US 8,138,172 B2Granted

8-oxoadenine derivatives acting as modulators of TLR7

AssigneesAstraZeneca AB, Dainippon Sumitomo Pharma Co., Ltd.

InventorsAnthony Cook, Tom McInally, Stephen Thom, Hiroki Wada

Life of this patent

Estimating the term…

Abstract

The present invention provides 8-oxoadenine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy. The 8-oxoadenine derivatives act as modulators of Toll-like Receptor (TLR) 7 and thus may be used in the treatment of asthma, hepatitis, allergic diseases, viral and bacterial infection as well as cancer.

Claims14

Dependent claims

A compound of formula (I)

wherein
R1 represents hydrogen, hydroxyl, or a C1-C6 alkoxy, C2-C5 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C6-C10 aryl, C5-C10 heteroaryl or C3-C8 cycloalkyl group, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C5 alkoxycarbonyl, amino (NH2), (mono)-C1-C6 alkylamino and (di)-C1-C6 alkylamino group;
Y1 represents a single bond or C1-C6 alkylene;
X1 represents a single bond, an oxygen, sulphur atom, sulphonyl (SO2) or NR3;
Z1 represents a C2-C6 alkylene or C3-C8 cycloalkylene group, each group being optionally substituted by at least one hydroxyl;
X2 represents NR4;
Y2 represents a single bond or C1-C6 alkylene;
Y3 represents a single bond or C1-C6 alkylene;
n is an integer 0, 1 or 2;
R represents halogen or a C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkoxy, C1-C6 haloalkoxy, amino (NH2), (mono)-C1-C6 alkylamino, (di)-C1-C6 alkylamino group or a C3-C8 saturated heterocyclic ring containing a ring nitrogen atom and optionally one or more further heteroatoms independently selected from nitrogen, oxygen and sulphur, the heterocyclic ring being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, C1-C6 alkyl, C1-C6 alkoxy, C2-C5 alkylcarbonyl and C2-C5 alkoxycarbonyl;
R2 represents hydrogen or a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl group, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl or a C1-C6 alkoxy, a C2-C10 acyloxy, group selected from a C2-5 alkylcarbonyloxy group, a C2-C5 alkenylcarbonyloxy group, a C2-C5 alkynylcarbonyloxy group, a C6-C9 arylcarbonyloxy group and a C5-C9 heteroarylcarbonyloxy group, each of which acyloxy groups may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C1-C3 alkoxy and phenyl providing that the total number of carbon atoms in the acyloxy group does not exceed 10, amino (NH2), (mono)-C1-C6 alkylamino, (di)-C1-C6 alkylamino group and a C3-C8 saturated heterocyclic ring containing a ring nitrogen atom and optionally one or more further heteroatoms independently selected from nitrogen, oxygen and sulphur, the heterocyclic ring in turn being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, C1-C6 alkyl, C1-C6 alkoxy, C2-C5 alkylcarbonyl and C2-C5 alkoxycarbonyl group;
R3 represents hydrogen or C1-C6 alkyl;
R4 represents CO2R5, SO2R5, COR5, SO2NR6R7 and CONR6R7;
R5 independently represents
(i) 3- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms selected from a ring group NR8, S(O)m or oxygen, the 3- to 8-membered heterocyclic ring being optionally substituted by one or more substituents independently selected from halogen, hydroxyl or a C1-C6 alkyl and C1-C6 alkoxy group, or
(ii) a C6-C10 aryl or C5-C10 heteroaryl group, each of which may be optionally substituted by one or more substituents independently selected from halogen, cyano, C1-C6 alkyl, C1-C3 haloalkyl, carboxyl, S(O)mR9, OR10, CO2R10, SO2NR10R11, CONR10R11, NR10R11, NR10SO2R9, NR10CO2R9, NR10COR9, or
(iii) a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl group, each of which may be optionally substituted by one or more substituents independently selected from halogen, CN, C3-C8 cycloalkyl, S(O)pR12, OR13, COR13, CO2R13, SO2NR13R14, CONR13R14, NR13R14, NR13SO2R12, NR13CO2R12, NR13COR12, NR13SO2R12 or a C6-C10 aryl or C5-C10 heteroaryl group or a heterocyclic ring, the latter three groups may be optionally substituted by one or more substituents independently selected from C1-C6 alkyl (optionally substituted by hydroxy, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, amino, C1-C6 alkylamino, di-C1-C6 alkylamino, NH2C(O)—, C1-C6 alkylNHC(O), di-C1-C6 alkyl NC(O), —OCH2CH2OH, pyrrolidinyl, pyrrolidinylcarbonyl, furanyl, piperidyl, methylpiperidyl or phenyl), C2-C6 alkenyl (optionally substituted by phenyl), halogen, hydroxy, cyano, carboxy, amino, C1-C6 alkylamino, di-C1-C6 alkylamino, NH2C(O)—, C1-C6 alkyl NHC(O)—,di-C1-C6 alkyl NC(O), C1-C6 alkoxycarbonyl, C1-C6 alkylsulphonyl, C1-C6 alkylcarbonylamino, C1-C6 alkylcarbonylmethylamino, phenyl (optionally substituted by hydroxy, fluoro or methyl), pyrrolidinyl, pyridyl, piperidinyl, benzothiazolyl or pyrimidinyl;
R6 represents hydrogen or a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl group or heterocyclic ring, each of which may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, OR15, S(O)qR15, CO2R16, COR16, NR16R17, CONR16R17, NR16COR17, NR16CO2R15, SO2NR16R17, NR16SO2R15, or a C6-C10 aryl or C5-C10 heteroaryl group or heterocyclic ring, the latter three groups being optionally substituted by one or more substituents independently selected from, C1-C6 alkyl, C3-C8 cycloalkyl, halogen, S(O)qR15, CO2R16, COR16, hydroxy or cyano;
and
R7 represents hydrogen, a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl group, each group may be optionally substituted by one or more substituents independently selected from halogen, C3-C8 cycloalkyl, a C6-C10 aryl or C5-C10 heteroaryl group, carboxy, cyano, OR15, hydroxy or NR18R19, or
R6 and R7 together with the nitrogen atom to which they are attached fowl a 3- to 8-membered saturated or partially saturated heterocyclic ring, optionally containing further heteroatoms or heterogroups selected from nitrogen, S(O)m or oxygen, the heterocyclic ring, may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, carboxyl, cyano, OR20, NR21R22, S(O)qR23, COR24, CO2R24, NR24R25, CONR24R25, NR24COR25, NR24CO2R23, SO2NR24R25, NR24SO2R23, C6-C10 aryl , C5-C10 heteroaryl group, heterocyclic ring, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl group, the latter seven groups being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, cyano, OR20, S(O)qR23, COR24, CO2R24, NR24R25, CONR24R25, NR24CO2R23, NR24COR25, SO2NR24R25, NR24SO2R23, a heterocyclic ring or a C6-C10 aryl or C5-C10 heteroaryl group, the latter three groups being optionally substituted by one or more substituents independently selected from C1-C6 alkyl, halogen, hydroxy or cyano;
R8 represents hydrogen, CO2R26, COR26, SO2R26, C1-C6 alkyl or C3-C6 cycloalkyl group, each group may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, and NR27R28;
R10, R11, R16, R17, R18, R19, R21, R22, R26, R27 or R28 each independently represents hydrogen, and a C1-C6 alkyl or C3-C6 cycloalkyl group;
R24and R25 each independently represents hydrogen, and a C1-C6 alkyl or C3-C6 cycloalkyl group;
or
R24 and R25 together with the nitrogen atom to which they are attached form a 3- to 8-membered saturated or partially saturated heterocyclic ring, optionally containing further heteroatoms or heterogroups selected from nitrogen, S(O)m or oxygen;
R9, R12, R15 and R23 represent C1-C6 alkyl or C3-C6 cycloalkyl;
R13 and R14 are defined as for R6 and R7 respectively;
R20 represents a C1-C6 alkyl optionally substituted by one or more substituents independently selected from halogen, hydroxyl or OR23;
m, p, q and r each independently represent an integer 0, 1 or 2;
and
A represents a C6-C10 aryl or C5-C12 heteroaryl group;
or a pharmaceutically acceptable salt thereof.

30 more elements

A compound selected from:

Methyl[4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(4-methylpiperazin-1-yl)acetyl]amino}methyl)phenyl]acetate,
Methyl(4-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](N,N-dimethylglycyl)amino]methyl}phenyl)acetate,
Methyl[4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(1-methylpiperidin-4-yl)carbonyl]amino}methyl)phenyl]acetate,
Methyl[4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][4-(dimethylamino)butanoyl]amino}methyl)phenyl]acetate,
Methyl(4-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](N,N-dimethyl-□-alanyl)amino]methyl}phenyl)acetate,
Methyl[4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][N,N-bis(2-hydroxyethyl)glycyl]amino}methyl)phenyl]acetate,
Methyl{4-[([3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]{[4-(2-hydroxyethyl)piperazin-1-yl]acetyl}amino)methyl]phenyl}acetate,
Methyl{4-[([3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]{[4-(methylsulfonyl)piperazin-1-yl]acetyl}amino)methyl]phenyl}acetate,
Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(1-methylpiperidin-4-yl)carbonyl]amino}methyl)phenyl]acetate,
Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(1-methylpiperidin-4-yl)carbonyl]amino}methyl)phenyl]acetate,
Methyl(3-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](glycyl)amino]methyl}phenyl)acetate,
Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(methylthio)acetyl]amino}methyl)phenyl]acetate,
Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(methylsulfinyl)acetyl]amino}methyl)phenyl]acetate,
Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(methylsulfonyl)acetyl]amino}methyl)phenyl]acetate,
Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(methylthio)propanoyl]amino}methyl)phenyl]acetate,
Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(methylsulfonyl)propanoyl]amino}methyl)phenyl]acetate,
Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][N-(methylsulfonyl)glycyl]amino}methyl)phenyl]acetate,
tert-Butyl 4-{[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(2-methoxy-2-oxoethyl)benzyl]amino}-4-oxobutanoate,
4-{[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(2-methoxy-2-oxoethyl)benzyl]amino}-4-oxobutanoic acid,
Methyl 3-{[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(2-methoxy-2-oxoethyl)benzyl]amino}-3-oxopropanoate,
Methyl[3-({acetyl[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}methyl)phenyl]acetate,
Methyl(3-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](methylsulfonyl)amino]methyl}phenyl)acetate,
(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)[2R]-propyl]-(pyrrolidine-2-carbonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester,
(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)-propyl][2S,4R](4-hydroxy-pyrrolidine-2-carbonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester,
(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)-propyl][2S]-(1-methyl-pyrrolidine-2-carbonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester,
(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)-propyl]-(3-piperazin-1-yl-propionyl)-amino]-methyl}-phenyl)-acetic acid methyl ester,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-[3-(1-piperidyl)propyl]piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[3-(diethylcarbamoyl)-1-piperidyl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-phenyl-1-piperidyl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(1-piperidyl)acetyl]amino]methyl]phenyl]acetate,
Ethyl 4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl]piperazine-1-carboxylate,
2-[[3-(6-Amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl-(2-cyanoethyl)amino]acetic acid,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(benzyl-(2-dimethylaminoethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-carbamoyl-1-piperidyl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(3R)-3-hydroxypyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,
tert-Butyl (2S)-1-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl]pyrrolidine-2-carboxylate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(2-cyanoethyl-(oxolan-2-ylmethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(ethyl-(pyridin-4-ylmethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-ethylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(methyl-(2-pyridin-4-ylethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-pyrrolidin-1-yl-1-piperidyl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2S)-2-carbamoylpyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(3,6-dihydro-2H-pyridin-1-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(ethyl-(2-hydroxyethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(cyclohexyl-(2-hydroxyethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(hydroxymethyl)-1-piperidyl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2-aminoethyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2-hydroxyethyl)-1-piperidyl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[methyl-(1-methyl-4-piperidyl)amino]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-benzyl-4-hydroxy-1-piperidyl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-cinnamylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(3-dimethylaminopropyl-methyl-amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(dimethylcarbamoylmethyl-methyl-amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2R)-2-carbamoylpyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2S,6R)-2,6-dimethylmorpholin-4-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-methyl-1,4-diazepan-1-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-(2-morpholin-4-ylacetyl)amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(3-hydroxyphenyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[[2-[3-(acetyl-methyl-amino)pyrrolidin-1-yl]acetyl]-[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(3S)-3-dimethylaminopyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-pyridin-4-ylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(3-dimethylaminopropyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-propan-2-ylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(dimethylcarbamoylmethyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2-hydroxy-2-phenyl-ethyl)-methyl-amino]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(aminomethyl)-1-piperidyl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(methyl-(2-methylaminoethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-(2-thiomorpholin-4-ylacetyl)amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-phenylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(1,3-dihydroisoindol-2-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-(2-piperazin-1-yl)acetyl)amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(1-piperidyl)-1-piperidyl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-pyridin-2-ylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-hydroxy-1-piperidyl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(4-fluorophenyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-methyl-1-piperidyl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(2,5-dihydropyrrol-1-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-benzothiazol-2-ylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(ethoxycarbonylmethyl)-1-piperidyl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2-dimethylaminoethyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2-methylphenyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-ethylsulfonylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate,
(2S,4R)-1-[[3-(6-Amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-(methoxycarbonylmethyl)-phenyl]methyl]carbamoyl]methyl]-4-hydroxy-pyrrolidine-2-carboxylic acid,
(2S)-2-[[3-(6-Amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-(methoxycarbonylmethyl)-phenyl]methyl]carbamoyl]methyl-methyl-amino]-3-phenyl-propanoic acid,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,
3-[[3-(6-Amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-(methoxycarbonylmethyl)-phenyl]methyl]carbamoyl]methyl-(1,1-dioxothiolan-3-yl)amino]propanoic acid,
3-[[3-(6-Amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-(methoxycarbonylmethyl)-phenyl]methyl]carbamoyl]methyl-cyclohexyl-amino]propanoic acid,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(ethyl-(2-ethylaminoethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(ethyl-(3-ethylaminopropyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(3,4-dihydro-1H-isoquinolin-2-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-[(1-methyl-4-piperidyl)methyl]piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(methyl-prop-2-ynyl-amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(1-methyl-4-piperidyl)-phenethyl-amino]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(oxolan-2-ylmethyl)piperazin-1-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(3R)-3-aminopyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,
tert-Butyl (2R)-1-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl]pyrrolidine-2-carboxylate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-pyrimidin-2-ylpiperazin-1-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-(2-pyrrolidin-1-ylacetyl)amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate, and
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]acetyl]amino]methyl]phenyl]acetate,
and pharmaceutically acceptable salts thereof.

101 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/305,801Filed 3 Jul 2007 · us provisional application
Priority: 5 Jul 2006
Published: US 2010/0240623 A123 Sep 2010
Granted: 20 Mar 2012
Term ends: Not estimatedThe source records don’t support an estimate.

Classification19 codes

C07D 473/18
With oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6: one oxygen and one nitrogen atom, e.g. guanine
A61P 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…
A61P 11/00
Drugs for disorders of the respiratory system
A61P 11/02
Drugs for disorders of the respiratory system: nasal agents, e.g. decongestants

Family

Application60/818,554Us provisional application · filed 5 Jul 2006
US 2010/0240623 A1Pre-grant publication · published 23 Sep 2010
US 8,138,172 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of formula (I)

wherein
R1 represents hydrogen, hydroxyl, or a C1-C6 alkoxy, C2-C5 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C6-C10 aryl, C5-C10 heteroaryl or C3-C8 cycloalkyl group, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C5 alkoxycarbonyl, amino (NH2), (mono)-C1-C6 alkylamino and (di)-C1-C6 alkylamino group;
Y1 represents a single bond or C1-C6 alkylene;
X1 represents a single bond, an oxygen, sulphur atom, sulphonyl (SO2) or NR3;
Z1 represents a C2-C6 alkylene or C3-C8 cycloalkylene group, each group being optionally substituted by at least one hydroxyl;
X2 represents NR4;
Y2 represents a single bond or C1-C6 alkylene;
Y3 represents a single bond or C1-C6 alkylene;
n is an integer 0, 1 or 2;
R represents halogen or a C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkoxy, C1-C6 haloalkoxy, amino (NH2), (mono)-C1-C6 alkylamino, (di)-C1-C6 alkylamino group or a C3-C8 saturated heterocyclic ring containing a ring nitrogen atom and optionally one or more further heteroatoms independently selected from nitrogen, oxygen and sulphur, the heterocyclic ring being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, C1-C6 alkyl, C1-C6 alkoxy, C2-C5 alkylcarbonyl and C2-C5 alkoxycarbonyl;
R2 represents hydrogen or a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl group, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl or a C1-C6 alkoxy, a C2-C10 acyloxy, group selected from a C2-5 alkylcarbonyloxy group, a C2-C5 alkenylcarbonyloxy group, a C2-C5 alkynylcarbonyloxy group, a C6-C9 arylcarbonyloxy group and a C5-C9 heteroarylcarbonyloxy group, each of which acyloxy groups may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C1-C3 alkoxy and phenyl providing that the total number of carbon atoms in the acyloxy group does not exceed 10, amino (NH2), (mono)-C1-C6 alkylamino, (di)-C1-C6 alkylamino group and a C3-C8 saturated heterocyclic ring containing a ring nitrogen atom and optionally one or more further heteroatoms independently selected from nitrogen, oxygen and sulphur, the heterocyclic ring in turn being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, C1-C6 alkyl, C1-C6 alkoxy, C2-C5 alkylcarbonyl and C2-C5 alkoxycarbonyl group;
R3 represents hydrogen or C1-C6 alkyl;
R4 represents CO2R5, SO2R5, COR5, SO2NR6R7 and CONR6R7;
R5 independently represents
(i) 3- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms selected from a ring group NR8, S(O)m or oxygen, the 3- to 8-membered heterocyclic ring being optionally substituted by one or more substituents independently selected from halogen, hydroxyl or a C1-C6 alkyl and C1-C6 alkoxy group, or
(ii) a C6-C10 aryl or C5-C10 heteroaryl group, each of which may be optionally substituted by one or more substituents independently selected from halogen, cyano, C1-C6 alkyl, C1-C3 haloalkyl, carboxyl, S(O)mR9, OR10, CO2R10, SO2NR10R11, CONR10R11, NR10R11, NR10SO2R9, NR10CO2R9, NR10COR9, or
(iii) a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl group, each of which may be optionally substituted by one or more substituents independently selected from halogen, CN, C3-C8 cycloalkyl, S(O)pR12, OR13, COR13, CO2R13, SO2NR13R14, CONR13R14, NR13R14, NR13SO2R12, NR13CO2R12, NR13COR12, NR13SO2R12 or a C6-C10 aryl or C5-C10 heteroaryl group or a heterocyclic ring, the latter three groups may be optionally substituted by one or more substituents independently selected from C1-C6 alkyl (optionally substituted by hydroxy, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, amino, C1-C6 alkylamino, di-C1-C6 alkylamino, NH2C(O)—, C1-C6 alkylNHC(O), di-C1-C6 alkyl NC(O), —OCH2CH2OH, pyrrolidinyl, pyrrolidinylcarbonyl, furanyl, piperidyl, methylpiperidyl or phenyl), C2-C6 alkenyl (optionally substituted by phenyl), halogen, hydroxy, cyano, carboxy, amino, C1-C6 alkylamino, di-C1-C6 alkylamino, NH2C(O)—, C1-C6 alkyl NHC(O)—,di-C1-C6 alkyl NC(O), C1-C6 alkoxycarbonyl, C1-C6 alkylsulphonyl, C1-C6 alkylcarbonylamino, C1-C6 alkylcarbonylmethylamino, phenyl (optionally substituted by hydroxy, fluoro or methyl), pyrrolidinyl, pyridyl, piperidinyl, benzothiazolyl or pyrimidinyl;
R6 represents hydrogen or a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl group or heterocyclic ring, each of which may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, OR15, S(O)qR15, CO2R16, COR16, NR16R17, CONR16R17, NR16COR17, NR16CO2R15, SO2NR16R17, NR16SO2R15, or a C6-C10 aryl or C5-C10 heteroaryl group or heterocyclic ring, the latter three groups being optionally substituted by one or more substituents independently selected from, C1-C6 alkyl, C3-C8 cycloalkyl, halogen, S(O)qR15, CO2R16, COR16, hydroxy or cyano;
and
R7 represents hydrogen, a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl group, each group may be optionally substituted by one or more substituents independently selected from halogen, C3-C8 cycloalkyl, a C6-C10 aryl or C5-C10 heteroaryl group, carboxy, cyano, OR15, hydroxy or NR18R19, or
R6 and R7 together with the nitrogen atom to which they are attached fowl a 3- to 8-membered saturated or partially saturated heterocyclic ring, optionally containing further heteroatoms or heterogroups selected from nitrogen, S(O)m or oxygen, the heterocyclic ring, may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, carboxyl, cyano, OR20, NR21R22, S(O)qR23, COR24, CO2R24, NR24R25, CONR24R25, NR24COR25, NR24CO2R23, SO2NR24R25, NR24SO2R23, C6-C10 aryl , C5-C10 heteroaryl group, heterocyclic ring, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl group, the latter seven groups being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, cyano, OR20, S(O)qR23, COR24, CO2R24, NR24R25, CONR24R25, NR24CO2R23, NR24COR25, SO2NR24R25, NR24SO2R23, a heterocyclic ring or a C6-C10 aryl or C5-C10 heteroaryl group, the latter three groups being optionally substituted by one or more substituents independently selected from C1-C6 alkyl, halogen, hydroxy or cyano;
R8 represents hydrogen, CO2R26, COR26, SO2R26, C1-C6 alkyl or C3-C6 cycloalkyl group, each group may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, and NR27R28;
R10, R11, R16, R17, R18, R19, R21, R22, R26, R27 or R28 each independently represents hydrogen, and a C1-C6 alkyl or C3-C6 cycloalkyl group;
R24and R25 each independently represents hydrogen, and a C1-C6 alkyl or C3-C6 cycloalkyl group;
or
R24 and R25 together with the nitrogen atom to which they are attached form a 3- to 8-membered saturated or partially saturated heterocyclic ring, optionally containing further heteroatoms or heterogroups selected from nitrogen, S(O)m or oxygen;
R9, R12, R15 and R23 represent C1-C6 alkyl or C3-C6 cycloalkyl;
R13 and R14 are defined as for R6 and R7 respectively;
R20 represents a C1-C6 alkyl optionally substituted by one or more substituents independently selected from halogen, hydroxyl or OR23;
m, p, q and r each independently represent an integer 0, 1 or 2;
and
A represents a C6-C10 aryl or C5-C12 heteroaryl group;
or a pharmaceutically acceptable salt thereof.

30 more elements

Facts

Application

12/305,801Filed 3 Jul 2007 · us provisional application

Priority

5 Jul 2006

Published

US 2010/0240623 A123 Sep 2010

Granted

20 Mar 2012

Term ends

Not estimatedThe source records don’t support an estimate.

Classification19 codes

C07D 473/18
With oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6: one oxygen and one nitrogen atom, e.g. guanine
A61P 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…
A61P 11/00
Drugs for disorders of the respiratory system
A61P 11/02
Drugs for disorders of the respiratory system: nasal agents, e.g. decongestants