WO2001098301A1 - Pyrazolopyridine compounds and use thereof as drugs - Google Patents

Pyrazolopyridine compounds and use thereof as drugs

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Publication number
WO2001098301A1
WO2001098301A1 PCT/JP2001/005187 JP0105187W WO0198301A1 WO 2001098301 A1 WO2001098301 A1 WO 2001098301A1 JP 0105187 W JP0105187 W JP 0105187W WO 0198301 A1 WO0198301 A1 WO 0198301A1
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WO
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Prior art keywords
group
le
compound
formula
pyridine
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PCT/JP2001/005187
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French (fr)
Japanese (ja)
Inventor
Hisashi Kawasaki
Koichi Ozawa
Kazuhiko Yamamoto
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Japan Tobacco Inc.
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems

Abstract

Pyrazolopyridine compounds of the general formula (1) or pharmaceutically acceptable salts thereof act specifically on Edg-5, which is sphingosine-1-phosphate receptor, and thus are useful as fibrosis remedies: (1) wherein R?1, R2 and R3¿ are each C¿1-8? alkyl or the like; R?4¿ is hydrogen or the like; R?5 and R6¿ are each independently hydrogen, C¿1-8? alkyl, C1-6 alkoxy, halogeno, or the like; X is NH-, -O-, -CH2-, or the like; Y is NH- or the like; Z is CO- or the like; W is NH- or the like; and A is aryl, heteroaryl, or the like.

Description

Vila oxazolidinedione compounds and their pharmaceutical use

Technical field

The present invention Sufuingoshin one 1-phosphate (hereinafter, referred to as "S pH-1 one P") relates to novel pyrazole 'mouth pyridine compounds and their pharmaceutical use having a receptor antagonism. Furthermore, S ph - about 1-P receptor compounds with antagonism or fibrosis therapeutic agent comprising a pharmaceutically acceptable Ru salt thereof as an active ingredient. More particularly, liver, kidney, on new Tadashii 匕合 thereof and pharmaceutical use thereof with arterial Kati 匕症 therapeutic effect by thickening of fibrosis and vascular smooth muscle in the lung.

Back the amount of technology

Lipids constituting the cell membrane, glycerin port phospholipids, are divided into cholesterol and Sufuin Gore lipids. Furthermore Sufuingo lipid in this is made larger than two. It a staple Ingo myelin is one of the major phosphorus effect substance, a variety of glycolipids sugar chains bound to the ceramide backbone, such as gangliosides. When these sphingolipids are stimulated from the outside, by the enzymatic action of staple-in dust collar kinase or Endoguri Kana Ichize, it is converted to ceramide subject to degradation in the cell membrane or Risoso Ichimu in further by the action of ceramidase Sufuingoshin It is metabolized to. The staple Ingoshin is subjected to the action of the staple Ingo thin kinase, the hydroxyl group of C 1 is phosphorylated S pH-1 one: the P. The S pH-1-: P also do not accumulate in the normal intracellular degraded by lyase immediately is changed to phosphoethanolamine § Min and palmitoyl aldehyde. Substances produced by the metabolic degradation pathways such membrane sphingolipids, it has been noted in recent years is a factor that regulates a variety of functions.

Functions of these sphingolipids with sphingosine basic skeleton mainly are involved in intracellular signal transduction, in particular ceramides Ya Sufuingoshin etc. Important Secondary as de messenger in cell proliferation 'differentiation' Apoptosis one cis such fine «to be involved in the function had been previously known.

On the other hand, S pH-1-P is accumulated platelets containing no rear one peptidase is an exploded enzyme, has been found to be released with the active I spoon. Released S pH-1 one P function as a cell movement factors that strongly inhibit PDGF-dependent cell movements of cancer cells and vascular smooth muscle cells, such melanogaster Ichima cells or growth promoting against fibroblasts It was elucidated to have an effect. Furthermore, it is pulled money of various complex cellular reaction, Ca + release from intracellular stores, regulation of Akuchin polymerization, deter cell death, it was also elucidated by performing modulation of MAP kinase signaling pathway.

Additionally, SPH 1-P acts via a receptor extracellular than the cell surface, functions as a so - called intercellular messengers are being elucidated. For example, Sp - 1 one P is to mobilize calcium from sites different from one to the IP 3 in cells, pe rtussis toxi n-sensitive G protein-dependent and -independent both cell Organization exist, they such as by Las have promoted the activation and DA synthesis of MAP kinases through, the point has been found that through the cell surface receptor rather than the cell. As the receptor, Edg- 1, Edg- 3, Edg-5 (AG Rl 6 / H218), Edg- 6 and Edg- 8 genes are recently black-learning, specifically S pH-1-P it has been reported to be of the receptor. From subsequent studies, Edg- 5 vascular flat 纖, heart, kidney, lung, be distributed specifically, such as the liver became apparent.

The present inventors have further SPH 1 one P result of study, in disease model for these organ, with the progress of the condition, found that is observed increase in mRNA levels Edg- 5 It was. Thus, Edg- 5 suggesting that has been implicated in disease expression in that it. Therefore, diseases (e.g., arteriosclerosis; renal fibrosis, pulmonary fibrosis, liver fibrosis) associated compound is Edg- 5 which act specifically on Edg- 5 can be developed as an excellent therapeutic agent for sex is considered, and such compounds are desired.

Incidentally, as the compound having such pyrazole port pyridine skeleton of the present invention, for example, in International Publication No. WO 00/06549, the following formula

Although in the compounds represented are disclosed, and that the compound having specific antagonistic action against such SPH 1-P receptors present, that they are useful as a fibrosis treatment or it is described just absolutely no, not at all disclosure of data to suggest them. Further, in this document, there is disclosed a herbicide as its application, there is no disclosure of the line fibrosis therapeutic agent, not even suggested.

Further, in JP-A-61- one hundred ninety-seven thousand five hundred and eighty, the following formula

Although in the compounds represented are disclosed, it, or they are useful as a fibrosis therapeutic agents to which the compound has a specific antagonistic action against such S pH-1 one P receptor of the present not only absolutely no mention of it, not at all disclosure of suggesting de Isseki them. Further, in this document, there is disclosed a herbicide as its application, there is no disclosure of the line fibrosis therapeutic agent, not even suggested.

Disclosure of the Invention

In view of the above problems, by specifically antagonizing sphingosine one 1-monophosphate receptor (Edg-5), which aims to treat diseases present receptor related. Specifically, Sufuingoshin one 1-phosphate receptor (Edg-5) takes place in connection with liver fibrosis, provides usefulness novel compound as pulmonary fibrosis, renal fibrosis and therapeutic agents, such as arteriosclerosis an object of the present invention is to.

The present inventors have, as a result of providing Subeku extensive studies the compounds, Vila oxazolidinedione compounds and pharmaceutically acceptable salts thereof represented by the following general formula (1) is Sufuin misdiagnosed one 1-monophosphate by specifically antagonize the receptor (Edg-5), and Heading that can be treated liver lines fibrosis, pulmonary fibrosis, renal fibrosis and atherosclerosis, leading to completion of the present invention It was.

More particularly, as shown in the following: 1. to 25..

1. the general formula (1)

R 1 is hydrogen atom, - 8 alkyl group or - COR 7 (wherein, R 7 is (8 Al kill group, an optionally substituted Ariru group, an optionally substituted Ararukiru group, C i one 6 alkoxy group, a is to have or which may § Li one Ruokishi substituted substituted V, also a good I Ararukiruokishi group);

Is an C 8 Anorekiru group or an optionally substituted § Li Ichiru group;

R 3 represents a hydrogen atom, C ^ - 8 alkyl group - 6 alkoxy groups, C 2 - 6 alkoxy force carbonyl haloalkyl group, a C 3 _ 7 cycloalkyl or optionally substituted good I Ariru group;

R 4 is a hydrogen atom or an alkyl group;

R 5 and R 6 are the same or different, a hydrogen atom, an alkyl group, (^ _ 6 alkoxy group, C 2 - 6 alkoxycarbonyl group, a carboxyl group, C 2 _ 6 alkynyl group, a halogen atom, Shiano group, nitro group, a haloalkyl group, alkylamino di (C ^ - s alkyl) amino group, Ashiru group, a hydroxyl group, an optionally substituted § Li - Ruokishi group, optionally Ararukiruokishi group which may be substituted, may be substituted good not § Li Ichiru group substituted by optionally may be Ararukiru group, alkoxyalkyl group or -CONHR 8 (wherein, R 8 is optionally Ararukiru group be a good Ariru or substituted also be substituted) It is in;

X is - N (R 9) one - (wherein, R 9 represents a hydrogen atom, (8 alkyl group or one NH R 10 (wherein, R 1Q is a carboxyl group or a C 2 _ 6 alkoxycarbonyl group is any)), single 0, one N = one CH two or one CH (R 11) - (wherein,; R 11 represents a hydrogen atom or - be 8 is an alkyl group);

Y is one N (12) (wherein, R 12 is a hydrogen atom, C ^ - s alkyl group, an optionally substituted Ararukiru group, C 2 _ 6 alkoxycarbonyl group, optionally substituted Yoi § reel O alkoxycarbonyl group, with by Ararukiruokishi force Ruponiru group or one optionally CONHR 13 (wherein substituted, R 13 is an optionally is not or which may § Li one Le group substituted substituted Ararukiru is a group)), = N-, -CH 2 one, = CH-, one 0, be single CO- or a single bond;

Z is one C_〇 one, One CS- one CH 2 -, be single 0 or a single bond;

W is, -N (R 14) -. ( Wherein, R 14 represents a hydrogen atom, 8 alkyl group, an optionally substituted § Lal Kill O propoxycarbonyl cycloalkenyl optionally substituted Ariru Okishi a carbonyl group or heteroaryl group is) one 0, one C

0-, -CONH- (provided that the nitrogen atom is bound to ring A), - CH 2 -, one NHC

H 2 - (provided that the carbon atom is bound to ring A) or a single bond; is is a double bond or a single bond;

Ring A is optionally substituted Ariru group, Heteroari Ichiru group or C 3 - 7 Vila oxazolidinedione compound or a pharmaceutically acceptable salt thereof represented by cycloalkyl is a group].

2.: R 1 represents a hydrogen atom, (1 -6 Arukiru group or one €; 01 ^ 7 (wherein, R 7 is, C, one 6 Arukinore group, § Li Ichiru group, Ararukiru CI- e alkoxy group , be § Li an Ruoki shea group or Ararukiruokishi group);

R 2 is - 6 an alkyl group or an Ariru group;

R 3 represents a hydrogen atom, an alkyl group, (^ _ 6 alkoxy groups, C 2 - be 6 alkoxy force carbonyl group, a haloalkyl group, C 3 _ 7 cycloalkyl group or Ariru group; R 4 is a hydrogen atom or an alkyl a group;

R 5 and R 6 are the same or different, a hydrogen atom, - 6 alkyl group, 6 alkoxy group C 2 - 6 alkoxycarbonyl group, a carboxyl group, C 2 - 6 alkynyl group, a halogen atom, Shiano group, a nitro group , a haloalkyl group, an alkylamino group, di - 6 alkyl) amino group, Ashiru group, hydroxyl Ariruokishi Araru Kiruokishi group or one C0NHR 8 (wherein, R 8 is at a a) Ariru group or Ararukiru group;

X is, - N (R 9) - ( wherein, R 9 represents a hydrogen atom, (6 alkyl or - NH R 10 (wherein, R 10 represents a carboxyl group or a C 2 - 6 alkoxycarbonyl group is any)), single 0, one N = one CH = or one CH (R 11) - (wherein, R 11 is a hydrogen atom or an alkyl group);

Y is one N (R 12) - (wherein, R 12 is a hydrogen atom, - 6 alkyl group, Araru kill group, C 2 _ 6 alkoxycarbonyl group, § reel O alkoxycarbonyl group, Araru Kill O butoxycarbonyl group or one CONHR 13 (wherein, R 13 is a is Ariru group or Ararukiru group))ヽ= N-, one CH 2 -, = CH-, one 0, be single CO one or single bond ;

Z is one CO-, _CS- one CH 2 -, be single 0 or a single bond;

W is one N (R 14) i (where,: R 14 is a hydrogen atom, (vii 6 alkyl group, Araru Kill O alkoxycarbonyl group, Teroari Ichiru C Bok § Li one Ruo alkoxycarbonyl group, or the 6 is an alkyl group), - 0-, - CO-, -C0NH- ( where the nitrogen atom binds to the ring a), - CH 2 -, -NHCH 2 - ( provided that the carbon atom binds to the ring a ) or a single bond; it is is a double bond or a single bond;

Ring A is Ariru group, Heteroariru group or C 3 - a cycloalkyl group, the above SL 1. Vila oxazolidinedione compound or a pharmaceutically acceptable salt thereof for.

3. R 3, R 4 and formula

In the substitution position on the pyridine ring of the substituent represented is, R 3 is h-position, R 4 is i-position, wherein

In substituents represented is position j, pyrazole port pyridine compound or a pharmaceutically acceptable salt of said 2.

Four. ! ^ Is Ari in Arukiru group, H 2 is an alkyl group, and R 4 is a hydrogen atom, the 3 leaflets oxazolidinedione compound or a pharmaceutically acceptable salt thereof.

5. Y is one NH- or = a N-, Z is an CO-, and W gar is NH-, pyrazole port pyridine compound or a pharmaceutically acceptable salt of the 4.

6. Ring A is § Li Ichiru group, pyrazole port pyridine compound or a pharmaceutically acceptable salt thereof manufactured drug above 5..

7. Ariru group is a phenyl group, pyrazole port pyridine compound or a pharmaceutically acceptable salt of the 6.

8. Ring A to is Teroariru group, pyrazole port pyridine compound or a pharmaceutically acceptable salt of said 5.

9. Heteroariru group is pyridyl group or thienyl group, pyrazole port pyridine compound or a pharmaceutically acceptable salt of the 8.

10. Heteroari Ichiru group is pyridyl group, Vila oxazolidinedione of compound or a pharmaceutically acceptable salt thereof of the 9..

11. X Gar NH- or - N a = upper word yourself 5. to any of Vila Zoropirijin compound or a pharmaceutically acceptable salt thereof 10..

12. X is - CH 2 - in which, the 5. to any one of the pyrazole port pyridinium Gin compound or a pharmaceutically acceptable salt thereof 10..

13. X is an 0-The 5. to any one of the pyrazole port pyridine I 匕合 thereof or a pharmaceutically acceptable salt thereof 10.. .

14. N- (1H- 4- isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridin-one 6- I le) Amino one N '- (2, 3_ jib port Mochiofen one 5- I le )urea,

N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6 _ I le) amino-N, one (2, 6-dichloropyridine one 4-I le) urea, N- (1H- 1, 3, 4- Torimechirupirazo port [3, 4-b] pyridine one 6- I le) amino-N, one (2-black opening one 6-propyl-pyridin _4 one I le) urea, N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino one N, one (2-black opening one 6-propyl-pyridin one 4 one ^ Γ Le) urea,

N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N '- (2-chloro-6-isopropyl-pyridin one 4 - I le) urea ,

N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N, - (2-black port _ 6 isobutyl pyridine _4 one I le) urea,

N- (1H- 1, 3, 4- Torimechirupirazo port [3, 4-b] pyridine one 6- I le) Amino one N, - (2-black opening one 6-isopentyl ruby ​​lysine one 4- I le ) urea, N- (1H-4 one ^ f an isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N, - (2-chloro-6-isopentyl ruby ​​lysine one 4 one I le) urea,

N-(IH-4 one ^ T an isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N '- (2-methoxy-one 6-methylpyridin-one 4-I Norre) K,

N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N '- (3, 5- dimethyl-phenylalanine) urea,

N- (1H- 1, 3, 4- Torimechirupirazo port [3, 4-b] pyridine one 6- I le) Amino one N, i (2 black port hexyl one 6- (3-methyl) pyridine one 4-I le) urea,

N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N '- (2-black opening one 6- (hexyl 3-methyl) Pi lysine one 4-I le) urea,

N-(1H-4 one isopropyl _ 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N, - (2, 3-dichloro Chio phen one 5- I le) Urine arsenide,

N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N, - (2-chloro-6-pentylbicyclo lysine one 4-I le) urea , N- (lH-l, 3, 4- Torimechirupirazo port [3, 4-b] pyridine one 6- I le) Amino one N '- (2-black opening one 6-pentylbicyclo lysine one 4- I le ) urea, N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N '- (2-black opening one 6- to Kishirubirijin one 4 - I le) urea,

N- (1H- 1, 3, 4 one Torimechirupirazo port [3, 4-b] pyridine one 6- I le) Amino one N '- (2-black opening one 6-hexyl pyridine one 4- I le ) urea, N- (1H- 1, 3, 4- Torimechirupirazo port [3, 4-b] pyridine one 6- I le) Amino one N '- (2-butyl-one 6- black port pyridine one 4- I le) urea, N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino one N '- (2-black opening one 6- Hue two Rubirijin one 4-I le) urea,

N- (1H-1, 3, 4- Torimechirupirazo port [3, 4-b] pyridine one 6- I le) Amino one N '- (2-black opening one 6-phenylene Rubirijin one 4- I le ) urea, N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino one N, - (2-chloro Chio phen one 4- I le ) urea, N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N, i (3, 5-di (methoxycarbonyl) phenyl)

N-(1H-4-isopropyl _ 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N '- (2-black opening one 6- (2-Fueniruechiru) pin lysine one 4-I le) urea,

N- (1H- 1, 3, 4- Torimechirupirazo port [3, 4-b] pyridine one 6- I le) Amino one N, one (2-black opening one 6- (2-Fuweniruechiru) pyridine one 4 one Inore) urea,

N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N, one (2-black opening one 6-butylpyridine one 4- I le )

N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino one N '- (3, 5 _ dibromo-phenylalanine) urea,

N-(1H-1, 3, 4-Torimechirupirazo port [3, 4-b] pyridine one 6- I le) amino-N, i (3, 5-dibromo-phenylalanine) urea,

N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino one N, i (3-bromo-one 2-methylthiophene one 5- I le ) urea,

N- (1H- 1, 3, 4- Torimechirupirazo port [3, 4-b] pyridine one 6- I le) amino-N '- (2-black opening one 6-isobutyl-pyridin one 4-I le) urea , N-(1H-1, 3, 4 Torimechirupirazo port [3, 4-b] pyridine one 6- I le) amino-N, - (2-chloro to 6- Puchirubirijin one 4-I le) urea, N- (1H-4- isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino one N '- (Puchirubirijin _4 over I le 2 Clos port one 6- to ) urea,

N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-] NT - (2-chloro-6- ((4-fluorophenyl) methyl) pyridine one 4 one I le) urea,

N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino one N, - (3- (methoxymethyl) Single 5 Mechirufue two Le) urea,

N-(1H-4_ isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino one N, i (3 black port phenyl) urea,

N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N '- (3, 5- dichloro port phenyl) urea,

N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N, one (3 Buromofueniru) urea,

N-(1H-1, 3, 4 Torimechirupirazo port [3, 4-b] pyridine one 6- I le) Amino one N, one (2, 6-dichloro port pyridine one 4-I le) urea,

N-(1H-4 one isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N, - (2-black opening one 6-methoxypyridin-one 4-I le ) urea,

N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino one N '- (2-black opening one 6-ethoxy-pyridin-one 4- I Le) urea,

N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino one N, - (2-black port pyridine one 4-I le) urea, N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N, - (2-black opening one 6-methylpyridin-one 4 one I le )

N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N '- (2, 6-diethoxy-pyridin one 4-I le) Urine arsenide,

N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino one N, one (6 Benjiruokishi one 2-black port pyridine one 4- I Le) urea,

N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino one N, one (2, 6-dimethoxypyridine one 4-I le) Urine

N-(IH-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6 ^ f le) amino-N 'i (2-chloro-6- Echirupirijin one 4-I le)

N- (1H- 1, 3, 4- Torimechirupirazo port [3, 4-b] pyridine one 6- I le) amino-N '- (2-black opening one 6-methylpyridin-one 4 one I le) urea , N- (1H- 1, 3, 4- Torimechirupirazo port [3, 4-b] pyridine one 6- I le) Amino one N, one (2-black opening one 6- Echirupirijin one 4-I le) urea, 1H-6- (((2- black opening one 6-methylpyridin-one 4-I le) Amino) carbonylation Ruazo) Single 4 f an isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridine down,

1H-6- (((2, 6- dichloropyridine one 4 one I le) Amino) Karuboniruazo) one 4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridine, N-(1H-4 - isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I) methyl one N, - (2, 6-dichloropyridine one 4-I le) urea, N-(1H- 4_ isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I) methyl one N, - (3, 5-dichlorophenyl) urea,

N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I) methyl one N, - (2-black opening one 6- Echirupirijin one 4 one I le )

N-(1H-4-isopropyl _ 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6 f) methyl one N, - (2-black opening one 6-methylpyridin-one 4- I le )

N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Okishi one N'(2, 6-dichloropyridine one 4-I le) urea ,

N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Okishi _N, - (3-black port phenyl) urea,

N-(1H-4-isopropyl _ 1, 3-dimethyl-pyrazolo [3, 4-b] pyridinium Jin _ 6 I le) Okishi one N '- (3-Buromofueniru) urea and

N-(1H-4 one isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Okishi one - (3, 5-dichlorophenyl) urea

The selected from the group consisting of: 1. pyrazole port pyridine compound or a pharmaceutically acceptable salt thereof for.

15. the word 31. to either pyrazole port pyridine compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable pharmaceutical composition comprising a carrier 14..

16. the words himself 1. to either Vila oxazolidinedione compound or Sufuingoshin one 1-phosphate receptor 拮 anti agent containing a pharmaceutically acceptable salt thereof as an active ingredient 14..

17. ± 1. to fibrosis therapeutic agent containing either Vila oxazolidinedione I 匕合 thereof or a pharmaceutically acceptable salt thereof 14. as an active ingredient.

18. the words himself 1. to either pyrazole port Pirijini 匕合 product or liver fibrosis therapeutic agents containing a pharmaceutically acceptable salt thereof as an active ingredient 14..

19. the words himself 1. to pulmonary fibrosis therapeutic agent containing either Vila oxazolidinedione I 匕合 thereof or a pharmaceutically acceptable salt thereof as an active ingredient 14..

20. sphingosine - 1-phosphate receptor compound having antagonism or fibrosis therapeutic agent, which comprises the manufacturing drugs acceptable salt thereof as an active ingredient.

21. Sufuingoshin one 1-phosphate receptor is an E DG-5, above 20.

22. sphingosine - 1 monophosphate acceptor compounds having an antagonism or liver fibrosis therapeutic agent comprising the manufacturing drugs acceptable salt thereof as an active ingredient.

23. Sphingosine one 1 monophosphate receptor is E dg-5, liver fibrosis treatment of the 22..

24. Sphingosine one 1-monophosphate acceptor compounds having an antagonism or pulmonary fibrosis therapeutic agent, which comprises the manufacturing drugs acceptable salt thereof as an active ingredient.

25. Sufuingoshin one 1 monophosphate receptor is E DG-5, pulmonary fibrosis therapeutic agent above 24.. The definition of each substituent used in the present specification are as follows.

The term "halogen atom", chlorine atom, bromine atom, a fluorine atom, an iodine atom. Preferably a chlorine atom in R 5 and R 6, a fluorine atom, an iodine atom or a bromine atom

C, Mel o

The term "(8 alkyl group" having 1 to 8 carbon atoms, preferably 1 to 6 carbon straight or branched may be an alkyl group such as methyl group, Echiru propyl, Isopuropinore group, butyl group , Isobuchiru group, sec- butyl tert- butyl group, pentyl group, isopentyl group, neopentyl group, tert- pentyl group, a hexyl group, a heptyl group, a 3-methyl hexyl group, or Okuchiru group, is preferable properly is also an alkyl group with the number 1 to 4 straight or branched carbon. particularly preferred properly methyl Echiru group or an isopropyl group. in R 1 is preferably a methyl group, preferably methyl at R 2 Ri group or t Ert- heptyl der, preferably in R 3 is a methyl group, Echiru group, t Ert- heptyl group, Isobu ethyl group or an isopropyl group, preferably in R 4 Ku is a methyl group, and preferably a methyl Echiru group in R 6, a propyl group Isopuropiru group, butyl group, isobutyl group, tert - butyl pentyl group, an isopentyl group, a hexyl group, a cyclohexyl group 3-methyl, heptyl a group or Okuchiru group, Oite to R 7 is preferably a methyl group or Echiru group, preferably in R 9 (particularly preferably a methyl group) C 4 alkyl group is, preferably in R 1 1 (^ _ (particularly preferably a methyl group) 4 alkyl group is, preferably in R 1 2 is a methyl group, preferably in R 1 4 is a methyl group.

The "alkoxy group" represents the number 1 to 6 straight-chain or branched which may be § alkoxy group having a carbon such as a methoxy group, an ethoxy group, a propoxy group, Isopurobo alkoxy group, a butoxy group, tert _ butoxy , Penchiruokishi group, a tert- Bae Nchiruokishi group or to Kishiruokishi group, preferably a linear or optionally branched alkoxy group having 1 to 4 carbon atoms (e.g., methoxy, ethoxy, isopropoxy port epoxy butoxy group, it is a tert- butoxy group). Particularly preferably meth alkoxy group or an ethoxy group. Preferably in R 3 is a methoxy group, preferably the R 5及beauty R 6 is a methoxy group or an ethoxy group, rather preferable in R 7 is methoxy group.

The "alkoxyalkyl group", an alkoxy portion is Ri The alkoxy group as defined der, and the alkyl portion is an alkoxyalkyl group as defined above alkyl group, such as methoxymethyl group, ethoxymethyl group, propoxymethyl group, Butokishime butyl group, pentyl Ruo carboxymethyl group, a hexyl O carboxymethyl group, etc. Etokishechiru group. Preferably the R 5 and R 6 are methoxy methyl group.

The "C 2 _ 6 alkoxycarbonyl group", methoxycarbonyl group, Etokishika carbonyl group, propoxy carboxymethyl group, isopropoxycarbonyl group, an alkyl portion or a butoxy carbonyl group, I Su Wu butoxycarbonyl group or a tert- butoxycarbonyl group There an alkoxyalkyl carbonylation Le group has 1 to 5 carbon atoms. The preferred properly methoxycarbonyl group, E butoxycarbonyl group or a tert- Butokishika Ruponiru group. Preferably, in R 3, R 5 and R 6 are methoxy carbonyl group, preferably in R 1 Q is a methoxycarbonyl group or an ethoxycarbonyl group, preferably in R 1 2 in a methoxycarbonyl group or a tert- butoxy aryloxycarbonyl group is there.

The "haloalkyl group", the - 8 alkyl group has been substituted by the above halogen atom, such as chloromethyl group, bromomethyl group, Furuoromechiru group, Jifuruoromechiru group triflate Ruo b methyl trichloromethyl group, tribromo methyl group, trichloroacetic port Echiru group, a pen evening Furuoropuropiru group or click every mouth butyl group, preferably a chloromethyl group, bromomethyl group, Furuoromechiru group, preparative Rifuruoromechiru group or trichloromethyl group. Particularly preferably Torifuruo Romechiru group. Preferably in R 3, R 5 and R 6 are triflate Ruo b methyl or Jifuruo port methyl.

The "C 2 _ 6 alkynyl group" is a good § Rukiniru groups be straight or branched having 2 to 6 carbon atoms, for example Echiniru group, propynyl group, heptynyl group, 2-pentynyl group, 3 - pentynyl group, a hexynyl group or the like to 2 to hexynyl group 3, good Mashiku is alkynyl which may be straight or branched having 2 to 4 carbon atoms. In R 5 and R 6 are preferably Echiniru group.

The alkylamino group ", 1 to 8 carbon atoms, preferably represents an amino group substituted with 1 to 6 alkyl groups, for example Mechiruamino grave Echirua amino group, propylamino group, Puchiruamino group. Preferably, and the like Mechiruamino group or Echiruamino group. Preferably the R 5 and R 6 are Mechiruamino group or Echiruamino group.

"Di ((^ - C8 alkyl) amino group" and, 1 to 8 carbon atoms, preferably an disubstituted amino group in 1 乃 optimum 6 alkyl groups, for example Jimechiruamino group, Jechiruamino group, di propyl amino Jibuchiruamino group, preferably a like Jimechiruamino group or Jechiruamino group. rather preferable in R 5 and R 6 are Jimechiruamino group or Jechiruamino group.

The "Ashiru group", a formyl group having 1 carbon atoms; having 2 to 6 Arukanoiru group carbon (e.g., Asechiru group, a propionyl group, Puchiriru properly is Bibaroinore group); or from 1-3 on Ariru group an optionally substituted Aroiru group (e.g., base Nzoiru group or the like; the substituent here, following Ru synonymous der the substituent of the "Ariru group") is. Preferably a formyl group Asechiru group, pivaloyl group or Benzoiru group. In R 5 and R 6 are preferably Asechiru group.

The "Ariru group", for example phenyl group, a naphthyl group, a biphenyl group and the like, preferably a phenyl group. Wherein the Ariru group may be substituted Ri by the 1 to 3 substituents. Here, "1 to 3 substituents may be substituted with" the substituent to definitive, the same or may be different from, and position of the substituents is optional, limited in particular is not. Specifically, (for example, a methyl group, Echiru group, a propyl group, an isopropyl group, a butyl group, tert - butyl group) C i 6 alkyl group, a hydroxyl group, (^ alkoxy (e.g., methoxy group, an ethoxy group , propoxy group, butoxy group); a halogen atom (e.g., full Uz atom, a chlorine atom, a bromine atom); nitro group; Shiano group; Ashiru group (e.g., formyl group Asechiru group, propionyl group, etc.); Ashiruokishi group (e.g., Horumiruokishi group, Asechiruoki shea group, a propionyloxy Ruo alkoxy group); a mercapto group; C DOO 6 alkylthio group (e.g., methylthio group, Echiruchio propylthio group, Puchiruchio group, isobutylthio group); an amino group; C ^ - e alkylamino group (e.g., Mechiruamino group, Echirua amino group, propylamino group, Puchiruamino Etc.); di-alkyl) amino group

(E.g., Jimechiruamino group Jechiruamino group, dipropylamino group, dibutyl Ruamino group); a carboxyl group; C 2 - 6 alkoxycarbonyl group (e.g., meth alkoxycarbonyl group, an ethoxycarbonyl group, propoxycarbonyl group and the like); amide group; triflate Ruo b methyl group; (g 6 alkylsulfonyl group (e.g., Mechirusuru Honiru group, Echirusuruhoniru group); aminosulfonyl group; C 3 _ 7 cycloalkyl group (e.g., cyclohexyl group, etc. cyclopentyl group, cyclohexylene); phenyl group; Ashiruami de group (e.g., Asetoamido group, propionylamide group) and the like, preferably hydroxyl ¾ C s alkyl group, C 6 alkoxy group, a mercapto group, - 6 alkyl thio group, a halogen atom, Torifuruo Romechiru group, Ashiru group, c 2 _ 6 alkoxy months Boniru a group or Ashiruamido group.

Preferably in R \ R 2 and R 3 are phenyl groups; preferably at R 8 is phenyl group substituted by phenyl group or a halogen atom (e.g., Puromofue such as a secondary le group), preferably in R 1 3 phenyl or substituted phenyl group with a halogen atom (e.g., Buromofue sulfonyl chloride port Hue group, Jikurorofu etc. Eniru group), preferably in the ring a is a phenyl group, preferably the R 5 and R 6 phenyl group, black hole Hue group, Metokishifue alkenyl group or a methoxycarbonylphenyl group.

The "Ararukiru group" is a Ariru portion phenyl group (wherein the Hue alkenyl group may be 1 to 3 substituted with a substituent described above § Li Ichiru group), and alkyl portions carbon number 1 to 8, preferably 1 to 6 § Li one Ruaru kill group which is an alkyl group, e.g., benzyl group, Fueniruechiru group, phenylpropyl group, a cyclohexyl group phenylbutyl group or a phenylene Le etc., and is preferably a benzyl group or Fueniruechiru group. Preferably in R 7, RR 1 2 and R 1 4 is a benzyl group, preferably in R 5 and H 6 is Fueniruechiru group or Furuoro benzyl group.

The "Ariruokishi group", Ariru unit is § Li one Ruokishi group as defined above Ariru group, wherein Yo Ariru portion is 1 to 3 substituted with a substituent described above § Li Ichiru group it may be. For example, Fuwenokishi group, Nafuchiruokishi group and the like et be, preferably phenoxy group. Preferably R 5, R 6 and R 7 are Hue phenoxy group.

The "Ararukiruokishi group", Ariru portion is as defined above § Li Ichiru group, or One alkoxy portion is a Ararukiruokishi group has 1 to 4 alkoxy groups having a carbon number, wherein Yo § Li Ichiru parts may be 1 to 3 substituted with a substituent described above § Li Ichiru group. For example, Benjiruokishi group, Fuenechiruokishi Fuenirupuropi Ruokishi group, full We sulfonyl butyl O alkoxy group and the like, preferably a base Njiruokishi group. R 5, R 6 and R 7 are preferably Benjiruokishi or 2-Hue Niruechiru group.

The "§ reel O alkoxycarbonyl group" is a § reel O alkoxycarbonyl group Ariru portion is as defined above Ariru group, wherein Yo Ariru part 1 to 3 substituted with a substituent described above Ariru group it may be. For example, phenoxyethanol carbonyl group, naphthyl O butoxycarbonyl group and the like, preferably Fuwenokishikarubo two Le group. Preferably the R 1 2 and R 1 4 is phenoxyethanol group. The "§ Lal Kill O alkoxycarbonyl group", Ariru portion is as defined above Ariru group, and an alkoxy portion is a Ararukiru O alkoxycarbonyl group is a number 1 to 4 alkoxy groups carbons, wherein Yo § Li Ichiru unit may be 1 to 3 substituents at location substituent set forth above Ariru group. For example, benzyl O alkoxycarbonyl group, Hue phenethyl Ruo alkoxycarbonyl group, phenylpropyl O propoxycarbonyl sulfonyl Fuenirubu chill O butoxycarbonyl group and the like, preferably base Nji Ruo alkoxycarbonyl group. Preferably in R 1 2 and R 1 4 is a base Nji Ruo alkoxycarbonyl group.

The "〇 3 _ 7 cycloalkyl group", a cycloalkyl group having 3 to 7 carbon was meaning taste, specifically cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group consequent opening, 1- methylcyclohexane a hexyl, heptyl and the like cyclohexylene. Preferably rather is a cycloalkyl group having 3 to 6 carbon atoms, specifically a cyclopropyl group, a cyclobutyl group, a cyclohexyl group a cyclopentyl group or a cycloalkyl. Particularly preferably a cyclohexyl group a propyl group or a cycloalkyl. Preferably in R 3 is consequent opening propyl. Preferably the ring A is a cyclohexyl group.

And "Heteroariru group", in addition to carbon atoms as atoms constituting the ring, ChissoHara child, aromatic heterocyclic oxygen atom and 5 or 6 membered heterocyclic atoms containing 1 to 3 substituents selected from sulfur atoms, saturated heterocyclic ring, unsaturated heterocycle j means a fused heterocycle these heterocyclic ring and a benzene ring is condensed, specifically, Chiofen one 2-I group, Chiofue down one 3-I group, furan one 2 - I group, furan one 3-I group, pyrosulfate Ichiru one 1-I group, pyrosulfate Ichiru one 2-I group, pyro Ichiru - 3-I le Imidazo Ichiru one 1-I le radical , imidazo one rule 2 I group, imidazo Ichiru one 4 Iru group, pyrazole Ichiru one 1-I le pyrazole one rule 3 I le pyrazole one rule 4 I group, thiazole Ichiru one 2- I group, thiazole Ichiru -4 Iru thiazole Ichiru one 5- I group, Okisazoru one 2 - I le group Okisazo one route 4-I Group, Okisazo one rule 5 I group, Isookisa zone Ichiru one 3- pray Isookisazo one route 4 Iru group, Isookisazo one rule 5 I group, pyrimidine one 2-I le pyrimidin one 4-I group, pyrimidine one 5 _ I le pyridine one 2-I group, pyridine one 3-I group, pyridine one 4 Iru group, Benzochiofen one 2- ^ f group, Benzochiofen one 3-I group, benzofuran-2-I le group, benzofuran one 3- ^ f group, India Ichiru one 2-I group, India one rule 3 I group, benzoimidazol one rule 1 I le Benzoimidazo one rule 2 I le benzothiazole Ichiru one 2 - I group, benzo O benzoxazole one 2-I le ¾ ^ key Norin one 2-I group, quinoline one 3-I group, quinoline one 4 Iru group, isoquino phosphorus one 1-I group, Isokinorin one 3-I group, Isokinorin one 4- I Group, 1,. 3, 4 Chiajiazo Ichiru one 2-group, morpholine _ 4 one I le group.

Preferably the ring A is a pyridyl group (e.g., pyridine one 2-I group, pyridine Hmm 3 I group, pyridine - 4 I le group, etc.), Benzookisazo Ichiru one 2-I group, morpholine one 4 f group, Benzoimidazo one rule 2 I group, pyrimidine one 2 _ I le group pyrimidine one 4-I le thienyl group (e.g., Chiofen one 2-I group, such as Chiofen one 3-I le group), furan one 2-I group, furan one 3-I group, pyrosulfate Ichiru one 2 T group, pyrosulfate Ichiru one 3-I group, pyrazole one rule 3 I group, thiazolium Ichiru one 4- I group, Chiazo Ichiru one 5-^ gamma le-benzimidazol Ichiru - 2-I le benzo, Chiofen one 2-I group, benzofuran one 2-I le group, more preferably a pyridyl group or a thienyl group , and particularly preferably a pyridyl group (preferred properly pyridine one 3-I le group or Pyridine is one 4 Iru group).

The "Heteroariru alkyl group", Heteroariru unit means Teroa reel group to above and 1 to 8 alkyl portion carbons, preferably a heteroarylalkyl group to a 1 to 6 alkyl groups , for example, Pirijirumechi Le group (e.g., 2-pyridylmethyl group, 3-pyridylmethyl group, 4-Pirijirume butyl group, etc.), quinolinylmethyl group (e.g., 2-quinolinylmethyl group), India Rirumechiru group (e.g., 2-in- indolylmethyl, 3-indolylmethyl group, etc.), Chiofen one 2-Irumechiru group, Chiofen one 3-Irumechiru group, 2-furanyl-methyl group, 3-furanylmethyl group, 1 H- benzoimidazol Ichiru one 2- Irumechiru benzo Chiazoru 2 Irumechiru group, 2- (Chiofen one 2-I le) E Ji group, 2 - (furan one 2-I le) Chinore is a group, and the like. Preferably, a 2-pyridyl methyl 3-pyridylmethyl group, 4-pyridylmethyl group, 3-Pirijiruechiru group, 4-Pirijiruechiru group. Preferably 3 Pirijiruechi Le group in R 1 4 (e.g., 2- (pyridin-one 3-I le) Echiru group).

The "Purodoradzugu" drug molecules chemically modified derivatives themselves not exhibit physiological activity in vivo after administration refers to showing a restore efficacy to the original drug molecule.

"Pharmaceutically acceptable salt", such as hydrochloride, hydrobromide, sulfate, various inorganic acid addition salts such as phosphate or nitrate; acetate, propionate, succinate, grayed Rico Ichiru, lactate, malate, oxalic acid, tartaric acid, Kuen salt, maleic acid salt, fumarate, methanesulfonate, benzenesulfonate, p- toluene sulfonate, various organic acid addition salts such as tosylate or Asukorubin salt; § aspartic acid salt, or salts with various amino acids such as glutamate, it is not limited to these. In some cases, water-containing product, hydrate walk may be a solvate. The general formula (1)

Wherein each symbol is as defined above]

In represented by pyrazole port pyridine compound (hereinafter, pyrazole port pyridine compound (1) will leave) or a pharmaceutically acceptable salt, Sufuingoshin one 1-phosphate receptor (E dg - 5) to specifically antagonize to order, related disorders E DG-5 is Sufuingoshin one 1-phosphate receptor (e.g., arteriosclerosis; kidney, lung, liver tissue fibrosis) is useful as an excellent treatment for.

The pyrazole port pyridine compounds in (1), R 3, R 4 and formula one XH - W

In the substitution position on the pyridine ring of the substituents represented is, R 3 is h-position, R 4 is i-position, and wherein

Preferably, in formula substituent is position j.

A preferred embodiment of each symbol in the above formula (1) are as follows.

Preferably in R 1 is a C I 6 alkyl group, particularly preferably Ru der methyl group.

Preferably the R 2 is C 6 alkyl group, particularly preferably Ru der methyl group.

Preferably in R 3 is C i _ 6 alkyl group, Nono port alkyl or C 3 _ 7 Shikuroa alkyl group, particularly preferably a C 6 alkyl group.

Preferably in R 4 is hydrogen atom.

Preferably a hydrogen atom in R 5 and R 6, an alkyl group, (^ _ 6 an alkoxy group, C 2 _ 6 alkynyl group, a halogen atom, Shiano group, a nitro group, a haloalkyl group, - 6 alkylamino group, di (Ci -e alkyl) amino group, Ashiru group, an Ari Ruokishi group or Ararukiruokishi group.

Preferably one N (R 9) one (Here, as preferable examples of R 9 is water atom or an alkyl group, particularly preferably a hydrogen atom) in X, - 0-, -N = (where , Y and bonded with a double bond) or single CH (R 11) i (where preferred examples of R 1 1 is a hydrogen atom or a C Bok 4 alkyl group, particularly preferably a hydrogen atom) , and the particularly preferred, - NH-, - 0-, _N = or chromatography CH 2 - it is.

Preferably the Y one N (R 12) i (where preferred examples of R 12 is a hydrogen atom or a C 6 alkyl group, particularly preferably a hydrogen atom), = N-, one CH 2 - , = CH-, a one hundred and one or one CO-, particularly preferably, a NH- or = is N-.

Preferably one CO- in Z, one CS-, one CH 2 - or an 0-, preferably in particular, is one CO-.

Preferably one N (R 14) it (where preferred examples of R 14 are a hydrogen atom or - an alkyl group, particularly preferably a hydrogen atom) in W is or a single bond, particularly preferably is one NH-.

Ring in preferably A is § Li Ichiru group or to Teroari Ichiru group, especially rather preferred is a phenyl group, Pirijinore group (pyridin one 2-I group, pyridine one 3-I group or pyridine one 4 it is a Iru group).

Here the present invention compounds, in some cases may be a hydrate or solvate, also intended to be encompassed also its Purodoradzukui 匕合 thereof and metabolites. When using the present invention as a therapeutic agent, such as liver fibrosis, systemically or topically, administered orally or parenterally. Dose age, body weight, symptoms, different from treatment effect and the like, usually per adult, in the range of 1 0 mg to lg once, once a day to several times is administered.

The compounds of the present invention, solid compositions and liquid compositions for oral administration, or parenteral dosing suitable diluents for the formulations such as injections for, dispersants, adsorbents, solubilizers, etc. it is possible to be mixed.

The compounds of the present invention human, of course, can be used non-human animals, in particular in the treatment and prevention of fibrosis and atherosclerosis in mammals.

Next, explaining the manufacturing method of the pyrazole port pyridine compound represented by the formula (1), the production method of the compound of the present invention is not limited thereto.

Further, when the reaction is carried out later, leave protected beforehand as necessary for functional groups other than the portion may be deprotected in an appropriate stage.

Further, in each step, the reaction may be carried out in a conventional method performed, isolation and purification sintering crystallization, recrystallization, column chromatography, the customary methods such as preparative HPLC appropriately selected or combined ί亍E it. Production Method 1 to 3

Production Method 1

(2)

H, N CN RN ΝΗ 2 steps DOO

(Four)

; ',

(Wherein, R \ R 2, R 4 , R 5, R 6 and A are as defined above, X 1 is a halo gen atom)

Production Method 1: general formula (1) (X, Y, Z, W) is, (- NH -, - NH- , - C 0-, -NH -), ( 10 - one CH 2 -, one CO-, - NH-) ヽ (one NH -, - dragon - one CO- ヽ single bond), (- NH-, - NH -, a single bond, one CO-), (one NH -, Ichi匪one, one CO-, one C0NH-)ヽ(one NH-, one Ryuichi, one CO-, - CH 2 -), (- NH-, - NH-, a single bond, a single bond), (one NH-, single bond, a single bond, - NH-) ヽ (one N =, = N-one CO -, one NH -), (one NH-, -NH one, one CO-, - 0-), (one CH =, = CH-, -CO-, one NH-) and (one CH 2 -ヽone CH 2 -, one CO-, method for producing compounds wherein one NH-)

Step 1 one 1

In the literature (Heterocycl. Chem. 11, 23 (1974)) and the same method, the general formula (2) and a compound represented by the general formula (3), compounds represented by alcohol solvent (eg, methanol , ethanol, to give a compound represented by by the heating to reflux in isopropanol) connexion general formula (4).

Further, the compound represented by the general formula (4) is, Helv. Chim. Acta 16, 306 (1958X Angew. Chem.86, cowpea to 237 (1974) or the method disclosed in JP-A-5- 140113 and it can be obtained as well.

Incidentally, the compounds obtained without isolation, can be used in the next step. Step 1 one 2

Acid catalyst (e.g., sulfuric acid, hydrochloric acid, formic acid, acetic acid, propionic acid, tosylate or main evening etc. Nsuruhon acid) in the presence of a compound represented by the compound represented by formula (4) and general formula (5) the by reacting under reflux, to give compound of represented Ru by the general formula (6). Specifically, for example, in the general formula (5) represented by reduction compounds with a mixture of an acidic catalyst, a compound represented by the general formula (4) is added and heated 撹 拌.

After step 1 2 ends, the general formula represented by general formula匕合product (6): was reacted with X 1 CH 2 C 0 halogeno acid derivative represented by OMe, further de-methoxy protection, and the general formula (18) By reaction with, X = - 0-, Y = - CH 2 -, Z = - CO-, W = - NH- , compound can be obtained.

The following formula

In the substituent represented is, compounds substituted at the h-position of the pyridine ring, a compound represented by the general formula (4), the general formula (5) compounds represented by (wherein, R 3 is alkoxy reacting the case of group), the general formula

Represented by a compound in further by reducing the compound of general formula

In can be obtained a compound represented by. By subjecting this compound to the same reaction as in Production method 2-2 to 2-4 described later, it is possible to obtain the desired compound.

Step 1 - 3

Aprotic solvents (e.g., tetrahydrofuran, 1, 4 one Jiokisan, benzene, toluene, Aniso Ichiru, Asetonitoriru, N, N-dimethylformamide, etc.) in, radical scavengers (e.g., benzene, toluene, Aniso Ichiru etc.) presence or absence of a compound represented by the general formula (6), Okishiharogen potash emissions (e.g., Okishi phosphorus chloride, Okishi oxybromide, etc.) or halogenated phosphorus (e.g., Sanshioi匕 phosphorus, by reaction with phosphorus pentabromide, etc.), it is possible to obtain a compound represented Ru by the general formula (7). Specifically, for example, the solution in the reaction solvent Okishiharogen phosphorus or phosphorus halide, the addition of the general formula (6) compounds represented by, heated and stirred.

After completion of the step 1-3, the resulting formula (7) similar reaction a compound represented by the manufacturing how 4-1 later in (but is reaction of acrylic acid derivatives in place of Jiamin compound) after subjected to. deprotection reaction, obtained by further reaction with I 匕合 compound represented by the below-described formula (18), the compound one X = Y- is an CH = CH- Rukoto can. Moreover, by reducing the compound obtained one X- Y- is one CH 2 - can be obtained in the I匕合product - CH 2.

Step 1 one 4

Polar solvent (e.g., methanol, ethanol, isopropanol Ichiru, Jimechirusu sulfoxide, etc.) in compound hydrazine compound represented by the general formula (7) (e.g., hydrazine, etc.) by reacting under reflux a general formula can be obtained represented by I 匕合 product (8). Specifically, for example, the solution in the reaction solvent of hydrazine compound, was added the general formula (7), compounds represented by heating and stirred.

Step 1 - 5

Aprotic solvents (e.g., acetic Echiru, black hole Holm, Asetonitoriru etc.) in a base (e.g., Toryechiruamin, pyridine, etc.) the presence of the azide agent with the compound represented by the general formula (9) (e.g., diphenyl enyl azide (DPPA), by reacting with sodium hydride) to obtain a compound represented by the general formula (10). Specifically, for example, the solution in the reaction solvent a compound and a base represented by the general formula (9) was added azide agent, and stirred.

Further, the compound represented by the general formula (10), after leading the compound represented by the acid anhydride or acid halide with the general formula (9), also obtained by connexion to that the action of azide agent be able to. Further, a compound represented by the general formula (9) after was guide, the hydrazide can be obtained even cowpea to Jiazo of. Compound represented by the general formula (9), or a commercially available product, or, for example, the following A - can be used after synthesized by or L way..

Alpha · - the compound represented by the general formula (9) (carboxylic acid derivative) can be obtained by acid 'or Al force Li hydrolysis of the ester derived thereof.

. B alkoxyalkyl benzoate desired:.. ^ Include, for example, analogously to literature Helv Chim Acta, 1 9_ (1 9 9 6) 1 9 6 7 The method described, an alkyl benzoic acid ester ether N- a halogeno-succinimide, methyl formate, ester solvents such as acetic Echiru; solvent under or carbon tetrachloride, light or 2, 2-§ zone bis isobutyronitrile Petit Roni preparative drill presence of a catalyst, is reacted under heating. The resulting halogenoalkyl acid ester le, alcohol solvents such as methyl alcohol; tetrahydrofuran, ether solvents such as Jiokisa emissions; or N, N- dimethylformamide, determined such as a metal alkoxide in a solvent under such as dimethyl sulfoxide nucleating agent at room temperature or is heated under reaction. The resulting alkoxyalkyl benzoates by subjecting to the method of A., can be obtained alkoxyalkyl benzoate Nozomu Tokoro.

. C in the case of 2-halogeno one 6-alkoxy-pyridin one 4-carboxylic acid is desired, 2, 6-di halogenopyridine one 4-carboxylic acid, § alcohol solvents such as methyl alcohol; tetrahydrofuran, etc. Jiokisan E one ether solvents; or N, N- dimethylformamide, dimethyl sulfoxide, in a solvent under such as toluene, by reacting a nucleophile with room temperature or under heating, such as a metal alkoxide, desired 2-halogeno-one 6- alkoxy it can be obtained pyridine one 4-carboxylic acid.

. D 2-halogeno _ when 6-alkyl or § Li one Rubirijin one 4-carboxylic acid is desired, the methyl ketone with a corresponding alkyl or Ariru group, alcohol solvents such as methylmercury alcohol; tetrahydrofuran, Jiokisan etc. of E - ether based solvents; ketone solvents such as Aseton; or N, N-dimethyl formamidine de, dimethyl sulfoxide, under a solvent such as toluene, sodium methoxide, Jechiru oxalic acid in the presence of a strong base such as hydride Natoriumu is reacted with oxalic acid esters etc., shed, obtain § over diketo acid ester. Tetrahydrofuran, ether solvents such as di Okisan; Konohi, alcohol solvents such as methyl alcohol an Jiketokarubon ester § ketone solvents such Aseton; or N, N-dimethylformamide, dimethyl sulfoxide, a solvent such as toluene lower, Toryechirua Min, piperidine, potassium carbonate, in the presence of a base such as sodium carbonate, is reacted under heating with Shianoa acetamide. The resulting 2-Hidoro 3- Shiano one 6-alkyl le or § reel pyridine _ 4 Ichiriki carboxylic acid ester, concentrated hydrochloric acid, heated under a strong acid such as sulfuric acid, by de Shiano reduction, 2-hydroxy-6 - alkyl or § Li one Rupirijin one 4-force carboxylic acid is obtained. 2-hydroxy one 6-alkyl or § reel pyridine one 4-carboxylic acid, Toryechiruamin, Jimechiruani phosphorus, tetra-alkyl ammonium Niu arm halide, N, the presence of a catalyst such as N- dimethylformamide, Okishi phosphorus chloride, phosphorus trichloride, phosphorus pentachloride, Okishi oxybromide, phosphorus tribromide, by reacting under heating with a halogenating agent such Gonioii匕 phosphorus, the desired 2-halogeno-_ 6 alkyl or § Li one Rubirijin one 4- carboxylic it is possible to get the acid.

E. 2 when primary alkyl or § Li one Ruchiazo one Roux 4- carboxylic acid is desired, the Chioamido with the corresponding alkyl or Ariru group, shed one Keto ^ Doha Rogenokarubon ester and alcohol such as methyl alcohol solvent; as tetrahydrofuran, ether solvents such as Jiokisan; or N, N-dimethylformamide § bromide, dimethyl sulfoxide, by heating under solvent such as toluene, 2-alkyl or § Li one Ruchiazo one Roux 4- carboxylic acid give the ester. The resulting 2-alkyl or § Li one Ruchiazoru 4-carboxylic acid ester by subjecting to the method of A., the desired 2 primary alkyl or § Li one Ruchiazoru - can be obtained 4 one carboxy phosphate.

. F If Chiofen one 2-force carboxylic acid derivative is desired, a hydrocarbon solvent cyclohexane and the like of the corresponding 2-hydrate Rochiofen; tetrahydrofuran, ether solvents such as Jiokisa emissions; or a solvent such as dimethyl sulfoxide lower, Puchirurichiu arm, with a strong base such as metal Natoriumu, under cooling, to produce a 2-main evening Le thiophene. By adding carbon dioxide to this, it is possible to obtain a desired Chiofen one 2 Ichiriki carboxylic acid derivative thereof.

Also, 2-if Horumiruchiofu Kon derivative is available, Al force Li of aqueous solution under nitrate or weakly basic aqueous solution under even cowpea to the action of sodium chlorite in 2-formyl thiophene derivatives it is possible to obtain.

G. If Chiofen one 3-force carboxylic acid derivative is desired, to obtain the corresponding 3-formyl-thiophene derivative, an aqueous alkaline solution under 硝麵 or weakly basic aqueous solution under by the action of sodium chlorite be able to.

. H 2 halogenoalkyl Chio phen one 4 - when the carboxylic acid derivative is desired, the corresponding 2 Hidorochiofen one 4-carboxylic acid or its ester, sulfuryl chloride, Harogeni 匕剤 such Kanioii 匕臭 of Pirijiniumu by the action of, obtaining 2 one halogenoalkyl Chio phen one 4 Ichiriki carboxylic acid or an ester thereof. When using the ester, by subjecting to the method of A., it is possible to obtain the desired 2-halogeno-Chio phen-4-carboxylic acid derivatives.

I. 2- formyl if mill thiophene one 4-carboxylic acid is desired, using the reaction conditions of F. 2-halogenocyclopropyl Chio phen one 4-force carboxylic acid derivative obtained in H. Manner, carbon dioxide Alternatively N, it is possible to get using N- dimethylformamide.

J 2 -. When (Jifuruoromechiru) Chiofen one 4 or 5 carboxylic acid is desired, the corresponding 2-formyl-thiophene one 4 or 5 force carboxylic acid ester derivative is allowed to act Jechiruamino sulfur trifluoride, resulting resulting 2- can be obtained by subjecting the (di Furuoromechiru) Chiofen one 4 or way of A. 5-force carboxylic acid ester derivative.

K. 2, 5 when disubstituted Chiofen one 3-carboxylic acid is desired, the corresponding 2, 5-disubstituted Chiofen presence of a halogenating agent such Okishi Shioi匕 phosphorus, under heating, N , it reacted with N- dimethylformamide, 2, to obtain a 5-disubstituted one 3-formyl Chiofen. The resulting 2, 5-disubstituted over 3-formyl thiophene by subjecting to the method of G., desired 2 can Rukoto give 5-disubstituted Chiofen one 3-carboxylic acid.

. L 1 or 2-alkyl pyrazole - when 3-carboxylic acid is desired, a corresponds to pyrazole one Roux-3-carboxylic acid esters, alcohols one Le solvents such as methyl alcohol; tetrahydrofuran, ether such Jiokisan solvent; ketone solvents such as Aseton; or N, N- dimethylformamide, a solvent under such as dimethyl sulfoxide, Toryechiruamin, piperidine, potassium carbonate, in the presence of a base such as sodium carbonate, alkyl halide such as methyl iodide and by reacting at room temperature or under heating, resulting in a mixture of 1 primary alkyl pyrazole one 3-carboxylic acid ester with 2-al Kirupirazo one Roux-3-carboxylic acid ester. The resulting mixture was made minute by subjecting to the process of each A., it is possible to obtain the desired 1 or 2 Arukirupirazo Ichiru one 3-carboxylic acid.

Step 1 one 6

Aprotic solvent (e.g., acetic Echiru, black hole Holm, benzene, toluene, etc.) in, by heating and stirring the compound represented by the general formula (10), Kuruchiu scan dislocation occurs, the general formula (11) it is possible to obtain a compound represented by. Specifically, for example, the solution in the reaction solvent of the compound represented by the general formula (10) heated and stirred. Further, the compound represented by the general formula (11) may be a compound represented by the general formula below (18), phosgene derivative (e.g., phosgene, diphosgene, etc.) obtained by the this the action of.

The compound represented by the general formula (11) without isolation, can be used in the next step.

Step 1 one 7

Aprotic solvents (e.g., tetrahydrofuran (THF), 1, 4-Jiokisa emissions, benzene, toluene, Asetonitoriru, N, N-dimethylformamide, etc.) in the general formula the compound represented by the general formula (8) (11 by reaction with a compound represented by), it is possible to obtain a compound represented by the general formula is one of the target compound (1 1). Specifically, for example, by adding a solution in the reaction solvent of the compound represented by the general formula (8) To a solution of reaction solvent of the compound represented by the general formula (11), to 撹 拌.

In general formula (1 1) compound and W is different from compounds represented by may be prepared by the following manufacturing method.

W is a single bond, and the compounds of the general ring A is pyridyl group formula (1) is an aprotic solvent (e.g., tetrahydrofuran, 1, 4 one Jiokisan, benzene, toluene, Asetonitoriru, N, N-dimethyl formamide, etc.), the general formula (the compound represented by the compound represented by the general formula 8) (10) (wherein ring a can be obtained by reacting a pyridyl group).

W is a single bond, and the compound of formula ring A is a phenyl group (1) is, in an aprotic solvent (e.g., tetrahydrofuran, benzene, black hole Holm, N, N-dimethylformamide, etc.), base (e.g., pyridine, Toryechiruamin etc.) the presence of the general formula represented by formula (8)

C1

In represented it can be obtained by reacting a compound.

W is - CONH- compound of the general formula (1) in which, in a reaction solvent (e.g., tetra hydrofuran, 1, 4 one Jiokisan, benzene, toluene, methanol, etc.), a base (e.g., sodium hydroxide, lithium hydroxide , sodium hydride, lithium Suisoi匕, the presence of sodium methylate, etc.), a compound represented by the general formula (8), the general formula

In represented it can be obtained by reacting a compound.

W is one CH 2 - compound of a is Formula (1) has the general formula

The, W is - 0- compound of the general formula (1) is the general formula

A compound represented by the general formula (8) and can be obtained by reacting, respectively. Another aspect X- Y- gar NH- is NH-, and the compounds of the general formula Z and W is a single bond (1) is higher compound represented by reactive by formula (8) Heteroari - Ruharaido (e.g., 2-halogeno-benzimidazole Ichiru etc.) can be obtained by reacting with.

Other one X = Y- is an N double N-, and compounds one Z- W- is an CO- Nyuita- general formula (1) is a non-aqueous solvent or aqueous solvent, a base ( for example, pyridinium Jin, the presence of a hydroxide Natoriumu etc.), the general formula (acid agent to the compound represented by the 1-1) (e.g., N- pro succinimide, is obtained Rukoto by the action of bromine) it can.

Also, instead of the compound represented by the general formula (11), the general formula (19) you express compounds and also with an equivalent thereof, it can be carried out step 1 one 7. For example, the Aminojikuro port pyrimidine, lithium butyl, after the action of a strong base such as Suisoi匕 sodium, by performing the black hole Horumirui spoon with triphosgene, equivalents of the compound represented by Formula (1 9) can get. The compound or represented by the general formula (19) the equivalent, by reaction with I 匕合 compound (8) can be obtained I 匕合 product (1-1).

Production method 2: - general formula of (1) (X, Y, Z, W) is, (-CH 2 -, one NH-, one CO-ヽone NH-), (-CH 2 -, one 0- , -CO-, - NH-) and (- CH =, = N-, one 0-one CO- or - C0NH-) producing how the compounds are

Step 2-1

Aprotic solvents (e.g., tetrahydrofuran, 1, 4-Jiokisan, cyclohexane and the like Jefferies Chirueteru,) in a strong base (e.g., n- butyl lithium, ter t one-heptyl lithium, sec- heptyl lithium, etc.), or aralkyl force Li metals (e.g., metal lithium, etc.) Horumirui the presence formylating agent (e.g., N, N-dimethylformamide § bromide, hexamethylene tetramine or the like Horumirupi Bae lysine to) represented by the general formula (7) compounds by the by spoon, it is possible to obtain a compound represented by the general formula (12). Specifically, for example, the solution in the reaction solvent of the compound represented by the general formula (7), after added Caro a strong base or an alkali metal, added Horumirui 匕剤, heated and stirred.

After the end of step 2 1, (for example example, Sojiumu, borohydride etc.) a reducing agent a compound represented by the obtained formula (12) after reduction with a compound represented by this general formula (11) by reacting, X is one CH 2 -, Y Gar 〇 one, Z gar CO-, it is possible to obtain a compound of W Gar NH- in which general formula (1).

Step 2 - 2

Polar solvents (e.g., main Yunoichiru, E evening Roh Ichiru, isopropanol Ichiru, 1, 4-di Okisan, tetrahydrofuran) or a mixed solvent of the water, a base (e.g., potassium carbonate, sodium carbonate, potassium Mizusani匕, sodium Mizusani匕, the presence of pyridine, etc.), the general formula (12) compound represented by the hydroxyl § amine such compounds (e.g., by reaction with hydroxyl § Min hydrochloride, etc.) , it is possible to obtain a compound represented by the general formula (1 3). Specifically, for example, stirring the solution in the reaction solvent a compound and a base represented by the general formula (12).

After step 2 2 ends, a base (e.g., pyridine, Toryechiruamin etc.) I the presence of a compound represented by the obtained formula (13), represented by Ashiruharaido or formula (1 1) spoon by reaction with compounds, X is one CH =, Y is = N-, Z is one 0-, W can be obtained an C 0- or one C 0 NH- compounds wherein. Step 2 - 3

By reducing the compound represented by the general formula (13) in a conventional manner, it is possible to obtain a compound represented by the general formula (14). The reduction method is being variously include, for example,

(1) acid solvent (e.g., acetic acid, etc.) in a reducing agent (e.g., zinc, iron, etc.); (2) an alcoholic solvent (e.g., methanol, ethanol, etc.) in sodium metal, platinum oxide and the like; ( 3) in an alcoholic solvent in the presence of a black hole Holm, platinum oxide or the like, and a method of reduction. Specifically, for example, the general formula (13) compound represented by the reducing agent, and stirred suspended in an acid solvent.

Step 2 - 4

In a similar manner to Step 1 one 7, by reacting I 匕合 compound represented by the compound represented by the general formula (14) and the general formula (11), the general formula is one of the target compound (1 it is possible to obtain a compound represented by -2). Production method 3: - X of general formula (1) is - 0-, Y is -NH-, Z gar CO-, process for the preparation of compounds where Z gar NH-

Step 3 - 1

Polar solvent (e.g., tetrahydrofuran, 1, 4 one Jiokisan, benzene, preparative Ruen, methanol, N, N-dimethylformamide, etc.) in a strong base (e.g., t Ert--butoxy potassium, sodium methoxide, sodium hydroxide, water acid lithium, sodium hydride, lithium hydride, n- exist below, the compound N-protected hydroxy § amine compound represented by the general formula (7) such as butyl lithium) (e.g., Echiru N- hydroxy § Se thymidylate dating by reacting with an equal), it is possible to obtain the I 匕合 of the general formula (1 5). Specifically, for example, the solution in the reaction solvent of N-protected tetrahydroisoquinoline Kishiamin compound, after addition of a strong base, the general formula (7) represented Ru compounds stirred added.

Step 3 - 2

Polar solvent (e.g., methanol, ethanol, tetrahydrofuran, etc.) mixed solvent of water or its acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, etc.) using, represented by the general formula (1 5) spoon the compound by hydrolysis, can be obtained I spoon compound represented by the general formula (16). Specifically, for example, the solution in the reaction solvent of the compound represented by the general formula (15) is stirred by adding an acid.

Step 3 - 3

In a similar manner to Step 1-7, by reacting a compound represented by the compound represented by the general formula (16) and the general formula (11), the general formula is one of the target compound (1 -3) in can be obtained a compound represented by.

Production method 4-7

Production Method 4

Made by

Step 5-1

(U) (1-5)

Production Method 6

(Wherein, RRR 3, RRRA and X 1 are as defined above, Ph is phenyl group, R 12 'is C 2 _ 6 alkoxycarbonyl group, substituted Moyoi Ararukiruokishi force carbonyl group or substituted it is also good Ariruokishi carbonyl group, R 14 'is an alkyl group or to Teroari Ichiru (^ one 8 Al kill groups (^ over 8, R 14 "is optionally substituted Araru Kiruokishikarubo alkenyl group or an optionally substituted good I § reel O alkoxycarbonyl group)

Production Method 4: general formula (1) X gar NH-; Y gar CH 2 - or a single bond; Z is -

'CH 2 - or a single bond; W is - method of manufacturing NH-, compound

Step 4-1

Literature (J. Org. Chem., 7240 (1996)) in the same manner as in (if example embodiment, tetrahydrofuran, 1, 4 one Jiokisan, benzene, toluene, dimethoxyethane Kishetan etc.) aprotic solvent, palladium metal and 2 , 2- bis (diphenyl phosphate minus Roh) - 1, 1, - the presence of mixed insect pollination and excess of a strong base and a ligand such as binaphthyl (e.g., t Ert- butoxy sodium, etc.), the general formula ( compounds of di Amini 匕合 compound represented by 7) (e.g., hydrazine, Mechirenjiamin by reaction with Echirenjiamin etc.), it is possible to obtain a compound represented by the general formula (17). Step 4 one 2

A compound represented by the general formula (17), at step 4-1 the same way, by reacting with the compound represented by Formula (1 8), the general formula is one of the target compound (1 it is possible to obtain a compound represented by the -4).

Production method 5: - X of general formula (1) is - CH 2 -, Y Gar NH-, Z is - CO-, W is one NR 14 '- (wherein, R 14' is a as defined above manufacturing process step 5) of compounds wherein - 1

Aprotic solvents (e.g., tetrahydrofuran, 1, 4-Jiokisan, benzene, toluene, Asetonitoriru, N, N-dimethylformamide, etc.) in the compound represented by the general formula (14), literature (Synth. Commun. 26, 331 (1996)) and by reacting with the compound represented by formula (19) obtained in a similar manner, the general formula is one of the purposes compound (1 one 5) to give compound. Note that in this reaction, instead of the compound represented by the general formula (19), For example, the general formula (22) (22)

(Wherein, R 14 'has the same meaning as defined above) can also be used carbonyl halide equivalents represented by.

Production method 6: - X of general formula (1) is - CH 2 -, Y is - N (R 12 ') one (wherein, R 12' are the same as defined above), Z is _C_〇 one, W manufacturing process steps of the compound is a guard NH- 6 - 1

Aprotic solvents (e.g., tetrahydrofuran, 1, 4-Jiokisan, benzene, toluene, etc.) in the general formula (1-2) with a base a compound represented (e.g., n - heptyl lithium, sec- butyl lithium, after t Ert- butyllithium, etc.) and reacted table by formula (1-6) is more to react with Ashiru agent represented this in general formula (20), one of the target compound it can be obtained the compound.

Production method 7: - general formula (1) X gar CH 2 of -; Y is - N (R 14 ") - (R 14" has the same meaning as before Symbol) or a NH-; Z is one CO- ; W gar N (R 14 ") - the production method of (R 14" are as defined above), compound

Step 7 - 1

Aprotic solvents (e.g., tetrahydrofuran, 1, 4-Jiokisan, benzene, toluene, etc.) a strong base a compound represented by the middle ヽ formula (1- 2) (e.g., lithium tetramethyl disilazide etc.) after reacting, which by reacting with Ashiru agent represented by the general formula (21), the general formula (1 one 7) and (1-7) by obtaining the I 匕合 compounds represented can.

Example

Hereinafter is a description of specifics of the present invention to examples, the present invention to these examples

Not intended to be P Ushitorajo. Further, in the table, a single bond is "single", "n- Pro" is n one propyl group, "i-Pro" is an isopropyl group, the term "n- But" n- butyl group, "i one Bu "and" What is the i- Butj Isopuchiru group, "tBu" and "t one

But "The t ert- heptyl group," n- Pen "is n- pentyl group," i- P en "The isopentyl group," n- Hex "is a hexyl group to n-," n- Hep "the Puchire group to n-, the" n- Oct "means n- Okuchiru group, phenylene and" Ph "Les group," Ac "means Asechiru group, the term" Bn "a benzyl group.

Example 1

N- (1 H-4- isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pin lysine one 6- I le) amino-N, - (2, 6-dichloropyridine one 4 f le) Urea

Step 1 one! :: A) 5_ amino-1, 3-dimethyl Vila tetrazole (4)

Over § Mino crotononitrile the (2) (253.28 g) and methyl hydrazine (3) (142. 10 g) was dissolved in isopropanol (0. 9 L), gently heated to reflux the solution in a nitrogen stream between 4:00 did. The reaction solution was concentrated, further azeotroped I isopropanol in toluene to give humbly product (310 g). To this toluene (1 L) was added, dissolved by heating, by treating with activated carbon (31. 1 g), 5-§ minnow 1, 3-dimethyl Vila tetrazole (4) (268. 74 g) as a pale It was obtained as a brown crystals. Without further purification crystal was used in the next reaction.

Step 1- 2: b) 1H- 6- hydroxy one 4-isopropyl one 1, 3-dimethyl-pyrazole port [3, 4-b] pyridine (6)

Propionic acid (3 62 mL) solution of Echiru isobutyryl acetate (5) (382. 50 g), 5-Amino one 1 obtained in a) of 麵例 1, 3- Jimechirubi Razoru (4) (268. 74 g) was dissolved, it was heated under reflux for 23 hours. After cooling, acetic acid Echiru the (1. 3L) and the mixture was heated under reflux for 1 hour. After slow cooling, was collected by filtration and the precipitated crystals were washed with acetic acid Echiru by ffi drying, 1H-6- hydroxy one 4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4 one b] pyridine ( 6) (9 1. 36 g) as white crystals.

Step 1- 3: c) 1H- 6- promoter 4-isopropyl one 1, 3-Jimechirupira Zorro [3, 4-b] pyridine (7)

Okishi the Aniso Ichiru (250 mL) solution of phosphorus tribromide (100 g), Example 1 b) obtained in 1H_ 6- hydroxy one 4-isopropyl one 1, 3-Jimechirubi Razoro [3, 4- b ] was dissolved in pyridine (6) (48. 67 g), under an oil bath at 130 ° C, and stirred for 3 hours. After cooling, toluene (400 mL) was added, under ice-cooling, water was added by reacting Okishi bromide phosphorus ¾]. After washing the organic ¾ϋ in 1 New carbonate forces potassium and saturated Japanese brine, dried over magnesium sulfate and concentrated, 1H-6 - promotion 4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridine down the (7) (1 18. 66 g) as an oil. Things Ku purifying this ffi preparations, was used in the next reaction.

Step 1- 4: d) 1H- 6- hydrazino one 4-isopropyl one 1, 3-dimethyl-pyrazole port [3, 4-b] pyridine (8)

Hydrazine in ethanol (23 OML) solution of (113 mL), Example obtained in 1 c) 1 H- 6- bromo-4 Isopuropiru one 1, 3-dimethyl-pyrazolo [3, 4-b] pyridine (7) dissolving crude 鏞製 product (1 18. 66g), under an oil bath at 110 ° C, and 23 hours heating 攪袢. After allowing to cool, the mixture was stirred for 4 hours in an ice bath, precipitated IH-6-Hidorajino 4 f an isopropyl one 1, was collected by filtration 3- dimethyl Vila Zorro [3, 4-b] manufacturing of pyridine (8). After washing it with 50% aqueous ethanol solution, by Ji dried at 60 ° C, 1H-6- hydrazino one 4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridine (8) (39 . was obtained 45 g) as white crystals.

Step 1- 5: e) 2, 6- dichloro port pyridine one 4- carbonyl azide (10)

2, 6-dichloro-isonicotinic acid (9) (40. 45 g) and dissolved Toriechiruamin the (3 8 mL) in acetic acid Echiru (4◦ OmL), under cooling with ice added dropwise DPPA (50 mL) to the solution and it was stirred at room temperature for 20 hours. Acetic acid Echiru added, diluted and washed with water and brine. After drying the over magnesium sulfate, and concentrated to give 2, 6 Jikuro port pyridine one 4 crude product of one carbonyl azide (10) and (70. 80 g). The crude crystals were dissolved in acetic acid Echiru, by treatment with activated carbon, 2, 6-dichloropyridine one 4- carbonyl azide (10) and (45. 67 g) was obtained as crystals.

Step 1-6 and 1-7: f) N- (1H- 4- isopropyl one 1, 3-dimethylcarbamoyl Rubirazoro [3, 4-b] pyridine one 6- I le) Amino one N '- (2, 6- Axis Roropirijin one 4-I le) urea (1 1) 2 obtained in e) of example 1, 6-dichloro port pyridine _ 4- carbonyl azide (10) (42.41 g) in toluene (41 OML) construed volume, and the solution was stirred for 4 hours at 100 ° C (11). After cooling, this «Example 1 d) 1H-6- hydrazino one 4 one isopropyl one 1 obtained in 3-dimethyl Vila Zorro [3, 4-b] pyridinium Jin (8) (39, 45 g THF (41 OML) was added and) the mixture was stirred at room temperature for 18 hours, and concentrated to give the coming 膽製 product (129. 59 g). This acetate Echiru - THF: was dissolved in (5 1), after treatment with activated carbon, Ri by the recrystallization with acetic Echiru, N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridine one 6- I le) Amino one N, - (2, 6-dichloropyridine one 4-I le) urea (1 1) (to give a 42. 74 g) as white crystals.

¾-NMR (300MHz, dppm 5 CDCl 3)

1.33 (6H 3 d, J = 6.8Hz), 2.62 (3H 5 s) 5 3.54 (lH 3 septet 3 J = 6.8Hz) 3 3.91 (3H, s) 5 6.43 (lH

, S), 6.45 (1H, S), 6.57 (1H, S), 7.50 (2H, S), 8.10 (1H, S)

FAB (+) MS (low resolution, m / z) 408

mp 222-225 ° C

Example 1 one 2~: L- 235

To give the compound of Example 1-2-1-235 in the same manner as in Example 1. The resulting reduction compound Table 1; shown in I 3.

However, Example 1-2 to: Among 1-235 compound, X is one NH-, Y gar NH -, Z is - for NH- in which I 匕合 compound other than the compound - CO- and W , as follows, the method of example 1, by connexion was produced or a method in which the part with the modification that analogous thereto.

With respect to Example 1 2, the general process steps 1- 4 (hereinafter, omit the "general method", illustrated only stroke number) Contact the L Te, using methylhydrazine instead of hydrazine, X is an NMe- compound of the general formula (8) (hereinafter, I 匕合 compound (8) and be substantially) was obtained. To give the desired compound subjected this to step 1 one 7.

With respect to Examples 1-5, with Raney one Nidzuke Le compound (8) before performing the step 1-7, and stirred under heating, - X- Y to obtain a compound of an NH 2 (8). This more E subjected to 1 one 7 to obtain the desired compound. With respect to Example 1-11, the compounds of the general formula (11) in the stroke 1-7 (hereinafter, 匕合 compound (11) and abbreviated) instead, by there use the corresponding thio iso Xia sulfonate compound to obtain the desired compound.

Example 1-16, with respect to 182 and 183, stroke 1 - compound in 7 instead of (1 1), to obtain the desired compound by using a benzylisothiocyanate Xia sulfonate compound.

With respect to Example 1 17, without going through the step 1-6, instead of the compound (11), to give the desired compound Rukoto using the corresponding 4-morpholinylcarbonyl chloride in the presence Toriechiruamin .

With respect to Example 1 one 25, using 3-black port phenyl acetate instead of I 匕合 compound (11), to obtain the desired compound by performing the method of stroke 1 one 7 appropriately.

With respect to Example 1-36, the compound obtained in Step 1-4 (8), to obtain the desired compound by subjecting the stroke 5-1 in place of the compound of general formula (14) described above. However, in the step 5-1, using a carbonic acid diester derivative of the corresponding place of the carbonic acid derivatives of general formula (19).

With respect to Example 1 one 61 and 62, I 匕合 object in stroke 1 one 7 (11) to the cash forte, using benzoyl chloride compound, is then related Similarly to compound 1 one 70 and 71, 3- pyridine to give the desired I 匕合 product with carbonyl chloride.

With respect to Example 1-63, stroke 1 - instead of the compound in 7 (11), one general formula

In a compound with shown to give N, N-dimethylformamide in the presence of hydroxybenztriazole Toriazo Ichiru, the desired compound by a condensation reaction with hexyl carbonitrile Jie bromide dicyclohexyl.

Example 1-64, with respect to 1 one 65 and 1-66, the target compound was obtained according to the manufacturing method 4.

With respect to Example 1-67, with Raney one two Uz Kell compound (8) before performing the step 1-7, and stirred under heating, - give X- Y is an NH 2 Compound (8), This compound was obtained by the subjecting more E 4 one 2.

With respect to Example 1-68 to give Compound 1 one 67 to force Π water splitting in an alkaline Therefore the object I 匕合 thereof.

Example 1 one 69, with respect to 1-90 and 1 one 91, respectively, Example 1 one 4 4, the compound obtained in 1 82 and 1 one 1 stroke 1 - with the dehydrogenation reaction to serial 7 to give the desired compound Succoth.

With respect to Example 1-73, Y used in the Example 1 one 5 a single bond of the compound (8) to give the desired compound a compound represented by the general formula (19) is reacted. With respect to Example 1 one 229, before performing the step 1 one 7, compound (8) tetra hydrofuran, the presence of Toriechiruamin, after reacting with black port formic acid Echiru, step a compound obtained 1 - to obtain the desired compound by subjecting to 7.

With respect to Example 1-231, the general formula of the compound and 3-Amino one 2-hydrate proxy benzoic acid methyl ester (7), tris dibenzylidene § Seto Nji palladium, 2, 2 '- bis (diphenyl phosphine Ino) one 1, 1, the presence of one binaphthyl and ter t-butoxy sodium, by toluene and tetrahydrofuran, are reacted under heating, benzoic acid methyl ester. This derivative in alkaline is hydrolyzed to give the benzoic acid derivatives. Furthermore the compounds represented by the benzoic acid derivative general formula (18), the presence of hydroxybenztriazole azo Ichiru, in dimethylformamide, to obtain a more objective compound to condensation reaction with dicyclohexylcarbodiimide.

Table one 1

Table one 2

Table one 3

Table one 4

Table one 5

8

9 over 辇

.8TS0 / I0df / X3d T0C86 / 10 OAV table one 7

Table one 8

Table one 9

Table one 1 0

Table one 1

Table one 1 2

Table one 13

Example 2

N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pin lysine one 6- I le) amino-N, - (2, 6-dichloropyridine one 4-I le) Urea methane sulfonate

Obtained in Example 1 N-(1H-4-isopropyl one 1, 3-Jimechirubirazo port [3, 4-b] pyridine one 6- ^ gamma Le) amino-N, one (2, 6-Jikuroropiri Gin one 4 - a I le) urea (386 mg) was dissolved during hot in acetone (2 mL), cooled to room temperature, it was added methanesulfonic acid (65〃L), and allowed to stand for one day at room temperature. Resulting crystals were collected by filtration, followed by drying, N-(1H-4-isopropyl one 1, 3-Jimechirubirazo 'mouth [3, 4-b] pyridine one 6- I le) Amino one N, - (2 to give 6-dichloro port pyridine one 4-I le) urea methanesulfonate (376m g).

¾-NMR (300MHz 5 dppm 5 DMS0) 1.26 (6H, d 3 J = 6.8Hz) 3 2.39 (3H, s) 3 2.49 (3H 3 s) 3 2.50 (3H 5 s) 3 3.44 (lH 5 septet 3 J = 6.8

Hz), 6.39 (lH, s ), 6.96 (2H, br.s), 7.81 (2H 5 br.s) 3 8.87 (lH, br.s)

mp 178-179 ° C

Example 2 - 2 to 2 - 24

In the same manner as in Example 2 to give the compound of Example 2 2~2- 24. The resulting reduction compound shown in Table 14 and Table 15.

Table one 14

Table one 15

Example 3

N-(111- 4 Isopuropiru one 1, 3-dimethyl-Vila Zorro [3, 4-b] pin lysine one 6- I le) methyl-N, one (2, 6-dichloropyridine one 4-I le) Urine step 2- l: a) 1H- 4- isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4 one b] pyridine one 6- Iruarudehido (12)

1H-6- Promo one 4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridine (7) was dissolved (10. 91 g) in THF (16 OML), dry ice down one ethanol bath in, it was added dropwise to this solution n- butyllithium in n- hexane solution (3 2. 5mL). After dropping 5 minutes, N, N-dimethylformamide (4. 7 mL) was added and 2.5 hours 攙拌 under dry ice one ethanol bath. Saturated chloride Anmoniumu solution was added, and 攪袢 at room temperature. The resulting organic layer was washed with saturated chloride Ann Moniumu solution was washed with saturated brine. This was dried over magnesium sulfate and concentrated reduced to give a dark brown oil (8. 85 g). By which is purified on silica gel force ram, 1H-4-isopropyl one 1 to give 3-dimethylamino Vila Zorro [3, 4-b] pyridine one 6- Iruarudehido the (12) (3. 65 g). Step 2- 2: b) 1H- 4- isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4 - b] pyridine one 6- Iruarudokishimu (13)

1H-4 one isopropyl one 1 obtained in a) of Example 3, 3- Jimechirubirazo port [3, 4-b] pyridine one 6- Iruarudehido (12) (3. 65 g) hydro Kishiruamin hydrochloride (2. 41 g) and potassium carbonate (2. 4 g) was dissolved in a mixed solvent of ethanol and (70 mL) and water (35 mL), which was 3 days stirred at room temperature. To this acetic acid Echiru added water and washed with brine. After drying over sulfate Maguneshiu beam recrystallization with Isopuropirue one ether and the resulting crude crystals was concentrated, 1 H- 4 one isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pin lysine one to give 6- Iruarudokishimu a (13) (2. 47 g).

Step 2- 3: c) 1H- 6- aminomethyl one 4 one isopropyl one 1, 3-dimethylcarbamoyl Rubirazoro [3, 4-b] pyridine (14)

Example 3 b) obtained in 1H-4-isopropyl one 1, 3-Jimechirubirazo 'mouth [3, 4-b] pyridine one 6- Iruarudokishimu the (13) (2. 48 g), zinc (6. It was suspended in acetic acid (85 mL) in the presence of 98 g), and the suspension was stirred for 1 hour under a water bath. Zinc was removed by filtration through Haifurosu one parcel, the filtrate was concentrated. The concentrate was diluted with acetic acid Echiru, washed with 1N potassium carbonate and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated, 1H-6- aminomethyl -4 one isopropyl one 1, 3-dimethyl-pyrazolo [3, 4-b] pyridine (14) (0.

79 g) as a pale yellow oil.

Step 2 - 4: (1) ^ chromatography (111-4 Isopuropiru one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridine one 6- I) methyl one N '- (2, 6-dichloropyridine one 4 one I le) urea (1 one 2)

1H-6- Hidorajino 4 one isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] instead of pyridine (18) was obtained in c) of Example 3 1H-6- § Minomechiru one 4- isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] except using pyridinium Jin (14) of example 1: Π a similar manner, N-(IH-4-isopropyl one 1, 3- dimethyl Vila Zorro [3, 4-b] pyridine one 6- I) methyl one N '- (2, gave 6- dichloropyridine one 4-I le) urea (1 2).¾-NMR (300MHz, dppm 5 CDCl 3)

1.36 (6H, d, J = 6.9Hz), 2.68 (3H, s), 3.60 (lH, septet, J = 6.9Hz), 3.94 (3H, s), 4.65 (2H, d, J = 4.8Hz), 6.30 (lH, s), 6.89 (lH, s), 7.42 (2H, s), 8.10 (lH, s)

FAB (+) MS (low resolution, m / z) 407

mp 233-236 ° C

Example 3 - 2~3-33

In the same manner as in Example 3, to give the compound of Example 3 2 3 33. The resulting reduction compound shown in Table 16 and Table 17.

However, among the I匕合of Example 3- 2~3- 33, X is - CH 2 -, Y is - NH -, Z is - for NH-, compound other than the compound - CO- and W , as follows, the method of example 3, by Ri was prepared in a method or process, a part was modified with analogous thereto.

For the ¾5¾ Examples 3-2 and 3-3, respectively, after the step 2-2 ended, the compounds of general formula (13) (hereinafter, I 匕合 compound (13) and abbreviated), the benzoyl chloride compound or compounds (11) were obtained using a.

With respect to Examples 3-7 and 3-8, after the step 2-2 finished, give I 匕合 of the general formula (12) the corresponding alcohols by reduction with borohydride Natoriumu, this higher E 2 - to obtain the desired compound by subjecting to 4.

With respect to Examples 3-9 and 3-10, by performing a Heck reaction with a compound of the general formula (7) and Echiru acrylic acid to give the acrylic acid ester derivative. This is then hydrolyzed with Al force Li and Akuriru acid derivative, further a compound of this derivative with the general formula (1 8), N, N- dimethylformamide in the presence of hydroxybenztriazole thoria zone Ichiru, dicyclohexyl to obtain the desired compound by a condensation reaction with hexyl Cal positive imide to.

With respect to Example 3 1 1 and 3-12, respectively, by subjecting the compound obtained in Example 3-9 and three to 10 in hydrogenation reaction, it is possible to obtain the desired compound.

With respect to Example 3 13, the compound of the general formula (14), the presence of a source Jiu arm methoxide is reacted with paraformaldehyde immediately by performing a reduction reaction with sodium borohydride is N- methylated It was to obtain a compound of general formula (14). To obtain the desired compound by subjecting it to step 2-4.

Object with respect to the embodiment 3-19, the compound obtained in Example 3-6, under cooling, in Tet Rahidorofuran, was reacted with n- heptyl lithium, by reaction with the compound (11) in the system to give compound.

Example 3 24, for 3- 25 and 3-26, using N, dimethyl § Seto amide instead of N--dimethylformamide in step 2-1 to give a Asechirupirazo port pyridine derivatives. This derivative and hydroxyl § Min hydrochloride in the presence of potassium carbonate © beam, in aqueous ethanol to give Okishimu derivative is reacted under heating. Derivative in acetic acid solvent in this, perform a reduction reaction at powdered zinc to obtain a Echiruamin derivatives. To obtain the desired compound by subjecting the Echiruamin derivative in Step 2 4. With respect to Example 3- 27, N- (2- (3- pyridyl) Echiru) -3, 5-Jikuroroa using diphosphate to synthesize I 匕合 of the general formula (19), which process 5 to obtain the desired compound by subjecting to 1.

Table one 1 6

Table one 1 Ί

Example 4

N-(1H-4 one isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pin lysine one 6- I le) Okishi one N '- (2, 6-dichloropyridine one 4-I le) Urine elementary

Step 3 l: a) Echiru N- (1H-4-isopropyl one 1, 3-Jimechirubi Razoro [3, 4-b] pyridine one 6- I le) O carboxymethyl § Se thymidylate Romantic (15) Echiru N- hydroxysuccinimide It was dissolved Asechimideto the (1. 26 g) N, the N- dimethylformamide (35 mL), under ice-cooling, a t Ert- butoxy potassium (1. 36 g) was added, 2. and stirred for 5 hours. To this solution, 1H-6- promoter 4-I an isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridine (7) (1. 20 g) N, N- dimethylformamide (25 mL) solution It was added under ice-cooling, followed by stirring at room temperature for 19 hours. After adding water thereto, and extracted with acetic acid Echiru. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and condensed, Echiru N-(111- 4_ Isopuropiru one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6 I le) O carboxymethyl § Se thymidylate Romantic (15) (to give a 1. 27 g).

Step 3 2: b) 〇 one (IH-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridine one 6- I le) hydroxyl § Min (16)

Echiru N-(1H-4 one isopropyl one 1 obtained in a) of Example 4, 3-dimethyl-Vila Zorro [3, 4-b] pyridine one 6- I le) O carboxymethyl § Se thymidylate Romantic (1 5 ) (1. was dissolved in 06 g) the main evening Nord (9 mL), this solution was added to 20. 5 N sulfuric acid (0. 9 mL), and stirred at room temperature for 2.5 hours. After neutralization with 1N sodium carbonate and extracted with acetic acid Echiru. The organic layer was washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated, 0- (1H-4-isopropyl one 1, 3-Jimechirubi Razoro [3, 4-b] pyridine one 6- I le) hydroxylamine to give Amin a (16) (781 mg).

Step 3- 3: c) N- (1 H- 4- isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridine one 6- I le) Okishi _N, one (2, 6-dichloro port pyridine one 4 one I le) urea (1- 3)

1 H- 6- Hidorajino 4-isopropyl one 1, 3-dimethyl Vila Zorro instead of [3, 4-b] pyridine (8), obtained in b) of ¾® Example 4 0- (1H-4 one isopropyl one 1, 3-dimethyl Vila Zorro [3, 4-b] pyridine one 6- ^ T Le) hydroxyl § Min (16) in a similar manner to all f of example 1) except for using, N- ( 1H-4-isopropyl one 1, 3-dimethyl-pyrazolo [3, 4-b] pyridinium Jin one 6- I le) Okishi one N, one (2, 6-dichloro port pyridine one 4-I le) urea (1 -3) was obtained.

¾-NMR (300MHz, dppm, CDCl 3)

1.36 (6H, d 3 J = 6.8Hz) 5 2.64 (3H 5 s) 5 3.57 (lH 3 septet 5 J = 6.8Hz) 5 3.95 (3H, s) 5 6.62 (lH

, S), 7.51 (2H, S), 7.82 (1H, S), 8.85 (1H, S)

MB (+) MS (low resolution, m / z) 409

amorphous

Example 4 one 2-4 one 22

To give the compound of Example 4-2~4- 22 in the same manner as in Example 4. The obtained compound are shown in Table 18 and Table 19.

However, of the compound of Example 4 one 2-4 one 22, X gar 〇 one, Y gar NH-, Z Gar C 0- and W compounds other than I 匕合 product is an NH- About the following good sea urchin, the method of example 4 was prepared by the method or methods part was modified with analogous thereto.

Example 4 one 5, with respect to 4-6 and 4 one 7, the target compound was obtained compound in step 3-3 (1 1) using 2 equivalents.

With respect to Example 4 one 8,4 one 9 and 4 one 10, the formula using the N-protected hydroxyl as § Min N- base Njiru N- (te rt-butoxycarbonyl) hydroxylamine § Min in Step 3-1 (15) give an analog of the compound, more pulling it, to obtain the desired compound by subjecting to step 3 2 and 3 3.

With respect to Example 4 11, 4 one 12 and 4 13, first, in dimethylformamide § bromide in the presence of t Ert- butoxy potassium, at room temperature or under cooling, the compound of the general formula (6) and Promo acetate Echiru It was reacted to give a hydro alkoxy acid compound and then hydrolyzed with Al force Li. A compound of this general formula (18), in dimethylformamide § bromide in the presence of hydroxybenztriazole azo Ichiru, in Kishirukarubojii bromide dicyclohexyl, to obtain the desired compound by subjecting to condensation reaction.

For the I 匕合 product 4 one 17 and 4 one 18, analog of the compound of N- methyl-N- as N-protected hydroxamate Shiruamin In step 3-1 the general formula with (tert-butoxycarbonyl) hydroxy Ruamin (15) a obtained, which subsequently, to obtain the desired compound by subjecting to step 3 one 2 and 3 3.

Table one 1 8

Table one 19

Pharmacological Test

Test Example (l): 3 H- Sph- 1- P debonding HAGR 16 expressing CHO cells DAL base for hAGR16 expressing CHO membranes Uz co modified Eagle MEM (low glucose, 10% © shea calf serum, 1 O. g / cultured in ml puromycin) medium, cells are replaced with serum-free medium when densely has decreased (0.3% © shea serum Arupumin, Dal base Uz co modified Eagle MEM ヽ low glucose), and over 晚 culture . Then the cells are detached, was crushed in a Teflon homogenizer, 100, was subjected to 1 hour X 2 times ultracentrifugation at 000G. The resulting membrane fraction was cryopreserved, were used in the following experiments.

After the test substance (final DMSO (Dimethyl sulf Oxide) Concentration 1. 0%) 125〃1 was added to 24-well plates, 3 H-labeled SPH 1 125〃 1 added Caro an P (final concentration 2 nM) did. Finally, hAGR 16 expressing CHO membranes (final concentration 100〃G / we 11) was 250 zl added. After stirring for 2 hours at 4 ° C, Roh, was Toradzupu to GF / B Phil evening one one base star (PACKARD). After drying this, it was added MicroScint activity was measured radiate in Top Count (PACKARD). I 匕合 was not added the difference in radioactivity values ​​for non-labeled S pH-1 one P addition of a final concentration of 10 / M in place when the compound of (Total binding) (Nonspeci fic binding) is 100% , of the test substance

I was determined I c 50 from inhibition rate ¾¾r activity. Test Example (2): r AGR 16 and hE dg 3 3 for expressing CHO membranes H- S ph-1-P bound suppression test

Evaluation methods of preparation and test substance in the membrane fraction was the same as in Test Example (1). Test Example (3): Sph- 1- P stimulated normal human lung fibroblasts (HLF) antiproliferative test

HLF (2000cel ls / 200 / l / we 11) a write to Ki wound on a 96-well plate, using RPMI 1640 10% © shea fetal serum medium was 2 days cultured at 37 ° C. Thereafter, cells were washed with PBS (Pho sphat e Buf ferd Saline), it was replaced with RPMI medium without © shea fetal serum, and cultured for one day. Furthermore, the test substance (final concentration 10- 3 M~: L 0- 5 M , final DMSO concentration 0.1%) was added Caro the 8〃 1, Sph-1-Ρ (final concentration 1 / M) 50 ^ 1 was added. 18 was added to hours after the 3 H-labeled thymidine, after a further 6 hours and then trapped GFZB fill evening foremost in hard Beth evening one (PA CKARD). After drying this, the micro-sheet wrench added 50〃1 was boss measure the hen activity in Top Count (PACKARD). Activity of the test substances were ffl a value that indicates a 50%脑活against I匕合was non-addition group as IC 5 ().

The test examples (1) Test Results to (3) are shown in Table 20 and Table 21.

Table one 20

Test Example (1) Test Example (2) Test Example (2) Test Example (3) 麵例 AGR16 rAGR16 hEdg3 HLF growth inhibition

IC50 (MM) IC50 (MM) 10 inhibition (%) ICBO (UM)

1 0.017 0.015 4.2 0.13

1-42 0.044 0.053 0 0.19

1-43 0,026 0.032 0 0.17

1-44 0,023 0.011 1.4 0.32

1-72 0.076 0.046 0.79

1 -76 0.012 - 0.16

1-80 0.0041 0.12

1-8 1 0.055 1.70

1-82 0.005 0.023 9.9 0.29

1 -83 0.01 - 0.18

1-85 0.053 0.04

1-86 0.01 0.32

1-87 0.0041 0.03 14.2 0.21

1-88 0.067 - 1.80

1 -89 0.027 - 0.59 -

1-90 0.042 - 0.23

1 9 1 0.049 - -

1 1 1 1 0.034 - 0.19

1 1 17 0.018 0.15

1 1 18 0.01 - - 0.023

1 120 0.068 - - 0.15

1 12 1 0.068 0.094

1 122 0.022 - 0.035

1 123 0.023 - 0.15

1 - 124 0.026 0.028

1 126 0.085 0.31

1 129 0.028 0.16

1 13 1 0.023 0.13

1 132 0.018 0.064

1 - 1 65 0.048 0.051

1 166 0.052 0.12

1 175 0.022 0.047

1 178 0.02 0.027 丄 - l ί ynn / 2 0.11

1 180 0.024 0.025

1 18 1 0.02 0.13

1 184 0.021

1 185 0.02

1 - 1 96 0.046

1-202 0.093

1-203 0.03 Table one 2

Test Example (4): DMN hepatitis test

0 SD Radzuto (SLC male 6W), those diluted with DMN (N- Dime thyl ni tr os o amine) so as to have a 12〃 1 / ml saline from the start of the test, 1, 2, 7 were 廳空 administration (lml / kg) on ​​days 8, 9 days. The test compound 3, 10, 3 2 times orally administered daily at a OmgZkg, also anti-TGF-/? Antibody 5mgZkg administered 0, 3, 7, 10 days into the vein as a positive control, 14 days It was dissected. The liver was excised, OH- Pr o 1 ine isolate sections of about 10 Omg for quantification, and stored the rest in formalin.

OH- Pro l ine quantitative measurements, KoTsuta in the following manner. Degreased · Fi½jc least 2 days in Aseton, dried in a vacuum desiccator Isseki within one liver sections were measured dry weight, placed in a glass test tube with a Teflon liner one cap, was added 6N HC 1 in 5ml It was hydrolyzed for 24 hours at 118 ° C Te. After was the HC 1 evaporation ■ dryness by blowing nitrogen gas while heated Caro at 65 ° C, 0 H- was P ro 1 i ne quantitative sample was dissolved in pure water 1 mL. 0. 5 ml of the sample solution in 3 ml of Kuen acid - phosphoric acid buffer solution, periodic acid solution 0. 5 ml added and mixed for 1 hour at room temperature yet 1. added toluene extract of 75 ml after shaking, and centrifuged 1500 r pm, 10 minutes. The organic layer 0. 6 ml was dispensed to a test tube was added E one Ruridzuhi reagent 0. 15 ml, allowed to stand at room temperature for 45 minutes, the absorbance was measured 565 nm. OH @ - Pro 1 ine amount is expressed by the value obtained by correcting a dry weight of tissue samples. The test results of the test example (4) shown in Table 22.

2 A

As is clear from the above test, the new Vila oxazolidinedione reduction and pharmaceutically acceptable salts thereof of the present invention selectively acts on Edg-5 receptions evening one. Also, significantly inhibited the growth of Sph-1-Ρ stimulated normal human lung fibroblasts. Furthermore, even in the D MN hepatitis model was amount significantly inhibited collagen hydrate Rokishipurorin contained in (the main cause of fibrosis) (OH- Pro l ine).

From the above, the compounds of the present invention, prevents vascular smooth muscle Ed g- 5 receptions evening one exists specifically, kidney, lung, therapeutic agents relates liver yarn positions, in particular the fiber I spoon of paper woven, it is useful as an excellent therapeutic agent. This application is filed in Japan, is based on application No. 2000- 185067 and No. 2001 -070593, the contents of which are incorporated in full herein.

Claims

The scope of the claims
[In the formula,
R 1 is hydrogen atom, - 8 alkyl group or one COR 7 (wherein, R 7 is (I 8 Al Kill group, optionally substituted § Li Ichiru group, an optionally substituted Ararukiru group ,
Ci-e alkoxy group, a is a) optionally substituted § Li one also be Ruokishi or substituted optionally be good I Ararukiruokishi group;
R 2 is - 8 an alkyl group or an optionally substituted Ariru group;
R 3 represents a hydrogen atom, C 8 alkyl group, CI- 6 alkoxy C 2 _ 6 alkoxy force carbonyl group, a haloalkyl group, C 3 _ 7 cycloalkyl or optionally substituted good I Ariru group;
R 4 is a hydrogen atom or a C - be 8 alkyl group;
R 5 and R 6 are the same or different, a hydrogen atom, Ci-s alkyl group, 0 6 alkoxy group, C 2 _ 6 alkoxycarbonyl group, a carboxyl group, C 2 _ 6 alkynyl group, a halogen atom, Shiano group , nitro group, haloalkyl group, (I 8 alkylamino group, di (C ^ -B alkyl) amino group, Ashiru group, hydroxyl group, optionally substituted § Li - Ruokishi group, an optionally substituted Ararukiruokishi group , substituted optionally be good I Ariru group, substituted optionally may be Ararukiru group, alkoxyalkyl group or -CONHR 8 (wherein, R 8 is an optionally being good Ariru or substituted also be substituted Ararukiru There in a is) group;
X is -N (R 9) i (wherein, R 9 represents a hydrogen atom, (8 alkyl or - NH R 10 (wherein, R 1Q is a carboxyl group or a C 2 - 6 alkoxycarbonyl two Honoré group a der Ru)), single 0, one N = one CH = or one CH (R 11) - (wherein, R 11 is a hydrogen atom or a 0 les 8 alkyl group); Y is one N (R 12) i (wherein, R 12 is a hydrogen atom, 8 alkyl group, an optionally substituted Ararukiru group, C 2 -. 6 alkoxycarbonyl group, an § substituted Li one Ruokishikarubo sulfonyl substituents on these Ararukiruokishi force Ruponiru group or one CONHR 13 also (wherein, R 13 is optionally substituted § Li one be the group or an optionally substituted Ararukiru group) in a), = N-, -CH 2 - , = CH-, - 0-, be single CO- or a single bond;
Z is one C_〇 one, One CS-, - CH 2 -, be single 0 or a single bond;
W is, - N (14) - (wherein, R 14 represents a hydrogen atom, an alkyl group, § Lal Kill optionally substituted O alkoxycarbonyl group, an optionally substituted Ariru O alkoxycarbonyl group, or heteroaryl (8 alkyl group), single 0, the - C 0-, -C0NH- (where the nitrogen atom binds to the ring a), - CH 2 -, -NHC Ε, - ( provided that the carbon atom It is binds to ring Alpha) or a single bond; is is a double bond or a single bond;
璟A is substituted optionally may be Ariru group, Heteroariru group or C 3 - 7 are allowed cycloalkyl Vila oxazolidinedione compound represented by the group is] or a pharmaceutically ο
2. R 1 is a hydrogen atom, (Bok 6 alkyl group or one COR 7 (wherein, R 7 is one 6 alkyl group Ariru group, Ararukiru group, (丄one 6 alkoxy group, § Li one Ruoki sheet group or There in Ararukiruokishi a group);
R 2 is, C ^ - be a 6 alkyl group or Ariru group;
R 3 represents a hydrogen atom, C ^ - 6 alkyl group, Ci-s-alkoxy C 2 - 6 alkoxy force carbonyl group, a haloalkyl group, C 3 - be a cycloalkyl group or Ariru group;
R 4 is a hydrogen atom or CI- e alkyl group;
R 5 and R 6 are the same or different, a hydrogen atom, an alkyl group, (6 alkoxy group, C 2 _ 6 alkoxycarbonyl group, a carboxyl group, C 2 _ 6 alkynyl group, a halogen atom, Shiano group, a nitro group , a haloalkyl group, CI- e alkylamino group, di - 6 alkyl) amino group, Ashiru group, a hydroxyl group, Ariruokishi Araru Kiruokishi group or one C0NHR 8 (wherein, R 8 is § Li Ichiru group or Ararukiru group) It is in;
X is -N (R 9) i (where, R 9 isヽhydrogen atom (G 6 alkyl group or one NH R 10 (wherein, R 1Q is a carboxyl group or a C 2 _ 6 alkoxycarbonyl group is any)), single 0, one N = one CH = or one CH (R 11) - (wherein, R 11 is an a hydrogen) atom or a Ci-e alkyl group;
Y is one N (R 12) i (wherein, R 12 is a hydrogen atom, (6 alkyl group, Araru Kill group C 2 - 6 alkoxycarbonyl group, § Li one Ruokishikarubo sulfonyl Araru Kill O alkoxycarbonyl group, or (wherein,; R 13 is § re Ichiru a group or Ararukiru group) single CONHR 13 is a), = N-one CH 2 -, = CH-, one 0- one CO - or a single bond It is in;
Z is, -CO-, - CS-, - CH 2 -, -0- or a single bond;
W is one N (R 14) i (wherein, R 14 represents a hydrogen atom, C ^ 6 alkyl group, Araru Kill O alkoxycarbonyl group, in § reel O alkoxycarbonyl group or to Teroari Ichiru C 6 alkyl group there), single 0, one CO-, one C0NH- (where the nitrogen atom binds to the ring a) one CH 2 _ one NHCH 2 - (provided that the carbon atom is bound to ring a) or single is a bond; is is a double bond or a single bond;
Ring A is Ariru group, Heteroari Ichiru a group or a C 3 _ 7 cycloalkyl group, pyrazole port pyridine compound or a pharmaceutically acceptable salt thereof billed range 1 wherein.
3. RR 4 and formula
In the substitution position on the pyridine ring of the substituent represented is, R 3 is h-position, R 4 is i-position of the formula - XH
In substituents represented is position j, pyrazole port pyridine compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein.
4. R 1 is an alkyl group, R 2 is CI- 6 alkyl group, and R 4 is a hydrogen atom, pyrazole port pyridine compound or salt thereof pharmaceutical allowable range 3 wherein claims.
5. Y is -NH- or = a N-, Z Gar a CO-, and W is - salt is NH-, acceptable range 4 pyrazole port pyridine compound according or a pharmaceutically claims.
6. Salts Ring A is Ariru group, pyrazole port pyridine compounds in the range 5 according claims or the acceptable pharmaceutically.
7. Ariru group is a phenyl group, pyrazole port pyridine of compounds or a pharmaceutically acceptable salt thereof according to claim 6, wherein.
8. Ring A to is Teroari Ichiru group, pyrazole port pyridine of compounds or a pharmaceutically acceptable salt thereof in the range 5 wherein claims.
9. Heteroari Ichiru group is pyridyl group or thienyl group, Vila oxazolidinedione compound or a pharmaceutically acceptable salt thereof according to claim 8, wherein.
10. Heteroari Ichiru group is pyridyl group, Pila range 9 wherein claims) mouth pin lysine compound or a pharmaceutically acceptable salt thereof.
11. X Gar NH- or - N a =, Vila oxazolidinedione compound or a pharmaceutically acceptable salt of the mounting serial to any range 5 to 10 claims.
12. X gar CH 2 - is, Vila Zoropirijin compound or a pharmaceutically acceptable salt thereof according to any one of claims 5 to 10 claims.
13. X Gar is 0, either the word pyrazole port pyridine compound or a pharmaceutically acceptable salt of his own mounting range 5 to 10 claims.
14. N- (1H- 4- isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridin-one 6- I le) Amino one N, - (2, 3-jib port Mochiofen one 5- I le ) urea,
N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino one N '- (2, 6-dichloropyridine one 4-I le) urea , N- (1H- 1, 3, 4 one Torimechirupirazo port [3, 4-b] Pirijin 6- I le) amino-N, one (2-black opening one 6-propyl-pyridin one 4 one I le) urea , N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino one N '- (2-black opening one 6-propyl-pyridin one 4- I le) urea,
N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N '- (2-black opening one 6-isopropyl-pyridin -4 one I le ) urea,
N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino one N '- (2-black opening one 6-isobutyl-pyridin one 4- I Le) urea,
N- (1H- 1, 3, 4- Torimechirupirazo port [3, 4-b] pyridine one 6- I le) Amino one N, one (2-black opening one 6-isopentyl ruby ​​lysine one 4- I le ) urea, N-(1H-4-isopropyl _ 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N, one (2-black opening one 6-isopentyl ruby ​​lysine one 4 - I le) urea,
N-(1 over 4_ Isopuropiru one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N '- (2-methoxy-6-methylpyridin-over 4-I le) urea,
N-(111 - 4 Isopuropiru one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino one N, i (3, 5-dimethyl-phenylalanine) urea,
N- (1H- 1, 3, 4- Torimechirupirazo port [3, 4-b] pyridine one 6- I le) amino-N, one (2-black opening one 6- (hexyl 3-methyl) pyridine one 4-I le) urea,
N-(111 over 4_ Isopuropiru 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin _ 6 I le) amino-N, one (hexyl 2-black opening one 6- (3-methyl) pin lysine one 4-I le) urea,
N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N, one (2, 3-dichloro Chio phen one 5- I le) Urine N-(1H-4-isopropyl one 1, 3-Jimechirubirazo, mouth [3, 4-b] pyridinium Jin one 6- I le) amino-N 'i (2-black opening one 6-pentylbicyclo lysine one 4- I le ) urea,
N- (1H-1, 3, 4- Torimechirupirazo port [3, 4-b] pyridine one 6- I le) amino-N '- (2-black opening one 6-pentylbicyclo lysine one 4 one I le) urea , N-(1 H- 4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N, - (2-black port hexyl pyridine one 4 _ 6 to - I le) urea,
N- (1H- 1, 3, 4_ Torimechirupirazo port [3, 4-b] pyridine one 6- I le) amino-N, one (2-black opening one 6-hexyl pyridine one 4-I le) urea, N- (1H- 1, 3, 4- Torimechirupirazo port [3, 4-b] pyridine one 6- I le) Amino one N, one (2-butyl one 6- black port pyridine one 4 Ichii Le) urea, N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino one N, one (2-black opening one 6- phenylene Rubirijin one 4-I le) urea,
N- (1H- 1, 3, 4- Torimechirupirazo port [3, 4-b] pyridine one 6- I le) amino-N, - (2-chloro-6-phenylene Rubirijin one 4-I le) urea, N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N '- (2-chloro Chio phen one 4-I le) urea, N - (1H-4 one isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino _Ν '- (3, 5- di (methoxycarbonyl) phenyl)
N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino one N '- (2-chloro-6- (2-Fueniruechiru) pin Rijin 4 one I Lumpur) urea,
N- (1H- 1, 3, 4_ Torimechirupirazo port [3, 4-b] pyridine one 6- I le) amino-N, - (2-chloro-6- (2-Fueniruechiru) pyridine one 4- I le )urea,
N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino one N, one (2-black opening one 6- Puchirubirijin one 4 one I le )
N-(111- 4-Isopuropiru one 1, 3-di Chirubirazoro [3, 4-b] pyridinium Gin - 6 I le) amino-N '- (3, 5 _ dibromo-phenylalanine) urea,
N-(1H-1, 3, 4-Torimechirupirazo port [3, 4-b] pyridine one 6- I le) amino-N, i (3, 5-jib port Mofuweniru) urea,
N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N, one (3-bromo-2-methylthiophene one 5- I le) urea ,
N- (1H- 1, 3, 4- Torimechirupirazo port [3, 4-b] pyridine one 6- I le) amino-N, - (2-chloro-6-isobutyl Petit ruby ​​lysine one 4-I le) urea, N- (1 H- 1, 3, 4_ Torimechirupirazo port [3, 4-b] pyridine one 6- I le) amino-N '- (2-chloro to 6- Puchirubirijin one 4-I le) urea, N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N, - (Puchirubirijin one 4- I Le 2- Clos port one 6- to ) urea,
N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N '- (2-chloro-6- ((4_ fluorophenyl) methyl) pyridine one 4-I le) urea,
N-(1H-4-isopropyl one 1, 3-dimethyl-pyrazolo [3, 4-b] pyridinium Jin one 6- I le) amino-N, _ (3- (methoxymethyl) Single 5 Mechirufue two Le) urea ,
N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N, - (3-black port phenyl) urea, '
N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino one N, - (3, 5-dichlorophenyl) urea,
N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin _ 6 I le) Amino _Ν '- (3- Buromofueniru) urea,
Ν- (1H- 1, 3, 4- Torimechirupirazo port [3, 4-b] pyridine one 6- I le) amino-N '- (2, 6-dichloropyridine one 4 one I le) urea,
N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4 one b] pyridinium Jin one 6- I le) amino-N, one (2-chloro-6-methoxypyridin-one 4-I le) urea ,
N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino one N, - (2-black opening one 6-ethoxy-pyridin-one 4 ^ I Le) urea,
N-(1H-4 one isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N, one (2-black port pyridine one 4-I le) urea, N - (1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N, one (2-chloro-6-methylpyridin-one 4-I le)
N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino one N, one (2, 6-diethoxy-pyridin one 4-I le) urea,
N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) amino-N, - (6-Benjiruokishi 2 black port pyridine one 4-I le) urea,
N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino one N, one (2, 6-dimethoxypyridine one 4-I le) Urine arsenide,
N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Amino one N, one (2-black opening one 6- Echirupirijin one 4- I le )
N- (1H- 1, 3, 4- Torimechirupirazo port [3, 4-b] pyridine one 6- I le) amino-N '- (2-black opening one 6-methylpyridin-one 4 one I le) urea , N- (1H-1, 3, 4- Torimechirupirazo port [3, 4-b] pyridine one 6- I le) Amino one N '- (2-black opening one 6- Echirupirijin one 4-I le) urea, 1H-6- (((2- chloro-6-methylpyridin-one 4-I le) Amino) carbonylation Ruazo) - f an isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridine down,
1H-6- (((2, 6- dichloro port pyridine one 4-I le) Amino) Karuboniruazo)
4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridine,
N-(1H-4 one isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I) methyl one N, - (2, 6-dichloropyridine one 4 f le) urea,
N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I) methyl one N '- (3, 5- dichloro port phenyl) urea,
N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) methyl-N, - (2-black opening one 6- Echirupirijin one 4 one ^ f le ) urea,
N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) methyl-N '- (2-black opening one 6-methylpyridin-one 4 one I le )
N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Okishi one N, - (2, 6-dichloropyridine one 4-I le) urea ,
N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin _ 6 I le) Okishi one N, - (3-black port phenyl) urea,
N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin-6-I le) Okishi - N '- (3-Buromofueniru) urea and
N-(1H-4-isopropyl one 1, 3-dimethyl-Vila Zorro [3, 4-b] pyridinium Jin one 6- I le) Okishi one N, - (3, 5-dichlorophenyl) urea
Pyrazole port pyridine compound or a pharmaceutically acceptable salt thereof manufactured drug according to claim 1, wherein the chosen from the group consisting of.
15. pyrazole port pyridine compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable pharmaceutical pirate product comprising a carrier according to any one of claims 1 to 14 claims.
16. Claims 1 to 14 or a pyrazole port pyridine compound or a sphingosine one 1-phosphate receptor antagonists o containing a pharmaceutically acceptable salt thereof as an active ingredient according to
1 7. Fibrosis therapeutics containing pyrazole port pyridine compound or a pharmaceutically acceptable salt thereof as an active ingredient according to any one of claims 1 to 1 4 of claims.
1 8. Pyrazole port pyridine compound or liver fibrosis therapeutic agent containing as an active ingredient a pharmaceutically acceptable salt thereof according to any one of claims 1 to 1 4 of claims.
1 9. Pulmonary fibrosis therapeutic agent containing a salt as an active ingredient acceptable pyrazole port pyridine compound or a pharmaceutical according to any range 1 to 1 4 of claims.
2 0. Sphingosine one 1 first compound having a phosphoric acid receptor antagonism or fibrosis therapeutic agent, which comprises the manufacturing drugs acceptable salt thereof as an active ingredient.
2 1. Sufuingoshin one 1-phosphate receptor is an E DG-5, fibrosis treatment in the range 2 0 according claims.
2 2. Sphingosine one 1-phosphate receptor antagonist compounds having the action or liver fibrosis therapeutic agent comprising the manufacturing drugs acceptable salt thereof as an active ingredient.
2 3. Sufuingoshin _ 1-phosphate receptor is E dg _ 5, liver fibrosis treatment in the range 2 wherein the claim.
. 2 4 sphingosine - 1-phosphate compound having a receptor antagonism or pulmonary fibrosis therapeutic agent, which comprises the manufacturing drugs acceptable salt thereof as an active ingredient.
2 5. Sufuingoshin one 1-phosphate receptor is an E DG-5, pulmonary fibrosis therapeutic agent in the range 2 4, wherein the billing.
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