Patent Application
20080269240
The present invention relates to a novel adenine compound useful as a prophylactic or therapeutic agent for allergic diseases, viral diseases, cancers, etc.
When a foreign substance such as bacteria, virus or parasite invades into a living body, immune system works to defend from the foreign substance. In acquired immune system, once a foreign substance invades, antigen is processed by antigen presenting cells such as dendritic cells (DC), and naive cells, via mutual action of DC/Th cells, functionally differentiate into Th1 cells or Th2 cells which contribute the main role to immune response in a living body. In this processing, when immune balance deviates to either one of Th1 cells or Th2 cells, it is considered that immune diseases develop.
Namely, in a body of a patient suffering from an allergic disease, cytokines such as interleukin-4 (IL-4) and interleukin-5 (IL-5) secreted from Th2 cells are excessively secreted. Therefore, compounds suppressing an immune response of Th2 cell can be expected as an agent for treating allergic diseases. On the other hand, compounds enhancing an immune response of Th1 cell can be expected as an agent for treating viral diseases, cancers, etc.
Natural immune system has been considered due to non specific phagocytosis. However, the presence of Toll-like receptor (TLR) is confirmed, and activation of the natural immune response is found to be mainly done via TLR, Once TLR recognizes ligands, it induces inflammatory cytokines such as IL-12, TNF, etc. As IL-12 induces naive T cells into Th1 cells, ligands of TLR have a function as a Th1/Th2 differentiation controlling agent, the ligands are expected as a prophylaxis or therapeutic agent for immune diseases. In fact it is known that Th2-cells are dominant in the patients suffering from asthma or atopic dermatitis, and asthma-targeted clinical trials are carried out for DNA (CpG DNA) derived from microorganism, TLR9 agonist. It is also known that imidazooquinoline derivatives, TLR7/8 agonist (See Patent Document 1) show an activity suppressing the production of Th2 cytokines, i.e. interleukin 4 (IL-4) and interleukin 5 (IL-5), and in fact are effective for treatment of allergic diseases in animal model.
On the other hand, compounds having an adenine structure and effective for treatment of immune diseases such as viral diseases or allergic diseases are disclosed in following patent documents 2 to 4.
[Patent Document 1] U.S. Pat. No. 4,689,338
The problem to be solved by the present invention is to provide TLR activating agents, in more detail, the novel adenine compounds having TLR7 activating effect, an immune modulator containing them, such as prophylactic or therapeutic agents for allergic diseases such as asthma, COPD, allergic rhinitis, allergic conjunctivitis and atopic dermatosis, viral diseases such as hepatitis B, hepatitis C, HIV and HPV, bacterial infectious diseases, cancers and dermatosis.
The present inventors earnestly investigated in order to find a therapeutic or prophylactic agent for allergic diseases, viral diseases or cancers, having excellent TLR activating effect and succeeded in finding a novel compound of the present invention. Namely the compound of the present invention is useful for therapeutic and prophylactic agent of allergic diseases, viral diseases and cancers.
Thus the present invention has been completed based on the above findings.
Namely, the present invention relates to the following invention.
[1] An adenine compound represented by the following formula (1):
[wherein
R1 is halogen atom, optionally substituted alkyl group, optionally substituted alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group, optionally substituted aryl group or optionally substituted heteroaryl group;
R2 is hydrogen atom, optionally substituted alkyl group, optionally substituted alkenyl group, optionally substituted alkynyl group or optionally substituted cycloalkyl group;
X is oxygen atom, sulfur atom, NR4 (wherein R4 is hydrogen atom or C1-6 alkyl group), SO, SO2 or a single bond, provided that X is a single bond when R1 is halogen atom;
A1 is optionally substituted and saturated or unsaturated 4 to 8 membered heterocyclic group containing 1 to 2 hetero atoms selected from 1 to 2 nitrogen atoms, 0 to 1 oxygen atom, and 0 to 1 sulfur atom;
A2 is optionally substituted 6 to 10 membered aromatic carbocyclic group or optionally substituted 5 to 10 membered aromatic heterocyclic group;
L3 is optionally substituted straight or branched alkylene or a single bond; and
L1 and L2 are independently, straight or branched alkylene or a single bond and any 1 to 3 methylene groups in said alkylene group may be replaced by oxygen atom, sulfur atom, NR5 (wherein R5 is hydrogen atom, optionally substituted alkyl group, optionally substituted cycloalkyl group, optionally substituted aryl group or optionally substituted heteroaryl group), SO, SO2, C═NR6 (wherein R6 is optionally substituted alkyl group, optionally substituted aryl group or optionally substituted heteroaryl group), or carbonyl group.]
or its pharmaceutically acceptable salt.
[2] The adenine compound or its pharmaceutically acceptable salt described in the above [1], wherein
substituted alkyl group, substituted alkenyl group or substituted alkynyl group in R1 and R2, and substituted alkyl group in R5 and R6 are substituted by one or more substituents independently selected from the group consisting of groups (a) to (c) below;
(a) halogen atom, hydroxy group, carboxy group, mercapto group and C1-6 haloalkoxy group;
(b) C1-6 alkoxy group, C2-6 alkylcarbonyl group, C2-6 alkoxycarbonyl group, C1-6 alkylsulfonyl group, C1-6 alkylsulfinyl group, C2-6 alkylcarbonyloxy group, and C1-6 alkylthio group (wherein the group of this group may be substituted by one or more substituents independently selected from the group consisting of halogen atom, hydroxy group, carboxy group, C1-6 alkoxy group, C2-6 alkoxycarbonyl group, amino group optionally substituted by the same or different and one or two C1-6 alkyl groups, carbamoyl group optionally substituted by the same or different and one or two C1-6 alkyl groups, sulfamoyl group optionally substituted by the same or different and one or two C1-6 alkyl groups, and C1-6 alkylsulfonyl group);
(c) optionally substituted amino group, optionally substituted carbamoyl group and optionally substituted sulfamoyl group (wherein the group of this group may be substituted by 1 or 2 substituents selected from the group consisting of groups (k), (l) and (m) below), optionally substituted 3 to 8 membered cycloalkyl group and optionally substituted 4 to 8 membered saturated heterocyclic group (wherein the group of this group may be substituted by one or more substituents selected from the group consisting of groups (d), (e) and (f) below), and optionally substituted 6 to 10 membered aryl group, optionally substituted 5 to 10 membered heteroaryl group, optionally substituted 6 to 10 membered aryloxy group and optionally substituted 5 to 10 membered heteroaryloxy group (wherein the group of this group may be substituted by one or more substituents selected from the group consisting of groups (g), (h) (i) and (j) below);
substituted cycloalkyl group in R1, R2 and R5 is substituted by one or more substituents independently selected from the group consisting of groups (d) to (f) below;
(d) halogen atom, hydroxy group, carboxy group, mercapto group, cyano group, nitro group, C1-6 haloalkyl group and C1-6 haloalkoxy group;
(e) C1-6 alkyl group, C1-6 alkoxy group, C2-6 alkenyl group, C2-6 alkynyl group, C2-6 alkoxycarbonyl group, and C1-6 alkylthio group (wherein the group of this group may be substituted by one or more substituents independently selected from the group consisting of halogen atom, hydroxy group, carboxy group, C1-6 alkoxy group, C2-6 alkoxycarbonyl group, amino group optionally substituted by the same or different and one or two C1-6 alkyl groups, carbamoyl group optionally substituted by the same or different and one or two C1-6 alkyl groups, sulfamoyl group optionally substituted by the same or different and one or two C1-6 alkyl groups, and C1-6 alkylsulfonyl group);
(f) optionally substituted amino group, optionally substituted carbamoyl group and optionally substituted sulfamoyl group (wherein the group of this group may be substituted by one or two substituents selected groups (k), (l) and (m) below), optionally substituted 6 to 10 membered aryl group and optionally substituted 5 to 10 membered heteroaryl group (the group of this group may be substituted by one or more substituents selected from the group consisting of groups (g), (h), (i) and (j) below);
substituted aryl group and substituted heteroaryl group in R1, R5 and R6 are substituted by one or more substituents independently selected from the group consisting of groups (g) to (j) below;
(g) halogen atom, hydroxy group, mercapto group, cyano group, nitro group, C1-6 haloalkyl group, and C1-6 haloalkoxy group;
(h) C1-6 alkyl group, C1-6 alkoxy group, C2-6 alkenyl group, C2-6 alkynyl group, and C1-6 alkylthio group (wherein the group of this group may be substituted by one or more substituents independently selected from a group consisting of halogen atom, hydroxy group, carboxy group, C1-6 alkoxy group, C2-6 alkoxycarbonyl group, amino group optionally substituted by the same or different and one or two C1-6 alkyl groups, carbamoyl group optionally substituted by the same or different and one or two C1-6 alkyl groups, sulfamoyl group optionally substituted by the same or different and one or two C1-6 alkyl groups, and C1-6 alkylsulfonyl group);
(i) 3 to 8 membered cycloalkyl group and 4 to 8 membered saturated heterocyclic group (the group of this group may be substituted by one or more substituents independently selected from group consisting of halogen atom, hydroxy group, carboxy group, C1-6 alkyl group and C1-6 alkoxy group);
(j) optionally substituted amino group, optionally substituted carbamoyl group, and optionally substituted sulfamoyl group (the group of this group may be substituted by one or two substituents selected from group consisting of groups (k), (l) and (m) below);
the substituted amino group, substituted carbamoyl group and substituted sulfamoyl group mentioned above are substituted by one or two substituents independently selected from the group consisting of groups (k) to (m) below;
(k) C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group, C2-6 alkylcarbonyl group, C2-6 alkoxycarbonyl group, C1-6 alkylsulfonyl group, C1-6 alkylsulfinyl group, 3 to 8 membered cycloalkyl group, 3 to 8 membered cycloalkylcarbonyl group, 3 to 8 membered cycloalkoxycarbonyl group, 3 to 8 membered cycloalkylsulfonyl group, and 3 to 8 membered cycloalkylsulfinyl group (wherein the group of this group may be substituted by one or more substituents independently selected from the group consisting of halogen atom, hydroxy group, carboxy group, C1-6 alkoxy group, and C2-6 alkoxycarbonyl group);
(l) 6 to 10 membered aryl group, 6 to 10 membered arylcarbonyl group, 6 to 10 membered aryloxycarbonyl group, 6 to 10 membered arylsulfonyl group, 6 to 10 membered arylsulfinyl group, 5 to 10 membered heteroaryl group, 5 to 10 membered heteroarylcarbonyl group, 5 to 10 membered heteroaryloxycarbonyl group, 5 to 10 membered heteroarylsulfonyl group, and 5 to 10 membered heteroarylsulfinyl group (wherein the group of this group may be substituted by halogen atom, hydroxy group, mercapto group, cyano group, nitro group, C1-6 alkyl group, C1-6 alkoxy group or C1-6 alkylthio group);
(m) 4 to 7 membered saturated heterocyclic group containing 1 to 4 hetero atoms selected from 1 to 2 nitrogen atoms, 0 to 1 oxygen atom, and 0 to 1 sulfur atom which is formed by combining two substituents with the nitrogen atom (said saturated heterocyclic group may be substituted on any carbon atom or nitrogen atom, if chemically stable, by halogen atom, hydroxy group, carboxy group, C1-6 alkyl group, C1-6 alkoxy group, C2-6 alkoxycarbonyl group or C2-6 alkylcarbonyl group);
substituted 4 to 8 membered heterocyclic group in A1 may be substituted by one or more substituents independently selected from a group consisting of halogen atom, hydroxy group, oxo group, C1-6 alkyl group, C1-6 alkoxy group, C2-6 alkylcarbonyl group and C2-6 alkoxycarbonyl group; substituted 6 to 10 membered aromatic carbocyclic group or substituted 5 to 10 membered aromatic heterocyclic group in A2 may be substituted by one or more substituents independently selected from a group consisting of halogen atom, C1-6 alkyl group, C1-6 alkoxy group, C1-6 haloalkyl group, C1-6 haloalkoxy group, amino group optionally substituted by the same or different and one or two C1-6 alkyl groups, 4 to 8 membered saturated heterocyclic group containing 1 to 2 hetero atoms selected from 1 to 2 nitrogen atoms, 0 to 1 oxygen atom, and 0 to 1 sulfur atom (said saturated heterocyclic group may be substituted by one or more substituents independently selected from a group consisting of halogen atom, hydroxy group, oxo group, C1-6 alkyl group, C1-6 alkoxy group, C2-6 alkylcarbonyl group and C2-6 alkoxycarbonyl group);
L3 is straight or branched C1-6 alkylene, or a single bond;
[3] The adenine compound or its pharmaceutically acceptable salt described in the above [1] or [2], wherein in the formula (1), A1 is pyrrolidine, piperidine, azetidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1-oxide, thiomorpholine-1,1-dioxide, 2,6-dimethylpiperidine, 3,5-dimethylpiperidine, 2,6-dimethylpiperazine, 2,6-dimethylmorpholine, 3,5-dimethylmorpholine, 2,6-dimethylthiomorpholine, or 3,5-dimethylthiomorpholine.
[4] The adenine compound or its pharmaceutically acceptable salt described in any one of the above [1] to [3], wherein in the formula (1), A2 is benzene, pyridine, furan, imidazole or thiophene.
[5] The adenine compound or its pharmaceutically acceptable salt described in any one of the above [1] to [4], wherein in the formula (1), R2 is C1-4 alkyl group.
[6] The adenine compound or its pharmaceutically acceptable salt described in the above [5], wherein in the formula (1), R2 is methyl group.
[7] The adenine compound or its pharmaceutically acceptable salt described in any one of the above [1] to [4], wherein in the formula (1), R2 is C2-8 alkyl group substituted by optionally substituted amino group.
[8] The adenine compound or its pharmaceutically acceptable salt described in any one of the above [1] to [7], wherein in the formula (1), L1 is the following formula:
(CH2)n—(Y4)m—(CH2)1a
[wherein, n and 1a are independently an integer of 0 to 5, m is 0 or 1, Y4 is oxygen atom or NR5 (wherein R5 is the same as defined in the above [1])], L2 is a single bond, oxygen atom, C1-10 straight alkylene or the following formula:
(CH2)a—(Y1)p—(CH2)q—(Y2)r—(CH2)t—(Y3)u
[wherein Y1 is carbonyl group, Y2 is NR5′ (R5′ is the same as the definition of R5), Y3 is oxygen atom, a, t and q are independently, an integer of 0 to 4, p, r and u are independently 0 or 1, provided that t is 2 or more when r and u are l], and
L3 is a single bond or C1-4 straight alkylene.
[9] The adenine compound or its pharmaceutically acceptable salt described in the above [8], wherein R5 is hydrogen atom, C1-6 alkyl group, C1-6 alkylcarbonyl group or C1-6 alkylsulfonyl group (these groups may be substituted by one or more substituents independently selected from a group consisting of halogen atom, hydroxy group, alkoxy group, 3 to 8 membered cycloalkyl group, 6 to 10 membered aryl group, 6 to 10 membered arylcarbonyl group and 5 to 10 membered heteroaryl group (this group may be substituted by one or more substituents independently selected from a group consisting of halogen atom, hydroxy group, nitro group, cyano group, C1-6 alkyl group, C1-6 alkoxy group, C1-6 haloalkyl group and C1-6 haloalkoxy group).
[10] The adenine compound or its pharmaceutically acceptable salt described in the above [1] selected from the group of the following compounds:
According to the present invention it is possible to provide a novel adenine compound useful as a prophylactic or therapeutic agent for allergic diseases, viral diseases, cancers, etc.
The present invention is described in detail below.
“Halogen atom” in the present specification includes fluorine atom, chlorine atom, bromine atom, or iodine atom, preferably fluorine atom or chlorine atom.
“Alkyl group” includes C1-12 straight or branched chain alkyl group, such as methyl group, ethyl group, propyl group, 1-methylethyl group, butyl group, 2-methylpropyl group, 1-methylpropyl group, 1,1-dimethylethyl group, pentyl group, 3-methylbutyl group, 2-methylbutyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 1,1-dimethylpropyl group, hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, heptyl group, 1-methylhexyl group, 1-ethylpentyl group, octyl group, 1-methylheptyl group, 2-ethylhexyl group, nonyl group, decyl group, etc., preferably C1-6 alkyl group, more preferably C1-4 alkyl group.
“Alkenyl group” includes C2-10 straight or branched chain alkenyl group, such as ethenyl group, propenyl group, 1-methylethenyl group, butenyl group, 2-methylpropenyl group, 1-methylpropenyl group, pentenyl group, 3-methylbutenyl group, 2-methylbutenyl group, 1-methylpropenyl group, hexenyl group, 4-methylpentenyl group, 3-methylpentenyl group, 2-methylpentenyl group, 1-methylpentenyl group, 3,3-dimethylbutenyl group, 1,2-dimethylbutenyl group, heptenyl group, 1-methylhexenyl group, 1-ethylpentenyl group, octenyl group, 1-methylheptenyl group, 2-ethylhexenyl group, nonenyl group, decenyl group, etc., preferably C2-6 alkenyl group, more preferably C2-4 alkenyl group.
“Alkynyl group” includes C2-10 straight or branched chain alkynyl group, such as ethynyl group, propynyl group, butynyl group, pentynyl group, 3-methylbutynyl group, hexynyl group, 4-methylpentynyl group, 3-methylpentynyl group, 3,3-dimethylbutynyl group, heptynyl group, octynyl group, 3-methylheptynyl group, 3-ethylhexynyl group, nonynyl group, decynyl group, etc., preferably C2-6 alkynyl group, more preferably, C2-4 alkynyl group.
“Cycloalkyl group” includes 3 to 8 membered monocyclic cycloalkyl group, such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, or cyclooctyl group.
“Cycloalkoxy group” includes 3 to 8 membered monocyclic cycloalkoxy group, such as cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group, or cyclooctyloxy group.
“Aryl group” includes 6 to 10 membered aryl group, such as phenyl group, 1-naphthyl group, or 2-naphthyl group.
“Heteroaryl group” includes 5 to 10 membered monocyclic or bicyclic heteroaryl group containing 1 to 4 hetero atoms selected from 0 to 3 nitrogen atoms, 0 to 1 oxygen atom and 0 to 1 sulfur atom, such as furyl group, thienyl group, pyrrolyl group, pyridyl group, indolyl group, isoindolyl group, quinolyl group, isoquinolyl group, pyrazolyl group, imidazolyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, thiazolyl group, oxazolyl group, etc. The binding position is not specifically limited, and it may be on any carbon atom or nitrogen atom, if chemically stable.
“Saturated heterocyclic group” includes 4 to 10 membered mono or bicyclic saturated heterocyclic group containing 1 to 3 hetero atoms selected from 0 to 3 nitrogen atoms, 0 to 1 oxygen atom and 0 to 1 sulfur atom and said sulfur atom may be submitted by one or two oxygen atoms, such as pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, 1-oxothiomorpholinyl group, 1,1-dioxothiomorpholinyl group, tetrahydrofuranyl group, oxazolydinyl group, etc. The binding position on the heterocyclic group is not specifically limited and it may be on any of nitrogen or carbon atoms, if chemically stable. The 4 to 8 membered monocyclic saturated heterocyclic group is preferably illustrated.
“Alkylene” includes straight or branched chain C1-12 alkylene, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, 1-methylmethylene, 1-ethylmethylene, 1-propylethylene, 1-methylethylene, 2-methylethylene, 1-methyltrimethylene, 2 methyltrimethylene, 2-methyltetramethylene, 3-methylpentamethylene, etc., preferably C1-10, more preferably C1-8, further more preferably C1-6 straight or branched chain alkylene.
“Haloalkyl group” includes alkyl group substituted by the same or different and 1 to 5 halogen atoms, such as trifluoromethyl group, 2,2,2-trifluoroethyl group, 2,2-difluoroethyl group, pentafluoroethyl group, etc.
“Alkoxy group” includes C, to straight or branched chain alkoxy group, for example methoxy group, ethoxy group, propoxy group, 1 methylethoxy group, butoxy group, 2-methylpropoxy group, 1-methylpropoxy group, 1,1-dimethylethoxy group, pentoxy group, 3-methylbutoxy group, 2-methylbutoxy group, 2,2-dimethylpropoxy group, 1-ethylpropoxy group, 1,1-dimethylpropoxy group, hexyloxy group, 4-methylpentyloxy group, 3-methylpentyloxy group, 2-methylpentyloxy group, 1-methylpentyloxy group, 3,3-dimethylbutoxy group, 2,2-dimethylbutoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, heptyloxy group, 1-methylhexyloxy group, 1-ethylpentyloxy group, octyloxy group, 1-methylheptyloxy group, 2-ethylhexyloxy group, nonyloxy group, decyloxy group, etc, preferably C1-6 alkoxy group, more preferably C1-4 alkoxy group.
“Haloalkoxy group” includes alkoxy group substituted by the same or different and 1 to 5 halogen atoms, such as trifluoromethoxy group, 2,2,2-trifluoroethoxy group, 2,2-difluoroethoxy group, 2-fluoroethoxy, pentafluoroethoxy group, etc.
“Alkylthio group” includes straight or branched chain C1-10 alkylthio group, such as methylthio group, ethylthio group, propylthio group, 1-methylethylthio group, butylthio group, 2-methylpropylthio group, 1-methylpropylthio group, 1,1-dimethylethylthio group, pentylthio group, 3-methylbutylthio group, 2-methylbutylthio group, 2,2-dimethylpropylthio group, 1-ethylpropylthio group, 1,1-dimethylpropylthio group, hexylthio group, 4-methylpentylthio group, 3-methylpentylthio group, 2-methylpentylthio group, 1-methylpentylthio group, 3,3-dimethylbutylthio group, 2,2-dimethylbutylthio group, 1,1-dimethylbutylthio group, 1,2-dimethylbutylthio group, heptylthio group, 1-methylhexylthio group, 1-ethylpentylthio group, octylthio group, 1-methylheptylthio group, 2-ethylhexylthio group, nonylthio group, decylthio group, etc., preferably C1-6 alkylthio group, more preferably C1-4 alkylthio group.
“Alkyl moiety” in “alkylcarbonyl group”, “alkylcarbonyloxy group”, “alkylsulfonyl group” or “alkylsulfinyl group” includes the same as the alkyl group as mentioned above.
“Alkylcarbonyl group” includes for example, acetyl group, propanoyl group, butanoyl group, 2-methylpropanoyl group, pentanoyl group, 3-methylbutanoyl group, 2-methylbutanoyl group, 2,2-dimethylpropanoyl (pivaloyl) group, hexanoyl group, 4-methylpentanoyl group, 3-methylpentanoyl group, 2-methylpentanoyl group, 3,3-dimethylbutanoyl group, 2,2-dimethylbutanoyl group, heptanoyl group, octanoyl group, 2-ethylhexanoyl group, nonanoyl group, decanoyl group, etc., preferably C2-6 alkylcarbonyl group, more preferably, C2-5 straight or branched chain alkylcarbonyl group.
“Alkylcarbonyloxy group” includes for example, acetoxy group, propanoyloxy group, butanoyloxy group, 2-methylpropanoyloxy group, pentanoyloxy group, 3-methylbutanoyloxy group, 2-methylbutanoyloxy group, 2,2-dimethylpropanoyloxy (pivaloyloxy) group, hexanoyloxy group, 4-methylpentanoyloxy group, 3-methylpentanoyloxy group, 2-methylpentanoyloxy group, 3,3-dimethylbutanoyloxy group, 2,2-dimethylbutanoyloxy group, heptanoyloxy group, octanoyloxy group, 2-ethylhexanoyloxy group, nonanoyloxy group, decanoyloxy group, etc., preferably C2-6 alkylcarbonyloxy group, more preferably C2-5 straight or branched chain alkylcarbonyloxy group.
“Alkylsulfonyl group” includes for example, as methanesulfonyl group, ethanesulfonyl group, propylsulfonyl group, 1-methylethylsulfonyl group, butylsulfonyl group, 2-methylpropylsulfonyl group, 1-methylpropylsulfonyl group, 1,1-dimethylethylsulfonyl group, pentylsulfonyl group, 3-methylbutylsulfonyl group, 2-methylbutylsulfonyl group, 2,2-dimethylpropylsulfonyl group, 1-ethylpropylsulfonyl group, 1,1-dimethylpropylsulfonyl group, hexylsulfonyl group, 4-methylpentylsulfonyl group, 3-methylpentylsulfonyl group, 2-methylpentylsulfonyl group, 1-methylpentylsulfonyl group, 3,3-dimethylbutylsulfonyl group, 2,2-dimethylbutylsulfonyl group, 1,1-dimethylbutylsulfonyl group, 1,2-dimethylbutylsulfonyl group, heptylsulfonyl group, 1-methylhecylsulfonyl group, 1-ethylpentylsulfonyl group, octylsulfonyl group, 1-methylheptylsulfonyl group, 2-ethylhexylsulfonyl group, nonylsulfonyl group, decylsulfonyl group, etc., preferably C1-6 alkylsulfonyl group, more preferably C1-4 straight or branched chain alkylsulfonyl group.
“Alkylsulfinyl group” includes such as methylsulfinyl group, ethylsulfinyl group, propylsulfinyl group, 1-methylethylsulfinyl group, butylsulfinyl group, 2-methylpropylsulfinyl group, 1-methylpropylsulfinyl group, 1,1-dimethylethylsulfinyl group, pentylsulfinyl group, 3-methylbutylsulfinyl group, 2-methylbutylsulfinyl group, 2,2-dimethylpropylsulfinyl group, 1-ethylpropylsulfinyl group, 1,1-dimethylpropylsulfinyl group, hexylsulfinyl group, 4-methylpentylsulfinyl group, 3-methylpentylsulfinyl group, 2-methylpentylsulfinyl group, 1-methylpentylsulfinyl group, 3,3-dimethylbutylsulfinyl group, 2,2-dimethylbutylsulfinyl group, 1,1-dimethylbutylsulfinyl group, 1,2-dimethylbutylsulfinyl group, heptylsulfinyl group, 1-methylhexylsulfinyl group, 1-ethylpentylsulfinyl group, octylsulfinyl group, 1-methylheptylsulfinyl group, 2-ethylhexylsulfinyl group, nonylsulfinyl group, decylsulfinyl group, etc., preferably C1-6 alkylsulfinyl group, more preferably C1-4 straight or branched chain alkylsulfinyl group.
“Alkoxy moiety” in “alkoxycarbonyl group” is the same as the alkoxy group mentioned above. Examples of “alkoxycarbonyl group” are methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, 1-methylethoxycarbonyl group, butoxycarbonyl group, 2-methylpropoxycarbonyl group, 1-methylpropoxycarbonyl group, 1,1-dimethylethoxycarbonyl group, pentoxycarbonyl group, 3-methylbutoxycarbonyl group, 2-methylbutoxycarbonyl group, 2,2-dimethylpropoxycarbonyl group, 1-ethylpropoxycarbonyl group, 1,1-dimethylpropoxycarbonyl group, hexyloxycarbonyl group, 4-methylpentyloxycarbonyl group, 3-methylpentyloxycarbonyl group, 2-methylpentyloxycarbonyl group, 1-methylpentyloxycarbonyl group, 3,3-dimethylbutoxycarbonyl group, 2,2-dimethylbutoxycarbonyl group, 1,1-dimethylbutoxycarbonyl group, 1,2-dimethylbutoxycarbonyl group, heptyloxycarbonyl group, 1-methylhexyloxycarbonyl group, 1-ethylpentyloxycarbonyl group, octyloxycarbonyl group, 1 methylheptyloxycarbonyl group, 2-ethylhexyloxycarbonyl group, nonyloxycarbonyl group, decyloxycarbonyl group, etc., preferably C2-6 alkoxycarbonyl group, more preferably C2-4 straight or branched chain alkoxycarbonyl group.
“Alkenyl moiety” in “alkenyloxy group”, “alkenyloxycarbonyl group”, “alkenylcarbonyl group”, “alkenylcarbonyloxy group”, “alkenylsulfonyl group”, and “alkenylsulfinyl group” is the same as the alkenyl group mentioned above.
“Alkenyloxy group” includes for example, ethenyloxy group, propenyloxy group, 1-methylethenyloxy group, butenyloxy group, 2-methylpropenyloxy group, 1 methylpropenyloxy group, pentenyloxy group, 3-methylbutenyloxy group, 2-methylbutenyloxy group, 1-ethylpropenyloxy group, hexenyloxy group, 4-methylpentenyloxy group, 3-methylpentenyloxy group, 2-methylpentenyloxy group, 1-methylpentenyloxy group, 3,3-dimethylbutenyloxy group, 1,2-dimethylbutenyloxy group, heptenyloxy group, 1-methylhexenyloxy group, 1-ethylpentenyloxy group, octenyloxy group, 1-methylheptenyloxy group, 2-ethylhexenyloxy group, nonenyloxy group, decenyloxy group, etc., preferably C2-6, more preferably C2-5 alkenyloxy group.
“Alkenylcarbonyl group” includes such as, ethenylcarbonyl group, propenylcarbonyl group, 1-methylethenylcarbonyl group, butenylcarbonyl group, 2-methylpropenylcarbonyl group, 1-methylpropenylcarbonyl group, pentenylcarbonyl group, 3-methylbutenylcarbonyl group, 2-methylbutenylcarbonyl group, 1-ethylpropenylcarbonyl group, hexenylcarbonyl group, 4-methylpentenylcarbonyl group, 3-methylpentenylcarbonyl group, 2-methylpentenylcarbonyl group, 1-methylpentenylcarbonyl group, 3,3-dimethylbutenylcarbonyl group, 1,2-dimethylbutenylcarbonyl group, heptenylcarbonyl group, 1-methylhexenylcarbonyl group, 1-ethylpentenylcarbonyl group, octenylcarbonyl group, 1-methylheptenylcarbonyl group, 2-ethylhexenylcarbonyl group, nonenylcarbonyl group, decenylcarbonyl group, etc., preferably C3-6, and more preferably C3-5 alkenylcarbonyl group.
“Alkenylcarbonyloxy group” includes one constituted by binding an oxygen atom to carbonyl moiety of alkenylcarbonyl group, preferably, C3-6, and more preferably C3-5 alkenylcarbonyloxy group.
“Alkenyloxycarbonyl group” includes for example, ethenyloxycarbonyl group, propenyloxycarbonyl group, 1-methylethenyloxycarbonyl group, butenyloxycarbonyl group, 2-methylpropenyloxycarbonyl group, 1-methylpropenyloxycarbonyl group, pentenyloxycarbonyl group, 3-methylbutenyloxycarbonyl group, 2-methylbutenyloxycarbonyl group, 1 ethylpropenyloxycarbonyl group, hexenyloxycarbonyl group, 4-methylpentenyloxycarbonyl group, 3-methylpentenyloxycarbonyl group, 2-methylpentenyloxycarbonyl group, 1-methylpentenyloxycarbonyl group, 3,3-dimethylbutenyloxycarbonyl group, 1,2-dimethylbutenyloxycarbonyl group, heptenyloxycarbonyl group, 1-methylhexenyloxycarbonyl group, 1 ethylpentenyloxycarbonyl group, octenyloxycarbonyl group, 1-methylheptenyloxycarbonyl group, 2-ethylhexenyloxycarbonyl group, nonenyloxycarbonyl group, decenyloxycarbonyl group, etc., preferably C3-6, and more preferably C3-5 alkenyloxycarbonyl group.
“Alkenylsulfonyl group” includes for example, ethenylsulfonyl group, propenylsulfonyl group, 1-methylethenylsulfonyl group, butenylsulfonyl group, 2-methylpropenylsulfonyl group, 1-methylpropenylsulfonyl group, pentenylsulfonyl group, 3-methylbutenylsulfonyl group, 2-methylbutenylsulfonyl group, 1-ethylpropenylsulfonyl group, hexenylsulfonyl group, 4-methylpentenylsulfonyl group, 3-methylpentenylsulfonyl group, 2-methylpentenylsulfonyl group, 1-methylpentenylsulfonyl group, 3,3-dimethylbutenylsulfonyl group, 1,2-dimethylbutenylsulfonyl group, heptenylsulfonyl group, 1 methylhexenylsulfonyl group, 1-ethylpentenylsulfonyl group, octenylsulfonyl group, 1-methylheptenylsulfonyl group, 2-ethylhexenylsulfonyl group, nonenylsulfonyl group, decenylsulfonyl group, etc., more preferably C2-6, more preferably C2-5 alkenylsulfonyl group.
“Alkenylsulfinyl group” includes such as ethenylsulfinyl group, propenylsulfinyl group, 1-methylethenylsulfinyl group, butenylsulfinyl group, 2-methylpropenylsulfinyl group, 1-methylpropenylsulfinyl group, pentenylsulfinyl group, 3-methylbutenylsulfinyl group, 2-methylbutenylsulfinyl group, 1-ethylpropenylsulfinyl group, hexenylsulfinyl group, 4-methylpentenylsulfinyl group, 3-methylpentenylsulfinyl group, 2-methylpentenylsulfinyl group, 1-methylpentenylsulfinyl group, 3,3-dimethylbutenylsulfinyl group, 1,2-dim-methylbutenylsulfinyl group, heptenylsulfinyl group, 1-methylhexenylsulfinyl group, 1-ethylpentenylsulfinyl group, octenylsulfinyl group, 1-methylheptenylsulfinyl group, 2-ethylhexenylsulfinyl group, nonenylsulfinyl group, decenylsulfinyl group, etc., preferably C2-6, more preferably C2-5 alkenylsulfinyl group.
“Alkynyl moiety” in “alkynyloxy group”, “alkynylcarbonyl group”, “alkylcarbonyloxy group”, “alkynylsulfonyl group”, “alkynylsulfinyl group” and “alkynyloxycarbonyl group” is the same as the alkynyl group as mentioned above.
“Alkynyloxy group” includes for example, ethynyloxy group, propynyloxy group, butynyloxy group, pentynyloxy group, 3-methylbutynyloxy group, hexynyloxy group, 4-methylpentynyloxy group, 3-methylpentynyloxy group, 3,3-dimethylbutynyloxy group, heptynyloxy group, octynyloxy group, 3-methylheptynyloxy group, 3-ethylhexynyloxy group, nonynyloxy group, decynyloxy group, etc., preferably C2-6 and more preferably C2-5 alkynyloxy group.
“Alkynylcarbonyl group” includes for example, ethynylcarbonyl group, propynylcarbonyl group, butynylcarbonyl group, pentynylcarbonyl group, 3-methylbutynylcarbonyl group, hexynylcarbonyl group, 4-methylpentynylcarbonyl group, 3-methylpentynylcarbonyl group, 3,3-dimethylbutynylcarbonyl group, heptynylcarbonyl group, octynylcarbonyl group, 3-methylheptynylcarbonyl group, 3-ethylhexynylcarbonyl group, nonynylcarbonyl group, decynylcarbonyl group, etc., preferably C3-6, more preferably C3-5 alkynylcarbonyl group.
“Alkynylcarbonyloxy group” includes for example, one constituted by combining an oxygen atom to carbonyl moiety of the above “alkynylcarbonyl group”. Preferably C3-6, and more preferably C3-5 alkynylcarbonyloxy groups are illustrated.
“Alkynylsulfonyl group”, includes for example, ethynylsulfonyl group, propynylsulfonyl group, butynylsulfonyl group, pentynylsulfonyl group, 3-methylbutynylsulfonyl group, hexynylsulfonyl group, 4-methylpentynylsulfonyl group, 3-methylpentynylsulfonyl group, 3,3-dimethylbutynylsulfonyl group, heptynylsulfonyl group, octynylsulfonyl group, 3-methylheptynylsulfonyl group, 3-ethylhexynylsulfonyl group, nonynylsulfonyl group, or decynylsulfonyl group, preferably C2-6, more preferably C2-5 alkynylsulfonyl group.
“Alkynylsulfinyl group” includes for example, ethynylsulfinyl group, propynylsulfinyl group, butynylsulfinyl group, pentynylsulfinyl group, 3-methylbutynylsulfinyl group, hexynylsulfinyl group, 4-methylpentynylsulfinyl group, 3-methylpentynylsulfinyl group, 3,3-dimethylbutynylsulfinyl group, heptynylsulfinyl group, octynylsulfinyl group, 3-methylheptynylsulfinyl group, 3-ethylhexynylsulfinyl group, nonynylsulfinyl group, or decynylsulfinyl group, preferably C2-6, more preferably C2-5 alkynylsulfinyl group.
“Alkynyloxycarbonyl group” includes for example, ethynyloxycarbonyl group, propynyloxycarbonyl group, butynyloxycarbonyl group, pentynyloxycarbonyl group, 3-methylbutynyloxycarbonyl group, hexynyloxycarbonyl group, 4-methylpentynyloxycarbonyl group, 3 methylpentynyloxycarbonyl group, 3,3-dimethylbutynyloxycarbonyl group, heptynyloxycarbonyl group, octynyloxycarbonyl group, 3-methylheptynyloxycarbonyl group, 3-ethylhexynyloxycarbonyl group, nonynyloxycarbonyl group, or decynyloxycarbonyl group, preferably C3-6, more preferably C3-5 alkynyloxycarbonyl group.
As “cycloalkyl moiety” in “cycloalkylcarbonyl group”, “cycloalkylcarbonyloxy group”, “cycloalkylsulfonyl group” and “cycloalkylsulfinyl group”, the same groups as the above cycloalkyl groups are illustrated.
As “cycloalkylcarbonyl group”, the following groups are illustrated; cyclopropylcarbonyl group, cyclobutylcarbonyl group, cyclopentylcarbonyl group, cyclohexylcarbonyl group, cycloheptylcarbonyl group, or cyclooctylcarbonyl group.
As “cycloalkylcarbonyloxy group”, one constituted by binding an oxygen atom to carbonyl moiety of “cloalkylcarbonyl group” are illustrated. For example, cyclopropylcarbonyloxy group, cyclobutylcarbonyloxy group, cyclopentylcarbonyloxy group, cyclohexylcarbonyloxy group, cycloheptylcarbonyloxy group, and cyclooctylcarbonyloxy group are illustrated.
As “cycloalkylsulfonyl group”, the following groups are illustrated; cyclopropylsulfonyl group, cyclobutylsulfonyl group, cyclopentylsulfonyl group, cyclohexylsulfonyl group, cycloheptylsulfonyl group, and cyclooctylsulfonyl group.
As “cycloalkylsulfinyl group”, the following groups are illustrated; cyclopropylsulfinyl group, cyclobutylsulfinyl group, cyclopentylsulfinyl group, cyclohexylsulfinyl group, cycloheptylsulfinyl group, and cyclooctylsulfinyl group.
As “cycloalkoxy” in “cycloalkoxycarbonyl group”, the same as the above cycloalkoxy group is illustrated. For example, cyclopropyloxycarbonyl group, cyclobutyloxycarbonyl group, cyclopentyloxycarbonyl group, cyclohexyloxycarbonyl group, cycloheptyloxycarbonyl group, or cyclooctyloxycarbonyl group is illustrated.
As aryl in “aryloxy group”, “arylcarbonyl group”, “aryloxycarbonyl group”, “arylcarbonyloxy group”, “arylsulfonyl group” and “arylsulfinyl group”, the same as the above aryl group is illustrated. As “aryloxy group” is illustrated phenoxy group, 1-naphthoxy group or 2-naphthoxy group. As “arylcarbonyl group” is illustrated benzoyl group, 1-naphthaloyl group or 2-naphthaloyl group. As “aryloxycarbonyl group” is illustrated phenoxycarbonyl group, 1-naphthoxycarbonyl group or 2-naphthoxycarbonyl group. As “arylcarbonyloxy group” is illustrated benzoyloxy group, 1-naphthoyloxy group or 2-naphthoyloxy group. As “arylsulfonyl group” is illustrated phenylsulfonyl group, 1-naphthylsulfonyl group, or 2-naphthylsulfonyl group. As “arylsulfinyl group” is illustrated phenylsulfinyl group, 1-naphthylsulfinyl group, or 2-naphthylsulfinyl group.
As heteroaryl group in “heteroaryloxy group”, “heteroarylcarbonyl group”, “heteroaryloxycarbonyl group”, “heteroarylcarbonyloxy group”, “heteroarylsulfonyl group” and “heteroarylsulfinyl group” is illustrated the same as the above heteroaryl groups. As “heteroaryloxy group” is illustrated pyrrolyloxy group, pyridyloxy group, pyrazinyloxy group, pyrimidinyloxy group, pyridazynyloxy group, furyloxy group, or thienyloxy group. As “heteroarylcarbonyl group” is illustrated pyrrolylcarbonyl group, pyridylcarbonyl group, pyrazinylcarbonyl group, pyrimidinylcarbonyl group, pyridazinylcarbonyl group, furylcarbonyl group, thienylcarbonyl group, etc. As “heteroaryloxycarbonyl group” is illustrated pyrrolyloxycarbonyl group, pyridyloxycarbonyl group, pyrazinyloxycarbonyl group, pyrimidinyloxycarbonyl group, pyridazinyloxycarbonyl group, furyloxycarbonyl group, or thienyloxycarbonyl group. As “heteroarylcarbonyloxy group” is illustrated pyrrolylcarbonyloxy group, pyridylcarbonyloxy group, pyrazinylcarbonyloxy group, pyrimidinylcarbonyloxy group, pyridazinylcarbonyloxy group, furylcarbonyloxy group, or thienylcarbonyloxy group. As “heteroarylsulfonyl group” is illustrated pyrrolylsulfonyl group, pyridylsulfonyl group, pyrazinylsulfonyl group, pyrimidinylsulfonyl group, pyridazinylsulfonyl group, furylsulfonyl group, or thienylsulfonyl group. As “heteroarylsulfinyl group” is illustrated pyrrolylsulfinyl group, pyridylsulfinyl group, pyrazinylsulfinyl group, pyrimidinylsulfinyl group, pyridazinylsulfinyl group, furylsulfinyl group, or thienylsulfinyl group.
As “saturated heterocyclic group” in A1 is illustrated saturated 4 to 8 membered heterocyclic ring containing 1 to 2 hetero atoms selected from 1 to 2 nitrogen atoms, 0 to 1 oxygen atom and 0 to 1 sulfur atom (containing at least one nitrogen atom) and the sulfur atom may be substituted by 1 or 2 oxygen atoms, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1-oxide, thiomorpholine-1,1-dioxide, perhydroazepine, 2,6-dimethylpiperidine, 3,5-dimethylpiperidine, 2,6-dimethylpiperazine, 2,6-dimethylmorpholine, 3,5-dimethylmorpholine, 2,6-dimethylthiomorpholine, 3,5-dimethylthiomorpholine, etc.
As “unsaturated heterocyclic group” in A1 is illustrated unsaturated 5 to 7 membered unsaturated heterocyclic ring containing 1 or 2 double bonds therein and containing 1 to 2 hetero atoms selected from 1 to 2 nitrogen atoms, 0 to 1 oxygen atom and 0 to 1 sulfur atom (containing at least one nitrogen atom) and the sulfur atom may be substituted by 1 or 2 oxygen atoms, for example, 5 membered nonaromatic unsaturated heterocyclic ring and containing a double bond therein, or 6 to 7 membered nonaromatic unsaturated heterocyclic ring and containing 1 or 2 double bonds therein
As “saturated or unsaturated heterocyclic ring group” in A1 is illustrated bivalent group of a saturated heterocyclic ring selected from the following formulas (2) to (14):
(wherein R3 and R3′ are independently hydrogen atom or optionally substituted alklyl group, and the substitution-position is not limited, if chemically stable.)
or bivalent group of an unsaturated nonaromatic hetero cyclic, wherein double bond is formed between one or two C—C bonds or C—N bonds in the above ring structure.
A1 is preferably selected from bivalent group of saturated heterocyclic group in the above formulas (2) to (14).
Aromatic carbocyclic group in A2 includes benzene ring and naphthalene ring and its binding position is not limited.
In A2 aromatic heterocyclic group includes 5 to 10 membered monocyclic or bicyclic heteroaromatic ring containing 1 to 4 hetero atoms selected from 0 to 3 nitrogen atoms, 0 to 1 oxygen atom and 0 to 1 sulfur atom, such as furan, thiophene, pyrrole, pyridine, indole, isoindole, quinoline, isoquinoline, pyrazole, imidazole, pyrimidine, pyrazine, pyridazine, thiazole, oxazole, etc. The binding position in the heterocyclic aromatic group is not specifically limited, if chemically stable.
“Substituent” in substituted alkyl group, substituted alkenyl group and substituted alkynyl group is selected from the group consisting of the following groups (a) to (c):
(a) halogen atom, hydroxy group, carboxy group, mercapto group and haloalkoxy group;
(b) alkoxy group, alkylcarbonyl group, alkoxycarbonyl group, alkylsulfonyl group, alkylsulfinyl group, alkylcarbonyloxy group, and alkylthio group (the group of this group may be substituted by halogen atom, hydroxy group, carboxyl group, alkoxy group, alkoxycarbonyl group, amino group optionally substituted by the same or different and one or two alkyl groups, carbamoyl group optionally substituted by the same or different and one or two alkyl groups, sulfamoyl group optionally substituted by the same or different and one or two alkyl groups, or alkylsulfonyl group.);
(c) optionally substituted amino group, optionally substituted carbamoyl group, optionally substituted sulfamoyl group, optionally substituted cycloalkyl group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted saturated heterocyclic group, optionally substituted aryloxy group, and optionally substituted heteroaryloxy group, and said group can be substituted by one or more, and the same or different groups, preferably 1 to 5, more preferably 1 to 3 substituents.
“Substituent” in optionally substituted cycloalkyl group and optionally substituted saturated heterocyclic group is selected from the group consisting of the following groups (d) to (f):
(d) halogen atom, hydroxy group, carboxy group, mercapto group, cyano group, nitro group, haloalkyl group, and haloalkoxy group;
(e) alkyl group, alkoxy group, alkenyl group, alkynyl group, alkoxycarbonyl group, and alkylthio group (the group of this group may be substituted by halogen atom, hydroxy group, carboxyl group, alkoxy group, alkoxycarbonyl group, amino group optionally substituted by the same or different and one or two alkyl groups, carbamoyl group optionally substituted by the same or different and one or two alkyl groups, sulfamoyl group optionally substituted by the same or different and one or two alkyl groups, or alkylsulfonyl group.);
(f) optionally substituted amino group, optionally substituted carbamoyl group or optionally substituted sulfamoyl group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aryloxy group, and optionally substituted heteroaryloxy group,
and this group can be substituted by one or more, and the same or different groups, preferably 1 to 5, more preferably 1 to 3 substituents.
“Substituent” in substituted aryl group, substituted heteroaryl group, substituted aryloxy group and substituted heteroaryloxy group is selected from the group consisting of the following groups (g) to (j);
(g) halogen atom, hydroxy group, carboxy group, mercapto group, cyano group, nitro group, haloalkyl group, and haloalkoxy group;
(h) alkyl group, alkoxy group, alkenyl group, alkynyl group, alkoxycarbonyl group, and alkylthio group (the group of this group may be substituted by halogen atom, hydroxy group, carboxyl group, alkoxy group, alkoxycarbonyl group, amino group optionally substituted by the same or different and one or two alkyl groups, carbamoyl group optionally substituted by the same or different and one or two alkyl groups, sulfamoyl group optionally substituted by the same or different and one or two alkyl groups, or alkylsulfonyl group.);
(i) cycloalkyl group and saturated heterocyclic group (wherein the group of this group may be substituted by halogen atom, hydroxy group, carboxy group, alkyl group or alkoxy group.);
(j) optionally substituted amino group, optionally substituted carbamoyl group and optionally substituted sulfamoyl group; And this group can be substituted by one or more, and the same or different groups, preferably 1 to 5, more preferably 1 to 3 substituents.
“Substituent” in substituted amino group, substituted carbamoyl group and substituted sulfamoyl group is selected from the group consisting of the following groups (k) to (m);
(k) alkyl group, alkenyl group, alkynyl group, alkylcarbonyl group, alkoxycarbonyl group, alkylsulfonyl group, alkylsulfinyl group, cycloalkyl group, cycloalkylcarbonyl group, cycloalkyloxycarbonyl group, cycloalkylsulfonyl group, and cycloalkylsulfinyl group (the group of this group may be substituted by halogen atom, hydroxy group, carboxyl group, alkoxy group or alkoxycarbonyl group.);
(l) aryl group, arylcarbonyl group, aryloxycarbonyl group, arylsulfonyl group, arylsulfinyl group, heteroaryl group, heteroarylcarbonyl group, heteroaryloxycarbonyl group, heteroarylsulfonyl group, and heteroarylsulfinyl group (the group of this group may be substituted halogen atom, hydroxy group, carboxy group, mercapto group, cyano group, nitro group, alkyl group, alkoxy group, alkoxycarbonyl group or alkylthio group.);
(m) 4 to 7 membered saturated heterocyclic group containing 1 to 4 hetero atoms selected from 1 to 2 nitrogen atoms, 0 to 1 oxygen atom and 0 to 1 sulfur atom which is formed by combining two substituents (this saturated heterocyclic group containing nitrogen atom may be substituted, if chemically stable, on any carbon atom or nitrogen atom, by halogen atom, hydroxy group, carboxyl group, alkyl group, alkoxy group, alkoxycarbonyl group or alkylcarbonyl group); And said group may be substituted by one or two substituents, if chemically stable.
“Saturated heterocyclic ring” mentioned above includes azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine 1 oxide, thiomorpholine-1,1-dioxide, perhydroazepine, etc.
In the present specification, “substituent” when alkylene is substituted includes halogen atom, hydroxy group, alkoxy group, etc., and said group may be substituted by the same or different and one or more substituents, preferably 1 to 5, more preferably 1 to 3 substituents.
A2 of the formula (1) is preferably benzene ring or 5 to 6 membered heteroaromatic ring containing at least one hetero atom selected from 0 to 2 nitrogen atoms, 0 to 1 oxygen atom and 0 to 1 sulfur atom, more preferably benzene, pyridine and furan, and its binding sites are not limited, if chemically stable.
L3 of the formula (1) is preferably a single bond or C1-4, preferably C1-3 straight or branched alkylene, more preferably a single bond, methylene, ethylene, 1-methylmethylene, or 1,1-dimethylmethylene.
Preferable mode of “-A2-L3-CO2R2” of the formula (1) is selected from following formulas (15) to (26):
(wherein R2 is the same as defined above, R7 and R8 are independently, hydrogen atom, or C1-3 alkyl group, R is hydrogen atom, halogen atom, haloalkyl group, C1-6 alkyl group, C1-6 alkoxy group, C1-6 haloalkyl group, C1-6 haloalkoxy group, amino group optionally substituted by the same or different and 1 or 2 C1-6 alkyl groups, or 4 to 8 membered saturated heterocyclic group containing 1 to 2 hetero atoms selected from 1 to 2 nitrogen atoms, 0 to 1 oxygen atom and 0 to 1 sulfur atom (this saturated heterocyclic group may be substituted by one or more substituents selected from halogen atom, hydroxy group, oxo group, C1-6 alkyl group, C1-6 alkoxy group, C2-6 alkylcarbonyl group and C2-6 alkoxycarbonyl group), n is an integer 0˜2 and when n is 2, R may be the same or different. The binding position thereof is not limited, if chemically stable.)
More preferable ones are the formulas (15) to (20) wherein R7 and R8 are hydrogen atom.
Preferable examples on “-L1-A1-L2” in the formula (1) are illustrated below.
When nitrogen atom in the ring in A1 is bound to L1, preferable L1 includes the group represented by the following formula (I) (wherein L1 is bound at its left side with the adenine structure.):
—(CH2)2-8—. (I)
When carbon atom in the ring in A1 is bound to L1, preferable L1 includes the group represented by the following formulas (II) or (III)(wherein L1 is bound in its left side to the adenine structure.),
—(CH2)0-8—, (II)
—(CH2)0-8—NR5— (III)
(wherein R5 is the same as defined above.).
When nitrogen atom in the ring in A1 is bound to L2, preferable L2 includes the group represented by the following formulas (IV) to (IX) (wherein L2 is bound at its left side with the adenine structure.),
—(CH2)0-5—, (IV)
—(CH2)2-5—O—, (V)
—(CH2)2-5—NR5′—(CH2)0-3—, (VI)
—(CH2)2-5—NR5′—(CH2)2-3—O—, (VII)
—(CH2)0-5—CO—(CH2)0-2—NR5′—(CH2)0-3—, (VIII)
—(CH2)0-5—CO—(CH2)0-2—NR5′—(CH2)2-3—O—. (IX)
When carbon atom in the ring in A1 is bound to L2, preferable L2 includes the group represented by the following formulas (X) to (XII) (wherein L2 is bound at its left side with the adenine structure.):
—(CH2)0-5—NR5′—(CH2)0-3—, (X)
(CH2)0-5—NR5′—(CH2)0-3—O—, (XI)
—(CH2)0-5, (XII)
—(CH2)0-5—O—. (XIII)
(wherein R5′ in the above (IV) to (XIII) is hydrogen atom or C1-3 alkyl group.)
R2 of the formula (1) is preferably C1-4 alkyl group, C3-8 alkylcarbonyloxyalkyl group, 6 to 10 membered arylcarbonyloxyalkyl group, 5 to 10 membered heteroarylcarbonyloxyalkyl group or alkyl group substituted by optionally substituted amino group. The alkyl group substituted by optionally substituted amino group preferably includes dialkylaminoaminoalkyl group, or alkyl group substituted by morpholino group, 1-piperidinyl group, piperazino group or 1-pyrrolidinyl, for example 4-dimethylaminobutyl group, 4-morpholinobutyl group, etc. As the above alkylcarbonyloxyalkyl group are illustrated acetoxymethyl group, 1-acetoxyethyl group, etc. As the above arylcarbonyloxyalkyl group is illustrated benzoyloxymethyl group. R2 is further preferably methyl group.
In the formula (1), X is preferably oxygen atom, or a single bond. When X is NR4, R4 is preferably hydrogen atom, or C1-3 alkyl group, preferably hydrogen atom or methyl group.
In the formula (1), R1 is preferably, optionally substituted C1-6 straight or branched alkyl group such as methyl group, ethyl group, propyl group, butyl group, pentyl group, 1-methylethyl group, 1 methylpropyl group, 2-methylbutyl group respectively optionally substituted, more preferably straight chained C1-4 alkyl group.
The substituent wherein R1 is substituted alkyl group includes the above substituent of alkyl group, preferably fluorine atom, hydroxy group, C1-4 straight or branched alkoxy group, or C1-4 straight or branched alkylthio group, more preferably hydroxy group, or C1-3 straight or branched alkoxy group, which may be substituted by one to three substituents.
The adenine compound of the present invention includes all tautomers, geometrical isomers and stereoisomers which are formed in accordance with the kind of the substituent, and a mixture thereof.
Namely, in a case where there are one or more asymmetrical carbon atoms in the compound of the formula (1), there exist diastereomers and optical isomers, and mixtures of those diastereomers and optical isomers and separated ones are also included in the present invention.
Additionally, the adenine compound shown by the formula (1) and its tautomer is chemically equivalent, and the adenine compound of the h present invention includes such a tautomer. The tautomer is specifically a hydroxy compound shown by the formula (1′):
(wherein R1, R2, R3, A1, A2, X, L1, L2 and L3 are the same as defined above.)
The pharmaceutically acceptable salt is exemplified by an acid salt and a base addition salt. The acid salt is, for example, an inorganic acid salt such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate and phosphate, and an organic acid salt such as citrate, oxalate, acetate, formate, propionate, benzoate, trifluoroacetate, fumarate, maleate, succinate, tartrate, lactate, pyruvate, methanesulfonate, benzenesulfonate and p-toluenesulfonate, and the base salt is exemplified by an inorganic base salt such as sodium salt, potassium salt, calcium salt, magnesium salt and ammonium salt, and an organic base salt such as triethylammonium salt, triethanolammonium salt, pyridinium salt and diisopropylammonium salt, and further a basic or acidic amino acid salt such as arginine salt, aspartic acid salt and glutamic acid salt. The compound shown by the formula (1) may be hydrate and a solvate such as ethanolate.
The compound of the generic formula (1) can be prepared by the following method. The starting materials which are not described can be prepared in accordance with the following method or by known methods or in accordance with the known methods.
(wherein L and L′ are the same or different and a leaving group, A1, A2, R1, R2, X, L1, L2 and L3 are the same as defined above.)
The leaving group included halogen atom in alkylation or acylation, hydroxy group in dehydrative condensation, oxo group in reductive alkylation of amine, etc.
Compound (I-II) can be prepared by reacting compound (I-I) and compound (I-VII) in the presence of base. The base includes, for example alkali metal carbonate such as sodium carbonate, potassium carbonate, etc., alkaline earth metal carbonate such as calcium carbonate, etc., metal hydroxide such as sodium hydroxide, potassium hydroxide, etc., metal hydride such as sodium hydride, etc, or metal alkoxide such as t-butoxy potassium, etc.
The solvent includes an aprotic solvent such as dimethylformamide, dimethyl sulfoxide, acetonitrile, etc., a halogenated hydrocarbon such as carbon tetrachloride, chloroform, methylene chloride, etc., an ether such as diethyl ether, tetrahydrofuran, 1,4-dioxne, etc. The reaction temperature is selected from the range of about 0° C. to around boiling point of the solvent.
Compound (I-III) can be prepared by treating compound (I-II) under acidic condition.
The acid includes an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc., or an organic acid such as trifluoroacetic acid, etc. The solvent includes water or a mixture of water and an organic solvent. The above organic solvent includes an ether such as diethyl ether, tetrahydrofuran etc., an aprotic solvent such as dimethylformamide, acetonitrile, etc., and an alcohol such as methanol, ethanol, etc. The reaction temperature is selected from the range of room temperature to around boiling point of the solvent.
In the step for preparing compound (I-II) from compound (I-I), the compound (I-II) can be prepared by reacting compound (I-I) and compound (I-VIII) in the same manner as the above step 1 to give compound (I-IV) and then reacting the product and compound (I-IX) by the well known method in the art as dehydrative condensation or reductive alkylation in the same manner as the above step 1.
In the step to compound (I-II) from compound (I-IV), compound (I-II) can be also prepared by reacting compound (I-IV) and compound (I-X) by a well known method in the art such as dehydrative condensation or reductive alkylation in the same manner as step 1 to obtain compound (I-V) and then reacting the compound (I-V) and compound (I-XI) in the same manner as the above step 1.
In the step to compound (I-V) from compound (I-I), compound (I-V) can be also prepared by reacting compound (I-I) and compound (I-XII) in the same manner as step 1 to obtain compound (I-VI) and then reacting the compound (I-VI) and compound (I-XIII) by the well known method in the art such as dehydrative condensation or reductive alkylation.
Compound (I-VII) and compound (I-IX) can be also prepared by the following methods.
(wherein L and L′ are the same or different and a leaving group, A1, A2, R2, L1, L2 and L3 are the same as defined above.)
Compound (I-XIV) can be prepared by reacting compound (I-X) and compound (I-IV) in the presence of a base. Then, compound (I-VII) can be prepared by reacting compound (I-IV) and compound (I-XI) in the presence of a base.
Compound (I-IX) can be prepared by reacting compound (I-X) and compound (I-XI) in the presence of a base.
The base includes, for example alkali metal carbonate such as sodium carbonate, potassium carbonate, etc., alkaline earth metal carbonate such as calcium carbonate, etc., metal hydroxide such as sodium hydroxide, potassium hydroxide, etc., an organic base such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, etc., or metal alkoxide such as sodium methoxide, etc.
The solvent includes a halogenated hydrocarbon such as carbon tetrachloride, chloroform, methylene chloride, etc., an ether such as diethyl ether, tetrahydrofuran, 1,4-dioxane, etc., an alcohol such as methanol, ethanol etc., an aprotic solvent such as dimethylformamide, dimethyl sulfoxide, acetonitrile, etc. The reaction temperature is selected from the range of about 0° C. to around boiling point of the solvent.
When the compound of the present invention or its intermediate has a functional group such as amino group, carboxy group, hydroxy group, or oxo group etc., the compound can be protected or deprotected, if necessary. The preferable protecting group, the protecting method and deprotecting method are described in detail in “Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.; 1990)” and so on.
Compound (I-I) can be also prepared by the following methods.
(wherein R1 and X are the same as defined above.)
Compound (I-XVI) can be prepared by reacting compound (I-XV) and ammonia in an aqueous solution, an organic solvent or a mixture thereof.
The solvent includes an alcohol such methanol, ethanol, propanol, butanol, etc., an ether such as tetrahydrofuran, 1,4-dioxane, diglyme, etc., an aprotic solvent such as acetonitrile, etc. The reaction temperature is selected from the range of about room temperature to 200° C. The reaction may be carried out in an autoclave, if necessary.
Compound (I-XVII) can be prepared by brominating compound (I-XVI). The brominating agent includes for example, bromine, hydrobromic acid perbromide, N-bromosuccinimide, etc. In this reaction, a reaction additive such as sodium acetate, etc., may be added. The solvent includes a halogenated hydrocarbon such as carbon tetrachloride, methylene chloride, dichloroethane, etc., an ether such as diethyl ether, etc., acetic acid, and carbon disulfide. The reaction temperature is selected from the range of about 0° C. to around boiling point of the solvent.
Compound (I-XVIII) can be prepared by reacting compound (I-XVII) and sodium methoxide.
The organic solvent used in the reaction includes an ether such as diethyl ether, tetrahydrofuran, 1,4-dioxane, etc., an aprotic solvent such as dimethylformamide, etc., an alcohol such as methanol, etc. The reaction temperature is selected from room temperature to around boiling point of the solvent.
Compound (I-XVIII) can be prepared by treating compound (I-XVII) in an aqueous alkaline solution containing methanol.
The aqueous alkaline solution is an aqueous solution containing alkali metal hydroxide such as sodium hydroxide or potassium hydroxide. The reaction temperature was selected from the range of room temperature to boiling point of the solvent.
Compound (I-XIX) can be prepared by reacting compound (I-XVIII) and compound (I-XXII).
The compound wherein X is NR4 (R4 is the same as defined above) can be reacted in the presence or absence of a base.
The base includes, for example alkali metal carbonate such as sodium carbonate, potassium carbonate, etc., alkaline earth metal carbonate such as calcium carbonate, etc., metal hydroxide such as sodium hydroxide, potassium hydroxide, etc., an organic base such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, etc.
The solvent includes an ether such as tetrahydrofuran, 1,4-dioxane, diglyme, etc., an alcohol such as propanol, butanol, etc., an aprotic solvent such as dimethylformamide, etc. The reaction may be carried out without a solvent. The reaction temperature is selected from the range of about 50° C. to 200° C.
The compound wherein X is oxygen atom or sulfur atom is reacted in the presence of a base. The base includes, for example alkali metal such as metallic sodium, metallic potassium, etc., or an alkali metal hydride such as sodium hydride, etc. The solvent includes an ether such as tetrahydrofuran, 1,4-dioxane, diglyme, etc., an aprotic solvent such as dimethylformamide, dimethyl sulfoxide, etc. The reaction may be carried out without a solvent. The reaction temperature is selected from the range of about 50° C. to 200° C.
The compound wherein X is SO2, can be prepared by oxidizing the intermediate wherein X is sulfur atom with Oxone® or m-chloroperbenzoic acid (mCPBA).
In the step to compound (I-XIX) from compound (I-XVI), the compound (I-XIX) can be also prepared by preparing compound (I-XX) in the same manner as above method and then after converting the compound into compound (I-XXI) to prepare compound (I-XIX).
Compound (I-I) can be prepared by treating compound (I-XIX) with trifluoroacetic acid in an organic solvent such as methanol solvent.
The acid includes an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc., or an organic acid such as trifluoroacetic acid, etc.
The solvent includes water or a mixture of water and an organic solvent. The above organic solvent includes an ether such as diethyl ether, tetrahydrofuran etc., an aprotic solvent such as dimethylformamide, acetonitrile, etc., and an alcohol such as methanol, ethanol, etc. The reaction temperature is selected from the range of room temperature to around boiling point of the solvent.
When L2 is a group represented by the following formula:
(wherein Z1 and Z2 are alkylene, and R5 is the same as defined.) the compound can be prepared by the following methods.
(wherein L, L1, A1, A2, R1, R2, R5, X, Z1, Z2 and L3 are the same as defined above, Z3 is alkylene which corresponds to the alkylene prepared by deleting the terminal alkylene from Z2.)
Namely compound (II-II) can be prepared by reacting compound (II-I) with aldehyde compound of compound (II-VII) in the presence of a reductive agent such as sodium borohydride (NaBH4) in a solvent such as methanol, etc.
Compound (II-II) can be also prepared by reacting compound (II-V) with compound (II-IX) in the presence or absence of a base. The base includes, for example alkali metal carbonate such as sodium carbonate, potassium carbonate, etc., alkaline earth metal carbonate such as calcium carbonate, etc., metal hydroxide such as sodium hydroxide, potassium hydroxide, etc., an organic base such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, etc.
The solvent includes an ether such as tetrahydrofuran, 1,4-dioxane, diglyme, etc., an alcohol such as propanol, butanol, etc., an aprotic solvent such as dimethylformamide, dimethyl sulfoxide, acetonitrile, etc. The reaction may be carried out without a solvent. The reaction temperature is selected from the range of room temperature to boiling point of the solvent.
In case of compound wherein R5 is other group except hydrogen atom, compound (II-III) can be prepared by reacting compound (II-II) and a alkyl halide reagent represented by compound (II-X) in the presence of a base such as potassium carbonate, etc., in a solvent such as acetonitrile, dimethylformamide, etc.
Compound (II-III) can be prepared by converting compound (II-I) into compound (II-VI) in the sane manner as the process of compound (II-III) from compound (II-II) in the preparation method 2, and then applying the same method as the process for preparing compound (II-II).
Compound (II-IV) being the same as compound (I-III) can be prepared in the same manner as the process of compound (I-III) from compound (I-II) in the preparation method 1.
(wherein L is a leaving group, A1, R1, R2, X, L1 and L2 are the same as defined above.)
Compound (III-II) can be prepared by reacting compound (III-I) and compound (I-IV) in the presence of a base.
The base includes, for example alkali metal carbonate such as sodium carbonate, potassium carbonate, etc., alkaline earth metal carbonate such as calcium carbonate, etc., metal hydroxide such as sodium hydroxide, potassium hydroxide, etc., metal hydride such as sodium hydride, etc, or metal alkoxide such as potassium t-butoxide, etc. The solvent includes a halogenated hydrocarbon such as carbon tetrachloride, chloroform, methylene chloride, etc., an ether such as diethyl ether, tetrahydrofuran, 1,4-dioxane, etc., an aprotic solvent such as dimethylformamide, dimethyl sulfoxide, acetonitrile, etc. The reaction temperature is selected from the range of about 0° C. to around boiling point of the solvent.
Compound (III-III) can be prepared by brominating compound (III-II). The brominating agent includes for example, bromine, hydrobromic acid perbromide, N-bromosuccinimide, etc. In this reaction, a reaction auxiliary such as sodium acetate, etc., may be added. The solvent includes a halogenated hydrocarbon such as carbon tetrachloride, methylene chloride, dichloroethane, etc., an ether such as diethyl ether, etc., acetic acid, or carbon disulfide. The reaction temperature is selected from the range of about 0° C. to around boiling point of the solvent.
Compound (III-IV) can be prepared by reacting compound (III-III) an metal alkoxide such as sodium methoxide and treating them in an acidic condition.
In case reacting the metal alkoxide, there can be used the solvent such as an ether such as diethyl ether, tetrahydrofuran, 1,4-dioxne, etc., an aprotic solvent such as dimethyfoemamide, etc. or an alcohol corresponding to the metal alkoxide such as methanol, etc. The reaction temperature is selected from the range of, for example, room temperature to boiling point of the solvent.
The acid includes an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc., or an organic acid such as trifluoroacetic acid, etc.
The solvent includes water or a mixture of water and an organic solvent. The above organic solvent includes an ether such as diethyl ether, tetrahydrofuran etc., an aprotic solvent such as dimethylformamide, acetonitrile, etc., and an alcohol such as methanol, ethanol, etc. The reaction temperature is selected from the range of room temperature to around boiling point of the solvent.
Compound (I-III) can be prepared by reacting compound (III-IV) and compound (III-VIII).
The compound wherein X is NR4 (R4 is the same as defined above) is reacted in the presence or absence of a base. The base includes, for example alkali metal carbonate such as sodium carbonate, potassium carbonate, etc., alkaline earth metal carbonate such as calcium carbonate, etc., metal hydroxide such as sodium hydroxide, potassium hydroxide, etc., an organic base such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, etc.
The solvent includes an ether such as tetrahydrofuran, 1,4-dioxane, diglyme, etc., an alcohol such as propanol, butanol, etc., an aprotic solvent such as dimethylformamide, etc. The reaction may be carried out without a solvent. The reaction temperature is selected from the range of about 50° C. to 200° C.
The compound wherein X is oxygen atom or sulfur atom is reacted in the presence of a base. The base includes, for example alkali metal such as metallic sodium, metallic potassium, etc., or an alkali metal hydride such as sodium hydride, etc. The solvent includes an ether such as tetrahydrofuran, 1,4-dioxane, diglyme, etc., an aprotic solvent such as dimethylformamide, dimethyl sulfoxide, etc. The reaction may be carried out without a solvent. The reaction temperature is selected from the range of about 50° C. to 200° C.
The compound wherein X is SO2 can be prepared by oxidizing the intermediate wherein X is sulfur atom with Oxone®W or m-chloroperbenzoic acid (mCPBA).
In the step to compound (I-III) from compound (III-I), compound (I-III) is prepared by preparing compound (III-VI) from compound (III-II) in the same manner as the above method or by preparing compound (III-VI) via compound (III-V) from compound (III-I), and then converting compound (III-VI) to compound (I-III) via compound (III-VII).
In case of reaction with benzoyl isocyanate, the base includes, for example alkali metal carbonate such as sodium carbonate, potassium carbonate, etc., alkaline earth metal carbonate such as calcium carbonate, etc., an organic base such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, etc.
The solvent includes a halogenated hydrocarbon such as methylene chloride, an ether such as tetrahydrofuran, 1,4-dioxane, etc., an aprotic solvent such as dimethylformamide, dimethyl sulfoxide, etc. The reaction temperature is selected from the range of about 0° C. to around boiling point of the solvent.
As the base used in the cyclization reaction, can be illustrated the base such as an alkali metal hydroxide, like sodium hydroxide or potassium hydroxide, or metal alkoxide, like sodium methoxide or potassium t-butoxide. Can be used the solvent such as an ether, like tetrahydrofuran, an alcohol, like ethanol or 2-propanol or an aprotic solvent, like dimethylformamide or dimethyl sulfoxide. The reaction temperature is selected from a range of around room temperature to around the boiling point of the solvent.
In a case where the compound of the present invention or its intermediate or the starting compound has a functional group, a reaction for increasing a carbon atom, a reaction for introducing a substituent or a reaction for conversion of the functional group can be conducted optionally according to a manner conventional to the skilled artisan in an appropriate step, namely in an intermittent step in each of the preparation methods described in the preparation method 1 or 2. For this purpose, the methods described in “JIKKEN KAGAKU-KOZA (edited by NIHON KAGAKU-KAI, MARUZEN)”, or “Comprehensive Organic Transformation, R. C. Lalock (VCH Publishers, Inc. 1989)” can be used. The reaction for increasing a carbon atom includes a method comprising converting an ester group to hydroxymethyl group using a reducing agent such as aluminum lithium hydride, introducing a leaving group and then introducing a cyano group. The reacting for conversion of a functional group includes a reaction for conducting acylation or sulfonylation using an acid halide, a sulfonyl halide, etc., a reaction for reacting an alkylation agent such as an alkyl halide, a hydrolysis reaction, a reaction for C—C bond formation such as Friedel-Crafts reaction and Wittig reaction, and oxidizing or reducing reaction, etc.
In a case where the compound of the present invention or its intermediate contains a functional group such as amino group, carboxy group, hydroxy group and oxo group, a technology of protection and de-protection can optionally be used. A preferable protective group, a protection method and a deprotection method are described in details in “Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.; 1990)”, etc.
The compound of the formula (1) of the present invention and the intermediate compound for production thereof can be purified by a method known to the skilled artisan. For instance, purification can be conducted by column chromatography (e.g. silica gel column chromatography or ion exchange chromatography) or recrystallization. As a recrystallization solvent, for instance, can be used an alcohol such as methanol, ethanol and 2-propanol, an ether such as diethyl ether, an ester such as ethyl acetate, an aromatic hydrocarbon such as benzene and toluene, a ketone such as acetone, a hydrocarbon such as hexane, an aprotic solvent such as dimethylformamide and acetonitrile, water and a mixture of two or more thereof. As other purification method, can be used those described in “JIKKEN KAGAKU-KOZA (edited by NIHON KAGAKU-KAI, MARUZEN) Vol. 1”, etc.
In a case where the compound of the formula (1) of the present invention contains one or more asymmetric carbon, its production can be conducted by using the starting material containing those asymmetric carbons or by the asymmetric induction during the production steps. For instance, in a case of an optical isomer, the object can be obtained by using an optically active starting material or by conducting an optical resolution at a suitable stage of the production steps. The optical resolution method can be conducted by a diastereomer method comprising allowing the compound of the formula (1) or its intermediate to form a salt with an optically active acid (e.g. a monocarboxylic acid such as mandelic acid, N-benzyloxyalanine and lactic acid, a dicarboxylic acid such as tartaric acid, o-diisopropylidene tartrate and malic acid, a sulfonic acid such as camphor sulfonic acid and bromocamphor sulfonic acid) in an inert solvent (e.g. an alcohol such as methanol, ethanol, and 2-propanol, an ether such as diethyl ether, an ester such as ethyl acetate, a hydrocarbon such as toluene, an aprotic solvent such as acetonitrile and a mixture thereof.
In a case where the compound of the formula (1) or its intermediate contains an acidic functional group such as carboxylic group, the object can be attained also by forming a salt with an optically active amine (e.g. an organic amine such as α-phenethylamine, quinine, quinidine, cinchonidine, cinchonine and strychnine).
The temperature for salt formation is selected from room temperature to the boiling point of the solvent. In order to increase optical purity, the temperature is preferably once increased up to the boiling point of the solvent. Upon recovering the salt formed by filtration, the yield can be increased optionally by cooling. An amount of the optical active acid or amine is about 0.5 to about 2.0 equivalent, preferably around 1 equivalent, relative to the substrate. An optically active salt with highly optical purity can be obtained optionally by recrystallization from an inert solvent (e.g. an alcohol such as methanol, ethanol and 2-propanol, an ether such as diethyl ether, an ester such as ethyl acetate, a hydrocarbon such as toluene, an aprotic solvent such as acetonitrile and a mixture thereof. If necessary, the optically resoluted salt can be converted into a free form by treating with an acid or a base by the conventional method.
The adenine compound or its pharmaceutically acceptable salt of the present invention activates Toll-like receptor (TLR), concretely TLR7 and is useful as an immuno-modulator and thus useful as a therapeutic and prophylactic agent for diseases associated with an abnormal immune response (e.g. autoimmune diseases and allergic diseases) and various infectious diseases and cancers which are required for activation of an immune response. For instance, the adenine compound or its pharmaceutically acceptable salt of the present invention is useful as a therapeutic and prophylactic agent for the diseases mentioned in the following (1)-(8).
(1) (Respiratory diseases): asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including NSAID such as aspirin and indomethacin) and dust-induced asthma both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicarnentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus;
(2) (Skin) psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrheic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus, lichen sclerosus et atrophicus, pyoderma gangrenosum, skin sarcoidosis, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis; cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions;
(3) (Eyes) blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune, degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral, fungal, and bacterial;
(4) (Genitourinary) nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvo-vaginitis; Peyronie's disease; erectile dysfunction (both male and female);
(5) (Allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;
(6) (Auto-immune diseases) other auto-immune and allergic disorders including rheumatoid arthritis, irritable bowel syndrome, systemic lupus erythematosus, multiple sclerosis, Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome;
(7) (Oncology) treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, liver bowel and colon, stomach, skin and brain tumors and malignant bone marrow neoplasm (including the leukaemias) and lymphoproliferative systems neoplasm, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastasis and tumor recurrences, and paraneoplastic syndromes; and
(8) (Infectious diseases) viral diseases such as genital warts, common warts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus, molluscum contagiosum, variola, acquired immunodeficiency syndrome (HIV), or infectious diseases due to human papilloma virus (HPV), cytomegalo virus (CMV), varicella zoster virus (VZV), rhinovirus, adenovirus, coronavirus, influenza, or para-influenza; bacterial diseases such as tuberculosis, mycobacterium avium, or leprosy; other infectious diseases, such as fungal diseases, candida, chlamydia, or aspergillus, cryptococcal meningitis, pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection, or leishmaniasis.
The adenine compounds or pharmaceutically acceptable salt thereof can also be used as vaccine adjuvant.
The adenine compound of the present invention, or its pharmaceutically acceptable salt has an activating effect of TLR, concretely TLR7. The adenine compound of the present invention, or its pharmaceutically acceptable salt shows an interferon-α or interferon-γ inducing activity and a suppressing activity of the production of IL-4 or IL-5, and thus shows an effect as a medicament having an immunomodulating activity specific against type 1 helper T-cell (Th1 cell)/type 2 helper T-cell (Th2 cell), namely, preferably useful as a prophylactic or therapeutic agent for allergic diseases such as asthma, COPD, allergic rhinitis, allergic conjunctivitis and atopic dermatosis due to the cell selective immuno-suppressive action. On the other hand, due to its immune activating effect, it is useful as a prophylactic or therapeutic agent for cancer, hepatitis 1, hepatitis C, acquired immunodeficiency syndrome (HIV) and viral disease caused by infection with human papilloma virus (HPV), a bacterial infectious disease and dermatosis such psoriasis.
The adenine compound of the present invention, or its pharmaceutically acceptable salt is useful as a prophylactic or therapeutic agent for airway obstruction such as asthma or COPD, or for reduction of the risk thereof.
The adenine compound of the present invention or its pharmaceutically acceptable salt has no limitation as to its administration formulation and is administered orally or parenterally. The preparation for oral administration can be exemplified by capsules, powders, tablets, granules, fine-grain, syrups, solutions, suspensions, etc., and the preparation for parenteral administration can be exemplified by injections, drips, eye-drops, intrarectal preparations, inhalations, sprays (e.g. liquids/suspensions for sprays, aerosols, or cartridge spray for inhalators or insulators), lotions, gels, ointments, creams, transdermal preparations, transmucosa preparations, nasal drops, ear drops, tapes, transdermal patches, cataplasms, powders for external application, and the like. Those preparations can be prepared by known manners, and acceptable conventional carriers, fillers, binders, lubricants, stabilizers, disintegrants, buffering agents, solubilizing agents, isotonic agents, surfactants, antiseptics, perfumes, and so on can be used. Two or more pharmaceutical carriers can be appropriately used.
The compound of the present invention, or its pharmaceutically acceptable salt is admixed with a pharmaceutically acceptable carrier by the conventional method for the person in the art to prepare the pharmaceutical composition suitable for administration. For example, the pharmaceutical composition containing the compound of the present invention or its pharmaceutically acceptable salt 0.05-99 weight %, preferably 0.05-80 weight %, more preferably 0.1-70 weight %, and further more preferably 0.1-50 weight % as an active ingredient can be prepared.
The liquid preparation such as emulsions and syrups, among the preparations for oral administration, can be prepared by using additives for a pharmaceutical preparation including water; a sugar such as sucrose, sorbitol and fructose; ethanol; a glycol such as polyethylene glycol and propylene glycol; an oil such as sesame oil, olive oil and soybean oil; an preservative such as p-hydroxybenzoate; a sweetening such as saccharin, a thickening agent such as carboxymethyl cellulose, a flavor such as strawberry flavor and peppermint flavor, a coloring agent and so on.
The solid preparation such as capsules, tablets, powders and granules can be prepared by appropriately using following fillers: a carrier such as lactose, glucose, sucrose sorbitol, mannitol, mannite and a cellulose derivative; a disintegrant such as starch (potato starch, corn starch, amylopectin, etc.) and sodium alginate; a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin and talc; a binder such as polyvinyl alcohol, polyvinyl pyrrolidone, hydroxypropyl cellulose and gelatin; a surfactant such as a fatty acid ester; or a plasticizer such as glycerin.
In case of preparation of sugar coated tablets, a condensed sugar solution, which may contain gum arabic, gelatin, talc, or titanium oxide is coated on the core of tables prepared by using filters as described above. There can be also prepared a film tablet, which is coated by a suitable polymer dissolved in an easily removable organic solvent.
In case of preparation of soft gelatin capsules, the capsules can be prepared by mixing the compound of the present invention with for example, vegetable oil or polyethylene glycol. In case of preparation of hard gelatin capsules, the capsules can be prepared by using granules of the compound of the present invention which are prepared by mixing it with a suitable filler as described above.
The liquid preparation such as injections, drips, eyedrops and ear drops, among the preparations for parenteral administration, can be prepared preferably as a sterilized isotonic liquid preparation. For instance, injections can be prepared by using an aqueous medium such as a salt solution, a glucose solution or a mixture of a salt solution and a glucose solution. The preparation for intrarectal administration can be prepared by using a carrier such as cacao butter usually in the form of suppository.
The ointments, creams and gels contain the compound of the present invention usually in an amount of 0.01-10 w/w %, and there may be incorporated a thickener suitable to an aqueous or oily base and/or a gelling agent and/or a solvent. The base is exemplified by water and/or an oil such as liquid paraffin, a vegetable oil such as arachis oil and castor oil, a solvent such as polyethylene glycol, and so on. The thickener and gelling agent are exemplified by soft paraffin, aluminum stearate, cetostearic alcohol, polyethylene glycol, sheep fat, beeswax, carboxypolymethylene and cellulose derivatives and/or glyceryl monostearate and/or nonionic emulsifiers.
The lotions contain the compound of the present invention usually in an amount of 0.01-10 w/w %, and it may be prepared with the use of an aqueous or oily base, it may contain generally emulsifiers, stabilizers, dispersing agents, precipitation inhibitors and also thickeners.
Powders for external use contain the compound of the present invention usually an amount of 0.01-10 w/w %, and it may be formulated using a suitable powdery base such as talc, lactose and starch.
The drips may be formulated by using an aqueous or non-aqueous base, and may contain dispersing agents, solubilizing agents, precipitation inhibitors or preservatives.
The sprays (sprays, aerosols, dry-powders, etc.) may be formulated into an aqueous solution or suspension using a suitable liquid propellant, or into an aerosol distributed from a pressured package such as a metered-dose inhaler. Dry-powders preparations can be used.
The aerosols suitable to inhalation may be a suspension or aqueous solution, and they contain generally the compound of the present invention and a suitable propellant such as fluorocarbon, hydrogen-containing chlorofluorocarbon and a mixture thereof, particularly hydrofluoroalkane, specifically 1,1,1,2-tetrafluoroethane, heptafluoroalkane (HFA) such as 1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof. The aerosols may contain optionally additional excipients well known in the art such as a surfactant, (e.g., oleic acid or lecithin) and a co-solvent such as ethanol. For example, an inhaler known as Turubuhaler® is illustrated.
The gelatin capsules or cartridges used for inhalator or insufflator may be formulated by using a powdery mixture of the compounds used in the present invention and a powdery base such as lactose and starch. They contain the compound of the present invention usually in an amount of 20 μg-10 mg. The compound of the present invention may be administered without using excipients such as lactose as an alternative method.
In case of being orally or nasally inhalated in the form of pressured HFA aerosols or dry-powders preparations, the adenine compound of the present invention, or its pharmaceutically acceptable salt is pulverized in a size of less than 10 μm and it is dispersed in a dispersing agent such as C8-20 fatty acid or its salt (e.g., oleic acid), bile salt, phospholipid, an alkyl saccharide, a completely fluorinated or polyethoxylated surfactant, or a pharmaceutically acceptable dispersing agent.
The adenine compound of the present invention is preferably parenterally administered as a preparation for topical administration. The suitable preparation is exemplified by ointments, lotions (solutions or suspensions), creams, gels, tapes, transdermal patches, cataplasms, sprays, aerosols, dry-powders, aqueous solutions/suspensions for cartridge spray for inhalators or insufflators, eye-drops, ear drops, nasal drops, transdermal agents, pulmonary absorbent, air-way absorbent, powders for external administrations and so on.
A ratio of the active compound of the present invention in the preparation for topical administration of the present invention is, though depending upon the formulation, generally 0.001-10 wt %, preferably 0.005-1%. The ratio used in powders for inhalation or insufflation is 011-5%.
In a case of aerosols, the compound of the present invention is preferably contained in an amount of 20-2000 μg, more preferably about 20 μg-500 μg per each a measured amount or one sprayed amount. The dosage is once or several times per day, for instance, 2, 3, 4 or 8 times, and one to three units are administered per each time.
The pharmacological activity can be measured by any of conventional evaluation methods, preferably by an in vitro evaluation method. An example of the methods is a method described in examples of the present specification.
The invention further relates to combination therapies wherein a compound of the formula (1) or its pharmaceutically acceptable salt or a pharmaceutical composition comprising a compound of the formula (1) or its pharmaceutically acceptable salt is administered concurrently or sequentially or as a combined preparation with other therapeutic agent(s), for the treatment of one or more of the conditions listed in the specification.
In particular, for the treatment of the inflammatory diseases, COPD, asthma and allergic rhinitis, the compounds of the invention may be combined with agents such as tumour necrosis factor alpha (TNF-α) inhibitors such as anti-TNF monoclonal antibodies (for example Remicade, CDP-870 and adalimumab) and TNF receptor immunoglobulin molecules (such as Enbrel); non-selective cyclo-oxygenase COX-1/COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin), COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); glucocorticosteroids (whether administered by topical, oral, intramuscular, intravenous, or intra-articular routes); methotrexate, leflunomide; hydroxychloroquine, d-penicillamine, auranofin or other parenteral or oral gold preparations.
The present invention still further relates to combination therapies of a compound of the invention together with a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; N-(5-substituted)-thiophene-2-alkylsulfonamides; 2,6-di-tert-butylphenol hydrazones; methoxytetrahydropyrans such as Zeneca ZD-2138; SB-210661; pyridinyl-substituted 2-cyanonaphthalene compounds such as L-739,010; 2-cyanoquinoline compounds such as L-746,530; MK-591, MK-886, and BAY-x-1005.
The present invention still further relates to combination therapies of a compound of the invention together with a receptor antagonist for leukotrienes (LT)B4, LTC4, LTD4 and LTE4 selected from the group consisting of phenothiazin compound such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY-x-7195.
The present invention still further relates to combination therapies of a compound of the invention together with a phosphodiesterase (PD E) inhibitor such as the methylxanthanines including theophylline and aminophylline; and selective PDE isoenzyme inhibitors including PDE4 inhibitors and inhibitors of isoform PDE4D, and inhibitors of PDE5.
The present invention still further relates to combination therapies of a compound of the invention together with histamine type 1 receptor antagonists such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine, which is applied orally, topically or parenterally.
The present invention still further relates to combination therapies of a compound of the invention together with a gastroprotective histamine type 2 receptor antagonist.
The present invention still further relates to combination therapies of a compound of the invention with an antagonist of the histamine type 4 receptor.
The present invention still further relates to combination therapies of a compound of the invention together with an alpha-1/alpha-2 adrenoceptor agonist, vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride, or ethylnorepinephrine hydrochloride.
The present invention still further relates to combination therapies of a compound of the invention together with an anticholinergic agent including muscarinic receptor (M1, M2 and M3) antagonists such as atropine, hyoscine, glycopyrrolate, ipratropium bromide; tiotropium bromide; oxitropium bromide; pirenzepine; or telenzepine.
The present invention still further relates to combination therapies of a compound of the invention together with a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, or pirbuterol.
The present invention still further relates to combination therapies of a compound of the invention together with a chromone, such as sodium cromoglycate or nedocromil sodium.
The present invention still further relates to combination therapies of a compound of the invention together with an insulin-like growth factor type I (IGF-1) mimetic.
The present invention still further relates to combination therapies of a compound of the invention together with an inhaled glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide, or mometasone furoate.
The present invention still further relates to combination therapies of a compound of the invention together with an inhibitor of matrix metalloproteases, i.e., an inhibitor of stromelysin, collagenase, gelatinase, aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), stromelysin-3 (MMP-11), MMP-9 or MMP-12.
The present invention still further relates to combination therapies of a compound of the invention together with modulators of chemokine receptor function such as antagonists of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C—C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C—X—C family) and CX3CR1 (for the C—X3-C family).
The present invention still further relates to combination therapies of a compound of the invention together with a cytokine or a modulator of cytokine function including agents which act on cytokine signalling pathways, such as alpha-, beta-, and gamma-interferon; interleukins (IL) including IL-1 to IL-15, and interleukin antagonists or inhibitors.
The present invention still further relates to combination therapies of a compound of the invention together with an immunoglobulin (Ig), an Ig preparation, or an antagonist or antibody modulating Ig function such as anti-IgE (omalizumab).
The present invention still further relates to combination therapies of a compound of the invention together with systemic or topically-applied anti-inflammatory agents such as thalidomide or its derivatives, retinoids, dithranol, or calcipotriol.
The present invention still further relates to combination therapies of a compound of the invention together with an antibacterial agent including penicillin derivatives, tetracyclines, macrolides, beta-lactams, fluoroquinolones, metronidazole and inhaled aminoglycosides; antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin; zanamavir and oseltamavir; enzyme inhibitors such as indinavir, nelfinavir, ritonavir, and saquinavir; nucleoside reverse transcriptase inhibitors such as didanosine, lamivudine, stavudine, zalcitabine and zidovudine; or non-nucleoside reverse transcriptase inhibitors such as nevirapine or efavirenz.
The present invention still further relates to combination therapies of a compound of the invention together with agents used for treatment of cancers. Suitable agents to be used in the combination therapies include: (i) antiproliferative/antineoplastic drugs and combinations thereof, which are used as an anticancer agent, such as alkylating agents (for example cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorarnbucil, busulphan or nitrosoureas); antimetabolites (for example fluoropyrimidines, like 5-fluorouracil and tegafur, antifolates such as raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); antitumour antibiotics (for example anthracyclines, like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); antimitotic agents (for example vinca alkaloids, like vincristine, vinblastine, vindesine and vinorelbine and taxoids, such as taxol and taxotere); or topoisomerase inhibitors (for example epipodophyllotoxins, such as etoposide, teniposide, amsacrine, topotecan or camptothecins);
(ii) cytostatic agents such as antiestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), estrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin or buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole or exemestane) and inhibitors of 5α-reductase such as finasteride;
(iii) agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors, such as marimastat or inhibitors of urokinase plasminogen activator receptor function);
(iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti erbb2 antibody trastuzumab or the anti erbb1 antibody cetuximab [C225]), farnesyl transferase inhibitors, tyrosine kinase inhibitors or serine/threonine kinase inhibitors; for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI 774) or 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)); for example inhibitors of the platelet-derived growth factor family; or for example inhibitors of the hepatocyte growth factor family;
(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti vascular endothelial cell growth factor antibody bevacizumab, compounds disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function or angiostatin);
(vi) vascular damaging agents such as combretastatin A4 or compounds disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
(vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
(viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi drug resistance gene therapy; or
(ix) immunotherapy approaches, including for example ex vivo and in vivo approaches to increase the immunogenicity of patient tumour cells, such as exposure of cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor (GM-CSF), approaches to decrease T-cell anergy, approaches using transplanted immune cells such as cytokine exposed dendritic cells, approaches using cytokine exposed tumour cell lines and approaches using anti idiotypic antibodies.
The following compounds were prepared in accordance with the method described in the present specification. The abbreviations used in the present specification are as follows:
EtOAc: Ethyl acetate
DMSO: dimethyl sulfoxide
THF: tetrahydrofuran
TFA: trifluoroacetic acid
MS: Mass spectrometry
HCl: Hydrochloric acid
In the present specification, in case of reverse-phase HPLC, “Waters Symmetry C8, Xterra or Phenomenex Gemini columns” was used, and the solvent such as acetonitrile and buffer (aqueous ammonium acetate, aqueous ammonia, aqueous formic acid or aqueous trifluoroacetic acid were used as an eluent. Silica gel was used as column chromatography. SCX means solid phase extraction using sulfonic acid absorbent and a mixture was absorbed in sulfonic acid absorbent and eluted into a solvent such as, methanol, acetonitrile, etc. and then, free basic substance is eluted into a solvent such as aqueous ammonia/methanol acetonitrile, etc.
The present invention is concretely explained by the following examples, but should not be limited by the examples.
To 4-hydroxylmethylpiperidine-1 carboxylic acid tert-butyl ester) 15.4 g (71.5 mmol) in THF (300 ml) were added triethylamine 25 ml (179 mmol), 4-dimethylaminopyridine 181 mg (1.48 mmol) and methanesulfonyl chloride 6.5 ml (84.0 mmol) at 0° C., and then the mixture was stirred at room temperature for 30 minutes. Thereto was added saturated brine 400 ml and the mixture was extracted with ethyl acetate (800 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. To the residue was added chloroform-hexane and the resulting solid was filtered to give the subtitled compound 19.4 g as a white solid. Yield 92%
1H NMR (CDCl3) δ 4.15 (2H, brd J=13.4 Hz), 4.07 (2H, d J=6.5 Hz), 3.02 (3H, s), 2.71 (2H, brt, J=13.4 Hz), 1.96-1.84 (1H, m), 1.74 (2H, brd J=13.4 Hz), 1.46 (9H, s), 1.27-1.16 (2H, m).
To 2-butoxy-8-methoxyadenine 3.03 g (9.08 mmol) in DMF (90 ml) were added potassium carbonate 3.19 g (23.0 mmol) and 4-(methanesulufonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester 3.19 g (10.9 mmol), and the mixture was stirred at 60° C. for 10 hours, at 80° C. for 2.5 hours and then at 100° C. for 2 hours. After removal of the solvent by distillation, thereto was added saturated brine 50 ml and the mixture was extracted three times with chloroform (50 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. To the residue was added diethyl ether-hexane and the resulting solid was filtered. The residue was repulp-purified with diethyl ether-hexane (1:2) to give the subtitled compound as a white solid 2.74 g. Yield 70%
1H NMR (CDCl3) δ 5.79 (2H, bs), 4.30 (2H, t, J=6.7 Hz), 4.12 (3H, s), 3.81 (2H, d, J=7.3 Hz), 2.70-2.60 (2H, m), 2.06-1.70 (4H, m), 1.58-1.40 (5H, m), 1.45 (9H, s), 1.28-1.14 (2H, m), 0.97 (3H, t, J=7.4 Hz).
Step (iii)
To the compound 305 mg (0.70 mmol) obtained in step (ii) was added trifluoroacetic acid 10 ml and the mixture was stirred at room temperature for 30 minutes. After removal of the solvent by distillation, to the residue was added DMF 5 ml. Thereto were added tert-butyl 3-chloropropylmethylcarboxylate 298 mg (1.43 mmol), potassium carbonate 488 mg (3.53 mmol) and potassium iodide 119 mg (0.715 mmol) at room temperature, and the mixture was stirred at room temperature for 18 hours, at 60° C. for 4 hours and then at 80° C. for 5.5 hours. After removal of the solvent by distillation, to the residue was added water 20 ml and the mixture was extracted with chloroform (60 ml). The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo and purified by silica gel column chromatography to give the subtitled compound 217 mg as a colorless oil. Yield 61%
1H NMR (CDCl3) δ 5.14 (2H, bs), 4.27 (2H, t, J=6.7 Hz), 4.11 (3H, s), 3.81 (2H, d, J=7.3 Hz), 3.24-3.18 (2H, m), 2.89-2.84 (2H, m), 2.83 (3H, s), 2.32-2.27 (2H, m), 1.93-1.66 (10H, m), 1.60-1.28 (6H, m), 1.44 (9H, s), 0.96 (3H, t, J=7.4 Hz).
To the compound 181 mg (0.357 mmol) obtained in step (iii) was added trifluoroacetic acid 5 ml and the mixture was stirred at room temperature for 35 minutes. After removal of the solvent by distillation, to the residue was added aqueous saturated sodium bicarbonate 20 ml and the mixture was extracted with 33% ethanol-chloroform (50 ml×3). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. To the resulting crude product in methanol (5 ml) were added sodium cyanoborohydride 96.7 mg (1.46 mmol) and methyl 3-formyl-phenyl-acetate 77.1 mg (0.432 mmol) at room temperature, and the mixture was stirred at room temperature for 4 days. After removal of the solvent by distillation, to the residue was added saturated brine 5 ml and the mixture was extracted with 33% ethanol-chloroform (10 ml×3). The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo and purified by silica gel column chromatography to give the subtitled compound 138 mg as a colorless oil. Yield 68%
1H NMR (CDCl3) δ 7.30-7.14 (4H, m), 5.22 (2H, bs), 4.27 (2H, t, J=6.7 Hz), 4.10 (3H, s), 3.81 (2H, d, J=7.3 Hz), 3.69 (3H, s), 3.61 (3H, s), 3.45 (2H, s), 2.93-2.86 (2H, m), 2.39-2.30 (4H, m), 2.17 (3H, s), 1.93-1.68 (10H, m), 1.60-1.30 (6H, m), 0.96 (3H, t, J=7.4 Hz).
To the compound 135 mg (0.238 mmol) obtained in step (iv) in methanol (10 ml) was added concentrated sulfuric acid (200 μl) and the mixture was refluxed for 3 hours. After neutralizing with aqueous saturated sodium bicarbonate, the resulting solid was filtered to give the titled compound 107 mg as a white solid. Yield 81%
1H NMR (DMSO-d6) δ 7.35-7.10 (4H, m), 6.64 (2H, bs), 4.13 (2H, t, J=6.6 Hz), 3.65 (2H, s), 3.60 (3H, s), 3.53 (2H, d, J=7.1 Hz), 3.40 (2H, s), 2.79-2.75 (2H, m), 2.30 (2H, t, J=6.9 Hz), 2.22 (2H, t, J=7.4 Hz), 2.08 (3H, s), 1.80-1.70 (3H, m), 1.68-1.52 (4H, m), 1.50-1.33 (4H, m), 1.20-1.10 (2H, m), 0.92 (3H, t, J=7.3 Hz).
To the compound 296 mg (0.682 mmol) obtained by example 1 step (i) was added trifluoroacetic acid 8 ml and the mixture was stirred for 40 minutes. After removal of the solvent by distillation, to the residue was added DMF 8 ml. Thereto were added 3-bromopropylphthalimide 311 mg (1.16 mmol), potassium carbonate 474 mg (3.43 mmol) and potassium iodide 113 mg (0.683 mmol) at room temperature, and the mixture was stirred at 80° C. for 5.5 hours. After removal of the solvent by distillation, to the residue was added water 20 ml and the mixture was extracted with chloroform (60 ml). The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo and purified by silica gel column chromatography to give the subtitled compound 327 mg as a colorless oil. Yield 92%
1H NMR (CDCl3) δ 7.85-7.82 (2H, m), 7.75-7.71 (2H, m), 5.13 (2H, bs), 4.26 (2H, t, J=6.7 Hz), 4.09 (3H, s), 3.80-3.73 (4H, m), 1.79-1.58 (10H, m), 1.53-1.43 (3H, m), 0.96 (3H, t, J=7.3 Hz).
To the compound 292 mg (0.559 mmol) obtained in step (i) in ethanol (100 ml) was added hydrazine monohydrate (1 ml) and the mixture was refluxed for 30 minutes. After being cooled to room temperature, the resulting solid was filtered off. After removal of the solvent by distillation, to the residue, was added aqueous saturated sodium bicarbonate 30 ml and the mixture was extracted with 33% ethanol-chloroform (150 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. To the obtained crude product in methanol (6 ml) were added sodium cyanoborohydride 178 mg (2.69 mmol) and methyl (3-formylphenyl)acetate 105 mg (0.588 mol) at room temperature, and the mixture was stirred at room temperature for 45 hours. After removal of the solvent by distillation, to the residue was added saturated brine 6 ml and the mixture was extracted with 33% ethanol-chloroform (45 ml). The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo and purified by silica gel column chromatography to give the subtitled compound 97.7 mg as a colorless oil. Yield 33%
1H NMR (CDCl3) δ 7.36-7.18 (4H, m), 5.14 (2H, brs), 4.26 (2H, t, J=6.7 Hz), 4.10 (3H, s), 3.87 (2H, brs), 3.76 (2H, d, J=7.3 Hz), 3.69 (3H, s), 3.64 (2H, s), 3.00-2.94 (2H, m), 2.84-2.78 (2H, m), 2.47-2.41 (2H, m), 1.93-1.70 (7H, m), 1.60-1.42 (4H, m), 1.34-1.23 (2H, m), 0.96 (3H, t, J=7.4 Hz).
Step (iii)
To the compound 97.2 mg (0.176 mmol) obtained in step (ii) in methanol (10 ml) was added concentrated sulfuric acid (200 μl) and the mixture was refluxed for 2.5 hours. After neutralizing with aqueous saturated sodium bicarbonate, the solvent was removed by distillation. To the residue was added water 20 ml and the mixture was extracted with 33% ethanol-chloroform (200 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. To the residue was added chloroform-hexane and the resulting solid was filtered to give the titled compound 62.1 mg as a white solid. Yield 66%
1H NMR (DMSO-d6) δ 9.85 (1H, bs), 7.34-7.14 (4H, m), 6.45 (2H, brs), 4.14 (2H, t, J=6.6 Hz), 3.81 (1H, brs), 3.68 (2H, s), 3.61 (3H, s), 3.53 (2H, d, J=7.2 Hz), 3.42 (2H, s), 2.89-2.80 (2H, m), 2.70-2.60 (2H, m), 2.36-2.28 (2H, m), 1.89-1.72 (3H, m), 1.68-1.58 (4H, m), 1.42-1.32 (2H, m), 1.20-1.11 (2H, m), 0.92 (3H, t, J=7.3 Hz),
To 2-{(2-Methoxyethoxy)}-8-methoxyadenine 10.0 g (41.8 mmol) in DMF (350 ml) were added potassium carbonate 7.52 g (54.4 mmol) and 4-(methanesulufonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester 14.7 g (50.2 mmol), and the mixture was stirred at 80° C. for 11 hours. After removal of the solvent by distillation, to the residue was added saturated brine 300 ml and the mixture was extracted with chloroform (750 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The solid residue was repulp-purified with diethyl ether to give the subtitled compound 12.5 g as a white solid. Yield 69%
1H NMR (CDCl3) δ 5.24 (2H, bs), 4.44 (2H, t, J=5.0 Hz), 4.11 (3H, s), 3.81 (2H, d, J=7.3 Hz), 3.76 (2H, t, J=5.0 Hz), 3.41 (3H, s), 2.70-2.58 (2H, m), 2.07-1.95 (1H, m), 1.84-1.72 (2H, m), 1.56-1.48 (2H, m), 1.45 (9H, s), 1.25-1.12 (2H, m).
To the compound 356 mg (0.816 mmol) obtained in step (i) was added trifluoroacetic acid 5 ml, and the mixture was stirred at room temperature for 35 minutes. After removal of the solvent by distillation, to the residue was added DMF 8 ml. Thereto were added 3-(2-bromoethoxy)phenyl]acetic acid methyl ester 356 mg (1.30 mmol) and potassium carbonate 702 mg (5.08 mmol) at room temperature, and the mixture was stirred at 60° C. for 2 hours. After removal of the solvent by distillation, to the residue was added saturated brine 20 ml, and the mixture was extracted with chloroform (60 ml). The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo and purified by silica gel column chromatography to give the subtitled compound 340 mg as colorless oil. Yield 79%
1H NMR (CDCl3) δ 7.22-7.21 (1H, m), 6.91-6.88 (1H, m), 6.83-6.77 (2H, m), 5.17 (2H, brs), 4.43 (4H, t, 35.0 Hz), 4.10 (2H, s), 3.87 (2H, d, J=6.3 Hz), 3.75 (2H, t J=5.0 Hz), 3.69 (3H, s), 3.59 (2H, s), 3.47 (3H, s), 2.20-2.05 (2H, m), 1.80-1.50 (7H, m).
Step (iii)
To the compound 314 mg (0.593 mmol) obtained in step (ii) in methanol (10 ml) was added concentrated sulfuric acid (200 μl) and the mixture was refluxed for 3 hours. The mixture was neutralized with aqueous saturated sodium bicarbonate and the resulting solid was filtered to give the titled compound 313 mg as a white solid. Yield 100%
1H NMR (DMSO-d6) ε 7.23-7.18 (1H, m), 6.84-6.76 (3H, m), 4.25 (2H, t, J=4.6 Hz), 4.02 (2H, t J=5.9 Hz), 3.67-3.59 (2H, m), 3.63 (2H, s), 3.61 (3H, s), 3.54 (2H, d, J=7.2 Hz), 3.29 (3H, s), 2.91-2.87 (2H, m), 2.64 (2H, t, J=5.9 Hz), 1.99-1.93 (2H, m), 1.86-1.70 (1H, m), 1.56-1.46 (2H, m), 1.28-1.14 (2H, m).
To the compound 1.01 g (2.30 mmol) obtained by example 3 step (i) was added trifluoroacetic acid 20 ml and the mixture was stirred at room temperature for 55 minutes. After removal of the solvent by distillation, to the residue was added DMF 25 ml. Thereto were added N-tert-butoxycarbonyl-N-(3-chloropropyl)-N-methylamine 964 mg (4.64 mmol) and potassium carbonate 2.93 g (21.2 mmol) at room temperature, and the mixture was stirred at 80° C. for 9 hours. After removal of the solvent by distillation, to the residue was added saturated brine 50 ml, and the mixture was extracted with 25% ethanol-chloroform (150 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo and purified by silica gel column chromatography to give the subtitled compound 983 mg as a pale yellow oil. Yield 84%
1H NMR (CDCl3) δ 5.40 (2H, bs), 4.43 (2H, t, J=5.0 Hz), 4.10 (3H, s), 3.81 (2H, d, J=7.3 Hz), 3.75 (2H, t, J=5.0 Hz), 3.43 (3H, s), 3.26-3.18 (2H, m), 2.95-2.86 (2H, m), 2.84 (3H, s), 2.34-2.26 (2H, m), 1.94-1.82 (3H, m), 1.75-1.66 (2H, m), 1.61-1.53 (2H, m), 1.44 (9H, s), 1.46-1.33 (2H, m).
To the compound 295 g (0.581 mmol) obtained in step (i) was added trifluoroacetic acid 5 ml and the mixture was stirred at room temperature for 40 minutes. After removal of the solvent by distillation, to the residue was added DMF 8 ml and thereto were added methyl [3-(2-bromoethoxy)phenyl]acetate 225 mg (0.825 mmol) and potassium carbonate 640 g (4.63 mmol) at room temperature, and the mixture was stirred at 60° C. for 4 hours. After removal of the solvent by distillation, thereto was added saturated brine 30 ml and the mixture was extracted with 33% ethanol-chloroform (150 ml). The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo and purified by silica gel column chromatography to give the subtitled compound 246 mg as a colorless oil. Yield 71%
1H NMR (CDCl3) δ 7.22-7.20 (1H, m), 6.85-6.78 (3H, m), 5.19 (2H, brs), 4.43 (2H, t, J=4.9 Hz), 4.10 (3H, s), 4.07 (2H, t, J=6.4 Hz), 3.83 (2H, d J=7.3 Hz), 3.75 (2H, t, J=4.9 Hz), 3.68 (3H, s), 3.58 (2H, s), 3.42 (3H, s), 2.80 (2H, t, J=5.6 Hz), 2.58-2.46 (2H, m), 2.17 (3H, m), 2.24-1.56 (11H, m).
Step (iii)
To the compound 244 mg (0.407 mmol) obtained in step (ii) in methanol (7.5 ml) was added concentrated sulfuric acid (150 μl) and the mixture was refluxed for 3.5 hours. After neutralized with aqueous saturated sodium bicarbonate, the solvent was removed by distillation. To the residue was added saturated brine 10 ml and the mixture was extracted with 33% ethanol-chloroform (60 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. To the residue was added chloroform-hexane and the resulting solid was filtered to give the titled compound 152 mg as a white solid. Yield 64%
1H NMR (DMSO-d6) δ 9.87 (1H, brs), 7.23-7.19 (4H, m), 6.83-6.80 (3H, m), 6.43 (2H, brs), 4.26 (2H, t, J=4.6 Hz), 4.01 (2H, t, J=5.8 Hz), 3.70-3.58 (2H, m), 3.63 (2H, s), 3.60 (3H, s), 3.54 (2H, d, J=7.2 Hz), 3.27 (3H, s), 2.83-2.74 (2H, m), 2.68 (2H, t, J=5.8 Hz), 2.38 (2H, t, J=5.8 Hz), 2.30-2.16 (2H, m), 2.22 (3H, s), 1.84-1.70 (3H, m), 1.58-1.44 (4H, m), 1.27-1.10 (3H, m).
To the compound 423 g (0.836 mmol) obtained by example 4 step (i) was added trifluoroacetic acid 15 ml and the mixture was stirred at room temperature for 45 minutes. To the obtained crude substance in methanol (10 ml) were added sodium cyanoborohydride 280 mg (4.24 mmol) and methyl 3-(formylphenyl)-acetate 228 mg (1.28 mmol) at room temperature, and the mixture was stirred at room temperature for 21 hours. After removal of the solvent by distillation, thereto was added saturated brine 50 ml and the mixture was extracted with 33% ethanol-chloroform (150 ml). The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo and purified by silica gel column chromatography to give the subtitled compound 316 mg as a colorless oil. Yield 67%
1H NMR (CDCl3) δ 7.32-7.14 (4H, m), 5.19 (2H, brs), 4.43 (2H, t, J=4.9 Hz), 4.10 (3H, s), 3.84 (2H, d, J=7.2 Hz), 3.75 (2H, t, J=4.9 Hz), 3.68 (3H, s), 3.63 (2H, s), 3.38 (3H, s), 2.44-2.40 (2H, m), 2.24 (3H, s), 2.30-1.80 (11H, m), 1.70-1.60 (2H, m).
To the compound 312 mg (0.548 mmol) obtained in step (i) in methanol (10 ml) was added concentrated sulfuric acid (200 μl) and the mixture was refluxed for 7 hours. After neutralized with aqueous saturated sodium bicarbonate, the solvent was removed by distillation. To the residue was added aqueous saturated sodium bicarbonate 15 ml and the mixture was extracted with 33% ethanol-chloroform (75 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. To the residue was added chloroform-hexane and the resulting solid was filtered to give the titled compound 251 mg as a white solid. Yield 82%
1H NMR (DMSO-d6) δ 9.88 (1H, brs), 7.28-7.25 (1H, m), 7.23-7.06 (3H, m), 6.49 (2H, brs), 4.26 (2H, t, J=4.7 Hz), 3.65 (2H, s), 3.60 (3H, s), 3.54 (2H, d, J=7.1 Hz), 3.39 (2H, s), 3.37 (2H, s), 3.29 (3H, s), 2.80-2.72 (2H, m), 2.32-2.20 (4H, m), 2.09 (3H, s), 1.82-1.68 (3H, m), 1.60-1.42 (4H, m), 1.24-1.10 (3H, m).
To the compound 260 mg (0.5976 mmol) obtained by example 1 step (i) was added trifluoroacetic acid 5 ml and the mixture was stirred at room temperature for 40 minutes. After removal of the solvent by distillation, to the residue was added DMF 5 ml. Thereto were added methyl [3-(2-bromoethoxy)-phenyl]-acetate 249 mg (0.911 mmol) and potassium carbonate 661 mg (4.78 mmol) at room temperature, and the mixture was stirred at 60° C. for 3 hours. After removal of the solvent by distillation, thereto added saturated brine 15 ml and the mixture was extracted with chloroform (90 ml). The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo and purified by silica gel column chromatography to give the subtitled compound 259 mg as a colorless oil. Yield 82%
1H NMR (CDCl3) δ 7.25-7.20 (1H, m), 6.88-6.79 (3H, m), 5.19 (2H, brs), 4.27 (2H, t, J=6.7 Hz), 4.21-4.12 (2H, m), 4.11 (3H, s), 3.90 (2H, t, J=7.2 Hz), 3.69 (3H, s), 3.59 (2H, s), 3.14-3.04 (2H, m), 2.90-2.83 (2H, m), 2.28-2.15 (2H, m), 2.00-1.66 (8H, m), 1.54-1.44 (2H, m), 1.42-1.22 (5H, m), 0.96 (3H, t, J=7.4 Hz).
To the compound 259 mg (0.491 mmol) obtained in step (i) in methanol (10 ml) was added concentrated sulfuric acid (200 μl) and the mixture was refluxed for 3 hours. After neutralized with aqueous saturated sodium bicarbonate, the resulting solid was filtered to give the titled compound 199 mg as a white solid. Yield 79%
1H NMR (DMSO-d6) δ 9.87 (1H, brs), 7.23-7.19 (1H, m), 6.83-6.80 (3H, m), 6.41 (2H, brs), 4.14 (2H, t, J=6.8 Hz), 4.02 (2H, t, J=5.8 Hz), 3.61 (2H, s), 3.56 (3H, s), 3.55 (2H, d, J=6.6 Hz), 3.34 (3H, s), 2.94-2.86 (2H, m), 2.64 (2H, t, J=5.8 Hz), 1.96 (2H, brt, J=7.0 Hz), 1.85-1.72 (1H, m), 1.68-1.58 (2H, m), 1.54-1.46 (2H, m), 1.41-1.30 (2H, m), 1.26-1.12 (2H, m), 0.92 (3H, t, J=7.3 Hz).
To the compound 239 mg (0.473 mmol) obtained by example 1, step (ii) was added trifluoroacetic acid 5 ml and the mixture was stirred at room temperature for 35 minutes. After removal of the solvent by distillation, to the residue was added DMF 5 ml. Thereto were added methyl [3-(2-bromoethoxy)-phenyl]-acetate 196 mg (0.718 mmol) and potassium carbonate 526 mg (3.81 mmol) at room temperature, and the mixture was stirred at 60° C. for 5 hours and at 80° C. for 1.5 hours. After removal of the solvent by distillation, thereto was added saturated brine 20 ml and the mixture was extracted with 33% ethanol-chloroform (90 ml). The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo and purified by silica gel column chromatography to give the subtitled compound 234 mg as a colorless oil Yield 83%
1H NMR (CDCl3) δ 7.27-7.20 (1H, m), 6.85-6.78 (3H, m), 5.19 (2H, brs), 4.26 (2H, t, J=6.6 Hz), 4.09 (3H, s), 4.07 (2H, t, J=5.6 Hz), 3.84 (2H, d, J=7.3 Hz), 3.68 (3H, s), 3.58 (2H, s), 2.80 (2H, t, J=5.6 Hz), 2.58-2.48 (2H, m), 2.35 (3H, s), 2.24-1.60 (15H, m), 1.54-1.43 (2H, m), 0.96 (3H, t, J=7.4 Hz).
To the compound 230 mg (0.385 mmol) obtained in step (i) in methanol (10 ml) was added concentrated sulfuric acid (200 μl) and the mixture was refluxed for 6.5 hours. After neutralized with aqueous saturated sodium bicarbonate, the resulting solid was filtered to give the titled compound 113 mg as a white solid. Yield 50%
1H NMR (DMSO-d6) δ 9.85 (1H, brs), 7.26-7.19 (1H, m), 6.88-6.63 (3H, m), 6.41 (2H, brs), 4.14 (2H, t, J=6.6 Hz), 4.01 (2H, t, J=5.8 Hz), 3.63 (2H, s), 3.60 (2H, s), 3.53 (2H, d, J=7.2 Hz), 2.84-2.76 (2H, m), 2.67 (2H, t, J=5.8 Hz), 2.50 (2H, t, J=5.8 Hz), 2.28-2.15 (2H, m), 2.21 (3H, s), 1.81-1.70 (3H, m), 1.68-1.57 (2H, m), 1.56-1.30 (6H, m), 1.22-1.10 (2H, m), 0.92 (3H, t, J=7.3 Hz).
Using 8-methoxy-2-(2-methoxyethoxy)adenine 3.27 g (13.7 mmol) and 4-[2-(methanesulufonyloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester 4.21 g (13.7 mmol), in the same manner as example 3 step (i), there was obtained the subtitled compound 3.62 g as a white solid. Yield 59%
1H NMR (CDCl3) δ 5.44 (2H, brs), 4.44 (2H, t, J=5.0 Hz), 4.12 (3H, s), 3.96 (2H, t, J=5.4 Hz), 3.75 (2H, t, J=5.0 Hz), 3.43 (3H, s), 2.67-2.06 (2H, m), 1.83-1.65 (6H, m), 1.45 (9H, s), 1.40-1.33 (1H, m), 1.18-1.11 (2H, m).
Using the compound 0.35 g (0.78 mmol) obtained in step (i), in the same manner as example 3 step (ii) there was obtained the subtitled compound 0.36 g as colorless oil. Yield 86%
1H NMR (DMSO-d6) δ 7.20 (1H, dd, J=8.4 Hz, 7.6 Hz), 6.83-6.77 (5H, m), 4.28 (2H, t, J=4.8 Hz), 4.03 (3H, s), 4.01 (2H, t, J=6.0 Hz), 3.86 (2H, t, J=6.9 Hz), 3.63 (2H, s), 3.63-3.59 (2H, m), 3.59 (3H, s), 3.29 (3H, s), 2.90-2.86 (2H, m), 2.62 (2H, t, J=5.8 Hz), 1.96-1.88 (2H, m), 1.72-1.66 (2H, m), 1.61-1.57 (2H, m), 1.18-1.11 (3H, m).
Step (iii)
Using the compound 0.36 g (0.66 mmol) obtained in step (ii), in the same manner as example 1 step (v) there was obtained the titled compound 0.31 g as a white solid. Yield 90%
1H NMR (DMSO-d6) δ 9.96 (1H, brs), 7.20 (1H, dd, J=8.4 Hz, 7.6 Hz), 6.83-6.77 (3H, m), 6.53 (2H, brs), 4.26 (2H, t, J=4.8 Hz), 4.02 (2H, t, J=5.9 Hz), 3.69 (2H, t, J=6.9 Hz), 3.63 (2H, s), 3.63-3.58 (2H, m), 3.60 (3H, s), 3.28 (3H, s), 2.90-2.86 (2H, m), 2.63 (2H, t, J=5.9 Hz), 1.96-1.88 (2H, m), 1.72-1.67 (2H, m), 1.58-1.55 (2H, m), 1.16-1.11 (3H, m).
Using the compound 1.02 g (2.25 mmol) obtained by example 8 step (i), in the same manner as example 1 step (iii), there was obtained the subtitled compound 0.81 g as a pale yellow oil. Yield 69%
1H NMR (CDCl3) δ 5.30 (2H, brs), 4.42 (2H, t, J=5.0 Hz), 4.11 (3H, s), 3.96 (2H, t, J=7.0 Hz), 3.75 (2H, t, J=5.0 Hz), 3.43 (3H, s), 3.25-2.20 (2H, m), 3.05-2.89 (2H, m), 2.84 (3H, s), 2.50-2.30 (2H, m), 2.10-1.65 (9H, m), 1.45 (9H, s), 1.45-1.19 (2H, m).
Using the compound 0.41 g (0.79 mmol) obtained in step (i) in the same manner as example 1 step (iv) there was obtained the subtitled compound 0.28 g as a colorless oil. Yield 60%
1H NMR (DMSO-d6) δ 7.23 (1H, dd, J=7.9 Hz, 7.4 Hz, 7.17 (1H, s), 7.15 (1H, d, J=7.9 Hz), 7.11 (1H, d, J=7.4 Hz), 6.81 (2H, brs), 4.28 (2H, t, J=4.8 Hz), 4.04 (3H, s), 3.86 (2H, t, J=6.9 Hz), 3.65 (2H, s), 3.62-3.59 (2H, m), 3.60 (3H, s), 3.40 (2H, s), 3.29 (3H, s), 2.80-2.75 (2H, m), 2.29 (2H, t, J=7.1 Hz), 2.22-2.05 (2H, m), 2.08 (3H, s), 1.75-1.63 (4H, m), 1.60-1.54 (4H, m), 1.10-1.05 (3H, m).
Step (iii)
Using the compound 0.26 g (0.45 mmol) obtained in step (ii), in the same as example 1 step (v) there was obtained the titled compound 0.22 g as a white solid. Yield 87%
1H NMR (DMSO-d6) δ 9.86 (1H, s), 7.25 (1H, dd, J=8.0 Hz, 7.5 Hz), 7.17 (1H, s), 7.15 (1H, d, J=8.0 Hz), 7.11 (1H, d, J=7.5 Hz), 6.43 (2H, brs), 4.25 (2H, t, J=4.7 Hz), 3.68 (2H, t, J=7.0 Hz), 3.65 (2H, s), 3.62-3.59 (2H, m), 3.60 (3H, s), 3.30 (2H, s), 3.28 (3H, s), 2.78-2.73 (2H, m), 2.29 (2H, t, J=7.1 Hz), 2.22-2.05 (2H, m), 2.08 (3H, s), 1.75-1.65 (4H, m), 1.58-1.54 (4H, m), 1.13-1.05 (3H, m).
Using compound 0.27 g (0.53 mmol) obtained by example 8 step (i), in the same manner as example 3 step (ii) there was obtained the subtitled compound 0.21 g as colorless oil. Yield 64%
1H NMR (DMSO-d6) δ 7.23-7.18 (1H, m), 6.87-6.77 (5H, m), 4.27 (2H, t, J=4.8 Hz), 4.04 (3H, s), 4.00 (2H, t, J=5.8 Hz), 3.85 (2H, t, J=6.9 Hz), 3.65 (2H, s), 3.62-3.58 (2H, m), 3.60 (3H, s), 3.28 (3H, s), 2.80-2.74 (2H, m), 2.66 (2H, t, J=5.8 Hz), 2.36 (2H, t, J=7.1 Hz), 2.23-2.17 (2H, m), 2.21 (3H, s), 1.68-1.63 (4H, m), 1.60-1.54 (4H, m), 1.12-1.05 (3H, m).
Using the compound 0.21 g (0.33 mmol) obtained in step (i), in the same manner as example 1 step (v) there was obtained the titled compound 0.17 g as a white solid. Yield 84%
1H NMR (DMSO-d6) δ 7.23-7.18 (1H, m), 6.83-6.78 (3H, m), 6.54 (2H, brs), 4.26 (2H, t, J=4.8 Hz), 4.00 (2H, t, J=5.9 Hz), 3.68 (2H, t, J=6.9 Hz), 3.63 (2H, s), 3.61-3.58 (2H, m), 3.60 (3H, s), 3.28 (3H, s), 2.80-2.74 (2H, m), 2.66 (2H, t, J=5.8 Hz), 2.36 (2H, t, J=7.1 Hz), 2.23-2.18 (2H, m), 2.21 (3H, s), 1.80-1.68 (4H, m), 1.58-1.51 (4H, m), 1.13-1.06 (3H, m.
Using 2-butoxy-9-(1-tert-butoxycarbonylpiperidin-4-ylethyl)-8-methoxyadenine 0.25 g (0.72 mmol), in the same manner as example 3 step (ii) there was obtained the subtitled compound 0.27 g as a pale yellow oil. Yield 69%
1H NMR (DMSO-d6) δ 7.20 (1H, dd, J=7.8 Hz, 7.4 Hz), 6.83-6.75 (5H, m), 4.15 (2H, t, J=6.6 Hz), 4.04 (3H, s), 4.01 (2H, t, J=5.8 Hz), 3.87 (2H, t, J=6.8 Hz), 3.63 (2H, s), 3.60 (3H, s), 2.90-2.86 (2H, m), 2.62 (2H, t, J=5.8 Hz), 1.96-1.88 (2H, m), 1.73-1.58 (6H, m), 1.43-1.37 (2H, m), 1.18-1.11 (3H, m), 0.91 (3H, t, J=7.4 Hz).
Using compound 0.25 g (0.47 mmol) obtained in step (i), in the same manner as example 1 step (v) there was obtained the titled compound 0.18 g as a white solid. Yield 73%
1H NMR (DMSO-d6) δ 9.87 (1H, brs), 7.20 (1H, dd, J=7.7 Hz, 7.5 Hz), 6.83-6.79 (3H, m), 6.40 (2H, brs), 4.14 (2H, t, J=6.6 Hz), 4.01 (2H, t, J=5.9 Hz), 3.69 (2H, t, J=6.8 Hz), 3.63 (2H, s), 3.60 (3H, s), 2.90-2.86 (2H, m), 2.62 (2H, t, J=5.8 Hz), 1.96-1.88 (2H, m), 1.73-1.55 (6H, m), 1.43-1,37 (2H, m), 1.18-1.11 (3H, m), 0.91 (3H, t, J=7.4 Hz).
Using 2-butoxy-9-(1-tert-butoxycarbonylpiperidin-4-ylethyl)-8-methoxyadenine 0.71 g (2.02 mmol), in the same manner as example 1 step (iii) there was obtained the subtitled compound 0.62 g as a pale yellow oil. Yield 59%
1H NMR (CDCl3) δ 6.77 (2H, brs), 4.15 (2H, t, J=6.6 Hz), 4.04 (3H, s), 3.86 (2H, t, J=6.8 Hz), 3.13 (2H, t, J=7.2 Hz), 2.83-2.75 (2H, m), 2.74 (3H, s), 2.22-2.18 (2H, m), 1.80-1.55 (10H, m), 1.42-1.37 (2H, m), 1.37 (9H, s), 1.15-1.08 (3H, m), 0.92 (3H, t, J=7.4 Hz).
Using the compound 0.29 g (0.55 mmol) obtained in step (i), in the same manner as example 3 step (ii) there was obtained the subtitled compound 0.22 g as a pale yellow oil. Yield 66%
1H NMR (DMSO-d6) δ 7.22-7.18 (1H, m), 6.87-6.70 (5H, m), 4.15 (2H, t, J=6.6 Hz), 4.04 (3H, s), 4.00 (2H, t, J=5.9 Hz), 3.85 (2H, t, J=6.8 Hz), 3.63 (2H, s), 3.60 (3H, s), 2.80-2.74 (2H, m), 2.66 (2H, t, J=5.8 Hz), 2.36 (2H, t, J=7.1 Hz), 2.23-2.17 (2H, m), 2.20 (3H, s), 1.75-1.60 (6H, m), 1.59-1.47 (4H, m), 1.44-1.34 (2H, m), 1.13-1.06 (3H, m), 0.91 (3H, t, J=7.4 Hz).
Step (iii)
Using the compound 0.22 g (0.37 mmol) obtained in step (ii), in the same manner as example 1 step (v) there was obtained the titled compound 0.20 g as a white solid. Yield 92%
1H NMR (DMSO-d6) δ 9.88 (1H, brs), 7.20 (1H, dd, J=7.3 Hz, 7.2 Hz), 6.82-6.79 (3H, m), 6.41 (2H, brs), 4.13 (2H, t, J=6.6 Hz), 4.00 (2H, t, J=5.8 Hz), 3.68 (2H, t, J=6.9 Hz), 3.62 (2H, s), 3.60 (3H, s), 2.79-2.74 (2H, m), 2.66 (2H, t, J=5.8 Hz), 2.36 (2H, t, J=7.1 Hz), 2.23-2.17 (2H, m), 2.21 (3H, s), 1.75-1.57 (6H, m), 1.56-1.47 (4H, m), 1.42-1.34 (2H, m), 1.13-1.06 (3H, m), 0.91 (3H, t, J=7.4 Hz).
To the compound 0.15 g (0.33 mmol) obtained by example 8 step (i) was added trifluoroacetic acid 2 ml and the mixture was stirred at room temperature for 20 minutes. After removal of trifluoroacetic acid by distillation, thereto were added DMF 10 ml, potassium carbonate 0.28 g (2.0 mmol) and 2-chloro-N-{3-(methoxycarbonylmethyl)phenyl}acetamide 84 mg (0.35 mmol), and the mixture was stirred at room temperature for 18 hours. After removal of the solvent by distillation, thereto was added water, and the mixture was extracted with chloroform/ethanol (3/1). The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo and purified by silica gel column chromatography to give the subtitled compound 0.1 g as a colorless oil. Yield 99%
1H NMR (DMSO-d6) δ 9.63 (1H, s), 7.54-7.52 (2H, m), 7.24 (1H, dd, J=8.6 Hz, 7.6 Hz), 6.94 (1H, d, J=7.6 Hz), 6.81 (2H, brs), 4.27 (2H, t, J=4.8 Hz), 4.05 (3H, s), 3.88 (2H, t, J=7.0 Hz), 3.64 (2H, s), 3.63-3.57 (2H, m), 3.61 (3H, s), 3.28 (3H, s), 3.04 (2H, s), 2.85-2.80 (2H, m), 2.10-2.01 (2H, m), 1.74-1.69 (2H, m), 1.66-1.60 (2H, m), 1.30-1.25 (2H, m), 1.14-1.11 (1H, m).
Using compound 0.17 g (0.31 mmol) obtained in step (ii), in the same manner as example 1 step (v) there was obtained the titled compound 0.27 g as a white solid. Yield 86%
1H NMR (DMSO-d6) δ 9.93 (1H, brs), 9.63 (1H, s), 7.55-7.52 (2H, m), 7.24 (1H, dd, J=8.6 Hz, 7.6 Hz), 6.94 (1H, d, J=7.6 Hz), 6.46 (2H, brs), 4.26 (2H, t, J=4.8 Hz), 3.71 (2H, t, J=7.1 Hz), 3.64 (2H, s), 3.63-3.57 (2H, m), 3.61 (3H, s), 3.28 (3H, s), 3.05 (2H, s), 2.85-2.80 (2H, m), 2.10-2.01 (2H, m), 1.74-1.69 (2H, m), 1.64-1.57 (2H, m), 1.30-1.10 (3H, m).
Using 2-butoxy-9-(1-tert-butoxycarbonylpiperidin-4-ylmethyl)-8-methoxyadenine 0.19 g (0.44 mmol) and 2-chloro-N-{3-(methoxycarbonylmethyl)phenyl}acetamide 0.12 g (0.49 mmol), in the same manner as example 13 step (i) and then step (ii), there was obtained the titled compound as a white solid 64 mg. Yield 28%
1H NMR (DMSO-d6) δ 9.95 (1H, brs), 9.63 (1H, s), 7.55 (1H, d, J=8.8 Hz), 7.54 (1H, s), 7.24 (1H, dd, J=8.8 Hz, 7.6 Hz), 6.94 (1H, d, J=7.6 Hz), 6.44 (2H, brs), 4.14 (2H, t, J=6.6 Hz), 3.64 (2H, s), 3.61 (3H, s), 3.57 (2H, d, J=7.3 Hz), 3.05 (2H, s), 2.85-2.80 (2H, m), 2.10-2.04 (2H, m), 1.85-1.74 (1H, m), 1.68-1.60 (2H, m), 1.54-1.50 (2H, m), 1.40-1.33 (4H, m), 0.91 (3H, t, J=7.4 Hz).
To the compound 2.0 g (4.6 mmol) obtained by example 1 step (ii) was added trifluoroacetic acid 5 ml and the mixture was stirred at room temperature for 1 hour. After removal of trifluoroacetic acid by distillation, thereto was added aqueous sodium hydrogencarbonate and the mixture was extracted with chloroform-ethanol. The organic layer was dried over sodium sulfate, concentrated and dried in vacuo to give the titled compound 1.54 g (4.6 mmol) as a yellow white solid.
1H NMR (DMSO-d6) δ 6.81 (2H, brs), 4.16 (2H, t, J=6.6 Hz), 4.05 (3H, s), 3.73 (2H, d, J=7.1 Hz), 3.09 (2H, m), 2.68-2.59 (2H, m), 1.99-1.92 (1H, m), 1.68-1.66 (2H, m), 1.58-1.53 (2H, m), 1.44-1.35 (2H, m), 1.23-1.19 (2H, m), 0.92 (3H, t, J=7.4 Hz).
To 2-butoxy-8-methoxy-9-(piperidin-4-ylmethyl)adenine 500 mg (1.15 mmol) obtained in step (ii) in DMF (10 ml) were added triethylamine 236 μl (1.73 mmol) and then chloroacetyl chloride 110 μl (1.38 mmol), and the mixture was stirred at room temperature for 25 minutes. After quenching the reaction with water, the solvent was removed by distillation. To the residue was added water and the mixture was extracted with chloroform-methanol. The organic layer was washed with water and saturated brine, concentrated and dried in vacuo. After addition of DMF 5 ml to the obtained residue, thereto were added diisopropylethylamine 772 μl (4.49 mmol), and then N-{2-[3-(methoxycarbonyl)phenoxy]ethyl}-N-methylamine hydrochloride 385 mg (1.15 mmol), and the mixture was stirred at 60° C. for 3 hours. After adding water, the mixture was extracted with chloroform-methanol. The organic layer was washed with water, saturated brine, dried over sodium sulfate, concentrated, purified by gel column chromatography and dried in vacuo.
To the residue were added methanol 10 ml and concentrated sulfuric acid 500 μl, and the mixture was stirred at 80° C. for 90 minutes. After neutralized with aqueous ammonia, methanol is removal by distillation. After adding water, the mixture was extracted with chloroform-methanol. The organic layer was washed with water, saturated brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography and dried in vacuo to give the subtitled compound 160 mg (0.27 mmol) as a pale pink solid. Yield 37%
1H NMR (DMSO-d6) δ 9.86 (1H, brs), 7.20 (1H, t, J=7.6 Hz), 6.82-6.79 (3H, m), 6.42 (2H, brs), 4.28 (1H, d, J=12.9 Hz), 4.13 (2H, t, J=6.6 Hz), 4.05-3.78 (3H, m), 3.62 (2H, s), 3.59 (3H, s), 3.53 (2H, d, J=7.2 Hz), 3.29 (1H, d, J=13.7 Hz), 3.15 (1H, d, J=13.7 Hz), 2.88 (1H, t, J=12.9 Hz), 2.80-2.71 (2H, m), 2.81-2.45 (1H, m), 2.27 (3H, s), 2.03-1.96 (1H, s), 1.66-1.59 (2H, s), 1.56-1.49 (2H, s), 1.42-1.33 (2H, s), 1.21-1.11 (2H, s), 1.02-0.97 (2H, s), 0.90 (3H, t, J=7.4 Hz).
In the same manner as example 3 step (i) and example 15, there was obtained the subtitled compound as a white solid. Yield 19%
1H NMR (DMSO-d6) δ 9.89 (1H, brs), 7.21 (1H, t, J=7.6 Hz, 6.84-6.77 (3H, m), 6.44 (2H, brs), 4.00-4.23 (3H, m), 4.07-3.98 (3H, m), 3.64-3.60 (2H, m), 3.62 (2H, s), 3.59 (3H, s), 3.53 (2H, d, J=7.2 Hz), 3.32-3.30 (1H, m), 3.27 (3H, s), 3.16 (1H, d, J=13.6 Hz), 2.97-2.85 (2H, m), 2.80-2.72 (2H, m), 2.27 (3H, s), 2.06-1.98 (1H, m), 1.55-1.50 (2H, m), 1.22-1.10 (2H, m), 1.06-0.95 (3H, t, J=7.4 Hz).
In the same manner as example 15 step (i) there was obtained the subtitled compound as a yellowish white solid. Yield 99%
1H NMR (DMSO-d6) δ 6.83 (2H, brs), 4.27 (2H, dd, J=4.6, 4.6 Hz), 4.05 (3H, s), 3.72 (2H, d, J=6.0 Hz), 3.46-3.41 (1H, m), 3.29 (3H, s), 3.08-3.02 (2H, m), 2.61-2.54 (2H, m), 1.98-1.89 (1H, m), 1.55-1.49 (2H, m), 1.25-1.14 (2H, m),
To N-{2-[3-(methoxycarbonylmethyl)phenoxy]ethyl}-N-methylamine 300 mg (1.16 mmol) in DMF (10 ml) were added triethylamine 474 μl (3.46 mmol) and then chloroacetyl chloride 110 μl (1.39 mmol) and the mixture was stirred at room temperature for 2 hours. The solvent is removed by distillation and the residue was dried in vacuo to give the subtitled compound as orange liquid.
Step (iii)
To the compound obtained in step (i) in DMF 7 ml were added diisopropylethylamine 597 μl (3.47 mmol) and then the compound 300 mg (1.16 mmol) obtained in step (ii), and the mixture was heated at 60° C. for 3 hours. After removal of the solvent by distillation, to the residue were added methanol 10 ml and then concentrated sulfuric acid 300 μl and the mixture was stirred at 80° C. for 2 hours. After neutralized with aqueous ammonia, the solvent was removed by distillation. After adding water, the mixture was extracted with chloroform-methanol. The organic layer was dried over sodium sulfate. After concentration, the residue was purified by column chromatography and dried in vacuo to give the titled compound 240 mg (0.41 mmol) as a white solid.
1H NMR (DMSO-d6) δ 9.85 (1H, brs), 7.26-7.18 (1H, m), 6.85-6.81 (3H, m), 6.43 (2H, brs), 4.25 (2H, dd, J=3.7, 4.6 Hz), 4.18-4.13 (1H, m), 4.05-4.01 (1H, m), 3.82-3.79 (1H, m), 3.65-3.60 (5H, m), 3.59 (3H, s), 3.52 (2H, d, J=7.2 Hz), 3.28 (3H, s), 3.14-3.08 (2H, m), 2.80-2.71 (2H, m), 2.51 (3H, s), 1.96-1.87 (2H, s), 1.80-1.69 (1H, m), 1.52-1.42 (2H, m), 1.24-1.11 (2H, m).
In the same manner as example 15 step (i) there was obtained the subtitled compound as whitish yellow liquid.
1H NMR (DMSO-d6) δ 6.79 (2H, brs), 4.14 (2H, t, J=6.6 Hz), 4.05 (3H, s), 3.87 (2H, t, J=6.8 Hz), 3.22-3.15 (2H, m), 2.77-2.69 (2H, m), 1.90-1.84 (2H, m), 1.68-1.59 (4H, m), 1.45-1.35 (3H, m), 1.30-1.18 (2H, m), 0.92 (3H, t, J=7.4 Hz).
In the same manner as example 15 step (ii), there was obtained the subtitled compound as whitish yellow liquid.
1H NMR (DMSO-d6) δ 9.84 (1H, brs), 7.23-7.18 (1H, m), 6.89-6.79 (3H, m), 6.40 (2H, brs), 4.29 (1H, d, J=12.6 Hz), 4.13 (2H, t, J=6.6 Hz), 4.02 (2H, t, J=5.6 Hz), 4.02-3.98 (1H, m), 3.69 (2H, t, J=6.9 Hz), 3.61 (2H, s), 3.59 (3H, s), 3.32-3.29 (1H, m), 3.18-3.13 (1H, m), 2.89-2.81 (1H, m), 2.80-2.74 (2H, m), 2.47-2.40 (1H, m), 2.28 (3H, s), 1.77-1.70 (2H, m), 1.67-1.59 (2H, m), 1.58-1.52 (2H, m), 1.46-1.32 (3H, m), 1.15-1.00 (1H, m), 0.97-0.93 (1H, m), 0.90 (3H, t, J=7.4 Hz).
To the compound 0350 mg (1.05 mmol) obtained by example 15 step (i) in DMF 10 ml were added triethylamine 215 μl (1.57 mmol) and then chloroacetyl chloride 100 μl, and the mixture was stirred at room temperature for 1 hour. After removal the solvent by distillation, to the residue was added water, and the mixture was extracted with chloroform-methanol. The extracted organic layer was washed with water and saturated brine, and dried. The residue was dissolved in DMF 10 ml and thereto were added diisopropylethylamine 360 μl (2.09 mmol) and then N-[2-methoxy-5-(methoxylcarbonylmethyl)phenoxy]-N-methyl]amine) 398 μl (1.57 mmol). The mixture was stirred at 50° C. for 6 hours. After removal of the solvent by distillation, to the residue were added methanol 10 ml and then concentrated sulfuric acid 300 μl, and the mixture was stirred at 80° C. for 3 hours. After neutralized with aqueous ammonia, the solvent was removed by distillation. To the residue was added water and the mixture was extracted with chloroform-methanol. The organic layer was washed with water and saturated brine and dried. After concentration, the residue was purified by column chromatography. Thereto was added diethyl ether, the resulting white solid was filtered, and dried to give the titled compound 182 mg as a white solid. Yield 28%
1H NMR (DMSO-d6) δ 9.87 (1H, brs), 6.86-6.84 (2H, m), 6.75 (1H, d, J=8.2 Hz), 6.41 (2H, brs), 4.31-4.25 (1H, m), 4.13 (2H, t, J=6.6 Hz), 4.03-4.00 (1H, m), 4.01 (2H, t, J=5.7 Hz), 3.70 (3H, s), 3.59 (3H, s), 3.56 (2H, s), 3.56-3.52 (2H, m), 3.27-3.23 (2H, m), 2.91-2.86 (1H, m), 2.78-2.71 (2H, m), 2.49-2.42 (1H, m), 2.28 (3H, s), 2.09-1.98 (1H, m), 1.66-1.58 (2H, m), 1.57-1.46 (2H, m), 1.42-1.32 (2H, m), 1.18-0.95 (1H, m), 0.90 (3H, t, J=7.4 Hz).
To bromide 1.5 g (6.17 mmol) in acetonitrile (20 ml) was added methylaminoethanol (1 ml) and the mixture was refluxed for 3 hours. After concentration of the solvent, the residue was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to give the titled compound 0.98 g as a colorless oil, Yield 67%
1H NMR (CDCl3) δ 7.31-7.20 (4H, m), 3.69 (3H, s), 3.67 (2H, t, J=5.3 Hz), 3.64 (2H, s), 3.63 (2H, s), 2.67 (2H, t, J=5.3 Hz), 2.31 (3H, s).
To the compound 0.90 g (3.79 mmol) obtained in step (i) in chloroform was added thionyl chloride 2.26 g (18.9 mmol) and the mixture was refluxed for 30 minutes. The solvent was concentrated to give the titled compound 0.97 g as a colorless oil. Quantitatively
1H NMR (CDCl3) δ 7.33-7.20 (4H, m), 3.75-3.59 (9H, m), 2.83 (2H, brs), 2.35 (3H, brs).
Step (iii)
To the compound 0.97 g (3.79 mmol) obtained in step (ii) and potassium carbonate 1.05 g (7.59 mmol) in acetonitrile was added N-butoxycarbonylpiperazine, and the mixture was refluxed for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to give the titled compound 0.74 g as colorless oil. Yield 48%
1H NMR (CDCl3) δ 7.31-7.18 (4H, m), 3.69 (3H, s), 3.64 (2H, s), 3.62 (2H, brs), 3.43 (4H, t, J=4.9 Hz), 2.59 (4H, brs), 2.41 (2H, t, J=4.59 Hz), 2.11 (3H, s), 1.45 (9H, s).
The compound obtained in step (iii) in 4N-hydrochloric acid-dioxane was stirred at room temperature for 3 hours. The solvent was concentrated to give the titled compound 743 mg as a white solid. Yield 57%
1H NMR (DMSO-d6) δ 9.38 (1H, brs), 7.55 (H, d, J=7.5 Hz), 7.50 (1H, s), 7.44 (1H, t, J=7.5 Hz), 7.38 (1H, d, J=7.5 Hz), 4.90 (2H, brs), 4.35 (2H, brs), 3.74 (3H, s), 3.64 (3H, s), 3.33 (2H, brs), 3.26 (4H, brs), 2.98 (4H, brs), 2.69 (3H, s).
To 2-butoxy-8-methoxyadenine 2.00 g (8.43 mmol) in DMF (30 ml) were added potassium carbonate 1.40 g (10.1 mmol) and 1,5-dibromopentane 3.87 g (16.9 mmol), and the mixture was stirred at room temperature for 6 hours. After removal of the solvent by distillation, thereto was added water 80 ml and the mixture was extracted with 5% methanol-chloroform (100 ml). The organic layer was washed with water and saturated brine, successively, dried over sodium sulfate, concentrated in vacuo and purified by silica gel column chromatography to give the subtitled compound 1.69 g as a pale pink solid. Yield 52%
1H NMR (DMSO-d6) δ 6.78 (2H, bs), 4.16 (2H, t, J=6.6 Hz), 4.03 (3H, s), 3.84 (2H, t, J=6.8 Hz), 1.86-1.78 (2H, m), 1.74-1.60 (4H, m), 1.45-1.35 (2H, m), 1.35-1.28 (2H, m), 0.92 (3H, t, J=7.4 Hz).
To the compound 212 mg (0.62 mmol) obtained in step (iv) in DMF (10 ml) were added N-diisopropylethylamine 335 mg (2.59 mmol), compound 200 mg (0.52 mmol) obtained in step (v) and dimethylaminopyridine 64 mg (0.62 mmol), and the mixture was stirred at room temperature for 12 hours. After removal of the solvent by distillation, thereto was added water 80 ml and the mixture was extracted with 5% methanol-chloroform (100 ml). The organic layer was washed with water, and saturated brine, successively, dried over sodium sulfate, concentrated in vacuo and the residue was purified by silica gel column chromatography to give the subtitled compound 149 mg as colorless oil. Yield 47%
1H NMR (CDCl3) δ 7.32-7.16 (4H, m), 5.17 (2H, s), 4.27 (2H, t, J=6.6 Hz), 4.10 (3H, s), 3.92 (2H, t, J=7.2 Hz), 3.69 (3H, s), 3.62 (2H, s), s) 5.12 (2H, s), 2.55-2.50 (4H, m), 2.33 (2H, brs), 2.24 (3H, s), 1.81-1.73 (2H, m), 1.54-1.46 (4H, m), 1.33-1.28 (2H, m), 0.96 (3H, t, J=7.4 Hz).
Step (vii)
To the compound 148 mg (0.24 mmol) obtained in step (vi) in methanol (10 ml) was added concentrated sulfuric acid (500 μl) and the mixture was refluxed for 4 hours. After neutralized with 28% aqueous ammonia, the solvent was removed by distillation. To the residue was added water and the resulting solid was filtered to give the titled compound 119 mg as a white solid. Yield 82%
1H NMR (DMSO-d6) δ 9.84 (1H, s), 7.33-7.12 (4H, m), 6.40 (2H, s), 4.14 (2H, t, J=6.6 Hz), 3.66-3.63 (4H, m), 3.61 (3H, s), 3.45 (2H, s), 2.41-2.18 (14H, m), 2.13 (3H, s), 1.66-1.62 (4H, m), 1.43-1.36 (4H, m), 1.23-1.20 (2H, m), 0.92 (3H, t, J=7.4 Hz).
Using 2-butoxy-8-methoxyadenine 3.00 g (8.54 mmol) and 1,7-dibromoheptane 4.4 mg (17.1 mmol), in the same manner as example 20 step (v) there was obtained the titled compound 1.75 g as a white solid. Yield 49%
1H NMR (CDCl3) δ 5.30 (2H, bs), 4.28 (2H, t, J=6.7 Hz), 4.11 (3H, s), 3.92 (2H, t, J=7.2 Hz), 3.39 (2H, t, J=6.8 Hz), 1.85-1.73 (8H, m), 1.52-1.47 (2H, m), 1.45-1.32 (4H, m), 0.96 (3H, t, J=7.4 Hz).
Using the compound 266 mg (0.78 mmol) obtained by example 20 step (iv) and the compound 200 mg (0.52 mmol) obtained in step (i), in the same manner as example 20 step (vi), there was obtained the titled compound 195 mg as colorless oil. Yield 59%
1H NMR (CDCl3) δ 7.31-7.16 (4H, m), 5.15 (2H, s), 4.27 (2H, t, J=6.7 Hz), 4.11 (3H, s), 3.90 (2H, t, J=7.2 Hz), 3.69 (3H, s), 3.62 (2H, s), 3.51 (2H, s), 2.61-2.32 (6H, m), 2.24 (3H, s), 1.78-1.71 (12H, m), 1.52-1.46 (4H, m), 1.30-1.25 (6H, m), 0.96 (3H, t, J=7.4 Hz).
Step (iii)
Using the compound 195 mg (0.31 mmol) obtained in step (vi) in the same manner as example 20 step (vii), there was obtained the titled compound 138 mg as a white solid. Yield 73%
1H NMR (DMSO-d6) δ 9.84 (1H, s), 7.43-7.22 (4H, m), 6.41 (2H, s), 4.14 (2H, t, J=6.6 Hz), 3.69-3.62 (7H, m), 3.36-3.32 (4H, m), 2.92 (8H, bs), 2.42-2.11 (5H, m), 1.66-1.62 (4H, m), 1.42-1.36 (4H, m), 1.28-1.25 (6H, m), 0.94 (3H, t, J=7.4 Hz).
To N-Boc-piperazine 579 mg (3.1 mmol) and potassium carbonate 716 mg (5.18 mmol) in dimethylformamide 20 ml was added the compound 1.0 g (2.59 mmol) obtained by example 20 step (v) and the mixture was stirred under an atmosphere of nitrogen at room temperature for 48 hours. After removal of the solvent by distillation, thereto was added water 20 ml and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate and the solvent was removed by distillation. The residue was purified by silica gel column chromatography to give the titled compound 1.25 g as colorless oil. Yield 98%
1H NMR (CDCl3) δ 5.14 (2H, bs), 4.27 (2H, t, J=6.7 Hz), 4.11 (3H, s), 3.92 (2H, t, J=7.1 Hz), 3.46 (4H, bs), 2.38 (4H, bs), 1.80-1.73 (4H, m), 1.62-1.57 (2H, m), 1.52-1.48 (4H, m), 1.46 (9H, s), 1.33-1.29 (2H, m), 0.96 (3H, t, J=7.4 Hz).
The compound 200 mg (0.41 mmol) obtained in step (i) in trifluoroacetic acid 2 ml was stirred at room temperature for 30 minutes. After removal of the solvent by distillation, the residue was dried in vacuo for 2 hours. Thereto were added potassium carbonate 281 mg (2.1 mmol), dimethylformamide 7 ml and methyl [3-(2-bromoethoxy)phenyl]acetate 167 mg (0.611 mmol), and the mixture was stirred under an atmosphere of nitrogen at 60° C. After removal of the solvent by distillation, thereto was added water 20 ml, and the mixture was extracted with chloroform. The organic layer washed with saturated brine, dried over magnesium sulfate and the solvent was removed by distillation. The residue was purified by silica gel column chromatography to give the titled compound 165 mg as a colorless oil. Yield 69%
1H NMR (CDCl3) δ 7.22 (1H, t, J=7.9 Hz), 6.87-6.79 (3H, m), 5.16 (2H, s), 4.27 (2H, t, J=6.7 Hz), 4.11 (3H, s), 4.10 (2H, t, J=5.8 Hz), 3.92 (2H, t, J=7.1 Hz), 3.69 (3H, s), 3.59 (2H, s), 2.82 (2H, t, J=5.8 Hz), 2.65 (2H, bs), 2.52 (2H, bs), 2.36 (2H, bs), 1.79-1.73 (8H, m), 1.53-1.46 (4H, m), 1.33-1.29 (2H, m), 0.96 (3H, t, J=7.4 Hz).
Step (iii)
Using the compound 164 mg (0.28 mmol) obtained in step (ii), in the same manner as example 20 step (vii), there was obtained the titled compound 140 mg as a white solid. Yield 90%
1H NMR (DMSO-d6) δ 9.76 (1H, bs), 7.14 (1H, t, J=7.4 Hz), 6.76-6.73 (3H, m), 6.32 (2H, s), 4.07 (2H, t, J=6.6 Hz), 3.94 (2H, t, J=5.8 Hz), 3.58-3.55 (4H, m), 3.53 (3H, s), 2.57 (2H, t, J=5.8 Hz), 2.41 (4H, bs), 2.38 (4H, bs), 2.12 (2H, bs), 1.58-1.54 (4H, m), 1.34-1.30 (4H, m), 1.16-1.12 (2H, m), 0.96 (3H, t, J=7.4 Hz).
Using the compound 1.0 g (2.41 mmol) obtained by example 21 step (i), in the same manner as example 22 step (i), there was obtained the titled compound 1.16 g as a colorless oil. Yield 92%
1H NMR (CDCl3) δ 5.16 (2H, bs), 4.27 (2H, t, J=6.7 Hz), 4.11 (3H, s), 3.91 (2H, t, J=7.2 Hz), 3.45 (2H, bs), 2.39 (2H, bs), 2.33 (2H, bs), 1.78-1.68 (8H, m), 1.52-1.48 (4H, m), 1.46 (9H, s), 1.31-1.27 (6H, m), 0.96 (3H, t, J=7.4 Hz).
Using the compound 200 mg (0.39 mmol) obtained in step (i), in the same manner as example 22 step (ii), there was obtained the titled compound 123 mg as a colorless oil. Yield 52%
1H NMR (CDCl3) δ 7.23 (1H, t, J=7.8 Hz), 6.87-6.79 (3H, m), 5.16 (2H, s), 4.27 (2H, t, J=6.7 Hz), 4.11 (3H, s), 4.10 (2H, t, J=5.8 Hz), 3.91 (2H, t, J=7.2 Hz), 3.69 (3H, s), 3.64 (2H, s), 2.83 (2H, t, J=5.8 Hz), 2.72 (2H, bs), 2.57 (4H, bs), 2.38 (2H, bs), 1.78-1.72 (6H, m), 1.54-1.46 (4H, m), 1.35-1.25 (6H, m), 0.96 (3H, t, J=7.4 Hz).
Step (iii)
Using the compound 123 mg (0.20 mmol) obtained in step (ii), in the same manner as example 20 step (vii), there was obtained the titled compound 112 mg as a white solid. Yield 93%
1H NMR (DMSO-d6) δ 7.22 (1H, t, J=8.0 Hz), 6.86-6.79 (3H, m), 6.44 (2H, bs), 4.14 (2H, t, J=6.6 Hz), 4.03 (2H, t, J=5.8 Hz), 3.66 (2H, t, J=7.1 Hz), 3.64 (2H, s), 3.61 (3H, s), 2.67 (2H, bs), 2.34 (6H, bs), 2.22 (4H, bs), 1.66-1.62 (4H, m), 1.42-1.36 (4H, m), 1.28-1.24 (6H, m), 0.92 (3H, t, J=7.4 Hz).
Using 2-butoxy-8-methoxyadenine 500 mg (2.11 mmol), in the same manner as example 20 step (v), there was obtained the subtitled compound 573 mg as a white solid. Yield 79%
1H NMR (CDCl3) δ 5.31 (2H, brs), 4.32 (2H, t, J=7.0 Hz), 4.27 (2H, t, J=6.7 Hz), 4.12 (3H, s), 3.66 (2H, t, J=7.0 Hz), 1.79-1.72 (2H, m), 1.52-1.46 (2H, m), 0.95 (3H, t, J=7.4 Hz).
Using the compound 200 mg (0.58 mmol) obtained in step (i), in the same manner as example 20 step (vi), there was obtained the subtitled compound 150 mg as a colorless oil, Yield 50%
1H NMR (DMSO-d6) δ 7.19 (1H, dd, J=7.6, 7.6 Hz), 6.82 (1H, s), 6.79 (2H, d, J=7.6 Hz), 6.76 (2H, bs), 4.36-4.28 (1H, m), 4.15 (2H, t, J=6.6 Hz), 4.04 (2H, s), 3.94 (2H, t, J=6.4 Hz), 3.60 (3H, s), 2.77-2.68 (2H, m), 2.62 (2H, t, J=6.4 Hz), 2.31-2.22 (2H, m), 1.90-1.80 (2H, m), 1.67-1.60 (2H, m), 1.56-1.45 (2H, m), 1.43-1.33 (2H, m), 0.90 (3H, t, J=−7.4 Hz).
Step (iii)
Using the compound 150 mg (0.29 mmol) obtained in step (ii), in the same manner as example 20 step (vii), there was obtained the subtitled compound 95 mg as a white solid. Yield 65%
1H NMR (DMSO-d6) δ 9.83 (1H, bs), 7.19 (1H, dd, J=7.6, 7.6 Hz), 6.82 (1H, s), 6.79 (2H, d, J=7.6 Hz), 6.39 (2H, bs), 4.35-4.28 (1H, m), 4.13 (1H, t, J=6.6 Hz), 3.78 (1H, t, J=6.4 Hz), 3.62 (2H, s), 3.60 (3H, s), 2.78-2.72 (2H, m), 2.59 (2H, t, J=6.4 Hz), 2.31-2.25 (2H, m), 1.89-1.82 (2H, m), 1.67-1.59 (2H, m), 1.55-1.46 (2H, m), 1.42-1.32 (2H, m), 0.89 (3H, t, J=7.6 Hz).
3-Methoxycarbonylmethylaniline 100 mg (0.61 mmol) was dissolved in butanol 6 ml. To the solution was added bis(2-chloroethyl)amine hydrochloride 324 mg (1.82 mmol) and the mixture was stirred at 140° C. for 22 hours. After removal of the solvent by distillation, thereto was added aqueous saturated sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, F dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the subtitled compound 65 mg as a pink oil. Yield 46%
1H NMR (DMSO-d6) δ 8.43 (1H, bs), 7.18 (1H, dd, J=7.6 Hz), 6.87 (1H, s), 6.86 (1H, d, J=7.6, 7.6 Hz), 6.73 (1H, d, J=7.6 Hz), 4.02 (2H, t, J=6.6 Hz), 3.59 (2H, s), 3.30-3.25 (4H, m), 3.15-3.11 (4H, m), 1.57-1.49 (2H, m), 1.33-1.24 (2H, m), 0.86 (3H, t, J=7.4 Hz).
Using the compound 300 mg (0.87 mmol) obtained by example 25 step (i) and compound 289 mg (1.05 mmol) obtained in step (i), in the same manner as example 20 step (vi), there was obtained the subtitled compound 200 mg as a yellow oil. Yield 43%
1H NMR (DMSO-d6) δ 7.12 (H, t, J=7.6 Hz), 6.79 (1H, s), 6.79 (1H, d, J=7.6 Hz), 6.78 (2H, bs), 6.64 (1H, d, J=7.6 Hz), 4.16 (2H, t, J=6.6 Hz), 4.25 (3H, s), 4.01 (2H, t, J=6.6 Hz), 3.98 (2H, t, J=6.3 Hz), 3.55 (2H, s), 3.06-3.00 (4H, m), 2.65 (2H, t, J=6.3 Hz), 2.59-2.54 (4H, m), 1.69-1.61 (2H, m), 1.56-1.48 (2H, m), 1.44-1.33 (2H, m), 1.33-1.23 (2H, m), 0.92 (3H, t, J=7.4 Hz), 0.85 (3H, t, J=7.4 Hz).
Step (iii)
Using the compound 200 mg (0.37 mmol) obtained in step (ii), in the same manner as example 20 step (vii), there was obtained the subtitled compound 160 mg as a white solid. Yield 89%
1H NMR (DMSO-d6) δ 9.85 (1H, bs), 7.12 (1H, dd, J=7.6 Hz), 6.79 (1H, s), 6.78 (1H, d, J=7.6 Hz), 6.65 (1H, d, J=7.6 Hz), 6.41 (2H, bs), 4.14 (2H, t, J=6.6 Hz), 3.82 (2H, t, J=6.4 Hz), 3.59 (3H, s), 3.57 (2H, s), 3.06-3.01 (4H, m), 2.63 (2H, t, J=6.4 Hz), 2.59-2.54 (4H, m), 1.68-1.60 (2H, m), 1.44-1.33 (2H, m), 0.91 (3H, t, J=7.4 Hz).
Using the compound 300 mg (0.87 mmol) obtained by example 24 step (i), in the same manner as example 20 step (vi), there was obtained the subtitled compound 220 mg as a colorless oil. Yield 50%
1H NMR (DMSO-d6) δ 7.25 (1H, dd, J=7.6, 7.6 Hz), 7.16 (1H, s), 7.14 (1H, d, J=7.6 Hz), 7.12 (1H, d, J=7.6 Hz), 6.76 (2H, bs), 4.13 (2H, t, J=6.6 Hz), 4.02 (3H, s), 3.92 (2H, t, J=6.4 Hz), 3.65 (2H, s), 3.60 (3H, s), 3.38 (2H, s), 2.58 (2H, t, J=6.4 Hz), 2.48-2.37 (4H, m), 2.33-2.22 (4H, m), 1.67-1.58 (2H, m), 1.42-1.33 (2H, m), 0.90 (3H, t, J=7.4 Hz).
Using compound 215 mg (0.42 mmol) obtained in step (i), in the same manner as example 20 step (vii), there was obtained the subtitled compound 140 mg as a colorless oil. Yield 67%
1H NMR (DMSO-d6) δ 9.84 (1H, bs), 7.25 (1H, dd, J=7.6, 7.6 Hz), 7.16 (1H, s), 7.14 (1H, d, J=7.6 Hz), 7.12 (1H, d, J=7.6 Hz, 6.43 (2H, bs), 4.13 (2H, t, J=6.6 Hz), 4.02 (3H, s), 3.92 (2H, t, J=6.4 Hz), 3.65 (2H, s), 3.60 (3H, s), 3.38 (2H, s), 2.58 (2H, t, J=6.4 Hz), 2.48-2.37 (4H, m), 2.33-2.22 (4H, m), 1.67-1.58 (2H, m), 1.42-1.33 (2H, m), 0.90 (3H, t, J=7.4 Hz).
To 4-butoxycarbonyl-2-chloropyridine 1.87 g (10.9 mmol) in no butanol were added diisopropylethylamine 5.7 ml (32.7 mmol) and piperazine 9.38 g (109 mmol), and the mixture was heated at 110° C. for 5 hours. After removal of the solvent by distillation, thereto was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to give the subtitled compound 1.70 g as an orange oil. Yield 59%
1H NMR (CDCl3) δ 8.28 (1H, d, J=5.1 Hz), 7.22 (1H, s), 7.12 (1H, d, J=5.1 Hz), 3.59-3.54 (4H, m), 3.10-2.97 (4H, m), 1.79-1.71 (2H, m), 1.50-1.42 (2H, m), 0.98 (3H, t, J=7.4 Hz).
Using the compound 300 mg (0.87 mmol) obtained by example 24 step (i) and the compound 344 mg (1.31 mmol) obtained in step (i), in the same manner as example 20 step (vi), there was obtained the subtitled compound 215 mg as a yellow oil. Yield 45%
1H NMR (DMSO-d6) δ 8.26 (1H, s), 7.16 (1H, s), 7.02 (1H, d, J=5.1 Hz), 6.76 (2H, bs), 4.27 (2H, t, J=6.6 Hz), 4.16 (2H, t, J=6.6 Hz), 4.05 (3H, s), 3.99 (2H, t, J=6.3 Hz), 3.47-3.42 (4H, m), 2.66 (2H, t, J=6.3 Hz), 2.56-2.51 (4H, m), 1.72-1.61 (4H, m), 1.45-1.35 (4H, m), 0.92 (6H, t, J=7.4 Hz).
Step (iii)
Using the compound 200 mg (0.35 mmol) obtained in step (ii), in the same manner as example 20 step (vii), there was obtained the subtitled compound 154 mg as a white solid. Yield 86%
1H NMR (DMSO-d6) δ 9.84 (1H, bs), 8.26 (1H, d, J=5.1 Hz), 7.18 (1H, s), 7.03 (1H, d, J=5.1 Hz), 6.40 (2H, s), 4.15 (2H, t, J=6.6 Hz), 3.86 (3H, s), 3.83 (2H, t, J=6.4 Hz), 3.48-3.42 (4H, m), 2.64 (2H, t, J=6.4 Hz), 2.57-2.52 (4H, m), 1.68-1.60 (2H, m), 1.44-1.34 (2H, m), 0.91 (3H, t, J=7.4 Hz).
Using 2-butoxy-8-methoxyadenine 2.00 g (8.43 mmol), in the same manner as example 20 step (v), there was obtained the subtitled compound 0.75 g as a white solid. Yield 25%
1H NMR (CDCl3) δ 5.21 (2H, brs), 4.28 (2H, t, J=6.6 Hz), 4.12 (3H, s), 4.09 (2H, t, J=6.6 Hz), 3.38 (2H, t, J=6.6 Hz), 2.36-2.32 (2H, m), 1.79-1.73 (2H, m), 1.52-1.46 (2H, m), 0.96 (3H, t, J=7.4 Hz).
Using the compound 150 mg (0.42 mmol) obtained in step (i), in the same manner as example 20 step (vi), there was obtained the subtitled compound 98 mg as a white solid. Yield 44%
1H NMR (CDCl3) δ 7.21 (1H, t, J=6.8 Hz), 6.84-6.78 (3H, m), 5.14 (2H, brs), 4.29 (1H, m), 4.27 (2H, t, J=6.7 Hz), 4.11 (3H, s), 3.99 (2H, t, J=7.0 Hz), 3.69 (3H, s), 3.58 (2H, s), 2.72-2.64 (2H, m), 2.39 (2H, t, J=7.4 Hz), 2.28-2.20 (2H, m), 2.05-1.91 (4H, m), 1.80-1.72 (4H, m), 1.51-1.45 (2H, m), 0.96 (3H, t, J=7.4 Hz).
Step (iii)
Using the compound 98 mg (0.19 mmol) obtained in step (ii), in the same manner as example 20 step (vii), there was obtained the titled compound 72 mg as a white solid. Yield 76%
1H NMR (DMSO-d6) δ 9.84 (1H, brs), 7.20 (1H, t, J=6.8 Hz), 6.83-6.78 (3H, m), 6.39 (2H, brs), 4.31 (1H, m), 4.15 (2H, t, J=6.6 Hz), 3.73 (2H, t, J=6.9 Hz), 3.63 (2H, s), 3.60 (3H, s), 2.67-2.59 (2H, m), 2.31 (2H, t, J=6.8 Hz), 2.18-2.10 (2H, m), 1.89-1.77 (4H, m), 1.65-1.48 (4H, m), 1.41-1.34 (2H, m), 0.91 (3H, t, J=7.4 Hz).
Using 2-butoxy-8-methoxyadenine 300 mg (1.26 mmol), in the same as example 20 step (v), there was obtained the titled compound 378 mg as a white solid. Yield 81%
1H NMR (CDCl3) δ 5.18 (2H, brs), 4.27 (2H, t, J=6.6 Hz), 4.12 (3H, s), 3.97 (2H, t, J=6.7 Hz), 3.44 (2H, t, J=6.5 Hz), 1.94-1.85 (4H, m), 1.78-1.75 (2H, m), 1.52-1.47 (2H, m), 0.97 (3H, t, J=7.4 Hz).
Using 9-(4-bromobutyl)-2-butoxy-8-methoxyadenine 200 mg (0.54 mmol), in the same manner as example 20 step (vi), there was obtained the subtitled compound 150 mg as a pale yellow oil. Yield 52%
1H NMR (CDCl3) δ 7.22 (1H, t, J=7.8 Hz), 6.85-6.79 (3H, m), 5.12 (2H, brs), 4.32-4.26 (3H, m), 4.11 (3H, s), 3.95 (2H, t, J=7.1 Hz), 3.69 (3H, s), 3.59 (2H, s), 2.70 (2H, m), 2.37 (2H, m), 2.62 (2H, m), 1.97 (2H, m), 1.82-1.73 (6H, m), 1.54-1.44 (4H, m), 0.96 (3H, t, J=7.4 Hz).
Step (iii)
Using the compound 150 mg (0.28 mmol) obtained in step (ii), in the same manner as example 20 step (vii), there was obtained the titled compound 126 mg as a white solid. Yield 86%
1H NMR (DMSO-d6) δ 9.84 (1H, brs), 7.20 (1H, t, J=7.5 Hz), 6.83-6.80 (3H, m), 6.40 (2H, brs), 4.32 (1H, m), 4.14 (2H, t, J=6.6 Hz), 3.68 (2H, t, J=7.0 Hz), 3.63 (2H, s), 3.60 (3H, s), 2.64 (2H, m), 2.29 (2H, m), 2.15 (2H, m), 1.88 (2H, m), 1.68-1.55 (6H, m), 1.42-1.36 (4H, m), 0.91 (3H, t, J=7.4 Hz).
Using 1-(3-methoxycarbonylmethylbenzyl)piperazine hydrochloride 306 mg (1.08 mmol) and 9-(4-bromobutyl)-2-butoxy-8-methoxyadenine 200 mg (0.54 mmol), as the same manner as example 20 step (vi), there was obtained the subtitled compound 175 mg as a pale yellow oil. Yield 60%
1H NMR (CDCl3) δ 7.29 (4H, m), 5.12 (2H, s), 4.27 (2H, t, J=6.7 Hz), 4.10 (3H, s), 3.93 (2H, t, J=7.1 Hz), 3.69 (3H, s), 3.62 (2H, s), 3.48 (2H, s), 2.56-2.39 (8H, m), 2.34 (2H, t, 7.6 Hz), 1.79-1.72 (4H, m), 1.51-1.44 (4H, m), 0.96 (3H, t, J=7.4 Hz).
Using the compound 175 mg (0.35 mmol) obtained in step (i), in the same manner as example 20 step (vii), there was obtained the titled compound 153 mg as a white solid. Yield 90%
1H NMR (DMSO-d6) δ 9.84 (1H, s), 7.28 (1H, t, J=6.6 Hz), 7.17-7.12 (3H, m), 6.40 (2H, brs), 4.14 (2H, t, J=6.6 Hz), 3.68-3.65 (4H, m), 3.61 (3H, s), 3.41 (2H, s), 2.41-2.20 (10H, m), 1.68-1.60 (4H, m), 1.43-1.34 (4H, m), 0.91 (3H, t, J=7.4 Hz).
Using 4-(4-Methoxycarbonylbenzyl)piperadine hydrochloride 217 mg (0.81 mmol) and 9-(4-bromobutyl)-2-butoxy-8-methoxyadenine 200 mg (0.54 mmol), in the same manner as example 20 step (vi), there was obtained the subtitled compound 257 mg as a pale yellow oil. Yield 91%
1H NMR (CDCl3) δ 7.98 (2H, d, J=8.2 Hz), 7.22 (2H, d, J=8.2 Hz), 5.13 (2H, brs), 4.26 (2H, t, J=6.6 Hz), 4.13 (3H, s), 3.96 (2H, t, J=6.8 Hz), 3.92 (3H, s), 3.45 (2H, m), 2.95 (2H, m), 2.66 (2H, m), 2.52 (2H, m), 2.10 (2H, m), 1.77-170 (7H, m), 1.53-1.44 (2H, m), 0.97 (3H, t, J=7.4 Hz).
Using the compound 257 mg (0.49 mmol) obtained in step (i), in the same manner as example 20 step (vii), there was obtained the titled compound 214 mg as a white solid. Yield 85%
1H NMR (DMSO-d6) δ 9.83 (1H, s), 7.87 (2H, d, J=8.2 Hz), 7.30 (2H, d, J=8.2 Hz), 6.41 (2H, brs), 4.14 (2H, t, J=6.6 Hz), 3.83 (3H, s), 3.65 (2H, t, J=6.8 Hz), 2.75 (2H, m), 2.55 (2H, d, J=6.6 Hz), 2.22 (2H, m), 1.75 (2H, m), 1.66-1.60 (4H, m), 1.47 (2H, m), 1.41-1.35 (4H, m), 1.49 (2H, m), 0.91 (3H, t, J=7.4 Hz).
To 8-bromo-2-butoxyadenine 0.30 g (1.05 mmol) in DMF 30 ml were added potassium carbonate 0.19 g (1.40 mmol) and 4-(methanesulufonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester 0.92 g (3.15 mmol) obtained by example 1 step (i), and the mixture was stirred at 120° C. for 5 hours. After removal of the solvent by distillation, the residue was extracted with chloroform. The organic layer was concentrated and purified by silica gel column chromatography to give the subtitled compound 0.37 g as a pale yellow solid. Yield 74%
1H NMR (CDCl3) δ 5.95 (2H, brs), 4.30 (2H, t, J=6.6 Hz), 4.11 (2H, m), 4.00 (2H, d, J=7.4 Hz), 2.66 (2H, m), 2.12 (1H, m), 1.78 (2H, m), 1.54 (4H, m), 1.46 (9H, s), 1.29 (2H, m), 0.97 (3H, t, J=7.3 Hz).
To 8-bromo-2-butoxy-9-(1 tert butoxycarbonylpiperidin-4-ylmethyl)adenine 0.15 g (0.30 mmol) obtained in step (i) was added 4N hydrochloric acid-dioxane 5 ml and the mixture was stirred for 30 minutes. After removal of the solvent by distillation, thereto were added potassium carbonate 68 mg (0.49 mmol) and 2-ethoxycarbonyl-5-bromomethylfuran 0.14 g (0.74 mmol) in DMF 6 ml and the mixture was stirred at room temperature for 2 hours. After removal of the solvent in vacuo, the residue was extracted with chloroform. The extract was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography to give the subtitled compound 0.11 g as a colorless liquid. Yield 67%
1H NMR (DMSO-d6) δ 7.35 (2H, brs), 7.21 (1H, d, J=3.4 Hz), 6.48 (1H, d, J=3.4 Hz), 4.26 (2H, q, J=7.1 Hz), 4.20 (2H, t, J=6.6 Hz), 3.92 (2H, d, J=7.3 Hz), 3.53 (2H, s), 2.80 (2H, m), 1.93 (2H, m), 1.83 (1H, m), 1.67 (2H, m), 1.48 (2H, m), 1.39 (2H, m), 1.30 (2H, m), 1.28 (3H, t, J=7.1 Hz), 0.91 (3H, t, J=7.3 Hz).
Step (iii)
2-Butoxy-8-chloro-9-[1-(5-ethoxycarbonylfuran-2-ylmethyl)piperidin-4-ylmethyl]adenine 0.11 g obtained in step (ii) was suspended in methanol 10 ml and thereto was added 5M aqueous sodium hydroxide 10 ml, followed by stirring under reflux for 7 hours. After neutralized with concentrated hydrochloric acid, the solvent was evaporated to dryness. Thereto were added methanol 20 ml and concentrated sulfuric acid 0.5 ml, and the mixture was stirred under reflux for 4 hours. After being cooled to 0° C., the mixture was neutralized with aqueous saturated sodium bicarbonate. The resulting solid was filtered and washed with water to give the titled compound 0.72 g as a white solid. Yield 77%
1H NMR (DMSO-d6) δ 9.86 (1H, s), 7.23 (1H, d, J=3.4 Hz), 6.48 (1H, d, J=3.4 Hz), 6.41 (2H, brs), 4.13 (2H, t, J=6.6 Hz), 3.78 (3H, s), 3.53 (2H, d, J=7.3 Hz), 3.52 (2H, s), 2.77 (2H, m), 1.91 (2H, m), 1.76 (1H, m), 1.63 (2H, m), 1.50 (2H, m), 1.39 (2H, m), 1.23 (2H, m), 0.90 (3H, t, J=7.3 Hz).
To 2-butoxy-8-methoxyadenine 2.00 g (8.43 mmol) in DMF (30 ml) were added potassium carbonate 1.40 g (10.1 mmol) and 1,5-dibromopentane 3.87 g (16.9 mmol), and the mixture was stirred at room temperature for 6 hours. After removal of the solvent by distillation, thereto was added water 80 ml and the mixture was extracted with 5% methanol-chloroform (100 ml). The organic layer was washed with water and saturated brine, successively and dried over sodium sulfate, followed by concentration in vacuo. The residue was purified by silica gel column chromatography to give the subtitled compound 1.69 g as a pale pink solid. Yield 52%
1H NMR (DMSO-d6) δ 6.78 (2H, bs), 4.16 (2H, t, J=6.6 Hz), 4.03 (3H, s), 3.84 (2H, t, J=6.8 Hz), 1.86-1.78 (2H, m), 1.74-1.60 (4H, m), 1.45-1.35 (2H, m), 1.35-1.28 (2H, m), 0.92 (3H, t, J=7.4 Hz).
Using the compound 200 mg (0.52 mmol) obtained in step (i) and 1-[3-(butoxycarbonylmethyl)phenyl]piperazine) 215 mg (0.78 mmol), in the same manner as example 20 step (vi), there was obtained the subtitled compound 215 mg as a yellow oil, Yield 71%
1H NMR (DMSO-d6) δ 7.13 (1H, t, J=7.6 Hz), 6.80 (1H, s), 6.79 (1H, d, J=7.6 Hz), 6.78 (2H, bs), 6.65 (1H, d, J=7.6 Hz), 4.16 (1H, d, J=6.6 Hz), 4.05 (3H, s), 4.01 (2H, t, J=6.6 Hz), 3.85 (2H, t, J=6.8 Hz), 3.57 (2H, s), 3.09-3.02 (4H, m), 2.46-2.40 (4H, m), 2.28-2.20 (2H, t, J=72 Hz), 1.76-1.67 (2H, m), 1.67-1.60 (2H, m), 1.56-1.49 (2H, m), 1.50-1.41 (2H, m), 1.42-1.33 (2H, m), 1.33-1.22 (2H, m), 1.25-1.91 (2H, m), 0.91 (3H, t, J=7.4 Hz), 0.85 (3H, t, J=7.4 Hz).
Using the compound 210 mg (0.36 mmol) obtained in step (i), in the same manner as example 20 step (vii), there was obtained the subtitled compound 180 mg as a yellow oil. Yield 95%
1H NMR (DMSO-d6) δ 9.85 (1H, bs), 7.13 (1H, dd, J=7.6 Hz), 6.81 (1H, s), 6.79 (1H, d, J=7.6 Hz), 6.65 (1H, t, J=7.6 Hz), 6.41 (2H, bs), 4.14 (2H, t, J=6.6 Hz), 3.66 (2H, t, J=6.8 Hz), 3.60 (3H, s), 3.58 (2H, s), 3.09-3.04 (4H, m), 2.47-2.41 (4H, m), 2.26 (2H, t, J=7.3 Hz), 1.71-1.59 (4H, m), 1.52-1.42 (2H, m), 1.42-1.32 (2H, m), 1.30-1.20 (2H, m), 0.91 (3H, t, J=7.4 Hz).
In the same manner as example 26, there was obtained the titled compound as a white solid.
1H NMR (DMSO-d6) δ 9.84 (1H, brs), 7.25 (1H, dd, J=7.6, 7.6 Hz), 7.16 (1H, s), 7.14 (1H, d, J=7.6 Hz), 7.12 (1H, d, J=7.6 Hz), 6.43 (2H, brs), 4.24 (2H, t, J=6.6 Hz), 3.76 (2H, t, J=6.4 Hz), 3.65 (2H, s), 3.60 (3H, s), 3.59-3.57 (2H, m), 3.39 (2H, s), 3.27 (3H, s), 2.59-2.54 (2H, m), 2.49-2.37 (4H, m), 2.33-2.22 (4H, m).
To the compound 53.6 mg (0.0097 mmol) obtained by example 1 was added 2N aqueous sodium hydroxide (5 ml) and the mixture was refluxed for 1.5 hours. After neutralized with 1N hydrochloric acid, the resulting solid was filtered to give the titled compound 32 mg as a white solid. Yield 61%
1H NMR (DMSO-d6) δ 10.96 (1H, bs), 7.21-7.04 (4H, m), 6.90 (2H, brs), 4.13 (2H, t, J=6.6 Hz), 3.53 (2H, s), 3.51 (2H, s), 3.50-3.30 (2H, m), 3.37 (3H, s), 2.79-2.75 (2H, m), 2.29 (2H, t, J=7.0 Hz), 2.22 (2H, t, J=7.1 Hz), 2.07 (3H, s), 1.76-1.34 (10H, m), 1.20-1.04 (2H, m), 0.91 (3H, t, J=7.3 Hz).
To the compound 76.7 mg (0.150 mmol) obtained by example 6 was added 2N aqueous sodium hydroxide (5 ml) and the mixture was refluxed for 2 hours. After neutralized with 1N hydrochloric acid, the resulting solid was filtered to give the titled compound 57.4 mg as a white solid. Yield 77%
1H NMR (DMSO-d6) δ 9.96 (1H, bs), 7.22 (1H, t, J=7.8 Hz), 6.85-6.82 (3H, m), 6.47 (2H, bs), 4.18-4.04 (2H, m), 4.14 (2H, t, J=6.6 Hz), 3.57 (2H, d, J=6.8 Hz), 3.53 (2H, s), 3.40-3.22 (7H, m), 1.96-1.80 (1H, m), 1.68-1.54 (4H, m), 1.40-1.24 (4H, m), 0.92 (3H, t, J=7.4 Hz).
To the compound 31.4 mg (0.0538 mmol) obtained by example 7 was added 2N aqueous sodium hydroxide (4 ml) and the mixture was refluxed for an hour. After neutralized with 1N hydrochloric acid, the solvent was removed by distillation. After adding a small amount of water, the resulting suspension was centrifuged to give the titled compound 34.4 mg as a white solid. Yield 100%
1H NMR (DMSO-d6) δ 11.35 (1H, brs), 7.15-7.07 (1H, m), 6.92-6.60 (5H, m), 4.13 (2H, t, J=6.5 Hz), 3.97 (2H, t, J=5.7 Hz), 3.53 (2H, d, J=6.6 Hz), 3.52-3.21 (5H, m), 2.80-2.76 (2H, m), 2.66 (2H, t, J=5.7 Hz), 2.36 (2H, t, J=7.2 Hz), 2.28-2.13 (1H, m), 2.20 (3H, s), 1.86-1.34 (9H, m), 1.23-1.08 (2H, m), 0.91 (3H, t, J=7.3 Hz).
Using the compound 88 mg (0.17 mmol) obtained by example 8, in the same manner as example 35, there was obtained the titled compound 66 mg as a white solid. Yield 77%
1H NMR (DMSO-d6) δ 11.79 (1H, brs), 7.09 (1H, dd, J=7.9 Hz, 7.4 Hz), 7.00 (2H, brs), 6.84 (1H, s), 6.75 (1H, d, J=7.4 Hz), 6.66 (1H, d, J=7.9 Hz), 4.24 (2H, t, J=4.6 Hz), 3.98 (2H, t, J=5.6 Hz), 3.68 (2H, t, J=6.5 Hz), 3.59 (2H, t, J=4.6 Hz), 3.27 (3H, s), 3.21 (2H, s), 2.87-2.83 (2H, m), 2.62 (2H, t, J=5.5 Hz), 1.96-1.88 (2H, m), 1.70-1.65 (2H, m), 1.56-1.53 (2H, m), 1.14-1.09 (3H, m).
Using compound 0.17 g (0.31 mmol) obtained by example 1, in the same manner as example 35, there was obtained the titled compound 0.15 g as a white solid. Yield 86%
1H NMR (DMSO-d6) δ 10.05 (1H, s), 7.20 (1H, dd, J=7.9 Hz, 7.7 Hz), 6.82-6.79 (3H, m), 6.50 (2H, brs), 4.14 (2H, t, J=6.6 Hz), 4.04 (2H, t, J=5.8 Hz), 3.69 (2H, t, J=6.8 Hz), 3.51 (2H, s), 2.94-2.90 (2H, m), 2.70-2.66 (2H, m), 2.10-1.98 (2H, m), 1.75-1.55 (6H, m), 1.42-1.32 (2H, m), 1.18-1.13 (3H, m), 0.91 (3H, t, J=7.4 Hz).
Using the compound 83 mg (0.14 mmol) obtained by example 12, in the same manner as example 35, there was obtained the titled compound 43 mg as a white solid, Yield 53%
1H NMR (DMSO-d) δ 10.17 (1H, brs), 7.21 (1H, dd, J=8.0 Hz, 7.6 Hz), 6.85-6.79 (3H, m), 6.57 (2H, brs), 4.13 (2H, t, J=6.6 Hz), 4.06 (2H, t, J=5.8 Hz), 3.70 (2H, t, J=6.7 Hz), 3.51 (2H, s), 3.27-3.23 (2H, m), 2.85-2.80 (2H, m), 2.78 (2H, t, J=5.6 Hz), 2.60-2.50 (4H, m), 2.30 (3H, s), 1.90-1.86 (2H, m), 1.79-1.73 (2H, m), 1.66-1.57 (4H, m), 1.42-1.33 (5H, m), 0.91 (3H, t, J=7.4 Hz).
Using the compound 61 mg (0.11 mmol) obtained by example 13, in the same manner as example 35, there was obtained the titled compound 25 mg as a white solid. Yield 43%
1H NMR (DMSO-d6) δ 12.42 (1H, brs), 9.90 (1H, brs), 9.65 (1H, s), 7.54-7.52 (2H, m), 7.23 (1H, dd, J=8.6 Hz, 7.6 Hz), 6.94 (1H, d, J=7.6 Hz), 6.45 (2H, brs), 4.26 (2H, t, J=4.7 Hz), 3.71 (2H, t, J=6.9 Hz), 3.61-3.57 (2H, m), 3.52 (2H, s), 3.28 (3H, s), 3.08 (2H, brs), 2.86-2.82 (2H, m), 2.12-2.06 (2H, m), 1.75-1.70 (2H, m), 1.63-1.57 (2H, m), 1.30-1.10 (3H, m).
Using compound 26 mg (0.050 mmol) obtained by example 14, in the same manner as example 35, there was obtained the titled compound 19 mg as a white solid. Yield 73%
1H NMR (DMSO-d6) δ 10.33 (1H, brs), 9.61 (1H, s), 7.52 (1H, d, J=8.3 Hz), 7.49 (1H, s), 7.21 (1H, dd, J=8.3 Hz, 7.6 Hz), 6.93 (1H, d, J=7.6 Hz), 6.56 (2H, brs), 4.14 (2H, t, J=6.6 Hz), 3.57 (2H, d, J=7.1 Hz), 3.46 (2H, s), 3.05 (2H, s), 2.85-2.80 (2H, m), 2.10-2.04 (2H, m), 1.85-1.74 (1H, m), 1.66-1.58 (2H, m), 1.54-1.50 (2H, m), 1.41-1.33 (4H, m), 0.91 (3H, t, J=7.4 Hz).
To the compound 100 mg (0.17 mmol) obtained by example 15 was added 1N aqueous sodium hydroxide (3 ml) and the mixture was refluxed for 1.5 hours. After neutralized with concentrated hydrochloric acid, the resulting solid was filtered to give the titled compound 80 mg as a white solid. Yield 82%
1H NMR (DMSO-d6) δ 10.06 (1H, brs), 9.68 (1H, brs), 7.24 (1H, t, J=7.6 Hz), 6.87-6.83 (3H, m), 6.51 (2H, brs), 4.25-4.21 (3H, m), 4.13 (2H, t, J=6.6 Hz), 3.78-3.65 (1H, m), 3.56 (2H, d, J=7.2 Hz), 3.54 (2H, s), 2.96 (1H, t, J=12.9 Hz), 2.78-2.65 (2H, m), 2.62-2.55 (1H, m), 2.50 (3H, s), 2.10-2.02 (1H, m), 1.67-1.56 (4H, m), 1.43-1.33 (2H, m), 1.25-1.12 (1H, m), 1.12-0.97 (1H, m), 0.91 (3H, t, J=7.4 Hz).
In the same manner as example 35, there was obtained the titled compound as a white solid. Yield 61%
1H NMR (DMSO-d6) δ 9.94 (1H, brs), 9.66 (1H, brs), 7.29-7.23 (1H, m), 6.90-6.83 (3H, m), 6.43 (2H, brs), 4.48-4.41 (2H, m), 4.41-4.28 (4H, m), 4.28-4.22 (2H, m), 3.61-3.52 (3H, m), 3.29 (3H, s), 3.06-2.95 (1H, m), 2.95-2.87 (3H, m), 2.69-2.52 (2H, m), 2.50 (3H, s), 2.13-2.04 (1H, m), 1.65-1.59 (2H, m), 1.26-1.16 (1H, m), 1.11-1.00 (1H, m).
In the same manner as example 35, there was obtained the titled compound as a white solid. Yield 40%
In the same manner as example 35, there was obtained the titled compound as whitish yellow liquid.
1H NMR (DMSO-d6) δ 12.27 (1H, brs), 9.86 (1H, brs), 7.20 (1H, t, J=7.6 Hz), 6.82-6.79 (3H, m), 6.41 (2H, brs), 4.30 (1H, d, J=12.4 Hz), 4.13 (2H, t, J=6.6 Hz), 4.09-4.03 (2H, m), 3.96 (1H, d, J=10.5 Hz), 3.69 (2H, t, J=6.7 Hz), 3.51 (2H, s), 3.40-3.25 (2H, m), 2.90-2.82 (3H, m), 2.49-2.41 (1H, m), 2.28 (3H, m), 1.78-1.71 (2H, m), 1.67-1.59 (2H, m), 1.58-1.53 (2H, m), 1.45-1.33 (3H, m), 1.13-1.03 (1H, m), 0.96-0.94 (1H, m), 0.91 (3H, t, J=7.4 Hz).
To the compound 55 mg (0.13 mmol) obtained by example 20 was added 1N aqueous sodium hydroxide (4 ml) and the mixture was refluxed for 1.5 hours. After neutralized with hydrochloric acid, the solvent was removed by distillation. To the residue was added water and the resulting solid was filtered to give the titled compound 30 mg as a white solid. Yield 55%
1H NMR (DMSO-d6) δ 9.32 (1H, bs), 7.24-7.06 (4H, m), 6.86 (2H, bs), 4.13 (2H, t, J=6.6 Hz), 3.66 (2H, t, J=6.4 Hz), 3.43 (4H, s), 2.34-2.13 (17H, m), 1.68-1.62 (4H, m), 1.40-1.36 (4H, m), 1.22-1.18 (2H, m), 0.92 (3H, t, J=7.4 Hz).
Using the compound 72 mg (0.12 mmol) obtained by example 21 step (iii), in the same manner as example 35, there was obtained the titled compound 26 mg as a white solid. Yield 37%
1H NMR (DMSO-dc,) δ 10.83 (1H, bs), 7.14-7.03 (4H, m), 6.69 (2H, bs), 4.07 (2H, t, J=6.6 Hz), 3.58 (2H, t, J=6.6 Hz), 3.37 (4H, s), 2.34-2.23 (12H, m), 2.15-2.09 (5H, m), 1.59-1.55 (4H, m), 1.33-1.14 (10H, m), 0.85 (3H, t, J=7.4 Hz).
Using the compound 50 mg (0.09 mmol) obtained in example 22, in the same manner as example 35, there was obtained the titled compound 35 mg as a white solid. Yield 72%
1H NMR (DMSO-d6) δ 12.09 (1H, bs), 7.12 (1H, t, J=7.8 Hz), 7.07 (2H, bs), 6.97 (1H, s), 6.75 (1H, d, J=7.8 Hz), 6.69 (1H, d, J=7.8 Hz), 4.13 (2H, t, J=6.6 Hz), 4.05 (2H, t, J=5.8 Hz), 3.67 (2H, t, J=7.1 Hz), 3.17 (2H, s), 2.65 (2H, t, J=5.8 Hz), 2.39 (4H, bs), 2.20 (4H, bs), 2.17 (2H, t, J=6.5 Hz), 1.70-1.61 (4H, m), 1.41-1.36 (4H, m), 1.21-1.18 (2H, m), 0.92 (3H, t, J=7.4 Hz).
Using the compound 50 mg (0.08 mmol) obtained by example 23, in the same manner as example 35, there was obtained the titled compound 38 mg as a white solid. Yield 78%
1H NMR (DMSO-d6) δ 11.66 (1H, bs), 7.13 (1H, t, J=7.8 Hz), 7.07 (2H, bs), 6.87 (1H, s), 6.77 (1H, d, J=7.8 Hz), 6.71 (1H, d, J=7.8 Hz), 4.13 (2H, t, J=6.6 Hz), 4.03 (2H, t, J=5.5 Hz), 3.64 (2H, t, J=7.1 Hz), 3.17 (2H, s), 2.70 (2H, t, J=5.5 Hz), 2.47 (4H, bs), 2.28 (4H, bs), 2.16 (2H, t, J=6.9 Hz), 1.65-1.63 (4H, m), 1.40-1.22 (10H, m), 0.92 (3H, t, J=7.4 Hz).
Using the compound 30 mg (0.06 mmol) obtained in example 24, in the same manner as example 35, there was obtained the subtitled compound 15 mg as a white solid. Yield 51%
1H NMR (DMSO-d6) δ 12.30 (1H, bs), 9.84 (1H, bs), 7.19 (1H, dd, J=7.6, 7.6 Hz), 6.82 (1H, s), 6.79 (2H, d, J=7.6 Hz), 6.41 (2H, bs), 4.35-4.26 (1H, m), 4.13 (1H, t, J=6.6 Hz), 3.78 (1H, t, J=6.4 Hz), 3.51 (2H, s), 2.78-2.72 (2H, m), 2.59 (2H, t, J=6.4 Hz), 2.31-2.25 (2H, m), 1.89-1.82 (2H, m), 1.67-1.59 (2H, m), 1.55-1.46 (2H, m), 1.42-1.32 (2H, m), 0.90 (3H, t, J=7.6 Hz).
Using compound 80 mg (0.17 mmol) obtained by example 25, in the same manner as example 35, there was obtained the titled compound 50 mg as a white solid. Yield 64%
1H NMR (DMSO-d6) δ 12.42 (1H, bs), 10.40 (1H, bs), 7.09 (1H, dd, J=7.6, 7.6 Hz), 6.79 (1H, s), 6.74 (1H, d, J=7.6 Hz), 6.65 (1H, d, J=7.6 Hz), 6.57 (2H, bs), 4.14 (2H, t, J=6.6 Hz), 3.82 (2H, t, J=6.4 Hz), 3.39 (2H, s), 3.06-3.00 (4H, m), 2.62 (2H, t, J=6.4 Hz), 2.58-2.55 (4H, m), 1.68-1.60 (2H, m), 1.44-1.33 (2H, m), 0.91 (3H, t, J=7.4 Hz).
Using the compound 30 mg (0.06 mmol) obtained by example 26, in the same manner as example 35, there was obtained the titled compound 26 mg as a colorless oil. Yield 89%
1H NMR (DMSO-d6) δ 11.22 (1H, bs), 7.14 (1H, s), 7.13 (1H, dd, J=7.6 Hz, 7.6 Hz), 7.07 (1H, d, J=7.6 Hz), 7.00 (1H, d, J=7.6 Hz, 6.90 (2H, bs), 4.10 (2H, t, J=6.6 Hz), 3.73 (2H, t, J=6.4 Hz), 3.34 (2H, s), 3.24 (2H, s), 2.52 (2H, t, J=6.4 Hz), 2.47-2.33 (4H, m), 2.33-2.23 (4H, m), 1.65-1.56 (2H, m), 1.41-1.31 (2H, m), 0.89 (3H, t, J=7.4 Hz).
Using the compound 50 mg (0.10 mmol) obtained by example 27, in the example manner as 35, there was obtained the titled compound 49 mg as a yellow oil. Yield 99%
1H NMR (DMSO-d6) δ 13.40 (1H, bs), 9.93 (1H, bs), 8.22 (1H, d, J=5.1 Hz), 7.17 (1H, s), 7.02 (1H, d, J=5.1 Hz), 6.43 (2H, bs), 4.05 (2H, t, J=6.6 Hz), 3.83 (2H, t, J=6.4 Hz), 3.47-3.42 (4H, m), 2.64 (2H, t, J=6.4 Hz), 2.58-2.51 (4H, m), 1.68-1.60 (2H, m), 1.44-1.34 (2H, m), 0.91 (3H, t, J=7.4 Hz).
Using the compound 37 mg (0.072 mmol) obtained by example 28, in the same manner as example 35, there was obtained the titled compound 23 mg as a white solid, Yield 64%
1H NMR (DMSO-d6) δ 7.12 (1H, t, J=7.8 Hz), 6.83-6.71 (3H, m), 6.69 (2H, brs), 4.28 (1H, m), 4.15 (2H, t, J=6.6 Hz), 3.70 (2H, t, J=6.9 Hz), 3.34 (2H, s), 2.68-2.58 (2H, m), 2.30 (2H, t, J=6.8 Hz), 2.16-2.08 (2H, m), 1.86-1.76 (4H, m), 1.65-1.48 (4H, m), 1.41-1.34 (2H, m), 0.90 (3H, t, J=7.4 Hz).
Using the compound 50 mg (0.10 mmol) obtained by example 29, in the same manner as example 351 there was obtained the titled compound 13 mg as a white solid. Yield 27%
1H NMR (DMSO-d6) δ 11.81 (1H, brs), 7.08 (1H, t, J=7.8 Hz), 6.98 (2H, brs), 6.88 (1H, s), 6.75-6.66 (2H, m), 4.25 (1H, m), 4.13 (2H, t, J=6.6 Hz), 3.66 (2H, t, J=6.7 Hz), 3.23 (2H, s), 2.56 (2H, m), 2.25 (2H, m), 2.09 (2H, m), 1.81 (2H, m), 1.67-1.53 (6H, m), 1.41-1.36 (4H, m) 0.92 (3H, t, J=7.4 Hz).
Using the compound 50 mg (0.10 mmol) obtained by example 30, in the same manner as example 35, there was obtained the titled compound 31 mg as a white solid. Yield 64%
1H NMR (DMSO-d6) δ 9.87 (1H, s), 7.25 (1H, t, J=7.5 Hz), 7.16-7.12 (3H, m), 6.41 (2H, brs), 4.14 (2H, t, J=6.6 Hz), 3.66 (2H, t, J=6.7 Hz), 3.54 (2H, s), 3.41 (2H, s), 2.33-2.26 (10H, m), 1.67-1.60 (4H, m), 1.41-1.34 (4H, m), 0.92 (3H, t, J=7.4 Hz).
Using the compound 50 mg (0.10 mmol) obtained by example 31, in the same manner as example 35 there was obtained the titled compound 32 mg as a white solid. Yield 65%
1H NMR (DMSO-d6) δ 11.69 (1H, brs), 7.78 (2H, d, J=8.1 Hz), 7.05 (2H, d, J=8.1 Hz), 7.01 (2H, brs), 4.14 (2H, t, J=6.6 Hz), 3.66 (2H, t, J=6.7 Hz), 2.74 (2H, m), 2.46 (2H, d, J=6.5 Hz), 2.21 (2H, m), 1.72 (2H, m), 1.65-1.62 (4H, m), 1.46 (2H, m), 1.41-1.35 (5H, m), 1.15 (2H, m), 0.92 (3H, t, J=7.4 Hz).
Using the compound 45 mg (0.09 mmol) obtained by example 33, in the same manner as example 35, there was obtained the titled compound 41 mg as a yellow oil. Yield 94%
1H NMR (DMSO-d6) δ 12.29 (1H, bs), 10.25 (1H, bs), 7.19 (1H, dd, J=7.6, 7.6 Hz), 6.89 (1H, s), 6.88 (1H, d, J=7.6 Hz), 6.76 (1H, d, J=7.6 Hz), 6.67 (2H, bs), 4.14 (2H, t, J=6.6 Hz), 3.80-3.73 (2H, m), 3.69 (2H, t, J=6.7 Hz), 3.57-3.50 (2H, m), 3.50 (2H, s), 3.14-3.00 (6H, m), 1.79-1.59 (6H, m), 1.44-1.33 (2H, m), 1.33-1.24 (2H, m), 0.91 (3H, t, J=7.4 Hz).
2,6-Dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine) (55 g) was dissolved in 7N-aqueous ammonia-methanol (500 ml) and the solution was heated at 100° C. for 6 hours in a sealed flask. The reaction mixture was cooled to room temperature and left overnight. The mixture was filtered to give the titled compound. Yield 40 g
1H NMR™ (CDCl3) 8.02 (1H, s), 5.94 (2H, brs), 5.71 (1H, dd), 4.15-4.22 (1H, m), 3.75-3.82 (1H, m), 1.27-2.12 (6H, m).
The compound (40 g) obtained in step (i) was dissolved in 19% (W/W) sodium n-butoxide/butanol (250 ml). The reaction mixture was stirred under reflux for 6 hours. The obtained suspension was cooled to room temperature, diluted with water and the mixture was extracted with diethyl ether. The combined organic layer was washed with water, dried over and concentrated in vacuo. The residue was crystallized from diethyl ether/isohexane and filtered to give the titled compound. Yield 19 g
1H NMR™ (CDCl3) 7.87 (1H, s), 5.56-5.68 (3H, m), 4.31-4.35 (2H, t), 4.14-4.17 (1H, m), 3.76-3.80 (1H, m), 1.49-2.08 (10H, m), 0.98 (3H, t).
Step (iii)
The product obtained in step (ii) was dissolved in dried dichloromethane (200 ml) and the solution was stirred at room temperature. Thereto was added dropwise N-bromosuccinimide (NBS) (27 g). The reaction mixture was stirred at room temperature overnight. Thereto was added 20% (w/w) sodium sulfate, and the mixture was separated by a separating funnel. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with aqueous saturated sodium hydrogencarbonate and saturated brine. After concentrated in vacuo, the residue was dissolved in ethyl acetate, washed with water and saturated brine and dried. The solution was filtered through silica gel and concentrated in vacuo. The residue was crushed in diethyl ether-isohexane and the titled compound was filtered (26 g). The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (ethyl acetate/isohexane) to obtain further the titled compound 2.5 g. These compounds were combined and obtained as a yellow solid. Yield 28.5 g, m.p. 148-50° C.
1H NMR™ (CDCl3) 5.59-5.64 (3H, m), 4.32 (2H, m), 4.17 (1H, m), 3.74 (1H, m), 3.08 (1H, m), 2.13 (1H, d), 1.48-1.83 (8H, m), 0.98 (3H, t).
Sodium (3.7 g) was added to anhydrous methanol (400 ml) under an atmosphere of nitrogen. Thereto was added the compound (28.5 g) obtained in step (iii) and the reaction mixture was stirred at 65° C. for 9 hours. After concentrated in vacuo, thereto was added water. The aqueous layer was extracted with ethyl acetate, washed with saturated brine and dried. The residue was crystallized from diethyl ether to give the titled compound. Yield 14.2 g
1H NMR™ (CDCl3) 5.51 (1H, dd), 5.28 (2H, brs), 4.29 (2H, t), 4.11-4.14 (4H, m), 3.70 (1H, m), 2.76-2.80 (1H, m), 2.05 (1H, d), 1.47-1.81 (8H, m), 0.97 (3H, t).
To the compound (24 g) obtained in step (iv) in anhydrous methanol (300 ml) was added TFA (30 ml). The reaction mixture was stirred at room temperature for 3 days, concentrated in vacuo and crushed in methanol/ethyl acetate to give the titled compound as white crystals. Yield 21 g
1H NMR™ (CD3OD) 4.48 (2H, t), 4.15 (3H, s), 1.80 (2H, quintet), 1.50 (2H, sextet), 0.99 (3H, t).
The compound (2 g) obtained in step (v) in DMF (20 ml) was dropped at the room temperature in a period of 10 minutes or more to the mixture of potassium carbonate (3.7 g) and 1,2-dibromoethane (0.6 ml) which was stirred in high speed, and then the mixture was stirred for 1.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extract was washed with saturated brine, dried over and purified by column chromatography to give the titled compound as a white solid, Yield 1.2 g
1H NMR™ (CDCl3) 5.15 (2H, s), 4.30 (4H, m), 4.13 (3H, s), 3.65 (2H, t), 1.82-1.72 (2H, m), 1.56-1.43 (2H, m), 0.97 (3H, t).
Step (vii)
To the compound (400 mg) obtained in step (vi) in acetonitrile (10 ml) was added tert-butylpiperidine-4-ylcarbamate (1.1 g) and the reaction mixture was stirred at 50° C. overnight. After cooled to room temperature, the reaction mixture was concentrated in vacuo and to the residue was added water. The suspension was stirred at room temperature overnight. The resulting solid was collected by filtration, left for 16 hours in vacuo, and dried to give the titled compound as a white solid. Yield 530 mg
1H NMR™ (DMSO-d6) 6.75 (2H, brs), 4.17 (2H, J=6.6 Hz, t), 4.06 (3H, s), 3.94 (2H, J=5.7 Hz, t), 2.88-2.51 (5H, m), 2.01-1.64 (6H, m), 1.45-1.21 (13H, m), 0.92 (3H, J=7.5 Hz, t).
Step (viii)
The compound (530 mg) obtained in step (vii) in methanol (5 ml) was treated with 4M hydrochloric acid/dioxane (1 ml). The reaction mixture was stirred at room temperature overnight, concentrated in vacuo and the residue was purified by SCX to give the titled compound as a white solid. Yield 400 mg
1H NMR™ (DMSO-d6) 6.40 (2H, brs), 4.17 (2H, J=6.6 Hz, t), 3.91 (2H, m), 2.85 (2H, m), 2.69-2.48 (3H, m), 1.98-1.60 (6H, m), 1.43-1.16 (4H, m), 0.92 (3H, J=7.5 Hz, t).
MS: APCI (+ve): 550 (M+H)
The compound (400 mg) obtained in step (viii), methyl (3-formylphenyl)-acetate (204 mg) and sodium triacetoxyborohydride (730 mg) were dissolved in methanol (10 ml), and the solution was stirred at room temperature overnight. The reaction mixture was treated with SCX, and purified by reverse-phase HPLC to give the titled compound. Yield 96 mg
1H NMR δ (DMSO-d6) 7.25-7.07 (4H, m), 6.37 (2H, brs), 4.14 (2H, J=6.8 Hz, t), 3.75 (2H, J=6.4 Hz, t), 3.66 (2H, s), 3.64 (2H, s), 3.60 (3H, s), 2.85 (2H, m), 2.55-2.32 (3H, m), 1.96-1.12 (10H, m), 0.92 (3H, J=7.2 Hz, t).
MS: APCI (+ve): 512 (M+H)
The compound (0.1 g) obtained by example 60, methanol (2 ml) and aqueous 2N lithium hydroxide were mixed and the mixture was stirred at room temperature overnight. After concentrated in vacuo, thereto was added water. The mixture was neutralized with acetic acid and purified by reverse-phase HPLC to give the titled compound. Yield 35 mg
1H NMR™ (DMSO-d6) 7.23-7.08 (4H, m), 6.44 (2H, brs), 4.13 (2H, J=6.8 Hz, t), 3.75 (2H, J=6.8 Hz, t), 3.68 (2H, s), 3.35 (2H, s), 2.85 (2H, m), 2.55-2.32 (3H, m), 1.96-1.15 (10H, m), 0.91 (3H, J=7.6 Hz, t).
MS: APCI (−ve): 496 (M−H)
HEK293 cells in which human TLR7 or rat TLR7 plasmid and reporter plasmid (NF-kB-SEAP) are stably introduced are dispersed in DMEM broth (10% FBS, 1% NEAA, 10 ug/mL blastocidin S HCl, 100 ug/mL Zeocin), and were seeded to 96 well plate per 90 μl/well (hTLR7/seap-293: 20000 cells/well, rTLR7/seap-293:25000 cells/well).
Test compound (DMSO stock solution (2 μl) was diluted with the broth (200 μl) by 100 times) was added to the seeded cells to a 96 well plate (10 μl/well) (final concentration; 1 nM-10 μM, common ratio). After stirring by tapping side of the plate, the cells were cultured in a CO2 incubator for 20 hours. A substrate (50 μl/well) for reporter assay (substrate for SEAP, pNPP) was added to cells stimulated by test sample. Ten minutes after adding the substrate, the reaction quenching solution (4N NaOH) was added by 50 μl/well to cease enzymatic reaction. Sealing a top seal A on the plate, the absorbance was measured by a micro plate reader (405 nm).
Human TLR7 binding activity (EC50) of each compound is shown in Table 1.
To 2-butoxy-8-methoxyadenine 5 g (14.2 mmol) in dimethylformamide (50 ml) was added 1,3-dibromobutane (7.2 ml) and potassium carbonate (9.2 g) and the mixture was stirred at room temperature for 1.5 hours. Thereto was added water (200 ml) and the mixture was extracted with ethyl acetate (75 ml) and further extracted with ethyl acetate (75 ml×2). The organic layers were combined, dried over magnesium sulfate and filtered. The solvent was removed in vacuo and to the residue was added diethyl ether (25 ml). The resulting crystals were filtered, washed with ether (5 ml) and dried to give the subtitled compound 3.6 g as a white solid. Yield 71%
1H NMR (CDCl3) δ 5.24 (2H, brs), 4.29 (2H, t, J=6.7 Hz), 4.13 (3H, s), 4.09 (2H, t, J=6.7 Hz), 3.38 (2H, t, J=6.6 Hz), 2.34 (2H, q, J=6.6 Hz), 1.80-1.73 (2H, m), 1.54-1.46 (2H, m), 0.96 (3H, t, J=7.4 Hz).
To the compound 1g (2.79 mmol) obtained in step (i) in methanol (2 ml) was added 4N-hydrochloric acid-dioxane (2 ml) and the mixture was stirred at room temperature for 3.5 hours. After neutralized at 0° C. with 28% aqueous ammonia, the mixture was stirred for 1 hour. The resulting crystals were filtered, washed with water (2 ml×2), and methanol (2 ml×2), and dried over to give the subtitled compound 882 mg as a white solid. Yield 92%
1H NMR (CDCl3) δ 9.89 (1H, brs), 6.43 (2H, s), 4.16 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=6.6 Hz), 3.53 (2H, t, J=6.6 Hz), 2.20 (2H, q, J=6.6 Hz), 1.68-1.61 (2H, m), 1.42-1.36 (2H, m), 0.92 (3H, t, J=7.4 Hz).
Step (iii)
To the compound 600 mg (1.74 mmol) obtained in step (ii) in dimethyl sulfoxide (1 ml) was added isobutylamine (2.55 g) and the mixture was stirred at room temperature for 2.5 hours. After removal of isobutylamine in vacuo, thereto was added at 0° C. acetonitrile (5 ml) and the mixture was stirred 1 hour. The resulting crystals were filtered and dried to give the titled compound 573 mg as a white solid. Yield 98%
1H NMR (DMSO-d6) δ 10.03 (1H, brs), 6.54 (2H, s), 4.15 (2H, t, J=6.6 Hz), 3.74 (2H, t, J=6.6 Hz), 2.72 (2H, brs), 2.54 (2H, d, J=6.8 Hz), 1.92-1.88 (2H, m), 1.81-1.93 (1H, m), 1.66-1.61 (2H, m), 1.42-1.37 (2H, m), 0.91 (9H, m).
To the compound 573 mg (1.70 mmol) obtained in step (iii) in N-methylpyrrolidinone were added N-boc-4-pyrollidone (305 mg) and sodium triacetoxyborohydride (469 mg), and the mixture was stirred at 50° C. for 12 hours. As the reaction was not completed, thereto were added additional N-Boc-4-pyrollidone (305 mg), and sodium triacetoxyborohydride (469 mg), and the mixture was stirred at 50° C. for 12 hours. The mixture was cooled to room temperature and neutralized at 0° C. with 1%-aqueous ammonia (30 ml), followed by stirring for 1 hour. The resulting crystals was filtered, washed with 1%-aqueous ammonia (2 ml) and dried to give the subtitled compound 659 mg as a white solid. Yield 75%
1H NMR (DMSO-d6) δ 9.96 (1H, brs), 6.43 (2H, s), 4.14 (2H, t) J=6.6 Hz), 3.97 (2H, brs), 3.67 (2H, t, J=7.2 Hz), 2.69-2.35 (3H, m), 2.41 (2H, t, J=6.8 Hz), 2.09 (2H, d, J=7.2 Hz), 1.77-1.72 (2H, m), 1.65-1.55 (5H, m), 1.40-1.37 (11H, m), 1.35-1.26 (2H, m), 0.91 (3H, t, J=7.4 Hz), 0.81 (6H, d, J=6.6 Hz),
Using the compound 200 mg (0.39 mmol) obtained in step (iv) and methyl [3-(2-bromoehoxy)phenyl]acetate 137 mg (0.50 mmol), in the same manner as example 6 step (i), there was obtained the titled compound 59 mg as a white solid. Yield 25%
1H NMR (DMSO-d6) δ 9.87 (1H, brs), 7.21 (1H, t, J=8.0 Hz), 6.83-6.80 (3H, m), 6.39 (2H, s), 4.15 (2H, t, J=6.6 Hz), 4.02 (2H, t, J=5.9 Hz), 3.68 (2H, t, J=7.3 Hz), 3.64 (2H, s), 3.61 (3H, s), 2.94 (2H, d, J=11.8 Hz), 2.63 (2H, t, J=5.8 Hz), 2.43 (2H, t, J=6.9 Hz), 2.40-2.36 (1H, m), 2.10 (2H, d, J=7.3 Hz), 1.97 (2H, t, J=10.9 Hz), 1.78-1.73 (2H, m), 1.68-1.54 (5H, m), 1.44-1.34 (4H, m), 0.91 (3H, t, J=7.4 Hz), 0.82 (6H, d, J=6.5 Hz).
Using compound 500 mg (1.45 mmol) obtained by example 63 step (ii) and N-Boc-4-aminopiperidine 349 mg (1.74 mmol), in the same manner as example 63 step (iii), there was obtained the subtitled compound 574 mg as a white solid. Yield 85%
1H NMR (CDCl3) δ 9.95 (1H, brs), 6.76 (1H, d, J=7.7 Hz), 6.43 (2H, s), 4.14 (2H, t, J=6.6 Hz), 3.68 (2H, t, J=7.0 Hz), 3.29-3.18 (1H, m), 2.77 (2H, d, J=11.1 Hz, 2.25 (2H, t, J=7.0 Hz), 1.83-1.74 (4H, m), 1.66-1.60 (4H, m), 1.42-1.32 (13H, m), 0.92 (3H, t, J=7.4 Hz).
To 4-bromomethylphenylacetic acid 25 g (109 mmol) in methanol (120 ml) was added thionyl chloride 120 μl (1.64 mmol) and the mixture was stirred at room temperature for 8 hours. After removal of the solvent in vacuo, the residue was neutralized with aqueous saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate (300 ml). The organic layer was washed aqueous saturated sodium bicarbonate, (50 ml) and saturated brine (20 ml), successively and dried over magnesium sulfate. The solvent was removed in vacuo to give the subtitled compound 25 g as colorless crystals. Yield 99%
1H NMR (CDCl3) δ 7.36 (2H, t, J=8.1 Hz), 7.26 (2H, d, J=8.1 Hz), 4.48 (2H, s), 3.69 (3H, s), 3.62 (2H, s).
Step (iii)
To the compound 5 g (20.6 mmol) obtained in step (i) in dimethyl sulfoxide (15 ml) was added N-methylmorpholine-N-oxide 3.61 g (30.9 mmol) and the mixture was stirred at room temperature for 1.5 hours. Thereto was added water 50 ml and the mixture was extracted with ethyl acetate (30 ml×3). The combined organic layer was washed with water (50 ml) and saturated brine (30 ml)b successively, dried over magnesium sulfate. The solvent was removed in vacuo, and the residue was purified by column chromatography (silica gel 100 g, hexane:ethyl acetate=10:1) to give the subtitled compound 1.65 g as colorless crystals. Yield 45%
1H NMR (CDCl3) δ 10.0 (1H, s), 7.86 (2H, t, J=8.1 Hz), 7.46 (2H, d, J=8.1 Hz), 3.72 (3H, s), 3.71 (2H, s).
To a suspension of the compound 200 mg (0.43 mmol) obtained in step (i) in methanol (1 ml) was added 6N-hydrochloric acid-methanol (1 ml), and the mixture was stirred at room temperature for 2 hours. After removal of the solvent in vacuo, the residue was dried for 2 hours. Thereto were added methanol (5 ml) and the compound 92 mg (0.52 mmol) obtained in step (iii), and the mixture was stirred at room temperature for 0.5 hours. Thereto was added sodium cyanoborohydride 43 mg (0.69 mmol) and the mixture was stirred at room temperature for 5 hours. After neutralized aqueous saturated sodium carbonate, the solution was extracted with chloroform (15 ml×2). The combined organic layer was dried over magnesium sulfate and the solvent was removed by distillation. The residue was purified by column chromatography (silica gel 6 mg, chloroform:methanol=50:1) to give the titled compound 185 mg as white crystals. Yield 82%
1H NMR (CDCl3) δ 9.92 (1H, brs), 7.27 (2H, d, J=8.0 Hz), 7.18 (2H, d, J=8.0 Hz), 6.41 (2H, s), 4.14 (2H, t, J=6.6 Hz), 3.70-3.66 (2H, m), 3.64 (2H, s), 3.60 (3H, s), 2.73 (2H, brs), 2.33-2.27 (1H, m), 2.24 (2H, t, J=6.9 Hz), 1.82-1.73 (6H, m), 1.68-1.60 (2H, m), 1.43-1.34 (2H, m), 1.24-1.15 (2H, m), 0.92 (3H, t, J=7.4 Hz).
Benzaldehyde (5.52 g, 52 mmol) was dissolved in toluene (200 ml), and thereto were added tert-butyl glycinate acetate (9.94 g, 52 mmol), triethylamine (7.25 ml, 52 mmol) and sodium sulfate (11.36 g, 80 ml), successively, followed by stirring overnight. The reaction mixture was washed with ice cooled-aqueous sodium bicarbonate and ice cooled saturated brine and was dried over sodium sulfate. The solvent was removed by distillation to give the subtitled compound 10.81 g as a yellow oil. Yield 94%
1H NMR (CDCl3) δ 8.26 (1H, s), 7.81-7.75 (2H, m), 7.47-7.36 (3H, m), 4.32 (2H, s), 1.49 (9H, s).
Diisopropylamine (8.91 ml, 68 mmol) was dissolved in tetrahydrofuran (136 ml) under an atmosphere of nitrogen, and thereto was added dropwise under ice cooling n-butyl lithium (hexane 1.57M, 43.3 ml, 68 ml). After stirring for 15 minutes, the reaction mixture was cooled in a dry ice-acetone bath and thereto was added dropwise methyl 4-(bromomethyl)benzoate (15.58 g, 68 mmol) in tetrahydrofuran (68 ml). After the reaction mixture was stirred for 30 minutes in a dry ice-acetone bath, the mixture was gradually warmed, and stirred at 0° C. for additional one hour. After addition of cooled water, the mixture was stirred and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate and the solvent was removed by distillation. The residue was dissolved in tetrahydrofuran (25 ml) and thereto was added ice cooled 6N aqueous hydrochloric acid (100 ml). After reacting at room temperature for 1 hour, the volume of the reaction mixture was concentrated to half in vacuo. The mixture was washed with hexane-ethyl acetate (1:1), and the aqueous layer was concentrated in vacuo. The residue was made alkaline with 2N aqueous sodium hydroxide under ice cooling, and thereto was added dropwise di-tert-butyldicarbonate (27.06 g, 124 mmol) in tetrahydrofuran (62 ml), followed by stirring under ice-cooling for 1 hour. Thereto was added hexane-toluene (1:1) and the mixture was stirred, followed by separating by a separating funnel. The aqueous layer was washed with hexane-toluene (1:1), adjusted to pH3-4 with aqueous 10% potassium hydrogensulfate under ice cooling and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography to give the subtitled compound 4.85 g as a yellow oil. Yield 24%
1H NMR (CDCl3) δ 7.98 (2H, d, J=8.2 Hz), 7.29-7.23 (2H, m), 6.32 (1H x1/4, br), 4.98 (1H x3/4, d, J=7.7 Hz), 4.69-4.60 (1H x3/4, m), 4.45-4.41 (1H x1/4, br), 3.91 (3H, s), 3.32-3.23 (1H, m), 3.17-3.08 (1H x3/4, m), 3.01-2.95 (1H x1/4, br), 1.42 (9H x3/4, s), 1.31 (9H x1/4, s).
Step (iii)
N-(tert-Butoxycarbonyl)-4-(methoxycarbonyl)phenylalanine (4.85 g, 15 mmol) and triethylamine (2.40 ml, 17 mmol) were dissolved in dimethylformamide (60 ml), and the solution was stirred. Thereto were added methyl N-methylglycinate hydrochloride (2.37 g, 17 mmol), HOBt (2.60 g, 17 mmol), and WSC (3.84 g, 20 mmol), successively and the mixture was stirred overnight. After addition of 10% aqueous citric acid-ethyl acetate, the mixture was stirred and separated by a separating funnel. The organic layer was washed with aqueous 10% citric acid, water, aqueous saturated sodium bicarbonate and saturated brine, and dried over sodium sulfate. The solvent was removed by distillation to give the subtitled compound 4.75 g as white crystals. Yield 77%
1H NMR (CDCl3) δ 7.99-7.92 (2H, m), 7.33-7.21 (2H, m), 5.33 (1H x3/4, d, J=8.6 Hz), 5.23 (1H x1/4, d, J=8.6 Hz), 4.95-4.86 (1H x3/4, m), 4.72-4.63 (1H x1/4, m), 4.20 (1H x3/4, d, J=17.2 Hz), 4.03 (1H x1/4, d, J=17.2 Hz), 3.98-3.85 (1H, m), 3.90 (3H, s), 3.74 (3H x3/4, s), 3.72 (3H x1/4, s), 3.17-3.04 (1H, m), 3.03-2.93 (1H, m), 2.94 (3H x1/4, s), 2.91 (3H x3/4, s), 1.40 (9H x3/4, s), 1.37 (9H x1/4, s).
N-(tert-Butoxycarbonyl)-4-(methoxycarbonyl)phenylalanyl-N-methylglycine methyl ester (4.75 g, 11.6 mmol) was treated with trifluoroacetic acid (30 ml) at room temperature for 1 hour, and after removal of the reaction solvent by distillation, the mixture was subjected to azeotropic distillation with chloroform three times. The residue was dissolved in methanol (120 ml), thereto was added triethylamine (8.4 ml, 60 mmol) and the mixture was refluxed for 4 hours. After being cooled, the reaction solvent was removal by distillation, and the residue was diluted with ethyl acetate. The mixture was subjected to azeotropic distillation with aqueous 10% citric acid. The aqueous layer was salted out and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, the solvent was removed by distillation and the residue was purified by silica gel column chromatography to give the subtitled compound 3.13 g as white crystals. Yield 97%
1H NMR (CDCl3) δ 8.00 (2H, dd, J=6.5, 1.6 Hz), 7.30-7.24 (2H, m), 6.69 (1H, s), 4.37-4.30 (1H, m), 3.92 (3H, s), 3.60 (1H, d, J=17.6 Hz), 3.25 (1H, dd, J=13.6, 5.8 Hz), 3.17 (1H, dd, J=13.6, 4.1 Hz), 3.06 (1H, d, J=17.6 Hz), 2.85 (3H, s).
To a suspension of lithium aluminum hydride (2.15 g, 56 mmol) in tetrahydrofuran (84 ml) was added dropwise under heating under stirring under an atmosphere of nitrogen a suspension of 4-[(4-methyl-3,6-dioxopiperazine-2-yl)methyl]benzoic acid methyl (3.13 g, 11.3 mmol) in tetrahydrofuran (92 ml). After refluxing for 4 hours, the reaction mixture was ice cooled, quenched with aqueous sodium sulfate and made alkaline with aqueous 2N sodium hydroxide. After filtration, the filtrate was concentrated and thereto was added dioxane (100 ml). Thereto was added under ice cooling di-tert-butyldicarbonate (3.49 g, 16 mmol) and the mixture was stirred at room temperature overnight. Thereto was added at room temperature additional di-tert-butyldicarbonate (3.49 g, 16 mmol) and the mixture was stirred for 2 hours. After addition of saturated brine, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was removed by distillation and the residue was purified by silica gel column chromatography to give the subtitled compound 3.15 g as a pale yellow oil. Yield 87%
1H NMR (CDCl3) δ 7.32-7.20 (4H, m), 4.66 (2H, d, J=5.9 Hz), 4.25-4.17 (1H, br), 3.97-3.89 (1H, br), 3.27-3.17 (1H, br), 3.13-3.03 (1H, br), 2.94-2.86 (1H, br), 2.85-2.75 (1H, br), 2.67-2.60 (1H, br), 2.27 (3H, brs), 2.04-1.94 (2H, br), 1.74 (1H, t, J=5.9 Hz), 1.38 (9H, s).
tert-Butyl 2-[4-(hydroxymethyl)benzyl]-4-methylpiperazine-1-carboxylate (1.28 g, 4 mmol), and triethylamine (0.56 mmol, 4 mmol) were dissolved in tetrahydrofuran (20 ml) and thereto was added dropwise under ice cooling methanesulfonyl chloride (0.31 ml, 4 mmol), followed by stirring under ice cooling for 1 hour. After filtration by a filter (0.5 μm), the filtrate was concentrated in vacuo and the residue was dissolved in dimethyl sulfoxide (10 ml). The solution was added to a suspension of sodium cyanide (588 mg, 12 mmol) and sodium carbonate (848 mg, 8 mmol) in dimethyl sulfoxide, and the mixture was reacted at room temperature for 22 hours. Thereto was added water-ethyl acetate and the mixture was separated by a separating funnel. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to give the subtitled compound 1.05 g as an orange oil. Yield 79%
1H NMR (CDCl3) δ 7.30-722 (4H, m), 4.27-4.17 (1H, br), 3.99-3.89 (1H, br), 3.70 (2H, s), 3.26-3.16 (1H, br), 3.11-3.01 (1H, br), 2.98-2.89 (1H, br), 2.85-2.75 (1H, br), 2.65-2.55 (1H, br), 2.27 (3H, brs), 2.05-1.97 (2H, br), 1.36 (9H, s).
Step (vii)
To methanol (6.08 ml, 150 mmol) was added dropwise under an atmosphere of nitrogen gas chloro(trimethyl)silane (9.5 ml, 75 mmol) and the mixture was stirred at room temperature. Thereto was added tert-butyl 2-[4 (cyanomethyl)benzyl]-4-methylpiperazine 1-carboxylate (984 mg, 2.99 mmol) and the mixture was stirred at 50° C. for 2 hours. After addition of water, the mixture was stirred for a while, made alkaline with aqueous saturated sodium bicarbonate and salted out with a small amount of sodium chloride. After extraction with chloroform, the organic layer was dried over sodium sulfate, and the solvent was removed by distillation to give the subtitled compound 536 mg as an orange oil. Yield 68%
1H NMR (CDCl3) δ 7.21 (2H, d, J=8.0 Hz), 7.16 (2H, d, J=8.0 Hz), 3.69 (3H, s), 3.60 (2H, s), 3.02-2.90 (2H, m), 2.87-2.65 (4H, m), 2.62-2.54 (1H, m), 2.27 (3H, s), 2.10-1.87 (2H, m), 1.80 (1H, t, J=10.4 Hz).
Step (viii)
3-(6-Amino-2-butoxy-8-methoxy-9H-purin-9-yl)propyl methanesulfonate (373 mg, 1 mmol), potassium iodide (166 mg, 1 mmol), potassium carbonate (207 mg, 1.5 mmol) and methyl {4-[(4-methylpiperazin-2-yl)methyl]phenyl}acetate (315 mg, 1.2 mmol) were dissolved in dimethylformamide (4 ml) and the suspension was stirred at 50° C. for 1 hour, and at 70° C. for 2 hours. After removal of the reaction solvent by distillation, to the residue was added water-ethyl acetate and the mixture was separated by a separating funnel. The organic layer was washed with saturated brine and sodium sulfate, the solvent was removed by distillation and the residue was purified by PTLC to give the subtitled compound 24 mg as colorless oil. Yield 4%
1H NMR (CDCl3) δ 7.16 (2H, d, J=8.0 Hz), 7.06 (2H, d, J=8.0 Hz), 5.15 (2H, s), 4.29-4.21 (2H, m), 4.10 (3H, s), 4.03-3.93 (2H, m), 3.68 (3H, s), 3.58 (2H, s), 2.88-2.79 (3H, m), 2.73-2.21 (6H, m), 2.17 (3H, s), 2.09-1.78 (4H, m), 1.77-1.68 (2H, m), 1.54-1.42 (2H, m), 0.94 (3H, t, J=7.3 Hz).
To methyl [4-({1-[3-(6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)propyl]-4-methylpiperazin-2-yl}methyl)phenyl]acetate (24 mg, 0.044 mmol) were added 4N hydrochloric acid-dioxane (4 ml) and 10% hydrochloric acid-methanol (1 ml) and the mixture was stirred at room temperature for 5 hours. After concentrated, the residue was subjected to azeotropic distillation with methanol four times. The residue was neutralized with aqueous saturated sodium bicarbonate and resulting solid was filtered and dried to give the subtitled compound 18 mg as a white solid. Yield 77%
1H NMR (DMSO-d6) δ 9.80 (1H, s), 7.13 (2H, d, J=7.8 Hz), 7.03 (2H, d, J=7.8 Hz), 6.31 (2H, s), 4.16-4.09 (2H, m), 3.78-3.69 (2H, m), 3.61 (3H, s), 3.60 (2H, s), 2.82-2.66 (3H, m), 2.62-2.40 (3H, m), 2.36-2.14 (3H, m), 2.09-1.92 (2H, m), 2.05 (3H, s), 1.92-1.74 (2H, m), 1.65-1.58 (2H, m), 1.41-1.31 (2H, m), 0.90 (3H, t, J=7.3 Hz).
Methyl 3-amino-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)benzoate (1.31 g, 3.82 mmol) was refluxed in an excess of ethyl formate until disappearance of the starting material. After removal of the reaction mixture, the residue was purified by silica gel column chromatography to give the subtitled compound 967 mg, Yield 78%
1H NMR (CDCl3) δ 8.95-8.62 (2H, m), 8.46 (s), 7.90 (s), 8.46-7.96 (1H), 7.31-7.19 (1H, m), 4.85-4.70 (2H, m), 3.99-3.84 (2H, m), 1.58 (2H, s), 0.90 (9H, s), 0.09 (6H, s).
To methyl 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(formylamino)benzoate (967 mg, 2.99 mmol) in dimethylformamide (10 ml) was added sodium hydride (157 mg, 3.6 mmol) under ice cooling and the mixture was stirred for 1 hour. Thereto was added methyl iodide (37 μl, 6 mmol) and the mixture was reacted at room temperature for 6 hours. After addition of aqueous sodium bicarbonate, the mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated brine. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to give the subtitled compound 885 mg as a white solid. Yield 87%
1H NMR (CDCl3) δ 8.31-8.00 (2H, m), 7.81 (1H, s), 7.72-7.66 (1H, m), 4.67 (s), 4.63 (s), 4.67-4.63 (2H), 3.93 (s), 3.91 (s), 3.93-3.91 (3H), 3.32 (s), 3.22 (s), 3.32-3.22 (3H), 0.93 (9H, s), 0.11 (6H, s).
Step (iii)
Methyl 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-[formyl(methyl)amino]benzoate (337 mg, 1 mmol) was dissolved in acetic acid (7.8 ml)-water (4.2 ml)-tetrahydrofuran (1.8 ml) and the solution was reacted overnight. After removal of the reaction solvent by distillation, the residue was subjected to azeotropic distillation with methanol three times, and dried in vacuo. The residue was dissolved in tetrahydrofuran (3 ml) under an atmosphere of nitrogen and thereto was added triethylamine (0.093 ml, 1.2 mmol). Thereto was added dropwise under ice cooling methanesulfonyl chloride (0.21 ml, 1.5 mmol), and the mixture was reacted under ice cooling for 1 hour. The reaction was quenched with ice cooled aqueous 10% citric acid, and extracted with ethyl acetate. The organic layer was washed with ice cooled aqueous 10% citric acid, cold water, ice cooled aqueous saturated sodium bicarbonate and ice cooled saturated brine and dried over sodium sulfate. After removal of the solvent by distillation, the residue, namely methyl 3-[formyl(methyl)amino]-4-{[(methylsulfonyl)oxy]methyl}benzoate was dissolved in dimethylformamide (1 ml), and the solution was added to a suspension of 2-butoxy-8-methoxy 9-(piperidin-3-ylmethyl)-9H-purin-6-amine (334 mg, 1 mmol), potassium carbonate (207 mg, 1.5 mmol) and dimethylformamide (2 ml). After reacting at room temperature for 6 hours, the reaction mixture was concentrated. Thereto was added water-ethyl acetate and the mixture was separated by a separating funnel. The organic layer was washed with water, aqueous saturated sodium bicarbonate and saturated brine and dried over sodium sulfate. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to give methyl 4-({3-[(6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)methyl]piperidin-1-yl}methyl)-3-[formyl(methyl)amino]benzoate 445 mg as a pale yellow oil. Yield 80%
To a suspension of lithium aluminum hydride (45 mg, 1.2 mmol) in tetrahydrofuran (2 ml) was added dropwise a suspension of methyl 4-({3-[(6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)methyl]piperidin-1-yl}methyl)-3-[formyl(methyl)amino]benzoate (455 mg, 0.84 mmol) in tetrahydrofuran 1 ml at room temperature under an atmosphere of nitrogen gas. After 2 hours, the reaction mixture was ice cooled, quenched with aqueous sodium sulfate and filtered. After the filtrate was extracted with ethyl acetate, the organic layer was washed with aqueous saturated sodium bicarbonate and saturated brine dried over sodium sulfate. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to give the subtitled compound 259 mg as a white solid. Yield 62%
1H NMR (CDCl3) δ 7.55-7.35 (1H, br), 7.25-6.90 (2H, m), 5.33-5.18 (2H, m), 4.70-4.60 (2H, m), 4.35-4.21 (2H, m), 4.18-4.00 (3H, m), 3.88-3.73 (2H, m), 3.64-2.98 (2H, br), 2.96-2.62 (7H, m), 2.52-2.30 (1H, br), 2.29-1.99 (2H, br), 1.97-1.58 (7H, m), 1.55-1.45 (2H, m), 1.00-0.92 (3H, m).
[4-({3-[(6-Amino-2-butoxy-8-methoxy-9H-purin-9-yl)methyl]piperidine 1-yl}methyl)-3-(dimethylamino)phenyl]methanol (259 mg, 0.52 mmol) was dissolved in tetrahydrofuran (4 ml) under an atmosphere of nitrogen gas, and thereto was added triethylamine (0.13 ml, 09 mmol). Thereto was added dropwise methanesulfonyl chloride (0.062 ml, 0.8 mmol) under ice cooling, and the mixture was reacted under ice cooling for 1 hour. After filtration, the filtrate was concentrated and the residue, namely 4-({3-[(6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)methyl]piperidin-1-yl}methyl)-3-(dimethylamino)benzyl methanesulfonate was dissolved in DMF (2 ml). The solution was added to a suspension of sodium cyanide (34 mg, 0.7 mmol), and potassium carbonate (138 mg, 1 mmol) in DMF (2 ml), and the mixture was reacted at room temperature overnight. The mixture was further stirred at 70° C. for 4 hours. After being cooled, the mixture was concentrated, to the residue was added water-chloroform and separated by a separating funnel. The organic layer was washed with saturated brine, and dried over sodium sulfate. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography [4-({3-[(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl]piperidin-1-yl}methyl)-3-(dimethylamino)phenyl]acetonitrile as a pale brown solid. Under an atmosphere of nitrogen gas, to methanol (0.4 ml, 10 mmol) was added dropwise chloro(trimethyl)silane (0.63 ml, 5 mmol) and the mixture was stirred at room temperature. Thereto was added [4-({3-[(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl]piperidin-1-yl}methyl)-3-(dimethylamino)phenyl]acetonitrile (64 mg, 0.12 mmol) and the mixture was stirred at 50° C. for 2 hours. After addition of water the mixture was stirred for a while, made alkaline with aqueous saturated sodium bicarbonate and extracted with chloroform. The organic layer was dried over sodium sulfate and the solvent was removed by distillation to give the titled compound 21 mg as a pale brown solid. Yield 30%
1H NMR (DMSO-d) δ 9.83 (1H, s), 7.27 (1H, d, J=7.6 Hz), 6.88 (1H, s), 6.83 (1H, d, J=7.6 Hz), 6.36 (2H, s), 4.14 (2H, t, J=6.6 Hz), 3.67-3.37 (9H, m), 2.73-2.42 (4H, m), 2.60 (6H, s), 2.18-1.78 (3H, m), 1.72-1.49 (3H, m), 1.46-1.20 (3H, m), 0.92 (3H, t, J=7.3 Hz).
To 3-[3-(Methoxycarbonylmethyl)phenoxy]propyl bromide 287 mg (1.0 mmol) in DMF (5.0 ml) were added diisopropylethylamine 387 mg (3.0 mmol) and N-methylethanolamine 75 mg (1.0 mmol), and the mixture was stirred at room temperature for 19 hours. After the reaction was completed, the mixture was concentrated in vacuo and the residue was purified and isolated by column chromatography (SiO2, CHCl3→2% MeOH—CHCl3→5% MeOH—CHCl3→10% MeOH—CHCl3) to give the subtitled compound 240 mg as a colorless oil, Yield 85%
1H NMR (CDCl3) δ 7.22 (1H, t J=7.82 Hz), 6.86 (1H, d J=7.61 Hz), 6.78-6.82 (1H, m), 4.06 (2H, t J=5.79 Hz), 3.89 (2H, t J=4.91 Hz), 3.69 (3H, s), 3.60 (2H, s), 3.13 (2H, t J=7.61 Hz), 3.05 (2H, t J=5.09 Hz), 2.71 (3H, s), 2.20-2.27 (2H, m), Rf=0.2 (10% MeOH—CHCl3).
To the compound 140 mg (0.50 mmol) obtained in step (i) in CDCl3 (10.0 ml) was added thionyl chloride 213 mg (1.8 mmol) and the mixture was stirred at 60° C. for 4 hours. After the reaction is completed, the mixture was concentrated in vacuo to give the subtitled compound 150 mg as a yellow oil, Yield 100%
1H NMR (CDCl3) δ 7.26 (1H, t, J=9.80 Hz), 6.88 (1H, d, J=7.35 Hz), 6.77-6.80 (1H, m), 4.08 (4H, brs), 3.70 (3H, s), 3.60 (2H, s), 3.55-3.60 (1H, m), 3.37-3.43 (2H, m), 3.30-3.33 (1H, m), 2.93 (2H, t, J=5.09 Hz), 2.40 (2H, bs), Rf=0.8 (10% MeOH—CHCl3).
Step (iii)
To the compound 150 mg (0.5 mmol) obtained in step (ii) in MeOH (2 mL) were added NaHCO3 (101 mg, 3.0 eq) and KI catalyst (10 mg) and further added NaHCO3 (101 mg, 3.0 eq) and KI catalyst (10 mg), and further added 2-butoxy-7,8-dihydro-9-[2-piperidine-2-yl)ethyl]-8-oxoadenin 134 mg (0.4 mmol), and the mixture was stirred in a bath at 60° C. for 8 hours. When the ratio of decrease of the starting material and increase of the product was not almost changed by LC, the mixture was cooled to room temperature, and the reaction product was isolated by PTLC to give the titled compound 17 mg as a white solid. Yield 7.1%
1H NMR (8, MeOH-d3) 7.05 (1H, t), 6.64-6.69 (3H, m), 4.15 (2H, t), 3.85 (2H, t), 3.74 (2H, t), 3.55 (3H, s), 3.23 (2H, s), 2.60-2.75 (2H, m), 2.21-2.55 (7H, m), 2.12 (3H, s), 2.00-2.10 (1H, m), 1.75-1.79 (3H, m), 1.57-1.62 (4H, m), 1.17-1.50 (6H, m), 1.06 (1H, t), 0.85 (3H, t). Rf=0.6 (10% methanol, 1% NH3 aq.-chloroform, NH PTLC).
To 4-(tert-butyloxycarbonylamino)piperidine 0.82 g (4.09 mmol) in DMF (30 ml) were added diisopropylethylamine 1.4 ml (81.12 mmol and [3-(2-bromoethoxy)phenyl]acetic acid methyl ester 1.12 mg (4.10 mmol) at room temperature, and the mixture was stirred for 30 hours. After addition of aqueous saturated sodium bicarbonate 30 ml, the mixture was extracted with ethyl acetate (50 ml×3). The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo and purified by silica gel column chromatography to give {2-[4-(tert-butyloxycarbonylamino)piperidin-1-yl]-ethoxy}phenyl)acetic acid methyl ester 1.12 g as a colorless oil. Yield 70%
The obtained compound 1.06 g (2.69 mmol) was dissolved in trifluoroacetic acid 5 ml at room temperature. The mixture was stirred for 1 hour and concentrated in vacuo to give {[2-(aminopiperidin-1-yl)-ethoxy]phenyl}acetic acid methyl ester 842 mg as a colorless oily crude product. To the obtained crude product 842 mg in dichloromethane (10 ml) were added triethylamine 0.94 ml (6.74 mmol) and o-nitrobenzenesulfonyl chloride 713 mg (3.22 mmol) at room temperature and the mixture was stirred for 1.5 hours. After addition of aqueous saturated sodium bicarbonate 30 ml, the mixture was extracted with chloroform (50 ml×3). The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo and the residue was purified by silica gel column chromatography to give [(2-{4-[2-(nitrobenzenesulfonyl)amino]piperidin-1-yl}-ethoxy)phenyl]acetic acid methyl ester 1.27 g as a colorless oil. Yield 99%
To the obtained compound 800 mg (1.68 mmol) in DMF (10 ml) was added 1-bromo-3-chloropropane 1.66 ml (16.8 mmol) and potassium carbonate 697 mg (5.04 mmol) at room temperature and the mixture was stirred for 15 hours. After addition of aqueous saturated sodium bicarbonate 30 ml, the mixture was extracted with chloroform (50 ml×3). The organic layer was dried over anhydrous magnesium sulfate, dried over, concentrated in vacuo and purified by silica gel column chromatography to give the subtitled compound 914 mg as colorless oil. Yield 99%
1H NMR (DMSO-d6) δ 8.12-8.03 (1H, m), 7.98-7.75 (5H, m), 7.24-7.16 (1H, m), 6.80-6.70 (3H, m), 4.02-3.94 (2H, m), 3.66-3.52 (5H, m), 3.58 (3H, s), 3.40-3.30 (2H, m), 2.98-2.86 (2H, m), 2.70-2.55 (2H, m), 2.10-1.85 (4H, m), 1.76-1.58 (2H, m), 1.50-1.43 (2H, m).
To 2-butoxy-8-methoxyadenine 724 mg (2.06 mmol) in DMF (15 ml) were added the compound 914 mg (1.64 mmol) obtained step (i) and potassium carbonate 750 mg (5.43 mmol), and the mixture was stirred at 80° C. for 15 hours. After removal of the solvent by distillation, thereto was added aqueous saturated sodium bicarbonate 50 ml, and the mixture was extracted with chloroform (50 ml×3). The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo and purified by silica gel column chromatography to give 2-butoxy-9-{[3-{N-[2-(3-methoxycarbonylmethylphenyl-1-yl)ethyl])piperidin-4-yl)aminopropyl-N-(2-nitrobenzenesulfonyl)}-8-methoxyadenine 795 mg as a colorless amorphous. Yield 51%
To the obtained compound 648 mg (0.858 mmol) in DMF (10 ml) were added 2-mercaptoethanol 0.18 ml (2.57 mmol) and potassium carbonate 360 mg (2.60 mmol) and the mixture was stirred at room temperature for 21 hours. After removal of the solvent by distillation, thereto added aqueous saturated sodium bicarbonate 50 ml and the mixture was extracted with chloroform (50 ml×3). The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo and purified by silica gel column chromatography to give the subtitled compound 398 mg as a colorless amorphous. Yield 81%
1H NMR (DMSO-d6) δ 7.23-7.19 (1H, m), 6.84-6.80 (3H, m), 6.77 (2H, brs), 4.17 (2H, t), 4.05 (3H, s), 4.02 (2H, t), 3.88 (2H, t), 3.64 (2H, s), 3.61 (3H, s), 2.83-2.80 (2H, m), 2.64 (2H, t), 2.45 (2H, t), 2.32-2.22 (1H, m), 2.04-1.97 (2H, m), 1.81-1.60 (6H, m), 1.45-1.35 (2H, m), 1.23-1.12 (2H, m), 0.92 (3H, t).
Step (iii)
To the compound 155 mg (0.272 mmol) obtained in step (iii) in methanol (5 ml) was added concentrated sulfuric acid (0.2 ml) and the mixture was refluxed for 5 hours. After neutralized with aqueous saturated sodium bicarbonate, the resulting solid was filtered to give the titled compound 141 mg as a white solid. Yield 93%
1H NMR (DMSO-d6) δ 9.92 (1H, brs), 7.23-7.19 (1H, m), 6.84-6.81 (3H, m), 6.44 (2H, brs), 4.16 (2H, t), 4.02 (2H, brt), 3.72 (2H, brt), 3.64 (2H, s), 3.61 (3H, s), 3.35 (2H, brs), 2.92-2.84 (2H, m), 2.65 (2H, t), 2.56 (1H, brs), 2.07-1.98 (2H, m), 1.82-1.72 (4H, m), 1.67-1.61 (2H, m), 1.44-1.34 (2H, m), 1.30-1.20 (2H, m), 0.91 (3H, t).
To the compound 256 mg (0.448 mmol) obtained by example 68 step (ii) in NMP (5 ml) were added 4-formylimidazole 131 mg (1.37 mmol), sodium triacetoxyborohydride 288 mg (1.36 mmol) at room temperature, and the mixture was stirred for 24 hours. Thereto added aqueous saturated sodium bicarbonate 50 ml and the mixture was extracted with chloroform (60 ml×3). The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo and purified by silica gel column chromatography to give the titled compound 163 mg as a colorless amorphous. Yield 56%
The obtained compound 158 mg was reacted in the same manner as example 1 step (iii) to give the titled compound 122 mg as a white solid. Yield 79%
1H NMR (DMSO-d6) δ 9.85 (1H, brs), 7.52 (1H, brs), 7.23-7.19 (1H, m), 6.83-6.80 (4H, m), 6.42 (2H, brs), 4.14 (2H, t), 4.01 (2H, brt), 3.68-3.62 (2H, m), 3.64 (2H, s), 3.61 (3H, s), 3.56 (2H, brs), 2.98-2.90 (2H, m), 2.66-2.60 (2H, m), 1.97-1.88 (2H, m), 1.81-1.72 (2H, m), 1.67-1.58 (4H, m), 1.47-1.32 (4H, m), 0.90 (3H, t).
Using the compound 20 mg (0.03 mmol) obtained by example 63, in L the same manner as example 35, there was obtained the titled compound 12 mg as a white solid. Yield 62%
1H NMR (DMSO-d6) δ 12.16 (1H, brs), 7.12-7.08 (3H, m), 6.95 (1H, s), 6.74 (1H, d, J=7.5 Hz), 6.68 (1H, d, J=7.9 Hz), 4.15 (2H, t, J=6.6 Hz), 3.98 (2H, t, J=5.3 Hz), 3.66 (2H, t, J=6.1 Hz), 3.23 (2H, s), 2.86 (2H, d, J=10.7 Hz), 2.59 (2H, t, J=5.3 Hz), 2.35 (2H, t, J=7.0 Hz), 2.30-2.24 (1H, m), 2.11 (2H, d, J=7.0 Hz), 1.92 (2H, t, J=10.7 Hz), 1.78 (2H, brs), 1.67-1.55 (3H, m), 1.46-1.34 (4H, m), 1.29-1.16 (2H, m), 0.91 (3H, t, J=7.4 Hz), 0.81 (6H, d, J=6.5 Hz).
Using the compound 15 mg (0.03 mmol) obtained by example 64, in the same manner as example 35, there was obtained the titled compound 16 mg as a white solid. Yield 97%
1H NMR (DMSO-d6) δ 10.66 (1H, s), 10.35 (1H, brs), 9.61 (2H, s), 7.53 (2H, d, J=8.0 Hz), 7.32 (2H, d, J=8.0 Hz), 7.03 (1H, brs), 4.21 (2H, t, J=6.6 Hz), 4.13 (2H, brs), 3.76 (2H, t, J=6.1 Hz), 3.60 (2H, s), 3.56 (2H, d, J=11.3 Hz), 3.22 (1H, brs), 3.03-2.93 (4H, m), 2.31 (2H, t, J=13.0 Hz), 2.09-2.02 (4H, m), 1.68-1.63 (2H, m), 1.44-1.38 (2H, m), 0.93 (3H, t, J=7.4 Hz).
To the compound 42.6 mg (0.0767 mmol) obtained by example 68 was added concentrated hydrochloric acid (2 ml) and the mixture was added for 3.5 hours. After diluted with 1,4-dioxane (2 ml), the mixture was concentrated in vacuo to give the titled compound 72.3 mg as a white solid. Yield 100%
1H NMR (DMSO-d6) δ 9.92 (1H, m), 7.23-7.19 (1H, m), 6.84-6.81 (3H, m), 6.44 (2H, m), 4.16 (2H, m), 4.02 (2H, m), 3.72 (2H, m), 3.64 (2H, brs), 3.35 (2H, m), 2.92-2.84 (2H, m), 2.65 (2H, m), 2.56 (1H, m), 2.07-1.98 (2H, m), 1.82-1.72 (4H, m), 1.67-1.61 (2H, m), 1.44-1.34 (2H, m), 1.30-1.20 (2H, m), 0.87 (3H, t).
To the compound 34.3 mg (0.0539 mmol) obtained by example 69 was added concentrated hydrochloric acid (2 ml) and the mixture was stirred for 5.5 hours. After diluted with 1,4-dioxane (2 ml), the mixture was concentrated in vacuo to give the titled compound 58.9 mg as a white solid. Yield 100%
1H NMR (DMSO-d6) δ 9.85 (1H, brs), 7.52 (1H, m), 7.23-7.19 (1H, m), 6.83-6.80 (4H, m), 6.42 (2H, m), 4.14 (2H, m), 4.01 (2H, m), 3.68-3.62 (2H, m), 3.64 (2H, m), 3.56 (2H, m), 2.98-2.90 (2H, m), 2.66-2.60 (2H, m), 1.97-1.88 (2H, m), 1.81-1.72 (2H, m), 1.67-1.58 (4H, m), 1.47-1.32 (4H, m), 0.87 (3H, t).
| Number | Date | Country | Kind |
|---|---|---|---|
| 2005-276172 | Sep 2005 | JP | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/JP2006/318758 | 9/21/2006 | WO | 00 | 5/16/2008 |
