US 7,528,140 B2
Substituted pyrrolo[3,2-d]pyrimidines as glycogen synthase kinase (GSK) inhibitors
Kenichiro Kataoka, Hino (Japan); Tomomi Kosugi, Hino (Japan); Toshihiro Ishii, Hino (Japan); Takahiro Takeuchi, Hino (Japan); Takaharu Tsutsumi, Hino (Japan); Akira Nakano, Hino (Japan); Gen Unoki, Hino (Japan); Masanori Yamamoto, Hino (Japan); and Yuri Sakai, Hino (Japan)
Assigned to Teijin Limited, Osaka (Japan)
Appl. No. 10/504,583
PCT Filed Feb. 24, 2003, PCT No. PCT/JP03/01977
§ 371(c)(1), (2), (4) Date Aug. 16, 2004,
PCT Pub. No. WO03/070729, PCT Pub. Date Aug. 28, 2003.
Claims priority of application No. 2002-046128 (JP), filed on Feb. 22, 2002; application No. 2002-365196 (JP), filed on Dec. 17, 2002; and application No. 2002-379827 (JP), filed on Dec. 27, 2002.
Prior Publication US 2005/0277773 A1, Dec. 15, 2005
Int. Cl. C07D 487/04 (2006.01); C07D 417/12 (2006.01); C07D 417/06 (2006.01); C07D 413/12 (2006.01); C07D 413/06 (2006.01); C07D 519/00 (2006.01); A61K 31/519 (2006.01); A61K 31/541 (2006.01); A61K 31/5355 (2006.01); A61K 31/497 (2006.01)
U.S. Cl. 514—265.1  [544/280; 544/262; 544/264; 544/117; 544/61; 514/263.1; 514/234.2; 514/228.5; 514/252.16; 514/262.1] 92 Claims
 
1. A pyrrolo[3,2-d]pyrimidine represented by formula (I), or a medically acceptable salt thereof

OG Complex Work Unit Drawing
wherein X represents sulfur atom;
A1 represents a group that links the nitrogen atom to which A1 is bonded and A2 in the form of N—(CH2)2-A2;
A2 represents a group binding A1 and G1 in the form of A1-C(═O)-G1, A1-NH-G1 or A1-NHC(═O)-G1;
G1 represents one group selected from among the following 1) to 4):
1) a single bond
2) a substituted or unsubstituted C3-8 alicyclic hydrocarbon group (as substituents there may be mentioned one or more selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, optionally substituted C1-7 alkoxy, C6-10 aryloxy, C7-9 aralkoxy, C2-7 acyloxy, oxo, C1-6 alkylsulfonyloxy, optionally substituted C2-7 acyl (the acyl is selected from acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and hexanoyl), carboxyl, C2-7 alkoxycarbonyl, carbamoyl, optionally substituted C2-7 alkylcarbamoyl, amino, optionally substituted C1-6 alkylamino, optionally substituted C2-7 acylamino, C2-8 alkoxycarbonylamino, C1-6 alkylsulfonylamino, cyano, nitro, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, sulfamoyl, C1-6 alkylaminosulfonyl, sulfo, optionally substituted C3-6 alicyclic hydrocarbons and optionally substituted C1-6 aliphatic hydrocarbons)
3) a substituted or unsubstituted C6-14 aromatic hydrocarbon group (as substituents there may be mentioned one or more selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, optionally substituted C1-7 alkoxy, C6-10 aryloxy, C7-9 aralkoxy, C2-7 acyloxy, C1-6 alkylsulfonyloxy, optionally substituted C2-7 acyl (the acyl is selected from acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and hexanoyl), carboxyl, C2-7 alkoxycarbonyl, carbamoyl, optionally substituted C2-7 alkylcarbamoyl, amino, optionally substituted C1-6 alkylamino, optionally substituted C2-7 acylamino, C2-8 alkoxycarbonylamino, C1-6 alkylsulfonylamino, cyano, nitro, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, sulfamoyl, C1-6 alkylaminosulfonyl, sulfo, optionally substituted C3-6 alicyclic hydrocarbons and optionally substituted C1-6 aliphatic hydrocarbons)
4) a substituted or unsubstituted divalent heterocyclic group selected from the group consisting of furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, oxazolidine, isooxazole, isooxazolidine, thiazole, thiazolidine, isothiazole, isothiazolidine, furazan, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, triazole, thiadiazole, oxadiazole, tetrazole, pyran, tetrahydropyran, thiopyran, tetrahydrothiopyran, tetrahydrofuran, 1,3-dioxolane, 1,4-dioxane, pyridine, pyrazine, pyrimidine, pyridazine, benzofuran, dibenzofuran, 1,4-dioxacycloheptane, benzothiophene, indole, 1,2-methylenedioxybenzene, benzimidazole, benzothiazole, benzoxazole, chromane, isochromane, quinoline, decahydroquinoline, isoquinoline, phthalazine, cinnoline, 1,8-naphthylidine, 1,2,3,4-tetrahydroisoquinoline, quinazoline, quinoxaline, purine, pteridine, azetidine, morpholine, thiomorpholine, piperidine, homopiperidine, piperazine, homopiperazine, indoline, isoindoline, phenoxazine, phenazine, phenothiazine, pyrrolopyrimidine, pyrazolopyrimidine and quinuclidine, wherein the heterocyclic group is bonded to A2 via a carbon or nitrogen atom (as substituents there may be mentioned one or more selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, optionally substituted C1-7 alkoxy, C6-10 aryloxy, C7-9 aralkoxy, C2-7 acyloxy, oxo, C1-6 alkylsulfonyloxy, optionally substituted C2-7 acyl (the acyl is selected from acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and hexanoyl), carboxyl, C2-7 alkoxycarbonyl, carbamoyl, optionally substituted C2-7 alkylcarbamoyl, amino, optionally substituted C1-6 alkylamino, optionally substituted C2-7 acylamino, C2-8 alkoxycarbonylamino, C1-6 alkylsulfonylamino, cyano, nitro, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, sulfamoyl, C1-6 alkylaminosulfonyl, sulfo, optionally substituted C3-6 alicyclic hydrocarbons and optionally substituted C1-6 aliphatic hydrocarbons);
A3 represents a single bond, or a C1-6 aliphatic hydrocarbon group having G1 and A4 bonded on the same or different carbon atoms;
A4 represents a single bond or a group binding A3 and G2 in the form of A3-C(═O)-G2, A3-C(═O)O-G2, A3-C(═O)NR121-G2, A3-C(═S)NR122-G2, A3-C(═NR123)-G2, A3-O-G2, A3-OC(═O)-G2, A3-NR124-G2, A3-NR125C(═O)-G2, A3-NR126S(═O)2-G2, A3-NR127C(═O)O-G2, A3-NR128C(═O)NR129-G2, A3-NR130C(═S)-G2, A3-NR131C(═S)NR132-G2, A3-S-G2, A3-S(═0)-G2, A3-S(═O)2-G2, A3-S(═O)2NR133-G2 or A3-S(═O)2O-G2 (where R121, R122, R123, R124, R125, R126, R127, R128, R129, R130, R131, R132, and R133 each independently represent hydrogen or a C1-4 aliphatic hydrocarbon group); and
G2 represents one group selected from among the following 1) to 5):
1) hydrogen;
2) a substituted or unsubstituted C1-10 aliphatic hydrocarbon group (as substituents there may be mentioned one or more selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, optionally substituted C1-7 alkoxy, C6-10 aryloxy, C7-9 aralkoxy, C2-7 acyloxy, oxo, C1-6 alkylsulfonyloxy, optionally substituted C2-7 acyl (the acyl is selected from acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and hexanoyl), carboxyl, C2-7 alkoxycarbonyl, carbamoyl, optionally substituted C2-7 alkylcarbamoyl, amino, optionally substituted C1-6 alkylamino, optionally substituted C2-7 acylamino, C2-8 alkoxycarbonylamino, C1-6 alkylsulfonylamino, cyano, nitro, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, sulfamoyl, C1-6 alkylaminosulfonyl, sulfo, optionally substituted C3-6 alicyclic hydrocarbons, optionally substituted C1-6 aliphatic hydrocarbons, optionally substituted C6-14 aromatic hydrocarbons and optionally substituted heterocyclic groups (having in the ring 1 to 4 atoms selected from the group consisting of oxygen, nitrogen and sulfur))
3) a substituted or unsubstituted C3-8 alicyclic hydrocarbon group (as substituents there may be mentioned one or more selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, optionally substituted C1-7 alkoxy, C6-10 aryloxy, C7-9 aralkoxy, C2-7 acyloxy, oxo, C1-6 alkylsulfonyloxy, optionally substituted C2-7 acyl (the acyl is selected from acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and hexanoyl), carboxyl, C2-7 alkoxycarbonyl, carbamoyl, optionally substituted C2-7 alkylcarbamoyl, amino, optionally substituted C1-6 alkylamino, optionally substituted C2-7 acylamino, C2-8 alkoxycarbonylamino, C1-6 alkylsulfonylamino, cyano, nitro, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, sulfamoyl, C1-6 alkylaminosulfonyl, sulfo, optionally substituted C3-6 alicyclic hydrocarbons, optionally substituted C1-6 aliphatic hydrocarbons, optionally substituted C6-14 aromatic hydrocarbons and optionally substituted heterocyclic groups (having in the ring 1 to 4 atoms selected from the group consisting of oxygen, nitrogen and sulfur))
4) a substituted or unsubstituted C6-14 aromatic hydrocarbon group (as substituents there may be mentioned one or more selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, optionally substituted C1-7 alkoxy, C6-10 aryloxy, C7-9 aralkoxy, C2-7 acyloxy, C1-6 alkylsulfonyloxy, optionally substituted C2-7 acyl (the acyl is selected from acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and hexanoyl), carboxyl, C2-7 alkoxycarbonyl, carbamoyl, optionally substituted C2-7 alkylcarbamoyl, amino, optionally substituted C1-6 alkylamino, optionally substituted C2-7 acylamino, C2-8 alkoxycarbonylamino, C1-6 alkylsulfonylamino, cyano, nitro, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, sulfamoyl, C1-6 alkylaminosulfonyl, sulfo, optionally substituted C3-6 alicyclic hydrocarbons, optionally substituted C1-6 aliphatic hydrocarbons, optionally substituted C6-14 aromatic hydrocarbons and optionally substituted heterocyclic groups (having in the ring 1 to 4 atoms selected from the group consisting of oxygen, nitrogen and sulfur))
5) a substituted or unsubstituted monovalent heterocyclic group selected from the group consisting of furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, oxazolidine, isooxazole, isooxazolidine, thiazole, thiazolidine, isothiazole, isothiazolidine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, triazole, thiadiazole, oxadiazole, tetrazole, pyran, tetrahydropyran, thiopyran, tetrahydrothiopyran, pyridine, pyrazine, pyrimidine, pyridazine, benzofuran, dibenzofuran, benzothiophene, indole, 1,2-methylenedioxybenzene, benzimidazole, benzothiazole, benzoxazole, chromane, isochromane, quinoline, decahydroquinoline, isoquinoline, quinazoline, quinoxaline, purine, pteridine, azetidine, morpholine, thiomorpholine, piperidine, homopiperidine, piperazine, homopiperazine, indoline, isoindoline, phenoxazine, phenazine, phenothiazine and quinuclidine, wherein the heterocyclic group is bonded to A4 via a carbon or nitrogen atom (as substituents there may be mentioned one or more selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, optionally substituted C1-7 alkoxy, C6-10 aryloxy, C7-9 aralkoxy, C2-7 acyloxy, oxo, C1-6 alkylsulfonyloxy, optionally substituted C2-7 acyl (the acyl is selected from acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and hexanoyl), carboxyl, C2-7 alkoxycarbonyl, carbamoyl, optionally substituted C2-7 alkylcarbamoyl, amino, optionally substituted C1-6 alkylamino, optionally substituted C2-7 acylamino, C2-8 alkoxycarbonylamino, C1-6 alkylsulfonylamino, cyano, nitro, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, sulfamoyl, C1-6 alkylaminosulfonyl, sulfo, optionally substituted C3-6 alicyclic hydrocarbons, optionally substituted C1-6 aliphatic hydrocarbons, optionally substituted C6-14 aromatic hydrocarbons and optionally substituted heterocyclic groups (having in the ring 1 to 4 atoms selected from the group consisting of oxygen, nitrogen and sulfur))
(the above being with the following provisos:
a) when G1 and A3 are both single bonds, then A1, A2, A4 and G2 together are A1-C(═O)—C(═O)-G2, and
b) when A3 represents a C1-6 aliphatic hydrocarbon group having G1 and A4 bonded on the same or different carbon atoms and G2 represents a substituted or unsubstituted C1-10 aliphatic hydrocarbon group, then A4 is not a single bond)
A5 represents a single bond, or a group binding the carbon atom of the pyrrole ring to which A5 is bonded and R2 in the form of R2—NR201-pyrrole ring carbon (where R201 represents hydrogen or a C1-4 aliphatic hydrocarbon group)
R2 represents one group selected from among the following 1) to 6):
1) hydrogen
2) fluorine, chlorine, bromine or iodine
3) a substituted or unsubstituted C1-10 aliphatic hydrocarbon group (as substituents there may be mentioned one or more selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, optionally substituted C1-7 alkoxy, C6-10 aryloxy, C7-9 aralkoxy, C2-7 acyloxy, oxo, C1-6 alkylsulfonyloxy, optionally substituted C2-7 acyl (the acyl is selected from acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and hexanoyl), carboxyl, C2-7 alkoxycarbonyl, carbamoyl, optionally substituted C2-7 alkylcarbamoyl, amino, optionally substituted C1-6 alkylamino, optionally substituted C2-7 acylamino, C2-8 alkoxycarbonylamino, C1-6 alkylsulfonylamino, cyano, nitro, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, sulfamoyl, C1-6 alkylaminosulfonyl, sulfo, optionally substituted C3-6 alicyclic hydrocarbons, optionally substituted C1-6 aliphatic hydrocarbons, optionally substituted C6-14 aromatic hydrocarbons and optionally substituted heterocyclic groups (having in the ring 1 to 4 atoms selected from the group consisting of oxygen, nitrogen and sulfur))
4) a substituted or unsubstituted C3-8 alicyclic hydrocarbon group (as substituents there may be mentioned one or more selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, optionally substituted C1-7 alkoxy, C6-10 aryloxy, C7-9 aralkoxy, C2-7 acyloxy, oxo, C1-6 alkylsulfonyloxy, optionally substituted C2-7 acyl (the acyl is selected from acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and hexanoyl), carboxyl, C2-7 alkoxycarbonyl, carbamoyl, optionally substituted C2-7 alkylcarbamoyl, amino, optionally substituted C1-6 alkylamino, optionally substituted C2-7 acylamino, C2-8 alkoxycarbonylamino, C1-6 alkylsulfonylamino, cyano, nitro, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, sulfamoyl, C1-6 alkylaminosulfonyl, sulfo, optionally substituted C3-6 alicyclic hydrocarbons, optionally substituted C1-6 aliphatic hydrocarbons, optionally substituted C6-14 aromatic hydrocarbons and optionally substituted heterocyclic groups (having in the ring 1 to 4 atoms selected from the group consisting of oxygen, nitrogen and sulfur))
5) a substituted or unsubstituted C6-14 aromatic hydrocarbon group (as substituents there may be mentioned one or more selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, optionally substituted C1-7 alkoxy, C6-10 aryloxy, C7-9 aralkoxy, C2-7 acyloxy, oxo, C1-6 alkylsulfonyloxy, optionally substituted C2-7 acyl (the acyl is selected from acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and hexanoyl), carboxyl, C2-7 alkoxycarbonyl, carbamoyl, optionally substituted C2-7 alkylcarbamoyl, amino, optionally substituted C1-6 alkylamino, optionally substituted C2-7 acylamino, C2-8 alkoxycarbonylamino, C1-6 alkylsulfonylamino, cyano, nitro, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, sulfamoyl, C1-6 alkylaminosulfonyl, sulfo, optionally substituted C3-6 alicyclic hydrocarbons, optionally substituted C1-6 aliphatic hydrocarbons, optionally substituted C6-14 aromatic hydrocarbons and optionally substituted heterocyclic groups (having in the ring 1 to 4 atoms selected from the group consisting of oxygen, nitrogen and sulfur))
6) a substituted or unsubstituted monovalent heterocyclic group selected from the group consisting of furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, oxazolidine, isooxazole, isooxazolidine, thiazole, thiazolidine, isothiazole, isothiazolidine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, triazole, thiadiazole, oxadiazole, tetrazole, pyran, tetrahydropyran, thiopyran, tetrahydrothiopyran, pyridine, pyrazine, pyrimidine, pyridazine, benzofuran, dibenzofuran, benzothiophene, indole, 1,2-methylenedioxybenzene, benzimidazole, benzothiazole, benzoxazole, chromane, isochromane, quinoline, decahydroquinoline, isoquinoline, quinazoline, quinoxaline, purine, pteridine, azetidine, morpholine, thiomorpholine, piperidine, homopiperidine, piperazine, homopiperazine, indoline, isoindoline, phenoxazine, phenazine, phenothiazine and quinuclidine, wherein the heterocyclic group is bonded to A5 via a carbon or nitrogen atom (as substituents there may be mentioned one or more selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, optionally substituted C1-7 alkoxy, C6-10 aryloxy, C7-9 aralkoxy, C2-7 acyloxy, oxo, C1-6 alkylsulfonyloxy, optionally substituted C2-7 acyl (the acyl is selected from acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and hexanoyl), carboxyl, C2-7 alkoxycarbonyl, carbamoyl, optionally substituted C2-7 alkylcarbamoyl, amino, optionally substituted C1-6 alkylamino, optionally substituted C2-7 acylamino, C2-8 alkoxycarbonylamino, C1-6 alkylsulfonylamino, cyano, nitro, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, sulfamoyl, C1-6 alkylaminosulfonyl, sulfo, optionally substituted C3-6 alicyclic hydrocarbons, optionally substituted C1-6 aliphatic hydrocarbons, optionally substituted C6-14 aromatic hydrocarbons and optionally substituted heterocyclic groups (having in the ring 1 to 4 atoms selected from the group consisting of oxygen, nitrogen and sulfur))
the above being with the proviso that when R2 is fluorine, chlorine, bromine or iodine, A5 is a single bond
wherein the heterocyclic groups as substituents for the C1-10 aliphatic hydrocarbon groups, the C3-8 alicyclic hydrocarbon groups, the C6-14 aromatic hydrocarbon groups, and the heterocyclic groups represented by G2 and R2 are monovalent heterocyclic groups independently selected from the group consisting of furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, oxazolidine, isooxazole, isooxazolidine, thiazole, thiazolidine, isothiazole, isothiazolidine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, triazole, thiadiazole, oxadiazole, tetrazole, pyran, tetrahydropyran, thiopyran, tetrahydrothiopyran, pyridine, pyrazine, pyrimidine, pyridazine, benzofuran, dibenzofuran, benzothiophene, indole, benzimidazole, benzothiazole, benzoxazole, chromane, isochromane, quinoline, decahydroquinoline, isoquinoline, quinazoline, quinoxaline, purine, pteridine, azetidine, morpholine, thiomorpholine, piperidine, homopiperidine, piperazine, homopiperazine, indoline, isoindoline, phenoxazine, phenazine, phenothiazine and quinuclidine, and which are bonded to the C1-10 aliphatic hydrocarbon groups, the C3-8 alicyclic hydrocarbon groups, the C6-14 aromatic hydrocarbon groups, and the heterocyclic groups represented by G2 and R2 via a carbon atom or a nitrogen atom.