Purine derivatives and medicaments comprising the same as active ingredient

[0004] This application is a continuation of application Ser. No. 09/554,077, filed Nov. 12, 1998, which is a National Stage Application of International Application No. PCT/JP98/05092, filed Nov. 12, 1998, which was not published in English under PCT Article 21(2), entering the national stage on May 11, 2000, and which claims priority of Japanese Application No. 9/310365, filed Nov. 12, 1997. The entire disclosure of application Ser. No. 09/554,077 is considered as being part of the disclosure of this application, and the entire disclosure of application Ser. No. 09/554,077 is expressly incorporated by reference herein in its entirety.

[0005] The present invention relates to novel purine derivatives. More precisely, it relates to purine derivatives having inhibitory activity against phosphodiesterase IV. The present invention also relates to synthetic intermediates for the preparation of said novel purine derivatives.

[0006] Cyclic AMP (cAMP) is an important second messenger which is involved in relaxation of respiratory tract smooth muscles and control of inflammatory cells, and the messenger is decomposed by phosphodiesterase (hereinafter abbreviated as “PDE” in the specification) to be converted into inactive 5′-AMP. Therefore, it is believed that suppression of the decomposition of cAMP by PDE may increase the concentration of cAMP, thereby bronchodilatation and anti-inflammatory action can be achieved. For this reason, PDE inhibitors having inhibitory action against the decomposition of cAMP have been focused as medicaments for the treatment of asthma. In addition, five PDE isozymes (PDE I, II, III, IV and V) have recently been isolated, and their specific tissue distributions have been revealed (Adv. Second Messenger Phosphoprotein Res., 22, 1 (1988); Trends Pharm., Sci., 11, 150 (1990)).

[0007] Among inhibitors for these isozymes, in particular, inhibitors specific for PDE IV have been suggested to be possibly useful for the treatment of asthma (Thorax 46, 512 (1991)). As a compound having specific inhibitory activity against PDE IV, for example, the compound disclosed in Japanese Patent Unexamined Publication (Kokai) No. 50-157360/1975 (Rolipram) has been known.

[0008] Although various compounds have been known as PDE IV inhibitors (for example, compounds disclosed in Japanese Patent Unexamined Publication (Kokai) No. 4-253945/1992, International Patent Publication in Japanese (Kohyo) Nos. 6-504782/1994, 7-504442/1995, 8-501318/1996 and 9-500376/1997 and so forth), they have not been used clinically so far, and development of novel compounds having PDE IV inhibitory activity has been desired.

[0009] An object of the present invention is to provide a novel compound having specific inhibitory activity against PDE IV, of which possible usefulness for treatment of asthma has been suggested. Another object of the present invention is to provide a medicament comprising a compound that has the aforementioned characteristic as an active ingredient. A further object of the present invention is to provide a synthetic intermediate useful for efficient preparation of the aforementioned compound.

[0010] The inventors of the present invention earnestly conducted researches to achieve the foregoing objects. As a result, they found that particular class of purine derivatives represented by the following formula had excellent inhibitory activity against PDE IV. They also found that these compounds were useful as active ingredients of medicaments, and they were extremely useful as, for example, as active ingredients of antiasthmatic agents. The present invention was achieved on the basis of these findings.

[0011] The present invention thus provides purine derivatives represented by the following formula (I), salts thereof, or N-oxides thereof, or hydrates thereof or solvates thereof:

[0012] wherein R¹represents a C₁-C₄alkyl group or difluoromethyl group; R²represents tetrahydrofuranyl group, a C₁-C₇alkyl group, a C₁-C₁haloalkyl group, a C₂-C₇alkenyl group, bicyclo[2,2,1]hept-2-yl group, or a C₃-C₈cycloalkyl group; X represents hydrogen atom, a halogen atom, or nitro group; and A represents a group represented by the following formula:

[0013] wherein R³represents hydrogen atom, a halogen atom, hydroxyl group, a C₁-C₄alkyl group, a C₁-C₄alkoxyl group, amino group, a C₁-C₄alkylamino group, or a C₂-C₈dialkylamino group; R⁴and R⁵each independently represent hydrogen atom, a halogen atom, a C₁-C₄alkyl group, a C₁-C₄alkoxyl group, amino group, a C₁-C₄alkylamino group, pyrrolidinyl group, morpholino group, a C₂-C₈dialkylamino group, or a group represented by —Y—(CH₂)_n—B {Y represents —O—, —S—, —NHCO—, or —N(R⁶)— (R⁶represents hydrogen atom or a C₁-C₄alkyl group), n represents an integer of from 0 to 4, and B represents a phenyl group, a naphthyl group, or a heterocyclic residue, each of which may be substituted},

[0014] provided that either R⁴or R⁵represents —Y—(CH₂)_n—B {Y represents —O—, —S—, —NHCO—, or —N(R⁶)— (R⁶represents hydrogen atom or a C₁-C₄alkyl group)} when X represents hydrogen atom, and

[0015] (i) n represents an integer of from 0 to 4, and B represents a phenyl group, a naphthyl group, or a heterocyclic residue, each of which may be substituted when Y represents —O—, —S—, or —NHCO—, or

[0016] (ii) n represents an integer of from 1 to 4, and B represents a heterocyclic residue when Y represents —N(R⁶)—.

[0017] According to preferred embodiments of the present invention, there are provided the aforementioned purine derivatives, salts thereof, or N-oxides thereof, or hydrates thereof or solvates thereof, wherein A is a group represented by the following formula:

[0018] wherein R³is hydrogen atom, a halogen atom, hydroxyl group, a C₁-C₄alkyl group, a C₁-C₄alkoxyl group, amino group, a C₁-C₄alkylamino group or a C₂-C₈dialkylamino group; one of R⁴and R⁵is hydrogen atom, a halogen atom, a C₁-C₄alkyl group, a C₁-C₄alkoxyl group, amino group, a C₁-C₄alkylamino group, pyrrolidinyl group, morpholino group, or a C₂-C₈dialkylamino group, and the other is —Y—(CH₂)_n—B (Y is —O—, —S—, —NHCO—, or —N(R⁶)— (R⁶represents hydrogen atom or a C₁-C₄alkyl group), n is an integer of from 0 to 4, and B represents a phenyl group, a naphthyl group, or a heterocyclic residue, each of which may be substituted);

[0019] the aforementioned purine derivatives, salts thereof, or N-oxides thereof, or hydrates thereof or solvates thereof, wherein R¹is a C₁-C₄alkyl group; R²is tetrahydrofuranyl group, a C₁-C₆alkyl group, a C₁-C₃haloalkyl group or a C₃-C₈cycloalkyl group, and A is a group represented by the following formula:

[0020] wherein R³is hydrogen atom, a halogen atom, hydroxyl group, a C₁-C₄alkyl group, or a C₁-C₄alkoxyl group; R⁴is hydrogen atom, a halogen atom, a C₁-C₄alkyl group, a C₁-C₄alkoxyl group, a C₁-C₄alkylamino group, or a C₂-C₈dialkylamino group, R⁵is —Y—(CH₂)_n—B (Y is —O—, —S—, or —NHCO—, n is an integer of from 1 to 4, and B represents a heterocyclic residue which may be substituted); and

[0021] the aforementioned purine derivatives, salts thereof, or N-oxides thereof, or hydrates thereof or solvates thereof, wherein R¹is a C₁-C₃alkyl group; R²is a C₃-C₈cycloalkyl group, and A is a group represented by the following formula:

[0022] wherein R³is hydrogen atom, a C₁-C₃alkyl group, or a C₁-C₃alkoxyl group; R⁴is a C₁-C₃alkyl group, a C₁-C₃alkoxyl group or a C₁-C₃alkylamino group; R⁵is —Y—(CH₂)_n—B (Y is —O—, n is an integer of from 1 to 4, and B is a heterocyclic residue which may be substituted).

[0023] According to another aspect of the present invention, medicaments are provided which contain a substance selected from the group consisting of the aforementioned purine derivatives, salts thereof, and N-oxide compounds thereof, and hydrates thereof and solvates thereof as an active ingredient. These medicaments are preferably provided as pharmaceutical compositions which contain the aforementioned active ingredient and an additive for pharmaceutical preparation, and they can be used as, for example, antiasthmatic agents for preventive and/or therapeutic treatment of asthma.

[0024] According to further aspects of the present invention, there are provided use of a substance selected from the group consisting of the aforementioned purine derivatives, salts thereof, and N-oxide compounds thereof, and hydrates thereof and solvates thereof for the manufacture of the aforementioned medicaments; methods for preventive and/or therapeutic treatment of asthma which comprise the step of administering an effective amount of a substance selected from the group consisting of the aforementioned purine derivatives, salts thereof, and N-oxide compounds thereof, and hydrates thereof and solvates thereof to a mammal including human; and phosphodiesterase IV inhibitors which comprise a substance selected from the group consisting of the aforementioned purine derivatives, salts thereof, and N-oxide compounds thereof, and hydrates thereof and solvates thereof.

[0025] According to further aspects of the present invention, there are provided compounds represented by the following formula (A):

[0026] wherein R¹represents a C₁-C₄alkyl group or difluoromethyl group; R²represents tetrahydrofuranyl group, a C₁-C₇alkyl group, a C₁-C₇haloalkyl group, a C₂-C₇alkenyl group, bicyclo[2,2,1]hept-2-yl group or a C₃-C₈cycloalkyl group; R⁴represents hydrogen atom, a halogen atom, a C₁-C₄alkyl group, a C₁-C₄alkoxyl group, amino group, a C₁-C₄alkylamino group, pyrrolidinyl group, morpholino group, a C₂-C₈dialkylamino group or —Y—(CH₂)_n—B {Y represents —O—, —S—, —NHCO—, or —N(R⁶)— (R⁶represents hydrogen atom or a C₁-C₄alkyl group), n represents an integer of from 0 to 4, B represents a phenyl group, a naphthyl group, or a heterocyclic residue, each of which may be substituted, and X²represents a halogen atom, and compounds represented by the following formula (B):

[0027] wherein R¹represents a C₁-C₄alkyl group or difluoromethyl group; R²represents tetrahydrofuranyl group, a C₁-C₇alkyl group, a C₁-C₇haloalkyl group, a C₂-C₇alkenyl group, bicyclo[2,2,1]hept-2-yl group, or a C₃-C₈cycloalkyl group; R⁴represents hydrogen atom, a halogen atom, a C₁-C₄alkyl group, a C₁-C₄alkoxyl group, amino group, a C₁-C₄alkylamino group, pyrrolidinyl group, morpholino group, a C₂-C₈dialkylamino group, or —Y—(CH₂)_n—B {Y represents —O—, —S—, —NHCO—, or —N(R⁶)— (R⁶represents hydrogen atom or a C₁-C₄alkyl group), n represents an integer of from 0 to 4, B represents a phenyl group, a naphthyl group, or a heterocyclic residue, each of which may be substituted, and X²represents a halogen atom. These compounds are useful as synthetic intermediates for preparation of the compounds represented by the aforementioned formula (I).

[0028] According to preferred embodiments of the synthetic intermediates represented by the formula (A) or (B), there are provided those wherein R¹is a C₁-C₄alkyl group, R²is tetrahydrofuranyl group, a C₁-C₆alkyl group, a C₁-C₃haloalkyl group, or a C₃-C₈cycloalkyl group, R⁴is hydrogen atom, a halogen atom, a C₁-C₄alkyl group, a C₁-C₄alkoxyl group, a C₁-C₄alkylamino group or a C₂-C₈dialkylamino group.

[0029] R¹represents a linear or branched C₁-C₄alkyl group (methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group and the like), or difluoromethyl group. R¹preferably represents a C₁-C₄alkyl group, more preferably a C₁-C₃alkyl group, further preferably methyl group or ethyl group, and most preferably methyl group.

[0030] R²represents tetrahydrofuranyl group, a C₁-C₇linear or branched alkyl group (methyl group R²represents, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group, n-pentyl group, 1,2-dimethylpropyl group, 1,1-dimethylpropyl group, n-hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 1,2,2-trimethylpropyl group, heptyl group, 5-methylhexyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 4,4-dimethylpentyl group, 1,2-dimethylpentyl group, 1,3-dimethylpentyl group, 1,4-dimethylpentyl group, 1,2,3-trimethylbutyl group, 1,1,2-trimethylbutyl group, 1,1,3-trimethylbutyl group and the like), a C₁-C₇haloalkyl group (chloromethyl group, bromomethyl group, dichloromethyl group, 1-chloroethyl group, 2-chloroethyl group, 3-chloropropyl group, 3-chlorobutyl group, 5-chloropentyl group, 6-chlorohexyl group, difluoromethyl group, trifluoromethyl group and the like), a C₂-C₇alkenyl group (vinyl group, allyl group, 2-propenyl group, isopropenyl group, 3-butenyl group, 4-pentenyl group, 5-hexenyl group and the like), bicyclo[2,2,1]hept-2-yl group, or a C₃-C₈cycloalkyl group (cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group and the like). R²preferably represents tetrahydrofuranyl group, a C₁-C₆alkyl group, a C₁-C₃haloalkyl group, or a C₃-C₈cycloalkyl group, more preferably a C₃-C₈cycloalkyl group, further preferably a C₄-C₆cycloalkyl group, and most preferably cyclopentyl group.

[0031] X represents hydrogen atom, a halogen atom (when a halogen is referred to in the specification, the halogen may be any of fluorine, chlorine, bromine, and iodine), or nitro group, preferably hydrogen atom. As symbol “A”, a group represented by the following formula is preferred.

[0032] In the above formula, R³represents hydrogen atom, a halogen atom, hydroxyl group, a linear or branched C₁-C₄alkyl group (methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group and the like), a linear or branched C₁-C₄alkoxyl group (methoxy group, isopropoxy group, butoxy group and the like), amino group, a linear or branched C₁-C₄alkylamino group (methylamino group, n-propylamino group, isopropylamino group, butylamino group and the like) or a linear or branched C₂-C₈dialkylamino group (dimethyl amino group, diethylamino group, dipropylamino group, dibutylamino group and the like). R³preferably represents hydrogen atom, a halogen atom, hydroxyl group, a linear or branched C₁-C₄alkyl group, a C₁-C₄linear or branched alkoxyl group, more preferably hydrogen atom, a C₁-C₃alkyl group or a C₁-C₃alkoxyl group.

[0033] In the aforementioned formula, R⁴and R⁵each independently represent hydrogen atom, halogen atom, a linear or branched C₁-C₄alkyl group (methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group and the like), a linear or branched C₁-C₄alkoxyl group (methoxy group, isopropoxy group, butoxy group and the like), amino group, a linear or branched C₁-C₄alkylamino group (methylamino group, n-propylamino group, isopropylamino group, butylamino group and the like), pyrrolidinyl group, morpholino group, a linear or branched C₂-C₈dialkylamino groups (dimethylamino group, diethylamino group, dipropylamino group, dibutylamino group and the like) or —Y—(CH₂)_n—B {Y is —O—, —S—, —NHCO—, or —N(R⁶)— (R⁶is hydrogen atom or a linear or branched C₁-C₄alkyl group (methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group and the like), and Y is preferably —O—)}. Symbol “n” represents an integer of from 0 to 4, preferably an integer of from 1 to 3.

[0034] B represents a phenyl group, a naphthyl group, or a heterocyclic residue. Each of these groups may have, on their rings, one or more substituents selected from the group consisting of a halogen atom, a linear or branched C₁-C₄alkyl groups (methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group and the like), a C₁-C₄haloalkyl group (chloromethyl group, bromomethyl group, dichloromethyl group, 1-chloroethyl group, 2-chloroethyl group, 3-chloropropyl group, 4-chlorobutyl group, difluoromethyl group, trifluoromethyl group and the like), a linear or branched C₁-C₄alkoxyl group (methoxy group, isopropoxy group, butoxy group and the like), a linear or branched C₁-C₄haloalkoxyl group (trifluoromethoxy group, difluoromethoxy group, 2,2,2-trifluoromethoxy group, 3-chloropropoxy group and the like), cyano group, nitro group, amino group, hydroxy group, carboxy group, a C₁-C₄acyl groups (formyl group, acetyl group, propionyl group and the like), a C₂-C₄alkoxycarbonyl group (methoxycarbonyl group, ethoxycarbonyl group and the like), a linear or branched C₁-C₄alkylamino group (methylamino group, isopropylamino group, butylamino group etc.), and a linear or branched C₂-C₆dialkylamino group (dimethylamino group, diethylamino group and the like), preferably one or more substituents selected from the group consisting of a halogen atom, a C₁-C₄alkyl group, a C₁-C₄alkoxyl group, a C₁-C₄haloalkoxyl group, carboxy group, and a C₂-C₄alkoxycarbonyl group.

[0035] As the heterocyclic residue, a heterocyclic residue having 1 to 5 hetero atoms selected from oxygen atom, sulfur atom and nitrogen atom and having 5 to 10 ring-constituting atoms may be used, such as thienyl group, furyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group tetrazolyl group, oxazolyl group, isooxazolyl group, thiazolyl group, isothiazolyl group, pyrrolidinyl group pyridyl group, pyridazinyl group, pyrazinyl group, pyrimidinyl group, triazinyl group, piperidyl group, piperidino group, morpholinyl group, morpholino group, piperazinyl group, benzimidazolyl group, indolyl group, quinolyl group, naphthylidinyl group, quinazolinyl group and the like, preferably thienyl group, furyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, pyridyl group, pyridazinyl group, pyrazinyl group, pyrimidinyl group, triazinyl group, piperidyl group, piperidino group, morpholinyl group, morpholino group, piperazinyl group, benzimidazolyl group and the like, more preferably a 6-membered heterocyclic residue having one or two nitrogen atoms as the hetero atom(s), for example, pyridyl group, pyridazinyl group, pyrazinyl group, pyrimidinyl group, triazinyl group, piperidyl group, piperidino group, morpholinyl group, morpholino group, piperazinyl group and the like. B represents a heterocyclic residue which may be substituted, and most preferably an unsubstituted heterocyclic residue.

[0036] As for R⁴and R⁵, R⁴preferably represents hydrogen atom, a halogen atom, a C₁-C₄alkyl group, a C₁-C₄alkoxyl group, a C₁-C₄alkylamino group, or a C₂-C₈dialkylamino group, more preferably a C₁-C₃alkyl group, a C₁-C₃alkoxyl group, or a C₁-C₃alkylamino group, and R⁵represents —Y—(CH₂)_n—B (Y, n, and B have the same meanings as already defined above).

[0037] When X represents hydrogen atom, either of R⁴or R⁵represents —Y—(CH₂)_n—B. In this case, Y represents —O—, —S—, —NHCO—, or —N(R⁶)— (R⁶represents hydrogen atom or a C₁-C₄alkyl group), and (i) when Y represents —O—, —S—, or —NHCO—, n represents an integer of from 0 to 4, and B represents a phenyl group, a naphthyl group, or a heterocyclic residue, each of which may be substituted, or (ii) when Y represents —N(R⁶)—, n represents an integer of from 1 to 4, and B represents a heterocyclic residue.

[0038] When R⁴or R⁵in the compounds represented by the aforementioned formula (I) represents —Y(CH₂)_n—B wherein B is a heterocyclic residue which has at least one nitrogen atom as the hetero atom, the compounds may exist as N-oxide compounds. The N-oxide compounds also fall within the scope of the present invention.

[0039] Specific examples of the compounds of the present invention are shown in Table 1 below. In the table, Me represents methyl group, Et represents ethyl group, and n-Pr represents normal propyl group.