the compound (2') is carried out through reflux with heat in phosphorus oxychloride. Particularly, the reaction for obtaining the key intermediate (10) from the compound (9) is preferably carried out in a solvent such as alcohol, tetrahydrofuran, dimethylformamide, or dirnethyl sulfoxide, in the presence of a base such as potassium carbonate or sodium carbonate in a temperature range from room temperature to 80°C.
When the compound (a?) or (2') is replaced by a 6-alkoxy-5-hydroxy-3-pyridinemethanol (Q3=N) or 5-alkoxy-6-hydroxy-2-picoline (Q'=N) , a compound of formula ( 1 ) in which Qz or Q3 is a nitrogen atom can be prepared.
In the above reactions, separation of compound (1) of the present invention frc>m reaction mixtures is carried out using a customary method, e.g., extraction with a solvent, recrystalization, or column chromatography.
The thus-obtained compound of the present invention exhibits selective and strong PDE IV inhibitory action and_ inhibitory action against the production of TNF-a..
Therefore, the compound is useful as a PDE IV inhibitor and a ~CNF-a-production inhibitor, and also as a drug led by one for the prevention and treatment of diseases involving PDE
IV and/or TNF-a. The drug of the present invention is useful as a therapeutic agent for the prevention and treatment of immediate or delayed asthma, allergies such as airway-hypersensitive allergy and other allergies stemming from the inhibition of acaivation of inflammatory blood cells such as eosinocyte:>, autoimmune diseases such as atopy and rheumatism, depression associated with disturbed metabolism of the cerebrum, cerebral infarction, senile dementia, and memory disorders associated with Parkinson's disease, as well as for osteoporosis, type I and type II
diabetes, inflammations, cancers, infections with HIV, AIDS, an~~ shock caused by intracellular toxins.
The compounds of thE: present invention may be processed into drugs having a variety of forms, including tablets, granules, powders, capsules, inhalants, suspensions, injections, suppositories, and external preparations. When so:Lid preparations are formed, the compound of the present in~rention is preferably mixed with a vehicle and if necessary with a binder, a disintegrant, an extender, a coating agent, an agent for sugar-coating, etc., and is subsequently formed into tablets, granules, capsules, suppositories, etc. When injections are prepared, the compound of the present invention is dissolved, dispersed,_ or emulsified in an aqueous carrier for injections in ad~rance, or alternatively the compound is dissolved or dig>persed, or suspended upon use of the compound. Injection preparations may be used by way of intravenous administration, arterial administration, intraperitoneal administration, subcutaneous administration, or dripping.
When the compounds of the present invention are used as preventive or therapeutic drugs for the aforementioned diseases, their doses, which may differ in accordance with the manner of administrat=ion and the age, body weight, and conditions of the patient., are preferably 5-100 mg/day in the case of oral administration to an adult.
EXAMPLES
The present invention will next be described by way of examples, which should not be construed as limiting the invention thereto.
Preparation Example 1 Synthesis of 4-subst=ituted-5-alkoxy-2-pyridinemethanols (5) (Process 1):
A 5-alkoxy-4-hydroxy-2-pyridinemethanol (2) (100 mmol) was dissolved in dimethylformamide (100 ml). To the so.Lution were added pota~.sium carbonate (150 mmol) and potassium iodide (3 mmol). While the mixture was stirred on a 65°C oil bath, a halide reagent (bromocyclopentane in the care of preparation of compound (5a)) (130 mmol) was added dropwise over one hour. 'rhe mixture was stirred for 6-12 additional hours under the same conditions. After being cooled, the reaction mixture was poured into cold water and extracted with ethyl acetate. The organic layer was se<~uentially washed with water and saturated brine, dried, anc~ then concentrated under reduced pressure. The residue wa~~ purified by recrystallization or silica gel column chromatography, to thereby obtain compounds (5a) through (5cl) shown below.

4-Cyclopentyloxy-5-methcxy-2-pyridinemethanol (5a) 'H-NM1R(CDC.~ 3) ~ : 1. 40-2. 20(8H, m), 3. 90(3H, s), =~. 68(2H, s), 4. 70-5. 00(1H, m), 5. 35(1H, s). 6. 82(1H, s), 8. 04(1H, s).
4-Cyclopentyloxy-5-ethoxy-2-pyridinemethanol (5b) 'H-N~9R(CDC.~ a) ~ : 1. 42(~~H, t, J=7. OHz), 1. 50-2. 10(8H, m), 4. 09(~;H, q, J=7. OHz), 4. 65C2H, s), 4. 70-4. 90(1H, m).

6. 73(1H, s), 8. 05(1H, s).
5-Methoxy-4-phenetlzyloxy-2-pyridinemethanol (Sc) 'H-N~9R(CDC.~ 3) ~ : 3. 18(.2H, t, J=7. OHz), 3. 91(3H, s).
4. 26(.2H, t, J=7. OHz), 4. 63(2H, s), 6. 75(1H, s), 7. 29(.SH, s), 8. 05(1H, s).
5-Methoxy-4-(3-phenylpropyloxy)-2-pyridinemethanol (5d) 'H-NMR(CDC.~ 3) ~ : 2. 00-2. 40(2H, m), 2. 83(2H, t, J=8. OHz), 3. 75(1H, br), 3. 92(3H, s), 4. 05(2H, t, J=8. OHz), 4. 63(2H, s), 6. 70(1H, s), 7. 24(5H, s), 8. 04(1H, s).
4-Butyloxy-5-methoxy-2-pyridinemethanol (5e) 'H-N~~(R(CDC.~ 3) ~ : 0. 98(3H, t. J=7. OHz), 1. 30-2. 00(4H, m), 3. 91(3H, s), 4. 07(2H, t, J=7. OHz), 4. 66(2H, s), 6. 79(1H, s), _ 8. 03(1H, s).
4-(1-Ethylpropyloxy)-5-methoxy-2-pyridinemethanol (5f) 'H-NO~fR(CDC.~ 3) ~ : 0. 96(6I-, t, J=7. OHz), 1. 58-2. 00(4H, m), 3. 90(3H, s), 4. 10-4. 40(1H, m), 4. 65(2H, s), 6. 75(1H, s), 8. 04(1H, s).
5-Methoxy-4-methoxymethyloxy-2-pyridinemethanol (5g) 'H-N~~(RCCDC.~ 3) ~ : 3.51(3H, s), 3. 95(3H, s). 4. 66(2H. s). 5. 31(2H. s).
7. 0=~(1H, s), 8. 11 (1H, s).

Preparation Example 2 Synthesis of 4-subst=ituted-5-alkoxy-2-benzyloxymethylpyridines (5'):
A 5-alkoxy-2-benzyloxymethyl-4-hydroxypyridine (2) (10 mmol), a secondary alcohol (2-indanol in the case of preparation of compound (5h')) (12.5 mmol), and triphenylphosphine (15 mniol) were dissolved in tetrahydrofuran (300 ml). Diethyl azodicarboxylate (15 mm~~l) was added dropwise to the solution under stirring at ro«m temperature, and the mixture was stirred for one hour.
After addition of water, the reaction mixture was extracted wivh in chloroform. The organic layer was sequentially wa:7hed with water and saturated brine, dried, and then concentrated under reduced pressure. An ether (100 ml) was added to the residue and insoluble substances were removed by filtration. After con~~entration of the filtrate, the residue was purified by recrystallization or silica gel co__umn chromatography, to thereby obtain compounds (5h') through (5j') shown below.
2-Benzyloxymethyl-4-(2-indanyloxy)-5-methoxypyridine ( 5h' ) 'H-N~~IR(CDC~ 3) ~ : 3. 00-3. 60(4H, m). 3. 83(3H, s). 4. 64(4H, s).
5: 10-5. 40C1H, m), 7. 06(1H, s), 7. 10-r. 50(9H, m), 8. 06(1H, s).
2-Benzyloxymethyl-5-methoxy-4-(exo-2-norbornyloxy)pyridine (5i') 'H-NhIR(CDG.~ 3) ~ : 1. 00-2. 65(IOH, m), 3. 90(3H, s).
4. 10-4. 90(1H, m), 4. 60(4H, s), 6. 95(1H, s), 7. 36(5H, s). 8. 0~(1H, s).
2-Benzyloxymethyl-5--methoxy-4-(tetrahydro-3-furanyloxy)pyridine (5j') 'H-N6(R(CDC.~ 3) ~ : 2. 05-2. ~0(2H, m), 3. 80-4. 10(4H, m), 3. 91(3H, s), 4. 60(2H. s), 4. 62(2H, s), ~. 90-5. 10(1H, m), 6. 92(1H, s), 7. 36(5H, s), 8. 08(1H, s).
Preparation Example 3 Synthesis of 4-subst=ituted-5-alkoxy-2-py:ridinemethanols (5) (Process 2):
A 4-substituted-5-a~_koxy-2-benzyloxymethylpyridine (5') (10 mmol) was dissolved in acetic acid (50 ml). Pd-black (2 g) was added to the solution, which was hydrogenated at room tem~~erature for 2-6 hours. After removal of the catalyst, the filtrate was concentrated under reduced pressure. The residue was fractionated by a chloroform-aqueous saturated sodium hydrogencarbonate so=Lution. The organic layer was dried and concentrated _ w under reduced pressure. The obtained crystalline residue was optionally recrystallized, to thereby obtain compounds (5h) through (5j) shown below.
4-(2-Indanyloxy)-5-methoxy-2-pyridinemethanol (5h) 'H-NMRCCDC.~ 3) ~ : 3. 00-3. 55(4H, m), 3. 84(3H, s), 4. 69(2H, s), 5. 10-5. ~0(1H, m), 6. 85(1H, s), 7. 10-7. 40(4H, m).
8. 04(1H~ s).
5-Methoxy-4-(exo-2-n.orbornyloxy)-2-pyridinemethanol (5i) 1 H-N~IR CCDC .~ 3 ) ~ : 1. 00-2. 00 (8H, m) . 2. 30-2. 60 C2H, m) , 3. 90 (3H, s) , 4. 10-4. 40(1H, m), 4. 65(2H, s), 6. 69(1H, s), 8. 03(1H, s).
5-Methoxy-4-(tetrahydro-3-furanyloxy)-2-pyridinemethanol (5j) H-NMR (CDC .~ 3 ) ~ : 2. 10-2., 40 (2H, m) , 3. 80-4. 20 C4H, m) , 3. 91 C3H, s) , 4. 66(2H, s), 4. 90-5. 10(1H, m). 6. 71 (1H, s). 8. 07(1H, s).
Preparation Example 4 Synthesis of 4-substituted-5-alkoxy-2-chloromethylpyridines (6);
A 4-substituted-5-al:koxy-2-pyridinemethanol (5) (0.2 mol) was dissolved in dichloromethane (200 ml). Thionyl chloride (0.3 mol) was added dropwise to the solution under stirring at 5°C. The mixture was allowed to react for 30 minutes under the same conditions. The resultant solution was concentrated under reduced pressure and the residue was fractionated by a chloroform-aqueous saturated sodium _ hydrogencarbonate solution. The organic layer was dried and concentrated under reduced pressure. Obtained crystalline or oily compounds (6a) through (6j) were used for the subsequent reaction without additional purification.
2-Chloromethyl-4-cyc:Lopentyloxy-5-methoxypyridine (6a) 'H-NN1R(CDC.~ 3) ~ : 1. 40-2. 10C8H, m), 3. 90C3H, s). 4. 60C2H, s).
4. 75-4. !37(1H, m), 6. 96(1H, s). 8. 07(1H, s).

2-Chloromethyl-4-cyclopentyloxy-5-ethoxypyridine (6b) 'H-N~~(RCCDC.~ 3) ~ : 1. 40(3H, t, J=7. OHz), 1. 60-2. 10(8H, m).
4. 11 (2H, q, J=7. OHz), 4. 59(2H, s), 4. 70-4. 90(1H, m), 6. 95(1H, s). 8. 05(1H, s).
2-Chloromethyl-5-met::~oxy-4-phenethyloxypyridine (6c) 'H-Nh~IRCCDC,~ 3) S : 3. 18C2H, t, J=7.OHz), 3. 92(3H, s), 4. 27(2H, t, J=7. OHz), 4. 57(2H, s). 6. 94C1H. s), 7. 30(5H, s), 8. 06(1H, s).
2-Chloromethyl-5-met:hoxy-4-(3-phenylpropyloxy)pyridine (6d) ' H-NMR (CDC .~ 3 ) ~ : 2. 00-2. 40 C2H, m) , 2. 83 C2H, t , J=8. OHz) , 3. 93(3H, s), 4. 07(2H, t. J=8. OHz). 4. 57(2H, s).
6. 88C1H, s). 7. 24C5H, s), 8. 06(1H, s).
4-Butyloxy-2-chloromethyl-5-methoxypyridine (6e) 'H-Nh(RCCDC.~ 3) s : 0. 99C3H, t, J=7. OHz), 1. 30-2. 00C4H, m), 3. 93(3H, s), 4. 09C2H, t, J=7. OHz), 4. 60(2H, s), 6. 97C1H, s). 8. 06(1H, s).
2-Chloromethyl-4-(1-ethylpropyloxy)-5-methoxypyridine (6f) 'H-NM1R~CDC.~ 3) cS : 0. 98C6~1, t, J=7. OHz), 1. 58-2. 00(4H, m), 3. 92(3H, s).
4. 10-4. 40(1H, m), 4. 60(2H, s), 6. 94(1H, s), 8. 07(1H. s).
2-Chloromethyl-5-met:hoxy-4-methoxymethyloxypyridine (6g) 'H-N~-fR(CDC~ 3) o : 3.52C3H, s). 3.96(3H, s), 4.59(2H. s), 5. 32(2H. s).
7. 23(1H, s), 8. 13(1H, s).
2-Chloromethyl-4-(2-indanyloxy)-5-methoxypyridine (6h) ' H-NhIR (CDC .~ 3 ) a : 3. 20 (2H. dd, J=4. 0, 17. OHz) , 3. 50(2H, dd, J=6. 0. 17. OHz). 3. 87(3H, s), 4. 63C2H, s), 5. 15-5. 40(1H, m). 7. 0~(1H, s), 7. 23C=1H, s), 8. 06(1H, s).
2-Chloromethyl-5-metlzoxy-4-(exo-2-norbornyloxy)pyridine (6i;~
' H-N~~IR (CDC .~ 3 ) ~ : 1. 00-2. 10 (8H, m) , 2. 25-2. 60 (2H, m) , 3. 91 (3H. s ) .
4. 15-4. 40C1H, m), 4. 60(2H, s), 6. 90(1H, s). 8. 04C1H, s).
2-Chloromethyl-5-metlzoxy-4-(tetrahydro-3-furanyloxy)pyridine (6j) 'H-N~~IR(CDC.~ 3) o : 2. 10-2. 40(2H, m), 3. 80-4. 20(4H, m). 3. 92(3H, s), 4. 61 C2H, s), 4. 90-5. 10(1H, m), 6. 90(1H. s). 8. 08(1H. s).
Preparation Example 5 Synthesis of 4-substituted-5-alkoxy-2-pyridineacetonitriles (3):
A 4-substituted-5-al:koxy-2-chloromethylpyridine (6) (0.20 mol) was dissolved in dimethyl sulfoxide (200 ml).
Sodium cyanide (0.24 mol) was added to the solution and the mixture was allowed to react at room temperature for 12 _ hours or at 100°C for one hour, depending on the reaction rate of the substrate. Th.e reaction mixture was poured into water (500 ml), extracted with ethyl acetate, sequentially washed with water and saturated brine, dried, and then concentrated under reduced pressure. The residue was purified by recrystallizai=ion or silica gel column chromatography, to thereby obtain compounds (3a) through (3j) shown below.

4-Cyclopentyloxy-5-methoxy-2-pyridineacetonitrile (3a) 'H-NMR(CDC.~ 3) o : 1. 46-2. 20(8H, m), 3. 84(2H, s). 3. 90(3H, s).
4. 72-5. 00(1H, m), 6. 90(1H, s), 8. 06(1H, s).
4-Cyclopentyloxy-5-ethoxy-2-pyridineacetonitrile (3b) 'H-N~~(RCCDC.~ 3) ~ : 1. 42(3H, t, J=7. OHz), 1. 60-2. 20C8H, m), 3. 84(2H, s), 4. 11 (2H, q, J=7. OHz), 4. 75-5. OOC1H, m), 6. 88C1H, s), 8. 04(1H, s).
5-Methoxy-4-phenethy:Loxy-2-pyridineacetonitrile (3c) 'H-N~~(R(CDC.~ 3) ~ : 3. 18C2H, t, J=7.OHz), 3. 82C2H, s), 3. 92(3H, s), 4. 27(2H, t. J=7. OHz), 6. 86(1H. s). 7. 30(5H. s), 8. 05C1H, s).
5-Methoxy-4-(3-pheny:Lpropyloxy)-2-pyridineacetonitrile (3d) 'H-N~dR(CDC.~ 3) S : 2. 00-2. ~O(2H, m). 2. 84(2H, t. J=8. OHz), 3. 82(2H, s), 3. 94(3H, s), 4. 08C2H. t, J=8. OHz), 6. 81C1H. s), 7. 25(5H, s), 8. 06(1H, s).
4-Butyloxy-5-methoxy--2-pyridineacetonitrile (3e) 'H-Nh~(RCCDC.~ 3) ~ : 0. 99~3H, ~;, J=7. OHz), 1. 35-2. 10(4H, m), 3. 86C2H, s),-3. 93C3H, ;>), 4. 09(2H, t. J=7. OHz), 6. 90(1H, s).
8. 05C1H, s).
4-(1-Ethylpropyloxy)--5-methoxy-2-pyridineacetonitrile (3f) 'H-N~~(R(CDC.~ 3) o : 0. 98(6H, t, J=7. OHz), 1. 60-2. 00(4H, m), 3. 85(2H, s), 3. 92(3H, s), 4. 10-4. 40(1N. m). 6. 88C1H, s), 8. 06C1H, s).

5-Methoxy-4-methoxymethyloxy-2-pyridineacetonitrile (3c.) 'H-NMR(CDC.~ 3) ~ : 3. 52(3H, ~), 3. 84C2H, s), 3. 96(3H, s), 5. 32(2H, s), 7. 14C1H, sO, 8. 13(1H, s).
4-(2-Indanyloxy)-S-methoxy-2-pyridineacetonitrile (3h) 'H-NII-1R(CDC.~ a) ~ : 3. 22C2H, cid. J=4. 0, 17. OHz), 3. 51 C2H, cld, J=6. 0, 17. OHz), 3. 86(3H, s), 3. 88C2H, s), 5. 10-5. 40(1H, m), 6. 97(1H. s), 7. 23(4H, s). 8. 05(1H, s).
5-Methoxy-4-(exo-2-norbornyloxy)-2-pyridineacetonitrile (3i) ' H-N~iR CCDC .~ 3 ) c~ : 1. 10-2. 00 (8H, m) , 2. 30-2. 70 C2H, m) , 3. 85 C2H, s) , 3. 90(3H, s), 4. 15-4. 40(1H, m). 6. 84(1H, s).
8. 03(1H, s).
5-Methoxy-4-(tetrahyc~ro-3-furanyloxy)-2-pyridineacetonitrile (3j) ' 1~-NMR CCDC .~ 3 ) ~ : 2. 10-2. 50 C2H, m), 3. 80-4. 20 (4H, m) , 3. 86 C2H, s ) , 3. 92(3H, s), 4. 90-5. 20(1H, m), 7. 28(1H, s).
8. 08(1H, s).
Preparation Example 6 Synthesis of methyl ~1-cyclopentyloxy-5-methoxy-2-pyridineacetate (3k):
A HC1-saturated methanol solution (30 ml) was added to 4-cylopentyloxy-5-methc>xy-2-pyridineacetonitrile (3a) (2.32 g, 10 mmol) and the solution was refluxed for 30 minutes. The reaction mixture was evaporated to dryness.
The residue was dissolved in chloroform and the solution was sequentially washed with ~iqueous saturated sodium hydrogencarbonate solution and saturated brine, then dried, and then concentrated undE:r reduced pressure, to thereby obtain the title compound (2.36 g, yield 89~).
'H-~~lfR(CDC.~ 3) ~ : 1. 60-2. 10(81, m). 3.72C3H, s). 3. 76C2H. s).
3. 89C3H. s). ~. 70-=>~. 90C1H, m). 6. 81C1H, s).
8. 0~(1H, s~.
Preparation Example 7 Synthesis of 3,5-dichloro-4-pyridinecarbaldehyde:
Under an argon atmosphere, to a solution of diisopropylamine (33.6 ml,. 0.24 mol) in tetrahydrofuran (400 ml) at -65°C was added a _L.6 M solution of n-butyl lithium in hexanes (156 ml). After 20 minutes later, a solution of 3,5-dichloropyridine (29.6 g, 0.20 mol) in tetrahydrofuran (150 ml) was added dropwise, and the mixture was stirred for 30 minutes. Subsequently, the mixture was treated with dimethylformamide (23.2 m=L, 0.30 mol) in tetrahydrofuran (50 ml), and then stirred for one hour under the same conditions The reaction mixture was poured into a 5% aqueous ammonium chloride solution (1,000 rnl) and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine,. dried, and then concentrated under reduced pressure. The residue was chromatographed on silica gel, to thereby obt=ain the title compound (27.2 g, yield 770).

'H-N~~fR(CDC.~ 3) ~ : 8. 6a3(2H, s), 10.44(1H, s).
Preparation Example 8 Synthesis of 3,5-dim~~thoxy-4-pyridinecarbaldehyde:
In a similar manner to that in Preparation Example 7, the title compound was prf~pared.
'H-N~~IR(CDC.~ 3) ~ : 4.02(6H, s). 8. 17(2H, s). 10. 50(1H, s).
Preparation Example 9 Synthesis of 5-alkox:y-4-chloro-2-chloromethylpyridines (8) Phosphorus oxychloric~e (10 ml) was added to a 5-alkoxy-4-hydroxy-2-pyridinemethanol (10 mmol) and the solution was refluxed for three hours. The reaction mixture was concentrated under reduced pressure and the residue was fractionated with a chloroform-aqueous saturated sodium hydrogencarbonate solution. The obtained organic layer was dried and then concentrated under reduced pressure. An obtained crystalline compound (8a) described below was used._ for the subsequent reaction without additional purification.
4-Chloro-2-chloromethyl-5-methoxypyridine (8a) 'H-NMR(CDC.~ 3) ~ : 4. 00(3H, s). 4. 60(2H. s), 7. 50(1H, s), 8. 25(1H, s).
Preparation Example 10 Synthesis of 5-alkoxy-4-chloro-2-pyridineacetonitrile (9) :
The procedure of Preparation Example 5 was repeated through use of 5-alkoxy-4--chloro-2-chloromethylpyridine (8) and sodium cyanide, to thereby obtain a compound (9a) shown below.
4-chloro-5-methoxy-2--pyridineacetonitrile (9a) 'H-NMR(CDC.~ 3) ~ : 3. 87C2H, ~;), 4. 01C3H, s), 7.44(1H, s), 8.23C1H, s).
Preparation Example 11 Synthesis of 4-substituted-thio-5-alkoxy-2-pyridineacetonitriles (10):
A 5-alkoxy-4-chloro-'<?-pyridineacetonitrile (9) (4.5 mmol) was dissolved in dimethylformamide (9 ml). To the solution were added potas:~ium carbonate (5.4 mmol) and R1'SH
(cyclopentanethiol in the case of preparation of compound (l0a)) (5.2 mmol) and the mixture was stirred on a 60°C oil bath for 3-12 hours. After being cooled, the reaction mixture was poured into cold water and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried, and then concentrated under reduced pressure. The residue was purified by _. _ recrystallization or silica gel column chromatography, to thereby obtain a compound (l0a) shown below.
4-Cyclopentylthio-5-rlethoxy-2-pyridineacetonitrile (103) 'f(-N~IRCCDC.~ ~) o : 1. 55-2. ~0(.BH, m). 3. 55-3. 80C1H, m;. 3. 87C2H. s).
3. 97C3H. s). 7. 20C1H, s). 7. 99C1H. s).
Preparation Example 12 Synthesis of 3-fluor~~-4-pyridinecarbaldehyde:
The procedure of Preparation Example 7 was repeated to thereby obtain the title compound.
'H-Nl(R(CDC.~ a) ~ : 7. 71(1H, t, J=5. OHz), 8. 65(1H, d. J=5. OHz).
8. 73(1H, d, J=1. OHz), 10. ~5(1H, s).
Preparation Example 13 Synthesis of 3,5-diclzloro-4-pyridinecarbaldehyde N-oxide:
To a benzene solution (100 ml) of 3,5-dichloro-4-pyridinecarbaldehyde (Preparation Example 7) (5.00 g, 28.4 mmol) were added ethylene glycol (10 ml) and p-toluenesulfonic acid hydrate (0.19 g, 1.0 mmol). The mixture, placed in a react=ion vessel equipped with a Dean-Stark water separator, wa:~ refluxed for eight hours. After being cooled, the reaction mixture was washed with water, dried, and then concentrated under reduced pressure, to thereby obtain the corresponding acetal compound (6.19 g, yield 99%) . - -' H-NbIR(CDC.~ ~) ~ : 3. 95-4. 22(=~H. m). 6. 38(1H. s). 8. =~9(2H. s).
The above-described acetal compound (5.50 g, 25 mmol) was dissolved in dichloromethane (50 ml). To the solution was added 85o m-chloroperbenzoic acid (6.10 g, 30 mmol), and the mixture was stirred at: room temperature for 15 hours.
The reaction mixture was crashed with an aqueous saturated sodium hydrogencarbonate aolution, dried, and then con~~entrated under reduced pressure. The residue was purified by silica gel column chromatography, to thereby obtain the corresponding lV-oxide compound (5.24 g, yield 89° ) .
'H-~iVR(CDC .~ ~) o : 3. 95-~. ;?2(=1H. m). 6. 28(1H, s). 8. 15C2~-~. s).
The above-described a~-oxide compound (4.72 g, 20 mmol) was dissolved in acetone (40 ml)-H~O (10 ml) solution. To the solution was added p-~~oluenesulfonic acid hydrate (3.80 g, 20 mmol). The mixture was refluxed for two hours. The reaction mixture was evaporated to dryness. An aqueous saturated sodium hydrogencarbonate solution was added to the residue, which was then e:~tracted with chloroform. The organic layer was washed, dried, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, to thereby obtain 3,5-dichloro-4-pyridinecarbaldehyde N-ox=_de (3.78 g, yield 98~).
'H-f~fR(CDC.~ 3) o : d. 19~;2H. s). 10.35C1H. s).
Preparation Example 14 Synthesis of 4- (2-inc~anyloxy) -5-methoxy-2- - -pyridinecarbaldehyde:
To a dimethyl sulfoxide solution (20 ml) of 4-(2-indanyloxy)-5-methoxy-2-p5~ridinemethanol (5h) (2.71 g, 10 mmo 1 ) and triethylamine ( ~~ . 03 g, 30 mmol ) was added sulfur tri~~xide-pyridine complex (4.77 g, 30 mmol), and the mixture was stirred at room temperature for 7 hours. The reaction mixture was poured into cold water to cause precipitation of crude crystals. The crude crystals were collected by filtration, dried, and purified by silica gel column chromatography, to thereb~~ obtain the title compound (1.95 g, yield 720).
'H-N~~iRCCDC.~ 3) ~ : 3. 10-3. '70(4H, m), 3. 96(3H, s), 5. 20-5. 42(1H, m), 7. 23(4H, s), 7. 55C1H, s), 8. 27(1H, s), 9. 95C1H, s).
Preparation Example 15 Synthesis of N-hydroayethyl-2-pyridone:
2-Pyridone (4.76 g, .'~0 mmol) and ethyl bromoacetate (10.02 g, 60 mmol) were dussolved in acetone (100 ml) .
Potassium carbonate (8.28 g, 60 mmol) was added to the solution and the mixture was refluxed for two hours with stirring. After being cooled, insoluble substances were removed by filtration and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography, to thereb~~ obtain N-ethoxycarbonylmethyl-2-pyridone (7.60 g, yield 8~~° ) .
'H-NMR(CDC.~ 3) o : 1. 29(3H, t, J=7.OHz), 4.2=1(2H, q, J=7. OHz).
4. 64(2H, s), 6. 10-6. 30(1H, m), 6. 60(1H, d, J=9. OHz)~ _ 7. 15-7. ~2(2H, m).
In 100 ml of dioxan.e, was dissolved N-ethoxycarbonylmethyl-2-pyridone (3.62 g, 20 mmol). To the solution was added 90 o LiF3H~ ( 0 . 96 g, 40 mmol ) and the mixture was refluxed for ~?0 minutes. Subsequently, ethyl acetate (20 ml) was added to the mixture and the refluxing was carried out for five minutes. The reaction mixture was evaporated to dryness and water was added to the residue.

The aqueous solution was extracted with chloroform (three tin.es), dried, and then c~~ncentrated under reduced pressure.
The residue was purified by silica gel column chromatography, to thereby obtain the title compound (1.15 g, yield 41°).
'H-I~N1R(CDC.~ 3) ~ : 3. 80-=1. 30(5H, m), 6. 10-6. 62(2H, m), 7. 20-7. 50 (2H, m) .
Preparation Example 16 Synthesis of 5-cyclopentyloxy-6-methoxy-3-pyridine acetonitrile:
The procedure of Pre~~aration Example 1 was repeated through use of 5-hydroxy-6-methoxy-3-pyridinemethanol and bromocyclopentane, to thereby obtain 5-cyclopentyloxy-6-methoxy-3-pyridinemethanol.
'H-N~~iR(CDC.~ 3) b : 1. 50-2. 20(8H, m). 3. 98(3H, s). 4. 60(2H, s).
4. 73C1H, m). 7. 10(1H, d. J=2. OHz). 7. 63(1H, d. J=2. OHz).
The procedure of Preparation Example 4 was repeated through use of 5-cyclopent:yloxy-6-methoxy-3-pyridinemethanol and thionyl chloride, to thereby obtain 3-chloromethyl-5- _ _ cyclopentyloxy-6-methoxypyridine.
'H-N~-~R(CDC.~ 3) ~ : 1. 50-2. 10C8H, m), 3. 93(3H, s). 4. 54C2H, s), 4. 70(lH, m). 7. 06C1H, d. J=2. OHz). 7. 67(1H, d, J=2. OHz).
The procedure of Preparation Example 5 was repeated through use of 3-chloromet:hyl-5-cyclopentyloxy-6-methoxypyridine and sodium cyanide, to thereby obtain 5-cyc:Lopentyloxy-6-methoxy-~~-pyridineacetonitrile.

'H-NMRCCDC.~ 3) ~ : 1. 50-2. 20C8H, m). 3. 67C2H, s), 3. 98C3H. s).
4. 75(1H, m), 6. 99C1H, d. J=2. OHz), 7. 61C1H, d, J=2. OHz).
Preparation Example 17 Synthesis of 6-cyclopentyloxy-5-methoxy-2-pyridineacetonitrile:
The procedure of Pr~epa~ation Example 1 was repeated through use of 6-hydroxy-!~-methoxy-2-picoline and bromocyclopentane, to thereby obtain 6-cyclopentyloxy-5-methoxy-2-picoline.
'E':-N~~iR(CDC.~ 3) ~ : 1. 58-2. 03C8H, m), 2. 36C3H, s), 3. 80(3H, s), 5. 44(1H, m), 6. 59(1H, d, J=8. OHz), 6. 92C1H, d, J=8. OHz).
6-Cyclopentyloxy-5-mf=thoxy-2-picoline (0.83 g, 4.0 mmol) and N-bromosuccinimide (0.80 g, 4.4 mmol) were dissolved in carbon tetrachloride (10 ml). The solution in which benzoyl peroxide was added in a catalytic amount was refluxed for two hours. P.fter being cooled, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water, dried, and then concentrated under reduced pressure, to thereby obtain a residue which was used for the subsequent reaction.
The procedure of Preparation Example 5 was repeated through use of the above-described residue and sodium cyanide, to thereby obtain 6-cyclopentyloxy-5-methoxy-2-pyridineacetonitrile (0.7a? g, yield 77=).
'H--Nl4iRCCDC.~ 3) ~ : 1. 50-2. 40(8H, m). 3. 73(2H, s). 3. 84(3H, s).
5. 40(1H, m), 6. 80(1H, d. J=8. OHz). 7. 00(1H, d. J=8. OHz).

Preparation Example 18 Synthesis of 5-methoxy-4-[2-(4-methyl-5-thiazolyl)ethyloxy]-2-pyr:idineacetonitrile:
The procedure of Preparation Example 1 was repeated through use of 4-hydroxy-:~-methoxy-2-pyridinemethanol and 5-(2-chloroethyl)-4-methyltlziazole, to thereby obtain 5-methoxy-4-[2-(4-methyl-5-'~hiazolyl)ethyloxy]-2-pyridinemethanol.
'H-N~~fRCCDC.~ 3) ~ : 2. 46(3H, s), 3. 33(2H, t. J=6. 5Hz), 3. 92(3H. s), 4. 22(2H, t, J=6. 5Hz), 4. 65C2H, s), 6. 75C1H, s), 8. 07(1H, s), 8. 61 (1H, s).
The procedure of Preparation Example 4 was repeated through use of 5-methoxy-~~-[2-(4-methyl-5-thiazolyl)ethyloxy]-2-pyr_Ldinemethanol and thionyl chloride, to thereby obtain 2-chloromethyl-5-methoxy-4-[2-(4-methyl-5-thiazolyl)ethyloxy]pyridine.
'H-Nb~(RCCDC.~ 3) o : 2. =17C3H, ~~), 3. 3=(C2H, t, J=6. 5Hz), 3. 94C3H, s).
4. 25C2H. t. J=6. 5Hz), 4. 59(2H, s), 6. 94(1H. s), 8. 08(1H, s), 8. 61(1H, s). -The procedure of Preparation Example 5 was repeated through use of 2-chloromet;hyl-5-methoxy-4-[2-(4-methyl-5-thiazolyl)ethyloxy]pyridine and sodium cyanide, to thereby obtain 5-methoxy-4-[2-(4-methyl-5-thiazolyl)ethyloxy]-2-pyridineacetonitrile.
'H-Nh(RCCDC~ 3) ~ : 2. 47(3H, s;~, 3. 35(2H, t, J=6. SHz~. 3. 85(2H, s), 3. 93(3H, s; , 4. 24(2H, t, J=6. SHz~. 6. 87(1H, s).
8. 07(1H, s;~, 8. 62C1H, s).

Example 1 Synthesis of (Z)-2-(4-cyclopentyloxy-5-methoxy-2-pyridyl)-3-(3,5-dichloro-4-pyridyl)propenenitrile (formula ( 1 ) , wherein R1 - cyclopentyl, Rz - CH3, R3 - CN, R~ - H, R' -3, ~~-dichloro-4-pyridyl, a:nd X = O) 4-Cyclopentyloxy-5-methoxy-2-pyridineacetonitrile (3a) (16.24 g, 70 mmol) and 3,5-dichloro-4-pyridinecarbaldehyde (Preparation Example 7) (12.94 g, 73.5 mmol) were dissolved in methanol (180 ml). While the solution was stirred at 5°C, a CH30Na-CH30H solution (1 M, 77 ml) was added dropwise. The mixture was stirred for 3~ additional minutes under the same conditions. Precipitated crystals were collected by filtration and recrystallized from ethanol, to thereby obtain the title compound (24.83 g, yield 91°).
Melting point: 126-126.5°C:
'H-N~1R(CDC.~ 3) ~ : 1. 60-2. 15(8H, m~. 3. 98C3H, s). ~. 92-4. 98(1H, m).
7.26(1H, s). 8. 19(1H, s). 8.20C1H, s). 8. 61C2H, s).
Example 2 _ The procedure of Example 1 was repeated through use of 4-cyclopentyloxy-5-methox:~-2-pyridineacetonitrile (3a) and 2,6-dichlorobenzaldehyde, to thereby obtain the compound shown below.
(Z)-2-(4-Cyclopentyl~~xy-5-methoxy-2-pyridyl)-3-(2,6-dichlorophenyl)propenenitrile (formula (1), wherein R1 -cyclopentyl, R' - CH3, R3 -- CN, Rq - H, R~ - 2, 6-dichlorophenyl, and X = Oj Melting point: 129-130°C
'H-N~dRCCDC.~ 3) d : 1. 60-2. 20(8H, m). 3. 97C3H, s), 4. 92-4. 98C1H, m).
7. 25(1H, s). 7. 26-7. 31 (1H, m). 7. =12C2H, d, J=7. OHz), 8. 20C1H, s). 8. 23C1H, s).
Example 3 The procedure of Example 1 was repeated through use of 4-cyclopentyloxy-5-methox~~-2-pyridineacetonitrile (3a) and 3-pyridinecarbaldehyde, to thereby obtain the compound shown below.
( Z ) -2- ( 4-Cyclopentyloxy-5-methoxy-2-pyridyl ) -3- ( 3-pyridyl)propenenitrile (formula (1), where,~n R1 -cyclopentyl, Rz - CH3, R3 -- CN, R9 - H, R' - 3-pyridyl, and X
- O) Melting point : 122 . 5-123 . !~°C
'I-:-NI4fR(CDC.~ 3) ~ : 1. 50-2. 20(:BH, m). 3. 98(3H. s). 4. 84-5. 06C1H, m).
7. 30(1H, s;. 7. 48(1H, dd. J=5. 0. 8. OHz), 8. 20(1H, s).
8. 38C1H, s;~. 8. 55(1H, dt, J=2. 0, 8. OHz), 8. 70C1H, dd. J=2. 0. 5. OHz), 8. 98C1H, d, J=2. OHz).
Example 4 The procedure of Example 1 was repeated through use of 4-cyclopentyloxy-5-methoxy-2-pyridineacetonitrile (3a) and 4-pyridinecarbaldehyde, to thereby obtain the compound shown below.
(Z)-2-(4-Cyclopentyloxy-5-methoxy-2-pyridyl)-3-(4-pyridyl)propenenitrile (formula (1), wherein R1 -cyclopentyl, R' - CH3, R3 -- CN, Ra - H, RJ - 4-pyridyl, and X
- O) Melting point: 142-142.5°C
' H--Nh~R (CDC .~ 3 ) ~ : 1. 64-2. 14 CBH, m) , 3. 97 C3H, s) . 4. 92-4. 98 C
1 H, m) .
7. 28(1H, s), 7. 74C2H, dd, J=2. 0. 6. OHz). 8. 16(1H, s), 8. 26(1H, s). 8. 74(2H, dd. J=2. 0. 6. OHz).
Example 5 The procedure of Example 1 was repeated through use of 4-cyclopentyloxy-5-methox~l-2-pyridineacetonitrile (3a) and 2-methoxy-1-naphthaldehyde, to thereby obtain the compound shown below.
(z)-2-(4-Cyclopentylc~xy-5-methoxy-2-pyridyl)-3-(2-methoxy-1-naphthyl)propenenitrile (formula (1), wherein R
cyclopentyl, Rz = CH3, R3 -- CN, Rq - H, RS - 2-methoxy-1-naphthyl, and X = 0) Melting point: 168-169°C
'H-N~~(R(CDC.~ ~) ~ : 1. 60-2. 15(8H, m), 3. 97(3H, s), 4. 04(3H, s).
=~. 80-5. 00 C 1. H. m) . 7 . 29 C 1 H, s ) , 7. 3=~-7. =~2 C2H, m) .
7. 48-7. 53C1.H, m). 7. 80-7. 93(3H, m). 8. 21C1H, s).
8. 69(1H, s).
Example 6 The procedure of Example 1 was repeated through use of 4-cyclopentyloxy-5-methox~,~-2-pyridineacetonitrile (3a) and 2-chlorobenzaldehyde, to i~hereby obtain the compound shown below.

(Z)-3-(2-chlorophenyl)-2-(4-cyclopentyloxy-5-methoxy-2-pyridyl)propenenitrile (formula (1), wherein R1 -cyclopentyl, Rz = CH3, R3 -- CN, R~ - H, R7 = 2-chlorophenyl, and X = 0) Melting point: 122-123°C
'H--N~IRCCDC.~ 3) o : 1. 60-2. 15(8H, m), 3. 96(3H, s), ~. 92-~. 97(1H, m).
7. 26(1H, s), 7. 35-7. 41(2H, m). 7. 46-7. 50(1H. m).
8. 10-8. 18( H, m), 8. 19(1H, s), 8. 63(1H, s).
Example 7 The procedure of Example 1 was repeated through use of 4-cyclopentyloxy-5-methoxy-2-pyridineacetonitrile (3a) and 4-cyanobenzaldehyde, to thereby obtain the compound shown below.
(Z)-3-(4-cyanophenyl)-2-(4-cyclopentyloxy-5-methoxy-2-pyridyl)propenenitrile (formula (1), wherein R1 -cyclopentyl, RZ - CH3, R3 -- CN, Ra - H, R' - 4-cyanophenyl, and X = 0 ) Melting point: 149-150°C
'H-N~4R(CDC.~ 3) ~ : 1. 55-2. 20(8H, m). 3. 97C3H. s), 4. 80-5. lOCIH, m), 7. 28(1H, s), 7. 75(2H. d. J=9. OHz), 8. 03C2H, d. J=9. OHz).
8. 15C1H, s), 8. 33(1H, s).
Example 8 The procedure of Example 1 was repeated through use of 4-cyclopentyloxy-5-methox:~-2-pyridineacetonitrile (3a) and 4-trifluoromethylbenzaldehyde, to thereby obtain the compound shown below.
( Z ) -2- ( 4-Cyclopentyloxy-5-methoxy-2-pyridyl ) -3- ( 4-trifluoromethylphenyl)propenenitrile (formula (1), wherein R1 - cyclopentyl, RZ = CH3, R3 = CN, R4 = H, RS = 4-trifluoromethylphenyl, and X = 0) Melting point: 116-117°C
'H-(~11(R(CDC:~ ~) ~ : 1. 55-2. 20(8H, m). 3. 97(3H, s). 4. 80-5. lOCIH, m), 7. 27(1H, s). 7. 72C2H, d. J=9. OHz).
8. 04C2H. d. J=9. OHz). 8.15C1H, s). 8. 35(1H. s).
Example 9 The procedure of Example 1 was repeated through use of 4-cyclopentyloxy-5-methoxy-2-pyridineacetonitrile (3a) and 2,6-dimethoxybenzaldehyde, to thereby obtain the compound shown below.
(Z)-2-(4-Cyclopentyloxy-5-me~hoxy-2-pyridyl)-3-(2,6-dimethoxyphenyl)propenenitrile (formula (1), wherein R1 cyclopentyl, R2 = CH3, R3 = CN, R' = H, RS = 2, 6-dimethoxyphenyl, and X = O) Melting point: 168-170°C
'H-NhiR(CDC ~C s) ~ : 1. 55-2.10(8H, m). 3. 89(6H. S). 3. 94(3H. S).
4. 80-5. lOClH. m). 6. 60(2H. d. J=8. OHz). 7. 24(1H. s).
7. 42(1H, t, J=8. OHz). 8.16(1H. s). ~ 8. 27(IH. s).
Example 10 The procedure of Example 1 was repeated through use of 4-cyclopentyloxy-5-methoxy-2-pyridineacetonitrile (3a) and 4-quinolinecarbaldehyde, to thereby obtain the compound shown below.
(Z)-2-(4-Cyclopentyloxy-5-methoxy-2-pyridyl)-3-(4-quinolyl)propenenitrile (~=ormula (1), wherein R1 -cyclopentyl, R' - CH3, R3 -- CN, R~ - H, RS = 4-quinolyl, and X = 0) Melting point: 160-161°C
'H-Niv(RCCDC.~ 3) ~ : 1. 55-2. 10(8H, m). ~. 00(3H, s), ~. 80-5. lOCIH, m), 7. 32(1H. s). 7. 45-8. 30(5H, m), 8. 21(1H. s), 9. 02(1H, s), 9. 04(1H, d, J=4. OHz).
Example 11 The procedure of Example 1 was repeated through use of 4-cyclopentyloxy-5-methoxy-2-pyridineacetonitrile (3a) and 3,5-dimethoxy-4-pyridinecarbaldehyde (Preparation Example 8), to thereby obtain the compound shown. below.
(Z)-2-(4-Cyclopentyl~~xy-5-methoxy-2-pyridyl)-3-(3,5-dimethoxy-4-pyridyl)propenenitrile (formula (1), wherein Ri - cyclopentyl, R2 - CH3, R3 - CN, R4 - H, R~' - 3, 5-dimethoxy-4-pyridyl, and X = O) Melting point: 143-144°C
'H-~N~~fR(CDC.~ ~) ~ : 1. 55-2. 10(8H. m), 3. 96(3H, s), 4. 00C6H, s), 4. 80-5. 10~;1H, m), 7. 25C1H, s). 8. 11 (2H, s), 8. 17(2H, s).
Example 12 The procedure of Example 1 was repeated through use of 4-cyclopentyloxy-5-methox:y-2-pyridineacetonitrile (3a) and benzaldehyde, to thereby ~~btain the compound shown below.
(Z)-2-(4-Cyclopentyloxy-5-methoxy-2-pyridyl)-3-phenylpropenenitrile (formula (1), wherein R1 - cyclopentyl, RZ -- CH3, R3 - CN, R4 = H, RS - phenyl, and X = O) Melting point: 107-108°C
'H-NhfR(CDC.~ 3) ~ : 1. :~0-2. 30(~~H, m). 3. 96(3H, s), ~. 80-5. 10(lH, m), 7. 26(1H, s), 7. 35-7. 60 (~>H, m) , 7. 80-8. 10 (2H, m) , 8. 15 C 1 H, s) , 8. 32(1H, s).
Example 13 The procedure of Example 1 was repeated through use of 4-cyclopentyloxy-5-methoxl~-2-pyridineacetonitrile (3a) and 2-t:hiophenecarbaldehyde, t:o thereby obtain the compound shown below.
(Z)-2-(4-Cyclopentyloxy-5-methoxy-2-pyridyl)-3-(2-thienyl)propenenitrile (formula (1), wherein R1 -cyclopentyl, Rz = CH3, R' -~ CN, Rq - H, R5 - 2-thienyl, and X
- O) Melting point: 89-90°C
' H-Nl4iR (CDC .~ 3 ) ~ : 1. 60-2. 20 (~~H, m) , 3. 95 ( 3H, s ) , ~. 80-5. 00 ( 1 H, m) , 7. 05-7. 25(lH, m). 7. 19(1H, s), 7. 57(1H, d, J=5. OHz), 7. 72(1H, d, :f=~. OHz), 8. 12(1H, s), 8. ~~(1H, s).
Example 14 The procedure of Example 1 was repeated through use of 5-m~thoxy-4-phenethyloxy-~'.-pyridineacetonitrile (3c) and 3,5-dichloro-4-pyridinecarbaldehyde (Preparation Example 7), to thereby obtain the compound shown below.
( Z ) -3- ( 3, 5-Dichloro-~l-pyridyl ) -2- ( 5-methoxy-4-phenethyloxy-2-pyridyl)propenenitrile (formula (1), wherein R1 -- phenethyl, R' - CH3, R3 - CN, R~ - H, R~' - 3, 5-dichloro-4-pyridyl, and X = O) Melting point: 141.5-142.5°C
'li-NIt-IR(CDC.~ 3) o : 3. 21(2H, t> .1=8. OHz). 4. 00(3H. sO.
4. 34C2H, t, J=8. OHz). 7. 20-7. ~OC6H, m).
8. 16C1H, s). 8. 22C1H, s). 8. 60(2H, s).
Example 15 The procedure of Example 1 was repeated through use of 5-methoxy-4-(3-phenylpropyloxy)-2-pyridineacetonitrile (3d) and 3,5-dichloro-4-pyridinecarbaldehyde (Preparation Example 7), to thereby obtain the compound shown below.
( Z ) -3- ( 3, 5-Dichloro-4-pyridyl ) -2- [ 5-methoxy-4- ( 3-phenylpropyloxy)-2-pyridy=L]propenenitrile (formula (1), wherein R1 - 3-phenylpropyl, Rz = CH=, R3 - CN, Rq - H, R5 -3,5-dichloro-4-pyridyl, and X = 0) Melting point: 101-102°C
'H-N~~(RCCDC.~ 3) ~ : 2. 00-2. 40(2H, m). 2. 86(2H, t. J=8. OHz). 4. 02(3H, s).
4. 15(2H, t, a=8. OHz). 7. 10-7. 40(6H, m). 8. 16(1H, s).
8. 22(1H, s). 8. 60(2H, s).
Example 16 The procedure of Example 1 was repeated through use of 4-butyloxy-5-methoxy-2-py~~idineacetonitrile (3e) and 3,5-dichloro-4-pyridinecarbalc~ehyde (Preparation Example 7), to thereby obtain the compound shown below.
( Z ) -2- ( 4-Butyloxy-5-methoxy-2-pyridyl ) -3- ( 3, 5-dichloro-4-pyridyl)propenenitrile (formula (1), wherein R1 -butyl, R'' - CH3, R3 = CN, Ra - H, R5 - 3, 5-dichloro-4-pyridyl, and X = 0 ) Melting point: 108-109°C
'H-NhiRCCDC.~ 3) o : 1. 00(3H, t, J=7. OHz), 1. 30-2. 10(4H, m), ~. 00(3H, s), 4. 16(2H, t, J=7. OHz), 7. 27(1H, s), 8. 19(1H, s), 8. 21 (1H, s), 8. 61 (2H, s).
Example 17 The procedure of Example 1 was repeated through use of 4-(1-ethylpropyloxy)-5-mei=boxy-2-pyridineacetonitrile (3f) and 3,5-dichloro-4-pyridinecarbaldehyde (Preparation Example 7), to thereby obtain the compound shown below.
( Z ) -3- ( 3, 5-Dichloro-~~-pyridyl ) -2- [ 4- ( 1-ethylpropyloxy)-5-methoxy--2-pyridyl]propenenitrile (formula ( 1 ) , wherein R- - 1-ethyl~~ropyl, RZ = CH3, R3 - CN, Rq - H, R' - 3,5-dichloro-4-pyridyl, and X = 0) Melting point: 127-127.5°C:
'H-N~~1R(CDC.~ 3) o : 1. 00(6H, t, J=7. OHz), 1. 60-2. 00(4H, m), =1. 00C3H, s), ~. 10-~!. 40(1H, m), r. 25(1H, s). 8. 19C1H, s), 8. 22(1H, s).
8. 61 (2H, s).
Example 18 The procedure of Example 1 was repeated through use of 4-cyclopentyloxy-5-ethoxy--2-pyridineacetonitrile (3d) and 3,5-dichloro-4-pyridineca:~baldehyde (Preparation Example 7), to thereby obtain the com~~ound shown below.
(Z)-2-(4-Cyclopentyl~~xy-5-ethoxy-2-pyridyl)-3-(3,5-dichloro-4-pyridyl)propenenitrile (formula (1), wherein R~ -cyclopentyl, R' - C2H5, R3 = CN, Rq - H, RS - 3, 5-dichloro-4-pyridyl, and X = 0) Melting point: 90-91°C
'H-:V~IR(CDC.~ 3) ~ : 1. 46(3H, t. J=7. OHz). 1. 60-2. 20(8H, m).
4. 19(2H, q. J=7. OHz). 4. 80-5. 00(1H, m). 7. 26(1H, s).
8. 18(1H, s). 8. 19(1H, s). 8. 61 C2H. s).
Example 19 The procedure of Example 1 was repeated through use of 4-(2-indanyloxy)-5-methoxy-2-pyridineacetonitrile (3h) and 3,5-dichloro-4-pyridinecarbaldehyde (Preparation Example 7), to thereby obtain the compound shown below.
(Z)-3-(3,5-Dichloro-4-pyridyl)-2-[4-(2-indanyloxy)-5-methoxy-2-pyridyl]propenenitrile (formula (1), wherein R1 -2-indanyl, RZ - CH3, R3 - <:N, Rq - H, RS - 3, 5-dichloro-4-pyridyl, and X = 0) Melting point: 185-185.5°C:
H-N~~(R (CDC .~ ~ ) d : 3. 28 (2H. ~Jd. J=3. 5. 17. OHz) .
3. 51 C2H. ~~d, J=6. 0. 17. OHz). 3. 92C3H, s).
5. 32-5. 3~3 C 1 H, m) . 7. 17-7. 28 CSH, m) . 8. 21 ( 1 H, s ) .
8. 22(1H. :>). 8. 61 (2H, s).
Example 20 The procedure of Example 1 was repeated through use of 5-methoxy-4-(tetrahydro-3--furanyloxy)-2-pyridineacetonitrile (3j) and 3,5-dichloro-4-p~~ridinecarbaldehyde (Preparation Example 7), to thereby obtain the compound shown below.
(Z)-3-(3,5-Dichloro-~~-pyridyl)-2-[5-methoxy-4-(tetrahydro-3-furanyloxy)--2-pyridyl]propenenitrile (formula ( 1 ) , wherein R1 - tetrahydro-3-furanyl, R' - CH3, R3 - CN, Ra - H, RS - 3, 5-dichloro-4-pyridyl, and X = 0) Melting point: 138-140°C
'H-~J~-(RCCDC.~ 3) ~ : 2. 10-2. 50C2I~, m), 3. 80-4. 20(4H, mi. 3. 99C3H, s), 5. 00-5. 20(11, m). 7. 20C1H, s), 8. 21 C1H, s~, 8. 24C1H, s), 8. 61C2H, s).
Example 21 The procedure of Exarlple 1 was repeated through use of 5-methoxy-4-(exo-2-norbornyloxy)-2-pyridineacetonitrile (3i) and 3,5-dichloro-4-pyridinecarbaldehyde (Preparation Example 7), to thereby obtain the compound shown below.
( Z ) -3- ( 3, 5-Dichloro-~l-pyridyl ) -2- [ 5-methoxy-4- ( exo-2-norhornyloxy)-2-pyridyl]propenenitrile (formula (1), wherein Rl -- exo-2-norbornyl, R' - CH3, R3 - CN, R4 - H, R~ - 3, 5-dic:zloro-4-pyridyl, and X = 0) Melting point: 145.5-146. 'i°C
'H-N6fR(CDC.~ 3) o : 1. 10-2. 00(8H, m), 2. 30-2. 70(2H, m), 3. 98C3H, sO
4. 30-4. 50(l~f, m). 7.21C1H, s), 8. 19(2H, s), 8. 61C2H, s).
Example 22 Synthesis of methyl (E)-2-(4-cyclopentyloxy-5-metlzoxy-2-pyridyl) -3- ( 3, 5-~dichloro-4-pyridyl) propenoate ( fo=rmula ( 1 ) , wherein R~ - cyclopentyl, RZ - CH3, R3 - COzCH3, Rq -- H, R5 - 3, 5-dichloro-4-pyridyl, and X = O) Under the same condi~~ions in Example 1 and through use of methyl 4-cyclopentylox~~-5-methoxy-2-pyridineacetate (3k) and 3,5-dichloro-4-pyridinecarbaldehyde (Preparation Example 7) in methanol containing a CH30Na-CH30H solution (1 M), the title compound was prepared.
Melting point: 119-120°C
'H-N~~1RCCDC.~ 3) ~ : 1. 55-1. 90C8H, m>, 3. 86C3H, s), 3. 91C3H, s), 4. 56-4. 60(1H, m), 6. 70(1H, s), 7. 57(1N, s), 7. 94(1H, s), 8. 40C2H, s).
Example 23 Synthesis of (Z)-3-(4-cyclopentyloxy-5-methoxy-2-pyridyl)-2-(3-pyridyl)propenenitrile (formula (1), wherein R1 -- cyclopentyl, Rz - CH3, R3 - H, Rq - CN, R' - 3-pyridyl, and X = 0 ) 4-Cyclopentyloxy-5-mE=_thoxy-2-pyridinecarbaldehyde (4.42 g, 20 mmol) and 3-p~lridineacetonitrile (2.36 g, 20 mmol) were dissolved in methanol (60 ml). While the solution was stirred at 5"C, a CH30Na-CH30H solution (1 M, 23 ml) was added dropwise. The mixture was stirred for 30 additional minutes under l.he same condition. The reaction mixture was poured into cold water and extracted with chloroform. The organic layer was dried and then concentrated under reduce<~ pressure. The residue was chromatographed on silica gel, to thereby obtain the title compound (4.54 g, yield 7_L°) from a lg (v/v) methanol-chloroform-eluted fraction.
Melting point: 119-119.5°C'.
H-NIdR CCDC .~ a ) o : 1. 60-2. 20 CBH, m) . 4. 00 (3H, s ) . 4. 92-'' . 98 C
1 H, m) , 7..-"tlClH. dd~ J=5. 0, 7. OHZ), 7. 6=~C1H, s). 7. r~(1_ia. s).
7. 98-8. 03(1H, m). 8. 26C1H. s).
8. 6~C1H, dd, J=1. 5, S. OHz). 8. 97(1H, d. J=2. 0Hz).
Example 24 The procedure of Example 23 was repeated through use of 4-cyclopentyloxy-5-methoxy-2-pyridinecarbaldehyde and 2-thiopheneacetonitrile, to thereby obtain the compound shown below.
(Z)-3-(4-Cyclopentyloxy-5-methoxy-2-pyridyl)-2-(2-thienyl)propenenitrile (formula (1), wherein Rl -cyclopentyl, Rz - CHI, R3 -- H, R~ - CN, RS - 2-thienyl, and X
- O) .
Melting point: 101-102°C
'H-Nh(RCGDC.~ 3) o : 1. 60-2. 15C8fi. m). 3. 98C3H, s); 4. 92-4. 98C1N, m).
7. 08C1H, dd, .1=a. 0. 5. OHz), 7. 33CiH. dd, .~=1. 0, 5. OHz), 7. ~3C1H, s). 7. =!='.C1H, dd, J=1. 0. 4. OHz).
7. 62(1H. s). 8. 22(1H, s).
Exa:~ple 25 The procedure of Example 23 was repeated through use of 4-cyclopentyloxy-5-methoxy-2-pyridinecarbaldehyde and phenylacetonitrile, to thereby obtain the compound shown belsw.

(Z)-3-(4-Cyclopentyloxy-5-methoxy-2-pyridyl)-2-phenylpropenenitrile (formula (1), wherein R1 - cyclopentyl, R'' -- CH3, R3 - H, Rq - CN, R' - phenyl, and X = 0) .
Melting point: 91-91.5°C
'H-N~dR(CDC~ 3) ~ : 1. 60-2. 20(8H, m), 3. 99(3H. s). 4. 92-~. 98(1H, m).
7. 38- 7. =~9 C3N, m) , 7. 62 C 1 H, s) , 7. 70-7. 75 C2H, m) .
7. 77(1H, s). 8. 23(1H, s).
Example 26 The procedure of Example 1 was repeated through use of 5-methoxy-4-methoxymethyloxy-2-pyridineacetonitrile (3g) and 3,5-dichloro-4-pyridinecarbaldehyde (Preparation Example 7), to thereby obtain the compound shown below.
(Z)-3-(3,5-Dichloro-4-pyridyl)-2-(5-methoxy-4-methoxymethyloxy-2-pyridy-L)propenenitrile (formula (1), wherein R1 - CHZOCH3, R' - CH3, R3 - CN, R~ - H, RS - 3, 5-dichloro-4-pyridyl, and X = 0).
Melting point: 140-141°C
'H-NI~fR(CDC.~ ~) ~ : 3. 5.~C3H. s). ~. 03C3H, s). 5. 38C2H, s). 7. 54C1H, s), 8. 14(1H, s), 8. 28(1H, s). 8. 61(2H, s).
Example 27 Synthesis of (Z) -3-~ (3, 5-dichloro-4-pyridyl) -2- (4-hydroxy-5-methoxy-2-pyridyl)propenenitrile (formula (1), wherein R1 - H, RZ - CH3, R3 = CN, R~ - H, R' - 3, 5-dichloro-4-pyridyl, and X = 0):
In 8 ml of dichloromethane, was dissolved (Z)-3-(3,5-dichloro-4-pyridyl)-2-(5-methoxy-4-methoxymethyloxy-2-pyridyl ) propenenitrile ( formula ( 1 ) , wherein R' = CH20CH3, RZ
- CH3, R3 = CN, R4 = H, RS = 3, 5-dichloro-4-pyridyl, and X =
0) (0.73 g, 2 mmol). While the solution was stirred at 0°C, trifluoroacetic acid (2 ml) was added. The mixture was stirred for additional two hours. The reaction mixture was evaporated to dryness. The residue was dissolved through addition of water, and the pH of the solution was adjusted to about 6 through addition of an aqueous saturated sodium hydrogencarbonate solution. Precipitated crystals were collected by filtration, washed with water, and recrystallized from ethanol, to thereby obtain the title compound (0.56 g, yield 88~).
Melting point: 218-219.5°C
'H-~lIfRCD~~SO-dB) o : 3. 94C3H. s). r. 33C1H. s). 8. 19C1H. s). o. 29C1H. s).
8. 81 C2H. s).
Example 28 Synthesis of (Z) -3- (3, 5-dichloro-4-pyridyl) -2- [4- (3-hydroxypropyloxy)-5-methoxy-2-pyridyl]propenenitrile (formula (1), wherein R1 = (CHZ)30H, RZ = CH3, R3 = CN, R4 = H, RS = 3, 5-dichloro-4-pyridyl, and X = 0) In 4 ml of dimethylformamide, was dissolved (Z)-3-(3,5-dichloro-4-pyridyl)'-2-(4-hydroxy-5-methoxy-2-pyridyl) propenenitrile ( formula ( 1 ) , wherein R1 = H, RZ = CH3, R3 = CN, R" - H, R5 = 3, 5-dichloro-4-pyridyl, and X = 0) (400 mg, 1.24 mmol). To the solution were added 3-bromopropanol (0.132 ml, 1.48 mmol) and potassium carbonate (204 mg, 1.48 mmol). The mixture was stirred on a 60°C oil bath for three hours. After being cooled., the reaction mixture was poured into cold water and extracted with in ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Crystals obtained from the lv hexane-ethyl acetate (1 . 1)-eluted friction were recrystallized from hexane-diethyl ether, to thereby obtain the title compound (360 mg, yield 76%).
Melting point: i11-113°C
' H-od~fRCCDC .~ 3) o : 1. 91C1H. t. J=5. OHz). 2. 12-2. 20(2H. m).
3. 87-3. °2C2H. m), =~. OOC3H, s). s. 33C2H, t, J=6. C~~z).
7. 30C1H. s). 8. 18C1H. s). 8. 22(1H. s). 3. 61C2H. s).
Example 29 The procedure of Example 1 was repeated through use of 4-cyclopentylthio-5-met:hoxy-2-pyridineacetonitrile (l0a) and 3,5-dichloro-4-pyridinecarbaldehyde (Preparation Example 7), to thereby obtain the compound shown below.
(Z)-2-(4-Cyclopentylthio-5-methoxy-2-pyridyl)-3-(3,5-dic:zloro-4-pyridyl)propenenitrile (formula (1), wherein R1 -cyc Lopentyl, R' - CH3, R3 - CN, R4 - H, RS - 3, 5-dichloro-4-pyridyl, and X = S).
Melting point: 147-148°C

'H-NI~IRCCDC.~ 3) d : 1. 50-2. ~0C8H. m), 3. 60-3. 95C1H. m), 4. 04C3H. s).
7. 59(1H, s), 8. 14(1H, s), 8. 18C1H, s), 8. 61C2H, s).
Example 30 The procedure of Example 23 was repeated through use of 4-cyclopentyloxy-5-met:hoxy-2-pyridinecarbaldehyde and 3,5-dichloro-4-pyridineacetonitrile, to thereby obtain the compound shown below.
(Z)-3-(4-Cyclopentyloxy-5-methoxy-2-pyridyl)-2-(3,5-dichloro-4-pyridyl ) propenenitrile ( formula ( 1 ) , wherein R' -cyclopentyl, R' - CH3, R3 -- H, Ra - CN, RS - 3, 5-dichloro-4-pyridyl, and X = 0) .
Melting point: 140.5-142°<:
lIi-N~4RCCDC.~ 3) ~ : 1. 50-2. 00(8H, m), 3. 88C3H, s). 4. 50-4. 70(1H, m), 6. 68C1H, s), 7. 51C1H, s). 7. 89C1H, s), 8.57C2H, s).
Example 31 Synthesis of (E)-2--(4-cyclopentyloxy-5-methoxy-2-pyridyl)-3-(3,5-dichloro-4-pyridyl)propenoic acid (formula ( 1 ) , wherein R1 = cyclopentyl, R' - CH3, R3 - CO~H, R~ - H, R5 - 3,5-dichloro-4-pyridyl, and X = O):
Methyl (E)-2-(4-cyclopentyloxy-5-methoxy-2-pyridyl)-3-(3,5-dichloro-4-pyridyl)propenoate (formula (1), wherein R1 - cyclopentyl, R' - CH3, R3 - CO~CH;, Ra - H, RS - 3, 5-dichloro-4-pyridyl, and X = 0) (423 mg, 1 mmol) was dissolved in methanol (4 nl). A 1N aqueous NaOH solution (2 ml) was added to the solution. The mixture was stirred for twc hours at room temperature and the reaction mixture was poured into a 5% aqueous ammonium chloride solution.
Precipitated crystals were collected by filtration, washed, and recrystallized from ethanol, to thereby obtain the title compound (240 mg, yield 59° ) .
Melting point: 178-180°C ;decomposition) 'H-I~~~9RCCDC.~ 3) ~ : 1. 40-2. 00(8H, m), 3. 77C3H, s). 4. 58-4. 80(1H, m), 6. 78C1H, s). 7. 50(1H, s). 7. 94C1H, s). 8. 56C2H. s).
Example 32 The procedure of Example 1 was repeated through use of 4-cyclopentyloxy-5-met:hoxy-2-pyridineacetonitrile (3a) and 3-nitrobenzaldehyde, to thereby obtain the compound shown below.
( Z ) -2- ( 4-Cyclopentyloxy-5-methoxy-2-pyridyl ) -3- ( 3-nitrophenyl)propenenitrile (formula (1), wherein R1 -cyclopentyl, Rz - CH3, R~ -- CN, R~ - H, R' - 3-nitrophenyl, and X = 0 ) .
Melting point: 126-127°C
'H-N~~1RCCDC.~ 3) ~ : 1. 50-2. 20(81-1, m), 3. 98C3H, s), 4. 82-5. 10(1H, m), 7. 28C1H, s), 7. 67C1H, t. J=8. OHz~, 8. 16(1H, s), 8. 20-8. 40 C3 H, m) , 8. 60-8. 70 ( 1 H, m) .
Example 33 The procedure of E~>ample 1 was repeated through use of 4-cyclopentyloxy-5-met:hoxy-2-pyridineacetonitrile (3a) and 3-fluoro-4-pyridinecarbaldehyde (Preparation Example 12), to thereby obtain the compound shown below.
(Z)-2-(4-Cyclopentyloxy-5-methoxy-2-pyridyl)-3-(3-fluoro-4-pyridyl)propenen.itrile (formula (1), wherein Ri -cyclopentyl, RZ - CH3, R3 -- CN, RQ - H, R' - 3-fluoro-4-pyridyl, and X = 0).
Melting point: 120-121°C
'H-N~dR(CDC.~ 3) o : 1. 60-2. 15(8H, m). 3. 98C3H, s), 4. 92-4. 97(1H. m).
7. 28(1H, s), 8. 10(1H, t, J=6. OHz), 8. 18(1N, s), 8. 47C1H, s), 8. 56C1H, d, J=5Hz), 8. 60C1H, d, J=2Hz).
Example 34 The procedure of E~;ample 1 was repeated through use of 4-(2-indanyloxy)-5-metlzoxy-2-pyridineacetonitrile (3h) and methyl 4-formyl-2-picolinate, to thereby obtain the compound shown below.
( Z ) -2- [ 4- ( 2-Indanyl_oxy-5-methoxy-2-pyridyl ] -3- ( 2-methoxycarbonyl-4-pyridyl)propenenitrile (formula (1), wherein R1 - 2-indanyl, R~ - CH3, R3 - CN, Rq - H, RS - 2-methoxycarbonyl-4-pyridyl, and X = O).
Melting point: 177-179°C
'H-N~dRCCDC.~ 3) ~ : 3. 14-3. 85C4H, m), 3. 93(3H, s), 4. 05C3H, s), 5. 29-5. 36(:lH, m), 7. 24-7. 37(5H, m), 8. Ol-8. 09(1H, m).
8. 18(1~~, s), 8. 35~1H, s), 8. 47(1H, s), 8. 89(1H, d, J=5. OHz).
Example 35 The procedure of E~;ample 1 was repeated through use of 4-(2-indanyloxy)-5-methoxy-2-pyridineacetonitrile (3h) and 4-pyridinecarbaldehyde, to thereby obtain the compound shown below.
( Z ) -2- [ 4- ( 2-Indany:Loxy) -5-methoxy-2-pyridyl ] -3- ( 4-pyridyl)propenenitrile (formula (1), wherein Rl - 2-indanyl, RZ - CH3, R3 - CN, R4 - H, R5 - 4-pyr idyl, and X = 0) .
Melting point: 205-206°C
' H-N~iR (CDC .~ 3 ) d : 3. 15-3. 75 C 4H, m) , 3. 92 C3H, s ) . 5. 20-5. 50 C
1 H, m) .
7. 2~(4H, s). 7. 36C1H, s). 7. 75C2H. d, J=7. OHz).
8. 17(1H, s). 8. 28C1H, s). 8. 78C2H, d. J=7. OHz).
Example 36 The procedure of Example 1 was repeated through use of 4-(2-indanyloxy)-5-methoxy-2-pyridineacetonitrile (3h) and 4-pyridinecarbaldehyde N-oxide, to thereby obtain the compound shown below.
4- [ ( Z ) -2-Cyano-2- ( ~~- ( 2-indanyloxy) -5-methoxy-2-pyridyl)-1-ethenyl]pyridine N-oxide (formula (1), wherein R' - 2-indanyl, Rz = CH3, R~ ~- CN, Ra - H, RS - 1-oxo-4-pyridyl, and X = 0 ) .
Melting point: 231-232°C
' H-NMR CCDC .~ s ) ~ : 3. 15-3. 72 (4H, m) . 3. 92 (3H, s ) , 5. 20-5. 45 ( 1 H, m) , 7. 2=~C4H, s), 7. 33C1H. s), 7. 85(2H, d, J=7. OHz), 8. 10-8. 30 ( ~H, m) .
Example 37 The procedure of Example 1 was repeated through use of 4-(2-indanyloxy)-5-methoxy-2-pyridineacetonitrile (3h) and 3,5-dichloro-4-pyridinecarbaldehyde N-oxide (Preparation Example 13), to thereby obtain the compound shown below.
4-[(Z)-2-Cyano-2-(4-(2-indanyloxy)-5-methoxy-2-pyridyl)-1-ethenyl]-3,5-dichloropyridine N-oxide (formula ( 1 ) , wherein R1 = 2-indanyl, R2 - CH,3, R3 - CN, R~ - H, RS -3,5-dichloro-1-oxo-4-pyridyl, and X = 0).
Melting point: 229-230°C
' H-N~~fRCCDC .C 3) o : 3. 10-3. 72(.4H, m). 3. 93C3H, s), 5. 20-5. 43C1H. m).
7. 23C5H. s;, 8. 13(1H, s). 8. 20(1H, s), 8. 26(2H, s).
Example 38 Synthesis of (Z)-3--(3-carboxyphenyl)-2-(4-cyclopentyloxy-5-methoxy-2-pyridyl)propenenitrile (formula (1) , wherein R1 - cyclopentyl, R' - CH3, R3 - CN, R~ - H, R5 -3-carboxyphenyl, and X = O):
4-Cyclopentyloxy-5--methoxy-2-pyridineacetonitrile (3a) (4.64 g, 20 mmol) and 3-formylbenzoic acid (3.00 g, 20 mmol) were dissolved in methanol (60 ml). While the solution was stirred at 5°C, 1 M aqueous CH30Na-CH30H
solution (46 ml) was added dropwise. The reaction mixture was stirred for 30 minute: under the same conditions and was poured into a 5% aqueous ammonium chloride solution.
Precipitated crystals were collected by filtration, washed, and recrystallized from ei=hanol, to thereby obtain the title compound (4.00 g, yield 550).
Melting point: 253-254°C

' H-N~1R (Dh~(SO-d s ) ~ : 1. 50-2. 20 (8H, m) . 3. 90 (3H, s ) , 4. 98-5. 20 ( 1 H, m) , 7. 49(1H, s). 7. 67(1H, t, J=7. 5Hz), 8. 00-8. 30(2H, m), 8. 25(1H, s). 8. 35(1H, s). 8. 56(1H, s).
Example 39 The procedure of Example 23 was repeated through use of 4-cyclopentyloxy-5-met:hoxy-2-pyridinecarbaldehyde and methyl 3-cyanomethylbenzoate, to thereby obtain the compound shown below.
(Z)-3-(4-Cyclopentyloxy-5-methoxy-2-pyridyl)-2-(3-methoxycarbonylphenyl)propenenitrile (formula (1), wherein R1 - cyclopentyl, RZ - CH3,. R3 - H, R~ - CN, RS - 3-methoxycarbonylphenyl, and X =
Melting point: 116-117°C
'H-N6-1R(CDC.~ 3) d : 1. 55-2. 30(8H, m), 3. 96(3H, s). 4. 00C3H, s), 4. 80-5. 10(:[H, m), 7. 42-8. 50(7H, m).
Example 40 The procedure of Example 23 was repeated through use of 4-(2-indanyloxy)-5-methoxy-2-pyridinecarbaldehyde (Preparation Example 14) and methyl 3-cyanomethylbenzoate, to thereby obtain the compound shown below.
( Z ) -3- [ 4- ( 2-Indanyloxy) -5-methoxy-2-pyridyl ] -2- ( 3-methoxycarbonylphenyl)propenenitrile (formula (1), wherein R1 - 2-indanyl, R' - CH3, F;j - H, R~ - CN, R' - 3-methoxycarbonylphenyl, and X = 0).
Melting point: 183-184°C

'H-N~-[RCDM1S0-ds) ~ : 3. 10-3. 70C4H, m). 3. 94C3H, s), 3. 96(3H, s).
5. 20-5. 40C1H, m). 7. 23C4H, s), 7. 40-8. 40C7H, m) Example 41 The procedure of Example 23 was repeated through use of 4-(2-indanyloxy)-5-metaoxy-2-pyridinecarbaldehyde (Preparation Example 14) and 4-pyridineacetonitrile, to thereby obtain the compound shown below.
(Z)-3-[4-(2-Indanyloxy)-5-methoxy-2-pyridyl]-2-(4-pyridyl)propenenitrile (formula (1), wherein R1 - 2-indanyl, R2 - CH3, R3 - H, R9 - CN, RS - 4-pyridyl, and X = O) .
Melting point: 195-197°C
'H-N~1R(CDC.~ 3) ~ : 3. 10-3. 75(4H. m), 3. 96(3H, s). 5. 20-5. 45(1H. m).
7. 23C4H, s). 7. 62(2H, d, J=6. OHz), 7. 82(1H, s).
7. 87(1H, s). 8. 29(1H, s), 8. 73(2H, d. J=6. OHz).
Example 42 The procedure of Example 28 was repeated through use of (Z)-3-(3,5-dichloro-4-pyridyl)-2-(4-hydroxy-5-methoxy-2-pyridyl ) propenenitrile ( formula ( 1 ) , wherein R1 - H, R' - CH3, R3 - CN, Rq - H, RS - 3, 5-dichloro-4-pyridyl, and X = O) and methyl bromoacetate, to thereby obtain the compound shown below.
(Z)-3-(3,5-Dichloro-4-pyridyl)-2-(5-methoxy-4-methoxycarbonylmethyloxy-2.-pyridyl)propenenitrile (formula ( 1 ) , wherein R1 - CH~COZCH3, R- - CH;, R' - CN, Ra - H, RS -3,5-dichloro-4-pyridyl., and X = 0).
Melting point: 131-132°C
'H-N~~R(CDC,~ ~) o : 3. 85(3H, s). 4. 04(3H, s); 4. 84(2H, s), 7. 14(1H, s), 8. 19(1H, s). 8. 27(1H, s), 8. 61 (2H, s).
Example 43 The procedure of Example 28 was repeated through use of (Z)-3-(3,5-dichloro-4-:pyridyl)-2-(4-hydroxy-5-methoxy-2-pyridyl ) propenenitrile ( formula ( 1 ) , wherein R1 - H, R' = CH3, R3 - CN, R9 - H, RS - 3, 5-dichloro-4-pyridyl, and X = 0) and 2-bromoethanol, to thereby obtain the compound shown below.
( Z ) -3- ( 3, 5-Dichloro-4-pyridyl ) -2- [ 4- ( 2-hydroxyethyloxy)-5-methoxy-2-pyridyl)propenenitrile (formula ( 1 ) , wherein R1 - (CHI ) 20H,, R' - CH3, R3 - CN, R~ - H, R5 -3, 5-dichloro-4-pyridyl, a:nd X = 0) .
Melting point: 159-160°C
'N-N~IR(CDC.~ 3) ~ : 2. 24(1H, t. J°=6. OHz). 4. O1(3H, s). 4. 04-4.
08(2H, m).
4. 27(2H, t, J~=4. OHz), 7. 29(1H, s>> 8. 19(1H, s), 8. 24(1H, s), 8. 61 (2H, s).
Example 44 The procedure of E~:ample 28 was repeated through use of ( Z ) -3- ( 3, 5-dichloro-4-pyridyl ) -2- ( 4-hydroxy-5-methoxy-2-pyridyl ) propenenitrile ( formula ( 1 ) , wherein R1 - H, Rz - CH ~, R3 - CN, Ra - H, R5 - 3, 5-dichloro-4-pyridyl, and X = 0) and 4-bromobutanol, to thereb:~ obtain the compound shown below.
( Z ) -3- ( 3, 5-Dich:loro-4-pyridyl ) -2- [ 4- ( 4-hydroxybutyloxy)-5-methoxy-2-pyridyl)propenenitrile (formula ( 1 ) , wherein R1 = ( CHI ) OOH, R' - CH3, R3 - CN, R~ - H, RS -3,5-dichloro-4-pyridyl, and X = 0).
Melting point: 120.5-122°C:
'N-N~4RCCDC.~ 3) ~ : 1. 74-1. 82<3H, m), 1. 99-2. 05(2H, m), 3. 75(2H, m?, 4. 00(3H, s). 4. 21 (2H. t, J=6. OHZ).
7.27(1H, s;~, 8. 19C1H, s), 8.21(1H, s), 8. 61C2H, s).
Example 45 The procedure of Example 28 was repeated through use of (Z)-3-(3,5-dichloro-4-pyridyl)-2-(4-hydroxy-5-methoxy-2-pyridyl ) propenenitrile ( formula ( 1 ) , wherein R1 - H, R' - CH,;, R3 - CN, R4 - H, Ry - 3, 5-~~ichloro-4-pyridyl, and X = 0) and 5-bromopentanol, to there:oy obtain the compound shown below.
(Z)-3-(3,5-Dichloro-4-pyridyl)-2-[4-(5-hydroxypentyloxy)-5-metho:xy-2-pyridyl)propenenitrile ( formula ( 1 ) , wherein R1 -- (CHI ) SOH, RZ = CHz, R3 - CN, R4 - H, RS - 3, 5-dichloro-4-pyridyl, and X = O) .
Melting point: 86-87°C
'H-NM(R(CDC.~ 3) o : 1. 35(1H, m>, 1. 58-1. 70(4H, m). 1. 93-1. 97C2H, m).
3. 71 C2H, m;>, 4. 00(3H, s), 4. 16C2H, t. J=6. OHZ).
7.26(1H, s), 8. 19(1H, s). 8. 21C1H, s). 8. 61(2H, s).
Example 46 Synthesis of (Z)-3-(3,5-dichloro-4-pyridyl)-2-[5-metboxy-4-(3,4-methylenedioxyphenylmethyloxy)-2-pyridyl]propenenitrile (formula (1), wherein Rl - 3,4-met:hylenedioxyphenylmethyl, R' - CH_3, R~' - CN, Ra - H, RS -3,5-dichloro-4-pyridyl, and X = 0):
(Z)-3-(3,5-Dichloro-4-pyridyl)-2-(4-hydroxy-5-methoxy-2-pyridyl ) propenenitrile ( formula ( 1 ) , wherein R1 - H, R' -CH3, R3 - CN, Ra - H, R5 - 3, 5-dichloro-4-pyridyl, and X = 0) (0.97 g, 3.0 mmol), 3,4-methylenedioxyphenylmethanol (0.50 g, 3.3 mmol), and triphenylphosphine (1.18 g, 4.5 mmol) were dissolved in tetrahydrofuran (100 ml). While the solution was stirred at room temperature, diethyl azodicarboxylate (0.78 g, 4.5 mmol) was added dropwise. The reaction mixture was stirred for four hours at room temperature and then water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried, and then concentrated under reduced pressure. (;rystals precipitated from the residue were recrystallized from an isopropyl ether-ethanol, to thereby obtain the title compound (1.01 g, yield 74~).
Melting point: 182-183°C
'H-N~~(RCCDC.~ 3) ~ : 4. 00C3H, s;, 5. 15C2H, s), 5. 98(2H, s), 6. 80-7. OOc;3H, m), 7. 36(1H, s), 8. 16(1H, s), 8.23(1H, s;~, 8. 61(2H, s).
Example 47 The procedure of Example 46 was repeated through use of (Z)-3-(3,5-dichloro-4-pyridyl)-2-(4-hydroxy-5-methoxy-2-pyridyl) propenenitrile ( f srmula ( 1 ) , wherein R1 - H, R- - CH;, R3 -- CN, Rq - H, RS - 3, 5-dichloro-4-pyridyl, and X = Oj and 4,5-dimethoxy-2-pyridinemethanol, to thereby obtain the compound shown below.
(Z)-3-(3,5-Dichloro-4-pyridyl)-2-[4-(4,5-dimethoxy-2-pyridylmethyloxy)-5-metho:xy-2-pyridyl]propenenitrile ( formula ( 1 ) , wherein R1 -- 4, 5-dimethoxy-2-pyridylmethyl, R' - CH3, R~ - CN, R~ - H, R~ - 3, 5-dichloro-4-pyridyl, and X =
0) .
Melting point: 146.5-147..5°C
'H-N~~fRCCDC.~ 3) ~ : 3. 94(31f, s), 3. 96C3H, s), 4. 03C3H, s). 5.31C2H, s).
7. 07(1H, s), 7. 52(1H, s). 8. 09(1H, s). 8. 14C1H. s).
8. 24(111, s). 8. 60(2H, s).
Example 48 The procedure of Example 46 was repeated through use of ( Z ) -3- ( 3, 5-dichloro-4-pyridyl ) -2- ( 4-hydroxy-5-methoxy-2-pyridyl ) propenenitrile ( formula ( 1 ) , wherein R1 - H, R' - CH;, R3 -- CN, R9 - H, R5 - 3, 5-dichloro-4-pyridyl, and X = 0) and cyclopropanemethanol, to i~hereby obtain the compound shown below.
(Z)-2-(4-Cyclopropylmethyloxy-5-methoxy-2-pyridyl)-3-(3,5-dichloro-4-pyridyl)propenenitrile (formula (1), wherein Rl -- cyclopropylmethyl, R' - CHI, R3 - CN, R~ - H, RJ - 3, 5-dichloro-4-pyridyl, and X = 0).
Melting point: 118-119°C
'H-N~1RCCDC.~ 3) ~ : 0. 44C21~, m), 0. 72(2H, m), 1. 36(1H. m).
3. 99C2H, d, .I=7. 5Hz), 4. 02(3H, s), 7. 23C1H, s).
8. 19(1H, s). 8.23(1H, s). 8. 61C2H, s).

Example 49 The procedure of Example 46 was repeated through use of (Z)-3-(3,5-dichloro-4-pyridyl)-2-(4-hydroxy-5-methoxy-2-pyridyl)propenenitrile (formula (1), wherein R1 - H, R' - CH3, R3 - CN, R~ - H, RS - 3, 5-dichloro-4-pyridyl, and X = 0) and 2-pyridineethanol, to thereby obtain the compound shown below.
(Z)-3-(3,5-Dichloro-4-pyridyl)-2-[5-methoxy-4-(2-(2-pyridyl)ethyloxy)-2-pyridyl]propenenitrile (formula (1), wherein R1 = 2- (2-pyridyl ) ethyl, R~ - CH3, R3 - CN, R~ - H, R
- 3,5-dichloro-4-pyridyl, and X = O).
Melting point: 134-135°C
'H-N~~1RCCDC.~ 3) ~ : 3. 38C2H. t, J=~. OHz). 3. 96(3H, s), 4. 58(2H, t, J=7. OHz), 7. 00-7. 30C2H, m), 7. 32C1H, s), 7. 65(1H, m), 8. 15(1H, s), 8. 21(1H, s), 8. 55C1H, m), 8. 61 C2H, s) .
Example 50 The procedure of Example 46 was repeated through use of (Z)-3-(3,5-dichloro-4-pyridyl)-2-(4-hydroxy-5-methoxy-2-pyridyl ) propenenitrile ( formula ( 1 ) , wherein R1 - H, R' - CH3, R3 - CN, R4 - H, RS - 3, 5-dichloro-4-pyridyl, and X = 0) and 4-methyl-5-thiazoleethanol, to thereby obtain the compound shown below.
(Z)-3-(3,5-Dichloro-4-pyridyl)-2-[5-methoxy-4-(2-(4-methyl-5-thiazolyl)ethyloxy)-2-pyridyl]propenenitrile ( formula ( 1 ) , wherein R' -- 2- ( 4-methyl-5-thiazolyl ) ethyl, R-- CH3, R3 - CN, Ra - H, RS - 3, 5-dichloro-4-pyridyl, and X =
0) .
Melting point: 136-137°C
'H-N~~R(CDC.~ 3) o : 2. 48C3H, s), 3. 36C2H, t, J=7. OHz), ~. OOC3H, s), 4. 31 C2H. t, J=7. OHz). 7. 22(1H, s), 8. 18(1H, s).
8.23(1H, si. 8. 61C2H, s). 8. 61(1H, s).
Example 51 The procedure of Example 46 was repeated through use of (Z)-3-(3,5-dichloro-4-pyridyl)-2-(4-hydroxy-5-methoxy-2-pyridyl ) propenenitrile ( formula ( 1 ) , wherein R1 - H, R' - CH;, R3 - CN, R9 - H, R5 - 3, 5-dichloro-4-pyridyl, and X = 0) and N-hydroxyethyl-2-pyridone (Preparation Example 15), to thereby obtain the compound shown below.
(Z)-3-(3,5-Dichloro-4-pyridyl)-2-[5-methoxy-4-(2-(2-pyridon-1-yl)ethyloxy)-2-;oyridyl]propenenitrile (formula (1), wherein R' - 2- (2-pyridon--1-yl) ethyl, R' - CH,, R3 - CN, Ra -H, RS - 3, 5-dichloro-4-pyridyl, and X = 0) .
Melting point: 142-143°C
' H-N~dR(CDC.~ 3) o : 3. 97(3H, s), 4. 41 C2H, t, J=5. OHz), 4. 48C2H, t, J=5. OHz), 6. 17-6. 22C1H, m), 6. 58(1H, d, J=10. OHz), 7. 26C1H, s), 7. 32-7. ~OC1H, m), 7. 45(1H, dd, J=2. 0, 7. OHz), 8. 10<,1H, s), 8. 22(1H, s).
8. 60C2H, s).
Example 52 The procedure of Example 46 was repeated through use of (Z)-3-(3,5-dichloro-4-pyridyl)-2-(4-hydroxy-5-methoxy-2-pyridyl ) propenenitrile ( f~~rmula ( 1 ) , wherein R1 - H, R' - CH3, R3 = CN, R4 - H, R5 - 3, 5-c~ichloro-4-pyridyl, and X = 0) and 3-~~yridinepropanol, to thereby obtain the compound shown below.
(Z)-3-(3,5-Dichloro-4-pyridyl)-2-[5-methoxy-4-(3-(3-pyridyl)propyloxy)-2-pyridyl]propenenitrile (formula (1), whe rein R1 - 3- ( 3-pyridyl ) propyl, R' - CH3, R3 - CN, R4 - H, R5 - 3, 5-dichloro-4-pyrid~~l, and X = 0) .
Melting point: 91-93°C
'H-Nh~R(D~~fSO-ds) o : 2. 12(2H, m), 2. 79C2H, t, J=6. SHz~. 3. 95(3H, s).
4. 21 (2H, t, J=6. 5Hz), 7. 30(1H, m), 7. 56(1H, s), 7. 67(1H, m~, 8. 28C1H, s), 8. 33(1H, s), 8. ~7C2H, m).
8. 82(2H, s).
Example 53 The procedure of Example 45 was repeated through use of (Z)-3-(3,5-dichloro-4-hyridyl)-2-(4-hydroxy-5-methoxy-2-pyridyl) propenenitrile ( formula ( 1 ) , wherein R1 - H, Rz - CH3, R3 -- CN, Ra - H, RS - 3, 5-<~ichloro-4-pyridyl, and X = 0) and 4-pyridinepropanol, to thereby obtain the compound shown below.
(Z)-3-(3,5-Dichloro-4-pyridyl)-2-[5-methoxy-4-(3-(4-pyridyl)propyloxy)-2-pyridyl]propenenitrile (formula (1), wherein R1 - 3- ( 4-pyridyl ) propyl, R' - CH3, R3 - CN, Ra - H, R5 -- 3, 5-dichloro-4-pyridy 1, and X = 0) .

Melting point: 124-125°C
' H-N~dR(CDC .~ 3) ~ : 2. 25C2H. m;~, 2. 87(2H, m), 4. Ol (3H, s), 4. 16(2H, t, J=6. OHz), 7. 17(2H, d, J=6. OHz), 7. 22C1H, s).
8. 19(1H, s;~, 8. 23(1H, s), 8. 50(2H, d, J=6. OHz), 8. 61 (2H. s;'.
Example 54 The procedure of Example 46 was repeated through use of (Z)-3-(3,5-dichloro-4-oyridyl)-2-(4-hydroxy-5-methoxy-2-pyridyl ) propenenitrile ( f~~rmula ( 1 ) , wherein R1 - H, R' - CH_j, R' - CN, Ra - H, Ry - 3, 5-c~ichloro-4-pyridyl, and X = 0) and N-r.ydroxyethylmorpholine, to thereby obtain the compound shown below.
(Z)-3-(3,5-Dichloro-4-pyridyl)-2-[5-methoxy-4-(2-(N-morpholino)ethyloxy)-2-pyridyl]propenenitrile (formula (1), whE:rein R1 - 2- (N-morpholino) ethyl, R' - CH3, R3 - CN, R~ - H, R5 - 3, 5-dichloro-4-pyrid5~l, and X = 0) .
Melting point: 130-131°C
'H--N~1R(CDC.~ 3) d : 2. 50-2. 70(~H, m). 2. 89(2H, t. J=6. OHz), 3. 60-3. 82C4H, m). 4. 00(3H, s), ~. 28C2H, t, J=6. OHz), 7. 29(1H, s), 8. 19(1H, s). 8. 22(1H, s). 8. 61 C2H, s).
Example 55 The procedure of Example 46 was repeated through use of (Z)-3-(3,5-dichloro-4-pyridyl)-2-(4-hydroxy-5-methoxy-2-pyridyl ) propenenitrile ( formula ( 1 ) , wherein R~ - H, R'' - CH,"
R3 - CN, R~ - H, R5 - 3, 5-c3ichloro-4-pyridyl, and X = O) and 1,~'~-bis(BOC-amino)-2-propanol, to thereby obtain the compound shown below.
(Z)-2-[4-(1,3-bis(BOC-amino)-2-propyloxy)-5-methoxy-2-pyridyl]-3-(3,5-dichloro-4-pyridyl)propenenitrile (formula ( 1 ) , wherein R1 - 1, 3-bis (BOC-amino ) -2-propyl, R~ - CH3, R3 -CN, Ra - H, RS - 3, 5-dichloro-4-pyridyl, and X = O) .
Melting point: 181-181.5°C:
':-I-N~iR(CDC~ 3) o : 1. 43C18H, s), 3. 23(2H, m), 3. 66C2H, m), 3. 99C3H, s), 4. 54(1H, m), 5. 21 C2H, m), 7. 93C1H, s), 8. 16C1H, s), 8. 25(1H, s), 8. 60C2H, s).
Example 56 The procedure of Example 46 was repeated through use of ( Z ) -3- ( 3, 5-dichloro-4-pyridyl ) -2- ( 4-hydroxy-5-methoxy-2-pyridyl ) propenenitrile ( formula ( 1 ) , wherein R1 - H, Rz - CH3, R3 -- CN, R4 - H, R5 - 3, 5-dichloro-4-pyridyl, and X = O) and cis-1,3-cyclopentanediol monoTBS-ether, to thereby obtain the compound shown below.
(Z)-3-(3,5-Dichloro-4-pyridyl)-2-[5-methoxy-4-(cis-3-(TBS-oxy)cyclopentyloxy-2--pyridyl]propenenitrile (formula (1) , wherein R1 - cis-3- (TBS-oxy) cyclopentyl, R- - CH3, R-3 -CN, R'' - H, RS - 3, 5-dichloro-4-pyridyl, and X = O) .
'H-f~MIRCCDC.~ 3) b : 0. 05(6H, s), 0. 88(9H, s), 1. 60-2. 62(6H, m).
3. 98(3H, s), 4. 20-4. 40(1H, m), 4. 75-5. 00(1H, m~, 7. 19C1H, s), 8. 19(2H, s), 8. 61 (2H, s).
Example 57 The procedure of Example 46 was repeated through use of (Z)-3-(3,5-dichloro-4-pyridyl)-2-(4-hydroxy-5-methoxy-2-pyridyl)propenenitrile (formula (1), wherein R1 - H, R' - CHI, R3 -- CN, Rq - H, R5 - 3, 5-<~ichloro-4-pyridyl, and X = 0) and trans-1,3-cyclopentanedio:l monoTBS-ether, to thereby obtain the compound shown below.
(Z)-3-(3,5-Dichloro-4-pyridyl)-2-[5-methoxy-4-(trans-3-(TBS-oxy)cyclopentyloxy-2-pyridyl]propenenitrile (formula ( 1 ) , wherein R1 = trans-3-~ (TBS-oxy) cyclopentyl, R'' - CH3, R3 - CN, R~ - H, Ry' - 3, 5-dichloro-4-pyridyl, and X = 0) .
'H-N~dRCCDC.~ 3) o : 0. 06(6H, s). 0. 89(9H, s). 1. 50-2. 50C6H, m).
3. 98(3H, s). 4. 30-4. 60C1H, m). 4. 95-5. 22C1H, m~.
7. 23~1H, s). 8. 17(1H, s). 8. 20C1H. s). 8. 61 C2H, s).
Example 58 Synthesis of ( Z ) -2- ( 3-carboxyphenyl ) -3- [ 4- ( 2-indanyloxy)-5-methoxy-2-p:yridyl]propenenitrile (formula (1), wherein R1 - 2-indanyl, RZ = CH3, R' - H, Ry - CN, R5 - 3-carboxyphenyl, and X = 0):
In 4 ml of dioxane, was dissolved (Z)-3-[4-(2-indanyloxy)-5-methoxy-2-p:yridyl]-2-(3-methoxycarbonylphenyl)propenenitrile (formula (1), wherein R1 - 2-indanyl, R' - CH3, R3 - H, Rq - CN, R' - 3-methoxycarbonylphenyl, and X = 0) (426 mg, 1 mmol). To the solution was added 1N aqueous NaOH solution (1.2 ml). The mixture was stirred for 0.5 hours at room Temperature. The reaction mixture was poured into 5~ aqueous ammonium chloirde solution. Precipitated crystals were collected by filtration, washed with w<~ter, and recrystallized from ethanol, to thereby obtain the title compound (353 mg, yield 86~) .
Melting point: 281.5-282..'°C
' H-~l~~iR (D~~1S0-d 6 ) ~ : 2. 90-3. 65 (4H, m) . 3. 89 (3H, s ) , 5. 20-5.
42 ( 1 H, m) .
7. 05-7. 40 (4H, m) , 7. 50-7. 75 (2H, m) , 7. 90-8. 10 (3H, m) , 8. 37(2H, s).
Example 59 The procedure of Example 58 was repeated through use of (Z)-2-[4-(2-indanyloxy;-5-methoxy-2-pyridyl]-3-(2-methoxycarbonyl-4-pyridyl;propenenitrile (formula (1), wherein R1 - 2-indanyl, R' - CH;, R3 - CN, R.~ - H, R5 - 2-methoxycarbonyl-4-pyridyl, and X = 0), to thereby obtain the compound shown below.
(Z) -3- (2-Carboxy-4-p~~ridyl) -2- [4- (2-indanyloxy) -5-methoxy-2-pyridyl]propenenitrile (formula !1), wherein R' 2-indanyl, R'' - CH3, R3 - C:N, R~ - H, R~' - 2-carboxy-4-pyridyl, and X = O).
Melting point: 224-225°C
'~-,-NMRCD~~SO-ds) b : 3. 08-3. 5fiC4H, m~. 3. 85C3H, s). 5. 50C1H, br).
7. 18-7. 30C4H, m). 7. 66(1H, s). 8. 09-8. lOClN. mJ.
8. 29C1H, s). 8. 39(1H, s). 8. 53(1H, s).
8. 89C1H, ci, J=5. 3Hz).
Example 60 The procedure of Exa::nple 58 was repeated through use of (Z)-3-(4-cyclopentylox:y-5-methoxy-2-pyridyl)-2-(3-methoxycarbonylphenyl)propenenitrile (formula (1), wherein R1 - cyclopentyl, R' - CH;,, R' - H, R~ - CN, RJ - 3-methoxycarbonylphenyl, an~~ X = 0), to thereby obtain the con.pound shown below.
(Z)-2-(3-Carboxyphenyl)-3-(4-cyclopentyloxy-5-methoxy-2-pyridyl)propenenitrile (formula (1), wherein R1 -cyclopentyl, Rz - CH3, R3 -- H, Ra - CN, R5 - 3-carboxyphenyl, anc. X = 0 ) .
Melting point: 264-266°C
H-N~~R (Dh~SO-d s ) ~ : 1. 58-1. f>2 C6H, m) , 1. 97-2. 10 (2H, m) , 3. 94 C3H, s ) .
4. 88-4. ~~4C1H, m). 7. 54(1H, s), 7. 63(1H, t, J=8. OHz).
7. 96-8. 03(3H, m). 8. 33(1H, s), 8. 35C1H, s).
Example 61 Synthesis of (Z)-2-[4-(1,3-diamino-2-propyloxy)-5-methoxy-2-pyridyl]-3-(3,5-dichloro-4-pyridyl)propenenitrile trihydrochloride (formula (1), wherein R'' -- 1,3-diamino-2-prcpyl, R' - CH3, R3 - CN, Ra - H, RS - 3, 5-dichloro-4-pyridyl, and X = 0) In 4 ml of ether, was dissolved (Z)-2-[4-(1,3-bis(BOC-amino)-2-propyloxy)-5-met:Boxy-2-pyridyl]-3-(3,5-dichloro-4-pyridyl)propenenitrile (formula (1), wherein R1 - 1,3-bis (BOC-amino) -2-propyl, R' - CH3, R3 - CN, R9 = H, R5 - 3, 5-dic.hloro-4-pyridyl, and X = 0) (594 mg, 1 mmol). To the solution was added 4N HCl-dioxane solution (2 ml). The mi~s:ture was stirred for three hours at room temperature.
Precipitated crystals were collected by filtration, washed with ether, and recrystallized from ethanol, to thereby obtain the title compound (450 mg, yield 89=).
Melting point: 174-177°C
' H-N~~iR CD~~4S0-d 6 ) o : 3. 23 (2H, m) . 3. 40 C2H, m) , 3. 97 (3H, s) , 5.
32 ( 1 H, m) .
8. 22(1H. ~;), 8. 41(1H, s). 8. 72(1H, s). 8. 83C2H, s).
Example 62 Synthesis of (Z)-3-(3,5-dichloro-4-pyridyl)-2-[4-(cis-(3-hydroxy)cyclopentyloxy)-5-methoxy-2-pyridyl]propenenitrile (formula (1), wherein R1 - cis-(3-hyc.roxy) cyclopentyl, Rz - CH3, R3 - CN, Ra - H, R' - 3, 5-dichloro-4-pyridyl, and X = 0):
In 2 ml of THF, was dissolved (Z)-3-(3,5-dichloro-4-pyridyl)-2-[5-methoxy-4-(cis-3-(TBS-oxy)cyclopentyloxy)-2-pyridyl]propenenitrile (formula (1), wherein R1 - cis-3-(TES-oxy) cyclopentyl, R2 -- CH3, R' - CN, R9 - H, R5 - 3, 5-dichloro-4-pyridyl, and X = 0) (520 mg, 1 mmol). To the solution was added 1M tetrabutylammnoium fluoride-THF
solution (2.2 ml), and the mixture was stirred for five hours at room temperature. The reaction mixture was evaporated to dryness and then water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography and rec:rystallized from a benzene-hexane, to t:zereby obtain the title compound (240 mg, yield 59~).
Melting point: 134-135°C
'11-N~dR(CDC.~ 3) d : 1. 90-2. 24~;6H, m), 2. 39C1H, d. J=8. OHz), 3. 98C3H, s;>, ~. 38-4. 50C1H, m). 5. 04-5. 08(1H, m), 7.26(1H, s), 8.20C1H. s). 8.22(1N. s~. 8. 61C2H, s).
Example 63 The procedure of Example 62 was repeated through use of (Z)-3-(3,5-dichloro-4-:pyridyl)-2-[5-methoxy-4-(trans-3-(TE,S-oxy)cyclopentyloxy)-2-pyridyl]propenenitrile (formula (1) , wherein R1 - trans-3-- (TBS-oxy) cyclopentyl, R' - CH3, R' - C'N, Rq - H, RS - 3, 5-dichloro-4-pyridyl, and X = 0) , to thereby obtain the compound shown below.
(Z)-3-(3,5-Dichloro-4-pyridyl}-2-[4-(trans-(3-hyc.roxy)cyclopentyloxy}-5-methoxy-2-pyridyl]propenenitrile(formula (1), wherein Ri - trans-(3-hydroxy) cyclopentyl, R' - CHI, R~ - CN, R' - H, R' - 3, 5-dichloro-4-pyridyl, and X = 0).
Melting point: 136-137°C
'H-N~~(R(CDC.~ 3) ~ : 1. 58(1H, ~~r), 1. 70-1. 80C1H, m), 1. 90-2. 00(1H, m), 2. 07-2. 28(3H, m). 2. 35-2. 46(1H, m). 3. 98C3H. s), 4. 58-4. 62(1H, m), 5. 04-5. 07(1H, m), 7. 24(1H, s), 8. 17(1H, s), 8.20(1H, s~, 8. 61(2H, s).
Example 64 The procedure of Example 1 was repeated through use of 5-c:yclopentyloxy-6-methoxy-3-pyridineacetonitrile (Preparation Example 16) and 3,5-dichloro-4-pyridinecarbaldehyde (Pre.oaration Example '7), to thereby obtain the compound shown below.
(Z)-2-(5-Cyclopentyloxy-6-methoxy-3-pyridyl)-3-(3,5-di c~hloro-4 -pyridyl ) propeneni tri 1 a .
Melting point: 143-144°C
'H-T~~dR(CDC.~ 3) ~ : 1. 60-2. 05(8H. m), 4. 05(8H, s). 4. 86(1H, m), 7. 25(1H, d, J=2. OHz). 7. 27(1H, s), 8. 11 (1H, d, J=2. OHz).
8. 62(2H, s).
Example 65 The procedure of Example 1 was repeated through use of 6-cyclopentyloxy-5-methox_~-2-pyridineacetonitrile (Preparation Example 17) and 3,5-dichloro-4-pyridinecarbaldehyde (Preparation Example 7), to thereby obtain the compound shown below.
(Z)-2-(6-Cyclopentyloxy-5-methoxy-2-pyridyl)-3-(3,5-dichloro-4-pyridyl)propenenitrile.
Melting point: 137-138°C
'H--NhiRCCDC.~ ~) o : 1. 61-2. 12(8H, m), 3. 91(3H, s), 5. 50(1H, m), 7. 06C1H, d. J=8. OHz), 7. 31 (1H, d. J=8. OHz), 8. 07C1H, s), 8. 60C2H, s).
Example 66 The procedure of Example 1 was repeated through use of 5-methoxy-4-[2-(4-methyl-:~-thiazolyl)ethyloxy]-2-pyridineacetonitrile (Preparation Example 18) and methyl 9-formyl-2-picolinate, to thereby obtain the compound shown below.
(Z)-2-[5-methoxy-4-(2-(4-methyl-5-thiazolyl)ethyloxy)-2-pyridyl]-3-(2-methoxycarbonyl-4-pyridyl)propenenitrile ( formula ( 1 ) , wherein R1 -- 2- ( 4-methyl-5-thiazolyl ) ethyl, R' - CH3, R3 - CN, R~ - H, R5 - 2-methoxycarbonyl-4-pyridyl, and X = 0) .
Melting point: 161-162°C
'N--N6fR(CDC.~ 3) o : 2. 49(3H, s), 3. 37(2H, t. J=6. 5Hz), 4.01(3H, s), 4. 05(3H, s), 4. 32(2H, t, J=6. 5Hz). 7. 25(1H, s), 8. 04C1H, dd, J=1. 0, 5. 5Hz). 8. 20(1H, s), 8. 34(1H, s), 8. 47(1H, d. .J=1. OHz). 8. 63C1H, s), 8. 89(1H, d, J=5. 5Hz).
Similarly, the folloiaing compounds can also be prepared.
( Z ) -2- ( 6-Cyclopentyloxy-5--methoxy-2-pyridyl ) -3- ( 2, 6-dic:~lorophenyl)propenenitrile (Z)-2-(6-Cyclopentyloxy-5-~methoxy-2-pyridyl)-3-(3-pyridyl)propenenitrile (Z)~-2-(6-Cyclopentyloxy-5-methoxy-2-pyridyl)-3-(4-pyr:idyl)propenenitrile (Z)--3-(3,5-Dichloro-4-pyridyl)-2-(5-methoxy-6-phenethyloxy-2-p~lridyl)propenenitrile (Z)--3-(3,5-Dichloro-4-pyridyl)-2-(5-methoxy-6-(3-phenylpropyloxy)-2-pyridyl)propenenitrile (Z)--2-(6-Butyloxy-5-methoxy-2-pyridyl)-3-(5,5-dichloro-4-pyridyl)propenenitrile (Z)-3-(3,5-Dichloro-4-pyridyl)-2-[6-(1-ethylpropyloxy)-5-met:boxy-2-pyridyl]propenenitrile ( Z ) -3- ( 3, 5-Dichloro-4-pyridyl ) -2- [ 6- ( 2-indanyloxy) -5-met:boxy-2-pyridyl]propenenitrile (Z)-3-(3,5-Dichloro-4-pyridyl)-2-[5-methoxy-6-(tetrahydro-3-furanyloxy)-2-pyridyl]propenenitrile (Z)-3-(3,5-Dichloro-4-pyridyl)-2-[5-methoxy-6-(exo-2-norbornyloxy)-2-pyridyl]propenenitrile (Z)-3-(3,5-Dichloro-4-pyridyl)-2-(5-methoxy-6-methoxymethyloxy-2-pyridy.l)propenenitrile (Z)-3-(3,5-Dichloro-4-pyr:idyl)-2-(6-hydroxy-5-methoxypyridyl)propenenit:rile (Z)-3-(3,5-Dichloro-4-pyr:idyl)-2-[6-(3-hydroxypropyloxy)-5-methoxy-2-pyridyl]propenenitrile ( Z ) -3- ( 6-Cyclopentyloxy-5--methoxy-2-pyridyl ) -2- ( 3, 5-dichloro-4-pyridyl)propenenitrile (Z)-2-(6-Cyclopentyloxy-5--methoxy-2-pyridyl)-3-(3-fluoro-4-pyridyl)propenenitrile ( Z ) -2- [ 6- ( 2-Indanyloxy) -5--methoxy-2-pyridyl_ ] -3- ( 2-methoxycarbonyl-4-pyridyl)propenenitrile ( Z ) -2- [ 6- ( 2-Indanyloxy) -5--methoxy-2-pyridyi ] -3- ( 4-pyridyl)propenenitrile 4-[(Z)-2-Cyano-2-(6-(2-indanyloxy)-5-methoxy-2-pyridyl)-1-eth~~nyl]pyridine N-oxide 4- [ ( Z ) -2-Cyano-2- ( 6- ( 2-inclanyloxy) -5-methoxy-2-pyridyl ) -1-ethenyl]-3,5-dichloropyricline N-oxide (Z)-3-(3-Carboxyphenyl)-2-(6-cyclopentyloxy-5-methoxy-2-pyridyl)propenenitrile (Z)-3-(6-Cyclopentyloxy-5-methoxy-2-pyridy:L)-2-(3-methoxycarbonylphenyl)propenenitrile (Z)-3-[6-(2-Indanyloxy)-5-methoxy-2-pyridyl]-2-(3-methoxycarbonylphenyl)pro~?enenitrile (Z)-3-[6-(2-Indanyloxy)-5-methoxy-2-pyridyl]-2-(4-pyridyl)propenenitrile ( Z ) -3- ( 3, 5-Dichloro-4-pyr:idyl ) -2- [ 6- ( 2-hydroxyethyloxy) -5-methoxy-2-pyridyl]propenenitrile ( Z ) -3- ( 3, 5-Dichloro-4-pyr:idyl ) -2- [ 6- ( 4-hydr_oxybutyloxy) -5-methoxy-2-pyridyl]propenenitrile (Z)-3-(3,5-Dichloro-4-pyr:Ldyl)-2-[6-(5-hydroxypentyloxy)-5-methoxy-2-pyridyl]propenenitrile (Z)-2-(6-Cyclopropylmethy:Loxy-5-methoxy-2-pyridyl)-3-(3,5-dichloro-4-pyridyl)propenenitrile ( Z ) -3- ( 3, 5-Dichloro-4-pyr=Ldyl ) -2- [ 5-methoxy-6- ( 2- ( 2-pyridyl ) ethyloxy) -2-pyrid~ll ] propenenitrile (Z)-3-(3,5-Dichloro-4-pyridyl)-2-[5-methoxy-6-(2-(4-methyl-5-thiazolyl)ethyloxy)-2-p~~ridyl]propenenitrile ( Z ) -3- ( 3, 5-Dichloro-4-pyr:_dyl ) -2- [ 5-methoxy-6- ( 2- ( 2-pyridone-1-yl)ethyloxy)-2--pyridyl]propenenitrile ( Z ) -3- ( 3, 5-Dichloro-4-pyridyl ) -2- [ 5-methoxy- 6- ( 3- ( 3-pyridyl)propyloxy)-2-pyridyl]propenenitrile ( Z ) -3- ( 3, 5-Dichloro-4-pyridyl ) -2- [ 5-methoxy-6- ( 3- ( 4-pyridyl)propyloxy)-2-pyric~yl]propenenitrile (Z) -3- (3, 5-Dichloro-4-pyridyl) -2- [5-methoxy-6- (2- (N-morpholino)ethyloxy)-2-pyridyl]propenenitrile (Z)-2-(3-Carboxyphenyl)-3--[6-(2-indanyloxy;-5-methoxy-2-pyridyl]propenenitrile (Z)-3-(2-Carboxy-4-pyridy:L)-2-[6-(2-indanyloxy)-5-methoxy-2-pyridyl]propenenitrile (Z)-2-(3-Carboxyphenyl)-3--(6-cyclopentyloxy-5-methoxy-2-pyridyl)propenenitrile (Z)-2-[5-Methoxy-6-(2-(4-methyl-5-thiazolyl_)ethyloxy)-2-pyridyl]-3-(2-methoxycarbonyl-4-pyridyl)propenenitrile (Z)-3-(3,5-Dichloro-4-pyridyl)-2-[5-methoxy-6-(cis-3-(TBS-oxy)cyclopentyloxy)-2-pyridyl]propenenitrile (Z) -3- (3, 5-Dichloro-4-pyr=idyl) -2- [ 5-methoxy-6- (trans-3- (TBS-oxy)cyclopentyloxy)-2-pyr__dyl]propenenitrile ( Z ) -3- ( 3, 5-Dichloro-4-pyr__dyl ) -2- [ 6- ( cis- ( 5-hydroxy) cyclopentyloxy)-5-methoxy--2-pyridyl]propenenitrile ( Z ) -3- ( 3, 5-Dichloro-4-pyridyl ) -2- [ 6- ( trans- ( 3-hydroxy) cyclopentyloxy)-5-methoxy--2-pyridyl]propenenitrile (Z)-2-(5-Cyclopentyloxy-6--methoxy-3-pyridyl)-3-(2,6-dichlorophenyl)propenenitrile (Z)-2-(5-Cyclopentyloxy-6--methoxy-3-pyridyl)-3-(3-pyridyl)propenenitrile ( Z ) -2- ( 5-Cyclopentyloxy-6--methoxy-3-pyridyl ) -3- ( 4-pyridyl)propenenitrile (Z)-3-(3,5-Dichloro-4-pyridyl)-2-(6-methoxy-5-phenethyloxy-3-pyridyl)propenenitrile (Z)-3-(3,5-Dichloro-4-pyridyl)-2-[6-methoxy-5-(3-phenylpropyloxy)-3-pyridy7-]propenenitrile (Z)-2-(5-Butyloxy-6-methoxy-3-pyridyl)-3-(3,5-dichloro-4-pyridyl)propenenitrile (Z) -3- (3, 5-Dichloro-4-pyridyl ) -2- [ 5- ( 1-ethylpropyloxy) -6-met:boxy-3-pyridyl]propenenitrile ( Z ) -3- ( 3, 5-Dichloro-4-pyridyl ) -2- [ 5- ( 2-indanyloxy) -6-met:boxy-3-pyridyl]propenenitrile (Z)-3-(3,5-Dichloro-4-pyridyl)-2-[6-methoxy-5-(tetrahydro-3-furanyloxy)-3-pyridyl]propenenitrile (Z)-3-(3,5-Dichloro-4-pyridyl)-2-[6-methox:y-5-(exo-2-norbornyloxy)-3-pyridyl]propenenitrile (Z)-3-(3,5-Dichloro-4-pyridyl)-2-(6-methoxy-5-met:hoxymethyloxy-3-pyridyl)propenenitrile (Z)-3-(3,5-Dichloro-4-pyridyl)-2-(5-hydroxy-6-methoxy-3-pyridyl)propenenitrile (Z)-3-(3,5-Dichloro-4-pyridyl)-2-[5-(3-hydroxypropyloxy)-6-methoxy-3-pyridyl]propene:nitrile (Z)-3-(5-Cyclopentyloxy-6-methoxy-3-pyridy:l)-2-(3,5-dic:hloro-4-pyridyl)propenenitrile (Z)-2-(5-Cyclopentyloxy-6-methoxy-3-pyridyl)-3-(3-fluoro-4-pyridyl)propenenitrile (Z)-2-[5-(2-Indanyloxy)-6-methoxy-3-pyridyl]-3-(2-methoxycarbonyl-4-pyridyl)propenenitrile (Z)-2-[5-(2-Indanyloxy)-6-methoxy-3-pyridyl]-3-(4-pyridyl)propenenitrile 4- [ ( Z ) -2-Cyano-2- ( 5- ( 2-inc~anyloxy) -6-methoxy-3-pyridyl j -1-ethenyl]pyridine N-oxide 4-[(Z)-2-Cyano-2-(5-(2-inc3anyloxy)-6-methoxy-3-pyridyl)-1-et~-~enyl]-3,5-dichloropyridine N-oxide (Z)-3-(3-Carboxyphenyl)-2-[5-cyclopentyloxy-6-methoxy-3-pyridyl]propenenitrile (Z)-3-(5-Cyclopentyloxy-6-methoxy-3-pyridyl)-2-(3-methoxycarbonylphenyl)pro:oenenitrile ( Z ) -3- [ 5- ( 2-Indanyloxy) -6-methoxy-3-pyridy:L ] -2- ( 3-methoxycarbonylphenyl)propenenitrile (Z)-3-[5-(2-Indanyloxy)-6-methoxy-3-pyridyl]-2-(4-pyridyl)propenenitrile (Z)-3-(3,5-Dichloro-4-pyr.idyl)-2-[5-(2-hydroxyethyloxy)-6-methoxy-3-pyridyl]propenenitrile (Z)-3-(3,5-Dichloro-4-pyr.idyl)-2-[5-(4-hydroxybutyloxy)-6-methoxy-3-pyridyl]propenenitrile (Z)-3-(3,5-Dichloro-4-pyr:idyl)-2-[5-(5-hydroxypentyloxy)-6-methoxy-3-pyridyl]propenenitrile (Z)-2-(5-Cyclopropylmethy:Loxy-6-methoxy-3-pyridyl)-3-(3,5-dichloro-4-pyridyl)propenE:nitrile (Z)-3-(3,5-Dichloro-4-pyridyl)-2-[6-methoxy-5-(2-(2-pyridyl)ethyloxy)-3-pyrid~~l]propenenitrile (Z)-3-(3,5-Dichloro-4-pyridyl)-2-[6-methoxy-5-(2-(4-methyl-5-thiazolyl)ethyloxy)-3-p~lridyl]propenenitrile ( Z ) -3- ( 3, 5-Dichloro-4-pyridyl ) -2- [ 6-methoxy-5- ( 2- ( 2-pyridone-1-yl)ethyloxy)-3--pyridyl]propenenitrile (Z)-3-(3,5-Dichloro-4-pyridyl)-2-[6-methoxy-5-(3-(3-pyridyl)propyloxy)-3-pyric~yl]propenenitrile ( Z ) -3- ( 3, 5-Dichloro-4-pyr:_dyl ) -2- [ 6-methoxy-5- ( 3- ( 4-pyridyl)propyloxy)-3-pyric~yl]propenenitrile ( Z ) -3- ( 3, 5-Dichloro-4-pyr idyl ) -2- [ 6-methoxy-5- ( 2- (N-morpholino)ethyloxy)-3-py:ridyl]propenenitrile ( Z ) -2- ( 3-Carboxyphenyl ) -3- [ 5- ( 2-indanyloxy) -6-methoxy-3-pyridyl]propenenitrile (Zj -3- (2-Carboxy-4-pyridy.L) -2- [5- (2-indany-Loxy) -6-methoxy-3-pyridyl]propenenitrile (Z)-2-(3-Carboxyphenyl)-3--(5-cyclopentyloxy-6-methoxy-3-pyridyl)propenenitrile (Z)-2-[6-Methoxy-5-(2-(4-methyl-5-thiazolyl)ethyloxy)-3-pyridyl]-3-(2-methoxycarbonyl-4-pyridyl)propenenitrile (Z)-3-(3,5-Dichloro-4-pyridyl)-2-[6-methoxy-5-(cis-3-(TBS-oxy)cyclopentyloxy)-3-pyr_Ldyl]propenenitrile (Z)-3-(3,5-Dichloro-4-pyridyl)-2-[6-methoxy-5-(trans-3-(TBS-oxy)cyclopentyloxy)-3-pyridyl]propenenitrile (Z)-3-(3,5-Dichloro-4-pyridyl)-2-[5-(cis-(3-hydroxy)cyclopentyloxy)-6--methoxy-3-pyridyl]propenenitrile ( Z ) -3- ( 3, 5-Dichloro-4-pyr=_dyl ) -2- [ 5- ( trans- ( 3-hydroxy)cyclopentyloxy)-6--methoxy-3-pyridyl]propenenitrile Test Example 1 PDE Inhibitory Activity Test A variety of PDE isoymes shown below were isolated fro::n human tissue and purified in accordance with the method described in literature.
PDE III Human platelet H.. Hidaka, et al., Bioph. Bioch. Acta, (1976), X29, p485 P. Grant, et al., Biochemistry, (1984), ~3, p1801 PDE IV Human histocytic~ lymphoma (U-937) T . Torphy, et al . , J. Pharm. Exp. Ther. , ( 1992 ) , X63, p1195 M. DiSanto, et al., BBRC;, (1993) , 197, pi.126 PDE V Human platelet H. Hidaka, et a1. , Bioph. Bioch. Acta, (1976) , ~9, p485 P. Grant, et al., Biochemistry, (1984), c3, p1801 C.D. Nicholson, et al., Trends Pharmacol. Sci., (1991), 1~, p19.
The PDE activity was determined through use of a modified two-step assay method described by Hidaka et al.
(Bioph. Bioch. Acta., (19'76), ,~9_, p485) .
Briefly, [3H]CAMP and [3H]cGMP are hydrolyzed by their respective PDE isozymes to form [3H] 5'-AMP and [~H] 5'-GMP, respectively. Subsequently, [3H] 51-AMP and [3H] 51-GMP are transformed into [3H]adencsine and [3H]guanosine, respectively, due to the action of nucleotidases. Unreacted [3HicAMP and [3H]cGMP are :removed, causing them to bond to ion exchange resin, and the quantity of eluted [3H]adenosine or [3H]guanosine was counted in a liquid scintillation counter.
The diluted enzyme solution contains 50 mM Tris-HC1 (pH 8. 0) , 5 mM MgCl2, and .'~0 ~,g of bovine serum albumin, wherein the concentration~> represent final concentrations.
The substrate concentratic>n is 1 ~.M. The concentration of eac;z test compound varies between 0.1 nM and 100 N.M. Each test sample is incubated for 20 minutes at 30°C, and the PDE
rea~~tion is terminated by boiling for 2 minutes. The nucleotidase reaction was induced by adding snake venom nucleotidase to the above--described reaction mixture and incubating the resultant rnixture for 20 minutes at 30°C.
The ICso values of the test compounds were obtained from concentration-reaction curves within the concentration range of 0.1 nM to 100 ~.M..
Table 1 PDE inhibitory Activity PDE III: PDE IV PDE V
Compound ICSO (~) IC~o (~.M) IC~o, (~.M) Example 1 10 0.0026 >100 Example 14 >100 0.0059 5.6 Example 15 91 0.0048 56 Example 16 15 0.015 31 Example 17 >100 0.036 >100 Example 18 18 0.036 12 Example 19 >100 0.00065 >100 Example 20 56 0.011 >100 Rolipram >100 5.0 >100 Test Example 2 TNF-a Production Inhibition Test Human promonocytic leukemia cells (U 937 cells, 1 x 105 cells/400 ~,1) were inocul~~ted on a 24-well culture plate.
By use of an RPMI 1640 cu7_ture liquid (supplemented with 10°
FCS) containing 50 nM PMA, the cells were incubated for 72 hours, to thereby induce differentiation into monacyte/macrophage (see t~arkiz Daniel-Issakani, Allem M.
Spiegel and Berta Strulovici (1989), J. Biol. Chem. ?~, p20240-20247). Subsequently, the culture supernatant was discarded, and an RPMI 1640 culture liquid (supplemented wit:z 10% FCS) containing 1.0 ng/ml of LPS
(li~opolysaccharide; E. cc>li, 0111: B4) was added. Each compound was added one hour before the LPS treatment, so as to achieve concentrations of 100 ~.M, 10 ~.M, 1 ~.M, and 0.1 ~.M.
Six: hours after addition of LPS, the quantity of produced TNF'-a in the supernatant was measured by use of a human TNF'-a ELISA kit (Amersham, code RPN 2758). For respective doses of each compound, ~~~ontrol was calculated, wherein the quantity of TNF-a produce~~ when LPS treatment was performed anc. the compound was not ;added was considered 1000. Further, based on primary regression curves, there were calculated ICS; values in terms of TNF-a production inhibitory activity for respective compounds.
Table 2 TNF'-a Production Inhibition Compound ICja (N,M) Example 1 10.2 Example 4 7.6 Example 10 10 Example 11 5.5 Example 16 13.1 Example 19 2.9 Example 20 7.1 Example 21 13.3 Rolipram 100 Preparation Example 1 Tablet Compound of Example 1 50 mg Crystalline cellulose 50 mg Lactose 50 mg Hydroxypropylcellulose 18 mg Magnesium stearate 2 mg Total 170 mg Tablets each having the above composition were prepared through a customary method. If necessary, these tablets may be processed into sugar-coated tablets or film-coated tablets.
Preparation Example 2 Capsule Compound of Example 1 50 mg Light silicic acid anhydride ?5 mg Lactose 100 mg Starch 50 mg Talc 25 mg Total 250 mg The above ingredients were filled in a No.l capsule, to thereby prepare capsule preparations.
Preparation Example 3 Granules Compound of Example L 50 mg Lactose 600 mg Cornstarch 200 mg Carboxymethylcellulo;~e-Na 20 mg Hydroxypropylcellulo;~e 130 mg Total 1000 mg Granules of the above composition were prepared using a customary method.
Preparation Example 4 Powder Compound of Example 1 50 mg Light silicic acid anhydride 20 mg Precipitated calcium carbonate 10 mg Lactose 250 mg Starch 70 mg Total 400 mg A powder product having the above composition was prepared using a customar:~ method.
Preparation Example 5 Injection Compound of Example 19 5 mg Hydrogenated castor oil 85 mg Propylene glycol 60 mg Glucose 50 mg Distilled water for injection Suitable amount Total 1 ml in total An injection having the above composi.'_ion was prepared through a customary method.
Preparation Example 6 Intravenous drip infusion Compound of Example 19 50 mg Glucose 5 g Na~HP04 anhydrate 10 mg Citric acid 14.5 mg Distilled water for injection Suitable amount Total 100 ml in total An intravenous drip infusion was prepared through a customary method.
INDUSTRIAL APPLICABILITY
The 2-substituted vinylpyridiene derivative of the present invention is endowed with strong and selective PDE
IV inhibitory activity, and strong TNF-a production inhibitory activity. Thu~~, drugs designed on the basis of the selective PDE IV inhibitory activity are useful for the prevention and treatment of various diseases, including immediate or delayed asthma; allergies such as airway-hypersensitive allergy anc3 other allergies stemming from the inhibition of activation of inflammatory blood cells such as eosinocytes; autoimmune diseases such as atopy and rheumatism; depression as:~ociated with disturbed metabolism of the cerebrum; cerebral infarction; seni,~e dementia; and memory disorders associated with Parkinson's disease. Also, drugs designed on the basis of the TNF-a, production inhibitory activity are useful for the prevention and treatment of various diseases, including rheumatism, osteoporosis, type I and type II diabetes, cancers, inj=ections with HIV, AIDS, and shock caused by intracellular to~:ins. Moreover, since 'she compounds of the present in~rention have both selective PDE IV inhibitory action and TNF-a production inhibitory action, they are useful for the prevention and treatment of a wide variety of inflammatory di;~eases and autoimmune diseases .

Claims (11)

CLAIMS:

1. A substituted vinylpyridine derivative represented by the following formula (I):

wherein R1 represents a hydrogen atom, a CI-CI2 linear, branched, cyclic, cyclic-linear or cyclic-branched alkyl group, a C2-C12 linear, branched or cyclic alkenyl group, a linear, branched or cyclic C2-C12 (mono, di) hydroxy-alkyl group which may be substituted with C1-C6 alkoxy-carbonyl group, C2-C6 acyl group, or t-butyldimethylsilyl group, a C2-C12 alkoxyalkyl group, a C3-C13 alkoxycarbonylalkyl group, a C3-C12 alkoxyalkoxyalkyl group, a C2-C12 linear or branched amino alkyl or diaminoalkyl group which may be substituted by C1-C6 alkoxy-carbonyl or C2-C6 acyl group, a 5-, 6-membered saturated heterocyclic group having an oxygen atom which may be substituted with 1-3 groups selected from hydroxy, halogeno, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenoalkyl, cyano and nitro, a phenyl C1-C6 alkyl group which may be substituted by C1-C6 alkoxy, C1-C6 alkoxy-carbonyl or alkylenedioxy group, a C9-C11 benzocycloalkyl group which may be substituted with 1-3 groups selected from hydroxy, halogeno, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenoalkyl, cyano and nitro, or a C1-C5 linear alkyl group substituted with 5-, 6-membered heterocycle having 1-3 nitrogen atom(s), oxygen atom(s) or sulfur atom(s) or 5-, 7-membered saturated or unsaturated heterocycle having 1-3 nitrogen atom(s), oxygen atom(s) or sulfur atom(s) ; R2 represents a C1-C6 alkyl group; one of R3 and R4, which are different from each other, represents a hydrogen atom and the other represents a nitrile group, a carboxyl group, or a C1-C6 alkoxycarbonyl group; R5 represents a phenyl group which may be substituted with 1-3 group(s) selected from halogeno, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenoalkyl, C1-C6 alkoxycarbonyl, carboxyl, cyano, and nitro; or naphthyl group which may be substituted with 1-3 group(s) selected from halogeno, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenoalkyl, C1-C6 alkoxycarbonyl, carboxyl, cyano, and nitro, or a 5-, 6-membered heteroaryl group having 1-3 nitrogen, oxygen or sulfur atom(s) which may be substituted with 1-3 group(s) selected from halogeno, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenoalkyl, C1-C6 alkoxycarbonyl, carboxyl, cyano, and nitro; or nitrogen-containing, ring-condensed heteroaryl group having 1-3 nitrogen, oxygen or sulfur atom(s) which may be substituted with 1-3 group(s) selected from halogeno, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenoalkyl, C1-C6 alkoxycarbonyl, carboxyl, cyano, and nitro; X
represents an oxygen atom or a sulfur atom: and one of Q1.
Q2, and Q3 represents a nitrogen atom and the other two represent CH; as well as a salt thereof, a hydrate thereon, or an N-oxide thereof.

2. A drug containing as the active ingredient a substituted vinylpyridine derivative as described in Claim 1, a salt thereof, a hydrate thereof, or an N-oxide thereof.

3. The drug according to Claim 2, which is a phosphodiesterase IV inhibitor.

4. The drug according to Claim 2, which is a tumor necrotizing factor-.alpha. production inhibitory agent.

5. The drug according to Claim 2, which is a preventive or therapeutic agent for diseases based on phosphodiesterase IV and/or tumor necrotizing factor-.alpha..

6. A pharmaceutical composition containing a substituted vinylpyridine derivative as described in Claim 1, a salt thereof, a hydrate thereof, or an N-oxide thereof, and a pharmaceutically acceptable carrier.

7. Use of a substituted vinylpyridine derivative as described in Claim 1, a salt thereof, a hydrate thereof, or an N-oxide thereof, or a pharmaceutical composition of claim 6, for treatment of diseases, based on selective phosphodiesterase IV inhibitory action, or based on tumor necrotizing factor-.alpha. production inhibitory action.

8. Use of the substituted vinylpyridine derivative as described in Claim 1, a salt thereof, a hydrate thereof, or an N-oxide thereof for the prevention or treatment of a disease caused by the enhancement of phosphodiesterase IV
activity in a mammal in need thereof.

9. Use of the substituted vinylpyridine derivative as described in Claim 1, a salt thereof, a hydrate thereof, or an N-oxide thereof for the prevention or treatment of a disease caused by the production of tumor necrotizing factor-.alpha. in a mammal in need thereof.

10. Use of the substituted vinylpyridine derivative as described in claim 1, a salt thereof, a hydrate thereof, or an N-oxide thereof for the manufacture of a medicament for the prevention or treatment of a disease caused by the enhancement of phosphodiesterase IV
activity, in a mammal in need thereof.

11. Use of the substituted vinylpyridine derivative as described in claim 1, a salt thereof, a hydrate thereof, or an N-oxide thereof for the manufacture of a drug for the prevention or treatment of a disease caused by the production of tumor necrotizing factor-.alpha. in a mammal in need thereof.