JP2006528623A - Nicotinamide derivatives useful as PDE4 inhibitors - Google Patents

Abstract

(式中、Ｒ¹、Ｒ²およびＲ³は、明細書に定義された意味を有する)のニコチンアミド誘導体、およびこのような誘導体を含んでなる組成物およびＰＤＥ４阻害剤としてのこのような誘導体の使用に関する。The present invention relates to general formula (I)
[Chemical 1]

Nicotinamide derivatives of the formula (wherein R ¹ , R ² and R ³ have the meanings defined in the specification), and compositions comprising such derivatives and such derivatives as PDE4 inhibitors About the use of.

Description

(式中、Ｒ¹、Ｒ²およびＲ³は、下記の意味を有する)のニコチンアミド誘導体、およびその製造方法、その製造に使用する中間体、それを含有してなる組成物およびその使用に関する。 The present invention relates to general formula (I):

(Wherein R ¹ , R ² and R ³ have the following meanings), nicotinamide derivatives of the same, intermediates used in the production thereof, compositions containing the same and uses thereof .

  3 ', 5'-cyclic nucleotide phosphodiesterases (PDEs) encompass a wide variety of enzymes and are divided into at least 11 different families, which are structurally, biochemically and pharmacologically related to each other. Is different. Enzymes within each family are commonly referred to as isoenzymes or isozymes. This class includes a total of more than 15 gene products, and further diversity arises from differential splicing and post-translational processing of those gene products. The present invention is primarily concerned with the four gene products of the fourth family of PDEs, namely PDE4A, PDE4B, PDE4C and PDE4D. These enzymes are collectively considered to be isoforms or subtypes of the PDE4 isozyme family.

  PDE4 is characterized by a selective high affinity hydrolysis of the second messenger cyclic nucleotide, adenosine 3 ′, 5′-cyclic monophosphate (cAMP), and sensitivity to inhibition by rolipram. In recent years, many selective inhibitors of PDE4 have been discovered and the beneficial pharmacological effects resulting from that inhibition have been shown in various disease models (eg Torphy et al., Environ. Health Perspect, 1994, 102 Suppl). 10, p. 79-84; Duplantier et al., J. Med. Chem., 1996, 39, p. 120-125; Schneider et al., Pharmacol. Biochem. Behav., 1995, 50, p. 211 -217; Banner and Page, Br. J. Pharmacol., 1995, 114, p. 93-98; Barnette et al., J. Pharmacol. Exp. Ther., 1995, 273, p. 674-679; Wright et al., Can. J. Physiol. Pharmacol., 1997, 75, p. 1001-1008; Manabe et al., Eur. J. Pharmacol., 1997, 332, p. 97-107 and Ukita et al., J Med. Chem., 1999, 42, p. 1088-1099). Accordingly, there remains considerable interest in the art for the discovery of additional selective inhibitors of PDE4.

Successful results have already been obtained in the art for the discovery and development of selective PDE4 inhibitors. In vivo, PDE4 inhibitors reduce the influx of eosinophils into the lungs of animals subjected to allergen challenge, while also reducing the increased bronchial responsiveness that occurs after bronchoconstriction and allergen challenge. PDE4 inhibitors also suppress the activity of immune cells (including CD4 ⁺ T-lymphocytes, monocytes, mast cells and basophils), reduce pulmonary edema, and excitatory, non-adrenergic, non-cholinergic. Inhibits non-adrenergic non-cholinergic neurotransmission (iNANC), reduces airway smooth muscle mitogenesis, and induces bronchodilation. PDE4 inhibitors also suppress the activity of many inflammatory cells associated with the pathophysiology of COPD, including monocytes / macrophages, CD4 ⁺ T-lymphocytes, eosinophils and neutrophils. PDE4 inhibitors also reduce mitogenesis of vascular smooth muscle and interfere with the ability of airway epithelial cells to produce potentially inflammatory mediators. Through the release of neutral proteases and acid hydrolases from fine granules and the generation of reactive oxygen species, neutrophils are responsible for tissue destruction associated with chronic inflammation and are further involved in conditions such as emphysema. Thus, PDE4 inhibitors are particularly useful in the treatment of many inflammatory, respiratory and allergic diseases, disorders or conditions and wounds, some of which are primarily for asthma, COPD, bronchitis and emphysema It is in clinical development for treatment.

  The effect of PDE4 inhibitors on various inflammatory cell responses can be used as a basis for inhibitor design and selection for further study. These effects include elevated cAMP and inhibition of superoxide production, degranulation, chemotaxis and tumor necrosis factor alpha (TNFα) release in eosinophils, neutrophils and monocytes.

  Some nicotinamide derivatives having PDE4 inhibitory activity have already been synthesized. For example, patent application WO 98/45268 discloses nicotinamide derivatives having activity as selective inhibitors of PDE4D isozymes.

  Patent applications WO 01/57036 and WO 03/068235 also disclose nicotinamide derivatives that are PDE4 inhibitors useful for the treatment of various inflammatory allergic and respiratory diseases and conditions.

  However, there is still a great need for additional PDE4 inhibitors that are good candidate drugs. In particular, preferred compounds should bind to the PDE4 enzyme strongly while exhibiting little affinity for other receptors and enzymes. It has good pharmacological and metabolic activity, is non-toxic and should show little side effects. Furthermore, the ideal candidate drug should exist in a physical form that is stable and easily prescribed.

の新しいニコチンアミド誘導体およびその医薬上許容しうる塩、プロドラッグ、溶媒和物および多形体を提供する。 Accordingly, the present invention provides a compound of formula (I)

New nicotinamide derivatives and pharmaceutically acceptable salts, prodrugs, solvates and polymorphs thereof.

In the formula:
R ¹ and R ² are each independently selected from the group consisting of hydrogen, halo and (C ₁ -C ₃ ) alkyl; and R ³ is a 9 or 10 membered bicyclic ring containing 1 to 4 nitrogen atoms Wherein the bicyclic heteroaryl is OH, halo, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, hydroxy (C ₁ -C ₄ ) alkyl and hydroxy It is optionally substituted by 1 or 2 groups selected from (C ₂ -C ₄₎ alkoxy.

Preferably R ¹ is H, F, Cl or methyl, more preferably R ¹ is F.
Preferably R ² is H or F, more preferably R ² is H.
Preferably R ³ is a 9 or 10 membered bicyclic heteroaryl containing 1 to 3 nitrogen atoms, wherein said bicyclic heterocyclic ring system is OH, halo, (C _1- C ₄₎ alkyl, are optionally substituted by 1 or 2 groups selected from (C ₁ -C ₄₎ alkoxy and hydroxy (C ₁ -C ₄₎ alkyl.

More preferably, R ³ is a C-linked 9 or 10 membered bicyclic heteroaryl containing 1 to 3 nitrogen atoms, wherein said bicyclic heteroaryl is OH, F, Cl , (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy and hydroxy (C ₁ -C ₄ ) alkyl are optionally substituted.

Even more preferably, R ³ is a C-linked 9 or 10 membered bicyclic heteroaryl containing 1 to 3 nitrogen atoms, wherein said bicyclic heteroaryl is OH, ( C ₁ -C ₃₎ alkyl, optionally substituted by 1 or 2 groups selected from (C ₁ -C ₃₎ alkoxy and hydroxy (C ₁ -C ₃₎ alkyl.

Particularly preferred R ³ groups are indole, isoindole, indolizine, indazole,
It is selected from the group consisting of benzimidazole, imidazopyridine, pyrrolopyridazine, pyrrolopyridine, benzotriazole, pyrazolopyridine, imidazopyridine, quinoline, isoquinoline, cinnoline, quinoxaline, quinazoline, phthalazine and naphthyridine. Highly preferred R ³ groups are selected from the group consisting of indazole, benzimidazole, benzotriazole, imidazo [1,2-a] pyridine, pyrrolo [1,2-b] pyridazine and quinoline.

Preferred optional substituents for the bicyclic ring system of R ³ are selected from OH, methyl, ethyl, propyl, hydroxymethyl and hydroxyethyl.

According to a further aspect, the present invention relates to a compound of formula (I) wherein R ¹ is H, F, Cl or methyl; R ² is H or F; and R ³ is 1 to 3 nitrogens C-linked 9- or 10-membered bicyclic heteroaryl containing atoms, wherein said bicyclic heteroaryl is OH, halo, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄₎ providing alkoxy and compounds of hydroxy (C ₁ -C ₄₎ 1 or more substituents the formulas optionally present by a group selected from alkyl (I).

According to a preferred embodiment, the present invention relates to a compound of formula (I) wherein R ¹ is F; R ² is F; and the ring system of R ³ is indazole, benzimidazole, benzotriazole, imidazo [1 , 2-a] pyridine, pyrrolo- [1,2-b] pyridazine, and quinoline, optionally substituted bicyclic heteroaryl, is provided for compounds of formula (I).

Preferred compounds according to the invention are:
Syn-pyrazolo [1,5-a] pyridine-2-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide ;
Syn-1-isopropyl-1H-benzimidazole-4-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide;
Syn-imidazo [1,2-a] pyridine-2-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino] -cyclohexyl) -amide ;
Syn-1H-indazole-3-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide;
Cin-2-methyl-3H-benzimidazole-4-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino] -cyclohexyl) -amide;
Syn-imidazo [1,2-a] pyridine-8-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide ;
Syn-3H-benzotriazole-4-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide;
Syn-quinoline-8-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide;
Syn-3-hydroxy-quinoline-8-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide; and syn- 1- (2-hydroxy-ethyl) -1H-indazole-3-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -Selected from the group consisting of amides and their pharmaceutically acceptable salts, prodrugs, solvates and polymorphs.

More preferred compounds are
Syn-2-methyl-3H-benzimidazole-4-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide;
Syn-imidazo [1,2-a] pyridine-8-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide ;
Syn-quinoline-8-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide; and syn-3-hydroxy- Quinoline-8-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide and pharmaceutically acceptable salts thereof, Selected from the group consisting of prodrugs, solvates and polymorphs.

The invention further relates to compounds of the formula (I) in which R ¹ , R ² and R ³ are as defined above, and optionally present substituents of R ³ further comprise hydroxymethoxy ).

  These nicotinamide derivatives are inhibitors of PDE4 isoenzymes and have been found to be particularly useful for the treatment of inflammatory, respiratory and allergic diseases and conditions or wounds.

  In the above general formula (I) of the present specification, halo represents a halogen atom selected from the group consisting of fluoro, chloro, bromo and iodo, particularly fluoro or chloro.

A (C ₁ -C ₃ ) alkyl or (C ₁ -C ₄ ) alkyl group represents a straight or branched group containing 1 to 3 and 1 to 4 carbon atoms, respectively. This is also the case when they carry substituents or are present as substituents on other groups, for example in (C ₁ -C ₄ ) alkoxy groups and hydroxy (C ₁ -C ₄ ) alkyl groups. Also applies. Examples of suitable (C ₁ -C ₃ ) alkyl and (C ₁ -C ₄ ) alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert- Butyl. Examples of suitable (C ₁ -C ₄ ) alkoxy groups are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-butyloxy, sec-butyloxy and tert-butyloxy. Hydroxy (C ₁ -C ₄ ) alkyl and hydroxy (C ₂ -C ₄ ) alkoxy groups can contain multiple hydroxy groups (—OH). According to a preferred embodiment of said invention, such groups contain one hydroxy substituent. Examples of suitable hydroxy (C ₁ -C ₄ ) alkyl groups are hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl.

In the general formula (I) herein, “9 or 10-membered bicyclic heteroaryl” means 1, 2, 3 or 4 nitrogen (N) atoms, depending on the number and quality of the total number of ring members. Means a bicyclic aromatic group having 9 or 10 ring members. Further examples of optional heteroatoms are oxygen (O) and sulfur (S). If it contains several heteroatoms, these can be the same or different. The heteroaryl group can also be unsubstituted, mono-substituted or poly-substituted as described in the definition of R ³ above for general formula (I) according to the present invention. Preferably, the bicyclic heteroaryl is a bicyclic aromatic group containing 1, 2 or 3 nitrogen (N). Examples of suitable bicyclic heteroaryl groups are indole, isoindole, indolizine, indazole, purine, naphthyridine, phthalazine, quinoline, quinazoline, quinoxaline, cinnoline, isoquinoline, benzimidazole, imidazo [1,2-a] pyridine , Benzotriazole, pyrazolo [1,5-a] pyridine and pyrazolopyrimidine. Particularly preferred are indole, isoindole, indolizine, indazole, benzimidazole, imidazopyridine, pyrrolopyridazine, pyrrolopyridine, benzotriazole, pyrazolopyridine, imidazopyridine, quinoline, isoquinoline, cinnoline, quinoxaline, quinazoline, phthalazine and naphthyridine. A bicyclic heterocyclic group selected from Nitrogen bicyclic heteroaryl groups can also exist as N-oxides or as quaternary salts.

  In the general formula (I) according to the invention, when the group is mono- or polysubstituted, the substituent can be located in any desired position. Also, when the group is polysubstituted, the substituents can be the same or different unless otherwise specified.

The nicotinamide derivatives of formula (I) can be prepared using conventional methods, for example by the following specific methods, wherein R ¹ , R ² and R ³ are of the formula unless otherwise specified. (I)
The nicotinamide derivative is as defined above.

  Compounds of formula (I) can be prepared by the methods illustrated in the examples and preparations disclosed below. Other methods can be used according to the knowledge of those skilled in the art.

Unless stated otherwise in this specification:
PyBOP ^(R) means benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate.
PyBrOP ^(R) means bromo-tris-pyrrolidino-phosphonium hexafluoro-phosphate.
CDI means N, N′-carbonyldiimidazole.
WSCDI means 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
Mukaiyama reagent means 2-chloro-1-methylpyridinium iodide.
HATU means O- (7-azabenzotriazol-1-yl) -N, N, N ′, N-tetramethyluronium hexafluorophosphate.
HBTU means O-benzotriazol-1-yl-N, N, N ′, N-tetramethyluronium hexafluorophosphate.
DCC means N, N′-dicyclohexylcarbodiimide.
CDI means N, N′-carbonyldiimidazole.
HOAT means 1-hydroxy-7-azabenzotriazole.
HOBT means 1-hydroxybenzotriazole hydrate.
Huenig base means N-ethyldiisopropylamine.
Et ₃ N means triethylamine.
NMM means N-methylmorpholine.
NMP means 1-methyl-2-pyrrolidinone.
DMAP means 4-dimethylaminopyridine.
NMO means 4-methylmorpholine N-oxide.
KHMDS means potassium bis (trimethylsilyl) amide.
NaHMDS means sodium bis (trimethylsilyl) amide.
DIAD means diisopropyl azodicarboxylate.
DEAD means diethyl azodicarboxylate.
DIBAL means diisobutylammonium hydride.
Dess-Martin periodinane means 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one.
TBDMS-Cl means tert-butyldimethylchlorosilane.
TMS-Cl means chlorotrimethylsilane.
Boc means tert-butoxycarbonyl.
CBz means benzyloxycarbonyl.
MeOH means methanol, EtOH means ethanol and EtOAc means ethyl acetate.
THF means tetrahydrofuran.
DMSO means dimethyl sulfoxide.
DCM means dichloromethane.
DMF means N, N-dimethylformamide.
AcOH means acetic acid.
TFA means trifluoroacetic acid.
RT means room temperature.
3 ° means tertiary.
eq means equivalent.
Me means methyl.
Et means ethyl.
Bn means benzyl.
Other abbreviations are used in accordance with standard synthetic chemistry conventions.

Route A

Nicotinic acid or acid derivatives of formula (II) are commercially available or Haylor et al. (EP 0634413 Examples 9 and 10, pages 12-13) or Marzi et al. (European Journal of Org. Chem. 2001 (7), 1371-1376). The protected amine of formula (III) is commercially available or can be prepared analogously to the method of Oku et al. (WO 99/54284, eg page 80, preparation 77 (1)). .
In the above scheme, R ¹ , R ² and R ³ are as previously defined, PG is a suitable amine protecting group, typically Boc, CBz or Bn, and preferably Boc, LG is then a suitable leaving group, typically halo, and preferably Cl.

Step (a)-Acid-Amine Coupling This acid / amine coupling consists of (i) acyl chloride derivative of acid or acid derivative (II) with an excess of acid acceptor in a suitable solvent + amine (III); or (ii) in an appropriate solvent with an excess of acid acceptor, optionally in the presence of a catalyst, using either acid or acid derivative (II) and a conventional coupling agent + amine (III): Can do.

Typically, the conditions are as follows:
(i) Acid (II) acid chloride (generated in situ), excess amine (III), optionally in excess of 3 ° amine, eg Et ₃ N, Huenig base or NMM in DCM or THF 1 to 24 hours without heating; or
(ii) Acid (II), WSCDI / DCC / CDI, excess amine (III), optionally in the presence of HOBT or HOAT, with excess NMM, Et ₃ N, Huenig base in THF, DCM or EtOAc at room temperature in 4 to 48 hours; or an acid ^{(II), PYBOP (R)} / PyBrOP (R) / Mukaiyama reagent, an excess of amine (III) an excess of NMM, Et ₃ N, THF with Huenig base in DCM or EtOAc, 4-24 hours at room temperature.
Preferred conditions are that (II) is treated with oxalyl chloride and catalytic DMF in DCM for 3 hours at room temperature followed by addition of Huenig base or Et ₃ N and amine and stirred for 18 hours at room temperature; Medium, treated with CDI for 1 hour at room temperature, followed by addition of amine and stirring for 72 hours at room temperature.

Step (b) -leaving group of ether-forming compound (IV), LG is substituted with a substituted phenol to give a compound of formula (V), wherein said leaving group is, for example, a halogen, and preferably Chlorine.
A compound of general formula (V) is prepared from a compound of general formula (IV) via treatment with optionally substituted 3-methylsulfanyl-phenol in the presence of a suitable base in a suitable solvent. Can do. Alkali metal salts are used as bases (eg Cs ₂ CO ₃ , K ₂ CO ₃ , NaOH), MeCN, dioxane, toluene or NMP are suitable solvents for use. The reaction is carried out at an elevated temperature.
Preferred conditions are: in dioxane or MeCN in the presence of cesium carbonate at about 100 ° C., optionally at reflux temperature for about 24 to about 72 hours, with compound (IV) (where LG is chlorine) and in excess Reaction with 3-methylsulfanyl-phenol substituted by

Step (c) —Removal of Protecting Group The deprotection of the N protecting group (PG) from the compound of general formula (V) to obtain the compound of general formula (VI) was carried out by TW Greene and P. Wutz by “Protective Groups in Perform using standard methodologies as described in "Organic Synthesis".
For example, when PG is Boc, preferred conditions are: treatment of compound (V) with a strong acid (eg, TFA, HCl) in a suitable solvent such as dioxane or DCM at room temperature. The preferred conditions for removal of the Boc group herein are treatment with hydrochloric acid in dioxane (preferably 4M HCl) for about 5 hours at room temperature. The production example 18 is described in this specification.

Step (d) - compounds of reaction formula with deprotected amino group and R ³ COOH (I), the amine formula steps formula according to the general method described for (a) (VI) R ₃ It can be prepared by a reaction with a suitable acid of COOH.
Preferred conditions are: Treatment of a solution of amine (VI) and acid R ³ COOH in NMP or DMF with WSCDI, HOBT and NMM or Huenig base for about 18 to about 72 hours at room temperature.
The conversion from (VI) to (I) is illustrated by Examples 1-9.

Path B
The compound of general formula (I) can alternatively be prepared by the following route.

Compounds of formula (VII) can be prepared from amine (III) by reaction with R ₃ COOH according to the method described above in route A, step (d). A preferred condition is to stir a solution of amine (III) in DCM with Huenig base, HOBT, WSCDI and acid R ³ COOH at room temperature for about 48 hours.

  A deprotected amine compound of the general formula (VIII) is obtained from a protected amine compound of the general formula (VII) in the same manner as described above for route A, step (c), preferably a protecting group PG, preferably It can be produced through removal of the Boc group. Under preferred conditions, a solution of (VII) in DCM at 0 ° C. is bubbled with hydrogen chloride gas for about 2 hours and then stirred at room temperature for about 90 minutes to give a compound of general formula (VIII).

  Amide compounds of general formula (IX) can be prepared by reacting an amine of general formula (VIII) with acid (II) according to the method described above in Route A, steps (a) and (d). Under preferred conditions, a solution of amine (VIII) and the appropriate nicotinic acid (II) in DCM is treated with Huenig base, HOBT and WSCDI and stirred at room temperature for about 18 hours to give amide (IX).

  The compound of formula (I) can be obtained by reacting the leaving group (LG) of the compound of formula (IX) with an optionally substituted 3-methylsulfanyl-phenol group as previously described in Route A, step (b). It can be manufactured by substitution. In preferred conditions, the compound of general formula (IX) and optionally substituted 3-methylsulfanyl-phenol are treated in MeCN and DMF in the presence of cesium carbonate at reflux temperature for about 18 to about 36 hours. The compound of I) is obtained.

Also, the compound of formula (I) can be prepared by the process described in Route C.
Path C

In which R ^alk represents a C ₁ -C ₄ alkyl group or Bn, preferably a C ₁ -C ₃ alkyl group, and more preferably Et.

  Compounds of formula (X) are commercially available or can be obtained from compounds of formula (II) using standard esterification conditions. The protected amines of formula (III) are commercially available or can be prepared analogously to the method of Oku et al. (WO 99/54284) described above.

  Compounds of formula (XI) can be prepared by reacting ester (X) with an optionally substituted 3-methylsulfanyl-phenol as described above in Route A, step (b). Suitable optional catalysts for use in this reaction include CuI.

  Preferred conditions for use herein are treatment with cesium carbonate in dioxane at about 100 ° C. for about 48 hours. In this description, it will be described by manufacturing 15.

Step (e) -Ester Hydrolysis The hydrolysis of ester (XI) can be carried out in a suitable solvent, optionally at elevated temperature, in the presence of an acid or base to give acid (XII). Typically, ester (XI) is converted to a suitable base, such as an alkali metal hydroxide (eg, LiOH, NaOH) or carbonate base (eg, K ₂ ) in an aqueous solvent (MeOH, EtOH, dioxane, THF) at room temperature. Treatment with CO ₃ , Cs ₂ CO ₃ ) gives the acid (XII). The preferred conditions herein are to treat ester (XI) in THF with a 1M aqueous solution of LiOH at room temperature for about 2 hours. In this specification, it will be described by manufacturing 16.

  Alternatively, the compound of formula (XII) can be prepared by reaction with an optionally substituted 3-methylsulfanyl-phenol from the compound of formula (II) as described above in Route A, step (b). Can be manufactured.

As described above in Route A, Step (a) and Route B, Step (a), an acid of formula (XII) is reacted with an amine of formula (VIII) to give a compound of formula (I). Preferred conditions for forming a compound of formula (I) from the corresponding acid of formula (XII) herein are the treatment of acid (XII) with oxalyl chloride in DCM and DMF for about 2 hours at room temperature ( Acid chloride), followed by treatment of a solution of amine (VIII) and Et ₃ N in DCM at room temperature for about 48 hours.

  The compound of formula (V) described in route A is alternatively prepared by reaction of acid (XII) with protected amine (III) according to the method described in route A, step (a) Can do. This is explained in manufacturing 17 herein.

Further Routes Certain R ³ groups can be converted to suitable functional group (FGI) and transformations, such as suitable alkali metal bases in an appropriate solvent such as acetonitrile and / or N, N-dimethylformamide at elevated temperatures. Alkylation of hydroxy substituents with a suitable alkyl bromide, optionally in the presence of (eg K ₂ CO ₃ ), optionally in the presence of a catalyst (eg KI), or treatment with lithium iodide in pyridine or collidine Or demethylation of the methoxy group by treatment with BBr ₃ in dichloromethane.

  Appropriate protecting group strategies can be used, as detailed above for specific compounds in the description. For example, the hydroxyl group can be protected with a tetrahydropyran group and deprotection treated with a solution of acetic acid: water: tetrahydrofuran (4: 1: 2 by volume) at room temperature for up to 18 hours. Can be implemented. Furthermore, the benzyloxy group can be used and deprotected, for example, by reduction (eg, using palladium black in acid) to give the corresponding hydroxyl compound.

For example, the reaction of amine (VI) with the formula QR ³ COOH (where Q is an alcohol protecting group (eg THP or phenyl, preferably THP)) with a carboxylic acid to obtain a protected amide can be represented by the scheme It can be carried out as described in step (c) of a. A preferred condition for such a reaction is to treat a solution of amine (VI) in NMP with carboxylic acid, QR ³ COOH, HOBT, WSCDI and Huenig base at room temperature for about 72 hours.

  Removal of the protecting group (Q) from the protected amide should be carried out by specific standard methods for the protecting group as described in “Protective Groups in Organic Synthesis” by TW Greene and P. Wutz. Can do. Preferred conditions for such deprotection herein are when Q = THP: (VII) is treated with an AcOH: water (4: 1 by volume) mixture at about 60 ° C. for about 17 hours. It is. Protection / deprotection strategies are described herein in Preparation 19 and Example 10.

  The preparation of all the above reactions and the new starting materials used in the above methods are conventional suitable reagents and the reaction conditions for their performance or preparation as well as methods for isolating the desired product are described in the literature. Would be well known to those skilled in the art with respect to the precedents of this and the examples and preparations herein.

  For some steps of the process for preparing nicotinamide derivatives of formula (I) described herein, it may be necessary to protect potentially reactive functional groups that are undesirable to react. In such cases, all compatible protecting groups can be used. Certain methods can be used, such as those described by T.W. GREENE (Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication, 1981) or by McOMIE (Protective Groups in Organic Chemistry, Plenum Press, 1973).

  Also, not only the nicotinamide derivatives of formula (I), but also the intermediates for their production can be purified by various well-known methods such as crystallization or chromatography.

Thus, according to a further embodiment, the present invention provides:
(i) reacting an amine of general formula (VI) via treatment with a suitable acid of formula R ³ COOH; or
(ii) replacing the leaving group (LG) of the compound of formula (IX) with an optionally substituted 3-methylsulfanyl-phenol group; or
(iii) reacting an acid of formula (XII) with an amine of formula (VIII);
2. A process for the preparation of a nicotinamide derivative of formula (I) as claimed in claim 1 comprising: wherein formulas (VI), (IX) and (XII) are as defined above.

The present invention further provides compounds of general formulas (VI), (IX) and (XII) as defined above.
According to yet another embodiment, the present invention provides a process for the preparation of compounds of general formula (VI), (IX) and (XII), wherein said process is a process of route A herein. (a) (b) and (c), route B steps (c) and (a) and route C steps (b) and (e).

  Also, the nicotinamide derivative of formula (I) can optionally be converted to a pharmaceutically acceptable salt. In particular, these pharmaceutically acceptable salts of nicotinamide derivatives of formula (I) include the acid addition salts and basic salts (including disalts) thereof.

  Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, hydrogen sulfate, cansylate, citrate, edisylate, esylate ), Fumarate, gluceptate, gluconate, glucuronate, hibenzic acid, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, hydrogen phosphate Salt, isethionate, D- and L-lactate, malate, maleate, malonate, mesylate, methyl sulfate, 2-naphthylate, nicotinate, nitrate, orotate, Palmoate, phosphate, saccharate, stearate, succinate, sulfate, D- and L-tartaric acid, 1-hydroxy-2-naphthoate, 3-hydroxy-2-naphthoate Contains acid and tosylate .

  Suitable basic salts are made from bases that form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

  For a review of suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Wiley-VCH, Weinheim, Germany (2002).

  Pharmaceutically acceptable salts of the nicotinamide derivative of formula (I) can be easily prepared by mixing together a solution of the nicotinamide derivative of formula (I) and optionally the desired acid or base. it can. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.

Pharmaceutically acceptable solvates according to the invention include hydrates and solvates, in which the crystallization solvent may be isotopically substituted, for example D 2 O, d ₆ - acetone, d _6-DMSO.

  Also within the scope of the present invention are inclusion compounds, drug-host inclusion complexes, wherein the drug and host are present in non-stoichiometric amounts, in contrast to the solvates described above. . For an overview of such complexes, see J Pharm Sci, 64 (8), 1269-1288 (August 1975) by Haleblian.

  All references to nicotinamide derivatives of formula (I) below include references to salts thereof, as well as solvates and inclusion compounds of compounds of formula (I) and salts thereof.

  The present invention includes all polymorphs of nicotinamide derivatives of formula (I).

  Also, so-called “prodrugs” of the nicotinamide derivatives of formula (I) are within the scope of the invention. Accordingly, certain derivatives of the nicotinamide derivatives of formula (I) that have little pharmacological activity per se have the desired activity when metabolized in the body or upon administration to the body. Nicotinamide derivatives can be generated. Such derivatives are referred to as “prodrugs”.

  Prodrugs according to the present invention can be prepared, for example, by suitable functional groups present in nicotinamide derivatives of the formula (I), eg “Pro-moiety” described by H Bundgaard in “Design of Prodrugs” (Elsevier, 1985). By replacing certain parts known to those skilled in the art.

  Finally, certain nicotinamide derivatives of formula (I) can themselves act as prodrugs of other nicotinamide derivatives of formula (I).

  Nicotinamide derivatives of formula (I) containing one or more asymmetric carbon atoms can exist as two or more optical isomers. Where the nicotinamide derivative of formula (I) contains an alkenyl or alkenylene group, cis / trans (or Z / E) geometric isomers are possible, where the nicotinamide derivative contains, for example, a keto or oxime group , Tautomeric isomerism ("tautomerism") can occur. This allows a single nicotinamide derivative to exhibit multiple isomeric forms.

  All optical isomers, geometric isomers and tautomeric forms of nicotinamide derivatives of formula (I), including compounds showing more than one isomeric form, and mixtures of one or more thereof are Are included within the scope of the present invention.

  Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as fractional crystallization and chromatography.

  Conventional techniques for the production / isolation of individual stereoisomers include conversion of the appropriate optically pure precursor, resolution of the racemate (or racemate of the salt or derivative), which can be, for example, Chiral HPLC or fractional crystallization of a salt of a diastereoisomer formed by reaction of the racemate with a suitable optically active acid or base, such as tartaric acid, is used.

  The present invention also includes all pharmaceutically acceptable isotopic variants of the nicotinamide derivatives of formula (I). Isotopic variants are defined as having at least one atom replaced with an atom having the same atomic number but having an atomic mass different from the atomic mass normally found in nature.

Examples of isotopes suitable for inclusion in the nicotinamide derivatives of the present invention include isotopes of hydrogen such as ² H and ³ H, carbon such as ¹³ C and ¹⁴ C, nitrogen such as ¹⁵ N, oxygen, Examples include ¹⁷ O and ¹⁸ O, phosphorus such as ³² P, sulfur such as ³⁵ S, fluorine such as ¹⁸ F and chlorine such as ³⁶ Cl.

Substitution of nicotinamide derivatives of formula (I) with isotopes such as deuterium (ie ² H) provides greater metabolic stability, eg, increased in vivo half-life, or required dose Can be reduced and thereby obtain certain therapeutic benefits, which is preferable in some situations.

Certain isotopic variants of the nicotinamide derivative of formula (I), for example those incorporating a radioactive isotope, are useful for drug and / or substrate tissue distribution studies. The radioactive isotopes tritium (ie ³ H) and carbon-14 (ie ¹⁴ C) are particularly useful for this purpose in terms of ease of incorporation and detectability.

  Isotopic variants of the nicotinamide derivatives of formula (I) are described by the conventional techniques known to those skilled in the art or by using the appropriate isotopic variants of the appropriate reagents in the appended examples and preparations. Generally, it can be produced by a method similar to

  According to a further aspect, the present invention provides not only mixtures of nicotinamide derivatives of formula (I) but also their pharmaceutically acceptable salts, solvates, polymorphs, isomeric forms and / or isotopic forms. Of or a mixture thereof.

  According to the present invention, all the above-mentioned forms of nicotinamide derivatives of formula (I), excluding pharmaceutically acceptable salts (i.e. said solvates, polymorphs, isomeric forms and isotopic forms) are: Is defined as “derived form” of the nicotinamide derivative of formula (I).

  Nicotinamide derivatives of formula (I), pharmaceutically acceptable salts and / or derived forms thereof are useful for the treatment of many disorders involving the PDE4 enzyme, in particular inflammatory disorders, allergic disorders, respiratory diseases and wounds and It is a valuable pharmaceutically active compound suitable for prevention.

  The nicotinamide derivatives of formula (I) and their pharmaceutically acceptable salts and derived forms as described above are administered according to the invention to animals, preferably mammals, and especially humans as medicaments for treatment or prevention. be able to. They can be administered by themselves, in mixtures thereof, or in combination with other drugs, or can be enterally (intragastric) or parenterally (intragastric) and active ingredients Pharmaceutical formulations containing as effective doses of at least one nicotinamide derivative of formula (I), pharmaceutically acceptable salts and / or derivatives thereof, as well as conventional pharmaceutically harmless excipients and / or additives Can be administered. The term “excipient” is used herein to describe any ingredient other than the compound of the invention. The choice of excipient will to a large extent depend on the particular mode of administration.

  The nicotinamide derivative of formula (I), pharmaceutically acceptable salt and / or derivative form thereof is lyophilized, spray dried or evaporated to obtain a solid plug, powder or a film of crystalline or amorphous material Can do. Microwave or radio frequency drying can be used for this purpose.

Oral Administration The nicotinamide derivatives of formula (I), their pharmaceutically acceptable salts and / or the derived forms of the present invention can be administered orally. Oral administration can include swallowing such that the compound enters the gastrointestinal tract, or oral or sublingual administration where the compound enters the bloodstream directly from the mouth.

  Formulations suitable for oral administration include solid dosage forms such as tablets, capsules containing microparticulate liquids or powders, lozenges (including those filled with liquids), chews, multi and nanoparticulates, gels, membranes ( Including mucoadhesive), cavity suppositories, sprays and liquid formulations.

  Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as fillers in soft or hard capsules and are typically carriers such as water, ethanol, propylene glycol, methylcellulose or suitable oils and one or more Emulsifiers and / or suspending agents. Liquid preparations can also be produced, for example, by reconstituting solids from sachets.

  Also, nicotinamide derivatives of formula (I), pharmaceutically acceptable salts thereof and / or derived forms of the present invention can be rapidly dissolved, rapidly disintegrating dosage forms such as Expert Opinion in Therapeutic Patents by Liang and Chen. 11 (6), 981-986 (2001).

A typical tablet composition according to the present invention may comprise:
Ingredient w / w%
Nicotinamide derivatives of formula (I) 10.00 ^*
Microcrystalline cellulose 64.12
Lactose 21.38
Croscarmellose sodium 3.00
Magnesium stearate 1.50
^* Amount adjusted according to drug activity

  A typical tablet can be manufactured using standard processes known to pharmaceutical chemists, for example by direct compression, granulation (wet, dry or melt), melt coagulation, or extrusion. Tablet formulations may include one or more layers and may be coated or uncoated.

  Examples of excipients suitable for oral administration include carriers such as cellulose, calcium carbonate, dicalcium phosphate, mannitol and sodium citrate, granulating binders such as polyvinylpyrrolidine, hydroxypropylcellulose, hydroxypropylmethylcellulose and gelatin, Disintegrants such as sodium starch glycolate and silicates, lubricants such as magnesium stearate and stearic acid, wetting agents such as sodium lauryl sulfate, preservatives, antioxidants, flavoring agents and coloring agents are included.

  Solid dosage forms for oral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled dual, targeted and programmed release. Details of suitable techniques to improve release, such as high energy dispersion, osmotic and coated particles are found in Verma et al, Pharmaceutical Technology On-line, 25 (2), 1-14 (2001). Other improved release formulations are described in US Pat. No. 6,106,864.

Parenteral Administration The nicotinamide derivatives of formula (I), pharmaceutically acceptable salts thereof and / or the derived forms of the invention can also be administered directly into the bloodstream, muscle or viscera. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Devices suitable for parenteral administration include needled (including microneedle) injectors, needleless injectors and infusion techniques.

  Parenteral preparations are typically aqueous solutions that may contain excipients such as salts, carbohydrates and buffering agents (preferably a pH of 3-9), although for some applications they are sterile non-aqueous solutions. Or as a dry form for use with an appropriate vehicle, eg, sterile pyrogen-free water.

  The production of parenteral formulations under sterile conditions, for example by lyophilization, can be easily carried out using standard pharmaceutical techniques well known to those skilled in the art.

  The solubility of the nicotinamide derivatives of formula (I) used for the preparation of parenteral solutions is determined by appropriate processing, for example by use of high energy spray dried dispersions (see WO 01/47495) and / or suitable formulations. It can be enhanced by techniques such as the use of solubility-accelerators.

  Formulations for parenteral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled dual, targeted and programmed release.

Topical Administration The nicotinamide derivatives of the present invention can also be administered topically to the skin or mucous membranes, transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, cachets, implants, sponges, fibers, bandages and microemulsions. included. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid paraffin, white petrolatum, glycerin and propylene glycol. Penetration enhancers can be incorporated, see J Pharm Sci, 88 (10), 955-958 (October 1999) by Finnin and Morgan.

  Alternative means for topical administration include iontophoresis, electroporation, phonophoresis, sonophoresis and delivery by needleless or microneedle injection.

  Formulations for topical administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled dual, targeted and programmed release. Accordingly, the nicotinamide derivatives of formula (I) can be formulated in a more solid form for administration as an implanted depot preparation in which the active compound is released over time.

Inhalation / Intranasal Administration The nicotinamide derivatives of formula (I) are also typically in the form of a dry powder (alone or as a mixture, eg in the anhydrous or monohydrate form, preferably the monohydrate Dry powder (in dry blends with lactose, mannitol, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose or trehalose in mixed form or as mixed particles, e.g. mixed particles with phospholipids) Using a suitable propellant, e.g. dichlorofluoromethane, from an inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydraulics to generate a fine mist) or nebulizer With or without nasal passage or by inhalation Can be administered.

  Pressurized containers, pumps, sprays, atomizers or nebulizers are suitable alternatives, solvents, for example to disperse, solubilize or prolong the release of active compound, eg ethanol (optionally aqueous ethanol) or active compound As a propellant and optionally a surfactant or a solution or suspension of the active compound, including sorbitan trioleate or oligolactic acid.

  Prior to use in a dry powder or suspension formulation, the drug product is comminuted to a size suitable for delivery by inhalation (typically less than 5 microns). This can be done by any suitable comminuting method, such as spiral jet ring, fluid bed jet ring, supercritical fluid treatment to form nanoparticles, high pressure homogenization or spray drying.

  A suitable solution formulation for use in an atomizer that uses electrohydrodynamics to generate a fine mist can contain 1 μg to 20 mg of a nicotinamide derivative of formula (I) per actuation, and the working volume is Can vary from 1 μl to 100 μl. A typical formulation may comprise a nicotinamide derivative of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

  Capsules, blisters and cartridges (eg made of gelatin or HPMC) for use in inhalers or ventilators are nicotinamide derivatives of formula (I), suitable powder bases such as lactose or starch and performance control An agent such as a powder mix of I-leucine, mannitol or magnesium stearate can be formulated.

  In the case of dry powder inhalers and aerosols, the dosage unit is measured by a valve that supplies a metered amount. The unit according to the invention is typically set up to administer a metered dose, ie a “puff” containing 1 μg to 4000 μg of the nicotinamide derivative of formula (I). The total daily dose is typically in the range of 1 μg to 20 mg, which can be administered in a single dose or, more generally, in divided doses throughout the day.

  Formulations for inhalation / intranasal administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled dual, targeted and programmed release. Sustained or controlled release can be obtained, for example, using poly (D, L-lactic acid-glycolic acid).

  Flavoring agents such as mentol (methol) and levomentol and / or sweetening agents such as saccharin or saccharin sodium can be added to the formulation.

Rectal / Vaginal Administration The nicotinamide derivatives of formula (I) can be administered rectally or vaginally, for example in the form of suppositories, pessaries or enemas. Cocoa butter is a conventional suppository base, but various alternatives can be used as needed.
Formulations for rectal / vaginal administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled dual, targeted and programmed release.

Ophthalmic / Early Administration Also, nicotinamide derivatives of formula (I) are typically pulverized suspensions or liquid droplets in isotonic, pH adjusted, sterile saline. Can be administered directly to the eye or ear. Other formulations suitable for ocular and otic administration include ointments, biodegradable (eg absorbable gel sponges, collagen) and non-biodegradable (eg silicone) implants, cachets, lenses and microparticles or vesicles. Systems such as niosomes or liposomes are included. Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose or methylcellulose, or heteropolysaccharide polymers such as gellan gum can be incorporated with preservatives such as benzalkonium chloride it can. Such formulations can also be supplied by iontophoresis.
Formulations for administration to the eye / ear can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled dual, targeted or programmed release.

Effective Techniques Nicotinamide derivatives of formula (I) are combined with polymers containing soluble polymeric units, such as cyclodextrin or polyethylene glycol, for solubility, dissolution rate, taste masking, bioavailability and / or Or stability can be improved.

  Drug-cyclodextrin complexes have been found to be useful, for example, for most dosage forms and administration routes in general. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with drugs, cyclodextrins can be used as auxiliary additives, ie as carriers, diluents or solubilizers. The most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which are described in International Patent Application Nos. WO 91/11172, WO 94/02518 and WO 98/55148. Can be found.

Dose For administration to human patients, the total daily dose of the nicotinamide derivative of formula (I) is typically in the range of 0.001 mg / kg to 100 mg / kg, and will of course depend on the mode of administration. The The total daily dose can be administered in a single dose or in divided doses. The physician can easily determine the dose for the patient depending on the age, weight, health status and gender of the patient as well as the severity of the disease.

  Also according to another embodiment of the invention, the nicotinamide derivative of formula (I), its pharmaceutically acceptable salt and / or its derivative form is in combination with one or more further therapeutic agents Can be used and co-administered to a patient to achieve some particularly favorable therapeutic outcomes. The second and further therapeutic agent is also a nicotinamide derivative of formula (I), a pharmaceutically acceptable salt thereof and / or a derivative form thereof, or one or more PDE4 inhibitions known in the art. An agent may be used. More typically, the second and further therapeutic agents are selected from different types of therapeutic agents.

As used herein, with respect to a nicotinamide derivative of formula (I) and one or more other therapeutic agents, the terms “administered in combination”, “administered in combination” and “in combination with” Means the following and includes:
Simultaneously administering such a combination of a nicotinamide derivative and a therapeutic agent to a patient in need of treatment, wherein the ingredients are formulated together in a single dosage form, the dosage form being substantially Release the ingredients at the same time;
Administering to a patient in need of such a combination of a nicotinamide derivative and a therapeutic agent substantially simultaneously, wherein such ingredients are formulated separately from each other into individual dosage forms When ingested at substantially the same time, the component is released to the patient at substantially the same time;
Sequential administration of such combinations of nicotinamide derivatives and therapeutic agents to patients in need of treatment, wherein such ingredients are formulated into separate individual dosage forms, each of which is administered When the patient ingests sequentially at significant time intervals, the components are released to the patient at substantially different times; and-nicotinamide derivatives and therapeutic agents are administered to the patient in need of treatment. When such combinations are administered sequentially, where such ingredients are formulated together into a single dosage form that releases the ingredients in a controlled manner, they are the same and / or different to the patient They are administered at the same time, sequentially and / or overlapping.

Suitable examples of other therapeutic agents that may be used in combination with the nicotinamide derivative of formula (I), pharmaceutically acceptable salts thereof and / or derivative forms thereof include, but are not limited to: Not:
(a) a 5-lipoxygenase (5-LO) inhibitor or a 5-lipoxygenase activating protein (FLAP) antagonist;
(b) leukotriene antagonists (LTRA), including antagonists of LTB4, LTC4, LTD4 and LTE4,
(c) histamine receptor antagonists including H1, H3 and H4 antagonists,
(d) α1- and α2-adrenergic receptor vasoconstrictive sympathomimetic agonists for use in decongestants;
(e) a muscarinic M3 receptor antagonist or an anticholinergic agent,
(f) β2-adrenergic receptor agonist,
(g) Theophylline,
(h) sodium cromoglycate,
(i) a COX-1 inhibitor (NSAID) and a COX-2 selective inhibitor,
(j) oral or inhaled glucocorticosteroids,
(k) a monoclonal antibody that is active against endogenous inflammatory elements;
(l) an anti-tumor necrosis factor (anti-TNF-α) drug,
(m) adhesion molecule inhibitors including VLA-4 antagonists,
(n) kinin-B1- and B2-receptor antagonists,
(o) an immunosuppressant,
(p) an inhibitor of matrix metalloprotease (MMP),
(q) tachykinin NK1, NK2 and NK3 receptor antagonists,
(r) an elastase inhibitor,
(s) an adenosine A2a receptor agonist,
(t) an inhibitor of urokinase,
(u) a compound acting on a dopamine receptor, such as a D2 agonist,
(v) a modulator of the NFkb pathway, such as an IKK inhibitor;
(w) a drug that can be classified as a mucolytic or antitussive,
(x) antibiotics and
(y) p38 MAP kinase inhibitor.

According to the invention, nicotinamide derivatives of formula (I) Including perenzepine and telenzepine,
Β2-adrenergic receptor agonists such as albutalol, salbutamol, formoterol and salmeterol,
A p38 MAP kinase inhibitor,
・ H3 antagonists,
Glucocorticosteroids, especially inhaled glucocorticosteroids with reduced systemic side effects, such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, and mometasone furanate, or adenosine An A2a receptor agonist,
The combination with is preferable.

  It will be appreciated that all references to treatment herein include curative, palliative and prophylactic treatment. The following description relates to therapeutic applications in which nicotinamide derivatives of formula (I) may be used.

  The nicotinamide derivatives of formula (I) inhibit the PDE4 isozyme, and as explained below, the PDE4 family of isozymes has a wide range of therapeutic uses because of the essential role it plays in all mammalian physiology. Have The role of the enzyme performed by the PDE4 isozyme is the intracellular hydrolysis of adenosine 3 ′, 5′-monophosphate (cAMP) in pro-inflammatory leukocytes. Thereby, cAMP mediates the effects of many hormones in the body, so that inhibition of PDE4 plays an important role in various physiological processes. In addition to increasing cAMP, PDEs in various inflammatory cell responses, including superoxide production, degranulation, chemotaxis and inhibition of tumor necrosis factor (TNF) release in eosinophils, neutrophils and monocytes There is extensive literature in the art describing the effects of inhibitors.

  Accordingly, a further aspect of the invention relates to the use of nicotinamide derivatives of formula (I), pharmaceutically acceptable salts and / or derived forms thereof in the treatment of diseases, disorders and conditions involving PDE4 isozymes. More particularly, the invention relates to the use of a nicotinamide derivative of formula (I), pharmaceutically acceptable salts and / or derived forms thereof in the treatment of diseases, disorders and conditions selected from the group consisting of:

All types, etiology or pathogenic asthma, especially atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, pathophysiological Endogenous asthma caused by disability, extrinsic asthma caused by environmental factors, essential asthma of unknown or occult causes, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen Induced asthma, cold-induced asthma, occupational asthma, infectious asthma caused by bacterial, fungal, protozoal or viral infections, non-allergic asthma, early asthma and wheezy infant syndrome Asthma, a member selected from the group consisting of
Chronic or acute bronchoconstriction, chronic bronchitis, small airway obstruction and emphysema,
All types, etiology or pathogenic obstructive or inflammatory airway diseases, especially chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD including chronic bronchitis, emphysema or associated dyspnea, COPD characterized by irreversible, progressive airway obstruction, adult respiratory distress syndrome (ARDS), and a member selected from the group consisting of worsening airway hyperresponsiveness resulting from other drug treatments obstructive or inflammatory Airway disease,
All types, etiology or pathogenic pneumoconiosis, especially aluminum pneumonia or bauxite worker's disease, charcoal or digger asthma, asbestosis or steam pipe asthma, stone disease or flint disease, Selected from the group consisting of ptilosis caused by inhalation of dust from ostrich feathers, iron disease caused by inhalation of iron particles, silicosis or grinder disease, cotton lung disease or cotton dust asthma and talc pneumonia Pneumoconiosis, which is a constituent member,
All types, etiology or pathogenic bronchitis, especially acute bronchitis, acute laryngotracheobronchitis, arachidic bronchitis, catarrhal bronchitis, croup bronchitis, dry bronchitis, infectious Bronchitis, a member selected from the group consisting of asthmatic bronchitis, productive bronchitis, staphylococcal or streptococcal bronchitis and alveolar bronchitis,

All types, etiology or pathogenic bronchiectasis, especially cylindrical bronchiectasis, saccular bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, saccular bronchiectasis, dry bronchiectasis and follicles Bronchiectasis that is a member selected from the group consisting of systemic bronchiectasis,
Seasonal allergic rhinitis or perennial allergic rhinitis or sinusitis, especially suppurative or non-suppurative sinusitis, acute or chronic sinusitis, and ethmoid, frontal, maxilla Or sinusitis, which is a member selected from the group consisting of sphenoid sinusitis,
Rheumatoid arthritis of all types, etiology or pathogenesis, especially acute arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis and spondyloarthritis Rheumatoid arthritis, a member selected from the group,
Gout and fever and pain associated with inflammation,
Eosinophil-related disorders of all types, etiology or pathology, especially eosinophilia, pulmonary infiltrating eosinophilia, Leffler syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchi Selected from the group consisting of pneumonia aspergillosis, aspergilloma, granulomas including eosinophils, allergic granulomatous vasculitis or Churg-Strauss syndrome, nodular polyarteritis (PAN) and systemic necrotizing vasculitis Disorders related to eosinophils that are constituent members,
Atopic dermatitis, allergic dermatitis, contact dermatitis or allergic or atopic eczema,
・ All types, etiology or pathogenic urticaria, especially immune-mediated urticaria, complement-mediated urticaria, urticaria-inducing urticaria, physical factor-induced urticaria , Stress-induced urticaria, idiopathic urticaria, acute urticaria, chronic urticaria, angioedema, cholinergic urticaria, autosomal dominant or acquired forms of cold urticaria, contact Urticaria, a member selected from the group consisting of urticaria, giant urticaria and papule urticaria,

・ Selected from the group consisting of all types, etiology or pathogenic conjunctivitis, especially irradiation conjunctivitis, acute catarrhal conjunctivitis, acute infectious conjunctivitis, allergic conjunctivitis, atopic conjunctivitis, chronic catarrhal conjunctivitis, purulent conjunctivitis and spring conjunctivitis Conjunctivitis, which is a constituent member,
Uveitis of all types, etiology or pathogenesis, especially inflammation of all or part of the uveitis, anterior uveitis, iritis, ciliitis, iridocyclitis, granulomatous uveitis Uveitis, a member selected from the group consisting of: non-granulomatous uveitis, lens antigenic uveitis, posterior uveitis, choroiditis; and chorioretinitis,
·psoriasis,
Multiple sclerosis, which is a member selected from the group consisting of multiple sclerosis of all types, etiology or pathogenesis, in particular primary progressive multiple sclerosis and relapsing-remitting multiple sclerosis,
Autoimmune / inflammatory diseases of all types, etiology or pathology, especially autoimmune blood diseases, hemolytic anemia, aplastic anemia, true erythrocytic anemia, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, Polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease, ulcerative colitis, Endocrine eye disorder, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonia, primary biliary cirrhosis, juvenile diabetes or type I diabetes mellitus, dry keratoconjunctivitis, epidemic keratoconjunctivitis, diffuse interstitial lung fiber Or interstitial pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, glomerulonephritis with and without nephrotic syndrome, acute glomerulonephritis, idiopathic nephrotic syndrome Autoimmunity / a member of the group selected from the group consisting of minimal change nephropathy, inflammatory / hyperproliferative skin disease, benign familial pemphigus, erythematous pemphigus, deciduous pemphigus, and pemphigus vulgaris Inflammatory diseases,

Prevention of allograft rejection after organ transplantation,
-Composition selected from the group consisting of all types, etiology or pathogenic inflammatory bowel disease (IBD), especially collagen accumulitis, colitis polyps, transmural colitis, ulcerative colitis and Crohn's disease (CD) Members of inflammatory bowel disease,
Septic shock of any type, etiology or pathology, especially renal failure, acute renal failure, cachexia, malaria cachexia, pituitary cachexia, uremic cachexia, cardiac cachexia, adrenal cachexia A septic shock that is a member selected from the group consisting of quality or Addison's disease, cancer cachexia and cachexia due to human immunodeficiency virus (HIV) infection,
Liver damage,
All types, etiology or pathogenic pulmonary hypertension, eg primary pulmonary hypertension / essential hypertension, secondary pulmonary hypertension for congestive heart failure, secondary pulmonary hypertension for chronic obstructive pulmonary disease, pulmonary venous hypertension Pulmonary arterial hypertension and hypoxia-induced pulmonary hypertension,
Bone loss disease, primary osteoporosis and secondary osteoporosis,
Central nervous system disorders of all types, etiology or pathology, especially depression, Alzheimer's disease, Parkinson's disease, learning and memory impairment, tardive dyskinesia, drug dependence, dementia with arteriosclerotic dementia and Huntington's chorea, Wilson Central nervous system disorders that are members selected from the group consisting of disease, tremor paralysis and thalamic atrophy,
Infectious diseases, particularly those caused by viruses that increase TNF-α production in the host or are susceptible to up-regulation of TNF-α in the host, so that replication or other vital activity is adversely affected, such as Infection by a virus that is a member selected from the group consisting of HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and herpesviruses including herpes zoster and herpes simplex,

• Yeast and fungal infections, wherein said yeast and fungi are sensitive to up-regulation by TNF-α or induce TNF-α production in the host, eg fungal meningitis Other drugs selected to treat systemic yeast and fungal infections, such as polymyxin, such as polymyxin B, imidazole, such as clotrimazole, econazole, miconazole and ketoconazole, triazole, such as fluconazole And itranazole, and amphotericin such as, but not limited to, amphotericin B and liposomal amphotericin B.
Ischemia-reperfusion injury, ischemic heart disease, autoimmune diabetes, retinal autoimmunity, chronic lymphocytic leukemia, HIV infection, lupus erythematosus, kidney and ureteral diseases, genitourinary and gastrointestinal disorders and prostate diseases,
Reduction of scar formation in the human or animal body, eg in the healing of acute wounds,
• Psoriasis, other dermatological and aesthetic applications, such as anti-inflammatory drugs, skin-softening, skin elasticity and water increasing activity.

According to one aspect, the present invention specifically relates to respiratory diseases such as adult respiratory distress syndrome (ARDS), bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, asthma, emphysema, bronchiectasis, It relates to the treatment of sinusitis and rhinitis.
According to another aspect, the invention relates to a gastrointestinal (GI) disorder, in particular an inflammatory bowel disease (IBD), such as Crohn's disease, ileitis, collagen accumulitis, colitis polyposa, transmural colon For inflammation and ulcerative colitis.

According to a further aspect, the present invention also relates to the reduction of scar formation.
Still further aspects of the invention relate to the use of a nicotinamide derivative of formula (I), a pharmaceutically acceptable salt and / or a derivatized form thereof for the manufacture of a drug having PDE4 inhibitory activity. In particular, the invention relates to the manufacture of a medicament for treating inflammatory, respiratory, allergic and scar-forming diseases, disorders and conditions, and more particularly for treating the aforementioned diseases, disorders and conditions. To the use of nicotinamide derivatives of formula (I), pharmaceutically acceptable salts and / or derivatized forms thereof.

  As a result, the present invention is a particularly interesting treatment for mammals, including humans, using a PDE4 inhibitor, comprising a nicotinamide derivative of formula (I), a pharmaceutically acceptable salt and / or a derivatized form thereof Wherein said method comprises treating said mammal with an effective amount of More particularly, the present invention is a particularly interesting treatment for mammals, including humans, for the treatment of inflammatory, respiratory, allergic and scar-forming diseases, disorders or conditions of the formula (I Wherein the mammal is treated with an effective amount of a nicotinamide derivative, pharmaceutically acceptable salt and / or derivative form thereof.

The following examples illustrate the preparation of nicotinamide derivatives of formula (I):
Where the manufacture or example is described as being carried out by another method “similar to”, this may be done, for example, using recrystallization rather than column chromatography in the purification step or using an alternative solvent in phase separation. This means that there may be slight differences in the actual method. However, when facing such a reaction, such small differences are considered to be within the general knowledge and experimental experience of skilled chemists.

エチル−２−クロロ−５−フルオロニコチネート（nicotinoate）(５０.４ｇ，０.２４７mol)(これはJ. Med. Chem., 1993, 36(18), 2676-88, 第2684頁, 第2欄, 実施例3、エチル−２−クロロ−５−フルオロピリジン−３−カルボキシレートの方法に従って製造することができる)を、テトラヒドロフラン(ＴＨＦ)(３５０ｍＬ)中に溶解し、水酸化リチウム(２４７ｍＬ，０.４９５mol)の２Ｍ水溶液を加えた。反応混合物を室温で３日撹拌した。６Ｍ塩酸を添加して溶液のｐＨをｐＨ１に低下させてから、ジクロロメタン(×３)で抽出した。合わせた抽出物を硫酸マグネシウムで乾燥させ、真空下で溶媒を濃縮して固形物を得、これをジエチルエーテルで摩砕してから乾燥させ、標題化合物を白色固形物４０.５６ｇとして得た。
¹ＨＮＭＲ(ＤＭＳＯ−Ｄ₆，４００ＭＨｚ)：8.20 (s, 1H), 8.62 (s, 1H)
ＭＳ ＥＳ＋ ｍ／ｚ １７４[ＭＨ]⁺ Manufacturing 1
2-chloro-5-fluoronicotinic acid

Ethyl-2-chloro-5-fluoronicotinate (50.4 g, 0.247 mol) (this is J. Med. Chem., 1993, 36 (18), 2676-88, 2684, 2nd). Column, Example 3, which can be prepared according to the method of ethyl-2-chloro-5-fluoropyridine-3-carboxylate) in tetrahydrofuran (THF) (350 mL) and lithium hydroxide (247 mL, 0.495 mol) of 2M aqueous solution was added. The reaction mixture was stirred at room temperature for 3 days. 6M hydrochloric acid was added to lower the pH of the solution to pH 1 and then extracted with dichloromethane (x3). The combined extracts were dried over magnesium sulfate and the solvent was concentrated under vacuum to give a solid that was triturated with diethyl ether and dried to give the title compound as a white solid, 40.56 g.
¹ HNMR (DMSO-D ₆ , 400 MHz): 8.20 (s, 1H), 8.62 (s, 1H)
MS ES + m / z 174 [MH] ⁺

木炭上の５％パラジウム(５ｇ)をトルエン(１０ｍＬ)と混合し、そしてメタノール(４００ｍＬ)中のシン−(４−アジド−シクロヘキシル)−カルバミン酸tert−ブチルエステル(１７０ｇ，０.７１mol)(ＷＯ ９９／５４２８４，第８０頁，製造７７(１)，シス−４−(Ｎ−tert−ブトキシカルボニルアミノ)シクロヘキシルアジドの方法に従って製造した)に加えた。混合物を室温で１８時間水素化(８０気圧)してから濾過した。溶媒を真空下で蒸発させ、残留物を酢酸エチル(５０ｍＬ)、それからヘキサン(２００ｍＬ)で摩砕した。得られた固形物を濾過により単離し、酢酸エチル(６００ｍＬ)中に溶解し、セライト^(R)に通して濾過した。濾液を真空下で濃縮しスラッシュを得、これをヘキサン(３００ｍＬ)で希釈した。得られる固形物を濾過により単離し、ヘキサン中の酢酸エチル(８０：２０)で洗浄した。母液を合わせて真空下で蒸発させた。残留物を、溶離液として酢酸エチル、次いでメタノールを用いてシリカゲル上のクロマトグラフィにより精製した。得られた物質を酢酸エチルおよびヘキサンから結晶化させ、最初に集めたものと合わせて標題化合物を白色固形物(７６.０ｇ)として得た。
Ｍｐｔ ８８〜９０℃
¹ＨＮＭＲ(ＣＤＣｌ₃，４００ＭＨｚ)：1.41 (s, 9H), 1.52-1.77(m, 8H), 1.82(m, 1H),
1.97(m, 1H), 2.61 (m, 1H), 3.62(m, 1H), 4.59(m, 1H)
ＭＳ ＥＳ＋ ｍ／ｚ ２１５[ＭＨ]⁺ Manufacturing 2
Syn-tert-butyl 4-aminocyclohexyl carbamate

5% palladium on charcoal (5 g) is mixed with toluene (10 mL) and syn- (4-azido-cyclohexyl) -carbamic acid tert-butyl ester (170 g, 0.71 mol) in methanol (400 mL) (WO 99/54284, page 80, preparation 77 (1), prepared according to the method of cis-4- (N-tert-butoxycarbonylamino) cyclohexyl azide). The mixture was hydrogenated (80 atm) at room temperature for 18 hours and then filtered. The solvent was evaporated under vacuum and the residue was triturated with ethyl acetate (50 mL) then hexane (200 mL). The resulting solid was isolated by filtration, dissolved in ethyl acetate (600 mL) and filtered through Celite ^(R) . The filtrate was concentrated in vacuo to give a slush that was diluted with hexane (300 mL). The resulting solid was isolated by filtration and washed with ethyl acetate in hexane (80:20). The mother liquors were combined and evaporated under vacuum. The residue was purified by chromatography on silica gel using ethyl acetate and then methanol as eluent. The resulting material was crystallized from ethyl acetate and hexane and combined with the first collection gave the title compound as a white solid (76.0 g).
Mpt 88-90 ° C
¹ HNMR (CDCl ₃ , 400 MHz): 1.41 (s, 9H), 1.52-1.77 (m, 8H), 1.82 (m, 1H),
1.97 (m, 1H), 2.61 (m, 1H), 3.62 (m, 1H), 4.59 (m, 1H)
MS ES + m / z 215 [MH] ⁺

インダゾール−３−エチル−カルボキシレート(Synthesis, 1984, (11), 982-983，第９８３頁，生成物６ｃａの方法に従って製造)(１.９０ｇ，１０.０mmol)、２−(２−ブロモエトキシ)テトラヒドロピラン(２.２５ｇ，１０.８mmol)、炭酸カリウム(１.４３ｇ，１０.４mmol)およびヨウ化リチウム(６７ｍｇ，０.５０mmol)を１−メチル−２−ピロリジノン(２０ｍＬ)中に溶解し、反応混合物を８０℃で１７時間撹拌した。反応混合物を酢酸エチル(２５０ｍＬ)と水(２５０ｍＬ)との間で分配し、有機層を水(３×２００ｍＬ)で洗浄し、硫酸マグネシウムで乾燥させて真空下で濃縮した。残留物を、ペンタン：酢酸エチル１０：１→５：１→３：１→２：１→１：１により溶離してシリカゲルのカラムクロマトグラフィで精製して標題生成物(１.８８ｇ)を得た。
¹ＨＮＭＲ(ＤＭＳＯ−Ｄ₆，４００ＭＨｚ)：1.20-1.53(m, 6H), 1.35)t, 3H), 3.30(m, 2H), 3.80(m, 1H), 4.00(m, 1H), 4.37(m, 2H), 4.48(m, 1H), 4.70(m, 2H), 7.32(t, 2H), 7.80(d, 1H), 8.05(d, 1H)
ＭＳ ＥＳ＋ ｍ／ｚ ３４１[ＭＮａ]⁺ Manufacturing 3
1- [2- (Tetrahydro-pyran-2-yloxy) -ethyl] -1H-indazole-3-carboxylic acid ethyl ester

Indazole-3-ethyl-carboxylate (prepared according to the method of Synthesis, 1984, (11), 982-983, page 983, product 6ca) (1.90 g, 10.0 mmol), 2- (2-bromoethoxy ) Tetrahydropyran (2.25 g, 10.8 mmol), potassium carbonate (1.43 g, 10.4 mmol) and lithium iodide (67 mg, 0.50 mmol) were dissolved in 1-methyl-2-pyrrolidinone (20 mL). The reaction mixture was stirred at 80 ° C. for 17 hours. The reaction mixture was partitioned between ethyl acetate (250 mL) and water (250 mL) and the organic layer was washed with water (3 × 200 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with pentane: ethyl acetate 10: 1 → 5: 1 → 3: 1 → 2: 1 → 1: 1 to give the title product (1.88 g). .
¹ HNMR (DMSO-D ₆ , 400 MHz): 1.20-1.53 (m, 6H), 1.35) t, 3H), 3.30 (m, 2H), 3.80 (m, 1H), 4.00 (m, 1H), 4.37 ( m, 2H), 4.48 (m, 1H), 4.70 (m, 2H), 7.32 (t, 2H), 7.80 (d, 1H), 8.05 (d, 1H)
MS ES + m / z 341 [MNa] ⁺

水(３.７５ｍＬ)中の水酸化ナトリウム(４１３ｍｇ，１０.３３mmol)の溶液をエタノール(１４.７ｍＬ)中の製造３のエステル(１.８３ｇ，５.７４mmol)の溶液に滴加し、反応混合物を室温で４８時間撹拌した。反応混合物を２Ｍ塩酸で処理してｐＨ３に調整した。溶液を、酢酸エチル(７５ｍＬ)と水(７５ｍＬ)との間で分配し、水性層を酢酸エチル(３×６０ｍＬ)で抽出した。有機層を合わせ、硫酸マグネシウムで乾燥させて真空下で濃縮し、標題生成物を白色固形物１.４４ｇとして得た。
¹ＨＮＭＲ(ＤＭＳＯ−Ｄ₆，４００ＭＨｚ)：1.20-1.55(m, 6H), 3.30(m, 2H), 3.80(m, 1H), 4.00(m, 1H), 4.48(m, 1H), 4.68(m, 2H), 7.28(m, 1H), 7.46(m, 1H), 7.80(d, 1H), 8.08(d, 1H), 12.90(s, 1H)
ＭＳ ＥＳ− ｍ／ｚ ２８９[Ｍ−Ｈ]^- Manufacturing 4
1- [2- (Tetrahydro-pyran-2-yloxy) -ethyl] -1H-indazole-3-carboxylic acid

A solution of sodium hydroxide (413 mg, 10.33 mmol) in water (3.75 mL) was added dropwise to a solution of the ester of preparation 3 (1.83 g, 5.74 mmol) in ethanol (14.7 mL) and reacted. The mixture was stirred at room temperature for 48 hours. The reaction mixture was adjusted to pH 3 by treatment with 2M hydrochloric acid. The solution was partitioned between ethyl acetate (75 mL) and water (75 mL) and the aqueous layer was extracted with ethyl acetate (3 × 60 mL). The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo to give the title product as a white solid, 1.44 g.
_{^{1 HNMR (DMSO-D 6,}} 400MHz): 1.20-1.55 (m, 6H), 3.30 (m, 2H), 3.80 (m, 1H), 4.00 (m, 1H), 4.48 (m, 1H), 4.68 ( m, 2H), 7.28 (m, 1H), 7.46 (m, 1H), 7.80 (d, 1H), 8.08 (d, 1H), 12.90 (s, 1H)
MS ES- m / z 289 [M-H] ⁻

エチルブロモピルベート(５１.９ｇ，２６６mmol)をエチレングリコールジメチルエーテル(２７０ｍＬ)中の２−アミノピリジン(２５ｇ，２６６mmol)の溶液に滴加し、次いで反応液を室温で１時間撹拌した。生成した沈殿を濾過し、固形物をエーテルで洗浄して乾燥させ、標題化合物を淡黄色の固形物７１.９ｇとして得た。
¹ＨＮＭＲ(ＣＤＣｌ₃，３００ＭＨｚ)：1.35 (t, 3H), 4.35 (q, 2H), 4.70 (d, 1H), 5.15 (d, 1H), 7.10-7.20 (m, 2H), 8.10 (m, 1H), 8.25 (d, 1H)。 Manufacturing 5
2-Amino-1- (3-ethoxy-2,3-dioxopropyl) pyridinium bromide

Ethyl bromopyruvate (51.9 g, 266 mmol) was added dropwise to a solution of 2-aminopyridine (25 g, 266 mmol) in ethylene glycol dimethyl ether (270 mL) and then the reaction was stirred at room temperature for 1 hour. The resulting precipitate was filtered and the solid was washed with ether and dried to give the title compound as a pale yellow solid, 71.9 g.
¹ HNMR (CDCl ₃ , 300 MHz): 1.35 (t, 3H), 4.35 (q, 2H), 4.70 (d, 1H), 5.15 (d, 1H), 7.10-7.20 (m, 2H), 8.10 (m, 1H), 8.25 (d, 1H).

エタノール(７５０ｍｌ)中の製造５の化合物(７１.９ｇ，２４９mmol)の懸濁液を還流で３時間加熱し、次いでさました。混合物を真空下で濃縮し、残留物をエーテルで摩砕し、濾過し、そして乾燥させて標題化合物を固形物(６４.１７ｇ)として得た。
¹ＨＮＭＲ(ＣＤ₃ＯＤ，３００ＭＨｚ)：1.45 (t, 3H), 4.50 (q, 2H), 7.55 (m, 1H), 7.95 (m, 1H), 8.10 (dd, 1H), 8.80 (s, 1H), 8.85 (d, 1H)。 Production 6
Ethylimidazo [1,2-a] pyridine-2-carboxylate hydrobromide

A suspension of the compound of Preparation 5 (71.9 g, 249 mmol) in ethanol (750 ml) was heated at reflux for 3 hours and then pressed. The mixture was concentrated in vacuo and the residue was triturated with ether, filtered and dried to give the title compound as a solid (64.17 g).
¹ HNMR (CD ₃ OD, 300 MHz): 1.45 (t, 3H), 4.50 (q, 2H), 7.55 (m, 1H), 7.95 (m, 1H), 8.10 (dd, 1H), 8.80 (s, 1H ), 8.85 (d, 1H).

１０％の水性臭化水素酸(９０ｍＬ)中の製造６のエステル(５.０ｇ，１８.４mmol)の溶液を還流下で６時間加熱した。さました混合物を真空下で濃縮し、残留物をジオキサンで摩砕した。生成した固形物を濾過し、ヘキサンで洗浄し、そして濾液を真空下で濃縮した。再び、残留物をジオキサンで摩砕し、固形物を濾過し、乾燥させてさらなる化合物を全部で３.８３ｇ得た。
¹ＨＮＭＲ(ＣＤ₃ＯＤ，３００ＭＨｚ)：7.57 (m, 1H), 7.96 (d, 1H), 8.06 (m, 1H), 8.78 (s, 1H), 8.84 (d, 1H)。
ＭＳ ＥＳ＋ ｍ／ｚ １６３[ＭＨ]⁺ Manufacturing 7
Imidazo [1,2-a] pyridine-2-carboxylic acid hydrobromide

A solution of the ester of Preparation 6 (5.0 g, 18.4 mmol) in 10% aqueous hydrobromic acid (90 mL) was heated at reflux for 6 hours. The triturated mixture was concentrated in vacuo and the residue was triturated with dioxane. The resulting solid was filtered, washed with hexane, and the filtrate was concentrated in vacuo. Again, the residue was triturated with dioxane and the solid was filtered and dried to give a total of 3.83 g of additional compound.
¹ HNMR (CD ₃ OD, 300 MHz): 7.57 (m, 1H), 7.96 (d, 1H), 8.06 (m, 1H), 8.78 (s, 1H), 8.84 (d, 1H).
MS ES + m / z 163 [MH] ⁺

エタノール(５ｍＬ)中のメチル２−アミノニコチネート(ＷＯ ８９／０１４８８，第３３頁，製造１７の方法に従って製造)(１ｇ，６.５６mmol)およびクロロアセトアルデヒド(１.０５ｍＬ，６.５６mmol)の混合物を還流下で１８時間加熱した。さました混合物を水(１０ｍＬ)で希釈し、０.８８アンモニア(１ｍＬ)を加え、溶液を真空下で濃縮した。残留物をメタノール中に溶解し、黒ずんだ溶液を木炭で処理し、混合物を濾過し、濾液を真空下で濃縮した。残留物を、ジクロロメタン：メタノール：０.８８アンモニア(９７：２.５：０.５)を溶離液として用いてシリカゲルのカラムクロマトグラフィで精製し、生成物をエーテルで摩砕して標題化合物(７６８ｍｇ)を得た。
¹ＨＮＭＲ(ＣＤＣｌ₃，４００ＭＨｚ)：4.02 (s, 3H), 6.83 (s, 1H), 7.63 (s, 1H), 7.79 (s, 1H), 8.00 (d, 1H), 8.31 (d, 1H)。
ＭＳ ＴＳＰ＋ ｍ／ｚ １７７.２[ＭＨ⁺] Manufacturing 8
Methylimidazo [1,2-a] pyridine-8-carboxylate

Mixture of methyl 2-aminonicotinate (prepared according to the method of WO 89/01488, page 33, preparation 17) (1 g, 6.56 mmol) and chloroacetaldehyde (1.05 mL, 6.56 mmol) in ethanol (5 mL) Was heated at reflux for 18 hours. The triturated mixture was diluted with water (10 mL), 0.88 ammonia (1 mL) was added and the solution was concentrated in vacuo. The residue was dissolved in methanol, the dark solution was treated with charcoal, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (97: 2.5: 0.5) as eluent and the product was triturated with ether to give the title compound (768 mg )
¹ HNMR (CDCl ₃ , 400 MHz): 4.02 (s, 3H), 6.83 (s, 1H), 7.63 (s, 1H), 7.79 (s, 1H), 8.00 (d, 1H), 8.31 (d, 1H) .
MS TSP + m / z 177.2 [MH ⁺ ]

水酸化リチウム溶液(２.５ｍＬ，水中１Ｍ)をメタノール(５ｍＬ)中の製造８のエステル(４００ｍｇ，２.２７mmol)の溶液に加え、溶液を室温で９０分間撹拌した。溶液を真空下で濃縮してメタノールを除去し、２Ｍ塩酸を用いて水溶液を酸性化し、そして混合物を真空下で濃縮し、標題化合物を黄色固形物として得た。
¹ＨＮＭＲ(ＤＭＳＯ−Ｄ₆，４００ＭＨｚ)：7.60 (dd, 1H), 8.10 (s, 1H), 8.41 (d, 1H), 8.55 (s, 1H), 9.18 (d, 1H)
ＭＳ ＴＳＰ＋ ｍ／ｚ １６３[ＭＨ]⁺ Manufacturing 9
Imidazo [1,2-a] pyridine-8-carboxylic acid

Lithium hydroxide solution (2.5 mL, 1 M in water) was added to a solution of the ester of Preparation 8 (400 mg, 2.27 mmol) in methanol (5 mL) and the solution was stirred at room temperature for 90 minutes. The solution was concentrated in vacuo to remove methanol, the aqueous solution was acidified with 2M hydrochloric acid, and the mixture was concentrated in vacuo to give the title compound as a yellow solid.
¹ HNMR (DMSO-D ₆ , 400 MHz): 7.60 (dd, 1H), 8.10 (s, 1H), 8.41 (d, 1H), 8.55 (s, 1H), 9.18 (d, 1H)
MS TSP + m / z 163 [MH] ⁺

２−ヨードプロパン(２.０ｍＬ，２０mmol)をＮ,Ｎ−ジメチルホルムアミド(２０ｍＬ)中のエチル２,３−ジアミノベンゾエート(ＷＯ ９７／１０２１９，第８１頁、実施例５１(１)の方法に従って製造)(３ｇ，１６.６７mmol)の溶液に加え、溶液を５０℃で３時間撹拌した。混合物を減圧下で濃縮し、残留物を酢酸エチル(２００ｍＬ)と水(５０ｍＬ)の間で分配し、層を分離した。有機層を水(５×５０ｍＬ)で洗浄し、硫酸マグネシウムで乾燥させて真空下で濃縮した。粗生成物を、酢酸エチル：ペンタン(５：９５→９０：１０)を用いてシリカゲルのカラムクロマトグラフィで精製し、標題化合物を黄色油１.４ｇとして得た。
¹ＨＮＭＲ(ＣＤＣｌ₃，４００ＭＨｚ)：1.20 (d, 6H), 1.38 (t, 3H), 3.56 (m, 1H), 4.31 (q, 2H), 5.60 (brs, 2H), 6.84 (m, 1H), 6.80 (d, 1H), 7.42 (d, 1H)。
ＭＳ ＥＳ＋ ｍ／ｚ ２２３[ＭＨ]⁺ Manufacturing 10
Ethyl 2-amino-3-isopropylamino-benzoate

2-Iodopropane (2.0 mL, 20 mmol) prepared according to the method of ethyl 2,3-diaminobenzoate (WO 97/10219, page 81, Example 51 (1) in N, N-dimethylformamide (20 mL). ) (3 g, 16.67 mmol) was added and the solution was stirred at 50 ° C. for 3 h. The mixture was concentrated under reduced pressure, the residue was partitioned between ethyl acetate (200 mL) and water (50 mL), and the layers were separated. The organic layer was washed with water (5 × 50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using ethyl acetate: pentane (5: 95 → 90: 10) to give the title compound as a yellow oil, 1.4 g.
¹ HNMR (CDCl ₃ , 400 MHz): 1.20 (d, 6H), 1.38 (t, 3H), 3.56 (m, 1H), 4.31 (q, 2H), 5.60 (brs, 2H), 6.84 (m, 1H) , 6.80 (d, 1H), 7.42 (d, 1H).
MS ES + m / z 223 [MH] ⁺

ギ酸(１５ｍＬ)中の製造１０のアミン(１.４ｇ，６.３１mmol)の溶液を６０℃で４５分間撹拌した。２Ｍ塩酸(２０ｍＬ)およびさらなるギ酸(１５ｍＬ)を加え、反応液を還流下で１２時間加熱した。さました混合物を真空下で濃縮し、残留物を最初に酢酸エチルで摩砕し、固形物を濾過して乾燥させた。この固形物を、次いで熱酢酸エチルで摩砕し、固形物を濾過して６０℃で乾燥させ、標題化合物を淡桃色の固形物１.１６ｇとして得た
¹ＨＮＭＲ(ＤＭＳＯ−Ｄ₆，４００ＭＨｚ)：1.61 (d, 6H), 5.10 (m, 1H), 7.72 (m, 1H), 8.13 (d, 1H), 8.39 (d, 1H), 9.75 (s, 1H)。
ＭＳ ＴＳＰ＋ ｍ／ｚ ２０５[ＭＨ]⁺ Manufacturing 11
1-Isopropyl-1H-benzimidazole-4-carboxylic acid

A solution of the preparation 10 amine (1.4 g, 6.31 mmol) in formic acid (15 mL) was stirred at 60 ° C. for 45 min. 2M hydrochloric acid (20 mL) and additional formic acid (15 mL) were added and the reaction was heated at reflux for 12 hours. The triturated mixture was concentrated in vacuo, the residue was first triturated with ethyl acetate and the solid was filtered and dried. This solid was then triturated with hot ethyl acetate and the solid filtered and dried at 60 ° C. to give the title compound as a pale pink solid 1.16 g.
¹ HNMR (DMSO-D ₆ , 400 MHz): 1.61 (d, 6H), 5.10 (m, 1H), 7.72 (m, 1H), 8.13 (d, 1H), 8.39 (d, 1H), 9.75 (s, 1H).
MS TSP + m / z 205 [MH] ⁺

２−クロロ−３−ニトロ安息香酸(２０.６ｇ，０.２４mol)を水酸化アンモニウム溶液(１２０ｍＬ)中に溶解し、反応混合物を密封容器中１２０℃で７時間撹拌した。反応混合物は水(２５０ｍＬ)で希釈し、塩酸を用いてｐＨ２に酸性化した。形成された沈殿を濾過し、真空下で乾燥させて標題生成物１５.０ｇ(８０％)を得た。
¹ＨＮＭＲ(ＣＤ₃ＯＤ，４００ＭＨｚ)：6.65(dd, 1H), 8.24(dd, 1H), 8.32(dd, 1H)。 Production 12
2-Amino-3-nitrobenzoic acid

2-Chloro-3-nitrobenzoic acid (20.6 g, 0.24 mol) was dissolved in ammonium hydroxide solution (120 mL) and the reaction mixture was stirred in a sealed vessel at 120 ° C. for 7 hours. The reaction mixture was diluted with water (250 mL) and acidified to pH 2 using hydrochloric acid. The formed precipitate was filtered and dried under vacuum to give 15.0 g (80%) of the title product.
¹ HNMR (CD ₃ OD, 400 MHz): 6.65 (dd, 1H), 8.24 (dd, 1H), 8.32 (dd, 1H).

製造１２のニトロ化合物(６.０ｇ，３３.０mmol)をメタノール(１５０ｍＬ)中に溶解し、溶液を１０％Ｐｄ／Ｃ(３００ｍｇ)で処理し、６０psiの水素下で１８時間撹拌した。反応混合物を濾過して触媒を除去し、濾液を真空下で濃縮した。残留物をメタノール(１５０ｍＬ)中に取り、木炭(５.０ｇ)で処理し、混合物を室温で１時間撹拌した。混合物を濾過し、濾液を真空下で濃縮して標題生成物(３.０ｇ)を得た。
¹ＨＮＭＲ(ＤＭＳＯ−Ｄ₆，４００ＭＨｚ)：6.29(m, 1H), 6.64(m, 1H), 7.03(m, 1H)。 Production 13
2,3-Diamino-benzoic acid

The nitro compound of Preparation 12 (6.0 g, 33.0 mmol) was dissolved in methanol (150 mL) and the solution was treated with 10% Pd / C (300 mg) and stirred under 60 psi of hydrogen for 18 hours. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated in vacuo. The residue was taken up in methanol (150 mL), treated with charcoal (5.0 g) and the mixture was stirred at room temperature for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo to give the title product (3.0 g).
¹ HNMR (DMSO-D ₆ , 400 MHz): 6.29 (m, 1H), 6.64 (m, 1H), 7.03 (m, 1H).

酢酸(１ｍＬ)および水(２ｍＬ)中の製造１３のジアミン(３００ｍｇ，１.９７mmol)の溶液を水(２ｍＬ)中の亜硝酸ナトリウム(１５１ｍｇ，２.２０mmol)の溶液で滴下処理し、反応混合物を室温で１８時間撹拌した。形成された褐色の固形物を濾過し、水で洗浄し、真空下で乾燥させて標題生成物(２２０ｍｇ)を得た。
¹ＨＮＭＲ(ＣＤ₃ＯＤ，４００ＭＨｚ))：7.53(dd, 1H), 8.16(dd, 1H), 8.24(m, 1H)。
ＭＳ ＥＳ＋ ｍ／ｚ １６４[ＭＨ]⁺ Production 14
1H-benzotriazole-4-carboxylic acid

A solution of the preparation 13 diamine (300 mg, 1.97 mmol) in acetic acid (1 mL) and water (2 mL) was treated dropwise with a solution of sodium nitrite (151 mg, 2.20 mmol) in water (2 mL) and the reaction mixture. Was stirred at room temperature for 18 hours. The formed brown solid was filtered, washed with water and dried under vacuum to give the title product (220 mg).
¹ HNMR (CD ₃ OD, 400 MHz)): 7.53 (dd, 1H), 8.16 (dd, 1H), 8.24 (m, 1H).
MS ES + m / z 164 [MH] ⁺

ジオキサン(３００ｍＬ)中のエチル−２−クロロ−５−フルオロ−ニコチネート(nicotinoate)(２９ｇ，０.１４３mol)(J. Med. Chem., 1993, 36(18), 2676-88，第２６８４頁，第２欄，３番目の化合物，エチル２−クロロ−５−フルオロピリジン−３−カルボン酸の方法に従って製造)および３−メチルスルファニル−フェノール(２０ｇ，０.１４３mol)(ＷＯ ９８／４５２６８，第６８頁、製造６１の方法に従って製造)の溶液を室温で炭酸セシウム(４６.５ｇ，０.１４３mol)で処理した。反応混合物を１００℃に加熱して４８時間撹拌した。反応混合物を真空下で濃縮し、残留物を水(６００ｍＬ)中に取り、酢酸エチル(３×２５０ｍＬ)で抽出した。有機層を合わせ、ブライン(２００ｍＬ)で洗浄し、硫酸マグネシウムで乾燥させて真空下で濃縮した。残留物を、ジクロロメタン：トルエン(９９.７５：０.２５→９９.５：０.５)により溶離してシリカゲルのカラムクロマトグラフィで精製して標題生成物を黄色油(２７.１ｇ)として得た。
¹ＨＮＭＲ(ＣＤＣｌ₃，４００ＭＨｚ)：1.37(t, 3H), 2.23(s, 3H), 4.40(q, 2H), 6.84(m, 1H), 7.01 (m, 1H) 7.08(m, 1H), 7.26(m, 1H), 7.98(m, 1H), 8.13(m, 1H)。
ＭＳ ＡＰＣＩ＋ ｍ／ｚ ３０８[ＭＨ]⁺ Production 15
5-Fluoro-2- (3-methylsulfanyl-phenoxy) -nicotinic acid ethyl ester

Ethyl-2-chloro-5-fluoro-nicotinate (29 g, 0.143 mol) in dioxane (300 mL) (J. Med. Chem., 1993, 36 (18), 2676-88, page 2684, Column 2, third compound, prepared according to the method of ethyl 2-chloro-5-fluoropyridine-3-carboxylic acid) and 3-methylsulfanyl-phenol (20 g, 0.143 mol) (WO 98/45268, 68) Solution prepared according to the method of page 61, preparation 61) at room temperature with cesium carbonate (46.5 g, 0.143 mol). The reaction mixture was heated to 100 ° C. and stirred for 48 hours. The reaction mixture was concentrated in vacuo and the residue was taken up in water (600 mL) and extracted with ethyl acetate (3 × 250 mL). The organic layers were combined, washed with brine (200 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: toluene (99.75: 0.25 → 99.5: 0.5) to give the title product as a yellow oil (27.1 g). .
¹ HNMR (CDCl ₃ , 400 MHz): 1.37 (t, 3H), 2.23 (s, 3H), 4.40 (q, 2H), 6.84 (m, 1H), 7.01 (m, 1H) 7.08 (m, 1H), 7.26 (m, 1H), 7.98 (m, 1H), 8.13 (m, 1H).
MS APCI + m / z 308 [MH] ⁺

製造１５のエステル(２７.１ｇ，８８.２mmol)をテトラヒドロフラン(３００ｍＬ)に溶解し、溶液を水酸化リチウム(２２０ｍＬ，２２０mmol)の１Ｍ水溶液で処理した。反応混合物を室温で２時間撹拌した。反応混合物を真空下で濃縮してテトラヒドロフランを除去し、水性部分を０℃に冷却した後、塩酸を用いてｐＨ１に酸性化した。生成した桃色沈殿を濾過により除去し、氷冷水で洗浄した。固形物をジクロロメタン(８００ｍＬ)に溶解し、酸性化されたブライン溶液(２００ｍＬ)で洗浄した。有機層を分離し、硫酸マグネシウムで乾燥させ、真空下で濃縮した。残留物をトルエンで摩砕し、標題生成物を白色固形物２２.１３ｇとして得た。
¹ＨＮＭＲ(ＣＤ₃ＯＤ，４００ＭＨｚ)：2.43(s, 3H), 6.83(m, 1H), 7.01(m, 1H), 7.06(m, 1H), 7.25(m, 1H), 8.03(m, 2H)。
ＭＳ ＡＰＣＩ＋ ｍ／ｚ ２８０[ＭＨ]⁺ Production 16
5-Fluoro-2- (3-methylsulfanyl-phenoxy) -nicotinic acid

The ester of Preparation 15 (27.1 g, 88.2 mmol) was dissolved in tetrahydrofuran (300 mL) and the solution was treated with a 1M aqueous solution of lithium hydroxide (220 mL, 220 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and the aqueous portion was cooled to 0 ° C. and then acidified to pH 1 with hydrochloric acid. The resulting pink precipitate was removed by filtration and washed with ice cold water. The solid was dissolved in dichloromethane (800 mL) and washed with acidified brine solution (200 mL). The organic layer was separated, dried over magnesium sulfate and concentrated under vacuum. The residue was triturated with toluene to give the title product as a white solid 22.13g.
¹ HNMR (CD ₃ OD, 400 MHz): 2.43 (s, 3H), 6.83 (m, 1H), 7.01 (m, 1H), 7.06 (m, 1H), 7.25 (m, 1H), 8.03 (m, 2H ).
MS APCI + m / z 280 [MH] ⁺

製造１６の酸(５ｇ，１７.９mmol)およびＮ,Ｎ−ジメチルホルムアミド(５滴)をジクロロメタン(１００ｍＬ)中に溶解し、溶液を０℃に冷却した。これを塩化オキサリル(３.１ｍＬ，３５.８mmol)で１５分かけて滴下処理してから室温で２時間撹拌した。反応混合物を真空下で濃縮し、残留物をジクロロメタン(１００ｍＬ)中に取った。溶液を０℃に冷却し、トリエチルアミン(７.５ｍＬ，５４mmol)および製造２のアミン(４.２ｇ，１９.６mmol)で処理した。反応混合物を室温に加温させて室温で４８時間撹拌した。反応混合物をジクロロメタン(１００ｍＬ)で希釈し、水(７０ｍＬ)、１０％クエン酸溶液(２×７０ｍＬ)、飽和炭酸水素ナトリウム溶液(２×７０ｍＬ)および水(７０ｍＬ)で洗浄した。有機層を硫酸マグネシウムで乾燥させ、真空下で濃縮して標題生成物８.０ｇを得た。
¹ＨＮＭＲ(ＣＤＣｌ₃，４００ＭＨｚ)：1.40(s, 9H), 1.53(m, 2H), 1.68(m, 2H), 1.77(m, 4H), 2.46(s, 3H), 3.60(m, 1H), 4.18(m, 1H), 4.37(m, 1H), 6.88(m, 1H), 7.02(m, 1H), 7.17(m, 1H), 7.37(m, 1H), 7.93(m, 1H), 8.06(m, 1H), 8.36(m, 1H)。
ＭＳ ＥＳ＋ ｍ／ｚ ４７６[ＭＨ]⁺ Production 17
Syn- (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -carbamic acid tert-butyl ester

Preparation 16 acid (5 g, 17.9 mmol) and N, N-dimethylformamide (5 drops) were dissolved in dichloromethane (100 mL) and the solution was cooled to 0 ° C. This was treated dropwise with oxalyl chloride (3.1 mL, 35.8 mmol) over 15 minutes and then stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum and the residue was taken up in dichloromethane (100 mL). The solution was cooled to 0 ° C. and treated with triethylamine (7.5 mL, 54 mmol) and Preparation 2 amine (4.2 g, 19.6 mmol). The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 48 hours. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (70 mL), 10% citric acid solution (2 × 70 mL), saturated sodium bicarbonate solution (2 × 70 mL) and water (70 mL). The organic layer was dried over magnesium sulfate and concentrated under vacuum to give 8.0 g of the title product.
¹ HNMR (CDCl ₃ , 400 MHz): 1.40 (s, 9H), 1.53 (m, 2H), 1.68 (m, 2H), 1.77 (m, 4H), 2.46 (s, 3H), 3.60 (m, 1H) , 4.18 (m, 1H), 4.37 (m, 1H), 6.88 (m, 1H), 7.02 (m, 1H), 7.17 (m, 1H), 7.37 (m, 1H), 7.93 (m, 1H), 8.06 (m, 1H), 8.36 (m, 1H).
MS ES + m / z 476 [MH] ⁺

製造１７の保護されたアミン(８.０ｇ，１６.８mmol)をジオキサン(５０ｍＬ)中に溶解し、溶液をジオキサン中の塩酸の４Ｍ溶液(２５ｍＬ)で処理した。反応混合物を室温で５時間撹拌した後、真空下で濃縮し、酢酸エチルおよびジクロロメタンを用いて共沸混合して標題生成物(５.０ｇ)を得た。
¹ＨＮＭＲ(ＣＤ₃ＯＤ，４００ＭＨｚ)：1.67(m, 2H), 1.80-2.01(m, 6H), 2.45(s, 3H), 3.24(m, 1H), 4.14(m, 1H), 6.92(m, 1H), 7.09(m, 1H), 7.17(m, 1H), 7.35(t, 1H), 8.08(m, 2H)。
ＭＳ ＥＳ＋ ｍ／ｚ ３７６[ＭＨ]⁺ Production 18
Syn-N- (4-amino-cyclohexyl) -5-fluoro-2- (3-methylsulfanyl-phenoxy) -nicotinamide hydrochloride

The protected amine of Preparation 17 (8.0 g, 16.8 mmol) was dissolved in dioxane (50 mL) and the solution was treated with a 4M solution of hydrochloric acid in dioxane (25 mL). The reaction mixture was stirred at room temperature for 5 hours, then concentrated in vacuo and azeotroped with ethyl acetate and dichloromethane to give the title product (5.0 g).
¹ HNMR (CD ₃ OD, 400 MHz): 1.67 (m, 2H), 1.80-2.01 (m, 6H), 2.45 (s, 3H), 3.24 (m, 1H), 4.14 (m, 1H), 6.92 (m , 1H), 7.09 (m, 1H), 7.17 (m, 1H), 7.35 (t, 1H), 8.08 (m, 2H).
MS ES + m / z 376 [MH] ⁺

製造４のカルボン酸(１４５ｍｇ，０.５０mmol)を１−メチル−２−ピロリジノン(３ｍＬ)中に溶解し、溶液を１−ヒドロキシベンゾトリアゾール水和物(７４.３ｍｇ，０.５５mmol)および１−(３−ジメチルアミノプロピル)−３−エチルカルボジイミド塩酸塩(１１５ｍｇ，０.６０mmol)で処理した。混合物を１０分間撹拌してから、製造１８のアミン(２００ｍｇ，０.４８mmol)およびＮ−エチルジイソプロピルアミン(１５５ｍｇ，１.２０mmol)で処理し、そして室温で７２時間撹拌した。反応混合物を酢酸エチル(７５ｍＬ)と水(７５ｍＬ)との間で分配し、有機層を水(２×７５ｍＬ)および５％炭酸ナトリウム溶液(７５ｍＬ)で洗浄し、硫酸マグネシウムで乾燥させて真空下で濃縮した。残留物をエーテル：ペンタン１：１で摩砕し、標題生成物を白色固形物２１８ｍｇとして得た。
¹ＨＮＭＲ(ＤＭＳＯ−Ｄ₆，４００ＭＨｚ)：1.20-1.55(m, 6H), 1.73(m, 8H), 2.40(s, 3H), 3.23(m, 1H), 3.32(m, 1H), 3.80(m, 1H), 3.94(m, 1H), 4.00(m, 2H), 4.48(m, 1H), 4.66(m, 2H), 6.95(m, 1H), 7.07(m, 2H), 7.23(m, 1H), 7.33(m, 1H), 7.44(m, 1H), 7.50(m, 1H), 7.75(m, 1H), 8.00(m, 1H), 8.12(m, 1H), 8.25(s, 1H), 8.29(m, 1H)。
ＭＳ ＥＳ＋ ｍ／ｚ ６７０[ＭＮａ]⁺ Production 19
Syn-1- [2- (tetrahydro-pyran-2-yloxy) -ethyl] -1H-indazole-3-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine- 3-carbonyl] -amino} -cyclohexyl) -amide

Preparation 4 carboxylic acid (145 mg, 0.50 mmol) was dissolved in 1-methyl-2-pyrrolidinone (3 mL) and the solution was dissolved in 1-hydroxybenzotriazole hydrate (74.3 mg, 0.55 mmol) and 1- Treated with (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (115 mg, 0.60 mmol). The mixture was stirred for 10 minutes before being treated with Preparation 18 amine (200 mg, 0.48 mmol) and N-ethyldiisopropylamine (155 mg, 1.20 mmol) and stirred at room temperature for 72 hours. The reaction mixture was partitioned between ethyl acetate (75 mL) and water (75 mL) and the organic layer was washed with water (2 × 75 mL) and 5% sodium carbonate solution (75 mL), dried over magnesium sulfate and under vacuum. Concentrated with. The residue was triturated with ether: pentane 1: 1 to give the title product as a white solid 218 mg.
¹ HNMR (DMSO-D ₆ , 400 MHz): 1.20-1.55 (m, 6H), 1.73 (m, 8H), 2.40 (s, 3H), 3.23 (m, 1H), 3.32 (m, 1H), 3.80 ( m, 1H), 3.94 (m, 1H), 4.00 (m, 2H), 4.48 (m, 1H), 4.66 (m, 2H), 6.95 (m, 1H), 7.07 (m, 2H), 7.23 (m , 1H), 7.33 (m, 1H), 7.44 (m, 1H), 7.50 (m, 1H), 7.75 (m, 1H), 8.00 (m, 1H), 8.12 (m, 1H), 8.25 (s, 1H), 8.29 (m, 1H).
MS ES + m / z 670 [MNa] ⁺

ピラゾロ[１,５−ａ]ピリジン−２−カルボン酸(J. Het. Chem., 18(6), 1981, 1149-1152, 第１１５２頁)(８１.８ｍｇ，０.５０mmol)を１−メチル−２−ピロリジノン(３ｍＬ)中に溶解し、溶液を１−ヒドロキシベンゾトリアゾール水和物(７４.３ｍｇ，０.５５mmol)および１−(３−ジメチルアミノプロピル)−３−エチルカルボジイミド塩酸塩(１１５ｍｇ，０.６０mmol)で処理し、混合物を室温で５分間撹拌した。次いで、混合物を、製造１８のアミン(２００ｍｇ，０.４８mmol)およびＮ−エチルジイソプロピルアミン(１５５ｍｇ，１.２０mmol)で処理し、反応混合物を室温で４８時間撹拌した。反応混合物を酢酸エチル(７５ｍＬ)と水(７５ｍＬ)との間で分配し、有機層を水(３×５０ｍＬ)および水中の０.８８０アンモニア(１００ｍＬ)で洗浄し、硫酸マグネシウムで乾燥させて真空下で濃縮した。残留物をエーテルで摩砕し、標題生成物を白色固形物２２３ｍｇとして得た。¹ＨＮＭＲ(ＤＭＳＯ−Ｄ₆，４００ＭＨｚ)：1.70(m, 8H), 2.41(s, 3H), 3.87(m, 1H), 3.98(m, 1H), 6.94(m, 2H), 7.00(m, 1H), 7.07(m, 2H), 7.38(m, 2H), 7.65(d, 1H), 7.74(m, 1H), 8.00(m, 1H), 8.22(m, 2H), 8.62(m, 1H)。
ＭＳ ＥＳ＋ ｍ／ｚ ５４２[ＭＮａ]⁺
微量分析：実測値−Ｃ＝６２.３９％，Ｈ＝５.０６％，Ｎ＝１３.３５％
Ｃ₂₇Ｈ₂₆ＦＮ₅Ｏ₃Ｓ計算値−Ｃ＝６２.４１％，Ｈ＝５.０４％，Ｎ＝１３.４８％ Example 1
Syn-pyrazolo [1,5-a] pyridine-2-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide

Pyrazolo [1,5-a] pyridine-2-carboxylic acid (J. Het. Chem., 18 (6), 1981, 1149-1152, p. 1152) (81.8 mg, 0.50 mmol) was converted to 1-methyl. Dissolve in 2-pyrrolidinone (3 mL) and dissolve the solution in 1-hydroxybenzotriazole hydrate (74.3 mg, 0.55 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (115 mg , 0.60 mmol) and the mixture was stirred at room temperature for 5 minutes. The mixture was then treated with Preparation 18 amine (200 mg, 0.48 mmol) and N-ethyldiisopropylamine (155 mg, 1.20 mmol) and the reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was partitioned between ethyl acetate (75 mL) and water (75 mL) and the organic layer was washed with water (3 × 50 mL) and 0.880 ammonia in water (100 mL), dried over magnesium sulfate and vacuum. Concentrated under. The residue was triturated with ether to give the title product as a white solid 223mg. ¹ HNMR (DMSO-D ₆ , 400 MHz): 1.70 (m, 8H), 2.41 (s, 3H), 3.87 (m, 1H), 3.98 (m, 1H), 6.94 (m, 2H), 7.00 (m, 1H), 7.07 (m, 2H), 7.38 (m, 2H), 7.65 (d, 1H), 7.74 (m, 1H), 8.00 (m, 1H), 8.22 (m, 2H), 8.62 (m, 1H ).
MS ES + m / z 542 [MNa] ⁺
Trace analysis: measured value -C = 62.39%, H = 5.06%, N = 13.35%
C ₂₇ H ₂₆ FN ₅ O ₃ S calculated value-C = 62.41%, H = 5.04%, N = 13.48%

The following compounds of the general formula below were prepared by a method similar to that described in Example 1 using the appropriate carboxylic acid (R ₃ COOH).

・実施例２−製造１１のカルボン酸を使用した。粗生成物を、ジクロロメタン：メタノール１００：１→５０：１→２５：１→１５：１により溶離してシリカゲルのカラムクロマトグラフィで精製した。
・実施例３−製造７のカルボン酸を使用した。粗生成物をジクロロメタン：メタノール１００：１→５０：１→２５：１→１５：１により溶離してシリカゲルのカラムクロマトグラフィで精製した。
・実施例４−Flukaから入手可能な１Ｈ−インダゾール−３−カルボン酸を使用した。粗生成物を、ジクロロメタン：メタノール１００：１→５０：１→２５：１→１５：１、次いでペンタン：酢酸エチル１０：１→３：１→２：１→１：１→１：２→１：３により溶離してシリカゲルのカラムクロマトグラフィで精製した。
・実施例５−２−メチル−３Ｈ−ベンゾイミダゾール−４−カルボン酸(J. Med. Chem., 43, 2000, 4084-4097，第４０９０頁，第２欄，６番目の化合物)は、使用したカルボン酸である。有機物を１０％クエン酸で洗浄した後、基本的な洗浄を行った。

Example 2-Carboxylic acid from Production 11 was used. The crude product was purified by column chromatography on silica gel eluting with dichloromethane: methanol 100: 1 → 50: 1 → 25: 1 → 15: 1.
Example 3-Carboxylic acid from Production 7 was used. The crude product was purified by column chromatography on silica gel eluting with dichloromethane: methanol 100: 1 → 50: 1 → 25: 1 → 15: 1.
Example 4-1H-indazole-3-carboxylic acid available from Fluka was used. The crude product is dissolved in dichloromethane: methanol 100: 1 → 50: 1 → 25: 1 → 15: 1, then pentane: ethyl acetate 10: 1 → 3: 1 → 2: 1 → 1: 1 → 1: 2 → 1. : Purified by column chromatography on silica gel eluting with 3:
Example 5-2-Methyl-3H-benzimidazole-4-carboxylic acid (J. Med. Chem., 43, 2000, 4084-4097, page 4090, second column, sixth compound) was used Carboxylic acid. The organics were washed with 10% citric acid followed by a basic wash.

製造１８のアミン(２５０ｍｇ，０.６０mmol)をＮ,Ｎ−ジメチルホルムアミド(７ｍＬ)中に溶解し、溶液を１−ヒドロキシベンゾトリアゾール水和物(８４ｍｇ，０.６０mmol)、１−(３−ジメチルアミノプロピル)−３−エチルカルボジイミド塩酸塩(１２４ｍｇ，０.６９mmol)、４−メチルモルホリン(２０５μＬ，１.８８mmol)および製造９のカルボン酸(９０ｍｇ，０.５５mmol)で処理した。反応混合物を、室温で１８時間撹拌した。混合物を酢酸エチル：水３：１(２８ｍＬ)で希釈し、水性層を酢酸エチル(×２)で抽出した。有機物を、１０％クエン酸溶液(７ｍＬ)、飽和炭酸水素ナトリウム溶液(７ｍＬ)およびブライン(７ｍＬ)で洗浄した。有機層を硫酸マグネシウムで乾燥させて真空下で濃縮した。残留物を、ペンタン：酢酸エチル７０：３０→２０：８０により溶離してシリカゲルのカラムクロマトグラフィで精製して標題生成物(８０ｍｇ)を得た。
¹ＨＮＭＲ(ＣＤＣｌ₃，４００ＭＨｚ)：1.91(m, 8H), 2.43(s, 3H), 4.23(m, 1H), 4.32(m, 1H), 6.94(m, 2H), 7.06(m, 1H), 7.14(m, 1H), 7.31(m, 1H), 7.37(m, 1H), 7.60(m, 1H), 8.01 (m, 1H), 8.06(m, 1H), 8.17(s, 1H), 8.24(d, 1H), 8.36(m, 1H), 10.53(m, 1H)。
ＭＳ ＥＳ＋ ｍ／ｚ ５２０[ＭＨ]⁺
微量分析：実測値−Ｃ＝６０.７１％，Ｈ＝５.０２％，Ｎ＝１３.０６％
Ｃ₂₇Ｈ₂₆ＦＮ₅Ｏ₃Ｓ計算値−Ｃ＝６０.７３％，Ｈ＝５.２１％，Ｎ＝１３.１１％ Example 6
Syn-imidazo [1,2-a] pyridine-8-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide

Preparation 18 Amine (250 mg, 0.60 mmol) was dissolved in N, N-dimethylformamide (7 mL) and the solution was dissolved in 1-hydroxybenzotriazole hydrate (84 mg, 0.60 mmol), 1- (3-dimethyl Aminopropyl) -3-ethylcarbodiimide hydrochloride (124 mg, 0.69 mmol), 4-methylmorpholine (205 μL, 1.88 mmol) and preparation 9 carboxylic acid (90 mg, 0.55 mmol). The reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate: water 3: 1 (28 mL) and the aqueous layer was extracted with ethyl acetate (x2). The organics were washed with 10% citric acid solution (7 mL), saturated sodium bicarbonate solution (7 mL) and brine (7 mL). The organic layer was dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with pentane: ethyl acetate 70: 30 → 20: 80 to give the title product (80 mg).
¹ HNMR (CDCl ₃ , 400 MHz): 1.91 (m, 8H), 2.43 (s, 3H), 4.23 (m, 1H), 4.32 (m, 1H), 6.94 (m, 2H), 7.06 (m, 1H) , 7.14 (m, 1H), 7.31 (m, 1H), 7.37 (m, 1H), 7.60 (m, 1H), 8.01 (m, 1H), 8.06 (m, 1H), 8.17 (s, 1H), 8.24 (d, 1H), 8.36 (m, 1H), 10.53 (m, 1H).
MS ES + m / z 520 [MH] ⁺
Trace analysis: measured value -C = 60.71%, H = 5.02%, N = 13.06%
C ₂₇ H ₂₆ FN ₅ O ₃ S calculated value-C = 60.73%, H = 5.21%, N = 13.11%

標題化合物を、製造１４のカルボン酸を使用して実施例６に記載されたものと同様の方法によって製造した。
¹ＨＮＭＲ(ＣＤ₃ＯＤ，４００ＭＨｚ)：1.93(m, 8H), 2.38(s, 3H), 4.14(m, 1H), 4.22(m, 1H), 6.93(m, 1H), 7.06(m, 2H), 7.28(m, 1H), 7.61(m, 1H), 8.01(m, 1H), 8.04(m, 2H), 8.12(m, 1H)。
ＭＳ ＥＳ＋ ｍ／ｚ ５２１[ＭＨ]⁺
微量分析：実測値−Ｃ＝５９.２８％，Ｈ＝４.９５％，Ｎ＝１５.７５％
Ｃ₂₆Ｈ₂₅ＦＮ₆Ｏ₃Ｓ計算値−Ｃ＝５９.１７％，Ｈ＝４.９３％，Ｎ＝１５.９２％ Example 7
Syn-3H-benzotriazole-4-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide

The title compound was prepared by a method similar to that described in Example 6 using the carboxylic acid of Preparation 14.
¹ HNMR (CD ₃ OD, 400 MHz): 1.93 (m, 8H), 2.38 (s, 3H), 4.14 (m, 1H), 4.22 (m, 1H), 6.93 (m, 1H), 7.06 (m, 2H ), 7.28 (m, 1H), 7.61 (m, 1H), 8.01 (m, 1H), 8.04 (m, 2H), 8.12 (m, 1H).
MS ES + m / z 521 [MH] ⁺
Trace analysis: measured value -C = 59.28%, H = 4.95%, N = 15.75%
Calculated value of C ₂₆ H ₂₅ FN ₆ O ₃ S −C = 59.17%, H = 4.93%, N = 15.92%

製造１８のアミン(１５０ｍｇ，０.３６mmol)、１−(３−ジメチルアミノプロピル)−３−エチルカルボジイミド塩酸塩(９１ｍｇ，０.４７mmol)、１−ヒドロキシベンゾトリアゾール水和物(７２ｍｇ，０.４７mmol)、Ｎ−エチルジイソプロピルアミン(０.２５ｍＬ，１.４０mmol)および８−キノリンカルボン酸(６９ｍｇ，０.４０mmol)をジクロロメタン(１０ｍＬ)中に溶解し、反応混合物を室温で１８時間撹拌した。反応混合物を、１０％クエン酸溶液で希釈し、層を相分離管に通した濾過によって分離した。有機層を濃縮し、残留物を、ジクロロメタン：メタノール９９：１→９８：２により溶離してシリカゲルのカラムクロマトグラフィによって精製し、標題生成物を白色固形物(５１ｍｇ)として得た。
¹ＨＮＭＲ(ＤＭＳＯ−Ｄ₆，４００ＭＨｚ)：1.64-1.86(m, 8H), 2.36(s, 3H), 3.93(m, 1H), 4.14(m, 1H), 7.09(m, 3H), 7.27(t, 1H), 7.58(m, 1H), 7.75(m, 1H), 8.01(m, 1H), 8.20(m, 2H), 8.42(d, 1H), 8.56(m, 2H), 8.82(m, 1H), 11.35(m, 1H)。
ＭＳ ＥＳ＋ ｍ／ｚ ５５３[ＭＮａ]⁺ Example 8
Syn-quinoline-8-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide

Preparation 18 amine (150 mg, 0.36 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (91 mg, 0.47 mmol), 1-hydroxybenzotriazole hydrate (72 mg, 0.47 mmol) ), N-ethyldiisopropylamine (0.25 mL, 1.40 mmol) and 8-quinolinecarboxylic acid (69 mg, 0.40 mmol) were dissolved in dichloromethane (10 mL) and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with 10% citric acid solution and the layers were separated by filtration through a phase separator tube. The organic layer was concentrated and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol 99: 1 → 98: 2 to give the title product as a white solid (51 mg).
¹ HNMR (DMSO-D ₆ , 400 MHz): 1.64-1.86 (m, 8H), 2.36 (s, 3H), 3.93 (m, 1H), 4.14 (m, 1H), 7.09 (m, 3H), 7.27 ( t, 1H), 7.58 (m, 1H), 7.75 (m, 1H), 8.01 (m, 1H), 8.20 (m, 2H), 8.42 (d, 1H), 8.56 (m, 2H), 8.82 (m , 1H), 11.35 (m, 1H).
MS ES + m / z 553 [MNa] ⁺

標題生成物は、出発酸として３−ヒドロキシ−キノリン−８−カルボン酸(Chem. Pharm. Bull., 17(11), 1969, 2293-2298, 第２２９７頁，化合物(XIV)の方法に従って製造)を使用して実施例８に記載されたものと同様の方法によって製造した。
¹ＨＮＭＲ(ＤＭＳＯ−Ｄ₆，４００ＭＨｚ)：1.64-1.82(m, 8H), 2.36(s, 3H), 3.92(m, 1H), 4.12(m, 1H), 6.93(m, 1H), 7.02(m, 2H), 7.25(t, 1H), 7.60(t, 1H), 7.67(m, 1H), 8.00(d, 2H), 8.22(m, 1H), 8.33(m, 1H), 8.46(m, 1H), 8.64(m, 1H), 10.59(s, 1H), 11.14(m, 1H)
ＭＳ ＥＳ＋ ｍ／ｚ ５６９[ＭＮａ]⁺ Example 9
Syn-3-hydroxy-quinoline-8-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} cyclohexyl) -amide

The title product is 3-hydroxy-quinoline-8-carboxylic acid as the starting acid (Chem. Pharm. Bull., 17 (11), 1969, 2293-2298, page 2297, prepared according to the method of compound (XIV)) Was prepared by a method similar to that described in Example 8.
¹ HNMR (DMSO-D ₆ , 400 MHz): 1.64-1.82 (m, 8H), 2.36 (s, 3H), 3.92 (m, 1H), 4.12 (m, 1H), 6.93 (m, 1H), 7.02 ( m, 2H), 7.25 (t, 1H), 7.60 (t, 1H), 7.67 (m, 1H), 8.00 (d, 2H), 8.22 (m, 1H), 8.33 (m, 1H), 8.46 (m , 1H), 8.64 (m, 1H), 10.59 (s, 1H), 11.14 (m, 1H)
MS ES + m / z 569 [MNa] ⁺

製造１９の生成物(２００ｍｇ，０.３１mmol)を酢酸(４ｍＬ)、テトラヒドロフラン(２ｍＬ)および水(１ｍＬ)中に溶解し、反応混合物を６０℃で１７時間撹拌した。反応混合物をさましてから、炭酸カリウムの１５％水溶液中に注ぎ、酢酸エチル(１×７５ｍＬ，３×４０ｍＬ)で抽出した。有機層を合わせ、硫酸マグネシウムで乾燥させて真空下で濃縮した。残留物を、ジクロロメタン：酢酸エチル５：１→３：１→１：１→１：２により溶離してシリカゲルのカラムクロマトグラフィで精製した。粗生成物をエーテルで摩砕し、標題生成物を白色固形物１０５ｍｇ(６０％)として得た。
¹ＨＮＭＲ(ＤＭＳＯ−Ｄ₆，４００ＭＨｚ)：1.70(m, 8H), 2.42(s, 3H), 3.82(m, 2H), 3.92(m, 1H), 4.00(m, 1H), 4.50(t, 2H), 4.90(t, 1H), 6.95(d, 1H), 7.09(m, 2H), 7.24(t, 1H), 7.33(1, 1H), 7.42(m, 1H), 7.54(d, 1H), 7.73(m, 1H), 8.05(m, 1H), 8.13(m, 1H), 8.25(s, 1H), 8.33(d, 1H)。
ＭＳ ＥＳ＋ ｍ／ｚ ５８６[ＭＮａ]⁺
微量分析：実測値−Ｃ＝６１.７３％，Ｈ＝５.４６％，Ｎ＝１２.２３％
Ｃ₂₉Ｈ₃₀ＦＮ₅Ｏ₄Ｓ計算値−Ｃ＝６１.８０％，Ｈ＝５.３６％，Ｎ＝１２.４２％ Example 10
Syn-1- (2-hydroxy-ethyl) -1H-indazole-3-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl-amino} -cyclohexyl -Amide

The product of Preparation 19 (200 mg, 0.31 mmol) was dissolved in acetic acid (4 mL), tetrahydrofuran (2 mL) and water (1 mL) and the reaction mixture was stirred at 60 ° C. for 17 hours. The reaction mixture was allowed to cool and then poured into a 15% aqueous solution of potassium carbonate and extracted with ethyl acetate (1 × 75 mL, 3 × 40 mL). The organic layers were combined, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with dichloromethane: ethyl acetate 5: 1 → 3: 1 → 1: 1 → 1: 2. The crude product was triturated with ether to give the title product as a white solid 105 mg (60%).
¹ HNMR (DMSO-D ₆ , 400 MHz): 1.70 (m, 8H), 2.42 (s, 3H), 3.82 (m, 2H), 3.92 (m, 1H), 4.00 (m, 1H), 4.50 (t, 2H), 4.90 (t, 1H), 6.95 (d, 1H), 7.09 (m, 2H), 7.24 (t, 1H), 7.33 (1, 1H), 7.42 (m, 1H), 7.54 (d, 1H ), 7.73 (m, 1H), 8.05 (m, 1H), 8.13 (m, 1H), 8.25 (s, 1H), 8.33 (d, 1H).
MS ES + m / z 586 [MNa] ⁺
Trace analysis: measured value -C = 61.73%, H = 5.46%, N = 12.23%
C ₂₉ H ₃₀ FN ₅ O ₄ S calculated value-C = 61.80%, H = 5.36%, N = 12.42%

In Vitro Activity of Nicotinamide Derivatives The PDE4 inhibitory activity of nicotinamide derivatives of formula (I) was measured by the ability of compounds to inhibit the hydrolysis of cAMP to AMP by PDE4 (see also literature 1). Tritium labeled cAMP was incubated with PDE4. After incubation, the generated radiolabeled AMP can be bound to yttrium silicate SPA beads. These SPA beads produce light that can later be quantified by scintillation counting. Addition of a PDE4 inhibitor prevents the formation of AMP from cAMP and decreases the count. The IC ₅₀ of a PDE4 inhibitor can be defined as the concentration of compound that results in a 50% reduction in count compared to a PDE4 only (no inhibitor) control well.

The anti-inflammatory properties of nicotinamide derivatives of formula (I) are indicated by their ability to inhibit TNFα release from human peripheral blood mononuclear cells (see also reference 2). Venous blood was collected from healthy volunteers and mononuclear cells were purified by centrifugation through a Histopaque (Ficoll) cushion. TNFα production from these cells is stimulated by the addition of lipopolysaccharide. After 18 hours of incubation in the presence of LPS, the cell supernatant was removed and the TNFα concentration in the supernatant was measured by ELISA. Addition of a PDE4 inhibitor reduces the amount of TNFα produced. An IC ₅₀ equal to the concentration of compound at which TNFα production was inhibited by 50% compared to LPS-stimulated control wells was determined.

All examples were tested in the above assay and found to have an IC ₅₀ (TNFα screen) of less than 10 nM. And most of the test compounds were found to have an IC ₅₀ (TNFα screen) of less than 1 nM.

For purposes of illustration, the following table shows the exact IC ₅₀ (TNFα screen) of some exemplary embodiments of the invention:

Literature
1. Thompson JW, Teraski WL, Epstein PM, Strada SJ., “Assay of nucleotidephosphodiesterase and resolution of multiple molecular forms of the isoenzyme”, Advances in cyclic nucleotides research, edited by Brooker G, Greengard P, Robinson GA. Raven Press, New York 1979, 10, p. 69-92.
2. Yoshimura T, Kurita C, Nagao T, Usami E, Nakao T, Watanabe S, Kobayashi J, Yamazaki F, Tanaka H, Nagai H., “Effects of cAMP-phosphodiesterase isozyme inhibitor on cytokine production by lipopolysaccharide-stimulated human peripheral blood mononuclear cells ", Gen. Pharmacol., 1997, 29 (4), p. 63

Claims (26)

Formula (I)

[Where:
R ¹ and R ² are each independently selected from the group consisting of hydrogen, halo and (C ₁ -C ₃ ) alkyl; and R ³ is a 9 or 10 membered bicyclic ring containing 1 to 4 nitrogen atoms Wherein the bicyclic heteroaryl is OH, halo, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, hydroxy (C ₁ -C ₄ ) alkyl and hydroxy Optionally substituted by one or two groups selected from (C ₂ -C ₄ ) alkoxy]
Nicotinamide derivatives and pharmaceutically acceptable salts, prodrugs, solvates and polymorphs thereof. 2. A compound according to claim 1 wherein R < ¹ > is H, F, Cl or methyl. The compound according to claim 1 or 2, wherein R ¹ is F. The compound according to any one of claims 1 to 3, wherein R ² is H or F. The compound according to any one of claims 1 to 4, wherein R ² is H. R ³ is a 9 or 10 membered bicyclic heteroaryl containing 1 to 3 nitrogen atoms, where the bicyclic heteroaryl is OH, halo, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄₎ alkoxy and hydroxy (C ₁ -C ₄₎ optionally one or two groups selected from alkyl substituted by a compound according to any one of claims 1 to 5. R ³ is a C-linked 9- or 10-membered bicyclic heteroaryl containing 1 to 3 nitrogen atoms, wherein the bicyclic heteroaryl is OH, F, Cl, (C _1- C ₄₎ alkyl, (C ₁ -C ₄₎ alkoxy and hydroxy (C ₁ -C ₄₎ are optionally substituted by 1 or 2 groups selected from alkyl, any one of the preceding claims Compound described in 1. R ³ is a C-linked 9- or 10-membered bicyclic heteroaryl containing 1 to 3 nitrogen atoms, where the bicyclic heteroaryl is OH, (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃₎ are optionally substituted by 1 or 2 groups selected from alkoxy and hydroxy (C ₁ -C ₃₎ alkyl, according to any one of claims 1-7 Compound. The ring system of R ³ is indole, isoindole, indolizine, indazole, benzimidazole, imidazopyridine, pyrrolopyridazine, pyrrolopyridine, benzotriazole, pyrazolopyridine, imidazopyridine, quinoline, isoquinoline, cinnoline, quinoxaline, quinazoline, phthalazine The compound according to any one of claims 1 to 8, which is selected from the group consisting of naphthyridine. The bicyclic heteroaryl of R ³ is selected from the group consisting of indazole, benzimidazole, benzotriazole, imidazo [1,2-a] pyridine, pyrrolo [1,2-b] pyridazine and quinoline. 10. The compound according to any one of 9 above. Bicyclic heteroaryl of R ³ is, OH, methyl, ethyl, propyl, optionally one or more groups selected from hydroxymethyl and hydroxyethyl substituted by, one of the claims 1 to 10 1 The compound according to item. R ¹ is H, F, Cl or methyl; R ² is H or F; and R ³ is a C-linked 9 or 10 membered bicyclic ring containing 1 to 3 nitrogen atoms. Wherein the bicyclic heteroaryl is selected from OH, halo, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy and hydroxy (C ₁ -C ₄ ) alkyl. 12. A compound according to any one of claims 1 to 11, optionally substituted by one or more groups. R ¹ is F; R ² is F; and the ring system of R ³ is indazole, benzimidazole, benzotriazole, imidazo [1,2-a] pyridine, pyrrolo- [1,2-b 13. A compound according to any one of claims 1 to 12, which is an optionally substituted bicyclic heteroaryl selected from the group consisting of pyridazine and quinoline. Syn-pyrazolo [1,5-a] pyridine-2-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide ;
Syn-1-isopropyl-1H-benzimidazole-4-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide;
Syn-imidazo [1,2-a] pyridine-2-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino] -cyclohexyl) -amide ;
Syn-1H-indazole-3-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide;
Cin-2-methyl-3H-benzimidazole-4-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino] -cyclohexyl) -amide;
Syn-imidazo [1,2-a] pyridine-8-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide ;
Syn-3H-benzotriazole-4-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide;
Syn-quinoline-8-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide;
Syn-3-hydroxy-quinoline-8-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide; and syn- 1- (2-hydroxy-ethyl) -1H-indazole-3-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) 14. A compound according to any one of claims 1 to 13 and their pharmaceutically acceptable salts, prodrugs, solvates and polymorphs selected from the group consisting of amides. Syn-2-methyl-3H-benzimidazole-4-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide;
Syn-imidazo [1,2-a] pyridine-8-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide ;
Syn-quinoline-8-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide; and syn-3-hydroxy- A quinoline-8-carboxylic acid (4-{[5-fluoro-2- (3-methylsulfanyl-phenoxy) -pyridine-3-carbonyl] -amino} -cyclohexyl) -amide is selected from the group consisting of: 15. Compounds according to any one of -14 and their pharmaceutically acceptable salts, prodrugs, solvates and polymorphs.   A medicament comprising a pharmaceutically acceptable excipient, diluent or carrier together with a nicotinamide derivative of formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt or solvate thereof. Composition.   16. A nicotinamide derivative of formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, solvate or composition thereof for use as a medicament.   16. A nicotinamide derivative of formula (I) or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 15 for use in the treatment of diseases, disorders and conditions involving PDE4 isozymes. Or composition.   16. A nicotinamide derivative of formula (I) according to any one of claims 1 to 15 or a pharmaceutical thereof for use in the treatment of inflammatory, respiratory and allergic diseases, disorders and conditions and in the treatment of wounds An acceptable salt, derivative form or composition. All types, etiology or pathogenic asthma, especially atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic causes caused by pathophysiological disorders Asthma, extrinsic asthma caused by environmental factors, essential asthma of unknown or occult cause, non-atopic asthma, bronchial asthma, emphysema asthma, exercise-induced asthma, allergen-induced asthma, cold-induced asthma Asthma, a member selected from the group consisting of occupational asthma, infectious asthma caused by bacterial, fungal, protozoan or viral infections, non-allergic asthma, early asthma and infantile dyspnea syndrome,
Chronic or acute bronchoconstriction, chronic bronchitis, small airway obstruction and emphysema,
All types, etiology or pathogenic obstructive or inflammatory airway diseases, especially chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD including chronic bronchitis, emphysema or associated dyspnea, Obstructive or inflammatory airways that are members selected from the group consisting of COPD characterized by irreversible, progressive airway obstruction, adult respiratory distress syndrome (ARDS) and exacerbated airway hyperresponsiveness resulting from other medications disease,
・ From all types, etiology or pathogenic pneumoconiosis, especially aluminum pneumonia or bauxite worker disease, charcoal or miner asthma, asbestosis or steam pipe asthma, stone disease or hay fever, ostrich feathers Ostrich pneumonia caused by inhalation of dust, iron disease caused by inhalation of iron particles, silicosis or grinder disease, pneumoconiosis or cotton dust asthma and pneumoconiosis, a member selected from the group consisting of talc pneumonia,
All types, etiology or pathogenic bronchitis, especially acute bronchitis, acute laryngotracheobronchitis, arachidic acid bronchitis, catarrhal bronchitis, croup bronchitis, dry bronchitis, infectious asthmatic bronchitis Bronchitis, a member selected from the group consisting of proliferative bronchitis, staphylococcal or streptococcal bronchitis and alveolar bronchitis,
All types, etiology or pathogenesis of bronchiectasis, especially columnar bronchiectasis, vesicular bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, saccular bronchiectasis, dry bronchiectasis and follicles Bronchiectasis being a member selected from the group consisting of sexual bronchiectasis,
Seasonal allergic rhinitis or perennial allergic rhinitis or sinusitis, especially purulent or non-purulent sinusitis, acute or chronic sinusitis, and ethmoid, frontal, maxilla Or sinusitis, a member selected from the group consisting of sphenoid sinusitis,
Rheumatoid arthritis of all types, etiology or pathogenesis, especially acute arthritis, acute gouty arthritis, chronic inflammatory arthritis, osteoarthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis and spondyloarthritis Rheumatoid arthritis, a member selected from the group,
Gout and fever and pain associated with inflammation,
Eosinophil-related disorders of any type, etiology or pathology, especially eosinophilia, pulmonary infiltrating eosinophilia, Leffler syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchi Selected from the group consisting of pneumonia aspergillosis, aspergilloma, granulomas including eosinophils, allergic granulomatous vasculitis or Churg-Strauss syndrome, nodular polyarteritis (PAN) and systemic necrotizing vasculitis Disorders related to eosinophils,
Atopic dermatitis, allergic dermatitis, contact dermatitis or allergic or atopic eczema,
Urticaria of all types, etiology or pathology, especially immune-mediated urticaria, complement-mediated urticaria, urticaria-inducing urticaria, physical factors-induced urticaria Stress-induced urticaria, idiopathic urticaria, acute urticaria, chronic urticaria, angioedema, cholinergic urticaria, autosomal dominant or acquired forms of cold urticaria, contact Urticaria, a member selected from the group consisting of urticaria, giant urticaria and papule urticaria,
-Selected from the group consisting of all types, etiology or pathogenic conjunctivitis, especially radiation conjunctivitis, acute catarrhal conjunctivitis, acute infectious conjunctivitis, allergic conjunctivitis, atopic conjunctivitis, chronic catarrhal conjunctivitis, suppurative conjunctivitis Member conjunctivitis,
Uveitis of all types, etiology or pathogenesis, especially inflammation of all or part of the uveitis, anterior uveitis, iritis, ciliitis, iridocyclitis, granulomatous uveitis Uveitis, a member selected from the group consisting of: non-granulomatous uveitis, lens antigenic uveitis, posterior uveitis, choroiditis; and chorioretinitis,
·psoriasis,
Multiple sclerosis, a member selected from the group consisting of multiple sclerosis of all types, etiology or pathogenesis, especially primary progressive multiple sclerosis and relapsing-remitting multiple sclerosis,
Autoimmune / inflammatory diseases of all types, etiology or pathology, especially autoimmune blood diseases, hemolytic anemia, aplastic anemia, true erythrocytic anemia, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, Polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease, ulcerative colitis, Endocrine eye disorder, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonia, primary biliary cirrhosis, juvenile diabetes or type I diabetes mellitus, dry keratoconjunctivitis, epidemic keratoconjunctivitis, diffuse interstitial lung fiber Or interstitial pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, glomerulonephritis with and without nephrotic syndrome, acute glomerulonephritis, idiopathic nephrotic syndrome Autoimmunity / member who is selected from the group consisting of: small change nephropathy, inflammatory / hyperproliferative skin disease, benign familial pemphigus, erythematous pemphigus, deciduous pemphigus, and pemphigus vulgaris Inflammatory diseases,
Prevention of allograft rejection after organ transplantation,
A member selected from the group consisting of all types, etiology or pathogenic inflammatory bowel disease (IBD), particularly collagen accumulative colitis, colitis polyps, transmural colitis, ulcerative colitis and Crohn's disease (CD) Inflammatory bowel disease, which is
Septic shock of any type, etiology or pathology, especially renal failure, acute renal failure, cachexia, malaria cachexia, pituitary cachexia, uremic cachexia, cardiac cachexia, adrenal cachexia A member selected from the group consisting of quality or Addison's disease, cancer cachexia and cachexia due to human immunodeficiency virus (HIV) infection,
Liver damage,
All types, etiology or pathogenic pulmonary hypertension (primary pulmonary hypertension / essential hypertension, secondary pulmonary hypertension for congestive heart failure, secondary pulmonary hypertension for chronic obstructive pulmonary disease, pulmonary venous hypertension , Including pulmonary arterial hypertension and hypoxia-induced pulmonary hypertension),
Bone loss disease, primary osteoporosis and secondary osteoporosis,
Central nervous system disorders of all types, etiology or pathology, especially depression, Alzheimer's disease, Parkinson's disease, learning and memory impairment, tardive dyskinesia, drug dependence, dementia with arteriosclerotic dementia and Huntington's chorea, Wilson CNS disorders that are members selected from the group consisting of illness, tremor paralysis and thalamic atrophy,
Infectious diseases, particularly those caused by viruses that increase TNF-α production in the host or are susceptible to up-regulation of TNF-α in the host, so that replication or other vital activity is adversely affected ( HIV-1, HIV-2 and HIV-3, including cytomegalovirus (CMV), influenza, adenovirus, and infection by a virus that is a member selected from the group consisting of herpes viruses including herpes zoster and herpes simplex) ,
Yeast and fungal infections, which are susceptible to up-regulation by TNF-α in the host or induce TNF-α production, such as fungal meningitis (especially When administered together with other drugs selected to treat systemic yeast and fungal infections, the drugs are polymyxins such as polymycin B, imidazoles such as clotrimazole, econazole, miconazole and ketoconazole, Triazoles such as, but not limited to, fluconazole and itranazole, and amphotericins such as amphotericin B and liposomal amphotericin B)
Ischemia-reperfusion injury, ischemic heart disease, autoimmune diabetes, retinal autoimmunity, chronic lymphocytic leukemia, HIV infection, lupus erythematosus, kidney and ureteral diseases, genitourinary and gastrointestinal disorders and prostate disease,
-Reduction of scar formation in the human or animal body, e.g. in scar healing, and-psoriasis, other dermatological and cosmetic applications, e.g. anti-inflammatory agents, skin-softening, skin elasticity and hydration activity 16. A nicotinamide derivative of formula (I) according to any one of claims 1 to 15, a pharmaceutically acceptable salt, solvate or composition thereof for use in therapy.   Use of a nicotinamide derivative of formula (I), a pharmaceutically acceptable salt, solvate or composition thereof according to any one of claims 1 to 15 for the manufacture of a drug having PDE4 inhibitory activity.   16. A nicotinamide derivative of formula (I) according to any one of claims 1 to 15 for the manufacture of a medicament useful for the treatment of inflammatory, respiratory and allergic diseases, disorders and conditions and for the treatment of wounds. , Use of a pharmaceutically acceptable salt, solvate or composition thereof.   A nicotinamide derivative of formula (I) according to any one of claims 1 to 15, for the manufacture of a medicament for the treatment of diseases, disorders and conditions selected from the group described in claim 20, Use of an acceptable salt, solvate or composition.   16. A PDE4 comprising administering to a mammal an effective amount of a nicotinamide derivative of formula (I) according to any one of claims 1 to 15, a pharmaceutically acceptable salt, solvate or composition thereof. A method for treating mammals, including humans, using an inhibitor.   27. The method of claim 26, wherein the disease, disorder, or condition to be treated is selected from the group described in claim 20. A nicotinamide derivative of formula (I) according to any one of claims 1 to 15, a pharmaceutically acceptable salt, solvate or composition thereof,
(a) a 5-lipoxygenase (5-LO) inhibitor or a 5-lipoxygenase activating protein (FLAP) antagonist;
(b) leukotriene antagonists (LTRA), including antagonists of LTB4, LTC4, LTD4 and LTE4,
(c) histamine receptor antagonists including H1, H3 and H4 antagonists,
(d) α1- and α2-adrenergic receptor vasoconstrictive sympathomimetic agonists for use in decongestants;
(e) a muscarinic M3 receptor antagonist or an anticholinergic agent,
(f) β2-adrenergic receptor agonist,
(g) Theophylline,
(h) sodium cromoglycate,
(i) a COX-1 inhibitor (NSAID) and a COX-2 selective inhibitor,
(j) oral or inhaled glucocorticosteroids,
(k) a monoclonal antibody that is active against endogenous inflammatory elements;
(l) an anti-tumor necrosis factor (anti-TNF-α) drug,
(m) adhesion molecule inhibitors including VLA-4 antagonists,
(n) kinin-B1- and B2-receptor antagonists,
(o) an immunosuppressant,
(p) an inhibitor of matrix metalloprotease (MMP),
(q) tachykinin NK1, NK2 and NK3 receptor antagonists,
(r) an elastase inhibitor,
(s) an adenosine A2a receptor agonist,
(t) an inhibitor of urokinase,
(u) a compound acting on a dopamine receptor, such as a D2 agonist,
(v) a modulator of the NFkb pathway, such as an IKK inhibitor;
(w) a drug that can be classified as a mucolytic or antitussive,
(x) antibiotics and
(y) A combination with a therapeutic agent selected from p38 MAP kinase inhibitors.