2-aminopyridine compounds and use thereof as drugs

专利摘要:
Provided are 2-aminopyridine compounds and salts thereof having the following excellent adenosine receptor (A1, A 2A , A 2B receptor) antagonisms: [Wherein, R 1 represents a cyano group, a carboxy group or a carbamoyl group which may have a substituent; R 2 is a hydrogen atom, a hydroxyl group, a C 1-6 alkoxy group which may have a substituent, a C 6-14 aromatic hydrocarbon cyclic group which may have a substituent or a 5-14 membered aromatic heterocyclic group which may have a substituent Represent; R 3 and R 4 are the same or different, and each represent a C 6-14 aromatic hydrocarbon cyclic group, a 5 to 14 membered non-aromatic heterocyclic group, a 5 to 14 membered aromatic heterocyclic group, etc. which may have a substituent;
公开号:KR20030022382A
申请号:KR10-2003-7001943
申请日:2001-08-09
公开日:2003-03-15
发明作者:하라다히토시；아사노오사무；미야자와슈헤이；우에다마사토；야스다마사히로；야스다노부유키
申请人:에자이 가부시키가이샤；
IPC主号:

专利说明:

2-aminopyridine compound and its pharmaceutical use {2-AMINOPYRIDINE COMPOUNDS AND USE THEREOF AS DRUGS}
[2] Adenosine is an important regulator of cellular metabolism, including the regulation of energy and cAMP levels in vivo, the opening and closing of potassium channels, and the influx of calcium ions into cells. By interaction, the physiological activity can be expressed. Adenosine receptors are initially classified into two groups, A ₁ receptor and A ₂ receptor, depending on their involvement in adenylate cyclase [J. Neurochem., 33, 999-1003, (1979)], and thereafter, according to the high level of affinity for the A ₂ receptor agonist NECA and CGS-21680, the A ₂ receptor was classified into two groups, A _2A and A _2B . (Mo1. Pharmaco1., 29, 331-346, (1986); J. Neurochem., 55, 1763-1771, (1990)). Thus, to date, A ₁ , A ₂ (A _2A , A _2A ), Four subtypes of A ₃ have been identified: The A ₁ receptor is a protein conjugated with proteins of the G _{i / o} family By binding a ligand, adenylate cyclase is inhibited to increase cAMP levels. inhibited, and further phosphorylation by activating the lipase C (PLC) to promote production and intracellular calcium ion release of inositol -1,4,5- triphosphate (IP _3). a ₃ receptor, a ₁ receptor and, like cAMP the receptors that inhibit level, again to enable the PLC is known to promote the IP ₃ production and the release of calcium ion. in contrast, a _2A and a _2B receptors, adenylate nilre By activating the bit Sickle la kinase, a receptor to stimulate the production of cAMP levels. A _2B is made of a conjugated with PLC via a G _q / G ₁₁ protein with respect to, or the IP ₃ levels of production and intracellular influx of calcium ions (Clin. Invest., 196, 1979-1986 (1995)), each subtype has a different distribution in tissues, such that A ₁ receptors are used in the heart, aorta, bladder, and A _2A receptors in the eye. , Skeletal muscle and the like, A ₃ receptors are relatively distributed in the spleen, uterus and prostate, respectively, while A _2B receptors are relatively high in the proximal colon, followed by eye, lung, uterus and bladder. [Br. J. Pharmaco1., 118, 1461-1468 (1996)] Each of the adenosine receptor subtypes is able to exert its own function, in addition to the differences in the distribution between tissues, the difference in local adenosine concentrations and each sub The difference in affinity for the type of ligand It is for a reason. The physiological functions involved in adenosine are truly versatile, such as platelet aggregation, heart rate, smooth muscle tension, inflammation, neurotransmitter release, neurotransmission, hormone release, cell differentiation, cell growth, cell death, and DNA biosynthesis. Therefore, it has been suggested that adenosine and central nervous system disease, cardiovascular disease, inflammatory disease, respiratory disease, immune disease, etc. have been conventionally associated with adenosine and agonist / antagonist. On the other hand, in recent years, there is an important report on the association between the adenosine A ₂ receptor and the intestinal tract. For example, it has been reported that colonic myofascial relaxation is via the A ₂ receptor [Naunyn-Schmiedeberg's Arch. Pharmaco1., 359, 140-146 (1999)], it has been reported that the adenosine relaxation of the morphologic distal colon freckles is via the A ₁ receptor and the A _2B receptor present in the fraudulent muscle itself [Br. J. Pharmaco 1, 129, 871-876 (2000)]. Conventionally, adenosine receptors, especially adenosine A ₂ receptor antagonists, have been pointed out as useful agents for the treatment or prevention of diabetes mellitus, diabetic complications, diabetic retinopathy, obesity, asthma, hypoglycemic agents, glucose tolerance improving agents, insulin sensitivity enhancers. It is expected to be useful as an antihypertensive, diuretic, osteoporosis therapeutic, anti-Parkinson's drug, Alzheimer's disease, inflammatory bowel disease, clonal disease, etc.
[3] In particular, a compound having an antagonistic action against the A _2B receptor, for example, there are reports as follows.
[4] [1] expression
[5]
[6] Compound represented by.
[7] [2] expression
[8]
[9] [Wherein, R ¹ is (1)
[10]
[11] Wherein X represents a hydrogen atom, a hydroxyl group, a lower alkyl group which may have a substituent, a lower alkoxy group which may have a substituent, etc. R ⁵ and R ⁶ are the same or different, and a hydrogen atom, a substituent Lower alkyl group which may have, saturated or unsaturated C _3-8 cycloalkyl group which may have a substituent, etc.) or (2) a 5 or 6 membered aromatic ring which may have a substituent and a hetero atom. do. W is an expression
[12]
[13] Means. R < ² > means the amino group etc. which may be substituted by the lower alkyl group etc. which may have a substituent. R ³ means a C _3-8 cycloalkyl group which may have a substituent, an aryl group which may have a substituent, or the like. R ⁴ means a lower alkyl group which may have a substituent or the like].
[14] [3] general formula
[15]
[16] [Wherein, R ¹ means a hydrogen atom, a hydroxyl group, a halogen atom, a C _1-8 alkyl group which may have a substituent, etc., R ² means an amino group which may be substituted with a C _1-8 alkyl group or the like R ³ means a C _3-8 alkynyl group which may be substituted with a halogen atom, a hydroxyl group or a C _1-4 alkyl group, and Ar is an aryl group which may have a substituent, or a hetero which may have a substituent. An aryl group and the like, Q and W are the same or different, and mean N or CH.] Purine compounds or pharmacologically acceptable salts or their hydrates.
[17] [4] Drug Development Research, 48: 95-103 (1999) and J. Med. Chem., 43: A _2B receptor antagonists described in 1165-1172 (2000).
[18] On the other hand, as a pyridine compound, for example, there are reports regarding 5,6-aromatic substituted pyridine compounds in WO96 / 24584, US Pat. No. 5,686,470, US Pat. No. 5,916,905 and the like. DE4117802A1 also discloses a report relating to 2-amino-3-pyridinecarbonitrile and a compound in which the 4, 5 and 6 positions of the pyridine ring are substituted with a phenyl group. However, there is no description or suggestion regarding the association between these compounds and adenosine receptors, and they are not known at all.
[19] With the compound having an adenosine receptor antagonism, particularly the adenosine A ₂ receptor (among which Fig. A _2B receptor) antagonistic action as described above, compounds may be expected that can exhibit an excellent action as a medicament, and is waiting for the service is urgently. However, no compound has been found that exhibits excellent antagonistic action against adenosine receptors and also functions effectively as a medicine. Accordingly, an object of the present invention is to search and find the above-mentioned receptor inhibitory compounds useful as a therapeutic or prophylactic agent for diseases involving adenosine receptors (particularly A ₂ receptors, A _2B receptors).
[1] The present invention relates to novel 2-aminopyridine compounds, their preparation and their use as medicaments.
[20] The present inventors conducted energetically in view of the above circumstances. As a result, the expression
[21]
[22] [Wherein, R ¹ represents a cyano group, a carboxy group or a carbamoyl group which may have a substituent; R ² is a hydrogen atom, a hydroxyl group, a C _1-6 alkoxy group which may have a substituent, a C _6-14 aromatic hydrocarbon cyclic group which may have a substituent or a 5-14 membered aromatic heterocyclic group which may have a substituent Represent; R ³ and R ⁴ are the same or different and each may have a C _3-8 cycloalkyl group, C _3-8 cycloalkenyl group, C _6-14 aromatic hydrocarboncyclic group, _5-14 membered non-aromatic heterocyclic group which may have a substituent Group or a 5-14 membered aromatic heterocyclic group; Provided that (1) when R ¹ is a cyano group, R ² is a 4-bromo-2-thienyl group, R ³ is a 3,4-dimethoxyphenyl group, and R ⁴ is a 2-thienyl group, ( 2) When R ¹ is a cyano group, R ² is a hydrogen atom, and R ³ and R ⁴ are phenyl groups, (3) R ¹ is a cyano group, R ² is a 4-chloro-phenyl group, and R ³ is When a phenyl group and R ⁴ is a 4- (3,4-dichlorophenyl) -1-oxo-2 (lH) -phthalazinyl group, (4) R ¹ is a cyano group, R ² is a hydrogen atom, When R ³ is a 4-pyridyl group and R ⁴ is a 1-piperazinyl group, (5) R ¹ is a cyano group, R ² is a hydrogen atom, R ³ is a 4-pyridyl group, and R ⁴ Is a 1-pyridyl group, (6) R ¹ is a cyano group, R ² is a hydrogen atom, R ³ is a 4-pyridyl group, and R ⁴ is a 4-diphenylmethyl-1-piperazinyl group If, (7) R ¹ is a cyano group, R ² is a hydrogen atom, and R ³ a group-4-pyridyl, and R ⁴ is 4-morpholinyl group If, (8) R ¹ is a cyano group, R ² is 4-methylphenyl group and, if also R ³ and R ⁴ is a phenyl group, and (9) R ¹ is a cyano group, and R ^2, R ^3, and Except for the case where R ⁴ is a phenyl group] for the first time, and unexpectedly, the compound and its salts have excellent antagonistic action against adenosine A ₂ receptors, especially A _2B receptors. found. As a result of further investigation, the compound or a salt thereof is associated with a disease involving adenosine receptors, particularly adenosine A ₂ receptors, especially adenosine A _2B receptors, for example, constipation, irritable bowel syndrome and irritable bowel syndrome. Constipation, organic constipation, constipation with intestinal palsy, constipation with congenital digestive tract dysfunction, constipation with intestinal obstruction, diabetes, diabetic complications, diabetic retinopathy, obesity, asthma, therapies, preventive agents or In addition to being useful as an improving agent, blood sugar lowering agents, impaired glucose tolerance, insulin sensitivity enhancers, hypertensive agents, diuretics, osteoporosis drugs, anti-Parkinson drugs, Alzheimer's disease drugs, inflammatory bowel disease drugs, clonal disease drugs, etc. Completed.
[23] That is, this invention is (1) the compound or its salt represented by said formula (I), (2) the compound or its salt whose R <^1> is cyano group in said (1), and (3) in said (1) R ¹ is
[24]
[25] [Wherein, R ⁵ and R ⁶ are the same or different and are a hydrogen atom, a C _1-6 alkyl group which may have a substituent, a C _2-6 alkenyl group which may have a substituent, a C which may have a substituent _{A 2-6} alkynyl group, a C _6-14 aromatic hydrocarbon cyclic group which may have a substituent or a 5-14 membered aromatic heterocyclic group which may have a substituent], or a compound thereof or a salt thereof, ( 4) The compound or a salt thereof according to (1), wherein R ² is a C _6-14 aromatic hydrocarbon cyclic group or a 5-14 membered aromatic heterocyclic group, each of which may have a substituent, (5) in (1) above , R ² is a phenyl group, naphthyl group, pyridyl group, thienyl group or furyl group, or a salt thereof, each of which may have a substituent, (6) In (1), R ² is substituted with a halogen atom A compound or a salt thereof, which may be a phenyl group, (7) The compound or a salt thereof, wherein R ² is a hydrogen atom in (1), (8) In (1), R ³ and R ⁴ are the same or different. And a C _6-14 aromatic hydrocarbon cyclic group or a 5-14 membered aromatic heterocyclic group or a salt thereof, each of which may have a substituent, (9) In (1), R ³ and R ⁴ are the same or different. A phenyl group, a pyrrolyl group, a pyridinyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a thienyl group, a thiazolyl group, a furyl group, a naphthyl group, a quinolinyl group and an isoqui, A compound or a salt thereof, which is a nolinyl group, a phthalazinyl group, a naphthyridinyl group, an indolyl group, or an isoindolinyl group, (10) The phenyl group in which R ³ and R ⁴ may each have a substituent, A compound which is a pyridyl group, thienyl group or furyl group or A salt thereof, (11) A 5 to 14 membered non-aromatic heterocyclic group, (C ₆ ) according to (1), wherein R ³ and / or R ⁴ may each be substituted with one or more groups selected from the following substituent group a. _{A -14} aromatic hydrocarbon cyclic group or a _5-14 membered aromatic heterocyclic group or a salt thereof: (The substituent group a is (1) hydroxyl group, (2) halogen atom, (3) nitrile group, (4) nitro group, ( 5) (i) hydroxyl group, (ii) nitrile group, (iii) halogen atom, (iii) C _1-6 alkylamino group, (v) di (C _1-6 alkyl) amino group, (iii) C _2-6 al Kenylamino group, (iii) di (C _2-6 alkenyl) amino group, (iii) C _2-6 alkynylamino group, (iii) di (C _2-6 alkynyl) amino group, (x) NC _1-6 alkyl -NC _2-6 alkenylamino group, (xi) NC _1-6 alkyl-NC _2-6 alkynylamino group, (xii) NC _2-6 alkenyl-NC _2-6 alkynylamino group, (x ') aralkyloxy group , (x ') TBDMSoxy group, (xv) C _1-6 alkylsulfonylamino group, (xvi) C _1-6 alkylcarbonyloxy group, (x Ⅶ) C _2-6 alkenyl carbonyloxy group, (xⅷ) C _2-6 alkynyl carbonyloxy group, (xix) NC _1-6 alkyl-carbamoyl group, (xx) NC _2-6 alkenyl carbamoyl C _1-6 alkyl group, C _2-6 alkenyl group or C _2-6 alkynyl group, which may each be substituted with one or more groups selected from diary and (xxi) NC _1-6 alkynylcarbamoyl group, (6) ( i) a C _1-6 alkoxy group, a C _2-6 alkenyloxy group or C _2- which may each be substituted with one or more groups selected from C _1-6 alkylamino groups, (ii) aralkyloxy groups and (iii) hydroxyl groups ₆ alkynyloxy group, (7) (i) hydroxyl group, (ii) nitrile group, (iii) halogen atom, (iii) C _1-6 alkylamino group, (v) aralkyloxy group, (vi) TBDMSoxy group, ( ⅶ) C _1-6 alkylsulfonyl group, (ⅷ) C _1-6 alkylcarbonyloxy group and (ix) C _1-6 C _1- which may be each substituted with alkyl groups at least one selected from a carbamoyl group ₆ alkylthio group, C _2-6 alkenylthio group or C _2-6 alkynylthio group, (8) (i) a C _1-6 alkoxy group, (ii) an amino group, (iii) a C _1-6 alkylamino group, (iii) a di (C _1-6 alkyl) amino group, (v) a C _2-6 alkenylamino group, ( vi) di (C _2-6 alkenyl) amino group, (iii) C _2-6 alkynylamino group, (iii) di (C _2-6 alkynyl) amino group, (iii) NC _1-6 alkyl-NC _2- A carbonyl group substituted with a group selected from a ₆ alkenylamino group, (ix) an NC _1-6 alkyl-NC _2-6 alkynylamino group and (x) an NC _2-6 alkenyl-NC _2-6 alkynylamino group, (9) (i) a C _1-6 alkyl group, (ii) a C _2-6 alkenyl group, (iii) a C _2-6 alkynyl group, (iii) a C _1-6 alkylsulfonyl group, (v) a C _2-6 alkenylsulfo 1 group selected from a nil group, (vi) a C _2-6 alkynylsulfonyl group, (iii) a C _1-6 alkylcarbonyl group, (iii) a C _2-6 alkenylcarbonyl group, and (ix) a C _2-6 alkynylcarbonyl group Or an amino group which may be substituted with two groups, (10) C _1-6 alkylsulfonyl group, (11) C _2-6 alkenylsulfonyl group, (12) C _2-6 alkynylsulfonyl group, (13) C _{1 -6} alkylsulfinyl group, (14) C _2-6 alkenyl, sulfinyl Group, (15) C _2-6 alkynyl, a sulfinyl group, (16) a formyl group, (17) (i) hydroxyl group, (ⅱ) halogen atom, (ⅲ) nitrile group, (ⅳ) C _1-6 alkyl group, ( v) a C _3-8 cycloalkyl group or C _3-, which may each be substituted with one or more groups selected from C _1-6 alkoxy groups, (vi) C _1-6 alkoxyC _1-6 alkyl groups and (iii) aralkyl groups ₈ cycloalkenyl group, (18) (i) hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iii) C _1-6 alkyl group, (v) C _1-6 alkoxy group, (vi) C _{1- A} 5-14 membered non-aromatic heterocyclic group which may be substituted with one or more groups selected from a ₆ alkoxyC _1-6 alkyl group and (iii) aralkyl group, (19) (i) hydroxyl group, (ii) halogen atom, (iii A nitrile group, (iii) a C _1-6 alkyl group, (v) a C _1-6 alkoxy group, (vi) a C _1-6 alkoxyC _1-6 alkyl group and (iii) an aralkyl group nitriles be C _6-14 aromatic hydrocarbon cyclic group, and (20) (i) hydroxyl group, (ⅱ) halogen atom, (ⅲ) which is , (Ⅳ) C _1-6 alkyl group, (v) C _1-6 alkoxy group, (vi) C _1-6 alkoxy C _1-6 alkyl group and (ⅶ) which may be substituted with one or more selected from an aralkyl group Means a group consisting of a 5 to 14 membered aromatic heterocyclic group), (12) In the above (1), R ³ and / or R ⁴ is a hydroxyl group, a halogen atom, a C _1-6 alkyl group and a C _1-6 alkoxy group may be substituted one or more with a phenyl group, pyridyl group, thienyl group or furyl group or a salt thereof which is selected from: (13) in the above (1), R ³ or R ⁴ has 6 that may have a substituent A compound or a salt thereof that is -oxo-1,6-dihydropyridyl group, (14) In the above (1), the following formula
[26]
[27] [Wherein, R ¹ represents a cyano group, a carboxy group or a carbamoyl group which may have a substituent; R ² is a hydrogen atom, a hydroxyl group, which may be a substituted C _1-6 alkoxy group, which may come to have a substituent, C _1-6 alkylthio, C _6-14 aromatic hydrocarbon group which may have a substituted cyclic group, Or a 5 to 14 membered aromatic heterocyclic group which may have a substituent; R ⁷ represents a group selected from the following substituent group b; R ⁸ each represents a C _6-14 aromatic hydrocarboncyclic group or a 5-14 membered aromatic heterocyclic group which may have a substituent; A ring represents a nitrogen-containing six-membered ring which may be substituted with 1 to 4 groups selected from the following substituent group b:
[28] <Substituent group b> A hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, an amino group, a C _1-6 alkyl group which may have a substituent, a C _1-6 alkyl group which may have a substituent, C ₂ which may have a substituent _-6 alkenyl group, C _2-6 alkynyl group which may have a substituent, C _1-6 alkoxy group which may have a substituent, C _2-6 alkenyloxy group which may have a substituent, may have a substituent C _2-6 alkynyloxy group, import that may have a substituent, C _1-6 alkylthio, C _2-6 alkenyl come nilti to be, which may have a substituent, C _2-6 alkynyl come nilti that may have a substituent that , C _2-7 aliphatic acyl group, carbamoyl group which may have a substituent, arylacyl group, heteroarylacyl group, amino group which may have a substituent, C _1-6 alkylsulfonyl group which may have a substituent, Has a substituent C _2-6 alkenyl which may be seen a sulfonyl group, that may have a substituent, C _2-6 alkynyl sulfonyl group, that may have a substituent, C _1-6 alkylsulfinyl group, that may have a substituent, C _2-6 alkenyl sulfinyl group, that may have a substituent, C _2-6 alkynyl, a sulfinyl group, a formyl group, that may have a C _3-8 cycloalkyl group, a substituent that may have a substituent, C _3-8 cycloalkyl alkenyl al , A group consisting of a 5-14 membered nonaromatic heterocyclic group which may have a substituent, a C _6-14 aromatic hydrocarboncyclic group which may have a substituent, and a 5-14 membered aromatic heterocyclic group which may have a substituent Or a salt thereof,
[29] (15) The compound or salt thereof according to (14), wherein R ¹ is a cyano group, (16) The compound or salt thereof according to (14), wherein R ¹ is a carboxy group, (17) in (14) , R ¹ is
[30]
[31] (Wherein R ⁵ and R ⁶ mean the same as defined above) or a compound thereof or a salt thereof (18) In (14) above, a compound wherein R ² is a hydrogen atom or its A salt, (19) The compound or its salt in which the substituents of A rings other than R <^7> and R <^7> are chosen from the said substituent group a in (14), (20) In said (14), R <^7> is a hydrogen atom , A C _1-6 alkyl group which may have a substituent, a C _2-6 alkenyl group which may have a substituent or a C _1-6 alkoxy group which may have a substituent, or a salt thereof, (21) (14) WHEREIN: The compound or its salt whose R <^8> may have a substituent, a pyridyl group, a furyl group, or a thienyl group, (22) In said (14), R <^8> may be respectively substituted by the halogen atom. , Pyridyl, furyl or thienyl The compound or a salt thereof, (23) The compound according to (1), wherein the compound is 2-amino-6- (2-furyl) -5- (4-pyridyl) -3-pyridinecarbonitrile, 2-amino-6 -(3-fluorophenyl) -5- (4-pyridyl) -3-pyridinecarbonitrile, 2-amino-6- (2-furyl) -5- (4-methoxy-3-pyridyl)- 3-pyridinecarbonitrile, 2-amino-6- (2-furyl) -5- (6-oxo-1,6-dihydro-3-pyridinyl) nicotinonitrile, 2-amino-5- (1- Ethyl-6-oxo-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotinonitrile, 2-amino-6- (2-furyl) -5- (1-methyl-6 -Oxo-1,6-dihydro-3-pyridinyl) nicotinonitrile, 2-amino-6- (3-fluorophenyl) -5- (6-oxo-1,6-dihydro-3-pyri Any selected from dinyne) nicotinonitrile and 2-amino-6- (3-fluorophenyl) -5- (1-methyl-6-oxo-1,6-dihydro-3-pyridinyl) nicotinonitrile One kind of compound or its salt, (24) The following formula
[32]
[33] [Wherein, R ¹ represents a cyano group, a carboxy group or a carbamoyl group which may have a substituent; R ² is a hydrogen atom, a hydroxyl group, a C _1-6 alkoxy group which may have a substituent, a C _6-14 aromatic hydrocarbon cyclic group which may have a substituent or a 5-14 membered aromatic heterocyclic group which may have a substituent Represent; R ³ and R ⁴ are the same or different and each may have a C _3-8 cycloalkyl group, C _3-8 cycloalkenyl group, C _6-14 aromatic hydrocarboncyclic group, _5-14 membered non-aromatic heterocyclic group which may have a substituent Group or a 5-14 membered aromatic heterocyclic group; Provided that (1) when R ¹ is a cyano group, R ² is a 4-bromo-2-thienyl group, R ³ is a 3,4-dimethoxyphenyl group, and R ⁴ is a 2-thienyl group, ( 2) When R ¹ is a cyano group, R ² is a hydrogen atom, and R ³ and R ⁴ are phenyl groups, (3) R ¹ is a cyano group, R ² is a 4-chloro-phenyl group, and R ³ is When a phenyl group and R ⁴ is a 4- (3,4-dichlorophenyl) -1-oxo-2 (lH) -phthalazinyl group, (4) R ¹ is a cyano group, R ² is a hydrogen atom, When R ³ is a 4-pyridyl group and R ⁴ is a 1-piperazinyl group, (5) R ¹ is a cyano group, R ² is a hydrogen atom, R ³ is a 4-pyridyl group, and R ⁴ Is a 1-pyridyl group, (6) R ¹ is a cyano group, R ² is a hydrogen atom, R ³ is a 4-pyridyl group, and R ⁴ is a 4-diphenylmethyl-1-piperazinyl group If, (7) R ¹ is a cyano group, R ² is a hydrogen atom, and R ³ a group-4-pyridyl, and R ⁴ is 4-morpholinyl group If, (8) R ¹ is a cyano group, R ² is 4-methylphenyl group and, if also R ³ and R ⁴ is a phenyl group, and (9) R ¹ is a cyano group, and R ^2, R ^3, and A pharmaceutical composition comprising a compound represented by the following formula, wherein R ⁴ is a phenyl group, or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier, (25) the disease in which adenosine receptor is involved in (24) above. A composition which is a therapeutic or prophylactic agent of (26) A composition which is a therapeutic or prophylactic agent of a disease involving adenosine A ₂ receptor according to (24) above, and (27) A disease involving adenosine A _2B receptor according to (24) above. in the therapeutic agent or prophylactic agent composition, (28) the above-mentioned (24), in the adenosine receptor antagonist composition, (29) in the above (24), adenosine a ₂ receptor antagonist composition, 30, the 24 , Adenosine A _2B receptor antagonist, (31) said ( (24) The composition used for promoting bowel movement, (32) The composition as described in said (24) which is a therapeutic agent, a preventive agent, or an improvement agent of constipation, (33) The composition as described in said (24) whose functional constipation is functional constipation (34) The agent for treating constipation according to (24) above, with constipation with irritable bowel syndrome, constipation with irritable bowel syndrome, organic constipation, constipation with intestinal palsy ileus, constipation with congenital gastrointestinal dysfunction, or constipation with bowel obstruction. (35) A composition which is a prophylactic or ameliorating agent, (35) The composition according to (24), which is used for the exclusion of intestinal contents during or after a gastrointestinal tract examination or before or after surgery, (36) The diabetes or diabetic complication according to (24), A composition which is a therapeutic or prophylactic agent for diabetic retinopathy, obesity or asthma, (37) The blood sugar lowering agent, impaired glucose tolerance improving agent or insulin sensitivity enhancement according to (24) above. The composition, (38) In the above (24), or the like relates to the voltage step-down, diuretics, osteoporosis drugs, antiparkinson drugs, Alzheimer Wan, IBD therapeutic drug or clone disease therapeutic drug composition.
[34] That is, the present invention relates to a pharmaceutical composition comprising the 2-aminopyridine compound or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier, the compound or a pharmacologically acceptable salt thereof, a therapeutic agent for a disease involving adenosine receptors or A method for treating or preventing a disease involving adenosine receptors by administering to a patient a pharmacologically effective amount of the compound or a pharmacologically acceptable salt thereof for use in the preparation of a prophylactic agent.
[35] Detailed description of the invention:
[36] Below, the meaning of symbols, terms, etc. which are described in this specification are demonstrated, and this invention is demonstrated in detail.
[37] As used herein, "antagonist" means an agonist that has affinity for adenosine receptors, especially adenosine A ₂ receptors (most preferably A _2B receptors), and which inactivates the receptors.
[38] As used herein, the term "a disease involving adenosine receptor" refers to a disease involving adenosine A ₁ receptor, A _2A receptor, A _2B receptor, or A ₃ receptor, and for example, various constipation, irritable bowel syndrome, and hypersensitivity. Constipation with intestinal syndrome, constipation with organic constipation, constipation with intestinal palsy, constipation with congenital gastrointestinal dysfunction, constipation with intestinal obstruction, diabetes, diabetic complications, diabetic retinopathy, obesity, asthma, etc. Or diseases in which blood glucose lowering agents, impaired glucose tolerance improvers, insulin sensitivity enhancers, hypertensive agents, diuretics, osteoporosis drugs, antiparkinson drugs, Alzheimer's drugs, inflammatory bowel disease drugs, and clonal disease drugs are effective.
[39] As used herein, the phrase “and / or” is used in the sense of including both “and” and “or”.
[40] In the present specification, although the structural formula of the compound may show a constant isomer for convenience, the present invention includes all geometric isomers, optical isomers based on sub-carbons, isomers such as rotamers, stereoisomers, tautomers, and isomer mixtures. It is not limited to what is described by a formula for convenience, and either isomer may be sufficient and a mixture may be sufficient as it. Therefore, the compound of the present invention may have an optically active agent and a racemate with a subsidiary carbon atom in the molecule, but is not limited in the present invention, and any one of them is included. Moreover, although there exist some crystal polymorphs, similarly, it is not limited, Any one crystal form may be single form, or a crystalline mixture may be sufficient. Compound (I) or a salt thereof according to the present invention may be an anhydride or a hydrate, either of which is included in the claims of the present specification. Metabolites resulting from the degradation of compound (I) according to the present invention in vivo, and prodrugs of compound (I) or salts thereof according to the present invention are also included in the claims of the present specification.
[41] As a "halogen atom" used by this specification, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc. are mentioned, for example, Preferably, they are a fluorine atom, a chlorine atom, and a bromine atom.
[42] As used herein, "C _1-6 alkyl group" means an alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso -Butyl group, sec-butyl group, tert-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2 -Ethylpropyl group, n-hexyl group, 1-methyl-2-ethylpropyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1-propylpropyl group, 1-methylbutyl Group, 2-methylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2- Linear or branched alkyl groups such as ethylbutyl group, 2-methylpentyl group and 3-methylpentyl group.
[43] As used herein, "C _2-6 alkenyl group" means an alkenyl group having 2 to 6 carbon atoms, and examples of preferred groups include vinyl group, allyl group, 1-propenyl group, 2-propenyl group, and iso Propenyl group, 2-methyl-1-propenyl group, 3-methyl-1-propenyl group, 2-methyl-2-propenyl group, 3-methyl-2-propenyl group, 1-butenyl group, 2-butenyl group, 3 -Butenyl group, 1-pentenyl group, 1-hexenyl group, 1,3-hexanedienyl group, 1,6-hexanedienyl group, etc. are mentioned.
[44] As used herein, "C _2-6 alkynyl group" means an alkynyl group having 2 to 6 carbon atoms, and as a preferred group, for example, an ethenyl group, 1-propynyl group, 2-propynyl group, 1-buty Nilyl group, 2-butynyl group, 3-butynyl group, 3-methyl-1-propynyl group, 1-ethynyl-2-propynyl group, 2-methyl-3-propynyl group, 1-pentynyl group, 1-hexynyl group, 1, 3- hexanediynyl group, a 1, 6- hexanediynyl group, etc. are mentioned.
[45] The "C _1-6 alkoxy group" used in the present specification means an alkoxy group having 1 to 6 carbon atoms, for example, a methoxy group, an ethoxy group, an n-propoxy group, an iso-propoxy group, sec-prop Fox group, n-butoxy group, iso-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, iso-pentyloxy group, sec-pentyloxy group, n-hexoxyoxy, iso-hex Sooxy group, 1,1-dimethylpropyloxy group, 1,2-dimethylpropoxy group, 2,2-dimethylpropyloxy group, 2-ethylpropoxy group, 1-methyl-2-ethylpropoxy group, 1- Ethyl-2-methylpropoxy group, 1,1,2-trimethylpropoxy group, 1,1,2-trimethylpropoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2,2 -Dimethylbutoxy group, 2,3-dimethylbutyloxy group, 1,3-dimethylbutyloxy group, 2-ethylbutoxy group, 1,3-dimethylbutoxy group, 2-methylpentoxy group, 3-methylpentoxy group, hex A siloxy group etc. are mentioned.
[46] The "C _2-6 alkenyloxy group" used in the present specification means an alkenyloxy group having 2 to 6 carbon atoms, and preferred groups include, for example, a vinyloxy group, an allyloxy group, and a 1-propenyloxy group. , 2-propenyloxy group, isopropenyloxy group, 2-methyl-1-propenyloxy group, 3-methyl-1-propenyloxy group, 2-methyl-2-propenyloxy group, 3-methyl 2-propenyloxy group, 1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group, 1-pentenyloxy group, 1-hexenyloxy group, 1,3-hexanedienyloxy group, 1, 6-hexanedienyloxy group etc. are mentioned.
[47] The "C _2-6 alkynyloxy group" used in the present specification means an alkynyloxy group having 2 to 6 carbon atoms, and preferred groups include, for example, an ethynyloxy group, a 1-propynyloxy group, and 2-propynyl octa. Period, 1-butynyloxy group, 2-butynyloxy group, 3-butynyloxy group, 3-methyl-1-propynyloxy group, 1-ethynyl-2-propynyloxy group, 2-methyl-3-propynyloxy group , 1-pentynyloxy group, 1-hexynyloxy group, 1,3-hexanediynyloxy group, 1,6-hexanediynyloxy group, and the like.
[48] As used herein, "C _1-6 alkylthio group" means an alkoxy group having 1 to 6 carbon atoms, for example, methylthio group, ethylthio group, n-propylthio group, iso-propylthio group, sec-propylthio group, n-butylthio group, iso-butylthio group, sec-butylthio group, tert-butylthio group, n-pentylthio group, iso-pentylthio group, sec-pentylthio group, n- Hexylthio group, iso-hexylthio group, 1,1-dimethylpropylthio group, 1,2-dimethylpropylthio group, 2,2-dimethylpropylthio group, 2-ethylpropylthio group, 1-methyl-2- Ethylpropylthio group, 1-ethyl-2-methylpropylthio group, 1,1,2-trimethylpropylthio group, 1,1,2-trimethylpropylthio group, 1,1-dimethylbutylthio group, 1,2 -Dimethylbutylthio group, 2,2-dimethylbutylthio group, 2,3-dimethylbutylthio group, 1,3-dimethylbutylthio group, 2-ethylbutylthio group, 1,3-dimethylbutylthio group, 2 -Methylpentylthio group, 3-methylpentylthio group, etc. are mentioned. The "C _2-6 alkenylthio group" used in the present specification means an alkenylthio group having 2 to 6 carbon atoms, and preferred groups include, for example, vinylthio group, allylthio group, and 1-propenylthio group. , 2-propenylthio group, isopropenylthio group, 2-methyl-1-propenylthio group, 3-methyl-1-propenylthio group, 2-methyl-2-propenylthio group, 3-methyl 2-propenylthio group, 1-butenylthio group, 2-butenylthio group, 3-butenylthio group, 1-pentenylthio group, 1-hexenylthio group, 1,3-hexanedienylthio group, 1, 6-hexanedienylthio group etc. are mentioned. As used herein, "C _2-6 alkynylthio group" means an alkynylthio group having 2 to 6 carbon atoms, and preferred groups include, for example, an ethynylthio group, a 1-propynylthio group, and 2-propynylthi group. Ogi, 1-butynylthio group, 2-butynylthio group, 3-butynylthio group, 3-methyl-1-propynylthio group, 1-ethynyl-2 propynylthio group, 2-methyl-3-propynylthio group, 1-pentynylthio group, 1-hexynylthio group, 1, 3- hexanediynyl thio group, 1, 6- hexanediynyl thio group, etc. are mentioned.
[49] As used herein, "C _3-8 cycloalkyl group" means a cycloalkyl group composed of 3 to 8 carbon atoms, and for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclohepp Tyl group, cyclooctyl group, etc. are mentioned.
[50] As used herein, "C _3-8 cycloalkenyl group" means a C _3-8 cycloalkenyl group composed of 3 to 8 carbon atoms, for example, cyclopropen-1-yl, cyclopropene- 3-day, cyclobuten-1-yl, cyclobuten-3-yl, 1,3-cyclobutadien-1-yl, cyclopenten-1-yl, cyclopenten-3-yl, cyclopenten-4-yl, 1,3-cyclopentadien-1-yl, 1,3-cyclopentadien-2-yl, 1,3-cyclopentadien-5-yl, cyclohexen-1-yl, cyclohexen-3-yl, Cyclohexen-4-yl, 1,3-cyclohexadien-1-yl, 1,3-cyclohexadien-2-yl, 1,3-cyclohexadien-5-yl, 1,4-cyclohexadiene -3-yl, 1,4-cyclohexadien-1-yl, cyclohepten-1-yl, cyclohepten-3-yl, cyclohepten-4-yl, cyclohepten-5-yl, 1,3-cyclo Hepten-2-yl, 1,3-cyclohepten-1-yl 1,3-cycloheptadiene-5-yl, 1,3-cycloheptadiene-6- , 1,4-cycloheptadien-3-yl, 1,4-cycloheptadien-2-yl, 1,4-cycloheptadien-1-yl, 1,4-cycloheptadien-6-yl, 1 , 3,5-cycloheptatrien-3-yl, 1,3,5-cycloheptatrien-2-yl, 1,3,5-cycloheptatrien-1-yl, 1,3,5- Cycloheptatrien-7-yl, cycloocten-1-yl, cycloocten-3-yl, cycloocten-4-yl, cycloocten-5-yl, 1,3-cyclooctadien-2-yl, 1 , 3-cyclooctadiene-1-yl, 1,3-cyclooctadiene-5-yl, 1,3-cyclooctadiene-6-yl, 1,4-cyclooctadiene-3-yl, 1,4 -Cyclooctadiene-2-yl, 1,4-cyclooctadiene-1-yl, 1,4-cyclooctadiene-6-yl, 1,4-cyclooctadiene-7-yl, 1,5-cyclo Octadien-3-yl, 1,5-cyclooctadien-2-yl, 1,3,5-cyclooctatrien-3-yl, 1,3,5-cyclooctatrien-2-yl, 1 , 3,5-cyclooctatrien-1-yl, 1,3,5-cyclooctatrien-7-yl, 1,3,6-cycloocta Lien-2-yl, 1,3,6-cyclooctatrien-1-yl 1,3,6-cyclooctatrien-5-yl, 1,3,6-cyclooctatrien-6-yl, etc. Can be mentioned.
[51] As used herein, a "5- to 14-membered non-aromatic heterocyclic group" is a monocyclic, bicyclic or tricyclic five-membered group containing one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. It refers to a 1 to 14 membered non-aromatic heterocyclic group. Specific examples of the group include a pyrrolidinyl group, a pyrrolyl group, a piperidinyl group, a piperazinyl group, an imidazolyl group, a pyrazolidyl group, an imidazolidyl group, a morpholinyl group, a tetrahydrofuryl group, and tetrahydro A pyranyl group, a pyrrolinyl group, a dihydrofuryl group, a dihydropyranyl group, an imidizolinyl group, an oxazolinyl group, etc. are mentioned. The non-aromatic heterocyclic group also includes a group derived from a pyridone ring, or a non-aromatic condensed ring (for example, a group derived from a phthalimide ring, a succinimide ring, and the like).
[52] As used herein, the term "C _6-14 aromatic hydrocarbon cyclic group" and "aryl" refers to an aromatic hydrocarbon cyclic group composed of 6 to 14 carbon atoms, and a condensed ring such as a monocyclic group, a bicyclic group, and a tricyclic group. Included. Specific examples of the group include a phenyl group, indenyl group, 1-naphthyl group, 2-naphthyl group, azulenyl group, heptalenyl group, biphenyl group, indasenyl group, acenaphthyl group, fluorenyl group, penalenyl group, Phenanthrenyl group, anthracenyl group, cyclopentacyclooctenyl group, benzocyclooctenyl group, etc. are mentioned.
[53] As used herein, the "5- to 14-membered aromatic heterocyclic group" and the "heteroaryl" are monocyclic, bicyclic or at least one hetero atom selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. Tricyclic 5- to 14-membered aromatic heterocyclic group. To give specific examples of the above group, for example, as the nitrogen-containing aromatic heterocyclic group, pyrrolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazolyl group, tetrazolyl group, benzotria Zolyl group, pyrazolyl group, imidazolyl group, benzimidazolyl group, indolyl group, isoindoleyl group, indolinyl group, furinyl group, indazolyl group, quinolyl group, isoquinolyl group, quinolyzyl group , Phthalazyl group, naphthyridinyl group, quinoxalyl group, quinazolinyl group, cinnaolinyl group, pterridinyl group, imidazotriazinyl group, pyrazinopyridazinyl group, acridinyl group, phenanthridinyl group, carboxyl Barzolyl group, carbazolinyl group, pyrimidinyl group, phenanthrolinyl group, phenacinyl group, imidazopyridinyl group, imidazopyrimidinyl group, pyrazolopyridinyl group, pyrazolopyridinyl group, etc .; (2) Sulfur-containing aromatic heterocyclic groups include thienyl group and benzothienyl group; (3) Oxygenated aromatic heterocyclic groups include furyl group, pyranyl group, cyclopentapyranyl group, benzofuryl group, isobenzofuryl group and the like; ④ Aromatic heterocyclic groups containing two or more hetero hetero atoms include thiazolyl group, isothiazolyl group, benzothiazolyl group, benzthiadiazolyl group, phenothiazinyl group, isoxazolyl group, furazanyl group, Phenoxazinyl, oxazolyl, isoxazolyl, benzooxazolyl, oxdiazolyl, pyrazolooxazolyl, imidazothiazolyl, thienofuranyl, furyrrolyl, pyridoxazinyl, etc. Can be mentioned.
[54] The "C _2-7 aliphatic acyl group" used in the present specification means an atomic group obtained by removing an OH group from a carboxy group of C _2-7 aliphatic carboxylic acid, and preferred groups include, for example, an acetyl group, propionyl group and butyro. A diary.
[55] As used herein, "arylacyl group" refers to a carbonyl group substituted with a C _6-14 aromatic hydrocarbon cyclic group, and "heteroarylacyl group" refers to a carbonyl group substituted with a 5 to 14 membered aromatic heterocyclic group. The "C _6-14 aromatic hydrocarbon cyclic group" and the "5 to 14 membered aromatic heterocyclic group" mean the same as the above definition.
[56] Preferable examples in the "C _1-6 alkylsulfonyl group", "C _2-6 alkenylsulfonyl group" and "C _2-6 alkynylsulfonyl group" used in the present specification include methylsulfonyl group and ethylsulfonyl group. , n-propylsulfonyl group, iso-propylsulfonyl group, n-butylsulfonyl group, tert-butylsulfonyl group, vinylsulfonyl group, allylsulfonyl group, iso-propenylsulfonyl group, iso-pentenylsulfonyl group, ethynylsulfo And a silyl group. Preferable examples in the "C _1-6 alkylsulfinyl group", "C _2-6 alkenylsulfinyl group" and "C _2-6 alkynylsulfinyl group" used in the present specification include methylsulfinyl group and ethylsulfinyl group. , n-propylsulfinyl group, iso-propylsulfinyl group, n-butylsulfinyl group, tert-butylsulfinyl group, vinylsulfinyl group, allylsulfinyl group, iso-propenylsulfinyl group, iso-pentenylsulfinyl group, ethynylsulfi And a silyl group.
[57] As the "substituent" in the "amino group which may have a substituent" used in the present specification, for example, a C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 , each of which may have a substituent alkynyl group, C _1-6 alkylsulfonyl group, C _2-6 alkenyl sulfonyl group, C _2-6 alkynyl, sulfonyl, C _1-6 alkylcarbonyl group, C _2-6 alkenyl group, C _2-6 alkynyl, One or two groups selected from a carbonyl group, etc. may be mentioned, In addition, the said substituent may form the 3-8 membered nitrogen ring together by mutual bond. The C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 alkylsulfonyl group, C _2-6 alkenylsulfonyl group, C _2-6 alkynylsulfonyl group, C _1- Preferred examples of the "substituent" of the ₆ alkylcarbonyl group, the C _2-6 alkenylcarbonyl group and the C _2-6 alkynylcarbonyl group include a hydroxyl group, a halogen atom, a nitrile group, a C _1-6 alkoxy group and a C _1-6 alkylthio group. Etc. can be mentioned. Specific examples of particularly preferred examples of the "amino group which may have a substituent" include methylamino group, ethylamino group, n-propylamino group, iso-propylamino group, n-butylamino group, iso-butylamino group and tert-butylamino group. , n-pentylamino group, iso-pentylamino group, neopentylamino group, n-hexylamino group, 1-methylpropylamino group, 1,2-dimethylpropylamino group, 2-ethylpropylamino group, 1-methyl-2-ethylpropylamino group, 1-ethyl-2-methylpropylamino group, 1,1,2-trimethylpropylamino group, 1-methylbutylamino group, 2-methylbutylamino group, 1,1-dimethylbutylamino group, 2,2-dimethylbutylamino group, 2- Ethylbutylamino group, 1,3-dimethylbutylamino group, 2-methylpentylamino group, 3-methylpentylamino group, N, N-dimethylamino group, N, N-diethylamino group, N, N-di (n-propyl) amino group , N, N-di (iso-propyl) amino group, N, N-di (n-butyl) amino group, N, N- Di (iso-butyl) amino group, N, N-di (tert-butyl) amino group, N, N-di (n-pentyl) amino group, N, N-di (iso-pentyl) amino group, N, N-di ( Neopentyl) amino group, N, N-di (n-hexyl) amino group, N, N-di (1-methylpropyl) amino group, N, N-di (1,2-dimethylpropyl) amino group, N-methyl-N -Ethylamino group, N-ethyl-N- (n-propyl) amino group, N-methyl-N- (i-propyl) amino group, vinylamino group, allylamino group, (1-propenyl) amino group, isopropenylamino group, ( 1-buten-1-yl) amino group, (1-buten-2-yl) amino group, (1-buten-3-yl) amino group, (2-buten-1-yl) amino group, (2-buten-2- I) amino group, N, N-divinylamino group, N, N-diallylamino group, N, N-di (1-propenyl) amino group, N, N-isopropenylamino group, N-vinyl-N-allylamino group , Ethynylamino group, 1-propynylamino group, 2-propynylamino group, butynylamino group, pentynylamino group, hexynylamino group, N, N-diethynylamino group, N, N- (1-propynyl) ami Group, N, N- (2-propynyl) amino group, N, N-dibutynylamino group, N, N-dipentynylamino group, N, N-dihexynylamino group, hydroxymethylamino group, 1-hydroxyethyl Amino group, 2-hydroxyethylamino group, 3-hydroxy-n-propyl group, methylsulfonylamino group, ethylsulfonylamino group, n-propylsulfonylamino group, iso-propylsulfonylamino group, n-butylsulfonylamino group, tert-butylsulfonylamino group, vinylsulfonylamino group, allylsulfonylamino group, iso-propenylsulfonylamino group, iso-pentenylsulfonylamino group, ethynylsulfonylamino group, methylcarbonylamino group, ethylcarbonylamino group, n-propyl Carbonylamino group, iso-propylcarbonylamino group, n-butylcarbonylamino group, tert-butylcarbonylamino group, vinylcarbonylamino group, allylcarbonylamino group, iso-propenylcarbonylamino group, iso-pentenylcarbonylamino group , Ethynylka And a carbonylamino group.
[58] Examples of the "substituent" in "which may have a substituent" as used herein include halogen atoms (for example, fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, etc.), hydroxyl groups, nitro groups, cyano groups, C _1-6 alkyl group (for example, methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, 1 , 1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-ethylpropyl group, n-hexyl group, 1-methyl-2-ethylpropyl group, etc. ), C _2-6 alkenyl group (for example, vinyl group, allyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 2-methyl-1-propenyl group, 3-methyl-1-propenyl group) , 2-methyl-2-propenyl group, 3-methyl-2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 1-hexenyl group, 1,3-hexane Dienyl group, 1,6-hexanedienyl group, etc.), C _2-6 alkynyl group (for example, ethynyl group, 1- Propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 3-methyl-1-propynyl group, 1-ethynyl-2-propynyl group, 2-methyl-3-propynyl group , 1-pentynyl group, 1-hexynyl group, 1,3-hexanediynyl group, 1,6-hexanediynyl group, etc., C _1-6 alkoxy group (for example, methoxy group, ethoxy group, n- Propoxy group, iso-propoxy group, sec-propoxy group, n-butoxy group, iso-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, iso-pentyloxy group, sec- Pentyloxy group, n-hexoxy group, etc.), C _2-6 alkenyloxy group (for example, vinyloxy group, allyloxy group, 1-propenyloxy group, 2-propenyloxy group, isopropenyl octa Season), C _2-6 alkynyloxy group (for example, ethynyloxy group, 1-propynyloxy group, 2-propynyloxy group, etc.), C _1-6 alkylthio group (for example, methylthio group, Ethylthio group, n-propylthio group, iso-propylthio group, sec-propylthio group, n-butylthio group, iso-butylthio group, sec-butyl Import, tert- butyl thio group, etc.), C _2-6 alkenyl nilti come (e. G., Vinyl thio, thio allyl, 1-phenylthio, 2-propenyl such as phenylthio), C _2-6 Alkynylthio group (for example, ethynylthio group, 1-propynylthio group, 2-propynylthio group, etc.), C _2-7 aliphatic acyl group (for example, acetyl group, propionyl group, butyroyl group, etc.) , Carbamoyl group, arylacyl group, heteroarylacyl group, amino group, C _1-6 alkylsulfonyl group, C _2-6 alkenylsulfonyl group, C _2-6 alkynylsulfonyl group, C _1-6 alkylsulfinyl group, C _2-6 alkenylsulfinyl group, C _2-6 alkynylsulfinyl group (for example, methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, iso-propylsulfonyl group, n-butylsulfonyl group, tert- Butyl sulfonyl group, vinyl sulfonyl group, allyl sulfonyl group, iso-propenyl sulfonyl group, iso-pentenyl sulfonyl group, ethynyl sulfonyl group, methyl sulfinyl group, ethyl sulfinyl group, n-propyl sulfinyl group, iso-propyl sulfinyl group , n-butylsulfur Group, a tert- butyl sulfinyl group, a sulfinyl group vinyl, allyl sulfinyl group, iso- propenyl sulfinyl group, iso- pentenyl a sulfinyl group, a sulfinyl group, etc.), formyl group, C _3-8 cycloalkyl group (for example, ethynyl , Cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, etc., C _3-8 cycloalkenyl group (e.g., cyclopropenyl, cyclobutenyl, cyclopentenyl , Cyclohexenyl group, etc.), 5- to 14-membered non-aromatic heterocyclic group (for example, pyrrolidinyl group, pyrrolyl group, piperidinyl group, piperazinyl group, imidazolyl group, pyrazolidyl group, imidazoli Dyl group, morpholinyl group, tetrahydrofuryl group, tetrahydropyranyl group, pyrrolinyl group, dihydrofuryl group, dihydropyranyl group, imidizolinyl group, oxazolinyl group, group derived from pyridone ring, phthalimide ring In or succinimide ring And C _6-14 aromatic hydrocarbon cyclic groups (for example, phenyl group, indenyl group, 1-naphthyl group, 2-naphthyl group, biphenyl group, indaseyl group, etc.), and 5 to 14 membered aromatic hetero groups. Cyclic group (for example, pyrrolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazolyl group, tetrazolyl group, benzotriazolyl group, pyrazolyl group, imidazolyl group, benzimi) Dazolyl group, indolyl group, isoindolinyl group, indolinyl group, furinyl group, indazolyl group, quinolyl group, isoquinolyl group, quinolizyl group, phthalazyl group, naphthyridinyl group, quinoxalyl group, Quinazolinyl group, cinnaolinyl group, putridinyl group, imidazotriazinyl group, pyrazinopyridazinyl group, acridinyl group, phenanthridinyl group, carbazolyl group, carbazolinyl group, perimidinyl group, phenane Trolnyl group, phenacinyl group, imidazopyridinyl group, imidazopyrimidinyl group, pyrazolopyridinyl group, Lazolopyridinyl group, thienyl group, benzothienyl group, furyl group, pyranyl group, cyclopentapyranyl group, benzofuryl group, isobenzofuryl group, thiazolyl group, isothiazolyl group, benzothiazolyl group, benzthiadia Zolyl group, phenothiazinyl group, isoxazolyl group, furazanyl group, phenoxazinyl group, oxazolyl group, isoxazolyl group, benzooxazolyl group, oxadiazolyl group, pyrazolooxazolyl group, imidazothiazolyl group Group, a thienofuranyl group, a furopyrrolyl group, a pyridoxadinyl group, etc.) etc. are mentioned, These substituents may have a substituent further.
[59] In said Formula (I), R <^1> represents the carbamoyl group which may have a cyano group, a carboxy group, or a substituent, and a most preferable group is not specifically limited. Preferred examples of the "substituent" in the "carbamoyl group which may have a substituent" include C _1-6 alkyl group which may have a substituent, C _2-6 alkenyl group which may have a substituent, and a substituent C _2-6 alkynyl group which may have substituent, C _3-8 cycloalkyl group which may have substituent, C _3-8 cycloalkenyl group which may have substituent, C _6-14 aromatic which may have substituent The group selected from a hydrocarbon cyclic group, the 5-14 membered aromatic heterocyclic group which may have a substituent, etc. are mentioned, The nitrogen atom of a carbamoyl group may be substituted by the 1 or 2 group chosen from the said substituent group. have. In addition, the substituents together with each other by a three to fourteen-membered nitrogen-containing ring (for example, pyrrolidyl group, pyrrolinyl group, piperidyl group, piperazinyl group, imidazolyl group, pyrazolidyl group, imidazolidyl group) , Morpholinyl group, tetrahydropyranyl group, aziridinyl group, oxiranyl group, oxathiolanyl group, phthalimidoyl group, succinimidoyl group, pyrrolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, Pyrazolyl group), and the nitrogen-containing ring may further have a substituent.
[60] In the above formula (I), the preferred group in R ² is not particularly limited, but the preferred group is a hydrogen atom, a C _1-6 alkoxy group which may each have a substituent, phenyl, naphthyl, pyridyl, pyridazyl, pyri Midyl, pyrazyl, thienyl, furyl, imidazolyl groups, and the like, and more preferred examples thereof include a hydrogen atom.
[61] In formula (I), R <^3> and R <^4> , independently of each other, may each independently have a C _3-8 cycloalkyl group, C _3-8 cycloalkenyl group, C _6-14 aromatic hydrocarbon cyclic group, 5 To a 14-membered non-aromatic heterocyclic group or a 5 to 14-membered aromatic heterocyclic group, and examples of the preferred group include C _6-14 aromatic hydrocarbon cyclic groups (for example, phenyl group and naphthyl group), and 5 to 14 membered non-aromatic heterocyclic groups. Cyclic groups (for example, pyrrolidinyl group, pyrrolinyl group, piperidinyl group, piperazinyl group, imidizolinyl group, pyrazolidinyl group, imidazolidinyl group, morpholinyl group, tetrahydropyranyl group, An aziridinyl group, an oxiranyl group, an oxathiolanyl group, a 6-oxo-1,6-dihydropyridyl group, etc., in which a nitrogen atom may be substituted, or a 5-14 membered aromatic heterocyclic group (for example, pyrrole) Reel group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyra Nyl group, pyrazolyl group, imidazolyl group, indolyl group, isoindolinyl group, indolinyl group, quinolinyl group, isoquinolinyl group, quinolinyl group, phthalazinyl group, naphthyridyl group, quinoxalyl group , Quinazolyl group, imidazotriazinyl group, pyrazinopyridazinyl group, thienyl group, benzothienyl group, furyl group, pyranyl group, cyclopentapyranyl group, benzofuryl group, isobenzofuryl group, thiazolyl group, iso Thiazolyl group, benzthiazolyl group, benzthiadiazolyl group, phenothiazyl group, isoxazolyl group, pyrazoloxazolyl group, imidazothiazolyl group, thienofuryl group, furypyrrolyl group, pyridoxazinyl group, etc.) These may be mentioned, and these group may have a substituent. More preferable examples in R ³ and R ⁴ include the following formulas which may each have a substituent
[62]
[63] The group represented by these etc. can be mentioned. Moreover, when the said 6-oxo-1, 6- dihydropyridyl group has a substituent, the case where the said substituent is couple | bonded with a nitrogen atom is also included.
[64] And R ³ "may be the substituted C _3-8 cycloalkyl group that" in R ^4, "that may have a substituent, C _3-8 cycloalkyl alkenyl group", "may be a substituted C _6-14 aromatic in [1] in the above-mentioned "substituents" in "hydrocarbon groups", "5-14 membered non-aromatic heterocyclic groups which may have substituents" and "5-14 membered aromatic heterocyclic groups which may have substituents" Preferred examples include hydroxyl group, halogen atom, cyano group, nitro group, C _1-6 alkyl group which may have a substituent, C _2-6 alkenyl group which may have a substituent, C _2- which may have a substituent ₆ alkynyl group, C _1-6 alkoxy group which may have substituent, C _2-6 alkenyloxy group which may have substituent, C _1-6 alkylthio group which may have substituent, may have substituent There Is a C _2-6 alkenylthio group, a C _2-6 alkynylthio group which may have a substituent, a substituted carbonyl group, an amino group which may have a substituent, a C _1-6 alkylsulfonyl group which may have a substituent, a substituent C _2-6 alkenylsulfonyl group which may have substituent, C _2-6 alkynylsulfonyl group which may have substituent, C _1-6 alkylsulfinyl group which may have substituent, C which may have substituent _2-6 alkenyl sulfinyl group, that may have a substituent, C _2-6 alkynyl, a sulfinyl group, a formyl group, that may have a substituent, C _3-8 cycloalkyl group, which may be the substituted C _3-8 cycloalkyl alkenyl group, 5- to 14-membered, which may be a substituted non-aromatic heterocyclic group, can also be had to that may be a substituted C _6-14 aromatic hydrocarbon cyclic group, and the substituents One or more groups chosen from a 5-14 membered aromatic heterocyclic group are mentioned, [2] More preferably, (1) a hydroxyl group, (2) a halogen atom, (3) cyano group, (4) nitro group, (5) (i) hydroxyl group, (ii) cyano group, (iii) halogen atom, (iv) C _1-6 alkylamino group, (v) di (C _1-6 alkyl) amino group, (vi) C _2-6 Alkenylamino group, (iii) di (C _2-6 alkenyl) amino group, (iii) C _2-6 alkynylamino group, (ix) di (C _1-6 alkynyl) amino group, (x) NC _1-6 Alkyl-NC _2-6 alkenylamino group, (xi) NC _1-6 alkyl-NC _2-6 alkynylamino group, (xii) NC _2-6 alkenyl-NC _2-6 alkynylamino group, (x ') aralkyl jade Period, (xiv) TBDMSoxy group, (xv) C _1-6 alkylsulfonylamino group, (xvi) C _1-6 alkylcarbonyloxy group, (x ') C _2-6 alkenylcarbonyloxy group, (x' ) From a C _2-6 alkynylcarbonyloxy group, (xix) NC _1-6 alkylcarbamoyl group, (xx) NC _2-6 alkenylcarbamoyl group and (xxi) NC _1-6 alkynylcarbamoyl group Selected C _1-6 alkyl group, C _1-6 alkenyl group or C _2-6 alkynyl group, (6) (i) C _1-6 alkylamino group, (ii) aralkyloxy group, which may each be substituted with one or more groups, and (Iii) a C _1-6 alkoxy group, a C _2-6 alkenyloxy group or a C _2-6 alkynyloxy group, each of which may be substituted with one or more groups selected from hydroxyl groups, (7) (i) hydroxyl group, (ii ) nitrile group, (ⅲ) halogen atom, (iv) C _1-6 alkylamino group, (v) aralkyl kilok time, (vi) TBDMS oxy group, (ⅶ) C _1-6 alkylsulfonyl group, (ⅷ) C _1-6 alkylcarbonyloxy group and (ix) C _1-6 alkyl carbamoyl groups, which come at least one selected from the group may be substituted respectively, C _1-6 alkylthio, C _2-6 alkenyl or C coming nilti _2-6 alkynylthio group, (8) (i) C _1-6 alkoxy group, (ii) amino group, (iii) C _1-6 alkylamino group, (iv) di (C _1-6 alkyl) amino group, (v ) C _2-6 alkenyl group, (vi) di (C _2-6 alkenyl) amino group, (ⅶ) C _2-6 alkynyl Amino group, (ⅶ) di (C _2-6 alkynyl) amino group, (ⅷ) NC _1-6 alkyl, -NC _2-6 alkenyl group, (ix) NC _1-6 alkyl, -NC _2-6 alkynyl group, and (x) a carbonyl group substituted with a group selected from an NC _2-6 alkenyl-NC _2-6 alkynylamino group, (9) (i) a C _1-6 alkyl group, (ii) a C _2-6 alkenyl group, (iii) C _2-6 alkynyl group, (iv) C _1-6 alkylsulfonyl group, (v) C _2-6 alkenylsulfonyl group, (vi) C _2-6 alkynylsulfonyl group, (iii) C _1-6 alkyl An amino group which may be substituted with one or two groups selected from a carbonyl group, (iii) a C _2-6 alkenylcarbonyl group and (ix) a C _2-6 alkynylcarbonyl group, (10) a C _1-6 alkylsulfonyl group, (11) C _2-6 alkenylsulfonyl group, (12) C _2-6 alkynylsulfonyl group, (13) C _1-6 alkylsulfinyl group, (14) C _2-6 alkenylsulfinyl group, (15) C _2-6 alkynylsulfinyl group, (16) formyl group, (17) (i) hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iv) C _1-6 alkyl group, (v) C _{1- 6} alkoxy group, (vi) C _1-6 alkoxy C _1-6 Kilgi and (ⅶ) C _3-8 aralkyl each of which may be substituted one or more groups selected from kilgi cycloalkyl group or C _3-8 cyclo alkenyl group, (18) (1) hydroxyl group, (ⅱ) halogen atom, ( V) one or more groups selected from nitrile groups, (iv) C _1-6 alkyl groups, (v) C _1-6 alkoxy groups, (vi) C _1-6 alkoxyC _1-6 alkyl groups, and (iii) aralkyl groups A 5- to 14-membered non-aromatic heterocyclic group which may be substituted, (19) (i) hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iv) C _1-6 alkyl group, (v) C _1- A C _6-14 aromatic hydrocarboncyclic group which may be substituted by one or more groups selected from a ₆ alkoxy group, (vi) a C _1-6 alkoxyC _1-6 alkyl group and (iii) an aralkyl group, and (20) (i ) Hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iv) C _1-6 alkyl group, (v) C _1-6 alkoxy group, (vi) C _1-6 alkoxyC _1-6 alkyl group and (-6 ) May be substituted with one or more groups selected from aralkyl groups And one or more groups selected from among 5 to 14 membered aromatic heterocyclic groups. [3] Most preferably, a hydroxyl group, a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.) is mentioned. ), Cyano group, nitro group, C _1-6 alkyl group (for example, methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, tert-butyl group, n-pen Tilyl group, i-pentyl group, neopentyl group, n-hexyl group, etc.), C _2-6 alkenyl group (for example, vinyl group, allyl group, 1-propenyl group, isopropenyl group, etc.), C _2-6 Alkynyl groups (e.g., ethynyl groups, 1-propynyl groups, 2-propynyl groups, butynyl groups, pentynyl groups, hexynyl groups, etc.), C _1-6 alkoxy groups (methoxy groups, ethoxy groups, n-propoxy groups, one or more groups selected from iso-propoxy group, n-butoxy group, etc.) and C _2-6 alkenyloxy groups (vinyloxy group, allyloxy group, 1-propenyloxy group, isopropenyloxy group, etc.) to be.
[65] Although the preferable aspect in the compound or its salt represented by said Formula (I) which concerns on this invention is not specifically limited, Among these, a more preferable aspect is given, R <^3> is a formula
[66]
[67] A compound represented by the formula [wherein R ⁷ represents a group selected from the substituent group b: A ring represents a nitrogen-containing six-membered ring which may be substituted with 1 to 4 groups selected from substituent group b] or Its salt, and also a preferable embodiment, the following formula
[68]
[69] [Wherein, R ¹ represents a cyano group, a carboxy group or a carbamoyl group which may have a substituent; R ² is a hydrogen atom, a hydroxyl group, which may be a substituted C _1-6 alkoxy group, which may come to have a substituent, C _1-6 alkylthio, which may be a substituted C _6-14 aromatic hydrocarbon cyclic group or 5 to 14 membered aromatic heterocyclic group which may have a substituent; R ⁷ represents a group selected from the substituent group b; R ⁸ each represents a C _6-14 aromatic hydrocarboncyclic group or a 5-14 membered aromatic heterocyclic group which may have a substituent; A ring represents a nitrogen-containing six-membered ring which may be substituted with 1 to 4 groups selected from the substituent group b]. Preferred embodiments of R ¹ , R ⁷ and R ⁸ are as exemplified above.
[70] The term "salt" in the present specification is not particularly limited as long as it forms a salt with a compound according to the present invention and is also pharmacologically acceptable, but is preferably a hydrochloride salt (for example, hydrofluoride, hydrochloride, brominated). Hydrochloride, hydroiodide, etc.), inorganic salts (e.g. sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate, etc.), organic carboxylates (e.g. acetate, trifluoroacetate, oxalate) , Maleate, tartarate, fumarate, citrate, etc.), organic sulfonates (e.g. methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, camphorsulfonate, etc.) , Amino acid salts (for example, asparagine salts, glutamate salts, etc.), quaternary amine salts, alkali metal salts (for example, sodium salts, potassium salts, etc.), alkaline earth metal salts (magnesium salts, calcium salts, etc.) And the pharmacologically acceptable salts thereof are more preferably hydrochloride, oxalate and the like.
[71] [Manufacturing method]
[72] It shows below about the typical manufacturing method of the compound represented by said Formula (I) which concerns on this invention. In addition, "room temperature" described below means O-40 degreeC vicinity.
[73] Recipe 1
[74]
[75] In the above formula, R ^{3a ′} is a 5 to 14 membered aromatic heterocyclic group which may have a nitrogen atom in the fourth position and may also have a substituent (for example, 4-pyridyl group, 4-pyrimidinyl group, 4 -pyridazinyl group and the like) represents a, R ^4a denotes also to have a C _6-14 aromatic hydrocarbon cyclic group or may be a substituted 5- to 14-membered aromatic heterocyclic group in which a substituent, R ⁹ is C _{1- 8} alkyl group. Non the formula (I) prepared as a raw material of 1,2-biaryl-1-ethanone of the compound represented by the compounds according to the invention (ⅱ) 'is the presence of a base, expression of an aromatic carboxylic acid ester (1) R ^3a' -CH It can react with the 4-methyl aromatic heterocyclic compound represented by ₃ in a solvent, and can manufacture by dealcohol condensation. The base to be used depends on the starting material, the solvent to be used and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, the metal salt of a secondary amine represented by lithium bis (trimethylsilyl) amide or lithium diisopropylamide is preferable. And so on. The solvent to be used depends on the starting materials, reagents and the like, and is not particularly limited as long as the starting material is dissolved to some extent without inhibiting the reaction. Preferably, tetrahydrofuran, dioxy acid, dimethoxyethane, diethylene glycol, Ethers. The reaction temperature is usually from -78 ° C to room temperature, and preferably around 0 ° C.
[76] Recipe 2
[77]
[78] Wherein R ^{3a "} is a C _6-14 aromatic hydrocarboncyclic group which may have a substituent or a 5-14 membered aromatic heterocyclic group which may have a substituent, R ^4a is as defined above and X ¹ is Halogen atom, alkylsulfonyloxy group or allylsulfonyloxy group. 1,2-biaryl-1-ethanone compound (ii) "as a raw material for the preparation of the compound represented by formula (I) according to the present invention is In addition to the manufacturing method 1, it can manufacture by this manufacturing method 2. That is, after condensation of an aromatic trialkylsilylcyanohydrin compound prepared from an aromatic aldehyde and a compound represented by the formula R ^{3a "} -CH ₂ X ¹ in the presence of a base, a fluorine compound is caused to function and dexylated tri As a reagent for preparing an aromatic trialkylsilylcyanohydrin from (i), it is preferable to use a cyanated trialkylsilyl compound represented by trimethylsilylcyanide, where zinc iodide ( It is also preferable to use together metal salts, such as ii), and it is possible to advance reaction rapidly .. The base to be used varies with starting materials, the solvent to be used, etc., and is not particularly limited as long as the reaction is not inhibited. Is a metal salt of a secondary amine represented by lithium bis (trimethylsilyl) amide or lithium diisopropylamide. The fluorine compound varies depending on the starting material, the solvent used, and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, the fluorine compound is hydrofluoric acid or hydrofluoric acid of an amine, more preferably tetrabutylammonium fluoride. The solvent used depends on the starting material, the reagent, and the like, and is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, but preferably tetrahydrofuran, dioxy acid, dimethoxyethane, diethylene glycol Ethers, etc. The reaction temperature is preferably -78 ° C to room temperature.
[79] Recipe 3
[80]
[81] In the above formula, R ^3a and R ^4a represent a C _6-14 aromatic hydrocarbon cyclic group which may have a substituent or a 5 to 14 membered aromatic heterocyclic group which may have a substituent. 3- (dimethylamino) -2-propen-l-one derivative (iv) is a raw material for preparing Compound (I) according to the present invention. (iv) may be prepared by reacting N, N-dimethylformamide dimethylacetal with the active methylene of (ii) prepared in Preparation Method 1 or 2. It is most preferable to carry out this reaction without a solvent, but a solvent (eg, N, N-dimethylformamide, tetrahydrofuran, deoxy acid, N, N-, which dissolves the starting material to some extent without inhibiting the reaction) is preferable. Dilution with methylpyrrolidone, benzene, toluene or the like) may be used to obtain a preferable result. The reaction temperature is usually from room temperature to 120 ° C., preferably around 100 ° C.
[82] (Iii) which is a compound which concerns on this invention can be manufactured as follows using the compound obtained by the said manufacturing methods 1-3.
[83] Recipe 4
[84]
[85] In the above formula, R ^3a and R ^4a represent synonyms with the above definition, and X ² represents a halogen atom. (Iii) can be manufactured from compound (iv) obtained by the above Production Method 3 via intermediates (v) and (vi) in turn (steps 4- (1) to 4- (3) in the formula). 2-oxo-1,2-dihydro-3-pyridylcarbonitrile derivative (v) can be prepared by reacting (iv) with 2-cyanoacetamide in the presence of a base [Step 4- (1)]. . The base to be used depends on the starting material, the solvent to be used, and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, alkali metals such as sodium methoxide, sodium ethoxide and potassium tert-butoxide are used. Although an alkoxide is preferable, a preferable result can also be obtained even if carbonate of alkali metals, such as potassium carbonate and sodium carbonate, is used. The solvent to be used depends on the starting materials, reagents and the like, and is not particularly limited as long as the starting materials are dissolved to some extent without inhibiting the reaction. Preferably, N, N-dimethylformamide, N-methylpyrrolidone, and dimethyl are preferred. Sulfoxide methanol, ethanol and the like. The reaction temperature is usually from room temperature to 120 ° C., more preferably around 80 ° C. The 2-halogeno-3-pyridylcarbonitrile derivative (vi) can be produced by converting the oxo group of (v) to a halogen atom [ Step 4- (2)]. Although the reaction is preferably carried out in a solvent-free, even if the starting material is dissolved to some extent without inhibiting the reaction, for example, suspended in a solvent such as acetonitrile, dioxy acid, tetrahydrofuran and the like, a preferable result is obtained. Can be. The halogenating agent used for halogen atom conversion of the oxo group depends on the starting material, the solvent to be used, and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, they are phosphorus oxychloride, phosphorus oxybromide, and the like. The reaction is preferably performed at a reaction temperature of 70 to 120 ° C. Further, addition of salts of tertiary amines such as tripropylamine, quaternary amines such as tetraethylammonium chloride, N, N-dimethylformamide, and the like to the present reaction system further promotes the reaction, thereby obtaining good results. The 2-amino-3-pyridylcarbonitrile compound (i) according to the present invention can be produced by reacting X ² (halogen atom) in (vi) with ammonia [step 4- (3)]. Although this reaction is normally performed at 0-150 degreeC, it is more preferable to carry out in autoclave (50-100 degreeC). The solvent to be used depends on the starting materials, reagents and the like, and is not particularly limited as long as it dissolves the starting materials to some extent without inhibiting the reaction. Preferably, alcohols such as methanol and ethanol, tetrahydrofuran, dioxy acid and dimethicone are used. Ethers such as oxyethane diethylene glycol dimethyl ether, N, N-dimethylformamide 1-methylpyrrolidinone and the like.
[86] Recipe 5
[87]
[88] Wherein R ^3b is a C _6-14 aromatic hydrocarboncyclic group which may have a substituent or a 5-14 membered aromatic heterocyclic group which may have a substituent, X ³ is a halogen atom, Y is a C _1-6 alkyl group Indicates. The aryltin reagent (ix) used in "Step 6- (4)" in Production method 6 can be prepared by rethiolating the aryl halide (v ') and then reacting with halogenotrialkyltin. In lithiation reaction, the use of alkyl lithium, such as n-butyl lithium, sec-butyl lithium, tert- butyl lithium, is preferable. The halogenotrialkyl tin to be used depends on the starting material, the solvent to be used and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, trimethyl tin chloride such as chlorotributyl tin or triethyl tin bromide are used. And so on. The solvent to be used varies depending on the starting materials, reagents and the like, and is not particularly limited as long as the starting materials are dissolved to some extent without inhibiting the reaction, but are preferably ethers such as tetrahydrofuran and diethyl ether. The reaction temperature is preferably -100 ° C to room temperature.
[89] In Production Method ₃ , 3- (dimethylamino) -2-pro obtained by reacting a compound in which R ^3a of (ii) is substituted with a hydrogen atom (acetylated aryl or acetylated heteroaryl represented by formula R ^4a -COCH ₃ ). When the phen-1-one derivative is further treated by "Step 4- (1)" in Production Method 4, Compound (x) in which R ^3a in (v) is substituted with a hydrogen atom is obtained. The method for producing the compound (x ') according to the present invention from the compound (x) is shown below.
[90] Recipe 6
[91]
[92] In the above formula, R ^3b and R ^4a represent synonyms with the above definition, and X ⁴ represents a halogen atom. The compound (xiv) which concerns on this invention can be manufactured through (x) through process 6- (1) thru | or 6- (4) (intermediate (xi) thru (xv)). Compound (xi) can be prepared by alkylating the oxygen atom at position 2 in (x) with 2-halogenoacetamide in the presence of a base (step 6- (1)). The 2-halogenoacetamide to be used depends on the starting material, the solvent to be used, and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, 2-chloroacetamide is used, and sodium iodide is also added. The reaction is more preferred. The base to be used depends on the starting material, the solvent to be used and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, the base is sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate. The solvent to be used depends on the starting materials, reagents and the like, and is not particularly limited as long as the starting materials are dissolved to some extent without inhibiting the reaction. Preferably, ketones such as acetone and methyl ethyl ketone, alcohols such as methanol and ethanol, Ethers, such as tetrahydrofuran, a dioxy acid, dimethoxyethane, diethylene glycol dimethyl ether, N, N- dimethylformamide dimethyl sulfoxide, 1-methylpyrrolidinone, etc. are preferable. Reaction temperature is 0-100 degreeC normally. Compound (xii) can be produced by amino group transfer of 2-aminocarbonylmethyloxy-3-cyanopyridine derivative (xi) in the presence of a base in a solvent (step 6- (2)). The base to be used depends on the starting material, the solvent to be used, and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, the base is sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, or the like. . The solvent to be used depends on the starting materials, reagents and the like, and is not particularly limited as long as it dissolves the starting materials to some extent without inhibiting the reaction. Preferably, ketones such as acetone methyl ethyl ketone, methanol, ethanol, propanol, butanol, etc. Ethers such as alcohols, tetrahydrofuran, dioxy acid, dimethoxyethane, diethylene glycol dimethyl ether, N, N-dimethylformamide dimethyl sulfoxide, 1-methylpyrrolidinone and the like. The reaction temperature is usually room temperature to 150 ° C. (xVIII) can be manufactured by halogenating the pyridine ring 5th position of the 2-aminonicotinonitrile derivative (xii) with a halogenating agent in a solvent [step 6- (3)]. As the halogenating agent to be used, N-bromosuccinimide, bromine, etc. are preferable, and the solvent used depends on starting materials, reagents, etc., and is not particularly limited as long as the starting material is dissolved to some extent without inhibiting the reaction. Preferably, alcohols, such as methanol and ethanol, ethers, such as tetrahydrofuran, a dioxy acid, dimethoxyethane, diethylene glycol dimethyl ether, N, N- dimethylformamide, 1-methylpyrrolidinone, etc. are preferable. The reaction temperature is usually from -20 ° C to room temperature. Compound (xiv) according to the present invention is reacted with a 2-amino-5-halogenonicotinonitrile derivative (x ') and the allyltin reagent obtained in Preparation Method 5 in the presence of a palladium catalyst in a solvent, and a pyridine ring of (x') It can manufacture by introducing an aromatic group into 5th position (step 6- (4)). The palladium catalyst to be used depends on the starting material, the solvent to be used and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, dichlorobis (triphenylphosphine) palladium (II) and palladium (II) acetate are used. And tetrakis (triphenylphosphine) palladium (O), tris (dibenzylideneacetone) dipalladium (O) and the like. The solvent to be used is not particularly limited as long as it varies depending on the starting materials and reagents and dissolves the starting materials to some extent without inhibiting the reaction. Preferably, alcohols such as methanol and ethanol, tetrahydrofuran, dioxy acid, dimethoxy Ethers such as ethane and diethylene glycol dimethyl ether, toluene, xylene, N, N-dimethylformamide, 1-methylpyrrolidinone and the like. The reaction temperature is usually room temperature to 150 ° C.
[93] Among the compounds represented by the above formula (I) according to the present invention, a compound having an α-hydroxy nitrogen-containing aromatic heterocyclic group in which R ² , R ³ and / or R ⁴ has a hydroxyl group on α of the nitrogen atom is as follows. It can manufacture.
[94] For example, the compound (xvi) which has the (alpha) -hydroxy nitrogen containing aromatic heterocyclic group in the 5th pyridine ring can be manufactured by hydrolysis of the (alpha)-alkoxy nitrogen containing aromatic heterocyclic compound (xvi).
[95] Recipe 7
[96]
[97] In the above formula, R ^4a represents the same definition as the above definition, R ¹⁰ represents a C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, and the like, and ring A ¹ represents a pyridinyl group and a pyrimidyl group , Pyrazinyl group, ring A ² represents a dihydrooxopyridinyl group, a dihydrooxopyrimidyl group, a dihydropyrazinyl group or a tetrahydropyrazinyl group. It is preferable to perform this reaction in aqueous solution of mineral acids, such as hydrochloric acid, hydrobromic acid, and sulfuric acid, or in the mixed solvent of the said mineral acid aqueous solution and acetic acid, for example. The reaction temperature is usually room temperature to 100 ° C.
[98] In addition, a substituent may be introduced into the α-hydroxy nitrogen-containing aromatic heterocycle of the compound (xvi) according to the present invention obtained in Preparation Method 7 as follows.
[99] Recipe 8
[100]
[101] In the above formula, R ^4a and ring A ² represent the same definitions as the above definitions, R ¹¹ represents a C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, and the like, X ⁵ represents a halogen atom . According to this process, by the presence of a base in a solvent, the reaction (xvi) as the alkyl halide compound, can be prepared a compound (xⅶ) by introducing a substituent to the nitrogen atom in the ring A ^2. The base to be used depends on the starting material, the solvent to be used and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, the base is sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, The solvent to be used depends on the starting materials, reagents, and the like, and is not particularly limited as long as the starting materials are dissolved to some extent without inhibiting the reaction. Preferably, alcohols such as methanol, ethanol, tetrahydrofuran, dioxane, dimethoxy Ethers such as ethane and diethylene glycol dimethyl ether, N, N-dimethylformamide, dimethyl sulfoxide, 1-methylpyrrolidinone and the like. Reaction temperature is 0-100 degreeC normally.
[102] Recipe 9
[103]
[104] Wherein R ^3a , R ^4a and X ⁴ represent the same definitions as defined above, and R ^2a represents a C _6-14 aromatic hydrocarbon cyclic group which may have a substituent or a 5 to 14 membered aromatic complex that may have a substituent A cyclic group is shown. Compound (xxv) according to the invention can be prepared from (xv ') and (xix) via steps 9- (1) to 9- (6) (intermediates (xx) to (xxiv)). Compound (xx) can be prepared by dehydration of (xv ') and (xix) in the presence of a base (step 9- (1)). The base to be used for the reaction depends on the starting material, the solvent to be used and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, the base is an inorganic salt such as potassium hydroxide or sodium hydroxide. The solvent to be used depends on the starting materials, reagents and the like, and is not particularly limited as long as the starting material is dissolved to some extent without inhibiting the reaction. Preferably, the solvent is a mixed solvent of alcohols such as ethanol and water. 2-oxo-1,2-dihydro-3-pyridylcarbonitrile derivative (xxi) can be prepared by reacting (xx) with 2-cyanoacetamide in the presence of a base [Step 9- (2)]. . The reaction is accelerated by conducting under oxygen atmosphere. The base to be used depends on the starting material, the solvent to be used and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, alkali metals such as sodium methoxide, sodium ethoxide and potassium tert-butoxide It is an alkoxide, and even if it uses carbonate of alkali metals, such as potassium carbonate and sodium carbonate, a preferable result can be obtained. The solvent to be used depends on the starting materials, reagents and the like, and is not particularly limited as long as it dissolves the starting materials to some extent without inhibiting the reaction. Sulfoxide, methanol, ethanol and the like. The reaction temperature is preferably room temperature to 120 ° C, more preferably around room temperature. Compound (xxii) can be prepared by alkylating the oxygen atom at the 2nd position of (xxi) with 2-halogenoacetamide in the presence of a base (step 9- (3)). The 2-halogenoacetamide to be used depends on the starting material, the solvent to be used, and the like, and is not particularly limited as long as it does not inhibit the reaction. Preferably, it is 2-chloroacetamide, and more preferably iodide It is a reaction performed by adding sodium. The base to be used depends on the starting material, the solvent to be used and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, the base is sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate. The solvent to be used depends on the starting materials, reagents and the like, and is not particularly limited as long as the starting materials are dissolved to some extent without inhibiting the reaction. Preferably, ketones such as acetone and methyl ethyl ketone, alcohols such as methanol and ethanol, tetra Ethers such as hydrofuran, dioxy acid, dimethoxyethane, diethylene glycol dimethyl ether, N, N-dimethylformamide, dimethyl sulfoxide, 1-methylpyrrolidinone and the like. Reaction temperature is 0-100 degreeC normally. The compound (xx ') can be prepared by the amino group transfer of 2-aminocarbonylmethyloxy-3-cyanopyridine derivative (xxii) in the presence of a base in a solvent (step 9- (4)). The base to be used depends on the starting material, the solvent to be used and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, for example, sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate and sodium carbonate And potassium carbonate, and the solvent used depends on the starting material, the reagent, and the like, and is not particularly limited as long as the starting material is dissolved to some extent without inhibiting the reaction. Alcohols such as ethanol propanol and butanol, ethers such as tetrahydrofuran, dioxy acid, dimethoxyethane and diethylene glycol dimethyl ether, as well as N, N-dimethylformamide, dimethyl sulfoxide and 1-methylpyrrolidinone Etc. are preferable. The reaction temperature is usually room temperature to 150 ° C. (xxiv) can be prepared by halogenating the pyridine ring 5th position of the 2-aminonicotinonitrile derivative (xx ') with a halogenating agent in a solvent (step 9- (5)). The halogenating agent to be used depends on the starting material, the solvent to be used, and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, the halogenating agent is N-bromosuccinimide, bromine or the like. Although it depends on a raw material, a reagent, etc., and dissolving a starting material to some extent without inhibiting reaction, it does not specifically limit, Preferably, alcohols, such as methanol and ethanol, tetrahydrofuran, a dioxy acid, dimethoxyethane, diethylene Ethers, such as glycol dimethyl ether, N, N- dimethylformamide 1-methylpyrrolidinone, etc. are preferable. The reaction temperature is usually from -20 ° C to room temperature. Compound (xxv) according to the present invention, in the presence of a palladium catalyst in a solvent, reacts 2-amino-5-halogenonicotinonitrile derivative (xxiv) with the allyltin reagent obtained in Preparation Method 5, and the pyridine ring of (xxiv) It can manufacture by introducing an aromatic group into 5th position (step 9- (6)). The palladium catalyst to be used depends on the starting material, the solvent to be used and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, dichlorobis (triphenylphosphine) palladium (II) and palladium (II) acetate are used. And tetrakis (triphenylphosphine) palladium (O), tris (dibenzylideneacetone) dipalladium (O), dichlorobis (acetonitrile) palladium (II) and the like. The solvent to be used depends on the starting materials, reagents and the like, and is not particularly limited as long as it dissolves the starting materials to some extent without inhibiting the reaction. Preferably, alcohols such as methanol and ethanol, tetrahydrofuran, dioxy acid, dimethoxy Ethers such as ethane and diethylene glycol dimethyl ether, toluene, xylene, N, N-dimethylformamide 1-methylpyrrolidinone and the like. The reaction temperature is usually room temperature to 150 ° C.
[105] Recipe 10
[106]
[107] In the above formula, R ^3a , R ^4a , and X ⁴ represent synonyms with the above definition, R ^2b represents an alkyl group which may be substituted, and Y represents a lower alkyl group. The compound (xxx ') according to the present invention can be prepared from (xxvi) and (xix) via steps 10- (1) to l0- (7) (intermediates (xx') to (xxxii)). Compound (xx ') can be prepared by condensation of (xxvi) and (xix) in the presence of a base (step 10- (1)). The base to be used for the reaction varies depending on the starting material, the solvent used and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, the base is potassium tert-butoxide, and the solvent used is a starting material, a reagent or the like. Although it does not restrict | limit especially if it changes to some extent and does not inhibit a reaction, and does not inhibit a reaction, Preferably it is tert-butanol. The reaction temperature is preferably room temperature to 120 ° C, more preferably near room temperature. The compound (xxxv ') can be prepared by alkylating (xx') with methyl halide in the presence of a base (step 10- (2)) The base used for the reaction depends on the starting material, the solvent used, and the like and inhibits the reaction. Although it does not specifically limit unless it does not specifically limit, Preferably it is inorganic bases, such as potassium carbonate, Preferable example in methyl halide is methyl iodide The solvent used varies with starting materials, reagents, etc., and starts without inhibiting reaction. Although it will not specifically limit, if it melt | dissolves a substance to some extent, Preferably it is ketones, such as acetone, methyl ethyl ketone, etc. The reaction temperature is preferably room temperature to 120 degreeC, More preferably, it is near room temperature. -Dihydro-3-pyridylcarbonitrile derivatives (xxix) can be prepared by reacting (xxv ') with 2-cyanoacetamide in the presence of a base. (Step 10- (3)] The base to be used depends on the starting material, the solvent to be used, and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, sodium methoxide and sodium ethoxide are used. And alkoxides of alkali metals such as sodium isopropoxy, potassium tert-butoxide, etc. The solvent used depends on the starting materials, reagents, etc., and is not particularly limited as long as the starting materials are dissolved to some extent without inhibiting the reaction. But preferably N-dimethylformamide N-methylpyrrolidone, dimethylsulfoxide, isopropanol, etc. The reaction temperature is preferably 0 ° C. to 120 ° C. Compound (xxx) is selected from (xxix) 2 in the presence of a base. It can be prepared by alkylating the above oxygen atom with 2-halogenoacetamide [Step 10- (4)] As the 2-halogenoacetamide used, 2-chloroacetamide is used. Preferably, the reaction is performed by further adding sodium iodide The base to be used depends on the starting material, the solvent to be used, and the like, and is not particularly limited as long as the reaction is not inhibited. , Sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, and the solvent used depends on the starting materials, reagents and the like, and is not particularly limited as long as the starting material is dissolved to some extent without inhibiting the reaction. Preferably, ketones such as acetone and methyl ethyl ketone, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether, N-dimethylformamide dimethyl sulfoxide and 1- Methylpyrrolidinone and the like. Reaction temperature is 0-100 degreeC normally. Compound (xxxi) can be produced by amino group transfer of 2-aminocarbonylmethyloxy-3-cyanopyridine derivative (xxx) in the presence of a base in a solvent (step 10- (5)). The base to be used depends on the starting material, the solvent to be used and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, the base is sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, or the like. The solvent to be used depends on the starting material, the solvent to be used and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, ketones such as acetone and methyl ethyl ketone, alcohols such as methanol, ethanol propanol and butanol, Ethers such as tetrahydrofuran, dioxy acid, dimethoxyethane and diethylene glycol dimethyl ether, as well as N, N-dimethylformamide dimethyl sulfoxide 1-methylpyrrolidinone. The reaction temperature is usually room temperature to 150 ° C. (xxii) can be prepared by halogenating the pyridine ring 5th position of the 2-aminonicotinonitrile derivative (xxxi) with a halogenating agent in a solvent (step 10- (6)). The halogenating agent to be used depends on the starting material, the solvent to be used and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, the halogenating agent is N-bromosuccinimide, bromine or the like. Although it depends on reagents and dissolves a starting material to some extent without inhibiting reaction, Although it does not specifically limit, Preferably, alcohols, such as methanol and ethanol, tetrahydrofuran, dioxy acid, dimethoxyethane, diethylene glycol dimethyl Ethers such as ether, N, N-dimethylformamide 1-methylpyrrolidinone and the like. The reaction temperature is usually from -20 ° C to room temperature. Compound (xxx ') according to the present invention reacts 2-amino-5-halogenonicotinonitrile derivative (xxxii) with the allyltin reagent obtained in Preparation Method 5 in the presence of a palladium catalyst in a solvent, and a pyridine ring of (xxxii) It can manufacture by introducing an aromatic group into 5th position (step 10- (7)). As a palladium catalyst to be used, dichlorobis (triphenylphosphine) palladium (II), palladium acetate (lI), tetrakis (triphenylphosphine) palladium (O), tris (dibenzylidene acetone), for example Dipalladium (O), dichlorobis (acetonitrile) palladium (II), etc. are preferable. The solvent to be used depends on the starting materials, reagents and the like, and is not particularly limited as long as it dissolves the starting materials to some extent without inhibiting the reaction. Preferably, alcohols such as methanol and ethanol, tetrahydrofuran, dioxy acid and dimethicone are used. Ethers such as oxyethane and diethylene glycol dimethyl ether, toluene, xylene, N, N-dimethylformamide 1-methylpyrrolidinone and the like are preferable. The reaction temperature is usually room temperature to 150 ° C.
[108] Recipe 11
[109]
[110] In the above formula, R ^2a and R ^4a represent the same definitions as the above definitions, R ¹⁰ represents a C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, and the like, and ring A ¹ represents a pyridinyl group, Ring a ² represents a pyrimidyl group or a pyrazinyl group, a dihydrooxopyridinyl group, a dihydrooxopyrimidyl group, a dihydropyrazinyl group or a tetrahydropyrazinyl group. The compound (xxxv) having an α-hydroxy nitrogen-containing aromatic heterocyclic group on the 5th pyridine ring can be produced by hydrolysis of the α-alkoxy nitrogen-containing aromatic heterocyclic compound (xxxiv). The solvent used in the present reaction varies depending on the starting materials, reagents and the like, and is not particularly limited as long as the starting materials are dissolved to some extent without inhibiting the reaction. Preferably, aqueous solutions of mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid are used. Or a mixed solvent of the aqueous mineral acid solution and acetic acid. The reaction temperature is usually room temperature to 100 ° C.
[111] Recipe 12
[112]
[113] In the above formula, R ^2b , R ^4a , ring A ¹ and ring A ² are the same as defined above, and R ¹⁰ represents a C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, or the like. . The compound (xxx ') which has the (alpha) -hydroxy nitrogen containing aromatic heterocyclic group in the 5th pyridine ring can be manufactured by hydrolysis of the (alpha)-alkoxy nitrogen containing aromatic heterocyclic compound (xxxvi). The solvent used in this reaction varies depending on the starting materials, reagents, and the like, and is not particularly limited as long as the starting materials are dissolved to some extent without inhibiting the reaction. Preferably, aqueous solutions of mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid are used. Or a mixed solvent of the aqueous mineral acid solution and acetic acid. The reaction temperature is usually room temperature to 100 ° C.
[114] Recipe 13
[115]
[116] Wherein R ^2c is a hydrogen atom, a hydroxyl group, a C _1-6 alkoxy group which may have a substituent, a C _1-6 alkyl group which may have a substituent, a C _6-14 aromatic hydrocarbon cyclic group which may have a substituent Or a 5 to 14 membered aromatic heterocyclic group which may have a substituent, R ^3c is a C _6-14 aromatic hydrocarboncyclic group which may have a substituent or a 5 to 14 membered aromatic heterocyclic group which may have a substituent, R ^4a and X ⁴ represent the definitions and synonyms above. The compound (xxv ') according to the present invention is reacted with a 2-amino-5-halogenonicotinonitrile derivative (xxxix) and an allylboron reagent or an allyltin reagent in a solvent, in the presence of a palladium catalyst and a base, It can manufacture by introducing an aromatic group into a pyridine ring 5th position. The palladium catalyst to be used depends on the starting material, the solvent to be used and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, dichlorobis (triphenylphosphine) palladium (lI) and palladium acetate (II) Tetrakis (triphenylphosphine) palladium (O), tris (dibenzylideneacetonedipalladium (O)), dichlorobis (acetonitrile) palladium (II) and the like. The base to be used depends on the starting material, the solvent to be used and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, inorganic bases such as potassium carbonate and potassium phosphate or organic amines such as ether diisopropylamine to be. The solvent to be used depends on the starting materials, reagents and the like, and is not particularly limited as long as it dissolves the starting materials to some extent without inhibiting the reaction. Preferably, alcohols such as methanol and ethanol, tetrahydrofuran, dioxy acid and dimethicone are used. Ethers such as oxyethanediethylene glycol dimethyl ether, toluene, xylene, N, N-dimethylformamide 1-methylpyrrolidinone and the like. The reaction temperature is usually room temperature to 150 ° C.
[117] Recipe 14
[118]
[119] Wherein R ^3d is a C _6-14 aromatic hydrocarboncyclic group which may have a substituent, a 5-14 membered aromatic heterocyclic group which may have a substituent or a 5-14 membered non-aromatic heterocyclic group which may have a substituent Wherein R ^2c and R ^4a represent the same definitions as above. Compound (xli) according to the present invention can be prepared by hydrolyzing the cyano group of compound (xl) in a solvent, in the presence of a base. The base to be used depends on the starting material, the solvent to be used, and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, the base is an inorganic base such as sodium hydroxide or potassium hydroxide. The solvent to be used varies depending on the starting materials, reagents and the like, and is not particularly limited as long as the starting materials are dissolved to some extent without inhibiting the reaction. The reaction temperature is usually room temperature to 150 ° C.
[120] Recipe 15
[121]
[122] In the above formula, R ^1b represents a carbamoyl group which may have a substituent, and R ^2c , R ^3d and R ^4a have the same definitions as the above definitions. The carbamoyl derivative (xlii) according to the present invention can be prepared by dehydrating a carboxylic acid derivative (xli) and an amine in the presence of a condensing agent in a solvent. As a condensing agent to be used, 3- (3--dimethylaminopropyl) -1-ethylcarbodiimide etc. are preferable. The reaction is accelerated by adding 1-hydroxybenzotriazole and the like. In addition, when the amine condensed to carboxylic acid forms a salt with hydrogen chloride or the like, an appropriate amount of tertiary amine such as triethylamine is added. As a solvent to be used, ethers, such as tetrahydrofuran, a dioxy acid, dimethoxyethane, diethylene glycol, N, N- dimethylformamide, 1-methylpyrrolidinone, etc. are preferable, for example. The reaction temperature is usually 0 to 50 ° C, more preferably near room temperature.
[123] Recipe 16
[124]
[125] Wherein R ^2d is a hydrogen atom, a C _1-6 alkoxy group which may have a substituent, a C _1-6 alkyl group which may have a substituent, a C _6-14 aromatic hydrocarbon cyclic group or a substituent which may have a substituent A 5-14 membered aromatic heterocyclic group which may have, Ring A ³ may have a pyridinyl group, a pyrimidyl group, a pyrazinyl group, R <^11> may have a _C1-6 alkyl group which may have a substituent, and may have a substituent C _2-6 alkenyl group or a C _2-6 alkynyl group may have to be in the substituent, X ⁵ is a group such as a sulfonate which may be desorbed with a halogen atom, an optionally substituted carbonate group, R ^4a and ring a ² are in the Represents definitions and agreements respectively. Compounds (xliv) and (xlv) according to the present invention can be prepared by reacting R ⁹ -X ⁵ with compound (xl ') in the presence of a base in a solvent. The base used for the reaction varies depending on the starting material, the solvent used and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, the base is an inorganic base represented by potassium carbonate, potassium hydrogencarbonate, sodium carbonate. The solvent to be used usually depends on starting materials, reagents and the like, and is not particularly limited as long as it dissolves the starting materials to some extent without inhibiting the reaction, but is preferably amides such as N, N-dimethylformamide. . Although the reaction temperature is suitably room temperature to 100 ° C, more preferably around 65 ° C.
[126] Recipe 17
[127]
[128] Wherein R ¹² is a C _6-14 aromatic hydrocarboncyclic group which may have a substituent or a 5-14 membered aromatic heterocyclic group which may have a substituent, R ^2c , R ^4a and ring A ² are identical to the above definition Each is represented. The compound (xl ') according to the present invention can be prepared by reacting compound (xlvi) with an allyl boron reagent in the presence of a base and a copper catalyst in a solvent. The base to be used for the reaction varies depending on the starting material, the solvent to be used and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, the base is a tertiary amine such as pyridine, diisopropylethylamine, triethylamine and the like. The copper catalyst to be used depends on the starting material, the solvent to be used and the like, and is not particularly limited as long as the reaction is not inhibited. Preferably, the copper catalyst is divalent copper such as copper acetate, copper bromide, copper lactate, and more preferably acetic acid. Copper. The solvent to be used depends on the starting materials, reagents and the like, and is not particularly limited as long as the starting materials are dissolved to some extent without inhibiting the reaction. Preferably, the solvent is N, N-dimethylformamide, tetrahydrofuran, ethyl acetate, or the like. . The reaction temperature is suitably around room temperature.
[129] Although the above is a typical example of the manufacturing method of the compound (I) which concerns on this invention, the raw material compound in the manufacture of the compound of this invention may form a salt and a hydrate, and if it does not inhibit a reaction, it will not specifically limit. Moreover, when compound (1) which concerns on this invention is obtained as a free body, it can convert into the state of the salt in which said compound (I) may be formed in accordance with a conventional method. In addition, various isomers obtained for the compound (I) according to the present invention (e.g., geometric isomers, optical isomers based on sub-carbons, rotamers, stereoisomers, tautomers, and the like) are ordinary separation means, for example For example, it can be purified and isolated by using recrystallization, diastereoisomer method, enzyme fractionation method and various chromatography (for example, thin layer chromatography, column chromatography, gas chromatography, etc.).
[130] The compound represented by the formula (I) according to the present invention or a salt thereof or a hydrate thereof can be formulated by a conventional method, and preferred formulations are tablets, powdered medicines, fine granules, granules, coated tablets, capsules, Syrups, troches, inhalants, suppositories, injections, ointments, eye ointments, eye drops, nasal drops, ear drops, pops, lotions and the like. For formulation, excipients, binders, disintegrants, lubricants, colorants, colloids, stabilizers, emulsifiers, absorption accelerators, surfactants, pH adjusters, preservatives, antioxidants, and the like, which are commonly used, can be used. The component used as a raw material of a pharmaceutical formulation can be mix | blended and can be formulated by a conventional method. As these components, For example, (1) Animal and vegetable oils, such as a soybean oil, tallow, synthetic glycerides; (2) hydrocarbons such as liquid paraffin, squalane and solid paraffin; (3) ester oils such as octylate acid octyldodecyl and myristic acid isopropyl; (4) higher alcohols such as cetostearyl alcohol and behenyl alcohol; (5) silicone resins; (6) silicone oils; (7) surfactants such as polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hardened castor oil, and polyoxyethylene polyoxypropylene block copolymers; (8) water-soluble polymers such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone, methyl cellulose; (9) lower alcohols such as ethanol and isopropanol; (10) polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol and sorbitol; (11) sugars such as glucose and sucrose; (12) inorganic powders such as silicic anhydride, magnesium aluminum silicate and aluminum silicate; (13) purified water, and the like. ① excipients include, for example, lactose, corn starch, white sugar, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide and the like; ② As the binder, for example, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone Polypropylene glycol polyoxyethylene block polymer, meglumine, calcium citrate, dextrin, pectin and the like; (3) Examples of disintegrating agents include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, carboxymethyl cellulose and calcium; (4) As the lubricant, for example, magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oil, etc .; ⑤ any colorant may be used as long as it is allowed to be added to the medicine; (6) Cocoagulant, cocoa horse, peppermint brain, aromatic acid, peppermint oil, dragon brain (龍 腦), cinnamon powder, etc .; ⑦ As antioxidants, ascorbic acid, α-tocopherol, etc., which are permitted to be added to medicines, are used respectively.
[131] (1) Oral preparations are prepared by adding excipients, binders, disintegrants, lubricants, coloring agents, copulation agents, etc., to the compound or salt thereof according to the present invention, and then powdered powder, granules, granules, tablets, Covered tablets, capsules and the like. ② In the case of tablets and granules, the coating of sugar, gelatin, and other needs appropriately, of course, does not interfere. (3) In the case of liquid preparations such as syrups, injectable preparations, and eye drops, a pH adjusting agent, a dissolving agent, an isotonic agent, and the like, and a dissolution aid, stabilizer, buffer, suspending agent, antioxidant, and the like, are formulated according to a conventional method as necessary. In the case of the liquid formulation, it may be made into a lyophilisate, and the injection may be administered intravenously, subcutaneously, or intramuscularly. Preferred examples of the suspending agent include methyl cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate and the like; Preferable examples of the dissolution aid include polyoxyethylene cured castor oil, polysorbate 80, nicotincinamide, polyoxyethylene sorbitan monolaurate and the like; Preferred examples of the stabilizer include sodium sulfite, sodium metasulfite, ether and the like; Preferred examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, chlorocresol and the like. Moreover, in the case of (4) external preparation, a manufacturing method is not specifically limited, It can manufacture by a normal method. As the base raw material to be used, it is possible to use various raw materials commonly used in medicines, quasi-drugs, cosmetics, etc., for example, animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, Raw materials such as phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, clay minerals, purified water, and the like, and pH-adjusting agents, antioxidants, chelating agents, preservatives, coloring agents, flavoring agents, and the like can be added as necessary. . If necessary, a component having a differentiation-inducing action, a blood flow promoting agent, a bactericide, an anti-inflammatory agent, a cell-activating agent, a vitamin, an amino acid, a humectant, a keratin soluble agent and the like may be blended.
[132] The dosage of the medicament according to the present invention varies depending on the severity of symptoms, age, sex, weight, type of dosage form, salt, difference in sensitivity to drugs, and specific types of diseases. 30 μg to 10 g, preferably 100 μg to 5 g, more preferably 100 μg to 100 mg, about 30 μg to 1 g, preferably 100 μg to 500 mg, more preferably 100 μg to 30 mg by injection The mg is administered one or several times each.
[133] According to the present invention, a novel 2-aminopyridine compound can be provided. The compounds according to the invention or salts thereof exhibit excellent antagonism against adenosine receptors (adenosine A ₁ , A _2A , A _2B or A ₃ receptors), in particular as antagonists of adenosine A ₂ receptors, in particular adenosine A _2B receptors. Do. The compounds according to the invention or salts thereof are useful as a therapeutic or prophylactic agent for diseases involving adenosine receptors (adenosine A ₁ , A _2A , A _2B or A ₃ receptors), and diseases in which antagonists of these receptors are effective. Compounds according to the present invention or salts thereof include constipation, irritable bowel syndrome, constipation with irritable bowel syndrome, organic constipation, constipation with bowel palsy bowel obstruction, constipation with congenital gastrointestinal dysfunction, constipation with bowel obstruction, diabetes It is not only useful for the treatment, prevention or improvement of diabetic complications, diabetic retinopathy, obesity, asthma, but also hypoglycemic agents, impaired glucose tolerance, insulin sensitivity enhancers, hypertensives, diuretics, osteoporosis drugs, anti-Parkinson drugs, Alzheimer's disease It is also useful as an inflammatory bowel disease treatment drug or a clonal disease treatment drug.
[134] Reference examples, examples, and test examples shown below are exemplary, and the compounds according to the present invention are not limited to the specific examples below in any case. Those skilled in the art can make the present invention to the maximum extent possible by adding various modifications to the claims according to the present specification as well as the examples shown below, and such modifications are included in the claims according to the present specification.
[135] Reference Example 1
[136] 1- (2-furyl) -2- (4-pyridyl) -1-ethanone
[137]
[138] Lithium bis (trimethylsilyl) amide (100 ml, 100 mmol) was dissolved in a tetrahydrofuran (40 ml) solution of 4-picoline (4.6 g, 49.4 mmol) and 2-furan carboxylate (7.7 g, 54.9 mmol). It was dripped over 1 hour at 0 degreeC under atmosphere, and it stirred for 2 hours as it is. Hexane (140 ml) was added to the reaction solution, and the resulting crystals were collected by filtration. The obtained crystals were dissolved in ethyl acetate and saturated aqueous ammonium chloride solution. The organic layer was washed with saturated aqueous ammonium chloride solution (× 2) and saturated brine, dried over anhydrous sodium sulfate and concentrated. Hexane was added to the residue, and the resulting precipitate was collected by filtration and washed with hexane to obtain the title compound (6.5 g, 70%) as a pale yellow solid.
[139]
[140]
[141] Reference Example 2
[142] 3- (dimethylamino) -1- (2-furyl) -2- (4-pyridyl) -2-propen-1-one
[143]
[144] N, N-dimethylformamide dimethylacetal (5 ml) was added to 1- (2-furyl) -2- (4-pyridyl) -1-ethanone (2.0 g, 10.7 mmol) and stirred at 100 ° C. for 2 hours. did. After cooling, the reaction solution was diluted with ethyl acetate and saturated aqueous ammonium chloride solution. The aqueous layer was extracted with ethyl acetate (× 6). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound (2.5 g, 97%) as a reddish brown oily substance.
[145]
[146] Reference Example 3
[147] 6- (2-furyl) -2-oxo-5- (4-pyridyl) -1,2-dihydro-3-pyridinecarbonitrile
[148]
[149] 3- (dimethylamino) -1- (2-furyl) -2- (4-pyridyl) -2-propen-1-one (2.27 g, 9.37 mmol) and 2-cyanoacetamide (950 mg, 11.3 mmol) of sodium methoxide (1.20 g, 22.2 mmol) was added to an N, N-dimethylformamide solution, and the mixture was stirred at 80 ° C. for 2 hours under a nitrogen atmosphere. After cooling, the reaction solution was concentrated and diluted with water. After neutralizing with 6N hydrochloric acid, the resulting solid was collected by filtration and washed with water to obtain the title compound (1.78 g, 72%) as a light brown solid.
[150]
[151] Reference Example 4
[152] 2-chloro-6- (2-furyl) -5- (4-pyridyl) -3-pyridinecarbonitrile
[153]
[154] A suspension of phosphorus oxychloride (90 g) of 6- (2-furyl) -2-oxo-5- (4-pyridyl) -1,2-dihydro-3-pyridinecarbonitrile (21.0 g, 79.8 mmol) Stir at 110 ° C. under a nitrogen separator. After 4 hours, phosphorus oxychloride (50 g) was added, followed by heating and stirring for 5 hours. After cooling, the reaction solution was concentrated. Ice was added to the residue, followed by neutralization with saturated sodium bicarbonate. After extraction with ethyl acetate (2 liter) -tetrahydrofuran (1 liter), the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. Diethyl ether was added to the residue, and the produced solid was collected by filtration and washed with diethyl ether to obtain the title compound (13.6 g, 61%) as a dark yellow solid.
[155]
[156] Reference Example 5
[157] 3- (dimethylamino) -1- (2-furyl) -2-propen-1-one
[158]
[159] A mixture of 2-acetylfuran (25.0 g, 0.227 mmol) and N, N-dimethylformamide dimethylacetal (40 ml) was stirred at 100 ° C. for 9 hours. The reaction solution was cooled and concentrated. Diethyl ether and hexane were added to the residue, and the resulting solid was collected by filtration and washed with hexane to obtain the title compound (36.5 g, 97%) as a brown solid.
[160]
[161] Reference Example 6
[162] 6- (2-furyl) -2-oxo-1,2-dihydro-3-pyridinecarbonitrile
[163]
[164] 3- (dimethylamino) -1- (2-furyl) -2-propen-1-one (15.0 g, 90.9 mmol), 2-cyanoacetamide (8.5 g, 101 mmol) and potassium carbonate (38.0 g , 275 mmol) of dimethylsulfoxide (80 ml) suspension was stirred at 120-140 ° C for 21 hours. After cooling, the reaction solution was diluted with water. After adjusting the pH to 3 with concentrated hydrochloric acid, the resulting solid was collected by filtration and washed with water to obtain the title compound (13.0 g, 77%) as a brown solid.
[165]
[166] Reference Example 7
[167] 2-[[3-cyano-6- (2-furyl) -2-pyridyl] oxy] acetamide
[168]
[169] Acetone (100 ml) of 6- (2-furyl) -2-oxo-1,2-dihydro-3-pyridinecarbonitrile (6.0 g, 32.3 mmol), 2-chloroacetamide (3.0 g, 37.3 mmol) The suspension was stirred at 60 ° C. for 6 hours. After cooling, the reaction solution was diluted with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (× 2) and saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate and concentrated. Diethyl ether was added to the residue, and the resulting precipitate was collected by filtration and washed with diethyl ether to obtain the title compound (4.2 g, 54%) as a brown solid.
[170]
[171] Reference Example 8
[172] 2-amino-6- (2-furyl) nicotinonitrile
[173]
[174] N, N-dimethylform of 2-[[3-cyano-6- (2-furyl) -2-pyridyl] oxy] acetamide (8.0 g, 32.9 mmol) and potassium carbonate (9.1 g, 65.9 mmol) The amide (80 ml) suspension was stirred at 120 ° C. for 1.5 hours. After cooling, the reaction solution was diluted with water and ethyl acetate and insolubles were filtered off. The aqueous layer of the filtrate was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous ammonium chloride solution (× 2), dried over anhydrous sodium sulfate and concentrated. The residue was suspended with methanol, and the resulting solid was collected by filtration and washed with methanol to obtain the title compound (3.81 g, 63%) as a brown solid.
[175]
[176] Reference Example 9
[177] 2-amino-5-bromo-6- (2-furyl) nicotinonitrile
[178]
[179] N-bromosuccinimide in N, N-dimethylformamide solution (60 ml) of 2-amino-6- (2-furyl) nicotinonitrile (4.0 g, 21.6 mmol) at 1-2 ° C. under nitrogen atmosphere (3.5 g, 19.7 mmol) was added and the mixture was stirred as it was. After 30 minutes, the reaction solution was diluted with ethyl acetate and saturated aqueous potassium carbonate solution. The organic layer was washed with a saturated aqueous potassium carbonate solution and a saturated aqueous ammonium chloride solution, then dried over anhydrous sodium sulfate and concentrated. Methanol was added to the residue, and the resulting solid was collected by filtration and washed with methanol to obtain the title compound (3.02 g, 53%) as a brown solid.
[180]
[181] Reference Example 10
[182] 5-bromo-2-methoxypyridine
[183]
[184] Sodium (10 g, 0.435 mmol) was dissolved in methanol (500 ml), then 2,5-dibromopyridine (50 g, 0.211 mol) was added and heated to reflux for 2 days. The reaction solution was allowed to cool, concentrated and then the residue was diluted with ethyl acetate and saturated aqueous ammonium chloride solution. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (33 g, 83%) as a pale brown oily substance.
[185]
[186] Reference Example 11
[187] 2-methoxy-5- (1,1,1-tributylstannyl) pyridine
[188]
[189] Tetrahydrofuran (100 ml) solution of 5-bromo-2-methoxypyridine (5.0 g, 26.6 mmol) in a hexane solution of 2.5M n-butyllithium (12.0 ml, 30.0 mmol) at -70 ° C. under nitrogen atmosphere. Was dripped over 30 minutes. Subsequently, a tetrahydrofuran (20 ml) solution of tributyl tin chloride (10.4 ml, 32.0 mmol) was added dropwise over 1 hour, and then the reaction solution was raised to room temperature and stirred as it was. After 30 minutes, the reaction solution was diluted with saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was treated by silica gel column chromatography (elution solvent; hexane, hexane: ethyl acetate = 40: 1) to obtain the title compound (7.9 g, 75%) as a colorless oily substance.
[190]
[191] Reference Example 12
[192] (E) -1,3-di (3-fluorophenyl) -2-propen-1-one
[193]
[194] A mixture of 3-fluorobenzaldehyde (7.63 ml, 72.4 mmol), 3-fluoroacetophenone (10 g, 72.4 mmol), potassium hydroxide (5.18 g, 92.6 mmol), ethanol (23 ml), and water (47 ml) Was stirred at room temperature overnight. After diluting the reaction solution with water, the solid was collected by filtration and washed with ethanol and diethyl ether to obtain the title compound (16.4 g, 93%).
[195]
[196] Reference Example 13
[197] 4,6-di (3-fluorophenyl) -2-oxo-1,2-dihydro-3-pyridinecarbonitrile
[198]
[199] Dimethylsulfoxide of (E) -1,3-di (3-fluorophenyl) -2-propen-1-one (16.4 g, 73.9 mmol), and potassium t-butoxide (30.2 g, 269 mmol) (131 ml) The solution was stirred overnight at room temperature under oxygen atmosphere. Water (300 ml) and 6N hydrochloric acid (390 ml) were added to the reaction solution. The solid was collected by filtration and washed with water to obtain the title compound (17.4 g, 84%).
[200]
[201] Reference Example 14
[202] Isopropyl 3- (2-furyl) -3-oxopropanethioate
[203]
[204] Isopropyl (methylsulfanyl) methanethioate (7.0 g, 46.7 mmol), 2-acetylfuran (5.14 g, 46.7 mmol), potassium t-butoxide (10.5 g, 93.5 mmol), and t-butanol (35 ml ) Was stirred overnight at room temperature. After adding hot to the reaction solution, it was made acidic with 5N hydrochloric acid. The solid was collected by filtration and washed with water to obtain the title compound (3.7 g, 37%).
[205]
[206] Reference Example 15
[207] (Z) -1- (2-furyl) -3-isopropoxy-3- (methylsulfanyl) -2-propene-1one
[208]
[209] A mixture of isopropyl 3- (2-furyl) -3-oxopropanethioate (3.7 g, 17.5 mmol), potassium carbonate (7.3 g, 52.4 mmol), and acetone (15 ml) was heated to reflux for 1 hour. After cooling to 0 degreeC, methyl iodide (2.17 ml, 34.9 mmol) was added, and it stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and insolubles were filtered off. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (elution solvent; ethyl acetate / hexane = 1: 1) to obtain the title compound (3.2 g, 81%).
[210]
[211] Reference Example 16
[212] 6- (2-furyl) -4-isopropoxy-2-oxo-1,2-dihydro-3-pyridinecarbonitrile
[213]
[214] Sodium (309 mg, 13.4 mmol) was dissolved in isopropanol (46 ml) and then (Z) -1- (2-furyl) -3-isopropoxy-3- (methylsulfanyl) -2-propene-1 Warm (3.03 g, 13.4 mmol) and 2-cyanoacetamide (1.13 g, 13.4 mmol) were added and stirred overnight at room temperature. After adding ice water to the reaction solution, the solid was collected by filtration and washed with water and diethyl ether to obtain the title compound (2.3 g, 70%).
[215]
[216] Example 1
[217] 2-amino-6- (2-furyl) -5- (4-pyridyl) -3-pyridinecarbonitrile
[218] 30 ml of ethanol solution of ammonia in 2-chloro-6- (2-furyl) -5- (4-pyridyl) -3-pyridinecarbonitrile (200 mg, 0.710 mmol) was saturated with ammonia gas in ethanol at 0 ° C. After adjusting, the mixture was sealed, and it sealed to the stainless autoclave, and heated and stirred at 100 degreeC. After 24 hours, the reaction solution was cooled and concentrated. The residue was treated by silica gel column chromatography (eluent; hexane, hexane: ethyl acetate = 2: 1, 1: 1, 1: 2), then suspended in diethyl ether, and the resulting precipitate was collected by filtration and diluted with diethyl. Washing with ether gave the title compound (50 mg, 27%) as a pale orange solid.
[219]
[220] Example 2
[221] 2-amino-6- (3-fluorophenyl) -5- (4-pyridyl) -3-pyridinecarbonitrile
[222] It synthesize | combined by the method similar to or equivalent to Examples 18-20 mentioned later.
[223]
[224] MS m / e (ESI) 291 (MH ⁺ )
[225] Example 3
[226] 2-amino-6- (2-furyl) -5- (4-methoxy-3-pyridyl) -3-pyridinecarbonitrile
[227] 2-amino-5-bromo-6- (2-furyl) nicotinonitrile (1.80 g, 6.82 mmol), 2-methoxy-5- (1,1,1-tributylstannyl) pyridine (5.20 g , 13.1 mmol) and a solution of N, N-dimethylformamide (18 ml) of dichlorobis (triphenylphosphine) palladium (II) (480 mg, 0.634 mmol) were stirred at 80 ° C. for 2 hours under a nitrogen atmosphere. The reaction solution was allowed to cool and diluted with ethyl acetate and saturated aqueous ammonium chloride solution. The organic layer was washed with saturated aqueous ammonium chloride solution (× 2), dried over anhydrous sodium sulfate and concentrated. The residue was treated by silica gel column chromatography (elution solvent; hexane, hexane: ethyl acetate = 8: 1, 4: 1), and then suspended in diethyl ether, and the resulting solid was collected by filtration and washed with diethyl ether to give the result. Compound (1.12 g, 56%) was obtained as a yellow solid.
[228]
[229] Example 4
[230] 2-amino-6- (2-furyl) -5- (6-oxo-1,6-dihydro-3-pyridinyl) nicotinonitrile
[231] Acetic acid (6 ml) -concent hydrobromic acid of 2-amino-6- (2-furyl) -5- (4-methoxy-3-pyridyl) -3-pyridinecarbonitrile (1.0 g, 3.42 mmol) ml) The solution was stirred at 100 ° C. for 1.5 hours. The reaction solution was allowed to cool and then adjusted to pH = 12-13 with 5N sodium hydroxide and washed with ethyl acetate. The organic layer was extracted with 1N sodium hydroxide (× 2), and the combined aqueous layers were neutralized with 5N hydrochloric acid. The produced solid was collected by filtration to obtain the title compound (760 mg) as a yellow crude crystal. This was suspended in methanol, dissolved by addition of 4N HCl / ethyl acetate and treated by silica gel column chromatography (elution solvent; dichloromethane, dichloromethane: methanol = 40: 1, 20: 1, 10: 1). The obtained crude product was suspended in water, neutralized with 5N sodium hydroxide, the solid was collected by filtration, washed with water to obtain the title compound (486 mg, 51%) as a yellow solid.
[232]
[233] Example 5
[234] 2-amino-5- (1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotinonitrile
[235] Nitrogen in a suspension of methanol (8 ml) of 2-amino-6- (2-furyl) -5- (6-oxo-1,6-dihydro-3-pyridinyl) nicotinonitrile (400 mg, 1.44 mmol) Sodium methoxide (155 mg, 2.87 mmol) was added and stirred at room temperature under atmosphere. After 15 minutes, iodoethane (0.35 ml, 4.38 mmol) was added and stirred as it was. After 15 hours, iodoethane (0.35 ml, 4.38 mmol) was added and stirred again. After 24 hours, the reaction solution was concentrated. The residue was treated by silica gel column chromatography (elution solvent; hexane, hexane: ethyl acetate = 2: 1, 1: 2, 1: 5). The obtained crude product was suspended in diethyl ether, and then the solid was collected by filtration and washed with diethyl ether to obtain the title compound (149 mg, 34%) as a pale yellow solid.
[236]
[237] MS m / e (ESI) 307 (MH ⁺ )
[238] Example 6
[239] 2-amino-6- (2-furyl) -5- (1-methyl-6-oxo-1,6-dihydro-3-pyridinyl) nicotinonitrile
[240] Synthesis was carried out in the same manner as in Example 30.
[241]
[242] Example 7
[243] 2-amino-6- (3-fluorophenyl) -5- (6-oxo-1,6-dihydro-3-pyridinyl) nicotinonitrile
[244] Synthesis was carried out in the same manner as in Examples 21 to 29.
[245]
[246] Example 8
[247] 2-amino-6- (3-fluorophenyl) -5- (1-methyl-6-oxo-1,6-dihydro-3-pyridinyl) nicotinonitrile
[248] Synthesis was carried out in the same manner as in Example 30, using 2-amino-6- (3-fluorophenyl) -5- (6-oxo-1,6-dihydro-3-pyridinyl) nicotinonitrile.
[249]
[250] Example 9
[251] 2-amino-5- (4-cyanophenyl) -6- (2-furyl) nicotinonitrile
[252]
[253] 2-amino-5-bromo-6- (2-furyl) nicotinonitrile (20 mg, 75.7 μmol), 4-cyanophenylboronic acid (30 mg, 204 μmol), dichlorobis (acetonitrile) baladium A solution of (II) (2 mg, 7.71 μmol) and 2M aqueous potassium carbonate solution (150 μl, 300 μmol) was stirred at 80 ° C. for 14 hours. The reaction solution was allowed to cool and diluted with ethyl acetate and water. After the insolubles were filtered off, the organic layer of the filtrate was concentrated. Half of the residue was purified by HPLC using a water-acetonitrile-trifluoroacetic acid system as an eluting solvent in a reverse phase column to obtain the title compound (3.33 mg).
[254] MS m / e (ESI) 401 (MH ⁺ )
[255] The title compound of Examples 10 to 76 below was prepared by the same method as in Example 3 or Example 9 or a method similar thereto.
[256] Example 10
[257] 2-amino-5,6-di (2-furyl) nicotinonitrile
[258] Example 11
[259] 2-amino-5- (4-cyanophenyl) -6- (2-furyl) nicotinonitrile
[260] Example 12
[261] 2-amino-6- (2-furyl) -5-phenylnicotinonitrile
[262] Example 13
[263] 2-amino-6- (2-furyl) -5- (4-methylphenyl) nicotinonitrile
[264] Example 14
[265] 2-amino-6- (2-furyl) -5- (3-methylphenyl) nicotinonitrile
[266] Example 15
[267] 2-amino-6- (2-furyl) -5- (2-methylphenyl) nicotinonitrile
[268] Example 16
[269] 2-amino-6- (2-furyl) -5- (4-methoxyphenyl) nicotinonitrile
[270] Example 17
[271] 2-amino-6- (2-furyl) -5- (3-methoxyphenyl) nicotinonitrile
[272] Example 18
[273] 2-amino-5- (2,4-dimethoxyphenyl) -6- (2-furyl) nicotinonitrile
[274] Example 19
[275] 2-amino-5- (3,4-dimethoxyphenyl) -6- (2-furyl) nicotinonitrile
[276] Example 20
[277] 2-amino-6- (2-furyl) -5- (3,4,5-trimethoxyphenyl) nicotinonitrile
[278] Example 21
[279] 2-amino-5- (1,3-benzodioxol-5-yl) -6- (2-furyl) nicotinonitrile
[280] Example 22
[281] 2-amino-5- [4- (benzyloxy) phenyl] -6- (2-furyl) nicotinonitrile
[282] Example 23
[283] 2-amino-5- [3- (benzyloxy) phenyl] -6- (2-furyl) nicotinonitrile
[284] Example 24
[285] 2-amino-6- (2-furyl) -5- (4-phenoxyphenyl) nicotinonitrile
[286] Example 25
[287] 2-amino-5- (3-ethoxyphenyl) -6- (2-furyl) nicotinonitrile
[288] Example 26
[289] 2-amino-6- (2-furyl) -5- [4- (trifluoromethoxy) phenyl] nicotinonitrile
[290] Example 27
[291] 2-amino-6- (2-furyl) -5- [3- (trifluoromethoxy) phenyl] nicotinonitrile
[292] Example 28
[293] 2-amino-5- (4-dimethylaminophenyl) -6- (2-furyl) nicotinonitrile
[294] Example 29
[295] 2-amino-6- (2-furyl) -5- [4- (methylsulfanyl) phenyl] nicotinonitrile
[296] Example 30
[297] 2-amino-5- (4-fluorophenyl) -6- (2-furyl) nicotinonitrile
[298] Example 31
[299] 2-amino-5- (3-fluorophenyl) -6- (2-furyl) nicotinonitrile
[300] Example 32
[301] 2-amino-5- (2-fluorophenyl) -6- (2-furyl) nicotinonitrile
[302] Example 33
[303] 2-amino-5- (2,4-difluorophenyl) -6- (2-furyl) nicotinonitrile
[304] Example 34
[305] 2-amino-6- (2-furyl) -5- (2,3,4,5,6-pentafluorophenyl) nicotinonitrile
[306] Example 35
[307] 2-amino-6- (2-furyl) -5- [4- (trifluoromethyl) phenyl] nicotinonitrile
[308] Example 36
[309] 2-amino-6- (2-furyl) -5- [3- (trifluoromethyl) phenyl] nicotinonitrile
[310] Example 37
[311] 2-amino-6- (2-furyl) -5- [2- (trifluoromethyl) phenyl] nicotinonitrile
[312] Example 38
[313] 2-amino-5- [3,5-di (trifluoromethyl) phenyl] -6- (2-furyl) nicotinonitrile
[314] Example 39
[315] 2-amino-6- (2-furyl) -5- (4-nitrophenyl) nicotinonitrile
[316] Example 40
[317] 2-amino-6- (2-furyl) -5- (3-nitrophenyl) nicotinonitrile
[318] Example 41
[319] 2-amino-6- (2-furyl) -5- (4-methyl-3-nitrophenyl) nicotinonitrile
[320] Example 42
[321] 2-amino-5- (2-fluoro-4-biphenylyl) -6- (2-furyl) nicotinonitrile
[322] Example 43
[323] 2-amino-6- (2-furyl) -5- (4-methylsulfonylphenyl) nicotinonitrile
[324] Example 44
[325] 2-amino-6- (2-furyl) -5- (4-methylsulfinylphenyl) nicotinonitrile
[326] Example 45
[327] 2-amino-5- (4-biphenylyl) -6- (2-furyl) nicotinonitrile
[328] Example 46
[329] 2-amino-5- (3-biphenylyl) -6- (2-furyl) nicotinonitrile
[330] Example 47
[331] 2-amino-5- (3-cyanophenyl) -6- (2-furyl) nicotinonitrile
[332] Example 48
[333] 5- (4-acetylphenyl) -2-amino-6- (2-furyl) nicotinonitrile
[334] Example 49
[335] 5- (3-acetylphenyl) -2-amino-6- (2-furyl) nicotinonitrile
[336] Example 50
[337] 5- (2-acetylphenyl) -2-amino-6- (2-furyl) nicotinonitrile
[338] Example 51
[339] 2-amino-5- (3-formylphenyl) -6- (2-furyl) nicotinonitrile
[340] Example 52
[341] 2-amino-5- (2-formylphenyl) -6- (2-furyl) nicotinonitrile
[342] Example 53
[343] 2-amino-5- (3-chlorophenyl) -6- (2-furyl) nicotinonitrile
[344] Example 54
[345] 2-amino-5- (2-chlorophenyl) -6- (2-furyl) nicotinonitrile
[346] Example 55
[347] 2-amino-5- (2,4-dichlorophenyl) -6- (2-furyl) nicotinonitrile
[348] Example 56
[349] 2-amino-5- (3,4-dichlorophenyl) -6- (2-furyl) nicotinonitrile
[350] Example 57
[351] 2-amino-5- (2,5-dichlorophenyl) -6- (2-furyl) nicotinonitrile
[352] Example 58
[353] 2-amino-5- (4-tert-butylphenyl) -6- (2-furyl) nicotinonitrile
[354] Example 59
[355] 2-amino-6- (2-furyl) -5- (1-naphthyl) nicotinonitrile
[356] Example 60
[357] 2-amino-6- (2-furyl) -5- (2-naphthyl) nicotinonitrile
[358] Example 61
[359] 2-amino-5-benzo [ b ] furan-2-yl-6- (2-furyl) nicotinonitrile
[360] Example 62
[361] 2-amino-5-dibenzo [ b, d ] furan-4-yl-6- (2-furyl) nicotinonitrile
[362] Example 63
[363] 2-amino-6- (2-furyl) -5- (3-furyl) nicotinonitrile
[364] Example 64
[365] 2-amino-6- (2-furyl) -5- (2-thienyl) nicotinonitrile
[366] Example 65
[367] 2-amino-6- (2-furyl) -5- (3-thienyl) nicotinonitrile
[368] Example 66
[369] 2-amino-6- (2-furyl) -5- (5-methyl-2-thienyl) nicotinonitrile
[370] Example 67
[371] 2-amino-6- (2-furyl) -5- (4-methyl-2-thienyl) nicotinonitrile
[372] Example 68
[373] 5- (5-acetyl-2-thienyl) -2-amino-6- (2-furyl) nicotinonitrile
[374] Example 69
[375] 2-amino-5- (2-formyl-3-thienyl) -6- (2-furyl) nicotinonitrile
[376] Example 70
[377] 2-amino-5- (3-formyl-2-thienyl) -6- (2-furyl) nicotinonitrile
[378] Example 71
[379] 2-amino-5- (5-chloro-2-thienyl) -6- (2-furyl) nicotinonitrile
[380] Example 72
[381] 2-amino-5-benzo [ b ] thiophen-2-yl-6- (2-furyl) nicotinonitrile
[382] Example 73
[383] 2-amino-5-benzo [ b ] thiophen-3-yl-6- (2-furyl) nicotinonitrile
[384] Example 74
[385] 2-amino-6- (2-furyl) -5- (3-pyridyl) nicotinonitrile
[386] Example 75
[387] 2-amino-6- (2-furyl) -5- (2-pyridyl) nicotinonitrile
[388] Example 76
[389] 2-amino-6- (2-furyl) -5- (4-vinylphenyl) nicotinonitrile
[390] Example 77
[391] 2-Amino-5- (1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotinic acid
[392]
[393] 2-amino-5- (1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotinonitrile (308 mg, 1.01 mmol) in ethanol (5 ml ) And 5N aqueous sodium hydroxide solution (10 ml) were added, and the mixture was heated to reflux for 4 hours. The reaction solution was allowed to cool and neutralized with 5N hydrochloric acid. The resulting solid was collected by filtration and washed with water to obtain the title compound (320 mg, 98%) as a yellow solid.
[394]
[395] The following superficial compounds of Examples 78 and 79 were obtained by the same method as or in accordance with Example 77.
[396] Example 78
[397] 2-Amino-6- (2-furyl) -5- (6-oxo-1,6-dihydro-3-pyridinyl) nicotinic acid
[398] Example 79
[399] 2-amino-6- (3-fluorophenyl) -5- (4-pyridyl) nicotinonitrile
[400] Example 80
[401] 2-amino-5- (1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotinamide
[402]
[403] 2-Amino-5- (1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotinic acid (20 mg. 61.5 μmol), 1-hydroxybenzotria Sol (28 mg, 183 μmol), 3- (3'-dimethylaminopropyl) -1-ethylcarbodiimide (29 mg, 187 μmol), ammonium chloride (16 mg, 299 μmol), and triethylamine (43 Μl, 309 μmol) of N, N-dimethylformamide (1.0 ml) suspension was stirred at room temperature for 18 hours. The reaction solution was diluted with water, and the resulting solid was collected by filtration and washed with water to obtain the title compound (9 mg, 45%) as a pale yellow solid.
[404]
[405] The following title compounds of Examples 81 to 102 were obtained by the same method as or in accordance with Example 80.
[406] Example 81
[407] 2-amino-6- (3-fluorophenyl) -5- (4-pyridyl) nicotinamide
[408] Example 82
[409] N- (2-hydroxyethyl) -2-amino-6- (2-furyl) -5- (6-oxo-1,6-dihydro-3-pyridinyl) nicotinamide
[410] Example 83
[411] N-cyclopropyl-2-amino-6- (2-furyl) -5- (6-oxo-1,6-dihydro-3-pyridinyl) nicotinamide
[412] Example 84
[413] N, N-dimethyl-2-amino-6- (2-furyl) -5- (6-oxo-1,6-dihydro-3-pyridinyl) nicotinamide
[414] Example 85
[415] N-cyclopropylmethyl-2-amino-5- (1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotinamide
[416] Example 86
[417] N- (2-fluoroethyl) -2-amino-5- (1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotinamide
[418] Example 87
[419] N-cyclopropyl-2-amino-5- (1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotinamide
[420] Example 88
[421] N- (3-diethylamino) propyl-2-amino-5- (1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotinamide
[422] Example 89
[423] N-methyl-2-amino-5- (1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotinamide
[424] Example 90
[425] N-phenyl-2-amino-5- (1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotinamide
[426] Example 91
[427] N-allyl-2-amino-5- (1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotinamide
[428] Example 92
[429] N- (2-amino-2-oxoethyl) -2-amino-5- (1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotinamide
[430] Example 93
[431] N-isobutyl-2-amino-5- (1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotinamide
[432] Example 94
[433] N- (5-cyanopentyl) -2-amino-5- (1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotinamide
[434] Example 95
[435] N- [3- (2-oxotetrahydro-1H-1-pyrrolyl) propyl] -2-amino-5- (1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)- 6- (2-furyl) nicotinamide
[436] Example 96
[437] N- (2-pyridylmethyl) -2-amino-5- (1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotinamide
[438] Example 97
[439] N- (3-pyridylmethyl) -2-amino-5- (1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotinamide
[440] Example 98
[441] N- [2- (4-pyridyl) ethyl] -2-amino-5- (1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotine amides
[442] Example 99
[443] N- [2- (2-pyridyl) ethyl] -2-amino-5- (1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotine amides
[444] Example 100
[445] N- (2-propynyl) -2-amino-5- (1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotinamide
[446] Example 101
[447] N- (3-hydroxypropyl) -2-amino-5- (1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotinamide
[448] Example 102
[449] N-ethyl-2-amino-5- (1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotinamide
[450] Example 103
[451] 103- (a):
[452] 2-amino-6- (2-furyl) -5- (6-oxo-1-propyl-1,6-dihydro-3-pyridinyl) nicotinonitrile
[453]
[454] 103- (b):
[455] 2-amino-6- (2-furyl) -5- (4-propyl-3-pyridyl) -3-pyridinecarbonitrile
[456]
[457] 2-amino-6- (2-furyl) -5- (6-oxo-1-propyl-1,6-dihydro-3-pyridinyl) nicotinonitrile (20 mg, 0.072 mmol) in a reaction vessel, carbonic acid Potassium (30 mg, 0.22 mmol) was added, dissolved in N, N-dimethylformamide (1 ml), propyl iodide (52 mg, 0.31 mmol) was added, and the mixture was stirred at 70 ° C for 18 hours. After the reaction was completed, water was added, followed by extraction with ethyl acetate. After removal of the aqueous layer, the organic layer was concentrated and purified by high performance liquid chromatography to give the title product as a yellow solid (2.6 mg, 11%, 1.8 mg, 7.8%), respectively.
[458] 103- (a): 2-amino-6- (2-furyl) -5- (6-oxo-1-propyl-1,6-dihydro-3-pyridinyl) nicotinonitrile
[459]
[460] s): MS (ESI) m / e 321 (MH ⁺ ).
[461] 103- (b): 2-amino-6- (2-furyl) -5- (4-propyl-3-pyridyl) -3-pyridinecarbonitrile
[462]
[463] Example 104
[464] 2-amino-5- [1- (4-cyanophenyl) -6-oxo-1,6-dihydro-3-pyridinyl] -6- (2-furyl) nicotinonitrile
[465]
[466] 2-amino-6- (2-furyl) -5- (6-oxo-1,6-dihydro-3-pyridinyl) nicotinonitrile (20 mg, 0.071 mmol) and 4-cyanophenyl in the reaction vessel Boronic acid (35 mg, 0.24 mmol) and copper acetate monohydrate (3.0 mg, 0.015 mmol), pyridine (0.015 ml, 0.19 mmol), and N, N-dimethylformamide (1.0 ml) were added and 20 hours at room temperature Stirred. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was dried, dissolved in dimethylsulfoxide (1.0 ml) and purified by high performance liquid chromatography to give the title compound as a yellow solid (8.32 mg, 62%).
[467]
[468]
[469] The title compound of Examples 105 to 146 below was obtained by the same method as in Example 5, 103 or 104 above or a method similar thereto.
[470] Example 105
[471] 2-amino-6- (2-furyl) -5- [6-oxo-1- (3-phenylpropyl) -1,6-dihydro-3-pyridinyl] nicotinonitrile
[472] Example 106
[473] 4-5- [6-Amino-5-cyano-6- (2-furyl) -3-pyridyl] -2-oxo-1,2-dihydro-1-pyridinylbutyrate ethyl
[474] Example 107
[475] 2-amino-5- [1- (3-cyanopropyl) -6-oxo-1,6-dihydro-3-pyridinyl] -6- (2-furyl) nicotinonitrile
[476] Example 108
[477] 2-amino-5- [1- (3-cyclobutylpropyl) -6-oxo-1,6-dihydro-3-pyridinyl] -6- (2-furyl) nicotinonitrile
[478] Example 109
[479] 2-amino-6- (2-furyl) -5- [6-oxo-1- (4,4,4-trifluorobutyl) -1,6-dihydro-3-pyridinyl] nicotinonitrile
[480] Example 110
[481] 2-amino-6- (2-furyl) -5- [6-oxo-1- (3,4,4, -trifluoro-3-butenyl) -1,6-dihydro-3-pyridinyl ] Nicotinonitrile
[482] Example 111
[483] 2-amino-6- (2-furyl) -5- [6-oxo-1- (3,3,3-trifluoropropyl) -1,6-dihydro-3-pyridinyl] nicotinonitrile
[484] Example 112
[485] 2-amino-5- (1-butyl-6-oxo-1,6-dihydro-3-pyridinyl] -6- (2-furyl) nicotinonitrile
[486] Example 113
[487] 2-amino-6- (2-furyl) -5- (1-heptyl-6-oxo-1,6-dihydro-3-pyridinyl) nicotinonitrile
[488] Example 114
[489] 2-amino-6- (2-furyl) -5- (1-isopentyl-6-oxo-1,6-dihydro-3-pyridinyl) nicotinonitrile
[490] Example 115
[491] 5- (1-allyl-6-oxo-1,6-dihydro-3-pyridinyl) -2-amino-6- (2-furyl) nicotinonitrile
[492] Example 116
[493] 2-amino-5- [1- (3-butenyl) -6-oxo-1,6-dihydro-3-pyridinyl] -6- (2-furyl) nicotinonitrile
[494] Example 117
[495] 2-amino-6- (2-furyl) -5- [6-oxo-1- (4-pentenyl) -1,6-dihydro-3-pyridinyl] nicotinonitrile
[496] Example 118
[497] 2-amino-6- (2-furyl) -5- [1- (3-hydroxypropyl) -6-oxo-1,6-dihydro-3-pyridinyl] nicotinonitrile
[498] Example 119
[499] 2-amino-5- [1- (2,3-dihydroxypropyl) -6-oxo-1,6-dihydro-3-pyridinyl] -6- (2-furyl) nicotinonitrile
[500] Example 120
[501] 2-amino-5- [1- (3-fluoropropyl) -6-oxo-1,6-dihydro-3-pyridinyl] -6- (2-furyl) nicotinonitrile
[502] Example 121
[503] 2-amino-5- [1- (3-chloropropyl) -6-oxo-1,6-dihydro-3-pyridinyl] -6- (2-furyl) nicotinonitrile
[504] Example 122
[505] 2-amino-5- [1- (4-chlorobutyl) -6-oxo-1,6-dihydro-3-pyridinyl] -6- (2-furyl) nicotinonitrile
[506] Example 123
[507] 2-amino-5- [1- (5-chloropentyl) -6-oxo-1,6-dihydro-3-pyridinyl] -6- (2-furyl) nicotinonitrile
[508] Example 124
[509] 2-amino-5- [1- (cyclohexylmethyl) -6-oxo-1,6-dihydro-3-pyridinyl] -6- (2-furyl) nicotinonitrile
[510] Example 125
[511] 2-amino-6- (2-furyl) -5- [6-oxo-1- (tetrahydro-2H-2-pyranylmethyl) -1,6-dihydro-3-pyridinyl] nicotinonitrile
[512] Example 126
[513] 2-amino-5- (1-benzyl-6-oxo-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotinonitrile
[514] Example 127
[515] 2-amino-5- [1- (2-cyanoethyl) -6-oxo-1,6-dihydro-3-pyridinyl] -6- (2-furyl) nicotinonitrile
[516] Example 128
[517] 2-amino-6- (2-furyl) -5- [6-oxo-1- (2-propynyl) -1,6-dihydro-3-pyridinyl] nicotinonitrile
[518] Example 129
[519] 2-amino-5- [1- (2-butynyl) -6-oxo-1,6-dihydro-3-pyridinyl] -6- (2-furyl) nicotinonitrile
[520] Example 130
[521] 2-amino-6- (2-furyl) -5- {6-oxo-1- [3- (1,1,1-trimethylsilyl) -2-propynyl] -1,6-dihydro-3- Pyridinyl} nicotinonitrile
[522] Example 131
[523] 2-amino-5- {1- [6,7-dimethoxy-2-oxo-2H-4-chromenyl) methyl] -6-oxo-1,6-dihydro-3-pyridinyl} nicotinonitrile
[524] Example 132
[525] 2-amino-5- {1- [4- (1,3-dioxo-2,3-dihydro-1H-2-isoindolyl) butyl] -6-oxo-1,6-dihydro-3 -Pyridinyl} -6- (2-furyl) nicotinonitrile
[526] Example 133
[527] 2-amino-6- (2-furyl) -5- {1- [2- (1H-3-indolyl) ethyl] -6-oxo-1,6-dihydro-3-pyridinyl} nicotinonitrile
[528] Example 134
[529] 2-amino-6- (2-furyl) -5- [6-oxo-1- (2-oxopropyl) -1,6-dihydro-3-pyridinyl] nicotinonitrile
[530] Example 135
[531] 2-amino-6- (2-furyl) -5- {6-oxo-1-2-oxo-2- [4- (trifluoromethyl) phenyl] ethyl-1,6-dihydro-3-pyri Dinil} nicotinonitrile
[532] Example 136
[533] 2-amino-6- (2-furyl) -5- (6-oxo-1-phenyl-1,6-dihydro-3-pyridinyl) -6- (2-furyl) nicotinonitrile
[534] Example 137
[535] 2-amino-5- [1- (4-cyanophenyl) -6-oxo-1,6-dihydro-3-pyridinyl] -6- (2-furyl) nicotinonitrile
[536] Example 138
[537] 2-amino-6- (2-furyl) -5- [6-oxo-1- (4-vinylphenyl) -1,6-dihydro-3-pyridinyl] nicotinonitrile
[538] Example 139
[539] 2-amino-6- (2-furyl) -5- [1- (4-methylphenyl) -6-oxo-1,6-dihydro-3-pyridinyl] nicotinonitrile
[540] Example 140
[541] 2-amino-6- (2-furyl) -5- [1- (2-methylphenyl) -6-oxo-1,6-dihydro-3-pyridinyl) nicotinonitrile
[542] Example 141
[543] 2-amino-6- (2-furyl) -5- [1- (4-methoxyphenyl) -6-oxo-1,6-dihydro-3-pyridinyl] nicotinonitrile
[544] Example 142
[545] 2-amino-6- (2-furyl) -5- [1- (3-methoxyphenyl) -6-oxo-1,6-dihydro-3-pyridinyl] nicotinonitrile
[546] Example 143
[547] 2-amino-6- (2-furyl) -5- [1- (2-methoxyphenyl) -6-oxo-1,6-dihydro-3-pyridinyl] nicotinonitrile
[548] Example 144
[549] 2-amino-5- [1- (4-fluorophenyl) -6-oxo-1,6-dihydro-3-pyridinyl] -6- (2-furyl) nicotinonitrile
[550] Example 145
[551] 2-amino-5- [1- (3-fluorophenyl) -6-oxo-1,6-dihydro-3-pyridinyl] -6- (2-furyl) nicotinonitrile
[552] Example 146
[553] 2-amino-5- [1- (2-fluorophenyl) -6-oxo-1,6-dihydro-3-pyridinyl] -6- (2-furyl) nicotinonitrile
[554] The title compound of Examples 147 to 175 below was obtained by the same or equivalent method as in Example 103 above.
[555] Example 147
[556] 6-amino-2- (2-furyl) -6 '-(3-phenylpropoxy)-[3,3'-] bipyridinyl-5-carbonitrile
[557] Example 148
[558] Ethyl 4- (6'-amino-5'-cyano-2 '-(2-furyl)-[3,3'] bipyridinyl-6-yloxy) butyrate
[559] Example 149
[560] 6-amino-6 '-(3-cyanopropoxy) -2- (2-furyl)-[3,3'] bipyridinyl-5-carbonitrile
[561] Example 150
[562] 6-amino-6'-cyclobutylmethoxy-2- (2-furyl)-[3,3 '] bipyridinyl-5-carbonitrile
[563] Example 151
[564] 6-amino-2- (2-furyl) -6 '-(4,4,4-trifluorobutoxy)-[3,3'] bipyridinyl-5-carbonitrile
[565] Example 152
[566] 6-amino-2- (2-furyl) -6 '-(3,4,4-trifluoro-3-butenyloxy)-[3,3'] bipyridinyl-5-carbonitrile
[567] Example 153
[568] 6-amino-2- (2-furyl) -6 '-(3,3,3-trifluoropropoxy)-[3,3'] bipyridinyl-5-carbonitrile
[569] Example 154
[570] 6-amino-6'-butoxy-2- (2-furyl)-[3,3 '] bipyridinyl-5-carbonitrile
[571] Example 155
[572] 6-amino-2- (2-furyl) -6'-heptyloxy- [3,3 '] bipyridinyl-5-carbonitrile
[573] Example 156
[574] 6-amino-2- (2-furyl) -6 '-(3-methylbutoxy)-[3,3'] bipyridinyl-5-carbonitrile
[575] Example 157
[576] 6'-allyloxy-6-amino-2- (2-furyl)-[3,3 '] bipyridinyl-5-carbonitrile
[577] Example 158
[578] 6-amino-6 '-(3-butenyloxy) -2- (2-furyl)-[3,3'] bipyridinyl-5-carbonitrile
[579] Example 159
[580] 6-amino-2- (2-furyl) -6 '-(4-pentenyloxy)-[3,3'] bipyridinyl-5-carbonitrile
[581] Example 160
[582] 6-amino-2- (2-furyl) -6 '-(3-hydroxypropoxy)-[3,3'] bipyridinyl-5-carbonitrile
[583] Example 161
[584] 6-amino-6 '-(2,3-dihydroxypropoxy) -2- (2-furyl)-[3,3'] bipyridinyl-5-carbonitrile
[585] Example 162
[586] 6-amino-6 '-(3-fluoropropoxy) -2- (2-furyl)-[3,3'] bipyridinyl-5-carbonitrile
[587] Example 163
[588] 6-amino-6 '-(3-chloropropoxy) -2- (2-furyl)-[3,3'] bipyridinyl-5-carbonitrile
[589] Example 164
[590] 6-amino-6 '-(4-chlorobutoxy) 2- (2-furyl)-[3,3'] bipyridinyl-5-carbonitrile
[591] Example 165
[592] 6-amino-6 '-(5-chloropentyloxy) -2- (2-furyl)-[3,3'] bipyridinyl-5-carbonitrile
[593] Example 166
[594] 6-amino-6'-cyclohexyloxy-2- (2-furyl)-[3,3 '] bipyridinyl-5-carbonitrile
[595] Example 167
[596] 6-amino-2- (2-furyl) -6 '-(2-tetrahydropyranyloxy)-[3,3'] bipyridinyl-5-carbonitrile
[597] Example 168
[598] 6-amino-2- (2-furyl) -6 '-(2-propyloxy)-[3,3'] bipyridinyl-5-carbonitrile
[599] Example 169
[600] 6-amino-6 '-(2-butenyloxy) -2- (2-furyl)-[3,3'] bipyridinyl-5-carbonitrile
[601] Example 170
[602] 6-amino-2- (2-furyl) -6 '-(3-trimethylsilanyl-2-propynyloxy)-[3,3'] bipyridinyl-5-carbonitrile
[603] Example 171
[604] 6-amino-6 '-(6,7-dimethoxy-2-oxo-2H-chromen-4-ylmethoxy) -2- (2-furyl)-[3,3'] bipyridinyl-5- Carbonitrile
[605] Example 172
[606] 6-amino-6 '-[4- (1,3-dioxo-1,3-dihydro-2-isoindolyl) butoxy] -2- (2-furyl)-[3,3'] BP Ridinyl-5-carbonitrile
[607] Example 173
[608] 6-amino-2- (2-furyl) -6 '-[2- (1H-3-indolyl) ethoxy]-[3,3'] bipyridinyl-5-carbonitrile
[609] Example 174
[610] 6-amino-2- (2-furyl) -6 '-(2-oxopropyl)-[3,3'] bipyridinyl-5-carbonitrile
[611] Example 175
[612] 6-amino-2- (2-furyl) -6 '-[2- [4- (trifluoromethyl) phenyl] ethoxy]-[3,3'] bipyridinyl-5-carbonitrile
[613] Example 176
[614] 2-amino-4,6-di (3-fluorophenyl) -5- (4-methoxy-3-pyridyl) -3-pyridinecarbonitrile
[615]
[616] The title compound was obtained in the same manner as or in the same manner as in Reference Examples 6 to 9 and Example 3.
[617]
[618] Example 177
[619] 2-amino-4,6-di (3-fluorophenyl) -5- (6-oxo-1,6-dihydro-3-pyridyl) nicotinonitrile hydrobromide
[620]
[621] The title compound was obtained in the same manner as in Example 4 or in a similar manner.
[622]
[623] Example 178
[624] 2-amino-6- (2-furyl) -4-isopropoxy-5- (4-methoxy-3-pyridyl) -3-pyridinecarbonitrile
[625]
[626] Using 6- (2-furyl) -4-isopropoxy-2-oxo-1,2-dihydro-3-pyridinecarbonitrile, the same method as in Reference Examples 7 to 9 and Example 3 or a method equivalent thereto The title compound was obtained.
[627]
[628] Example 179
[629] 2-amino-6- (2-furyl) -4-hydroxy-5- (6-oxo-1,6-dihydro-3-pyridinyl) nicotinonitrile hydrobromide
[630]
[631] The same method as in Example 4 or the equivalent thereto, using 2-amino-6- (2-furyl) -4-isopropoxy-5- (4-methoxy-3-pyridyl) -3-pyridinecarbonitrile The title compound was obtained.
[632]
[633] Example 180
[634] 2-amino-6- (3-fluorophenyl) -4-isopropoxy-5- (4-methoxy-3-pyridyl) -3-pyridinecarbonitrile
[635]
[636] The title compound was obtained in the same manner as or in the same manner as in Examples 14 to 16, Reference Examples 7 to 9 and Example 3.
[637]
[638] Example 181
[639] 2-amino-6- (3-fluorophenyl) -4-hydroxy-5- (6-oxo-1,6-dihydro-3-pyridinyl) nicotinonitrile hydrobromide
[640]
[641] The same method as in Example 4, using 2-amino-6- (3-fluorophenyl) -4-isopropoxy-5- (4-methoxy-3-pyridyl) -3-pyridinecarbonitrile or In the same manner, the title compound was obtained.
[642]
[643] Example 182
[644] 2-amino-6- (3-fluorophenyl) -5- (4-methoxy-3-pyridyl) -3-pyridinecarbonitrile
[645]
[646] The title compound was obtained in the same manner as the Reference Examples 7 to 9 and Example 3 or a method similar thereto.
[647]
[648] Example 183
[649] 2-amino-6- (3-fluorophenyl) -5- (6-oxo-1,6-dihydro-3-pyridinyl) nicotinonitrile
[650]
[651] The title compound in the same manner as in Example 4 or a method similar thereto using 2-amino-6- (3-fluorophenyl) -5- (4-methoxy-3-pyridyl) -3-pyridinecarbonitrile Got.
[652]
[653] Example 184
[654] 2-amino-6- (3-fluorophenyl) -5- (6-oxo-1,6-dihydro-3-pyridinyl) nicotinonitrile
[655]
[656] The title compound was obtained in the same manner as the Reference Examples 1 to 4 and Example 1 or a method similar thereto.
[657]
[658] The structural formulas of the title compounds of Examples 1 to 8, 10 to 76, 78, 79, 81 to 102, 105 to 175 are shown below.
[659]
[660] The compounds represented by formula (I) according to the present invention are useful as adenosine receptors (A ₁ , A _2A , A _2B or A ₃ receptor) antagonists, in particular A _2B receptor antagonists. The test example which shows utility of the compound of this invention as a medicine is shown below.
[661] Test Example 1
[662] [Measurement of Adenosine A ₁ Receptor Binding Ability]
[663] Human adenosine A ₁ receptor cDNA was overexpressed with CHOK1 cells and the membrane specimens were added and suspended in 20 mM HEPES buffer (containing ₁₀ mM MgC1 ₂ , 100 mM NaC1; pH 7.4) to a protein concentration of 66.7 μg / m1. Of this membrane sample suspension tritium-labeled 60nM in 0.45 ml chloro-cyclopentyl adenosine ⁽³ H-CCPA, NEN Co.) was added to 0.025 ml 0.025 ml test compound. After the mixture was left at 30 ° C. for 120 minutes, it was rapidly suction filtered on a glass fiber filter paper (GF / B; manufactured by Whatman) and washed twice with 5 ml of 50 mM Tris-HCl buffer, which was immediately water-cooled. Thereafter, the glass fiber filter paper was transferred to a vial bottle, a scintillator was added, and the amount of radioactivity on the filter paper was measured by a liquid scintillation counter. ³ calculate the inhibition rate of the test compound for the receptor binding of the A ₁ H-CCPA is obtained by the following formula was calculated the 50% inhibition concentration (IC _50), this on the basis of (formula below).
[664] % Inhibition = [1-{(binding amount-nonspecific binding amount in the presence of test compound) / (total binding amount-nonspecific binding amount)}] × 100
[665] In addition, total binding amount shows the ³ H-CCPA binding radioactivity amount in absence. Nonspecific binding refers to the amount of ³ H-CCPA binding radioactivity in the presence of 100 μM RPIA ([R]-[1-methyl-2-phenylethyl] adenosine); The amount of binding in the presence of the test compound refers to the amount of ³ H-CCPA binding radioactivity in the presence of various concentrations of the test compound. The inhibition constant (Ki value) in the table was obtained from Cheng-Prusoff's equation.
[666] Test Example 2
[667] [Measurement of Adenosine A _2A Receptor Binding Ability]
[668] Using adenosine A _2A receptor cDNA was over-expressed membrane sample (Receptor Biology Inc. Co., Ltd.), the adenosine A _2A receptor binding inhibition test was carried out. This membrane sample was suspended by adding 20 mM HEPES buffer (containing 10 mM MgC1 ₂ and 100 mM NaC1; pH 7.4) to a protein concentration of 22.2 μg / m1. Of this membrane sample suspension 0.45ml, tritium-labeled 2-p- [2- carboxyethyl] phenethyl-amino-N- ethyl carboxamide adenosine -5' of ^{500nM (3 H-CGS 21680;} NEN Co., Ltd.) and the test 0.025ml 0.025 ml of compound was added. The mixture was allowed to stand at 25 ° C. for 90 minutes, then rapidly suction filtered on a glass fiber filter paper (GF / B; manufactured by Whatman), and immediately washed twice with 5 ml of 50 mM Tris-HC1 buffer that was ice-cold. Thereafter, the glass fiber filter paper was transferred to a vial bottle, a scintillator was added, and the amount of radioactivity on the filter paper was measured by a liquid scintillation counter. ³ calculate the inhibition rate of the test compound for the receptor binding of the A _2A of H-CGS 21680 was calculated to 5O% inhibition concentration (IC ₅₀₎ on the basis of this, obtained by the following equation.
[669] % Inhibition = [1-{(binding amount-nonspecific binding amount in the presence of test compound) / (total binding amount-nonspecific binding amount)}] × 100
[670] In addition, the total amount of coupling is, represents the ³ H-CGS 2l680 binding radioactivity under the test compound in the absence; Nonspecific binding refers to the amount of ³ H-CGS 21680 binding radioactivity in the presence of 100 μM RPIA; The amount of binding in the presence of the test compound refers to the amount of ³ H-CGS 21680 binding radioactivity in the presence of various concentrations of the test compound. The inhibition constant (Ki value) in the table was obtained from Cheng-Prusoff's equation.
[671] Test Example 3
[672] [Inhibition of NECA-stimulated cAMP Production in Adenosine A _2B Receptor Expressing Cells]
[673] CHOK1 cells, 1.5 × 10 ⁵ cells / well, overexpressing the human adenosine A _2B receptor were evenly sprayed on a plate of 24Wel1, and then used for the experiment after overnight incubation. The inhibition rate of the test compound on the amount of cAMP produced by 30 nM 5'-N-ethylcarboxyamide adenosine (NECA; manufactured by Sigma) stimulation was evaluated as an affinity for the A _2B receptor. That is, the adhered cells were washed twice with 2 ml / wel1 of Krebs Ringer's buffer solution (containing 0.1% BSA; pH 7.4), and then preincubated at 0.5 ml / wel1 for 30 minutes. Subsequently, in the presence of Ro-20-1724 (manufactured by RBI), a phosphodiesterase inhibitor, a mixed solution containing NECA and the test compound is added at 0.1 ml / well. After 15 minutes of preincubation, the reaction is stopped with 300 μl / wel 1 of 0.1 HC1. The measurement of cAMP was performed using the cAMP enzyme immunoassay kit by Amersham. The calculation of the inhibition rate of the test compound on NECA stimulation cAMP production was obtained by the following formula.
[674] Inhibition rate (%) = [1-{(cAMP amount in NECA-Krebs Ringer's buffer solution only in coexistence with NECA) / (cAMP amount in NECA-only stimulation-Krebs Ringer's buffer solution)}] × 100
[675] Adenosine receptor binding ability or inhibitory activity of the compound according to the present invention was as follows.
[676] Table 1
[677] Test compoundKi (nM) Ki (nM) IC ₅₀ (nM) A1 A2a A2b Example 125990 23 2.766 22 3.7 400 7 6.5
[678] The compounds according to the present invention or salts thereof showed excellent inhibitory activity against adenosine receptors.
[679] Test Example 4
[680] [Evaluation of bowel movement]
[681] The bowel-promoting action of the adenosine A _2B receptor inhibitory compound, its salt, its hydrate, or the pharmaceutical composition containing these identified by measuring the binding ability and inhibitory ability to a receptor by the test example 1 was evaluated in the following method. That is, three SD IGS rats (6 weeks old; Charles River) are placed in each cage, and after 1 week preliminary breeding in the state of free feeding, an absorbent sheet weighing the outer packaging is installed under the cage until the end of the experiment. Will fast, free withdrawal. After 1.5 hours, the sides of the cages were collected, and the presence or absence of abnormalities before the experiments was observed. Compounds suspended or dissolved in 0.5% (W / V) methyl cellulose (MC) were orally administered at a dose of 5 ml / kg body weight, while only 0.5% (W / V) MC was orally administered to the control group. After compound administration, the rats were returned to a cage provided with a new absorbent sheet, and the sides on the absorbent sheet were recovered for each cage until 90 minutes after administration, and the appearance was counted after observation. The number of sides was shown as the value per cage. Moreover, after collect | recovering the stools, the absorbent sheet was weighed and the weight which subtracted the weight of the outer packaging was made into the quantity of urine.
[682] TABLE 2
[683] ExampleNumber of stools pellets Control0.50 ± 0.29 One1 mg / kg 1.75 ± 1.033 mg / kg 7.25 ± 1.6510 mg / kg 22.25 ± 2.93 21 mg / kg 7.80 ± 0.2010 mg / kg 18.00 ± 1.30 51 mg / kg 7.00 ± 1.233 mg / kg 14.25 ± 3.38
[684] The compounds according to the invention or their salts exhibited good bowel movement promoting action.

权利要求:
Claims (40)
[1" claim-type="Currently amended] A compound represented by the following formula or a salt thereof:

In the formula (I), R ¹ represents a cyano group, a carboxy group or a carbamoyl group which may have a substituent; R ² is a hydrogen atom, a hydroxyl group, a C _1-6 alkoxy group which may have a substituent, a C _6-14 aromatic hydrocarbon cyclic group which may have a substituent or a 5-14 membered aromatic heterocyclic group which may have a substituent Represent; R ³ and R ⁴ are the same or different and each may have a C _3-8 cycloalkyl group, C _3-8 cycloalkenyl group, C _6-14 aromatic hydrocarboncyclic group, _5-14 membered non-aromatic heterocyclic group which may have a substituent Group or a 5-14 membered aromatic heterocyclic group; Provided that (1) when R ¹ is a cyano group, R ² is a 4-bromo-2-thienyl group, R ³ is a 3,4-dimethoxyphenyl group, and R ⁴ is a 2-thienyl group, ( 2) When R ¹ is a cyano group, R ² is a hydrogen atom, and R ³ and R ⁴ are phenyl groups, (3) R ¹ is a cyano group, R ² is a 4-chloro-phenyl group, and R ³ is When a phenyl group and R ⁴ is a 4- (3,4-dichlorophenyl) -1-oxo-2 (lH) -phthalazinyl group, (4) R ¹ is a cyano group, R ² is a hydrogen atom, When R ³ is a 4-pyridyl group and R ⁴ is a 1-piperazinyl group, (5) R ¹ is a cyano group, R ² is a hydrogen atom, R ³ is a 4-pyridyl group, and R ⁴ Is a 1-pyridyl group, (6) R ¹ is a cyano group, R ² is a hydrogen atom, R ³ is a 4-pyridyl group, and R ⁴ is a 4-diphenylmethyl-1-piperazinyl group If, (7) R ¹ is a cyano group, R ² is a hydrogen atom, and R ³ a group-4-pyridyl, and R ⁴ is 4-morpholinyl group If, (8) R ¹ is a cyano group, R ² is 4-methylphenyl group and, if also R ³ and R ⁴ is a phenyl group, and (9) R ¹ is a cyano group, and R ^2, R ^3, and Except when R ⁴ is a phenyl group.
[2" claim-type="Currently amended] The method of claim 1,
R ¹ is a cyano group, or a compound thereof.
[3" claim-type="Currently amended] The method of claim 1,
A compound or a salt thereof wherein R ¹ is a carbamoyl group represented by the following formula:

Wherein R ⁵ and R ⁶ are the same or different and are a hydrogen atom, a C _1-6 alkyl group which may have a substituent, a C _2-6 alkenyl group which may have a substituent, C ₂ which may have a substituent _{-6 represents an} alkynyl group, a C _6-14 aromatic hydrocarboncyclic group which may have a substituent, or a 5-14 membered aromatic heterocyclic group which may have a substituent.
[4" claim-type="Currently amended] The method of claim 1,
A C _6-14 aromatic hydrocarboncyclic group or a 5-14 membered aromatic heterocyclic group, or a salt thereof, wherein R ² may each have a substituent.
[5" claim-type="Currently amended] The method of claim 1,
A compound or a salt thereof, wherein R ² is a phenyl group, naphthyl group, pyridyl group, thienyl group or furyl group, each of which may have a substituent.
[6" claim-type="Currently amended] The method of claim 1,
The compound or its salt whose R <^2> is the phenyl group which may be substituted by the halogen atom.
[7" claim-type="Currently amended] The method of claim 1,
The compound or its salt whose R <^2> is a hydrogen atom.
[8" claim-type="Currently amended] The method of claim 1,
A C _6-14 aromatic hydrocarboncyclic group or a 5-14 membered aromatic heterocyclic group or a salt thereof, wherein R ³ and R ⁴ are the same or different and may each have a substituent.
[9" claim-type="Currently amended] The method of claim 1,
R ³ and R ⁴ are the same or different and each may have a substituent, a phenyl group, a pyrrolyl group, a pyridinyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a thienyl group, a thiazolyl group, a furyl group, A compound or a salt thereof which is a naphthyl group, quinolinyl group, isoquinolinyl group, phthalazinyl group, naphthyridinyl group, indolyl group or isoindolinyl group.
[10" claim-type="Currently amended] The method of claim 1,
A compound or a salt thereof, wherein R ³ and R ⁴ are each a phenyl group, pyridyl group, thienyl group or furyl group which may have a substituent.
[11" claim-type="Currently amended] The method of claim 1,
A 5-14 membered non-aromatic heterocyclic group, a C _6-14 aromatic hydrocarboncyclic group or a 5-14 membered aromatic heterocycle, wherein R ³ and / or R ⁴ may each be substituted with one or more groups selected from the following substituent group a Cyclic group compounds or salts thereof:
<Substituent group a> is (1) hydroxyl group, (2) halogen atom, (3) nitrile group, (4) nitro group, (5) (i) hydroxyl group, (ii) nitrile group, (iii) halogen atom, ( (Iii) a C _1-6 alkylamino group, (v) a di (C _1-6 alkyl) amino group, (iii) a C _2-6 alkenylamino group, (iii) a di (C _2-6 alkenyl) amino group, (iii) C _2-6 alkynylamino group, (iii) di (C _2-6 alkynyl) amino group, (x) NC _1-6 alkyl-NC _2-6 alkenylamino group, (xi) NC _1-6 alkyl-NC _{2 -6} alkynylamino group, (xii) NC _2-6 alkenyl-NC _2-6 alkynylamino group, (x ') aralkyloxy group, (x') TBDMS oxy group, (xv) C _1-6 alkylsulfonylamino group, (xvi) C _1-6 alkylcarbonyloxy group, (xVII) C _2-6 alkenylcarbonyloxy group, (xVII) C _2-6 alkynylcarbonyloxy group, (xix) NC _1-6 alkylcarbon C _1-6 alkyl group, C _2-6 , which may each be substituted with one or more groups selected from a barmoyl group, (xx) NC _2-6 alkenylcarbamoyl group and (xxi) NC _1-6 alkynylcarbamoyl group Alkenyl or C _2-6 al C _1-6 alkoxy group, C _2-6 which may each be substituted with one or more groups selected from kinyl group, (6) (i) C _1-6 alkylamino group, (ii) aralkyloxy group and (iii) hydroxyl group Alkenyloxy group or C _2-6 alkynyloxy group, (7) (i) hydroxyl group, (ii) nitrile group, (iii) halogen atom, (iii) C _1-6 alkylamino group, (v) aralkyloxy group, ( vi) TBDMS oxy group, (ⅶ) C _1-6 alkylsulfonyl group, (ⅷ) C _1-6 alkylcarbonyloxy group and (ix) C _1-6 alkyl carbonyl group at least one selected from a carbamoyl group, respectively C _1-6 alkylthio group, C _2-6 alkenylthio group or C _2-6 alkynylthio group which may be substituted, (8) (i) C _1-6 alkoxy group, (ii) amino group, (iii) C _1-6 alkylamino group, (iii) di (C _1-6 alkyl) amino group, (v) C _2-6 alkenylamino group, (vi) di (C _2-6 alkenyl) amino group, (iii) C _{2- 6} alkynyl group, (ⅶ) di (C _2-6 alkynyl) amino group, (ⅷ) NC _1-6 alkyl, -NC _2-6 alkenyl group, (ix) NC _1-6 alkyl, -NC _2-6 Kinil amino group and (x) NC _2-6 carbonyl group substituted by a group selected from alkenyl, -NC _2-6 alkynyl group, (9) (i) C 1-6 alkyl, (ⅱ) C _2-6 alkenyl group, (Iii) C _2-6 alkynyl group, (iii) C _1-6 alkylsulfonyl group, (v) C _2-6 alkenylsulfonyl group, (vi) C _2-6 alkynylsulfonyl group, (iii) C _{1 -6} alkylcarbonyl group, (iii) C _2-6 alkenylcarbonyl group and (ix) C _2-6 alkynylcarbonyl group, amino group which may be substituted with one or two groups selected from (10) C _1-6 alkylsulfo Nyl group, (11) C _2-6 alkenylsulfonyl group, (12) C _2-6 alkynylsulfonyl group, (13) C _1-6 alkylsulfinyl group, (14) C _2-6 alkenylsulfinyl group, ( 15) C _2-6 alkynylsulfinyl group, (16) formyl group, (17) (i) hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iii) C _1-6 alkyl group, (v) C C _3-8 cycloalkyl group or C, which may each be substituted with one or more groups selected from _1-6 alkoxy group, (vi) C _1-6 alkoxyC _1-6 alkyl group and (iii) aralkyl group _3-8 cycloalkenyl group, (18) (i) hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iii) C _1-6 alkyl group, (v) C _1-6 alkoxy group, (vi) C _A 5-14 membered non-aromatic heterocyclic group which may be substituted with at least one group selected from _1-6 alkoxyC _1-6 alkyl group and (iii) aralkyl group, (19) (i) hydroxyl group, (ii) halogen atom, At least one selected from (i) nitrile groups, (iii) C _1-6 alkyl groups, (v) C _1-6 alkoxy groups, (vi) C _1-6 alkoxyC _1-6 alkyl groups and (iii) aralkyl groups C _6-14 aromatic hydrocarbon cyclic group which may be substituted with a group, and (20) (i) hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iii) C _1-6 alkyl group, (v) C _{1- A} group consisting of a 5 to 14 membered aromatic heterocyclic group which may be substituted with at least one group selected from a ₆ alkoxy group, (vi) a C _1-6 alkoxyC _1-6 alkyl group and (iii) an aralkyl group.
[12" claim-type="Currently amended] The method of claim 1,
R ³ and / or R ⁴ is a phenyl group, pyridyl group, thienyl group or furyl group which may be substituted with one or more groups selected from hydroxyl group, halogen atom, C _1-6 alkyl group and C _1-6 alkoxy group or salt.
[13" claim-type="Currently amended] The method of claim 1,
A compound or a salt thereof, wherein R ³ or R ⁴ is a 6-oxo-1,6-dihydropyridyl group which may have a substituent.
[14" claim-type="Currently amended] The method of claim 1,
A compound represented by the following formula or a salt thereof:

In the formula (II), R ¹ represents a cyano group, a carboxy group or a carbamoyl group which may have a substituent; R ² is a hydrogen atom, a hydroxyl group, which may be a substituted C _1-6 alkoxy group, which may come to have a substituent, C _1-6 alkylthio, C _6-14 aromatic hydrocarbon group which may have a substituted cyclic group, Or a 5 to 14 membered aromatic heterocyclic group which may have a substituent; R ⁷ represents a group selected from the following substituent group b; R ⁸ each represents a C _6-14 aromatic hydrocarboncyclic group or a 5-14 membered aromatic heterocyclic group which may have a substituent; A ring represents a nitrogen-containing 6-membered ring which may be substituted with 1 to 4 groups selected from the following substituent group b;
<Substituent group b>
Hydrogen atom, halogen atom, hydroxyl group, nitro group, amino group, C _1-6 alkyl group which may have substituent, C _1-6 alkyl group which may have substituent, C _2-6 alkenyl group which may have substituent, C _2-6 alkynyl group which may have a substituent, C _1-6 alkoxy group which may have a substituent, C _2-6 alkenyloxy group which may have a substituent, C _2-6 which may have a substituent Alkynyloxy group, C _1-6 alkylthio group which may have a substituent, C _2-6 alkenylthio group which may have a substituent, C _2-6 alkynylthio group which may have a substituent, C _2-7 It may have an aliphatic acyl group, a carbamoyl group which may have a substituent, an arylacyl group, a heteroarylacyl group, the amino group which may have a substituent, the C _1-6 alkylsulfonyl group which may have a substituent, and may have a substituent C _{2 -6} alkenylsulfonyl group, C _2-6 alkynylsulfonyl group which may have substituent, C _1-6 alkylsulfinyl group which may have substituent, C _2-6 alkenylsulfinyl group which may have substituent , that may have a substituent, C _2-6 alkynyl, a sulfinyl group, a formyl group, C _3-8 cycloalkyl group that may have a substituent, having a C _3-8 cycloalkyl al alkenyl group, the substituent that may have a substituent A group consisting of a 5 to 14 membered non-aromatic heterocyclic group which may be present, a C _6-14 aromatic hydrocarbon ring group which may have a substituent, and a 5 to 14 membered aromatic heterocyclic group which may have a substituent.
[15" claim-type="Currently amended] The method of claim 14,
R ¹ is a cyano group, or a compound thereof.
[16" claim-type="Currently amended] The method of claim 14,
A compound or a salt thereof, wherein R ¹ is a carboxy group.
[17" claim-type="Currently amended] The method of claim 14,
A compound or a salt thereof wherein R ¹ is a carbamoyl group represented by the following formula:

Wherein R ⁵ and R ⁶ are the same as defined above.
[18" claim-type="Currently amended] The method of claim 14,
The compound or its salt whose R <^2> is a hydrogen atom.
[19" claim-type="Currently amended] The method of claim 14,
The compound or its salt whose substituents of A rings other than R <^7> and R <^7> are chosen from the said substituent group a.
[20" claim-type="Currently amended] The method of claim 14,
A compound or a salt thereof, wherein R ⁷ is a hydrogen atom, a C _1-6 alkyl group which may have a substituent, a C _2-6 alkenyl group which may have a substituent, or a C _1-6 alkoxy group which may have a substituent.
[21" claim-type="Currently amended] The method of claim 14,
The compound or its salt whose R <^8> is a phenyl group, a pyridyl group, a furyl group, or a thienyl group which may have a substituent.
[22" claim-type="Currently amended] The method of claim 14,
The compound or its salt whose R <^8> is a phenyl group, a pyridyl group, a furyl group, or a thienyl group which may respectively be substituted by the halogen atom.
[23" claim-type="Currently amended] The method of claim 1,
The compound is 2-amino-6- (2-furyl) -5- (4-pyridyl) -3-pyridinecarbonitrile, 2-amino-6- (3-fluorophenyl) -5- (4-pyri Diyl) -3-pyridinecarbonitrile, 2-amino-6- (2-furyl) -5- (4-methoxy-3-pyridyl) -3-pyridinecarbonitrile, 2-amino-6- (2- Furyl) -5- (6-oxo-1,6-dihydro-3-pyridinyl) nicotinonitrile, 2-amino-5- (1-ethyl-6-oxo-1,6-dihydro-3- Pyridinyl) -6- (2-furyl) nicotinonitrile, 2-amino-6- (2-furyl) -5- (1-methyl-6-oxo-1,6-dihydro-3-pyridinyl) Nicotinonitrile, 2-amino-6- (3-fluorophenyl) -5- (6-oxo-1,6-dihydro-3-pyridinyl) nicotinonitrile and 2-amino-6- (3- A compound or a salt thereof, which is any one selected from fluorophenyl) -5- (1-methyl-6-oxo-1,6-dihydro-3-pyridinyl) nicotinonitrile.
[24" claim-type="Currently amended] A pharmaceutical composition comprising a compound represented by the following formula or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier:

In the formula (I), R ¹ represents a cyano group, a carboxy group or a carbamoyl group which may have a substituent; R ² is a hydrogen atom, a hydroxyl group, a C _1-6 alkoxy group which may have a substituent, a C _6-14 aromatic hydrocarbon cyclic group which may have a substituent or a 5-14 membered aromatic heterocyclic group which may have a substituent Represent; R ³ and R ⁴ are the same or different, each of which may have a substituted C _3- 8 cycloalkyl group, C _3-8 cyclo alkenyl group, C _6-14 aromatic hydrocarbon cyclic group, a 5- to 14-membered non-aromatic heterocyclic Group or a 5-14 membered aromatic heterocyclic group; Provided that (1) when R ¹ is a cyano group, R ² is a 4-bromo-2-thienyl group, R ³ is a 3,4-dimethoxyphenyl group, and R ⁴ is a 2-thienyl group, ( 2) When R ¹ is a cyano group, R ² is a hydrogen atom, and R ³ and R ⁴ are phenyl groups, (3) R ¹ is a cyano group, R ² is a 4-chloro-phenyl group, and R ³ is When a phenyl group and R ⁴ is a 4- (3,4-dichlorophenyl) -1-oxo-2 (lH) -phthalazinyl group, (4) R ¹ is a cyano group, R ² is a hydrogen atom, When R ³ is a 4-pyridyl group and R ⁴ is a 1-piperazinyl group, (5) R ¹ is a cyano group, R ² is a hydrogen atom, R ³ is a 4-pyridyl group, and R ⁴ Is a 1-pyridyl group, (6) R ¹ is a cyano group, R ² is a hydrogen atom, R ³ is a 4-pyridyl group, and R ⁴ is a 4-diphenylmethyl-1-piperazinyl group If, (7) R ¹ is a cyano group, R ² is a hydrogen atom, and R ³ a group-4-pyridyl, and R ⁴ is 4-morpholinyl group If, (8) R ¹ is a cyano group, R ² is 4-methylphenyl group and, if also R ³ and R ⁴ is a phenyl group, and (9) R ¹ is a cyano group, and R ^2, R ^3, and Except when R ⁴ is a phenyl group.
[25" claim-type="Currently amended] The method of claim 24,
A composition which is a therapeutic or prophylactic agent of a disease involving adenosine receptors.
[26" claim-type="Currently amended] The method of claim 24,
A composition which is a therapeutic or prophylactic agent of a disease involving adenosine A ₂ receptor.
[27" claim-type="Currently amended] The method of claim 24,
A composition which is a therapeutic or prophylactic agent of a disease involving adenosine A _2B receptor.
[28" claim-type="Currently amended] The method of claim 24,
A composition that is an adenosine receptor antagonist.
[29" claim-type="Currently amended] The method of claim 24,
A composition which is an adenosine A ₂ receptor antagonist.
[30" claim-type="Currently amended] The method of claim 24,
A composition which is an adenosine A _2B receptor antagonist.
[31" claim-type="Currently amended] The method of claim 24,
A composition used to promote bowel movements.
[32" claim-type="Currently amended] The method of claim 24,
A composition that is a treatment, prevention or amelioration of constipation.
[33" claim-type="Currently amended] The method of claim 24,
Wherein said constipation is functional constipation.
[34" claim-type="Currently amended] The method of claim 24,
A composition which is a therapeutic, prophylactic or ameliorating agent for irritable bowel syndrome, constipation with irritable bowel syndrome, organic constipation, constipation with intestinal palsy bowel obstruction, constipation with congenital digestive tract dysfunction or constipation with bowel obstruction.
[35" claim-type="Currently amended] The method of claim 24,
A composition used for the exclusion of intestinal contents during or after a gastrointestinal tract examination.
[36" claim-type="Currently amended] The method of claim 24,
A composition which is a therapeutic or prophylactic agent for diabetes, diabetic complications, diabetic retinopathy, obesity or asthma.
[37" claim-type="Currently amended] The method of claim 24,
A composition that is a hypoglycemic agent, a glucose tolerance disorder enhancer, or an insulin sensitivity enhancer.
[38" claim-type="Currently amended] The method of claim 24,
A composition which is an antihypertensive agent, a diuretic drug, an osteoporosis drug, an anti-Parkinson drug, an Alzheimer's disease drug, an inflammatory bowel disease drug or a clonal drug drug.
[39" claim-type="Currently amended] Use of the compound of claim 1 or a pharmacologically acceptable salt thereof for the preparation of a therapeutic or preventive agent for a disease involving adenosine receptors.
[40" claim-type="Currently amended] A method of treating or preventing a disease involving adenosine receptors by administering to a patient a pharmacologically effective amount of the compound of claim 1 or a pharmacologically acceptable salt thereof.

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同族专利:

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JPWO2002014282A1|2004-06-10|

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KR100804111B1|2008-02-18|

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2000-08-11|Priority to JPJP-P-2000-00245056

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2000-08-11|Priority to JP2000245056

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2001-08-09|Application filed by 에자이 가부시키가이샤

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2001-08-09|Priority to PCT/JP2001/006870

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2003-03-15|Publication of KR20030022382A

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2008-02-18|Application granted

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2008-02-18|Publication of KR100804111B1

优先权:

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申请号 | 申请日 | 专利标题

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JPJP-P-2000-00245056|2000-08-11|

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JP2000245056|2000-08-11|

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PCT/JP2001/006870|WO2002014282A1|2000-08-11|2001-08-09|2-aminopyridine compounds and use thereof as drugs|