Heterocyclic janus kinase 3 inhibitors   

The present invention relates to a novel condensed heterocyclic compound and to a medicament containing the compound as an active ingredient, and more particularly, to an immune disease treating agent.

BACKGROUND ART

Janus kinase 3 (hereafter referred to as JAK3) is a family of protein kinases. Although kinases in this family, other than JAK3, are expressed in a wide range of tissues, JAK3 is expressed locally in hematopoietic cells. This does not contradict the fact that JAK3 plays an important role in signal transmission via various receptors, such as interleukin (hereafter referred to as IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 by noncovalent association with the common γ chain (refer to nonpatent literature 1 and nonpatent literature 2).

In XSCID (X-linked severe combined immunodeficiency) patient populations, JAK3 protein level lowers or a genetic defect is found in the common γ chain. It is indicated that this problem occurs because immunosuppression blocks JAK3-dependent signaling pathways (refer to nonpatent literature 3 and nonpatent literature 4). Animal experiments have shown that JAK3 not only plays an important role in maturation of B-lymphocytes and T-lymphocytes but also in maintaining the function of T-cells. Hence, it is expected that diseases involving proliferative abnormality of T-cells, such as rejection during organ/tissue transplantation and autoimmune diseases, can be treated by controlling immune response through this mechanism.

On the other hand, a pyrrolopyridine derivative (patent literature 1) represented by formula (A) or (B) or an imidazopyridine derivative (refer to patent literature 2) is known as a compound having JAK3 inhibition activity.

(For the symbols in the formulas, refer to the corresponding patent publications.)

Furthermore, a pyrrolopyrimidine derivative (refer to patent literature 3, patent literature 4, patent literature 5, and patent literature 6) represented by formula (C) is also known as a compound having JAK3 inhibition activity.

(For the symbols in the formula, refer to the corresponding patent publications.)

Still further, a pyrrolopyridine derivative (refer to patent literature 7) represented by formula (D) is also known as a compound having JAK3 inhibition activity.

(For the symbols in the formula, refer to the corresponding patent publication.)

However, in any literature, the compound according to the present invention is not disclosed specifically.

[Nonpatent literature 1] J. J. O\'shea et al, Cell, Vol. 109 (suppl.), 5121, 2002 [Nonpatent literature 2] K. Ozaki et al, Science, Vol. 298, p. 1630, 2002 [Nonpatent literature 3] P. Macchi et al, Nature, Vol. 377, p. 65, 1995 [Nonpatent literature 4] S. M. Russell et al, Science, Vol. 270, p. 797, 1995 [Patent literature 1] WO 2004/099205 [Patent literature 2] WO 2004/099204 [Patent literature 3] WO 99/065908 [Patent literature 4] WO 99/065909 [Patent literature 5] WO 01/042246 [Patent literature 6] WO 02/000661 [Patent literature 7] WO 2006/069080

DISCLOSURE OF THE INVENTION

As a result of intensive studies with an object of providing a useful pharmaceutical composition having JAK3 inhibition activity, the inventors have found that a novel condensed heterocyclic compound has an excellent JAK3 inhibition activity, and have completed the present invention.

More specifically, the present invention provides a novel condensed heterocyclic compound represented by the following formula (I) or pharmaceutically acceptable salts thereof, and a pharmaceutical composition containing the compound, more particularly, a pharmaceutical composition serving as an agent for treating and/or preventing autoimmune diseases, inflammatory diseases, and allergic diseases.

The condensed heterocyclic compound is a condensed pyridine compound represented by the following formula (I):

wherein

X is N or CR3,

M is (CH2)m; m is 0 or 1,

R1 is —H or lower alkyl which may be substituted,

R2 is —H or lower alkyl which may be substituted,

R3 is —H, halogen, or lower alkyl which may be substituted,

R41 is —H or heteroaryl which may be substituted,

R42 is a bridged ring group which may be substituted,

R5 is a group selected from the group consisting of halogen, cyano, acyl, acylamino, lower alkyl, lower alkenyl, —O-lower alkyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heterocycloalkenyl, and 5-membered heteroaryl, each of which may be substituted,

provided that when R5 is 5-membered heteroaryl, X is —CR3,

or R41 and R5 may be linked via a specific functional group to form bivalent groups shown below:

wherein RA is —H or acyl which may be substituted, or pharmaceutically acceptable salts thereof.

The compound according to the present invention has JAK3 inhibition activity and is thus useful as an active ingredient of an agent for treating and/or preventing diseases caused by undesirable cytokine signal transmission (e.g., rejection during organ/tissue transplantation, autoimmune diseases, asthma, atopic dermatitis, Alzheimer\'s disease, and atherosclerotic disease), or diseases caused by abnormal cytokine signal transmission (e.g., cancer and leukemia).

The compound according to the present invention represented by the formula (I) is characterized in its chemical structure that the compound has a cross-linked amine and also has a skeleton in which 5- and 6-membered heterocycles are condensed, just as in 1H-pyrrolo[2,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, or pyrazolo[1,5-a]pyrimidine, and is further characterized in pharmacology that the compound has a JAK3 inhibition activity.

The present invention is described below in detail.

The term “alkyl” in this specification is a straight or branched monovalent group.

The term “lower alkyl” in the specification is a C1-C6 straight or branched alkyl and may include, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, neopentyl, and n-hexyl, preferably methyl, ethyl, n-propyl, isopropyl, and isobutyl, and particularly preferably methyl and ethyl.

The term “lower alkenyl” in the specification is C2-C6 straight or branched alkenyl having a double bond at each possible site, and may include, such as ethenyl (vinyl), 1-propenyl, 2-propenyl(allyl), 1-methylethen-1-yl, 1-buten-1-yl, 2-buten-1-yl, 3-buten-1-yl, 1-methyl-1-propen-1-yl, 2-methyl-1-propen-1-yl, 1-methyl-2-propen-1-yl, and 2-methyl-2-propen-1-yl, preferably 1-methyl-2-propen-1-yl.

The term “halogen” means fluoro, chloro, bromo, and iodo, preferably fluoro.

The term “cycloalkyl” is a C3-C8 monovalent nonaromatic carbocyclic group, and may partially have unsaturated bonds or may be condensed with a benzene ring. However, bridged cycloc hydrocarbons are excluded. Cycloalkyl may include, such as cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutenyl, cyclohexenyl, cyclooctadienyl, indanyl, and tetrahydronaphthyl, preferably cyclohexyl.

The term “heterocycloalkyl” is a 5- to 6-membered nonaromatic saturated heterocycle which may have one or more identical or different hetero atoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms which may be oxidized. Heterocycloalkyl may be partially unsaturated or may be condensed with a benzene ring. However, aza-bridged cyclic hydrocarbons are excluded. Heterocycloalkyl may include, such as aziridinyl, azetidinyl, pyrrolizinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, indolynyl, tetrahydroquinolyl, tetrahydroisoquinolyl, and benzoxazinyl, preferably dihydrooxazolyl, oxadiazolyl, oxadiazolanyl, and furanyl.

The term “heterocycloalkenyl” is partially substituted “heterocycloalkyl”.

The term “cyclic amino” is, among groups defined in “heterocycloalkyl” a monovalent 3- to 8-membered nonaromatic cyclic amine which has at least one nitrogen atom, and may have one or more identical or different hetero atoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms which may be oxidized, wherein at least one nitrogen atom has a bond. However, aza-bridged cyclic hydrocarbons are excluded. The “Cyclic amino” may include, such as aziridino, azetidino, pyrrolidino, piperidino, homopiperidino, morpholino, thiomorpholino, and piperazino.

The term “aryl” is an aromatic hydrocarbon group and may include, phenyl, naphthyl, and indenyl, preferably C6-C10 aryl, and more preferably phenyl.

The term “heteroaryl” is a monovalent 5- or 6-membered aromatic heterocyclic group having one or more identical or different hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, and may be condensed with a benzene ring. “Heteroaryl” may include, such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thienyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indolyl, indazolyl, quinoxalyl, and quinazolyl, preferably pyridazinyl, pyridyl, pyrazinyl, thiazolyl, pyrazolyl, and thioxazolyl.

The term “bridged ring group” means “bridged cyclic hydrocarbon” and “aza-bridged cyclic hydrocarbon”.

The term “bridged cyclic hydrocarbon” is a saturated or unsaturated, bicyclic or polycyclic bridged hydrocarbon group having two or three C3-C10 cycloalkyl rings. Non bridged cycloalkyls are excluded. Bicyclic or polycyclic C4-C16 bridged hydrocarbon groups are particularly preferable. Bridged cyclic hydrocarbon may include, such as bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[4.3.1]decyl, bicyclo[3.3.1]nonyl, bornyl, bornenyl, norbornyl, norbornenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, tricyclobutyl, and adamantyl, preferably adamantyl or bicyclo[2.2.1]heptyl.

The term “aza-bridged cyclic hydrocarbon” is a saturated or unsaturated, bicyclic or polycyclic bridged hydrocarbon group in which at least one of atoms constituting a ring is a nitrogen atom. Non bridged heterocycloalkyls are excluded. Bicyclic or polycyclic C4-C16 aza-bridged hydrocarbon groups are particularly preferable. The term “aza-bridged cyclic hydrocarbon” may include, such as azanorbornyl, quinuclidinyl, isoquinuclidinyl, tropanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.2.1]heptanyl, 2-azabicyclo[3.2.1]octanyl, azabicyclo[3.2.1]octanyl, azabicyclo[3.2.2]nonanyl, azabicyclo[3.3.0]nonanyl, and azabicyclo[3.3.1]nonanyl, preferably tropanyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl.

The term “acyl” means —C(=0)-lower alkyl, —C(=0)-cycloalkyl, —C(=0)-heterocycloalkyl, —C(=0)-aryl, —C(=0)-heteroaryl, carbamoyl, lower alkylcarbamoyl, —C(=0)-C (=0)-NH-lower alkyl, cycloalkylcarbamoyl, heterocycloalkylcarbamoyl, arylcarbamoyl, and heteroarylcarbamoyl. The term “lower alkyl,” “cycloalkyl,” “heterocycloalkyl,” “aryl” and “heteroaryl” have the above-mentioned meanings.

X in the formula (I) is preferably CH.

R1 in the formula (I) is preferably —H. R2 in the formula (I) is preferably —H or CH3, and more preferably —H.

R41 in the formula (I) is preferably —H.

Furthermore, R42 in the formula (I) is preferably adamantyl or tropanyl, each of which may be substituted with OH.

Still further, R5 in the formula (I) is preferably carbamoyl which may be substituted or —C(═O)-lower alkyl which may have OH more preferably —CONH2 or hydroxyacetyl. As another embodiment, R41 and R5 are bonded via a specific functional group to form a cyclic structure described above, preferably formula (I-C).

As substituents which are allowed to be used for “which may be substituted” of R1, R2, R3, R41, R42 and/or R5, the following groups described in items (a) to (g) are included: (a) Halogen (b) —OH, —O—RZ, —O-phenyl, —OCO—RZ, —OCONH—RZ, oxo (═O); (c) —SH, —S—RZ, —S-phenyl, —S-heteroaryl, —SO—RZ, —SO-phenyl, —SO-heteroaryl, —SO3H, —SO2—RZ, —SO2-phenyl, —SO2-heteroaryl, sulfamoyl which may be substituted with one or two RZ groups. (d) Amino which may be substituted with one or two RZ groups, —NHCO—RZ, —NHCO-phenyl, —NHCO2—RZ, —NHCONH2, —NHCONH—RZ, —NHSO2—R0, —NHSO2-phenyl, —NHSO2NH2, —NO2, ═N—O—RZ; (e) —CHO, —CO—RZ, —CO2H, —CO2—RZ, carbamoyl which may be substituted with one or two RZ groups, —CO-cyclic amino, —COCO—RZ, cyano; (f) RZ (g) Phenyl which may be substituted with one or more groups selected from the substituents described in the above items (a) to (f), 5- or 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocycloaryl.

RZ in the above items (a) to (g) may include “cyano; —OH; and lower alkyl which may be substituted with one to three groups selected from the group consisting of —O-lower alkyl, —NH-lower alkyl, —CONH-lower alkyl, 5- or 6-membered heterocycloalkyl, and 5- or 6-membered heteroaryl.”

The compound according to the present invention may include geometric isomers and tautomeric isomers depending on the type of constituent. In addition, the compound according to the present invention may have asymmetric carbon atoms. All of the isomers, including separated isomers and mixtures thereof, are included within the scope of the present invention. Furthermore, labeled compounds, that is, compounds obtained by substituting one or more atoms of the compound according to the present invention with radioactive or nonradioactive isotopes are also included in the scope of the present invention.

Furthermore, the pharmaceutically acceptable prodrug of the compound of the present invention is also included in the scope of the present invention. The pharmaceutically acceptable prodrug is a compound having a group that can be converted into amino group, hydroxyl group, carboxyl group, etc. through solvolysis or under physiological conditions. The groups described in Prog. Med., Vol. 5, p. 2157-2161, 1985 and “Iyakuhin No Kaihatsu (Development of Medicines)” (Hirokawa Pub. Co., 1990), Vol. 7, Molecular Design, p. 163-198 are taken as examples of groups forming such prodrugs.

The compound represented by the formula (I) may form acid or base addition salts. These salts should only be pharmaceutically acceptable salts. More specifically, the salts may include an acid addition salt with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, and phosphoric acid), and an acid addition salt with an organic acid (e.g., formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, and glutamic acid); a salt with an inorganic base (e.g., sodium, potassium, magnesium, calcium, and aluminum), and a salt with an organic base (e.g., methylamine, ethylamine, ethanolamine, lysine, and ornithine); an ammonium salt; and the like.

Still further, various hydrates, solvates, and crystalline polymorphic forms of the compound represented by the formula (I) and salts thereof are also included in the scope of the present invention.

The compound according to the present invention can be produced using the characteristics based on the basic skeleton or the type of substituent thereof and by applying various known synthesis methods. During the production, protecting the relevant functional group with a suitable protective group or replacing the relevant functional group with a group that can be easily converted into the functional group at the stage of a starting substance or an intermediate may occasionally be effective depending on the type of the functional group in production technology. This kind of functional group may include, for example, amino group, hydroxyl group, and carboxyl group. The protective group for such a functional group may include, for example, the protective groups described in “Protective Groups in Organic Synthesis (3rd. Ed, 1999)” written by T. W. Greene and P. G. Wuts, and one of these should only be selected and used as necessary depending on reaction conditions. In this kind of method, the desired component can be obtained by introducing the protective group, by carrying out reaction and by eliminating the protective group as necessary, or by converting the group into a desired group.

In addition, the prodrug of the compound according to the present invention can be produced by introducing a specific group or by carrying out reaction using the obtained compound represented by the formula (I) at the stage of a starting substance or an intermediate, just as in the case of the above-mentioned protective group. The reaction can be carried out using methods known to those skilled in the art, such as ordinary esterification, amidation, and dehydration.

The abbreviations used in the specification are as follows:

Pr: Preparation number; Ex: Example number; Structure: chemical structure; Rf-Syn: the number of an Example to which reference was made (the number indicates that the relevant compound was produced according to a production method similar to that for producing the compound described in the Example designated by the number.); HPLC: high performance liquid chromatography; TLC: thin layer chromatography; Rf: rate of flow value; Data: NMR data and/or MS data; 1H-NMR: 1H-nuclear magnetic resonance; MS: mass spectrometry; (M+H)+:(M+H)+; (M+Na)+:(M+Na)+; (M−H)−:(M−H)−.

[wherein R1, R2, R41, R42, R5, M and X are as defined above, and Lv is a leaving group.]

In this process, the compound represented by the formula (I-a) and having a leaving group is reacted with the amine represented by the formula (I-b) to produce the compound according to the present invention represented by the formula (I). The leaving group Lv may include halogen (e.g., chloro and bromo); sulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, and trifluorometanesulfonyloxy); etc.

In Step 1, the leaving group Lv of the compound represented by the formula (I-a) is substituted with amine. This reaction is carried out under atmospheric pressure or under pressure in the absence of a solvent or in the presence of a suitable solvent.

The solvent may include, for example, aromatic hydrocarbons (e.g., toluene and xylene); ketones (e.g., acetone and methyl ethyl ketone); ethers (e.g., diethylether, tetrahydrofuran(THF), dioxane, and diethoxyethane); alcohols (e.g., methanol (MeOH), ethanol (EtOH), 2-propanol (i-PrOH), and 1-butanol (n-BuOH)); halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride); acetonitrile; aprotic solvents (e.g., dimethylformamide (DMF), 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone (NMP), and dimethylsulfoxide (DMSO)); water; or a mixture of these. It is preferable that the reaction is carried out in the presence of a base, and the base may include, for example, alkaline carbonates (e.g., sodium carbonate and potassium carbonate); alkaline hydrogencarbonates (e.g., sodium hydrogencarbonate and potassium hydrogencarbonate); alkoxides (e.g., sodium methoxide, sodium ethoxide, and potassium t-butoxide); tertiary amines (e.g., triethylamine, tributylamine, and diisopropylethylamine); organic bases (e.g., 1,8-diazabicyclo[5.4.0]undeca-7-ene, pyridine, and lutidine). However, an excess amount of the compound (I-b) can also be used. Although the reaction temperature differs depending on the type of a starting compound and reaction conditions, the reaction can usually be carried out at a temperature approximately ranging from ambient temperature to the refluxing temperature of a solvent. The reaction can also usually be carried out in the presence of a base, such as sodium hydroxide and sodium carbonate, in an organic solvent inert to the reaction, such as N,N-dimethylformamide and N,N-dimethylacetamide, under ambient temperature to heating. In addition, the amine represented by the formula (I-b) can also be used as a salt thereof for the reaction.

Furthermore, microwave irradiation can also be carried out under heating. Still further, the reaction can also be carried out by a coupling reaction using a phosphorus reagent, such as 2-(di-t-butylphosphino)biphenyl, and a palladium catalyst, such as palladium acetate, in the presence of a base, such as cesium carbonate.

For the reaction, it is possible to use the methods described in the Preparations) or the Example(s) of the present specification or methods similar to those. The compound represented by the formula (I-a) can thus be produced using known methods, methods obvious to those skilled in the art, or the methods described in the reference examples or the Examples of the present specification or methods similar to those.

[wherein R1, R2, R41, R42, R5, M and Lv are as defined forgoing.]

In this process, the nitropyridine compound represented by the formula (2-a) is reacted with the amine represented by the formula (2-b), and the leaving group at the second position is substituted with the amine to derive the aminonitropyridine compound represented by the formula (2-c). The derived compound is used to produce the compound according to the present invention represented by the formula (I-2).

The method used in Step 1 of the first process can be incorporated in Step 2-1. The amine represented by the formula (2-b) can also be used as a salt thereof for the reaction.

In Step 2-2 in the case that —R2 is —H, an imidazole ring can be constructed by reacting an orthoformate, such as ethyl orthoformate, in the presence of an acid catalyst. It is desirable that the nitro group should be reduced before the orthoformate is used for the reaction. Furthermore, the method to be used in the case that the compound represented by the formula (I-2) wherein —R2 is not —H is synthesized may include, for example, the method in which the amino group of the compound represented by the formula (2-c) is acylated in advance, the method in which tetraalkylorthocarbonate or alkylisothiocyanate is used instead of the orthoformate, and the method in which carboxylic acid or carboxylic anhydride is reacted with a strong acid, such as sulfonic acid. These actions can be carried out in a solvent inert to the reactions or in the absence of a solvent, under ambient temperature to heating or under heating and refluxing.

[wherein R1, R2, R42, X, and M are as defined forgoing.]

In this process, the compound according to the present invention represented by the formula (3-a) and having a carboxyl group is used as a starting compound to produce the compound according to the present invention represented by the formula (I-3).

In Step 3, the carboxyl group of the compound represented by the formula (3-a) is reacted with an azidation agent, such as diphenylphosphoryl azide (DPPA) and sodium azide, to construct an imidazolone ring according to the so-called Curtius rearrangement reaction. It is advantageous that the reaction is carried out in the presence of a base.

Usually, triethylamine, pyridine, etc. can be used as a base, and the reaction can be carried out under ambient temperature to heating or under heating and refluxing.

[wherein R1, R2, R42, M, X and Lv are as defined forgoing.]

In this process, the carboxylic compound represented by the formula (4-a) is reacted with the hydrazine derivative represented by the formula (4-b) to obtain the hydrazide represented by the formula (4-c). From the hydrazide, the compound according to the present invention represented by the formula (I-4) is produced.

Step 4-1 can be carried out similarly to the reaction in which the compound represented by the formula (4-a) and the compound represented by the formula (4-b) are condensed by amidation. The compound (4-a) can be used as a free acid for the reaction, and the reactive derivative thereof can also be used for the reaction. The reactive derivative of the compound (4-a) may include an acid halide (e.g., acid chloride and acid bromide); an ordinary ester (e.g., methyl ester, ethyl ester, and benzyl ester); acid azide; an activated ester with N-hydroxybenzotriazole (HOBt), p-nitrophenyl, or N-hydroxysuccinimide); a symmetric acid anhydride; a mixed acid anhydride with a halocarboxylic acid alkyl ester (e.g., alkyl halide carbonate), pivaloyl halide, p-toluenesulfonic acid chloride, etc.; and a mixed acid anhydride, such as a phosphoric acid-type mixed acid anhydride obtained by reaction with diphenylphosphoryl chloride or N-methylmorpholine; etc.

When the compound (4-a) is reacted in the form of a free acid or reacted without isolating the activated ester, it is preferable to use a condensing agent, such as dicyclohexyl-carbodiimide (DCC), 1,1′-carbonylbis-1H-imidazole (CDI), diphenylphosphoryl azide (DPPA), diethyphosphoryl cyanide(DEPC), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI HCl).

The reaction is carried out in an organic solvent inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters (e.g., ethyl acetate), acetonitrile, DMF, and DMSO, under cooling, under cooling to ambient temperature, or under ambient temperature to heating, although the conditions differ depending on the reactive derivative or the condensing agent to be used.

In order to smoothly advance the reaction, it is occasionally advantageous that an excess amount of the compound (4-b) is used for the reaction or the reaction is carried out in the presence of a base, such as N-methylmorpholine, trimethylamine, triethylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine, 4-(N,N-dimethylamino)pyridine, picoline, and lutidine. Pyridine can also be used as a solvent.

The method used in Step 1 of the first process can be incorporated in Step 4-2.

[wherein R1, R2, R41, R42 and M are as defined above, R′ is suitable substituent. The carboxylic acid represented by the formula (5-f) is a marketed product or can be prepared using a marketed product.]

In step 5-2, step 5-4 and step 5-6, a reaction for constructing an oxadiazole ring at R5 is carried out.

In Step 5-1, a reaction for synthesizing an acid hydrazide from the carboxylic acid represented by the formula (5-a) is carried out. Furthermore, the intermediate represented by the formula (5-c) can also be synthesized from the carboxylic acid represented by the formula (5-a). The reaction in Step 4-1 can be incorporated in each of these reactions.

In Step 5-2, Step 5-4, and step 5-6, a reaction for constructing an oxadiazole ring is carried out under ambient temperature to heating. An organic base may be added to advance the reaction.

In Step 5-5, the aromatic nitrile compound represented by the formula (5-d) is reacted with hydroxylamine to obtain hydroxyamidine represented by the formula (5-e). The obtained hydroxyamidine is reacted with the carboxylic acid represented by the formula (5-f) to produce the compound according to the present invention represented by the formula (I-53).

In Step 5-5, the reaction with free hydroxylamine or hydroxylamine hydrochloride is carried out in the presence of a base, whereby the hydroxyamidine represented by the formula (5-e) can be produced.

The reaction can be carried out in a solvent inert to the reaction. The solvent may include, for example, alcohols (e.g., methanol (MeOH), ethanol (EtOH), and 2-propanol (iPrOH)); aromatic hydrocarbons (e.g., toluene and xylene); ethers (e.g., diethylether, tetrahydrofuran (THF), dioxane, and diethoxyethane); halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride); aprotic solvents (e.g., DMF, 1,3-dimethyl-2-imidazolidinone, and DMSO); water; or a mixture of these. Usually, alcohols are used for the reaction. In the case that hydroxylamine hydrochloride is used for the reaction as described above, it is preferable that the reaction is carried out in the presence of a base, and the base may include, for example, alkaline carbonates (e.g., sodium carbonate and potassium carbonate); alkaline hydrogencarbonates (e.g., sodium hydrogencarbonate and potassium hydrogencarbonate); alkoxides (e.g., sodium methoxide, sodium ethoxide, and potassium t-butoxide); tertiary amines (e.g., triethylamine and diisopropylethylamine); and organic bases (e.g., 1,8-diazabicyclo[5.4.0]undeca-7-ene, pyridine, and lutidine). Although the reaction temperature differs depending on the type of a starting compound and reaction conditions, the reaction can usually be carried out at a temperature approximately ranging from ambient temperature to the refluxing temperature of a solvent. The reaction can usually be carried out in the presence of a base, such as sodium carbonate, in an organic solvent inert to the reaction, such as methanol, under ambient temperature to heating.

Step 5-6 consists of two stages: acylation of hydroxyamidine and subsequent cyclization. The intermediate producing method in Step 4-1 can be incorporated in the acylation in the first stage. However, the reaction is usually carried out under ambient temperature to heating, or under heating and refluxing. The cyclization in the second stage can be carried out by isolating and purifying an acyl and by heating the acyl in an organic solvent inert to the reaction, such as ethanol and dioxane, in the presence or absence of a base. The base may include an inorganic base, such as sodium acetate, or an organic base, such as diisopropylethylamine. The reaction consisting of the two stages can be carried out by one operation by performing ordinary acylation and then by directly heating the reaction mixture or by carrying out reaction under microwave irradiation.

The solvent may include, for example, aromatics (e.g., toluene, xylene, and pyridine); ethers (e.g., diethylether, tetrahydrofuran, dioxane, and diethoxyethane); halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride); acetonitrile; aprotic solvents (e.g., DMF, N,N-dimethylacetamide (DMA), 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone (NMP), and DMSO)); water; or a mixture of these. Although the reaction temperature differs depending on the type of a starting compound and reaction conditions, the reaction can be carried out under ambient temperature to heating.

[wherein R1, R2, R42, M, m and Lv are as defined above; R″ is suitable substituent.]

In Step 6, in the case that the compound represented by the formula (6-a) is reacted with the primary amine represented by the formula (6-b), after ipso substitution, the oxadiazole ring is opened to construct an aminopyrazolone ring. The reaction conditions described in Step 1 can be incorporated herein as the reaction conditions. The reaction can be carrying out under ambient temperature to refluxing temperature.

In addition, some of the compounds represented by the formula (I) can also be produced from the compound according to the present invention produced as described above by appropriately combining processes usually used by those skilled in the art, such as known alkylation, acylation, substitution, oxidation, reduction, hydrolysis, deprotection, halogenation, and Mannich reaction. For example, when the compound according to the present invention wherein —R5 is —CO2H is produced from the compound according to the present invention wherein R5 is lower alkyloxycarbonyl, hydrolysis can be used referring to the method described in “Jikken Kagaku Koza (Courses in Experimental Chemistry) (5th Ed., 2003).” Moreover, when the compound according to the present invention wherein R5 is halogen is produced from the compound according to the present invention wherein both R3 and R5 are —H, halogenation can be used referring to the method described in “Jikken Kagaku Koza (Courses in Experimental Chemistry) (5th Ed., 2003).” Still further, when the compound according to the present invention wherein R3 is a lower alkyl substituted with a group selected from the group consisting of mono (lower alkyl)amino, di(lower alkyl)amino, and cyclic amino is produced from the compound according to the present invention wherein R3 is —H, the Mannich reaction can be used referring to the methods described in “Jikken Kagaku Koza (Courses in Experimental Chemistry) (5th Ed., 2003)”; C. Mannich et al., Arch. Pharm., 1912, Vol. 250, p. 647; J. H. Brewster et al., Org. React., 1953, Vol. 7, p. 99; F. F. Blicke, Org. React., 1942, Vol. 1, p. 303; K. W. Merz et al., Pharmazie, 1956, Vol. 11, p. 505; etc.

The processes capable of being usually used by those skilled in the art are not only used for the compound according to the present invention but can also be used for intermediates formed during production. The processes can also advance to subsequent processes.

The compound produced as described above is in a free form or subjected to salt-forming processing using a conventional method and isolated and purified as a salt thereof. The isolation and purification are carried out by performing ordinary chemical operations, such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, and various types of chromatography.

Various types of isomers can be isolated by utilizing the difference in physicochemical properties between the isomers using a conventional method. For example, a racemic mixture can be converted into an optically pure isomer using a general racemic resolution method, such as the method in which the racemic mixture is converted into a diastereomer salt with a general optically-active acid, such as tartaric acid, and subjected to optical resolution. Furthermore, the diastereo mixture can be separated by fractional crystallization or various types of chromatography, for example. Still further, the optically-active compound can also be produced using a suitable optically-active material.

The pharmacological activity of the compound according to the present invention was verified by carrying out the following test.

The JAK3 inhibition test was performed as described below according to the method of Okimoto et al.

Purified human JAK3 kinase domain was purchased from Carna Biosciences, Inc. (Kobe, Japan). This is obtained as described below. His-tag (41 kDa) was attached to the N-terminal of the 796-1124 (C-terminal) fragment of the human JAK3 protein (accession number #NM—000215), expressed using baculovirus expression system, and then purified using Ni-NTA affinity column chromatography.

As substrates, Biotin-Lyn-Substrate-2 (Biotin-XEQED EPEGF YFEWL EPE, X=ε-Acp (PEPTIDE INSTITUTE, INC., Osaka, Japan) and ATP were used. As an assay buffer, 15 mM Tris-HCl pH 7.5 containing 0.01% Tween 20 and 2 mM DTT was used. Normally, 20 μL of a substrate solution (an assay buffer containing 627 nM Biotin-Lyn-Substrate-2, 20 μM ATP, and 25 mM MgCl2), an assay buffer containing 10 μL of a substance to be tested, and 20 μL of an enzyme solution were added to a microplate, and stirred sufficiently.

After incubation at ambient temperature for one hour, the plate was washed with a cleaning buffer (50 mM Tris-HCl pH 7.5, 150 mM NaCl, 0.02% Tween 20), and a blocking buffer (a cleaning buffer containing 0.1% bovine serum albumin) was added to the plate. After incubation at ambient temperature for 30 minutes, the blocking buffer was removed, and an HRP-PY-20 solution (obtained by diluting HRP-PY-20 solution with the blocking buffer 500 times) was added. After incubation at ambient temperature for 30 minutes, the plate was washed four times, and a TMB substrate solution (Sigma) was added to the plate. After incubation at ambient temperature for four minutes, 1M sulfuric acid was added to stop the reaction. Enzyme activity was measured as absorbance at 450 nm. The efficacy of the test compound as a JAK3 inhibitor was expressed as an IC50 value.

The IC50 values described below are results obtained in the test.

The results of those tests are shown in the Table 1. Table 1: JAK3 inhibitory activity of the compound of the present invention.

TABLE 1 Ex IC50 (nM) Ex IC50 (nM) 29 2.3 379 1.2

Download full PDF for full patent description/claims.




You can also Monitor Keywords and Search for tracking patents relating to this Heterocyclic janus kinase 3 inhibitors patent application.

Patent Applications in related categories:

20130123231 - Acc inhibitors and uses thereof - The present invention provides compounds useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same. ...

20130123234 - Aryl- or heteroaryl-substituted benzene compounds - The present invention relates to aryl- or heteroaryl-substituted benzene compounds. The present invention also relates to pharmaceutical compositions containing these compounds and methods of treating cancer by administering these compounds and pharmaceutical compositions to subjects in need thereof. The present invention also relates to the use of such compounds for ...

20130123232 - Azetidinyl diamides as monoacylglycerol lipase inhibitors - wherein Y, Z, R1, and s are defined herein. Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula (I) as follows: ...

20130123233 - Azetidinyl diamides as monoacylglycerol lipase inhibitors - wherein Y, Z, R1, and s are defined herein. Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula (I) as follows: ...


###