JP2007186434A - Medicinal composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound useful as a nitrogen monoxide production enhancer and/or endothelial nitrogen monoxide synthetase activator. <P>SOLUTION: The phenethyl nicotinamide compound used as an active component of the medicine has blood circulation improving action based on excellent vascular endothelial nitrogen monoxide production enhancing action and/or endothelial nitrogen monoxide synthetase activating action. The medicine is useful as an agent for ameliorating diseases or pathological states caused by vascular endothelial function insufficiency, especially as a treating agent for peripheral artery obstruction, arteriosclerosis, ischemic heart disease, etc. It is useful also as a preventing or treating agent for dementia and an agent for the enhancement and/or promotion of the functional disorder recovery enhancing action or functional recovery exercising effect including the motility disorder caused by central neurodegeneration diseases such as cerebral apoplexy, brain injury and spinal cord injury. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a vascular endothelial cell-derived nitric oxide (NO) production promoter and / or a phenethylnicotinamide compound having an endothelial nitric oxide synthase (eNOS) activating action, and a pharmaceutically acceptable salt thereof. It is related with the medicine which uses as an active ingredient. In particular, it relates to a vascular endothelial NO production promoting action and / or an eNOS activator.

NO (nitrogen monoxide) is produced when L-arginine is oxidized to L-citrulline, and the reaction is catalyzed by NO synthase (NOS). Although NO production is observed in various tissues and cell types in the living body, typical cell types that constantly produce and release NO are vascular endothelial cells. It has been reported that NO (vascular endothelial NO) produced in vascular endothelial cells is an endothelium-derived relaxing factor (EDRF) (Nature, 1987, 327, 524-526; Proc. Natl. Acad. Sci. USA, 1987, 84, 9265-9269).
Vascular endothelium dysfunction in hyperlipidemia, arteriosclerosis and other arteriosclerotic diseases, as well as diabetes, is largely due to a decrease in endothelium-dependent vasorelaxation / dilation (EDR) caused by a decrease in NO produced by eNOS It is said to be the cause.
In addition, vascular endothelial NO produced by eNOS has not only a vasorelaxant action, but also platelet aggregation inhibition, antithrombotic action, antiproliferative action, anti-inflammatory action, etc. (History of Medicine, 2003, 204 (4), 621 -625).

Since NO was found to be the main body of EDRF, and NO was also found to play an important role in systemic circulation control, NO-donating preparations such as nitroglycerin preparations (as circulatory failure drugs) (Nitric acid) has been frequently used clinically. However, the NO-donating preparation has a short duration of action and tends to be resistant to long-term use. In addition, due to poor target organ specificity, systemic blood pressure drop, tachycardia due to blood pressure drop, headache, and dizziness appear as side effects. Excessive NO production is also known to cause cytotoxicity.
Moreover, the effect of L-arginine, a substrate for NOS, has been studied in diseases related to NO, but the effect of long-term administration of L-arginine has been reported to be weak and partial (Hypertension, 1994, 23 752-756; Hypertension, 1996, 25, 898-902).

On the other hand, as vasodilators, potassium channel opening agents are generally known to have vasodilatory effects, but they also have a blood pressure lowering effect, so that the blood pressure lowering amount is greater than the amount that causes blood pressure reduction to improve blood circulation. Has been reported to be necessary (Eur. J. Pharmacol., 1994, 264, 285-293; Gen. Pharmacol., 1998, 31, 59-62). Therefore, development of a blood flow circulation improving agent with little influence on blood pressure is eagerly desired.
Based on these findings, compounds that promote spontaneous and sufficient NO production in vascular endothelial cells and / or compounds that have an eNOS activation effect are due to the mechanism involved in vascular endothelial NO and the improvement of blood circulation. Due to its mechanism, it improves vascular endothelial function, resulting from decreased vascular endothelial function such as impaired blood flow, arteriosclerosis, hyperlipidemia, diabetic complications, ischemic heart disease and circulatory failure in various organs It is considered to be an excellent therapeutic agent for diseases such as diseases.

In addition, cerebral circulation, especially cerebral microcirculation, is maintained almost constant by autoregulation of cerebral blood flow, which is not found in other tissues, but the energy supply to the brain tissue is controlled for this regulation. It is known that the blood-brain barrier is deeply involved. Vascular endothelial cells are the main body of the blood-brain barrier, and NO produced by eNOS in vascular endothelial cells plays a very important role in regulating vascular permeability enhancement and maintaining the ability to automatically regulate cerebral blood flow. (Journal Pharmacology, 1999, 113, 203-210; J. Creb. Blood. Flow. Metab., 1984, 4, 574-585).
eNOS has been reported to be widely distributed in the brain, and is particularly expressed in neurons such as cerebral cortex and hippocampus (Neuroscience 2003, 119, 979-990). The activation of eNOS is involved in the formation of long-term potentiation (LTP), which is considered to be a neuronal level model of memory / learning, and learning disorders are induced in animals by administration of NOS inhibitors. Since NO learning preparations have been reported to avoid learning impairment, NO produced by eNOS is thought to play a very important role in memory and learning (Brain res., 2003 , 964, 159-163; Prog. Neurobiol., 2001, 64, 51-68; Cell, 1996, 87, 1015-1023).
Furthermore, it has been reported that eNOS activity is decreased in the cerebral cortex and hippocampus of old animals with learning disabilities (Neurosci. Letters, 2004, 370, 175-179), while humans also have Alzheimer's disease. An abnormality in eNOS expression has been reported in neurons (Neurobiol. Aging, 2000, 21, 309-319). From these findings, a compound that promotes spontaneous and sufficient amount of NO production in vascular endothelial cells and / or nerve cells and / or a compound having an eNOS activation action is excellent for dementia and other cognitive disorders. It is thought to be a therapeutic agent.

  In addition, it promotes vascular endothelial NO production or eNOS activation, and promotes recovery of dysfunction, including motor dysfunction due to central nervous degenerative diseases such as stroke, brain trauma, spinal cord injury, or functional recovery training (rehabilitation medicine) It has been suggested that the effect is enhanced and / or promoted. In animals, recovery of dysfunction after brain injury has been reported to be promoted / enhanced by NO-donating preparations (Ann. Nueol., 2001, 50, 602-611). It has been reported that angiogenesis by activation of eNOS is deeply involved in Stroke, 2005, 36, 847-852; Circ. Res., 2003, 92, 308-313.

  Conventionally known compounds having an action related to vascular endothelial NO production promotion or eNOS mainly increase the amount of eNOS. For example, it has been reported that an HMG-CoA reductase inhibitor (cholesterol synthesis inhibitor) promotes NO production by increasing the amount of eNOS mRNA in vascular endothelial cells. In addition, 4-fluoro-N-indan-2-ylbenzamide (Patent Document 1), an indane derivative substituted with heterocycle-CONH- or aryl-CONH- (Patent Document 2), heterocycle-CONH- or aryl- 6,7,8,9-tetrahydro-5H-benzocycloheptene derivative substituted with CONH- (Patent Document 3), 1,2,3,4-tetrahydronaphthalene substituted with heterocycle-CONH-, etc. (Patent Document 4) discloses that it has an eNOS expression enhancing action. In addition, soysterol, pyridoxine, riboflavin, taurine, inositol hexanicotinate and pantethine are also known to promote the synthesis of vascular endothelial nitric oxide and / or to maintain and improve the blood concentration of endothelial nitric oxide. (Patent Document 5). However, when only eNOS expression is enhanced, eNOS whose cofactor is uncoupled increases depending on the degree. It has been reported that the uncoupled eNOS produces active oxygen instead of NO, which reduces NO bioavailability and may worsen cardiovascular diseases such as arteriosclerosis (J. Clin. Invest., 2002, 110, 331-340).

（表中、(Hal)_mの欄のハロゲンの前の数字は置換位置を表し、2,4-diClは２位と４位それぞれにClが存在することを示す。）
化合物Aは、製造中間体として開示されているとともに（特許文献６）、弱いカリウムチャンネル開口作用及び弱い血管拡張作用を有することが開示されている（非特許文献１及び２）。
化合物B（非特許文献３）、D（特許文献７）、J（特許文献６）及びL（特許文献８）は、いずれも製造中間体として開示されている。
化合物C、E、F、G、H、I、K及びMは試薬カタログ上の公知化合物であり、用途に関する開示はない。
しかしながら、これらの化合物が血管内皮性NO産生促進作用及び／又はeNOS活性化作用を有することは、これらの文献には開示も示唆もない。 Moreover, the following compounds are known as phenethyl nicotinamide derivatives.

(In the table, the number in front of the halogen in the (Hal) _m column represents the substitution position, and 2,4-diCl indicates that Cl exists at the 2-position and 4-position, respectively.)
Compound A is disclosed as a production intermediate (Patent Document 6) and disclosed to have a weak potassium channel opening action and a weak vasodilatory action (Non-Patent Documents 1 and 2).
Compound B (Non-patent Document 3), D (Patent Document 7), J (Patent Document 6) and L (Patent Document 8) are all disclosed as production intermediates.
Compounds C, E, F, G, H, I, K, and M are known compounds on the reagent catalog, and there is no disclosure regarding their use.
However, these documents neither disclose nor suggest that these compounds have a vascular endothelial NO production promoting action and / or an eNOS activation action.

International Publication WO02 / 064146 Pamphlet International Publication WO02 / 64545 Pamphlet International Publication WO02 / 64546 Pamphlet International Publication WO02 / 64565 Brochure JP 2004-115507 A JP-A-7-33729 JP-A-61-289087 International Publication WO02 / 18327 Pamphlet Bioorganic & Medicinal Chemistry Letters, 1994, 4 (20), 2485-2488 Archives Internationales de Pharmacodynamie et de Therapie 1994, 328 (3), 297-306 Nippon Kagaku Zasshi 1970, 91 (6), 575-577

  An object of the present invention is to provide a novel vascular endothelial NO production promoter and / or eNOS activator.

As a result of intensive studies on a compound having a vascular endothelial NO production promoting action and / or an eNOS activating action, the present inventors have found that a phenethylnicotinamide compound in which a benzene ring is substituted with at least one halogen is excellent. The present invention was completed by discovering that it has an effect of promoting vascular endothelial NO production.
That is, the present invention provides vascular endothelial NO production promotion and / or eNOS comprising a phenethylnicotinamide compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Peripheral artery occlusion (PAOD) (intermittent claudication, etc.) comprising an activator and a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier It relates to a therapeutic agent. In addition, prophylactic or therapeutic agents for dementia (Alzheimer-type dementia, cerebrovascular dementia (cerebrovascular dementia), etc.), and motor dysfunction caused by central nervous degenerative diseases such as stroke, brain injury, spinal cord injury, etc. The present invention also relates to an agent for promoting the recovery of functional disorder or enhancing and / or promoting the effect of functional recovery training (rehabilitation medicine).

（式中の記号は以下の意味を示す。
X¹：N又はC-R¹、
X²：N又はC-R²、
X³：N又はC-R³、
但し、X¹、X²又はX³のうち、１個がNのとき、他の２個はNではない、
R¹、R²、R³及びR⁴：同一又は互いに異なって、-H、-ハロゲン、-R^A、-OH、-O-R^A、-S-R^A、-ハロゲノ低級アルキル、-N(R¹¹)(R¹²)、-O-シクロアルキル、-O-(置換されていてもよい含窒素飽和へテロ環)、-CN、-CO₂H、-CO₂-R⁰又は-CO-N(R¹³)(R¹⁴)、
R^A：-OH、-O-R⁰、-CO₂H及び-CO₂-R⁰から選択される１個以上の基で置換されていてもよい低級アルキル、
R⁰：-低級アルキル、
R¹¹及びR¹²：同一又は互いに異なって、-H、-R⁰又は-CO-R⁰、
R¹³及びR¹⁴：同一又は互いに異なって、-H、-R⁰、-低級アルキレン-OH、-低級アルキレン-O-R⁰又は-シクロアルキル、或いは、結合する窒素原子とともに、置換されていてもよい含窒素飽和へテロ環を形成してもよい、
R⁵：-H、-R⁰、-低級アルキレン-CO₂H、-低級アルキレン-CO₂-R⁰又は-低級アルキレン-CO-N(R¹⁵)(R¹⁶)、
R¹⁵及びR¹⁶：同一又は互いに異なって、-H又は-R⁰、
Hal：ハロゲン、
R⁶：-NO₂、-CN、-R⁰、-OH、-ハロゲノ低級アルキル、-CO₂H、-O-R⁰、-CO₂-R⁰、-CO-N(R¹³)(R¹⁴)又は-低級アルキレン-O-R⁰、
m：１、２、３、４又は５、
但し、mが２以上のとき、Halは同一又は互いに異なっていてもよい、
n：０又は１、但し、m+nは５以下、
k：０又は１。以下同様。）

(The symbols in the formula have the following meanings.
X ¹ : N or CR ¹
X ² : N or CR ² ,
X ³ : N or CR ³ ,
However, when ^one of X ¹ , X ² or X ³ is N, the other two are not N.
R ¹ , R ² , R ³ and R ⁴ : the same or different from each other, —H, —halogen, —R ^A , —OH, —OR ^A , —SR ^A , —halogeno lower alkyl, —N (R ¹¹ ) (R ¹² ), -O-cycloalkyl, -O- (optionally substituted nitrogen-containing saturated heterocyclic ring), -CN, -CO ₂ H, -CO ₂ -R ⁰ or -CO-N (R ¹³⁾ (R ^14),
R ^A : lower alkyl optionally substituted with one or more groups selected from —OH, —OR ⁰ , —CO ₂ H and —CO ₂ —R ⁰ ,
R ⁰ : -lower alkyl,
R ¹¹ and R ¹² are the same or different from each other, -H, -R ⁰ or -CO-R ⁰ ,
R ¹³ and R ¹⁴ are the same or different from each other, and may be substituted with -H, -R ⁰ , -lower alkylene-OH, -lower alkylene-OR ⁰ or -cycloalkyl, or a nitrogen atom to which they are bonded. A nitrogen-containing saturated heterocyclic ring may be formed,
R ⁵ : -H, -R ⁰ , -lower alkylene-CO ₂ H, -lower alkylene-CO ₂ -R ⁰ or -lower alkylene-CO-N (R ¹⁵ ) (R ¹⁶ ),
R ¹⁵ and R ¹⁶ are the same or different from each other, -H or -R ⁰ ,
Hal: halogen,
R ⁶ : —NO ₂ , —CN, —R ⁰ , —OH, —halogeno lower alkyl, —CO ₂ H, —OR ⁰ , —CO ₂ —R ⁰ , —CO—N (R ¹³ ) (R ¹⁴ ) Or -lower alkylene-OR ⁰ ,
m: 1, 2, 3, 4 or 5,
However, when m is 2 or more, Hal may be the same or different from each other.
n: 0 or 1, provided that m + n is 5 or less,
k: 0 or 1. The same applies below. )

（式中の記号は以下の意味を示す。
X¹：N又はC-R¹、
X²：N又はC-R²、
X³：N又はC-R³、
但し、X¹、X²又はX³のうち、１個がNのとき、他の２個はNではない、
R¹、R²、R³及びR⁴：同一又は互いに異なって、-H、-ハロゲン、-R^A、-OH、-O-R^A、-S-R^A、-ハロゲノ低級アルキル、-N(R¹¹)(R¹²)、-O-シクロアルキル、-O-(置換されていてもよい含窒素飽和へテロ環)、-CN、-CO₂H、-CO₂-R⁰又は-CO-N(R¹³)(R¹⁴)、
R^A：-OH、-O-R⁰、-CO₂H及び-CO₂-R⁰から選択される１個以上の基で置換されていてもよい低級アルキル、
R⁰：-低級アルキル、
R¹¹及びR¹²：同一又は互いに異なって、-H、-R⁰又は-CO-R⁰、
R¹³及びR¹⁴：同一又は互いに異なって、-H、-R⁰、-低級アルキレン-OH、-低級アルキレン-O-R⁰又は-シクロアルキル、或いは、結合する窒素原子とともに、置換されていてもよい含窒素飽和へテロ環を形成してもよい、
R⁵：-H、-R⁰、-低級アルキレン-CO₂H、-低級アルキレン-CO₂-R⁰又は-低級アルキレン-CO-N(R¹⁵)(R¹⁶)、
R¹⁵及びR¹⁶：同一又は互いに異なって、-H又は-R⁰、
Hal：ハロゲン、
R⁶：-NO₂、-CN、-R⁰、-OH、-ハロゲノ低級アルキル、-CO₂H、-O-R⁰、-CO₂-R⁰、-CO-N(R¹³)(R¹⁴)又は-低級アルキレン-O-R⁰、
m：１、２、３、４又は５、
但し、mが２以上のとき、Halは同一又は互いに異なっていてもよい、
n：０又は１、但し、m+nは５以下、
k：０又は１。
但し、以下の化合物を除く：

表中、(Hal)_mの欄のハロゲンの前の数字は置換位置を表し、2,4-diClは２位と４位それぞれにClが存在することを示す。以下同様。） The present invention also relates to a pharmaceutical composition comprising a compound of the following formula (I ′) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

(The symbols in the formula have the following meanings.
X ¹ : N or CR ¹
X ² : N or CR ² ,
X ³ : N or CR ³ ,
However, when ^one of X ¹ , X ² or X ³ is N, the other two are not N.
R ¹ , R ² , R ³ and R ⁴ : the same or different from each other, —H, —halogen, —R ^A , —OH, —OR ^A , —SR ^A , —halogeno lower alkyl, —N (R ¹¹ ) (R ¹² ), -O-cycloalkyl, -O- (optionally substituted nitrogen-containing saturated heterocyclic ring), -CN, -CO ₂ H, -CO ₂ -R ⁰ or -CO-N (R ¹³⁾ (R ^14),
R ^A : lower alkyl optionally substituted with one or more groups selected from —OH, —OR ⁰ , —CO ₂ H and —CO ₂ —R ⁰ ,
R ⁰ : -lower alkyl,
R ¹¹ and R ¹² are the same or different from each other, -H, -R ⁰ or -CO-R ⁰ ,
R ¹³ and R ¹⁴ are the same or different from each other, and may be substituted with -H, -R ⁰ , -lower alkylene-OH, -lower alkylene-OR ⁰ or -cycloalkyl, or a nitrogen atom to which they are bonded. A nitrogen-containing saturated heterocyclic ring may be formed,
R ⁵ : -H, -R ⁰ , -lower alkylene-CO ₂ H, -lower alkylene-CO ₂ -R ⁰ or -lower alkylene-CO-N (R ¹⁵ ) (R ¹⁶ ),
R ¹⁵ and R ¹⁶ are the same or different from each other, -H or -R ⁰ ,
Hal: halogen,
R ⁶ : —NO ₂ , —CN, —R ⁰ , —OH, —halogeno lower alkyl, —CO ₂ H, —OR ⁰ , —CO ₂ —R ⁰ , —CO—N (R ¹³ ) (R ¹⁴ ) Or -lower alkylene-OR ⁰ ,
m: 1, 2, 3, 4 or 5,
However, when m is 2 or more, Hal may be the same or different from each other.
n: 0 or 1, provided that m + n is 5 or less,
k: 0 or 1.
Except for the following compounds:

In the table, the number in front of the halogen in the (Hal) _m column represents the substitution position, and 2,4-diCl indicates that Cl exists at the 2-position and 4-position, respectively. The same applies below. )

  Furthermore, the present invention relates to the promotion of vascular endothelial NO production and / or eNOS activator or PAOD treatment of a phenethylnicotinamide compound represented by the above formula (I) or (I ′) or a pharmaceutically acceptable salt thereof. Also used for preparation of agents, vascular endothelial NO production promotion and / or eNOS activation method, and PAOD, treatment method for dementia or dysfunction recovery promotion effect or function recovery training effect enhancement and / or promotion method Related.

The phenethyl nicotinamide compound or a salt thereof, which is an active ingredient of the pharmaceutical of the present invention, has an excellent blood circulation improvement effect by promoting vascular endothelial NO production and / or activating eNOS. That is, the pharmaceutical of the present invention has a mechanism involving vascular endothelial NO and a mechanism by improving blood circulation, and by the action of one or both of them, it treats various diseases caused by vascular endothelial dysfunction. Useful. Examples of the disease caused by vascular endothelial dysfunction include peripheral artery occlusion (PAOD). PAOD is classified into grades I to IV (Fontain classification, degree I: numbness / coldness, degree II: intermittent claudication, degree III: resting pain, degree IV: ulcer / necrosis) The invention medicine is expected to be effective for any of these symptoms, and is considered to be particularly effective for intermittent claudication. In addition, the pharmaceutical of the present invention can be expected to have little influence on blood pressure and heart rate.
Further, the phenethyl nicotinamide compound or a salt thereof, which is an active ingredient of the pharmaceutical of the present invention, is effective in promoting recovery of dysfunction including motor dysfunction due to central neurodegenerative diseases such as stroke, brain trauma, spinal cord injury, or function recovery training effect. It is useful as an enhancer and / or accelerator.

Hereinafter, the present invention will be described in detail.
In the present specification, “alkyl” and “alkylene” mean a linear or branched hydrocarbon chain. “Lower alkyl” is preferably an alkyl group having 1 to 6 carbon atoms (hereinafter abbreviated as C _1-6 ), more preferably methyl, ethyl, 2-propyl and hexyl. “Lower alkylene” means a divalent group (C _1-6 alkylene) formed by removing any one hydrogen atom of the above “lower alkyl”, preferably C _1-4 alkylene, more preferably Methylene, ethylene, propylene and dimethylmethylene.
“Halogen” refers to F, Cl, Br and I. “Halogeno lower alkyl” preferably means C _1-6 alkyl substituted with one or more halogens, more preferably halogeno C _1-3 alkyl, still more preferably fluoromethyl, difluoromethyl, Trifluoromethyl and 2,2,2-trifluoroethyl are more preferable, and trifluoromethyl and 2,2,2-trifluoroethyl are more preferable.

“Cycloalkyl” is preferably C _3-10 cycloalkyl, which may be bridged. More preferred are cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl.
The “nitrogen-containing saturated heterocycle” is a monocyclic 3 to 8 member which has one nitrogen atom and may further have one heteroatom selected from O, S and N, preferably Represents a 5- to 7-membered saturated heterocyclic group. Examples include piperidyl, pyrrolidinyl, piperazinyl, azepanyl, diazepanyl, morpholinyl, and thiomorpholinyl groups.

“Optionally substituted” means “unsubstituted” or “having 1 to 5 identical or different substituents”. The substituent in the “optionally substituted nitrogen-containing saturated heterocyclic ring” is preferably R ^0- , R ⁰ -CO- or R ⁰ -O-CO-, more preferably R ⁰ -or R ^0-. CO-, more preferably R ^0- .

The compound of the formula (I ′) which is an active ingredient of the medicament of the present invention is included in the compound of the formula (I). Therefore, in the following description, it may be simply abbreviated as “compound (I)”.
Preferred embodiments of compound (I) which is an active ingredient of the medicament of the present invention are shown below.
(1) X ¹ is CR ¹ ; X ² is CR ² ; X ³ is CR ³ ; ^one of R ¹ , R ² , R ³ and R ⁴ is -H, -halogen, -R ⁰ , -OR ^A compound selected from ⁰ , -SR ⁰ and -halogeno lower alkyl, the other three being -H.
(2) A compound wherein m is an integer of 2 to 5 and n is 0.
(3) A compound wherein m is 1 to 3, n is 0, X ¹ , X ² and X ³ are both CH, R ⁴ is H and k is 0.
(4) A compound in which m is 2, n is 0, X ¹ , X ² and X ³ are both CH, R ⁴ is H and k is 0.
(5) A compound in which m is 1 to 3, and Hal is the same or different and is F or Cl. In particular, compounds in which m is 2.
(6) The compound wherein R ⁵ is H.
(7) A compound in which k is 1.
(8) A compound in which X ¹ is N or CR ¹ , and X ² and X ³ are both CH.
(9) A compound wherein X ² is N or CR ² , and X ¹ and X ³ are both CH.
(10) In the above (8) or (9), R ¹ or R ² is from -H, -OH, -R ⁰ , -OR ⁰ , -NH ₂ , -NHR ⁰ and -N (R ⁰ ) ₂ A compound that is a selected group.
(11) A compound wherein R ⁵ is H, X ¹ is N or CH, and X ² and X ³ are both CH.
(12) A compound wherein R ⁵ is H, X ² is N or CH, and X ¹ and X ³ are both CH.
(13) The compound wherein k is 1 in the above (1), (2), (5), (6) and (8) to (12).
(14) The compound in which k is 0 in the above (1), (2), (5), (6) and (8) to (12).
(15) The compound in which X ¹ , X ² and X ³ are all CH among any of the above (1) to (14).
(16) The compound wherein m is 2 among any of the above (1) to (15).
And / or
(17) The compound wherein m is 3 among any of the above (1) to (3) and (5) to (15).

Particularly preferred are the following compounds:
N- [2- (2-chloro-4-fluorophenyl) ethyl] nicotinamide, N- [2- (3-bromophenyl) ethyl] nicotinamide, N- [2- (2,4,5-trifluoro Phenyl) ethyl] nicotinamide, N- [2- (2-chloro-4-fluorophenyl) ethyl] -5- (isopropylamino) nicotinamide, N- [2- (2-chloro-4-fluorophenyl) ethyl ] Nicotinamide 1-oxide, N- [2- (2-chloro-4-fluorophenyl) ethyl] pyridazine-4-carboxamide, N- [2- (2-chloro-4,5-difluorophenyl) ethyl] nicotine Amido, N- [2- (2-chloro-4-fluorophenyl) ethyl] -5-hydroxynicotinamide, N- [2- (2-chlorophenyl) ethyl] -5-methylnicotinamide, N- [2- (2-Chloro-4-fluorophenyl) ethyl] -5-ethoxynicotinamide 1-oxide and N- [2- (2-chloro-4,5-difluorophenyl) ethyl] pyrimidine-5-carboxamide.

“Dementia” refers to a condition in which a normal intellectual function that has been normally developed continuously declines and the ability is clearly reduced socially and professionally.
Dementia symptoms include memory impairment and cognitive dysfunction as core symptoms, various psychiatric symptoms (spontaneous / motivated, depression, hallucination / delusion, anxiety, mental state, etc.) and behavioral disorders (徘徊, insomnia, day / night reversal, night delirium, etc.) and cerebral dysfunction (aphasia, apraxia, disapproval, etc.)
"Prevention of dementia" means "dementia" in the future by early diagnosis of imaging findings such as cephalometric X-ray CT, MRI, PET, SPECT, EEG findings, various intellectual function tests, neuropsychological tests, etc. By implementing pharmacotherapy at the stage of the onset of onset, the onset of “dementia symptoms” can be prevented in advance, or the onset of “dementia symptoms” can be delayed, impairing the original function in daily life. It means to keep it at a level that doesn't hurt you.
"Dementia treatment" means that "dementia symptoms" are manifested by diagnoses such as imaging findings such as cephalometric X-ray CT, MRI, PET, SPECT, EEG findings, various intellectual function tests, neuropsychological tests, etc. Delaying the progression of “dementia symptoms” by carrying out drug therapy at a stage where it is confirmed that it is confirmed, or minimizing or eliminating problems in daily life by inhibiting the progression means.
“Behavioral and psychological symptoms of dementia (BPSD)” refers to various mental symptoms and behavioral disorders as symptoms associated with dementia (peripheral symptoms).
“Mild cognitive impairment (MCI)” is an objective evidence of memory decline or cognitive decline (family observation, neuropsychological examination, etc.), but it causes obvious problems in social life. Indicates no state.

“Dysfunction due to central neurodegenerative disease” means a brain disorder due to a central neurodegenerative disease such as stroke, a motor dysfunction or a sensory disorder due to a neurological function disorder controlled by a brain damaged site. Preferably, it is a motor dysfunction.
“Stroke” is classified into hemorrhagic and non-hemorrhagic. Examples of hemorrhage include cerebral hemorrhage, subarachnoid hemorrhage, intracranial hemorrhage associated with cerebral artery malformation, and non-hemorrhagic cerebral infarction.
“Brain injury” refers to a condition in which the brain has been traumatically damaged due to a traffic accident, etc., including brain contusion, epidural hematoma, subdural hematoma, intracerebral hematoma, diffuse axonal injury Etc.
“Spinal cord injury” refers to a condition in which the spinal cord is compressed or crushed to cause dysfunction due to fracture or dislocation of the spine.
“Neurodegenerative disease” refers to a group of diseases in which nerve cells belonging to a specific functional system die chronically and progressively. Examples include Parkinson's disease, spinocerebellar degeneration, multiple system atrophy, and amyotrophic lateral sclerosis.

“Motor dysfunction” means a state in which voluntary movement is difficult or impossible, or cannot be performed smoothly, and means movement paralysis and ataxia. Specifically, skillful movement disorders, Babinski signs, spastic paralysis, spasticity (chronic phase), deep tendon reflexes (chronic phase), muscle rigidity (rigidity), slow movement, involuntary movements (tremors, choreography) , Athetosis, dystonia, etc.), ataxia (limbs / trunk), speech disorder, eating / swallowing disorder. Gait dysfunction and upper limb dysfunction are preferred.
“Sensory dysfunction” refers to superficial sensations such as tactile sensation, pressure sensation, and warm sensation, deep sensations such as position sensation, and vibration sensation, and complex sensations such as point recognition and skin writing. This refers to a state in which the sensation is not normally recognized. Depending on the level, there are loss of sensation (loss), dull sensation (decrease), hypersensitivity, and abnormal sensation (illusion). In addition, sensory disturbances due to sites where sensory disturbances such as half-body sensory disorders, superficial sensory disorders, and total sensory disorders are included.
"Language dysfunction" means aphasia with impaired language ability such as listening to, reading, speaking, and writing due to damage to the area that controls language function, and paralysis of speech and speech organs such as lips, tongue, and vocal cords Or a dysarthria exhibiting symptoms such as difficulty in speaking and pronunciation due to a disorder of movement regulation (ataxia), preferably a dysarthria.

“Promoting the recovery of dysfunction” is aimed at shortening the length of hospitalization after onset, early independence of self-care, and improving QOL (quality of life), etc. It means that
A preferred use of the present invention relates to stroke, brain trauma, neurodegenerative disease, motor dysfunction due to spinal cord injury, more preferably gait dysfunction after stroke and upper limb dysfunction.
“Functional impairment recovery training” refers to muscle strength enhancement during the acute, recovery, and maintenance periods, joint range of motion exercises such as fingers and knees, walking, etc., depending on the time after the onset of the central nervous system disease and the patient's condition It means motor function recovery training, language function recovery training, cognitive function recovery training, etc. Preferably, it is exercise function recovery training.
“Enhancement of functional disorder recovery training effect” means that the function is restored to a higher level and the disorder is reduced as compared with the case where only training is performed.
“Promotion of functional disorder recovery training effect” means that functional recovery is promoted in a shorter period of time compared to the case where only training is performed.

Compound (I), which is an active ingredient of the medicament of the present invention, may have geometrical isomers and tautomers depending on the kind of substituents. In the present invention, these isomers are separated or mixed. Is included.
In addition, compound (I) may have an asymmetric carbon atom, and (R) -isomer and (S) -isomer optical isomers based on this may exist. The present invention includes all of these optical isomers and isolated ones.
Furthermore, the compound (I) includes a pharmacologically acceptable prodrug. A pharmacologically acceptable prodrug is a compound having a group that can be converted to NH ₂ , OH, CO ₂ H or the like of the present invention by solvolysis or under physiological conditions. Examples of groups that form prodrugs include groups described in Prog. Med., 5, 2157-2161 (1985) and “Development of Pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198. .

Compound (I) may form a salt with a base depending on the type of acid addition salt or substituent. Such salts are pharmaceutically acceptable salts, specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid. , Oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, acid addition salts with organic acids such as aspartic acid, glutamic acid, sodium, Examples thereof include inorganic bases such as potassium, magnesium, calcium and aluminum, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine, and ammonium salts.
Furthermore, the present invention also includes various hydrates and solvates of the compound (I) and salts thereof and crystalline polymorphic substances.

(Production method)
The compound (I), which is an active ingredient of the present invention, and a pharmaceutically acceptable salt thereof are produced by applying various known synthetic methods utilizing characteristics based on the basic skeleton or the type of substituent. be able to. In this case, depending on the type of functional group, it is effective in terms of production technology to protect the functional group with an appropriate protective group at the raw material or intermediate stage, or to replace it with a group that can be easily converted to the functional group. There is a case. Examples of such a functional group include an amino group, a hydroxyl group, a carboxyl group, and the like, and examples of protective groups thereof include those described in “Protective Groups in Organic Synthesis (3rd edition, by TW Greene) and Utz (PGM Wuts)”. 1999) ”, which may be appropriately selected depending on the reaction conditions. In such a method, after carrying out the reaction by introducing the protecting group, the desired compound can be obtained by removing the protecting group as necessary or converting it to a desired group.
Further, the prodrug of compound (I) can be produced by introducing a specific group at the stage of a raw material or an intermediate, or reacting with the obtained compound (I) in the same manner as the above protecting group. The reaction can be carried out by applying a method known by those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
Hereinafter, typical production methods of compound (I) will be described. In addition, the manufacturing method of this invention is not necessarily restricted to the following examples.

First production method (amidation)

Compound (I) is prepared by reacting the corresponding carboxylic acid compound (II) and phenethylamine represented by formula (III) by a known method (for example, M. Bodanszky, Peptide Chemistry, p55-73 (1988); Nobuo Izumiya et al., Peptide synthesis (See p. 89-142 (1985)). Compound (I) which is a compound (N-oxide) in which k is 1 can be produced using the N-oxide of the corresponding carboxylic acid derivative (II).
Preferably, the carboxylic acid compound (II) is a reactive derivative (for example, acid halide such as acid chloride or acid bromide; acid azide; methanol, ethanol, benzyl alcohol, optionally substituted phenol, N-hydroxysuccinimide (HONSu)) , 1-hydroxybenzotriazole (HOBt) and the like, which can be prepared using an active ester; a symmetric acid anhydride; a mixed acid anhydride with an alkyl carbonate, p-toluenesulfonic acid, etc.] It can be performed by reacting. When a reactive derivative of carboxylic acid is used, it is preferable to add a base (an inorganic base such as sodium hydroxide or an organic base such as triethylamine (TEA), diisopropylethylamine, or pyridine). Alternatively, using a carboxylic acid, a condensing agent (for example, dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), 1,1′-carbonylbis-1H-imidazole (CDI) Etc.). At that time, additives such as HOBt and HONSu may be added.
The reaction temperature can be appropriately selected depending on the raw material compound. Examples of the solvent include inert solvents such as aromatic hydrocarbon solvents such as benzene and toluene, ether solvents such as 1,4-dioxane and tetrahydrofuran (THF), N, N-dimethylformamide (DMF), and the like. It is appropriately selected according to the type of raw material compound and the like, and is used alone or in combination of two or more.

Second production method (alkylation)

(Y is a leaving group such as halogen or sulfonate, R ^5a is lower alkyl, and —Z—CO ₂ R ⁰ (Z is a lower alkylene group).
In the present invention compounds, among the compounds represented by formula (I), R ⁵ is lower alkyl or -Z-CO ₂ R ⁰ amide compounds substituted with (Ib) is the corresponding R ⁵ is H compound (Ia ) In the N-alkylation reaction.
The reaction is performed in an appropriate inert solvent (preferably an ether solvent such as THF or DMF) using an excess amount of compound (Ia) and / or compound (IV) corresponding to the reaction, and if necessary, sodium hydride. It is advantageous to carry out under cooling to heating by adding an inorganic or organic base such as potassium tert-butoxide, potassium carbonate or TEA.

Third production method (oxidation)
A compound (N-oxide) in which k is 1 can be produced by subjecting the compound of the present invention in which k is 0 to an oxidation reaction.
In the reaction, the present compound in which k is 0 is used with an appropriate oxidizing agent (for example, a peracid or peroxide such as hydrogen peroxide, m-chloroperbenzoic acid, peracetic acid, etc.) If necessary, an inorganic base such as sodium bicarbonate can be added, and the reaction can be carried out under cooling to heating. Examples of the solvent include halogen solvents such as chloroform and methylene chloride, acetone, acetonitrile, acetic acid, trifluoroacetic acid, and the like, and are appropriately selected according to the type of raw material compound and oxidizing agent.

Fourth Production Method Various substituents on the group R ¹ , R ² , R ³ , R ⁴ or R ^{5 in the} formula (I) are reactions that are obvious to those skilled in the art, starting from the compound (I) of the present invention, or By using these modified methods, it can be easily converted to other functional groups. For example, the following reaction can be applied.
(1) Hydrolysis The present compound having a carboxyl group can be produced by hydrolyzing a carboxylic acid ester. For the reaction, a conventional method of hydrolysis can be used. For example, the method described in the above-mentioned deprotection reaction of the carboxyl group in “Protective Groups in Organic Synthesis (3rd edition)” can be applied.
(2) Amidation Various compounds of the amide can be produced using the compound of the present invention having a carboxyl group as a raw material. For the reaction, the method of the first production method (amidation) can be applied.

The reaction product obtained by each of the above production methods is isolated and purified as various solvates such as a free compound, its salt or hydrate. The salt can be produced by subjecting it to normal salt formation treatment.
Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatography.
Various isomers can be isolated by conventional methods utilizing the difference in physicochemical properties between isomers. For example, optical isomers can be separated by a general optical resolution method such as fractional crystallization or chromatography. Optical isomers can also be produced from appropriate optically active raw material compounds.

A preparation containing one or more of compound (I) or a salt thereof as an active ingredient is usually prepared using carriers, excipients, and other additives used for formulation.
Administration is orally by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, ointments Any form of parenteral administration such as an agent, a transdermal patch, a transmucosal solution, a transmucosal patch, a nasal agent or an inhalant may be used.
The dose is appropriately determined according to the individual case in consideration of symptoms, age of the subject, sex, etc. In general, in the case of oral administration, about 0.001 mg / kg to 1000 mg / kg per day for adults, preferably Is suitably 0.1 to 300 mg / kg, more preferably 0.1 to 100 mg / kg, which is administered once or divided into 2 to 4 times. In addition, when intravenously administered depending on symptoms, 0.0001 mg / kg to 500 mg / kg per day for an adult is usually appropriate, and is administered once to several times a day. In the case of a transmucosal agent such as a nasal agent or an inhaler, it is usually administered once or multiple times a day in the range of 0.001 mg / kg to 500 mg / kg for an adult.
As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, one or more active ingredients are combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, and / or Alternatively, it is mixed with magnesium aluminate metasilicate. The composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, and a solubilizing agent according to a conventional method. If necessary, tablets or pills may be coated with a sugar coating or a gastric or enteric coating agent.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert solvents such as purified water, Contains ethanol. In addition to the inert solvent, the composition may contain adjuvants such as solubilizers, wetting agents, and suspending agents, sweeteners, corrigents, fragrances, and preservatives.
Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of the aqueous solvent include distilled water for injection and physiological saline. Non-aqueous solvents include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 (Pharmacopeia name), and the like. Such a composition may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving and suspending it in sterile water or a sterile solvent for injection before use.

Transmucosal agents such as inhalants and nasal agents are used in the form of solids, liquids, and semisolids, and can be produced according to conventionally known methods. For example, excipients such as lactose and starch, and pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be added as appropriate. For administration, an appropriate device for inhalation or insufflation can be used. For example, using a known device such as a metered dose inhalation device or a nebulizer, the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to. The dry powder inhaler or the like may be for single or multiple administration, and a dry powder or a powder-containing capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like. Contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like. For example, as an ointment or lotion base, polyethylene glycol, carboxyvinyl polymer, white petrolatum, honey beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. Is mentioned.

Hereinafter, based on a manufacture example, the manufacturing method of compound (I) which is an active ingredient of this invention is demonstrated in detail. Moreover, the manufacturing method of a raw material compound is shown in a reference example, and manufacture of a well-known compound is shown in a reference manufacturing example, respectively.
In addition, the following abbreviations are used in Production Examples, Reference Examples and Tables below. Pre: Production example number, REx: Reference example number, RPr: Reference production example number, Dat: Physicochemical data (FAB: FAB-MS (M + H) ⁺ , FAB-N: FAB-MS (MH) ⁻ , ESI: ESI-MS (M + H) ⁺ , EI: EI-MS (M ⁺ ), NMR: δ (ppm) of the characteristic peak in ¹ H NMR in DMSO-d ₆ , Sal: salt (HCl: Hydrochloride, 2HCl: dihydrochloride, HBr: hydrobromide,-or not described: free form), Me: methyl, Et: ethyl, iPr: 2-propyl, cHex: cyclohexyl, Ac: acetyl, Bn: Benzyl, Boc: tert-butoxycarbonyl, null: absent.

Reference example 1
To a solution of 2.6 g of (4-bromo-2-chlorophenyl) methanol in 30 ml of chloroform, 1.7 ml of thionyl chloride was added at room temperature and stirred for 1 hour. The solvent was distilled off under reduced pressure to obtain 2.4 g of a residue. To a 30 ml solution of the residue in acetonitrile, 2.4 g of potassium cyanide and 3.4 g of 18-crown-6-ether were sequentially added at room temperature, followed by stirring at 80 ° C. overnight. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; ethyl acetate: n-hexane) to give a pale yellow oil. To a 20 ml THF solution of the obtained pale yellow oily substance, 20 ml of borane-THF complex (1M THF solution) was added and heated to reflux for 4 hours. After cooling to room temperature, 1M aqueous hydrochloric acid solution was added and the mixture was further heated to reflux for 1 hour. After cooling to room temperature again, 1M aqueous sodium hydroxide solution was added to basify the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was extracted with a 1M aqueous hydrochloric acid solution, made basic by adding a 1M aqueous sodium hydroxide solution, and then extracted again with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 772 mg of 2- (4-bromo-2-chlorophenyl) ethylamine as a pale yellow oil. FAB: 234, 236.
Reference example 2
[2-Chloro-5- (trifluoromethyl) phenyl] acetonitrile 1.66 ml of borane-dimethyl sulfide complex was added to a solution of 787 mg of THF in 7 ml of THF and heated to reflux for 6 hours. After cooling to room temperature, 4M aqueous hydrochloric acid solution was added and the mixture was further heated to reflux for 1 hour. After cooling to room temperature again, the aqueous layer was washed with diethyl ether, and 1M aqueous sodium hydroxide solution was added to make the aqueous layer basic. Extraction was performed with diethyl ether, and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 682 mg of 2- [2-chloro-5- (trifluoromethyl) phenyl] ethylamine as a colorless oil. FAB: 224, 226.

Reference example 3
To a solution of 1.0 g of 4-bromo-2-fluorobenzyl chloride in 30 ml of acetonitrile, 874 mg of potassium cyanide and 1.4 g of 18-crown-6-ether were sequentially added at room temperature, followed by stirring at 60 ° C. overnight. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To a THF 10 ml solution of the obtained product, 20 ml of borane-THF complex (1M THF solution) was added and heated to reflux for 2 hours. After cooling to room temperature, 1M aqueous hydrochloric acid solution was added and the mixture was further heated to reflux for 1 hour. After cooling to room temperature again, 1M aqueous sodium hydroxide solution was added to basify the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was extracted with a 1M aqueous hydrochloric acid solution, made basic by adding a 1M aqueous sodium hydroxide solution, and then extracted again with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 388 mg of 2- (4-bromo-2-fluorophenyl) ethylamine as a pale yellow oil. FAB: 218, 220.
Reference example 4
To a solution of 5.3 g of (4-chloro-2-methoxyphenyl) methanol in 100 ml of THF was added 2.7 ml of thionyl chloride under ice-cooling, and the mixture was stirred for 30 minutes. After raising the temperature to room temperature, the solvent was distilled off under reduced pressure to obtain the residue as a colorless oil. To a solution of the obtained oily substance in 100 ml of acetonitrile, 3.0 g of potassium cyanide and 12.3 g of 18-crown-6-ether were sequentially added at room temperature, followed by stirring at 60 ° C. overnight. After cooling to room temperature, the reaction solution was evaporated under reduced pressure to some extent, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate-n-hexane) to give (4-chloro-2-methoxyphenyl) Acetonitrile 3.6 g was obtained as a pale yellow solid. FAB-N: 180.

Reference Example 5
A mixture of 3.6 g of (4-chloro-4-methoxyphenyl) acetonitrile, about 10 g of Raney nickel, a 30% aqueous ammonia solution and ethanol was stirred for 6 hours under a hydrogen stream. After filtration using celite, the solvent was evaporated under reduced pressure to obtain 3.5 g of 2- (4-chloro-4-methoxyphenyl) ethylamine as a colorless oil. ESI: 186, 188.
Reference Example 6
To a solution of 498 mg of 3-bromo-2-fluorobenzoic acid in 4.4 ml of THF, 1.05 ml of borane-dimethyl sulfide complex was added at room temperature and stirred overnight. Methanol was added, and the solvent was evaporated under reduced pressure to obtain 455 mg of (3-bromo-2-fluorophenyl) methanol as a brown oil. EI: 204, 206.
Reference Example 7
To a solution of 455 mg of (3-bromo-2-fluorophenyl) methanol in 4.4 ml of dichloromethane, 0.08 ml of phosphorus tribromide was added at room temperature and stirred for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added, extracted with chloroform, and the organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 427 mg of 3-bromo-2-fluorobenzyl bromide as a brown oil. EI: 266, 268, 270.

Reference Example 8
To a solution of 3-bromo-2-fluorobenzyl bromide (427 mg) in ethanol (1.6 ml) was added 1M aqueous sodium cyanide solution (2.4 ml), and the mixture was stirred at 80 ° C. for 2 hours. After cooling, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 427 mg of (3-bromo-2-fluorophenyl) acetonitrile as a pale yellow oil. EI: 213, 215.
Reference Example 9
To a solution of 5.1 g of 5-bromo-2-fluorobenzaldehyde in 25 ml of methanol, 1.13 g of sodium borohydride was added under ice cooling, and the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 5.0 g of (5-bromo-2-fluorophenyl) methanol as a white solid. EI: 204, 206.
Reference Example 10
To a solution of 1.99 g of 3-bromo-4-fluorophenylacetic acid in 25 ml of DMF, 1.25 g of HOBt and 2.42 g of WSC hydrochloride were sequentially added at room temperature. After 30 minutes, 2.69 mg of ammonium carbonate was added, and the mixture was further stirred overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 2.29 g of 2- (3-bromo-4-fluorophenyl) acetamide as a pale yellow solid. EI: 231, 233.

Reference Example 11
Borane-dimethyl sulfide complex (3.36 ml) was added to 2- (3-bromo-4-fluorophenyl) acetamide (2.29 g) in THF (14 ml), and the mixture was heated to reflux for 6 hours. After cooling to room temperature, concentrated hydrochloric acid was added and the mixture was further heated to reflux for 1 hour. After cooling to room temperature again, 4M aqueous sodium hydroxide solution was added to make the aqueous layer basic, and the mixture was extracted with diethyl ether. A 4M aqueous hydrochloric acid solution was added to the organic layer and washed with diethyl ether. A 1M aqueous sodium hydroxide solution was added to make the aqueous layer basic, and the mixture was extracted again with diethyl ether, and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting product was converted to hydrochloride according to a conventional method to give 1.18 g of 2- (3-bromo-4-fluorophenyl) ethylamine hydrochloride as a colorless solid Got as. FAB: 218, 220.
Reference Example 12
Ethanol 0.34 ml, triphenylphosphine 1.6 g and diethyl azodicarboxylate 0.95 ml were sequentially added at room temperature to a THF solution of 766 mg of methyl 5-human hydroxynicotinate at room temperature and stirred overnight at the same temperature. 5 g of silica gel was added, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane) to obtain 990 mg of a product containing methyl 5-ethoxynicotinate. This product was used in the next reaction without further purification. FAB: 182.
Reference Example 13
Product of Reference Example 12 To a solution of 990 mg of ethanol in 10 ml of ethanol, 7.5 ml of 1M sodium hydroxide aqueous solution was added at room temperature and stirred at the same temperature for 3 hours. After completion of the reaction, 7.5 ml of 1M hydrochloric acid aqueous solution was added to neutralize the reaction system. The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration to obtain 522 mg of 5-ethoxynicotinic acid as a white solid. FAB: 168.

Reference Example 14
Methyl 5-bromonicotinate 432 mg in a mixed solution of toluene 2.0 ml and isopropylamine 2.0 ml was mixed with sodium tert-butoxide 288 mg, (±) -2,2'-bis (diphenylphosphino) -1,1 ' -37 mg of binaphthyl and 12 mg of tris (dibenzylideneacetone) dipalladium were sequentially added, and the mixture was stirred overnight at 100 ° C. in a sealed tube. After completion of the reaction, the mixture was filtered through celite, water was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane) to give N-isopropyl-5- (isopropylamino) nicotinamide. 180 mg was obtained. FAB: 222.
Reference Example 15
To a solution of diisopropylamine (6.3 ml) in THF (150 ml) was added 1.6M n-butyllithium / n-hexane solution (30 ml) at -78 ° C under an argon atmosphere, and the mixture was stirred at -10 ° C for 30 minutes. Again, a solution of 4.47 g of 4-chloropyridine in 50 ml of THF was added at −78 ° C., and the mixture was further stirred at the same temperature for 4 hours. At the same temperature, 12 ml of DMF was added, and the mixture was further stirred for 2 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate, and washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane) to obtain 3.35 g of 4-chloronicotinaldehyde as a yellow solid. Obtained. EI: 141.

Reference Example 16
To 200 ml of an aqueous solution of 2.85 g of the compound of Reference Example 15, 6.3 g of potassium permanganate was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. After completion of the reaction, about 25 ml of ethanol was added and stirred for 1 hour. After filtration using celite, the solvent was distilled off under reduced pressure to obtain 4.2 g of a product. 2.2 g of the product was used and heated to reflux overnight in 100 ml of 6M aqueous hydrochloric acid. The solvent was then distilled off under reduced pressure, 5.0 ml of concentrated sulfuric acid was added to a 50 ml solution of the residue in methanol, and the mixture was heated to reflux overnight. Under ice-cooling, saturated sodium hydrogen carbonate was added to neutralize the reaction solution, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: methanol: chloroform), thereby elution with low polarity. From the part, 712 mg of methyl 4-methoxynicotinate was obtained as a white solid, and from the highly polar effluent part, 124 mg of methyl 4-hydroxynicotinate was obtained as a white solid. Methyl 4-methoxynicotinate FAB: 168; Methyl 4-hydroxynicotinate EI: 153.
Reference Example 17
After oxidation of 4-chloronicotinaldehyde in the same manner as in Reference Example 16, the mixture was heated to reflux overnight in ethanol in the presence of concentrated sulfuric acid, and purified in the same manner to obtain 893 mg of ethyl 4-ethoxynicotinate as a white solid. It was. FAB: 196.

  In the same manner as in Reference Example 2, the compounds of Reference Examples 18 to 54, the same as Reference Example 6, the compounds of Reference Examples 55 to 59, the same as Reference Example 7, the compounds of Reference Examples 60 to 65, and the Reference Example The compounds of Reference Examples 66 to 73 were produced in the same manner as in Example 8, the compounds of Reference Examples 74 to 78 were produced in the same manner as in Reference Example 12, and the compounds of Reference Examples 79 to 82 were produced in the same manner as in Reference Example 13. did. The structures and physicochemical data of the compounds of Reference Examples 18 to 82 are shown in Tables 4 to 6, respectively.

Reference production example 1
To a mixed solution of 2- (2-chlorophenyl) ethylamine 778 mg of pyridine 4 ml and 1,4-dioxane 4 ml, 890 mg of nicotinic acid chloride hydrochloride was gradually added and stirred at 80 ° C. for 2 hours. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was made into hydrochloride using 4M hydrogen chloride / ethyl acetate solution, and the crystals precipitated from methanol-ethyl acetate were collected by filtration, and N- [2- (2-chlorophenyl) ethyl] nicotinamide hydrochloride was collected. 1.36 g of salt was obtained as a white solid.
In the same manner as in Reference Production Example 1, the compounds of Reference Production Examples 2 to 4 were produced in the same manner as in Production Example 51 described below, and the compounds of Reference Production Examples 5 and 6 were produced. The structure and physicochemical data of the compounds are shown in Table 7.

Production Example 1
In the same manner as in Reference Production Example 1, the compound of Production Example 1 shown in the table below was produced.
Production Example 2
To a mixed solution of 2- (2-chloro-4-fluorophenyl) ethylamine 1.05 g of pyridine 3 ml and 1,4-dioxane 4 ml, nicotinic acid chloride hydrochloride 1.2 g was gradually added and stirred at 80 ° C. for 1 hour. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was converted into a hydrochloride using 4M hydrogen chloride / ethyl acetate solution, and crystals precipitated from ethanol-ethyl acetate were collected by filtration. The obtained crystals were recrystallized from ethanol to obtain 1.18 g of N- [2- (2-chloro-4-fluorophenyl) ethyl] nicotinamide hydrochloride as a white solid.

Production Examples 3-39
In the same manner as in Production Example 2, the compounds of Production Examples 3-39 shown in the table below were produced.
Production Example 40
Borane-dimethylsulfide complex 1.19 ml was added to a THF (5 ml) solution of (2,3,4-trifluorophenyl) acetonitrile (428 mg), and the mixture was heated to reflux for 6 hours. After cooling to room temperature, 4M aqueous hydrochloric acid solution was added, and the mixture was further heated to reflux for 1 hr. After cooling to room temperature again, the aqueous layer was washed with diethyl ether. A 1M aqueous sodium hydroxide solution was added to make the aqueous layer basic, followed by extraction with diethyl ether, and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. 329 mg of nicotinic acid chloride hydrochloride was added to a mixed solution of 3.1 ml of pyridine of the obtained product and 6.2 ml of 1,4-dioxane, and the mixture was stirred at 80 ° C. for 30 minutes. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was converted into hydrochloride using 4M hydrogen chloride / ethyl acetate solution, and the crystals precipitated from ethanol were collected by filtration to give N- [2- (2,3,4-trifluorophenyl) ethyl]. Nicotinamide hydrochloride 235 mg was obtained as a white solid.
Production Example 41
In the same manner as in Production Example 40, the compound of Production Example 41 shown in the table below was produced.

Production Example 42
To a solution of 2-methylnicotinic acid 206 mg in DMF 4 ml, room temperature HOBt 243 mg and WSC hydrochloride 575 mg were sequentially added. After 30 minutes, 347 mg of 2- (2-chloro-4-fluorophenyl) ethylamine was added, and the mixture was further stirred for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate) and converted into hydrochloride using 4M hydrogen chloride / ethyl acetate solution. The crystals precipitated from ethanol-diethyl ether were collected by filtration to obtain 371 mg of N- [2- (2-chloro-4-fluorophenyl) ethyl] -2-methylnicotinamide hydrochloride as a white solid.
Production Examples 43-50
In the same manner as in Production Example 42, the compounds of Production Examples 43 to 50 shown in the table below were synthesized.

Production Example 51
To a solution of 1.0 g of 2-methoxynicotinic acid in 20 ml of THF, 2.73 ml of TEA, 1.87 ml of ethyl chloroformate and 0.98 ml of 2- (2,4-dichlorophenyl) ethylamine were sequentially added and stirred for 5 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. From the obtained residue, crystals precipitated from ethyl acetate-hexane were collected by filtration to obtain 1.25 g of N- [2- (2,4-dichlorophenyl) ethyl] -2-methoxynicotinamide as a white solid.

Production Examples 52-57
In the same manner as in Production Example 51, the compounds of Production Examples 52 to 57 shown in the table below were synthesized.

Production Example 58
To a solution of 2.9 g of N- [2- (2,4-dichlorophenyl) ethyl] nicotinamide in 50 ml of THF, 520 mg of 60% oily sodium hydride was gradually added under ice-cooling and stirring. After 30 minutes, the temperature was raised to room temperature, 1.6 ml of ethyl bromoacetate was added, and the mixture was further stirred for 2 hours. Ammonium chloride and 1M aqueous hydrochloric acid were sequentially added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate: n-hexane) to obtain 873 mg of a pale yellow oil. To a solution of the obtained pale yellow oily substance in 673 mg of methanol in 15 ml, 3.4 ml of 1M aqueous sodium hydroxide solution was added at room temperature and stirred for 1 hour. To the reaction mixture was added 3.4 ml of 1M aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. From the obtained residue, crystals precipitated from ethyl acetate-n-hexane were collected by filtration, and 562 mg of {[2- (2,4-dichlorophenyl) ethyl] (pyridin-3-ylcarbonyl) amino} acetic acid was added as a white solid. Got as.
Production Example 59
To a solution of the compound of Production Example 58 in 331 mg of DMF in 6 ml, 153 mg of HOBt and 360 mg of WSC hydrochloride were sequentially added at room temperature. After 30 minutes, about 500 mg of ammonium carbonate was added, and the mixture was further stirred for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Crystals precipitated with ethyl acetate-hexane from the resulting residue were collected by filtration, and N- (2-amino-2-oxoethyl) -N- [2- (2,4-dichlorophenyl) ethyl] nicotinamide 310 mg Was obtained as a white solid.
Production Examples 60 and 61
In the same manner as in Production Example 59, the compounds of Production Examples 60 and 61 shown in the table below were synthesized.

Production Example 62
To a solution of 1.0 g of N- [2- (2,4-dichlorophenyl) ethyl] nicotinamide in 15 ml of THF, 203 mg of 60% oily sodium hydride was gradually added under ice-cooling and stirring. After 1 hour, 0.57 ml of methyl iodide was added, and the mixture was immediately warmed to room temperature and further stirred for 1 hour. Ammonium chloride and 1M aqueous hydrochloric acid were sequentially added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane), converted into hydrobromide using ethanolic hydrobromic acid solution, and crystals precipitated from ethanol-diethyl ether were filtered. Taking, 1.23 g of N- [2- (2,4-dichlorophenyl) ethyl] -N-methylnicotinamide hydrobromide was obtained as a white solid.
Production Example 63
Add 0.06 ml of 2- (3-bromo-4-methoxyphenyl) ethylamine 6.9 mg N-methyl-2-pyrrolidinone solution to 5.3 ml THF solution of nicotinic acid chloride hydrochloride and add PS-diisopropylethylamine (Argonaut Technologies After adding 21 mg, 3.57 mmol / g), the mixture was stirred at room temperature for 1 day. After adding 27 mg of PS-trisamine (Argonaut Technologies, 3.38 mmol / g) and 34 mg of PS-isocyanate (Argonaut Technologies, 1.47 mmol / g) to the reaction solution, the mixture was stirred at room temperature for 2 hours. The solution obtained by filtering the reaction solution was subjected to HPLC (column: CAPCELLPAK C18 AQ 5 μM 30 x 50 mm (manufactured by Shiseido); solvent: MeOH / 0.1% HCOOH-H ₂ O = 10/90 (0 min) -10 / 90 (1 min)-100/0 (9 min) -100/0 (12 min); flow rate 30 ml / min), preparative purification, and N- [2- (3-bromo-4-methoxyphenyl) ) Ethyl] nicotinamide was obtained quantitatively.
Production Example 64
In the same manner as in Production Example 2, the compound of Production Example 64 shown in the table below was produced.

Production Example 65
To a solution of 8.34 g of dimethyl pyridine-3,5-dicarboxylate in 100 ml of methanol was added 43 ml of 1M aqueous sodium hydroxide solution at room temperature, and the mixture was stirred at the same temperature for 2 hours. After completion of the reaction, 43 ml of 1M aqueous hydrochloric acid was added and the solvent was distilled off under reduced pressure to some extent, and the precipitated crystals were collected by filtration to obtain 6.44 g of product. To a solution of 1.8 g of the obtained product in 8.0 ml of DMF, 1.5 g of HOBt and 2.3 g of WSC hydrochloride were sequentially added at room temperature. After 30 minutes, 2.5 g of 2- (2-chloro-4-fluorophenyl) ethylamine hydrochloride and 6.9 ml of TEA were sequentially added, and the mixture was further stirred for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane) to give 5-({[2- (2-chloro Obtained 2.72 g of methyl 4-fluorophenyl) ethyl] amino} carbonyl) nicotinate as a white solid. According to an ordinary method, 300 mg of the obtained compound was obtained as hydrochloride 304 mg as a white solid.
Production Example 66
To a solution of 2.41 g of the compound of Production Example 65 in 25 ml of methanol was added 8 ml of 1M aqueous sodium hydroxide solution at room temperature, and the mixture was stirred at the same temperature for 3 hours. After completion of the reaction, 8 ml of 1M hydrochloric acid aqueous solution was added, and the solvent was distilled off under reduced pressure to some extent. 2.3 g of carbonyl) nicotinic acid were obtained as a white solid. 200 mg of the obtained compound was converted into hydrochloride according to a conventional method, and then crystals precipitated from ethanol-ethyl acetate were collected by filtration to obtain 205 mg of hydrochloride as a white solid.

Production Example 67
HOBt 126 mg and WSC hydrochloride 224 mg were sequentially added to a 5.0 ml DMF solution containing 250 mg of the free compound of Production Example 66 at room temperature. After 30 minutes, 100 mg of methylamine hydrochloride and 0.55 ml of TEA were sequentially added, and the mixture was further stirred overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; methanol: chloroform), converted into hydrochloride according to a conventional method, and then ethanol-ethyl acetate. The precipitated crystals were collected by filtration to obtain 167 mg of N- [2- (2-chloro-4-fluorophenyl) ethyl] -N′-methylpyridine-3,5-dicarboxamide hydrochloride as a white solid.
Production Example 68
A mixture of 5- [2- (benzyloxy) ethoxy] nicotinic acid 771 mg, ethanol 25 ml, methanol 25 ml and palladium carbon 70 mg was stirred overnight under a hydrogen atmosphere. After filtration using celite, the solvent was distilled off under reduced pressure to give 537 mg of 5- (2-hydroxyethoxy) nicotinic acid. To a 10 ml solution of the obtained compound in DMF, 762 mg of HOBt and 1.6 g of WSC hydrochloride were sequentially added at room temperature. After 30 minutes, 1.78 g of 2- (2-chloro-4-fluorophenyl) ethylamine hydrochloride and 2.0 ml of TEA were sequentially added, and the mixture was stirred overnight at the same temperature. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; methanol: chloroform), converted into hydrochloride according to a conventional method, and then ethanol-diethyl ether. The precipitated crystals were collected by filtration to obtain 414 mg of N- [2- (2-chloro-4-fluorophenyl) ethyl] -5- (2-hydroxyethoxy) nicotinamide hydrochloride as a white solid.

Production Example 69
To a solution of 1.14 g of methyl 5- (2-methoxyethoxy) nicotinate in 10 ml of methanol was added 10 ml of 1M aqueous sodium hydroxide solution at room temperature, and the mixture was stirred at the same temperature for 3 hours. After completion of the reaction, 10 ml of 1M aqueous hydrochloric acid solution was added to neutralize the reaction system. Using 5- (2-methoxyethoxy) nicotinic acid obtained by distilling off the solvent under reduced pressure, N- [2- (2-chloro-4-fluorophenyl) ethyl] -5 was prepared in the same manner as in Production Example 68. 721 mg of-(2-methoxyethoxy) nicotinamide hydrochloride was obtained as a white solid.
Production Example 70
To a solution of 180 mg of N-isopropyl-5- (isopropylamino) nicotinamide in 1.0 ml of methanol was added 1.0 ml of 4M aqueous sodium hydroxide solution, and the mixture was stirred at 50 ° C. for 3 hours. After completion of the reaction, 1M aqueous hydrochloric acid solution was added to neutralize the reaction system. Using 5- (isopropylamino) nicotinic acid obtained by evaporating the solvent under reduced pressure, N- [2- (2-chloro-4-fluorophenyl) ethyl] -5- ( 153 mg of isopropylamino) nicotinamide hydrochloride was obtained as a white solid.

Production Example 71
5-amino-N- [2- (2-chloro-4-fluorophenyl) ethyl] nicotinamide 200 mg of pyridine in 6.0 ml was gradually added at 0 ° C with 0.07 ml of acetyl chloride, and the mixture was stirred at the same temperature. Stir for minutes. After completion of the reaction, methanol was added and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol: chloroform), converted into hydrochloride according to a conventional method, and the crystals precipitated from ethanol-ethyl acetate were collected by filtration to give 5- (acetylamino) -N- 153 mg of [2- (2-chloro-4-fluorophenyl) ethyl] nicotinamide hydrochloride was obtained as a white solid.
Production Example 72
tert-butyl 4-{[5-({[2- (2-chloro-4-fluorophenyl) ethyl] amino} carbonyl) pyridin-3-yl] oxy} piperidine-1-carboxylate (5-{[1 -(tert-Butoxycarbonyl) piperidin-4-yl] oxy} nicotinic acid, prepared in the same manner as in Production Example 42 In addition, the mixture was stirred at the same temperature for 3 hours. After the solvent was distilled off under reduced pressure, the crystals precipitated from ethanol-ethyl acetate were collected by filtration, and N- [2- (2-chloro-4-fluorophenyl) ethyl] -5- (piperidin-4-yloxy) nicotinamide 2 Hydrochloride 817 mg was obtained as a white solid.
Production Example 73
The compound of Production Example 72 was prepared in a free form according to a conventional method (173 mg). Stir overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; aqueous ammonia: methanol: chloroform), converted into hydrochloride according to a conventional method, then ethanol- The crystals precipitated from ethyl acetate were collected by filtration, and N- [2- (2-chloro-4-fluorophenyl) ethyl] -5-[(1-methylpiperidin-4-yl) oxy] nicotinamide dihydrochloride 176 mg was obtained as a white solid.

Production Example 74
To a solution of ethyl 4-ethoxynicotinate (893 mg) in ethanol (10 ml) was added 1M aqueous sodium hydroxide solution (6.9 ml) at room temperature, and the mixture was stirred at the same temperature for 2 hours. After completion of the reaction, 1M aqueous hydrochloric acid solution (6.9 ml) was added, the solvent was distilled off under reduced pressure, and 1.13 g of the resulting product was used. 159 mg of (fluorophenyl) ethyl] -4-ethoxynicotinamide hydrochloride was obtained as a white solid.
Production Example 75
To a solution of nicotinic acid 1-oxide (278 mg) in DMF (8.0 ml), HOBt (324 mg) and WSC hydrochloride (575 mg) were sequentially added at room temperature. After 30 minutes, 421 mg of 2- (2-chloro-4,5-difluorophenyl) ethylamine hydrochloride and 0.85 ml of TEA were sequentially added, and the mixture was stirred at the same temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: methanol: chloroform), and crystals precipitated from ethyl acetate-n-hexane are collected by filtration. N- [2- (2-Chloro-4,5-difluorophenyl) ethyl] -4-ethoxynicotinamide 1-oxide 519 mg was obtained as a white solid.
Production Example 76
To a solution of nicotinic acid 1-oxide 206 mg in DMF 6.0 ml, HOBt 486 mg and WSC hydrochloride 1.1 g were sequentially added at room temperature. After 30 minutes, 756 mg of 2- (2-chloro-4-fluorophenyl) ethylamine hydrochloride and 1.2 ml of TEA were sequentially added, and the mixture was stirred overnight at the same temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the precipitated crystals were collected by filtration. After the crystals were dried, the crystals precipitated from ethanol-ethyl acetate were collected by filtration to obtain 435 mg of N- [2- (2-chloro-4-fluorophenyl) ethyl] nicotinamide 1-oxide as a white solid.

Production Example 77
To a chloroform solution of 146 mg of N- [2- (2-chloro-4,5-difluorophenyl) ethyl] -4-methoxynicotinamide was added 163 mg of m-chloroperbenzoic acid at room temperature. Stir for hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (eluent; methanol: chloroform), and crystals precipitated from ethyl acetate were collected by filtration, and N- [ There were obtained 123 mg of 2- (2-chloro-4,5-difluorophenyl) ethyl] -4-methoxynicotinamide 1-oxide as a white solid.
Production Example 78
5-({[2- (2-Chloro-4-fluorophenyl) ethyl] amino} carbonyl) methyl nicotinate 1-oxide Add 192 mg of methanol to 5.0 ml of methanol and add 1M aqueous sodium hydroxide solution 0.6 ml at room temperature. And stirred at the same temperature overnight. After completion of the reaction, 0.6 ml of 1M aqueous hydrochloric acid was added, the solvent was distilled off under reduced pressure to some extent, and the precipitated crystals were collected by filtration to give 5-({[2- (2-chloro-4-fluorophenyl) ethyl] amino} 148 mg of carbonyl) nicotinic acid 1-oxide was obtained.
Production Example 79
N- [2- (2-Chloro-4-fluorophenyl) ethyl] -N '-(2-hydroxyethyl) pyridine-3,5-dicarboxamide 30% hydrogen peroxide solution in 383 mg of acetic acid in 5.0 ml solution 1.0 ml was added and it stirred at 80 degreeC for 2 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (eluent; methanol: chloroform), and crystals precipitated from diisopropyl ether were collected by filtration, and N- [ 45 mg of 2- (2-chloro-4-fluorophenyl) ethyl] -N ′-(2-hydroxyethyl) pyridine-3,5-dicarboxamide 1-oxide was obtained as a white solid.

Production Example 80
To a 14 ml acetic acid solution of 1.39 g of 5-hydroxynicotinic acid, 2.0 ml of 30% hydrogen peroxide was added and stirred at 100 ° C. for 7 hours. After completion of the reaction, the precipitated crystals were collected by washing with water to obtain 1.4 g of the product as a white solid. To a solution of the obtained product 173 mg in DMF 2.0 ml, HOBt 149 mg, WSC hydrochloride 288 mg and 2- (2-chlorophenyl) ethylamine 156 mg were sequentially added at room temperature and stirred at the same temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and crystals precipitated from methanol-water were collected by filtration to give 59 mg of N- [2- (2-chlorophenyl) ethyl] -5-hydroxynicotinamide 1-oxide. Obtained as a white solid.
Production Example 81
To a solution of 372 mg of 4-pyrazinecarboxylic acid in 5.0 ml of DMF, 486 mg of HOBt and 1.15 g of WSC hydrochloride were sequentially added at room temperature. After 30 minutes, 756 mg of 2- (2-chloro-4-fluorophenyl) ethylamine hydrochloride and 2.0 ml of TEA were sequentially added, and the mixture was stirred overnight at the same temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane), and crystals precipitated from ethyl acetate-n-hexane were obtained. By filtration, 726 mg of N- [2- (2-chloro-4-fluorophenyl) ethyl] pyrazine-4-carboxamide was obtained as a white solid.

  In the same manner as in Production Example 2, the compounds in Production Examples 82 to 94, the same as in Production Example 67, the compounds in Production Examples 95 to 102, the same as in Production Example 42, the compounds in Production Examples 103 to 123 and 128 to 130 In the same manner as in Production Example 71, the compound of Production Example 124, the same as Production Example 74, the compounds of Production Examples 125-127, the same as Production Example 75, the compounds of Production Examples 131-132, The compounds of Production Examples 133 to 134 were produced in the same manner as 80, the compounds of Production Examples 135 to 147 were produced in the same manner as Production Example 77, and the compounds of Production Examples 148 to 155 were produced in the same manner as Production Example 81. did. The structures and physicochemical data of the production example compounds are shown in Tables 8 to 19, respectively.

表に示すように、これらの化合物はNO産生促進活性を有することが確認された。 Example 1 Measurement of culture supernatant NOx amount After culturing human aorta-derived vascular endothelial cells (HAEC, manufactured by Clonetics) to a collagen type IV-treated 24-well plate (manufactured by Iwaki Co., Ltd.) until confluent, the medium was changed to a serum-free medium. The culture was continued for 16 hours. After removing the medium, the cells were treated with a serum-free medium containing 10 μM of the test compound for 30 minutes. The amount of NO released from the cells was calculated by measuring the amount of NOx (NO ₂ ⁻ and NO ₃ ⁻ ) in the culture supernatant. The amount of NO ₂ ⁻ and NO ₃ ⁻ was measured using a nitric oxide analysis system (Eicom) according to the attached method.
The increase rate of NOx in the culture supernatant is shown in the following table as a relative ratio to the solvent addition (0.1% DMSO) group.

As shown in the table, these compounds were confirmed to have NO production promoting activity.

Example 2 Relaxation of blood vessels in isolated rat blood vessels
Wistar male rats were anesthetized with pentobarbital and exsanguinated by carotid amputation. Thereafter, the thoracic aorta was removed to prepare a ring specimen. The prepared specimens were suspended in an organ bath (10 mL) filled with Krebs-Hanseleit buffer (pH 7.4, 95% O ₂ , 5% CO ₂ , 37 ° C) under a static tension of 1 g, and 10 ^-6 M Contraction was induced by phenylephrine hydrochloride (PE). Isometric shrinkage of the specimen under PE stimulation conditions was measured using a tension transducer. The isolated blood vessel specimens were allowed to accumulate for 30 to 60 minutes under PE-stimulated conditions, and then the test compound was added cumulatively. The concentration of the test compound that relaxes the contraction by PE by 50% was calculated by the logistic method as an IC ₅₀ value, and used as an index of the activity of the test compound. Furthermore, after washing the bath with a new buffer, [L-NAME (+)] in the presence of NG-nitro-L-arginine methyl ester hydrochloride (L-NAME: 10 ^-5 M), an inhibitor of eNOS, Again, the contraction by PE and the relaxation by the test compound were measured in the same manner as in the absence of L-NAME [L-NAME (−)], and the NO dependence of the relaxation reaction by the test compound was confirmed. For example, the compound of Production Example 14 had an IC ₅₀ value reduced to 70 μM in the presence of L-NAME, confirming that the action was mediated by eNOS.
The measurement results in the absence of L-NAME are shown in the table below.

Example 3 Intracellular eNOS activity measurement with ³ H-arginine
^The measurement of intracellular eNOS activity by ³ H-arginine followed the report of Rajesh KD et al. (Rajesh KD et al., Hypertension, 1993, 21, 939-94). Human aorta-derived vascular endothelial cells (HAEC, manufactured by Clonetics) were cultured until they became confluent in collagen type IV-treated 24-well plates (manufactured by Iwaki Co., Ltd.), then the medium was changed to serum-free medium without L-Arg, and 16 hours The culture was continued. After removal of the medium, ³ H-Arg (final concentration 1.5 μCi / mL), modified HEPES solution containing test compound (25 mM Hepes (pH 7.4), 140 mM NaCl, 5.4 mM KCl, 1.8 mM CaCl ₂ , 1.0 mM MgCl ₂ , 5.0 mM glucose). Ice-cold 1.3N trichloroacetic acid was added at 400 μL / well to stop the reaction, and the cells were disrupted by freezing and thawing. After the cell lysate is treated with ether, stop buffer (200 mM Hepes (pH5.5), 20 mM EDTA) and Dowex resin (Bio-Rad) are added and mixed, then Dowex resin is removed by filtration, and ³ H-Citrullin amount Was measured with a liquid scintillation counter.

Example 4 Anesthetic Rat Hindlimb Blood Flow Increasing Action Regarding the compounds of Reference Production Examples and Production Examples of the present invention, the hindlimb blood flow increasing action in pentobarbital anesthetized rats was confirmed by the following test method.
Wistar male rats were used. Test compound 30 mg / 5 mL / kg (0.5% methylcellulose) was orally administered, and 2 hours later, pentobarbital 60 mg / kg was intraperitoneally administered and anesthetized. The hindlimb blood flow was measured using a laser blood flow imaging device (PIM II; Integral).
As a result of this test, the compound of Production Example 87 shows a blood flow improvement effect of 132%, and the compounds of Production Examples 2, 28, 76, 81, 105, 121, and 139 show a blood flow improvement effect of 117 to 164%. It was.
As a result of the above tests, it was confirmed that the compound of the present invention has NO production promoting activity, eNOS activation activity, and blood flow increasing action. From this, it is clear that it is useful as a therapeutic agent for various diseases caused by vascular endothelial dysfunction such as PAOD including intermittent claudication, arteriosclerosis, and ischemic heart disease.

Example 5 Learning disorder improving action in old rats (sound fear conditioning reaction test)
F344 male rats (Charles River Japan) 28-30 months old (old) were used for the experiment. Training was conducted on the first day of the test. Rats were brought into the laboratory more than 1 hour before the start of training. Test compound or placebo was administered orally. The test compound was suspended in a 0.5% aqueous methylcellulose solution, and the administration volume was 3 ml per kg body weight. The same amount of 0.5% methylcellulose aqueous solution was administered as a placebo. One hour later, the rat was placed in an acrylic box (with electrical stimulator) in a soundproof box, and an electric shock (0.12 mA, 1 second) was applied while listening to the sound (10 kHz, 60 dB, 20 seconds). did. A total of 3 runs were performed at 40 second intervals. The rat was removed and returned to the home cage to complete the training. After that, it was left in the laboratory for over 1 hour and returned to the breeding room. The test was conducted two days later. Rats were brought into the laboratory more than 1 hour before the start of the test. Rats were placed in an acrylic box separate from the acrylic box with an electrical stimulator used during training, and after 1 minute, only a sound stimulus (10 kHz, 60 dB, once for 180 seconds) was applied. While the sound stimulus is applied, a marked decrease in the amount of activity / freezing behavior occurs. The time (in seconds) during which this freezing occurs is measured and used as an index for the formation of memory / learning ability. . The behavior was observed with a CCD camera installed at the top of the acrylic box, and sound and electric shock loads and freezing time were all measured by computer control. The presence or absence of the learning disorder-improving effect of the test compound was determined by comparing the time of freezing between the rat group administered with the placebo and the rat group administered with the test compound by Dunnett's test. It was determined that there was a significant difference at p <0.05. The minimum effective dose of the compound of Production Example 76 was 3 mg / kg.

Example 6 Learning disorder improving action in a rat model of cerebral embolism induced by microsphere injection (passive avoidance reaction test)
For the preparation of cerebral embolism model animals, rats were anesthetized with pentobarbital, and after the midline neck incision, the right external carotid artery and pterygopalatary artery were temporarily driven and suspended in a physiological saline containing 20% dextran. 500 microspheres (diameter 50 μm) were injected from the right common carotid artery via a catheter, and the microbrain was occluded. Thereafter, the catheter was removed, and blood flow in the right external carotid artery and pterygopalatary artery was resumed. A sham-operated rat was injected with 20% dextran-containing physiological saline in which microspheres were not suspended. The passive avoidance response test was conducted with a recovery period of 7 days after surgery. Training was conducted on the first day of the test. Rats were brought into the laboratory at least 1 hour before the start of the test and acclimated. Test compound or placebo was administered orally. The test compound was suspended in a 0.5% aqueous methylcellulose solution, and the administration volume was 10 ml per kg body weight. The same amount of 0.5% methylcellulose aqueous solution was administered as a placebo. One hour later, the rat was placed in the light room, 30 seconds later, the light / dark partition door was opened, and after the rat entered the dark room, the light / dark partition door was closed, and the photo beam sensor in the dark room was crossed to make electricity from the metal grit on the floor. A shock (intensity 0.25 mA, delay 1 second, duration 3-5 seconds) was applied. After exposure to electric shock, the light / dark partition door was opened and confirmed to escape to the light room. After leaving for 30 seconds, the rat was removed and returned to the home cage to complete training. After that, it was left in the laboratory for more than 1 hour and returned to the breeding room. The test was conducted on the second day of the test. Rats were brought into the laboratory more than 1 hour before the start of the test. Place the rat in the light room of the passive avoidance reaction device, leave it for 30 seconds, open the light / dark partition door, cross the photo beam sensor in the dark room, measure the time until the rat's limbs completely enter the dark room and react It was set as step-through latency. Step-through latency (in seconds) was used as an index of memory and learning ability formation. The presence or absence of learning impairment due to microsphere injection-induced cerebral embolism was determined by comparing the step-through latency of the cerebral embolic rat group administered with placebo and the sham operated rat group using the Wilcoxon rank sum test. The presence or absence of the test compound's ability to improve learning impairment was determined by comparing the step-through latency of the cerebral embolus rat group administered with the placebo and the cerebral embolus rat group administered with the test compound by a two-sided Steel test. In each test, it was determined that there was a significant difference at p <0.05. The minimum effective dose of the compound of Production Example 76 was 10 mg / kg.
As a result of the tests of Examples 5 and 6 above, the compounds of the present invention showed a learning disorder improving action, and thus were confirmed to be useful as a dementia therapeutic agent.

Example 7 Function recovery enhancing / promoting action in cerebral infarction model rats (stair case test)
Male spontaneously hypertensive rats (Hoshino test animals) weighing 253 to 344 g were used. The forelimb function is the same as the method described in J Neurosci Methods 36, 219-228, 1991. The test using the case) was evaluated. Rats previously restricted in food were placed in the steer case to acquire the skill of ingesting food placed in the depressions of each step of the stairs. The number of foods picked up by the left and right forelimbs and the number of foods eaten were measured. After acquiring ingestion skills, cerebral infarction was created. Cerebral infarction model animals were prepared using the method described in J Cereb. Blood Flow Metab. 8, 474-485, 1988 with the left common carotid artery and ipsilateral middle cerebral artery occluded. Paralysis occurred in the right forelimb. The test compound was orally administered 5 days a week from the week after the preparation of cerebral infarction to the 6th week. The test compound was suspended in an aqueous 0.5% methylcellulose solution, the dose volume was 3 ml per kg body weight, and the dose was 1 mg / kg. The same amount of 0.5% methylcellulose aqueous solution was administered to the control group. The test was conducted 1 hour after drug administration. In order to determine the presence or absence of the function recovery enhancing / promoting action, the maximum value of each individual in the amount of food intake by the right forelimb in the last week of function recovery training was compared by Dunnett's test. As a result of comparing the dysfunction of the right forelimb that was paralyzed using the number of foods taken and the number of foods eaten as an index, the compound administration group of Production Example 76 showed a significant improvement effect compared to the control group (p < 0.05).
As a result of the test of Example 7 above, since the compound of the present invention showed an improvement effect on the forelimb motor dysfunction, it may be useful as a dysfunction recovery promoter or a functional recovery training effect enhancement and / or promoter. confirmed.

  Moreover, the regulation of the diameter of arterioles that form vascular resistance has been reported to involve greater involvement of endothelium-derived hyperpolarizing factor (EDHF) than EDRF (NO) (Am. J. Physiol., 1999) , 277, H1252-H1259; Acta Physiol. Scand., 2000, 168, 505-510), the pharmaceutical of the present invention can also be expected to have little effect on blood pressure and heart rate. Further, the compound (I), particularly an N-oxide compound in which k is 1, has little influence on drug-drug interactions and metabolic enzymes (particularly cytochrome P450 enzymes such as CYP3A4), and is considered preferable as a pharmaceutical.

Since the phenethylnicotinamide compound or a salt thereof, which is an active ingredient of the medicament of the present invention, has an excellent blood vessel circulation improvement action by promoting vascular endothelial NO production and / or eNOS activation action, there are various vascular endothelial dysfunctions. It is effective for diseases or pathological conditions in which is caused, or diseases that cause vascular endothelial dysfunction or decline. In particular, heart diseases such as heart failure, myocardial infarction, angina pectoris; peripheral arterial diseases (PAD) such as arteriosclerosis, hypertension, pulmonary hypertension, obstructive arteriosclerosis, PAOD, occlusive thromboangiitis, aortitis syndrome; Vascular diseases such as restenosis; Thrombosis; Intervertebral stenosis; Diabetes; Diabetic complications such as diabetic retinopathy, diabetic neuropathy, diabetic vasculopathy, diabetic limb lesions, diabetic vasculopathy; It is useful as a therapeutic agent for gastrointestinal diseases such as gastric ulcer and ischemic bowel disease; renal diseases such as renal disorder, renal failure, nephritis and nephrosclerosis; and urological diseases such as erectile dysfunction. Furthermore, it is useful as a preventive or therapeutic agent for dementia. Dementia includes Alzheimer-type dementia; cerebrovascular dementia (cerebrovascular dementia); Lewy body dementia; Alzheimer's disease, Pick disease, Creutzfeldt-Jakob disease, Kraepelin disease, Parkinson's disease, Huntington chorea, Hallervorden -Spats disease, spinocerebellar degeneration, progressive myoclonic epilepsy, progressive supranuclear palsy, viscous edema, parathyroid disease, Wilson disease, liver disease, hypoglycemia, distant symptoms of cancer, Cushing syndrome, uremia, arteriosclerosis Disease, cerebral arteriosclerosis (chronic cerebral circulatory insufficiency), cerebral hemorrhage, cerebral infarction, cerebral embolism, subarachnoid hemorrhage, chronic subdural hemorrhage, pseudobulbar paralysis, aortic arch syndrome, Binswanger disease, arteriovenous malformation-occlusive thrombosis Arteritis, hypoxia, anoxia, normobaric hydrocephalus, Wernicke-Korsakoff syndrome, pellagra, Marchiafava-Bignami disease, vitamin B12 deficiency, poisons or drugs (metals, organic compounds, carbon monoxide, drugs) ,brain Ulcer, open and closed head trauma, Bunchy syndrome, fever, infection, bacterial meningitis, fungal meningitis, encephalitis, progressive multifocal leukoencephalopathy, Behcet syndrome, Kuru, syphilis, multiple Sclerosis, muscular dystrophy, Whipple disease, camp syndrome, disseminated lupus erythematosus, cardiac arrest, AIDS encephalopathy, hypothyroidism, hypopituitarism or chronic alcoholism dementia; mild cognitive impairment : MCI); or behavioral and psychological symptoms of dementia (BPSD), which are various mental symptoms and behavioral disorders associated with dementia (peripheral symptoms). Furthermore, it is also useful as an agent for enhancing and / or promoting the recovery promoting action or functional recovery training (rehabilitation medicine) effect of dysfunction including motor dysfunction caused by central nervous degenerative diseases such as stroke, brain trauma and spinal cord injury. In addition, the pharmaceutical of the present invention can be expected to have little influence on blood pressure and heart rate.

Claims (16)

Vascular endothelial nitric oxide production promotion and / or endothelial monoxide comprising a phenethylnicotinamide compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier: Nitrogen synthase activator.

(The symbols in the formula have the following meanings.
X ¹ : N or CR ¹
X ² : N or CR ² ,
X ³ : N or CR ³ ,
However, when ^one of X ¹ , X ² or X ³ is N, the other two are not N.
R ¹ , R ² , R ³ and R ⁴ : the same or different from each other, —H, —halogen, —R ^A , —OH, —OR ^A , —SR ^A , —halogeno lower alkyl, —N (R ¹¹ ) (R ¹² ), -O-cycloalkyl, -O- (optionally substituted nitrogen-containing saturated heterocyclic ring), -CN, -CO ₂ H, -CO ₂ -R ⁰ or -CO-N (R ¹³⁾ (R ^14),
R ^A : lower alkyl optionally substituted with one or more groups selected from —OH, —OR ⁰ , —CO ₂ H and —CO ₂ —R ⁰ ,
R ⁰ : -lower alkyl,
R ¹¹ and R ¹² are the same or different from each other, -H, -R ⁰ or -CO-R ⁰ ,
R ¹³ and R ¹⁴ are the same or different from each other, and may be substituted with -H, -R ⁰ , -lower alkylene-OH, -lower alkylene-OR ⁰ or -cycloalkyl, or a nitrogen atom to which they are bonded. A nitrogen-containing saturated heterocyclic ring may be formed,
R ⁵ : -H, -R ⁰ , -lower alkylene-CO ₂ H, -lower alkylene-CO ₂ -R ⁰ or -lower alkylene-CO-N (R ¹⁵ ) (R ¹⁶ ),
R ¹⁵ and R ¹⁶ are the same or different from each other, -H or -R ⁰ ,
Hal: halogen,
R ⁶ : —NO ₂ , —CN, —R ⁰ , —OH, —halogeno lower alkyl, —CO ₂ H, —OR ⁰ , —CO ₂ —R ⁰ , —CO—N (R ¹³ ) (R ¹⁴ ) Or -lower alkylene-OR ⁰ ,
m: 1, 2, 3, 4 or 5,
However, when m is 2 or more, Hal may be the same or different from each other.
n: 0 or 1, provided that m + n is 5 or less,
k: 0 or 1. A therapeutic agent for peripheral arterial occlusive disease comprising a phenethylnicotinamide compound represented by the formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The therapeutic agent according to claim 2, wherein the peripheral artery occlusion is intermittent claudication. A preventive or therapeutic agent for dementia comprising the phenethylnicotinamide compound represented by the formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The preventive or therapeutic agent according to claim 4, wherein the dementia is Alzheimer type dementia, cerebrovascular dementia (cerebrovascular dementia) or Lewy body type dementia. Dementia is Alzheimer's disease, Pick's disease, Creutzfeldt-Jakob disease, Kraepelin's disease, Parkinson's disease, Huntington's disease, Hallervorden-Spats disease, spinocerebellar degeneration, progressive myoclonic epilepsy, progressive supranuclear palsy, viscous edema, parathyroid gland Disease, Wilson disease, liver disease, hypoglycemia, distant symptoms of cancer, Cushing syndrome, uremia, arteriosclerosis, cerebral arteriosclerosis (chronic cerebral circulatory insufficiency), cerebral hemorrhage, cerebral infarction, cerebral embolism, subarachnoid hemorrhage Chronic subdural hemorrhage, pseudobulbar paralysis, aortic arch syndrome, Binswanger disease, arteriovenous malformation-occlusive thrombotic arteritis, hypoxia, anoxia, normobaric hydrocephalus, Wernicke-Korsakoff syndrome, Pellagra, Marchiafava -Bignami disease, vitamin B12 deficiency, damage caused by poisons or drugs (metals, organic compounds, carbon monoxide, drugs), brain tumors, open and closed head trauma, Bunchy syndrome, fever attacks, infections, bacterial meninges Flame, fungal marrow Inflammation, encephalitis, progressive multifocal leukoencephalopathy, Behcet syndrome, Kuru, syphilis, multiple sclerosis, muscular dystrophy, Whipple disease, camp syndrome, disseminated lupus erythematosus, cardiac arrest, AIDS encephalopathy, hypothyroidism 5. Dementia caused by hypopituitarism or chronic alcoholism; mild cognitive impairment; or various psychological symptoms as symptoms associated with dementia (peripheral symptoms) and behavioral psychological symptoms as behavioral disorders Prophylactic or therapeutic agent. The dysfunction recovery promoter after onset of a central nervous disease comprising the phenethylnicotinamide compound represented by the formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. . The dysfunction recovery training effect after CNS onset comprising the phenethylnicotinamide compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Enhancers and / or accelerators. The agent according to claim 7 or 8, wherein the central nervous disease is stroke, brain injury, spinal cord injury or neurodegenerative disease. The agent according to claim 9, wherein the dysfunction is motor dysfunction, sensory dysfunction or speech dysfunction. A pharmaceutical composition comprising a phenethylnicotinamide compound represented by the following formula (I ') or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

(The symbols in the formula have the following meanings.
X ¹ : N or CR ¹
X ² : N or CR ² ,
X ³ : N or CR ³ ,
However, when ^one of X ¹ , X ² or X ³ is N, the other two are not N.
R ¹ , R ² , R ³ and R ⁴ : the same or different from each other, —H, —halogen, —R ^A , —OH, —OR ^A , —SR ^A , —halogeno lower alkyl, —N (R ¹¹ ) (R ¹² ), -O-cycloalkyl, -O- (optionally substituted nitrogen-containing saturated heterocyclic ring), -CN, -CO ₂ H, -CO ₂ -R ⁰ or -CO-N (R ¹³⁾ (R ^14),
R ^A : lower alkyl optionally substituted with one or more groups selected from —OH, —OR ⁰ , —CO ₂ H and —CO ₂ —R ⁰ ,
R ⁰ : -lower alkyl,
R ¹¹ and R ¹² are the same or different from each other, -H, -R ⁰ or -CO-R ⁰ ,
R ¹³ and R ¹⁴ are the same or different from each other, and may be substituted with -H, -R ⁰ , -lower alkylene-OH, -lower alkylene-OR ⁰ or -cycloalkyl, or a nitrogen atom to which they are bonded. A nitrogen-containing saturated heterocyclic ring may be formed,
R ⁵ : -H, -R ⁰ , -lower alkylene-CO ₂ H, -lower alkylene-CO ₂ -R ⁰ or -lower alkylene-CO-N (R ¹⁵ ) (R ¹⁶ ),
R ¹⁵ and R ¹⁶ are the same or different from each other, -H or -R ⁰ ,
Hal: halogen,
R ⁶ : —NO ₂ , —CN, —R ⁰ , —OH, —halogeno lower alkyl, —CO ₂ H, —OR ⁰ , —CO ₂ —R ⁰ , —CO—N (R ¹³ ) (R ¹⁴ ) Or -lower alkylene-OR ⁰ ,
m: 1, 2, 3, 4 or 5,
However, when m is 2 or more, Hal may be the same or different from each other.
n: 0 or 1, provided that m + n is 5 or less,
k: 0 or 1.
Except for the following compounds:

In the table, the number in front of the halogen in the (Hal) _m column represents the substitution position, and 2,4-diCl indicates that Cl exists at the 2-position and 4-position, respectively. ) X ¹ is CR ¹ ; X ² is CR ² ; X ³ is CR ³ ; ^one of R ¹ , R ² , R ³ and R ⁴ is —H, —halogen, —R ⁰ , —OR ⁰ , — The pharmaceutical composition according to claim 11, which is a group selected from SR ⁰ and -halogeno lower alkyl, and the other three are -H. The pharmaceutical composition according to claim 11, wherein R ⁵ is H. The pharmaceutical composition according to claim 13, wherein X ¹ is N or CR ¹ , X ² and X ³ are both CH. The pharmaceutical composition according to claim 14, wherein k is 1. The pharmaceutical composition according to claim 11, wherein the phenethylnicotinamide compound represented by the formula (I ') according to claim 11 is selected from the following group: N- [2- (2-chloro-4-fluoro) Phenyl) ethyl] nicotinamide, N- [2- (3-bromophenyl) ethyl] nicotinamide, N- [2- (2,4,5-trifluorophenyl) ethyl] nicotinamide, N- [2- ( 2-chloro-4-fluorophenyl) ethyl] -5- (isopropylamino) nicotinamide, N- [2- (2-chloro-4-fluorophenyl) ethyl] nicotinamide 1-oxide, N- [2- ( 2-chloro-4-fluorophenyl) ethyl] pyridazine-4-carboxamide, N- [2- (2-chloro-4,5-difluorophenyl) ethyl] nicotinamide, N- [2- (2-chloro-4 -Fluorophenyl) ethyl] -5-hydroxynicotinamide, N- [2- (2-chlorophenyl) ethyl] -5-methylnicotinamide, N- [2- (2-chloro-4-fur) Rofeniru) ethyl] -5-ethoxy-nicotinamide 1-oxide and N- [2- (2- chloro-4,5-difluorophenyl) ethyl] pyrimidine-5-carboxamide.